RESEARCH PROJECT 3: Development, Validation and Application of Biomarkers for Alk

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The long-term objective of this project is to develop molecular biomarker strategies for alkylanilines that are based on DMA and protein adducts and reveal exposure and biologically effective dose in people. Alkylanilines are a class of aromatic amines that have been linked to a variety of health outcomes, including bladder cancer in humans. Present understanding of their mechanisms of action is imperfect but indicates that their toxic properties may be considerably greater in terms of both potency and variety than currently recognized. Moreover, as this project has previously discovered, human exposure to alkylanilines is nearly universal and is associated with atmospheric contamination. The specific aims are to characterize the genotoxicity of the reactive metabolites of alkylanilines, to identify the DNA adducts that the metabolites produce, to determine the role of phenolic metabolites in generating oxidative stress, to assess exposure through hemoglobin adducts in selected populations and relate the biomarker-based exposure assessment with ambient air concentration measurements, and to develop urinary biomarkers to assess the effects of chemointerventions. Accelerator mass spectrometry will be used to determine the fate and transport of C-14 labeled alkylanilines in experimental systems used to characterize metabolism, biomarker formation, and mechanisms of action. State-of-the-art conventional mass spectrometry will be the principal means of chemical structure identification and development of methods for quantitative analysis of biomarkers. This project is designed to develop the advanced exposure assessment methods needed to discern hazards for human populations where ambient exposure levels are low, but the toxicologic hazards of the exposures remain high. Application of the biomarker methods will enable studies that have the power to assess the importance of prevalent ambient exposures to human health. The biomarker methods developed in this project will also enable studies that can assess the effects of chemointervention on human health risk.