Development of a preliminary physiologically based toxicokinetic (PBTK) model for 1,3-butadiene risk assessment

Potential health effects of human exposure to 1,3-butadiene (BD) are of concern due to the use of BD in industry and its low-level presence throughout the environment. Physiologically based toxicokinetic (PBTK) models of BD in rodents have been developed by multiple research groups in an effort to explain species differences in toxicity (especially carcinogenic potency) through toxicokinetics. PBTK modeling of dose metrics related to a non-cancer endpoint, ovotoxicity in experimental animals, was conducted. The cumulative area under the blood concentration vs. time curve (AUC) for the metabolite diepoxybutane (butadiene diepoxide, DEB) was found to be consistent with ovotoxicity in mice and rats exposed to BD by inhalation or epoxybutene (butadiene monoepoxide, EB) or DEB by intraperitoneal injection. This suggests that cumulative DEB AUC may also be an appropriate metric for possible human risk. A preliminary human PBTK model was assembled for the eventual assessment of reproductive risk to humans and for prioritizing the determination of model parameters. The preliminary model accurately predicted published data on exhaled breath BD concentrations in a human volunteer exposed to BD by inhalation. The fit was relatively insensitive to the rate constant for BD epoxidation. Sensitivity analyses were conducted on this human PBTK model. Using a range of published rate constants, human blood DEB was found to be sensitive to rates of epoxidation of EB to DEB and hydrolysis of EB and DEB, but not BD epoxidation. Because of the large ranges of rates measured in vitro for these reactions, different combinations of in-vitro rates produce varying predictions of blood DEB concentration. Thus, validation of a human PBTK model with human biomonitoring data will be essential to produce a PBTK model that can be applied to risk assessment.