Assessment of combinations of antiandrogenic compounds vinclozolin and flutamide in a yeast based reporter assay

Abstract

Humans are exposed to a combination of various substances such as cosmetic ingredients, drugs, biocides, pesticides and natural-occurring substances in food. The combined toxicological effects of two or more substances can simply be additive on the basis of response-addition, or it can be greater (synergistic) or smaller (antagonistic) than this. The need to assess combined effects of compounds with endocrine activity is currently discussed for regulatory risk assessment. We have used a well described yeast based androgen receptor transactivation assay YAS to assess the combinatorial effects of vinclozolin and flutamide; both mediating antiandrogenicity via the androgen receptor. Both vinclozolin and flutamide were antiandrogens of similar potency in the YAS assay. In the concentration range tested the two antiandrogens vinclozolin and flutamide did not act synergistically. Concentration additivity was observed in the linear, non-receptor-saturated concentration range. At high concentrations of one of the two substances tested the contribution of the second at lower concentration levels was less than additive. The combined response of both compounds at high concentration levels was also less than additive (saturation effect). At concentration levels which did not elicit a response of the individual compounds, the combination of these compounds also did not elicit a response.