Hemoglobin adducts in 1,3-butadiene exposed Czech workers: Female–male comparisons

Abstract

We previously reported results of a molecular epidemiological study of female and male 1,3-butadiene (BD) exposed Czech workers showing that females appeared to absorb or metabolize less BD per unit exposure concentration than did males, based on metabolite concentrations in urine (Chem. Biol. Interact. 166 (2007) 63–77). However, that unexpected observation could not be verified at the time because the only additional BD metabolite measurement attempted was for 1,2,3,4-diepoxybutane (DEB) as reflected in specific N,N[2,3-dihydroxy-1,4-butyl]valine ( pyr-Val) hemoglobin adduct concentrations, which were not quantifiable in any subject with the method then employed. Neither somatic gene mutations nor chromosome aberrations were associated with BD exposure levels in that study, consistent with findings in an earlier Czech study of males only. We have since measured production and accumulation of the 1,2-dihydroxy-3,4-epoxybutane (EBD) metabolite as reflected in N-[2,3,4-trihydroxy-butyl]valine (THB-Val) hemoglobin adduct concentrations. The mean THB-Val concentration was significantly higher in exposed males than in control males (922.3 pmol/g and 275.5 pmol/g, respectively), but exposed and control females did not differ significantly (224.5 pmol/g and 181.1 pmol/g, respectively). In both the control and exposed groups mean THB-Val concentrations were significantly higher for males than females. THB-Val concentrations were significantly correlated with mean 8-h TWA exposures for both males and females, but the rate of increase with increasing BD exposure was significantly lower for females. THB-Val concentrations also increased with increasing urine M2 metabolite [isomeric mixture of 1-hydroxy-2-{N-actylcysteinyl}-3-butene and 2-hydroxy-1-{N-acetylcysteinyl}-3-butene] concentrations in both sexes but the rate of increase was also lower in females than in males. There were no significant correlations between THB-Val concentrations and either somatic gene mutations or chromosome aberrations in either males or females. These results using another biomarker to measure a second metabolite of BD support the original conclusion that females absorb or metabolize less BD than males per unit exposure and indicate that the size of the difference increases with exposure. This observation in humans differs from findings in rodents where at prolonged exposures to high BD levels the females form higher amounts of hemoglobin adducts than do males, a difference that disappears at shorter duration lower exposure levels, while female susceptibility to BD induced mutations and tumorgenesis in rodents appears to persist at all BD exposure levels.