An Updated Weight of the Evidence Evaluation of Reproductive and Developmental Effects of Low Doses of Bisphenol A

Abstract

There is controversy over whether low doses of bisphenol A (BPA, CAS no. 80-05-7) cause reproductive and developmental effects in humans. We update the 2004 weight-of-evidence assessment of an expert panel convened by Harvard's Center for Risk Analysis by critically evaluating over 50 additional studies published between April 2002 and February 2006 that examine in vivo reproductive and developmental toxicity in mammals at doses ≤5 mg/kg-d. Our findings are consistent with the Harvard study: some statistically significant findings in rats and mice exist but they are generally countered by more numerous studies showing no effect for similar endpoints. No effect is marked or consistent across species, doses, and time points. Some mouse studies report morphological changes in testes and sperm and some non-oral mouse studies report morphological changes in female reproductive organs. Owing to lack of first-pass metabolism, results from non-oral studies are of limited relevance to oral human exposure. Human biomonitoring indicates exposures lower than the “low” doses in the reviewed animal studies. Reports of human health impact are very limited and inconsistent. Taken together, the weight of evidence does not support the hypothesis that low oral doses of BPA adversely affect human reproductive and developmental health.

Key words :

• Endocrine-Disruptor
• Human Exposure
• Low-Dose
• Bisphenol A

Notes

Lorenz R. Rhomberg, Ernest E. McConnell, and I. Glenn Sipes were members of this Harvard Panel.

Lorenz R. Rhomberg was on the Androgens and Antiandrogens Subcommittee of this NTP peer review, but was not on the Bisphenol A Subcommittee.

Chitra et al. (2003a), (2003b), Iida et al. (2002) and Iwasaki and Totsukawa (2003) were the only studies which noted dose-response trends for specific endpoints, although none described any statistical tests confirming these. Furthermore, Iwasaki and Totsukawa (2003) claimed dose-response trends for pup birth weight and day of vaginal opening, but in both cases, control values were between those of the treated groups: The lowest BPA-dosed pups weighed (significantly) less than controls at birth, while the other treated animals weighed the same or (non-significantly) more than controls. Vaginal opening day was (significantly) delayed at the lowest dose, unchanged at the middle dose, and (significantly) advanced at the highest dose.

Although the doses were originally reported as 5, 25, or 100 ng/kg-day, an erratum published by Al-Hiyasat et al. in 2003 noted that the correct doses were actually 5, 25, or 100 μg/kg-day (corresponding to 0.005, 0.025, or 0.1 mg/kg-d).

Note that Markey et al. (2003) originally reported doses of 0.25 and 0.025 mg/kg-d, which were then revised to the lower values in an erratum Markey et al. (2004).