A physiological model for tert-amyl methyl ether and tert-amyl alcohol: Hypothesis testing of model structures

The oxygenate tert-amyl methyl ether (TAME) is a gasoline fuel additive use d to reduce carbon monoxide in automobile emissions. To evaluate the relati ve health risk of TAME as a gasoline additive, information is needed on its pharmacokinetics and toxicity. The objective of this study was to use a ph ysiologically-based pharmacokinetic (PBPK) model to describe the dispositio n of TAME and its major metabolite, tert-amyl alcohol (TAA), in male Fische r-344 rats. The model compartments for TAME and TAA were Bow-limited. The T AME physiological model had 6 compartments: lung, liver, rapidly perfused t issues, slowly perfused tissues, fat, and kidney. The TAA model had 3 compa rtments: lung, liver, and total-body water, The 2 models were linked throug h metabolism of TAME to TAA in the liver, Model simulations were compared w ith data on blood concentrations of TAME and TAA taken from male Fischer-34 4 rats during and after a 6-hour inhalation exposure to 2500, 500, or 100 p pm TAME. The PBPK model predicted TAME pharmacokinetics when 2 saturable pa thways for TAME oxidation were included. The TAA model, which included path ways for oxidation and glucuronide conjugation of TAA, underpredicted the e xperimental data collected at later times postexposure. To account for biol ogical processes occurring during this time, three hypotheses were develope d: nonspecific binding of TAA, diffusion-limited transport of TAA, and ente rohepatic circulation of TAA glucuronide, These hypotheses were tested usin g three different model structures. Visual inspection and statistical evalu ation involving maximum likelihood techniques indicated that the model inco rporating nonspecific binding of TAA provided the best fit to the data. A c orrect model structure, based upon experimental data, statistical analyses, and biological interpretation, will allow a more accurate extrapolation to humans and, consequently, a greater understanding of human risk from expos ure to TAME.