Toxins Have Become the Primary Drivers of Disease · Peripheral Artery Disease Peripheral...
Transcript of Toxins Have Become the Primary Drivers of Disease · Peripheral Artery Disease Peripheral...
Toxins Have Become the
Primary Drivers of Disease
Dr Joseph Pizzorno ND
President Emeritus Bastyr University
Editor Integrative Medicine A Clinicianrsquos Journal
Chair Scientific Advisory Board Bioclinic Naturals
President SaluGenecists Incmail2DrPizzornocom
Copyright copy 2016
1 Worldwide Epidemic of Chronic Disease
2 Causes
3 Methodology Disease Risk to Disease Cause
4 Most Chronic Disease is Now Caused by Toxins
5 The Worst Toxins
6 Sources of Toxins
7 Toxicity has Become the New Normal ldquoNormalrdquo Laboratory Ranges Are Toxic Ranges
8 Summary
Overview
There is Some Good Newsbull Banning lead in gasoline
and paint workedmdashblood levels down dramatically
bull No threshold for safety ndash
Children who had whole blood
lead concentrations of lt5 microgdL
(supposedly safe) associated
with decreased IQ
24 million children at levels
between 5 and 99 ugdL
bull July 2012 CDC changed recommended level to intervene in children from 10 to 50 ugdL Also eliminated term ldquolevel of concernrdquo to avoid giving false sense of safety
Iqbal S et al Estimated burden of blood lead levels 5 microgdl in 1999-2002 and declines from 1988 to 1994
Environ Res 2008
httpwwwcdcgovncehleadacclppcdc_response_lead_exposure_recspdf
httpwwwenvironmentuclaedureportcardarticle3772html
bull Human data
bull Primarily US as a lot more research available
bull Spot checking toxins in other countries shows the same toxin overload but variations in which are most prevalent
Australia (higher PDBEs)
Canada (higher lead)
New Zealand (higher cadmium)
Sweden (higher most toxic metals)
UK (highest PDBEs in world 3x OCP of US)
A Note About the Data
AD
HD
Ep
idem
ic
httpwwwcdcgovmmwrpreviewmmwrhtmlmm6433a11htm
Obesity Epidemic
httpwwwtheobesityepidemicorgintroduction (Accessed 616)
Kidney Disease Epidemic
Stevens L httpwwwslidesharenetringer21liaison-meeting-esrd-presentation (accessed 616)
Dia
be
tes
Ep
ide
mic
Diabetes Increasing World-Wide
SourcesAIHW analysis of ABS NHS 1989ndash90 1995 2001 2004ndash05 and 2007ndash08 NHS (reissue) and ABS 2011ndash12 Australian
Health Survey data (Release 7 June 2013)
Co-ordinaring Committee Epidemiology Study of Childhood amp Adolescent Diabetes Hong Kong KF Huen et al
Australian Adults
Childhood diabetes in Hong Kong
WHY THE CHRONIC DISEASE
EPIDEMICS
Increase in Diabetes Due to Sugar
httpwholehealthsourceblogspotcom201202by-2606-us-diet-will-be-100-percenthtml
Dia
bete
s 1
How About Persistent Organic Pollutants
Neel BA Robert M Sargis RM The paradox of progress Environmental disruption of metabolism and the diabetes epidemic DIABETES 2011 601838-48
Lars Jaumlrup Br Med Bull 200368167-182copy The British Council 2003 all rights reserved
Global Production and Consumption of
Selected Toxic Metals 1850ndash1990
Cadmium World Production
Mercury in the Air
EPA-452R-97-003 December 1997
Mercury in Water
httpwaterepagovscitechdataitmodelsmapspostercfm
Ground Water Sources of Arsenic
bull 10 of US public water supplies have levels of arsenic known to induce disease
bull No data on private water supplies
httpwwwatsdrcdcgovcsemarsenicdocsarsenicpdf (accessed 2015-08-18)
Example POPs
Chemical Abbr Uses Exposure
Bisphenol A BPA Plastics Canned food
Organochlorine
pesticides
OCPs Pesticide Food fumigation
Organophosphate
pesticides
OPPs Pesticide Food
Polybrominated
diphenyl ethers
PBDEs Flame retardant Clothing
Polychlorinated
biphenyls
PCBs Industrial Everywhere
Perflourinated PFOAs Non-stick stain prevention
water repellant
Teflon Gortex
Scotchguard
Phthalates Plastics fragrances Shower curtains
cosmetics
POPs - Prediabetes
bull Over 1200 participants fasting
glucose and OGTT performed
with serum levels of 5 POPs
bull All individual POPs tested were
associated with progressive
increase in prevalence of
prediabetes
bull More than triple prevalence of
prediabetes seen in those in the
5th quartile with a synergistic
effect from 5 POPs
Ukropec J et al High prevalence of prediabetes and diabetes in a population exposed to high levels of an organochlorine cocktail
Diabetologia 2010 May53(5)899-906
POPs and Diabetes Risk
Graph httpwwwourstolenfutureorgNewScienceobesity20062006-0715leeetalhtml
Data Lee DH Lee IK Song K et al A strong dose-response relation between serum
concentrations of persistent organic pollutants and diabetes results from the National Health and
Examination Survey 1999-2002 Diabetes Care 2006 Jul29(7)1638-44
Toxic Load and Disease Risk
References for Toxins and Disease Risk
Converting Disease Risk to Caused
Attributable Fraction Calculation
p = underlying prevalence of risk factor in the population
rr = relative risk (risk of contracting a disease in an exposed population divided by the risk of contracting the disease in an unexposed population)
AF = of disease due to the toxin
Levin M The occurrence of lung cancer in man Acta Unio Int Contra Cancrum 1953 9 531-541
Example Smoking and Lung Cancer
B = 5Number of smokers
who contract Lung Cancer notdue to smoking
A = 5Number of smokerswho contract Lung
Cancer due to smoking
C = 15Number of
nonsmokerswho contract Lung Cancer
0
2
4
6
8
10
12
14
16
Smokers (N=100) Nonsmokers (N=300)Num
ber
of
people
who c
ontr
act
Lung C
ancer
per
year
Baseline Additional due to smoking
Number of smokers and nonsmokers who contract lung cancer
Our Process In Summary
1 Determine threshold for increased disease risk
2 Determine of population above threshold
3 Determine incidence of disease (OR) in those above threshold
4 Determine incidence of disease in ldquounexposed populationrdquo
5 Calculate AF ie of disease
As whole population is exposed probably UNDERESTIMATES of disease
To
xic
ity H
as B
eco
me t
he N
ew
ldquoN
orm
alrdquo
Toxin Type Use Threshold for
disease
association
of US
above
threshold
Disease Associations
Chlordane OC pesticide Termites corn citrus lawns
gardens
145ngg lipid 63
(diabetes)
Diabetes (20)
BPA Plasticizer Water bottles canned food
water pipes thermal sales
receipts
48 men 51
women (urine
ngmL)
~18
(diabetes)
Diabetes hypertension
Octachloro
dibenzo-p-
dioxin
(OCDD)
Polychlorinated
dibenzo-p-
dioxin
Incineration or burning of
waste bleaching processes
used in pulp and paper mills
1010 pgg
lipid (highest
quartile)
10-25
(hypertensio
n)
Hypertension (79 for
women highest
quartile) diabetes (21)
obesity learning
disability (272)
MEP
(mono-
ethyl
phthalate)
Phthalate
(plasticizer
fragrance)
Toothbrushes automobile
parts tools toys and food
packaging aspirin
cosmetics food packaging
gt175 ngmL
(urine)
~60
(diabetes)
Diabetes (148) lower
BMD obesity
pp-DDE DDT
metabolite (OC
pesticide)
Agricultural crops 1560ngg
lipid
25
(diabetes)
Diabetes (23-43)
early menopause
impaired cognitive
function (2-3x 65x in
highest 5th percentile)
peripheral arterial
disease
Arsenic Toxic metal Miningsmelting wood
preservative pesticides
74ugL total
arsenic (urine)
20
(diabetes)
Cancers diabetes (26-
46) dyslipidemia gout
AF OR Prevalence
Rosen L An intuitive approach to understanding the attributable fraction of disease due to a risk factor the case of smoking Int J Environ Res Public Health 2013 Jul 1610(7)2932-43
Smoking Lung cancer
Arsenic Gout in women
BPA Diabetes
Status of Our Research
bull 26 toxins and toxin classes eg lead mercury BPA OCPs
100s of chemicals and POPs in some classes
bull 18 cancers
bull 24 chronic diseases
bull 1092 cells in spreadsheet
Large Personal Ongoing Research Investment
Huge Amount of Research Work
Toxins StudiedAluminum
Arsenic
Cadmium
Fluoride
Lead
Manganese
Mercury
Acrylamide
Acrylonitrile
Benzene
Bisphenol A (BPA)
Chloroform
DDT
Dioxins
Glyphosate
Organochlorine pesticides (OCPs)
Organophosphate pesticides
Parabens
Phthalates
Polybrominated diphenyl ethers (PBDEs)
Polycyclic aromatic hydrocarbons (PAHs)
Polychlorinated biphenols (PCBs)
Vinyl chloride
Diseases Studied
ADHD
Alzheimers Disease
ALS
Angiosarcoma
Anxiety
Atopic Conditions
Diabetes
Dyslipidemia
Gout
Fetal Abnormalities
Hyperuricemia
Infertility
Juvenile IQ
Cancer Bladder
Cancer Bone
Cancer Brain
Cancer Breast
Cancer Cervix
Cancer Colorectal
Cancer Endometrial
Cancer Head amp Neck
Cancer Liver
Cancer Lung
Cancer Lymph amp Blood
Cancer Ovarian
Cancer Pancreatic
Cancer Prostate
Cancer Renal
Cancer Skin
Cancer Testicular
Cancer Thyroid
Juvenile Obesity
Metabolic Syndrome
Mitochondrial dysfunction
Myocardial Infarction
Obstructive Lung Disease
Osteoporosis
Peripheral Artery Disease
Peripheral Neuropathy
Prediabetes
Renal Disease
Rheumatoid Arthritis
Thyroid Dysfunction
OC
Ps
Th
rou
gh
ou
t th
e W
orl
d
Rathore HS Nollet LML Pesticides Evaluation of Environmental Pollution CRC Press
2012 page 562
Threshold ndash Threshold exposure at which there is an increased risk of disease outcome
Above Threshold ndash Percentage of the population with higher exposure than the threshold
Odds Ratio ndash Increased disease risk in those above threshold
of Dz ndash Percent contribution of the toxin to that disease outcome
How to Interpret the Following Slides
Attention Deficit Hyperactivity Disorder
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
DDT 126 ngg
serum (pp-
DDE)
250 18 166 20106937
Lead 23 ugdL 13 254 20 27659349
Mercury 16 24952233
Organophosphate
pesticides
20
Polycyclic
Aromatic
Hydrocarbons
227 ngm3 940 125 190 22440811
PCBs 104 ngg
serum (sum
of 50 PCBs)
250 176 160 20106937
DiabetesToxin Threshold Above
Threshold
Odds
Ratio
of Dz Reference
PMID
Arsenic 165 ugL 200 21 180 18714061
BPA 28 ugL 280 145 112 26119400
DDE 545 ngg serum
(pp-DDE)
200 230 31 26119400
Dioxins2 pgg lipid 50 191 43
26119400
PCBs104 ngg (PCB 153) 250 239 258
26119400
Phthalates175 ugL 690 148 249
26119400
1-naphthalene 167 ugdL 152 182 111 26340343
2-napthalene 414 ugdL 550 224 214 26340343
1-phenanthrene 167 ngL 570 178 151 26340343
1-pyrene 85 ngL 660 180 174 26340343
Lung Cancer
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Acrylonitrile Uncertain Uncertain 125 25
occupational
exposure
17114112
Arsenic 1213 ugL 436 of Asian
Americans
~01 of total
US population
34 95 in AA
01-1
PMC2682945
Cadmium Uncertain+ Uncertain 467 10 in
smokers
17184399
DDT Any exposure All US pop
below LOD
17 76 increased
risk
8923607
Breast Cancer
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Cadmium 0580 ugg
creatinine
126 205 479 16788160
PCB 138 396 ngg
creatinine
202 316 630 27717745
PCB 187 108 ngg lipid 600 194 360 21480306
Miscellaneous Diseases
Toxin Disease Threshold Above
Threshold
Odds
Ratio
of Dz Reference PMID
Aluminum Alzheimer
Dz
01 mgL
drinking
H20
400 203 05-44 26592479
Benzene AML 100ppmyrs 1-3 320 60 PMC2903550
DDT NHL 0512 ugL 1-2 240 01 17722095
Lead ALS 238 ugdL
blood
330 181 210 25479292
Lead Brain CA 0005 ugdL 14 19 ~500 17164378
Dioxin-like
PCBs
RA 326 ngg
lipid
250 219 220 17589595
PAHs Asthma 124 ngm3 935 200 483 19221603
The Potency of Arsenic
Disease Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Bladder CA 10ugL H20 100 27 145 24889821
Pancreatic CA 1332 ugg 200 246 230 23800676
Prostate CA 1332 ugg 200 33 315 23800676
Gout 125 ugL 245 546 522 25499256
Diabetes 165 ugL 200 21 180 18714061
Arsenic (180 of Diabetes)
How it causes diabetes
bull Blocks sugar stimulating insulin secretion
bull Epigenetic inhibition of sugar regulation
Where it comes from
bull Water (gt10 of US water supplies have high levels)
bull Rice (naturally absorbs if in the water)
bull Chicken (added to make meat whiter)
Pan W-C Seow WJ Kile ML et al Association of low to moderate levels of arsenic exposure with risk of Type 2 diabetes in Bangladesh American Journal of Epidemiology 2013178(10)1563-70
Portion of Population with Toxin Load Which
Doubles Disease Risk
Toxin Disease with Doubled Risk
Polycyclic aromatic hydrocarbons Asthma 94
PCB187 Breast Cancer 60
Phthalates Diabetes 55
Lead ALS 33
Aluminum Alzheimers Disease 25
DDT ADHD 25
PCBs Diabetes 25
Dioxin-like PCBs Rheumatoid Arthritis 25
Arsenic Gout 23
Bisphenol A Diabetes 22
Cigarette smoking Lung Cancer 21
Arsenic Diabetes 20
Polycyclic aromatic hydrocarbons Diabetes 20
Huge Detoxification Variability
bull CYP2C19
Proton pump inhibitors and some antidepressants
5-fold difference in activity between poor metabolizers and extensive metabolizers more so if CYP3A4 is also inhibited
Ultrarapid allele in 18 of both Swedes and Ethiopians
bull CYP2D6
Metabolizes a large number of drugs (~25)
7 of Caucasians poor metabolizers
~30 ultra rapid metabolizers in Arabian and Eastern African populations
More adverse effects in poor metabolizers and ineffective dosing in ultrarapid metabolizers
Inhibited by ginger
Desta Z et al Clinical significance of the cytochrome P450 2C19 genetic polymorphism Clin Pharmaco 2002
Sim SC et al A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug
response to proton pump inhibitors and antidepressants Clin Pharmacol Ther 2006
Wilkinson GR Drug metabolism and variability among patients in drug response N Engl J Med 2005
Kirchheiner J et al Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to
CYP2D6 duplication Pharmacogenomics J 2007
Toxin Half Lives in BloodToxin ldquoNormalrdquo (mgL) Acute Toxic (mgL) Half-Life
Arsenic 0002-007 005-025 2-4 days (CDC)
Benzene 00002 05-10 days
Cadmium 00003-00065 0015-005 16 years
Chlordane 0001 00025 3-4 days
DDTDDE 2-10 years
Dieldrin 00015 015-030 2-12 months
Ethanol 1000-2000 15hour
Lead 009 04-06 1-15 mo (2+ yrs bone)
Mercury 00015-0002 005-02 2 months (CDC)
PCBs 3-25 years
Toluene 05-3 days
Schulz M et al Therapeutic and toxic blood concentrations of nearly 1000 drugs and other xenobiotics Crit Care 2012 Jul 2616(4)R136
Bioaccumulation (POPs)
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
DDT banned in 1972 PCBs banned in 1977
Bioaccumulation (Cd)
Think BroadlyExogenous
Metals
Chemicalsbull Inorganic
bull Fluoride
bull Organic
bull POPs
bull Drugs
Particulate matter
Molds
Microbial
Radiationbull Light
bull Medical
bull Cell phone
Endogenous
Gut-derived toxins
Non-end product metabolites
Poorly detoxified hormones
Catecholamines (if SNP)
Toxins of Choice
Alcohol
Marijuana
Food constituents
High fructose corn syrup
Salt (acid-forming diet)
Wheat if zonulin (70)
Obesity Epidemic ndash POPs AND HFCS
47Bray GA Fructose should we worry Int J Obes (Lond) 2008 Dec32 Suppl 7S127-31
How Toxins Cause Damage 13
bull Increase free radical production
Cd induces production of ROS
Malathion inhibits catalase and glutathione peroxidase
Homocysteine oxidizes LDL cholesterol
bull Poison enzyme systems (compete with nutritional cofactors for binding sites)
Pb poisons delta aminolevulinic acid dehydratase
Cd inhibits catalase glutathione reductase and lowers
glutathione levels
bull Replace structural minerals
Pb displaces Ca in bone
How Toxins Cause Damage 23
bull Damage DNA
Benzene - causes chromosomal damage
Pesticides ndash fruit growers have more DNA damage
Phthalates and insecticides ndash damage sperm DNA
4-hydroxy catechol estrogen (4-OHE) damages breast DNA
bull Epigenetic dysmodulation
Higher cord blood levels of hexachlorobenzene associated
with 2x greater risk for obesity in children
bull Damage cell membranes
Common mechanism for heavy metals inactivates
membrane enzymes ion channels and pumps
How Toxins Cause Damage 33
bull Block insulin receptor sites
PCBs and phthalates
bull Highest levels associated with a 4 to 20-fold greater diabetes risk
bull Imbalance hormones many toxin examples
Arsenic
bull Disrupts thyroid hormone and retinoic acid receptors
Phthalates
bull Act as anti-androgens
bull More than 75 of the US population has measurable levels of
several phthalate metabolites in the urine
PCBs
bull Lower testosterone levels in men
Which are the Worst Toxins
bull According to the CDC
Toxicity
Population toxic load
Prevalence in toxic waste sites
bull According to clinical importance
Exposure
of disease
Ability of the body to detoxifyexcrete
Ag
en
cy
fo
r T
oxic
Su
bs
tan
ce
s a
nd
Dis
ea
se
Reg
istr
y
Pri
ori
ty L
ist
The Worst Toxins Clinically
My Rank Toxin Diseases Primary Sources
1 Arsenic Cancers diabetes gout Water chicken rice
2 DDT ADHD dementia diabetes Everywhere
3 Phthalates ADHD diabetes Soft plastics HABAs
4 PBDEs ADHD diabetes Flame retardant fabrics
5 PAHs ADHD cancers dyslipidemia Smoking charbroiling
6 PCBs Cancers diabetes MI RA Everywhere
7 Mercury Dementia ldquoSilverrdquo fillings fish
8 Lead Cardiovascular disease IQ Paint water
Glyphosate Research invalid
Conventional Laboratory Tests Reflect
Toxic Load in ldquoNormalrdquo Range
bull Surprising number show toxin exposure
CBC RBC WBC platelet count hemoglobin basophilic
stippling
Liver enzymes ALT GGTP
Inflammatory markers CRP
Lipids LDL oxLDL triglycerides
Blood sugar insulin FBS 2-hour PP
Metabolites bilirubin uric acid homocysteine 8-OHdG
Thyroid T3 T4 TSH
bull The historic ldquonormalrdquo range has been changing as the population has become more toxic
WBC Lowered by PCB and OCP Exposure
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
0
1
2
3
4
5
6
7
8
1st Quartrile 2nd Quartile 3rd Quartile 4th Quartile
WBCbull Strong inverse correlation with PCBs and OCPs and CBC
bull Linear with almost all PCBs
bull High variability with OCPs
bull Within ldquonormalrdquo range
Effects on WBC Worsen with Years
of Exposure to Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Platelet Count Decreases with Years
of Exposure tp Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Solvents Decrease Platelet Count
bull Compared workers exposed 23 hrday to those exposed most of day to toluene
bull All wore face masks and protective gear
bull Platelet count 14 lower 252 versus 216ml
bull Impairment of sympathetic nerves (OR = 413)
bull Impairment of peripheral nerves (OR = 694)
bull Positive relationship between neurological abnormalities and a self-reported neuropsychiatric measurement (r = 035-066)
Shih HT et al Subclinical abnormalities in workers with continuous low-level toluene exposure Toxicol Ind Health 2011 Sep27(8)691-9
Basophilic Stippling of Red Cells
Toxinsbull Arsenic
bull Lead
Diseasesbull Alpha-thalassemia HbH Disease
bull Beta thalassemia
bull Hereditary pyrimidine 5-nucleotidase deficiency
bull Myelodysplastic syndrome
bull Sideroblastic anemia
bull Thrombotic thrombocytopenic purpura
GGT Indirect Measure of POPsbull Glutathione is key intracellular defense against oxidative stress
bull Cellular GGT metabolizes extracellular GSH allowing precursor amino acids to be reutilized for intracellular GSH
bull Exposure to POPs induces GGT as a defensive mechanism
bull Within normal range predicts type 2 diabetes coronary heart disease hypertension stroke dyslipidemia chronic kidney disease and cancer
bull Men with GGT gt50 UI had ~26 fold risk for diabetes compared to those with lt10 Those with 40-49 had a ~20 fold risk
bull Levels within normal range occur with obesity xs alcohol cigarette smoking physical inactivity high meat low fruit and vegetable intake
bull Cumulative biomarker for environmental pollutants
Lee DH et al (2003) Gamma-glutamyltransferase and diabetesmdasha 4 year follow-up study Diabetologia 46359ndash364
Pamela A et al Serum gamma-glutamyltransferase linking together environmental pollution redox equilibria and progression of atherosclerosis Clin Chem
Lab Med 200947(12)1583-4
Lee DH et al Serum gamma-glutamyltransferase new insights about an old enzyme J Epidemiol Community Health 2009 Nov63(11)884-6
Lee DH et alSerum gamma-glutamyltransferase predicts non-fatal myocardial infarction and fatal coronary heart disease among 28838 middle-aged men and
women Eur Heart J 2006272170ndash6
Lee DH et al Gamma-glutamyltransferase and diabetes--a 4 year follow-up study Diabetologia 2003 Mar46(3)359-64
Lee DH et al Can persistent organic pollutants explain the association between serum gamma-glutamyltransferase and type 2 diabetes Diabetologia 2008
Mar51(3)402-7
GGT and Alcohol Consumption
bull GGT directly correlates with alcohol consumption
bull In a non-uniform population 40 gd will elevate GGT ~15
bull Watch for false negatives
bull Genomic variation
bull Are these the ones most
sensitive todamaged by
chemical toxins
bull Could up-regulation of GGT in light alcohol consumption be reason for benefit
0
10
20
30
40
50
60
70
80
0 200 400 600 800
Grams of Ethanol per Week
Adapted from Nagaya T et al Dose-response relationships between drinking and serum tests in Japanese men
aged 40ndash59 years Alcohol 1999 Feb 17(2) 133ndash8
GGT Correlates With Toxic Metal Levels
Lee DH et al Graded associations of blood lead and urinary cadmium concentrations with oxidative-stress-related markers in the
US population results from the third National Health and Nutrition Examination Survey Environ Health
perspect 2006 Mar114(3)350-4
GGT and Diabetes Risk
0
5
10
15
20
25
30
lt10 10-19 20-29 30-39 40-49 gt50
Dia
bete
s R
isk
GGT
bull GGT over 50 associated with tripling of death rate
bull 30-40 associated with doubling
GGT Levels
Correlate with
Risk of Death
Brenner H et al Distribution determinants and prognostic value of gamma-glutamyltransferase for all-cause
mortality in a cohort of construction workers from southern Germany Prev Med 1997 26 305ndash10
GGT From Small US Company
with Young Workers
0
10
20
30
40
50
60
0 20 40 60 80 100
GGT Data from Canadian Oil Field
Workers
0
50
100
150
200
250
300
350
400
450
lt10 10-20 20-30 30-40 40-50 50-60 60-07 70-80 80-90 90-100 100-110 110-120 gt120
GGTP
20-fold increased risk of diabetes
Uric Acid Indirect Measure of POPs
bull Poly-fluorinated hydrocarbons (PFOA and PFOS) associated
with increased serum uric acid
Lin CY et al Association among serum perfluoroalkyl chemicals glucose homeostasis and metabolic syndrome
in adolescents and adults Diabetes Care 2009 Apr32(4)702-7
Steenland K et al Association of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) with uric
acid among adults with elevated community exposure to PFOA Environ Health Perspect 2010 Feb118229-33
Steenland 2010 Open Access
ALT Indirect Measure of POPs
bull ALT (proxy marker) elevation in 104 (not including viral
hepatitis hemochromatosis or alcoholic liver disease) of
NHANES 03-04 subset
bull Risk of elevated ALT increased dose-dependently with
cadmium lead mercury and PCB exposure
bull 100 of individuals had detectable PCBs 925 mercury
and 996 had detectable lead
bull In 2005-08 prevalence of NAFLD in US was 11 a
growing cause of chronic liver disease
Cave M et al Polychlorinated biphenyls lead and mercury are associated with liver disease in American adults
NHANES 2003-2004 Environ Health Perspect 2010 Dec118(12)1735-42
Younossi ZM et al Changes in the prevalence of the most common causes of chronic liver diseases in the United
States from 1988 to 2008 Clin Gastroenterol Hepatol 2011 Jun9(6)524-530e1
Bilirubin as a Marker of POPs
bull Degree of serum bilirubin increase is prognostically significant in chronic liver dysfunction
bull Mono-ortho PCB TEQ values were found to be significantly positively associated with bilirubin (β=071 P=0008) following adjustment for multiple potential confounders
bull Bilirubin levels significantly correlated with PCBs -105-118-126 and -194
bull Smoking appears to be the biggest confounder
Dufour DR et al 2000 Diagnosis and monitoring of hepatic injury II Recommendations for use of laboratory
tests in screening diagnosis and monitoring Clin Chem 46 2050ndash68
Kumar J et al Persistent organic pollutants and liver dysfunction biomarkers in a population-based human sample
of men and women Environ Res 2014134251-256
Perf
luo
rin
ate
dP
OP
s a
nd
Co
mm
on
Blo
od
Tests
Gleason JA et al Associations of perfluorinated chemical serum concentrations and biomarkers of liver function and uric acid in the
US population (NHANES) 2007-2010 Environ Res 20151368-14
Liver Enzymes Reflect Toxic Load
bull AST ALT and GGT increase with body load of PCBs and OCPs
bull Some non-linear
bull Oxychlordanetop quartile
ALT 10
GGT 25
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
LDL-Cholesterol as Measure of POPs
bull 5-year prospective study to determine if POP levels predict future elevation in LDL-cholesterol
bull 598 subjects initially at age 70
bull Looked at 23 POPs
bull Best correlation with PCB 194
Penell J Lind L Salihovic S et al Persistent organic pollutants are related to change in circulating
lipid levels during a 5 year follow-up Environ Res 134(2014)190ndash197
oxLDL as Measure of POPs
bull 992 70-year old individuals (50 women)
bull Sum of PCBs showed strong significant positive associations with ox-LDL and significant negative associations with glutathione-related markers (GSSG and GSSGGSH)
bull A number of POPs (PCB-99 138 153 156 170 180 194 206 and 209) showed strong significant positive association with ox-LDL
Kumar J et al Influence of persistent organic pollutants on oxidative stress in population-based samples
Chemosphere 2014114303-309
Homocysteine is Increased by Pb amp Cd
Guallar E et al Confounding of the relation between homocysteine and peripheral arterial disease by lead cadmium and renal function Am J Epidemiol 2006 Apr 15163(8)700-8
Nutrient Deficiencies Accentuate
Effects of Lead on Homocysteine
bull Deficiencies in folate B6 or B12 make lead more toxic
Lee YM Et al Association of homocysteine levels with blood lead levels and micronutrients in the US general population J Prev Med Public Health 2012 Nov45(6)387-93
T4 amp T3 and PCBs
bull PCBs decrease T4 production
bull PCBs inhibit iodotyrosinedeiodinase activity
bull Study done in pregnant women which implies effect on fetus IQ
Kim S Park J Kim HJ et al Association between several persistent organic pollutants and thyroid hormone levels in serum among the pregnant women of Korea Environ Int 2013 Sep59442-8Shimizu R Yamaguchi M Uramaru N et al Structure-activity relationships of 44 halogenated compounds for iodotyrosinedeiodinase-inhibitory activity Toxicology 2013 Dec 6314(1)22-9
T4 amp T3 and PCBs
bull Not just humans being affected
bull Large study of dolphins shows exactly the same effects
Schwacke LH Zolman ES Balmer BC et al Anaemia hypothyroidism and immune suppression associated with polychlorinated biphenyl exposure in bottlenose dolphins (Tursiops truncatus) Proceed Royal Society B doi101098rspb20110665
8-OHdG
bull Oxidized nucleoside
bull Direct measure of DNA damage
bull Indirect measure of oxidative stress and toxin load
bull Correlates with
Multiple cancers
Mitochondrial damage
Rate of aging
Smoking
Several toxinsWalter Crinnion ldquoTotal Toxic Loadrdquo AANP 2015
8-OHdG Correlates with Pack-Years
of Smoking
Yano T et al Significance of the urinary 8-OHdG level as an oxidative stress marker in lung cancer patients Lung Cancer
2009 Jan63(1)111-4
8-OHdG Correlates
with Mercury
Chen C et al Increased oxidative DNA damage as assessed by urinary 8-hydroxy-2-deoxyguanosine
concentrations and serum redox status in persons exposed to mercury Clin Chem 2005 Apr51(4)759-67
Toxin Effects Worse with Aging
bull Thyroid function decreases with PFOA levels
bull But only after age 63
Shrestha S Bloom MS Yucel R et al Perfluoroalkyl substances and thyroid function in older adults Environ Int 2015 Feb75206-14
Insightful 23-Year Prospective Study
1 lt 50 there is no difference between those with the lowest and highest PCBs
2 In youngest group insulin production increases in response to toxin level As expected since blocking of
insulin receptor sites by PCBs
requires more insulin
3 That adaptive ability decreases with aging
4 At age 50 all the measures show very strong toxin-dose response
Cumulative damage impairs ability to adapt
Suarez-Lopez JR et al Persistent organic pollutants in young adults and changes in glucose related metabolism over a 23-year follow-up Environ Res 2015 Feb137485-94
Recommendations
High body toxic load
GGT gt 25
Uric acid gt 50 mgdl
ALT gt30 UL
Bilirubin gt08 mgdl
CBC lt 6000
Platelet lt 250000
Low T3 andor T4
Monitor Total Toxic Load
8-OHdG gt4
ldquoUnconventionalrdquo Laboratory Tests
bull Challenge testing
bull Hair analysis
bull Direct measures of solvents and POPs in blood urine adipose tissue
Evaluation of Metal Exposure ndash Provocation
bull Provocation ndash the use of a chelating agent ndash before urine collection often done clinically but several limitations
No ldquoofficialrdquo reference range for provoked urine
Most chelating agents do not extract metals from all tissues thus
does not necessarily represent total body burden
bull Example Brain is one of the main target organs for both elemental and organic
mercury yet agents do not chelate brain mercury
bull Despite limitations widely used and advocated by clinicians in part to see efficacy of chelating agent as a guide to treatment and based on empirical evidence
Rooney JP The role of thiols dithiols nutritional factors and interacting ligands in the toxicology of mercury
Toxicology 2007
Is Challenge Testing Valid
bull Poor correlations of standard tests for mercury
bull Unpublished research from corporate wellness project
bull Published amalgam number correlation
bull Published fish consumption correlation
What We Found In Canada
bull Deviations from the mean of 14 29 and 91 respectively
bull DMPS is spreading distribution suggesting that it is better at differentiating mercury body load
bull Some VERY high
Hg Assessment Correlations
bull Extensive measurements in 65 Whole blood Hg
Oral DMPS challenge
Amalgam surfaces
bull Correlations Whole blood w pre urine r = 040
Whole blood w post urine r = 057
Pre urine w post urine r = 068
Amalgams w pre urine r = 026
Amalgams w whole blood r = 036
Amalgams with post urine 044
bull Clear documentation that
challenge testing is better00
100
200
300
400
500
600
0 10 20 30 40 50
Po
st
Uri
ne H
g u
gg
Number of amalgams
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
1 Worldwide Epidemic of Chronic Disease
2 Causes
3 Methodology Disease Risk to Disease Cause
4 Most Chronic Disease is Now Caused by Toxins
5 The Worst Toxins
6 Sources of Toxins
7 Toxicity has Become the New Normal ldquoNormalrdquo Laboratory Ranges Are Toxic Ranges
8 Summary
Overview
There is Some Good Newsbull Banning lead in gasoline
and paint workedmdashblood levels down dramatically
bull No threshold for safety ndash
Children who had whole blood
lead concentrations of lt5 microgdL
(supposedly safe) associated
with decreased IQ
24 million children at levels
between 5 and 99 ugdL
bull July 2012 CDC changed recommended level to intervene in children from 10 to 50 ugdL Also eliminated term ldquolevel of concernrdquo to avoid giving false sense of safety
Iqbal S et al Estimated burden of blood lead levels 5 microgdl in 1999-2002 and declines from 1988 to 1994
Environ Res 2008
httpwwwcdcgovncehleadacclppcdc_response_lead_exposure_recspdf
httpwwwenvironmentuclaedureportcardarticle3772html
bull Human data
bull Primarily US as a lot more research available
bull Spot checking toxins in other countries shows the same toxin overload but variations in which are most prevalent
Australia (higher PDBEs)
Canada (higher lead)
New Zealand (higher cadmium)
Sweden (higher most toxic metals)
UK (highest PDBEs in world 3x OCP of US)
A Note About the Data
AD
HD
Ep
idem
ic
httpwwwcdcgovmmwrpreviewmmwrhtmlmm6433a11htm
Obesity Epidemic
httpwwwtheobesityepidemicorgintroduction (Accessed 616)
Kidney Disease Epidemic
Stevens L httpwwwslidesharenetringer21liaison-meeting-esrd-presentation (accessed 616)
Dia
be
tes
Ep
ide
mic
Diabetes Increasing World-Wide
SourcesAIHW analysis of ABS NHS 1989ndash90 1995 2001 2004ndash05 and 2007ndash08 NHS (reissue) and ABS 2011ndash12 Australian
Health Survey data (Release 7 June 2013)
Co-ordinaring Committee Epidemiology Study of Childhood amp Adolescent Diabetes Hong Kong KF Huen et al
Australian Adults
Childhood diabetes in Hong Kong
WHY THE CHRONIC DISEASE
EPIDEMICS
Increase in Diabetes Due to Sugar
httpwholehealthsourceblogspotcom201202by-2606-us-diet-will-be-100-percenthtml
Dia
bete
s 1
How About Persistent Organic Pollutants
Neel BA Robert M Sargis RM The paradox of progress Environmental disruption of metabolism and the diabetes epidemic DIABETES 2011 601838-48
Lars Jaumlrup Br Med Bull 200368167-182copy The British Council 2003 all rights reserved
Global Production and Consumption of
Selected Toxic Metals 1850ndash1990
Cadmium World Production
Mercury in the Air
EPA-452R-97-003 December 1997
Mercury in Water
httpwaterepagovscitechdataitmodelsmapspostercfm
Ground Water Sources of Arsenic
bull 10 of US public water supplies have levels of arsenic known to induce disease
bull No data on private water supplies
httpwwwatsdrcdcgovcsemarsenicdocsarsenicpdf (accessed 2015-08-18)
Example POPs
Chemical Abbr Uses Exposure
Bisphenol A BPA Plastics Canned food
Organochlorine
pesticides
OCPs Pesticide Food fumigation
Organophosphate
pesticides
OPPs Pesticide Food
Polybrominated
diphenyl ethers
PBDEs Flame retardant Clothing
Polychlorinated
biphenyls
PCBs Industrial Everywhere
Perflourinated PFOAs Non-stick stain prevention
water repellant
Teflon Gortex
Scotchguard
Phthalates Plastics fragrances Shower curtains
cosmetics
POPs - Prediabetes
bull Over 1200 participants fasting
glucose and OGTT performed
with serum levels of 5 POPs
bull All individual POPs tested were
associated with progressive
increase in prevalence of
prediabetes
bull More than triple prevalence of
prediabetes seen in those in the
5th quartile with a synergistic
effect from 5 POPs
Ukropec J et al High prevalence of prediabetes and diabetes in a population exposed to high levels of an organochlorine cocktail
Diabetologia 2010 May53(5)899-906
POPs and Diabetes Risk
Graph httpwwwourstolenfutureorgNewScienceobesity20062006-0715leeetalhtml
Data Lee DH Lee IK Song K et al A strong dose-response relation between serum
concentrations of persistent organic pollutants and diabetes results from the National Health and
Examination Survey 1999-2002 Diabetes Care 2006 Jul29(7)1638-44
Toxic Load and Disease Risk
References for Toxins and Disease Risk
Converting Disease Risk to Caused
Attributable Fraction Calculation
p = underlying prevalence of risk factor in the population
rr = relative risk (risk of contracting a disease in an exposed population divided by the risk of contracting the disease in an unexposed population)
AF = of disease due to the toxin
Levin M The occurrence of lung cancer in man Acta Unio Int Contra Cancrum 1953 9 531-541
Example Smoking and Lung Cancer
B = 5Number of smokers
who contract Lung Cancer notdue to smoking
A = 5Number of smokerswho contract Lung
Cancer due to smoking
C = 15Number of
nonsmokerswho contract Lung Cancer
0
2
4
6
8
10
12
14
16
Smokers (N=100) Nonsmokers (N=300)Num
ber
of
people
who c
ontr
act
Lung C
ancer
per
year
Baseline Additional due to smoking
Number of smokers and nonsmokers who contract lung cancer
Our Process In Summary
1 Determine threshold for increased disease risk
2 Determine of population above threshold
3 Determine incidence of disease (OR) in those above threshold
4 Determine incidence of disease in ldquounexposed populationrdquo
5 Calculate AF ie of disease
As whole population is exposed probably UNDERESTIMATES of disease
To
xic
ity H
as B
eco
me t
he N
ew
ldquoN
orm
alrdquo
Toxin Type Use Threshold for
disease
association
of US
above
threshold
Disease Associations
Chlordane OC pesticide Termites corn citrus lawns
gardens
145ngg lipid 63
(diabetes)
Diabetes (20)
BPA Plasticizer Water bottles canned food
water pipes thermal sales
receipts
48 men 51
women (urine
ngmL)
~18
(diabetes)
Diabetes hypertension
Octachloro
dibenzo-p-
dioxin
(OCDD)
Polychlorinated
dibenzo-p-
dioxin
Incineration or burning of
waste bleaching processes
used in pulp and paper mills
1010 pgg
lipid (highest
quartile)
10-25
(hypertensio
n)
Hypertension (79 for
women highest
quartile) diabetes (21)
obesity learning
disability (272)
MEP
(mono-
ethyl
phthalate)
Phthalate
(plasticizer
fragrance)
Toothbrushes automobile
parts tools toys and food
packaging aspirin
cosmetics food packaging
gt175 ngmL
(urine)
~60
(diabetes)
Diabetes (148) lower
BMD obesity
pp-DDE DDT
metabolite (OC
pesticide)
Agricultural crops 1560ngg
lipid
25
(diabetes)
Diabetes (23-43)
early menopause
impaired cognitive
function (2-3x 65x in
highest 5th percentile)
peripheral arterial
disease
Arsenic Toxic metal Miningsmelting wood
preservative pesticides
74ugL total
arsenic (urine)
20
(diabetes)
Cancers diabetes (26-
46) dyslipidemia gout
AF OR Prevalence
Rosen L An intuitive approach to understanding the attributable fraction of disease due to a risk factor the case of smoking Int J Environ Res Public Health 2013 Jul 1610(7)2932-43
Smoking Lung cancer
Arsenic Gout in women
BPA Diabetes
Status of Our Research
bull 26 toxins and toxin classes eg lead mercury BPA OCPs
100s of chemicals and POPs in some classes
bull 18 cancers
bull 24 chronic diseases
bull 1092 cells in spreadsheet
Large Personal Ongoing Research Investment
Huge Amount of Research Work
Toxins StudiedAluminum
Arsenic
Cadmium
Fluoride
Lead
Manganese
Mercury
Acrylamide
Acrylonitrile
Benzene
Bisphenol A (BPA)
Chloroform
DDT
Dioxins
Glyphosate
Organochlorine pesticides (OCPs)
Organophosphate pesticides
Parabens
Phthalates
Polybrominated diphenyl ethers (PBDEs)
Polycyclic aromatic hydrocarbons (PAHs)
Polychlorinated biphenols (PCBs)
Vinyl chloride
Diseases Studied
ADHD
Alzheimers Disease
ALS
Angiosarcoma
Anxiety
Atopic Conditions
Diabetes
Dyslipidemia
Gout
Fetal Abnormalities
Hyperuricemia
Infertility
Juvenile IQ
Cancer Bladder
Cancer Bone
Cancer Brain
Cancer Breast
Cancer Cervix
Cancer Colorectal
Cancer Endometrial
Cancer Head amp Neck
Cancer Liver
Cancer Lung
Cancer Lymph amp Blood
Cancer Ovarian
Cancer Pancreatic
Cancer Prostate
Cancer Renal
Cancer Skin
Cancer Testicular
Cancer Thyroid
Juvenile Obesity
Metabolic Syndrome
Mitochondrial dysfunction
Myocardial Infarction
Obstructive Lung Disease
Osteoporosis
Peripheral Artery Disease
Peripheral Neuropathy
Prediabetes
Renal Disease
Rheumatoid Arthritis
Thyroid Dysfunction
OC
Ps
Th
rou
gh
ou
t th
e W
orl
d
Rathore HS Nollet LML Pesticides Evaluation of Environmental Pollution CRC Press
2012 page 562
Threshold ndash Threshold exposure at which there is an increased risk of disease outcome
Above Threshold ndash Percentage of the population with higher exposure than the threshold
Odds Ratio ndash Increased disease risk in those above threshold
of Dz ndash Percent contribution of the toxin to that disease outcome
How to Interpret the Following Slides
Attention Deficit Hyperactivity Disorder
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
DDT 126 ngg
serum (pp-
DDE)
250 18 166 20106937
Lead 23 ugdL 13 254 20 27659349
Mercury 16 24952233
Organophosphate
pesticides
20
Polycyclic
Aromatic
Hydrocarbons
227 ngm3 940 125 190 22440811
PCBs 104 ngg
serum (sum
of 50 PCBs)
250 176 160 20106937
DiabetesToxin Threshold Above
Threshold
Odds
Ratio
of Dz Reference
PMID
Arsenic 165 ugL 200 21 180 18714061
BPA 28 ugL 280 145 112 26119400
DDE 545 ngg serum
(pp-DDE)
200 230 31 26119400
Dioxins2 pgg lipid 50 191 43
26119400
PCBs104 ngg (PCB 153) 250 239 258
26119400
Phthalates175 ugL 690 148 249
26119400
1-naphthalene 167 ugdL 152 182 111 26340343
2-napthalene 414 ugdL 550 224 214 26340343
1-phenanthrene 167 ngL 570 178 151 26340343
1-pyrene 85 ngL 660 180 174 26340343
Lung Cancer
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Acrylonitrile Uncertain Uncertain 125 25
occupational
exposure
17114112
Arsenic 1213 ugL 436 of Asian
Americans
~01 of total
US population
34 95 in AA
01-1
PMC2682945
Cadmium Uncertain+ Uncertain 467 10 in
smokers
17184399
DDT Any exposure All US pop
below LOD
17 76 increased
risk
8923607
Breast Cancer
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Cadmium 0580 ugg
creatinine
126 205 479 16788160
PCB 138 396 ngg
creatinine
202 316 630 27717745
PCB 187 108 ngg lipid 600 194 360 21480306
Miscellaneous Diseases
Toxin Disease Threshold Above
Threshold
Odds
Ratio
of Dz Reference PMID
Aluminum Alzheimer
Dz
01 mgL
drinking
H20
400 203 05-44 26592479
Benzene AML 100ppmyrs 1-3 320 60 PMC2903550
DDT NHL 0512 ugL 1-2 240 01 17722095
Lead ALS 238 ugdL
blood
330 181 210 25479292
Lead Brain CA 0005 ugdL 14 19 ~500 17164378
Dioxin-like
PCBs
RA 326 ngg
lipid
250 219 220 17589595
PAHs Asthma 124 ngm3 935 200 483 19221603
The Potency of Arsenic
Disease Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Bladder CA 10ugL H20 100 27 145 24889821
Pancreatic CA 1332 ugg 200 246 230 23800676
Prostate CA 1332 ugg 200 33 315 23800676
Gout 125 ugL 245 546 522 25499256
Diabetes 165 ugL 200 21 180 18714061
Arsenic (180 of Diabetes)
How it causes diabetes
bull Blocks sugar stimulating insulin secretion
bull Epigenetic inhibition of sugar regulation
Where it comes from
bull Water (gt10 of US water supplies have high levels)
bull Rice (naturally absorbs if in the water)
bull Chicken (added to make meat whiter)
Pan W-C Seow WJ Kile ML et al Association of low to moderate levels of arsenic exposure with risk of Type 2 diabetes in Bangladesh American Journal of Epidemiology 2013178(10)1563-70
Portion of Population with Toxin Load Which
Doubles Disease Risk
Toxin Disease with Doubled Risk
Polycyclic aromatic hydrocarbons Asthma 94
PCB187 Breast Cancer 60
Phthalates Diabetes 55
Lead ALS 33
Aluminum Alzheimers Disease 25
DDT ADHD 25
PCBs Diabetes 25
Dioxin-like PCBs Rheumatoid Arthritis 25
Arsenic Gout 23
Bisphenol A Diabetes 22
Cigarette smoking Lung Cancer 21
Arsenic Diabetes 20
Polycyclic aromatic hydrocarbons Diabetes 20
Huge Detoxification Variability
bull CYP2C19
Proton pump inhibitors and some antidepressants
5-fold difference in activity between poor metabolizers and extensive metabolizers more so if CYP3A4 is also inhibited
Ultrarapid allele in 18 of both Swedes and Ethiopians
bull CYP2D6
Metabolizes a large number of drugs (~25)
7 of Caucasians poor metabolizers
~30 ultra rapid metabolizers in Arabian and Eastern African populations
More adverse effects in poor metabolizers and ineffective dosing in ultrarapid metabolizers
Inhibited by ginger
Desta Z et al Clinical significance of the cytochrome P450 2C19 genetic polymorphism Clin Pharmaco 2002
Sim SC et al A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug
response to proton pump inhibitors and antidepressants Clin Pharmacol Ther 2006
Wilkinson GR Drug metabolism and variability among patients in drug response N Engl J Med 2005
Kirchheiner J et al Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to
CYP2D6 duplication Pharmacogenomics J 2007
Toxin Half Lives in BloodToxin ldquoNormalrdquo (mgL) Acute Toxic (mgL) Half-Life
Arsenic 0002-007 005-025 2-4 days (CDC)
Benzene 00002 05-10 days
Cadmium 00003-00065 0015-005 16 years
Chlordane 0001 00025 3-4 days
DDTDDE 2-10 years
Dieldrin 00015 015-030 2-12 months
Ethanol 1000-2000 15hour
Lead 009 04-06 1-15 mo (2+ yrs bone)
Mercury 00015-0002 005-02 2 months (CDC)
PCBs 3-25 years
Toluene 05-3 days
Schulz M et al Therapeutic and toxic blood concentrations of nearly 1000 drugs and other xenobiotics Crit Care 2012 Jul 2616(4)R136
Bioaccumulation (POPs)
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
DDT banned in 1972 PCBs banned in 1977
Bioaccumulation (Cd)
Think BroadlyExogenous
Metals
Chemicalsbull Inorganic
bull Fluoride
bull Organic
bull POPs
bull Drugs
Particulate matter
Molds
Microbial
Radiationbull Light
bull Medical
bull Cell phone
Endogenous
Gut-derived toxins
Non-end product metabolites
Poorly detoxified hormones
Catecholamines (if SNP)
Toxins of Choice
Alcohol
Marijuana
Food constituents
High fructose corn syrup
Salt (acid-forming diet)
Wheat if zonulin (70)
Obesity Epidemic ndash POPs AND HFCS
47Bray GA Fructose should we worry Int J Obes (Lond) 2008 Dec32 Suppl 7S127-31
How Toxins Cause Damage 13
bull Increase free radical production
Cd induces production of ROS
Malathion inhibits catalase and glutathione peroxidase
Homocysteine oxidizes LDL cholesterol
bull Poison enzyme systems (compete with nutritional cofactors for binding sites)
Pb poisons delta aminolevulinic acid dehydratase
Cd inhibits catalase glutathione reductase and lowers
glutathione levels
bull Replace structural minerals
Pb displaces Ca in bone
How Toxins Cause Damage 23
bull Damage DNA
Benzene - causes chromosomal damage
Pesticides ndash fruit growers have more DNA damage
Phthalates and insecticides ndash damage sperm DNA
4-hydroxy catechol estrogen (4-OHE) damages breast DNA
bull Epigenetic dysmodulation
Higher cord blood levels of hexachlorobenzene associated
with 2x greater risk for obesity in children
bull Damage cell membranes
Common mechanism for heavy metals inactivates
membrane enzymes ion channels and pumps
How Toxins Cause Damage 33
bull Block insulin receptor sites
PCBs and phthalates
bull Highest levels associated with a 4 to 20-fold greater diabetes risk
bull Imbalance hormones many toxin examples
Arsenic
bull Disrupts thyroid hormone and retinoic acid receptors
Phthalates
bull Act as anti-androgens
bull More than 75 of the US population has measurable levels of
several phthalate metabolites in the urine
PCBs
bull Lower testosterone levels in men
Which are the Worst Toxins
bull According to the CDC
Toxicity
Population toxic load
Prevalence in toxic waste sites
bull According to clinical importance
Exposure
of disease
Ability of the body to detoxifyexcrete
Ag
en
cy
fo
r T
oxic
Su
bs
tan
ce
s a
nd
Dis
ea
se
Reg
istr
y
Pri
ori
ty L
ist
The Worst Toxins Clinically
My Rank Toxin Diseases Primary Sources
1 Arsenic Cancers diabetes gout Water chicken rice
2 DDT ADHD dementia diabetes Everywhere
3 Phthalates ADHD diabetes Soft plastics HABAs
4 PBDEs ADHD diabetes Flame retardant fabrics
5 PAHs ADHD cancers dyslipidemia Smoking charbroiling
6 PCBs Cancers diabetes MI RA Everywhere
7 Mercury Dementia ldquoSilverrdquo fillings fish
8 Lead Cardiovascular disease IQ Paint water
Glyphosate Research invalid
Conventional Laboratory Tests Reflect
Toxic Load in ldquoNormalrdquo Range
bull Surprising number show toxin exposure
CBC RBC WBC platelet count hemoglobin basophilic
stippling
Liver enzymes ALT GGTP
Inflammatory markers CRP
Lipids LDL oxLDL triglycerides
Blood sugar insulin FBS 2-hour PP
Metabolites bilirubin uric acid homocysteine 8-OHdG
Thyroid T3 T4 TSH
bull The historic ldquonormalrdquo range has been changing as the population has become more toxic
WBC Lowered by PCB and OCP Exposure
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
0
1
2
3
4
5
6
7
8
1st Quartrile 2nd Quartile 3rd Quartile 4th Quartile
WBCbull Strong inverse correlation with PCBs and OCPs and CBC
bull Linear with almost all PCBs
bull High variability with OCPs
bull Within ldquonormalrdquo range
Effects on WBC Worsen with Years
of Exposure to Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Platelet Count Decreases with Years
of Exposure tp Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Solvents Decrease Platelet Count
bull Compared workers exposed 23 hrday to those exposed most of day to toluene
bull All wore face masks and protective gear
bull Platelet count 14 lower 252 versus 216ml
bull Impairment of sympathetic nerves (OR = 413)
bull Impairment of peripheral nerves (OR = 694)
bull Positive relationship between neurological abnormalities and a self-reported neuropsychiatric measurement (r = 035-066)
Shih HT et al Subclinical abnormalities in workers with continuous low-level toluene exposure Toxicol Ind Health 2011 Sep27(8)691-9
Basophilic Stippling of Red Cells
Toxinsbull Arsenic
bull Lead
Diseasesbull Alpha-thalassemia HbH Disease
bull Beta thalassemia
bull Hereditary pyrimidine 5-nucleotidase deficiency
bull Myelodysplastic syndrome
bull Sideroblastic anemia
bull Thrombotic thrombocytopenic purpura
GGT Indirect Measure of POPsbull Glutathione is key intracellular defense against oxidative stress
bull Cellular GGT metabolizes extracellular GSH allowing precursor amino acids to be reutilized for intracellular GSH
bull Exposure to POPs induces GGT as a defensive mechanism
bull Within normal range predicts type 2 diabetes coronary heart disease hypertension stroke dyslipidemia chronic kidney disease and cancer
bull Men with GGT gt50 UI had ~26 fold risk for diabetes compared to those with lt10 Those with 40-49 had a ~20 fold risk
bull Levels within normal range occur with obesity xs alcohol cigarette smoking physical inactivity high meat low fruit and vegetable intake
bull Cumulative biomarker for environmental pollutants
Lee DH et al (2003) Gamma-glutamyltransferase and diabetesmdasha 4 year follow-up study Diabetologia 46359ndash364
Pamela A et al Serum gamma-glutamyltransferase linking together environmental pollution redox equilibria and progression of atherosclerosis Clin Chem
Lab Med 200947(12)1583-4
Lee DH et al Serum gamma-glutamyltransferase new insights about an old enzyme J Epidemiol Community Health 2009 Nov63(11)884-6
Lee DH et alSerum gamma-glutamyltransferase predicts non-fatal myocardial infarction and fatal coronary heart disease among 28838 middle-aged men and
women Eur Heart J 2006272170ndash6
Lee DH et al Gamma-glutamyltransferase and diabetes--a 4 year follow-up study Diabetologia 2003 Mar46(3)359-64
Lee DH et al Can persistent organic pollutants explain the association between serum gamma-glutamyltransferase and type 2 diabetes Diabetologia 2008
Mar51(3)402-7
GGT and Alcohol Consumption
bull GGT directly correlates with alcohol consumption
bull In a non-uniform population 40 gd will elevate GGT ~15
bull Watch for false negatives
bull Genomic variation
bull Are these the ones most
sensitive todamaged by
chemical toxins
bull Could up-regulation of GGT in light alcohol consumption be reason for benefit
0
10
20
30
40
50
60
70
80
0 200 400 600 800
Grams of Ethanol per Week
Adapted from Nagaya T et al Dose-response relationships between drinking and serum tests in Japanese men
aged 40ndash59 years Alcohol 1999 Feb 17(2) 133ndash8
GGT Correlates With Toxic Metal Levels
Lee DH et al Graded associations of blood lead and urinary cadmium concentrations with oxidative-stress-related markers in the
US population results from the third National Health and Nutrition Examination Survey Environ Health
perspect 2006 Mar114(3)350-4
GGT and Diabetes Risk
0
5
10
15
20
25
30
lt10 10-19 20-29 30-39 40-49 gt50
Dia
bete
s R
isk
GGT
bull GGT over 50 associated with tripling of death rate
bull 30-40 associated with doubling
GGT Levels
Correlate with
Risk of Death
Brenner H et al Distribution determinants and prognostic value of gamma-glutamyltransferase for all-cause
mortality in a cohort of construction workers from southern Germany Prev Med 1997 26 305ndash10
GGT From Small US Company
with Young Workers
0
10
20
30
40
50
60
0 20 40 60 80 100
GGT Data from Canadian Oil Field
Workers
0
50
100
150
200
250
300
350
400
450
lt10 10-20 20-30 30-40 40-50 50-60 60-07 70-80 80-90 90-100 100-110 110-120 gt120
GGTP
20-fold increased risk of diabetes
Uric Acid Indirect Measure of POPs
bull Poly-fluorinated hydrocarbons (PFOA and PFOS) associated
with increased serum uric acid
Lin CY et al Association among serum perfluoroalkyl chemicals glucose homeostasis and metabolic syndrome
in adolescents and adults Diabetes Care 2009 Apr32(4)702-7
Steenland K et al Association of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) with uric
acid among adults with elevated community exposure to PFOA Environ Health Perspect 2010 Feb118229-33
Steenland 2010 Open Access
ALT Indirect Measure of POPs
bull ALT (proxy marker) elevation in 104 (not including viral
hepatitis hemochromatosis or alcoholic liver disease) of
NHANES 03-04 subset
bull Risk of elevated ALT increased dose-dependently with
cadmium lead mercury and PCB exposure
bull 100 of individuals had detectable PCBs 925 mercury
and 996 had detectable lead
bull In 2005-08 prevalence of NAFLD in US was 11 a
growing cause of chronic liver disease
Cave M et al Polychlorinated biphenyls lead and mercury are associated with liver disease in American adults
NHANES 2003-2004 Environ Health Perspect 2010 Dec118(12)1735-42
Younossi ZM et al Changes in the prevalence of the most common causes of chronic liver diseases in the United
States from 1988 to 2008 Clin Gastroenterol Hepatol 2011 Jun9(6)524-530e1
Bilirubin as a Marker of POPs
bull Degree of serum bilirubin increase is prognostically significant in chronic liver dysfunction
bull Mono-ortho PCB TEQ values were found to be significantly positively associated with bilirubin (β=071 P=0008) following adjustment for multiple potential confounders
bull Bilirubin levels significantly correlated with PCBs -105-118-126 and -194
bull Smoking appears to be the biggest confounder
Dufour DR et al 2000 Diagnosis and monitoring of hepatic injury II Recommendations for use of laboratory
tests in screening diagnosis and monitoring Clin Chem 46 2050ndash68
Kumar J et al Persistent organic pollutants and liver dysfunction biomarkers in a population-based human sample
of men and women Environ Res 2014134251-256
Perf
luo
rin
ate
dP
OP
s a
nd
Co
mm
on
Blo
od
Tests
Gleason JA et al Associations of perfluorinated chemical serum concentrations and biomarkers of liver function and uric acid in the
US population (NHANES) 2007-2010 Environ Res 20151368-14
Liver Enzymes Reflect Toxic Load
bull AST ALT and GGT increase with body load of PCBs and OCPs
bull Some non-linear
bull Oxychlordanetop quartile
ALT 10
GGT 25
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
LDL-Cholesterol as Measure of POPs
bull 5-year prospective study to determine if POP levels predict future elevation in LDL-cholesterol
bull 598 subjects initially at age 70
bull Looked at 23 POPs
bull Best correlation with PCB 194
Penell J Lind L Salihovic S et al Persistent organic pollutants are related to change in circulating
lipid levels during a 5 year follow-up Environ Res 134(2014)190ndash197
oxLDL as Measure of POPs
bull 992 70-year old individuals (50 women)
bull Sum of PCBs showed strong significant positive associations with ox-LDL and significant negative associations with glutathione-related markers (GSSG and GSSGGSH)
bull A number of POPs (PCB-99 138 153 156 170 180 194 206 and 209) showed strong significant positive association with ox-LDL
Kumar J et al Influence of persistent organic pollutants on oxidative stress in population-based samples
Chemosphere 2014114303-309
Homocysteine is Increased by Pb amp Cd
Guallar E et al Confounding of the relation between homocysteine and peripheral arterial disease by lead cadmium and renal function Am J Epidemiol 2006 Apr 15163(8)700-8
Nutrient Deficiencies Accentuate
Effects of Lead on Homocysteine
bull Deficiencies in folate B6 or B12 make lead more toxic
Lee YM Et al Association of homocysteine levels with blood lead levels and micronutrients in the US general population J Prev Med Public Health 2012 Nov45(6)387-93
T4 amp T3 and PCBs
bull PCBs decrease T4 production
bull PCBs inhibit iodotyrosinedeiodinase activity
bull Study done in pregnant women which implies effect on fetus IQ
Kim S Park J Kim HJ et al Association between several persistent organic pollutants and thyroid hormone levels in serum among the pregnant women of Korea Environ Int 2013 Sep59442-8Shimizu R Yamaguchi M Uramaru N et al Structure-activity relationships of 44 halogenated compounds for iodotyrosinedeiodinase-inhibitory activity Toxicology 2013 Dec 6314(1)22-9
T4 amp T3 and PCBs
bull Not just humans being affected
bull Large study of dolphins shows exactly the same effects
Schwacke LH Zolman ES Balmer BC et al Anaemia hypothyroidism and immune suppression associated with polychlorinated biphenyl exposure in bottlenose dolphins (Tursiops truncatus) Proceed Royal Society B doi101098rspb20110665
8-OHdG
bull Oxidized nucleoside
bull Direct measure of DNA damage
bull Indirect measure of oxidative stress and toxin load
bull Correlates with
Multiple cancers
Mitochondrial damage
Rate of aging
Smoking
Several toxinsWalter Crinnion ldquoTotal Toxic Loadrdquo AANP 2015
8-OHdG Correlates with Pack-Years
of Smoking
Yano T et al Significance of the urinary 8-OHdG level as an oxidative stress marker in lung cancer patients Lung Cancer
2009 Jan63(1)111-4
8-OHdG Correlates
with Mercury
Chen C et al Increased oxidative DNA damage as assessed by urinary 8-hydroxy-2-deoxyguanosine
concentrations and serum redox status in persons exposed to mercury Clin Chem 2005 Apr51(4)759-67
Toxin Effects Worse with Aging
bull Thyroid function decreases with PFOA levels
bull But only after age 63
Shrestha S Bloom MS Yucel R et al Perfluoroalkyl substances and thyroid function in older adults Environ Int 2015 Feb75206-14
Insightful 23-Year Prospective Study
1 lt 50 there is no difference between those with the lowest and highest PCBs
2 In youngest group insulin production increases in response to toxin level As expected since blocking of
insulin receptor sites by PCBs
requires more insulin
3 That adaptive ability decreases with aging
4 At age 50 all the measures show very strong toxin-dose response
Cumulative damage impairs ability to adapt
Suarez-Lopez JR et al Persistent organic pollutants in young adults and changes in glucose related metabolism over a 23-year follow-up Environ Res 2015 Feb137485-94
Recommendations
High body toxic load
GGT gt 25
Uric acid gt 50 mgdl
ALT gt30 UL
Bilirubin gt08 mgdl
CBC lt 6000
Platelet lt 250000
Low T3 andor T4
Monitor Total Toxic Load
8-OHdG gt4
ldquoUnconventionalrdquo Laboratory Tests
bull Challenge testing
bull Hair analysis
bull Direct measures of solvents and POPs in blood urine adipose tissue
Evaluation of Metal Exposure ndash Provocation
bull Provocation ndash the use of a chelating agent ndash before urine collection often done clinically but several limitations
No ldquoofficialrdquo reference range for provoked urine
Most chelating agents do not extract metals from all tissues thus
does not necessarily represent total body burden
bull Example Brain is one of the main target organs for both elemental and organic
mercury yet agents do not chelate brain mercury
bull Despite limitations widely used and advocated by clinicians in part to see efficacy of chelating agent as a guide to treatment and based on empirical evidence
Rooney JP The role of thiols dithiols nutritional factors and interacting ligands in the toxicology of mercury
Toxicology 2007
Is Challenge Testing Valid
bull Poor correlations of standard tests for mercury
bull Unpublished research from corporate wellness project
bull Published amalgam number correlation
bull Published fish consumption correlation
What We Found In Canada
bull Deviations from the mean of 14 29 and 91 respectively
bull DMPS is spreading distribution suggesting that it is better at differentiating mercury body load
bull Some VERY high
Hg Assessment Correlations
bull Extensive measurements in 65 Whole blood Hg
Oral DMPS challenge
Amalgam surfaces
bull Correlations Whole blood w pre urine r = 040
Whole blood w post urine r = 057
Pre urine w post urine r = 068
Amalgams w pre urine r = 026
Amalgams w whole blood r = 036
Amalgams with post urine 044
bull Clear documentation that
challenge testing is better00
100
200
300
400
500
600
0 10 20 30 40 50
Po
st
Uri
ne H
g u
gg
Number of amalgams
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
There is Some Good Newsbull Banning lead in gasoline
and paint workedmdashblood levels down dramatically
bull No threshold for safety ndash
Children who had whole blood
lead concentrations of lt5 microgdL
(supposedly safe) associated
with decreased IQ
24 million children at levels
between 5 and 99 ugdL
bull July 2012 CDC changed recommended level to intervene in children from 10 to 50 ugdL Also eliminated term ldquolevel of concernrdquo to avoid giving false sense of safety
Iqbal S et al Estimated burden of blood lead levels 5 microgdl in 1999-2002 and declines from 1988 to 1994
Environ Res 2008
httpwwwcdcgovncehleadacclppcdc_response_lead_exposure_recspdf
httpwwwenvironmentuclaedureportcardarticle3772html
bull Human data
bull Primarily US as a lot more research available
bull Spot checking toxins in other countries shows the same toxin overload but variations in which are most prevalent
Australia (higher PDBEs)
Canada (higher lead)
New Zealand (higher cadmium)
Sweden (higher most toxic metals)
UK (highest PDBEs in world 3x OCP of US)
A Note About the Data
AD
HD
Ep
idem
ic
httpwwwcdcgovmmwrpreviewmmwrhtmlmm6433a11htm
Obesity Epidemic
httpwwwtheobesityepidemicorgintroduction (Accessed 616)
Kidney Disease Epidemic
Stevens L httpwwwslidesharenetringer21liaison-meeting-esrd-presentation (accessed 616)
Dia
be
tes
Ep
ide
mic
Diabetes Increasing World-Wide
SourcesAIHW analysis of ABS NHS 1989ndash90 1995 2001 2004ndash05 and 2007ndash08 NHS (reissue) and ABS 2011ndash12 Australian
Health Survey data (Release 7 June 2013)
Co-ordinaring Committee Epidemiology Study of Childhood amp Adolescent Diabetes Hong Kong KF Huen et al
Australian Adults
Childhood diabetes in Hong Kong
WHY THE CHRONIC DISEASE
EPIDEMICS
Increase in Diabetes Due to Sugar
httpwholehealthsourceblogspotcom201202by-2606-us-diet-will-be-100-percenthtml
Dia
bete
s 1
How About Persistent Organic Pollutants
Neel BA Robert M Sargis RM The paradox of progress Environmental disruption of metabolism and the diabetes epidemic DIABETES 2011 601838-48
Lars Jaumlrup Br Med Bull 200368167-182copy The British Council 2003 all rights reserved
Global Production and Consumption of
Selected Toxic Metals 1850ndash1990
Cadmium World Production
Mercury in the Air
EPA-452R-97-003 December 1997
Mercury in Water
httpwaterepagovscitechdataitmodelsmapspostercfm
Ground Water Sources of Arsenic
bull 10 of US public water supplies have levels of arsenic known to induce disease
bull No data on private water supplies
httpwwwatsdrcdcgovcsemarsenicdocsarsenicpdf (accessed 2015-08-18)
Example POPs
Chemical Abbr Uses Exposure
Bisphenol A BPA Plastics Canned food
Organochlorine
pesticides
OCPs Pesticide Food fumigation
Organophosphate
pesticides
OPPs Pesticide Food
Polybrominated
diphenyl ethers
PBDEs Flame retardant Clothing
Polychlorinated
biphenyls
PCBs Industrial Everywhere
Perflourinated PFOAs Non-stick stain prevention
water repellant
Teflon Gortex
Scotchguard
Phthalates Plastics fragrances Shower curtains
cosmetics
POPs - Prediabetes
bull Over 1200 participants fasting
glucose and OGTT performed
with serum levels of 5 POPs
bull All individual POPs tested were
associated with progressive
increase in prevalence of
prediabetes
bull More than triple prevalence of
prediabetes seen in those in the
5th quartile with a synergistic
effect from 5 POPs
Ukropec J et al High prevalence of prediabetes and diabetes in a population exposed to high levels of an organochlorine cocktail
Diabetologia 2010 May53(5)899-906
POPs and Diabetes Risk
Graph httpwwwourstolenfutureorgNewScienceobesity20062006-0715leeetalhtml
Data Lee DH Lee IK Song K et al A strong dose-response relation between serum
concentrations of persistent organic pollutants and diabetes results from the National Health and
Examination Survey 1999-2002 Diabetes Care 2006 Jul29(7)1638-44
Toxic Load and Disease Risk
References for Toxins and Disease Risk
Converting Disease Risk to Caused
Attributable Fraction Calculation
p = underlying prevalence of risk factor in the population
rr = relative risk (risk of contracting a disease in an exposed population divided by the risk of contracting the disease in an unexposed population)
AF = of disease due to the toxin
Levin M The occurrence of lung cancer in man Acta Unio Int Contra Cancrum 1953 9 531-541
Example Smoking and Lung Cancer
B = 5Number of smokers
who contract Lung Cancer notdue to smoking
A = 5Number of smokerswho contract Lung
Cancer due to smoking
C = 15Number of
nonsmokerswho contract Lung Cancer
0
2
4
6
8
10
12
14
16
Smokers (N=100) Nonsmokers (N=300)Num
ber
of
people
who c
ontr
act
Lung C
ancer
per
year
Baseline Additional due to smoking
Number of smokers and nonsmokers who contract lung cancer
Our Process In Summary
1 Determine threshold for increased disease risk
2 Determine of population above threshold
3 Determine incidence of disease (OR) in those above threshold
4 Determine incidence of disease in ldquounexposed populationrdquo
5 Calculate AF ie of disease
As whole population is exposed probably UNDERESTIMATES of disease
To
xic
ity H
as B
eco
me t
he N
ew
ldquoN
orm
alrdquo
Toxin Type Use Threshold for
disease
association
of US
above
threshold
Disease Associations
Chlordane OC pesticide Termites corn citrus lawns
gardens
145ngg lipid 63
(diabetes)
Diabetes (20)
BPA Plasticizer Water bottles canned food
water pipes thermal sales
receipts
48 men 51
women (urine
ngmL)
~18
(diabetes)
Diabetes hypertension
Octachloro
dibenzo-p-
dioxin
(OCDD)
Polychlorinated
dibenzo-p-
dioxin
Incineration or burning of
waste bleaching processes
used in pulp and paper mills
1010 pgg
lipid (highest
quartile)
10-25
(hypertensio
n)
Hypertension (79 for
women highest
quartile) diabetes (21)
obesity learning
disability (272)
MEP
(mono-
ethyl
phthalate)
Phthalate
(plasticizer
fragrance)
Toothbrushes automobile
parts tools toys and food
packaging aspirin
cosmetics food packaging
gt175 ngmL
(urine)
~60
(diabetes)
Diabetes (148) lower
BMD obesity
pp-DDE DDT
metabolite (OC
pesticide)
Agricultural crops 1560ngg
lipid
25
(diabetes)
Diabetes (23-43)
early menopause
impaired cognitive
function (2-3x 65x in
highest 5th percentile)
peripheral arterial
disease
Arsenic Toxic metal Miningsmelting wood
preservative pesticides
74ugL total
arsenic (urine)
20
(diabetes)
Cancers diabetes (26-
46) dyslipidemia gout
AF OR Prevalence
Rosen L An intuitive approach to understanding the attributable fraction of disease due to a risk factor the case of smoking Int J Environ Res Public Health 2013 Jul 1610(7)2932-43
Smoking Lung cancer
Arsenic Gout in women
BPA Diabetes
Status of Our Research
bull 26 toxins and toxin classes eg lead mercury BPA OCPs
100s of chemicals and POPs in some classes
bull 18 cancers
bull 24 chronic diseases
bull 1092 cells in spreadsheet
Large Personal Ongoing Research Investment
Huge Amount of Research Work
Toxins StudiedAluminum
Arsenic
Cadmium
Fluoride
Lead
Manganese
Mercury
Acrylamide
Acrylonitrile
Benzene
Bisphenol A (BPA)
Chloroform
DDT
Dioxins
Glyphosate
Organochlorine pesticides (OCPs)
Organophosphate pesticides
Parabens
Phthalates
Polybrominated diphenyl ethers (PBDEs)
Polycyclic aromatic hydrocarbons (PAHs)
Polychlorinated biphenols (PCBs)
Vinyl chloride
Diseases Studied
ADHD
Alzheimers Disease
ALS
Angiosarcoma
Anxiety
Atopic Conditions
Diabetes
Dyslipidemia
Gout
Fetal Abnormalities
Hyperuricemia
Infertility
Juvenile IQ
Cancer Bladder
Cancer Bone
Cancer Brain
Cancer Breast
Cancer Cervix
Cancer Colorectal
Cancer Endometrial
Cancer Head amp Neck
Cancer Liver
Cancer Lung
Cancer Lymph amp Blood
Cancer Ovarian
Cancer Pancreatic
Cancer Prostate
Cancer Renal
Cancer Skin
Cancer Testicular
Cancer Thyroid
Juvenile Obesity
Metabolic Syndrome
Mitochondrial dysfunction
Myocardial Infarction
Obstructive Lung Disease
Osteoporosis
Peripheral Artery Disease
Peripheral Neuropathy
Prediabetes
Renal Disease
Rheumatoid Arthritis
Thyroid Dysfunction
OC
Ps
Th
rou
gh
ou
t th
e W
orl
d
Rathore HS Nollet LML Pesticides Evaluation of Environmental Pollution CRC Press
2012 page 562
Threshold ndash Threshold exposure at which there is an increased risk of disease outcome
Above Threshold ndash Percentage of the population with higher exposure than the threshold
Odds Ratio ndash Increased disease risk in those above threshold
of Dz ndash Percent contribution of the toxin to that disease outcome
How to Interpret the Following Slides
Attention Deficit Hyperactivity Disorder
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
DDT 126 ngg
serum (pp-
DDE)
250 18 166 20106937
Lead 23 ugdL 13 254 20 27659349
Mercury 16 24952233
Organophosphate
pesticides
20
Polycyclic
Aromatic
Hydrocarbons
227 ngm3 940 125 190 22440811
PCBs 104 ngg
serum (sum
of 50 PCBs)
250 176 160 20106937
DiabetesToxin Threshold Above
Threshold
Odds
Ratio
of Dz Reference
PMID
Arsenic 165 ugL 200 21 180 18714061
BPA 28 ugL 280 145 112 26119400
DDE 545 ngg serum
(pp-DDE)
200 230 31 26119400
Dioxins2 pgg lipid 50 191 43
26119400
PCBs104 ngg (PCB 153) 250 239 258
26119400
Phthalates175 ugL 690 148 249
26119400
1-naphthalene 167 ugdL 152 182 111 26340343
2-napthalene 414 ugdL 550 224 214 26340343
1-phenanthrene 167 ngL 570 178 151 26340343
1-pyrene 85 ngL 660 180 174 26340343
Lung Cancer
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Acrylonitrile Uncertain Uncertain 125 25
occupational
exposure
17114112
Arsenic 1213 ugL 436 of Asian
Americans
~01 of total
US population
34 95 in AA
01-1
PMC2682945
Cadmium Uncertain+ Uncertain 467 10 in
smokers
17184399
DDT Any exposure All US pop
below LOD
17 76 increased
risk
8923607
Breast Cancer
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Cadmium 0580 ugg
creatinine
126 205 479 16788160
PCB 138 396 ngg
creatinine
202 316 630 27717745
PCB 187 108 ngg lipid 600 194 360 21480306
Miscellaneous Diseases
Toxin Disease Threshold Above
Threshold
Odds
Ratio
of Dz Reference PMID
Aluminum Alzheimer
Dz
01 mgL
drinking
H20
400 203 05-44 26592479
Benzene AML 100ppmyrs 1-3 320 60 PMC2903550
DDT NHL 0512 ugL 1-2 240 01 17722095
Lead ALS 238 ugdL
blood
330 181 210 25479292
Lead Brain CA 0005 ugdL 14 19 ~500 17164378
Dioxin-like
PCBs
RA 326 ngg
lipid
250 219 220 17589595
PAHs Asthma 124 ngm3 935 200 483 19221603
The Potency of Arsenic
Disease Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Bladder CA 10ugL H20 100 27 145 24889821
Pancreatic CA 1332 ugg 200 246 230 23800676
Prostate CA 1332 ugg 200 33 315 23800676
Gout 125 ugL 245 546 522 25499256
Diabetes 165 ugL 200 21 180 18714061
Arsenic (180 of Diabetes)
How it causes diabetes
bull Blocks sugar stimulating insulin secretion
bull Epigenetic inhibition of sugar regulation
Where it comes from
bull Water (gt10 of US water supplies have high levels)
bull Rice (naturally absorbs if in the water)
bull Chicken (added to make meat whiter)
Pan W-C Seow WJ Kile ML et al Association of low to moderate levels of arsenic exposure with risk of Type 2 diabetes in Bangladesh American Journal of Epidemiology 2013178(10)1563-70
Portion of Population with Toxin Load Which
Doubles Disease Risk
Toxin Disease with Doubled Risk
Polycyclic aromatic hydrocarbons Asthma 94
PCB187 Breast Cancer 60
Phthalates Diabetes 55
Lead ALS 33
Aluminum Alzheimers Disease 25
DDT ADHD 25
PCBs Diabetes 25
Dioxin-like PCBs Rheumatoid Arthritis 25
Arsenic Gout 23
Bisphenol A Diabetes 22
Cigarette smoking Lung Cancer 21
Arsenic Diabetes 20
Polycyclic aromatic hydrocarbons Diabetes 20
Huge Detoxification Variability
bull CYP2C19
Proton pump inhibitors and some antidepressants
5-fold difference in activity between poor metabolizers and extensive metabolizers more so if CYP3A4 is also inhibited
Ultrarapid allele in 18 of both Swedes and Ethiopians
bull CYP2D6
Metabolizes a large number of drugs (~25)
7 of Caucasians poor metabolizers
~30 ultra rapid metabolizers in Arabian and Eastern African populations
More adverse effects in poor metabolizers and ineffective dosing in ultrarapid metabolizers
Inhibited by ginger
Desta Z et al Clinical significance of the cytochrome P450 2C19 genetic polymorphism Clin Pharmaco 2002
Sim SC et al A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug
response to proton pump inhibitors and antidepressants Clin Pharmacol Ther 2006
Wilkinson GR Drug metabolism and variability among patients in drug response N Engl J Med 2005
Kirchheiner J et al Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to
CYP2D6 duplication Pharmacogenomics J 2007
Toxin Half Lives in BloodToxin ldquoNormalrdquo (mgL) Acute Toxic (mgL) Half-Life
Arsenic 0002-007 005-025 2-4 days (CDC)
Benzene 00002 05-10 days
Cadmium 00003-00065 0015-005 16 years
Chlordane 0001 00025 3-4 days
DDTDDE 2-10 years
Dieldrin 00015 015-030 2-12 months
Ethanol 1000-2000 15hour
Lead 009 04-06 1-15 mo (2+ yrs bone)
Mercury 00015-0002 005-02 2 months (CDC)
PCBs 3-25 years
Toluene 05-3 days
Schulz M et al Therapeutic and toxic blood concentrations of nearly 1000 drugs and other xenobiotics Crit Care 2012 Jul 2616(4)R136
Bioaccumulation (POPs)
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
DDT banned in 1972 PCBs banned in 1977
Bioaccumulation (Cd)
Think BroadlyExogenous
Metals
Chemicalsbull Inorganic
bull Fluoride
bull Organic
bull POPs
bull Drugs
Particulate matter
Molds
Microbial
Radiationbull Light
bull Medical
bull Cell phone
Endogenous
Gut-derived toxins
Non-end product metabolites
Poorly detoxified hormones
Catecholamines (if SNP)
Toxins of Choice
Alcohol
Marijuana
Food constituents
High fructose corn syrup
Salt (acid-forming diet)
Wheat if zonulin (70)
Obesity Epidemic ndash POPs AND HFCS
47Bray GA Fructose should we worry Int J Obes (Lond) 2008 Dec32 Suppl 7S127-31
How Toxins Cause Damage 13
bull Increase free radical production
Cd induces production of ROS
Malathion inhibits catalase and glutathione peroxidase
Homocysteine oxidizes LDL cholesterol
bull Poison enzyme systems (compete with nutritional cofactors for binding sites)
Pb poisons delta aminolevulinic acid dehydratase
Cd inhibits catalase glutathione reductase and lowers
glutathione levels
bull Replace structural minerals
Pb displaces Ca in bone
How Toxins Cause Damage 23
bull Damage DNA
Benzene - causes chromosomal damage
Pesticides ndash fruit growers have more DNA damage
Phthalates and insecticides ndash damage sperm DNA
4-hydroxy catechol estrogen (4-OHE) damages breast DNA
bull Epigenetic dysmodulation
Higher cord blood levels of hexachlorobenzene associated
with 2x greater risk for obesity in children
bull Damage cell membranes
Common mechanism for heavy metals inactivates
membrane enzymes ion channels and pumps
How Toxins Cause Damage 33
bull Block insulin receptor sites
PCBs and phthalates
bull Highest levels associated with a 4 to 20-fold greater diabetes risk
bull Imbalance hormones many toxin examples
Arsenic
bull Disrupts thyroid hormone and retinoic acid receptors
Phthalates
bull Act as anti-androgens
bull More than 75 of the US population has measurable levels of
several phthalate metabolites in the urine
PCBs
bull Lower testosterone levels in men
Which are the Worst Toxins
bull According to the CDC
Toxicity
Population toxic load
Prevalence in toxic waste sites
bull According to clinical importance
Exposure
of disease
Ability of the body to detoxifyexcrete
Ag
en
cy
fo
r T
oxic
Su
bs
tan
ce
s a
nd
Dis
ea
se
Reg
istr
y
Pri
ori
ty L
ist
The Worst Toxins Clinically
My Rank Toxin Diseases Primary Sources
1 Arsenic Cancers diabetes gout Water chicken rice
2 DDT ADHD dementia diabetes Everywhere
3 Phthalates ADHD diabetes Soft plastics HABAs
4 PBDEs ADHD diabetes Flame retardant fabrics
5 PAHs ADHD cancers dyslipidemia Smoking charbroiling
6 PCBs Cancers diabetes MI RA Everywhere
7 Mercury Dementia ldquoSilverrdquo fillings fish
8 Lead Cardiovascular disease IQ Paint water
Glyphosate Research invalid
Conventional Laboratory Tests Reflect
Toxic Load in ldquoNormalrdquo Range
bull Surprising number show toxin exposure
CBC RBC WBC platelet count hemoglobin basophilic
stippling
Liver enzymes ALT GGTP
Inflammatory markers CRP
Lipids LDL oxLDL triglycerides
Blood sugar insulin FBS 2-hour PP
Metabolites bilirubin uric acid homocysteine 8-OHdG
Thyroid T3 T4 TSH
bull The historic ldquonormalrdquo range has been changing as the population has become more toxic
WBC Lowered by PCB and OCP Exposure
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
0
1
2
3
4
5
6
7
8
1st Quartrile 2nd Quartile 3rd Quartile 4th Quartile
WBCbull Strong inverse correlation with PCBs and OCPs and CBC
bull Linear with almost all PCBs
bull High variability with OCPs
bull Within ldquonormalrdquo range
Effects on WBC Worsen with Years
of Exposure to Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Platelet Count Decreases with Years
of Exposure tp Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Solvents Decrease Platelet Count
bull Compared workers exposed 23 hrday to those exposed most of day to toluene
bull All wore face masks and protective gear
bull Platelet count 14 lower 252 versus 216ml
bull Impairment of sympathetic nerves (OR = 413)
bull Impairment of peripheral nerves (OR = 694)
bull Positive relationship between neurological abnormalities and a self-reported neuropsychiatric measurement (r = 035-066)
Shih HT et al Subclinical abnormalities in workers with continuous low-level toluene exposure Toxicol Ind Health 2011 Sep27(8)691-9
Basophilic Stippling of Red Cells
Toxinsbull Arsenic
bull Lead
Diseasesbull Alpha-thalassemia HbH Disease
bull Beta thalassemia
bull Hereditary pyrimidine 5-nucleotidase deficiency
bull Myelodysplastic syndrome
bull Sideroblastic anemia
bull Thrombotic thrombocytopenic purpura
GGT Indirect Measure of POPsbull Glutathione is key intracellular defense against oxidative stress
bull Cellular GGT metabolizes extracellular GSH allowing precursor amino acids to be reutilized for intracellular GSH
bull Exposure to POPs induces GGT as a defensive mechanism
bull Within normal range predicts type 2 diabetes coronary heart disease hypertension stroke dyslipidemia chronic kidney disease and cancer
bull Men with GGT gt50 UI had ~26 fold risk for diabetes compared to those with lt10 Those with 40-49 had a ~20 fold risk
bull Levels within normal range occur with obesity xs alcohol cigarette smoking physical inactivity high meat low fruit and vegetable intake
bull Cumulative biomarker for environmental pollutants
Lee DH et al (2003) Gamma-glutamyltransferase and diabetesmdasha 4 year follow-up study Diabetologia 46359ndash364
Pamela A et al Serum gamma-glutamyltransferase linking together environmental pollution redox equilibria and progression of atherosclerosis Clin Chem
Lab Med 200947(12)1583-4
Lee DH et al Serum gamma-glutamyltransferase new insights about an old enzyme J Epidemiol Community Health 2009 Nov63(11)884-6
Lee DH et alSerum gamma-glutamyltransferase predicts non-fatal myocardial infarction and fatal coronary heart disease among 28838 middle-aged men and
women Eur Heart J 2006272170ndash6
Lee DH et al Gamma-glutamyltransferase and diabetes--a 4 year follow-up study Diabetologia 2003 Mar46(3)359-64
Lee DH et al Can persistent organic pollutants explain the association between serum gamma-glutamyltransferase and type 2 diabetes Diabetologia 2008
Mar51(3)402-7
GGT and Alcohol Consumption
bull GGT directly correlates with alcohol consumption
bull In a non-uniform population 40 gd will elevate GGT ~15
bull Watch for false negatives
bull Genomic variation
bull Are these the ones most
sensitive todamaged by
chemical toxins
bull Could up-regulation of GGT in light alcohol consumption be reason for benefit
0
10
20
30
40
50
60
70
80
0 200 400 600 800
Grams of Ethanol per Week
Adapted from Nagaya T et al Dose-response relationships between drinking and serum tests in Japanese men
aged 40ndash59 years Alcohol 1999 Feb 17(2) 133ndash8
GGT Correlates With Toxic Metal Levels
Lee DH et al Graded associations of blood lead and urinary cadmium concentrations with oxidative-stress-related markers in the
US population results from the third National Health and Nutrition Examination Survey Environ Health
perspect 2006 Mar114(3)350-4
GGT and Diabetes Risk
0
5
10
15
20
25
30
lt10 10-19 20-29 30-39 40-49 gt50
Dia
bete
s R
isk
GGT
bull GGT over 50 associated with tripling of death rate
bull 30-40 associated with doubling
GGT Levels
Correlate with
Risk of Death
Brenner H et al Distribution determinants and prognostic value of gamma-glutamyltransferase for all-cause
mortality in a cohort of construction workers from southern Germany Prev Med 1997 26 305ndash10
GGT From Small US Company
with Young Workers
0
10
20
30
40
50
60
0 20 40 60 80 100
GGT Data from Canadian Oil Field
Workers
0
50
100
150
200
250
300
350
400
450
lt10 10-20 20-30 30-40 40-50 50-60 60-07 70-80 80-90 90-100 100-110 110-120 gt120
GGTP
20-fold increased risk of diabetes
Uric Acid Indirect Measure of POPs
bull Poly-fluorinated hydrocarbons (PFOA and PFOS) associated
with increased serum uric acid
Lin CY et al Association among serum perfluoroalkyl chemicals glucose homeostasis and metabolic syndrome
in adolescents and adults Diabetes Care 2009 Apr32(4)702-7
Steenland K et al Association of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) with uric
acid among adults with elevated community exposure to PFOA Environ Health Perspect 2010 Feb118229-33
Steenland 2010 Open Access
ALT Indirect Measure of POPs
bull ALT (proxy marker) elevation in 104 (not including viral
hepatitis hemochromatosis or alcoholic liver disease) of
NHANES 03-04 subset
bull Risk of elevated ALT increased dose-dependently with
cadmium lead mercury and PCB exposure
bull 100 of individuals had detectable PCBs 925 mercury
and 996 had detectable lead
bull In 2005-08 prevalence of NAFLD in US was 11 a
growing cause of chronic liver disease
Cave M et al Polychlorinated biphenyls lead and mercury are associated with liver disease in American adults
NHANES 2003-2004 Environ Health Perspect 2010 Dec118(12)1735-42
Younossi ZM et al Changes in the prevalence of the most common causes of chronic liver diseases in the United
States from 1988 to 2008 Clin Gastroenterol Hepatol 2011 Jun9(6)524-530e1
Bilirubin as a Marker of POPs
bull Degree of serum bilirubin increase is prognostically significant in chronic liver dysfunction
bull Mono-ortho PCB TEQ values were found to be significantly positively associated with bilirubin (β=071 P=0008) following adjustment for multiple potential confounders
bull Bilirubin levels significantly correlated with PCBs -105-118-126 and -194
bull Smoking appears to be the biggest confounder
Dufour DR et al 2000 Diagnosis and monitoring of hepatic injury II Recommendations for use of laboratory
tests in screening diagnosis and monitoring Clin Chem 46 2050ndash68
Kumar J et al Persistent organic pollutants and liver dysfunction biomarkers in a population-based human sample
of men and women Environ Res 2014134251-256
Perf
luo
rin
ate
dP
OP
s a
nd
Co
mm
on
Blo
od
Tests
Gleason JA et al Associations of perfluorinated chemical serum concentrations and biomarkers of liver function and uric acid in the
US population (NHANES) 2007-2010 Environ Res 20151368-14
Liver Enzymes Reflect Toxic Load
bull AST ALT and GGT increase with body load of PCBs and OCPs
bull Some non-linear
bull Oxychlordanetop quartile
ALT 10
GGT 25
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
LDL-Cholesterol as Measure of POPs
bull 5-year prospective study to determine if POP levels predict future elevation in LDL-cholesterol
bull 598 subjects initially at age 70
bull Looked at 23 POPs
bull Best correlation with PCB 194
Penell J Lind L Salihovic S et al Persistent organic pollutants are related to change in circulating
lipid levels during a 5 year follow-up Environ Res 134(2014)190ndash197
oxLDL as Measure of POPs
bull 992 70-year old individuals (50 women)
bull Sum of PCBs showed strong significant positive associations with ox-LDL and significant negative associations with glutathione-related markers (GSSG and GSSGGSH)
bull A number of POPs (PCB-99 138 153 156 170 180 194 206 and 209) showed strong significant positive association with ox-LDL
Kumar J et al Influence of persistent organic pollutants on oxidative stress in population-based samples
Chemosphere 2014114303-309
Homocysteine is Increased by Pb amp Cd
Guallar E et al Confounding of the relation between homocysteine and peripheral arterial disease by lead cadmium and renal function Am J Epidemiol 2006 Apr 15163(8)700-8
Nutrient Deficiencies Accentuate
Effects of Lead on Homocysteine
bull Deficiencies in folate B6 or B12 make lead more toxic
Lee YM Et al Association of homocysteine levels with blood lead levels and micronutrients in the US general population J Prev Med Public Health 2012 Nov45(6)387-93
T4 amp T3 and PCBs
bull PCBs decrease T4 production
bull PCBs inhibit iodotyrosinedeiodinase activity
bull Study done in pregnant women which implies effect on fetus IQ
Kim S Park J Kim HJ et al Association between several persistent organic pollutants and thyroid hormone levels in serum among the pregnant women of Korea Environ Int 2013 Sep59442-8Shimizu R Yamaguchi M Uramaru N et al Structure-activity relationships of 44 halogenated compounds for iodotyrosinedeiodinase-inhibitory activity Toxicology 2013 Dec 6314(1)22-9
T4 amp T3 and PCBs
bull Not just humans being affected
bull Large study of dolphins shows exactly the same effects
Schwacke LH Zolman ES Balmer BC et al Anaemia hypothyroidism and immune suppression associated with polychlorinated biphenyl exposure in bottlenose dolphins (Tursiops truncatus) Proceed Royal Society B doi101098rspb20110665
8-OHdG
bull Oxidized nucleoside
bull Direct measure of DNA damage
bull Indirect measure of oxidative stress and toxin load
bull Correlates with
Multiple cancers
Mitochondrial damage
Rate of aging
Smoking
Several toxinsWalter Crinnion ldquoTotal Toxic Loadrdquo AANP 2015
8-OHdG Correlates with Pack-Years
of Smoking
Yano T et al Significance of the urinary 8-OHdG level as an oxidative stress marker in lung cancer patients Lung Cancer
2009 Jan63(1)111-4
8-OHdG Correlates
with Mercury
Chen C et al Increased oxidative DNA damage as assessed by urinary 8-hydroxy-2-deoxyguanosine
concentrations and serum redox status in persons exposed to mercury Clin Chem 2005 Apr51(4)759-67
Toxin Effects Worse with Aging
bull Thyroid function decreases with PFOA levels
bull But only after age 63
Shrestha S Bloom MS Yucel R et al Perfluoroalkyl substances and thyroid function in older adults Environ Int 2015 Feb75206-14
Insightful 23-Year Prospective Study
1 lt 50 there is no difference between those with the lowest and highest PCBs
2 In youngest group insulin production increases in response to toxin level As expected since blocking of
insulin receptor sites by PCBs
requires more insulin
3 That adaptive ability decreases with aging
4 At age 50 all the measures show very strong toxin-dose response
Cumulative damage impairs ability to adapt
Suarez-Lopez JR et al Persistent organic pollutants in young adults and changes in glucose related metabolism over a 23-year follow-up Environ Res 2015 Feb137485-94
Recommendations
High body toxic load
GGT gt 25
Uric acid gt 50 mgdl
ALT gt30 UL
Bilirubin gt08 mgdl
CBC lt 6000
Platelet lt 250000
Low T3 andor T4
Monitor Total Toxic Load
8-OHdG gt4
ldquoUnconventionalrdquo Laboratory Tests
bull Challenge testing
bull Hair analysis
bull Direct measures of solvents and POPs in blood urine adipose tissue
Evaluation of Metal Exposure ndash Provocation
bull Provocation ndash the use of a chelating agent ndash before urine collection often done clinically but several limitations
No ldquoofficialrdquo reference range for provoked urine
Most chelating agents do not extract metals from all tissues thus
does not necessarily represent total body burden
bull Example Brain is one of the main target organs for both elemental and organic
mercury yet agents do not chelate brain mercury
bull Despite limitations widely used and advocated by clinicians in part to see efficacy of chelating agent as a guide to treatment and based on empirical evidence
Rooney JP The role of thiols dithiols nutritional factors and interacting ligands in the toxicology of mercury
Toxicology 2007
Is Challenge Testing Valid
bull Poor correlations of standard tests for mercury
bull Unpublished research from corporate wellness project
bull Published amalgam number correlation
bull Published fish consumption correlation
What We Found In Canada
bull Deviations from the mean of 14 29 and 91 respectively
bull DMPS is spreading distribution suggesting that it is better at differentiating mercury body load
bull Some VERY high
Hg Assessment Correlations
bull Extensive measurements in 65 Whole blood Hg
Oral DMPS challenge
Amalgam surfaces
bull Correlations Whole blood w pre urine r = 040
Whole blood w post urine r = 057
Pre urine w post urine r = 068
Amalgams w pre urine r = 026
Amalgams w whole blood r = 036
Amalgams with post urine 044
bull Clear documentation that
challenge testing is better00
100
200
300
400
500
600
0 10 20 30 40 50
Po
st
Uri
ne H
g u
gg
Number of amalgams
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
bull Human data
bull Primarily US as a lot more research available
bull Spot checking toxins in other countries shows the same toxin overload but variations in which are most prevalent
Australia (higher PDBEs)
Canada (higher lead)
New Zealand (higher cadmium)
Sweden (higher most toxic metals)
UK (highest PDBEs in world 3x OCP of US)
A Note About the Data
AD
HD
Ep
idem
ic
httpwwwcdcgovmmwrpreviewmmwrhtmlmm6433a11htm
Obesity Epidemic
httpwwwtheobesityepidemicorgintroduction (Accessed 616)
Kidney Disease Epidemic
Stevens L httpwwwslidesharenetringer21liaison-meeting-esrd-presentation (accessed 616)
Dia
be
tes
Ep
ide
mic
Diabetes Increasing World-Wide
SourcesAIHW analysis of ABS NHS 1989ndash90 1995 2001 2004ndash05 and 2007ndash08 NHS (reissue) and ABS 2011ndash12 Australian
Health Survey data (Release 7 June 2013)
Co-ordinaring Committee Epidemiology Study of Childhood amp Adolescent Diabetes Hong Kong KF Huen et al
Australian Adults
Childhood diabetes in Hong Kong
WHY THE CHRONIC DISEASE
EPIDEMICS
Increase in Diabetes Due to Sugar
httpwholehealthsourceblogspotcom201202by-2606-us-diet-will-be-100-percenthtml
Dia
bete
s 1
How About Persistent Organic Pollutants
Neel BA Robert M Sargis RM The paradox of progress Environmental disruption of metabolism and the diabetes epidemic DIABETES 2011 601838-48
Lars Jaumlrup Br Med Bull 200368167-182copy The British Council 2003 all rights reserved
Global Production and Consumption of
Selected Toxic Metals 1850ndash1990
Cadmium World Production
Mercury in the Air
EPA-452R-97-003 December 1997
Mercury in Water
httpwaterepagovscitechdataitmodelsmapspostercfm
Ground Water Sources of Arsenic
bull 10 of US public water supplies have levels of arsenic known to induce disease
bull No data on private water supplies
httpwwwatsdrcdcgovcsemarsenicdocsarsenicpdf (accessed 2015-08-18)
Example POPs
Chemical Abbr Uses Exposure
Bisphenol A BPA Plastics Canned food
Organochlorine
pesticides
OCPs Pesticide Food fumigation
Organophosphate
pesticides
OPPs Pesticide Food
Polybrominated
diphenyl ethers
PBDEs Flame retardant Clothing
Polychlorinated
biphenyls
PCBs Industrial Everywhere
Perflourinated PFOAs Non-stick stain prevention
water repellant
Teflon Gortex
Scotchguard
Phthalates Plastics fragrances Shower curtains
cosmetics
POPs - Prediabetes
bull Over 1200 participants fasting
glucose and OGTT performed
with serum levels of 5 POPs
bull All individual POPs tested were
associated with progressive
increase in prevalence of
prediabetes
bull More than triple prevalence of
prediabetes seen in those in the
5th quartile with a synergistic
effect from 5 POPs
Ukropec J et al High prevalence of prediabetes and diabetes in a population exposed to high levels of an organochlorine cocktail
Diabetologia 2010 May53(5)899-906
POPs and Diabetes Risk
Graph httpwwwourstolenfutureorgNewScienceobesity20062006-0715leeetalhtml
Data Lee DH Lee IK Song K et al A strong dose-response relation between serum
concentrations of persistent organic pollutants and diabetes results from the National Health and
Examination Survey 1999-2002 Diabetes Care 2006 Jul29(7)1638-44
Toxic Load and Disease Risk
References for Toxins and Disease Risk
Converting Disease Risk to Caused
Attributable Fraction Calculation
p = underlying prevalence of risk factor in the population
rr = relative risk (risk of contracting a disease in an exposed population divided by the risk of contracting the disease in an unexposed population)
AF = of disease due to the toxin
Levin M The occurrence of lung cancer in man Acta Unio Int Contra Cancrum 1953 9 531-541
Example Smoking and Lung Cancer
B = 5Number of smokers
who contract Lung Cancer notdue to smoking
A = 5Number of smokerswho contract Lung
Cancer due to smoking
C = 15Number of
nonsmokerswho contract Lung Cancer
0
2
4
6
8
10
12
14
16
Smokers (N=100) Nonsmokers (N=300)Num
ber
of
people
who c
ontr
act
Lung C
ancer
per
year
Baseline Additional due to smoking
Number of smokers and nonsmokers who contract lung cancer
Our Process In Summary
1 Determine threshold for increased disease risk
2 Determine of population above threshold
3 Determine incidence of disease (OR) in those above threshold
4 Determine incidence of disease in ldquounexposed populationrdquo
5 Calculate AF ie of disease
As whole population is exposed probably UNDERESTIMATES of disease
To
xic
ity H
as B
eco
me t
he N
ew
ldquoN
orm
alrdquo
Toxin Type Use Threshold for
disease
association
of US
above
threshold
Disease Associations
Chlordane OC pesticide Termites corn citrus lawns
gardens
145ngg lipid 63
(diabetes)
Diabetes (20)
BPA Plasticizer Water bottles canned food
water pipes thermal sales
receipts
48 men 51
women (urine
ngmL)
~18
(diabetes)
Diabetes hypertension
Octachloro
dibenzo-p-
dioxin
(OCDD)
Polychlorinated
dibenzo-p-
dioxin
Incineration or burning of
waste bleaching processes
used in pulp and paper mills
1010 pgg
lipid (highest
quartile)
10-25
(hypertensio
n)
Hypertension (79 for
women highest
quartile) diabetes (21)
obesity learning
disability (272)
MEP
(mono-
ethyl
phthalate)
Phthalate
(plasticizer
fragrance)
Toothbrushes automobile
parts tools toys and food
packaging aspirin
cosmetics food packaging
gt175 ngmL
(urine)
~60
(diabetes)
Diabetes (148) lower
BMD obesity
pp-DDE DDT
metabolite (OC
pesticide)
Agricultural crops 1560ngg
lipid
25
(diabetes)
Diabetes (23-43)
early menopause
impaired cognitive
function (2-3x 65x in
highest 5th percentile)
peripheral arterial
disease
Arsenic Toxic metal Miningsmelting wood
preservative pesticides
74ugL total
arsenic (urine)
20
(diabetes)
Cancers diabetes (26-
46) dyslipidemia gout
AF OR Prevalence
Rosen L An intuitive approach to understanding the attributable fraction of disease due to a risk factor the case of smoking Int J Environ Res Public Health 2013 Jul 1610(7)2932-43
Smoking Lung cancer
Arsenic Gout in women
BPA Diabetes
Status of Our Research
bull 26 toxins and toxin classes eg lead mercury BPA OCPs
100s of chemicals and POPs in some classes
bull 18 cancers
bull 24 chronic diseases
bull 1092 cells in spreadsheet
Large Personal Ongoing Research Investment
Huge Amount of Research Work
Toxins StudiedAluminum
Arsenic
Cadmium
Fluoride
Lead
Manganese
Mercury
Acrylamide
Acrylonitrile
Benzene
Bisphenol A (BPA)
Chloroform
DDT
Dioxins
Glyphosate
Organochlorine pesticides (OCPs)
Organophosphate pesticides
Parabens
Phthalates
Polybrominated diphenyl ethers (PBDEs)
Polycyclic aromatic hydrocarbons (PAHs)
Polychlorinated biphenols (PCBs)
Vinyl chloride
Diseases Studied
ADHD
Alzheimers Disease
ALS
Angiosarcoma
Anxiety
Atopic Conditions
Diabetes
Dyslipidemia
Gout
Fetal Abnormalities
Hyperuricemia
Infertility
Juvenile IQ
Cancer Bladder
Cancer Bone
Cancer Brain
Cancer Breast
Cancer Cervix
Cancer Colorectal
Cancer Endometrial
Cancer Head amp Neck
Cancer Liver
Cancer Lung
Cancer Lymph amp Blood
Cancer Ovarian
Cancer Pancreatic
Cancer Prostate
Cancer Renal
Cancer Skin
Cancer Testicular
Cancer Thyroid
Juvenile Obesity
Metabolic Syndrome
Mitochondrial dysfunction
Myocardial Infarction
Obstructive Lung Disease
Osteoporosis
Peripheral Artery Disease
Peripheral Neuropathy
Prediabetes
Renal Disease
Rheumatoid Arthritis
Thyroid Dysfunction
OC
Ps
Th
rou
gh
ou
t th
e W
orl
d
Rathore HS Nollet LML Pesticides Evaluation of Environmental Pollution CRC Press
2012 page 562
Threshold ndash Threshold exposure at which there is an increased risk of disease outcome
Above Threshold ndash Percentage of the population with higher exposure than the threshold
Odds Ratio ndash Increased disease risk in those above threshold
of Dz ndash Percent contribution of the toxin to that disease outcome
How to Interpret the Following Slides
Attention Deficit Hyperactivity Disorder
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
DDT 126 ngg
serum (pp-
DDE)
250 18 166 20106937
Lead 23 ugdL 13 254 20 27659349
Mercury 16 24952233
Organophosphate
pesticides
20
Polycyclic
Aromatic
Hydrocarbons
227 ngm3 940 125 190 22440811
PCBs 104 ngg
serum (sum
of 50 PCBs)
250 176 160 20106937
DiabetesToxin Threshold Above
Threshold
Odds
Ratio
of Dz Reference
PMID
Arsenic 165 ugL 200 21 180 18714061
BPA 28 ugL 280 145 112 26119400
DDE 545 ngg serum
(pp-DDE)
200 230 31 26119400
Dioxins2 pgg lipid 50 191 43
26119400
PCBs104 ngg (PCB 153) 250 239 258
26119400
Phthalates175 ugL 690 148 249
26119400
1-naphthalene 167 ugdL 152 182 111 26340343
2-napthalene 414 ugdL 550 224 214 26340343
1-phenanthrene 167 ngL 570 178 151 26340343
1-pyrene 85 ngL 660 180 174 26340343
Lung Cancer
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Acrylonitrile Uncertain Uncertain 125 25
occupational
exposure
17114112
Arsenic 1213 ugL 436 of Asian
Americans
~01 of total
US population
34 95 in AA
01-1
PMC2682945
Cadmium Uncertain+ Uncertain 467 10 in
smokers
17184399
DDT Any exposure All US pop
below LOD
17 76 increased
risk
8923607
Breast Cancer
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Cadmium 0580 ugg
creatinine
126 205 479 16788160
PCB 138 396 ngg
creatinine
202 316 630 27717745
PCB 187 108 ngg lipid 600 194 360 21480306
Miscellaneous Diseases
Toxin Disease Threshold Above
Threshold
Odds
Ratio
of Dz Reference PMID
Aluminum Alzheimer
Dz
01 mgL
drinking
H20
400 203 05-44 26592479
Benzene AML 100ppmyrs 1-3 320 60 PMC2903550
DDT NHL 0512 ugL 1-2 240 01 17722095
Lead ALS 238 ugdL
blood
330 181 210 25479292
Lead Brain CA 0005 ugdL 14 19 ~500 17164378
Dioxin-like
PCBs
RA 326 ngg
lipid
250 219 220 17589595
PAHs Asthma 124 ngm3 935 200 483 19221603
The Potency of Arsenic
Disease Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Bladder CA 10ugL H20 100 27 145 24889821
Pancreatic CA 1332 ugg 200 246 230 23800676
Prostate CA 1332 ugg 200 33 315 23800676
Gout 125 ugL 245 546 522 25499256
Diabetes 165 ugL 200 21 180 18714061
Arsenic (180 of Diabetes)
How it causes diabetes
bull Blocks sugar stimulating insulin secretion
bull Epigenetic inhibition of sugar regulation
Where it comes from
bull Water (gt10 of US water supplies have high levels)
bull Rice (naturally absorbs if in the water)
bull Chicken (added to make meat whiter)
Pan W-C Seow WJ Kile ML et al Association of low to moderate levels of arsenic exposure with risk of Type 2 diabetes in Bangladesh American Journal of Epidemiology 2013178(10)1563-70
Portion of Population with Toxin Load Which
Doubles Disease Risk
Toxin Disease with Doubled Risk
Polycyclic aromatic hydrocarbons Asthma 94
PCB187 Breast Cancer 60
Phthalates Diabetes 55
Lead ALS 33
Aluminum Alzheimers Disease 25
DDT ADHD 25
PCBs Diabetes 25
Dioxin-like PCBs Rheumatoid Arthritis 25
Arsenic Gout 23
Bisphenol A Diabetes 22
Cigarette smoking Lung Cancer 21
Arsenic Diabetes 20
Polycyclic aromatic hydrocarbons Diabetes 20
Huge Detoxification Variability
bull CYP2C19
Proton pump inhibitors and some antidepressants
5-fold difference in activity between poor metabolizers and extensive metabolizers more so if CYP3A4 is also inhibited
Ultrarapid allele in 18 of both Swedes and Ethiopians
bull CYP2D6
Metabolizes a large number of drugs (~25)
7 of Caucasians poor metabolizers
~30 ultra rapid metabolizers in Arabian and Eastern African populations
More adverse effects in poor metabolizers and ineffective dosing in ultrarapid metabolizers
Inhibited by ginger
Desta Z et al Clinical significance of the cytochrome P450 2C19 genetic polymorphism Clin Pharmaco 2002
Sim SC et al A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug
response to proton pump inhibitors and antidepressants Clin Pharmacol Ther 2006
Wilkinson GR Drug metabolism and variability among patients in drug response N Engl J Med 2005
Kirchheiner J et al Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to
CYP2D6 duplication Pharmacogenomics J 2007
Toxin Half Lives in BloodToxin ldquoNormalrdquo (mgL) Acute Toxic (mgL) Half-Life
Arsenic 0002-007 005-025 2-4 days (CDC)
Benzene 00002 05-10 days
Cadmium 00003-00065 0015-005 16 years
Chlordane 0001 00025 3-4 days
DDTDDE 2-10 years
Dieldrin 00015 015-030 2-12 months
Ethanol 1000-2000 15hour
Lead 009 04-06 1-15 mo (2+ yrs bone)
Mercury 00015-0002 005-02 2 months (CDC)
PCBs 3-25 years
Toluene 05-3 days
Schulz M et al Therapeutic and toxic blood concentrations of nearly 1000 drugs and other xenobiotics Crit Care 2012 Jul 2616(4)R136
Bioaccumulation (POPs)
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
DDT banned in 1972 PCBs banned in 1977
Bioaccumulation (Cd)
Think BroadlyExogenous
Metals
Chemicalsbull Inorganic
bull Fluoride
bull Organic
bull POPs
bull Drugs
Particulate matter
Molds
Microbial
Radiationbull Light
bull Medical
bull Cell phone
Endogenous
Gut-derived toxins
Non-end product metabolites
Poorly detoxified hormones
Catecholamines (if SNP)
Toxins of Choice
Alcohol
Marijuana
Food constituents
High fructose corn syrup
Salt (acid-forming diet)
Wheat if zonulin (70)
Obesity Epidemic ndash POPs AND HFCS
47Bray GA Fructose should we worry Int J Obes (Lond) 2008 Dec32 Suppl 7S127-31
How Toxins Cause Damage 13
bull Increase free radical production
Cd induces production of ROS
Malathion inhibits catalase and glutathione peroxidase
Homocysteine oxidizes LDL cholesterol
bull Poison enzyme systems (compete with nutritional cofactors for binding sites)
Pb poisons delta aminolevulinic acid dehydratase
Cd inhibits catalase glutathione reductase and lowers
glutathione levels
bull Replace structural minerals
Pb displaces Ca in bone
How Toxins Cause Damage 23
bull Damage DNA
Benzene - causes chromosomal damage
Pesticides ndash fruit growers have more DNA damage
Phthalates and insecticides ndash damage sperm DNA
4-hydroxy catechol estrogen (4-OHE) damages breast DNA
bull Epigenetic dysmodulation
Higher cord blood levels of hexachlorobenzene associated
with 2x greater risk for obesity in children
bull Damage cell membranes
Common mechanism for heavy metals inactivates
membrane enzymes ion channels and pumps
How Toxins Cause Damage 33
bull Block insulin receptor sites
PCBs and phthalates
bull Highest levels associated with a 4 to 20-fold greater diabetes risk
bull Imbalance hormones many toxin examples
Arsenic
bull Disrupts thyroid hormone and retinoic acid receptors
Phthalates
bull Act as anti-androgens
bull More than 75 of the US population has measurable levels of
several phthalate metabolites in the urine
PCBs
bull Lower testosterone levels in men
Which are the Worst Toxins
bull According to the CDC
Toxicity
Population toxic load
Prevalence in toxic waste sites
bull According to clinical importance
Exposure
of disease
Ability of the body to detoxifyexcrete
Ag
en
cy
fo
r T
oxic
Su
bs
tan
ce
s a
nd
Dis
ea
se
Reg
istr
y
Pri
ori
ty L
ist
The Worst Toxins Clinically
My Rank Toxin Diseases Primary Sources
1 Arsenic Cancers diabetes gout Water chicken rice
2 DDT ADHD dementia diabetes Everywhere
3 Phthalates ADHD diabetes Soft plastics HABAs
4 PBDEs ADHD diabetes Flame retardant fabrics
5 PAHs ADHD cancers dyslipidemia Smoking charbroiling
6 PCBs Cancers diabetes MI RA Everywhere
7 Mercury Dementia ldquoSilverrdquo fillings fish
8 Lead Cardiovascular disease IQ Paint water
Glyphosate Research invalid
Conventional Laboratory Tests Reflect
Toxic Load in ldquoNormalrdquo Range
bull Surprising number show toxin exposure
CBC RBC WBC platelet count hemoglobin basophilic
stippling
Liver enzymes ALT GGTP
Inflammatory markers CRP
Lipids LDL oxLDL triglycerides
Blood sugar insulin FBS 2-hour PP
Metabolites bilirubin uric acid homocysteine 8-OHdG
Thyroid T3 T4 TSH
bull The historic ldquonormalrdquo range has been changing as the population has become more toxic
WBC Lowered by PCB and OCP Exposure
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
0
1
2
3
4
5
6
7
8
1st Quartrile 2nd Quartile 3rd Quartile 4th Quartile
WBCbull Strong inverse correlation with PCBs and OCPs and CBC
bull Linear with almost all PCBs
bull High variability with OCPs
bull Within ldquonormalrdquo range
Effects on WBC Worsen with Years
of Exposure to Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Platelet Count Decreases with Years
of Exposure tp Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Solvents Decrease Platelet Count
bull Compared workers exposed 23 hrday to those exposed most of day to toluene
bull All wore face masks and protective gear
bull Platelet count 14 lower 252 versus 216ml
bull Impairment of sympathetic nerves (OR = 413)
bull Impairment of peripheral nerves (OR = 694)
bull Positive relationship between neurological abnormalities and a self-reported neuropsychiatric measurement (r = 035-066)
Shih HT et al Subclinical abnormalities in workers with continuous low-level toluene exposure Toxicol Ind Health 2011 Sep27(8)691-9
Basophilic Stippling of Red Cells
Toxinsbull Arsenic
bull Lead
Diseasesbull Alpha-thalassemia HbH Disease
bull Beta thalassemia
bull Hereditary pyrimidine 5-nucleotidase deficiency
bull Myelodysplastic syndrome
bull Sideroblastic anemia
bull Thrombotic thrombocytopenic purpura
GGT Indirect Measure of POPsbull Glutathione is key intracellular defense against oxidative stress
bull Cellular GGT metabolizes extracellular GSH allowing precursor amino acids to be reutilized for intracellular GSH
bull Exposure to POPs induces GGT as a defensive mechanism
bull Within normal range predicts type 2 diabetes coronary heart disease hypertension stroke dyslipidemia chronic kidney disease and cancer
bull Men with GGT gt50 UI had ~26 fold risk for diabetes compared to those with lt10 Those with 40-49 had a ~20 fold risk
bull Levels within normal range occur with obesity xs alcohol cigarette smoking physical inactivity high meat low fruit and vegetable intake
bull Cumulative biomarker for environmental pollutants
Lee DH et al (2003) Gamma-glutamyltransferase and diabetesmdasha 4 year follow-up study Diabetologia 46359ndash364
Pamela A et al Serum gamma-glutamyltransferase linking together environmental pollution redox equilibria and progression of atherosclerosis Clin Chem
Lab Med 200947(12)1583-4
Lee DH et al Serum gamma-glutamyltransferase new insights about an old enzyme J Epidemiol Community Health 2009 Nov63(11)884-6
Lee DH et alSerum gamma-glutamyltransferase predicts non-fatal myocardial infarction and fatal coronary heart disease among 28838 middle-aged men and
women Eur Heart J 2006272170ndash6
Lee DH et al Gamma-glutamyltransferase and diabetes--a 4 year follow-up study Diabetologia 2003 Mar46(3)359-64
Lee DH et al Can persistent organic pollutants explain the association between serum gamma-glutamyltransferase and type 2 diabetes Diabetologia 2008
Mar51(3)402-7
GGT and Alcohol Consumption
bull GGT directly correlates with alcohol consumption
bull In a non-uniform population 40 gd will elevate GGT ~15
bull Watch for false negatives
bull Genomic variation
bull Are these the ones most
sensitive todamaged by
chemical toxins
bull Could up-regulation of GGT in light alcohol consumption be reason for benefit
0
10
20
30
40
50
60
70
80
0 200 400 600 800
Grams of Ethanol per Week
Adapted from Nagaya T et al Dose-response relationships between drinking and serum tests in Japanese men
aged 40ndash59 years Alcohol 1999 Feb 17(2) 133ndash8
GGT Correlates With Toxic Metal Levels
Lee DH et al Graded associations of blood lead and urinary cadmium concentrations with oxidative-stress-related markers in the
US population results from the third National Health and Nutrition Examination Survey Environ Health
perspect 2006 Mar114(3)350-4
GGT and Diabetes Risk
0
5
10
15
20
25
30
lt10 10-19 20-29 30-39 40-49 gt50
Dia
bete
s R
isk
GGT
bull GGT over 50 associated with tripling of death rate
bull 30-40 associated with doubling
GGT Levels
Correlate with
Risk of Death
Brenner H et al Distribution determinants and prognostic value of gamma-glutamyltransferase for all-cause
mortality in a cohort of construction workers from southern Germany Prev Med 1997 26 305ndash10
GGT From Small US Company
with Young Workers
0
10
20
30
40
50
60
0 20 40 60 80 100
GGT Data from Canadian Oil Field
Workers
0
50
100
150
200
250
300
350
400
450
lt10 10-20 20-30 30-40 40-50 50-60 60-07 70-80 80-90 90-100 100-110 110-120 gt120
GGTP
20-fold increased risk of diabetes
Uric Acid Indirect Measure of POPs
bull Poly-fluorinated hydrocarbons (PFOA and PFOS) associated
with increased serum uric acid
Lin CY et al Association among serum perfluoroalkyl chemicals glucose homeostasis and metabolic syndrome
in adolescents and adults Diabetes Care 2009 Apr32(4)702-7
Steenland K et al Association of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) with uric
acid among adults with elevated community exposure to PFOA Environ Health Perspect 2010 Feb118229-33
Steenland 2010 Open Access
ALT Indirect Measure of POPs
bull ALT (proxy marker) elevation in 104 (not including viral
hepatitis hemochromatosis or alcoholic liver disease) of
NHANES 03-04 subset
bull Risk of elevated ALT increased dose-dependently with
cadmium lead mercury and PCB exposure
bull 100 of individuals had detectable PCBs 925 mercury
and 996 had detectable lead
bull In 2005-08 prevalence of NAFLD in US was 11 a
growing cause of chronic liver disease
Cave M et al Polychlorinated biphenyls lead and mercury are associated with liver disease in American adults
NHANES 2003-2004 Environ Health Perspect 2010 Dec118(12)1735-42
Younossi ZM et al Changes in the prevalence of the most common causes of chronic liver diseases in the United
States from 1988 to 2008 Clin Gastroenterol Hepatol 2011 Jun9(6)524-530e1
Bilirubin as a Marker of POPs
bull Degree of serum bilirubin increase is prognostically significant in chronic liver dysfunction
bull Mono-ortho PCB TEQ values were found to be significantly positively associated with bilirubin (β=071 P=0008) following adjustment for multiple potential confounders
bull Bilirubin levels significantly correlated with PCBs -105-118-126 and -194
bull Smoking appears to be the biggest confounder
Dufour DR et al 2000 Diagnosis and monitoring of hepatic injury II Recommendations for use of laboratory
tests in screening diagnosis and monitoring Clin Chem 46 2050ndash68
Kumar J et al Persistent organic pollutants and liver dysfunction biomarkers in a population-based human sample
of men and women Environ Res 2014134251-256
Perf
luo
rin
ate
dP
OP
s a
nd
Co
mm
on
Blo
od
Tests
Gleason JA et al Associations of perfluorinated chemical serum concentrations and biomarkers of liver function and uric acid in the
US population (NHANES) 2007-2010 Environ Res 20151368-14
Liver Enzymes Reflect Toxic Load
bull AST ALT and GGT increase with body load of PCBs and OCPs
bull Some non-linear
bull Oxychlordanetop quartile
ALT 10
GGT 25
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
LDL-Cholesterol as Measure of POPs
bull 5-year prospective study to determine if POP levels predict future elevation in LDL-cholesterol
bull 598 subjects initially at age 70
bull Looked at 23 POPs
bull Best correlation with PCB 194
Penell J Lind L Salihovic S et al Persistent organic pollutants are related to change in circulating
lipid levels during a 5 year follow-up Environ Res 134(2014)190ndash197
oxLDL as Measure of POPs
bull 992 70-year old individuals (50 women)
bull Sum of PCBs showed strong significant positive associations with ox-LDL and significant negative associations with glutathione-related markers (GSSG and GSSGGSH)
bull A number of POPs (PCB-99 138 153 156 170 180 194 206 and 209) showed strong significant positive association with ox-LDL
Kumar J et al Influence of persistent organic pollutants on oxidative stress in population-based samples
Chemosphere 2014114303-309
Homocysteine is Increased by Pb amp Cd
Guallar E et al Confounding of the relation between homocysteine and peripheral arterial disease by lead cadmium and renal function Am J Epidemiol 2006 Apr 15163(8)700-8
Nutrient Deficiencies Accentuate
Effects of Lead on Homocysteine
bull Deficiencies in folate B6 or B12 make lead more toxic
Lee YM Et al Association of homocysteine levels with blood lead levels and micronutrients in the US general population J Prev Med Public Health 2012 Nov45(6)387-93
T4 amp T3 and PCBs
bull PCBs decrease T4 production
bull PCBs inhibit iodotyrosinedeiodinase activity
bull Study done in pregnant women which implies effect on fetus IQ
Kim S Park J Kim HJ et al Association between several persistent organic pollutants and thyroid hormone levels in serum among the pregnant women of Korea Environ Int 2013 Sep59442-8Shimizu R Yamaguchi M Uramaru N et al Structure-activity relationships of 44 halogenated compounds for iodotyrosinedeiodinase-inhibitory activity Toxicology 2013 Dec 6314(1)22-9
T4 amp T3 and PCBs
bull Not just humans being affected
bull Large study of dolphins shows exactly the same effects
Schwacke LH Zolman ES Balmer BC et al Anaemia hypothyroidism and immune suppression associated with polychlorinated biphenyl exposure in bottlenose dolphins (Tursiops truncatus) Proceed Royal Society B doi101098rspb20110665
8-OHdG
bull Oxidized nucleoside
bull Direct measure of DNA damage
bull Indirect measure of oxidative stress and toxin load
bull Correlates with
Multiple cancers
Mitochondrial damage
Rate of aging
Smoking
Several toxinsWalter Crinnion ldquoTotal Toxic Loadrdquo AANP 2015
8-OHdG Correlates with Pack-Years
of Smoking
Yano T et al Significance of the urinary 8-OHdG level as an oxidative stress marker in lung cancer patients Lung Cancer
2009 Jan63(1)111-4
8-OHdG Correlates
with Mercury
Chen C et al Increased oxidative DNA damage as assessed by urinary 8-hydroxy-2-deoxyguanosine
concentrations and serum redox status in persons exposed to mercury Clin Chem 2005 Apr51(4)759-67
Toxin Effects Worse with Aging
bull Thyroid function decreases with PFOA levels
bull But only after age 63
Shrestha S Bloom MS Yucel R et al Perfluoroalkyl substances and thyroid function in older adults Environ Int 2015 Feb75206-14
Insightful 23-Year Prospective Study
1 lt 50 there is no difference between those with the lowest and highest PCBs
2 In youngest group insulin production increases in response to toxin level As expected since blocking of
insulin receptor sites by PCBs
requires more insulin
3 That adaptive ability decreases with aging
4 At age 50 all the measures show very strong toxin-dose response
Cumulative damage impairs ability to adapt
Suarez-Lopez JR et al Persistent organic pollutants in young adults and changes in glucose related metabolism over a 23-year follow-up Environ Res 2015 Feb137485-94
Recommendations
High body toxic load
GGT gt 25
Uric acid gt 50 mgdl
ALT gt30 UL
Bilirubin gt08 mgdl
CBC lt 6000
Platelet lt 250000
Low T3 andor T4
Monitor Total Toxic Load
8-OHdG gt4
ldquoUnconventionalrdquo Laboratory Tests
bull Challenge testing
bull Hair analysis
bull Direct measures of solvents and POPs in blood urine adipose tissue
Evaluation of Metal Exposure ndash Provocation
bull Provocation ndash the use of a chelating agent ndash before urine collection often done clinically but several limitations
No ldquoofficialrdquo reference range for provoked urine
Most chelating agents do not extract metals from all tissues thus
does not necessarily represent total body burden
bull Example Brain is one of the main target organs for both elemental and organic
mercury yet agents do not chelate brain mercury
bull Despite limitations widely used and advocated by clinicians in part to see efficacy of chelating agent as a guide to treatment and based on empirical evidence
Rooney JP The role of thiols dithiols nutritional factors and interacting ligands in the toxicology of mercury
Toxicology 2007
Is Challenge Testing Valid
bull Poor correlations of standard tests for mercury
bull Unpublished research from corporate wellness project
bull Published amalgam number correlation
bull Published fish consumption correlation
What We Found In Canada
bull Deviations from the mean of 14 29 and 91 respectively
bull DMPS is spreading distribution suggesting that it is better at differentiating mercury body load
bull Some VERY high
Hg Assessment Correlations
bull Extensive measurements in 65 Whole blood Hg
Oral DMPS challenge
Amalgam surfaces
bull Correlations Whole blood w pre urine r = 040
Whole blood w post urine r = 057
Pre urine w post urine r = 068
Amalgams w pre urine r = 026
Amalgams w whole blood r = 036
Amalgams with post urine 044
bull Clear documentation that
challenge testing is better00
100
200
300
400
500
600
0 10 20 30 40 50
Po
st
Uri
ne H
g u
gg
Number of amalgams
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
AD
HD
Ep
idem
ic
httpwwwcdcgovmmwrpreviewmmwrhtmlmm6433a11htm
Obesity Epidemic
httpwwwtheobesityepidemicorgintroduction (Accessed 616)
Kidney Disease Epidemic
Stevens L httpwwwslidesharenetringer21liaison-meeting-esrd-presentation (accessed 616)
Dia
be
tes
Ep
ide
mic
Diabetes Increasing World-Wide
SourcesAIHW analysis of ABS NHS 1989ndash90 1995 2001 2004ndash05 and 2007ndash08 NHS (reissue) and ABS 2011ndash12 Australian
Health Survey data (Release 7 June 2013)
Co-ordinaring Committee Epidemiology Study of Childhood amp Adolescent Diabetes Hong Kong KF Huen et al
Australian Adults
Childhood diabetes in Hong Kong
WHY THE CHRONIC DISEASE
EPIDEMICS
Increase in Diabetes Due to Sugar
httpwholehealthsourceblogspotcom201202by-2606-us-diet-will-be-100-percenthtml
Dia
bete
s 1
How About Persistent Organic Pollutants
Neel BA Robert M Sargis RM The paradox of progress Environmental disruption of metabolism and the diabetes epidemic DIABETES 2011 601838-48
Lars Jaumlrup Br Med Bull 200368167-182copy The British Council 2003 all rights reserved
Global Production and Consumption of
Selected Toxic Metals 1850ndash1990
Cadmium World Production
Mercury in the Air
EPA-452R-97-003 December 1997
Mercury in Water
httpwaterepagovscitechdataitmodelsmapspostercfm
Ground Water Sources of Arsenic
bull 10 of US public water supplies have levels of arsenic known to induce disease
bull No data on private water supplies
httpwwwatsdrcdcgovcsemarsenicdocsarsenicpdf (accessed 2015-08-18)
Example POPs
Chemical Abbr Uses Exposure
Bisphenol A BPA Plastics Canned food
Organochlorine
pesticides
OCPs Pesticide Food fumigation
Organophosphate
pesticides
OPPs Pesticide Food
Polybrominated
diphenyl ethers
PBDEs Flame retardant Clothing
Polychlorinated
biphenyls
PCBs Industrial Everywhere
Perflourinated PFOAs Non-stick stain prevention
water repellant
Teflon Gortex
Scotchguard
Phthalates Plastics fragrances Shower curtains
cosmetics
POPs - Prediabetes
bull Over 1200 participants fasting
glucose and OGTT performed
with serum levels of 5 POPs
bull All individual POPs tested were
associated with progressive
increase in prevalence of
prediabetes
bull More than triple prevalence of
prediabetes seen in those in the
5th quartile with a synergistic
effect from 5 POPs
Ukropec J et al High prevalence of prediabetes and diabetes in a population exposed to high levels of an organochlorine cocktail
Diabetologia 2010 May53(5)899-906
POPs and Diabetes Risk
Graph httpwwwourstolenfutureorgNewScienceobesity20062006-0715leeetalhtml
Data Lee DH Lee IK Song K et al A strong dose-response relation between serum
concentrations of persistent organic pollutants and diabetes results from the National Health and
Examination Survey 1999-2002 Diabetes Care 2006 Jul29(7)1638-44
Toxic Load and Disease Risk
References for Toxins and Disease Risk
Converting Disease Risk to Caused
Attributable Fraction Calculation
p = underlying prevalence of risk factor in the population
rr = relative risk (risk of contracting a disease in an exposed population divided by the risk of contracting the disease in an unexposed population)
AF = of disease due to the toxin
Levin M The occurrence of lung cancer in man Acta Unio Int Contra Cancrum 1953 9 531-541
Example Smoking and Lung Cancer
B = 5Number of smokers
who contract Lung Cancer notdue to smoking
A = 5Number of smokerswho contract Lung
Cancer due to smoking
C = 15Number of
nonsmokerswho contract Lung Cancer
0
2
4
6
8
10
12
14
16
Smokers (N=100) Nonsmokers (N=300)Num
ber
of
people
who c
ontr
act
Lung C
ancer
per
year
Baseline Additional due to smoking
Number of smokers and nonsmokers who contract lung cancer
Our Process In Summary
1 Determine threshold for increased disease risk
2 Determine of population above threshold
3 Determine incidence of disease (OR) in those above threshold
4 Determine incidence of disease in ldquounexposed populationrdquo
5 Calculate AF ie of disease
As whole population is exposed probably UNDERESTIMATES of disease
To
xic
ity H
as B
eco
me t
he N
ew
ldquoN
orm
alrdquo
Toxin Type Use Threshold for
disease
association
of US
above
threshold
Disease Associations
Chlordane OC pesticide Termites corn citrus lawns
gardens
145ngg lipid 63
(diabetes)
Diabetes (20)
BPA Plasticizer Water bottles canned food
water pipes thermal sales
receipts
48 men 51
women (urine
ngmL)
~18
(diabetes)
Diabetes hypertension
Octachloro
dibenzo-p-
dioxin
(OCDD)
Polychlorinated
dibenzo-p-
dioxin
Incineration or burning of
waste bleaching processes
used in pulp and paper mills
1010 pgg
lipid (highest
quartile)
10-25
(hypertensio
n)
Hypertension (79 for
women highest
quartile) diabetes (21)
obesity learning
disability (272)
MEP
(mono-
ethyl
phthalate)
Phthalate
(plasticizer
fragrance)
Toothbrushes automobile
parts tools toys and food
packaging aspirin
cosmetics food packaging
gt175 ngmL
(urine)
~60
(diabetes)
Diabetes (148) lower
BMD obesity
pp-DDE DDT
metabolite (OC
pesticide)
Agricultural crops 1560ngg
lipid
25
(diabetes)
Diabetes (23-43)
early menopause
impaired cognitive
function (2-3x 65x in
highest 5th percentile)
peripheral arterial
disease
Arsenic Toxic metal Miningsmelting wood
preservative pesticides
74ugL total
arsenic (urine)
20
(diabetes)
Cancers diabetes (26-
46) dyslipidemia gout
AF OR Prevalence
Rosen L An intuitive approach to understanding the attributable fraction of disease due to a risk factor the case of smoking Int J Environ Res Public Health 2013 Jul 1610(7)2932-43
Smoking Lung cancer
Arsenic Gout in women
BPA Diabetes
Status of Our Research
bull 26 toxins and toxin classes eg lead mercury BPA OCPs
100s of chemicals and POPs in some classes
bull 18 cancers
bull 24 chronic diseases
bull 1092 cells in spreadsheet
Large Personal Ongoing Research Investment
Huge Amount of Research Work
Toxins StudiedAluminum
Arsenic
Cadmium
Fluoride
Lead
Manganese
Mercury
Acrylamide
Acrylonitrile
Benzene
Bisphenol A (BPA)
Chloroform
DDT
Dioxins
Glyphosate
Organochlorine pesticides (OCPs)
Organophosphate pesticides
Parabens
Phthalates
Polybrominated diphenyl ethers (PBDEs)
Polycyclic aromatic hydrocarbons (PAHs)
Polychlorinated biphenols (PCBs)
Vinyl chloride
Diseases Studied
ADHD
Alzheimers Disease
ALS
Angiosarcoma
Anxiety
Atopic Conditions
Diabetes
Dyslipidemia
Gout
Fetal Abnormalities
Hyperuricemia
Infertility
Juvenile IQ
Cancer Bladder
Cancer Bone
Cancer Brain
Cancer Breast
Cancer Cervix
Cancer Colorectal
Cancer Endometrial
Cancer Head amp Neck
Cancer Liver
Cancer Lung
Cancer Lymph amp Blood
Cancer Ovarian
Cancer Pancreatic
Cancer Prostate
Cancer Renal
Cancer Skin
Cancer Testicular
Cancer Thyroid
Juvenile Obesity
Metabolic Syndrome
Mitochondrial dysfunction
Myocardial Infarction
Obstructive Lung Disease
Osteoporosis
Peripheral Artery Disease
Peripheral Neuropathy
Prediabetes
Renal Disease
Rheumatoid Arthritis
Thyroid Dysfunction
OC
Ps
Th
rou
gh
ou
t th
e W
orl
d
Rathore HS Nollet LML Pesticides Evaluation of Environmental Pollution CRC Press
2012 page 562
Threshold ndash Threshold exposure at which there is an increased risk of disease outcome
Above Threshold ndash Percentage of the population with higher exposure than the threshold
Odds Ratio ndash Increased disease risk in those above threshold
of Dz ndash Percent contribution of the toxin to that disease outcome
How to Interpret the Following Slides
Attention Deficit Hyperactivity Disorder
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
DDT 126 ngg
serum (pp-
DDE)
250 18 166 20106937
Lead 23 ugdL 13 254 20 27659349
Mercury 16 24952233
Organophosphate
pesticides
20
Polycyclic
Aromatic
Hydrocarbons
227 ngm3 940 125 190 22440811
PCBs 104 ngg
serum (sum
of 50 PCBs)
250 176 160 20106937
DiabetesToxin Threshold Above
Threshold
Odds
Ratio
of Dz Reference
PMID
Arsenic 165 ugL 200 21 180 18714061
BPA 28 ugL 280 145 112 26119400
DDE 545 ngg serum
(pp-DDE)
200 230 31 26119400
Dioxins2 pgg lipid 50 191 43
26119400
PCBs104 ngg (PCB 153) 250 239 258
26119400
Phthalates175 ugL 690 148 249
26119400
1-naphthalene 167 ugdL 152 182 111 26340343
2-napthalene 414 ugdL 550 224 214 26340343
1-phenanthrene 167 ngL 570 178 151 26340343
1-pyrene 85 ngL 660 180 174 26340343
Lung Cancer
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Acrylonitrile Uncertain Uncertain 125 25
occupational
exposure
17114112
Arsenic 1213 ugL 436 of Asian
Americans
~01 of total
US population
34 95 in AA
01-1
PMC2682945
Cadmium Uncertain+ Uncertain 467 10 in
smokers
17184399
DDT Any exposure All US pop
below LOD
17 76 increased
risk
8923607
Breast Cancer
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Cadmium 0580 ugg
creatinine
126 205 479 16788160
PCB 138 396 ngg
creatinine
202 316 630 27717745
PCB 187 108 ngg lipid 600 194 360 21480306
Miscellaneous Diseases
Toxin Disease Threshold Above
Threshold
Odds
Ratio
of Dz Reference PMID
Aluminum Alzheimer
Dz
01 mgL
drinking
H20
400 203 05-44 26592479
Benzene AML 100ppmyrs 1-3 320 60 PMC2903550
DDT NHL 0512 ugL 1-2 240 01 17722095
Lead ALS 238 ugdL
blood
330 181 210 25479292
Lead Brain CA 0005 ugdL 14 19 ~500 17164378
Dioxin-like
PCBs
RA 326 ngg
lipid
250 219 220 17589595
PAHs Asthma 124 ngm3 935 200 483 19221603
The Potency of Arsenic
Disease Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Bladder CA 10ugL H20 100 27 145 24889821
Pancreatic CA 1332 ugg 200 246 230 23800676
Prostate CA 1332 ugg 200 33 315 23800676
Gout 125 ugL 245 546 522 25499256
Diabetes 165 ugL 200 21 180 18714061
Arsenic (180 of Diabetes)
How it causes diabetes
bull Blocks sugar stimulating insulin secretion
bull Epigenetic inhibition of sugar regulation
Where it comes from
bull Water (gt10 of US water supplies have high levels)
bull Rice (naturally absorbs if in the water)
bull Chicken (added to make meat whiter)
Pan W-C Seow WJ Kile ML et al Association of low to moderate levels of arsenic exposure with risk of Type 2 diabetes in Bangladesh American Journal of Epidemiology 2013178(10)1563-70
Portion of Population with Toxin Load Which
Doubles Disease Risk
Toxin Disease with Doubled Risk
Polycyclic aromatic hydrocarbons Asthma 94
PCB187 Breast Cancer 60
Phthalates Diabetes 55
Lead ALS 33
Aluminum Alzheimers Disease 25
DDT ADHD 25
PCBs Diabetes 25
Dioxin-like PCBs Rheumatoid Arthritis 25
Arsenic Gout 23
Bisphenol A Diabetes 22
Cigarette smoking Lung Cancer 21
Arsenic Diabetes 20
Polycyclic aromatic hydrocarbons Diabetes 20
Huge Detoxification Variability
bull CYP2C19
Proton pump inhibitors and some antidepressants
5-fold difference in activity between poor metabolizers and extensive metabolizers more so if CYP3A4 is also inhibited
Ultrarapid allele in 18 of both Swedes and Ethiopians
bull CYP2D6
Metabolizes a large number of drugs (~25)
7 of Caucasians poor metabolizers
~30 ultra rapid metabolizers in Arabian and Eastern African populations
More adverse effects in poor metabolizers and ineffective dosing in ultrarapid metabolizers
Inhibited by ginger
Desta Z et al Clinical significance of the cytochrome P450 2C19 genetic polymorphism Clin Pharmaco 2002
Sim SC et al A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug
response to proton pump inhibitors and antidepressants Clin Pharmacol Ther 2006
Wilkinson GR Drug metabolism and variability among patients in drug response N Engl J Med 2005
Kirchheiner J et al Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to
CYP2D6 duplication Pharmacogenomics J 2007
Toxin Half Lives in BloodToxin ldquoNormalrdquo (mgL) Acute Toxic (mgL) Half-Life
Arsenic 0002-007 005-025 2-4 days (CDC)
Benzene 00002 05-10 days
Cadmium 00003-00065 0015-005 16 years
Chlordane 0001 00025 3-4 days
DDTDDE 2-10 years
Dieldrin 00015 015-030 2-12 months
Ethanol 1000-2000 15hour
Lead 009 04-06 1-15 mo (2+ yrs bone)
Mercury 00015-0002 005-02 2 months (CDC)
PCBs 3-25 years
Toluene 05-3 days
Schulz M et al Therapeutic and toxic blood concentrations of nearly 1000 drugs and other xenobiotics Crit Care 2012 Jul 2616(4)R136
Bioaccumulation (POPs)
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
DDT banned in 1972 PCBs banned in 1977
Bioaccumulation (Cd)
Think BroadlyExogenous
Metals
Chemicalsbull Inorganic
bull Fluoride
bull Organic
bull POPs
bull Drugs
Particulate matter
Molds
Microbial
Radiationbull Light
bull Medical
bull Cell phone
Endogenous
Gut-derived toxins
Non-end product metabolites
Poorly detoxified hormones
Catecholamines (if SNP)
Toxins of Choice
Alcohol
Marijuana
Food constituents
High fructose corn syrup
Salt (acid-forming diet)
Wheat if zonulin (70)
Obesity Epidemic ndash POPs AND HFCS
47Bray GA Fructose should we worry Int J Obes (Lond) 2008 Dec32 Suppl 7S127-31
How Toxins Cause Damage 13
bull Increase free radical production
Cd induces production of ROS
Malathion inhibits catalase and glutathione peroxidase
Homocysteine oxidizes LDL cholesterol
bull Poison enzyme systems (compete with nutritional cofactors for binding sites)
Pb poisons delta aminolevulinic acid dehydratase
Cd inhibits catalase glutathione reductase and lowers
glutathione levels
bull Replace structural minerals
Pb displaces Ca in bone
How Toxins Cause Damage 23
bull Damage DNA
Benzene - causes chromosomal damage
Pesticides ndash fruit growers have more DNA damage
Phthalates and insecticides ndash damage sperm DNA
4-hydroxy catechol estrogen (4-OHE) damages breast DNA
bull Epigenetic dysmodulation
Higher cord blood levels of hexachlorobenzene associated
with 2x greater risk for obesity in children
bull Damage cell membranes
Common mechanism for heavy metals inactivates
membrane enzymes ion channels and pumps
How Toxins Cause Damage 33
bull Block insulin receptor sites
PCBs and phthalates
bull Highest levels associated with a 4 to 20-fold greater diabetes risk
bull Imbalance hormones many toxin examples
Arsenic
bull Disrupts thyroid hormone and retinoic acid receptors
Phthalates
bull Act as anti-androgens
bull More than 75 of the US population has measurable levels of
several phthalate metabolites in the urine
PCBs
bull Lower testosterone levels in men
Which are the Worst Toxins
bull According to the CDC
Toxicity
Population toxic load
Prevalence in toxic waste sites
bull According to clinical importance
Exposure
of disease
Ability of the body to detoxifyexcrete
Ag
en
cy
fo
r T
oxic
Su
bs
tan
ce
s a
nd
Dis
ea
se
Reg
istr
y
Pri
ori
ty L
ist
The Worst Toxins Clinically
My Rank Toxin Diseases Primary Sources
1 Arsenic Cancers diabetes gout Water chicken rice
2 DDT ADHD dementia diabetes Everywhere
3 Phthalates ADHD diabetes Soft plastics HABAs
4 PBDEs ADHD diabetes Flame retardant fabrics
5 PAHs ADHD cancers dyslipidemia Smoking charbroiling
6 PCBs Cancers diabetes MI RA Everywhere
7 Mercury Dementia ldquoSilverrdquo fillings fish
8 Lead Cardiovascular disease IQ Paint water
Glyphosate Research invalid
Conventional Laboratory Tests Reflect
Toxic Load in ldquoNormalrdquo Range
bull Surprising number show toxin exposure
CBC RBC WBC platelet count hemoglobin basophilic
stippling
Liver enzymes ALT GGTP
Inflammatory markers CRP
Lipids LDL oxLDL triglycerides
Blood sugar insulin FBS 2-hour PP
Metabolites bilirubin uric acid homocysteine 8-OHdG
Thyroid T3 T4 TSH
bull The historic ldquonormalrdquo range has been changing as the population has become more toxic
WBC Lowered by PCB and OCP Exposure
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
0
1
2
3
4
5
6
7
8
1st Quartrile 2nd Quartile 3rd Quartile 4th Quartile
WBCbull Strong inverse correlation with PCBs and OCPs and CBC
bull Linear with almost all PCBs
bull High variability with OCPs
bull Within ldquonormalrdquo range
Effects on WBC Worsen with Years
of Exposure to Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Platelet Count Decreases with Years
of Exposure tp Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Solvents Decrease Platelet Count
bull Compared workers exposed 23 hrday to those exposed most of day to toluene
bull All wore face masks and protective gear
bull Platelet count 14 lower 252 versus 216ml
bull Impairment of sympathetic nerves (OR = 413)
bull Impairment of peripheral nerves (OR = 694)
bull Positive relationship between neurological abnormalities and a self-reported neuropsychiatric measurement (r = 035-066)
Shih HT et al Subclinical abnormalities in workers with continuous low-level toluene exposure Toxicol Ind Health 2011 Sep27(8)691-9
Basophilic Stippling of Red Cells
Toxinsbull Arsenic
bull Lead
Diseasesbull Alpha-thalassemia HbH Disease
bull Beta thalassemia
bull Hereditary pyrimidine 5-nucleotidase deficiency
bull Myelodysplastic syndrome
bull Sideroblastic anemia
bull Thrombotic thrombocytopenic purpura
GGT Indirect Measure of POPsbull Glutathione is key intracellular defense against oxidative stress
bull Cellular GGT metabolizes extracellular GSH allowing precursor amino acids to be reutilized for intracellular GSH
bull Exposure to POPs induces GGT as a defensive mechanism
bull Within normal range predicts type 2 diabetes coronary heart disease hypertension stroke dyslipidemia chronic kidney disease and cancer
bull Men with GGT gt50 UI had ~26 fold risk for diabetes compared to those with lt10 Those with 40-49 had a ~20 fold risk
bull Levels within normal range occur with obesity xs alcohol cigarette smoking physical inactivity high meat low fruit and vegetable intake
bull Cumulative biomarker for environmental pollutants
Lee DH et al (2003) Gamma-glutamyltransferase and diabetesmdasha 4 year follow-up study Diabetologia 46359ndash364
Pamela A et al Serum gamma-glutamyltransferase linking together environmental pollution redox equilibria and progression of atherosclerosis Clin Chem
Lab Med 200947(12)1583-4
Lee DH et al Serum gamma-glutamyltransferase new insights about an old enzyme J Epidemiol Community Health 2009 Nov63(11)884-6
Lee DH et alSerum gamma-glutamyltransferase predicts non-fatal myocardial infarction and fatal coronary heart disease among 28838 middle-aged men and
women Eur Heart J 2006272170ndash6
Lee DH et al Gamma-glutamyltransferase and diabetes--a 4 year follow-up study Diabetologia 2003 Mar46(3)359-64
Lee DH et al Can persistent organic pollutants explain the association between serum gamma-glutamyltransferase and type 2 diabetes Diabetologia 2008
Mar51(3)402-7
GGT and Alcohol Consumption
bull GGT directly correlates with alcohol consumption
bull In a non-uniform population 40 gd will elevate GGT ~15
bull Watch for false negatives
bull Genomic variation
bull Are these the ones most
sensitive todamaged by
chemical toxins
bull Could up-regulation of GGT in light alcohol consumption be reason for benefit
0
10
20
30
40
50
60
70
80
0 200 400 600 800
Grams of Ethanol per Week
Adapted from Nagaya T et al Dose-response relationships between drinking and serum tests in Japanese men
aged 40ndash59 years Alcohol 1999 Feb 17(2) 133ndash8
GGT Correlates With Toxic Metal Levels
Lee DH et al Graded associations of blood lead and urinary cadmium concentrations with oxidative-stress-related markers in the
US population results from the third National Health and Nutrition Examination Survey Environ Health
perspect 2006 Mar114(3)350-4
GGT and Diabetes Risk
0
5
10
15
20
25
30
lt10 10-19 20-29 30-39 40-49 gt50
Dia
bete
s R
isk
GGT
bull GGT over 50 associated with tripling of death rate
bull 30-40 associated with doubling
GGT Levels
Correlate with
Risk of Death
Brenner H et al Distribution determinants and prognostic value of gamma-glutamyltransferase for all-cause
mortality in a cohort of construction workers from southern Germany Prev Med 1997 26 305ndash10
GGT From Small US Company
with Young Workers
0
10
20
30
40
50
60
0 20 40 60 80 100
GGT Data from Canadian Oil Field
Workers
0
50
100
150
200
250
300
350
400
450
lt10 10-20 20-30 30-40 40-50 50-60 60-07 70-80 80-90 90-100 100-110 110-120 gt120
GGTP
20-fold increased risk of diabetes
Uric Acid Indirect Measure of POPs
bull Poly-fluorinated hydrocarbons (PFOA and PFOS) associated
with increased serum uric acid
Lin CY et al Association among serum perfluoroalkyl chemicals glucose homeostasis and metabolic syndrome
in adolescents and adults Diabetes Care 2009 Apr32(4)702-7
Steenland K et al Association of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) with uric
acid among adults with elevated community exposure to PFOA Environ Health Perspect 2010 Feb118229-33
Steenland 2010 Open Access
ALT Indirect Measure of POPs
bull ALT (proxy marker) elevation in 104 (not including viral
hepatitis hemochromatosis or alcoholic liver disease) of
NHANES 03-04 subset
bull Risk of elevated ALT increased dose-dependently with
cadmium lead mercury and PCB exposure
bull 100 of individuals had detectable PCBs 925 mercury
and 996 had detectable lead
bull In 2005-08 prevalence of NAFLD in US was 11 a
growing cause of chronic liver disease
Cave M et al Polychlorinated biphenyls lead and mercury are associated with liver disease in American adults
NHANES 2003-2004 Environ Health Perspect 2010 Dec118(12)1735-42
Younossi ZM et al Changes in the prevalence of the most common causes of chronic liver diseases in the United
States from 1988 to 2008 Clin Gastroenterol Hepatol 2011 Jun9(6)524-530e1
Bilirubin as a Marker of POPs
bull Degree of serum bilirubin increase is prognostically significant in chronic liver dysfunction
bull Mono-ortho PCB TEQ values were found to be significantly positively associated with bilirubin (β=071 P=0008) following adjustment for multiple potential confounders
bull Bilirubin levels significantly correlated with PCBs -105-118-126 and -194
bull Smoking appears to be the biggest confounder
Dufour DR et al 2000 Diagnosis and monitoring of hepatic injury II Recommendations for use of laboratory
tests in screening diagnosis and monitoring Clin Chem 46 2050ndash68
Kumar J et al Persistent organic pollutants and liver dysfunction biomarkers in a population-based human sample
of men and women Environ Res 2014134251-256
Perf
luo
rin
ate
dP
OP
s a
nd
Co
mm
on
Blo
od
Tests
Gleason JA et al Associations of perfluorinated chemical serum concentrations and biomarkers of liver function and uric acid in the
US population (NHANES) 2007-2010 Environ Res 20151368-14
Liver Enzymes Reflect Toxic Load
bull AST ALT and GGT increase with body load of PCBs and OCPs
bull Some non-linear
bull Oxychlordanetop quartile
ALT 10
GGT 25
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
LDL-Cholesterol as Measure of POPs
bull 5-year prospective study to determine if POP levels predict future elevation in LDL-cholesterol
bull 598 subjects initially at age 70
bull Looked at 23 POPs
bull Best correlation with PCB 194
Penell J Lind L Salihovic S et al Persistent organic pollutants are related to change in circulating
lipid levels during a 5 year follow-up Environ Res 134(2014)190ndash197
oxLDL as Measure of POPs
bull 992 70-year old individuals (50 women)
bull Sum of PCBs showed strong significant positive associations with ox-LDL and significant negative associations with glutathione-related markers (GSSG and GSSGGSH)
bull A number of POPs (PCB-99 138 153 156 170 180 194 206 and 209) showed strong significant positive association with ox-LDL
Kumar J et al Influence of persistent organic pollutants on oxidative stress in population-based samples
Chemosphere 2014114303-309
Homocysteine is Increased by Pb amp Cd
Guallar E et al Confounding of the relation between homocysteine and peripheral arterial disease by lead cadmium and renal function Am J Epidemiol 2006 Apr 15163(8)700-8
Nutrient Deficiencies Accentuate
Effects of Lead on Homocysteine
bull Deficiencies in folate B6 or B12 make lead more toxic
Lee YM Et al Association of homocysteine levels with blood lead levels and micronutrients in the US general population J Prev Med Public Health 2012 Nov45(6)387-93
T4 amp T3 and PCBs
bull PCBs decrease T4 production
bull PCBs inhibit iodotyrosinedeiodinase activity
bull Study done in pregnant women which implies effect on fetus IQ
Kim S Park J Kim HJ et al Association between several persistent organic pollutants and thyroid hormone levels in serum among the pregnant women of Korea Environ Int 2013 Sep59442-8Shimizu R Yamaguchi M Uramaru N et al Structure-activity relationships of 44 halogenated compounds for iodotyrosinedeiodinase-inhibitory activity Toxicology 2013 Dec 6314(1)22-9
T4 amp T3 and PCBs
bull Not just humans being affected
bull Large study of dolphins shows exactly the same effects
Schwacke LH Zolman ES Balmer BC et al Anaemia hypothyroidism and immune suppression associated with polychlorinated biphenyl exposure in bottlenose dolphins (Tursiops truncatus) Proceed Royal Society B doi101098rspb20110665
8-OHdG
bull Oxidized nucleoside
bull Direct measure of DNA damage
bull Indirect measure of oxidative stress and toxin load
bull Correlates with
Multiple cancers
Mitochondrial damage
Rate of aging
Smoking
Several toxinsWalter Crinnion ldquoTotal Toxic Loadrdquo AANP 2015
8-OHdG Correlates with Pack-Years
of Smoking
Yano T et al Significance of the urinary 8-OHdG level as an oxidative stress marker in lung cancer patients Lung Cancer
2009 Jan63(1)111-4
8-OHdG Correlates
with Mercury
Chen C et al Increased oxidative DNA damage as assessed by urinary 8-hydroxy-2-deoxyguanosine
concentrations and serum redox status in persons exposed to mercury Clin Chem 2005 Apr51(4)759-67
Toxin Effects Worse with Aging
bull Thyroid function decreases with PFOA levels
bull But only after age 63
Shrestha S Bloom MS Yucel R et al Perfluoroalkyl substances and thyroid function in older adults Environ Int 2015 Feb75206-14
Insightful 23-Year Prospective Study
1 lt 50 there is no difference between those with the lowest and highest PCBs
2 In youngest group insulin production increases in response to toxin level As expected since blocking of
insulin receptor sites by PCBs
requires more insulin
3 That adaptive ability decreases with aging
4 At age 50 all the measures show very strong toxin-dose response
Cumulative damage impairs ability to adapt
Suarez-Lopez JR et al Persistent organic pollutants in young adults and changes in glucose related metabolism over a 23-year follow-up Environ Res 2015 Feb137485-94
Recommendations
High body toxic load
GGT gt 25
Uric acid gt 50 mgdl
ALT gt30 UL
Bilirubin gt08 mgdl
CBC lt 6000
Platelet lt 250000
Low T3 andor T4
Monitor Total Toxic Load
8-OHdG gt4
ldquoUnconventionalrdquo Laboratory Tests
bull Challenge testing
bull Hair analysis
bull Direct measures of solvents and POPs in blood urine adipose tissue
Evaluation of Metal Exposure ndash Provocation
bull Provocation ndash the use of a chelating agent ndash before urine collection often done clinically but several limitations
No ldquoofficialrdquo reference range for provoked urine
Most chelating agents do not extract metals from all tissues thus
does not necessarily represent total body burden
bull Example Brain is one of the main target organs for both elemental and organic
mercury yet agents do not chelate brain mercury
bull Despite limitations widely used and advocated by clinicians in part to see efficacy of chelating agent as a guide to treatment and based on empirical evidence
Rooney JP The role of thiols dithiols nutritional factors and interacting ligands in the toxicology of mercury
Toxicology 2007
Is Challenge Testing Valid
bull Poor correlations of standard tests for mercury
bull Unpublished research from corporate wellness project
bull Published amalgam number correlation
bull Published fish consumption correlation
What We Found In Canada
bull Deviations from the mean of 14 29 and 91 respectively
bull DMPS is spreading distribution suggesting that it is better at differentiating mercury body load
bull Some VERY high
Hg Assessment Correlations
bull Extensive measurements in 65 Whole blood Hg
Oral DMPS challenge
Amalgam surfaces
bull Correlations Whole blood w pre urine r = 040
Whole blood w post urine r = 057
Pre urine w post urine r = 068
Amalgams w pre urine r = 026
Amalgams w whole blood r = 036
Amalgams with post urine 044
bull Clear documentation that
challenge testing is better00
100
200
300
400
500
600
0 10 20 30 40 50
Po
st
Uri
ne H
g u
gg
Number of amalgams
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
Obesity Epidemic
httpwwwtheobesityepidemicorgintroduction (Accessed 616)
Kidney Disease Epidemic
Stevens L httpwwwslidesharenetringer21liaison-meeting-esrd-presentation (accessed 616)
Dia
be
tes
Ep
ide
mic
Diabetes Increasing World-Wide
SourcesAIHW analysis of ABS NHS 1989ndash90 1995 2001 2004ndash05 and 2007ndash08 NHS (reissue) and ABS 2011ndash12 Australian
Health Survey data (Release 7 June 2013)
Co-ordinaring Committee Epidemiology Study of Childhood amp Adolescent Diabetes Hong Kong KF Huen et al
Australian Adults
Childhood diabetes in Hong Kong
WHY THE CHRONIC DISEASE
EPIDEMICS
Increase in Diabetes Due to Sugar
httpwholehealthsourceblogspotcom201202by-2606-us-diet-will-be-100-percenthtml
Dia
bete
s 1
How About Persistent Organic Pollutants
Neel BA Robert M Sargis RM The paradox of progress Environmental disruption of metabolism and the diabetes epidemic DIABETES 2011 601838-48
Lars Jaumlrup Br Med Bull 200368167-182copy The British Council 2003 all rights reserved
Global Production and Consumption of
Selected Toxic Metals 1850ndash1990
Cadmium World Production
Mercury in the Air
EPA-452R-97-003 December 1997
Mercury in Water
httpwaterepagovscitechdataitmodelsmapspostercfm
Ground Water Sources of Arsenic
bull 10 of US public water supplies have levels of arsenic known to induce disease
bull No data on private water supplies
httpwwwatsdrcdcgovcsemarsenicdocsarsenicpdf (accessed 2015-08-18)
Example POPs
Chemical Abbr Uses Exposure
Bisphenol A BPA Plastics Canned food
Organochlorine
pesticides
OCPs Pesticide Food fumigation
Organophosphate
pesticides
OPPs Pesticide Food
Polybrominated
diphenyl ethers
PBDEs Flame retardant Clothing
Polychlorinated
biphenyls
PCBs Industrial Everywhere
Perflourinated PFOAs Non-stick stain prevention
water repellant
Teflon Gortex
Scotchguard
Phthalates Plastics fragrances Shower curtains
cosmetics
POPs - Prediabetes
bull Over 1200 participants fasting
glucose and OGTT performed
with serum levels of 5 POPs
bull All individual POPs tested were
associated with progressive
increase in prevalence of
prediabetes
bull More than triple prevalence of
prediabetes seen in those in the
5th quartile with a synergistic
effect from 5 POPs
Ukropec J et al High prevalence of prediabetes and diabetes in a population exposed to high levels of an organochlorine cocktail
Diabetologia 2010 May53(5)899-906
POPs and Diabetes Risk
Graph httpwwwourstolenfutureorgNewScienceobesity20062006-0715leeetalhtml
Data Lee DH Lee IK Song K et al A strong dose-response relation between serum
concentrations of persistent organic pollutants and diabetes results from the National Health and
Examination Survey 1999-2002 Diabetes Care 2006 Jul29(7)1638-44
Toxic Load and Disease Risk
References for Toxins and Disease Risk
Converting Disease Risk to Caused
Attributable Fraction Calculation
p = underlying prevalence of risk factor in the population
rr = relative risk (risk of contracting a disease in an exposed population divided by the risk of contracting the disease in an unexposed population)
AF = of disease due to the toxin
Levin M The occurrence of lung cancer in man Acta Unio Int Contra Cancrum 1953 9 531-541
Example Smoking and Lung Cancer
B = 5Number of smokers
who contract Lung Cancer notdue to smoking
A = 5Number of smokerswho contract Lung
Cancer due to smoking
C = 15Number of
nonsmokerswho contract Lung Cancer
0
2
4
6
8
10
12
14
16
Smokers (N=100) Nonsmokers (N=300)Num
ber
of
people
who c
ontr
act
Lung C
ancer
per
year
Baseline Additional due to smoking
Number of smokers and nonsmokers who contract lung cancer
Our Process In Summary
1 Determine threshold for increased disease risk
2 Determine of population above threshold
3 Determine incidence of disease (OR) in those above threshold
4 Determine incidence of disease in ldquounexposed populationrdquo
5 Calculate AF ie of disease
As whole population is exposed probably UNDERESTIMATES of disease
To
xic
ity H
as B
eco
me t
he N
ew
ldquoN
orm
alrdquo
Toxin Type Use Threshold for
disease
association
of US
above
threshold
Disease Associations
Chlordane OC pesticide Termites corn citrus lawns
gardens
145ngg lipid 63
(diabetes)
Diabetes (20)
BPA Plasticizer Water bottles canned food
water pipes thermal sales
receipts
48 men 51
women (urine
ngmL)
~18
(diabetes)
Diabetes hypertension
Octachloro
dibenzo-p-
dioxin
(OCDD)
Polychlorinated
dibenzo-p-
dioxin
Incineration or burning of
waste bleaching processes
used in pulp and paper mills
1010 pgg
lipid (highest
quartile)
10-25
(hypertensio
n)
Hypertension (79 for
women highest
quartile) diabetes (21)
obesity learning
disability (272)
MEP
(mono-
ethyl
phthalate)
Phthalate
(plasticizer
fragrance)
Toothbrushes automobile
parts tools toys and food
packaging aspirin
cosmetics food packaging
gt175 ngmL
(urine)
~60
(diabetes)
Diabetes (148) lower
BMD obesity
pp-DDE DDT
metabolite (OC
pesticide)
Agricultural crops 1560ngg
lipid
25
(diabetes)
Diabetes (23-43)
early menopause
impaired cognitive
function (2-3x 65x in
highest 5th percentile)
peripheral arterial
disease
Arsenic Toxic metal Miningsmelting wood
preservative pesticides
74ugL total
arsenic (urine)
20
(diabetes)
Cancers diabetes (26-
46) dyslipidemia gout
AF OR Prevalence
Rosen L An intuitive approach to understanding the attributable fraction of disease due to a risk factor the case of smoking Int J Environ Res Public Health 2013 Jul 1610(7)2932-43
Smoking Lung cancer
Arsenic Gout in women
BPA Diabetes
Status of Our Research
bull 26 toxins and toxin classes eg lead mercury BPA OCPs
100s of chemicals and POPs in some classes
bull 18 cancers
bull 24 chronic diseases
bull 1092 cells in spreadsheet
Large Personal Ongoing Research Investment
Huge Amount of Research Work
Toxins StudiedAluminum
Arsenic
Cadmium
Fluoride
Lead
Manganese
Mercury
Acrylamide
Acrylonitrile
Benzene
Bisphenol A (BPA)
Chloroform
DDT
Dioxins
Glyphosate
Organochlorine pesticides (OCPs)
Organophosphate pesticides
Parabens
Phthalates
Polybrominated diphenyl ethers (PBDEs)
Polycyclic aromatic hydrocarbons (PAHs)
Polychlorinated biphenols (PCBs)
Vinyl chloride
Diseases Studied
ADHD
Alzheimers Disease
ALS
Angiosarcoma
Anxiety
Atopic Conditions
Diabetes
Dyslipidemia
Gout
Fetal Abnormalities
Hyperuricemia
Infertility
Juvenile IQ
Cancer Bladder
Cancer Bone
Cancer Brain
Cancer Breast
Cancer Cervix
Cancer Colorectal
Cancer Endometrial
Cancer Head amp Neck
Cancer Liver
Cancer Lung
Cancer Lymph amp Blood
Cancer Ovarian
Cancer Pancreatic
Cancer Prostate
Cancer Renal
Cancer Skin
Cancer Testicular
Cancer Thyroid
Juvenile Obesity
Metabolic Syndrome
Mitochondrial dysfunction
Myocardial Infarction
Obstructive Lung Disease
Osteoporosis
Peripheral Artery Disease
Peripheral Neuropathy
Prediabetes
Renal Disease
Rheumatoid Arthritis
Thyroid Dysfunction
OC
Ps
Th
rou
gh
ou
t th
e W
orl
d
Rathore HS Nollet LML Pesticides Evaluation of Environmental Pollution CRC Press
2012 page 562
Threshold ndash Threshold exposure at which there is an increased risk of disease outcome
Above Threshold ndash Percentage of the population with higher exposure than the threshold
Odds Ratio ndash Increased disease risk in those above threshold
of Dz ndash Percent contribution of the toxin to that disease outcome
How to Interpret the Following Slides
Attention Deficit Hyperactivity Disorder
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
DDT 126 ngg
serum (pp-
DDE)
250 18 166 20106937
Lead 23 ugdL 13 254 20 27659349
Mercury 16 24952233
Organophosphate
pesticides
20
Polycyclic
Aromatic
Hydrocarbons
227 ngm3 940 125 190 22440811
PCBs 104 ngg
serum (sum
of 50 PCBs)
250 176 160 20106937
DiabetesToxin Threshold Above
Threshold
Odds
Ratio
of Dz Reference
PMID
Arsenic 165 ugL 200 21 180 18714061
BPA 28 ugL 280 145 112 26119400
DDE 545 ngg serum
(pp-DDE)
200 230 31 26119400
Dioxins2 pgg lipid 50 191 43
26119400
PCBs104 ngg (PCB 153) 250 239 258
26119400
Phthalates175 ugL 690 148 249
26119400
1-naphthalene 167 ugdL 152 182 111 26340343
2-napthalene 414 ugdL 550 224 214 26340343
1-phenanthrene 167 ngL 570 178 151 26340343
1-pyrene 85 ngL 660 180 174 26340343
Lung Cancer
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Acrylonitrile Uncertain Uncertain 125 25
occupational
exposure
17114112
Arsenic 1213 ugL 436 of Asian
Americans
~01 of total
US population
34 95 in AA
01-1
PMC2682945
Cadmium Uncertain+ Uncertain 467 10 in
smokers
17184399
DDT Any exposure All US pop
below LOD
17 76 increased
risk
8923607
Breast Cancer
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Cadmium 0580 ugg
creatinine
126 205 479 16788160
PCB 138 396 ngg
creatinine
202 316 630 27717745
PCB 187 108 ngg lipid 600 194 360 21480306
Miscellaneous Diseases
Toxin Disease Threshold Above
Threshold
Odds
Ratio
of Dz Reference PMID
Aluminum Alzheimer
Dz
01 mgL
drinking
H20
400 203 05-44 26592479
Benzene AML 100ppmyrs 1-3 320 60 PMC2903550
DDT NHL 0512 ugL 1-2 240 01 17722095
Lead ALS 238 ugdL
blood
330 181 210 25479292
Lead Brain CA 0005 ugdL 14 19 ~500 17164378
Dioxin-like
PCBs
RA 326 ngg
lipid
250 219 220 17589595
PAHs Asthma 124 ngm3 935 200 483 19221603
The Potency of Arsenic
Disease Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Bladder CA 10ugL H20 100 27 145 24889821
Pancreatic CA 1332 ugg 200 246 230 23800676
Prostate CA 1332 ugg 200 33 315 23800676
Gout 125 ugL 245 546 522 25499256
Diabetes 165 ugL 200 21 180 18714061
Arsenic (180 of Diabetes)
How it causes diabetes
bull Blocks sugar stimulating insulin secretion
bull Epigenetic inhibition of sugar regulation
Where it comes from
bull Water (gt10 of US water supplies have high levels)
bull Rice (naturally absorbs if in the water)
bull Chicken (added to make meat whiter)
Pan W-C Seow WJ Kile ML et al Association of low to moderate levels of arsenic exposure with risk of Type 2 diabetes in Bangladesh American Journal of Epidemiology 2013178(10)1563-70
Portion of Population with Toxin Load Which
Doubles Disease Risk
Toxin Disease with Doubled Risk
Polycyclic aromatic hydrocarbons Asthma 94
PCB187 Breast Cancer 60
Phthalates Diabetes 55
Lead ALS 33
Aluminum Alzheimers Disease 25
DDT ADHD 25
PCBs Diabetes 25
Dioxin-like PCBs Rheumatoid Arthritis 25
Arsenic Gout 23
Bisphenol A Diabetes 22
Cigarette smoking Lung Cancer 21
Arsenic Diabetes 20
Polycyclic aromatic hydrocarbons Diabetes 20
Huge Detoxification Variability
bull CYP2C19
Proton pump inhibitors and some antidepressants
5-fold difference in activity between poor metabolizers and extensive metabolizers more so if CYP3A4 is also inhibited
Ultrarapid allele in 18 of both Swedes and Ethiopians
bull CYP2D6
Metabolizes a large number of drugs (~25)
7 of Caucasians poor metabolizers
~30 ultra rapid metabolizers in Arabian and Eastern African populations
More adverse effects in poor metabolizers and ineffective dosing in ultrarapid metabolizers
Inhibited by ginger
Desta Z et al Clinical significance of the cytochrome P450 2C19 genetic polymorphism Clin Pharmaco 2002
Sim SC et al A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug
response to proton pump inhibitors and antidepressants Clin Pharmacol Ther 2006
Wilkinson GR Drug metabolism and variability among patients in drug response N Engl J Med 2005
Kirchheiner J et al Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to
CYP2D6 duplication Pharmacogenomics J 2007
Toxin Half Lives in BloodToxin ldquoNormalrdquo (mgL) Acute Toxic (mgL) Half-Life
Arsenic 0002-007 005-025 2-4 days (CDC)
Benzene 00002 05-10 days
Cadmium 00003-00065 0015-005 16 years
Chlordane 0001 00025 3-4 days
DDTDDE 2-10 years
Dieldrin 00015 015-030 2-12 months
Ethanol 1000-2000 15hour
Lead 009 04-06 1-15 mo (2+ yrs bone)
Mercury 00015-0002 005-02 2 months (CDC)
PCBs 3-25 years
Toluene 05-3 days
Schulz M et al Therapeutic and toxic blood concentrations of nearly 1000 drugs and other xenobiotics Crit Care 2012 Jul 2616(4)R136
Bioaccumulation (POPs)
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
DDT banned in 1972 PCBs banned in 1977
Bioaccumulation (Cd)
Think BroadlyExogenous
Metals
Chemicalsbull Inorganic
bull Fluoride
bull Organic
bull POPs
bull Drugs
Particulate matter
Molds
Microbial
Radiationbull Light
bull Medical
bull Cell phone
Endogenous
Gut-derived toxins
Non-end product metabolites
Poorly detoxified hormones
Catecholamines (if SNP)
Toxins of Choice
Alcohol
Marijuana
Food constituents
High fructose corn syrup
Salt (acid-forming diet)
Wheat if zonulin (70)
Obesity Epidemic ndash POPs AND HFCS
47Bray GA Fructose should we worry Int J Obes (Lond) 2008 Dec32 Suppl 7S127-31
How Toxins Cause Damage 13
bull Increase free radical production
Cd induces production of ROS
Malathion inhibits catalase and glutathione peroxidase
Homocysteine oxidizes LDL cholesterol
bull Poison enzyme systems (compete with nutritional cofactors for binding sites)
Pb poisons delta aminolevulinic acid dehydratase
Cd inhibits catalase glutathione reductase and lowers
glutathione levels
bull Replace structural minerals
Pb displaces Ca in bone
How Toxins Cause Damage 23
bull Damage DNA
Benzene - causes chromosomal damage
Pesticides ndash fruit growers have more DNA damage
Phthalates and insecticides ndash damage sperm DNA
4-hydroxy catechol estrogen (4-OHE) damages breast DNA
bull Epigenetic dysmodulation
Higher cord blood levels of hexachlorobenzene associated
with 2x greater risk for obesity in children
bull Damage cell membranes
Common mechanism for heavy metals inactivates
membrane enzymes ion channels and pumps
How Toxins Cause Damage 33
bull Block insulin receptor sites
PCBs and phthalates
bull Highest levels associated with a 4 to 20-fold greater diabetes risk
bull Imbalance hormones many toxin examples
Arsenic
bull Disrupts thyroid hormone and retinoic acid receptors
Phthalates
bull Act as anti-androgens
bull More than 75 of the US population has measurable levels of
several phthalate metabolites in the urine
PCBs
bull Lower testosterone levels in men
Which are the Worst Toxins
bull According to the CDC
Toxicity
Population toxic load
Prevalence in toxic waste sites
bull According to clinical importance
Exposure
of disease
Ability of the body to detoxifyexcrete
Ag
en
cy
fo
r T
oxic
Su
bs
tan
ce
s a
nd
Dis
ea
se
Reg
istr
y
Pri
ori
ty L
ist
The Worst Toxins Clinically
My Rank Toxin Diseases Primary Sources
1 Arsenic Cancers diabetes gout Water chicken rice
2 DDT ADHD dementia diabetes Everywhere
3 Phthalates ADHD diabetes Soft plastics HABAs
4 PBDEs ADHD diabetes Flame retardant fabrics
5 PAHs ADHD cancers dyslipidemia Smoking charbroiling
6 PCBs Cancers diabetes MI RA Everywhere
7 Mercury Dementia ldquoSilverrdquo fillings fish
8 Lead Cardiovascular disease IQ Paint water
Glyphosate Research invalid
Conventional Laboratory Tests Reflect
Toxic Load in ldquoNormalrdquo Range
bull Surprising number show toxin exposure
CBC RBC WBC platelet count hemoglobin basophilic
stippling
Liver enzymes ALT GGTP
Inflammatory markers CRP
Lipids LDL oxLDL triglycerides
Blood sugar insulin FBS 2-hour PP
Metabolites bilirubin uric acid homocysteine 8-OHdG
Thyroid T3 T4 TSH
bull The historic ldquonormalrdquo range has been changing as the population has become more toxic
WBC Lowered by PCB and OCP Exposure
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
0
1
2
3
4
5
6
7
8
1st Quartrile 2nd Quartile 3rd Quartile 4th Quartile
WBCbull Strong inverse correlation with PCBs and OCPs and CBC
bull Linear with almost all PCBs
bull High variability with OCPs
bull Within ldquonormalrdquo range
Effects on WBC Worsen with Years
of Exposure to Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Platelet Count Decreases with Years
of Exposure tp Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Solvents Decrease Platelet Count
bull Compared workers exposed 23 hrday to those exposed most of day to toluene
bull All wore face masks and protective gear
bull Platelet count 14 lower 252 versus 216ml
bull Impairment of sympathetic nerves (OR = 413)
bull Impairment of peripheral nerves (OR = 694)
bull Positive relationship between neurological abnormalities and a self-reported neuropsychiatric measurement (r = 035-066)
Shih HT et al Subclinical abnormalities in workers with continuous low-level toluene exposure Toxicol Ind Health 2011 Sep27(8)691-9
Basophilic Stippling of Red Cells
Toxinsbull Arsenic
bull Lead
Diseasesbull Alpha-thalassemia HbH Disease
bull Beta thalassemia
bull Hereditary pyrimidine 5-nucleotidase deficiency
bull Myelodysplastic syndrome
bull Sideroblastic anemia
bull Thrombotic thrombocytopenic purpura
GGT Indirect Measure of POPsbull Glutathione is key intracellular defense against oxidative stress
bull Cellular GGT metabolizes extracellular GSH allowing precursor amino acids to be reutilized for intracellular GSH
bull Exposure to POPs induces GGT as a defensive mechanism
bull Within normal range predicts type 2 diabetes coronary heart disease hypertension stroke dyslipidemia chronic kidney disease and cancer
bull Men with GGT gt50 UI had ~26 fold risk for diabetes compared to those with lt10 Those with 40-49 had a ~20 fold risk
bull Levels within normal range occur with obesity xs alcohol cigarette smoking physical inactivity high meat low fruit and vegetable intake
bull Cumulative biomarker for environmental pollutants
Lee DH et al (2003) Gamma-glutamyltransferase and diabetesmdasha 4 year follow-up study Diabetologia 46359ndash364
Pamela A et al Serum gamma-glutamyltransferase linking together environmental pollution redox equilibria and progression of atherosclerosis Clin Chem
Lab Med 200947(12)1583-4
Lee DH et al Serum gamma-glutamyltransferase new insights about an old enzyme J Epidemiol Community Health 2009 Nov63(11)884-6
Lee DH et alSerum gamma-glutamyltransferase predicts non-fatal myocardial infarction and fatal coronary heart disease among 28838 middle-aged men and
women Eur Heart J 2006272170ndash6
Lee DH et al Gamma-glutamyltransferase and diabetes--a 4 year follow-up study Diabetologia 2003 Mar46(3)359-64
Lee DH et al Can persistent organic pollutants explain the association between serum gamma-glutamyltransferase and type 2 diabetes Diabetologia 2008
Mar51(3)402-7
GGT and Alcohol Consumption
bull GGT directly correlates with alcohol consumption
bull In a non-uniform population 40 gd will elevate GGT ~15
bull Watch for false negatives
bull Genomic variation
bull Are these the ones most
sensitive todamaged by
chemical toxins
bull Could up-regulation of GGT in light alcohol consumption be reason for benefit
0
10
20
30
40
50
60
70
80
0 200 400 600 800
Grams of Ethanol per Week
Adapted from Nagaya T et al Dose-response relationships between drinking and serum tests in Japanese men
aged 40ndash59 years Alcohol 1999 Feb 17(2) 133ndash8
GGT Correlates With Toxic Metal Levels
Lee DH et al Graded associations of blood lead and urinary cadmium concentrations with oxidative-stress-related markers in the
US population results from the third National Health and Nutrition Examination Survey Environ Health
perspect 2006 Mar114(3)350-4
GGT and Diabetes Risk
0
5
10
15
20
25
30
lt10 10-19 20-29 30-39 40-49 gt50
Dia
bete
s R
isk
GGT
bull GGT over 50 associated with tripling of death rate
bull 30-40 associated with doubling
GGT Levels
Correlate with
Risk of Death
Brenner H et al Distribution determinants and prognostic value of gamma-glutamyltransferase for all-cause
mortality in a cohort of construction workers from southern Germany Prev Med 1997 26 305ndash10
GGT From Small US Company
with Young Workers
0
10
20
30
40
50
60
0 20 40 60 80 100
GGT Data from Canadian Oil Field
Workers
0
50
100
150
200
250
300
350
400
450
lt10 10-20 20-30 30-40 40-50 50-60 60-07 70-80 80-90 90-100 100-110 110-120 gt120
GGTP
20-fold increased risk of diabetes
Uric Acid Indirect Measure of POPs
bull Poly-fluorinated hydrocarbons (PFOA and PFOS) associated
with increased serum uric acid
Lin CY et al Association among serum perfluoroalkyl chemicals glucose homeostasis and metabolic syndrome
in adolescents and adults Diabetes Care 2009 Apr32(4)702-7
Steenland K et al Association of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) with uric
acid among adults with elevated community exposure to PFOA Environ Health Perspect 2010 Feb118229-33
Steenland 2010 Open Access
ALT Indirect Measure of POPs
bull ALT (proxy marker) elevation in 104 (not including viral
hepatitis hemochromatosis or alcoholic liver disease) of
NHANES 03-04 subset
bull Risk of elevated ALT increased dose-dependently with
cadmium lead mercury and PCB exposure
bull 100 of individuals had detectable PCBs 925 mercury
and 996 had detectable lead
bull In 2005-08 prevalence of NAFLD in US was 11 a
growing cause of chronic liver disease
Cave M et al Polychlorinated biphenyls lead and mercury are associated with liver disease in American adults
NHANES 2003-2004 Environ Health Perspect 2010 Dec118(12)1735-42
Younossi ZM et al Changes in the prevalence of the most common causes of chronic liver diseases in the United
States from 1988 to 2008 Clin Gastroenterol Hepatol 2011 Jun9(6)524-530e1
Bilirubin as a Marker of POPs
bull Degree of serum bilirubin increase is prognostically significant in chronic liver dysfunction
bull Mono-ortho PCB TEQ values were found to be significantly positively associated with bilirubin (β=071 P=0008) following adjustment for multiple potential confounders
bull Bilirubin levels significantly correlated with PCBs -105-118-126 and -194
bull Smoking appears to be the biggest confounder
Dufour DR et al 2000 Diagnosis and monitoring of hepatic injury II Recommendations for use of laboratory
tests in screening diagnosis and monitoring Clin Chem 46 2050ndash68
Kumar J et al Persistent organic pollutants and liver dysfunction biomarkers in a population-based human sample
of men and women Environ Res 2014134251-256
Perf
luo
rin
ate
dP
OP
s a
nd
Co
mm
on
Blo
od
Tests
Gleason JA et al Associations of perfluorinated chemical serum concentrations and biomarkers of liver function and uric acid in the
US population (NHANES) 2007-2010 Environ Res 20151368-14
Liver Enzymes Reflect Toxic Load
bull AST ALT and GGT increase with body load of PCBs and OCPs
bull Some non-linear
bull Oxychlordanetop quartile
ALT 10
GGT 25
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
LDL-Cholesterol as Measure of POPs
bull 5-year prospective study to determine if POP levels predict future elevation in LDL-cholesterol
bull 598 subjects initially at age 70
bull Looked at 23 POPs
bull Best correlation with PCB 194
Penell J Lind L Salihovic S et al Persistent organic pollutants are related to change in circulating
lipid levels during a 5 year follow-up Environ Res 134(2014)190ndash197
oxLDL as Measure of POPs
bull 992 70-year old individuals (50 women)
bull Sum of PCBs showed strong significant positive associations with ox-LDL and significant negative associations with glutathione-related markers (GSSG and GSSGGSH)
bull A number of POPs (PCB-99 138 153 156 170 180 194 206 and 209) showed strong significant positive association with ox-LDL
Kumar J et al Influence of persistent organic pollutants on oxidative stress in population-based samples
Chemosphere 2014114303-309
Homocysteine is Increased by Pb amp Cd
Guallar E et al Confounding of the relation between homocysteine and peripheral arterial disease by lead cadmium and renal function Am J Epidemiol 2006 Apr 15163(8)700-8
Nutrient Deficiencies Accentuate
Effects of Lead on Homocysteine
bull Deficiencies in folate B6 or B12 make lead more toxic
Lee YM Et al Association of homocysteine levels with blood lead levels and micronutrients in the US general population J Prev Med Public Health 2012 Nov45(6)387-93
T4 amp T3 and PCBs
bull PCBs decrease T4 production
bull PCBs inhibit iodotyrosinedeiodinase activity
bull Study done in pregnant women which implies effect on fetus IQ
Kim S Park J Kim HJ et al Association between several persistent organic pollutants and thyroid hormone levels in serum among the pregnant women of Korea Environ Int 2013 Sep59442-8Shimizu R Yamaguchi M Uramaru N et al Structure-activity relationships of 44 halogenated compounds for iodotyrosinedeiodinase-inhibitory activity Toxicology 2013 Dec 6314(1)22-9
T4 amp T3 and PCBs
bull Not just humans being affected
bull Large study of dolphins shows exactly the same effects
Schwacke LH Zolman ES Balmer BC et al Anaemia hypothyroidism and immune suppression associated with polychlorinated biphenyl exposure in bottlenose dolphins (Tursiops truncatus) Proceed Royal Society B doi101098rspb20110665
8-OHdG
bull Oxidized nucleoside
bull Direct measure of DNA damage
bull Indirect measure of oxidative stress and toxin load
bull Correlates with
Multiple cancers
Mitochondrial damage
Rate of aging
Smoking
Several toxinsWalter Crinnion ldquoTotal Toxic Loadrdquo AANP 2015
8-OHdG Correlates with Pack-Years
of Smoking
Yano T et al Significance of the urinary 8-OHdG level as an oxidative stress marker in lung cancer patients Lung Cancer
2009 Jan63(1)111-4
8-OHdG Correlates
with Mercury
Chen C et al Increased oxidative DNA damage as assessed by urinary 8-hydroxy-2-deoxyguanosine
concentrations and serum redox status in persons exposed to mercury Clin Chem 2005 Apr51(4)759-67
Toxin Effects Worse with Aging
bull Thyroid function decreases with PFOA levels
bull But only after age 63
Shrestha S Bloom MS Yucel R et al Perfluoroalkyl substances and thyroid function in older adults Environ Int 2015 Feb75206-14
Insightful 23-Year Prospective Study
1 lt 50 there is no difference between those with the lowest and highest PCBs
2 In youngest group insulin production increases in response to toxin level As expected since blocking of
insulin receptor sites by PCBs
requires more insulin
3 That adaptive ability decreases with aging
4 At age 50 all the measures show very strong toxin-dose response
Cumulative damage impairs ability to adapt
Suarez-Lopez JR et al Persistent organic pollutants in young adults and changes in glucose related metabolism over a 23-year follow-up Environ Res 2015 Feb137485-94
Recommendations
High body toxic load
GGT gt 25
Uric acid gt 50 mgdl
ALT gt30 UL
Bilirubin gt08 mgdl
CBC lt 6000
Platelet lt 250000
Low T3 andor T4
Monitor Total Toxic Load
8-OHdG gt4
ldquoUnconventionalrdquo Laboratory Tests
bull Challenge testing
bull Hair analysis
bull Direct measures of solvents and POPs in blood urine adipose tissue
Evaluation of Metal Exposure ndash Provocation
bull Provocation ndash the use of a chelating agent ndash before urine collection often done clinically but several limitations
No ldquoofficialrdquo reference range for provoked urine
Most chelating agents do not extract metals from all tissues thus
does not necessarily represent total body burden
bull Example Brain is one of the main target organs for both elemental and organic
mercury yet agents do not chelate brain mercury
bull Despite limitations widely used and advocated by clinicians in part to see efficacy of chelating agent as a guide to treatment and based on empirical evidence
Rooney JP The role of thiols dithiols nutritional factors and interacting ligands in the toxicology of mercury
Toxicology 2007
Is Challenge Testing Valid
bull Poor correlations of standard tests for mercury
bull Unpublished research from corporate wellness project
bull Published amalgam number correlation
bull Published fish consumption correlation
What We Found In Canada
bull Deviations from the mean of 14 29 and 91 respectively
bull DMPS is spreading distribution suggesting that it is better at differentiating mercury body load
bull Some VERY high
Hg Assessment Correlations
bull Extensive measurements in 65 Whole blood Hg
Oral DMPS challenge
Amalgam surfaces
bull Correlations Whole blood w pre urine r = 040
Whole blood w post urine r = 057
Pre urine w post urine r = 068
Amalgams w pre urine r = 026
Amalgams w whole blood r = 036
Amalgams with post urine 044
bull Clear documentation that
challenge testing is better00
100
200
300
400
500
600
0 10 20 30 40 50
Po
st
Uri
ne H
g u
gg
Number of amalgams
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
Kidney Disease Epidemic
Stevens L httpwwwslidesharenetringer21liaison-meeting-esrd-presentation (accessed 616)
Dia
be
tes
Ep
ide
mic
Diabetes Increasing World-Wide
SourcesAIHW analysis of ABS NHS 1989ndash90 1995 2001 2004ndash05 and 2007ndash08 NHS (reissue) and ABS 2011ndash12 Australian
Health Survey data (Release 7 June 2013)
Co-ordinaring Committee Epidemiology Study of Childhood amp Adolescent Diabetes Hong Kong KF Huen et al
Australian Adults
Childhood diabetes in Hong Kong
WHY THE CHRONIC DISEASE
EPIDEMICS
Increase in Diabetes Due to Sugar
httpwholehealthsourceblogspotcom201202by-2606-us-diet-will-be-100-percenthtml
Dia
bete
s 1
How About Persistent Organic Pollutants
Neel BA Robert M Sargis RM The paradox of progress Environmental disruption of metabolism and the diabetes epidemic DIABETES 2011 601838-48
Lars Jaumlrup Br Med Bull 200368167-182copy The British Council 2003 all rights reserved
Global Production and Consumption of
Selected Toxic Metals 1850ndash1990
Cadmium World Production
Mercury in the Air
EPA-452R-97-003 December 1997
Mercury in Water
httpwaterepagovscitechdataitmodelsmapspostercfm
Ground Water Sources of Arsenic
bull 10 of US public water supplies have levels of arsenic known to induce disease
bull No data on private water supplies
httpwwwatsdrcdcgovcsemarsenicdocsarsenicpdf (accessed 2015-08-18)
Example POPs
Chemical Abbr Uses Exposure
Bisphenol A BPA Plastics Canned food
Organochlorine
pesticides
OCPs Pesticide Food fumigation
Organophosphate
pesticides
OPPs Pesticide Food
Polybrominated
diphenyl ethers
PBDEs Flame retardant Clothing
Polychlorinated
biphenyls
PCBs Industrial Everywhere
Perflourinated PFOAs Non-stick stain prevention
water repellant
Teflon Gortex
Scotchguard
Phthalates Plastics fragrances Shower curtains
cosmetics
POPs - Prediabetes
bull Over 1200 participants fasting
glucose and OGTT performed
with serum levels of 5 POPs
bull All individual POPs tested were
associated with progressive
increase in prevalence of
prediabetes
bull More than triple prevalence of
prediabetes seen in those in the
5th quartile with a synergistic
effect from 5 POPs
Ukropec J et al High prevalence of prediabetes and diabetes in a population exposed to high levels of an organochlorine cocktail
Diabetologia 2010 May53(5)899-906
POPs and Diabetes Risk
Graph httpwwwourstolenfutureorgNewScienceobesity20062006-0715leeetalhtml
Data Lee DH Lee IK Song K et al A strong dose-response relation between serum
concentrations of persistent organic pollutants and diabetes results from the National Health and
Examination Survey 1999-2002 Diabetes Care 2006 Jul29(7)1638-44
Toxic Load and Disease Risk
References for Toxins and Disease Risk
Converting Disease Risk to Caused
Attributable Fraction Calculation
p = underlying prevalence of risk factor in the population
rr = relative risk (risk of contracting a disease in an exposed population divided by the risk of contracting the disease in an unexposed population)
AF = of disease due to the toxin
Levin M The occurrence of lung cancer in man Acta Unio Int Contra Cancrum 1953 9 531-541
Example Smoking and Lung Cancer
B = 5Number of smokers
who contract Lung Cancer notdue to smoking
A = 5Number of smokerswho contract Lung
Cancer due to smoking
C = 15Number of
nonsmokerswho contract Lung Cancer
0
2
4
6
8
10
12
14
16
Smokers (N=100) Nonsmokers (N=300)Num
ber
of
people
who c
ontr
act
Lung C
ancer
per
year
Baseline Additional due to smoking
Number of smokers and nonsmokers who contract lung cancer
Our Process In Summary
1 Determine threshold for increased disease risk
2 Determine of population above threshold
3 Determine incidence of disease (OR) in those above threshold
4 Determine incidence of disease in ldquounexposed populationrdquo
5 Calculate AF ie of disease
As whole population is exposed probably UNDERESTIMATES of disease
To
xic
ity H
as B
eco
me t
he N
ew
ldquoN
orm
alrdquo
Toxin Type Use Threshold for
disease
association
of US
above
threshold
Disease Associations
Chlordane OC pesticide Termites corn citrus lawns
gardens
145ngg lipid 63
(diabetes)
Diabetes (20)
BPA Plasticizer Water bottles canned food
water pipes thermal sales
receipts
48 men 51
women (urine
ngmL)
~18
(diabetes)
Diabetes hypertension
Octachloro
dibenzo-p-
dioxin
(OCDD)
Polychlorinated
dibenzo-p-
dioxin
Incineration or burning of
waste bleaching processes
used in pulp and paper mills
1010 pgg
lipid (highest
quartile)
10-25
(hypertensio
n)
Hypertension (79 for
women highest
quartile) diabetes (21)
obesity learning
disability (272)
MEP
(mono-
ethyl
phthalate)
Phthalate
(plasticizer
fragrance)
Toothbrushes automobile
parts tools toys and food
packaging aspirin
cosmetics food packaging
gt175 ngmL
(urine)
~60
(diabetes)
Diabetes (148) lower
BMD obesity
pp-DDE DDT
metabolite (OC
pesticide)
Agricultural crops 1560ngg
lipid
25
(diabetes)
Diabetes (23-43)
early menopause
impaired cognitive
function (2-3x 65x in
highest 5th percentile)
peripheral arterial
disease
Arsenic Toxic metal Miningsmelting wood
preservative pesticides
74ugL total
arsenic (urine)
20
(diabetes)
Cancers diabetes (26-
46) dyslipidemia gout
AF OR Prevalence
Rosen L An intuitive approach to understanding the attributable fraction of disease due to a risk factor the case of smoking Int J Environ Res Public Health 2013 Jul 1610(7)2932-43
Smoking Lung cancer
Arsenic Gout in women
BPA Diabetes
Status of Our Research
bull 26 toxins and toxin classes eg lead mercury BPA OCPs
100s of chemicals and POPs in some classes
bull 18 cancers
bull 24 chronic diseases
bull 1092 cells in spreadsheet
Large Personal Ongoing Research Investment
Huge Amount of Research Work
Toxins StudiedAluminum
Arsenic
Cadmium
Fluoride
Lead
Manganese
Mercury
Acrylamide
Acrylonitrile
Benzene
Bisphenol A (BPA)
Chloroform
DDT
Dioxins
Glyphosate
Organochlorine pesticides (OCPs)
Organophosphate pesticides
Parabens
Phthalates
Polybrominated diphenyl ethers (PBDEs)
Polycyclic aromatic hydrocarbons (PAHs)
Polychlorinated biphenols (PCBs)
Vinyl chloride
Diseases Studied
ADHD
Alzheimers Disease
ALS
Angiosarcoma
Anxiety
Atopic Conditions
Diabetes
Dyslipidemia
Gout
Fetal Abnormalities
Hyperuricemia
Infertility
Juvenile IQ
Cancer Bladder
Cancer Bone
Cancer Brain
Cancer Breast
Cancer Cervix
Cancer Colorectal
Cancer Endometrial
Cancer Head amp Neck
Cancer Liver
Cancer Lung
Cancer Lymph amp Blood
Cancer Ovarian
Cancer Pancreatic
Cancer Prostate
Cancer Renal
Cancer Skin
Cancer Testicular
Cancer Thyroid
Juvenile Obesity
Metabolic Syndrome
Mitochondrial dysfunction
Myocardial Infarction
Obstructive Lung Disease
Osteoporosis
Peripheral Artery Disease
Peripheral Neuropathy
Prediabetes
Renal Disease
Rheumatoid Arthritis
Thyroid Dysfunction
OC
Ps
Th
rou
gh
ou
t th
e W
orl
d
Rathore HS Nollet LML Pesticides Evaluation of Environmental Pollution CRC Press
2012 page 562
Threshold ndash Threshold exposure at which there is an increased risk of disease outcome
Above Threshold ndash Percentage of the population with higher exposure than the threshold
Odds Ratio ndash Increased disease risk in those above threshold
of Dz ndash Percent contribution of the toxin to that disease outcome
How to Interpret the Following Slides
Attention Deficit Hyperactivity Disorder
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
DDT 126 ngg
serum (pp-
DDE)
250 18 166 20106937
Lead 23 ugdL 13 254 20 27659349
Mercury 16 24952233
Organophosphate
pesticides
20
Polycyclic
Aromatic
Hydrocarbons
227 ngm3 940 125 190 22440811
PCBs 104 ngg
serum (sum
of 50 PCBs)
250 176 160 20106937
DiabetesToxin Threshold Above
Threshold
Odds
Ratio
of Dz Reference
PMID
Arsenic 165 ugL 200 21 180 18714061
BPA 28 ugL 280 145 112 26119400
DDE 545 ngg serum
(pp-DDE)
200 230 31 26119400
Dioxins2 pgg lipid 50 191 43
26119400
PCBs104 ngg (PCB 153) 250 239 258
26119400
Phthalates175 ugL 690 148 249
26119400
1-naphthalene 167 ugdL 152 182 111 26340343
2-napthalene 414 ugdL 550 224 214 26340343
1-phenanthrene 167 ngL 570 178 151 26340343
1-pyrene 85 ngL 660 180 174 26340343
Lung Cancer
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Acrylonitrile Uncertain Uncertain 125 25
occupational
exposure
17114112
Arsenic 1213 ugL 436 of Asian
Americans
~01 of total
US population
34 95 in AA
01-1
PMC2682945
Cadmium Uncertain+ Uncertain 467 10 in
smokers
17184399
DDT Any exposure All US pop
below LOD
17 76 increased
risk
8923607
Breast Cancer
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Cadmium 0580 ugg
creatinine
126 205 479 16788160
PCB 138 396 ngg
creatinine
202 316 630 27717745
PCB 187 108 ngg lipid 600 194 360 21480306
Miscellaneous Diseases
Toxin Disease Threshold Above
Threshold
Odds
Ratio
of Dz Reference PMID
Aluminum Alzheimer
Dz
01 mgL
drinking
H20
400 203 05-44 26592479
Benzene AML 100ppmyrs 1-3 320 60 PMC2903550
DDT NHL 0512 ugL 1-2 240 01 17722095
Lead ALS 238 ugdL
blood
330 181 210 25479292
Lead Brain CA 0005 ugdL 14 19 ~500 17164378
Dioxin-like
PCBs
RA 326 ngg
lipid
250 219 220 17589595
PAHs Asthma 124 ngm3 935 200 483 19221603
The Potency of Arsenic
Disease Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Bladder CA 10ugL H20 100 27 145 24889821
Pancreatic CA 1332 ugg 200 246 230 23800676
Prostate CA 1332 ugg 200 33 315 23800676
Gout 125 ugL 245 546 522 25499256
Diabetes 165 ugL 200 21 180 18714061
Arsenic (180 of Diabetes)
How it causes diabetes
bull Blocks sugar stimulating insulin secretion
bull Epigenetic inhibition of sugar regulation
Where it comes from
bull Water (gt10 of US water supplies have high levels)
bull Rice (naturally absorbs if in the water)
bull Chicken (added to make meat whiter)
Pan W-C Seow WJ Kile ML et al Association of low to moderate levels of arsenic exposure with risk of Type 2 diabetes in Bangladesh American Journal of Epidemiology 2013178(10)1563-70
Portion of Population with Toxin Load Which
Doubles Disease Risk
Toxin Disease with Doubled Risk
Polycyclic aromatic hydrocarbons Asthma 94
PCB187 Breast Cancer 60
Phthalates Diabetes 55
Lead ALS 33
Aluminum Alzheimers Disease 25
DDT ADHD 25
PCBs Diabetes 25
Dioxin-like PCBs Rheumatoid Arthritis 25
Arsenic Gout 23
Bisphenol A Diabetes 22
Cigarette smoking Lung Cancer 21
Arsenic Diabetes 20
Polycyclic aromatic hydrocarbons Diabetes 20
Huge Detoxification Variability
bull CYP2C19
Proton pump inhibitors and some antidepressants
5-fold difference in activity between poor metabolizers and extensive metabolizers more so if CYP3A4 is also inhibited
Ultrarapid allele in 18 of both Swedes and Ethiopians
bull CYP2D6
Metabolizes a large number of drugs (~25)
7 of Caucasians poor metabolizers
~30 ultra rapid metabolizers in Arabian and Eastern African populations
More adverse effects in poor metabolizers and ineffective dosing in ultrarapid metabolizers
Inhibited by ginger
Desta Z et al Clinical significance of the cytochrome P450 2C19 genetic polymorphism Clin Pharmaco 2002
Sim SC et al A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug
response to proton pump inhibitors and antidepressants Clin Pharmacol Ther 2006
Wilkinson GR Drug metabolism and variability among patients in drug response N Engl J Med 2005
Kirchheiner J et al Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to
CYP2D6 duplication Pharmacogenomics J 2007
Toxin Half Lives in BloodToxin ldquoNormalrdquo (mgL) Acute Toxic (mgL) Half-Life
Arsenic 0002-007 005-025 2-4 days (CDC)
Benzene 00002 05-10 days
Cadmium 00003-00065 0015-005 16 years
Chlordane 0001 00025 3-4 days
DDTDDE 2-10 years
Dieldrin 00015 015-030 2-12 months
Ethanol 1000-2000 15hour
Lead 009 04-06 1-15 mo (2+ yrs bone)
Mercury 00015-0002 005-02 2 months (CDC)
PCBs 3-25 years
Toluene 05-3 days
Schulz M et al Therapeutic and toxic blood concentrations of nearly 1000 drugs and other xenobiotics Crit Care 2012 Jul 2616(4)R136
Bioaccumulation (POPs)
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
DDT banned in 1972 PCBs banned in 1977
Bioaccumulation (Cd)
Think BroadlyExogenous
Metals
Chemicalsbull Inorganic
bull Fluoride
bull Organic
bull POPs
bull Drugs
Particulate matter
Molds
Microbial
Radiationbull Light
bull Medical
bull Cell phone
Endogenous
Gut-derived toxins
Non-end product metabolites
Poorly detoxified hormones
Catecholamines (if SNP)
Toxins of Choice
Alcohol
Marijuana
Food constituents
High fructose corn syrup
Salt (acid-forming diet)
Wheat if zonulin (70)
Obesity Epidemic ndash POPs AND HFCS
47Bray GA Fructose should we worry Int J Obes (Lond) 2008 Dec32 Suppl 7S127-31
How Toxins Cause Damage 13
bull Increase free radical production
Cd induces production of ROS
Malathion inhibits catalase and glutathione peroxidase
Homocysteine oxidizes LDL cholesterol
bull Poison enzyme systems (compete with nutritional cofactors for binding sites)
Pb poisons delta aminolevulinic acid dehydratase
Cd inhibits catalase glutathione reductase and lowers
glutathione levels
bull Replace structural minerals
Pb displaces Ca in bone
How Toxins Cause Damage 23
bull Damage DNA
Benzene - causes chromosomal damage
Pesticides ndash fruit growers have more DNA damage
Phthalates and insecticides ndash damage sperm DNA
4-hydroxy catechol estrogen (4-OHE) damages breast DNA
bull Epigenetic dysmodulation
Higher cord blood levels of hexachlorobenzene associated
with 2x greater risk for obesity in children
bull Damage cell membranes
Common mechanism for heavy metals inactivates
membrane enzymes ion channels and pumps
How Toxins Cause Damage 33
bull Block insulin receptor sites
PCBs and phthalates
bull Highest levels associated with a 4 to 20-fold greater diabetes risk
bull Imbalance hormones many toxin examples
Arsenic
bull Disrupts thyroid hormone and retinoic acid receptors
Phthalates
bull Act as anti-androgens
bull More than 75 of the US population has measurable levels of
several phthalate metabolites in the urine
PCBs
bull Lower testosterone levels in men
Which are the Worst Toxins
bull According to the CDC
Toxicity
Population toxic load
Prevalence in toxic waste sites
bull According to clinical importance
Exposure
of disease
Ability of the body to detoxifyexcrete
Ag
en
cy
fo
r T
oxic
Su
bs
tan
ce
s a
nd
Dis
ea
se
Reg
istr
y
Pri
ori
ty L
ist
The Worst Toxins Clinically
My Rank Toxin Diseases Primary Sources
1 Arsenic Cancers diabetes gout Water chicken rice
2 DDT ADHD dementia diabetes Everywhere
3 Phthalates ADHD diabetes Soft plastics HABAs
4 PBDEs ADHD diabetes Flame retardant fabrics
5 PAHs ADHD cancers dyslipidemia Smoking charbroiling
6 PCBs Cancers diabetes MI RA Everywhere
7 Mercury Dementia ldquoSilverrdquo fillings fish
8 Lead Cardiovascular disease IQ Paint water
Glyphosate Research invalid
Conventional Laboratory Tests Reflect
Toxic Load in ldquoNormalrdquo Range
bull Surprising number show toxin exposure
CBC RBC WBC platelet count hemoglobin basophilic
stippling
Liver enzymes ALT GGTP
Inflammatory markers CRP
Lipids LDL oxLDL triglycerides
Blood sugar insulin FBS 2-hour PP
Metabolites bilirubin uric acid homocysteine 8-OHdG
Thyroid T3 T4 TSH
bull The historic ldquonormalrdquo range has been changing as the population has become more toxic
WBC Lowered by PCB and OCP Exposure
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
0
1
2
3
4
5
6
7
8
1st Quartrile 2nd Quartile 3rd Quartile 4th Quartile
WBCbull Strong inverse correlation with PCBs and OCPs and CBC
bull Linear with almost all PCBs
bull High variability with OCPs
bull Within ldquonormalrdquo range
Effects on WBC Worsen with Years
of Exposure to Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Platelet Count Decreases with Years
of Exposure tp Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Solvents Decrease Platelet Count
bull Compared workers exposed 23 hrday to those exposed most of day to toluene
bull All wore face masks and protective gear
bull Platelet count 14 lower 252 versus 216ml
bull Impairment of sympathetic nerves (OR = 413)
bull Impairment of peripheral nerves (OR = 694)
bull Positive relationship between neurological abnormalities and a self-reported neuropsychiatric measurement (r = 035-066)
Shih HT et al Subclinical abnormalities in workers with continuous low-level toluene exposure Toxicol Ind Health 2011 Sep27(8)691-9
Basophilic Stippling of Red Cells
Toxinsbull Arsenic
bull Lead
Diseasesbull Alpha-thalassemia HbH Disease
bull Beta thalassemia
bull Hereditary pyrimidine 5-nucleotidase deficiency
bull Myelodysplastic syndrome
bull Sideroblastic anemia
bull Thrombotic thrombocytopenic purpura
GGT Indirect Measure of POPsbull Glutathione is key intracellular defense against oxidative stress
bull Cellular GGT metabolizes extracellular GSH allowing precursor amino acids to be reutilized for intracellular GSH
bull Exposure to POPs induces GGT as a defensive mechanism
bull Within normal range predicts type 2 diabetes coronary heart disease hypertension stroke dyslipidemia chronic kidney disease and cancer
bull Men with GGT gt50 UI had ~26 fold risk for diabetes compared to those with lt10 Those with 40-49 had a ~20 fold risk
bull Levels within normal range occur with obesity xs alcohol cigarette smoking physical inactivity high meat low fruit and vegetable intake
bull Cumulative biomarker for environmental pollutants
Lee DH et al (2003) Gamma-glutamyltransferase and diabetesmdasha 4 year follow-up study Diabetologia 46359ndash364
Pamela A et al Serum gamma-glutamyltransferase linking together environmental pollution redox equilibria and progression of atherosclerosis Clin Chem
Lab Med 200947(12)1583-4
Lee DH et al Serum gamma-glutamyltransferase new insights about an old enzyme J Epidemiol Community Health 2009 Nov63(11)884-6
Lee DH et alSerum gamma-glutamyltransferase predicts non-fatal myocardial infarction and fatal coronary heart disease among 28838 middle-aged men and
women Eur Heart J 2006272170ndash6
Lee DH et al Gamma-glutamyltransferase and diabetes--a 4 year follow-up study Diabetologia 2003 Mar46(3)359-64
Lee DH et al Can persistent organic pollutants explain the association between serum gamma-glutamyltransferase and type 2 diabetes Diabetologia 2008
Mar51(3)402-7
GGT and Alcohol Consumption
bull GGT directly correlates with alcohol consumption
bull In a non-uniform population 40 gd will elevate GGT ~15
bull Watch for false negatives
bull Genomic variation
bull Are these the ones most
sensitive todamaged by
chemical toxins
bull Could up-regulation of GGT in light alcohol consumption be reason for benefit
0
10
20
30
40
50
60
70
80
0 200 400 600 800
Grams of Ethanol per Week
Adapted from Nagaya T et al Dose-response relationships between drinking and serum tests in Japanese men
aged 40ndash59 years Alcohol 1999 Feb 17(2) 133ndash8
GGT Correlates With Toxic Metal Levels
Lee DH et al Graded associations of blood lead and urinary cadmium concentrations with oxidative-stress-related markers in the
US population results from the third National Health and Nutrition Examination Survey Environ Health
perspect 2006 Mar114(3)350-4
GGT and Diabetes Risk
0
5
10
15
20
25
30
lt10 10-19 20-29 30-39 40-49 gt50
Dia
bete
s R
isk
GGT
bull GGT over 50 associated with tripling of death rate
bull 30-40 associated with doubling
GGT Levels
Correlate with
Risk of Death
Brenner H et al Distribution determinants and prognostic value of gamma-glutamyltransferase for all-cause
mortality in a cohort of construction workers from southern Germany Prev Med 1997 26 305ndash10
GGT From Small US Company
with Young Workers
0
10
20
30
40
50
60
0 20 40 60 80 100
GGT Data from Canadian Oil Field
Workers
0
50
100
150
200
250
300
350
400
450
lt10 10-20 20-30 30-40 40-50 50-60 60-07 70-80 80-90 90-100 100-110 110-120 gt120
GGTP
20-fold increased risk of diabetes
Uric Acid Indirect Measure of POPs
bull Poly-fluorinated hydrocarbons (PFOA and PFOS) associated
with increased serum uric acid
Lin CY et al Association among serum perfluoroalkyl chemicals glucose homeostasis and metabolic syndrome
in adolescents and adults Diabetes Care 2009 Apr32(4)702-7
Steenland K et al Association of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) with uric
acid among adults with elevated community exposure to PFOA Environ Health Perspect 2010 Feb118229-33
Steenland 2010 Open Access
ALT Indirect Measure of POPs
bull ALT (proxy marker) elevation in 104 (not including viral
hepatitis hemochromatosis or alcoholic liver disease) of
NHANES 03-04 subset
bull Risk of elevated ALT increased dose-dependently with
cadmium lead mercury and PCB exposure
bull 100 of individuals had detectable PCBs 925 mercury
and 996 had detectable lead
bull In 2005-08 prevalence of NAFLD in US was 11 a
growing cause of chronic liver disease
Cave M et al Polychlorinated biphenyls lead and mercury are associated with liver disease in American adults
NHANES 2003-2004 Environ Health Perspect 2010 Dec118(12)1735-42
Younossi ZM et al Changes in the prevalence of the most common causes of chronic liver diseases in the United
States from 1988 to 2008 Clin Gastroenterol Hepatol 2011 Jun9(6)524-530e1
Bilirubin as a Marker of POPs
bull Degree of serum bilirubin increase is prognostically significant in chronic liver dysfunction
bull Mono-ortho PCB TEQ values were found to be significantly positively associated with bilirubin (β=071 P=0008) following adjustment for multiple potential confounders
bull Bilirubin levels significantly correlated with PCBs -105-118-126 and -194
bull Smoking appears to be the biggest confounder
Dufour DR et al 2000 Diagnosis and monitoring of hepatic injury II Recommendations for use of laboratory
tests in screening diagnosis and monitoring Clin Chem 46 2050ndash68
Kumar J et al Persistent organic pollutants and liver dysfunction biomarkers in a population-based human sample
of men and women Environ Res 2014134251-256
Perf
luo
rin
ate
dP
OP
s a
nd
Co
mm
on
Blo
od
Tests
Gleason JA et al Associations of perfluorinated chemical serum concentrations and biomarkers of liver function and uric acid in the
US population (NHANES) 2007-2010 Environ Res 20151368-14
Liver Enzymes Reflect Toxic Load
bull AST ALT and GGT increase with body load of PCBs and OCPs
bull Some non-linear
bull Oxychlordanetop quartile
ALT 10
GGT 25
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
LDL-Cholesterol as Measure of POPs
bull 5-year prospective study to determine if POP levels predict future elevation in LDL-cholesterol
bull 598 subjects initially at age 70
bull Looked at 23 POPs
bull Best correlation with PCB 194
Penell J Lind L Salihovic S et al Persistent organic pollutants are related to change in circulating
lipid levels during a 5 year follow-up Environ Res 134(2014)190ndash197
oxLDL as Measure of POPs
bull 992 70-year old individuals (50 women)
bull Sum of PCBs showed strong significant positive associations with ox-LDL and significant negative associations with glutathione-related markers (GSSG and GSSGGSH)
bull A number of POPs (PCB-99 138 153 156 170 180 194 206 and 209) showed strong significant positive association with ox-LDL
Kumar J et al Influence of persistent organic pollutants on oxidative stress in population-based samples
Chemosphere 2014114303-309
Homocysteine is Increased by Pb amp Cd
Guallar E et al Confounding of the relation between homocysteine and peripheral arterial disease by lead cadmium and renal function Am J Epidemiol 2006 Apr 15163(8)700-8
Nutrient Deficiencies Accentuate
Effects of Lead on Homocysteine
bull Deficiencies in folate B6 or B12 make lead more toxic
Lee YM Et al Association of homocysteine levels with blood lead levels and micronutrients in the US general population J Prev Med Public Health 2012 Nov45(6)387-93
T4 amp T3 and PCBs
bull PCBs decrease T4 production
bull PCBs inhibit iodotyrosinedeiodinase activity
bull Study done in pregnant women which implies effect on fetus IQ
Kim S Park J Kim HJ et al Association between several persistent organic pollutants and thyroid hormone levels in serum among the pregnant women of Korea Environ Int 2013 Sep59442-8Shimizu R Yamaguchi M Uramaru N et al Structure-activity relationships of 44 halogenated compounds for iodotyrosinedeiodinase-inhibitory activity Toxicology 2013 Dec 6314(1)22-9
T4 amp T3 and PCBs
bull Not just humans being affected
bull Large study of dolphins shows exactly the same effects
Schwacke LH Zolman ES Balmer BC et al Anaemia hypothyroidism and immune suppression associated with polychlorinated biphenyl exposure in bottlenose dolphins (Tursiops truncatus) Proceed Royal Society B doi101098rspb20110665
8-OHdG
bull Oxidized nucleoside
bull Direct measure of DNA damage
bull Indirect measure of oxidative stress and toxin load
bull Correlates with
Multiple cancers
Mitochondrial damage
Rate of aging
Smoking
Several toxinsWalter Crinnion ldquoTotal Toxic Loadrdquo AANP 2015
8-OHdG Correlates with Pack-Years
of Smoking
Yano T et al Significance of the urinary 8-OHdG level as an oxidative stress marker in lung cancer patients Lung Cancer
2009 Jan63(1)111-4
8-OHdG Correlates
with Mercury
Chen C et al Increased oxidative DNA damage as assessed by urinary 8-hydroxy-2-deoxyguanosine
concentrations and serum redox status in persons exposed to mercury Clin Chem 2005 Apr51(4)759-67
Toxin Effects Worse with Aging
bull Thyroid function decreases with PFOA levels
bull But only after age 63
Shrestha S Bloom MS Yucel R et al Perfluoroalkyl substances and thyroid function in older adults Environ Int 2015 Feb75206-14
Insightful 23-Year Prospective Study
1 lt 50 there is no difference between those with the lowest and highest PCBs
2 In youngest group insulin production increases in response to toxin level As expected since blocking of
insulin receptor sites by PCBs
requires more insulin
3 That adaptive ability decreases with aging
4 At age 50 all the measures show very strong toxin-dose response
Cumulative damage impairs ability to adapt
Suarez-Lopez JR et al Persistent organic pollutants in young adults and changes in glucose related metabolism over a 23-year follow-up Environ Res 2015 Feb137485-94
Recommendations
High body toxic load
GGT gt 25
Uric acid gt 50 mgdl
ALT gt30 UL
Bilirubin gt08 mgdl
CBC lt 6000
Platelet lt 250000
Low T3 andor T4
Monitor Total Toxic Load
8-OHdG gt4
ldquoUnconventionalrdquo Laboratory Tests
bull Challenge testing
bull Hair analysis
bull Direct measures of solvents and POPs in blood urine adipose tissue
Evaluation of Metal Exposure ndash Provocation
bull Provocation ndash the use of a chelating agent ndash before urine collection often done clinically but several limitations
No ldquoofficialrdquo reference range for provoked urine
Most chelating agents do not extract metals from all tissues thus
does not necessarily represent total body burden
bull Example Brain is one of the main target organs for both elemental and organic
mercury yet agents do not chelate brain mercury
bull Despite limitations widely used and advocated by clinicians in part to see efficacy of chelating agent as a guide to treatment and based on empirical evidence
Rooney JP The role of thiols dithiols nutritional factors and interacting ligands in the toxicology of mercury
Toxicology 2007
Is Challenge Testing Valid
bull Poor correlations of standard tests for mercury
bull Unpublished research from corporate wellness project
bull Published amalgam number correlation
bull Published fish consumption correlation
What We Found In Canada
bull Deviations from the mean of 14 29 and 91 respectively
bull DMPS is spreading distribution suggesting that it is better at differentiating mercury body load
bull Some VERY high
Hg Assessment Correlations
bull Extensive measurements in 65 Whole blood Hg
Oral DMPS challenge
Amalgam surfaces
bull Correlations Whole blood w pre urine r = 040
Whole blood w post urine r = 057
Pre urine w post urine r = 068
Amalgams w pre urine r = 026
Amalgams w whole blood r = 036
Amalgams with post urine 044
bull Clear documentation that
challenge testing is better00
100
200
300
400
500
600
0 10 20 30 40 50
Po
st
Uri
ne H
g u
gg
Number of amalgams
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
Dia
be
tes
Ep
ide
mic
Diabetes Increasing World-Wide
SourcesAIHW analysis of ABS NHS 1989ndash90 1995 2001 2004ndash05 and 2007ndash08 NHS (reissue) and ABS 2011ndash12 Australian
Health Survey data (Release 7 June 2013)
Co-ordinaring Committee Epidemiology Study of Childhood amp Adolescent Diabetes Hong Kong KF Huen et al
Australian Adults
Childhood diabetes in Hong Kong
WHY THE CHRONIC DISEASE
EPIDEMICS
Increase in Diabetes Due to Sugar
httpwholehealthsourceblogspotcom201202by-2606-us-diet-will-be-100-percenthtml
Dia
bete
s 1
How About Persistent Organic Pollutants
Neel BA Robert M Sargis RM The paradox of progress Environmental disruption of metabolism and the diabetes epidemic DIABETES 2011 601838-48
Lars Jaumlrup Br Med Bull 200368167-182copy The British Council 2003 all rights reserved
Global Production and Consumption of
Selected Toxic Metals 1850ndash1990
Cadmium World Production
Mercury in the Air
EPA-452R-97-003 December 1997
Mercury in Water
httpwaterepagovscitechdataitmodelsmapspostercfm
Ground Water Sources of Arsenic
bull 10 of US public water supplies have levels of arsenic known to induce disease
bull No data on private water supplies
httpwwwatsdrcdcgovcsemarsenicdocsarsenicpdf (accessed 2015-08-18)
Example POPs
Chemical Abbr Uses Exposure
Bisphenol A BPA Plastics Canned food
Organochlorine
pesticides
OCPs Pesticide Food fumigation
Organophosphate
pesticides
OPPs Pesticide Food
Polybrominated
diphenyl ethers
PBDEs Flame retardant Clothing
Polychlorinated
biphenyls
PCBs Industrial Everywhere
Perflourinated PFOAs Non-stick stain prevention
water repellant
Teflon Gortex
Scotchguard
Phthalates Plastics fragrances Shower curtains
cosmetics
POPs - Prediabetes
bull Over 1200 participants fasting
glucose and OGTT performed
with serum levels of 5 POPs
bull All individual POPs tested were
associated with progressive
increase in prevalence of
prediabetes
bull More than triple prevalence of
prediabetes seen in those in the
5th quartile with a synergistic
effect from 5 POPs
Ukropec J et al High prevalence of prediabetes and diabetes in a population exposed to high levels of an organochlorine cocktail
Diabetologia 2010 May53(5)899-906
POPs and Diabetes Risk
Graph httpwwwourstolenfutureorgNewScienceobesity20062006-0715leeetalhtml
Data Lee DH Lee IK Song K et al A strong dose-response relation between serum
concentrations of persistent organic pollutants and diabetes results from the National Health and
Examination Survey 1999-2002 Diabetes Care 2006 Jul29(7)1638-44
Toxic Load and Disease Risk
References for Toxins and Disease Risk
Converting Disease Risk to Caused
Attributable Fraction Calculation
p = underlying prevalence of risk factor in the population
rr = relative risk (risk of contracting a disease in an exposed population divided by the risk of contracting the disease in an unexposed population)
AF = of disease due to the toxin
Levin M The occurrence of lung cancer in man Acta Unio Int Contra Cancrum 1953 9 531-541
Example Smoking and Lung Cancer
B = 5Number of smokers
who contract Lung Cancer notdue to smoking
A = 5Number of smokerswho contract Lung
Cancer due to smoking
C = 15Number of
nonsmokerswho contract Lung Cancer
0
2
4
6
8
10
12
14
16
Smokers (N=100) Nonsmokers (N=300)Num
ber
of
people
who c
ontr
act
Lung C
ancer
per
year
Baseline Additional due to smoking
Number of smokers and nonsmokers who contract lung cancer
Our Process In Summary
1 Determine threshold for increased disease risk
2 Determine of population above threshold
3 Determine incidence of disease (OR) in those above threshold
4 Determine incidence of disease in ldquounexposed populationrdquo
5 Calculate AF ie of disease
As whole population is exposed probably UNDERESTIMATES of disease
To
xic
ity H
as B
eco
me t
he N
ew
ldquoN
orm
alrdquo
Toxin Type Use Threshold for
disease
association
of US
above
threshold
Disease Associations
Chlordane OC pesticide Termites corn citrus lawns
gardens
145ngg lipid 63
(diabetes)
Diabetes (20)
BPA Plasticizer Water bottles canned food
water pipes thermal sales
receipts
48 men 51
women (urine
ngmL)
~18
(diabetes)
Diabetes hypertension
Octachloro
dibenzo-p-
dioxin
(OCDD)
Polychlorinated
dibenzo-p-
dioxin
Incineration or burning of
waste bleaching processes
used in pulp and paper mills
1010 pgg
lipid (highest
quartile)
10-25
(hypertensio
n)
Hypertension (79 for
women highest
quartile) diabetes (21)
obesity learning
disability (272)
MEP
(mono-
ethyl
phthalate)
Phthalate
(plasticizer
fragrance)
Toothbrushes automobile
parts tools toys and food
packaging aspirin
cosmetics food packaging
gt175 ngmL
(urine)
~60
(diabetes)
Diabetes (148) lower
BMD obesity
pp-DDE DDT
metabolite (OC
pesticide)
Agricultural crops 1560ngg
lipid
25
(diabetes)
Diabetes (23-43)
early menopause
impaired cognitive
function (2-3x 65x in
highest 5th percentile)
peripheral arterial
disease
Arsenic Toxic metal Miningsmelting wood
preservative pesticides
74ugL total
arsenic (urine)
20
(diabetes)
Cancers diabetes (26-
46) dyslipidemia gout
AF OR Prevalence
Rosen L An intuitive approach to understanding the attributable fraction of disease due to a risk factor the case of smoking Int J Environ Res Public Health 2013 Jul 1610(7)2932-43
Smoking Lung cancer
Arsenic Gout in women
BPA Diabetes
Status of Our Research
bull 26 toxins and toxin classes eg lead mercury BPA OCPs
100s of chemicals and POPs in some classes
bull 18 cancers
bull 24 chronic diseases
bull 1092 cells in spreadsheet
Large Personal Ongoing Research Investment
Huge Amount of Research Work
Toxins StudiedAluminum
Arsenic
Cadmium
Fluoride
Lead
Manganese
Mercury
Acrylamide
Acrylonitrile
Benzene
Bisphenol A (BPA)
Chloroform
DDT
Dioxins
Glyphosate
Organochlorine pesticides (OCPs)
Organophosphate pesticides
Parabens
Phthalates
Polybrominated diphenyl ethers (PBDEs)
Polycyclic aromatic hydrocarbons (PAHs)
Polychlorinated biphenols (PCBs)
Vinyl chloride
Diseases Studied
ADHD
Alzheimers Disease
ALS
Angiosarcoma
Anxiety
Atopic Conditions
Diabetes
Dyslipidemia
Gout
Fetal Abnormalities
Hyperuricemia
Infertility
Juvenile IQ
Cancer Bladder
Cancer Bone
Cancer Brain
Cancer Breast
Cancer Cervix
Cancer Colorectal
Cancer Endometrial
Cancer Head amp Neck
Cancer Liver
Cancer Lung
Cancer Lymph amp Blood
Cancer Ovarian
Cancer Pancreatic
Cancer Prostate
Cancer Renal
Cancer Skin
Cancer Testicular
Cancer Thyroid
Juvenile Obesity
Metabolic Syndrome
Mitochondrial dysfunction
Myocardial Infarction
Obstructive Lung Disease
Osteoporosis
Peripheral Artery Disease
Peripheral Neuropathy
Prediabetes
Renal Disease
Rheumatoid Arthritis
Thyroid Dysfunction
OC
Ps
Th
rou
gh
ou
t th
e W
orl
d
Rathore HS Nollet LML Pesticides Evaluation of Environmental Pollution CRC Press
2012 page 562
Threshold ndash Threshold exposure at which there is an increased risk of disease outcome
Above Threshold ndash Percentage of the population with higher exposure than the threshold
Odds Ratio ndash Increased disease risk in those above threshold
of Dz ndash Percent contribution of the toxin to that disease outcome
How to Interpret the Following Slides
Attention Deficit Hyperactivity Disorder
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
DDT 126 ngg
serum (pp-
DDE)
250 18 166 20106937
Lead 23 ugdL 13 254 20 27659349
Mercury 16 24952233
Organophosphate
pesticides
20
Polycyclic
Aromatic
Hydrocarbons
227 ngm3 940 125 190 22440811
PCBs 104 ngg
serum (sum
of 50 PCBs)
250 176 160 20106937
DiabetesToxin Threshold Above
Threshold
Odds
Ratio
of Dz Reference
PMID
Arsenic 165 ugL 200 21 180 18714061
BPA 28 ugL 280 145 112 26119400
DDE 545 ngg serum
(pp-DDE)
200 230 31 26119400
Dioxins2 pgg lipid 50 191 43
26119400
PCBs104 ngg (PCB 153) 250 239 258
26119400
Phthalates175 ugL 690 148 249
26119400
1-naphthalene 167 ugdL 152 182 111 26340343
2-napthalene 414 ugdL 550 224 214 26340343
1-phenanthrene 167 ngL 570 178 151 26340343
1-pyrene 85 ngL 660 180 174 26340343
Lung Cancer
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Acrylonitrile Uncertain Uncertain 125 25
occupational
exposure
17114112
Arsenic 1213 ugL 436 of Asian
Americans
~01 of total
US population
34 95 in AA
01-1
PMC2682945
Cadmium Uncertain+ Uncertain 467 10 in
smokers
17184399
DDT Any exposure All US pop
below LOD
17 76 increased
risk
8923607
Breast Cancer
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Cadmium 0580 ugg
creatinine
126 205 479 16788160
PCB 138 396 ngg
creatinine
202 316 630 27717745
PCB 187 108 ngg lipid 600 194 360 21480306
Miscellaneous Diseases
Toxin Disease Threshold Above
Threshold
Odds
Ratio
of Dz Reference PMID
Aluminum Alzheimer
Dz
01 mgL
drinking
H20
400 203 05-44 26592479
Benzene AML 100ppmyrs 1-3 320 60 PMC2903550
DDT NHL 0512 ugL 1-2 240 01 17722095
Lead ALS 238 ugdL
blood
330 181 210 25479292
Lead Brain CA 0005 ugdL 14 19 ~500 17164378
Dioxin-like
PCBs
RA 326 ngg
lipid
250 219 220 17589595
PAHs Asthma 124 ngm3 935 200 483 19221603
The Potency of Arsenic
Disease Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Bladder CA 10ugL H20 100 27 145 24889821
Pancreatic CA 1332 ugg 200 246 230 23800676
Prostate CA 1332 ugg 200 33 315 23800676
Gout 125 ugL 245 546 522 25499256
Diabetes 165 ugL 200 21 180 18714061
Arsenic (180 of Diabetes)
How it causes diabetes
bull Blocks sugar stimulating insulin secretion
bull Epigenetic inhibition of sugar regulation
Where it comes from
bull Water (gt10 of US water supplies have high levels)
bull Rice (naturally absorbs if in the water)
bull Chicken (added to make meat whiter)
Pan W-C Seow WJ Kile ML et al Association of low to moderate levels of arsenic exposure with risk of Type 2 diabetes in Bangladesh American Journal of Epidemiology 2013178(10)1563-70
Portion of Population with Toxin Load Which
Doubles Disease Risk
Toxin Disease with Doubled Risk
Polycyclic aromatic hydrocarbons Asthma 94
PCB187 Breast Cancer 60
Phthalates Diabetes 55
Lead ALS 33
Aluminum Alzheimers Disease 25
DDT ADHD 25
PCBs Diabetes 25
Dioxin-like PCBs Rheumatoid Arthritis 25
Arsenic Gout 23
Bisphenol A Diabetes 22
Cigarette smoking Lung Cancer 21
Arsenic Diabetes 20
Polycyclic aromatic hydrocarbons Diabetes 20
Huge Detoxification Variability
bull CYP2C19
Proton pump inhibitors and some antidepressants
5-fold difference in activity between poor metabolizers and extensive metabolizers more so if CYP3A4 is also inhibited
Ultrarapid allele in 18 of both Swedes and Ethiopians
bull CYP2D6
Metabolizes a large number of drugs (~25)
7 of Caucasians poor metabolizers
~30 ultra rapid metabolizers in Arabian and Eastern African populations
More adverse effects in poor metabolizers and ineffective dosing in ultrarapid metabolizers
Inhibited by ginger
Desta Z et al Clinical significance of the cytochrome P450 2C19 genetic polymorphism Clin Pharmaco 2002
Sim SC et al A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug
response to proton pump inhibitors and antidepressants Clin Pharmacol Ther 2006
Wilkinson GR Drug metabolism and variability among patients in drug response N Engl J Med 2005
Kirchheiner J et al Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to
CYP2D6 duplication Pharmacogenomics J 2007
Toxin Half Lives in BloodToxin ldquoNormalrdquo (mgL) Acute Toxic (mgL) Half-Life
Arsenic 0002-007 005-025 2-4 days (CDC)
Benzene 00002 05-10 days
Cadmium 00003-00065 0015-005 16 years
Chlordane 0001 00025 3-4 days
DDTDDE 2-10 years
Dieldrin 00015 015-030 2-12 months
Ethanol 1000-2000 15hour
Lead 009 04-06 1-15 mo (2+ yrs bone)
Mercury 00015-0002 005-02 2 months (CDC)
PCBs 3-25 years
Toluene 05-3 days
Schulz M et al Therapeutic and toxic blood concentrations of nearly 1000 drugs and other xenobiotics Crit Care 2012 Jul 2616(4)R136
Bioaccumulation (POPs)
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
DDT banned in 1972 PCBs banned in 1977
Bioaccumulation (Cd)
Think BroadlyExogenous
Metals
Chemicalsbull Inorganic
bull Fluoride
bull Organic
bull POPs
bull Drugs
Particulate matter
Molds
Microbial
Radiationbull Light
bull Medical
bull Cell phone
Endogenous
Gut-derived toxins
Non-end product metabolites
Poorly detoxified hormones
Catecholamines (if SNP)
Toxins of Choice
Alcohol
Marijuana
Food constituents
High fructose corn syrup
Salt (acid-forming diet)
Wheat if zonulin (70)
Obesity Epidemic ndash POPs AND HFCS
47Bray GA Fructose should we worry Int J Obes (Lond) 2008 Dec32 Suppl 7S127-31
How Toxins Cause Damage 13
bull Increase free radical production
Cd induces production of ROS
Malathion inhibits catalase and glutathione peroxidase
Homocysteine oxidizes LDL cholesterol
bull Poison enzyme systems (compete with nutritional cofactors for binding sites)
Pb poisons delta aminolevulinic acid dehydratase
Cd inhibits catalase glutathione reductase and lowers
glutathione levels
bull Replace structural minerals
Pb displaces Ca in bone
How Toxins Cause Damage 23
bull Damage DNA
Benzene - causes chromosomal damage
Pesticides ndash fruit growers have more DNA damage
Phthalates and insecticides ndash damage sperm DNA
4-hydroxy catechol estrogen (4-OHE) damages breast DNA
bull Epigenetic dysmodulation
Higher cord blood levels of hexachlorobenzene associated
with 2x greater risk for obesity in children
bull Damage cell membranes
Common mechanism for heavy metals inactivates
membrane enzymes ion channels and pumps
How Toxins Cause Damage 33
bull Block insulin receptor sites
PCBs and phthalates
bull Highest levels associated with a 4 to 20-fold greater diabetes risk
bull Imbalance hormones many toxin examples
Arsenic
bull Disrupts thyroid hormone and retinoic acid receptors
Phthalates
bull Act as anti-androgens
bull More than 75 of the US population has measurable levels of
several phthalate metabolites in the urine
PCBs
bull Lower testosterone levels in men
Which are the Worst Toxins
bull According to the CDC
Toxicity
Population toxic load
Prevalence in toxic waste sites
bull According to clinical importance
Exposure
of disease
Ability of the body to detoxifyexcrete
Ag
en
cy
fo
r T
oxic
Su
bs
tan
ce
s a
nd
Dis
ea
se
Reg
istr
y
Pri
ori
ty L
ist
The Worst Toxins Clinically
My Rank Toxin Diseases Primary Sources
1 Arsenic Cancers diabetes gout Water chicken rice
2 DDT ADHD dementia diabetes Everywhere
3 Phthalates ADHD diabetes Soft plastics HABAs
4 PBDEs ADHD diabetes Flame retardant fabrics
5 PAHs ADHD cancers dyslipidemia Smoking charbroiling
6 PCBs Cancers diabetes MI RA Everywhere
7 Mercury Dementia ldquoSilverrdquo fillings fish
8 Lead Cardiovascular disease IQ Paint water
Glyphosate Research invalid
Conventional Laboratory Tests Reflect
Toxic Load in ldquoNormalrdquo Range
bull Surprising number show toxin exposure
CBC RBC WBC platelet count hemoglobin basophilic
stippling
Liver enzymes ALT GGTP
Inflammatory markers CRP
Lipids LDL oxLDL triglycerides
Blood sugar insulin FBS 2-hour PP
Metabolites bilirubin uric acid homocysteine 8-OHdG
Thyroid T3 T4 TSH
bull The historic ldquonormalrdquo range has been changing as the population has become more toxic
WBC Lowered by PCB and OCP Exposure
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
0
1
2
3
4
5
6
7
8
1st Quartrile 2nd Quartile 3rd Quartile 4th Quartile
WBCbull Strong inverse correlation with PCBs and OCPs and CBC
bull Linear with almost all PCBs
bull High variability with OCPs
bull Within ldquonormalrdquo range
Effects on WBC Worsen with Years
of Exposure to Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Platelet Count Decreases with Years
of Exposure tp Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Solvents Decrease Platelet Count
bull Compared workers exposed 23 hrday to those exposed most of day to toluene
bull All wore face masks and protective gear
bull Platelet count 14 lower 252 versus 216ml
bull Impairment of sympathetic nerves (OR = 413)
bull Impairment of peripheral nerves (OR = 694)
bull Positive relationship between neurological abnormalities and a self-reported neuropsychiatric measurement (r = 035-066)
Shih HT et al Subclinical abnormalities in workers with continuous low-level toluene exposure Toxicol Ind Health 2011 Sep27(8)691-9
Basophilic Stippling of Red Cells
Toxinsbull Arsenic
bull Lead
Diseasesbull Alpha-thalassemia HbH Disease
bull Beta thalassemia
bull Hereditary pyrimidine 5-nucleotidase deficiency
bull Myelodysplastic syndrome
bull Sideroblastic anemia
bull Thrombotic thrombocytopenic purpura
GGT Indirect Measure of POPsbull Glutathione is key intracellular defense against oxidative stress
bull Cellular GGT metabolizes extracellular GSH allowing precursor amino acids to be reutilized for intracellular GSH
bull Exposure to POPs induces GGT as a defensive mechanism
bull Within normal range predicts type 2 diabetes coronary heart disease hypertension stroke dyslipidemia chronic kidney disease and cancer
bull Men with GGT gt50 UI had ~26 fold risk for diabetes compared to those with lt10 Those with 40-49 had a ~20 fold risk
bull Levels within normal range occur with obesity xs alcohol cigarette smoking physical inactivity high meat low fruit and vegetable intake
bull Cumulative biomarker for environmental pollutants
Lee DH et al (2003) Gamma-glutamyltransferase and diabetesmdasha 4 year follow-up study Diabetologia 46359ndash364
Pamela A et al Serum gamma-glutamyltransferase linking together environmental pollution redox equilibria and progression of atherosclerosis Clin Chem
Lab Med 200947(12)1583-4
Lee DH et al Serum gamma-glutamyltransferase new insights about an old enzyme J Epidemiol Community Health 2009 Nov63(11)884-6
Lee DH et alSerum gamma-glutamyltransferase predicts non-fatal myocardial infarction and fatal coronary heart disease among 28838 middle-aged men and
women Eur Heart J 2006272170ndash6
Lee DH et al Gamma-glutamyltransferase and diabetes--a 4 year follow-up study Diabetologia 2003 Mar46(3)359-64
Lee DH et al Can persistent organic pollutants explain the association between serum gamma-glutamyltransferase and type 2 diabetes Diabetologia 2008
Mar51(3)402-7
GGT and Alcohol Consumption
bull GGT directly correlates with alcohol consumption
bull In a non-uniform population 40 gd will elevate GGT ~15
bull Watch for false negatives
bull Genomic variation
bull Are these the ones most
sensitive todamaged by
chemical toxins
bull Could up-regulation of GGT in light alcohol consumption be reason for benefit
0
10
20
30
40
50
60
70
80
0 200 400 600 800
Grams of Ethanol per Week
Adapted from Nagaya T et al Dose-response relationships between drinking and serum tests in Japanese men
aged 40ndash59 years Alcohol 1999 Feb 17(2) 133ndash8
GGT Correlates With Toxic Metal Levels
Lee DH et al Graded associations of blood lead and urinary cadmium concentrations with oxidative-stress-related markers in the
US population results from the third National Health and Nutrition Examination Survey Environ Health
perspect 2006 Mar114(3)350-4
GGT and Diabetes Risk
0
5
10
15
20
25
30
lt10 10-19 20-29 30-39 40-49 gt50
Dia
bete
s R
isk
GGT
bull GGT over 50 associated with tripling of death rate
bull 30-40 associated with doubling
GGT Levels
Correlate with
Risk of Death
Brenner H et al Distribution determinants and prognostic value of gamma-glutamyltransferase for all-cause
mortality in a cohort of construction workers from southern Germany Prev Med 1997 26 305ndash10
GGT From Small US Company
with Young Workers
0
10
20
30
40
50
60
0 20 40 60 80 100
GGT Data from Canadian Oil Field
Workers
0
50
100
150
200
250
300
350
400
450
lt10 10-20 20-30 30-40 40-50 50-60 60-07 70-80 80-90 90-100 100-110 110-120 gt120
GGTP
20-fold increased risk of diabetes
Uric Acid Indirect Measure of POPs
bull Poly-fluorinated hydrocarbons (PFOA and PFOS) associated
with increased serum uric acid
Lin CY et al Association among serum perfluoroalkyl chemicals glucose homeostasis and metabolic syndrome
in adolescents and adults Diabetes Care 2009 Apr32(4)702-7
Steenland K et al Association of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) with uric
acid among adults with elevated community exposure to PFOA Environ Health Perspect 2010 Feb118229-33
Steenland 2010 Open Access
ALT Indirect Measure of POPs
bull ALT (proxy marker) elevation in 104 (not including viral
hepatitis hemochromatosis or alcoholic liver disease) of
NHANES 03-04 subset
bull Risk of elevated ALT increased dose-dependently with
cadmium lead mercury and PCB exposure
bull 100 of individuals had detectable PCBs 925 mercury
and 996 had detectable lead
bull In 2005-08 prevalence of NAFLD in US was 11 a
growing cause of chronic liver disease
Cave M et al Polychlorinated biphenyls lead and mercury are associated with liver disease in American adults
NHANES 2003-2004 Environ Health Perspect 2010 Dec118(12)1735-42
Younossi ZM et al Changes in the prevalence of the most common causes of chronic liver diseases in the United
States from 1988 to 2008 Clin Gastroenterol Hepatol 2011 Jun9(6)524-530e1
Bilirubin as a Marker of POPs
bull Degree of serum bilirubin increase is prognostically significant in chronic liver dysfunction
bull Mono-ortho PCB TEQ values were found to be significantly positively associated with bilirubin (β=071 P=0008) following adjustment for multiple potential confounders
bull Bilirubin levels significantly correlated with PCBs -105-118-126 and -194
bull Smoking appears to be the biggest confounder
Dufour DR et al 2000 Diagnosis and monitoring of hepatic injury II Recommendations for use of laboratory
tests in screening diagnosis and monitoring Clin Chem 46 2050ndash68
Kumar J et al Persistent organic pollutants and liver dysfunction biomarkers in a population-based human sample
of men and women Environ Res 2014134251-256
Perf
luo
rin
ate
dP
OP
s a
nd
Co
mm
on
Blo
od
Tests
Gleason JA et al Associations of perfluorinated chemical serum concentrations and biomarkers of liver function and uric acid in the
US population (NHANES) 2007-2010 Environ Res 20151368-14
Liver Enzymes Reflect Toxic Load
bull AST ALT and GGT increase with body load of PCBs and OCPs
bull Some non-linear
bull Oxychlordanetop quartile
ALT 10
GGT 25
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
LDL-Cholesterol as Measure of POPs
bull 5-year prospective study to determine if POP levels predict future elevation in LDL-cholesterol
bull 598 subjects initially at age 70
bull Looked at 23 POPs
bull Best correlation with PCB 194
Penell J Lind L Salihovic S et al Persistent organic pollutants are related to change in circulating
lipid levels during a 5 year follow-up Environ Res 134(2014)190ndash197
oxLDL as Measure of POPs
bull 992 70-year old individuals (50 women)
bull Sum of PCBs showed strong significant positive associations with ox-LDL and significant negative associations with glutathione-related markers (GSSG and GSSGGSH)
bull A number of POPs (PCB-99 138 153 156 170 180 194 206 and 209) showed strong significant positive association with ox-LDL
Kumar J et al Influence of persistent organic pollutants on oxidative stress in population-based samples
Chemosphere 2014114303-309
Homocysteine is Increased by Pb amp Cd
Guallar E et al Confounding of the relation between homocysteine and peripheral arterial disease by lead cadmium and renal function Am J Epidemiol 2006 Apr 15163(8)700-8
Nutrient Deficiencies Accentuate
Effects of Lead on Homocysteine
bull Deficiencies in folate B6 or B12 make lead more toxic
Lee YM Et al Association of homocysteine levels with blood lead levels and micronutrients in the US general population J Prev Med Public Health 2012 Nov45(6)387-93
T4 amp T3 and PCBs
bull PCBs decrease T4 production
bull PCBs inhibit iodotyrosinedeiodinase activity
bull Study done in pregnant women which implies effect on fetus IQ
Kim S Park J Kim HJ et al Association between several persistent organic pollutants and thyroid hormone levels in serum among the pregnant women of Korea Environ Int 2013 Sep59442-8Shimizu R Yamaguchi M Uramaru N et al Structure-activity relationships of 44 halogenated compounds for iodotyrosinedeiodinase-inhibitory activity Toxicology 2013 Dec 6314(1)22-9
T4 amp T3 and PCBs
bull Not just humans being affected
bull Large study of dolphins shows exactly the same effects
Schwacke LH Zolman ES Balmer BC et al Anaemia hypothyroidism and immune suppression associated with polychlorinated biphenyl exposure in bottlenose dolphins (Tursiops truncatus) Proceed Royal Society B doi101098rspb20110665
8-OHdG
bull Oxidized nucleoside
bull Direct measure of DNA damage
bull Indirect measure of oxidative stress and toxin load
bull Correlates with
Multiple cancers
Mitochondrial damage
Rate of aging
Smoking
Several toxinsWalter Crinnion ldquoTotal Toxic Loadrdquo AANP 2015
8-OHdG Correlates with Pack-Years
of Smoking
Yano T et al Significance of the urinary 8-OHdG level as an oxidative stress marker in lung cancer patients Lung Cancer
2009 Jan63(1)111-4
8-OHdG Correlates
with Mercury
Chen C et al Increased oxidative DNA damage as assessed by urinary 8-hydroxy-2-deoxyguanosine
concentrations and serum redox status in persons exposed to mercury Clin Chem 2005 Apr51(4)759-67
Toxin Effects Worse with Aging
bull Thyroid function decreases with PFOA levels
bull But only after age 63
Shrestha S Bloom MS Yucel R et al Perfluoroalkyl substances and thyroid function in older adults Environ Int 2015 Feb75206-14
Insightful 23-Year Prospective Study
1 lt 50 there is no difference between those with the lowest and highest PCBs
2 In youngest group insulin production increases in response to toxin level As expected since blocking of
insulin receptor sites by PCBs
requires more insulin
3 That adaptive ability decreases with aging
4 At age 50 all the measures show very strong toxin-dose response
Cumulative damage impairs ability to adapt
Suarez-Lopez JR et al Persistent organic pollutants in young adults and changes in glucose related metabolism over a 23-year follow-up Environ Res 2015 Feb137485-94
Recommendations
High body toxic load
GGT gt 25
Uric acid gt 50 mgdl
ALT gt30 UL
Bilirubin gt08 mgdl
CBC lt 6000
Platelet lt 250000
Low T3 andor T4
Monitor Total Toxic Load
8-OHdG gt4
ldquoUnconventionalrdquo Laboratory Tests
bull Challenge testing
bull Hair analysis
bull Direct measures of solvents and POPs in blood urine adipose tissue
Evaluation of Metal Exposure ndash Provocation
bull Provocation ndash the use of a chelating agent ndash before urine collection often done clinically but several limitations
No ldquoofficialrdquo reference range for provoked urine
Most chelating agents do not extract metals from all tissues thus
does not necessarily represent total body burden
bull Example Brain is one of the main target organs for both elemental and organic
mercury yet agents do not chelate brain mercury
bull Despite limitations widely used and advocated by clinicians in part to see efficacy of chelating agent as a guide to treatment and based on empirical evidence
Rooney JP The role of thiols dithiols nutritional factors and interacting ligands in the toxicology of mercury
Toxicology 2007
Is Challenge Testing Valid
bull Poor correlations of standard tests for mercury
bull Unpublished research from corporate wellness project
bull Published amalgam number correlation
bull Published fish consumption correlation
What We Found In Canada
bull Deviations from the mean of 14 29 and 91 respectively
bull DMPS is spreading distribution suggesting that it is better at differentiating mercury body load
bull Some VERY high
Hg Assessment Correlations
bull Extensive measurements in 65 Whole blood Hg
Oral DMPS challenge
Amalgam surfaces
bull Correlations Whole blood w pre urine r = 040
Whole blood w post urine r = 057
Pre urine w post urine r = 068
Amalgams w pre urine r = 026
Amalgams w whole blood r = 036
Amalgams with post urine 044
bull Clear documentation that
challenge testing is better00
100
200
300
400
500
600
0 10 20 30 40 50
Po
st
Uri
ne H
g u
gg
Number of amalgams
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
Diabetes Increasing World-Wide
SourcesAIHW analysis of ABS NHS 1989ndash90 1995 2001 2004ndash05 and 2007ndash08 NHS (reissue) and ABS 2011ndash12 Australian
Health Survey data (Release 7 June 2013)
Co-ordinaring Committee Epidemiology Study of Childhood amp Adolescent Diabetes Hong Kong KF Huen et al
Australian Adults
Childhood diabetes in Hong Kong
WHY THE CHRONIC DISEASE
EPIDEMICS
Increase in Diabetes Due to Sugar
httpwholehealthsourceblogspotcom201202by-2606-us-diet-will-be-100-percenthtml
Dia
bete
s 1
How About Persistent Organic Pollutants
Neel BA Robert M Sargis RM The paradox of progress Environmental disruption of metabolism and the diabetes epidemic DIABETES 2011 601838-48
Lars Jaumlrup Br Med Bull 200368167-182copy The British Council 2003 all rights reserved
Global Production and Consumption of
Selected Toxic Metals 1850ndash1990
Cadmium World Production
Mercury in the Air
EPA-452R-97-003 December 1997
Mercury in Water
httpwaterepagovscitechdataitmodelsmapspostercfm
Ground Water Sources of Arsenic
bull 10 of US public water supplies have levels of arsenic known to induce disease
bull No data on private water supplies
httpwwwatsdrcdcgovcsemarsenicdocsarsenicpdf (accessed 2015-08-18)
Example POPs
Chemical Abbr Uses Exposure
Bisphenol A BPA Plastics Canned food
Organochlorine
pesticides
OCPs Pesticide Food fumigation
Organophosphate
pesticides
OPPs Pesticide Food
Polybrominated
diphenyl ethers
PBDEs Flame retardant Clothing
Polychlorinated
biphenyls
PCBs Industrial Everywhere
Perflourinated PFOAs Non-stick stain prevention
water repellant
Teflon Gortex
Scotchguard
Phthalates Plastics fragrances Shower curtains
cosmetics
POPs - Prediabetes
bull Over 1200 participants fasting
glucose and OGTT performed
with serum levels of 5 POPs
bull All individual POPs tested were
associated with progressive
increase in prevalence of
prediabetes
bull More than triple prevalence of
prediabetes seen in those in the
5th quartile with a synergistic
effect from 5 POPs
Ukropec J et al High prevalence of prediabetes and diabetes in a population exposed to high levels of an organochlorine cocktail
Diabetologia 2010 May53(5)899-906
POPs and Diabetes Risk
Graph httpwwwourstolenfutureorgNewScienceobesity20062006-0715leeetalhtml
Data Lee DH Lee IK Song K et al A strong dose-response relation between serum
concentrations of persistent organic pollutants and diabetes results from the National Health and
Examination Survey 1999-2002 Diabetes Care 2006 Jul29(7)1638-44
Toxic Load and Disease Risk
References for Toxins and Disease Risk
Converting Disease Risk to Caused
Attributable Fraction Calculation
p = underlying prevalence of risk factor in the population
rr = relative risk (risk of contracting a disease in an exposed population divided by the risk of contracting the disease in an unexposed population)
AF = of disease due to the toxin
Levin M The occurrence of lung cancer in man Acta Unio Int Contra Cancrum 1953 9 531-541
Example Smoking and Lung Cancer
B = 5Number of smokers
who contract Lung Cancer notdue to smoking
A = 5Number of smokerswho contract Lung
Cancer due to smoking
C = 15Number of
nonsmokerswho contract Lung Cancer
0
2
4
6
8
10
12
14
16
Smokers (N=100) Nonsmokers (N=300)Num
ber
of
people
who c
ontr
act
Lung C
ancer
per
year
Baseline Additional due to smoking
Number of smokers and nonsmokers who contract lung cancer
Our Process In Summary
1 Determine threshold for increased disease risk
2 Determine of population above threshold
3 Determine incidence of disease (OR) in those above threshold
4 Determine incidence of disease in ldquounexposed populationrdquo
5 Calculate AF ie of disease
As whole population is exposed probably UNDERESTIMATES of disease
To
xic
ity H
as B
eco
me t
he N
ew
ldquoN
orm
alrdquo
Toxin Type Use Threshold for
disease
association
of US
above
threshold
Disease Associations
Chlordane OC pesticide Termites corn citrus lawns
gardens
145ngg lipid 63
(diabetes)
Diabetes (20)
BPA Plasticizer Water bottles canned food
water pipes thermal sales
receipts
48 men 51
women (urine
ngmL)
~18
(diabetes)
Diabetes hypertension
Octachloro
dibenzo-p-
dioxin
(OCDD)
Polychlorinated
dibenzo-p-
dioxin
Incineration or burning of
waste bleaching processes
used in pulp and paper mills
1010 pgg
lipid (highest
quartile)
10-25
(hypertensio
n)
Hypertension (79 for
women highest
quartile) diabetes (21)
obesity learning
disability (272)
MEP
(mono-
ethyl
phthalate)
Phthalate
(plasticizer
fragrance)
Toothbrushes automobile
parts tools toys and food
packaging aspirin
cosmetics food packaging
gt175 ngmL
(urine)
~60
(diabetes)
Diabetes (148) lower
BMD obesity
pp-DDE DDT
metabolite (OC
pesticide)
Agricultural crops 1560ngg
lipid
25
(diabetes)
Diabetes (23-43)
early menopause
impaired cognitive
function (2-3x 65x in
highest 5th percentile)
peripheral arterial
disease
Arsenic Toxic metal Miningsmelting wood
preservative pesticides
74ugL total
arsenic (urine)
20
(diabetes)
Cancers diabetes (26-
46) dyslipidemia gout
AF OR Prevalence
Rosen L An intuitive approach to understanding the attributable fraction of disease due to a risk factor the case of smoking Int J Environ Res Public Health 2013 Jul 1610(7)2932-43
Smoking Lung cancer
Arsenic Gout in women
BPA Diabetes
Status of Our Research
bull 26 toxins and toxin classes eg lead mercury BPA OCPs
100s of chemicals and POPs in some classes
bull 18 cancers
bull 24 chronic diseases
bull 1092 cells in spreadsheet
Large Personal Ongoing Research Investment
Huge Amount of Research Work
Toxins StudiedAluminum
Arsenic
Cadmium
Fluoride
Lead
Manganese
Mercury
Acrylamide
Acrylonitrile
Benzene
Bisphenol A (BPA)
Chloroform
DDT
Dioxins
Glyphosate
Organochlorine pesticides (OCPs)
Organophosphate pesticides
Parabens
Phthalates
Polybrominated diphenyl ethers (PBDEs)
Polycyclic aromatic hydrocarbons (PAHs)
Polychlorinated biphenols (PCBs)
Vinyl chloride
Diseases Studied
ADHD
Alzheimers Disease
ALS
Angiosarcoma
Anxiety
Atopic Conditions
Diabetes
Dyslipidemia
Gout
Fetal Abnormalities
Hyperuricemia
Infertility
Juvenile IQ
Cancer Bladder
Cancer Bone
Cancer Brain
Cancer Breast
Cancer Cervix
Cancer Colorectal
Cancer Endometrial
Cancer Head amp Neck
Cancer Liver
Cancer Lung
Cancer Lymph amp Blood
Cancer Ovarian
Cancer Pancreatic
Cancer Prostate
Cancer Renal
Cancer Skin
Cancer Testicular
Cancer Thyroid
Juvenile Obesity
Metabolic Syndrome
Mitochondrial dysfunction
Myocardial Infarction
Obstructive Lung Disease
Osteoporosis
Peripheral Artery Disease
Peripheral Neuropathy
Prediabetes
Renal Disease
Rheumatoid Arthritis
Thyroid Dysfunction
OC
Ps
Th
rou
gh
ou
t th
e W
orl
d
Rathore HS Nollet LML Pesticides Evaluation of Environmental Pollution CRC Press
2012 page 562
Threshold ndash Threshold exposure at which there is an increased risk of disease outcome
Above Threshold ndash Percentage of the population with higher exposure than the threshold
Odds Ratio ndash Increased disease risk in those above threshold
of Dz ndash Percent contribution of the toxin to that disease outcome
How to Interpret the Following Slides
Attention Deficit Hyperactivity Disorder
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
DDT 126 ngg
serum (pp-
DDE)
250 18 166 20106937
Lead 23 ugdL 13 254 20 27659349
Mercury 16 24952233
Organophosphate
pesticides
20
Polycyclic
Aromatic
Hydrocarbons
227 ngm3 940 125 190 22440811
PCBs 104 ngg
serum (sum
of 50 PCBs)
250 176 160 20106937
DiabetesToxin Threshold Above
Threshold
Odds
Ratio
of Dz Reference
PMID
Arsenic 165 ugL 200 21 180 18714061
BPA 28 ugL 280 145 112 26119400
DDE 545 ngg serum
(pp-DDE)
200 230 31 26119400
Dioxins2 pgg lipid 50 191 43
26119400
PCBs104 ngg (PCB 153) 250 239 258
26119400
Phthalates175 ugL 690 148 249
26119400
1-naphthalene 167 ugdL 152 182 111 26340343
2-napthalene 414 ugdL 550 224 214 26340343
1-phenanthrene 167 ngL 570 178 151 26340343
1-pyrene 85 ngL 660 180 174 26340343
Lung Cancer
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Acrylonitrile Uncertain Uncertain 125 25
occupational
exposure
17114112
Arsenic 1213 ugL 436 of Asian
Americans
~01 of total
US population
34 95 in AA
01-1
PMC2682945
Cadmium Uncertain+ Uncertain 467 10 in
smokers
17184399
DDT Any exposure All US pop
below LOD
17 76 increased
risk
8923607
Breast Cancer
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Cadmium 0580 ugg
creatinine
126 205 479 16788160
PCB 138 396 ngg
creatinine
202 316 630 27717745
PCB 187 108 ngg lipid 600 194 360 21480306
Miscellaneous Diseases
Toxin Disease Threshold Above
Threshold
Odds
Ratio
of Dz Reference PMID
Aluminum Alzheimer
Dz
01 mgL
drinking
H20
400 203 05-44 26592479
Benzene AML 100ppmyrs 1-3 320 60 PMC2903550
DDT NHL 0512 ugL 1-2 240 01 17722095
Lead ALS 238 ugdL
blood
330 181 210 25479292
Lead Brain CA 0005 ugdL 14 19 ~500 17164378
Dioxin-like
PCBs
RA 326 ngg
lipid
250 219 220 17589595
PAHs Asthma 124 ngm3 935 200 483 19221603
The Potency of Arsenic
Disease Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Bladder CA 10ugL H20 100 27 145 24889821
Pancreatic CA 1332 ugg 200 246 230 23800676
Prostate CA 1332 ugg 200 33 315 23800676
Gout 125 ugL 245 546 522 25499256
Diabetes 165 ugL 200 21 180 18714061
Arsenic (180 of Diabetes)
How it causes diabetes
bull Blocks sugar stimulating insulin secretion
bull Epigenetic inhibition of sugar regulation
Where it comes from
bull Water (gt10 of US water supplies have high levels)
bull Rice (naturally absorbs if in the water)
bull Chicken (added to make meat whiter)
Pan W-C Seow WJ Kile ML et al Association of low to moderate levels of arsenic exposure with risk of Type 2 diabetes in Bangladesh American Journal of Epidemiology 2013178(10)1563-70
Portion of Population with Toxin Load Which
Doubles Disease Risk
Toxin Disease with Doubled Risk
Polycyclic aromatic hydrocarbons Asthma 94
PCB187 Breast Cancer 60
Phthalates Diabetes 55
Lead ALS 33
Aluminum Alzheimers Disease 25
DDT ADHD 25
PCBs Diabetes 25
Dioxin-like PCBs Rheumatoid Arthritis 25
Arsenic Gout 23
Bisphenol A Diabetes 22
Cigarette smoking Lung Cancer 21
Arsenic Diabetes 20
Polycyclic aromatic hydrocarbons Diabetes 20
Huge Detoxification Variability
bull CYP2C19
Proton pump inhibitors and some antidepressants
5-fold difference in activity between poor metabolizers and extensive metabolizers more so if CYP3A4 is also inhibited
Ultrarapid allele in 18 of both Swedes and Ethiopians
bull CYP2D6
Metabolizes a large number of drugs (~25)
7 of Caucasians poor metabolizers
~30 ultra rapid metabolizers in Arabian and Eastern African populations
More adverse effects in poor metabolizers and ineffective dosing in ultrarapid metabolizers
Inhibited by ginger
Desta Z et al Clinical significance of the cytochrome P450 2C19 genetic polymorphism Clin Pharmaco 2002
Sim SC et al A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug
response to proton pump inhibitors and antidepressants Clin Pharmacol Ther 2006
Wilkinson GR Drug metabolism and variability among patients in drug response N Engl J Med 2005
Kirchheiner J et al Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to
CYP2D6 duplication Pharmacogenomics J 2007
Toxin Half Lives in BloodToxin ldquoNormalrdquo (mgL) Acute Toxic (mgL) Half-Life
Arsenic 0002-007 005-025 2-4 days (CDC)
Benzene 00002 05-10 days
Cadmium 00003-00065 0015-005 16 years
Chlordane 0001 00025 3-4 days
DDTDDE 2-10 years
Dieldrin 00015 015-030 2-12 months
Ethanol 1000-2000 15hour
Lead 009 04-06 1-15 mo (2+ yrs bone)
Mercury 00015-0002 005-02 2 months (CDC)
PCBs 3-25 years
Toluene 05-3 days
Schulz M et al Therapeutic and toxic blood concentrations of nearly 1000 drugs and other xenobiotics Crit Care 2012 Jul 2616(4)R136
Bioaccumulation (POPs)
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
DDT banned in 1972 PCBs banned in 1977
Bioaccumulation (Cd)
Think BroadlyExogenous
Metals
Chemicalsbull Inorganic
bull Fluoride
bull Organic
bull POPs
bull Drugs
Particulate matter
Molds
Microbial
Radiationbull Light
bull Medical
bull Cell phone
Endogenous
Gut-derived toxins
Non-end product metabolites
Poorly detoxified hormones
Catecholamines (if SNP)
Toxins of Choice
Alcohol
Marijuana
Food constituents
High fructose corn syrup
Salt (acid-forming diet)
Wheat if zonulin (70)
Obesity Epidemic ndash POPs AND HFCS
47Bray GA Fructose should we worry Int J Obes (Lond) 2008 Dec32 Suppl 7S127-31
How Toxins Cause Damage 13
bull Increase free radical production
Cd induces production of ROS
Malathion inhibits catalase and glutathione peroxidase
Homocysteine oxidizes LDL cholesterol
bull Poison enzyme systems (compete with nutritional cofactors for binding sites)
Pb poisons delta aminolevulinic acid dehydratase
Cd inhibits catalase glutathione reductase and lowers
glutathione levels
bull Replace structural minerals
Pb displaces Ca in bone
How Toxins Cause Damage 23
bull Damage DNA
Benzene - causes chromosomal damage
Pesticides ndash fruit growers have more DNA damage
Phthalates and insecticides ndash damage sperm DNA
4-hydroxy catechol estrogen (4-OHE) damages breast DNA
bull Epigenetic dysmodulation
Higher cord blood levels of hexachlorobenzene associated
with 2x greater risk for obesity in children
bull Damage cell membranes
Common mechanism for heavy metals inactivates
membrane enzymes ion channels and pumps
How Toxins Cause Damage 33
bull Block insulin receptor sites
PCBs and phthalates
bull Highest levels associated with a 4 to 20-fold greater diabetes risk
bull Imbalance hormones many toxin examples
Arsenic
bull Disrupts thyroid hormone and retinoic acid receptors
Phthalates
bull Act as anti-androgens
bull More than 75 of the US population has measurable levels of
several phthalate metabolites in the urine
PCBs
bull Lower testosterone levels in men
Which are the Worst Toxins
bull According to the CDC
Toxicity
Population toxic load
Prevalence in toxic waste sites
bull According to clinical importance
Exposure
of disease
Ability of the body to detoxifyexcrete
Ag
en
cy
fo
r T
oxic
Su
bs
tan
ce
s a
nd
Dis
ea
se
Reg
istr
y
Pri
ori
ty L
ist
The Worst Toxins Clinically
My Rank Toxin Diseases Primary Sources
1 Arsenic Cancers diabetes gout Water chicken rice
2 DDT ADHD dementia diabetes Everywhere
3 Phthalates ADHD diabetes Soft plastics HABAs
4 PBDEs ADHD diabetes Flame retardant fabrics
5 PAHs ADHD cancers dyslipidemia Smoking charbroiling
6 PCBs Cancers diabetes MI RA Everywhere
7 Mercury Dementia ldquoSilverrdquo fillings fish
8 Lead Cardiovascular disease IQ Paint water
Glyphosate Research invalid
Conventional Laboratory Tests Reflect
Toxic Load in ldquoNormalrdquo Range
bull Surprising number show toxin exposure
CBC RBC WBC platelet count hemoglobin basophilic
stippling
Liver enzymes ALT GGTP
Inflammatory markers CRP
Lipids LDL oxLDL triglycerides
Blood sugar insulin FBS 2-hour PP
Metabolites bilirubin uric acid homocysteine 8-OHdG
Thyroid T3 T4 TSH
bull The historic ldquonormalrdquo range has been changing as the population has become more toxic
WBC Lowered by PCB and OCP Exposure
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
0
1
2
3
4
5
6
7
8
1st Quartrile 2nd Quartile 3rd Quartile 4th Quartile
WBCbull Strong inverse correlation with PCBs and OCPs and CBC
bull Linear with almost all PCBs
bull High variability with OCPs
bull Within ldquonormalrdquo range
Effects on WBC Worsen with Years
of Exposure to Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Platelet Count Decreases with Years
of Exposure tp Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Solvents Decrease Platelet Count
bull Compared workers exposed 23 hrday to those exposed most of day to toluene
bull All wore face masks and protective gear
bull Platelet count 14 lower 252 versus 216ml
bull Impairment of sympathetic nerves (OR = 413)
bull Impairment of peripheral nerves (OR = 694)
bull Positive relationship between neurological abnormalities and a self-reported neuropsychiatric measurement (r = 035-066)
Shih HT et al Subclinical abnormalities in workers with continuous low-level toluene exposure Toxicol Ind Health 2011 Sep27(8)691-9
Basophilic Stippling of Red Cells
Toxinsbull Arsenic
bull Lead
Diseasesbull Alpha-thalassemia HbH Disease
bull Beta thalassemia
bull Hereditary pyrimidine 5-nucleotidase deficiency
bull Myelodysplastic syndrome
bull Sideroblastic anemia
bull Thrombotic thrombocytopenic purpura
GGT Indirect Measure of POPsbull Glutathione is key intracellular defense against oxidative stress
bull Cellular GGT metabolizes extracellular GSH allowing precursor amino acids to be reutilized for intracellular GSH
bull Exposure to POPs induces GGT as a defensive mechanism
bull Within normal range predicts type 2 diabetes coronary heart disease hypertension stroke dyslipidemia chronic kidney disease and cancer
bull Men with GGT gt50 UI had ~26 fold risk for diabetes compared to those with lt10 Those with 40-49 had a ~20 fold risk
bull Levels within normal range occur with obesity xs alcohol cigarette smoking physical inactivity high meat low fruit and vegetable intake
bull Cumulative biomarker for environmental pollutants
Lee DH et al (2003) Gamma-glutamyltransferase and diabetesmdasha 4 year follow-up study Diabetologia 46359ndash364
Pamela A et al Serum gamma-glutamyltransferase linking together environmental pollution redox equilibria and progression of atherosclerosis Clin Chem
Lab Med 200947(12)1583-4
Lee DH et al Serum gamma-glutamyltransferase new insights about an old enzyme J Epidemiol Community Health 2009 Nov63(11)884-6
Lee DH et alSerum gamma-glutamyltransferase predicts non-fatal myocardial infarction and fatal coronary heart disease among 28838 middle-aged men and
women Eur Heart J 2006272170ndash6
Lee DH et al Gamma-glutamyltransferase and diabetes--a 4 year follow-up study Diabetologia 2003 Mar46(3)359-64
Lee DH et al Can persistent organic pollutants explain the association between serum gamma-glutamyltransferase and type 2 diabetes Diabetologia 2008
Mar51(3)402-7
GGT and Alcohol Consumption
bull GGT directly correlates with alcohol consumption
bull In a non-uniform population 40 gd will elevate GGT ~15
bull Watch for false negatives
bull Genomic variation
bull Are these the ones most
sensitive todamaged by
chemical toxins
bull Could up-regulation of GGT in light alcohol consumption be reason for benefit
0
10
20
30
40
50
60
70
80
0 200 400 600 800
Grams of Ethanol per Week
Adapted from Nagaya T et al Dose-response relationships between drinking and serum tests in Japanese men
aged 40ndash59 years Alcohol 1999 Feb 17(2) 133ndash8
GGT Correlates With Toxic Metal Levels
Lee DH et al Graded associations of blood lead and urinary cadmium concentrations with oxidative-stress-related markers in the
US population results from the third National Health and Nutrition Examination Survey Environ Health
perspect 2006 Mar114(3)350-4
GGT and Diabetes Risk
0
5
10
15
20
25
30
lt10 10-19 20-29 30-39 40-49 gt50
Dia
bete
s R
isk
GGT
bull GGT over 50 associated with tripling of death rate
bull 30-40 associated with doubling
GGT Levels
Correlate with
Risk of Death
Brenner H et al Distribution determinants and prognostic value of gamma-glutamyltransferase for all-cause
mortality in a cohort of construction workers from southern Germany Prev Med 1997 26 305ndash10
GGT From Small US Company
with Young Workers
0
10
20
30
40
50
60
0 20 40 60 80 100
GGT Data from Canadian Oil Field
Workers
0
50
100
150
200
250
300
350
400
450
lt10 10-20 20-30 30-40 40-50 50-60 60-07 70-80 80-90 90-100 100-110 110-120 gt120
GGTP
20-fold increased risk of diabetes
Uric Acid Indirect Measure of POPs
bull Poly-fluorinated hydrocarbons (PFOA and PFOS) associated
with increased serum uric acid
Lin CY et al Association among serum perfluoroalkyl chemicals glucose homeostasis and metabolic syndrome
in adolescents and adults Diabetes Care 2009 Apr32(4)702-7
Steenland K et al Association of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) with uric
acid among adults with elevated community exposure to PFOA Environ Health Perspect 2010 Feb118229-33
Steenland 2010 Open Access
ALT Indirect Measure of POPs
bull ALT (proxy marker) elevation in 104 (not including viral
hepatitis hemochromatosis or alcoholic liver disease) of
NHANES 03-04 subset
bull Risk of elevated ALT increased dose-dependently with
cadmium lead mercury and PCB exposure
bull 100 of individuals had detectable PCBs 925 mercury
and 996 had detectable lead
bull In 2005-08 prevalence of NAFLD in US was 11 a
growing cause of chronic liver disease
Cave M et al Polychlorinated biphenyls lead and mercury are associated with liver disease in American adults
NHANES 2003-2004 Environ Health Perspect 2010 Dec118(12)1735-42
Younossi ZM et al Changes in the prevalence of the most common causes of chronic liver diseases in the United
States from 1988 to 2008 Clin Gastroenterol Hepatol 2011 Jun9(6)524-530e1
Bilirubin as a Marker of POPs
bull Degree of serum bilirubin increase is prognostically significant in chronic liver dysfunction
bull Mono-ortho PCB TEQ values were found to be significantly positively associated with bilirubin (β=071 P=0008) following adjustment for multiple potential confounders
bull Bilirubin levels significantly correlated with PCBs -105-118-126 and -194
bull Smoking appears to be the biggest confounder
Dufour DR et al 2000 Diagnosis and monitoring of hepatic injury II Recommendations for use of laboratory
tests in screening diagnosis and monitoring Clin Chem 46 2050ndash68
Kumar J et al Persistent organic pollutants and liver dysfunction biomarkers in a population-based human sample
of men and women Environ Res 2014134251-256
Perf
luo
rin
ate
dP
OP
s a
nd
Co
mm
on
Blo
od
Tests
Gleason JA et al Associations of perfluorinated chemical serum concentrations and biomarkers of liver function and uric acid in the
US population (NHANES) 2007-2010 Environ Res 20151368-14
Liver Enzymes Reflect Toxic Load
bull AST ALT and GGT increase with body load of PCBs and OCPs
bull Some non-linear
bull Oxychlordanetop quartile
ALT 10
GGT 25
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
LDL-Cholesterol as Measure of POPs
bull 5-year prospective study to determine if POP levels predict future elevation in LDL-cholesterol
bull 598 subjects initially at age 70
bull Looked at 23 POPs
bull Best correlation with PCB 194
Penell J Lind L Salihovic S et al Persistent organic pollutants are related to change in circulating
lipid levels during a 5 year follow-up Environ Res 134(2014)190ndash197
oxLDL as Measure of POPs
bull 992 70-year old individuals (50 women)
bull Sum of PCBs showed strong significant positive associations with ox-LDL and significant negative associations with glutathione-related markers (GSSG and GSSGGSH)
bull A number of POPs (PCB-99 138 153 156 170 180 194 206 and 209) showed strong significant positive association with ox-LDL
Kumar J et al Influence of persistent organic pollutants on oxidative stress in population-based samples
Chemosphere 2014114303-309
Homocysteine is Increased by Pb amp Cd
Guallar E et al Confounding of the relation between homocysteine and peripheral arterial disease by lead cadmium and renal function Am J Epidemiol 2006 Apr 15163(8)700-8
Nutrient Deficiencies Accentuate
Effects of Lead on Homocysteine
bull Deficiencies in folate B6 or B12 make lead more toxic
Lee YM Et al Association of homocysteine levels with blood lead levels and micronutrients in the US general population J Prev Med Public Health 2012 Nov45(6)387-93
T4 amp T3 and PCBs
bull PCBs decrease T4 production
bull PCBs inhibit iodotyrosinedeiodinase activity
bull Study done in pregnant women which implies effect on fetus IQ
Kim S Park J Kim HJ et al Association between several persistent organic pollutants and thyroid hormone levels in serum among the pregnant women of Korea Environ Int 2013 Sep59442-8Shimizu R Yamaguchi M Uramaru N et al Structure-activity relationships of 44 halogenated compounds for iodotyrosinedeiodinase-inhibitory activity Toxicology 2013 Dec 6314(1)22-9
T4 amp T3 and PCBs
bull Not just humans being affected
bull Large study of dolphins shows exactly the same effects
Schwacke LH Zolman ES Balmer BC et al Anaemia hypothyroidism and immune suppression associated with polychlorinated biphenyl exposure in bottlenose dolphins (Tursiops truncatus) Proceed Royal Society B doi101098rspb20110665
8-OHdG
bull Oxidized nucleoside
bull Direct measure of DNA damage
bull Indirect measure of oxidative stress and toxin load
bull Correlates with
Multiple cancers
Mitochondrial damage
Rate of aging
Smoking
Several toxinsWalter Crinnion ldquoTotal Toxic Loadrdquo AANP 2015
8-OHdG Correlates with Pack-Years
of Smoking
Yano T et al Significance of the urinary 8-OHdG level as an oxidative stress marker in lung cancer patients Lung Cancer
2009 Jan63(1)111-4
8-OHdG Correlates
with Mercury
Chen C et al Increased oxidative DNA damage as assessed by urinary 8-hydroxy-2-deoxyguanosine
concentrations and serum redox status in persons exposed to mercury Clin Chem 2005 Apr51(4)759-67
Toxin Effects Worse with Aging
bull Thyroid function decreases with PFOA levels
bull But only after age 63
Shrestha S Bloom MS Yucel R et al Perfluoroalkyl substances and thyroid function in older adults Environ Int 2015 Feb75206-14
Insightful 23-Year Prospective Study
1 lt 50 there is no difference between those with the lowest and highest PCBs
2 In youngest group insulin production increases in response to toxin level As expected since blocking of
insulin receptor sites by PCBs
requires more insulin
3 That adaptive ability decreases with aging
4 At age 50 all the measures show very strong toxin-dose response
Cumulative damage impairs ability to adapt
Suarez-Lopez JR et al Persistent organic pollutants in young adults and changes in glucose related metabolism over a 23-year follow-up Environ Res 2015 Feb137485-94
Recommendations
High body toxic load
GGT gt 25
Uric acid gt 50 mgdl
ALT gt30 UL
Bilirubin gt08 mgdl
CBC lt 6000
Platelet lt 250000
Low T3 andor T4
Monitor Total Toxic Load
8-OHdG gt4
ldquoUnconventionalrdquo Laboratory Tests
bull Challenge testing
bull Hair analysis
bull Direct measures of solvents and POPs in blood urine adipose tissue
Evaluation of Metal Exposure ndash Provocation
bull Provocation ndash the use of a chelating agent ndash before urine collection often done clinically but several limitations
No ldquoofficialrdquo reference range for provoked urine
Most chelating agents do not extract metals from all tissues thus
does not necessarily represent total body burden
bull Example Brain is one of the main target organs for both elemental and organic
mercury yet agents do not chelate brain mercury
bull Despite limitations widely used and advocated by clinicians in part to see efficacy of chelating agent as a guide to treatment and based on empirical evidence
Rooney JP The role of thiols dithiols nutritional factors and interacting ligands in the toxicology of mercury
Toxicology 2007
Is Challenge Testing Valid
bull Poor correlations of standard tests for mercury
bull Unpublished research from corporate wellness project
bull Published amalgam number correlation
bull Published fish consumption correlation
What We Found In Canada
bull Deviations from the mean of 14 29 and 91 respectively
bull DMPS is spreading distribution suggesting that it is better at differentiating mercury body load
bull Some VERY high
Hg Assessment Correlations
bull Extensive measurements in 65 Whole blood Hg
Oral DMPS challenge
Amalgam surfaces
bull Correlations Whole blood w pre urine r = 040
Whole blood w post urine r = 057
Pre urine w post urine r = 068
Amalgams w pre urine r = 026
Amalgams w whole blood r = 036
Amalgams with post urine 044
bull Clear documentation that
challenge testing is better00
100
200
300
400
500
600
0 10 20 30 40 50
Po
st
Uri
ne H
g u
gg
Number of amalgams
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
WHY THE CHRONIC DISEASE
EPIDEMICS
Increase in Diabetes Due to Sugar
httpwholehealthsourceblogspotcom201202by-2606-us-diet-will-be-100-percenthtml
Dia
bete
s 1
How About Persistent Organic Pollutants
Neel BA Robert M Sargis RM The paradox of progress Environmental disruption of metabolism and the diabetes epidemic DIABETES 2011 601838-48
Lars Jaumlrup Br Med Bull 200368167-182copy The British Council 2003 all rights reserved
Global Production and Consumption of
Selected Toxic Metals 1850ndash1990
Cadmium World Production
Mercury in the Air
EPA-452R-97-003 December 1997
Mercury in Water
httpwaterepagovscitechdataitmodelsmapspostercfm
Ground Water Sources of Arsenic
bull 10 of US public water supplies have levels of arsenic known to induce disease
bull No data on private water supplies
httpwwwatsdrcdcgovcsemarsenicdocsarsenicpdf (accessed 2015-08-18)
Example POPs
Chemical Abbr Uses Exposure
Bisphenol A BPA Plastics Canned food
Organochlorine
pesticides
OCPs Pesticide Food fumigation
Organophosphate
pesticides
OPPs Pesticide Food
Polybrominated
diphenyl ethers
PBDEs Flame retardant Clothing
Polychlorinated
biphenyls
PCBs Industrial Everywhere
Perflourinated PFOAs Non-stick stain prevention
water repellant
Teflon Gortex
Scotchguard
Phthalates Plastics fragrances Shower curtains
cosmetics
POPs - Prediabetes
bull Over 1200 participants fasting
glucose and OGTT performed
with serum levels of 5 POPs
bull All individual POPs tested were
associated with progressive
increase in prevalence of
prediabetes
bull More than triple prevalence of
prediabetes seen in those in the
5th quartile with a synergistic
effect from 5 POPs
Ukropec J et al High prevalence of prediabetes and diabetes in a population exposed to high levels of an organochlorine cocktail
Diabetologia 2010 May53(5)899-906
POPs and Diabetes Risk
Graph httpwwwourstolenfutureorgNewScienceobesity20062006-0715leeetalhtml
Data Lee DH Lee IK Song K et al A strong dose-response relation between serum
concentrations of persistent organic pollutants and diabetes results from the National Health and
Examination Survey 1999-2002 Diabetes Care 2006 Jul29(7)1638-44
Toxic Load and Disease Risk
References for Toxins and Disease Risk
Converting Disease Risk to Caused
Attributable Fraction Calculation
p = underlying prevalence of risk factor in the population
rr = relative risk (risk of contracting a disease in an exposed population divided by the risk of contracting the disease in an unexposed population)
AF = of disease due to the toxin
Levin M The occurrence of lung cancer in man Acta Unio Int Contra Cancrum 1953 9 531-541
Example Smoking and Lung Cancer
B = 5Number of smokers
who contract Lung Cancer notdue to smoking
A = 5Number of smokerswho contract Lung
Cancer due to smoking
C = 15Number of
nonsmokerswho contract Lung Cancer
0
2
4
6
8
10
12
14
16
Smokers (N=100) Nonsmokers (N=300)Num
ber
of
people
who c
ontr
act
Lung C
ancer
per
year
Baseline Additional due to smoking
Number of smokers and nonsmokers who contract lung cancer
Our Process In Summary
1 Determine threshold for increased disease risk
2 Determine of population above threshold
3 Determine incidence of disease (OR) in those above threshold
4 Determine incidence of disease in ldquounexposed populationrdquo
5 Calculate AF ie of disease
As whole population is exposed probably UNDERESTIMATES of disease
To
xic
ity H
as B
eco
me t
he N
ew
ldquoN
orm
alrdquo
Toxin Type Use Threshold for
disease
association
of US
above
threshold
Disease Associations
Chlordane OC pesticide Termites corn citrus lawns
gardens
145ngg lipid 63
(diabetes)
Diabetes (20)
BPA Plasticizer Water bottles canned food
water pipes thermal sales
receipts
48 men 51
women (urine
ngmL)
~18
(diabetes)
Diabetes hypertension
Octachloro
dibenzo-p-
dioxin
(OCDD)
Polychlorinated
dibenzo-p-
dioxin
Incineration or burning of
waste bleaching processes
used in pulp and paper mills
1010 pgg
lipid (highest
quartile)
10-25
(hypertensio
n)
Hypertension (79 for
women highest
quartile) diabetes (21)
obesity learning
disability (272)
MEP
(mono-
ethyl
phthalate)
Phthalate
(plasticizer
fragrance)
Toothbrushes automobile
parts tools toys and food
packaging aspirin
cosmetics food packaging
gt175 ngmL
(urine)
~60
(diabetes)
Diabetes (148) lower
BMD obesity
pp-DDE DDT
metabolite (OC
pesticide)
Agricultural crops 1560ngg
lipid
25
(diabetes)
Diabetes (23-43)
early menopause
impaired cognitive
function (2-3x 65x in
highest 5th percentile)
peripheral arterial
disease
Arsenic Toxic metal Miningsmelting wood
preservative pesticides
74ugL total
arsenic (urine)
20
(diabetes)
Cancers diabetes (26-
46) dyslipidemia gout
AF OR Prevalence
Rosen L An intuitive approach to understanding the attributable fraction of disease due to a risk factor the case of smoking Int J Environ Res Public Health 2013 Jul 1610(7)2932-43
Smoking Lung cancer
Arsenic Gout in women
BPA Diabetes
Status of Our Research
bull 26 toxins and toxin classes eg lead mercury BPA OCPs
100s of chemicals and POPs in some classes
bull 18 cancers
bull 24 chronic diseases
bull 1092 cells in spreadsheet
Large Personal Ongoing Research Investment
Huge Amount of Research Work
Toxins StudiedAluminum
Arsenic
Cadmium
Fluoride
Lead
Manganese
Mercury
Acrylamide
Acrylonitrile
Benzene
Bisphenol A (BPA)
Chloroform
DDT
Dioxins
Glyphosate
Organochlorine pesticides (OCPs)
Organophosphate pesticides
Parabens
Phthalates
Polybrominated diphenyl ethers (PBDEs)
Polycyclic aromatic hydrocarbons (PAHs)
Polychlorinated biphenols (PCBs)
Vinyl chloride
Diseases Studied
ADHD
Alzheimers Disease
ALS
Angiosarcoma
Anxiety
Atopic Conditions
Diabetes
Dyslipidemia
Gout
Fetal Abnormalities
Hyperuricemia
Infertility
Juvenile IQ
Cancer Bladder
Cancer Bone
Cancer Brain
Cancer Breast
Cancer Cervix
Cancer Colorectal
Cancer Endometrial
Cancer Head amp Neck
Cancer Liver
Cancer Lung
Cancer Lymph amp Blood
Cancer Ovarian
Cancer Pancreatic
Cancer Prostate
Cancer Renal
Cancer Skin
Cancer Testicular
Cancer Thyroid
Juvenile Obesity
Metabolic Syndrome
Mitochondrial dysfunction
Myocardial Infarction
Obstructive Lung Disease
Osteoporosis
Peripheral Artery Disease
Peripheral Neuropathy
Prediabetes
Renal Disease
Rheumatoid Arthritis
Thyroid Dysfunction
OC
Ps
Th
rou
gh
ou
t th
e W
orl
d
Rathore HS Nollet LML Pesticides Evaluation of Environmental Pollution CRC Press
2012 page 562
Threshold ndash Threshold exposure at which there is an increased risk of disease outcome
Above Threshold ndash Percentage of the population with higher exposure than the threshold
Odds Ratio ndash Increased disease risk in those above threshold
of Dz ndash Percent contribution of the toxin to that disease outcome
How to Interpret the Following Slides
Attention Deficit Hyperactivity Disorder
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
DDT 126 ngg
serum (pp-
DDE)
250 18 166 20106937
Lead 23 ugdL 13 254 20 27659349
Mercury 16 24952233
Organophosphate
pesticides
20
Polycyclic
Aromatic
Hydrocarbons
227 ngm3 940 125 190 22440811
PCBs 104 ngg
serum (sum
of 50 PCBs)
250 176 160 20106937
DiabetesToxin Threshold Above
Threshold
Odds
Ratio
of Dz Reference
PMID
Arsenic 165 ugL 200 21 180 18714061
BPA 28 ugL 280 145 112 26119400
DDE 545 ngg serum
(pp-DDE)
200 230 31 26119400
Dioxins2 pgg lipid 50 191 43
26119400
PCBs104 ngg (PCB 153) 250 239 258
26119400
Phthalates175 ugL 690 148 249
26119400
1-naphthalene 167 ugdL 152 182 111 26340343
2-napthalene 414 ugdL 550 224 214 26340343
1-phenanthrene 167 ngL 570 178 151 26340343
1-pyrene 85 ngL 660 180 174 26340343
Lung Cancer
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Acrylonitrile Uncertain Uncertain 125 25
occupational
exposure
17114112
Arsenic 1213 ugL 436 of Asian
Americans
~01 of total
US population
34 95 in AA
01-1
PMC2682945
Cadmium Uncertain+ Uncertain 467 10 in
smokers
17184399
DDT Any exposure All US pop
below LOD
17 76 increased
risk
8923607
Breast Cancer
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Cadmium 0580 ugg
creatinine
126 205 479 16788160
PCB 138 396 ngg
creatinine
202 316 630 27717745
PCB 187 108 ngg lipid 600 194 360 21480306
Miscellaneous Diseases
Toxin Disease Threshold Above
Threshold
Odds
Ratio
of Dz Reference PMID
Aluminum Alzheimer
Dz
01 mgL
drinking
H20
400 203 05-44 26592479
Benzene AML 100ppmyrs 1-3 320 60 PMC2903550
DDT NHL 0512 ugL 1-2 240 01 17722095
Lead ALS 238 ugdL
blood
330 181 210 25479292
Lead Brain CA 0005 ugdL 14 19 ~500 17164378
Dioxin-like
PCBs
RA 326 ngg
lipid
250 219 220 17589595
PAHs Asthma 124 ngm3 935 200 483 19221603
The Potency of Arsenic
Disease Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Bladder CA 10ugL H20 100 27 145 24889821
Pancreatic CA 1332 ugg 200 246 230 23800676
Prostate CA 1332 ugg 200 33 315 23800676
Gout 125 ugL 245 546 522 25499256
Diabetes 165 ugL 200 21 180 18714061
Arsenic (180 of Diabetes)
How it causes diabetes
bull Blocks sugar stimulating insulin secretion
bull Epigenetic inhibition of sugar regulation
Where it comes from
bull Water (gt10 of US water supplies have high levels)
bull Rice (naturally absorbs if in the water)
bull Chicken (added to make meat whiter)
Pan W-C Seow WJ Kile ML et al Association of low to moderate levels of arsenic exposure with risk of Type 2 diabetes in Bangladesh American Journal of Epidemiology 2013178(10)1563-70
Portion of Population with Toxin Load Which
Doubles Disease Risk
Toxin Disease with Doubled Risk
Polycyclic aromatic hydrocarbons Asthma 94
PCB187 Breast Cancer 60
Phthalates Diabetes 55
Lead ALS 33
Aluminum Alzheimers Disease 25
DDT ADHD 25
PCBs Diabetes 25
Dioxin-like PCBs Rheumatoid Arthritis 25
Arsenic Gout 23
Bisphenol A Diabetes 22
Cigarette smoking Lung Cancer 21
Arsenic Diabetes 20
Polycyclic aromatic hydrocarbons Diabetes 20
Huge Detoxification Variability
bull CYP2C19
Proton pump inhibitors and some antidepressants
5-fold difference in activity between poor metabolizers and extensive metabolizers more so if CYP3A4 is also inhibited
Ultrarapid allele in 18 of both Swedes and Ethiopians
bull CYP2D6
Metabolizes a large number of drugs (~25)
7 of Caucasians poor metabolizers
~30 ultra rapid metabolizers in Arabian and Eastern African populations
More adverse effects in poor metabolizers and ineffective dosing in ultrarapid metabolizers
Inhibited by ginger
Desta Z et al Clinical significance of the cytochrome P450 2C19 genetic polymorphism Clin Pharmaco 2002
Sim SC et al A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug
response to proton pump inhibitors and antidepressants Clin Pharmacol Ther 2006
Wilkinson GR Drug metabolism and variability among patients in drug response N Engl J Med 2005
Kirchheiner J et al Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to
CYP2D6 duplication Pharmacogenomics J 2007
Toxin Half Lives in BloodToxin ldquoNormalrdquo (mgL) Acute Toxic (mgL) Half-Life
Arsenic 0002-007 005-025 2-4 days (CDC)
Benzene 00002 05-10 days
Cadmium 00003-00065 0015-005 16 years
Chlordane 0001 00025 3-4 days
DDTDDE 2-10 years
Dieldrin 00015 015-030 2-12 months
Ethanol 1000-2000 15hour
Lead 009 04-06 1-15 mo (2+ yrs bone)
Mercury 00015-0002 005-02 2 months (CDC)
PCBs 3-25 years
Toluene 05-3 days
Schulz M et al Therapeutic and toxic blood concentrations of nearly 1000 drugs and other xenobiotics Crit Care 2012 Jul 2616(4)R136
Bioaccumulation (POPs)
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
DDT banned in 1972 PCBs banned in 1977
Bioaccumulation (Cd)
Think BroadlyExogenous
Metals
Chemicalsbull Inorganic
bull Fluoride
bull Organic
bull POPs
bull Drugs
Particulate matter
Molds
Microbial
Radiationbull Light
bull Medical
bull Cell phone
Endogenous
Gut-derived toxins
Non-end product metabolites
Poorly detoxified hormones
Catecholamines (if SNP)
Toxins of Choice
Alcohol
Marijuana
Food constituents
High fructose corn syrup
Salt (acid-forming diet)
Wheat if zonulin (70)
Obesity Epidemic ndash POPs AND HFCS
47Bray GA Fructose should we worry Int J Obes (Lond) 2008 Dec32 Suppl 7S127-31
How Toxins Cause Damage 13
bull Increase free radical production
Cd induces production of ROS
Malathion inhibits catalase and glutathione peroxidase
Homocysteine oxidizes LDL cholesterol
bull Poison enzyme systems (compete with nutritional cofactors for binding sites)
Pb poisons delta aminolevulinic acid dehydratase
Cd inhibits catalase glutathione reductase and lowers
glutathione levels
bull Replace structural minerals
Pb displaces Ca in bone
How Toxins Cause Damage 23
bull Damage DNA
Benzene - causes chromosomal damage
Pesticides ndash fruit growers have more DNA damage
Phthalates and insecticides ndash damage sperm DNA
4-hydroxy catechol estrogen (4-OHE) damages breast DNA
bull Epigenetic dysmodulation
Higher cord blood levels of hexachlorobenzene associated
with 2x greater risk for obesity in children
bull Damage cell membranes
Common mechanism for heavy metals inactivates
membrane enzymes ion channels and pumps
How Toxins Cause Damage 33
bull Block insulin receptor sites
PCBs and phthalates
bull Highest levels associated with a 4 to 20-fold greater diabetes risk
bull Imbalance hormones many toxin examples
Arsenic
bull Disrupts thyroid hormone and retinoic acid receptors
Phthalates
bull Act as anti-androgens
bull More than 75 of the US population has measurable levels of
several phthalate metabolites in the urine
PCBs
bull Lower testosterone levels in men
Which are the Worst Toxins
bull According to the CDC
Toxicity
Population toxic load
Prevalence in toxic waste sites
bull According to clinical importance
Exposure
of disease
Ability of the body to detoxifyexcrete
Ag
en
cy
fo
r T
oxic
Su
bs
tan
ce
s a
nd
Dis
ea
se
Reg
istr
y
Pri
ori
ty L
ist
The Worst Toxins Clinically
My Rank Toxin Diseases Primary Sources
1 Arsenic Cancers diabetes gout Water chicken rice
2 DDT ADHD dementia diabetes Everywhere
3 Phthalates ADHD diabetes Soft plastics HABAs
4 PBDEs ADHD diabetes Flame retardant fabrics
5 PAHs ADHD cancers dyslipidemia Smoking charbroiling
6 PCBs Cancers diabetes MI RA Everywhere
7 Mercury Dementia ldquoSilverrdquo fillings fish
8 Lead Cardiovascular disease IQ Paint water
Glyphosate Research invalid
Conventional Laboratory Tests Reflect
Toxic Load in ldquoNormalrdquo Range
bull Surprising number show toxin exposure
CBC RBC WBC platelet count hemoglobin basophilic
stippling
Liver enzymes ALT GGTP
Inflammatory markers CRP
Lipids LDL oxLDL triglycerides
Blood sugar insulin FBS 2-hour PP
Metabolites bilirubin uric acid homocysteine 8-OHdG
Thyroid T3 T4 TSH
bull The historic ldquonormalrdquo range has been changing as the population has become more toxic
WBC Lowered by PCB and OCP Exposure
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
0
1
2
3
4
5
6
7
8
1st Quartrile 2nd Quartile 3rd Quartile 4th Quartile
WBCbull Strong inverse correlation with PCBs and OCPs and CBC
bull Linear with almost all PCBs
bull High variability with OCPs
bull Within ldquonormalrdquo range
Effects on WBC Worsen with Years
of Exposure to Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Platelet Count Decreases with Years
of Exposure tp Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Solvents Decrease Platelet Count
bull Compared workers exposed 23 hrday to those exposed most of day to toluene
bull All wore face masks and protective gear
bull Platelet count 14 lower 252 versus 216ml
bull Impairment of sympathetic nerves (OR = 413)
bull Impairment of peripheral nerves (OR = 694)
bull Positive relationship between neurological abnormalities and a self-reported neuropsychiatric measurement (r = 035-066)
Shih HT et al Subclinical abnormalities in workers with continuous low-level toluene exposure Toxicol Ind Health 2011 Sep27(8)691-9
Basophilic Stippling of Red Cells
Toxinsbull Arsenic
bull Lead
Diseasesbull Alpha-thalassemia HbH Disease
bull Beta thalassemia
bull Hereditary pyrimidine 5-nucleotidase deficiency
bull Myelodysplastic syndrome
bull Sideroblastic anemia
bull Thrombotic thrombocytopenic purpura
GGT Indirect Measure of POPsbull Glutathione is key intracellular defense against oxidative stress
bull Cellular GGT metabolizes extracellular GSH allowing precursor amino acids to be reutilized for intracellular GSH
bull Exposure to POPs induces GGT as a defensive mechanism
bull Within normal range predicts type 2 diabetes coronary heart disease hypertension stroke dyslipidemia chronic kidney disease and cancer
bull Men with GGT gt50 UI had ~26 fold risk for diabetes compared to those with lt10 Those with 40-49 had a ~20 fold risk
bull Levels within normal range occur with obesity xs alcohol cigarette smoking physical inactivity high meat low fruit and vegetable intake
bull Cumulative biomarker for environmental pollutants
Lee DH et al (2003) Gamma-glutamyltransferase and diabetesmdasha 4 year follow-up study Diabetologia 46359ndash364
Pamela A et al Serum gamma-glutamyltransferase linking together environmental pollution redox equilibria and progression of atherosclerosis Clin Chem
Lab Med 200947(12)1583-4
Lee DH et al Serum gamma-glutamyltransferase new insights about an old enzyme J Epidemiol Community Health 2009 Nov63(11)884-6
Lee DH et alSerum gamma-glutamyltransferase predicts non-fatal myocardial infarction and fatal coronary heart disease among 28838 middle-aged men and
women Eur Heart J 2006272170ndash6
Lee DH et al Gamma-glutamyltransferase and diabetes--a 4 year follow-up study Diabetologia 2003 Mar46(3)359-64
Lee DH et al Can persistent organic pollutants explain the association between serum gamma-glutamyltransferase and type 2 diabetes Diabetologia 2008
Mar51(3)402-7
GGT and Alcohol Consumption
bull GGT directly correlates with alcohol consumption
bull In a non-uniform population 40 gd will elevate GGT ~15
bull Watch for false negatives
bull Genomic variation
bull Are these the ones most
sensitive todamaged by
chemical toxins
bull Could up-regulation of GGT in light alcohol consumption be reason for benefit
0
10
20
30
40
50
60
70
80
0 200 400 600 800
Grams of Ethanol per Week
Adapted from Nagaya T et al Dose-response relationships between drinking and serum tests in Japanese men
aged 40ndash59 years Alcohol 1999 Feb 17(2) 133ndash8
GGT Correlates With Toxic Metal Levels
Lee DH et al Graded associations of blood lead and urinary cadmium concentrations with oxidative-stress-related markers in the
US population results from the third National Health and Nutrition Examination Survey Environ Health
perspect 2006 Mar114(3)350-4
GGT and Diabetes Risk
0
5
10
15
20
25
30
lt10 10-19 20-29 30-39 40-49 gt50
Dia
bete
s R
isk
GGT
bull GGT over 50 associated with tripling of death rate
bull 30-40 associated with doubling
GGT Levels
Correlate with
Risk of Death
Brenner H et al Distribution determinants and prognostic value of gamma-glutamyltransferase for all-cause
mortality in a cohort of construction workers from southern Germany Prev Med 1997 26 305ndash10
GGT From Small US Company
with Young Workers
0
10
20
30
40
50
60
0 20 40 60 80 100
GGT Data from Canadian Oil Field
Workers
0
50
100
150
200
250
300
350
400
450
lt10 10-20 20-30 30-40 40-50 50-60 60-07 70-80 80-90 90-100 100-110 110-120 gt120
GGTP
20-fold increased risk of diabetes
Uric Acid Indirect Measure of POPs
bull Poly-fluorinated hydrocarbons (PFOA and PFOS) associated
with increased serum uric acid
Lin CY et al Association among serum perfluoroalkyl chemicals glucose homeostasis and metabolic syndrome
in adolescents and adults Diabetes Care 2009 Apr32(4)702-7
Steenland K et al Association of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) with uric
acid among adults with elevated community exposure to PFOA Environ Health Perspect 2010 Feb118229-33
Steenland 2010 Open Access
ALT Indirect Measure of POPs
bull ALT (proxy marker) elevation in 104 (not including viral
hepatitis hemochromatosis or alcoholic liver disease) of
NHANES 03-04 subset
bull Risk of elevated ALT increased dose-dependently with
cadmium lead mercury and PCB exposure
bull 100 of individuals had detectable PCBs 925 mercury
and 996 had detectable lead
bull In 2005-08 prevalence of NAFLD in US was 11 a
growing cause of chronic liver disease
Cave M et al Polychlorinated biphenyls lead and mercury are associated with liver disease in American adults
NHANES 2003-2004 Environ Health Perspect 2010 Dec118(12)1735-42
Younossi ZM et al Changes in the prevalence of the most common causes of chronic liver diseases in the United
States from 1988 to 2008 Clin Gastroenterol Hepatol 2011 Jun9(6)524-530e1
Bilirubin as a Marker of POPs
bull Degree of serum bilirubin increase is prognostically significant in chronic liver dysfunction
bull Mono-ortho PCB TEQ values were found to be significantly positively associated with bilirubin (β=071 P=0008) following adjustment for multiple potential confounders
bull Bilirubin levels significantly correlated with PCBs -105-118-126 and -194
bull Smoking appears to be the biggest confounder
Dufour DR et al 2000 Diagnosis and monitoring of hepatic injury II Recommendations for use of laboratory
tests in screening diagnosis and monitoring Clin Chem 46 2050ndash68
Kumar J et al Persistent organic pollutants and liver dysfunction biomarkers in a population-based human sample
of men and women Environ Res 2014134251-256
Perf
luo
rin
ate
dP
OP
s a
nd
Co
mm
on
Blo
od
Tests
Gleason JA et al Associations of perfluorinated chemical serum concentrations and biomarkers of liver function and uric acid in the
US population (NHANES) 2007-2010 Environ Res 20151368-14
Liver Enzymes Reflect Toxic Load
bull AST ALT and GGT increase with body load of PCBs and OCPs
bull Some non-linear
bull Oxychlordanetop quartile
ALT 10
GGT 25
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
LDL-Cholesterol as Measure of POPs
bull 5-year prospective study to determine if POP levels predict future elevation in LDL-cholesterol
bull 598 subjects initially at age 70
bull Looked at 23 POPs
bull Best correlation with PCB 194
Penell J Lind L Salihovic S et al Persistent organic pollutants are related to change in circulating
lipid levels during a 5 year follow-up Environ Res 134(2014)190ndash197
oxLDL as Measure of POPs
bull 992 70-year old individuals (50 women)
bull Sum of PCBs showed strong significant positive associations with ox-LDL and significant negative associations with glutathione-related markers (GSSG and GSSGGSH)
bull A number of POPs (PCB-99 138 153 156 170 180 194 206 and 209) showed strong significant positive association with ox-LDL
Kumar J et al Influence of persistent organic pollutants on oxidative stress in population-based samples
Chemosphere 2014114303-309
Homocysteine is Increased by Pb amp Cd
Guallar E et al Confounding of the relation between homocysteine and peripheral arterial disease by lead cadmium and renal function Am J Epidemiol 2006 Apr 15163(8)700-8
Nutrient Deficiencies Accentuate
Effects of Lead on Homocysteine
bull Deficiencies in folate B6 or B12 make lead more toxic
Lee YM Et al Association of homocysteine levels with blood lead levels and micronutrients in the US general population J Prev Med Public Health 2012 Nov45(6)387-93
T4 amp T3 and PCBs
bull PCBs decrease T4 production
bull PCBs inhibit iodotyrosinedeiodinase activity
bull Study done in pregnant women which implies effect on fetus IQ
Kim S Park J Kim HJ et al Association between several persistent organic pollutants and thyroid hormone levels in serum among the pregnant women of Korea Environ Int 2013 Sep59442-8Shimizu R Yamaguchi M Uramaru N et al Structure-activity relationships of 44 halogenated compounds for iodotyrosinedeiodinase-inhibitory activity Toxicology 2013 Dec 6314(1)22-9
T4 amp T3 and PCBs
bull Not just humans being affected
bull Large study of dolphins shows exactly the same effects
Schwacke LH Zolman ES Balmer BC et al Anaemia hypothyroidism and immune suppression associated with polychlorinated biphenyl exposure in bottlenose dolphins (Tursiops truncatus) Proceed Royal Society B doi101098rspb20110665
8-OHdG
bull Oxidized nucleoside
bull Direct measure of DNA damage
bull Indirect measure of oxidative stress and toxin load
bull Correlates with
Multiple cancers
Mitochondrial damage
Rate of aging
Smoking
Several toxinsWalter Crinnion ldquoTotal Toxic Loadrdquo AANP 2015
8-OHdG Correlates with Pack-Years
of Smoking
Yano T et al Significance of the urinary 8-OHdG level as an oxidative stress marker in lung cancer patients Lung Cancer
2009 Jan63(1)111-4
8-OHdG Correlates
with Mercury
Chen C et al Increased oxidative DNA damage as assessed by urinary 8-hydroxy-2-deoxyguanosine
concentrations and serum redox status in persons exposed to mercury Clin Chem 2005 Apr51(4)759-67
Toxin Effects Worse with Aging
bull Thyroid function decreases with PFOA levels
bull But only after age 63
Shrestha S Bloom MS Yucel R et al Perfluoroalkyl substances and thyroid function in older adults Environ Int 2015 Feb75206-14
Insightful 23-Year Prospective Study
1 lt 50 there is no difference between those with the lowest and highest PCBs
2 In youngest group insulin production increases in response to toxin level As expected since blocking of
insulin receptor sites by PCBs
requires more insulin
3 That adaptive ability decreases with aging
4 At age 50 all the measures show very strong toxin-dose response
Cumulative damage impairs ability to adapt
Suarez-Lopez JR et al Persistent organic pollutants in young adults and changes in glucose related metabolism over a 23-year follow-up Environ Res 2015 Feb137485-94
Recommendations
High body toxic load
GGT gt 25
Uric acid gt 50 mgdl
ALT gt30 UL
Bilirubin gt08 mgdl
CBC lt 6000
Platelet lt 250000
Low T3 andor T4
Monitor Total Toxic Load
8-OHdG gt4
ldquoUnconventionalrdquo Laboratory Tests
bull Challenge testing
bull Hair analysis
bull Direct measures of solvents and POPs in blood urine adipose tissue
Evaluation of Metal Exposure ndash Provocation
bull Provocation ndash the use of a chelating agent ndash before urine collection often done clinically but several limitations
No ldquoofficialrdquo reference range for provoked urine
Most chelating agents do not extract metals from all tissues thus
does not necessarily represent total body burden
bull Example Brain is one of the main target organs for both elemental and organic
mercury yet agents do not chelate brain mercury
bull Despite limitations widely used and advocated by clinicians in part to see efficacy of chelating agent as a guide to treatment and based on empirical evidence
Rooney JP The role of thiols dithiols nutritional factors and interacting ligands in the toxicology of mercury
Toxicology 2007
Is Challenge Testing Valid
bull Poor correlations of standard tests for mercury
bull Unpublished research from corporate wellness project
bull Published amalgam number correlation
bull Published fish consumption correlation
What We Found In Canada
bull Deviations from the mean of 14 29 and 91 respectively
bull DMPS is spreading distribution suggesting that it is better at differentiating mercury body load
bull Some VERY high
Hg Assessment Correlations
bull Extensive measurements in 65 Whole blood Hg
Oral DMPS challenge
Amalgam surfaces
bull Correlations Whole blood w pre urine r = 040
Whole blood w post urine r = 057
Pre urine w post urine r = 068
Amalgams w pre urine r = 026
Amalgams w whole blood r = 036
Amalgams with post urine 044
bull Clear documentation that
challenge testing is better00
100
200
300
400
500
600
0 10 20 30 40 50
Po
st
Uri
ne H
g u
gg
Number of amalgams
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
Increase in Diabetes Due to Sugar
httpwholehealthsourceblogspotcom201202by-2606-us-diet-will-be-100-percenthtml
Dia
bete
s 1
How About Persistent Organic Pollutants
Neel BA Robert M Sargis RM The paradox of progress Environmental disruption of metabolism and the diabetes epidemic DIABETES 2011 601838-48
Lars Jaumlrup Br Med Bull 200368167-182copy The British Council 2003 all rights reserved
Global Production and Consumption of
Selected Toxic Metals 1850ndash1990
Cadmium World Production
Mercury in the Air
EPA-452R-97-003 December 1997
Mercury in Water
httpwaterepagovscitechdataitmodelsmapspostercfm
Ground Water Sources of Arsenic
bull 10 of US public water supplies have levels of arsenic known to induce disease
bull No data on private water supplies
httpwwwatsdrcdcgovcsemarsenicdocsarsenicpdf (accessed 2015-08-18)
Example POPs
Chemical Abbr Uses Exposure
Bisphenol A BPA Plastics Canned food
Organochlorine
pesticides
OCPs Pesticide Food fumigation
Organophosphate
pesticides
OPPs Pesticide Food
Polybrominated
diphenyl ethers
PBDEs Flame retardant Clothing
Polychlorinated
biphenyls
PCBs Industrial Everywhere
Perflourinated PFOAs Non-stick stain prevention
water repellant
Teflon Gortex
Scotchguard
Phthalates Plastics fragrances Shower curtains
cosmetics
POPs - Prediabetes
bull Over 1200 participants fasting
glucose and OGTT performed
with serum levels of 5 POPs
bull All individual POPs tested were
associated with progressive
increase in prevalence of
prediabetes
bull More than triple prevalence of
prediabetes seen in those in the
5th quartile with a synergistic
effect from 5 POPs
Ukropec J et al High prevalence of prediabetes and diabetes in a population exposed to high levels of an organochlorine cocktail
Diabetologia 2010 May53(5)899-906
POPs and Diabetes Risk
Graph httpwwwourstolenfutureorgNewScienceobesity20062006-0715leeetalhtml
Data Lee DH Lee IK Song K et al A strong dose-response relation between serum
concentrations of persistent organic pollutants and diabetes results from the National Health and
Examination Survey 1999-2002 Diabetes Care 2006 Jul29(7)1638-44
Toxic Load and Disease Risk
References for Toxins and Disease Risk
Converting Disease Risk to Caused
Attributable Fraction Calculation
p = underlying prevalence of risk factor in the population
rr = relative risk (risk of contracting a disease in an exposed population divided by the risk of contracting the disease in an unexposed population)
AF = of disease due to the toxin
Levin M The occurrence of lung cancer in man Acta Unio Int Contra Cancrum 1953 9 531-541
Example Smoking and Lung Cancer
B = 5Number of smokers
who contract Lung Cancer notdue to smoking
A = 5Number of smokerswho contract Lung
Cancer due to smoking
C = 15Number of
nonsmokerswho contract Lung Cancer
0
2
4
6
8
10
12
14
16
Smokers (N=100) Nonsmokers (N=300)Num
ber
of
people
who c
ontr
act
Lung C
ancer
per
year
Baseline Additional due to smoking
Number of smokers and nonsmokers who contract lung cancer
Our Process In Summary
1 Determine threshold for increased disease risk
2 Determine of population above threshold
3 Determine incidence of disease (OR) in those above threshold
4 Determine incidence of disease in ldquounexposed populationrdquo
5 Calculate AF ie of disease
As whole population is exposed probably UNDERESTIMATES of disease
To
xic
ity H
as B
eco
me t
he N
ew
ldquoN
orm
alrdquo
Toxin Type Use Threshold for
disease
association
of US
above
threshold
Disease Associations
Chlordane OC pesticide Termites corn citrus lawns
gardens
145ngg lipid 63
(diabetes)
Diabetes (20)
BPA Plasticizer Water bottles canned food
water pipes thermal sales
receipts
48 men 51
women (urine
ngmL)
~18
(diabetes)
Diabetes hypertension
Octachloro
dibenzo-p-
dioxin
(OCDD)
Polychlorinated
dibenzo-p-
dioxin
Incineration or burning of
waste bleaching processes
used in pulp and paper mills
1010 pgg
lipid (highest
quartile)
10-25
(hypertensio
n)
Hypertension (79 for
women highest
quartile) diabetes (21)
obesity learning
disability (272)
MEP
(mono-
ethyl
phthalate)
Phthalate
(plasticizer
fragrance)
Toothbrushes automobile
parts tools toys and food
packaging aspirin
cosmetics food packaging
gt175 ngmL
(urine)
~60
(diabetes)
Diabetes (148) lower
BMD obesity
pp-DDE DDT
metabolite (OC
pesticide)
Agricultural crops 1560ngg
lipid
25
(diabetes)
Diabetes (23-43)
early menopause
impaired cognitive
function (2-3x 65x in
highest 5th percentile)
peripheral arterial
disease
Arsenic Toxic metal Miningsmelting wood
preservative pesticides
74ugL total
arsenic (urine)
20
(diabetes)
Cancers diabetes (26-
46) dyslipidemia gout
AF OR Prevalence
Rosen L An intuitive approach to understanding the attributable fraction of disease due to a risk factor the case of smoking Int J Environ Res Public Health 2013 Jul 1610(7)2932-43
Smoking Lung cancer
Arsenic Gout in women
BPA Diabetes
Status of Our Research
bull 26 toxins and toxin classes eg lead mercury BPA OCPs
100s of chemicals and POPs in some classes
bull 18 cancers
bull 24 chronic diseases
bull 1092 cells in spreadsheet
Large Personal Ongoing Research Investment
Huge Amount of Research Work
Toxins StudiedAluminum
Arsenic
Cadmium
Fluoride
Lead
Manganese
Mercury
Acrylamide
Acrylonitrile
Benzene
Bisphenol A (BPA)
Chloroform
DDT
Dioxins
Glyphosate
Organochlorine pesticides (OCPs)
Organophosphate pesticides
Parabens
Phthalates
Polybrominated diphenyl ethers (PBDEs)
Polycyclic aromatic hydrocarbons (PAHs)
Polychlorinated biphenols (PCBs)
Vinyl chloride
Diseases Studied
ADHD
Alzheimers Disease
ALS
Angiosarcoma
Anxiety
Atopic Conditions
Diabetes
Dyslipidemia
Gout
Fetal Abnormalities
Hyperuricemia
Infertility
Juvenile IQ
Cancer Bladder
Cancer Bone
Cancer Brain
Cancer Breast
Cancer Cervix
Cancer Colorectal
Cancer Endometrial
Cancer Head amp Neck
Cancer Liver
Cancer Lung
Cancer Lymph amp Blood
Cancer Ovarian
Cancer Pancreatic
Cancer Prostate
Cancer Renal
Cancer Skin
Cancer Testicular
Cancer Thyroid
Juvenile Obesity
Metabolic Syndrome
Mitochondrial dysfunction
Myocardial Infarction
Obstructive Lung Disease
Osteoporosis
Peripheral Artery Disease
Peripheral Neuropathy
Prediabetes
Renal Disease
Rheumatoid Arthritis
Thyroid Dysfunction
OC
Ps
Th
rou
gh
ou
t th
e W
orl
d
Rathore HS Nollet LML Pesticides Evaluation of Environmental Pollution CRC Press
2012 page 562
Threshold ndash Threshold exposure at which there is an increased risk of disease outcome
Above Threshold ndash Percentage of the population with higher exposure than the threshold
Odds Ratio ndash Increased disease risk in those above threshold
of Dz ndash Percent contribution of the toxin to that disease outcome
How to Interpret the Following Slides
Attention Deficit Hyperactivity Disorder
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
DDT 126 ngg
serum (pp-
DDE)
250 18 166 20106937
Lead 23 ugdL 13 254 20 27659349
Mercury 16 24952233
Organophosphate
pesticides
20
Polycyclic
Aromatic
Hydrocarbons
227 ngm3 940 125 190 22440811
PCBs 104 ngg
serum (sum
of 50 PCBs)
250 176 160 20106937
DiabetesToxin Threshold Above
Threshold
Odds
Ratio
of Dz Reference
PMID
Arsenic 165 ugL 200 21 180 18714061
BPA 28 ugL 280 145 112 26119400
DDE 545 ngg serum
(pp-DDE)
200 230 31 26119400
Dioxins2 pgg lipid 50 191 43
26119400
PCBs104 ngg (PCB 153) 250 239 258
26119400
Phthalates175 ugL 690 148 249
26119400
1-naphthalene 167 ugdL 152 182 111 26340343
2-napthalene 414 ugdL 550 224 214 26340343
1-phenanthrene 167 ngL 570 178 151 26340343
1-pyrene 85 ngL 660 180 174 26340343
Lung Cancer
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Acrylonitrile Uncertain Uncertain 125 25
occupational
exposure
17114112
Arsenic 1213 ugL 436 of Asian
Americans
~01 of total
US population
34 95 in AA
01-1
PMC2682945
Cadmium Uncertain+ Uncertain 467 10 in
smokers
17184399
DDT Any exposure All US pop
below LOD
17 76 increased
risk
8923607
Breast Cancer
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Cadmium 0580 ugg
creatinine
126 205 479 16788160
PCB 138 396 ngg
creatinine
202 316 630 27717745
PCB 187 108 ngg lipid 600 194 360 21480306
Miscellaneous Diseases
Toxin Disease Threshold Above
Threshold
Odds
Ratio
of Dz Reference PMID
Aluminum Alzheimer
Dz
01 mgL
drinking
H20
400 203 05-44 26592479
Benzene AML 100ppmyrs 1-3 320 60 PMC2903550
DDT NHL 0512 ugL 1-2 240 01 17722095
Lead ALS 238 ugdL
blood
330 181 210 25479292
Lead Brain CA 0005 ugdL 14 19 ~500 17164378
Dioxin-like
PCBs
RA 326 ngg
lipid
250 219 220 17589595
PAHs Asthma 124 ngm3 935 200 483 19221603
The Potency of Arsenic
Disease Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Bladder CA 10ugL H20 100 27 145 24889821
Pancreatic CA 1332 ugg 200 246 230 23800676
Prostate CA 1332 ugg 200 33 315 23800676
Gout 125 ugL 245 546 522 25499256
Diabetes 165 ugL 200 21 180 18714061
Arsenic (180 of Diabetes)
How it causes diabetes
bull Blocks sugar stimulating insulin secretion
bull Epigenetic inhibition of sugar regulation
Where it comes from
bull Water (gt10 of US water supplies have high levels)
bull Rice (naturally absorbs if in the water)
bull Chicken (added to make meat whiter)
Pan W-C Seow WJ Kile ML et al Association of low to moderate levels of arsenic exposure with risk of Type 2 diabetes in Bangladesh American Journal of Epidemiology 2013178(10)1563-70
Portion of Population with Toxin Load Which
Doubles Disease Risk
Toxin Disease with Doubled Risk
Polycyclic aromatic hydrocarbons Asthma 94
PCB187 Breast Cancer 60
Phthalates Diabetes 55
Lead ALS 33
Aluminum Alzheimers Disease 25
DDT ADHD 25
PCBs Diabetes 25
Dioxin-like PCBs Rheumatoid Arthritis 25
Arsenic Gout 23
Bisphenol A Diabetes 22
Cigarette smoking Lung Cancer 21
Arsenic Diabetes 20
Polycyclic aromatic hydrocarbons Diabetes 20
Huge Detoxification Variability
bull CYP2C19
Proton pump inhibitors and some antidepressants
5-fold difference in activity between poor metabolizers and extensive metabolizers more so if CYP3A4 is also inhibited
Ultrarapid allele in 18 of both Swedes and Ethiopians
bull CYP2D6
Metabolizes a large number of drugs (~25)
7 of Caucasians poor metabolizers
~30 ultra rapid metabolizers in Arabian and Eastern African populations
More adverse effects in poor metabolizers and ineffective dosing in ultrarapid metabolizers
Inhibited by ginger
Desta Z et al Clinical significance of the cytochrome P450 2C19 genetic polymorphism Clin Pharmaco 2002
Sim SC et al A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug
response to proton pump inhibitors and antidepressants Clin Pharmacol Ther 2006
Wilkinson GR Drug metabolism and variability among patients in drug response N Engl J Med 2005
Kirchheiner J et al Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to
CYP2D6 duplication Pharmacogenomics J 2007
Toxin Half Lives in BloodToxin ldquoNormalrdquo (mgL) Acute Toxic (mgL) Half-Life
Arsenic 0002-007 005-025 2-4 days (CDC)
Benzene 00002 05-10 days
Cadmium 00003-00065 0015-005 16 years
Chlordane 0001 00025 3-4 days
DDTDDE 2-10 years
Dieldrin 00015 015-030 2-12 months
Ethanol 1000-2000 15hour
Lead 009 04-06 1-15 mo (2+ yrs bone)
Mercury 00015-0002 005-02 2 months (CDC)
PCBs 3-25 years
Toluene 05-3 days
Schulz M et al Therapeutic and toxic blood concentrations of nearly 1000 drugs and other xenobiotics Crit Care 2012 Jul 2616(4)R136
Bioaccumulation (POPs)
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
DDT banned in 1972 PCBs banned in 1977
Bioaccumulation (Cd)
Think BroadlyExogenous
Metals
Chemicalsbull Inorganic
bull Fluoride
bull Organic
bull POPs
bull Drugs
Particulate matter
Molds
Microbial
Radiationbull Light
bull Medical
bull Cell phone
Endogenous
Gut-derived toxins
Non-end product metabolites
Poorly detoxified hormones
Catecholamines (if SNP)
Toxins of Choice
Alcohol
Marijuana
Food constituents
High fructose corn syrup
Salt (acid-forming diet)
Wheat if zonulin (70)
Obesity Epidemic ndash POPs AND HFCS
47Bray GA Fructose should we worry Int J Obes (Lond) 2008 Dec32 Suppl 7S127-31
How Toxins Cause Damage 13
bull Increase free radical production
Cd induces production of ROS
Malathion inhibits catalase and glutathione peroxidase
Homocysteine oxidizes LDL cholesterol
bull Poison enzyme systems (compete with nutritional cofactors for binding sites)
Pb poisons delta aminolevulinic acid dehydratase
Cd inhibits catalase glutathione reductase and lowers
glutathione levels
bull Replace structural minerals
Pb displaces Ca in bone
How Toxins Cause Damage 23
bull Damage DNA
Benzene - causes chromosomal damage
Pesticides ndash fruit growers have more DNA damage
Phthalates and insecticides ndash damage sperm DNA
4-hydroxy catechol estrogen (4-OHE) damages breast DNA
bull Epigenetic dysmodulation
Higher cord blood levels of hexachlorobenzene associated
with 2x greater risk for obesity in children
bull Damage cell membranes
Common mechanism for heavy metals inactivates
membrane enzymes ion channels and pumps
How Toxins Cause Damage 33
bull Block insulin receptor sites
PCBs and phthalates
bull Highest levels associated with a 4 to 20-fold greater diabetes risk
bull Imbalance hormones many toxin examples
Arsenic
bull Disrupts thyroid hormone and retinoic acid receptors
Phthalates
bull Act as anti-androgens
bull More than 75 of the US population has measurable levels of
several phthalate metabolites in the urine
PCBs
bull Lower testosterone levels in men
Which are the Worst Toxins
bull According to the CDC
Toxicity
Population toxic load
Prevalence in toxic waste sites
bull According to clinical importance
Exposure
of disease
Ability of the body to detoxifyexcrete
Ag
en
cy
fo
r T
oxic
Su
bs
tan
ce
s a
nd
Dis
ea
se
Reg
istr
y
Pri
ori
ty L
ist
The Worst Toxins Clinically
My Rank Toxin Diseases Primary Sources
1 Arsenic Cancers diabetes gout Water chicken rice
2 DDT ADHD dementia diabetes Everywhere
3 Phthalates ADHD diabetes Soft plastics HABAs
4 PBDEs ADHD diabetes Flame retardant fabrics
5 PAHs ADHD cancers dyslipidemia Smoking charbroiling
6 PCBs Cancers diabetes MI RA Everywhere
7 Mercury Dementia ldquoSilverrdquo fillings fish
8 Lead Cardiovascular disease IQ Paint water
Glyphosate Research invalid
Conventional Laboratory Tests Reflect
Toxic Load in ldquoNormalrdquo Range
bull Surprising number show toxin exposure
CBC RBC WBC platelet count hemoglobin basophilic
stippling
Liver enzymes ALT GGTP
Inflammatory markers CRP
Lipids LDL oxLDL triglycerides
Blood sugar insulin FBS 2-hour PP
Metabolites bilirubin uric acid homocysteine 8-OHdG
Thyroid T3 T4 TSH
bull The historic ldquonormalrdquo range has been changing as the population has become more toxic
WBC Lowered by PCB and OCP Exposure
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
0
1
2
3
4
5
6
7
8
1st Quartrile 2nd Quartile 3rd Quartile 4th Quartile
WBCbull Strong inverse correlation with PCBs and OCPs and CBC
bull Linear with almost all PCBs
bull High variability with OCPs
bull Within ldquonormalrdquo range
Effects on WBC Worsen with Years
of Exposure to Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Platelet Count Decreases with Years
of Exposure tp Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Solvents Decrease Platelet Count
bull Compared workers exposed 23 hrday to those exposed most of day to toluene
bull All wore face masks and protective gear
bull Platelet count 14 lower 252 versus 216ml
bull Impairment of sympathetic nerves (OR = 413)
bull Impairment of peripheral nerves (OR = 694)
bull Positive relationship between neurological abnormalities and a self-reported neuropsychiatric measurement (r = 035-066)
Shih HT et al Subclinical abnormalities in workers with continuous low-level toluene exposure Toxicol Ind Health 2011 Sep27(8)691-9
Basophilic Stippling of Red Cells
Toxinsbull Arsenic
bull Lead
Diseasesbull Alpha-thalassemia HbH Disease
bull Beta thalassemia
bull Hereditary pyrimidine 5-nucleotidase deficiency
bull Myelodysplastic syndrome
bull Sideroblastic anemia
bull Thrombotic thrombocytopenic purpura
GGT Indirect Measure of POPsbull Glutathione is key intracellular defense against oxidative stress
bull Cellular GGT metabolizes extracellular GSH allowing precursor amino acids to be reutilized for intracellular GSH
bull Exposure to POPs induces GGT as a defensive mechanism
bull Within normal range predicts type 2 diabetes coronary heart disease hypertension stroke dyslipidemia chronic kidney disease and cancer
bull Men with GGT gt50 UI had ~26 fold risk for diabetes compared to those with lt10 Those with 40-49 had a ~20 fold risk
bull Levels within normal range occur with obesity xs alcohol cigarette smoking physical inactivity high meat low fruit and vegetable intake
bull Cumulative biomarker for environmental pollutants
Lee DH et al (2003) Gamma-glutamyltransferase and diabetesmdasha 4 year follow-up study Diabetologia 46359ndash364
Pamela A et al Serum gamma-glutamyltransferase linking together environmental pollution redox equilibria and progression of atherosclerosis Clin Chem
Lab Med 200947(12)1583-4
Lee DH et al Serum gamma-glutamyltransferase new insights about an old enzyme J Epidemiol Community Health 2009 Nov63(11)884-6
Lee DH et alSerum gamma-glutamyltransferase predicts non-fatal myocardial infarction and fatal coronary heart disease among 28838 middle-aged men and
women Eur Heart J 2006272170ndash6
Lee DH et al Gamma-glutamyltransferase and diabetes--a 4 year follow-up study Diabetologia 2003 Mar46(3)359-64
Lee DH et al Can persistent organic pollutants explain the association between serum gamma-glutamyltransferase and type 2 diabetes Diabetologia 2008
Mar51(3)402-7
GGT and Alcohol Consumption
bull GGT directly correlates with alcohol consumption
bull In a non-uniform population 40 gd will elevate GGT ~15
bull Watch for false negatives
bull Genomic variation
bull Are these the ones most
sensitive todamaged by
chemical toxins
bull Could up-regulation of GGT in light alcohol consumption be reason for benefit
0
10
20
30
40
50
60
70
80
0 200 400 600 800
Grams of Ethanol per Week
Adapted from Nagaya T et al Dose-response relationships between drinking and serum tests in Japanese men
aged 40ndash59 years Alcohol 1999 Feb 17(2) 133ndash8
GGT Correlates With Toxic Metal Levels
Lee DH et al Graded associations of blood lead and urinary cadmium concentrations with oxidative-stress-related markers in the
US population results from the third National Health and Nutrition Examination Survey Environ Health
perspect 2006 Mar114(3)350-4
GGT and Diabetes Risk
0
5
10
15
20
25
30
lt10 10-19 20-29 30-39 40-49 gt50
Dia
bete
s R
isk
GGT
bull GGT over 50 associated with tripling of death rate
bull 30-40 associated with doubling
GGT Levels
Correlate with
Risk of Death
Brenner H et al Distribution determinants and prognostic value of gamma-glutamyltransferase for all-cause
mortality in a cohort of construction workers from southern Germany Prev Med 1997 26 305ndash10
GGT From Small US Company
with Young Workers
0
10
20
30
40
50
60
0 20 40 60 80 100
GGT Data from Canadian Oil Field
Workers
0
50
100
150
200
250
300
350
400
450
lt10 10-20 20-30 30-40 40-50 50-60 60-07 70-80 80-90 90-100 100-110 110-120 gt120
GGTP
20-fold increased risk of diabetes
Uric Acid Indirect Measure of POPs
bull Poly-fluorinated hydrocarbons (PFOA and PFOS) associated
with increased serum uric acid
Lin CY et al Association among serum perfluoroalkyl chemicals glucose homeostasis and metabolic syndrome
in adolescents and adults Diabetes Care 2009 Apr32(4)702-7
Steenland K et al Association of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) with uric
acid among adults with elevated community exposure to PFOA Environ Health Perspect 2010 Feb118229-33
Steenland 2010 Open Access
ALT Indirect Measure of POPs
bull ALT (proxy marker) elevation in 104 (not including viral
hepatitis hemochromatosis or alcoholic liver disease) of
NHANES 03-04 subset
bull Risk of elevated ALT increased dose-dependently with
cadmium lead mercury and PCB exposure
bull 100 of individuals had detectable PCBs 925 mercury
and 996 had detectable lead
bull In 2005-08 prevalence of NAFLD in US was 11 a
growing cause of chronic liver disease
Cave M et al Polychlorinated biphenyls lead and mercury are associated with liver disease in American adults
NHANES 2003-2004 Environ Health Perspect 2010 Dec118(12)1735-42
Younossi ZM et al Changes in the prevalence of the most common causes of chronic liver diseases in the United
States from 1988 to 2008 Clin Gastroenterol Hepatol 2011 Jun9(6)524-530e1
Bilirubin as a Marker of POPs
bull Degree of serum bilirubin increase is prognostically significant in chronic liver dysfunction
bull Mono-ortho PCB TEQ values were found to be significantly positively associated with bilirubin (β=071 P=0008) following adjustment for multiple potential confounders
bull Bilirubin levels significantly correlated with PCBs -105-118-126 and -194
bull Smoking appears to be the biggest confounder
Dufour DR et al 2000 Diagnosis and monitoring of hepatic injury II Recommendations for use of laboratory
tests in screening diagnosis and monitoring Clin Chem 46 2050ndash68
Kumar J et al Persistent organic pollutants and liver dysfunction biomarkers in a population-based human sample
of men and women Environ Res 2014134251-256
Perf
luo
rin
ate
dP
OP
s a
nd
Co
mm
on
Blo
od
Tests
Gleason JA et al Associations of perfluorinated chemical serum concentrations and biomarkers of liver function and uric acid in the
US population (NHANES) 2007-2010 Environ Res 20151368-14
Liver Enzymes Reflect Toxic Load
bull AST ALT and GGT increase with body load of PCBs and OCPs
bull Some non-linear
bull Oxychlordanetop quartile
ALT 10
GGT 25
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
LDL-Cholesterol as Measure of POPs
bull 5-year prospective study to determine if POP levels predict future elevation in LDL-cholesterol
bull 598 subjects initially at age 70
bull Looked at 23 POPs
bull Best correlation with PCB 194
Penell J Lind L Salihovic S et al Persistent organic pollutants are related to change in circulating
lipid levels during a 5 year follow-up Environ Res 134(2014)190ndash197
oxLDL as Measure of POPs
bull 992 70-year old individuals (50 women)
bull Sum of PCBs showed strong significant positive associations with ox-LDL and significant negative associations with glutathione-related markers (GSSG and GSSGGSH)
bull A number of POPs (PCB-99 138 153 156 170 180 194 206 and 209) showed strong significant positive association with ox-LDL
Kumar J et al Influence of persistent organic pollutants on oxidative stress in population-based samples
Chemosphere 2014114303-309
Homocysteine is Increased by Pb amp Cd
Guallar E et al Confounding of the relation between homocysteine and peripheral arterial disease by lead cadmium and renal function Am J Epidemiol 2006 Apr 15163(8)700-8
Nutrient Deficiencies Accentuate
Effects of Lead on Homocysteine
bull Deficiencies in folate B6 or B12 make lead more toxic
Lee YM Et al Association of homocysteine levels with blood lead levels and micronutrients in the US general population J Prev Med Public Health 2012 Nov45(6)387-93
T4 amp T3 and PCBs
bull PCBs decrease T4 production
bull PCBs inhibit iodotyrosinedeiodinase activity
bull Study done in pregnant women which implies effect on fetus IQ
Kim S Park J Kim HJ et al Association between several persistent organic pollutants and thyroid hormone levels in serum among the pregnant women of Korea Environ Int 2013 Sep59442-8Shimizu R Yamaguchi M Uramaru N et al Structure-activity relationships of 44 halogenated compounds for iodotyrosinedeiodinase-inhibitory activity Toxicology 2013 Dec 6314(1)22-9
T4 amp T3 and PCBs
bull Not just humans being affected
bull Large study of dolphins shows exactly the same effects
Schwacke LH Zolman ES Balmer BC et al Anaemia hypothyroidism and immune suppression associated with polychlorinated biphenyl exposure in bottlenose dolphins (Tursiops truncatus) Proceed Royal Society B doi101098rspb20110665
8-OHdG
bull Oxidized nucleoside
bull Direct measure of DNA damage
bull Indirect measure of oxidative stress and toxin load
bull Correlates with
Multiple cancers
Mitochondrial damage
Rate of aging
Smoking
Several toxinsWalter Crinnion ldquoTotal Toxic Loadrdquo AANP 2015
8-OHdG Correlates with Pack-Years
of Smoking
Yano T et al Significance of the urinary 8-OHdG level as an oxidative stress marker in lung cancer patients Lung Cancer
2009 Jan63(1)111-4
8-OHdG Correlates
with Mercury
Chen C et al Increased oxidative DNA damage as assessed by urinary 8-hydroxy-2-deoxyguanosine
concentrations and serum redox status in persons exposed to mercury Clin Chem 2005 Apr51(4)759-67
Toxin Effects Worse with Aging
bull Thyroid function decreases with PFOA levels
bull But only after age 63
Shrestha S Bloom MS Yucel R et al Perfluoroalkyl substances and thyroid function in older adults Environ Int 2015 Feb75206-14
Insightful 23-Year Prospective Study
1 lt 50 there is no difference between those with the lowest and highest PCBs
2 In youngest group insulin production increases in response to toxin level As expected since blocking of
insulin receptor sites by PCBs
requires more insulin
3 That adaptive ability decreases with aging
4 At age 50 all the measures show very strong toxin-dose response
Cumulative damage impairs ability to adapt
Suarez-Lopez JR et al Persistent organic pollutants in young adults and changes in glucose related metabolism over a 23-year follow-up Environ Res 2015 Feb137485-94
Recommendations
High body toxic load
GGT gt 25
Uric acid gt 50 mgdl
ALT gt30 UL
Bilirubin gt08 mgdl
CBC lt 6000
Platelet lt 250000
Low T3 andor T4
Monitor Total Toxic Load
8-OHdG gt4
ldquoUnconventionalrdquo Laboratory Tests
bull Challenge testing
bull Hair analysis
bull Direct measures of solvents and POPs in blood urine adipose tissue
Evaluation of Metal Exposure ndash Provocation
bull Provocation ndash the use of a chelating agent ndash before urine collection often done clinically but several limitations
No ldquoofficialrdquo reference range for provoked urine
Most chelating agents do not extract metals from all tissues thus
does not necessarily represent total body burden
bull Example Brain is one of the main target organs for both elemental and organic
mercury yet agents do not chelate brain mercury
bull Despite limitations widely used and advocated by clinicians in part to see efficacy of chelating agent as a guide to treatment and based on empirical evidence
Rooney JP The role of thiols dithiols nutritional factors and interacting ligands in the toxicology of mercury
Toxicology 2007
Is Challenge Testing Valid
bull Poor correlations of standard tests for mercury
bull Unpublished research from corporate wellness project
bull Published amalgam number correlation
bull Published fish consumption correlation
What We Found In Canada
bull Deviations from the mean of 14 29 and 91 respectively
bull DMPS is spreading distribution suggesting that it is better at differentiating mercury body load
bull Some VERY high
Hg Assessment Correlations
bull Extensive measurements in 65 Whole blood Hg
Oral DMPS challenge
Amalgam surfaces
bull Correlations Whole blood w pre urine r = 040
Whole blood w post urine r = 057
Pre urine w post urine r = 068
Amalgams w pre urine r = 026
Amalgams w whole blood r = 036
Amalgams with post urine 044
bull Clear documentation that
challenge testing is better00
100
200
300
400
500
600
0 10 20 30 40 50
Po
st
Uri
ne H
g u
gg
Number of amalgams
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
How About Persistent Organic Pollutants
Neel BA Robert M Sargis RM The paradox of progress Environmental disruption of metabolism and the diabetes epidemic DIABETES 2011 601838-48
Lars Jaumlrup Br Med Bull 200368167-182copy The British Council 2003 all rights reserved
Global Production and Consumption of
Selected Toxic Metals 1850ndash1990
Cadmium World Production
Mercury in the Air
EPA-452R-97-003 December 1997
Mercury in Water
httpwaterepagovscitechdataitmodelsmapspostercfm
Ground Water Sources of Arsenic
bull 10 of US public water supplies have levels of arsenic known to induce disease
bull No data on private water supplies
httpwwwatsdrcdcgovcsemarsenicdocsarsenicpdf (accessed 2015-08-18)
Example POPs
Chemical Abbr Uses Exposure
Bisphenol A BPA Plastics Canned food
Organochlorine
pesticides
OCPs Pesticide Food fumigation
Organophosphate
pesticides
OPPs Pesticide Food
Polybrominated
diphenyl ethers
PBDEs Flame retardant Clothing
Polychlorinated
biphenyls
PCBs Industrial Everywhere
Perflourinated PFOAs Non-stick stain prevention
water repellant
Teflon Gortex
Scotchguard
Phthalates Plastics fragrances Shower curtains
cosmetics
POPs - Prediabetes
bull Over 1200 participants fasting
glucose and OGTT performed
with serum levels of 5 POPs
bull All individual POPs tested were
associated with progressive
increase in prevalence of
prediabetes
bull More than triple prevalence of
prediabetes seen in those in the
5th quartile with a synergistic
effect from 5 POPs
Ukropec J et al High prevalence of prediabetes and diabetes in a population exposed to high levels of an organochlorine cocktail
Diabetologia 2010 May53(5)899-906
POPs and Diabetes Risk
Graph httpwwwourstolenfutureorgNewScienceobesity20062006-0715leeetalhtml
Data Lee DH Lee IK Song K et al A strong dose-response relation between serum
concentrations of persistent organic pollutants and diabetes results from the National Health and
Examination Survey 1999-2002 Diabetes Care 2006 Jul29(7)1638-44
Toxic Load and Disease Risk
References for Toxins and Disease Risk
Converting Disease Risk to Caused
Attributable Fraction Calculation
p = underlying prevalence of risk factor in the population
rr = relative risk (risk of contracting a disease in an exposed population divided by the risk of contracting the disease in an unexposed population)
AF = of disease due to the toxin
Levin M The occurrence of lung cancer in man Acta Unio Int Contra Cancrum 1953 9 531-541
Example Smoking and Lung Cancer
B = 5Number of smokers
who contract Lung Cancer notdue to smoking
A = 5Number of smokerswho contract Lung
Cancer due to smoking
C = 15Number of
nonsmokerswho contract Lung Cancer
0
2
4
6
8
10
12
14
16
Smokers (N=100) Nonsmokers (N=300)Num
ber
of
people
who c
ontr
act
Lung C
ancer
per
year
Baseline Additional due to smoking
Number of smokers and nonsmokers who contract lung cancer
Our Process In Summary
1 Determine threshold for increased disease risk
2 Determine of population above threshold
3 Determine incidence of disease (OR) in those above threshold
4 Determine incidence of disease in ldquounexposed populationrdquo
5 Calculate AF ie of disease
As whole population is exposed probably UNDERESTIMATES of disease
To
xic
ity H
as B
eco
me t
he N
ew
ldquoN
orm
alrdquo
Toxin Type Use Threshold for
disease
association
of US
above
threshold
Disease Associations
Chlordane OC pesticide Termites corn citrus lawns
gardens
145ngg lipid 63
(diabetes)
Diabetes (20)
BPA Plasticizer Water bottles canned food
water pipes thermal sales
receipts
48 men 51
women (urine
ngmL)
~18
(diabetes)
Diabetes hypertension
Octachloro
dibenzo-p-
dioxin
(OCDD)
Polychlorinated
dibenzo-p-
dioxin
Incineration or burning of
waste bleaching processes
used in pulp and paper mills
1010 pgg
lipid (highest
quartile)
10-25
(hypertensio
n)
Hypertension (79 for
women highest
quartile) diabetes (21)
obesity learning
disability (272)
MEP
(mono-
ethyl
phthalate)
Phthalate
(plasticizer
fragrance)
Toothbrushes automobile
parts tools toys and food
packaging aspirin
cosmetics food packaging
gt175 ngmL
(urine)
~60
(diabetes)
Diabetes (148) lower
BMD obesity
pp-DDE DDT
metabolite (OC
pesticide)
Agricultural crops 1560ngg
lipid
25
(diabetes)
Diabetes (23-43)
early menopause
impaired cognitive
function (2-3x 65x in
highest 5th percentile)
peripheral arterial
disease
Arsenic Toxic metal Miningsmelting wood
preservative pesticides
74ugL total
arsenic (urine)
20
(diabetes)
Cancers diabetes (26-
46) dyslipidemia gout
AF OR Prevalence
Rosen L An intuitive approach to understanding the attributable fraction of disease due to a risk factor the case of smoking Int J Environ Res Public Health 2013 Jul 1610(7)2932-43
Smoking Lung cancer
Arsenic Gout in women
BPA Diabetes
Status of Our Research
bull 26 toxins and toxin classes eg lead mercury BPA OCPs
100s of chemicals and POPs in some classes
bull 18 cancers
bull 24 chronic diseases
bull 1092 cells in spreadsheet
Large Personal Ongoing Research Investment
Huge Amount of Research Work
Toxins StudiedAluminum
Arsenic
Cadmium
Fluoride
Lead
Manganese
Mercury
Acrylamide
Acrylonitrile
Benzene
Bisphenol A (BPA)
Chloroform
DDT
Dioxins
Glyphosate
Organochlorine pesticides (OCPs)
Organophosphate pesticides
Parabens
Phthalates
Polybrominated diphenyl ethers (PBDEs)
Polycyclic aromatic hydrocarbons (PAHs)
Polychlorinated biphenols (PCBs)
Vinyl chloride
Diseases Studied
ADHD
Alzheimers Disease
ALS
Angiosarcoma
Anxiety
Atopic Conditions
Diabetes
Dyslipidemia
Gout
Fetal Abnormalities
Hyperuricemia
Infertility
Juvenile IQ
Cancer Bladder
Cancer Bone
Cancer Brain
Cancer Breast
Cancer Cervix
Cancer Colorectal
Cancer Endometrial
Cancer Head amp Neck
Cancer Liver
Cancer Lung
Cancer Lymph amp Blood
Cancer Ovarian
Cancer Pancreatic
Cancer Prostate
Cancer Renal
Cancer Skin
Cancer Testicular
Cancer Thyroid
Juvenile Obesity
Metabolic Syndrome
Mitochondrial dysfunction
Myocardial Infarction
Obstructive Lung Disease
Osteoporosis
Peripheral Artery Disease
Peripheral Neuropathy
Prediabetes
Renal Disease
Rheumatoid Arthritis
Thyroid Dysfunction
OC
Ps
Th
rou
gh
ou
t th
e W
orl
d
Rathore HS Nollet LML Pesticides Evaluation of Environmental Pollution CRC Press
2012 page 562
Threshold ndash Threshold exposure at which there is an increased risk of disease outcome
Above Threshold ndash Percentage of the population with higher exposure than the threshold
Odds Ratio ndash Increased disease risk in those above threshold
of Dz ndash Percent contribution of the toxin to that disease outcome
How to Interpret the Following Slides
Attention Deficit Hyperactivity Disorder
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
DDT 126 ngg
serum (pp-
DDE)
250 18 166 20106937
Lead 23 ugdL 13 254 20 27659349
Mercury 16 24952233
Organophosphate
pesticides
20
Polycyclic
Aromatic
Hydrocarbons
227 ngm3 940 125 190 22440811
PCBs 104 ngg
serum (sum
of 50 PCBs)
250 176 160 20106937
DiabetesToxin Threshold Above
Threshold
Odds
Ratio
of Dz Reference
PMID
Arsenic 165 ugL 200 21 180 18714061
BPA 28 ugL 280 145 112 26119400
DDE 545 ngg serum
(pp-DDE)
200 230 31 26119400
Dioxins2 pgg lipid 50 191 43
26119400
PCBs104 ngg (PCB 153) 250 239 258
26119400
Phthalates175 ugL 690 148 249
26119400
1-naphthalene 167 ugdL 152 182 111 26340343
2-napthalene 414 ugdL 550 224 214 26340343
1-phenanthrene 167 ngL 570 178 151 26340343
1-pyrene 85 ngL 660 180 174 26340343
Lung Cancer
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Acrylonitrile Uncertain Uncertain 125 25
occupational
exposure
17114112
Arsenic 1213 ugL 436 of Asian
Americans
~01 of total
US population
34 95 in AA
01-1
PMC2682945
Cadmium Uncertain+ Uncertain 467 10 in
smokers
17184399
DDT Any exposure All US pop
below LOD
17 76 increased
risk
8923607
Breast Cancer
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Cadmium 0580 ugg
creatinine
126 205 479 16788160
PCB 138 396 ngg
creatinine
202 316 630 27717745
PCB 187 108 ngg lipid 600 194 360 21480306
Miscellaneous Diseases
Toxin Disease Threshold Above
Threshold
Odds
Ratio
of Dz Reference PMID
Aluminum Alzheimer
Dz
01 mgL
drinking
H20
400 203 05-44 26592479
Benzene AML 100ppmyrs 1-3 320 60 PMC2903550
DDT NHL 0512 ugL 1-2 240 01 17722095
Lead ALS 238 ugdL
blood
330 181 210 25479292
Lead Brain CA 0005 ugdL 14 19 ~500 17164378
Dioxin-like
PCBs
RA 326 ngg
lipid
250 219 220 17589595
PAHs Asthma 124 ngm3 935 200 483 19221603
The Potency of Arsenic
Disease Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Bladder CA 10ugL H20 100 27 145 24889821
Pancreatic CA 1332 ugg 200 246 230 23800676
Prostate CA 1332 ugg 200 33 315 23800676
Gout 125 ugL 245 546 522 25499256
Diabetes 165 ugL 200 21 180 18714061
Arsenic (180 of Diabetes)
How it causes diabetes
bull Blocks sugar stimulating insulin secretion
bull Epigenetic inhibition of sugar regulation
Where it comes from
bull Water (gt10 of US water supplies have high levels)
bull Rice (naturally absorbs if in the water)
bull Chicken (added to make meat whiter)
Pan W-C Seow WJ Kile ML et al Association of low to moderate levels of arsenic exposure with risk of Type 2 diabetes in Bangladesh American Journal of Epidemiology 2013178(10)1563-70
Portion of Population with Toxin Load Which
Doubles Disease Risk
Toxin Disease with Doubled Risk
Polycyclic aromatic hydrocarbons Asthma 94
PCB187 Breast Cancer 60
Phthalates Diabetes 55
Lead ALS 33
Aluminum Alzheimers Disease 25
DDT ADHD 25
PCBs Diabetes 25
Dioxin-like PCBs Rheumatoid Arthritis 25
Arsenic Gout 23
Bisphenol A Diabetes 22
Cigarette smoking Lung Cancer 21
Arsenic Diabetes 20
Polycyclic aromatic hydrocarbons Diabetes 20
Huge Detoxification Variability
bull CYP2C19
Proton pump inhibitors and some antidepressants
5-fold difference in activity between poor metabolizers and extensive metabolizers more so if CYP3A4 is also inhibited
Ultrarapid allele in 18 of both Swedes and Ethiopians
bull CYP2D6
Metabolizes a large number of drugs (~25)
7 of Caucasians poor metabolizers
~30 ultra rapid metabolizers in Arabian and Eastern African populations
More adverse effects in poor metabolizers and ineffective dosing in ultrarapid metabolizers
Inhibited by ginger
Desta Z et al Clinical significance of the cytochrome P450 2C19 genetic polymorphism Clin Pharmaco 2002
Sim SC et al A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug
response to proton pump inhibitors and antidepressants Clin Pharmacol Ther 2006
Wilkinson GR Drug metabolism and variability among patients in drug response N Engl J Med 2005
Kirchheiner J et al Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to
CYP2D6 duplication Pharmacogenomics J 2007
Toxin Half Lives in BloodToxin ldquoNormalrdquo (mgL) Acute Toxic (mgL) Half-Life
Arsenic 0002-007 005-025 2-4 days (CDC)
Benzene 00002 05-10 days
Cadmium 00003-00065 0015-005 16 years
Chlordane 0001 00025 3-4 days
DDTDDE 2-10 years
Dieldrin 00015 015-030 2-12 months
Ethanol 1000-2000 15hour
Lead 009 04-06 1-15 mo (2+ yrs bone)
Mercury 00015-0002 005-02 2 months (CDC)
PCBs 3-25 years
Toluene 05-3 days
Schulz M et al Therapeutic and toxic blood concentrations of nearly 1000 drugs and other xenobiotics Crit Care 2012 Jul 2616(4)R136
Bioaccumulation (POPs)
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
DDT banned in 1972 PCBs banned in 1977
Bioaccumulation (Cd)
Think BroadlyExogenous
Metals
Chemicalsbull Inorganic
bull Fluoride
bull Organic
bull POPs
bull Drugs
Particulate matter
Molds
Microbial
Radiationbull Light
bull Medical
bull Cell phone
Endogenous
Gut-derived toxins
Non-end product metabolites
Poorly detoxified hormones
Catecholamines (if SNP)
Toxins of Choice
Alcohol
Marijuana
Food constituents
High fructose corn syrup
Salt (acid-forming diet)
Wheat if zonulin (70)
Obesity Epidemic ndash POPs AND HFCS
47Bray GA Fructose should we worry Int J Obes (Lond) 2008 Dec32 Suppl 7S127-31
How Toxins Cause Damage 13
bull Increase free radical production
Cd induces production of ROS
Malathion inhibits catalase and glutathione peroxidase
Homocysteine oxidizes LDL cholesterol
bull Poison enzyme systems (compete with nutritional cofactors for binding sites)
Pb poisons delta aminolevulinic acid dehydratase
Cd inhibits catalase glutathione reductase and lowers
glutathione levels
bull Replace structural minerals
Pb displaces Ca in bone
How Toxins Cause Damage 23
bull Damage DNA
Benzene - causes chromosomal damage
Pesticides ndash fruit growers have more DNA damage
Phthalates and insecticides ndash damage sperm DNA
4-hydroxy catechol estrogen (4-OHE) damages breast DNA
bull Epigenetic dysmodulation
Higher cord blood levels of hexachlorobenzene associated
with 2x greater risk for obesity in children
bull Damage cell membranes
Common mechanism for heavy metals inactivates
membrane enzymes ion channels and pumps
How Toxins Cause Damage 33
bull Block insulin receptor sites
PCBs and phthalates
bull Highest levels associated with a 4 to 20-fold greater diabetes risk
bull Imbalance hormones many toxin examples
Arsenic
bull Disrupts thyroid hormone and retinoic acid receptors
Phthalates
bull Act as anti-androgens
bull More than 75 of the US population has measurable levels of
several phthalate metabolites in the urine
PCBs
bull Lower testosterone levels in men
Which are the Worst Toxins
bull According to the CDC
Toxicity
Population toxic load
Prevalence in toxic waste sites
bull According to clinical importance
Exposure
of disease
Ability of the body to detoxifyexcrete
Ag
en
cy
fo
r T
oxic
Su
bs
tan
ce
s a
nd
Dis
ea
se
Reg
istr
y
Pri
ori
ty L
ist
The Worst Toxins Clinically
My Rank Toxin Diseases Primary Sources
1 Arsenic Cancers diabetes gout Water chicken rice
2 DDT ADHD dementia diabetes Everywhere
3 Phthalates ADHD diabetes Soft plastics HABAs
4 PBDEs ADHD diabetes Flame retardant fabrics
5 PAHs ADHD cancers dyslipidemia Smoking charbroiling
6 PCBs Cancers diabetes MI RA Everywhere
7 Mercury Dementia ldquoSilverrdquo fillings fish
8 Lead Cardiovascular disease IQ Paint water
Glyphosate Research invalid
Conventional Laboratory Tests Reflect
Toxic Load in ldquoNormalrdquo Range
bull Surprising number show toxin exposure
CBC RBC WBC platelet count hemoglobin basophilic
stippling
Liver enzymes ALT GGTP
Inflammatory markers CRP
Lipids LDL oxLDL triglycerides
Blood sugar insulin FBS 2-hour PP
Metabolites bilirubin uric acid homocysteine 8-OHdG
Thyroid T3 T4 TSH
bull The historic ldquonormalrdquo range has been changing as the population has become more toxic
WBC Lowered by PCB and OCP Exposure
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
0
1
2
3
4
5
6
7
8
1st Quartrile 2nd Quartile 3rd Quartile 4th Quartile
WBCbull Strong inverse correlation with PCBs and OCPs and CBC
bull Linear with almost all PCBs
bull High variability with OCPs
bull Within ldquonormalrdquo range
Effects on WBC Worsen with Years
of Exposure to Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Platelet Count Decreases with Years
of Exposure tp Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Solvents Decrease Platelet Count
bull Compared workers exposed 23 hrday to those exposed most of day to toluene
bull All wore face masks and protective gear
bull Platelet count 14 lower 252 versus 216ml
bull Impairment of sympathetic nerves (OR = 413)
bull Impairment of peripheral nerves (OR = 694)
bull Positive relationship between neurological abnormalities and a self-reported neuropsychiatric measurement (r = 035-066)
Shih HT et al Subclinical abnormalities in workers with continuous low-level toluene exposure Toxicol Ind Health 2011 Sep27(8)691-9
Basophilic Stippling of Red Cells
Toxinsbull Arsenic
bull Lead
Diseasesbull Alpha-thalassemia HbH Disease
bull Beta thalassemia
bull Hereditary pyrimidine 5-nucleotidase deficiency
bull Myelodysplastic syndrome
bull Sideroblastic anemia
bull Thrombotic thrombocytopenic purpura
GGT Indirect Measure of POPsbull Glutathione is key intracellular defense against oxidative stress
bull Cellular GGT metabolizes extracellular GSH allowing precursor amino acids to be reutilized for intracellular GSH
bull Exposure to POPs induces GGT as a defensive mechanism
bull Within normal range predicts type 2 diabetes coronary heart disease hypertension stroke dyslipidemia chronic kidney disease and cancer
bull Men with GGT gt50 UI had ~26 fold risk for diabetes compared to those with lt10 Those with 40-49 had a ~20 fold risk
bull Levels within normal range occur with obesity xs alcohol cigarette smoking physical inactivity high meat low fruit and vegetable intake
bull Cumulative biomarker for environmental pollutants
Lee DH et al (2003) Gamma-glutamyltransferase and diabetesmdasha 4 year follow-up study Diabetologia 46359ndash364
Pamela A et al Serum gamma-glutamyltransferase linking together environmental pollution redox equilibria and progression of atherosclerosis Clin Chem
Lab Med 200947(12)1583-4
Lee DH et al Serum gamma-glutamyltransferase new insights about an old enzyme J Epidemiol Community Health 2009 Nov63(11)884-6
Lee DH et alSerum gamma-glutamyltransferase predicts non-fatal myocardial infarction and fatal coronary heart disease among 28838 middle-aged men and
women Eur Heart J 2006272170ndash6
Lee DH et al Gamma-glutamyltransferase and diabetes--a 4 year follow-up study Diabetologia 2003 Mar46(3)359-64
Lee DH et al Can persistent organic pollutants explain the association between serum gamma-glutamyltransferase and type 2 diabetes Diabetologia 2008
Mar51(3)402-7
GGT and Alcohol Consumption
bull GGT directly correlates with alcohol consumption
bull In a non-uniform population 40 gd will elevate GGT ~15
bull Watch for false negatives
bull Genomic variation
bull Are these the ones most
sensitive todamaged by
chemical toxins
bull Could up-regulation of GGT in light alcohol consumption be reason for benefit
0
10
20
30
40
50
60
70
80
0 200 400 600 800
Grams of Ethanol per Week
Adapted from Nagaya T et al Dose-response relationships between drinking and serum tests in Japanese men
aged 40ndash59 years Alcohol 1999 Feb 17(2) 133ndash8
GGT Correlates With Toxic Metal Levels
Lee DH et al Graded associations of blood lead and urinary cadmium concentrations with oxidative-stress-related markers in the
US population results from the third National Health and Nutrition Examination Survey Environ Health
perspect 2006 Mar114(3)350-4
GGT and Diabetes Risk
0
5
10
15
20
25
30
lt10 10-19 20-29 30-39 40-49 gt50
Dia
bete
s R
isk
GGT
bull GGT over 50 associated with tripling of death rate
bull 30-40 associated with doubling
GGT Levels
Correlate with
Risk of Death
Brenner H et al Distribution determinants and prognostic value of gamma-glutamyltransferase for all-cause
mortality in a cohort of construction workers from southern Germany Prev Med 1997 26 305ndash10
GGT From Small US Company
with Young Workers
0
10
20
30
40
50
60
0 20 40 60 80 100
GGT Data from Canadian Oil Field
Workers
0
50
100
150
200
250
300
350
400
450
lt10 10-20 20-30 30-40 40-50 50-60 60-07 70-80 80-90 90-100 100-110 110-120 gt120
GGTP
20-fold increased risk of diabetes
Uric Acid Indirect Measure of POPs
bull Poly-fluorinated hydrocarbons (PFOA and PFOS) associated
with increased serum uric acid
Lin CY et al Association among serum perfluoroalkyl chemicals glucose homeostasis and metabolic syndrome
in adolescents and adults Diabetes Care 2009 Apr32(4)702-7
Steenland K et al Association of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) with uric
acid among adults with elevated community exposure to PFOA Environ Health Perspect 2010 Feb118229-33
Steenland 2010 Open Access
ALT Indirect Measure of POPs
bull ALT (proxy marker) elevation in 104 (not including viral
hepatitis hemochromatosis or alcoholic liver disease) of
NHANES 03-04 subset
bull Risk of elevated ALT increased dose-dependently with
cadmium lead mercury and PCB exposure
bull 100 of individuals had detectable PCBs 925 mercury
and 996 had detectable lead
bull In 2005-08 prevalence of NAFLD in US was 11 a
growing cause of chronic liver disease
Cave M et al Polychlorinated biphenyls lead and mercury are associated with liver disease in American adults
NHANES 2003-2004 Environ Health Perspect 2010 Dec118(12)1735-42
Younossi ZM et al Changes in the prevalence of the most common causes of chronic liver diseases in the United
States from 1988 to 2008 Clin Gastroenterol Hepatol 2011 Jun9(6)524-530e1
Bilirubin as a Marker of POPs
bull Degree of serum bilirubin increase is prognostically significant in chronic liver dysfunction
bull Mono-ortho PCB TEQ values were found to be significantly positively associated with bilirubin (β=071 P=0008) following adjustment for multiple potential confounders
bull Bilirubin levels significantly correlated with PCBs -105-118-126 and -194
bull Smoking appears to be the biggest confounder
Dufour DR et al 2000 Diagnosis and monitoring of hepatic injury II Recommendations for use of laboratory
tests in screening diagnosis and monitoring Clin Chem 46 2050ndash68
Kumar J et al Persistent organic pollutants and liver dysfunction biomarkers in a population-based human sample
of men and women Environ Res 2014134251-256
Perf
luo
rin
ate
dP
OP
s a
nd
Co
mm
on
Blo
od
Tests
Gleason JA et al Associations of perfluorinated chemical serum concentrations and biomarkers of liver function and uric acid in the
US population (NHANES) 2007-2010 Environ Res 20151368-14
Liver Enzymes Reflect Toxic Load
bull AST ALT and GGT increase with body load of PCBs and OCPs
bull Some non-linear
bull Oxychlordanetop quartile
ALT 10
GGT 25
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
LDL-Cholesterol as Measure of POPs
bull 5-year prospective study to determine if POP levels predict future elevation in LDL-cholesterol
bull 598 subjects initially at age 70
bull Looked at 23 POPs
bull Best correlation with PCB 194
Penell J Lind L Salihovic S et al Persistent organic pollutants are related to change in circulating
lipid levels during a 5 year follow-up Environ Res 134(2014)190ndash197
oxLDL as Measure of POPs
bull 992 70-year old individuals (50 women)
bull Sum of PCBs showed strong significant positive associations with ox-LDL and significant negative associations with glutathione-related markers (GSSG and GSSGGSH)
bull A number of POPs (PCB-99 138 153 156 170 180 194 206 and 209) showed strong significant positive association with ox-LDL
Kumar J et al Influence of persistent organic pollutants on oxidative stress in population-based samples
Chemosphere 2014114303-309
Homocysteine is Increased by Pb amp Cd
Guallar E et al Confounding of the relation between homocysteine and peripheral arterial disease by lead cadmium and renal function Am J Epidemiol 2006 Apr 15163(8)700-8
Nutrient Deficiencies Accentuate
Effects of Lead on Homocysteine
bull Deficiencies in folate B6 or B12 make lead more toxic
Lee YM Et al Association of homocysteine levels with blood lead levels and micronutrients in the US general population J Prev Med Public Health 2012 Nov45(6)387-93
T4 amp T3 and PCBs
bull PCBs decrease T4 production
bull PCBs inhibit iodotyrosinedeiodinase activity
bull Study done in pregnant women which implies effect on fetus IQ
Kim S Park J Kim HJ et al Association between several persistent organic pollutants and thyroid hormone levels in serum among the pregnant women of Korea Environ Int 2013 Sep59442-8Shimizu R Yamaguchi M Uramaru N et al Structure-activity relationships of 44 halogenated compounds for iodotyrosinedeiodinase-inhibitory activity Toxicology 2013 Dec 6314(1)22-9
T4 amp T3 and PCBs
bull Not just humans being affected
bull Large study of dolphins shows exactly the same effects
Schwacke LH Zolman ES Balmer BC et al Anaemia hypothyroidism and immune suppression associated with polychlorinated biphenyl exposure in bottlenose dolphins (Tursiops truncatus) Proceed Royal Society B doi101098rspb20110665
8-OHdG
bull Oxidized nucleoside
bull Direct measure of DNA damage
bull Indirect measure of oxidative stress and toxin load
bull Correlates with
Multiple cancers
Mitochondrial damage
Rate of aging
Smoking
Several toxinsWalter Crinnion ldquoTotal Toxic Loadrdquo AANP 2015
8-OHdG Correlates with Pack-Years
of Smoking
Yano T et al Significance of the urinary 8-OHdG level as an oxidative stress marker in lung cancer patients Lung Cancer
2009 Jan63(1)111-4
8-OHdG Correlates
with Mercury
Chen C et al Increased oxidative DNA damage as assessed by urinary 8-hydroxy-2-deoxyguanosine
concentrations and serum redox status in persons exposed to mercury Clin Chem 2005 Apr51(4)759-67
Toxin Effects Worse with Aging
bull Thyroid function decreases with PFOA levels
bull But only after age 63
Shrestha S Bloom MS Yucel R et al Perfluoroalkyl substances and thyroid function in older adults Environ Int 2015 Feb75206-14
Insightful 23-Year Prospective Study
1 lt 50 there is no difference between those with the lowest and highest PCBs
2 In youngest group insulin production increases in response to toxin level As expected since blocking of
insulin receptor sites by PCBs
requires more insulin
3 That adaptive ability decreases with aging
4 At age 50 all the measures show very strong toxin-dose response
Cumulative damage impairs ability to adapt
Suarez-Lopez JR et al Persistent organic pollutants in young adults and changes in glucose related metabolism over a 23-year follow-up Environ Res 2015 Feb137485-94
Recommendations
High body toxic load
GGT gt 25
Uric acid gt 50 mgdl
ALT gt30 UL
Bilirubin gt08 mgdl
CBC lt 6000
Platelet lt 250000
Low T3 andor T4
Monitor Total Toxic Load
8-OHdG gt4
ldquoUnconventionalrdquo Laboratory Tests
bull Challenge testing
bull Hair analysis
bull Direct measures of solvents and POPs in blood urine adipose tissue
Evaluation of Metal Exposure ndash Provocation
bull Provocation ndash the use of a chelating agent ndash before urine collection often done clinically but several limitations
No ldquoofficialrdquo reference range for provoked urine
Most chelating agents do not extract metals from all tissues thus
does not necessarily represent total body burden
bull Example Brain is one of the main target organs for both elemental and organic
mercury yet agents do not chelate brain mercury
bull Despite limitations widely used and advocated by clinicians in part to see efficacy of chelating agent as a guide to treatment and based on empirical evidence
Rooney JP The role of thiols dithiols nutritional factors and interacting ligands in the toxicology of mercury
Toxicology 2007
Is Challenge Testing Valid
bull Poor correlations of standard tests for mercury
bull Unpublished research from corporate wellness project
bull Published amalgam number correlation
bull Published fish consumption correlation
What We Found In Canada
bull Deviations from the mean of 14 29 and 91 respectively
bull DMPS is spreading distribution suggesting that it is better at differentiating mercury body load
bull Some VERY high
Hg Assessment Correlations
bull Extensive measurements in 65 Whole blood Hg
Oral DMPS challenge
Amalgam surfaces
bull Correlations Whole blood w pre urine r = 040
Whole blood w post urine r = 057
Pre urine w post urine r = 068
Amalgams w pre urine r = 026
Amalgams w whole blood r = 036
Amalgams with post urine 044
bull Clear documentation that
challenge testing is better00
100
200
300
400
500
600
0 10 20 30 40 50
Po
st
Uri
ne H
g u
gg
Number of amalgams
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
Lars Jaumlrup Br Med Bull 200368167-182copy The British Council 2003 all rights reserved
Global Production and Consumption of
Selected Toxic Metals 1850ndash1990
Cadmium World Production
Mercury in the Air
EPA-452R-97-003 December 1997
Mercury in Water
httpwaterepagovscitechdataitmodelsmapspostercfm
Ground Water Sources of Arsenic
bull 10 of US public water supplies have levels of arsenic known to induce disease
bull No data on private water supplies
httpwwwatsdrcdcgovcsemarsenicdocsarsenicpdf (accessed 2015-08-18)
Example POPs
Chemical Abbr Uses Exposure
Bisphenol A BPA Plastics Canned food
Organochlorine
pesticides
OCPs Pesticide Food fumigation
Organophosphate
pesticides
OPPs Pesticide Food
Polybrominated
diphenyl ethers
PBDEs Flame retardant Clothing
Polychlorinated
biphenyls
PCBs Industrial Everywhere
Perflourinated PFOAs Non-stick stain prevention
water repellant
Teflon Gortex
Scotchguard
Phthalates Plastics fragrances Shower curtains
cosmetics
POPs - Prediabetes
bull Over 1200 participants fasting
glucose and OGTT performed
with serum levels of 5 POPs
bull All individual POPs tested were
associated with progressive
increase in prevalence of
prediabetes
bull More than triple prevalence of
prediabetes seen in those in the
5th quartile with a synergistic
effect from 5 POPs
Ukropec J et al High prevalence of prediabetes and diabetes in a population exposed to high levels of an organochlorine cocktail
Diabetologia 2010 May53(5)899-906
POPs and Diabetes Risk
Graph httpwwwourstolenfutureorgNewScienceobesity20062006-0715leeetalhtml
Data Lee DH Lee IK Song K et al A strong dose-response relation between serum
concentrations of persistent organic pollutants and diabetes results from the National Health and
Examination Survey 1999-2002 Diabetes Care 2006 Jul29(7)1638-44
Toxic Load and Disease Risk
References for Toxins and Disease Risk
Converting Disease Risk to Caused
Attributable Fraction Calculation
p = underlying prevalence of risk factor in the population
rr = relative risk (risk of contracting a disease in an exposed population divided by the risk of contracting the disease in an unexposed population)
AF = of disease due to the toxin
Levin M The occurrence of lung cancer in man Acta Unio Int Contra Cancrum 1953 9 531-541
Example Smoking and Lung Cancer
B = 5Number of smokers
who contract Lung Cancer notdue to smoking
A = 5Number of smokerswho contract Lung
Cancer due to smoking
C = 15Number of
nonsmokerswho contract Lung Cancer
0
2
4
6
8
10
12
14
16
Smokers (N=100) Nonsmokers (N=300)Num
ber
of
people
who c
ontr
act
Lung C
ancer
per
year
Baseline Additional due to smoking
Number of smokers and nonsmokers who contract lung cancer
Our Process In Summary
1 Determine threshold for increased disease risk
2 Determine of population above threshold
3 Determine incidence of disease (OR) in those above threshold
4 Determine incidence of disease in ldquounexposed populationrdquo
5 Calculate AF ie of disease
As whole population is exposed probably UNDERESTIMATES of disease
To
xic
ity H
as B
eco
me t
he N
ew
ldquoN
orm
alrdquo
Toxin Type Use Threshold for
disease
association
of US
above
threshold
Disease Associations
Chlordane OC pesticide Termites corn citrus lawns
gardens
145ngg lipid 63
(diabetes)
Diabetes (20)
BPA Plasticizer Water bottles canned food
water pipes thermal sales
receipts
48 men 51
women (urine
ngmL)
~18
(diabetes)
Diabetes hypertension
Octachloro
dibenzo-p-
dioxin
(OCDD)
Polychlorinated
dibenzo-p-
dioxin
Incineration or burning of
waste bleaching processes
used in pulp and paper mills
1010 pgg
lipid (highest
quartile)
10-25
(hypertensio
n)
Hypertension (79 for
women highest
quartile) diabetes (21)
obesity learning
disability (272)
MEP
(mono-
ethyl
phthalate)
Phthalate
(plasticizer
fragrance)
Toothbrushes automobile
parts tools toys and food
packaging aspirin
cosmetics food packaging
gt175 ngmL
(urine)
~60
(diabetes)
Diabetes (148) lower
BMD obesity
pp-DDE DDT
metabolite (OC
pesticide)
Agricultural crops 1560ngg
lipid
25
(diabetes)
Diabetes (23-43)
early menopause
impaired cognitive
function (2-3x 65x in
highest 5th percentile)
peripheral arterial
disease
Arsenic Toxic metal Miningsmelting wood
preservative pesticides
74ugL total
arsenic (urine)
20
(diabetes)
Cancers diabetes (26-
46) dyslipidemia gout
AF OR Prevalence
Rosen L An intuitive approach to understanding the attributable fraction of disease due to a risk factor the case of smoking Int J Environ Res Public Health 2013 Jul 1610(7)2932-43
Smoking Lung cancer
Arsenic Gout in women
BPA Diabetes
Status of Our Research
bull 26 toxins and toxin classes eg lead mercury BPA OCPs
100s of chemicals and POPs in some classes
bull 18 cancers
bull 24 chronic diseases
bull 1092 cells in spreadsheet
Large Personal Ongoing Research Investment
Huge Amount of Research Work
Toxins StudiedAluminum
Arsenic
Cadmium
Fluoride
Lead
Manganese
Mercury
Acrylamide
Acrylonitrile
Benzene
Bisphenol A (BPA)
Chloroform
DDT
Dioxins
Glyphosate
Organochlorine pesticides (OCPs)
Organophosphate pesticides
Parabens
Phthalates
Polybrominated diphenyl ethers (PBDEs)
Polycyclic aromatic hydrocarbons (PAHs)
Polychlorinated biphenols (PCBs)
Vinyl chloride
Diseases Studied
ADHD
Alzheimers Disease
ALS
Angiosarcoma
Anxiety
Atopic Conditions
Diabetes
Dyslipidemia
Gout
Fetal Abnormalities
Hyperuricemia
Infertility
Juvenile IQ
Cancer Bladder
Cancer Bone
Cancer Brain
Cancer Breast
Cancer Cervix
Cancer Colorectal
Cancer Endometrial
Cancer Head amp Neck
Cancer Liver
Cancer Lung
Cancer Lymph amp Blood
Cancer Ovarian
Cancer Pancreatic
Cancer Prostate
Cancer Renal
Cancer Skin
Cancer Testicular
Cancer Thyroid
Juvenile Obesity
Metabolic Syndrome
Mitochondrial dysfunction
Myocardial Infarction
Obstructive Lung Disease
Osteoporosis
Peripheral Artery Disease
Peripheral Neuropathy
Prediabetes
Renal Disease
Rheumatoid Arthritis
Thyroid Dysfunction
OC
Ps
Th
rou
gh
ou
t th
e W
orl
d
Rathore HS Nollet LML Pesticides Evaluation of Environmental Pollution CRC Press
2012 page 562
Threshold ndash Threshold exposure at which there is an increased risk of disease outcome
Above Threshold ndash Percentage of the population with higher exposure than the threshold
Odds Ratio ndash Increased disease risk in those above threshold
of Dz ndash Percent contribution of the toxin to that disease outcome
How to Interpret the Following Slides
Attention Deficit Hyperactivity Disorder
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
DDT 126 ngg
serum (pp-
DDE)
250 18 166 20106937
Lead 23 ugdL 13 254 20 27659349
Mercury 16 24952233
Organophosphate
pesticides
20
Polycyclic
Aromatic
Hydrocarbons
227 ngm3 940 125 190 22440811
PCBs 104 ngg
serum (sum
of 50 PCBs)
250 176 160 20106937
DiabetesToxin Threshold Above
Threshold
Odds
Ratio
of Dz Reference
PMID
Arsenic 165 ugL 200 21 180 18714061
BPA 28 ugL 280 145 112 26119400
DDE 545 ngg serum
(pp-DDE)
200 230 31 26119400
Dioxins2 pgg lipid 50 191 43
26119400
PCBs104 ngg (PCB 153) 250 239 258
26119400
Phthalates175 ugL 690 148 249
26119400
1-naphthalene 167 ugdL 152 182 111 26340343
2-napthalene 414 ugdL 550 224 214 26340343
1-phenanthrene 167 ngL 570 178 151 26340343
1-pyrene 85 ngL 660 180 174 26340343
Lung Cancer
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Acrylonitrile Uncertain Uncertain 125 25
occupational
exposure
17114112
Arsenic 1213 ugL 436 of Asian
Americans
~01 of total
US population
34 95 in AA
01-1
PMC2682945
Cadmium Uncertain+ Uncertain 467 10 in
smokers
17184399
DDT Any exposure All US pop
below LOD
17 76 increased
risk
8923607
Breast Cancer
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Cadmium 0580 ugg
creatinine
126 205 479 16788160
PCB 138 396 ngg
creatinine
202 316 630 27717745
PCB 187 108 ngg lipid 600 194 360 21480306
Miscellaneous Diseases
Toxin Disease Threshold Above
Threshold
Odds
Ratio
of Dz Reference PMID
Aluminum Alzheimer
Dz
01 mgL
drinking
H20
400 203 05-44 26592479
Benzene AML 100ppmyrs 1-3 320 60 PMC2903550
DDT NHL 0512 ugL 1-2 240 01 17722095
Lead ALS 238 ugdL
blood
330 181 210 25479292
Lead Brain CA 0005 ugdL 14 19 ~500 17164378
Dioxin-like
PCBs
RA 326 ngg
lipid
250 219 220 17589595
PAHs Asthma 124 ngm3 935 200 483 19221603
The Potency of Arsenic
Disease Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Bladder CA 10ugL H20 100 27 145 24889821
Pancreatic CA 1332 ugg 200 246 230 23800676
Prostate CA 1332 ugg 200 33 315 23800676
Gout 125 ugL 245 546 522 25499256
Diabetes 165 ugL 200 21 180 18714061
Arsenic (180 of Diabetes)
How it causes diabetes
bull Blocks sugar stimulating insulin secretion
bull Epigenetic inhibition of sugar regulation
Where it comes from
bull Water (gt10 of US water supplies have high levels)
bull Rice (naturally absorbs if in the water)
bull Chicken (added to make meat whiter)
Pan W-C Seow WJ Kile ML et al Association of low to moderate levels of arsenic exposure with risk of Type 2 diabetes in Bangladesh American Journal of Epidemiology 2013178(10)1563-70
Portion of Population with Toxin Load Which
Doubles Disease Risk
Toxin Disease with Doubled Risk
Polycyclic aromatic hydrocarbons Asthma 94
PCB187 Breast Cancer 60
Phthalates Diabetes 55
Lead ALS 33
Aluminum Alzheimers Disease 25
DDT ADHD 25
PCBs Diabetes 25
Dioxin-like PCBs Rheumatoid Arthritis 25
Arsenic Gout 23
Bisphenol A Diabetes 22
Cigarette smoking Lung Cancer 21
Arsenic Diabetes 20
Polycyclic aromatic hydrocarbons Diabetes 20
Huge Detoxification Variability
bull CYP2C19
Proton pump inhibitors and some antidepressants
5-fold difference in activity between poor metabolizers and extensive metabolizers more so if CYP3A4 is also inhibited
Ultrarapid allele in 18 of both Swedes and Ethiopians
bull CYP2D6
Metabolizes a large number of drugs (~25)
7 of Caucasians poor metabolizers
~30 ultra rapid metabolizers in Arabian and Eastern African populations
More adverse effects in poor metabolizers and ineffective dosing in ultrarapid metabolizers
Inhibited by ginger
Desta Z et al Clinical significance of the cytochrome P450 2C19 genetic polymorphism Clin Pharmaco 2002
Sim SC et al A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug
response to proton pump inhibitors and antidepressants Clin Pharmacol Ther 2006
Wilkinson GR Drug metabolism and variability among patients in drug response N Engl J Med 2005
Kirchheiner J et al Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to
CYP2D6 duplication Pharmacogenomics J 2007
Toxin Half Lives in BloodToxin ldquoNormalrdquo (mgL) Acute Toxic (mgL) Half-Life
Arsenic 0002-007 005-025 2-4 days (CDC)
Benzene 00002 05-10 days
Cadmium 00003-00065 0015-005 16 years
Chlordane 0001 00025 3-4 days
DDTDDE 2-10 years
Dieldrin 00015 015-030 2-12 months
Ethanol 1000-2000 15hour
Lead 009 04-06 1-15 mo (2+ yrs bone)
Mercury 00015-0002 005-02 2 months (CDC)
PCBs 3-25 years
Toluene 05-3 days
Schulz M et al Therapeutic and toxic blood concentrations of nearly 1000 drugs and other xenobiotics Crit Care 2012 Jul 2616(4)R136
Bioaccumulation (POPs)
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
DDT banned in 1972 PCBs banned in 1977
Bioaccumulation (Cd)
Think BroadlyExogenous
Metals
Chemicalsbull Inorganic
bull Fluoride
bull Organic
bull POPs
bull Drugs
Particulate matter
Molds
Microbial
Radiationbull Light
bull Medical
bull Cell phone
Endogenous
Gut-derived toxins
Non-end product metabolites
Poorly detoxified hormones
Catecholamines (if SNP)
Toxins of Choice
Alcohol
Marijuana
Food constituents
High fructose corn syrup
Salt (acid-forming diet)
Wheat if zonulin (70)
Obesity Epidemic ndash POPs AND HFCS
47Bray GA Fructose should we worry Int J Obes (Lond) 2008 Dec32 Suppl 7S127-31
How Toxins Cause Damage 13
bull Increase free radical production
Cd induces production of ROS
Malathion inhibits catalase and glutathione peroxidase
Homocysteine oxidizes LDL cholesterol
bull Poison enzyme systems (compete with nutritional cofactors for binding sites)
Pb poisons delta aminolevulinic acid dehydratase
Cd inhibits catalase glutathione reductase and lowers
glutathione levels
bull Replace structural minerals
Pb displaces Ca in bone
How Toxins Cause Damage 23
bull Damage DNA
Benzene - causes chromosomal damage
Pesticides ndash fruit growers have more DNA damage
Phthalates and insecticides ndash damage sperm DNA
4-hydroxy catechol estrogen (4-OHE) damages breast DNA
bull Epigenetic dysmodulation
Higher cord blood levels of hexachlorobenzene associated
with 2x greater risk for obesity in children
bull Damage cell membranes
Common mechanism for heavy metals inactivates
membrane enzymes ion channels and pumps
How Toxins Cause Damage 33
bull Block insulin receptor sites
PCBs and phthalates
bull Highest levels associated with a 4 to 20-fold greater diabetes risk
bull Imbalance hormones many toxin examples
Arsenic
bull Disrupts thyroid hormone and retinoic acid receptors
Phthalates
bull Act as anti-androgens
bull More than 75 of the US population has measurable levels of
several phthalate metabolites in the urine
PCBs
bull Lower testosterone levels in men
Which are the Worst Toxins
bull According to the CDC
Toxicity
Population toxic load
Prevalence in toxic waste sites
bull According to clinical importance
Exposure
of disease
Ability of the body to detoxifyexcrete
Ag
en
cy
fo
r T
oxic
Su
bs
tan
ce
s a
nd
Dis
ea
se
Reg
istr
y
Pri
ori
ty L
ist
The Worst Toxins Clinically
My Rank Toxin Diseases Primary Sources
1 Arsenic Cancers diabetes gout Water chicken rice
2 DDT ADHD dementia diabetes Everywhere
3 Phthalates ADHD diabetes Soft plastics HABAs
4 PBDEs ADHD diabetes Flame retardant fabrics
5 PAHs ADHD cancers dyslipidemia Smoking charbroiling
6 PCBs Cancers diabetes MI RA Everywhere
7 Mercury Dementia ldquoSilverrdquo fillings fish
8 Lead Cardiovascular disease IQ Paint water
Glyphosate Research invalid
Conventional Laboratory Tests Reflect
Toxic Load in ldquoNormalrdquo Range
bull Surprising number show toxin exposure
CBC RBC WBC platelet count hemoglobin basophilic
stippling
Liver enzymes ALT GGTP
Inflammatory markers CRP
Lipids LDL oxLDL triglycerides
Blood sugar insulin FBS 2-hour PP
Metabolites bilirubin uric acid homocysteine 8-OHdG
Thyroid T3 T4 TSH
bull The historic ldquonormalrdquo range has been changing as the population has become more toxic
WBC Lowered by PCB and OCP Exposure
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
0
1
2
3
4
5
6
7
8
1st Quartrile 2nd Quartile 3rd Quartile 4th Quartile
WBCbull Strong inverse correlation with PCBs and OCPs and CBC
bull Linear with almost all PCBs
bull High variability with OCPs
bull Within ldquonormalrdquo range
Effects on WBC Worsen with Years
of Exposure to Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Platelet Count Decreases with Years
of Exposure tp Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Solvents Decrease Platelet Count
bull Compared workers exposed 23 hrday to those exposed most of day to toluene
bull All wore face masks and protective gear
bull Platelet count 14 lower 252 versus 216ml
bull Impairment of sympathetic nerves (OR = 413)
bull Impairment of peripheral nerves (OR = 694)
bull Positive relationship between neurological abnormalities and a self-reported neuropsychiatric measurement (r = 035-066)
Shih HT et al Subclinical abnormalities in workers with continuous low-level toluene exposure Toxicol Ind Health 2011 Sep27(8)691-9
Basophilic Stippling of Red Cells
Toxinsbull Arsenic
bull Lead
Diseasesbull Alpha-thalassemia HbH Disease
bull Beta thalassemia
bull Hereditary pyrimidine 5-nucleotidase deficiency
bull Myelodysplastic syndrome
bull Sideroblastic anemia
bull Thrombotic thrombocytopenic purpura
GGT Indirect Measure of POPsbull Glutathione is key intracellular defense against oxidative stress
bull Cellular GGT metabolizes extracellular GSH allowing precursor amino acids to be reutilized for intracellular GSH
bull Exposure to POPs induces GGT as a defensive mechanism
bull Within normal range predicts type 2 diabetes coronary heart disease hypertension stroke dyslipidemia chronic kidney disease and cancer
bull Men with GGT gt50 UI had ~26 fold risk for diabetes compared to those with lt10 Those with 40-49 had a ~20 fold risk
bull Levels within normal range occur with obesity xs alcohol cigarette smoking physical inactivity high meat low fruit and vegetable intake
bull Cumulative biomarker for environmental pollutants
Lee DH et al (2003) Gamma-glutamyltransferase and diabetesmdasha 4 year follow-up study Diabetologia 46359ndash364
Pamela A et al Serum gamma-glutamyltransferase linking together environmental pollution redox equilibria and progression of atherosclerosis Clin Chem
Lab Med 200947(12)1583-4
Lee DH et al Serum gamma-glutamyltransferase new insights about an old enzyme J Epidemiol Community Health 2009 Nov63(11)884-6
Lee DH et alSerum gamma-glutamyltransferase predicts non-fatal myocardial infarction and fatal coronary heart disease among 28838 middle-aged men and
women Eur Heart J 2006272170ndash6
Lee DH et al Gamma-glutamyltransferase and diabetes--a 4 year follow-up study Diabetologia 2003 Mar46(3)359-64
Lee DH et al Can persistent organic pollutants explain the association between serum gamma-glutamyltransferase and type 2 diabetes Diabetologia 2008
Mar51(3)402-7
GGT and Alcohol Consumption
bull GGT directly correlates with alcohol consumption
bull In a non-uniform population 40 gd will elevate GGT ~15
bull Watch for false negatives
bull Genomic variation
bull Are these the ones most
sensitive todamaged by
chemical toxins
bull Could up-regulation of GGT in light alcohol consumption be reason for benefit
0
10
20
30
40
50
60
70
80
0 200 400 600 800
Grams of Ethanol per Week
Adapted from Nagaya T et al Dose-response relationships between drinking and serum tests in Japanese men
aged 40ndash59 years Alcohol 1999 Feb 17(2) 133ndash8
GGT Correlates With Toxic Metal Levels
Lee DH et al Graded associations of blood lead and urinary cadmium concentrations with oxidative-stress-related markers in the
US population results from the third National Health and Nutrition Examination Survey Environ Health
perspect 2006 Mar114(3)350-4
GGT and Diabetes Risk
0
5
10
15
20
25
30
lt10 10-19 20-29 30-39 40-49 gt50
Dia
bete
s R
isk
GGT
bull GGT over 50 associated with tripling of death rate
bull 30-40 associated with doubling
GGT Levels
Correlate with
Risk of Death
Brenner H et al Distribution determinants and prognostic value of gamma-glutamyltransferase for all-cause
mortality in a cohort of construction workers from southern Germany Prev Med 1997 26 305ndash10
GGT From Small US Company
with Young Workers
0
10
20
30
40
50
60
0 20 40 60 80 100
GGT Data from Canadian Oil Field
Workers
0
50
100
150
200
250
300
350
400
450
lt10 10-20 20-30 30-40 40-50 50-60 60-07 70-80 80-90 90-100 100-110 110-120 gt120
GGTP
20-fold increased risk of diabetes
Uric Acid Indirect Measure of POPs
bull Poly-fluorinated hydrocarbons (PFOA and PFOS) associated
with increased serum uric acid
Lin CY et al Association among serum perfluoroalkyl chemicals glucose homeostasis and metabolic syndrome
in adolescents and adults Diabetes Care 2009 Apr32(4)702-7
Steenland K et al Association of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) with uric
acid among adults with elevated community exposure to PFOA Environ Health Perspect 2010 Feb118229-33
Steenland 2010 Open Access
ALT Indirect Measure of POPs
bull ALT (proxy marker) elevation in 104 (not including viral
hepatitis hemochromatosis or alcoholic liver disease) of
NHANES 03-04 subset
bull Risk of elevated ALT increased dose-dependently with
cadmium lead mercury and PCB exposure
bull 100 of individuals had detectable PCBs 925 mercury
and 996 had detectable lead
bull In 2005-08 prevalence of NAFLD in US was 11 a
growing cause of chronic liver disease
Cave M et al Polychlorinated biphenyls lead and mercury are associated with liver disease in American adults
NHANES 2003-2004 Environ Health Perspect 2010 Dec118(12)1735-42
Younossi ZM et al Changes in the prevalence of the most common causes of chronic liver diseases in the United
States from 1988 to 2008 Clin Gastroenterol Hepatol 2011 Jun9(6)524-530e1
Bilirubin as a Marker of POPs
bull Degree of serum bilirubin increase is prognostically significant in chronic liver dysfunction
bull Mono-ortho PCB TEQ values were found to be significantly positively associated with bilirubin (β=071 P=0008) following adjustment for multiple potential confounders
bull Bilirubin levels significantly correlated with PCBs -105-118-126 and -194
bull Smoking appears to be the biggest confounder
Dufour DR et al 2000 Diagnosis and monitoring of hepatic injury II Recommendations for use of laboratory
tests in screening diagnosis and monitoring Clin Chem 46 2050ndash68
Kumar J et al Persistent organic pollutants and liver dysfunction biomarkers in a population-based human sample
of men and women Environ Res 2014134251-256
Perf
luo
rin
ate
dP
OP
s a
nd
Co
mm
on
Blo
od
Tests
Gleason JA et al Associations of perfluorinated chemical serum concentrations and biomarkers of liver function and uric acid in the
US population (NHANES) 2007-2010 Environ Res 20151368-14
Liver Enzymes Reflect Toxic Load
bull AST ALT and GGT increase with body load of PCBs and OCPs
bull Some non-linear
bull Oxychlordanetop quartile
ALT 10
GGT 25
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
LDL-Cholesterol as Measure of POPs
bull 5-year prospective study to determine if POP levels predict future elevation in LDL-cholesterol
bull 598 subjects initially at age 70
bull Looked at 23 POPs
bull Best correlation with PCB 194
Penell J Lind L Salihovic S et al Persistent organic pollutants are related to change in circulating
lipid levels during a 5 year follow-up Environ Res 134(2014)190ndash197
oxLDL as Measure of POPs
bull 992 70-year old individuals (50 women)
bull Sum of PCBs showed strong significant positive associations with ox-LDL and significant negative associations with glutathione-related markers (GSSG and GSSGGSH)
bull A number of POPs (PCB-99 138 153 156 170 180 194 206 and 209) showed strong significant positive association with ox-LDL
Kumar J et al Influence of persistent organic pollutants on oxidative stress in population-based samples
Chemosphere 2014114303-309
Homocysteine is Increased by Pb amp Cd
Guallar E et al Confounding of the relation between homocysteine and peripheral arterial disease by lead cadmium and renal function Am J Epidemiol 2006 Apr 15163(8)700-8
Nutrient Deficiencies Accentuate
Effects of Lead on Homocysteine
bull Deficiencies in folate B6 or B12 make lead more toxic
Lee YM Et al Association of homocysteine levels with blood lead levels and micronutrients in the US general population J Prev Med Public Health 2012 Nov45(6)387-93
T4 amp T3 and PCBs
bull PCBs decrease T4 production
bull PCBs inhibit iodotyrosinedeiodinase activity
bull Study done in pregnant women which implies effect on fetus IQ
Kim S Park J Kim HJ et al Association between several persistent organic pollutants and thyroid hormone levels in serum among the pregnant women of Korea Environ Int 2013 Sep59442-8Shimizu R Yamaguchi M Uramaru N et al Structure-activity relationships of 44 halogenated compounds for iodotyrosinedeiodinase-inhibitory activity Toxicology 2013 Dec 6314(1)22-9
T4 amp T3 and PCBs
bull Not just humans being affected
bull Large study of dolphins shows exactly the same effects
Schwacke LH Zolman ES Balmer BC et al Anaemia hypothyroidism and immune suppression associated with polychlorinated biphenyl exposure in bottlenose dolphins (Tursiops truncatus) Proceed Royal Society B doi101098rspb20110665
8-OHdG
bull Oxidized nucleoside
bull Direct measure of DNA damage
bull Indirect measure of oxidative stress and toxin load
bull Correlates with
Multiple cancers
Mitochondrial damage
Rate of aging
Smoking
Several toxinsWalter Crinnion ldquoTotal Toxic Loadrdquo AANP 2015
8-OHdG Correlates with Pack-Years
of Smoking
Yano T et al Significance of the urinary 8-OHdG level as an oxidative stress marker in lung cancer patients Lung Cancer
2009 Jan63(1)111-4
8-OHdG Correlates
with Mercury
Chen C et al Increased oxidative DNA damage as assessed by urinary 8-hydroxy-2-deoxyguanosine
concentrations and serum redox status in persons exposed to mercury Clin Chem 2005 Apr51(4)759-67
Toxin Effects Worse with Aging
bull Thyroid function decreases with PFOA levels
bull But only after age 63
Shrestha S Bloom MS Yucel R et al Perfluoroalkyl substances and thyroid function in older adults Environ Int 2015 Feb75206-14
Insightful 23-Year Prospective Study
1 lt 50 there is no difference between those with the lowest and highest PCBs
2 In youngest group insulin production increases in response to toxin level As expected since blocking of
insulin receptor sites by PCBs
requires more insulin
3 That adaptive ability decreases with aging
4 At age 50 all the measures show very strong toxin-dose response
Cumulative damage impairs ability to adapt
Suarez-Lopez JR et al Persistent organic pollutants in young adults and changes in glucose related metabolism over a 23-year follow-up Environ Res 2015 Feb137485-94
Recommendations
High body toxic load
GGT gt 25
Uric acid gt 50 mgdl
ALT gt30 UL
Bilirubin gt08 mgdl
CBC lt 6000
Platelet lt 250000
Low T3 andor T4
Monitor Total Toxic Load
8-OHdG gt4
ldquoUnconventionalrdquo Laboratory Tests
bull Challenge testing
bull Hair analysis
bull Direct measures of solvents and POPs in blood urine adipose tissue
Evaluation of Metal Exposure ndash Provocation
bull Provocation ndash the use of a chelating agent ndash before urine collection often done clinically but several limitations
No ldquoofficialrdquo reference range for provoked urine
Most chelating agents do not extract metals from all tissues thus
does not necessarily represent total body burden
bull Example Brain is one of the main target organs for both elemental and organic
mercury yet agents do not chelate brain mercury
bull Despite limitations widely used and advocated by clinicians in part to see efficacy of chelating agent as a guide to treatment and based on empirical evidence
Rooney JP The role of thiols dithiols nutritional factors and interacting ligands in the toxicology of mercury
Toxicology 2007
Is Challenge Testing Valid
bull Poor correlations of standard tests for mercury
bull Unpublished research from corporate wellness project
bull Published amalgam number correlation
bull Published fish consumption correlation
What We Found In Canada
bull Deviations from the mean of 14 29 and 91 respectively
bull DMPS is spreading distribution suggesting that it is better at differentiating mercury body load
bull Some VERY high
Hg Assessment Correlations
bull Extensive measurements in 65 Whole blood Hg
Oral DMPS challenge
Amalgam surfaces
bull Correlations Whole blood w pre urine r = 040
Whole blood w post urine r = 057
Pre urine w post urine r = 068
Amalgams w pre urine r = 026
Amalgams w whole blood r = 036
Amalgams with post urine 044
bull Clear documentation that
challenge testing is better00
100
200
300
400
500
600
0 10 20 30 40 50
Po
st
Uri
ne H
g u
gg
Number of amalgams
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
Cadmium World Production
Mercury in the Air
EPA-452R-97-003 December 1997
Mercury in Water
httpwaterepagovscitechdataitmodelsmapspostercfm
Ground Water Sources of Arsenic
bull 10 of US public water supplies have levels of arsenic known to induce disease
bull No data on private water supplies
httpwwwatsdrcdcgovcsemarsenicdocsarsenicpdf (accessed 2015-08-18)
Example POPs
Chemical Abbr Uses Exposure
Bisphenol A BPA Plastics Canned food
Organochlorine
pesticides
OCPs Pesticide Food fumigation
Organophosphate
pesticides
OPPs Pesticide Food
Polybrominated
diphenyl ethers
PBDEs Flame retardant Clothing
Polychlorinated
biphenyls
PCBs Industrial Everywhere
Perflourinated PFOAs Non-stick stain prevention
water repellant
Teflon Gortex
Scotchguard
Phthalates Plastics fragrances Shower curtains
cosmetics
POPs - Prediabetes
bull Over 1200 participants fasting
glucose and OGTT performed
with serum levels of 5 POPs
bull All individual POPs tested were
associated with progressive
increase in prevalence of
prediabetes
bull More than triple prevalence of
prediabetes seen in those in the
5th quartile with a synergistic
effect from 5 POPs
Ukropec J et al High prevalence of prediabetes and diabetes in a population exposed to high levels of an organochlorine cocktail
Diabetologia 2010 May53(5)899-906
POPs and Diabetes Risk
Graph httpwwwourstolenfutureorgNewScienceobesity20062006-0715leeetalhtml
Data Lee DH Lee IK Song K et al A strong dose-response relation between serum
concentrations of persistent organic pollutants and diabetes results from the National Health and
Examination Survey 1999-2002 Diabetes Care 2006 Jul29(7)1638-44
Toxic Load and Disease Risk
References for Toxins and Disease Risk
Converting Disease Risk to Caused
Attributable Fraction Calculation
p = underlying prevalence of risk factor in the population
rr = relative risk (risk of contracting a disease in an exposed population divided by the risk of contracting the disease in an unexposed population)
AF = of disease due to the toxin
Levin M The occurrence of lung cancer in man Acta Unio Int Contra Cancrum 1953 9 531-541
Example Smoking and Lung Cancer
B = 5Number of smokers
who contract Lung Cancer notdue to smoking
A = 5Number of smokerswho contract Lung
Cancer due to smoking
C = 15Number of
nonsmokerswho contract Lung Cancer
0
2
4
6
8
10
12
14
16
Smokers (N=100) Nonsmokers (N=300)Num
ber
of
people
who c
ontr
act
Lung C
ancer
per
year
Baseline Additional due to smoking
Number of smokers and nonsmokers who contract lung cancer
Our Process In Summary
1 Determine threshold for increased disease risk
2 Determine of population above threshold
3 Determine incidence of disease (OR) in those above threshold
4 Determine incidence of disease in ldquounexposed populationrdquo
5 Calculate AF ie of disease
As whole population is exposed probably UNDERESTIMATES of disease
To
xic
ity H
as B
eco
me t
he N
ew
ldquoN
orm
alrdquo
Toxin Type Use Threshold for
disease
association
of US
above
threshold
Disease Associations
Chlordane OC pesticide Termites corn citrus lawns
gardens
145ngg lipid 63
(diabetes)
Diabetes (20)
BPA Plasticizer Water bottles canned food
water pipes thermal sales
receipts
48 men 51
women (urine
ngmL)
~18
(diabetes)
Diabetes hypertension
Octachloro
dibenzo-p-
dioxin
(OCDD)
Polychlorinated
dibenzo-p-
dioxin
Incineration or burning of
waste bleaching processes
used in pulp and paper mills
1010 pgg
lipid (highest
quartile)
10-25
(hypertensio
n)
Hypertension (79 for
women highest
quartile) diabetes (21)
obesity learning
disability (272)
MEP
(mono-
ethyl
phthalate)
Phthalate
(plasticizer
fragrance)
Toothbrushes automobile
parts tools toys and food
packaging aspirin
cosmetics food packaging
gt175 ngmL
(urine)
~60
(diabetes)
Diabetes (148) lower
BMD obesity
pp-DDE DDT
metabolite (OC
pesticide)
Agricultural crops 1560ngg
lipid
25
(diabetes)
Diabetes (23-43)
early menopause
impaired cognitive
function (2-3x 65x in
highest 5th percentile)
peripheral arterial
disease
Arsenic Toxic metal Miningsmelting wood
preservative pesticides
74ugL total
arsenic (urine)
20
(diabetes)
Cancers diabetes (26-
46) dyslipidemia gout
AF OR Prevalence
Rosen L An intuitive approach to understanding the attributable fraction of disease due to a risk factor the case of smoking Int J Environ Res Public Health 2013 Jul 1610(7)2932-43
Smoking Lung cancer
Arsenic Gout in women
BPA Diabetes
Status of Our Research
bull 26 toxins and toxin classes eg lead mercury BPA OCPs
100s of chemicals and POPs in some classes
bull 18 cancers
bull 24 chronic diseases
bull 1092 cells in spreadsheet
Large Personal Ongoing Research Investment
Huge Amount of Research Work
Toxins StudiedAluminum
Arsenic
Cadmium
Fluoride
Lead
Manganese
Mercury
Acrylamide
Acrylonitrile
Benzene
Bisphenol A (BPA)
Chloroform
DDT
Dioxins
Glyphosate
Organochlorine pesticides (OCPs)
Organophosphate pesticides
Parabens
Phthalates
Polybrominated diphenyl ethers (PBDEs)
Polycyclic aromatic hydrocarbons (PAHs)
Polychlorinated biphenols (PCBs)
Vinyl chloride
Diseases Studied
ADHD
Alzheimers Disease
ALS
Angiosarcoma
Anxiety
Atopic Conditions
Diabetes
Dyslipidemia
Gout
Fetal Abnormalities
Hyperuricemia
Infertility
Juvenile IQ
Cancer Bladder
Cancer Bone
Cancer Brain
Cancer Breast
Cancer Cervix
Cancer Colorectal
Cancer Endometrial
Cancer Head amp Neck
Cancer Liver
Cancer Lung
Cancer Lymph amp Blood
Cancer Ovarian
Cancer Pancreatic
Cancer Prostate
Cancer Renal
Cancer Skin
Cancer Testicular
Cancer Thyroid
Juvenile Obesity
Metabolic Syndrome
Mitochondrial dysfunction
Myocardial Infarction
Obstructive Lung Disease
Osteoporosis
Peripheral Artery Disease
Peripheral Neuropathy
Prediabetes
Renal Disease
Rheumatoid Arthritis
Thyroid Dysfunction
OC
Ps
Th
rou
gh
ou
t th
e W
orl
d
Rathore HS Nollet LML Pesticides Evaluation of Environmental Pollution CRC Press
2012 page 562
Threshold ndash Threshold exposure at which there is an increased risk of disease outcome
Above Threshold ndash Percentage of the population with higher exposure than the threshold
Odds Ratio ndash Increased disease risk in those above threshold
of Dz ndash Percent contribution of the toxin to that disease outcome
How to Interpret the Following Slides
Attention Deficit Hyperactivity Disorder
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
DDT 126 ngg
serum (pp-
DDE)
250 18 166 20106937
Lead 23 ugdL 13 254 20 27659349
Mercury 16 24952233
Organophosphate
pesticides
20
Polycyclic
Aromatic
Hydrocarbons
227 ngm3 940 125 190 22440811
PCBs 104 ngg
serum (sum
of 50 PCBs)
250 176 160 20106937
DiabetesToxin Threshold Above
Threshold
Odds
Ratio
of Dz Reference
PMID
Arsenic 165 ugL 200 21 180 18714061
BPA 28 ugL 280 145 112 26119400
DDE 545 ngg serum
(pp-DDE)
200 230 31 26119400
Dioxins2 pgg lipid 50 191 43
26119400
PCBs104 ngg (PCB 153) 250 239 258
26119400
Phthalates175 ugL 690 148 249
26119400
1-naphthalene 167 ugdL 152 182 111 26340343
2-napthalene 414 ugdL 550 224 214 26340343
1-phenanthrene 167 ngL 570 178 151 26340343
1-pyrene 85 ngL 660 180 174 26340343
Lung Cancer
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Acrylonitrile Uncertain Uncertain 125 25
occupational
exposure
17114112
Arsenic 1213 ugL 436 of Asian
Americans
~01 of total
US population
34 95 in AA
01-1
PMC2682945
Cadmium Uncertain+ Uncertain 467 10 in
smokers
17184399
DDT Any exposure All US pop
below LOD
17 76 increased
risk
8923607
Breast Cancer
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Cadmium 0580 ugg
creatinine
126 205 479 16788160
PCB 138 396 ngg
creatinine
202 316 630 27717745
PCB 187 108 ngg lipid 600 194 360 21480306
Miscellaneous Diseases
Toxin Disease Threshold Above
Threshold
Odds
Ratio
of Dz Reference PMID
Aluminum Alzheimer
Dz
01 mgL
drinking
H20
400 203 05-44 26592479
Benzene AML 100ppmyrs 1-3 320 60 PMC2903550
DDT NHL 0512 ugL 1-2 240 01 17722095
Lead ALS 238 ugdL
blood
330 181 210 25479292
Lead Brain CA 0005 ugdL 14 19 ~500 17164378
Dioxin-like
PCBs
RA 326 ngg
lipid
250 219 220 17589595
PAHs Asthma 124 ngm3 935 200 483 19221603
The Potency of Arsenic
Disease Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Bladder CA 10ugL H20 100 27 145 24889821
Pancreatic CA 1332 ugg 200 246 230 23800676
Prostate CA 1332 ugg 200 33 315 23800676
Gout 125 ugL 245 546 522 25499256
Diabetes 165 ugL 200 21 180 18714061
Arsenic (180 of Diabetes)
How it causes diabetes
bull Blocks sugar stimulating insulin secretion
bull Epigenetic inhibition of sugar regulation
Where it comes from
bull Water (gt10 of US water supplies have high levels)
bull Rice (naturally absorbs if in the water)
bull Chicken (added to make meat whiter)
Pan W-C Seow WJ Kile ML et al Association of low to moderate levels of arsenic exposure with risk of Type 2 diabetes in Bangladesh American Journal of Epidemiology 2013178(10)1563-70
Portion of Population with Toxin Load Which
Doubles Disease Risk
Toxin Disease with Doubled Risk
Polycyclic aromatic hydrocarbons Asthma 94
PCB187 Breast Cancer 60
Phthalates Diabetes 55
Lead ALS 33
Aluminum Alzheimers Disease 25
DDT ADHD 25
PCBs Diabetes 25
Dioxin-like PCBs Rheumatoid Arthritis 25
Arsenic Gout 23
Bisphenol A Diabetes 22
Cigarette smoking Lung Cancer 21
Arsenic Diabetes 20
Polycyclic aromatic hydrocarbons Diabetes 20
Huge Detoxification Variability
bull CYP2C19
Proton pump inhibitors and some antidepressants
5-fold difference in activity between poor metabolizers and extensive metabolizers more so if CYP3A4 is also inhibited
Ultrarapid allele in 18 of both Swedes and Ethiopians
bull CYP2D6
Metabolizes a large number of drugs (~25)
7 of Caucasians poor metabolizers
~30 ultra rapid metabolizers in Arabian and Eastern African populations
More adverse effects in poor metabolizers and ineffective dosing in ultrarapid metabolizers
Inhibited by ginger
Desta Z et al Clinical significance of the cytochrome P450 2C19 genetic polymorphism Clin Pharmaco 2002
Sim SC et al A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug
response to proton pump inhibitors and antidepressants Clin Pharmacol Ther 2006
Wilkinson GR Drug metabolism and variability among patients in drug response N Engl J Med 2005
Kirchheiner J et al Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to
CYP2D6 duplication Pharmacogenomics J 2007
Toxin Half Lives in BloodToxin ldquoNormalrdquo (mgL) Acute Toxic (mgL) Half-Life
Arsenic 0002-007 005-025 2-4 days (CDC)
Benzene 00002 05-10 days
Cadmium 00003-00065 0015-005 16 years
Chlordane 0001 00025 3-4 days
DDTDDE 2-10 years
Dieldrin 00015 015-030 2-12 months
Ethanol 1000-2000 15hour
Lead 009 04-06 1-15 mo (2+ yrs bone)
Mercury 00015-0002 005-02 2 months (CDC)
PCBs 3-25 years
Toluene 05-3 days
Schulz M et al Therapeutic and toxic blood concentrations of nearly 1000 drugs and other xenobiotics Crit Care 2012 Jul 2616(4)R136
Bioaccumulation (POPs)
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
DDT banned in 1972 PCBs banned in 1977
Bioaccumulation (Cd)
Think BroadlyExogenous
Metals
Chemicalsbull Inorganic
bull Fluoride
bull Organic
bull POPs
bull Drugs
Particulate matter
Molds
Microbial
Radiationbull Light
bull Medical
bull Cell phone
Endogenous
Gut-derived toxins
Non-end product metabolites
Poorly detoxified hormones
Catecholamines (if SNP)
Toxins of Choice
Alcohol
Marijuana
Food constituents
High fructose corn syrup
Salt (acid-forming diet)
Wheat if zonulin (70)
Obesity Epidemic ndash POPs AND HFCS
47Bray GA Fructose should we worry Int J Obes (Lond) 2008 Dec32 Suppl 7S127-31
How Toxins Cause Damage 13
bull Increase free radical production
Cd induces production of ROS
Malathion inhibits catalase and glutathione peroxidase
Homocysteine oxidizes LDL cholesterol
bull Poison enzyme systems (compete with nutritional cofactors for binding sites)
Pb poisons delta aminolevulinic acid dehydratase
Cd inhibits catalase glutathione reductase and lowers
glutathione levels
bull Replace structural minerals
Pb displaces Ca in bone
How Toxins Cause Damage 23
bull Damage DNA
Benzene - causes chromosomal damage
Pesticides ndash fruit growers have more DNA damage
Phthalates and insecticides ndash damage sperm DNA
4-hydroxy catechol estrogen (4-OHE) damages breast DNA
bull Epigenetic dysmodulation
Higher cord blood levels of hexachlorobenzene associated
with 2x greater risk for obesity in children
bull Damage cell membranes
Common mechanism for heavy metals inactivates
membrane enzymes ion channels and pumps
How Toxins Cause Damage 33
bull Block insulin receptor sites
PCBs and phthalates
bull Highest levels associated with a 4 to 20-fold greater diabetes risk
bull Imbalance hormones many toxin examples
Arsenic
bull Disrupts thyroid hormone and retinoic acid receptors
Phthalates
bull Act as anti-androgens
bull More than 75 of the US population has measurable levels of
several phthalate metabolites in the urine
PCBs
bull Lower testosterone levels in men
Which are the Worst Toxins
bull According to the CDC
Toxicity
Population toxic load
Prevalence in toxic waste sites
bull According to clinical importance
Exposure
of disease
Ability of the body to detoxifyexcrete
Ag
en
cy
fo
r T
oxic
Su
bs
tan
ce
s a
nd
Dis
ea
se
Reg
istr
y
Pri
ori
ty L
ist
The Worst Toxins Clinically
My Rank Toxin Diseases Primary Sources
1 Arsenic Cancers diabetes gout Water chicken rice
2 DDT ADHD dementia diabetes Everywhere
3 Phthalates ADHD diabetes Soft plastics HABAs
4 PBDEs ADHD diabetes Flame retardant fabrics
5 PAHs ADHD cancers dyslipidemia Smoking charbroiling
6 PCBs Cancers diabetes MI RA Everywhere
7 Mercury Dementia ldquoSilverrdquo fillings fish
8 Lead Cardiovascular disease IQ Paint water
Glyphosate Research invalid
Conventional Laboratory Tests Reflect
Toxic Load in ldquoNormalrdquo Range
bull Surprising number show toxin exposure
CBC RBC WBC platelet count hemoglobin basophilic
stippling
Liver enzymes ALT GGTP
Inflammatory markers CRP
Lipids LDL oxLDL triglycerides
Blood sugar insulin FBS 2-hour PP
Metabolites bilirubin uric acid homocysteine 8-OHdG
Thyroid T3 T4 TSH
bull The historic ldquonormalrdquo range has been changing as the population has become more toxic
WBC Lowered by PCB and OCP Exposure
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
0
1
2
3
4
5
6
7
8
1st Quartrile 2nd Quartile 3rd Quartile 4th Quartile
WBCbull Strong inverse correlation with PCBs and OCPs and CBC
bull Linear with almost all PCBs
bull High variability with OCPs
bull Within ldquonormalrdquo range
Effects on WBC Worsen with Years
of Exposure to Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Platelet Count Decreases with Years
of Exposure tp Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Solvents Decrease Platelet Count
bull Compared workers exposed 23 hrday to those exposed most of day to toluene
bull All wore face masks and protective gear
bull Platelet count 14 lower 252 versus 216ml
bull Impairment of sympathetic nerves (OR = 413)
bull Impairment of peripheral nerves (OR = 694)
bull Positive relationship between neurological abnormalities and a self-reported neuropsychiatric measurement (r = 035-066)
Shih HT et al Subclinical abnormalities in workers with continuous low-level toluene exposure Toxicol Ind Health 2011 Sep27(8)691-9
Basophilic Stippling of Red Cells
Toxinsbull Arsenic
bull Lead
Diseasesbull Alpha-thalassemia HbH Disease
bull Beta thalassemia
bull Hereditary pyrimidine 5-nucleotidase deficiency
bull Myelodysplastic syndrome
bull Sideroblastic anemia
bull Thrombotic thrombocytopenic purpura
GGT Indirect Measure of POPsbull Glutathione is key intracellular defense against oxidative stress
bull Cellular GGT metabolizes extracellular GSH allowing precursor amino acids to be reutilized for intracellular GSH
bull Exposure to POPs induces GGT as a defensive mechanism
bull Within normal range predicts type 2 diabetes coronary heart disease hypertension stroke dyslipidemia chronic kidney disease and cancer
bull Men with GGT gt50 UI had ~26 fold risk for diabetes compared to those with lt10 Those with 40-49 had a ~20 fold risk
bull Levels within normal range occur with obesity xs alcohol cigarette smoking physical inactivity high meat low fruit and vegetable intake
bull Cumulative biomarker for environmental pollutants
Lee DH et al (2003) Gamma-glutamyltransferase and diabetesmdasha 4 year follow-up study Diabetologia 46359ndash364
Pamela A et al Serum gamma-glutamyltransferase linking together environmental pollution redox equilibria and progression of atherosclerosis Clin Chem
Lab Med 200947(12)1583-4
Lee DH et al Serum gamma-glutamyltransferase new insights about an old enzyme J Epidemiol Community Health 2009 Nov63(11)884-6
Lee DH et alSerum gamma-glutamyltransferase predicts non-fatal myocardial infarction and fatal coronary heart disease among 28838 middle-aged men and
women Eur Heart J 2006272170ndash6
Lee DH et al Gamma-glutamyltransferase and diabetes--a 4 year follow-up study Diabetologia 2003 Mar46(3)359-64
Lee DH et al Can persistent organic pollutants explain the association between serum gamma-glutamyltransferase and type 2 diabetes Diabetologia 2008
Mar51(3)402-7
GGT and Alcohol Consumption
bull GGT directly correlates with alcohol consumption
bull In a non-uniform population 40 gd will elevate GGT ~15
bull Watch for false negatives
bull Genomic variation
bull Are these the ones most
sensitive todamaged by
chemical toxins
bull Could up-regulation of GGT in light alcohol consumption be reason for benefit
0
10
20
30
40
50
60
70
80
0 200 400 600 800
Grams of Ethanol per Week
Adapted from Nagaya T et al Dose-response relationships between drinking and serum tests in Japanese men
aged 40ndash59 years Alcohol 1999 Feb 17(2) 133ndash8
GGT Correlates With Toxic Metal Levels
Lee DH et al Graded associations of blood lead and urinary cadmium concentrations with oxidative-stress-related markers in the
US population results from the third National Health and Nutrition Examination Survey Environ Health
perspect 2006 Mar114(3)350-4
GGT and Diabetes Risk
0
5
10
15
20
25
30
lt10 10-19 20-29 30-39 40-49 gt50
Dia
bete
s R
isk
GGT
bull GGT over 50 associated with tripling of death rate
bull 30-40 associated with doubling
GGT Levels
Correlate with
Risk of Death
Brenner H et al Distribution determinants and prognostic value of gamma-glutamyltransferase for all-cause
mortality in a cohort of construction workers from southern Germany Prev Med 1997 26 305ndash10
GGT From Small US Company
with Young Workers
0
10
20
30
40
50
60
0 20 40 60 80 100
GGT Data from Canadian Oil Field
Workers
0
50
100
150
200
250
300
350
400
450
lt10 10-20 20-30 30-40 40-50 50-60 60-07 70-80 80-90 90-100 100-110 110-120 gt120
GGTP
20-fold increased risk of diabetes
Uric Acid Indirect Measure of POPs
bull Poly-fluorinated hydrocarbons (PFOA and PFOS) associated
with increased serum uric acid
Lin CY et al Association among serum perfluoroalkyl chemicals glucose homeostasis and metabolic syndrome
in adolescents and adults Diabetes Care 2009 Apr32(4)702-7
Steenland K et al Association of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) with uric
acid among adults with elevated community exposure to PFOA Environ Health Perspect 2010 Feb118229-33
Steenland 2010 Open Access
ALT Indirect Measure of POPs
bull ALT (proxy marker) elevation in 104 (not including viral
hepatitis hemochromatosis or alcoholic liver disease) of
NHANES 03-04 subset
bull Risk of elevated ALT increased dose-dependently with
cadmium lead mercury and PCB exposure
bull 100 of individuals had detectable PCBs 925 mercury
and 996 had detectable lead
bull In 2005-08 prevalence of NAFLD in US was 11 a
growing cause of chronic liver disease
Cave M et al Polychlorinated biphenyls lead and mercury are associated with liver disease in American adults
NHANES 2003-2004 Environ Health Perspect 2010 Dec118(12)1735-42
Younossi ZM et al Changes in the prevalence of the most common causes of chronic liver diseases in the United
States from 1988 to 2008 Clin Gastroenterol Hepatol 2011 Jun9(6)524-530e1
Bilirubin as a Marker of POPs
bull Degree of serum bilirubin increase is prognostically significant in chronic liver dysfunction
bull Mono-ortho PCB TEQ values were found to be significantly positively associated with bilirubin (β=071 P=0008) following adjustment for multiple potential confounders
bull Bilirubin levels significantly correlated with PCBs -105-118-126 and -194
bull Smoking appears to be the biggest confounder
Dufour DR et al 2000 Diagnosis and monitoring of hepatic injury II Recommendations for use of laboratory
tests in screening diagnosis and monitoring Clin Chem 46 2050ndash68
Kumar J et al Persistent organic pollutants and liver dysfunction biomarkers in a population-based human sample
of men and women Environ Res 2014134251-256
Perf
luo
rin
ate
dP
OP
s a
nd
Co
mm
on
Blo
od
Tests
Gleason JA et al Associations of perfluorinated chemical serum concentrations and biomarkers of liver function and uric acid in the
US population (NHANES) 2007-2010 Environ Res 20151368-14
Liver Enzymes Reflect Toxic Load
bull AST ALT and GGT increase with body load of PCBs and OCPs
bull Some non-linear
bull Oxychlordanetop quartile
ALT 10
GGT 25
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
LDL-Cholesterol as Measure of POPs
bull 5-year prospective study to determine if POP levels predict future elevation in LDL-cholesterol
bull 598 subjects initially at age 70
bull Looked at 23 POPs
bull Best correlation with PCB 194
Penell J Lind L Salihovic S et al Persistent organic pollutants are related to change in circulating
lipid levels during a 5 year follow-up Environ Res 134(2014)190ndash197
oxLDL as Measure of POPs
bull 992 70-year old individuals (50 women)
bull Sum of PCBs showed strong significant positive associations with ox-LDL and significant negative associations with glutathione-related markers (GSSG and GSSGGSH)
bull A number of POPs (PCB-99 138 153 156 170 180 194 206 and 209) showed strong significant positive association with ox-LDL
Kumar J et al Influence of persistent organic pollutants on oxidative stress in population-based samples
Chemosphere 2014114303-309
Homocysteine is Increased by Pb amp Cd
Guallar E et al Confounding of the relation between homocysteine and peripheral arterial disease by lead cadmium and renal function Am J Epidemiol 2006 Apr 15163(8)700-8
Nutrient Deficiencies Accentuate
Effects of Lead on Homocysteine
bull Deficiencies in folate B6 or B12 make lead more toxic
Lee YM Et al Association of homocysteine levels with blood lead levels and micronutrients in the US general population J Prev Med Public Health 2012 Nov45(6)387-93
T4 amp T3 and PCBs
bull PCBs decrease T4 production
bull PCBs inhibit iodotyrosinedeiodinase activity
bull Study done in pregnant women which implies effect on fetus IQ
Kim S Park J Kim HJ et al Association between several persistent organic pollutants and thyroid hormone levels in serum among the pregnant women of Korea Environ Int 2013 Sep59442-8Shimizu R Yamaguchi M Uramaru N et al Structure-activity relationships of 44 halogenated compounds for iodotyrosinedeiodinase-inhibitory activity Toxicology 2013 Dec 6314(1)22-9
T4 amp T3 and PCBs
bull Not just humans being affected
bull Large study of dolphins shows exactly the same effects
Schwacke LH Zolman ES Balmer BC et al Anaemia hypothyroidism and immune suppression associated with polychlorinated biphenyl exposure in bottlenose dolphins (Tursiops truncatus) Proceed Royal Society B doi101098rspb20110665
8-OHdG
bull Oxidized nucleoside
bull Direct measure of DNA damage
bull Indirect measure of oxidative stress and toxin load
bull Correlates with
Multiple cancers
Mitochondrial damage
Rate of aging
Smoking
Several toxinsWalter Crinnion ldquoTotal Toxic Loadrdquo AANP 2015
8-OHdG Correlates with Pack-Years
of Smoking
Yano T et al Significance of the urinary 8-OHdG level as an oxidative stress marker in lung cancer patients Lung Cancer
2009 Jan63(1)111-4
8-OHdG Correlates
with Mercury
Chen C et al Increased oxidative DNA damage as assessed by urinary 8-hydroxy-2-deoxyguanosine
concentrations and serum redox status in persons exposed to mercury Clin Chem 2005 Apr51(4)759-67
Toxin Effects Worse with Aging
bull Thyroid function decreases with PFOA levels
bull But only after age 63
Shrestha S Bloom MS Yucel R et al Perfluoroalkyl substances and thyroid function in older adults Environ Int 2015 Feb75206-14
Insightful 23-Year Prospective Study
1 lt 50 there is no difference between those with the lowest and highest PCBs
2 In youngest group insulin production increases in response to toxin level As expected since blocking of
insulin receptor sites by PCBs
requires more insulin
3 That adaptive ability decreases with aging
4 At age 50 all the measures show very strong toxin-dose response
Cumulative damage impairs ability to adapt
Suarez-Lopez JR et al Persistent organic pollutants in young adults and changes in glucose related metabolism over a 23-year follow-up Environ Res 2015 Feb137485-94
Recommendations
High body toxic load
GGT gt 25
Uric acid gt 50 mgdl
ALT gt30 UL
Bilirubin gt08 mgdl
CBC lt 6000
Platelet lt 250000
Low T3 andor T4
Monitor Total Toxic Load
8-OHdG gt4
ldquoUnconventionalrdquo Laboratory Tests
bull Challenge testing
bull Hair analysis
bull Direct measures of solvents and POPs in blood urine adipose tissue
Evaluation of Metal Exposure ndash Provocation
bull Provocation ndash the use of a chelating agent ndash before urine collection often done clinically but several limitations
No ldquoofficialrdquo reference range for provoked urine
Most chelating agents do not extract metals from all tissues thus
does not necessarily represent total body burden
bull Example Brain is one of the main target organs for both elemental and organic
mercury yet agents do not chelate brain mercury
bull Despite limitations widely used and advocated by clinicians in part to see efficacy of chelating agent as a guide to treatment and based on empirical evidence
Rooney JP The role of thiols dithiols nutritional factors and interacting ligands in the toxicology of mercury
Toxicology 2007
Is Challenge Testing Valid
bull Poor correlations of standard tests for mercury
bull Unpublished research from corporate wellness project
bull Published amalgam number correlation
bull Published fish consumption correlation
What We Found In Canada
bull Deviations from the mean of 14 29 and 91 respectively
bull DMPS is spreading distribution suggesting that it is better at differentiating mercury body load
bull Some VERY high
Hg Assessment Correlations
bull Extensive measurements in 65 Whole blood Hg
Oral DMPS challenge
Amalgam surfaces
bull Correlations Whole blood w pre urine r = 040
Whole blood w post urine r = 057
Pre urine w post urine r = 068
Amalgams w pre urine r = 026
Amalgams w whole blood r = 036
Amalgams with post urine 044
bull Clear documentation that
challenge testing is better00
100
200
300
400
500
600
0 10 20 30 40 50
Po
st
Uri
ne H
g u
gg
Number of amalgams
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
Mercury in the Air
EPA-452R-97-003 December 1997
Mercury in Water
httpwaterepagovscitechdataitmodelsmapspostercfm
Ground Water Sources of Arsenic
bull 10 of US public water supplies have levels of arsenic known to induce disease
bull No data on private water supplies
httpwwwatsdrcdcgovcsemarsenicdocsarsenicpdf (accessed 2015-08-18)
Example POPs
Chemical Abbr Uses Exposure
Bisphenol A BPA Plastics Canned food
Organochlorine
pesticides
OCPs Pesticide Food fumigation
Organophosphate
pesticides
OPPs Pesticide Food
Polybrominated
diphenyl ethers
PBDEs Flame retardant Clothing
Polychlorinated
biphenyls
PCBs Industrial Everywhere
Perflourinated PFOAs Non-stick stain prevention
water repellant
Teflon Gortex
Scotchguard
Phthalates Plastics fragrances Shower curtains
cosmetics
POPs - Prediabetes
bull Over 1200 participants fasting
glucose and OGTT performed
with serum levels of 5 POPs
bull All individual POPs tested were
associated with progressive
increase in prevalence of
prediabetes
bull More than triple prevalence of
prediabetes seen in those in the
5th quartile with a synergistic
effect from 5 POPs
Ukropec J et al High prevalence of prediabetes and diabetes in a population exposed to high levels of an organochlorine cocktail
Diabetologia 2010 May53(5)899-906
POPs and Diabetes Risk
Graph httpwwwourstolenfutureorgNewScienceobesity20062006-0715leeetalhtml
Data Lee DH Lee IK Song K et al A strong dose-response relation between serum
concentrations of persistent organic pollutants and diabetes results from the National Health and
Examination Survey 1999-2002 Diabetes Care 2006 Jul29(7)1638-44
Toxic Load and Disease Risk
References for Toxins and Disease Risk
Converting Disease Risk to Caused
Attributable Fraction Calculation
p = underlying prevalence of risk factor in the population
rr = relative risk (risk of contracting a disease in an exposed population divided by the risk of contracting the disease in an unexposed population)
AF = of disease due to the toxin
Levin M The occurrence of lung cancer in man Acta Unio Int Contra Cancrum 1953 9 531-541
Example Smoking and Lung Cancer
B = 5Number of smokers
who contract Lung Cancer notdue to smoking
A = 5Number of smokerswho contract Lung
Cancer due to smoking
C = 15Number of
nonsmokerswho contract Lung Cancer
0
2
4
6
8
10
12
14
16
Smokers (N=100) Nonsmokers (N=300)Num
ber
of
people
who c
ontr
act
Lung C
ancer
per
year
Baseline Additional due to smoking
Number of smokers and nonsmokers who contract lung cancer
Our Process In Summary
1 Determine threshold for increased disease risk
2 Determine of population above threshold
3 Determine incidence of disease (OR) in those above threshold
4 Determine incidence of disease in ldquounexposed populationrdquo
5 Calculate AF ie of disease
As whole population is exposed probably UNDERESTIMATES of disease
To
xic
ity H
as B
eco
me t
he N
ew
ldquoN
orm
alrdquo
Toxin Type Use Threshold for
disease
association
of US
above
threshold
Disease Associations
Chlordane OC pesticide Termites corn citrus lawns
gardens
145ngg lipid 63
(diabetes)
Diabetes (20)
BPA Plasticizer Water bottles canned food
water pipes thermal sales
receipts
48 men 51
women (urine
ngmL)
~18
(diabetes)
Diabetes hypertension
Octachloro
dibenzo-p-
dioxin
(OCDD)
Polychlorinated
dibenzo-p-
dioxin
Incineration or burning of
waste bleaching processes
used in pulp and paper mills
1010 pgg
lipid (highest
quartile)
10-25
(hypertensio
n)
Hypertension (79 for
women highest
quartile) diabetes (21)
obesity learning
disability (272)
MEP
(mono-
ethyl
phthalate)
Phthalate
(plasticizer
fragrance)
Toothbrushes automobile
parts tools toys and food
packaging aspirin
cosmetics food packaging
gt175 ngmL
(urine)
~60
(diabetes)
Diabetes (148) lower
BMD obesity
pp-DDE DDT
metabolite (OC
pesticide)
Agricultural crops 1560ngg
lipid
25
(diabetes)
Diabetes (23-43)
early menopause
impaired cognitive
function (2-3x 65x in
highest 5th percentile)
peripheral arterial
disease
Arsenic Toxic metal Miningsmelting wood
preservative pesticides
74ugL total
arsenic (urine)
20
(diabetes)
Cancers diabetes (26-
46) dyslipidemia gout
AF OR Prevalence
Rosen L An intuitive approach to understanding the attributable fraction of disease due to a risk factor the case of smoking Int J Environ Res Public Health 2013 Jul 1610(7)2932-43
Smoking Lung cancer
Arsenic Gout in women
BPA Diabetes
Status of Our Research
bull 26 toxins and toxin classes eg lead mercury BPA OCPs
100s of chemicals and POPs in some classes
bull 18 cancers
bull 24 chronic diseases
bull 1092 cells in spreadsheet
Large Personal Ongoing Research Investment
Huge Amount of Research Work
Toxins StudiedAluminum
Arsenic
Cadmium
Fluoride
Lead
Manganese
Mercury
Acrylamide
Acrylonitrile
Benzene
Bisphenol A (BPA)
Chloroform
DDT
Dioxins
Glyphosate
Organochlorine pesticides (OCPs)
Organophosphate pesticides
Parabens
Phthalates
Polybrominated diphenyl ethers (PBDEs)
Polycyclic aromatic hydrocarbons (PAHs)
Polychlorinated biphenols (PCBs)
Vinyl chloride
Diseases Studied
ADHD
Alzheimers Disease
ALS
Angiosarcoma
Anxiety
Atopic Conditions
Diabetes
Dyslipidemia
Gout
Fetal Abnormalities
Hyperuricemia
Infertility
Juvenile IQ
Cancer Bladder
Cancer Bone
Cancer Brain
Cancer Breast
Cancer Cervix
Cancer Colorectal
Cancer Endometrial
Cancer Head amp Neck
Cancer Liver
Cancer Lung
Cancer Lymph amp Blood
Cancer Ovarian
Cancer Pancreatic
Cancer Prostate
Cancer Renal
Cancer Skin
Cancer Testicular
Cancer Thyroid
Juvenile Obesity
Metabolic Syndrome
Mitochondrial dysfunction
Myocardial Infarction
Obstructive Lung Disease
Osteoporosis
Peripheral Artery Disease
Peripheral Neuropathy
Prediabetes
Renal Disease
Rheumatoid Arthritis
Thyroid Dysfunction
OC
Ps
Th
rou
gh
ou
t th
e W
orl
d
Rathore HS Nollet LML Pesticides Evaluation of Environmental Pollution CRC Press
2012 page 562
Threshold ndash Threshold exposure at which there is an increased risk of disease outcome
Above Threshold ndash Percentage of the population with higher exposure than the threshold
Odds Ratio ndash Increased disease risk in those above threshold
of Dz ndash Percent contribution of the toxin to that disease outcome
How to Interpret the Following Slides
Attention Deficit Hyperactivity Disorder
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
DDT 126 ngg
serum (pp-
DDE)
250 18 166 20106937
Lead 23 ugdL 13 254 20 27659349
Mercury 16 24952233
Organophosphate
pesticides
20
Polycyclic
Aromatic
Hydrocarbons
227 ngm3 940 125 190 22440811
PCBs 104 ngg
serum (sum
of 50 PCBs)
250 176 160 20106937
DiabetesToxin Threshold Above
Threshold
Odds
Ratio
of Dz Reference
PMID
Arsenic 165 ugL 200 21 180 18714061
BPA 28 ugL 280 145 112 26119400
DDE 545 ngg serum
(pp-DDE)
200 230 31 26119400
Dioxins2 pgg lipid 50 191 43
26119400
PCBs104 ngg (PCB 153) 250 239 258
26119400
Phthalates175 ugL 690 148 249
26119400
1-naphthalene 167 ugdL 152 182 111 26340343
2-napthalene 414 ugdL 550 224 214 26340343
1-phenanthrene 167 ngL 570 178 151 26340343
1-pyrene 85 ngL 660 180 174 26340343
Lung Cancer
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Acrylonitrile Uncertain Uncertain 125 25
occupational
exposure
17114112
Arsenic 1213 ugL 436 of Asian
Americans
~01 of total
US population
34 95 in AA
01-1
PMC2682945
Cadmium Uncertain+ Uncertain 467 10 in
smokers
17184399
DDT Any exposure All US pop
below LOD
17 76 increased
risk
8923607
Breast Cancer
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Cadmium 0580 ugg
creatinine
126 205 479 16788160
PCB 138 396 ngg
creatinine
202 316 630 27717745
PCB 187 108 ngg lipid 600 194 360 21480306
Miscellaneous Diseases
Toxin Disease Threshold Above
Threshold
Odds
Ratio
of Dz Reference PMID
Aluminum Alzheimer
Dz
01 mgL
drinking
H20
400 203 05-44 26592479
Benzene AML 100ppmyrs 1-3 320 60 PMC2903550
DDT NHL 0512 ugL 1-2 240 01 17722095
Lead ALS 238 ugdL
blood
330 181 210 25479292
Lead Brain CA 0005 ugdL 14 19 ~500 17164378
Dioxin-like
PCBs
RA 326 ngg
lipid
250 219 220 17589595
PAHs Asthma 124 ngm3 935 200 483 19221603
The Potency of Arsenic
Disease Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Bladder CA 10ugL H20 100 27 145 24889821
Pancreatic CA 1332 ugg 200 246 230 23800676
Prostate CA 1332 ugg 200 33 315 23800676
Gout 125 ugL 245 546 522 25499256
Diabetes 165 ugL 200 21 180 18714061
Arsenic (180 of Diabetes)
How it causes diabetes
bull Blocks sugar stimulating insulin secretion
bull Epigenetic inhibition of sugar regulation
Where it comes from
bull Water (gt10 of US water supplies have high levels)
bull Rice (naturally absorbs if in the water)
bull Chicken (added to make meat whiter)
Pan W-C Seow WJ Kile ML et al Association of low to moderate levels of arsenic exposure with risk of Type 2 diabetes in Bangladesh American Journal of Epidemiology 2013178(10)1563-70
Portion of Population with Toxin Load Which
Doubles Disease Risk
Toxin Disease with Doubled Risk
Polycyclic aromatic hydrocarbons Asthma 94
PCB187 Breast Cancer 60
Phthalates Diabetes 55
Lead ALS 33
Aluminum Alzheimers Disease 25
DDT ADHD 25
PCBs Diabetes 25
Dioxin-like PCBs Rheumatoid Arthritis 25
Arsenic Gout 23
Bisphenol A Diabetes 22
Cigarette smoking Lung Cancer 21
Arsenic Diabetes 20
Polycyclic aromatic hydrocarbons Diabetes 20
Huge Detoxification Variability
bull CYP2C19
Proton pump inhibitors and some antidepressants
5-fold difference in activity between poor metabolizers and extensive metabolizers more so if CYP3A4 is also inhibited
Ultrarapid allele in 18 of both Swedes and Ethiopians
bull CYP2D6
Metabolizes a large number of drugs (~25)
7 of Caucasians poor metabolizers
~30 ultra rapid metabolizers in Arabian and Eastern African populations
More adverse effects in poor metabolizers and ineffective dosing in ultrarapid metabolizers
Inhibited by ginger
Desta Z et al Clinical significance of the cytochrome P450 2C19 genetic polymorphism Clin Pharmaco 2002
Sim SC et al A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug
response to proton pump inhibitors and antidepressants Clin Pharmacol Ther 2006
Wilkinson GR Drug metabolism and variability among patients in drug response N Engl J Med 2005
Kirchheiner J et al Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to
CYP2D6 duplication Pharmacogenomics J 2007
Toxin Half Lives in BloodToxin ldquoNormalrdquo (mgL) Acute Toxic (mgL) Half-Life
Arsenic 0002-007 005-025 2-4 days (CDC)
Benzene 00002 05-10 days
Cadmium 00003-00065 0015-005 16 years
Chlordane 0001 00025 3-4 days
DDTDDE 2-10 years
Dieldrin 00015 015-030 2-12 months
Ethanol 1000-2000 15hour
Lead 009 04-06 1-15 mo (2+ yrs bone)
Mercury 00015-0002 005-02 2 months (CDC)
PCBs 3-25 years
Toluene 05-3 days
Schulz M et al Therapeutic and toxic blood concentrations of nearly 1000 drugs and other xenobiotics Crit Care 2012 Jul 2616(4)R136
Bioaccumulation (POPs)
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
DDT banned in 1972 PCBs banned in 1977
Bioaccumulation (Cd)
Think BroadlyExogenous
Metals
Chemicalsbull Inorganic
bull Fluoride
bull Organic
bull POPs
bull Drugs
Particulate matter
Molds
Microbial
Radiationbull Light
bull Medical
bull Cell phone
Endogenous
Gut-derived toxins
Non-end product metabolites
Poorly detoxified hormones
Catecholamines (if SNP)
Toxins of Choice
Alcohol
Marijuana
Food constituents
High fructose corn syrup
Salt (acid-forming diet)
Wheat if zonulin (70)
Obesity Epidemic ndash POPs AND HFCS
47Bray GA Fructose should we worry Int J Obes (Lond) 2008 Dec32 Suppl 7S127-31
How Toxins Cause Damage 13
bull Increase free radical production
Cd induces production of ROS
Malathion inhibits catalase and glutathione peroxidase
Homocysteine oxidizes LDL cholesterol
bull Poison enzyme systems (compete with nutritional cofactors for binding sites)
Pb poisons delta aminolevulinic acid dehydratase
Cd inhibits catalase glutathione reductase and lowers
glutathione levels
bull Replace structural minerals
Pb displaces Ca in bone
How Toxins Cause Damage 23
bull Damage DNA
Benzene - causes chromosomal damage
Pesticides ndash fruit growers have more DNA damage
Phthalates and insecticides ndash damage sperm DNA
4-hydroxy catechol estrogen (4-OHE) damages breast DNA
bull Epigenetic dysmodulation
Higher cord blood levels of hexachlorobenzene associated
with 2x greater risk for obesity in children
bull Damage cell membranes
Common mechanism for heavy metals inactivates
membrane enzymes ion channels and pumps
How Toxins Cause Damage 33
bull Block insulin receptor sites
PCBs and phthalates
bull Highest levels associated with a 4 to 20-fold greater diabetes risk
bull Imbalance hormones many toxin examples
Arsenic
bull Disrupts thyroid hormone and retinoic acid receptors
Phthalates
bull Act as anti-androgens
bull More than 75 of the US population has measurable levels of
several phthalate metabolites in the urine
PCBs
bull Lower testosterone levels in men
Which are the Worst Toxins
bull According to the CDC
Toxicity
Population toxic load
Prevalence in toxic waste sites
bull According to clinical importance
Exposure
of disease
Ability of the body to detoxifyexcrete
Ag
en
cy
fo
r T
oxic
Su
bs
tan
ce
s a
nd
Dis
ea
se
Reg
istr
y
Pri
ori
ty L
ist
The Worst Toxins Clinically
My Rank Toxin Diseases Primary Sources
1 Arsenic Cancers diabetes gout Water chicken rice
2 DDT ADHD dementia diabetes Everywhere
3 Phthalates ADHD diabetes Soft plastics HABAs
4 PBDEs ADHD diabetes Flame retardant fabrics
5 PAHs ADHD cancers dyslipidemia Smoking charbroiling
6 PCBs Cancers diabetes MI RA Everywhere
7 Mercury Dementia ldquoSilverrdquo fillings fish
8 Lead Cardiovascular disease IQ Paint water
Glyphosate Research invalid
Conventional Laboratory Tests Reflect
Toxic Load in ldquoNormalrdquo Range
bull Surprising number show toxin exposure
CBC RBC WBC platelet count hemoglobin basophilic
stippling
Liver enzymes ALT GGTP
Inflammatory markers CRP
Lipids LDL oxLDL triglycerides
Blood sugar insulin FBS 2-hour PP
Metabolites bilirubin uric acid homocysteine 8-OHdG
Thyroid T3 T4 TSH
bull The historic ldquonormalrdquo range has been changing as the population has become more toxic
WBC Lowered by PCB and OCP Exposure
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
0
1
2
3
4
5
6
7
8
1st Quartrile 2nd Quartile 3rd Quartile 4th Quartile
WBCbull Strong inverse correlation with PCBs and OCPs and CBC
bull Linear with almost all PCBs
bull High variability with OCPs
bull Within ldquonormalrdquo range
Effects on WBC Worsen with Years
of Exposure to Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Platelet Count Decreases with Years
of Exposure tp Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Solvents Decrease Platelet Count
bull Compared workers exposed 23 hrday to those exposed most of day to toluene
bull All wore face masks and protective gear
bull Platelet count 14 lower 252 versus 216ml
bull Impairment of sympathetic nerves (OR = 413)
bull Impairment of peripheral nerves (OR = 694)
bull Positive relationship between neurological abnormalities and a self-reported neuropsychiatric measurement (r = 035-066)
Shih HT et al Subclinical abnormalities in workers with continuous low-level toluene exposure Toxicol Ind Health 2011 Sep27(8)691-9
Basophilic Stippling of Red Cells
Toxinsbull Arsenic
bull Lead
Diseasesbull Alpha-thalassemia HbH Disease
bull Beta thalassemia
bull Hereditary pyrimidine 5-nucleotidase deficiency
bull Myelodysplastic syndrome
bull Sideroblastic anemia
bull Thrombotic thrombocytopenic purpura
GGT Indirect Measure of POPsbull Glutathione is key intracellular defense against oxidative stress
bull Cellular GGT metabolizes extracellular GSH allowing precursor amino acids to be reutilized for intracellular GSH
bull Exposure to POPs induces GGT as a defensive mechanism
bull Within normal range predicts type 2 diabetes coronary heart disease hypertension stroke dyslipidemia chronic kidney disease and cancer
bull Men with GGT gt50 UI had ~26 fold risk for diabetes compared to those with lt10 Those with 40-49 had a ~20 fold risk
bull Levels within normal range occur with obesity xs alcohol cigarette smoking physical inactivity high meat low fruit and vegetable intake
bull Cumulative biomarker for environmental pollutants
Lee DH et al (2003) Gamma-glutamyltransferase and diabetesmdasha 4 year follow-up study Diabetologia 46359ndash364
Pamela A et al Serum gamma-glutamyltransferase linking together environmental pollution redox equilibria and progression of atherosclerosis Clin Chem
Lab Med 200947(12)1583-4
Lee DH et al Serum gamma-glutamyltransferase new insights about an old enzyme J Epidemiol Community Health 2009 Nov63(11)884-6
Lee DH et alSerum gamma-glutamyltransferase predicts non-fatal myocardial infarction and fatal coronary heart disease among 28838 middle-aged men and
women Eur Heart J 2006272170ndash6
Lee DH et al Gamma-glutamyltransferase and diabetes--a 4 year follow-up study Diabetologia 2003 Mar46(3)359-64
Lee DH et al Can persistent organic pollutants explain the association between serum gamma-glutamyltransferase and type 2 diabetes Diabetologia 2008
Mar51(3)402-7
GGT and Alcohol Consumption
bull GGT directly correlates with alcohol consumption
bull In a non-uniform population 40 gd will elevate GGT ~15
bull Watch for false negatives
bull Genomic variation
bull Are these the ones most
sensitive todamaged by
chemical toxins
bull Could up-regulation of GGT in light alcohol consumption be reason for benefit
0
10
20
30
40
50
60
70
80
0 200 400 600 800
Grams of Ethanol per Week
Adapted from Nagaya T et al Dose-response relationships between drinking and serum tests in Japanese men
aged 40ndash59 years Alcohol 1999 Feb 17(2) 133ndash8
GGT Correlates With Toxic Metal Levels
Lee DH et al Graded associations of blood lead and urinary cadmium concentrations with oxidative-stress-related markers in the
US population results from the third National Health and Nutrition Examination Survey Environ Health
perspect 2006 Mar114(3)350-4
GGT and Diabetes Risk
0
5
10
15
20
25
30
lt10 10-19 20-29 30-39 40-49 gt50
Dia
bete
s R
isk
GGT
bull GGT over 50 associated with tripling of death rate
bull 30-40 associated with doubling
GGT Levels
Correlate with
Risk of Death
Brenner H et al Distribution determinants and prognostic value of gamma-glutamyltransferase for all-cause
mortality in a cohort of construction workers from southern Germany Prev Med 1997 26 305ndash10
GGT From Small US Company
with Young Workers
0
10
20
30
40
50
60
0 20 40 60 80 100
GGT Data from Canadian Oil Field
Workers
0
50
100
150
200
250
300
350
400
450
lt10 10-20 20-30 30-40 40-50 50-60 60-07 70-80 80-90 90-100 100-110 110-120 gt120
GGTP
20-fold increased risk of diabetes
Uric Acid Indirect Measure of POPs
bull Poly-fluorinated hydrocarbons (PFOA and PFOS) associated
with increased serum uric acid
Lin CY et al Association among serum perfluoroalkyl chemicals glucose homeostasis and metabolic syndrome
in adolescents and adults Diabetes Care 2009 Apr32(4)702-7
Steenland K et al Association of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) with uric
acid among adults with elevated community exposure to PFOA Environ Health Perspect 2010 Feb118229-33
Steenland 2010 Open Access
ALT Indirect Measure of POPs
bull ALT (proxy marker) elevation in 104 (not including viral
hepatitis hemochromatosis or alcoholic liver disease) of
NHANES 03-04 subset
bull Risk of elevated ALT increased dose-dependently with
cadmium lead mercury and PCB exposure
bull 100 of individuals had detectable PCBs 925 mercury
and 996 had detectable lead
bull In 2005-08 prevalence of NAFLD in US was 11 a
growing cause of chronic liver disease
Cave M et al Polychlorinated biphenyls lead and mercury are associated with liver disease in American adults
NHANES 2003-2004 Environ Health Perspect 2010 Dec118(12)1735-42
Younossi ZM et al Changes in the prevalence of the most common causes of chronic liver diseases in the United
States from 1988 to 2008 Clin Gastroenterol Hepatol 2011 Jun9(6)524-530e1
Bilirubin as a Marker of POPs
bull Degree of serum bilirubin increase is prognostically significant in chronic liver dysfunction
bull Mono-ortho PCB TEQ values were found to be significantly positively associated with bilirubin (β=071 P=0008) following adjustment for multiple potential confounders
bull Bilirubin levels significantly correlated with PCBs -105-118-126 and -194
bull Smoking appears to be the biggest confounder
Dufour DR et al 2000 Diagnosis and monitoring of hepatic injury II Recommendations for use of laboratory
tests in screening diagnosis and monitoring Clin Chem 46 2050ndash68
Kumar J et al Persistent organic pollutants and liver dysfunction biomarkers in a population-based human sample
of men and women Environ Res 2014134251-256
Perf
luo
rin
ate
dP
OP
s a
nd
Co
mm
on
Blo
od
Tests
Gleason JA et al Associations of perfluorinated chemical serum concentrations and biomarkers of liver function and uric acid in the
US population (NHANES) 2007-2010 Environ Res 20151368-14
Liver Enzymes Reflect Toxic Load
bull AST ALT and GGT increase with body load of PCBs and OCPs
bull Some non-linear
bull Oxychlordanetop quartile
ALT 10
GGT 25
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
LDL-Cholesterol as Measure of POPs
bull 5-year prospective study to determine if POP levels predict future elevation in LDL-cholesterol
bull 598 subjects initially at age 70
bull Looked at 23 POPs
bull Best correlation with PCB 194
Penell J Lind L Salihovic S et al Persistent organic pollutants are related to change in circulating
lipid levels during a 5 year follow-up Environ Res 134(2014)190ndash197
oxLDL as Measure of POPs
bull 992 70-year old individuals (50 women)
bull Sum of PCBs showed strong significant positive associations with ox-LDL and significant negative associations with glutathione-related markers (GSSG and GSSGGSH)
bull A number of POPs (PCB-99 138 153 156 170 180 194 206 and 209) showed strong significant positive association with ox-LDL
Kumar J et al Influence of persistent organic pollutants on oxidative stress in population-based samples
Chemosphere 2014114303-309
Homocysteine is Increased by Pb amp Cd
Guallar E et al Confounding of the relation between homocysteine and peripheral arterial disease by lead cadmium and renal function Am J Epidemiol 2006 Apr 15163(8)700-8
Nutrient Deficiencies Accentuate
Effects of Lead on Homocysteine
bull Deficiencies in folate B6 or B12 make lead more toxic
Lee YM Et al Association of homocysteine levels with blood lead levels and micronutrients in the US general population J Prev Med Public Health 2012 Nov45(6)387-93
T4 amp T3 and PCBs
bull PCBs decrease T4 production
bull PCBs inhibit iodotyrosinedeiodinase activity
bull Study done in pregnant women which implies effect on fetus IQ
Kim S Park J Kim HJ et al Association between several persistent organic pollutants and thyroid hormone levels in serum among the pregnant women of Korea Environ Int 2013 Sep59442-8Shimizu R Yamaguchi M Uramaru N et al Structure-activity relationships of 44 halogenated compounds for iodotyrosinedeiodinase-inhibitory activity Toxicology 2013 Dec 6314(1)22-9
T4 amp T3 and PCBs
bull Not just humans being affected
bull Large study of dolphins shows exactly the same effects
Schwacke LH Zolman ES Balmer BC et al Anaemia hypothyroidism and immune suppression associated with polychlorinated biphenyl exposure in bottlenose dolphins (Tursiops truncatus) Proceed Royal Society B doi101098rspb20110665
8-OHdG
bull Oxidized nucleoside
bull Direct measure of DNA damage
bull Indirect measure of oxidative stress and toxin load
bull Correlates with
Multiple cancers
Mitochondrial damage
Rate of aging
Smoking
Several toxinsWalter Crinnion ldquoTotal Toxic Loadrdquo AANP 2015
8-OHdG Correlates with Pack-Years
of Smoking
Yano T et al Significance of the urinary 8-OHdG level as an oxidative stress marker in lung cancer patients Lung Cancer
2009 Jan63(1)111-4
8-OHdG Correlates
with Mercury
Chen C et al Increased oxidative DNA damage as assessed by urinary 8-hydroxy-2-deoxyguanosine
concentrations and serum redox status in persons exposed to mercury Clin Chem 2005 Apr51(4)759-67
Toxin Effects Worse with Aging
bull Thyroid function decreases with PFOA levels
bull But only after age 63
Shrestha S Bloom MS Yucel R et al Perfluoroalkyl substances and thyroid function in older adults Environ Int 2015 Feb75206-14
Insightful 23-Year Prospective Study
1 lt 50 there is no difference between those with the lowest and highest PCBs
2 In youngest group insulin production increases in response to toxin level As expected since blocking of
insulin receptor sites by PCBs
requires more insulin
3 That adaptive ability decreases with aging
4 At age 50 all the measures show very strong toxin-dose response
Cumulative damage impairs ability to adapt
Suarez-Lopez JR et al Persistent organic pollutants in young adults and changes in glucose related metabolism over a 23-year follow-up Environ Res 2015 Feb137485-94
Recommendations
High body toxic load
GGT gt 25
Uric acid gt 50 mgdl
ALT gt30 UL
Bilirubin gt08 mgdl
CBC lt 6000
Platelet lt 250000
Low T3 andor T4
Monitor Total Toxic Load
8-OHdG gt4
ldquoUnconventionalrdquo Laboratory Tests
bull Challenge testing
bull Hair analysis
bull Direct measures of solvents and POPs in blood urine adipose tissue
Evaluation of Metal Exposure ndash Provocation
bull Provocation ndash the use of a chelating agent ndash before urine collection often done clinically but several limitations
No ldquoofficialrdquo reference range for provoked urine
Most chelating agents do not extract metals from all tissues thus
does not necessarily represent total body burden
bull Example Brain is one of the main target organs for both elemental and organic
mercury yet agents do not chelate brain mercury
bull Despite limitations widely used and advocated by clinicians in part to see efficacy of chelating agent as a guide to treatment and based on empirical evidence
Rooney JP The role of thiols dithiols nutritional factors and interacting ligands in the toxicology of mercury
Toxicology 2007
Is Challenge Testing Valid
bull Poor correlations of standard tests for mercury
bull Unpublished research from corporate wellness project
bull Published amalgam number correlation
bull Published fish consumption correlation
What We Found In Canada
bull Deviations from the mean of 14 29 and 91 respectively
bull DMPS is spreading distribution suggesting that it is better at differentiating mercury body load
bull Some VERY high
Hg Assessment Correlations
bull Extensive measurements in 65 Whole blood Hg
Oral DMPS challenge
Amalgam surfaces
bull Correlations Whole blood w pre urine r = 040
Whole blood w post urine r = 057
Pre urine w post urine r = 068
Amalgams w pre urine r = 026
Amalgams w whole blood r = 036
Amalgams with post urine 044
bull Clear documentation that
challenge testing is better00
100
200
300
400
500
600
0 10 20 30 40 50
Po
st
Uri
ne H
g u
gg
Number of amalgams
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
Mercury in Water
httpwaterepagovscitechdataitmodelsmapspostercfm
Ground Water Sources of Arsenic
bull 10 of US public water supplies have levels of arsenic known to induce disease
bull No data on private water supplies
httpwwwatsdrcdcgovcsemarsenicdocsarsenicpdf (accessed 2015-08-18)
Example POPs
Chemical Abbr Uses Exposure
Bisphenol A BPA Plastics Canned food
Organochlorine
pesticides
OCPs Pesticide Food fumigation
Organophosphate
pesticides
OPPs Pesticide Food
Polybrominated
diphenyl ethers
PBDEs Flame retardant Clothing
Polychlorinated
biphenyls
PCBs Industrial Everywhere
Perflourinated PFOAs Non-stick stain prevention
water repellant
Teflon Gortex
Scotchguard
Phthalates Plastics fragrances Shower curtains
cosmetics
POPs - Prediabetes
bull Over 1200 participants fasting
glucose and OGTT performed
with serum levels of 5 POPs
bull All individual POPs tested were
associated with progressive
increase in prevalence of
prediabetes
bull More than triple prevalence of
prediabetes seen in those in the
5th quartile with a synergistic
effect from 5 POPs
Ukropec J et al High prevalence of prediabetes and diabetes in a population exposed to high levels of an organochlorine cocktail
Diabetologia 2010 May53(5)899-906
POPs and Diabetes Risk
Graph httpwwwourstolenfutureorgNewScienceobesity20062006-0715leeetalhtml
Data Lee DH Lee IK Song K et al A strong dose-response relation between serum
concentrations of persistent organic pollutants and diabetes results from the National Health and
Examination Survey 1999-2002 Diabetes Care 2006 Jul29(7)1638-44
Toxic Load and Disease Risk
References for Toxins and Disease Risk
Converting Disease Risk to Caused
Attributable Fraction Calculation
p = underlying prevalence of risk factor in the population
rr = relative risk (risk of contracting a disease in an exposed population divided by the risk of contracting the disease in an unexposed population)
AF = of disease due to the toxin
Levin M The occurrence of lung cancer in man Acta Unio Int Contra Cancrum 1953 9 531-541
Example Smoking and Lung Cancer
B = 5Number of smokers
who contract Lung Cancer notdue to smoking
A = 5Number of smokerswho contract Lung
Cancer due to smoking
C = 15Number of
nonsmokerswho contract Lung Cancer
0
2
4
6
8
10
12
14
16
Smokers (N=100) Nonsmokers (N=300)Num
ber
of
people
who c
ontr
act
Lung C
ancer
per
year
Baseline Additional due to smoking
Number of smokers and nonsmokers who contract lung cancer
Our Process In Summary
1 Determine threshold for increased disease risk
2 Determine of population above threshold
3 Determine incidence of disease (OR) in those above threshold
4 Determine incidence of disease in ldquounexposed populationrdquo
5 Calculate AF ie of disease
As whole population is exposed probably UNDERESTIMATES of disease
To
xic
ity H
as B
eco
me t
he N
ew
ldquoN
orm
alrdquo
Toxin Type Use Threshold for
disease
association
of US
above
threshold
Disease Associations
Chlordane OC pesticide Termites corn citrus lawns
gardens
145ngg lipid 63
(diabetes)
Diabetes (20)
BPA Plasticizer Water bottles canned food
water pipes thermal sales
receipts
48 men 51
women (urine
ngmL)
~18
(diabetes)
Diabetes hypertension
Octachloro
dibenzo-p-
dioxin
(OCDD)
Polychlorinated
dibenzo-p-
dioxin
Incineration or burning of
waste bleaching processes
used in pulp and paper mills
1010 pgg
lipid (highest
quartile)
10-25
(hypertensio
n)
Hypertension (79 for
women highest
quartile) diabetes (21)
obesity learning
disability (272)
MEP
(mono-
ethyl
phthalate)
Phthalate
(plasticizer
fragrance)
Toothbrushes automobile
parts tools toys and food
packaging aspirin
cosmetics food packaging
gt175 ngmL
(urine)
~60
(diabetes)
Diabetes (148) lower
BMD obesity
pp-DDE DDT
metabolite (OC
pesticide)
Agricultural crops 1560ngg
lipid
25
(diabetes)
Diabetes (23-43)
early menopause
impaired cognitive
function (2-3x 65x in
highest 5th percentile)
peripheral arterial
disease
Arsenic Toxic metal Miningsmelting wood
preservative pesticides
74ugL total
arsenic (urine)
20
(diabetes)
Cancers diabetes (26-
46) dyslipidemia gout
AF OR Prevalence
Rosen L An intuitive approach to understanding the attributable fraction of disease due to a risk factor the case of smoking Int J Environ Res Public Health 2013 Jul 1610(7)2932-43
Smoking Lung cancer
Arsenic Gout in women
BPA Diabetes
Status of Our Research
bull 26 toxins and toxin classes eg lead mercury BPA OCPs
100s of chemicals and POPs in some classes
bull 18 cancers
bull 24 chronic diseases
bull 1092 cells in spreadsheet
Large Personal Ongoing Research Investment
Huge Amount of Research Work
Toxins StudiedAluminum
Arsenic
Cadmium
Fluoride
Lead
Manganese
Mercury
Acrylamide
Acrylonitrile
Benzene
Bisphenol A (BPA)
Chloroform
DDT
Dioxins
Glyphosate
Organochlorine pesticides (OCPs)
Organophosphate pesticides
Parabens
Phthalates
Polybrominated diphenyl ethers (PBDEs)
Polycyclic aromatic hydrocarbons (PAHs)
Polychlorinated biphenols (PCBs)
Vinyl chloride
Diseases Studied
ADHD
Alzheimers Disease
ALS
Angiosarcoma
Anxiety
Atopic Conditions
Diabetes
Dyslipidemia
Gout
Fetal Abnormalities
Hyperuricemia
Infertility
Juvenile IQ
Cancer Bladder
Cancer Bone
Cancer Brain
Cancer Breast
Cancer Cervix
Cancer Colorectal
Cancer Endometrial
Cancer Head amp Neck
Cancer Liver
Cancer Lung
Cancer Lymph amp Blood
Cancer Ovarian
Cancer Pancreatic
Cancer Prostate
Cancer Renal
Cancer Skin
Cancer Testicular
Cancer Thyroid
Juvenile Obesity
Metabolic Syndrome
Mitochondrial dysfunction
Myocardial Infarction
Obstructive Lung Disease
Osteoporosis
Peripheral Artery Disease
Peripheral Neuropathy
Prediabetes
Renal Disease
Rheumatoid Arthritis
Thyroid Dysfunction
OC
Ps
Th
rou
gh
ou
t th
e W
orl
d
Rathore HS Nollet LML Pesticides Evaluation of Environmental Pollution CRC Press
2012 page 562
Threshold ndash Threshold exposure at which there is an increased risk of disease outcome
Above Threshold ndash Percentage of the population with higher exposure than the threshold
Odds Ratio ndash Increased disease risk in those above threshold
of Dz ndash Percent contribution of the toxin to that disease outcome
How to Interpret the Following Slides
Attention Deficit Hyperactivity Disorder
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
DDT 126 ngg
serum (pp-
DDE)
250 18 166 20106937
Lead 23 ugdL 13 254 20 27659349
Mercury 16 24952233
Organophosphate
pesticides
20
Polycyclic
Aromatic
Hydrocarbons
227 ngm3 940 125 190 22440811
PCBs 104 ngg
serum (sum
of 50 PCBs)
250 176 160 20106937
DiabetesToxin Threshold Above
Threshold
Odds
Ratio
of Dz Reference
PMID
Arsenic 165 ugL 200 21 180 18714061
BPA 28 ugL 280 145 112 26119400
DDE 545 ngg serum
(pp-DDE)
200 230 31 26119400
Dioxins2 pgg lipid 50 191 43
26119400
PCBs104 ngg (PCB 153) 250 239 258
26119400
Phthalates175 ugL 690 148 249
26119400
1-naphthalene 167 ugdL 152 182 111 26340343
2-napthalene 414 ugdL 550 224 214 26340343
1-phenanthrene 167 ngL 570 178 151 26340343
1-pyrene 85 ngL 660 180 174 26340343
Lung Cancer
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Acrylonitrile Uncertain Uncertain 125 25
occupational
exposure
17114112
Arsenic 1213 ugL 436 of Asian
Americans
~01 of total
US population
34 95 in AA
01-1
PMC2682945
Cadmium Uncertain+ Uncertain 467 10 in
smokers
17184399
DDT Any exposure All US pop
below LOD
17 76 increased
risk
8923607
Breast Cancer
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Cadmium 0580 ugg
creatinine
126 205 479 16788160
PCB 138 396 ngg
creatinine
202 316 630 27717745
PCB 187 108 ngg lipid 600 194 360 21480306
Miscellaneous Diseases
Toxin Disease Threshold Above
Threshold
Odds
Ratio
of Dz Reference PMID
Aluminum Alzheimer
Dz
01 mgL
drinking
H20
400 203 05-44 26592479
Benzene AML 100ppmyrs 1-3 320 60 PMC2903550
DDT NHL 0512 ugL 1-2 240 01 17722095
Lead ALS 238 ugdL
blood
330 181 210 25479292
Lead Brain CA 0005 ugdL 14 19 ~500 17164378
Dioxin-like
PCBs
RA 326 ngg
lipid
250 219 220 17589595
PAHs Asthma 124 ngm3 935 200 483 19221603
The Potency of Arsenic
Disease Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Bladder CA 10ugL H20 100 27 145 24889821
Pancreatic CA 1332 ugg 200 246 230 23800676
Prostate CA 1332 ugg 200 33 315 23800676
Gout 125 ugL 245 546 522 25499256
Diabetes 165 ugL 200 21 180 18714061
Arsenic (180 of Diabetes)
How it causes diabetes
bull Blocks sugar stimulating insulin secretion
bull Epigenetic inhibition of sugar regulation
Where it comes from
bull Water (gt10 of US water supplies have high levels)
bull Rice (naturally absorbs if in the water)
bull Chicken (added to make meat whiter)
Pan W-C Seow WJ Kile ML et al Association of low to moderate levels of arsenic exposure with risk of Type 2 diabetes in Bangladesh American Journal of Epidemiology 2013178(10)1563-70
Portion of Population with Toxin Load Which
Doubles Disease Risk
Toxin Disease with Doubled Risk
Polycyclic aromatic hydrocarbons Asthma 94
PCB187 Breast Cancer 60
Phthalates Diabetes 55
Lead ALS 33
Aluminum Alzheimers Disease 25
DDT ADHD 25
PCBs Diabetes 25
Dioxin-like PCBs Rheumatoid Arthritis 25
Arsenic Gout 23
Bisphenol A Diabetes 22
Cigarette smoking Lung Cancer 21
Arsenic Diabetes 20
Polycyclic aromatic hydrocarbons Diabetes 20
Huge Detoxification Variability
bull CYP2C19
Proton pump inhibitors and some antidepressants
5-fold difference in activity between poor metabolizers and extensive metabolizers more so if CYP3A4 is also inhibited
Ultrarapid allele in 18 of both Swedes and Ethiopians
bull CYP2D6
Metabolizes a large number of drugs (~25)
7 of Caucasians poor metabolizers
~30 ultra rapid metabolizers in Arabian and Eastern African populations
More adverse effects in poor metabolizers and ineffective dosing in ultrarapid metabolizers
Inhibited by ginger
Desta Z et al Clinical significance of the cytochrome P450 2C19 genetic polymorphism Clin Pharmaco 2002
Sim SC et al A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug
response to proton pump inhibitors and antidepressants Clin Pharmacol Ther 2006
Wilkinson GR Drug metabolism and variability among patients in drug response N Engl J Med 2005
Kirchheiner J et al Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to
CYP2D6 duplication Pharmacogenomics J 2007
Toxin Half Lives in BloodToxin ldquoNormalrdquo (mgL) Acute Toxic (mgL) Half-Life
Arsenic 0002-007 005-025 2-4 days (CDC)
Benzene 00002 05-10 days
Cadmium 00003-00065 0015-005 16 years
Chlordane 0001 00025 3-4 days
DDTDDE 2-10 years
Dieldrin 00015 015-030 2-12 months
Ethanol 1000-2000 15hour
Lead 009 04-06 1-15 mo (2+ yrs bone)
Mercury 00015-0002 005-02 2 months (CDC)
PCBs 3-25 years
Toluene 05-3 days
Schulz M et al Therapeutic and toxic blood concentrations of nearly 1000 drugs and other xenobiotics Crit Care 2012 Jul 2616(4)R136
Bioaccumulation (POPs)
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
DDT banned in 1972 PCBs banned in 1977
Bioaccumulation (Cd)
Think BroadlyExogenous
Metals
Chemicalsbull Inorganic
bull Fluoride
bull Organic
bull POPs
bull Drugs
Particulate matter
Molds
Microbial
Radiationbull Light
bull Medical
bull Cell phone
Endogenous
Gut-derived toxins
Non-end product metabolites
Poorly detoxified hormones
Catecholamines (if SNP)
Toxins of Choice
Alcohol
Marijuana
Food constituents
High fructose corn syrup
Salt (acid-forming diet)
Wheat if zonulin (70)
Obesity Epidemic ndash POPs AND HFCS
47Bray GA Fructose should we worry Int J Obes (Lond) 2008 Dec32 Suppl 7S127-31
How Toxins Cause Damage 13
bull Increase free radical production
Cd induces production of ROS
Malathion inhibits catalase and glutathione peroxidase
Homocysteine oxidizes LDL cholesterol
bull Poison enzyme systems (compete with nutritional cofactors for binding sites)
Pb poisons delta aminolevulinic acid dehydratase
Cd inhibits catalase glutathione reductase and lowers
glutathione levels
bull Replace structural minerals
Pb displaces Ca in bone
How Toxins Cause Damage 23
bull Damage DNA
Benzene - causes chromosomal damage
Pesticides ndash fruit growers have more DNA damage
Phthalates and insecticides ndash damage sperm DNA
4-hydroxy catechol estrogen (4-OHE) damages breast DNA
bull Epigenetic dysmodulation
Higher cord blood levels of hexachlorobenzene associated
with 2x greater risk for obesity in children
bull Damage cell membranes
Common mechanism for heavy metals inactivates
membrane enzymes ion channels and pumps
How Toxins Cause Damage 33
bull Block insulin receptor sites
PCBs and phthalates
bull Highest levels associated with a 4 to 20-fold greater diabetes risk
bull Imbalance hormones many toxin examples
Arsenic
bull Disrupts thyroid hormone and retinoic acid receptors
Phthalates
bull Act as anti-androgens
bull More than 75 of the US population has measurable levels of
several phthalate metabolites in the urine
PCBs
bull Lower testosterone levels in men
Which are the Worst Toxins
bull According to the CDC
Toxicity
Population toxic load
Prevalence in toxic waste sites
bull According to clinical importance
Exposure
of disease
Ability of the body to detoxifyexcrete
Ag
en
cy
fo
r T
oxic
Su
bs
tan
ce
s a
nd
Dis
ea
se
Reg
istr
y
Pri
ori
ty L
ist
The Worst Toxins Clinically
My Rank Toxin Diseases Primary Sources
1 Arsenic Cancers diabetes gout Water chicken rice
2 DDT ADHD dementia diabetes Everywhere
3 Phthalates ADHD diabetes Soft plastics HABAs
4 PBDEs ADHD diabetes Flame retardant fabrics
5 PAHs ADHD cancers dyslipidemia Smoking charbroiling
6 PCBs Cancers diabetes MI RA Everywhere
7 Mercury Dementia ldquoSilverrdquo fillings fish
8 Lead Cardiovascular disease IQ Paint water
Glyphosate Research invalid
Conventional Laboratory Tests Reflect
Toxic Load in ldquoNormalrdquo Range
bull Surprising number show toxin exposure
CBC RBC WBC platelet count hemoglobin basophilic
stippling
Liver enzymes ALT GGTP
Inflammatory markers CRP
Lipids LDL oxLDL triglycerides
Blood sugar insulin FBS 2-hour PP
Metabolites bilirubin uric acid homocysteine 8-OHdG
Thyroid T3 T4 TSH
bull The historic ldquonormalrdquo range has been changing as the population has become more toxic
WBC Lowered by PCB and OCP Exposure
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
0
1
2
3
4
5
6
7
8
1st Quartrile 2nd Quartile 3rd Quartile 4th Quartile
WBCbull Strong inverse correlation with PCBs and OCPs and CBC
bull Linear with almost all PCBs
bull High variability with OCPs
bull Within ldquonormalrdquo range
Effects on WBC Worsen with Years
of Exposure to Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Platelet Count Decreases with Years
of Exposure tp Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Solvents Decrease Platelet Count
bull Compared workers exposed 23 hrday to those exposed most of day to toluene
bull All wore face masks and protective gear
bull Platelet count 14 lower 252 versus 216ml
bull Impairment of sympathetic nerves (OR = 413)
bull Impairment of peripheral nerves (OR = 694)
bull Positive relationship between neurological abnormalities and a self-reported neuropsychiatric measurement (r = 035-066)
Shih HT et al Subclinical abnormalities in workers with continuous low-level toluene exposure Toxicol Ind Health 2011 Sep27(8)691-9
Basophilic Stippling of Red Cells
Toxinsbull Arsenic
bull Lead
Diseasesbull Alpha-thalassemia HbH Disease
bull Beta thalassemia
bull Hereditary pyrimidine 5-nucleotidase deficiency
bull Myelodysplastic syndrome
bull Sideroblastic anemia
bull Thrombotic thrombocytopenic purpura
GGT Indirect Measure of POPsbull Glutathione is key intracellular defense against oxidative stress
bull Cellular GGT metabolizes extracellular GSH allowing precursor amino acids to be reutilized for intracellular GSH
bull Exposure to POPs induces GGT as a defensive mechanism
bull Within normal range predicts type 2 diabetes coronary heart disease hypertension stroke dyslipidemia chronic kidney disease and cancer
bull Men with GGT gt50 UI had ~26 fold risk for diabetes compared to those with lt10 Those with 40-49 had a ~20 fold risk
bull Levels within normal range occur with obesity xs alcohol cigarette smoking physical inactivity high meat low fruit and vegetable intake
bull Cumulative biomarker for environmental pollutants
Lee DH et al (2003) Gamma-glutamyltransferase and diabetesmdasha 4 year follow-up study Diabetologia 46359ndash364
Pamela A et al Serum gamma-glutamyltransferase linking together environmental pollution redox equilibria and progression of atherosclerosis Clin Chem
Lab Med 200947(12)1583-4
Lee DH et al Serum gamma-glutamyltransferase new insights about an old enzyme J Epidemiol Community Health 2009 Nov63(11)884-6
Lee DH et alSerum gamma-glutamyltransferase predicts non-fatal myocardial infarction and fatal coronary heart disease among 28838 middle-aged men and
women Eur Heart J 2006272170ndash6
Lee DH et al Gamma-glutamyltransferase and diabetes--a 4 year follow-up study Diabetologia 2003 Mar46(3)359-64
Lee DH et al Can persistent organic pollutants explain the association between serum gamma-glutamyltransferase and type 2 diabetes Diabetologia 2008
Mar51(3)402-7
GGT and Alcohol Consumption
bull GGT directly correlates with alcohol consumption
bull In a non-uniform population 40 gd will elevate GGT ~15
bull Watch for false negatives
bull Genomic variation
bull Are these the ones most
sensitive todamaged by
chemical toxins
bull Could up-regulation of GGT in light alcohol consumption be reason for benefit
0
10
20
30
40
50
60
70
80
0 200 400 600 800
Grams of Ethanol per Week
Adapted from Nagaya T et al Dose-response relationships between drinking and serum tests in Japanese men
aged 40ndash59 years Alcohol 1999 Feb 17(2) 133ndash8
GGT Correlates With Toxic Metal Levels
Lee DH et al Graded associations of blood lead and urinary cadmium concentrations with oxidative-stress-related markers in the
US population results from the third National Health and Nutrition Examination Survey Environ Health
perspect 2006 Mar114(3)350-4
GGT and Diabetes Risk
0
5
10
15
20
25
30
lt10 10-19 20-29 30-39 40-49 gt50
Dia
bete
s R
isk
GGT
bull GGT over 50 associated with tripling of death rate
bull 30-40 associated with doubling
GGT Levels
Correlate with
Risk of Death
Brenner H et al Distribution determinants and prognostic value of gamma-glutamyltransferase for all-cause
mortality in a cohort of construction workers from southern Germany Prev Med 1997 26 305ndash10
GGT From Small US Company
with Young Workers
0
10
20
30
40
50
60
0 20 40 60 80 100
GGT Data from Canadian Oil Field
Workers
0
50
100
150
200
250
300
350
400
450
lt10 10-20 20-30 30-40 40-50 50-60 60-07 70-80 80-90 90-100 100-110 110-120 gt120
GGTP
20-fold increased risk of diabetes
Uric Acid Indirect Measure of POPs
bull Poly-fluorinated hydrocarbons (PFOA and PFOS) associated
with increased serum uric acid
Lin CY et al Association among serum perfluoroalkyl chemicals glucose homeostasis and metabolic syndrome
in adolescents and adults Diabetes Care 2009 Apr32(4)702-7
Steenland K et al Association of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) with uric
acid among adults with elevated community exposure to PFOA Environ Health Perspect 2010 Feb118229-33
Steenland 2010 Open Access
ALT Indirect Measure of POPs
bull ALT (proxy marker) elevation in 104 (not including viral
hepatitis hemochromatosis or alcoholic liver disease) of
NHANES 03-04 subset
bull Risk of elevated ALT increased dose-dependently with
cadmium lead mercury and PCB exposure
bull 100 of individuals had detectable PCBs 925 mercury
and 996 had detectable lead
bull In 2005-08 prevalence of NAFLD in US was 11 a
growing cause of chronic liver disease
Cave M et al Polychlorinated biphenyls lead and mercury are associated with liver disease in American adults
NHANES 2003-2004 Environ Health Perspect 2010 Dec118(12)1735-42
Younossi ZM et al Changes in the prevalence of the most common causes of chronic liver diseases in the United
States from 1988 to 2008 Clin Gastroenterol Hepatol 2011 Jun9(6)524-530e1
Bilirubin as a Marker of POPs
bull Degree of serum bilirubin increase is prognostically significant in chronic liver dysfunction
bull Mono-ortho PCB TEQ values were found to be significantly positively associated with bilirubin (β=071 P=0008) following adjustment for multiple potential confounders
bull Bilirubin levels significantly correlated with PCBs -105-118-126 and -194
bull Smoking appears to be the biggest confounder
Dufour DR et al 2000 Diagnosis and monitoring of hepatic injury II Recommendations for use of laboratory
tests in screening diagnosis and monitoring Clin Chem 46 2050ndash68
Kumar J et al Persistent organic pollutants and liver dysfunction biomarkers in a population-based human sample
of men and women Environ Res 2014134251-256
Perf
luo
rin
ate
dP
OP
s a
nd
Co
mm
on
Blo
od
Tests
Gleason JA et al Associations of perfluorinated chemical serum concentrations and biomarkers of liver function and uric acid in the
US population (NHANES) 2007-2010 Environ Res 20151368-14
Liver Enzymes Reflect Toxic Load
bull AST ALT and GGT increase with body load of PCBs and OCPs
bull Some non-linear
bull Oxychlordanetop quartile
ALT 10
GGT 25
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
LDL-Cholesterol as Measure of POPs
bull 5-year prospective study to determine if POP levels predict future elevation in LDL-cholesterol
bull 598 subjects initially at age 70
bull Looked at 23 POPs
bull Best correlation with PCB 194
Penell J Lind L Salihovic S et al Persistent organic pollutants are related to change in circulating
lipid levels during a 5 year follow-up Environ Res 134(2014)190ndash197
oxLDL as Measure of POPs
bull 992 70-year old individuals (50 women)
bull Sum of PCBs showed strong significant positive associations with ox-LDL and significant negative associations with glutathione-related markers (GSSG and GSSGGSH)
bull A number of POPs (PCB-99 138 153 156 170 180 194 206 and 209) showed strong significant positive association with ox-LDL
Kumar J et al Influence of persistent organic pollutants on oxidative stress in population-based samples
Chemosphere 2014114303-309
Homocysteine is Increased by Pb amp Cd
Guallar E et al Confounding of the relation between homocysteine and peripheral arterial disease by lead cadmium and renal function Am J Epidemiol 2006 Apr 15163(8)700-8
Nutrient Deficiencies Accentuate
Effects of Lead on Homocysteine
bull Deficiencies in folate B6 or B12 make lead more toxic
Lee YM Et al Association of homocysteine levels with blood lead levels and micronutrients in the US general population J Prev Med Public Health 2012 Nov45(6)387-93
T4 amp T3 and PCBs
bull PCBs decrease T4 production
bull PCBs inhibit iodotyrosinedeiodinase activity
bull Study done in pregnant women which implies effect on fetus IQ
Kim S Park J Kim HJ et al Association between several persistent organic pollutants and thyroid hormone levels in serum among the pregnant women of Korea Environ Int 2013 Sep59442-8Shimizu R Yamaguchi M Uramaru N et al Structure-activity relationships of 44 halogenated compounds for iodotyrosinedeiodinase-inhibitory activity Toxicology 2013 Dec 6314(1)22-9
T4 amp T3 and PCBs
bull Not just humans being affected
bull Large study of dolphins shows exactly the same effects
Schwacke LH Zolman ES Balmer BC et al Anaemia hypothyroidism and immune suppression associated with polychlorinated biphenyl exposure in bottlenose dolphins (Tursiops truncatus) Proceed Royal Society B doi101098rspb20110665
8-OHdG
bull Oxidized nucleoside
bull Direct measure of DNA damage
bull Indirect measure of oxidative stress and toxin load
bull Correlates with
Multiple cancers
Mitochondrial damage
Rate of aging
Smoking
Several toxinsWalter Crinnion ldquoTotal Toxic Loadrdquo AANP 2015
8-OHdG Correlates with Pack-Years
of Smoking
Yano T et al Significance of the urinary 8-OHdG level as an oxidative stress marker in lung cancer patients Lung Cancer
2009 Jan63(1)111-4
8-OHdG Correlates
with Mercury
Chen C et al Increased oxidative DNA damage as assessed by urinary 8-hydroxy-2-deoxyguanosine
concentrations and serum redox status in persons exposed to mercury Clin Chem 2005 Apr51(4)759-67
Toxin Effects Worse with Aging
bull Thyroid function decreases with PFOA levels
bull But only after age 63
Shrestha S Bloom MS Yucel R et al Perfluoroalkyl substances and thyroid function in older adults Environ Int 2015 Feb75206-14
Insightful 23-Year Prospective Study
1 lt 50 there is no difference between those with the lowest and highest PCBs
2 In youngest group insulin production increases in response to toxin level As expected since blocking of
insulin receptor sites by PCBs
requires more insulin
3 That adaptive ability decreases with aging
4 At age 50 all the measures show very strong toxin-dose response
Cumulative damage impairs ability to adapt
Suarez-Lopez JR et al Persistent organic pollutants in young adults and changes in glucose related metabolism over a 23-year follow-up Environ Res 2015 Feb137485-94
Recommendations
High body toxic load
GGT gt 25
Uric acid gt 50 mgdl
ALT gt30 UL
Bilirubin gt08 mgdl
CBC lt 6000
Platelet lt 250000
Low T3 andor T4
Monitor Total Toxic Load
8-OHdG gt4
ldquoUnconventionalrdquo Laboratory Tests
bull Challenge testing
bull Hair analysis
bull Direct measures of solvents and POPs in blood urine adipose tissue
Evaluation of Metal Exposure ndash Provocation
bull Provocation ndash the use of a chelating agent ndash before urine collection often done clinically but several limitations
No ldquoofficialrdquo reference range for provoked urine
Most chelating agents do not extract metals from all tissues thus
does not necessarily represent total body burden
bull Example Brain is one of the main target organs for both elemental and organic
mercury yet agents do not chelate brain mercury
bull Despite limitations widely used and advocated by clinicians in part to see efficacy of chelating agent as a guide to treatment and based on empirical evidence
Rooney JP The role of thiols dithiols nutritional factors and interacting ligands in the toxicology of mercury
Toxicology 2007
Is Challenge Testing Valid
bull Poor correlations of standard tests for mercury
bull Unpublished research from corporate wellness project
bull Published amalgam number correlation
bull Published fish consumption correlation
What We Found In Canada
bull Deviations from the mean of 14 29 and 91 respectively
bull DMPS is spreading distribution suggesting that it is better at differentiating mercury body load
bull Some VERY high
Hg Assessment Correlations
bull Extensive measurements in 65 Whole blood Hg
Oral DMPS challenge
Amalgam surfaces
bull Correlations Whole blood w pre urine r = 040
Whole blood w post urine r = 057
Pre urine w post urine r = 068
Amalgams w pre urine r = 026
Amalgams w whole blood r = 036
Amalgams with post urine 044
bull Clear documentation that
challenge testing is better00
100
200
300
400
500
600
0 10 20 30 40 50
Po
st
Uri
ne H
g u
gg
Number of amalgams
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
Ground Water Sources of Arsenic
bull 10 of US public water supplies have levels of arsenic known to induce disease
bull No data on private water supplies
httpwwwatsdrcdcgovcsemarsenicdocsarsenicpdf (accessed 2015-08-18)
Example POPs
Chemical Abbr Uses Exposure
Bisphenol A BPA Plastics Canned food
Organochlorine
pesticides
OCPs Pesticide Food fumigation
Organophosphate
pesticides
OPPs Pesticide Food
Polybrominated
diphenyl ethers
PBDEs Flame retardant Clothing
Polychlorinated
biphenyls
PCBs Industrial Everywhere
Perflourinated PFOAs Non-stick stain prevention
water repellant
Teflon Gortex
Scotchguard
Phthalates Plastics fragrances Shower curtains
cosmetics
POPs - Prediabetes
bull Over 1200 participants fasting
glucose and OGTT performed
with serum levels of 5 POPs
bull All individual POPs tested were
associated with progressive
increase in prevalence of
prediabetes
bull More than triple prevalence of
prediabetes seen in those in the
5th quartile with a synergistic
effect from 5 POPs
Ukropec J et al High prevalence of prediabetes and diabetes in a population exposed to high levels of an organochlorine cocktail
Diabetologia 2010 May53(5)899-906
POPs and Diabetes Risk
Graph httpwwwourstolenfutureorgNewScienceobesity20062006-0715leeetalhtml
Data Lee DH Lee IK Song K et al A strong dose-response relation between serum
concentrations of persistent organic pollutants and diabetes results from the National Health and
Examination Survey 1999-2002 Diabetes Care 2006 Jul29(7)1638-44
Toxic Load and Disease Risk
References for Toxins and Disease Risk
Converting Disease Risk to Caused
Attributable Fraction Calculation
p = underlying prevalence of risk factor in the population
rr = relative risk (risk of contracting a disease in an exposed population divided by the risk of contracting the disease in an unexposed population)
AF = of disease due to the toxin
Levin M The occurrence of lung cancer in man Acta Unio Int Contra Cancrum 1953 9 531-541
Example Smoking and Lung Cancer
B = 5Number of smokers
who contract Lung Cancer notdue to smoking
A = 5Number of smokerswho contract Lung
Cancer due to smoking
C = 15Number of
nonsmokerswho contract Lung Cancer
0
2
4
6
8
10
12
14
16
Smokers (N=100) Nonsmokers (N=300)Num
ber
of
people
who c
ontr
act
Lung C
ancer
per
year
Baseline Additional due to smoking
Number of smokers and nonsmokers who contract lung cancer
Our Process In Summary
1 Determine threshold for increased disease risk
2 Determine of population above threshold
3 Determine incidence of disease (OR) in those above threshold
4 Determine incidence of disease in ldquounexposed populationrdquo
5 Calculate AF ie of disease
As whole population is exposed probably UNDERESTIMATES of disease
To
xic
ity H
as B
eco
me t
he N
ew
ldquoN
orm
alrdquo
Toxin Type Use Threshold for
disease
association
of US
above
threshold
Disease Associations
Chlordane OC pesticide Termites corn citrus lawns
gardens
145ngg lipid 63
(diabetes)
Diabetes (20)
BPA Plasticizer Water bottles canned food
water pipes thermal sales
receipts
48 men 51
women (urine
ngmL)
~18
(diabetes)
Diabetes hypertension
Octachloro
dibenzo-p-
dioxin
(OCDD)
Polychlorinated
dibenzo-p-
dioxin
Incineration or burning of
waste bleaching processes
used in pulp and paper mills
1010 pgg
lipid (highest
quartile)
10-25
(hypertensio
n)
Hypertension (79 for
women highest
quartile) diabetes (21)
obesity learning
disability (272)
MEP
(mono-
ethyl
phthalate)
Phthalate
(plasticizer
fragrance)
Toothbrushes automobile
parts tools toys and food
packaging aspirin
cosmetics food packaging
gt175 ngmL
(urine)
~60
(diabetes)
Diabetes (148) lower
BMD obesity
pp-DDE DDT
metabolite (OC
pesticide)
Agricultural crops 1560ngg
lipid
25
(diabetes)
Diabetes (23-43)
early menopause
impaired cognitive
function (2-3x 65x in
highest 5th percentile)
peripheral arterial
disease
Arsenic Toxic metal Miningsmelting wood
preservative pesticides
74ugL total
arsenic (urine)
20
(diabetes)
Cancers diabetes (26-
46) dyslipidemia gout
AF OR Prevalence
Rosen L An intuitive approach to understanding the attributable fraction of disease due to a risk factor the case of smoking Int J Environ Res Public Health 2013 Jul 1610(7)2932-43
Smoking Lung cancer
Arsenic Gout in women
BPA Diabetes
Status of Our Research
bull 26 toxins and toxin classes eg lead mercury BPA OCPs
100s of chemicals and POPs in some classes
bull 18 cancers
bull 24 chronic diseases
bull 1092 cells in spreadsheet
Large Personal Ongoing Research Investment
Huge Amount of Research Work
Toxins StudiedAluminum
Arsenic
Cadmium
Fluoride
Lead
Manganese
Mercury
Acrylamide
Acrylonitrile
Benzene
Bisphenol A (BPA)
Chloroform
DDT
Dioxins
Glyphosate
Organochlorine pesticides (OCPs)
Organophosphate pesticides
Parabens
Phthalates
Polybrominated diphenyl ethers (PBDEs)
Polycyclic aromatic hydrocarbons (PAHs)
Polychlorinated biphenols (PCBs)
Vinyl chloride
Diseases Studied
ADHD
Alzheimers Disease
ALS
Angiosarcoma
Anxiety
Atopic Conditions
Diabetes
Dyslipidemia
Gout
Fetal Abnormalities
Hyperuricemia
Infertility
Juvenile IQ
Cancer Bladder
Cancer Bone
Cancer Brain
Cancer Breast
Cancer Cervix
Cancer Colorectal
Cancer Endometrial
Cancer Head amp Neck
Cancer Liver
Cancer Lung
Cancer Lymph amp Blood
Cancer Ovarian
Cancer Pancreatic
Cancer Prostate
Cancer Renal
Cancer Skin
Cancer Testicular
Cancer Thyroid
Juvenile Obesity
Metabolic Syndrome
Mitochondrial dysfunction
Myocardial Infarction
Obstructive Lung Disease
Osteoporosis
Peripheral Artery Disease
Peripheral Neuropathy
Prediabetes
Renal Disease
Rheumatoid Arthritis
Thyroid Dysfunction
OC
Ps
Th
rou
gh
ou
t th
e W
orl
d
Rathore HS Nollet LML Pesticides Evaluation of Environmental Pollution CRC Press
2012 page 562
Threshold ndash Threshold exposure at which there is an increased risk of disease outcome
Above Threshold ndash Percentage of the population with higher exposure than the threshold
Odds Ratio ndash Increased disease risk in those above threshold
of Dz ndash Percent contribution of the toxin to that disease outcome
How to Interpret the Following Slides
Attention Deficit Hyperactivity Disorder
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
DDT 126 ngg
serum (pp-
DDE)
250 18 166 20106937
Lead 23 ugdL 13 254 20 27659349
Mercury 16 24952233
Organophosphate
pesticides
20
Polycyclic
Aromatic
Hydrocarbons
227 ngm3 940 125 190 22440811
PCBs 104 ngg
serum (sum
of 50 PCBs)
250 176 160 20106937
DiabetesToxin Threshold Above
Threshold
Odds
Ratio
of Dz Reference
PMID
Arsenic 165 ugL 200 21 180 18714061
BPA 28 ugL 280 145 112 26119400
DDE 545 ngg serum
(pp-DDE)
200 230 31 26119400
Dioxins2 pgg lipid 50 191 43
26119400
PCBs104 ngg (PCB 153) 250 239 258
26119400
Phthalates175 ugL 690 148 249
26119400
1-naphthalene 167 ugdL 152 182 111 26340343
2-napthalene 414 ugdL 550 224 214 26340343
1-phenanthrene 167 ngL 570 178 151 26340343
1-pyrene 85 ngL 660 180 174 26340343
Lung Cancer
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Acrylonitrile Uncertain Uncertain 125 25
occupational
exposure
17114112
Arsenic 1213 ugL 436 of Asian
Americans
~01 of total
US population
34 95 in AA
01-1
PMC2682945
Cadmium Uncertain+ Uncertain 467 10 in
smokers
17184399
DDT Any exposure All US pop
below LOD
17 76 increased
risk
8923607
Breast Cancer
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Cadmium 0580 ugg
creatinine
126 205 479 16788160
PCB 138 396 ngg
creatinine
202 316 630 27717745
PCB 187 108 ngg lipid 600 194 360 21480306
Miscellaneous Diseases
Toxin Disease Threshold Above
Threshold
Odds
Ratio
of Dz Reference PMID
Aluminum Alzheimer
Dz
01 mgL
drinking
H20
400 203 05-44 26592479
Benzene AML 100ppmyrs 1-3 320 60 PMC2903550
DDT NHL 0512 ugL 1-2 240 01 17722095
Lead ALS 238 ugdL
blood
330 181 210 25479292
Lead Brain CA 0005 ugdL 14 19 ~500 17164378
Dioxin-like
PCBs
RA 326 ngg
lipid
250 219 220 17589595
PAHs Asthma 124 ngm3 935 200 483 19221603
The Potency of Arsenic
Disease Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Bladder CA 10ugL H20 100 27 145 24889821
Pancreatic CA 1332 ugg 200 246 230 23800676
Prostate CA 1332 ugg 200 33 315 23800676
Gout 125 ugL 245 546 522 25499256
Diabetes 165 ugL 200 21 180 18714061
Arsenic (180 of Diabetes)
How it causes diabetes
bull Blocks sugar stimulating insulin secretion
bull Epigenetic inhibition of sugar regulation
Where it comes from
bull Water (gt10 of US water supplies have high levels)
bull Rice (naturally absorbs if in the water)
bull Chicken (added to make meat whiter)
Pan W-C Seow WJ Kile ML et al Association of low to moderate levels of arsenic exposure with risk of Type 2 diabetes in Bangladesh American Journal of Epidemiology 2013178(10)1563-70
Portion of Population with Toxin Load Which
Doubles Disease Risk
Toxin Disease with Doubled Risk
Polycyclic aromatic hydrocarbons Asthma 94
PCB187 Breast Cancer 60
Phthalates Diabetes 55
Lead ALS 33
Aluminum Alzheimers Disease 25
DDT ADHD 25
PCBs Diabetes 25
Dioxin-like PCBs Rheumatoid Arthritis 25
Arsenic Gout 23
Bisphenol A Diabetes 22
Cigarette smoking Lung Cancer 21
Arsenic Diabetes 20
Polycyclic aromatic hydrocarbons Diabetes 20
Huge Detoxification Variability
bull CYP2C19
Proton pump inhibitors and some antidepressants
5-fold difference in activity between poor metabolizers and extensive metabolizers more so if CYP3A4 is also inhibited
Ultrarapid allele in 18 of both Swedes and Ethiopians
bull CYP2D6
Metabolizes a large number of drugs (~25)
7 of Caucasians poor metabolizers
~30 ultra rapid metabolizers in Arabian and Eastern African populations
More adverse effects in poor metabolizers and ineffective dosing in ultrarapid metabolizers
Inhibited by ginger
Desta Z et al Clinical significance of the cytochrome P450 2C19 genetic polymorphism Clin Pharmaco 2002
Sim SC et al A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug
response to proton pump inhibitors and antidepressants Clin Pharmacol Ther 2006
Wilkinson GR Drug metabolism and variability among patients in drug response N Engl J Med 2005
Kirchheiner J et al Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to
CYP2D6 duplication Pharmacogenomics J 2007
Toxin Half Lives in BloodToxin ldquoNormalrdquo (mgL) Acute Toxic (mgL) Half-Life
Arsenic 0002-007 005-025 2-4 days (CDC)
Benzene 00002 05-10 days
Cadmium 00003-00065 0015-005 16 years
Chlordane 0001 00025 3-4 days
DDTDDE 2-10 years
Dieldrin 00015 015-030 2-12 months
Ethanol 1000-2000 15hour
Lead 009 04-06 1-15 mo (2+ yrs bone)
Mercury 00015-0002 005-02 2 months (CDC)
PCBs 3-25 years
Toluene 05-3 days
Schulz M et al Therapeutic and toxic blood concentrations of nearly 1000 drugs and other xenobiotics Crit Care 2012 Jul 2616(4)R136
Bioaccumulation (POPs)
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
DDT banned in 1972 PCBs banned in 1977
Bioaccumulation (Cd)
Think BroadlyExogenous
Metals
Chemicalsbull Inorganic
bull Fluoride
bull Organic
bull POPs
bull Drugs
Particulate matter
Molds
Microbial
Radiationbull Light
bull Medical
bull Cell phone
Endogenous
Gut-derived toxins
Non-end product metabolites
Poorly detoxified hormones
Catecholamines (if SNP)
Toxins of Choice
Alcohol
Marijuana
Food constituents
High fructose corn syrup
Salt (acid-forming diet)
Wheat if zonulin (70)
Obesity Epidemic ndash POPs AND HFCS
47Bray GA Fructose should we worry Int J Obes (Lond) 2008 Dec32 Suppl 7S127-31
How Toxins Cause Damage 13
bull Increase free radical production
Cd induces production of ROS
Malathion inhibits catalase and glutathione peroxidase
Homocysteine oxidizes LDL cholesterol
bull Poison enzyme systems (compete with nutritional cofactors for binding sites)
Pb poisons delta aminolevulinic acid dehydratase
Cd inhibits catalase glutathione reductase and lowers
glutathione levels
bull Replace structural minerals
Pb displaces Ca in bone
How Toxins Cause Damage 23
bull Damage DNA
Benzene - causes chromosomal damage
Pesticides ndash fruit growers have more DNA damage
Phthalates and insecticides ndash damage sperm DNA
4-hydroxy catechol estrogen (4-OHE) damages breast DNA
bull Epigenetic dysmodulation
Higher cord blood levels of hexachlorobenzene associated
with 2x greater risk for obesity in children
bull Damage cell membranes
Common mechanism for heavy metals inactivates
membrane enzymes ion channels and pumps
How Toxins Cause Damage 33
bull Block insulin receptor sites
PCBs and phthalates
bull Highest levels associated with a 4 to 20-fold greater diabetes risk
bull Imbalance hormones many toxin examples
Arsenic
bull Disrupts thyroid hormone and retinoic acid receptors
Phthalates
bull Act as anti-androgens
bull More than 75 of the US population has measurable levels of
several phthalate metabolites in the urine
PCBs
bull Lower testosterone levels in men
Which are the Worst Toxins
bull According to the CDC
Toxicity
Population toxic load
Prevalence in toxic waste sites
bull According to clinical importance
Exposure
of disease
Ability of the body to detoxifyexcrete
Ag
en
cy
fo
r T
oxic
Su
bs
tan
ce
s a
nd
Dis
ea
se
Reg
istr
y
Pri
ori
ty L
ist
The Worst Toxins Clinically
My Rank Toxin Diseases Primary Sources
1 Arsenic Cancers diabetes gout Water chicken rice
2 DDT ADHD dementia diabetes Everywhere
3 Phthalates ADHD diabetes Soft plastics HABAs
4 PBDEs ADHD diabetes Flame retardant fabrics
5 PAHs ADHD cancers dyslipidemia Smoking charbroiling
6 PCBs Cancers diabetes MI RA Everywhere
7 Mercury Dementia ldquoSilverrdquo fillings fish
8 Lead Cardiovascular disease IQ Paint water
Glyphosate Research invalid
Conventional Laboratory Tests Reflect
Toxic Load in ldquoNormalrdquo Range
bull Surprising number show toxin exposure
CBC RBC WBC platelet count hemoglobin basophilic
stippling
Liver enzymes ALT GGTP
Inflammatory markers CRP
Lipids LDL oxLDL triglycerides
Blood sugar insulin FBS 2-hour PP
Metabolites bilirubin uric acid homocysteine 8-OHdG
Thyroid T3 T4 TSH
bull The historic ldquonormalrdquo range has been changing as the population has become more toxic
WBC Lowered by PCB and OCP Exposure
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
0
1
2
3
4
5
6
7
8
1st Quartrile 2nd Quartile 3rd Quartile 4th Quartile
WBCbull Strong inverse correlation with PCBs and OCPs and CBC
bull Linear with almost all PCBs
bull High variability with OCPs
bull Within ldquonormalrdquo range
Effects on WBC Worsen with Years
of Exposure to Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Platelet Count Decreases with Years
of Exposure tp Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Solvents Decrease Platelet Count
bull Compared workers exposed 23 hrday to those exposed most of day to toluene
bull All wore face masks and protective gear
bull Platelet count 14 lower 252 versus 216ml
bull Impairment of sympathetic nerves (OR = 413)
bull Impairment of peripheral nerves (OR = 694)
bull Positive relationship between neurological abnormalities and a self-reported neuropsychiatric measurement (r = 035-066)
Shih HT et al Subclinical abnormalities in workers with continuous low-level toluene exposure Toxicol Ind Health 2011 Sep27(8)691-9
Basophilic Stippling of Red Cells
Toxinsbull Arsenic
bull Lead
Diseasesbull Alpha-thalassemia HbH Disease
bull Beta thalassemia
bull Hereditary pyrimidine 5-nucleotidase deficiency
bull Myelodysplastic syndrome
bull Sideroblastic anemia
bull Thrombotic thrombocytopenic purpura
GGT Indirect Measure of POPsbull Glutathione is key intracellular defense against oxidative stress
bull Cellular GGT metabolizes extracellular GSH allowing precursor amino acids to be reutilized for intracellular GSH
bull Exposure to POPs induces GGT as a defensive mechanism
bull Within normal range predicts type 2 diabetes coronary heart disease hypertension stroke dyslipidemia chronic kidney disease and cancer
bull Men with GGT gt50 UI had ~26 fold risk for diabetes compared to those with lt10 Those with 40-49 had a ~20 fold risk
bull Levels within normal range occur with obesity xs alcohol cigarette smoking physical inactivity high meat low fruit and vegetable intake
bull Cumulative biomarker for environmental pollutants
Lee DH et al (2003) Gamma-glutamyltransferase and diabetesmdasha 4 year follow-up study Diabetologia 46359ndash364
Pamela A et al Serum gamma-glutamyltransferase linking together environmental pollution redox equilibria and progression of atherosclerosis Clin Chem
Lab Med 200947(12)1583-4
Lee DH et al Serum gamma-glutamyltransferase new insights about an old enzyme J Epidemiol Community Health 2009 Nov63(11)884-6
Lee DH et alSerum gamma-glutamyltransferase predicts non-fatal myocardial infarction and fatal coronary heart disease among 28838 middle-aged men and
women Eur Heart J 2006272170ndash6
Lee DH et al Gamma-glutamyltransferase and diabetes--a 4 year follow-up study Diabetologia 2003 Mar46(3)359-64
Lee DH et al Can persistent organic pollutants explain the association between serum gamma-glutamyltransferase and type 2 diabetes Diabetologia 2008
Mar51(3)402-7
GGT and Alcohol Consumption
bull GGT directly correlates with alcohol consumption
bull In a non-uniform population 40 gd will elevate GGT ~15
bull Watch for false negatives
bull Genomic variation
bull Are these the ones most
sensitive todamaged by
chemical toxins
bull Could up-regulation of GGT in light alcohol consumption be reason for benefit
0
10
20
30
40
50
60
70
80
0 200 400 600 800
Grams of Ethanol per Week
Adapted from Nagaya T et al Dose-response relationships between drinking and serum tests in Japanese men
aged 40ndash59 years Alcohol 1999 Feb 17(2) 133ndash8
GGT Correlates With Toxic Metal Levels
Lee DH et al Graded associations of blood lead and urinary cadmium concentrations with oxidative-stress-related markers in the
US population results from the third National Health and Nutrition Examination Survey Environ Health
perspect 2006 Mar114(3)350-4
GGT and Diabetes Risk
0
5
10
15
20
25
30
lt10 10-19 20-29 30-39 40-49 gt50
Dia
bete
s R
isk
GGT
bull GGT over 50 associated with tripling of death rate
bull 30-40 associated with doubling
GGT Levels
Correlate with
Risk of Death
Brenner H et al Distribution determinants and prognostic value of gamma-glutamyltransferase for all-cause
mortality in a cohort of construction workers from southern Germany Prev Med 1997 26 305ndash10
GGT From Small US Company
with Young Workers
0
10
20
30
40
50
60
0 20 40 60 80 100
GGT Data from Canadian Oil Field
Workers
0
50
100
150
200
250
300
350
400
450
lt10 10-20 20-30 30-40 40-50 50-60 60-07 70-80 80-90 90-100 100-110 110-120 gt120
GGTP
20-fold increased risk of diabetes
Uric Acid Indirect Measure of POPs
bull Poly-fluorinated hydrocarbons (PFOA and PFOS) associated
with increased serum uric acid
Lin CY et al Association among serum perfluoroalkyl chemicals glucose homeostasis and metabolic syndrome
in adolescents and adults Diabetes Care 2009 Apr32(4)702-7
Steenland K et al Association of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) with uric
acid among adults with elevated community exposure to PFOA Environ Health Perspect 2010 Feb118229-33
Steenland 2010 Open Access
ALT Indirect Measure of POPs
bull ALT (proxy marker) elevation in 104 (not including viral
hepatitis hemochromatosis or alcoholic liver disease) of
NHANES 03-04 subset
bull Risk of elevated ALT increased dose-dependently with
cadmium lead mercury and PCB exposure
bull 100 of individuals had detectable PCBs 925 mercury
and 996 had detectable lead
bull In 2005-08 prevalence of NAFLD in US was 11 a
growing cause of chronic liver disease
Cave M et al Polychlorinated biphenyls lead and mercury are associated with liver disease in American adults
NHANES 2003-2004 Environ Health Perspect 2010 Dec118(12)1735-42
Younossi ZM et al Changes in the prevalence of the most common causes of chronic liver diseases in the United
States from 1988 to 2008 Clin Gastroenterol Hepatol 2011 Jun9(6)524-530e1
Bilirubin as a Marker of POPs
bull Degree of serum bilirubin increase is prognostically significant in chronic liver dysfunction
bull Mono-ortho PCB TEQ values were found to be significantly positively associated with bilirubin (β=071 P=0008) following adjustment for multiple potential confounders
bull Bilirubin levels significantly correlated with PCBs -105-118-126 and -194
bull Smoking appears to be the biggest confounder
Dufour DR et al 2000 Diagnosis and monitoring of hepatic injury II Recommendations for use of laboratory
tests in screening diagnosis and monitoring Clin Chem 46 2050ndash68
Kumar J et al Persistent organic pollutants and liver dysfunction biomarkers in a population-based human sample
of men and women Environ Res 2014134251-256
Perf
luo
rin
ate
dP
OP
s a
nd
Co
mm
on
Blo
od
Tests
Gleason JA et al Associations of perfluorinated chemical serum concentrations and biomarkers of liver function and uric acid in the
US population (NHANES) 2007-2010 Environ Res 20151368-14
Liver Enzymes Reflect Toxic Load
bull AST ALT and GGT increase with body load of PCBs and OCPs
bull Some non-linear
bull Oxychlordanetop quartile
ALT 10
GGT 25
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
LDL-Cholesterol as Measure of POPs
bull 5-year prospective study to determine if POP levels predict future elevation in LDL-cholesterol
bull 598 subjects initially at age 70
bull Looked at 23 POPs
bull Best correlation with PCB 194
Penell J Lind L Salihovic S et al Persistent organic pollutants are related to change in circulating
lipid levels during a 5 year follow-up Environ Res 134(2014)190ndash197
oxLDL as Measure of POPs
bull 992 70-year old individuals (50 women)
bull Sum of PCBs showed strong significant positive associations with ox-LDL and significant negative associations with glutathione-related markers (GSSG and GSSGGSH)
bull A number of POPs (PCB-99 138 153 156 170 180 194 206 and 209) showed strong significant positive association with ox-LDL
Kumar J et al Influence of persistent organic pollutants on oxidative stress in population-based samples
Chemosphere 2014114303-309
Homocysteine is Increased by Pb amp Cd
Guallar E et al Confounding of the relation between homocysteine and peripheral arterial disease by lead cadmium and renal function Am J Epidemiol 2006 Apr 15163(8)700-8
Nutrient Deficiencies Accentuate
Effects of Lead on Homocysteine
bull Deficiencies in folate B6 or B12 make lead more toxic
Lee YM Et al Association of homocysteine levels with blood lead levels and micronutrients in the US general population J Prev Med Public Health 2012 Nov45(6)387-93
T4 amp T3 and PCBs
bull PCBs decrease T4 production
bull PCBs inhibit iodotyrosinedeiodinase activity
bull Study done in pregnant women which implies effect on fetus IQ
Kim S Park J Kim HJ et al Association between several persistent organic pollutants and thyroid hormone levels in serum among the pregnant women of Korea Environ Int 2013 Sep59442-8Shimizu R Yamaguchi M Uramaru N et al Structure-activity relationships of 44 halogenated compounds for iodotyrosinedeiodinase-inhibitory activity Toxicology 2013 Dec 6314(1)22-9
T4 amp T3 and PCBs
bull Not just humans being affected
bull Large study of dolphins shows exactly the same effects
Schwacke LH Zolman ES Balmer BC et al Anaemia hypothyroidism and immune suppression associated with polychlorinated biphenyl exposure in bottlenose dolphins (Tursiops truncatus) Proceed Royal Society B doi101098rspb20110665
8-OHdG
bull Oxidized nucleoside
bull Direct measure of DNA damage
bull Indirect measure of oxidative stress and toxin load
bull Correlates with
Multiple cancers
Mitochondrial damage
Rate of aging
Smoking
Several toxinsWalter Crinnion ldquoTotal Toxic Loadrdquo AANP 2015
8-OHdG Correlates with Pack-Years
of Smoking
Yano T et al Significance of the urinary 8-OHdG level as an oxidative stress marker in lung cancer patients Lung Cancer
2009 Jan63(1)111-4
8-OHdG Correlates
with Mercury
Chen C et al Increased oxidative DNA damage as assessed by urinary 8-hydroxy-2-deoxyguanosine
concentrations and serum redox status in persons exposed to mercury Clin Chem 2005 Apr51(4)759-67
Toxin Effects Worse with Aging
bull Thyroid function decreases with PFOA levels
bull But only after age 63
Shrestha S Bloom MS Yucel R et al Perfluoroalkyl substances and thyroid function in older adults Environ Int 2015 Feb75206-14
Insightful 23-Year Prospective Study
1 lt 50 there is no difference between those with the lowest and highest PCBs
2 In youngest group insulin production increases in response to toxin level As expected since blocking of
insulin receptor sites by PCBs
requires more insulin
3 That adaptive ability decreases with aging
4 At age 50 all the measures show very strong toxin-dose response
Cumulative damage impairs ability to adapt
Suarez-Lopez JR et al Persistent organic pollutants in young adults and changes in glucose related metabolism over a 23-year follow-up Environ Res 2015 Feb137485-94
Recommendations
High body toxic load
GGT gt 25
Uric acid gt 50 mgdl
ALT gt30 UL
Bilirubin gt08 mgdl
CBC lt 6000
Platelet lt 250000
Low T3 andor T4
Monitor Total Toxic Load
8-OHdG gt4
ldquoUnconventionalrdquo Laboratory Tests
bull Challenge testing
bull Hair analysis
bull Direct measures of solvents and POPs in blood urine adipose tissue
Evaluation of Metal Exposure ndash Provocation
bull Provocation ndash the use of a chelating agent ndash before urine collection often done clinically but several limitations
No ldquoofficialrdquo reference range for provoked urine
Most chelating agents do not extract metals from all tissues thus
does not necessarily represent total body burden
bull Example Brain is one of the main target organs for both elemental and organic
mercury yet agents do not chelate brain mercury
bull Despite limitations widely used and advocated by clinicians in part to see efficacy of chelating agent as a guide to treatment and based on empirical evidence
Rooney JP The role of thiols dithiols nutritional factors and interacting ligands in the toxicology of mercury
Toxicology 2007
Is Challenge Testing Valid
bull Poor correlations of standard tests for mercury
bull Unpublished research from corporate wellness project
bull Published amalgam number correlation
bull Published fish consumption correlation
What We Found In Canada
bull Deviations from the mean of 14 29 and 91 respectively
bull DMPS is spreading distribution suggesting that it is better at differentiating mercury body load
bull Some VERY high
Hg Assessment Correlations
bull Extensive measurements in 65 Whole blood Hg
Oral DMPS challenge
Amalgam surfaces
bull Correlations Whole blood w pre urine r = 040
Whole blood w post urine r = 057
Pre urine w post urine r = 068
Amalgams w pre urine r = 026
Amalgams w whole blood r = 036
Amalgams with post urine 044
bull Clear documentation that
challenge testing is better00
100
200
300
400
500
600
0 10 20 30 40 50
Po
st
Uri
ne H
g u
gg
Number of amalgams
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
Example POPs
Chemical Abbr Uses Exposure
Bisphenol A BPA Plastics Canned food
Organochlorine
pesticides
OCPs Pesticide Food fumigation
Organophosphate
pesticides
OPPs Pesticide Food
Polybrominated
diphenyl ethers
PBDEs Flame retardant Clothing
Polychlorinated
biphenyls
PCBs Industrial Everywhere
Perflourinated PFOAs Non-stick stain prevention
water repellant
Teflon Gortex
Scotchguard
Phthalates Plastics fragrances Shower curtains
cosmetics
POPs - Prediabetes
bull Over 1200 participants fasting
glucose and OGTT performed
with serum levels of 5 POPs
bull All individual POPs tested were
associated with progressive
increase in prevalence of
prediabetes
bull More than triple prevalence of
prediabetes seen in those in the
5th quartile with a synergistic
effect from 5 POPs
Ukropec J et al High prevalence of prediabetes and diabetes in a population exposed to high levels of an organochlorine cocktail
Diabetologia 2010 May53(5)899-906
POPs and Diabetes Risk
Graph httpwwwourstolenfutureorgNewScienceobesity20062006-0715leeetalhtml
Data Lee DH Lee IK Song K et al A strong dose-response relation between serum
concentrations of persistent organic pollutants and diabetes results from the National Health and
Examination Survey 1999-2002 Diabetes Care 2006 Jul29(7)1638-44
Toxic Load and Disease Risk
References for Toxins and Disease Risk
Converting Disease Risk to Caused
Attributable Fraction Calculation
p = underlying prevalence of risk factor in the population
rr = relative risk (risk of contracting a disease in an exposed population divided by the risk of contracting the disease in an unexposed population)
AF = of disease due to the toxin
Levin M The occurrence of lung cancer in man Acta Unio Int Contra Cancrum 1953 9 531-541
Example Smoking and Lung Cancer
B = 5Number of smokers
who contract Lung Cancer notdue to smoking
A = 5Number of smokerswho contract Lung
Cancer due to smoking
C = 15Number of
nonsmokerswho contract Lung Cancer
0
2
4
6
8
10
12
14
16
Smokers (N=100) Nonsmokers (N=300)Num
ber
of
people
who c
ontr
act
Lung C
ancer
per
year
Baseline Additional due to smoking
Number of smokers and nonsmokers who contract lung cancer
Our Process In Summary
1 Determine threshold for increased disease risk
2 Determine of population above threshold
3 Determine incidence of disease (OR) in those above threshold
4 Determine incidence of disease in ldquounexposed populationrdquo
5 Calculate AF ie of disease
As whole population is exposed probably UNDERESTIMATES of disease
To
xic
ity H
as B
eco
me t
he N
ew
ldquoN
orm
alrdquo
Toxin Type Use Threshold for
disease
association
of US
above
threshold
Disease Associations
Chlordane OC pesticide Termites corn citrus lawns
gardens
145ngg lipid 63
(diabetes)
Diabetes (20)
BPA Plasticizer Water bottles canned food
water pipes thermal sales
receipts
48 men 51
women (urine
ngmL)
~18
(diabetes)
Diabetes hypertension
Octachloro
dibenzo-p-
dioxin
(OCDD)
Polychlorinated
dibenzo-p-
dioxin
Incineration or burning of
waste bleaching processes
used in pulp and paper mills
1010 pgg
lipid (highest
quartile)
10-25
(hypertensio
n)
Hypertension (79 for
women highest
quartile) diabetes (21)
obesity learning
disability (272)
MEP
(mono-
ethyl
phthalate)
Phthalate
(plasticizer
fragrance)
Toothbrushes automobile
parts tools toys and food
packaging aspirin
cosmetics food packaging
gt175 ngmL
(urine)
~60
(diabetes)
Diabetes (148) lower
BMD obesity
pp-DDE DDT
metabolite (OC
pesticide)
Agricultural crops 1560ngg
lipid
25
(diabetes)
Diabetes (23-43)
early menopause
impaired cognitive
function (2-3x 65x in
highest 5th percentile)
peripheral arterial
disease
Arsenic Toxic metal Miningsmelting wood
preservative pesticides
74ugL total
arsenic (urine)
20
(diabetes)
Cancers diabetes (26-
46) dyslipidemia gout
AF OR Prevalence
Rosen L An intuitive approach to understanding the attributable fraction of disease due to a risk factor the case of smoking Int J Environ Res Public Health 2013 Jul 1610(7)2932-43
Smoking Lung cancer
Arsenic Gout in women
BPA Diabetes
Status of Our Research
bull 26 toxins and toxin classes eg lead mercury BPA OCPs
100s of chemicals and POPs in some classes
bull 18 cancers
bull 24 chronic diseases
bull 1092 cells in spreadsheet
Large Personal Ongoing Research Investment
Huge Amount of Research Work
Toxins StudiedAluminum
Arsenic
Cadmium
Fluoride
Lead
Manganese
Mercury
Acrylamide
Acrylonitrile
Benzene
Bisphenol A (BPA)
Chloroform
DDT
Dioxins
Glyphosate
Organochlorine pesticides (OCPs)
Organophosphate pesticides
Parabens
Phthalates
Polybrominated diphenyl ethers (PBDEs)
Polycyclic aromatic hydrocarbons (PAHs)
Polychlorinated biphenols (PCBs)
Vinyl chloride
Diseases Studied
ADHD
Alzheimers Disease
ALS
Angiosarcoma
Anxiety
Atopic Conditions
Diabetes
Dyslipidemia
Gout
Fetal Abnormalities
Hyperuricemia
Infertility
Juvenile IQ
Cancer Bladder
Cancer Bone
Cancer Brain
Cancer Breast
Cancer Cervix
Cancer Colorectal
Cancer Endometrial
Cancer Head amp Neck
Cancer Liver
Cancer Lung
Cancer Lymph amp Blood
Cancer Ovarian
Cancer Pancreatic
Cancer Prostate
Cancer Renal
Cancer Skin
Cancer Testicular
Cancer Thyroid
Juvenile Obesity
Metabolic Syndrome
Mitochondrial dysfunction
Myocardial Infarction
Obstructive Lung Disease
Osteoporosis
Peripheral Artery Disease
Peripheral Neuropathy
Prediabetes
Renal Disease
Rheumatoid Arthritis
Thyroid Dysfunction
OC
Ps
Th
rou
gh
ou
t th
e W
orl
d
Rathore HS Nollet LML Pesticides Evaluation of Environmental Pollution CRC Press
2012 page 562
Threshold ndash Threshold exposure at which there is an increased risk of disease outcome
Above Threshold ndash Percentage of the population with higher exposure than the threshold
Odds Ratio ndash Increased disease risk in those above threshold
of Dz ndash Percent contribution of the toxin to that disease outcome
How to Interpret the Following Slides
Attention Deficit Hyperactivity Disorder
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
DDT 126 ngg
serum (pp-
DDE)
250 18 166 20106937
Lead 23 ugdL 13 254 20 27659349
Mercury 16 24952233
Organophosphate
pesticides
20
Polycyclic
Aromatic
Hydrocarbons
227 ngm3 940 125 190 22440811
PCBs 104 ngg
serum (sum
of 50 PCBs)
250 176 160 20106937
DiabetesToxin Threshold Above
Threshold
Odds
Ratio
of Dz Reference
PMID
Arsenic 165 ugL 200 21 180 18714061
BPA 28 ugL 280 145 112 26119400
DDE 545 ngg serum
(pp-DDE)
200 230 31 26119400
Dioxins2 pgg lipid 50 191 43
26119400
PCBs104 ngg (PCB 153) 250 239 258
26119400
Phthalates175 ugL 690 148 249
26119400
1-naphthalene 167 ugdL 152 182 111 26340343
2-napthalene 414 ugdL 550 224 214 26340343
1-phenanthrene 167 ngL 570 178 151 26340343
1-pyrene 85 ngL 660 180 174 26340343
Lung Cancer
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Acrylonitrile Uncertain Uncertain 125 25
occupational
exposure
17114112
Arsenic 1213 ugL 436 of Asian
Americans
~01 of total
US population
34 95 in AA
01-1
PMC2682945
Cadmium Uncertain+ Uncertain 467 10 in
smokers
17184399
DDT Any exposure All US pop
below LOD
17 76 increased
risk
8923607
Breast Cancer
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Cadmium 0580 ugg
creatinine
126 205 479 16788160
PCB 138 396 ngg
creatinine
202 316 630 27717745
PCB 187 108 ngg lipid 600 194 360 21480306
Miscellaneous Diseases
Toxin Disease Threshold Above
Threshold
Odds
Ratio
of Dz Reference PMID
Aluminum Alzheimer
Dz
01 mgL
drinking
H20
400 203 05-44 26592479
Benzene AML 100ppmyrs 1-3 320 60 PMC2903550
DDT NHL 0512 ugL 1-2 240 01 17722095
Lead ALS 238 ugdL
blood
330 181 210 25479292
Lead Brain CA 0005 ugdL 14 19 ~500 17164378
Dioxin-like
PCBs
RA 326 ngg
lipid
250 219 220 17589595
PAHs Asthma 124 ngm3 935 200 483 19221603
The Potency of Arsenic
Disease Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Bladder CA 10ugL H20 100 27 145 24889821
Pancreatic CA 1332 ugg 200 246 230 23800676
Prostate CA 1332 ugg 200 33 315 23800676
Gout 125 ugL 245 546 522 25499256
Diabetes 165 ugL 200 21 180 18714061
Arsenic (180 of Diabetes)
How it causes diabetes
bull Blocks sugar stimulating insulin secretion
bull Epigenetic inhibition of sugar regulation
Where it comes from
bull Water (gt10 of US water supplies have high levels)
bull Rice (naturally absorbs if in the water)
bull Chicken (added to make meat whiter)
Pan W-C Seow WJ Kile ML et al Association of low to moderate levels of arsenic exposure with risk of Type 2 diabetes in Bangladesh American Journal of Epidemiology 2013178(10)1563-70
Portion of Population with Toxin Load Which
Doubles Disease Risk
Toxin Disease with Doubled Risk
Polycyclic aromatic hydrocarbons Asthma 94
PCB187 Breast Cancer 60
Phthalates Diabetes 55
Lead ALS 33
Aluminum Alzheimers Disease 25
DDT ADHD 25
PCBs Diabetes 25
Dioxin-like PCBs Rheumatoid Arthritis 25
Arsenic Gout 23
Bisphenol A Diabetes 22
Cigarette smoking Lung Cancer 21
Arsenic Diabetes 20
Polycyclic aromatic hydrocarbons Diabetes 20
Huge Detoxification Variability
bull CYP2C19
Proton pump inhibitors and some antidepressants
5-fold difference in activity between poor metabolizers and extensive metabolizers more so if CYP3A4 is also inhibited
Ultrarapid allele in 18 of both Swedes and Ethiopians
bull CYP2D6
Metabolizes a large number of drugs (~25)
7 of Caucasians poor metabolizers
~30 ultra rapid metabolizers in Arabian and Eastern African populations
More adverse effects in poor metabolizers and ineffective dosing in ultrarapid metabolizers
Inhibited by ginger
Desta Z et al Clinical significance of the cytochrome P450 2C19 genetic polymorphism Clin Pharmaco 2002
Sim SC et al A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug
response to proton pump inhibitors and antidepressants Clin Pharmacol Ther 2006
Wilkinson GR Drug metabolism and variability among patients in drug response N Engl J Med 2005
Kirchheiner J et al Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to
CYP2D6 duplication Pharmacogenomics J 2007
Toxin Half Lives in BloodToxin ldquoNormalrdquo (mgL) Acute Toxic (mgL) Half-Life
Arsenic 0002-007 005-025 2-4 days (CDC)
Benzene 00002 05-10 days
Cadmium 00003-00065 0015-005 16 years
Chlordane 0001 00025 3-4 days
DDTDDE 2-10 years
Dieldrin 00015 015-030 2-12 months
Ethanol 1000-2000 15hour
Lead 009 04-06 1-15 mo (2+ yrs bone)
Mercury 00015-0002 005-02 2 months (CDC)
PCBs 3-25 years
Toluene 05-3 days
Schulz M et al Therapeutic and toxic blood concentrations of nearly 1000 drugs and other xenobiotics Crit Care 2012 Jul 2616(4)R136
Bioaccumulation (POPs)
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
DDT banned in 1972 PCBs banned in 1977
Bioaccumulation (Cd)
Think BroadlyExogenous
Metals
Chemicalsbull Inorganic
bull Fluoride
bull Organic
bull POPs
bull Drugs
Particulate matter
Molds
Microbial
Radiationbull Light
bull Medical
bull Cell phone
Endogenous
Gut-derived toxins
Non-end product metabolites
Poorly detoxified hormones
Catecholamines (if SNP)
Toxins of Choice
Alcohol
Marijuana
Food constituents
High fructose corn syrup
Salt (acid-forming diet)
Wheat if zonulin (70)
Obesity Epidemic ndash POPs AND HFCS
47Bray GA Fructose should we worry Int J Obes (Lond) 2008 Dec32 Suppl 7S127-31
How Toxins Cause Damage 13
bull Increase free radical production
Cd induces production of ROS
Malathion inhibits catalase and glutathione peroxidase
Homocysteine oxidizes LDL cholesterol
bull Poison enzyme systems (compete with nutritional cofactors for binding sites)
Pb poisons delta aminolevulinic acid dehydratase
Cd inhibits catalase glutathione reductase and lowers
glutathione levels
bull Replace structural minerals
Pb displaces Ca in bone
How Toxins Cause Damage 23
bull Damage DNA
Benzene - causes chromosomal damage
Pesticides ndash fruit growers have more DNA damage
Phthalates and insecticides ndash damage sperm DNA
4-hydroxy catechol estrogen (4-OHE) damages breast DNA
bull Epigenetic dysmodulation
Higher cord blood levels of hexachlorobenzene associated
with 2x greater risk for obesity in children
bull Damage cell membranes
Common mechanism for heavy metals inactivates
membrane enzymes ion channels and pumps
How Toxins Cause Damage 33
bull Block insulin receptor sites
PCBs and phthalates
bull Highest levels associated with a 4 to 20-fold greater diabetes risk
bull Imbalance hormones many toxin examples
Arsenic
bull Disrupts thyroid hormone and retinoic acid receptors
Phthalates
bull Act as anti-androgens
bull More than 75 of the US population has measurable levels of
several phthalate metabolites in the urine
PCBs
bull Lower testosterone levels in men
Which are the Worst Toxins
bull According to the CDC
Toxicity
Population toxic load
Prevalence in toxic waste sites
bull According to clinical importance
Exposure
of disease
Ability of the body to detoxifyexcrete
Ag
en
cy
fo
r T
oxic
Su
bs
tan
ce
s a
nd
Dis
ea
se
Reg
istr
y
Pri
ori
ty L
ist
The Worst Toxins Clinically
My Rank Toxin Diseases Primary Sources
1 Arsenic Cancers diabetes gout Water chicken rice
2 DDT ADHD dementia diabetes Everywhere
3 Phthalates ADHD diabetes Soft plastics HABAs
4 PBDEs ADHD diabetes Flame retardant fabrics
5 PAHs ADHD cancers dyslipidemia Smoking charbroiling
6 PCBs Cancers diabetes MI RA Everywhere
7 Mercury Dementia ldquoSilverrdquo fillings fish
8 Lead Cardiovascular disease IQ Paint water
Glyphosate Research invalid
Conventional Laboratory Tests Reflect
Toxic Load in ldquoNormalrdquo Range
bull Surprising number show toxin exposure
CBC RBC WBC platelet count hemoglobin basophilic
stippling
Liver enzymes ALT GGTP
Inflammatory markers CRP
Lipids LDL oxLDL triglycerides
Blood sugar insulin FBS 2-hour PP
Metabolites bilirubin uric acid homocysteine 8-OHdG
Thyroid T3 T4 TSH
bull The historic ldquonormalrdquo range has been changing as the population has become more toxic
WBC Lowered by PCB and OCP Exposure
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
0
1
2
3
4
5
6
7
8
1st Quartrile 2nd Quartile 3rd Quartile 4th Quartile
WBCbull Strong inverse correlation with PCBs and OCPs and CBC
bull Linear with almost all PCBs
bull High variability with OCPs
bull Within ldquonormalrdquo range
Effects on WBC Worsen with Years
of Exposure to Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Platelet Count Decreases with Years
of Exposure tp Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Solvents Decrease Platelet Count
bull Compared workers exposed 23 hrday to those exposed most of day to toluene
bull All wore face masks and protective gear
bull Platelet count 14 lower 252 versus 216ml
bull Impairment of sympathetic nerves (OR = 413)
bull Impairment of peripheral nerves (OR = 694)
bull Positive relationship between neurological abnormalities and a self-reported neuropsychiatric measurement (r = 035-066)
Shih HT et al Subclinical abnormalities in workers with continuous low-level toluene exposure Toxicol Ind Health 2011 Sep27(8)691-9
Basophilic Stippling of Red Cells
Toxinsbull Arsenic
bull Lead
Diseasesbull Alpha-thalassemia HbH Disease
bull Beta thalassemia
bull Hereditary pyrimidine 5-nucleotidase deficiency
bull Myelodysplastic syndrome
bull Sideroblastic anemia
bull Thrombotic thrombocytopenic purpura
GGT Indirect Measure of POPsbull Glutathione is key intracellular defense against oxidative stress
bull Cellular GGT metabolizes extracellular GSH allowing precursor amino acids to be reutilized for intracellular GSH
bull Exposure to POPs induces GGT as a defensive mechanism
bull Within normal range predicts type 2 diabetes coronary heart disease hypertension stroke dyslipidemia chronic kidney disease and cancer
bull Men with GGT gt50 UI had ~26 fold risk for diabetes compared to those with lt10 Those with 40-49 had a ~20 fold risk
bull Levels within normal range occur with obesity xs alcohol cigarette smoking physical inactivity high meat low fruit and vegetable intake
bull Cumulative biomarker for environmental pollutants
Lee DH et al (2003) Gamma-glutamyltransferase and diabetesmdasha 4 year follow-up study Diabetologia 46359ndash364
Pamela A et al Serum gamma-glutamyltransferase linking together environmental pollution redox equilibria and progression of atherosclerosis Clin Chem
Lab Med 200947(12)1583-4
Lee DH et al Serum gamma-glutamyltransferase new insights about an old enzyme J Epidemiol Community Health 2009 Nov63(11)884-6
Lee DH et alSerum gamma-glutamyltransferase predicts non-fatal myocardial infarction and fatal coronary heart disease among 28838 middle-aged men and
women Eur Heart J 2006272170ndash6
Lee DH et al Gamma-glutamyltransferase and diabetes--a 4 year follow-up study Diabetologia 2003 Mar46(3)359-64
Lee DH et al Can persistent organic pollutants explain the association between serum gamma-glutamyltransferase and type 2 diabetes Diabetologia 2008
Mar51(3)402-7
GGT and Alcohol Consumption
bull GGT directly correlates with alcohol consumption
bull In a non-uniform population 40 gd will elevate GGT ~15
bull Watch for false negatives
bull Genomic variation
bull Are these the ones most
sensitive todamaged by
chemical toxins
bull Could up-regulation of GGT in light alcohol consumption be reason for benefit
0
10
20
30
40
50
60
70
80
0 200 400 600 800
Grams of Ethanol per Week
Adapted from Nagaya T et al Dose-response relationships between drinking and serum tests in Japanese men
aged 40ndash59 years Alcohol 1999 Feb 17(2) 133ndash8
GGT Correlates With Toxic Metal Levels
Lee DH et al Graded associations of blood lead and urinary cadmium concentrations with oxidative-stress-related markers in the
US population results from the third National Health and Nutrition Examination Survey Environ Health
perspect 2006 Mar114(3)350-4
GGT and Diabetes Risk
0
5
10
15
20
25
30
lt10 10-19 20-29 30-39 40-49 gt50
Dia
bete
s R
isk
GGT
bull GGT over 50 associated with tripling of death rate
bull 30-40 associated with doubling
GGT Levels
Correlate with
Risk of Death
Brenner H et al Distribution determinants and prognostic value of gamma-glutamyltransferase for all-cause
mortality in a cohort of construction workers from southern Germany Prev Med 1997 26 305ndash10
GGT From Small US Company
with Young Workers
0
10
20
30
40
50
60
0 20 40 60 80 100
GGT Data from Canadian Oil Field
Workers
0
50
100
150
200
250
300
350
400
450
lt10 10-20 20-30 30-40 40-50 50-60 60-07 70-80 80-90 90-100 100-110 110-120 gt120
GGTP
20-fold increased risk of diabetes
Uric Acid Indirect Measure of POPs
bull Poly-fluorinated hydrocarbons (PFOA and PFOS) associated
with increased serum uric acid
Lin CY et al Association among serum perfluoroalkyl chemicals glucose homeostasis and metabolic syndrome
in adolescents and adults Diabetes Care 2009 Apr32(4)702-7
Steenland K et al Association of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) with uric
acid among adults with elevated community exposure to PFOA Environ Health Perspect 2010 Feb118229-33
Steenland 2010 Open Access
ALT Indirect Measure of POPs
bull ALT (proxy marker) elevation in 104 (not including viral
hepatitis hemochromatosis or alcoholic liver disease) of
NHANES 03-04 subset
bull Risk of elevated ALT increased dose-dependently with
cadmium lead mercury and PCB exposure
bull 100 of individuals had detectable PCBs 925 mercury
and 996 had detectable lead
bull In 2005-08 prevalence of NAFLD in US was 11 a
growing cause of chronic liver disease
Cave M et al Polychlorinated biphenyls lead and mercury are associated with liver disease in American adults
NHANES 2003-2004 Environ Health Perspect 2010 Dec118(12)1735-42
Younossi ZM et al Changes in the prevalence of the most common causes of chronic liver diseases in the United
States from 1988 to 2008 Clin Gastroenterol Hepatol 2011 Jun9(6)524-530e1
Bilirubin as a Marker of POPs
bull Degree of serum bilirubin increase is prognostically significant in chronic liver dysfunction
bull Mono-ortho PCB TEQ values were found to be significantly positively associated with bilirubin (β=071 P=0008) following adjustment for multiple potential confounders
bull Bilirubin levels significantly correlated with PCBs -105-118-126 and -194
bull Smoking appears to be the biggest confounder
Dufour DR et al 2000 Diagnosis and monitoring of hepatic injury II Recommendations for use of laboratory
tests in screening diagnosis and monitoring Clin Chem 46 2050ndash68
Kumar J et al Persistent organic pollutants and liver dysfunction biomarkers in a population-based human sample
of men and women Environ Res 2014134251-256
Perf
luo
rin
ate
dP
OP
s a
nd
Co
mm
on
Blo
od
Tests
Gleason JA et al Associations of perfluorinated chemical serum concentrations and biomarkers of liver function and uric acid in the
US population (NHANES) 2007-2010 Environ Res 20151368-14
Liver Enzymes Reflect Toxic Load
bull AST ALT and GGT increase with body load of PCBs and OCPs
bull Some non-linear
bull Oxychlordanetop quartile
ALT 10
GGT 25
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
LDL-Cholesterol as Measure of POPs
bull 5-year prospective study to determine if POP levels predict future elevation in LDL-cholesterol
bull 598 subjects initially at age 70
bull Looked at 23 POPs
bull Best correlation with PCB 194
Penell J Lind L Salihovic S et al Persistent organic pollutants are related to change in circulating
lipid levels during a 5 year follow-up Environ Res 134(2014)190ndash197
oxLDL as Measure of POPs
bull 992 70-year old individuals (50 women)
bull Sum of PCBs showed strong significant positive associations with ox-LDL and significant negative associations with glutathione-related markers (GSSG and GSSGGSH)
bull A number of POPs (PCB-99 138 153 156 170 180 194 206 and 209) showed strong significant positive association with ox-LDL
Kumar J et al Influence of persistent organic pollutants on oxidative stress in population-based samples
Chemosphere 2014114303-309
Homocysteine is Increased by Pb amp Cd
Guallar E et al Confounding of the relation between homocysteine and peripheral arterial disease by lead cadmium and renal function Am J Epidemiol 2006 Apr 15163(8)700-8
Nutrient Deficiencies Accentuate
Effects of Lead on Homocysteine
bull Deficiencies in folate B6 or B12 make lead more toxic
Lee YM Et al Association of homocysteine levels with blood lead levels and micronutrients in the US general population J Prev Med Public Health 2012 Nov45(6)387-93
T4 amp T3 and PCBs
bull PCBs decrease T4 production
bull PCBs inhibit iodotyrosinedeiodinase activity
bull Study done in pregnant women which implies effect on fetus IQ
Kim S Park J Kim HJ et al Association between several persistent organic pollutants and thyroid hormone levels in serum among the pregnant women of Korea Environ Int 2013 Sep59442-8Shimizu R Yamaguchi M Uramaru N et al Structure-activity relationships of 44 halogenated compounds for iodotyrosinedeiodinase-inhibitory activity Toxicology 2013 Dec 6314(1)22-9
T4 amp T3 and PCBs
bull Not just humans being affected
bull Large study of dolphins shows exactly the same effects
Schwacke LH Zolman ES Balmer BC et al Anaemia hypothyroidism and immune suppression associated with polychlorinated biphenyl exposure in bottlenose dolphins (Tursiops truncatus) Proceed Royal Society B doi101098rspb20110665
8-OHdG
bull Oxidized nucleoside
bull Direct measure of DNA damage
bull Indirect measure of oxidative stress and toxin load
bull Correlates with
Multiple cancers
Mitochondrial damage
Rate of aging
Smoking
Several toxinsWalter Crinnion ldquoTotal Toxic Loadrdquo AANP 2015
8-OHdG Correlates with Pack-Years
of Smoking
Yano T et al Significance of the urinary 8-OHdG level as an oxidative stress marker in lung cancer patients Lung Cancer
2009 Jan63(1)111-4
8-OHdG Correlates
with Mercury
Chen C et al Increased oxidative DNA damage as assessed by urinary 8-hydroxy-2-deoxyguanosine
concentrations and serum redox status in persons exposed to mercury Clin Chem 2005 Apr51(4)759-67
Toxin Effects Worse with Aging
bull Thyroid function decreases with PFOA levels
bull But only after age 63
Shrestha S Bloom MS Yucel R et al Perfluoroalkyl substances and thyroid function in older adults Environ Int 2015 Feb75206-14
Insightful 23-Year Prospective Study
1 lt 50 there is no difference between those with the lowest and highest PCBs
2 In youngest group insulin production increases in response to toxin level As expected since blocking of
insulin receptor sites by PCBs
requires more insulin
3 That adaptive ability decreases with aging
4 At age 50 all the measures show very strong toxin-dose response
Cumulative damage impairs ability to adapt
Suarez-Lopez JR et al Persistent organic pollutants in young adults and changes in glucose related metabolism over a 23-year follow-up Environ Res 2015 Feb137485-94
Recommendations
High body toxic load
GGT gt 25
Uric acid gt 50 mgdl
ALT gt30 UL
Bilirubin gt08 mgdl
CBC lt 6000
Platelet lt 250000
Low T3 andor T4
Monitor Total Toxic Load
8-OHdG gt4
ldquoUnconventionalrdquo Laboratory Tests
bull Challenge testing
bull Hair analysis
bull Direct measures of solvents and POPs in blood urine adipose tissue
Evaluation of Metal Exposure ndash Provocation
bull Provocation ndash the use of a chelating agent ndash before urine collection often done clinically but several limitations
No ldquoofficialrdquo reference range for provoked urine
Most chelating agents do not extract metals from all tissues thus
does not necessarily represent total body burden
bull Example Brain is one of the main target organs for both elemental and organic
mercury yet agents do not chelate brain mercury
bull Despite limitations widely used and advocated by clinicians in part to see efficacy of chelating agent as a guide to treatment and based on empirical evidence
Rooney JP The role of thiols dithiols nutritional factors and interacting ligands in the toxicology of mercury
Toxicology 2007
Is Challenge Testing Valid
bull Poor correlations of standard tests for mercury
bull Unpublished research from corporate wellness project
bull Published amalgam number correlation
bull Published fish consumption correlation
What We Found In Canada
bull Deviations from the mean of 14 29 and 91 respectively
bull DMPS is spreading distribution suggesting that it is better at differentiating mercury body load
bull Some VERY high
Hg Assessment Correlations
bull Extensive measurements in 65 Whole blood Hg
Oral DMPS challenge
Amalgam surfaces
bull Correlations Whole blood w pre urine r = 040
Whole blood w post urine r = 057
Pre urine w post urine r = 068
Amalgams w pre urine r = 026
Amalgams w whole blood r = 036
Amalgams with post urine 044
bull Clear documentation that
challenge testing is better00
100
200
300
400
500
600
0 10 20 30 40 50
Po
st
Uri
ne H
g u
gg
Number of amalgams
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
POPs - Prediabetes
bull Over 1200 participants fasting
glucose and OGTT performed
with serum levels of 5 POPs
bull All individual POPs tested were
associated with progressive
increase in prevalence of
prediabetes
bull More than triple prevalence of
prediabetes seen in those in the
5th quartile with a synergistic
effect from 5 POPs
Ukropec J et al High prevalence of prediabetes and diabetes in a population exposed to high levels of an organochlorine cocktail
Diabetologia 2010 May53(5)899-906
POPs and Diabetes Risk
Graph httpwwwourstolenfutureorgNewScienceobesity20062006-0715leeetalhtml
Data Lee DH Lee IK Song K et al A strong dose-response relation between serum
concentrations of persistent organic pollutants and diabetes results from the National Health and
Examination Survey 1999-2002 Diabetes Care 2006 Jul29(7)1638-44
Toxic Load and Disease Risk
References for Toxins and Disease Risk
Converting Disease Risk to Caused
Attributable Fraction Calculation
p = underlying prevalence of risk factor in the population
rr = relative risk (risk of contracting a disease in an exposed population divided by the risk of contracting the disease in an unexposed population)
AF = of disease due to the toxin
Levin M The occurrence of lung cancer in man Acta Unio Int Contra Cancrum 1953 9 531-541
Example Smoking and Lung Cancer
B = 5Number of smokers
who contract Lung Cancer notdue to smoking
A = 5Number of smokerswho contract Lung
Cancer due to smoking
C = 15Number of
nonsmokerswho contract Lung Cancer
0
2
4
6
8
10
12
14
16
Smokers (N=100) Nonsmokers (N=300)Num
ber
of
people
who c
ontr
act
Lung C
ancer
per
year
Baseline Additional due to smoking
Number of smokers and nonsmokers who contract lung cancer
Our Process In Summary
1 Determine threshold for increased disease risk
2 Determine of population above threshold
3 Determine incidence of disease (OR) in those above threshold
4 Determine incidence of disease in ldquounexposed populationrdquo
5 Calculate AF ie of disease
As whole population is exposed probably UNDERESTIMATES of disease
To
xic
ity H
as B
eco
me t
he N
ew
ldquoN
orm
alrdquo
Toxin Type Use Threshold for
disease
association
of US
above
threshold
Disease Associations
Chlordane OC pesticide Termites corn citrus lawns
gardens
145ngg lipid 63
(diabetes)
Diabetes (20)
BPA Plasticizer Water bottles canned food
water pipes thermal sales
receipts
48 men 51
women (urine
ngmL)
~18
(diabetes)
Diabetes hypertension
Octachloro
dibenzo-p-
dioxin
(OCDD)
Polychlorinated
dibenzo-p-
dioxin
Incineration or burning of
waste bleaching processes
used in pulp and paper mills
1010 pgg
lipid (highest
quartile)
10-25
(hypertensio
n)
Hypertension (79 for
women highest
quartile) diabetes (21)
obesity learning
disability (272)
MEP
(mono-
ethyl
phthalate)
Phthalate
(plasticizer
fragrance)
Toothbrushes automobile
parts tools toys and food
packaging aspirin
cosmetics food packaging
gt175 ngmL
(urine)
~60
(diabetes)
Diabetes (148) lower
BMD obesity
pp-DDE DDT
metabolite (OC
pesticide)
Agricultural crops 1560ngg
lipid
25
(diabetes)
Diabetes (23-43)
early menopause
impaired cognitive
function (2-3x 65x in
highest 5th percentile)
peripheral arterial
disease
Arsenic Toxic metal Miningsmelting wood
preservative pesticides
74ugL total
arsenic (urine)
20
(diabetes)
Cancers diabetes (26-
46) dyslipidemia gout
AF OR Prevalence
Rosen L An intuitive approach to understanding the attributable fraction of disease due to a risk factor the case of smoking Int J Environ Res Public Health 2013 Jul 1610(7)2932-43
Smoking Lung cancer
Arsenic Gout in women
BPA Diabetes
Status of Our Research
bull 26 toxins and toxin classes eg lead mercury BPA OCPs
100s of chemicals and POPs in some classes
bull 18 cancers
bull 24 chronic diseases
bull 1092 cells in spreadsheet
Large Personal Ongoing Research Investment
Huge Amount of Research Work
Toxins StudiedAluminum
Arsenic
Cadmium
Fluoride
Lead
Manganese
Mercury
Acrylamide
Acrylonitrile
Benzene
Bisphenol A (BPA)
Chloroform
DDT
Dioxins
Glyphosate
Organochlorine pesticides (OCPs)
Organophosphate pesticides
Parabens
Phthalates
Polybrominated diphenyl ethers (PBDEs)
Polycyclic aromatic hydrocarbons (PAHs)
Polychlorinated biphenols (PCBs)
Vinyl chloride
Diseases Studied
ADHD
Alzheimers Disease
ALS
Angiosarcoma
Anxiety
Atopic Conditions
Diabetes
Dyslipidemia
Gout
Fetal Abnormalities
Hyperuricemia
Infertility
Juvenile IQ
Cancer Bladder
Cancer Bone
Cancer Brain
Cancer Breast
Cancer Cervix
Cancer Colorectal
Cancer Endometrial
Cancer Head amp Neck
Cancer Liver
Cancer Lung
Cancer Lymph amp Blood
Cancer Ovarian
Cancer Pancreatic
Cancer Prostate
Cancer Renal
Cancer Skin
Cancer Testicular
Cancer Thyroid
Juvenile Obesity
Metabolic Syndrome
Mitochondrial dysfunction
Myocardial Infarction
Obstructive Lung Disease
Osteoporosis
Peripheral Artery Disease
Peripheral Neuropathy
Prediabetes
Renal Disease
Rheumatoid Arthritis
Thyroid Dysfunction
OC
Ps
Th
rou
gh
ou
t th
e W
orl
d
Rathore HS Nollet LML Pesticides Evaluation of Environmental Pollution CRC Press
2012 page 562
Threshold ndash Threshold exposure at which there is an increased risk of disease outcome
Above Threshold ndash Percentage of the population with higher exposure than the threshold
Odds Ratio ndash Increased disease risk in those above threshold
of Dz ndash Percent contribution of the toxin to that disease outcome
How to Interpret the Following Slides
Attention Deficit Hyperactivity Disorder
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
DDT 126 ngg
serum (pp-
DDE)
250 18 166 20106937
Lead 23 ugdL 13 254 20 27659349
Mercury 16 24952233
Organophosphate
pesticides
20
Polycyclic
Aromatic
Hydrocarbons
227 ngm3 940 125 190 22440811
PCBs 104 ngg
serum (sum
of 50 PCBs)
250 176 160 20106937
DiabetesToxin Threshold Above
Threshold
Odds
Ratio
of Dz Reference
PMID
Arsenic 165 ugL 200 21 180 18714061
BPA 28 ugL 280 145 112 26119400
DDE 545 ngg serum
(pp-DDE)
200 230 31 26119400
Dioxins2 pgg lipid 50 191 43
26119400
PCBs104 ngg (PCB 153) 250 239 258
26119400
Phthalates175 ugL 690 148 249
26119400
1-naphthalene 167 ugdL 152 182 111 26340343
2-napthalene 414 ugdL 550 224 214 26340343
1-phenanthrene 167 ngL 570 178 151 26340343
1-pyrene 85 ngL 660 180 174 26340343
Lung Cancer
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Acrylonitrile Uncertain Uncertain 125 25
occupational
exposure
17114112
Arsenic 1213 ugL 436 of Asian
Americans
~01 of total
US population
34 95 in AA
01-1
PMC2682945
Cadmium Uncertain+ Uncertain 467 10 in
smokers
17184399
DDT Any exposure All US pop
below LOD
17 76 increased
risk
8923607
Breast Cancer
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Cadmium 0580 ugg
creatinine
126 205 479 16788160
PCB 138 396 ngg
creatinine
202 316 630 27717745
PCB 187 108 ngg lipid 600 194 360 21480306
Miscellaneous Diseases
Toxin Disease Threshold Above
Threshold
Odds
Ratio
of Dz Reference PMID
Aluminum Alzheimer
Dz
01 mgL
drinking
H20
400 203 05-44 26592479
Benzene AML 100ppmyrs 1-3 320 60 PMC2903550
DDT NHL 0512 ugL 1-2 240 01 17722095
Lead ALS 238 ugdL
blood
330 181 210 25479292
Lead Brain CA 0005 ugdL 14 19 ~500 17164378
Dioxin-like
PCBs
RA 326 ngg
lipid
250 219 220 17589595
PAHs Asthma 124 ngm3 935 200 483 19221603
The Potency of Arsenic
Disease Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Bladder CA 10ugL H20 100 27 145 24889821
Pancreatic CA 1332 ugg 200 246 230 23800676
Prostate CA 1332 ugg 200 33 315 23800676
Gout 125 ugL 245 546 522 25499256
Diabetes 165 ugL 200 21 180 18714061
Arsenic (180 of Diabetes)
How it causes diabetes
bull Blocks sugar stimulating insulin secretion
bull Epigenetic inhibition of sugar regulation
Where it comes from
bull Water (gt10 of US water supplies have high levels)
bull Rice (naturally absorbs if in the water)
bull Chicken (added to make meat whiter)
Pan W-C Seow WJ Kile ML et al Association of low to moderate levels of arsenic exposure with risk of Type 2 diabetes in Bangladesh American Journal of Epidemiology 2013178(10)1563-70
Portion of Population with Toxin Load Which
Doubles Disease Risk
Toxin Disease with Doubled Risk
Polycyclic aromatic hydrocarbons Asthma 94
PCB187 Breast Cancer 60
Phthalates Diabetes 55
Lead ALS 33
Aluminum Alzheimers Disease 25
DDT ADHD 25
PCBs Diabetes 25
Dioxin-like PCBs Rheumatoid Arthritis 25
Arsenic Gout 23
Bisphenol A Diabetes 22
Cigarette smoking Lung Cancer 21
Arsenic Diabetes 20
Polycyclic aromatic hydrocarbons Diabetes 20
Huge Detoxification Variability
bull CYP2C19
Proton pump inhibitors and some antidepressants
5-fold difference in activity between poor metabolizers and extensive metabolizers more so if CYP3A4 is also inhibited
Ultrarapid allele in 18 of both Swedes and Ethiopians
bull CYP2D6
Metabolizes a large number of drugs (~25)
7 of Caucasians poor metabolizers
~30 ultra rapid metabolizers in Arabian and Eastern African populations
More adverse effects in poor metabolizers and ineffective dosing in ultrarapid metabolizers
Inhibited by ginger
Desta Z et al Clinical significance of the cytochrome P450 2C19 genetic polymorphism Clin Pharmaco 2002
Sim SC et al A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug
response to proton pump inhibitors and antidepressants Clin Pharmacol Ther 2006
Wilkinson GR Drug metabolism and variability among patients in drug response N Engl J Med 2005
Kirchheiner J et al Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to
CYP2D6 duplication Pharmacogenomics J 2007
Toxin Half Lives in BloodToxin ldquoNormalrdquo (mgL) Acute Toxic (mgL) Half-Life
Arsenic 0002-007 005-025 2-4 days (CDC)
Benzene 00002 05-10 days
Cadmium 00003-00065 0015-005 16 years
Chlordane 0001 00025 3-4 days
DDTDDE 2-10 years
Dieldrin 00015 015-030 2-12 months
Ethanol 1000-2000 15hour
Lead 009 04-06 1-15 mo (2+ yrs bone)
Mercury 00015-0002 005-02 2 months (CDC)
PCBs 3-25 years
Toluene 05-3 days
Schulz M et al Therapeutic and toxic blood concentrations of nearly 1000 drugs and other xenobiotics Crit Care 2012 Jul 2616(4)R136
Bioaccumulation (POPs)
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
DDT banned in 1972 PCBs banned in 1977
Bioaccumulation (Cd)
Think BroadlyExogenous
Metals
Chemicalsbull Inorganic
bull Fluoride
bull Organic
bull POPs
bull Drugs
Particulate matter
Molds
Microbial
Radiationbull Light
bull Medical
bull Cell phone
Endogenous
Gut-derived toxins
Non-end product metabolites
Poorly detoxified hormones
Catecholamines (if SNP)
Toxins of Choice
Alcohol
Marijuana
Food constituents
High fructose corn syrup
Salt (acid-forming diet)
Wheat if zonulin (70)
Obesity Epidemic ndash POPs AND HFCS
47Bray GA Fructose should we worry Int J Obes (Lond) 2008 Dec32 Suppl 7S127-31
How Toxins Cause Damage 13
bull Increase free radical production
Cd induces production of ROS
Malathion inhibits catalase and glutathione peroxidase
Homocysteine oxidizes LDL cholesterol
bull Poison enzyme systems (compete with nutritional cofactors for binding sites)
Pb poisons delta aminolevulinic acid dehydratase
Cd inhibits catalase glutathione reductase and lowers
glutathione levels
bull Replace structural minerals
Pb displaces Ca in bone
How Toxins Cause Damage 23
bull Damage DNA
Benzene - causes chromosomal damage
Pesticides ndash fruit growers have more DNA damage
Phthalates and insecticides ndash damage sperm DNA
4-hydroxy catechol estrogen (4-OHE) damages breast DNA
bull Epigenetic dysmodulation
Higher cord blood levels of hexachlorobenzene associated
with 2x greater risk for obesity in children
bull Damage cell membranes
Common mechanism for heavy metals inactivates
membrane enzymes ion channels and pumps
How Toxins Cause Damage 33
bull Block insulin receptor sites
PCBs and phthalates
bull Highest levels associated with a 4 to 20-fold greater diabetes risk
bull Imbalance hormones many toxin examples
Arsenic
bull Disrupts thyroid hormone and retinoic acid receptors
Phthalates
bull Act as anti-androgens
bull More than 75 of the US population has measurable levels of
several phthalate metabolites in the urine
PCBs
bull Lower testosterone levels in men
Which are the Worst Toxins
bull According to the CDC
Toxicity
Population toxic load
Prevalence in toxic waste sites
bull According to clinical importance
Exposure
of disease
Ability of the body to detoxifyexcrete
Ag
en
cy
fo
r T
oxic
Su
bs
tan
ce
s a
nd
Dis
ea
se
Reg
istr
y
Pri
ori
ty L
ist
The Worst Toxins Clinically
My Rank Toxin Diseases Primary Sources
1 Arsenic Cancers diabetes gout Water chicken rice
2 DDT ADHD dementia diabetes Everywhere
3 Phthalates ADHD diabetes Soft plastics HABAs
4 PBDEs ADHD diabetes Flame retardant fabrics
5 PAHs ADHD cancers dyslipidemia Smoking charbroiling
6 PCBs Cancers diabetes MI RA Everywhere
7 Mercury Dementia ldquoSilverrdquo fillings fish
8 Lead Cardiovascular disease IQ Paint water
Glyphosate Research invalid
Conventional Laboratory Tests Reflect
Toxic Load in ldquoNormalrdquo Range
bull Surprising number show toxin exposure
CBC RBC WBC platelet count hemoglobin basophilic
stippling
Liver enzymes ALT GGTP
Inflammatory markers CRP
Lipids LDL oxLDL triglycerides
Blood sugar insulin FBS 2-hour PP
Metabolites bilirubin uric acid homocysteine 8-OHdG
Thyroid T3 T4 TSH
bull The historic ldquonormalrdquo range has been changing as the population has become more toxic
WBC Lowered by PCB and OCP Exposure
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
0
1
2
3
4
5
6
7
8
1st Quartrile 2nd Quartile 3rd Quartile 4th Quartile
WBCbull Strong inverse correlation with PCBs and OCPs and CBC
bull Linear with almost all PCBs
bull High variability with OCPs
bull Within ldquonormalrdquo range
Effects on WBC Worsen with Years
of Exposure to Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Platelet Count Decreases with Years
of Exposure tp Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Solvents Decrease Platelet Count
bull Compared workers exposed 23 hrday to those exposed most of day to toluene
bull All wore face masks and protective gear
bull Platelet count 14 lower 252 versus 216ml
bull Impairment of sympathetic nerves (OR = 413)
bull Impairment of peripheral nerves (OR = 694)
bull Positive relationship between neurological abnormalities and a self-reported neuropsychiatric measurement (r = 035-066)
Shih HT et al Subclinical abnormalities in workers with continuous low-level toluene exposure Toxicol Ind Health 2011 Sep27(8)691-9
Basophilic Stippling of Red Cells
Toxinsbull Arsenic
bull Lead
Diseasesbull Alpha-thalassemia HbH Disease
bull Beta thalassemia
bull Hereditary pyrimidine 5-nucleotidase deficiency
bull Myelodysplastic syndrome
bull Sideroblastic anemia
bull Thrombotic thrombocytopenic purpura
GGT Indirect Measure of POPsbull Glutathione is key intracellular defense against oxidative stress
bull Cellular GGT metabolizes extracellular GSH allowing precursor amino acids to be reutilized for intracellular GSH
bull Exposure to POPs induces GGT as a defensive mechanism
bull Within normal range predicts type 2 diabetes coronary heart disease hypertension stroke dyslipidemia chronic kidney disease and cancer
bull Men with GGT gt50 UI had ~26 fold risk for diabetes compared to those with lt10 Those with 40-49 had a ~20 fold risk
bull Levels within normal range occur with obesity xs alcohol cigarette smoking physical inactivity high meat low fruit and vegetable intake
bull Cumulative biomarker for environmental pollutants
Lee DH et al (2003) Gamma-glutamyltransferase and diabetesmdasha 4 year follow-up study Diabetologia 46359ndash364
Pamela A et al Serum gamma-glutamyltransferase linking together environmental pollution redox equilibria and progression of atherosclerosis Clin Chem
Lab Med 200947(12)1583-4
Lee DH et al Serum gamma-glutamyltransferase new insights about an old enzyme J Epidemiol Community Health 2009 Nov63(11)884-6
Lee DH et alSerum gamma-glutamyltransferase predicts non-fatal myocardial infarction and fatal coronary heart disease among 28838 middle-aged men and
women Eur Heart J 2006272170ndash6
Lee DH et al Gamma-glutamyltransferase and diabetes--a 4 year follow-up study Diabetologia 2003 Mar46(3)359-64
Lee DH et al Can persistent organic pollutants explain the association between serum gamma-glutamyltransferase and type 2 diabetes Diabetologia 2008
Mar51(3)402-7
GGT and Alcohol Consumption
bull GGT directly correlates with alcohol consumption
bull In a non-uniform population 40 gd will elevate GGT ~15
bull Watch for false negatives
bull Genomic variation
bull Are these the ones most
sensitive todamaged by
chemical toxins
bull Could up-regulation of GGT in light alcohol consumption be reason for benefit
0
10
20
30
40
50
60
70
80
0 200 400 600 800
Grams of Ethanol per Week
Adapted from Nagaya T et al Dose-response relationships between drinking and serum tests in Japanese men
aged 40ndash59 years Alcohol 1999 Feb 17(2) 133ndash8
GGT Correlates With Toxic Metal Levels
Lee DH et al Graded associations of blood lead and urinary cadmium concentrations with oxidative-stress-related markers in the
US population results from the third National Health and Nutrition Examination Survey Environ Health
perspect 2006 Mar114(3)350-4
GGT and Diabetes Risk
0
5
10
15
20
25
30
lt10 10-19 20-29 30-39 40-49 gt50
Dia
bete
s R
isk
GGT
bull GGT over 50 associated with tripling of death rate
bull 30-40 associated with doubling
GGT Levels
Correlate with
Risk of Death
Brenner H et al Distribution determinants and prognostic value of gamma-glutamyltransferase for all-cause
mortality in a cohort of construction workers from southern Germany Prev Med 1997 26 305ndash10
GGT From Small US Company
with Young Workers
0
10
20
30
40
50
60
0 20 40 60 80 100
GGT Data from Canadian Oil Field
Workers
0
50
100
150
200
250
300
350
400
450
lt10 10-20 20-30 30-40 40-50 50-60 60-07 70-80 80-90 90-100 100-110 110-120 gt120
GGTP
20-fold increased risk of diabetes
Uric Acid Indirect Measure of POPs
bull Poly-fluorinated hydrocarbons (PFOA and PFOS) associated
with increased serum uric acid
Lin CY et al Association among serum perfluoroalkyl chemicals glucose homeostasis and metabolic syndrome
in adolescents and adults Diabetes Care 2009 Apr32(4)702-7
Steenland K et al Association of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) with uric
acid among adults with elevated community exposure to PFOA Environ Health Perspect 2010 Feb118229-33
Steenland 2010 Open Access
ALT Indirect Measure of POPs
bull ALT (proxy marker) elevation in 104 (not including viral
hepatitis hemochromatosis or alcoholic liver disease) of
NHANES 03-04 subset
bull Risk of elevated ALT increased dose-dependently with
cadmium lead mercury and PCB exposure
bull 100 of individuals had detectable PCBs 925 mercury
and 996 had detectable lead
bull In 2005-08 prevalence of NAFLD in US was 11 a
growing cause of chronic liver disease
Cave M et al Polychlorinated biphenyls lead and mercury are associated with liver disease in American adults
NHANES 2003-2004 Environ Health Perspect 2010 Dec118(12)1735-42
Younossi ZM et al Changes in the prevalence of the most common causes of chronic liver diseases in the United
States from 1988 to 2008 Clin Gastroenterol Hepatol 2011 Jun9(6)524-530e1
Bilirubin as a Marker of POPs
bull Degree of serum bilirubin increase is prognostically significant in chronic liver dysfunction
bull Mono-ortho PCB TEQ values were found to be significantly positively associated with bilirubin (β=071 P=0008) following adjustment for multiple potential confounders
bull Bilirubin levels significantly correlated with PCBs -105-118-126 and -194
bull Smoking appears to be the biggest confounder
Dufour DR et al 2000 Diagnosis and monitoring of hepatic injury II Recommendations for use of laboratory
tests in screening diagnosis and monitoring Clin Chem 46 2050ndash68
Kumar J et al Persistent organic pollutants and liver dysfunction biomarkers in a population-based human sample
of men and women Environ Res 2014134251-256
Perf
luo
rin
ate
dP
OP
s a
nd
Co
mm
on
Blo
od
Tests
Gleason JA et al Associations of perfluorinated chemical serum concentrations and biomarkers of liver function and uric acid in the
US population (NHANES) 2007-2010 Environ Res 20151368-14
Liver Enzymes Reflect Toxic Load
bull AST ALT and GGT increase with body load of PCBs and OCPs
bull Some non-linear
bull Oxychlordanetop quartile
ALT 10
GGT 25
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
LDL-Cholesterol as Measure of POPs
bull 5-year prospective study to determine if POP levels predict future elevation in LDL-cholesterol
bull 598 subjects initially at age 70
bull Looked at 23 POPs
bull Best correlation with PCB 194
Penell J Lind L Salihovic S et al Persistent organic pollutants are related to change in circulating
lipid levels during a 5 year follow-up Environ Res 134(2014)190ndash197
oxLDL as Measure of POPs
bull 992 70-year old individuals (50 women)
bull Sum of PCBs showed strong significant positive associations with ox-LDL and significant negative associations with glutathione-related markers (GSSG and GSSGGSH)
bull A number of POPs (PCB-99 138 153 156 170 180 194 206 and 209) showed strong significant positive association with ox-LDL
Kumar J et al Influence of persistent organic pollutants on oxidative stress in population-based samples
Chemosphere 2014114303-309
Homocysteine is Increased by Pb amp Cd
Guallar E et al Confounding of the relation between homocysteine and peripheral arterial disease by lead cadmium and renal function Am J Epidemiol 2006 Apr 15163(8)700-8
Nutrient Deficiencies Accentuate
Effects of Lead on Homocysteine
bull Deficiencies in folate B6 or B12 make lead more toxic
Lee YM Et al Association of homocysteine levels with blood lead levels and micronutrients in the US general population J Prev Med Public Health 2012 Nov45(6)387-93
T4 amp T3 and PCBs
bull PCBs decrease T4 production
bull PCBs inhibit iodotyrosinedeiodinase activity
bull Study done in pregnant women which implies effect on fetus IQ
Kim S Park J Kim HJ et al Association between several persistent organic pollutants and thyroid hormone levels in serum among the pregnant women of Korea Environ Int 2013 Sep59442-8Shimizu R Yamaguchi M Uramaru N et al Structure-activity relationships of 44 halogenated compounds for iodotyrosinedeiodinase-inhibitory activity Toxicology 2013 Dec 6314(1)22-9
T4 amp T3 and PCBs
bull Not just humans being affected
bull Large study of dolphins shows exactly the same effects
Schwacke LH Zolman ES Balmer BC et al Anaemia hypothyroidism and immune suppression associated with polychlorinated biphenyl exposure in bottlenose dolphins (Tursiops truncatus) Proceed Royal Society B doi101098rspb20110665
8-OHdG
bull Oxidized nucleoside
bull Direct measure of DNA damage
bull Indirect measure of oxidative stress and toxin load
bull Correlates with
Multiple cancers
Mitochondrial damage
Rate of aging
Smoking
Several toxinsWalter Crinnion ldquoTotal Toxic Loadrdquo AANP 2015
8-OHdG Correlates with Pack-Years
of Smoking
Yano T et al Significance of the urinary 8-OHdG level as an oxidative stress marker in lung cancer patients Lung Cancer
2009 Jan63(1)111-4
8-OHdG Correlates
with Mercury
Chen C et al Increased oxidative DNA damage as assessed by urinary 8-hydroxy-2-deoxyguanosine
concentrations and serum redox status in persons exposed to mercury Clin Chem 2005 Apr51(4)759-67
Toxin Effects Worse with Aging
bull Thyroid function decreases with PFOA levels
bull But only after age 63
Shrestha S Bloom MS Yucel R et al Perfluoroalkyl substances and thyroid function in older adults Environ Int 2015 Feb75206-14
Insightful 23-Year Prospective Study
1 lt 50 there is no difference between those with the lowest and highest PCBs
2 In youngest group insulin production increases in response to toxin level As expected since blocking of
insulin receptor sites by PCBs
requires more insulin
3 That adaptive ability decreases with aging
4 At age 50 all the measures show very strong toxin-dose response
Cumulative damage impairs ability to adapt
Suarez-Lopez JR et al Persistent organic pollutants in young adults and changes in glucose related metabolism over a 23-year follow-up Environ Res 2015 Feb137485-94
Recommendations
High body toxic load
GGT gt 25
Uric acid gt 50 mgdl
ALT gt30 UL
Bilirubin gt08 mgdl
CBC lt 6000
Platelet lt 250000
Low T3 andor T4
Monitor Total Toxic Load
8-OHdG gt4
ldquoUnconventionalrdquo Laboratory Tests
bull Challenge testing
bull Hair analysis
bull Direct measures of solvents and POPs in blood urine adipose tissue
Evaluation of Metal Exposure ndash Provocation
bull Provocation ndash the use of a chelating agent ndash before urine collection often done clinically but several limitations
No ldquoofficialrdquo reference range for provoked urine
Most chelating agents do not extract metals from all tissues thus
does not necessarily represent total body burden
bull Example Brain is one of the main target organs for both elemental and organic
mercury yet agents do not chelate brain mercury
bull Despite limitations widely used and advocated by clinicians in part to see efficacy of chelating agent as a guide to treatment and based on empirical evidence
Rooney JP The role of thiols dithiols nutritional factors and interacting ligands in the toxicology of mercury
Toxicology 2007
Is Challenge Testing Valid
bull Poor correlations of standard tests for mercury
bull Unpublished research from corporate wellness project
bull Published amalgam number correlation
bull Published fish consumption correlation
What We Found In Canada
bull Deviations from the mean of 14 29 and 91 respectively
bull DMPS is spreading distribution suggesting that it is better at differentiating mercury body load
bull Some VERY high
Hg Assessment Correlations
bull Extensive measurements in 65 Whole blood Hg
Oral DMPS challenge
Amalgam surfaces
bull Correlations Whole blood w pre urine r = 040
Whole blood w post urine r = 057
Pre urine w post urine r = 068
Amalgams w pre urine r = 026
Amalgams w whole blood r = 036
Amalgams with post urine 044
bull Clear documentation that
challenge testing is better00
100
200
300
400
500
600
0 10 20 30 40 50
Po
st
Uri
ne H
g u
gg
Number of amalgams
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
POPs and Diabetes Risk
Graph httpwwwourstolenfutureorgNewScienceobesity20062006-0715leeetalhtml
Data Lee DH Lee IK Song K et al A strong dose-response relation between serum
concentrations of persistent organic pollutants and diabetes results from the National Health and
Examination Survey 1999-2002 Diabetes Care 2006 Jul29(7)1638-44
Toxic Load and Disease Risk
References for Toxins and Disease Risk
Converting Disease Risk to Caused
Attributable Fraction Calculation
p = underlying prevalence of risk factor in the population
rr = relative risk (risk of contracting a disease in an exposed population divided by the risk of contracting the disease in an unexposed population)
AF = of disease due to the toxin
Levin M The occurrence of lung cancer in man Acta Unio Int Contra Cancrum 1953 9 531-541
Example Smoking and Lung Cancer
B = 5Number of smokers
who contract Lung Cancer notdue to smoking
A = 5Number of smokerswho contract Lung
Cancer due to smoking
C = 15Number of
nonsmokerswho contract Lung Cancer
0
2
4
6
8
10
12
14
16
Smokers (N=100) Nonsmokers (N=300)Num
ber
of
people
who c
ontr
act
Lung C
ancer
per
year
Baseline Additional due to smoking
Number of smokers and nonsmokers who contract lung cancer
Our Process In Summary
1 Determine threshold for increased disease risk
2 Determine of population above threshold
3 Determine incidence of disease (OR) in those above threshold
4 Determine incidence of disease in ldquounexposed populationrdquo
5 Calculate AF ie of disease
As whole population is exposed probably UNDERESTIMATES of disease
To
xic
ity H
as B
eco
me t
he N
ew
ldquoN
orm
alrdquo
Toxin Type Use Threshold for
disease
association
of US
above
threshold
Disease Associations
Chlordane OC pesticide Termites corn citrus lawns
gardens
145ngg lipid 63
(diabetes)
Diabetes (20)
BPA Plasticizer Water bottles canned food
water pipes thermal sales
receipts
48 men 51
women (urine
ngmL)
~18
(diabetes)
Diabetes hypertension
Octachloro
dibenzo-p-
dioxin
(OCDD)
Polychlorinated
dibenzo-p-
dioxin
Incineration or burning of
waste bleaching processes
used in pulp and paper mills
1010 pgg
lipid (highest
quartile)
10-25
(hypertensio
n)
Hypertension (79 for
women highest
quartile) diabetes (21)
obesity learning
disability (272)
MEP
(mono-
ethyl
phthalate)
Phthalate
(plasticizer
fragrance)
Toothbrushes automobile
parts tools toys and food
packaging aspirin
cosmetics food packaging
gt175 ngmL
(urine)
~60
(diabetes)
Diabetes (148) lower
BMD obesity
pp-DDE DDT
metabolite (OC
pesticide)
Agricultural crops 1560ngg
lipid
25
(diabetes)
Diabetes (23-43)
early menopause
impaired cognitive
function (2-3x 65x in
highest 5th percentile)
peripheral arterial
disease
Arsenic Toxic metal Miningsmelting wood
preservative pesticides
74ugL total
arsenic (urine)
20
(diabetes)
Cancers diabetes (26-
46) dyslipidemia gout
AF OR Prevalence
Rosen L An intuitive approach to understanding the attributable fraction of disease due to a risk factor the case of smoking Int J Environ Res Public Health 2013 Jul 1610(7)2932-43
Smoking Lung cancer
Arsenic Gout in women
BPA Diabetes
Status of Our Research
bull 26 toxins and toxin classes eg lead mercury BPA OCPs
100s of chemicals and POPs in some classes
bull 18 cancers
bull 24 chronic diseases
bull 1092 cells in spreadsheet
Large Personal Ongoing Research Investment
Huge Amount of Research Work
Toxins StudiedAluminum
Arsenic
Cadmium
Fluoride
Lead
Manganese
Mercury
Acrylamide
Acrylonitrile
Benzene
Bisphenol A (BPA)
Chloroform
DDT
Dioxins
Glyphosate
Organochlorine pesticides (OCPs)
Organophosphate pesticides
Parabens
Phthalates
Polybrominated diphenyl ethers (PBDEs)
Polycyclic aromatic hydrocarbons (PAHs)
Polychlorinated biphenols (PCBs)
Vinyl chloride
Diseases Studied
ADHD
Alzheimers Disease
ALS
Angiosarcoma
Anxiety
Atopic Conditions
Diabetes
Dyslipidemia
Gout
Fetal Abnormalities
Hyperuricemia
Infertility
Juvenile IQ
Cancer Bladder
Cancer Bone
Cancer Brain
Cancer Breast
Cancer Cervix
Cancer Colorectal
Cancer Endometrial
Cancer Head amp Neck
Cancer Liver
Cancer Lung
Cancer Lymph amp Blood
Cancer Ovarian
Cancer Pancreatic
Cancer Prostate
Cancer Renal
Cancer Skin
Cancer Testicular
Cancer Thyroid
Juvenile Obesity
Metabolic Syndrome
Mitochondrial dysfunction
Myocardial Infarction
Obstructive Lung Disease
Osteoporosis
Peripheral Artery Disease
Peripheral Neuropathy
Prediabetes
Renal Disease
Rheumatoid Arthritis
Thyroid Dysfunction
OC
Ps
Th
rou
gh
ou
t th
e W
orl
d
Rathore HS Nollet LML Pesticides Evaluation of Environmental Pollution CRC Press
2012 page 562
Threshold ndash Threshold exposure at which there is an increased risk of disease outcome
Above Threshold ndash Percentage of the population with higher exposure than the threshold
Odds Ratio ndash Increased disease risk in those above threshold
of Dz ndash Percent contribution of the toxin to that disease outcome
How to Interpret the Following Slides
Attention Deficit Hyperactivity Disorder
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
DDT 126 ngg
serum (pp-
DDE)
250 18 166 20106937
Lead 23 ugdL 13 254 20 27659349
Mercury 16 24952233
Organophosphate
pesticides
20
Polycyclic
Aromatic
Hydrocarbons
227 ngm3 940 125 190 22440811
PCBs 104 ngg
serum (sum
of 50 PCBs)
250 176 160 20106937
DiabetesToxin Threshold Above
Threshold
Odds
Ratio
of Dz Reference
PMID
Arsenic 165 ugL 200 21 180 18714061
BPA 28 ugL 280 145 112 26119400
DDE 545 ngg serum
(pp-DDE)
200 230 31 26119400
Dioxins2 pgg lipid 50 191 43
26119400
PCBs104 ngg (PCB 153) 250 239 258
26119400
Phthalates175 ugL 690 148 249
26119400
1-naphthalene 167 ugdL 152 182 111 26340343
2-napthalene 414 ugdL 550 224 214 26340343
1-phenanthrene 167 ngL 570 178 151 26340343
1-pyrene 85 ngL 660 180 174 26340343
Lung Cancer
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Acrylonitrile Uncertain Uncertain 125 25
occupational
exposure
17114112
Arsenic 1213 ugL 436 of Asian
Americans
~01 of total
US population
34 95 in AA
01-1
PMC2682945
Cadmium Uncertain+ Uncertain 467 10 in
smokers
17184399
DDT Any exposure All US pop
below LOD
17 76 increased
risk
8923607
Breast Cancer
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Cadmium 0580 ugg
creatinine
126 205 479 16788160
PCB 138 396 ngg
creatinine
202 316 630 27717745
PCB 187 108 ngg lipid 600 194 360 21480306
Miscellaneous Diseases
Toxin Disease Threshold Above
Threshold
Odds
Ratio
of Dz Reference PMID
Aluminum Alzheimer
Dz
01 mgL
drinking
H20
400 203 05-44 26592479
Benzene AML 100ppmyrs 1-3 320 60 PMC2903550
DDT NHL 0512 ugL 1-2 240 01 17722095
Lead ALS 238 ugdL
blood
330 181 210 25479292
Lead Brain CA 0005 ugdL 14 19 ~500 17164378
Dioxin-like
PCBs
RA 326 ngg
lipid
250 219 220 17589595
PAHs Asthma 124 ngm3 935 200 483 19221603
The Potency of Arsenic
Disease Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Bladder CA 10ugL H20 100 27 145 24889821
Pancreatic CA 1332 ugg 200 246 230 23800676
Prostate CA 1332 ugg 200 33 315 23800676
Gout 125 ugL 245 546 522 25499256
Diabetes 165 ugL 200 21 180 18714061
Arsenic (180 of Diabetes)
How it causes diabetes
bull Blocks sugar stimulating insulin secretion
bull Epigenetic inhibition of sugar regulation
Where it comes from
bull Water (gt10 of US water supplies have high levels)
bull Rice (naturally absorbs if in the water)
bull Chicken (added to make meat whiter)
Pan W-C Seow WJ Kile ML et al Association of low to moderate levels of arsenic exposure with risk of Type 2 diabetes in Bangladesh American Journal of Epidemiology 2013178(10)1563-70
Portion of Population with Toxin Load Which
Doubles Disease Risk
Toxin Disease with Doubled Risk
Polycyclic aromatic hydrocarbons Asthma 94
PCB187 Breast Cancer 60
Phthalates Diabetes 55
Lead ALS 33
Aluminum Alzheimers Disease 25
DDT ADHD 25
PCBs Diabetes 25
Dioxin-like PCBs Rheumatoid Arthritis 25
Arsenic Gout 23
Bisphenol A Diabetes 22
Cigarette smoking Lung Cancer 21
Arsenic Diabetes 20
Polycyclic aromatic hydrocarbons Diabetes 20
Huge Detoxification Variability
bull CYP2C19
Proton pump inhibitors and some antidepressants
5-fold difference in activity between poor metabolizers and extensive metabolizers more so if CYP3A4 is also inhibited
Ultrarapid allele in 18 of both Swedes and Ethiopians
bull CYP2D6
Metabolizes a large number of drugs (~25)
7 of Caucasians poor metabolizers
~30 ultra rapid metabolizers in Arabian and Eastern African populations
More adverse effects in poor metabolizers and ineffective dosing in ultrarapid metabolizers
Inhibited by ginger
Desta Z et al Clinical significance of the cytochrome P450 2C19 genetic polymorphism Clin Pharmaco 2002
Sim SC et al A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug
response to proton pump inhibitors and antidepressants Clin Pharmacol Ther 2006
Wilkinson GR Drug metabolism and variability among patients in drug response N Engl J Med 2005
Kirchheiner J et al Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to
CYP2D6 duplication Pharmacogenomics J 2007
Toxin Half Lives in BloodToxin ldquoNormalrdquo (mgL) Acute Toxic (mgL) Half-Life
Arsenic 0002-007 005-025 2-4 days (CDC)
Benzene 00002 05-10 days
Cadmium 00003-00065 0015-005 16 years
Chlordane 0001 00025 3-4 days
DDTDDE 2-10 years
Dieldrin 00015 015-030 2-12 months
Ethanol 1000-2000 15hour
Lead 009 04-06 1-15 mo (2+ yrs bone)
Mercury 00015-0002 005-02 2 months (CDC)
PCBs 3-25 years
Toluene 05-3 days
Schulz M et al Therapeutic and toxic blood concentrations of nearly 1000 drugs and other xenobiotics Crit Care 2012 Jul 2616(4)R136
Bioaccumulation (POPs)
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
DDT banned in 1972 PCBs banned in 1977
Bioaccumulation (Cd)
Think BroadlyExogenous
Metals
Chemicalsbull Inorganic
bull Fluoride
bull Organic
bull POPs
bull Drugs
Particulate matter
Molds
Microbial
Radiationbull Light
bull Medical
bull Cell phone
Endogenous
Gut-derived toxins
Non-end product metabolites
Poorly detoxified hormones
Catecholamines (if SNP)
Toxins of Choice
Alcohol
Marijuana
Food constituents
High fructose corn syrup
Salt (acid-forming diet)
Wheat if zonulin (70)
Obesity Epidemic ndash POPs AND HFCS
47Bray GA Fructose should we worry Int J Obes (Lond) 2008 Dec32 Suppl 7S127-31
How Toxins Cause Damage 13
bull Increase free radical production
Cd induces production of ROS
Malathion inhibits catalase and glutathione peroxidase
Homocysteine oxidizes LDL cholesterol
bull Poison enzyme systems (compete with nutritional cofactors for binding sites)
Pb poisons delta aminolevulinic acid dehydratase
Cd inhibits catalase glutathione reductase and lowers
glutathione levels
bull Replace structural minerals
Pb displaces Ca in bone
How Toxins Cause Damage 23
bull Damage DNA
Benzene - causes chromosomal damage
Pesticides ndash fruit growers have more DNA damage
Phthalates and insecticides ndash damage sperm DNA
4-hydroxy catechol estrogen (4-OHE) damages breast DNA
bull Epigenetic dysmodulation
Higher cord blood levels of hexachlorobenzene associated
with 2x greater risk for obesity in children
bull Damage cell membranes
Common mechanism for heavy metals inactivates
membrane enzymes ion channels and pumps
How Toxins Cause Damage 33
bull Block insulin receptor sites
PCBs and phthalates
bull Highest levels associated with a 4 to 20-fold greater diabetes risk
bull Imbalance hormones many toxin examples
Arsenic
bull Disrupts thyroid hormone and retinoic acid receptors
Phthalates
bull Act as anti-androgens
bull More than 75 of the US population has measurable levels of
several phthalate metabolites in the urine
PCBs
bull Lower testosterone levels in men
Which are the Worst Toxins
bull According to the CDC
Toxicity
Population toxic load
Prevalence in toxic waste sites
bull According to clinical importance
Exposure
of disease
Ability of the body to detoxifyexcrete
Ag
en
cy
fo
r T
oxic
Su
bs
tan
ce
s a
nd
Dis
ea
se
Reg
istr
y
Pri
ori
ty L
ist
The Worst Toxins Clinically
My Rank Toxin Diseases Primary Sources
1 Arsenic Cancers diabetes gout Water chicken rice
2 DDT ADHD dementia diabetes Everywhere
3 Phthalates ADHD diabetes Soft plastics HABAs
4 PBDEs ADHD diabetes Flame retardant fabrics
5 PAHs ADHD cancers dyslipidemia Smoking charbroiling
6 PCBs Cancers diabetes MI RA Everywhere
7 Mercury Dementia ldquoSilverrdquo fillings fish
8 Lead Cardiovascular disease IQ Paint water
Glyphosate Research invalid
Conventional Laboratory Tests Reflect
Toxic Load in ldquoNormalrdquo Range
bull Surprising number show toxin exposure
CBC RBC WBC platelet count hemoglobin basophilic
stippling
Liver enzymes ALT GGTP
Inflammatory markers CRP
Lipids LDL oxLDL triglycerides
Blood sugar insulin FBS 2-hour PP
Metabolites bilirubin uric acid homocysteine 8-OHdG
Thyroid T3 T4 TSH
bull The historic ldquonormalrdquo range has been changing as the population has become more toxic
WBC Lowered by PCB and OCP Exposure
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
0
1
2
3
4
5
6
7
8
1st Quartrile 2nd Quartile 3rd Quartile 4th Quartile
WBCbull Strong inverse correlation with PCBs and OCPs and CBC
bull Linear with almost all PCBs
bull High variability with OCPs
bull Within ldquonormalrdquo range
Effects on WBC Worsen with Years
of Exposure to Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Platelet Count Decreases with Years
of Exposure tp Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Solvents Decrease Platelet Count
bull Compared workers exposed 23 hrday to those exposed most of day to toluene
bull All wore face masks and protective gear
bull Platelet count 14 lower 252 versus 216ml
bull Impairment of sympathetic nerves (OR = 413)
bull Impairment of peripheral nerves (OR = 694)
bull Positive relationship between neurological abnormalities and a self-reported neuropsychiatric measurement (r = 035-066)
Shih HT et al Subclinical abnormalities in workers with continuous low-level toluene exposure Toxicol Ind Health 2011 Sep27(8)691-9
Basophilic Stippling of Red Cells
Toxinsbull Arsenic
bull Lead
Diseasesbull Alpha-thalassemia HbH Disease
bull Beta thalassemia
bull Hereditary pyrimidine 5-nucleotidase deficiency
bull Myelodysplastic syndrome
bull Sideroblastic anemia
bull Thrombotic thrombocytopenic purpura
GGT Indirect Measure of POPsbull Glutathione is key intracellular defense against oxidative stress
bull Cellular GGT metabolizes extracellular GSH allowing precursor amino acids to be reutilized for intracellular GSH
bull Exposure to POPs induces GGT as a defensive mechanism
bull Within normal range predicts type 2 diabetes coronary heart disease hypertension stroke dyslipidemia chronic kidney disease and cancer
bull Men with GGT gt50 UI had ~26 fold risk for diabetes compared to those with lt10 Those with 40-49 had a ~20 fold risk
bull Levels within normal range occur with obesity xs alcohol cigarette smoking physical inactivity high meat low fruit and vegetable intake
bull Cumulative biomarker for environmental pollutants
Lee DH et al (2003) Gamma-glutamyltransferase and diabetesmdasha 4 year follow-up study Diabetologia 46359ndash364
Pamela A et al Serum gamma-glutamyltransferase linking together environmental pollution redox equilibria and progression of atherosclerosis Clin Chem
Lab Med 200947(12)1583-4
Lee DH et al Serum gamma-glutamyltransferase new insights about an old enzyme J Epidemiol Community Health 2009 Nov63(11)884-6
Lee DH et alSerum gamma-glutamyltransferase predicts non-fatal myocardial infarction and fatal coronary heart disease among 28838 middle-aged men and
women Eur Heart J 2006272170ndash6
Lee DH et al Gamma-glutamyltransferase and diabetes--a 4 year follow-up study Diabetologia 2003 Mar46(3)359-64
Lee DH et al Can persistent organic pollutants explain the association between serum gamma-glutamyltransferase and type 2 diabetes Diabetologia 2008
Mar51(3)402-7
GGT and Alcohol Consumption
bull GGT directly correlates with alcohol consumption
bull In a non-uniform population 40 gd will elevate GGT ~15
bull Watch for false negatives
bull Genomic variation
bull Are these the ones most
sensitive todamaged by
chemical toxins
bull Could up-regulation of GGT in light alcohol consumption be reason for benefit
0
10
20
30
40
50
60
70
80
0 200 400 600 800
Grams of Ethanol per Week
Adapted from Nagaya T et al Dose-response relationships between drinking and serum tests in Japanese men
aged 40ndash59 years Alcohol 1999 Feb 17(2) 133ndash8
GGT Correlates With Toxic Metal Levels
Lee DH et al Graded associations of blood lead and urinary cadmium concentrations with oxidative-stress-related markers in the
US population results from the third National Health and Nutrition Examination Survey Environ Health
perspect 2006 Mar114(3)350-4
GGT and Diabetes Risk
0
5
10
15
20
25
30
lt10 10-19 20-29 30-39 40-49 gt50
Dia
bete
s R
isk
GGT
bull GGT over 50 associated with tripling of death rate
bull 30-40 associated with doubling
GGT Levels
Correlate with
Risk of Death
Brenner H et al Distribution determinants and prognostic value of gamma-glutamyltransferase for all-cause
mortality in a cohort of construction workers from southern Germany Prev Med 1997 26 305ndash10
GGT From Small US Company
with Young Workers
0
10
20
30
40
50
60
0 20 40 60 80 100
GGT Data from Canadian Oil Field
Workers
0
50
100
150
200
250
300
350
400
450
lt10 10-20 20-30 30-40 40-50 50-60 60-07 70-80 80-90 90-100 100-110 110-120 gt120
GGTP
20-fold increased risk of diabetes
Uric Acid Indirect Measure of POPs
bull Poly-fluorinated hydrocarbons (PFOA and PFOS) associated
with increased serum uric acid
Lin CY et al Association among serum perfluoroalkyl chemicals glucose homeostasis and metabolic syndrome
in adolescents and adults Diabetes Care 2009 Apr32(4)702-7
Steenland K et al Association of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) with uric
acid among adults with elevated community exposure to PFOA Environ Health Perspect 2010 Feb118229-33
Steenland 2010 Open Access
ALT Indirect Measure of POPs
bull ALT (proxy marker) elevation in 104 (not including viral
hepatitis hemochromatosis or alcoholic liver disease) of
NHANES 03-04 subset
bull Risk of elevated ALT increased dose-dependently with
cadmium lead mercury and PCB exposure
bull 100 of individuals had detectable PCBs 925 mercury
and 996 had detectable lead
bull In 2005-08 prevalence of NAFLD in US was 11 a
growing cause of chronic liver disease
Cave M et al Polychlorinated biphenyls lead and mercury are associated with liver disease in American adults
NHANES 2003-2004 Environ Health Perspect 2010 Dec118(12)1735-42
Younossi ZM et al Changes in the prevalence of the most common causes of chronic liver diseases in the United
States from 1988 to 2008 Clin Gastroenterol Hepatol 2011 Jun9(6)524-530e1
Bilirubin as a Marker of POPs
bull Degree of serum bilirubin increase is prognostically significant in chronic liver dysfunction
bull Mono-ortho PCB TEQ values were found to be significantly positively associated with bilirubin (β=071 P=0008) following adjustment for multiple potential confounders
bull Bilirubin levels significantly correlated with PCBs -105-118-126 and -194
bull Smoking appears to be the biggest confounder
Dufour DR et al 2000 Diagnosis and monitoring of hepatic injury II Recommendations for use of laboratory
tests in screening diagnosis and monitoring Clin Chem 46 2050ndash68
Kumar J et al Persistent organic pollutants and liver dysfunction biomarkers in a population-based human sample
of men and women Environ Res 2014134251-256
Perf
luo
rin
ate
dP
OP
s a
nd
Co
mm
on
Blo
od
Tests
Gleason JA et al Associations of perfluorinated chemical serum concentrations and biomarkers of liver function and uric acid in the
US population (NHANES) 2007-2010 Environ Res 20151368-14
Liver Enzymes Reflect Toxic Load
bull AST ALT and GGT increase with body load of PCBs and OCPs
bull Some non-linear
bull Oxychlordanetop quartile
ALT 10
GGT 25
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
LDL-Cholesterol as Measure of POPs
bull 5-year prospective study to determine if POP levels predict future elevation in LDL-cholesterol
bull 598 subjects initially at age 70
bull Looked at 23 POPs
bull Best correlation with PCB 194
Penell J Lind L Salihovic S et al Persistent organic pollutants are related to change in circulating
lipid levels during a 5 year follow-up Environ Res 134(2014)190ndash197
oxLDL as Measure of POPs
bull 992 70-year old individuals (50 women)
bull Sum of PCBs showed strong significant positive associations with ox-LDL and significant negative associations with glutathione-related markers (GSSG and GSSGGSH)
bull A number of POPs (PCB-99 138 153 156 170 180 194 206 and 209) showed strong significant positive association with ox-LDL
Kumar J et al Influence of persistent organic pollutants on oxidative stress in population-based samples
Chemosphere 2014114303-309
Homocysteine is Increased by Pb amp Cd
Guallar E et al Confounding of the relation between homocysteine and peripheral arterial disease by lead cadmium and renal function Am J Epidemiol 2006 Apr 15163(8)700-8
Nutrient Deficiencies Accentuate
Effects of Lead on Homocysteine
bull Deficiencies in folate B6 or B12 make lead more toxic
Lee YM Et al Association of homocysteine levels with blood lead levels and micronutrients in the US general population J Prev Med Public Health 2012 Nov45(6)387-93
T4 amp T3 and PCBs
bull PCBs decrease T4 production
bull PCBs inhibit iodotyrosinedeiodinase activity
bull Study done in pregnant women which implies effect on fetus IQ
Kim S Park J Kim HJ et al Association between several persistent organic pollutants and thyroid hormone levels in serum among the pregnant women of Korea Environ Int 2013 Sep59442-8Shimizu R Yamaguchi M Uramaru N et al Structure-activity relationships of 44 halogenated compounds for iodotyrosinedeiodinase-inhibitory activity Toxicology 2013 Dec 6314(1)22-9
T4 amp T3 and PCBs
bull Not just humans being affected
bull Large study of dolphins shows exactly the same effects
Schwacke LH Zolman ES Balmer BC et al Anaemia hypothyroidism and immune suppression associated with polychlorinated biphenyl exposure in bottlenose dolphins (Tursiops truncatus) Proceed Royal Society B doi101098rspb20110665
8-OHdG
bull Oxidized nucleoside
bull Direct measure of DNA damage
bull Indirect measure of oxidative stress and toxin load
bull Correlates with
Multiple cancers
Mitochondrial damage
Rate of aging
Smoking
Several toxinsWalter Crinnion ldquoTotal Toxic Loadrdquo AANP 2015
8-OHdG Correlates with Pack-Years
of Smoking
Yano T et al Significance of the urinary 8-OHdG level as an oxidative stress marker in lung cancer patients Lung Cancer
2009 Jan63(1)111-4
8-OHdG Correlates
with Mercury
Chen C et al Increased oxidative DNA damage as assessed by urinary 8-hydroxy-2-deoxyguanosine
concentrations and serum redox status in persons exposed to mercury Clin Chem 2005 Apr51(4)759-67
Toxin Effects Worse with Aging
bull Thyroid function decreases with PFOA levels
bull But only after age 63
Shrestha S Bloom MS Yucel R et al Perfluoroalkyl substances and thyroid function in older adults Environ Int 2015 Feb75206-14
Insightful 23-Year Prospective Study
1 lt 50 there is no difference between those with the lowest and highest PCBs
2 In youngest group insulin production increases in response to toxin level As expected since blocking of
insulin receptor sites by PCBs
requires more insulin
3 That adaptive ability decreases with aging
4 At age 50 all the measures show very strong toxin-dose response
Cumulative damage impairs ability to adapt
Suarez-Lopez JR et al Persistent organic pollutants in young adults and changes in glucose related metabolism over a 23-year follow-up Environ Res 2015 Feb137485-94
Recommendations
High body toxic load
GGT gt 25
Uric acid gt 50 mgdl
ALT gt30 UL
Bilirubin gt08 mgdl
CBC lt 6000
Platelet lt 250000
Low T3 andor T4
Monitor Total Toxic Load
8-OHdG gt4
ldquoUnconventionalrdquo Laboratory Tests
bull Challenge testing
bull Hair analysis
bull Direct measures of solvents and POPs in blood urine adipose tissue
Evaluation of Metal Exposure ndash Provocation
bull Provocation ndash the use of a chelating agent ndash before urine collection often done clinically but several limitations
No ldquoofficialrdquo reference range for provoked urine
Most chelating agents do not extract metals from all tissues thus
does not necessarily represent total body burden
bull Example Brain is one of the main target organs for both elemental and organic
mercury yet agents do not chelate brain mercury
bull Despite limitations widely used and advocated by clinicians in part to see efficacy of chelating agent as a guide to treatment and based on empirical evidence
Rooney JP The role of thiols dithiols nutritional factors and interacting ligands in the toxicology of mercury
Toxicology 2007
Is Challenge Testing Valid
bull Poor correlations of standard tests for mercury
bull Unpublished research from corporate wellness project
bull Published amalgam number correlation
bull Published fish consumption correlation
What We Found In Canada
bull Deviations from the mean of 14 29 and 91 respectively
bull DMPS is spreading distribution suggesting that it is better at differentiating mercury body load
bull Some VERY high
Hg Assessment Correlations
bull Extensive measurements in 65 Whole blood Hg
Oral DMPS challenge
Amalgam surfaces
bull Correlations Whole blood w pre urine r = 040
Whole blood w post urine r = 057
Pre urine w post urine r = 068
Amalgams w pre urine r = 026
Amalgams w whole blood r = 036
Amalgams with post urine 044
bull Clear documentation that
challenge testing is better00
100
200
300
400
500
600
0 10 20 30 40 50
Po
st
Uri
ne H
g u
gg
Number of amalgams
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
Toxic Load and Disease Risk
References for Toxins and Disease Risk
Converting Disease Risk to Caused
Attributable Fraction Calculation
p = underlying prevalence of risk factor in the population
rr = relative risk (risk of contracting a disease in an exposed population divided by the risk of contracting the disease in an unexposed population)
AF = of disease due to the toxin
Levin M The occurrence of lung cancer in man Acta Unio Int Contra Cancrum 1953 9 531-541
Example Smoking and Lung Cancer
B = 5Number of smokers
who contract Lung Cancer notdue to smoking
A = 5Number of smokerswho contract Lung
Cancer due to smoking
C = 15Number of
nonsmokerswho contract Lung Cancer
0
2
4
6
8
10
12
14
16
Smokers (N=100) Nonsmokers (N=300)Num
ber
of
people
who c
ontr
act
Lung C
ancer
per
year
Baseline Additional due to smoking
Number of smokers and nonsmokers who contract lung cancer
Our Process In Summary
1 Determine threshold for increased disease risk
2 Determine of population above threshold
3 Determine incidence of disease (OR) in those above threshold
4 Determine incidence of disease in ldquounexposed populationrdquo
5 Calculate AF ie of disease
As whole population is exposed probably UNDERESTIMATES of disease
To
xic
ity H
as B
eco
me t
he N
ew
ldquoN
orm
alrdquo
Toxin Type Use Threshold for
disease
association
of US
above
threshold
Disease Associations
Chlordane OC pesticide Termites corn citrus lawns
gardens
145ngg lipid 63
(diabetes)
Diabetes (20)
BPA Plasticizer Water bottles canned food
water pipes thermal sales
receipts
48 men 51
women (urine
ngmL)
~18
(diabetes)
Diabetes hypertension
Octachloro
dibenzo-p-
dioxin
(OCDD)
Polychlorinated
dibenzo-p-
dioxin
Incineration or burning of
waste bleaching processes
used in pulp and paper mills
1010 pgg
lipid (highest
quartile)
10-25
(hypertensio
n)
Hypertension (79 for
women highest
quartile) diabetes (21)
obesity learning
disability (272)
MEP
(mono-
ethyl
phthalate)
Phthalate
(plasticizer
fragrance)
Toothbrushes automobile
parts tools toys and food
packaging aspirin
cosmetics food packaging
gt175 ngmL
(urine)
~60
(diabetes)
Diabetes (148) lower
BMD obesity
pp-DDE DDT
metabolite (OC
pesticide)
Agricultural crops 1560ngg
lipid
25
(diabetes)
Diabetes (23-43)
early menopause
impaired cognitive
function (2-3x 65x in
highest 5th percentile)
peripheral arterial
disease
Arsenic Toxic metal Miningsmelting wood
preservative pesticides
74ugL total
arsenic (urine)
20
(diabetes)
Cancers diabetes (26-
46) dyslipidemia gout
AF OR Prevalence
Rosen L An intuitive approach to understanding the attributable fraction of disease due to a risk factor the case of smoking Int J Environ Res Public Health 2013 Jul 1610(7)2932-43
Smoking Lung cancer
Arsenic Gout in women
BPA Diabetes
Status of Our Research
bull 26 toxins and toxin classes eg lead mercury BPA OCPs
100s of chemicals and POPs in some classes
bull 18 cancers
bull 24 chronic diseases
bull 1092 cells in spreadsheet
Large Personal Ongoing Research Investment
Huge Amount of Research Work
Toxins StudiedAluminum
Arsenic
Cadmium
Fluoride
Lead
Manganese
Mercury
Acrylamide
Acrylonitrile
Benzene
Bisphenol A (BPA)
Chloroform
DDT
Dioxins
Glyphosate
Organochlorine pesticides (OCPs)
Organophosphate pesticides
Parabens
Phthalates
Polybrominated diphenyl ethers (PBDEs)
Polycyclic aromatic hydrocarbons (PAHs)
Polychlorinated biphenols (PCBs)
Vinyl chloride
Diseases Studied
ADHD
Alzheimers Disease
ALS
Angiosarcoma
Anxiety
Atopic Conditions
Diabetes
Dyslipidemia
Gout
Fetal Abnormalities
Hyperuricemia
Infertility
Juvenile IQ
Cancer Bladder
Cancer Bone
Cancer Brain
Cancer Breast
Cancer Cervix
Cancer Colorectal
Cancer Endometrial
Cancer Head amp Neck
Cancer Liver
Cancer Lung
Cancer Lymph amp Blood
Cancer Ovarian
Cancer Pancreatic
Cancer Prostate
Cancer Renal
Cancer Skin
Cancer Testicular
Cancer Thyroid
Juvenile Obesity
Metabolic Syndrome
Mitochondrial dysfunction
Myocardial Infarction
Obstructive Lung Disease
Osteoporosis
Peripheral Artery Disease
Peripheral Neuropathy
Prediabetes
Renal Disease
Rheumatoid Arthritis
Thyroid Dysfunction
OC
Ps
Th
rou
gh
ou
t th
e W
orl
d
Rathore HS Nollet LML Pesticides Evaluation of Environmental Pollution CRC Press
2012 page 562
Threshold ndash Threshold exposure at which there is an increased risk of disease outcome
Above Threshold ndash Percentage of the population with higher exposure than the threshold
Odds Ratio ndash Increased disease risk in those above threshold
of Dz ndash Percent contribution of the toxin to that disease outcome
How to Interpret the Following Slides
Attention Deficit Hyperactivity Disorder
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
DDT 126 ngg
serum (pp-
DDE)
250 18 166 20106937
Lead 23 ugdL 13 254 20 27659349
Mercury 16 24952233
Organophosphate
pesticides
20
Polycyclic
Aromatic
Hydrocarbons
227 ngm3 940 125 190 22440811
PCBs 104 ngg
serum (sum
of 50 PCBs)
250 176 160 20106937
DiabetesToxin Threshold Above
Threshold
Odds
Ratio
of Dz Reference
PMID
Arsenic 165 ugL 200 21 180 18714061
BPA 28 ugL 280 145 112 26119400
DDE 545 ngg serum
(pp-DDE)
200 230 31 26119400
Dioxins2 pgg lipid 50 191 43
26119400
PCBs104 ngg (PCB 153) 250 239 258
26119400
Phthalates175 ugL 690 148 249
26119400
1-naphthalene 167 ugdL 152 182 111 26340343
2-napthalene 414 ugdL 550 224 214 26340343
1-phenanthrene 167 ngL 570 178 151 26340343
1-pyrene 85 ngL 660 180 174 26340343
Lung Cancer
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Acrylonitrile Uncertain Uncertain 125 25
occupational
exposure
17114112
Arsenic 1213 ugL 436 of Asian
Americans
~01 of total
US population
34 95 in AA
01-1
PMC2682945
Cadmium Uncertain+ Uncertain 467 10 in
smokers
17184399
DDT Any exposure All US pop
below LOD
17 76 increased
risk
8923607
Breast Cancer
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Cadmium 0580 ugg
creatinine
126 205 479 16788160
PCB 138 396 ngg
creatinine
202 316 630 27717745
PCB 187 108 ngg lipid 600 194 360 21480306
Miscellaneous Diseases
Toxin Disease Threshold Above
Threshold
Odds
Ratio
of Dz Reference PMID
Aluminum Alzheimer
Dz
01 mgL
drinking
H20
400 203 05-44 26592479
Benzene AML 100ppmyrs 1-3 320 60 PMC2903550
DDT NHL 0512 ugL 1-2 240 01 17722095
Lead ALS 238 ugdL
blood
330 181 210 25479292
Lead Brain CA 0005 ugdL 14 19 ~500 17164378
Dioxin-like
PCBs
RA 326 ngg
lipid
250 219 220 17589595
PAHs Asthma 124 ngm3 935 200 483 19221603
The Potency of Arsenic
Disease Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Bladder CA 10ugL H20 100 27 145 24889821
Pancreatic CA 1332 ugg 200 246 230 23800676
Prostate CA 1332 ugg 200 33 315 23800676
Gout 125 ugL 245 546 522 25499256
Diabetes 165 ugL 200 21 180 18714061
Arsenic (180 of Diabetes)
How it causes diabetes
bull Blocks sugar stimulating insulin secretion
bull Epigenetic inhibition of sugar regulation
Where it comes from
bull Water (gt10 of US water supplies have high levels)
bull Rice (naturally absorbs if in the water)
bull Chicken (added to make meat whiter)
Pan W-C Seow WJ Kile ML et al Association of low to moderate levels of arsenic exposure with risk of Type 2 diabetes in Bangladesh American Journal of Epidemiology 2013178(10)1563-70
Portion of Population with Toxin Load Which
Doubles Disease Risk
Toxin Disease with Doubled Risk
Polycyclic aromatic hydrocarbons Asthma 94
PCB187 Breast Cancer 60
Phthalates Diabetes 55
Lead ALS 33
Aluminum Alzheimers Disease 25
DDT ADHD 25
PCBs Diabetes 25
Dioxin-like PCBs Rheumatoid Arthritis 25
Arsenic Gout 23
Bisphenol A Diabetes 22
Cigarette smoking Lung Cancer 21
Arsenic Diabetes 20
Polycyclic aromatic hydrocarbons Diabetes 20
Huge Detoxification Variability
bull CYP2C19
Proton pump inhibitors and some antidepressants
5-fold difference in activity between poor metabolizers and extensive metabolizers more so if CYP3A4 is also inhibited
Ultrarapid allele in 18 of both Swedes and Ethiopians
bull CYP2D6
Metabolizes a large number of drugs (~25)
7 of Caucasians poor metabolizers
~30 ultra rapid metabolizers in Arabian and Eastern African populations
More adverse effects in poor metabolizers and ineffective dosing in ultrarapid metabolizers
Inhibited by ginger
Desta Z et al Clinical significance of the cytochrome P450 2C19 genetic polymorphism Clin Pharmaco 2002
Sim SC et al A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug
response to proton pump inhibitors and antidepressants Clin Pharmacol Ther 2006
Wilkinson GR Drug metabolism and variability among patients in drug response N Engl J Med 2005
Kirchheiner J et al Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to
CYP2D6 duplication Pharmacogenomics J 2007
Toxin Half Lives in BloodToxin ldquoNormalrdquo (mgL) Acute Toxic (mgL) Half-Life
Arsenic 0002-007 005-025 2-4 days (CDC)
Benzene 00002 05-10 days
Cadmium 00003-00065 0015-005 16 years
Chlordane 0001 00025 3-4 days
DDTDDE 2-10 years
Dieldrin 00015 015-030 2-12 months
Ethanol 1000-2000 15hour
Lead 009 04-06 1-15 mo (2+ yrs bone)
Mercury 00015-0002 005-02 2 months (CDC)
PCBs 3-25 years
Toluene 05-3 days
Schulz M et al Therapeutic and toxic blood concentrations of nearly 1000 drugs and other xenobiotics Crit Care 2012 Jul 2616(4)R136
Bioaccumulation (POPs)
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
DDT banned in 1972 PCBs banned in 1977
Bioaccumulation (Cd)
Think BroadlyExogenous
Metals
Chemicalsbull Inorganic
bull Fluoride
bull Organic
bull POPs
bull Drugs
Particulate matter
Molds
Microbial
Radiationbull Light
bull Medical
bull Cell phone
Endogenous
Gut-derived toxins
Non-end product metabolites
Poorly detoxified hormones
Catecholamines (if SNP)
Toxins of Choice
Alcohol
Marijuana
Food constituents
High fructose corn syrup
Salt (acid-forming diet)
Wheat if zonulin (70)
Obesity Epidemic ndash POPs AND HFCS
47Bray GA Fructose should we worry Int J Obes (Lond) 2008 Dec32 Suppl 7S127-31
How Toxins Cause Damage 13
bull Increase free radical production
Cd induces production of ROS
Malathion inhibits catalase and glutathione peroxidase
Homocysteine oxidizes LDL cholesterol
bull Poison enzyme systems (compete with nutritional cofactors for binding sites)
Pb poisons delta aminolevulinic acid dehydratase
Cd inhibits catalase glutathione reductase and lowers
glutathione levels
bull Replace structural minerals
Pb displaces Ca in bone
How Toxins Cause Damage 23
bull Damage DNA
Benzene - causes chromosomal damage
Pesticides ndash fruit growers have more DNA damage
Phthalates and insecticides ndash damage sperm DNA
4-hydroxy catechol estrogen (4-OHE) damages breast DNA
bull Epigenetic dysmodulation
Higher cord blood levels of hexachlorobenzene associated
with 2x greater risk for obesity in children
bull Damage cell membranes
Common mechanism for heavy metals inactivates
membrane enzymes ion channels and pumps
How Toxins Cause Damage 33
bull Block insulin receptor sites
PCBs and phthalates
bull Highest levels associated with a 4 to 20-fold greater diabetes risk
bull Imbalance hormones many toxin examples
Arsenic
bull Disrupts thyroid hormone and retinoic acid receptors
Phthalates
bull Act as anti-androgens
bull More than 75 of the US population has measurable levels of
several phthalate metabolites in the urine
PCBs
bull Lower testosterone levels in men
Which are the Worst Toxins
bull According to the CDC
Toxicity
Population toxic load
Prevalence in toxic waste sites
bull According to clinical importance
Exposure
of disease
Ability of the body to detoxifyexcrete
Ag
en
cy
fo
r T
oxic
Su
bs
tan
ce
s a
nd
Dis
ea
se
Reg
istr
y
Pri
ori
ty L
ist
The Worst Toxins Clinically
My Rank Toxin Diseases Primary Sources
1 Arsenic Cancers diabetes gout Water chicken rice
2 DDT ADHD dementia diabetes Everywhere
3 Phthalates ADHD diabetes Soft plastics HABAs
4 PBDEs ADHD diabetes Flame retardant fabrics
5 PAHs ADHD cancers dyslipidemia Smoking charbroiling
6 PCBs Cancers diabetes MI RA Everywhere
7 Mercury Dementia ldquoSilverrdquo fillings fish
8 Lead Cardiovascular disease IQ Paint water
Glyphosate Research invalid
Conventional Laboratory Tests Reflect
Toxic Load in ldquoNormalrdquo Range
bull Surprising number show toxin exposure
CBC RBC WBC platelet count hemoglobin basophilic
stippling
Liver enzymes ALT GGTP
Inflammatory markers CRP
Lipids LDL oxLDL triglycerides
Blood sugar insulin FBS 2-hour PP
Metabolites bilirubin uric acid homocysteine 8-OHdG
Thyroid T3 T4 TSH
bull The historic ldquonormalrdquo range has been changing as the population has become more toxic
WBC Lowered by PCB and OCP Exposure
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
0
1
2
3
4
5
6
7
8
1st Quartrile 2nd Quartile 3rd Quartile 4th Quartile
WBCbull Strong inverse correlation with PCBs and OCPs and CBC
bull Linear with almost all PCBs
bull High variability with OCPs
bull Within ldquonormalrdquo range
Effects on WBC Worsen with Years
of Exposure to Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Platelet Count Decreases with Years
of Exposure tp Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Solvents Decrease Platelet Count
bull Compared workers exposed 23 hrday to those exposed most of day to toluene
bull All wore face masks and protective gear
bull Platelet count 14 lower 252 versus 216ml
bull Impairment of sympathetic nerves (OR = 413)
bull Impairment of peripheral nerves (OR = 694)
bull Positive relationship between neurological abnormalities and a self-reported neuropsychiatric measurement (r = 035-066)
Shih HT et al Subclinical abnormalities in workers with continuous low-level toluene exposure Toxicol Ind Health 2011 Sep27(8)691-9
Basophilic Stippling of Red Cells
Toxinsbull Arsenic
bull Lead
Diseasesbull Alpha-thalassemia HbH Disease
bull Beta thalassemia
bull Hereditary pyrimidine 5-nucleotidase deficiency
bull Myelodysplastic syndrome
bull Sideroblastic anemia
bull Thrombotic thrombocytopenic purpura
GGT Indirect Measure of POPsbull Glutathione is key intracellular defense against oxidative stress
bull Cellular GGT metabolizes extracellular GSH allowing precursor amino acids to be reutilized for intracellular GSH
bull Exposure to POPs induces GGT as a defensive mechanism
bull Within normal range predicts type 2 diabetes coronary heart disease hypertension stroke dyslipidemia chronic kidney disease and cancer
bull Men with GGT gt50 UI had ~26 fold risk for diabetes compared to those with lt10 Those with 40-49 had a ~20 fold risk
bull Levels within normal range occur with obesity xs alcohol cigarette smoking physical inactivity high meat low fruit and vegetable intake
bull Cumulative biomarker for environmental pollutants
Lee DH et al (2003) Gamma-glutamyltransferase and diabetesmdasha 4 year follow-up study Diabetologia 46359ndash364
Pamela A et al Serum gamma-glutamyltransferase linking together environmental pollution redox equilibria and progression of atherosclerosis Clin Chem
Lab Med 200947(12)1583-4
Lee DH et al Serum gamma-glutamyltransferase new insights about an old enzyme J Epidemiol Community Health 2009 Nov63(11)884-6
Lee DH et alSerum gamma-glutamyltransferase predicts non-fatal myocardial infarction and fatal coronary heart disease among 28838 middle-aged men and
women Eur Heart J 2006272170ndash6
Lee DH et al Gamma-glutamyltransferase and diabetes--a 4 year follow-up study Diabetologia 2003 Mar46(3)359-64
Lee DH et al Can persistent organic pollutants explain the association between serum gamma-glutamyltransferase and type 2 diabetes Diabetologia 2008
Mar51(3)402-7
GGT and Alcohol Consumption
bull GGT directly correlates with alcohol consumption
bull In a non-uniform population 40 gd will elevate GGT ~15
bull Watch for false negatives
bull Genomic variation
bull Are these the ones most
sensitive todamaged by
chemical toxins
bull Could up-regulation of GGT in light alcohol consumption be reason for benefit
0
10
20
30
40
50
60
70
80
0 200 400 600 800
Grams of Ethanol per Week
Adapted from Nagaya T et al Dose-response relationships between drinking and serum tests in Japanese men
aged 40ndash59 years Alcohol 1999 Feb 17(2) 133ndash8
GGT Correlates With Toxic Metal Levels
Lee DH et al Graded associations of blood lead and urinary cadmium concentrations with oxidative-stress-related markers in the
US population results from the third National Health and Nutrition Examination Survey Environ Health
perspect 2006 Mar114(3)350-4
GGT and Diabetes Risk
0
5
10
15
20
25
30
lt10 10-19 20-29 30-39 40-49 gt50
Dia
bete
s R
isk
GGT
bull GGT over 50 associated with tripling of death rate
bull 30-40 associated with doubling
GGT Levels
Correlate with
Risk of Death
Brenner H et al Distribution determinants and prognostic value of gamma-glutamyltransferase for all-cause
mortality in a cohort of construction workers from southern Germany Prev Med 1997 26 305ndash10
GGT From Small US Company
with Young Workers
0
10
20
30
40
50
60
0 20 40 60 80 100
GGT Data from Canadian Oil Field
Workers
0
50
100
150
200
250
300
350
400
450
lt10 10-20 20-30 30-40 40-50 50-60 60-07 70-80 80-90 90-100 100-110 110-120 gt120
GGTP
20-fold increased risk of diabetes
Uric Acid Indirect Measure of POPs
bull Poly-fluorinated hydrocarbons (PFOA and PFOS) associated
with increased serum uric acid
Lin CY et al Association among serum perfluoroalkyl chemicals glucose homeostasis and metabolic syndrome
in adolescents and adults Diabetes Care 2009 Apr32(4)702-7
Steenland K et al Association of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) with uric
acid among adults with elevated community exposure to PFOA Environ Health Perspect 2010 Feb118229-33
Steenland 2010 Open Access
ALT Indirect Measure of POPs
bull ALT (proxy marker) elevation in 104 (not including viral
hepatitis hemochromatosis or alcoholic liver disease) of
NHANES 03-04 subset
bull Risk of elevated ALT increased dose-dependently with
cadmium lead mercury and PCB exposure
bull 100 of individuals had detectable PCBs 925 mercury
and 996 had detectable lead
bull In 2005-08 prevalence of NAFLD in US was 11 a
growing cause of chronic liver disease
Cave M et al Polychlorinated biphenyls lead and mercury are associated with liver disease in American adults
NHANES 2003-2004 Environ Health Perspect 2010 Dec118(12)1735-42
Younossi ZM et al Changes in the prevalence of the most common causes of chronic liver diseases in the United
States from 1988 to 2008 Clin Gastroenterol Hepatol 2011 Jun9(6)524-530e1
Bilirubin as a Marker of POPs
bull Degree of serum bilirubin increase is prognostically significant in chronic liver dysfunction
bull Mono-ortho PCB TEQ values were found to be significantly positively associated with bilirubin (β=071 P=0008) following adjustment for multiple potential confounders
bull Bilirubin levels significantly correlated with PCBs -105-118-126 and -194
bull Smoking appears to be the biggest confounder
Dufour DR et al 2000 Diagnosis and monitoring of hepatic injury II Recommendations for use of laboratory
tests in screening diagnosis and monitoring Clin Chem 46 2050ndash68
Kumar J et al Persistent organic pollutants and liver dysfunction biomarkers in a population-based human sample
of men and women Environ Res 2014134251-256
Perf
luo
rin
ate
dP
OP
s a
nd
Co
mm
on
Blo
od
Tests
Gleason JA et al Associations of perfluorinated chemical serum concentrations and biomarkers of liver function and uric acid in the
US population (NHANES) 2007-2010 Environ Res 20151368-14
Liver Enzymes Reflect Toxic Load
bull AST ALT and GGT increase with body load of PCBs and OCPs
bull Some non-linear
bull Oxychlordanetop quartile
ALT 10
GGT 25
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
LDL-Cholesterol as Measure of POPs
bull 5-year prospective study to determine if POP levels predict future elevation in LDL-cholesterol
bull 598 subjects initially at age 70
bull Looked at 23 POPs
bull Best correlation with PCB 194
Penell J Lind L Salihovic S et al Persistent organic pollutants are related to change in circulating
lipid levels during a 5 year follow-up Environ Res 134(2014)190ndash197
oxLDL as Measure of POPs
bull 992 70-year old individuals (50 women)
bull Sum of PCBs showed strong significant positive associations with ox-LDL and significant negative associations with glutathione-related markers (GSSG and GSSGGSH)
bull A number of POPs (PCB-99 138 153 156 170 180 194 206 and 209) showed strong significant positive association with ox-LDL
Kumar J et al Influence of persistent organic pollutants on oxidative stress in population-based samples
Chemosphere 2014114303-309
Homocysteine is Increased by Pb amp Cd
Guallar E et al Confounding of the relation between homocysteine and peripheral arterial disease by lead cadmium and renal function Am J Epidemiol 2006 Apr 15163(8)700-8
Nutrient Deficiencies Accentuate
Effects of Lead on Homocysteine
bull Deficiencies in folate B6 or B12 make lead more toxic
Lee YM Et al Association of homocysteine levels with blood lead levels and micronutrients in the US general population J Prev Med Public Health 2012 Nov45(6)387-93
T4 amp T3 and PCBs
bull PCBs decrease T4 production
bull PCBs inhibit iodotyrosinedeiodinase activity
bull Study done in pregnant women which implies effect on fetus IQ
Kim S Park J Kim HJ et al Association between several persistent organic pollutants and thyroid hormone levels in serum among the pregnant women of Korea Environ Int 2013 Sep59442-8Shimizu R Yamaguchi M Uramaru N et al Structure-activity relationships of 44 halogenated compounds for iodotyrosinedeiodinase-inhibitory activity Toxicology 2013 Dec 6314(1)22-9
T4 amp T3 and PCBs
bull Not just humans being affected
bull Large study of dolphins shows exactly the same effects
Schwacke LH Zolman ES Balmer BC et al Anaemia hypothyroidism and immune suppression associated with polychlorinated biphenyl exposure in bottlenose dolphins (Tursiops truncatus) Proceed Royal Society B doi101098rspb20110665
8-OHdG
bull Oxidized nucleoside
bull Direct measure of DNA damage
bull Indirect measure of oxidative stress and toxin load
bull Correlates with
Multiple cancers
Mitochondrial damage
Rate of aging
Smoking
Several toxinsWalter Crinnion ldquoTotal Toxic Loadrdquo AANP 2015
8-OHdG Correlates with Pack-Years
of Smoking
Yano T et al Significance of the urinary 8-OHdG level as an oxidative stress marker in lung cancer patients Lung Cancer
2009 Jan63(1)111-4
8-OHdG Correlates
with Mercury
Chen C et al Increased oxidative DNA damage as assessed by urinary 8-hydroxy-2-deoxyguanosine
concentrations and serum redox status in persons exposed to mercury Clin Chem 2005 Apr51(4)759-67
Toxin Effects Worse with Aging
bull Thyroid function decreases with PFOA levels
bull But only after age 63
Shrestha S Bloom MS Yucel R et al Perfluoroalkyl substances and thyroid function in older adults Environ Int 2015 Feb75206-14
Insightful 23-Year Prospective Study
1 lt 50 there is no difference between those with the lowest and highest PCBs
2 In youngest group insulin production increases in response to toxin level As expected since blocking of
insulin receptor sites by PCBs
requires more insulin
3 That adaptive ability decreases with aging
4 At age 50 all the measures show very strong toxin-dose response
Cumulative damage impairs ability to adapt
Suarez-Lopez JR et al Persistent organic pollutants in young adults and changes in glucose related metabolism over a 23-year follow-up Environ Res 2015 Feb137485-94
Recommendations
High body toxic load
GGT gt 25
Uric acid gt 50 mgdl
ALT gt30 UL
Bilirubin gt08 mgdl
CBC lt 6000
Platelet lt 250000
Low T3 andor T4
Monitor Total Toxic Load
8-OHdG gt4
ldquoUnconventionalrdquo Laboratory Tests
bull Challenge testing
bull Hair analysis
bull Direct measures of solvents and POPs in blood urine adipose tissue
Evaluation of Metal Exposure ndash Provocation
bull Provocation ndash the use of a chelating agent ndash before urine collection often done clinically but several limitations
No ldquoofficialrdquo reference range for provoked urine
Most chelating agents do not extract metals from all tissues thus
does not necessarily represent total body burden
bull Example Brain is one of the main target organs for both elemental and organic
mercury yet agents do not chelate brain mercury
bull Despite limitations widely used and advocated by clinicians in part to see efficacy of chelating agent as a guide to treatment and based on empirical evidence
Rooney JP The role of thiols dithiols nutritional factors and interacting ligands in the toxicology of mercury
Toxicology 2007
Is Challenge Testing Valid
bull Poor correlations of standard tests for mercury
bull Unpublished research from corporate wellness project
bull Published amalgam number correlation
bull Published fish consumption correlation
What We Found In Canada
bull Deviations from the mean of 14 29 and 91 respectively
bull DMPS is spreading distribution suggesting that it is better at differentiating mercury body load
bull Some VERY high
Hg Assessment Correlations
bull Extensive measurements in 65 Whole blood Hg
Oral DMPS challenge
Amalgam surfaces
bull Correlations Whole blood w pre urine r = 040
Whole blood w post urine r = 057
Pre urine w post urine r = 068
Amalgams w pre urine r = 026
Amalgams w whole blood r = 036
Amalgams with post urine 044
bull Clear documentation that
challenge testing is better00
100
200
300
400
500
600
0 10 20 30 40 50
Po
st
Uri
ne H
g u
gg
Number of amalgams
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
References for Toxins and Disease Risk
Converting Disease Risk to Caused
Attributable Fraction Calculation
p = underlying prevalence of risk factor in the population
rr = relative risk (risk of contracting a disease in an exposed population divided by the risk of contracting the disease in an unexposed population)
AF = of disease due to the toxin
Levin M The occurrence of lung cancer in man Acta Unio Int Contra Cancrum 1953 9 531-541
Example Smoking and Lung Cancer
B = 5Number of smokers
who contract Lung Cancer notdue to smoking
A = 5Number of smokerswho contract Lung
Cancer due to smoking
C = 15Number of
nonsmokerswho contract Lung Cancer
0
2
4
6
8
10
12
14
16
Smokers (N=100) Nonsmokers (N=300)Num
ber
of
people
who c
ontr
act
Lung C
ancer
per
year
Baseline Additional due to smoking
Number of smokers and nonsmokers who contract lung cancer
Our Process In Summary
1 Determine threshold for increased disease risk
2 Determine of population above threshold
3 Determine incidence of disease (OR) in those above threshold
4 Determine incidence of disease in ldquounexposed populationrdquo
5 Calculate AF ie of disease
As whole population is exposed probably UNDERESTIMATES of disease
To
xic
ity H
as B
eco
me t
he N
ew
ldquoN
orm
alrdquo
Toxin Type Use Threshold for
disease
association
of US
above
threshold
Disease Associations
Chlordane OC pesticide Termites corn citrus lawns
gardens
145ngg lipid 63
(diabetes)
Diabetes (20)
BPA Plasticizer Water bottles canned food
water pipes thermal sales
receipts
48 men 51
women (urine
ngmL)
~18
(diabetes)
Diabetes hypertension
Octachloro
dibenzo-p-
dioxin
(OCDD)
Polychlorinated
dibenzo-p-
dioxin
Incineration or burning of
waste bleaching processes
used in pulp and paper mills
1010 pgg
lipid (highest
quartile)
10-25
(hypertensio
n)
Hypertension (79 for
women highest
quartile) diabetes (21)
obesity learning
disability (272)
MEP
(mono-
ethyl
phthalate)
Phthalate
(plasticizer
fragrance)
Toothbrushes automobile
parts tools toys and food
packaging aspirin
cosmetics food packaging
gt175 ngmL
(urine)
~60
(diabetes)
Diabetes (148) lower
BMD obesity
pp-DDE DDT
metabolite (OC
pesticide)
Agricultural crops 1560ngg
lipid
25
(diabetes)
Diabetes (23-43)
early menopause
impaired cognitive
function (2-3x 65x in
highest 5th percentile)
peripheral arterial
disease
Arsenic Toxic metal Miningsmelting wood
preservative pesticides
74ugL total
arsenic (urine)
20
(diabetes)
Cancers diabetes (26-
46) dyslipidemia gout
AF OR Prevalence
Rosen L An intuitive approach to understanding the attributable fraction of disease due to a risk factor the case of smoking Int J Environ Res Public Health 2013 Jul 1610(7)2932-43
Smoking Lung cancer
Arsenic Gout in women
BPA Diabetes
Status of Our Research
bull 26 toxins and toxin classes eg lead mercury BPA OCPs
100s of chemicals and POPs in some classes
bull 18 cancers
bull 24 chronic diseases
bull 1092 cells in spreadsheet
Large Personal Ongoing Research Investment
Huge Amount of Research Work
Toxins StudiedAluminum
Arsenic
Cadmium
Fluoride
Lead
Manganese
Mercury
Acrylamide
Acrylonitrile
Benzene
Bisphenol A (BPA)
Chloroform
DDT
Dioxins
Glyphosate
Organochlorine pesticides (OCPs)
Organophosphate pesticides
Parabens
Phthalates
Polybrominated diphenyl ethers (PBDEs)
Polycyclic aromatic hydrocarbons (PAHs)
Polychlorinated biphenols (PCBs)
Vinyl chloride
Diseases Studied
ADHD
Alzheimers Disease
ALS
Angiosarcoma
Anxiety
Atopic Conditions
Diabetes
Dyslipidemia
Gout
Fetal Abnormalities
Hyperuricemia
Infertility
Juvenile IQ
Cancer Bladder
Cancer Bone
Cancer Brain
Cancer Breast
Cancer Cervix
Cancer Colorectal
Cancer Endometrial
Cancer Head amp Neck
Cancer Liver
Cancer Lung
Cancer Lymph amp Blood
Cancer Ovarian
Cancer Pancreatic
Cancer Prostate
Cancer Renal
Cancer Skin
Cancer Testicular
Cancer Thyroid
Juvenile Obesity
Metabolic Syndrome
Mitochondrial dysfunction
Myocardial Infarction
Obstructive Lung Disease
Osteoporosis
Peripheral Artery Disease
Peripheral Neuropathy
Prediabetes
Renal Disease
Rheumatoid Arthritis
Thyroid Dysfunction
OC
Ps
Th
rou
gh
ou
t th
e W
orl
d
Rathore HS Nollet LML Pesticides Evaluation of Environmental Pollution CRC Press
2012 page 562
Threshold ndash Threshold exposure at which there is an increased risk of disease outcome
Above Threshold ndash Percentage of the population with higher exposure than the threshold
Odds Ratio ndash Increased disease risk in those above threshold
of Dz ndash Percent contribution of the toxin to that disease outcome
How to Interpret the Following Slides
Attention Deficit Hyperactivity Disorder
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
DDT 126 ngg
serum (pp-
DDE)
250 18 166 20106937
Lead 23 ugdL 13 254 20 27659349
Mercury 16 24952233
Organophosphate
pesticides
20
Polycyclic
Aromatic
Hydrocarbons
227 ngm3 940 125 190 22440811
PCBs 104 ngg
serum (sum
of 50 PCBs)
250 176 160 20106937
DiabetesToxin Threshold Above
Threshold
Odds
Ratio
of Dz Reference
PMID
Arsenic 165 ugL 200 21 180 18714061
BPA 28 ugL 280 145 112 26119400
DDE 545 ngg serum
(pp-DDE)
200 230 31 26119400
Dioxins2 pgg lipid 50 191 43
26119400
PCBs104 ngg (PCB 153) 250 239 258
26119400
Phthalates175 ugL 690 148 249
26119400
1-naphthalene 167 ugdL 152 182 111 26340343
2-napthalene 414 ugdL 550 224 214 26340343
1-phenanthrene 167 ngL 570 178 151 26340343
1-pyrene 85 ngL 660 180 174 26340343
Lung Cancer
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Acrylonitrile Uncertain Uncertain 125 25
occupational
exposure
17114112
Arsenic 1213 ugL 436 of Asian
Americans
~01 of total
US population
34 95 in AA
01-1
PMC2682945
Cadmium Uncertain+ Uncertain 467 10 in
smokers
17184399
DDT Any exposure All US pop
below LOD
17 76 increased
risk
8923607
Breast Cancer
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Cadmium 0580 ugg
creatinine
126 205 479 16788160
PCB 138 396 ngg
creatinine
202 316 630 27717745
PCB 187 108 ngg lipid 600 194 360 21480306
Miscellaneous Diseases
Toxin Disease Threshold Above
Threshold
Odds
Ratio
of Dz Reference PMID
Aluminum Alzheimer
Dz
01 mgL
drinking
H20
400 203 05-44 26592479
Benzene AML 100ppmyrs 1-3 320 60 PMC2903550
DDT NHL 0512 ugL 1-2 240 01 17722095
Lead ALS 238 ugdL
blood
330 181 210 25479292
Lead Brain CA 0005 ugdL 14 19 ~500 17164378
Dioxin-like
PCBs
RA 326 ngg
lipid
250 219 220 17589595
PAHs Asthma 124 ngm3 935 200 483 19221603
The Potency of Arsenic
Disease Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Bladder CA 10ugL H20 100 27 145 24889821
Pancreatic CA 1332 ugg 200 246 230 23800676
Prostate CA 1332 ugg 200 33 315 23800676
Gout 125 ugL 245 546 522 25499256
Diabetes 165 ugL 200 21 180 18714061
Arsenic (180 of Diabetes)
How it causes diabetes
bull Blocks sugar stimulating insulin secretion
bull Epigenetic inhibition of sugar regulation
Where it comes from
bull Water (gt10 of US water supplies have high levels)
bull Rice (naturally absorbs if in the water)
bull Chicken (added to make meat whiter)
Pan W-C Seow WJ Kile ML et al Association of low to moderate levels of arsenic exposure with risk of Type 2 diabetes in Bangladesh American Journal of Epidemiology 2013178(10)1563-70
Portion of Population with Toxin Load Which
Doubles Disease Risk
Toxin Disease with Doubled Risk
Polycyclic aromatic hydrocarbons Asthma 94
PCB187 Breast Cancer 60
Phthalates Diabetes 55
Lead ALS 33
Aluminum Alzheimers Disease 25
DDT ADHD 25
PCBs Diabetes 25
Dioxin-like PCBs Rheumatoid Arthritis 25
Arsenic Gout 23
Bisphenol A Diabetes 22
Cigarette smoking Lung Cancer 21
Arsenic Diabetes 20
Polycyclic aromatic hydrocarbons Diabetes 20
Huge Detoxification Variability
bull CYP2C19
Proton pump inhibitors and some antidepressants
5-fold difference in activity between poor metabolizers and extensive metabolizers more so if CYP3A4 is also inhibited
Ultrarapid allele in 18 of both Swedes and Ethiopians
bull CYP2D6
Metabolizes a large number of drugs (~25)
7 of Caucasians poor metabolizers
~30 ultra rapid metabolizers in Arabian and Eastern African populations
More adverse effects in poor metabolizers and ineffective dosing in ultrarapid metabolizers
Inhibited by ginger
Desta Z et al Clinical significance of the cytochrome P450 2C19 genetic polymorphism Clin Pharmaco 2002
Sim SC et al A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug
response to proton pump inhibitors and antidepressants Clin Pharmacol Ther 2006
Wilkinson GR Drug metabolism and variability among patients in drug response N Engl J Med 2005
Kirchheiner J et al Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to
CYP2D6 duplication Pharmacogenomics J 2007
Toxin Half Lives in BloodToxin ldquoNormalrdquo (mgL) Acute Toxic (mgL) Half-Life
Arsenic 0002-007 005-025 2-4 days (CDC)
Benzene 00002 05-10 days
Cadmium 00003-00065 0015-005 16 years
Chlordane 0001 00025 3-4 days
DDTDDE 2-10 years
Dieldrin 00015 015-030 2-12 months
Ethanol 1000-2000 15hour
Lead 009 04-06 1-15 mo (2+ yrs bone)
Mercury 00015-0002 005-02 2 months (CDC)
PCBs 3-25 years
Toluene 05-3 days
Schulz M et al Therapeutic and toxic blood concentrations of nearly 1000 drugs and other xenobiotics Crit Care 2012 Jul 2616(4)R136
Bioaccumulation (POPs)
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
DDT banned in 1972 PCBs banned in 1977
Bioaccumulation (Cd)
Think BroadlyExogenous
Metals
Chemicalsbull Inorganic
bull Fluoride
bull Organic
bull POPs
bull Drugs
Particulate matter
Molds
Microbial
Radiationbull Light
bull Medical
bull Cell phone
Endogenous
Gut-derived toxins
Non-end product metabolites
Poorly detoxified hormones
Catecholamines (if SNP)
Toxins of Choice
Alcohol
Marijuana
Food constituents
High fructose corn syrup
Salt (acid-forming diet)
Wheat if zonulin (70)
Obesity Epidemic ndash POPs AND HFCS
47Bray GA Fructose should we worry Int J Obes (Lond) 2008 Dec32 Suppl 7S127-31
How Toxins Cause Damage 13
bull Increase free radical production
Cd induces production of ROS
Malathion inhibits catalase and glutathione peroxidase
Homocysteine oxidizes LDL cholesterol
bull Poison enzyme systems (compete with nutritional cofactors for binding sites)
Pb poisons delta aminolevulinic acid dehydratase
Cd inhibits catalase glutathione reductase and lowers
glutathione levels
bull Replace structural minerals
Pb displaces Ca in bone
How Toxins Cause Damage 23
bull Damage DNA
Benzene - causes chromosomal damage
Pesticides ndash fruit growers have more DNA damage
Phthalates and insecticides ndash damage sperm DNA
4-hydroxy catechol estrogen (4-OHE) damages breast DNA
bull Epigenetic dysmodulation
Higher cord blood levels of hexachlorobenzene associated
with 2x greater risk for obesity in children
bull Damage cell membranes
Common mechanism for heavy metals inactivates
membrane enzymes ion channels and pumps
How Toxins Cause Damage 33
bull Block insulin receptor sites
PCBs and phthalates
bull Highest levels associated with a 4 to 20-fold greater diabetes risk
bull Imbalance hormones many toxin examples
Arsenic
bull Disrupts thyroid hormone and retinoic acid receptors
Phthalates
bull Act as anti-androgens
bull More than 75 of the US population has measurable levels of
several phthalate metabolites in the urine
PCBs
bull Lower testosterone levels in men
Which are the Worst Toxins
bull According to the CDC
Toxicity
Population toxic load
Prevalence in toxic waste sites
bull According to clinical importance
Exposure
of disease
Ability of the body to detoxifyexcrete
Ag
en
cy
fo
r T
oxic
Su
bs
tan
ce
s a
nd
Dis
ea
se
Reg
istr
y
Pri
ori
ty L
ist
The Worst Toxins Clinically
My Rank Toxin Diseases Primary Sources
1 Arsenic Cancers diabetes gout Water chicken rice
2 DDT ADHD dementia diabetes Everywhere
3 Phthalates ADHD diabetes Soft plastics HABAs
4 PBDEs ADHD diabetes Flame retardant fabrics
5 PAHs ADHD cancers dyslipidemia Smoking charbroiling
6 PCBs Cancers diabetes MI RA Everywhere
7 Mercury Dementia ldquoSilverrdquo fillings fish
8 Lead Cardiovascular disease IQ Paint water
Glyphosate Research invalid
Conventional Laboratory Tests Reflect
Toxic Load in ldquoNormalrdquo Range
bull Surprising number show toxin exposure
CBC RBC WBC platelet count hemoglobin basophilic
stippling
Liver enzymes ALT GGTP
Inflammatory markers CRP
Lipids LDL oxLDL triglycerides
Blood sugar insulin FBS 2-hour PP
Metabolites bilirubin uric acid homocysteine 8-OHdG
Thyroid T3 T4 TSH
bull The historic ldquonormalrdquo range has been changing as the population has become more toxic
WBC Lowered by PCB and OCP Exposure
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
0
1
2
3
4
5
6
7
8
1st Quartrile 2nd Quartile 3rd Quartile 4th Quartile
WBCbull Strong inverse correlation with PCBs and OCPs and CBC
bull Linear with almost all PCBs
bull High variability with OCPs
bull Within ldquonormalrdquo range
Effects on WBC Worsen with Years
of Exposure to Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Platelet Count Decreases with Years
of Exposure tp Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Solvents Decrease Platelet Count
bull Compared workers exposed 23 hrday to those exposed most of day to toluene
bull All wore face masks and protective gear
bull Platelet count 14 lower 252 versus 216ml
bull Impairment of sympathetic nerves (OR = 413)
bull Impairment of peripheral nerves (OR = 694)
bull Positive relationship between neurological abnormalities and a self-reported neuropsychiatric measurement (r = 035-066)
Shih HT et al Subclinical abnormalities in workers with continuous low-level toluene exposure Toxicol Ind Health 2011 Sep27(8)691-9
Basophilic Stippling of Red Cells
Toxinsbull Arsenic
bull Lead
Diseasesbull Alpha-thalassemia HbH Disease
bull Beta thalassemia
bull Hereditary pyrimidine 5-nucleotidase deficiency
bull Myelodysplastic syndrome
bull Sideroblastic anemia
bull Thrombotic thrombocytopenic purpura
GGT Indirect Measure of POPsbull Glutathione is key intracellular defense against oxidative stress
bull Cellular GGT metabolizes extracellular GSH allowing precursor amino acids to be reutilized for intracellular GSH
bull Exposure to POPs induces GGT as a defensive mechanism
bull Within normal range predicts type 2 diabetes coronary heart disease hypertension stroke dyslipidemia chronic kidney disease and cancer
bull Men with GGT gt50 UI had ~26 fold risk for diabetes compared to those with lt10 Those with 40-49 had a ~20 fold risk
bull Levels within normal range occur with obesity xs alcohol cigarette smoking physical inactivity high meat low fruit and vegetable intake
bull Cumulative biomarker for environmental pollutants
Lee DH et al (2003) Gamma-glutamyltransferase and diabetesmdasha 4 year follow-up study Diabetologia 46359ndash364
Pamela A et al Serum gamma-glutamyltransferase linking together environmental pollution redox equilibria and progression of atherosclerosis Clin Chem
Lab Med 200947(12)1583-4
Lee DH et al Serum gamma-glutamyltransferase new insights about an old enzyme J Epidemiol Community Health 2009 Nov63(11)884-6
Lee DH et alSerum gamma-glutamyltransferase predicts non-fatal myocardial infarction and fatal coronary heart disease among 28838 middle-aged men and
women Eur Heart J 2006272170ndash6
Lee DH et al Gamma-glutamyltransferase and diabetes--a 4 year follow-up study Diabetologia 2003 Mar46(3)359-64
Lee DH et al Can persistent organic pollutants explain the association between serum gamma-glutamyltransferase and type 2 diabetes Diabetologia 2008
Mar51(3)402-7
GGT and Alcohol Consumption
bull GGT directly correlates with alcohol consumption
bull In a non-uniform population 40 gd will elevate GGT ~15
bull Watch for false negatives
bull Genomic variation
bull Are these the ones most
sensitive todamaged by
chemical toxins
bull Could up-regulation of GGT in light alcohol consumption be reason for benefit
0
10
20
30
40
50
60
70
80
0 200 400 600 800
Grams of Ethanol per Week
Adapted from Nagaya T et al Dose-response relationships between drinking and serum tests in Japanese men
aged 40ndash59 years Alcohol 1999 Feb 17(2) 133ndash8
GGT Correlates With Toxic Metal Levels
Lee DH et al Graded associations of blood lead and urinary cadmium concentrations with oxidative-stress-related markers in the
US population results from the third National Health and Nutrition Examination Survey Environ Health
perspect 2006 Mar114(3)350-4
GGT and Diabetes Risk
0
5
10
15
20
25
30
lt10 10-19 20-29 30-39 40-49 gt50
Dia
bete
s R
isk
GGT
bull GGT over 50 associated with tripling of death rate
bull 30-40 associated with doubling
GGT Levels
Correlate with
Risk of Death
Brenner H et al Distribution determinants and prognostic value of gamma-glutamyltransferase for all-cause
mortality in a cohort of construction workers from southern Germany Prev Med 1997 26 305ndash10
GGT From Small US Company
with Young Workers
0
10
20
30
40
50
60
0 20 40 60 80 100
GGT Data from Canadian Oil Field
Workers
0
50
100
150
200
250
300
350
400
450
lt10 10-20 20-30 30-40 40-50 50-60 60-07 70-80 80-90 90-100 100-110 110-120 gt120
GGTP
20-fold increased risk of diabetes
Uric Acid Indirect Measure of POPs
bull Poly-fluorinated hydrocarbons (PFOA and PFOS) associated
with increased serum uric acid
Lin CY et al Association among serum perfluoroalkyl chemicals glucose homeostasis and metabolic syndrome
in adolescents and adults Diabetes Care 2009 Apr32(4)702-7
Steenland K et al Association of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) with uric
acid among adults with elevated community exposure to PFOA Environ Health Perspect 2010 Feb118229-33
Steenland 2010 Open Access
ALT Indirect Measure of POPs
bull ALT (proxy marker) elevation in 104 (not including viral
hepatitis hemochromatosis or alcoholic liver disease) of
NHANES 03-04 subset
bull Risk of elevated ALT increased dose-dependently with
cadmium lead mercury and PCB exposure
bull 100 of individuals had detectable PCBs 925 mercury
and 996 had detectable lead
bull In 2005-08 prevalence of NAFLD in US was 11 a
growing cause of chronic liver disease
Cave M et al Polychlorinated biphenyls lead and mercury are associated with liver disease in American adults
NHANES 2003-2004 Environ Health Perspect 2010 Dec118(12)1735-42
Younossi ZM et al Changes in the prevalence of the most common causes of chronic liver diseases in the United
States from 1988 to 2008 Clin Gastroenterol Hepatol 2011 Jun9(6)524-530e1
Bilirubin as a Marker of POPs
bull Degree of serum bilirubin increase is prognostically significant in chronic liver dysfunction
bull Mono-ortho PCB TEQ values were found to be significantly positively associated with bilirubin (β=071 P=0008) following adjustment for multiple potential confounders
bull Bilirubin levels significantly correlated with PCBs -105-118-126 and -194
bull Smoking appears to be the biggest confounder
Dufour DR et al 2000 Diagnosis and monitoring of hepatic injury II Recommendations for use of laboratory
tests in screening diagnosis and monitoring Clin Chem 46 2050ndash68
Kumar J et al Persistent organic pollutants and liver dysfunction biomarkers in a population-based human sample
of men and women Environ Res 2014134251-256
Perf
luo
rin
ate
dP
OP
s a
nd
Co
mm
on
Blo
od
Tests
Gleason JA et al Associations of perfluorinated chemical serum concentrations and biomarkers of liver function and uric acid in the
US population (NHANES) 2007-2010 Environ Res 20151368-14
Liver Enzymes Reflect Toxic Load
bull AST ALT and GGT increase with body load of PCBs and OCPs
bull Some non-linear
bull Oxychlordanetop quartile
ALT 10
GGT 25
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
LDL-Cholesterol as Measure of POPs
bull 5-year prospective study to determine if POP levels predict future elevation in LDL-cholesterol
bull 598 subjects initially at age 70
bull Looked at 23 POPs
bull Best correlation with PCB 194
Penell J Lind L Salihovic S et al Persistent organic pollutants are related to change in circulating
lipid levels during a 5 year follow-up Environ Res 134(2014)190ndash197
oxLDL as Measure of POPs
bull 992 70-year old individuals (50 women)
bull Sum of PCBs showed strong significant positive associations with ox-LDL and significant negative associations with glutathione-related markers (GSSG and GSSGGSH)
bull A number of POPs (PCB-99 138 153 156 170 180 194 206 and 209) showed strong significant positive association with ox-LDL
Kumar J et al Influence of persistent organic pollutants on oxidative stress in population-based samples
Chemosphere 2014114303-309
Homocysteine is Increased by Pb amp Cd
Guallar E et al Confounding of the relation between homocysteine and peripheral arterial disease by lead cadmium and renal function Am J Epidemiol 2006 Apr 15163(8)700-8
Nutrient Deficiencies Accentuate
Effects of Lead on Homocysteine
bull Deficiencies in folate B6 or B12 make lead more toxic
Lee YM Et al Association of homocysteine levels with blood lead levels and micronutrients in the US general population J Prev Med Public Health 2012 Nov45(6)387-93
T4 amp T3 and PCBs
bull PCBs decrease T4 production
bull PCBs inhibit iodotyrosinedeiodinase activity
bull Study done in pregnant women which implies effect on fetus IQ
Kim S Park J Kim HJ et al Association between several persistent organic pollutants and thyroid hormone levels in serum among the pregnant women of Korea Environ Int 2013 Sep59442-8Shimizu R Yamaguchi M Uramaru N et al Structure-activity relationships of 44 halogenated compounds for iodotyrosinedeiodinase-inhibitory activity Toxicology 2013 Dec 6314(1)22-9
T4 amp T3 and PCBs
bull Not just humans being affected
bull Large study of dolphins shows exactly the same effects
Schwacke LH Zolman ES Balmer BC et al Anaemia hypothyroidism and immune suppression associated with polychlorinated biphenyl exposure in bottlenose dolphins (Tursiops truncatus) Proceed Royal Society B doi101098rspb20110665
8-OHdG
bull Oxidized nucleoside
bull Direct measure of DNA damage
bull Indirect measure of oxidative stress and toxin load
bull Correlates with
Multiple cancers
Mitochondrial damage
Rate of aging
Smoking
Several toxinsWalter Crinnion ldquoTotal Toxic Loadrdquo AANP 2015
8-OHdG Correlates with Pack-Years
of Smoking
Yano T et al Significance of the urinary 8-OHdG level as an oxidative stress marker in lung cancer patients Lung Cancer
2009 Jan63(1)111-4
8-OHdG Correlates
with Mercury
Chen C et al Increased oxidative DNA damage as assessed by urinary 8-hydroxy-2-deoxyguanosine
concentrations and serum redox status in persons exposed to mercury Clin Chem 2005 Apr51(4)759-67
Toxin Effects Worse with Aging
bull Thyroid function decreases with PFOA levels
bull But only after age 63
Shrestha S Bloom MS Yucel R et al Perfluoroalkyl substances and thyroid function in older adults Environ Int 2015 Feb75206-14
Insightful 23-Year Prospective Study
1 lt 50 there is no difference between those with the lowest and highest PCBs
2 In youngest group insulin production increases in response to toxin level As expected since blocking of
insulin receptor sites by PCBs
requires more insulin
3 That adaptive ability decreases with aging
4 At age 50 all the measures show very strong toxin-dose response
Cumulative damage impairs ability to adapt
Suarez-Lopez JR et al Persistent organic pollutants in young adults and changes in glucose related metabolism over a 23-year follow-up Environ Res 2015 Feb137485-94
Recommendations
High body toxic load
GGT gt 25
Uric acid gt 50 mgdl
ALT gt30 UL
Bilirubin gt08 mgdl
CBC lt 6000
Platelet lt 250000
Low T3 andor T4
Monitor Total Toxic Load
8-OHdG gt4
ldquoUnconventionalrdquo Laboratory Tests
bull Challenge testing
bull Hair analysis
bull Direct measures of solvents and POPs in blood urine adipose tissue
Evaluation of Metal Exposure ndash Provocation
bull Provocation ndash the use of a chelating agent ndash before urine collection often done clinically but several limitations
No ldquoofficialrdquo reference range for provoked urine
Most chelating agents do not extract metals from all tissues thus
does not necessarily represent total body burden
bull Example Brain is one of the main target organs for both elemental and organic
mercury yet agents do not chelate brain mercury
bull Despite limitations widely used and advocated by clinicians in part to see efficacy of chelating agent as a guide to treatment and based on empirical evidence
Rooney JP The role of thiols dithiols nutritional factors and interacting ligands in the toxicology of mercury
Toxicology 2007
Is Challenge Testing Valid
bull Poor correlations of standard tests for mercury
bull Unpublished research from corporate wellness project
bull Published amalgam number correlation
bull Published fish consumption correlation
What We Found In Canada
bull Deviations from the mean of 14 29 and 91 respectively
bull DMPS is spreading distribution suggesting that it is better at differentiating mercury body load
bull Some VERY high
Hg Assessment Correlations
bull Extensive measurements in 65 Whole blood Hg
Oral DMPS challenge
Amalgam surfaces
bull Correlations Whole blood w pre urine r = 040
Whole blood w post urine r = 057
Pre urine w post urine r = 068
Amalgams w pre urine r = 026
Amalgams w whole blood r = 036
Amalgams with post urine 044
bull Clear documentation that
challenge testing is better00
100
200
300
400
500
600
0 10 20 30 40 50
Po
st
Uri
ne H
g u
gg
Number of amalgams
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
Converting Disease Risk to Caused
Attributable Fraction Calculation
p = underlying prevalence of risk factor in the population
rr = relative risk (risk of contracting a disease in an exposed population divided by the risk of contracting the disease in an unexposed population)
AF = of disease due to the toxin
Levin M The occurrence of lung cancer in man Acta Unio Int Contra Cancrum 1953 9 531-541
Example Smoking and Lung Cancer
B = 5Number of smokers
who contract Lung Cancer notdue to smoking
A = 5Number of smokerswho contract Lung
Cancer due to smoking
C = 15Number of
nonsmokerswho contract Lung Cancer
0
2
4
6
8
10
12
14
16
Smokers (N=100) Nonsmokers (N=300)Num
ber
of
people
who c
ontr
act
Lung C
ancer
per
year
Baseline Additional due to smoking
Number of smokers and nonsmokers who contract lung cancer
Our Process In Summary
1 Determine threshold for increased disease risk
2 Determine of population above threshold
3 Determine incidence of disease (OR) in those above threshold
4 Determine incidence of disease in ldquounexposed populationrdquo
5 Calculate AF ie of disease
As whole population is exposed probably UNDERESTIMATES of disease
To
xic
ity H
as B
eco
me t
he N
ew
ldquoN
orm
alrdquo
Toxin Type Use Threshold for
disease
association
of US
above
threshold
Disease Associations
Chlordane OC pesticide Termites corn citrus lawns
gardens
145ngg lipid 63
(diabetes)
Diabetes (20)
BPA Plasticizer Water bottles canned food
water pipes thermal sales
receipts
48 men 51
women (urine
ngmL)
~18
(diabetes)
Diabetes hypertension
Octachloro
dibenzo-p-
dioxin
(OCDD)
Polychlorinated
dibenzo-p-
dioxin
Incineration or burning of
waste bleaching processes
used in pulp and paper mills
1010 pgg
lipid (highest
quartile)
10-25
(hypertensio
n)
Hypertension (79 for
women highest
quartile) diabetes (21)
obesity learning
disability (272)
MEP
(mono-
ethyl
phthalate)
Phthalate
(plasticizer
fragrance)
Toothbrushes automobile
parts tools toys and food
packaging aspirin
cosmetics food packaging
gt175 ngmL
(urine)
~60
(diabetes)
Diabetes (148) lower
BMD obesity
pp-DDE DDT
metabolite (OC
pesticide)
Agricultural crops 1560ngg
lipid
25
(diabetes)
Diabetes (23-43)
early menopause
impaired cognitive
function (2-3x 65x in
highest 5th percentile)
peripheral arterial
disease
Arsenic Toxic metal Miningsmelting wood
preservative pesticides
74ugL total
arsenic (urine)
20
(diabetes)
Cancers diabetes (26-
46) dyslipidemia gout
AF OR Prevalence
Rosen L An intuitive approach to understanding the attributable fraction of disease due to a risk factor the case of smoking Int J Environ Res Public Health 2013 Jul 1610(7)2932-43
Smoking Lung cancer
Arsenic Gout in women
BPA Diabetes
Status of Our Research
bull 26 toxins and toxin classes eg lead mercury BPA OCPs
100s of chemicals and POPs in some classes
bull 18 cancers
bull 24 chronic diseases
bull 1092 cells in spreadsheet
Large Personal Ongoing Research Investment
Huge Amount of Research Work
Toxins StudiedAluminum
Arsenic
Cadmium
Fluoride
Lead
Manganese
Mercury
Acrylamide
Acrylonitrile
Benzene
Bisphenol A (BPA)
Chloroform
DDT
Dioxins
Glyphosate
Organochlorine pesticides (OCPs)
Organophosphate pesticides
Parabens
Phthalates
Polybrominated diphenyl ethers (PBDEs)
Polycyclic aromatic hydrocarbons (PAHs)
Polychlorinated biphenols (PCBs)
Vinyl chloride
Diseases Studied
ADHD
Alzheimers Disease
ALS
Angiosarcoma
Anxiety
Atopic Conditions
Diabetes
Dyslipidemia
Gout
Fetal Abnormalities
Hyperuricemia
Infertility
Juvenile IQ
Cancer Bladder
Cancer Bone
Cancer Brain
Cancer Breast
Cancer Cervix
Cancer Colorectal
Cancer Endometrial
Cancer Head amp Neck
Cancer Liver
Cancer Lung
Cancer Lymph amp Blood
Cancer Ovarian
Cancer Pancreatic
Cancer Prostate
Cancer Renal
Cancer Skin
Cancer Testicular
Cancer Thyroid
Juvenile Obesity
Metabolic Syndrome
Mitochondrial dysfunction
Myocardial Infarction
Obstructive Lung Disease
Osteoporosis
Peripheral Artery Disease
Peripheral Neuropathy
Prediabetes
Renal Disease
Rheumatoid Arthritis
Thyroid Dysfunction
OC
Ps
Th
rou
gh
ou
t th
e W
orl
d
Rathore HS Nollet LML Pesticides Evaluation of Environmental Pollution CRC Press
2012 page 562
Threshold ndash Threshold exposure at which there is an increased risk of disease outcome
Above Threshold ndash Percentage of the population with higher exposure than the threshold
Odds Ratio ndash Increased disease risk in those above threshold
of Dz ndash Percent contribution of the toxin to that disease outcome
How to Interpret the Following Slides
Attention Deficit Hyperactivity Disorder
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
DDT 126 ngg
serum (pp-
DDE)
250 18 166 20106937
Lead 23 ugdL 13 254 20 27659349
Mercury 16 24952233
Organophosphate
pesticides
20
Polycyclic
Aromatic
Hydrocarbons
227 ngm3 940 125 190 22440811
PCBs 104 ngg
serum (sum
of 50 PCBs)
250 176 160 20106937
DiabetesToxin Threshold Above
Threshold
Odds
Ratio
of Dz Reference
PMID
Arsenic 165 ugL 200 21 180 18714061
BPA 28 ugL 280 145 112 26119400
DDE 545 ngg serum
(pp-DDE)
200 230 31 26119400
Dioxins2 pgg lipid 50 191 43
26119400
PCBs104 ngg (PCB 153) 250 239 258
26119400
Phthalates175 ugL 690 148 249
26119400
1-naphthalene 167 ugdL 152 182 111 26340343
2-napthalene 414 ugdL 550 224 214 26340343
1-phenanthrene 167 ngL 570 178 151 26340343
1-pyrene 85 ngL 660 180 174 26340343
Lung Cancer
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Acrylonitrile Uncertain Uncertain 125 25
occupational
exposure
17114112
Arsenic 1213 ugL 436 of Asian
Americans
~01 of total
US population
34 95 in AA
01-1
PMC2682945
Cadmium Uncertain+ Uncertain 467 10 in
smokers
17184399
DDT Any exposure All US pop
below LOD
17 76 increased
risk
8923607
Breast Cancer
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Cadmium 0580 ugg
creatinine
126 205 479 16788160
PCB 138 396 ngg
creatinine
202 316 630 27717745
PCB 187 108 ngg lipid 600 194 360 21480306
Miscellaneous Diseases
Toxin Disease Threshold Above
Threshold
Odds
Ratio
of Dz Reference PMID
Aluminum Alzheimer
Dz
01 mgL
drinking
H20
400 203 05-44 26592479
Benzene AML 100ppmyrs 1-3 320 60 PMC2903550
DDT NHL 0512 ugL 1-2 240 01 17722095
Lead ALS 238 ugdL
blood
330 181 210 25479292
Lead Brain CA 0005 ugdL 14 19 ~500 17164378
Dioxin-like
PCBs
RA 326 ngg
lipid
250 219 220 17589595
PAHs Asthma 124 ngm3 935 200 483 19221603
The Potency of Arsenic
Disease Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Bladder CA 10ugL H20 100 27 145 24889821
Pancreatic CA 1332 ugg 200 246 230 23800676
Prostate CA 1332 ugg 200 33 315 23800676
Gout 125 ugL 245 546 522 25499256
Diabetes 165 ugL 200 21 180 18714061
Arsenic (180 of Diabetes)
How it causes diabetes
bull Blocks sugar stimulating insulin secretion
bull Epigenetic inhibition of sugar regulation
Where it comes from
bull Water (gt10 of US water supplies have high levels)
bull Rice (naturally absorbs if in the water)
bull Chicken (added to make meat whiter)
Pan W-C Seow WJ Kile ML et al Association of low to moderate levels of arsenic exposure with risk of Type 2 diabetes in Bangladesh American Journal of Epidemiology 2013178(10)1563-70
Portion of Population with Toxin Load Which
Doubles Disease Risk
Toxin Disease with Doubled Risk
Polycyclic aromatic hydrocarbons Asthma 94
PCB187 Breast Cancer 60
Phthalates Diabetes 55
Lead ALS 33
Aluminum Alzheimers Disease 25
DDT ADHD 25
PCBs Diabetes 25
Dioxin-like PCBs Rheumatoid Arthritis 25
Arsenic Gout 23
Bisphenol A Diabetes 22
Cigarette smoking Lung Cancer 21
Arsenic Diabetes 20
Polycyclic aromatic hydrocarbons Diabetes 20
Huge Detoxification Variability
bull CYP2C19
Proton pump inhibitors and some antidepressants
5-fold difference in activity between poor metabolizers and extensive metabolizers more so if CYP3A4 is also inhibited
Ultrarapid allele in 18 of both Swedes and Ethiopians
bull CYP2D6
Metabolizes a large number of drugs (~25)
7 of Caucasians poor metabolizers
~30 ultra rapid metabolizers in Arabian and Eastern African populations
More adverse effects in poor metabolizers and ineffective dosing in ultrarapid metabolizers
Inhibited by ginger
Desta Z et al Clinical significance of the cytochrome P450 2C19 genetic polymorphism Clin Pharmaco 2002
Sim SC et al A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug
response to proton pump inhibitors and antidepressants Clin Pharmacol Ther 2006
Wilkinson GR Drug metabolism and variability among patients in drug response N Engl J Med 2005
Kirchheiner J et al Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to
CYP2D6 duplication Pharmacogenomics J 2007
Toxin Half Lives in BloodToxin ldquoNormalrdquo (mgL) Acute Toxic (mgL) Half-Life
Arsenic 0002-007 005-025 2-4 days (CDC)
Benzene 00002 05-10 days
Cadmium 00003-00065 0015-005 16 years
Chlordane 0001 00025 3-4 days
DDTDDE 2-10 years
Dieldrin 00015 015-030 2-12 months
Ethanol 1000-2000 15hour
Lead 009 04-06 1-15 mo (2+ yrs bone)
Mercury 00015-0002 005-02 2 months (CDC)
PCBs 3-25 years
Toluene 05-3 days
Schulz M et al Therapeutic and toxic blood concentrations of nearly 1000 drugs and other xenobiotics Crit Care 2012 Jul 2616(4)R136
Bioaccumulation (POPs)
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
DDT banned in 1972 PCBs banned in 1977
Bioaccumulation (Cd)
Think BroadlyExogenous
Metals
Chemicalsbull Inorganic
bull Fluoride
bull Organic
bull POPs
bull Drugs
Particulate matter
Molds
Microbial
Radiationbull Light
bull Medical
bull Cell phone
Endogenous
Gut-derived toxins
Non-end product metabolites
Poorly detoxified hormones
Catecholamines (if SNP)
Toxins of Choice
Alcohol
Marijuana
Food constituents
High fructose corn syrup
Salt (acid-forming diet)
Wheat if zonulin (70)
Obesity Epidemic ndash POPs AND HFCS
47Bray GA Fructose should we worry Int J Obes (Lond) 2008 Dec32 Suppl 7S127-31
How Toxins Cause Damage 13
bull Increase free radical production
Cd induces production of ROS
Malathion inhibits catalase and glutathione peroxidase
Homocysteine oxidizes LDL cholesterol
bull Poison enzyme systems (compete with nutritional cofactors for binding sites)
Pb poisons delta aminolevulinic acid dehydratase
Cd inhibits catalase glutathione reductase and lowers
glutathione levels
bull Replace structural minerals
Pb displaces Ca in bone
How Toxins Cause Damage 23
bull Damage DNA
Benzene - causes chromosomal damage
Pesticides ndash fruit growers have more DNA damage
Phthalates and insecticides ndash damage sperm DNA
4-hydroxy catechol estrogen (4-OHE) damages breast DNA
bull Epigenetic dysmodulation
Higher cord blood levels of hexachlorobenzene associated
with 2x greater risk for obesity in children
bull Damage cell membranes
Common mechanism for heavy metals inactivates
membrane enzymes ion channels and pumps
How Toxins Cause Damage 33
bull Block insulin receptor sites
PCBs and phthalates
bull Highest levels associated with a 4 to 20-fold greater diabetes risk
bull Imbalance hormones many toxin examples
Arsenic
bull Disrupts thyroid hormone and retinoic acid receptors
Phthalates
bull Act as anti-androgens
bull More than 75 of the US population has measurable levels of
several phthalate metabolites in the urine
PCBs
bull Lower testosterone levels in men
Which are the Worst Toxins
bull According to the CDC
Toxicity
Population toxic load
Prevalence in toxic waste sites
bull According to clinical importance
Exposure
of disease
Ability of the body to detoxifyexcrete
Ag
en
cy
fo
r T
oxic
Su
bs
tan
ce
s a
nd
Dis
ea
se
Reg
istr
y
Pri
ori
ty L
ist
The Worst Toxins Clinically
My Rank Toxin Diseases Primary Sources
1 Arsenic Cancers diabetes gout Water chicken rice
2 DDT ADHD dementia diabetes Everywhere
3 Phthalates ADHD diabetes Soft plastics HABAs
4 PBDEs ADHD diabetes Flame retardant fabrics
5 PAHs ADHD cancers dyslipidemia Smoking charbroiling
6 PCBs Cancers diabetes MI RA Everywhere
7 Mercury Dementia ldquoSilverrdquo fillings fish
8 Lead Cardiovascular disease IQ Paint water
Glyphosate Research invalid
Conventional Laboratory Tests Reflect
Toxic Load in ldquoNormalrdquo Range
bull Surprising number show toxin exposure
CBC RBC WBC platelet count hemoglobin basophilic
stippling
Liver enzymes ALT GGTP
Inflammatory markers CRP
Lipids LDL oxLDL triglycerides
Blood sugar insulin FBS 2-hour PP
Metabolites bilirubin uric acid homocysteine 8-OHdG
Thyroid T3 T4 TSH
bull The historic ldquonormalrdquo range has been changing as the population has become more toxic
WBC Lowered by PCB and OCP Exposure
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
0
1
2
3
4
5
6
7
8
1st Quartrile 2nd Quartile 3rd Quartile 4th Quartile
WBCbull Strong inverse correlation with PCBs and OCPs and CBC
bull Linear with almost all PCBs
bull High variability with OCPs
bull Within ldquonormalrdquo range
Effects on WBC Worsen with Years
of Exposure to Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Platelet Count Decreases with Years
of Exposure tp Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Solvents Decrease Platelet Count
bull Compared workers exposed 23 hrday to those exposed most of day to toluene
bull All wore face masks and protective gear
bull Platelet count 14 lower 252 versus 216ml
bull Impairment of sympathetic nerves (OR = 413)
bull Impairment of peripheral nerves (OR = 694)
bull Positive relationship between neurological abnormalities and a self-reported neuropsychiatric measurement (r = 035-066)
Shih HT et al Subclinical abnormalities in workers with continuous low-level toluene exposure Toxicol Ind Health 2011 Sep27(8)691-9
Basophilic Stippling of Red Cells
Toxinsbull Arsenic
bull Lead
Diseasesbull Alpha-thalassemia HbH Disease
bull Beta thalassemia
bull Hereditary pyrimidine 5-nucleotidase deficiency
bull Myelodysplastic syndrome
bull Sideroblastic anemia
bull Thrombotic thrombocytopenic purpura
GGT Indirect Measure of POPsbull Glutathione is key intracellular defense against oxidative stress
bull Cellular GGT metabolizes extracellular GSH allowing precursor amino acids to be reutilized for intracellular GSH
bull Exposure to POPs induces GGT as a defensive mechanism
bull Within normal range predicts type 2 diabetes coronary heart disease hypertension stroke dyslipidemia chronic kidney disease and cancer
bull Men with GGT gt50 UI had ~26 fold risk for diabetes compared to those with lt10 Those with 40-49 had a ~20 fold risk
bull Levels within normal range occur with obesity xs alcohol cigarette smoking physical inactivity high meat low fruit and vegetable intake
bull Cumulative biomarker for environmental pollutants
Lee DH et al (2003) Gamma-glutamyltransferase and diabetesmdasha 4 year follow-up study Diabetologia 46359ndash364
Pamela A et al Serum gamma-glutamyltransferase linking together environmental pollution redox equilibria and progression of atherosclerosis Clin Chem
Lab Med 200947(12)1583-4
Lee DH et al Serum gamma-glutamyltransferase new insights about an old enzyme J Epidemiol Community Health 2009 Nov63(11)884-6
Lee DH et alSerum gamma-glutamyltransferase predicts non-fatal myocardial infarction and fatal coronary heart disease among 28838 middle-aged men and
women Eur Heart J 2006272170ndash6
Lee DH et al Gamma-glutamyltransferase and diabetes--a 4 year follow-up study Diabetologia 2003 Mar46(3)359-64
Lee DH et al Can persistent organic pollutants explain the association between serum gamma-glutamyltransferase and type 2 diabetes Diabetologia 2008
Mar51(3)402-7
GGT and Alcohol Consumption
bull GGT directly correlates with alcohol consumption
bull In a non-uniform population 40 gd will elevate GGT ~15
bull Watch for false negatives
bull Genomic variation
bull Are these the ones most
sensitive todamaged by
chemical toxins
bull Could up-regulation of GGT in light alcohol consumption be reason for benefit
0
10
20
30
40
50
60
70
80
0 200 400 600 800
Grams of Ethanol per Week
Adapted from Nagaya T et al Dose-response relationships between drinking and serum tests in Japanese men
aged 40ndash59 years Alcohol 1999 Feb 17(2) 133ndash8
GGT Correlates With Toxic Metal Levels
Lee DH et al Graded associations of blood lead and urinary cadmium concentrations with oxidative-stress-related markers in the
US population results from the third National Health and Nutrition Examination Survey Environ Health
perspect 2006 Mar114(3)350-4
GGT and Diabetes Risk
0
5
10
15
20
25
30
lt10 10-19 20-29 30-39 40-49 gt50
Dia
bete
s R
isk
GGT
bull GGT over 50 associated with tripling of death rate
bull 30-40 associated with doubling
GGT Levels
Correlate with
Risk of Death
Brenner H et al Distribution determinants and prognostic value of gamma-glutamyltransferase for all-cause
mortality in a cohort of construction workers from southern Germany Prev Med 1997 26 305ndash10
GGT From Small US Company
with Young Workers
0
10
20
30
40
50
60
0 20 40 60 80 100
GGT Data from Canadian Oil Field
Workers
0
50
100
150
200
250
300
350
400
450
lt10 10-20 20-30 30-40 40-50 50-60 60-07 70-80 80-90 90-100 100-110 110-120 gt120
GGTP
20-fold increased risk of diabetes
Uric Acid Indirect Measure of POPs
bull Poly-fluorinated hydrocarbons (PFOA and PFOS) associated
with increased serum uric acid
Lin CY et al Association among serum perfluoroalkyl chemicals glucose homeostasis and metabolic syndrome
in adolescents and adults Diabetes Care 2009 Apr32(4)702-7
Steenland K et al Association of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) with uric
acid among adults with elevated community exposure to PFOA Environ Health Perspect 2010 Feb118229-33
Steenland 2010 Open Access
ALT Indirect Measure of POPs
bull ALT (proxy marker) elevation in 104 (not including viral
hepatitis hemochromatosis or alcoholic liver disease) of
NHANES 03-04 subset
bull Risk of elevated ALT increased dose-dependently with
cadmium lead mercury and PCB exposure
bull 100 of individuals had detectable PCBs 925 mercury
and 996 had detectable lead
bull In 2005-08 prevalence of NAFLD in US was 11 a
growing cause of chronic liver disease
Cave M et al Polychlorinated biphenyls lead and mercury are associated with liver disease in American adults
NHANES 2003-2004 Environ Health Perspect 2010 Dec118(12)1735-42
Younossi ZM et al Changes in the prevalence of the most common causes of chronic liver diseases in the United
States from 1988 to 2008 Clin Gastroenterol Hepatol 2011 Jun9(6)524-530e1
Bilirubin as a Marker of POPs
bull Degree of serum bilirubin increase is prognostically significant in chronic liver dysfunction
bull Mono-ortho PCB TEQ values were found to be significantly positively associated with bilirubin (β=071 P=0008) following adjustment for multiple potential confounders
bull Bilirubin levels significantly correlated with PCBs -105-118-126 and -194
bull Smoking appears to be the biggest confounder
Dufour DR et al 2000 Diagnosis and monitoring of hepatic injury II Recommendations for use of laboratory
tests in screening diagnosis and monitoring Clin Chem 46 2050ndash68
Kumar J et al Persistent organic pollutants and liver dysfunction biomarkers in a population-based human sample
of men and women Environ Res 2014134251-256
Perf
luo
rin
ate
dP
OP
s a
nd
Co
mm
on
Blo
od
Tests
Gleason JA et al Associations of perfluorinated chemical serum concentrations and biomarkers of liver function and uric acid in the
US population (NHANES) 2007-2010 Environ Res 20151368-14
Liver Enzymes Reflect Toxic Load
bull AST ALT and GGT increase with body load of PCBs and OCPs
bull Some non-linear
bull Oxychlordanetop quartile
ALT 10
GGT 25
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
LDL-Cholesterol as Measure of POPs
bull 5-year prospective study to determine if POP levels predict future elevation in LDL-cholesterol
bull 598 subjects initially at age 70
bull Looked at 23 POPs
bull Best correlation with PCB 194
Penell J Lind L Salihovic S et al Persistent organic pollutants are related to change in circulating
lipid levels during a 5 year follow-up Environ Res 134(2014)190ndash197
oxLDL as Measure of POPs
bull 992 70-year old individuals (50 women)
bull Sum of PCBs showed strong significant positive associations with ox-LDL and significant negative associations with glutathione-related markers (GSSG and GSSGGSH)
bull A number of POPs (PCB-99 138 153 156 170 180 194 206 and 209) showed strong significant positive association with ox-LDL
Kumar J et al Influence of persistent organic pollutants on oxidative stress in population-based samples
Chemosphere 2014114303-309
Homocysteine is Increased by Pb amp Cd
Guallar E et al Confounding of the relation between homocysteine and peripheral arterial disease by lead cadmium and renal function Am J Epidemiol 2006 Apr 15163(8)700-8
Nutrient Deficiencies Accentuate
Effects of Lead on Homocysteine
bull Deficiencies in folate B6 or B12 make lead more toxic
Lee YM Et al Association of homocysteine levels with blood lead levels and micronutrients in the US general population J Prev Med Public Health 2012 Nov45(6)387-93
T4 amp T3 and PCBs
bull PCBs decrease T4 production
bull PCBs inhibit iodotyrosinedeiodinase activity
bull Study done in pregnant women which implies effect on fetus IQ
Kim S Park J Kim HJ et al Association between several persistent organic pollutants and thyroid hormone levels in serum among the pregnant women of Korea Environ Int 2013 Sep59442-8Shimizu R Yamaguchi M Uramaru N et al Structure-activity relationships of 44 halogenated compounds for iodotyrosinedeiodinase-inhibitory activity Toxicology 2013 Dec 6314(1)22-9
T4 amp T3 and PCBs
bull Not just humans being affected
bull Large study of dolphins shows exactly the same effects
Schwacke LH Zolman ES Balmer BC et al Anaemia hypothyroidism and immune suppression associated with polychlorinated biphenyl exposure in bottlenose dolphins (Tursiops truncatus) Proceed Royal Society B doi101098rspb20110665
8-OHdG
bull Oxidized nucleoside
bull Direct measure of DNA damage
bull Indirect measure of oxidative stress and toxin load
bull Correlates with
Multiple cancers
Mitochondrial damage
Rate of aging
Smoking
Several toxinsWalter Crinnion ldquoTotal Toxic Loadrdquo AANP 2015
8-OHdG Correlates with Pack-Years
of Smoking
Yano T et al Significance of the urinary 8-OHdG level as an oxidative stress marker in lung cancer patients Lung Cancer
2009 Jan63(1)111-4
8-OHdG Correlates
with Mercury
Chen C et al Increased oxidative DNA damage as assessed by urinary 8-hydroxy-2-deoxyguanosine
concentrations and serum redox status in persons exposed to mercury Clin Chem 2005 Apr51(4)759-67
Toxin Effects Worse with Aging
bull Thyroid function decreases with PFOA levels
bull But only after age 63
Shrestha S Bloom MS Yucel R et al Perfluoroalkyl substances and thyroid function in older adults Environ Int 2015 Feb75206-14
Insightful 23-Year Prospective Study
1 lt 50 there is no difference between those with the lowest and highest PCBs
2 In youngest group insulin production increases in response to toxin level As expected since blocking of
insulin receptor sites by PCBs
requires more insulin
3 That adaptive ability decreases with aging
4 At age 50 all the measures show very strong toxin-dose response
Cumulative damage impairs ability to adapt
Suarez-Lopez JR et al Persistent organic pollutants in young adults and changes in glucose related metabolism over a 23-year follow-up Environ Res 2015 Feb137485-94
Recommendations
High body toxic load
GGT gt 25
Uric acid gt 50 mgdl
ALT gt30 UL
Bilirubin gt08 mgdl
CBC lt 6000
Platelet lt 250000
Low T3 andor T4
Monitor Total Toxic Load
8-OHdG gt4
ldquoUnconventionalrdquo Laboratory Tests
bull Challenge testing
bull Hair analysis
bull Direct measures of solvents and POPs in blood urine adipose tissue
Evaluation of Metal Exposure ndash Provocation
bull Provocation ndash the use of a chelating agent ndash before urine collection often done clinically but several limitations
No ldquoofficialrdquo reference range for provoked urine
Most chelating agents do not extract metals from all tissues thus
does not necessarily represent total body burden
bull Example Brain is one of the main target organs for both elemental and organic
mercury yet agents do not chelate brain mercury
bull Despite limitations widely used and advocated by clinicians in part to see efficacy of chelating agent as a guide to treatment and based on empirical evidence
Rooney JP The role of thiols dithiols nutritional factors and interacting ligands in the toxicology of mercury
Toxicology 2007
Is Challenge Testing Valid
bull Poor correlations of standard tests for mercury
bull Unpublished research from corporate wellness project
bull Published amalgam number correlation
bull Published fish consumption correlation
What We Found In Canada
bull Deviations from the mean of 14 29 and 91 respectively
bull DMPS is spreading distribution suggesting that it is better at differentiating mercury body load
bull Some VERY high
Hg Assessment Correlations
bull Extensive measurements in 65 Whole blood Hg
Oral DMPS challenge
Amalgam surfaces
bull Correlations Whole blood w pre urine r = 040
Whole blood w post urine r = 057
Pre urine w post urine r = 068
Amalgams w pre urine r = 026
Amalgams w whole blood r = 036
Amalgams with post urine 044
bull Clear documentation that
challenge testing is better00
100
200
300
400
500
600
0 10 20 30 40 50
Po
st
Uri
ne H
g u
gg
Number of amalgams
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
Example Smoking and Lung Cancer
B = 5Number of smokers
who contract Lung Cancer notdue to smoking
A = 5Number of smokerswho contract Lung
Cancer due to smoking
C = 15Number of
nonsmokerswho contract Lung Cancer
0
2
4
6
8
10
12
14
16
Smokers (N=100) Nonsmokers (N=300)Num
ber
of
people
who c
ontr
act
Lung C
ancer
per
year
Baseline Additional due to smoking
Number of smokers and nonsmokers who contract lung cancer
Our Process In Summary
1 Determine threshold for increased disease risk
2 Determine of population above threshold
3 Determine incidence of disease (OR) in those above threshold
4 Determine incidence of disease in ldquounexposed populationrdquo
5 Calculate AF ie of disease
As whole population is exposed probably UNDERESTIMATES of disease
To
xic
ity H
as B
eco
me t
he N
ew
ldquoN
orm
alrdquo
Toxin Type Use Threshold for
disease
association
of US
above
threshold
Disease Associations
Chlordane OC pesticide Termites corn citrus lawns
gardens
145ngg lipid 63
(diabetes)
Diabetes (20)
BPA Plasticizer Water bottles canned food
water pipes thermal sales
receipts
48 men 51
women (urine
ngmL)
~18
(diabetes)
Diabetes hypertension
Octachloro
dibenzo-p-
dioxin
(OCDD)
Polychlorinated
dibenzo-p-
dioxin
Incineration or burning of
waste bleaching processes
used in pulp and paper mills
1010 pgg
lipid (highest
quartile)
10-25
(hypertensio
n)
Hypertension (79 for
women highest
quartile) diabetes (21)
obesity learning
disability (272)
MEP
(mono-
ethyl
phthalate)
Phthalate
(plasticizer
fragrance)
Toothbrushes automobile
parts tools toys and food
packaging aspirin
cosmetics food packaging
gt175 ngmL
(urine)
~60
(diabetes)
Diabetes (148) lower
BMD obesity
pp-DDE DDT
metabolite (OC
pesticide)
Agricultural crops 1560ngg
lipid
25
(diabetes)
Diabetes (23-43)
early menopause
impaired cognitive
function (2-3x 65x in
highest 5th percentile)
peripheral arterial
disease
Arsenic Toxic metal Miningsmelting wood
preservative pesticides
74ugL total
arsenic (urine)
20
(diabetes)
Cancers diabetes (26-
46) dyslipidemia gout
AF OR Prevalence
Rosen L An intuitive approach to understanding the attributable fraction of disease due to a risk factor the case of smoking Int J Environ Res Public Health 2013 Jul 1610(7)2932-43
Smoking Lung cancer
Arsenic Gout in women
BPA Diabetes
Status of Our Research
bull 26 toxins and toxin classes eg lead mercury BPA OCPs
100s of chemicals and POPs in some classes
bull 18 cancers
bull 24 chronic diseases
bull 1092 cells in spreadsheet
Large Personal Ongoing Research Investment
Huge Amount of Research Work
Toxins StudiedAluminum
Arsenic
Cadmium
Fluoride
Lead
Manganese
Mercury
Acrylamide
Acrylonitrile
Benzene
Bisphenol A (BPA)
Chloroform
DDT
Dioxins
Glyphosate
Organochlorine pesticides (OCPs)
Organophosphate pesticides
Parabens
Phthalates
Polybrominated diphenyl ethers (PBDEs)
Polycyclic aromatic hydrocarbons (PAHs)
Polychlorinated biphenols (PCBs)
Vinyl chloride
Diseases Studied
ADHD
Alzheimers Disease
ALS
Angiosarcoma
Anxiety
Atopic Conditions
Diabetes
Dyslipidemia
Gout
Fetal Abnormalities
Hyperuricemia
Infertility
Juvenile IQ
Cancer Bladder
Cancer Bone
Cancer Brain
Cancer Breast
Cancer Cervix
Cancer Colorectal
Cancer Endometrial
Cancer Head amp Neck
Cancer Liver
Cancer Lung
Cancer Lymph amp Blood
Cancer Ovarian
Cancer Pancreatic
Cancer Prostate
Cancer Renal
Cancer Skin
Cancer Testicular
Cancer Thyroid
Juvenile Obesity
Metabolic Syndrome
Mitochondrial dysfunction
Myocardial Infarction
Obstructive Lung Disease
Osteoporosis
Peripheral Artery Disease
Peripheral Neuropathy
Prediabetes
Renal Disease
Rheumatoid Arthritis
Thyroid Dysfunction
OC
Ps
Th
rou
gh
ou
t th
e W
orl
d
Rathore HS Nollet LML Pesticides Evaluation of Environmental Pollution CRC Press
2012 page 562
Threshold ndash Threshold exposure at which there is an increased risk of disease outcome
Above Threshold ndash Percentage of the population with higher exposure than the threshold
Odds Ratio ndash Increased disease risk in those above threshold
of Dz ndash Percent contribution of the toxin to that disease outcome
How to Interpret the Following Slides
Attention Deficit Hyperactivity Disorder
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
DDT 126 ngg
serum (pp-
DDE)
250 18 166 20106937
Lead 23 ugdL 13 254 20 27659349
Mercury 16 24952233
Organophosphate
pesticides
20
Polycyclic
Aromatic
Hydrocarbons
227 ngm3 940 125 190 22440811
PCBs 104 ngg
serum (sum
of 50 PCBs)
250 176 160 20106937
DiabetesToxin Threshold Above
Threshold
Odds
Ratio
of Dz Reference
PMID
Arsenic 165 ugL 200 21 180 18714061
BPA 28 ugL 280 145 112 26119400
DDE 545 ngg serum
(pp-DDE)
200 230 31 26119400
Dioxins2 pgg lipid 50 191 43
26119400
PCBs104 ngg (PCB 153) 250 239 258
26119400
Phthalates175 ugL 690 148 249
26119400
1-naphthalene 167 ugdL 152 182 111 26340343
2-napthalene 414 ugdL 550 224 214 26340343
1-phenanthrene 167 ngL 570 178 151 26340343
1-pyrene 85 ngL 660 180 174 26340343
Lung Cancer
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Acrylonitrile Uncertain Uncertain 125 25
occupational
exposure
17114112
Arsenic 1213 ugL 436 of Asian
Americans
~01 of total
US population
34 95 in AA
01-1
PMC2682945
Cadmium Uncertain+ Uncertain 467 10 in
smokers
17184399
DDT Any exposure All US pop
below LOD
17 76 increased
risk
8923607
Breast Cancer
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Cadmium 0580 ugg
creatinine
126 205 479 16788160
PCB 138 396 ngg
creatinine
202 316 630 27717745
PCB 187 108 ngg lipid 600 194 360 21480306
Miscellaneous Diseases
Toxin Disease Threshold Above
Threshold
Odds
Ratio
of Dz Reference PMID
Aluminum Alzheimer
Dz
01 mgL
drinking
H20
400 203 05-44 26592479
Benzene AML 100ppmyrs 1-3 320 60 PMC2903550
DDT NHL 0512 ugL 1-2 240 01 17722095
Lead ALS 238 ugdL
blood
330 181 210 25479292
Lead Brain CA 0005 ugdL 14 19 ~500 17164378
Dioxin-like
PCBs
RA 326 ngg
lipid
250 219 220 17589595
PAHs Asthma 124 ngm3 935 200 483 19221603
The Potency of Arsenic
Disease Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Bladder CA 10ugL H20 100 27 145 24889821
Pancreatic CA 1332 ugg 200 246 230 23800676
Prostate CA 1332 ugg 200 33 315 23800676
Gout 125 ugL 245 546 522 25499256
Diabetes 165 ugL 200 21 180 18714061
Arsenic (180 of Diabetes)
How it causes diabetes
bull Blocks sugar stimulating insulin secretion
bull Epigenetic inhibition of sugar regulation
Where it comes from
bull Water (gt10 of US water supplies have high levels)
bull Rice (naturally absorbs if in the water)
bull Chicken (added to make meat whiter)
Pan W-C Seow WJ Kile ML et al Association of low to moderate levels of arsenic exposure with risk of Type 2 diabetes in Bangladesh American Journal of Epidemiology 2013178(10)1563-70
Portion of Population with Toxin Load Which
Doubles Disease Risk
Toxin Disease with Doubled Risk
Polycyclic aromatic hydrocarbons Asthma 94
PCB187 Breast Cancer 60
Phthalates Diabetes 55
Lead ALS 33
Aluminum Alzheimers Disease 25
DDT ADHD 25
PCBs Diabetes 25
Dioxin-like PCBs Rheumatoid Arthritis 25
Arsenic Gout 23
Bisphenol A Diabetes 22
Cigarette smoking Lung Cancer 21
Arsenic Diabetes 20
Polycyclic aromatic hydrocarbons Diabetes 20
Huge Detoxification Variability
bull CYP2C19
Proton pump inhibitors and some antidepressants
5-fold difference in activity between poor metabolizers and extensive metabolizers more so if CYP3A4 is also inhibited
Ultrarapid allele in 18 of both Swedes and Ethiopians
bull CYP2D6
Metabolizes a large number of drugs (~25)
7 of Caucasians poor metabolizers
~30 ultra rapid metabolizers in Arabian and Eastern African populations
More adverse effects in poor metabolizers and ineffective dosing in ultrarapid metabolizers
Inhibited by ginger
Desta Z et al Clinical significance of the cytochrome P450 2C19 genetic polymorphism Clin Pharmaco 2002
Sim SC et al A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug
response to proton pump inhibitors and antidepressants Clin Pharmacol Ther 2006
Wilkinson GR Drug metabolism and variability among patients in drug response N Engl J Med 2005
Kirchheiner J et al Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to
CYP2D6 duplication Pharmacogenomics J 2007
Toxin Half Lives in BloodToxin ldquoNormalrdquo (mgL) Acute Toxic (mgL) Half-Life
Arsenic 0002-007 005-025 2-4 days (CDC)
Benzene 00002 05-10 days
Cadmium 00003-00065 0015-005 16 years
Chlordane 0001 00025 3-4 days
DDTDDE 2-10 years
Dieldrin 00015 015-030 2-12 months
Ethanol 1000-2000 15hour
Lead 009 04-06 1-15 mo (2+ yrs bone)
Mercury 00015-0002 005-02 2 months (CDC)
PCBs 3-25 years
Toluene 05-3 days
Schulz M et al Therapeutic and toxic blood concentrations of nearly 1000 drugs and other xenobiotics Crit Care 2012 Jul 2616(4)R136
Bioaccumulation (POPs)
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
DDT banned in 1972 PCBs banned in 1977
Bioaccumulation (Cd)
Think BroadlyExogenous
Metals
Chemicalsbull Inorganic
bull Fluoride
bull Organic
bull POPs
bull Drugs
Particulate matter
Molds
Microbial
Radiationbull Light
bull Medical
bull Cell phone
Endogenous
Gut-derived toxins
Non-end product metabolites
Poorly detoxified hormones
Catecholamines (if SNP)
Toxins of Choice
Alcohol
Marijuana
Food constituents
High fructose corn syrup
Salt (acid-forming diet)
Wheat if zonulin (70)
Obesity Epidemic ndash POPs AND HFCS
47Bray GA Fructose should we worry Int J Obes (Lond) 2008 Dec32 Suppl 7S127-31
How Toxins Cause Damage 13
bull Increase free radical production
Cd induces production of ROS
Malathion inhibits catalase and glutathione peroxidase
Homocysteine oxidizes LDL cholesterol
bull Poison enzyme systems (compete with nutritional cofactors for binding sites)
Pb poisons delta aminolevulinic acid dehydratase
Cd inhibits catalase glutathione reductase and lowers
glutathione levels
bull Replace structural minerals
Pb displaces Ca in bone
How Toxins Cause Damage 23
bull Damage DNA
Benzene - causes chromosomal damage
Pesticides ndash fruit growers have more DNA damage
Phthalates and insecticides ndash damage sperm DNA
4-hydroxy catechol estrogen (4-OHE) damages breast DNA
bull Epigenetic dysmodulation
Higher cord blood levels of hexachlorobenzene associated
with 2x greater risk for obesity in children
bull Damage cell membranes
Common mechanism for heavy metals inactivates
membrane enzymes ion channels and pumps
How Toxins Cause Damage 33
bull Block insulin receptor sites
PCBs and phthalates
bull Highest levels associated with a 4 to 20-fold greater diabetes risk
bull Imbalance hormones many toxin examples
Arsenic
bull Disrupts thyroid hormone and retinoic acid receptors
Phthalates
bull Act as anti-androgens
bull More than 75 of the US population has measurable levels of
several phthalate metabolites in the urine
PCBs
bull Lower testosterone levels in men
Which are the Worst Toxins
bull According to the CDC
Toxicity
Population toxic load
Prevalence in toxic waste sites
bull According to clinical importance
Exposure
of disease
Ability of the body to detoxifyexcrete
Ag
en
cy
fo
r T
oxic
Su
bs
tan
ce
s a
nd
Dis
ea
se
Reg
istr
y
Pri
ori
ty L
ist
The Worst Toxins Clinically
My Rank Toxin Diseases Primary Sources
1 Arsenic Cancers diabetes gout Water chicken rice
2 DDT ADHD dementia diabetes Everywhere
3 Phthalates ADHD diabetes Soft plastics HABAs
4 PBDEs ADHD diabetes Flame retardant fabrics
5 PAHs ADHD cancers dyslipidemia Smoking charbroiling
6 PCBs Cancers diabetes MI RA Everywhere
7 Mercury Dementia ldquoSilverrdquo fillings fish
8 Lead Cardiovascular disease IQ Paint water
Glyphosate Research invalid
Conventional Laboratory Tests Reflect
Toxic Load in ldquoNormalrdquo Range
bull Surprising number show toxin exposure
CBC RBC WBC platelet count hemoglobin basophilic
stippling
Liver enzymes ALT GGTP
Inflammatory markers CRP
Lipids LDL oxLDL triglycerides
Blood sugar insulin FBS 2-hour PP
Metabolites bilirubin uric acid homocysteine 8-OHdG
Thyroid T3 T4 TSH
bull The historic ldquonormalrdquo range has been changing as the population has become more toxic
WBC Lowered by PCB and OCP Exposure
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
0
1
2
3
4
5
6
7
8
1st Quartrile 2nd Quartile 3rd Quartile 4th Quartile
WBCbull Strong inverse correlation with PCBs and OCPs and CBC
bull Linear with almost all PCBs
bull High variability with OCPs
bull Within ldquonormalrdquo range
Effects on WBC Worsen with Years
of Exposure to Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Platelet Count Decreases with Years
of Exposure tp Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Solvents Decrease Platelet Count
bull Compared workers exposed 23 hrday to those exposed most of day to toluene
bull All wore face masks and protective gear
bull Platelet count 14 lower 252 versus 216ml
bull Impairment of sympathetic nerves (OR = 413)
bull Impairment of peripheral nerves (OR = 694)
bull Positive relationship between neurological abnormalities and a self-reported neuropsychiatric measurement (r = 035-066)
Shih HT et al Subclinical abnormalities in workers with continuous low-level toluene exposure Toxicol Ind Health 2011 Sep27(8)691-9
Basophilic Stippling of Red Cells
Toxinsbull Arsenic
bull Lead
Diseasesbull Alpha-thalassemia HbH Disease
bull Beta thalassemia
bull Hereditary pyrimidine 5-nucleotidase deficiency
bull Myelodysplastic syndrome
bull Sideroblastic anemia
bull Thrombotic thrombocytopenic purpura
GGT Indirect Measure of POPsbull Glutathione is key intracellular defense against oxidative stress
bull Cellular GGT metabolizes extracellular GSH allowing precursor amino acids to be reutilized for intracellular GSH
bull Exposure to POPs induces GGT as a defensive mechanism
bull Within normal range predicts type 2 diabetes coronary heart disease hypertension stroke dyslipidemia chronic kidney disease and cancer
bull Men with GGT gt50 UI had ~26 fold risk for diabetes compared to those with lt10 Those with 40-49 had a ~20 fold risk
bull Levels within normal range occur with obesity xs alcohol cigarette smoking physical inactivity high meat low fruit and vegetable intake
bull Cumulative biomarker for environmental pollutants
Lee DH et al (2003) Gamma-glutamyltransferase and diabetesmdasha 4 year follow-up study Diabetologia 46359ndash364
Pamela A et al Serum gamma-glutamyltransferase linking together environmental pollution redox equilibria and progression of atherosclerosis Clin Chem
Lab Med 200947(12)1583-4
Lee DH et al Serum gamma-glutamyltransferase new insights about an old enzyme J Epidemiol Community Health 2009 Nov63(11)884-6
Lee DH et alSerum gamma-glutamyltransferase predicts non-fatal myocardial infarction and fatal coronary heart disease among 28838 middle-aged men and
women Eur Heart J 2006272170ndash6
Lee DH et al Gamma-glutamyltransferase and diabetes--a 4 year follow-up study Diabetologia 2003 Mar46(3)359-64
Lee DH et al Can persistent organic pollutants explain the association between serum gamma-glutamyltransferase and type 2 diabetes Diabetologia 2008
Mar51(3)402-7
GGT and Alcohol Consumption
bull GGT directly correlates with alcohol consumption
bull In a non-uniform population 40 gd will elevate GGT ~15
bull Watch for false negatives
bull Genomic variation
bull Are these the ones most
sensitive todamaged by
chemical toxins
bull Could up-regulation of GGT in light alcohol consumption be reason for benefit
0
10
20
30
40
50
60
70
80
0 200 400 600 800
Grams of Ethanol per Week
Adapted from Nagaya T et al Dose-response relationships between drinking and serum tests in Japanese men
aged 40ndash59 years Alcohol 1999 Feb 17(2) 133ndash8
GGT Correlates With Toxic Metal Levels
Lee DH et al Graded associations of blood lead and urinary cadmium concentrations with oxidative-stress-related markers in the
US population results from the third National Health and Nutrition Examination Survey Environ Health
perspect 2006 Mar114(3)350-4
GGT and Diabetes Risk
0
5
10
15
20
25
30
lt10 10-19 20-29 30-39 40-49 gt50
Dia
bete
s R
isk
GGT
bull GGT over 50 associated with tripling of death rate
bull 30-40 associated with doubling
GGT Levels
Correlate with
Risk of Death
Brenner H et al Distribution determinants and prognostic value of gamma-glutamyltransferase for all-cause
mortality in a cohort of construction workers from southern Germany Prev Med 1997 26 305ndash10
GGT From Small US Company
with Young Workers
0
10
20
30
40
50
60
0 20 40 60 80 100
GGT Data from Canadian Oil Field
Workers
0
50
100
150
200
250
300
350
400
450
lt10 10-20 20-30 30-40 40-50 50-60 60-07 70-80 80-90 90-100 100-110 110-120 gt120
GGTP
20-fold increased risk of diabetes
Uric Acid Indirect Measure of POPs
bull Poly-fluorinated hydrocarbons (PFOA and PFOS) associated
with increased serum uric acid
Lin CY et al Association among serum perfluoroalkyl chemicals glucose homeostasis and metabolic syndrome
in adolescents and adults Diabetes Care 2009 Apr32(4)702-7
Steenland K et al Association of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) with uric
acid among adults with elevated community exposure to PFOA Environ Health Perspect 2010 Feb118229-33
Steenland 2010 Open Access
ALT Indirect Measure of POPs
bull ALT (proxy marker) elevation in 104 (not including viral
hepatitis hemochromatosis or alcoholic liver disease) of
NHANES 03-04 subset
bull Risk of elevated ALT increased dose-dependently with
cadmium lead mercury and PCB exposure
bull 100 of individuals had detectable PCBs 925 mercury
and 996 had detectable lead
bull In 2005-08 prevalence of NAFLD in US was 11 a
growing cause of chronic liver disease
Cave M et al Polychlorinated biphenyls lead and mercury are associated with liver disease in American adults
NHANES 2003-2004 Environ Health Perspect 2010 Dec118(12)1735-42
Younossi ZM et al Changes in the prevalence of the most common causes of chronic liver diseases in the United
States from 1988 to 2008 Clin Gastroenterol Hepatol 2011 Jun9(6)524-530e1
Bilirubin as a Marker of POPs
bull Degree of serum bilirubin increase is prognostically significant in chronic liver dysfunction
bull Mono-ortho PCB TEQ values were found to be significantly positively associated with bilirubin (β=071 P=0008) following adjustment for multiple potential confounders
bull Bilirubin levels significantly correlated with PCBs -105-118-126 and -194
bull Smoking appears to be the biggest confounder
Dufour DR et al 2000 Diagnosis and monitoring of hepatic injury II Recommendations for use of laboratory
tests in screening diagnosis and monitoring Clin Chem 46 2050ndash68
Kumar J et al Persistent organic pollutants and liver dysfunction biomarkers in a population-based human sample
of men and women Environ Res 2014134251-256
Perf
luo
rin
ate
dP
OP
s a
nd
Co
mm
on
Blo
od
Tests
Gleason JA et al Associations of perfluorinated chemical serum concentrations and biomarkers of liver function and uric acid in the
US population (NHANES) 2007-2010 Environ Res 20151368-14
Liver Enzymes Reflect Toxic Load
bull AST ALT and GGT increase with body load of PCBs and OCPs
bull Some non-linear
bull Oxychlordanetop quartile
ALT 10
GGT 25
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
LDL-Cholesterol as Measure of POPs
bull 5-year prospective study to determine if POP levels predict future elevation in LDL-cholesterol
bull 598 subjects initially at age 70
bull Looked at 23 POPs
bull Best correlation with PCB 194
Penell J Lind L Salihovic S et al Persistent organic pollutants are related to change in circulating
lipid levels during a 5 year follow-up Environ Res 134(2014)190ndash197
oxLDL as Measure of POPs
bull 992 70-year old individuals (50 women)
bull Sum of PCBs showed strong significant positive associations with ox-LDL and significant negative associations with glutathione-related markers (GSSG and GSSGGSH)
bull A number of POPs (PCB-99 138 153 156 170 180 194 206 and 209) showed strong significant positive association with ox-LDL
Kumar J et al Influence of persistent organic pollutants on oxidative stress in population-based samples
Chemosphere 2014114303-309
Homocysteine is Increased by Pb amp Cd
Guallar E et al Confounding of the relation between homocysteine and peripheral arterial disease by lead cadmium and renal function Am J Epidemiol 2006 Apr 15163(8)700-8
Nutrient Deficiencies Accentuate
Effects of Lead on Homocysteine
bull Deficiencies in folate B6 or B12 make lead more toxic
Lee YM Et al Association of homocysteine levels with blood lead levels and micronutrients in the US general population J Prev Med Public Health 2012 Nov45(6)387-93
T4 amp T3 and PCBs
bull PCBs decrease T4 production
bull PCBs inhibit iodotyrosinedeiodinase activity
bull Study done in pregnant women which implies effect on fetus IQ
Kim S Park J Kim HJ et al Association between several persistent organic pollutants and thyroid hormone levels in serum among the pregnant women of Korea Environ Int 2013 Sep59442-8Shimizu R Yamaguchi M Uramaru N et al Structure-activity relationships of 44 halogenated compounds for iodotyrosinedeiodinase-inhibitory activity Toxicology 2013 Dec 6314(1)22-9
T4 amp T3 and PCBs
bull Not just humans being affected
bull Large study of dolphins shows exactly the same effects
Schwacke LH Zolman ES Balmer BC et al Anaemia hypothyroidism and immune suppression associated with polychlorinated biphenyl exposure in bottlenose dolphins (Tursiops truncatus) Proceed Royal Society B doi101098rspb20110665
8-OHdG
bull Oxidized nucleoside
bull Direct measure of DNA damage
bull Indirect measure of oxidative stress and toxin load
bull Correlates with
Multiple cancers
Mitochondrial damage
Rate of aging
Smoking
Several toxinsWalter Crinnion ldquoTotal Toxic Loadrdquo AANP 2015
8-OHdG Correlates with Pack-Years
of Smoking
Yano T et al Significance of the urinary 8-OHdG level as an oxidative stress marker in lung cancer patients Lung Cancer
2009 Jan63(1)111-4
8-OHdG Correlates
with Mercury
Chen C et al Increased oxidative DNA damage as assessed by urinary 8-hydroxy-2-deoxyguanosine
concentrations and serum redox status in persons exposed to mercury Clin Chem 2005 Apr51(4)759-67
Toxin Effects Worse with Aging
bull Thyroid function decreases with PFOA levels
bull But only after age 63
Shrestha S Bloom MS Yucel R et al Perfluoroalkyl substances and thyroid function in older adults Environ Int 2015 Feb75206-14
Insightful 23-Year Prospective Study
1 lt 50 there is no difference between those with the lowest and highest PCBs
2 In youngest group insulin production increases in response to toxin level As expected since blocking of
insulin receptor sites by PCBs
requires more insulin
3 That adaptive ability decreases with aging
4 At age 50 all the measures show very strong toxin-dose response
Cumulative damage impairs ability to adapt
Suarez-Lopez JR et al Persistent organic pollutants in young adults and changes in glucose related metabolism over a 23-year follow-up Environ Res 2015 Feb137485-94
Recommendations
High body toxic load
GGT gt 25
Uric acid gt 50 mgdl
ALT gt30 UL
Bilirubin gt08 mgdl
CBC lt 6000
Platelet lt 250000
Low T3 andor T4
Monitor Total Toxic Load
8-OHdG gt4
ldquoUnconventionalrdquo Laboratory Tests
bull Challenge testing
bull Hair analysis
bull Direct measures of solvents and POPs in blood urine adipose tissue
Evaluation of Metal Exposure ndash Provocation
bull Provocation ndash the use of a chelating agent ndash before urine collection often done clinically but several limitations
No ldquoofficialrdquo reference range for provoked urine
Most chelating agents do not extract metals from all tissues thus
does not necessarily represent total body burden
bull Example Brain is one of the main target organs for both elemental and organic
mercury yet agents do not chelate brain mercury
bull Despite limitations widely used and advocated by clinicians in part to see efficacy of chelating agent as a guide to treatment and based on empirical evidence
Rooney JP The role of thiols dithiols nutritional factors and interacting ligands in the toxicology of mercury
Toxicology 2007
Is Challenge Testing Valid
bull Poor correlations of standard tests for mercury
bull Unpublished research from corporate wellness project
bull Published amalgam number correlation
bull Published fish consumption correlation
What We Found In Canada
bull Deviations from the mean of 14 29 and 91 respectively
bull DMPS is spreading distribution suggesting that it is better at differentiating mercury body load
bull Some VERY high
Hg Assessment Correlations
bull Extensive measurements in 65 Whole blood Hg
Oral DMPS challenge
Amalgam surfaces
bull Correlations Whole blood w pre urine r = 040
Whole blood w post urine r = 057
Pre urine w post urine r = 068
Amalgams w pre urine r = 026
Amalgams w whole blood r = 036
Amalgams with post urine 044
bull Clear documentation that
challenge testing is better00
100
200
300
400
500
600
0 10 20 30 40 50
Po
st
Uri
ne H
g u
gg
Number of amalgams
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
Our Process In Summary
1 Determine threshold for increased disease risk
2 Determine of population above threshold
3 Determine incidence of disease (OR) in those above threshold
4 Determine incidence of disease in ldquounexposed populationrdquo
5 Calculate AF ie of disease
As whole population is exposed probably UNDERESTIMATES of disease
To
xic
ity H
as B
eco
me t
he N
ew
ldquoN
orm
alrdquo
Toxin Type Use Threshold for
disease
association
of US
above
threshold
Disease Associations
Chlordane OC pesticide Termites corn citrus lawns
gardens
145ngg lipid 63
(diabetes)
Diabetes (20)
BPA Plasticizer Water bottles canned food
water pipes thermal sales
receipts
48 men 51
women (urine
ngmL)
~18
(diabetes)
Diabetes hypertension
Octachloro
dibenzo-p-
dioxin
(OCDD)
Polychlorinated
dibenzo-p-
dioxin
Incineration or burning of
waste bleaching processes
used in pulp and paper mills
1010 pgg
lipid (highest
quartile)
10-25
(hypertensio
n)
Hypertension (79 for
women highest
quartile) diabetes (21)
obesity learning
disability (272)
MEP
(mono-
ethyl
phthalate)
Phthalate
(plasticizer
fragrance)
Toothbrushes automobile
parts tools toys and food
packaging aspirin
cosmetics food packaging
gt175 ngmL
(urine)
~60
(diabetes)
Diabetes (148) lower
BMD obesity
pp-DDE DDT
metabolite (OC
pesticide)
Agricultural crops 1560ngg
lipid
25
(diabetes)
Diabetes (23-43)
early menopause
impaired cognitive
function (2-3x 65x in
highest 5th percentile)
peripheral arterial
disease
Arsenic Toxic metal Miningsmelting wood
preservative pesticides
74ugL total
arsenic (urine)
20
(diabetes)
Cancers diabetes (26-
46) dyslipidemia gout
AF OR Prevalence
Rosen L An intuitive approach to understanding the attributable fraction of disease due to a risk factor the case of smoking Int J Environ Res Public Health 2013 Jul 1610(7)2932-43
Smoking Lung cancer
Arsenic Gout in women
BPA Diabetes
Status of Our Research
bull 26 toxins and toxin classes eg lead mercury BPA OCPs
100s of chemicals and POPs in some classes
bull 18 cancers
bull 24 chronic diseases
bull 1092 cells in spreadsheet
Large Personal Ongoing Research Investment
Huge Amount of Research Work
Toxins StudiedAluminum
Arsenic
Cadmium
Fluoride
Lead
Manganese
Mercury
Acrylamide
Acrylonitrile
Benzene
Bisphenol A (BPA)
Chloroform
DDT
Dioxins
Glyphosate
Organochlorine pesticides (OCPs)
Organophosphate pesticides
Parabens
Phthalates
Polybrominated diphenyl ethers (PBDEs)
Polycyclic aromatic hydrocarbons (PAHs)
Polychlorinated biphenols (PCBs)
Vinyl chloride
Diseases Studied
ADHD
Alzheimers Disease
ALS
Angiosarcoma
Anxiety
Atopic Conditions
Diabetes
Dyslipidemia
Gout
Fetal Abnormalities
Hyperuricemia
Infertility
Juvenile IQ
Cancer Bladder
Cancer Bone
Cancer Brain
Cancer Breast
Cancer Cervix
Cancer Colorectal
Cancer Endometrial
Cancer Head amp Neck
Cancer Liver
Cancer Lung
Cancer Lymph amp Blood
Cancer Ovarian
Cancer Pancreatic
Cancer Prostate
Cancer Renal
Cancer Skin
Cancer Testicular
Cancer Thyroid
Juvenile Obesity
Metabolic Syndrome
Mitochondrial dysfunction
Myocardial Infarction
Obstructive Lung Disease
Osteoporosis
Peripheral Artery Disease
Peripheral Neuropathy
Prediabetes
Renal Disease
Rheumatoid Arthritis
Thyroid Dysfunction
OC
Ps
Th
rou
gh
ou
t th
e W
orl
d
Rathore HS Nollet LML Pesticides Evaluation of Environmental Pollution CRC Press
2012 page 562
Threshold ndash Threshold exposure at which there is an increased risk of disease outcome
Above Threshold ndash Percentage of the population with higher exposure than the threshold
Odds Ratio ndash Increased disease risk in those above threshold
of Dz ndash Percent contribution of the toxin to that disease outcome
How to Interpret the Following Slides
Attention Deficit Hyperactivity Disorder
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
DDT 126 ngg
serum (pp-
DDE)
250 18 166 20106937
Lead 23 ugdL 13 254 20 27659349
Mercury 16 24952233
Organophosphate
pesticides
20
Polycyclic
Aromatic
Hydrocarbons
227 ngm3 940 125 190 22440811
PCBs 104 ngg
serum (sum
of 50 PCBs)
250 176 160 20106937
DiabetesToxin Threshold Above
Threshold
Odds
Ratio
of Dz Reference
PMID
Arsenic 165 ugL 200 21 180 18714061
BPA 28 ugL 280 145 112 26119400
DDE 545 ngg serum
(pp-DDE)
200 230 31 26119400
Dioxins2 pgg lipid 50 191 43
26119400
PCBs104 ngg (PCB 153) 250 239 258
26119400
Phthalates175 ugL 690 148 249
26119400
1-naphthalene 167 ugdL 152 182 111 26340343
2-napthalene 414 ugdL 550 224 214 26340343
1-phenanthrene 167 ngL 570 178 151 26340343
1-pyrene 85 ngL 660 180 174 26340343
Lung Cancer
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Acrylonitrile Uncertain Uncertain 125 25
occupational
exposure
17114112
Arsenic 1213 ugL 436 of Asian
Americans
~01 of total
US population
34 95 in AA
01-1
PMC2682945
Cadmium Uncertain+ Uncertain 467 10 in
smokers
17184399
DDT Any exposure All US pop
below LOD
17 76 increased
risk
8923607
Breast Cancer
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Cadmium 0580 ugg
creatinine
126 205 479 16788160
PCB 138 396 ngg
creatinine
202 316 630 27717745
PCB 187 108 ngg lipid 600 194 360 21480306
Miscellaneous Diseases
Toxin Disease Threshold Above
Threshold
Odds
Ratio
of Dz Reference PMID
Aluminum Alzheimer
Dz
01 mgL
drinking
H20
400 203 05-44 26592479
Benzene AML 100ppmyrs 1-3 320 60 PMC2903550
DDT NHL 0512 ugL 1-2 240 01 17722095
Lead ALS 238 ugdL
blood
330 181 210 25479292
Lead Brain CA 0005 ugdL 14 19 ~500 17164378
Dioxin-like
PCBs
RA 326 ngg
lipid
250 219 220 17589595
PAHs Asthma 124 ngm3 935 200 483 19221603
The Potency of Arsenic
Disease Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Bladder CA 10ugL H20 100 27 145 24889821
Pancreatic CA 1332 ugg 200 246 230 23800676
Prostate CA 1332 ugg 200 33 315 23800676
Gout 125 ugL 245 546 522 25499256
Diabetes 165 ugL 200 21 180 18714061
Arsenic (180 of Diabetes)
How it causes diabetes
bull Blocks sugar stimulating insulin secretion
bull Epigenetic inhibition of sugar regulation
Where it comes from
bull Water (gt10 of US water supplies have high levels)
bull Rice (naturally absorbs if in the water)
bull Chicken (added to make meat whiter)
Pan W-C Seow WJ Kile ML et al Association of low to moderate levels of arsenic exposure with risk of Type 2 diabetes in Bangladesh American Journal of Epidemiology 2013178(10)1563-70
Portion of Population with Toxin Load Which
Doubles Disease Risk
Toxin Disease with Doubled Risk
Polycyclic aromatic hydrocarbons Asthma 94
PCB187 Breast Cancer 60
Phthalates Diabetes 55
Lead ALS 33
Aluminum Alzheimers Disease 25
DDT ADHD 25
PCBs Diabetes 25
Dioxin-like PCBs Rheumatoid Arthritis 25
Arsenic Gout 23
Bisphenol A Diabetes 22
Cigarette smoking Lung Cancer 21
Arsenic Diabetes 20
Polycyclic aromatic hydrocarbons Diabetes 20
Huge Detoxification Variability
bull CYP2C19
Proton pump inhibitors and some antidepressants
5-fold difference in activity between poor metabolizers and extensive metabolizers more so if CYP3A4 is also inhibited
Ultrarapid allele in 18 of both Swedes and Ethiopians
bull CYP2D6
Metabolizes a large number of drugs (~25)
7 of Caucasians poor metabolizers
~30 ultra rapid metabolizers in Arabian and Eastern African populations
More adverse effects in poor metabolizers and ineffective dosing in ultrarapid metabolizers
Inhibited by ginger
Desta Z et al Clinical significance of the cytochrome P450 2C19 genetic polymorphism Clin Pharmaco 2002
Sim SC et al A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug
response to proton pump inhibitors and antidepressants Clin Pharmacol Ther 2006
Wilkinson GR Drug metabolism and variability among patients in drug response N Engl J Med 2005
Kirchheiner J et al Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to
CYP2D6 duplication Pharmacogenomics J 2007
Toxin Half Lives in BloodToxin ldquoNormalrdquo (mgL) Acute Toxic (mgL) Half-Life
Arsenic 0002-007 005-025 2-4 days (CDC)
Benzene 00002 05-10 days
Cadmium 00003-00065 0015-005 16 years
Chlordane 0001 00025 3-4 days
DDTDDE 2-10 years
Dieldrin 00015 015-030 2-12 months
Ethanol 1000-2000 15hour
Lead 009 04-06 1-15 mo (2+ yrs bone)
Mercury 00015-0002 005-02 2 months (CDC)
PCBs 3-25 years
Toluene 05-3 days
Schulz M et al Therapeutic and toxic blood concentrations of nearly 1000 drugs and other xenobiotics Crit Care 2012 Jul 2616(4)R136
Bioaccumulation (POPs)
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
DDT banned in 1972 PCBs banned in 1977
Bioaccumulation (Cd)
Think BroadlyExogenous
Metals
Chemicalsbull Inorganic
bull Fluoride
bull Organic
bull POPs
bull Drugs
Particulate matter
Molds
Microbial
Radiationbull Light
bull Medical
bull Cell phone
Endogenous
Gut-derived toxins
Non-end product metabolites
Poorly detoxified hormones
Catecholamines (if SNP)
Toxins of Choice
Alcohol
Marijuana
Food constituents
High fructose corn syrup
Salt (acid-forming diet)
Wheat if zonulin (70)
Obesity Epidemic ndash POPs AND HFCS
47Bray GA Fructose should we worry Int J Obes (Lond) 2008 Dec32 Suppl 7S127-31
How Toxins Cause Damage 13
bull Increase free radical production
Cd induces production of ROS
Malathion inhibits catalase and glutathione peroxidase
Homocysteine oxidizes LDL cholesterol
bull Poison enzyme systems (compete with nutritional cofactors for binding sites)
Pb poisons delta aminolevulinic acid dehydratase
Cd inhibits catalase glutathione reductase and lowers
glutathione levels
bull Replace structural minerals
Pb displaces Ca in bone
How Toxins Cause Damage 23
bull Damage DNA
Benzene - causes chromosomal damage
Pesticides ndash fruit growers have more DNA damage
Phthalates and insecticides ndash damage sperm DNA
4-hydroxy catechol estrogen (4-OHE) damages breast DNA
bull Epigenetic dysmodulation
Higher cord blood levels of hexachlorobenzene associated
with 2x greater risk for obesity in children
bull Damage cell membranes
Common mechanism for heavy metals inactivates
membrane enzymes ion channels and pumps
How Toxins Cause Damage 33
bull Block insulin receptor sites
PCBs and phthalates
bull Highest levels associated with a 4 to 20-fold greater diabetes risk
bull Imbalance hormones many toxin examples
Arsenic
bull Disrupts thyroid hormone and retinoic acid receptors
Phthalates
bull Act as anti-androgens
bull More than 75 of the US population has measurable levels of
several phthalate metabolites in the urine
PCBs
bull Lower testosterone levels in men
Which are the Worst Toxins
bull According to the CDC
Toxicity
Population toxic load
Prevalence in toxic waste sites
bull According to clinical importance
Exposure
of disease
Ability of the body to detoxifyexcrete
Ag
en
cy
fo
r T
oxic
Su
bs
tan
ce
s a
nd
Dis
ea
se
Reg
istr
y
Pri
ori
ty L
ist
The Worst Toxins Clinically
My Rank Toxin Diseases Primary Sources
1 Arsenic Cancers diabetes gout Water chicken rice
2 DDT ADHD dementia diabetes Everywhere
3 Phthalates ADHD diabetes Soft plastics HABAs
4 PBDEs ADHD diabetes Flame retardant fabrics
5 PAHs ADHD cancers dyslipidemia Smoking charbroiling
6 PCBs Cancers diabetes MI RA Everywhere
7 Mercury Dementia ldquoSilverrdquo fillings fish
8 Lead Cardiovascular disease IQ Paint water
Glyphosate Research invalid
Conventional Laboratory Tests Reflect
Toxic Load in ldquoNormalrdquo Range
bull Surprising number show toxin exposure
CBC RBC WBC platelet count hemoglobin basophilic
stippling
Liver enzymes ALT GGTP
Inflammatory markers CRP
Lipids LDL oxLDL triglycerides
Blood sugar insulin FBS 2-hour PP
Metabolites bilirubin uric acid homocysteine 8-OHdG
Thyroid T3 T4 TSH
bull The historic ldquonormalrdquo range has been changing as the population has become more toxic
WBC Lowered by PCB and OCP Exposure
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
0
1
2
3
4
5
6
7
8
1st Quartrile 2nd Quartile 3rd Quartile 4th Quartile
WBCbull Strong inverse correlation with PCBs and OCPs and CBC
bull Linear with almost all PCBs
bull High variability with OCPs
bull Within ldquonormalrdquo range
Effects on WBC Worsen with Years
of Exposure to Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Platelet Count Decreases with Years
of Exposure tp Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Solvents Decrease Platelet Count
bull Compared workers exposed 23 hrday to those exposed most of day to toluene
bull All wore face masks and protective gear
bull Platelet count 14 lower 252 versus 216ml
bull Impairment of sympathetic nerves (OR = 413)
bull Impairment of peripheral nerves (OR = 694)
bull Positive relationship between neurological abnormalities and a self-reported neuropsychiatric measurement (r = 035-066)
Shih HT et al Subclinical abnormalities in workers with continuous low-level toluene exposure Toxicol Ind Health 2011 Sep27(8)691-9
Basophilic Stippling of Red Cells
Toxinsbull Arsenic
bull Lead
Diseasesbull Alpha-thalassemia HbH Disease
bull Beta thalassemia
bull Hereditary pyrimidine 5-nucleotidase deficiency
bull Myelodysplastic syndrome
bull Sideroblastic anemia
bull Thrombotic thrombocytopenic purpura
GGT Indirect Measure of POPsbull Glutathione is key intracellular defense against oxidative stress
bull Cellular GGT metabolizes extracellular GSH allowing precursor amino acids to be reutilized for intracellular GSH
bull Exposure to POPs induces GGT as a defensive mechanism
bull Within normal range predicts type 2 diabetes coronary heart disease hypertension stroke dyslipidemia chronic kidney disease and cancer
bull Men with GGT gt50 UI had ~26 fold risk for diabetes compared to those with lt10 Those with 40-49 had a ~20 fold risk
bull Levels within normal range occur with obesity xs alcohol cigarette smoking physical inactivity high meat low fruit and vegetable intake
bull Cumulative biomarker for environmental pollutants
Lee DH et al (2003) Gamma-glutamyltransferase and diabetesmdasha 4 year follow-up study Diabetologia 46359ndash364
Pamela A et al Serum gamma-glutamyltransferase linking together environmental pollution redox equilibria and progression of atherosclerosis Clin Chem
Lab Med 200947(12)1583-4
Lee DH et al Serum gamma-glutamyltransferase new insights about an old enzyme J Epidemiol Community Health 2009 Nov63(11)884-6
Lee DH et alSerum gamma-glutamyltransferase predicts non-fatal myocardial infarction and fatal coronary heart disease among 28838 middle-aged men and
women Eur Heart J 2006272170ndash6
Lee DH et al Gamma-glutamyltransferase and diabetes--a 4 year follow-up study Diabetologia 2003 Mar46(3)359-64
Lee DH et al Can persistent organic pollutants explain the association between serum gamma-glutamyltransferase and type 2 diabetes Diabetologia 2008
Mar51(3)402-7
GGT and Alcohol Consumption
bull GGT directly correlates with alcohol consumption
bull In a non-uniform population 40 gd will elevate GGT ~15
bull Watch for false negatives
bull Genomic variation
bull Are these the ones most
sensitive todamaged by
chemical toxins
bull Could up-regulation of GGT in light alcohol consumption be reason for benefit
0
10
20
30
40
50
60
70
80
0 200 400 600 800
Grams of Ethanol per Week
Adapted from Nagaya T et al Dose-response relationships between drinking and serum tests in Japanese men
aged 40ndash59 years Alcohol 1999 Feb 17(2) 133ndash8
GGT Correlates With Toxic Metal Levels
Lee DH et al Graded associations of blood lead and urinary cadmium concentrations with oxidative-stress-related markers in the
US population results from the third National Health and Nutrition Examination Survey Environ Health
perspect 2006 Mar114(3)350-4
GGT and Diabetes Risk
0
5
10
15
20
25
30
lt10 10-19 20-29 30-39 40-49 gt50
Dia
bete
s R
isk
GGT
bull GGT over 50 associated with tripling of death rate
bull 30-40 associated with doubling
GGT Levels
Correlate with
Risk of Death
Brenner H et al Distribution determinants and prognostic value of gamma-glutamyltransferase for all-cause
mortality in a cohort of construction workers from southern Germany Prev Med 1997 26 305ndash10
GGT From Small US Company
with Young Workers
0
10
20
30
40
50
60
0 20 40 60 80 100
GGT Data from Canadian Oil Field
Workers
0
50
100
150
200
250
300
350
400
450
lt10 10-20 20-30 30-40 40-50 50-60 60-07 70-80 80-90 90-100 100-110 110-120 gt120
GGTP
20-fold increased risk of diabetes
Uric Acid Indirect Measure of POPs
bull Poly-fluorinated hydrocarbons (PFOA and PFOS) associated
with increased serum uric acid
Lin CY et al Association among serum perfluoroalkyl chemicals glucose homeostasis and metabolic syndrome
in adolescents and adults Diabetes Care 2009 Apr32(4)702-7
Steenland K et al Association of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) with uric
acid among adults with elevated community exposure to PFOA Environ Health Perspect 2010 Feb118229-33
Steenland 2010 Open Access
ALT Indirect Measure of POPs
bull ALT (proxy marker) elevation in 104 (not including viral
hepatitis hemochromatosis or alcoholic liver disease) of
NHANES 03-04 subset
bull Risk of elevated ALT increased dose-dependently with
cadmium lead mercury and PCB exposure
bull 100 of individuals had detectable PCBs 925 mercury
and 996 had detectable lead
bull In 2005-08 prevalence of NAFLD in US was 11 a
growing cause of chronic liver disease
Cave M et al Polychlorinated biphenyls lead and mercury are associated with liver disease in American adults
NHANES 2003-2004 Environ Health Perspect 2010 Dec118(12)1735-42
Younossi ZM et al Changes in the prevalence of the most common causes of chronic liver diseases in the United
States from 1988 to 2008 Clin Gastroenterol Hepatol 2011 Jun9(6)524-530e1
Bilirubin as a Marker of POPs
bull Degree of serum bilirubin increase is prognostically significant in chronic liver dysfunction
bull Mono-ortho PCB TEQ values were found to be significantly positively associated with bilirubin (β=071 P=0008) following adjustment for multiple potential confounders
bull Bilirubin levels significantly correlated with PCBs -105-118-126 and -194
bull Smoking appears to be the biggest confounder
Dufour DR et al 2000 Diagnosis and monitoring of hepatic injury II Recommendations for use of laboratory
tests in screening diagnosis and monitoring Clin Chem 46 2050ndash68
Kumar J et al Persistent organic pollutants and liver dysfunction biomarkers in a population-based human sample
of men and women Environ Res 2014134251-256
Perf
luo
rin
ate
dP
OP
s a
nd
Co
mm
on
Blo
od
Tests
Gleason JA et al Associations of perfluorinated chemical serum concentrations and biomarkers of liver function and uric acid in the
US population (NHANES) 2007-2010 Environ Res 20151368-14
Liver Enzymes Reflect Toxic Load
bull AST ALT and GGT increase with body load of PCBs and OCPs
bull Some non-linear
bull Oxychlordanetop quartile
ALT 10
GGT 25
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
LDL-Cholesterol as Measure of POPs
bull 5-year prospective study to determine if POP levels predict future elevation in LDL-cholesterol
bull 598 subjects initially at age 70
bull Looked at 23 POPs
bull Best correlation with PCB 194
Penell J Lind L Salihovic S et al Persistent organic pollutants are related to change in circulating
lipid levels during a 5 year follow-up Environ Res 134(2014)190ndash197
oxLDL as Measure of POPs
bull 992 70-year old individuals (50 women)
bull Sum of PCBs showed strong significant positive associations with ox-LDL and significant negative associations with glutathione-related markers (GSSG and GSSGGSH)
bull A number of POPs (PCB-99 138 153 156 170 180 194 206 and 209) showed strong significant positive association with ox-LDL
Kumar J et al Influence of persistent organic pollutants on oxidative stress in population-based samples
Chemosphere 2014114303-309
Homocysteine is Increased by Pb amp Cd
Guallar E et al Confounding of the relation between homocysteine and peripheral arterial disease by lead cadmium and renal function Am J Epidemiol 2006 Apr 15163(8)700-8
Nutrient Deficiencies Accentuate
Effects of Lead on Homocysteine
bull Deficiencies in folate B6 or B12 make lead more toxic
Lee YM Et al Association of homocysteine levels with blood lead levels and micronutrients in the US general population J Prev Med Public Health 2012 Nov45(6)387-93
T4 amp T3 and PCBs
bull PCBs decrease T4 production
bull PCBs inhibit iodotyrosinedeiodinase activity
bull Study done in pregnant women which implies effect on fetus IQ
Kim S Park J Kim HJ et al Association between several persistent organic pollutants and thyroid hormone levels in serum among the pregnant women of Korea Environ Int 2013 Sep59442-8Shimizu R Yamaguchi M Uramaru N et al Structure-activity relationships of 44 halogenated compounds for iodotyrosinedeiodinase-inhibitory activity Toxicology 2013 Dec 6314(1)22-9
T4 amp T3 and PCBs
bull Not just humans being affected
bull Large study of dolphins shows exactly the same effects
Schwacke LH Zolman ES Balmer BC et al Anaemia hypothyroidism and immune suppression associated with polychlorinated biphenyl exposure in bottlenose dolphins (Tursiops truncatus) Proceed Royal Society B doi101098rspb20110665
8-OHdG
bull Oxidized nucleoside
bull Direct measure of DNA damage
bull Indirect measure of oxidative stress and toxin load
bull Correlates with
Multiple cancers
Mitochondrial damage
Rate of aging
Smoking
Several toxinsWalter Crinnion ldquoTotal Toxic Loadrdquo AANP 2015
8-OHdG Correlates with Pack-Years
of Smoking
Yano T et al Significance of the urinary 8-OHdG level as an oxidative stress marker in lung cancer patients Lung Cancer
2009 Jan63(1)111-4
8-OHdG Correlates
with Mercury
Chen C et al Increased oxidative DNA damage as assessed by urinary 8-hydroxy-2-deoxyguanosine
concentrations and serum redox status in persons exposed to mercury Clin Chem 2005 Apr51(4)759-67
Toxin Effects Worse with Aging
bull Thyroid function decreases with PFOA levels
bull But only after age 63
Shrestha S Bloom MS Yucel R et al Perfluoroalkyl substances and thyroid function in older adults Environ Int 2015 Feb75206-14
Insightful 23-Year Prospective Study
1 lt 50 there is no difference between those with the lowest and highest PCBs
2 In youngest group insulin production increases in response to toxin level As expected since blocking of
insulin receptor sites by PCBs
requires more insulin
3 That adaptive ability decreases with aging
4 At age 50 all the measures show very strong toxin-dose response
Cumulative damage impairs ability to adapt
Suarez-Lopez JR et al Persistent organic pollutants in young adults and changes in glucose related metabolism over a 23-year follow-up Environ Res 2015 Feb137485-94
Recommendations
High body toxic load
GGT gt 25
Uric acid gt 50 mgdl
ALT gt30 UL
Bilirubin gt08 mgdl
CBC lt 6000
Platelet lt 250000
Low T3 andor T4
Monitor Total Toxic Load
8-OHdG gt4
ldquoUnconventionalrdquo Laboratory Tests
bull Challenge testing
bull Hair analysis
bull Direct measures of solvents and POPs in blood urine adipose tissue
Evaluation of Metal Exposure ndash Provocation
bull Provocation ndash the use of a chelating agent ndash before urine collection often done clinically but several limitations
No ldquoofficialrdquo reference range for provoked urine
Most chelating agents do not extract metals from all tissues thus
does not necessarily represent total body burden
bull Example Brain is one of the main target organs for both elemental and organic
mercury yet agents do not chelate brain mercury
bull Despite limitations widely used and advocated by clinicians in part to see efficacy of chelating agent as a guide to treatment and based on empirical evidence
Rooney JP The role of thiols dithiols nutritional factors and interacting ligands in the toxicology of mercury
Toxicology 2007
Is Challenge Testing Valid
bull Poor correlations of standard tests for mercury
bull Unpublished research from corporate wellness project
bull Published amalgam number correlation
bull Published fish consumption correlation
What We Found In Canada
bull Deviations from the mean of 14 29 and 91 respectively
bull DMPS is spreading distribution suggesting that it is better at differentiating mercury body load
bull Some VERY high
Hg Assessment Correlations
bull Extensive measurements in 65 Whole blood Hg
Oral DMPS challenge
Amalgam surfaces
bull Correlations Whole blood w pre urine r = 040
Whole blood w post urine r = 057
Pre urine w post urine r = 068
Amalgams w pre urine r = 026
Amalgams w whole blood r = 036
Amalgams with post urine 044
bull Clear documentation that
challenge testing is better00
100
200
300
400
500
600
0 10 20 30 40 50
Po
st
Uri
ne H
g u
gg
Number of amalgams
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
To
xic
ity H
as B
eco
me t
he N
ew
ldquoN
orm
alrdquo
Toxin Type Use Threshold for
disease
association
of US
above
threshold
Disease Associations
Chlordane OC pesticide Termites corn citrus lawns
gardens
145ngg lipid 63
(diabetes)
Diabetes (20)
BPA Plasticizer Water bottles canned food
water pipes thermal sales
receipts
48 men 51
women (urine
ngmL)
~18
(diabetes)
Diabetes hypertension
Octachloro
dibenzo-p-
dioxin
(OCDD)
Polychlorinated
dibenzo-p-
dioxin
Incineration or burning of
waste bleaching processes
used in pulp and paper mills
1010 pgg
lipid (highest
quartile)
10-25
(hypertensio
n)
Hypertension (79 for
women highest
quartile) diabetes (21)
obesity learning
disability (272)
MEP
(mono-
ethyl
phthalate)
Phthalate
(plasticizer
fragrance)
Toothbrushes automobile
parts tools toys and food
packaging aspirin
cosmetics food packaging
gt175 ngmL
(urine)
~60
(diabetes)
Diabetes (148) lower
BMD obesity
pp-DDE DDT
metabolite (OC
pesticide)
Agricultural crops 1560ngg
lipid
25
(diabetes)
Diabetes (23-43)
early menopause
impaired cognitive
function (2-3x 65x in
highest 5th percentile)
peripheral arterial
disease
Arsenic Toxic metal Miningsmelting wood
preservative pesticides
74ugL total
arsenic (urine)
20
(diabetes)
Cancers diabetes (26-
46) dyslipidemia gout
AF OR Prevalence
Rosen L An intuitive approach to understanding the attributable fraction of disease due to a risk factor the case of smoking Int J Environ Res Public Health 2013 Jul 1610(7)2932-43
Smoking Lung cancer
Arsenic Gout in women
BPA Diabetes
Status of Our Research
bull 26 toxins and toxin classes eg lead mercury BPA OCPs
100s of chemicals and POPs in some classes
bull 18 cancers
bull 24 chronic diseases
bull 1092 cells in spreadsheet
Large Personal Ongoing Research Investment
Huge Amount of Research Work
Toxins StudiedAluminum
Arsenic
Cadmium
Fluoride
Lead
Manganese
Mercury
Acrylamide
Acrylonitrile
Benzene
Bisphenol A (BPA)
Chloroform
DDT
Dioxins
Glyphosate
Organochlorine pesticides (OCPs)
Organophosphate pesticides
Parabens
Phthalates
Polybrominated diphenyl ethers (PBDEs)
Polycyclic aromatic hydrocarbons (PAHs)
Polychlorinated biphenols (PCBs)
Vinyl chloride
Diseases Studied
ADHD
Alzheimers Disease
ALS
Angiosarcoma
Anxiety
Atopic Conditions
Diabetes
Dyslipidemia
Gout
Fetal Abnormalities
Hyperuricemia
Infertility
Juvenile IQ
Cancer Bladder
Cancer Bone
Cancer Brain
Cancer Breast
Cancer Cervix
Cancer Colorectal
Cancer Endometrial
Cancer Head amp Neck
Cancer Liver
Cancer Lung
Cancer Lymph amp Blood
Cancer Ovarian
Cancer Pancreatic
Cancer Prostate
Cancer Renal
Cancer Skin
Cancer Testicular
Cancer Thyroid
Juvenile Obesity
Metabolic Syndrome
Mitochondrial dysfunction
Myocardial Infarction
Obstructive Lung Disease
Osteoporosis
Peripheral Artery Disease
Peripheral Neuropathy
Prediabetes
Renal Disease
Rheumatoid Arthritis
Thyroid Dysfunction
OC
Ps
Th
rou
gh
ou
t th
e W
orl
d
Rathore HS Nollet LML Pesticides Evaluation of Environmental Pollution CRC Press
2012 page 562
Threshold ndash Threshold exposure at which there is an increased risk of disease outcome
Above Threshold ndash Percentage of the population with higher exposure than the threshold
Odds Ratio ndash Increased disease risk in those above threshold
of Dz ndash Percent contribution of the toxin to that disease outcome
How to Interpret the Following Slides
Attention Deficit Hyperactivity Disorder
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
DDT 126 ngg
serum (pp-
DDE)
250 18 166 20106937
Lead 23 ugdL 13 254 20 27659349
Mercury 16 24952233
Organophosphate
pesticides
20
Polycyclic
Aromatic
Hydrocarbons
227 ngm3 940 125 190 22440811
PCBs 104 ngg
serum (sum
of 50 PCBs)
250 176 160 20106937
DiabetesToxin Threshold Above
Threshold
Odds
Ratio
of Dz Reference
PMID
Arsenic 165 ugL 200 21 180 18714061
BPA 28 ugL 280 145 112 26119400
DDE 545 ngg serum
(pp-DDE)
200 230 31 26119400
Dioxins2 pgg lipid 50 191 43
26119400
PCBs104 ngg (PCB 153) 250 239 258
26119400
Phthalates175 ugL 690 148 249
26119400
1-naphthalene 167 ugdL 152 182 111 26340343
2-napthalene 414 ugdL 550 224 214 26340343
1-phenanthrene 167 ngL 570 178 151 26340343
1-pyrene 85 ngL 660 180 174 26340343
Lung Cancer
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Acrylonitrile Uncertain Uncertain 125 25
occupational
exposure
17114112
Arsenic 1213 ugL 436 of Asian
Americans
~01 of total
US population
34 95 in AA
01-1
PMC2682945
Cadmium Uncertain+ Uncertain 467 10 in
smokers
17184399
DDT Any exposure All US pop
below LOD
17 76 increased
risk
8923607
Breast Cancer
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Cadmium 0580 ugg
creatinine
126 205 479 16788160
PCB 138 396 ngg
creatinine
202 316 630 27717745
PCB 187 108 ngg lipid 600 194 360 21480306
Miscellaneous Diseases
Toxin Disease Threshold Above
Threshold
Odds
Ratio
of Dz Reference PMID
Aluminum Alzheimer
Dz
01 mgL
drinking
H20
400 203 05-44 26592479
Benzene AML 100ppmyrs 1-3 320 60 PMC2903550
DDT NHL 0512 ugL 1-2 240 01 17722095
Lead ALS 238 ugdL
blood
330 181 210 25479292
Lead Brain CA 0005 ugdL 14 19 ~500 17164378
Dioxin-like
PCBs
RA 326 ngg
lipid
250 219 220 17589595
PAHs Asthma 124 ngm3 935 200 483 19221603
The Potency of Arsenic
Disease Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Bladder CA 10ugL H20 100 27 145 24889821
Pancreatic CA 1332 ugg 200 246 230 23800676
Prostate CA 1332 ugg 200 33 315 23800676
Gout 125 ugL 245 546 522 25499256
Diabetes 165 ugL 200 21 180 18714061
Arsenic (180 of Diabetes)
How it causes diabetes
bull Blocks sugar stimulating insulin secretion
bull Epigenetic inhibition of sugar regulation
Where it comes from
bull Water (gt10 of US water supplies have high levels)
bull Rice (naturally absorbs if in the water)
bull Chicken (added to make meat whiter)
Pan W-C Seow WJ Kile ML et al Association of low to moderate levels of arsenic exposure with risk of Type 2 diabetes in Bangladesh American Journal of Epidemiology 2013178(10)1563-70
Portion of Population with Toxin Load Which
Doubles Disease Risk
Toxin Disease with Doubled Risk
Polycyclic aromatic hydrocarbons Asthma 94
PCB187 Breast Cancer 60
Phthalates Diabetes 55
Lead ALS 33
Aluminum Alzheimers Disease 25
DDT ADHD 25
PCBs Diabetes 25
Dioxin-like PCBs Rheumatoid Arthritis 25
Arsenic Gout 23
Bisphenol A Diabetes 22
Cigarette smoking Lung Cancer 21
Arsenic Diabetes 20
Polycyclic aromatic hydrocarbons Diabetes 20
Huge Detoxification Variability
bull CYP2C19
Proton pump inhibitors and some antidepressants
5-fold difference in activity between poor metabolizers and extensive metabolizers more so if CYP3A4 is also inhibited
Ultrarapid allele in 18 of both Swedes and Ethiopians
bull CYP2D6
Metabolizes a large number of drugs (~25)
7 of Caucasians poor metabolizers
~30 ultra rapid metabolizers in Arabian and Eastern African populations
More adverse effects in poor metabolizers and ineffective dosing in ultrarapid metabolizers
Inhibited by ginger
Desta Z et al Clinical significance of the cytochrome P450 2C19 genetic polymorphism Clin Pharmaco 2002
Sim SC et al A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug
response to proton pump inhibitors and antidepressants Clin Pharmacol Ther 2006
Wilkinson GR Drug metabolism and variability among patients in drug response N Engl J Med 2005
Kirchheiner J et al Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to
CYP2D6 duplication Pharmacogenomics J 2007
Toxin Half Lives in BloodToxin ldquoNormalrdquo (mgL) Acute Toxic (mgL) Half-Life
Arsenic 0002-007 005-025 2-4 days (CDC)
Benzene 00002 05-10 days
Cadmium 00003-00065 0015-005 16 years
Chlordane 0001 00025 3-4 days
DDTDDE 2-10 years
Dieldrin 00015 015-030 2-12 months
Ethanol 1000-2000 15hour
Lead 009 04-06 1-15 mo (2+ yrs bone)
Mercury 00015-0002 005-02 2 months (CDC)
PCBs 3-25 years
Toluene 05-3 days
Schulz M et al Therapeutic and toxic blood concentrations of nearly 1000 drugs and other xenobiotics Crit Care 2012 Jul 2616(4)R136
Bioaccumulation (POPs)
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
DDT banned in 1972 PCBs banned in 1977
Bioaccumulation (Cd)
Think BroadlyExogenous
Metals
Chemicalsbull Inorganic
bull Fluoride
bull Organic
bull POPs
bull Drugs
Particulate matter
Molds
Microbial
Radiationbull Light
bull Medical
bull Cell phone
Endogenous
Gut-derived toxins
Non-end product metabolites
Poorly detoxified hormones
Catecholamines (if SNP)
Toxins of Choice
Alcohol
Marijuana
Food constituents
High fructose corn syrup
Salt (acid-forming diet)
Wheat if zonulin (70)
Obesity Epidemic ndash POPs AND HFCS
47Bray GA Fructose should we worry Int J Obes (Lond) 2008 Dec32 Suppl 7S127-31
How Toxins Cause Damage 13
bull Increase free radical production
Cd induces production of ROS
Malathion inhibits catalase and glutathione peroxidase
Homocysteine oxidizes LDL cholesterol
bull Poison enzyme systems (compete with nutritional cofactors for binding sites)
Pb poisons delta aminolevulinic acid dehydratase
Cd inhibits catalase glutathione reductase and lowers
glutathione levels
bull Replace structural minerals
Pb displaces Ca in bone
How Toxins Cause Damage 23
bull Damage DNA
Benzene - causes chromosomal damage
Pesticides ndash fruit growers have more DNA damage
Phthalates and insecticides ndash damage sperm DNA
4-hydroxy catechol estrogen (4-OHE) damages breast DNA
bull Epigenetic dysmodulation
Higher cord blood levels of hexachlorobenzene associated
with 2x greater risk for obesity in children
bull Damage cell membranes
Common mechanism for heavy metals inactivates
membrane enzymes ion channels and pumps
How Toxins Cause Damage 33
bull Block insulin receptor sites
PCBs and phthalates
bull Highest levels associated with a 4 to 20-fold greater diabetes risk
bull Imbalance hormones many toxin examples
Arsenic
bull Disrupts thyroid hormone and retinoic acid receptors
Phthalates
bull Act as anti-androgens
bull More than 75 of the US population has measurable levels of
several phthalate metabolites in the urine
PCBs
bull Lower testosterone levels in men
Which are the Worst Toxins
bull According to the CDC
Toxicity
Population toxic load
Prevalence in toxic waste sites
bull According to clinical importance
Exposure
of disease
Ability of the body to detoxifyexcrete
Ag
en
cy
fo
r T
oxic
Su
bs
tan
ce
s a
nd
Dis
ea
se
Reg
istr
y
Pri
ori
ty L
ist
The Worst Toxins Clinically
My Rank Toxin Diseases Primary Sources
1 Arsenic Cancers diabetes gout Water chicken rice
2 DDT ADHD dementia diabetes Everywhere
3 Phthalates ADHD diabetes Soft plastics HABAs
4 PBDEs ADHD diabetes Flame retardant fabrics
5 PAHs ADHD cancers dyslipidemia Smoking charbroiling
6 PCBs Cancers diabetes MI RA Everywhere
7 Mercury Dementia ldquoSilverrdquo fillings fish
8 Lead Cardiovascular disease IQ Paint water
Glyphosate Research invalid
Conventional Laboratory Tests Reflect
Toxic Load in ldquoNormalrdquo Range
bull Surprising number show toxin exposure
CBC RBC WBC platelet count hemoglobin basophilic
stippling
Liver enzymes ALT GGTP
Inflammatory markers CRP
Lipids LDL oxLDL triglycerides
Blood sugar insulin FBS 2-hour PP
Metabolites bilirubin uric acid homocysteine 8-OHdG
Thyroid T3 T4 TSH
bull The historic ldquonormalrdquo range has been changing as the population has become more toxic
WBC Lowered by PCB and OCP Exposure
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
0
1
2
3
4
5
6
7
8
1st Quartrile 2nd Quartile 3rd Quartile 4th Quartile
WBCbull Strong inverse correlation with PCBs and OCPs and CBC
bull Linear with almost all PCBs
bull High variability with OCPs
bull Within ldquonormalrdquo range
Effects on WBC Worsen with Years
of Exposure to Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Platelet Count Decreases with Years
of Exposure tp Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Solvents Decrease Platelet Count
bull Compared workers exposed 23 hrday to those exposed most of day to toluene
bull All wore face masks and protective gear
bull Platelet count 14 lower 252 versus 216ml
bull Impairment of sympathetic nerves (OR = 413)
bull Impairment of peripheral nerves (OR = 694)
bull Positive relationship between neurological abnormalities and a self-reported neuropsychiatric measurement (r = 035-066)
Shih HT et al Subclinical abnormalities in workers with continuous low-level toluene exposure Toxicol Ind Health 2011 Sep27(8)691-9
Basophilic Stippling of Red Cells
Toxinsbull Arsenic
bull Lead
Diseasesbull Alpha-thalassemia HbH Disease
bull Beta thalassemia
bull Hereditary pyrimidine 5-nucleotidase deficiency
bull Myelodysplastic syndrome
bull Sideroblastic anemia
bull Thrombotic thrombocytopenic purpura
GGT Indirect Measure of POPsbull Glutathione is key intracellular defense against oxidative stress
bull Cellular GGT metabolizes extracellular GSH allowing precursor amino acids to be reutilized for intracellular GSH
bull Exposure to POPs induces GGT as a defensive mechanism
bull Within normal range predicts type 2 diabetes coronary heart disease hypertension stroke dyslipidemia chronic kidney disease and cancer
bull Men with GGT gt50 UI had ~26 fold risk for diabetes compared to those with lt10 Those with 40-49 had a ~20 fold risk
bull Levels within normal range occur with obesity xs alcohol cigarette smoking physical inactivity high meat low fruit and vegetable intake
bull Cumulative biomarker for environmental pollutants
Lee DH et al (2003) Gamma-glutamyltransferase and diabetesmdasha 4 year follow-up study Diabetologia 46359ndash364
Pamela A et al Serum gamma-glutamyltransferase linking together environmental pollution redox equilibria and progression of atherosclerosis Clin Chem
Lab Med 200947(12)1583-4
Lee DH et al Serum gamma-glutamyltransferase new insights about an old enzyme J Epidemiol Community Health 2009 Nov63(11)884-6
Lee DH et alSerum gamma-glutamyltransferase predicts non-fatal myocardial infarction and fatal coronary heart disease among 28838 middle-aged men and
women Eur Heart J 2006272170ndash6
Lee DH et al Gamma-glutamyltransferase and diabetes--a 4 year follow-up study Diabetologia 2003 Mar46(3)359-64
Lee DH et al Can persistent organic pollutants explain the association between serum gamma-glutamyltransferase and type 2 diabetes Diabetologia 2008
Mar51(3)402-7
GGT and Alcohol Consumption
bull GGT directly correlates with alcohol consumption
bull In a non-uniform population 40 gd will elevate GGT ~15
bull Watch for false negatives
bull Genomic variation
bull Are these the ones most
sensitive todamaged by
chemical toxins
bull Could up-regulation of GGT in light alcohol consumption be reason for benefit
0
10
20
30
40
50
60
70
80
0 200 400 600 800
Grams of Ethanol per Week
Adapted from Nagaya T et al Dose-response relationships between drinking and serum tests in Japanese men
aged 40ndash59 years Alcohol 1999 Feb 17(2) 133ndash8
GGT Correlates With Toxic Metal Levels
Lee DH et al Graded associations of blood lead and urinary cadmium concentrations with oxidative-stress-related markers in the
US population results from the third National Health and Nutrition Examination Survey Environ Health
perspect 2006 Mar114(3)350-4
GGT and Diabetes Risk
0
5
10
15
20
25
30
lt10 10-19 20-29 30-39 40-49 gt50
Dia
bete
s R
isk
GGT
bull GGT over 50 associated with tripling of death rate
bull 30-40 associated with doubling
GGT Levels
Correlate with
Risk of Death
Brenner H et al Distribution determinants and prognostic value of gamma-glutamyltransferase for all-cause
mortality in a cohort of construction workers from southern Germany Prev Med 1997 26 305ndash10
GGT From Small US Company
with Young Workers
0
10
20
30
40
50
60
0 20 40 60 80 100
GGT Data from Canadian Oil Field
Workers
0
50
100
150
200
250
300
350
400
450
lt10 10-20 20-30 30-40 40-50 50-60 60-07 70-80 80-90 90-100 100-110 110-120 gt120
GGTP
20-fold increased risk of diabetes
Uric Acid Indirect Measure of POPs
bull Poly-fluorinated hydrocarbons (PFOA and PFOS) associated
with increased serum uric acid
Lin CY et al Association among serum perfluoroalkyl chemicals glucose homeostasis and metabolic syndrome
in adolescents and adults Diabetes Care 2009 Apr32(4)702-7
Steenland K et al Association of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) with uric
acid among adults with elevated community exposure to PFOA Environ Health Perspect 2010 Feb118229-33
Steenland 2010 Open Access
ALT Indirect Measure of POPs
bull ALT (proxy marker) elevation in 104 (not including viral
hepatitis hemochromatosis or alcoholic liver disease) of
NHANES 03-04 subset
bull Risk of elevated ALT increased dose-dependently with
cadmium lead mercury and PCB exposure
bull 100 of individuals had detectable PCBs 925 mercury
and 996 had detectable lead
bull In 2005-08 prevalence of NAFLD in US was 11 a
growing cause of chronic liver disease
Cave M et al Polychlorinated biphenyls lead and mercury are associated with liver disease in American adults
NHANES 2003-2004 Environ Health Perspect 2010 Dec118(12)1735-42
Younossi ZM et al Changes in the prevalence of the most common causes of chronic liver diseases in the United
States from 1988 to 2008 Clin Gastroenterol Hepatol 2011 Jun9(6)524-530e1
Bilirubin as a Marker of POPs
bull Degree of serum bilirubin increase is prognostically significant in chronic liver dysfunction
bull Mono-ortho PCB TEQ values were found to be significantly positively associated with bilirubin (β=071 P=0008) following adjustment for multiple potential confounders
bull Bilirubin levels significantly correlated with PCBs -105-118-126 and -194
bull Smoking appears to be the biggest confounder
Dufour DR et al 2000 Diagnosis and monitoring of hepatic injury II Recommendations for use of laboratory
tests in screening diagnosis and monitoring Clin Chem 46 2050ndash68
Kumar J et al Persistent organic pollutants and liver dysfunction biomarkers in a population-based human sample
of men and women Environ Res 2014134251-256
Perf
luo
rin
ate
dP
OP
s a
nd
Co
mm
on
Blo
od
Tests
Gleason JA et al Associations of perfluorinated chemical serum concentrations and biomarkers of liver function and uric acid in the
US population (NHANES) 2007-2010 Environ Res 20151368-14
Liver Enzymes Reflect Toxic Load
bull AST ALT and GGT increase with body load of PCBs and OCPs
bull Some non-linear
bull Oxychlordanetop quartile
ALT 10
GGT 25
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
LDL-Cholesterol as Measure of POPs
bull 5-year prospective study to determine if POP levels predict future elevation in LDL-cholesterol
bull 598 subjects initially at age 70
bull Looked at 23 POPs
bull Best correlation with PCB 194
Penell J Lind L Salihovic S et al Persistent organic pollutants are related to change in circulating
lipid levels during a 5 year follow-up Environ Res 134(2014)190ndash197
oxLDL as Measure of POPs
bull 992 70-year old individuals (50 women)
bull Sum of PCBs showed strong significant positive associations with ox-LDL and significant negative associations with glutathione-related markers (GSSG and GSSGGSH)
bull A number of POPs (PCB-99 138 153 156 170 180 194 206 and 209) showed strong significant positive association with ox-LDL
Kumar J et al Influence of persistent organic pollutants on oxidative stress in population-based samples
Chemosphere 2014114303-309
Homocysteine is Increased by Pb amp Cd
Guallar E et al Confounding of the relation between homocysteine and peripheral arterial disease by lead cadmium and renal function Am J Epidemiol 2006 Apr 15163(8)700-8
Nutrient Deficiencies Accentuate
Effects of Lead on Homocysteine
bull Deficiencies in folate B6 or B12 make lead more toxic
Lee YM Et al Association of homocysteine levels with blood lead levels and micronutrients in the US general population J Prev Med Public Health 2012 Nov45(6)387-93
T4 amp T3 and PCBs
bull PCBs decrease T4 production
bull PCBs inhibit iodotyrosinedeiodinase activity
bull Study done in pregnant women which implies effect on fetus IQ
Kim S Park J Kim HJ et al Association between several persistent organic pollutants and thyroid hormone levels in serum among the pregnant women of Korea Environ Int 2013 Sep59442-8Shimizu R Yamaguchi M Uramaru N et al Structure-activity relationships of 44 halogenated compounds for iodotyrosinedeiodinase-inhibitory activity Toxicology 2013 Dec 6314(1)22-9
T4 amp T3 and PCBs
bull Not just humans being affected
bull Large study of dolphins shows exactly the same effects
Schwacke LH Zolman ES Balmer BC et al Anaemia hypothyroidism and immune suppression associated with polychlorinated biphenyl exposure in bottlenose dolphins (Tursiops truncatus) Proceed Royal Society B doi101098rspb20110665
8-OHdG
bull Oxidized nucleoside
bull Direct measure of DNA damage
bull Indirect measure of oxidative stress and toxin load
bull Correlates with
Multiple cancers
Mitochondrial damage
Rate of aging
Smoking
Several toxinsWalter Crinnion ldquoTotal Toxic Loadrdquo AANP 2015
8-OHdG Correlates with Pack-Years
of Smoking
Yano T et al Significance of the urinary 8-OHdG level as an oxidative stress marker in lung cancer patients Lung Cancer
2009 Jan63(1)111-4
8-OHdG Correlates
with Mercury
Chen C et al Increased oxidative DNA damage as assessed by urinary 8-hydroxy-2-deoxyguanosine
concentrations and serum redox status in persons exposed to mercury Clin Chem 2005 Apr51(4)759-67
Toxin Effects Worse with Aging
bull Thyroid function decreases with PFOA levels
bull But only after age 63
Shrestha S Bloom MS Yucel R et al Perfluoroalkyl substances and thyroid function in older adults Environ Int 2015 Feb75206-14
Insightful 23-Year Prospective Study
1 lt 50 there is no difference between those with the lowest and highest PCBs
2 In youngest group insulin production increases in response to toxin level As expected since blocking of
insulin receptor sites by PCBs
requires more insulin
3 That adaptive ability decreases with aging
4 At age 50 all the measures show very strong toxin-dose response
Cumulative damage impairs ability to adapt
Suarez-Lopez JR et al Persistent organic pollutants in young adults and changes in glucose related metabolism over a 23-year follow-up Environ Res 2015 Feb137485-94
Recommendations
High body toxic load
GGT gt 25
Uric acid gt 50 mgdl
ALT gt30 UL
Bilirubin gt08 mgdl
CBC lt 6000
Platelet lt 250000
Low T3 andor T4
Monitor Total Toxic Load
8-OHdG gt4
ldquoUnconventionalrdquo Laboratory Tests
bull Challenge testing
bull Hair analysis
bull Direct measures of solvents and POPs in blood urine adipose tissue
Evaluation of Metal Exposure ndash Provocation
bull Provocation ndash the use of a chelating agent ndash before urine collection often done clinically but several limitations
No ldquoofficialrdquo reference range for provoked urine
Most chelating agents do not extract metals from all tissues thus
does not necessarily represent total body burden
bull Example Brain is one of the main target organs for both elemental and organic
mercury yet agents do not chelate brain mercury
bull Despite limitations widely used and advocated by clinicians in part to see efficacy of chelating agent as a guide to treatment and based on empirical evidence
Rooney JP The role of thiols dithiols nutritional factors and interacting ligands in the toxicology of mercury
Toxicology 2007
Is Challenge Testing Valid
bull Poor correlations of standard tests for mercury
bull Unpublished research from corporate wellness project
bull Published amalgam number correlation
bull Published fish consumption correlation
What We Found In Canada
bull Deviations from the mean of 14 29 and 91 respectively
bull DMPS is spreading distribution suggesting that it is better at differentiating mercury body load
bull Some VERY high
Hg Assessment Correlations
bull Extensive measurements in 65 Whole blood Hg
Oral DMPS challenge
Amalgam surfaces
bull Correlations Whole blood w pre urine r = 040
Whole blood w post urine r = 057
Pre urine w post urine r = 068
Amalgams w pre urine r = 026
Amalgams w whole blood r = 036
Amalgams with post urine 044
bull Clear documentation that
challenge testing is better00
100
200
300
400
500
600
0 10 20 30 40 50
Po
st
Uri
ne H
g u
gg
Number of amalgams
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
AF OR Prevalence
Rosen L An intuitive approach to understanding the attributable fraction of disease due to a risk factor the case of smoking Int J Environ Res Public Health 2013 Jul 1610(7)2932-43
Smoking Lung cancer
Arsenic Gout in women
BPA Diabetes
Status of Our Research
bull 26 toxins and toxin classes eg lead mercury BPA OCPs
100s of chemicals and POPs in some classes
bull 18 cancers
bull 24 chronic diseases
bull 1092 cells in spreadsheet
Large Personal Ongoing Research Investment
Huge Amount of Research Work
Toxins StudiedAluminum
Arsenic
Cadmium
Fluoride
Lead
Manganese
Mercury
Acrylamide
Acrylonitrile
Benzene
Bisphenol A (BPA)
Chloroform
DDT
Dioxins
Glyphosate
Organochlorine pesticides (OCPs)
Organophosphate pesticides
Parabens
Phthalates
Polybrominated diphenyl ethers (PBDEs)
Polycyclic aromatic hydrocarbons (PAHs)
Polychlorinated biphenols (PCBs)
Vinyl chloride
Diseases Studied
ADHD
Alzheimers Disease
ALS
Angiosarcoma
Anxiety
Atopic Conditions
Diabetes
Dyslipidemia
Gout
Fetal Abnormalities
Hyperuricemia
Infertility
Juvenile IQ
Cancer Bladder
Cancer Bone
Cancer Brain
Cancer Breast
Cancer Cervix
Cancer Colorectal
Cancer Endometrial
Cancer Head amp Neck
Cancer Liver
Cancer Lung
Cancer Lymph amp Blood
Cancer Ovarian
Cancer Pancreatic
Cancer Prostate
Cancer Renal
Cancer Skin
Cancer Testicular
Cancer Thyroid
Juvenile Obesity
Metabolic Syndrome
Mitochondrial dysfunction
Myocardial Infarction
Obstructive Lung Disease
Osteoporosis
Peripheral Artery Disease
Peripheral Neuropathy
Prediabetes
Renal Disease
Rheumatoid Arthritis
Thyroid Dysfunction
OC
Ps
Th
rou
gh
ou
t th
e W
orl
d
Rathore HS Nollet LML Pesticides Evaluation of Environmental Pollution CRC Press
2012 page 562
Threshold ndash Threshold exposure at which there is an increased risk of disease outcome
Above Threshold ndash Percentage of the population with higher exposure than the threshold
Odds Ratio ndash Increased disease risk in those above threshold
of Dz ndash Percent contribution of the toxin to that disease outcome
How to Interpret the Following Slides
Attention Deficit Hyperactivity Disorder
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
DDT 126 ngg
serum (pp-
DDE)
250 18 166 20106937
Lead 23 ugdL 13 254 20 27659349
Mercury 16 24952233
Organophosphate
pesticides
20
Polycyclic
Aromatic
Hydrocarbons
227 ngm3 940 125 190 22440811
PCBs 104 ngg
serum (sum
of 50 PCBs)
250 176 160 20106937
DiabetesToxin Threshold Above
Threshold
Odds
Ratio
of Dz Reference
PMID
Arsenic 165 ugL 200 21 180 18714061
BPA 28 ugL 280 145 112 26119400
DDE 545 ngg serum
(pp-DDE)
200 230 31 26119400
Dioxins2 pgg lipid 50 191 43
26119400
PCBs104 ngg (PCB 153) 250 239 258
26119400
Phthalates175 ugL 690 148 249
26119400
1-naphthalene 167 ugdL 152 182 111 26340343
2-napthalene 414 ugdL 550 224 214 26340343
1-phenanthrene 167 ngL 570 178 151 26340343
1-pyrene 85 ngL 660 180 174 26340343
Lung Cancer
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Acrylonitrile Uncertain Uncertain 125 25
occupational
exposure
17114112
Arsenic 1213 ugL 436 of Asian
Americans
~01 of total
US population
34 95 in AA
01-1
PMC2682945
Cadmium Uncertain+ Uncertain 467 10 in
smokers
17184399
DDT Any exposure All US pop
below LOD
17 76 increased
risk
8923607
Breast Cancer
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Cadmium 0580 ugg
creatinine
126 205 479 16788160
PCB 138 396 ngg
creatinine
202 316 630 27717745
PCB 187 108 ngg lipid 600 194 360 21480306
Miscellaneous Diseases
Toxin Disease Threshold Above
Threshold
Odds
Ratio
of Dz Reference PMID
Aluminum Alzheimer
Dz
01 mgL
drinking
H20
400 203 05-44 26592479
Benzene AML 100ppmyrs 1-3 320 60 PMC2903550
DDT NHL 0512 ugL 1-2 240 01 17722095
Lead ALS 238 ugdL
blood
330 181 210 25479292
Lead Brain CA 0005 ugdL 14 19 ~500 17164378
Dioxin-like
PCBs
RA 326 ngg
lipid
250 219 220 17589595
PAHs Asthma 124 ngm3 935 200 483 19221603
The Potency of Arsenic
Disease Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Bladder CA 10ugL H20 100 27 145 24889821
Pancreatic CA 1332 ugg 200 246 230 23800676
Prostate CA 1332 ugg 200 33 315 23800676
Gout 125 ugL 245 546 522 25499256
Diabetes 165 ugL 200 21 180 18714061
Arsenic (180 of Diabetes)
How it causes diabetes
bull Blocks sugar stimulating insulin secretion
bull Epigenetic inhibition of sugar regulation
Where it comes from
bull Water (gt10 of US water supplies have high levels)
bull Rice (naturally absorbs if in the water)
bull Chicken (added to make meat whiter)
Pan W-C Seow WJ Kile ML et al Association of low to moderate levels of arsenic exposure with risk of Type 2 diabetes in Bangladesh American Journal of Epidemiology 2013178(10)1563-70
Portion of Population with Toxin Load Which
Doubles Disease Risk
Toxin Disease with Doubled Risk
Polycyclic aromatic hydrocarbons Asthma 94
PCB187 Breast Cancer 60
Phthalates Diabetes 55
Lead ALS 33
Aluminum Alzheimers Disease 25
DDT ADHD 25
PCBs Diabetes 25
Dioxin-like PCBs Rheumatoid Arthritis 25
Arsenic Gout 23
Bisphenol A Diabetes 22
Cigarette smoking Lung Cancer 21
Arsenic Diabetes 20
Polycyclic aromatic hydrocarbons Diabetes 20
Huge Detoxification Variability
bull CYP2C19
Proton pump inhibitors and some antidepressants
5-fold difference in activity between poor metabolizers and extensive metabolizers more so if CYP3A4 is also inhibited
Ultrarapid allele in 18 of both Swedes and Ethiopians
bull CYP2D6
Metabolizes a large number of drugs (~25)
7 of Caucasians poor metabolizers
~30 ultra rapid metabolizers in Arabian and Eastern African populations
More adverse effects in poor metabolizers and ineffective dosing in ultrarapid metabolizers
Inhibited by ginger
Desta Z et al Clinical significance of the cytochrome P450 2C19 genetic polymorphism Clin Pharmaco 2002
Sim SC et al A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug
response to proton pump inhibitors and antidepressants Clin Pharmacol Ther 2006
Wilkinson GR Drug metabolism and variability among patients in drug response N Engl J Med 2005
Kirchheiner J et al Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to
CYP2D6 duplication Pharmacogenomics J 2007
Toxin Half Lives in BloodToxin ldquoNormalrdquo (mgL) Acute Toxic (mgL) Half-Life
Arsenic 0002-007 005-025 2-4 days (CDC)
Benzene 00002 05-10 days
Cadmium 00003-00065 0015-005 16 years
Chlordane 0001 00025 3-4 days
DDTDDE 2-10 years
Dieldrin 00015 015-030 2-12 months
Ethanol 1000-2000 15hour
Lead 009 04-06 1-15 mo (2+ yrs bone)
Mercury 00015-0002 005-02 2 months (CDC)
PCBs 3-25 years
Toluene 05-3 days
Schulz M et al Therapeutic and toxic blood concentrations of nearly 1000 drugs and other xenobiotics Crit Care 2012 Jul 2616(4)R136
Bioaccumulation (POPs)
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
DDT banned in 1972 PCBs banned in 1977
Bioaccumulation (Cd)
Think BroadlyExogenous
Metals
Chemicalsbull Inorganic
bull Fluoride
bull Organic
bull POPs
bull Drugs
Particulate matter
Molds
Microbial
Radiationbull Light
bull Medical
bull Cell phone
Endogenous
Gut-derived toxins
Non-end product metabolites
Poorly detoxified hormones
Catecholamines (if SNP)
Toxins of Choice
Alcohol
Marijuana
Food constituents
High fructose corn syrup
Salt (acid-forming diet)
Wheat if zonulin (70)
Obesity Epidemic ndash POPs AND HFCS
47Bray GA Fructose should we worry Int J Obes (Lond) 2008 Dec32 Suppl 7S127-31
How Toxins Cause Damage 13
bull Increase free radical production
Cd induces production of ROS
Malathion inhibits catalase and glutathione peroxidase
Homocysteine oxidizes LDL cholesterol
bull Poison enzyme systems (compete with nutritional cofactors for binding sites)
Pb poisons delta aminolevulinic acid dehydratase
Cd inhibits catalase glutathione reductase and lowers
glutathione levels
bull Replace structural minerals
Pb displaces Ca in bone
How Toxins Cause Damage 23
bull Damage DNA
Benzene - causes chromosomal damage
Pesticides ndash fruit growers have more DNA damage
Phthalates and insecticides ndash damage sperm DNA
4-hydroxy catechol estrogen (4-OHE) damages breast DNA
bull Epigenetic dysmodulation
Higher cord blood levels of hexachlorobenzene associated
with 2x greater risk for obesity in children
bull Damage cell membranes
Common mechanism for heavy metals inactivates
membrane enzymes ion channels and pumps
How Toxins Cause Damage 33
bull Block insulin receptor sites
PCBs and phthalates
bull Highest levels associated with a 4 to 20-fold greater diabetes risk
bull Imbalance hormones many toxin examples
Arsenic
bull Disrupts thyroid hormone and retinoic acid receptors
Phthalates
bull Act as anti-androgens
bull More than 75 of the US population has measurable levels of
several phthalate metabolites in the urine
PCBs
bull Lower testosterone levels in men
Which are the Worst Toxins
bull According to the CDC
Toxicity
Population toxic load
Prevalence in toxic waste sites
bull According to clinical importance
Exposure
of disease
Ability of the body to detoxifyexcrete
Ag
en
cy
fo
r T
oxic
Su
bs
tan
ce
s a
nd
Dis
ea
se
Reg
istr
y
Pri
ori
ty L
ist
The Worst Toxins Clinically
My Rank Toxin Diseases Primary Sources
1 Arsenic Cancers diabetes gout Water chicken rice
2 DDT ADHD dementia diabetes Everywhere
3 Phthalates ADHD diabetes Soft plastics HABAs
4 PBDEs ADHD diabetes Flame retardant fabrics
5 PAHs ADHD cancers dyslipidemia Smoking charbroiling
6 PCBs Cancers diabetes MI RA Everywhere
7 Mercury Dementia ldquoSilverrdquo fillings fish
8 Lead Cardiovascular disease IQ Paint water
Glyphosate Research invalid
Conventional Laboratory Tests Reflect
Toxic Load in ldquoNormalrdquo Range
bull Surprising number show toxin exposure
CBC RBC WBC platelet count hemoglobin basophilic
stippling
Liver enzymes ALT GGTP
Inflammatory markers CRP
Lipids LDL oxLDL triglycerides
Blood sugar insulin FBS 2-hour PP
Metabolites bilirubin uric acid homocysteine 8-OHdG
Thyroid T3 T4 TSH
bull The historic ldquonormalrdquo range has been changing as the population has become more toxic
WBC Lowered by PCB and OCP Exposure
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
0
1
2
3
4
5
6
7
8
1st Quartrile 2nd Quartile 3rd Quartile 4th Quartile
WBCbull Strong inverse correlation with PCBs and OCPs and CBC
bull Linear with almost all PCBs
bull High variability with OCPs
bull Within ldquonormalrdquo range
Effects on WBC Worsen with Years
of Exposure to Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Platelet Count Decreases with Years
of Exposure tp Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Solvents Decrease Platelet Count
bull Compared workers exposed 23 hrday to those exposed most of day to toluene
bull All wore face masks and protective gear
bull Platelet count 14 lower 252 versus 216ml
bull Impairment of sympathetic nerves (OR = 413)
bull Impairment of peripheral nerves (OR = 694)
bull Positive relationship between neurological abnormalities and a self-reported neuropsychiatric measurement (r = 035-066)
Shih HT et al Subclinical abnormalities in workers with continuous low-level toluene exposure Toxicol Ind Health 2011 Sep27(8)691-9
Basophilic Stippling of Red Cells
Toxinsbull Arsenic
bull Lead
Diseasesbull Alpha-thalassemia HbH Disease
bull Beta thalassemia
bull Hereditary pyrimidine 5-nucleotidase deficiency
bull Myelodysplastic syndrome
bull Sideroblastic anemia
bull Thrombotic thrombocytopenic purpura
GGT Indirect Measure of POPsbull Glutathione is key intracellular defense against oxidative stress
bull Cellular GGT metabolizes extracellular GSH allowing precursor amino acids to be reutilized for intracellular GSH
bull Exposure to POPs induces GGT as a defensive mechanism
bull Within normal range predicts type 2 diabetes coronary heart disease hypertension stroke dyslipidemia chronic kidney disease and cancer
bull Men with GGT gt50 UI had ~26 fold risk for diabetes compared to those with lt10 Those with 40-49 had a ~20 fold risk
bull Levels within normal range occur with obesity xs alcohol cigarette smoking physical inactivity high meat low fruit and vegetable intake
bull Cumulative biomarker for environmental pollutants
Lee DH et al (2003) Gamma-glutamyltransferase and diabetesmdasha 4 year follow-up study Diabetologia 46359ndash364
Pamela A et al Serum gamma-glutamyltransferase linking together environmental pollution redox equilibria and progression of atherosclerosis Clin Chem
Lab Med 200947(12)1583-4
Lee DH et al Serum gamma-glutamyltransferase new insights about an old enzyme J Epidemiol Community Health 2009 Nov63(11)884-6
Lee DH et alSerum gamma-glutamyltransferase predicts non-fatal myocardial infarction and fatal coronary heart disease among 28838 middle-aged men and
women Eur Heart J 2006272170ndash6
Lee DH et al Gamma-glutamyltransferase and diabetes--a 4 year follow-up study Diabetologia 2003 Mar46(3)359-64
Lee DH et al Can persistent organic pollutants explain the association between serum gamma-glutamyltransferase and type 2 diabetes Diabetologia 2008
Mar51(3)402-7
GGT and Alcohol Consumption
bull GGT directly correlates with alcohol consumption
bull In a non-uniform population 40 gd will elevate GGT ~15
bull Watch for false negatives
bull Genomic variation
bull Are these the ones most
sensitive todamaged by
chemical toxins
bull Could up-regulation of GGT in light alcohol consumption be reason for benefit
0
10
20
30
40
50
60
70
80
0 200 400 600 800
Grams of Ethanol per Week
Adapted from Nagaya T et al Dose-response relationships between drinking and serum tests in Japanese men
aged 40ndash59 years Alcohol 1999 Feb 17(2) 133ndash8
GGT Correlates With Toxic Metal Levels
Lee DH et al Graded associations of blood lead and urinary cadmium concentrations with oxidative-stress-related markers in the
US population results from the third National Health and Nutrition Examination Survey Environ Health
perspect 2006 Mar114(3)350-4
GGT and Diabetes Risk
0
5
10
15
20
25
30
lt10 10-19 20-29 30-39 40-49 gt50
Dia
bete
s R
isk
GGT
bull GGT over 50 associated with tripling of death rate
bull 30-40 associated with doubling
GGT Levels
Correlate with
Risk of Death
Brenner H et al Distribution determinants and prognostic value of gamma-glutamyltransferase for all-cause
mortality in a cohort of construction workers from southern Germany Prev Med 1997 26 305ndash10
GGT From Small US Company
with Young Workers
0
10
20
30
40
50
60
0 20 40 60 80 100
GGT Data from Canadian Oil Field
Workers
0
50
100
150
200
250
300
350
400
450
lt10 10-20 20-30 30-40 40-50 50-60 60-07 70-80 80-90 90-100 100-110 110-120 gt120
GGTP
20-fold increased risk of diabetes
Uric Acid Indirect Measure of POPs
bull Poly-fluorinated hydrocarbons (PFOA and PFOS) associated
with increased serum uric acid
Lin CY et al Association among serum perfluoroalkyl chemicals glucose homeostasis and metabolic syndrome
in adolescents and adults Diabetes Care 2009 Apr32(4)702-7
Steenland K et al Association of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) with uric
acid among adults with elevated community exposure to PFOA Environ Health Perspect 2010 Feb118229-33
Steenland 2010 Open Access
ALT Indirect Measure of POPs
bull ALT (proxy marker) elevation in 104 (not including viral
hepatitis hemochromatosis or alcoholic liver disease) of
NHANES 03-04 subset
bull Risk of elevated ALT increased dose-dependently with
cadmium lead mercury and PCB exposure
bull 100 of individuals had detectable PCBs 925 mercury
and 996 had detectable lead
bull In 2005-08 prevalence of NAFLD in US was 11 a
growing cause of chronic liver disease
Cave M et al Polychlorinated biphenyls lead and mercury are associated with liver disease in American adults
NHANES 2003-2004 Environ Health Perspect 2010 Dec118(12)1735-42
Younossi ZM et al Changes in the prevalence of the most common causes of chronic liver diseases in the United
States from 1988 to 2008 Clin Gastroenterol Hepatol 2011 Jun9(6)524-530e1
Bilirubin as a Marker of POPs
bull Degree of serum bilirubin increase is prognostically significant in chronic liver dysfunction
bull Mono-ortho PCB TEQ values were found to be significantly positively associated with bilirubin (β=071 P=0008) following adjustment for multiple potential confounders
bull Bilirubin levels significantly correlated with PCBs -105-118-126 and -194
bull Smoking appears to be the biggest confounder
Dufour DR et al 2000 Diagnosis and monitoring of hepatic injury II Recommendations for use of laboratory
tests in screening diagnosis and monitoring Clin Chem 46 2050ndash68
Kumar J et al Persistent organic pollutants and liver dysfunction biomarkers in a population-based human sample
of men and women Environ Res 2014134251-256
Perf
luo
rin
ate
dP
OP
s a
nd
Co
mm
on
Blo
od
Tests
Gleason JA et al Associations of perfluorinated chemical serum concentrations and biomarkers of liver function and uric acid in the
US population (NHANES) 2007-2010 Environ Res 20151368-14
Liver Enzymes Reflect Toxic Load
bull AST ALT and GGT increase with body load of PCBs and OCPs
bull Some non-linear
bull Oxychlordanetop quartile
ALT 10
GGT 25
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
LDL-Cholesterol as Measure of POPs
bull 5-year prospective study to determine if POP levels predict future elevation in LDL-cholesterol
bull 598 subjects initially at age 70
bull Looked at 23 POPs
bull Best correlation with PCB 194
Penell J Lind L Salihovic S et al Persistent organic pollutants are related to change in circulating
lipid levels during a 5 year follow-up Environ Res 134(2014)190ndash197
oxLDL as Measure of POPs
bull 992 70-year old individuals (50 women)
bull Sum of PCBs showed strong significant positive associations with ox-LDL and significant negative associations with glutathione-related markers (GSSG and GSSGGSH)
bull A number of POPs (PCB-99 138 153 156 170 180 194 206 and 209) showed strong significant positive association with ox-LDL
Kumar J et al Influence of persistent organic pollutants on oxidative stress in population-based samples
Chemosphere 2014114303-309
Homocysteine is Increased by Pb amp Cd
Guallar E et al Confounding of the relation between homocysteine and peripheral arterial disease by lead cadmium and renal function Am J Epidemiol 2006 Apr 15163(8)700-8
Nutrient Deficiencies Accentuate
Effects of Lead on Homocysteine
bull Deficiencies in folate B6 or B12 make lead more toxic
Lee YM Et al Association of homocysteine levels with blood lead levels and micronutrients in the US general population J Prev Med Public Health 2012 Nov45(6)387-93
T4 amp T3 and PCBs
bull PCBs decrease T4 production
bull PCBs inhibit iodotyrosinedeiodinase activity
bull Study done in pregnant women which implies effect on fetus IQ
Kim S Park J Kim HJ et al Association between several persistent organic pollutants and thyroid hormone levels in serum among the pregnant women of Korea Environ Int 2013 Sep59442-8Shimizu R Yamaguchi M Uramaru N et al Structure-activity relationships of 44 halogenated compounds for iodotyrosinedeiodinase-inhibitory activity Toxicology 2013 Dec 6314(1)22-9
T4 amp T3 and PCBs
bull Not just humans being affected
bull Large study of dolphins shows exactly the same effects
Schwacke LH Zolman ES Balmer BC et al Anaemia hypothyroidism and immune suppression associated with polychlorinated biphenyl exposure in bottlenose dolphins (Tursiops truncatus) Proceed Royal Society B doi101098rspb20110665
8-OHdG
bull Oxidized nucleoside
bull Direct measure of DNA damage
bull Indirect measure of oxidative stress and toxin load
bull Correlates with
Multiple cancers
Mitochondrial damage
Rate of aging
Smoking
Several toxinsWalter Crinnion ldquoTotal Toxic Loadrdquo AANP 2015
8-OHdG Correlates with Pack-Years
of Smoking
Yano T et al Significance of the urinary 8-OHdG level as an oxidative stress marker in lung cancer patients Lung Cancer
2009 Jan63(1)111-4
8-OHdG Correlates
with Mercury
Chen C et al Increased oxidative DNA damage as assessed by urinary 8-hydroxy-2-deoxyguanosine
concentrations and serum redox status in persons exposed to mercury Clin Chem 2005 Apr51(4)759-67
Toxin Effects Worse with Aging
bull Thyroid function decreases with PFOA levels
bull But only after age 63
Shrestha S Bloom MS Yucel R et al Perfluoroalkyl substances and thyroid function in older adults Environ Int 2015 Feb75206-14
Insightful 23-Year Prospective Study
1 lt 50 there is no difference between those with the lowest and highest PCBs
2 In youngest group insulin production increases in response to toxin level As expected since blocking of
insulin receptor sites by PCBs
requires more insulin
3 That adaptive ability decreases with aging
4 At age 50 all the measures show very strong toxin-dose response
Cumulative damage impairs ability to adapt
Suarez-Lopez JR et al Persistent organic pollutants in young adults and changes in glucose related metabolism over a 23-year follow-up Environ Res 2015 Feb137485-94
Recommendations
High body toxic load
GGT gt 25
Uric acid gt 50 mgdl
ALT gt30 UL
Bilirubin gt08 mgdl
CBC lt 6000
Platelet lt 250000
Low T3 andor T4
Monitor Total Toxic Load
8-OHdG gt4
ldquoUnconventionalrdquo Laboratory Tests
bull Challenge testing
bull Hair analysis
bull Direct measures of solvents and POPs in blood urine adipose tissue
Evaluation of Metal Exposure ndash Provocation
bull Provocation ndash the use of a chelating agent ndash before urine collection often done clinically but several limitations
No ldquoofficialrdquo reference range for provoked urine
Most chelating agents do not extract metals from all tissues thus
does not necessarily represent total body burden
bull Example Brain is one of the main target organs for both elemental and organic
mercury yet agents do not chelate brain mercury
bull Despite limitations widely used and advocated by clinicians in part to see efficacy of chelating agent as a guide to treatment and based on empirical evidence
Rooney JP The role of thiols dithiols nutritional factors and interacting ligands in the toxicology of mercury
Toxicology 2007
Is Challenge Testing Valid
bull Poor correlations of standard tests for mercury
bull Unpublished research from corporate wellness project
bull Published amalgam number correlation
bull Published fish consumption correlation
What We Found In Canada
bull Deviations from the mean of 14 29 and 91 respectively
bull DMPS is spreading distribution suggesting that it is better at differentiating mercury body load
bull Some VERY high
Hg Assessment Correlations
bull Extensive measurements in 65 Whole blood Hg
Oral DMPS challenge
Amalgam surfaces
bull Correlations Whole blood w pre urine r = 040
Whole blood w post urine r = 057
Pre urine w post urine r = 068
Amalgams w pre urine r = 026
Amalgams w whole blood r = 036
Amalgams with post urine 044
bull Clear documentation that
challenge testing is better00
100
200
300
400
500
600
0 10 20 30 40 50
Po
st
Uri
ne H
g u
gg
Number of amalgams
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
Status of Our Research
bull 26 toxins and toxin classes eg lead mercury BPA OCPs
100s of chemicals and POPs in some classes
bull 18 cancers
bull 24 chronic diseases
bull 1092 cells in spreadsheet
Large Personal Ongoing Research Investment
Huge Amount of Research Work
Toxins StudiedAluminum
Arsenic
Cadmium
Fluoride
Lead
Manganese
Mercury
Acrylamide
Acrylonitrile
Benzene
Bisphenol A (BPA)
Chloroform
DDT
Dioxins
Glyphosate
Organochlorine pesticides (OCPs)
Organophosphate pesticides
Parabens
Phthalates
Polybrominated diphenyl ethers (PBDEs)
Polycyclic aromatic hydrocarbons (PAHs)
Polychlorinated biphenols (PCBs)
Vinyl chloride
Diseases Studied
ADHD
Alzheimers Disease
ALS
Angiosarcoma
Anxiety
Atopic Conditions
Diabetes
Dyslipidemia
Gout
Fetal Abnormalities
Hyperuricemia
Infertility
Juvenile IQ
Cancer Bladder
Cancer Bone
Cancer Brain
Cancer Breast
Cancer Cervix
Cancer Colorectal
Cancer Endometrial
Cancer Head amp Neck
Cancer Liver
Cancer Lung
Cancer Lymph amp Blood
Cancer Ovarian
Cancer Pancreatic
Cancer Prostate
Cancer Renal
Cancer Skin
Cancer Testicular
Cancer Thyroid
Juvenile Obesity
Metabolic Syndrome
Mitochondrial dysfunction
Myocardial Infarction
Obstructive Lung Disease
Osteoporosis
Peripheral Artery Disease
Peripheral Neuropathy
Prediabetes
Renal Disease
Rheumatoid Arthritis
Thyroid Dysfunction
OC
Ps
Th
rou
gh
ou
t th
e W
orl
d
Rathore HS Nollet LML Pesticides Evaluation of Environmental Pollution CRC Press
2012 page 562
Threshold ndash Threshold exposure at which there is an increased risk of disease outcome
Above Threshold ndash Percentage of the population with higher exposure than the threshold
Odds Ratio ndash Increased disease risk in those above threshold
of Dz ndash Percent contribution of the toxin to that disease outcome
How to Interpret the Following Slides
Attention Deficit Hyperactivity Disorder
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
DDT 126 ngg
serum (pp-
DDE)
250 18 166 20106937
Lead 23 ugdL 13 254 20 27659349
Mercury 16 24952233
Organophosphate
pesticides
20
Polycyclic
Aromatic
Hydrocarbons
227 ngm3 940 125 190 22440811
PCBs 104 ngg
serum (sum
of 50 PCBs)
250 176 160 20106937
DiabetesToxin Threshold Above
Threshold
Odds
Ratio
of Dz Reference
PMID
Arsenic 165 ugL 200 21 180 18714061
BPA 28 ugL 280 145 112 26119400
DDE 545 ngg serum
(pp-DDE)
200 230 31 26119400
Dioxins2 pgg lipid 50 191 43
26119400
PCBs104 ngg (PCB 153) 250 239 258
26119400
Phthalates175 ugL 690 148 249
26119400
1-naphthalene 167 ugdL 152 182 111 26340343
2-napthalene 414 ugdL 550 224 214 26340343
1-phenanthrene 167 ngL 570 178 151 26340343
1-pyrene 85 ngL 660 180 174 26340343
Lung Cancer
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Acrylonitrile Uncertain Uncertain 125 25
occupational
exposure
17114112
Arsenic 1213 ugL 436 of Asian
Americans
~01 of total
US population
34 95 in AA
01-1
PMC2682945
Cadmium Uncertain+ Uncertain 467 10 in
smokers
17184399
DDT Any exposure All US pop
below LOD
17 76 increased
risk
8923607
Breast Cancer
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Cadmium 0580 ugg
creatinine
126 205 479 16788160
PCB 138 396 ngg
creatinine
202 316 630 27717745
PCB 187 108 ngg lipid 600 194 360 21480306
Miscellaneous Diseases
Toxin Disease Threshold Above
Threshold
Odds
Ratio
of Dz Reference PMID
Aluminum Alzheimer
Dz
01 mgL
drinking
H20
400 203 05-44 26592479
Benzene AML 100ppmyrs 1-3 320 60 PMC2903550
DDT NHL 0512 ugL 1-2 240 01 17722095
Lead ALS 238 ugdL
blood
330 181 210 25479292
Lead Brain CA 0005 ugdL 14 19 ~500 17164378
Dioxin-like
PCBs
RA 326 ngg
lipid
250 219 220 17589595
PAHs Asthma 124 ngm3 935 200 483 19221603
The Potency of Arsenic
Disease Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Bladder CA 10ugL H20 100 27 145 24889821
Pancreatic CA 1332 ugg 200 246 230 23800676
Prostate CA 1332 ugg 200 33 315 23800676
Gout 125 ugL 245 546 522 25499256
Diabetes 165 ugL 200 21 180 18714061
Arsenic (180 of Diabetes)
How it causes diabetes
bull Blocks sugar stimulating insulin secretion
bull Epigenetic inhibition of sugar regulation
Where it comes from
bull Water (gt10 of US water supplies have high levels)
bull Rice (naturally absorbs if in the water)
bull Chicken (added to make meat whiter)
Pan W-C Seow WJ Kile ML et al Association of low to moderate levels of arsenic exposure with risk of Type 2 diabetes in Bangladesh American Journal of Epidemiology 2013178(10)1563-70
Portion of Population with Toxin Load Which
Doubles Disease Risk
Toxin Disease with Doubled Risk
Polycyclic aromatic hydrocarbons Asthma 94
PCB187 Breast Cancer 60
Phthalates Diabetes 55
Lead ALS 33
Aluminum Alzheimers Disease 25
DDT ADHD 25
PCBs Diabetes 25
Dioxin-like PCBs Rheumatoid Arthritis 25
Arsenic Gout 23
Bisphenol A Diabetes 22
Cigarette smoking Lung Cancer 21
Arsenic Diabetes 20
Polycyclic aromatic hydrocarbons Diabetes 20
Huge Detoxification Variability
bull CYP2C19
Proton pump inhibitors and some antidepressants
5-fold difference in activity between poor metabolizers and extensive metabolizers more so if CYP3A4 is also inhibited
Ultrarapid allele in 18 of both Swedes and Ethiopians
bull CYP2D6
Metabolizes a large number of drugs (~25)
7 of Caucasians poor metabolizers
~30 ultra rapid metabolizers in Arabian and Eastern African populations
More adverse effects in poor metabolizers and ineffective dosing in ultrarapid metabolizers
Inhibited by ginger
Desta Z et al Clinical significance of the cytochrome P450 2C19 genetic polymorphism Clin Pharmaco 2002
Sim SC et al A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug
response to proton pump inhibitors and antidepressants Clin Pharmacol Ther 2006
Wilkinson GR Drug metabolism and variability among patients in drug response N Engl J Med 2005
Kirchheiner J et al Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to
CYP2D6 duplication Pharmacogenomics J 2007
Toxin Half Lives in BloodToxin ldquoNormalrdquo (mgL) Acute Toxic (mgL) Half-Life
Arsenic 0002-007 005-025 2-4 days (CDC)
Benzene 00002 05-10 days
Cadmium 00003-00065 0015-005 16 years
Chlordane 0001 00025 3-4 days
DDTDDE 2-10 years
Dieldrin 00015 015-030 2-12 months
Ethanol 1000-2000 15hour
Lead 009 04-06 1-15 mo (2+ yrs bone)
Mercury 00015-0002 005-02 2 months (CDC)
PCBs 3-25 years
Toluene 05-3 days
Schulz M et al Therapeutic and toxic blood concentrations of nearly 1000 drugs and other xenobiotics Crit Care 2012 Jul 2616(4)R136
Bioaccumulation (POPs)
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
DDT banned in 1972 PCBs banned in 1977
Bioaccumulation (Cd)
Think BroadlyExogenous
Metals
Chemicalsbull Inorganic
bull Fluoride
bull Organic
bull POPs
bull Drugs
Particulate matter
Molds
Microbial
Radiationbull Light
bull Medical
bull Cell phone
Endogenous
Gut-derived toxins
Non-end product metabolites
Poorly detoxified hormones
Catecholamines (if SNP)
Toxins of Choice
Alcohol
Marijuana
Food constituents
High fructose corn syrup
Salt (acid-forming diet)
Wheat if zonulin (70)
Obesity Epidemic ndash POPs AND HFCS
47Bray GA Fructose should we worry Int J Obes (Lond) 2008 Dec32 Suppl 7S127-31
How Toxins Cause Damage 13
bull Increase free radical production
Cd induces production of ROS
Malathion inhibits catalase and glutathione peroxidase
Homocysteine oxidizes LDL cholesterol
bull Poison enzyme systems (compete with nutritional cofactors for binding sites)
Pb poisons delta aminolevulinic acid dehydratase
Cd inhibits catalase glutathione reductase and lowers
glutathione levels
bull Replace structural minerals
Pb displaces Ca in bone
How Toxins Cause Damage 23
bull Damage DNA
Benzene - causes chromosomal damage
Pesticides ndash fruit growers have more DNA damage
Phthalates and insecticides ndash damage sperm DNA
4-hydroxy catechol estrogen (4-OHE) damages breast DNA
bull Epigenetic dysmodulation
Higher cord blood levels of hexachlorobenzene associated
with 2x greater risk for obesity in children
bull Damage cell membranes
Common mechanism for heavy metals inactivates
membrane enzymes ion channels and pumps
How Toxins Cause Damage 33
bull Block insulin receptor sites
PCBs and phthalates
bull Highest levels associated with a 4 to 20-fold greater diabetes risk
bull Imbalance hormones many toxin examples
Arsenic
bull Disrupts thyroid hormone and retinoic acid receptors
Phthalates
bull Act as anti-androgens
bull More than 75 of the US population has measurable levels of
several phthalate metabolites in the urine
PCBs
bull Lower testosterone levels in men
Which are the Worst Toxins
bull According to the CDC
Toxicity
Population toxic load
Prevalence in toxic waste sites
bull According to clinical importance
Exposure
of disease
Ability of the body to detoxifyexcrete
Ag
en
cy
fo
r T
oxic
Su
bs
tan
ce
s a
nd
Dis
ea
se
Reg
istr
y
Pri
ori
ty L
ist
The Worst Toxins Clinically
My Rank Toxin Diseases Primary Sources
1 Arsenic Cancers diabetes gout Water chicken rice
2 DDT ADHD dementia diabetes Everywhere
3 Phthalates ADHD diabetes Soft plastics HABAs
4 PBDEs ADHD diabetes Flame retardant fabrics
5 PAHs ADHD cancers dyslipidemia Smoking charbroiling
6 PCBs Cancers diabetes MI RA Everywhere
7 Mercury Dementia ldquoSilverrdquo fillings fish
8 Lead Cardiovascular disease IQ Paint water
Glyphosate Research invalid
Conventional Laboratory Tests Reflect
Toxic Load in ldquoNormalrdquo Range
bull Surprising number show toxin exposure
CBC RBC WBC platelet count hemoglobin basophilic
stippling
Liver enzymes ALT GGTP
Inflammatory markers CRP
Lipids LDL oxLDL triglycerides
Blood sugar insulin FBS 2-hour PP
Metabolites bilirubin uric acid homocysteine 8-OHdG
Thyroid T3 T4 TSH
bull The historic ldquonormalrdquo range has been changing as the population has become more toxic
WBC Lowered by PCB and OCP Exposure
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
0
1
2
3
4
5
6
7
8
1st Quartrile 2nd Quartile 3rd Quartile 4th Quartile
WBCbull Strong inverse correlation with PCBs and OCPs and CBC
bull Linear with almost all PCBs
bull High variability with OCPs
bull Within ldquonormalrdquo range
Effects on WBC Worsen with Years
of Exposure to Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Platelet Count Decreases with Years
of Exposure tp Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Solvents Decrease Platelet Count
bull Compared workers exposed 23 hrday to those exposed most of day to toluene
bull All wore face masks and protective gear
bull Platelet count 14 lower 252 versus 216ml
bull Impairment of sympathetic nerves (OR = 413)
bull Impairment of peripheral nerves (OR = 694)
bull Positive relationship between neurological abnormalities and a self-reported neuropsychiatric measurement (r = 035-066)
Shih HT et al Subclinical abnormalities in workers with continuous low-level toluene exposure Toxicol Ind Health 2011 Sep27(8)691-9
Basophilic Stippling of Red Cells
Toxinsbull Arsenic
bull Lead
Diseasesbull Alpha-thalassemia HbH Disease
bull Beta thalassemia
bull Hereditary pyrimidine 5-nucleotidase deficiency
bull Myelodysplastic syndrome
bull Sideroblastic anemia
bull Thrombotic thrombocytopenic purpura
GGT Indirect Measure of POPsbull Glutathione is key intracellular defense against oxidative stress
bull Cellular GGT metabolizes extracellular GSH allowing precursor amino acids to be reutilized for intracellular GSH
bull Exposure to POPs induces GGT as a defensive mechanism
bull Within normal range predicts type 2 diabetes coronary heart disease hypertension stroke dyslipidemia chronic kidney disease and cancer
bull Men with GGT gt50 UI had ~26 fold risk for diabetes compared to those with lt10 Those with 40-49 had a ~20 fold risk
bull Levels within normal range occur with obesity xs alcohol cigarette smoking physical inactivity high meat low fruit and vegetable intake
bull Cumulative biomarker for environmental pollutants
Lee DH et al (2003) Gamma-glutamyltransferase and diabetesmdasha 4 year follow-up study Diabetologia 46359ndash364
Pamela A et al Serum gamma-glutamyltransferase linking together environmental pollution redox equilibria and progression of atherosclerosis Clin Chem
Lab Med 200947(12)1583-4
Lee DH et al Serum gamma-glutamyltransferase new insights about an old enzyme J Epidemiol Community Health 2009 Nov63(11)884-6
Lee DH et alSerum gamma-glutamyltransferase predicts non-fatal myocardial infarction and fatal coronary heart disease among 28838 middle-aged men and
women Eur Heart J 2006272170ndash6
Lee DH et al Gamma-glutamyltransferase and diabetes--a 4 year follow-up study Diabetologia 2003 Mar46(3)359-64
Lee DH et al Can persistent organic pollutants explain the association between serum gamma-glutamyltransferase and type 2 diabetes Diabetologia 2008
Mar51(3)402-7
GGT and Alcohol Consumption
bull GGT directly correlates with alcohol consumption
bull In a non-uniform population 40 gd will elevate GGT ~15
bull Watch for false negatives
bull Genomic variation
bull Are these the ones most
sensitive todamaged by
chemical toxins
bull Could up-regulation of GGT in light alcohol consumption be reason for benefit
0
10
20
30
40
50
60
70
80
0 200 400 600 800
Grams of Ethanol per Week
Adapted from Nagaya T et al Dose-response relationships between drinking and serum tests in Japanese men
aged 40ndash59 years Alcohol 1999 Feb 17(2) 133ndash8
GGT Correlates With Toxic Metal Levels
Lee DH et al Graded associations of blood lead and urinary cadmium concentrations with oxidative-stress-related markers in the
US population results from the third National Health and Nutrition Examination Survey Environ Health
perspect 2006 Mar114(3)350-4
GGT and Diabetes Risk
0
5
10
15
20
25
30
lt10 10-19 20-29 30-39 40-49 gt50
Dia
bete
s R
isk
GGT
bull GGT over 50 associated with tripling of death rate
bull 30-40 associated with doubling
GGT Levels
Correlate with
Risk of Death
Brenner H et al Distribution determinants and prognostic value of gamma-glutamyltransferase for all-cause
mortality in a cohort of construction workers from southern Germany Prev Med 1997 26 305ndash10
GGT From Small US Company
with Young Workers
0
10
20
30
40
50
60
0 20 40 60 80 100
GGT Data from Canadian Oil Field
Workers
0
50
100
150
200
250
300
350
400
450
lt10 10-20 20-30 30-40 40-50 50-60 60-07 70-80 80-90 90-100 100-110 110-120 gt120
GGTP
20-fold increased risk of diabetes
Uric Acid Indirect Measure of POPs
bull Poly-fluorinated hydrocarbons (PFOA and PFOS) associated
with increased serum uric acid
Lin CY et al Association among serum perfluoroalkyl chemicals glucose homeostasis and metabolic syndrome
in adolescents and adults Diabetes Care 2009 Apr32(4)702-7
Steenland K et al Association of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) with uric
acid among adults with elevated community exposure to PFOA Environ Health Perspect 2010 Feb118229-33
Steenland 2010 Open Access
ALT Indirect Measure of POPs
bull ALT (proxy marker) elevation in 104 (not including viral
hepatitis hemochromatosis or alcoholic liver disease) of
NHANES 03-04 subset
bull Risk of elevated ALT increased dose-dependently with
cadmium lead mercury and PCB exposure
bull 100 of individuals had detectable PCBs 925 mercury
and 996 had detectable lead
bull In 2005-08 prevalence of NAFLD in US was 11 a
growing cause of chronic liver disease
Cave M et al Polychlorinated biphenyls lead and mercury are associated with liver disease in American adults
NHANES 2003-2004 Environ Health Perspect 2010 Dec118(12)1735-42
Younossi ZM et al Changes in the prevalence of the most common causes of chronic liver diseases in the United
States from 1988 to 2008 Clin Gastroenterol Hepatol 2011 Jun9(6)524-530e1
Bilirubin as a Marker of POPs
bull Degree of serum bilirubin increase is prognostically significant in chronic liver dysfunction
bull Mono-ortho PCB TEQ values were found to be significantly positively associated with bilirubin (β=071 P=0008) following adjustment for multiple potential confounders
bull Bilirubin levels significantly correlated with PCBs -105-118-126 and -194
bull Smoking appears to be the biggest confounder
Dufour DR et al 2000 Diagnosis and monitoring of hepatic injury II Recommendations for use of laboratory
tests in screening diagnosis and monitoring Clin Chem 46 2050ndash68
Kumar J et al Persistent organic pollutants and liver dysfunction biomarkers in a population-based human sample
of men and women Environ Res 2014134251-256
Perf
luo
rin
ate
dP
OP
s a
nd
Co
mm
on
Blo
od
Tests
Gleason JA et al Associations of perfluorinated chemical serum concentrations and biomarkers of liver function and uric acid in the
US population (NHANES) 2007-2010 Environ Res 20151368-14
Liver Enzymes Reflect Toxic Load
bull AST ALT and GGT increase with body load of PCBs and OCPs
bull Some non-linear
bull Oxychlordanetop quartile
ALT 10
GGT 25
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
LDL-Cholesterol as Measure of POPs
bull 5-year prospective study to determine if POP levels predict future elevation in LDL-cholesterol
bull 598 subjects initially at age 70
bull Looked at 23 POPs
bull Best correlation with PCB 194
Penell J Lind L Salihovic S et al Persistent organic pollutants are related to change in circulating
lipid levels during a 5 year follow-up Environ Res 134(2014)190ndash197
oxLDL as Measure of POPs
bull 992 70-year old individuals (50 women)
bull Sum of PCBs showed strong significant positive associations with ox-LDL and significant negative associations with glutathione-related markers (GSSG and GSSGGSH)
bull A number of POPs (PCB-99 138 153 156 170 180 194 206 and 209) showed strong significant positive association with ox-LDL
Kumar J et al Influence of persistent organic pollutants on oxidative stress in population-based samples
Chemosphere 2014114303-309
Homocysteine is Increased by Pb amp Cd
Guallar E et al Confounding of the relation between homocysteine and peripheral arterial disease by lead cadmium and renal function Am J Epidemiol 2006 Apr 15163(8)700-8
Nutrient Deficiencies Accentuate
Effects of Lead on Homocysteine
bull Deficiencies in folate B6 or B12 make lead more toxic
Lee YM Et al Association of homocysteine levels with blood lead levels and micronutrients in the US general population J Prev Med Public Health 2012 Nov45(6)387-93
T4 amp T3 and PCBs
bull PCBs decrease T4 production
bull PCBs inhibit iodotyrosinedeiodinase activity
bull Study done in pregnant women which implies effect on fetus IQ
Kim S Park J Kim HJ et al Association between several persistent organic pollutants and thyroid hormone levels in serum among the pregnant women of Korea Environ Int 2013 Sep59442-8Shimizu R Yamaguchi M Uramaru N et al Structure-activity relationships of 44 halogenated compounds for iodotyrosinedeiodinase-inhibitory activity Toxicology 2013 Dec 6314(1)22-9
T4 amp T3 and PCBs
bull Not just humans being affected
bull Large study of dolphins shows exactly the same effects
Schwacke LH Zolman ES Balmer BC et al Anaemia hypothyroidism and immune suppression associated with polychlorinated biphenyl exposure in bottlenose dolphins (Tursiops truncatus) Proceed Royal Society B doi101098rspb20110665
8-OHdG
bull Oxidized nucleoside
bull Direct measure of DNA damage
bull Indirect measure of oxidative stress and toxin load
bull Correlates with
Multiple cancers
Mitochondrial damage
Rate of aging
Smoking
Several toxinsWalter Crinnion ldquoTotal Toxic Loadrdquo AANP 2015
8-OHdG Correlates with Pack-Years
of Smoking
Yano T et al Significance of the urinary 8-OHdG level as an oxidative stress marker in lung cancer patients Lung Cancer
2009 Jan63(1)111-4
8-OHdG Correlates
with Mercury
Chen C et al Increased oxidative DNA damage as assessed by urinary 8-hydroxy-2-deoxyguanosine
concentrations and serum redox status in persons exposed to mercury Clin Chem 2005 Apr51(4)759-67
Toxin Effects Worse with Aging
bull Thyroid function decreases with PFOA levels
bull But only after age 63
Shrestha S Bloom MS Yucel R et al Perfluoroalkyl substances and thyroid function in older adults Environ Int 2015 Feb75206-14
Insightful 23-Year Prospective Study
1 lt 50 there is no difference between those with the lowest and highest PCBs
2 In youngest group insulin production increases in response to toxin level As expected since blocking of
insulin receptor sites by PCBs
requires more insulin
3 That adaptive ability decreases with aging
4 At age 50 all the measures show very strong toxin-dose response
Cumulative damage impairs ability to adapt
Suarez-Lopez JR et al Persistent organic pollutants in young adults and changes in glucose related metabolism over a 23-year follow-up Environ Res 2015 Feb137485-94
Recommendations
High body toxic load
GGT gt 25
Uric acid gt 50 mgdl
ALT gt30 UL
Bilirubin gt08 mgdl
CBC lt 6000
Platelet lt 250000
Low T3 andor T4
Monitor Total Toxic Load
8-OHdG gt4
ldquoUnconventionalrdquo Laboratory Tests
bull Challenge testing
bull Hair analysis
bull Direct measures of solvents and POPs in blood urine adipose tissue
Evaluation of Metal Exposure ndash Provocation
bull Provocation ndash the use of a chelating agent ndash before urine collection often done clinically but several limitations
No ldquoofficialrdquo reference range for provoked urine
Most chelating agents do not extract metals from all tissues thus
does not necessarily represent total body burden
bull Example Brain is one of the main target organs for both elemental and organic
mercury yet agents do not chelate brain mercury
bull Despite limitations widely used and advocated by clinicians in part to see efficacy of chelating agent as a guide to treatment and based on empirical evidence
Rooney JP The role of thiols dithiols nutritional factors and interacting ligands in the toxicology of mercury
Toxicology 2007
Is Challenge Testing Valid
bull Poor correlations of standard tests for mercury
bull Unpublished research from corporate wellness project
bull Published amalgam number correlation
bull Published fish consumption correlation
What We Found In Canada
bull Deviations from the mean of 14 29 and 91 respectively
bull DMPS is spreading distribution suggesting that it is better at differentiating mercury body load
bull Some VERY high
Hg Assessment Correlations
bull Extensive measurements in 65 Whole blood Hg
Oral DMPS challenge
Amalgam surfaces
bull Correlations Whole blood w pre urine r = 040
Whole blood w post urine r = 057
Pre urine w post urine r = 068
Amalgams w pre urine r = 026
Amalgams w whole blood r = 036
Amalgams with post urine 044
bull Clear documentation that
challenge testing is better00
100
200
300
400
500
600
0 10 20 30 40 50
Po
st
Uri
ne H
g u
gg
Number of amalgams
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
Huge Amount of Research Work
Toxins StudiedAluminum
Arsenic
Cadmium
Fluoride
Lead
Manganese
Mercury
Acrylamide
Acrylonitrile
Benzene
Bisphenol A (BPA)
Chloroform
DDT
Dioxins
Glyphosate
Organochlorine pesticides (OCPs)
Organophosphate pesticides
Parabens
Phthalates
Polybrominated diphenyl ethers (PBDEs)
Polycyclic aromatic hydrocarbons (PAHs)
Polychlorinated biphenols (PCBs)
Vinyl chloride
Diseases Studied
ADHD
Alzheimers Disease
ALS
Angiosarcoma
Anxiety
Atopic Conditions
Diabetes
Dyslipidemia
Gout
Fetal Abnormalities
Hyperuricemia
Infertility
Juvenile IQ
Cancer Bladder
Cancer Bone
Cancer Brain
Cancer Breast
Cancer Cervix
Cancer Colorectal
Cancer Endometrial
Cancer Head amp Neck
Cancer Liver
Cancer Lung
Cancer Lymph amp Blood
Cancer Ovarian
Cancer Pancreatic
Cancer Prostate
Cancer Renal
Cancer Skin
Cancer Testicular
Cancer Thyroid
Juvenile Obesity
Metabolic Syndrome
Mitochondrial dysfunction
Myocardial Infarction
Obstructive Lung Disease
Osteoporosis
Peripheral Artery Disease
Peripheral Neuropathy
Prediabetes
Renal Disease
Rheumatoid Arthritis
Thyroid Dysfunction
OC
Ps
Th
rou
gh
ou
t th
e W
orl
d
Rathore HS Nollet LML Pesticides Evaluation of Environmental Pollution CRC Press
2012 page 562
Threshold ndash Threshold exposure at which there is an increased risk of disease outcome
Above Threshold ndash Percentage of the population with higher exposure than the threshold
Odds Ratio ndash Increased disease risk in those above threshold
of Dz ndash Percent contribution of the toxin to that disease outcome
How to Interpret the Following Slides
Attention Deficit Hyperactivity Disorder
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
DDT 126 ngg
serum (pp-
DDE)
250 18 166 20106937
Lead 23 ugdL 13 254 20 27659349
Mercury 16 24952233
Organophosphate
pesticides
20
Polycyclic
Aromatic
Hydrocarbons
227 ngm3 940 125 190 22440811
PCBs 104 ngg
serum (sum
of 50 PCBs)
250 176 160 20106937
DiabetesToxin Threshold Above
Threshold
Odds
Ratio
of Dz Reference
PMID
Arsenic 165 ugL 200 21 180 18714061
BPA 28 ugL 280 145 112 26119400
DDE 545 ngg serum
(pp-DDE)
200 230 31 26119400
Dioxins2 pgg lipid 50 191 43
26119400
PCBs104 ngg (PCB 153) 250 239 258
26119400
Phthalates175 ugL 690 148 249
26119400
1-naphthalene 167 ugdL 152 182 111 26340343
2-napthalene 414 ugdL 550 224 214 26340343
1-phenanthrene 167 ngL 570 178 151 26340343
1-pyrene 85 ngL 660 180 174 26340343
Lung Cancer
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Acrylonitrile Uncertain Uncertain 125 25
occupational
exposure
17114112
Arsenic 1213 ugL 436 of Asian
Americans
~01 of total
US population
34 95 in AA
01-1
PMC2682945
Cadmium Uncertain+ Uncertain 467 10 in
smokers
17184399
DDT Any exposure All US pop
below LOD
17 76 increased
risk
8923607
Breast Cancer
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Cadmium 0580 ugg
creatinine
126 205 479 16788160
PCB 138 396 ngg
creatinine
202 316 630 27717745
PCB 187 108 ngg lipid 600 194 360 21480306
Miscellaneous Diseases
Toxin Disease Threshold Above
Threshold
Odds
Ratio
of Dz Reference PMID
Aluminum Alzheimer
Dz
01 mgL
drinking
H20
400 203 05-44 26592479
Benzene AML 100ppmyrs 1-3 320 60 PMC2903550
DDT NHL 0512 ugL 1-2 240 01 17722095
Lead ALS 238 ugdL
blood
330 181 210 25479292
Lead Brain CA 0005 ugdL 14 19 ~500 17164378
Dioxin-like
PCBs
RA 326 ngg
lipid
250 219 220 17589595
PAHs Asthma 124 ngm3 935 200 483 19221603
The Potency of Arsenic
Disease Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Bladder CA 10ugL H20 100 27 145 24889821
Pancreatic CA 1332 ugg 200 246 230 23800676
Prostate CA 1332 ugg 200 33 315 23800676
Gout 125 ugL 245 546 522 25499256
Diabetes 165 ugL 200 21 180 18714061
Arsenic (180 of Diabetes)
How it causes diabetes
bull Blocks sugar stimulating insulin secretion
bull Epigenetic inhibition of sugar regulation
Where it comes from
bull Water (gt10 of US water supplies have high levels)
bull Rice (naturally absorbs if in the water)
bull Chicken (added to make meat whiter)
Pan W-C Seow WJ Kile ML et al Association of low to moderate levels of arsenic exposure with risk of Type 2 diabetes in Bangladesh American Journal of Epidemiology 2013178(10)1563-70
Portion of Population with Toxin Load Which
Doubles Disease Risk
Toxin Disease with Doubled Risk
Polycyclic aromatic hydrocarbons Asthma 94
PCB187 Breast Cancer 60
Phthalates Diabetes 55
Lead ALS 33
Aluminum Alzheimers Disease 25
DDT ADHD 25
PCBs Diabetes 25
Dioxin-like PCBs Rheumatoid Arthritis 25
Arsenic Gout 23
Bisphenol A Diabetes 22
Cigarette smoking Lung Cancer 21
Arsenic Diabetes 20
Polycyclic aromatic hydrocarbons Diabetes 20
Huge Detoxification Variability
bull CYP2C19
Proton pump inhibitors and some antidepressants
5-fold difference in activity between poor metabolizers and extensive metabolizers more so if CYP3A4 is also inhibited
Ultrarapid allele in 18 of both Swedes and Ethiopians
bull CYP2D6
Metabolizes a large number of drugs (~25)
7 of Caucasians poor metabolizers
~30 ultra rapid metabolizers in Arabian and Eastern African populations
More adverse effects in poor metabolizers and ineffective dosing in ultrarapid metabolizers
Inhibited by ginger
Desta Z et al Clinical significance of the cytochrome P450 2C19 genetic polymorphism Clin Pharmaco 2002
Sim SC et al A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug
response to proton pump inhibitors and antidepressants Clin Pharmacol Ther 2006
Wilkinson GR Drug metabolism and variability among patients in drug response N Engl J Med 2005
Kirchheiner J et al Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to
CYP2D6 duplication Pharmacogenomics J 2007
Toxin Half Lives in BloodToxin ldquoNormalrdquo (mgL) Acute Toxic (mgL) Half-Life
Arsenic 0002-007 005-025 2-4 days (CDC)
Benzene 00002 05-10 days
Cadmium 00003-00065 0015-005 16 years
Chlordane 0001 00025 3-4 days
DDTDDE 2-10 years
Dieldrin 00015 015-030 2-12 months
Ethanol 1000-2000 15hour
Lead 009 04-06 1-15 mo (2+ yrs bone)
Mercury 00015-0002 005-02 2 months (CDC)
PCBs 3-25 years
Toluene 05-3 days
Schulz M et al Therapeutic and toxic blood concentrations of nearly 1000 drugs and other xenobiotics Crit Care 2012 Jul 2616(4)R136
Bioaccumulation (POPs)
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
DDT banned in 1972 PCBs banned in 1977
Bioaccumulation (Cd)
Think BroadlyExogenous
Metals
Chemicalsbull Inorganic
bull Fluoride
bull Organic
bull POPs
bull Drugs
Particulate matter
Molds
Microbial
Radiationbull Light
bull Medical
bull Cell phone
Endogenous
Gut-derived toxins
Non-end product metabolites
Poorly detoxified hormones
Catecholamines (if SNP)
Toxins of Choice
Alcohol
Marijuana
Food constituents
High fructose corn syrup
Salt (acid-forming diet)
Wheat if zonulin (70)
Obesity Epidemic ndash POPs AND HFCS
47Bray GA Fructose should we worry Int J Obes (Lond) 2008 Dec32 Suppl 7S127-31
How Toxins Cause Damage 13
bull Increase free radical production
Cd induces production of ROS
Malathion inhibits catalase and glutathione peroxidase
Homocysteine oxidizes LDL cholesterol
bull Poison enzyme systems (compete with nutritional cofactors for binding sites)
Pb poisons delta aminolevulinic acid dehydratase
Cd inhibits catalase glutathione reductase and lowers
glutathione levels
bull Replace structural minerals
Pb displaces Ca in bone
How Toxins Cause Damage 23
bull Damage DNA
Benzene - causes chromosomal damage
Pesticides ndash fruit growers have more DNA damage
Phthalates and insecticides ndash damage sperm DNA
4-hydroxy catechol estrogen (4-OHE) damages breast DNA
bull Epigenetic dysmodulation
Higher cord blood levels of hexachlorobenzene associated
with 2x greater risk for obesity in children
bull Damage cell membranes
Common mechanism for heavy metals inactivates
membrane enzymes ion channels and pumps
How Toxins Cause Damage 33
bull Block insulin receptor sites
PCBs and phthalates
bull Highest levels associated with a 4 to 20-fold greater diabetes risk
bull Imbalance hormones many toxin examples
Arsenic
bull Disrupts thyroid hormone and retinoic acid receptors
Phthalates
bull Act as anti-androgens
bull More than 75 of the US population has measurable levels of
several phthalate metabolites in the urine
PCBs
bull Lower testosterone levels in men
Which are the Worst Toxins
bull According to the CDC
Toxicity
Population toxic load
Prevalence in toxic waste sites
bull According to clinical importance
Exposure
of disease
Ability of the body to detoxifyexcrete
Ag
en
cy
fo
r T
oxic
Su
bs
tan
ce
s a
nd
Dis
ea
se
Reg
istr
y
Pri
ori
ty L
ist
The Worst Toxins Clinically
My Rank Toxin Diseases Primary Sources
1 Arsenic Cancers diabetes gout Water chicken rice
2 DDT ADHD dementia diabetes Everywhere
3 Phthalates ADHD diabetes Soft plastics HABAs
4 PBDEs ADHD diabetes Flame retardant fabrics
5 PAHs ADHD cancers dyslipidemia Smoking charbroiling
6 PCBs Cancers diabetes MI RA Everywhere
7 Mercury Dementia ldquoSilverrdquo fillings fish
8 Lead Cardiovascular disease IQ Paint water
Glyphosate Research invalid
Conventional Laboratory Tests Reflect
Toxic Load in ldquoNormalrdquo Range
bull Surprising number show toxin exposure
CBC RBC WBC platelet count hemoglobin basophilic
stippling
Liver enzymes ALT GGTP
Inflammatory markers CRP
Lipids LDL oxLDL triglycerides
Blood sugar insulin FBS 2-hour PP
Metabolites bilirubin uric acid homocysteine 8-OHdG
Thyroid T3 T4 TSH
bull The historic ldquonormalrdquo range has been changing as the population has become more toxic
WBC Lowered by PCB and OCP Exposure
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
0
1
2
3
4
5
6
7
8
1st Quartrile 2nd Quartile 3rd Quartile 4th Quartile
WBCbull Strong inverse correlation with PCBs and OCPs and CBC
bull Linear with almost all PCBs
bull High variability with OCPs
bull Within ldquonormalrdquo range
Effects on WBC Worsen with Years
of Exposure to Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Platelet Count Decreases with Years
of Exposure tp Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Solvents Decrease Platelet Count
bull Compared workers exposed 23 hrday to those exposed most of day to toluene
bull All wore face masks and protective gear
bull Platelet count 14 lower 252 versus 216ml
bull Impairment of sympathetic nerves (OR = 413)
bull Impairment of peripheral nerves (OR = 694)
bull Positive relationship between neurological abnormalities and a self-reported neuropsychiatric measurement (r = 035-066)
Shih HT et al Subclinical abnormalities in workers with continuous low-level toluene exposure Toxicol Ind Health 2011 Sep27(8)691-9
Basophilic Stippling of Red Cells
Toxinsbull Arsenic
bull Lead
Diseasesbull Alpha-thalassemia HbH Disease
bull Beta thalassemia
bull Hereditary pyrimidine 5-nucleotidase deficiency
bull Myelodysplastic syndrome
bull Sideroblastic anemia
bull Thrombotic thrombocytopenic purpura
GGT Indirect Measure of POPsbull Glutathione is key intracellular defense against oxidative stress
bull Cellular GGT metabolizes extracellular GSH allowing precursor amino acids to be reutilized for intracellular GSH
bull Exposure to POPs induces GGT as a defensive mechanism
bull Within normal range predicts type 2 diabetes coronary heart disease hypertension stroke dyslipidemia chronic kidney disease and cancer
bull Men with GGT gt50 UI had ~26 fold risk for diabetes compared to those with lt10 Those with 40-49 had a ~20 fold risk
bull Levels within normal range occur with obesity xs alcohol cigarette smoking physical inactivity high meat low fruit and vegetable intake
bull Cumulative biomarker for environmental pollutants
Lee DH et al (2003) Gamma-glutamyltransferase and diabetesmdasha 4 year follow-up study Diabetologia 46359ndash364
Pamela A et al Serum gamma-glutamyltransferase linking together environmental pollution redox equilibria and progression of atherosclerosis Clin Chem
Lab Med 200947(12)1583-4
Lee DH et al Serum gamma-glutamyltransferase new insights about an old enzyme J Epidemiol Community Health 2009 Nov63(11)884-6
Lee DH et alSerum gamma-glutamyltransferase predicts non-fatal myocardial infarction and fatal coronary heart disease among 28838 middle-aged men and
women Eur Heart J 2006272170ndash6
Lee DH et al Gamma-glutamyltransferase and diabetes--a 4 year follow-up study Diabetologia 2003 Mar46(3)359-64
Lee DH et al Can persistent organic pollutants explain the association between serum gamma-glutamyltransferase and type 2 diabetes Diabetologia 2008
Mar51(3)402-7
GGT and Alcohol Consumption
bull GGT directly correlates with alcohol consumption
bull In a non-uniform population 40 gd will elevate GGT ~15
bull Watch for false negatives
bull Genomic variation
bull Are these the ones most
sensitive todamaged by
chemical toxins
bull Could up-regulation of GGT in light alcohol consumption be reason for benefit
0
10
20
30
40
50
60
70
80
0 200 400 600 800
Grams of Ethanol per Week
Adapted from Nagaya T et al Dose-response relationships between drinking and serum tests in Japanese men
aged 40ndash59 years Alcohol 1999 Feb 17(2) 133ndash8
GGT Correlates With Toxic Metal Levels
Lee DH et al Graded associations of blood lead and urinary cadmium concentrations with oxidative-stress-related markers in the
US population results from the third National Health and Nutrition Examination Survey Environ Health
perspect 2006 Mar114(3)350-4
GGT and Diabetes Risk
0
5
10
15
20
25
30
lt10 10-19 20-29 30-39 40-49 gt50
Dia
bete
s R
isk
GGT
bull GGT over 50 associated with tripling of death rate
bull 30-40 associated with doubling
GGT Levels
Correlate with
Risk of Death
Brenner H et al Distribution determinants and prognostic value of gamma-glutamyltransferase for all-cause
mortality in a cohort of construction workers from southern Germany Prev Med 1997 26 305ndash10
GGT From Small US Company
with Young Workers
0
10
20
30
40
50
60
0 20 40 60 80 100
GGT Data from Canadian Oil Field
Workers
0
50
100
150
200
250
300
350
400
450
lt10 10-20 20-30 30-40 40-50 50-60 60-07 70-80 80-90 90-100 100-110 110-120 gt120
GGTP
20-fold increased risk of diabetes
Uric Acid Indirect Measure of POPs
bull Poly-fluorinated hydrocarbons (PFOA and PFOS) associated
with increased serum uric acid
Lin CY et al Association among serum perfluoroalkyl chemicals glucose homeostasis and metabolic syndrome
in adolescents and adults Diabetes Care 2009 Apr32(4)702-7
Steenland K et al Association of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) with uric
acid among adults with elevated community exposure to PFOA Environ Health Perspect 2010 Feb118229-33
Steenland 2010 Open Access
ALT Indirect Measure of POPs
bull ALT (proxy marker) elevation in 104 (not including viral
hepatitis hemochromatosis or alcoholic liver disease) of
NHANES 03-04 subset
bull Risk of elevated ALT increased dose-dependently with
cadmium lead mercury and PCB exposure
bull 100 of individuals had detectable PCBs 925 mercury
and 996 had detectable lead
bull In 2005-08 prevalence of NAFLD in US was 11 a
growing cause of chronic liver disease
Cave M et al Polychlorinated biphenyls lead and mercury are associated with liver disease in American adults
NHANES 2003-2004 Environ Health Perspect 2010 Dec118(12)1735-42
Younossi ZM et al Changes in the prevalence of the most common causes of chronic liver diseases in the United
States from 1988 to 2008 Clin Gastroenterol Hepatol 2011 Jun9(6)524-530e1
Bilirubin as a Marker of POPs
bull Degree of serum bilirubin increase is prognostically significant in chronic liver dysfunction
bull Mono-ortho PCB TEQ values were found to be significantly positively associated with bilirubin (β=071 P=0008) following adjustment for multiple potential confounders
bull Bilirubin levels significantly correlated with PCBs -105-118-126 and -194
bull Smoking appears to be the biggest confounder
Dufour DR et al 2000 Diagnosis and monitoring of hepatic injury II Recommendations for use of laboratory
tests in screening diagnosis and monitoring Clin Chem 46 2050ndash68
Kumar J et al Persistent organic pollutants and liver dysfunction biomarkers in a population-based human sample
of men and women Environ Res 2014134251-256
Perf
luo
rin
ate
dP
OP
s a
nd
Co
mm
on
Blo
od
Tests
Gleason JA et al Associations of perfluorinated chemical serum concentrations and biomarkers of liver function and uric acid in the
US population (NHANES) 2007-2010 Environ Res 20151368-14
Liver Enzymes Reflect Toxic Load
bull AST ALT and GGT increase with body load of PCBs and OCPs
bull Some non-linear
bull Oxychlordanetop quartile
ALT 10
GGT 25
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
LDL-Cholesterol as Measure of POPs
bull 5-year prospective study to determine if POP levels predict future elevation in LDL-cholesterol
bull 598 subjects initially at age 70
bull Looked at 23 POPs
bull Best correlation with PCB 194
Penell J Lind L Salihovic S et al Persistent organic pollutants are related to change in circulating
lipid levels during a 5 year follow-up Environ Res 134(2014)190ndash197
oxLDL as Measure of POPs
bull 992 70-year old individuals (50 women)
bull Sum of PCBs showed strong significant positive associations with ox-LDL and significant negative associations with glutathione-related markers (GSSG and GSSGGSH)
bull A number of POPs (PCB-99 138 153 156 170 180 194 206 and 209) showed strong significant positive association with ox-LDL
Kumar J et al Influence of persistent organic pollutants on oxidative stress in population-based samples
Chemosphere 2014114303-309
Homocysteine is Increased by Pb amp Cd
Guallar E et al Confounding of the relation between homocysteine and peripheral arterial disease by lead cadmium and renal function Am J Epidemiol 2006 Apr 15163(8)700-8
Nutrient Deficiencies Accentuate
Effects of Lead on Homocysteine
bull Deficiencies in folate B6 or B12 make lead more toxic
Lee YM Et al Association of homocysteine levels with blood lead levels and micronutrients in the US general population J Prev Med Public Health 2012 Nov45(6)387-93
T4 amp T3 and PCBs
bull PCBs decrease T4 production
bull PCBs inhibit iodotyrosinedeiodinase activity
bull Study done in pregnant women which implies effect on fetus IQ
Kim S Park J Kim HJ et al Association between several persistent organic pollutants and thyroid hormone levels in serum among the pregnant women of Korea Environ Int 2013 Sep59442-8Shimizu R Yamaguchi M Uramaru N et al Structure-activity relationships of 44 halogenated compounds for iodotyrosinedeiodinase-inhibitory activity Toxicology 2013 Dec 6314(1)22-9
T4 amp T3 and PCBs
bull Not just humans being affected
bull Large study of dolphins shows exactly the same effects
Schwacke LH Zolman ES Balmer BC et al Anaemia hypothyroidism and immune suppression associated with polychlorinated biphenyl exposure in bottlenose dolphins (Tursiops truncatus) Proceed Royal Society B doi101098rspb20110665
8-OHdG
bull Oxidized nucleoside
bull Direct measure of DNA damage
bull Indirect measure of oxidative stress and toxin load
bull Correlates with
Multiple cancers
Mitochondrial damage
Rate of aging
Smoking
Several toxinsWalter Crinnion ldquoTotal Toxic Loadrdquo AANP 2015
8-OHdG Correlates with Pack-Years
of Smoking
Yano T et al Significance of the urinary 8-OHdG level as an oxidative stress marker in lung cancer patients Lung Cancer
2009 Jan63(1)111-4
8-OHdG Correlates
with Mercury
Chen C et al Increased oxidative DNA damage as assessed by urinary 8-hydroxy-2-deoxyguanosine
concentrations and serum redox status in persons exposed to mercury Clin Chem 2005 Apr51(4)759-67
Toxin Effects Worse with Aging
bull Thyroid function decreases with PFOA levels
bull But only after age 63
Shrestha S Bloom MS Yucel R et al Perfluoroalkyl substances and thyroid function in older adults Environ Int 2015 Feb75206-14
Insightful 23-Year Prospective Study
1 lt 50 there is no difference between those with the lowest and highest PCBs
2 In youngest group insulin production increases in response to toxin level As expected since blocking of
insulin receptor sites by PCBs
requires more insulin
3 That adaptive ability decreases with aging
4 At age 50 all the measures show very strong toxin-dose response
Cumulative damage impairs ability to adapt
Suarez-Lopez JR et al Persistent organic pollutants in young adults and changes in glucose related metabolism over a 23-year follow-up Environ Res 2015 Feb137485-94
Recommendations
High body toxic load
GGT gt 25
Uric acid gt 50 mgdl
ALT gt30 UL
Bilirubin gt08 mgdl
CBC lt 6000
Platelet lt 250000
Low T3 andor T4
Monitor Total Toxic Load
8-OHdG gt4
ldquoUnconventionalrdquo Laboratory Tests
bull Challenge testing
bull Hair analysis
bull Direct measures of solvents and POPs in blood urine adipose tissue
Evaluation of Metal Exposure ndash Provocation
bull Provocation ndash the use of a chelating agent ndash before urine collection often done clinically but several limitations
No ldquoofficialrdquo reference range for provoked urine
Most chelating agents do not extract metals from all tissues thus
does not necessarily represent total body burden
bull Example Brain is one of the main target organs for both elemental and organic
mercury yet agents do not chelate brain mercury
bull Despite limitations widely used and advocated by clinicians in part to see efficacy of chelating agent as a guide to treatment and based on empirical evidence
Rooney JP The role of thiols dithiols nutritional factors and interacting ligands in the toxicology of mercury
Toxicology 2007
Is Challenge Testing Valid
bull Poor correlations of standard tests for mercury
bull Unpublished research from corporate wellness project
bull Published amalgam number correlation
bull Published fish consumption correlation
What We Found In Canada
bull Deviations from the mean of 14 29 and 91 respectively
bull DMPS is spreading distribution suggesting that it is better at differentiating mercury body load
bull Some VERY high
Hg Assessment Correlations
bull Extensive measurements in 65 Whole blood Hg
Oral DMPS challenge
Amalgam surfaces
bull Correlations Whole blood w pre urine r = 040
Whole blood w post urine r = 057
Pre urine w post urine r = 068
Amalgams w pre urine r = 026
Amalgams w whole blood r = 036
Amalgams with post urine 044
bull Clear documentation that
challenge testing is better00
100
200
300
400
500
600
0 10 20 30 40 50
Po
st
Uri
ne H
g u
gg
Number of amalgams
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
Toxins StudiedAluminum
Arsenic
Cadmium
Fluoride
Lead
Manganese
Mercury
Acrylamide
Acrylonitrile
Benzene
Bisphenol A (BPA)
Chloroform
DDT
Dioxins
Glyphosate
Organochlorine pesticides (OCPs)
Organophosphate pesticides
Parabens
Phthalates
Polybrominated diphenyl ethers (PBDEs)
Polycyclic aromatic hydrocarbons (PAHs)
Polychlorinated biphenols (PCBs)
Vinyl chloride
Diseases Studied
ADHD
Alzheimers Disease
ALS
Angiosarcoma
Anxiety
Atopic Conditions
Diabetes
Dyslipidemia
Gout
Fetal Abnormalities
Hyperuricemia
Infertility
Juvenile IQ
Cancer Bladder
Cancer Bone
Cancer Brain
Cancer Breast
Cancer Cervix
Cancer Colorectal
Cancer Endometrial
Cancer Head amp Neck
Cancer Liver
Cancer Lung
Cancer Lymph amp Blood
Cancer Ovarian
Cancer Pancreatic
Cancer Prostate
Cancer Renal
Cancer Skin
Cancer Testicular
Cancer Thyroid
Juvenile Obesity
Metabolic Syndrome
Mitochondrial dysfunction
Myocardial Infarction
Obstructive Lung Disease
Osteoporosis
Peripheral Artery Disease
Peripheral Neuropathy
Prediabetes
Renal Disease
Rheumatoid Arthritis
Thyroid Dysfunction
OC
Ps
Th
rou
gh
ou
t th
e W
orl
d
Rathore HS Nollet LML Pesticides Evaluation of Environmental Pollution CRC Press
2012 page 562
Threshold ndash Threshold exposure at which there is an increased risk of disease outcome
Above Threshold ndash Percentage of the population with higher exposure than the threshold
Odds Ratio ndash Increased disease risk in those above threshold
of Dz ndash Percent contribution of the toxin to that disease outcome
How to Interpret the Following Slides
Attention Deficit Hyperactivity Disorder
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
DDT 126 ngg
serum (pp-
DDE)
250 18 166 20106937
Lead 23 ugdL 13 254 20 27659349
Mercury 16 24952233
Organophosphate
pesticides
20
Polycyclic
Aromatic
Hydrocarbons
227 ngm3 940 125 190 22440811
PCBs 104 ngg
serum (sum
of 50 PCBs)
250 176 160 20106937
DiabetesToxin Threshold Above
Threshold
Odds
Ratio
of Dz Reference
PMID
Arsenic 165 ugL 200 21 180 18714061
BPA 28 ugL 280 145 112 26119400
DDE 545 ngg serum
(pp-DDE)
200 230 31 26119400
Dioxins2 pgg lipid 50 191 43
26119400
PCBs104 ngg (PCB 153) 250 239 258
26119400
Phthalates175 ugL 690 148 249
26119400
1-naphthalene 167 ugdL 152 182 111 26340343
2-napthalene 414 ugdL 550 224 214 26340343
1-phenanthrene 167 ngL 570 178 151 26340343
1-pyrene 85 ngL 660 180 174 26340343
Lung Cancer
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Acrylonitrile Uncertain Uncertain 125 25
occupational
exposure
17114112
Arsenic 1213 ugL 436 of Asian
Americans
~01 of total
US population
34 95 in AA
01-1
PMC2682945
Cadmium Uncertain+ Uncertain 467 10 in
smokers
17184399
DDT Any exposure All US pop
below LOD
17 76 increased
risk
8923607
Breast Cancer
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Cadmium 0580 ugg
creatinine
126 205 479 16788160
PCB 138 396 ngg
creatinine
202 316 630 27717745
PCB 187 108 ngg lipid 600 194 360 21480306
Miscellaneous Diseases
Toxin Disease Threshold Above
Threshold
Odds
Ratio
of Dz Reference PMID
Aluminum Alzheimer
Dz
01 mgL
drinking
H20
400 203 05-44 26592479
Benzene AML 100ppmyrs 1-3 320 60 PMC2903550
DDT NHL 0512 ugL 1-2 240 01 17722095
Lead ALS 238 ugdL
blood
330 181 210 25479292
Lead Brain CA 0005 ugdL 14 19 ~500 17164378
Dioxin-like
PCBs
RA 326 ngg
lipid
250 219 220 17589595
PAHs Asthma 124 ngm3 935 200 483 19221603
The Potency of Arsenic
Disease Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Bladder CA 10ugL H20 100 27 145 24889821
Pancreatic CA 1332 ugg 200 246 230 23800676
Prostate CA 1332 ugg 200 33 315 23800676
Gout 125 ugL 245 546 522 25499256
Diabetes 165 ugL 200 21 180 18714061
Arsenic (180 of Diabetes)
How it causes diabetes
bull Blocks sugar stimulating insulin secretion
bull Epigenetic inhibition of sugar regulation
Where it comes from
bull Water (gt10 of US water supplies have high levels)
bull Rice (naturally absorbs if in the water)
bull Chicken (added to make meat whiter)
Pan W-C Seow WJ Kile ML et al Association of low to moderate levels of arsenic exposure with risk of Type 2 diabetes in Bangladesh American Journal of Epidemiology 2013178(10)1563-70
Portion of Population with Toxin Load Which
Doubles Disease Risk
Toxin Disease with Doubled Risk
Polycyclic aromatic hydrocarbons Asthma 94
PCB187 Breast Cancer 60
Phthalates Diabetes 55
Lead ALS 33
Aluminum Alzheimers Disease 25
DDT ADHD 25
PCBs Diabetes 25
Dioxin-like PCBs Rheumatoid Arthritis 25
Arsenic Gout 23
Bisphenol A Diabetes 22
Cigarette smoking Lung Cancer 21
Arsenic Diabetes 20
Polycyclic aromatic hydrocarbons Diabetes 20
Huge Detoxification Variability
bull CYP2C19
Proton pump inhibitors and some antidepressants
5-fold difference in activity between poor metabolizers and extensive metabolizers more so if CYP3A4 is also inhibited
Ultrarapid allele in 18 of both Swedes and Ethiopians
bull CYP2D6
Metabolizes a large number of drugs (~25)
7 of Caucasians poor metabolizers
~30 ultra rapid metabolizers in Arabian and Eastern African populations
More adverse effects in poor metabolizers and ineffective dosing in ultrarapid metabolizers
Inhibited by ginger
Desta Z et al Clinical significance of the cytochrome P450 2C19 genetic polymorphism Clin Pharmaco 2002
Sim SC et al A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug
response to proton pump inhibitors and antidepressants Clin Pharmacol Ther 2006
Wilkinson GR Drug metabolism and variability among patients in drug response N Engl J Med 2005
Kirchheiner J et al Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to
CYP2D6 duplication Pharmacogenomics J 2007
Toxin Half Lives in BloodToxin ldquoNormalrdquo (mgL) Acute Toxic (mgL) Half-Life
Arsenic 0002-007 005-025 2-4 days (CDC)
Benzene 00002 05-10 days
Cadmium 00003-00065 0015-005 16 years
Chlordane 0001 00025 3-4 days
DDTDDE 2-10 years
Dieldrin 00015 015-030 2-12 months
Ethanol 1000-2000 15hour
Lead 009 04-06 1-15 mo (2+ yrs bone)
Mercury 00015-0002 005-02 2 months (CDC)
PCBs 3-25 years
Toluene 05-3 days
Schulz M et al Therapeutic and toxic blood concentrations of nearly 1000 drugs and other xenobiotics Crit Care 2012 Jul 2616(4)R136
Bioaccumulation (POPs)
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
DDT banned in 1972 PCBs banned in 1977
Bioaccumulation (Cd)
Think BroadlyExogenous
Metals
Chemicalsbull Inorganic
bull Fluoride
bull Organic
bull POPs
bull Drugs
Particulate matter
Molds
Microbial
Radiationbull Light
bull Medical
bull Cell phone
Endogenous
Gut-derived toxins
Non-end product metabolites
Poorly detoxified hormones
Catecholamines (if SNP)
Toxins of Choice
Alcohol
Marijuana
Food constituents
High fructose corn syrup
Salt (acid-forming diet)
Wheat if zonulin (70)
Obesity Epidemic ndash POPs AND HFCS
47Bray GA Fructose should we worry Int J Obes (Lond) 2008 Dec32 Suppl 7S127-31
How Toxins Cause Damage 13
bull Increase free radical production
Cd induces production of ROS
Malathion inhibits catalase and glutathione peroxidase
Homocysteine oxidizes LDL cholesterol
bull Poison enzyme systems (compete with nutritional cofactors for binding sites)
Pb poisons delta aminolevulinic acid dehydratase
Cd inhibits catalase glutathione reductase and lowers
glutathione levels
bull Replace structural minerals
Pb displaces Ca in bone
How Toxins Cause Damage 23
bull Damage DNA
Benzene - causes chromosomal damage
Pesticides ndash fruit growers have more DNA damage
Phthalates and insecticides ndash damage sperm DNA
4-hydroxy catechol estrogen (4-OHE) damages breast DNA
bull Epigenetic dysmodulation
Higher cord blood levels of hexachlorobenzene associated
with 2x greater risk for obesity in children
bull Damage cell membranes
Common mechanism for heavy metals inactivates
membrane enzymes ion channels and pumps
How Toxins Cause Damage 33
bull Block insulin receptor sites
PCBs and phthalates
bull Highest levels associated with a 4 to 20-fold greater diabetes risk
bull Imbalance hormones many toxin examples
Arsenic
bull Disrupts thyroid hormone and retinoic acid receptors
Phthalates
bull Act as anti-androgens
bull More than 75 of the US population has measurable levels of
several phthalate metabolites in the urine
PCBs
bull Lower testosterone levels in men
Which are the Worst Toxins
bull According to the CDC
Toxicity
Population toxic load
Prevalence in toxic waste sites
bull According to clinical importance
Exposure
of disease
Ability of the body to detoxifyexcrete
Ag
en
cy
fo
r T
oxic
Su
bs
tan
ce
s a
nd
Dis
ea
se
Reg
istr
y
Pri
ori
ty L
ist
The Worst Toxins Clinically
My Rank Toxin Diseases Primary Sources
1 Arsenic Cancers diabetes gout Water chicken rice
2 DDT ADHD dementia diabetes Everywhere
3 Phthalates ADHD diabetes Soft plastics HABAs
4 PBDEs ADHD diabetes Flame retardant fabrics
5 PAHs ADHD cancers dyslipidemia Smoking charbroiling
6 PCBs Cancers diabetes MI RA Everywhere
7 Mercury Dementia ldquoSilverrdquo fillings fish
8 Lead Cardiovascular disease IQ Paint water
Glyphosate Research invalid
Conventional Laboratory Tests Reflect
Toxic Load in ldquoNormalrdquo Range
bull Surprising number show toxin exposure
CBC RBC WBC platelet count hemoglobin basophilic
stippling
Liver enzymes ALT GGTP
Inflammatory markers CRP
Lipids LDL oxLDL triglycerides
Blood sugar insulin FBS 2-hour PP
Metabolites bilirubin uric acid homocysteine 8-OHdG
Thyroid T3 T4 TSH
bull The historic ldquonormalrdquo range has been changing as the population has become more toxic
WBC Lowered by PCB and OCP Exposure
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
0
1
2
3
4
5
6
7
8
1st Quartrile 2nd Quartile 3rd Quartile 4th Quartile
WBCbull Strong inverse correlation with PCBs and OCPs and CBC
bull Linear with almost all PCBs
bull High variability with OCPs
bull Within ldquonormalrdquo range
Effects on WBC Worsen with Years
of Exposure to Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Platelet Count Decreases with Years
of Exposure tp Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Solvents Decrease Platelet Count
bull Compared workers exposed 23 hrday to those exposed most of day to toluene
bull All wore face masks and protective gear
bull Platelet count 14 lower 252 versus 216ml
bull Impairment of sympathetic nerves (OR = 413)
bull Impairment of peripheral nerves (OR = 694)
bull Positive relationship between neurological abnormalities and a self-reported neuropsychiatric measurement (r = 035-066)
Shih HT et al Subclinical abnormalities in workers with continuous low-level toluene exposure Toxicol Ind Health 2011 Sep27(8)691-9
Basophilic Stippling of Red Cells
Toxinsbull Arsenic
bull Lead
Diseasesbull Alpha-thalassemia HbH Disease
bull Beta thalassemia
bull Hereditary pyrimidine 5-nucleotidase deficiency
bull Myelodysplastic syndrome
bull Sideroblastic anemia
bull Thrombotic thrombocytopenic purpura
GGT Indirect Measure of POPsbull Glutathione is key intracellular defense against oxidative stress
bull Cellular GGT metabolizes extracellular GSH allowing precursor amino acids to be reutilized for intracellular GSH
bull Exposure to POPs induces GGT as a defensive mechanism
bull Within normal range predicts type 2 diabetes coronary heart disease hypertension stroke dyslipidemia chronic kidney disease and cancer
bull Men with GGT gt50 UI had ~26 fold risk for diabetes compared to those with lt10 Those with 40-49 had a ~20 fold risk
bull Levels within normal range occur with obesity xs alcohol cigarette smoking physical inactivity high meat low fruit and vegetable intake
bull Cumulative biomarker for environmental pollutants
Lee DH et al (2003) Gamma-glutamyltransferase and diabetesmdasha 4 year follow-up study Diabetologia 46359ndash364
Pamela A et al Serum gamma-glutamyltransferase linking together environmental pollution redox equilibria and progression of atherosclerosis Clin Chem
Lab Med 200947(12)1583-4
Lee DH et al Serum gamma-glutamyltransferase new insights about an old enzyme J Epidemiol Community Health 2009 Nov63(11)884-6
Lee DH et alSerum gamma-glutamyltransferase predicts non-fatal myocardial infarction and fatal coronary heart disease among 28838 middle-aged men and
women Eur Heart J 2006272170ndash6
Lee DH et al Gamma-glutamyltransferase and diabetes--a 4 year follow-up study Diabetologia 2003 Mar46(3)359-64
Lee DH et al Can persistent organic pollutants explain the association between serum gamma-glutamyltransferase and type 2 diabetes Diabetologia 2008
Mar51(3)402-7
GGT and Alcohol Consumption
bull GGT directly correlates with alcohol consumption
bull In a non-uniform population 40 gd will elevate GGT ~15
bull Watch for false negatives
bull Genomic variation
bull Are these the ones most
sensitive todamaged by
chemical toxins
bull Could up-regulation of GGT in light alcohol consumption be reason for benefit
0
10
20
30
40
50
60
70
80
0 200 400 600 800
Grams of Ethanol per Week
Adapted from Nagaya T et al Dose-response relationships between drinking and serum tests in Japanese men
aged 40ndash59 years Alcohol 1999 Feb 17(2) 133ndash8
GGT Correlates With Toxic Metal Levels
Lee DH et al Graded associations of blood lead and urinary cadmium concentrations with oxidative-stress-related markers in the
US population results from the third National Health and Nutrition Examination Survey Environ Health
perspect 2006 Mar114(3)350-4
GGT and Diabetes Risk
0
5
10
15
20
25
30
lt10 10-19 20-29 30-39 40-49 gt50
Dia
bete
s R
isk
GGT
bull GGT over 50 associated with tripling of death rate
bull 30-40 associated with doubling
GGT Levels
Correlate with
Risk of Death
Brenner H et al Distribution determinants and prognostic value of gamma-glutamyltransferase for all-cause
mortality in a cohort of construction workers from southern Germany Prev Med 1997 26 305ndash10
GGT From Small US Company
with Young Workers
0
10
20
30
40
50
60
0 20 40 60 80 100
GGT Data from Canadian Oil Field
Workers
0
50
100
150
200
250
300
350
400
450
lt10 10-20 20-30 30-40 40-50 50-60 60-07 70-80 80-90 90-100 100-110 110-120 gt120
GGTP
20-fold increased risk of diabetes
Uric Acid Indirect Measure of POPs
bull Poly-fluorinated hydrocarbons (PFOA and PFOS) associated
with increased serum uric acid
Lin CY et al Association among serum perfluoroalkyl chemicals glucose homeostasis and metabolic syndrome
in adolescents and adults Diabetes Care 2009 Apr32(4)702-7
Steenland K et al Association of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) with uric
acid among adults with elevated community exposure to PFOA Environ Health Perspect 2010 Feb118229-33
Steenland 2010 Open Access
ALT Indirect Measure of POPs
bull ALT (proxy marker) elevation in 104 (not including viral
hepatitis hemochromatosis or alcoholic liver disease) of
NHANES 03-04 subset
bull Risk of elevated ALT increased dose-dependently with
cadmium lead mercury and PCB exposure
bull 100 of individuals had detectable PCBs 925 mercury
and 996 had detectable lead
bull In 2005-08 prevalence of NAFLD in US was 11 a
growing cause of chronic liver disease
Cave M et al Polychlorinated biphenyls lead and mercury are associated with liver disease in American adults
NHANES 2003-2004 Environ Health Perspect 2010 Dec118(12)1735-42
Younossi ZM et al Changes in the prevalence of the most common causes of chronic liver diseases in the United
States from 1988 to 2008 Clin Gastroenterol Hepatol 2011 Jun9(6)524-530e1
Bilirubin as a Marker of POPs
bull Degree of serum bilirubin increase is prognostically significant in chronic liver dysfunction
bull Mono-ortho PCB TEQ values were found to be significantly positively associated with bilirubin (β=071 P=0008) following adjustment for multiple potential confounders
bull Bilirubin levels significantly correlated with PCBs -105-118-126 and -194
bull Smoking appears to be the biggest confounder
Dufour DR et al 2000 Diagnosis and monitoring of hepatic injury II Recommendations for use of laboratory
tests in screening diagnosis and monitoring Clin Chem 46 2050ndash68
Kumar J et al Persistent organic pollutants and liver dysfunction biomarkers in a population-based human sample
of men and women Environ Res 2014134251-256
Perf
luo
rin
ate
dP
OP
s a
nd
Co
mm
on
Blo
od
Tests
Gleason JA et al Associations of perfluorinated chemical serum concentrations and biomarkers of liver function and uric acid in the
US population (NHANES) 2007-2010 Environ Res 20151368-14
Liver Enzymes Reflect Toxic Load
bull AST ALT and GGT increase with body load of PCBs and OCPs
bull Some non-linear
bull Oxychlordanetop quartile
ALT 10
GGT 25
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
LDL-Cholesterol as Measure of POPs
bull 5-year prospective study to determine if POP levels predict future elevation in LDL-cholesterol
bull 598 subjects initially at age 70
bull Looked at 23 POPs
bull Best correlation with PCB 194
Penell J Lind L Salihovic S et al Persistent organic pollutants are related to change in circulating
lipid levels during a 5 year follow-up Environ Res 134(2014)190ndash197
oxLDL as Measure of POPs
bull 992 70-year old individuals (50 women)
bull Sum of PCBs showed strong significant positive associations with ox-LDL and significant negative associations with glutathione-related markers (GSSG and GSSGGSH)
bull A number of POPs (PCB-99 138 153 156 170 180 194 206 and 209) showed strong significant positive association with ox-LDL
Kumar J et al Influence of persistent organic pollutants on oxidative stress in population-based samples
Chemosphere 2014114303-309
Homocysteine is Increased by Pb amp Cd
Guallar E et al Confounding of the relation between homocysteine and peripheral arterial disease by lead cadmium and renal function Am J Epidemiol 2006 Apr 15163(8)700-8
Nutrient Deficiencies Accentuate
Effects of Lead on Homocysteine
bull Deficiencies in folate B6 or B12 make lead more toxic
Lee YM Et al Association of homocysteine levels with blood lead levels and micronutrients in the US general population J Prev Med Public Health 2012 Nov45(6)387-93
T4 amp T3 and PCBs
bull PCBs decrease T4 production
bull PCBs inhibit iodotyrosinedeiodinase activity
bull Study done in pregnant women which implies effect on fetus IQ
Kim S Park J Kim HJ et al Association between several persistent organic pollutants and thyroid hormone levels in serum among the pregnant women of Korea Environ Int 2013 Sep59442-8Shimizu R Yamaguchi M Uramaru N et al Structure-activity relationships of 44 halogenated compounds for iodotyrosinedeiodinase-inhibitory activity Toxicology 2013 Dec 6314(1)22-9
T4 amp T3 and PCBs
bull Not just humans being affected
bull Large study of dolphins shows exactly the same effects
Schwacke LH Zolman ES Balmer BC et al Anaemia hypothyroidism and immune suppression associated with polychlorinated biphenyl exposure in bottlenose dolphins (Tursiops truncatus) Proceed Royal Society B doi101098rspb20110665
8-OHdG
bull Oxidized nucleoside
bull Direct measure of DNA damage
bull Indirect measure of oxidative stress and toxin load
bull Correlates with
Multiple cancers
Mitochondrial damage
Rate of aging
Smoking
Several toxinsWalter Crinnion ldquoTotal Toxic Loadrdquo AANP 2015
8-OHdG Correlates with Pack-Years
of Smoking
Yano T et al Significance of the urinary 8-OHdG level as an oxidative stress marker in lung cancer patients Lung Cancer
2009 Jan63(1)111-4
8-OHdG Correlates
with Mercury
Chen C et al Increased oxidative DNA damage as assessed by urinary 8-hydroxy-2-deoxyguanosine
concentrations and serum redox status in persons exposed to mercury Clin Chem 2005 Apr51(4)759-67
Toxin Effects Worse with Aging
bull Thyroid function decreases with PFOA levels
bull But only after age 63
Shrestha S Bloom MS Yucel R et al Perfluoroalkyl substances and thyroid function in older adults Environ Int 2015 Feb75206-14
Insightful 23-Year Prospective Study
1 lt 50 there is no difference between those with the lowest and highest PCBs
2 In youngest group insulin production increases in response to toxin level As expected since blocking of
insulin receptor sites by PCBs
requires more insulin
3 That adaptive ability decreases with aging
4 At age 50 all the measures show very strong toxin-dose response
Cumulative damage impairs ability to adapt
Suarez-Lopez JR et al Persistent organic pollutants in young adults and changes in glucose related metabolism over a 23-year follow-up Environ Res 2015 Feb137485-94
Recommendations
High body toxic load
GGT gt 25
Uric acid gt 50 mgdl
ALT gt30 UL
Bilirubin gt08 mgdl
CBC lt 6000
Platelet lt 250000
Low T3 andor T4
Monitor Total Toxic Load
8-OHdG gt4
ldquoUnconventionalrdquo Laboratory Tests
bull Challenge testing
bull Hair analysis
bull Direct measures of solvents and POPs in blood urine adipose tissue
Evaluation of Metal Exposure ndash Provocation
bull Provocation ndash the use of a chelating agent ndash before urine collection often done clinically but several limitations
No ldquoofficialrdquo reference range for provoked urine
Most chelating agents do not extract metals from all tissues thus
does not necessarily represent total body burden
bull Example Brain is one of the main target organs for both elemental and organic
mercury yet agents do not chelate brain mercury
bull Despite limitations widely used and advocated by clinicians in part to see efficacy of chelating agent as a guide to treatment and based on empirical evidence
Rooney JP The role of thiols dithiols nutritional factors and interacting ligands in the toxicology of mercury
Toxicology 2007
Is Challenge Testing Valid
bull Poor correlations of standard tests for mercury
bull Unpublished research from corporate wellness project
bull Published amalgam number correlation
bull Published fish consumption correlation
What We Found In Canada
bull Deviations from the mean of 14 29 and 91 respectively
bull DMPS is spreading distribution suggesting that it is better at differentiating mercury body load
bull Some VERY high
Hg Assessment Correlations
bull Extensive measurements in 65 Whole blood Hg
Oral DMPS challenge
Amalgam surfaces
bull Correlations Whole blood w pre urine r = 040
Whole blood w post urine r = 057
Pre urine w post urine r = 068
Amalgams w pre urine r = 026
Amalgams w whole blood r = 036
Amalgams with post urine 044
bull Clear documentation that
challenge testing is better00
100
200
300
400
500
600
0 10 20 30 40 50
Po
st
Uri
ne H
g u
gg
Number of amalgams
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
Diseases Studied
ADHD
Alzheimers Disease
ALS
Angiosarcoma
Anxiety
Atopic Conditions
Diabetes
Dyslipidemia
Gout
Fetal Abnormalities
Hyperuricemia
Infertility
Juvenile IQ
Cancer Bladder
Cancer Bone
Cancer Brain
Cancer Breast
Cancer Cervix
Cancer Colorectal
Cancer Endometrial
Cancer Head amp Neck
Cancer Liver
Cancer Lung
Cancer Lymph amp Blood
Cancer Ovarian
Cancer Pancreatic
Cancer Prostate
Cancer Renal
Cancer Skin
Cancer Testicular
Cancer Thyroid
Juvenile Obesity
Metabolic Syndrome
Mitochondrial dysfunction
Myocardial Infarction
Obstructive Lung Disease
Osteoporosis
Peripheral Artery Disease
Peripheral Neuropathy
Prediabetes
Renal Disease
Rheumatoid Arthritis
Thyroid Dysfunction
OC
Ps
Th
rou
gh
ou
t th
e W
orl
d
Rathore HS Nollet LML Pesticides Evaluation of Environmental Pollution CRC Press
2012 page 562
Threshold ndash Threshold exposure at which there is an increased risk of disease outcome
Above Threshold ndash Percentage of the population with higher exposure than the threshold
Odds Ratio ndash Increased disease risk in those above threshold
of Dz ndash Percent contribution of the toxin to that disease outcome
How to Interpret the Following Slides
Attention Deficit Hyperactivity Disorder
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
DDT 126 ngg
serum (pp-
DDE)
250 18 166 20106937
Lead 23 ugdL 13 254 20 27659349
Mercury 16 24952233
Organophosphate
pesticides
20
Polycyclic
Aromatic
Hydrocarbons
227 ngm3 940 125 190 22440811
PCBs 104 ngg
serum (sum
of 50 PCBs)
250 176 160 20106937
DiabetesToxin Threshold Above
Threshold
Odds
Ratio
of Dz Reference
PMID
Arsenic 165 ugL 200 21 180 18714061
BPA 28 ugL 280 145 112 26119400
DDE 545 ngg serum
(pp-DDE)
200 230 31 26119400
Dioxins2 pgg lipid 50 191 43
26119400
PCBs104 ngg (PCB 153) 250 239 258
26119400
Phthalates175 ugL 690 148 249
26119400
1-naphthalene 167 ugdL 152 182 111 26340343
2-napthalene 414 ugdL 550 224 214 26340343
1-phenanthrene 167 ngL 570 178 151 26340343
1-pyrene 85 ngL 660 180 174 26340343
Lung Cancer
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Acrylonitrile Uncertain Uncertain 125 25
occupational
exposure
17114112
Arsenic 1213 ugL 436 of Asian
Americans
~01 of total
US population
34 95 in AA
01-1
PMC2682945
Cadmium Uncertain+ Uncertain 467 10 in
smokers
17184399
DDT Any exposure All US pop
below LOD
17 76 increased
risk
8923607
Breast Cancer
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Cadmium 0580 ugg
creatinine
126 205 479 16788160
PCB 138 396 ngg
creatinine
202 316 630 27717745
PCB 187 108 ngg lipid 600 194 360 21480306
Miscellaneous Diseases
Toxin Disease Threshold Above
Threshold
Odds
Ratio
of Dz Reference PMID
Aluminum Alzheimer
Dz
01 mgL
drinking
H20
400 203 05-44 26592479
Benzene AML 100ppmyrs 1-3 320 60 PMC2903550
DDT NHL 0512 ugL 1-2 240 01 17722095
Lead ALS 238 ugdL
blood
330 181 210 25479292
Lead Brain CA 0005 ugdL 14 19 ~500 17164378
Dioxin-like
PCBs
RA 326 ngg
lipid
250 219 220 17589595
PAHs Asthma 124 ngm3 935 200 483 19221603
The Potency of Arsenic
Disease Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Bladder CA 10ugL H20 100 27 145 24889821
Pancreatic CA 1332 ugg 200 246 230 23800676
Prostate CA 1332 ugg 200 33 315 23800676
Gout 125 ugL 245 546 522 25499256
Diabetes 165 ugL 200 21 180 18714061
Arsenic (180 of Diabetes)
How it causes diabetes
bull Blocks sugar stimulating insulin secretion
bull Epigenetic inhibition of sugar regulation
Where it comes from
bull Water (gt10 of US water supplies have high levels)
bull Rice (naturally absorbs if in the water)
bull Chicken (added to make meat whiter)
Pan W-C Seow WJ Kile ML et al Association of low to moderate levels of arsenic exposure with risk of Type 2 diabetes in Bangladesh American Journal of Epidemiology 2013178(10)1563-70
Portion of Population with Toxin Load Which
Doubles Disease Risk
Toxin Disease with Doubled Risk
Polycyclic aromatic hydrocarbons Asthma 94
PCB187 Breast Cancer 60
Phthalates Diabetes 55
Lead ALS 33
Aluminum Alzheimers Disease 25
DDT ADHD 25
PCBs Diabetes 25
Dioxin-like PCBs Rheumatoid Arthritis 25
Arsenic Gout 23
Bisphenol A Diabetes 22
Cigarette smoking Lung Cancer 21
Arsenic Diabetes 20
Polycyclic aromatic hydrocarbons Diabetes 20
Huge Detoxification Variability
bull CYP2C19
Proton pump inhibitors and some antidepressants
5-fold difference in activity between poor metabolizers and extensive metabolizers more so if CYP3A4 is also inhibited
Ultrarapid allele in 18 of both Swedes and Ethiopians
bull CYP2D6
Metabolizes a large number of drugs (~25)
7 of Caucasians poor metabolizers
~30 ultra rapid metabolizers in Arabian and Eastern African populations
More adverse effects in poor metabolizers and ineffective dosing in ultrarapid metabolizers
Inhibited by ginger
Desta Z et al Clinical significance of the cytochrome P450 2C19 genetic polymorphism Clin Pharmaco 2002
Sim SC et al A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug
response to proton pump inhibitors and antidepressants Clin Pharmacol Ther 2006
Wilkinson GR Drug metabolism and variability among patients in drug response N Engl J Med 2005
Kirchheiner J et al Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to
CYP2D6 duplication Pharmacogenomics J 2007
Toxin Half Lives in BloodToxin ldquoNormalrdquo (mgL) Acute Toxic (mgL) Half-Life
Arsenic 0002-007 005-025 2-4 days (CDC)
Benzene 00002 05-10 days
Cadmium 00003-00065 0015-005 16 years
Chlordane 0001 00025 3-4 days
DDTDDE 2-10 years
Dieldrin 00015 015-030 2-12 months
Ethanol 1000-2000 15hour
Lead 009 04-06 1-15 mo (2+ yrs bone)
Mercury 00015-0002 005-02 2 months (CDC)
PCBs 3-25 years
Toluene 05-3 days
Schulz M et al Therapeutic and toxic blood concentrations of nearly 1000 drugs and other xenobiotics Crit Care 2012 Jul 2616(4)R136
Bioaccumulation (POPs)
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
DDT banned in 1972 PCBs banned in 1977
Bioaccumulation (Cd)
Think BroadlyExogenous
Metals
Chemicalsbull Inorganic
bull Fluoride
bull Organic
bull POPs
bull Drugs
Particulate matter
Molds
Microbial
Radiationbull Light
bull Medical
bull Cell phone
Endogenous
Gut-derived toxins
Non-end product metabolites
Poorly detoxified hormones
Catecholamines (if SNP)
Toxins of Choice
Alcohol
Marijuana
Food constituents
High fructose corn syrup
Salt (acid-forming diet)
Wheat if zonulin (70)
Obesity Epidemic ndash POPs AND HFCS
47Bray GA Fructose should we worry Int J Obes (Lond) 2008 Dec32 Suppl 7S127-31
How Toxins Cause Damage 13
bull Increase free radical production
Cd induces production of ROS
Malathion inhibits catalase and glutathione peroxidase
Homocysteine oxidizes LDL cholesterol
bull Poison enzyme systems (compete with nutritional cofactors for binding sites)
Pb poisons delta aminolevulinic acid dehydratase
Cd inhibits catalase glutathione reductase and lowers
glutathione levels
bull Replace structural minerals
Pb displaces Ca in bone
How Toxins Cause Damage 23
bull Damage DNA
Benzene - causes chromosomal damage
Pesticides ndash fruit growers have more DNA damage
Phthalates and insecticides ndash damage sperm DNA
4-hydroxy catechol estrogen (4-OHE) damages breast DNA
bull Epigenetic dysmodulation
Higher cord blood levels of hexachlorobenzene associated
with 2x greater risk for obesity in children
bull Damage cell membranes
Common mechanism for heavy metals inactivates
membrane enzymes ion channels and pumps
How Toxins Cause Damage 33
bull Block insulin receptor sites
PCBs and phthalates
bull Highest levels associated with a 4 to 20-fold greater diabetes risk
bull Imbalance hormones many toxin examples
Arsenic
bull Disrupts thyroid hormone and retinoic acid receptors
Phthalates
bull Act as anti-androgens
bull More than 75 of the US population has measurable levels of
several phthalate metabolites in the urine
PCBs
bull Lower testosterone levels in men
Which are the Worst Toxins
bull According to the CDC
Toxicity
Population toxic load
Prevalence in toxic waste sites
bull According to clinical importance
Exposure
of disease
Ability of the body to detoxifyexcrete
Ag
en
cy
fo
r T
oxic
Su
bs
tan
ce
s a
nd
Dis
ea
se
Reg
istr
y
Pri
ori
ty L
ist
The Worst Toxins Clinically
My Rank Toxin Diseases Primary Sources
1 Arsenic Cancers diabetes gout Water chicken rice
2 DDT ADHD dementia diabetes Everywhere
3 Phthalates ADHD diabetes Soft plastics HABAs
4 PBDEs ADHD diabetes Flame retardant fabrics
5 PAHs ADHD cancers dyslipidemia Smoking charbroiling
6 PCBs Cancers diabetes MI RA Everywhere
7 Mercury Dementia ldquoSilverrdquo fillings fish
8 Lead Cardiovascular disease IQ Paint water
Glyphosate Research invalid
Conventional Laboratory Tests Reflect
Toxic Load in ldquoNormalrdquo Range
bull Surprising number show toxin exposure
CBC RBC WBC platelet count hemoglobin basophilic
stippling
Liver enzymes ALT GGTP
Inflammatory markers CRP
Lipids LDL oxLDL triglycerides
Blood sugar insulin FBS 2-hour PP
Metabolites bilirubin uric acid homocysteine 8-OHdG
Thyroid T3 T4 TSH
bull The historic ldquonormalrdquo range has been changing as the population has become more toxic
WBC Lowered by PCB and OCP Exposure
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
0
1
2
3
4
5
6
7
8
1st Quartrile 2nd Quartile 3rd Quartile 4th Quartile
WBCbull Strong inverse correlation with PCBs and OCPs and CBC
bull Linear with almost all PCBs
bull High variability with OCPs
bull Within ldquonormalrdquo range
Effects on WBC Worsen with Years
of Exposure to Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Platelet Count Decreases with Years
of Exposure tp Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Solvents Decrease Platelet Count
bull Compared workers exposed 23 hrday to those exposed most of day to toluene
bull All wore face masks and protective gear
bull Platelet count 14 lower 252 versus 216ml
bull Impairment of sympathetic nerves (OR = 413)
bull Impairment of peripheral nerves (OR = 694)
bull Positive relationship between neurological abnormalities and a self-reported neuropsychiatric measurement (r = 035-066)
Shih HT et al Subclinical abnormalities in workers with continuous low-level toluene exposure Toxicol Ind Health 2011 Sep27(8)691-9
Basophilic Stippling of Red Cells
Toxinsbull Arsenic
bull Lead
Diseasesbull Alpha-thalassemia HbH Disease
bull Beta thalassemia
bull Hereditary pyrimidine 5-nucleotidase deficiency
bull Myelodysplastic syndrome
bull Sideroblastic anemia
bull Thrombotic thrombocytopenic purpura
GGT Indirect Measure of POPsbull Glutathione is key intracellular defense against oxidative stress
bull Cellular GGT metabolizes extracellular GSH allowing precursor amino acids to be reutilized for intracellular GSH
bull Exposure to POPs induces GGT as a defensive mechanism
bull Within normal range predicts type 2 diabetes coronary heart disease hypertension stroke dyslipidemia chronic kidney disease and cancer
bull Men with GGT gt50 UI had ~26 fold risk for diabetes compared to those with lt10 Those with 40-49 had a ~20 fold risk
bull Levels within normal range occur with obesity xs alcohol cigarette smoking physical inactivity high meat low fruit and vegetable intake
bull Cumulative biomarker for environmental pollutants
Lee DH et al (2003) Gamma-glutamyltransferase and diabetesmdasha 4 year follow-up study Diabetologia 46359ndash364
Pamela A et al Serum gamma-glutamyltransferase linking together environmental pollution redox equilibria and progression of atherosclerosis Clin Chem
Lab Med 200947(12)1583-4
Lee DH et al Serum gamma-glutamyltransferase new insights about an old enzyme J Epidemiol Community Health 2009 Nov63(11)884-6
Lee DH et alSerum gamma-glutamyltransferase predicts non-fatal myocardial infarction and fatal coronary heart disease among 28838 middle-aged men and
women Eur Heart J 2006272170ndash6
Lee DH et al Gamma-glutamyltransferase and diabetes--a 4 year follow-up study Diabetologia 2003 Mar46(3)359-64
Lee DH et al Can persistent organic pollutants explain the association between serum gamma-glutamyltransferase and type 2 diabetes Diabetologia 2008
Mar51(3)402-7
GGT and Alcohol Consumption
bull GGT directly correlates with alcohol consumption
bull In a non-uniform population 40 gd will elevate GGT ~15
bull Watch for false negatives
bull Genomic variation
bull Are these the ones most
sensitive todamaged by
chemical toxins
bull Could up-regulation of GGT in light alcohol consumption be reason for benefit
0
10
20
30
40
50
60
70
80
0 200 400 600 800
Grams of Ethanol per Week
Adapted from Nagaya T et al Dose-response relationships between drinking and serum tests in Japanese men
aged 40ndash59 years Alcohol 1999 Feb 17(2) 133ndash8
GGT Correlates With Toxic Metal Levels
Lee DH et al Graded associations of blood lead and urinary cadmium concentrations with oxidative-stress-related markers in the
US population results from the third National Health and Nutrition Examination Survey Environ Health
perspect 2006 Mar114(3)350-4
GGT and Diabetes Risk
0
5
10
15
20
25
30
lt10 10-19 20-29 30-39 40-49 gt50
Dia
bete
s R
isk
GGT
bull GGT over 50 associated with tripling of death rate
bull 30-40 associated with doubling
GGT Levels
Correlate with
Risk of Death
Brenner H et al Distribution determinants and prognostic value of gamma-glutamyltransferase for all-cause
mortality in a cohort of construction workers from southern Germany Prev Med 1997 26 305ndash10
GGT From Small US Company
with Young Workers
0
10
20
30
40
50
60
0 20 40 60 80 100
GGT Data from Canadian Oil Field
Workers
0
50
100
150
200
250
300
350
400
450
lt10 10-20 20-30 30-40 40-50 50-60 60-07 70-80 80-90 90-100 100-110 110-120 gt120
GGTP
20-fold increased risk of diabetes
Uric Acid Indirect Measure of POPs
bull Poly-fluorinated hydrocarbons (PFOA and PFOS) associated
with increased serum uric acid
Lin CY et al Association among serum perfluoroalkyl chemicals glucose homeostasis and metabolic syndrome
in adolescents and adults Diabetes Care 2009 Apr32(4)702-7
Steenland K et al Association of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) with uric
acid among adults with elevated community exposure to PFOA Environ Health Perspect 2010 Feb118229-33
Steenland 2010 Open Access
ALT Indirect Measure of POPs
bull ALT (proxy marker) elevation in 104 (not including viral
hepatitis hemochromatosis or alcoholic liver disease) of
NHANES 03-04 subset
bull Risk of elevated ALT increased dose-dependently with
cadmium lead mercury and PCB exposure
bull 100 of individuals had detectable PCBs 925 mercury
and 996 had detectable lead
bull In 2005-08 prevalence of NAFLD in US was 11 a
growing cause of chronic liver disease
Cave M et al Polychlorinated biphenyls lead and mercury are associated with liver disease in American adults
NHANES 2003-2004 Environ Health Perspect 2010 Dec118(12)1735-42
Younossi ZM et al Changes in the prevalence of the most common causes of chronic liver diseases in the United
States from 1988 to 2008 Clin Gastroenterol Hepatol 2011 Jun9(6)524-530e1
Bilirubin as a Marker of POPs
bull Degree of serum bilirubin increase is prognostically significant in chronic liver dysfunction
bull Mono-ortho PCB TEQ values were found to be significantly positively associated with bilirubin (β=071 P=0008) following adjustment for multiple potential confounders
bull Bilirubin levels significantly correlated with PCBs -105-118-126 and -194
bull Smoking appears to be the biggest confounder
Dufour DR et al 2000 Diagnosis and monitoring of hepatic injury II Recommendations for use of laboratory
tests in screening diagnosis and monitoring Clin Chem 46 2050ndash68
Kumar J et al Persistent organic pollutants and liver dysfunction biomarkers in a population-based human sample
of men and women Environ Res 2014134251-256
Perf
luo
rin
ate
dP
OP
s a
nd
Co
mm
on
Blo
od
Tests
Gleason JA et al Associations of perfluorinated chemical serum concentrations and biomarkers of liver function and uric acid in the
US population (NHANES) 2007-2010 Environ Res 20151368-14
Liver Enzymes Reflect Toxic Load
bull AST ALT and GGT increase with body load of PCBs and OCPs
bull Some non-linear
bull Oxychlordanetop quartile
ALT 10
GGT 25
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
LDL-Cholesterol as Measure of POPs
bull 5-year prospective study to determine if POP levels predict future elevation in LDL-cholesterol
bull 598 subjects initially at age 70
bull Looked at 23 POPs
bull Best correlation with PCB 194
Penell J Lind L Salihovic S et al Persistent organic pollutants are related to change in circulating
lipid levels during a 5 year follow-up Environ Res 134(2014)190ndash197
oxLDL as Measure of POPs
bull 992 70-year old individuals (50 women)
bull Sum of PCBs showed strong significant positive associations with ox-LDL and significant negative associations with glutathione-related markers (GSSG and GSSGGSH)
bull A number of POPs (PCB-99 138 153 156 170 180 194 206 and 209) showed strong significant positive association with ox-LDL
Kumar J et al Influence of persistent organic pollutants on oxidative stress in population-based samples
Chemosphere 2014114303-309
Homocysteine is Increased by Pb amp Cd
Guallar E et al Confounding of the relation between homocysteine and peripheral arterial disease by lead cadmium and renal function Am J Epidemiol 2006 Apr 15163(8)700-8
Nutrient Deficiencies Accentuate
Effects of Lead on Homocysteine
bull Deficiencies in folate B6 or B12 make lead more toxic
Lee YM Et al Association of homocysteine levels with blood lead levels and micronutrients in the US general population J Prev Med Public Health 2012 Nov45(6)387-93
T4 amp T3 and PCBs
bull PCBs decrease T4 production
bull PCBs inhibit iodotyrosinedeiodinase activity
bull Study done in pregnant women which implies effect on fetus IQ
Kim S Park J Kim HJ et al Association between several persistent organic pollutants and thyroid hormone levels in serum among the pregnant women of Korea Environ Int 2013 Sep59442-8Shimizu R Yamaguchi M Uramaru N et al Structure-activity relationships of 44 halogenated compounds for iodotyrosinedeiodinase-inhibitory activity Toxicology 2013 Dec 6314(1)22-9
T4 amp T3 and PCBs
bull Not just humans being affected
bull Large study of dolphins shows exactly the same effects
Schwacke LH Zolman ES Balmer BC et al Anaemia hypothyroidism and immune suppression associated with polychlorinated biphenyl exposure in bottlenose dolphins (Tursiops truncatus) Proceed Royal Society B doi101098rspb20110665
8-OHdG
bull Oxidized nucleoside
bull Direct measure of DNA damage
bull Indirect measure of oxidative stress and toxin load
bull Correlates with
Multiple cancers
Mitochondrial damage
Rate of aging
Smoking
Several toxinsWalter Crinnion ldquoTotal Toxic Loadrdquo AANP 2015
8-OHdG Correlates with Pack-Years
of Smoking
Yano T et al Significance of the urinary 8-OHdG level as an oxidative stress marker in lung cancer patients Lung Cancer
2009 Jan63(1)111-4
8-OHdG Correlates
with Mercury
Chen C et al Increased oxidative DNA damage as assessed by urinary 8-hydroxy-2-deoxyguanosine
concentrations and serum redox status in persons exposed to mercury Clin Chem 2005 Apr51(4)759-67
Toxin Effects Worse with Aging
bull Thyroid function decreases with PFOA levels
bull But only after age 63
Shrestha S Bloom MS Yucel R et al Perfluoroalkyl substances and thyroid function in older adults Environ Int 2015 Feb75206-14
Insightful 23-Year Prospective Study
1 lt 50 there is no difference between those with the lowest and highest PCBs
2 In youngest group insulin production increases in response to toxin level As expected since blocking of
insulin receptor sites by PCBs
requires more insulin
3 That adaptive ability decreases with aging
4 At age 50 all the measures show very strong toxin-dose response
Cumulative damage impairs ability to adapt
Suarez-Lopez JR et al Persistent organic pollutants in young adults and changes in glucose related metabolism over a 23-year follow-up Environ Res 2015 Feb137485-94
Recommendations
High body toxic load
GGT gt 25
Uric acid gt 50 mgdl
ALT gt30 UL
Bilirubin gt08 mgdl
CBC lt 6000
Platelet lt 250000
Low T3 andor T4
Monitor Total Toxic Load
8-OHdG gt4
ldquoUnconventionalrdquo Laboratory Tests
bull Challenge testing
bull Hair analysis
bull Direct measures of solvents and POPs in blood urine adipose tissue
Evaluation of Metal Exposure ndash Provocation
bull Provocation ndash the use of a chelating agent ndash before urine collection often done clinically but several limitations
No ldquoofficialrdquo reference range for provoked urine
Most chelating agents do not extract metals from all tissues thus
does not necessarily represent total body burden
bull Example Brain is one of the main target organs for both elemental and organic
mercury yet agents do not chelate brain mercury
bull Despite limitations widely used and advocated by clinicians in part to see efficacy of chelating agent as a guide to treatment and based on empirical evidence
Rooney JP The role of thiols dithiols nutritional factors and interacting ligands in the toxicology of mercury
Toxicology 2007
Is Challenge Testing Valid
bull Poor correlations of standard tests for mercury
bull Unpublished research from corporate wellness project
bull Published amalgam number correlation
bull Published fish consumption correlation
What We Found In Canada
bull Deviations from the mean of 14 29 and 91 respectively
bull DMPS is spreading distribution suggesting that it is better at differentiating mercury body load
bull Some VERY high
Hg Assessment Correlations
bull Extensive measurements in 65 Whole blood Hg
Oral DMPS challenge
Amalgam surfaces
bull Correlations Whole blood w pre urine r = 040
Whole blood w post urine r = 057
Pre urine w post urine r = 068
Amalgams w pre urine r = 026
Amalgams w whole blood r = 036
Amalgams with post urine 044
bull Clear documentation that
challenge testing is better00
100
200
300
400
500
600
0 10 20 30 40 50
Po
st
Uri
ne H
g u
gg
Number of amalgams
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
OC
Ps
Th
rou
gh
ou
t th
e W
orl
d
Rathore HS Nollet LML Pesticides Evaluation of Environmental Pollution CRC Press
2012 page 562
Threshold ndash Threshold exposure at which there is an increased risk of disease outcome
Above Threshold ndash Percentage of the population with higher exposure than the threshold
Odds Ratio ndash Increased disease risk in those above threshold
of Dz ndash Percent contribution of the toxin to that disease outcome
How to Interpret the Following Slides
Attention Deficit Hyperactivity Disorder
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
DDT 126 ngg
serum (pp-
DDE)
250 18 166 20106937
Lead 23 ugdL 13 254 20 27659349
Mercury 16 24952233
Organophosphate
pesticides
20
Polycyclic
Aromatic
Hydrocarbons
227 ngm3 940 125 190 22440811
PCBs 104 ngg
serum (sum
of 50 PCBs)
250 176 160 20106937
DiabetesToxin Threshold Above
Threshold
Odds
Ratio
of Dz Reference
PMID
Arsenic 165 ugL 200 21 180 18714061
BPA 28 ugL 280 145 112 26119400
DDE 545 ngg serum
(pp-DDE)
200 230 31 26119400
Dioxins2 pgg lipid 50 191 43
26119400
PCBs104 ngg (PCB 153) 250 239 258
26119400
Phthalates175 ugL 690 148 249
26119400
1-naphthalene 167 ugdL 152 182 111 26340343
2-napthalene 414 ugdL 550 224 214 26340343
1-phenanthrene 167 ngL 570 178 151 26340343
1-pyrene 85 ngL 660 180 174 26340343
Lung Cancer
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Acrylonitrile Uncertain Uncertain 125 25
occupational
exposure
17114112
Arsenic 1213 ugL 436 of Asian
Americans
~01 of total
US population
34 95 in AA
01-1
PMC2682945
Cadmium Uncertain+ Uncertain 467 10 in
smokers
17184399
DDT Any exposure All US pop
below LOD
17 76 increased
risk
8923607
Breast Cancer
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Cadmium 0580 ugg
creatinine
126 205 479 16788160
PCB 138 396 ngg
creatinine
202 316 630 27717745
PCB 187 108 ngg lipid 600 194 360 21480306
Miscellaneous Diseases
Toxin Disease Threshold Above
Threshold
Odds
Ratio
of Dz Reference PMID
Aluminum Alzheimer
Dz
01 mgL
drinking
H20
400 203 05-44 26592479
Benzene AML 100ppmyrs 1-3 320 60 PMC2903550
DDT NHL 0512 ugL 1-2 240 01 17722095
Lead ALS 238 ugdL
blood
330 181 210 25479292
Lead Brain CA 0005 ugdL 14 19 ~500 17164378
Dioxin-like
PCBs
RA 326 ngg
lipid
250 219 220 17589595
PAHs Asthma 124 ngm3 935 200 483 19221603
The Potency of Arsenic
Disease Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Bladder CA 10ugL H20 100 27 145 24889821
Pancreatic CA 1332 ugg 200 246 230 23800676
Prostate CA 1332 ugg 200 33 315 23800676
Gout 125 ugL 245 546 522 25499256
Diabetes 165 ugL 200 21 180 18714061
Arsenic (180 of Diabetes)
How it causes diabetes
bull Blocks sugar stimulating insulin secretion
bull Epigenetic inhibition of sugar regulation
Where it comes from
bull Water (gt10 of US water supplies have high levels)
bull Rice (naturally absorbs if in the water)
bull Chicken (added to make meat whiter)
Pan W-C Seow WJ Kile ML et al Association of low to moderate levels of arsenic exposure with risk of Type 2 diabetes in Bangladesh American Journal of Epidemiology 2013178(10)1563-70
Portion of Population with Toxin Load Which
Doubles Disease Risk
Toxin Disease with Doubled Risk
Polycyclic aromatic hydrocarbons Asthma 94
PCB187 Breast Cancer 60
Phthalates Diabetes 55
Lead ALS 33
Aluminum Alzheimers Disease 25
DDT ADHD 25
PCBs Diabetes 25
Dioxin-like PCBs Rheumatoid Arthritis 25
Arsenic Gout 23
Bisphenol A Diabetes 22
Cigarette smoking Lung Cancer 21
Arsenic Diabetes 20
Polycyclic aromatic hydrocarbons Diabetes 20
Huge Detoxification Variability
bull CYP2C19
Proton pump inhibitors and some antidepressants
5-fold difference in activity between poor metabolizers and extensive metabolizers more so if CYP3A4 is also inhibited
Ultrarapid allele in 18 of both Swedes and Ethiopians
bull CYP2D6
Metabolizes a large number of drugs (~25)
7 of Caucasians poor metabolizers
~30 ultra rapid metabolizers in Arabian and Eastern African populations
More adverse effects in poor metabolizers and ineffective dosing in ultrarapid metabolizers
Inhibited by ginger
Desta Z et al Clinical significance of the cytochrome P450 2C19 genetic polymorphism Clin Pharmaco 2002
Sim SC et al A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug
response to proton pump inhibitors and antidepressants Clin Pharmacol Ther 2006
Wilkinson GR Drug metabolism and variability among patients in drug response N Engl J Med 2005
Kirchheiner J et al Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to
CYP2D6 duplication Pharmacogenomics J 2007
Toxin Half Lives in BloodToxin ldquoNormalrdquo (mgL) Acute Toxic (mgL) Half-Life
Arsenic 0002-007 005-025 2-4 days (CDC)
Benzene 00002 05-10 days
Cadmium 00003-00065 0015-005 16 years
Chlordane 0001 00025 3-4 days
DDTDDE 2-10 years
Dieldrin 00015 015-030 2-12 months
Ethanol 1000-2000 15hour
Lead 009 04-06 1-15 mo (2+ yrs bone)
Mercury 00015-0002 005-02 2 months (CDC)
PCBs 3-25 years
Toluene 05-3 days
Schulz M et al Therapeutic and toxic blood concentrations of nearly 1000 drugs and other xenobiotics Crit Care 2012 Jul 2616(4)R136
Bioaccumulation (POPs)
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
DDT banned in 1972 PCBs banned in 1977
Bioaccumulation (Cd)
Think BroadlyExogenous
Metals
Chemicalsbull Inorganic
bull Fluoride
bull Organic
bull POPs
bull Drugs
Particulate matter
Molds
Microbial
Radiationbull Light
bull Medical
bull Cell phone
Endogenous
Gut-derived toxins
Non-end product metabolites
Poorly detoxified hormones
Catecholamines (if SNP)
Toxins of Choice
Alcohol
Marijuana
Food constituents
High fructose corn syrup
Salt (acid-forming diet)
Wheat if zonulin (70)
Obesity Epidemic ndash POPs AND HFCS
47Bray GA Fructose should we worry Int J Obes (Lond) 2008 Dec32 Suppl 7S127-31
How Toxins Cause Damage 13
bull Increase free radical production
Cd induces production of ROS
Malathion inhibits catalase and glutathione peroxidase
Homocysteine oxidizes LDL cholesterol
bull Poison enzyme systems (compete with nutritional cofactors for binding sites)
Pb poisons delta aminolevulinic acid dehydratase
Cd inhibits catalase glutathione reductase and lowers
glutathione levels
bull Replace structural minerals
Pb displaces Ca in bone
How Toxins Cause Damage 23
bull Damage DNA
Benzene - causes chromosomal damage
Pesticides ndash fruit growers have more DNA damage
Phthalates and insecticides ndash damage sperm DNA
4-hydroxy catechol estrogen (4-OHE) damages breast DNA
bull Epigenetic dysmodulation
Higher cord blood levels of hexachlorobenzene associated
with 2x greater risk for obesity in children
bull Damage cell membranes
Common mechanism for heavy metals inactivates
membrane enzymes ion channels and pumps
How Toxins Cause Damage 33
bull Block insulin receptor sites
PCBs and phthalates
bull Highest levels associated with a 4 to 20-fold greater diabetes risk
bull Imbalance hormones many toxin examples
Arsenic
bull Disrupts thyroid hormone and retinoic acid receptors
Phthalates
bull Act as anti-androgens
bull More than 75 of the US population has measurable levels of
several phthalate metabolites in the urine
PCBs
bull Lower testosterone levels in men
Which are the Worst Toxins
bull According to the CDC
Toxicity
Population toxic load
Prevalence in toxic waste sites
bull According to clinical importance
Exposure
of disease
Ability of the body to detoxifyexcrete
Ag
en
cy
fo
r T
oxic
Su
bs
tan
ce
s a
nd
Dis
ea
se
Reg
istr
y
Pri
ori
ty L
ist
The Worst Toxins Clinically
My Rank Toxin Diseases Primary Sources
1 Arsenic Cancers diabetes gout Water chicken rice
2 DDT ADHD dementia diabetes Everywhere
3 Phthalates ADHD diabetes Soft plastics HABAs
4 PBDEs ADHD diabetes Flame retardant fabrics
5 PAHs ADHD cancers dyslipidemia Smoking charbroiling
6 PCBs Cancers diabetes MI RA Everywhere
7 Mercury Dementia ldquoSilverrdquo fillings fish
8 Lead Cardiovascular disease IQ Paint water
Glyphosate Research invalid
Conventional Laboratory Tests Reflect
Toxic Load in ldquoNormalrdquo Range
bull Surprising number show toxin exposure
CBC RBC WBC platelet count hemoglobin basophilic
stippling
Liver enzymes ALT GGTP
Inflammatory markers CRP
Lipids LDL oxLDL triglycerides
Blood sugar insulin FBS 2-hour PP
Metabolites bilirubin uric acid homocysteine 8-OHdG
Thyroid T3 T4 TSH
bull The historic ldquonormalrdquo range has been changing as the population has become more toxic
WBC Lowered by PCB and OCP Exposure
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
0
1
2
3
4
5
6
7
8
1st Quartrile 2nd Quartile 3rd Quartile 4th Quartile
WBCbull Strong inverse correlation with PCBs and OCPs and CBC
bull Linear with almost all PCBs
bull High variability with OCPs
bull Within ldquonormalrdquo range
Effects on WBC Worsen with Years
of Exposure to Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Platelet Count Decreases with Years
of Exposure tp Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Solvents Decrease Platelet Count
bull Compared workers exposed 23 hrday to those exposed most of day to toluene
bull All wore face masks and protective gear
bull Platelet count 14 lower 252 versus 216ml
bull Impairment of sympathetic nerves (OR = 413)
bull Impairment of peripheral nerves (OR = 694)
bull Positive relationship between neurological abnormalities and a self-reported neuropsychiatric measurement (r = 035-066)
Shih HT et al Subclinical abnormalities in workers with continuous low-level toluene exposure Toxicol Ind Health 2011 Sep27(8)691-9
Basophilic Stippling of Red Cells
Toxinsbull Arsenic
bull Lead
Diseasesbull Alpha-thalassemia HbH Disease
bull Beta thalassemia
bull Hereditary pyrimidine 5-nucleotidase deficiency
bull Myelodysplastic syndrome
bull Sideroblastic anemia
bull Thrombotic thrombocytopenic purpura
GGT Indirect Measure of POPsbull Glutathione is key intracellular defense against oxidative stress
bull Cellular GGT metabolizes extracellular GSH allowing precursor amino acids to be reutilized for intracellular GSH
bull Exposure to POPs induces GGT as a defensive mechanism
bull Within normal range predicts type 2 diabetes coronary heart disease hypertension stroke dyslipidemia chronic kidney disease and cancer
bull Men with GGT gt50 UI had ~26 fold risk for diabetes compared to those with lt10 Those with 40-49 had a ~20 fold risk
bull Levels within normal range occur with obesity xs alcohol cigarette smoking physical inactivity high meat low fruit and vegetable intake
bull Cumulative biomarker for environmental pollutants
Lee DH et al (2003) Gamma-glutamyltransferase and diabetesmdasha 4 year follow-up study Diabetologia 46359ndash364
Pamela A et al Serum gamma-glutamyltransferase linking together environmental pollution redox equilibria and progression of atherosclerosis Clin Chem
Lab Med 200947(12)1583-4
Lee DH et al Serum gamma-glutamyltransferase new insights about an old enzyme J Epidemiol Community Health 2009 Nov63(11)884-6
Lee DH et alSerum gamma-glutamyltransferase predicts non-fatal myocardial infarction and fatal coronary heart disease among 28838 middle-aged men and
women Eur Heart J 2006272170ndash6
Lee DH et al Gamma-glutamyltransferase and diabetes--a 4 year follow-up study Diabetologia 2003 Mar46(3)359-64
Lee DH et al Can persistent organic pollutants explain the association between serum gamma-glutamyltransferase and type 2 diabetes Diabetologia 2008
Mar51(3)402-7
GGT and Alcohol Consumption
bull GGT directly correlates with alcohol consumption
bull In a non-uniform population 40 gd will elevate GGT ~15
bull Watch for false negatives
bull Genomic variation
bull Are these the ones most
sensitive todamaged by
chemical toxins
bull Could up-regulation of GGT in light alcohol consumption be reason for benefit
0
10
20
30
40
50
60
70
80
0 200 400 600 800
Grams of Ethanol per Week
Adapted from Nagaya T et al Dose-response relationships between drinking and serum tests in Japanese men
aged 40ndash59 years Alcohol 1999 Feb 17(2) 133ndash8
GGT Correlates With Toxic Metal Levels
Lee DH et al Graded associations of blood lead and urinary cadmium concentrations with oxidative-stress-related markers in the
US population results from the third National Health and Nutrition Examination Survey Environ Health
perspect 2006 Mar114(3)350-4
GGT and Diabetes Risk
0
5
10
15
20
25
30
lt10 10-19 20-29 30-39 40-49 gt50
Dia
bete
s R
isk
GGT
bull GGT over 50 associated with tripling of death rate
bull 30-40 associated with doubling
GGT Levels
Correlate with
Risk of Death
Brenner H et al Distribution determinants and prognostic value of gamma-glutamyltransferase for all-cause
mortality in a cohort of construction workers from southern Germany Prev Med 1997 26 305ndash10
GGT From Small US Company
with Young Workers
0
10
20
30
40
50
60
0 20 40 60 80 100
GGT Data from Canadian Oil Field
Workers
0
50
100
150
200
250
300
350
400
450
lt10 10-20 20-30 30-40 40-50 50-60 60-07 70-80 80-90 90-100 100-110 110-120 gt120
GGTP
20-fold increased risk of diabetes
Uric Acid Indirect Measure of POPs
bull Poly-fluorinated hydrocarbons (PFOA and PFOS) associated
with increased serum uric acid
Lin CY et al Association among serum perfluoroalkyl chemicals glucose homeostasis and metabolic syndrome
in adolescents and adults Diabetes Care 2009 Apr32(4)702-7
Steenland K et al Association of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) with uric
acid among adults with elevated community exposure to PFOA Environ Health Perspect 2010 Feb118229-33
Steenland 2010 Open Access
ALT Indirect Measure of POPs
bull ALT (proxy marker) elevation in 104 (not including viral
hepatitis hemochromatosis or alcoholic liver disease) of
NHANES 03-04 subset
bull Risk of elevated ALT increased dose-dependently with
cadmium lead mercury and PCB exposure
bull 100 of individuals had detectable PCBs 925 mercury
and 996 had detectable lead
bull In 2005-08 prevalence of NAFLD in US was 11 a
growing cause of chronic liver disease
Cave M et al Polychlorinated biphenyls lead and mercury are associated with liver disease in American adults
NHANES 2003-2004 Environ Health Perspect 2010 Dec118(12)1735-42
Younossi ZM et al Changes in the prevalence of the most common causes of chronic liver diseases in the United
States from 1988 to 2008 Clin Gastroenterol Hepatol 2011 Jun9(6)524-530e1
Bilirubin as a Marker of POPs
bull Degree of serum bilirubin increase is prognostically significant in chronic liver dysfunction
bull Mono-ortho PCB TEQ values were found to be significantly positively associated with bilirubin (β=071 P=0008) following adjustment for multiple potential confounders
bull Bilirubin levels significantly correlated with PCBs -105-118-126 and -194
bull Smoking appears to be the biggest confounder
Dufour DR et al 2000 Diagnosis and monitoring of hepatic injury II Recommendations for use of laboratory
tests in screening diagnosis and monitoring Clin Chem 46 2050ndash68
Kumar J et al Persistent organic pollutants and liver dysfunction biomarkers in a population-based human sample
of men and women Environ Res 2014134251-256
Perf
luo
rin
ate
dP
OP
s a
nd
Co
mm
on
Blo
od
Tests
Gleason JA et al Associations of perfluorinated chemical serum concentrations and biomarkers of liver function and uric acid in the
US population (NHANES) 2007-2010 Environ Res 20151368-14
Liver Enzymes Reflect Toxic Load
bull AST ALT and GGT increase with body load of PCBs and OCPs
bull Some non-linear
bull Oxychlordanetop quartile
ALT 10
GGT 25
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
LDL-Cholesterol as Measure of POPs
bull 5-year prospective study to determine if POP levels predict future elevation in LDL-cholesterol
bull 598 subjects initially at age 70
bull Looked at 23 POPs
bull Best correlation with PCB 194
Penell J Lind L Salihovic S et al Persistent organic pollutants are related to change in circulating
lipid levels during a 5 year follow-up Environ Res 134(2014)190ndash197
oxLDL as Measure of POPs
bull 992 70-year old individuals (50 women)
bull Sum of PCBs showed strong significant positive associations with ox-LDL and significant negative associations with glutathione-related markers (GSSG and GSSGGSH)
bull A number of POPs (PCB-99 138 153 156 170 180 194 206 and 209) showed strong significant positive association with ox-LDL
Kumar J et al Influence of persistent organic pollutants on oxidative stress in population-based samples
Chemosphere 2014114303-309
Homocysteine is Increased by Pb amp Cd
Guallar E et al Confounding of the relation between homocysteine and peripheral arterial disease by lead cadmium and renal function Am J Epidemiol 2006 Apr 15163(8)700-8
Nutrient Deficiencies Accentuate
Effects of Lead on Homocysteine
bull Deficiencies in folate B6 or B12 make lead more toxic
Lee YM Et al Association of homocysteine levels with blood lead levels and micronutrients in the US general population J Prev Med Public Health 2012 Nov45(6)387-93
T4 amp T3 and PCBs
bull PCBs decrease T4 production
bull PCBs inhibit iodotyrosinedeiodinase activity
bull Study done in pregnant women which implies effect on fetus IQ
Kim S Park J Kim HJ et al Association between several persistent organic pollutants and thyroid hormone levels in serum among the pregnant women of Korea Environ Int 2013 Sep59442-8Shimizu R Yamaguchi M Uramaru N et al Structure-activity relationships of 44 halogenated compounds for iodotyrosinedeiodinase-inhibitory activity Toxicology 2013 Dec 6314(1)22-9
T4 amp T3 and PCBs
bull Not just humans being affected
bull Large study of dolphins shows exactly the same effects
Schwacke LH Zolman ES Balmer BC et al Anaemia hypothyroidism and immune suppression associated with polychlorinated biphenyl exposure in bottlenose dolphins (Tursiops truncatus) Proceed Royal Society B doi101098rspb20110665
8-OHdG
bull Oxidized nucleoside
bull Direct measure of DNA damage
bull Indirect measure of oxidative stress and toxin load
bull Correlates with
Multiple cancers
Mitochondrial damage
Rate of aging
Smoking
Several toxinsWalter Crinnion ldquoTotal Toxic Loadrdquo AANP 2015
8-OHdG Correlates with Pack-Years
of Smoking
Yano T et al Significance of the urinary 8-OHdG level as an oxidative stress marker in lung cancer patients Lung Cancer
2009 Jan63(1)111-4
8-OHdG Correlates
with Mercury
Chen C et al Increased oxidative DNA damage as assessed by urinary 8-hydroxy-2-deoxyguanosine
concentrations and serum redox status in persons exposed to mercury Clin Chem 2005 Apr51(4)759-67
Toxin Effects Worse with Aging
bull Thyroid function decreases with PFOA levels
bull But only after age 63
Shrestha S Bloom MS Yucel R et al Perfluoroalkyl substances and thyroid function in older adults Environ Int 2015 Feb75206-14
Insightful 23-Year Prospective Study
1 lt 50 there is no difference between those with the lowest and highest PCBs
2 In youngest group insulin production increases in response to toxin level As expected since blocking of
insulin receptor sites by PCBs
requires more insulin
3 That adaptive ability decreases with aging
4 At age 50 all the measures show very strong toxin-dose response
Cumulative damage impairs ability to adapt
Suarez-Lopez JR et al Persistent organic pollutants in young adults and changes in glucose related metabolism over a 23-year follow-up Environ Res 2015 Feb137485-94
Recommendations
High body toxic load
GGT gt 25
Uric acid gt 50 mgdl
ALT gt30 UL
Bilirubin gt08 mgdl
CBC lt 6000
Platelet lt 250000
Low T3 andor T4
Monitor Total Toxic Load
8-OHdG gt4
ldquoUnconventionalrdquo Laboratory Tests
bull Challenge testing
bull Hair analysis
bull Direct measures of solvents and POPs in blood urine adipose tissue
Evaluation of Metal Exposure ndash Provocation
bull Provocation ndash the use of a chelating agent ndash before urine collection often done clinically but several limitations
No ldquoofficialrdquo reference range for provoked urine
Most chelating agents do not extract metals from all tissues thus
does not necessarily represent total body burden
bull Example Brain is one of the main target organs for both elemental and organic
mercury yet agents do not chelate brain mercury
bull Despite limitations widely used and advocated by clinicians in part to see efficacy of chelating agent as a guide to treatment and based on empirical evidence
Rooney JP The role of thiols dithiols nutritional factors and interacting ligands in the toxicology of mercury
Toxicology 2007
Is Challenge Testing Valid
bull Poor correlations of standard tests for mercury
bull Unpublished research from corporate wellness project
bull Published amalgam number correlation
bull Published fish consumption correlation
What We Found In Canada
bull Deviations from the mean of 14 29 and 91 respectively
bull DMPS is spreading distribution suggesting that it is better at differentiating mercury body load
bull Some VERY high
Hg Assessment Correlations
bull Extensive measurements in 65 Whole blood Hg
Oral DMPS challenge
Amalgam surfaces
bull Correlations Whole blood w pre urine r = 040
Whole blood w post urine r = 057
Pre urine w post urine r = 068
Amalgams w pre urine r = 026
Amalgams w whole blood r = 036
Amalgams with post urine 044
bull Clear documentation that
challenge testing is better00
100
200
300
400
500
600
0 10 20 30 40 50
Po
st
Uri
ne H
g u
gg
Number of amalgams
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
Threshold ndash Threshold exposure at which there is an increased risk of disease outcome
Above Threshold ndash Percentage of the population with higher exposure than the threshold
Odds Ratio ndash Increased disease risk in those above threshold
of Dz ndash Percent contribution of the toxin to that disease outcome
How to Interpret the Following Slides
Attention Deficit Hyperactivity Disorder
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
DDT 126 ngg
serum (pp-
DDE)
250 18 166 20106937
Lead 23 ugdL 13 254 20 27659349
Mercury 16 24952233
Organophosphate
pesticides
20
Polycyclic
Aromatic
Hydrocarbons
227 ngm3 940 125 190 22440811
PCBs 104 ngg
serum (sum
of 50 PCBs)
250 176 160 20106937
DiabetesToxin Threshold Above
Threshold
Odds
Ratio
of Dz Reference
PMID
Arsenic 165 ugL 200 21 180 18714061
BPA 28 ugL 280 145 112 26119400
DDE 545 ngg serum
(pp-DDE)
200 230 31 26119400
Dioxins2 pgg lipid 50 191 43
26119400
PCBs104 ngg (PCB 153) 250 239 258
26119400
Phthalates175 ugL 690 148 249
26119400
1-naphthalene 167 ugdL 152 182 111 26340343
2-napthalene 414 ugdL 550 224 214 26340343
1-phenanthrene 167 ngL 570 178 151 26340343
1-pyrene 85 ngL 660 180 174 26340343
Lung Cancer
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Acrylonitrile Uncertain Uncertain 125 25
occupational
exposure
17114112
Arsenic 1213 ugL 436 of Asian
Americans
~01 of total
US population
34 95 in AA
01-1
PMC2682945
Cadmium Uncertain+ Uncertain 467 10 in
smokers
17184399
DDT Any exposure All US pop
below LOD
17 76 increased
risk
8923607
Breast Cancer
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Cadmium 0580 ugg
creatinine
126 205 479 16788160
PCB 138 396 ngg
creatinine
202 316 630 27717745
PCB 187 108 ngg lipid 600 194 360 21480306
Miscellaneous Diseases
Toxin Disease Threshold Above
Threshold
Odds
Ratio
of Dz Reference PMID
Aluminum Alzheimer
Dz
01 mgL
drinking
H20
400 203 05-44 26592479
Benzene AML 100ppmyrs 1-3 320 60 PMC2903550
DDT NHL 0512 ugL 1-2 240 01 17722095
Lead ALS 238 ugdL
blood
330 181 210 25479292
Lead Brain CA 0005 ugdL 14 19 ~500 17164378
Dioxin-like
PCBs
RA 326 ngg
lipid
250 219 220 17589595
PAHs Asthma 124 ngm3 935 200 483 19221603
The Potency of Arsenic
Disease Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Bladder CA 10ugL H20 100 27 145 24889821
Pancreatic CA 1332 ugg 200 246 230 23800676
Prostate CA 1332 ugg 200 33 315 23800676
Gout 125 ugL 245 546 522 25499256
Diabetes 165 ugL 200 21 180 18714061
Arsenic (180 of Diabetes)
How it causes diabetes
bull Blocks sugar stimulating insulin secretion
bull Epigenetic inhibition of sugar regulation
Where it comes from
bull Water (gt10 of US water supplies have high levels)
bull Rice (naturally absorbs if in the water)
bull Chicken (added to make meat whiter)
Pan W-C Seow WJ Kile ML et al Association of low to moderate levels of arsenic exposure with risk of Type 2 diabetes in Bangladesh American Journal of Epidemiology 2013178(10)1563-70
Portion of Population with Toxin Load Which
Doubles Disease Risk
Toxin Disease with Doubled Risk
Polycyclic aromatic hydrocarbons Asthma 94
PCB187 Breast Cancer 60
Phthalates Diabetes 55
Lead ALS 33
Aluminum Alzheimers Disease 25
DDT ADHD 25
PCBs Diabetes 25
Dioxin-like PCBs Rheumatoid Arthritis 25
Arsenic Gout 23
Bisphenol A Diabetes 22
Cigarette smoking Lung Cancer 21
Arsenic Diabetes 20
Polycyclic aromatic hydrocarbons Diabetes 20
Huge Detoxification Variability
bull CYP2C19
Proton pump inhibitors and some antidepressants
5-fold difference in activity between poor metabolizers and extensive metabolizers more so if CYP3A4 is also inhibited
Ultrarapid allele in 18 of both Swedes and Ethiopians
bull CYP2D6
Metabolizes a large number of drugs (~25)
7 of Caucasians poor metabolizers
~30 ultra rapid metabolizers in Arabian and Eastern African populations
More adverse effects in poor metabolizers and ineffective dosing in ultrarapid metabolizers
Inhibited by ginger
Desta Z et al Clinical significance of the cytochrome P450 2C19 genetic polymorphism Clin Pharmaco 2002
Sim SC et al A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug
response to proton pump inhibitors and antidepressants Clin Pharmacol Ther 2006
Wilkinson GR Drug metabolism and variability among patients in drug response N Engl J Med 2005
Kirchheiner J et al Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to
CYP2D6 duplication Pharmacogenomics J 2007
Toxin Half Lives in BloodToxin ldquoNormalrdquo (mgL) Acute Toxic (mgL) Half-Life
Arsenic 0002-007 005-025 2-4 days (CDC)
Benzene 00002 05-10 days
Cadmium 00003-00065 0015-005 16 years
Chlordane 0001 00025 3-4 days
DDTDDE 2-10 years
Dieldrin 00015 015-030 2-12 months
Ethanol 1000-2000 15hour
Lead 009 04-06 1-15 mo (2+ yrs bone)
Mercury 00015-0002 005-02 2 months (CDC)
PCBs 3-25 years
Toluene 05-3 days
Schulz M et al Therapeutic and toxic blood concentrations of nearly 1000 drugs and other xenobiotics Crit Care 2012 Jul 2616(4)R136
Bioaccumulation (POPs)
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
DDT banned in 1972 PCBs banned in 1977
Bioaccumulation (Cd)
Think BroadlyExogenous
Metals
Chemicalsbull Inorganic
bull Fluoride
bull Organic
bull POPs
bull Drugs
Particulate matter
Molds
Microbial
Radiationbull Light
bull Medical
bull Cell phone
Endogenous
Gut-derived toxins
Non-end product metabolites
Poorly detoxified hormones
Catecholamines (if SNP)
Toxins of Choice
Alcohol
Marijuana
Food constituents
High fructose corn syrup
Salt (acid-forming diet)
Wheat if zonulin (70)
Obesity Epidemic ndash POPs AND HFCS
47Bray GA Fructose should we worry Int J Obes (Lond) 2008 Dec32 Suppl 7S127-31
How Toxins Cause Damage 13
bull Increase free radical production
Cd induces production of ROS
Malathion inhibits catalase and glutathione peroxidase
Homocysteine oxidizes LDL cholesterol
bull Poison enzyme systems (compete with nutritional cofactors for binding sites)
Pb poisons delta aminolevulinic acid dehydratase
Cd inhibits catalase glutathione reductase and lowers
glutathione levels
bull Replace structural minerals
Pb displaces Ca in bone
How Toxins Cause Damage 23
bull Damage DNA
Benzene - causes chromosomal damage
Pesticides ndash fruit growers have more DNA damage
Phthalates and insecticides ndash damage sperm DNA
4-hydroxy catechol estrogen (4-OHE) damages breast DNA
bull Epigenetic dysmodulation
Higher cord blood levels of hexachlorobenzene associated
with 2x greater risk for obesity in children
bull Damage cell membranes
Common mechanism for heavy metals inactivates
membrane enzymes ion channels and pumps
How Toxins Cause Damage 33
bull Block insulin receptor sites
PCBs and phthalates
bull Highest levels associated with a 4 to 20-fold greater diabetes risk
bull Imbalance hormones many toxin examples
Arsenic
bull Disrupts thyroid hormone and retinoic acid receptors
Phthalates
bull Act as anti-androgens
bull More than 75 of the US population has measurable levels of
several phthalate metabolites in the urine
PCBs
bull Lower testosterone levels in men
Which are the Worst Toxins
bull According to the CDC
Toxicity
Population toxic load
Prevalence in toxic waste sites
bull According to clinical importance
Exposure
of disease
Ability of the body to detoxifyexcrete
Ag
en
cy
fo
r T
oxic
Su
bs
tan
ce
s a
nd
Dis
ea
se
Reg
istr
y
Pri
ori
ty L
ist
The Worst Toxins Clinically
My Rank Toxin Diseases Primary Sources
1 Arsenic Cancers diabetes gout Water chicken rice
2 DDT ADHD dementia diabetes Everywhere
3 Phthalates ADHD diabetes Soft plastics HABAs
4 PBDEs ADHD diabetes Flame retardant fabrics
5 PAHs ADHD cancers dyslipidemia Smoking charbroiling
6 PCBs Cancers diabetes MI RA Everywhere
7 Mercury Dementia ldquoSilverrdquo fillings fish
8 Lead Cardiovascular disease IQ Paint water
Glyphosate Research invalid
Conventional Laboratory Tests Reflect
Toxic Load in ldquoNormalrdquo Range
bull Surprising number show toxin exposure
CBC RBC WBC platelet count hemoglobin basophilic
stippling
Liver enzymes ALT GGTP
Inflammatory markers CRP
Lipids LDL oxLDL triglycerides
Blood sugar insulin FBS 2-hour PP
Metabolites bilirubin uric acid homocysteine 8-OHdG
Thyroid T3 T4 TSH
bull The historic ldquonormalrdquo range has been changing as the population has become more toxic
WBC Lowered by PCB and OCP Exposure
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
0
1
2
3
4
5
6
7
8
1st Quartrile 2nd Quartile 3rd Quartile 4th Quartile
WBCbull Strong inverse correlation with PCBs and OCPs and CBC
bull Linear with almost all PCBs
bull High variability with OCPs
bull Within ldquonormalrdquo range
Effects on WBC Worsen with Years
of Exposure to Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Platelet Count Decreases with Years
of Exposure tp Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Solvents Decrease Platelet Count
bull Compared workers exposed 23 hrday to those exposed most of day to toluene
bull All wore face masks and protective gear
bull Platelet count 14 lower 252 versus 216ml
bull Impairment of sympathetic nerves (OR = 413)
bull Impairment of peripheral nerves (OR = 694)
bull Positive relationship between neurological abnormalities and a self-reported neuropsychiatric measurement (r = 035-066)
Shih HT et al Subclinical abnormalities in workers with continuous low-level toluene exposure Toxicol Ind Health 2011 Sep27(8)691-9
Basophilic Stippling of Red Cells
Toxinsbull Arsenic
bull Lead
Diseasesbull Alpha-thalassemia HbH Disease
bull Beta thalassemia
bull Hereditary pyrimidine 5-nucleotidase deficiency
bull Myelodysplastic syndrome
bull Sideroblastic anemia
bull Thrombotic thrombocytopenic purpura
GGT Indirect Measure of POPsbull Glutathione is key intracellular defense against oxidative stress
bull Cellular GGT metabolizes extracellular GSH allowing precursor amino acids to be reutilized for intracellular GSH
bull Exposure to POPs induces GGT as a defensive mechanism
bull Within normal range predicts type 2 diabetes coronary heart disease hypertension stroke dyslipidemia chronic kidney disease and cancer
bull Men with GGT gt50 UI had ~26 fold risk for diabetes compared to those with lt10 Those with 40-49 had a ~20 fold risk
bull Levels within normal range occur with obesity xs alcohol cigarette smoking physical inactivity high meat low fruit and vegetable intake
bull Cumulative biomarker for environmental pollutants
Lee DH et al (2003) Gamma-glutamyltransferase and diabetesmdasha 4 year follow-up study Diabetologia 46359ndash364
Pamela A et al Serum gamma-glutamyltransferase linking together environmental pollution redox equilibria and progression of atherosclerosis Clin Chem
Lab Med 200947(12)1583-4
Lee DH et al Serum gamma-glutamyltransferase new insights about an old enzyme J Epidemiol Community Health 2009 Nov63(11)884-6
Lee DH et alSerum gamma-glutamyltransferase predicts non-fatal myocardial infarction and fatal coronary heart disease among 28838 middle-aged men and
women Eur Heart J 2006272170ndash6
Lee DH et al Gamma-glutamyltransferase and diabetes--a 4 year follow-up study Diabetologia 2003 Mar46(3)359-64
Lee DH et al Can persistent organic pollutants explain the association between serum gamma-glutamyltransferase and type 2 diabetes Diabetologia 2008
Mar51(3)402-7
GGT and Alcohol Consumption
bull GGT directly correlates with alcohol consumption
bull In a non-uniform population 40 gd will elevate GGT ~15
bull Watch for false negatives
bull Genomic variation
bull Are these the ones most
sensitive todamaged by
chemical toxins
bull Could up-regulation of GGT in light alcohol consumption be reason for benefit
0
10
20
30
40
50
60
70
80
0 200 400 600 800
Grams of Ethanol per Week
Adapted from Nagaya T et al Dose-response relationships between drinking and serum tests in Japanese men
aged 40ndash59 years Alcohol 1999 Feb 17(2) 133ndash8
GGT Correlates With Toxic Metal Levels
Lee DH et al Graded associations of blood lead and urinary cadmium concentrations with oxidative-stress-related markers in the
US population results from the third National Health and Nutrition Examination Survey Environ Health
perspect 2006 Mar114(3)350-4
GGT and Diabetes Risk
0
5
10
15
20
25
30
lt10 10-19 20-29 30-39 40-49 gt50
Dia
bete
s R
isk
GGT
bull GGT over 50 associated with tripling of death rate
bull 30-40 associated with doubling
GGT Levels
Correlate with
Risk of Death
Brenner H et al Distribution determinants and prognostic value of gamma-glutamyltransferase for all-cause
mortality in a cohort of construction workers from southern Germany Prev Med 1997 26 305ndash10
GGT From Small US Company
with Young Workers
0
10
20
30
40
50
60
0 20 40 60 80 100
GGT Data from Canadian Oil Field
Workers
0
50
100
150
200
250
300
350
400
450
lt10 10-20 20-30 30-40 40-50 50-60 60-07 70-80 80-90 90-100 100-110 110-120 gt120
GGTP
20-fold increased risk of diabetes
Uric Acid Indirect Measure of POPs
bull Poly-fluorinated hydrocarbons (PFOA and PFOS) associated
with increased serum uric acid
Lin CY et al Association among serum perfluoroalkyl chemicals glucose homeostasis and metabolic syndrome
in adolescents and adults Diabetes Care 2009 Apr32(4)702-7
Steenland K et al Association of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) with uric
acid among adults with elevated community exposure to PFOA Environ Health Perspect 2010 Feb118229-33
Steenland 2010 Open Access
ALT Indirect Measure of POPs
bull ALT (proxy marker) elevation in 104 (not including viral
hepatitis hemochromatosis or alcoholic liver disease) of
NHANES 03-04 subset
bull Risk of elevated ALT increased dose-dependently with
cadmium lead mercury and PCB exposure
bull 100 of individuals had detectable PCBs 925 mercury
and 996 had detectable lead
bull In 2005-08 prevalence of NAFLD in US was 11 a
growing cause of chronic liver disease
Cave M et al Polychlorinated biphenyls lead and mercury are associated with liver disease in American adults
NHANES 2003-2004 Environ Health Perspect 2010 Dec118(12)1735-42
Younossi ZM et al Changes in the prevalence of the most common causes of chronic liver diseases in the United
States from 1988 to 2008 Clin Gastroenterol Hepatol 2011 Jun9(6)524-530e1
Bilirubin as a Marker of POPs
bull Degree of serum bilirubin increase is prognostically significant in chronic liver dysfunction
bull Mono-ortho PCB TEQ values were found to be significantly positively associated with bilirubin (β=071 P=0008) following adjustment for multiple potential confounders
bull Bilirubin levels significantly correlated with PCBs -105-118-126 and -194
bull Smoking appears to be the biggest confounder
Dufour DR et al 2000 Diagnosis and monitoring of hepatic injury II Recommendations for use of laboratory
tests in screening diagnosis and monitoring Clin Chem 46 2050ndash68
Kumar J et al Persistent organic pollutants and liver dysfunction biomarkers in a population-based human sample
of men and women Environ Res 2014134251-256
Perf
luo
rin
ate
dP
OP
s a
nd
Co
mm
on
Blo
od
Tests
Gleason JA et al Associations of perfluorinated chemical serum concentrations and biomarkers of liver function and uric acid in the
US population (NHANES) 2007-2010 Environ Res 20151368-14
Liver Enzymes Reflect Toxic Load
bull AST ALT and GGT increase with body load of PCBs and OCPs
bull Some non-linear
bull Oxychlordanetop quartile
ALT 10
GGT 25
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
LDL-Cholesterol as Measure of POPs
bull 5-year prospective study to determine if POP levels predict future elevation in LDL-cholesterol
bull 598 subjects initially at age 70
bull Looked at 23 POPs
bull Best correlation with PCB 194
Penell J Lind L Salihovic S et al Persistent organic pollutants are related to change in circulating
lipid levels during a 5 year follow-up Environ Res 134(2014)190ndash197
oxLDL as Measure of POPs
bull 992 70-year old individuals (50 women)
bull Sum of PCBs showed strong significant positive associations with ox-LDL and significant negative associations with glutathione-related markers (GSSG and GSSGGSH)
bull A number of POPs (PCB-99 138 153 156 170 180 194 206 and 209) showed strong significant positive association with ox-LDL
Kumar J et al Influence of persistent organic pollutants on oxidative stress in population-based samples
Chemosphere 2014114303-309
Homocysteine is Increased by Pb amp Cd
Guallar E et al Confounding of the relation between homocysteine and peripheral arterial disease by lead cadmium and renal function Am J Epidemiol 2006 Apr 15163(8)700-8
Nutrient Deficiencies Accentuate
Effects of Lead on Homocysteine
bull Deficiencies in folate B6 or B12 make lead more toxic
Lee YM Et al Association of homocysteine levels with blood lead levels and micronutrients in the US general population J Prev Med Public Health 2012 Nov45(6)387-93
T4 amp T3 and PCBs
bull PCBs decrease T4 production
bull PCBs inhibit iodotyrosinedeiodinase activity
bull Study done in pregnant women which implies effect on fetus IQ
Kim S Park J Kim HJ et al Association between several persistent organic pollutants and thyroid hormone levels in serum among the pregnant women of Korea Environ Int 2013 Sep59442-8Shimizu R Yamaguchi M Uramaru N et al Structure-activity relationships of 44 halogenated compounds for iodotyrosinedeiodinase-inhibitory activity Toxicology 2013 Dec 6314(1)22-9
T4 amp T3 and PCBs
bull Not just humans being affected
bull Large study of dolphins shows exactly the same effects
Schwacke LH Zolman ES Balmer BC et al Anaemia hypothyroidism and immune suppression associated with polychlorinated biphenyl exposure in bottlenose dolphins (Tursiops truncatus) Proceed Royal Society B doi101098rspb20110665
8-OHdG
bull Oxidized nucleoside
bull Direct measure of DNA damage
bull Indirect measure of oxidative stress and toxin load
bull Correlates with
Multiple cancers
Mitochondrial damage
Rate of aging
Smoking
Several toxinsWalter Crinnion ldquoTotal Toxic Loadrdquo AANP 2015
8-OHdG Correlates with Pack-Years
of Smoking
Yano T et al Significance of the urinary 8-OHdG level as an oxidative stress marker in lung cancer patients Lung Cancer
2009 Jan63(1)111-4
8-OHdG Correlates
with Mercury
Chen C et al Increased oxidative DNA damage as assessed by urinary 8-hydroxy-2-deoxyguanosine
concentrations and serum redox status in persons exposed to mercury Clin Chem 2005 Apr51(4)759-67
Toxin Effects Worse with Aging
bull Thyroid function decreases with PFOA levels
bull But only after age 63
Shrestha S Bloom MS Yucel R et al Perfluoroalkyl substances and thyroid function in older adults Environ Int 2015 Feb75206-14
Insightful 23-Year Prospective Study
1 lt 50 there is no difference between those with the lowest and highest PCBs
2 In youngest group insulin production increases in response to toxin level As expected since blocking of
insulin receptor sites by PCBs
requires more insulin
3 That adaptive ability decreases with aging
4 At age 50 all the measures show very strong toxin-dose response
Cumulative damage impairs ability to adapt
Suarez-Lopez JR et al Persistent organic pollutants in young adults and changes in glucose related metabolism over a 23-year follow-up Environ Res 2015 Feb137485-94
Recommendations
High body toxic load
GGT gt 25
Uric acid gt 50 mgdl
ALT gt30 UL
Bilirubin gt08 mgdl
CBC lt 6000
Platelet lt 250000
Low T3 andor T4
Monitor Total Toxic Load
8-OHdG gt4
ldquoUnconventionalrdquo Laboratory Tests
bull Challenge testing
bull Hair analysis
bull Direct measures of solvents and POPs in blood urine adipose tissue
Evaluation of Metal Exposure ndash Provocation
bull Provocation ndash the use of a chelating agent ndash before urine collection often done clinically but several limitations
No ldquoofficialrdquo reference range for provoked urine
Most chelating agents do not extract metals from all tissues thus
does not necessarily represent total body burden
bull Example Brain is one of the main target organs for both elemental and organic
mercury yet agents do not chelate brain mercury
bull Despite limitations widely used and advocated by clinicians in part to see efficacy of chelating agent as a guide to treatment and based on empirical evidence
Rooney JP The role of thiols dithiols nutritional factors and interacting ligands in the toxicology of mercury
Toxicology 2007
Is Challenge Testing Valid
bull Poor correlations of standard tests for mercury
bull Unpublished research from corporate wellness project
bull Published amalgam number correlation
bull Published fish consumption correlation
What We Found In Canada
bull Deviations from the mean of 14 29 and 91 respectively
bull DMPS is spreading distribution suggesting that it is better at differentiating mercury body load
bull Some VERY high
Hg Assessment Correlations
bull Extensive measurements in 65 Whole blood Hg
Oral DMPS challenge
Amalgam surfaces
bull Correlations Whole blood w pre urine r = 040
Whole blood w post urine r = 057
Pre urine w post urine r = 068
Amalgams w pre urine r = 026
Amalgams w whole blood r = 036
Amalgams with post urine 044
bull Clear documentation that
challenge testing is better00
100
200
300
400
500
600
0 10 20 30 40 50
Po
st
Uri
ne H
g u
gg
Number of amalgams
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
Attention Deficit Hyperactivity Disorder
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
DDT 126 ngg
serum (pp-
DDE)
250 18 166 20106937
Lead 23 ugdL 13 254 20 27659349
Mercury 16 24952233
Organophosphate
pesticides
20
Polycyclic
Aromatic
Hydrocarbons
227 ngm3 940 125 190 22440811
PCBs 104 ngg
serum (sum
of 50 PCBs)
250 176 160 20106937
DiabetesToxin Threshold Above
Threshold
Odds
Ratio
of Dz Reference
PMID
Arsenic 165 ugL 200 21 180 18714061
BPA 28 ugL 280 145 112 26119400
DDE 545 ngg serum
(pp-DDE)
200 230 31 26119400
Dioxins2 pgg lipid 50 191 43
26119400
PCBs104 ngg (PCB 153) 250 239 258
26119400
Phthalates175 ugL 690 148 249
26119400
1-naphthalene 167 ugdL 152 182 111 26340343
2-napthalene 414 ugdL 550 224 214 26340343
1-phenanthrene 167 ngL 570 178 151 26340343
1-pyrene 85 ngL 660 180 174 26340343
Lung Cancer
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Acrylonitrile Uncertain Uncertain 125 25
occupational
exposure
17114112
Arsenic 1213 ugL 436 of Asian
Americans
~01 of total
US population
34 95 in AA
01-1
PMC2682945
Cadmium Uncertain+ Uncertain 467 10 in
smokers
17184399
DDT Any exposure All US pop
below LOD
17 76 increased
risk
8923607
Breast Cancer
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Cadmium 0580 ugg
creatinine
126 205 479 16788160
PCB 138 396 ngg
creatinine
202 316 630 27717745
PCB 187 108 ngg lipid 600 194 360 21480306
Miscellaneous Diseases
Toxin Disease Threshold Above
Threshold
Odds
Ratio
of Dz Reference PMID
Aluminum Alzheimer
Dz
01 mgL
drinking
H20
400 203 05-44 26592479
Benzene AML 100ppmyrs 1-3 320 60 PMC2903550
DDT NHL 0512 ugL 1-2 240 01 17722095
Lead ALS 238 ugdL
blood
330 181 210 25479292
Lead Brain CA 0005 ugdL 14 19 ~500 17164378
Dioxin-like
PCBs
RA 326 ngg
lipid
250 219 220 17589595
PAHs Asthma 124 ngm3 935 200 483 19221603
The Potency of Arsenic
Disease Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Bladder CA 10ugL H20 100 27 145 24889821
Pancreatic CA 1332 ugg 200 246 230 23800676
Prostate CA 1332 ugg 200 33 315 23800676
Gout 125 ugL 245 546 522 25499256
Diabetes 165 ugL 200 21 180 18714061
Arsenic (180 of Diabetes)
How it causes diabetes
bull Blocks sugar stimulating insulin secretion
bull Epigenetic inhibition of sugar regulation
Where it comes from
bull Water (gt10 of US water supplies have high levels)
bull Rice (naturally absorbs if in the water)
bull Chicken (added to make meat whiter)
Pan W-C Seow WJ Kile ML et al Association of low to moderate levels of arsenic exposure with risk of Type 2 diabetes in Bangladesh American Journal of Epidemiology 2013178(10)1563-70
Portion of Population with Toxin Load Which
Doubles Disease Risk
Toxin Disease with Doubled Risk
Polycyclic aromatic hydrocarbons Asthma 94
PCB187 Breast Cancer 60
Phthalates Diabetes 55
Lead ALS 33
Aluminum Alzheimers Disease 25
DDT ADHD 25
PCBs Diabetes 25
Dioxin-like PCBs Rheumatoid Arthritis 25
Arsenic Gout 23
Bisphenol A Diabetes 22
Cigarette smoking Lung Cancer 21
Arsenic Diabetes 20
Polycyclic aromatic hydrocarbons Diabetes 20
Huge Detoxification Variability
bull CYP2C19
Proton pump inhibitors and some antidepressants
5-fold difference in activity between poor metabolizers and extensive metabolizers more so if CYP3A4 is also inhibited
Ultrarapid allele in 18 of both Swedes and Ethiopians
bull CYP2D6
Metabolizes a large number of drugs (~25)
7 of Caucasians poor metabolizers
~30 ultra rapid metabolizers in Arabian and Eastern African populations
More adverse effects in poor metabolizers and ineffective dosing in ultrarapid metabolizers
Inhibited by ginger
Desta Z et al Clinical significance of the cytochrome P450 2C19 genetic polymorphism Clin Pharmaco 2002
Sim SC et al A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug
response to proton pump inhibitors and antidepressants Clin Pharmacol Ther 2006
Wilkinson GR Drug metabolism and variability among patients in drug response N Engl J Med 2005
Kirchheiner J et al Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to
CYP2D6 duplication Pharmacogenomics J 2007
Toxin Half Lives in BloodToxin ldquoNormalrdquo (mgL) Acute Toxic (mgL) Half-Life
Arsenic 0002-007 005-025 2-4 days (CDC)
Benzene 00002 05-10 days
Cadmium 00003-00065 0015-005 16 years
Chlordane 0001 00025 3-4 days
DDTDDE 2-10 years
Dieldrin 00015 015-030 2-12 months
Ethanol 1000-2000 15hour
Lead 009 04-06 1-15 mo (2+ yrs bone)
Mercury 00015-0002 005-02 2 months (CDC)
PCBs 3-25 years
Toluene 05-3 days
Schulz M et al Therapeutic and toxic blood concentrations of nearly 1000 drugs and other xenobiotics Crit Care 2012 Jul 2616(4)R136
Bioaccumulation (POPs)
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
DDT banned in 1972 PCBs banned in 1977
Bioaccumulation (Cd)
Think BroadlyExogenous
Metals
Chemicalsbull Inorganic
bull Fluoride
bull Organic
bull POPs
bull Drugs
Particulate matter
Molds
Microbial
Radiationbull Light
bull Medical
bull Cell phone
Endogenous
Gut-derived toxins
Non-end product metabolites
Poorly detoxified hormones
Catecholamines (if SNP)
Toxins of Choice
Alcohol
Marijuana
Food constituents
High fructose corn syrup
Salt (acid-forming diet)
Wheat if zonulin (70)
Obesity Epidemic ndash POPs AND HFCS
47Bray GA Fructose should we worry Int J Obes (Lond) 2008 Dec32 Suppl 7S127-31
How Toxins Cause Damage 13
bull Increase free radical production
Cd induces production of ROS
Malathion inhibits catalase and glutathione peroxidase
Homocysteine oxidizes LDL cholesterol
bull Poison enzyme systems (compete with nutritional cofactors for binding sites)
Pb poisons delta aminolevulinic acid dehydratase
Cd inhibits catalase glutathione reductase and lowers
glutathione levels
bull Replace structural minerals
Pb displaces Ca in bone
How Toxins Cause Damage 23
bull Damage DNA
Benzene - causes chromosomal damage
Pesticides ndash fruit growers have more DNA damage
Phthalates and insecticides ndash damage sperm DNA
4-hydroxy catechol estrogen (4-OHE) damages breast DNA
bull Epigenetic dysmodulation
Higher cord blood levels of hexachlorobenzene associated
with 2x greater risk for obesity in children
bull Damage cell membranes
Common mechanism for heavy metals inactivates
membrane enzymes ion channels and pumps
How Toxins Cause Damage 33
bull Block insulin receptor sites
PCBs and phthalates
bull Highest levels associated with a 4 to 20-fold greater diabetes risk
bull Imbalance hormones many toxin examples
Arsenic
bull Disrupts thyroid hormone and retinoic acid receptors
Phthalates
bull Act as anti-androgens
bull More than 75 of the US population has measurable levels of
several phthalate metabolites in the urine
PCBs
bull Lower testosterone levels in men
Which are the Worst Toxins
bull According to the CDC
Toxicity
Population toxic load
Prevalence in toxic waste sites
bull According to clinical importance
Exposure
of disease
Ability of the body to detoxifyexcrete
Ag
en
cy
fo
r T
oxic
Su
bs
tan
ce
s a
nd
Dis
ea
se
Reg
istr
y
Pri
ori
ty L
ist
The Worst Toxins Clinically
My Rank Toxin Diseases Primary Sources
1 Arsenic Cancers diabetes gout Water chicken rice
2 DDT ADHD dementia diabetes Everywhere
3 Phthalates ADHD diabetes Soft plastics HABAs
4 PBDEs ADHD diabetes Flame retardant fabrics
5 PAHs ADHD cancers dyslipidemia Smoking charbroiling
6 PCBs Cancers diabetes MI RA Everywhere
7 Mercury Dementia ldquoSilverrdquo fillings fish
8 Lead Cardiovascular disease IQ Paint water
Glyphosate Research invalid
Conventional Laboratory Tests Reflect
Toxic Load in ldquoNormalrdquo Range
bull Surprising number show toxin exposure
CBC RBC WBC platelet count hemoglobin basophilic
stippling
Liver enzymes ALT GGTP
Inflammatory markers CRP
Lipids LDL oxLDL triglycerides
Blood sugar insulin FBS 2-hour PP
Metabolites bilirubin uric acid homocysteine 8-OHdG
Thyroid T3 T4 TSH
bull The historic ldquonormalrdquo range has been changing as the population has become more toxic
WBC Lowered by PCB and OCP Exposure
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
0
1
2
3
4
5
6
7
8
1st Quartrile 2nd Quartile 3rd Quartile 4th Quartile
WBCbull Strong inverse correlation with PCBs and OCPs and CBC
bull Linear with almost all PCBs
bull High variability with OCPs
bull Within ldquonormalrdquo range
Effects on WBC Worsen with Years
of Exposure to Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Platelet Count Decreases with Years
of Exposure tp Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Solvents Decrease Platelet Count
bull Compared workers exposed 23 hrday to those exposed most of day to toluene
bull All wore face masks and protective gear
bull Platelet count 14 lower 252 versus 216ml
bull Impairment of sympathetic nerves (OR = 413)
bull Impairment of peripheral nerves (OR = 694)
bull Positive relationship between neurological abnormalities and a self-reported neuropsychiatric measurement (r = 035-066)
Shih HT et al Subclinical abnormalities in workers with continuous low-level toluene exposure Toxicol Ind Health 2011 Sep27(8)691-9
Basophilic Stippling of Red Cells
Toxinsbull Arsenic
bull Lead
Diseasesbull Alpha-thalassemia HbH Disease
bull Beta thalassemia
bull Hereditary pyrimidine 5-nucleotidase deficiency
bull Myelodysplastic syndrome
bull Sideroblastic anemia
bull Thrombotic thrombocytopenic purpura
GGT Indirect Measure of POPsbull Glutathione is key intracellular defense against oxidative stress
bull Cellular GGT metabolizes extracellular GSH allowing precursor amino acids to be reutilized for intracellular GSH
bull Exposure to POPs induces GGT as a defensive mechanism
bull Within normal range predicts type 2 diabetes coronary heart disease hypertension stroke dyslipidemia chronic kidney disease and cancer
bull Men with GGT gt50 UI had ~26 fold risk for diabetes compared to those with lt10 Those with 40-49 had a ~20 fold risk
bull Levels within normal range occur with obesity xs alcohol cigarette smoking physical inactivity high meat low fruit and vegetable intake
bull Cumulative biomarker for environmental pollutants
Lee DH et al (2003) Gamma-glutamyltransferase and diabetesmdasha 4 year follow-up study Diabetologia 46359ndash364
Pamela A et al Serum gamma-glutamyltransferase linking together environmental pollution redox equilibria and progression of atherosclerosis Clin Chem
Lab Med 200947(12)1583-4
Lee DH et al Serum gamma-glutamyltransferase new insights about an old enzyme J Epidemiol Community Health 2009 Nov63(11)884-6
Lee DH et alSerum gamma-glutamyltransferase predicts non-fatal myocardial infarction and fatal coronary heart disease among 28838 middle-aged men and
women Eur Heart J 2006272170ndash6
Lee DH et al Gamma-glutamyltransferase and diabetes--a 4 year follow-up study Diabetologia 2003 Mar46(3)359-64
Lee DH et al Can persistent organic pollutants explain the association between serum gamma-glutamyltransferase and type 2 diabetes Diabetologia 2008
Mar51(3)402-7
GGT and Alcohol Consumption
bull GGT directly correlates with alcohol consumption
bull In a non-uniform population 40 gd will elevate GGT ~15
bull Watch for false negatives
bull Genomic variation
bull Are these the ones most
sensitive todamaged by
chemical toxins
bull Could up-regulation of GGT in light alcohol consumption be reason for benefit
0
10
20
30
40
50
60
70
80
0 200 400 600 800
Grams of Ethanol per Week
Adapted from Nagaya T et al Dose-response relationships between drinking and serum tests in Japanese men
aged 40ndash59 years Alcohol 1999 Feb 17(2) 133ndash8
GGT Correlates With Toxic Metal Levels
Lee DH et al Graded associations of blood lead and urinary cadmium concentrations with oxidative-stress-related markers in the
US population results from the third National Health and Nutrition Examination Survey Environ Health
perspect 2006 Mar114(3)350-4
GGT and Diabetes Risk
0
5
10
15
20
25
30
lt10 10-19 20-29 30-39 40-49 gt50
Dia
bete
s R
isk
GGT
bull GGT over 50 associated with tripling of death rate
bull 30-40 associated with doubling
GGT Levels
Correlate with
Risk of Death
Brenner H et al Distribution determinants and prognostic value of gamma-glutamyltransferase for all-cause
mortality in a cohort of construction workers from southern Germany Prev Med 1997 26 305ndash10
GGT From Small US Company
with Young Workers
0
10
20
30
40
50
60
0 20 40 60 80 100
GGT Data from Canadian Oil Field
Workers
0
50
100
150
200
250
300
350
400
450
lt10 10-20 20-30 30-40 40-50 50-60 60-07 70-80 80-90 90-100 100-110 110-120 gt120
GGTP
20-fold increased risk of diabetes
Uric Acid Indirect Measure of POPs
bull Poly-fluorinated hydrocarbons (PFOA and PFOS) associated
with increased serum uric acid
Lin CY et al Association among serum perfluoroalkyl chemicals glucose homeostasis and metabolic syndrome
in adolescents and adults Diabetes Care 2009 Apr32(4)702-7
Steenland K et al Association of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) with uric
acid among adults with elevated community exposure to PFOA Environ Health Perspect 2010 Feb118229-33
Steenland 2010 Open Access
ALT Indirect Measure of POPs
bull ALT (proxy marker) elevation in 104 (not including viral
hepatitis hemochromatosis or alcoholic liver disease) of
NHANES 03-04 subset
bull Risk of elevated ALT increased dose-dependently with
cadmium lead mercury and PCB exposure
bull 100 of individuals had detectable PCBs 925 mercury
and 996 had detectable lead
bull In 2005-08 prevalence of NAFLD in US was 11 a
growing cause of chronic liver disease
Cave M et al Polychlorinated biphenyls lead and mercury are associated with liver disease in American adults
NHANES 2003-2004 Environ Health Perspect 2010 Dec118(12)1735-42
Younossi ZM et al Changes in the prevalence of the most common causes of chronic liver diseases in the United
States from 1988 to 2008 Clin Gastroenterol Hepatol 2011 Jun9(6)524-530e1
Bilirubin as a Marker of POPs
bull Degree of serum bilirubin increase is prognostically significant in chronic liver dysfunction
bull Mono-ortho PCB TEQ values were found to be significantly positively associated with bilirubin (β=071 P=0008) following adjustment for multiple potential confounders
bull Bilirubin levels significantly correlated with PCBs -105-118-126 and -194
bull Smoking appears to be the biggest confounder
Dufour DR et al 2000 Diagnosis and monitoring of hepatic injury II Recommendations for use of laboratory
tests in screening diagnosis and monitoring Clin Chem 46 2050ndash68
Kumar J et al Persistent organic pollutants and liver dysfunction biomarkers in a population-based human sample
of men and women Environ Res 2014134251-256
Perf
luo
rin
ate
dP
OP
s a
nd
Co
mm
on
Blo
od
Tests
Gleason JA et al Associations of perfluorinated chemical serum concentrations and biomarkers of liver function and uric acid in the
US population (NHANES) 2007-2010 Environ Res 20151368-14
Liver Enzymes Reflect Toxic Load
bull AST ALT and GGT increase with body load of PCBs and OCPs
bull Some non-linear
bull Oxychlordanetop quartile
ALT 10
GGT 25
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
LDL-Cholesterol as Measure of POPs
bull 5-year prospective study to determine if POP levels predict future elevation in LDL-cholesterol
bull 598 subjects initially at age 70
bull Looked at 23 POPs
bull Best correlation with PCB 194
Penell J Lind L Salihovic S et al Persistent organic pollutants are related to change in circulating
lipid levels during a 5 year follow-up Environ Res 134(2014)190ndash197
oxLDL as Measure of POPs
bull 992 70-year old individuals (50 women)
bull Sum of PCBs showed strong significant positive associations with ox-LDL and significant negative associations with glutathione-related markers (GSSG and GSSGGSH)
bull A number of POPs (PCB-99 138 153 156 170 180 194 206 and 209) showed strong significant positive association with ox-LDL
Kumar J et al Influence of persistent organic pollutants on oxidative stress in population-based samples
Chemosphere 2014114303-309
Homocysteine is Increased by Pb amp Cd
Guallar E et al Confounding of the relation between homocysteine and peripheral arterial disease by lead cadmium and renal function Am J Epidemiol 2006 Apr 15163(8)700-8
Nutrient Deficiencies Accentuate
Effects of Lead on Homocysteine
bull Deficiencies in folate B6 or B12 make lead more toxic
Lee YM Et al Association of homocysteine levels with blood lead levels and micronutrients in the US general population J Prev Med Public Health 2012 Nov45(6)387-93
T4 amp T3 and PCBs
bull PCBs decrease T4 production
bull PCBs inhibit iodotyrosinedeiodinase activity
bull Study done in pregnant women which implies effect on fetus IQ
Kim S Park J Kim HJ et al Association between several persistent organic pollutants and thyroid hormone levels in serum among the pregnant women of Korea Environ Int 2013 Sep59442-8Shimizu R Yamaguchi M Uramaru N et al Structure-activity relationships of 44 halogenated compounds for iodotyrosinedeiodinase-inhibitory activity Toxicology 2013 Dec 6314(1)22-9
T4 amp T3 and PCBs
bull Not just humans being affected
bull Large study of dolphins shows exactly the same effects
Schwacke LH Zolman ES Balmer BC et al Anaemia hypothyroidism and immune suppression associated with polychlorinated biphenyl exposure in bottlenose dolphins (Tursiops truncatus) Proceed Royal Society B doi101098rspb20110665
8-OHdG
bull Oxidized nucleoside
bull Direct measure of DNA damage
bull Indirect measure of oxidative stress and toxin load
bull Correlates with
Multiple cancers
Mitochondrial damage
Rate of aging
Smoking
Several toxinsWalter Crinnion ldquoTotal Toxic Loadrdquo AANP 2015
8-OHdG Correlates with Pack-Years
of Smoking
Yano T et al Significance of the urinary 8-OHdG level as an oxidative stress marker in lung cancer patients Lung Cancer
2009 Jan63(1)111-4
8-OHdG Correlates
with Mercury
Chen C et al Increased oxidative DNA damage as assessed by urinary 8-hydroxy-2-deoxyguanosine
concentrations and serum redox status in persons exposed to mercury Clin Chem 2005 Apr51(4)759-67
Toxin Effects Worse with Aging
bull Thyroid function decreases with PFOA levels
bull But only after age 63
Shrestha S Bloom MS Yucel R et al Perfluoroalkyl substances and thyroid function in older adults Environ Int 2015 Feb75206-14
Insightful 23-Year Prospective Study
1 lt 50 there is no difference between those with the lowest and highest PCBs
2 In youngest group insulin production increases in response to toxin level As expected since blocking of
insulin receptor sites by PCBs
requires more insulin
3 That adaptive ability decreases with aging
4 At age 50 all the measures show very strong toxin-dose response
Cumulative damage impairs ability to adapt
Suarez-Lopez JR et al Persistent organic pollutants in young adults and changes in glucose related metabolism over a 23-year follow-up Environ Res 2015 Feb137485-94
Recommendations
High body toxic load
GGT gt 25
Uric acid gt 50 mgdl
ALT gt30 UL
Bilirubin gt08 mgdl
CBC lt 6000
Platelet lt 250000
Low T3 andor T4
Monitor Total Toxic Load
8-OHdG gt4
ldquoUnconventionalrdquo Laboratory Tests
bull Challenge testing
bull Hair analysis
bull Direct measures of solvents and POPs in blood urine adipose tissue
Evaluation of Metal Exposure ndash Provocation
bull Provocation ndash the use of a chelating agent ndash before urine collection often done clinically but several limitations
No ldquoofficialrdquo reference range for provoked urine
Most chelating agents do not extract metals from all tissues thus
does not necessarily represent total body burden
bull Example Brain is one of the main target organs for both elemental and organic
mercury yet agents do not chelate brain mercury
bull Despite limitations widely used and advocated by clinicians in part to see efficacy of chelating agent as a guide to treatment and based on empirical evidence
Rooney JP The role of thiols dithiols nutritional factors and interacting ligands in the toxicology of mercury
Toxicology 2007
Is Challenge Testing Valid
bull Poor correlations of standard tests for mercury
bull Unpublished research from corporate wellness project
bull Published amalgam number correlation
bull Published fish consumption correlation
What We Found In Canada
bull Deviations from the mean of 14 29 and 91 respectively
bull DMPS is spreading distribution suggesting that it is better at differentiating mercury body load
bull Some VERY high
Hg Assessment Correlations
bull Extensive measurements in 65 Whole blood Hg
Oral DMPS challenge
Amalgam surfaces
bull Correlations Whole blood w pre urine r = 040
Whole blood w post urine r = 057
Pre urine w post urine r = 068
Amalgams w pre urine r = 026
Amalgams w whole blood r = 036
Amalgams with post urine 044
bull Clear documentation that
challenge testing is better00
100
200
300
400
500
600
0 10 20 30 40 50
Po
st
Uri
ne H
g u
gg
Number of amalgams
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
DiabetesToxin Threshold Above
Threshold
Odds
Ratio
of Dz Reference
PMID
Arsenic 165 ugL 200 21 180 18714061
BPA 28 ugL 280 145 112 26119400
DDE 545 ngg serum
(pp-DDE)
200 230 31 26119400
Dioxins2 pgg lipid 50 191 43
26119400
PCBs104 ngg (PCB 153) 250 239 258
26119400
Phthalates175 ugL 690 148 249
26119400
1-naphthalene 167 ugdL 152 182 111 26340343
2-napthalene 414 ugdL 550 224 214 26340343
1-phenanthrene 167 ngL 570 178 151 26340343
1-pyrene 85 ngL 660 180 174 26340343
Lung Cancer
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Acrylonitrile Uncertain Uncertain 125 25
occupational
exposure
17114112
Arsenic 1213 ugL 436 of Asian
Americans
~01 of total
US population
34 95 in AA
01-1
PMC2682945
Cadmium Uncertain+ Uncertain 467 10 in
smokers
17184399
DDT Any exposure All US pop
below LOD
17 76 increased
risk
8923607
Breast Cancer
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Cadmium 0580 ugg
creatinine
126 205 479 16788160
PCB 138 396 ngg
creatinine
202 316 630 27717745
PCB 187 108 ngg lipid 600 194 360 21480306
Miscellaneous Diseases
Toxin Disease Threshold Above
Threshold
Odds
Ratio
of Dz Reference PMID
Aluminum Alzheimer
Dz
01 mgL
drinking
H20
400 203 05-44 26592479
Benzene AML 100ppmyrs 1-3 320 60 PMC2903550
DDT NHL 0512 ugL 1-2 240 01 17722095
Lead ALS 238 ugdL
blood
330 181 210 25479292
Lead Brain CA 0005 ugdL 14 19 ~500 17164378
Dioxin-like
PCBs
RA 326 ngg
lipid
250 219 220 17589595
PAHs Asthma 124 ngm3 935 200 483 19221603
The Potency of Arsenic
Disease Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Bladder CA 10ugL H20 100 27 145 24889821
Pancreatic CA 1332 ugg 200 246 230 23800676
Prostate CA 1332 ugg 200 33 315 23800676
Gout 125 ugL 245 546 522 25499256
Diabetes 165 ugL 200 21 180 18714061
Arsenic (180 of Diabetes)
How it causes diabetes
bull Blocks sugar stimulating insulin secretion
bull Epigenetic inhibition of sugar regulation
Where it comes from
bull Water (gt10 of US water supplies have high levels)
bull Rice (naturally absorbs if in the water)
bull Chicken (added to make meat whiter)
Pan W-C Seow WJ Kile ML et al Association of low to moderate levels of arsenic exposure with risk of Type 2 diabetes in Bangladesh American Journal of Epidemiology 2013178(10)1563-70
Portion of Population with Toxin Load Which
Doubles Disease Risk
Toxin Disease with Doubled Risk
Polycyclic aromatic hydrocarbons Asthma 94
PCB187 Breast Cancer 60
Phthalates Diabetes 55
Lead ALS 33
Aluminum Alzheimers Disease 25
DDT ADHD 25
PCBs Diabetes 25
Dioxin-like PCBs Rheumatoid Arthritis 25
Arsenic Gout 23
Bisphenol A Diabetes 22
Cigarette smoking Lung Cancer 21
Arsenic Diabetes 20
Polycyclic aromatic hydrocarbons Diabetes 20
Huge Detoxification Variability
bull CYP2C19
Proton pump inhibitors and some antidepressants
5-fold difference in activity between poor metabolizers and extensive metabolizers more so if CYP3A4 is also inhibited
Ultrarapid allele in 18 of both Swedes and Ethiopians
bull CYP2D6
Metabolizes a large number of drugs (~25)
7 of Caucasians poor metabolizers
~30 ultra rapid metabolizers in Arabian and Eastern African populations
More adverse effects in poor metabolizers and ineffective dosing in ultrarapid metabolizers
Inhibited by ginger
Desta Z et al Clinical significance of the cytochrome P450 2C19 genetic polymorphism Clin Pharmaco 2002
Sim SC et al A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug
response to proton pump inhibitors and antidepressants Clin Pharmacol Ther 2006
Wilkinson GR Drug metabolism and variability among patients in drug response N Engl J Med 2005
Kirchheiner J et al Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to
CYP2D6 duplication Pharmacogenomics J 2007
Toxin Half Lives in BloodToxin ldquoNormalrdquo (mgL) Acute Toxic (mgL) Half-Life
Arsenic 0002-007 005-025 2-4 days (CDC)
Benzene 00002 05-10 days
Cadmium 00003-00065 0015-005 16 years
Chlordane 0001 00025 3-4 days
DDTDDE 2-10 years
Dieldrin 00015 015-030 2-12 months
Ethanol 1000-2000 15hour
Lead 009 04-06 1-15 mo (2+ yrs bone)
Mercury 00015-0002 005-02 2 months (CDC)
PCBs 3-25 years
Toluene 05-3 days
Schulz M et al Therapeutic and toxic blood concentrations of nearly 1000 drugs and other xenobiotics Crit Care 2012 Jul 2616(4)R136
Bioaccumulation (POPs)
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
DDT banned in 1972 PCBs banned in 1977
Bioaccumulation (Cd)
Think BroadlyExogenous
Metals
Chemicalsbull Inorganic
bull Fluoride
bull Organic
bull POPs
bull Drugs
Particulate matter
Molds
Microbial
Radiationbull Light
bull Medical
bull Cell phone
Endogenous
Gut-derived toxins
Non-end product metabolites
Poorly detoxified hormones
Catecholamines (if SNP)
Toxins of Choice
Alcohol
Marijuana
Food constituents
High fructose corn syrup
Salt (acid-forming diet)
Wheat if zonulin (70)
Obesity Epidemic ndash POPs AND HFCS
47Bray GA Fructose should we worry Int J Obes (Lond) 2008 Dec32 Suppl 7S127-31
How Toxins Cause Damage 13
bull Increase free radical production
Cd induces production of ROS
Malathion inhibits catalase and glutathione peroxidase
Homocysteine oxidizes LDL cholesterol
bull Poison enzyme systems (compete with nutritional cofactors for binding sites)
Pb poisons delta aminolevulinic acid dehydratase
Cd inhibits catalase glutathione reductase and lowers
glutathione levels
bull Replace structural minerals
Pb displaces Ca in bone
How Toxins Cause Damage 23
bull Damage DNA
Benzene - causes chromosomal damage
Pesticides ndash fruit growers have more DNA damage
Phthalates and insecticides ndash damage sperm DNA
4-hydroxy catechol estrogen (4-OHE) damages breast DNA
bull Epigenetic dysmodulation
Higher cord blood levels of hexachlorobenzene associated
with 2x greater risk for obesity in children
bull Damage cell membranes
Common mechanism for heavy metals inactivates
membrane enzymes ion channels and pumps
How Toxins Cause Damage 33
bull Block insulin receptor sites
PCBs and phthalates
bull Highest levels associated with a 4 to 20-fold greater diabetes risk
bull Imbalance hormones many toxin examples
Arsenic
bull Disrupts thyroid hormone and retinoic acid receptors
Phthalates
bull Act as anti-androgens
bull More than 75 of the US population has measurable levels of
several phthalate metabolites in the urine
PCBs
bull Lower testosterone levels in men
Which are the Worst Toxins
bull According to the CDC
Toxicity
Population toxic load
Prevalence in toxic waste sites
bull According to clinical importance
Exposure
of disease
Ability of the body to detoxifyexcrete
Ag
en
cy
fo
r T
oxic
Su
bs
tan
ce
s a
nd
Dis
ea
se
Reg
istr
y
Pri
ori
ty L
ist
The Worst Toxins Clinically
My Rank Toxin Diseases Primary Sources
1 Arsenic Cancers diabetes gout Water chicken rice
2 DDT ADHD dementia diabetes Everywhere
3 Phthalates ADHD diabetes Soft plastics HABAs
4 PBDEs ADHD diabetes Flame retardant fabrics
5 PAHs ADHD cancers dyslipidemia Smoking charbroiling
6 PCBs Cancers diabetes MI RA Everywhere
7 Mercury Dementia ldquoSilverrdquo fillings fish
8 Lead Cardiovascular disease IQ Paint water
Glyphosate Research invalid
Conventional Laboratory Tests Reflect
Toxic Load in ldquoNormalrdquo Range
bull Surprising number show toxin exposure
CBC RBC WBC platelet count hemoglobin basophilic
stippling
Liver enzymes ALT GGTP
Inflammatory markers CRP
Lipids LDL oxLDL triglycerides
Blood sugar insulin FBS 2-hour PP
Metabolites bilirubin uric acid homocysteine 8-OHdG
Thyroid T3 T4 TSH
bull The historic ldquonormalrdquo range has been changing as the population has become more toxic
WBC Lowered by PCB and OCP Exposure
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
0
1
2
3
4
5
6
7
8
1st Quartrile 2nd Quartile 3rd Quartile 4th Quartile
WBCbull Strong inverse correlation with PCBs and OCPs and CBC
bull Linear with almost all PCBs
bull High variability with OCPs
bull Within ldquonormalrdquo range
Effects on WBC Worsen with Years
of Exposure to Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Platelet Count Decreases with Years
of Exposure tp Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Solvents Decrease Platelet Count
bull Compared workers exposed 23 hrday to those exposed most of day to toluene
bull All wore face masks and protective gear
bull Platelet count 14 lower 252 versus 216ml
bull Impairment of sympathetic nerves (OR = 413)
bull Impairment of peripheral nerves (OR = 694)
bull Positive relationship between neurological abnormalities and a self-reported neuropsychiatric measurement (r = 035-066)
Shih HT et al Subclinical abnormalities in workers with continuous low-level toluene exposure Toxicol Ind Health 2011 Sep27(8)691-9
Basophilic Stippling of Red Cells
Toxinsbull Arsenic
bull Lead
Diseasesbull Alpha-thalassemia HbH Disease
bull Beta thalassemia
bull Hereditary pyrimidine 5-nucleotidase deficiency
bull Myelodysplastic syndrome
bull Sideroblastic anemia
bull Thrombotic thrombocytopenic purpura
GGT Indirect Measure of POPsbull Glutathione is key intracellular defense against oxidative stress
bull Cellular GGT metabolizes extracellular GSH allowing precursor amino acids to be reutilized for intracellular GSH
bull Exposure to POPs induces GGT as a defensive mechanism
bull Within normal range predicts type 2 diabetes coronary heart disease hypertension stroke dyslipidemia chronic kidney disease and cancer
bull Men with GGT gt50 UI had ~26 fold risk for diabetes compared to those with lt10 Those with 40-49 had a ~20 fold risk
bull Levels within normal range occur with obesity xs alcohol cigarette smoking physical inactivity high meat low fruit and vegetable intake
bull Cumulative biomarker for environmental pollutants
Lee DH et al (2003) Gamma-glutamyltransferase and diabetesmdasha 4 year follow-up study Diabetologia 46359ndash364
Pamela A et al Serum gamma-glutamyltransferase linking together environmental pollution redox equilibria and progression of atherosclerosis Clin Chem
Lab Med 200947(12)1583-4
Lee DH et al Serum gamma-glutamyltransferase new insights about an old enzyme J Epidemiol Community Health 2009 Nov63(11)884-6
Lee DH et alSerum gamma-glutamyltransferase predicts non-fatal myocardial infarction and fatal coronary heart disease among 28838 middle-aged men and
women Eur Heart J 2006272170ndash6
Lee DH et al Gamma-glutamyltransferase and diabetes--a 4 year follow-up study Diabetologia 2003 Mar46(3)359-64
Lee DH et al Can persistent organic pollutants explain the association between serum gamma-glutamyltransferase and type 2 diabetes Diabetologia 2008
Mar51(3)402-7
GGT and Alcohol Consumption
bull GGT directly correlates with alcohol consumption
bull In a non-uniform population 40 gd will elevate GGT ~15
bull Watch for false negatives
bull Genomic variation
bull Are these the ones most
sensitive todamaged by
chemical toxins
bull Could up-regulation of GGT in light alcohol consumption be reason for benefit
0
10
20
30
40
50
60
70
80
0 200 400 600 800
Grams of Ethanol per Week
Adapted from Nagaya T et al Dose-response relationships between drinking and serum tests in Japanese men
aged 40ndash59 years Alcohol 1999 Feb 17(2) 133ndash8
GGT Correlates With Toxic Metal Levels
Lee DH et al Graded associations of blood lead and urinary cadmium concentrations with oxidative-stress-related markers in the
US population results from the third National Health and Nutrition Examination Survey Environ Health
perspect 2006 Mar114(3)350-4
GGT and Diabetes Risk
0
5
10
15
20
25
30
lt10 10-19 20-29 30-39 40-49 gt50
Dia
bete
s R
isk
GGT
bull GGT over 50 associated with tripling of death rate
bull 30-40 associated with doubling
GGT Levels
Correlate with
Risk of Death
Brenner H et al Distribution determinants and prognostic value of gamma-glutamyltransferase for all-cause
mortality in a cohort of construction workers from southern Germany Prev Med 1997 26 305ndash10
GGT From Small US Company
with Young Workers
0
10
20
30
40
50
60
0 20 40 60 80 100
GGT Data from Canadian Oil Field
Workers
0
50
100
150
200
250
300
350
400
450
lt10 10-20 20-30 30-40 40-50 50-60 60-07 70-80 80-90 90-100 100-110 110-120 gt120
GGTP
20-fold increased risk of diabetes
Uric Acid Indirect Measure of POPs
bull Poly-fluorinated hydrocarbons (PFOA and PFOS) associated
with increased serum uric acid
Lin CY et al Association among serum perfluoroalkyl chemicals glucose homeostasis and metabolic syndrome
in adolescents and adults Diabetes Care 2009 Apr32(4)702-7
Steenland K et al Association of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) with uric
acid among adults with elevated community exposure to PFOA Environ Health Perspect 2010 Feb118229-33
Steenland 2010 Open Access
ALT Indirect Measure of POPs
bull ALT (proxy marker) elevation in 104 (not including viral
hepatitis hemochromatosis or alcoholic liver disease) of
NHANES 03-04 subset
bull Risk of elevated ALT increased dose-dependently with
cadmium lead mercury and PCB exposure
bull 100 of individuals had detectable PCBs 925 mercury
and 996 had detectable lead
bull In 2005-08 prevalence of NAFLD in US was 11 a
growing cause of chronic liver disease
Cave M et al Polychlorinated biphenyls lead and mercury are associated with liver disease in American adults
NHANES 2003-2004 Environ Health Perspect 2010 Dec118(12)1735-42
Younossi ZM et al Changes in the prevalence of the most common causes of chronic liver diseases in the United
States from 1988 to 2008 Clin Gastroenterol Hepatol 2011 Jun9(6)524-530e1
Bilirubin as a Marker of POPs
bull Degree of serum bilirubin increase is prognostically significant in chronic liver dysfunction
bull Mono-ortho PCB TEQ values were found to be significantly positively associated with bilirubin (β=071 P=0008) following adjustment for multiple potential confounders
bull Bilirubin levels significantly correlated with PCBs -105-118-126 and -194
bull Smoking appears to be the biggest confounder
Dufour DR et al 2000 Diagnosis and monitoring of hepatic injury II Recommendations for use of laboratory
tests in screening diagnosis and monitoring Clin Chem 46 2050ndash68
Kumar J et al Persistent organic pollutants and liver dysfunction biomarkers in a population-based human sample
of men and women Environ Res 2014134251-256
Perf
luo
rin
ate
dP
OP
s a
nd
Co
mm
on
Blo
od
Tests
Gleason JA et al Associations of perfluorinated chemical serum concentrations and biomarkers of liver function and uric acid in the
US population (NHANES) 2007-2010 Environ Res 20151368-14
Liver Enzymes Reflect Toxic Load
bull AST ALT and GGT increase with body load of PCBs and OCPs
bull Some non-linear
bull Oxychlordanetop quartile
ALT 10
GGT 25
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
LDL-Cholesterol as Measure of POPs
bull 5-year prospective study to determine if POP levels predict future elevation in LDL-cholesterol
bull 598 subjects initially at age 70
bull Looked at 23 POPs
bull Best correlation with PCB 194
Penell J Lind L Salihovic S et al Persistent organic pollutants are related to change in circulating
lipid levels during a 5 year follow-up Environ Res 134(2014)190ndash197
oxLDL as Measure of POPs
bull 992 70-year old individuals (50 women)
bull Sum of PCBs showed strong significant positive associations with ox-LDL and significant negative associations with glutathione-related markers (GSSG and GSSGGSH)
bull A number of POPs (PCB-99 138 153 156 170 180 194 206 and 209) showed strong significant positive association with ox-LDL
Kumar J et al Influence of persistent organic pollutants on oxidative stress in population-based samples
Chemosphere 2014114303-309
Homocysteine is Increased by Pb amp Cd
Guallar E et al Confounding of the relation between homocysteine and peripheral arterial disease by lead cadmium and renal function Am J Epidemiol 2006 Apr 15163(8)700-8
Nutrient Deficiencies Accentuate
Effects of Lead on Homocysteine
bull Deficiencies in folate B6 or B12 make lead more toxic
Lee YM Et al Association of homocysteine levels with blood lead levels and micronutrients in the US general population J Prev Med Public Health 2012 Nov45(6)387-93
T4 amp T3 and PCBs
bull PCBs decrease T4 production
bull PCBs inhibit iodotyrosinedeiodinase activity
bull Study done in pregnant women which implies effect on fetus IQ
Kim S Park J Kim HJ et al Association between several persistent organic pollutants and thyroid hormone levels in serum among the pregnant women of Korea Environ Int 2013 Sep59442-8Shimizu R Yamaguchi M Uramaru N et al Structure-activity relationships of 44 halogenated compounds for iodotyrosinedeiodinase-inhibitory activity Toxicology 2013 Dec 6314(1)22-9
T4 amp T3 and PCBs
bull Not just humans being affected
bull Large study of dolphins shows exactly the same effects
Schwacke LH Zolman ES Balmer BC et al Anaemia hypothyroidism and immune suppression associated with polychlorinated biphenyl exposure in bottlenose dolphins (Tursiops truncatus) Proceed Royal Society B doi101098rspb20110665
8-OHdG
bull Oxidized nucleoside
bull Direct measure of DNA damage
bull Indirect measure of oxidative stress and toxin load
bull Correlates with
Multiple cancers
Mitochondrial damage
Rate of aging
Smoking
Several toxinsWalter Crinnion ldquoTotal Toxic Loadrdquo AANP 2015
8-OHdG Correlates with Pack-Years
of Smoking
Yano T et al Significance of the urinary 8-OHdG level as an oxidative stress marker in lung cancer patients Lung Cancer
2009 Jan63(1)111-4
8-OHdG Correlates
with Mercury
Chen C et al Increased oxidative DNA damage as assessed by urinary 8-hydroxy-2-deoxyguanosine
concentrations and serum redox status in persons exposed to mercury Clin Chem 2005 Apr51(4)759-67
Toxin Effects Worse with Aging
bull Thyroid function decreases with PFOA levels
bull But only after age 63
Shrestha S Bloom MS Yucel R et al Perfluoroalkyl substances and thyroid function in older adults Environ Int 2015 Feb75206-14
Insightful 23-Year Prospective Study
1 lt 50 there is no difference between those with the lowest and highest PCBs
2 In youngest group insulin production increases in response to toxin level As expected since blocking of
insulin receptor sites by PCBs
requires more insulin
3 That adaptive ability decreases with aging
4 At age 50 all the measures show very strong toxin-dose response
Cumulative damage impairs ability to adapt
Suarez-Lopez JR et al Persistent organic pollutants in young adults and changes in glucose related metabolism over a 23-year follow-up Environ Res 2015 Feb137485-94
Recommendations
High body toxic load
GGT gt 25
Uric acid gt 50 mgdl
ALT gt30 UL
Bilirubin gt08 mgdl
CBC lt 6000
Platelet lt 250000
Low T3 andor T4
Monitor Total Toxic Load
8-OHdG gt4
ldquoUnconventionalrdquo Laboratory Tests
bull Challenge testing
bull Hair analysis
bull Direct measures of solvents and POPs in blood urine adipose tissue
Evaluation of Metal Exposure ndash Provocation
bull Provocation ndash the use of a chelating agent ndash before urine collection often done clinically but several limitations
No ldquoofficialrdquo reference range for provoked urine
Most chelating agents do not extract metals from all tissues thus
does not necessarily represent total body burden
bull Example Brain is one of the main target organs for both elemental and organic
mercury yet agents do not chelate brain mercury
bull Despite limitations widely used and advocated by clinicians in part to see efficacy of chelating agent as a guide to treatment and based on empirical evidence
Rooney JP The role of thiols dithiols nutritional factors and interacting ligands in the toxicology of mercury
Toxicology 2007
Is Challenge Testing Valid
bull Poor correlations of standard tests for mercury
bull Unpublished research from corporate wellness project
bull Published amalgam number correlation
bull Published fish consumption correlation
What We Found In Canada
bull Deviations from the mean of 14 29 and 91 respectively
bull DMPS is spreading distribution suggesting that it is better at differentiating mercury body load
bull Some VERY high
Hg Assessment Correlations
bull Extensive measurements in 65 Whole blood Hg
Oral DMPS challenge
Amalgam surfaces
bull Correlations Whole blood w pre urine r = 040
Whole blood w post urine r = 057
Pre urine w post urine r = 068
Amalgams w pre urine r = 026
Amalgams w whole blood r = 036
Amalgams with post urine 044
bull Clear documentation that
challenge testing is better00
100
200
300
400
500
600
0 10 20 30 40 50
Po
st
Uri
ne H
g u
gg
Number of amalgams
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
Lung Cancer
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Acrylonitrile Uncertain Uncertain 125 25
occupational
exposure
17114112
Arsenic 1213 ugL 436 of Asian
Americans
~01 of total
US population
34 95 in AA
01-1
PMC2682945
Cadmium Uncertain+ Uncertain 467 10 in
smokers
17184399
DDT Any exposure All US pop
below LOD
17 76 increased
risk
8923607
Breast Cancer
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Cadmium 0580 ugg
creatinine
126 205 479 16788160
PCB 138 396 ngg
creatinine
202 316 630 27717745
PCB 187 108 ngg lipid 600 194 360 21480306
Miscellaneous Diseases
Toxin Disease Threshold Above
Threshold
Odds
Ratio
of Dz Reference PMID
Aluminum Alzheimer
Dz
01 mgL
drinking
H20
400 203 05-44 26592479
Benzene AML 100ppmyrs 1-3 320 60 PMC2903550
DDT NHL 0512 ugL 1-2 240 01 17722095
Lead ALS 238 ugdL
blood
330 181 210 25479292
Lead Brain CA 0005 ugdL 14 19 ~500 17164378
Dioxin-like
PCBs
RA 326 ngg
lipid
250 219 220 17589595
PAHs Asthma 124 ngm3 935 200 483 19221603
The Potency of Arsenic
Disease Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Bladder CA 10ugL H20 100 27 145 24889821
Pancreatic CA 1332 ugg 200 246 230 23800676
Prostate CA 1332 ugg 200 33 315 23800676
Gout 125 ugL 245 546 522 25499256
Diabetes 165 ugL 200 21 180 18714061
Arsenic (180 of Diabetes)
How it causes diabetes
bull Blocks sugar stimulating insulin secretion
bull Epigenetic inhibition of sugar regulation
Where it comes from
bull Water (gt10 of US water supplies have high levels)
bull Rice (naturally absorbs if in the water)
bull Chicken (added to make meat whiter)
Pan W-C Seow WJ Kile ML et al Association of low to moderate levels of arsenic exposure with risk of Type 2 diabetes in Bangladesh American Journal of Epidemiology 2013178(10)1563-70
Portion of Population with Toxin Load Which
Doubles Disease Risk
Toxin Disease with Doubled Risk
Polycyclic aromatic hydrocarbons Asthma 94
PCB187 Breast Cancer 60
Phthalates Diabetes 55
Lead ALS 33
Aluminum Alzheimers Disease 25
DDT ADHD 25
PCBs Diabetes 25
Dioxin-like PCBs Rheumatoid Arthritis 25
Arsenic Gout 23
Bisphenol A Diabetes 22
Cigarette smoking Lung Cancer 21
Arsenic Diabetes 20
Polycyclic aromatic hydrocarbons Diabetes 20
Huge Detoxification Variability
bull CYP2C19
Proton pump inhibitors and some antidepressants
5-fold difference in activity between poor metabolizers and extensive metabolizers more so if CYP3A4 is also inhibited
Ultrarapid allele in 18 of both Swedes and Ethiopians
bull CYP2D6
Metabolizes a large number of drugs (~25)
7 of Caucasians poor metabolizers
~30 ultra rapid metabolizers in Arabian and Eastern African populations
More adverse effects in poor metabolizers and ineffective dosing in ultrarapid metabolizers
Inhibited by ginger
Desta Z et al Clinical significance of the cytochrome P450 2C19 genetic polymorphism Clin Pharmaco 2002
Sim SC et al A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug
response to proton pump inhibitors and antidepressants Clin Pharmacol Ther 2006
Wilkinson GR Drug metabolism and variability among patients in drug response N Engl J Med 2005
Kirchheiner J et al Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to
CYP2D6 duplication Pharmacogenomics J 2007
Toxin Half Lives in BloodToxin ldquoNormalrdquo (mgL) Acute Toxic (mgL) Half-Life
Arsenic 0002-007 005-025 2-4 days (CDC)
Benzene 00002 05-10 days
Cadmium 00003-00065 0015-005 16 years
Chlordane 0001 00025 3-4 days
DDTDDE 2-10 years
Dieldrin 00015 015-030 2-12 months
Ethanol 1000-2000 15hour
Lead 009 04-06 1-15 mo (2+ yrs bone)
Mercury 00015-0002 005-02 2 months (CDC)
PCBs 3-25 years
Toluene 05-3 days
Schulz M et al Therapeutic and toxic blood concentrations of nearly 1000 drugs and other xenobiotics Crit Care 2012 Jul 2616(4)R136
Bioaccumulation (POPs)
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
DDT banned in 1972 PCBs banned in 1977
Bioaccumulation (Cd)
Think BroadlyExogenous
Metals
Chemicalsbull Inorganic
bull Fluoride
bull Organic
bull POPs
bull Drugs
Particulate matter
Molds
Microbial
Radiationbull Light
bull Medical
bull Cell phone
Endogenous
Gut-derived toxins
Non-end product metabolites
Poorly detoxified hormones
Catecholamines (if SNP)
Toxins of Choice
Alcohol
Marijuana
Food constituents
High fructose corn syrup
Salt (acid-forming diet)
Wheat if zonulin (70)
Obesity Epidemic ndash POPs AND HFCS
47Bray GA Fructose should we worry Int J Obes (Lond) 2008 Dec32 Suppl 7S127-31
How Toxins Cause Damage 13
bull Increase free radical production
Cd induces production of ROS
Malathion inhibits catalase and glutathione peroxidase
Homocysteine oxidizes LDL cholesterol
bull Poison enzyme systems (compete with nutritional cofactors for binding sites)
Pb poisons delta aminolevulinic acid dehydratase
Cd inhibits catalase glutathione reductase and lowers
glutathione levels
bull Replace structural minerals
Pb displaces Ca in bone
How Toxins Cause Damage 23
bull Damage DNA
Benzene - causes chromosomal damage
Pesticides ndash fruit growers have more DNA damage
Phthalates and insecticides ndash damage sperm DNA
4-hydroxy catechol estrogen (4-OHE) damages breast DNA
bull Epigenetic dysmodulation
Higher cord blood levels of hexachlorobenzene associated
with 2x greater risk for obesity in children
bull Damage cell membranes
Common mechanism for heavy metals inactivates
membrane enzymes ion channels and pumps
How Toxins Cause Damage 33
bull Block insulin receptor sites
PCBs and phthalates
bull Highest levels associated with a 4 to 20-fold greater diabetes risk
bull Imbalance hormones many toxin examples
Arsenic
bull Disrupts thyroid hormone and retinoic acid receptors
Phthalates
bull Act as anti-androgens
bull More than 75 of the US population has measurable levels of
several phthalate metabolites in the urine
PCBs
bull Lower testosterone levels in men
Which are the Worst Toxins
bull According to the CDC
Toxicity
Population toxic load
Prevalence in toxic waste sites
bull According to clinical importance
Exposure
of disease
Ability of the body to detoxifyexcrete
Ag
en
cy
fo
r T
oxic
Su
bs
tan
ce
s a
nd
Dis
ea
se
Reg
istr
y
Pri
ori
ty L
ist
The Worst Toxins Clinically
My Rank Toxin Diseases Primary Sources
1 Arsenic Cancers diabetes gout Water chicken rice
2 DDT ADHD dementia diabetes Everywhere
3 Phthalates ADHD diabetes Soft plastics HABAs
4 PBDEs ADHD diabetes Flame retardant fabrics
5 PAHs ADHD cancers dyslipidemia Smoking charbroiling
6 PCBs Cancers diabetes MI RA Everywhere
7 Mercury Dementia ldquoSilverrdquo fillings fish
8 Lead Cardiovascular disease IQ Paint water
Glyphosate Research invalid
Conventional Laboratory Tests Reflect
Toxic Load in ldquoNormalrdquo Range
bull Surprising number show toxin exposure
CBC RBC WBC platelet count hemoglobin basophilic
stippling
Liver enzymes ALT GGTP
Inflammatory markers CRP
Lipids LDL oxLDL triglycerides
Blood sugar insulin FBS 2-hour PP
Metabolites bilirubin uric acid homocysteine 8-OHdG
Thyroid T3 T4 TSH
bull The historic ldquonormalrdquo range has been changing as the population has become more toxic
WBC Lowered by PCB and OCP Exposure
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
0
1
2
3
4
5
6
7
8
1st Quartrile 2nd Quartile 3rd Quartile 4th Quartile
WBCbull Strong inverse correlation with PCBs and OCPs and CBC
bull Linear with almost all PCBs
bull High variability with OCPs
bull Within ldquonormalrdquo range
Effects on WBC Worsen with Years
of Exposure to Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Platelet Count Decreases with Years
of Exposure tp Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Solvents Decrease Platelet Count
bull Compared workers exposed 23 hrday to those exposed most of day to toluene
bull All wore face masks and protective gear
bull Platelet count 14 lower 252 versus 216ml
bull Impairment of sympathetic nerves (OR = 413)
bull Impairment of peripheral nerves (OR = 694)
bull Positive relationship between neurological abnormalities and a self-reported neuropsychiatric measurement (r = 035-066)
Shih HT et al Subclinical abnormalities in workers with continuous low-level toluene exposure Toxicol Ind Health 2011 Sep27(8)691-9
Basophilic Stippling of Red Cells
Toxinsbull Arsenic
bull Lead
Diseasesbull Alpha-thalassemia HbH Disease
bull Beta thalassemia
bull Hereditary pyrimidine 5-nucleotidase deficiency
bull Myelodysplastic syndrome
bull Sideroblastic anemia
bull Thrombotic thrombocytopenic purpura
GGT Indirect Measure of POPsbull Glutathione is key intracellular defense against oxidative stress
bull Cellular GGT metabolizes extracellular GSH allowing precursor amino acids to be reutilized for intracellular GSH
bull Exposure to POPs induces GGT as a defensive mechanism
bull Within normal range predicts type 2 diabetes coronary heart disease hypertension stroke dyslipidemia chronic kidney disease and cancer
bull Men with GGT gt50 UI had ~26 fold risk for diabetes compared to those with lt10 Those with 40-49 had a ~20 fold risk
bull Levels within normal range occur with obesity xs alcohol cigarette smoking physical inactivity high meat low fruit and vegetable intake
bull Cumulative biomarker for environmental pollutants
Lee DH et al (2003) Gamma-glutamyltransferase and diabetesmdasha 4 year follow-up study Diabetologia 46359ndash364
Pamela A et al Serum gamma-glutamyltransferase linking together environmental pollution redox equilibria and progression of atherosclerosis Clin Chem
Lab Med 200947(12)1583-4
Lee DH et al Serum gamma-glutamyltransferase new insights about an old enzyme J Epidemiol Community Health 2009 Nov63(11)884-6
Lee DH et alSerum gamma-glutamyltransferase predicts non-fatal myocardial infarction and fatal coronary heart disease among 28838 middle-aged men and
women Eur Heart J 2006272170ndash6
Lee DH et al Gamma-glutamyltransferase and diabetes--a 4 year follow-up study Diabetologia 2003 Mar46(3)359-64
Lee DH et al Can persistent organic pollutants explain the association between serum gamma-glutamyltransferase and type 2 diabetes Diabetologia 2008
Mar51(3)402-7
GGT and Alcohol Consumption
bull GGT directly correlates with alcohol consumption
bull In a non-uniform population 40 gd will elevate GGT ~15
bull Watch for false negatives
bull Genomic variation
bull Are these the ones most
sensitive todamaged by
chemical toxins
bull Could up-regulation of GGT in light alcohol consumption be reason for benefit
0
10
20
30
40
50
60
70
80
0 200 400 600 800
Grams of Ethanol per Week
Adapted from Nagaya T et al Dose-response relationships between drinking and serum tests in Japanese men
aged 40ndash59 years Alcohol 1999 Feb 17(2) 133ndash8
GGT Correlates With Toxic Metal Levels
Lee DH et al Graded associations of blood lead and urinary cadmium concentrations with oxidative-stress-related markers in the
US population results from the third National Health and Nutrition Examination Survey Environ Health
perspect 2006 Mar114(3)350-4
GGT and Diabetes Risk
0
5
10
15
20
25
30
lt10 10-19 20-29 30-39 40-49 gt50
Dia
bete
s R
isk
GGT
bull GGT over 50 associated with tripling of death rate
bull 30-40 associated with doubling
GGT Levels
Correlate with
Risk of Death
Brenner H et al Distribution determinants and prognostic value of gamma-glutamyltransferase for all-cause
mortality in a cohort of construction workers from southern Germany Prev Med 1997 26 305ndash10
GGT From Small US Company
with Young Workers
0
10
20
30
40
50
60
0 20 40 60 80 100
GGT Data from Canadian Oil Field
Workers
0
50
100
150
200
250
300
350
400
450
lt10 10-20 20-30 30-40 40-50 50-60 60-07 70-80 80-90 90-100 100-110 110-120 gt120
GGTP
20-fold increased risk of diabetes
Uric Acid Indirect Measure of POPs
bull Poly-fluorinated hydrocarbons (PFOA and PFOS) associated
with increased serum uric acid
Lin CY et al Association among serum perfluoroalkyl chemicals glucose homeostasis and metabolic syndrome
in adolescents and adults Diabetes Care 2009 Apr32(4)702-7
Steenland K et al Association of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) with uric
acid among adults with elevated community exposure to PFOA Environ Health Perspect 2010 Feb118229-33
Steenland 2010 Open Access
ALT Indirect Measure of POPs
bull ALT (proxy marker) elevation in 104 (not including viral
hepatitis hemochromatosis or alcoholic liver disease) of
NHANES 03-04 subset
bull Risk of elevated ALT increased dose-dependently with
cadmium lead mercury and PCB exposure
bull 100 of individuals had detectable PCBs 925 mercury
and 996 had detectable lead
bull In 2005-08 prevalence of NAFLD in US was 11 a
growing cause of chronic liver disease
Cave M et al Polychlorinated biphenyls lead and mercury are associated with liver disease in American adults
NHANES 2003-2004 Environ Health Perspect 2010 Dec118(12)1735-42
Younossi ZM et al Changes in the prevalence of the most common causes of chronic liver diseases in the United
States from 1988 to 2008 Clin Gastroenterol Hepatol 2011 Jun9(6)524-530e1
Bilirubin as a Marker of POPs
bull Degree of serum bilirubin increase is prognostically significant in chronic liver dysfunction
bull Mono-ortho PCB TEQ values were found to be significantly positively associated with bilirubin (β=071 P=0008) following adjustment for multiple potential confounders
bull Bilirubin levels significantly correlated with PCBs -105-118-126 and -194
bull Smoking appears to be the biggest confounder
Dufour DR et al 2000 Diagnosis and monitoring of hepatic injury II Recommendations for use of laboratory
tests in screening diagnosis and monitoring Clin Chem 46 2050ndash68
Kumar J et al Persistent organic pollutants and liver dysfunction biomarkers in a population-based human sample
of men and women Environ Res 2014134251-256
Perf
luo
rin
ate
dP
OP
s a
nd
Co
mm
on
Blo
od
Tests
Gleason JA et al Associations of perfluorinated chemical serum concentrations and biomarkers of liver function and uric acid in the
US population (NHANES) 2007-2010 Environ Res 20151368-14
Liver Enzymes Reflect Toxic Load
bull AST ALT and GGT increase with body load of PCBs and OCPs
bull Some non-linear
bull Oxychlordanetop quartile
ALT 10
GGT 25
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
LDL-Cholesterol as Measure of POPs
bull 5-year prospective study to determine if POP levels predict future elevation in LDL-cholesterol
bull 598 subjects initially at age 70
bull Looked at 23 POPs
bull Best correlation with PCB 194
Penell J Lind L Salihovic S et al Persistent organic pollutants are related to change in circulating
lipid levels during a 5 year follow-up Environ Res 134(2014)190ndash197
oxLDL as Measure of POPs
bull 992 70-year old individuals (50 women)
bull Sum of PCBs showed strong significant positive associations with ox-LDL and significant negative associations with glutathione-related markers (GSSG and GSSGGSH)
bull A number of POPs (PCB-99 138 153 156 170 180 194 206 and 209) showed strong significant positive association with ox-LDL
Kumar J et al Influence of persistent organic pollutants on oxidative stress in population-based samples
Chemosphere 2014114303-309
Homocysteine is Increased by Pb amp Cd
Guallar E et al Confounding of the relation between homocysteine and peripheral arterial disease by lead cadmium and renal function Am J Epidemiol 2006 Apr 15163(8)700-8
Nutrient Deficiencies Accentuate
Effects of Lead on Homocysteine
bull Deficiencies in folate B6 or B12 make lead more toxic
Lee YM Et al Association of homocysteine levels with blood lead levels and micronutrients in the US general population J Prev Med Public Health 2012 Nov45(6)387-93
T4 amp T3 and PCBs
bull PCBs decrease T4 production
bull PCBs inhibit iodotyrosinedeiodinase activity
bull Study done in pregnant women which implies effect on fetus IQ
Kim S Park J Kim HJ et al Association between several persistent organic pollutants and thyroid hormone levels in serum among the pregnant women of Korea Environ Int 2013 Sep59442-8Shimizu R Yamaguchi M Uramaru N et al Structure-activity relationships of 44 halogenated compounds for iodotyrosinedeiodinase-inhibitory activity Toxicology 2013 Dec 6314(1)22-9
T4 amp T3 and PCBs
bull Not just humans being affected
bull Large study of dolphins shows exactly the same effects
Schwacke LH Zolman ES Balmer BC et al Anaemia hypothyroidism and immune suppression associated with polychlorinated biphenyl exposure in bottlenose dolphins (Tursiops truncatus) Proceed Royal Society B doi101098rspb20110665
8-OHdG
bull Oxidized nucleoside
bull Direct measure of DNA damage
bull Indirect measure of oxidative stress and toxin load
bull Correlates with
Multiple cancers
Mitochondrial damage
Rate of aging
Smoking
Several toxinsWalter Crinnion ldquoTotal Toxic Loadrdquo AANP 2015
8-OHdG Correlates with Pack-Years
of Smoking
Yano T et al Significance of the urinary 8-OHdG level as an oxidative stress marker in lung cancer patients Lung Cancer
2009 Jan63(1)111-4
8-OHdG Correlates
with Mercury
Chen C et al Increased oxidative DNA damage as assessed by urinary 8-hydroxy-2-deoxyguanosine
concentrations and serum redox status in persons exposed to mercury Clin Chem 2005 Apr51(4)759-67
Toxin Effects Worse with Aging
bull Thyroid function decreases with PFOA levels
bull But only after age 63
Shrestha S Bloom MS Yucel R et al Perfluoroalkyl substances and thyroid function in older adults Environ Int 2015 Feb75206-14
Insightful 23-Year Prospective Study
1 lt 50 there is no difference between those with the lowest and highest PCBs
2 In youngest group insulin production increases in response to toxin level As expected since blocking of
insulin receptor sites by PCBs
requires more insulin
3 That adaptive ability decreases with aging
4 At age 50 all the measures show very strong toxin-dose response
Cumulative damage impairs ability to adapt
Suarez-Lopez JR et al Persistent organic pollutants in young adults and changes in glucose related metabolism over a 23-year follow-up Environ Res 2015 Feb137485-94
Recommendations
High body toxic load
GGT gt 25
Uric acid gt 50 mgdl
ALT gt30 UL
Bilirubin gt08 mgdl
CBC lt 6000
Platelet lt 250000
Low T3 andor T4
Monitor Total Toxic Load
8-OHdG gt4
ldquoUnconventionalrdquo Laboratory Tests
bull Challenge testing
bull Hair analysis
bull Direct measures of solvents and POPs in blood urine adipose tissue
Evaluation of Metal Exposure ndash Provocation
bull Provocation ndash the use of a chelating agent ndash before urine collection often done clinically but several limitations
No ldquoofficialrdquo reference range for provoked urine
Most chelating agents do not extract metals from all tissues thus
does not necessarily represent total body burden
bull Example Brain is one of the main target organs for both elemental and organic
mercury yet agents do not chelate brain mercury
bull Despite limitations widely used and advocated by clinicians in part to see efficacy of chelating agent as a guide to treatment and based on empirical evidence
Rooney JP The role of thiols dithiols nutritional factors and interacting ligands in the toxicology of mercury
Toxicology 2007
Is Challenge Testing Valid
bull Poor correlations of standard tests for mercury
bull Unpublished research from corporate wellness project
bull Published amalgam number correlation
bull Published fish consumption correlation
What We Found In Canada
bull Deviations from the mean of 14 29 and 91 respectively
bull DMPS is spreading distribution suggesting that it is better at differentiating mercury body load
bull Some VERY high
Hg Assessment Correlations
bull Extensive measurements in 65 Whole blood Hg
Oral DMPS challenge
Amalgam surfaces
bull Correlations Whole blood w pre urine r = 040
Whole blood w post urine r = 057
Pre urine w post urine r = 068
Amalgams w pre urine r = 026
Amalgams w whole blood r = 036
Amalgams with post urine 044
bull Clear documentation that
challenge testing is better00
100
200
300
400
500
600
0 10 20 30 40 50
Po
st
Uri
ne H
g u
gg
Number of amalgams
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
Breast Cancer
Toxin Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Cadmium 0580 ugg
creatinine
126 205 479 16788160
PCB 138 396 ngg
creatinine
202 316 630 27717745
PCB 187 108 ngg lipid 600 194 360 21480306
Miscellaneous Diseases
Toxin Disease Threshold Above
Threshold
Odds
Ratio
of Dz Reference PMID
Aluminum Alzheimer
Dz
01 mgL
drinking
H20
400 203 05-44 26592479
Benzene AML 100ppmyrs 1-3 320 60 PMC2903550
DDT NHL 0512 ugL 1-2 240 01 17722095
Lead ALS 238 ugdL
blood
330 181 210 25479292
Lead Brain CA 0005 ugdL 14 19 ~500 17164378
Dioxin-like
PCBs
RA 326 ngg
lipid
250 219 220 17589595
PAHs Asthma 124 ngm3 935 200 483 19221603
The Potency of Arsenic
Disease Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Bladder CA 10ugL H20 100 27 145 24889821
Pancreatic CA 1332 ugg 200 246 230 23800676
Prostate CA 1332 ugg 200 33 315 23800676
Gout 125 ugL 245 546 522 25499256
Diabetes 165 ugL 200 21 180 18714061
Arsenic (180 of Diabetes)
How it causes diabetes
bull Blocks sugar stimulating insulin secretion
bull Epigenetic inhibition of sugar regulation
Where it comes from
bull Water (gt10 of US water supplies have high levels)
bull Rice (naturally absorbs if in the water)
bull Chicken (added to make meat whiter)
Pan W-C Seow WJ Kile ML et al Association of low to moderate levels of arsenic exposure with risk of Type 2 diabetes in Bangladesh American Journal of Epidemiology 2013178(10)1563-70
Portion of Population with Toxin Load Which
Doubles Disease Risk
Toxin Disease with Doubled Risk
Polycyclic aromatic hydrocarbons Asthma 94
PCB187 Breast Cancer 60
Phthalates Diabetes 55
Lead ALS 33
Aluminum Alzheimers Disease 25
DDT ADHD 25
PCBs Diabetes 25
Dioxin-like PCBs Rheumatoid Arthritis 25
Arsenic Gout 23
Bisphenol A Diabetes 22
Cigarette smoking Lung Cancer 21
Arsenic Diabetes 20
Polycyclic aromatic hydrocarbons Diabetes 20
Huge Detoxification Variability
bull CYP2C19
Proton pump inhibitors and some antidepressants
5-fold difference in activity between poor metabolizers and extensive metabolizers more so if CYP3A4 is also inhibited
Ultrarapid allele in 18 of both Swedes and Ethiopians
bull CYP2D6
Metabolizes a large number of drugs (~25)
7 of Caucasians poor metabolizers
~30 ultra rapid metabolizers in Arabian and Eastern African populations
More adverse effects in poor metabolizers and ineffective dosing in ultrarapid metabolizers
Inhibited by ginger
Desta Z et al Clinical significance of the cytochrome P450 2C19 genetic polymorphism Clin Pharmaco 2002
Sim SC et al A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug
response to proton pump inhibitors and antidepressants Clin Pharmacol Ther 2006
Wilkinson GR Drug metabolism and variability among patients in drug response N Engl J Med 2005
Kirchheiner J et al Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to
CYP2D6 duplication Pharmacogenomics J 2007
Toxin Half Lives in BloodToxin ldquoNormalrdquo (mgL) Acute Toxic (mgL) Half-Life
Arsenic 0002-007 005-025 2-4 days (CDC)
Benzene 00002 05-10 days
Cadmium 00003-00065 0015-005 16 years
Chlordane 0001 00025 3-4 days
DDTDDE 2-10 years
Dieldrin 00015 015-030 2-12 months
Ethanol 1000-2000 15hour
Lead 009 04-06 1-15 mo (2+ yrs bone)
Mercury 00015-0002 005-02 2 months (CDC)
PCBs 3-25 years
Toluene 05-3 days
Schulz M et al Therapeutic and toxic blood concentrations of nearly 1000 drugs and other xenobiotics Crit Care 2012 Jul 2616(4)R136
Bioaccumulation (POPs)
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
DDT banned in 1972 PCBs banned in 1977
Bioaccumulation (Cd)
Think BroadlyExogenous
Metals
Chemicalsbull Inorganic
bull Fluoride
bull Organic
bull POPs
bull Drugs
Particulate matter
Molds
Microbial
Radiationbull Light
bull Medical
bull Cell phone
Endogenous
Gut-derived toxins
Non-end product metabolites
Poorly detoxified hormones
Catecholamines (if SNP)
Toxins of Choice
Alcohol
Marijuana
Food constituents
High fructose corn syrup
Salt (acid-forming diet)
Wheat if zonulin (70)
Obesity Epidemic ndash POPs AND HFCS
47Bray GA Fructose should we worry Int J Obes (Lond) 2008 Dec32 Suppl 7S127-31
How Toxins Cause Damage 13
bull Increase free radical production
Cd induces production of ROS
Malathion inhibits catalase and glutathione peroxidase
Homocysteine oxidizes LDL cholesterol
bull Poison enzyme systems (compete with nutritional cofactors for binding sites)
Pb poisons delta aminolevulinic acid dehydratase
Cd inhibits catalase glutathione reductase and lowers
glutathione levels
bull Replace structural minerals
Pb displaces Ca in bone
How Toxins Cause Damage 23
bull Damage DNA
Benzene - causes chromosomal damage
Pesticides ndash fruit growers have more DNA damage
Phthalates and insecticides ndash damage sperm DNA
4-hydroxy catechol estrogen (4-OHE) damages breast DNA
bull Epigenetic dysmodulation
Higher cord blood levels of hexachlorobenzene associated
with 2x greater risk for obesity in children
bull Damage cell membranes
Common mechanism for heavy metals inactivates
membrane enzymes ion channels and pumps
How Toxins Cause Damage 33
bull Block insulin receptor sites
PCBs and phthalates
bull Highest levels associated with a 4 to 20-fold greater diabetes risk
bull Imbalance hormones many toxin examples
Arsenic
bull Disrupts thyroid hormone and retinoic acid receptors
Phthalates
bull Act as anti-androgens
bull More than 75 of the US population has measurable levels of
several phthalate metabolites in the urine
PCBs
bull Lower testosterone levels in men
Which are the Worst Toxins
bull According to the CDC
Toxicity
Population toxic load
Prevalence in toxic waste sites
bull According to clinical importance
Exposure
of disease
Ability of the body to detoxifyexcrete
Ag
en
cy
fo
r T
oxic
Su
bs
tan
ce
s a
nd
Dis
ea
se
Reg
istr
y
Pri
ori
ty L
ist
The Worst Toxins Clinically
My Rank Toxin Diseases Primary Sources
1 Arsenic Cancers diabetes gout Water chicken rice
2 DDT ADHD dementia diabetes Everywhere
3 Phthalates ADHD diabetes Soft plastics HABAs
4 PBDEs ADHD diabetes Flame retardant fabrics
5 PAHs ADHD cancers dyslipidemia Smoking charbroiling
6 PCBs Cancers diabetes MI RA Everywhere
7 Mercury Dementia ldquoSilverrdquo fillings fish
8 Lead Cardiovascular disease IQ Paint water
Glyphosate Research invalid
Conventional Laboratory Tests Reflect
Toxic Load in ldquoNormalrdquo Range
bull Surprising number show toxin exposure
CBC RBC WBC platelet count hemoglobin basophilic
stippling
Liver enzymes ALT GGTP
Inflammatory markers CRP
Lipids LDL oxLDL triglycerides
Blood sugar insulin FBS 2-hour PP
Metabolites bilirubin uric acid homocysteine 8-OHdG
Thyroid T3 T4 TSH
bull The historic ldquonormalrdquo range has been changing as the population has become more toxic
WBC Lowered by PCB and OCP Exposure
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
0
1
2
3
4
5
6
7
8
1st Quartrile 2nd Quartile 3rd Quartile 4th Quartile
WBCbull Strong inverse correlation with PCBs and OCPs and CBC
bull Linear with almost all PCBs
bull High variability with OCPs
bull Within ldquonormalrdquo range
Effects on WBC Worsen with Years
of Exposure to Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Platelet Count Decreases with Years
of Exposure tp Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Solvents Decrease Platelet Count
bull Compared workers exposed 23 hrday to those exposed most of day to toluene
bull All wore face masks and protective gear
bull Platelet count 14 lower 252 versus 216ml
bull Impairment of sympathetic nerves (OR = 413)
bull Impairment of peripheral nerves (OR = 694)
bull Positive relationship between neurological abnormalities and a self-reported neuropsychiatric measurement (r = 035-066)
Shih HT et al Subclinical abnormalities in workers with continuous low-level toluene exposure Toxicol Ind Health 2011 Sep27(8)691-9
Basophilic Stippling of Red Cells
Toxinsbull Arsenic
bull Lead
Diseasesbull Alpha-thalassemia HbH Disease
bull Beta thalassemia
bull Hereditary pyrimidine 5-nucleotidase deficiency
bull Myelodysplastic syndrome
bull Sideroblastic anemia
bull Thrombotic thrombocytopenic purpura
GGT Indirect Measure of POPsbull Glutathione is key intracellular defense against oxidative stress
bull Cellular GGT metabolizes extracellular GSH allowing precursor amino acids to be reutilized for intracellular GSH
bull Exposure to POPs induces GGT as a defensive mechanism
bull Within normal range predicts type 2 diabetes coronary heart disease hypertension stroke dyslipidemia chronic kidney disease and cancer
bull Men with GGT gt50 UI had ~26 fold risk for diabetes compared to those with lt10 Those with 40-49 had a ~20 fold risk
bull Levels within normal range occur with obesity xs alcohol cigarette smoking physical inactivity high meat low fruit and vegetable intake
bull Cumulative biomarker for environmental pollutants
Lee DH et al (2003) Gamma-glutamyltransferase and diabetesmdasha 4 year follow-up study Diabetologia 46359ndash364
Pamela A et al Serum gamma-glutamyltransferase linking together environmental pollution redox equilibria and progression of atherosclerosis Clin Chem
Lab Med 200947(12)1583-4
Lee DH et al Serum gamma-glutamyltransferase new insights about an old enzyme J Epidemiol Community Health 2009 Nov63(11)884-6
Lee DH et alSerum gamma-glutamyltransferase predicts non-fatal myocardial infarction and fatal coronary heart disease among 28838 middle-aged men and
women Eur Heart J 2006272170ndash6
Lee DH et al Gamma-glutamyltransferase and diabetes--a 4 year follow-up study Diabetologia 2003 Mar46(3)359-64
Lee DH et al Can persistent organic pollutants explain the association between serum gamma-glutamyltransferase and type 2 diabetes Diabetologia 2008
Mar51(3)402-7
GGT and Alcohol Consumption
bull GGT directly correlates with alcohol consumption
bull In a non-uniform population 40 gd will elevate GGT ~15
bull Watch for false negatives
bull Genomic variation
bull Are these the ones most
sensitive todamaged by
chemical toxins
bull Could up-regulation of GGT in light alcohol consumption be reason for benefit
0
10
20
30
40
50
60
70
80
0 200 400 600 800
Grams of Ethanol per Week
Adapted from Nagaya T et al Dose-response relationships between drinking and serum tests in Japanese men
aged 40ndash59 years Alcohol 1999 Feb 17(2) 133ndash8
GGT Correlates With Toxic Metal Levels
Lee DH et al Graded associations of blood lead and urinary cadmium concentrations with oxidative-stress-related markers in the
US population results from the third National Health and Nutrition Examination Survey Environ Health
perspect 2006 Mar114(3)350-4
GGT and Diabetes Risk
0
5
10
15
20
25
30
lt10 10-19 20-29 30-39 40-49 gt50
Dia
bete
s R
isk
GGT
bull GGT over 50 associated with tripling of death rate
bull 30-40 associated with doubling
GGT Levels
Correlate with
Risk of Death
Brenner H et al Distribution determinants and prognostic value of gamma-glutamyltransferase for all-cause
mortality in a cohort of construction workers from southern Germany Prev Med 1997 26 305ndash10
GGT From Small US Company
with Young Workers
0
10
20
30
40
50
60
0 20 40 60 80 100
GGT Data from Canadian Oil Field
Workers
0
50
100
150
200
250
300
350
400
450
lt10 10-20 20-30 30-40 40-50 50-60 60-07 70-80 80-90 90-100 100-110 110-120 gt120
GGTP
20-fold increased risk of diabetes
Uric Acid Indirect Measure of POPs
bull Poly-fluorinated hydrocarbons (PFOA and PFOS) associated
with increased serum uric acid
Lin CY et al Association among serum perfluoroalkyl chemicals glucose homeostasis and metabolic syndrome
in adolescents and adults Diabetes Care 2009 Apr32(4)702-7
Steenland K et al Association of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) with uric
acid among adults with elevated community exposure to PFOA Environ Health Perspect 2010 Feb118229-33
Steenland 2010 Open Access
ALT Indirect Measure of POPs
bull ALT (proxy marker) elevation in 104 (not including viral
hepatitis hemochromatosis or alcoholic liver disease) of
NHANES 03-04 subset
bull Risk of elevated ALT increased dose-dependently with
cadmium lead mercury and PCB exposure
bull 100 of individuals had detectable PCBs 925 mercury
and 996 had detectable lead
bull In 2005-08 prevalence of NAFLD in US was 11 a
growing cause of chronic liver disease
Cave M et al Polychlorinated biphenyls lead and mercury are associated with liver disease in American adults
NHANES 2003-2004 Environ Health Perspect 2010 Dec118(12)1735-42
Younossi ZM et al Changes in the prevalence of the most common causes of chronic liver diseases in the United
States from 1988 to 2008 Clin Gastroenterol Hepatol 2011 Jun9(6)524-530e1
Bilirubin as a Marker of POPs
bull Degree of serum bilirubin increase is prognostically significant in chronic liver dysfunction
bull Mono-ortho PCB TEQ values were found to be significantly positively associated with bilirubin (β=071 P=0008) following adjustment for multiple potential confounders
bull Bilirubin levels significantly correlated with PCBs -105-118-126 and -194
bull Smoking appears to be the biggest confounder
Dufour DR et al 2000 Diagnosis and monitoring of hepatic injury II Recommendations for use of laboratory
tests in screening diagnosis and monitoring Clin Chem 46 2050ndash68
Kumar J et al Persistent organic pollutants and liver dysfunction biomarkers in a population-based human sample
of men and women Environ Res 2014134251-256
Perf
luo
rin
ate
dP
OP
s a
nd
Co
mm
on
Blo
od
Tests
Gleason JA et al Associations of perfluorinated chemical serum concentrations and biomarkers of liver function and uric acid in the
US population (NHANES) 2007-2010 Environ Res 20151368-14
Liver Enzymes Reflect Toxic Load
bull AST ALT and GGT increase with body load of PCBs and OCPs
bull Some non-linear
bull Oxychlordanetop quartile
ALT 10
GGT 25
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
LDL-Cholesterol as Measure of POPs
bull 5-year prospective study to determine if POP levels predict future elevation in LDL-cholesterol
bull 598 subjects initially at age 70
bull Looked at 23 POPs
bull Best correlation with PCB 194
Penell J Lind L Salihovic S et al Persistent organic pollutants are related to change in circulating
lipid levels during a 5 year follow-up Environ Res 134(2014)190ndash197
oxLDL as Measure of POPs
bull 992 70-year old individuals (50 women)
bull Sum of PCBs showed strong significant positive associations with ox-LDL and significant negative associations with glutathione-related markers (GSSG and GSSGGSH)
bull A number of POPs (PCB-99 138 153 156 170 180 194 206 and 209) showed strong significant positive association with ox-LDL
Kumar J et al Influence of persistent organic pollutants on oxidative stress in population-based samples
Chemosphere 2014114303-309
Homocysteine is Increased by Pb amp Cd
Guallar E et al Confounding of the relation between homocysteine and peripheral arterial disease by lead cadmium and renal function Am J Epidemiol 2006 Apr 15163(8)700-8
Nutrient Deficiencies Accentuate
Effects of Lead on Homocysteine
bull Deficiencies in folate B6 or B12 make lead more toxic
Lee YM Et al Association of homocysteine levels with blood lead levels and micronutrients in the US general population J Prev Med Public Health 2012 Nov45(6)387-93
T4 amp T3 and PCBs
bull PCBs decrease T4 production
bull PCBs inhibit iodotyrosinedeiodinase activity
bull Study done in pregnant women which implies effect on fetus IQ
Kim S Park J Kim HJ et al Association between several persistent organic pollutants and thyroid hormone levels in serum among the pregnant women of Korea Environ Int 2013 Sep59442-8Shimizu R Yamaguchi M Uramaru N et al Structure-activity relationships of 44 halogenated compounds for iodotyrosinedeiodinase-inhibitory activity Toxicology 2013 Dec 6314(1)22-9
T4 amp T3 and PCBs
bull Not just humans being affected
bull Large study of dolphins shows exactly the same effects
Schwacke LH Zolman ES Balmer BC et al Anaemia hypothyroidism and immune suppression associated with polychlorinated biphenyl exposure in bottlenose dolphins (Tursiops truncatus) Proceed Royal Society B doi101098rspb20110665
8-OHdG
bull Oxidized nucleoside
bull Direct measure of DNA damage
bull Indirect measure of oxidative stress and toxin load
bull Correlates with
Multiple cancers
Mitochondrial damage
Rate of aging
Smoking
Several toxinsWalter Crinnion ldquoTotal Toxic Loadrdquo AANP 2015
8-OHdG Correlates with Pack-Years
of Smoking
Yano T et al Significance of the urinary 8-OHdG level as an oxidative stress marker in lung cancer patients Lung Cancer
2009 Jan63(1)111-4
8-OHdG Correlates
with Mercury
Chen C et al Increased oxidative DNA damage as assessed by urinary 8-hydroxy-2-deoxyguanosine
concentrations and serum redox status in persons exposed to mercury Clin Chem 2005 Apr51(4)759-67
Toxin Effects Worse with Aging
bull Thyroid function decreases with PFOA levels
bull But only after age 63
Shrestha S Bloom MS Yucel R et al Perfluoroalkyl substances and thyroid function in older adults Environ Int 2015 Feb75206-14
Insightful 23-Year Prospective Study
1 lt 50 there is no difference between those with the lowest and highest PCBs
2 In youngest group insulin production increases in response to toxin level As expected since blocking of
insulin receptor sites by PCBs
requires more insulin
3 That adaptive ability decreases with aging
4 At age 50 all the measures show very strong toxin-dose response
Cumulative damage impairs ability to adapt
Suarez-Lopez JR et al Persistent organic pollutants in young adults and changes in glucose related metabolism over a 23-year follow-up Environ Res 2015 Feb137485-94
Recommendations
High body toxic load
GGT gt 25
Uric acid gt 50 mgdl
ALT gt30 UL
Bilirubin gt08 mgdl
CBC lt 6000
Platelet lt 250000
Low T3 andor T4
Monitor Total Toxic Load
8-OHdG gt4
ldquoUnconventionalrdquo Laboratory Tests
bull Challenge testing
bull Hair analysis
bull Direct measures of solvents and POPs in blood urine adipose tissue
Evaluation of Metal Exposure ndash Provocation
bull Provocation ndash the use of a chelating agent ndash before urine collection often done clinically but several limitations
No ldquoofficialrdquo reference range for provoked urine
Most chelating agents do not extract metals from all tissues thus
does not necessarily represent total body burden
bull Example Brain is one of the main target organs for both elemental and organic
mercury yet agents do not chelate brain mercury
bull Despite limitations widely used and advocated by clinicians in part to see efficacy of chelating agent as a guide to treatment and based on empirical evidence
Rooney JP The role of thiols dithiols nutritional factors and interacting ligands in the toxicology of mercury
Toxicology 2007
Is Challenge Testing Valid
bull Poor correlations of standard tests for mercury
bull Unpublished research from corporate wellness project
bull Published amalgam number correlation
bull Published fish consumption correlation
What We Found In Canada
bull Deviations from the mean of 14 29 and 91 respectively
bull DMPS is spreading distribution suggesting that it is better at differentiating mercury body load
bull Some VERY high
Hg Assessment Correlations
bull Extensive measurements in 65 Whole blood Hg
Oral DMPS challenge
Amalgam surfaces
bull Correlations Whole blood w pre urine r = 040
Whole blood w post urine r = 057
Pre urine w post urine r = 068
Amalgams w pre urine r = 026
Amalgams w whole blood r = 036
Amalgams with post urine 044
bull Clear documentation that
challenge testing is better00
100
200
300
400
500
600
0 10 20 30 40 50
Po
st
Uri
ne H
g u
gg
Number of amalgams
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
Miscellaneous Diseases
Toxin Disease Threshold Above
Threshold
Odds
Ratio
of Dz Reference PMID
Aluminum Alzheimer
Dz
01 mgL
drinking
H20
400 203 05-44 26592479
Benzene AML 100ppmyrs 1-3 320 60 PMC2903550
DDT NHL 0512 ugL 1-2 240 01 17722095
Lead ALS 238 ugdL
blood
330 181 210 25479292
Lead Brain CA 0005 ugdL 14 19 ~500 17164378
Dioxin-like
PCBs
RA 326 ngg
lipid
250 219 220 17589595
PAHs Asthma 124 ngm3 935 200 483 19221603
The Potency of Arsenic
Disease Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Bladder CA 10ugL H20 100 27 145 24889821
Pancreatic CA 1332 ugg 200 246 230 23800676
Prostate CA 1332 ugg 200 33 315 23800676
Gout 125 ugL 245 546 522 25499256
Diabetes 165 ugL 200 21 180 18714061
Arsenic (180 of Diabetes)
How it causes diabetes
bull Blocks sugar stimulating insulin secretion
bull Epigenetic inhibition of sugar regulation
Where it comes from
bull Water (gt10 of US water supplies have high levels)
bull Rice (naturally absorbs if in the water)
bull Chicken (added to make meat whiter)
Pan W-C Seow WJ Kile ML et al Association of low to moderate levels of arsenic exposure with risk of Type 2 diabetes in Bangladesh American Journal of Epidemiology 2013178(10)1563-70
Portion of Population with Toxin Load Which
Doubles Disease Risk
Toxin Disease with Doubled Risk
Polycyclic aromatic hydrocarbons Asthma 94
PCB187 Breast Cancer 60
Phthalates Diabetes 55
Lead ALS 33
Aluminum Alzheimers Disease 25
DDT ADHD 25
PCBs Diabetes 25
Dioxin-like PCBs Rheumatoid Arthritis 25
Arsenic Gout 23
Bisphenol A Diabetes 22
Cigarette smoking Lung Cancer 21
Arsenic Diabetes 20
Polycyclic aromatic hydrocarbons Diabetes 20
Huge Detoxification Variability
bull CYP2C19
Proton pump inhibitors and some antidepressants
5-fold difference in activity between poor metabolizers and extensive metabolizers more so if CYP3A4 is also inhibited
Ultrarapid allele in 18 of both Swedes and Ethiopians
bull CYP2D6
Metabolizes a large number of drugs (~25)
7 of Caucasians poor metabolizers
~30 ultra rapid metabolizers in Arabian and Eastern African populations
More adverse effects in poor metabolizers and ineffective dosing in ultrarapid metabolizers
Inhibited by ginger
Desta Z et al Clinical significance of the cytochrome P450 2C19 genetic polymorphism Clin Pharmaco 2002
Sim SC et al A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug
response to proton pump inhibitors and antidepressants Clin Pharmacol Ther 2006
Wilkinson GR Drug metabolism and variability among patients in drug response N Engl J Med 2005
Kirchheiner J et al Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to
CYP2D6 duplication Pharmacogenomics J 2007
Toxin Half Lives in BloodToxin ldquoNormalrdquo (mgL) Acute Toxic (mgL) Half-Life
Arsenic 0002-007 005-025 2-4 days (CDC)
Benzene 00002 05-10 days
Cadmium 00003-00065 0015-005 16 years
Chlordane 0001 00025 3-4 days
DDTDDE 2-10 years
Dieldrin 00015 015-030 2-12 months
Ethanol 1000-2000 15hour
Lead 009 04-06 1-15 mo (2+ yrs bone)
Mercury 00015-0002 005-02 2 months (CDC)
PCBs 3-25 years
Toluene 05-3 days
Schulz M et al Therapeutic and toxic blood concentrations of nearly 1000 drugs and other xenobiotics Crit Care 2012 Jul 2616(4)R136
Bioaccumulation (POPs)
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
DDT banned in 1972 PCBs banned in 1977
Bioaccumulation (Cd)
Think BroadlyExogenous
Metals
Chemicalsbull Inorganic
bull Fluoride
bull Organic
bull POPs
bull Drugs
Particulate matter
Molds
Microbial
Radiationbull Light
bull Medical
bull Cell phone
Endogenous
Gut-derived toxins
Non-end product metabolites
Poorly detoxified hormones
Catecholamines (if SNP)
Toxins of Choice
Alcohol
Marijuana
Food constituents
High fructose corn syrup
Salt (acid-forming diet)
Wheat if zonulin (70)
Obesity Epidemic ndash POPs AND HFCS
47Bray GA Fructose should we worry Int J Obes (Lond) 2008 Dec32 Suppl 7S127-31
How Toxins Cause Damage 13
bull Increase free radical production
Cd induces production of ROS
Malathion inhibits catalase and glutathione peroxidase
Homocysteine oxidizes LDL cholesterol
bull Poison enzyme systems (compete with nutritional cofactors for binding sites)
Pb poisons delta aminolevulinic acid dehydratase
Cd inhibits catalase glutathione reductase and lowers
glutathione levels
bull Replace structural minerals
Pb displaces Ca in bone
How Toxins Cause Damage 23
bull Damage DNA
Benzene - causes chromosomal damage
Pesticides ndash fruit growers have more DNA damage
Phthalates and insecticides ndash damage sperm DNA
4-hydroxy catechol estrogen (4-OHE) damages breast DNA
bull Epigenetic dysmodulation
Higher cord blood levels of hexachlorobenzene associated
with 2x greater risk for obesity in children
bull Damage cell membranes
Common mechanism for heavy metals inactivates
membrane enzymes ion channels and pumps
How Toxins Cause Damage 33
bull Block insulin receptor sites
PCBs and phthalates
bull Highest levels associated with a 4 to 20-fold greater diabetes risk
bull Imbalance hormones many toxin examples
Arsenic
bull Disrupts thyroid hormone and retinoic acid receptors
Phthalates
bull Act as anti-androgens
bull More than 75 of the US population has measurable levels of
several phthalate metabolites in the urine
PCBs
bull Lower testosterone levels in men
Which are the Worst Toxins
bull According to the CDC
Toxicity
Population toxic load
Prevalence in toxic waste sites
bull According to clinical importance
Exposure
of disease
Ability of the body to detoxifyexcrete
Ag
en
cy
fo
r T
oxic
Su
bs
tan
ce
s a
nd
Dis
ea
se
Reg
istr
y
Pri
ori
ty L
ist
The Worst Toxins Clinically
My Rank Toxin Diseases Primary Sources
1 Arsenic Cancers diabetes gout Water chicken rice
2 DDT ADHD dementia diabetes Everywhere
3 Phthalates ADHD diabetes Soft plastics HABAs
4 PBDEs ADHD diabetes Flame retardant fabrics
5 PAHs ADHD cancers dyslipidemia Smoking charbroiling
6 PCBs Cancers diabetes MI RA Everywhere
7 Mercury Dementia ldquoSilverrdquo fillings fish
8 Lead Cardiovascular disease IQ Paint water
Glyphosate Research invalid
Conventional Laboratory Tests Reflect
Toxic Load in ldquoNormalrdquo Range
bull Surprising number show toxin exposure
CBC RBC WBC platelet count hemoglobin basophilic
stippling
Liver enzymes ALT GGTP
Inflammatory markers CRP
Lipids LDL oxLDL triglycerides
Blood sugar insulin FBS 2-hour PP
Metabolites bilirubin uric acid homocysteine 8-OHdG
Thyroid T3 T4 TSH
bull The historic ldquonormalrdquo range has been changing as the population has become more toxic
WBC Lowered by PCB and OCP Exposure
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
0
1
2
3
4
5
6
7
8
1st Quartrile 2nd Quartile 3rd Quartile 4th Quartile
WBCbull Strong inverse correlation with PCBs and OCPs and CBC
bull Linear with almost all PCBs
bull High variability with OCPs
bull Within ldquonormalrdquo range
Effects on WBC Worsen with Years
of Exposure to Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Platelet Count Decreases with Years
of Exposure tp Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Solvents Decrease Platelet Count
bull Compared workers exposed 23 hrday to those exposed most of day to toluene
bull All wore face masks and protective gear
bull Platelet count 14 lower 252 versus 216ml
bull Impairment of sympathetic nerves (OR = 413)
bull Impairment of peripheral nerves (OR = 694)
bull Positive relationship between neurological abnormalities and a self-reported neuropsychiatric measurement (r = 035-066)
Shih HT et al Subclinical abnormalities in workers with continuous low-level toluene exposure Toxicol Ind Health 2011 Sep27(8)691-9
Basophilic Stippling of Red Cells
Toxinsbull Arsenic
bull Lead
Diseasesbull Alpha-thalassemia HbH Disease
bull Beta thalassemia
bull Hereditary pyrimidine 5-nucleotidase deficiency
bull Myelodysplastic syndrome
bull Sideroblastic anemia
bull Thrombotic thrombocytopenic purpura
GGT Indirect Measure of POPsbull Glutathione is key intracellular defense against oxidative stress
bull Cellular GGT metabolizes extracellular GSH allowing precursor amino acids to be reutilized for intracellular GSH
bull Exposure to POPs induces GGT as a defensive mechanism
bull Within normal range predicts type 2 diabetes coronary heart disease hypertension stroke dyslipidemia chronic kidney disease and cancer
bull Men with GGT gt50 UI had ~26 fold risk for diabetes compared to those with lt10 Those with 40-49 had a ~20 fold risk
bull Levels within normal range occur with obesity xs alcohol cigarette smoking physical inactivity high meat low fruit and vegetable intake
bull Cumulative biomarker for environmental pollutants
Lee DH et al (2003) Gamma-glutamyltransferase and diabetesmdasha 4 year follow-up study Diabetologia 46359ndash364
Pamela A et al Serum gamma-glutamyltransferase linking together environmental pollution redox equilibria and progression of atherosclerosis Clin Chem
Lab Med 200947(12)1583-4
Lee DH et al Serum gamma-glutamyltransferase new insights about an old enzyme J Epidemiol Community Health 2009 Nov63(11)884-6
Lee DH et alSerum gamma-glutamyltransferase predicts non-fatal myocardial infarction and fatal coronary heart disease among 28838 middle-aged men and
women Eur Heart J 2006272170ndash6
Lee DH et al Gamma-glutamyltransferase and diabetes--a 4 year follow-up study Diabetologia 2003 Mar46(3)359-64
Lee DH et al Can persistent organic pollutants explain the association between serum gamma-glutamyltransferase and type 2 diabetes Diabetologia 2008
Mar51(3)402-7
GGT and Alcohol Consumption
bull GGT directly correlates with alcohol consumption
bull In a non-uniform population 40 gd will elevate GGT ~15
bull Watch for false negatives
bull Genomic variation
bull Are these the ones most
sensitive todamaged by
chemical toxins
bull Could up-regulation of GGT in light alcohol consumption be reason for benefit
0
10
20
30
40
50
60
70
80
0 200 400 600 800
Grams of Ethanol per Week
Adapted from Nagaya T et al Dose-response relationships between drinking and serum tests in Japanese men
aged 40ndash59 years Alcohol 1999 Feb 17(2) 133ndash8
GGT Correlates With Toxic Metal Levels
Lee DH et al Graded associations of blood lead and urinary cadmium concentrations with oxidative-stress-related markers in the
US population results from the third National Health and Nutrition Examination Survey Environ Health
perspect 2006 Mar114(3)350-4
GGT and Diabetes Risk
0
5
10
15
20
25
30
lt10 10-19 20-29 30-39 40-49 gt50
Dia
bete
s R
isk
GGT
bull GGT over 50 associated with tripling of death rate
bull 30-40 associated with doubling
GGT Levels
Correlate with
Risk of Death
Brenner H et al Distribution determinants and prognostic value of gamma-glutamyltransferase for all-cause
mortality in a cohort of construction workers from southern Germany Prev Med 1997 26 305ndash10
GGT From Small US Company
with Young Workers
0
10
20
30
40
50
60
0 20 40 60 80 100
GGT Data from Canadian Oil Field
Workers
0
50
100
150
200
250
300
350
400
450
lt10 10-20 20-30 30-40 40-50 50-60 60-07 70-80 80-90 90-100 100-110 110-120 gt120
GGTP
20-fold increased risk of diabetes
Uric Acid Indirect Measure of POPs
bull Poly-fluorinated hydrocarbons (PFOA and PFOS) associated
with increased serum uric acid
Lin CY et al Association among serum perfluoroalkyl chemicals glucose homeostasis and metabolic syndrome
in adolescents and adults Diabetes Care 2009 Apr32(4)702-7
Steenland K et al Association of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) with uric
acid among adults with elevated community exposure to PFOA Environ Health Perspect 2010 Feb118229-33
Steenland 2010 Open Access
ALT Indirect Measure of POPs
bull ALT (proxy marker) elevation in 104 (not including viral
hepatitis hemochromatosis or alcoholic liver disease) of
NHANES 03-04 subset
bull Risk of elevated ALT increased dose-dependently with
cadmium lead mercury and PCB exposure
bull 100 of individuals had detectable PCBs 925 mercury
and 996 had detectable lead
bull In 2005-08 prevalence of NAFLD in US was 11 a
growing cause of chronic liver disease
Cave M et al Polychlorinated biphenyls lead and mercury are associated with liver disease in American adults
NHANES 2003-2004 Environ Health Perspect 2010 Dec118(12)1735-42
Younossi ZM et al Changes in the prevalence of the most common causes of chronic liver diseases in the United
States from 1988 to 2008 Clin Gastroenterol Hepatol 2011 Jun9(6)524-530e1
Bilirubin as a Marker of POPs
bull Degree of serum bilirubin increase is prognostically significant in chronic liver dysfunction
bull Mono-ortho PCB TEQ values were found to be significantly positively associated with bilirubin (β=071 P=0008) following adjustment for multiple potential confounders
bull Bilirubin levels significantly correlated with PCBs -105-118-126 and -194
bull Smoking appears to be the biggest confounder
Dufour DR et al 2000 Diagnosis and monitoring of hepatic injury II Recommendations for use of laboratory
tests in screening diagnosis and monitoring Clin Chem 46 2050ndash68
Kumar J et al Persistent organic pollutants and liver dysfunction biomarkers in a population-based human sample
of men and women Environ Res 2014134251-256
Perf
luo
rin
ate
dP
OP
s a
nd
Co
mm
on
Blo
od
Tests
Gleason JA et al Associations of perfluorinated chemical serum concentrations and biomarkers of liver function and uric acid in the
US population (NHANES) 2007-2010 Environ Res 20151368-14
Liver Enzymes Reflect Toxic Load
bull AST ALT and GGT increase with body load of PCBs and OCPs
bull Some non-linear
bull Oxychlordanetop quartile
ALT 10
GGT 25
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
LDL-Cholesterol as Measure of POPs
bull 5-year prospective study to determine if POP levels predict future elevation in LDL-cholesterol
bull 598 subjects initially at age 70
bull Looked at 23 POPs
bull Best correlation with PCB 194
Penell J Lind L Salihovic S et al Persistent organic pollutants are related to change in circulating
lipid levels during a 5 year follow-up Environ Res 134(2014)190ndash197
oxLDL as Measure of POPs
bull 992 70-year old individuals (50 women)
bull Sum of PCBs showed strong significant positive associations with ox-LDL and significant negative associations with glutathione-related markers (GSSG and GSSGGSH)
bull A number of POPs (PCB-99 138 153 156 170 180 194 206 and 209) showed strong significant positive association with ox-LDL
Kumar J et al Influence of persistent organic pollutants on oxidative stress in population-based samples
Chemosphere 2014114303-309
Homocysteine is Increased by Pb amp Cd
Guallar E et al Confounding of the relation between homocysteine and peripheral arterial disease by lead cadmium and renal function Am J Epidemiol 2006 Apr 15163(8)700-8
Nutrient Deficiencies Accentuate
Effects of Lead on Homocysteine
bull Deficiencies in folate B6 or B12 make lead more toxic
Lee YM Et al Association of homocysteine levels with blood lead levels and micronutrients in the US general population J Prev Med Public Health 2012 Nov45(6)387-93
T4 amp T3 and PCBs
bull PCBs decrease T4 production
bull PCBs inhibit iodotyrosinedeiodinase activity
bull Study done in pregnant women which implies effect on fetus IQ
Kim S Park J Kim HJ et al Association between several persistent organic pollutants and thyroid hormone levels in serum among the pregnant women of Korea Environ Int 2013 Sep59442-8Shimizu R Yamaguchi M Uramaru N et al Structure-activity relationships of 44 halogenated compounds for iodotyrosinedeiodinase-inhibitory activity Toxicology 2013 Dec 6314(1)22-9
T4 amp T3 and PCBs
bull Not just humans being affected
bull Large study of dolphins shows exactly the same effects
Schwacke LH Zolman ES Balmer BC et al Anaemia hypothyroidism and immune suppression associated with polychlorinated biphenyl exposure in bottlenose dolphins (Tursiops truncatus) Proceed Royal Society B doi101098rspb20110665
8-OHdG
bull Oxidized nucleoside
bull Direct measure of DNA damage
bull Indirect measure of oxidative stress and toxin load
bull Correlates with
Multiple cancers
Mitochondrial damage
Rate of aging
Smoking
Several toxinsWalter Crinnion ldquoTotal Toxic Loadrdquo AANP 2015
8-OHdG Correlates with Pack-Years
of Smoking
Yano T et al Significance of the urinary 8-OHdG level as an oxidative stress marker in lung cancer patients Lung Cancer
2009 Jan63(1)111-4
8-OHdG Correlates
with Mercury
Chen C et al Increased oxidative DNA damage as assessed by urinary 8-hydroxy-2-deoxyguanosine
concentrations and serum redox status in persons exposed to mercury Clin Chem 2005 Apr51(4)759-67
Toxin Effects Worse with Aging
bull Thyroid function decreases with PFOA levels
bull But only after age 63
Shrestha S Bloom MS Yucel R et al Perfluoroalkyl substances and thyroid function in older adults Environ Int 2015 Feb75206-14
Insightful 23-Year Prospective Study
1 lt 50 there is no difference between those with the lowest and highest PCBs
2 In youngest group insulin production increases in response to toxin level As expected since blocking of
insulin receptor sites by PCBs
requires more insulin
3 That adaptive ability decreases with aging
4 At age 50 all the measures show very strong toxin-dose response
Cumulative damage impairs ability to adapt
Suarez-Lopez JR et al Persistent organic pollutants in young adults and changes in glucose related metabolism over a 23-year follow-up Environ Res 2015 Feb137485-94
Recommendations
High body toxic load
GGT gt 25
Uric acid gt 50 mgdl
ALT gt30 UL
Bilirubin gt08 mgdl
CBC lt 6000
Platelet lt 250000
Low T3 andor T4
Monitor Total Toxic Load
8-OHdG gt4
ldquoUnconventionalrdquo Laboratory Tests
bull Challenge testing
bull Hair analysis
bull Direct measures of solvents and POPs in blood urine adipose tissue
Evaluation of Metal Exposure ndash Provocation
bull Provocation ndash the use of a chelating agent ndash before urine collection often done clinically but several limitations
No ldquoofficialrdquo reference range for provoked urine
Most chelating agents do not extract metals from all tissues thus
does not necessarily represent total body burden
bull Example Brain is one of the main target organs for both elemental and organic
mercury yet agents do not chelate brain mercury
bull Despite limitations widely used and advocated by clinicians in part to see efficacy of chelating agent as a guide to treatment and based on empirical evidence
Rooney JP The role of thiols dithiols nutritional factors and interacting ligands in the toxicology of mercury
Toxicology 2007
Is Challenge Testing Valid
bull Poor correlations of standard tests for mercury
bull Unpublished research from corporate wellness project
bull Published amalgam number correlation
bull Published fish consumption correlation
What We Found In Canada
bull Deviations from the mean of 14 29 and 91 respectively
bull DMPS is spreading distribution suggesting that it is better at differentiating mercury body load
bull Some VERY high
Hg Assessment Correlations
bull Extensive measurements in 65 Whole blood Hg
Oral DMPS challenge
Amalgam surfaces
bull Correlations Whole blood w pre urine r = 040
Whole blood w post urine r = 057
Pre urine w post urine r = 068
Amalgams w pre urine r = 026
Amalgams w whole blood r = 036
Amalgams with post urine 044
bull Clear documentation that
challenge testing is better00
100
200
300
400
500
600
0 10 20 30 40 50
Po
st
Uri
ne H
g u
gg
Number of amalgams
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
The Potency of Arsenic
Disease Threshold Above
Threshold
Odds Ratio of Dz Reference
PMID
Bladder CA 10ugL H20 100 27 145 24889821
Pancreatic CA 1332 ugg 200 246 230 23800676
Prostate CA 1332 ugg 200 33 315 23800676
Gout 125 ugL 245 546 522 25499256
Diabetes 165 ugL 200 21 180 18714061
Arsenic (180 of Diabetes)
How it causes diabetes
bull Blocks sugar stimulating insulin secretion
bull Epigenetic inhibition of sugar regulation
Where it comes from
bull Water (gt10 of US water supplies have high levels)
bull Rice (naturally absorbs if in the water)
bull Chicken (added to make meat whiter)
Pan W-C Seow WJ Kile ML et al Association of low to moderate levels of arsenic exposure with risk of Type 2 diabetes in Bangladesh American Journal of Epidemiology 2013178(10)1563-70
Portion of Population with Toxin Load Which
Doubles Disease Risk
Toxin Disease with Doubled Risk
Polycyclic aromatic hydrocarbons Asthma 94
PCB187 Breast Cancer 60
Phthalates Diabetes 55
Lead ALS 33
Aluminum Alzheimers Disease 25
DDT ADHD 25
PCBs Diabetes 25
Dioxin-like PCBs Rheumatoid Arthritis 25
Arsenic Gout 23
Bisphenol A Diabetes 22
Cigarette smoking Lung Cancer 21
Arsenic Diabetes 20
Polycyclic aromatic hydrocarbons Diabetes 20
Huge Detoxification Variability
bull CYP2C19
Proton pump inhibitors and some antidepressants
5-fold difference in activity between poor metabolizers and extensive metabolizers more so if CYP3A4 is also inhibited
Ultrarapid allele in 18 of both Swedes and Ethiopians
bull CYP2D6
Metabolizes a large number of drugs (~25)
7 of Caucasians poor metabolizers
~30 ultra rapid metabolizers in Arabian and Eastern African populations
More adverse effects in poor metabolizers and ineffective dosing in ultrarapid metabolizers
Inhibited by ginger
Desta Z et al Clinical significance of the cytochrome P450 2C19 genetic polymorphism Clin Pharmaco 2002
Sim SC et al A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug
response to proton pump inhibitors and antidepressants Clin Pharmacol Ther 2006
Wilkinson GR Drug metabolism and variability among patients in drug response N Engl J Med 2005
Kirchheiner J et al Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to
CYP2D6 duplication Pharmacogenomics J 2007
Toxin Half Lives in BloodToxin ldquoNormalrdquo (mgL) Acute Toxic (mgL) Half-Life
Arsenic 0002-007 005-025 2-4 days (CDC)
Benzene 00002 05-10 days
Cadmium 00003-00065 0015-005 16 years
Chlordane 0001 00025 3-4 days
DDTDDE 2-10 years
Dieldrin 00015 015-030 2-12 months
Ethanol 1000-2000 15hour
Lead 009 04-06 1-15 mo (2+ yrs bone)
Mercury 00015-0002 005-02 2 months (CDC)
PCBs 3-25 years
Toluene 05-3 days
Schulz M et al Therapeutic and toxic blood concentrations of nearly 1000 drugs and other xenobiotics Crit Care 2012 Jul 2616(4)R136
Bioaccumulation (POPs)
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
DDT banned in 1972 PCBs banned in 1977
Bioaccumulation (Cd)
Think BroadlyExogenous
Metals
Chemicalsbull Inorganic
bull Fluoride
bull Organic
bull POPs
bull Drugs
Particulate matter
Molds
Microbial
Radiationbull Light
bull Medical
bull Cell phone
Endogenous
Gut-derived toxins
Non-end product metabolites
Poorly detoxified hormones
Catecholamines (if SNP)
Toxins of Choice
Alcohol
Marijuana
Food constituents
High fructose corn syrup
Salt (acid-forming diet)
Wheat if zonulin (70)
Obesity Epidemic ndash POPs AND HFCS
47Bray GA Fructose should we worry Int J Obes (Lond) 2008 Dec32 Suppl 7S127-31
How Toxins Cause Damage 13
bull Increase free radical production
Cd induces production of ROS
Malathion inhibits catalase and glutathione peroxidase
Homocysteine oxidizes LDL cholesterol
bull Poison enzyme systems (compete with nutritional cofactors for binding sites)
Pb poisons delta aminolevulinic acid dehydratase
Cd inhibits catalase glutathione reductase and lowers
glutathione levels
bull Replace structural minerals
Pb displaces Ca in bone
How Toxins Cause Damage 23
bull Damage DNA
Benzene - causes chromosomal damage
Pesticides ndash fruit growers have more DNA damage
Phthalates and insecticides ndash damage sperm DNA
4-hydroxy catechol estrogen (4-OHE) damages breast DNA
bull Epigenetic dysmodulation
Higher cord blood levels of hexachlorobenzene associated
with 2x greater risk for obesity in children
bull Damage cell membranes
Common mechanism for heavy metals inactivates
membrane enzymes ion channels and pumps
How Toxins Cause Damage 33
bull Block insulin receptor sites
PCBs and phthalates
bull Highest levels associated with a 4 to 20-fold greater diabetes risk
bull Imbalance hormones many toxin examples
Arsenic
bull Disrupts thyroid hormone and retinoic acid receptors
Phthalates
bull Act as anti-androgens
bull More than 75 of the US population has measurable levels of
several phthalate metabolites in the urine
PCBs
bull Lower testosterone levels in men
Which are the Worst Toxins
bull According to the CDC
Toxicity
Population toxic load
Prevalence in toxic waste sites
bull According to clinical importance
Exposure
of disease
Ability of the body to detoxifyexcrete
Ag
en
cy
fo
r T
oxic
Su
bs
tan
ce
s a
nd
Dis
ea
se
Reg
istr
y
Pri
ori
ty L
ist
The Worst Toxins Clinically
My Rank Toxin Diseases Primary Sources
1 Arsenic Cancers diabetes gout Water chicken rice
2 DDT ADHD dementia diabetes Everywhere
3 Phthalates ADHD diabetes Soft plastics HABAs
4 PBDEs ADHD diabetes Flame retardant fabrics
5 PAHs ADHD cancers dyslipidemia Smoking charbroiling
6 PCBs Cancers diabetes MI RA Everywhere
7 Mercury Dementia ldquoSilverrdquo fillings fish
8 Lead Cardiovascular disease IQ Paint water
Glyphosate Research invalid
Conventional Laboratory Tests Reflect
Toxic Load in ldquoNormalrdquo Range
bull Surprising number show toxin exposure
CBC RBC WBC platelet count hemoglobin basophilic
stippling
Liver enzymes ALT GGTP
Inflammatory markers CRP
Lipids LDL oxLDL triglycerides
Blood sugar insulin FBS 2-hour PP
Metabolites bilirubin uric acid homocysteine 8-OHdG
Thyroid T3 T4 TSH
bull The historic ldquonormalrdquo range has been changing as the population has become more toxic
WBC Lowered by PCB and OCP Exposure
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
0
1
2
3
4
5
6
7
8
1st Quartrile 2nd Quartile 3rd Quartile 4th Quartile
WBCbull Strong inverse correlation with PCBs and OCPs and CBC
bull Linear with almost all PCBs
bull High variability with OCPs
bull Within ldquonormalrdquo range
Effects on WBC Worsen with Years
of Exposure to Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Platelet Count Decreases with Years
of Exposure tp Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Solvents Decrease Platelet Count
bull Compared workers exposed 23 hrday to those exposed most of day to toluene
bull All wore face masks and protective gear
bull Platelet count 14 lower 252 versus 216ml
bull Impairment of sympathetic nerves (OR = 413)
bull Impairment of peripheral nerves (OR = 694)
bull Positive relationship between neurological abnormalities and a self-reported neuropsychiatric measurement (r = 035-066)
Shih HT et al Subclinical abnormalities in workers with continuous low-level toluene exposure Toxicol Ind Health 2011 Sep27(8)691-9
Basophilic Stippling of Red Cells
Toxinsbull Arsenic
bull Lead
Diseasesbull Alpha-thalassemia HbH Disease
bull Beta thalassemia
bull Hereditary pyrimidine 5-nucleotidase deficiency
bull Myelodysplastic syndrome
bull Sideroblastic anemia
bull Thrombotic thrombocytopenic purpura
GGT Indirect Measure of POPsbull Glutathione is key intracellular defense against oxidative stress
bull Cellular GGT metabolizes extracellular GSH allowing precursor amino acids to be reutilized for intracellular GSH
bull Exposure to POPs induces GGT as a defensive mechanism
bull Within normal range predicts type 2 diabetes coronary heart disease hypertension stroke dyslipidemia chronic kidney disease and cancer
bull Men with GGT gt50 UI had ~26 fold risk for diabetes compared to those with lt10 Those with 40-49 had a ~20 fold risk
bull Levels within normal range occur with obesity xs alcohol cigarette smoking physical inactivity high meat low fruit and vegetable intake
bull Cumulative biomarker for environmental pollutants
Lee DH et al (2003) Gamma-glutamyltransferase and diabetesmdasha 4 year follow-up study Diabetologia 46359ndash364
Pamela A et al Serum gamma-glutamyltransferase linking together environmental pollution redox equilibria and progression of atherosclerosis Clin Chem
Lab Med 200947(12)1583-4
Lee DH et al Serum gamma-glutamyltransferase new insights about an old enzyme J Epidemiol Community Health 2009 Nov63(11)884-6
Lee DH et alSerum gamma-glutamyltransferase predicts non-fatal myocardial infarction and fatal coronary heart disease among 28838 middle-aged men and
women Eur Heart J 2006272170ndash6
Lee DH et al Gamma-glutamyltransferase and diabetes--a 4 year follow-up study Diabetologia 2003 Mar46(3)359-64
Lee DH et al Can persistent organic pollutants explain the association between serum gamma-glutamyltransferase and type 2 diabetes Diabetologia 2008
Mar51(3)402-7
GGT and Alcohol Consumption
bull GGT directly correlates with alcohol consumption
bull In a non-uniform population 40 gd will elevate GGT ~15
bull Watch for false negatives
bull Genomic variation
bull Are these the ones most
sensitive todamaged by
chemical toxins
bull Could up-regulation of GGT in light alcohol consumption be reason for benefit
0
10
20
30
40
50
60
70
80
0 200 400 600 800
Grams of Ethanol per Week
Adapted from Nagaya T et al Dose-response relationships between drinking and serum tests in Japanese men
aged 40ndash59 years Alcohol 1999 Feb 17(2) 133ndash8
GGT Correlates With Toxic Metal Levels
Lee DH et al Graded associations of blood lead and urinary cadmium concentrations with oxidative-stress-related markers in the
US population results from the third National Health and Nutrition Examination Survey Environ Health
perspect 2006 Mar114(3)350-4
GGT and Diabetes Risk
0
5
10
15
20
25
30
lt10 10-19 20-29 30-39 40-49 gt50
Dia
bete
s R
isk
GGT
bull GGT over 50 associated with tripling of death rate
bull 30-40 associated with doubling
GGT Levels
Correlate with
Risk of Death
Brenner H et al Distribution determinants and prognostic value of gamma-glutamyltransferase for all-cause
mortality in a cohort of construction workers from southern Germany Prev Med 1997 26 305ndash10
GGT From Small US Company
with Young Workers
0
10
20
30
40
50
60
0 20 40 60 80 100
GGT Data from Canadian Oil Field
Workers
0
50
100
150
200
250
300
350
400
450
lt10 10-20 20-30 30-40 40-50 50-60 60-07 70-80 80-90 90-100 100-110 110-120 gt120
GGTP
20-fold increased risk of diabetes
Uric Acid Indirect Measure of POPs
bull Poly-fluorinated hydrocarbons (PFOA and PFOS) associated
with increased serum uric acid
Lin CY et al Association among serum perfluoroalkyl chemicals glucose homeostasis and metabolic syndrome
in adolescents and adults Diabetes Care 2009 Apr32(4)702-7
Steenland K et al Association of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) with uric
acid among adults with elevated community exposure to PFOA Environ Health Perspect 2010 Feb118229-33
Steenland 2010 Open Access
ALT Indirect Measure of POPs
bull ALT (proxy marker) elevation in 104 (not including viral
hepatitis hemochromatosis or alcoholic liver disease) of
NHANES 03-04 subset
bull Risk of elevated ALT increased dose-dependently with
cadmium lead mercury and PCB exposure
bull 100 of individuals had detectable PCBs 925 mercury
and 996 had detectable lead
bull In 2005-08 prevalence of NAFLD in US was 11 a
growing cause of chronic liver disease
Cave M et al Polychlorinated biphenyls lead and mercury are associated with liver disease in American adults
NHANES 2003-2004 Environ Health Perspect 2010 Dec118(12)1735-42
Younossi ZM et al Changes in the prevalence of the most common causes of chronic liver diseases in the United
States from 1988 to 2008 Clin Gastroenterol Hepatol 2011 Jun9(6)524-530e1
Bilirubin as a Marker of POPs
bull Degree of serum bilirubin increase is prognostically significant in chronic liver dysfunction
bull Mono-ortho PCB TEQ values were found to be significantly positively associated with bilirubin (β=071 P=0008) following adjustment for multiple potential confounders
bull Bilirubin levels significantly correlated with PCBs -105-118-126 and -194
bull Smoking appears to be the biggest confounder
Dufour DR et al 2000 Diagnosis and monitoring of hepatic injury II Recommendations for use of laboratory
tests in screening diagnosis and monitoring Clin Chem 46 2050ndash68
Kumar J et al Persistent organic pollutants and liver dysfunction biomarkers in a population-based human sample
of men and women Environ Res 2014134251-256
Perf
luo
rin
ate
dP
OP
s a
nd
Co
mm
on
Blo
od
Tests
Gleason JA et al Associations of perfluorinated chemical serum concentrations and biomarkers of liver function and uric acid in the
US population (NHANES) 2007-2010 Environ Res 20151368-14
Liver Enzymes Reflect Toxic Load
bull AST ALT and GGT increase with body load of PCBs and OCPs
bull Some non-linear
bull Oxychlordanetop quartile
ALT 10
GGT 25
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
LDL-Cholesterol as Measure of POPs
bull 5-year prospective study to determine if POP levels predict future elevation in LDL-cholesterol
bull 598 subjects initially at age 70
bull Looked at 23 POPs
bull Best correlation with PCB 194
Penell J Lind L Salihovic S et al Persistent organic pollutants are related to change in circulating
lipid levels during a 5 year follow-up Environ Res 134(2014)190ndash197
oxLDL as Measure of POPs
bull 992 70-year old individuals (50 women)
bull Sum of PCBs showed strong significant positive associations with ox-LDL and significant negative associations with glutathione-related markers (GSSG and GSSGGSH)
bull A number of POPs (PCB-99 138 153 156 170 180 194 206 and 209) showed strong significant positive association with ox-LDL
Kumar J et al Influence of persistent organic pollutants on oxidative stress in population-based samples
Chemosphere 2014114303-309
Homocysteine is Increased by Pb amp Cd
Guallar E et al Confounding of the relation between homocysteine and peripheral arterial disease by lead cadmium and renal function Am J Epidemiol 2006 Apr 15163(8)700-8
Nutrient Deficiencies Accentuate
Effects of Lead on Homocysteine
bull Deficiencies in folate B6 or B12 make lead more toxic
Lee YM Et al Association of homocysteine levels with blood lead levels and micronutrients in the US general population J Prev Med Public Health 2012 Nov45(6)387-93
T4 amp T3 and PCBs
bull PCBs decrease T4 production
bull PCBs inhibit iodotyrosinedeiodinase activity
bull Study done in pregnant women which implies effect on fetus IQ
Kim S Park J Kim HJ et al Association between several persistent organic pollutants and thyroid hormone levels in serum among the pregnant women of Korea Environ Int 2013 Sep59442-8Shimizu R Yamaguchi M Uramaru N et al Structure-activity relationships of 44 halogenated compounds for iodotyrosinedeiodinase-inhibitory activity Toxicology 2013 Dec 6314(1)22-9
T4 amp T3 and PCBs
bull Not just humans being affected
bull Large study of dolphins shows exactly the same effects
Schwacke LH Zolman ES Balmer BC et al Anaemia hypothyroidism and immune suppression associated with polychlorinated biphenyl exposure in bottlenose dolphins (Tursiops truncatus) Proceed Royal Society B doi101098rspb20110665
8-OHdG
bull Oxidized nucleoside
bull Direct measure of DNA damage
bull Indirect measure of oxidative stress and toxin load
bull Correlates with
Multiple cancers
Mitochondrial damage
Rate of aging
Smoking
Several toxinsWalter Crinnion ldquoTotal Toxic Loadrdquo AANP 2015
8-OHdG Correlates with Pack-Years
of Smoking
Yano T et al Significance of the urinary 8-OHdG level as an oxidative stress marker in lung cancer patients Lung Cancer
2009 Jan63(1)111-4
8-OHdG Correlates
with Mercury
Chen C et al Increased oxidative DNA damage as assessed by urinary 8-hydroxy-2-deoxyguanosine
concentrations and serum redox status in persons exposed to mercury Clin Chem 2005 Apr51(4)759-67
Toxin Effects Worse with Aging
bull Thyroid function decreases with PFOA levels
bull But only after age 63
Shrestha S Bloom MS Yucel R et al Perfluoroalkyl substances and thyroid function in older adults Environ Int 2015 Feb75206-14
Insightful 23-Year Prospective Study
1 lt 50 there is no difference between those with the lowest and highest PCBs
2 In youngest group insulin production increases in response to toxin level As expected since blocking of
insulin receptor sites by PCBs
requires more insulin
3 That adaptive ability decreases with aging
4 At age 50 all the measures show very strong toxin-dose response
Cumulative damage impairs ability to adapt
Suarez-Lopez JR et al Persistent organic pollutants in young adults and changes in glucose related metabolism over a 23-year follow-up Environ Res 2015 Feb137485-94
Recommendations
High body toxic load
GGT gt 25
Uric acid gt 50 mgdl
ALT gt30 UL
Bilirubin gt08 mgdl
CBC lt 6000
Platelet lt 250000
Low T3 andor T4
Monitor Total Toxic Load
8-OHdG gt4
ldquoUnconventionalrdquo Laboratory Tests
bull Challenge testing
bull Hair analysis
bull Direct measures of solvents and POPs in blood urine adipose tissue
Evaluation of Metal Exposure ndash Provocation
bull Provocation ndash the use of a chelating agent ndash before urine collection often done clinically but several limitations
No ldquoofficialrdquo reference range for provoked urine
Most chelating agents do not extract metals from all tissues thus
does not necessarily represent total body burden
bull Example Brain is one of the main target organs for both elemental and organic
mercury yet agents do not chelate brain mercury
bull Despite limitations widely used and advocated by clinicians in part to see efficacy of chelating agent as a guide to treatment and based on empirical evidence
Rooney JP The role of thiols dithiols nutritional factors and interacting ligands in the toxicology of mercury
Toxicology 2007
Is Challenge Testing Valid
bull Poor correlations of standard tests for mercury
bull Unpublished research from corporate wellness project
bull Published amalgam number correlation
bull Published fish consumption correlation
What We Found In Canada
bull Deviations from the mean of 14 29 and 91 respectively
bull DMPS is spreading distribution suggesting that it is better at differentiating mercury body load
bull Some VERY high
Hg Assessment Correlations
bull Extensive measurements in 65 Whole blood Hg
Oral DMPS challenge
Amalgam surfaces
bull Correlations Whole blood w pre urine r = 040
Whole blood w post urine r = 057
Pre urine w post urine r = 068
Amalgams w pre urine r = 026
Amalgams w whole blood r = 036
Amalgams with post urine 044
bull Clear documentation that
challenge testing is better00
100
200
300
400
500
600
0 10 20 30 40 50
Po
st
Uri
ne H
g u
gg
Number of amalgams
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
Arsenic (180 of Diabetes)
How it causes diabetes
bull Blocks sugar stimulating insulin secretion
bull Epigenetic inhibition of sugar regulation
Where it comes from
bull Water (gt10 of US water supplies have high levels)
bull Rice (naturally absorbs if in the water)
bull Chicken (added to make meat whiter)
Pan W-C Seow WJ Kile ML et al Association of low to moderate levels of arsenic exposure with risk of Type 2 diabetes in Bangladesh American Journal of Epidemiology 2013178(10)1563-70
Portion of Population with Toxin Load Which
Doubles Disease Risk
Toxin Disease with Doubled Risk
Polycyclic aromatic hydrocarbons Asthma 94
PCB187 Breast Cancer 60
Phthalates Diabetes 55
Lead ALS 33
Aluminum Alzheimers Disease 25
DDT ADHD 25
PCBs Diabetes 25
Dioxin-like PCBs Rheumatoid Arthritis 25
Arsenic Gout 23
Bisphenol A Diabetes 22
Cigarette smoking Lung Cancer 21
Arsenic Diabetes 20
Polycyclic aromatic hydrocarbons Diabetes 20
Huge Detoxification Variability
bull CYP2C19
Proton pump inhibitors and some antidepressants
5-fold difference in activity between poor metabolizers and extensive metabolizers more so if CYP3A4 is also inhibited
Ultrarapid allele in 18 of both Swedes and Ethiopians
bull CYP2D6
Metabolizes a large number of drugs (~25)
7 of Caucasians poor metabolizers
~30 ultra rapid metabolizers in Arabian and Eastern African populations
More adverse effects in poor metabolizers and ineffective dosing in ultrarapid metabolizers
Inhibited by ginger
Desta Z et al Clinical significance of the cytochrome P450 2C19 genetic polymorphism Clin Pharmaco 2002
Sim SC et al A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug
response to proton pump inhibitors and antidepressants Clin Pharmacol Ther 2006
Wilkinson GR Drug metabolism and variability among patients in drug response N Engl J Med 2005
Kirchheiner J et al Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to
CYP2D6 duplication Pharmacogenomics J 2007
Toxin Half Lives in BloodToxin ldquoNormalrdquo (mgL) Acute Toxic (mgL) Half-Life
Arsenic 0002-007 005-025 2-4 days (CDC)
Benzene 00002 05-10 days
Cadmium 00003-00065 0015-005 16 years
Chlordane 0001 00025 3-4 days
DDTDDE 2-10 years
Dieldrin 00015 015-030 2-12 months
Ethanol 1000-2000 15hour
Lead 009 04-06 1-15 mo (2+ yrs bone)
Mercury 00015-0002 005-02 2 months (CDC)
PCBs 3-25 years
Toluene 05-3 days
Schulz M et al Therapeutic and toxic blood concentrations of nearly 1000 drugs and other xenobiotics Crit Care 2012 Jul 2616(4)R136
Bioaccumulation (POPs)
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
DDT banned in 1972 PCBs banned in 1977
Bioaccumulation (Cd)
Think BroadlyExogenous
Metals
Chemicalsbull Inorganic
bull Fluoride
bull Organic
bull POPs
bull Drugs
Particulate matter
Molds
Microbial
Radiationbull Light
bull Medical
bull Cell phone
Endogenous
Gut-derived toxins
Non-end product metabolites
Poorly detoxified hormones
Catecholamines (if SNP)
Toxins of Choice
Alcohol
Marijuana
Food constituents
High fructose corn syrup
Salt (acid-forming diet)
Wheat if zonulin (70)
Obesity Epidemic ndash POPs AND HFCS
47Bray GA Fructose should we worry Int J Obes (Lond) 2008 Dec32 Suppl 7S127-31
How Toxins Cause Damage 13
bull Increase free radical production
Cd induces production of ROS
Malathion inhibits catalase and glutathione peroxidase
Homocysteine oxidizes LDL cholesterol
bull Poison enzyme systems (compete with nutritional cofactors for binding sites)
Pb poisons delta aminolevulinic acid dehydratase
Cd inhibits catalase glutathione reductase and lowers
glutathione levels
bull Replace structural minerals
Pb displaces Ca in bone
How Toxins Cause Damage 23
bull Damage DNA
Benzene - causes chromosomal damage
Pesticides ndash fruit growers have more DNA damage
Phthalates and insecticides ndash damage sperm DNA
4-hydroxy catechol estrogen (4-OHE) damages breast DNA
bull Epigenetic dysmodulation
Higher cord blood levels of hexachlorobenzene associated
with 2x greater risk for obesity in children
bull Damage cell membranes
Common mechanism for heavy metals inactivates
membrane enzymes ion channels and pumps
How Toxins Cause Damage 33
bull Block insulin receptor sites
PCBs and phthalates
bull Highest levels associated with a 4 to 20-fold greater diabetes risk
bull Imbalance hormones many toxin examples
Arsenic
bull Disrupts thyroid hormone and retinoic acid receptors
Phthalates
bull Act as anti-androgens
bull More than 75 of the US population has measurable levels of
several phthalate metabolites in the urine
PCBs
bull Lower testosterone levels in men
Which are the Worst Toxins
bull According to the CDC
Toxicity
Population toxic load
Prevalence in toxic waste sites
bull According to clinical importance
Exposure
of disease
Ability of the body to detoxifyexcrete
Ag
en
cy
fo
r T
oxic
Su
bs
tan
ce
s a
nd
Dis
ea
se
Reg
istr
y
Pri
ori
ty L
ist
The Worst Toxins Clinically
My Rank Toxin Diseases Primary Sources
1 Arsenic Cancers diabetes gout Water chicken rice
2 DDT ADHD dementia diabetes Everywhere
3 Phthalates ADHD diabetes Soft plastics HABAs
4 PBDEs ADHD diabetes Flame retardant fabrics
5 PAHs ADHD cancers dyslipidemia Smoking charbroiling
6 PCBs Cancers diabetes MI RA Everywhere
7 Mercury Dementia ldquoSilverrdquo fillings fish
8 Lead Cardiovascular disease IQ Paint water
Glyphosate Research invalid
Conventional Laboratory Tests Reflect
Toxic Load in ldquoNormalrdquo Range
bull Surprising number show toxin exposure
CBC RBC WBC platelet count hemoglobin basophilic
stippling
Liver enzymes ALT GGTP
Inflammatory markers CRP
Lipids LDL oxLDL triglycerides
Blood sugar insulin FBS 2-hour PP
Metabolites bilirubin uric acid homocysteine 8-OHdG
Thyroid T3 T4 TSH
bull The historic ldquonormalrdquo range has been changing as the population has become more toxic
WBC Lowered by PCB and OCP Exposure
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
0
1
2
3
4
5
6
7
8
1st Quartrile 2nd Quartile 3rd Quartile 4th Quartile
WBCbull Strong inverse correlation with PCBs and OCPs and CBC
bull Linear with almost all PCBs
bull High variability with OCPs
bull Within ldquonormalrdquo range
Effects on WBC Worsen with Years
of Exposure to Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Platelet Count Decreases with Years
of Exposure tp Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Solvents Decrease Platelet Count
bull Compared workers exposed 23 hrday to those exposed most of day to toluene
bull All wore face masks and protective gear
bull Platelet count 14 lower 252 versus 216ml
bull Impairment of sympathetic nerves (OR = 413)
bull Impairment of peripheral nerves (OR = 694)
bull Positive relationship between neurological abnormalities and a self-reported neuropsychiatric measurement (r = 035-066)
Shih HT et al Subclinical abnormalities in workers with continuous low-level toluene exposure Toxicol Ind Health 2011 Sep27(8)691-9
Basophilic Stippling of Red Cells
Toxinsbull Arsenic
bull Lead
Diseasesbull Alpha-thalassemia HbH Disease
bull Beta thalassemia
bull Hereditary pyrimidine 5-nucleotidase deficiency
bull Myelodysplastic syndrome
bull Sideroblastic anemia
bull Thrombotic thrombocytopenic purpura
GGT Indirect Measure of POPsbull Glutathione is key intracellular defense against oxidative stress
bull Cellular GGT metabolizes extracellular GSH allowing precursor amino acids to be reutilized for intracellular GSH
bull Exposure to POPs induces GGT as a defensive mechanism
bull Within normal range predicts type 2 diabetes coronary heart disease hypertension stroke dyslipidemia chronic kidney disease and cancer
bull Men with GGT gt50 UI had ~26 fold risk for diabetes compared to those with lt10 Those with 40-49 had a ~20 fold risk
bull Levels within normal range occur with obesity xs alcohol cigarette smoking physical inactivity high meat low fruit and vegetable intake
bull Cumulative biomarker for environmental pollutants
Lee DH et al (2003) Gamma-glutamyltransferase and diabetesmdasha 4 year follow-up study Diabetologia 46359ndash364
Pamela A et al Serum gamma-glutamyltransferase linking together environmental pollution redox equilibria and progression of atherosclerosis Clin Chem
Lab Med 200947(12)1583-4
Lee DH et al Serum gamma-glutamyltransferase new insights about an old enzyme J Epidemiol Community Health 2009 Nov63(11)884-6
Lee DH et alSerum gamma-glutamyltransferase predicts non-fatal myocardial infarction and fatal coronary heart disease among 28838 middle-aged men and
women Eur Heart J 2006272170ndash6
Lee DH et al Gamma-glutamyltransferase and diabetes--a 4 year follow-up study Diabetologia 2003 Mar46(3)359-64
Lee DH et al Can persistent organic pollutants explain the association between serum gamma-glutamyltransferase and type 2 diabetes Diabetologia 2008
Mar51(3)402-7
GGT and Alcohol Consumption
bull GGT directly correlates with alcohol consumption
bull In a non-uniform population 40 gd will elevate GGT ~15
bull Watch for false negatives
bull Genomic variation
bull Are these the ones most
sensitive todamaged by
chemical toxins
bull Could up-regulation of GGT in light alcohol consumption be reason for benefit
0
10
20
30
40
50
60
70
80
0 200 400 600 800
Grams of Ethanol per Week
Adapted from Nagaya T et al Dose-response relationships between drinking and serum tests in Japanese men
aged 40ndash59 years Alcohol 1999 Feb 17(2) 133ndash8
GGT Correlates With Toxic Metal Levels
Lee DH et al Graded associations of blood lead and urinary cadmium concentrations with oxidative-stress-related markers in the
US population results from the third National Health and Nutrition Examination Survey Environ Health
perspect 2006 Mar114(3)350-4
GGT and Diabetes Risk
0
5
10
15
20
25
30
lt10 10-19 20-29 30-39 40-49 gt50
Dia
bete
s R
isk
GGT
bull GGT over 50 associated with tripling of death rate
bull 30-40 associated with doubling
GGT Levels
Correlate with
Risk of Death
Brenner H et al Distribution determinants and prognostic value of gamma-glutamyltransferase for all-cause
mortality in a cohort of construction workers from southern Germany Prev Med 1997 26 305ndash10
GGT From Small US Company
with Young Workers
0
10
20
30
40
50
60
0 20 40 60 80 100
GGT Data from Canadian Oil Field
Workers
0
50
100
150
200
250
300
350
400
450
lt10 10-20 20-30 30-40 40-50 50-60 60-07 70-80 80-90 90-100 100-110 110-120 gt120
GGTP
20-fold increased risk of diabetes
Uric Acid Indirect Measure of POPs
bull Poly-fluorinated hydrocarbons (PFOA and PFOS) associated
with increased serum uric acid
Lin CY et al Association among serum perfluoroalkyl chemicals glucose homeostasis and metabolic syndrome
in adolescents and adults Diabetes Care 2009 Apr32(4)702-7
Steenland K et al Association of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) with uric
acid among adults with elevated community exposure to PFOA Environ Health Perspect 2010 Feb118229-33
Steenland 2010 Open Access
ALT Indirect Measure of POPs
bull ALT (proxy marker) elevation in 104 (not including viral
hepatitis hemochromatosis or alcoholic liver disease) of
NHANES 03-04 subset
bull Risk of elevated ALT increased dose-dependently with
cadmium lead mercury and PCB exposure
bull 100 of individuals had detectable PCBs 925 mercury
and 996 had detectable lead
bull In 2005-08 prevalence of NAFLD in US was 11 a
growing cause of chronic liver disease
Cave M et al Polychlorinated biphenyls lead and mercury are associated with liver disease in American adults
NHANES 2003-2004 Environ Health Perspect 2010 Dec118(12)1735-42
Younossi ZM et al Changes in the prevalence of the most common causes of chronic liver diseases in the United
States from 1988 to 2008 Clin Gastroenterol Hepatol 2011 Jun9(6)524-530e1
Bilirubin as a Marker of POPs
bull Degree of serum bilirubin increase is prognostically significant in chronic liver dysfunction
bull Mono-ortho PCB TEQ values were found to be significantly positively associated with bilirubin (β=071 P=0008) following adjustment for multiple potential confounders
bull Bilirubin levels significantly correlated with PCBs -105-118-126 and -194
bull Smoking appears to be the biggest confounder
Dufour DR et al 2000 Diagnosis and monitoring of hepatic injury II Recommendations for use of laboratory
tests in screening diagnosis and monitoring Clin Chem 46 2050ndash68
Kumar J et al Persistent organic pollutants and liver dysfunction biomarkers in a population-based human sample
of men and women Environ Res 2014134251-256
Perf
luo
rin
ate
dP
OP
s a
nd
Co
mm
on
Blo
od
Tests
Gleason JA et al Associations of perfluorinated chemical serum concentrations and biomarkers of liver function and uric acid in the
US population (NHANES) 2007-2010 Environ Res 20151368-14
Liver Enzymes Reflect Toxic Load
bull AST ALT and GGT increase with body load of PCBs and OCPs
bull Some non-linear
bull Oxychlordanetop quartile
ALT 10
GGT 25
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
LDL-Cholesterol as Measure of POPs
bull 5-year prospective study to determine if POP levels predict future elevation in LDL-cholesterol
bull 598 subjects initially at age 70
bull Looked at 23 POPs
bull Best correlation with PCB 194
Penell J Lind L Salihovic S et al Persistent organic pollutants are related to change in circulating
lipid levels during a 5 year follow-up Environ Res 134(2014)190ndash197
oxLDL as Measure of POPs
bull 992 70-year old individuals (50 women)
bull Sum of PCBs showed strong significant positive associations with ox-LDL and significant negative associations with glutathione-related markers (GSSG and GSSGGSH)
bull A number of POPs (PCB-99 138 153 156 170 180 194 206 and 209) showed strong significant positive association with ox-LDL
Kumar J et al Influence of persistent organic pollutants on oxidative stress in population-based samples
Chemosphere 2014114303-309
Homocysteine is Increased by Pb amp Cd
Guallar E et al Confounding of the relation between homocysteine and peripheral arterial disease by lead cadmium and renal function Am J Epidemiol 2006 Apr 15163(8)700-8
Nutrient Deficiencies Accentuate
Effects of Lead on Homocysteine
bull Deficiencies in folate B6 or B12 make lead more toxic
Lee YM Et al Association of homocysteine levels with blood lead levels and micronutrients in the US general population J Prev Med Public Health 2012 Nov45(6)387-93
T4 amp T3 and PCBs
bull PCBs decrease T4 production
bull PCBs inhibit iodotyrosinedeiodinase activity
bull Study done in pregnant women which implies effect on fetus IQ
Kim S Park J Kim HJ et al Association between several persistent organic pollutants and thyroid hormone levels in serum among the pregnant women of Korea Environ Int 2013 Sep59442-8Shimizu R Yamaguchi M Uramaru N et al Structure-activity relationships of 44 halogenated compounds for iodotyrosinedeiodinase-inhibitory activity Toxicology 2013 Dec 6314(1)22-9
T4 amp T3 and PCBs
bull Not just humans being affected
bull Large study of dolphins shows exactly the same effects
Schwacke LH Zolman ES Balmer BC et al Anaemia hypothyroidism and immune suppression associated with polychlorinated biphenyl exposure in bottlenose dolphins (Tursiops truncatus) Proceed Royal Society B doi101098rspb20110665
8-OHdG
bull Oxidized nucleoside
bull Direct measure of DNA damage
bull Indirect measure of oxidative stress and toxin load
bull Correlates with
Multiple cancers
Mitochondrial damage
Rate of aging
Smoking
Several toxinsWalter Crinnion ldquoTotal Toxic Loadrdquo AANP 2015
8-OHdG Correlates with Pack-Years
of Smoking
Yano T et al Significance of the urinary 8-OHdG level as an oxidative stress marker in lung cancer patients Lung Cancer
2009 Jan63(1)111-4
8-OHdG Correlates
with Mercury
Chen C et al Increased oxidative DNA damage as assessed by urinary 8-hydroxy-2-deoxyguanosine
concentrations and serum redox status in persons exposed to mercury Clin Chem 2005 Apr51(4)759-67
Toxin Effects Worse with Aging
bull Thyroid function decreases with PFOA levels
bull But only after age 63
Shrestha S Bloom MS Yucel R et al Perfluoroalkyl substances and thyroid function in older adults Environ Int 2015 Feb75206-14
Insightful 23-Year Prospective Study
1 lt 50 there is no difference between those with the lowest and highest PCBs
2 In youngest group insulin production increases in response to toxin level As expected since blocking of
insulin receptor sites by PCBs
requires more insulin
3 That adaptive ability decreases with aging
4 At age 50 all the measures show very strong toxin-dose response
Cumulative damage impairs ability to adapt
Suarez-Lopez JR et al Persistent organic pollutants in young adults and changes in glucose related metabolism over a 23-year follow-up Environ Res 2015 Feb137485-94
Recommendations
High body toxic load
GGT gt 25
Uric acid gt 50 mgdl
ALT gt30 UL
Bilirubin gt08 mgdl
CBC lt 6000
Platelet lt 250000
Low T3 andor T4
Monitor Total Toxic Load
8-OHdG gt4
ldquoUnconventionalrdquo Laboratory Tests
bull Challenge testing
bull Hair analysis
bull Direct measures of solvents and POPs in blood urine adipose tissue
Evaluation of Metal Exposure ndash Provocation
bull Provocation ndash the use of a chelating agent ndash before urine collection often done clinically but several limitations
No ldquoofficialrdquo reference range for provoked urine
Most chelating agents do not extract metals from all tissues thus
does not necessarily represent total body burden
bull Example Brain is one of the main target organs for both elemental and organic
mercury yet agents do not chelate brain mercury
bull Despite limitations widely used and advocated by clinicians in part to see efficacy of chelating agent as a guide to treatment and based on empirical evidence
Rooney JP The role of thiols dithiols nutritional factors and interacting ligands in the toxicology of mercury
Toxicology 2007
Is Challenge Testing Valid
bull Poor correlations of standard tests for mercury
bull Unpublished research from corporate wellness project
bull Published amalgam number correlation
bull Published fish consumption correlation
What We Found In Canada
bull Deviations from the mean of 14 29 and 91 respectively
bull DMPS is spreading distribution suggesting that it is better at differentiating mercury body load
bull Some VERY high
Hg Assessment Correlations
bull Extensive measurements in 65 Whole blood Hg
Oral DMPS challenge
Amalgam surfaces
bull Correlations Whole blood w pre urine r = 040
Whole blood w post urine r = 057
Pre urine w post urine r = 068
Amalgams w pre urine r = 026
Amalgams w whole blood r = 036
Amalgams with post urine 044
bull Clear documentation that
challenge testing is better00
100
200
300
400
500
600
0 10 20 30 40 50
Po
st
Uri
ne H
g u
gg
Number of amalgams
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
Portion of Population with Toxin Load Which
Doubles Disease Risk
Toxin Disease with Doubled Risk
Polycyclic aromatic hydrocarbons Asthma 94
PCB187 Breast Cancer 60
Phthalates Diabetes 55
Lead ALS 33
Aluminum Alzheimers Disease 25
DDT ADHD 25
PCBs Diabetes 25
Dioxin-like PCBs Rheumatoid Arthritis 25
Arsenic Gout 23
Bisphenol A Diabetes 22
Cigarette smoking Lung Cancer 21
Arsenic Diabetes 20
Polycyclic aromatic hydrocarbons Diabetes 20
Huge Detoxification Variability
bull CYP2C19
Proton pump inhibitors and some antidepressants
5-fold difference in activity between poor metabolizers and extensive metabolizers more so if CYP3A4 is also inhibited
Ultrarapid allele in 18 of both Swedes and Ethiopians
bull CYP2D6
Metabolizes a large number of drugs (~25)
7 of Caucasians poor metabolizers
~30 ultra rapid metabolizers in Arabian and Eastern African populations
More adverse effects in poor metabolizers and ineffective dosing in ultrarapid metabolizers
Inhibited by ginger
Desta Z et al Clinical significance of the cytochrome P450 2C19 genetic polymorphism Clin Pharmaco 2002
Sim SC et al A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug
response to proton pump inhibitors and antidepressants Clin Pharmacol Ther 2006
Wilkinson GR Drug metabolism and variability among patients in drug response N Engl J Med 2005
Kirchheiner J et al Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to
CYP2D6 duplication Pharmacogenomics J 2007
Toxin Half Lives in BloodToxin ldquoNormalrdquo (mgL) Acute Toxic (mgL) Half-Life
Arsenic 0002-007 005-025 2-4 days (CDC)
Benzene 00002 05-10 days
Cadmium 00003-00065 0015-005 16 years
Chlordane 0001 00025 3-4 days
DDTDDE 2-10 years
Dieldrin 00015 015-030 2-12 months
Ethanol 1000-2000 15hour
Lead 009 04-06 1-15 mo (2+ yrs bone)
Mercury 00015-0002 005-02 2 months (CDC)
PCBs 3-25 years
Toluene 05-3 days
Schulz M et al Therapeutic and toxic blood concentrations of nearly 1000 drugs and other xenobiotics Crit Care 2012 Jul 2616(4)R136
Bioaccumulation (POPs)
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
DDT banned in 1972 PCBs banned in 1977
Bioaccumulation (Cd)
Think BroadlyExogenous
Metals
Chemicalsbull Inorganic
bull Fluoride
bull Organic
bull POPs
bull Drugs
Particulate matter
Molds
Microbial
Radiationbull Light
bull Medical
bull Cell phone
Endogenous
Gut-derived toxins
Non-end product metabolites
Poorly detoxified hormones
Catecholamines (if SNP)
Toxins of Choice
Alcohol
Marijuana
Food constituents
High fructose corn syrup
Salt (acid-forming diet)
Wheat if zonulin (70)
Obesity Epidemic ndash POPs AND HFCS
47Bray GA Fructose should we worry Int J Obes (Lond) 2008 Dec32 Suppl 7S127-31
How Toxins Cause Damage 13
bull Increase free radical production
Cd induces production of ROS
Malathion inhibits catalase and glutathione peroxidase
Homocysteine oxidizes LDL cholesterol
bull Poison enzyme systems (compete with nutritional cofactors for binding sites)
Pb poisons delta aminolevulinic acid dehydratase
Cd inhibits catalase glutathione reductase and lowers
glutathione levels
bull Replace structural minerals
Pb displaces Ca in bone
How Toxins Cause Damage 23
bull Damage DNA
Benzene - causes chromosomal damage
Pesticides ndash fruit growers have more DNA damage
Phthalates and insecticides ndash damage sperm DNA
4-hydroxy catechol estrogen (4-OHE) damages breast DNA
bull Epigenetic dysmodulation
Higher cord blood levels of hexachlorobenzene associated
with 2x greater risk for obesity in children
bull Damage cell membranes
Common mechanism for heavy metals inactivates
membrane enzymes ion channels and pumps
How Toxins Cause Damage 33
bull Block insulin receptor sites
PCBs and phthalates
bull Highest levels associated with a 4 to 20-fold greater diabetes risk
bull Imbalance hormones many toxin examples
Arsenic
bull Disrupts thyroid hormone and retinoic acid receptors
Phthalates
bull Act as anti-androgens
bull More than 75 of the US population has measurable levels of
several phthalate metabolites in the urine
PCBs
bull Lower testosterone levels in men
Which are the Worst Toxins
bull According to the CDC
Toxicity
Population toxic load
Prevalence in toxic waste sites
bull According to clinical importance
Exposure
of disease
Ability of the body to detoxifyexcrete
Ag
en
cy
fo
r T
oxic
Su
bs
tan
ce
s a
nd
Dis
ea
se
Reg
istr
y
Pri
ori
ty L
ist
The Worst Toxins Clinically
My Rank Toxin Diseases Primary Sources
1 Arsenic Cancers diabetes gout Water chicken rice
2 DDT ADHD dementia diabetes Everywhere
3 Phthalates ADHD diabetes Soft plastics HABAs
4 PBDEs ADHD diabetes Flame retardant fabrics
5 PAHs ADHD cancers dyslipidemia Smoking charbroiling
6 PCBs Cancers diabetes MI RA Everywhere
7 Mercury Dementia ldquoSilverrdquo fillings fish
8 Lead Cardiovascular disease IQ Paint water
Glyphosate Research invalid
Conventional Laboratory Tests Reflect
Toxic Load in ldquoNormalrdquo Range
bull Surprising number show toxin exposure
CBC RBC WBC platelet count hemoglobin basophilic
stippling
Liver enzymes ALT GGTP
Inflammatory markers CRP
Lipids LDL oxLDL triglycerides
Blood sugar insulin FBS 2-hour PP
Metabolites bilirubin uric acid homocysteine 8-OHdG
Thyroid T3 T4 TSH
bull The historic ldquonormalrdquo range has been changing as the population has become more toxic
WBC Lowered by PCB and OCP Exposure
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
0
1
2
3
4
5
6
7
8
1st Quartrile 2nd Quartile 3rd Quartile 4th Quartile
WBCbull Strong inverse correlation with PCBs and OCPs and CBC
bull Linear with almost all PCBs
bull High variability with OCPs
bull Within ldquonormalrdquo range
Effects on WBC Worsen with Years
of Exposure to Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Platelet Count Decreases with Years
of Exposure tp Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Solvents Decrease Platelet Count
bull Compared workers exposed 23 hrday to those exposed most of day to toluene
bull All wore face masks and protective gear
bull Platelet count 14 lower 252 versus 216ml
bull Impairment of sympathetic nerves (OR = 413)
bull Impairment of peripheral nerves (OR = 694)
bull Positive relationship between neurological abnormalities and a self-reported neuropsychiatric measurement (r = 035-066)
Shih HT et al Subclinical abnormalities in workers with continuous low-level toluene exposure Toxicol Ind Health 2011 Sep27(8)691-9
Basophilic Stippling of Red Cells
Toxinsbull Arsenic
bull Lead
Diseasesbull Alpha-thalassemia HbH Disease
bull Beta thalassemia
bull Hereditary pyrimidine 5-nucleotidase deficiency
bull Myelodysplastic syndrome
bull Sideroblastic anemia
bull Thrombotic thrombocytopenic purpura
GGT Indirect Measure of POPsbull Glutathione is key intracellular defense against oxidative stress
bull Cellular GGT metabolizes extracellular GSH allowing precursor amino acids to be reutilized for intracellular GSH
bull Exposure to POPs induces GGT as a defensive mechanism
bull Within normal range predicts type 2 diabetes coronary heart disease hypertension stroke dyslipidemia chronic kidney disease and cancer
bull Men with GGT gt50 UI had ~26 fold risk for diabetes compared to those with lt10 Those with 40-49 had a ~20 fold risk
bull Levels within normal range occur with obesity xs alcohol cigarette smoking physical inactivity high meat low fruit and vegetable intake
bull Cumulative biomarker for environmental pollutants
Lee DH et al (2003) Gamma-glutamyltransferase and diabetesmdasha 4 year follow-up study Diabetologia 46359ndash364
Pamela A et al Serum gamma-glutamyltransferase linking together environmental pollution redox equilibria and progression of atherosclerosis Clin Chem
Lab Med 200947(12)1583-4
Lee DH et al Serum gamma-glutamyltransferase new insights about an old enzyme J Epidemiol Community Health 2009 Nov63(11)884-6
Lee DH et alSerum gamma-glutamyltransferase predicts non-fatal myocardial infarction and fatal coronary heart disease among 28838 middle-aged men and
women Eur Heart J 2006272170ndash6
Lee DH et al Gamma-glutamyltransferase and diabetes--a 4 year follow-up study Diabetologia 2003 Mar46(3)359-64
Lee DH et al Can persistent organic pollutants explain the association between serum gamma-glutamyltransferase and type 2 diabetes Diabetologia 2008
Mar51(3)402-7
GGT and Alcohol Consumption
bull GGT directly correlates with alcohol consumption
bull In a non-uniform population 40 gd will elevate GGT ~15
bull Watch for false negatives
bull Genomic variation
bull Are these the ones most
sensitive todamaged by
chemical toxins
bull Could up-regulation of GGT in light alcohol consumption be reason for benefit
0
10
20
30
40
50
60
70
80
0 200 400 600 800
Grams of Ethanol per Week
Adapted from Nagaya T et al Dose-response relationships between drinking and serum tests in Japanese men
aged 40ndash59 years Alcohol 1999 Feb 17(2) 133ndash8
GGT Correlates With Toxic Metal Levels
Lee DH et al Graded associations of blood lead and urinary cadmium concentrations with oxidative-stress-related markers in the
US population results from the third National Health and Nutrition Examination Survey Environ Health
perspect 2006 Mar114(3)350-4
GGT and Diabetes Risk
0
5
10
15
20
25
30
lt10 10-19 20-29 30-39 40-49 gt50
Dia
bete
s R
isk
GGT
bull GGT over 50 associated with tripling of death rate
bull 30-40 associated with doubling
GGT Levels
Correlate with
Risk of Death
Brenner H et al Distribution determinants and prognostic value of gamma-glutamyltransferase for all-cause
mortality in a cohort of construction workers from southern Germany Prev Med 1997 26 305ndash10
GGT From Small US Company
with Young Workers
0
10
20
30
40
50
60
0 20 40 60 80 100
GGT Data from Canadian Oil Field
Workers
0
50
100
150
200
250
300
350
400
450
lt10 10-20 20-30 30-40 40-50 50-60 60-07 70-80 80-90 90-100 100-110 110-120 gt120
GGTP
20-fold increased risk of diabetes
Uric Acid Indirect Measure of POPs
bull Poly-fluorinated hydrocarbons (PFOA and PFOS) associated
with increased serum uric acid
Lin CY et al Association among serum perfluoroalkyl chemicals glucose homeostasis and metabolic syndrome
in adolescents and adults Diabetes Care 2009 Apr32(4)702-7
Steenland K et al Association of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) with uric
acid among adults with elevated community exposure to PFOA Environ Health Perspect 2010 Feb118229-33
Steenland 2010 Open Access
ALT Indirect Measure of POPs
bull ALT (proxy marker) elevation in 104 (not including viral
hepatitis hemochromatosis or alcoholic liver disease) of
NHANES 03-04 subset
bull Risk of elevated ALT increased dose-dependently with
cadmium lead mercury and PCB exposure
bull 100 of individuals had detectable PCBs 925 mercury
and 996 had detectable lead
bull In 2005-08 prevalence of NAFLD in US was 11 a
growing cause of chronic liver disease
Cave M et al Polychlorinated biphenyls lead and mercury are associated with liver disease in American adults
NHANES 2003-2004 Environ Health Perspect 2010 Dec118(12)1735-42
Younossi ZM et al Changes in the prevalence of the most common causes of chronic liver diseases in the United
States from 1988 to 2008 Clin Gastroenterol Hepatol 2011 Jun9(6)524-530e1
Bilirubin as a Marker of POPs
bull Degree of serum bilirubin increase is prognostically significant in chronic liver dysfunction
bull Mono-ortho PCB TEQ values were found to be significantly positively associated with bilirubin (β=071 P=0008) following adjustment for multiple potential confounders
bull Bilirubin levels significantly correlated with PCBs -105-118-126 and -194
bull Smoking appears to be the biggest confounder
Dufour DR et al 2000 Diagnosis and monitoring of hepatic injury II Recommendations for use of laboratory
tests in screening diagnosis and monitoring Clin Chem 46 2050ndash68
Kumar J et al Persistent organic pollutants and liver dysfunction biomarkers in a population-based human sample
of men and women Environ Res 2014134251-256
Perf
luo
rin
ate
dP
OP
s a
nd
Co
mm
on
Blo
od
Tests
Gleason JA et al Associations of perfluorinated chemical serum concentrations and biomarkers of liver function and uric acid in the
US population (NHANES) 2007-2010 Environ Res 20151368-14
Liver Enzymes Reflect Toxic Load
bull AST ALT and GGT increase with body load of PCBs and OCPs
bull Some non-linear
bull Oxychlordanetop quartile
ALT 10
GGT 25
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
LDL-Cholesterol as Measure of POPs
bull 5-year prospective study to determine if POP levels predict future elevation in LDL-cholesterol
bull 598 subjects initially at age 70
bull Looked at 23 POPs
bull Best correlation with PCB 194
Penell J Lind L Salihovic S et al Persistent organic pollutants are related to change in circulating
lipid levels during a 5 year follow-up Environ Res 134(2014)190ndash197
oxLDL as Measure of POPs
bull 992 70-year old individuals (50 women)
bull Sum of PCBs showed strong significant positive associations with ox-LDL and significant negative associations with glutathione-related markers (GSSG and GSSGGSH)
bull A number of POPs (PCB-99 138 153 156 170 180 194 206 and 209) showed strong significant positive association with ox-LDL
Kumar J et al Influence of persistent organic pollutants on oxidative stress in population-based samples
Chemosphere 2014114303-309
Homocysteine is Increased by Pb amp Cd
Guallar E et al Confounding of the relation between homocysteine and peripheral arterial disease by lead cadmium and renal function Am J Epidemiol 2006 Apr 15163(8)700-8
Nutrient Deficiencies Accentuate
Effects of Lead on Homocysteine
bull Deficiencies in folate B6 or B12 make lead more toxic
Lee YM Et al Association of homocysteine levels with blood lead levels and micronutrients in the US general population J Prev Med Public Health 2012 Nov45(6)387-93
T4 amp T3 and PCBs
bull PCBs decrease T4 production
bull PCBs inhibit iodotyrosinedeiodinase activity
bull Study done in pregnant women which implies effect on fetus IQ
Kim S Park J Kim HJ et al Association between several persistent organic pollutants and thyroid hormone levels in serum among the pregnant women of Korea Environ Int 2013 Sep59442-8Shimizu R Yamaguchi M Uramaru N et al Structure-activity relationships of 44 halogenated compounds for iodotyrosinedeiodinase-inhibitory activity Toxicology 2013 Dec 6314(1)22-9
T4 amp T3 and PCBs
bull Not just humans being affected
bull Large study of dolphins shows exactly the same effects
Schwacke LH Zolman ES Balmer BC et al Anaemia hypothyroidism and immune suppression associated with polychlorinated biphenyl exposure in bottlenose dolphins (Tursiops truncatus) Proceed Royal Society B doi101098rspb20110665
8-OHdG
bull Oxidized nucleoside
bull Direct measure of DNA damage
bull Indirect measure of oxidative stress and toxin load
bull Correlates with
Multiple cancers
Mitochondrial damage
Rate of aging
Smoking
Several toxinsWalter Crinnion ldquoTotal Toxic Loadrdquo AANP 2015
8-OHdG Correlates with Pack-Years
of Smoking
Yano T et al Significance of the urinary 8-OHdG level as an oxidative stress marker in lung cancer patients Lung Cancer
2009 Jan63(1)111-4
8-OHdG Correlates
with Mercury
Chen C et al Increased oxidative DNA damage as assessed by urinary 8-hydroxy-2-deoxyguanosine
concentrations and serum redox status in persons exposed to mercury Clin Chem 2005 Apr51(4)759-67
Toxin Effects Worse with Aging
bull Thyroid function decreases with PFOA levels
bull But only after age 63
Shrestha S Bloom MS Yucel R et al Perfluoroalkyl substances and thyroid function in older adults Environ Int 2015 Feb75206-14
Insightful 23-Year Prospective Study
1 lt 50 there is no difference between those with the lowest and highest PCBs
2 In youngest group insulin production increases in response to toxin level As expected since blocking of
insulin receptor sites by PCBs
requires more insulin
3 That adaptive ability decreases with aging
4 At age 50 all the measures show very strong toxin-dose response
Cumulative damage impairs ability to adapt
Suarez-Lopez JR et al Persistent organic pollutants in young adults and changes in glucose related metabolism over a 23-year follow-up Environ Res 2015 Feb137485-94
Recommendations
High body toxic load
GGT gt 25
Uric acid gt 50 mgdl
ALT gt30 UL
Bilirubin gt08 mgdl
CBC lt 6000
Platelet lt 250000
Low T3 andor T4
Monitor Total Toxic Load
8-OHdG gt4
ldquoUnconventionalrdquo Laboratory Tests
bull Challenge testing
bull Hair analysis
bull Direct measures of solvents and POPs in blood urine adipose tissue
Evaluation of Metal Exposure ndash Provocation
bull Provocation ndash the use of a chelating agent ndash before urine collection often done clinically but several limitations
No ldquoofficialrdquo reference range for provoked urine
Most chelating agents do not extract metals from all tissues thus
does not necessarily represent total body burden
bull Example Brain is one of the main target organs for both elemental and organic
mercury yet agents do not chelate brain mercury
bull Despite limitations widely used and advocated by clinicians in part to see efficacy of chelating agent as a guide to treatment and based on empirical evidence
Rooney JP The role of thiols dithiols nutritional factors and interacting ligands in the toxicology of mercury
Toxicology 2007
Is Challenge Testing Valid
bull Poor correlations of standard tests for mercury
bull Unpublished research from corporate wellness project
bull Published amalgam number correlation
bull Published fish consumption correlation
What We Found In Canada
bull Deviations from the mean of 14 29 and 91 respectively
bull DMPS is spreading distribution suggesting that it is better at differentiating mercury body load
bull Some VERY high
Hg Assessment Correlations
bull Extensive measurements in 65 Whole blood Hg
Oral DMPS challenge
Amalgam surfaces
bull Correlations Whole blood w pre urine r = 040
Whole blood w post urine r = 057
Pre urine w post urine r = 068
Amalgams w pre urine r = 026
Amalgams w whole blood r = 036
Amalgams with post urine 044
bull Clear documentation that
challenge testing is better00
100
200
300
400
500
600
0 10 20 30 40 50
Po
st
Uri
ne H
g u
gg
Number of amalgams
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
Huge Detoxification Variability
bull CYP2C19
Proton pump inhibitors and some antidepressants
5-fold difference in activity between poor metabolizers and extensive metabolizers more so if CYP3A4 is also inhibited
Ultrarapid allele in 18 of both Swedes and Ethiopians
bull CYP2D6
Metabolizes a large number of drugs (~25)
7 of Caucasians poor metabolizers
~30 ultra rapid metabolizers in Arabian and Eastern African populations
More adverse effects in poor metabolizers and ineffective dosing in ultrarapid metabolizers
Inhibited by ginger
Desta Z et al Clinical significance of the cytochrome P450 2C19 genetic polymorphism Clin Pharmaco 2002
Sim SC et al A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug
response to proton pump inhibitors and antidepressants Clin Pharmacol Ther 2006
Wilkinson GR Drug metabolism and variability among patients in drug response N Engl J Med 2005
Kirchheiner J et al Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to
CYP2D6 duplication Pharmacogenomics J 2007
Toxin Half Lives in BloodToxin ldquoNormalrdquo (mgL) Acute Toxic (mgL) Half-Life
Arsenic 0002-007 005-025 2-4 days (CDC)
Benzene 00002 05-10 days
Cadmium 00003-00065 0015-005 16 years
Chlordane 0001 00025 3-4 days
DDTDDE 2-10 years
Dieldrin 00015 015-030 2-12 months
Ethanol 1000-2000 15hour
Lead 009 04-06 1-15 mo (2+ yrs bone)
Mercury 00015-0002 005-02 2 months (CDC)
PCBs 3-25 years
Toluene 05-3 days
Schulz M et al Therapeutic and toxic blood concentrations of nearly 1000 drugs and other xenobiotics Crit Care 2012 Jul 2616(4)R136
Bioaccumulation (POPs)
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
DDT banned in 1972 PCBs banned in 1977
Bioaccumulation (Cd)
Think BroadlyExogenous
Metals
Chemicalsbull Inorganic
bull Fluoride
bull Organic
bull POPs
bull Drugs
Particulate matter
Molds
Microbial
Radiationbull Light
bull Medical
bull Cell phone
Endogenous
Gut-derived toxins
Non-end product metabolites
Poorly detoxified hormones
Catecholamines (if SNP)
Toxins of Choice
Alcohol
Marijuana
Food constituents
High fructose corn syrup
Salt (acid-forming diet)
Wheat if zonulin (70)
Obesity Epidemic ndash POPs AND HFCS
47Bray GA Fructose should we worry Int J Obes (Lond) 2008 Dec32 Suppl 7S127-31
How Toxins Cause Damage 13
bull Increase free radical production
Cd induces production of ROS
Malathion inhibits catalase and glutathione peroxidase
Homocysteine oxidizes LDL cholesterol
bull Poison enzyme systems (compete with nutritional cofactors for binding sites)
Pb poisons delta aminolevulinic acid dehydratase
Cd inhibits catalase glutathione reductase and lowers
glutathione levels
bull Replace structural minerals
Pb displaces Ca in bone
How Toxins Cause Damage 23
bull Damage DNA
Benzene - causes chromosomal damage
Pesticides ndash fruit growers have more DNA damage
Phthalates and insecticides ndash damage sperm DNA
4-hydroxy catechol estrogen (4-OHE) damages breast DNA
bull Epigenetic dysmodulation
Higher cord blood levels of hexachlorobenzene associated
with 2x greater risk for obesity in children
bull Damage cell membranes
Common mechanism for heavy metals inactivates
membrane enzymes ion channels and pumps
How Toxins Cause Damage 33
bull Block insulin receptor sites
PCBs and phthalates
bull Highest levels associated with a 4 to 20-fold greater diabetes risk
bull Imbalance hormones many toxin examples
Arsenic
bull Disrupts thyroid hormone and retinoic acid receptors
Phthalates
bull Act as anti-androgens
bull More than 75 of the US population has measurable levels of
several phthalate metabolites in the urine
PCBs
bull Lower testosterone levels in men
Which are the Worst Toxins
bull According to the CDC
Toxicity
Population toxic load
Prevalence in toxic waste sites
bull According to clinical importance
Exposure
of disease
Ability of the body to detoxifyexcrete
Ag
en
cy
fo
r T
oxic
Su
bs
tan
ce
s a
nd
Dis
ea
se
Reg
istr
y
Pri
ori
ty L
ist
The Worst Toxins Clinically
My Rank Toxin Diseases Primary Sources
1 Arsenic Cancers diabetes gout Water chicken rice
2 DDT ADHD dementia diabetes Everywhere
3 Phthalates ADHD diabetes Soft plastics HABAs
4 PBDEs ADHD diabetes Flame retardant fabrics
5 PAHs ADHD cancers dyslipidemia Smoking charbroiling
6 PCBs Cancers diabetes MI RA Everywhere
7 Mercury Dementia ldquoSilverrdquo fillings fish
8 Lead Cardiovascular disease IQ Paint water
Glyphosate Research invalid
Conventional Laboratory Tests Reflect
Toxic Load in ldquoNormalrdquo Range
bull Surprising number show toxin exposure
CBC RBC WBC platelet count hemoglobin basophilic
stippling
Liver enzymes ALT GGTP
Inflammatory markers CRP
Lipids LDL oxLDL triglycerides
Blood sugar insulin FBS 2-hour PP
Metabolites bilirubin uric acid homocysteine 8-OHdG
Thyroid T3 T4 TSH
bull The historic ldquonormalrdquo range has been changing as the population has become more toxic
WBC Lowered by PCB and OCP Exposure
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
0
1
2
3
4
5
6
7
8
1st Quartrile 2nd Quartile 3rd Quartile 4th Quartile
WBCbull Strong inverse correlation with PCBs and OCPs and CBC
bull Linear with almost all PCBs
bull High variability with OCPs
bull Within ldquonormalrdquo range
Effects on WBC Worsen with Years
of Exposure to Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Platelet Count Decreases with Years
of Exposure tp Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Solvents Decrease Platelet Count
bull Compared workers exposed 23 hrday to those exposed most of day to toluene
bull All wore face masks and protective gear
bull Platelet count 14 lower 252 versus 216ml
bull Impairment of sympathetic nerves (OR = 413)
bull Impairment of peripheral nerves (OR = 694)
bull Positive relationship between neurological abnormalities and a self-reported neuropsychiatric measurement (r = 035-066)
Shih HT et al Subclinical abnormalities in workers with continuous low-level toluene exposure Toxicol Ind Health 2011 Sep27(8)691-9
Basophilic Stippling of Red Cells
Toxinsbull Arsenic
bull Lead
Diseasesbull Alpha-thalassemia HbH Disease
bull Beta thalassemia
bull Hereditary pyrimidine 5-nucleotidase deficiency
bull Myelodysplastic syndrome
bull Sideroblastic anemia
bull Thrombotic thrombocytopenic purpura
GGT Indirect Measure of POPsbull Glutathione is key intracellular defense against oxidative stress
bull Cellular GGT metabolizes extracellular GSH allowing precursor amino acids to be reutilized for intracellular GSH
bull Exposure to POPs induces GGT as a defensive mechanism
bull Within normal range predicts type 2 diabetes coronary heart disease hypertension stroke dyslipidemia chronic kidney disease and cancer
bull Men with GGT gt50 UI had ~26 fold risk for diabetes compared to those with lt10 Those with 40-49 had a ~20 fold risk
bull Levels within normal range occur with obesity xs alcohol cigarette smoking physical inactivity high meat low fruit and vegetable intake
bull Cumulative biomarker for environmental pollutants
Lee DH et al (2003) Gamma-glutamyltransferase and diabetesmdasha 4 year follow-up study Diabetologia 46359ndash364
Pamela A et al Serum gamma-glutamyltransferase linking together environmental pollution redox equilibria and progression of atherosclerosis Clin Chem
Lab Med 200947(12)1583-4
Lee DH et al Serum gamma-glutamyltransferase new insights about an old enzyme J Epidemiol Community Health 2009 Nov63(11)884-6
Lee DH et alSerum gamma-glutamyltransferase predicts non-fatal myocardial infarction and fatal coronary heart disease among 28838 middle-aged men and
women Eur Heart J 2006272170ndash6
Lee DH et al Gamma-glutamyltransferase and diabetes--a 4 year follow-up study Diabetologia 2003 Mar46(3)359-64
Lee DH et al Can persistent organic pollutants explain the association between serum gamma-glutamyltransferase and type 2 diabetes Diabetologia 2008
Mar51(3)402-7
GGT and Alcohol Consumption
bull GGT directly correlates with alcohol consumption
bull In a non-uniform population 40 gd will elevate GGT ~15
bull Watch for false negatives
bull Genomic variation
bull Are these the ones most
sensitive todamaged by
chemical toxins
bull Could up-regulation of GGT in light alcohol consumption be reason for benefit
0
10
20
30
40
50
60
70
80
0 200 400 600 800
Grams of Ethanol per Week
Adapted from Nagaya T et al Dose-response relationships between drinking and serum tests in Japanese men
aged 40ndash59 years Alcohol 1999 Feb 17(2) 133ndash8
GGT Correlates With Toxic Metal Levels
Lee DH et al Graded associations of blood lead and urinary cadmium concentrations with oxidative-stress-related markers in the
US population results from the third National Health and Nutrition Examination Survey Environ Health
perspect 2006 Mar114(3)350-4
GGT and Diabetes Risk
0
5
10
15
20
25
30
lt10 10-19 20-29 30-39 40-49 gt50
Dia
bete
s R
isk
GGT
bull GGT over 50 associated with tripling of death rate
bull 30-40 associated with doubling
GGT Levels
Correlate with
Risk of Death
Brenner H et al Distribution determinants and prognostic value of gamma-glutamyltransferase for all-cause
mortality in a cohort of construction workers from southern Germany Prev Med 1997 26 305ndash10
GGT From Small US Company
with Young Workers
0
10
20
30
40
50
60
0 20 40 60 80 100
GGT Data from Canadian Oil Field
Workers
0
50
100
150
200
250
300
350
400
450
lt10 10-20 20-30 30-40 40-50 50-60 60-07 70-80 80-90 90-100 100-110 110-120 gt120
GGTP
20-fold increased risk of diabetes
Uric Acid Indirect Measure of POPs
bull Poly-fluorinated hydrocarbons (PFOA and PFOS) associated
with increased serum uric acid
Lin CY et al Association among serum perfluoroalkyl chemicals glucose homeostasis and metabolic syndrome
in adolescents and adults Diabetes Care 2009 Apr32(4)702-7
Steenland K et al Association of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) with uric
acid among adults with elevated community exposure to PFOA Environ Health Perspect 2010 Feb118229-33
Steenland 2010 Open Access
ALT Indirect Measure of POPs
bull ALT (proxy marker) elevation in 104 (not including viral
hepatitis hemochromatosis or alcoholic liver disease) of
NHANES 03-04 subset
bull Risk of elevated ALT increased dose-dependently with
cadmium lead mercury and PCB exposure
bull 100 of individuals had detectable PCBs 925 mercury
and 996 had detectable lead
bull In 2005-08 prevalence of NAFLD in US was 11 a
growing cause of chronic liver disease
Cave M et al Polychlorinated biphenyls lead and mercury are associated with liver disease in American adults
NHANES 2003-2004 Environ Health Perspect 2010 Dec118(12)1735-42
Younossi ZM et al Changes in the prevalence of the most common causes of chronic liver diseases in the United
States from 1988 to 2008 Clin Gastroenterol Hepatol 2011 Jun9(6)524-530e1
Bilirubin as a Marker of POPs
bull Degree of serum bilirubin increase is prognostically significant in chronic liver dysfunction
bull Mono-ortho PCB TEQ values were found to be significantly positively associated with bilirubin (β=071 P=0008) following adjustment for multiple potential confounders
bull Bilirubin levels significantly correlated with PCBs -105-118-126 and -194
bull Smoking appears to be the biggest confounder
Dufour DR et al 2000 Diagnosis and monitoring of hepatic injury II Recommendations for use of laboratory
tests in screening diagnosis and monitoring Clin Chem 46 2050ndash68
Kumar J et al Persistent organic pollutants and liver dysfunction biomarkers in a population-based human sample
of men and women Environ Res 2014134251-256
Perf
luo
rin
ate
dP
OP
s a
nd
Co
mm
on
Blo
od
Tests
Gleason JA et al Associations of perfluorinated chemical serum concentrations and biomarkers of liver function and uric acid in the
US population (NHANES) 2007-2010 Environ Res 20151368-14
Liver Enzymes Reflect Toxic Load
bull AST ALT and GGT increase with body load of PCBs and OCPs
bull Some non-linear
bull Oxychlordanetop quartile
ALT 10
GGT 25
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
LDL-Cholesterol as Measure of POPs
bull 5-year prospective study to determine if POP levels predict future elevation in LDL-cholesterol
bull 598 subjects initially at age 70
bull Looked at 23 POPs
bull Best correlation with PCB 194
Penell J Lind L Salihovic S et al Persistent organic pollutants are related to change in circulating
lipid levels during a 5 year follow-up Environ Res 134(2014)190ndash197
oxLDL as Measure of POPs
bull 992 70-year old individuals (50 women)
bull Sum of PCBs showed strong significant positive associations with ox-LDL and significant negative associations with glutathione-related markers (GSSG and GSSGGSH)
bull A number of POPs (PCB-99 138 153 156 170 180 194 206 and 209) showed strong significant positive association with ox-LDL
Kumar J et al Influence of persistent organic pollutants on oxidative stress in population-based samples
Chemosphere 2014114303-309
Homocysteine is Increased by Pb amp Cd
Guallar E et al Confounding of the relation between homocysteine and peripheral arterial disease by lead cadmium and renal function Am J Epidemiol 2006 Apr 15163(8)700-8
Nutrient Deficiencies Accentuate
Effects of Lead on Homocysteine
bull Deficiencies in folate B6 or B12 make lead more toxic
Lee YM Et al Association of homocysteine levels with blood lead levels and micronutrients in the US general population J Prev Med Public Health 2012 Nov45(6)387-93
T4 amp T3 and PCBs
bull PCBs decrease T4 production
bull PCBs inhibit iodotyrosinedeiodinase activity
bull Study done in pregnant women which implies effect on fetus IQ
Kim S Park J Kim HJ et al Association between several persistent organic pollutants and thyroid hormone levels in serum among the pregnant women of Korea Environ Int 2013 Sep59442-8Shimizu R Yamaguchi M Uramaru N et al Structure-activity relationships of 44 halogenated compounds for iodotyrosinedeiodinase-inhibitory activity Toxicology 2013 Dec 6314(1)22-9
T4 amp T3 and PCBs
bull Not just humans being affected
bull Large study of dolphins shows exactly the same effects
Schwacke LH Zolman ES Balmer BC et al Anaemia hypothyroidism and immune suppression associated with polychlorinated biphenyl exposure in bottlenose dolphins (Tursiops truncatus) Proceed Royal Society B doi101098rspb20110665
8-OHdG
bull Oxidized nucleoside
bull Direct measure of DNA damage
bull Indirect measure of oxidative stress and toxin load
bull Correlates with
Multiple cancers
Mitochondrial damage
Rate of aging
Smoking
Several toxinsWalter Crinnion ldquoTotal Toxic Loadrdquo AANP 2015
8-OHdG Correlates with Pack-Years
of Smoking
Yano T et al Significance of the urinary 8-OHdG level as an oxidative stress marker in lung cancer patients Lung Cancer
2009 Jan63(1)111-4
8-OHdG Correlates
with Mercury
Chen C et al Increased oxidative DNA damage as assessed by urinary 8-hydroxy-2-deoxyguanosine
concentrations and serum redox status in persons exposed to mercury Clin Chem 2005 Apr51(4)759-67
Toxin Effects Worse with Aging
bull Thyroid function decreases with PFOA levels
bull But only after age 63
Shrestha S Bloom MS Yucel R et al Perfluoroalkyl substances and thyroid function in older adults Environ Int 2015 Feb75206-14
Insightful 23-Year Prospective Study
1 lt 50 there is no difference between those with the lowest and highest PCBs
2 In youngest group insulin production increases in response to toxin level As expected since blocking of
insulin receptor sites by PCBs
requires more insulin
3 That adaptive ability decreases with aging
4 At age 50 all the measures show very strong toxin-dose response
Cumulative damage impairs ability to adapt
Suarez-Lopez JR et al Persistent organic pollutants in young adults and changes in glucose related metabolism over a 23-year follow-up Environ Res 2015 Feb137485-94
Recommendations
High body toxic load
GGT gt 25
Uric acid gt 50 mgdl
ALT gt30 UL
Bilirubin gt08 mgdl
CBC lt 6000
Platelet lt 250000
Low T3 andor T4
Monitor Total Toxic Load
8-OHdG gt4
ldquoUnconventionalrdquo Laboratory Tests
bull Challenge testing
bull Hair analysis
bull Direct measures of solvents and POPs in blood urine adipose tissue
Evaluation of Metal Exposure ndash Provocation
bull Provocation ndash the use of a chelating agent ndash before urine collection often done clinically but several limitations
No ldquoofficialrdquo reference range for provoked urine
Most chelating agents do not extract metals from all tissues thus
does not necessarily represent total body burden
bull Example Brain is one of the main target organs for both elemental and organic
mercury yet agents do not chelate brain mercury
bull Despite limitations widely used and advocated by clinicians in part to see efficacy of chelating agent as a guide to treatment and based on empirical evidence
Rooney JP The role of thiols dithiols nutritional factors and interacting ligands in the toxicology of mercury
Toxicology 2007
Is Challenge Testing Valid
bull Poor correlations of standard tests for mercury
bull Unpublished research from corporate wellness project
bull Published amalgam number correlation
bull Published fish consumption correlation
What We Found In Canada
bull Deviations from the mean of 14 29 and 91 respectively
bull DMPS is spreading distribution suggesting that it is better at differentiating mercury body load
bull Some VERY high
Hg Assessment Correlations
bull Extensive measurements in 65 Whole blood Hg
Oral DMPS challenge
Amalgam surfaces
bull Correlations Whole blood w pre urine r = 040
Whole blood w post urine r = 057
Pre urine w post urine r = 068
Amalgams w pre urine r = 026
Amalgams w whole blood r = 036
Amalgams with post urine 044
bull Clear documentation that
challenge testing is better00
100
200
300
400
500
600
0 10 20 30 40 50
Po
st
Uri
ne H
g u
gg
Number of amalgams
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
Toxin Half Lives in BloodToxin ldquoNormalrdquo (mgL) Acute Toxic (mgL) Half-Life
Arsenic 0002-007 005-025 2-4 days (CDC)
Benzene 00002 05-10 days
Cadmium 00003-00065 0015-005 16 years
Chlordane 0001 00025 3-4 days
DDTDDE 2-10 years
Dieldrin 00015 015-030 2-12 months
Ethanol 1000-2000 15hour
Lead 009 04-06 1-15 mo (2+ yrs bone)
Mercury 00015-0002 005-02 2 months (CDC)
PCBs 3-25 years
Toluene 05-3 days
Schulz M et al Therapeutic and toxic blood concentrations of nearly 1000 drugs and other xenobiotics Crit Care 2012 Jul 2616(4)R136
Bioaccumulation (POPs)
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
DDT banned in 1972 PCBs banned in 1977
Bioaccumulation (Cd)
Think BroadlyExogenous
Metals
Chemicalsbull Inorganic
bull Fluoride
bull Organic
bull POPs
bull Drugs
Particulate matter
Molds
Microbial
Radiationbull Light
bull Medical
bull Cell phone
Endogenous
Gut-derived toxins
Non-end product metabolites
Poorly detoxified hormones
Catecholamines (if SNP)
Toxins of Choice
Alcohol
Marijuana
Food constituents
High fructose corn syrup
Salt (acid-forming diet)
Wheat if zonulin (70)
Obesity Epidemic ndash POPs AND HFCS
47Bray GA Fructose should we worry Int J Obes (Lond) 2008 Dec32 Suppl 7S127-31
How Toxins Cause Damage 13
bull Increase free radical production
Cd induces production of ROS
Malathion inhibits catalase and glutathione peroxidase
Homocysteine oxidizes LDL cholesterol
bull Poison enzyme systems (compete with nutritional cofactors for binding sites)
Pb poisons delta aminolevulinic acid dehydratase
Cd inhibits catalase glutathione reductase and lowers
glutathione levels
bull Replace structural minerals
Pb displaces Ca in bone
How Toxins Cause Damage 23
bull Damage DNA
Benzene - causes chromosomal damage
Pesticides ndash fruit growers have more DNA damage
Phthalates and insecticides ndash damage sperm DNA
4-hydroxy catechol estrogen (4-OHE) damages breast DNA
bull Epigenetic dysmodulation
Higher cord blood levels of hexachlorobenzene associated
with 2x greater risk for obesity in children
bull Damage cell membranes
Common mechanism for heavy metals inactivates
membrane enzymes ion channels and pumps
How Toxins Cause Damage 33
bull Block insulin receptor sites
PCBs and phthalates
bull Highest levels associated with a 4 to 20-fold greater diabetes risk
bull Imbalance hormones many toxin examples
Arsenic
bull Disrupts thyroid hormone and retinoic acid receptors
Phthalates
bull Act as anti-androgens
bull More than 75 of the US population has measurable levels of
several phthalate metabolites in the urine
PCBs
bull Lower testosterone levels in men
Which are the Worst Toxins
bull According to the CDC
Toxicity
Population toxic load
Prevalence in toxic waste sites
bull According to clinical importance
Exposure
of disease
Ability of the body to detoxifyexcrete
Ag
en
cy
fo
r T
oxic
Su
bs
tan
ce
s a
nd
Dis
ea
se
Reg
istr
y
Pri
ori
ty L
ist
The Worst Toxins Clinically
My Rank Toxin Diseases Primary Sources
1 Arsenic Cancers diabetes gout Water chicken rice
2 DDT ADHD dementia diabetes Everywhere
3 Phthalates ADHD diabetes Soft plastics HABAs
4 PBDEs ADHD diabetes Flame retardant fabrics
5 PAHs ADHD cancers dyslipidemia Smoking charbroiling
6 PCBs Cancers diabetes MI RA Everywhere
7 Mercury Dementia ldquoSilverrdquo fillings fish
8 Lead Cardiovascular disease IQ Paint water
Glyphosate Research invalid
Conventional Laboratory Tests Reflect
Toxic Load in ldquoNormalrdquo Range
bull Surprising number show toxin exposure
CBC RBC WBC platelet count hemoglobin basophilic
stippling
Liver enzymes ALT GGTP
Inflammatory markers CRP
Lipids LDL oxLDL triglycerides
Blood sugar insulin FBS 2-hour PP
Metabolites bilirubin uric acid homocysteine 8-OHdG
Thyroid T3 T4 TSH
bull The historic ldquonormalrdquo range has been changing as the population has become more toxic
WBC Lowered by PCB and OCP Exposure
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
0
1
2
3
4
5
6
7
8
1st Quartrile 2nd Quartile 3rd Quartile 4th Quartile
WBCbull Strong inverse correlation with PCBs and OCPs and CBC
bull Linear with almost all PCBs
bull High variability with OCPs
bull Within ldquonormalrdquo range
Effects on WBC Worsen with Years
of Exposure to Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Platelet Count Decreases with Years
of Exposure tp Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Solvents Decrease Platelet Count
bull Compared workers exposed 23 hrday to those exposed most of day to toluene
bull All wore face masks and protective gear
bull Platelet count 14 lower 252 versus 216ml
bull Impairment of sympathetic nerves (OR = 413)
bull Impairment of peripheral nerves (OR = 694)
bull Positive relationship between neurological abnormalities and a self-reported neuropsychiatric measurement (r = 035-066)
Shih HT et al Subclinical abnormalities in workers with continuous low-level toluene exposure Toxicol Ind Health 2011 Sep27(8)691-9
Basophilic Stippling of Red Cells
Toxinsbull Arsenic
bull Lead
Diseasesbull Alpha-thalassemia HbH Disease
bull Beta thalassemia
bull Hereditary pyrimidine 5-nucleotidase deficiency
bull Myelodysplastic syndrome
bull Sideroblastic anemia
bull Thrombotic thrombocytopenic purpura
GGT Indirect Measure of POPsbull Glutathione is key intracellular defense against oxidative stress
bull Cellular GGT metabolizes extracellular GSH allowing precursor amino acids to be reutilized for intracellular GSH
bull Exposure to POPs induces GGT as a defensive mechanism
bull Within normal range predicts type 2 diabetes coronary heart disease hypertension stroke dyslipidemia chronic kidney disease and cancer
bull Men with GGT gt50 UI had ~26 fold risk for diabetes compared to those with lt10 Those with 40-49 had a ~20 fold risk
bull Levels within normal range occur with obesity xs alcohol cigarette smoking physical inactivity high meat low fruit and vegetable intake
bull Cumulative biomarker for environmental pollutants
Lee DH et al (2003) Gamma-glutamyltransferase and diabetesmdasha 4 year follow-up study Diabetologia 46359ndash364
Pamela A et al Serum gamma-glutamyltransferase linking together environmental pollution redox equilibria and progression of atherosclerosis Clin Chem
Lab Med 200947(12)1583-4
Lee DH et al Serum gamma-glutamyltransferase new insights about an old enzyme J Epidemiol Community Health 2009 Nov63(11)884-6
Lee DH et alSerum gamma-glutamyltransferase predicts non-fatal myocardial infarction and fatal coronary heart disease among 28838 middle-aged men and
women Eur Heart J 2006272170ndash6
Lee DH et al Gamma-glutamyltransferase and diabetes--a 4 year follow-up study Diabetologia 2003 Mar46(3)359-64
Lee DH et al Can persistent organic pollutants explain the association between serum gamma-glutamyltransferase and type 2 diabetes Diabetologia 2008
Mar51(3)402-7
GGT and Alcohol Consumption
bull GGT directly correlates with alcohol consumption
bull In a non-uniform population 40 gd will elevate GGT ~15
bull Watch for false negatives
bull Genomic variation
bull Are these the ones most
sensitive todamaged by
chemical toxins
bull Could up-regulation of GGT in light alcohol consumption be reason for benefit
0
10
20
30
40
50
60
70
80
0 200 400 600 800
Grams of Ethanol per Week
Adapted from Nagaya T et al Dose-response relationships between drinking and serum tests in Japanese men
aged 40ndash59 years Alcohol 1999 Feb 17(2) 133ndash8
GGT Correlates With Toxic Metal Levels
Lee DH et al Graded associations of blood lead and urinary cadmium concentrations with oxidative-stress-related markers in the
US population results from the third National Health and Nutrition Examination Survey Environ Health
perspect 2006 Mar114(3)350-4
GGT and Diabetes Risk
0
5
10
15
20
25
30
lt10 10-19 20-29 30-39 40-49 gt50
Dia
bete
s R
isk
GGT
bull GGT over 50 associated with tripling of death rate
bull 30-40 associated with doubling
GGT Levels
Correlate with
Risk of Death
Brenner H et al Distribution determinants and prognostic value of gamma-glutamyltransferase for all-cause
mortality in a cohort of construction workers from southern Germany Prev Med 1997 26 305ndash10
GGT From Small US Company
with Young Workers
0
10
20
30
40
50
60
0 20 40 60 80 100
GGT Data from Canadian Oil Field
Workers
0
50
100
150
200
250
300
350
400
450
lt10 10-20 20-30 30-40 40-50 50-60 60-07 70-80 80-90 90-100 100-110 110-120 gt120
GGTP
20-fold increased risk of diabetes
Uric Acid Indirect Measure of POPs
bull Poly-fluorinated hydrocarbons (PFOA and PFOS) associated
with increased serum uric acid
Lin CY et al Association among serum perfluoroalkyl chemicals glucose homeostasis and metabolic syndrome
in adolescents and adults Diabetes Care 2009 Apr32(4)702-7
Steenland K et al Association of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) with uric
acid among adults with elevated community exposure to PFOA Environ Health Perspect 2010 Feb118229-33
Steenland 2010 Open Access
ALT Indirect Measure of POPs
bull ALT (proxy marker) elevation in 104 (not including viral
hepatitis hemochromatosis or alcoholic liver disease) of
NHANES 03-04 subset
bull Risk of elevated ALT increased dose-dependently with
cadmium lead mercury and PCB exposure
bull 100 of individuals had detectable PCBs 925 mercury
and 996 had detectable lead
bull In 2005-08 prevalence of NAFLD in US was 11 a
growing cause of chronic liver disease
Cave M et al Polychlorinated biphenyls lead and mercury are associated with liver disease in American adults
NHANES 2003-2004 Environ Health Perspect 2010 Dec118(12)1735-42
Younossi ZM et al Changes in the prevalence of the most common causes of chronic liver diseases in the United
States from 1988 to 2008 Clin Gastroenterol Hepatol 2011 Jun9(6)524-530e1
Bilirubin as a Marker of POPs
bull Degree of serum bilirubin increase is prognostically significant in chronic liver dysfunction
bull Mono-ortho PCB TEQ values were found to be significantly positively associated with bilirubin (β=071 P=0008) following adjustment for multiple potential confounders
bull Bilirubin levels significantly correlated with PCBs -105-118-126 and -194
bull Smoking appears to be the biggest confounder
Dufour DR et al 2000 Diagnosis and monitoring of hepatic injury II Recommendations for use of laboratory
tests in screening diagnosis and monitoring Clin Chem 46 2050ndash68
Kumar J et al Persistent organic pollutants and liver dysfunction biomarkers in a population-based human sample
of men and women Environ Res 2014134251-256
Perf
luo
rin
ate
dP
OP
s a
nd
Co
mm
on
Blo
od
Tests
Gleason JA et al Associations of perfluorinated chemical serum concentrations and biomarkers of liver function and uric acid in the
US population (NHANES) 2007-2010 Environ Res 20151368-14
Liver Enzymes Reflect Toxic Load
bull AST ALT and GGT increase with body load of PCBs and OCPs
bull Some non-linear
bull Oxychlordanetop quartile
ALT 10
GGT 25
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
LDL-Cholesterol as Measure of POPs
bull 5-year prospective study to determine if POP levels predict future elevation in LDL-cholesterol
bull 598 subjects initially at age 70
bull Looked at 23 POPs
bull Best correlation with PCB 194
Penell J Lind L Salihovic S et al Persistent organic pollutants are related to change in circulating
lipid levels during a 5 year follow-up Environ Res 134(2014)190ndash197
oxLDL as Measure of POPs
bull 992 70-year old individuals (50 women)
bull Sum of PCBs showed strong significant positive associations with ox-LDL and significant negative associations with glutathione-related markers (GSSG and GSSGGSH)
bull A number of POPs (PCB-99 138 153 156 170 180 194 206 and 209) showed strong significant positive association with ox-LDL
Kumar J et al Influence of persistent organic pollutants on oxidative stress in population-based samples
Chemosphere 2014114303-309
Homocysteine is Increased by Pb amp Cd
Guallar E et al Confounding of the relation between homocysteine and peripheral arterial disease by lead cadmium and renal function Am J Epidemiol 2006 Apr 15163(8)700-8
Nutrient Deficiencies Accentuate
Effects of Lead on Homocysteine
bull Deficiencies in folate B6 or B12 make lead more toxic
Lee YM Et al Association of homocysteine levels with blood lead levels and micronutrients in the US general population J Prev Med Public Health 2012 Nov45(6)387-93
T4 amp T3 and PCBs
bull PCBs decrease T4 production
bull PCBs inhibit iodotyrosinedeiodinase activity
bull Study done in pregnant women which implies effect on fetus IQ
Kim S Park J Kim HJ et al Association between several persistent organic pollutants and thyroid hormone levels in serum among the pregnant women of Korea Environ Int 2013 Sep59442-8Shimizu R Yamaguchi M Uramaru N et al Structure-activity relationships of 44 halogenated compounds for iodotyrosinedeiodinase-inhibitory activity Toxicology 2013 Dec 6314(1)22-9
T4 amp T3 and PCBs
bull Not just humans being affected
bull Large study of dolphins shows exactly the same effects
Schwacke LH Zolman ES Balmer BC et al Anaemia hypothyroidism and immune suppression associated with polychlorinated biphenyl exposure in bottlenose dolphins (Tursiops truncatus) Proceed Royal Society B doi101098rspb20110665
8-OHdG
bull Oxidized nucleoside
bull Direct measure of DNA damage
bull Indirect measure of oxidative stress and toxin load
bull Correlates with
Multiple cancers
Mitochondrial damage
Rate of aging
Smoking
Several toxinsWalter Crinnion ldquoTotal Toxic Loadrdquo AANP 2015
8-OHdG Correlates with Pack-Years
of Smoking
Yano T et al Significance of the urinary 8-OHdG level as an oxidative stress marker in lung cancer patients Lung Cancer
2009 Jan63(1)111-4
8-OHdG Correlates
with Mercury
Chen C et al Increased oxidative DNA damage as assessed by urinary 8-hydroxy-2-deoxyguanosine
concentrations and serum redox status in persons exposed to mercury Clin Chem 2005 Apr51(4)759-67
Toxin Effects Worse with Aging
bull Thyroid function decreases with PFOA levels
bull But only after age 63
Shrestha S Bloom MS Yucel R et al Perfluoroalkyl substances and thyroid function in older adults Environ Int 2015 Feb75206-14
Insightful 23-Year Prospective Study
1 lt 50 there is no difference between those with the lowest and highest PCBs
2 In youngest group insulin production increases in response to toxin level As expected since blocking of
insulin receptor sites by PCBs
requires more insulin
3 That adaptive ability decreases with aging
4 At age 50 all the measures show very strong toxin-dose response
Cumulative damage impairs ability to adapt
Suarez-Lopez JR et al Persistent organic pollutants in young adults and changes in glucose related metabolism over a 23-year follow-up Environ Res 2015 Feb137485-94
Recommendations
High body toxic load
GGT gt 25
Uric acid gt 50 mgdl
ALT gt30 UL
Bilirubin gt08 mgdl
CBC lt 6000
Platelet lt 250000
Low T3 andor T4
Monitor Total Toxic Load
8-OHdG gt4
ldquoUnconventionalrdquo Laboratory Tests
bull Challenge testing
bull Hair analysis
bull Direct measures of solvents and POPs in blood urine adipose tissue
Evaluation of Metal Exposure ndash Provocation
bull Provocation ndash the use of a chelating agent ndash before urine collection often done clinically but several limitations
No ldquoofficialrdquo reference range for provoked urine
Most chelating agents do not extract metals from all tissues thus
does not necessarily represent total body burden
bull Example Brain is one of the main target organs for both elemental and organic
mercury yet agents do not chelate brain mercury
bull Despite limitations widely used and advocated by clinicians in part to see efficacy of chelating agent as a guide to treatment and based on empirical evidence
Rooney JP The role of thiols dithiols nutritional factors and interacting ligands in the toxicology of mercury
Toxicology 2007
Is Challenge Testing Valid
bull Poor correlations of standard tests for mercury
bull Unpublished research from corporate wellness project
bull Published amalgam number correlation
bull Published fish consumption correlation
What We Found In Canada
bull Deviations from the mean of 14 29 and 91 respectively
bull DMPS is spreading distribution suggesting that it is better at differentiating mercury body load
bull Some VERY high
Hg Assessment Correlations
bull Extensive measurements in 65 Whole blood Hg
Oral DMPS challenge
Amalgam surfaces
bull Correlations Whole blood w pre urine r = 040
Whole blood w post urine r = 057
Pre urine w post urine r = 068
Amalgams w pre urine r = 026
Amalgams w whole blood r = 036
Amalgams with post urine 044
bull Clear documentation that
challenge testing is better00
100
200
300
400
500
600
0 10 20 30 40 50
Po
st
Uri
ne H
g u
gg
Number of amalgams
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
Bioaccumulation (POPs)
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
DDT banned in 1972 PCBs banned in 1977
Bioaccumulation (Cd)
Think BroadlyExogenous
Metals
Chemicalsbull Inorganic
bull Fluoride
bull Organic
bull POPs
bull Drugs
Particulate matter
Molds
Microbial
Radiationbull Light
bull Medical
bull Cell phone
Endogenous
Gut-derived toxins
Non-end product metabolites
Poorly detoxified hormones
Catecholamines (if SNP)
Toxins of Choice
Alcohol
Marijuana
Food constituents
High fructose corn syrup
Salt (acid-forming diet)
Wheat if zonulin (70)
Obesity Epidemic ndash POPs AND HFCS
47Bray GA Fructose should we worry Int J Obes (Lond) 2008 Dec32 Suppl 7S127-31
How Toxins Cause Damage 13
bull Increase free radical production
Cd induces production of ROS
Malathion inhibits catalase and glutathione peroxidase
Homocysteine oxidizes LDL cholesterol
bull Poison enzyme systems (compete with nutritional cofactors for binding sites)
Pb poisons delta aminolevulinic acid dehydratase
Cd inhibits catalase glutathione reductase and lowers
glutathione levels
bull Replace structural minerals
Pb displaces Ca in bone
How Toxins Cause Damage 23
bull Damage DNA
Benzene - causes chromosomal damage
Pesticides ndash fruit growers have more DNA damage
Phthalates and insecticides ndash damage sperm DNA
4-hydroxy catechol estrogen (4-OHE) damages breast DNA
bull Epigenetic dysmodulation
Higher cord blood levels of hexachlorobenzene associated
with 2x greater risk for obesity in children
bull Damage cell membranes
Common mechanism for heavy metals inactivates
membrane enzymes ion channels and pumps
How Toxins Cause Damage 33
bull Block insulin receptor sites
PCBs and phthalates
bull Highest levels associated with a 4 to 20-fold greater diabetes risk
bull Imbalance hormones many toxin examples
Arsenic
bull Disrupts thyroid hormone and retinoic acid receptors
Phthalates
bull Act as anti-androgens
bull More than 75 of the US population has measurable levels of
several phthalate metabolites in the urine
PCBs
bull Lower testosterone levels in men
Which are the Worst Toxins
bull According to the CDC
Toxicity
Population toxic load
Prevalence in toxic waste sites
bull According to clinical importance
Exposure
of disease
Ability of the body to detoxifyexcrete
Ag
en
cy
fo
r T
oxic
Su
bs
tan
ce
s a
nd
Dis
ea
se
Reg
istr
y
Pri
ori
ty L
ist
The Worst Toxins Clinically
My Rank Toxin Diseases Primary Sources
1 Arsenic Cancers diabetes gout Water chicken rice
2 DDT ADHD dementia diabetes Everywhere
3 Phthalates ADHD diabetes Soft plastics HABAs
4 PBDEs ADHD diabetes Flame retardant fabrics
5 PAHs ADHD cancers dyslipidemia Smoking charbroiling
6 PCBs Cancers diabetes MI RA Everywhere
7 Mercury Dementia ldquoSilverrdquo fillings fish
8 Lead Cardiovascular disease IQ Paint water
Glyphosate Research invalid
Conventional Laboratory Tests Reflect
Toxic Load in ldquoNormalrdquo Range
bull Surprising number show toxin exposure
CBC RBC WBC platelet count hemoglobin basophilic
stippling
Liver enzymes ALT GGTP
Inflammatory markers CRP
Lipids LDL oxLDL triglycerides
Blood sugar insulin FBS 2-hour PP
Metabolites bilirubin uric acid homocysteine 8-OHdG
Thyroid T3 T4 TSH
bull The historic ldquonormalrdquo range has been changing as the population has become more toxic
WBC Lowered by PCB and OCP Exposure
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
0
1
2
3
4
5
6
7
8
1st Quartrile 2nd Quartile 3rd Quartile 4th Quartile
WBCbull Strong inverse correlation with PCBs and OCPs and CBC
bull Linear with almost all PCBs
bull High variability with OCPs
bull Within ldquonormalrdquo range
Effects on WBC Worsen with Years
of Exposure to Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Platelet Count Decreases with Years
of Exposure tp Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Solvents Decrease Platelet Count
bull Compared workers exposed 23 hrday to those exposed most of day to toluene
bull All wore face masks and protective gear
bull Platelet count 14 lower 252 versus 216ml
bull Impairment of sympathetic nerves (OR = 413)
bull Impairment of peripheral nerves (OR = 694)
bull Positive relationship between neurological abnormalities and a self-reported neuropsychiatric measurement (r = 035-066)
Shih HT et al Subclinical abnormalities in workers with continuous low-level toluene exposure Toxicol Ind Health 2011 Sep27(8)691-9
Basophilic Stippling of Red Cells
Toxinsbull Arsenic
bull Lead
Diseasesbull Alpha-thalassemia HbH Disease
bull Beta thalassemia
bull Hereditary pyrimidine 5-nucleotidase deficiency
bull Myelodysplastic syndrome
bull Sideroblastic anemia
bull Thrombotic thrombocytopenic purpura
GGT Indirect Measure of POPsbull Glutathione is key intracellular defense against oxidative stress
bull Cellular GGT metabolizes extracellular GSH allowing precursor amino acids to be reutilized for intracellular GSH
bull Exposure to POPs induces GGT as a defensive mechanism
bull Within normal range predicts type 2 diabetes coronary heart disease hypertension stroke dyslipidemia chronic kidney disease and cancer
bull Men with GGT gt50 UI had ~26 fold risk for diabetes compared to those with lt10 Those with 40-49 had a ~20 fold risk
bull Levels within normal range occur with obesity xs alcohol cigarette smoking physical inactivity high meat low fruit and vegetable intake
bull Cumulative biomarker for environmental pollutants
Lee DH et al (2003) Gamma-glutamyltransferase and diabetesmdasha 4 year follow-up study Diabetologia 46359ndash364
Pamela A et al Serum gamma-glutamyltransferase linking together environmental pollution redox equilibria and progression of atherosclerosis Clin Chem
Lab Med 200947(12)1583-4
Lee DH et al Serum gamma-glutamyltransferase new insights about an old enzyme J Epidemiol Community Health 2009 Nov63(11)884-6
Lee DH et alSerum gamma-glutamyltransferase predicts non-fatal myocardial infarction and fatal coronary heart disease among 28838 middle-aged men and
women Eur Heart J 2006272170ndash6
Lee DH et al Gamma-glutamyltransferase and diabetes--a 4 year follow-up study Diabetologia 2003 Mar46(3)359-64
Lee DH et al Can persistent organic pollutants explain the association between serum gamma-glutamyltransferase and type 2 diabetes Diabetologia 2008
Mar51(3)402-7
GGT and Alcohol Consumption
bull GGT directly correlates with alcohol consumption
bull In a non-uniform population 40 gd will elevate GGT ~15
bull Watch for false negatives
bull Genomic variation
bull Are these the ones most
sensitive todamaged by
chemical toxins
bull Could up-regulation of GGT in light alcohol consumption be reason for benefit
0
10
20
30
40
50
60
70
80
0 200 400 600 800
Grams of Ethanol per Week
Adapted from Nagaya T et al Dose-response relationships between drinking and serum tests in Japanese men
aged 40ndash59 years Alcohol 1999 Feb 17(2) 133ndash8
GGT Correlates With Toxic Metal Levels
Lee DH et al Graded associations of blood lead and urinary cadmium concentrations with oxidative-stress-related markers in the
US population results from the third National Health and Nutrition Examination Survey Environ Health
perspect 2006 Mar114(3)350-4
GGT and Diabetes Risk
0
5
10
15
20
25
30
lt10 10-19 20-29 30-39 40-49 gt50
Dia
bete
s R
isk
GGT
bull GGT over 50 associated with tripling of death rate
bull 30-40 associated with doubling
GGT Levels
Correlate with
Risk of Death
Brenner H et al Distribution determinants and prognostic value of gamma-glutamyltransferase for all-cause
mortality in a cohort of construction workers from southern Germany Prev Med 1997 26 305ndash10
GGT From Small US Company
with Young Workers
0
10
20
30
40
50
60
0 20 40 60 80 100
GGT Data from Canadian Oil Field
Workers
0
50
100
150
200
250
300
350
400
450
lt10 10-20 20-30 30-40 40-50 50-60 60-07 70-80 80-90 90-100 100-110 110-120 gt120
GGTP
20-fold increased risk of diabetes
Uric Acid Indirect Measure of POPs
bull Poly-fluorinated hydrocarbons (PFOA and PFOS) associated
with increased serum uric acid
Lin CY et al Association among serum perfluoroalkyl chemicals glucose homeostasis and metabolic syndrome
in adolescents and adults Diabetes Care 2009 Apr32(4)702-7
Steenland K et al Association of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) with uric
acid among adults with elevated community exposure to PFOA Environ Health Perspect 2010 Feb118229-33
Steenland 2010 Open Access
ALT Indirect Measure of POPs
bull ALT (proxy marker) elevation in 104 (not including viral
hepatitis hemochromatosis or alcoholic liver disease) of
NHANES 03-04 subset
bull Risk of elevated ALT increased dose-dependently with
cadmium lead mercury and PCB exposure
bull 100 of individuals had detectable PCBs 925 mercury
and 996 had detectable lead
bull In 2005-08 prevalence of NAFLD in US was 11 a
growing cause of chronic liver disease
Cave M et al Polychlorinated biphenyls lead and mercury are associated with liver disease in American adults
NHANES 2003-2004 Environ Health Perspect 2010 Dec118(12)1735-42
Younossi ZM et al Changes in the prevalence of the most common causes of chronic liver diseases in the United
States from 1988 to 2008 Clin Gastroenterol Hepatol 2011 Jun9(6)524-530e1
Bilirubin as a Marker of POPs
bull Degree of serum bilirubin increase is prognostically significant in chronic liver dysfunction
bull Mono-ortho PCB TEQ values were found to be significantly positively associated with bilirubin (β=071 P=0008) following adjustment for multiple potential confounders
bull Bilirubin levels significantly correlated with PCBs -105-118-126 and -194
bull Smoking appears to be the biggest confounder
Dufour DR et al 2000 Diagnosis and monitoring of hepatic injury II Recommendations for use of laboratory
tests in screening diagnosis and monitoring Clin Chem 46 2050ndash68
Kumar J et al Persistent organic pollutants and liver dysfunction biomarkers in a population-based human sample
of men and women Environ Res 2014134251-256
Perf
luo
rin
ate
dP
OP
s a
nd
Co
mm
on
Blo
od
Tests
Gleason JA et al Associations of perfluorinated chemical serum concentrations and biomarkers of liver function and uric acid in the
US population (NHANES) 2007-2010 Environ Res 20151368-14
Liver Enzymes Reflect Toxic Load
bull AST ALT and GGT increase with body load of PCBs and OCPs
bull Some non-linear
bull Oxychlordanetop quartile
ALT 10
GGT 25
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
LDL-Cholesterol as Measure of POPs
bull 5-year prospective study to determine if POP levels predict future elevation in LDL-cholesterol
bull 598 subjects initially at age 70
bull Looked at 23 POPs
bull Best correlation with PCB 194
Penell J Lind L Salihovic S et al Persistent organic pollutants are related to change in circulating
lipid levels during a 5 year follow-up Environ Res 134(2014)190ndash197
oxLDL as Measure of POPs
bull 992 70-year old individuals (50 women)
bull Sum of PCBs showed strong significant positive associations with ox-LDL and significant negative associations with glutathione-related markers (GSSG and GSSGGSH)
bull A number of POPs (PCB-99 138 153 156 170 180 194 206 and 209) showed strong significant positive association with ox-LDL
Kumar J et al Influence of persistent organic pollutants on oxidative stress in population-based samples
Chemosphere 2014114303-309
Homocysteine is Increased by Pb amp Cd
Guallar E et al Confounding of the relation between homocysteine and peripheral arterial disease by lead cadmium and renal function Am J Epidemiol 2006 Apr 15163(8)700-8
Nutrient Deficiencies Accentuate
Effects of Lead on Homocysteine
bull Deficiencies in folate B6 or B12 make lead more toxic
Lee YM Et al Association of homocysteine levels with blood lead levels and micronutrients in the US general population J Prev Med Public Health 2012 Nov45(6)387-93
T4 amp T3 and PCBs
bull PCBs decrease T4 production
bull PCBs inhibit iodotyrosinedeiodinase activity
bull Study done in pregnant women which implies effect on fetus IQ
Kim S Park J Kim HJ et al Association between several persistent organic pollutants and thyroid hormone levels in serum among the pregnant women of Korea Environ Int 2013 Sep59442-8Shimizu R Yamaguchi M Uramaru N et al Structure-activity relationships of 44 halogenated compounds for iodotyrosinedeiodinase-inhibitory activity Toxicology 2013 Dec 6314(1)22-9
T4 amp T3 and PCBs
bull Not just humans being affected
bull Large study of dolphins shows exactly the same effects
Schwacke LH Zolman ES Balmer BC et al Anaemia hypothyroidism and immune suppression associated with polychlorinated biphenyl exposure in bottlenose dolphins (Tursiops truncatus) Proceed Royal Society B doi101098rspb20110665
8-OHdG
bull Oxidized nucleoside
bull Direct measure of DNA damage
bull Indirect measure of oxidative stress and toxin load
bull Correlates with
Multiple cancers
Mitochondrial damage
Rate of aging
Smoking
Several toxinsWalter Crinnion ldquoTotal Toxic Loadrdquo AANP 2015
8-OHdG Correlates with Pack-Years
of Smoking
Yano T et al Significance of the urinary 8-OHdG level as an oxidative stress marker in lung cancer patients Lung Cancer
2009 Jan63(1)111-4
8-OHdG Correlates
with Mercury
Chen C et al Increased oxidative DNA damage as assessed by urinary 8-hydroxy-2-deoxyguanosine
concentrations and serum redox status in persons exposed to mercury Clin Chem 2005 Apr51(4)759-67
Toxin Effects Worse with Aging
bull Thyroid function decreases with PFOA levels
bull But only after age 63
Shrestha S Bloom MS Yucel R et al Perfluoroalkyl substances and thyroid function in older adults Environ Int 2015 Feb75206-14
Insightful 23-Year Prospective Study
1 lt 50 there is no difference between those with the lowest and highest PCBs
2 In youngest group insulin production increases in response to toxin level As expected since blocking of
insulin receptor sites by PCBs
requires more insulin
3 That adaptive ability decreases with aging
4 At age 50 all the measures show very strong toxin-dose response
Cumulative damage impairs ability to adapt
Suarez-Lopez JR et al Persistent organic pollutants in young adults and changes in glucose related metabolism over a 23-year follow-up Environ Res 2015 Feb137485-94
Recommendations
High body toxic load
GGT gt 25
Uric acid gt 50 mgdl
ALT gt30 UL
Bilirubin gt08 mgdl
CBC lt 6000
Platelet lt 250000
Low T3 andor T4
Monitor Total Toxic Load
8-OHdG gt4
ldquoUnconventionalrdquo Laboratory Tests
bull Challenge testing
bull Hair analysis
bull Direct measures of solvents and POPs in blood urine adipose tissue
Evaluation of Metal Exposure ndash Provocation
bull Provocation ndash the use of a chelating agent ndash before urine collection often done clinically but several limitations
No ldquoofficialrdquo reference range for provoked urine
Most chelating agents do not extract metals from all tissues thus
does not necessarily represent total body burden
bull Example Brain is one of the main target organs for both elemental and organic
mercury yet agents do not chelate brain mercury
bull Despite limitations widely used and advocated by clinicians in part to see efficacy of chelating agent as a guide to treatment and based on empirical evidence
Rooney JP The role of thiols dithiols nutritional factors and interacting ligands in the toxicology of mercury
Toxicology 2007
Is Challenge Testing Valid
bull Poor correlations of standard tests for mercury
bull Unpublished research from corporate wellness project
bull Published amalgam number correlation
bull Published fish consumption correlation
What We Found In Canada
bull Deviations from the mean of 14 29 and 91 respectively
bull DMPS is spreading distribution suggesting that it is better at differentiating mercury body load
bull Some VERY high
Hg Assessment Correlations
bull Extensive measurements in 65 Whole blood Hg
Oral DMPS challenge
Amalgam surfaces
bull Correlations Whole blood w pre urine r = 040
Whole blood w post urine r = 057
Pre urine w post urine r = 068
Amalgams w pre urine r = 026
Amalgams w whole blood r = 036
Amalgams with post urine 044
bull Clear documentation that
challenge testing is better00
100
200
300
400
500
600
0 10 20 30 40 50
Po
st
Uri
ne H
g u
gg
Number of amalgams
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
Bioaccumulation (Cd)
Think BroadlyExogenous
Metals
Chemicalsbull Inorganic
bull Fluoride
bull Organic
bull POPs
bull Drugs
Particulate matter
Molds
Microbial
Radiationbull Light
bull Medical
bull Cell phone
Endogenous
Gut-derived toxins
Non-end product metabolites
Poorly detoxified hormones
Catecholamines (if SNP)
Toxins of Choice
Alcohol
Marijuana
Food constituents
High fructose corn syrup
Salt (acid-forming diet)
Wheat if zonulin (70)
Obesity Epidemic ndash POPs AND HFCS
47Bray GA Fructose should we worry Int J Obes (Lond) 2008 Dec32 Suppl 7S127-31
How Toxins Cause Damage 13
bull Increase free radical production
Cd induces production of ROS
Malathion inhibits catalase and glutathione peroxidase
Homocysteine oxidizes LDL cholesterol
bull Poison enzyme systems (compete with nutritional cofactors for binding sites)
Pb poisons delta aminolevulinic acid dehydratase
Cd inhibits catalase glutathione reductase and lowers
glutathione levels
bull Replace structural minerals
Pb displaces Ca in bone
How Toxins Cause Damage 23
bull Damage DNA
Benzene - causes chromosomal damage
Pesticides ndash fruit growers have more DNA damage
Phthalates and insecticides ndash damage sperm DNA
4-hydroxy catechol estrogen (4-OHE) damages breast DNA
bull Epigenetic dysmodulation
Higher cord blood levels of hexachlorobenzene associated
with 2x greater risk for obesity in children
bull Damage cell membranes
Common mechanism for heavy metals inactivates
membrane enzymes ion channels and pumps
How Toxins Cause Damage 33
bull Block insulin receptor sites
PCBs and phthalates
bull Highest levels associated with a 4 to 20-fold greater diabetes risk
bull Imbalance hormones many toxin examples
Arsenic
bull Disrupts thyroid hormone and retinoic acid receptors
Phthalates
bull Act as anti-androgens
bull More than 75 of the US population has measurable levels of
several phthalate metabolites in the urine
PCBs
bull Lower testosterone levels in men
Which are the Worst Toxins
bull According to the CDC
Toxicity
Population toxic load
Prevalence in toxic waste sites
bull According to clinical importance
Exposure
of disease
Ability of the body to detoxifyexcrete
Ag
en
cy
fo
r T
oxic
Su
bs
tan
ce
s a
nd
Dis
ea
se
Reg
istr
y
Pri
ori
ty L
ist
The Worst Toxins Clinically
My Rank Toxin Diseases Primary Sources
1 Arsenic Cancers diabetes gout Water chicken rice
2 DDT ADHD dementia diabetes Everywhere
3 Phthalates ADHD diabetes Soft plastics HABAs
4 PBDEs ADHD diabetes Flame retardant fabrics
5 PAHs ADHD cancers dyslipidemia Smoking charbroiling
6 PCBs Cancers diabetes MI RA Everywhere
7 Mercury Dementia ldquoSilverrdquo fillings fish
8 Lead Cardiovascular disease IQ Paint water
Glyphosate Research invalid
Conventional Laboratory Tests Reflect
Toxic Load in ldquoNormalrdquo Range
bull Surprising number show toxin exposure
CBC RBC WBC platelet count hemoglobin basophilic
stippling
Liver enzymes ALT GGTP
Inflammatory markers CRP
Lipids LDL oxLDL triglycerides
Blood sugar insulin FBS 2-hour PP
Metabolites bilirubin uric acid homocysteine 8-OHdG
Thyroid T3 T4 TSH
bull The historic ldquonormalrdquo range has been changing as the population has become more toxic
WBC Lowered by PCB and OCP Exposure
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
0
1
2
3
4
5
6
7
8
1st Quartrile 2nd Quartile 3rd Quartile 4th Quartile
WBCbull Strong inverse correlation with PCBs and OCPs and CBC
bull Linear with almost all PCBs
bull High variability with OCPs
bull Within ldquonormalrdquo range
Effects on WBC Worsen with Years
of Exposure to Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Platelet Count Decreases with Years
of Exposure tp Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Solvents Decrease Platelet Count
bull Compared workers exposed 23 hrday to those exposed most of day to toluene
bull All wore face masks and protective gear
bull Platelet count 14 lower 252 versus 216ml
bull Impairment of sympathetic nerves (OR = 413)
bull Impairment of peripheral nerves (OR = 694)
bull Positive relationship between neurological abnormalities and a self-reported neuropsychiatric measurement (r = 035-066)
Shih HT et al Subclinical abnormalities in workers with continuous low-level toluene exposure Toxicol Ind Health 2011 Sep27(8)691-9
Basophilic Stippling of Red Cells
Toxinsbull Arsenic
bull Lead
Diseasesbull Alpha-thalassemia HbH Disease
bull Beta thalassemia
bull Hereditary pyrimidine 5-nucleotidase deficiency
bull Myelodysplastic syndrome
bull Sideroblastic anemia
bull Thrombotic thrombocytopenic purpura
GGT Indirect Measure of POPsbull Glutathione is key intracellular defense against oxidative stress
bull Cellular GGT metabolizes extracellular GSH allowing precursor amino acids to be reutilized for intracellular GSH
bull Exposure to POPs induces GGT as a defensive mechanism
bull Within normal range predicts type 2 diabetes coronary heart disease hypertension stroke dyslipidemia chronic kidney disease and cancer
bull Men with GGT gt50 UI had ~26 fold risk for diabetes compared to those with lt10 Those with 40-49 had a ~20 fold risk
bull Levels within normal range occur with obesity xs alcohol cigarette smoking physical inactivity high meat low fruit and vegetable intake
bull Cumulative biomarker for environmental pollutants
Lee DH et al (2003) Gamma-glutamyltransferase and diabetesmdasha 4 year follow-up study Diabetologia 46359ndash364
Pamela A et al Serum gamma-glutamyltransferase linking together environmental pollution redox equilibria and progression of atherosclerosis Clin Chem
Lab Med 200947(12)1583-4
Lee DH et al Serum gamma-glutamyltransferase new insights about an old enzyme J Epidemiol Community Health 2009 Nov63(11)884-6
Lee DH et alSerum gamma-glutamyltransferase predicts non-fatal myocardial infarction and fatal coronary heart disease among 28838 middle-aged men and
women Eur Heart J 2006272170ndash6
Lee DH et al Gamma-glutamyltransferase and diabetes--a 4 year follow-up study Diabetologia 2003 Mar46(3)359-64
Lee DH et al Can persistent organic pollutants explain the association between serum gamma-glutamyltransferase and type 2 diabetes Diabetologia 2008
Mar51(3)402-7
GGT and Alcohol Consumption
bull GGT directly correlates with alcohol consumption
bull In a non-uniform population 40 gd will elevate GGT ~15
bull Watch for false negatives
bull Genomic variation
bull Are these the ones most
sensitive todamaged by
chemical toxins
bull Could up-regulation of GGT in light alcohol consumption be reason for benefit
0
10
20
30
40
50
60
70
80
0 200 400 600 800
Grams of Ethanol per Week
Adapted from Nagaya T et al Dose-response relationships between drinking and serum tests in Japanese men
aged 40ndash59 years Alcohol 1999 Feb 17(2) 133ndash8
GGT Correlates With Toxic Metal Levels
Lee DH et al Graded associations of blood lead and urinary cadmium concentrations with oxidative-stress-related markers in the
US population results from the third National Health and Nutrition Examination Survey Environ Health
perspect 2006 Mar114(3)350-4
GGT and Diabetes Risk
0
5
10
15
20
25
30
lt10 10-19 20-29 30-39 40-49 gt50
Dia
bete
s R
isk
GGT
bull GGT over 50 associated with tripling of death rate
bull 30-40 associated with doubling
GGT Levels
Correlate with
Risk of Death
Brenner H et al Distribution determinants and prognostic value of gamma-glutamyltransferase for all-cause
mortality in a cohort of construction workers from southern Germany Prev Med 1997 26 305ndash10
GGT From Small US Company
with Young Workers
0
10
20
30
40
50
60
0 20 40 60 80 100
GGT Data from Canadian Oil Field
Workers
0
50
100
150
200
250
300
350
400
450
lt10 10-20 20-30 30-40 40-50 50-60 60-07 70-80 80-90 90-100 100-110 110-120 gt120
GGTP
20-fold increased risk of diabetes
Uric Acid Indirect Measure of POPs
bull Poly-fluorinated hydrocarbons (PFOA and PFOS) associated
with increased serum uric acid
Lin CY et al Association among serum perfluoroalkyl chemicals glucose homeostasis and metabolic syndrome
in adolescents and adults Diabetes Care 2009 Apr32(4)702-7
Steenland K et al Association of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) with uric
acid among adults with elevated community exposure to PFOA Environ Health Perspect 2010 Feb118229-33
Steenland 2010 Open Access
ALT Indirect Measure of POPs
bull ALT (proxy marker) elevation in 104 (not including viral
hepatitis hemochromatosis or alcoholic liver disease) of
NHANES 03-04 subset
bull Risk of elevated ALT increased dose-dependently with
cadmium lead mercury and PCB exposure
bull 100 of individuals had detectable PCBs 925 mercury
and 996 had detectable lead
bull In 2005-08 prevalence of NAFLD in US was 11 a
growing cause of chronic liver disease
Cave M et al Polychlorinated biphenyls lead and mercury are associated with liver disease in American adults
NHANES 2003-2004 Environ Health Perspect 2010 Dec118(12)1735-42
Younossi ZM et al Changes in the prevalence of the most common causes of chronic liver diseases in the United
States from 1988 to 2008 Clin Gastroenterol Hepatol 2011 Jun9(6)524-530e1
Bilirubin as a Marker of POPs
bull Degree of serum bilirubin increase is prognostically significant in chronic liver dysfunction
bull Mono-ortho PCB TEQ values were found to be significantly positively associated with bilirubin (β=071 P=0008) following adjustment for multiple potential confounders
bull Bilirubin levels significantly correlated with PCBs -105-118-126 and -194
bull Smoking appears to be the biggest confounder
Dufour DR et al 2000 Diagnosis and monitoring of hepatic injury II Recommendations for use of laboratory
tests in screening diagnosis and monitoring Clin Chem 46 2050ndash68
Kumar J et al Persistent organic pollutants and liver dysfunction biomarkers in a population-based human sample
of men and women Environ Res 2014134251-256
Perf
luo
rin
ate
dP
OP
s a
nd
Co
mm
on
Blo
od
Tests
Gleason JA et al Associations of perfluorinated chemical serum concentrations and biomarkers of liver function and uric acid in the
US population (NHANES) 2007-2010 Environ Res 20151368-14
Liver Enzymes Reflect Toxic Load
bull AST ALT and GGT increase with body load of PCBs and OCPs
bull Some non-linear
bull Oxychlordanetop quartile
ALT 10
GGT 25
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
LDL-Cholesterol as Measure of POPs
bull 5-year prospective study to determine if POP levels predict future elevation in LDL-cholesterol
bull 598 subjects initially at age 70
bull Looked at 23 POPs
bull Best correlation with PCB 194
Penell J Lind L Salihovic S et al Persistent organic pollutants are related to change in circulating
lipid levels during a 5 year follow-up Environ Res 134(2014)190ndash197
oxLDL as Measure of POPs
bull 992 70-year old individuals (50 women)
bull Sum of PCBs showed strong significant positive associations with ox-LDL and significant negative associations with glutathione-related markers (GSSG and GSSGGSH)
bull A number of POPs (PCB-99 138 153 156 170 180 194 206 and 209) showed strong significant positive association with ox-LDL
Kumar J et al Influence of persistent organic pollutants on oxidative stress in population-based samples
Chemosphere 2014114303-309
Homocysteine is Increased by Pb amp Cd
Guallar E et al Confounding of the relation between homocysteine and peripheral arterial disease by lead cadmium and renal function Am J Epidemiol 2006 Apr 15163(8)700-8
Nutrient Deficiencies Accentuate
Effects of Lead on Homocysteine
bull Deficiencies in folate B6 or B12 make lead more toxic
Lee YM Et al Association of homocysteine levels with blood lead levels and micronutrients in the US general population J Prev Med Public Health 2012 Nov45(6)387-93
T4 amp T3 and PCBs
bull PCBs decrease T4 production
bull PCBs inhibit iodotyrosinedeiodinase activity
bull Study done in pregnant women which implies effect on fetus IQ
Kim S Park J Kim HJ et al Association between several persistent organic pollutants and thyroid hormone levels in serum among the pregnant women of Korea Environ Int 2013 Sep59442-8Shimizu R Yamaguchi M Uramaru N et al Structure-activity relationships of 44 halogenated compounds for iodotyrosinedeiodinase-inhibitory activity Toxicology 2013 Dec 6314(1)22-9
T4 amp T3 and PCBs
bull Not just humans being affected
bull Large study of dolphins shows exactly the same effects
Schwacke LH Zolman ES Balmer BC et al Anaemia hypothyroidism and immune suppression associated with polychlorinated biphenyl exposure in bottlenose dolphins (Tursiops truncatus) Proceed Royal Society B doi101098rspb20110665
8-OHdG
bull Oxidized nucleoside
bull Direct measure of DNA damage
bull Indirect measure of oxidative stress and toxin load
bull Correlates with
Multiple cancers
Mitochondrial damage
Rate of aging
Smoking
Several toxinsWalter Crinnion ldquoTotal Toxic Loadrdquo AANP 2015
8-OHdG Correlates with Pack-Years
of Smoking
Yano T et al Significance of the urinary 8-OHdG level as an oxidative stress marker in lung cancer patients Lung Cancer
2009 Jan63(1)111-4
8-OHdG Correlates
with Mercury
Chen C et al Increased oxidative DNA damage as assessed by urinary 8-hydroxy-2-deoxyguanosine
concentrations and serum redox status in persons exposed to mercury Clin Chem 2005 Apr51(4)759-67
Toxin Effects Worse with Aging
bull Thyroid function decreases with PFOA levels
bull But only after age 63
Shrestha S Bloom MS Yucel R et al Perfluoroalkyl substances and thyroid function in older adults Environ Int 2015 Feb75206-14
Insightful 23-Year Prospective Study
1 lt 50 there is no difference between those with the lowest and highest PCBs
2 In youngest group insulin production increases in response to toxin level As expected since blocking of
insulin receptor sites by PCBs
requires more insulin
3 That adaptive ability decreases with aging
4 At age 50 all the measures show very strong toxin-dose response
Cumulative damage impairs ability to adapt
Suarez-Lopez JR et al Persistent organic pollutants in young adults and changes in glucose related metabolism over a 23-year follow-up Environ Res 2015 Feb137485-94
Recommendations
High body toxic load
GGT gt 25
Uric acid gt 50 mgdl
ALT gt30 UL
Bilirubin gt08 mgdl
CBC lt 6000
Platelet lt 250000
Low T3 andor T4
Monitor Total Toxic Load
8-OHdG gt4
ldquoUnconventionalrdquo Laboratory Tests
bull Challenge testing
bull Hair analysis
bull Direct measures of solvents and POPs in blood urine adipose tissue
Evaluation of Metal Exposure ndash Provocation
bull Provocation ndash the use of a chelating agent ndash before urine collection often done clinically but several limitations
No ldquoofficialrdquo reference range for provoked urine
Most chelating agents do not extract metals from all tissues thus
does not necessarily represent total body burden
bull Example Brain is one of the main target organs for both elemental and organic
mercury yet agents do not chelate brain mercury
bull Despite limitations widely used and advocated by clinicians in part to see efficacy of chelating agent as a guide to treatment and based on empirical evidence
Rooney JP The role of thiols dithiols nutritional factors and interacting ligands in the toxicology of mercury
Toxicology 2007
Is Challenge Testing Valid
bull Poor correlations of standard tests for mercury
bull Unpublished research from corporate wellness project
bull Published amalgam number correlation
bull Published fish consumption correlation
What We Found In Canada
bull Deviations from the mean of 14 29 and 91 respectively
bull DMPS is spreading distribution suggesting that it is better at differentiating mercury body load
bull Some VERY high
Hg Assessment Correlations
bull Extensive measurements in 65 Whole blood Hg
Oral DMPS challenge
Amalgam surfaces
bull Correlations Whole blood w pre urine r = 040
Whole blood w post urine r = 057
Pre urine w post urine r = 068
Amalgams w pre urine r = 026
Amalgams w whole blood r = 036
Amalgams with post urine 044
bull Clear documentation that
challenge testing is better00
100
200
300
400
500
600
0 10 20 30 40 50
Po
st
Uri
ne H
g u
gg
Number of amalgams
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
Think BroadlyExogenous
Metals
Chemicalsbull Inorganic
bull Fluoride
bull Organic
bull POPs
bull Drugs
Particulate matter
Molds
Microbial
Radiationbull Light
bull Medical
bull Cell phone
Endogenous
Gut-derived toxins
Non-end product metabolites
Poorly detoxified hormones
Catecholamines (if SNP)
Toxins of Choice
Alcohol
Marijuana
Food constituents
High fructose corn syrup
Salt (acid-forming diet)
Wheat if zonulin (70)
Obesity Epidemic ndash POPs AND HFCS
47Bray GA Fructose should we worry Int J Obes (Lond) 2008 Dec32 Suppl 7S127-31
How Toxins Cause Damage 13
bull Increase free radical production
Cd induces production of ROS
Malathion inhibits catalase and glutathione peroxidase
Homocysteine oxidizes LDL cholesterol
bull Poison enzyme systems (compete with nutritional cofactors for binding sites)
Pb poisons delta aminolevulinic acid dehydratase
Cd inhibits catalase glutathione reductase and lowers
glutathione levels
bull Replace structural minerals
Pb displaces Ca in bone
How Toxins Cause Damage 23
bull Damage DNA
Benzene - causes chromosomal damage
Pesticides ndash fruit growers have more DNA damage
Phthalates and insecticides ndash damage sperm DNA
4-hydroxy catechol estrogen (4-OHE) damages breast DNA
bull Epigenetic dysmodulation
Higher cord blood levels of hexachlorobenzene associated
with 2x greater risk for obesity in children
bull Damage cell membranes
Common mechanism for heavy metals inactivates
membrane enzymes ion channels and pumps
How Toxins Cause Damage 33
bull Block insulin receptor sites
PCBs and phthalates
bull Highest levels associated with a 4 to 20-fold greater diabetes risk
bull Imbalance hormones many toxin examples
Arsenic
bull Disrupts thyroid hormone and retinoic acid receptors
Phthalates
bull Act as anti-androgens
bull More than 75 of the US population has measurable levels of
several phthalate metabolites in the urine
PCBs
bull Lower testosterone levels in men
Which are the Worst Toxins
bull According to the CDC
Toxicity
Population toxic load
Prevalence in toxic waste sites
bull According to clinical importance
Exposure
of disease
Ability of the body to detoxifyexcrete
Ag
en
cy
fo
r T
oxic
Su
bs
tan
ce
s a
nd
Dis
ea
se
Reg
istr
y
Pri
ori
ty L
ist
The Worst Toxins Clinically
My Rank Toxin Diseases Primary Sources
1 Arsenic Cancers diabetes gout Water chicken rice
2 DDT ADHD dementia diabetes Everywhere
3 Phthalates ADHD diabetes Soft plastics HABAs
4 PBDEs ADHD diabetes Flame retardant fabrics
5 PAHs ADHD cancers dyslipidemia Smoking charbroiling
6 PCBs Cancers diabetes MI RA Everywhere
7 Mercury Dementia ldquoSilverrdquo fillings fish
8 Lead Cardiovascular disease IQ Paint water
Glyphosate Research invalid
Conventional Laboratory Tests Reflect
Toxic Load in ldquoNormalrdquo Range
bull Surprising number show toxin exposure
CBC RBC WBC platelet count hemoglobin basophilic
stippling
Liver enzymes ALT GGTP
Inflammatory markers CRP
Lipids LDL oxLDL triglycerides
Blood sugar insulin FBS 2-hour PP
Metabolites bilirubin uric acid homocysteine 8-OHdG
Thyroid T3 T4 TSH
bull The historic ldquonormalrdquo range has been changing as the population has become more toxic
WBC Lowered by PCB and OCP Exposure
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
0
1
2
3
4
5
6
7
8
1st Quartrile 2nd Quartile 3rd Quartile 4th Quartile
WBCbull Strong inverse correlation with PCBs and OCPs and CBC
bull Linear with almost all PCBs
bull High variability with OCPs
bull Within ldquonormalrdquo range
Effects on WBC Worsen with Years
of Exposure to Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Platelet Count Decreases with Years
of Exposure tp Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Solvents Decrease Platelet Count
bull Compared workers exposed 23 hrday to those exposed most of day to toluene
bull All wore face masks and protective gear
bull Platelet count 14 lower 252 versus 216ml
bull Impairment of sympathetic nerves (OR = 413)
bull Impairment of peripheral nerves (OR = 694)
bull Positive relationship between neurological abnormalities and a self-reported neuropsychiatric measurement (r = 035-066)
Shih HT et al Subclinical abnormalities in workers with continuous low-level toluene exposure Toxicol Ind Health 2011 Sep27(8)691-9
Basophilic Stippling of Red Cells
Toxinsbull Arsenic
bull Lead
Diseasesbull Alpha-thalassemia HbH Disease
bull Beta thalassemia
bull Hereditary pyrimidine 5-nucleotidase deficiency
bull Myelodysplastic syndrome
bull Sideroblastic anemia
bull Thrombotic thrombocytopenic purpura
GGT Indirect Measure of POPsbull Glutathione is key intracellular defense against oxidative stress
bull Cellular GGT metabolizes extracellular GSH allowing precursor amino acids to be reutilized for intracellular GSH
bull Exposure to POPs induces GGT as a defensive mechanism
bull Within normal range predicts type 2 diabetes coronary heart disease hypertension stroke dyslipidemia chronic kidney disease and cancer
bull Men with GGT gt50 UI had ~26 fold risk for diabetes compared to those with lt10 Those with 40-49 had a ~20 fold risk
bull Levels within normal range occur with obesity xs alcohol cigarette smoking physical inactivity high meat low fruit and vegetable intake
bull Cumulative biomarker for environmental pollutants
Lee DH et al (2003) Gamma-glutamyltransferase and diabetesmdasha 4 year follow-up study Diabetologia 46359ndash364
Pamela A et al Serum gamma-glutamyltransferase linking together environmental pollution redox equilibria and progression of atherosclerosis Clin Chem
Lab Med 200947(12)1583-4
Lee DH et al Serum gamma-glutamyltransferase new insights about an old enzyme J Epidemiol Community Health 2009 Nov63(11)884-6
Lee DH et alSerum gamma-glutamyltransferase predicts non-fatal myocardial infarction and fatal coronary heart disease among 28838 middle-aged men and
women Eur Heart J 2006272170ndash6
Lee DH et al Gamma-glutamyltransferase and diabetes--a 4 year follow-up study Diabetologia 2003 Mar46(3)359-64
Lee DH et al Can persistent organic pollutants explain the association between serum gamma-glutamyltransferase and type 2 diabetes Diabetologia 2008
Mar51(3)402-7
GGT and Alcohol Consumption
bull GGT directly correlates with alcohol consumption
bull In a non-uniform population 40 gd will elevate GGT ~15
bull Watch for false negatives
bull Genomic variation
bull Are these the ones most
sensitive todamaged by
chemical toxins
bull Could up-regulation of GGT in light alcohol consumption be reason for benefit
0
10
20
30
40
50
60
70
80
0 200 400 600 800
Grams of Ethanol per Week
Adapted from Nagaya T et al Dose-response relationships between drinking and serum tests in Japanese men
aged 40ndash59 years Alcohol 1999 Feb 17(2) 133ndash8
GGT Correlates With Toxic Metal Levels
Lee DH et al Graded associations of blood lead and urinary cadmium concentrations with oxidative-stress-related markers in the
US population results from the third National Health and Nutrition Examination Survey Environ Health
perspect 2006 Mar114(3)350-4
GGT and Diabetes Risk
0
5
10
15
20
25
30
lt10 10-19 20-29 30-39 40-49 gt50
Dia
bete
s R
isk
GGT
bull GGT over 50 associated with tripling of death rate
bull 30-40 associated with doubling
GGT Levels
Correlate with
Risk of Death
Brenner H et al Distribution determinants and prognostic value of gamma-glutamyltransferase for all-cause
mortality in a cohort of construction workers from southern Germany Prev Med 1997 26 305ndash10
GGT From Small US Company
with Young Workers
0
10
20
30
40
50
60
0 20 40 60 80 100
GGT Data from Canadian Oil Field
Workers
0
50
100
150
200
250
300
350
400
450
lt10 10-20 20-30 30-40 40-50 50-60 60-07 70-80 80-90 90-100 100-110 110-120 gt120
GGTP
20-fold increased risk of diabetes
Uric Acid Indirect Measure of POPs
bull Poly-fluorinated hydrocarbons (PFOA and PFOS) associated
with increased serum uric acid
Lin CY et al Association among serum perfluoroalkyl chemicals glucose homeostasis and metabolic syndrome
in adolescents and adults Diabetes Care 2009 Apr32(4)702-7
Steenland K et al Association of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) with uric
acid among adults with elevated community exposure to PFOA Environ Health Perspect 2010 Feb118229-33
Steenland 2010 Open Access
ALT Indirect Measure of POPs
bull ALT (proxy marker) elevation in 104 (not including viral
hepatitis hemochromatosis or alcoholic liver disease) of
NHANES 03-04 subset
bull Risk of elevated ALT increased dose-dependently with
cadmium lead mercury and PCB exposure
bull 100 of individuals had detectable PCBs 925 mercury
and 996 had detectable lead
bull In 2005-08 prevalence of NAFLD in US was 11 a
growing cause of chronic liver disease
Cave M et al Polychlorinated biphenyls lead and mercury are associated with liver disease in American adults
NHANES 2003-2004 Environ Health Perspect 2010 Dec118(12)1735-42
Younossi ZM et al Changes in the prevalence of the most common causes of chronic liver diseases in the United
States from 1988 to 2008 Clin Gastroenterol Hepatol 2011 Jun9(6)524-530e1
Bilirubin as a Marker of POPs
bull Degree of serum bilirubin increase is prognostically significant in chronic liver dysfunction
bull Mono-ortho PCB TEQ values were found to be significantly positively associated with bilirubin (β=071 P=0008) following adjustment for multiple potential confounders
bull Bilirubin levels significantly correlated with PCBs -105-118-126 and -194
bull Smoking appears to be the biggest confounder
Dufour DR et al 2000 Diagnosis and monitoring of hepatic injury II Recommendations for use of laboratory
tests in screening diagnosis and monitoring Clin Chem 46 2050ndash68
Kumar J et al Persistent organic pollutants and liver dysfunction biomarkers in a population-based human sample
of men and women Environ Res 2014134251-256
Perf
luo
rin
ate
dP
OP
s a
nd
Co
mm
on
Blo
od
Tests
Gleason JA et al Associations of perfluorinated chemical serum concentrations and biomarkers of liver function and uric acid in the
US population (NHANES) 2007-2010 Environ Res 20151368-14
Liver Enzymes Reflect Toxic Load
bull AST ALT and GGT increase with body load of PCBs and OCPs
bull Some non-linear
bull Oxychlordanetop quartile
ALT 10
GGT 25
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
LDL-Cholesterol as Measure of POPs
bull 5-year prospective study to determine if POP levels predict future elevation in LDL-cholesterol
bull 598 subjects initially at age 70
bull Looked at 23 POPs
bull Best correlation with PCB 194
Penell J Lind L Salihovic S et al Persistent organic pollutants are related to change in circulating
lipid levels during a 5 year follow-up Environ Res 134(2014)190ndash197
oxLDL as Measure of POPs
bull 992 70-year old individuals (50 women)
bull Sum of PCBs showed strong significant positive associations with ox-LDL and significant negative associations with glutathione-related markers (GSSG and GSSGGSH)
bull A number of POPs (PCB-99 138 153 156 170 180 194 206 and 209) showed strong significant positive association with ox-LDL
Kumar J et al Influence of persistent organic pollutants on oxidative stress in population-based samples
Chemosphere 2014114303-309
Homocysteine is Increased by Pb amp Cd
Guallar E et al Confounding of the relation between homocysteine and peripheral arterial disease by lead cadmium and renal function Am J Epidemiol 2006 Apr 15163(8)700-8
Nutrient Deficiencies Accentuate
Effects of Lead on Homocysteine
bull Deficiencies in folate B6 or B12 make lead more toxic
Lee YM Et al Association of homocysteine levels with blood lead levels and micronutrients in the US general population J Prev Med Public Health 2012 Nov45(6)387-93
T4 amp T3 and PCBs
bull PCBs decrease T4 production
bull PCBs inhibit iodotyrosinedeiodinase activity
bull Study done in pregnant women which implies effect on fetus IQ
Kim S Park J Kim HJ et al Association between several persistent organic pollutants and thyroid hormone levels in serum among the pregnant women of Korea Environ Int 2013 Sep59442-8Shimizu R Yamaguchi M Uramaru N et al Structure-activity relationships of 44 halogenated compounds for iodotyrosinedeiodinase-inhibitory activity Toxicology 2013 Dec 6314(1)22-9
T4 amp T3 and PCBs
bull Not just humans being affected
bull Large study of dolphins shows exactly the same effects
Schwacke LH Zolman ES Balmer BC et al Anaemia hypothyroidism and immune suppression associated with polychlorinated biphenyl exposure in bottlenose dolphins (Tursiops truncatus) Proceed Royal Society B doi101098rspb20110665
8-OHdG
bull Oxidized nucleoside
bull Direct measure of DNA damage
bull Indirect measure of oxidative stress and toxin load
bull Correlates with
Multiple cancers
Mitochondrial damage
Rate of aging
Smoking
Several toxinsWalter Crinnion ldquoTotal Toxic Loadrdquo AANP 2015
8-OHdG Correlates with Pack-Years
of Smoking
Yano T et al Significance of the urinary 8-OHdG level as an oxidative stress marker in lung cancer patients Lung Cancer
2009 Jan63(1)111-4
8-OHdG Correlates
with Mercury
Chen C et al Increased oxidative DNA damage as assessed by urinary 8-hydroxy-2-deoxyguanosine
concentrations and serum redox status in persons exposed to mercury Clin Chem 2005 Apr51(4)759-67
Toxin Effects Worse with Aging
bull Thyroid function decreases with PFOA levels
bull But only after age 63
Shrestha S Bloom MS Yucel R et al Perfluoroalkyl substances and thyroid function in older adults Environ Int 2015 Feb75206-14
Insightful 23-Year Prospective Study
1 lt 50 there is no difference between those with the lowest and highest PCBs
2 In youngest group insulin production increases in response to toxin level As expected since blocking of
insulin receptor sites by PCBs
requires more insulin
3 That adaptive ability decreases with aging
4 At age 50 all the measures show very strong toxin-dose response
Cumulative damage impairs ability to adapt
Suarez-Lopez JR et al Persistent organic pollutants in young adults and changes in glucose related metabolism over a 23-year follow-up Environ Res 2015 Feb137485-94
Recommendations
High body toxic load
GGT gt 25
Uric acid gt 50 mgdl
ALT gt30 UL
Bilirubin gt08 mgdl
CBC lt 6000
Platelet lt 250000
Low T3 andor T4
Monitor Total Toxic Load
8-OHdG gt4
ldquoUnconventionalrdquo Laboratory Tests
bull Challenge testing
bull Hair analysis
bull Direct measures of solvents and POPs in blood urine adipose tissue
Evaluation of Metal Exposure ndash Provocation
bull Provocation ndash the use of a chelating agent ndash before urine collection often done clinically but several limitations
No ldquoofficialrdquo reference range for provoked urine
Most chelating agents do not extract metals from all tissues thus
does not necessarily represent total body burden
bull Example Brain is one of the main target organs for both elemental and organic
mercury yet agents do not chelate brain mercury
bull Despite limitations widely used and advocated by clinicians in part to see efficacy of chelating agent as a guide to treatment and based on empirical evidence
Rooney JP The role of thiols dithiols nutritional factors and interacting ligands in the toxicology of mercury
Toxicology 2007
Is Challenge Testing Valid
bull Poor correlations of standard tests for mercury
bull Unpublished research from corporate wellness project
bull Published amalgam number correlation
bull Published fish consumption correlation
What We Found In Canada
bull Deviations from the mean of 14 29 and 91 respectively
bull DMPS is spreading distribution suggesting that it is better at differentiating mercury body load
bull Some VERY high
Hg Assessment Correlations
bull Extensive measurements in 65 Whole blood Hg
Oral DMPS challenge
Amalgam surfaces
bull Correlations Whole blood w pre urine r = 040
Whole blood w post urine r = 057
Pre urine w post urine r = 068
Amalgams w pre urine r = 026
Amalgams w whole blood r = 036
Amalgams with post urine 044
bull Clear documentation that
challenge testing is better00
100
200
300
400
500
600
0 10 20 30 40 50
Po
st
Uri
ne H
g u
gg
Number of amalgams
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
Obesity Epidemic ndash POPs AND HFCS
47Bray GA Fructose should we worry Int J Obes (Lond) 2008 Dec32 Suppl 7S127-31
How Toxins Cause Damage 13
bull Increase free radical production
Cd induces production of ROS
Malathion inhibits catalase and glutathione peroxidase
Homocysteine oxidizes LDL cholesterol
bull Poison enzyme systems (compete with nutritional cofactors for binding sites)
Pb poisons delta aminolevulinic acid dehydratase
Cd inhibits catalase glutathione reductase and lowers
glutathione levels
bull Replace structural minerals
Pb displaces Ca in bone
How Toxins Cause Damage 23
bull Damage DNA
Benzene - causes chromosomal damage
Pesticides ndash fruit growers have more DNA damage
Phthalates and insecticides ndash damage sperm DNA
4-hydroxy catechol estrogen (4-OHE) damages breast DNA
bull Epigenetic dysmodulation
Higher cord blood levels of hexachlorobenzene associated
with 2x greater risk for obesity in children
bull Damage cell membranes
Common mechanism for heavy metals inactivates
membrane enzymes ion channels and pumps
How Toxins Cause Damage 33
bull Block insulin receptor sites
PCBs and phthalates
bull Highest levels associated with a 4 to 20-fold greater diabetes risk
bull Imbalance hormones many toxin examples
Arsenic
bull Disrupts thyroid hormone and retinoic acid receptors
Phthalates
bull Act as anti-androgens
bull More than 75 of the US population has measurable levels of
several phthalate metabolites in the urine
PCBs
bull Lower testosterone levels in men
Which are the Worst Toxins
bull According to the CDC
Toxicity
Population toxic load
Prevalence in toxic waste sites
bull According to clinical importance
Exposure
of disease
Ability of the body to detoxifyexcrete
Ag
en
cy
fo
r T
oxic
Su
bs
tan
ce
s a
nd
Dis
ea
se
Reg
istr
y
Pri
ori
ty L
ist
The Worst Toxins Clinically
My Rank Toxin Diseases Primary Sources
1 Arsenic Cancers diabetes gout Water chicken rice
2 DDT ADHD dementia diabetes Everywhere
3 Phthalates ADHD diabetes Soft plastics HABAs
4 PBDEs ADHD diabetes Flame retardant fabrics
5 PAHs ADHD cancers dyslipidemia Smoking charbroiling
6 PCBs Cancers diabetes MI RA Everywhere
7 Mercury Dementia ldquoSilverrdquo fillings fish
8 Lead Cardiovascular disease IQ Paint water
Glyphosate Research invalid
Conventional Laboratory Tests Reflect
Toxic Load in ldquoNormalrdquo Range
bull Surprising number show toxin exposure
CBC RBC WBC platelet count hemoglobin basophilic
stippling
Liver enzymes ALT GGTP
Inflammatory markers CRP
Lipids LDL oxLDL triglycerides
Blood sugar insulin FBS 2-hour PP
Metabolites bilirubin uric acid homocysteine 8-OHdG
Thyroid T3 T4 TSH
bull The historic ldquonormalrdquo range has been changing as the population has become more toxic
WBC Lowered by PCB and OCP Exposure
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
0
1
2
3
4
5
6
7
8
1st Quartrile 2nd Quartile 3rd Quartile 4th Quartile
WBCbull Strong inverse correlation with PCBs and OCPs and CBC
bull Linear with almost all PCBs
bull High variability with OCPs
bull Within ldquonormalrdquo range
Effects on WBC Worsen with Years
of Exposure to Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Platelet Count Decreases with Years
of Exposure tp Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Solvents Decrease Platelet Count
bull Compared workers exposed 23 hrday to those exposed most of day to toluene
bull All wore face masks and protective gear
bull Platelet count 14 lower 252 versus 216ml
bull Impairment of sympathetic nerves (OR = 413)
bull Impairment of peripheral nerves (OR = 694)
bull Positive relationship between neurological abnormalities and a self-reported neuropsychiatric measurement (r = 035-066)
Shih HT et al Subclinical abnormalities in workers with continuous low-level toluene exposure Toxicol Ind Health 2011 Sep27(8)691-9
Basophilic Stippling of Red Cells
Toxinsbull Arsenic
bull Lead
Diseasesbull Alpha-thalassemia HbH Disease
bull Beta thalassemia
bull Hereditary pyrimidine 5-nucleotidase deficiency
bull Myelodysplastic syndrome
bull Sideroblastic anemia
bull Thrombotic thrombocytopenic purpura
GGT Indirect Measure of POPsbull Glutathione is key intracellular defense against oxidative stress
bull Cellular GGT metabolizes extracellular GSH allowing precursor amino acids to be reutilized for intracellular GSH
bull Exposure to POPs induces GGT as a defensive mechanism
bull Within normal range predicts type 2 diabetes coronary heart disease hypertension stroke dyslipidemia chronic kidney disease and cancer
bull Men with GGT gt50 UI had ~26 fold risk for diabetes compared to those with lt10 Those with 40-49 had a ~20 fold risk
bull Levels within normal range occur with obesity xs alcohol cigarette smoking physical inactivity high meat low fruit and vegetable intake
bull Cumulative biomarker for environmental pollutants
Lee DH et al (2003) Gamma-glutamyltransferase and diabetesmdasha 4 year follow-up study Diabetologia 46359ndash364
Pamela A et al Serum gamma-glutamyltransferase linking together environmental pollution redox equilibria and progression of atherosclerosis Clin Chem
Lab Med 200947(12)1583-4
Lee DH et al Serum gamma-glutamyltransferase new insights about an old enzyme J Epidemiol Community Health 2009 Nov63(11)884-6
Lee DH et alSerum gamma-glutamyltransferase predicts non-fatal myocardial infarction and fatal coronary heart disease among 28838 middle-aged men and
women Eur Heart J 2006272170ndash6
Lee DH et al Gamma-glutamyltransferase and diabetes--a 4 year follow-up study Diabetologia 2003 Mar46(3)359-64
Lee DH et al Can persistent organic pollutants explain the association between serum gamma-glutamyltransferase and type 2 diabetes Diabetologia 2008
Mar51(3)402-7
GGT and Alcohol Consumption
bull GGT directly correlates with alcohol consumption
bull In a non-uniform population 40 gd will elevate GGT ~15
bull Watch for false negatives
bull Genomic variation
bull Are these the ones most
sensitive todamaged by
chemical toxins
bull Could up-regulation of GGT in light alcohol consumption be reason for benefit
0
10
20
30
40
50
60
70
80
0 200 400 600 800
Grams of Ethanol per Week
Adapted from Nagaya T et al Dose-response relationships between drinking and serum tests in Japanese men
aged 40ndash59 years Alcohol 1999 Feb 17(2) 133ndash8
GGT Correlates With Toxic Metal Levels
Lee DH et al Graded associations of blood lead and urinary cadmium concentrations with oxidative-stress-related markers in the
US population results from the third National Health and Nutrition Examination Survey Environ Health
perspect 2006 Mar114(3)350-4
GGT and Diabetes Risk
0
5
10
15
20
25
30
lt10 10-19 20-29 30-39 40-49 gt50
Dia
bete
s R
isk
GGT
bull GGT over 50 associated with tripling of death rate
bull 30-40 associated with doubling
GGT Levels
Correlate with
Risk of Death
Brenner H et al Distribution determinants and prognostic value of gamma-glutamyltransferase for all-cause
mortality in a cohort of construction workers from southern Germany Prev Med 1997 26 305ndash10
GGT From Small US Company
with Young Workers
0
10
20
30
40
50
60
0 20 40 60 80 100
GGT Data from Canadian Oil Field
Workers
0
50
100
150
200
250
300
350
400
450
lt10 10-20 20-30 30-40 40-50 50-60 60-07 70-80 80-90 90-100 100-110 110-120 gt120
GGTP
20-fold increased risk of diabetes
Uric Acid Indirect Measure of POPs
bull Poly-fluorinated hydrocarbons (PFOA and PFOS) associated
with increased serum uric acid
Lin CY et al Association among serum perfluoroalkyl chemicals glucose homeostasis and metabolic syndrome
in adolescents and adults Diabetes Care 2009 Apr32(4)702-7
Steenland K et al Association of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) with uric
acid among adults with elevated community exposure to PFOA Environ Health Perspect 2010 Feb118229-33
Steenland 2010 Open Access
ALT Indirect Measure of POPs
bull ALT (proxy marker) elevation in 104 (not including viral
hepatitis hemochromatosis or alcoholic liver disease) of
NHANES 03-04 subset
bull Risk of elevated ALT increased dose-dependently with
cadmium lead mercury and PCB exposure
bull 100 of individuals had detectable PCBs 925 mercury
and 996 had detectable lead
bull In 2005-08 prevalence of NAFLD in US was 11 a
growing cause of chronic liver disease
Cave M et al Polychlorinated biphenyls lead and mercury are associated with liver disease in American adults
NHANES 2003-2004 Environ Health Perspect 2010 Dec118(12)1735-42
Younossi ZM et al Changes in the prevalence of the most common causes of chronic liver diseases in the United
States from 1988 to 2008 Clin Gastroenterol Hepatol 2011 Jun9(6)524-530e1
Bilirubin as a Marker of POPs
bull Degree of serum bilirubin increase is prognostically significant in chronic liver dysfunction
bull Mono-ortho PCB TEQ values were found to be significantly positively associated with bilirubin (β=071 P=0008) following adjustment for multiple potential confounders
bull Bilirubin levels significantly correlated with PCBs -105-118-126 and -194
bull Smoking appears to be the biggest confounder
Dufour DR et al 2000 Diagnosis and monitoring of hepatic injury II Recommendations for use of laboratory
tests in screening diagnosis and monitoring Clin Chem 46 2050ndash68
Kumar J et al Persistent organic pollutants and liver dysfunction biomarkers in a population-based human sample
of men and women Environ Res 2014134251-256
Perf
luo
rin
ate
dP
OP
s a
nd
Co
mm
on
Blo
od
Tests
Gleason JA et al Associations of perfluorinated chemical serum concentrations and biomarkers of liver function and uric acid in the
US population (NHANES) 2007-2010 Environ Res 20151368-14
Liver Enzymes Reflect Toxic Load
bull AST ALT and GGT increase with body load of PCBs and OCPs
bull Some non-linear
bull Oxychlordanetop quartile
ALT 10
GGT 25
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
LDL-Cholesterol as Measure of POPs
bull 5-year prospective study to determine if POP levels predict future elevation in LDL-cholesterol
bull 598 subjects initially at age 70
bull Looked at 23 POPs
bull Best correlation with PCB 194
Penell J Lind L Salihovic S et al Persistent organic pollutants are related to change in circulating
lipid levels during a 5 year follow-up Environ Res 134(2014)190ndash197
oxLDL as Measure of POPs
bull 992 70-year old individuals (50 women)
bull Sum of PCBs showed strong significant positive associations with ox-LDL and significant negative associations with glutathione-related markers (GSSG and GSSGGSH)
bull A number of POPs (PCB-99 138 153 156 170 180 194 206 and 209) showed strong significant positive association with ox-LDL
Kumar J et al Influence of persistent organic pollutants on oxidative stress in population-based samples
Chemosphere 2014114303-309
Homocysteine is Increased by Pb amp Cd
Guallar E et al Confounding of the relation between homocysteine and peripheral arterial disease by lead cadmium and renal function Am J Epidemiol 2006 Apr 15163(8)700-8
Nutrient Deficiencies Accentuate
Effects of Lead on Homocysteine
bull Deficiencies in folate B6 or B12 make lead more toxic
Lee YM Et al Association of homocysteine levels with blood lead levels and micronutrients in the US general population J Prev Med Public Health 2012 Nov45(6)387-93
T4 amp T3 and PCBs
bull PCBs decrease T4 production
bull PCBs inhibit iodotyrosinedeiodinase activity
bull Study done in pregnant women which implies effect on fetus IQ
Kim S Park J Kim HJ et al Association between several persistent organic pollutants and thyroid hormone levels in serum among the pregnant women of Korea Environ Int 2013 Sep59442-8Shimizu R Yamaguchi M Uramaru N et al Structure-activity relationships of 44 halogenated compounds for iodotyrosinedeiodinase-inhibitory activity Toxicology 2013 Dec 6314(1)22-9
T4 amp T3 and PCBs
bull Not just humans being affected
bull Large study of dolphins shows exactly the same effects
Schwacke LH Zolman ES Balmer BC et al Anaemia hypothyroidism and immune suppression associated with polychlorinated biphenyl exposure in bottlenose dolphins (Tursiops truncatus) Proceed Royal Society B doi101098rspb20110665
8-OHdG
bull Oxidized nucleoside
bull Direct measure of DNA damage
bull Indirect measure of oxidative stress and toxin load
bull Correlates with
Multiple cancers
Mitochondrial damage
Rate of aging
Smoking
Several toxinsWalter Crinnion ldquoTotal Toxic Loadrdquo AANP 2015
8-OHdG Correlates with Pack-Years
of Smoking
Yano T et al Significance of the urinary 8-OHdG level as an oxidative stress marker in lung cancer patients Lung Cancer
2009 Jan63(1)111-4
8-OHdG Correlates
with Mercury
Chen C et al Increased oxidative DNA damage as assessed by urinary 8-hydroxy-2-deoxyguanosine
concentrations and serum redox status in persons exposed to mercury Clin Chem 2005 Apr51(4)759-67
Toxin Effects Worse with Aging
bull Thyroid function decreases with PFOA levels
bull But only after age 63
Shrestha S Bloom MS Yucel R et al Perfluoroalkyl substances and thyroid function in older adults Environ Int 2015 Feb75206-14
Insightful 23-Year Prospective Study
1 lt 50 there is no difference between those with the lowest and highest PCBs
2 In youngest group insulin production increases in response to toxin level As expected since blocking of
insulin receptor sites by PCBs
requires more insulin
3 That adaptive ability decreases with aging
4 At age 50 all the measures show very strong toxin-dose response
Cumulative damage impairs ability to adapt
Suarez-Lopez JR et al Persistent organic pollutants in young adults and changes in glucose related metabolism over a 23-year follow-up Environ Res 2015 Feb137485-94
Recommendations
High body toxic load
GGT gt 25
Uric acid gt 50 mgdl
ALT gt30 UL
Bilirubin gt08 mgdl
CBC lt 6000
Platelet lt 250000
Low T3 andor T4
Monitor Total Toxic Load
8-OHdG gt4
ldquoUnconventionalrdquo Laboratory Tests
bull Challenge testing
bull Hair analysis
bull Direct measures of solvents and POPs in blood urine adipose tissue
Evaluation of Metal Exposure ndash Provocation
bull Provocation ndash the use of a chelating agent ndash before urine collection often done clinically but several limitations
No ldquoofficialrdquo reference range for provoked urine
Most chelating agents do not extract metals from all tissues thus
does not necessarily represent total body burden
bull Example Brain is one of the main target organs for both elemental and organic
mercury yet agents do not chelate brain mercury
bull Despite limitations widely used and advocated by clinicians in part to see efficacy of chelating agent as a guide to treatment and based on empirical evidence
Rooney JP The role of thiols dithiols nutritional factors and interacting ligands in the toxicology of mercury
Toxicology 2007
Is Challenge Testing Valid
bull Poor correlations of standard tests for mercury
bull Unpublished research from corporate wellness project
bull Published amalgam number correlation
bull Published fish consumption correlation
What We Found In Canada
bull Deviations from the mean of 14 29 and 91 respectively
bull DMPS is spreading distribution suggesting that it is better at differentiating mercury body load
bull Some VERY high
Hg Assessment Correlations
bull Extensive measurements in 65 Whole blood Hg
Oral DMPS challenge
Amalgam surfaces
bull Correlations Whole blood w pre urine r = 040
Whole blood w post urine r = 057
Pre urine w post urine r = 068
Amalgams w pre urine r = 026
Amalgams w whole blood r = 036
Amalgams with post urine 044
bull Clear documentation that
challenge testing is better00
100
200
300
400
500
600
0 10 20 30 40 50
Po
st
Uri
ne H
g u
gg
Number of amalgams
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
How Toxins Cause Damage 13
bull Increase free radical production
Cd induces production of ROS
Malathion inhibits catalase and glutathione peroxidase
Homocysteine oxidizes LDL cholesterol
bull Poison enzyme systems (compete with nutritional cofactors for binding sites)
Pb poisons delta aminolevulinic acid dehydratase
Cd inhibits catalase glutathione reductase and lowers
glutathione levels
bull Replace structural minerals
Pb displaces Ca in bone
How Toxins Cause Damage 23
bull Damage DNA
Benzene - causes chromosomal damage
Pesticides ndash fruit growers have more DNA damage
Phthalates and insecticides ndash damage sperm DNA
4-hydroxy catechol estrogen (4-OHE) damages breast DNA
bull Epigenetic dysmodulation
Higher cord blood levels of hexachlorobenzene associated
with 2x greater risk for obesity in children
bull Damage cell membranes
Common mechanism for heavy metals inactivates
membrane enzymes ion channels and pumps
How Toxins Cause Damage 33
bull Block insulin receptor sites
PCBs and phthalates
bull Highest levels associated with a 4 to 20-fold greater diabetes risk
bull Imbalance hormones many toxin examples
Arsenic
bull Disrupts thyroid hormone and retinoic acid receptors
Phthalates
bull Act as anti-androgens
bull More than 75 of the US population has measurable levels of
several phthalate metabolites in the urine
PCBs
bull Lower testosterone levels in men
Which are the Worst Toxins
bull According to the CDC
Toxicity
Population toxic load
Prevalence in toxic waste sites
bull According to clinical importance
Exposure
of disease
Ability of the body to detoxifyexcrete
Ag
en
cy
fo
r T
oxic
Su
bs
tan
ce
s a
nd
Dis
ea
se
Reg
istr
y
Pri
ori
ty L
ist
The Worst Toxins Clinically
My Rank Toxin Diseases Primary Sources
1 Arsenic Cancers diabetes gout Water chicken rice
2 DDT ADHD dementia diabetes Everywhere
3 Phthalates ADHD diabetes Soft plastics HABAs
4 PBDEs ADHD diabetes Flame retardant fabrics
5 PAHs ADHD cancers dyslipidemia Smoking charbroiling
6 PCBs Cancers diabetes MI RA Everywhere
7 Mercury Dementia ldquoSilverrdquo fillings fish
8 Lead Cardiovascular disease IQ Paint water
Glyphosate Research invalid
Conventional Laboratory Tests Reflect
Toxic Load in ldquoNormalrdquo Range
bull Surprising number show toxin exposure
CBC RBC WBC platelet count hemoglobin basophilic
stippling
Liver enzymes ALT GGTP
Inflammatory markers CRP
Lipids LDL oxLDL triglycerides
Blood sugar insulin FBS 2-hour PP
Metabolites bilirubin uric acid homocysteine 8-OHdG
Thyroid T3 T4 TSH
bull The historic ldquonormalrdquo range has been changing as the population has become more toxic
WBC Lowered by PCB and OCP Exposure
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
0
1
2
3
4
5
6
7
8
1st Quartrile 2nd Quartile 3rd Quartile 4th Quartile
WBCbull Strong inverse correlation with PCBs and OCPs and CBC
bull Linear with almost all PCBs
bull High variability with OCPs
bull Within ldquonormalrdquo range
Effects on WBC Worsen with Years
of Exposure to Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Platelet Count Decreases with Years
of Exposure tp Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Solvents Decrease Platelet Count
bull Compared workers exposed 23 hrday to those exposed most of day to toluene
bull All wore face masks and protective gear
bull Platelet count 14 lower 252 versus 216ml
bull Impairment of sympathetic nerves (OR = 413)
bull Impairment of peripheral nerves (OR = 694)
bull Positive relationship between neurological abnormalities and a self-reported neuropsychiatric measurement (r = 035-066)
Shih HT et al Subclinical abnormalities in workers with continuous low-level toluene exposure Toxicol Ind Health 2011 Sep27(8)691-9
Basophilic Stippling of Red Cells
Toxinsbull Arsenic
bull Lead
Diseasesbull Alpha-thalassemia HbH Disease
bull Beta thalassemia
bull Hereditary pyrimidine 5-nucleotidase deficiency
bull Myelodysplastic syndrome
bull Sideroblastic anemia
bull Thrombotic thrombocytopenic purpura
GGT Indirect Measure of POPsbull Glutathione is key intracellular defense against oxidative stress
bull Cellular GGT metabolizes extracellular GSH allowing precursor amino acids to be reutilized for intracellular GSH
bull Exposure to POPs induces GGT as a defensive mechanism
bull Within normal range predicts type 2 diabetes coronary heart disease hypertension stroke dyslipidemia chronic kidney disease and cancer
bull Men with GGT gt50 UI had ~26 fold risk for diabetes compared to those with lt10 Those with 40-49 had a ~20 fold risk
bull Levels within normal range occur with obesity xs alcohol cigarette smoking physical inactivity high meat low fruit and vegetable intake
bull Cumulative biomarker for environmental pollutants
Lee DH et al (2003) Gamma-glutamyltransferase and diabetesmdasha 4 year follow-up study Diabetologia 46359ndash364
Pamela A et al Serum gamma-glutamyltransferase linking together environmental pollution redox equilibria and progression of atherosclerosis Clin Chem
Lab Med 200947(12)1583-4
Lee DH et al Serum gamma-glutamyltransferase new insights about an old enzyme J Epidemiol Community Health 2009 Nov63(11)884-6
Lee DH et alSerum gamma-glutamyltransferase predicts non-fatal myocardial infarction and fatal coronary heart disease among 28838 middle-aged men and
women Eur Heart J 2006272170ndash6
Lee DH et al Gamma-glutamyltransferase and diabetes--a 4 year follow-up study Diabetologia 2003 Mar46(3)359-64
Lee DH et al Can persistent organic pollutants explain the association between serum gamma-glutamyltransferase and type 2 diabetes Diabetologia 2008
Mar51(3)402-7
GGT and Alcohol Consumption
bull GGT directly correlates with alcohol consumption
bull In a non-uniform population 40 gd will elevate GGT ~15
bull Watch for false negatives
bull Genomic variation
bull Are these the ones most
sensitive todamaged by
chemical toxins
bull Could up-regulation of GGT in light alcohol consumption be reason for benefit
0
10
20
30
40
50
60
70
80
0 200 400 600 800
Grams of Ethanol per Week
Adapted from Nagaya T et al Dose-response relationships between drinking and serum tests in Japanese men
aged 40ndash59 years Alcohol 1999 Feb 17(2) 133ndash8
GGT Correlates With Toxic Metal Levels
Lee DH et al Graded associations of blood lead and urinary cadmium concentrations with oxidative-stress-related markers in the
US population results from the third National Health and Nutrition Examination Survey Environ Health
perspect 2006 Mar114(3)350-4
GGT and Diabetes Risk
0
5
10
15
20
25
30
lt10 10-19 20-29 30-39 40-49 gt50
Dia
bete
s R
isk
GGT
bull GGT over 50 associated with tripling of death rate
bull 30-40 associated with doubling
GGT Levels
Correlate with
Risk of Death
Brenner H et al Distribution determinants and prognostic value of gamma-glutamyltransferase for all-cause
mortality in a cohort of construction workers from southern Germany Prev Med 1997 26 305ndash10
GGT From Small US Company
with Young Workers
0
10
20
30
40
50
60
0 20 40 60 80 100
GGT Data from Canadian Oil Field
Workers
0
50
100
150
200
250
300
350
400
450
lt10 10-20 20-30 30-40 40-50 50-60 60-07 70-80 80-90 90-100 100-110 110-120 gt120
GGTP
20-fold increased risk of diabetes
Uric Acid Indirect Measure of POPs
bull Poly-fluorinated hydrocarbons (PFOA and PFOS) associated
with increased serum uric acid
Lin CY et al Association among serum perfluoroalkyl chemicals glucose homeostasis and metabolic syndrome
in adolescents and adults Diabetes Care 2009 Apr32(4)702-7
Steenland K et al Association of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) with uric
acid among adults with elevated community exposure to PFOA Environ Health Perspect 2010 Feb118229-33
Steenland 2010 Open Access
ALT Indirect Measure of POPs
bull ALT (proxy marker) elevation in 104 (not including viral
hepatitis hemochromatosis or alcoholic liver disease) of
NHANES 03-04 subset
bull Risk of elevated ALT increased dose-dependently with
cadmium lead mercury and PCB exposure
bull 100 of individuals had detectable PCBs 925 mercury
and 996 had detectable lead
bull In 2005-08 prevalence of NAFLD in US was 11 a
growing cause of chronic liver disease
Cave M et al Polychlorinated biphenyls lead and mercury are associated with liver disease in American adults
NHANES 2003-2004 Environ Health Perspect 2010 Dec118(12)1735-42
Younossi ZM et al Changes in the prevalence of the most common causes of chronic liver diseases in the United
States from 1988 to 2008 Clin Gastroenterol Hepatol 2011 Jun9(6)524-530e1
Bilirubin as a Marker of POPs
bull Degree of serum bilirubin increase is prognostically significant in chronic liver dysfunction
bull Mono-ortho PCB TEQ values were found to be significantly positively associated with bilirubin (β=071 P=0008) following adjustment for multiple potential confounders
bull Bilirubin levels significantly correlated with PCBs -105-118-126 and -194
bull Smoking appears to be the biggest confounder
Dufour DR et al 2000 Diagnosis and monitoring of hepatic injury II Recommendations for use of laboratory
tests in screening diagnosis and monitoring Clin Chem 46 2050ndash68
Kumar J et al Persistent organic pollutants and liver dysfunction biomarkers in a population-based human sample
of men and women Environ Res 2014134251-256
Perf
luo
rin
ate
dP
OP
s a
nd
Co
mm
on
Blo
od
Tests
Gleason JA et al Associations of perfluorinated chemical serum concentrations and biomarkers of liver function and uric acid in the
US population (NHANES) 2007-2010 Environ Res 20151368-14
Liver Enzymes Reflect Toxic Load
bull AST ALT and GGT increase with body load of PCBs and OCPs
bull Some non-linear
bull Oxychlordanetop quartile
ALT 10
GGT 25
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
LDL-Cholesterol as Measure of POPs
bull 5-year prospective study to determine if POP levels predict future elevation in LDL-cholesterol
bull 598 subjects initially at age 70
bull Looked at 23 POPs
bull Best correlation with PCB 194
Penell J Lind L Salihovic S et al Persistent organic pollutants are related to change in circulating
lipid levels during a 5 year follow-up Environ Res 134(2014)190ndash197
oxLDL as Measure of POPs
bull 992 70-year old individuals (50 women)
bull Sum of PCBs showed strong significant positive associations with ox-LDL and significant negative associations with glutathione-related markers (GSSG and GSSGGSH)
bull A number of POPs (PCB-99 138 153 156 170 180 194 206 and 209) showed strong significant positive association with ox-LDL
Kumar J et al Influence of persistent organic pollutants on oxidative stress in population-based samples
Chemosphere 2014114303-309
Homocysteine is Increased by Pb amp Cd
Guallar E et al Confounding of the relation between homocysteine and peripheral arterial disease by lead cadmium and renal function Am J Epidemiol 2006 Apr 15163(8)700-8
Nutrient Deficiencies Accentuate
Effects of Lead on Homocysteine
bull Deficiencies in folate B6 or B12 make lead more toxic
Lee YM Et al Association of homocysteine levels with blood lead levels and micronutrients in the US general population J Prev Med Public Health 2012 Nov45(6)387-93
T4 amp T3 and PCBs
bull PCBs decrease T4 production
bull PCBs inhibit iodotyrosinedeiodinase activity
bull Study done in pregnant women which implies effect on fetus IQ
Kim S Park J Kim HJ et al Association between several persistent organic pollutants and thyroid hormone levels in serum among the pregnant women of Korea Environ Int 2013 Sep59442-8Shimizu R Yamaguchi M Uramaru N et al Structure-activity relationships of 44 halogenated compounds for iodotyrosinedeiodinase-inhibitory activity Toxicology 2013 Dec 6314(1)22-9
T4 amp T3 and PCBs
bull Not just humans being affected
bull Large study of dolphins shows exactly the same effects
Schwacke LH Zolman ES Balmer BC et al Anaemia hypothyroidism and immune suppression associated with polychlorinated biphenyl exposure in bottlenose dolphins (Tursiops truncatus) Proceed Royal Society B doi101098rspb20110665
8-OHdG
bull Oxidized nucleoside
bull Direct measure of DNA damage
bull Indirect measure of oxidative stress and toxin load
bull Correlates with
Multiple cancers
Mitochondrial damage
Rate of aging
Smoking
Several toxinsWalter Crinnion ldquoTotal Toxic Loadrdquo AANP 2015
8-OHdG Correlates with Pack-Years
of Smoking
Yano T et al Significance of the urinary 8-OHdG level as an oxidative stress marker in lung cancer patients Lung Cancer
2009 Jan63(1)111-4
8-OHdG Correlates
with Mercury
Chen C et al Increased oxidative DNA damage as assessed by urinary 8-hydroxy-2-deoxyguanosine
concentrations and serum redox status in persons exposed to mercury Clin Chem 2005 Apr51(4)759-67
Toxin Effects Worse with Aging
bull Thyroid function decreases with PFOA levels
bull But only after age 63
Shrestha S Bloom MS Yucel R et al Perfluoroalkyl substances and thyroid function in older adults Environ Int 2015 Feb75206-14
Insightful 23-Year Prospective Study
1 lt 50 there is no difference between those with the lowest and highest PCBs
2 In youngest group insulin production increases in response to toxin level As expected since blocking of
insulin receptor sites by PCBs
requires more insulin
3 That adaptive ability decreases with aging
4 At age 50 all the measures show very strong toxin-dose response
Cumulative damage impairs ability to adapt
Suarez-Lopez JR et al Persistent organic pollutants in young adults and changes in glucose related metabolism over a 23-year follow-up Environ Res 2015 Feb137485-94
Recommendations
High body toxic load
GGT gt 25
Uric acid gt 50 mgdl
ALT gt30 UL
Bilirubin gt08 mgdl
CBC lt 6000
Platelet lt 250000
Low T3 andor T4
Monitor Total Toxic Load
8-OHdG gt4
ldquoUnconventionalrdquo Laboratory Tests
bull Challenge testing
bull Hair analysis
bull Direct measures of solvents and POPs in blood urine adipose tissue
Evaluation of Metal Exposure ndash Provocation
bull Provocation ndash the use of a chelating agent ndash before urine collection often done clinically but several limitations
No ldquoofficialrdquo reference range for provoked urine
Most chelating agents do not extract metals from all tissues thus
does not necessarily represent total body burden
bull Example Brain is one of the main target organs for both elemental and organic
mercury yet agents do not chelate brain mercury
bull Despite limitations widely used and advocated by clinicians in part to see efficacy of chelating agent as a guide to treatment and based on empirical evidence
Rooney JP The role of thiols dithiols nutritional factors and interacting ligands in the toxicology of mercury
Toxicology 2007
Is Challenge Testing Valid
bull Poor correlations of standard tests for mercury
bull Unpublished research from corporate wellness project
bull Published amalgam number correlation
bull Published fish consumption correlation
What We Found In Canada
bull Deviations from the mean of 14 29 and 91 respectively
bull DMPS is spreading distribution suggesting that it is better at differentiating mercury body load
bull Some VERY high
Hg Assessment Correlations
bull Extensive measurements in 65 Whole blood Hg
Oral DMPS challenge
Amalgam surfaces
bull Correlations Whole blood w pre urine r = 040
Whole blood w post urine r = 057
Pre urine w post urine r = 068
Amalgams w pre urine r = 026
Amalgams w whole blood r = 036
Amalgams with post urine 044
bull Clear documentation that
challenge testing is better00
100
200
300
400
500
600
0 10 20 30 40 50
Po
st
Uri
ne H
g u
gg
Number of amalgams
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
How Toxins Cause Damage 23
bull Damage DNA
Benzene - causes chromosomal damage
Pesticides ndash fruit growers have more DNA damage
Phthalates and insecticides ndash damage sperm DNA
4-hydroxy catechol estrogen (4-OHE) damages breast DNA
bull Epigenetic dysmodulation
Higher cord blood levels of hexachlorobenzene associated
with 2x greater risk for obesity in children
bull Damage cell membranes
Common mechanism for heavy metals inactivates
membrane enzymes ion channels and pumps
How Toxins Cause Damage 33
bull Block insulin receptor sites
PCBs and phthalates
bull Highest levels associated with a 4 to 20-fold greater diabetes risk
bull Imbalance hormones many toxin examples
Arsenic
bull Disrupts thyroid hormone and retinoic acid receptors
Phthalates
bull Act as anti-androgens
bull More than 75 of the US population has measurable levels of
several phthalate metabolites in the urine
PCBs
bull Lower testosterone levels in men
Which are the Worst Toxins
bull According to the CDC
Toxicity
Population toxic load
Prevalence in toxic waste sites
bull According to clinical importance
Exposure
of disease
Ability of the body to detoxifyexcrete
Ag
en
cy
fo
r T
oxic
Su
bs
tan
ce
s a
nd
Dis
ea
se
Reg
istr
y
Pri
ori
ty L
ist
The Worst Toxins Clinically
My Rank Toxin Diseases Primary Sources
1 Arsenic Cancers diabetes gout Water chicken rice
2 DDT ADHD dementia diabetes Everywhere
3 Phthalates ADHD diabetes Soft plastics HABAs
4 PBDEs ADHD diabetes Flame retardant fabrics
5 PAHs ADHD cancers dyslipidemia Smoking charbroiling
6 PCBs Cancers diabetes MI RA Everywhere
7 Mercury Dementia ldquoSilverrdquo fillings fish
8 Lead Cardiovascular disease IQ Paint water
Glyphosate Research invalid
Conventional Laboratory Tests Reflect
Toxic Load in ldquoNormalrdquo Range
bull Surprising number show toxin exposure
CBC RBC WBC platelet count hemoglobin basophilic
stippling
Liver enzymes ALT GGTP
Inflammatory markers CRP
Lipids LDL oxLDL triglycerides
Blood sugar insulin FBS 2-hour PP
Metabolites bilirubin uric acid homocysteine 8-OHdG
Thyroid T3 T4 TSH
bull The historic ldquonormalrdquo range has been changing as the population has become more toxic
WBC Lowered by PCB and OCP Exposure
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
0
1
2
3
4
5
6
7
8
1st Quartrile 2nd Quartile 3rd Quartile 4th Quartile
WBCbull Strong inverse correlation with PCBs and OCPs and CBC
bull Linear with almost all PCBs
bull High variability with OCPs
bull Within ldquonormalrdquo range
Effects on WBC Worsen with Years
of Exposure to Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Platelet Count Decreases with Years
of Exposure tp Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Solvents Decrease Platelet Count
bull Compared workers exposed 23 hrday to those exposed most of day to toluene
bull All wore face masks and protective gear
bull Platelet count 14 lower 252 versus 216ml
bull Impairment of sympathetic nerves (OR = 413)
bull Impairment of peripheral nerves (OR = 694)
bull Positive relationship between neurological abnormalities and a self-reported neuropsychiatric measurement (r = 035-066)
Shih HT et al Subclinical abnormalities in workers with continuous low-level toluene exposure Toxicol Ind Health 2011 Sep27(8)691-9
Basophilic Stippling of Red Cells
Toxinsbull Arsenic
bull Lead
Diseasesbull Alpha-thalassemia HbH Disease
bull Beta thalassemia
bull Hereditary pyrimidine 5-nucleotidase deficiency
bull Myelodysplastic syndrome
bull Sideroblastic anemia
bull Thrombotic thrombocytopenic purpura
GGT Indirect Measure of POPsbull Glutathione is key intracellular defense against oxidative stress
bull Cellular GGT metabolizes extracellular GSH allowing precursor amino acids to be reutilized for intracellular GSH
bull Exposure to POPs induces GGT as a defensive mechanism
bull Within normal range predicts type 2 diabetes coronary heart disease hypertension stroke dyslipidemia chronic kidney disease and cancer
bull Men with GGT gt50 UI had ~26 fold risk for diabetes compared to those with lt10 Those with 40-49 had a ~20 fold risk
bull Levels within normal range occur with obesity xs alcohol cigarette smoking physical inactivity high meat low fruit and vegetable intake
bull Cumulative biomarker for environmental pollutants
Lee DH et al (2003) Gamma-glutamyltransferase and diabetesmdasha 4 year follow-up study Diabetologia 46359ndash364
Pamela A et al Serum gamma-glutamyltransferase linking together environmental pollution redox equilibria and progression of atherosclerosis Clin Chem
Lab Med 200947(12)1583-4
Lee DH et al Serum gamma-glutamyltransferase new insights about an old enzyme J Epidemiol Community Health 2009 Nov63(11)884-6
Lee DH et alSerum gamma-glutamyltransferase predicts non-fatal myocardial infarction and fatal coronary heart disease among 28838 middle-aged men and
women Eur Heart J 2006272170ndash6
Lee DH et al Gamma-glutamyltransferase and diabetes--a 4 year follow-up study Diabetologia 2003 Mar46(3)359-64
Lee DH et al Can persistent organic pollutants explain the association between serum gamma-glutamyltransferase and type 2 diabetes Diabetologia 2008
Mar51(3)402-7
GGT and Alcohol Consumption
bull GGT directly correlates with alcohol consumption
bull In a non-uniform population 40 gd will elevate GGT ~15
bull Watch for false negatives
bull Genomic variation
bull Are these the ones most
sensitive todamaged by
chemical toxins
bull Could up-regulation of GGT in light alcohol consumption be reason for benefit
0
10
20
30
40
50
60
70
80
0 200 400 600 800
Grams of Ethanol per Week
Adapted from Nagaya T et al Dose-response relationships between drinking and serum tests in Japanese men
aged 40ndash59 years Alcohol 1999 Feb 17(2) 133ndash8
GGT Correlates With Toxic Metal Levels
Lee DH et al Graded associations of blood lead and urinary cadmium concentrations with oxidative-stress-related markers in the
US population results from the third National Health and Nutrition Examination Survey Environ Health
perspect 2006 Mar114(3)350-4
GGT and Diabetes Risk
0
5
10
15
20
25
30
lt10 10-19 20-29 30-39 40-49 gt50
Dia
bete
s R
isk
GGT
bull GGT over 50 associated with tripling of death rate
bull 30-40 associated with doubling
GGT Levels
Correlate with
Risk of Death
Brenner H et al Distribution determinants and prognostic value of gamma-glutamyltransferase for all-cause
mortality in a cohort of construction workers from southern Germany Prev Med 1997 26 305ndash10
GGT From Small US Company
with Young Workers
0
10
20
30
40
50
60
0 20 40 60 80 100
GGT Data from Canadian Oil Field
Workers
0
50
100
150
200
250
300
350
400
450
lt10 10-20 20-30 30-40 40-50 50-60 60-07 70-80 80-90 90-100 100-110 110-120 gt120
GGTP
20-fold increased risk of diabetes
Uric Acid Indirect Measure of POPs
bull Poly-fluorinated hydrocarbons (PFOA and PFOS) associated
with increased serum uric acid
Lin CY et al Association among serum perfluoroalkyl chemicals glucose homeostasis and metabolic syndrome
in adolescents and adults Diabetes Care 2009 Apr32(4)702-7
Steenland K et al Association of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) with uric
acid among adults with elevated community exposure to PFOA Environ Health Perspect 2010 Feb118229-33
Steenland 2010 Open Access
ALT Indirect Measure of POPs
bull ALT (proxy marker) elevation in 104 (not including viral
hepatitis hemochromatosis or alcoholic liver disease) of
NHANES 03-04 subset
bull Risk of elevated ALT increased dose-dependently with
cadmium lead mercury and PCB exposure
bull 100 of individuals had detectable PCBs 925 mercury
and 996 had detectable lead
bull In 2005-08 prevalence of NAFLD in US was 11 a
growing cause of chronic liver disease
Cave M et al Polychlorinated biphenyls lead and mercury are associated with liver disease in American adults
NHANES 2003-2004 Environ Health Perspect 2010 Dec118(12)1735-42
Younossi ZM et al Changes in the prevalence of the most common causes of chronic liver diseases in the United
States from 1988 to 2008 Clin Gastroenterol Hepatol 2011 Jun9(6)524-530e1
Bilirubin as a Marker of POPs
bull Degree of serum bilirubin increase is prognostically significant in chronic liver dysfunction
bull Mono-ortho PCB TEQ values were found to be significantly positively associated with bilirubin (β=071 P=0008) following adjustment for multiple potential confounders
bull Bilirubin levels significantly correlated with PCBs -105-118-126 and -194
bull Smoking appears to be the biggest confounder
Dufour DR et al 2000 Diagnosis and monitoring of hepatic injury II Recommendations for use of laboratory
tests in screening diagnosis and monitoring Clin Chem 46 2050ndash68
Kumar J et al Persistent organic pollutants and liver dysfunction biomarkers in a population-based human sample
of men and women Environ Res 2014134251-256
Perf
luo
rin
ate
dP
OP
s a
nd
Co
mm
on
Blo
od
Tests
Gleason JA et al Associations of perfluorinated chemical serum concentrations and biomarkers of liver function and uric acid in the
US population (NHANES) 2007-2010 Environ Res 20151368-14
Liver Enzymes Reflect Toxic Load
bull AST ALT and GGT increase with body load of PCBs and OCPs
bull Some non-linear
bull Oxychlordanetop quartile
ALT 10
GGT 25
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
LDL-Cholesterol as Measure of POPs
bull 5-year prospective study to determine if POP levels predict future elevation in LDL-cholesterol
bull 598 subjects initially at age 70
bull Looked at 23 POPs
bull Best correlation with PCB 194
Penell J Lind L Salihovic S et al Persistent organic pollutants are related to change in circulating
lipid levels during a 5 year follow-up Environ Res 134(2014)190ndash197
oxLDL as Measure of POPs
bull 992 70-year old individuals (50 women)
bull Sum of PCBs showed strong significant positive associations with ox-LDL and significant negative associations with glutathione-related markers (GSSG and GSSGGSH)
bull A number of POPs (PCB-99 138 153 156 170 180 194 206 and 209) showed strong significant positive association with ox-LDL
Kumar J et al Influence of persistent organic pollutants on oxidative stress in population-based samples
Chemosphere 2014114303-309
Homocysteine is Increased by Pb amp Cd
Guallar E et al Confounding of the relation between homocysteine and peripheral arterial disease by lead cadmium and renal function Am J Epidemiol 2006 Apr 15163(8)700-8
Nutrient Deficiencies Accentuate
Effects of Lead on Homocysteine
bull Deficiencies in folate B6 or B12 make lead more toxic
Lee YM Et al Association of homocysteine levels with blood lead levels and micronutrients in the US general population J Prev Med Public Health 2012 Nov45(6)387-93
T4 amp T3 and PCBs
bull PCBs decrease T4 production
bull PCBs inhibit iodotyrosinedeiodinase activity
bull Study done in pregnant women which implies effect on fetus IQ
Kim S Park J Kim HJ et al Association between several persistent organic pollutants and thyroid hormone levels in serum among the pregnant women of Korea Environ Int 2013 Sep59442-8Shimizu R Yamaguchi M Uramaru N et al Structure-activity relationships of 44 halogenated compounds for iodotyrosinedeiodinase-inhibitory activity Toxicology 2013 Dec 6314(1)22-9
T4 amp T3 and PCBs
bull Not just humans being affected
bull Large study of dolphins shows exactly the same effects
Schwacke LH Zolman ES Balmer BC et al Anaemia hypothyroidism and immune suppression associated with polychlorinated biphenyl exposure in bottlenose dolphins (Tursiops truncatus) Proceed Royal Society B doi101098rspb20110665
8-OHdG
bull Oxidized nucleoside
bull Direct measure of DNA damage
bull Indirect measure of oxidative stress and toxin load
bull Correlates with
Multiple cancers
Mitochondrial damage
Rate of aging
Smoking
Several toxinsWalter Crinnion ldquoTotal Toxic Loadrdquo AANP 2015
8-OHdG Correlates with Pack-Years
of Smoking
Yano T et al Significance of the urinary 8-OHdG level as an oxidative stress marker in lung cancer patients Lung Cancer
2009 Jan63(1)111-4
8-OHdG Correlates
with Mercury
Chen C et al Increased oxidative DNA damage as assessed by urinary 8-hydroxy-2-deoxyguanosine
concentrations and serum redox status in persons exposed to mercury Clin Chem 2005 Apr51(4)759-67
Toxin Effects Worse with Aging
bull Thyroid function decreases with PFOA levels
bull But only after age 63
Shrestha S Bloom MS Yucel R et al Perfluoroalkyl substances and thyroid function in older adults Environ Int 2015 Feb75206-14
Insightful 23-Year Prospective Study
1 lt 50 there is no difference between those with the lowest and highest PCBs
2 In youngest group insulin production increases in response to toxin level As expected since blocking of
insulin receptor sites by PCBs
requires more insulin
3 That adaptive ability decreases with aging
4 At age 50 all the measures show very strong toxin-dose response
Cumulative damage impairs ability to adapt
Suarez-Lopez JR et al Persistent organic pollutants in young adults and changes in glucose related metabolism over a 23-year follow-up Environ Res 2015 Feb137485-94
Recommendations
High body toxic load
GGT gt 25
Uric acid gt 50 mgdl
ALT gt30 UL
Bilirubin gt08 mgdl
CBC lt 6000
Platelet lt 250000
Low T3 andor T4
Monitor Total Toxic Load
8-OHdG gt4
ldquoUnconventionalrdquo Laboratory Tests
bull Challenge testing
bull Hair analysis
bull Direct measures of solvents and POPs in blood urine adipose tissue
Evaluation of Metal Exposure ndash Provocation
bull Provocation ndash the use of a chelating agent ndash before urine collection often done clinically but several limitations
No ldquoofficialrdquo reference range for provoked urine
Most chelating agents do not extract metals from all tissues thus
does not necessarily represent total body burden
bull Example Brain is one of the main target organs for both elemental and organic
mercury yet agents do not chelate brain mercury
bull Despite limitations widely used and advocated by clinicians in part to see efficacy of chelating agent as a guide to treatment and based on empirical evidence
Rooney JP The role of thiols dithiols nutritional factors and interacting ligands in the toxicology of mercury
Toxicology 2007
Is Challenge Testing Valid
bull Poor correlations of standard tests for mercury
bull Unpublished research from corporate wellness project
bull Published amalgam number correlation
bull Published fish consumption correlation
What We Found In Canada
bull Deviations from the mean of 14 29 and 91 respectively
bull DMPS is spreading distribution suggesting that it is better at differentiating mercury body load
bull Some VERY high
Hg Assessment Correlations
bull Extensive measurements in 65 Whole blood Hg
Oral DMPS challenge
Amalgam surfaces
bull Correlations Whole blood w pre urine r = 040
Whole blood w post urine r = 057
Pre urine w post urine r = 068
Amalgams w pre urine r = 026
Amalgams w whole blood r = 036
Amalgams with post urine 044
bull Clear documentation that
challenge testing is better00
100
200
300
400
500
600
0 10 20 30 40 50
Po
st
Uri
ne H
g u
gg
Number of amalgams
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
How Toxins Cause Damage 33
bull Block insulin receptor sites
PCBs and phthalates
bull Highest levels associated with a 4 to 20-fold greater diabetes risk
bull Imbalance hormones many toxin examples
Arsenic
bull Disrupts thyroid hormone and retinoic acid receptors
Phthalates
bull Act as anti-androgens
bull More than 75 of the US population has measurable levels of
several phthalate metabolites in the urine
PCBs
bull Lower testosterone levels in men
Which are the Worst Toxins
bull According to the CDC
Toxicity
Population toxic load
Prevalence in toxic waste sites
bull According to clinical importance
Exposure
of disease
Ability of the body to detoxifyexcrete
Ag
en
cy
fo
r T
oxic
Su
bs
tan
ce
s a
nd
Dis
ea
se
Reg
istr
y
Pri
ori
ty L
ist
The Worst Toxins Clinically
My Rank Toxin Diseases Primary Sources
1 Arsenic Cancers diabetes gout Water chicken rice
2 DDT ADHD dementia diabetes Everywhere
3 Phthalates ADHD diabetes Soft plastics HABAs
4 PBDEs ADHD diabetes Flame retardant fabrics
5 PAHs ADHD cancers dyslipidemia Smoking charbroiling
6 PCBs Cancers diabetes MI RA Everywhere
7 Mercury Dementia ldquoSilverrdquo fillings fish
8 Lead Cardiovascular disease IQ Paint water
Glyphosate Research invalid
Conventional Laboratory Tests Reflect
Toxic Load in ldquoNormalrdquo Range
bull Surprising number show toxin exposure
CBC RBC WBC platelet count hemoglobin basophilic
stippling
Liver enzymes ALT GGTP
Inflammatory markers CRP
Lipids LDL oxLDL triglycerides
Blood sugar insulin FBS 2-hour PP
Metabolites bilirubin uric acid homocysteine 8-OHdG
Thyroid T3 T4 TSH
bull The historic ldquonormalrdquo range has been changing as the population has become more toxic
WBC Lowered by PCB and OCP Exposure
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
0
1
2
3
4
5
6
7
8
1st Quartrile 2nd Quartile 3rd Quartile 4th Quartile
WBCbull Strong inverse correlation with PCBs and OCPs and CBC
bull Linear with almost all PCBs
bull High variability with OCPs
bull Within ldquonormalrdquo range
Effects on WBC Worsen with Years
of Exposure to Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Platelet Count Decreases with Years
of Exposure tp Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Solvents Decrease Platelet Count
bull Compared workers exposed 23 hrday to those exposed most of day to toluene
bull All wore face masks and protective gear
bull Platelet count 14 lower 252 versus 216ml
bull Impairment of sympathetic nerves (OR = 413)
bull Impairment of peripheral nerves (OR = 694)
bull Positive relationship between neurological abnormalities and a self-reported neuropsychiatric measurement (r = 035-066)
Shih HT et al Subclinical abnormalities in workers with continuous low-level toluene exposure Toxicol Ind Health 2011 Sep27(8)691-9
Basophilic Stippling of Red Cells
Toxinsbull Arsenic
bull Lead
Diseasesbull Alpha-thalassemia HbH Disease
bull Beta thalassemia
bull Hereditary pyrimidine 5-nucleotidase deficiency
bull Myelodysplastic syndrome
bull Sideroblastic anemia
bull Thrombotic thrombocytopenic purpura
GGT Indirect Measure of POPsbull Glutathione is key intracellular defense against oxidative stress
bull Cellular GGT metabolizes extracellular GSH allowing precursor amino acids to be reutilized for intracellular GSH
bull Exposure to POPs induces GGT as a defensive mechanism
bull Within normal range predicts type 2 diabetes coronary heart disease hypertension stroke dyslipidemia chronic kidney disease and cancer
bull Men with GGT gt50 UI had ~26 fold risk for diabetes compared to those with lt10 Those with 40-49 had a ~20 fold risk
bull Levels within normal range occur with obesity xs alcohol cigarette smoking physical inactivity high meat low fruit and vegetable intake
bull Cumulative biomarker for environmental pollutants
Lee DH et al (2003) Gamma-glutamyltransferase and diabetesmdasha 4 year follow-up study Diabetologia 46359ndash364
Pamela A et al Serum gamma-glutamyltransferase linking together environmental pollution redox equilibria and progression of atherosclerosis Clin Chem
Lab Med 200947(12)1583-4
Lee DH et al Serum gamma-glutamyltransferase new insights about an old enzyme J Epidemiol Community Health 2009 Nov63(11)884-6
Lee DH et alSerum gamma-glutamyltransferase predicts non-fatal myocardial infarction and fatal coronary heart disease among 28838 middle-aged men and
women Eur Heart J 2006272170ndash6
Lee DH et al Gamma-glutamyltransferase and diabetes--a 4 year follow-up study Diabetologia 2003 Mar46(3)359-64
Lee DH et al Can persistent organic pollutants explain the association between serum gamma-glutamyltransferase and type 2 diabetes Diabetologia 2008
Mar51(3)402-7
GGT and Alcohol Consumption
bull GGT directly correlates with alcohol consumption
bull In a non-uniform population 40 gd will elevate GGT ~15
bull Watch for false negatives
bull Genomic variation
bull Are these the ones most
sensitive todamaged by
chemical toxins
bull Could up-regulation of GGT in light alcohol consumption be reason for benefit
0
10
20
30
40
50
60
70
80
0 200 400 600 800
Grams of Ethanol per Week
Adapted from Nagaya T et al Dose-response relationships between drinking and serum tests in Japanese men
aged 40ndash59 years Alcohol 1999 Feb 17(2) 133ndash8
GGT Correlates With Toxic Metal Levels
Lee DH et al Graded associations of blood lead and urinary cadmium concentrations with oxidative-stress-related markers in the
US population results from the third National Health and Nutrition Examination Survey Environ Health
perspect 2006 Mar114(3)350-4
GGT and Diabetes Risk
0
5
10
15
20
25
30
lt10 10-19 20-29 30-39 40-49 gt50
Dia
bete
s R
isk
GGT
bull GGT over 50 associated with tripling of death rate
bull 30-40 associated with doubling
GGT Levels
Correlate with
Risk of Death
Brenner H et al Distribution determinants and prognostic value of gamma-glutamyltransferase for all-cause
mortality in a cohort of construction workers from southern Germany Prev Med 1997 26 305ndash10
GGT From Small US Company
with Young Workers
0
10
20
30
40
50
60
0 20 40 60 80 100
GGT Data from Canadian Oil Field
Workers
0
50
100
150
200
250
300
350
400
450
lt10 10-20 20-30 30-40 40-50 50-60 60-07 70-80 80-90 90-100 100-110 110-120 gt120
GGTP
20-fold increased risk of diabetes
Uric Acid Indirect Measure of POPs
bull Poly-fluorinated hydrocarbons (PFOA and PFOS) associated
with increased serum uric acid
Lin CY et al Association among serum perfluoroalkyl chemicals glucose homeostasis and metabolic syndrome
in adolescents and adults Diabetes Care 2009 Apr32(4)702-7
Steenland K et al Association of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) with uric
acid among adults with elevated community exposure to PFOA Environ Health Perspect 2010 Feb118229-33
Steenland 2010 Open Access
ALT Indirect Measure of POPs
bull ALT (proxy marker) elevation in 104 (not including viral
hepatitis hemochromatosis or alcoholic liver disease) of
NHANES 03-04 subset
bull Risk of elevated ALT increased dose-dependently with
cadmium lead mercury and PCB exposure
bull 100 of individuals had detectable PCBs 925 mercury
and 996 had detectable lead
bull In 2005-08 prevalence of NAFLD in US was 11 a
growing cause of chronic liver disease
Cave M et al Polychlorinated biphenyls lead and mercury are associated with liver disease in American adults
NHANES 2003-2004 Environ Health Perspect 2010 Dec118(12)1735-42
Younossi ZM et al Changes in the prevalence of the most common causes of chronic liver diseases in the United
States from 1988 to 2008 Clin Gastroenterol Hepatol 2011 Jun9(6)524-530e1
Bilirubin as a Marker of POPs
bull Degree of serum bilirubin increase is prognostically significant in chronic liver dysfunction
bull Mono-ortho PCB TEQ values were found to be significantly positively associated with bilirubin (β=071 P=0008) following adjustment for multiple potential confounders
bull Bilirubin levels significantly correlated with PCBs -105-118-126 and -194
bull Smoking appears to be the biggest confounder
Dufour DR et al 2000 Diagnosis and monitoring of hepatic injury II Recommendations for use of laboratory
tests in screening diagnosis and monitoring Clin Chem 46 2050ndash68
Kumar J et al Persistent organic pollutants and liver dysfunction biomarkers in a population-based human sample
of men and women Environ Res 2014134251-256
Perf
luo
rin
ate
dP
OP
s a
nd
Co
mm
on
Blo
od
Tests
Gleason JA et al Associations of perfluorinated chemical serum concentrations and biomarkers of liver function and uric acid in the
US population (NHANES) 2007-2010 Environ Res 20151368-14
Liver Enzymes Reflect Toxic Load
bull AST ALT and GGT increase with body load of PCBs and OCPs
bull Some non-linear
bull Oxychlordanetop quartile
ALT 10
GGT 25
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
LDL-Cholesterol as Measure of POPs
bull 5-year prospective study to determine if POP levels predict future elevation in LDL-cholesterol
bull 598 subjects initially at age 70
bull Looked at 23 POPs
bull Best correlation with PCB 194
Penell J Lind L Salihovic S et al Persistent organic pollutants are related to change in circulating
lipid levels during a 5 year follow-up Environ Res 134(2014)190ndash197
oxLDL as Measure of POPs
bull 992 70-year old individuals (50 women)
bull Sum of PCBs showed strong significant positive associations with ox-LDL and significant negative associations with glutathione-related markers (GSSG and GSSGGSH)
bull A number of POPs (PCB-99 138 153 156 170 180 194 206 and 209) showed strong significant positive association with ox-LDL
Kumar J et al Influence of persistent organic pollutants on oxidative stress in population-based samples
Chemosphere 2014114303-309
Homocysteine is Increased by Pb amp Cd
Guallar E et al Confounding of the relation between homocysteine and peripheral arterial disease by lead cadmium and renal function Am J Epidemiol 2006 Apr 15163(8)700-8
Nutrient Deficiencies Accentuate
Effects of Lead on Homocysteine
bull Deficiencies in folate B6 or B12 make lead more toxic
Lee YM Et al Association of homocysteine levels with blood lead levels and micronutrients in the US general population J Prev Med Public Health 2012 Nov45(6)387-93
T4 amp T3 and PCBs
bull PCBs decrease T4 production
bull PCBs inhibit iodotyrosinedeiodinase activity
bull Study done in pregnant women which implies effect on fetus IQ
Kim S Park J Kim HJ et al Association between several persistent organic pollutants and thyroid hormone levels in serum among the pregnant women of Korea Environ Int 2013 Sep59442-8Shimizu R Yamaguchi M Uramaru N et al Structure-activity relationships of 44 halogenated compounds for iodotyrosinedeiodinase-inhibitory activity Toxicology 2013 Dec 6314(1)22-9
T4 amp T3 and PCBs
bull Not just humans being affected
bull Large study of dolphins shows exactly the same effects
Schwacke LH Zolman ES Balmer BC et al Anaemia hypothyroidism and immune suppression associated with polychlorinated biphenyl exposure in bottlenose dolphins (Tursiops truncatus) Proceed Royal Society B doi101098rspb20110665
8-OHdG
bull Oxidized nucleoside
bull Direct measure of DNA damage
bull Indirect measure of oxidative stress and toxin load
bull Correlates with
Multiple cancers
Mitochondrial damage
Rate of aging
Smoking
Several toxinsWalter Crinnion ldquoTotal Toxic Loadrdquo AANP 2015
8-OHdG Correlates with Pack-Years
of Smoking
Yano T et al Significance of the urinary 8-OHdG level as an oxidative stress marker in lung cancer patients Lung Cancer
2009 Jan63(1)111-4
8-OHdG Correlates
with Mercury
Chen C et al Increased oxidative DNA damage as assessed by urinary 8-hydroxy-2-deoxyguanosine
concentrations and serum redox status in persons exposed to mercury Clin Chem 2005 Apr51(4)759-67
Toxin Effects Worse with Aging
bull Thyroid function decreases with PFOA levels
bull But only after age 63
Shrestha S Bloom MS Yucel R et al Perfluoroalkyl substances and thyroid function in older adults Environ Int 2015 Feb75206-14
Insightful 23-Year Prospective Study
1 lt 50 there is no difference between those with the lowest and highest PCBs
2 In youngest group insulin production increases in response to toxin level As expected since blocking of
insulin receptor sites by PCBs
requires more insulin
3 That adaptive ability decreases with aging
4 At age 50 all the measures show very strong toxin-dose response
Cumulative damage impairs ability to adapt
Suarez-Lopez JR et al Persistent organic pollutants in young adults and changes in glucose related metabolism over a 23-year follow-up Environ Res 2015 Feb137485-94
Recommendations
High body toxic load
GGT gt 25
Uric acid gt 50 mgdl
ALT gt30 UL
Bilirubin gt08 mgdl
CBC lt 6000
Platelet lt 250000
Low T3 andor T4
Monitor Total Toxic Load
8-OHdG gt4
ldquoUnconventionalrdquo Laboratory Tests
bull Challenge testing
bull Hair analysis
bull Direct measures of solvents and POPs in blood urine adipose tissue
Evaluation of Metal Exposure ndash Provocation
bull Provocation ndash the use of a chelating agent ndash before urine collection often done clinically but several limitations
No ldquoofficialrdquo reference range for provoked urine
Most chelating agents do not extract metals from all tissues thus
does not necessarily represent total body burden
bull Example Brain is one of the main target organs for both elemental and organic
mercury yet agents do not chelate brain mercury
bull Despite limitations widely used and advocated by clinicians in part to see efficacy of chelating agent as a guide to treatment and based on empirical evidence
Rooney JP The role of thiols dithiols nutritional factors and interacting ligands in the toxicology of mercury
Toxicology 2007
Is Challenge Testing Valid
bull Poor correlations of standard tests for mercury
bull Unpublished research from corporate wellness project
bull Published amalgam number correlation
bull Published fish consumption correlation
What We Found In Canada
bull Deviations from the mean of 14 29 and 91 respectively
bull DMPS is spreading distribution suggesting that it is better at differentiating mercury body load
bull Some VERY high
Hg Assessment Correlations
bull Extensive measurements in 65 Whole blood Hg
Oral DMPS challenge
Amalgam surfaces
bull Correlations Whole blood w pre urine r = 040
Whole blood w post urine r = 057
Pre urine w post urine r = 068
Amalgams w pre urine r = 026
Amalgams w whole blood r = 036
Amalgams with post urine 044
bull Clear documentation that
challenge testing is better00
100
200
300
400
500
600
0 10 20 30 40 50
Po
st
Uri
ne H
g u
gg
Number of amalgams
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
Which are the Worst Toxins
bull According to the CDC
Toxicity
Population toxic load
Prevalence in toxic waste sites
bull According to clinical importance
Exposure
of disease
Ability of the body to detoxifyexcrete
Ag
en
cy
fo
r T
oxic
Su
bs
tan
ce
s a
nd
Dis
ea
se
Reg
istr
y
Pri
ori
ty L
ist
The Worst Toxins Clinically
My Rank Toxin Diseases Primary Sources
1 Arsenic Cancers diabetes gout Water chicken rice
2 DDT ADHD dementia diabetes Everywhere
3 Phthalates ADHD diabetes Soft plastics HABAs
4 PBDEs ADHD diabetes Flame retardant fabrics
5 PAHs ADHD cancers dyslipidemia Smoking charbroiling
6 PCBs Cancers diabetes MI RA Everywhere
7 Mercury Dementia ldquoSilverrdquo fillings fish
8 Lead Cardiovascular disease IQ Paint water
Glyphosate Research invalid
Conventional Laboratory Tests Reflect
Toxic Load in ldquoNormalrdquo Range
bull Surprising number show toxin exposure
CBC RBC WBC platelet count hemoglobin basophilic
stippling
Liver enzymes ALT GGTP
Inflammatory markers CRP
Lipids LDL oxLDL triglycerides
Blood sugar insulin FBS 2-hour PP
Metabolites bilirubin uric acid homocysteine 8-OHdG
Thyroid T3 T4 TSH
bull The historic ldquonormalrdquo range has been changing as the population has become more toxic
WBC Lowered by PCB and OCP Exposure
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
0
1
2
3
4
5
6
7
8
1st Quartrile 2nd Quartile 3rd Quartile 4th Quartile
WBCbull Strong inverse correlation with PCBs and OCPs and CBC
bull Linear with almost all PCBs
bull High variability with OCPs
bull Within ldquonormalrdquo range
Effects on WBC Worsen with Years
of Exposure to Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Platelet Count Decreases with Years
of Exposure tp Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Solvents Decrease Platelet Count
bull Compared workers exposed 23 hrday to those exposed most of day to toluene
bull All wore face masks and protective gear
bull Platelet count 14 lower 252 versus 216ml
bull Impairment of sympathetic nerves (OR = 413)
bull Impairment of peripheral nerves (OR = 694)
bull Positive relationship between neurological abnormalities and a self-reported neuropsychiatric measurement (r = 035-066)
Shih HT et al Subclinical abnormalities in workers with continuous low-level toluene exposure Toxicol Ind Health 2011 Sep27(8)691-9
Basophilic Stippling of Red Cells
Toxinsbull Arsenic
bull Lead
Diseasesbull Alpha-thalassemia HbH Disease
bull Beta thalassemia
bull Hereditary pyrimidine 5-nucleotidase deficiency
bull Myelodysplastic syndrome
bull Sideroblastic anemia
bull Thrombotic thrombocytopenic purpura
GGT Indirect Measure of POPsbull Glutathione is key intracellular defense against oxidative stress
bull Cellular GGT metabolizes extracellular GSH allowing precursor amino acids to be reutilized for intracellular GSH
bull Exposure to POPs induces GGT as a defensive mechanism
bull Within normal range predicts type 2 diabetes coronary heart disease hypertension stroke dyslipidemia chronic kidney disease and cancer
bull Men with GGT gt50 UI had ~26 fold risk for diabetes compared to those with lt10 Those with 40-49 had a ~20 fold risk
bull Levels within normal range occur with obesity xs alcohol cigarette smoking physical inactivity high meat low fruit and vegetable intake
bull Cumulative biomarker for environmental pollutants
Lee DH et al (2003) Gamma-glutamyltransferase and diabetesmdasha 4 year follow-up study Diabetologia 46359ndash364
Pamela A et al Serum gamma-glutamyltransferase linking together environmental pollution redox equilibria and progression of atherosclerosis Clin Chem
Lab Med 200947(12)1583-4
Lee DH et al Serum gamma-glutamyltransferase new insights about an old enzyme J Epidemiol Community Health 2009 Nov63(11)884-6
Lee DH et alSerum gamma-glutamyltransferase predicts non-fatal myocardial infarction and fatal coronary heart disease among 28838 middle-aged men and
women Eur Heart J 2006272170ndash6
Lee DH et al Gamma-glutamyltransferase and diabetes--a 4 year follow-up study Diabetologia 2003 Mar46(3)359-64
Lee DH et al Can persistent organic pollutants explain the association between serum gamma-glutamyltransferase and type 2 diabetes Diabetologia 2008
Mar51(3)402-7
GGT and Alcohol Consumption
bull GGT directly correlates with alcohol consumption
bull In a non-uniform population 40 gd will elevate GGT ~15
bull Watch for false negatives
bull Genomic variation
bull Are these the ones most
sensitive todamaged by
chemical toxins
bull Could up-regulation of GGT in light alcohol consumption be reason for benefit
0
10
20
30
40
50
60
70
80
0 200 400 600 800
Grams of Ethanol per Week
Adapted from Nagaya T et al Dose-response relationships between drinking and serum tests in Japanese men
aged 40ndash59 years Alcohol 1999 Feb 17(2) 133ndash8
GGT Correlates With Toxic Metal Levels
Lee DH et al Graded associations of blood lead and urinary cadmium concentrations with oxidative-stress-related markers in the
US population results from the third National Health and Nutrition Examination Survey Environ Health
perspect 2006 Mar114(3)350-4
GGT and Diabetes Risk
0
5
10
15
20
25
30
lt10 10-19 20-29 30-39 40-49 gt50
Dia
bete
s R
isk
GGT
bull GGT over 50 associated with tripling of death rate
bull 30-40 associated with doubling
GGT Levels
Correlate with
Risk of Death
Brenner H et al Distribution determinants and prognostic value of gamma-glutamyltransferase for all-cause
mortality in a cohort of construction workers from southern Germany Prev Med 1997 26 305ndash10
GGT From Small US Company
with Young Workers
0
10
20
30
40
50
60
0 20 40 60 80 100
GGT Data from Canadian Oil Field
Workers
0
50
100
150
200
250
300
350
400
450
lt10 10-20 20-30 30-40 40-50 50-60 60-07 70-80 80-90 90-100 100-110 110-120 gt120
GGTP
20-fold increased risk of diabetes
Uric Acid Indirect Measure of POPs
bull Poly-fluorinated hydrocarbons (PFOA and PFOS) associated
with increased serum uric acid
Lin CY et al Association among serum perfluoroalkyl chemicals glucose homeostasis and metabolic syndrome
in adolescents and adults Diabetes Care 2009 Apr32(4)702-7
Steenland K et al Association of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) with uric
acid among adults with elevated community exposure to PFOA Environ Health Perspect 2010 Feb118229-33
Steenland 2010 Open Access
ALT Indirect Measure of POPs
bull ALT (proxy marker) elevation in 104 (not including viral
hepatitis hemochromatosis or alcoholic liver disease) of
NHANES 03-04 subset
bull Risk of elevated ALT increased dose-dependently with
cadmium lead mercury and PCB exposure
bull 100 of individuals had detectable PCBs 925 mercury
and 996 had detectable lead
bull In 2005-08 prevalence of NAFLD in US was 11 a
growing cause of chronic liver disease
Cave M et al Polychlorinated biphenyls lead and mercury are associated with liver disease in American adults
NHANES 2003-2004 Environ Health Perspect 2010 Dec118(12)1735-42
Younossi ZM et al Changes in the prevalence of the most common causes of chronic liver diseases in the United
States from 1988 to 2008 Clin Gastroenterol Hepatol 2011 Jun9(6)524-530e1
Bilirubin as a Marker of POPs
bull Degree of serum bilirubin increase is prognostically significant in chronic liver dysfunction
bull Mono-ortho PCB TEQ values were found to be significantly positively associated with bilirubin (β=071 P=0008) following adjustment for multiple potential confounders
bull Bilirubin levels significantly correlated with PCBs -105-118-126 and -194
bull Smoking appears to be the biggest confounder
Dufour DR et al 2000 Diagnosis and monitoring of hepatic injury II Recommendations for use of laboratory
tests in screening diagnosis and monitoring Clin Chem 46 2050ndash68
Kumar J et al Persistent organic pollutants and liver dysfunction biomarkers in a population-based human sample
of men and women Environ Res 2014134251-256
Perf
luo
rin
ate
dP
OP
s a
nd
Co
mm
on
Blo
od
Tests
Gleason JA et al Associations of perfluorinated chemical serum concentrations and biomarkers of liver function and uric acid in the
US population (NHANES) 2007-2010 Environ Res 20151368-14
Liver Enzymes Reflect Toxic Load
bull AST ALT and GGT increase with body load of PCBs and OCPs
bull Some non-linear
bull Oxychlordanetop quartile
ALT 10
GGT 25
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
LDL-Cholesterol as Measure of POPs
bull 5-year prospective study to determine if POP levels predict future elevation in LDL-cholesterol
bull 598 subjects initially at age 70
bull Looked at 23 POPs
bull Best correlation with PCB 194
Penell J Lind L Salihovic S et al Persistent organic pollutants are related to change in circulating
lipid levels during a 5 year follow-up Environ Res 134(2014)190ndash197
oxLDL as Measure of POPs
bull 992 70-year old individuals (50 women)
bull Sum of PCBs showed strong significant positive associations with ox-LDL and significant negative associations with glutathione-related markers (GSSG and GSSGGSH)
bull A number of POPs (PCB-99 138 153 156 170 180 194 206 and 209) showed strong significant positive association with ox-LDL
Kumar J et al Influence of persistent organic pollutants on oxidative stress in population-based samples
Chemosphere 2014114303-309
Homocysteine is Increased by Pb amp Cd
Guallar E et al Confounding of the relation between homocysteine and peripheral arterial disease by lead cadmium and renal function Am J Epidemiol 2006 Apr 15163(8)700-8
Nutrient Deficiencies Accentuate
Effects of Lead on Homocysteine
bull Deficiencies in folate B6 or B12 make lead more toxic
Lee YM Et al Association of homocysteine levels with blood lead levels and micronutrients in the US general population J Prev Med Public Health 2012 Nov45(6)387-93
T4 amp T3 and PCBs
bull PCBs decrease T4 production
bull PCBs inhibit iodotyrosinedeiodinase activity
bull Study done in pregnant women which implies effect on fetus IQ
Kim S Park J Kim HJ et al Association between several persistent organic pollutants and thyroid hormone levels in serum among the pregnant women of Korea Environ Int 2013 Sep59442-8Shimizu R Yamaguchi M Uramaru N et al Structure-activity relationships of 44 halogenated compounds for iodotyrosinedeiodinase-inhibitory activity Toxicology 2013 Dec 6314(1)22-9
T4 amp T3 and PCBs
bull Not just humans being affected
bull Large study of dolphins shows exactly the same effects
Schwacke LH Zolman ES Balmer BC et al Anaemia hypothyroidism and immune suppression associated with polychlorinated biphenyl exposure in bottlenose dolphins (Tursiops truncatus) Proceed Royal Society B doi101098rspb20110665
8-OHdG
bull Oxidized nucleoside
bull Direct measure of DNA damage
bull Indirect measure of oxidative stress and toxin load
bull Correlates with
Multiple cancers
Mitochondrial damage
Rate of aging
Smoking
Several toxinsWalter Crinnion ldquoTotal Toxic Loadrdquo AANP 2015
8-OHdG Correlates with Pack-Years
of Smoking
Yano T et al Significance of the urinary 8-OHdG level as an oxidative stress marker in lung cancer patients Lung Cancer
2009 Jan63(1)111-4
8-OHdG Correlates
with Mercury
Chen C et al Increased oxidative DNA damage as assessed by urinary 8-hydroxy-2-deoxyguanosine
concentrations and serum redox status in persons exposed to mercury Clin Chem 2005 Apr51(4)759-67
Toxin Effects Worse with Aging
bull Thyroid function decreases with PFOA levels
bull But only after age 63
Shrestha S Bloom MS Yucel R et al Perfluoroalkyl substances and thyroid function in older adults Environ Int 2015 Feb75206-14
Insightful 23-Year Prospective Study
1 lt 50 there is no difference between those with the lowest and highest PCBs
2 In youngest group insulin production increases in response to toxin level As expected since blocking of
insulin receptor sites by PCBs
requires more insulin
3 That adaptive ability decreases with aging
4 At age 50 all the measures show very strong toxin-dose response
Cumulative damage impairs ability to adapt
Suarez-Lopez JR et al Persistent organic pollutants in young adults and changes in glucose related metabolism over a 23-year follow-up Environ Res 2015 Feb137485-94
Recommendations
High body toxic load
GGT gt 25
Uric acid gt 50 mgdl
ALT gt30 UL
Bilirubin gt08 mgdl
CBC lt 6000
Platelet lt 250000
Low T3 andor T4
Monitor Total Toxic Load
8-OHdG gt4
ldquoUnconventionalrdquo Laboratory Tests
bull Challenge testing
bull Hair analysis
bull Direct measures of solvents and POPs in blood urine adipose tissue
Evaluation of Metal Exposure ndash Provocation
bull Provocation ndash the use of a chelating agent ndash before urine collection often done clinically but several limitations
No ldquoofficialrdquo reference range for provoked urine
Most chelating agents do not extract metals from all tissues thus
does not necessarily represent total body burden
bull Example Brain is one of the main target organs for both elemental and organic
mercury yet agents do not chelate brain mercury
bull Despite limitations widely used and advocated by clinicians in part to see efficacy of chelating agent as a guide to treatment and based on empirical evidence
Rooney JP The role of thiols dithiols nutritional factors and interacting ligands in the toxicology of mercury
Toxicology 2007
Is Challenge Testing Valid
bull Poor correlations of standard tests for mercury
bull Unpublished research from corporate wellness project
bull Published amalgam number correlation
bull Published fish consumption correlation
What We Found In Canada
bull Deviations from the mean of 14 29 and 91 respectively
bull DMPS is spreading distribution suggesting that it is better at differentiating mercury body load
bull Some VERY high
Hg Assessment Correlations
bull Extensive measurements in 65 Whole blood Hg
Oral DMPS challenge
Amalgam surfaces
bull Correlations Whole blood w pre urine r = 040
Whole blood w post urine r = 057
Pre urine w post urine r = 068
Amalgams w pre urine r = 026
Amalgams w whole blood r = 036
Amalgams with post urine 044
bull Clear documentation that
challenge testing is better00
100
200
300
400
500
600
0 10 20 30 40 50
Po
st
Uri
ne H
g u
gg
Number of amalgams
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
Ag
en
cy
fo
r T
oxic
Su
bs
tan
ce
s a
nd
Dis
ea
se
Reg
istr
y
Pri
ori
ty L
ist
The Worst Toxins Clinically
My Rank Toxin Diseases Primary Sources
1 Arsenic Cancers diabetes gout Water chicken rice
2 DDT ADHD dementia diabetes Everywhere
3 Phthalates ADHD diabetes Soft plastics HABAs
4 PBDEs ADHD diabetes Flame retardant fabrics
5 PAHs ADHD cancers dyslipidemia Smoking charbroiling
6 PCBs Cancers diabetes MI RA Everywhere
7 Mercury Dementia ldquoSilverrdquo fillings fish
8 Lead Cardiovascular disease IQ Paint water
Glyphosate Research invalid
Conventional Laboratory Tests Reflect
Toxic Load in ldquoNormalrdquo Range
bull Surprising number show toxin exposure
CBC RBC WBC platelet count hemoglobin basophilic
stippling
Liver enzymes ALT GGTP
Inflammatory markers CRP
Lipids LDL oxLDL triglycerides
Blood sugar insulin FBS 2-hour PP
Metabolites bilirubin uric acid homocysteine 8-OHdG
Thyroid T3 T4 TSH
bull The historic ldquonormalrdquo range has been changing as the population has become more toxic
WBC Lowered by PCB and OCP Exposure
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
0
1
2
3
4
5
6
7
8
1st Quartrile 2nd Quartile 3rd Quartile 4th Quartile
WBCbull Strong inverse correlation with PCBs and OCPs and CBC
bull Linear with almost all PCBs
bull High variability with OCPs
bull Within ldquonormalrdquo range
Effects on WBC Worsen with Years
of Exposure to Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Platelet Count Decreases with Years
of Exposure tp Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Solvents Decrease Platelet Count
bull Compared workers exposed 23 hrday to those exposed most of day to toluene
bull All wore face masks and protective gear
bull Platelet count 14 lower 252 versus 216ml
bull Impairment of sympathetic nerves (OR = 413)
bull Impairment of peripheral nerves (OR = 694)
bull Positive relationship between neurological abnormalities and a self-reported neuropsychiatric measurement (r = 035-066)
Shih HT et al Subclinical abnormalities in workers with continuous low-level toluene exposure Toxicol Ind Health 2011 Sep27(8)691-9
Basophilic Stippling of Red Cells
Toxinsbull Arsenic
bull Lead
Diseasesbull Alpha-thalassemia HbH Disease
bull Beta thalassemia
bull Hereditary pyrimidine 5-nucleotidase deficiency
bull Myelodysplastic syndrome
bull Sideroblastic anemia
bull Thrombotic thrombocytopenic purpura
GGT Indirect Measure of POPsbull Glutathione is key intracellular defense against oxidative stress
bull Cellular GGT metabolizes extracellular GSH allowing precursor amino acids to be reutilized for intracellular GSH
bull Exposure to POPs induces GGT as a defensive mechanism
bull Within normal range predicts type 2 diabetes coronary heart disease hypertension stroke dyslipidemia chronic kidney disease and cancer
bull Men with GGT gt50 UI had ~26 fold risk for diabetes compared to those with lt10 Those with 40-49 had a ~20 fold risk
bull Levels within normal range occur with obesity xs alcohol cigarette smoking physical inactivity high meat low fruit and vegetable intake
bull Cumulative biomarker for environmental pollutants
Lee DH et al (2003) Gamma-glutamyltransferase and diabetesmdasha 4 year follow-up study Diabetologia 46359ndash364
Pamela A et al Serum gamma-glutamyltransferase linking together environmental pollution redox equilibria and progression of atherosclerosis Clin Chem
Lab Med 200947(12)1583-4
Lee DH et al Serum gamma-glutamyltransferase new insights about an old enzyme J Epidemiol Community Health 2009 Nov63(11)884-6
Lee DH et alSerum gamma-glutamyltransferase predicts non-fatal myocardial infarction and fatal coronary heart disease among 28838 middle-aged men and
women Eur Heart J 2006272170ndash6
Lee DH et al Gamma-glutamyltransferase and diabetes--a 4 year follow-up study Diabetologia 2003 Mar46(3)359-64
Lee DH et al Can persistent organic pollutants explain the association between serum gamma-glutamyltransferase and type 2 diabetes Diabetologia 2008
Mar51(3)402-7
GGT and Alcohol Consumption
bull GGT directly correlates with alcohol consumption
bull In a non-uniform population 40 gd will elevate GGT ~15
bull Watch for false negatives
bull Genomic variation
bull Are these the ones most
sensitive todamaged by
chemical toxins
bull Could up-regulation of GGT in light alcohol consumption be reason for benefit
0
10
20
30
40
50
60
70
80
0 200 400 600 800
Grams of Ethanol per Week
Adapted from Nagaya T et al Dose-response relationships between drinking and serum tests in Japanese men
aged 40ndash59 years Alcohol 1999 Feb 17(2) 133ndash8
GGT Correlates With Toxic Metal Levels
Lee DH et al Graded associations of blood lead and urinary cadmium concentrations with oxidative-stress-related markers in the
US population results from the third National Health and Nutrition Examination Survey Environ Health
perspect 2006 Mar114(3)350-4
GGT and Diabetes Risk
0
5
10
15
20
25
30
lt10 10-19 20-29 30-39 40-49 gt50
Dia
bete
s R
isk
GGT
bull GGT over 50 associated with tripling of death rate
bull 30-40 associated with doubling
GGT Levels
Correlate with
Risk of Death
Brenner H et al Distribution determinants and prognostic value of gamma-glutamyltransferase for all-cause
mortality in a cohort of construction workers from southern Germany Prev Med 1997 26 305ndash10
GGT From Small US Company
with Young Workers
0
10
20
30
40
50
60
0 20 40 60 80 100
GGT Data from Canadian Oil Field
Workers
0
50
100
150
200
250
300
350
400
450
lt10 10-20 20-30 30-40 40-50 50-60 60-07 70-80 80-90 90-100 100-110 110-120 gt120
GGTP
20-fold increased risk of diabetes
Uric Acid Indirect Measure of POPs
bull Poly-fluorinated hydrocarbons (PFOA and PFOS) associated
with increased serum uric acid
Lin CY et al Association among serum perfluoroalkyl chemicals glucose homeostasis and metabolic syndrome
in adolescents and adults Diabetes Care 2009 Apr32(4)702-7
Steenland K et al Association of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) with uric
acid among adults with elevated community exposure to PFOA Environ Health Perspect 2010 Feb118229-33
Steenland 2010 Open Access
ALT Indirect Measure of POPs
bull ALT (proxy marker) elevation in 104 (not including viral
hepatitis hemochromatosis or alcoholic liver disease) of
NHANES 03-04 subset
bull Risk of elevated ALT increased dose-dependently with
cadmium lead mercury and PCB exposure
bull 100 of individuals had detectable PCBs 925 mercury
and 996 had detectable lead
bull In 2005-08 prevalence of NAFLD in US was 11 a
growing cause of chronic liver disease
Cave M et al Polychlorinated biphenyls lead and mercury are associated with liver disease in American adults
NHANES 2003-2004 Environ Health Perspect 2010 Dec118(12)1735-42
Younossi ZM et al Changes in the prevalence of the most common causes of chronic liver diseases in the United
States from 1988 to 2008 Clin Gastroenterol Hepatol 2011 Jun9(6)524-530e1
Bilirubin as a Marker of POPs
bull Degree of serum bilirubin increase is prognostically significant in chronic liver dysfunction
bull Mono-ortho PCB TEQ values were found to be significantly positively associated with bilirubin (β=071 P=0008) following adjustment for multiple potential confounders
bull Bilirubin levels significantly correlated with PCBs -105-118-126 and -194
bull Smoking appears to be the biggest confounder
Dufour DR et al 2000 Diagnosis and monitoring of hepatic injury II Recommendations for use of laboratory
tests in screening diagnosis and monitoring Clin Chem 46 2050ndash68
Kumar J et al Persistent organic pollutants and liver dysfunction biomarkers in a population-based human sample
of men and women Environ Res 2014134251-256
Perf
luo
rin
ate
dP
OP
s a
nd
Co
mm
on
Blo
od
Tests
Gleason JA et al Associations of perfluorinated chemical serum concentrations and biomarkers of liver function and uric acid in the
US population (NHANES) 2007-2010 Environ Res 20151368-14
Liver Enzymes Reflect Toxic Load
bull AST ALT and GGT increase with body load of PCBs and OCPs
bull Some non-linear
bull Oxychlordanetop quartile
ALT 10
GGT 25
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
LDL-Cholesterol as Measure of POPs
bull 5-year prospective study to determine if POP levels predict future elevation in LDL-cholesterol
bull 598 subjects initially at age 70
bull Looked at 23 POPs
bull Best correlation with PCB 194
Penell J Lind L Salihovic S et al Persistent organic pollutants are related to change in circulating
lipid levels during a 5 year follow-up Environ Res 134(2014)190ndash197
oxLDL as Measure of POPs
bull 992 70-year old individuals (50 women)
bull Sum of PCBs showed strong significant positive associations with ox-LDL and significant negative associations with glutathione-related markers (GSSG and GSSGGSH)
bull A number of POPs (PCB-99 138 153 156 170 180 194 206 and 209) showed strong significant positive association with ox-LDL
Kumar J et al Influence of persistent organic pollutants on oxidative stress in population-based samples
Chemosphere 2014114303-309
Homocysteine is Increased by Pb amp Cd
Guallar E et al Confounding of the relation between homocysteine and peripheral arterial disease by lead cadmium and renal function Am J Epidemiol 2006 Apr 15163(8)700-8
Nutrient Deficiencies Accentuate
Effects of Lead on Homocysteine
bull Deficiencies in folate B6 or B12 make lead more toxic
Lee YM Et al Association of homocysteine levels with blood lead levels and micronutrients in the US general population J Prev Med Public Health 2012 Nov45(6)387-93
T4 amp T3 and PCBs
bull PCBs decrease T4 production
bull PCBs inhibit iodotyrosinedeiodinase activity
bull Study done in pregnant women which implies effect on fetus IQ
Kim S Park J Kim HJ et al Association between several persistent organic pollutants and thyroid hormone levels in serum among the pregnant women of Korea Environ Int 2013 Sep59442-8Shimizu R Yamaguchi M Uramaru N et al Structure-activity relationships of 44 halogenated compounds for iodotyrosinedeiodinase-inhibitory activity Toxicology 2013 Dec 6314(1)22-9
T4 amp T3 and PCBs
bull Not just humans being affected
bull Large study of dolphins shows exactly the same effects
Schwacke LH Zolman ES Balmer BC et al Anaemia hypothyroidism and immune suppression associated with polychlorinated biphenyl exposure in bottlenose dolphins (Tursiops truncatus) Proceed Royal Society B doi101098rspb20110665
8-OHdG
bull Oxidized nucleoside
bull Direct measure of DNA damage
bull Indirect measure of oxidative stress and toxin load
bull Correlates with
Multiple cancers
Mitochondrial damage
Rate of aging
Smoking
Several toxinsWalter Crinnion ldquoTotal Toxic Loadrdquo AANP 2015
8-OHdG Correlates with Pack-Years
of Smoking
Yano T et al Significance of the urinary 8-OHdG level as an oxidative stress marker in lung cancer patients Lung Cancer
2009 Jan63(1)111-4
8-OHdG Correlates
with Mercury
Chen C et al Increased oxidative DNA damage as assessed by urinary 8-hydroxy-2-deoxyguanosine
concentrations and serum redox status in persons exposed to mercury Clin Chem 2005 Apr51(4)759-67
Toxin Effects Worse with Aging
bull Thyroid function decreases with PFOA levels
bull But only after age 63
Shrestha S Bloom MS Yucel R et al Perfluoroalkyl substances and thyroid function in older adults Environ Int 2015 Feb75206-14
Insightful 23-Year Prospective Study
1 lt 50 there is no difference between those with the lowest and highest PCBs
2 In youngest group insulin production increases in response to toxin level As expected since blocking of
insulin receptor sites by PCBs
requires more insulin
3 That adaptive ability decreases with aging
4 At age 50 all the measures show very strong toxin-dose response
Cumulative damage impairs ability to adapt
Suarez-Lopez JR et al Persistent organic pollutants in young adults and changes in glucose related metabolism over a 23-year follow-up Environ Res 2015 Feb137485-94
Recommendations
High body toxic load
GGT gt 25
Uric acid gt 50 mgdl
ALT gt30 UL
Bilirubin gt08 mgdl
CBC lt 6000
Platelet lt 250000
Low T3 andor T4
Monitor Total Toxic Load
8-OHdG gt4
ldquoUnconventionalrdquo Laboratory Tests
bull Challenge testing
bull Hair analysis
bull Direct measures of solvents and POPs in blood urine adipose tissue
Evaluation of Metal Exposure ndash Provocation
bull Provocation ndash the use of a chelating agent ndash before urine collection often done clinically but several limitations
No ldquoofficialrdquo reference range for provoked urine
Most chelating agents do not extract metals from all tissues thus
does not necessarily represent total body burden
bull Example Brain is one of the main target organs for both elemental and organic
mercury yet agents do not chelate brain mercury
bull Despite limitations widely used and advocated by clinicians in part to see efficacy of chelating agent as a guide to treatment and based on empirical evidence
Rooney JP The role of thiols dithiols nutritional factors and interacting ligands in the toxicology of mercury
Toxicology 2007
Is Challenge Testing Valid
bull Poor correlations of standard tests for mercury
bull Unpublished research from corporate wellness project
bull Published amalgam number correlation
bull Published fish consumption correlation
What We Found In Canada
bull Deviations from the mean of 14 29 and 91 respectively
bull DMPS is spreading distribution suggesting that it is better at differentiating mercury body load
bull Some VERY high
Hg Assessment Correlations
bull Extensive measurements in 65 Whole blood Hg
Oral DMPS challenge
Amalgam surfaces
bull Correlations Whole blood w pre urine r = 040
Whole blood w post urine r = 057
Pre urine w post urine r = 068
Amalgams w pre urine r = 026
Amalgams w whole blood r = 036
Amalgams with post urine 044
bull Clear documentation that
challenge testing is better00
100
200
300
400
500
600
0 10 20 30 40 50
Po
st
Uri
ne H
g u
gg
Number of amalgams
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
The Worst Toxins Clinically
My Rank Toxin Diseases Primary Sources
1 Arsenic Cancers diabetes gout Water chicken rice
2 DDT ADHD dementia diabetes Everywhere
3 Phthalates ADHD diabetes Soft plastics HABAs
4 PBDEs ADHD diabetes Flame retardant fabrics
5 PAHs ADHD cancers dyslipidemia Smoking charbroiling
6 PCBs Cancers diabetes MI RA Everywhere
7 Mercury Dementia ldquoSilverrdquo fillings fish
8 Lead Cardiovascular disease IQ Paint water
Glyphosate Research invalid
Conventional Laboratory Tests Reflect
Toxic Load in ldquoNormalrdquo Range
bull Surprising number show toxin exposure
CBC RBC WBC platelet count hemoglobin basophilic
stippling
Liver enzymes ALT GGTP
Inflammatory markers CRP
Lipids LDL oxLDL triglycerides
Blood sugar insulin FBS 2-hour PP
Metabolites bilirubin uric acid homocysteine 8-OHdG
Thyroid T3 T4 TSH
bull The historic ldquonormalrdquo range has been changing as the population has become more toxic
WBC Lowered by PCB and OCP Exposure
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
0
1
2
3
4
5
6
7
8
1st Quartrile 2nd Quartile 3rd Quartile 4th Quartile
WBCbull Strong inverse correlation with PCBs and OCPs and CBC
bull Linear with almost all PCBs
bull High variability with OCPs
bull Within ldquonormalrdquo range
Effects on WBC Worsen with Years
of Exposure to Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Platelet Count Decreases with Years
of Exposure tp Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Solvents Decrease Platelet Count
bull Compared workers exposed 23 hrday to those exposed most of day to toluene
bull All wore face masks and protective gear
bull Platelet count 14 lower 252 versus 216ml
bull Impairment of sympathetic nerves (OR = 413)
bull Impairment of peripheral nerves (OR = 694)
bull Positive relationship between neurological abnormalities and a self-reported neuropsychiatric measurement (r = 035-066)
Shih HT et al Subclinical abnormalities in workers with continuous low-level toluene exposure Toxicol Ind Health 2011 Sep27(8)691-9
Basophilic Stippling of Red Cells
Toxinsbull Arsenic
bull Lead
Diseasesbull Alpha-thalassemia HbH Disease
bull Beta thalassemia
bull Hereditary pyrimidine 5-nucleotidase deficiency
bull Myelodysplastic syndrome
bull Sideroblastic anemia
bull Thrombotic thrombocytopenic purpura
GGT Indirect Measure of POPsbull Glutathione is key intracellular defense against oxidative stress
bull Cellular GGT metabolizes extracellular GSH allowing precursor amino acids to be reutilized for intracellular GSH
bull Exposure to POPs induces GGT as a defensive mechanism
bull Within normal range predicts type 2 diabetes coronary heart disease hypertension stroke dyslipidemia chronic kidney disease and cancer
bull Men with GGT gt50 UI had ~26 fold risk for diabetes compared to those with lt10 Those with 40-49 had a ~20 fold risk
bull Levels within normal range occur with obesity xs alcohol cigarette smoking physical inactivity high meat low fruit and vegetable intake
bull Cumulative biomarker for environmental pollutants
Lee DH et al (2003) Gamma-glutamyltransferase and diabetesmdasha 4 year follow-up study Diabetologia 46359ndash364
Pamela A et al Serum gamma-glutamyltransferase linking together environmental pollution redox equilibria and progression of atherosclerosis Clin Chem
Lab Med 200947(12)1583-4
Lee DH et al Serum gamma-glutamyltransferase new insights about an old enzyme J Epidemiol Community Health 2009 Nov63(11)884-6
Lee DH et alSerum gamma-glutamyltransferase predicts non-fatal myocardial infarction and fatal coronary heart disease among 28838 middle-aged men and
women Eur Heart J 2006272170ndash6
Lee DH et al Gamma-glutamyltransferase and diabetes--a 4 year follow-up study Diabetologia 2003 Mar46(3)359-64
Lee DH et al Can persistent organic pollutants explain the association between serum gamma-glutamyltransferase and type 2 diabetes Diabetologia 2008
Mar51(3)402-7
GGT and Alcohol Consumption
bull GGT directly correlates with alcohol consumption
bull In a non-uniform population 40 gd will elevate GGT ~15
bull Watch for false negatives
bull Genomic variation
bull Are these the ones most
sensitive todamaged by
chemical toxins
bull Could up-regulation of GGT in light alcohol consumption be reason for benefit
0
10
20
30
40
50
60
70
80
0 200 400 600 800
Grams of Ethanol per Week
Adapted from Nagaya T et al Dose-response relationships between drinking and serum tests in Japanese men
aged 40ndash59 years Alcohol 1999 Feb 17(2) 133ndash8
GGT Correlates With Toxic Metal Levels
Lee DH et al Graded associations of blood lead and urinary cadmium concentrations with oxidative-stress-related markers in the
US population results from the third National Health and Nutrition Examination Survey Environ Health
perspect 2006 Mar114(3)350-4
GGT and Diabetes Risk
0
5
10
15
20
25
30
lt10 10-19 20-29 30-39 40-49 gt50
Dia
bete
s R
isk
GGT
bull GGT over 50 associated with tripling of death rate
bull 30-40 associated with doubling
GGT Levels
Correlate with
Risk of Death
Brenner H et al Distribution determinants and prognostic value of gamma-glutamyltransferase for all-cause
mortality in a cohort of construction workers from southern Germany Prev Med 1997 26 305ndash10
GGT From Small US Company
with Young Workers
0
10
20
30
40
50
60
0 20 40 60 80 100
GGT Data from Canadian Oil Field
Workers
0
50
100
150
200
250
300
350
400
450
lt10 10-20 20-30 30-40 40-50 50-60 60-07 70-80 80-90 90-100 100-110 110-120 gt120
GGTP
20-fold increased risk of diabetes
Uric Acid Indirect Measure of POPs
bull Poly-fluorinated hydrocarbons (PFOA and PFOS) associated
with increased serum uric acid
Lin CY et al Association among serum perfluoroalkyl chemicals glucose homeostasis and metabolic syndrome
in adolescents and adults Diabetes Care 2009 Apr32(4)702-7
Steenland K et al Association of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) with uric
acid among adults with elevated community exposure to PFOA Environ Health Perspect 2010 Feb118229-33
Steenland 2010 Open Access
ALT Indirect Measure of POPs
bull ALT (proxy marker) elevation in 104 (not including viral
hepatitis hemochromatosis or alcoholic liver disease) of
NHANES 03-04 subset
bull Risk of elevated ALT increased dose-dependently with
cadmium lead mercury and PCB exposure
bull 100 of individuals had detectable PCBs 925 mercury
and 996 had detectable lead
bull In 2005-08 prevalence of NAFLD in US was 11 a
growing cause of chronic liver disease
Cave M et al Polychlorinated biphenyls lead and mercury are associated with liver disease in American adults
NHANES 2003-2004 Environ Health Perspect 2010 Dec118(12)1735-42
Younossi ZM et al Changes in the prevalence of the most common causes of chronic liver diseases in the United
States from 1988 to 2008 Clin Gastroenterol Hepatol 2011 Jun9(6)524-530e1
Bilirubin as a Marker of POPs
bull Degree of serum bilirubin increase is prognostically significant in chronic liver dysfunction
bull Mono-ortho PCB TEQ values were found to be significantly positively associated with bilirubin (β=071 P=0008) following adjustment for multiple potential confounders
bull Bilirubin levels significantly correlated with PCBs -105-118-126 and -194
bull Smoking appears to be the biggest confounder
Dufour DR et al 2000 Diagnosis and monitoring of hepatic injury II Recommendations for use of laboratory
tests in screening diagnosis and monitoring Clin Chem 46 2050ndash68
Kumar J et al Persistent organic pollutants and liver dysfunction biomarkers in a population-based human sample
of men and women Environ Res 2014134251-256
Perf
luo
rin
ate
dP
OP
s a
nd
Co
mm
on
Blo
od
Tests
Gleason JA et al Associations of perfluorinated chemical serum concentrations and biomarkers of liver function and uric acid in the
US population (NHANES) 2007-2010 Environ Res 20151368-14
Liver Enzymes Reflect Toxic Load
bull AST ALT and GGT increase with body load of PCBs and OCPs
bull Some non-linear
bull Oxychlordanetop quartile
ALT 10
GGT 25
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
LDL-Cholesterol as Measure of POPs
bull 5-year prospective study to determine if POP levels predict future elevation in LDL-cholesterol
bull 598 subjects initially at age 70
bull Looked at 23 POPs
bull Best correlation with PCB 194
Penell J Lind L Salihovic S et al Persistent organic pollutants are related to change in circulating
lipid levels during a 5 year follow-up Environ Res 134(2014)190ndash197
oxLDL as Measure of POPs
bull 992 70-year old individuals (50 women)
bull Sum of PCBs showed strong significant positive associations with ox-LDL and significant negative associations with glutathione-related markers (GSSG and GSSGGSH)
bull A number of POPs (PCB-99 138 153 156 170 180 194 206 and 209) showed strong significant positive association with ox-LDL
Kumar J et al Influence of persistent organic pollutants on oxidative stress in population-based samples
Chemosphere 2014114303-309
Homocysteine is Increased by Pb amp Cd
Guallar E et al Confounding of the relation between homocysteine and peripheral arterial disease by lead cadmium and renal function Am J Epidemiol 2006 Apr 15163(8)700-8
Nutrient Deficiencies Accentuate
Effects of Lead on Homocysteine
bull Deficiencies in folate B6 or B12 make lead more toxic
Lee YM Et al Association of homocysteine levels with blood lead levels and micronutrients in the US general population J Prev Med Public Health 2012 Nov45(6)387-93
T4 amp T3 and PCBs
bull PCBs decrease T4 production
bull PCBs inhibit iodotyrosinedeiodinase activity
bull Study done in pregnant women which implies effect on fetus IQ
Kim S Park J Kim HJ et al Association between several persistent organic pollutants and thyroid hormone levels in serum among the pregnant women of Korea Environ Int 2013 Sep59442-8Shimizu R Yamaguchi M Uramaru N et al Structure-activity relationships of 44 halogenated compounds for iodotyrosinedeiodinase-inhibitory activity Toxicology 2013 Dec 6314(1)22-9
T4 amp T3 and PCBs
bull Not just humans being affected
bull Large study of dolphins shows exactly the same effects
Schwacke LH Zolman ES Balmer BC et al Anaemia hypothyroidism and immune suppression associated with polychlorinated biphenyl exposure in bottlenose dolphins (Tursiops truncatus) Proceed Royal Society B doi101098rspb20110665
8-OHdG
bull Oxidized nucleoside
bull Direct measure of DNA damage
bull Indirect measure of oxidative stress and toxin load
bull Correlates with
Multiple cancers
Mitochondrial damage
Rate of aging
Smoking
Several toxinsWalter Crinnion ldquoTotal Toxic Loadrdquo AANP 2015
8-OHdG Correlates with Pack-Years
of Smoking
Yano T et al Significance of the urinary 8-OHdG level as an oxidative stress marker in lung cancer patients Lung Cancer
2009 Jan63(1)111-4
8-OHdG Correlates
with Mercury
Chen C et al Increased oxidative DNA damage as assessed by urinary 8-hydroxy-2-deoxyguanosine
concentrations and serum redox status in persons exposed to mercury Clin Chem 2005 Apr51(4)759-67
Toxin Effects Worse with Aging
bull Thyroid function decreases with PFOA levels
bull But only after age 63
Shrestha S Bloom MS Yucel R et al Perfluoroalkyl substances and thyroid function in older adults Environ Int 2015 Feb75206-14
Insightful 23-Year Prospective Study
1 lt 50 there is no difference between those with the lowest and highest PCBs
2 In youngest group insulin production increases in response to toxin level As expected since blocking of
insulin receptor sites by PCBs
requires more insulin
3 That adaptive ability decreases with aging
4 At age 50 all the measures show very strong toxin-dose response
Cumulative damage impairs ability to adapt
Suarez-Lopez JR et al Persistent organic pollutants in young adults and changes in glucose related metabolism over a 23-year follow-up Environ Res 2015 Feb137485-94
Recommendations
High body toxic load
GGT gt 25
Uric acid gt 50 mgdl
ALT gt30 UL
Bilirubin gt08 mgdl
CBC lt 6000
Platelet lt 250000
Low T3 andor T4
Monitor Total Toxic Load
8-OHdG gt4
ldquoUnconventionalrdquo Laboratory Tests
bull Challenge testing
bull Hair analysis
bull Direct measures of solvents and POPs in blood urine adipose tissue
Evaluation of Metal Exposure ndash Provocation
bull Provocation ndash the use of a chelating agent ndash before urine collection often done clinically but several limitations
No ldquoofficialrdquo reference range for provoked urine
Most chelating agents do not extract metals from all tissues thus
does not necessarily represent total body burden
bull Example Brain is one of the main target organs for both elemental and organic
mercury yet agents do not chelate brain mercury
bull Despite limitations widely used and advocated by clinicians in part to see efficacy of chelating agent as a guide to treatment and based on empirical evidence
Rooney JP The role of thiols dithiols nutritional factors and interacting ligands in the toxicology of mercury
Toxicology 2007
Is Challenge Testing Valid
bull Poor correlations of standard tests for mercury
bull Unpublished research from corporate wellness project
bull Published amalgam number correlation
bull Published fish consumption correlation
What We Found In Canada
bull Deviations from the mean of 14 29 and 91 respectively
bull DMPS is spreading distribution suggesting that it is better at differentiating mercury body load
bull Some VERY high
Hg Assessment Correlations
bull Extensive measurements in 65 Whole blood Hg
Oral DMPS challenge
Amalgam surfaces
bull Correlations Whole blood w pre urine r = 040
Whole blood w post urine r = 057
Pre urine w post urine r = 068
Amalgams w pre urine r = 026
Amalgams w whole blood r = 036
Amalgams with post urine 044
bull Clear documentation that
challenge testing is better00
100
200
300
400
500
600
0 10 20 30 40 50
Po
st
Uri
ne H
g u
gg
Number of amalgams
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
Conventional Laboratory Tests Reflect
Toxic Load in ldquoNormalrdquo Range
bull Surprising number show toxin exposure
CBC RBC WBC platelet count hemoglobin basophilic
stippling
Liver enzymes ALT GGTP
Inflammatory markers CRP
Lipids LDL oxLDL triglycerides
Blood sugar insulin FBS 2-hour PP
Metabolites bilirubin uric acid homocysteine 8-OHdG
Thyroid T3 T4 TSH
bull The historic ldquonormalrdquo range has been changing as the population has become more toxic
WBC Lowered by PCB and OCP Exposure
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
0
1
2
3
4
5
6
7
8
1st Quartrile 2nd Quartile 3rd Quartile 4th Quartile
WBCbull Strong inverse correlation with PCBs and OCPs and CBC
bull Linear with almost all PCBs
bull High variability with OCPs
bull Within ldquonormalrdquo range
Effects on WBC Worsen with Years
of Exposure to Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Platelet Count Decreases with Years
of Exposure tp Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Solvents Decrease Platelet Count
bull Compared workers exposed 23 hrday to those exposed most of day to toluene
bull All wore face masks and protective gear
bull Platelet count 14 lower 252 versus 216ml
bull Impairment of sympathetic nerves (OR = 413)
bull Impairment of peripheral nerves (OR = 694)
bull Positive relationship between neurological abnormalities and a self-reported neuropsychiatric measurement (r = 035-066)
Shih HT et al Subclinical abnormalities in workers with continuous low-level toluene exposure Toxicol Ind Health 2011 Sep27(8)691-9
Basophilic Stippling of Red Cells
Toxinsbull Arsenic
bull Lead
Diseasesbull Alpha-thalassemia HbH Disease
bull Beta thalassemia
bull Hereditary pyrimidine 5-nucleotidase deficiency
bull Myelodysplastic syndrome
bull Sideroblastic anemia
bull Thrombotic thrombocytopenic purpura
GGT Indirect Measure of POPsbull Glutathione is key intracellular defense against oxidative stress
bull Cellular GGT metabolizes extracellular GSH allowing precursor amino acids to be reutilized for intracellular GSH
bull Exposure to POPs induces GGT as a defensive mechanism
bull Within normal range predicts type 2 diabetes coronary heart disease hypertension stroke dyslipidemia chronic kidney disease and cancer
bull Men with GGT gt50 UI had ~26 fold risk for diabetes compared to those with lt10 Those with 40-49 had a ~20 fold risk
bull Levels within normal range occur with obesity xs alcohol cigarette smoking physical inactivity high meat low fruit and vegetable intake
bull Cumulative biomarker for environmental pollutants
Lee DH et al (2003) Gamma-glutamyltransferase and diabetesmdasha 4 year follow-up study Diabetologia 46359ndash364
Pamela A et al Serum gamma-glutamyltransferase linking together environmental pollution redox equilibria and progression of atherosclerosis Clin Chem
Lab Med 200947(12)1583-4
Lee DH et al Serum gamma-glutamyltransferase new insights about an old enzyme J Epidemiol Community Health 2009 Nov63(11)884-6
Lee DH et alSerum gamma-glutamyltransferase predicts non-fatal myocardial infarction and fatal coronary heart disease among 28838 middle-aged men and
women Eur Heart J 2006272170ndash6
Lee DH et al Gamma-glutamyltransferase and diabetes--a 4 year follow-up study Diabetologia 2003 Mar46(3)359-64
Lee DH et al Can persistent organic pollutants explain the association between serum gamma-glutamyltransferase and type 2 diabetes Diabetologia 2008
Mar51(3)402-7
GGT and Alcohol Consumption
bull GGT directly correlates with alcohol consumption
bull In a non-uniform population 40 gd will elevate GGT ~15
bull Watch for false negatives
bull Genomic variation
bull Are these the ones most
sensitive todamaged by
chemical toxins
bull Could up-regulation of GGT in light alcohol consumption be reason for benefit
0
10
20
30
40
50
60
70
80
0 200 400 600 800
Grams of Ethanol per Week
Adapted from Nagaya T et al Dose-response relationships between drinking and serum tests in Japanese men
aged 40ndash59 years Alcohol 1999 Feb 17(2) 133ndash8
GGT Correlates With Toxic Metal Levels
Lee DH et al Graded associations of blood lead and urinary cadmium concentrations with oxidative-stress-related markers in the
US population results from the third National Health and Nutrition Examination Survey Environ Health
perspect 2006 Mar114(3)350-4
GGT and Diabetes Risk
0
5
10
15
20
25
30
lt10 10-19 20-29 30-39 40-49 gt50
Dia
bete
s R
isk
GGT
bull GGT over 50 associated with tripling of death rate
bull 30-40 associated with doubling
GGT Levels
Correlate with
Risk of Death
Brenner H et al Distribution determinants and prognostic value of gamma-glutamyltransferase for all-cause
mortality in a cohort of construction workers from southern Germany Prev Med 1997 26 305ndash10
GGT From Small US Company
with Young Workers
0
10
20
30
40
50
60
0 20 40 60 80 100
GGT Data from Canadian Oil Field
Workers
0
50
100
150
200
250
300
350
400
450
lt10 10-20 20-30 30-40 40-50 50-60 60-07 70-80 80-90 90-100 100-110 110-120 gt120
GGTP
20-fold increased risk of diabetes
Uric Acid Indirect Measure of POPs
bull Poly-fluorinated hydrocarbons (PFOA and PFOS) associated
with increased serum uric acid
Lin CY et al Association among serum perfluoroalkyl chemicals glucose homeostasis and metabolic syndrome
in adolescents and adults Diabetes Care 2009 Apr32(4)702-7
Steenland K et al Association of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) with uric
acid among adults with elevated community exposure to PFOA Environ Health Perspect 2010 Feb118229-33
Steenland 2010 Open Access
ALT Indirect Measure of POPs
bull ALT (proxy marker) elevation in 104 (not including viral
hepatitis hemochromatosis or alcoholic liver disease) of
NHANES 03-04 subset
bull Risk of elevated ALT increased dose-dependently with
cadmium lead mercury and PCB exposure
bull 100 of individuals had detectable PCBs 925 mercury
and 996 had detectable lead
bull In 2005-08 prevalence of NAFLD in US was 11 a
growing cause of chronic liver disease
Cave M et al Polychlorinated biphenyls lead and mercury are associated with liver disease in American adults
NHANES 2003-2004 Environ Health Perspect 2010 Dec118(12)1735-42
Younossi ZM et al Changes in the prevalence of the most common causes of chronic liver diseases in the United
States from 1988 to 2008 Clin Gastroenterol Hepatol 2011 Jun9(6)524-530e1
Bilirubin as a Marker of POPs
bull Degree of serum bilirubin increase is prognostically significant in chronic liver dysfunction
bull Mono-ortho PCB TEQ values were found to be significantly positively associated with bilirubin (β=071 P=0008) following adjustment for multiple potential confounders
bull Bilirubin levels significantly correlated with PCBs -105-118-126 and -194
bull Smoking appears to be the biggest confounder
Dufour DR et al 2000 Diagnosis and monitoring of hepatic injury II Recommendations for use of laboratory
tests in screening diagnosis and monitoring Clin Chem 46 2050ndash68
Kumar J et al Persistent organic pollutants and liver dysfunction biomarkers in a population-based human sample
of men and women Environ Res 2014134251-256
Perf
luo
rin
ate
dP
OP
s a
nd
Co
mm
on
Blo
od
Tests
Gleason JA et al Associations of perfluorinated chemical serum concentrations and biomarkers of liver function and uric acid in the
US population (NHANES) 2007-2010 Environ Res 20151368-14
Liver Enzymes Reflect Toxic Load
bull AST ALT and GGT increase with body load of PCBs and OCPs
bull Some non-linear
bull Oxychlordanetop quartile
ALT 10
GGT 25
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
LDL-Cholesterol as Measure of POPs
bull 5-year prospective study to determine if POP levels predict future elevation in LDL-cholesterol
bull 598 subjects initially at age 70
bull Looked at 23 POPs
bull Best correlation with PCB 194
Penell J Lind L Salihovic S et al Persistent organic pollutants are related to change in circulating
lipid levels during a 5 year follow-up Environ Res 134(2014)190ndash197
oxLDL as Measure of POPs
bull 992 70-year old individuals (50 women)
bull Sum of PCBs showed strong significant positive associations with ox-LDL and significant negative associations with glutathione-related markers (GSSG and GSSGGSH)
bull A number of POPs (PCB-99 138 153 156 170 180 194 206 and 209) showed strong significant positive association with ox-LDL
Kumar J et al Influence of persistent organic pollutants on oxidative stress in population-based samples
Chemosphere 2014114303-309
Homocysteine is Increased by Pb amp Cd
Guallar E et al Confounding of the relation between homocysteine and peripheral arterial disease by lead cadmium and renal function Am J Epidemiol 2006 Apr 15163(8)700-8
Nutrient Deficiencies Accentuate
Effects of Lead on Homocysteine
bull Deficiencies in folate B6 or B12 make lead more toxic
Lee YM Et al Association of homocysteine levels with blood lead levels and micronutrients in the US general population J Prev Med Public Health 2012 Nov45(6)387-93
T4 amp T3 and PCBs
bull PCBs decrease T4 production
bull PCBs inhibit iodotyrosinedeiodinase activity
bull Study done in pregnant women which implies effect on fetus IQ
Kim S Park J Kim HJ et al Association between several persistent organic pollutants and thyroid hormone levels in serum among the pregnant women of Korea Environ Int 2013 Sep59442-8Shimizu R Yamaguchi M Uramaru N et al Structure-activity relationships of 44 halogenated compounds for iodotyrosinedeiodinase-inhibitory activity Toxicology 2013 Dec 6314(1)22-9
T4 amp T3 and PCBs
bull Not just humans being affected
bull Large study of dolphins shows exactly the same effects
Schwacke LH Zolman ES Balmer BC et al Anaemia hypothyroidism and immune suppression associated with polychlorinated biphenyl exposure in bottlenose dolphins (Tursiops truncatus) Proceed Royal Society B doi101098rspb20110665
8-OHdG
bull Oxidized nucleoside
bull Direct measure of DNA damage
bull Indirect measure of oxidative stress and toxin load
bull Correlates with
Multiple cancers
Mitochondrial damage
Rate of aging
Smoking
Several toxinsWalter Crinnion ldquoTotal Toxic Loadrdquo AANP 2015
8-OHdG Correlates with Pack-Years
of Smoking
Yano T et al Significance of the urinary 8-OHdG level as an oxidative stress marker in lung cancer patients Lung Cancer
2009 Jan63(1)111-4
8-OHdG Correlates
with Mercury
Chen C et al Increased oxidative DNA damage as assessed by urinary 8-hydroxy-2-deoxyguanosine
concentrations and serum redox status in persons exposed to mercury Clin Chem 2005 Apr51(4)759-67
Toxin Effects Worse with Aging
bull Thyroid function decreases with PFOA levels
bull But only after age 63
Shrestha S Bloom MS Yucel R et al Perfluoroalkyl substances and thyroid function in older adults Environ Int 2015 Feb75206-14
Insightful 23-Year Prospective Study
1 lt 50 there is no difference between those with the lowest and highest PCBs
2 In youngest group insulin production increases in response to toxin level As expected since blocking of
insulin receptor sites by PCBs
requires more insulin
3 That adaptive ability decreases with aging
4 At age 50 all the measures show very strong toxin-dose response
Cumulative damage impairs ability to adapt
Suarez-Lopez JR et al Persistent organic pollutants in young adults and changes in glucose related metabolism over a 23-year follow-up Environ Res 2015 Feb137485-94
Recommendations
High body toxic load
GGT gt 25
Uric acid gt 50 mgdl
ALT gt30 UL
Bilirubin gt08 mgdl
CBC lt 6000
Platelet lt 250000
Low T3 andor T4
Monitor Total Toxic Load
8-OHdG gt4
ldquoUnconventionalrdquo Laboratory Tests
bull Challenge testing
bull Hair analysis
bull Direct measures of solvents and POPs in blood urine adipose tissue
Evaluation of Metal Exposure ndash Provocation
bull Provocation ndash the use of a chelating agent ndash before urine collection often done clinically but several limitations
No ldquoofficialrdquo reference range for provoked urine
Most chelating agents do not extract metals from all tissues thus
does not necessarily represent total body burden
bull Example Brain is one of the main target organs for both elemental and organic
mercury yet agents do not chelate brain mercury
bull Despite limitations widely used and advocated by clinicians in part to see efficacy of chelating agent as a guide to treatment and based on empirical evidence
Rooney JP The role of thiols dithiols nutritional factors and interacting ligands in the toxicology of mercury
Toxicology 2007
Is Challenge Testing Valid
bull Poor correlations of standard tests for mercury
bull Unpublished research from corporate wellness project
bull Published amalgam number correlation
bull Published fish consumption correlation
What We Found In Canada
bull Deviations from the mean of 14 29 and 91 respectively
bull DMPS is spreading distribution suggesting that it is better at differentiating mercury body load
bull Some VERY high
Hg Assessment Correlations
bull Extensive measurements in 65 Whole blood Hg
Oral DMPS challenge
Amalgam surfaces
bull Correlations Whole blood w pre urine r = 040
Whole blood w post urine r = 057
Pre urine w post urine r = 068
Amalgams w pre urine r = 026
Amalgams w whole blood r = 036
Amalgams with post urine 044
bull Clear documentation that
challenge testing is better00
100
200
300
400
500
600
0 10 20 30 40 50
Po
st
Uri
ne H
g u
gg
Number of amalgams
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
WBC Lowered by PCB and OCP Exposure
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
0
1
2
3
4
5
6
7
8
1st Quartrile 2nd Quartile 3rd Quartile 4th Quartile
WBCbull Strong inverse correlation with PCBs and OCPs and CBC
bull Linear with almost all PCBs
bull High variability with OCPs
bull Within ldquonormalrdquo range
Effects on WBC Worsen with Years
of Exposure to Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Platelet Count Decreases with Years
of Exposure tp Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Solvents Decrease Platelet Count
bull Compared workers exposed 23 hrday to those exposed most of day to toluene
bull All wore face masks and protective gear
bull Platelet count 14 lower 252 versus 216ml
bull Impairment of sympathetic nerves (OR = 413)
bull Impairment of peripheral nerves (OR = 694)
bull Positive relationship between neurological abnormalities and a self-reported neuropsychiatric measurement (r = 035-066)
Shih HT et al Subclinical abnormalities in workers with continuous low-level toluene exposure Toxicol Ind Health 2011 Sep27(8)691-9
Basophilic Stippling of Red Cells
Toxinsbull Arsenic
bull Lead
Diseasesbull Alpha-thalassemia HbH Disease
bull Beta thalassemia
bull Hereditary pyrimidine 5-nucleotidase deficiency
bull Myelodysplastic syndrome
bull Sideroblastic anemia
bull Thrombotic thrombocytopenic purpura
GGT Indirect Measure of POPsbull Glutathione is key intracellular defense against oxidative stress
bull Cellular GGT metabolizes extracellular GSH allowing precursor amino acids to be reutilized for intracellular GSH
bull Exposure to POPs induces GGT as a defensive mechanism
bull Within normal range predicts type 2 diabetes coronary heart disease hypertension stroke dyslipidemia chronic kidney disease and cancer
bull Men with GGT gt50 UI had ~26 fold risk for diabetes compared to those with lt10 Those with 40-49 had a ~20 fold risk
bull Levels within normal range occur with obesity xs alcohol cigarette smoking physical inactivity high meat low fruit and vegetable intake
bull Cumulative biomarker for environmental pollutants
Lee DH et al (2003) Gamma-glutamyltransferase and diabetesmdasha 4 year follow-up study Diabetologia 46359ndash364
Pamela A et al Serum gamma-glutamyltransferase linking together environmental pollution redox equilibria and progression of atherosclerosis Clin Chem
Lab Med 200947(12)1583-4
Lee DH et al Serum gamma-glutamyltransferase new insights about an old enzyme J Epidemiol Community Health 2009 Nov63(11)884-6
Lee DH et alSerum gamma-glutamyltransferase predicts non-fatal myocardial infarction and fatal coronary heart disease among 28838 middle-aged men and
women Eur Heart J 2006272170ndash6
Lee DH et al Gamma-glutamyltransferase and diabetes--a 4 year follow-up study Diabetologia 2003 Mar46(3)359-64
Lee DH et al Can persistent organic pollutants explain the association between serum gamma-glutamyltransferase and type 2 diabetes Diabetologia 2008
Mar51(3)402-7
GGT and Alcohol Consumption
bull GGT directly correlates with alcohol consumption
bull In a non-uniform population 40 gd will elevate GGT ~15
bull Watch for false negatives
bull Genomic variation
bull Are these the ones most
sensitive todamaged by
chemical toxins
bull Could up-regulation of GGT in light alcohol consumption be reason for benefit
0
10
20
30
40
50
60
70
80
0 200 400 600 800
Grams of Ethanol per Week
Adapted from Nagaya T et al Dose-response relationships between drinking and serum tests in Japanese men
aged 40ndash59 years Alcohol 1999 Feb 17(2) 133ndash8
GGT Correlates With Toxic Metal Levels
Lee DH et al Graded associations of blood lead and urinary cadmium concentrations with oxidative-stress-related markers in the
US population results from the third National Health and Nutrition Examination Survey Environ Health
perspect 2006 Mar114(3)350-4
GGT and Diabetes Risk
0
5
10
15
20
25
30
lt10 10-19 20-29 30-39 40-49 gt50
Dia
bete
s R
isk
GGT
bull GGT over 50 associated with tripling of death rate
bull 30-40 associated with doubling
GGT Levels
Correlate with
Risk of Death
Brenner H et al Distribution determinants and prognostic value of gamma-glutamyltransferase for all-cause
mortality in a cohort of construction workers from southern Germany Prev Med 1997 26 305ndash10
GGT From Small US Company
with Young Workers
0
10
20
30
40
50
60
0 20 40 60 80 100
GGT Data from Canadian Oil Field
Workers
0
50
100
150
200
250
300
350
400
450
lt10 10-20 20-30 30-40 40-50 50-60 60-07 70-80 80-90 90-100 100-110 110-120 gt120
GGTP
20-fold increased risk of diabetes
Uric Acid Indirect Measure of POPs
bull Poly-fluorinated hydrocarbons (PFOA and PFOS) associated
with increased serum uric acid
Lin CY et al Association among serum perfluoroalkyl chemicals glucose homeostasis and metabolic syndrome
in adolescents and adults Diabetes Care 2009 Apr32(4)702-7
Steenland K et al Association of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) with uric
acid among adults with elevated community exposure to PFOA Environ Health Perspect 2010 Feb118229-33
Steenland 2010 Open Access
ALT Indirect Measure of POPs
bull ALT (proxy marker) elevation in 104 (not including viral
hepatitis hemochromatosis or alcoholic liver disease) of
NHANES 03-04 subset
bull Risk of elevated ALT increased dose-dependently with
cadmium lead mercury and PCB exposure
bull 100 of individuals had detectable PCBs 925 mercury
and 996 had detectable lead
bull In 2005-08 prevalence of NAFLD in US was 11 a
growing cause of chronic liver disease
Cave M et al Polychlorinated biphenyls lead and mercury are associated with liver disease in American adults
NHANES 2003-2004 Environ Health Perspect 2010 Dec118(12)1735-42
Younossi ZM et al Changes in the prevalence of the most common causes of chronic liver diseases in the United
States from 1988 to 2008 Clin Gastroenterol Hepatol 2011 Jun9(6)524-530e1
Bilirubin as a Marker of POPs
bull Degree of serum bilirubin increase is prognostically significant in chronic liver dysfunction
bull Mono-ortho PCB TEQ values were found to be significantly positively associated with bilirubin (β=071 P=0008) following adjustment for multiple potential confounders
bull Bilirubin levels significantly correlated with PCBs -105-118-126 and -194
bull Smoking appears to be the biggest confounder
Dufour DR et al 2000 Diagnosis and monitoring of hepatic injury II Recommendations for use of laboratory
tests in screening diagnosis and monitoring Clin Chem 46 2050ndash68
Kumar J et al Persistent organic pollutants and liver dysfunction biomarkers in a population-based human sample
of men and women Environ Res 2014134251-256
Perf
luo
rin
ate
dP
OP
s a
nd
Co
mm
on
Blo
od
Tests
Gleason JA et al Associations of perfluorinated chemical serum concentrations and biomarkers of liver function and uric acid in the
US population (NHANES) 2007-2010 Environ Res 20151368-14
Liver Enzymes Reflect Toxic Load
bull AST ALT and GGT increase with body load of PCBs and OCPs
bull Some non-linear
bull Oxychlordanetop quartile
ALT 10
GGT 25
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
LDL-Cholesterol as Measure of POPs
bull 5-year prospective study to determine if POP levels predict future elevation in LDL-cholesterol
bull 598 subjects initially at age 70
bull Looked at 23 POPs
bull Best correlation with PCB 194
Penell J Lind L Salihovic S et al Persistent organic pollutants are related to change in circulating
lipid levels during a 5 year follow-up Environ Res 134(2014)190ndash197
oxLDL as Measure of POPs
bull 992 70-year old individuals (50 women)
bull Sum of PCBs showed strong significant positive associations with ox-LDL and significant negative associations with glutathione-related markers (GSSG and GSSGGSH)
bull A number of POPs (PCB-99 138 153 156 170 180 194 206 and 209) showed strong significant positive association with ox-LDL
Kumar J et al Influence of persistent organic pollutants on oxidative stress in population-based samples
Chemosphere 2014114303-309
Homocysteine is Increased by Pb amp Cd
Guallar E et al Confounding of the relation between homocysteine and peripheral arterial disease by lead cadmium and renal function Am J Epidemiol 2006 Apr 15163(8)700-8
Nutrient Deficiencies Accentuate
Effects of Lead on Homocysteine
bull Deficiencies in folate B6 or B12 make lead more toxic
Lee YM Et al Association of homocysteine levels with blood lead levels and micronutrients in the US general population J Prev Med Public Health 2012 Nov45(6)387-93
T4 amp T3 and PCBs
bull PCBs decrease T4 production
bull PCBs inhibit iodotyrosinedeiodinase activity
bull Study done in pregnant women which implies effect on fetus IQ
Kim S Park J Kim HJ et al Association between several persistent organic pollutants and thyroid hormone levels in serum among the pregnant women of Korea Environ Int 2013 Sep59442-8Shimizu R Yamaguchi M Uramaru N et al Structure-activity relationships of 44 halogenated compounds for iodotyrosinedeiodinase-inhibitory activity Toxicology 2013 Dec 6314(1)22-9
T4 amp T3 and PCBs
bull Not just humans being affected
bull Large study of dolphins shows exactly the same effects
Schwacke LH Zolman ES Balmer BC et al Anaemia hypothyroidism and immune suppression associated with polychlorinated biphenyl exposure in bottlenose dolphins (Tursiops truncatus) Proceed Royal Society B doi101098rspb20110665
8-OHdG
bull Oxidized nucleoside
bull Direct measure of DNA damage
bull Indirect measure of oxidative stress and toxin load
bull Correlates with
Multiple cancers
Mitochondrial damage
Rate of aging
Smoking
Several toxinsWalter Crinnion ldquoTotal Toxic Loadrdquo AANP 2015
8-OHdG Correlates with Pack-Years
of Smoking
Yano T et al Significance of the urinary 8-OHdG level as an oxidative stress marker in lung cancer patients Lung Cancer
2009 Jan63(1)111-4
8-OHdG Correlates
with Mercury
Chen C et al Increased oxidative DNA damage as assessed by urinary 8-hydroxy-2-deoxyguanosine
concentrations and serum redox status in persons exposed to mercury Clin Chem 2005 Apr51(4)759-67
Toxin Effects Worse with Aging
bull Thyroid function decreases with PFOA levels
bull But only after age 63
Shrestha S Bloom MS Yucel R et al Perfluoroalkyl substances and thyroid function in older adults Environ Int 2015 Feb75206-14
Insightful 23-Year Prospective Study
1 lt 50 there is no difference between those with the lowest and highest PCBs
2 In youngest group insulin production increases in response to toxin level As expected since blocking of
insulin receptor sites by PCBs
requires more insulin
3 That adaptive ability decreases with aging
4 At age 50 all the measures show very strong toxin-dose response
Cumulative damage impairs ability to adapt
Suarez-Lopez JR et al Persistent organic pollutants in young adults and changes in glucose related metabolism over a 23-year follow-up Environ Res 2015 Feb137485-94
Recommendations
High body toxic load
GGT gt 25
Uric acid gt 50 mgdl
ALT gt30 UL
Bilirubin gt08 mgdl
CBC lt 6000
Platelet lt 250000
Low T3 andor T4
Monitor Total Toxic Load
8-OHdG gt4
ldquoUnconventionalrdquo Laboratory Tests
bull Challenge testing
bull Hair analysis
bull Direct measures of solvents and POPs in blood urine adipose tissue
Evaluation of Metal Exposure ndash Provocation
bull Provocation ndash the use of a chelating agent ndash before urine collection often done clinically but several limitations
No ldquoofficialrdquo reference range for provoked urine
Most chelating agents do not extract metals from all tissues thus
does not necessarily represent total body burden
bull Example Brain is one of the main target organs for both elemental and organic
mercury yet agents do not chelate brain mercury
bull Despite limitations widely used and advocated by clinicians in part to see efficacy of chelating agent as a guide to treatment and based on empirical evidence
Rooney JP The role of thiols dithiols nutritional factors and interacting ligands in the toxicology of mercury
Toxicology 2007
Is Challenge Testing Valid
bull Poor correlations of standard tests for mercury
bull Unpublished research from corporate wellness project
bull Published amalgam number correlation
bull Published fish consumption correlation
What We Found In Canada
bull Deviations from the mean of 14 29 and 91 respectively
bull DMPS is spreading distribution suggesting that it is better at differentiating mercury body load
bull Some VERY high
Hg Assessment Correlations
bull Extensive measurements in 65 Whole blood Hg
Oral DMPS challenge
Amalgam surfaces
bull Correlations Whole blood w pre urine r = 040
Whole blood w post urine r = 057
Pre urine w post urine r = 068
Amalgams w pre urine r = 026
Amalgams w whole blood r = 036
Amalgams with post urine 044
bull Clear documentation that
challenge testing is better00
100
200
300
400
500
600
0 10 20 30 40 50
Po
st
Uri
ne H
g u
gg
Number of amalgams
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
Effects on WBC Worsen with Years
of Exposure to Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Platelet Count Decreases with Years
of Exposure tp Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Solvents Decrease Platelet Count
bull Compared workers exposed 23 hrday to those exposed most of day to toluene
bull All wore face masks and protective gear
bull Platelet count 14 lower 252 versus 216ml
bull Impairment of sympathetic nerves (OR = 413)
bull Impairment of peripheral nerves (OR = 694)
bull Positive relationship between neurological abnormalities and a self-reported neuropsychiatric measurement (r = 035-066)
Shih HT et al Subclinical abnormalities in workers with continuous low-level toluene exposure Toxicol Ind Health 2011 Sep27(8)691-9
Basophilic Stippling of Red Cells
Toxinsbull Arsenic
bull Lead
Diseasesbull Alpha-thalassemia HbH Disease
bull Beta thalassemia
bull Hereditary pyrimidine 5-nucleotidase deficiency
bull Myelodysplastic syndrome
bull Sideroblastic anemia
bull Thrombotic thrombocytopenic purpura
GGT Indirect Measure of POPsbull Glutathione is key intracellular defense against oxidative stress
bull Cellular GGT metabolizes extracellular GSH allowing precursor amino acids to be reutilized for intracellular GSH
bull Exposure to POPs induces GGT as a defensive mechanism
bull Within normal range predicts type 2 diabetes coronary heart disease hypertension stroke dyslipidemia chronic kidney disease and cancer
bull Men with GGT gt50 UI had ~26 fold risk for diabetes compared to those with lt10 Those with 40-49 had a ~20 fold risk
bull Levels within normal range occur with obesity xs alcohol cigarette smoking physical inactivity high meat low fruit and vegetable intake
bull Cumulative biomarker for environmental pollutants
Lee DH et al (2003) Gamma-glutamyltransferase and diabetesmdasha 4 year follow-up study Diabetologia 46359ndash364
Pamela A et al Serum gamma-glutamyltransferase linking together environmental pollution redox equilibria and progression of atherosclerosis Clin Chem
Lab Med 200947(12)1583-4
Lee DH et al Serum gamma-glutamyltransferase new insights about an old enzyme J Epidemiol Community Health 2009 Nov63(11)884-6
Lee DH et alSerum gamma-glutamyltransferase predicts non-fatal myocardial infarction and fatal coronary heart disease among 28838 middle-aged men and
women Eur Heart J 2006272170ndash6
Lee DH et al Gamma-glutamyltransferase and diabetes--a 4 year follow-up study Diabetologia 2003 Mar46(3)359-64
Lee DH et al Can persistent organic pollutants explain the association between serum gamma-glutamyltransferase and type 2 diabetes Diabetologia 2008
Mar51(3)402-7
GGT and Alcohol Consumption
bull GGT directly correlates with alcohol consumption
bull In a non-uniform population 40 gd will elevate GGT ~15
bull Watch for false negatives
bull Genomic variation
bull Are these the ones most
sensitive todamaged by
chemical toxins
bull Could up-regulation of GGT in light alcohol consumption be reason for benefit
0
10
20
30
40
50
60
70
80
0 200 400 600 800
Grams of Ethanol per Week
Adapted from Nagaya T et al Dose-response relationships between drinking and serum tests in Japanese men
aged 40ndash59 years Alcohol 1999 Feb 17(2) 133ndash8
GGT Correlates With Toxic Metal Levels
Lee DH et al Graded associations of blood lead and urinary cadmium concentrations with oxidative-stress-related markers in the
US population results from the third National Health and Nutrition Examination Survey Environ Health
perspect 2006 Mar114(3)350-4
GGT and Diabetes Risk
0
5
10
15
20
25
30
lt10 10-19 20-29 30-39 40-49 gt50
Dia
bete
s R
isk
GGT
bull GGT over 50 associated with tripling of death rate
bull 30-40 associated with doubling
GGT Levels
Correlate with
Risk of Death
Brenner H et al Distribution determinants and prognostic value of gamma-glutamyltransferase for all-cause
mortality in a cohort of construction workers from southern Germany Prev Med 1997 26 305ndash10
GGT From Small US Company
with Young Workers
0
10
20
30
40
50
60
0 20 40 60 80 100
GGT Data from Canadian Oil Field
Workers
0
50
100
150
200
250
300
350
400
450
lt10 10-20 20-30 30-40 40-50 50-60 60-07 70-80 80-90 90-100 100-110 110-120 gt120
GGTP
20-fold increased risk of diabetes
Uric Acid Indirect Measure of POPs
bull Poly-fluorinated hydrocarbons (PFOA and PFOS) associated
with increased serum uric acid
Lin CY et al Association among serum perfluoroalkyl chemicals glucose homeostasis and metabolic syndrome
in adolescents and adults Diabetes Care 2009 Apr32(4)702-7
Steenland K et al Association of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) with uric
acid among adults with elevated community exposure to PFOA Environ Health Perspect 2010 Feb118229-33
Steenland 2010 Open Access
ALT Indirect Measure of POPs
bull ALT (proxy marker) elevation in 104 (not including viral
hepatitis hemochromatosis or alcoholic liver disease) of
NHANES 03-04 subset
bull Risk of elevated ALT increased dose-dependently with
cadmium lead mercury and PCB exposure
bull 100 of individuals had detectable PCBs 925 mercury
and 996 had detectable lead
bull In 2005-08 prevalence of NAFLD in US was 11 a
growing cause of chronic liver disease
Cave M et al Polychlorinated biphenyls lead and mercury are associated with liver disease in American adults
NHANES 2003-2004 Environ Health Perspect 2010 Dec118(12)1735-42
Younossi ZM et al Changes in the prevalence of the most common causes of chronic liver diseases in the United
States from 1988 to 2008 Clin Gastroenterol Hepatol 2011 Jun9(6)524-530e1
Bilirubin as a Marker of POPs
bull Degree of serum bilirubin increase is prognostically significant in chronic liver dysfunction
bull Mono-ortho PCB TEQ values were found to be significantly positively associated with bilirubin (β=071 P=0008) following adjustment for multiple potential confounders
bull Bilirubin levels significantly correlated with PCBs -105-118-126 and -194
bull Smoking appears to be the biggest confounder
Dufour DR et al 2000 Diagnosis and monitoring of hepatic injury II Recommendations for use of laboratory
tests in screening diagnosis and monitoring Clin Chem 46 2050ndash68
Kumar J et al Persistent organic pollutants and liver dysfunction biomarkers in a population-based human sample
of men and women Environ Res 2014134251-256
Perf
luo
rin
ate
dP
OP
s a
nd
Co
mm
on
Blo
od
Tests
Gleason JA et al Associations of perfluorinated chemical serum concentrations and biomarkers of liver function and uric acid in the
US population (NHANES) 2007-2010 Environ Res 20151368-14
Liver Enzymes Reflect Toxic Load
bull AST ALT and GGT increase with body load of PCBs and OCPs
bull Some non-linear
bull Oxychlordanetop quartile
ALT 10
GGT 25
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
LDL-Cholesterol as Measure of POPs
bull 5-year prospective study to determine if POP levels predict future elevation in LDL-cholesterol
bull 598 subjects initially at age 70
bull Looked at 23 POPs
bull Best correlation with PCB 194
Penell J Lind L Salihovic S et al Persistent organic pollutants are related to change in circulating
lipid levels during a 5 year follow-up Environ Res 134(2014)190ndash197
oxLDL as Measure of POPs
bull 992 70-year old individuals (50 women)
bull Sum of PCBs showed strong significant positive associations with ox-LDL and significant negative associations with glutathione-related markers (GSSG and GSSGGSH)
bull A number of POPs (PCB-99 138 153 156 170 180 194 206 and 209) showed strong significant positive association with ox-LDL
Kumar J et al Influence of persistent organic pollutants on oxidative stress in population-based samples
Chemosphere 2014114303-309
Homocysteine is Increased by Pb amp Cd
Guallar E et al Confounding of the relation between homocysteine and peripheral arterial disease by lead cadmium and renal function Am J Epidemiol 2006 Apr 15163(8)700-8
Nutrient Deficiencies Accentuate
Effects of Lead on Homocysteine
bull Deficiencies in folate B6 or B12 make lead more toxic
Lee YM Et al Association of homocysteine levels with blood lead levels and micronutrients in the US general population J Prev Med Public Health 2012 Nov45(6)387-93
T4 amp T3 and PCBs
bull PCBs decrease T4 production
bull PCBs inhibit iodotyrosinedeiodinase activity
bull Study done in pregnant women which implies effect on fetus IQ
Kim S Park J Kim HJ et al Association between several persistent organic pollutants and thyroid hormone levels in serum among the pregnant women of Korea Environ Int 2013 Sep59442-8Shimizu R Yamaguchi M Uramaru N et al Structure-activity relationships of 44 halogenated compounds for iodotyrosinedeiodinase-inhibitory activity Toxicology 2013 Dec 6314(1)22-9
T4 amp T3 and PCBs
bull Not just humans being affected
bull Large study of dolphins shows exactly the same effects
Schwacke LH Zolman ES Balmer BC et al Anaemia hypothyroidism and immune suppression associated with polychlorinated biphenyl exposure in bottlenose dolphins (Tursiops truncatus) Proceed Royal Society B doi101098rspb20110665
8-OHdG
bull Oxidized nucleoside
bull Direct measure of DNA damage
bull Indirect measure of oxidative stress and toxin load
bull Correlates with
Multiple cancers
Mitochondrial damage
Rate of aging
Smoking
Several toxinsWalter Crinnion ldquoTotal Toxic Loadrdquo AANP 2015
8-OHdG Correlates with Pack-Years
of Smoking
Yano T et al Significance of the urinary 8-OHdG level as an oxidative stress marker in lung cancer patients Lung Cancer
2009 Jan63(1)111-4
8-OHdG Correlates
with Mercury
Chen C et al Increased oxidative DNA damage as assessed by urinary 8-hydroxy-2-deoxyguanosine
concentrations and serum redox status in persons exposed to mercury Clin Chem 2005 Apr51(4)759-67
Toxin Effects Worse with Aging
bull Thyroid function decreases with PFOA levels
bull But only after age 63
Shrestha S Bloom MS Yucel R et al Perfluoroalkyl substances and thyroid function in older adults Environ Int 2015 Feb75206-14
Insightful 23-Year Prospective Study
1 lt 50 there is no difference between those with the lowest and highest PCBs
2 In youngest group insulin production increases in response to toxin level As expected since blocking of
insulin receptor sites by PCBs
requires more insulin
3 That adaptive ability decreases with aging
4 At age 50 all the measures show very strong toxin-dose response
Cumulative damage impairs ability to adapt
Suarez-Lopez JR et al Persistent organic pollutants in young adults and changes in glucose related metabolism over a 23-year follow-up Environ Res 2015 Feb137485-94
Recommendations
High body toxic load
GGT gt 25
Uric acid gt 50 mgdl
ALT gt30 UL
Bilirubin gt08 mgdl
CBC lt 6000
Platelet lt 250000
Low T3 andor T4
Monitor Total Toxic Load
8-OHdG gt4
ldquoUnconventionalrdquo Laboratory Tests
bull Challenge testing
bull Hair analysis
bull Direct measures of solvents and POPs in blood urine adipose tissue
Evaluation of Metal Exposure ndash Provocation
bull Provocation ndash the use of a chelating agent ndash before urine collection often done clinically but several limitations
No ldquoofficialrdquo reference range for provoked urine
Most chelating agents do not extract metals from all tissues thus
does not necessarily represent total body burden
bull Example Brain is one of the main target organs for both elemental and organic
mercury yet agents do not chelate brain mercury
bull Despite limitations widely used and advocated by clinicians in part to see efficacy of chelating agent as a guide to treatment and based on empirical evidence
Rooney JP The role of thiols dithiols nutritional factors and interacting ligands in the toxicology of mercury
Toxicology 2007
Is Challenge Testing Valid
bull Poor correlations of standard tests for mercury
bull Unpublished research from corporate wellness project
bull Published amalgam number correlation
bull Published fish consumption correlation
What We Found In Canada
bull Deviations from the mean of 14 29 and 91 respectively
bull DMPS is spreading distribution suggesting that it is better at differentiating mercury body load
bull Some VERY high
Hg Assessment Correlations
bull Extensive measurements in 65 Whole blood Hg
Oral DMPS challenge
Amalgam surfaces
bull Correlations Whole blood w pre urine r = 040
Whole blood w post urine r = 057
Pre urine w post urine r = 068
Amalgams w pre urine r = 026
Amalgams w whole blood r = 036
Amalgams with post urine 044
bull Clear documentation that
challenge testing is better00
100
200
300
400
500
600
0 10 20 30 40 50
Po
st
Uri
ne H
g u
gg
Number of amalgams
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
Platelet Count Decreases with Years
of Exposure tp Benzene and CO
bull Petrol filling workers
bull ldquoHealthyrdquo non-smokers
Uzma N Salar BM Kumar BS et al Impact of organic solvents and environmental pollutants on the physiological function in petrol filling workers Int J Environ Res Public Health 2008 Sep5(3)139-46
Solvents Decrease Platelet Count
bull Compared workers exposed 23 hrday to those exposed most of day to toluene
bull All wore face masks and protective gear
bull Platelet count 14 lower 252 versus 216ml
bull Impairment of sympathetic nerves (OR = 413)
bull Impairment of peripheral nerves (OR = 694)
bull Positive relationship between neurological abnormalities and a self-reported neuropsychiatric measurement (r = 035-066)
Shih HT et al Subclinical abnormalities in workers with continuous low-level toluene exposure Toxicol Ind Health 2011 Sep27(8)691-9
Basophilic Stippling of Red Cells
Toxinsbull Arsenic
bull Lead
Diseasesbull Alpha-thalassemia HbH Disease
bull Beta thalassemia
bull Hereditary pyrimidine 5-nucleotidase deficiency
bull Myelodysplastic syndrome
bull Sideroblastic anemia
bull Thrombotic thrombocytopenic purpura
GGT Indirect Measure of POPsbull Glutathione is key intracellular defense against oxidative stress
bull Cellular GGT metabolizes extracellular GSH allowing precursor amino acids to be reutilized for intracellular GSH
bull Exposure to POPs induces GGT as a defensive mechanism
bull Within normal range predicts type 2 diabetes coronary heart disease hypertension stroke dyslipidemia chronic kidney disease and cancer
bull Men with GGT gt50 UI had ~26 fold risk for diabetes compared to those with lt10 Those with 40-49 had a ~20 fold risk
bull Levels within normal range occur with obesity xs alcohol cigarette smoking physical inactivity high meat low fruit and vegetable intake
bull Cumulative biomarker for environmental pollutants
Lee DH et al (2003) Gamma-glutamyltransferase and diabetesmdasha 4 year follow-up study Diabetologia 46359ndash364
Pamela A et al Serum gamma-glutamyltransferase linking together environmental pollution redox equilibria and progression of atherosclerosis Clin Chem
Lab Med 200947(12)1583-4
Lee DH et al Serum gamma-glutamyltransferase new insights about an old enzyme J Epidemiol Community Health 2009 Nov63(11)884-6
Lee DH et alSerum gamma-glutamyltransferase predicts non-fatal myocardial infarction and fatal coronary heart disease among 28838 middle-aged men and
women Eur Heart J 2006272170ndash6
Lee DH et al Gamma-glutamyltransferase and diabetes--a 4 year follow-up study Diabetologia 2003 Mar46(3)359-64
Lee DH et al Can persistent organic pollutants explain the association between serum gamma-glutamyltransferase and type 2 diabetes Diabetologia 2008
Mar51(3)402-7
GGT and Alcohol Consumption
bull GGT directly correlates with alcohol consumption
bull In a non-uniform population 40 gd will elevate GGT ~15
bull Watch for false negatives
bull Genomic variation
bull Are these the ones most
sensitive todamaged by
chemical toxins
bull Could up-regulation of GGT in light alcohol consumption be reason for benefit
0
10
20
30
40
50
60
70
80
0 200 400 600 800
Grams of Ethanol per Week
Adapted from Nagaya T et al Dose-response relationships between drinking and serum tests in Japanese men
aged 40ndash59 years Alcohol 1999 Feb 17(2) 133ndash8
GGT Correlates With Toxic Metal Levels
Lee DH et al Graded associations of blood lead and urinary cadmium concentrations with oxidative-stress-related markers in the
US population results from the third National Health and Nutrition Examination Survey Environ Health
perspect 2006 Mar114(3)350-4
GGT and Diabetes Risk
0
5
10
15
20
25
30
lt10 10-19 20-29 30-39 40-49 gt50
Dia
bete
s R
isk
GGT
bull GGT over 50 associated with tripling of death rate
bull 30-40 associated with doubling
GGT Levels
Correlate with
Risk of Death
Brenner H et al Distribution determinants and prognostic value of gamma-glutamyltransferase for all-cause
mortality in a cohort of construction workers from southern Germany Prev Med 1997 26 305ndash10
GGT From Small US Company
with Young Workers
0
10
20
30
40
50
60
0 20 40 60 80 100
GGT Data from Canadian Oil Field
Workers
0
50
100
150
200
250
300
350
400
450
lt10 10-20 20-30 30-40 40-50 50-60 60-07 70-80 80-90 90-100 100-110 110-120 gt120
GGTP
20-fold increased risk of diabetes
Uric Acid Indirect Measure of POPs
bull Poly-fluorinated hydrocarbons (PFOA and PFOS) associated
with increased serum uric acid
Lin CY et al Association among serum perfluoroalkyl chemicals glucose homeostasis and metabolic syndrome
in adolescents and adults Diabetes Care 2009 Apr32(4)702-7
Steenland K et al Association of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) with uric
acid among adults with elevated community exposure to PFOA Environ Health Perspect 2010 Feb118229-33
Steenland 2010 Open Access
ALT Indirect Measure of POPs
bull ALT (proxy marker) elevation in 104 (not including viral
hepatitis hemochromatosis or alcoholic liver disease) of
NHANES 03-04 subset
bull Risk of elevated ALT increased dose-dependently with
cadmium lead mercury and PCB exposure
bull 100 of individuals had detectable PCBs 925 mercury
and 996 had detectable lead
bull In 2005-08 prevalence of NAFLD in US was 11 a
growing cause of chronic liver disease
Cave M et al Polychlorinated biphenyls lead and mercury are associated with liver disease in American adults
NHANES 2003-2004 Environ Health Perspect 2010 Dec118(12)1735-42
Younossi ZM et al Changes in the prevalence of the most common causes of chronic liver diseases in the United
States from 1988 to 2008 Clin Gastroenterol Hepatol 2011 Jun9(6)524-530e1
Bilirubin as a Marker of POPs
bull Degree of serum bilirubin increase is prognostically significant in chronic liver dysfunction
bull Mono-ortho PCB TEQ values were found to be significantly positively associated with bilirubin (β=071 P=0008) following adjustment for multiple potential confounders
bull Bilirubin levels significantly correlated with PCBs -105-118-126 and -194
bull Smoking appears to be the biggest confounder
Dufour DR et al 2000 Diagnosis and monitoring of hepatic injury II Recommendations for use of laboratory
tests in screening diagnosis and monitoring Clin Chem 46 2050ndash68
Kumar J et al Persistent organic pollutants and liver dysfunction biomarkers in a population-based human sample
of men and women Environ Res 2014134251-256
Perf
luo
rin
ate
dP
OP
s a
nd
Co
mm
on
Blo
od
Tests
Gleason JA et al Associations of perfluorinated chemical serum concentrations and biomarkers of liver function and uric acid in the
US population (NHANES) 2007-2010 Environ Res 20151368-14
Liver Enzymes Reflect Toxic Load
bull AST ALT and GGT increase with body load of PCBs and OCPs
bull Some non-linear
bull Oxychlordanetop quartile
ALT 10
GGT 25
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
LDL-Cholesterol as Measure of POPs
bull 5-year prospective study to determine if POP levels predict future elevation in LDL-cholesterol
bull 598 subjects initially at age 70
bull Looked at 23 POPs
bull Best correlation with PCB 194
Penell J Lind L Salihovic S et al Persistent organic pollutants are related to change in circulating
lipid levels during a 5 year follow-up Environ Res 134(2014)190ndash197
oxLDL as Measure of POPs
bull 992 70-year old individuals (50 women)
bull Sum of PCBs showed strong significant positive associations with ox-LDL and significant negative associations with glutathione-related markers (GSSG and GSSGGSH)
bull A number of POPs (PCB-99 138 153 156 170 180 194 206 and 209) showed strong significant positive association with ox-LDL
Kumar J et al Influence of persistent organic pollutants on oxidative stress in population-based samples
Chemosphere 2014114303-309
Homocysteine is Increased by Pb amp Cd
Guallar E et al Confounding of the relation between homocysteine and peripheral arterial disease by lead cadmium and renal function Am J Epidemiol 2006 Apr 15163(8)700-8
Nutrient Deficiencies Accentuate
Effects of Lead on Homocysteine
bull Deficiencies in folate B6 or B12 make lead more toxic
Lee YM Et al Association of homocysteine levels with blood lead levels and micronutrients in the US general population J Prev Med Public Health 2012 Nov45(6)387-93
T4 amp T3 and PCBs
bull PCBs decrease T4 production
bull PCBs inhibit iodotyrosinedeiodinase activity
bull Study done in pregnant women which implies effect on fetus IQ
Kim S Park J Kim HJ et al Association between several persistent organic pollutants and thyroid hormone levels in serum among the pregnant women of Korea Environ Int 2013 Sep59442-8Shimizu R Yamaguchi M Uramaru N et al Structure-activity relationships of 44 halogenated compounds for iodotyrosinedeiodinase-inhibitory activity Toxicology 2013 Dec 6314(1)22-9
T4 amp T3 and PCBs
bull Not just humans being affected
bull Large study of dolphins shows exactly the same effects
Schwacke LH Zolman ES Balmer BC et al Anaemia hypothyroidism and immune suppression associated with polychlorinated biphenyl exposure in bottlenose dolphins (Tursiops truncatus) Proceed Royal Society B doi101098rspb20110665
8-OHdG
bull Oxidized nucleoside
bull Direct measure of DNA damage
bull Indirect measure of oxidative stress and toxin load
bull Correlates with
Multiple cancers
Mitochondrial damage
Rate of aging
Smoking
Several toxinsWalter Crinnion ldquoTotal Toxic Loadrdquo AANP 2015
8-OHdG Correlates with Pack-Years
of Smoking
Yano T et al Significance of the urinary 8-OHdG level as an oxidative stress marker in lung cancer patients Lung Cancer
2009 Jan63(1)111-4
8-OHdG Correlates
with Mercury
Chen C et al Increased oxidative DNA damage as assessed by urinary 8-hydroxy-2-deoxyguanosine
concentrations and serum redox status in persons exposed to mercury Clin Chem 2005 Apr51(4)759-67
Toxin Effects Worse with Aging
bull Thyroid function decreases with PFOA levels
bull But only after age 63
Shrestha S Bloom MS Yucel R et al Perfluoroalkyl substances and thyroid function in older adults Environ Int 2015 Feb75206-14
Insightful 23-Year Prospective Study
1 lt 50 there is no difference between those with the lowest and highest PCBs
2 In youngest group insulin production increases in response to toxin level As expected since blocking of
insulin receptor sites by PCBs
requires more insulin
3 That adaptive ability decreases with aging
4 At age 50 all the measures show very strong toxin-dose response
Cumulative damage impairs ability to adapt
Suarez-Lopez JR et al Persistent organic pollutants in young adults and changes in glucose related metabolism over a 23-year follow-up Environ Res 2015 Feb137485-94
Recommendations
High body toxic load
GGT gt 25
Uric acid gt 50 mgdl
ALT gt30 UL
Bilirubin gt08 mgdl
CBC lt 6000
Platelet lt 250000
Low T3 andor T4
Monitor Total Toxic Load
8-OHdG gt4
ldquoUnconventionalrdquo Laboratory Tests
bull Challenge testing
bull Hair analysis
bull Direct measures of solvents and POPs in blood urine adipose tissue
Evaluation of Metal Exposure ndash Provocation
bull Provocation ndash the use of a chelating agent ndash before urine collection often done clinically but several limitations
No ldquoofficialrdquo reference range for provoked urine
Most chelating agents do not extract metals from all tissues thus
does not necessarily represent total body burden
bull Example Brain is one of the main target organs for both elemental and organic
mercury yet agents do not chelate brain mercury
bull Despite limitations widely used and advocated by clinicians in part to see efficacy of chelating agent as a guide to treatment and based on empirical evidence
Rooney JP The role of thiols dithiols nutritional factors and interacting ligands in the toxicology of mercury
Toxicology 2007
Is Challenge Testing Valid
bull Poor correlations of standard tests for mercury
bull Unpublished research from corporate wellness project
bull Published amalgam number correlation
bull Published fish consumption correlation
What We Found In Canada
bull Deviations from the mean of 14 29 and 91 respectively
bull DMPS is spreading distribution suggesting that it is better at differentiating mercury body load
bull Some VERY high
Hg Assessment Correlations
bull Extensive measurements in 65 Whole blood Hg
Oral DMPS challenge
Amalgam surfaces
bull Correlations Whole blood w pre urine r = 040
Whole blood w post urine r = 057
Pre urine w post urine r = 068
Amalgams w pre urine r = 026
Amalgams w whole blood r = 036
Amalgams with post urine 044
bull Clear documentation that
challenge testing is better00
100
200
300
400
500
600
0 10 20 30 40 50
Po
st
Uri
ne H
g u
gg
Number of amalgams
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
Solvents Decrease Platelet Count
bull Compared workers exposed 23 hrday to those exposed most of day to toluene
bull All wore face masks and protective gear
bull Platelet count 14 lower 252 versus 216ml
bull Impairment of sympathetic nerves (OR = 413)
bull Impairment of peripheral nerves (OR = 694)
bull Positive relationship between neurological abnormalities and a self-reported neuropsychiatric measurement (r = 035-066)
Shih HT et al Subclinical abnormalities in workers with continuous low-level toluene exposure Toxicol Ind Health 2011 Sep27(8)691-9
Basophilic Stippling of Red Cells
Toxinsbull Arsenic
bull Lead
Diseasesbull Alpha-thalassemia HbH Disease
bull Beta thalassemia
bull Hereditary pyrimidine 5-nucleotidase deficiency
bull Myelodysplastic syndrome
bull Sideroblastic anemia
bull Thrombotic thrombocytopenic purpura
GGT Indirect Measure of POPsbull Glutathione is key intracellular defense against oxidative stress
bull Cellular GGT metabolizes extracellular GSH allowing precursor amino acids to be reutilized for intracellular GSH
bull Exposure to POPs induces GGT as a defensive mechanism
bull Within normal range predicts type 2 diabetes coronary heart disease hypertension stroke dyslipidemia chronic kidney disease and cancer
bull Men with GGT gt50 UI had ~26 fold risk for diabetes compared to those with lt10 Those with 40-49 had a ~20 fold risk
bull Levels within normal range occur with obesity xs alcohol cigarette smoking physical inactivity high meat low fruit and vegetable intake
bull Cumulative biomarker for environmental pollutants
Lee DH et al (2003) Gamma-glutamyltransferase and diabetesmdasha 4 year follow-up study Diabetologia 46359ndash364
Pamela A et al Serum gamma-glutamyltransferase linking together environmental pollution redox equilibria and progression of atherosclerosis Clin Chem
Lab Med 200947(12)1583-4
Lee DH et al Serum gamma-glutamyltransferase new insights about an old enzyme J Epidemiol Community Health 2009 Nov63(11)884-6
Lee DH et alSerum gamma-glutamyltransferase predicts non-fatal myocardial infarction and fatal coronary heart disease among 28838 middle-aged men and
women Eur Heart J 2006272170ndash6
Lee DH et al Gamma-glutamyltransferase and diabetes--a 4 year follow-up study Diabetologia 2003 Mar46(3)359-64
Lee DH et al Can persistent organic pollutants explain the association between serum gamma-glutamyltransferase and type 2 diabetes Diabetologia 2008
Mar51(3)402-7
GGT and Alcohol Consumption
bull GGT directly correlates with alcohol consumption
bull In a non-uniform population 40 gd will elevate GGT ~15
bull Watch for false negatives
bull Genomic variation
bull Are these the ones most
sensitive todamaged by
chemical toxins
bull Could up-regulation of GGT in light alcohol consumption be reason for benefit
0
10
20
30
40
50
60
70
80
0 200 400 600 800
Grams of Ethanol per Week
Adapted from Nagaya T et al Dose-response relationships between drinking and serum tests in Japanese men
aged 40ndash59 years Alcohol 1999 Feb 17(2) 133ndash8
GGT Correlates With Toxic Metal Levels
Lee DH et al Graded associations of blood lead and urinary cadmium concentrations with oxidative-stress-related markers in the
US population results from the third National Health and Nutrition Examination Survey Environ Health
perspect 2006 Mar114(3)350-4
GGT and Diabetes Risk
0
5
10
15
20
25
30
lt10 10-19 20-29 30-39 40-49 gt50
Dia
bete
s R
isk
GGT
bull GGT over 50 associated with tripling of death rate
bull 30-40 associated with doubling
GGT Levels
Correlate with
Risk of Death
Brenner H et al Distribution determinants and prognostic value of gamma-glutamyltransferase for all-cause
mortality in a cohort of construction workers from southern Germany Prev Med 1997 26 305ndash10
GGT From Small US Company
with Young Workers
0
10
20
30
40
50
60
0 20 40 60 80 100
GGT Data from Canadian Oil Field
Workers
0
50
100
150
200
250
300
350
400
450
lt10 10-20 20-30 30-40 40-50 50-60 60-07 70-80 80-90 90-100 100-110 110-120 gt120
GGTP
20-fold increased risk of diabetes
Uric Acid Indirect Measure of POPs
bull Poly-fluorinated hydrocarbons (PFOA and PFOS) associated
with increased serum uric acid
Lin CY et al Association among serum perfluoroalkyl chemicals glucose homeostasis and metabolic syndrome
in adolescents and adults Diabetes Care 2009 Apr32(4)702-7
Steenland K et al Association of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) with uric
acid among adults with elevated community exposure to PFOA Environ Health Perspect 2010 Feb118229-33
Steenland 2010 Open Access
ALT Indirect Measure of POPs
bull ALT (proxy marker) elevation in 104 (not including viral
hepatitis hemochromatosis or alcoholic liver disease) of
NHANES 03-04 subset
bull Risk of elevated ALT increased dose-dependently with
cadmium lead mercury and PCB exposure
bull 100 of individuals had detectable PCBs 925 mercury
and 996 had detectable lead
bull In 2005-08 prevalence of NAFLD in US was 11 a
growing cause of chronic liver disease
Cave M et al Polychlorinated biphenyls lead and mercury are associated with liver disease in American adults
NHANES 2003-2004 Environ Health Perspect 2010 Dec118(12)1735-42
Younossi ZM et al Changes in the prevalence of the most common causes of chronic liver diseases in the United
States from 1988 to 2008 Clin Gastroenterol Hepatol 2011 Jun9(6)524-530e1
Bilirubin as a Marker of POPs
bull Degree of serum bilirubin increase is prognostically significant in chronic liver dysfunction
bull Mono-ortho PCB TEQ values were found to be significantly positively associated with bilirubin (β=071 P=0008) following adjustment for multiple potential confounders
bull Bilirubin levels significantly correlated with PCBs -105-118-126 and -194
bull Smoking appears to be the biggest confounder
Dufour DR et al 2000 Diagnosis and monitoring of hepatic injury II Recommendations for use of laboratory
tests in screening diagnosis and monitoring Clin Chem 46 2050ndash68
Kumar J et al Persistent organic pollutants and liver dysfunction biomarkers in a population-based human sample
of men and women Environ Res 2014134251-256
Perf
luo
rin
ate
dP
OP
s a
nd
Co
mm
on
Blo
od
Tests
Gleason JA et al Associations of perfluorinated chemical serum concentrations and biomarkers of liver function and uric acid in the
US population (NHANES) 2007-2010 Environ Res 20151368-14
Liver Enzymes Reflect Toxic Load
bull AST ALT and GGT increase with body load of PCBs and OCPs
bull Some non-linear
bull Oxychlordanetop quartile
ALT 10
GGT 25
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
LDL-Cholesterol as Measure of POPs
bull 5-year prospective study to determine if POP levels predict future elevation in LDL-cholesterol
bull 598 subjects initially at age 70
bull Looked at 23 POPs
bull Best correlation with PCB 194
Penell J Lind L Salihovic S et al Persistent organic pollutants are related to change in circulating
lipid levels during a 5 year follow-up Environ Res 134(2014)190ndash197
oxLDL as Measure of POPs
bull 992 70-year old individuals (50 women)
bull Sum of PCBs showed strong significant positive associations with ox-LDL and significant negative associations with glutathione-related markers (GSSG and GSSGGSH)
bull A number of POPs (PCB-99 138 153 156 170 180 194 206 and 209) showed strong significant positive association with ox-LDL
Kumar J et al Influence of persistent organic pollutants on oxidative stress in population-based samples
Chemosphere 2014114303-309
Homocysteine is Increased by Pb amp Cd
Guallar E et al Confounding of the relation between homocysteine and peripheral arterial disease by lead cadmium and renal function Am J Epidemiol 2006 Apr 15163(8)700-8
Nutrient Deficiencies Accentuate
Effects of Lead on Homocysteine
bull Deficiencies in folate B6 or B12 make lead more toxic
Lee YM Et al Association of homocysteine levels with blood lead levels and micronutrients in the US general population J Prev Med Public Health 2012 Nov45(6)387-93
T4 amp T3 and PCBs
bull PCBs decrease T4 production
bull PCBs inhibit iodotyrosinedeiodinase activity
bull Study done in pregnant women which implies effect on fetus IQ
Kim S Park J Kim HJ et al Association between several persistent organic pollutants and thyroid hormone levels in serum among the pregnant women of Korea Environ Int 2013 Sep59442-8Shimizu R Yamaguchi M Uramaru N et al Structure-activity relationships of 44 halogenated compounds for iodotyrosinedeiodinase-inhibitory activity Toxicology 2013 Dec 6314(1)22-9
T4 amp T3 and PCBs
bull Not just humans being affected
bull Large study of dolphins shows exactly the same effects
Schwacke LH Zolman ES Balmer BC et al Anaemia hypothyroidism and immune suppression associated with polychlorinated biphenyl exposure in bottlenose dolphins (Tursiops truncatus) Proceed Royal Society B doi101098rspb20110665
8-OHdG
bull Oxidized nucleoside
bull Direct measure of DNA damage
bull Indirect measure of oxidative stress and toxin load
bull Correlates with
Multiple cancers
Mitochondrial damage
Rate of aging
Smoking
Several toxinsWalter Crinnion ldquoTotal Toxic Loadrdquo AANP 2015
8-OHdG Correlates with Pack-Years
of Smoking
Yano T et al Significance of the urinary 8-OHdG level as an oxidative stress marker in lung cancer patients Lung Cancer
2009 Jan63(1)111-4
8-OHdG Correlates
with Mercury
Chen C et al Increased oxidative DNA damage as assessed by urinary 8-hydroxy-2-deoxyguanosine
concentrations and serum redox status in persons exposed to mercury Clin Chem 2005 Apr51(4)759-67
Toxin Effects Worse with Aging
bull Thyroid function decreases with PFOA levels
bull But only after age 63
Shrestha S Bloom MS Yucel R et al Perfluoroalkyl substances and thyroid function in older adults Environ Int 2015 Feb75206-14
Insightful 23-Year Prospective Study
1 lt 50 there is no difference between those with the lowest and highest PCBs
2 In youngest group insulin production increases in response to toxin level As expected since blocking of
insulin receptor sites by PCBs
requires more insulin
3 That adaptive ability decreases with aging
4 At age 50 all the measures show very strong toxin-dose response
Cumulative damage impairs ability to adapt
Suarez-Lopez JR et al Persistent organic pollutants in young adults and changes in glucose related metabolism over a 23-year follow-up Environ Res 2015 Feb137485-94
Recommendations
High body toxic load
GGT gt 25
Uric acid gt 50 mgdl
ALT gt30 UL
Bilirubin gt08 mgdl
CBC lt 6000
Platelet lt 250000
Low T3 andor T4
Monitor Total Toxic Load
8-OHdG gt4
ldquoUnconventionalrdquo Laboratory Tests
bull Challenge testing
bull Hair analysis
bull Direct measures of solvents and POPs in blood urine adipose tissue
Evaluation of Metal Exposure ndash Provocation
bull Provocation ndash the use of a chelating agent ndash before urine collection often done clinically but several limitations
No ldquoofficialrdquo reference range for provoked urine
Most chelating agents do not extract metals from all tissues thus
does not necessarily represent total body burden
bull Example Brain is one of the main target organs for both elemental and organic
mercury yet agents do not chelate brain mercury
bull Despite limitations widely used and advocated by clinicians in part to see efficacy of chelating agent as a guide to treatment and based on empirical evidence
Rooney JP The role of thiols dithiols nutritional factors and interacting ligands in the toxicology of mercury
Toxicology 2007
Is Challenge Testing Valid
bull Poor correlations of standard tests for mercury
bull Unpublished research from corporate wellness project
bull Published amalgam number correlation
bull Published fish consumption correlation
What We Found In Canada
bull Deviations from the mean of 14 29 and 91 respectively
bull DMPS is spreading distribution suggesting that it is better at differentiating mercury body load
bull Some VERY high
Hg Assessment Correlations
bull Extensive measurements in 65 Whole blood Hg
Oral DMPS challenge
Amalgam surfaces
bull Correlations Whole blood w pre urine r = 040
Whole blood w post urine r = 057
Pre urine w post urine r = 068
Amalgams w pre urine r = 026
Amalgams w whole blood r = 036
Amalgams with post urine 044
bull Clear documentation that
challenge testing is better00
100
200
300
400
500
600
0 10 20 30 40 50
Po
st
Uri
ne H
g u
gg
Number of amalgams
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
Basophilic Stippling of Red Cells
Toxinsbull Arsenic
bull Lead
Diseasesbull Alpha-thalassemia HbH Disease
bull Beta thalassemia
bull Hereditary pyrimidine 5-nucleotidase deficiency
bull Myelodysplastic syndrome
bull Sideroblastic anemia
bull Thrombotic thrombocytopenic purpura
GGT Indirect Measure of POPsbull Glutathione is key intracellular defense against oxidative stress
bull Cellular GGT metabolizes extracellular GSH allowing precursor amino acids to be reutilized for intracellular GSH
bull Exposure to POPs induces GGT as a defensive mechanism
bull Within normal range predicts type 2 diabetes coronary heart disease hypertension stroke dyslipidemia chronic kidney disease and cancer
bull Men with GGT gt50 UI had ~26 fold risk for diabetes compared to those with lt10 Those with 40-49 had a ~20 fold risk
bull Levels within normal range occur with obesity xs alcohol cigarette smoking physical inactivity high meat low fruit and vegetable intake
bull Cumulative biomarker for environmental pollutants
Lee DH et al (2003) Gamma-glutamyltransferase and diabetesmdasha 4 year follow-up study Diabetologia 46359ndash364
Pamela A et al Serum gamma-glutamyltransferase linking together environmental pollution redox equilibria and progression of atherosclerosis Clin Chem
Lab Med 200947(12)1583-4
Lee DH et al Serum gamma-glutamyltransferase new insights about an old enzyme J Epidemiol Community Health 2009 Nov63(11)884-6
Lee DH et alSerum gamma-glutamyltransferase predicts non-fatal myocardial infarction and fatal coronary heart disease among 28838 middle-aged men and
women Eur Heart J 2006272170ndash6
Lee DH et al Gamma-glutamyltransferase and diabetes--a 4 year follow-up study Diabetologia 2003 Mar46(3)359-64
Lee DH et al Can persistent organic pollutants explain the association between serum gamma-glutamyltransferase and type 2 diabetes Diabetologia 2008
Mar51(3)402-7
GGT and Alcohol Consumption
bull GGT directly correlates with alcohol consumption
bull In a non-uniform population 40 gd will elevate GGT ~15
bull Watch for false negatives
bull Genomic variation
bull Are these the ones most
sensitive todamaged by
chemical toxins
bull Could up-regulation of GGT in light alcohol consumption be reason for benefit
0
10
20
30
40
50
60
70
80
0 200 400 600 800
Grams of Ethanol per Week
Adapted from Nagaya T et al Dose-response relationships between drinking and serum tests in Japanese men
aged 40ndash59 years Alcohol 1999 Feb 17(2) 133ndash8
GGT Correlates With Toxic Metal Levels
Lee DH et al Graded associations of blood lead and urinary cadmium concentrations with oxidative-stress-related markers in the
US population results from the third National Health and Nutrition Examination Survey Environ Health
perspect 2006 Mar114(3)350-4
GGT and Diabetes Risk
0
5
10
15
20
25
30
lt10 10-19 20-29 30-39 40-49 gt50
Dia
bete
s R
isk
GGT
bull GGT over 50 associated with tripling of death rate
bull 30-40 associated with doubling
GGT Levels
Correlate with
Risk of Death
Brenner H et al Distribution determinants and prognostic value of gamma-glutamyltransferase for all-cause
mortality in a cohort of construction workers from southern Germany Prev Med 1997 26 305ndash10
GGT From Small US Company
with Young Workers
0
10
20
30
40
50
60
0 20 40 60 80 100
GGT Data from Canadian Oil Field
Workers
0
50
100
150
200
250
300
350
400
450
lt10 10-20 20-30 30-40 40-50 50-60 60-07 70-80 80-90 90-100 100-110 110-120 gt120
GGTP
20-fold increased risk of diabetes
Uric Acid Indirect Measure of POPs
bull Poly-fluorinated hydrocarbons (PFOA and PFOS) associated
with increased serum uric acid
Lin CY et al Association among serum perfluoroalkyl chemicals glucose homeostasis and metabolic syndrome
in adolescents and adults Diabetes Care 2009 Apr32(4)702-7
Steenland K et al Association of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) with uric
acid among adults with elevated community exposure to PFOA Environ Health Perspect 2010 Feb118229-33
Steenland 2010 Open Access
ALT Indirect Measure of POPs
bull ALT (proxy marker) elevation in 104 (not including viral
hepatitis hemochromatosis or alcoholic liver disease) of
NHANES 03-04 subset
bull Risk of elevated ALT increased dose-dependently with
cadmium lead mercury and PCB exposure
bull 100 of individuals had detectable PCBs 925 mercury
and 996 had detectable lead
bull In 2005-08 prevalence of NAFLD in US was 11 a
growing cause of chronic liver disease
Cave M et al Polychlorinated biphenyls lead and mercury are associated with liver disease in American adults
NHANES 2003-2004 Environ Health Perspect 2010 Dec118(12)1735-42
Younossi ZM et al Changes in the prevalence of the most common causes of chronic liver diseases in the United
States from 1988 to 2008 Clin Gastroenterol Hepatol 2011 Jun9(6)524-530e1
Bilirubin as a Marker of POPs
bull Degree of serum bilirubin increase is prognostically significant in chronic liver dysfunction
bull Mono-ortho PCB TEQ values were found to be significantly positively associated with bilirubin (β=071 P=0008) following adjustment for multiple potential confounders
bull Bilirubin levels significantly correlated with PCBs -105-118-126 and -194
bull Smoking appears to be the biggest confounder
Dufour DR et al 2000 Diagnosis and monitoring of hepatic injury II Recommendations for use of laboratory
tests in screening diagnosis and monitoring Clin Chem 46 2050ndash68
Kumar J et al Persistent organic pollutants and liver dysfunction biomarkers in a population-based human sample
of men and women Environ Res 2014134251-256
Perf
luo
rin
ate
dP
OP
s a
nd
Co
mm
on
Blo
od
Tests
Gleason JA et al Associations of perfluorinated chemical serum concentrations and biomarkers of liver function and uric acid in the
US population (NHANES) 2007-2010 Environ Res 20151368-14
Liver Enzymes Reflect Toxic Load
bull AST ALT and GGT increase with body load of PCBs and OCPs
bull Some non-linear
bull Oxychlordanetop quartile
ALT 10
GGT 25
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
LDL-Cholesterol as Measure of POPs
bull 5-year prospective study to determine if POP levels predict future elevation in LDL-cholesterol
bull 598 subjects initially at age 70
bull Looked at 23 POPs
bull Best correlation with PCB 194
Penell J Lind L Salihovic S et al Persistent organic pollutants are related to change in circulating
lipid levels during a 5 year follow-up Environ Res 134(2014)190ndash197
oxLDL as Measure of POPs
bull 992 70-year old individuals (50 women)
bull Sum of PCBs showed strong significant positive associations with ox-LDL and significant negative associations with glutathione-related markers (GSSG and GSSGGSH)
bull A number of POPs (PCB-99 138 153 156 170 180 194 206 and 209) showed strong significant positive association with ox-LDL
Kumar J et al Influence of persistent organic pollutants on oxidative stress in population-based samples
Chemosphere 2014114303-309
Homocysteine is Increased by Pb amp Cd
Guallar E et al Confounding of the relation between homocysteine and peripheral arterial disease by lead cadmium and renal function Am J Epidemiol 2006 Apr 15163(8)700-8
Nutrient Deficiencies Accentuate
Effects of Lead on Homocysteine
bull Deficiencies in folate B6 or B12 make lead more toxic
Lee YM Et al Association of homocysteine levels with blood lead levels and micronutrients in the US general population J Prev Med Public Health 2012 Nov45(6)387-93
T4 amp T3 and PCBs
bull PCBs decrease T4 production
bull PCBs inhibit iodotyrosinedeiodinase activity
bull Study done in pregnant women which implies effect on fetus IQ
Kim S Park J Kim HJ et al Association between several persistent organic pollutants and thyroid hormone levels in serum among the pregnant women of Korea Environ Int 2013 Sep59442-8Shimizu R Yamaguchi M Uramaru N et al Structure-activity relationships of 44 halogenated compounds for iodotyrosinedeiodinase-inhibitory activity Toxicology 2013 Dec 6314(1)22-9
T4 amp T3 and PCBs
bull Not just humans being affected
bull Large study of dolphins shows exactly the same effects
Schwacke LH Zolman ES Balmer BC et al Anaemia hypothyroidism and immune suppression associated with polychlorinated biphenyl exposure in bottlenose dolphins (Tursiops truncatus) Proceed Royal Society B doi101098rspb20110665
8-OHdG
bull Oxidized nucleoside
bull Direct measure of DNA damage
bull Indirect measure of oxidative stress and toxin load
bull Correlates with
Multiple cancers
Mitochondrial damage
Rate of aging
Smoking
Several toxinsWalter Crinnion ldquoTotal Toxic Loadrdquo AANP 2015
8-OHdG Correlates with Pack-Years
of Smoking
Yano T et al Significance of the urinary 8-OHdG level as an oxidative stress marker in lung cancer patients Lung Cancer
2009 Jan63(1)111-4
8-OHdG Correlates
with Mercury
Chen C et al Increased oxidative DNA damage as assessed by urinary 8-hydroxy-2-deoxyguanosine
concentrations and serum redox status in persons exposed to mercury Clin Chem 2005 Apr51(4)759-67
Toxin Effects Worse with Aging
bull Thyroid function decreases with PFOA levels
bull But only after age 63
Shrestha S Bloom MS Yucel R et al Perfluoroalkyl substances and thyroid function in older adults Environ Int 2015 Feb75206-14
Insightful 23-Year Prospective Study
1 lt 50 there is no difference between those with the lowest and highest PCBs
2 In youngest group insulin production increases in response to toxin level As expected since blocking of
insulin receptor sites by PCBs
requires more insulin
3 That adaptive ability decreases with aging
4 At age 50 all the measures show very strong toxin-dose response
Cumulative damage impairs ability to adapt
Suarez-Lopez JR et al Persistent organic pollutants in young adults and changes in glucose related metabolism over a 23-year follow-up Environ Res 2015 Feb137485-94
Recommendations
High body toxic load
GGT gt 25
Uric acid gt 50 mgdl
ALT gt30 UL
Bilirubin gt08 mgdl
CBC lt 6000
Platelet lt 250000
Low T3 andor T4
Monitor Total Toxic Load
8-OHdG gt4
ldquoUnconventionalrdquo Laboratory Tests
bull Challenge testing
bull Hair analysis
bull Direct measures of solvents and POPs in blood urine adipose tissue
Evaluation of Metal Exposure ndash Provocation
bull Provocation ndash the use of a chelating agent ndash before urine collection often done clinically but several limitations
No ldquoofficialrdquo reference range for provoked urine
Most chelating agents do not extract metals from all tissues thus
does not necessarily represent total body burden
bull Example Brain is one of the main target organs for both elemental and organic
mercury yet agents do not chelate brain mercury
bull Despite limitations widely used and advocated by clinicians in part to see efficacy of chelating agent as a guide to treatment and based on empirical evidence
Rooney JP The role of thiols dithiols nutritional factors and interacting ligands in the toxicology of mercury
Toxicology 2007
Is Challenge Testing Valid
bull Poor correlations of standard tests for mercury
bull Unpublished research from corporate wellness project
bull Published amalgam number correlation
bull Published fish consumption correlation
What We Found In Canada
bull Deviations from the mean of 14 29 and 91 respectively
bull DMPS is spreading distribution suggesting that it is better at differentiating mercury body load
bull Some VERY high
Hg Assessment Correlations
bull Extensive measurements in 65 Whole blood Hg
Oral DMPS challenge
Amalgam surfaces
bull Correlations Whole blood w pre urine r = 040
Whole blood w post urine r = 057
Pre urine w post urine r = 068
Amalgams w pre urine r = 026
Amalgams w whole blood r = 036
Amalgams with post urine 044
bull Clear documentation that
challenge testing is better00
100
200
300
400
500
600
0 10 20 30 40 50
Po
st
Uri
ne H
g u
gg
Number of amalgams
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
GGT Indirect Measure of POPsbull Glutathione is key intracellular defense against oxidative stress
bull Cellular GGT metabolizes extracellular GSH allowing precursor amino acids to be reutilized for intracellular GSH
bull Exposure to POPs induces GGT as a defensive mechanism
bull Within normal range predicts type 2 diabetes coronary heart disease hypertension stroke dyslipidemia chronic kidney disease and cancer
bull Men with GGT gt50 UI had ~26 fold risk for diabetes compared to those with lt10 Those with 40-49 had a ~20 fold risk
bull Levels within normal range occur with obesity xs alcohol cigarette smoking physical inactivity high meat low fruit and vegetable intake
bull Cumulative biomarker for environmental pollutants
Lee DH et al (2003) Gamma-glutamyltransferase and diabetesmdasha 4 year follow-up study Diabetologia 46359ndash364
Pamela A et al Serum gamma-glutamyltransferase linking together environmental pollution redox equilibria and progression of atherosclerosis Clin Chem
Lab Med 200947(12)1583-4
Lee DH et al Serum gamma-glutamyltransferase new insights about an old enzyme J Epidemiol Community Health 2009 Nov63(11)884-6
Lee DH et alSerum gamma-glutamyltransferase predicts non-fatal myocardial infarction and fatal coronary heart disease among 28838 middle-aged men and
women Eur Heart J 2006272170ndash6
Lee DH et al Gamma-glutamyltransferase and diabetes--a 4 year follow-up study Diabetologia 2003 Mar46(3)359-64
Lee DH et al Can persistent organic pollutants explain the association between serum gamma-glutamyltransferase and type 2 diabetes Diabetologia 2008
Mar51(3)402-7
GGT and Alcohol Consumption
bull GGT directly correlates with alcohol consumption
bull In a non-uniform population 40 gd will elevate GGT ~15
bull Watch for false negatives
bull Genomic variation
bull Are these the ones most
sensitive todamaged by
chemical toxins
bull Could up-regulation of GGT in light alcohol consumption be reason for benefit
0
10
20
30
40
50
60
70
80
0 200 400 600 800
Grams of Ethanol per Week
Adapted from Nagaya T et al Dose-response relationships between drinking and serum tests in Japanese men
aged 40ndash59 years Alcohol 1999 Feb 17(2) 133ndash8
GGT Correlates With Toxic Metal Levels
Lee DH et al Graded associations of blood lead and urinary cadmium concentrations with oxidative-stress-related markers in the
US population results from the third National Health and Nutrition Examination Survey Environ Health
perspect 2006 Mar114(3)350-4
GGT and Diabetes Risk
0
5
10
15
20
25
30
lt10 10-19 20-29 30-39 40-49 gt50
Dia
bete
s R
isk
GGT
bull GGT over 50 associated with tripling of death rate
bull 30-40 associated with doubling
GGT Levels
Correlate with
Risk of Death
Brenner H et al Distribution determinants and prognostic value of gamma-glutamyltransferase for all-cause
mortality in a cohort of construction workers from southern Germany Prev Med 1997 26 305ndash10
GGT From Small US Company
with Young Workers
0
10
20
30
40
50
60
0 20 40 60 80 100
GGT Data from Canadian Oil Field
Workers
0
50
100
150
200
250
300
350
400
450
lt10 10-20 20-30 30-40 40-50 50-60 60-07 70-80 80-90 90-100 100-110 110-120 gt120
GGTP
20-fold increased risk of diabetes
Uric Acid Indirect Measure of POPs
bull Poly-fluorinated hydrocarbons (PFOA and PFOS) associated
with increased serum uric acid
Lin CY et al Association among serum perfluoroalkyl chemicals glucose homeostasis and metabolic syndrome
in adolescents and adults Diabetes Care 2009 Apr32(4)702-7
Steenland K et al Association of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) with uric
acid among adults with elevated community exposure to PFOA Environ Health Perspect 2010 Feb118229-33
Steenland 2010 Open Access
ALT Indirect Measure of POPs
bull ALT (proxy marker) elevation in 104 (not including viral
hepatitis hemochromatosis or alcoholic liver disease) of
NHANES 03-04 subset
bull Risk of elevated ALT increased dose-dependently with
cadmium lead mercury and PCB exposure
bull 100 of individuals had detectable PCBs 925 mercury
and 996 had detectable lead
bull In 2005-08 prevalence of NAFLD in US was 11 a
growing cause of chronic liver disease
Cave M et al Polychlorinated biphenyls lead and mercury are associated with liver disease in American adults
NHANES 2003-2004 Environ Health Perspect 2010 Dec118(12)1735-42
Younossi ZM et al Changes in the prevalence of the most common causes of chronic liver diseases in the United
States from 1988 to 2008 Clin Gastroenterol Hepatol 2011 Jun9(6)524-530e1
Bilirubin as a Marker of POPs
bull Degree of serum bilirubin increase is prognostically significant in chronic liver dysfunction
bull Mono-ortho PCB TEQ values were found to be significantly positively associated with bilirubin (β=071 P=0008) following adjustment for multiple potential confounders
bull Bilirubin levels significantly correlated with PCBs -105-118-126 and -194
bull Smoking appears to be the biggest confounder
Dufour DR et al 2000 Diagnosis and monitoring of hepatic injury II Recommendations for use of laboratory
tests in screening diagnosis and monitoring Clin Chem 46 2050ndash68
Kumar J et al Persistent organic pollutants and liver dysfunction biomarkers in a population-based human sample
of men and women Environ Res 2014134251-256
Perf
luo
rin
ate
dP
OP
s a
nd
Co
mm
on
Blo
od
Tests
Gleason JA et al Associations of perfluorinated chemical serum concentrations and biomarkers of liver function and uric acid in the
US population (NHANES) 2007-2010 Environ Res 20151368-14
Liver Enzymes Reflect Toxic Load
bull AST ALT and GGT increase with body load of PCBs and OCPs
bull Some non-linear
bull Oxychlordanetop quartile
ALT 10
GGT 25
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
LDL-Cholesterol as Measure of POPs
bull 5-year prospective study to determine if POP levels predict future elevation in LDL-cholesterol
bull 598 subjects initially at age 70
bull Looked at 23 POPs
bull Best correlation with PCB 194
Penell J Lind L Salihovic S et al Persistent organic pollutants are related to change in circulating
lipid levels during a 5 year follow-up Environ Res 134(2014)190ndash197
oxLDL as Measure of POPs
bull 992 70-year old individuals (50 women)
bull Sum of PCBs showed strong significant positive associations with ox-LDL and significant negative associations with glutathione-related markers (GSSG and GSSGGSH)
bull A number of POPs (PCB-99 138 153 156 170 180 194 206 and 209) showed strong significant positive association with ox-LDL
Kumar J et al Influence of persistent organic pollutants on oxidative stress in population-based samples
Chemosphere 2014114303-309
Homocysteine is Increased by Pb amp Cd
Guallar E et al Confounding of the relation between homocysteine and peripheral arterial disease by lead cadmium and renal function Am J Epidemiol 2006 Apr 15163(8)700-8
Nutrient Deficiencies Accentuate
Effects of Lead on Homocysteine
bull Deficiencies in folate B6 or B12 make lead more toxic
Lee YM Et al Association of homocysteine levels with blood lead levels and micronutrients in the US general population J Prev Med Public Health 2012 Nov45(6)387-93
T4 amp T3 and PCBs
bull PCBs decrease T4 production
bull PCBs inhibit iodotyrosinedeiodinase activity
bull Study done in pregnant women which implies effect on fetus IQ
Kim S Park J Kim HJ et al Association between several persistent organic pollutants and thyroid hormone levels in serum among the pregnant women of Korea Environ Int 2013 Sep59442-8Shimizu R Yamaguchi M Uramaru N et al Structure-activity relationships of 44 halogenated compounds for iodotyrosinedeiodinase-inhibitory activity Toxicology 2013 Dec 6314(1)22-9
T4 amp T3 and PCBs
bull Not just humans being affected
bull Large study of dolphins shows exactly the same effects
Schwacke LH Zolman ES Balmer BC et al Anaemia hypothyroidism and immune suppression associated with polychlorinated biphenyl exposure in bottlenose dolphins (Tursiops truncatus) Proceed Royal Society B doi101098rspb20110665
8-OHdG
bull Oxidized nucleoside
bull Direct measure of DNA damage
bull Indirect measure of oxidative stress and toxin load
bull Correlates with
Multiple cancers
Mitochondrial damage
Rate of aging
Smoking
Several toxinsWalter Crinnion ldquoTotal Toxic Loadrdquo AANP 2015
8-OHdG Correlates with Pack-Years
of Smoking
Yano T et al Significance of the urinary 8-OHdG level as an oxidative stress marker in lung cancer patients Lung Cancer
2009 Jan63(1)111-4
8-OHdG Correlates
with Mercury
Chen C et al Increased oxidative DNA damage as assessed by urinary 8-hydroxy-2-deoxyguanosine
concentrations and serum redox status in persons exposed to mercury Clin Chem 2005 Apr51(4)759-67
Toxin Effects Worse with Aging
bull Thyroid function decreases with PFOA levels
bull But only after age 63
Shrestha S Bloom MS Yucel R et al Perfluoroalkyl substances and thyroid function in older adults Environ Int 2015 Feb75206-14
Insightful 23-Year Prospective Study
1 lt 50 there is no difference between those with the lowest and highest PCBs
2 In youngest group insulin production increases in response to toxin level As expected since blocking of
insulin receptor sites by PCBs
requires more insulin
3 That adaptive ability decreases with aging
4 At age 50 all the measures show very strong toxin-dose response
Cumulative damage impairs ability to adapt
Suarez-Lopez JR et al Persistent organic pollutants in young adults and changes in glucose related metabolism over a 23-year follow-up Environ Res 2015 Feb137485-94
Recommendations
High body toxic load
GGT gt 25
Uric acid gt 50 mgdl
ALT gt30 UL
Bilirubin gt08 mgdl
CBC lt 6000
Platelet lt 250000
Low T3 andor T4
Monitor Total Toxic Load
8-OHdG gt4
ldquoUnconventionalrdquo Laboratory Tests
bull Challenge testing
bull Hair analysis
bull Direct measures of solvents and POPs in blood urine adipose tissue
Evaluation of Metal Exposure ndash Provocation
bull Provocation ndash the use of a chelating agent ndash before urine collection often done clinically but several limitations
No ldquoofficialrdquo reference range for provoked urine
Most chelating agents do not extract metals from all tissues thus
does not necessarily represent total body burden
bull Example Brain is one of the main target organs for both elemental and organic
mercury yet agents do not chelate brain mercury
bull Despite limitations widely used and advocated by clinicians in part to see efficacy of chelating agent as a guide to treatment and based on empirical evidence
Rooney JP The role of thiols dithiols nutritional factors and interacting ligands in the toxicology of mercury
Toxicology 2007
Is Challenge Testing Valid
bull Poor correlations of standard tests for mercury
bull Unpublished research from corporate wellness project
bull Published amalgam number correlation
bull Published fish consumption correlation
What We Found In Canada
bull Deviations from the mean of 14 29 and 91 respectively
bull DMPS is spreading distribution suggesting that it is better at differentiating mercury body load
bull Some VERY high
Hg Assessment Correlations
bull Extensive measurements in 65 Whole blood Hg
Oral DMPS challenge
Amalgam surfaces
bull Correlations Whole blood w pre urine r = 040
Whole blood w post urine r = 057
Pre urine w post urine r = 068
Amalgams w pre urine r = 026
Amalgams w whole blood r = 036
Amalgams with post urine 044
bull Clear documentation that
challenge testing is better00
100
200
300
400
500
600
0 10 20 30 40 50
Po
st
Uri
ne H
g u
gg
Number of amalgams
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
GGT and Alcohol Consumption
bull GGT directly correlates with alcohol consumption
bull In a non-uniform population 40 gd will elevate GGT ~15
bull Watch for false negatives
bull Genomic variation
bull Are these the ones most
sensitive todamaged by
chemical toxins
bull Could up-regulation of GGT in light alcohol consumption be reason for benefit
0
10
20
30
40
50
60
70
80
0 200 400 600 800
Grams of Ethanol per Week
Adapted from Nagaya T et al Dose-response relationships between drinking and serum tests in Japanese men
aged 40ndash59 years Alcohol 1999 Feb 17(2) 133ndash8
GGT Correlates With Toxic Metal Levels
Lee DH et al Graded associations of blood lead and urinary cadmium concentrations with oxidative-stress-related markers in the
US population results from the third National Health and Nutrition Examination Survey Environ Health
perspect 2006 Mar114(3)350-4
GGT and Diabetes Risk
0
5
10
15
20
25
30
lt10 10-19 20-29 30-39 40-49 gt50
Dia
bete
s R
isk
GGT
bull GGT over 50 associated with tripling of death rate
bull 30-40 associated with doubling
GGT Levels
Correlate with
Risk of Death
Brenner H et al Distribution determinants and prognostic value of gamma-glutamyltransferase for all-cause
mortality in a cohort of construction workers from southern Germany Prev Med 1997 26 305ndash10
GGT From Small US Company
with Young Workers
0
10
20
30
40
50
60
0 20 40 60 80 100
GGT Data from Canadian Oil Field
Workers
0
50
100
150
200
250
300
350
400
450
lt10 10-20 20-30 30-40 40-50 50-60 60-07 70-80 80-90 90-100 100-110 110-120 gt120
GGTP
20-fold increased risk of diabetes
Uric Acid Indirect Measure of POPs
bull Poly-fluorinated hydrocarbons (PFOA and PFOS) associated
with increased serum uric acid
Lin CY et al Association among serum perfluoroalkyl chemicals glucose homeostasis and metabolic syndrome
in adolescents and adults Diabetes Care 2009 Apr32(4)702-7
Steenland K et al Association of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) with uric
acid among adults with elevated community exposure to PFOA Environ Health Perspect 2010 Feb118229-33
Steenland 2010 Open Access
ALT Indirect Measure of POPs
bull ALT (proxy marker) elevation in 104 (not including viral
hepatitis hemochromatosis or alcoholic liver disease) of
NHANES 03-04 subset
bull Risk of elevated ALT increased dose-dependently with
cadmium lead mercury and PCB exposure
bull 100 of individuals had detectable PCBs 925 mercury
and 996 had detectable lead
bull In 2005-08 prevalence of NAFLD in US was 11 a
growing cause of chronic liver disease
Cave M et al Polychlorinated biphenyls lead and mercury are associated with liver disease in American adults
NHANES 2003-2004 Environ Health Perspect 2010 Dec118(12)1735-42
Younossi ZM et al Changes in the prevalence of the most common causes of chronic liver diseases in the United
States from 1988 to 2008 Clin Gastroenterol Hepatol 2011 Jun9(6)524-530e1
Bilirubin as a Marker of POPs
bull Degree of serum bilirubin increase is prognostically significant in chronic liver dysfunction
bull Mono-ortho PCB TEQ values were found to be significantly positively associated with bilirubin (β=071 P=0008) following adjustment for multiple potential confounders
bull Bilirubin levels significantly correlated with PCBs -105-118-126 and -194
bull Smoking appears to be the biggest confounder
Dufour DR et al 2000 Diagnosis and monitoring of hepatic injury II Recommendations for use of laboratory
tests in screening diagnosis and monitoring Clin Chem 46 2050ndash68
Kumar J et al Persistent organic pollutants and liver dysfunction biomarkers in a population-based human sample
of men and women Environ Res 2014134251-256
Perf
luo
rin
ate
dP
OP
s a
nd
Co
mm
on
Blo
od
Tests
Gleason JA et al Associations of perfluorinated chemical serum concentrations and biomarkers of liver function and uric acid in the
US population (NHANES) 2007-2010 Environ Res 20151368-14
Liver Enzymes Reflect Toxic Load
bull AST ALT and GGT increase with body load of PCBs and OCPs
bull Some non-linear
bull Oxychlordanetop quartile
ALT 10
GGT 25
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
LDL-Cholesterol as Measure of POPs
bull 5-year prospective study to determine if POP levels predict future elevation in LDL-cholesterol
bull 598 subjects initially at age 70
bull Looked at 23 POPs
bull Best correlation with PCB 194
Penell J Lind L Salihovic S et al Persistent organic pollutants are related to change in circulating
lipid levels during a 5 year follow-up Environ Res 134(2014)190ndash197
oxLDL as Measure of POPs
bull 992 70-year old individuals (50 women)
bull Sum of PCBs showed strong significant positive associations with ox-LDL and significant negative associations with glutathione-related markers (GSSG and GSSGGSH)
bull A number of POPs (PCB-99 138 153 156 170 180 194 206 and 209) showed strong significant positive association with ox-LDL
Kumar J et al Influence of persistent organic pollutants on oxidative stress in population-based samples
Chemosphere 2014114303-309
Homocysteine is Increased by Pb amp Cd
Guallar E et al Confounding of the relation between homocysteine and peripheral arterial disease by lead cadmium and renal function Am J Epidemiol 2006 Apr 15163(8)700-8
Nutrient Deficiencies Accentuate
Effects of Lead on Homocysteine
bull Deficiencies in folate B6 or B12 make lead more toxic
Lee YM Et al Association of homocysteine levels with blood lead levels and micronutrients in the US general population J Prev Med Public Health 2012 Nov45(6)387-93
T4 amp T3 and PCBs
bull PCBs decrease T4 production
bull PCBs inhibit iodotyrosinedeiodinase activity
bull Study done in pregnant women which implies effect on fetus IQ
Kim S Park J Kim HJ et al Association between several persistent organic pollutants and thyroid hormone levels in serum among the pregnant women of Korea Environ Int 2013 Sep59442-8Shimizu R Yamaguchi M Uramaru N et al Structure-activity relationships of 44 halogenated compounds for iodotyrosinedeiodinase-inhibitory activity Toxicology 2013 Dec 6314(1)22-9
T4 amp T3 and PCBs
bull Not just humans being affected
bull Large study of dolphins shows exactly the same effects
Schwacke LH Zolman ES Balmer BC et al Anaemia hypothyroidism and immune suppression associated with polychlorinated biphenyl exposure in bottlenose dolphins (Tursiops truncatus) Proceed Royal Society B doi101098rspb20110665
8-OHdG
bull Oxidized nucleoside
bull Direct measure of DNA damage
bull Indirect measure of oxidative stress and toxin load
bull Correlates with
Multiple cancers
Mitochondrial damage
Rate of aging
Smoking
Several toxinsWalter Crinnion ldquoTotal Toxic Loadrdquo AANP 2015
8-OHdG Correlates with Pack-Years
of Smoking
Yano T et al Significance of the urinary 8-OHdG level as an oxidative stress marker in lung cancer patients Lung Cancer
2009 Jan63(1)111-4
8-OHdG Correlates
with Mercury
Chen C et al Increased oxidative DNA damage as assessed by urinary 8-hydroxy-2-deoxyguanosine
concentrations and serum redox status in persons exposed to mercury Clin Chem 2005 Apr51(4)759-67
Toxin Effects Worse with Aging
bull Thyroid function decreases with PFOA levels
bull But only after age 63
Shrestha S Bloom MS Yucel R et al Perfluoroalkyl substances and thyroid function in older adults Environ Int 2015 Feb75206-14
Insightful 23-Year Prospective Study
1 lt 50 there is no difference between those with the lowest and highest PCBs
2 In youngest group insulin production increases in response to toxin level As expected since blocking of
insulin receptor sites by PCBs
requires more insulin
3 That adaptive ability decreases with aging
4 At age 50 all the measures show very strong toxin-dose response
Cumulative damage impairs ability to adapt
Suarez-Lopez JR et al Persistent organic pollutants in young adults and changes in glucose related metabolism over a 23-year follow-up Environ Res 2015 Feb137485-94
Recommendations
High body toxic load
GGT gt 25
Uric acid gt 50 mgdl
ALT gt30 UL
Bilirubin gt08 mgdl
CBC lt 6000
Platelet lt 250000
Low T3 andor T4
Monitor Total Toxic Load
8-OHdG gt4
ldquoUnconventionalrdquo Laboratory Tests
bull Challenge testing
bull Hair analysis
bull Direct measures of solvents and POPs in blood urine adipose tissue
Evaluation of Metal Exposure ndash Provocation
bull Provocation ndash the use of a chelating agent ndash before urine collection often done clinically but several limitations
No ldquoofficialrdquo reference range for provoked urine
Most chelating agents do not extract metals from all tissues thus
does not necessarily represent total body burden
bull Example Brain is one of the main target organs for both elemental and organic
mercury yet agents do not chelate brain mercury
bull Despite limitations widely used and advocated by clinicians in part to see efficacy of chelating agent as a guide to treatment and based on empirical evidence
Rooney JP The role of thiols dithiols nutritional factors and interacting ligands in the toxicology of mercury
Toxicology 2007
Is Challenge Testing Valid
bull Poor correlations of standard tests for mercury
bull Unpublished research from corporate wellness project
bull Published amalgam number correlation
bull Published fish consumption correlation
What We Found In Canada
bull Deviations from the mean of 14 29 and 91 respectively
bull DMPS is spreading distribution suggesting that it is better at differentiating mercury body load
bull Some VERY high
Hg Assessment Correlations
bull Extensive measurements in 65 Whole blood Hg
Oral DMPS challenge
Amalgam surfaces
bull Correlations Whole blood w pre urine r = 040
Whole blood w post urine r = 057
Pre urine w post urine r = 068
Amalgams w pre urine r = 026
Amalgams w whole blood r = 036
Amalgams with post urine 044
bull Clear documentation that
challenge testing is better00
100
200
300
400
500
600
0 10 20 30 40 50
Po
st
Uri
ne H
g u
gg
Number of amalgams
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
GGT Correlates With Toxic Metal Levels
Lee DH et al Graded associations of blood lead and urinary cadmium concentrations with oxidative-stress-related markers in the
US population results from the third National Health and Nutrition Examination Survey Environ Health
perspect 2006 Mar114(3)350-4
GGT and Diabetes Risk
0
5
10
15
20
25
30
lt10 10-19 20-29 30-39 40-49 gt50
Dia
bete
s R
isk
GGT
bull GGT over 50 associated with tripling of death rate
bull 30-40 associated with doubling
GGT Levels
Correlate with
Risk of Death
Brenner H et al Distribution determinants and prognostic value of gamma-glutamyltransferase for all-cause
mortality in a cohort of construction workers from southern Germany Prev Med 1997 26 305ndash10
GGT From Small US Company
with Young Workers
0
10
20
30
40
50
60
0 20 40 60 80 100
GGT Data from Canadian Oil Field
Workers
0
50
100
150
200
250
300
350
400
450
lt10 10-20 20-30 30-40 40-50 50-60 60-07 70-80 80-90 90-100 100-110 110-120 gt120
GGTP
20-fold increased risk of diabetes
Uric Acid Indirect Measure of POPs
bull Poly-fluorinated hydrocarbons (PFOA and PFOS) associated
with increased serum uric acid
Lin CY et al Association among serum perfluoroalkyl chemicals glucose homeostasis and metabolic syndrome
in adolescents and adults Diabetes Care 2009 Apr32(4)702-7
Steenland K et al Association of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) with uric
acid among adults with elevated community exposure to PFOA Environ Health Perspect 2010 Feb118229-33
Steenland 2010 Open Access
ALT Indirect Measure of POPs
bull ALT (proxy marker) elevation in 104 (not including viral
hepatitis hemochromatosis or alcoholic liver disease) of
NHANES 03-04 subset
bull Risk of elevated ALT increased dose-dependently with
cadmium lead mercury and PCB exposure
bull 100 of individuals had detectable PCBs 925 mercury
and 996 had detectable lead
bull In 2005-08 prevalence of NAFLD in US was 11 a
growing cause of chronic liver disease
Cave M et al Polychlorinated biphenyls lead and mercury are associated with liver disease in American adults
NHANES 2003-2004 Environ Health Perspect 2010 Dec118(12)1735-42
Younossi ZM et al Changes in the prevalence of the most common causes of chronic liver diseases in the United
States from 1988 to 2008 Clin Gastroenterol Hepatol 2011 Jun9(6)524-530e1
Bilirubin as a Marker of POPs
bull Degree of serum bilirubin increase is prognostically significant in chronic liver dysfunction
bull Mono-ortho PCB TEQ values were found to be significantly positively associated with bilirubin (β=071 P=0008) following adjustment for multiple potential confounders
bull Bilirubin levels significantly correlated with PCBs -105-118-126 and -194
bull Smoking appears to be the biggest confounder
Dufour DR et al 2000 Diagnosis and monitoring of hepatic injury II Recommendations for use of laboratory
tests in screening diagnosis and monitoring Clin Chem 46 2050ndash68
Kumar J et al Persistent organic pollutants and liver dysfunction biomarkers in a population-based human sample
of men and women Environ Res 2014134251-256
Perf
luo
rin
ate
dP
OP
s a
nd
Co
mm
on
Blo
od
Tests
Gleason JA et al Associations of perfluorinated chemical serum concentrations and biomarkers of liver function and uric acid in the
US population (NHANES) 2007-2010 Environ Res 20151368-14
Liver Enzymes Reflect Toxic Load
bull AST ALT and GGT increase with body load of PCBs and OCPs
bull Some non-linear
bull Oxychlordanetop quartile
ALT 10
GGT 25
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
LDL-Cholesterol as Measure of POPs
bull 5-year prospective study to determine if POP levels predict future elevation in LDL-cholesterol
bull 598 subjects initially at age 70
bull Looked at 23 POPs
bull Best correlation with PCB 194
Penell J Lind L Salihovic S et al Persistent organic pollutants are related to change in circulating
lipid levels during a 5 year follow-up Environ Res 134(2014)190ndash197
oxLDL as Measure of POPs
bull 992 70-year old individuals (50 women)
bull Sum of PCBs showed strong significant positive associations with ox-LDL and significant negative associations with glutathione-related markers (GSSG and GSSGGSH)
bull A number of POPs (PCB-99 138 153 156 170 180 194 206 and 209) showed strong significant positive association with ox-LDL
Kumar J et al Influence of persistent organic pollutants on oxidative stress in population-based samples
Chemosphere 2014114303-309
Homocysteine is Increased by Pb amp Cd
Guallar E et al Confounding of the relation between homocysteine and peripheral arterial disease by lead cadmium and renal function Am J Epidemiol 2006 Apr 15163(8)700-8
Nutrient Deficiencies Accentuate
Effects of Lead on Homocysteine
bull Deficiencies in folate B6 or B12 make lead more toxic
Lee YM Et al Association of homocysteine levels with blood lead levels and micronutrients in the US general population J Prev Med Public Health 2012 Nov45(6)387-93
T4 amp T3 and PCBs
bull PCBs decrease T4 production
bull PCBs inhibit iodotyrosinedeiodinase activity
bull Study done in pregnant women which implies effect on fetus IQ
Kim S Park J Kim HJ et al Association between several persistent organic pollutants and thyroid hormone levels in serum among the pregnant women of Korea Environ Int 2013 Sep59442-8Shimizu R Yamaguchi M Uramaru N et al Structure-activity relationships of 44 halogenated compounds for iodotyrosinedeiodinase-inhibitory activity Toxicology 2013 Dec 6314(1)22-9
T4 amp T3 and PCBs
bull Not just humans being affected
bull Large study of dolphins shows exactly the same effects
Schwacke LH Zolman ES Balmer BC et al Anaemia hypothyroidism and immune suppression associated with polychlorinated biphenyl exposure in bottlenose dolphins (Tursiops truncatus) Proceed Royal Society B doi101098rspb20110665
8-OHdG
bull Oxidized nucleoside
bull Direct measure of DNA damage
bull Indirect measure of oxidative stress and toxin load
bull Correlates with
Multiple cancers
Mitochondrial damage
Rate of aging
Smoking
Several toxinsWalter Crinnion ldquoTotal Toxic Loadrdquo AANP 2015
8-OHdG Correlates with Pack-Years
of Smoking
Yano T et al Significance of the urinary 8-OHdG level as an oxidative stress marker in lung cancer patients Lung Cancer
2009 Jan63(1)111-4
8-OHdG Correlates
with Mercury
Chen C et al Increased oxidative DNA damage as assessed by urinary 8-hydroxy-2-deoxyguanosine
concentrations and serum redox status in persons exposed to mercury Clin Chem 2005 Apr51(4)759-67
Toxin Effects Worse with Aging
bull Thyroid function decreases with PFOA levels
bull But only after age 63
Shrestha S Bloom MS Yucel R et al Perfluoroalkyl substances and thyroid function in older adults Environ Int 2015 Feb75206-14
Insightful 23-Year Prospective Study
1 lt 50 there is no difference between those with the lowest and highest PCBs
2 In youngest group insulin production increases in response to toxin level As expected since blocking of
insulin receptor sites by PCBs
requires more insulin
3 That adaptive ability decreases with aging
4 At age 50 all the measures show very strong toxin-dose response
Cumulative damage impairs ability to adapt
Suarez-Lopez JR et al Persistent organic pollutants in young adults and changes in glucose related metabolism over a 23-year follow-up Environ Res 2015 Feb137485-94
Recommendations
High body toxic load
GGT gt 25
Uric acid gt 50 mgdl
ALT gt30 UL
Bilirubin gt08 mgdl
CBC lt 6000
Platelet lt 250000
Low T3 andor T4
Monitor Total Toxic Load
8-OHdG gt4
ldquoUnconventionalrdquo Laboratory Tests
bull Challenge testing
bull Hair analysis
bull Direct measures of solvents and POPs in blood urine adipose tissue
Evaluation of Metal Exposure ndash Provocation
bull Provocation ndash the use of a chelating agent ndash before urine collection often done clinically but several limitations
No ldquoofficialrdquo reference range for provoked urine
Most chelating agents do not extract metals from all tissues thus
does not necessarily represent total body burden
bull Example Brain is one of the main target organs for both elemental and organic
mercury yet agents do not chelate brain mercury
bull Despite limitations widely used and advocated by clinicians in part to see efficacy of chelating agent as a guide to treatment and based on empirical evidence
Rooney JP The role of thiols dithiols nutritional factors and interacting ligands in the toxicology of mercury
Toxicology 2007
Is Challenge Testing Valid
bull Poor correlations of standard tests for mercury
bull Unpublished research from corporate wellness project
bull Published amalgam number correlation
bull Published fish consumption correlation
What We Found In Canada
bull Deviations from the mean of 14 29 and 91 respectively
bull DMPS is spreading distribution suggesting that it is better at differentiating mercury body load
bull Some VERY high
Hg Assessment Correlations
bull Extensive measurements in 65 Whole blood Hg
Oral DMPS challenge
Amalgam surfaces
bull Correlations Whole blood w pre urine r = 040
Whole blood w post urine r = 057
Pre urine w post urine r = 068
Amalgams w pre urine r = 026
Amalgams w whole blood r = 036
Amalgams with post urine 044
bull Clear documentation that
challenge testing is better00
100
200
300
400
500
600
0 10 20 30 40 50
Po
st
Uri
ne H
g u
gg
Number of amalgams
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
GGT and Diabetes Risk
0
5
10
15
20
25
30
lt10 10-19 20-29 30-39 40-49 gt50
Dia
bete
s R
isk
GGT
bull GGT over 50 associated with tripling of death rate
bull 30-40 associated with doubling
GGT Levels
Correlate with
Risk of Death
Brenner H et al Distribution determinants and prognostic value of gamma-glutamyltransferase for all-cause
mortality in a cohort of construction workers from southern Germany Prev Med 1997 26 305ndash10
GGT From Small US Company
with Young Workers
0
10
20
30
40
50
60
0 20 40 60 80 100
GGT Data from Canadian Oil Field
Workers
0
50
100
150
200
250
300
350
400
450
lt10 10-20 20-30 30-40 40-50 50-60 60-07 70-80 80-90 90-100 100-110 110-120 gt120
GGTP
20-fold increased risk of diabetes
Uric Acid Indirect Measure of POPs
bull Poly-fluorinated hydrocarbons (PFOA and PFOS) associated
with increased serum uric acid
Lin CY et al Association among serum perfluoroalkyl chemicals glucose homeostasis and metabolic syndrome
in adolescents and adults Diabetes Care 2009 Apr32(4)702-7
Steenland K et al Association of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) with uric
acid among adults with elevated community exposure to PFOA Environ Health Perspect 2010 Feb118229-33
Steenland 2010 Open Access
ALT Indirect Measure of POPs
bull ALT (proxy marker) elevation in 104 (not including viral
hepatitis hemochromatosis or alcoholic liver disease) of
NHANES 03-04 subset
bull Risk of elevated ALT increased dose-dependently with
cadmium lead mercury and PCB exposure
bull 100 of individuals had detectable PCBs 925 mercury
and 996 had detectable lead
bull In 2005-08 prevalence of NAFLD in US was 11 a
growing cause of chronic liver disease
Cave M et al Polychlorinated biphenyls lead and mercury are associated with liver disease in American adults
NHANES 2003-2004 Environ Health Perspect 2010 Dec118(12)1735-42
Younossi ZM et al Changes in the prevalence of the most common causes of chronic liver diseases in the United
States from 1988 to 2008 Clin Gastroenterol Hepatol 2011 Jun9(6)524-530e1
Bilirubin as a Marker of POPs
bull Degree of serum bilirubin increase is prognostically significant in chronic liver dysfunction
bull Mono-ortho PCB TEQ values were found to be significantly positively associated with bilirubin (β=071 P=0008) following adjustment for multiple potential confounders
bull Bilirubin levels significantly correlated with PCBs -105-118-126 and -194
bull Smoking appears to be the biggest confounder
Dufour DR et al 2000 Diagnosis and monitoring of hepatic injury II Recommendations for use of laboratory
tests in screening diagnosis and monitoring Clin Chem 46 2050ndash68
Kumar J et al Persistent organic pollutants and liver dysfunction biomarkers in a population-based human sample
of men and women Environ Res 2014134251-256
Perf
luo
rin
ate
dP
OP
s a
nd
Co
mm
on
Blo
od
Tests
Gleason JA et al Associations of perfluorinated chemical serum concentrations and biomarkers of liver function and uric acid in the
US population (NHANES) 2007-2010 Environ Res 20151368-14
Liver Enzymes Reflect Toxic Load
bull AST ALT and GGT increase with body load of PCBs and OCPs
bull Some non-linear
bull Oxychlordanetop quartile
ALT 10
GGT 25
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
LDL-Cholesterol as Measure of POPs
bull 5-year prospective study to determine if POP levels predict future elevation in LDL-cholesterol
bull 598 subjects initially at age 70
bull Looked at 23 POPs
bull Best correlation with PCB 194
Penell J Lind L Salihovic S et al Persistent organic pollutants are related to change in circulating
lipid levels during a 5 year follow-up Environ Res 134(2014)190ndash197
oxLDL as Measure of POPs
bull 992 70-year old individuals (50 women)
bull Sum of PCBs showed strong significant positive associations with ox-LDL and significant negative associations with glutathione-related markers (GSSG and GSSGGSH)
bull A number of POPs (PCB-99 138 153 156 170 180 194 206 and 209) showed strong significant positive association with ox-LDL
Kumar J et al Influence of persistent organic pollutants on oxidative stress in population-based samples
Chemosphere 2014114303-309
Homocysteine is Increased by Pb amp Cd
Guallar E et al Confounding of the relation between homocysteine and peripheral arterial disease by lead cadmium and renal function Am J Epidemiol 2006 Apr 15163(8)700-8
Nutrient Deficiencies Accentuate
Effects of Lead on Homocysteine
bull Deficiencies in folate B6 or B12 make lead more toxic
Lee YM Et al Association of homocysteine levels with blood lead levels and micronutrients in the US general population J Prev Med Public Health 2012 Nov45(6)387-93
T4 amp T3 and PCBs
bull PCBs decrease T4 production
bull PCBs inhibit iodotyrosinedeiodinase activity
bull Study done in pregnant women which implies effect on fetus IQ
Kim S Park J Kim HJ et al Association between several persistent organic pollutants and thyroid hormone levels in serum among the pregnant women of Korea Environ Int 2013 Sep59442-8Shimizu R Yamaguchi M Uramaru N et al Structure-activity relationships of 44 halogenated compounds for iodotyrosinedeiodinase-inhibitory activity Toxicology 2013 Dec 6314(1)22-9
T4 amp T3 and PCBs
bull Not just humans being affected
bull Large study of dolphins shows exactly the same effects
Schwacke LH Zolman ES Balmer BC et al Anaemia hypothyroidism and immune suppression associated with polychlorinated biphenyl exposure in bottlenose dolphins (Tursiops truncatus) Proceed Royal Society B doi101098rspb20110665
8-OHdG
bull Oxidized nucleoside
bull Direct measure of DNA damage
bull Indirect measure of oxidative stress and toxin load
bull Correlates with
Multiple cancers
Mitochondrial damage
Rate of aging
Smoking
Several toxinsWalter Crinnion ldquoTotal Toxic Loadrdquo AANP 2015
8-OHdG Correlates with Pack-Years
of Smoking
Yano T et al Significance of the urinary 8-OHdG level as an oxidative stress marker in lung cancer patients Lung Cancer
2009 Jan63(1)111-4
8-OHdG Correlates
with Mercury
Chen C et al Increased oxidative DNA damage as assessed by urinary 8-hydroxy-2-deoxyguanosine
concentrations and serum redox status in persons exposed to mercury Clin Chem 2005 Apr51(4)759-67
Toxin Effects Worse with Aging
bull Thyroid function decreases with PFOA levels
bull But only after age 63
Shrestha S Bloom MS Yucel R et al Perfluoroalkyl substances and thyroid function in older adults Environ Int 2015 Feb75206-14
Insightful 23-Year Prospective Study
1 lt 50 there is no difference between those with the lowest and highest PCBs
2 In youngest group insulin production increases in response to toxin level As expected since blocking of
insulin receptor sites by PCBs
requires more insulin
3 That adaptive ability decreases with aging
4 At age 50 all the measures show very strong toxin-dose response
Cumulative damage impairs ability to adapt
Suarez-Lopez JR et al Persistent organic pollutants in young adults and changes in glucose related metabolism over a 23-year follow-up Environ Res 2015 Feb137485-94
Recommendations
High body toxic load
GGT gt 25
Uric acid gt 50 mgdl
ALT gt30 UL
Bilirubin gt08 mgdl
CBC lt 6000
Platelet lt 250000
Low T3 andor T4
Monitor Total Toxic Load
8-OHdG gt4
ldquoUnconventionalrdquo Laboratory Tests
bull Challenge testing
bull Hair analysis
bull Direct measures of solvents and POPs in blood urine adipose tissue
Evaluation of Metal Exposure ndash Provocation
bull Provocation ndash the use of a chelating agent ndash before urine collection often done clinically but several limitations
No ldquoofficialrdquo reference range for provoked urine
Most chelating agents do not extract metals from all tissues thus
does not necessarily represent total body burden
bull Example Brain is one of the main target organs for both elemental and organic
mercury yet agents do not chelate brain mercury
bull Despite limitations widely used and advocated by clinicians in part to see efficacy of chelating agent as a guide to treatment and based on empirical evidence
Rooney JP The role of thiols dithiols nutritional factors and interacting ligands in the toxicology of mercury
Toxicology 2007
Is Challenge Testing Valid
bull Poor correlations of standard tests for mercury
bull Unpublished research from corporate wellness project
bull Published amalgam number correlation
bull Published fish consumption correlation
What We Found In Canada
bull Deviations from the mean of 14 29 and 91 respectively
bull DMPS is spreading distribution suggesting that it is better at differentiating mercury body load
bull Some VERY high
Hg Assessment Correlations
bull Extensive measurements in 65 Whole blood Hg
Oral DMPS challenge
Amalgam surfaces
bull Correlations Whole blood w pre urine r = 040
Whole blood w post urine r = 057
Pre urine w post urine r = 068
Amalgams w pre urine r = 026
Amalgams w whole blood r = 036
Amalgams with post urine 044
bull Clear documentation that
challenge testing is better00
100
200
300
400
500
600
0 10 20 30 40 50
Po
st
Uri
ne H
g u
gg
Number of amalgams
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
bull GGT over 50 associated with tripling of death rate
bull 30-40 associated with doubling
GGT Levels
Correlate with
Risk of Death
Brenner H et al Distribution determinants and prognostic value of gamma-glutamyltransferase for all-cause
mortality in a cohort of construction workers from southern Germany Prev Med 1997 26 305ndash10
GGT From Small US Company
with Young Workers
0
10
20
30
40
50
60
0 20 40 60 80 100
GGT Data from Canadian Oil Field
Workers
0
50
100
150
200
250
300
350
400
450
lt10 10-20 20-30 30-40 40-50 50-60 60-07 70-80 80-90 90-100 100-110 110-120 gt120
GGTP
20-fold increased risk of diabetes
Uric Acid Indirect Measure of POPs
bull Poly-fluorinated hydrocarbons (PFOA and PFOS) associated
with increased serum uric acid
Lin CY et al Association among serum perfluoroalkyl chemicals glucose homeostasis and metabolic syndrome
in adolescents and adults Diabetes Care 2009 Apr32(4)702-7
Steenland K et al Association of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) with uric
acid among adults with elevated community exposure to PFOA Environ Health Perspect 2010 Feb118229-33
Steenland 2010 Open Access
ALT Indirect Measure of POPs
bull ALT (proxy marker) elevation in 104 (not including viral
hepatitis hemochromatosis or alcoholic liver disease) of
NHANES 03-04 subset
bull Risk of elevated ALT increased dose-dependently with
cadmium lead mercury and PCB exposure
bull 100 of individuals had detectable PCBs 925 mercury
and 996 had detectable lead
bull In 2005-08 prevalence of NAFLD in US was 11 a
growing cause of chronic liver disease
Cave M et al Polychlorinated biphenyls lead and mercury are associated with liver disease in American adults
NHANES 2003-2004 Environ Health Perspect 2010 Dec118(12)1735-42
Younossi ZM et al Changes in the prevalence of the most common causes of chronic liver diseases in the United
States from 1988 to 2008 Clin Gastroenterol Hepatol 2011 Jun9(6)524-530e1
Bilirubin as a Marker of POPs
bull Degree of serum bilirubin increase is prognostically significant in chronic liver dysfunction
bull Mono-ortho PCB TEQ values were found to be significantly positively associated with bilirubin (β=071 P=0008) following adjustment for multiple potential confounders
bull Bilirubin levels significantly correlated with PCBs -105-118-126 and -194
bull Smoking appears to be the biggest confounder
Dufour DR et al 2000 Diagnosis and monitoring of hepatic injury II Recommendations for use of laboratory
tests in screening diagnosis and monitoring Clin Chem 46 2050ndash68
Kumar J et al Persistent organic pollutants and liver dysfunction biomarkers in a population-based human sample
of men and women Environ Res 2014134251-256
Perf
luo
rin
ate
dP
OP
s a
nd
Co
mm
on
Blo
od
Tests
Gleason JA et al Associations of perfluorinated chemical serum concentrations and biomarkers of liver function and uric acid in the
US population (NHANES) 2007-2010 Environ Res 20151368-14
Liver Enzymes Reflect Toxic Load
bull AST ALT and GGT increase with body load of PCBs and OCPs
bull Some non-linear
bull Oxychlordanetop quartile
ALT 10
GGT 25
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
LDL-Cholesterol as Measure of POPs
bull 5-year prospective study to determine if POP levels predict future elevation in LDL-cholesterol
bull 598 subjects initially at age 70
bull Looked at 23 POPs
bull Best correlation with PCB 194
Penell J Lind L Salihovic S et al Persistent organic pollutants are related to change in circulating
lipid levels during a 5 year follow-up Environ Res 134(2014)190ndash197
oxLDL as Measure of POPs
bull 992 70-year old individuals (50 women)
bull Sum of PCBs showed strong significant positive associations with ox-LDL and significant negative associations with glutathione-related markers (GSSG and GSSGGSH)
bull A number of POPs (PCB-99 138 153 156 170 180 194 206 and 209) showed strong significant positive association with ox-LDL
Kumar J et al Influence of persistent organic pollutants on oxidative stress in population-based samples
Chemosphere 2014114303-309
Homocysteine is Increased by Pb amp Cd
Guallar E et al Confounding of the relation between homocysteine and peripheral arterial disease by lead cadmium and renal function Am J Epidemiol 2006 Apr 15163(8)700-8
Nutrient Deficiencies Accentuate
Effects of Lead on Homocysteine
bull Deficiencies in folate B6 or B12 make lead more toxic
Lee YM Et al Association of homocysteine levels with blood lead levels and micronutrients in the US general population J Prev Med Public Health 2012 Nov45(6)387-93
T4 amp T3 and PCBs
bull PCBs decrease T4 production
bull PCBs inhibit iodotyrosinedeiodinase activity
bull Study done in pregnant women which implies effect on fetus IQ
Kim S Park J Kim HJ et al Association between several persistent organic pollutants and thyroid hormone levels in serum among the pregnant women of Korea Environ Int 2013 Sep59442-8Shimizu R Yamaguchi M Uramaru N et al Structure-activity relationships of 44 halogenated compounds for iodotyrosinedeiodinase-inhibitory activity Toxicology 2013 Dec 6314(1)22-9
T4 amp T3 and PCBs
bull Not just humans being affected
bull Large study of dolphins shows exactly the same effects
Schwacke LH Zolman ES Balmer BC et al Anaemia hypothyroidism and immune suppression associated with polychlorinated biphenyl exposure in bottlenose dolphins (Tursiops truncatus) Proceed Royal Society B doi101098rspb20110665
8-OHdG
bull Oxidized nucleoside
bull Direct measure of DNA damage
bull Indirect measure of oxidative stress and toxin load
bull Correlates with
Multiple cancers
Mitochondrial damage
Rate of aging
Smoking
Several toxinsWalter Crinnion ldquoTotal Toxic Loadrdquo AANP 2015
8-OHdG Correlates with Pack-Years
of Smoking
Yano T et al Significance of the urinary 8-OHdG level as an oxidative stress marker in lung cancer patients Lung Cancer
2009 Jan63(1)111-4
8-OHdG Correlates
with Mercury
Chen C et al Increased oxidative DNA damage as assessed by urinary 8-hydroxy-2-deoxyguanosine
concentrations and serum redox status in persons exposed to mercury Clin Chem 2005 Apr51(4)759-67
Toxin Effects Worse with Aging
bull Thyroid function decreases with PFOA levels
bull But only after age 63
Shrestha S Bloom MS Yucel R et al Perfluoroalkyl substances and thyroid function in older adults Environ Int 2015 Feb75206-14
Insightful 23-Year Prospective Study
1 lt 50 there is no difference between those with the lowest and highest PCBs
2 In youngest group insulin production increases in response to toxin level As expected since blocking of
insulin receptor sites by PCBs
requires more insulin
3 That adaptive ability decreases with aging
4 At age 50 all the measures show very strong toxin-dose response
Cumulative damage impairs ability to adapt
Suarez-Lopez JR et al Persistent organic pollutants in young adults and changes in glucose related metabolism over a 23-year follow-up Environ Res 2015 Feb137485-94
Recommendations
High body toxic load
GGT gt 25
Uric acid gt 50 mgdl
ALT gt30 UL
Bilirubin gt08 mgdl
CBC lt 6000
Platelet lt 250000
Low T3 andor T4
Monitor Total Toxic Load
8-OHdG gt4
ldquoUnconventionalrdquo Laboratory Tests
bull Challenge testing
bull Hair analysis
bull Direct measures of solvents and POPs in blood urine adipose tissue
Evaluation of Metal Exposure ndash Provocation
bull Provocation ndash the use of a chelating agent ndash before urine collection often done clinically but several limitations
No ldquoofficialrdquo reference range for provoked urine
Most chelating agents do not extract metals from all tissues thus
does not necessarily represent total body burden
bull Example Brain is one of the main target organs for both elemental and organic
mercury yet agents do not chelate brain mercury
bull Despite limitations widely used and advocated by clinicians in part to see efficacy of chelating agent as a guide to treatment and based on empirical evidence
Rooney JP The role of thiols dithiols nutritional factors and interacting ligands in the toxicology of mercury
Toxicology 2007
Is Challenge Testing Valid
bull Poor correlations of standard tests for mercury
bull Unpublished research from corporate wellness project
bull Published amalgam number correlation
bull Published fish consumption correlation
What We Found In Canada
bull Deviations from the mean of 14 29 and 91 respectively
bull DMPS is spreading distribution suggesting that it is better at differentiating mercury body load
bull Some VERY high
Hg Assessment Correlations
bull Extensive measurements in 65 Whole blood Hg
Oral DMPS challenge
Amalgam surfaces
bull Correlations Whole blood w pre urine r = 040
Whole blood w post urine r = 057
Pre urine w post urine r = 068
Amalgams w pre urine r = 026
Amalgams w whole blood r = 036
Amalgams with post urine 044
bull Clear documentation that
challenge testing is better00
100
200
300
400
500
600
0 10 20 30 40 50
Po
st
Uri
ne H
g u
gg
Number of amalgams
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
GGT From Small US Company
with Young Workers
0
10
20
30
40
50
60
0 20 40 60 80 100
GGT Data from Canadian Oil Field
Workers
0
50
100
150
200
250
300
350
400
450
lt10 10-20 20-30 30-40 40-50 50-60 60-07 70-80 80-90 90-100 100-110 110-120 gt120
GGTP
20-fold increased risk of diabetes
Uric Acid Indirect Measure of POPs
bull Poly-fluorinated hydrocarbons (PFOA and PFOS) associated
with increased serum uric acid
Lin CY et al Association among serum perfluoroalkyl chemicals glucose homeostasis and metabolic syndrome
in adolescents and adults Diabetes Care 2009 Apr32(4)702-7
Steenland K et al Association of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) with uric
acid among adults with elevated community exposure to PFOA Environ Health Perspect 2010 Feb118229-33
Steenland 2010 Open Access
ALT Indirect Measure of POPs
bull ALT (proxy marker) elevation in 104 (not including viral
hepatitis hemochromatosis or alcoholic liver disease) of
NHANES 03-04 subset
bull Risk of elevated ALT increased dose-dependently with
cadmium lead mercury and PCB exposure
bull 100 of individuals had detectable PCBs 925 mercury
and 996 had detectable lead
bull In 2005-08 prevalence of NAFLD in US was 11 a
growing cause of chronic liver disease
Cave M et al Polychlorinated biphenyls lead and mercury are associated with liver disease in American adults
NHANES 2003-2004 Environ Health Perspect 2010 Dec118(12)1735-42
Younossi ZM et al Changes in the prevalence of the most common causes of chronic liver diseases in the United
States from 1988 to 2008 Clin Gastroenterol Hepatol 2011 Jun9(6)524-530e1
Bilirubin as a Marker of POPs
bull Degree of serum bilirubin increase is prognostically significant in chronic liver dysfunction
bull Mono-ortho PCB TEQ values were found to be significantly positively associated with bilirubin (β=071 P=0008) following adjustment for multiple potential confounders
bull Bilirubin levels significantly correlated with PCBs -105-118-126 and -194
bull Smoking appears to be the biggest confounder
Dufour DR et al 2000 Diagnosis and monitoring of hepatic injury II Recommendations for use of laboratory
tests in screening diagnosis and monitoring Clin Chem 46 2050ndash68
Kumar J et al Persistent organic pollutants and liver dysfunction biomarkers in a population-based human sample
of men and women Environ Res 2014134251-256
Perf
luo
rin
ate
dP
OP
s a
nd
Co
mm
on
Blo
od
Tests
Gleason JA et al Associations of perfluorinated chemical serum concentrations and biomarkers of liver function and uric acid in the
US population (NHANES) 2007-2010 Environ Res 20151368-14
Liver Enzymes Reflect Toxic Load
bull AST ALT and GGT increase with body load of PCBs and OCPs
bull Some non-linear
bull Oxychlordanetop quartile
ALT 10
GGT 25
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
LDL-Cholesterol as Measure of POPs
bull 5-year prospective study to determine if POP levels predict future elevation in LDL-cholesterol
bull 598 subjects initially at age 70
bull Looked at 23 POPs
bull Best correlation with PCB 194
Penell J Lind L Salihovic S et al Persistent organic pollutants are related to change in circulating
lipid levels during a 5 year follow-up Environ Res 134(2014)190ndash197
oxLDL as Measure of POPs
bull 992 70-year old individuals (50 women)
bull Sum of PCBs showed strong significant positive associations with ox-LDL and significant negative associations with glutathione-related markers (GSSG and GSSGGSH)
bull A number of POPs (PCB-99 138 153 156 170 180 194 206 and 209) showed strong significant positive association with ox-LDL
Kumar J et al Influence of persistent organic pollutants on oxidative stress in population-based samples
Chemosphere 2014114303-309
Homocysteine is Increased by Pb amp Cd
Guallar E et al Confounding of the relation between homocysteine and peripheral arterial disease by lead cadmium and renal function Am J Epidemiol 2006 Apr 15163(8)700-8
Nutrient Deficiencies Accentuate
Effects of Lead on Homocysteine
bull Deficiencies in folate B6 or B12 make lead more toxic
Lee YM Et al Association of homocysteine levels with blood lead levels and micronutrients in the US general population J Prev Med Public Health 2012 Nov45(6)387-93
T4 amp T3 and PCBs
bull PCBs decrease T4 production
bull PCBs inhibit iodotyrosinedeiodinase activity
bull Study done in pregnant women which implies effect on fetus IQ
Kim S Park J Kim HJ et al Association between several persistent organic pollutants and thyroid hormone levels in serum among the pregnant women of Korea Environ Int 2013 Sep59442-8Shimizu R Yamaguchi M Uramaru N et al Structure-activity relationships of 44 halogenated compounds for iodotyrosinedeiodinase-inhibitory activity Toxicology 2013 Dec 6314(1)22-9
T4 amp T3 and PCBs
bull Not just humans being affected
bull Large study of dolphins shows exactly the same effects
Schwacke LH Zolman ES Balmer BC et al Anaemia hypothyroidism and immune suppression associated with polychlorinated biphenyl exposure in bottlenose dolphins (Tursiops truncatus) Proceed Royal Society B doi101098rspb20110665
8-OHdG
bull Oxidized nucleoside
bull Direct measure of DNA damage
bull Indirect measure of oxidative stress and toxin load
bull Correlates with
Multiple cancers
Mitochondrial damage
Rate of aging
Smoking
Several toxinsWalter Crinnion ldquoTotal Toxic Loadrdquo AANP 2015
8-OHdG Correlates with Pack-Years
of Smoking
Yano T et al Significance of the urinary 8-OHdG level as an oxidative stress marker in lung cancer patients Lung Cancer
2009 Jan63(1)111-4
8-OHdG Correlates
with Mercury
Chen C et al Increased oxidative DNA damage as assessed by urinary 8-hydroxy-2-deoxyguanosine
concentrations and serum redox status in persons exposed to mercury Clin Chem 2005 Apr51(4)759-67
Toxin Effects Worse with Aging
bull Thyroid function decreases with PFOA levels
bull But only after age 63
Shrestha S Bloom MS Yucel R et al Perfluoroalkyl substances and thyroid function in older adults Environ Int 2015 Feb75206-14
Insightful 23-Year Prospective Study
1 lt 50 there is no difference between those with the lowest and highest PCBs
2 In youngest group insulin production increases in response to toxin level As expected since blocking of
insulin receptor sites by PCBs
requires more insulin
3 That adaptive ability decreases with aging
4 At age 50 all the measures show very strong toxin-dose response
Cumulative damage impairs ability to adapt
Suarez-Lopez JR et al Persistent organic pollutants in young adults and changes in glucose related metabolism over a 23-year follow-up Environ Res 2015 Feb137485-94
Recommendations
High body toxic load
GGT gt 25
Uric acid gt 50 mgdl
ALT gt30 UL
Bilirubin gt08 mgdl
CBC lt 6000
Platelet lt 250000
Low T3 andor T4
Monitor Total Toxic Load
8-OHdG gt4
ldquoUnconventionalrdquo Laboratory Tests
bull Challenge testing
bull Hair analysis
bull Direct measures of solvents and POPs in blood urine adipose tissue
Evaluation of Metal Exposure ndash Provocation
bull Provocation ndash the use of a chelating agent ndash before urine collection often done clinically but several limitations
No ldquoofficialrdquo reference range for provoked urine
Most chelating agents do not extract metals from all tissues thus
does not necessarily represent total body burden
bull Example Brain is one of the main target organs for both elemental and organic
mercury yet agents do not chelate brain mercury
bull Despite limitations widely used and advocated by clinicians in part to see efficacy of chelating agent as a guide to treatment and based on empirical evidence
Rooney JP The role of thiols dithiols nutritional factors and interacting ligands in the toxicology of mercury
Toxicology 2007
Is Challenge Testing Valid
bull Poor correlations of standard tests for mercury
bull Unpublished research from corporate wellness project
bull Published amalgam number correlation
bull Published fish consumption correlation
What We Found In Canada
bull Deviations from the mean of 14 29 and 91 respectively
bull DMPS is spreading distribution suggesting that it is better at differentiating mercury body load
bull Some VERY high
Hg Assessment Correlations
bull Extensive measurements in 65 Whole blood Hg
Oral DMPS challenge
Amalgam surfaces
bull Correlations Whole blood w pre urine r = 040
Whole blood w post urine r = 057
Pre urine w post urine r = 068
Amalgams w pre urine r = 026
Amalgams w whole blood r = 036
Amalgams with post urine 044
bull Clear documentation that
challenge testing is better00
100
200
300
400
500
600
0 10 20 30 40 50
Po
st
Uri
ne H
g u
gg
Number of amalgams
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
GGT Data from Canadian Oil Field
Workers
0
50
100
150
200
250
300
350
400
450
lt10 10-20 20-30 30-40 40-50 50-60 60-07 70-80 80-90 90-100 100-110 110-120 gt120
GGTP
20-fold increased risk of diabetes
Uric Acid Indirect Measure of POPs
bull Poly-fluorinated hydrocarbons (PFOA and PFOS) associated
with increased serum uric acid
Lin CY et al Association among serum perfluoroalkyl chemicals glucose homeostasis and metabolic syndrome
in adolescents and adults Diabetes Care 2009 Apr32(4)702-7
Steenland K et al Association of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) with uric
acid among adults with elevated community exposure to PFOA Environ Health Perspect 2010 Feb118229-33
Steenland 2010 Open Access
ALT Indirect Measure of POPs
bull ALT (proxy marker) elevation in 104 (not including viral
hepatitis hemochromatosis or alcoholic liver disease) of
NHANES 03-04 subset
bull Risk of elevated ALT increased dose-dependently with
cadmium lead mercury and PCB exposure
bull 100 of individuals had detectable PCBs 925 mercury
and 996 had detectable lead
bull In 2005-08 prevalence of NAFLD in US was 11 a
growing cause of chronic liver disease
Cave M et al Polychlorinated biphenyls lead and mercury are associated with liver disease in American adults
NHANES 2003-2004 Environ Health Perspect 2010 Dec118(12)1735-42
Younossi ZM et al Changes in the prevalence of the most common causes of chronic liver diseases in the United
States from 1988 to 2008 Clin Gastroenterol Hepatol 2011 Jun9(6)524-530e1
Bilirubin as a Marker of POPs
bull Degree of serum bilirubin increase is prognostically significant in chronic liver dysfunction
bull Mono-ortho PCB TEQ values were found to be significantly positively associated with bilirubin (β=071 P=0008) following adjustment for multiple potential confounders
bull Bilirubin levels significantly correlated with PCBs -105-118-126 and -194
bull Smoking appears to be the biggest confounder
Dufour DR et al 2000 Diagnosis and monitoring of hepatic injury II Recommendations for use of laboratory
tests in screening diagnosis and monitoring Clin Chem 46 2050ndash68
Kumar J et al Persistent organic pollutants and liver dysfunction biomarkers in a population-based human sample
of men and women Environ Res 2014134251-256
Perf
luo
rin
ate
dP
OP
s a
nd
Co
mm
on
Blo
od
Tests
Gleason JA et al Associations of perfluorinated chemical serum concentrations and biomarkers of liver function and uric acid in the
US population (NHANES) 2007-2010 Environ Res 20151368-14
Liver Enzymes Reflect Toxic Load
bull AST ALT and GGT increase with body load of PCBs and OCPs
bull Some non-linear
bull Oxychlordanetop quartile
ALT 10
GGT 25
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
LDL-Cholesterol as Measure of POPs
bull 5-year prospective study to determine if POP levels predict future elevation in LDL-cholesterol
bull 598 subjects initially at age 70
bull Looked at 23 POPs
bull Best correlation with PCB 194
Penell J Lind L Salihovic S et al Persistent organic pollutants are related to change in circulating
lipid levels during a 5 year follow-up Environ Res 134(2014)190ndash197
oxLDL as Measure of POPs
bull 992 70-year old individuals (50 women)
bull Sum of PCBs showed strong significant positive associations with ox-LDL and significant negative associations with glutathione-related markers (GSSG and GSSGGSH)
bull A number of POPs (PCB-99 138 153 156 170 180 194 206 and 209) showed strong significant positive association with ox-LDL
Kumar J et al Influence of persistent organic pollutants on oxidative stress in population-based samples
Chemosphere 2014114303-309
Homocysteine is Increased by Pb amp Cd
Guallar E et al Confounding of the relation between homocysteine and peripheral arterial disease by lead cadmium and renal function Am J Epidemiol 2006 Apr 15163(8)700-8
Nutrient Deficiencies Accentuate
Effects of Lead on Homocysteine
bull Deficiencies in folate B6 or B12 make lead more toxic
Lee YM Et al Association of homocysteine levels with blood lead levels and micronutrients in the US general population J Prev Med Public Health 2012 Nov45(6)387-93
T4 amp T3 and PCBs
bull PCBs decrease T4 production
bull PCBs inhibit iodotyrosinedeiodinase activity
bull Study done in pregnant women which implies effect on fetus IQ
Kim S Park J Kim HJ et al Association between several persistent organic pollutants and thyroid hormone levels in serum among the pregnant women of Korea Environ Int 2013 Sep59442-8Shimizu R Yamaguchi M Uramaru N et al Structure-activity relationships of 44 halogenated compounds for iodotyrosinedeiodinase-inhibitory activity Toxicology 2013 Dec 6314(1)22-9
T4 amp T3 and PCBs
bull Not just humans being affected
bull Large study of dolphins shows exactly the same effects
Schwacke LH Zolman ES Balmer BC et al Anaemia hypothyroidism and immune suppression associated with polychlorinated biphenyl exposure in bottlenose dolphins (Tursiops truncatus) Proceed Royal Society B doi101098rspb20110665
8-OHdG
bull Oxidized nucleoside
bull Direct measure of DNA damage
bull Indirect measure of oxidative stress and toxin load
bull Correlates with
Multiple cancers
Mitochondrial damage
Rate of aging
Smoking
Several toxinsWalter Crinnion ldquoTotal Toxic Loadrdquo AANP 2015
8-OHdG Correlates with Pack-Years
of Smoking
Yano T et al Significance of the urinary 8-OHdG level as an oxidative stress marker in lung cancer patients Lung Cancer
2009 Jan63(1)111-4
8-OHdG Correlates
with Mercury
Chen C et al Increased oxidative DNA damage as assessed by urinary 8-hydroxy-2-deoxyguanosine
concentrations and serum redox status in persons exposed to mercury Clin Chem 2005 Apr51(4)759-67
Toxin Effects Worse with Aging
bull Thyroid function decreases with PFOA levels
bull But only after age 63
Shrestha S Bloom MS Yucel R et al Perfluoroalkyl substances and thyroid function in older adults Environ Int 2015 Feb75206-14
Insightful 23-Year Prospective Study
1 lt 50 there is no difference between those with the lowest and highest PCBs
2 In youngest group insulin production increases in response to toxin level As expected since blocking of
insulin receptor sites by PCBs
requires more insulin
3 That adaptive ability decreases with aging
4 At age 50 all the measures show very strong toxin-dose response
Cumulative damage impairs ability to adapt
Suarez-Lopez JR et al Persistent organic pollutants in young adults and changes in glucose related metabolism over a 23-year follow-up Environ Res 2015 Feb137485-94
Recommendations
High body toxic load
GGT gt 25
Uric acid gt 50 mgdl
ALT gt30 UL
Bilirubin gt08 mgdl
CBC lt 6000
Platelet lt 250000
Low T3 andor T4
Monitor Total Toxic Load
8-OHdG gt4
ldquoUnconventionalrdquo Laboratory Tests
bull Challenge testing
bull Hair analysis
bull Direct measures of solvents and POPs in blood urine adipose tissue
Evaluation of Metal Exposure ndash Provocation
bull Provocation ndash the use of a chelating agent ndash before urine collection often done clinically but several limitations
No ldquoofficialrdquo reference range for provoked urine
Most chelating agents do not extract metals from all tissues thus
does not necessarily represent total body burden
bull Example Brain is one of the main target organs for both elemental and organic
mercury yet agents do not chelate brain mercury
bull Despite limitations widely used and advocated by clinicians in part to see efficacy of chelating agent as a guide to treatment and based on empirical evidence
Rooney JP The role of thiols dithiols nutritional factors and interacting ligands in the toxicology of mercury
Toxicology 2007
Is Challenge Testing Valid
bull Poor correlations of standard tests for mercury
bull Unpublished research from corporate wellness project
bull Published amalgam number correlation
bull Published fish consumption correlation
What We Found In Canada
bull Deviations from the mean of 14 29 and 91 respectively
bull DMPS is spreading distribution suggesting that it is better at differentiating mercury body load
bull Some VERY high
Hg Assessment Correlations
bull Extensive measurements in 65 Whole blood Hg
Oral DMPS challenge
Amalgam surfaces
bull Correlations Whole blood w pre urine r = 040
Whole blood w post urine r = 057
Pre urine w post urine r = 068
Amalgams w pre urine r = 026
Amalgams w whole blood r = 036
Amalgams with post urine 044
bull Clear documentation that
challenge testing is better00
100
200
300
400
500
600
0 10 20 30 40 50
Po
st
Uri
ne H
g u
gg
Number of amalgams
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
Uric Acid Indirect Measure of POPs
bull Poly-fluorinated hydrocarbons (PFOA and PFOS) associated
with increased serum uric acid
Lin CY et al Association among serum perfluoroalkyl chemicals glucose homeostasis and metabolic syndrome
in adolescents and adults Diabetes Care 2009 Apr32(4)702-7
Steenland K et al Association of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) with uric
acid among adults with elevated community exposure to PFOA Environ Health Perspect 2010 Feb118229-33
Steenland 2010 Open Access
ALT Indirect Measure of POPs
bull ALT (proxy marker) elevation in 104 (not including viral
hepatitis hemochromatosis or alcoholic liver disease) of
NHANES 03-04 subset
bull Risk of elevated ALT increased dose-dependently with
cadmium lead mercury and PCB exposure
bull 100 of individuals had detectable PCBs 925 mercury
and 996 had detectable lead
bull In 2005-08 prevalence of NAFLD in US was 11 a
growing cause of chronic liver disease
Cave M et al Polychlorinated biphenyls lead and mercury are associated with liver disease in American adults
NHANES 2003-2004 Environ Health Perspect 2010 Dec118(12)1735-42
Younossi ZM et al Changes in the prevalence of the most common causes of chronic liver diseases in the United
States from 1988 to 2008 Clin Gastroenterol Hepatol 2011 Jun9(6)524-530e1
Bilirubin as a Marker of POPs
bull Degree of serum bilirubin increase is prognostically significant in chronic liver dysfunction
bull Mono-ortho PCB TEQ values were found to be significantly positively associated with bilirubin (β=071 P=0008) following adjustment for multiple potential confounders
bull Bilirubin levels significantly correlated with PCBs -105-118-126 and -194
bull Smoking appears to be the biggest confounder
Dufour DR et al 2000 Diagnosis and monitoring of hepatic injury II Recommendations for use of laboratory
tests in screening diagnosis and monitoring Clin Chem 46 2050ndash68
Kumar J et al Persistent organic pollutants and liver dysfunction biomarkers in a population-based human sample
of men and women Environ Res 2014134251-256
Perf
luo
rin
ate
dP
OP
s a
nd
Co
mm
on
Blo
od
Tests
Gleason JA et al Associations of perfluorinated chemical serum concentrations and biomarkers of liver function and uric acid in the
US population (NHANES) 2007-2010 Environ Res 20151368-14
Liver Enzymes Reflect Toxic Load
bull AST ALT and GGT increase with body load of PCBs and OCPs
bull Some non-linear
bull Oxychlordanetop quartile
ALT 10
GGT 25
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
LDL-Cholesterol as Measure of POPs
bull 5-year prospective study to determine if POP levels predict future elevation in LDL-cholesterol
bull 598 subjects initially at age 70
bull Looked at 23 POPs
bull Best correlation with PCB 194
Penell J Lind L Salihovic S et al Persistent organic pollutants are related to change in circulating
lipid levels during a 5 year follow-up Environ Res 134(2014)190ndash197
oxLDL as Measure of POPs
bull 992 70-year old individuals (50 women)
bull Sum of PCBs showed strong significant positive associations with ox-LDL and significant negative associations with glutathione-related markers (GSSG and GSSGGSH)
bull A number of POPs (PCB-99 138 153 156 170 180 194 206 and 209) showed strong significant positive association with ox-LDL
Kumar J et al Influence of persistent organic pollutants on oxidative stress in population-based samples
Chemosphere 2014114303-309
Homocysteine is Increased by Pb amp Cd
Guallar E et al Confounding of the relation between homocysteine and peripheral arterial disease by lead cadmium and renal function Am J Epidemiol 2006 Apr 15163(8)700-8
Nutrient Deficiencies Accentuate
Effects of Lead on Homocysteine
bull Deficiencies in folate B6 or B12 make lead more toxic
Lee YM Et al Association of homocysteine levels with blood lead levels and micronutrients in the US general population J Prev Med Public Health 2012 Nov45(6)387-93
T4 amp T3 and PCBs
bull PCBs decrease T4 production
bull PCBs inhibit iodotyrosinedeiodinase activity
bull Study done in pregnant women which implies effect on fetus IQ
Kim S Park J Kim HJ et al Association between several persistent organic pollutants and thyroid hormone levels in serum among the pregnant women of Korea Environ Int 2013 Sep59442-8Shimizu R Yamaguchi M Uramaru N et al Structure-activity relationships of 44 halogenated compounds for iodotyrosinedeiodinase-inhibitory activity Toxicology 2013 Dec 6314(1)22-9
T4 amp T3 and PCBs
bull Not just humans being affected
bull Large study of dolphins shows exactly the same effects
Schwacke LH Zolman ES Balmer BC et al Anaemia hypothyroidism and immune suppression associated with polychlorinated biphenyl exposure in bottlenose dolphins (Tursiops truncatus) Proceed Royal Society B doi101098rspb20110665
8-OHdG
bull Oxidized nucleoside
bull Direct measure of DNA damage
bull Indirect measure of oxidative stress and toxin load
bull Correlates with
Multiple cancers
Mitochondrial damage
Rate of aging
Smoking
Several toxinsWalter Crinnion ldquoTotal Toxic Loadrdquo AANP 2015
8-OHdG Correlates with Pack-Years
of Smoking
Yano T et al Significance of the urinary 8-OHdG level as an oxidative stress marker in lung cancer patients Lung Cancer
2009 Jan63(1)111-4
8-OHdG Correlates
with Mercury
Chen C et al Increased oxidative DNA damage as assessed by urinary 8-hydroxy-2-deoxyguanosine
concentrations and serum redox status in persons exposed to mercury Clin Chem 2005 Apr51(4)759-67
Toxin Effects Worse with Aging
bull Thyroid function decreases with PFOA levels
bull But only after age 63
Shrestha S Bloom MS Yucel R et al Perfluoroalkyl substances and thyroid function in older adults Environ Int 2015 Feb75206-14
Insightful 23-Year Prospective Study
1 lt 50 there is no difference between those with the lowest and highest PCBs
2 In youngest group insulin production increases in response to toxin level As expected since blocking of
insulin receptor sites by PCBs
requires more insulin
3 That adaptive ability decreases with aging
4 At age 50 all the measures show very strong toxin-dose response
Cumulative damage impairs ability to adapt
Suarez-Lopez JR et al Persistent organic pollutants in young adults and changes in glucose related metabolism over a 23-year follow-up Environ Res 2015 Feb137485-94
Recommendations
High body toxic load
GGT gt 25
Uric acid gt 50 mgdl
ALT gt30 UL
Bilirubin gt08 mgdl
CBC lt 6000
Platelet lt 250000
Low T3 andor T4
Monitor Total Toxic Load
8-OHdG gt4
ldquoUnconventionalrdquo Laboratory Tests
bull Challenge testing
bull Hair analysis
bull Direct measures of solvents and POPs in blood urine adipose tissue
Evaluation of Metal Exposure ndash Provocation
bull Provocation ndash the use of a chelating agent ndash before urine collection often done clinically but several limitations
No ldquoofficialrdquo reference range for provoked urine
Most chelating agents do not extract metals from all tissues thus
does not necessarily represent total body burden
bull Example Brain is one of the main target organs for both elemental and organic
mercury yet agents do not chelate brain mercury
bull Despite limitations widely used and advocated by clinicians in part to see efficacy of chelating agent as a guide to treatment and based on empirical evidence
Rooney JP The role of thiols dithiols nutritional factors and interacting ligands in the toxicology of mercury
Toxicology 2007
Is Challenge Testing Valid
bull Poor correlations of standard tests for mercury
bull Unpublished research from corporate wellness project
bull Published amalgam number correlation
bull Published fish consumption correlation
What We Found In Canada
bull Deviations from the mean of 14 29 and 91 respectively
bull DMPS is spreading distribution suggesting that it is better at differentiating mercury body load
bull Some VERY high
Hg Assessment Correlations
bull Extensive measurements in 65 Whole blood Hg
Oral DMPS challenge
Amalgam surfaces
bull Correlations Whole blood w pre urine r = 040
Whole blood w post urine r = 057
Pre urine w post urine r = 068
Amalgams w pre urine r = 026
Amalgams w whole blood r = 036
Amalgams with post urine 044
bull Clear documentation that
challenge testing is better00
100
200
300
400
500
600
0 10 20 30 40 50
Po
st
Uri
ne H
g u
gg
Number of amalgams
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
ALT Indirect Measure of POPs
bull ALT (proxy marker) elevation in 104 (not including viral
hepatitis hemochromatosis or alcoholic liver disease) of
NHANES 03-04 subset
bull Risk of elevated ALT increased dose-dependently with
cadmium lead mercury and PCB exposure
bull 100 of individuals had detectable PCBs 925 mercury
and 996 had detectable lead
bull In 2005-08 prevalence of NAFLD in US was 11 a
growing cause of chronic liver disease
Cave M et al Polychlorinated biphenyls lead and mercury are associated with liver disease in American adults
NHANES 2003-2004 Environ Health Perspect 2010 Dec118(12)1735-42
Younossi ZM et al Changes in the prevalence of the most common causes of chronic liver diseases in the United
States from 1988 to 2008 Clin Gastroenterol Hepatol 2011 Jun9(6)524-530e1
Bilirubin as a Marker of POPs
bull Degree of serum bilirubin increase is prognostically significant in chronic liver dysfunction
bull Mono-ortho PCB TEQ values were found to be significantly positively associated with bilirubin (β=071 P=0008) following adjustment for multiple potential confounders
bull Bilirubin levels significantly correlated with PCBs -105-118-126 and -194
bull Smoking appears to be the biggest confounder
Dufour DR et al 2000 Diagnosis and monitoring of hepatic injury II Recommendations for use of laboratory
tests in screening diagnosis and monitoring Clin Chem 46 2050ndash68
Kumar J et al Persistent organic pollutants and liver dysfunction biomarkers in a population-based human sample
of men and women Environ Res 2014134251-256
Perf
luo
rin
ate
dP
OP
s a
nd
Co
mm
on
Blo
od
Tests
Gleason JA et al Associations of perfluorinated chemical serum concentrations and biomarkers of liver function and uric acid in the
US population (NHANES) 2007-2010 Environ Res 20151368-14
Liver Enzymes Reflect Toxic Load
bull AST ALT and GGT increase with body load of PCBs and OCPs
bull Some non-linear
bull Oxychlordanetop quartile
ALT 10
GGT 25
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
LDL-Cholesterol as Measure of POPs
bull 5-year prospective study to determine if POP levels predict future elevation in LDL-cholesterol
bull 598 subjects initially at age 70
bull Looked at 23 POPs
bull Best correlation with PCB 194
Penell J Lind L Salihovic S et al Persistent organic pollutants are related to change in circulating
lipid levels during a 5 year follow-up Environ Res 134(2014)190ndash197
oxLDL as Measure of POPs
bull 992 70-year old individuals (50 women)
bull Sum of PCBs showed strong significant positive associations with ox-LDL and significant negative associations with glutathione-related markers (GSSG and GSSGGSH)
bull A number of POPs (PCB-99 138 153 156 170 180 194 206 and 209) showed strong significant positive association with ox-LDL
Kumar J et al Influence of persistent organic pollutants on oxidative stress in population-based samples
Chemosphere 2014114303-309
Homocysteine is Increased by Pb amp Cd
Guallar E et al Confounding of the relation between homocysteine and peripheral arterial disease by lead cadmium and renal function Am J Epidemiol 2006 Apr 15163(8)700-8
Nutrient Deficiencies Accentuate
Effects of Lead on Homocysteine
bull Deficiencies in folate B6 or B12 make lead more toxic
Lee YM Et al Association of homocysteine levels with blood lead levels and micronutrients in the US general population J Prev Med Public Health 2012 Nov45(6)387-93
T4 amp T3 and PCBs
bull PCBs decrease T4 production
bull PCBs inhibit iodotyrosinedeiodinase activity
bull Study done in pregnant women which implies effect on fetus IQ
Kim S Park J Kim HJ et al Association between several persistent organic pollutants and thyroid hormone levels in serum among the pregnant women of Korea Environ Int 2013 Sep59442-8Shimizu R Yamaguchi M Uramaru N et al Structure-activity relationships of 44 halogenated compounds for iodotyrosinedeiodinase-inhibitory activity Toxicology 2013 Dec 6314(1)22-9
T4 amp T3 and PCBs
bull Not just humans being affected
bull Large study of dolphins shows exactly the same effects
Schwacke LH Zolman ES Balmer BC et al Anaemia hypothyroidism and immune suppression associated with polychlorinated biphenyl exposure in bottlenose dolphins (Tursiops truncatus) Proceed Royal Society B doi101098rspb20110665
8-OHdG
bull Oxidized nucleoside
bull Direct measure of DNA damage
bull Indirect measure of oxidative stress and toxin load
bull Correlates with
Multiple cancers
Mitochondrial damage
Rate of aging
Smoking
Several toxinsWalter Crinnion ldquoTotal Toxic Loadrdquo AANP 2015
8-OHdG Correlates with Pack-Years
of Smoking
Yano T et al Significance of the urinary 8-OHdG level as an oxidative stress marker in lung cancer patients Lung Cancer
2009 Jan63(1)111-4
8-OHdG Correlates
with Mercury
Chen C et al Increased oxidative DNA damage as assessed by urinary 8-hydroxy-2-deoxyguanosine
concentrations and serum redox status in persons exposed to mercury Clin Chem 2005 Apr51(4)759-67
Toxin Effects Worse with Aging
bull Thyroid function decreases with PFOA levels
bull But only after age 63
Shrestha S Bloom MS Yucel R et al Perfluoroalkyl substances and thyroid function in older adults Environ Int 2015 Feb75206-14
Insightful 23-Year Prospective Study
1 lt 50 there is no difference between those with the lowest and highest PCBs
2 In youngest group insulin production increases in response to toxin level As expected since blocking of
insulin receptor sites by PCBs
requires more insulin
3 That adaptive ability decreases with aging
4 At age 50 all the measures show very strong toxin-dose response
Cumulative damage impairs ability to adapt
Suarez-Lopez JR et al Persistent organic pollutants in young adults and changes in glucose related metabolism over a 23-year follow-up Environ Res 2015 Feb137485-94
Recommendations
High body toxic load
GGT gt 25
Uric acid gt 50 mgdl
ALT gt30 UL
Bilirubin gt08 mgdl
CBC lt 6000
Platelet lt 250000
Low T3 andor T4
Monitor Total Toxic Load
8-OHdG gt4
ldquoUnconventionalrdquo Laboratory Tests
bull Challenge testing
bull Hair analysis
bull Direct measures of solvents and POPs in blood urine adipose tissue
Evaluation of Metal Exposure ndash Provocation
bull Provocation ndash the use of a chelating agent ndash before urine collection often done clinically but several limitations
No ldquoofficialrdquo reference range for provoked urine
Most chelating agents do not extract metals from all tissues thus
does not necessarily represent total body burden
bull Example Brain is one of the main target organs for both elemental and organic
mercury yet agents do not chelate brain mercury
bull Despite limitations widely used and advocated by clinicians in part to see efficacy of chelating agent as a guide to treatment and based on empirical evidence
Rooney JP The role of thiols dithiols nutritional factors and interacting ligands in the toxicology of mercury
Toxicology 2007
Is Challenge Testing Valid
bull Poor correlations of standard tests for mercury
bull Unpublished research from corporate wellness project
bull Published amalgam number correlation
bull Published fish consumption correlation
What We Found In Canada
bull Deviations from the mean of 14 29 and 91 respectively
bull DMPS is spreading distribution suggesting that it is better at differentiating mercury body load
bull Some VERY high
Hg Assessment Correlations
bull Extensive measurements in 65 Whole blood Hg
Oral DMPS challenge
Amalgam surfaces
bull Correlations Whole blood w pre urine r = 040
Whole blood w post urine r = 057
Pre urine w post urine r = 068
Amalgams w pre urine r = 026
Amalgams w whole blood r = 036
Amalgams with post urine 044
bull Clear documentation that
challenge testing is better00
100
200
300
400
500
600
0 10 20 30 40 50
Po
st
Uri
ne H
g u
gg
Number of amalgams
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
Bilirubin as a Marker of POPs
bull Degree of serum bilirubin increase is prognostically significant in chronic liver dysfunction
bull Mono-ortho PCB TEQ values were found to be significantly positively associated with bilirubin (β=071 P=0008) following adjustment for multiple potential confounders
bull Bilirubin levels significantly correlated with PCBs -105-118-126 and -194
bull Smoking appears to be the biggest confounder
Dufour DR et al 2000 Diagnosis and monitoring of hepatic injury II Recommendations for use of laboratory
tests in screening diagnosis and monitoring Clin Chem 46 2050ndash68
Kumar J et al Persistent organic pollutants and liver dysfunction biomarkers in a population-based human sample
of men and women Environ Res 2014134251-256
Perf
luo
rin
ate
dP
OP
s a
nd
Co
mm
on
Blo
od
Tests
Gleason JA et al Associations of perfluorinated chemical serum concentrations and biomarkers of liver function and uric acid in the
US population (NHANES) 2007-2010 Environ Res 20151368-14
Liver Enzymes Reflect Toxic Load
bull AST ALT and GGT increase with body load of PCBs and OCPs
bull Some non-linear
bull Oxychlordanetop quartile
ALT 10
GGT 25
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
LDL-Cholesterol as Measure of POPs
bull 5-year prospective study to determine if POP levels predict future elevation in LDL-cholesterol
bull 598 subjects initially at age 70
bull Looked at 23 POPs
bull Best correlation with PCB 194
Penell J Lind L Salihovic S et al Persistent organic pollutants are related to change in circulating
lipid levels during a 5 year follow-up Environ Res 134(2014)190ndash197
oxLDL as Measure of POPs
bull 992 70-year old individuals (50 women)
bull Sum of PCBs showed strong significant positive associations with ox-LDL and significant negative associations with glutathione-related markers (GSSG and GSSGGSH)
bull A number of POPs (PCB-99 138 153 156 170 180 194 206 and 209) showed strong significant positive association with ox-LDL
Kumar J et al Influence of persistent organic pollutants on oxidative stress in population-based samples
Chemosphere 2014114303-309
Homocysteine is Increased by Pb amp Cd
Guallar E et al Confounding of the relation between homocysteine and peripheral arterial disease by lead cadmium and renal function Am J Epidemiol 2006 Apr 15163(8)700-8
Nutrient Deficiencies Accentuate
Effects of Lead on Homocysteine
bull Deficiencies in folate B6 or B12 make lead more toxic
Lee YM Et al Association of homocysteine levels with blood lead levels and micronutrients in the US general population J Prev Med Public Health 2012 Nov45(6)387-93
T4 amp T3 and PCBs
bull PCBs decrease T4 production
bull PCBs inhibit iodotyrosinedeiodinase activity
bull Study done in pregnant women which implies effect on fetus IQ
Kim S Park J Kim HJ et al Association between several persistent organic pollutants and thyroid hormone levels in serum among the pregnant women of Korea Environ Int 2013 Sep59442-8Shimizu R Yamaguchi M Uramaru N et al Structure-activity relationships of 44 halogenated compounds for iodotyrosinedeiodinase-inhibitory activity Toxicology 2013 Dec 6314(1)22-9
T4 amp T3 and PCBs
bull Not just humans being affected
bull Large study of dolphins shows exactly the same effects
Schwacke LH Zolman ES Balmer BC et al Anaemia hypothyroidism and immune suppression associated with polychlorinated biphenyl exposure in bottlenose dolphins (Tursiops truncatus) Proceed Royal Society B doi101098rspb20110665
8-OHdG
bull Oxidized nucleoside
bull Direct measure of DNA damage
bull Indirect measure of oxidative stress and toxin load
bull Correlates with
Multiple cancers
Mitochondrial damage
Rate of aging
Smoking
Several toxinsWalter Crinnion ldquoTotal Toxic Loadrdquo AANP 2015
8-OHdG Correlates with Pack-Years
of Smoking
Yano T et al Significance of the urinary 8-OHdG level as an oxidative stress marker in lung cancer patients Lung Cancer
2009 Jan63(1)111-4
8-OHdG Correlates
with Mercury
Chen C et al Increased oxidative DNA damage as assessed by urinary 8-hydroxy-2-deoxyguanosine
concentrations and serum redox status in persons exposed to mercury Clin Chem 2005 Apr51(4)759-67
Toxin Effects Worse with Aging
bull Thyroid function decreases with PFOA levels
bull But only after age 63
Shrestha S Bloom MS Yucel R et al Perfluoroalkyl substances and thyroid function in older adults Environ Int 2015 Feb75206-14
Insightful 23-Year Prospective Study
1 lt 50 there is no difference between those with the lowest and highest PCBs
2 In youngest group insulin production increases in response to toxin level As expected since blocking of
insulin receptor sites by PCBs
requires more insulin
3 That adaptive ability decreases with aging
4 At age 50 all the measures show very strong toxin-dose response
Cumulative damage impairs ability to adapt
Suarez-Lopez JR et al Persistent organic pollutants in young adults and changes in glucose related metabolism over a 23-year follow-up Environ Res 2015 Feb137485-94
Recommendations
High body toxic load
GGT gt 25
Uric acid gt 50 mgdl
ALT gt30 UL
Bilirubin gt08 mgdl
CBC lt 6000
Platelet lt 250000
Low T3 andor T4
Monitor Total Toxic Load
8-OHdG gt4
ldquoUnconventionalrdquo Laboratory Tests
bull Challenge testing
bull Hair analysis
bull Direct measures of solvents and POPs in blood urine adipose tissue
Evaluation of Metal Exposure ndash Provocation
bull Provocation ndash the use of a chelating agent ndash before urine collection often done clinically but several limitations
No ldquoofficialrdquo reference range for provoked urine
Most chelating agents do not extract metals from all tissues thus
does not necessarily represent total body burden
bull Example Brain is one of the main target organs for both elemental and organic
mercury yet agents do not chelate brain mercury
bull Despite limitations widely used and advocated by clinicians in part to see efficacy of chelating agent as a guide to treatment and based on empirical evidence
Rooney JP The role of thiols dithiols nutritional factors and interacting ligands in the toxicology of mercury
Toxicology 2007
Is Challenge Testing Valid
bull Poor correlations of standard tests for mercury
bull Unpublished research from corporate wellness project
bull Published amalgam number correlation
bull Published fish consumption correlation
What We Found In Canada
bull Deviations from the mean of 14 29 and 91 respectively
bull DMPS is spreading distribution suggesting that it is better at differentiating mercury body load
bull Some VERY high
Hg Assessment Correlations
bull Extensive measurements in 65 Whole blood Hg
Oral DMPS challenge
Amalgam surfaces
bull Correlations Whole blood w pre urine r = 040
Whole blood w post urine r = 057
Pre urine w post urine r = 068
Amalgams w pre urine r = 026
Amalgams w whole blood r = 036
Amalgams with post urine 044
bull Clear documentation that
challenge testing is better00
100
200
300
400
500
600
0 10 20 30 40 50
Po
st
Uri
ne H
g u
gg
Number of amalgams
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
Perf
luo
rin
ate
dP
OP
s a
nd
Co
mm
on
Blo
od
Tests
Gleason JA et al Associations of perfluorinated chemical serum concentrations and biomarkers of liver function and uric acid in the
US population (NHANES) 2007-2010 Environ Res 20151368-14
Liver Enzymes Reflect Toxic Load
bull AST ALT and GGT increase with body load of PCBs and OCPs
bull Some non-linear
bull Oxychlordanetop quartile
ALT 10
GGT 25
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
LDL-Cholesterol as Measure of POPs
bull 5-year prospective study to determine if POP levels predict future elevation in LDL-cholesterol
bull 598 subjects initially at age 70
bull Looked at 23 POPs
bull Best correlation with PCB 194
Penell J Lind L Salihovic S et al Persistent organic pollutants are related to change in circulating
lipid levels during a 5 year follow-up Environ Res 134(2014)190ndash197
oxLDL as Measure of POPs
bull 992 70-year old individuals (50 women)
bull Sum of PCBs showed strong significant positive associations with ox-LDL and significant negative associations with glutathione-related markers (GSSG and GSSGGSH)
bull A number of POPs (PCB-99 138 153 156 170 180 194 206 and 209) showed strong significant positive association with ox-LDL
Kumar J et al Influence of persistent organic pollutants on oxidative stress in population-based samples
Chemosphere 2014114303-309
Homocysteine is Increased by Pb amp Cd
Guallar E et al Confounding of the relation between homocysteine and peripheral arterial disease by lead cadmium and renal function Am J Epidemiol 2006 Apr 15163(8)700-8
Nutrient Deficiencies Accentuate
Effects of Lead on Homocysteine
bull Deficiencies in folate B6 or B12 make lead more toxic
Lee YM Et al Association of homocysteine levels with blood lead levels and micronutrients in the US general population J Prev Med Public Health 2012 Nov45(6)387-93
T4 amp T3 and PCBs
bull PCBs decrease T4 production
bull PCBs inhibit iodotyrosinedeiodinase activity
bull Study done in pregnant women which implies effect on fetus IQ
Kim S Park J Kim HJ et al Association between several persistent organic pollutants and thyroid hormone levels in serum among the pregnant women of Korea Environ Int 2013 Sep59442-8Shimizu R Yamaguchi M Uramaru N et al Structure-activity relationships of 44 halogenated compounds for iodotyrosinedeiodinase-inhibitory activity Toxicology 2013 Dec 6314(1)22-9
T4 amp T3 and PCBs
bull Not just humans being affected
bull Large study of dolphins shows exactly the same effects
Schwacke LH Zolman ES Balmer BC et al Anaemia hypothyroidism and immune suppression associated with polychlorinated biphenyl exposure in bottlenose dolphins (Tursiops truncatus) Proceed Royal Society B doi101098rspb20110665
8-OHdG
bull Oxidized nucleoside
bull Direct measure of DNA damage
bull Indirect measure of oxidative stress and toxin load
bull Correlates with
Multiple cancers
Mitochondrial damage
Rate of aging
Smoking
Several toxinsWalter Crinnion ldquoTotal Toxic Loadrdquo AANP 2015
8-OHdG Correlates with Pack-Years
of Smoking
Yano T et al Significance of the urinary 8-OHdG level as an oxidative stress marker in lung cancer patients Lung Cancer
2009 Jan63(1)111-4
8-OHdG Correlates
with Mercury
Chen C et al Increased oxidative DNA damage as assessed by urinary 8-hydroxy-2-deoxyguanosine
concentrations and serum redox status in persons exposed to mercury Clin Chem 2005 Apr51(4)759-67
Toxin Effects Worse with Aging
bull Thyroid function decreases with PFOA levels
bull But only after age 63
Shrestha S Bloom MS Yucel R et al Perfluoroalkyl substances and thyroid function in older adults Environ Int 2015 Feb75206-14
Insightful 23-Year Prospective Study
1 lt 50 there is no difference between those with the lowest and highest PCBs
2 In youngest group insulin production increases in response to toxin level As expected since blocking of
insulin receptor sites by PCBs
requires more insulin
3 That adaptive ability decreases with aging
4 At age 50 all the measures show very strong toxin-dose response
Cumulative damage impairs ability to adapt
Suarez-Lopez JR et al Persistent organic pollutants in young adults and changes in glucose related metabolism over a 23-year follow-up Environ Res 2015 Feb137485-94
Recommendations
High body toxic load
GGT gt 25
Uric acid gt 50 mgdl
ALT gt30 UL
Bilirubin gt08 mgdl
CBC lt 6000
Platelet lt 250000
Low T3 andor T4
Monitor Total Toxic Load
8-OHdG gt4
ldquoUnconventionalrdquo Laboratory Tests
bull Challenge testing
bull Hair analysis
bull Direct measures of solvents and POPs in blood urine adipose tissue
Evaluation of Metal Exposure ndash Provocation
bull Provocation ndash the use of a chelating agent ndash before urine collection often done clinically but several limitations
No ldquoofficialrdquo reference range for provoked urine
Most chelating agents do not extract metals from all tissues thus
does not necessarily represent total body burden
bull Example Brain is one of the main target organs for both elemental and organic
mercury yet agents do not chelate brain mercury
bull Despite limitations widely used and advocated by clinicians in part to see efficacy of chelating agent as a guide to treatment and based on empirical evidence
Rooney JP The role of thiols dithiols nutritional factors and interacting ligands in the toxicology of mercury
Toxicology 2007
Is Challenge Testing Valid
bull Poor correlations of standard tests for mercury
bull Unpublished research from corporate wellness project
bull Published amalgam number correlation
bull Published fish consumption correlation
What We Found In Canada
bull Deviations from the mean of 14 29 and 91 respectively
bull DMPS is spreading distribution suggesting that it is better at differentiating mercury body load
bull Some VERY high
Hg Assessment Correlations
bull Extensive measurements in 65 Whole blood Hg
Oral DMPS challenge
Amalgam surfaces
bull Correlations Whole blood w pre urine r = 040
Whole blood w post urine r = 057
Pre urine w post urine r = 068
Amalgams w pre urine r = 026
Amalgams w whole blood r = 036
Amalgams with post urine 044
bull Clear documentation that
challenge testing is better00
100
200
300
400
500
600
0 10 20 30 40 50
Po
st
Uri
ne H
g u
gg
Number of amalgams
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
Liver Enzymes Reflect Toxic Load
bull AST ALT and GGT increase with body load of PCBs and OCPs
bull Some non-linear
bull Oxychlordanetop quartile
ALT 10
GGT 25
Serdar B et al Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides
(OCPs) on immune cells and blood biochemistry measures a cross-sectional assessment of the NHANES 2003-
2004 data Environ Health 201413114
LDL-Cholesterol as Measure of POPs
bull 5-year prospective study to determine if POP levels predict future elevation in LDL-cholesterol
bull 598 subjects initially at age 70
bull Looked at 23 POPs
bull Best correlation with PCB 194
Penell J Lind L Salihovic S et al Persistent organic pollutants are related to change in circulating
lipid levels during a 5 year follow-up Environ Res 134(2014)190ndash197
oxLDL as Measure of POPs
bull 992 70-year old individuals (50 women)
bull Sum of PCBs showed strong significant positive associations with ox-LDL and significant negative associations with glutathione-related markers (GSSG and GSSGGSH)
bull A number of POPs (PCB-99 138 153 156 170 180 194 206 and 209) showed strong significant positive association with ox-LDL
Kumar J et al Influence of persistent organic pollutants on oxidative stress in population-based samples
Chemosphere 2014114303-309
Homocysteine is Increased by Pb amp Cd
Guallar E et al Confounding of the relation between homocysteine and peripheral arterial disease by lead cadmium and renal function Am J Epidemiol 2006 Apr 15163(8)700-8
Nutrient Deficiencies Accentuate
Effects of Lead on Homocysteine
bull Deficiencies in folate B6 or B12 make lead more toxic
Lee YM Et al Association of homocysteine levels with blood lead levels and micronutrients in the US general population J Prev Med Public Health 2012 Nov45(6)387-93
T4 amp T3 and PCBs
bull PCBs decrease T4 production
bull PCBs inhibit iodotyrosinedeiodinase activity
bull Study done in pregnant women which implies effect on fetus IQ
Kim S Park J Kim HJ et al Association between several persistent organic pollutants and thyroid hormone levels in serum among the pregnant women of Korea Environ Int 2013 Sep59442-8Shimizu R Yamaguchi M Uramaru N et al Structure-activity relationships of 44 halogenated compounds for iodotyrosinedeiodinase-inhibitory activity Toxicology 2013 Dec 6314(1)22-9
T4 amp T3 and PCBs
bull Not just humans being affected
bull Large study of dolphins shows exactly the same effects
Schwacke LH Zolman ES Balmer BC et al Anaemia hypothyroidism and immune suppression associated with polychlorinated biphenyl exposure in bottlenose dolphins (Tursiops truncatus) Proceed Royal Society B doi101098rspb20110665
8-OHdG
bull Oxidized nucleoside
bull Direct measure of DNA damage
bull Indirect measure of oxidative stress and toxin load
bull Correlates with
Multiple cancers
Mitochondrial damage
Rate of aging
Smoking
Several toxinsWalter Crinnion ldquoTotal Toxic Loadrdquo AANP 2015
8-OHdG Correlates with Pack-Years
of Smoking
Yano T et al Significance of the urinary 8-OHdG level as an oxidative stress marker in lung cancer patients Lung Cancer
2009 Jan63(1)111-4
8-OHdG Correlates
with Mercury
Chen C et al Increased oxidative DNA damage as assessed by urinary 8-hydroxy-2-deoxyguanosine
concentrations and serum redox status in persons exposed to mercury Clin Chem 2005 Apr51(4)759-67
Toxin Effects Worse with Aging
bull Thyroid function decreases with PFOA levels
bull But only after age 63
Shrestha S Bloom MS Yucel R et al Perfluoroalkyl substances and thyroid function in older adults Environ Int 2015 Feb75206-14
Insightful 23-Year Prospective Study
1 lt 50 there is no difference between those with the lowest and highest PCBs
2 In youngest group insulin production increases in response to toxin level As expected since blocking of
insulin receptor sites by PCBs
requires more insulin
3 That adaptive ability decreases with aging
4 At age 50 all the measures show very strong toxin-dose response
Cumulative damage impairs ability to adapt
Suarez-Lopez JR et al Persistent organic pollutants in young adults and changes in glucose related metabolism over a 23-year follow-up Environ Res 2015 Feb137485-94
Recommendations
High body toxic load
GGT gt 25
Uric acid gt 50 mgdl
ALT gt30 UL
Bilirubin gt08 mgdl
CBC lt 6000
Platelet lt 250000
Low T3 andor T4
Monitor Total Toxic Load
8-OHdG gt4
ldquoUnconventionalrdquo Laboratory Tests
bull Challenge testing
bull Hair analysis
bull Direct measures of solvents and POPs in blood urine adipose tissue
Evaluation of Metal Exposure ndash Provocation
bull Provocation ndash the use of a chelating agent ndash before urine collection often done clinically but several limitations
No ldquoofficialrdquo reference range for provoked urine
Most chelating agents do not extract metals from all tissues thus
does not necessarily represent total body burden
bull Example Brain is one of the main target organs for both elemental and organic
mercury yet agents do not chelate brain mercury
bull Despite limitations widely used and advocated by clinicians in part to see efficacy of chelating agent as a guide to treatment and based on empirical evidence
Rooney JP The role of thiols dithiols nutritional factors and interacting ligands in the toxicology of mercury
Toxicology 2007
Is Challenge Testing Valid
bull Poor correlations of standard tests for mercury
bull Unpublished research from corporate wellness project
bull Published amalgam number correlation
bull Published fish consumption correlation
What We Found In Canada
bull Deviations from the mean of 14 29 and 91 respectively
bull DMPS is spreading distribution suggesting that it is better at differentiating mercury body load
bull Some VERY high
Hg Assessment Correlations
bull Extensive measurements in 65 Whole blood Hg
Oral DMPS challenge
Amalgam surfaces
bull Correlations Whole blood w pre urine r = 040
Whole blood w post urine r = 057
Pre urine w post urine r = 068
Amalgams w pre urine r = 026
Amalgams w whole blood r = 036
Amalgams with post urine 044
bull Clear documentation that
challenge testing is better00
100
200
300
400
500
600
0 10 20 30 40 50
Po
st
Uri
ne H
g u
gg
Number of amalgams
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
LDL-Cholesterol as Measure of POPs
bull 5-year prospective study to determine if POP levels predict future elevation in LDL-cholesterol
bull 598 subjects initially at age 70
bull Looked at 23 POPs
bull Best correlation with PCB 194
Penell J Lind L Salihovic S et al Persistent organic pollutants are related to change in circulating
lipid levels during a 5 year follow-up Environ Res 134(2014)190ndash197
oxLDL as Measure of POPs
bull 992 70-year old individuals (50 women)
bull Sum of PCBs showed strong significant positive associations with ox-LDL and significant negative associations with glutathione-related markers (GSSG and GSSGGSH)
bull A number of POPs (PCB-99 138 153 156 170 180 194 206 and 209) showed strong significant positive association with ox-LDL
Kumar J et al Influence of persistent organic pollutants on oxidative stress in population-based samples
Chemosphere 2014114303-309
Homocysteine is Increased by Pb amp Cd
Guallar E et al Confounding of the relation between homocysteine and peripheral arterial disease by lead cadmium and renal function Am J Epidemiol 2006 Apr 15163(8)700-8
Nutrient Deficiencies Accentuate
Effects of Lead on Homocysteine
bull Deficiencies in folate B6 or B12 make lead more toxic
Lee YM Et al Association of homocysteine levels with blood lead levels and micronutrients in the US general population J Prev Med Public Health 2012 Nov45(6)387-93
T4 amp T3 and PCBs
bull PCBs decrease T4 production
bull PCBs inhibit iodotyrosinedeiodinase activity
bull Study done in pregnant women which implies effect on fetus IQ
Kim S Park J Kim HJ et al Association between several persistent organic pollutants and thyroid hormone levels in serum among the pregnant women of Korea Environ Int 2013 Sep59442-8Shimizu R Yamaguchi M Uramaru N et al Structure-activity relationships of 44 halogenated compounds for iodotyrosinedeiodinase-inhibitory activity Toxicology 2013 Dec 6314(1)22-9
T4 amp T3 and PCBs
bull Not just humans being affected
bull Large study of dolphins shows exactly the same effects
Schwacke LH Zolman ES Balmer BC et al Anaemia hypothyroidism and immune suppression associated with polychlorinated biphenyl exposure in bottlenose dolphins (Tursiops truncatus) Proceed Royal Society B doi101098rspb20110665
8-OHdG
bull Oxidized nucleoside
bull Direct measure of DNA damage
bull Indirect measure of oxidative stress and toxin load
bull Correlates with
Multiple cancers
Mitochondrial damage
Rate of aging
Smoking
Several toxinsWalter Crinnion ldquoTotal Toxic Loadrdquo AANP 2015
8-OHdG Correlates with Pack-Years
of Smoking
Yano T et al Significance of the urinary 8-OHdG level as an oxidative stress marker in lung cancer patients Lung Cancer
2009 Jan63(1)111-4
8-OHdG Correlates
with Mercury
Chen C et al Increased oxidative DNA damage as assessed by urinary 8-hydroxy-2-deoxyguanosine
concentrations and serum redox status in persons exposed to mercury Clin Chem 2005 Apr51(4)759-67
Toxin Effects Worse with Aging
bull Thyroid function decreases with PFOA levels
bull But only after age 63
Shrestha S Bloom MS Yucel R et al Perfluoroalkyl substances and thyroid function in older adults Environ Int 2015 Feb75206-14
Insightful 23-Year Prospective Study
1 lt 50 there is no difference between those with the lowest and highest PCBs
2 In youngest group insulin production increases in response to toxin level As expected since blocking of
insulin receptor sites by PCBs
requires more insulin
3 That adaptive ability decreases with aging
4 At age 50 all the measures show very strong toxin-dose response
Cumulative damage impairs ability to adapt
Suarez-Lopez JR et al Persistent organic pollutants in young adults and changes in glucose related metabolism over a 23-year follow-up Environ Res 2015 Feb137485-94
Recommendations
High body toxic load
GGT gt 25
Uric acid gt 50 mgdl
ALT gt30 UL
Bilirubin gt08 mgdl
CBC lt 6000
Platelet lt 250000
Low T3 andor T4
Monitor Total Toxic Load
8-OHdG gt4
ldquoUnconventionalrdquo Laboratory Tests
bull Challenge testing
bull Hair analysis
bull Direct measures of solvents and POPs in blood urine adipose tissue
Evaluation of Metal Exposure ndash Provocation
bull Provocation ndash the use of a chelating agent ndash before urine collection often done clinically but several limitations
No ldquoofficialrdquo reference range for provoked urine
Most chelating agents do not extract metals from all tissues thus
does not necessarily represent total body burden
bull Example Brain is one of the main target organs for both elemental and organic
mercury yet agents do not chelate brain mercury
bull Despite limitations widely used and advocated by clinicians in part to see efficacy of chelating agent as a guide to treatment and based on empirical evidence
Rooney JP The role of thiols dithiols nutritional factors and interacting ligands in the toxicology of mercury
Toxicology 2007
Is Challenge Testing Valid
bull Poor correlations of standard tests for mercury
bull Unpublished research from corporate wellness project
bull Published amalgam number correlation
bull Published fish consumption correlation
What We Found In Canada
bull Deviations from the mean of 14 29 and 91 respectively
bull DMPS is spreading distribution suggesting that it is better at differentiating mercury body load
bull Some VERY high
Hg Assessment Correlations
bull Extensive measurements in 65 Whole blood Hg
Oral DMPS challenge
Amalgam surfaces
bull Correlations Whole blood w pre urine r = 040
Whole blood w post urine r = 057
Pre urine w post urine r = 068
Amalgams w pre urine r = 026
Amalgams w whole blood r = 036
Amalgams with post urine 044
bull Clear documentation that
challenge testing is better00
100
200
300
400
500
600
0 10 20 30 40 50
Po
st
Uri
ne H
g u
gg
Number of amalgams
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
oxLDL as Measure of POPs
bull 992 70-year old individuals (50 women)
bull Sum of PCBs showed strong significant positive associations with ox-LDL and significant negative associations with glutathione-related markers (GSSG and GSSGGSH)
bull A number of POPs (PCB-99 138 153 156 170 180 194 206 and 209) showed strong significant positive association with ox-LDL
Kumar J et al Influence of persistent organic pollutants on oxidative stress in population-based samples
Chemosphere 2014114303-309
Homocysteine is Increased by Pb amp Cd
Guallar E et al Confounding of the relation between homocysteine and peripheral arterial disease by lead cadmium and renal function Am J Epidemiol 2006 Apr 15163(8)700-8
Nutrient Deficiencies Accentuate
Effects of Lead on Homocysteine
bull Deficiencies in folate B6 or B12 make lead more toxic
Lee YM Et al Association of homocysteine levels with blood lead levels and micronutrients in the US general population J Prev Med Public Health 2012 Nov45(6)387-93
T4 amp T3 and PCBs
bull PCBs decrease T4 production
bull PCBs inhibit iodotyrosinedeiodinase activity
bull Study done in pregnant women which implies effect on fetus IQ
Kim S Park J Kim HJ et al Association between several persistent organic pollutants and thyroid hormone levels in serum among the pregnant women of Korea Environ Int 2013 Sep59442-8Shimizu R Yamaguchi M Uramaru N et al Structure-activity relationships of 44 halogenated compounds for iodotyrosinedeiodinase-inhibitory activity Toxicology 2013 Dec 6314(1)22-9
T4 amp T3 and PCBs
bull Not just humans being affected
bull Large study of dolphins shows exactly the same effects
Schwacke LH Zolman ES Balmer BC et al Anaemia hypothyroidism and immune suppression associated with polychlorinated biphenyl exposure in bottlenose dolphins (Tursiops truncatus) Proceed Royal Society B doi101098rspb20110665
8-OHdG
bull Oxidized nucleoside
bull Direct measure of DNA damage
bull Indirect measure of oxidative stress and toxin load
bull Correlates with
Multiple cancers
Mitochondrial damage
Rate of aging
Smoking
Several toxinsWalter Crinnion ldquoTotal Toxic Loadrdquo AANP 2015
8-OHdG Correlates with Pack-Years
of Smoking
Yano T et al Significance of the urinary 8-OHdG level as an oxidative stress marker in lung cancer patients Lung Cancer
2009 Jan63(1)111-4
8-OHdG Correlates
with Mercury
Chen C et al Increased oxidative DNA damage as assessed by urinary 8-hydroxy-2-deoxyguanosine
concentrations and serum redox status in persons exposed to mercury Clin Chem 2005 Apr51(4)759-67
Toxin Effects Worse with Aging
bull Thyroid function decreases with PFOA levels
bull But only after age 63
Shrestha S Bloom MS Yucel R et al Perfluoroalkyl substances and thyroid function in older adults Environ Int 2015 Feb75206-14
Insightful 23-Year Prospective Study
1 lt 50 there is no difference between those with the lowest and highest PCBs
2 In youngest group insulin production increases in response to toxin level As expected since blocking of
insulin receptor sites by PCBs
requires more insulin
3 That adaptive ability decreases with aging
4 At age 50 all the measures show very strong toxin-dose response
Cumulative damage impairs ability to adapt
Suarez-Lopez JR et al Persistent organic pollutants in young adults and changes in glucose related metabolism over a 23-year follow-up Environ Res 2015 Feb137485-94
Recommendations
High body toxic load
GGT gt 25
Uric acid gt 50 mgdl
ALT gt30 UL
Bilirubin gt08 mgdl
CBC lt 6000
Platelet lt 250000
Low T3 andor T4
Monitor Total Toxic Load
8-OHdG gt4
ldquoUnconventionalrdquo Laboratory Tests
bull Challenge testing
bull Hair analysis
bull Direct measures of solvents and POPs in blood urine adipose tissue
Evaluation of Metal Exposure ndash Provocation
bull Provocation ndash the use of a chelating agent ndash before urine collection often done clinically but several limitations
No ldquoofficialrdquo reference range for provoked urine
Most chelating agents do not extract metals from all tissues thus
does not necessarily represent total body burden
bull Example Brain is one of the main target organs for both elemental and organic
mercury yet agents do not chelate brain mercury
bull Despite limitations widely used and advocated by clinicians in part to see efficacy of chelating agent as a guide to treatment and based on empirical evidence
Rooney JP The role of thiols dithiols nutritional factors and interacting ligands in the toxicology of mercury
Toxicology 2007
Is Challenge Testing Valid
bull Poor correlations of standard tests for mercury
bull Unpublished research from corporate wellness project
bull Published amalgam number correlation
bull Published fish consumption correlation
What We Found In Canada
bull Deviations from the mean of 14 29 and 91 respectively
bull DMPS is spreading distribution suggesting that it is better at differentiating mercury body load
bull Some VERY high
Hg Assessment Correlations
bull Extensive measurements in 65 Whole blood Hg
Oral DMPS challenge
Amalgam surfaces
bull Correlations Whole blood w pre urine r = 040
Whole blood w post urine r = 057
Pre urine w post urine r = 068
Amalgams w pre urine r = 026
Amalgams w whole blood r = 036
Amalgams with post urine 044
bull Clear documentation that
challenge testing is better00
100
200
300
400
500
600
0 10 20 30 40 50
Po
st
Uri
ne H
g u
gg
Number of amalgams
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
Homocysteine is Increased by Pb amp Cd
Guallar E et al Confounding of the relation between homocysteine and peripheral arterial disease by lead cadmium and renal function Am J Epidemiol 2006 Apr 15163(8)700-8
Nutrient Deficiencies Accentuate
Effects of Lead on Homocysteine
bull Deficiencies in folate B6 or B12 make lead more toxic
Lee YM Et al Association of homocysteine levels with blood lead levels and micronutrients in the US general population J Prev Med Public Health 2012 Nov45(6)387-93
T4 amp T3 and PCBs
bull PCBs decrease T4 production
bull PCBs inhibit iodotyrosinedeiodinase activity
bull Study done in pregnant women which implies effect on fetus IQ
Kim S Park J Kim HJ et al Association between several persistent organic pollutants and thyroid hormone levels in serum among the pregnant women of Korea Environ Int 2013 Sep59442-8Shimizu R Yamaguchi M Uramaru N et al Structure-activity relationships of 44 halogenated compounds for iodotyrosinedeiodinase-inhibitory activity Toxicology 2013 Dec 6314(1)22-9
T4 amp T3 and PCBs
bull Not just humans being affected
bull Large study of dolphins shows exactly the same effects
Schwacke LH Zolman ES Balmer BC et al Anaemia hypothyroidism and immune suppression associated with polychlorinated biphenyl exposure in bottlenose dolphins (Tursiops truncatus) Proceed Royal Society B doi101098rspb20110665
8-OHdG
bull Oxidized nucleoside
bull Direct measure of DNA damage
bull Indirect measure of oxidative stress and toxin load
bull Correlates with
Multiple cancers
Mitochondrial damage
Rate of aging
Smoking
Several toxinsWalter Crinnion ldquoTotal Toxic Loadrdquo AANP 2015
8-OHdG Correlates with Pack-Years
of Smoking
Yano T et al Significance of the urinary 8-OHdG level as an oxidative stress marker in lung cancer patients Lung Cancer
2009 Jan63(1)111-4
8-OHdG Correlates
with Mercury
Chen C et al Increased oxidative DNA damage as assessed by urinary 8-hydroxy-2-deoxyguanosine
concentrations and serum redox status in persons exposed to mercury Clin Chem 2005 Apr51(4)759-67
Toxin Effects Worse with Aging
bull Thyroid function decreases with PFOA levels
bull But only after age 63
Shrestha S Bloom MS Yucel R et al Perfluoroalkyl substances and thyroid function in older adults Environ Int 2015 Feb75206-14
Insightful 23-Year Prospective Study
1 lt 50 there is no difference between those with the lowest and highest PCBs
2 In youngest group insulin production increases in response to toxin level As expected since blocking of
insulin receptor sites by PCBs
requires more insulin
3 That adaptive ability decreases with aging
4 At age 50 all the measures show very strong toxin-dose response
Cumulative damage impairs ability to adapt
Suarez-Lopez JR et al Persistent organic pollutants in young adults and changes in glucose related metabolism over a 23-year follow-up Environ Res 2015 Feb137485-94
Recommendations
High body toxic load
GGT gt 25
Uric acid gt 50 mgdl
ALT gt30 UL
Bilirubin gt08 mgdl
CBC lt 6000
Platelet lt 250000
Low T3 andor T4
Monitor Total Toxic Load
8-OHdG gt4
ldquoUnconventionalrdquo Laboratory Tests
bull Challenge testing
bull Hair analysis
bull Direct measures of solvents and POPs in blood urine adipose tissue
Evaluation of Metal Exposure ndash Provocation
bull Provocation ndash the use of a chelating agent ndash before urine collection often done clinically but several limitations
No ldquoofficialrdquo reference range for provoked urine
Most chelating agents do not extract metals from all tissues thus
does not necessarily represent total body burden
bull Example Brain is one of the main target organs for both elemental and organic
mercury yet agents do not chelate brain mercury
bull Despite limitations widely used and advocated by clinicians in part to see efficacy of chelating agent as a guide to treatment and based on empirical evidence
Rooney JP The role of thiols dithiols nutritional factors and interacting ligands in the toxicology of mercury
Toxicology 2007
Is Challenge Testing Valid
bull Poor correlations of standard tests for mercury
bull Unpublished research from corporate wellness project
bull Published amalgam number correlation
bull Published fish consumption correlation
What We Found In Canada
bull Deviations from the mean of 14 29 and 91 respectively
bull DMPS is spreading distribution suggesting that it is better at differentiating mercury body load
bull Some VERY high
Hg Assessment Correlations
bull Extensive measurements in 65 Whole blood Hg
Oral DMPS challenge
Amalgam surfaces
bull Correlations Whole blood w pre urine r = 040
Whole blood w post urine r = 057
Pre urine w post urine r = 068
Amalgams w pre urine r = 026
Amalgams w whole blood r = 036
Amalgams with post urine 044
bull Clear documentation that
challenge testing is better00
100
200
300
400
500
600
0 10 20 30 40 50
Po
st
Uri
ne H
g u
gg
Number of amalgams
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
Nutrient Deficiencies Accentuate
Effects of Lead on Homocysteine
bull Deficiencies in folate B6 or B12 make lead more toxic
Lee YM Et al Association of homocysteine levels with blood lead levels and micronutrients in the US general population J Prev Med Public Health 2012 Nov45(6)387-93
T4 amp T3 and PCBs
bull PCBs decrease T4 production
bull PCBs inhibit iodotyrosinedeiodinase activity
bull Study done in pregnant women which implies effect on fetus IQ
Kim S Park J Kim HJ et al Association between several persistent organic pollutants and thyroid hormone levels in serum among the pregnant women of Korea Environ Int 2013 Sep59442-8Shimizu R Yamaguchi M Uramaru N et al Structure-activity relationships of 44 halogenated compounds for iodotyrosinedeiodinase-inhibitory activity Toxicology 2013 Dec 6314(1)22-9
T4 amp T3 and PCBs
bull Not just humans being affected
bull Large study of dolphins shows exactly the same effects
Schwacke LH Zolman ES Balmer BC et al Anaemia hypothyroidism and immune suppression associated with polychlorinated biphenyl exposure in bottlenose dolphins (Tursiops truncatus) Proceed Royal Society B doi101098rspb20110665
8-OHdG
bull Oxidized nucleoside
bull Direct measure of DNA damage
bull Indirect measure of oxidative stress and toxin load
bull Correlates with
Multiple cancers
Mitochondrial damage
Rate of aging
Smoking
Several toxinsWalter Crinnion ldquoTotal Toxic Loadrdquo AANP 2015
8-OHdG Correlates with Pack-Years
of Smoking
Yano T et al Significance of the urinary 8-OHdG level as an oxidative stress marker in lung cancer patients Lung Cancer
2009 Jan63(1)111-4
8-OHdG Correlates
with Mercury
Chen C et al Increased oxidative DNA damage as assessed by urinary 8-hydroxy-2-deoxyguanosine
concentrations and serum redox status in persons exposed to mercury Clin Chem 2005 Apr51(4)759-67
Toxin Effects Worse with Aging
bull Thyroid function decreases with PFOA levels
bull But only after age 63
Shrestha S Bloom MS Yucel R et al Perfluoroalkyl substances and thyroid function in older adults Environ Int 2015 Feb75206-14
Insightful 23-Year Prospective Study
1 lt 50 there is no difference between those with the lowest and highest PCBs
2 In youngest group insulin production increases in response to toxin level As expected since blocking of
insulin receptor sites by PCBs
requires more insulin
3 That adaptive ability decreases with aging
4 At age 50 all the measures show very strong toxin-dose response
Cumulative damage impairs ability to adapt
Suarez-Lopez JR et al Persistent organic pollutants in young adults and changes in glucose related metabolism over a 23-year follow-up Environ Res 2015 Feb137485-94
Recommendations
High body toxic load
GGT gt 25
Uric acid gt 50 mgdl
ALT gt30 UL
Bilirubin gt08 mgdl
CBC lt 6000
Platelet lt 250000
Low T3 andor T4
Monitor Total Toxic Load
8-OHdG gt4
ldquoUnconventionalrdquo Laboratory Tests
bull Challenge testing
bull Hair analysis
bull Direct measures of solvents and POPs in blood urine adipose tissue
Evaluation of Metal Exposure ndash Provocation
bull Provocation ndash the use of a chelating agent ndash before urine collection often done clinically but several limitations
No ldquoofficialrdquo reference range for provoked urine
Most chelating agents do not extract metals from all tissues thus
does not necessarily represent total body burden
bull Example Brain is one of the main target organs for both elemental and organic
mercury yet agents do not chelate brain mercury
bull Despite limitations widely used and advocated by clinicians in part to see efficacy of chelating agent as a guide to treatment and based on empirical evidence
Rooney JP The role of thiols dithiols nutritional factors and interacting ligands in the toxicology of mercury
Toxicology 2007
Is Challenge Testing Valid
bull Poor correlations of standard tests for mercury
bull Unpublished research from corporate wellness project
bull Published amalgam number correlation
bull Published fish consumption correlation
What We Found In Canada
bull Deviations from the mean of 14 29 and 91 respectively
bull DMPS is spreading distribution suggesting that it is better at differentiating mercury body load
bull Some VERY high
Hg Assessment Correlations
bull Extensive measurements in 65 Whole blood Hg
Oral DMPS challenge
Amalgam surfaces
bull Correlations Whole blood w pre urine r = 040
Whole blood w post urine r = 057
Pre urine w post urine r = 068
Amalgams w pre urine r = 026
Amalgams w whole blood r = 036
Amalgams with post urine 044
bull Clear documentation that
challenge testing is better00
100
200
300
400
500
600
0 10 20 30 40 50
Po
st
Uri
ne H
g u
gg
Number of amalgams
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
T4 amp T3 and PCBs
bull PCBs decrease T4 production
bull PCBs inhibit iodotyrosinedeiodinase activity
bull Study done in pregnant women which implies effect on fetus IQ
Kim S Park J Kim HJ et al Association between several persistent organic pollutants and thyroid hormone levels in serum among the pregnant women of Korea Environ Int 2013 Sep59442-8Shimizu R Yamaguchi M Uramaru N et al Structure-activity relationships of 44 halogenated compounds for iodotyrosinedeiodinase-inhibitory activity Toxicology 2013 Dec 6314(1)22-9
T4 amp T3 and PCBs
bull Not just humans being affected
bull Large study of dolphins shows exactly the same effects
Schwacke LH Zolman ES Balmer BC et al Anaemia hypothyroidism and immune suppression associated with polychlorinated biphenyl exposure in bottlenose dolphins (Tursiops truncatus) Proceed Royal Society B doi101098rspb20110665
8-OHdG
bull Oxidized nucleoside
bull Direct measure of DNA damage
bull Indirect measure of oxidative stress and toxin load
bull Correlates with
Multiple cancers
Mitochondrial damage
Rate of aging
Smoking
Several toxinsWalter Crinnion ldquoTotal Toxic Loadrdquo AANP 2015
8-OHdG Correlates with Pack-Years
of Smoking
Yano T et al Significance of the urinary 8-OHdG level as an oxidative stress marker in lung cancer patients Lung Cancer
2009 Jan63(1)111-4
8-OHdG Correlates
with Mercury
Chen C et al Increased oxidative DNA damage as assessed by urinary 8-hydroxy-2-deoxyguanosine
concentrations and serum redox status in persons exposed to mercury Clin Chem 2005 Apr51(4)759-67
Toxin Effects Worse with Aging
bull Thyroid function decreases with PFOA levels
bull But only after age 63
Shrestha S Bloom MS Yucel R et al Perfluoroalkyl substances and thyroid function in older adults Environ Int 2015 Feb75206-14
Insightful 23-Year Prospective Study
1 lt 50 there is no difference between those with the lowest and highest PCBs
2 In youngest group insulin production increases in response to toxin level As expected since blocking of
insulin receptor sites by PCBs
requires more insulin
3 That adaptive ability decreases with aging
4 At age 50 all the measures show very strong toxin-dose response
Cumulative damage impairs ability to adapt
Suarez-Lopez JR et al Persistent organic pollutants in young adults and changes in glucose related metabolism over a 23-year follow-up Environ Res 2015 Feb137485-94
Recommendations
High body toxic load
GGT gt 25
Uric acid gt 50 mgdl
ALT gt30 UL
Bilirubin gt08 mgdl
CBC lt 6000
Platelet lt 250000
Low T3 andor T4
Monitor Total Toxic Load
8-OHdG gt4
ldquoUnconventionalrdquo Laboratory Tests
bull Challenge testing
bull Hair analysis
bull Direct measures of solvents and POPs in blood urine adipose tissue
Evaluation of Metal Exposure ndash Provocation
bull Provocation ndash the use of a chelating agent ndash before urine collection often done clinically but several limitations
No ldquoofficialrdquo reference range for provoked urine
Most chelating agents do not extract metals from all tissues thus
does not necessarily represent total body burden
bull Example Brain is one of the main target organs for both elemental and organic
mercury yet agents do not chelate brain mercury
bull Despite limitations widely used and advocated by clinicians in part to see efficacy of chelating agent as a guide to treatment and based on empirical evidence
Rooney JP The role of thiols dithiols nutritional factors and interacting ligands in the toxicology of mercury
Toxicology 2007
Is Challenge Testing Valid
bull Poor correlations of standard tests for mercury
bull Unpublished research from corporate wellness project
bull Published amalgam number correlation
bull Published fish consumption correlation
What We Found In Canada
bull Deviations from the mean of 14 29 and 91 respectively
bull DMPS is spreading distribution suggesting that it is better at differentiating mercury body load
bull Some VERY high
Hg Assessment Correlations
bull Extensive measurements in 65 Whole blood Hg
Oral DMPS challenge
Amalgam surfaces
bull Correlations Whole blood w pre urine r = 040
Whole blood w post urine r = 057
Pre urine w post urine r = 068
Amalgams w pre urine r = 026
Amalgams w whole blood r = 036
Amalgams with post urine 044
bull Clear documentation that
challenge testing is better00
100
200
300
400
500
600
0 10 20 30 40 50
Po
st
Uri
ne H
g u
gg
Number of amalgams
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
T4 amp T3 and PCBs
bull Not just humans being affected
bull Large study of dolphins shows exactly the same effects
Schwacke LH Zolman ES Balmer BC et al Anaemia hypothyroidism and immune suppression associated with polychlorinated biphenyl exposure in bottlenose dolphins (Tursiops truncatus) Proceed Royal Society B doi101098rspb20110665
8-OHdG
bull Oxidized nucleoside
bull Direct measure of DNA damage
bull Indirect measure of oxidative stress and toxin load
bull Correlates with
Multiple cancers
Mitochondrial damage
Rate of aging
Smoking
Several toxinsWalter Crinnion ldquoTotal Toxic Loadrdquo AANP 2015
8-OHdG Correlates with Pack-Years
of Smoking
Yano T et al Significance of the urinary 8-OHdG level as an oxidative stress marker in lung cancer patients Lung Cancer
2009 Jan63(1)111-4
8-OHdG Correlates
with Mercury
Chen C et al Increased oxidative DNA damage as assessed by urinary 8-hydroxy-2-deoxyguanosine
concentrations and serum redox status in persons exposed to mercury Clin Chem 2005 Apr51(4)759-67
Toxin Effects Worse with Aging
bull Thyroid function decreases with PFOA levels
bull But only after age 63
Shrestha S Bloom MS Yucel R et al Perfluoroalkyl substances and thyroid function in older adults Environ Int 2015 Feb75206-14
Insightful 23-Year Prospective Study
1 lt 50 there is no difference between those with the lowest and highest PCBs
2 In youngest group insulin production increases in response to toxin level As expected since blocking of
insulin receptor sites by PCBs
requires more insulin
3 That adaptive ability decreases with aging
4 At age 50 all the measures show very strong toxin-dose response
Cumulative damage impairs ability to adapt
Suarez-Lopez JR et al Persistent organic pollutants in young adults and changes in glucose related metabolism over a 23-year follow-up Environ Res 2015 Feb137485-94
Recommendations
High body toxic load
GGT gt 25
Uric acid gt 50 mgdl
ALT gt30 UL
Bilirubin gt08 mgdl
CBC lt 6000
Platelet lt 250000
Low T3 andor T4
Monitor Total Toxic Load
8-OHdG gt4
ldquoUnconventionalrdquo Laboratory Tests
bull Challenge testing
bull Hair analysis
bull Direct measures of solvents and POPs in blood urine adipose tissue
Evaluation of Metal Exposure ndash Provocation
bull Provocation ndash the use of a chelating agent ndash before urine collection often done clinically but several limitations
No ldquoofficialrdquo reference range for provoked urine
Most chelating agents do not extract metals from all tissues thus
does not necessarily represent total body burden
bull Example Brain is one of the main target organs for both elemental and organic
mercury yet agents do not chelate brain mercury
bull Despite limitations widely used and advocated by clinicians in part to see efficacy of chelating agent as a guide to treatment and based on empirical evidence
Rooney JP The role of thiols dithiols nutritional factors and interacting ligands in the toxicology of mercury
Toxicology 2007
Is Challenge Testing Valid
bull Poor correlations of standard tests for mercury
bull Unpublished research from corporate wellness project
bull Published amalgam number correlation
bull Published fish consumption correlation
What We Found In Canada
bull Deviations from the mean of 14 29 and 91 respectively
bull DMPS is spreading distribution suggesting that it is better at differentiating mercury body load
bull Some VERY high
Hg Assessment Correlations
bull Extensive measurements in 65 Whole blood Hg
Oral DMPS challenge
Amalgam surfaces
bull Correlations Whole blood w pre urine r = 040
Whole blood w post urine r = 057
Pre urine w post urine r = 068
Amalgams w pre urine r = 026
Amalgams w whole blood r = 036
Amalgams with post urine 044
bull Clear documentation that
challenge testing is better00
100
200
300
400
500
600
0 10 20 30 40 50
Po
st
Uri
ne H
g u
gg
Number of amalgams
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
8-OHdG
bull Oxidized nucleoside
bull Direct measure of DNA damage
bull Indirect measure of oxidative stress and toxin load
bull Correlates with
Multiple cancers
Mitochondrial damage
Rate of aging
Smoking
Several toxinsWalter Crinnion ldquoTotal Toxic Loadrdquo AANP 2015
8-OHdG Correlates with Pack-Years
of Smoking
Yano T et al Significance of the urinary 8-OHdG level as an oxidative stress marker in lung cancer patients Lung Cancer
2009 Jan63(1)111-4
8-OHdG Correlates
with Mercury
Chen C et al Increased oxidative DNA damage as assessed by urinary 8-hydroxy-2-deoxyguanosine
concentrations and serum redox status in persons exposed to mercury Clin Chem 2005 Apr51(4)759-67
Toxin Effects Worse with Aging
bull Thyroid function decreases with PFOA levels
bull But only after age 63
Shrestha S Bloom MS Yucel R et al Perfluoroalkyl substances and thyroid function in older adults Environ Int 2015 Feb75206-14
Insightful 23-Year Prospective Study
1 lt 50 there is no difference between those with the lowest and highest PCBs
2 In youngest group insulin production increases in response to toxin level As expected since blocking of
insulin receptor sites by PCBs
requires more insulin
3 That adaptive ability decreases with aging
4 At age 50 all the measures show very strong toxin-dose response
Cumulative damage impairs ability to adapt
Suarez-Lopez JR et al Persistent organic pollutants in young adults and changes in glucose related metabolism over a 23-year follow-up Environ Res 2015 Feb137485-94
Recommendations
High body toxic load
GGT gt 25
Uric acid gt 50 mgdl
ALT gt30 UL
Bilirubin gt08 mgdl
CBC lt 6000
Platelet lt 250000
Low T3 andor T4
Monitor Total Toxic Load
8-OHdG gt4
ldquoUnconventionalrdquo Laboratory Tests
bull Challenge testing
bull Hair analysis
bull Direct measures of solvents and POPs in blood urine adipose tissue
Evaluation of Metal Exposure ndash Provocation
bull Provocation ndash the use of a chelating agent ndash before urine collection often done clinically but several limitations
No ldquoofficialrdquo reference range for provoked urine
Most chelating agents do not extract metals from all tissues thus
does not necessarily represent total body burden
bull Example Brain is one of the main target organs for both elemental and organic
mercury yet agents do not chelate brain mercury
bull Despite limitations widely used and advocated by clinicians in part to see efficacy of chelating agent as a guide to treatment and based on empirical evidence
Rooney JP The role of thiols dithiols nutritional factors and interacting ligands in the toxicology of mercury
Toxicology 2007
Is Challenge Testing Valid
bull Poor correlations of standard tests for mercury
bull Unpublished research from corporate wellness project
bull Published amalgam number correlation
bull Published fish consumption correlation
What We Found In Canada
bull Deviations from the mean of 14 29 and 91 respectively
bull DMPS is spreading distribution suggesting that it is better at differentiating mercury body load
bull Some VERY high
Hg Assessment Correlations
bull Extensive measurements in 65 Whole blood Hg
Oral DMPS challenge
Amalgam surfaces
bull Correlations Whole blood w pre urine r = 040
Whole blood w post urine r = 057
Pre urine w post urine r = 068
Amalgams w pre urine r = 026
Amalgams w whole blood r = 036
Amalgams with post urine 044
bull Clear documentation that
challenge testing is better00
100
200
300
400
500
600
0 10 20 30 40 50
Po
st
Uri
ne H
g u
gg
Number of amalgams
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
8-OHdG Correlates with Pack-Years
of Smoking
Yano T et al Significance of the urinary 8-OHdG level as an oxidative stress marker in lung cancer patients Lung Cancer
2009 Jan63(1)111-4
8-OHdG Correlates
with Mercury
Chen C et al Increased oxidative DNA damage as assessed by urinary 8-hydroxy-2-deoxyguanosine
concentrations and serum redox status in persons exposed to mercury Clin Chem 2005 Apr51(4)759-67
Toxin Effects Worse with Aging
bull Thyroid function decreases with PFOA levels
bull But only after age 63
Shrestha S Bloom MS Yucel R et al Perfluoroalkyl substances and thyroid function in older adults Environ Int 2015 Feb75206-14
Insightful 23-Year Prospective Study
1 lt 50 there is no difference between those with the lowest and highest PCBs
2 In youngest group insulin production increases in response to toxin level As expected since blocking of
insulin receptor sites by PCBs
requires more insulin
3 That adaptive ability decreases with aging
4 At age 50 all the measures show very strong toxin-dose response
Cumulative damage impairs ability to adapt
Suarez-Lopez JR et al Persistent organic pollutants in young adults and changes in glucose related metabolism over a 23-year follow-up Environ Res 2015 Feb137485-94
Recommendations
High body toxic load
GGT gt 25
Uric acid gt 50 mgdl
ALT gt30 UL
Bilirubin gt08 mgdl
CBC lt 6000
Platelet lt 250000
Low T3 andor T4
Monitor Total Toxic Load
8-OHdG gt4
ldquoUnconventionalrdquo Laboratory Tests
bull Challenge testing
bull Hair analysis
bull Direct measures of solvents and POPs in blood urine adipose tissue
Evaluation of Metal Exposure ndash Provocation
bull Provocation ndash the use of a chelating agent ndash before urine collection often done clinically but several limitations
No ldquoofficialrdquo reference range for provoked urine
Most chelating agents do not extract metals from all tissues thus
does not necessarily represent total body burden
bull Example Brain is one of the main target organs for both elemental and organic
mercury yet agents do not chelate brain mercury
bull Despite limitations widely used and advocated by clinicians in part to see efficacy of chelating agent as a guide to treatment and based on empirical evidence
Rooney JP The role of thiols dithiols nutritional factors and interacting ligands in the toxicology of mercury
Toxicology 2007
Is Challenge Testing Valid
bull Poor correlations of standard tests for mercury
bull Unpublished research from corporate wellness project
bull Published amalgam number correlation
bull Published fish consumption correlation
What We Found In Canada
bull Deviations from the mean of 14 29 and 91 respectively
bull DMPS is spreading distribution suggesting that it is better at differentiating mercury body load
bull Some VERY high
Hg Assessment Correlations
bull Extensive measurements in 65 Whole blood Hg
Oral DMPS challenge
Amalgam surfaces
bull Correlations Whole blood w pre urine r = 040
Whole blood w post urine r = 057
Pre urine w post urine r = 068
Amalgams w pre urine r = 026
Amalgams w whole blood r = 036
Amalgams with post urine 044
bull Clear documentation that
challenge testing is better00
100
200
300
400
500
600
0 10 20 30 40 50
Po
st
Uri
ne H
g u
gg
Number of amalgams
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
8-OHdG Correlates
with Mercury
Chen C et al Increased oxidative DNA damage as assessed by urinary 8-hydroxy-2-deoxyguanosine
concentrations and serum redox status in persons exposed to mercury Clin Chem 2005 Apr51(4)759-67
Toxin Effects Worse with Aging
bull Thyroid function decreases with PFOA levels
bull But only after age 63
Shrestha S Bloom MS Yucel R et al Perfluoroalkyl substances and thyroid function in older adults Environ Int 2015 Feb75206-14
Insightful 23-Year Prospective Study
1 lt 50 there is no difference between those with the lowest and highest PCBs
2 In youngest group insulin production increases in response to toxin level As expected since blocking of
insulin receptor sites by PCBs
requires more insulin
3 That adaptive ability decreases with aging
4 At age 50 all the measures show very strong toxin-dose response
Cumulative damage impairs ability to adapt
Suarez-Lopez JR et al Persistent organic pollutants in young adults and changes in glucose related metabolism over a 23-year follow-up Environ Res 2015 Feb137485-94
Recommendations
High body toxic load
GGT gt 25
Uric acid gt 50 mgdl
ALT gt30 UL
Bilirubin gt08 mgdl
CBC lt 6000
Platelet lt 250000
Low T3 andor T4
Monitor Total Toxic Load
8-OHdG gt4
ldquoUnconventionalrdquo Laboratory Tests
bull Challenge testing
bull Hair analysis
bull Direct measures of solvents and POPs in blood urine adipose tissue
Evaluation of Metal Exposure ndash Provocation
bull Provocation ndash the use of a chelating agent ndash before urine collection often done clinically but several limitations
No ldquoofficialrdquo reference range for provoked urine
Most chelating agents do not extract metals from all tissues thus
does not necessarily represent total body burden
bull Example Brain is one of the main target organs for both elemental and organic
mercury yet agents do not chelate brain mercury
bull Despite limitations widely used and advocated by clinicians in part to see efficacy of chelating agent as a guide to treatment and based on empirical evidence
Rooney JP The role of thiols dithiols nutritional factors and interacting ligands in the toxicology of mercury
Toxicology 2007
Is Challenge Testing Valid
bull Poor correlations of standard tests for mercury
bull Unpublished research from corporate wellness project
bull Published amalgam number correlation
bull Published fish consumption correlation
What We Found In Canada
bull Deviations from the mean of 14 29 and 91 respectively
bull DMPS is spreading distribution suggesting that it is better at differentiating mercury body load
bull Some VERY high
Hg Assessment Correlations
bull Extensive measurements in 65 Whole blood Hg
Oral DMPS challenge
Amalgam surfaces
bull Correlations Whole blood w pre urine r = 040
Whole blood w post urine r = 057
Pre urine w post urine r = 068
Amalgams w pre urine r = 026
Amalgams w whole blood r = 036
Amalgams with post urine 044
bull Clear documentation that
challenge testing is better00
100
200
300
400
500
600
0 10 20 30 40 50
Po
st
Uri
ne H
g u
gg
Number of amalgams
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
Toxin Effects Worse with Aging
bull Thyroid function decreases with PFOA levels
bull But only after age 63
Shrestha S Bloom MS Yucel R et al Perfluoroalkyl substances and thyroid function in older adults Environ Int 2015 Feb75206-14
Insightful 23-Year Prospective Study
1 lt 50 there is no difference between those with the lowest and highest PCBs
2 In youngest group insulin production increases in response to toxin level As expected since blocking of
insulin receptor sites by PCBs
requires more insulin
3 That adaptive ability decreases with aging
4 At age 50 all the measures show very strong toxin-dose response
Cumulative damage impairs ability to adapt
Suarez-Lopez JR et al Persistent organic pollutants in young adults and changes in glucose related metabolism over a 23-year follow-up Environ Res 2015 Feb137485-94
Recommendations
High body toxic load
GGT gt 25
Uric acid gt 50 mgdl
ALT gt30 UL
Bilirubin gt08 mgdl
CBC lt 6000
Platelet lt 250000
Low T3 andor T4
Monitor Total Toxic Load
8-OHdG gt4
ldquoUnconventionalrdquo Laboratory Tests
bull Challenge testing
bull Hair analysis
bull Direct measures of solvents and POPs in blood urine adipose tissue
Evaluation of Metal Exposure ndash Provocation
bull Provocation ndash the use of a chelating agent ndash before urine collection often done clinically but several limitations
No ldquoofficialrdquo reference range for provoked urine
Most chelating agents do not extract metals from all tissues thus
does not necessarily represent total body burden
bull Example Brain is one of the main target organs for both elemental and organic
mercury yet agents do not chelate brain mercury
bull Despite limitations widely used and advocated by clinicians in part to see efficacy of chelating agent as a guide to treatment and based on empirical evidence
Rooney JP The role of thiols dithiols nutritional factors and interacting ligands in the toxicology of mercury
Toxicology 2007
Is Challenge Testing Valid
bull Poor correlations of standard tests for mercury
bull Unpublished research from corporate wellness project
bull Published amalgam number correlation
bull Published fish consumption correlation
What We Found In Canada
bull Deviations from the mean of 14 29 and 91 respectively
bull DMPS is spreading distribution suggesting that it is better at differentiating mercury body load
bull Some VERY high
Hg Assessment Correlations
bull Extensive measurements in 65 Whole blood Hg
Oral DMPS challenge
Amalgam surfaces
bull Correlations Whole blood w pre urine r = 040
Whole blood w post urine r = 057
Pre urine w post urine r = 068
Amalgams w pre urine r = 026
Amalgams w whole blood r = 036
Amalgams with post urine 044
bull Clear documentation that
challenge testing is better00
100
200
300
400
500
600
0 10 20 30 40 50
Po
st
Uri
ne H
g u
gg
Number of amalgams
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
Insightful 23-Year Prospective Study
1 lt 50 there is no difference between those with the lowest and highest PCBs
2 In youngest group insulin production increases in response to toxin level As expected since blocking of
insulin receptor sites by PCBs
requires more insulin
3 That adaptive ability decreases with aging
4 At age 50 all the measures show very strong toxin-dose response
Cumulative damage impairs ability to adapt
Suarez-Lopez JR et al Persistent organic pollutants in young adults and changes in glucose related metabolism over a 23-year follow-up Environ Res 2015 Feb137485-94
Recommendations
High body toxic load
GGT gt 25
Uric acid gt 50 mgdl
ALT gt30 UL
Bilirubin gt08 mgdl
CBC lt 6000
Platelet lt 250000
Low T3 andor T4
Monitor Total Toxic Load
8-OHdG gt4
ldquoUnconventionalrdquo Laboratory Tests
bull Challenge testing
bull Hair analysis
bull Direct measures of solvents and POPs in blood urine adipose tissue
Evaluation of Metal Exposure ndash Provocation
bull Provocation ndash the use of a chelating agent ndash before urine collection often done clinically but several limitations
No ldquoofficialrdquo reference range for provoked urine
Most chelating agents do not extract metals from all tissues thus
does not necessarily represent total body burden
bull Example Brain is one of the main target organs for both elemental and organic
mercury yet agents do not chelate brain mercury
bull Despite limitations widely used and advocated by clinicians in part to see efficacy of chelating agent as a guide to treatment and based on empirical evidence
Rooney JP The role of thiols dithiols nutritional factors and interacting ligands in the toxicology of mercury
Toxicology 2007
Is Challenge Testing Valid
bull Poor correlations of standard tests for mercury
bull Unpublished research from corporate wellness project
bull Published amalgam number correlation
bull Published fish consumption correlation
What We Found In Canada
bull Deviations from the mean of 14 29 and 91 respectively
bull DMPS is spreading distribution suggesting that it is better at differentiating mercury body load
bull Some VERY high
Hg Assessment Correlations
bull Extensive measurements in 65 Whole blood Hg
Oral DMPS challenge
Amalgam surfaces
bull Correlations Whole blood w pre urine r = 040
Whole blood w post urine r = 057
Pre urine w post urine r = 068
Amalgams w pre urine r = 026
Amalgams w whole blood r = 036
Amalgams with post urine 044
bull Clear documentation that
challenge testing is better00
100
200
300
400
500
600
0 10 20 30 40 50
Po
st
Uri
ne H
g u
gg
Number of amalgams
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
Recommendations
High body toxic load
GGT gt 25
Uric acid gt 50 mgdl
ALT gt30 UL
Bilirubin gt08 mgdl
CBC lt 6000
Platelet lt 250000
Low T3 andor T4
Monitor Total Toxic Load
8-OHdG gt4
ldquoUnconventionalrdquo Laboratory Tests
bull Challenge testing
bull Hair analysis
bull Direct measures of solvents and POPs in blood urine adipose tissue
Evaluation of Metal Exposure ndash Provocation
bull Provocation ndash the use of a chelating agent ndash before urine collection often done clinically but several limitations
No ldquoofficialrdquo reference range for provoked urine
Most chelating agents do not extract metals from all tissues thus
does not necessarily represent total body burden
bull Example Brain is one of the main target organs for both elemental and organic
mercury yet agents do not chelate brain mercury
bull Despite limitations widely used and advocated by clinicians in part to see efficacy of chelating agent as a guide to treatment and based on empirical evidence
Rooney JP The role of thiols dithiols nutritional factors and interacting ligands in the toxicology of mercury
Toxicology 2007
Is Challenge Testing Valid
bull Poor correlations of standard tests for mercury
bull Unpublished research from corporate wellness project
bull Published amalgam number correlation
bull Published fish consumption correlation
What We Found In Canada
bull Deviations from the mean of 14 29 and 91 respectively
bull DMPS is spreading distribution suggesting that it is better at differentiating mercury body load
bull Some VERY high
Hg Assessment Correlations
bull Extensive measurements in 65 Whole blood Hg
Oral DMPS challenge
Amalgam surfaces
bull Correlations Whole blood w pre urine r = 040
Whole blood w post urine r = 057
Pre urine w post urine r = 068
Amalgams w pre urine r = 026
Amalgams w whole blood r = 036
Amalgams with post urine 044
bull Clear documentation that
challenge testing is better00
100
200
300
400
500
600
0 10 20 30 40 50
Po
st
Uri
ne H
g u
gg
Number of amalgams
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
ldquoUnconventionalrdquo Laboratory Tests
bull Challenge testing
bull Hair analysis
bull Direct measures of solvents and POPs in blood urine adipose tissue
Evaluation of Metal Exposure ndash Provocation
bull Provocation ndash the use of a chelating agent ndash before urine collection often done clinically but several limitations
No ldquoofficialrdquo reference range for provoked urine
Most chelating agents do not extract metals from all tissues thus
does not necessarily represent total body burden
bull Example Brain is one of the main target organs for both elemental and organic
mercury yet agents do not chelate brain mercury
bull Despite limitations widely used and advocated by clinicians in part to see efficacy of chelating agent as a guide to treatment and based on empirical evidence
Rooney JP The role of thiols dithiols nutritional factors and interacting ligands in the toxicology of mercury
Toxicology 2007
Is Challenge Testing Valid
bull Poor correlations of standard tests for mercury
bull Unpublished research from corporate wellness project
bull Published amalgam number correlation
bull Published fish consumption correlation
What We Found In Canada
bull Deviations from the mean of 14 29 and 91 respectively
bull DMPS is spreading distribution suggesting that it is better at differentiating mercury body load
bull Some VERY high
Hg Assessment Correlations
bull Extensive measurements in 65 Whole blood Hg
Oral DMPS challenge
Amalgam surfaces
bull Correlations Whole blood w pre urine r = 040
Whole blood w post urine r = 057
Pre urine w post urine r = 068
Amalgams w pre urine r = 026
Amalgams w whole blood r = 036
Amalgams with post urine 044
bull Clear documentation that
challenge testing is better00
100
200
300
400
500
600
0 10 20 30 40 50
Po
st
Uri
ne H
g u
gg
Number of amalgams
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
Evaluation of Metal Exposure ndash Provocation
bull Provocation ndash the use of a chelating agent ndash before urine collection often done clinically but several limitations
No ldquoofficialrdquo reference range for provoked urine
Most chelating agents do not extract metals from all tissues thus
does not necessarily represent total body burden
bull Example Brain is one of the main target organs for both elemental and organic
mercury yet agents do not chelate brain mercury
bull Despite limitations widely used and advocated by clinicians in part to see efficacy of chelating agent as a guide to treatment and based on empirical evidence
Rooney JP The role of thiols dithiols nutritional factors and interacting ligands in the toxicology of mercury
Toxicology 2007
Is Challenge Testing Valid
bull Poor correlations of standard tests for mercury
bull Unpublished research from corporate wellness project
bull Published amalgam number correlation
bull Published fish consumption correlation
What We Found In Canada
bull Deviations from the mean of 14 29 and 91 respectively
bull DMPS is spreading distribution suggesting that it is better at differentiating mercury body load
bull Some VERY high
Hg Assessment Correlations
bull Extensive measurements in 65 Whole blood Hg
Oral DMPS challenge
Amalgam surfaces
bull Correlations Whole blood w pre urine r = 040
Whole blood w post urine r = 057
Pre urine w post urine r = 068
Amalgams w pre urine r = 026
Amalgams w whole blood r = 036
Amalgams with post urine 044
bull Clear documentation that
challenge testing is better00
100
200
300
400
500
600
0 10 20 30 40 50
Po
st
Uri
ne H
g u
gg
Number of amalgams
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
Is Challenge Testing Valid
bull Poor correlations of standard tests for mercury
bull Unpublished research from corporate wellness project
bull Published amalgam number correlation
bull Published fish consumption correlation
What We Found In Canada
bull Deviations from the mean of 14 29 and 91 respectively
bull DMPS is spreading distribution suggesting that it is better at differentiating mercury body load
bull Some VERY high
Hg Assessment Correlations
bull Extensive measurements in 65 Whole blood Hg
Oral DMPS challenge
Amalgam surfaces
bull Correlations Whole blood w pre urine r = 040
Whole blood w post urine r = 057
Pre urine w post urine r = 068
Amalgams w pre urine r = 026
Amalgams w whole blood r = 036
Amalgams with post urine 044
bull Clear documentation that
challenge testing is better00
100
200
300
400
500
600
0 10 20 30 40 50
Po
st
Uri
ne H
g u
gg
Number of amalgams
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
What We Found In Canada
bull Deviations from the mean of 14 29 and 91 respectively
bull DMPS is spreading distribution suggesting that it is better at differentiating mercury body load
bull Some VERY high
Hg Assessment Correlations
bull Extensive measurements in 65 Whole blood Hg
Oral DMPS challenge
Amalgam surfaces
bull Correlations Whole blood w pre urine r = 040
Whole blood w post urine r = 057
Pre urine w post urine r = 068
Amalgams w pre urine r = 026
Amalgams w whole blood r = 036
Amalgams with post urine 044
bull Clear documentation that
challenge testing is better00
100
200
300
400
500
600
0 10 20 30 40 50
Po
st
Uri
ne H
g u
gg
Number of amalgams
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
Hg Assessment Correlations
bull Extensive measurements in 65 Whole blood Hg
Oral DMPS challenge
Amalgam surfaces
bull Correlations Whole blood w pre urine r = 040
Whole blood w post urine r = 057
Pre urine w post urine r = 068
Amalgams w pre urine r = 026
Amalgams w whole blood r = 036
Amalgams with post urine 044
bull Clear documentation that
challenge testing is better00
100
200
300
400
500
600
0 10 20 30 40 50
Po
st
Uri
ne H
g u
gg
Number of amalgams
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
Modest Correlation with of Fillings
bull Very large study
bull Surprisingly only reported none versus 1 or more fillings
bull Huge overlap
bull Not controlled for fish consumption
Dutton DJ et al The association between amalgam dental surfaces and urinary mercury levels in a sample of
Albertans a prevalence study J Occup Med Toxicol 20138(1)22
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
Strong Correlation with Fish
Consumption
bull Compared 0 to 1-2 to 3 or more servings per week
bull First urine showed essentially no differentiation
bull Challenge testing showed clear correlation
bull Still a lot of variation
Ruha AM et al Urine mercury excretion following meso-dimercaptosuccinic acid challenge in fish eaters Arch
Pathol Lab Med 2009133(1)87-92
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
Measuring POP
Levels Directly
bull Urine sample
bull 150+ environmental chemicals
bull $287
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
Sources of Toxins
bull 70 Food
bull 10 Water
bull 10 House and yard chemicals
bull 5 Air
bull 5 Health and beauty aids
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
Eating Conventionally Grown Foods
Dramatically Increases POP Load
bull Study done in Seattle children
bull 10-fold increase in POPs doubles ADHD
bull Levels drop measurably within 3 days of eating only organically grown foods
Curl CL et al Organophosphorus pesticide exposure of urban and suburban preschool children with organic and
conventional diets Env Health Perspect 2003111377-82
Bouchard MF et al Attention-deficithyperactivity disorder and urinary metabolites of organophosphate pesticides
Pediatrics 2010 Jun125(6)e1270-7
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
Hg From Fish
bull Total Hg urinary excretion proportional to amount of fish eaten
bull Impaired psychomotor performance
R = 038 blood
R = 077 urine
bull Huge variation in amount of Hg in fish
94
Apostoli P ICortesi I Mangili A et al Assessment of reference values for mercury in urine the results of an Italian
polycentric study The Science of the Total Environment 289 (2002)13-24
Carta P et al Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through
fish consumption NeuroToxicology 24 (2003) 617ndash623
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
POPs Fish
Consumption and
Breast Feedingbull Eating fish increases POPs
bull Breast feeding decreases POPs
Bjermo H et al Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population Environ Int 2013 Jan5188-96
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
BPA Canned Versus Home-Made Soup
Soymilk in Cans Versus Glassbull One 12oz serving daily for 1 week of
either fresh soup or canned soup (Progresso)
12-fold increase in BPA
bull 2 servings of 6 ounces Soy milk in can compared to glass
16-fold increase in BPA
Systolic BP elevated 45 mm Hg
bull Diabetes risk thresholdCarwile JL1 Ye X Zhou X et al Canned soup consumption and urinary bisphenol A a randomized
crossover trial JAMA 2011 Nov 23306(20)2218-20
Bae S1 Hong YC2 Exposure to bisphenol A from drinking canned beverages increases blood
pressure randomized crossover trial Hypertension 2015 Feb65(2)313-9
0
5
10
15
20
25
Soy in Glass Soy in Can Made Soup Canned Soup
BPA (ugL urine)
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
HABAs Can Be Significant
Source of POPs
Duty SM et al Personal care product use predicts urinary concentrations of some phthalate monoesters Environ
Health Perspect 2005 Nov113(11)1530-5
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
Case Histories
bull gt35 at wwwthetoxinsolutioncom
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
Am I Losing my
Mind April 2012bull 67 yo white woman
bull I had the odd feeling that I was living in a fog that things were very fuzzy and that my memory was very sporadic I was having trouble sleeping and had a lot of muscle aches during the night I always had a metal taste in my mouth and felt that my breath lacked freshness other than the first few minutes after brushing my teeth My skin and scalp were always sore and especially dry
Hg = 50
2 years IV chelation discontinued
due to side effects amp no benefit
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
November 2012
bull I do know that things really improved once I started your protocol and I was happy to see the light at the end of the Mercury tunnel
Hg = 12
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
June 2013
bull With each successive test the symptoms were lessening and I was feeling more normal
Hg = 73
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
December 2013
bull It was a day of celebration when I received the last test results
bull I would caution people to remember that clearing mercury out of onersquos system is a long process but it is worth the effort even if it takes many years Being healthy is a good reward for all the patience required to do the heavy mercury lifting
bull Good luck with your seminars I will always be in your debt for your help
Hg = 35
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
No More Kidney Stonesbull 40 yo male (emergency room physician)
bull Wants to enter space medicine BUT
Kidney stone attack every 4-6 months
bull Otherwise healthy
bull Intervention
50 decrease in salt intake
Increased attention to Mediterranean diet with emphasis
on whole citrus fruit
Calcium carbonate 05 g bid
Magnesium citrate 250 mg bid
Potassium citrate 50 mg bid
bull No attacks for 3 years
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
ldquoNormalrdquo is Degeneration with Aging
But the Degeneration is Actually
Accumulated Avoidable Damage
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
4 G
en
era
tio
ns
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
Mo
torc
yclin
g A
ustr
alia o
n t
he
ldquoW
ron
g S
ide
of
the
Ro
ad
rdquo
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
Summary
1 Toxins are now ubiquitous in the industrialized world
2 Toxins are now the primary drivers of chronic disease
3 Standard laboratory tests now include in ldquonormalrdquo range the bodyrsquos adaptations to and damage from toxins
Thank you
Chrissie Cirovic ND amp Geoff Bender ND
For Your Excellent Research Work
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND
2 New Books
The Toxin Solution
Clinical Environmental Medicine
With Walter Crinnion ND