STATISTICAL PROPERTIES OF FITTED ESTIMATES OF APPARENT IN-VIVO METABOLIC CONSTANTS OBTAINED FROM GAS UPTAKE DATA - I - LIPOPHILIC AND SLOWLY METABOLIZED VOCS

Gargas et al. (1986) demonstrated that the physiologically based simul ation approach could be used to obtain information about rodent in viv o metabolic kinetics from gas uptake data. This statistical approach h as been widely used to estimate apparent in vivo metabolic constants f or use in physiologically based pharmacokinetics (PBPK) models. Despit e extensive use of this methodology and the potential importance of th e resulting fitted estimates of metabolic constants to the estimation of health risk, a formal evaluation of the statistical properties of t his estimation procedure as applied to gas uptake data has not been pe rformed. This article describes results from a computer simulation stu dy to investigate three important statistical properties of this estim ation procedure: bias (whether fitted estimates on average predict the true population mean), efficiency (whether fitted estimates tend to c oncentrate over a narrow range), and consistency (whether filled estim ates concentrate in a narrower and narrower range as sample size incre ases). These three statistical properties were evaluated as a function of (1) the number of experimental replicates per concentration range, (2) the choice of initial chamber concentrations, (3) the knowledge o f animal-specific physiology, and (4) the conduct of experiments with a single versus multiple animals in a chamber. Carbon tetrachloride wa s used as a lipophilic and slowly metabolized model compound. Simulate d gas uptake data were generated to reflect two major sources of varia tion: experimental error (2% coefficient of variation, CVI and animal- to-animal heterogeneity in physiologic and anatomic quantities (5-10% CV). Fitted estimates of metabolic constants obtained from simulated d ata were generally found not to exhibit significant bias. However, the physiologically based simulation approach as usually applied was foun d to be a relatively inefficient estimation procedure for the model co mpound tie., a large spread in fitted estimates of apparent in vivo me tabolic constants about the true population mean). A single simulated data set consisting of triplicate gas uptake experiments at each of 4 different chamber concentrations was capable of giving fitted estimate s of metabolic constants differing from the specified population mean by 50 to 100%. Simulation studies also indicated that the usual error model invoked for gas uptake data is incorrect, with the deleterious c onsequence of giving overly precise estimates of precision for fitted estimates of metabolic constants. Based on the simulation results, a t iered approach is proposed for design and conduct of gas uptake studie s, with the objective of identifying a more efficient design for estim ating metabolic constants.