ToxSci Advance Access originally published online on January 31, 2003
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Toxicological Sciences 72, 3-18 (2003)
Copyright © 2003 by the Society of Toxicology
BIOTRANSFORMATION AND TOXICOKINETICS |
Physiological Modeling of Inhalation Kinetics of Octamethylcyclotetrasiloxane in Humans during Rest and Exercise
* Quantitative and Computational Toxicology Group, Center for Environmental Toxicology and Technology, Colorado State University, Fort Collins, Colorado 80523;
University of Rochester Medical Center, Departments of Medicine and Environmental Medicine, Pulmonary/Critical Care Division, Rochester, New York 14642; and
Toxicology, Health and Environmental Sciences, Dow Corning Corporation, Midland, Michigan 48686
In a recent pharmacokinetic study, six human volunteers were exposed by inhalation to 10 ppm 14C-D4 for 1 h during alternating periods of rest and exercise. Octamethylcyclotetrasiloxane (D4) concentrations were determined in exhaled breath and blood. Total metabolite concentrations were estimated in blood, while the amounts of individual metabolites were measured in urine. Here, we use these data to develop a physiologically based pharmacokinetic (PBPK) model for D4 in humans. Consistent with PBPK modeling efforts for D4 in the rat, a conventional inhalation PBPK model assuming flow-limited tissue uptake failed to adequately describe these data. A refined model with sequestered D4 in blood, diffusion-limited tissue uptake, and an explicit pathway for D4 metabolism to short-chain linear siloxanes successfully described all data. Hepatic extraction in these volunteers, calculated from model parameters, was 0.65 to 0.8, i.e., hepatic clearance was nearly flow-limited. The decreased retention of inhaled D4 seen in humans during periods of exercise was explained by altered ventilation/perfusion characteristics during exercise and a rapid approach to steady-state conditions. The urinary time course excretion of metabolites was consistent with a metabolic scheme in which sequential hydrolysis of linear siloxanes followed oxidative demethylation and ring opening. The unusual properties of D4 (high lipophilicity coupled with high hepatic and exhalation clearance) lead to rapid decreases in free D4 in blood. The success of D4 PBPK models with a similar physiological structure in both humans and rats increases confidence in the utility of the model for predicting human tissue concentrations of D4 and metabolites during inhalation exposures.
Key Words: octamethylcylcotetrasiloxane; D4; inhalation pharmacokinetics; PBPK modeling; vapor retention; flow-limited metabolism; lipid sequestration.
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