Sex-Specific Formation of 1,2:3,4-Diepoxybutane-Derived Hemoglobin Adducts in 1,3-Butadiene-Exposed Workers

1,3-Butadiene (BD) is an important industrial chemical that is classified as a human carcinogen. BD carcinogenicity has been attributed to several reactive epoxide metabolites, and the formation of highly mutagenic 1,2:3,4-diepoxybutane (DEB) has been suggested to drive mutagenesis and carcinogenesis at exposures experienced in humans. We report herein the formation of DEB-specific <i>N</i>,<i>N</i>-(2,3-dihydroxy-1,4-butadiyl)-valine (<i>pyr</i>-Val) in occupationally BD-exposed workers as an indirect biomarker of DEB-induced mutagenicity. <i>pyr</i>-Val was determined in BD-monomer and -polymer plant workers that had been previously analyzed for several other biomarkers of exposure and effect. In this second study, <i>pyr</i>-Val was detected in 92 out of 94 (98%) individuals, ranging from 0.001 to 0.697 pmol/g of globin. Surprisingly, <i>pyr</i>-Val was observed in 43 of 44 administrative control subjects not known to be exposed to BD, suggesting environmental sources of BD. The mean ± SD amounts of <i>pyr</i>-Val were 0.049 ± 0.044, 0.029 ± 0.032, 0.030 ± 0.035, and 0.074 ± 0.093 pmol/g globin in female control, female exposed, male control, and male exposed, respectively, clearly demonstrating the formation of DEB in environmentally and occupationally exposed BD workers. The amounts of <i>pyr</i>-Val found in this study suggest that humans are much less efficient in the formation of DEB than mice or rats at similar BD exposures. The formation of <i>pyr</i>-Val was lower than that associated with increased mutagenesis in rodents.