PHYSIOLOGICALLY-BASED PHARMACOKINETIC MODELING OF 1,3-BUTADIENE, 1,2-EPOXY-3-BUTENE, AND 1,2-3,4-DIEPOXYBUTANE TOXICOKINETICS IN MICE AND RATS

1,3-Butadiene (BD) is a more potent tumor inducer in mice than in rats , BD also shows striking differences in metabolic activation, with sub stantially higher blood concentrations of 1,2:3,4-diepoxybutane (butad iene diepoxide; BDE) in BD-exposed mice than in similarly exposed rats , The objective of this study was to develop a single mechanistic mode l structure capable of describing BD disposition in both species. To a chieve this objective, known pathways of 1,2-epoxy-3-butene (butadiene monoepoxide; BMO) and BDE metabolism were incorporated into a physiol ogically based pharmacokinetic model by scaling rates determined in vi tro, With this model structure, epoxide clearance was underestimated f or both rats and mice, Improved simulation of blood epoxide concentrat ions was achieved by addition of first-order metabolism in the slowly perfused tissues, verified by simulation of data on the time course fo r BMO elimination after i.v. injection of BMO, Blood concentrations of BD were accurately predicted for mice and rats exposed by inhalation to constant concentrations of BD. However, if all BD was assumed to be metabolized to BMO, blood concentrations of BMO were overpredicted, B y assuming that only a fraction of BD metabolism produces BMO, blood c oncentrations of BMO could be predicted over a range of BD exposure co ncentrations for both species, In vitro and in vivo studies suggest an alternative cytochrome P-450-mediated pathway for BD metabolism that does not yield BMO, Including an alternative pathway for BD metabolism in the model also gave accurate predictions of blood BDE concentratio ns after inhalation of BD. Blood concentrations of BMO and BDE observe d in both mice and rats are best explained by the existence of an alte rnative pathway for BD metabolism which does not produce BMO.