PBPK Model Structure

Arterial and venous blood are also coded to have B-esterase inhibition fat is not coded to have B-esterase inhibition. 

The model is capable of simulating exposure from three routes intravenous, subcutaneous and dermal. Although the intravenous route may not be a very probable real world exposure route, data from intravenous dosing allow for the estimation of unknown parameters without the uncertainty of route specific kinetics such as permeability or absorption. Intravenous exposures are modeled as injections directly into the venous blood supply over a short period of time. 

The current model can simulate various endpoints for blood and tissues including free VX concentrations and B-esterase activity (AChE, BuChE and CaE). The model also has the capability to adjust cardiac output and tissue blood flows based on the level of brain AChE activity in order to mimic the physiological response to AChE inhibition. This adjustment assumes that cardiac output and tissue blood flows decrease over time by the same fraction as brain AChE activity. This adjustment is made when simulating data where the animals were not given atropine and were not artificially ventilated otherwise, the adjustment was not made. 

---

FIGURE 43.1 Schematic of the structure of the PBPK model structure used in the example. (Adapted from Roy et al. (46).)... 

PBPK Model Structure Parameters (e.g. modeled compar tmen ts) ... 

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 models for 2,3,7,8-TCDD are discussed below. The pharmacokinetic behavior of 2,3,7,8-TCDD, especially distribution, has been shown to be dose-dependent and involves protein binding and enzyme induction in hepatic tissue. Thus, terms describing these interactions have been included in the animal models described below. Furthermore, since induction of these dioxin-binding proteins is a process mediated by the interaction of a dioxin-receptor (the Ah receptor) complex with specific binding sites on DNA additional terms were included in the models. For a detailed explanation regarding the Ah receptor and its involvement in the mechanism of action of 2,3,7,8-TCDD and structurally related halogenated aromatic hydrocarbons, see Section 2.4.2. 

Poulin and Krishnan (1995) developed a method to predict tissue blood PCs for incorporation into physiologically based pharmacokinetic (PBPK) models. Tissue blood partitioning was calculated as an additive function of partitioning into the water, neutral lipids and phospholipids constituent of individual tissues. These were calculated using published values for lipid and water content of tissues and the octanol-water PC of the compounds. Poulin and Krishnan (1998 1999) used this method to predict tissue blood PCs that were subsequently incorporated into a quantitative structure-toxicokinetic model. The prediction of tissue plasma PCs to describe distribution processes and as input parameters for PBPK models has been extensively researched by Poulin and coworkers a great deal of further information can be obtained from their references (Poulin and Theil, 2000 Poulin et al., 2001 Poulin and Theil, 2002a Poulin and Theil, 2002b). 

CWAs are represented by any one of a number of chemicals exhibiting a very high toxicity by various mechanisms. The present Handbook exhibits CWAs with structures as simple as carbon monoxide (CO) and as complex as botulinum toxin or ricin proteins. While this chapter could address the development of PBPK models of CWAs in general, the focus will primarily be on the organophosphate (OP)-based nerve agents typically represented by sarin (GB - isopropyl methylfluoro-phosphonate). 

FIGURE 51.1. PBPK-PD model schematic of sarin in Hartley guinea pig. This model structure allows for the simulation of experimental studies with dosing hy intravenous or subcutaneous dosing, and inhalation exposure. This model design was after Gearhart et al. (1990) and was adapted to simulate the pharmacokinetics and pharmacodynamics of sarin in the guinea pig. 

---