Airborne PCBs are those that have higher vapor pressures, lower chlorination, and should be substrates formetabolic activation. We hypothesize that the lower halogenated biphenyls are activated by hepaticenzymes to oxygenated species that are electrophilic and bind to proteins and DNA. Our preliminary dataindeed show that PCBs are metabolized to electrophiles and free radicals that bind to cellular targets andthat the metabolism of PCBs produces reactive oxygen species, resulting in DNA strand breaks and 8-oxodeoxyguanosine formation in DNA and that a quinone/semiquinone may be a/the major metaboliteinvolved in these effects. Employing the Solt-Farber initiation-selection protocol, we also identified severallower chlorinated biphenyls as initiators of hepatocarcinogenesis in the rat. We therefore propose to extendour studies to: 1) determine the initiating potential of airborne, semi-volatile PCBs and to analyze thestructural and metabolic requirements needed for carcinogenic potency, 2) analyze for oncogenemutations and karyoptypic changes during PCB carcinogenesis in the Solt-Farber experiments, 3)investigate the types of genotypic damage induced by PCBs and their metabolites in vitro, in cells inculture, and in vivo, 4) examine the ease of formation and the reactivity of PCB-derived semiquinoneradicals, and 5) determine the biologic effects and the influence of Route of Exposure (IP vs. inhalation)of airborne PCBs (a typical 'air mixture' of PCBs, or single PCB congeners, or hydroxy-PCBs) on specificchanges in expression of xenobiotic-metabolizing enzymes, antioxidant enzymes or redox indicators inthe rat. Jointly these studies may explain why some PCBs are activated to genotoxins, while others arenot, which target genes are involved, the nature of the DNA lesions, and the mutations that ensue. Thesedata may also provide clues about whether nutritional or other interventions are warranted to protect highlyexposedhumans. These mechanistic and susceptibility issues will form a basis for the quantitative humanhealth risk assessment for these important Superfund Chemicals, arising from multiple sources.
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