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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines
Khamisiyah, Iraq. The degree of exposure of U.S. troops located within the path of a sarin–cyclosarin plume, which is being remodeled in an upcoming DoD study, is at this point presumed to be low on the basis of previous exposure modeling and in the absence of medical personnel or veterans’ reporting symptoms of an acute cholinergic syndrome.
The remainder of this chapter examines the scientific literature on the adverse health effects of sarin. It begins with a discussion of the toxicology of sarin and its effects on animals. It then summarizes the modest number of published toxicology studies on cyclosarin. The chapter next proceeds to its major focus, the health effects of sarin in humans. Most, if not all, toxicological and epidemiological studies focused on the health effects of sarin, as opposed to sarin in combination with other agents.
Sarin (GB; o-isopropyl methylphosphonofluoridate) is an organophosphate ester with high potency as an anticholinesterase nerve agent. It is a clear, colorless liquid with a molecular weight of 140.11, a boiling point of 158°C, and a vapor pressure of 1.48–2.9 mm Hg at 25°C (making it highly volatile). Sarin presents a liquid and a vapor hazard. In the liquid state, sarin can rapidly penetrate skin (as well as clothing), and in the vapor state it can contact the eye directly or be inhaled into the lungs, whereupon it is rapidly absorbed (Spencer et al., 2000). Exposure of the eye to vapor, which produces pinpoint pupils (miosis) and blurring of vision, accounts for one of the earliest signs of sarin exposure (Gunderson et al., 1992; Stewart and Sullivan, 1992).
Mechanisms of Acute Toxicity
Inhibition of Acetylcholinesterase
There is widespread agreement that the principal mechanism of toxicity after sarin exposure is by inhibition of acetylcholinesterase and consequent rise in ACh, leading to overstimulation at cholinergic synapses (Somani, 1992; Lotti, 2000; Spencer et al., 2000). These effects are dose related. The degree of inhibition of AChE in the mouse brain depends directly on the administered intravenous (i.v.) dose of sarin (Tripathi and Dewey, 1989). High doses of sarin (100 μg/kg) administered subcutaneously to rats produce a 32 percent increase in ACh levels (Flynn and Wecker, 1986).
Sarin inhibits AChE by phosphorylating a serine hydroxyl on the ester portion of the active site of this enzyme.2 The phosphorylated enzyme is hydrolyzed very slowly, with a half-life of reactivation of hours to days (Gray, 1984). The
During its normal function, AChE hydrolyzes acetylcholine to produce choline, acetic acid, and the reactivated enzyme. The reactivated enzyme is available to bind to another acetylcholine molecule. AChE has one of the fastest turnover rates known.