Physiologically Based Toxicokinetic Modeling

For many chemicals, their metabolism is the major determinant of the risk and for a number of hazardous compounds, there is a considerable knowledge from experimental studies on the relationship between metabolism and toxicity. In particular, in vitro studies using cell cultures, subcellular fractions, or pure enzymes have provided information on the nature of reactive intermediates as well as on detoxification pathways. Moreover, the significance of these processes has been demonstrated in several species of experimental animals and humans. 

Physiologically Based Toxicokinetic (PBTK) models are derived similarly to Physiologically Based Pharmacokinetic (PBPK) models, which have been used for a number of years in the development of medicinal drugs. They describe the rat or man as a set of tissue compartments, i.e., liver, adipose tissues, poorly perfused tissues, and richly perfused tissues along with a description of metabolism in the liver. In case of volatile organic compounds a description of gas exchange at the level of the lung is included, see also Section 4.3.6. 

In order to use PBTK modeling in the assessment of mixtures, Cassee et al. (1998) suggest that one of the components is first modeled and regarded as the prime toxicant being modified by the other components. Based on in vitro data on the other components, effects of, e.g., inhibition or induction of specific biotransformation isoenzymes can be incorporated in the model. Effects of competition between chemicals in a mixture for the same biotransformation enzymes may also be incorporated by translating the effects into effects on the Michaelis-Menten parameters that are then incorporated into the model. 

PBTK models can potentially be extended to include the toxicodynamic phase (PBTK/TD model) if a direct relationship exists between the concentration of the active metabolite (or parent compound) and the toxic effect (Yang et al. 1995). 

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Physiologically based toxicokinetic models are nowadays used increasingly for toxicological risk assessment. These models are based on human physiology, and thus take into consideration the actual toxicokinetic processes more accurately than the one- or two-compartment models. In these models, all of the relevant information regarding absorption, distribution, biotransformarion, and elimination of a compound is utilized. The principles of physiologically based pharmaco/ toxicokinetic models are depicted in Fig. 5.41a and h. The... 

Nichols, J.W., K.M. Jensen, J.E. Tietge, and R.D. Johnson. 1998. Physiologically based toxicokinetic model for maternal transfer of 2,3,7,8-tetrachlorodibenzo-p-dioxin in brook trout (Salvelinus fontinalis). Environ. Toxicol. Chem. 17 2422-2434. 

Haddad S, Tardif GC, Tardif R (2006) Development of physiologically based toxicokinetic models for improving the human indoor exposure assessment to water contaminants trichloroethylene and trihalomethanes. J Toxicol Environ Health A 69(23) 2095-2136... 

Evelo, C.T.A., Oostendorp, J.G.M., Ten Berge, W.F. Borm, P.J.A. (1993) Physiologically based toxicokinetic modeling of 1,3-butadiene lung metabolism in mice becomes more important at low doses. Environ. Health Perspect., 101, 496-502... 

Tardif et al. (1992, 1993 a, 1997) have developed a physiologically based toxicokinetic model for toluene in rats (and humans—see Section 4.1.1). They determined the conditions under which interaction between toluene and xylene(s) occurred during inhalation exposure, leading to increased blood concentrations of these solvents, and decreased levels of the hippurates in urine. Similar metabolic interactions have been observed for toluene and benzene in rats (Purcell et al., 1990) toluene inhibited benzene metabolism more effectively than the reverse. Tardif et al. (1997) also studied the exposure of rats (and humans) to mixtures of toluene, we/a-xylene and ethylbenzene, using their physiologically based pharmacokinetic model the mutual inhibition constants for their metabolism were used for simulation of the human situation. 

Nichols, J.W., J.M. McKim, M.E. Andersen, M.L. Gargas, H.J. Clewell III, and R.J. Erickson. 1990. A physiology based toxicokinetic model for the uptake and disposition of waterborne organic chemicals in fish. Toxicol. Appl. Pharmacol. 106 433-447. 

Nihlen, A., and G. Johanson. 1999. Physiologically based toxicokinetic modeling of inhaled ethyl tertiary-butyl ether in humans. Toxicol. Sci. 51 (2) 184-194. 

Data-Based and Physiologically Based Toxicokinetic Models.55... 

Namdari R. 1998. A physiologically based toxicokinetic model of pyrene and its major metabolites in starry flounder, Platichthys stellatus. Thesis dissertation, Burnaby, British Columbia (CA) Simon Fraser University. 

Nichols JW, Fitzsimmons PN, Whiteman FW. 2004a. A physiologically based toxicokinetic model for dietary uptake of hydrophobic organic compounds by fish. II. Simulation of chronic exposure scenarios. Toxicol Sci 77 219-229. 

IV. Tissue distribution Physiologically based toxicokinetic models... 

Lien, G.J., J.M. McKim, A.D. Hoffman and C.T. Jenson. A physiologically based toxicokinetic model for lake trout (Salvelinus namaycush). Aquat. Toxicol. 51 335-350, 2001. 

McKim, J. and J. Nichols. Use of physiologically based toxicokinetic models in a mechanistic approach to aquatic toxicology. In Aquatic Toxicology Molecular, Biochemical and Cellular Perspectives, edited by D.C. Malins and G.K. Ostrander, Boca Raton, FL, Lewis Publishers, pp. 469-519, 1994. 

The subcommittee also recommends that toxicokinetic studies be conducted so that existing human studies on JP-8 and related fuels can be better interpreted. Those studies should provide quantitative information on the relationship of blood and tissue concentrations of JP-8 components after vapor and aerosol exposures to JP-8. Traditional compartmental and physiologically-based toxicokinetic models that take into account absorption, distribution, metabolism, and elimination should include studies on JP-8 and on longer-chain -alkancs, naphthalene, benzene, and other components of JP-8. With improved dosimetry, available human data from a recently com-... 

The generated toxicokinetic data can be used for validation of physiologically based toxicokinetic models. Such models should take into account that sulfur mustard may influence physiological parameters in a dose... 

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