Uncertainties in physiologically based pharmacokinetic models caused by several input parameters.

Abstract

OBJECTIVE: One of the problems in the application of physiologically based pharmacokinetic (PB-PK) models is that authors often use different input parameters, with unknown influence on the results. Differences in the simulation results obtained with various sets of parameters are examined herein.

METHOD: Chemicals considered were perchloroethylene, toluene, and styrene. Simulations of alveolar concentrations, blood concentrations, and urinary metabolite excretions were performed for the three solvents. The input parameters discussed herein are physiological values, metabolic constants, and partition coefficients. The influence of metabolic constants and partition coefficients is studied by comparison of models against one another.

RESULTS: Metabolic parameters such as Vmax and K(m) varied considerably between authors. Tissue-gas partition coefficients, especially for the fat compartment, also differed according to the authors. Such differences in input parameter values proved to have a large influence on PB-PK model results and, therefore, increased their uncertainties. Uncertainties were much more significant in urinary metabolite concentration than in alveolar and blood concentration for chemicals that are poorly metabolized. On the other hand, uncertainties were more significant in alveolar and blood concentrations than in urinary metabolite excretions for chemicals that are well metabolized.

CONCLUSION: Careful attention is necessary in the selection and/or citation of values from published data. The validity of PB-PK models should be simultaneously confirmed with both the blood and/or alveolar concentration and urinary metabolite concentrations.