Polychlorinated biphenyls (PCBs) are industrial chemicals which persist in our environment. They are found in Superfund sites including the sites in Kentucky and are the direct cause of 5 fish consumption advisories currently in place in Kentucky. The lipophilicy of PCBs and their tendency to bioaccumulate raise concern about the health risks associated with exposure to PCBs and related compounds. Commercial PCB mixtures are complete carcinogens, producing hepatocellular carcinomas in rats and mice, but the mechanisms by which they do so have not been determined. We and others have shown that higher halogenated PCBs (especially, tetra-, penta-, and hexa-chlorinated biphenyls) act as promoters of liver carcinogenesis, but their initiating or DNA damaging activity has not been conclusively demonstrated. Here we present considerable data to support the concept that the lower halogenated biphenyls (especially mono- and di-chlorobiphenyls) may be activated by hepatic enzymes. These PCBs are metabolized to oxygenated species which are electrophilic and which bind to DNA. Of particular interest are quinone metabolites which are oxidation products of dihyroxylated biphenyls. Our preliminary data were generated in in vitro systems. We propose to extend our studies to investigate these activation pathways in the rat. We propose 1) To determine if selected lower halogenated PCBs are metabolized (activated) in vivo to electrophilic species which interact with cellular DNA, forming adducts detectable by sensitive 32P-postlabeling methods, 2) To determine if PCBs activated in vitro and in vivo to electrophiles can act as initiators in an in vivo rat liver initiation model, a modified Solf-Farber protocol, and 3) To determine if those PCBs activated to electrophiles in vitro and in vivo and found positive in the Solt Farber protocol will initiate tow stage hepatocarcinogenesis. Specific lower halogenated PCB initiators and higher halogenated PCB promotors will be used. Jointly these activities may explain why PCB mixtures are complete rodent carcinogens. In these studies rats will be administered highly- purified synthetic PCB congeners. The number and volume of altered hepatic foci, putative preneoplastic lesions, and tumors will be determined. Our project therefore addresses the fundamental question of the mechanisms of toxicity, specifically, genotoxicity of individual PCBs. Clarification of these fundamental questions concerning PCBs as carcinogens, their metabolism in vivo, the nature of their interactions with cellular DNA, their ability to initiate hepatocarcinogenesis and cause liver tumors, will form a basis for the quantitative human health risk assessment for these Superfund Chemicals.
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