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

Abstract

Recent public concern has focused on potential reproductive and developmental effects from exposure to low levels of bisphenol A (BPA, CAS number 80-05-7). Two previous published reviews (; ) conducted weight-of-evidence evaluations of in vivo reproductive/developmental toxicity from BPA exposure ≤ 5 mg/kg-d based on studies published through February 2006. Here, an update of those analyses presents additional relevant studies that were published through July 25, 2008, and a weight-of-evidence analysis of the studies evaluated in all three reviews. As with the earlier literature, positive findings: (1) are countered by null findings in more numerous studies; (2) have not been replicated; (3) do not exhibit coherence and plausibility; (4) do not show consistency across species, doses, and time points; and/or (5) were from studies using non-oral exposure routes. Owing to the lack of first-pass metabolism, results from non-oral studies are of limited relevance to human exposure. Exposure levels in most of the low-dose oral and non-oral animal studies are generally much higher than those experienced by even the most exposed people in the general population. The weight of evidence does not support the hypothesis that low oral doses of BPA adversely affect human reproductive and developmental health.

Keywords:

• Dose-response
• endocrine-active agents
• human exposure
• low-dose

ACKNOWLEDGMENT

This work was funded by the Polycarbonate/BPA Global Group, who compensated Gradient Corporation on a time and materials basis for work conducted by Gradient employees (JEG, TMS, CJY, AMF, LRR). The other authors were provided honoraria by Gradient Corporation (EEM, IGS, RJW). This review represents the individual professional views of the authors and not necessarily the views of the Polycarbonate/BPA Global Group.

Notes

*BPA exposure via inhalation, which can occur in certain occupational settings, will not undergo first-pass metabolism, although there are no data on the toxicokinetics of inhaled BPA (EU, 2008). We are not aware of any studies or reports that suggest inhaling BPA leads to reproductive or developmental effects.

*Because larger animals may have larger organs owing to their size, many studies compare organ weights relative to body weight.

*Tyl et al. (2008b) conducted their study using CD-1 mice under OECD Test Guideline 416 with enhancements. Mice were exposed to five dietary exposure levels of E2 ranging from 0.001 to 0.5 ppm (∼ 0.2 to 100 μ g/kg -d). The F0 generation was exposed for 8 weeks before breeding, for 2 weeks during mating, for about 3 weeks of gestation, and for 3 weeks of lactation. Selected F1 offspring were exposed after weaning to the same dietary concentrations and durations as the F0 generation. The study was terminated when the F2 pups were weaned. A wide range of endpoints was examined and estrogenic effects were found at the three highest doses. There was no evidence for nonmonotonic dose-response in any endpoint examined.