EWG Supports California BPA assessments

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April 17, 2008

Ms. Cynthia Oshita
Office of Environmental Health Hazard Assessment
Proposition 65 Implementation
P.O. Box 401
1001 I Street, 19th Floor
Sacramento, CA 95812-4010

Dear Ms. Oshita: The Environmental Working Group (EWG) strongly supports OEHHA’s decision to assess the reproductive and developmental toxicity of the plastics chemical Bisphenol A (BPA). There is a growing body of science that supports the listing of BPA under California’s Proposition 65 as a chemical that may pose risks to human reproduction and development. This science has been recognized in the past week by an important new assessment and determination by the National Toxicology Program (NTP) of the National Institutes of Health. NTP’s most important findings are listed below:

• With regards to exposure, NTP notes “Although biomonitoring data are not available for infants and children less than 6 years of age, blood and urine levels of free bisphenol A are predicted to be higher in these age groups” (NTP 2008).
• NTP notes “there is some concern for neural and behavioral effects in fetuses, infants, and children at current human exposures. The NTP also has some concern for bisphenol A exposure in these populations based on effects in the prostate gland, mammary gland, and an earlier age for puberty in females” (NTP 2008).
• NTP concludes, “the possibility that bisphenol A may alter human development cannot be dismissed” (NTP 2008).

In addition, a Canadian news agency also reported this week that Health Canada, the government agency that deals with national public health issues, is expected to classify BPA as a toxic substance (Canadian Broadcasting Corporation 2008). In response to this imminent announcement, several major retailers including Wal-Mart Canada and Home Depot have begun removing BPA-containing plastic products from their shelves (National Post 2008). These actions by NTP and Health Canada are based on numerous animal studies conducted over the last decade linking in-utero and early life BPA exposures to a number of adverse health effects as diverse as obesity, behavioral problems, impaired fertility, early puberty, and cancer. The body of scientific knowledge on BPA toxicity, and concern over its use in consumer products, is growing at a rapid pace. In the last seven months since OEHHA prepared its study summary of the available scientific information on BPA’s potential to cause reproductive and developmental toxicity, there have been several new developments that we would like to bring to your attention:

• Infant formula manufacturers do not adequately test for BPA in their products to ensure their safety.
• FDA has based its public assurances of the safety of BPA-containing consumer products on just 2 industry studies, one of which is unpublished.
• Several recent studies that highlight the links between BPA exposure and adverse health effects have been published.
• New research shows that commonly used plastic water bottles leach BPA under typical conditions of use.
• New research confirms the relevance of low-dose BPA studies that use nonoral routes of administration.

Each of these new developments will be discussed in detail below: Major infant formula manufacturers fail to test products adequately to ensure they are safe: In December of 2007, EWG released the results of an investigation revealing that BPA is used by major manufacturers to line the metal portions of infant formula cans (EWG 2007a). Previous formula testing by EWG and the Food and Drug Administration (FDA) had shown that BPA leaches from the plastic lining of metal cans into liquid formula, exposing formula-fed babies to BPA concentrations in excess of levels that caused harm in animal studies (FDA 1996, EWG 2007b). Of the many types of consumer products made with BPA, contamination of infant formula with this chemical is of particular concern since many animal studies show that BPA exposures during early life are especially potent and result in adverse health effects later in life (EWG 2007a). US Congressmen John D. Dingell and Bart Stupak with the House of Representatives Committee on Energy and Commerce have launched an investigation into the use of BPA in baby formula, asking major manufacturers of BPA to divulge whether they use BPA in their products and if they had tested their products for BPA (Committee on Energy and Commerce 2008). They’ve also launched an investigation of the private scientific firm, the Weinberg Group, demanding that the group reveal the extent and nature of their work for BPA manufacturers and asking them to clarify “whether science is for sale” (Committee on Energy and Commerce 2008). Infant formula manufacturers provided the requested information but the Weinberg Group has not responded to the inquiry to date. Based on their responses, only 2 manufacturers have tested their formula for BPA contamination, Hain-Celestial and Abbott (Committee on Energy and Commerce 2008). However, both companies relied on methods with limits of detection that were so high that they would fail to detect BPA at the levels typically found in formula (EWG 2007a, FDA 1996). In essence, infant formula manufacturers, while acknowledging the use of BPA in their metal cans are either not testing for the chemical or have relied on tests with limits of detection that exceed FDA’s allowable leaching rate and that are higher than levels that have been shown to be harmful in laboratory studies. FDA relies on 2 industry studies in assertions of BPA safety, ignoring low-dose toxicity: As part of their investigation into the use of BPA in infant formula, the Committee on Energy and Commerce also demanded that FDA clarify its position on the safety of BPA and provide evidence to support their assertion that there is “no safety concern at the current exposure level” (Committee on Energy and Commerce 2008). The FDA response to the congressional inquiry revealed that their assertion that current levels of exposure do not pose a health concern are based on two studies that were sponsored by the American Plastics Council (APC) (Committee on Energy and Commerce 2008). One of these studies has not been made available to the public and has not been published in a peer-reviewed journal to date. In the second study, which did not find low dose BPA toxicity in rats, researchers failed to include positive controls and thus could not determine if the study provided conditions that would allow for BPA-related effects to be observed (Tyl 2002). This response to the Committee reveals that FDA has chosen to disregard all of the low-dose BPA studies found by NTP to pose risks to human development, instead relying heavily on two industry-funded studies. FDA also provided an “estimated worst-case daily intake” of BPA from infant formula and baby bottles of 7 ug/infant/day in their response. For a seven-pound newborn (3.1 kg), FDA’s “worst-case” scenario, which they claim is not a cause for concern, is just 10% below the levels shown in numerous animal studies to cause adverse health effects (2.2 ug/kg/day for FDA’s worst-case infant exposure, versus a 2.4 ug/kg/day toxic dose in animal studies) (Howdeshell 1999, Honma 2002, Akingbemi 2004). Of greater concern still, EWG analysis finds that many bottle-fed infants are exposed to BPA in doses that exceed FDA’s “worst-case” scenario. For instance, a baby of average size (4.5 kg) would exceed FDA’s “worst-case” dose if he or she drank more than 2.5 bottles (20 ounces) per day of formula contaminated with BPA at the maximum levels measured in an FDA testing programs (13 bbp) (FDA 1996, EWG 2007). In response to FDA’s reply, Congressmen Dingell and Stupak have asked the FDA commissioner to explain their dependence on two industry funded studies in reaching their determination of BPA safety while ignoring the dozens of independent studies showing low dose toxicity (Committee on Energy and Commerce 2008). This congressional investigation is still ongoing but it illustrates the concerns at the highest levels of government regarding the toxicity and risk to children’s health presented by this chemical. Recent publications further reinforce the link between BPA exposure and adverse health effects: Several new peer-reviewed studies have been published since OEHHA’s literature review that further bolster the body of knowledge on BPA’s developmental and reproductive toxicity. A summary of relevant findings from these studies, which include 3 reviews and one new study linking low-dose BPA exposure to adverse effects in the murine female reproductive tract is provided below: 1. An evaluation of evidence for the carcinogenic activity of bisphenol A (review). Keri, RA., Ho, SM., Hunt, PA., Knudsen, KE., Soto, AM., Prins, GS. Reproductive Toxicology 2007 Aug-Sep; 24(2): 225-39. Study authors conducted a review of the current BPA literature related to carcinogenicity and concluded the following with confidence: BPA acts as an endocrine disruptor with some estrogenic properties among other hormonal activities. Study authors concluded that the following are likely but require more evidence: BPA alters microtubule function and can induce aneuploidy in some cells and tissues. Early life exposures to BPA may induce or predispose to pre-neoplastic lesions of the mammary gland and prostate gland in adult life. Prenatal exposure to diverse and environmentally relevant doses of BPA alters mammary gland development in mice, increasing endpoints that are considered markers of breast cancer risk in humans. 2. Long-term adverse effects of neonatal exposure to bisphenol A on the murine female reproductive tract. Newbold, RR, Jefferson, WN, Padilla-Banks, E. Reproductive Toxicology 2007 Aug-Sep; 24(2): 253-8. Researchers treated female CD-1 mice on post-natal days 1 to 5 with BPA at 10,100 and 1000 ug/kg/day concentrations, administered via subcutaneous injection. Reproductive tract tissues were examined at 18 months of age. They found that while animals in all three treated groups had adverse effects in their reproductive tracts, those animals in the 100 ug/kg/day dose were most seriously affected. Animals in this group had increased incidence of adenomyosis, ovarian cysts, stromal polyps, and leiomyomas. Study authors concluded that “the findings of the present developmental study raise concerns over BPA contained in products used by infants and children”. 3. In vivo effects of bisphenol A in laboratory rodent studies (review). Richter, CA., Birnbaum, LS, Farabollini, F., Newbold, RR., Rubin, BS., Talsness, CE., Vandenbergh, JG., Walser-Kuntz, DR., vom Saal, FS. Reproductive Toxicology 2007 Aug-Sep; 24(2): 199-224. Study authors reviewed BPA studies that involved rodent animal models and concluded the following with confidence: Low doses of BPA during development have persistent effects on brain structure, function and behavior in rats and mice. There is extensive evidence for effects of exposure during critical periods to low doses of BPA on subsequent brain structure and chemistry, receptors for hormones and neurotransmitters, and behavior. We can thus state with confidence that low doses of BPA during development have persistent effects on brain structure, function, and behavior in rats and mice. There is extensive evidence that BPA impacts the reproductive system in male rats and mice, although there appears to be species and strain difference in the sensitivity of specific outcomes to BPA. Study authors conclude the following are likely but require confirmation: There is extensive evidence for effects of BPA on development of the mammary gland. Studies in both rats and mice have shown effects of developmental exposure to BPA on mammary gland morphology that may predispose animals to develop cancer. 4. Human exposure to bisphenol A (review). Vandenberg, LN., Hauser, R., Marcus, M., Olea, N., Welshons, WV. Reproductive Toxicology 2007 Aug-Sep;24(2): 139-77. Study authors conducted a comprehensive review of BPA literature and concluded the following: “The reported levels of BPA in human fluids are higher than the BPA concentrations reported to stimulate molecular endpoints in vitro and appear to be within an order of magnitude of the levels needed to induce effects in animal models”. Taken as a whole, these reviews include data from almost 200 different studies and provide strong evidence of the link between BPA exposure during early life and adverse health effects ranging from reproductive dysfunction and cancer to behavioral problems. BPA leaches from reusable plastic water bottles: A recent study from researchers at the University of Cincinnati found that reusable water bottles that are commonly used by millions of people every day leach BPA under normal conditions of use (Le 2008). The researchers found that BPA leached into water that was stored within these bottles and that leaching rates were independent of the age of the bottles. However, when hot water (100 degrees Celsius) was stored in these bottles, as might commonly occur during cold weather activities, leaching rates increased 15 to 55 fold, with rates ranging from 8 to 32 ng/hour. In the most recent CDC biomonitoring study, researchers found BPA in the urine of 93% of almost 2,500 Americans ages six and older who are representative of the US population (Calafat 2008). Sources of exposure varies from individual to individual but this study from the University of Cincinnati suggests that for a significant number of people, reusable plastic bottles may contribute a considerable portion to their daily BPA intake. This study also adds to the body of research that confirms the ubiquitous presence of this chemical in a variety of products that people use on a daily basis. There is now a movement within the marketplace to provide water bottles that are BPA free; there are also baby toys and bottles, sippy cups, and a number of other products that are marketed as “BPA free”. This suggests that in many of its current uses, BPA can easily be substituted with safer alternatives. However, these exclusive products are only available to those who are aware of the health concerns related to BPA exposure, and those that have the means to afford these products. Listing BPA under Proposition 65 as a developmental and reproductive toxin would encourage manufacturers to adopt safer alternatives or at least warn consumers of the risks associated with use of their products. New research confirms relevance of BPA studies that used non-oral routes of administration: Many of the studies that illustrate BPA’s low dose toxicity have used non-oral routes of administration. The relevance of these studies for human exposures was recently confirmed by researchers from the University of Missouri, who conducted a study in which they administered BPA to two different groups of neonatal mice by either oral or subcutaneous routes (Taylor 2008). They found no significant difference in plasma levels of unconjugated BPA, leading study authors to conclude “the large numbers of BPA studies that used non-oral administration at very low doses during the neonatal period should not be dismissed by scientists or the regulatory community based on the route of administration”. In summary, these recent developments and new studies add to a growing body of research that clearly illustrate the potential health risks associated with BPA exposure. Especially of concern are exposures among the developing fetus, infants, and children; recent CDC biomonitoring data revealed that children ages 6 to 11 years had least square geometric mean concentrations (LSGM) of BPA in urine that were almost double that in adults (4.5 micrograms/liter vs. 2.5 micrograms/liter) (Calafat 2008). This study did not include participants younger than age 6. In addition to these recent developments, there are a few other important points that we would like to bring to your attention:

• Current body of literature: To date, almost 100 animal studies have been published in peer reviewed journals that show significant adverse health effects related to BPA exposures that fall below the current ‘lowest adverse effect level’ (LOAEL) for BPA of 50 mg/kg/day defined by EPA (EPA 1993). These independent studies originated from scientists and labs at academic institutions and government agencies from all over the world. In many of these studies, exposure occurred in-utero and adverse health effects were observed in offspring. As a whole, these studies illustrate that BPA has adverse effects on diverse systems within the body, ranging from the immune system, to the reproductive, neurological, and endocrine systems.


• Adverse health effects related to BPA exposure mirror US health trends: In animal studies, BPA exposure at low doses has been linked to structural changes in mammary and prostate tissues that result in cancer later in life, in addition to a number of other adverse health effects including impaired fertility, insulin resistance, and recurrent miscarriage. These findings are especially worrisome in light of current US health trends since all of these adverse health effects are either on the rise or common among our population. While we may never have definitive epidemiological evidence showing cause and effect, the fact that the vast majority of Americans are chronically exposed to BPA, coupled with current health trends provides a compelling reason to exercise the precautionary principle.


• NIH sponsored panel finds concern: An NIH sponsored panel consisting of 38 BPA experts has expressed strong concerns about the risks to human health posed by current BPA exposures. In their consensus statement, they note the following “The published scientific literature on human and animal exposure to low doses of BPA in relation to in vitro mechanistic studies reveals that human exposure to BPA is within the range that is predicted to be biologically active in over 95% of people sampled. The wide range of adverse effects of low doses of BPA in laboratory animals exposed both during development and in adulthood is a great cause for concern with regard to the potential for similar adverse effects in humans. Recent trends in human diseases relate to adverse effects observed in experimental animals exposed to low doses of BPA. Specific examples include: the increase in prostate and breast cancer, uro-genital abnormalities in male babies, a decline in semen quality in men, early onset of puberty in girls, metabolic disorders including insulin resistant (type 2) diabetes and obesity, and neurobehavioral problems such as attention deficit hyperactivity disorder (ADHD)” (vom Saal 2007).

In conclusion, EWG would again like to reiterate our strong support for OEHHA’s decision to consider listing BPA as a developmental and reproductive toxin under Proposition 65. There is compelling evidence of its potential developmental and reproductive toxicity from the current science linking BPA exposure at low doses to a number of adverse health effects. This has led to increasing concern among legislators, consumers and manufacturers, prompting actions ranging from congressional inquiry to the introduction of BPA-free products into the marketplace. A health-protective decision by OEHHA that recognizes BPA as a developmental and reproductive toxin has the potential to set a precedent that could have far reaching implications for the public health.


Sincerely, Anila Jacob, M.D., M.P.H.
Senior Scientist
Environmental Working Group

References:

Akingbemi BT, Sottas CM, Koulova AI, Klinefelter GR, Hardy MP. 2004. Inhibition of testicular steroidogenesis by the xenoestrogen bisphenol A is associated with reduced pituitary luteinizing hormone secretion and decreased steroidogenic enzyme gene expression in rat Leydig cells. Endocrinology. 145(2):592-603. Canadian Broadcasting Company. 2008. Health Canada Bisphenol A announcement imminent. Available online at http://www.cbc.ca/consumer/story/2008/04/15/bisphenol.html?ref=rss. Calafat AM, Ye X, Wong LY, Reidy JA, Needham LL. 2008. Exposure of the U.S. population to bisphenol A and 4-tertiary-octylphenol: 2003-2004. Environ Health Perspect. 2008 Jan;116(1):39-44. Committee on Energy and Commerce. 2008. Bisphenol A in Infant Formula. Available at: http://energycommerce.house.gov/investigations/Bisphenol.shtml. EPA (U.S. Environmental Protection Agency), Bisphenol A, CASRN 80-05-7, IRIS, Integrated Risk Information System, on-line, 1993. Available at http://www.epa.gov/iriswebp/iris/subst/0356.htm. EWG (Environmental Working Group). 2007a. EWG’g guide to infant formula. Available at https://www.ewg.org/reports/infantformula. EWG (Environmental Working Group. 2007b. Bisphenol A: Toxic Plastics Chemical in Canned Food. Available online at https://www.ewg.org/reports/bisphenola. FDA (U.S. Food and Drug Administration) 1996. Cumulative exposure estimated for bisphenol A (BPA), individually for adults and infants from its use in epoxy-based can coatings and polycarbonate (PC) articles, verbal request of 10-23-95, memorandum to G. Diachenki, Ph.D., Division of Product Manufacture and Use, HGS-245, from Allan B. Bailey, Ph.D., Chemistry Review Branch, HFS-245. Honma S, Suzuki, A., Buchanan, D.L., Katsu, Y., Watanabe, H., Iguchi, T. 2002. Low dose effect of in utero exposure to bisphenol A and diethylstilbestrol on female mouse reproduction. Reprod Toxicol 16(2): 117-22. Howdeshell KL, Hotchkiss AK, Thayer KA, Vandenbergh JG, vom Saal FS. 1999. Exposure to bisphenol A advances puberty. Nature 401(6755): 763-4. Le HH, Carlson EM, Chua JP, Belcher SM. 2008. Bisphenol A is released from polycarbonate drinking bottles and mimics the neurotoxic actions of estrogen in developing cerebellar neurons. Toxicology Letters 176(2): 149-56. National Post. 2008. Ottawa will release bishpenol A decision in due time: Clement. Available at: http://www.nationalpost.com/news/story.html?id=450448. National Toxicology Program. (2008). Draft NTP report on bisphenol A. Available at: http://cerhr.niehs.nih.gov/chemicals/bisphenol/bisphenol.html. Taylor JA, Welshons WV, vom Saal FS. 2008. No effect of route of exposure (oral; subcutaneous injection) on plasma bisphenol A throughout 24h after administration in neonatal female mice. Reproductive Toxicology 25(2): 169-76. Tyl R. 2002. Three-generation reproductive toxicity evaluation of Bisphenol A in the feed of CD (Sprague-Dawley) rats. Toxicological Sciences 68, 121-146. vom Saal FS, Belcher SM, Guillette LJ, Hauser R, Myers JP, Prins GS, et al. 2007. Chapel Hill Bisphenol A Expert Panel Consensus Statement: Integration of mechanisms, effects in animals and potential impact to human health at current exposure levels. Reproductive Toxicology 24(2).