New approaches for estimating risk from exposure to diethylstilbestrol.

Abstract

A subgroup from a National Institute of Environmental Health Sciences, workshop concerned with characterizing the effects of endocrine disruptors on human health at environmental exposure levels considered the question, If diethylstilbestrol (DES) were introduced into the market for human use today and likely to result in low-dose exposure of the human fetus, what would be required to assess risk? On the basis of an analysis of the quality of data on human DES exposure, the critical times and doses for inducing genital tract malformations and cancer must be determined. This would be facilitated through analysis of the ontogeny of estrogen receptor expression in the developing human genital tract. Models of low-dose estrogenic effects will have to be developed for human and rodent genital tract development. Mouse models offer many advantages over other potential animal models because of the wealth of the earlier literature, the availability of sensitive end points, the availability of mutant lines, and the possibility of generating genetically engineered model systems. Through multidisciplinary approaches, it should be possible to elucidate the cellular and molecular mechanisms of endocrine disruption elicited by estrogens during development and facilitate an assessment of risk to humans. (4,5) and were thought to cross the placenta in humans (6,7), direct evidence of teratogenicity of estrogens in humans was unknown until after the association between DES and vaginal adenocarcinoma was reported. In any case, despite the tragedy of the DES episode, the human DES clinical data offer an unprecedented opportunity to learn about the consequences of in utero exposure to a potent estrogen and thus to infer potential risks following exposure to less potent environmental estrogens.If properly interpreted, lessons from the DES episode may prove invaluable for judging potential effects of compounds that have been or will be identified as potential endocrine disruptors. It will be important, however, to keep in mind the considerable differences in potency between such compounds when inferences are drawn concerning potential effects. For example, the carcinogenicity of DES was identified in a human study including only 8 cases and 32 controls (8). Normal sample size calculations would rule such a study as inadequate. However, because the cancer induced by DES (clear cell vaginal adenocarcinoma) was so rare in young women, the association between prenatal DES exposure and development of clear cell adenocarcinoma of the vagina was easily identified. Clearly, most chemicals with significantly less potent endocrine (e.g., estrogenic) effects will convey much-reduced risks, particularly at low doses. Thus, study designs for other endocrine disruptors will have to be more precise and more powerful, especially if the background incidence of a particular lesion is substantial. Given the history of the DES episode, we have considered this issue: If DES were introduced into the market for human use today and were likely to result in ...

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Effects of Neonatal Exposure to Diethylstilbestrol, Tamoxifen, and Toremifene on the BALB/c Mouse Mammary Gland1

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Assessment of thyroid function in pesticide formulators

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