Abstract
Physiologically-based toxicokinetic (PB-TK) models are developed to simulate absorption, distribution and excretion of xenobiotics. PB-TK models consist of several groups of compartments, where tissues are grouped together according to physiological parameters (tissue blood flows, tissue group volumes) and physicochemical properties (partition coefficients, metabolic constants). Tetramethylbenzene (TETMB), a mixture of its three isomers: prenitene (1,2,3,4-TETMB), isodurene (1,2,3,5-TETMB), and durene (1,2,4,5-TETMB) is an essential component of numerous commercial preparations of organic solvents. The aim of the study was to develop the PB-TK model for two TETMB isomers, durene and isodurene, in humans. The assumed PB-TK model groups organs and tissues into five physiological compartments: fat tissue, muscles, organs, liver, and brain. The brain has been considered as a separate compartment due to the potential neurotoxicity of TETMB. Water/air, oil/air and blood/air partition coefficients for durene and isodurene were measured in vitro. Tissue/air partition coefficients were calculated from values of olive/air and water/air partition coefficients and the average fat and water content in different tissues. Tissue/blood partition coefficients were calculated as a tissue/air quotient and the blood/air partition coefficient measured in vitro. The Michaelis-Menten constant (KM) values and maximum metabolism rate constant (VMAX) for selected metabolites of durene and isodurene were obtained in vitro using microsomal fraction of the human liver. The developed model was validated against experimental data obtained earlier as a result of an 8-h exposure of volunteers to durene and isodurene vapors of 10 and 25 mg/m3. The prediction of both TETMB isomers concentration in blood as well as of the elimination rates of 2,4,5-TMBA and 2,3,5-TMBA were close to the results of experimental exposures. Simulations of one working week inhalation exposure to aromatic hydrocarbons indicate that the elaborated PB-TK model may be used to predict the chemical distribution in different body compartments, based on physicochemical properties.
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More From: International Journal of Occupational Medicine and Environmental Health
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