This project proposes to conduct several interrelated studies with individual polycyclic aromatic hydrocarbons (PAHs) and reconstituted PAH mixtures to determine the interactions of these compounds and the role of these interactions in PAH-induced carcinogenicity. The classes of PAH compounds to be studied include the polychlorinated biphenyls (PCBs), polychlorinated dibenzo-p-dioxins (PCDDs) and the polychlorinated dibenzofurans (PCDFs). The proposed studies include: (1) analysis of the comparative induction of CYP1A1 and CYP1A2 gene expression by a reconstituted PAH mixture and the 2-,3- and > 4-ring PAH fractions to determine the relative contributions of the different fractions to the overall induction potency of the mixture; (2) extension of (1) to include other Ah receptor-mediated responses; (3) investigation of the selective induction of CYP1A2 by acenaphthylene with regard to its toxicologic and carcinogenic significance; and (4) investigation of the interactions of strong carcinogens that are poor microsomal P450 enzyme inducers and weak carcinogens that are potent microsomal P450 enzyme inducers. The results obtained will determine the extent of the non-additive interactions between PCBs and PCDDs/PCDFs and provide critical data which can be used to evaluate the utility of the TEF model for risk assessment of HAHs.
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