Hulet S W, McDonough J H, Shih T-M
Neurotoxicology and Applied Pharmacology Branches, US Army Medical Research Institute of Chemical Defense, MCMR-UV-PN, Aberdeen Proving Grounds, MD 21010-5400, USA.
Pharmacol Biochem Behav. 2002 Jul;72(4):835-45. doi: 10.1016/s0091-3057(02)00761-x.
The present study assessed the effects of repeated subacute exposure to the organophosphorous nerve agent, sarin. Guinea pigs were injected five times per week (Monday-Friday) for 2 weeks with fractions of the established LD(50) dose of sarin (42 microg/kg sc). The animals were assessed for the development of cortical EEG seizures. Changes in body weight, red blood cell (RBC) acetylcholinesterase (AChE) levels and neurobehavioral reactions to a functional observational battery were monitored over the 2 weeks of sarin exposure and for an extended postinjection period. There were dose-related changes in body weight and RBC AChE levels. No guinea pigs receiving 0.3, 0.4 or 0.5 x LD(50) of sarin showed signs of cortical EEG seizures despite decreases in RBC AChE levels to as low as 10% of baseline. Seizures were evident in animals receiving 0.6 x LD(50) of sarin as early as the second day, and subsequent injections led to incapacitation and death. Animals receiving 0.5 x LD(50) sarin showed obvious signs of cholinergic toxicity, which included a significant increase in their angle of gait. Overall, 2/13 animals receiving 0.5 x LD(50) sarin died before all 10 injections were given. By the 10th day of injections, the animals receiving saline were significantly easier to remove from their cages and handle as compared to the first day of injections. They were also significantly less responsive to an approaching pencil and touch on the rump in comparison to the first day of testing. In contrast, the animals receiving 0.4 x LD(50) sarin failed to show any significant reductions in their responses to an approaching pencil and a touch on the rump as compared to the first day. The 0.5 x LD(50) sarin animals failed to show any significant changes to the approach response and touch response and did not adjust to handling or cage removal from the first day of injections to the last day of handling. In summary, the guinea pigs receiving the 0.4 x LD(50) and 0.5 x LD(50) doses of sarin failed to habituate to some aspects of the functional observational battery testing.
本研究评估了反复亚急性暴露于有机磷神经毒剂沙林的影响。豚鼠每周（周一至周五）注射5次，持续2周，注射剂量为已确定的沙林半数致死剂量（LD50）的几分之一（42微克/千克，皮下注射）。评估动物皮质脑电图癫痫发作的发展情况。在沙林暴露的2周期间以及延长的注射后期间，监测体重变化、红细胞（RBC）乙酰胆碱酯酶（AChE）水平以及对功能性观察组合测试的神经行为反应。体重和红细胞乙酰胆碱酯酶水平存在剂量相关变化。接受0.3、0.4或0.5倍LD50沙林的豚鼠均未表现出皮质脑电图癫痫发作的迹象，尽管红细胞乙酰胆碱酯酶水平降至基线的10%。接受0.6倍LD50沙林的动物早在第二天就出现癫痫发作，随后的注射导致动物丧失能力并死亡。接受0.5倍LD50沙林的动物表现出明显的胆碱能毒性迹象，包括步态角度显著增加。总体而言，13只接受0.5倍LD50沙林的动物中有2只在完成全部10次注射前死亡。到注射第10天时，与注射第一天相比，接受生理盐水注射的动物明显更容易从笼中取出并处理。与测试第一天相比，它们对靠近的铅笔和臀部触摸的反应也明显降低。相比之下，接受0.4倍LD50沙林的动物与第一天相比，对靠近的铅笔和臀部触摸的反应未显示出任何显著降低。接受0.5倍LD50沙林的动物对接近反应和触摸反应未显示出任何显著变化，并且从注射第一天到处理的最后一天，对处理或从笼中取出均未适应。总之，接受0.4倍和0.5倍LD50剂量沙林的豚鼠未能适应功能性观察组合测试的某些方面。
