Sensitivity Analysis and the Design of Gas Uptake Inhalation Studies

Abstract

Gas uptake studies analyzed by physiologically based pharmacokinetic (PBPK) models have been used to estimate metabolic parameters for many volatiles. The metabolic constants for a saturable pathway (V_max′ mg/h and K_m′, mg/L) and for a first-order process (K_f′ h⁻¹) are typically inferred from the decline in chemical concentration observed in closed chamber exposures. Sensitivity analysis was used to quantify the identifiability of these metabolic parameters with PBPK models for three compounds: chloroform (V_max = 2.25 mg/h), dichloromethane (V_max = 1.33 mg/h), and carbon tetrachloride (V_max=0.11 mg/h). Further sensitivity analysis related the increased ability to estimate V_max for chloroform and dichloromethane with their higher metabolic rates, indicating the value of V_max to be an important determinant in its identifiability. The optimal experimental concentration needed for estimating V_max was lower for carbon tetrachloride (12-18 ppm) than for either chloroform (740-770 ppm) or dichloromethane (680-740 ppm), and was shown to increase as a function of V_max. In addition to V_max, blood/air and fat/air partition coefficients were found to be important determinants of sensitivity to V_max estimation. Three-dimensional sensitivity surfaces were generated in order to study the combined effect of initial chamber concentration and partition coefficients on identifiability of V_max. Within the range of parameters investigated (blood/air partition was varied between 1 and 100; the fat/air partition was varied between 1 and 800), increased sensitivity toward V_max was achieved as the blood partition increased and the fat partition decreased in value. In summary, sensitivity analysis was useful in selecting appropriate initial concentrations for identifying kinetic constants and provided increased understanding of factors determining the applicability of gas uptake techniques for assessing rates of metabolism with various volatiles.