1,3-BUTADIENE WORKING GROUP-REPORT

During the Workshop in North Carolina, the in vivo metabolism, adduct formation and genotoxicity data available from rodent and human exposu re to 1,3-butadiente (ED) were reviewed and they are summarized in the present report. ED is metabolized by cytochrome P-450-dependent monox ygenases to the primary metabolite 1,2-epoxybutene-3 (epoxybutene, EB) . EB is subjected to further metabolism: oxidation to 1,2: 3,4-diepoxy butane (DEB), hydrolysis to 3-butene-1,2-diol and conjugation to gluta thione. The first pathway seems to prevail in mice while the latter is characteristic for rats and possibly for humans. Species differences exist in adduct formation of the monoepoxide to hemoglobin, for which the following pattern has been found: mice > rats > humans, Genotoxity of ED was found in mice with all applied tests; however, negative res ults were obtained in rats. In exposed humans, the cytogenetic studies in peripheral blood lymphocytes did not show genotoxic effects, altho ugh one report described elevated hprt variant levels in peripheral bl ood lymphocytes of exposed workers. It was concluded that the presentl y available data are insufficient for the application of the parallelo gram model to estimate genetic risk for humans. As an alternative appr oach, a tentative estimate of the doubling dose for induction of hprt mutations in somatic cells of mice and men was performed and the calcu lated values were surprisingly similar, i.e. 9000 ppmh. However, this estimate is burdened with a number of caveats which were discussed in detail. The working group identified a series of urgent research needs to provide the appropriate data for the application of the parallelog ram model, such as identification of metabolic pathways in different r odent species and humans, metabolic studies in mice, rats and humans c onsidering metabolic polymorphisms, studies of adducts to DNA and hemo globin especially of DEB and other butadiene metabolites in rodents an d humans, studies of mutational spectra (mutational fingerprinting) in somatic and germinal cells, confirmation of the human hprt mutation d ata, confirmation of the rodent malformation data, dose-response studi es in rodent germ cell tests and studies on repair kinetics of mono-ad ducts induced by EB as opposed to repair of cross-links produced by DE B. Finally, it was suggested that the original parallelogram consistin g of data from somatic cell studies in rodents and humans plus studies of heritable effects in rodents to extrapolate to germ cell risk for humans should be supplemented with studies in sperm of experimental an imals and exposed men.