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CUMULATIVE REPRODUCTIVE EFFECTS OF IN UTERO ADMINISTRATION OF A MIXTURE OF TEN “ANTIANDROGENS” IN MALE SD RATS: SYNERGY OR ADDITIVITY?
Citation:
GRAY, L. E., C. V. RIDER, AND J. R. FURR. CUMULATIVE REPRODUCTIVE EFFECTS OF IN UTERO ADMINISTRATION OF A MIXTURE OF TEN “ANTIANDROGENS” IN MALE SD RATS: SYNERGY OR ADDITIVITY? Presented at 2009 SOT Annual Meeting, Baltimore, MD, March 15 - 19, 2009.
Impact/Purpose:
This study will assist the Agency in establishing a science based framework for cumulative risk assessments. A systems biology approach.
Description:
In 1996, the USEPA was charged under FQPA to consider the cumulative effects of chemicals in their risk assessments. We are conducting studies to provide a framework for assessing the cumulative effects of antiandrogens. In the current study, ten “antiandrogenic” chemicals were administered orally to pregnant rats on gestational days 14-18 and the reproductive development of the male offspring is being evaluated. Data were analyzed to determine if the chemicals behaved in a response-, integrated or dose-additive fashion. The experimental design is a fixed ratio mixture of ten chemicals with a control group, a top dose group and five dilutions of the top dose (100%, 80, 60, 40, 20, 10 and 0% of the top dose). The top dose included dosages of each chemical that are at or below the no observed effect level for hypospadias induction (vinclozolin - 30 mg/kg, procymidone - 30 mg/kg, linuron - 40 mg/kg, prochloraz - 60 mg/kg/d and six phthalate esters: DEHP, DBP, BBP, DiBP, DiHP -150 mg/kg/d/phthalate and DPP – 50 mg/kg/d). F1 male rats displayed retained female-like areolae at 14 days of age and reduced anogenital distance (AGD) at 3 days of age in the 20% and 40% groups and above, respectively. F1 female rat AGD was unaffected. In addition, malformed external genitalia were seen at puberty in males in the 40% and above groups. Dose addition was the only model that accurately predicted the malformations in the top three dose groups (observed and dose addition=100%; integrated addition=0-16%; response addition=0%) or retained nipples induced by this complex mixture. The observation that dose- but not response- or integrated-addition models accurately predict the effects of chemical mixtures that act via diverse mechanisms suggests that dose additivity may commonly occur among chemicals that disrupt the same signaling pathway at different molecular sites during sexual differentiation. This abstract does not necessarily reflect EPA policy.