Development of a Guinea pig model for low-dose, long-term exposure to organophosphorus nerve agents

An animal dosing model and related maximum tolerated dose (MTD) were developed for repeated exposures in guinea pigs to three organophosphorus chemical warfare nerve agents (CWNA). Male animals were injected subcutaneously with sarin (GB), soman (GD) or VX once a day (Monday through Friday) for 2-, 4-, or 13-weeks. An initial 13-week study for each CWNA employed doses of vehicle (normal saline), 0.2x, 0.4x, 0.6x, and 0.8x the previously established acute LD(50). A 2-week and 4-week exposure were also performed for each agent at doses less than the 13-week MTD to verify lack of toxicity. Animals dosed daily for 13 weeks with 0.4x LD(50) of GB or GD or with 0.2x LD(50) of VX did not display signs of acute cholinergic toxicity. In animals dosed daily for either 2- or 4-weeks, the MTDs were 0.4x the acute LD(50) for all three CWNA. There were no differences among these groups and their respective vehicle controls for weight gains, body temperature, complete blood cell counts, blood chemistries, nor by histopathology. At the MTD in all groups, red blood cell cholinesterase activity one hour after the last exposure was inhibited up to 90% compared with controls. The toxicity observed with repeated doses above the MTD for up to chronic exposure durations was not significantly different from symptoms observed after acute exposure. For all three nerve agents the MTDs for subacute exposure durations can be expressed by the same constant fraction of the acute LD(50), despite differences in the absolute amount of nerve agent administered.