Intra- and Inter-Species Variability in Urinary N7-(1-Hydroxy-3-buten-2-yl)guanine Adducts Following Inhalation Exposure to 1,3-Butadiene

1,3-Butadiene is a known carcinogen primarily targeting lymphoid tissues, lung, and liver. Cytochrome P450 activates butadiene to epoxides which form covalent DNA adducts that are thought to be a key mechanistic event in cancer. Previous studies suggested that inter-species, -tissue, and -individual susceptibility to adverse health effects of butadiene exposure may be due to differences in metabolism and other mechanisms. In this study, we aimed to examine the extent of inter-individual and inter-species variability in the urinary N7-(1-hydroxy-3-buten-2-yl)guanine (EB-GII) DNA adduct, a well-known biomarker of exposure to butadiene. For a population variability study in mice, we used the collaborative cross model. Female and male mice from five strains were exposed to filtered air or butadiene (590 ppm, 6 h/day, 5 days/week for 2 weeks) by inhalation. Urine samples were collected, and the metabolic activation of butadiene by DNA-reactive species was quantified as urinary EB-GII adducts. We quantified the degree of EB-GII variation across mouse strains and sexes; then, we compared this variation with the data from rats (exposed to 62.5 or 200 ppm butadiene) and humans (0.004-2.2 ppm butadiene). We show that sex and strain are significant contributors to the variability in urinary EB-GII levels in mice. In addition, we find that the degree of variability in urinary EB-GII in collaborative cross mice, when expressed as an uncertainty factor for the inter-individual variability (UFH), is relatively modest (<= threefold) possibly due to metabolic saturation. By contrast, the variability in urinary EBGII (adjusted for exposure) observed in humans, while larger than the default value of 10-fold, is largely consistent with UFH estimates for other chemicals based on human data for non-cancer endpoints. Overall, these data demonstrate that urinary EB-GII levels, particularly from human studies, may be useful for quantitative characterization of human variability in cancer risks to butadiene.

Automated summary

The study focused on examining the variability of urinary N7-(1-hydroxy-3-buten-2-yl)guanine (EB-GII) DNA adduct, a biomarker of exposure to 1,3-butadiene, in mice, rats, and humans. Variability in EB-GII levels in mice was influenced by sex and strain, with metabolic saturation possibly contributing to modest variability. In humans, despite larger variability, urinary EB-GII levels were consistent with estimates for other chemicals based on non-cancer endpoints data.