INVESTIGATION OF THE IMPACT OF PHARMACOKINETIC VARIABILITY AND UNCERTAINTY ON RISKS PREDICTED WITH A PHARMACOKINETIC MODEL FOR CHLOROFORM

A sensitivity and uncertainty analysis was performed on the Reitz et a l. (Toxicol. Appl. Pharmacol., 1990: 105, 443) physiologically based p harmacokinetic (PBPK) risk assessment model for chloroform. The analyt ical approach attempted to separately consider the impacts of interind ividual variability and parameter uncertainty on the predicted values of the dose metrics in the model, as well as on liver cancer risk esti mates obtained with the model. An important feature of the analytical approach was that an attempt was made to incorporate information on co rrelation between important parameters, for example, the observed corr elation between total blood how and alveolar ventilation rate. Using t he published PBPK model for chloroform, the best estimate of the avera ge population risk based on the preferred pharmacodynamic dose metric (PTDEAD), representing cell death, is 9.2 x 10(-7); this estimate is m ore than 500-fold lower than the risk estimate of 5.3 x 10(-4) based o n an alternative pharmacokinetic dose metric (AVEMMB), which represent s tissue adduct formation. However, when interindividual variability w as considered the range of individual risks (from the 5th to the 95th percentile of the population) predicted with PTDEAD was extremely broa d (from 3.0 x 10(-13) to 3.2 x 10(-4)), while individual risks predict ed with AVEMMB only varied over a factor of four (from 1.9 x 10(-4) to 7.4 x 10(-4)). As a result, the upper 95th percentile of the distribu tion of individual risk estimates based on the preferred cell death me tric were within a factor of three of the 95th percentile for the phar macokinetic alternative. The crucial factor with respect to the much g reater variability of chloroform risk estimates based on cell death is that the dose metric, PTDEAD, is exquisitely sensitive to variation o f the parameters in the model defining the response of cells to the cy totoxicity of chloroform. Unfortunately, these key parameters are also highly uncertain, as well as strongly correlated. As a result it prov ed impossible to accurately quantify the additional impact of paramete r uncertainty on the dose metrics and risk estimates for chloroform. I n general, however, the approach used in this study should be useful f or differentiating the impact of interindividual variability and param eter uncertainty on PBPK-based risk assessments of other chemicals whe re the sensitivity, uncertainty, and correlation of the key parameters are more limited.