A physiologically based simulation approach for determining metabolic constants from gas uptake data.

In vivo metabolic constants were determined in male Fischer rats for five chemicals: 1,1-dichloroethylene (1,1-DCE), diethyl ether (DE), bromochloromethane (BCM), methyl chloroform (MC), and carbon tetrachloride (CCl4). A closed recirculated exposure system was used to collect a series of uptake curves for each chemical at a range of initial concentrations. The shapes of these curves were a function of the tissue partition coefficients and the kinetic characteristics of the metabolism of these chemicals. Tissue:air partition coefficients were experimentally determined for each chemical and incorporated into a physiological kinetic model which was then used to simulate the uptake process. An optimal fit of the family of uptake curves for each chemical was obtained by adjusting the biochemical constants for metabolism of the chemical. Metabolism of both 1,1-DCE and CCl4 was represented by a single saturable process while MC required only a first-order pathway. BCM and DE exhibited a combination of both a saturable and a first-order process. Pyrazole, which blocks oxidative microsomal metabolism, inhibited the saturable pathways of 1,1-DCE, BCM, DE, and CCl4 metabolism and abolished the first-order pathway for MC. The maximum velocity of metabolism for the saturable pathway with 1,1-DCE, BCM, DE, and CCl4 for a 225-g rat was 27.2, 19.9, 26.1, and 0.92 mol/hr, respectively. The simulation approach for analyzing gas uptake data distinguishes between single and multiple metabolic pathways and provides kinetic constants that can be used in predictive toxicokinetic models for describing constant concentration inhalation exposure as well as exposures by other routes of administration.