Uncertainty in fitted estimates of apparent in vivo metabolic constants for chloroform

It has become common practice to rely on fitted estimates of apparent in vivo metabolic constants (e.g., Vmax and KM) in the parameterization of PBPK models. Yet, quantitative estimates of precision in these fitted parameters are not routinely reported. Such information is needed to assess the reliability of model predictions. The purpose of this study was to assess the precision in estimates of Vmax and KM for chloroform, accounting for both the statistical uncertainties in parameter estimates from individual data sets and any additional uncertainty due to differences in the parameter estimates derived from various experiments. Joint confidence regions for Vmax and KM from each experiment, generated using maximum likelihood techniques, were used to evaluate these questions. Three previously published data sets were considered. Estimates of Vmax and KM obtained from these data sets differed more than could be explained as a consequence of a limited number of observations, measurement error, or stochastic error. Issues associated with the use of maximum likelihood techniques to estimate joint confidence regions, the estimation of metabolic constants from individual experiments within a gas uptake study versus the full data set, the degree of overlap in the joint confidence regions for metabolic constants obtained from separate data sets, and the implications for risk assessment are discussed.