Pbpk Modeling Assessment of the Competitive Metabolic Interactions

PBPK MODELING ASSESSMENT OF THE COMPETITIVE METABOLIC INTERACTIONSFOR M-XYLENE, ETHYLBENZENE, AND A LUMPED AROMATIC FRACTION OF JP-8JET FUEL VAPORJerry L. Campbell and Jeffrey W. Fisher Jet Propellant 8 (JP-8), a kerosene-based jet fuel used in the military, is composed of hundreds of hydrocarbons. A PBPK model was developed to assess the metabolic interactions of JP-8 vapor on two prominent aromatic constituents of JP-8 vapor, m-xylene (XYL) and ethylbenzene (EBZ). A limited number of rats were exposed to JP-8 vapor in a Leach chamber for 4 hr to 390, 1100, or 2700 mg/m3. The chamber atmosphere was monitored during exposure with severalindividual hydrocarbons being quantified, including XYL, EBZ and the total hydrocarbonconcentration. Blood and liver were harvested (end of exposure and 0.5 h post exposure) andanalyzed by a novel headspace SPME/GC-MS method which allowed for identification andquantification of low levels of individual hydrocarbons. The PBPK model was able to describeboth the single exposure data previously published for XYL and EBZ as well as the metabolicinteractions between XYL, EBZ and a lumped aromatic fraction of JP-8 vapor that was estimatedto be approximately 25% of the fuel vapor. Competitive inhibition of XYL and EBZ metabolismwas observed for JP-8 vapor inhalation exposures of 1100 and 2700 mg/m3. Future inhalationstudies with jet fuel include aerosol exposures and expansion of the PBPK models to includeother hydrocarbons such as n-alkanes and upper respiratory tract dosimetry of aerosol droplets.