Toxicological Sciences, Vol 49, 15-28, Copyright © 1999 by Society of Toxicology
AS Collins, SC Sumner, SJ Borghoff and MA Medinsky
The oxygenate tert-amyl methyl ether (TAME) is a gasoline fuel additive
used to reduce carbon monoxide in automobile emissions. To evaluate the
relative 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 physiologically-based pharmacokinetic (PBPK) model to describe the
disposition of TAME and its major metabolite, tert-amyl alcohol (TAA), in
male Fischer-344 rats. The model compartments for TAME and TAA were
flow-limited. The TAME physiological model had 6 compartments: lung, liver,
rapidly perfused tissues, slowly perfused tissues, fat, and kidney. The TAA
model had 3 compartments: lung, liver, and total-body water. The 2 models
were linked through metabolism of TAME to TAA in the liver. Model
simulations were compared with data on blood concentrations of TAME and TAA
taken from male Fischer-344 rats during and after a 6-hour inhalation
exposure to 2500, 500, or 100 ppm TAME. The PBPK model predicted TAME
pharmacokinetics when 2 saturable pathways for TAME oxidation were
included. The TAA model, which included pathways for oxidation and
glucuronide conjugation of TAA, underpredicted the experimental data
collected at later times postexposure. To account for biological processes
occurring during this time, three hypotheses were developed: nonspecific
binding of TAA, diffusion-limited transport of TAA, and enterohepatic
circulation of TAA glucuronide. These hypotheses were tested using three
different model structures. Visual inspection and statistical evaluation
involving maximum likelihood techniques indicated that the model
incorporating nonspecific binding of TAA provided the best fit to the data.
A correct 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 exposure to TAME.
ARTICLES
A physiological model for tert-amyl methyl ether and tert-amyl alcohol: hypothesis testing of model structures
Chemical Industry Institute of Toxicology, Research Triangle Park, North Carolina 27709-2137, USA. ascollin@stat.ncsu.edu
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