PHARMACOKINETICS OF INHALED CHLOROBENZENE IN THE SPRAGUE-DAWLEY RAT
Abstract
Male Sprague-Dawley rats were treated with 8-hour inhalation exposures to three concentrations of chlorobenzene vapor (100, 400, and 700 ppm). The objective of the study was to examine the dose dependence of parameters indicative of the toxicity process. Measurements were made of the kinetics of elimination via urine and expired air, urinary metabolite profile, tissue reduced glutathione concentrations, and covalent binding. Tissue burdens of chlorobenzene and its metabolites were also measured at zero, 16, and 48 hours post-exposure. Evidence that two aspects of chlorobenzene metabolism are saturable was presented. The capacity of the metabolic enzymes which clear the blood was saturable, resulting in a prolonged period of maximum rates of metabolism due to reflux of chlorobenzene from adipose storage. Conjugation of chlorobenzene metabolites with glutathione was also saturable, due to depletion of glutathione concentrations during periods of maximum rates of metabolism. Saturation of these aspects of metabolism can increase the incidence and severity of toxicity, since chlorobenzene toxicity is mediated by the formation of a reactive epoxide which, in the rat, is detoxified predominately by glutathione conjugation. Evidence of both types of saturation was manifested at 400 ppm, and was more pronounced following 700 ppm exposures. There were few differences seen between rats exposed for five consecutive days and rats exposed only once. The implications concerning assessment of risks from exposure to low concentrations are discussed in light of recent regulatory action by the Environmental Protection Agency under the Toxic Substances Control Act.
Degree
Ph.D.
Subject Area
Environmental science
Off-Campus Purdue Users:
To access this dissertation, please log in to our
proxy server.