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Gulf War and Health: Updated Literature Review of Sarin (2004)

Chapter: 3 Human Health Outcome Studies

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Suggested Citation:"3 Human Health Outcome Studies." Institute of Medicine. 2004. Gulf War and Health: Updated Literature Review of Sarin. Washington, DC: The National Academies Press. doi: 10.17226/11064.
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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

Suggested Citation:"3 Human Health Outcome Studies." Institute of Medicine. 2004. Gulf War and Health: Updated Literature Review of Sarin. Washington, DC: The National Academies Press. doi: 10.17226/11064.
×

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

Suggested Citation:"3 Human Health Outcome Studies." Institute of Medicine. 2004. Gulf War and Health: Updated Literature Review of Sarin. Washington, DC: The National Academies Press. doi: 10.17226/11064.
×

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

Suggested Citation:"3 Human Health Outcome Studies." Institute of Medicine. 2004. Gulf War and Health: Updated Literature Review of Sarin. Washington, DC: The National Academies Press. doi: 10.17226/11064.
×

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.

Suggested Citation:"3 Human Health Outcome Studies." Institute of Medicine. 2004. Gulf War and Health: Updated Literature Review of Sarin. Washington, DC: The National Academies Press. doi: 10.17226/11064.
×

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

Suggested Citation:"3 Human Health Outcome Studies." Institute of Medicine. 2004. Gulf War and Health: Updated Literature Review of Sarin. Washington, DC: The National Academies Press. doi: 10.17226/11064.
×

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

Suggested Citation:"3 Human Health Outcome Studies." Institute of Medicine. 2004. Gulf War and Health: Updated Literature Review of Sarin. Washington, DC: The National Academies Press. doi: 10.17226/11064.
×

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

Suggested Citation:"3 Human Health Outcome Studies." Institute of Medicine. 2004. Gulf War and Health: Updated Literature Review of Sarin. Washington, DC: The National Academies Press. doi: 10.17226/11064.
×

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-

Suggested Citation:"3 Human Health Outcome Studies." Institute of Medicine. 2004. Gulf War and Health: Updated Literature Review of Sarin. Washington, DC: The National Academies Press. doi: 10.17226/11064.
×

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-

Suggested Citation:"3 Human Health Outcome Studies." Institute of Medicine. 2004. Gulf War and Health: Updated Literature Review of Sarin. Washington, DC: The National Academies Press. doi: 10.17226/11064.
×

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-

Suggested Citation:"3 Human Health Outcome Studies." Institute of Medicine. 2004. Gulf War and Health: Updated Literature Review of Sarin. Washington, DC: The National Academies Press. doi: 10.17226/11064.
×

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

Suggested Citation:"3 Human Health Outcome Studies." Institute of Medicine. 2004. Gulf War and Health: Updated Literature Review of Sarin. Washington, DC: The National Academies Press. doi: 10.17226/11064.
×

TABLE 3-2 Studies of Gulf War Veterans Potentially Relevant to Sarin Exposures

Reference

Population

Exposure Assessment for Relevant Agents

Studies of Veterans Potentially Exposed at Khamisiyah Not Reviewed in GW1

Smith et al., 2003

431,762 active-duty US military deployed to Gulf War divided into two groups: Nonexposed (n = 318,458) Possibly exposed (n = 99,614). Active-duty includes all active duty up to 10 years after the war (until separation) and reserve only while on active-duty status (follow-up to Gray et al., 1999)

Second exposure model by DOD of nerve agent release data, meteorological models, and atmospheric removal mechanisms combined with troop positions

Gray et al., 1999

349,291 active-duty US military deployed to Gulf War divided into three groups: Not exposed (n = 224,804) Uncertain low dose exposure (n = 75,717) Estimated subclinical exposure (n = 48,770)

First exposure model by DOD of nerve agent release data, meteorological models combined with troop positions

McCauley et al., 2002

923 Khamisiyah-exposed US Gulf War veterans vs 927 Khamisiyah nonexposed Gulf War veterans vs 1,369 non-Gulf War-deployed veterans from Oregon, Washington, California, Georgia, or North Carolina

Exposure defined by DOD as troop location within a 50-kilometer radius of Khamisiyah

Suggested Citation:"3 Human Health Outcome Studies." Institute of Medicine. 2004. Gulf War and Health: Updated Literature Review of Sarin. Washington, DC: The National Academies Press. doi: 10.17226/11064.
×

Timeframe and Health-Outcome Assessment

Results

Limitations

DOD hospitalizations (1991–2000) for any cause, diagnoses from 15 categories and specific diagnoses proposed by expert panel

Using Cox modeling, 2 of 37 models showed an increase adjusted risk of hospitalization for cardiac dysrhythmias, circulatory system diseases (RR, 1.07; 95% CI, 1.0–1.13), specifically for cardiac dysrhythmias (RR, 1.23; 95% CI, 1.04–1.44)

Limited to DOD hospitals. Hospitalization data available for only active and reserve Gulf War veterans who remained on active duty or retired with medical benefits after the end of the war. No outpatient data available

DOD hospitalizations (1991–1995) for any cause, diagnoses from 15 categories and specific diagnoses proposed by expert panel

Using Cox modeling, none of the models suggested a dose–response relation or neurologic sequelae

Limited to DOD hospitals. Hospitalization data available for only active and reserve Gulf War veterans who remained on active duty or retired with medical benefits after the end of the war. No outpatient data available.

No adjustment for confounding exposures

Computer-assisted telephone interview about Khamisiyah-related exposures, medical conditions diagnosed by a physician, hospitalizations, and disability; interview conducted 8 years after Khamisiyah demolition

No differences between Khamisiyah-exposed and Khamisiyah-nonexposed Gulf War veterans in health conditions. Deployed troops significantly more likely than nondeployed troops to report physician-diagnosed high blood pressure (OR,1.7; 95% CI, 1.3–2.4), heart disease (OR, 2.5; 95% CI, 1.1–6.6), slipped disk or pinched nerve (OR, 1.5; 95% CI, 1.1–2.0), PTSD (OR, 14.9; 95% CI 5.6–60.9), hospitalization for depression (OR, 5.1; 95% CI, 1.5–32.1), periodontal disease (OR, 1.8; 95% CI, 1.2–2.8 )

Self-reported conditions recalled 9 yrs after exposure, DOD’s models of nerve agent exposure not yet available, not representative of entire Gulf War cohort

Suggested Citation:"3 Human Health Outcome Studies." Institute of Medicine. 2004. Gulf War and Health: Updated Literature Review of Sarin. Washington, DC: The National Academies Press. doi: 10.17226/11064.
×

Reference

Population

Exposure Assessment for Relevant Agents

McCauley et al., 2001

2,918 veterans from Oregon, Washington, California, Georgia, or North Carolina

Exposure defined by DOD as troop location within a 50-kilometer radius of Khamisiyah

Self-Reported Exposures: Population-Based Studies

New Studies

Reid et al., 2001

Subgroups of UK veterans meeting case criteria for MCS and CFS (same cohort as Unwin et al., 1999)

Three relevant environmental exposures: “NBC suits”, “hear chemical alarms”, “chemical/nerve gas attack”

Suadicani et al., 1999

686 Gulf War-deployed peacekeepers vs matched controls from Danish armed forces

One relevant exposure: “nerve gas”

Ishoy et al., 1999a

686 Gulf War-deployed peacekeepers vs matched controls from Danish armed forces (same cohort as Suadicani et al., 1999)

One relevant exposure: “nerve gas”

Suggested Citation:"3 Human Health Outcome Studies." Institute of Medicine. 2004. Gulf War and Health: Updated Literature Review of Sarin. Washington, DC: The National Academies Press. doi: 10.17226/11064.
×

Timeframe and Health-Outcome Assessment

Results

Limitations

Computer-assisted telephone interview about Khamisiyah-related exposures, 24-item symptom checklist during Khamisiyah operations, and current symptom checklist

No significant differences between Khamisiyah-exposed vs nonexposed in current or past symptoms. Numerous significant differences between Khamisiyah-witnesses versus nonwitnesses in past and current symptom reporting. Current symptoms in Khamisiyah-witnesses vs nonwitness: tingling or burning sensations of the skin (OR, 1.7; 95% CI, 1.1–2.8), changes in memory (OR, 1.7; 95% CI, 1.2–2.4), difficulty sleeping (OR, 2.0; 95% CI, 1.2–3.5), persistent fatigue (OR, 1.8; 95% CI, 1.2–2.6), depression (OR, 1.6; 95% CI, 1.1–2.4), and bloody diarrhea (OR, 3.1; 95% CI, 1.6–6.0)

Self-reported symptoms recalled 9 yrs after exposure, DOD’s models of nerve agent exposure not yet available, not representative of entire Gulf War cohort

Symptom questionnaires, exposure questionnaire, both 6–7 years after Khamisiyah demolition

In Gulf War veterans, MCS associated with “hear chemical alarms” (OR, 2.5; 95%, CI 1.0–5.9), “chemical/ nerve gas attack” (OR, 4.6; 95% CI, 1.6–13.3), CFS associated with “hear chemical alarms” (OR, 2.5; 95% CI, 1.2–5.3)

Self-reported symptoms and exposures

Symptom questionnaires, exposure questionnaire up to 6 years after return

In Gulf War cohort, “nerve gas” not significantly associated with neuropsychologic symptoms

Self-reported symptoms and exposures

Symptom questionnaires (GI symptoms), exposure questionnaire, clinical examination up to 6 years after return

After multivariate adjustment, nerve gas not significantly associated with GI symptoms

Self-reported symptoms and exposures

Suggested Citation:"3 Human Health Outcome Studies." Institute of Medicine. 2004. Gulf War and Health: Updated Literature Review of Sarin. Washington, DC: The National Academies Press. doi: 10.17226/11064.
×

Reference

Population

Exposure Assessment for Relevant Agents

Spencer et al., 2001

Random sample (n = 2,343) of 23,711 Gulf War veterans from Oregon or Washington state, nested case–control study

Three relevant exposures: “chemical decontamination bottles”, “inadequate protection during chemical/SCUD alarms”, “worked around chemical warfare agents”

Kang et al., 2002

11,441 US veterans deployed to Gulf War vs 9,476 non–Gulf War-deployed, nested case–control study

One relevant exposure: “nerve gas”

Kang et al., 2003

11,441 US veterans deployed to Gulf War vs 9,476 non–Gulf War-deployed, nested case–control study

“Had worn chemical protective gear or heard chemical alarms sounding” was one of three combat stressors; other combat stressors: “had been involved in direct combat duty” and “had witnessed any deaths”

Suggested Citation:"3 Human Health Outcome Studies." Institute of Medicine. 2004. Gulf War and Health: Updated Literature Review of Sarin. Washington, DC: The National Academies Press. doi: 10.17226/11064.
×

Timeframe and Health-Outcome Assessment

Results

Limitations

Exposure questionnaire, symptom questionnaires collected 4–7 years after Khamisiyah demolition, clinical examination to verify case of unexplained illness

By simple logistic regression, cases of unexplained illness (n = 241) more likely than healthy Gulf War-deployed controls (n = 113) to report “inadequate protection during chemical/SCUD alarm”

Self-reported symptoms and exposures, multivariate analysis not performed on exposures of interest

Potentially new neurologic syndrome via factor analysis, symptom questionnaires, exposure questionnaire, surveys conducted in 1995

“Nerve gas” among nine self-reported exposures at least three times more common in 277 Gulf War-deployed veterans (cases) with these symptoms (loss of balance or dizziness, speech difficulty, sudden loss of strength, tremors or shaking) than in Gulf War-deployed noncases (42.3% of cases reported nerve gas exposure vs 4.6% of Gulf War-deployed noncases)

Self-reported symptoms and exposures, no analysis for dose–response relationship

PTSD, CFS; surveys conducted from 1995–1997

PTSD excess (adjusted OR, 3.1; 95% CI, 2.7–3.4), CFS excess (adjusted OR, 4.8; 95% CI, 3.9–5.9), PTSD prevalence increased with combat stress intensity, from 3.3 to 22.6% (test for trend, p > 0.15)

Self-reported symptoms and exposures, lack of analysis solely of sarin-related exposure

Suggested Citation:"3 Human Health Outcome Studies." Institute of Medicine. 2004. Gulf War and Health: Updated Literature Review of Sarin. Washington, DC: The National Academies Press. doi: 10.17226/11064.
×

Reference

Population

Exposure Assessment for Relevant Agents

Studies Reviewed in GW1

Iowa Persian Gulf Study Group, 1997

1,896 deployed veterans from Iowa as home of record vs 1,799 nondeployed veterans from Iowa as home of record

One relevant exposure: “chemical warfare agents”

Goss Gilroy Inc., 1998

3,113 Canadian veterans deployed to Gulf War vs 3,439 deployed elsewhere

Over 30 exposures divided into six categories; one category was relevant: “chemical warfare agents” (nerve gas and mustard gas or other blistering agent)

Unwin et al., 1999

2,735 UK veterans deployed to Gulf War vs 2,393 deployed to Bosnia vs 2,422 deployed elsewhere

Three relevant environmental exposures: “NBC suits”, “hear chemical alarms”, “chemical/ nerve gas attack”

Suggested Citation:"3 Human Health Outcome Studies." Institute of Medicine. 2004. Gulf War and Health: Updated Literature Review of Sarin. Washington, DC: The National Academies Press. doi: 10.17226/11064.
×

Timeframe and Health-Outcome Assessment

Results

Limitations

Symptom questionnaires, exposure questionnaire no more than 6 years after Khamisiyah demolition

In Gulf War veterans, exposure to “chemical warfare agents” associated with symptoms of cognitive dysfunction (prevalence difference, 6.8%; p < 0.001), depression (prevalence difference, 8.6%; p < 0.001), fibromyalgia (prevalence difference, 8.1%; p < 0.0

Self-reported symptoms and exposures, low proportion of minority-group subjects, internal validation of responses not assessed, no adjustment for multiple comparisons, multiple associations between variety of exposures and variety of outcomes

Symptom questionnaires, exposure questionnaire 6 years after Khamisiyah demolition

In Gulf War cohort, exposure to “chemical warfare agents”, in multivariate analysis, not associated with symptoms of cognitive dysfunction, chronic fatigue, fibromyalgia; significantly associated with PTSD diagnosed by health-care provider (OR, 5.25; 95% major depression (OR, 3.66; 95% CI, 1.21–11.03), anxiety (OR, 5.59; 95% CI, 1.48–21.07)

Self-reported symptoms and exposures, subset of Canadian veterans not exposed to many agents (because they were based at sea) reported symptoms as frequently as did land-based veterans, no adjustment for multiple comparisons, multiple associations between various exposures and various outcomes, not clear which relevant exposures related to outcome

Symptom questionnaires, exposure questionnaire, both 6–7 years after Khamisiyah demolition

In Gulf War cohort only, three exposures associated with chronic multisymptom illness and PTSD; for chronic multisymptom illness, ORs for three exposures, 2.2–2.7, CIs do not include 1; for PTSD, ORs for the three exposures, 2.1–3.1, CIs do not include 1

Self-reported symptoms and exposures, lack of adjustment for interrelationships between multiple exposures, use of p value of 0.05 despite multiple comparisons

Suggested Citation:"3 Human Health Outcome Studies." Institute of Medicine. 2004. Gulf War and Health: Updated Literature Review of Sarin. Washington, DC: The National Academies Press. doi: 10.17226/11064.
×

Reference

Population

Exposure Assessment for Relevant Agents

Self-Reported Exposures: Military-Unit-Based Studies

New Studies

White et al., 2001

273 deployed veterans from Massachusetts (Fort Devens) and New Orleans vs 50 Germany-deployed veterans, 1994–1996 (same cohort as Proctor et al., 1998)

One relevant exposure: “chemical or biological warfare (CBW) agents”

Wolfe et al., 2002

1,290 Gulf War-deployed veterans from Massachusetts (Ft. Devens), 1997 (same cohort as Proctor et al., 1998)

Two relevant exposures: “exposure to poison gas or germ warfare” and “placement on formal alert for chemical and biological warfare”

Nisenbaum et al., 2000

1,002 US veterans from four Air Force units; nested case–control survey of 459 Gulf War veteran cases of chronic multisymptom illness vs 543 controls without chronic multisymptom illness (followup to Fukuda et al., 1998)

One relevant exposure: “thought biological or chemical weapons were being used”

Gray et al., 1999

527 active-duty US Seabees formerly deployed to Gulf War vs 969 nondeployed veterans from same Seabee commands

One relevant exposure: “chemical warfare”

Suggested Citation:"3 Human Health Outcome Studies." Institute of Medicine. 2004. Gulf War and Health: Updated Literature Review of Sarin. Washington, DC: The National Academies Press. doi: 10.17226/11064.
×

Timeframe and Health-Outcome Assessment

Results

Limitations

15 neurobehavioral tests: WAIS-R, tests of attention, executive function, motor–psychomotor, visuospatial, memory, mood (POMS), motivation; exposure questionnaires; diagnostic interviews for PTSD; 3–5 years after Khamisiyah demolition

In regression analyses, Gulf War veterans exposed to CBW agents (vs nonexposed) more likely to have mood, memory, cognitive deficits; in particular, their scores significantly worse (p < 0.05) on POMS tension and confusion scales, three tests of recall memory, backward digit span test (WMS-R) of attention, executive system function (after controlling for PTSD and depression)

Self-reported exposures, not representative of entire Gulf War cohort

Psychologic-symptom questionnaire, combat-exposure questionnaire, 6 years after Khamisiyah demolition

In multivariate analysis, none of two exposures significantly associated with mild to moderate or severe multisymptom illness

Self-reported exposures, limited representativeness of entire Gulf War cohort

Symptom questionnaires, exposure questionnaire, 4 years after Khamisiyah demolition

“Thought biological or chemical weapons were being used”, in logistic regression adjusting for presence of other exposures, associated with criteria for severe case of multisymptom illness (OR, 3.46; 95% CI, 1.73–6.91)and mild–moderate case (OR, 2.25; 95 1.54–3.27)

Self-reported symptoms and exposures, no reporting on exact time of exposure, exclusion of Gulf War veterans no longer in active service, no adjustment of p value despite multiple comparisons, limited representativeness of entire Gulf War cohort

Symptom questionnaire, exposure questionnaire, clinical examination, handgrip strength, pulmonary function, serum collection, covered from 1991–1995

“Chemical warfare” not 1 of the 11 exposures studied in analyses

Self-reported symptoms and exposures, potential recall bias in symptom reporting, moderate to low response rate, exclusion of veterans no longer in active service, results of multivariate analysis not reported, limited representativeness of entire Gulf War cohort

Suggested Citation:"3 Human Health Outcome Studies." Institute of Medicine. 2004. Gulf War and Health: Updated Literature Review of Sarin. Washington, DC: The National Academies Press. doi: 10.17226/11064.
×

Reference

Population

Exposure Assessment for Relevant Agents

Gray et al., 2002

Gulf War-era active-duty and reserve US Seabees: 3,831 Gulf War Seabees, 4,933 Seabees deployed elsewhere, 3,104 nondeployed Seabees (followup to Gray et al., 1999)

One relevant exposure: “use of gas masks”

Kroenke et al., 1998

18,495 US Gulf War veterans in DOD Comprehensive Clinical Evaluation Program

One relevant exposure: “nerve gas/agents”

Studies Reviewed in GW1

Proctor et al., 1998

291 deployed veterans from Massachusetts (Ft. Devens) and New Orleans vs 50 Germany-deployed veterans, 1994–1996

One relevant exposure: “chemical or biological warfare (CBW) agents”

Suggested Citation:"3 Human Health Outcome Studies." Institute of Medicine. 2004. Gulf War and Health: Updated Literature Review of Sarin. Washington, DC: The National Academies Press. doi: 10.17226/11064.
×

Timeframe and Health-Outcome Assessment

Results

Limitations

Health behaviors; physician-diagnosed illnesses; self-reported persistent or recurring medical problems; exposure questionnaire, at least 6 years after Khamisiyah demolition

22% of Gulf War veterans met definition of Gulf War illness: 1 or more physician-diagnosed multisymptom illnesses or at least 12 self-reported persistent or recurring medical problems; in multivariate analysis, Gulf War illness associated with “use of gas masks” (OR, 1.40; 95% CI, 1.07–1.84)

Conducted 5–7 years after Gulf War, self-reported symptoms and exposures, potential recall bias in symptom reporting, limited representativeness of entire Gulf War cohort

Physician-administered symptom checklist, exposure questionnaire, combat and work-loss questionnaires no more than 6 years after Khamisiyah demolition

No association between individual symptoms and specific exposures

Included only subjects who presented for evaluation, self-reported symptoms and exposures, lack of control group, lack of statistical analysis, limited representativeness

Symptom questionnaires; exposure questionnaires; clinical evaluations for PTSD; evaluations conducted in 1991, 1993–1994, and 1995–1997

In Gulf War cohort, exposure to CBW agents, in multivariate analysis, significantly associated with musculoskeletal (p = 0.001),a neurologic symptoms (p = 0.013),b neuropsychologic (p = 0.009),c psychologicd (p = 0.001) symptoms

Self-reported symptoms and exposures, moderate to low response rate, limited representativeness of entire Gulf War cohort

Suggested Citation:"3 Human Health Outcome Studies." Institute of Medicine. 2004. Gulf War and Health: Updated Literature Review of Sarin. Washington, DC: The National Academies Press. doi: 10.17226/11064.
×

Reference

Population

Exposure Assessment for Relevant Agents

Haley and Kurt, 1997

23 US veterans with up to three newly defined syndromes (derived from factor analysis) vs 229 veterans without newly defined syndromes

One relevant exposure: “chemical warfare agents”

aJoint pains, backaches, and neckaches or stiffness.

bHeadaches, numbness in arms or legs, and dizziness.

cDifficulties in learning new material, difficulty in concentrating, and confusion.

dInability to fall asleep, frequent periods of feeling depressed, and frequent periods of anxiety or nervousness.

have been exposed. That was based on proximity (within 50 km) to the demolition site. Subsequently, an exposure assessment was conducted that incorporated experimental tests for release rates for the chemicals, dispersion models that included weather estimates, and unit locations (CIA–DOD, 1997). Following criticisms of that exposure assessment, a revised exposure assessment was conducted that utilized updated unit locations, revised meteorologic models, and different estimates of sarin and cyclosarin releases (Winkenwerder, 2002). Although each subsequent exposure assessment technique improved upon the previous one, many uncertainties remain with respect to the actual exposures at Khamisiyah. No blood was tested for sarin exposures and, at this time, there is no way to determine what the actual exposures were. Despite those limitations, epidemiology studies have been conducted using the various exposure assessments that are available.

A number of studies published since the preparation of GW1 (IOM, 2000) have looked at the health of soldiers potentially exposed to sarin at Khamisiyah. Gray et al. (1999) examined hospitalization over a 5-year timeframe (March 10, 1991–September 1995) in relation to potential exposure to nerve agents among 349,291 active-duty military deployed to the Gulf War theater during the time of the Khamisiyah demolition. Hospitalization experience was limited to active-duty military because they seldom receive care outside of Department of

Suggested Citation:"3 Human Health Outcome Studies." Institute of Medicine. 2004. Gulf War and Health: Updated Literature Review of Sarin. Washington, DC: The National Academies Press. doi: 10.17226/11064.
×

Timeframe and Health-Outcome Assessment

Results

Limitations

Symptom questionnaire, exposure questionnaire, within 5 years of Gulf War

“Chemical warfare agents” exposure associated with one of three newly defined syndromes (“confusion–ataxia”) (RR, 7.8; 95% CI, 2.3–25.9); synergy between exposure to “chemical warfare agents” and scores on scale of advance adverse effects from pyridostigmine bromide in predicting “confusion–ataxia syndrome”

Self-reported symptoms and exposures, no control group in original cohort, limited representativeness of entire Gulf War cohort

Abbreviations: CBW, chemical or biologic warfare; CFS, chronic fatigue syndrome; CI, confidence interval; DOD, Department of Defense; GI, gastrointestinal; MCS, multiple chemical sensitivity; NBC, nuclear, biologic, and chemical warfare; OR, odds ratio; POMS, profile of mood states; PTSD, posttraumatic stress disorder; RR, relative risk; UK, United Kingdom.

Defense (DOD) hospitals and because of the availability of automated data. Reserve veterans called to active duty were included only for the 3-month period of active-duty Gulf War service and potential Khamisiyah exposure (March 1991–June 10, 1991). The study included those on active duty after the end of the war and those retired with medical benefits. (When veterans return to reserve status, they are ineligible to receive care at DOD hospitals, but can be eligible for Veterans’ Administration hospitals.) Exposure status was determined by whether active-duty military were within the plume area defined by meteorologic-dispersion modeling, according to DOD’s initial plume-dispersion model (Rostker, 2000; Winkenwerder, 2002), and were within a military unit determined by geographic information systems data to have been exposed, during a 3-day period, to an extent set by the Centers for Disease Control and Prevention (CDC) as the general population limit (GPL), below which no symptoms were expected. Troops were considered exposed if concentrations were above the GPL of 0.0126 mg-min/m3 for sarin and 0.00001 mg-min/m3 for cyclosarin. Information on troop locations was provided from the Defense Manpower Data Center and Desert Shield-Desert Storm personnel files. Several exposure categories were created, but only three were used for studying possible dose–response relationships: not exposed (n = 224,804), uncertain low exposure (n = 75,717), and estimated subclinical exposure (n = 48,770). Three outcome measures were

Suggested Citation:"3 Human Health Outcome Studies." Institute of Medicine. 2004. Gulf War and Health: Updated Literature Review of Sarin. Washington, DC: The National Academies Press. doi: 10.17226/11064.
×

used: hospitalizations for any cause, hospitalization diagnoses in 15 categories, and specific diagnoses proposed by an expert panel to be possible long-term effects of sarin, including such disorders as mononeuritis of the upper limb and myoneural disorders.

About 21% of active-duty personnel were hospitalized over the 5-year period regardless of exposure category. Cox proportional hazard modeling, adjusted for covariates, found that exposed and nonexposed personnel had similar adjusted risks for each category of hospitalization (all causes, 15 general categories, diagnosis-specific categories). The authors concluded that their data do not support a relationship between postwar hospitalizations and exposure to nerve-agent plume from demolition at Khamisiyah. The authors identified study limitations as restriction to DOD hospitals (because of the availability of computerized records), restriction to hospitalizations of active-duty Gulf War veterans who remained on active duty after the war, and restriction to hospitalization because outpatient data were unavailable. It was also not possible to adjust for potential confounding exposures.

Smith et al. (2003), in a followup of Gray et al. (1999), investigated hospitalizations over a 10-year period (March 10, 1991–December 31, 2000) among 418,072 (of 431,762) military personnel deployed to the Gulf War theater during the time of the Khamisiyah demolition on whom demographic and exposure data were complete and available. Of the personnel, 99,614 were considered exposed to sarin or cyclosarin, and 318,458 were considered nonexposed. The methods used were similar to those of Gray et al. (1999) except that exposure status was determined according to DOD’s revised modeling in 2000 (Rostker, 2000; Winkenwerder, 2002) and the GPL was adjusted because of the briefer duration of troops’ potential exposure. Troops were considered exposed at the exposure rate of 0.0432 mg-min/m3 for sarin and 0.0144 mg-min/m3 for cyclosarin. Outcome measures were the same as those of Gray et al. (1999).

Over the course of the 10-year observation time, no differences in the percentage of personnel hospitalized (18.4% of exposed, 18.8% of nonexposed) were seen. Exposed and nonexposed personnel also had similar attrition, about 57–58% separating from the military over the 10-year period. For any-cause hospitalization, the adjusted risk for exposed veterans was not significantly different from that for nonexposed veterans, but there were differences for some demographic and occupational variables. Using Cox’s proportional hazard modeling, only one category of disease—circulatory system disease—showed a significant relationship with exposure (RR, 1.07; 95% CI, 1.0–1.13) after adjustment for other variables in the model. More specifically, only one of the 10 specific cardiac diagnoses was more frequent in the exposed than in the nonexposed: cardiac dysrhythmias (RR, 1.23; 95% CI, 1.04–1.44). The investigators, acknowledging that the finding could have resulted by chance, concluded that the excess in dysrhythmias was “small in comparison with potential

Suggested Citation:"3 Human Health Outcome Studies." Institute of Medicine. 2004. Gulf War and Health: Updated Literature Review of Sarin. Washington, DC: The National Academies Press. doi: 10.17226/11064.
×

observational variability, but the findings are provocative and warrant further evaluation.”

McCauley et al. (2001) published findings of self-reported symptoms based on questionnaire responses from a cohort of veterans deployed to the Gulf War from five states (Oregon, Washington, California, Georgia, and North Carolina). Those states were chosen because of the geographic distribution of units serving in the Khamisiyah area. The sample was divided into Gulf War veterans potentially exposed to sarin and cyclosarin on the basis of their units being located within 50 km (according to DOD information) of the demolition at Khamisiyah (Khamisiyah-exposed veterans; n = 653) and military personnel deployed to the Gulf War during the Gulf War combat period but not within 50 km of the Khamisiyah demolition (nonexposed veterans, n = 610). A third group, nondeployed veterans (n = 516), was drawn from the same states on the basis of their active duty or activation from reserve status during the Gulf War. The three groups were interviewed by telephone in 1999 about a 24-item list of self-reported symptoms during the 2-week period surrounding demolitions, their current symptoms, and more details about past exposure. In addition, McCauley et al. (2001) further divided the Khamisiyah-exposed veterans into those who reported—by responding yes to either “Involved in the munitions-demolition activity at Khamisiyah” or “Observed the demolition”—that they had been involved in or had watched the demolitions at Khamisiyah (Khamisiyah-witness, n = 162) and those who reported they had not been involved in and had not watched the demolitions at Khamisiyah (Khamisiyah-nonwitness, n = 405); the remainder of the 653 were unsure (n = 86).

There were no differences between the Khamisiyah-exposed and Khamisiyah-nonexposed groups in symptoms experienced during the first 2 weeks after the ground war. There were many differences, however, between the Khamisiyah-witness group and the Khamisiyah-nonwitness group. When questioned about symptoms that occurred at the time of demolitions, the Khamisiyah-witness group was more likely to recall 16 of 24 symptoms. They were also more likely to report three or more symptoms of sarin poisoning (vision problems, headache, running nose, coughing, tearing of eyes, and reddening of eyes) (OR, 2.13; 95% CI, 1.4–3.3). They were also, however, more likely to report three individual symptoms of mustard gas exposure (coarse voice, blisters on the skin, and rashes) despite the lack of evidence of such exposure and of a connection between those symptoms and sarin or cyclosarin exposure.

The veterans were also questioned about symptoms present in 1999, when the study was conducted. As in other Gulf War studies, both Gulf War-deployed groups (Khamisiyah-exposed and Khamisiyah-nonexposed) had higher current symptom reporting than did nondeployed veterans. However, the only difference between the two groups was that the Khamisiyah-exposed group reported fewer effects of being in a confined place (OR, 0.6; 95% CI, 0.4–0.9; OR adjusted for age, sex, and region of residence) than did the Khamisiyah-

Suggested Citation:"3 Human Health Outcome Studies." Institute of Medicine. 2004. Gulf War and Health: Updated Literature Review of Sarin. Washington, DC: The National Academies Press. doi: 10.17226/11064.
×

nonexposed group. Significant differences (in ORs adjusted for age and sex) were seen in current symptom reporting between the Khamisiyah-witness group and the Khamisiyah-nonwitness group. The Khamisiyah-witness group reported more tingling or burning sensations of the skin (OR, 1.7; 95% CI, 1.1–2.8), changes in memory (OR, 1.7; 95% CI, 1.2–2.4), difficulty in sleeping (OR, 2.0; 95% CI, 1.2–3.5), persistent fatigue (OR, 1.8; 95% CI, 1.2–2.6), depression (OR, 1.6; 95% CI, 1.1–2.4), and bloody diarrhea (OR, 3.1; 95% CI, 1.6–6.0). In light of the excess of symptoms among those who self-reported witnessing the demolitions, the investigators concluded that the DOD 50-km designation was too broad. The investigators also pointed out that the current symptom excess among those witnessing the demolitions is consistent with chronic effects of low exposure to organophosphates.

The same research group conducted a factor analysis of the symptom findings from McCauley et al. (2001), in part to determine whether a unique pattern of symptoms was present among veterans potentially exposed to chemical-warfare agents (Shapiro et al., 2002). Although a number of symptoms were identified, no unique pattern of symptoms was identified in veterans who were potentially exposed to sarin and cyclosarin by being within 50 km of the Khamisiyah demolition (Khamisiyah-exposed). The investigators were unable to perform a factor analysis on the Khamisiyah-witness group, because there were too few in the group (n = 162).

McCauley et al. (2002) published a second study of veterans (n = 2,918) from the same five states as their earlier study (McCauley et al., 1999). The 2002 publication focused on self-reports, during a telephone interview, of physician-diagnosed health conditions, hospitalizations, and disability related to exposures at Khamisiyah. As in the earlier study, exposure was designated as being within 50 km of Khamisiyah. Khamisiyah-exposed Gulf War veterans were compared with Khamisiyah-nonexposed Gulf War veterans and nondeployed veterans. (No analyses of Khamisiyah-witness versus Khamisiyah-nonwitness groups were reported.) All health outcomes were based on veterans’ self-reports regarding conditions diagnosed by a physician since the Gulf War, their employment status, hospitalizations, and disability. The method was the same as that of McCauley et al. (2001).

Deployed troops were significantly more likely than nondeployed troops to report physician-diagnosed high blood pressure (OR, 1.7; 95% CI, 1.3–2.4), heart disease (OR, 2.5; 95% CI, 1.1–6.6), slipped disk or pinched nerve (OR, 1.5; 95% CI, 1.1–2.0), PTSD (OR, 14.9; 95% CI, 5.6–60.9), hospitalization for depression (OR, 5.1; 95% CI, 1.5–32.1), and periodontal disease (OR, 1.8; 95% CI, 1.2–2.8). There was an excess of cancer in the deployed group, but the results became nonsignificant when skin cancer was removed from the analysis. None of the nearly 20 medical conditions, however, was reported to be more common among Khamisiyah-exposed than Khamisiyah-nonexposed Gulf War veterans. There

Suggested Citation:"3 Human Health Outcome Studies." Institute of Medicine. 2004. Gulf War and Health: Updated Literature Review of Sarin. Washington, DC: The National Academies Press. doi: 10.17226/11064.
×

were no differences between deployed and nondeployed veterans in functional status, hospitalizations, and service-connected disability rates.

The committee is aware that currently a study is being conducted investigating the long-term health effects associated with potential low exposures to sarin and cyclosarin at Khamisiyah, Iraq, and the effect of notification of such exposure. That study, however, is not yet published.

Self-Reported Exposures

This section summarizes studies of Gulf War veterans in which possible indications of potential exposure to sarin or cyclosarin are self-reported. They include studies that report multiple symptoms and investigate their relationship to any response on a questionnaire or in an interview that might indicate potential exposure to an agent of interest to the present committee. This discussion focuses on the results that might be associated with potential exposures to sarin or cyclosarin. Most of the studies are large-scale epidemiologic studies of the health of veterans, including American, Canadian, British, and Danish veterans. A number of studies on those populations of veterans do not examine the relationship between symptoms and specific exposures or do not investigate exposures of interest to this committee, and such studies are not reviewed in this report. The studies summarized below are grouped according to whether the study design was population-based or military-unit-based. A population-based study is a methodologically robust type of epidemiologic study because its goal is to obtain information that is representative of the population of interest, in this case, Gulf War veterans. The cohort may be the entire population of interest or a random selection from the population of interest. Population-based studies of Gulf War veterans sample a cohort of veterans by contacting them where they live, as opposed to where they seek treatment or where they serve in the military (for example, a particular base, a particular branch such as the Air Force). Studies of military units or other military subgroups are less representative of the broader Gulf War veteran population than are population-based studies. The relevant findings are summarized in Table 3-2.

Population-Based Studies

The “Iowa study”, a major population-based study of US Gulf War veterans reviewed in GW1, was a cross-sectional survey of a representative sample of 4,886 military personnel who had active military service at some time from August 2, 1990, to July 31, 1991, and who listed Iowa as their home of record at the time of enlistment (Iowa Persian Gulf Study Group, 1997). The study examined the health of military personnel in all branches of military service who were still serving or had left service. The sample was randomly selected from about

Suggested Citation:"3 Human Health Outcome Studies." Institute of Medicine. 2004. Gulf War and Health: Updated Literature Review of Sarin. Washington, DC: The National Academies Press. doi: 10.17226/11064.
×

29,000 military personnel and was stratified by age, sex, rank, race, and type of military service. Of the eligible study subjects, 3,695 (76%) completed a telephone interview. Study subjects were divided into four groups: two that had been deployed to the Gulf War (n = 1,896) and two that had not (n = 1,799). Trained examiners using standardized questions, instruments, and scales interviewed the subjects by telephone.1 The two groups deployed to the Gulf War reported roughly twice the prevalence of symptoms suggestive of the following conditions: fibromyalgia, cognitive dysfunction, depression, alcohol abuse, asthma, PTSD, sexual discomfort, or chronic fatigue.2

The Iowa study assessed exposure by asking Gulf War veterans to report on their exposures to over 20 items, one of which was “chemical-warfare agents”. In Gulf War veterans, self-reported exposure to “chemical-warfare agents” was associated with symptoms of cognitive dysfunction (prevalence difference, 6.8% between exposed and nonexposed; p < 0.001), depression (prevalence difference, 8.6%; p < 0.001), and fibromyalgia (prevalence difference, 8.1%; p < 0.001). It was not reported whether there was a relationship between self-reported exposure to “chemical-warfare agents” and PTSD symptoms.

Goss Gilroy Inc. (1998; IOM, 2000) mailed a questionnaire to the entire cohort of almost 10,000 Canadian Gulf War veterans and Canadian forces deployed elsewhere during the same period. The response rate was 73% for Gulf War veterans and 60.3% for controls. Of the Gulf War veterans responding, 2,924 were male and 189 were female. Deployed forces (n = 3,113) had significantly higher rates than controls (n = 3,439) of self-reported chronic conditions and symptoms of a variety of symptom-derived clinical outcomes (chronic fatigue, cognitive dysfunction, multiple chemical sensitivities, major depression, PTSD, chronic dysphoria, anxiety, fibromyalgia, asthma, bronchitis, and respiratory diseases). Several of the reported health conditions or symptoms were combined to form clinically meaningful outcomes (Goss Gilroy Inc., 1998). The greatest differences between deployed and nondeployed forces were in chronic fatigue, cognitive dysfunction, and multiple chemical sensitivities.

1  

Sources of questions included National Health Interview Survey, Behavioral Risk Factor Surveillance Survey, National Medical Expenditures Survey, Primary Care Evaluation of Mental Disorders, Brief Symptom Inventory, CAGE questionnaire, PTSD Checklist—Military, CDC Chronic Fatigue Syndrome Questionnaire, Chalder Fatigue Scale, American Thoracic Society questionnaire, Sickness Impact Profile, and questions to assess fibromyalgia, sexual functioning, and military exposures.

2  

Conditions listed were not diagnosed, because no clinical examinations were performed. Rather, before conducting their telephone survey, researchers grouped sets of symptoms from their symptom checklists into a priori categories of diseases or disorders. If a veteran identified himself or herself as having a requisite set of symptoms, researchers analyzing responses considered the veteran to have symptoms “suggestive” of or consistent with a particular disorder, but not its formal diagnosis.

Suggested Citation:"3 Human Health Outcome Studies." Institute of Medicine. 2004. Gulf War and Health: Updated Literature Review of Sarin. Washington, DC: The National Academies Press. doi: 10.17226/11064.
×

In multivariate analyses, researchers examined over 30 self-reported exposures in six categories, two of which indicate a potential exposure to sarin or cyclosarin: self-reported exposure to “chemical-warfare agents”, a category combining self-reported exposure to a nerve gas or to mustard gas or other blistering agent, and self-reported exposure to “psychologic stressors”, which included answering yes to any of 10 occurrences, of which only two (“wearing protective gear other than for training” and “hearing chemical alarms sounding”) might be indicative of potential exposure to sarin or cyclosarin. The heterogeneity of the “psychologic stressors” category, however, which included exposure to dead bodies of animals and humans, makes it difficult to tie any health effect directly to sarin-related exposures.

In the multivariate analysis, self-reported exposure to “chemical-warfare agents” was not associated with symptoms of cognitive dysfunction, chronic fatigue, or fibromyalgia. It was significantly associated with self-report of PTSD diagnosed by a health-care provider through a question on the symptom questionnaire rather than a structured clinical interview (OR, 5.25; 95% CI, 1.36–20.30) or by symptom reporting (OR, 10.79; CI, 3.11–37.49). Self-reported exposure to “chemical-warfare agents” was also associated with symptoms of major depression (OR, 3.66; CI, 1.21–11.03) and anxiety (OR, 5.59; CI, 1.48–21.07). A subset of Canadian veterans who were based at sea and could not have been exposed to many of the agents reported symptoms as frequently as did land-based veterans in this study. Also, no more than one-third of Canadian troops were on land in March, 1991, at the time of the Khamisiyah demolitions (personal communication with L. Smith; March 30, 2004).

Unwin et al. (1999; see IOM, 2000) investigated the health of servicemen from the UK in a cohort study. A survey was sent to 4,246 veterans—a stratified random sample of the entire UK contingent of about 53,000 personnel deployed to the Persian Gulf—and to two comparison groups. One of the comparison groups was deployed to the conflict in Bosnia (n = 4,250); this study was the only one to use a comparison population with combat experience during the time of the Gulf War. The second comparison group was deployed to other noncombat locations outside the UK over the same period (n = 4,246). The overall response rate was 65.1%. The study was stratified by branch of service, age, sex, regular or reserve status, rank, and fitness. Through a mailed questionnaire, the investigators asked about symptoms (50 items), medical disorders (39 items), and functional capacity. Many of the questions were taken from previously validated instruments, such as the Mississippi scale for PTSD, the SF-36, and the 12-item General Health Questionnaire. The principal outcome measures were the subjective health perception and physical functioning subscales of the SF-36. The authors used other item scales to put together syndromes to correspond to posttraumatic stress reaction or to the CDC-defined Gulf War syndrome. The study controlled for potential confounding factors (including sociodemographic and lifestyle factors) with logistic regression analysis. Only male veterans’ results

Suggested Citation:"3 Human Health Outcome Studies." Institute of Medicine. 2004. Gulf War and Health: Updated Literature Review of Sarin. Washington, DC: The National Academies Press. doi: 10.17226/11064.
×

were analyzed, because female veterans’ roles and symptoms were distinct enough to warrant separate consideration.

Gulf War-deployed veterans reported higher prevalence of symptoms and diminished functioning than did both comparison groups. Gulf War veterans reported having the symptom-based criteria for chronic fatigue, posttraumatic stress reaction, and “chronic multisymptom illness” more often than comparison subjects. The fact that the Bosnia cohort, which also was deployed to a combat setting, reported fewer symptoms than the Gulf War cohort, suggests that combat deployment itself does not account for higher symptom reporting.

Of the more than 17 questions related to exposures, veterans’ responses that they had used, heard, or been subjected to any of the following three situations might be relevant to potential sarin or cyclosarin exposure: “NBC suits” (NBC = nuclear, biologic, and chemical warfare), “hear chemical alarms”, and “chemical/ nerve gas attack”. When the various exposures were analyzed, veterans reporting each of those three occurrences that might be relevant to sarin or cyclosarin had a higher likelihood of CDC multisymptom syndrome and posttraumatic stress reaction. The odds of having chronic CDC multisymptom illness were higher in veterans who reported any of those three occurrences than in those who did not report them (OR, 2.7; 95% CI, 2.3–3.3; OR, 2.2; 95% CI, 1.9–2.6 and OR 2.6; 95% CI, 1.9–3.5 for responding yes to the three items, respectively), as were the odds of having posttraumatic stress (OR, 3.0; 95% CI, 2.1–4.4; OR 2.1, 95% CI, 1.6–2.8; and OR 3.1, 2.3–4.1 for responding yes to the three items, respectively). Those analyses, however, did not include a correction for multiple comparisons, and some of the ORs for the same self-reported exposures and health outcomes were also increased in Bosnia-deployed veterans and era veterans, for both of whom there is no evidence of possible sarin or cyclosarin exposures; suggesting that perception of the event, rather than sarin or cyclosarin itself, might be causing the effect. The authors interpreted the findings as evidence that the exposures were not specifically associated with Gulf War-related illnesses.

Since the preparation of GW1 (IOM, 2000), Reid et al. (2001) further analyzed the results from Unwin et al. (1999) to estimate the prevalence of multiple chemical sensitivity (MCS) and chronic fatigue syndrome (CFS) and to determine whether these two conditions were associated with the same self-reported exposures or occurrences discussed above. The MCS case definition required symptoms in at least three organ systems (including the CNS) for 3 months or more and self-reported sensitivity to four or more substances on a list of 11; this combination was chosen to correspond as closely as possible to the criteria established by Simon et al. (1993). A case of CFS was defined by using veterans’ responses to the study’s fatigue scale and the SF-36 measure of functional disability; this combination was chosen to approximate the CDC criteria for CFS (Fukuda et al., 1994). Exposures and the response rate were the same as for Unwin et al. (1999). The prevalence of MCS was significantly greater in Gulf War veterans (1.3%) than in the two control groups (adjusted OR, 7.2; 95% CI,

Suggested Citation:"3 Human Health Outcome Studies." Institute of Medicine. 2004. Gulf War and Health: Updated Literature Review of Sarin. Washington, DC: The National Academies Press. doi: 10.17226/11064.
×

2.8–18.2). In Gulf War veterans, MCS was associated with self-reports of hearing chemical alarms (OR, 2.5; 95% CI, 1.0–5.9) and self-reports of having a chemical or nerve-gas attack (OR, 4.6; 95% CI 1.6–13.3). The prevalence of CFS in Gulf War veterans (2.1%) was not significantly higher than that in one of the two control groups. It was, however, significantly associated with self-reports of hearing chemical alarms (OR, 2.5; 95% CI, 1.2–5.3).

Danish Persian Gulf veterans were almost all involved in peacekeeping or humanitarian roles after the end of the war, from the end of April 1991 through 1996 (Ishoy et al., 1999b). The vast majority of those veterans, therefore, were not in the Persian Gulf at the time of the Khamisiyah demolitions. A number of studies have been conducted on Danish gulf veterans, including studies of symptoms and diseases (Ishoy et al., 1999a), male reproductive problems (Ishoy et al., 2001a) and sexual problems (Ishoy et al., 2001b), gastrointestinal problems (Ishoy et al., 1999b), and neuropsychologic symptoms (Suadicani et al., 1999). Only the latter two studies, however, examined possible relationships between potential chemical exposures and health outcomes. Danish troops were successively replaced every 6 months, so most respondents were not in the gulf until years after the end of the war; about 60% were deployed between 1992 and 1994, and 20% after 1995. The gulf-area veterans were matched by age, sex, and profession to 400 members of the Danish armed forces who could have been, but were not, deployed to the gulf.

Suadicani et al. (1999) investigated whether 22 self-reported neuropsychologic symptoms in Danish gulf veterans were associated with self-reported exposures assessed up to 6 years after the war. A total of 821 veterans were eligible for the study by virtue of having served at any time during August 1990–December 1997. The response rate was 84% and 58% in gulf-area veterans and controls, respectively (Ishoy et al., 1999b). A combination of health and exposure questionnaires and health examinations were used, but only the results of the questionnaires are reported in Suadicani et al. (1999). The symptom questionnaire contained 17 neuropsychologic symptoms. Each of the 17 self-reported symptoms was significantly more prevalent among gulf-area veterans than controls; many of the symptoms were correlated with one another. Multiple logistic regression analysis with adjustments for age and sex was used to find the “most relevant” symptoms. Five of the 17 symptoms (concentration or memory problems, repeated fits of headache, balance disturbances or fits of dizziness, abnormal fatigue not caused by physical activity, and problems in sleeping all night) remained significant after this analysis. About 21% of gulf-area veterans reported a clustering of three to five of these relevant symptoms versus 6.2% of controls (p < 0.001). Of the 26 questions regarding exposures that are reported by Suadicani et al. (1999; see Table 4 and its footnote), only self-reported exposure to “nerve gas” is potentially relevant to the present report. Self-reported exposure to “nerve gas” was not significantly associated with the neuropsychologic symptoms in the gulf-area veterans.

Suggested Citation:"3 Human Health Outcome Studies." Institute of Medicine. 2004. Gulf War and Health: Updated Literature Review of Sarin. Washington, DC: The National Academies Press. doi: 10.17226/11064.
×

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

Suggested Citation:"3 Human Health Outcome Studies." Institute of Medicine. 2004. Gulf War and Health: Updated Literature Review of Sarin. Washington, DC: The National Academies Press. doi: 10.17226/11064.
×

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”.

Suggested Citation:"3 Human Health Outcome Studies." Institute of Medicine. 2004. Gulf War and Health: Updated Literature Review of Sarin. Washington, DC: The National Academies Press. doi: 10.17226/11064.
×

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.

Suggested Citation:"3 Human Health Outcome Studies." Institute of Medicine. 2004. Gulf War and Health: Updated Literature Review of Sarin. Washington, DC: The National Academies Press. doi: 10.17226/11064.
×

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

Suggested Citation:"3 Human Health Outcome Studies." Institute of Medicine. 2004. Gulf War and Health: Updated Literature Review of Sarin. Washington, DC: The National Academies Press. doi: 10.17226/11064.
×

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

Suggested Citation:"3 Human Health Outcome Studies." Institute of Medicine. 2004. Gulf War and Health: Updated Literature Review of Sarin. Washington, DC: The National Academies Press. doi: 10.17226/11064.
×

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.

Suggested Citation:"3 Human Health Outcome Studies." Institute of Medicine. 2004. Gulf War and Health: Updated Literature Review of Sarin. Washington, DC: The National Academies Press. doi: 10.17226/11064.
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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.

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×

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The Gulf War in 1990-1991 was considered a brief and successful military operation, with few injuries or deaths of US troops. The war began in August 1990, and the last US ground troops returned home by June 1991. Although most Gulf War veterans resumed their normal activities, many soon began reporting a variety of nonexplained health problems that they attributed to their participation in the Gulf War, including chronic fatigue, muscle and joint pain, loss of concentration, forgetfulness, headache, and rash. Because of concerns about the veterans' health problems, the Department of Veterans Affairs (VA) requested that the Institute of Medicine (IOM) review the scientific and medical literature on the long-term adverse health effects of agents to which the Gulf War veterans may have been exposed. This report is a broad overview of the toxicology of sarin and cyclosarin. It assesses the biologic plausibility with respect to the compounds in question and health effects.

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