QUANTIFYING NITROARENE GENOTOXICITY IN COMPLEX MIXTURES

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The biological activity of nitrated polycyclic aromatic hydrocarbons (nitroarenes) has ben the subject of extensive study primarily because of the potent mutagenicity and carcinogenicity of some nitroarenes as well as their widespread occurrence in the environment, principally as the result of incomplete combustion processes. However, most of us are not exposed primarily to individual compounds but rather to complex mixtures both outdoors (emissions from automobiles, power plants, etc.) and indoors (cigarette smoke, heaters, stoves, ovens etc). The objective of the work proposed in this application is to relate the genotoxic and carcinogenic activities of individual nitroarenes to activities of artificial mixtures and extracts of emission particulates in order to use data for single chemicals to evaluate the risk of exposure to complex mixtures. The proposed project, which employs both computerized and experimental methodologies, will involve professionals with expertise in chemistry, biochemistry, microbiology, artificial intelligence and risk assessment, and with extensive experience in the study of nitroarenes. Two computerized techniques will be used. First, Computer Automated Structure Evaluation (CASE), an artificial intelligence program which was developed to predict the mutagenicity of nitroarenes, will be used to identify structural determinants of mutagenicity, genotoxicity and carcinogenicity. Second, the Carcinogenicity Prediction and Battery Selection (CPBS) method will used to identify appropriate batteries of short-term tests for screening individual nitroarenes and mixtures and to predict potential carcinogenicity, including carcinogenic potency. Experimental studies will be directed towards assessing the activities of compounds in mixtures. Artificial mixtures of pairs of nitroarenes or related compounds, as well as extracts of combustion emissions combined with individual chemicals, will be tested for mutagenicity, metabolic activation and deactivation of mutagenicity, mammalian genotoxicity and metabolic biotransformation. Three issues will be addressed: whether activities are additive or are influenced by competition for enzymatic activation, whether inactivating structures identified by CASE represent alternative biotransformation or competition and how the presence of a complex mixture influences the metabolism, mutagenicity and genotoxicity of individual chemicals. Resolving these questions about the extrapolation from individual components to mixtures would allow data for individual chemicals concerning bioavailability, metabolism, genotoxicity, detoxification and excretion to be used to reduce uncertainty in the assessment of human risk from exposure in incomplete combustion products and other complex mixtures.