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A mixture of seven antiandrogens induces reproductive malformations in rats.
Citation:
RIDER, C. V., J. R. FURR, V. S. WILSON, AND L. E. GRAY. A mixture of seven antiandrogens induces reproductive malformations in rats. International Journal of Andrology. Blackwell Publishing, Malden, MA, 31(2):249-262, (2008).
Impact/Purpose:
The results of this study indicate that significant changes are needed in the approach that regulatory agencies include the USEPA take in conducting cumulative risk assessments. The current approach has been limited to chemicals within the same class that act via the same mode of action. This paper shows that chemicals from different classes with that act on different fetal tissues directly via diverse cellular and molecular targets can produce dose additive effects on reproductive development. Hence, the assumption that mixtures of low doses of chemicals with different modes of action will not produce adverse effects underestimates, grossly in some cases, the actual toxicity produced by the mixture.
Description:
To date, regulatory agencies have not considered conducting cumulative risk assessments for mixtures of chemicals with diverse mechanisms of toxicity because it is assumed that the chemicals will act independently and the individual chemical doses are not additive. However, this assumption is not supported by new research addressing the joint effects of chemicals that disrupt reproductive tract development in the male rat by disrupting the androgen signalling pathway via diverse mechanisms of toxicity [i.e. androgen receptor (AR) antagonism in the reproductive tract vs. inhibition of androgen synthesis in the foetal testis]. In this study, pregnant rats were exposed to four dilutions of a mixture containing vinclozolin, procymidone, linuron, prochloraz, benzyl butyl phthalate, dibutyl phthalate and diethylhexyl phthalate during the period of sexual differentiation and male offspring were assessed for effects on hormone sensitive endpoints including: anogenital distance, infant areolae retention and reproductive tract tissue weights and malformations. The ratio of the chemicals in the mixture was based upon each chemical's ED(50) for inducing reproductive tract malformations (hypospadias or epididymal agenesis). The observed responses from the mixture were compared with predicted responses generated with a toxic equivalency approach and models of dose addition, response addition or integrated addition. As hypothesized, we found that the mixture of chemicals that alter the androgen signalling pathway via diverse mechanisms disrupted male rat reproductive tract differentiation and induced malformations in a cumulative, dose-additive manner. The toxic equivalency and dose addition models provided the best fit to observed responses even though the chemicals do not act via a common cellular mechanism of action. The current regulatory framework for conducting cumulative risk assessments needs to consider the results, including those presented herein, which indicate that chemicals that disrupt foetal tissues during sexual differentiation act in a cumulative, dose-additive manner irrespective of the specific cellular mechanism of toxicity.
