Physiologically-Based Pharmacokinetic and Toxicokinetic Models in Cancer Risk Assessment

Abstract

Physiologically-based pharmacokinetic (PBPK) and toxicokinetic models are increasingly being used for the conduct of high dose to low dose and interspecies extrapolations required in cancer risk assessment. These models, by simulating tissue dose of toxic chemicals, help address the uncertainty associated with the default approaches for interspecies and high dose to low dose extrapolations. The applicability of PBPK models in cancer risk assessment has been demonstrated with a number of chemicals (e.g., acrylonitrile, 2-butoxyethanol, chloroform, 1,4-dioxane, methyl chloroform, methylene chloride, styrene, trichloroethylene, tetrachloroethylene, vinyl chloride, vinyl acetate). Recent advances in PBPK modeling facilitate the consideration of population distribution of parameter values, age-dependent changes in physiology and metabolism, multi-route exposures as well as multichemical interactions for application in cancer risk assessment. Whereas the average values for various input parameters have been used to evaluate the age-dependency of tissue dose, the Markov Chain Monte Carlo technique can be applied to address variability and uncertainty in parameter estimates, thus facilitating a more accurate estimation of cancer risk in the population. The PBPK models also uniquely facilitate the simulation of tissue dose, and thereby cancer risks, associated with multi-route and multichemical exposure situations. Overall, the recent advances reviewed in this article point to the continued enhancement of the scientific basis and applicability of PBPK models in cancer risk assessment.

Keywords:

• PBPK models
• pharmacokinetics
• risk assessment
• toxicokinetics

ACKNOWLEDGEMENTS

KK's work in the subject area has been partly supported by Health Canada and U.S. EPA (4W-0322-NASX). GJ has been funded by Swedish Council for Working Life and Research.

Notes

¹From Krishnan and Andersen (17).

² Q _alv , Q _c , Q _t , V _t , P _ba , P _tb , V _max and K _m refer to alveolar ventilation rate, cardiac output, tissue blood flow rate, tissue volume, blood:air partition coefficient, tissue:blood partition coefficient, maximal velocity for metabolism and Michaelis-Menten constant; C refers to concentration and subscripts i, v, a, t, met and vt refer to inhaled, venous, arterial, tissue, metabolite and venous blood leaving tissue.