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Med. Pr. 2000;51(5)

Application of physiologically-based toxicokinetic models for toxicokinetic studies

Zastosowanie symulacyjnego języka ACSL w fizjologicznych modelach toksyko-kinetycznych

P. Kostrzewski, P. Jałowiecki

Abstract

For the description of the processes of absorption, excretion or elimination of chemicals, the open one- or two-compartment models have been used thus far. The latter consist mainly of the fast (central) and slow (peripheral) compartments. The toxicological studies were based on an assumption that the organic processes develop according to is the first order kinetic reaction. However, the absorption, elimination or excretion of toxic chemicals are in fact much more complicated processes that should be explained using, e.g. the physiologically-based toxicokinetic (PBTK) models, covering physiological, biochemical and metabolic parameters, as well as the allometric calibration of selected parameters for interspecies extrapolations, and in vitro/in vivo extrapolations of metabolic parameters. Simulation languages, e.g. ACSL (Advanced Continuous Simulation Language) are indispensable application tools to be operated with PBTK models. They have been developed for modelling systems described by time-dependent non-linear differential equations and/or transfer functions. ACSL with its interfaces (ACSL Builder, ACSL Graphic Modeller, ACSL Math) ensures data input and communication inside the model by the control,transfer and computed parameters. The physiologically-based toxicokinetic models employ a large number of different parameters, which enables, e.g. forecasting the dose/effect or dose/response relationship absorption rate, metabolic pathways, excretion or elimination according to the absorbed dose of xenobiotic; evaluation of risk assessment; extrapolation from high to low doses characteristic of environmental exposure or setting biological exposure limits.