Gulf War and Health Volume 1: Depleted Uranium, Sarin, Pyridostigmine Bromide, and Vaccines (2000) / Chapter Skim
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Sarin
Sarin
Pages 169-206
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A few highly toxic members of this large class are chemical warfare agents, but most are insecticides (Table 5.1) (Lotti, 2000~.
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nerve agents. ACUTE CHOLINERGIC SYNDROME In humans, exposure to high doses of sarin produces a well-characterized acute cholinergic syndrome featuring a variety of signs and symptoms affecting the peripheral and central nervous systems (Gunderson et al., 1992)
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Finally, low-level exposure may have occurred even though there are no immediately detectable cholinergic signs and symptoms (Brown and Brix, 1998~. The health effects of low levels of sarin exposure are of
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UNSCOM reporting and intelligence summaries of the amount, purity, and type of chemical warfare agents stored at Khamisiyah; (2) the results of experiments performed later at Dugway Proving Ground to simulate the demolition at Khamisiyah and thus estimate the amount of sarin and cyclosarin released, the release rate, and the associated type of release (instantaneous, continuous, or fly-out)
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Nevertheless, low-level exposure, as noted earlier, could have occurred without producing acute cholinergic effects. Two other storage sites in central Iraq sustained damage from air attacks during the Gulf War, but chemical agent releases were too far removed from U.S.
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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.
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Recovery of AChE function occurs only with synthesis of new enzyme. Inhibition of AChE prevents the breakdown of acetylcholine, which accumulates in central and peripheral nerve synapses, leading to the acute cholinergic syndrome.
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Since this effect was also seen after administration of the OF nerve agents soman and tabun, it most likely is not agent specific, but rather is a likely consequence of an acute increase of acetylcholine in the striatum (Fernando et al., 19844. Neuropathological damage in the hippocampus, dorsal thalamus, and piriform cortex was found in about 70 percent of rats within 24 hours of administering a single dose of sarin (95 Agog, i.m., or 1 LDso (Kadar et al., 1995~.
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The acute cholinergic syndrome occurs when RBC AChE is inhibited by 75-80 percent (Sidell and Borak, 1992 3. Distribution and Elimination The tissue distribution of sarin and its metabolites has been studied in rodents.
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In blood, the extent of inhibition of RBC AChE is considered the best marker of acute exposure. Sarin preferentially inhibits RBC AChE more than BuChE; however, after high-level sarin exposure, complete inhibition of both esterases occurs (Sidell and Borak, 1992~.
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There is some variability depending on the species and the route of administration. Table 5.3 outlines the doses and routes of administration that produce acute lethality (within 24 hours)
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Therefore, the cause of death after sarin exposure is rapid inhibition of respiratory centers in the medulla followed by inhibition of phrenic nerve activity, which causes respiration to cease. The diaphragm muscle is paralyzed last.
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The high dose was sufficient to produce an acute cholinergic syndrome, whereas each small dose produced few, if any, signs of acute poisoning. Animals given the large dose were pretreated with gallamine triethiodide and artificially respired to preclude the possibility of anoxic brain damage.
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From these studies, most investigators concluded that sarin was unlikely to produce delayed neurotoxicity at sublethal doses. In two more recent studies, however, sublethal doses were administered.
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were much more severe (Husain et al., 1995~. Platelet acetylcholinesterase activity was inhibited by 72 percent, but no indication is provided on whether cholinergic symptoms were observed.
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184 I: o .> a- ° Z O o .~ Cal o so · 50 I o :O o o au Ad a' so Ct C)
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This section reports on the limited number of toxicological studies of cyclosarin, whereas a later section reports on a study of military volunteers exposed to anticholinesterase nerve agents, including sarin and cyclosarin. Cyclosarin produces maximal inhibition of AChE in less than 1 minute, with inhibition rate constants of 7.4 and 3.8 x 108 W~ mind for AChE and BuChE, respectively (Worek et al., 1998~.
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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, 19859; industrial workers
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The possibility of low-level sarin exposure of U.S. troops during the Gulf War has generated much interest in whether sarin has long-term effects after a relatively short exposure at levels that are insufficient to produce an acute cholinergic syndrome.
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Army studied servicemen exposed voluntarily to an array of chemical warfare agents (NRC, 1982, 1985~. During the program, the Army investigated only acute short-term effects.
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military volunteers (n = 8) exposed to sarin vapors at 15 mg/min/m3, soldiers quickly displayed some signs of the acute cholinergic syndrome (e.g., miosis and depressed RBC AChE levels)
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About 600 people (residents and rescue teams) developed acute symptoms of sarin exposure (i.e., the acute cholinergic syndrome)
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, about 27 percent of the cohort (n = 471) was classified as "victims" based on their reports of either receiving a diagnosis or reporting symptoms of acute cholinergic syndrome.
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The Matsumoto experience shows that direct exposure to sarin, particularly at intermediate to high levels, is associated with the acute cholinergic syndrome. In the majority of sarin victims in Matsumoto, clinical signs and symptoms of acute sarin poisoning disappeared within a matter of days or weeks if victims survived the acute effects of respiratory failure and convulsions.
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All but five patients were discharged from the hospital by the fifth day. More than 20 percent of the hospital staff who treated victims developed acute cholinergic symptoms from secondary exposure (Nozaki et al., 1995; Ohtu et al., 1997~.
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still reported symptoms related to the exposure, such as fear of subways, sleep disturbance, flashbacks, nightmares, and mood changes symptoms that the authors interpreted as indicative of posttraumatic stress disorder (PTSD; Ohbu et al., 1997~. Six to eight months later, 18 symptom-free survivors with previous intermediate- and high-level exposure to sarin were tested for persistent CNS effects (Murata et al., 1997; Yokoyama et al., 1998a,b,c)
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The authors viewed their findings as suggestive of a gender difference in a "delayed" effect of acute sarin poisoning on the vestibulocerebellar system. Their characterization of this effect as "delayed" is questionable, since there is no evidence of this postural testing having been performed at an earlier point after sarin exposure.
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The Q allozyme, on the other hand, has high activity toward organophosphate nerve agents (and low activity toward paraoxon)
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The committee concludes that there is stuff cient evidence of a causal relationship between exposure to sarin and a dose-dependent acute cholinergic syndrome that is evident seconds to hours subsequent to sarin exposure and resolves in days to months. The acute cholinergic syndrome has been recognized for decades and has been documented in human studies summarized in this chapter.
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1998. Review of health consequences from high-, intermediateand low-level exposure to organophosphorous nerve agents.
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1997. Modeling the Chemical Warfare Agent Release at the Khamisiyah Pit.
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arylesterase activity with neurologic symptom complexes in Gulf War veterans. Toxicol Appl Pharmacol 157~31:227-233.
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1997. Asymptomatic sequelae to acute sarin poisoning in the central and autonomic nervous system 6 months after the Tokyo subway attack.
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.1996. Presidential Advisory Committee on Gulf War Veterans' Illnesses: Final Report.
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1998c. Chronic neurobehavioral effects of Tokyo subway sarin poisoning in relation to posttraumatic stress disorder.
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, and serum cholinesterase activity in normal subjects. Br JAnaesth 57~2~:204-207.
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CONTENTS TOXICOLOGY 209 Structure and Mechanism of Action, 210 Animal Studies, 211 Interactions with Other Agents, 217 Genetic Susceptibility, 220 HUMAN STUDIES 222 Clinical Studies, 222 Healthy-Volunteer Studies, 231 Epidemiologic Studies, 245 CONCLUSIONS Acute Effects, 250 Chronic Effects, 252 REFERENCES .250 253
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