Molecular Epidemiologic Studies in 1,3-Butadiene-Exposed Czech Workers

Abstract

SS3-03 Introduction: 1,3-butadiene's (BD) mode of action as a rodent carcinogen is genotoxicity, an important precursor for cancer. Methods: A continuum of biomarkers was measured in BD-exposed workers in the Czech Republic after extensive exposure assessments over several months. Results: Mean 8-hour TWA BD exposure levels for the 25 controls, 24 monomer production workers, and 34 polymerization workers (all male) in an initial study were 0.010, 0.290, and 0.810 ppm. Biomarkers measured included urinary metabolites, hemoglobin adducts, SCEs, HPRT gene mutations, chromosome aberrations, and metabolic genotypes at several loci. Urinary metabolite and hemoglobin adduct concentrations were significantly elevated, correlating with BD exposure levels. Detoxification metabolism as reflected by urinary metabolite ratios showed the dominance of hydrolysis. No significant relationships were seen between BD exposures and gene mutations or cytogenetic end points. Some polymorphisms did modulate detoxification metabolism but did not otherwise influence biomarker responses. A second study compared females and males. In addition to the hemoglobin adducts measured in the first study, analysis of a diepoxide-specific adduct was added. BD levels had fallen since the first study, TWAs are now 0.180 and 0.0035 ppm for 23 female-exposed and 26 female control workers, respectively, and 0.370 and 0.007 ppm for 30 male-exposed and 25 male control workers, respectively. Urinary metabolite concentrations again reflected BD exposures in males, but not in females who actually excreted less urine metabolite per unit BD exposure than did males. Metabolite ratios again reflected the dominance of hydrolytic detoxification and were not different between the sexes. Although hemoglobin adduct determinations are incomplete, diepoxide specific adducts were nondetectible in any subjects. Again, neither HPRT mutations nor cytogenetic changes were related to BD exposures in either sex. Discussion and Conclusions: Biomarkers are useful for mechanistic cancer assessments allowing comparisons between animal experiments and human molecular epidemiologic studies. Metabolism, metabolite accumulations, and genotoxic effects can now be quantified by molecular epidemiology. The BD studies are illustrative. BD's genotoxicity and therefore its carcinogenicity depend on electrophilic metabolites, particularly the diepoxide, that result from oxidative metabolism. Humans form much less of this metabolite per unit dose of BD than do rodents. This is reflected in its diminished genotoxicity in humans with the weight of evidence (including these Czech studies) indicating that it has yet to be demonstrated under modern exposure conditions. This has implications for assessing its cancer risk.