Complex Mixtures: Array PBPK Modeling of Jet Fuel Components

Abstract

An array physiologically-based pharmacokinetic (PBPK) model represents a streamlined method to simultaneously quantify dosimetry of multiple compounds. To predict internal dosimetry of jet fuel components simultaneously, an array PBPK model was coded to simulate inhalation exposures to one or more selected compounds: toluene, ethylbenzene, xylenes, n-nonane, n-decane, and naphthalene. The model structure accounts for metabolism of compounds in the lung and liver, as well as kinetics of each compound in multiple tissues, including the cochlea and brain regions associated with auditory signaling (brainstem and temporal lobe). The model can accommodate either diffusion-limited or flow-limited kinetics (or a combination), allowing the same structure to be utilized for compounds with different characteristics. The resulting model satisfactorily simulated blood concentration and tissue dosimetry data from multiple published single chemical rat studies. The model was then utilized to predict tissue kinetics for the jet fuel hearing loss study (JTEH A, 25:1-14). The model was also used to predict rat kinetic comparisons between hypothetical exposures to JP-8 or a Virent Synthesized Aromatic Kerosene (SAK):JP-8 50:50 blend at the occupational exposure limit (200 mg/m3). The array model has proven useful for comparing potential tissue burdens resulting from complex mixture exposures.