Species differences in the production and clearance of 1,3-butadiene metabolites: a mechanistic model indicates predominantly physiological, not biochemical, control

Abstract

Inhaled 1,3-butadiene, a monomer used in the production of synthetic rubber and other resins, is metabolized to mutagenic and carcinogenic epoxide intermediates. A physiologically based pharmacokinetic model of the uptake, tissue distribution, and metabolism of butadiene was constructed to determine if the biochemical kinetic constants obtained from in vitro studies are consistent with the observed in vivo uptake and metabolism. The model includes compartments for lung, blood, fat, liver, other rapidly perfused tissues ('viscera') and slowly perfused tissues. Metabolism of butadiene was assumed to occur in viscera in addition to lung and liver. Enzymatic reaction rate equations for the formation of 1,2-epoxy-3-butene, for hydrolysis of this epoxide, and for its conjugation with glutathione were also included. Physiological and biochemical parameters for the mouse, rat and human were obtained from the literature; they were not adjusted to produce a fit to experimental data. The model was used to test the hypothesis that differences in uptake and clearance of butadiene by the three species are due to differences in the activities of the metabolizing enzymes. The model reproduces whole-body observations for the mouse and rat. It predicts that inhalation uptake of butadiene and formation and retention of epoxybutene are controlled to a much greater extent by physiological parameters than by biochemical parameters and that storage in the fat represents a significant fraction of the retained butadiene. Accumulation of epoxybutene in the blood is predicted to be higher in mice than in rats or humans, but accumulation of the epoxide intermediate in the liver is predicted to be highest in humans. The epoxide tissue concentrations predicted by the model do not, by themselves, correlate with tumor incidence in mice and rats, indicating that other factors are crucial for carcinogenesis induced by butadiene.