Dose physiologically based pharmacokinetic

The newer physiologically based pharmacokinetic (PBPK) models take nonlinearity of physiological processes such as chemical metabolism and excretion into consideration. At the high dose levels used in animal experiments, these mechanisms become saturated with the result that the tissues may be exposed to a different composition of pure compound and metabolites than at the low dose levels encountered in real-life human exposure. 

Another model, which is increasingly being used, is the physiologically based pharmacokinetic model. This uses data on the absorption, distribution, metabolism, tissue sequestration, kinetics, elimination, and mechanism to determine the target dose used for the extrapolation, but it requires extensive data. 

The explanation of the pharmacokinetics or toxicokinetics involved in absorption, distribution, and elimination processes is a highly specialized branch of toxicology, and is beyond the scope of this chapter. However, here we introduce a few basic concepts that are related to the several transport rate processes that we described earlier in this chapter. Toxicokinetics is an extension of pharmacokinetics in that these studies are conducted at higher doses than pharmacokinetic studies and the principles of pharmacokinetics are applied to xenobiotics. In addition these studies are essential to provide information on the fate of the xenobiotic following exposure by a define route. This information is essential if one is to adequately interpret the dose-response relationship in the risk assessment process. In recent years these toxicokinetic data from laboratory animals have started to be utilized in physiologically based pharmacokinetic (PBPK) models to help extrapolations to low-dose exposures in humans. The ultimate aim in all of these analyses is to provide an estimate of tissue concentrations at the target site associated with the toxicity. 

Much of the research efforts in risk assessment are therefore aimed at reducing the need to use these default uncertainty factors, although the risk assessor is limited by data quality of the chemical of interest. With sufficient data and the advent of sophisticated and validated physiologically based pharmacokinetic models and biologically based dose-response models (Conolly and Butterworth, 1995), these default values can be replaced with science-based factors. In some instances there may be sufficient data to be able to obtain distributions rather than point estimates. 

REITZ, R., MCDOUGAL, J.N., HIMMELSTEIN, M.W., NOLAN, R.J. and SCHUMANN, A.M. (1988). Physiologically-based pharmacokinetic modeling with methylchloroform Implications for interspecies, high dose/low dose, and dose-route extrapolations, Toxicol. Appl. Pharmacol. 95, 185-192. 

Physiologically based pharmacokinetic (PBPK) models are used to estimate the dose of toxic metabolites reaching target tissues. Model outputs provide internal dose estimates for specific life stages and differences between sexes, species, dose routes, and exposure patterns. These models provide a tool for understanding the... 

The ATSDR use of QSAR and models to predict toxicity is well described by El-Masri et al. (2002). In 1998, the ATSDR established a computational toxicology laboratory and initiated efforts to use Physiologically Based PharmacoKinetic (PBPK) models, BenchMark Dose (BMD) models, and QSARs. PBPK models are used by the ATSDR to ... 

C. Tanaka, R. Kawai, and M. Rowland Physiologically based pharmacokinetics of cyclosporine A Reevaluation of dose-nonlinear kinetics in rats. J. Pharmacokin. Biopharm. 1999, 27 597-623. 

G. L., Gargas, M. L, Strother, D. E. Improving cancer dose-response characterization by using physiologically based pharmacokinetic modeling An analysis of pooled data for acrylonitrile-induced brain tumors to assess cancer potency in the rat. Risk Anal 2000, 20 135-151. 

Physiologically based pharmacokinetic (PBPK) modelling sometimes constitutes a basis for replacement of default components of uncertainty for toxicokinetics and a portion of toxicodynamics. Where data are sufficient, a full biologically based dose-response model addresses additional uncertainties with respect to both interspecies differences and interindividual variability in both kinetics and dynamics. 

Clewell RA, Merrill EA, Yu KO, Mahle DA, Sterner TR, Mattie DR, Robinson PJ, Fisher JW, Gearhart JM. 2003. Predicting fetal perchlorate dose and inhibition of iodide kinetics during gestation a physiologically-based pharmacokinetic analysis of perchlorate and iodide kinetics in the rat. Toxicol Sci 73 235-255. 

Frederick CB, Potter DW, Chang-Mateu MI, Andersen ME. 1992. A physiologically based pharmacokinetic and pharmacodynamic model to describe the oral dosing of rats with ethyl acrylate and its implications for risk assessment. Toxicol Appl Pharmacol 114 246-260. 

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