SENSITIVITY ANALYSIS AND THE DESIGN OF GAS UPTAKE INHALATION STUDIES

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-l, h(-1)) are typic ally inferred from the decline in chemical concentration observed in c losed chamber exposures. Sensitivity analysis was used to quantify the identifiability of these metabolic parameters with PBPK models for th ree 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 se nsitivity analysis related the increased ability to estimate V-max for chloroform and dichloromethane with their higher metabolic rates, ind icating the value of V-max to be an important determinant in its ident ifiability. The optimal experimental concentration needed for estimati ng V-max was lower for carbon tetrachloride (12-18 ppm) than for eithe r chloroform (740-770 ppm) or dichloromethane (680-740 ppm), and was s hown to increase as a function of V-max. In addition to V-max, blood/a ir and fat/air partition coefficients were found to be important deter minants of sensitivity to V-max estimation. Three-dimensional sensitiv ity surfaces were generated in order to study the combined effect of i nitial chamber concentration and partition coefficients on identifiabi lity of V-max. Within the range of parameters investigated (blood/air partition was varied between 1 and 100; the fat/air partition was vari ed between 1 and 800), increased sensitivity toward V-max was achieved as the blood partition increased and the fat partition decreased in v alue. In summary, sensitivity analysis was useful in selecting appropr iate initial concentrations for identifying kinetic constants and prov ided increased understanding of factors determining the applicability of gas uptake techniques for assessing rates of metabolism with variou s volatiles.