Styrene PBPK modeling

PBPK models have also been used to explain the rate of excretion of inhaled trichloroethylene and its major metabolites (Bogen 1988 Fisher et al. 1989, 1990, 1991 Ikeda et al. 1972 Ramsey and Anderson 1984 Sato et al. 1977). One model was based on the results of trichloroethylene inhalation studies using volunteers who inhaled 100 ppm trichloroethylene for 4 horns (Sato et al. 1977). The model used first-order kinetics to describe the major metabolic pathways for trichloroethylene in vessel-rich tissues (brain, liver, kidney), low perfused muscle tissue, and poorly perfused fat tissue and assumed that the compartments were at equilibrium. A value of 104 L/hour for whole-body metabolic clearance of trichloroethylene was predicted. Another PBPK model was developed to fit human metabolism data to urinary metabolites measured in chronically exposed workers (Bogen 1988). This model assumed that pulmonary uptake is continuous, so that the alveolar concentration is in equilibrium with that in the blood and all tissue compartments, and was an expansion of a model developed to predict the behavior of styrene (another volatile organic compound) in four tissue groups (Ramsey and Andersen 1984). 

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. 

Prior to 2002, most studies published on physiologically-based pharmacokinetic models focused on the distribution and elimination of environmental toxins such as dioxin, styrene, and organic solvents [68-70]. PBPK models for drug molecules generally relied on tissue/plasma partition coefficients (Kps) measured in rat [71-73]. 

The application of PBPK modeling to better understand the disposition of potentially toxic compounds soon followed. Styrene and dichloromethane (DCM, or methylene chloride) are notable examples (Angelo et al. 1984 Angelo and Pritchard 1984 Ramsey and Andersen 1984 Andasen et al. 1987) and applications continue well into the current era (Blancato et al. 2007). 

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