3
Human Health Outcome Studies

This chapter focuses on epidemiologic studies that were not reviewed in Gulf War and Health: Volume 1, hereafter referred to as GW1 (IOM, 2000). 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, Iraq, and a number of studies that evaluate the relationship between symptoms and possible exposures, including to sarin or cyclosarin, on the basis of a self-reporting questionnaire. Studies reviewed in GW1 (IOM, 2000) are briefly reviewed to provide a complete picture of the available data. This chapter reviews and critiques those studies. The data from those studies are summarized by health outcome in Chapter 4.

A major limitation of most human studies of the health effects of sarin is a lack of exposure information. Most studies of sarin were undertaken after occupational accidents or terrorist attacks, and the magnitudes of exposures can only be inferred from clinical effects. High exposure is inferred from the presence of the acute cholinergic syndrome (see Chapter 2 for description) that requires hospitalization or emergency treatment. Intermediate exposure is inferred from minimal or threshold cholinergic effects (miosis or rhinorrhea) and a small decrease (less than 20%) in blood cholinesterase activity. Low exposure is inferred from proximity to a documented exposure and the absence of clinically detectable



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Gulf War and Health: Updated Literature Review of Sarin 3 Human Health Outcome Studies This chapter focuses on epidemiologic studies that were not reviewed in Gulf War and Health: Volume 1, hereafter referred to as GW1 (IOM, 2000). 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, Iraq, and a number of studies that evaluate the relationship between symptoms and possible exposures, including to sarin or cyclosarin, on the basis of a self-reporting questionnaire. Studies reviewed in GW1 (IOM, 2000) are briefly reviewed to provide a complete picture of the available data. This chapter reviews and critiques those studies. The data from those studies are summarized by health outcome in Chapter 4. A major limitation of most human studies of the health effects of sarin is a lack of exposure information. Most studies of sarin were undertaken after occupational accidents or terrorist attacks, and the magnitudes of exposures can only be inferred from clinical effects. High exposure is inferred from the presence of the acute cholinergic syndrome (see Chapter 2 for description) that requires hospitalization or emergency treatment. Intermediate exposure is inferred from minimal or threshold cholinergic effects (miosis or rhinorrhea) and a small decrease (less than 20%) in blood cholinesterase activity. Low exposure is inferred from proximity to a documented exposure and the absence of clinically detectable

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Gulf War and Health: Updated Literature Review of Sarin cholinergic signs or symptoms or detectable change in blood cholinesterase activity (Brown and Brix, 1998). Although there were no medical reports at the time of the release at Khamisiyah that were consistent with the signs and symptoms of acute exposure to sarin (PAC, 1996), there is concern that exposure of US troops during the Gulf War might have occurred. The level of exposure would have been insufficient to produce the acute cholinergic syndrome. Therefore, this chapter reviews available human studies, focusing mainly on epidemiologic studies of the long-term health effects of sarin, and is organized by study population. Relatively few studies have looked at the long-term health effects of low-dose exposure to sarin or cyclosarin, but a number of epidemiologic studies have been conducted on organophosphorus (OP) insecticides, which have some common mechanisms of action. The health effects of those insecticides are reviewed in Gulf War and Health: Volume 2 (IOM, 2003), and the conclusions of that report and epidemiologic studies that have been published since that report was prepared are discussed in Appendix A. INTENTIONALLY EXPOSED MILITARY VOLUNTEERS In the past, military authorities (including those of the US and the UK) have conducted dosing studies of chemicals in healthy servicemen who volunteer after being informed of the protocol and risks involved. Although questions remain regarding the ethics of such studies and their ethical acceptability by current standards, such studies have been conducted in the past with servicemen voluntarily exposed to sarin and other chemical-warfare agents. The studies are reviewed in this section, and those published since the preparation of GW1 are summarized in Table 3-1. US Military Studies From 1958 to 1975, the US Army studied nearly 7,000 servicemen who had voluntarily agreed to be exposed to an array of chemical-warfare agents at Edgewood Arsenal, Maryland. At the request of the Army, the Medical Follow-up Agency (MFUA; now part of the Institute of Medicine) of the National Research Council designed and conducted two studies of the long-term health effects of those exposures. The first, a followup at least 10 years after exposure (NRC, 1985), was described in GW1 (IOM, 2000). The study examined current health status and hospital admissions to military or Veterans’ Administration hospitals. In that survey, the subgroup exposed to a variety of anticholinesterases as a class had no long-term health consequences of exposure, but the study had low statistical power and other methodologic problems acknowledged by the authors. Since the preparation of GW1 (IOM, 2000), MFUA conducted a second

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Gulf War and Health: Updated Literature Review of Sarin study using a survey almost identical with the 1985 one (Page, 2003). The study, which was conducted at least 25 years after the end of the testing program, included a mortality study and a telephone survey of 4,022 members of the program. The survey was designed to assess neuropsychologic, neurologic, and vestibular symptoms possibly related to anticholinesterase exposure in the three exposure groups: a group exposed to anticholinesterase, a group exposed to two or more nonanticholinesterase agents (such as, scopolamine and atropine), and a nonexposed group that at the program’s inception was ineligible for participation because of low scores on general intelligence tests and the Minnesota Multiphasic Personality Inventory. The anticholinesterase-exposed group was exposed to at least one of 15 anticholinesterase agents, the most common being Agent VX (n = 740), sarin (n = 246), and eserine (physostigmine, n = 138). Exact doses are not known, but in an appendix to the 2003 study, the authors note that their review of original records found 17 of 25 sarin-exposed servicemen to have experienced the acute cholinergic syndrome. The authors were unable to assemble a sarin-only group because three-fourths of the original sample of 246 either had died (n = 67) or had unusable dose data. As noted earlier, a mortality study was also conducted. There were no statistically significant differences among the three groups in overall health, disability, reproductive history, and psychologic symptoms after adjustment for age, initial fitness, race, and chemical exposures outside the program. However, MFUA believed that, because of selection bias, the nonexposed group was less healthy than the anticholinesterase-exposed group, whereas the nonanticholinesterase group was likely to be healthier. Only sleep disturbances were more prevalent in the anticholinesterase group than in the nonexposed group (sleep disturbances score, 0–9; mean difference, +0.28; 95% CI did not include 1). Attention problems were reported less frequently in the anticholinesterase group than in the nonanticholinesterase group. There was, however, significantly lower all-cause mortality in the anticholinesterase group than in the nonexposed group (relative risk [RR] for all-cause mortality, 0.82; 95% CI, 0.68–0.99). There were no mortality differences for specific conditions, such as suicide, accidental deaths, cancer, and heart disease. Although the results of the study show no association, it is somewhat uninformative for the purpose of this committee because of the lack of dose information, the fact that the nonexposed control group was likely to be less healthy, and the mixed nature of the exposures analyzed (there was no analysis of a sarin-only group). UK Military Studies In an uncontrolled study of UK servicemen who volunteered to be exposed to sarin (sarin vapors at 15 mg/min-m3, in 1983–1984) and displayed some signs of the acute cholinergic syndrome (Baker and Sedgwick, 1996; discussed in IOM, 2000), the authors interpreted an increased jitter 3 h after exposure and still

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Gulf War and Health: Updated Literature Review of Sarin TABLE 3-1 Non-Gulf War Veteran Studies of Sarin Not Discussed in Gulf War and Health: Volume 1 Reference Type of Study and Study Population Exposure Determination Health Outcome, and How and When Measured Page, 2003 Follow-up study of military volunteers for 1955–1975 Edgewood, Maryland, program; one group with anticholinesterase exposure (n = 1,339) vs exposed to two or more nonanticholinesterase agents (n = 1,359) vs no chemical test (nonexposed) (n = 1,324) Military deliberately administered 250 agents, including sarin, cyclosarin, and 13 other anticholinesterases; doses not carefully recorded; sarin doses may have ranged from 3.0 to 4.0 µg/kg Mortality records from VA and Social Security Administration, survey of neuropsychologic impairment, illness attitudes, peripheral nerve disease, vestibular dysfunction, sleep disorders, and reproductive history. Surveys conducted at least 25 years after exposures Nishiwaki et al., 2001 56 exposed rescue workers and police officers vs 52 nonexposed matched controls in same departments High- and low-exposure group from self-reports of hospitalizations vs outpatient treatment Five neurobehavioral tests, stabilometry, vibration perception, and IES-R-J and general health questionnaire conducted 3 years after exposure Kawana et al., 2001 Follow-up of 582 patients treated at St. Luke’s hospital in Toyko at 2, 3, and 5 years No control group Not clear from study 33-item mailed questionnaire at three times (1997, 1998, 2000; 2, 3, and 5 years after exposure) covering physical and psychologic symptoms related to sarin; PTSD assessed three ways Abbreviations: IES-R-J, Impact of Event Scale; PTSD, posttraumatic stress disorder; SES, socioeconomic status.

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Gulf War and Health: Updated Literature Review of Sarin Results Adjusted RR or OR (95% CI or p) Limitations No excess mortality from particular conditions, but less mortality from all causes in anticholinesterase-exposed than unexposed; fewer attention problems in anticholinesterase-exposed vs other warfare agents; greater sleep disturbances than nonexposed RR for all-cause mortality 0.89 in anticholinesterase-exposed vs nonexposed (95% CI, 0.68–0.99) Lack of dose information and inability to assemble a sarin-only cohort Dose–effect relationship with backward digit span memory performance, using multiple logistic regression, and findings independent of trauma symptoms; adjusted tapping interval for dominant hand worse in high-exposed group than controls; stabilometry measures with eyes open significantly worse in low-exposed group than controls, but no dose effect Backward digit span: high-dose adjusted OR, 3.19 (95% CI, 1.06–10.38) and low-dose OR, 1.17 (95% CI, 0.42–3.23) Not clear whether medical-record check conducted to verify self-reported level of exposure Most-frequent symptoms: eye symptoms (tiredness of eyes, dim vision, difficulty focusing), tiredness, fatigue, stiff muscles, headache, depressed mood; prevalence (1997, 1998, 2000): DSM-IV PTSD (2.8, 2.9, 2.1%); partial PTSD (7.1, 7.3, 8.4%), PTSD–Nakano (12.4, 9.7, 14.1%)   No control group, low response rate, methods of dose determination or subject selection not reported

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Gulf War and Health: Updated Literature Review of Sarin apparent 1 year but not 2 years after exposure as a possible indicator of the intermediate syndrome (see Chapter 2). (Jitter is a variation in time of onset of second action potential within motor unit after initial discharge. It is one indication of potential failure of transmission at the neuromuscular junction.) The intermediate syndrome itself did not occur. No studies of UK veterans have been published since the preparation of GW1. ACCIDENTALLY EXPOSED INDUSTRIAL WORKERS In the first controlled study of long-term central nervous system (CNS) effects in workers accidentally exposed to sarin, researchers compared electroencephalographic (EEG) activity in workers at a manufacturing plant known to have been accidentally exposed to sarin (n = 77) with activity in nonexposed controls at the same plant (n = 38) (Duffy et al., 1979; Burchfiel and Duffy, 1982). Exposed workers had not been exposed within a year of the study, but had had one or more exposure incidents (clinical signs and at least a 25% inhibition of red-cell cholinesterase activity) within the previous 6 years. Although some differences in EEG results were seen, the clinical significance of the changes was not clear. Exposed workers also reported increased dreaming, instances of irritability, disturbed memory, and difficulty in maintaining alertness and attention (Burchfiel and Duffy, 1982), but methodologic details of symptom reporting were not provided. No studies of people accidentally exposed to sarin in industrial accidents have been published since the preparation of GW1. JAPANESE TERRORIST ATTACKS Matsumoto In 1994, Japanese terrorists spread sarin vapor with a heater and fan mounted on a truck in a residential neighborhood near the center of Matsumoto, Japan (Nakajima et al., 1997). About 600 people (residents and rescue teams) developed the acute cholinergic syndrome; 253 sought medical assistance, 58 were admitted to hospitals, and 7 died. Several case reports, case series, and a population-based epidemiologic study conducted after that attack were described in GW1 (IOM, 2000). One of the case series found that four of six severely poisoned patients displayed visual-field defects, hypoxia, low-grade fever, and what were described as “epileptic electroencephalographic changes” up to 2 years after exposure (Sekijima et al., 1997). At 7 months after exposure, one patient also developed sensory polyneuropathy and reduced sensory-nerve conduction velocity, but the characteristics are not consistent with classic organophosphate-induced delayed neuropathy (OPIDN) (IOM, 2000). The population-based study

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Gulf War and Health: Updated Literature Review of Sarin used mailed questionnaires and identified symptoms that persisted up to 3 years after exposure (odds ratios were highest for fatigue, headache, and the visual disturbances asthenopia, blurred vision, and narrowing of visual field) among those closest to the site of sarin release (Nakajima et al., 1998, 1999). Since the preparation of GW1, a non-English-language study with an English abstract (Nohara, 1999) had reported detailed ophthalmologic tests, EEG results, and electrocardiographic (ECG) test results in people living close to the site of sarin release 45 months after the attack. The abstract does not state the number of subjects or how cases were ascertained. Findings reported in the abstract include visual-field constriction, posttraumatic stress disorder (PTSD), and abnormal EEG and ECG readings up to 45 months after the attack. Tokyo On March 20, 1995, terrorists released diluted sarin vapor simultaneously into three converging lines of the Tokyo subway system. About 1,000 people were symptomatic after the attack, and 12 died. GW1 (IOM, 2000) described in detail the findings of several epidemiologic studies conducted months after the attack. Those studies were of patients who had been seen at the hospital that treated the largest number of patients (n = 641), St. Luke’s International. About 83% had intermediate exposure and 17% had high exposure, on the basis of symptom profiles and as verified by more than a 20% decrease in blood cholinesterase activity. Detailed neurophysiologic and neuropsychologic testing was conducted several months later on 18 symptom-free survivors with previous intermediate or high exposure. By symptom-free, the authors meant absence of obvious ophthalmologic, cardiovascular, neurologic or other confounding disorders, such as ischemic heart disease, multiple sclerosis, diabetes, or alcohol dependence. Cholinesterase, measured in 13 of the 18 survivors, had returned to normal. The studies described in GW1 (IOM, 2000) found the 18 to have significantly more symptoms of PTSD, impaired performance on one (the digit-symbol test) of nine neurobehavioral tests, and significant changes in event-related potential, visual-evoked potential, and postural sway testing (Murata et al., 1997; Yokoyama et al., 1998a,b,c). Studies published since the preparation of GW1 (IOM, 2000) are summarized in Table 3-1 and are discussed below. Yokoyama et al. (2002) have published further information on the health of survivors. The investigators previously had reported, in a study evaluated in GW1, that 6–8 months after the attacks female (n = 9), but not male, survivors with confirmed intermediate or high exposure had abnormal findings on computerized posturography (Yokoyama et al, 1998a). The more recent study compares the computerized posturography data on the nine sarin-poisoned females and matched controls of the earlier study with those on cohorts exposed to lead or solvents to clarify which of the cerebellar pathways is most affected. This study, however, is not as useful for determining the effects of sarin, in that it reports

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Gulf War and Health: Updated Literature Review of Sarin only the results in the sarin-poisoned females that were previously reported (Yokoyama et al., 1998a). Nishiwaki et al. (2001) compared neurophysiologic performance 3 years after the Tokyo attack in 56 exposed men in rescue teams (fire department rescue workers and police) with that in 52 nonexposed controls matched for age and occupation in the same departments. Rescue workers responding at the site were unaware of the sarin release and did not wear protective gear. Exposed workers were divided into high-exposure and low-exposure groups, on the basis of self-reports of hospitalization or outpatient treatment, respectively. Although the authors report that they “check[ed] the self administered questionnaire”, it is unclear from the publication whether they used medical records to verify self-reports about the site of treatment. Exposed and nonexposed groups were evaluated with five neurobehavioral tests (finger-tapping test for dominant and nondominant hands, simple reaction time, choice reaction time, backward digit span, and Benton Visual Retention), stabilometry, vibration perception, and two questionnaires (the Japanese-language version of the Impact of Events Scale-Revised (IES-R-J) and the General Health Questionnaire). With multiple logistic regression, a dose-effect relationship was found for the backward-digit-span test, which is a test of attention and concentration. The mean maximal digit number was 4.24 ± 0.72 and 4.69 ± 1.37 in the high- and low-exposure group, respectively. Those results, however, do not appear to be of clinical significance. The finding was independent of trauma symptoms from the IES-R-J. Adjusted tapping interval for dominant hand was worse in the high-exposure group than in controls, and stabilometry measures with eyes open were significantly worse in the low-exposure group than in controls, but no dose-effect relationship was found for those end points. Scores on the IES-R-J and the General Health Questionnaire were higher in both exposed groups than in controls, but the difference was not statistically significant. Although the results of the study are intriguing, the result of only one test or a small number of tests (three) was affected, and further study of neurophysiologic performance is needed. Kawana et al. (2001) reports on results of a 33-item questionnaire of physical and psychologic symptoms mailed at three times—1997, 1998, and 2000—to 582 patients who had been treated at St. Luke’s International Hospital on the day of the sarin attack. The relationship of this cohort to a cohort of 610 patients surveyed by the same hospital 1, 3, and 6 months after the attack (Ohbu et al., 1997) is unclear. According to Kawana et al. (2001), the Ohbu et al. (1997) study found 60% of respondents reporting symptoms of PTSD. Kawana et al. (2001) did not have a control population, although it did compare its findings on PTSD with those from other studies of Tokyo and Matsumoto sarin attacks, and the response rate was low (49% in 1997, 35% in 1998, and 32.8% in 2000). The investigators applied symptom-based criteria for PTSD with three sets of criteria: DSM-IV, “partial PTSD” (one symptom from each PTSD symptom cat-

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Gulf War and Health: Updated Literature Review of Sarin egory of avoidance, hyperarousal, and re-experience), and a new method, “PTSD-Nakano”, named after the Japanese researcher who revised PTSD diagnostic criteria “to require at least one physical symptom in addition to one avoidance symptom, and one hyperarousal or one re-experiencing symptom.” No validation or reference is provided for the third category. The most frequently reported symptoms, reported by more than 15% of respondents in all years, were ocular symptoms (tiredness of eyes, dim vision, and difficulty focusing), tiredness, fatigue, stiff muscles, and headache. Depressed mood was reported by 13%, 24%, and 17% of respondents in 1997, 1998, 2000, respectively—showing a significant change over time. Depressed mood was one of the few symptoms that changed significantly over the 5-year period. The prevalence of symptoms was comparable with rates reported in other studies of Japanese survivors of sarin attacks. The prevalence of PTSD (DSM-IV), partial PTSD, and PTSD-Nakano ranged from 2.1–2.9%, 7.1–8.4%, and 9.7–14.1%, respectively, depending on the questionnaire year. Asukai et al. (2002) studied the reliability and validity of a Japanese-language version of the IES-R-J. That scale has been validated in the United States for assessing magnitude of traumatic-stress exposure for a potential PTSD diagnosis, but little such research has been conducted in non-Western countries. The scale contains 22 items grouped into clusters of symptoms for diagnosing PTSD (hyperarousal, avoidance, and intrusion). Survivors of the Tokyo sarin attack made up one of four groups (workers with lifetime mixed traumatic events, survivors of an arsenic poisoning case, and survivors of the Hanshin-Awaji earthquake made up the other three) in which the new instrument was studied. It is not clear how many people were sent the survey, but investigators report that 658 survivors replied, a substantial number of whom were litigants (the exact number was not reported). The year of the survey was not reported, but a later book chapter by the authors states that the survey was conducted 5 years after the Tokyo attack (Asukai and Maekawa, 2002). The prevalence of high scorers on the IES-R-J in the Tokyo group was 24.6% of males and 35.8% of females, which are within the range of the other three Japanese groups studied. Two of those other groups were also given clinical examinations with the PTSD module of the Structural Clinical Interview for DSM-III-R and the Clinical Administered PTSD Scale. In those clinical evaluations, PTSD was diagnosed in 9–16% of subjects. GULF WAR VETERANS After the Gulf War, veterans reported higher rates of fatigue, headache, pain, and cognitive symptoms than did nondeployed military personnel, according to numerous population-based studies in the United States (Iowa Persian Gulf Study Group, 1997; Kang et al., 2000), the United Kingdom (Unwin et al., 1999; Cherry et al., 2001), Canada (Goss Gilroy Inc., 1998), and Denmark (Suadicani et al., 1999). Veterans’ symptoms or symptom clusters have been characterized as “un-

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Gulf War and Health: Updated Literature Review of Sarin explained illnesses” because they do not fit established diagnoses. Health outcomes in the studies were not restricted to established diagnoses, they could be symptoms, sets of symptoms, syndromes, or diagnoses. More than 20 exposures in the Gulf War, from vaccines to nerve agents, have been studied in relation to veterans’ symptoms. This section examines a set of those exposures that are relevant to sarin. Specifically, it examines the nature and quality of the evidence regarding associations between any health effect in veterans and any possible exposure related to sarin, including nerve agents at Khamisiyah, hearing of chemical-weapon alarms, and wearing of chemical-protection gear. Most studies summarized here have been evaluated in previous IOM volumes because they covered multiple exposures (IOM, 2000, 2003); because of their mandates, past IOM committees’ evaluations focused on separate exposures. Most studies of Gulf War veterans were designed to detect the nature and prevalence of veterans’ symptoms and illnesses and whether they constituted a new syndrome rather than specifically to assess the effects of exposure to particular agents of interest. When the effects of exposure to various agents were assessed, numerous potential agents were evaluated in the same study. Most of the veteran health studies were cross-sectional and were conducted years after the war. Cross-sectional studies limit opportunities to learn about symptom duration and latency of onset; outcomes and exposure to various agents were measured simultaneously after the Gulf War had ended (IOM, 2000). Most Gulf War studies relied on self-reports of exposure, and in most cases the self-reports came years after the end of the war. Most studies did not identify specific environmental agents. Because the studies used self-reported data generally gathered years after the events in question, there is a strong possibility of recall bias—that is, veterans with symptoms would be more likely than those without symptoms to recall exposure. Only one cohort was studied soon after the war and then longitudinally (Proctor et al., 1998). Further, self-reports can be unreliable. A study by McCauley et al. (1999) found low test–retest reliability for the belief in exposure to chemical warfare when veterans responded to the same exposure questions 3 months apart. In addition, symptoms reported in cross-sectional studies do not necessarily represent accurately the total symptom experience after an exposure. Most of the studies relied on symptom self-reports elicited via questionnaire or structured interview. Several approaches were taken to combine reported symptoms into outcome variables. One approach was to use factor analysis to uncover an underlying structure in reported symptoms (Haley and Kurt, 1997; Fukuda et al., 1998; Cherry et al., 2001). A second approach attempted to match symptoms in some way to previously defined syndromes or illnesses (Iowa Persian Gulf Study Group, 1997; Unwin et al., 1999; Nisenbaum et al., 2000). In some cases, previously validated instruments were used. In others, symptoms were assembled into established syndromes on the basis of criteria devised by the investigators; sub-

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Gulf War and Health: Updated Literature Review of Sarin jects who did not meet the criteria of established syndromes or diagnoses were said to have nonexplained symptoms that could be related to a Gulf War exposure. Other studies did not attempt a synthesis of any sort but searched for associations between exposures to various agents during the Gulf War and individual symptoms. Another limitation of Gulf War studies was the problem of multiple comparisons between exposure to numerous agents and health outcomes. When investigators examine a large number of exposure–symptom associations, the chances of reporting a spurious association as statistically significant (a type I error) are increased. Some Gulf War studies took a wide variety of statistical approaches to adjust for the problem of multiple comparisons. However, many did not account for the problem and reported as statistically significant any association with a p value of 0.05 or less. In some of those studies, the investigators did not adjust for multiple comparisons because of the exploratory nature of the study and because of their desire to reduce the probability of not finding a true association (a type II error). Other investigators were more conservative and set a more stringent significance level to reduce the probability of a type I error (Haley and Kurt, 1997; Cherry et al., 2001; White et al., 2001). Many studies noted that many agents were associated with the outcomes they measured, but only one attempted to examine the association between specific agents and found them to be strongly correlated (Cherry et al., 2001). The remainder of this section discusses the studies of Gulf War veterans that are relevant to sarin exposure. The discussion is divided into two parts: a discussion of studies on troops who were determined, because of their unit locations, to have been potentially exposed to sarin after the weapons demolition at Khamisiyah; and a discussion of studies that examine a number or symptoms of health outcomes in relation to numerous self-reported exposures. Those studies are summarized in Table 3-2. Studies of Veterans Potentially Exposed at Khamisiyah As discussed in Chapter 1, it is estimated that almost 100,000 US troops were potentially exposed to low concentrations of sarin and cyclosarin released from the US military demolition of hundreds of rockets at Khamisiyah, Iraq, on March 10, 1991. Troops performing demolitions were unaware of the presence of nerve agent because their alarms, which are sensitive to lethal or near-lethal concentrations of sarin, did not sound. The total amount of chemicals released, according to the most recently published estimates, is 371 kg of sarin and cyclosarin (Winkenwerder, 2002). None of the troops had the acute cholinergic syndrome, according to the US Army Medical Corps and a later survey of 20,000 veterans, but the possibility of low, asymptomatic exposures cannot be discounted. Different methods have been used to estimate possible troop exposures to sarin. Initially, approximately 100,000 soldiers were notified that they might

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Gulf War and Health: Updated Literature Review of Sarin Ishoy et al. (1999b) studied gastrointestinal (GI) symptoms in Danish gulf-area veterans and matched controls. On a questionnaire, eight of 14 GI symptoms were reported significantly more frequently in veterans than in controls. After adjustment for the interrelationship of variables, only two of the eight GI symptoms remained significant: 1-year prevalence of recurrent diarrhea and rumbling in the stomach more than twice a week. Ishoy et al. (1999b) used both symptoms as the combined main GI outcome measure and investigated its relationship to numerous environmental exposures. In the gulf-area cohort, of 24 exposures reported in the article, only self-reported exposure to “nerve gas” is relevant to the present report, and it was not significantly associated with the main GI outcome measure in univariate and multivariate analyses. Spencer et al. (2001) conducted a nested case–control study of the exposure-symptom relationships in Gulf War veterans with unexplained illness (n = 241) and healthy Gulf War-deployed controls (n = 113) drawn from their population-based sample of 23,711 Gulf War veterans from Oregon or Washington state. Clinical evaluation was conducted to verify symptoms and to exclude known conditions that could explain them. The self-reported exposure questionnaire was reduced from 144 items to 44 items on the basis of test–retest reliability and other factors. Of the 44 exposures asked about, three are potentially relevant to the present report: “chemical decontamination bottles”, “inadequate protection during chemical/SCUD alarms”, and “worked around chemical-warfare agents”. Only answering yes to “inadequate protection during chemical/SCUD alarms” was found (with simple logistic regression) to be associated with unexplained illness defined by this research team (see McCauley et al., 1999 for description; OR, 2.39; 95% CI, 1.03–5.56) and by CDC’s case definition of multisymptom illness (OR, 3.16; 95% CI, 1.28–7.80). None of the three self-reported exposures that are potentially relevant to the present report was assessed in the multivariate analysis. The cases of unexplained illness defined in Spencer et al. (2001) have been followed up with neurobehavioral and other testing. Storzbach et al. (2000) found that subjects (n = 241) had small but statistically significant deficits on some neurobehavioral tests of memory, attention, and response speed and were significantly more likely to report increased distress and psychiatric symptoms than controls (n = 113). A later analysis focused on a subgroup of 30 of the 241 whose performance was slowest on the Oregon Dual Task Procedure (ODTP), a relatively new test of digit recognition that assesses motivation, attention, and memory (Storzbach et al., 2001). In comparison with other subjects, the “slow ODTP” group performed worse on other neurobehavioral tests of memory, attention, and reaction time but not on psychologic tests. None of those studies, however, examined symptoms in relation to any potential exposures in the Gulf War. Kang et al. (2000) conducted a large population-based cohort study of Gulf War veterans. Although they did not assess the relationship between any potential exposures and symptoms in that study (11,441 Gulf War veterans and 9,476

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Gulf War and Health: Updated Literature Review of Sarin non-Gulf War veterans who were in the military at the time of the war but were not deployed to the Gulf War), they have since investigated potential relationships between symptoms and possible exposures in two nested case–control studies (Kang et al., 2002, 2003). Kang et al. (2002) conducted factor analyses of 47 symptoms that were included in the earlier questionnaire (Kang et al., 2000) responded to by the cohort of Gulf War veterans (n = 10,423) and non-Gulf War veterans controls (n = 8,960) (participants with incomplete survey data were excluded from the analyses). The factor analyses were conducted in an attempt to identify one or more clusters of symptoms in the two groups. On the basis of the analyses, it was possible that a cluster of four symptoms—loss of balance or dizziness, speech difficulty, blurred vision, and tremors or shaking—made up a possible syndrome unique to veterans deployed to the Gulf. A group of 277 of the deployed veteran respondents (2.4%) and 43 of the non–Gulf War-deployed veterans (0.45%) met the case definition, reporting all four symptoms. The results of the analyses were then examined to determine which of 23 possible exposures based on self-reports were more common among the 277 Gulf War-deployed veterans who exhibited all four symptoms (cases) than among Gulf War veterans who lacked any of the four symptoms (controls; n = 6,730). Cases reported exposure to nine potential exposures on the questionnaire at a rate three or more times higher than Gulf War veterans who did not exhibit all four symptoms (controls). Self-reported exposure to “nerve gas” is the only one of those potential exposures relevant to the present report. Exposure to “nerve gas” was reported by 42.3% of deployed cases and 4.6% of deployed controls. In another nested case–control study, Kang et al. (2003) evaluated the prevalence of PTSD and CFS in the same cohort of Gulf War and non-Gulf War veterans discussed above and investigated whether the “extent of deployment-related stress” was related to either syndrome. Although “wore chemical protective gear (other than for training) or heard chemical alarms sounding” was one of three experiences3 that were used to define the high-stress group, the analyses were not reported with respect to the number of stressors present (0, 1, 2, or 3) and no data specific to “wore chemical protective gear (other than for training) or heard chemical alarms sounding” were presented. The study did find that an increased number of stressors was related, in a dose-related manner, to an increased likelihood of PTSD. Military-Unit-Based Studies A number of studies of veterans potentially exposed to sarin at Khamisiyah were discussed in GW1. In a series of studies of members of a naval battalion 3   The other two were “involved in direct combat duty” and “witnessed any deaths”.

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Gulf War and Health: Updated Literature Review of Sarin called to active duty for the Gulf War, Haley and Kurt (1997) found that veterans who believed themselves to have been exposed to chemical weapons4 were more likely to be classified as having “confusion–ataxia”, one of six new proposed syndromes, which features problems with thinking, disorientation, balance disturbances, vertigo, and impotence (Haley et al., 1997a). A follow-up study of vestibular function was performed on a subset of veterans who had the highest factor scores on three of the syndromes identified in 1997 by Haley and Kurt (Roland et al., 2000). The study was designed to probe the nature of veterans’ vestibular symptoms, rather than to examine the relationship between vestibular performance and exposure in the Gulf War. The study concluded that there was subjective and objective evidence of injury to the vestibular system in this group of Gulf War veterans with newly defined syndromes. Haley and Kurt (1997) hypothesized that those chronic syndromes represent variants of OPIDN. Haley et al. (1997a; see IOM, 2000) conducted factor analysis to define a potential cluster of veterans’ unexplained symptoms to define a unique syndrome. The analysis was conducted on data collected from reservists of the Naval Mobile Construction Battalion 24 (Seabees) who were called to active duty for the Gulf War and had worked in Saudi Arabia building airports, ammunition supply points, and roads. Of the 606 battalion members, 249 (41%) responded to the survey. Of the 249, 175 (79%) reported having had a serious health problem since returning from the Gulf War, and the other 74 (30%) reported having no serious health problems. A list of 22 major symptoms was developed from the major symptoms commonly associated with Gulf War illness in the clinical examinations performed by DOD and Veterans Administration (VA) physicians. Survey booklets were prepared that required a yes or no response for the presence of each of those symptoms. When veterans responded yes to having a major symptom, they were presented with a battery of 4 to 20 follow-up questions designed to define their exact symptoms (for example, to differentiate daytime sleepiness from muscle exhaustion after exercise when veterans reported “fatigue”). A factor analysis was done for each of the 22 major symptoms with the responses to the followup items. The result of that analysis was 51 “unambiguous symptom factors that appeared clinically meaningful”. Those 51 factors were converted to symptom scales, to which was added a 52nd scale to measure tinnitus. A second factor analysis was then conducted with the 52 symptom scales to attempt to cluster symptoms and define one or more Gulf War syndromes. Through that process, six syndromes were defined: impaired cognition, confusion–ataxia, arthromyoneuropathy, phobia–apraxia, fever–adenopathy, and weakness–incontinence. The distribution of the 249 veterans 4   On the basis of self-reports about their perceptions of chemical-warfare exposure rather than evidence of symptoms. Their location in relation to the Khamisiyah demolition site was not reported. The questionnaire was sent to participants in 1994, before the Department of Defense reported that chemical-weapons exposure could have occurred.

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Gulf War and Health: Updated Literature Review of Sarin on each of the six syndrome factor scales was plotted in a single scatter plot. Visual inspection of the distributions suggested that a factor score of 1.5 would be appropriate for dichotomizing each of the six factor scales. Any veteran scoring higher than 1.5 on a given factor scale was said to have a case of that “syndrome”. About one-fourth of the veterans (63) were classified as having one or more of the six syndromes. The first three syndromes had the strongest clustering of symptoms. Haley and Kurt (1997; see IOM, 2000) investigated the relationship between those symptom clusters and self-reported exposure to organophosphates and related chemicals that inhibit cholinesterase. Specifically, the relationship between the three “syndromes” identified as having the strongest clustering—(1) impaired cognition, (2) confusion–ataxia, and (3) arthromyoneuropathy (Haley et al., 1997a)—was examined. Exposures of veterans with syndrome 1 (12 veterans), 2 (21 veterans), or 3 (22 veterans) were compared with veterans in the same battalion who did not have the syndrome (controls). Some individuals had more than one syndrome. At the time of the initial data collection, investigators had asked 249 participants about their exposures via a detailed questionnaire on 18 potential exposures during the Gulf War. Those reporting an exposure were asked additional questions to elicit duration and dose of exposure, anatomic areas exposed, and other modifying information. One question, whether the veteran was exposed to “chemical-warfare agents”, is relevant to the present report. Each of the three syndromes was first screened against all the risk-factor variables in a univariate analysis. Adjusted step-wise logistic regressions were then performed with each syndrome to adjust for correlations between exposures. The p criterion was set at 0.005 because of the multiple comparisons performed. Exposure to “chemical-warfare agents” was associated with one of three newly defined syndromes, “confusion–ataxia” (RR, 7.8; 95% CI, 2.3–25.9). That particular syndrome featured problems with thinking, disorientation, balance, vertigo, and impotence. The investigators also found synergy between exposure to “chemical-warfare agents” and scores on a scale of adverse effects of pyridostigmine bromide for the confusion–ataxia syndrome. At least four additional studies by Haley and collaborators delineate further the nature of the neurotoxic deficit in veterans (n = 20–23) with syndrome 1, syndrome 2, or syndrome 3 (Haley et al., 1997b, 1999, 2000; Hom et al., 1997; Roland et al., 2000). None of those studies, however, examined the relationship between the presence of the syndromes and possible exposures during service in the Persian Gulf. Gray et al. (1999) assessed symptom–exposure relationships in Seabees but limited their cohort to active-duty Seabees (that is, they did not include reservists) who remained in the Navy at the time of the study. Both Gulf War-deployed Seabees and Seabees not deployed to the Gulf War were evaluated. The exposure questionnaire for the Seabees included a question about exposure to “chemical-warfare”. Self-reported exposure to “chemical-warfare” was greater in the Gulf

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Gulf War and Health: Updated Literature Review of Sarin War veterans than in the nondeployed veterans (OR, 3.1; 95% CI, 1.5–6.3; prevalence in Gulf War veterans, 3.2%). Further analysis of the symptom–exposure relationships, however, was limited to exposures with a prevalence of at least 5% or an OR of at least 3.0 to reduce the number of exploratory comparisons. Therefore, associations between symptoms and “chemical-warfare” exposure were not analyzed. Beginning in May 1997, Gray et al. (2002) conducted a larger investigation of all Gulf-War era Seabees, regardless of whether they were still in active service. Of the 18,945 eligible Seabees, 11,868 (63%) completed the questionnaire (3,831 Gulf War Seabees, 4,933 Seabees deployed elsewhere, and 3,104 nondeployed Seabees). Survey questionnaires covered health behaviors, self-reported physician-diagnosed illnesses, and self-reported persistent or recurring medical problems. Gulf War-deployed Seabees were also asked about 34 possible exposures in the Gulf War. Gulf War Seabees were more likely to be smokers or to have been smokers in the past, to report being in fair or poor health, to report all 33 self-reported persistent or recurring medical problems, and to report a variety of physician-diagnosed illnesses, particularly CFS, PTSD, MCS, and irritable bowel syndrome. There was a high correlation between those four multisymptom illnesses, high scores on the Cognitive Failures Questionnaire, and self-reporting of 12 or more medical problems. The investigators created a case definition of Gulf War illness: having one or more of the four self-reported physician-diagnosed multisymptom illnesses or at least 12 self-reported persistent or recurring medical problems. Of the Gulf War veterans, 22% met the case definition. The authors report that “no Seabees had been located under the atmospheric plume subsequent to the March 1991 destruction of munitions at the Khamisiyah site”, a statement for which they cited another of their studies (Gray et al., 1999). Using multivariate logistic regression, they found that 12 of 34 Gulf War-related exposures were associated with the case definition. One was relevant to the present report: “use of gas masks” (OR, 1.40; 95% CI, 1.07–1.84). Nisenbaum et al. (2000) used a nested case–control design to determine whether environmental exposures were associated with cases of chronic multisymptom illness versus Gulf War-deployed controls without the illness. Overall, 1,002 of 1,155 originally contacted veterans were surveyed, for a response rate of 87%. The 459 veterans who met case criteria were divided into “severe” and “mild–moderate” cases according to symptom severity. Of the six environmental exposures that were studied in the exposure section of the questionnaire, one was relevant to the present report: “thought biological or chemical weapons were being used”. Through logistic regression that adjusted for the presence of other exposures, that exposure was associated with meeting criteria for a severe case of multisymptom illness (OR, 3.46; 95% CI, 1.73–6.91) and a mild–moderate case (OR, 2.25; CI, 1.54–3.27). The symptom experience of Gulf War veterans from Massachusetts (Ft. Devens) and New Orleans was studied by Proctor and colleagues in a series of

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Gulf War and Health: Updated Literature Review of Sarin longitudinal studies. The original cohort included 2,949 troops from Ft. Devens and 928 from New Orleans; both groups consisted of active-duty, reserve, and National Guard troops deployed to the gulf. Studies were carried out in 1991, 1992–1993, and 1994–1996. The 1994–1996 study (Proctor et al., 1998) was the first to examine symptom–exposure relationships. The study’s nearly 300 subjects represented a stratified random sample of troops who had participated in an earlier survey, selected to give equal representation of higher and lower symptom reporters. The participation rates were 58% (Ft. Devens) and 85% (New Orleans) of those who participated in the earlier study and who could be located and contacted. The control group was 50 Gulf War-era veterans deployed to Germany (85% participation rate). Subjects were given symptom checklists (covering the previous 30 days), exposure questionnaires, and a neuropsychologic test battery and were interviewed about combat exposure and PTSD. Each of the 52 symptoms on the symptom checklist was assigned to one of nine body systems by four independent judges (an occupational-health physician, an environmental-health specialist, an environmental epidemiologist, and a neuropsychologist). A score was calculated for each body system, on the basis of the number of symptoms reported. The exposure questionnaire, given only to Gulf War-deployed subjects, contained eight items, one of which, self-reported “exposure to chemical or biological warfare (CBW) agents”, was relevant to the present report. Relationships between self-reported exposures and body-symptom scores were examined in the Gulf War-deployed cohort, and analyses were restricted to exposure–symptom pairs for which there was a supporting a priori hypothesis. In multiple regression—adjusting for age, sex, education, war-zone stressors, and PTSD diagnosis—self-reported exposure to CBW agents was significantly associated with musculoskeletal5 (p = 0.001), neurologic6 (p = 0.013), neuropsychologic7 (p = 0.009), and psychologic8 (p = 0.001) symptoms but not dermatologic symptoms, whether the exposure was evaluated individually or simultaneously with all other exposure variables in the regression model. The findings were unchanged when subjects who met criteria for PTSD were removed from analyses. White et al. (2001) also studied the cohort of Gulf War veterans from Massachusetts (Ft. Devens) and New Orleans. A total of 343 subjects participated in at least one part of the study: 293 Gulf War-deployed veterans and 50 Gulf War-era veterans deployed to Germany. Subjects were given a battery of neuropsychologic tests and an exposure questionnaire. The neuropsychological test battery covered 5   Joint pains, backaches, and neckaches or stiffness. 6   Headaches, numbness in arms or legs, and dizziness. 7   Difficulties in learning new material, difficulty concentrating, and confusion. 8   Inability to fall asleep, frequent periods of feeling depressed, and frequent periods of anxiety or nervousness.

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Gulf War and Health: Updated Literature Review of Sarin 52 measures involving seven functional domains: general intelligence, attention and executive function, motor ability, visuospatial processing, verbal and visual memory, mood, and motivation. The exposure questionnaire asked about eight environmental exposures, one of which, “exposure to chemical or biological warfare (CBW) agents”, was relevant to the present report. In regression analyses, Gulf War veterans exposed to CBW agents were more likely than nonexposed Gulf War veterans to have mood, memory, and cognitive deficits. In particular, their scores were significantly worse (p < 0.05) on profile of mood states, tension and confusion scales, and tests of recall memory (including the backward digit span test, WMS-R). The authors attempted to control for PTSD, depression, and other covariates in the analyses, however, the ability to control for those covariates in this situation is questionable. In a series of longitudinal studies of a cohort of Gulf War veterans from Massachusetts (Ft. Devens) in 1997, 1,290 subjects were given a 52-item health questionnaire of symptoms and a separate questionnaire about 12 environmental exposures (Wolfe et al., 2002). Two of the exposures were relevant to the present report: “exposure to poison gas or germ warfare” and “placement on formal alert for chemical and biological warfare”. About 60% of respondents met CDC’s case criteria for multisymptom illness (either a “mild-to-moderate” or “severe” case) (Fukuda et al., 1998). In Gulf War-deployed veterans, univariate analyses revealed an association between high frequency of “placement on formal alert for chemical and biological warfare” and mild-to-moderate or severe multisymptom illness. After multivariate adjustment, neither of the two exposures was associated with multisymptom illness. Kroenke et al. (1998) reported on a case series of 18,495 Gulf War veterans who sought a medical evaluation through the DOD volunteer registry program known as the Comprehensive Clinical Evaluation Program. The evaluation followed a standard protocol that included a structured clinical assessment, a physician-administered symptom checklist, and a questionnaire about self-reported exposures, combat experiences, and work loss. One of 18 exposures, “nerve gas/agents”, was relevant to the present report. The authors indicate that “no apparent association” between individual symptoms and any of the specific exposures was found, and that no tests of statistical significance were conducted, citing the large sample and multiple comparisons. REFERENCES Asukai N, Maekawa K. 2002. Psychological and physical health effects of the 1995 Sarin attack in the Tokyo subway system. In: Havenaar J, Cwikel J, eds. Toxic Turmoil: Psychological and Societal Consequences of Ecological Disasters. New York, NY: Kluwer Academic/Plenum Publishers. Pp. 149–162.

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Gulf War and Health: Updated Literature Review of Sarin Spencer PS, McCauley LA, Lapidus JA, Lasarev M, Joos SK, Storzbach D. 2001. Self-reported exposures and their association with unexplained illness in a population-based case–control study of Gulf War veterans. Journal of Occupational and Environmental Medicine 43(12):1041–1056. Storzbach D, Campbell KA, Binder LM, McCauley L, Anger WK, Rohlman DS, Kovera CA. 2000. Psychological differences between veterans with and without Gulf War unexplained symptoms. Psychosomatic Medicine 62(5):726–735. Storzbach D, Rohlman DS, Anger WK, Binder LM, Campbell KA. 2001. Neurobehavioral deficits in Persian Gulf veterans: Additional evidence from a population-based study. Environmental Research 85(1):1–13. Suadicani P, Ishoy T, Guldager B, Appleyard M, Gyntelberg F. 1999. Determinants of long-term neuropsychological symptoms. Danish Medical Bulletin 46(5):423–427. 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. 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. Winkenwerder W. 2002. US demolition operations at Khamisiyah. Final Report. Washington, DC: Department of Defense. http://www.gulflink.osd.mil/khamisiyah_iii/. 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. Yokoyama K, Araki S, Nishikitani M, Sato H. 2002. Computerized posturography with sway frequency analysis: Application in occupational and environmental health. Industrial Health 40(1):14–22.