Inhalation pharmacokinetics of 1,3-butadiene and 1,2-epoxybutene-3 in rats and mice

Studies were conducted on inhalation pharmacokinetics of 1,3-butadiene and of its primary reactive metabolic intermediate 1,2-epoxybutene-3 in rats (Sprague-Dawley) and mice (B6C3F₁). Investigations of inhalation pharmacokinetics of 1,3-butadiene revealed saturation kinetics of 1,3-butadiene metabolism in both species. For rats and mice linear pharmacokinetics apply at exposure concentrations below 1000 ppm 1,3-butadiene; saturation of 1,3-butadiene metabolism is observed at atmospheric concentrations of about 2000 ppm. The estimated maximal metabolic elimination rates were 400 μmole/hr/kg for mice and 200 μmole/hr/kg for rats. This shows that 1,3-butadiene is metabolized by mice at about twice the rate of rats. Investigations of inhalation pharmacokinetics of 1,2-epoxybutene-3 revealed major differences in metabolism of this compound between both species. No indication of saturation kinetics of 1,2-epoxybutene-3 metabolism could be observed in rats up to exposure concentrations of 5000 ppm, whereas in mice the saturation of epoxybutene metabolism became apparent at atmospheric concentrations of about 500 ppm. The estimated maximal metabolic rate for 1,2-epoxybutene-3 was 350 μmole/hr/kg in mice and > 2600 μmole/hr/kg in rats. When the animals are exposed to high concentrations of 1,3-butadiene, 1,2-epoxybutene-3 is exhaled by rats and mice. For rats 1,2-epoxybutene-3 concentration in the gas phase of the system reaches a plateau at about 4 ppm. For mice, 1,2-epoxybutene-3 concentration increases with exposure time until, at about 10 ppm, signs of acute toxicity are observed. Under these conditions hepatic nonprotein sulfhydryl compounds are virtually depleted in mice but not in rats. After exposure of rats and mice to (1,4-¹⁴C)1,3-butadiene, covalent binding of (¹⁴C)butadiene-derived radioactivity could be detected. In both species, comparable amounts of radioactivity were associated with liver DNA. Covalent binding to nucleoproteins was twice as high in mice when compared to rats, and thus it paralleled the higher metabolic rate for 1,3-butadiene in this species. We conclude, that in addition to the higher metabolism of 1,3-butadiene in mice, limited detoxification and thus accumulation of its primary reactive intermediate 1,2-epoxybutene-3 must be a major determinant for the higher susceptibility of mice to 1,3-butadiene-induced carcinogenesis.