Uncertainties in physiologically based pharmacokinetic models caused by several input parameters

Objective: One of the problems in the application of physiologically based pharmacokinetic (PB-PK) models is that authors often use different input pa rameters, with unknown influence on the results. Differences in the simulat ion results obtained with various sets of parameters are examined herein. M ethod: Chemicals considered were perchloroethylene, toluene, and styrene. S imulations of alveolar concentrations, blood concentrations, and urinary me tabolite excretions were performed for the three solvents. The input parame ters discussed herein are physiological values, metabolic constants, and pa rtition coefficients. The influence of metabolic constants and partition co efficients is studied by comparison of models against one another. Results: Metabolic parameters such as V-max and K-m varied considerably between aut hors. Tissue-gas partition coefficients, especially for the fat compartment , also differed according to the authors. Such differences in input paramet er values proved to have a large influence on PB-PK model results and, ther efore, increased their uncertainties. Uncertainties were much more signific ant in urinary metabolite concentration than in alveolar and blood concentr ation for chemicals that are poorly metabolized. On the other hand, uncerta inties were more significant in alveolar and blood concentrations than in u rinary metabolite excretions for chemicals that are well metabolized. Concl usion: Careful attention is necessary in the selection and/or citation of v alues from published data. The validity of PB-PK models should be simultane ously confirmed with both the blood and/or alveolar concentration and urina ry metabolite concentrations.