Toxic Chemicals in the Daily Environment

1. Toxic Chemicals in the Daily Environment Reducing Chronic Diseases and DisordersThrough Safer Solutions Ted Schettler MD, MPH Science and Environmental Health Network www.sehn.org

2. Health environment Poverty Racism Stress Access to health care Social support Nutrition Toxic chemicals Radiation Infections Physical agents Genes and environment are in continuous conversation Environmental factors can alter gene function, gene expression genes

3. Status of Developmental Toxicity Testingfor the 2,863 ChemicalsProduced Above 1 million pounds/year Some Data On Developmental Toxicity ~ 30 Tested for Neurodevelopmental Toxicity According to EPA Guidelines No Data On Developmental Toxicity In Harm’s Way, www.preventingharm.org

4. 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.

5. 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

6. 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

7. 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

8. 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

9. Bisphenol A--exposures • Childhood exposure estimates: • Most studies estimate 2-20 microgm/kg/day from dietary sources for infants and young children (CERHR, 2008)

10. 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

11. Bisphenol A at ‘everyday levels’ Human, (free BPA)

12. BPA in blood and breast milk CERHR, Natl Toxicol Program, 2008

13. Fig. 2. Concentrations (in ng/ml) of unconjugated BPA in plasma in female mouse pups throughout the 24 h after a single dose, administered either orally (solid line) or by subcutaneous injection (dashed line). BPA was administered at either 35microg/kg (low dose, circles) or 395microg/kg (high dose, squares). Values represent mean plasma values at each time point (±S.E.M.). Note the log scale for the Y-axis. (Taylor et al. Repro Toxicology, 2008)

14. 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

15. Health questions about BPA Impaired brain development Hyperactivity Aneuploidy: Down’s Prostate, breast cancer Low sperm count Long-term memory formation Dementia Obesity and diabetes

16. 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; 2008 Munoz-de-Toro; Endocrinology; 2005

17. 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)

18. 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)

19. 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)

20. Aneuploidy… cell division gone wrong

21. Bisphenol A causes aneuploidy

22. Bisphenol A causes insulin resistance in mice Rapid response: 30 min after addition of BPA or estradiol: Blood sugar drops because insulin increased Slower response: After 4 days BPA-treatment, insulin increases but animals no longer respond Alonso-Magdalena; EHP, 2006 Ropero, Intl J Androl, 2008

23. 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)

24. 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)

25. 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

26. 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)

27. 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

28. 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

29. 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

30. 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