Comparisons of the Effects of Three Estrogenic Agents in Comprehensive Rodent Bioassays. K. B. Delclos, R. R. Newbold, J. R. Latendresse, B. Blaydes, and C. C. Weis, National Center for Toxicological Research, National Institute and Environmental Health Sciences, PA
Appropriate screening and testing assays for endocrine active agents and the need to evaluate test compounds at doses lower than those that would be tested under classical dose setting procedures have been subjects of debate in recent years. A series of studies is being conducted under an Interagency Agreement between the NIEHS/NTP and FDA/NCTR to evaluate three compounds (genistein, nonylphenol, and ethinyl estradiol) with varying estrogenic potencies in single and multi generation studies. Compounds are administered via a soy- and alfalfa-free diet to control for background phytoestrogen levels. Dose range finding studies utilized 7 dose groups to evaluate multiple endpoints, including some that are not typically included in reproductive toxicity testing batteries. The main studies include reproductive evaluations over 5 generations with dosing terminated at weaning of the F3 generation, and chronic studies with varying windows of exposure. For practical reasons, the 5 generation studies utilize 4 dose groups. Dose selection for the main studies focused on the lower dose range, with the goal being choice of a high dose predicted to have little or no toxicity in the parental generation and mild toxicity in the pups. The dose range finding studies indicated several organs, including the prostate, male mammary gland, and kidney, as being potentially sensitive endpoints with differing dose-response patterns depending on the endpoint and test compound. Data from the main studies are still being collected and analyzed, but thus far confirm that the male mammary gland is a sensitive endpoint for genistein and ethinyl estradiol. The effect is at least partially reversed on removal of dose and will require the histological evaluation of chronically exposed animals to determine if this is an adverse effect. How the datasets from these studies may address the issues of appropriate endpoints and dose ranges in tests of endocrine active agents will be discussed.
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