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Cumulative effects of in utero administration of mixtures of "antiandrogens" on male rat reproductive development
Citation:
GRAY, L. E., J. R. FURR, K. HOWDESHELL, A. K. HOTCHKISS, V. S. WILSON, AND C. V. RIDER. Cumulative effects of in utero administration of mixtures of "antiandrogens" on male rat reproductive development. Presented at British Toxicology Society, Surrey, UK, April 15 - 18, 2007.
Impact/Purpose:
Presentation
Description:
Although risk assessments are typically conducted on a chemical-by-chemical basis, the 1996 Food Quality Protection Act requires the USEPA to consider cumulative risk of chemicals that act via a common mechanism of toxicity. To this end, we are conducting studies to provide a framework for assessing the cumulative effects of "antiandrogenic" chemicals. The objectives of these studies were to determine whether compounds that act by similar or disparate mechanisms of toxicity display cumulative, dose-additive effects when present in combination and to assess the ability of different modeling approaches to accurately predict these mixture effects based on data from single chemical exposures. Two methods are being used to predict the “expected” reproductive effects of the mixtures. The first method uses a toxic equivalency approach. Relative potency factors (RPFs) are generated for each chemical in relation to a reference chemical. If the effects are dose-additive then the summation of the seven chemicals (RPF x dose in each treatment group) would yield a predicted total dose and the mixture effect can be estimated from the dose-response curve of the reference chemical. The second approach is described at www.tox.ncsu.edu/faculty/leblanc/web1/index.html. In this approach, mixture effects can be predicted using either a dose addition model or a mixed model that includes both dose and response addition. In our first set of studies, SD rats were dosed during sexual differentiation with antiandrogens singly or in pairs at dosage levels equivalent to about one half of the ED50 for hypospadias or epididymal agenesis. The chemical pairs include: AR antagonists (vinclozolin plus procymidone), a phthalate esters with a common active metabolite (DBP and BBP), phthalate esters with different active metabolites (DEHP and DBP), a phthalate ester plus an AR antagonist (DBP plus procymidone) and linuron plus BBP. We also conducted a mixture study combining seven “antiandrogens” together. These chemicals elicit effects at two different sites in the androgen signaling pathway (i.e. AR antagonist or inhibition of androgen synthesis). In the “high dose” group, termed the ED100, each chemical in the mixture was administered at 1/7th of estimated ED100 for inducing malformations. The mixture was administered at the ED100 and 75%, 50% and 25% of the ED100 level and the reproductive tract was examined during after birth. In the mixture studies with pairs of chemicals, we predicted that, at the doses used herein, each chemical by itself would induce few malformations, but when any two chemicals were mixed together about 50% of the males would be malformed. The results indicate that all combinations produced cumulative, dose-additive effects on the androgen-dependent tissues. In the study with a mixture of seven chemicals, the mixture also behaved in a dose additive manner. Male reproductive tract malformations were displayed by 100% of the males in the group predicted initially to be the ED100. Clearly, risk assessments for “antiandrogens” conducted on a chemical-by-chemical basis will underestimate the potential hazard posed if exposure also includes more than one antiandrogenic chemical.