Characterization of population variability of 1,3-butadiene derived protein adducts in humans and mice

Abstract

1,3-butadiene is a known human carcinogen and a chemical to which humans are exposed occupationally and through environmental pollution. Inhalation risk assessment of 1,3-butadiene was completed several decades ago before data on molecular biomarkers of exposure and effect have been reported from both human studies of workers and experimental studies in mice. To improve risk assessment of 1,3-butadiene, the quantitative characterization of uncertainty in estimations of inter-individual variability in cancer-related effects is needed. For this, we ought to take advantage of the availability of the data on 1,3-butadiene hemoglobin adducts, well established biomarkers of the internal dose of the reactive epoxides, from several large-scale human studies and from a study in a Collaborative Cross mouse population. We found that in humans, toxicokinetic uncertainty factor for 99th percentile of the population ranged from 3.27 to 7.9, depending on the hemoglobin adduct. For mice, these values ranged from less than 2 to 7.51, depending on the dose and the adduct. Quantitative estimated from this study can be used to reduce uncertainties in the parameter estimates used in the models to derive the inhalation unit risk, as well as to address possible differences in variability in 1,3-butadiene metabolism that may be dose-related.