Weight of the Evidence Evaluation of Low-Dose Reproductive and Developmental Effects of Bisphenol A

ABSTRACT

A panel convened by the Harvard Center for Risk Analysis (HCRA) evaluated the weight of evidence for potential developmental and reproductive toxicity of bisphenol A (BPA, CASRN 80-05-7) in animals at doses well below the Lowest Observed Adverse Effect Level (LOAEL) of 50 mg/kg-day previously identified by the U.S. Environmental Protection Agency (US EPA) and even US EPA's reference dose (RfD) of 0.05 mg/kg-day. The effects are hypothesized to occur through an endocrine-modulating mode of action, specifically through estrogen receptors. The panel focused on potential male reproductive effects but also examined other endpoints possibly associated with hormone-like effects. The review considered studies published through April 2002. A formal deliberation framework focused on consistency, generalizability, and biological plausibility. The panel found no consistent affirmative evidence of low-dose BPA effects for any endpoint. Inconsistent responses across rodent species and strains made generalizability of low-dose BPA effects questionable. Lack of adverse effects in two multiple-generation reproductive and developmental studies casts doubt on suggestions of significant physiological or functional impairment. The panel was concerned about generalization of non-oral administration results to oral exposures. Differences in the pattern of BPA responses compared to estradiol or diethylstilbestrol (DES) cast doubt on estrogenicity as a low-dose mechanism of action for BPA. Finally, there is indirect evidence that humans may be less sensitive to possible estrogenic effects from BPA exposure due to pharmacodynamic factors. The panel recommended replication of existing studies under carefully controlled conditions and further study of BPA's pharmacokinetics and pharmacodynamics. The study was funded by a grant from the American Plastics Council.

Keywords:

• bisphenol A
• endocrine disruption
• reproductive toxicity
• developmental toxicity
• weight of evidence.

ACKNOWLEDGMENTS

This work was funded by a grant from the American Plastics Council. The authors thank Drs. Paul Foster (National Institute of Environmental Health Sciences), Marvin Meistrich (University of Texas M. D. Anderson Cancer, Houston), Heinz Nau (Veterinary Medical University of Hannover), and Richard Sherins (Genetics and IVF Institute) for helpful comments and guidance.

Notes

¹ The main source of difference was related to exposure in wine. Both assessments assumed consumption of 750 ml (one standard bottle) of wine per day but with different estimates of BPA levels in wine. Wine accounted for 23% of the total BPA exposure estimated by the Scientific Committee on Food, and 83% of the total BPA exposure estimated in the European Union Risk Assessment.

² A recent paper, not reviewed by the panel, was unable to replicate the findings of Sakaue et al.—J. Ashby, H. Tinwell, P. A. Lefevre, R. Joiner, and J. Haseman, The Effect on Sperm Production in Adult Sprague-Dawley Rats Exposed by Gavage to Bisphenol A between Postnatal Days 91–97, Toxicol. Sci. 2003 74: 129–138

³ Also see footnote 2.