This project will build upon our previous innovations in developing biomarkers of exposure to benzene and polycyclic aromatic hydrocarbons (PAHs) and in applying these biomarkers in exposed populations. The biomarkers will include urinary analytes (unmetabolized parent compounds and stable metabolites) and blood-protein adducts of the reactive metabolites. Human cancers and other toxic effects of benzene and PAHs arise from metabolism of the parent compounds to toxic intermediates, including epoxides, diolepoxides, and quinones. Human metabolism can vary among individuals due to a host of factors. The following two hypotheses will be considered in this project: Hypothesis 1: biomarkers of exposure can be used to elucidate the human metabolism of benzene and PAHs. Hypothesis 2: biomarkers of exposure can be used to quantify interindividual variability of metabolism of benzene and PAHs, due to differences in gender, age, and physiological, lifestyle, and genetic factors. To test these hypotheses, we will pursue three specific aims. First, we will gather appropriate samples of urine and blood with which to evaluate exposure-biomarker relationships. Populations will include both high/moderate exposures (coke ovens, asphalt and rubber workers, persons using smoky coal for cooking and residential heating) and low/background exposures (workers exposed to diesel exhausts and jet fuel, smokers and nonsmokers in the general public). Second, we will develop or adapt ultra-trace mass spectrometric (GC-MS and LC-MS/MS) methods to measure the urinary and blood analytes. These methods will build upon existing GC-MS assays of protein adducts from our laboratory and will be expanded to include state-of-the-art LC-MS/MS methods for the urinary metabolites. Third, we will employ statistical models to characterize the exposure-biomarker relationships, paying particular attention to evidence of concavity, due to saturation of metabolism, and to the low-dose linear slope. Adding available covariates for gender, age, physiological and lifestyle factors, and genetic factors, we will explore the sources of interindividual variability in the exposure-specific levels of biomarkers. Blood samples from a study of childhood leukemias will also be analyzed for protein adducts of benzene and PAHs in collaboration with the U.C. Berkeley SBRP. This will allow Berkeley investigators to achieve additional specific aims in their program.
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