Human and Ecological Risk Assessment, 10: 875–921, 2004 Copyright C  ASP ISSN: 1080-7039 print / 1549-7680 online DOI: 10.1080/10807030490513883 CONTRIBUTED ARTICLES Weight of the Evidence Evaluation of Low-Dose Reproductive and Developmental Effects of Bisphenol A George M. Gray, 1 Joshua T. Cohen, 1 Gerald Cunha, 2 Claude Hughes, 3 Ernest E. McConnell, 4 Lorenz Rhomberg, 5 I. Glenn Sipes, 6 and Donald Mattison 7 1 Harvard Center for Risk Analysis, Harvard School of Public Health, Boston, Massachussets 02115, USA; 2 Department of Anatomy, University of California, San Francisco, California, USA; 3 Quintiles, Inc.; 4 ToxPath, Inc.; 5 Gradient Corporation; 6 Department of Pharmacology/Toxicology, University of Arizona; 7 Center for Research for Mothers and Children, National Institute of Child Health and Human Development, Bethesda, Maryland, USA ABSTRACT A panel convened by the Harvard Center for Risk Analysis (HCRA) evaluated the weight of evidence for potential developmental and reproductive toxicity of bisphe- nol 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. En- vironmental 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 pub- lished 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 ro- dent 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 impair- ment. 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 mech- anism of action for BPA. Finally, there is indirect evidence that humans may be less Received 1 December 2003; revised manuscript accepted 7 May 2004. Address correspondence to George Gray, Harvard Center for Risk Analysis, Harvard School of Public Health, 718 Huntington Ave., Boston, MA 02115, USA. E-mail: ggray@ hsph.harvard.edu 875