Download a PDF of the letter below, plus attachment.
January 25, 2008
Dr. Michael D. Shelby
Director
Center for the Evaluation of Risks to Human Reproduction
National Institute of Environmental Health Services
Department of Health and Human Services
P.O. Box 12233
MD EC-32
Research Triangle Park, NC27709
Re: Comments on the Bisphenol A (BPA) Expert Panel Report
Dear Dr. Shelby:
We are writing to provide comments to the National Toxicology Program (NTP) as the agency develops its final position on the extent to which the toxic plastics chemical bisphenol A (BPA) poses a risk to human reproduction and development. As you conduct your review, we urge you to consider fully the following important data and information that is highly relevant to a determination of BPA’s potential impacts on human health:
- The objectivity of CERHR’s review of BPA toxicity remains in question. Sciences International, a contractor who was subsequently fired by the National Institutes of Health for potential conflict of interest, prepared the initial BPA review document for the Center for the Evaluation of Risks to Human Reproduction (CERHR). This document continued to be used by the expert panel despite the fact that several prominent scientists and public health advocates questioned its objectivity. We understand that CERHR’s final version of this review document (CERHR 2000a) will be used as a basis for NTP’s determination. The objectivity of the findings in this document remain in question and should be reviewed in full by NTP.
- The CERHR final expert panel report contains many errors and inconsistencies: In their review of the CERHR expert panel interim draft (CERHR 200b), independent BPA experts identified hundreds of errors and inconsistencies (EWG 2007a); review of the final expert panel draft finds that many of these errors and inconsistencies were not adequately addressed. NTP must ensure that its determination is based on accurate information, and must not rely on the inconsistent and incorrect findings that still plague the CERHR assessment.
- The CERHR expert panel failed to consider the significant, high exposures to BPA for formula fed infants (EWG 2007b). NTP’s consideration of these exposures is essential if the agency is to reach an accurate determination on BPA’s risks.
- New data confirms the relevance of BPA studies that used non-oral routes of administration. These studies were categorically excluded by the expert panel in reaching their final decision. In light of the new data, NTP should incorporate findings from these excluded studies in making its determination.
- BPA experts raise serious concerns about potential human health impacts from BPA exposures. A NIEHS-sponsored panel of 38 BPA experts, which convened in Chapel Hill, North Carolina in November of 2006, published a comprehensive consensus statement regarding BPA toxicity and determined that BPA exposure is a risk to human health (vom Saal 2007); the NTP’s thorough consideration of this expert panel’s findings is critical.
Each of these points is described in detail below.
The objectivity of CERHR’s review of BPA toxicity remains in question. In March of 2007, the National Institutes of Health fired the contractor (Sciences International) that was hired to prepare the initial BPA review document, citing potential conflicts of interest when information became available that showed that Sciences International staff had previously worked with BPA manufacturers. The document that was prepared by this contractor, however, continued to be used by the expert panel, despite the fact that several prominent scientists and public health advocates had questioned the objectivity of the Sciences International review. CERHR’s final report is derived from this original, conflicted document. The objectivity of findings in this final report remains in question and must be thoroughly reviewed by NTP.
The CERHR final expert panel report contains many errors and inconsistencies. In April of 2007, CERHR released an interim draft expert panel report (CERHR 2007b); instead of addressing the issues that were brought up regarding the objectivity of the initial review prepared by Sciences International, the interim draft was even more error-riddled and even less objective that the initial review. In fact, BPA experts who reviewed this interim draft noted hundreds of errors in documentation, analysis, and interpretation; they submitted these findings in written comments to the expert panel in June of 2007 (EWG 2007a). These BPA experts found the following:
- 297 potential errors in documentation and analysis of study results, and in interpretation of the study findings and their significance that are in conflict with the peer reviewed literature
- 195 instances where the panel assessment is incomplete, including incomplete documentation of relevant test results or missing justifications for panel assertions
- 48 instances in which the panel inconsistently applied criteria for study evaluation
Our detailed evaluation of these errors and inconsistencies in the April 2007 draft in included as an attachment to this letter (attachment 1). These issues with documentation, analysis, and interpretation resulted in an assessment that heavily favored industry studies over government and independent studies. In this interim draft, the expert panel rejected government and independent studies at 3 times the rate of industry studies.
Only some of these issues have been addressed in the final expert panel report that was released in November of 2007 (CERHR 2007a). Significant inconsistencies and errors remain within this report.
In just one example, the panel reviewed a study from Cagen et al in section 3.2.3.2 in which they noted “the lack of much effect with diethylstilbestrol treatment is a weakness”, but they go on to conclude “the panel considered this study adequate and of high utility”. However, in a review of a second study by Cagen et al in section 3.2.5.1 in which there were also problems with the positive control, the panel noted “this paper is inadequate for the evaluation process due to absence of response of the positive control group”. It is unclear why two studies in which there are serious issues with the positive control are judged so differently.
The expert panel had also noted in the interim draft that they had specific concerns with the use of DMSO as a vehicle for BPA because of its biological activity: in response to this, we had noted in our public comments from June of 2007 that while the panel singled out DMSO, they did not raise any objections to the use of oil vehicles which have been shown to often have background estrogenicity. This issue does not appear to have been addressed at all by the expert panel.
The fact that there are still inconsistencies in the expert panel’s final draft illustrates how the CERHR expert panel continues to apply arbitrary standards throughout this evaluation.
The CERHR expert panel failed to consider the significant, high exposures to BPA for formula fed infants. We would also bring your attention to our recent report on the presence of BPA in canned infant formula (EWG 2007b). Laboratory studies of canned infant formula conducted by the Food and Drug Administration (FDA) and a certified commercial laboratory commissioned by EWG reveal that BPA leaches from metal can linings into formula. EWG analysis of these results revealed the following:
- One of every 16 infants fed ready-to-eat canned formula would be exposed to BPA at doses exceeding those that altered testosterone levels, affected neurodevelopment, and caused other permanent damage to male and female reproductive systems (2.0 and 2.4 ug/kg/day- Howdeshell et al 1999, Honma et al 2002- studies cited as ‘adequate’ by the expert panel)
- At the highest BPA levels found in formula (17 parts per billion), nearly two-thirds of all infants fed ready-to-eat formula would be exposed above doses that proved harmful in animal tests (2.0 and 2.4 ug/kg/day- Howdeshell et al 1999, Honma et al 2002)
Laboratory studies have consistently shown that the most sensitive periods of exposure to BPA are during pregnancy and early life (Maffini 2006). These infant formula findings reveal that millions of formula fed infants may have daily, sustained exposures to BPA at levels that have been shown to cause harm in lab animals. These exposures could be relatively continuous throughout their first 6 months of life and should be fully considered by NTP as the agency reaches a determination on BPA’s potential impacts on human health.
New data confirms the relevance of BPA studies that used non-oral routes of administration. At the close of the second expert panel meeting in August of 2007, the CERHR expert panel issued conclusions regarding the potential reproductive and developmental toxicity of BPA. They expressed “some concern” that exposure to BPA may cause neural and behavioral effects in the developing fetus, infants, and children, but expressed “minimal concern” about other potential health effects. The panel came to these conclusions by discarding a large number of independent, peer-reviewed studies linking BPA exposure to mammary and prostate gland lesions, impaired fertility, and ovarian dysfunction in lab animals.
The panel made a decision to include data from only those studies in which BPA was administered to lab animals via oral routes of administration. This decision by the expert panel resulted in the exclusion of many well-conducted studies from academic labs from across the United States; most importantly, the studies that were excluded had all passed through the rigors of peer review and had been published in a number of prestigious scientific journals. In addition, this decision to exclude data from studies in which BPA was administered to lab animals via non-oral routes of administration is not backed up by the scientific literature and is highly unusual in public health evaluations.
In fact, a recent study published in the journal Reproductive Toxicology finds that non-oral routes of BPA administration are completely valid in assessing potential health effects (Taylor 2008). In this study, scientists administered BPA to neonatal mice by both oral and subcutaneous routes and found no significant difference in plasma levels of unconjugated BPA, leading study authors to concluded “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 route of administration”.
This definitive scientific study refutes the faulty reasoning that the expert panel used in discarding many valid and scientifically sound studies that linked low dose BPA exposure with adverse health effects such as breast and prostate cancer, infertility, and early puberty. In fact, the decision by the expert panel to disregard studies that used a non-oral route of administration is just one more in an long list of missteps that has plagued this review and leads us to question the validity of the conclusions.
BPA experts raise serious concerns about potential human health impacts from BPA exposures. Lastly, we would like to draw your attention to a series of papers that were published in the journal Reproductive Toxicology in 2007. These papers were published by a group of 38 BPA experts from around the world who systematically reviewed over 700 BPA related scientific papers.
In contrast to the CERHR expert panel, none of whom were BPA experts, this group of 38 scientists included many of the world’s most published BPA experts from top academic universities and government institutions. These scientists conducted a highly structured and organized review of the BPA literature that focused on consensus building; their findings were condensed into a consensus statement in which they concluded:
- The similar effects observed in wildlife and laboratory animals exposed to BPA predict that similar effects are also occurring in humans and
- Much evidence suggests that these adverse effects are occurring in animals within the range of exposure to BPA of the typical human living in a developed country, where virtually everyone is exposed to measurable blood, tissue and urine levels of BPA that exceed the levels produced by doses used in the low dose animal experiments” (vom Saal 2007)
The final decision rendered by NTP regarding the reproductive and developmental toxicity of BPA will have repercussions on the public health, and as such, should not be based on the flawed and biased CERHR evaluation. We urge NTP to recognize the merits of the review conducted by the 38 BPA experts, in comparison with the CERHR evaluation. The scientific data clearly backs up their concerns about the reproductive and developmental toxicity of BPA and we urge NTP to recognize the low dose developmental and reproductive toxicity of BPA.
Sincerely,
Anila Jacob, M.D., M.P.H.
Senior Scientist
Environmental Working Group
References:
1) CERHR 2007a. Expert panel report on Bisphenol A. Bisphenol A evaluation. Center for the Evaluation of Risks to Human Reproduction.
2) CERHR 2007b. Interim draft expert panel report. Bisphenol A evaluation. Center for the Evaluation of Risks to Human Reproduction.
3) EWG (Environmental Working Group) 2007a. Failure of CERHR assessment of BPA to meet basic scientific standards. Attachment 1.
4) EWG (Environmental Working Group) 2007b. Toxic plastics chemical in infant formula. Available online at: https://www.ewg.org/node/22233.
5) Honma S, Suzuki A, Buchanan DL, Katsu Y, Watanabe H, Iguchi T. (2002). Low dose effects of in-utero exposure to bisphenol A and diethylstilbestrol on female mouse reproduction. Reproductive Toxicology 16: 117-22.
6) Howdeshell K, Hotchkiss AK, Thayer KA, Vandenbergh JG, vom Saal FS. 1999. Plastic bisphenol A speeds growth and puberty. Nature 401: 762-64.
7) vom Saal FS, Belcher SM, Guillette LJ, Hauser R, Myers JP, Prins GS, Welshons WV 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: 131-38.
8) Maffini MV, Sonnenscheim C, Soto AM. 2006. Endocrine disruptors and reproductive health: the case of bisphenol A. Molecular and Cellular Endocrinology 8: 254-55.
9) Taylor JA, Welshons WV, vom Saal FS. 2008. No effect of route of exposure (oral; subcutaneous injection) on plasma Bisphenol A throughout 24 hr after administration in neonatal female mice. Reproductive Toxicology 25(2): in press.