Abstract
1. To examine the bioequivalence of an isotope-labelled tracer to study toxicant disposition, we conducted 33 controlled human exposures to a mixture of 50 ppm Htoluene and 50 ppm H-toluene for 2h, and measured concentrations in blood and breath, and metabolite levels in urine for 100h post-exposure. 2. A physiologically based kinetic (PBK) model found that compared with H-toluene, H-toluene had a 6.4 13% (mean SD) lower AUC, a 6.5 13% higher systemic clearance (1.46 0.27 versus 1.38 0.25 l h-kg), a 17 22% larger terminal volume of distribution (66.4 14 versus 57.2 10 l kg) and a 9.7 26% longer terminal half-life (38 12 versus 34 10h) (p0.05 for all comparisons). 3. The higher H-toluene clearance may have been due to an increased rate of ring oxidation, consistent with the 17% higher observed fraction of H- versus H-cresol metabolites in urine. 4. The larger terminal volume and half-lives for H-toluene suggested a higher adipose tissue blood partition coefficient. 5. Observed isotope differences were small compared with interindividual differences in H-toluene kinetics from previous studies. 6. The PBK model allowed us to ascribe observed isotope differences in solvent toxicokinetics to underlying physiologic mechanisms.
Published Version
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