Process-induced Toxicants in Food June 3, 2014 Chi-Tang Ho.
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Transcript of Process-induced Toxicants in Food June 3, 2014 Chi-Tang Ho.
From Diet to Disease
High-fat foods are rich in the lipid phosphatidylcholine (PC) and its metabolite choline (C). Intestinal bacteria convert C to TMA. In the liver, the enzyme FMO3 processes TMA to TMAO — a metabolite that makes its way into the blood. Wang et al.1 show that circulating TMAO may contribute to greater plaque development in the arteries, and so to heart disease.
Definition of a Process Toxicant
Processing toxicants are defined as those substances present in food as a result of food processing/preparation that are considered to exert adverse physiological (toxicological) effects in humans, i.e., substances that create a potential of real risk to human health.
Trans Fatty Acids
Trans fats, unsaturated fatty acids with at least one double bond in the trans configuration
Formed during the partial hydrogenation of vegetable oils
The average consumption of industrially produced trans fatty acids in the US is 2-3% of total calories consumed
Trans Fat regulation
In April 2004, the FDA Food Advisory Committee voted in favor of recommending that trans fatty acid intake level be reduced to "less than 1% of energy (2g per day of a 2000 kcal diet)“
The FDA ruled that, effective January 1, 2006, the nutrition labels for all conventional foods and supplements must indicate the content of trans fatty acids
The New York City has asked 20,000 restaurants and 14,000 food suppliers to eliminate partially hydrogenated oils from kitchens
Typical trans fatty acid contents of foods produced by partially hydrogenated vegetable oils
Food g/serving % of daily energy
intake for 2000-kcal diet
French fries: 4.7-6.1 2.1-2.7 Fish burger 5.6 2.5 Chicken nuggets 5.0 2.3 Pizza 1.1 0.5 Popcorn 1.2 0.5 Doughnuts 2.7 1.2
Intake of trans fat and diseases
Cardiovascular disease: 2% increase in energy intake from trans fatty acids was associated with a 23% increase in the incidence of coronary heart disease Raise levels of low-density lipoprotein cholesterol Reduce levels of high-density lipoprotein cholesterol Increase the ratio of total cholesterol to HDL
cholesterol
Intake of trans fat and diseases
Increase the risk of sudden death from cardiac causes.
May increase the risk of diabetes Trans fats promote inflammation Trans fats may cause endothelial
dysfunction
Produced during oxidation of poly-unsaturated fatty acids
Acrolein, malonaldehyde, and 4-hydroxy-2-nonenal
React with protein and DNA and as a result are toxic and mutagenic.
O
Acrolein Malonaldehyde 4-hydroxy2-nonenal (HNE)
O
OH
Lipid-derived Bioactive Carbonyls Species
CO
CH2
H
O
H
Formation Pathway of Malonaldehyde
L.L
LH
.
O O
.
LH
O O
+ O2+ O2
OOH
O
O
Malonaldehyde
BicycloendoperoxidesHydroperoxy Epidioxides
O O OOH
Pryor et al, 1976
Linolenic acid
←
How is its formation mechanism ?
Acrolein
Strongest electrophile among α,β-unsaturated aldehydes react with thiol and amino groups of protein causing alteration
of the structure and function of matrix protein React with DNA at guanine residues to form 8-hydroxy-
propanodeoxyguanosine (OHPdG)
Generated in biological systems under oxidative stress Environmental and industrial pollutant, automobile
exhaust, wood smoke, cigarette smoke
O
Acrolein
Acrelein will produce abundantly through autoxidation of ω-3 polyunsaturated fatty acids, such as fish oil
ω-3 eicosapentaenoic acid (EPA) (20:5)
ω-3 docosahexaenoic acid (DHA) (22:6)
C5H11
CO2H
arachidonic acid
C5H11
CO2H
beta-cleavage of alkoxy radical
HOO
C5H11
O
C5H11
O
OOH
O2
O2
beta-cleavage of alkoxy radical
C5H11O+ O
acrolein
Proposed formation pathway for undesirable acrolein
Reactive Carbonyl Species (RCS) from Maillard Reaction
Deoxyosone, methylglyoxal (MGO) and glyoxal (GO)
Produce through Maillard reaction Strong electrophiles, react with proteins
and DNA
RCS Generation in Vitro
R-NH2 + Glucose
C
H
C
NH
OHH
C HHO
C
C
OHH
OH
CH2OH
H
Schiff's base
HO
HOH2C O
OH OHNH_Protein
H
H
O
O
Glyoxal
C
H
C O
CH2
C
C
OHH
OH
CH2OH
H
O
3-DG
-Glyceraldehyde,
H3C
H
O
O
Methylglyoxal
"Classical" Amadorirearangement
CH
C
HNR
OH
C HHO
C
C
OHH
OH
CH2OH
H
CH2
C
HNR
O
C HHO
C
C
OHH
OH
CH2OH
H
HOO
OHOH
Fructosamine
NHROH
-H2O, -RNH2
-Erythritol orerythrose andH2O2, -RNH2
Maillard Reaction
Methylglyoxal Generation in Vivo
Fatty acid
Acetone
Acetyl-CoA
Fats
Glycerol
Dihydroxyacetone phosphateGlyceraldehyde-3-phosphate
Methylglyoxal
Glycerol-3-phosphateFructose-1,6-bisphosphate
Fructose-6-phosphate
Glucose-6-phosphate
GlucoseProtein
Gly, Thr
Aminoacetone
Aldose reductase
NADPH
D-LactateAdvanced glycation
end products1,2-propanediol
Glyoxalase I
Glyoxalase II
GSH
MG
Protein Glycation
DNA GlycationAGEs
Inflammation
Thrombosis
Angiogenesis
Tissue Injury
Protein
Cross Linking
Cellular
Apoptosis
Gene
Transcription
Ramasamy, R., Yan, S. F., and Schmidt, A. M., 2006, Cell 124, 258-260
Glycation of Transcription Modulators
Changes Caused by Methylglyoxal (MG)
Diabetesretinopathyneuropathy and nephropathy
Non-diabetic nephropathy Macrovascular disease (atherosclerosis) Alzheimer's disease Cataracts Aging
Health Concerns with MG
Human plasma MG level in different studies
MG (μg/dL) Quantifying method† Source
Patients Control
15.84.6 (n=20)4.7 1.2
(n=15)2,3-diaminonaphthalene; 3,4-hexanedione; ESI/LC/MS
Odani, Hinzato, and Matsumoto, 1999
20.63.8 (n*=15)4.9 1.2
(n=15)Methanol; Meso-stilbenediamine; HPLC (358nm)
Khuhawar and Kandhro, 2006
† Quantifying method is listed with the sequence of deproteinization agents, derivatization agents, internal standard, and equipment.
* This study included both diabetes and ketosis patients.
MG in Human Plasma
MG in Beverages
minimum
Mean
Maximum
050
100150200
250300350
400
450
500
MG
ug
/ 1
00
mlMG in Beverages
minimum
Mean
Maximum
One can of soda: 300 mlBlood volume in kid: 2.5 LAvg. MG in Soda: 196 μg/dLMG in one can: 196*3 = 588μgMG Con. in kid: 588/25 =23.5 μg/dLMG Con. in diabetes: 20.6 μg/dL
Consuming soda may increase MG level in Blood
Carbonated Soft Drinks and Carbonyl Stress Burden Thirty minutes after consuming 300 mL of
carbonated cola (11.3 g carbohydrate/100 mL; 7.2 μM MG), the blood MG levels of subjects were raised from 113±22 to 136±34 nM, and the blood glucose levels were raised from 94±8 to 113±18 mg/dL.
Glucose and MG containing carbonated soft drinks appear to lead to transient increase in plasma MG levels. It is of great interest whether habitual intake of carbonated drinks enhances human carbonyl stress. Nakayama et al., J. Toxicol. Sci. 34(6):
699-702, 2009
MG in Commercial Cookies
MG levels in commercial cookies range from 3.7 to 81.4 mg/Kg
Commercial cookies made from ammonium bicarbonate and fructose showed the highest levels of MG
MG was rapidly formed on the upper site of the cookies regardless of shape or thickness of the samples
Dietary exposure of Spanish population to MG from cookies was estimated to be 216 μg/person/day
Arribas-Lorenzo and Morales, 2010Arribas-Lorenzo and Morales, 2010
5.8
17.1
36.7
27.1
45.7
33.8
27.8
63.160.0
66.6
0
10
20
30
40
50
60
70
80
INC GA EC ECG EGC EGCG PY TF1 TF2 TF3
•MG: Polyphenolic compound mixed with molar ratio 3:1 •Incubation of 1 hour
O
OR1
HO
OH
OH
OH
R2
R1 R2
EC H H
ECG Gallate H
EGC H OH
EGCG Gallate OH
Green Tea Catechins
O
OR1
O
OH
HO
HO
OHOR2
OH
OH
OH
O
R1 = R2 = H ; Theaflavin(TF1)
R1 = G , R2 = H or R1 = H , R2 = G ; Theaflavin monogallate esters(TF2)
R1 = R2 = G ; Theaflavin digallate ester(TF3)
G = Galloyl
Black Tea Theaflavins
Inhibition by Tea Polyphenols
Figure 12.
8-Mono-MGOEGCG
O
OH
OH
OH
OH
O
OOH
OH
OH
HO
6
8
O
HO
OHO
O
OH
OH
OH
OH
O
OOH
OH
OH
HO8
OHO
O
OH
OH
OH
OH
O
OOH
OH
OH
HO
6
O
HO
6-Mono-MGOEGCG 6,8-Di-MGOEGCG
MGO× 1 MGO × 2
MGO× 1
O
O
OH
OH
OH
O
OOH
OH
OH
HO
H
OH-
O
O
H
O
O
H
Formation of EGCG-MG Adduct
Another Maillard Reaction-derived Toxicants: Heterocyclic Amines (HAs)
Heterocyclic amines occur at the ppb range in foods
Most of them demonstrated potent mutagenicity and as probably human carcinogens
IQ has even demonstrated carcinogenic activity in monkeys
Their capability of formation even during ordinary cooking practices implies frequent exposure by the general public
Abbreviation Z R1 R2 R3
IQ C H H H
MeIQ C Me H H
MeIQx N H H Me
4,8-DiMeIQx N Me H Me
Commonly occurred Heterocyclic amines
COOH
NH2
O
x
1
2
12
Compound 1
Compound 2
Phenylalanine
Phenylacetaldehyde
O
O
OH
OH
OH
HO
OHO
OH
OH
OH
O
O
OH
OH
OH
HO
OHO
OH
OH
OH
Phenylethenyl
O
O
OH
OH
OH
HO
OHO
OH
OH
OH
Phenylethenyl
N N
N
CH3
NH2
PhIP
N
NO
CH3
NH2
Creatinine
Postulated Pathways for EGCG’s Inhibitory Activity in PhIP Formation
Factors affect formation of HAs Temperature Time Precursors: creatinine, phenylalanine, (reducing sugars,
amino acids) Involvement of Lipids Direct involvement of Strecker aldehydes Water content Concentration of polyunsaturated fats Metal ions Antioxidants
Acrylamide - toxicology
Proven neurotoxic compound in animals and in humans
Effects range from drowsiness to incoordination, hallucinations, confusion, abnormal sensation, muscle weakness, incoordination
Genotoxic compound with the potential to affect the germinal cells thus leading to hereditary changes
Causing cancer in laboratory animals (rats) Studies in humans (e.g. 8000 workers in China)
which were positive on neurotoxicity failed to prove relationship with cancer in humans (too small numbers ?)
How do we know ...
... whether somebody had been exposed to acrylamide ?
Acrylamide binds to haemoglobin!
Biomarker: AA-Hb adduct
Level of adduct may reflect exposure to acrylamide over last four months
Research before 1999
“Clear-cut dose-response associations were found between the Hb-adduct levels and peripheral nervous functions symptoms. Thirty-nine percent of those with Hb-adduct levels exceeding 1 nmol/g globin experienced tingling or numbness in their hands or feet. For 23 workers there was strong evidence of PNS impairment due to occupational exposure to acrylamide. All but two had recovered 18 months after the cessation of exposure.”
Sweden: April 2002“ A scientific group at the University of Stockholm ... has found that acrylamide is formed during heating of starch-rich foods to high temperatures.The Swedish National Food Administration has developed a new, rapid method for the analysis of acrylamide in foods.Analysis has shown that acrylamide is present in a large number of foods, including many regarded as staple foods. The levels of acrylamide differ widely within each food group analysed.”
Chloropropanols
A group of chemical contaminants comprising three carbon alcohols and diols with one or two chlorine atoms that are hypothetically derived from glycerol
Dichloropropanols and chloropropanediols were identified as contaminants of the savory food ingredient acid-hydrolyzed vegetable protein (acid-HVP) in the 1970s and 1980s.
In view of 3-MCPD (3-monochloropropane-1,2-diol) toxicity, the EC has proposed a provisional tolerable daily intake amount of 2 ug/kg body weight/day.
Background– Non-genotoxic carcinogen (JECFA, EU SCF) threshold– Kidney toxicity at chronic exposure– Inhibits male fertility at high doses
Occurrence– Hydrolyzed vegetable proteins (HVP)– Low levels in foods (biscuits, bread, cooked/cured fish and meat)– Migration (food contact materials)
Human dietary exposure– 2 g/person/day from savory foods– 140-1100 g/person/day from soy sauce
EU Restriction of 3-MCPD in process flavor is 20 ppb (liquid base) and 50 ppb (dry base)
3-MCPD (3-monochloropropane-1,2-
diol)
3-MCPD esters
Potential concern — Occurrence of 3-MCPD esters in a wide range of cooked foods
and breast milk (data published 2004 – 2006)
— 3-MCPD-esters in the diet may release some free 3-MCPD by
action of gut lipases, potentially contributing to the overall
dietary exposure to free 3-MCPD
O
R O
O
R O
Cl
O
R O
Cl
OH O
R O
OH
Cl
OH
OH
Cl
R = alkyl
3-MCPD 3-MCPD diesters 3-MCPD monoesters
Proposed mechanism for the formation of 3-MCPD diesters from DAG. L represents lipid.
Published in: Xiaowei Zhang; Boyan Gao; Fang Qin; Haiming Shi; Yuangrong Jiang; Xuebing Xu; Liangli (Lucy) Yu; J. Agric. Food Chem. 2013, 61, 2548-2555.DOI: 10.1021/jf305252qCopyright © 2013 American Chemical Society
Furan in baby foods & infant formula
0
20
40
60
80
100
120
baby foods in glassjarrs (vegetables,
meat, fruit)
baby food (powderfor porridge)
baby beverage(juices & teas)
infant formula
211 4 10 27
co
nc
. (p
pb
)
25%ilemean
medianmax95%ile
75%ile
Potential concernFoods, especially jarred and canned foods, subject to heat treatment can contain furan (in particular baby foods in jars)
- causes liver cancer in animal studies with high potency- genotoxic carcinogen (IARC class 2B ‘possibly carcinogenic to
humans’)- no human epidemiological data on cancer
Furan
ExposureNo reliable exposure Estimates
(~ 1 µg/kg bw/day )
U.S. Food and Drug Administration (May 7, 2004; updated June 7, 2004) (http://www.cfsan.fda.gov/~dms/furandat.html)Reinhard et al., Mitt. Lebensmit. Hyg. 2004, 95, 532-535.
Ascorbic acid is the major furan precursor under thermal conditions
E Erythrose
TAG Threonine+Alanine+Glucose
GA Glycolaldehyde+Alanine
GS Glycolaldehyde+Serine
E TAG GA GS
Maillard type systems
LA Linoleic acid (C18:2)
T Trilinoleate
LnA Linolenic acid (C18:3)
Tn Trilinolenate
LA T LnA Tn
Lipids
AA Ascorbic acid
DAA Dehydroasc. acid
AA DAA0
2x103
4x103
6x103
8x103
1x104
mo
l/mo
l Fu
ran
Ascorbic acid
(Maerk et al., J. Agric. Food Chem. 2006, 54, 2786-2793)