CritiCal literature on Human HealtH

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. Comment: This study represents a relatively new approach in toxicological research. The EPA has called for studies of compounds in combination. There is little that gives us much insight into the problem of chemicals in combination. Of interest in this paper is the finding of additive effects when compounds hit different receptors. This situation might be thought of as a set up for multiplied effects. But, we will have to wait for generalizations and they may be different for each system under study. There is much to be learned but clinical medicine will surely be informed and the data may not be easy to incorporate into clinical decision making. Stay tuned. – L.K.G.