BPA characteristics: used for polymerization to form polycarbonate plastic

1. BPA characteristics: used for polymerization to form polycarbonate plastic Diagram depicting hydrolysis of the ester bond linking BPA molecules to form polycarbonate plastic. BPA is a symmetrical aromatic molecule that reacts on both phenolic ends in polymerization reactions. For polycarbonate, BPA typically reacts with phosgene forming an ester linkage, which is subject to an increase in hydrolysis as temperature increases and in response to acidic or basic conditions.

2. BPA characteristics: acts on estrogen receptor BPA has synthetic estrogen properties, and belong to the group of selective estrogen receptor modulators (SERM) due to: its interaction with different ligand binding domains of ERs and transcriptional regulators like estrogen, can induce strong response in cells through non-genomic mechanisms shows different affinity to ERα and ERβ (10x higher affinity) in target cells Overall balance of the relative expression levels of ER subtype and ER coregulators is an important determinant of the tissue specificity BPA, and marked differences in estrogen-responsive target organs have been observed at doses far below those previously predicted to cause biological effects. BPA Estrogen bound to ER BPA bound to estrogen receptor (ER)

3. Sources of BPA Polycarbonated plastic used in baby bottles, sippy cups, water bottles, medical and dental equipment. Also used to make epoxy resin lining of food cans. - Products containing BPA are may be labeled with recycling category 7 that includes polycarbonated plastic, but also other types of plastic that don’t have BPA.

4. Production and transformation of BPA Bisphenol A (BPA) is a high production volume chemical with a U.S. volume estimated at 2.4 billion pounds in 2007, and an estimated value of almost $2 billion. Bisphenol A may enter the environment from industrial sources or from product leaching, disposal, and use. In1999-2000, bisphenol A was detected in 41.2% of 139 U.S. streams in 30 states. In animal and human studies, bisphenol A is well absorbed orally. In humans, little free bisphenol A circulates after oral absorption due to the high degree of glucuronidation by the liver. The glucuronidated bisphenol A is excreted in the urine within 24 hours with no evidence of accumulation

5. Routes of human exposure General population exposure to bisphenol A may occur through ingestion of foods in contact with bisphenol A containing materials. People appear to be exposed primarily through food packaging uses of products manufactured using BPA, although those products account for less than 5% of the BPA used in this country. For small children, hand-to-mouth and direct oral contact with materials containing bisphenol A are possible. Exposure from indoor air and consumer products are a small component of total exposure estimates.

6. Exposure effects in animals Animal studies showed: > 50 mg/kg/day (delayed puberty in male and female rats and male mice) > 235 mg/kg/day (reduced fetal or birth weight or growth early in life, effects on testis of male rats) > 500 mg/kg/day (possible decreased fertility in mice, altered estrous cycling in female rats, and reduced survival of fetuses) systemic effects (reduction in body weight, changes in relative organ weights, and increases in liver toxicity) were observed at doses above 5 mg/kg/day. - low-dose effects are endocrine-related and include effects on puberty and developmental neurotoxicological effects (brain, behavior) at doses in animal studies as low as 2 μg/kg/day. Low doses of BPA are more relevant because these are observed in human exposure.

7. Reasons for concern Overview of 75 studies showing negative effects on human health:

8. Methods for measuring human exposure Concentrations of BPA presented in this table are in µg/g creatinine. BPA has been found in human biological samples (serum, breast milk, urine, fetal blood, and umbilical cord blood). The literature reporting these results reflects both a variety of analytical techniques and the BPA forms measured (i.e., total BPA , free-BPA and BPA-glucuronide). - Urinary levels of BPA (both conjugated and unconjugated) reflect recent exposure. National Health and Nutrition Examination Survey (NHANES) measured urinary BPA in 2,514 participants in 2003-2004 survey and detected BPA in 93% of the samples. Women, children and lower income strata had higher urinary BPA levels.

9. BPA history and policies The story of Bisphenol A (BPA): –1930‟s: BPA A found to have synthetic estrogen properties –1940‟s: BPA used to make “polycarbonate” plastics –1982: National Toxicology Program: Lowest Adverse Effect Level: 50 mg/kg/d –1997: First study showing toxic effects in humans at much lower doses –2003: NIH nominates BPA for evaluation, and hires Scientific International (independentresearch contractor to evaluate effects of BPA) –SI hand-picks 15 scientists for expert panel, but excludes scientists with most research experience with BPA to minimize “bias” –2006: SI, and therefore FDA, conclude that “BPA is safe” at current exposure levels –February 2007: SI found to have corporate clients such as DOW and BASF (manufacturers of BPA) –April 2007: Chapel Hill Panel (independent scientific researchers only): “BPA toxic at very low levels” –2008: Health Canada deems BPA “toxic” based on scientific review of over 100 studies demonstrate toxic effects at low dose (breast and prostate damage, early puberty, behavioral problems) –2008: Nestle, Abbott and Mead Johnson announce intent to eliminate BPA –2009:*)Harvard study: students who drink from plastic bottles have 70% higher concentrations of BPA than those who drink from stainless steel *) Several states ban use of BPA in manufacturing

10. Strategies for limiting human exposure 1) Ban: - Connecticut, Minnesota, Wisconsin, Washington, Chicago and Suffolk County, N.Y., have banned the sale of polycarbonate baby bottles, food containers and cups that contain BPA. Maryland passed the bill and is being signed into the law, while California and Oregon failed to pass the bill. In 2009, Canada became the first country to take regulatory action against BPA. Canada announced that it was moving forward with proposed regulations to prohibit the advertisement, sale and importation of polycarbonate plastic baby bottles that contain BPA, to reduce newborn and infant exposure to this substance. 2) Improved understanding of risk: - National Institute of Environmental Health Sciences (NIEHS) is investing approximately $30 million over two years on BPA research. The new two-year animal and human studies will focus on either developmental exposure or adult chronic exposures to low doses of BPA. Researchers will be looking at a number of health effects including behavior, obesity, diabetes, reproductive disorders, development of prostate, breast and uterine cancer, asthma, cardiovascular diseases and transgenerational or epigenetic effects.

11. Conclusions Human exposure to BPA is highly prevalent: over 90% of people in the US have detectable BPA levels in urine. Leeching of BPA from packaging of food products containing polycarbonates or epoxy resin are the main source of exposure. Ban of BPA products is the safest approach and has been implemented in Canada and Europe and some US states, at least for products intended for use by children. Recent data suggests that chronic low-dose exposure may have detrimental health effects. Further research is needed to improve understanding of risk associated with low doses of BPA and may lead to further limitations of BPA use.

12. References Volkel W et al; Chem Res Toxicol 15 (10): 1281-7 (2002) Morrissey RE et al; Fund Appl Toxicol 8 (4): 571-82 (1987) Shin BS et al; J Toxicol Environ Health A 65 (5-6): 395-406 (2002) Yoo SD et al; J Toxicol Environ Health A 64 (5): 417-26 (2001) Mu X et al; Environ Toxicol Chem 24 (1): 146-52 (2005) Razzoli M et al; Brain Res Bull 65 (3): 249-54 (2004) Sugiura-Ogasawara M et al; Hum Reprod 20 (8): 2325-9 (2005) National Toxicology Program, U.S. Department of Health and Human Services (2007-11-26). "Update on Bisphenol A for Use in Food Contact Applications: January 2010". U.S. Food and Drug Administration. 15 January 2010. Josephson J; EHP:108:A468-9. (2000) Welshons WV et al; Endocrinology 147;s56-69 (2006) Vandenberg LN et al; Endocr Rev 30;75-95 (2009) Sekizawa J; J Toxicol Sci 33;398-403 (2008) Taylor JA et al.; EHP: doi: 10.1289/ehp.1002514 (available at http://dx.doi.org/) Online 20 September 2010 Beronius A et al.; Reprod Toxicol 29 ;132-46 (2010) Small M. The Latest Science on Bisphenol A, Health and Exposure – January to July 2010. Available at: https://pincdn.s3.amazonaws.com/assets/09ef51935765fe93b1bb0b1d5a2f11b7/The-Latest-Science-on-BPA-Health-and-Exposure-Report.pdf Centers for Disease Control and Prevention. Department of Health and Human Services. “Fourth National Report on Human Exposure to Environmental Chemicals.” July 2010. http://www.cdc.gov/ExposureReport/pdf/FourthReport.pdf Dr Nimi Singh’s class presentation