You are here:
Cumulative Effects of in Uetro Administration of Mixtures of "Antiandrogens" on Male Rat Reproductive Development
Citation:
RIDER, C V., V. S. WILSON, K. HOWDESHELL, A. K. HOTCHKISS, J. R. FURR, C. R. LAMBRIGHT, AND L. E. GRAY. Cumulative Effects of in Uetro Administration of Mixtures of "Antiandrogens" on Male Rat Reproductive Development. Journal of Toxicologic Pathology. The Japanese Society of Toxicologic Pathology, TOKYO, Japan, 37(1):100-113, (2009).
Impact/Purpose:
Impact Statement This is a review article describing the work of our lab on mixtures of chemicals that target androgen signaling. It could have a major impact on the current risk assessment paradigm for assessing cumulative risk of pesticides. Currently, only chemicals that have the same mechanism of action are potential candidates for cumulative risk assessments. Further, some groups of “antiandrogenic” chemicals that share a common mechanism of action (e.g. dicarboximide fungicides: vinclozolin and procymidone; and phthalates such as dibutyl phthalate, benzyl butyl phthalate, and diethylhexyl phthalate) have not been included in cumulative risk assessments. The work described in this review demonstrates that chemicals which target a common biological pathway (i.e. androgen signaling) display dose additivity and should, therefore, be included in cumulative risk assessments.
Description:
Although risk assessments are typically conducted on a chemical-by-chemical basis, the 1996 FQPA required the EPA to consider cumulative risk of chemicals that act via a common mechanism of toxicity. To this end, we are conducting studies with mixtures to provide a framework for assessing the cumulative effects of "antiandrogenic" chemicals. Rats were dosed during pregnancy with antiandrogens singly or in pairs at dosage levels equivalent to about one half of the ED50 for hypospadias or epididymal agenesis. The pairs include: AR antagonists (vinclozolin plus procymidone), phthalate esters (DBP plus BBP and DEHP plus DBP), a phthalate ester plus an AR antagonist (DBP plus procymidone) and linuron plus BBP. We predicted that each chemical by itself would induce few malformations; however, by mixing any two chemicals together, about 50% of the males would be malformed. All binary combinations produced cumulative, dose-additive effects on the androgen-dependent tissues. We also conducted a mixture study combining seven “antiandrogens” together. These chemicals elicit antiandrogenic effects at two different sites in the androgen signaling pathway (i.e. AR antagonist or inhibition of androgen synthesis). In this study, the complex mixture behaved in a dose additive manner. Our results indicate that compounds that act by disparate mechanisms of toxicity display cumulative, dose-additive effects when present in combination.