Subchronic and chronic studies in rats of the
gasoline oxygenates
ethyl tert-butyl ether (
ETBE) and
tert-butanol (TBA) report similar noncancer kidney and liver effects but differing results with respect to kidney and liver
tumors. Because TBA is a major metabolite of
ETBE, it is possible that TBA is the active toxic moiety in all these studies, with reported differences due simply to differences in the internal dose. To test this hypothesis, a physiologically-based pharmacokinetic (PBPK) model was developed for
ETBE and TBA to calculate internal dosimetrics of TBA following either TBA or
ETBE exposure. This model, based on earlier PBPK models of
methyl tert-butyl ether (
MTBE), was used to evaluate whether kidney and liver effects are consistent across routes of exposure, as well as between
ETBE and TBA studies, on the basis of estimated internal dose. The results demonstrate that noncancer kidney effects, including kidney weight changes, urothelial
hyperplasia, and chronic progressive nephropathy (CPN), yielded consistent dose-response relationships across routes of exposure and across
ETBE and TBA studies using TBA blood concentration as the dose metric. Relative liver weights were also consistent across studies on the basis of TBA metabolism, which is proportional to TBA liver concentrations. However, kidney and liver
tumors were not consistent using any dose metric. These results support the hypothesis that TBA mediates the noncancer kidney and liver effects following
ETBE administration; however, additional factors besides internal dose are necessary to explain the induction of liver and kidney
tumors.