Physiologically based pharmacokinetics and cancer risk assessment.

Abstract

Physiologically based pharmacokinetic (PBPK) modeling involves mathematically describing the complex interplay of the critical physicochemical and biological determinants involved in the disposition of chemicals. In this approach, the body is divided into a number ofbiologically relevant tissue compartments, arranged in an anatomically accurate manner, anddefined with appropriae physiologicalcharacteristic The extapolation ofpharmaconeicbehavior ofeas from high dose to low dose for various exposure routes and species is possible with this approach because these models are developed by integrating quantitative information on the critical determinnts ofcemi disposition undera biological modeling framework. The principal application of PBPK models is in the prediction of tissue dosimetry of toxic moiety (e.g., parent chemical, reactive metabolite, macromolecular adduct) of a chemical. Such an application has been demonstrated with dichloromethane, a liver and lung carcinogen in the B6C3F~mouse. The PBPK model-based risk assessment approach estimated a cancer risk to people of3.7x10-8 for a lifetime inhalation exposure of 1 Ag/m3, which is lower by more than two orders of magnitude than that calculated by the U.S. Environmental Protection Agency using the linearized multistage model (for low-dose extrapolation) and body surface correction factor (for interspecies scaling).The capability of predicting the target tissue exposure to toxic moiety in people with PBPK models should help reduce the uncertainty associated with the extrapolation procedures adopted in conventional dose-response assessment.

In silico methods for physiologically based biokinetic models describing bioactivation and detoxification of coumarin and estragole: Implications for risk assessment

“…Uncertainties about the shape of the dose–response curve at dose levels relevant for dietary human intake, and about species differences in metabolic activation and detoxification, make it difficult to perform such extrapolations. PBBK modeling can provide a method to obtain a better mechanistic basis for extrapolations of data obtained in experimental animal studies to the human situation 31–33.…”

Physiologically-Based Pharmacokinetic and Toxicokinetic Models in Cancer Risk Assessment

“…The PBPK models have been applied in cancer risk assessments with the intent of reducing the uncertainty associated with species to species, route to route and high dose to low dose extrapolations required for dose-response assessment (3,(18)(19)(20)(21). This article reviews the application of PBPK models in cancer risk assessment, with particular emphasis on recent advances regarding the consideration of sensitive subpopulations, exposure scenarios and population-based approaches.…”

Genetic Polymorphisms in Assessing Interindividual Variability in Delivered Dose

“…A lower affinity, higher capacity pathway occurs in the cytosol via GST, producing formaldehyde and carbon dioxide. Pharmacokinetic modeling studies have found that tumorigenicity correlates with production of metabolites in the lung and liver via the GST pathway and that the production of metabolites via the CYP pathway does not affect tumorigenicity (Reitz, 1990;Andersen and Krishnan, 1994;Casanova et ai., 1996). The lung carcinogenici ty of methylene chloride in mice, but not in rats, has been attributed to the greater degree of metabolism occurring via the GST pathway in mice.…”