Toxicological Sciences 71, 27-40 (2003)
Copyright © 2003 by the Society of Toxicology
BIOTRANSFORMATION AND TOXICOKINETICS |
Physiologically Based Pharmacokinetic Model Parameter Estimation and Sensitivity and Variability Analyses for Acrylonitrile Disposition in Humans
* The Sapphire Group, 4027 Colonel Glenn Highway, Fourth Floor, Dayton, Ohio 45431;
BP, Arlington, Virginia 22209;
1803 Jones Ferry Road, Chapel Hill, North Carolina 27516
A physiologically based pharmacokinetic (PBPK) model of acrylonitrile (ACN) and cyanoethylene oxide (CEO) disposition in humans was developed and is based on human in vitro data and scaling from a rat model (G. L. Kedderis et al ., 1996, Toxicol. Appl. Pharmacol .140, 422–435) for application to risk assessment. All of the major biotransformation and reactivity pathways, including metabolism of ACN to glutathione conjugates and CEO, reaction rates of ACN and CEO with glutathione and tissues, and the metabolism of CEO by hydrolysis and glutathione conjugation, were described in the human PBPK model. Model simulations indicated that predicted blood and brain ACN and CEO concentrations were similar in rats and humans exposed to ACN by inhalation. In contrast, rats consuming ACN in drinking water had higher predicted blood concentrations of ACN than humans exposed to the same concentration in water. Sensitivity and variability analyses were conducted on the model. While many parameters contributed to the estimated variability of the model predictions, the reaction rate of CEO with glutathione, hydrolysis rate for CEO, and blood:brain partition coefficient of CEO were the parameters predicted to make the greatest contributions to variability of blood and brain CEO concentrations in humans. The main contributor to predicted variance in human blood ACN concentrations in people exposed through drinking water was the Vmax for conversion of ACN to CEO. In contrast, the main contributors for variance in people exposed by inhalation were expected to be the rate of blood flow to the liver and alveolar ventilation rate, with the brain:blood partition coefficient also contributing to variability in predicted concentrations of ACN in the brain. Expected variability in blood CEO concentrations (peak or average) in humans exposed by inhalation or drinking water was modest, with a 95th-percentile individual expected to have blood concentrations 1.8-times higher than an average individual.
Key Words: acrylonitrile; cyanoethylene oxide; physiologically based pharmacokinetic modeling; interspecies extrapolation; sensitivity analysis; variability analysis.
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