COMPUTER-SIMULATION OF THE LACTATIONAL TRANSFER OF TETRACHLOROETHYLENE IN RATS USING A PHYSIOLOGICALLY-BASED MODEL

A physiologically based pharmacokinetic (PBPK) model describing transf er of inhaled tetrachloroethylene (PCE) into breast milk with the cons equent exposure of the nursing pups was developed and validated in lac tating rats. The PBPK model was based on partition coefficients (PCs), which were determined by the equilibration of tissues with known conc entrations of PCE vapor. The blood/air and milk/blood PCs for the dam were 33.5 and 12.0, the liver/blood and fat/blood PCs for the dam were 1.9 and 42.4, and the slowly perfused tissues/blood and rapidly perfu sed tissues/blood PCs for the dam were 0.9 and 1.7, respectively. The blood/air PC for the pup was 24.3, and the solid tissues/blood PC for the pup was 4.5. Metabolic constants were determined by a gas uptake m ethod. The pseudo-maximal velocity of PCE metabolism in the dam was lo w, 0.03 mg/kg/hr, and the apparent Michaelis-Menten constant was 0.3 m g/liter. The lactating Sprague-Dawley females were exposed to PCE vapo r for 2 hr with concentrations ranging from 20 to 1000 ppm PCE. The da ms were returned to the pups after exposure and the pups received PCE via breast milk while they nursed. PCE concentrations in the air, bloo d, milk, and tissues were determined by gas chromatography and compare d to PBPK model predictions. Nursing resulted in a peak pup blood PCE concentration of 0.9 mg/liter and a peak pup solid tissue PCE concentr ation of 8 mg/kg. The PBPK lactation model adequately described the di stribution of inhaled PCE in maternal blood and milk, as well as in th e nursed pup's gastrointestinal tract, blood, and solid tissues. It is concluded that the predictions based on PBPK modeling for disposition of PCE in lactating rats and their pups were in good agreement with t he experimental data. (C) 1994 Academic Press, Inc.