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.

The Application of a Physiologically Based Toxicokinetic Model in Health Risk Assessment

“…Figure 2B illustrates a common human semi-PBTK model with a respiratory exposure route. In this model, organs or tissues not directly relevant to the study are categorized as richly perfused tissues (e.g., brain, heart, spleen, intestines, kidneys, adrenal glands, thyroid, lungs, and bone marrow) or poorly perfused tissues (e.g., muscle and skin) [11]. The structure of the PBTK model is based on physiological and anatomical considerations; it can be either a whole-body PBTK model or a semi-PBTK model, depending on the complexity required.…”

“…In the PBTK model, the absorption process of xenobiotics by organs or tissues obeys the simple diffusion principle in Fick's law [1,11]. Based on the distribution characteristics of xenobiotics in organs or tissues, PBTK models can be categorized into three types:…”

“…The metabolism of xenobiotics can be described as first-order kinetic, second-order kinetic, and saturation process [11,15]. Table 1 provides commonly used mathematical equations to describe the ADME processes in PBTK models [15].…”

“…For xenobiotics with insufficient documented physicochemical parameters, data can be obtained through three approaches. Firstly, in vivo experiments can provide distribution coefficients based on steady-state toxicokinetic data from repeated administration or dynamic data from single intravenous administration [11,[30][31][32][33][34]. Secondly, in vitro experiments such as vial equilibration [35][36][37][38][39][40][41][42][43][44], equilibrium dialysis [45][46][47], ultrafiltration [46], and others have been reported for determining distribution coefficients.…”

“…It is important to note that metabolic parameters obtained from in vitro experiments cannot be directly used in an in vivo PBTK model. Appropriate data transformation should be performed, considering the metabolic differences between in vitro and in vivo stud-ies [11,70,71]. In order to identify the most sensitive parameters within existing mammalian models, Schneckener et al [72] extrapolated a validated rabbit PBTK model to six other mammalian species using established species-specific models.…”