Toxicokinetics modeling

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... 

Working with rats, Lntz et al. (1977) compared the rates of loss from blood of 4,-CB (rapidly metabolized) with that of 2,2, 4,4, 5 -HCB (slowly metabolized). Both showed biphasic elimination, with the former disappearing much more rapidly than the latter. Estimations were made of the rates of hepatic metabolism in vitro, which were then incorporated into toxicokinetic models to predict rates of loss. The predictions for HCB were very close to actual rates of loss for the entire period of... 

Andersen ME. Toxicokinetic modeling and its applications in chemical risk assessment. Toxicol Lett 2003 Feb 18 138(l-2) 9-27. Review. 

Toxicokinetic model to predict risk National Institute of factors for lead toxicity Environmental Health... 

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. 

McKim, J.M., P.K. Schmieder, and R.J. Erickson. 1986. Toxicokinetic modeling of (14C) pentachlorophenol in the rainbow trout (Salmo gairdneri). Aquat. Toxicol. 9 59-80. 

Law, F.C.P., S. Abedini, and C.J. Kennedy. 1991. A biologically based toxicokinetic model for pyrene in rainbow trout. Toxicol. Appl. Pharmacol. 110 390-402. 

In order to fill in these blanks and to give a more real reflection of the picture of exposure, the biological monitoring of harmful substances should be carried out and, especially its kinetic properties in the body should be established. Toxicokinetic models allow to estimate the Biological Threshold Limit Values (Reference Values), which serve to protect the individuals effectively from chemical-induced health risks. 

It has been shown that all doses of arsenic trioxide are characterized by different toxicokinetics parameters. Arsenic compounds have long half-times and the tendency to accumulate in the body. The excretion rate decreased with decreasing blood concentration. The present study confirms the ability of toxicokinetic models to improve the study of various toxic substances and to estimate the Biological Threshold Limit Values. 

The application of toxicokinetic modeling to the assessment of interactive effects between hexane, ketones and aromatic compounds. Investigation of dermal absorption of polycyclic aromatic compounds (PAHs). Research indicates dermal absorption of PAHs in a number of industries including aluminum smelting, coke ovens, creosote production and others is significantly more important than previously recognized. 

Short-term non-invasive biomarkers for processes producing long-term lung damage-evaluation of the feasibility of candidate measurement systems. Toxicokinetic models have been developed to determine whether breath analysis of pentane and ethane can be used to estimate chronic lung damage from toxicants. 

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... 

The Nickel Producers Environmental Research Association (NiPERA) is sponsoring research to develop toxicokinetic models to be used to predict health effects in humans and is comparing the toxicokinetic properties of nickel in various animal species. 

Gaigas et al. (1995) have developed a physiological toxicokinetic model of acrylonitrile in rats which includes the behaviour of CEO. In-vitro kinetic studies of the metabolism of both acrylonitrile and CEO showed that epoxidation to CEO is saturable, while glutathione conjugation of acrylonitrile follows first-order kinetics. The model combines these kinetic parameters with tissue partition data to allow simulation of the urinary excretion of acrylonitrile metabolites and the fonnation of haemoglobin adducts (see below). The model has been further refined by Kedderis et al. (1996) to predict the behaviour of acrylonitrile and CEO after inhalation exposure to acrylonitrile. 

Bond et al. (1994) simulated interactions of butadiene with styrene or with benzene in rats using their own physiological toxicokinetic model for butadiene and published... 

In order to analyse these observations, Leavens and Bond (1996) developed a physiological toxicokinetic model based on the model of Medinsky et al. (1994) for butadiene and the model of Csanady et al. (1994) for styrene. As previously found by Laib et al. (1992), a reasonable model prediction of the reduced butadiene uptake was obtained only by including two oxidation pathways for both butadiene and styrene, one... 

The differences in methodology complicate the direct comparison of the results. For physiological toxicokinetic modelling, the data obtained by the first two methods were used. 

Table 19. Fmaj/ mapp values of the NADPH-dependent oxidation of butadiene and epoxybutene, as determined in cell fractions and used for physiological toxicokinetic modelling...

Physiological toxicokinetic (or pharmacokinetic) models represent descriptions of biological systems and can be used to describe the behaviour of chemicals in the intact animal. Such models have been used to predict the disposition of butadiene and metabolites in rats, mice, and humans. For the case of rats and mice, these predictions can be compared with experimental data. In some cases (see below), the models successfully describe (and accurately predict) the disposition of butadiene and metabolites. Human physiological toxicokinetic model predictions normally cannot be verified due to lack of experimental data. 

Physiological toxicokinetic models have been presented describing the behaviour of inhaled butadiene in the human body. Partition coefficients for tissue air and tissue blood, respectively, had been measured directly using human tissue samples or were calculated based on theoretical considerations. Parameters of butadiene metabolism were obtained from in-vitro studies in human liver and lung cell constituents and by extrapolation of parameters from experiments with rats and mice in vivo (see above). In these models, metabolism of butadiene is assumed to follow Michaelis-Menten kinetics. 

Physiological toxicokinetic models of butadiene metabolite disposition... 

Csanady, G.A., Kreuzer, P.E., Baur, C. Filser, J.G. (1996) A physiological toxicokinetic model for 1,3-butadiene in rodents and man blood concentrations of 1,3-butadiene, its metabolically formed epoxides, and of haemoglobin adducts—relevance of glutathione depletion. Toxicology, 113, 300-305... 

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... 

Kohn, M.C. Melnick, R.L. (1996) Effects of the structure of a toxicokinetic model of butadiene inhalation exposure on computed production of carcinogenic intennediates. Toxicology, 113, 31-39... 

A number of physiological toxicokinetic models have been developed to describe the metabolism of dichloromethane in mouse, rat, Syrian hamster and man following exposure either by inhalation or in drinking-water (Andersen et al., 1987 ECETOC, 1988 Reitz et al., 1989 Andersen et al., 1991). 

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