Project Summary (1997-1999)

This project is addressing the fundamental question of the mechanisms of toxicity of polychlorinated biphenyls (PCBs), specifically, the genotoxicity of individual PCBs and the associated oxidative damage. The hypothesis being tested is that lower halogenated biphenyls possess initiating potential while the higher halogenated PCBs are responsible for the well-documented promoting activity for this class of compounds. Jointly these activities may explain the fact that PCB mixtures are complete rodent carcinogens. Current research is designed to determine the role of PCB electrophiles in the toxicity of PCBs in vivo. There are three specific goals of the project. The first is to determine if selected PCBs and other halogenated biphenyls are metabolized (activated) in vivo to electrophilic species which interact with cellular DNA. The second is to determine if PCBs activated in vitro and in vivo to electrophiles can act as initiators in an in vivo rat liver initiation model. Lastly, the project will determine if those PCBs activated to electrophiles will initiate two stage hepatocarcinogenesis. This experiment will address the question of whether one group of PCBs may act as initiators while another group or groups may act as promoters of carcinogenesis.