Both in vivo and in vitro immune effects have been seen, but they are not consistent and they depend on the cell types studied. Recent studies have investigated persistent effects of sarin on the immune system. Modest and inconsistent effects on lymphocyte proliferation and production of N-oxides were seen in rats 3 months after a single or repeated (three times in 1 week) 1-hour inhalation-chamber exposure.

In general, genotoxicity studies (of mutagenesis, chromosomal damage, unscheduled DNA synthesis, or sister chromatid exchange) are negative. In a subchronic (90-day) toxicologic study of sarin (three different doses that produced profound inhibition of AChE and some deaths), one of two formulations of sarin was associated with one neoplastic lesion, a lymphoma, in one male in the high-dose group.

No chronic animal studies have been conducted to determine the carcinogenic effects of exposure to sarin.

One of the mechanisms of sarin inactivation is hydrolysis with the enzyme paraoxonase (PON1), an esterase synthesized and secreted by the liver. The human PON1 gene has polymorphisms that affect serum PON1 activity and therefore might significantly alter susceptibility to the toxicity of sarin. The relationship between illness in Gulf War veterans and PON1 genotype and serum activity has been investigated. The results of one study suggested that low PON1 activity due to the polymorphism might be a risk factor for illness in Gulf War veterans, but another study did not find any differences in PON1 activity between symptomatic and asymptomatic Gulf War veterans.

Four populations have been studied in large epidemiologic studies after exposure to sarin: military volunteers who were exposed several decades ago to nonlethal doses of sarin and other chemical-warfare agents, industrial workers with documented acute exposure to sarin, victims of the sarin terrorist attacks in Matsumoto City in 1994 and Tokyo in 1995, and Gulf War veterans. Studies of Gulf War veterans include studies of veterans potentially exposed to sarin after demolition of rockets at Khamisiyah and a number of studies on Gulf War veterans that evaluate the relationship between symptoms and possible exposures on

Front Matter (R1-R12)

Executive Summary (1-12)

1 Introduction (13-25)

2 Toxicology (26-46)

3 Human Health Outcome Studies (47-90)

4 Conclusions (91-102)

Appendix: Organophosphorus Insecticides (103-120)