The long-term objective of this project is to develop molecular biomarker strategies for alkylanilines that arebased 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, includingbladder cancer in humans. Present understanding of their mechanisms of action is imperfect but indicatesthat their toxic properties may be considerably greater in terms of both potency and variety than currentlyrecognized. Moreover, as this project has previously discovered, human exposure to alkylanilines is nearlyuniversal and is associated with atmospheric contamination.
The specific aims are to characterize thegenotoxicity of the reactive metabolites of alkylanilines, to identify the DNA adducts that the metabolitesproduce, to determine the role of phenolic metabolites in generating oxidative stress, to assess exposurethrough hemoglobin adducts in selected populations and relate the biomarker-based exposure assessmentwith ambient air concentration measurements, and to develop urinary biomarkers to assess the effects ofchemointerventions. Accelerator mass spectrometry will be used to determine the fate and transport of C-14labeled alkylanilines in experimental systems used to characterize metabolism, biomarker formation, andmechanisms of action. State-of-the-art conventional mass spectrometry will be the principal means ofchemical structure identification and development of methods for quantitative analysis of biomarkers. Thisproject is designed to develop the advanced exposure assessment methods needed to discern hazards forhuman populations where ambient exposure levels are low, but the toxicologic hazards of the exposuresremain high. Application of the biomarker methods will enable studies that have the power to assess theimportance of prevalent ambient exposures to human health. The biomarker methods developed in thisproject will also enable studies that can assess the effects of chemointervention on human health risk.
Showing the most recent 10 out of 234 publications
