Politics of plastics: the “sound science” of bisphenol A Sarah A. Vogel,PhD Candidate Columbia University Dept of Sociomedical Sciences Center for the History and Ethics of Public Health

“When we look into a mirror we think the image that confronts us is accurate. But move a millimetre and the image changes. We are actually looking at a never- ending range of reflections. But sometimes a writer has to smash the mirror - for it is on the other side of that mirror that the truth stares at us. I believe that despite the enormous odds which exist, unflinching, unswerving, fierce intellectual determination, as citizens, to define the real truth of our lives and our societies is a crucial obligation which devolves upon us all. It is in fact mandatory.” ~ Harold Pinter, Nobel Prize for Literature, 2005 acceptance speech.

Diethylstilbestrol (DES) Estradiol bisphenol A

U.S. Bisphenol A Production Volume

Biomonitoring studies BPA levels in pregnant women (Germany): ppb (Schönfelder et al. 2002) BPA in breast milk: ng/ml (mean = 0.61 ng/ml) (Sun et al. 2004) BPA in colostrum breast milk: 1-7 ng/ml (mean = 3.41 ng/ml) (Kuruto-Niwa et al. 2006) Adult human urine: 95% of samples in reference population of 394 Americans, conducted by the U.S. C.D.C. mean = 1.63 ng/ml (males), 1.12 ng/ml (females) (Calafat et al, 2005)

Endocrine disruption thesis Re-examines dose-response relationship Timing of exposure related to effect observed Effects can be transgenerational and outside traditional toxicological endpoints

Biological stakes: selected adverse effects of low doses of BPA altered mammary gland and prostate gland development that may result in increased susceptibility to cancer (Ho et al., 2006; Vandenberg et al., 2006 and 2007) increase in polycystic ovarian disease (Newbold et al. 2007) aneuploidy: disruption of chromosomal alignment during meiosis; results in miscarriage (Hunt et al. 2003; Susiarjo et al. 2007) Changes in brain structure (sexually dimorphic) (Kubo et al and 2003; Funabashit et al. 2004; Rubin et al. 2006)

Defining low dose LOAEL from the 1982 NTP Carcinogenesis Bioassay of 50 mg/kg based on estimates of consumption of feed exposed to 1000 mg/kg (ppm). EPA reference dose: 50 mg/kg/1000 (uncertainty/safety factor) = 50  g/kg Vom Saal male reproductive studies exposed mice to 2 and 20 µg/kg during in utero development

Stakes of the BPA debate Biologically - bisphenol A is an endocrine disruptor found in human tissue and blood. Economic - billions of dollars! Over 6 billion pounds produced per year; future regulatory costs and potential liability. Political – implications of a new testing paradigm in regulatory toxicology to consider environmentally relevant doses and long-term developmental effects.

NTP Low Dose Report 2001 “…there is credible evidence that low doses of BPA can cause effects on specific endpoints. However, due to the inability of other credible studies in several different laboratories to observe low dose effects of BPA, and the consistency of these negative studies, the Subpanel is not persuaded that a low dose effect of BPA has been established as a general or reproducible finding.” *R. Melnick et al., "Summary of the National Toxicology Program's report of the endocrine disruptors low-dose peer review," Environ Health Perspect 110, no. 4 (2002):

NTP Low Dose Report 2001 “low dose effects were clearly demonstrated for estradiol and several other estrogenic compounds. The shape of the dose-response curves for effects of estrogenic compounds varies with the end point and the dosing regimen…that the current testing paradigm used for assessments of reproductive and developmental toxicity should be revisited to see if changes are needed regarding dose selection, animal model selection, age when animals are evaluated, and the end points being measured following exposure to endocrine-active agents.”

“sound science” network Graham Annapolis Center Gradient Dauber t ACC/SPI Data Quality Act OMB Advancement of Sound Science Coalition Center for Regulatory Effectiveness George Gray EPA/ORD Harvard Center for Risk Analysis

“sound science”movement 1991: Peter Huper coins “junk science” to explain the flood of toxic tort cases. 1993: Supreme Court responds to cries of “junk science” in Daubert v. Merrell Dow Pharmaceuticals Evidentiary rules: reliability and relevance Shelby Amendment 1998 Data Quality Act 2001

“sound science” network Graham Annapolis Center Gradient Dauber t ACC/SPI Data Quality Act OMB Advancement of Sound Science Coalition Center for Regulatory Effectiveness George Gray EPA/ORD Harvard Center for Risk Analysis

Annapolis Accords on the Use of Toxicology in Risk Assessment and Decision-Making Rigor: “proper conduct and analysis” Power: ability to detect an effect if one exists Corroboration: replication of findings Universality: effect seen in multiple species Proximity: effect seen in animals more closely related to humans Relevance: mechanisms of action are similar in humans Cohesion: data are consistent and “subject to single biologically plausible explanation”

questioning reliability and relevance Non-oral route of exposure Problem of relevance/proximity Difference in species response Problem of reliability Difference in endpoint response Problem of reliability Lack of response with DES exposure Problem of reliability

Call for a new risk assessment in 2005 vom Saal and Hughes in Environmental Health Perspectives (2005) reported the following: As of 2005, they found 115 low dose studies of bisphenol A in the published, peer-reviewed literature. Of the 115, 104 funded by government institution, 94 of which reported some significant effect. 11 of 115 funded by private industry, none of which reported any effects.

vom Saal and Hughes (2005) call for a new risk assessment Increase postnatal growth Early onset of sexual maturation in females Increased prostate size Altered mammary gland development Decreased sperm production and fertility in males Chromosomal alignment disruption Altered immune function Decreased antioxidant enzymes in adult males Changes in hormone receptors in brain Behavioral changes: hyperactivity, aggressiveness, changes in sexual behavior

Chapel Hill Consensus Statement “we are certain of the following…” (excerpts) Sensitivity to BPA varies with life stage In vitro studies provide “two routes of plausibility for low dose in vivo effects of BPA”: binding to nuclear estrogen receptors and binding to estrogen receptors on the cell membrane, which is more sensitive to BPA. “The similar effects observed in wildlife and laboratory animals exposed to BPA predict that similar effects are also occurring in humans.”

Chapel Hill Consensus Statement “we are certain of the following…” (excerpts) BPA alters “epigenetic programming” of genes in experimental animals and wildlife that results in persistent effects that are expressed later in life…Specifically, prenatal and/or neonatal exposure to low doses of BPA results in organizational changes in the prostate, breast, testis, mammary glands, body size, brain structure and chemistry, and behavior of laboratory animals.” BPA level in the fetal mouse exposed to BPA by maternal delivery of 25 ug/kg, a dose that has produced adverse effects in multiple experiments, are well within the range of unconjugated [estrogenic] BPA levels in human fetal blood.

“I believe that despite the enormous odds which exist, unflinching, unswerving, fierce intellectual determination, as citizens, to define the real truth of our lives and our societies is a crucial obligation which devolves upon us all. It is in fact mandatory.” ~ Harold Pinter, Nobel Prize for Literature, 2005 acceptance speech.