Toxicology of Industrial Compounds

N.FEDTKE 171
PBPK models are based on the blood and tissue solubility of chemicals,
their metabolism in various tissues and the physiology of the organism,
thus incorporating the specific physiological description of animal species as
well as specific physico-chemical descriptions of agents. Uptake,
distribution, metabolism and excretion are described in physiologically
realistic compartments (tissue groups) using computer simulation. The
compartments are linked in parallel, represent the actual mammalian
architecture, and include tissues such as lung and arterial blood, fatty
tissue, poorly perfused tissues (muscles, skin), richly perfused tissues
(brain, kidneys, heart, endocrine gland, gastro-intestinal tract), liver as the
main metabolizing tissue, and mixed venous blood. The compartments are
connected by arterial and venous blood flow and are characterized by a set
of mass balance differential equations. The rate constants that describe the
flow of material between the tissue groups and the rate of change in the
chemical concentration of each compartment are proportional to blood
flow, tissue solubility and compartment volumes. The basic mathematical
description of a PBPK model for a volatile compound has been provided by
Ramsey and Andersen (1984) and additional details may be found in
appendices of manuscripts dealing with the development of PBPK models.
Estimation of the constants used in PBPK models may be based on the
literature in the case of physiological parameters such as ventilation rates,
cardiac output, blood flow to tissues and tissue volumes. The EPA has
compiled reference values for these parameters and their scaling (Arms and
Travis, 1988). Chemical specific parameters such as blood and tissue
solubilities may be determined from in vitro preparation (Sato and
Nakajima, 1979; Gargas et al., 1989). The biochemical constants for
metabolism may be derived from in vitro studies (Reitz et al. 1988;
Carfagna and Kedderis, 1992; Johanson and Filser, 1993), in vivo
toxicokinetic studies (Potter and Tran, 1993; Frederick et al., 1992) or in
the case of volatile substances from gas uptake studies (Gargas et al., 1986,
1990; Filser, 1992).
Since the tissue groups have a defined biological meaning, scaling of the
associated parameters between species is possible since many of the
parameters used are correlated to body weight. Cardiac output, alveolar
ventilation rate and V max are scaled by the 3/4 power of body weight
whereas K m is assumed to be constant across species. However, the
substitution of the physiological parameters with the appropriate values
characteristic for the species of interest is preferred.
The development of PBPK models is an iterative process involving
comparison of the model simulations with experimental data and
refinement of the estimates when the model fails to accurately predict the
kinetic behaviour. Different exposure scenarios can be used to predict the
concentrations of the parent chemical or its metabolites in the blood or the
tissues, which are the target of toxic effects. The level of glutathione