Variability of physiologically based pharmacokinetic (PBPK) model parameters and their effects on PBPK model predictions in a risk assessment for perchloroethylene (PCE).
When used in the risk assessment process, the output from physiologically based pharmacokinetic (PBPK) models has usually been considered as an exact estimate of dose, ignoring uncertainties in the parameter values used in the model and their impact on model predictions. We have collected experimental data on the variability of key parameters in a PBPK model for tetrachloroethylene (PCE) and have used Monte Carlo analysis to estimate the resulting variability in the model predictions. Blood/air and tissue/blood partition coefficients and the interanimal variability of these data were determined for tetrachloroethylene (PCE). The mean values and variability for these and other published model parameters were incorporated into a PBPK model for PCE and a Monte Carlo analysis (n = 600) was performed to determine the effect on model predicted dose surrogates for a PCE risk assessment. For a typical dose surrogate, area under the blood time curve for metabolite in the liver (AUCLM), the coefficient of variation was 25% and the mean value for AUCLM was within a factor of two of the maximum and minimum values generated in the 600 simulations. These calculations demonstrate that parameter uncertainty is not a significant potential source of variability in the use of PBPK models in risk assessment. However, we did not in this study consider uncertainties as to metabolic pathways, mechanism of carcinogenicity, or appropriateness of dose surrogates.
Gearhart
J M
JM
ManTech Environmental Technology, Inc., Dayton, OH 45437-0009.
Mahle
D A
DA
Greene
R J
RJ
Seckel
C S
CS
Flemming
C D
CD
Fisher
J W
JW
Clewell
H J
HJ
D000280:Administration, Inhalation; D000284:Administration, Oral; D000818:Animals; D051379:Mice; D008815:Mice, Inbred Strains; D008954:Models, Biological; D009369:Neoplasms / Q000139:chemically induced; D011237:Predictive Value of Tests; D012306:Risk; D013750:Tetrachloroethylene / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*; D014018:Tissue Distribution
D013750:Tetrachloroethylene