Toxic Chemicals in the Daily Environment
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Transcript of Toxic Chemicals in the Daily Environment
Toxic Chemicals in the Daily Environment
Reducing Chronic Diseases and Disorders
Through Safer Solutions
Ted Schettler MD, MPHScience and Environmental Health Network
www.sehn.org
environment
Poverty
Racism
Stress
Access to health care
Social support
Nutrition Toxic chemicalsRadiationInfectionsPhysical agents
genesGenes and environment are in continuousconversation
Environmental factors can altergene function, gene expression
Health
Status of Developmental Toxicity Testingfor the 2,863 Chemicals
Produced Above 1 million pounds/year
21.4%
0.4%
78.2%
No DataOn DevelopmentalToxicity
~ 30 Tested for NeurodevelopmentalToxicityAccording to EPAGuidelines
Some DataOn DevelopmentalToxicity
In Harm’s Way, www.preventingharm.org
Chemicals in consumer products
• Many different potential health effects; e.g. asthma; cancer; birth defects; altered fetal, infant, child, development; infertility, etc.
• Level, timing, duration of exposure are important; windows of vulnerability
• Susceptible sub-populations for a variety of reasons; e.g. multiple, cumulative exposures; associated stressors; life stage; genetic determinants, etc.
This presentation
• Focus on one chemical (bisphenol A) used in many different consumer products– An example of a more general set of issues– Ubiquitous exposures– Increasingly well studied; instructive with respect
to toxic properties
• Policy implications and options
Bisphenol A
• First synthesized in late 19th century
• Determined to be estrogenic in 1920s
• Polymerized in polycarbonate plastic and also used in some resins and flame retardants
• Annual global production > 6 billion pounds
Bisphenol A uses• food and drink packaging; • CDs and other hard plastics• lacquers that coat metal products such as food cans,
bottle tops, and water supply pipes. • polyester resins, polysulfone resins, polyacrylate resins,
flame retardants. • processing of polyvinyl chloride plastic and in the
recycling of thermal paper. • Some polymers used in dental sealants and tooth
coatings contain bisphenol A
Bisphenol A—exposures
• Widespread in general population– 93% of representative study population have
detectable levels of BPA in urine (NHANES, included no children less than 6 yrs old)
– Levels higher in children than adults
– Male median 1.63 ng/ml urine– Female median 1.12 ng/ml urine
Bisphenol A--exposures
• Childhood exposure estimates:– Most studies estimate 2-20 microgm/kg/day from
dietary sources for infants and young children(CERHR, 2008)
Bisphenol A metabolism• Bisphenol A absorbed from intestinal tract• Metabolism involves glucuronidation, which
renders the BPA less active and facilitates excretion
• A debate about the speed with which this occurs and whether free BPA is in the blood has been featured in scientific literature
• Fetus and infant have undeveloped glucuronidation capacity
Bisphenol A at ‘everyday levels’
Human, (free BPA)
BPA in blood and breast milk
CERHR, Natl Toxicol Program, 2008
Fig. 2. Concentrations (in ng/ml) of unconjugated BPA in plasma in femalemouse pups throughout the 24 h after a single dose, administered either orally(solid line) or by subcutaneous injection (dashed line). BPA was administeredat either 35microg/kg (low dose, circles) or 395microg/kg (high dose, squares). Valuesrepresent mean plasma values at each time point (±S.E.M.). Note the log scalefor the Y-axis. (Taylor et al. Repro Toxicology, 2008)
Bisphenol A—toxicity
• Estrogenic activity through classic estrogen receptor has received considerable attention
• We now know that BPA can also act through other receptors and other mechanisms, including modifying thyroid hormone status
• Concentrate here on low dose effects
Health questions about BPA
Aneuploidy: Down’s
Prostate, breast cancer
Impaired brain development
Long-term memory formation
Obesity and diabetes
Low sperm count
Dementia
Hyperactivity
BPA—breast cancer
• Peri-natal exposure to environmentally relevant doses of BPA (subcutaneously)—mice
• Female offspring with increased number of terminal end buds in mammary glands and decreased apoptosis (programmed cell death); intraductal hyperplasia
Vandenberg et al; Repro Toxicol; 2008Munoz-de-Toro; Endocrinology; 2005
BPA—breast cancer
• Mice—neonatal and pre-pubertal exposure to BPA via lactation resulted in increased numbers and shorter latency of tumors in mammary glands of female offspring after exposure to a carcinogen (DMBA) in adulthood
• Various proteins associated with cell proliferation and decreased apoptosis upregulated in adults (Jenkins, EHP, 2009)
BPA—prostate cancer
• Mice—prenatal exposure to environmentally relevant doses of BPA causes proliferation of ducts and prostatic intraepithelial neoplasia in male offspring
• Rats—perinatal exposure to BPA increases precancerous lesions and susceptibility to hormonally related adult prostate cancer (Prins, 2008)
BPA--aneuploidy
• Mice—low level BPA exposure interferes with chromosomal separation during cell division resulting in aneuploid cells (abnormal numbers of chromosomes in daughter cells)
(Hunt, Curr Biol, 2003)
Aneuploidy… cell division gone wrong
Bisphenol A causes aneuploidy
Bisphenol A causes insulin resistance in mice
Rapid response:Rapid response:30 min after addition of 30 min after addition of
BPA or estradiol:BPA or estradiol:Blood sugar drops becauseBlood sugar drops because
insulin increasedinsulin increased
Slower response:Slower response:After 4 days BPA-treatment, After 4 days BPA-treatment,
insulin increases but animals no insulin increases but animals no longer respond longer respond
Alonso-Magdalena; EHP, 2006Ropero, Intl J Androl, 2008
Bisphenol A—diabetes, humans
• Higher BPA concentrations were associated with diabetes (OR per 1-SD increase in BPA concentration, 1.39; 95% confidence interval [CI], 1.21-1.60; P < .001)
NHANES population-wide survey(Lang et al.; JAMA; 2008)
Bisphenol A—heart disease, human
• Higher urinary BPA concentrations were associated with cardiovascular diagnoses in age-, sex-, and fully adjusted models (OR per 1-SD increase in BPA concentration, 1.39; 95% confidence interval [CI], 1.18-1.63; P = .001 with full adjustment).
NHANES; representative population(Lang, et al.; JAMA; 2008)
Bisphenol A suppresses adiponectin release from human adipose tissue (in vitro explants); Adiponectin is a hormone that protects against insulin resistance, metabolic syndrome, inflammation.
Hugo, Environ Health Perspect; 2008
Bisphenol A—brain • Many studies of developmental exposures to
BPA in rodents and impacts on behavior– Decreased response to novelty; increased general
activity in females – in all different experimental settings, while a
significant sex difference was observed in the control group, exposure to BPA decreased or eliminated the sex difference in behavior
– Associated with altered levels of neurotransmitters in sexually dimorphic brain
areas (Palanza; Environ Res, 2008)
Bisphenol A—brain • exposure of
ovariectomized young adult nonhuman primates to BPA at 50 microg/kg/d
completely abolishes the synapse-forming effect of estradiol in all hippocampal subregions (memory, learning)
Leranth, PNAS, 2008
CERHR—Natl Toxicology Program
• The NTP has some concern for effects on the brain, behavior, and prostate gland in fetuses, infants, and children at current human exposures to bisphenol A.
CERHR, Natl Toxicology Program, 2008
Conclusion• Multiple lines of evidence show that BPA is
causally associated with and correlates with a number of health effects of concern to humans at current exposure levels
• Virtually the ENTIRE human population is exposed• From a public health perspective, this means that
the entire population is at risk• Even if the additional risk from BPA is small for
any given endpoint, the public health implications are highly significant
Taking action
• Goal: Protect public health; primary prevention
• Choose between false positive vs. false negative errors (who decides?)
• Locate the burden of proof in the system• Seek and implement safer alternatives• Reduce uncertainties by pre-market safety
testing of chemicals and materials; e.g REACH in the EU