1,3-Butadiene: Biomarkers and application to risk assessment

Abstract

1,3-Butadiene (BD) is a known rodent and human carcinogen that is metabolized mainly by P450 2E1 to three epoxides, 1,2-epoxy-3-butene (EB), 1,2:3,4-diepoxybutane (DEB) and 1,2-epoxy-3,4-butanediol (EB-diol). The individual epoxides vary up to 200-fold in their mutagenic potency, with DEB being the most mutagenic metabolite. It is important to understand the internal formation of the individual epoxides to assign the relative risk for each metabolite and to understand the molecular mechanisms responsible for major species differences in carcinogenicity. We have conducted extensive exposure-biomarker studies on mice, rats and humans. Using low exposures that range from current occupational levels to human exposures from tobacco smoke has provided evidence that mice are very different from humans, with mice forming ~200 times more DEB than humans at exposures of 0.1–1.5 ppm BD. While no gender differences have been noted in mice and rats for globin adducts or N-7 guanine adducts, female rats and mice had 2–3-fold higher Hprt mutations and DNA-DNA cross-links, suggesting a gender difference in DNA repair. Numerous molecular epidemiology studies have evaluated globin adducts and Hprt mutations, SCEs and chromosomal abnormalities. None of the blinded studies have shown evidence of human genotoxicity at current occupational exposures and studies of globin adducts have shown similar or lower formation of adducts in females than males. If one calculates the EB dose-equivalents for the three species, mice clearly differ from rats and humans, being ~44 and 174 times greater than rats and humans, respectively. These data provide a scientific basis for improved risk assessment of BD.

1,3-Butadiene Exposure and Metabolism among Japanese American, Native Hawaiian, and White Smokers

“…Alternatively, EB and HMVK can be conjugated with glutathione and excreted in urine as the corresponding mercapturic acids, MHBMA and DHBMA(38). If not detoxified, EB acts as a direct mutagen via the formation of promutagenic DNA adducts or can be further bioactivated to an even more genotoxic diepoxide(39). …”

In vivo doses of butadiene epoxides as estimated from in vitro enzyme kinetics by using cob(I)alamin and measured hemoglobin adducts: An inter-species extrapolation approach

“…By using values from either the rat or the mouse (EEs in Table 1 and AUCs in Table 3), the AUC of DEB in human was calculated to be 0.082 and 0.075 nM h, respectively. This finding gives a mean AUC of 0.078 nM h of DEB for exposure to 1 ppm of BD for 1 h, which is in the same order of magnitude as the mean AUC (0.023 nM h/ppm h BD, Table 3) calculated from the measured Hb adducts in vivo in exposed humans (Boysen et al, 2012;Swenberg et al, 2011); insert in Fig. 1.…”

“…With the knowledge obtained from this study, it could be concluded that a combination of in vitro metabolism tests, short-term exposures at low doses in few animals for determining the relation between AUC and exposure dose in vivo, and in vitro tests of relative genotoxic potency, might be able to provide a more accurate answer about the relative risk in BD-exposed humans than the animal carcinogenicity tests. Even though DEB metabolism variation among species is known to be an important determinant of BD-induced carcinogenicity (Fred et al, 2008;US EPA, 2002), other factors such as differences in DNA repair of DNA-DNA cross-links and mutations between gender might contribute to species differences in susceptibility (Pianalto et al, 2013;Swenberg et al, 2011). Another complexity with regard to DEB is the conjugation of glutathione that could cross-link DNA as suggested by Cho et al (2010).…”

“…Most of the published data concern the measurement of adducts from EBdiol, and only a few human studies address adducts from EB. DEB adducts from human exposures are even more scarce (Boysen et al, 2012;Swenberg et al, 2011). The adduct level increments of BD epoxides in humans were calculated by using the published Hb adduct levels (Albertini et al, 2003;Boysen et al, 2012) together with Eq.…”

“…Data on Hb adduct levels from BD monoepoxides is available from a relatively large number of Toxicology and Applied Pharmacology xxx (2014) xxx-xxx workers with BD exposure (Albertini et al, 2003;Begemann et al, 2001;Boysen et al, 2012;Osterman-Golkar et al, 1996;Vacek et al, 2010;van Sittert et al, 2000). DEB has been much more difficult to measure, and the relatively few data on Hb adduct measurements in exposed humans have only recently been published (Boysen et al, 2012;Swenberg et al, 2011). Measured Hb-adduct levels could be used to infer the "area under the concentrationtime curve" (AUC) in blood, which also reflects absorption and metabolic rates (Ehrenberg et al, 1983;Törnqvist et al, 2002).…”