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Cumulative reproductive effects of in utero administration of mixtures of antiandrogens in male SD rats: synergy or additivity?
Citation:
GRAY, L. E., J. R. FURR, V. S. WILSON, A. K. HOTCHKISS, K. HOWDESHELL, AND C. V. RIDER. Cumulative reproductive effects of in utero administration of mixtures of antiandrogens in male SD rats: synergy or additivity? Presented at Copenhagen Workshop on Endocrine Disruptors, Copenhagen, DENMARK, May 28 - 31, 2007.
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Presentation
Description:
In 1996 the USEPA was charged under the FQPA to consider the cumulative effects of chemicals in their risk assessments. Our studies were conducted to provide a framework for assessing the cumulative effects of antiandrogens. Toxicants were administered individually or as mixtures to rats on GD 14-18 and the development of the male offspring evaluated. Data were analyzed to determine if the chemicals behaved in a response- or dose-additive fashion. When seven antiandrogenic chemicals were combined at doses that individually produce little or no hypospadias or epididymal agenesis 100% of the male offspring were malformed (vinclozolin (V-15 mg/kg/d), procymidone (P-15 mg/kg/d), linuron (L-20 mg/kg/d), prochloraz (PZ-35 mg/kg/d) and three phthalate esters (DBP, DEHP, and BBP-150 mg/kg/d/phthalate)). Dose addition was the only model that accurately predicted the malformations induced by this complex mixture. When pairs of chemicals that act via similar and dissimilar mechanisms of action were combined, we found that dose addition was the appropriate model to predict hypospadias and other malformations. For example, mixtures of androgen receptor antagonists with phthalates that reduce fetal testosterone produced effects consistent with dose- but not response- additivity. Individually, the chemicals induced low rates of hypospadias P (1.5%), and L, BBP and DBP (0%) as compared to L plus BBP (56%) or P plus DBP (49%). The observation that dose- but not response-addition accurately predicts the effects of chemical mixtures that act via diverse mechanisms suggests that additive interactions may commonly occur among chemicals that disrupt the same signaling pathway at different molecular sites during sexual differentiation.