A physiologically-based algorithm for predicting internal dose of inhaled toluene: applications for high dose to low dose and rodent to human extrapolations

ABSTRACT

The objective of this study was to develop a physiologically-based algorithm for predicting the steady-state internal dose of inhaled volatile organic chemicals (VOCs) in rats and humans at various exposure concentrations, using toluene as the model chemical. This was accomplished by the systematic development of the solution to the set of equations constituting pulmonary uptake and metabolic clearance, including the consideration of dose-dependent change in the free concentration of chemical at the metabolizing site (liver). The resulting algorithm, based on critical determinants of the internal dose during chronic exposure to VOCs (i.e., alveolar ventilation rate, blood flow rate to liver, blood:air partition coefficient, maximal velocity of metabolism, Michaelis affinity constant and free concentration of chemical at the metabolizing site) provides predictions of dose metrics (i.e., arterial blood concentration and rate of amount metabolized) identical to those of the full-fledged PBPK models. The algorithm was then applied to conduct high dose to low dose and rodent to human extrapolations of internal dose of inhaled toluene. The physiologically-based algorithm, developed in this study, for the first time facilitates the direct computation of steady-state internal dose for a variety of exposure concentrations of toluene, by consistently accounting for the non-linear processes.

REFERENCES

• 1: M. E. Andersen. A physiologically based toxicokinetic description of the metabolism of inhaled gases and vapors: analysis at steady state. Toxicol Appl Pharmacol, 60(3):509--26, Sep 30 1981.
• 2: K. T. Bogen. Pharmacokinetics for regulatory risk analysis: the case of trichloroethylene. Regul Toxicol Pharmacol, 8(4):447--66, Dec 1988.
• 3: W. A. Chiu and P. White. Steady-state solutions to PBPK models and their applications to risk assessment I: Route-to-route extrapolation of volatile chemicals. Risk Anal, 26(3):769--80, Jun 2006.
• 4: G. A. Csanady and J. G. Filser. The relevance of physical activity for the kinetics of inhaled gaseous substances. Archives of Toxicology, 74(11):663--672, Jan 2001.
• 5: J. I. Delic, P. D. Lilly, A. J. MacDonald, and G. D. Loizou. The utility of PBPK in the safety assessment of chloroform and carbon tetrachloride. Regul Toxicol Pharmacol, 32(2):144--55, Oct 2000.
• 6: P. R. Gentry, T. R. Covington, M. E. Andersen, and 3rd Clewell, H. J. Application of a physiologically based pharma-cokinetic model for isopropanol in the derivation of a reference dose and reference concentration. Regul Toxicol Pharmacol, 36(1):51--68, Aug 2002.
• 7: S. Haddad, G. Charest-Tardif, R. Tardif, and K. Krishnan. Validation of a physiological modeling framework for simulating the toxicokinetics of chemicals in mixtures. Toxicol Appl Pharmacol, 167(3):199--209, Sep 15 2000.
• 8: F. Jonsson and G. Johanson. A bayesian analysis of the influence of gstt1 polymorphism on the cancer risk estimate for dichloromethane. Toxicol Appl Pharmacol, 174(2):99--112, Jul 15 2001.
• 9: J. C. Lipscomb, M. E. Meek, K. Krishnan, G. L. Kedderis, H. Clewell, and L. Haber. Incorporation of pharmacokinetic and pharmacodynamic data into risk assessments. Toxicology Mechanisms and Methods, 14(3):145--158, May-Jun 2004.
• 10: A. Nong, D. G. McCarver, R. N. Hines, and K. Krishnan. Modeling interchild differences in pharmacokinetics on the basis of subject-specific data on physiology and hepatic CYP2E1 levels: a case study with toluene. Toxicol Appl Pharmacol, 214(1):78--87, Jul 1 2006.
• 11: M. Pelekis, D. Krewski, and K. Krishnan. Physiologically based algebraic expressions for predicting steady-state toxi-cokinetics of inhaled vapors. Toxicology Methods, 7(3):205--225, Jul-Sep 1997.
• 12: L. M. Sweeney, T. R. Tyler, C. R. Kirman, R. A. Corley, R. H. Reitz, D. J. Paustenbach, J. F. Holson, M. D. Whorton, K. M. Thompson, and M. L. Gargas. Proposed occupational exposure limits for select ethylene glycol ethers using PBPK models and Monte Carlo simulations. Toxicol Sci, 62(1):124--39, Jul 2001.
• 13: R. Tardif, S. Lapare, G. Charest-Tardif, J. Brodeur, and K. Krishnan. Physiologically-based pharmacokinetic modeling of a mixture of toluene and xylene in humans. Risk Anal, 15(3):335--42, Jun 1995.
• 14: USEPA. Approaches for the application of physiologically based pharmacokinetic (PBPK) models and supporting data in risk assessment (final report). Technical Report EPA/600/R-05/043F, U.S. Environmental Protection Agency, Washington, D.C, 2006.

INDEX TERMS

Keywords:
PBPK modeling, inhalation, pharmacometrics, toluene