A Graphical Application of Sensitivity Analysis for Gas Uptake Experiments Using Chloroform as an Example

Abstract

The accurate quantification of metabolism is essential for performing dosimetry of volatile organic compounds because metabolism is typically required for toxicity. One approach available to measure metabolism is gas uptake analysis, which combines experimental data with physiologically based pharmacokinetic (PBPK) modeling in order to obtain metabolic parameters. One of the primary concerns when using modeling to infer parameter values arises from the uncertainty involved in this process. In this article, we illustrate the use of sensitivity analysis, a numerical technique, typically used to identify optimal exposure times aimed at improving future experiments. This particular analysis was performed using a previously published PBPK model for chloroform, which was chosen as a model volatile compound. In order to illustrate the interpretation of sensitivity coefficients, three different time-course plots are generated for liver concentration by varying the metabolism parameter Vmax plus or minus 10%. We then graphically relate these three plots to a single sensitivity coefficient plot. This process is repeated for three additional concentrations in order to illustrate how sensitivity coefficients vary with exposure length and initial chamber concentration. In general, the maximal sensitivity regions indicate the best sampling times, which vary for different initial concentrations. This work provides an intuitive illustration of sensitivity analysis in the hope of facilitating the application of sensitivity analysis to design informative metabolic studies.

Key Words:

• chloroform
• PBPK models
• sensitivity coefficients