frontal and entorhinal cortex, amygdala and caudate nuclei, hippocampus, and thalamus—regions frequently affected by organophosphate poisoning. Cardiomyopathy and skeletal muscle lesions were the primary nonneural lesions.

This study also compared the efficacy of pretreatment with pyridostigmine and treatment with atropine and either 2-PAM or HI-6 given immediately after cyclosarin administration. All animals survived lethal doses of cyclosarin regardless of the oxime they received, and all were clinically normal 24 hours after dosing. Minimal nervous system lesions were observed in these animals. Cardiomyopathy and skeletal muscle lesions were apparent in about a third of protected animals.

In a subsequent study using an identical protection paradigm in rhesus monkeys, Young and Koplovitz (1995) examined biochemical and hematological parameters. They found elevated creatine kinase, lactate dehydrogenase, aspartate and alanine transaminases, and potassium ion in both oxime treatment groups 2 days after cyclosarin poisoning. The elevated biochemical markers are indications of striated muscle damage. The blood values returned to normal at 7 days. The RBC count, hemoglobin, hematocrit, and serum protein and albumin were significantly decreased at 7 days.

SUMMARY OF TOXICOLOGY

Sarin is toxic to animals in a dose-dependent manner. Animals exposed to high doses display the same acute cholinergic syndrome as displayed by humans. The main mechanism of toxicity is through inhibition of AChE. Sarin is readily and rapidly absorbed into the circulation where it is hydrolyzed or bound to blood esterases. Sarin that is not inactivated in the blood quickly distributes to the brain and other tissues where it inhibits AChE. Massive acute doses of sarin, through the inhibition of NTE, can induce delayed neurotoxicity in some, but not all, animal species. Lower doses over longer periods may also exert this effect, but more research is needed to substantiate these findings. Long-term alterations in the EEG of nonhuman primates were found after sarin administration at high doses, as well as at doses that did not produce acute signs of toxicity. The clinical significance of the EEG changes is unclear. There is no evidence of genotoxicity or reproductive or developmental toxicity. The toxicology of cyclosarin appears to be similar to that of sarin, but few studies have been reported. There are no studies of the long-term or delayed effects of toxic interactions between sarin–cyclosarin and pyridostigmine.

HUMAN STUDIES

This section reviews studies of sarin’s acute and long-term health effects on humans. Four human populations have been studied following exposure to sarin: military volunteers who were exposed several decades ago to nonlethal doses of sarin and other chemical warfare agents (NRC, 1982, 1985); industrial workers



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