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POLYCHLORINATED BIPHENYLS AS HORMONALLY ACTIVE STRUCTURAL ANALOGUES
Citation:
McKinney, J. AND C. Waller. POLYCHLORINATED BIPHENYLS AS HORMONALLY ACTIVE STRUCTURAL ANALOGUES. U.S. Environmental Protection Agency, Washington, D.C., EPA/600/J-95/103.
Description:
Among the environmental chemicals believed to have the potential to disrupt the endocrine systems of animals including humans, the polychlorinated biphenyls are a chemical class of considerable concern. Possible mechanisms by which these chemicals may interfere with endocrine function include their ability to mimic natural hormones. These actions reflect a close relationship between the physicochemical properties encoded in the PCB molecular structure and the responses they evoke in biological systems. "Coplanarity" of PCB phenyl rings and "laterality" of chlorine atoms have been shown to be important structural features determining their specific binding behavior with proteins and certain toxic responses in biological systems. Qualitative structure-activity relationships for PCBs are compared and contrasted with the limited information emerging on the related noncoplanar chlorinated diphenyl ethers, providing further insights into the nature of the molecular recognition processes involved in their toxic action and support for the structural relationship to thyroid hormones. Steroid-like activity requires hydroxylation and conformational restriction. Some relatively simple molecular recognition models are offered to account for the importance of these different structural features in the structure-activity relationships and permit one to express PCB reactivities in terms of dioxin, thyroxine, and estradiol equivalents. To some extent, quantitative differences in responses appear to be due to variations in degrees of coplanarity or conformational restriction (both dependent on degrees of ortho-substitution) or accessibility of planar faces and laterality that exists among the PCB congeners. Other responses appear to be associates with metabolic activation processes (to introduce hydroxyl groups). The available data supports the involvement of PCBs as mimics for thyroid and other steroidal hormones. Toxicity could result from over- or underexpression of normal hormonal responses (separately or via multihormonal regulating systems) through PCB interactions with both receptor and nonreceptor proteins. The potential for reproductive and developmental toxicity associated with human exposure to PCBs is of particular concern.