Development of a Physiologically Based Pharmacokinetic Model for Methyltertiary-Butyl Ether andtertiary-Butanol in Male Fischer-344 Rats

Abstract

Methyltertiary-butyl ether (MTBE) and its metabolitetertiary-butanol (TBA) both cause renal tumors in chronically exposed male rats. Knowledge of the kinetic behavior of MTBE and TBA in rats and its comparison to the kinetics of these chemicals in humans will aid in assessing human risk. The objective of this study was to develop a physiologically based pharmacokinetic (PBPK) model for MTBE and TBA in rats that will form the basis for a human model. Physiological parameters such as blood flows, tissue volumes, and alveolar ventilation were obtained from the literature. Chemical-specific parameters such as the solubility of MTBE and TBA in blood and selected tissues and metabolic rate constants to describe whole-body metabolism of MTBE in rats were measured using vial equilibration and gas uptake techniques, respectively. MTBE metabolism was described in the model as occurring through two saturable pathways. The model was able to predict gas uptake data (100 to 2000 ppm starting concentrations) and levels of MTBE in blood of rats exposed to MTBE by inhalation (400 and 8000 ppm, 6 hr), iv (40 mg/kg), and oral (40 or 400 mg/kg) administration. Two different models to describe the dosimetry of TBA in a rat were tested for their ability to predict TBA blood levels after MTBE exposure. TBA blood levels were predicted best at low MTBE exposure concentrations using a two-compartment model. The pharmacokinetics of TBA appear to be far more complex than those of MTBE, and additional experimental data on TBA distribution and elimination will be necessary to refine this submodel. With a quantitative description of the important determinants of MTBE and TBA dosimetry understood, a better assessment of the potential toxic and cancer risk for humans exposed to MTBE can be made.