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Ulla Hass,¹ Martin Scholze,² Sofie Christiansen,¹ Majken Dalgaard ,¹ Anne Marie Vinggaard,¹ Marta Axelstad,¹ Stine Broeng Metzdorff,¹ and Andreas Kortenkamp²

¹Danish Institute for Food and Veterinary Research, Department of Toxicology and Risk Assessment, Søborg, Denmark; ²The School of Pharmacy, University of London, London, United Kingdom

Abstract
Objective: The aim of this study was to assess whether the joint effects of three androgen receptor antagonists (vinclozolin, flutamide, procymidone) on male sexual differentiation after in utero and postnatal exposures can be predicted based on dose–response data of the individual chemicals.

Methods: Test chemicals and mixtures were administered by gavage to time-mated nulliparous, young adult Wistar rats from gestational day 7 to the day before expected birth, and from postnatal days 1–16. Changes in anogenital distance (AGD) and nipple retention (NR) in male offspring rats were chosen as end points for extensive dose–response studies. Vinclozolin, flutamide, and procymidone were combined at a mixture ratio proportional to their individual potencies for causing retention of six nipples in male offspring.

Results: With AGD as the end point, the joint effects of the three anti-androgens were essentially dose additive. The observed responses for NR were slightly higher than those expected on the basis of dose addition. A combination of doses of each chemical, which on its own did not produce statistically significant AGD alterations, induced half-maximal mixture effects. At individual doses associated with only modest effects on NR, the mixture induced NR approaching female values in the males.

Conclusions: Effects of a mixture of similarly acting anti-androgens can be predicted fairly accurately on the basis of the potency of the individual mixture components by using the dose addition concept. Exposure to anti-androgens, which individually appears to exert only small effects, may induce marked responses in concert with, possibly unrecognized, similarly acting chemicals.

Key words: AGD, anti-androgen, combination effect, developmental exposure, flutamide, mixture, nipple retention, procymidone, vinclozolin. Environ Health Perspect 115(suppl 1) : 122–128 (2007) . doi:10.1289/ehp.9360 available via http://dx.doi.org/ [Online 8 June 2007]

Address correspondence to U. Hass, Danish Institute for Food and Veterinary Research, Dept. of Toxicology and Risk Assessment, Mørkhøj Bygade 19, DK-2860 Søborg, Denmark. Telephone: 45 72347544. Fax: 45 72347001. E-mail: ulh@dfvf.dk

This article is part of the monograph "Endocrine Disruptors—Exposure Assessment, Novel End Points, and Low-Dose and Mixture Effects."

We thank D. Hansen and B. Herbst for their excellent technical assistance.

This work is part of the European Union-supported EDEN-project "Endocrine Disrupters: Exploring Novel Endpoints, Exposure, Low Dose- and Mixture-Effects in Humans, Aquatic Wildlife and Laboratory Animal" (QLK4-CT-2002-00603) , and financial support from the European Commission is gratefully acknowledged.

The author declares he has no competing financial interests.

Received 22 May 2006 ; accepted 4 December 2006.