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A DYNAMIC PHYSIOLOGICALLY-BASED TOXICOKINETIC (DPBTK) MODEL FOR SIMULATION OF COMPLEX TOLUENE EXPOSURE SCENARIOS IN HUMANS
Citation:
Kenyon, E M., T. N. Coleman, C R. Eklund, AND V A. Benignus. A DYNAMIC PHYSIOLOGICALLY-BASED TOXICOKINETIC (DPBTK) MODEL FOR SIMULATION OF COMPLEX TOLUENE EXPOSURE SCENARIOS IN HUMANS. Presented at Society of Toxicology, Baltimore, MD, March 21-25, 2004.
Description:
A GENERAL PHYSIOLOGICAL AND TOXICOKINETIC (GPAT) MODEL FOR SIMULATION OF COMPLEX TOLUENE EXPOSURE SCENARIOS IN HUMANS. E M Kenyon1, T Colemen2, C R Eklund1 and V A Benignus3. 1U.S. EPA, ORD, NHEERL, ETD, PKB, RTP, NC, USA; 2Biological Simulators, Inc., Jackson MS, USA, 3U.S. EPA, ORD, NHEERL, HSD, Chapel Hill, NC, USA
Many environmental exposure scenarios require dynamic methods in which exposures and human activities vary continuously as a function of time. Simulation of physiological scenarios with commonly available software packages and simulation languages is often highly programming intensive and complex. To simplify this process, a "whole-body" human physiological simulation model, Quantitative Circulatory Physiology, Research Version 4.0, (QCP4), was coupled with a physiologically-based toxicokinetic (PBTK) model for toluene. Chemical-specific parameters and initial organ volumes and blood flow rates were obtained from the literature. Compartments in the model included lung, slowly and rapidly perfused tissue groups, fat, liver, gut and brain. QCP4 updated changing physiological parameters required by the PBTK model appropriate to varying activity level of the human subject as the model was iteratively executed over time. The GPAT model adequately predicted toluene blood concentrations under varying exercise levels and exposure scenarios from 4 different studies reported in the peer reviewed literature. In comparison to a similar model executed in Advanced Continuous Simulation Language (ACSL), the GPAT model required less coding and had greater flexibility to vary activity levels. The coupled GPAT modeling framework can also simulate physiological alterations in response to changes in altitude, temperature, diet, and illness. When linked with a toxicokinetic model this provides a powerful tool for both risk assessment (e.g., effects on sensitive subpopulations) and experimental design applications. (This abstract does not necessarily reflect EPA policy.)