Both authors contributed equally to this work.
A mixture of seven antiandrogens induces reproductive malformations in rats
Version of Record online: 16 JAN 2008
No claim to original US government works
International Journal of Andrology
Volume 31, Issue 2, pages 249–262, April 2008
How to Cite
Rider, C. V., Furr, J., Wilson, V. S. and Gray, L. E. (2008), A mixture of seven antiandrogens induces reproductive malformations in rats. International Journal of Andrology, 31: 249–262. doi: 10.1111/j.1365-2605.2007.00859.x
- Issue online: 16 JAN 2008
- Version of Record online: 16 JAN 2008
- Received 25 October 2007; revised 17 November 2007; accepted 27 November 2007
- dose addition;
- endocrine disruption;
- reproductive malformations;
- toxic equivalency
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 ED50 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.