Humans are exposed to polycyclic aromatic hydrocarbons (PAH) in complex environmental mixtures and this exposure is linked to human cancer. Determination of the total levels of PAH-DNA adducts formed by complex mixtures is insufficient to provide the information necessary to assess human risk, because specific PAH metabolites differ greatly in carcinogenic potency. The hypothesis of the proposed studies is that by assessment of how two major classes of carcinogenic PAH are activated within complex mixtures, it will be possible to predict the potential of that mixture to affect activation of carcinogenic PAH present within that mixture and allow rapid estimation of the relative carcinogenic potency of complex mixtures. This hypothesis will be evaluated by examining the effect of environmental PAH mixtures on both PAH-DNA adduct formation and PAH-induced tumor induction in mouse skin by accomplishing four specific aims: 1. To extend our recent studies on the effect of environmental PAH mixtures on the metabolic activation and DNA binding of representative examples of the two major classes of carcinogenic PAH in mouse epidermis. We will compare our recent results from a standard mixture of PAH extracted from coal tar, SRM 1597, to two extracts derived from urban dust, SAM 1649 and from diesel exhaust (SRM 1650) obtained from the NIST. In order to determine how this type of environmental PAH mixture affects the metabolic activation of carcinogenic PAH, we will conduct PAH-DNA binding and tumor initiation-promotion studies in mouse epidermis. 2. To study the DNA-binding effect of complex PAH mixtures in human cells in culture. These studies will utilize MCF-7 human mammary carcinoma cell line and human MCF-10A human mammary carcinoma cell line which we have previously characterized with respect to their ability to metabolically activate individual carcinogenic PAH including B[a]P and DB[a,l]P to DNA binding metabolites. These studies will help us to relate the effects of complex PAH mixtures on DNA binding, tumor initiation and enzyme activation in mouse skin to how these mixtures affect carcinogen activation in humans. 3. To evaluate the carcinogenic potency of the above complex environmental PAH mixtures, as well as the effect of these mixtures on the carcinogenic activity of DB[a,l]P and B[a]P in tumor initiation-promotion assays in Sencar mice. 4. To determine the mechanism by which this complex PAH mixture affects activation of hindered bay-region and unhindered bay-region carcinogenic PAH through studies of the effect of complex PAH mixtures on CYP enzymes present in mouse skin. The proposed studies will determine whether the analysis of PAH-DNA adducts formed in mouse skin will provide a rapid approach for assessment of the relative carcinogenic potential of complex environmental mixtures of PAH. This will aid in the development of methods for predicting the relative carcinogenic potency based upon the PAH composition of complex environmental mixtures.
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