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Potential of Physiologically Based Pharmacokinetics to Amalgamate Kinetic Data of Trichloroethylene and Tetrachloroethylene Obtained in Rats and Man
British Journal of Industrial Medicine
Vol. 46, No. 4 (Apr., 1989), pp. 239-249
Published by: BMJ
Stable URL: http://www.jstor.org/stable/27726772
Page Count: 11
You can always find the topics here!Topics: Simulations, Metabolism, Pharmacokinetics, Drug design, Blood, Potable water, Coefficients, Body tissues, Inhalation, Parametric models
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A physiologically based pharmacokinetic model was used to amalgamate information obtained in rats and man by various routes of exposure to trichloroethylene (TRI) and tetrachloroethylene (TETRA). Since there have been no pharmacokinetic data on drinking water exposure, drinking water exposure to TRI was conducted in rats using 14C-TRI. Several partition coefficients of TRI and TETRA were also determined in the present study. Simulations of the kinetics of TRI and TETRA were made with the unified physiologically based pharmacokinetic model to determine whether reported pharmacokinetic data from different routes of exposure to TRI and TETRA (inhalation, intravenous, drinking water in rats, and inhalation in man) could be simulated. The results indicated that the unified model used in this study successfully simulates the pharmacokinetics of TRI and TETRA irrespective of the routes and exposure intensities. Subsequently, sensitivity analyses were performed. Since both TRI and TETRA require bioactivation to produce their toxicity, the amounts metabolised in the body were used as indicators of toxicity. Vmax (maximum velocity of metabolism in the liver), alveolar ventilation, and the blood/air partition coefficient had a more profound effect than other factors on the amounts of these chemicals metabolised when parameter values were altered. The model was applied to simulate the biologically permissible values of exhaled air concentration and blood concentration of these compounds for monitoring exposure intensities in occupational settings. The simulated maximum permissible values showed good agreement with those obtained by field studies. Finally, the model was applied to the risk assessment of drinking water exposures to TRI and TETRA, assuming that a man weighing 70 kg drinks 21 of the most contaminated drinking water ever reported in the US; 32 ppb for TRI and 5 ppb for TETRA. The simulated metabolised amounts of TRI and TETRA under steady state condition in man were a fifth of an order of magnitude lower than non-cancer causing metabolised amounts of TRI and TETRA in rats through inhalation.
British Journal of Industrial Medicine © 1989 BMJ