Cumulative Effects of In Utero Administration of Mixtures of “Antiandrogens” on Male Rat Reproductive Development

• Published in: Toxicologic pathology Vol. 37; no. 1; pp. 100 - 113
• Main Authors: Rider, Cynthia V., Wilson, Vickie S., Howdeshell, Kembra L., Hotchkiss, Andrew K., Furr, Johnathan R., Lambright, Christy R., Earl Gray, L.
• Format: Journal Article Conference Proceeding
• Language: English
• Published: Los Angeles, CA SAGE Publications 01-01-2009; Sage Publications
• Subjects: Androgen Antagonists - toxicity; Animals; Biological and medical sciences; Bridged Bicyclo Compounds - toxicity; Complex Mixtures - toxicity; Dibutyl Phthalate - toxicity; Diethylhexyl Phthalate - toxicity; Drug Combinations; Drug Synergism; Female; Fungicides, Industrial - toxicity; Genital Diseases, Male - chemically induced; Genital Diseases, Male - embryology; Genitalia, Male - abnormalities; Genitalia, Male - drug effects; Hypospadias - chemically induced; Male; Maternal Exposure; Medical sciences; Oxazoles - toxicity; Phthalic Acids - toxicity; Pregnancy; Rats; Receptors, Androgen - drug effects; Receptors, Androgen - metabolism; Sexual Maturation - drug effects; Toxicology; endocrine disrupters; male reproduction; reproductive system; Rat; Rodentia; Antiandrogen; Male; Endocrine disruptor; Antihormone; In utero; Mixture; Pregnancy; Vertebrata; Reproduction; Mammalia; Animal; Development; Reproductive system
• ISSN: 0192-6233; 1533-1601
• DOI: 10.1177/0192623308329478

Although risk assessments are typically conducted on a chemical-by-chemical basis, the 1996 Food Quality Protection Act (FQPA) required the Environmental Protection Agency (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.