Gas Uptake Inhalation Techniques and the Rates of Metabolism of Chloromethanes, Chloroethanes, and Chloroethylenes in the Rat

Abstract

Closed atmosphere gas uptake exposures have been used to estimate the kinetic constants of metabolism for the chlorinated methanes, chlorinated ethylenes, and four of the chlorinated ethanes in the male Fischer 344 rat. A physiologically based pharmacokinetic (PB-PK) model was used to analyze a group of four to five uptake curves for each chemical. Eight of the fourteen compounds have been studied previously by gas uptake techniques, and these data sets were reanalyzed by computer optimization. With 1,2-dichloroethane and methyl chloride, the PB-PK model had to be expanded to account for glutathione depletion, while with cis- and trans-1,2 dich-loroethylene the model had to be expanded to accommodate suicide enzyme inhibition-resynthesis to adequately describe the observed uptake behaviot The effects of pyrazole pretreatment, known to inhibit cytochrome P-450 oxidase activities, were also investigated. The kinetic behaviors determined for these compounds were either saturable, first-order, or a combination of these two processes. Tetrachloroethy-lene and 1, 1, 1,-trichloroethane displayed behaviors consistent with first-order metabolism only (0.3 and 5.0 h⁻¹ respectively), indicating very low overall metabolism. The maximum metabolic rates (V_maxc) for the chemicals exhibiting saturable reactions ranged from 2.6 μmol h⁻¹kg⁻¹ for carbon tetrachloride to 96.9 μmol h⁻¹kg⁻¹ for chloromethane. The saturable reactions were all high affinity, with K_m values less than 20 μM in all cases, and less than 5 μM for most. These kinetic constants can be utilized in PB-PK models to predict kinetic behavior for various routes of exposure, varied exposure scenarios, and for interspecies extrapolations. Insights into structural requirements for metabolic rates are also presented.