You are here:
A MIXTURE OF SEVEN ANTIANDROGENIC COMPOUNDS ELICITS ADDITIVE EFFECTS ON THE MALE RAT REPRODUCTIVE TRACT THAT CORRESPOND TO MODELED PREDICTIONS
Citation:
RIDER, C. V., JONATHAN R. FURR, V. S. WILSON, AND L. E. GRAY. A MIXTURE OF SEVEN ANTIANDROGENIC COMPOUNDS ELICITS ADDITIVE EFFECTS ON THE MALE RAT REPRODUCTIVE TRACT THAT CORRESPOND TO MODELED PREDICTIONS. Presented at Society for the Study of Reproduction, Omaha, NE, July 29 - August 01, 2006.
Description:
The main objectives of this study were to: (1) determine whether dissimilar antiandrogenic compounds display additive effects when present in combination and (2) to assess the ability of modelling approaches to accurately predict these mixture effects based on data from single chemical exposures. Pregnant rats were exposed to a combination of seven antiandrogens and male offspring assessed for effects on androgen sensitive endpoints including: anogenital distance (AGD), infant areolae/nipple retention, sex accessory tissue weights, and reproductive tract malformations. The selected compounds (vinclozolin, procymidone, prochloraz, linuron, and three phthalates; BBP, DBP, and DEHP) interfere with androgen signalling at multiple levels, from inhibition of androgen synthesis to androgen receptor antagonism. The high dose of the mixture was based on the relative potencies of individual chemicals with respect to inducing malformations (15 mg/kg/d vinclozolin, 15 mg/kg/d procymidone, 35 mg/kg/d prochloraz, 20 mg/kg/d linuron, and 150 mg/kg/d each of BBP, DBP and DEHP). The remaining treatment groups were dosed with dilutions equalling 75%, 50%, and 25% of the high dose. We found that the effects of the mixtures were additive for all measured endpoints. However, there were subtle differences in response profiles. AGD decreased linearly with increasing mixture concentration, whereas, organ weights appeared to have a threshold concentration below which no significant effect was observed. Observed data were compared to predicted data generated with various modelling approaches. Modelling approaches were based on concepts of toxic equivalencies, concentration addition, response addition, or integrated addition. Initial findings indicate that mixture effects on AGD correspond to those predicted by the models. Model assumptions did not significantly impact this conclusion. Analysis of the remaining endpoints is ongoing. In summary, our results indicate that mixtures of antiandrogens that act at different levels of a common signalling pathway can display additive effects. Funding was provided by the NCSU/EPA Cooperative Training Program CT826512010. Disclaimer: This is an abstract of a proposed presentation and does not necessarily reflect USEPA policy.