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DEVELOPMENT OF A PHYSIOLOGICALLY-BASED PHARMACOKINETIC (PBPK) MODEL FOR THE INHALATION OF 2,2,4-TRIMETHYLPENTANE (TMP) IN LONG EVANS RATS.
Citation:
EL-MASRI, H. A., J. E. SIMMONS, R. A. PEGRAM, R. A. HARRISON, S. YAVANHXAY, S. M. DOWD, AND M. V. EVANS. DEVELOPMENT OF A PHYSIOLOGICALLY-BASED PHARMACOKINETIC (PBPK) MODEL FOR THE INHALATION OF 2,2,4-TRIMETHYLPENTANE (TMP) IN LONG EVANS RATS. Presented at Society of Toxicology Annual Meeting, Seattle, WA, March 16 - 20, 2008.
Impact/Purpose:
In order to relate target tissue dose to inhalation exposure levels, we developed a physiologically-based pharmacokinetic (PBPK) model for TMP in rats using in vivo gas uptake experiments.
Description:
TMP (2,2,4-trimethylpentane,“isooctane”) is a colorless liquid used primarily in the alkylation of isobutene and butylene reactions to derive high-octane fuels. TMP is released in the environment through the manufacture, use, and disposal of products associated with the gasoline and petroleum industry. TMP leads to tumors in male rat kidneys possibly due to increased nephropathy associated with α2u-globulin hyaline droplet accumulation. Several short-term studies (less than 4 hours) have shown TMP to cause sensory and motor irritations in rats and mice at inhalation exposures greater than 1000 ppm. In order to relate target tissue dose to inhalation exposure levels, we developed a physiologically-based pharmacokinetic (PBPK) model for TMP in rats using in vivo gas uptake experiments. Gas uptake experiments were conducted by exposing male Long Evans rats (80-90 days old) to initial TMP concentrations of 50, 100, 500, and 1000 ppm. The model consisted of compartments for the gas uptake chamber, lung, fat, kidney, liver, muscle, and brain. Physiological parameters were fixed from literature. Partition coefficients for the model were experimentally determined for blood, fat, liver, kidney, muscle, brain, and lung tissues using vial equilibration. Metabolism of TMP was assumed to occur in liver and kidney. Initial model simulations depicting temporal levels of TMP in the gas uptake chamber closely resembled data. The availability of a calibrated PBPK model for TMP is useful in establishing dose-response relationship between in vivo brain levels of the chemical and ensuing neurotoxicity measures. (This abstract does not reflect EPA policy.)