DESCRIPTION: Humans are exposed 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, for 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 assessment of the relative carcinogenic potency of complex mixtures. This hypothesis will be evaluated by utilizing two approaches that examine the effect of environmental PAH mixtures on both PAH-DNA adduct formation and PAH-induced tumor formation in mouse skin by accomplishing four specific aims: (1) To determine the effect of complex environmental PAH mixtures on the binding of the two major classes of carcinogenic PAH to DNA in mouse epidermis after single and multiple treatments. The effect of three NIST standard reference samples (complex mixture of PAH from coal tar, urban dust/organics, and diesel particulate matter) on DNA-binding of PAH with hindered bay-regions (potent carcinogens that bind mainly to dA such as dibenzo(a,l)pyrene(DB(a,l)P) and 7,12-dimethylbenz(a)anthracence (DMBA) and PAH with unhindered bay-regions (less potent carcinogens that bind mainly to dG such as benzo(a)pyrene (BaP) will be measured by 33P or 35S postlabeling, immobilized boronate chromatography and HPLC. (2) To utilize antisera (selective for PAH-dA adducts or adducts formed by R,S,S,R PAHDE) to prepare immunoaffinity columns to isolate the low levels of DNA adducts formed in mouse skin treated with complex PAH mixtures and to analyze the isolated adducts by 33P or 35S postlabeling, immobilized boronate chromatography and HPLC. (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, BaP and DMBA, in initiation- promotion and complete carcinogenesis assays in Sencar mice. (4) To determine the mechanism by which complex PAH mixtures affect activation of hindered bay-region and unhindered bay-region carcinogenic PAH through studies of the effect of complex PAH mixtures on CYP isozymes present in mouse skin and metabolism of carcinogenic PAH in mouse epidermal homogenates. The proposed studies will determine whether the analysis of specific PAH-DNA adducts or classes of PAH-DNA adducts formed in mouse skin will provide a rapid approach for assessment of the carcinogenic potential of complex environmental mixtures of PAH and allow us to begin to develop methods for predicting carcinogenic potency based upon the PAH composition of environmental mixtures.