Polyhalogenated biphenyls, particularly polychlorinated biphenyls (PCBs), are industrial chemicals which are stable and persist in our environment. Their lipophilicity and resistance to chemical or biological degradation result in their accumulation in fatty tissues of humans and other animals and eventual secretion into milk fat. These characteristics raise concern about the health risks associated with long-term exposure to these compounds. Numerous studies have found that PCBs and the closely-related polybrominated biphenyls (PBBs) induce hepatocellular carcinomas in mice and rats, but the mechanism by which they do so has not been determined. We and others have shown that PCBs/PBBs act as promoters of liver carcinogenesis; but their initiating or DNA-damaging activity has not been conclusively demonstrated. We therefore propose to test the hypotheses that biphenyl and halogenated biphenyls 1) induce mutations, cytogenetic damage and cell transformation in in vitro systems, 2) form quinoid metabolites that (at least in part) are responsible for genotoxic effects seen, 3) induce DNA adducts in rats. The potential of biphenyl and halogenated biphenyls to induce mutations in mammalian cells will be examined, while their ability to interact with cellular DNA will be monitored by sensitive 32P-postlabeling methods. Of particular interest is the identification of the reactive species responsible for the genotoxicity. Using these test systems, we shall define structure-activity relationships, identify critical metabolic parameters (which enzymes, cofactors are involved), identify mammalian targets and determine the structures of active metabolites. Our preliminary data indicate that several lower halogenated biphenyls are mutagenic in Salmonella and in V79 cells in the presence of an exogenous activation system. The spectra of genotoxicity seen with these compounds indicate that two mechanisms of activation (via expoxides and quinones) are operative. Our most recent data showing that mono- and dichlorobiphenyls are enzymatically activated to species that form adducts with guanine and/or adenine strongly support the involvement of quinones in the genotoxicity of these compounds. Clarification of the mechanism by which individual PCBs cause liver tumors will form a basis for the human health risk assessment for exposure to these chemicals.
