Development of a physiologically based pharmacokinetic model for inhalation of jet fuels in the rat

Abstract

The pharmacokinetic behavior of the majority of jet fuel constituents has not been previously described in the framework of a physiologically based pharmacokinetic (PBPK) model for inhalation exposure. Toxic effects have been reported in multiple organ systems, though exposure methods varied across studies, utilizing either vaporized or aerosolized fuels. The purpose of this work was to assess the pharmacokinetics of aerosolized and vaporized fuels, and develop a PBPK model capable of describing both types of exposures. To support model development, n-tetradecane and n-octane exposures were conducted at 89 mg/m³ aerosol+vapor and 1000–5000 ppm vapor, respectively. Exposures to JP-8 and S-8 were conducted at ~900–1000 mg/m³, and ~200 mg/m³ to a 50:50 blend of both fuels. Sub-models were developed to assess the behavior of representative constituents and grouped unquantified constituents, termed “lumps”, accounting for the remaining fuel mass. The sub-models were combined into the first PBPK model for petroleum and synthetic jet fuels. Inhalation of hydrocarbon vapors was described with simple gas-exchange assumptions for uptake and exhalation. For aerosol droplets systemic uptake occurred in the thoracic region. Visceral tissues were described using perfusion and diffusion-limited equations. The model described kinetics at multiple fuel concentrations, utilizing a chemical “lumping” strategy to estimate parameters for fractions of speciated and unspeciated hydrocarbons and gauge metabolic interactions. The model more accurately simulated aromatic and lower molecular weight (MW) n-alkanes than some higher MW chemicals. Metabolic interactions were more pronounced at high (~2700–1000 mg/m³) concentrations. This research represents the most detailed assessment of fuel pharmacokinetics to date.

Keywords::

• JP-8
• S-8
• n-alkanes
• PBPK modeling
• inhalation
• aerosol
• hydrocarbon mixtures

Acknowledgements

The authors thank Kristyn Brunson, Christine Kendrick, Ghanashyam Joshi, Dr. Babatope Fatuyi, Dr. Oluseye Ogunmoroti, Libby Myers, Dr. Eva McLanahan, Dr. Matthew Henderson, and James Reboulet for assistance with development of experimental systems and during animal exposures. We also thank Dr. Lisa Sweeney for her kind edits and suggestions that have improved this work and Dr. David Mattie for supplying jet fuels and project guidance. This document has been reviewed and approved for publication by the U.S. Food and Drug Administration(FDA) National Center for Toxicological Research (NCTR) but does not necessarily reflect the positions, opinions, or recommendations of the FDA NCTR.

Declaration of interest

This work was supported by Air Force Office of Scientific Research (AFOSR) grant FA9550-07-1-0132 and an equipment grant, FA9550-04-1-0334.