ToxSci Advance Access originally published online on April 29, 2008
Toxicological Sciences 2008 104(2):362-384; doi:10.1093/toxsci/kfn084
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Two-Generation Reproductive Toxicity Study of Dietary Bisphenol A in CD-1 (Swiss) Mice
* Health Sciences Unit, RTI International, Research Triangle Park, North Carolina 27709
Experimental Pathology Laboratories, Inc., Research Triangle Park, North Carolina 27709
SABIC Innovative Plastics, Pittsfield, Massachusetts 02101
Toxicology/Regulatory Services, Inc., Charlottesville, Virginia 22911
¶ Bayer Material Science, Pittsburgh, Pennsylvania 15205
|| Bayer Healthcare AG, Wuppertal, Germany D-42096
||| American Chemistry Council, Arlington, Virginia 22209
|||| The Dow Chemical Co., Midland, Michigan 48674
1 To whom correspondence should be addressed at RTI International, 3040 Cornwallis Road, P.O. Box 12194, Hermann Laboratory Bldg., Research Triangle Park, NC 27709-2194. Fax: (919) 541-5956. E-mail: rwt{at}rti.org.
Received January 21, 2008; accepted April 15, 2008
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Abstract |
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Dietary bisphenol A (BPA) was evaluated in a mouse two-generation study at 0, 0.018, 0.18, 1.8, 30, 300, or 3500 ppm (0, 0.003, 0.03, 0.3, 5, 50, or 600 mg BPA/kg/day, 28 per sex per group). A concurrent positive control group of dietary 17β-estradiol (0.5 ppm; 28 per sex) confirmed the sensitivity of CD-1 mice to an endogenous estrogen. There were no BPA-related effects on adult mating, fertility or gestational indices, ovarian primordial follicle counts, estrous cyclicity, precoital interval, offspring sex ratios or postnatal survival, sperm parameters or reproductive organ weights or histopathology (including the testes and prostate). Adult systemic effects: at 300 ppm, only centrilobular hepatocyte hypertrophy; at 3500 ppm, reduced body weight, increased kidney and liver weights, centrilobular hepatocyte hypertrophy, and renal nephropathy in males. At 3500 ppm, BPA also reduced F1/F2 weanling body weight, reduced weanling spleen and testes weights (with seminiferous tubule hypoplasia), slightly delayed preputial separation (PPS), and apparently increased the incidence of treatment-related, undescended testes only in weanlings, which did not result in adverse effects on adult reproductive structures or functions; this last finding is considered a developmental delay in the normal process of testes descent. It is likely that these transient effects were secondary to (and caused by) systemic toxicity. Gestational length was increased by 0.3 days in F1/F2 generations; the toxicological significance, if any, of this marginal difference is unknown. At lower doses (0.018–30 ppm), there were no treatment-related effects and no evidence of nonmonotonic dose-response curves for any parameter. The systemic no observable effect level (NOEL) was 30 ppm BPA (
5 mg/kg/day); the reproductive/developmental NOEL was 300 ppm (50 mg/kg/day). Therefore, BPA is not considered a selective reproductive or developmental toxicant in mice.
Key Words: bisphenol A; CAS No. 80-05-7; 17β-estradiol, CAS No. 50-28-2; CD-1 Swiss mice; two-generation reproductive toxicity study; OECD 416; puberty; andrology.
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