Pharmacokinetics of halogenated ethylenes in rats

Abstract

Inhalation pharmacokinetics of the halogenated ethylenes vinyl fluoride (VF), vinylidene fluoride (VF2), vinyl chloride (VC1), vinylidene chloride (VC12), cis- and trans-dichloroethylene (cis-DCE and trans-DCE), trichloroethylene (Tri), perchloroethylene (Per), and vinyl bromide (VBr) have been comparatively studied in the rat. Rats were exposed in a closed inhalation system to various initial atmospheric levels of halogenated ethylenes, and the decline of atmospheric concentration was followed using gas Chromatographic analysis. From pharmacokinetic analysis of the experimental curves the following general patterns of the halogenated ethylenes were derived. Distribution of the compounds in the organism and in the gas phase is determined by physical factors. For practical purposes, a relation of the equilibrium constants with the volatilities of the compounds, expressed by the boiling points, may be used: compounds with a low boiling point are enriched in tissues much less than those of a higher boiling point, and vice versa. Compounds with high accumulation in tissues (Tri, Per) need much more time for completion of the equilibration process than more volatile compounds. Metabolic elimination of halogenated ethylenes is a saturable, dose-dependent process. If animals are exposed to atmospheric concentrations of a halogenated ethylene which exceed the "point of saturation (Sp)", elimination is determined by a zero-order law, i.e., its rate is independent of the concentration of the compound. In contrast, below saturation normal first-order kinetics apply. If the rate of metabolic elimination is related to the concentrations of the compounds in the tissue compartment, very similar rates for first-order elimination of the different halogenated ethylenes are found. This suggests a common rate limiting factor applicable for the lower concentration range. The maximal velocities (Vmax) of metabolic elimination of halogenated ethylenes which are reached above the "saturation points" depend on the chemical structures of the individual compounds. In general, with the exception of Tri, further halogen substitution inhibits metabolic conversion. Of the halogenated ethylenes, VF2 and Per are extremely slowly metabolized. The present report also provides the data necessary for calculation of the rates of metabolism of halogenated ethylenes in rats at a given concentration of atmospheric exposure. © 1979 Springer-Verlag.