Environmental endocrine modulators and human health: an assessment of the biological evidence

Recently, a great deal of attention and interest has been directed toward the hypothesis that exposure, particularly in utero exposure, to certain environmental chemicals might be capable of causing a spectrum of adverse effects as a result of endocrine modulation. In particular, the hypothesis has focused on the idea that certain organochlorine and other compounds acting as weak estrogens have the capability, either alone or in combination, to produce a variety of adverse effects, including breast, testicular and prostate cancer, adverse effects on male reproductive tract, endometriosis, fertility problems, alterations of sexual behavior, learning disability or delay, and adverse effects on immune and thyroid function. While hormones are potent modulators of biochemical and physiological function, the implication that exposure to environmental hormones (e.g., xenoestrogens) has this capability is uncertain. While it is reasonable to hypothesize that exposure to estrogen-like compounds, whatever their source, could adversely affect human health, biological plausibility alone is an insufficient basis for concluding that environmental endocrine modulators have adversely affected humans. Diethylstilbestrol (DES) is a potent, synthetic estrogen administered under a variety of dosing protocols to millions of women in the belief (now known to be mistaken) that it would prevent miscarriage. As a result of this use, substantial in utero exposure to large numbers of male and female offspring occurred. Numerous studies have been conducted on the health consequences of in utero DES exposure among the adult offspring of these women. There are also extensive animal data on the effects of DES and there is a high degree of concordance between effects observed in animals and humans. The extensive human data in DES-exposed cohorts provide a useful basis for assessing the biological plausibility that potential adverse effects might occur following in utero exposure to compounds identified as environmental estrogens. The effects observed in both animals and humans following in utero exposure to sufficient doses of DES are consistent with basic principles of dose response as well as the possibility of maternal dose levels below which potential non-cancer effects may not occur. Significant differences in estrogenic potency between DES and chemicals identified to date as environmental estrogens, as well as an even larger number of naturally occurring dietary phytoestrogens, must be taken into account when inferring potential effects from in utero exposure to any of these substances. The antiestrogenic properties of many of these same exogenous compounds might also diminish net estrogenic effects. Based on the extensive data on DES-exposed cohorts, it appears unlikely that in utero exposure to usual levels of environmental estrogenic substances, from whatever source, would be sufficient to produce many of the effects (i.e., endometriosis, adverse effects on the male reproductive tract, male and female fertility problems, alterations of sexual behavior, learning problems, immune system effects or thyroid effects) hypothesized as potentially resulting from exposure to chemicals identified to date as environmental estrogens.