title: Evaluation of stable isotope-labeled probes in the study of solvent pharmacokinetics in human subjects.
abstract: The relationship between biomarkers of exposure (such as concentrations of toxicants in blood or breath, or metabolites in urine) and toxicant dose for individuals is influenced by many person- and episode-specific factors which contribute to overall variability in biomarker level for a given dose. This variability results in imprecise biological marker-based estimates of dose for individuals. We hypothesize that pharmacokinetic data from stable-isotope (deuterated) analogs can be used with a pharmacokinetic model to account for individual-related sources of variation, leading to more precise methods of dose estimation for individuals. To establish the degree of similarity in the pharmacokinetics of unlabeled (d0-) and fully deuterated (D8-) toluene, 21 men (ages 20-45) inhaled an equal molar mixture for 2h. Washout kinetics for both compounds were followed for 4 d in alveolar air and blood. Both compounds exhibited three-phase elimination kinetics in both fluids. The third phase was not always definable for d0-toluene because of concurrent uncontrolled environmental exposures. Considering data from only the first two phases, concentrations of d0- and d8-toluene in alveolar air and blood were well correlated for all subjects, even though pharmacokinetic parameters varied among individuals by 5-9 folds. Further experiments are needed to discern whether correlations between d0- and d8-toluene for the third phase are influenced by an isotope effect; present data support use of d8-toluene as a suitable probe for d0-kinetics.
authors.affiliation: Department of Environmental Health, University of Washington, Seattle 98195.
authors.forename: M S
authors.initials: MS
authors.lastname: Morgan
authors.forename: R L
authors.initials: RL
authors.lastname: Dills
authors.forename: D A
authors.initials: DA
authors.lastname: Kalman
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000032:analysis; D003903:Deuterium; D004781:Environmental Exposure / Q000032:analysis; D004784:Environmental Monitoring / Q000379:methods*; D006801:Humans; D007553:Isotope Labeling; D008297:Male; D008954:Models, Biological; D012997:Solvents / Q000493:pharmacokinetics*; D014050:Toluene / Q000031:analogs & derivatives / Q000493:pharmacokinetics*
chemical_list: D015415:Biomarkers; D012997:Solvents; D014050:Toluene; D003903:Deuterium