Physiologically based pharmacokinetic models for gasoline oxygenates: Implementing statistical and mathematical analyses

Methyl tert-butyl ether (MTBE) is added to gasoline to reduce carbon monoxide and ozone precursors from automobile emis-sions. The objectives of this study were to verify the ability of a physiologically based pharmacokinetic (PBPK) model to predict MTBE blood levels in humans and to investigate the effect of variability in the metabolism of MTBE and its influence on the predicted MTBE blood levels. The model structure for MTBE was flow-limited and had six essential compartments: lung, liver, rap-idly perfused tissues, slowly perfused tissues, fat, and kidney. In this model, two pathways of metabolism are described to occur in the liver by Michaelis-Menten kinetics. Metabolic rate constants were measured in vitro using human liver microsomes and extrap-olated to in vivo whole-body metabolism. Model predictions were compared with data on blood levels of MTBE taken from humans during and after a 1-h inhalation exposure to 1.7 ppm MTBE an