Disposition. PBPK models

The structure and mathematical expressions used in PBPK models significantly simplify the true complexities of biological systems. If the uptake and disposition of the chemical substance(s) is adequately described, however, this simplification is desirable because data are often unavailable for many biological processes. A simplified scheme reduces the magnitude of cumulative uncertainty. The adequacy of the model is, therefore, of great importance, and model validation is essential to the use of PBPK models in risk assessment. 

The structure and mathematical expressions used in PBPK models significantly simplify the true complexities of biological systems. If the uptake and disposition of the chemical substance(s) is... 

PBPK modeling is the development of mathematical descriptions of the uptake and disposition of chemicals based on quantitative interrelationships among the critical biological determinants of these processes. These determinants include partition coefficients, rates of biochemical reactions and physiological characteristics of the animal species. The biological and mechanistic basis of the PBPK models... 

Description of the Model. The Corley chloroform PBPK model was based on an earlier PBPK model developed by Ramsey and Andersen (1984) to describe the disposition of styrene exposure in rats, mice, and humans. A schematic representation of the Corley model (taken from Corley et al. 1990) is shown in Figure 2-5 with oral, inhalation, and intraperitoneal routes represented. The dermal route of exposure is not represented in this model however, others have modified the Corley model to include this route of exposure (see below). Liver and kidney are represented as separate compartments since both are target organs for chloroform. 

PBPK models rely on a series of simultaneous differential equations that simulate chemical delivery to tissues via the arterial circulation and removal via the venous circulation. The models are run in time steps such that the entire course of chemical disposition can be presented for calculation of the area-under-the-curve (AUC) dose, often a key metric for chronic risk assessment. The physiologic parameters can be adapted for different species, sexes, age groups, and genetic variants to facilitate extrapolation from one type of receptor to another. 

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