Environmental estrogens.

The estrogenic equivalent analysis that Dr. Safe presented recently in EHP (103:346-351) is a welcome addition to the literature , and development of this toxicologic approach is an important step in evaluating new endpoints for environmental agents (1,2). The hormonal potential of chemical contaminants offers many opportunities for further research, including study of the environmental etiology of breast cancer. Complex mixtures are of great importance for human environmental exposures, but we understand neither exposure nor effect very well. Safe, as a basis for evaluating one hormonal endpoint, offers estro-genic equivalents acting in an additive fashion. In future research, we need to learn whether these combinations of chemicals , such as DDT and estrogen, may be additive or multiplicative. Examples of both exist. Thus, in vitro assays using MCF7 breast tumor cells found an additive effect for 10 pesticides (3), and in vivo assays of two PCB metabolites produced an apparent multiplicative effect in altering gender determination in turtles (4). We also need to investigate hormonally active compounds for other relevant biological activity. For example, vinclozilin has androgenic potential (5); genistein may act as a free radical scavenger (6); and pp'-DDE demonstrated potent anti-andro-genic responses in the rat (8). Estrogenicity of genistein and other phytoestrogens may be relevant to breast cancer, but countries with high dietary intake of such compounds are generally at low risk for breast cancer. Therefore, it is possible that exoge-nously derived phytoestrogens act differently from steroid hormones, perhaps by altering levels of free versus bound estrogen or by increasing estrogen excretion through the biliary/fecal route (8). It has become more and more apparent that toxicokinetics of chemicals is a critical component of dose-response relationships. Endogenous levels of organochlorines in women today are 10-fold higher than those of estrogen (9), and their effects are prolonged because of their persistence in the body. Toxicokinetics are also closely tied