4
Conclusions

This chapter presents the committee’s conclusions regarding the association between exposure to sarin or cyclosarin and various health outcomes in humans. It summarizes the literature discussed in Chapter 3 by health outcome, and discusses the biologic plausibility of an association between a given health outcome and exposure to sarin or cyclosarin on the basis of experimental animal and in vitro studies discussed in Chapter 2. As discussed in Chapter 1, human data form the main basis of the committee’s conclusions. Chapter 1 contains a more detailed discussion of the committee’s approach to evaluating the evidence, and the criteria for various categories of evidence are presented in Box 1-1.

A conclusion is not reached for every health outcome discussed in every article. For some health outcomes too little information is available to support a conclusion. For each relevant health outcome, epidemiology studies that examined that outcome are reviewed followed by the conclusions for that outcome and the rationale behind that conclusion.

NEUROLOGIC EFFECTS

A number of studies have evaluated the possible relationship between exposure to sarin or cyclosarin and long-lasting neurologic effects. Those outcomes have been the focus of the largest number of studies because of the neurotoxic actions of the chemicals. The studies are divided by the short-term and long-term effects of acute exposures and by the effects of chronic exposures.



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Gulf War and Health: Updated Literature Review of Sarin 4 Conclusions This chapter presents the committee’s conclusions regarding the association between exposure to sarin or cyclosarin and various health outcomes in humans. It summarizes the literature discussed in Chapter 3 by health outcome, and discusses the biologic plausibility of an association between a given health outcome and exposure to sarin or cyclosarin on the basis of experimental animal and in vitro studies discussed in Chapter 2. As discussed in Chapter 1, human data form the main basis of the committee’s conclusions. Chapter 1 contains a more detailed discussion of the committee’s approach to evaluating the evidence, and the criteria for various categories of evidence are presented in Box 1-1. A conclusion is not reached for every health outcome discussed in every article. For some health outcomes too little information is available to support a conclusion. For each relevant health outcome, epidemiology studies that examined that outcome are reviewed followed by the conclusions for that outcome and the rationale behind that conclusion. NEUROLOGIC EFFECTS A number of studies have evaluated the possible relationship between exposure to sarin or cyclosarin and long-lasting neurologic effects. Those outcomes have been the focus of the largest number of studies because of the neurotoxic actions of the chemicals. The studies are divided by the short-term and long-term effects of acute exposures and by the effects of chronic exposures.

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Gulf War and Health: Updated Literature Review of Sarin Effects Following Acute High-Dose Sarin Short-Term Effects It is well established that high doses of sarin can have severe effects that are termed the acute cholinergic syndrome. The effects of acute poisonings from sarin have been seen in studies of servicemen who volunteered for studies of the health effects of low-dose exposure to sarin and other chemical-warfare (CW) agents (NRC, 1985; Baker and Sedgwick, 1996), a study of workers accidentally exposed to sarin (Duffy et al., 1979; Burchfiel and Duffy, 1982), and studies after terrorist attacks in Matsumoto and Tokyo, Japan (Murata et al., 1997; Nakajima et al., 1998, 1999; Yokoyama et al., 1998a,b,c). The following conclusion was reached in the present report after a review of the literature on sarin: There is sufficient 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 Chapter 3. As discussed in Chapter 2, animal and mechanistic data are consistent with the effects seen in humans. The syndrome, as well as cholinergic signs and symptoms, is evident seconds to hours after exposure and usually resolves in days to months. The syndrome and the cholinergic signs and symptoms are produced by sarin’s irreversible inhibition of the enzyme acetylcholinesterase. Inactivation of the enzyme that normally breaks down the neurotransmitter acetylcholine leads to the accumulation of acetylcholine at cholinergic synapses. Excess quantities of acetylcholine result in widespread overstimulation of muscles and nerves. At high doses, convulsions and death can occur. Long-Term Effects Many health effects are reported in the literature to persist after sarin exposure: fatigue, headache, visual disturbances (asthenopia, blurred vision, and narrowing of the visual field), asthenia, shoulder stiffness, and symptoms of posttraumatic stress disorder (PTSD). Sarin exposure has been followed by abnormal test results, of unknown clinical significance, on the digit symbol test of psychomotor performance, electroencephalographic (EEG) records of sleep, event-related potential, visual evoked potential, and computerized posturography. Studies of servicemen who volunteered for a study of the health effects of low-dose exposure to sarin and other CW agents did not demonstrate any long-term health effects of exposure to cholinesterase inhibitors (NRC, 1985; Page,

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Gulf War and Health: Updated Literature Review of Sarin 2003). A small, noncontrolled study of British servicemen who volunteered for a study of sarin exposure showed indications of potential failure of transmission at the neuromuscular junction 2 years after exposure, but the indicators had disappeared by a year later (Baker and Sedgwick, 1996). Although the exact doses received in the US study are not known, in both the US and British studies some people experienced the acute cholinergic syndrome. A study of workers accidentally exposed to sarin who exhibited the acute cholinergic syndrome showed changes in EEG findings, but their clinical significance is not known (Duffy et al., 1979; Burchfiel and Duffy, 1982). Studies have followed health effects in people who exhibited the acute cholinergic syndrome after terrorist attacks in Matsumoto and Tokyo, Japan. Three years after the Matsumoto attack, fatigue, headache, and the visual disturbances asthenopia, blurred vision, and narrowing of visual field were more common among people who reported signs of the acute cholinergic syndrome than among those who lived near the sarin release site who did not have signs of the cholinergic syndrome (Nakajima et al., 1998, 1999). An English abstract also showed visual-field constriction and abnormal EEG 45 months after the attacks (Nohara et al., 1999). Some 6–8 months after the Tokyo attack, symptom-free survivors of intermediate to high exposures were impaired on only one of nine neurobehavioral tests, and significant changes in some EEG findings and postural sway tests were seen in females (Murata et al., 1997, Yokoyama et al., 1998a,b,c). Three years after the Tokyo attack, a dose-effect relationship was found in previously poisoned people on a measure of memory performance (the backward digit span test), and tapping interval for dominant hand and stabilometry measures with eyes open were affected in exposed people (Nishiwaki et al., 2001). A noncontrolled study of patients from the Tokyo attack showed ocular effects (tiredness of eyes, dim vision, and difficulty in focusing), tiredness, fatigue, stiff muscles, and headache up to 5 years after the attack (Kawana et al., 2001). The present committee concluded that: There is limited/suggestive evidence of an association between exposure to sarin at doses sufficient to cause acute cholinergic signs and symptoms and a variety of subsequent long-term neurological effects. The conclusion is based on the persistent effects seen in retrospective studies, discussed above, of three exposed populations in which acute cholinergic signs and symptoms were documented as acute effects of exposure. The findings from the studies were based on comparisons with control populations. One exposed population consisted of industrial workers accidentally exposed to sarin in the United States; the other two populations were of civilians exposed during terrorism episodes in Japan. The health effects listed above were documented at least 6 months after sarin exposure, and some persisted up to 3 years, depending on the study. A review of the literature published since the preparation of GW1 confirmed that the effects were seen in those populations, but taken together the

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Gulf War and Health: Updated Literature Review of Sarin data were not adequate to increase confidence in the evidence to that of sufficient evidence of an association. Effects Following Low-Level Exposures Studies of forces deployed to the Gulf War have investigated the possible long-term neurologic effects that might be related to exposure to low levels of sarin. General neurologic effects and posttraumatic stress disorder (PTSD) are discussed separately below. General Neurologic Effects The most relevant studies have been conducted on US troops who were potentially exposed to sarin after munitions demolition at Khamisiyah, Iraq. There are no reports that any of those or other troops had signs of the acute cholinergic syndrome. Hospitalization studies found no difference in hospitalizations for nervous system diseases between exposed and nonexposed veterans (Gray et al., 1999; Smith et al., 2003). Studies of veterans from five states who were present when the demolition occurred showed no differences between troops who were and who were not present at Khamisiyah (McCauley et al., 2001). When those who did and those who did not witness the explosion were questioned about symptoms present 8 years after the explosion, however, those who reported witnessing the explosion had changes in memory, difficulty in sleeping, persistent fatigue, and depression (McCauley et al., 2001). It is difficult to determine if those effects are biased by the knowledge that the individuals might have been exposed to sarin. As discussed in Chapter 3, the uncertainties surrounding the exposure assessments for Khamisiyah limit the ability of those studies to provide strong evidence for the presence or absence of any associations. A number of studies have been conducted on cohorts from the Gulf War based on analyses of self-reports of possible indicators of sarin exposure on questionnaires. People’s reports that they had exposure to “chemical-warfare agents” have been associated with neurologic findings in several studies: cognitive dysfunction, depression, and fibromyalgia (Iowa Persian Gulf Study Group, 1997); major depression and anxiety (Goss Gilroy Inc., 1998); a syndrome termed “confusion–ataxia” (problems with thinking, disorientation, balance disturbances, vertigo, and impotence) (Haley and Kurt, 1997); mood, memory, and cognitive deficits (profile of mood states, tension and confusion scales, three tests of recall memory, and the WMS-R backward digit span test) (White et al., 2001); and musculoskeletal, neurologic, neuropsychologic, and psychologic symptoms (Proctor et al., 1998). In those studies, however, there is no documentation of actual exposure to chemical or biological warfare agents. In the absence of any exposure data beyond self-reports, the committee concluded that such effects could not be attributed to sarin or cyclosarin.

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Gulf War and Health: Updated Literature Review of Sarin Other studies have not shown such effects or have shown inconsistent effects. In a study of Danish Gulf War veterans, all of whom were involved in peacekeeping or humanitarian roles after the end of the war, self-reported exposure to “nerve gas” was not significantly associated with the neuropsychologic symptoms in the Gulf War cohort (Suadicani et al., 1999). Goss Gilroy Inc. (1998) reported no association with symptoms of cognitive dysfunction, chronic fatigue, and fibromyalgia in Canadian veterans. Because the servicemen and women in those two studies were not present in the gulf or not on the ground in the gulf at the time of the Khamisiyah demolition, however, they provide little information on the possible effects of sarin. Posttraumatic Stress Disorder PTSD has been seen in survivors of the Matsumoto (Nohara et al., 1999; English abstract) and Tokyo (Yokoyama et al., 1998c; Kawana, 2001) sarin terrorist attacks; however, those individuals had exhibited the acute cholinergic syndrome. McCauley et al. (2002) found deployed veterans to be more likely to have PTSD than nondeployed veterans. They did not find PTSD to be more common among Khamisiyah-exposed than Khamisiyah-nonexposed Gulf War veterans. As noted above, there were many uncertainties surrounding exposure assessments. Studies of Gulf War veterans found PTSD associated with self-reports of potential exposures in the Gulf War (e.g., Goss Gilroy Inc., 1998; Proctor et al., 1998). Those potential exposures relating to sarin for which associations were found include self-reports of exposure to chemical-warfare agents, self-reports of hearing chemical alarms, and wearing protective gear. British veterans reported either wearing “nuclear, biological, and chemical warfare suits”, “hearing chemical alarms”, or having a “chemical/nerve gas attack” (Unwin et al., 1999). Exposure assessment in those Gulf War studies is weak, relying on self-reports of exposure to sarin or other CW agents. It is not clear, therefore, whether PTSD-related effects are mediated by sarin itself. Although PTSD and related neurologic effects hypothetically might be toxicologic effects mediated by sarin, they might also be emotional and physiologic responses to the psychologic trauma of chemical agent exposure, which could be actual or perceived, or by the trauma of war itself. Many of the questionnaires were administered after there was knowledge of potential exposure. Exposure to severe psychological trauma is a nonspecific cause of PTSD, according to numerous studies in military, occupational, and civilian populations (see Kessler, 2000 for review). Military and occupational groups with psychological trauma exposure show similar signs of PTSD to those with self-reported exposures that might indicate exposure to sarin. Those groups include police and other rescue workers (Weiss et al., 1995; Asukai et al., 2002) and other veteran populations (Kulka et al., 1990). As discussed in GW1 (IOM,

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Gulf War and Health: Updated Literature Review of Sarin 2000), the belief in chemical-warfare exposure is sufficiently traumatic by itself that it can produce anxiety and depression symptoms in the absence of actual exposure, according to research on military trainees undergoing mock chemical-warfare exercises (Fullerton and Ursano, 1990). Further, in Canadian veterans of the Gulf War, self-reported chemical warfare agent exposure was associated with depression and anxiety symptoms, yet most Canadian veterans are unlikely to have been exposed to sarin because they were based at sea or had left the Gulf theatre at the time of the Khamisiyah demolitions (Goss Gilroy Inc., 1998). Finally, other traumatic and life-threatening exposures during the Gulf War were associated with neurological effects and could have accounted for neurological and psychiatric symptoms or diagnoses. PTSD symptoms or diagnoses were more likely in Gulf War veterans with combat exposure or injury (Baker et al., 1997; Labbate et al., 1998; Wolfe et al., 1998), with exposure to missile attack (Perconte et al., 1993), and with grave-registration duties (Sutker et al., 1994). It should also be noted that during the Khamisiyah demolitions, no chemical alarms were heard because the sarin concentration was below the sensitivity of the instruments to detect it. Chemical alarms also were triggered by substances other than chemical-warfare agents, such as organic solvents, exhaust fumes, and insecticides. Therefore, hearing chemical alarms is a poor indicator of exposure to chemical-warfare agents. The wide range of traumatic exposures associated with PTSD prompted Veterans Administration researchers to examine, in a large population-based study of Gulf War veterans, the combined effect of what they defined as three major combat stressors: 1) “hearing chemical alarms or wearing protective gear”; 2) “direct combat duty”; and 3) “witnessed any deaths.” The study found that the likelihood of developing PTSD after the war increased with increasing levels of traumatic exposure in a dose-dependent manner (Kang et al., 2003). Conclusion The present committee concluded that: There is inadequate/insufficient evidence to determine whether an association does or does not exist between exposure to sarin at low doses insufficient to cause acute cholinergic signs and symptoms and subsequent long-term adverse neurological health effects. On the basis of findings in a study of organophosphorus (OP) insecticides in nonhuman primates and in some studies of humans exposed to them, the question is raised whether there are long-term adverse health effects of exposure to low doses of sarin. Studies of low exposure of workers find that OP insecticides are associated with a higher prevalence of neurologic or psychiatric symptom reporting. Similar studies of low-dose exposure to sarin do not exist. As dis-

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Gulf War and Health: Updated Literature Review of Sarin cussed in Appendix A, the committee does not believe that it is possible to extrapolate the long-term, low-level effects of OP insecticides to the case of sarin and cyclosarin. Although the OP insecticides and the OP nerve agents are known to share a mechanism of action underlying their acute effects (inhibition of cholinesterase), the mechanism that underlies any potential low-level effects of OP insecticides is less established. Furthermore, the committee responsible for Gulf War and Health: Volume 2 (GW2; IOM, 2003) was unable to reach a consensus as to whether the evidence of those effects following exposure to OP insecticides was “inadequate/insufficient” or “limited/suggestive”. The present committee reviewed articles published since the preparation of GW2 and did not believe that any published studies definitively demonstrate those effects or lack thereof. As discussed above, none of the studies using exposure information showed persistent neurologic effects in Khamisiyah-exposed troops compared to Khamisiyah-nonexposed troops. Because of the uncertainty in the exposure assessment models discussed previously, however, those studies do not provide strong evidence for or against the presence of neurologic effects. A number of studies of Gulf War veterans found a variety of neurological effects associated with self-reports of potential exposures in the Gulf War. Those potential exposures related to sarin for which associations have been seen include self-reports of hearing chemical alarms and wearing protective gear. As discussed earlier, those self-reports of potential indicators of exposure do not provide strong evidence of an exposure–effect relationship and, therefore, those studies provide little evidence that those effects are mediated by sarin itself. In the case of PTSD and related neurologic effects, hypothetically those effects might be toxicologic effects mediated by sarin, but the committee believes that those effects are more likely emotional and physiologic responses to psychologic trauma. Many different traumatic exposures not related to sarin were also associated with PTSD in the Gulf War veterans. Data on experimental animals, especially from studies by Henderson et al. (2001, 2002), which were designed to mimic the potential exposures in the Gulf War, have demonstrated changes in muscarinic receptor density in specific brain areas. Those data are an important step in determining whether a biologically plausible mechanism could underlie any long-term effects of low exposure to chemical nerve agents, but more work needs to be conducted to elucidate potential mechanisms and clarify how the cellular effects are related to any clinical effects that might be seen. Therefore, in the absence of carefully designed human studies expressly of sarin’s or cyclosarin’s long-term health effects at doses that do not produce acute signs and symptoms, the committee concludes that the data remain inadequate or insufficient to determine whether persistent long-term effects are associated with low-level sarin exposure.

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Gulf War and Health: Updated Literature Review of Sarin CARDIOVASCULAR EFFECTS Persistent cardiovascular effects have been reported after the sarin attacks in Japan and in veterans of the Gulf War. A cardiovascular effect (sudden palpitation) was noted up to 6 months after the Tokyo sarin attack (Kawana, 2001), and an English-language abstract of a study of Matsumoto attack survivors discussed electrocardiographic (ECG) effects (Nohara et al., 1999). In other studies, however, 6–8 months after the Tokyo attack no changes in ECG were evident in people who recovered from an acute poisoning episode (Murata et al., 1997, Yokoyama et al., 1998a,b,c). In a study of military deployed during the time of Khamisiyah, Smith et al. (2003) found 1 of 10 specific cardiac diagnoses (cardiac dysrhythmia) to be more frequent in the exposed than in nonexposed people. Other studies of veterans showed various cardiovascular effects, but only for deployed versus nondeployed veterans, with no analysis for exposure to sarin (McCauley et al., 2002). The present committee concluded that: There is inadequate/insufficient evidence to determine whether an association does or does not exist between exposure to sarin and subsequent long-term cardiovascular effects. As discussed above, reports of persistent cardiovascular effects after the sarin attacks in Japan have been inconsistent. Only one study of military deployed during the time of Khamisiyah showed cardiovascular effects. On the basis of those data, the committee concluded that the data are inadequate or insufficient to determine whether an association exists. Furthermore, the cardiovascular effects of sarin and related compounds have not been studied to any great extent in animals to determine their biological plausibility. OTHER HEALTH EFFECTS A number of other health effects have been seen in people potentially exposed to sarin. Some are established disorders, and others are groups of symptoms that have been clustered into syndromes or illnesses. The presence of multisymptom illness, Gulf War illness, or unexplained illness and their relationship to possible indicators of exposure to CW agents have been studied in Gulf War veterans. Gray et al. (2002) found a case of Gulf War illness associated with “use of gas masks”, Nisenbaum et al. (2000) found that responding yes to “thought biological or chemical weapons were being used” was associated with meeting the criteria for a severe or mild-to-moderate case of multisymptom illness, and Wolfe et al. (2002) found an association between high frequency of “placement on formal alert for chemical and biological warfare” and mild-to-moderate or severe multisymptom illness. Reid et al. (2001) found the prevalence of multiple chemical sensitivity to be associated with hearing chemical alarms and self-

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Gulf War and Health: Updated Literature Review of Sarin reports of having a chemical or nerve-gas attack. The prevalence of chronic fatigue syndrome was associated with hearing chemical alarms. There is too little information for the committee to draw conclusions on any of those health outcomes in relation to sarin exposure. REFERENCES Asukai N, Kato H, Kawamura N, Kim Y, Yamamoto K, Kishimoto J, Miyake Y, Nishizono-Maher A. 2002. Reliability and validity of the Japanese-language version of the impact of event scale-revised (IES-R-J): Four studies of different traumatic events. Journal of Nervous and Mental Disease 190(3):175–182. Baker DJ, Sedgwick EM. 1996. Single fibre electromyographic changes in man after organophosphate exposure. Human and Experimental Toxicology 15(5):369–375. Baker DG, Mendenhall CL, Simbartl LA, Magan LK, Steinberg JL. 1997. Relationship between posttraumatic stress disorder and self-reported physical symptoms in Persian Gulf War veterans. Archives of Internal Medicine 157(18):2076–2078. Burchfiel JL, Duffy FH. 1982. Organophosphate neurotoxicity: Chronic effects of sarin on the electroencephalogram of monkey and man. Neurobehavioral Toxicology and Teratology 4(6):767–778. Duffy FH, Burchfiel JL, Bartels PH, Gaon M, Sim VM. 1979. Long-term effects of an organophosphate upon the human electroencephalogram. Toxicology and Applied Pharmacology 47(1):161–176. Fullerton CS, Ursano RJ. 1990. Behavioral and psychological responses to chemical and biological warfare. Military Medicine 155(2):54–59. Goss Gilroy Inc. 1998. Health Study of Canadian Forces Personnel Involved in the 1991 Conflict in the Persian Gulf, Vol. 1. Ottawa, Ontario: Goss Gilroy Inc. Prepared for the Department of National Defence. Gray GC, Kaiser KS, Hawksworth AW, Hall FW, Barrett-Connor E. 1999. Increased postwar symptoms and psychological morbidity among US Navy Gulf War veterans. American Journal of Tropical Medicine and Hygiene 60(5):758–766. Gray GC, Reed RJ, Kaiser KS, Smith TC, Gastanaga VM. 2002. Self-reported symptoms and medical conditions among 11,868 Gulf War-era veterans: The Seabee Health Study. American Journal of Epidemiology 155(11):1033–1044. Haley RW, Kurt TL. 1997. Self-reported exposure to neurotoxic chemical combinations in the Gulf War. A cross-sectional epidemiologic study. Journal of the American Medical Association 277(3):231–237. Henderson RF, Barr EB, Blackwell WB, Clark CR, Conn CA, Kalra R, March TH, Sopori ML, Tesfaigzi Y, Menache MG, Mash DC, Dokladny K, Kozak W, Kozak A, Wachulec M, Rudolph K, Kluger MJ, Singh SP, Razani-Boroujerdi S, Langley RJ. 2001. Response of F344 rats to inhalation of subclinical levels of sarin: Exploring potential causes of Gulf War illness. Toxicology and Industrial Health 17(5–10):294–297. Henderson RF, Barr EB, Blackwell WB, Clark CR, Conn CA, Kalra R, March TH, Sopori ML, Tesfaigzi Y, Menache MG, Mash DC. 2002. Response of rats to low levels of sarin. Toxicology and Applied Pharmacology 184(2):67–76. IOM (Institute of Medicine). 2000. Gulf War and Health, Volume 1: Depleted Uranium, Pyridostigmine Bromide, Sarin, and Vaccines. Washington, DC: National Academy Press. IOM. 2003. Gulf War and Health, Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press.

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Gulf War and Health: Updated Literature Review of Sarin Proctor SP, Heeren T, White RF, Wolfe J, Borgos MS, Davis JD, Pepper L, Clapp R, Sutker PB, Vasterling JJ, Ozonoff D. 1998. Health status of Persian Gulf War veterans: Self-reported symptoms, environmental exposures and the effect of stress. International Journal of Epidemiology 27(6):1000–1010. Reid S, Hotopf M, Hull L, Ismail K, Unwin C, Wessely S. 2001. Multiple chemical sensitivity and chronic fatigue syndrome in British Gulf War veterans. American Journal of Epidemiology 153(6):604–609. Smith TC, Gray GC, Weir JC, Heller JM, Ryan MA. 2003. Gulf War veterans and Iraqi nerve agents at Khamisiyah: Postwar hospitalization data revisited. American Journal of Epidemiology 158(5):457–467. Suadicani P, Ishoy T, Guldager B, Appleyard M, Gyntelberg F. 1999. Determinants of long-term neuropsychological symptoms. Danish Medical Bulletin 46(5):423–427. Sutker PB, Uddo M, Brailey K, Allain AN, Errera P. 1994. Psychological symptoms and psychiatric diagnoses in Operation Desert Storm troops serving grave registration duty. Journal of Traumatic Stress 7(2):159–171. Unwin C, Blatchley N, Coker W, Ferry S, Hotopf M, Hull L, Ismail K, Palmer I, David A, Wessely S. 1999. Health of UK servicemen who served in the Persian Gulf War. Lancet 353(9148):169–178. Weiss DS, Marmar CR, Metzler TJ, Ronfeldt HM. 1995. Predicting symptomatic distress in emergency services personnel. Journal of Consulting and Clinical Psychology 63(3):361–368. White RF, Proctor SP, Heeren T, Wolfe J, Krengel M, Vasterling J, Lindem K, Heaton KJ, Sutker P, Ozonoff DM. 2001. Neuropsychological function in Gulf War veterans: Relationships to self-reported toxicant exposures. American Journal of Industrial Medicine 40(1):42–54. Wolfe J, Proctor SP, Davis JD, Borgos MS, Friedman MJ. 1998. Health symptoms reported by Persian Gulf War veterans two years after return. American Journal of Industrial Medicine 33(2):104–113. Wolfe J, Proctor SP, Erickson DJ, Hu H. 2002. Risk factors for multisymptom illness in US Army veterans of the Gulf War. Journal of Occupational and Environmental Medicine 44(3):271–281. Yokoyama K, Araki S, Murata K, Nishikitani M, Okumura T, Ishimatsu S, Takasu N. 1998a. A preliminary study on delayed vestibulo-cerebellar effects of Tokyo Subway sarin poisoning in relation to gender difference: Frequency analysis of postural sway. Journal of Occupational and Environmental Medicine 40(1):17–21. Yokoyama K, Araki S, Murata K, Nishikitani M, Okumura T, Ishimatsu S, Takasu N. 1998b. Chronic neurobehavioral and central and autonomic nervous system effects of Tokyo subway sarin poisoning. Journal of Physiology, Paris 92(3-4):317–323. Yokoyama K, Araki S, Murata K, Nishikitani M, Okumura T, Ishimatsu S, Takasu N, White RF. 1998c. Chronic neurobehavioral effects of Tokyo subway sarin poisoning in relation to posttraumatic stress disorder. Archives of Environmental Health 53(4):249–256.

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