Conjugated dienes such as 1,3-butadiene, 2-methyl-1,3-butadiene (isoprene), and styrene are petrochemicals used extensively in many industries including the manufacture of synthetic rubber and plastics. Human and animal exposure to these chemicals has been associated with the development of a wide variety of toxic responses, including cancer and bone marrow, liver, and gonadal toxicities. Because current evidence implicates metabolism of 1,3-butadiene by cytochrome P450s and myeloperoxidase in the mechanisms of 1,3-butadiene toxicity, specific experimental objectives are as follows: A) To determine the relative roles of various P450 isozymes in conjugated diene metabolism in male and female mouse, rat, and human tissue microsomes. B) To investigate the chemical reactivity and acute and subacute toxicity of selected conjugated diene metabolites. This will include characterization of the interactions of selected 1,3-butadiene metabolites with nucleic acids, and histopathological and functional assessment of liver, kidney, testis, and bone marrow after rats and mice are given selected metabolites. C) To develop noninvasive biomonitoring methods to assess 1,3-butadiene exposure. These methods will be based upon both determinations of metabolite concentrations in urine, and analyses of covalent adducts of reactive metabolites with blood hemoglobin. The proposed studies should allow for a better understanding of the mechanisms of conjugated diene toxicity and may facilitate and improve human epidemiologic studies.
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