This project is designed to improve our understanding of the genotoxic effects of complex mixtures. Because of the large number of complex mixtures to which the public is exposed, the research will be of value to bother health professionals and the regulatory community. The research will focus on mixtures of polycyclic aromatic hydrocarbons (PAHs), such as coal tar or petroleum waste; and mixtures of PAHs and halogenated aromatic hydrocarbons (HAHs), such as wood preserving waste. Samples to be evaluated will include complex mixtures, isolated fractions, model compounds, and reconstituted mixtures. These samples will be evaluated using a tier system. The first tier will employ microbial genotoxicity assays to characterize the potential of a sample to induce point mutations, and gap junctional intercellular communication to measure the epigenetic potential of a sample. Tier two will measure the formation of DNA adducts in vivo as well as gene expression (primarily metabolic enzymes) as affected by exposure to complex mixtures. In addition, studies will be conducted to measure expression of p53, p21, or Gadd45 proteins following exposure to mixtures or model chemicals. These initial studies will be used to identify proteins following exposure to mixtures of model chemicals. These initial studies will be used to identify factors governing the metabolism of mixtures, as well as the initiation, promotion and progression of malignant cells. From these studies, two complex mixtures (and appropriate model compounds and reconstituted fractions) will be selected for investigation in a long-term rodent study. Two sensitive models will be employed based on the results of tiers one and two. The purpose of the third tier will be to determine if the effects and interactions observed in tier one and two testing are replicated in an animal model; and, do these effects have relevance to human cancer.
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