Toxic Chemicals in the Daily Environment Reducing Chronic Diseases and Disorders Through Safer Solutions Ted Schettler MD, MPH Science and Environmental Health Network

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

Status of Developmental Toxicity Testing for the 2,863 Chemicals Produced Above 1 million pounds/year No Data On Developmental Toxicity ~ 30 Tested for Neurodevelopmental Toxicity According to EPA Guidelines Some Data On Developmental Toxicity In Harm’s Way,

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 19 th 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 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)

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; 2008 Munoz-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: 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

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], ; 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], ; 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