Modeling of Complex Mixtures: JP-8 Toxicokinetics

摘要

This report culminates a three year project to develop appropriately parameterized and validated physiologically-based pharmacokinetic (PBPK) models for representative components of jet fuel JP-8, and combine them into a complex mixture interaction model of JP-8 itself for use in a mechanism-based assessment of human health effects resulting from exposure to aerosol, vapor and (via skin) liquid. Single chemical models of selected representative components (nonane, decane and naphthalene) were used to predict systemic dose for dose-response assessment using kinetic data from in-house and published studies. To harmonize single chemical models, we developed a modeling framework that included generic tissue compartments in which we have combined diffusion limitation and deep tissue (global tissue model). We also applied a QSAR approach for estimating blood and tissue partition coefficients, and in integrating our kinetic model with exposure models. A complex mixture model of jet fuel was developed for an arbitrarily large number of components, in which interactions are modeled for the specific case of competitive metabolic inhibition of a specific enzyme (P450-2E1). Applications of this approach include the ability to integrate animal, human and in vitro data in a form that allows internal dose and health effects predictions to be made concerning specific real-world exposures to JP-8 and new alternative fuels.