Estrogenic activity of certain
xenobiotics is an established mechanism of toxicity that can impair reproductive function in adults of either sex, lead to irreversible abnormalities when administered during development, or cause
cancer. The concern has been raised that exposure to ambient levels of estrogenic
xenobiotics may be having widespread adverse effects on reproductive health of humans and wildlife. The purpose of this review is to evaluate (a) the nature of the evidence supporting this concern, and (b) the adequacy of toxicity screening to detect, and risk assessment procedures to establish safe levels for, agents acting by this mechanism. Observations such as adverse developmental effects after maternal exposure to therapeutic levels of the potent
estrogen diethylstilbestrol or male fertility problems after exposure to high levels of the weak
estrogen chlordecone clearly demonstrate that estrogenicity is active as a toxic mechanism in humans. High level exposures to
estrogenic compounds have also been shown to affect specific wildlife populations. However, there is little direct evidence to indicate that exposures to ambient levels of estrogenic
xenobiotics are affecting reproductive health. Reports of historical trends showing decreasing reproductive capacity (e.g., decreased sperm production over the last 50 years) are either inconsistent with other data or have significant methodologic inadequacies that hinder interpretation. More reliable historical trend data show an increase in
breast cancer rate, but the most comprehensive epidemiology study to data failed to show an association between exposure to persistent, estrogenic
organochlorine compounds and
breast cancer. Clearly, more work needs to be done to characterize historical trends in humans and background incidence of abnormalities in wildlife populations, and to test hypotheses about ambient exposure to environmental contaminants and toxic effects, before conclusions can be reached about the extent or possible causes of adverse effects. It is unlikely that current lab animal testing protocols are failing to detect agents with estrogenic activity, as a wide array of
estrogen-responsive endpoints are measured in standard testing batteries. Routine testing for aquatic and wildlife toxicity is more limited in this respect, and work should be done to assess the validity of applying mammalian toxicology data for submammalian hazard identification. Current risk assessment methods appear to be valid for
estrogenic agents, although the database for evaluating this is limited. In conclusion, estrogenicity is an important mechanism of reproductive and developmental toxicity; however, there is little evidence at this point that low level exposures constitute a human or ecologic health risk. Given the potential consequences of an undetected risk, more research is needed to investigate associations between exposures and effects, both in people and animals, and a number of research questions are identified herein. The lack of evidence demonstrating widespread
xenobiotic-induced estrogenic risk suggests that far-reaching policy decisions can await these research findings.