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CUMULATIVE EFFECTS OF IN UTERO ADMINISTRATION OF A MIXTURE OF SEVEN ANTIANDROGENS ON MALE RAT REPRODUCTIVE DEVELOPMENT
Citation:
GRAY, L. E. AND J. FURR. CUMULATIVE EFFECTS OF IN UTERO ADMINISTRATION OF A MIXTURE OF SEVEN ANTIANDROGENS ON MALE RAT REPRODUCTIVE DEVELOPMENT. Presented at Society of Toxicology, San Diego, CA, March 05 - 09, 2006.
Description:
Although risk assessments are typically conducted on a chemical-by-chemical basis, the 1996 FQPA requires the USEPA to consider cumulative risk from chemicals that act via a common mechanism of action. To this end, we are conducting studies with mixtures to provide a framework for assessing the cumulative in utero effects of EDCs. In this study, we measured the effects of in utero exposure to a combination of seven relatively well characterized 'antiandrogens' on anogenital distance (AGD) in newborn male SD rats. We predicted the potency of each chemical relative to vinclozolin (V) by comparing ED50s from linear regression models of the dose response data for each chemical, linear models being appropriate for AGD data within this range of potencies. The R-square values for the regressions of AGD treatment means versus dose were 96, 87, 89, 98 and 93% and relative potency factors were 1.0, 0.56, 0.17, 0.8 and 0.12 for V, procymidone, linuron, prochloraz and the three phthalate esters, respectively. In the 'high dose' group, termed the ED100, each chemical in the mixture was administered by gavage to the dam on gestational days 14-18 at 1/7th of estimated ED100 for inducing malformations (V 15 mg/kg/d, procymidone 15 mg/kg/d, prochloraz 35 mg/kg/d, linuron 20 mg/kg/d, and BBP, DBP and DEHP at 150 mg/kg/d/phthalate). The mixture also was administered at 75%, 50% and 25% of the ED100 level. Using these data, we estimated that the ED100 treatment was equivalent to 100 mg V/kg/d and calculated a predicted reduction in AGD from each treatment using the V model. The results of the study demonstrate that the mixture reduced AGD in a linear fashion that is consistent with an interaction model assuming dose-additive effects of the seven chemicals. As neonatal reductions in AGD in male rats are highly correlated with an increase in reproductive tract malformations it is likely that cumulative toxicity will be seen on other reproductive endpoints later in life. This is an abstract of a proposed presentation and does not necessarily reflect EPA.