Physiologically based pharmacokinetic modeling of the pregnant rat: a multiroute exposure model for trichloroethylene and its metabolite, trichloroacetic acid.
A physiologically based pharmacokinetic (PB-PK) model was developed to describe trichloroethylene (TCE) kinetics in the pregnant rat exposed to TCE by inhalation, by bolus gavage, or by oral ingestion in drinking water. The kinetics of trichloroacetic acid (TCA), an oxidative metabolite of TCE, were described by a classical one-compartment pharmacokinetic model. Among the required model parameters for TCE, partition coefficients (PCs) and kinetic constants for oxidation were determined by vial equilibration and gas uptake methods, respectively. The fat:blood PC was 33.9; the blood:air PC was 13.2; and the fetal tissue:fetal blood PC was 0.51. TCE was readily metabolized with high substrate affinity. In naive and pregnant female rats the maximum velocities of oxidative metabolism were 10.98 +/- 0.155 and 9.18 +/- 0.078 mg/kg/hr, while the estimated Michaelis constant for the two groups of rats was very low, 0.25 mg/liter. The first-order rate constant for oral absorption of TCE from water was 5.4 +/- 0.42/hr-1 in naive rats. With TCA, the volume of distribution (0.618 liter/kg) and the plasma elimination rate constant (0.045 +/- 0.0024/hour) were estimated both from intravenous dosing studies with TCA and from an inhalation study with TCE. By comparison of the two routes of administration, the stoichiometric yield of TCA from TCE was estimated to be 0.12 in pregnant rats. To develop a data base for testing the fidelity of the PB-PK model, inhalation and bolus gavage exposures were conducted from Day 3 to Day 21 of pregnancy and a drinking water exposure from Day 3 to Day 22 of pregnancy. Inhalation exposures with TCE vapor were 4 hr/day at 618 ppm. The TCE concentration in drinking water was 350 micrograms/ml and the gavaged rats received single daily doses of 2.3 mg TCE/kg. Time varying physiological parameters for compartment volumes and blood flows during pregnancy were obtained from the published literature. Using the kinetic parameters determined by experimentation, TCE concentrations in maternal and fetal blood and TCA concentrations in maternal and fetal plasma were predicted from the PB-PK model by computer simulation and compared favorably with limited data obtained at restricted time points during pregnancy for all three routes of exposure. On the basis of the PB-PK model, fetal exposure to TCE, as area-under-the-curve, ranged from 67 to 76% of maternal exposure. For TCA the fetal exposure was 63 to 64% of the maternal exposure. The fetus is clearly at risk both to parent TCE and its TCA metabolite.(ABSTRACT TRUNCATED AT 400 WORDS)
Fisher
J W
JW
Toxic Hazards Division, Harry G. Armstrong Aerospace Medical Research Laboratory, Wright-Patterson Air Force Base, Ohio 45433-6573.
Whittaker
T A
TA
Taylor
D H
DH
Clewell
H J
HJ
Andersen
M E
ME
D000280:Administration, Inhalation; D000284:Administration, Oral; D000818:Animals; D005260:Female; D005333:Fetus / Q000378:metabolism; D007275:Injections, Intravenous; D008954:Models, Biological; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D014238:Trichloroacetic Acid / Q000493:pharmacokinetics*; D014241:Trichloroethylene / Q000493:pharmacokinetics*
D014241:Trichloroethylene; D014238:Trichloroacetic Acid