Interaction of Exposure Concentration and Duration in Determining Acute Toxic Effects of Sarin Vapor in Rats

摘要

These studies were conducted as part of the 'Low Level Operational Toxicology' program which began by addressing the question of how low do chemical agent detectors need to go to measure toxicologically significant effects of the classical chemical warfare (CW) agents. Initial phases of the program have focused on GB vapor. The objective of these studies was to (1) identify threshold exposure conditions at which toxicologically significant effects occur in the rat and (2) develop models for predicting dose-response effects of low CW agent concentrations as a function of exposure duration. Sarin (GB) vapor exposure is associated with both systemic and local toxic effects occurring primarily via the inhalation and ocular routes. These studies examined the effects of varying exposure concentration and duration on the probability of lethality occurring in rats exposed to Sarin (GB) vapor. Groups of male and female rats (Sprague-Dawley) were exposed to one of a series of GB vapor concentrations for a single duration (5- 360 minutes) in a whole-body dynamic chamber. The onset of clinical signs and changes in blood cholinesterase activity were measured with each exposure. Separate effective concentrations for lethality (LC50) and miosis (EC50) in 50% of the exposed population and corresponding dose-response slopes were determined for each exposure (duration) by the Bliss probit method. A predictive model derived from multifactor probit analysis describing the relationship between exposure conditions and probability of lethality in the rat is presented. Contrary to that predicted by Haber's rule, LCt50 values increased with exposure duration (i.e., the CT for 50% lethality exposed population and corresponding dose- response slope was not constant over time). A plot of Log (LCt50) versus Log (Exposure Time) showed significant curvature. To account for this curvature, an interactive term, Log (C)(star)Log(T), was added to the toxic load model.