Journal Article

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

Gunnar Boysen, Nadia I. Georgieva, Narisa K. Bordeerat, Radim J. Šram, Pamela Vacek, Richard J. Albertini and James A. Swenberg

in Toxicological Sciences

Volume 125, issue 1, pages 30-40
Published in print January 2012 | ISSN: 1096-6080
Published online October 2011 | e-ISSN: 1096-0929 | DOI: http://dx.doi.org/10.1093/toxsci/kfr272
Formation of 1,2:3,4-Diepoxybutane-Specific Hemoglobin Adducts in 1,3-Butadiene Exposed Workers

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1,3-Butadiene (BD) is an important industrial chemical that is classified as a human carcinogen. BD carcinogenicity has been attributed to its metabolism to several reactive epoxide metabolites and formation of the highly mutagenic 1,2:3,4-diepoxybutane (DEB) has been hypothesized to drive mutagenesis and carcinogenesis at exposures experienced in humans. We report herein the formation of DEB-specific N,N-(2,3-dihydroxy-1,4-butadiyl)valine (pyr-Val) in BD-exposed workers as a biomarker of DEB formation. pyr-Val was determined in BD monomer and polymer plant workers that had been previously analyzed for several other biomarkers of exposure and effect. pyr-Val was detected in 68 of 81 (84%) samples ranging from 0.08 to 0.86 pmol/g globin. Surprisingly, pyr-Val was observed in 19 of 23 administrative control subjects not known to be exposed to BD, suggesting exposure from environmental sources of BD. The mean ± SD amounts of pyr-Val were 0.11 ± 0.07, 0.16 ± 0.12, and 0.29 ± 0.20 pmol/g globin in the controls, monomer, and polymer workers, respectively, clearly demonstrating formation of DEB in humans. The amounts of pyr-Val found in this study suggest that humans are much less efficient in the formation of DEB than mice or rats at similar exposures. Formation of pyr-Val was more than 50-fold lower than has been associated with increased mutagenesis in rodents. The results further suggest that formation of DEB relative to other epoxides is significantly different in the highest exposed polymer workers compared with controls and BD monomer workers. Whether this is due to saturation of metabolic formation or increased GST-mediated detoxification could not be determined.

Keywords: biomonitoring; exposure response; risk assessment; exposure assessment; 1,3-butadiene; globin adducts

Journal Article.  6744 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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