DEVELOPMENT OF A PHYSIOLOGICALLY-BASED PHARMACOKINETIC MODEL FOR METHYL TERTIARY-BUTYL ETHER AND TERTIARY-BUTANOL IN MALE FISCHER-344 RATS

Methyl tertiary-butyl ether (MTBE) and its metabolite tertiary-butanol (TBA) both cause renal tumors in chronically exposed male rats. Knowl edge of the kinetic behavior of MTBE and TBA in rats and its compariso n to the kinetics of these chemicals in humans will aid in assessing h uman risk. The objective of this study was to develop a physiologicall y based pharmacokinetic (PBPK) model for MTBE and TBA in rats that wil l form the basis for a human model. Physiological parameters such as b lood flows, tissue volumes, and alveolar ventilation were obtained fro m the literature. Chemical-specific parameters such as the solubility of MTBE and TBA in blood and selected tissues and metabolic rate const ants to describe whole-body metabolism of MTBE in rats were measured u sing vial equilibration and gas uptake techniques, respectively. MTBE metabolism was described in the model as occurring through two saturab le pathways. The model was able to predict gas uptake data (100 to 200 0 ppm starting concentrations) and levels of MTBE in blood of rats exp osed to MTBE by inhalation (400 and 8000 ppm, 6 hr), iv (40 mg/kg), an d oral (40 or 400 mg/kg) administration. Two different models to descr ibe the dosimetry of TBA in a rat were tested for their ability to pre dict TBA blood levels after MTBE exposure. TBA blood levels were predi cted 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 an d elimination will be necessary to refine this submodel. With a quanti tative description of the important determinants of MTBE and TBA dosim etry understood, a better assessment of the potential toxic and cancer risk for humans exposed to MTBE can be made. (C) 1996 Society of Toxi cology