1,3-Butadiene (BD) is a petrochemical diene used extensively in the manufacture of synthetic rubber and plastics. In 1996, the Occupational Safety and Health Administration (OSHA) reduced the 8-hr time-weighted average workroom standard for BD from 1000 ppm to 1 ppm because human and animal exposure to BD has been associated with development of cancer. Key target tissues, in both humans and animals, include bone marrow, lung, heart, and liver. Mice, which were much more sensitive to BD-induced carcinogenicity than rats, exhibited sex and tissue differences in susceptibility. However, the biochemical basis for BD- induced carcinogenicity remains unclear. We have previously characterized BD oxidation to yield mutagenic metabolites, butadiene monoxide and diepoxybutane, in mouse, rat, and human liver. The results provided evidence for significant species differences in hepatic BD bioactivation and indicated major roles for P450 2E1 and 2A6 in BD oxidation in human liver. However, the sex- related differences in BD bioactivation in mouse, rat, and human tissues have not been investigated. Also, BD bioactivation in other target tissues (heart, lung, and bone marrow) remains unclear. Recently, we have obtained preliminary data indicating a major role for P450 4B1 in BD oxidation in male and female mouse lung and male mouse kidney. Thus, current experimental objectives are: A) To investigate sex-related differences in BD bioactivation in target (lung, heart, bone marrow, and liver) and non-target (kidney) tissues of both mice and rats, investigate the roles of P450s 2A, 2E, and 4B in BD bioactivation in these tissues, and characterize BD bioactivation in male and female human lung and liver. B) To characterize the specific DNA adducts of butadiene monoxide and diepoxybutane that are formed in vivo in various mouse and rat tissues, and investigate their potential role in species, sex, and tissue differences in susceptibility. C) To develop biomonitoring methods to assess exposure of mice and rats to BD, using GC/MS, LC/MS, and postlabeling techniques. These methods will be based upon characterization of covalent adducts of butadiene monoxide with hemoglobin and determinations of concentrations of modified, excised DNA bases in urine. The proposed studies will allow for a better understanding of the mechanisms of BD carcinogenicity and may facilitate and improve human epidemiologic studies. This may lead to a more accurate assessment of human risk.
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