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Gulf War and Health: Insecticides and Solvents, Volume 2 APPENDICES

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Gulf War and Health: Insecticides and Solvents, Volume 2 A OVERVIEW OF ILLNESSES IN GULF WAR VETERANS Miriam Davis, PhD1 A decade after the Gulf War, questions persist about illnesses reported by veterans. About 20% of Gulf War-deployed veterans receive some form of disability compensation.2 A sizable number of veterans report having fatigue, rash, headache, muscle and joint pain, and loss of memory (Joseph, 1997; Murphy et al., 1999). An increased prevalence of those symptoms has been borne out by large controlled studies of deployed and nondeployed military personnel3 from four countries—the United States, the United Kingdom, Denmark, and Canada. That so many Gulf War veterans report unexplained4 symptoms and disability has prompted concerns about their exposure to potentially hazardous agents during the Gulf War. The US government has invested substantially in health research to understand veterans’ illnesses, search for their causes, and find effective treatments (CDC, 1999; IOM, 2001; Research Working Group, 1999). This appendix describes the research that has addressed three fundamental questions about illnesses in Gulf War veterans:5 What are the nature and prevalence of veterans’ symptoms and illnesses? Do their unexplained symptoms warrant classification as a new syndrome? Are exposures to specific biologic, chemical, and radiologic agents during the Gulf War associated with veterans’ symptoms and illnesses? Those questions are designed to guide the reader through a complex body of research. The appendix summarizes studies of Gulf War veterans’ symptoms, diagnosable illnesses, mortality, and hospitalizations; and it provides a brief overview of the Gulf War veterans registry programs established by the Department of Veterans Affairs (VA) and the Department of Defense (DOD). The 1   Department of Epidemiology and Biostatistics, School of Public Health and Health Services, George Washington University, and independent medical writer. 2   About 155,000 of the more than 700,000 Gulf War veterans receive various degrees of disability compensation or a disability pension from the Department of Veterans Affairs (Sullivan, P, personal communication, Dec. 14, 2001). 3   Many studies have compared the health of military personnel deployed to the Gulf War with that of military personnel who were not deployed to the Gulf War but served during the same period (Gulf War era). Some studies have a comparison cohort of military personnel who served in another deployment (such as Bosnia). 4   Unexplained symptoms or unexplained illnesses mean that health complaints cannot be accounted for or explained by current medical diagnoses. 5   This appendix uses the term Gulf War veterans in the broadest sense. Unless otherwise specified, the term denotes all military personnel who served in the Gulf War theater between August 2, 1990, and June 13, 1991, regardless of whether they later continued on active duty, returned to the reserves or National Guard, or left military service.

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Gulf War and Health: Insecticides and Solvents, Volume 2 information presented here offers background for the reader and offers context for members of the IOM committee. This appendix updates a previous chapter on Gulf War illnesses contained in the first volume (IOM, 2000). Some studies of Gulf War veterans covered here are also discussed more thoroughly in the body of this volume because they are relevant to understanding the health effects of insecticides and solvents. There, they are incorporated into the body of evidence evaluated by the committee to reach its conclusions about the health effects of insecticides and solvents. REGISTRY PROGRAMS Some 700,000 US servicemen and servicewomen were deployed in the Gulf War in 1990 and 1991 (PAC, 1996). The demographic composition of the deployment was more diverse than that of previous deployments; there were greater racial and ethnic diversity, more women, and more reserves and National Guard troops (Table A.1). TABLE A.1 Demographic Characteristics of US Gulf War Troops Characteristic Percentage of Troopsa Sex Male 93 Female 7 Age (mean) in 1991 (years) 27 Race or ethnicity Non-Hispanic/White 70 Black 23 Hispanic 5 Other 2 Rank Enlisted 90 Officer 10 Military branch Army 50 Navy 23 Marines 15 Air Force 12 Military Status Active DutyReserves or 83 National Guard 17 SOURCE: Joseph, 1997 aTotal about 697,000 US military personnel. Soon after the war ended in 1991, veterans began to seek medical treatment for a variety of symptoms and illnesses (PAC, 1996). DOD and VA responded to veterans’ health concerns by establishing programs for veterans to voluntarily receive clinical examinations largely for diagnostic purposes. By 1994, those registry programs had been revised and renamed the Comprehensive Clinical Evaluation Program (hereinafter called the DOD registry) and the Persian Gulf Registry and Uniform Case Assessment Protocol (hereinafter called the VA registry). The programs are similarly structured. They begin with an initial physical examination, including patient and exposure history and screening laboratory tests, which are followed by an opportunity for referral to more-specialized testing and

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Gulf War and Health: Insecticides and Solvents, Volume 2 consultation if needed (Joseph, 1997; Murphy et al., 1999).6 About 125,000 Gulf War veterans underwent registry health examinations through March 1999 (IOM, 1999a), most conducted under VA auspices. The programs continue to register participants. The symptoms most commonly reported in 1992–1997 by the 52,835 participants in the VA registry were fatigue, rash, headache, muscle and joint pain, and loss of memory (Table A.2) (Murphy et al., 1999). An almost identical set of symptoms was reported most frequently among the roughly 20,000 participants in the DOD registry (CDC, 1999). Veterans classified in the DOD registry as having “symptoms, signs, and ill-defined conditions” complained most frequently of fatigue, headache, and memory loss (Roy et al., 1998). Clinicians were able to arrive at a primary diagnosis for about 82% of symptomatic DOD registry participants (Joseph, 1997) and for a similar fraction of VA registry participants (Murphy et al., 1999) (Table A.2). TABLE A.2 Most Frequent Symptoms and Diagnoses 53,835 Participants in VA Registry (1992–1997). Symptoms or Diagnoses Frequency, % Self-Reported Symptoms   Fatigue 20.5 Skin rash 18.4 Headache 18.0 Muscle and joint pain 16.8 Loss of memory 14.0 Shortness of breath 7.9 Sleep disturbances 5.9 Diarrhea and other gastrointestinal symptoms 4.6 Other symptoms involving skin 3.6 Chest pain 3.5 No complaint 12.3 Diagnosis (ICD-9-CM)   No medical diagnosis 26.8 Musculoskeletal and connective tissue 25.4 Mental disorders 14.7 Respiratory system 14.0 Skin and subcutaneous tissue 13.4 Digestive system 11.1 Nervous system 8.0 Infectious diseases 7.1 Circulatory system 6.4 Injury and poisoning 5.3 Genitourinary system 3.0 Neoplasm 0.4   SOURCE: Murphy et al., 1999. A registry program established by the United Kingdom Ministry of Defence for UK Gulf War veterans found similar types and frequencies of symptoms and diagnoses (Coker et al., 1999). The most recent publication from the British registry found 20% to be unwell, predominantly with psychiatric diagnoses, especially posttraumatic stress disorder (Lee et al., 2001). Across the registries, musculoskeletal disease; mental disorder; and symptoms, signs, and ill-defined conditions7 were the three most common diagnostic categories, 6   Several independent advisory committees have reviewed these programs and made recommendations for their refinement (NIH, 1994; IOM, 1995, 1996, 1997, 1998; PAC, 1996). 7   “Symptoms, signs, and ill-defined conditions” refers to International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes 780–799, which are reserved for 160 subclassifications of ill-defined common conditions not coded elsewhere in ICD-9-CM or lacking distinct physiologic or psychologic basis (US DHHS, 1998).

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Gulf War and Health: Insecticides and Solvents, Volume 2 together accounting for more than 50% of primary diagnoses (CDC, 1999). Registries are self-selected case series of veterans who presented for care, so they cannot and were not intended to be representative of the symptoms and illnesses of the entire group of Gulf War veterans. Nor were registries designed with control groups or with diagnostic standardization across the multiple sites at which examinations took place (Joseph, 1997; Roy et al., 1998). Finally, owing to their reliance on standard diagnostic classifications, registries were not designed to probe for novel diagnoses8 or to search for biologic correlates. Thus, because of their methodologic limitations, registry studies cannot stand alone as a basis of conclusions or of the conduct of research. Registry programs, do, however, provide a glimpse into veterans’ symptoms and the difficulties of fitting them into standard diagnoses. Registry programs are a valuable source of information for generating hypotheses. The hypotheses can be tested in rigorous epidemiologic studies with control groups to estimate the population prevalences of symptoms among Gulf War veterans and compare them to rates among otherwise similar troops who were not deployed to the Gulf War. EPIDEMIOLOGIC STUDIES OF VETERANS’ SYMPTOMS AND GENERAL HEALTH STATUS A number of epidemiologic studies have been conducted on the health status of Gulf War veterans. The driving issues behind many of the studies have been to determine the nature of symptoms and symptom clusters, whether symptom clusters constitute a new and unique syndrome, and what types of exposures might have produced the symptoms. The second issue—the quest to define a new syndrome—requires some explanation. The question is whether unexplained symptoms constitute a syndrome and, if so, whether they are best studied and treated as a unique, new syndrome or a variant form of a known syndrome (IOM, 2000). The finding of a new set of unexplained symptoms in a group of patients does not automatically mean that a new syndrome has been found. Rather, it constitutes the beginning of a process to demonstrate that the patients are affected by a unique clinical entity distinct from established clinical diagnoses. The process of defining a new syndrome usually begins with a case definition that lists classification criteria to distinguish the potentially new patient population from patients with known clinical diagnoses. Development of the first case definition is a vital milestone intended to spur research and surveillance. More like a hypothesis than a conclusion, it is an early step in the process; it is often revised as more evidence comes to light. Case definitions usually are a mixture of clinical, demographic, and laboratory criteria. Clinical criteria are signs (physical-examination findings) and symptoms (subjective complaints of patients). Demographic criteria refer to age, sex, ethnicity, or other individual characteristics or exposure-related variables. Laboratory criteria refer to biologic measures of pathology or etiology (such as x-ray pictures and blood test results). One method of developing an operational case definition is a statistical technique known as factor analysis (Ismail et al., 1999). Factor analysis is useful in identifying a small number of correlated variables from among a much larger number of observed variables, such as the symptoms that are reported in a survey of veterans. Factor analysis 8   Registries rely on the ICD-9-CM (Joseph, 1997; Murphy et al., 1999).

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Gulf War and Health: Insecticides and Solvents, Volume 2 aggregates survey responses into statistical groupings of factors that might or might not have biologic plausibility or clinical relevance. Several researchers have used factor analysis in their studies (described later in this appendix) of the health of Gulf War veterans. When factor analysis is used in studies of veterans, the observed variables are measurements of veterans’ symptoms, and the fundamental factors are symptom groupings that might represent a potential new syndrome. Any new syndrome (defined by factor analysis or other means) can have a distinct, albeit often unknown, etiology and pathogenesis (Taub et al., 1995). It is recognized that factor analysis has the potential to generate syndromes that might not be reproduced when a new population is examined. When evidence is presented that the case definition—defined by factor analysis or other methods—successfully singles out a new patient population from comparison groups, the case definition may gain recognition by the medical establishment as a new syndrome (IOM, 2000). There are many advantages to defining and classifying a new syndrome, among them the creation of a more homogeneous patient population, which is a crucial step for determining prevalence and improving diagnosis and treatment. A potential disadvantage is the mislabeling or misclassification of a condition, which can thwart progress for years, if not decades (Aronowitz, 1991). Classification of a new patient population also stimulates further understanding of the natural history of a disease, risk factors, and ultimately etiology and pathogenesis. As more knowledge unfolds about etiology and pathogenesis an established syndrome can rise to the level of a disease. The renaming of a syndrome as a disease implies that the etiology or pathology has been identified. Population-Based Studies This section summarizes findings of population-based studies of Gulf War veterans. The next section summarizes findings of other types of epidemiologic studies. 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 (such as a particular base or a particular branch of the service). Studies of military units or other military subgroups are less representative of the broader Gulf War veteran population than are population-based studies. Large population-based studies of Gulf War veterans have been conducted in several countries that participated in the Gulf War coalition (the United States, Canada, Denmark, and the United Kingdom). They have shown consistent findings in the nature of unexplained symptoms and in their deleterious effects on functioning. Summary features of the studies appear in Table A.3 with those of other major epidemiologic studies. Virtually all epidemiologic studies of Gulf War veterans, regardless of study design, rely on self-reports of symptoms and exposures. As discussed in Chapter 2, studies based on self-reports have inherent limitations because of potential inaccuracies in recall of past events and difficulty in verifying the reports. Most of the larger epidemiologic studies described here were conducted through mail or telephone surveys, which precluded clinical examination and diagnosis. Comparison groups were veterans of the same era who were not deployed to the Gulf War.

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Gulf War and Health: Insecticides and Solvents, Volume 2 TABLE A.3 Major Studies of Gulf War Veterans’ Symptoms and Syndromes Reference Subjects/Controls (n) Study Design Military Branch and Status Response Rate (%) Major Findings Population-Based Studies Iowa Persian Gulf Study Group, 1997; Doebbeling et al., 2000 1896/1799 Population-based survey, factor analysis All US branches and duty status 76 Symptoms (subjects vs control Fibromyalgia: 19.2% vs 9.6% Cognitive dysfunction: 18.7% 7.6% Depression: 17.0% vs 10.9% Three factors (somatic distress, psychological distress, and panic) higher in prevalence but not unique to Gulf War veterans Kang et al., 2000, 2002 11,441/9476 Population-based survey, factor analysis All US branches and duty status 70 All 48 symptoms significantly more common in deployed vs non-deployed (p<0.05) Numerous chronic medical conditions reported twice as often (see Table A.5); possible neurological syndrome requiring further evidence Goss Gilroy Inc., 1998 3113/3439 Survey All Canadian Gulf War veterans 64.5 Symptoms Chronic fatigue (OR=5.27) Cognitive dysfunction (OR=4.36) Multiple chemical sensitivity (OR=4.01) Unwin et al., 1999; Ismail et al., 1999 2961/2620, 2614a Population-based survey, factor analysis UK Gulf War veterans (U. London) 65.1 Symptoms Fatigue (OR=2.2) Posttraumatic stress (OR=2.6 Psychological distress (OR=1.6) Three factors (mood, respiratory system, peripheral nervous system) higher in prevalence, but not unique to Gulf War veterans Cherry et al., 2001a; Cherry et al., 2001b 9585/4790b Population-based survey, factor analysis UK Gulf War veterans (U. Manchester) 85.5 Symptoms Almost all 95 symptoms were more common in deployed versus nondeployed. Numbness and tingling and widespread panic were about two times more prevalent Five factors (psychological, peripheral, respiratory, gastrointestinal, and concentration) higher in prevalence, but not unique to Gulf War veterans

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Gulf War and Health: Insecticides and Solvents, Volume 2 Reference Subjects/Controls (n) Study Design Military Branch and Status Response Rate (%) Major Findings Ishoy et al., 1999b; Suadicani et al., 1999 821/400 Population-based survey, multivariate analysis Danish peacekeeping veterans 58–84 Symptoms Greater prevalence of neuropsychological, gastrointestinal and dermatological symptoms, but not musculoskeletal, among deployed versus nondeployed About 21 percent of veterans reported a clustering of 3–5 neuropsychological symptoms vs 6.2 percent of controls (p<0.001) Other Epidemiologic Studies Haley et al., 1997b 249/no controls Survey, factor analysis Navy reserve 41 25% have one of six syndromes: impaired cognition, confusion-ataxia, arthro-myo-neuropathy, phobia-apraxia, fever-adenopathy, weakness-incontinence Fukuda et al., 1998 1163/2538 Survey, clinical exam, factor analysis Air Force National Guard and 3 other Air Force units 35–70 31 of 33 symptoms significantly more prevalent in Gulf War veterans; defined case as 1 or more symptoms from 2 of 3 categories: fatigue, mood-cognition, musculoskeletal; case not unique to Gulf War veterans Proctor et al., 1998 300c/48 Survey or clinical interview All US branches and duty status 38–62 PTSD diagnosis: 5, 7% vs 0% Dermatological symptoms (OR =9.6, 6.9)c Gastrointestinal symptoms (OR =8.0, 5.8)c Neuropsychological symptoms (OR=6.4, 5.2)c NOTE: OR=odds ratio; PTSD=posttraumatic stress disorder. aTwo comparison groups (Bosnia, Gulf era). bThe deployed group consisted of a main cohort (n=4795) and a validation cohort (n=4790). cThe 300 Gulf War veterans came from two study groups—one from Ft. Devens and the other from New Orleans. The control group was deployed to Germany. The Iowa Study The “Iowa study,” a major population-based study of US Gulf War veterans, was a cross-sectional survey of a representative sample of 4886 military personnel 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 service who were still serving or had left service. The sample was randomly selected from and representative of about 29,000 military personnel. Of the eligible study subjects, 3695 (76%) completed a telephone interview. Study subjects were divided into four groups, two that had been deployed to the Gulf War and two that had not been. Trained examiners using standardized questions,

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Gulf War and Health: Insecticides and Solvents, Volume 2 instruments, and scales interviewed the subjects.9 The two groups of Gulf War military personnel reported roughly twice the prevalence of symptoms suggestive of the following conditions: fibromyalgia, cognitive dysfunction, depression, alcohol abuse, asthma, posttraumatic stress disorder (PTSD), sexual discomfort, and chronic fatigue (Table A.4).10 Furthermore, on a standardized instrument for assessing functioning (the Medical Outcome Study’s 36-item questionnaire known as the Short Form-36, or SF-36), Gulf War veterans displayed significantly lower scores in all eight subscales for physical and mental health. The subscales profile aspects of quality of life. The subscales for bodily pain, general health, and vitality showed the greatest absolute differences between deployed and nondeployed veterans. In short, this large, well-controlled study demonstrated that some sets of symptoms were more frequent and quality of life poorer among Gulf War veterans than among nondeployed military controls. Symptom clustering. The Iowa study was the first major population-based study to group sets of symptoms into categories suggestive of existing syndromes or disorders, such as fibromyalgia or depression. Its finding of considerably higher prevalence among Gulf War veterans of symptom groups suggestive of fibromyalgia, depression, and cognitive dysfunction (see Table A.4) motivated other researchers to examine—through factor analysis—the potential for a new syndrome that would group and classify veterans’ symptoms. Several years later, the same team of investigators performed a factor analysis on the Iowa cohort (Doebelling et al., 2000). They identified three symptom factors in deployed veterans—somatic distress, psychologic distress, and panic—but the factors were not exclusive to deployed veterans. Thus, the study did not support the existence of a new syndrome. Exposure-symptom relationships. The Iowa study assessed exposure-symptom relationships by asking veterans to report on their exposures in the Gulf War. Researchers found that many of the self-reported exposures were significantly associated with health conditions. For example, symptoms of cognitive dysfunction were found to have been associated with self-reports of exposure to solvents or petrochemicals, smoke or combustion products, lead from fuels, pesticides, ionizing or nonionizing radiation, chemical-warfare agents, use of pyridostigmine, infectious agents, and physical trauma. A similar set of exposures was associated with symptoms of depression or fibromyalgia. The study concluded that no exposure to any single agent was related to the conditions that the authors found to be more prevalent in Gulf War veterans (Iowa Persian Gulf Study Group, 1997). 9   Sources of questions included the National Health Interview Survey, the Behavioral Risk Factor Surveillance Survey, the National Medical Expenditures Survey, the Primary Care Evaluation of Mental Disorders, the Brief Symptom Inventory, the CAGE questionnaire, the PTSD (Posttraumatic Stress Disorder) Checklist—Military, the Centers for Disease Control and Prevention Chronic Fatigue Syndrome Questionnaire, the Chalder Fatigue Scale, the American Thoracic Society questionnaire, and the Sickness Impact Profile. 10   The 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. After a veteran identified himself or herself as having the requisite set of symptoms, researchers analyzing responses considered the veteran as having symptoms “suggestive” of or consistent with a particular disorder but not as having a formal diagnosis of the disorder.

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Gulf War and Health: Insecticides and Solvents, Volume 2 TABLE A.4 Results of the Iowa Study Symptoms (in order of frequency)a Prevalence in Gulf War Veterans (%) Prevalence in Non-Gulf War Veterans (%) Fibromyalgia 19.2 9.6 Cognitive dysfunction 18.7 7.6 Alcohol abuse 17.4 12.6 Depression 17.0 10.9 Asthma 7.2 4.1 PTSD 1.9 0.8 Sexual discomfort 1.5 1.1 Chronic fatigue 1.3 0.3 SOURCE: Iowa Persian Gulf Study Group, 1997. aBased on survey instrument designed by investigators to incorporate structured instruments and standardized questions. VA Study A major population-based study of US veterans was mandated by Public Law 103–446. It is a retrospective cohort study conducted by VA. Its purpose is to estimate the prevalence of symptoms and other health outcomes in Gulf War veterans versus non-Gulf War veterans.11 This population-based survey had three phases. The first phase was a questionnaire mailed to 30,000 veterans. The second phase validated self-reported data with medical-record review and analyzes characteristics of those who did not respond to the mailed survey. The third phase is a comprehensive medical examination and laboratory testing of a random sample of 2000 veterans drawn from both the Gulf War and the comparison group (Research Working Group, 1998). The purpose of the third phase is to establish diagnoses that will make it possible to see what proportion of self-reported symptoms are due to established diseases rather than unexplained illnesses. The findings of only the first two phases have been published. The study was designed to be representative of the nearly 700,000 US veterans sent to the Persian Gulf and 800,680 non-Gulf veterans of the same era. Questionnaires were mailed to a stratified random sample of 15,000 Gulf War and 15,000 non-Gulf War veterans identified by DOD and representing various military branches and units. The questionnaires contained a list of 48 symptoms and questions about chronic medical conditions, functional limitations, and other items from the National Health Interview Survey. A questionnaire about exposures was also included. The response rate was about 70%. The investigation found significantly higher symptom prevalence of all 48 symptoms among Gulf War veterans (Kang et al., 2000). Four of the 10 most frequently reported symptoms are runny nose, headache, unrefreshing sleep, and anxiety (Table A.5). Numerous chronic medical conditions—such as sinusitis, gastritis and dermatitis—were reported more frequently among Gulf War veterans; many were reported twice as often. Ten symptoms and 12 medical conditions were remarkably similar in prevalence to those in a UK cohort (Unwin et al., 1999). Finally, Gulf War veterans reported significantly higher rates of functional impairment (27.8% versus 14.2%), limitations of employment (17.2% versus 11.6%), and health-care use, as assessed by clinic visits (50.8% versus 40.5%) or hospitalizations (7.8% versus 6.4%). In a randomly selected subset of veterans, medical-record reviews verified more than 90% of self-reported reasons for clinic visits or hospitalizations. 11   Health outcomes include reproductive outcomes in spouses and birth defects in children.

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Gulf War and Health: Insecticides and Solvents, Volume 2 EPIDEMIOLOGIC STUDIES OF SPECIFIC HEALTH END POINTS Mortality Studies A large mortality study of nearly all Gulf War-deployed veterans identified no excess postwar mortality, with the exception of a rise in death from motor-vehicle accidents (Kang and Bullman, 1996). The study examined mortality patterns through 1993 by using two databases, 1) the VA Beneficiary Identification and Records Locator Subsystem and 2) deaths reported to the Social Security Administration.20 It compared deployed veterans with a similarly sized cohort of veterans who did not serve in the Gulf War. The most recent publication by the authors found that by 1997 the excess mortality risk from motor-vehicle accidents had disappeared, a finding consistent with the mortality pattern after the Vietnam War (Kang and Bullman, 2001). A second mortality study of US active-duty military personnel focused exclusively on the Gulf War period. It compared noncombat mortality among troops stationed in the Gulf War and troops on active duty elsewhere. There was no excess noncombat mortality in deployed veterans, except for unintentional injury (due to vehicle accidents and other causes; Writer et al., 1996). Similarly, a recently published study of UK veterans of the Gulf War in relation to contemporaneous controls found no increase in mortality other than an increase in accidental death (Macfarlane et al., 2001). The principal limitation of published mortality studies is the short duration of their followup observation. More time must elapse before excess mortality would be expected from illnesses with long latency, such as cancer, or with a gradually deteriorating course, such as multiple sclerosis.21 Hospitalization Studies The risk of hospitalization was the subject of two large studies of active-duty personnel discharged from DOD hospitals before and after the Gulf War. The first study compared almost 550,000 Gulf War veterans with almost 620,000 nondeployed veterans and found no significant and consistent differences in hospitalizations after the war (Gray et al., 1996). Before the Gulf War, from 1988 to 1990, those later deployed to the Persian Gulf were at lower risk for hospitalization than their nondeployed counterparts, probably because of the healthy-warrior effect. To permit valid before-after comparisons, the investigators used statistical methods to remove bias introduced by the “healthy-warrior effect” (also called the “healthy-worker effect”). A second hospitalization study re-examined the same dataset of active-duty personnel discharged from DOD hospitals to search for excess hospital admissions for 20   The degree of completeness of using these record systems was assessed with a validation study that used state vital-statistics data. Ascertainment was estimated at 89% of all deaths in the Gulf War cohort and comparison group. 21   Critics assert that the mortality study by Kang and Bullman (1996) made errors in calculating confidence intervals around mortality and did not adequately account for the “healthy-warrior effect,” the possibility that troops mobilized to the Gulf War were healthier than nondeployed troops and thereby biased the study toward not finding a mortality difference (Haley, 1998). The study authors disagreed and demonstrated that other statistical techniques, recommended by critics, had negligible impact on their confidence intervals (Kang and Bullman, 1998). To counter the charge of selection bias, the study authors pointed out that effects of any potential selection bias were minimal inasmuch as they found no differences in mortality risk between troops mobilized to sites other than the Gulf War and troops not mobilized at all (Kang and Bullman, 1998).

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Gulf War and Health: Insecticides and Solvents, Volume 2 unexplained illnesses. The authors reasoned that the first study might have missed hospitalizations for a new or poorly recognized syndrome. Hospital discharge coding might have inconsistently classified such hospitalizations by many diagnoses and masked an effect if one were present. The second study operationally defined unexplained illnesses as diagnoses falling into several catchall International Classification of Diseases, Ninth Revision—Clinical Modification (ICD-9-CM) diagnostic categories comprising nonspecific infections and other ill-defined conditions. After adjusting for hospitalizations only for evaluation (as opposed to treatment) in the DOD registry program, the authors found no significant differences between deployed and nondeployed active-duty military (Knoke and Gray, 1998). Those hospitalization studies provide some reassurance that excess hospitalizations did not occur among veterans of the Gulf War who remained on active duty through 1993. Like the mortality studies, however, they did not capture illnesses that might have longer latency, such as cancer, or illnesses in people separated from the military and admitted to nonmilitary (VA and civilian) hospitals (Haley, 1998). The studies did not measure the use of outpatient treatment and thus only detected illnesses that required hospitalization (Gray et al., 1996; Knoke and Gray, 1998). Studies of Birth Defects and Reproductive Outcomes Several studies failed to identify an excess of birth defects in offspring of deployed versus nondeployed veterans. A small study of two Mississippi National Guard units (n=282) deployed to the Gulf War found no excess rate of birth defects in National Guard members’ children compared with rates expected on the basis of surveillance systems and previous surveys (Penman et al., 1996). A much larger study of all live births in military hospitals (n=75,000), from 1991 to 1993, included a comparison population of births to nondeployed personnel. The risk of birth defects in children of Gulf War personnel was the same as in the control population (Cowan et al., 1997). This important study, the largest to date on birth defects, was limited to military hospitals and thereby excluded persons ineligible for care in military hospitals (members of the National Guard, reserves, and those who left the military over the course of study). National Guard and reserve troops, as noted earlier, constituted a relatively high percentage of US troops deployed to the Gulf War (Table A.1). Anecdotal reports of an excess of Goldenhar syndrome, a rare congenital anomaly that affects the development of facial structures, prompted another study of birth defects. The syndrome is not specifically coded for in reporting birth defects, so the study reviewed medical records of all listings in several more inclusive birth defect categories that would have subsumed it. Araneta and colleagues (1997) found too few cases of Goldenhar syndrome from which to draw definitive conclusions. The recently published population-based VA study of US Gulf War veterans found that male veterans reported a significantly higher rate of miscarriage than did controls, and both male and female veterans reported significantly higher birth defects among liveborn infants. Concerned about reporting bias, the investigators suggested that the observation needs to be confirmed by a review of medical records (Kang et al., 2001). Several ongoing studies are addressing the limitations of previous studies. Population-based studies to capture births in all hospitals—both military and civilian—are under way in the United States and the UK. A large US study will pool birth-defect data from several states by matching statewide birth certificates with military records (Araneta et

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Gulf War and Health: Insecticides and Solvents, Volume 2 al., 1999). Another UK study is probing the prevalence of birth defects, problems in reproduction and fertility, and cancer in children; this study covers all UK Gulf War veterans and Gulf War-era controls, a total of 106,000 veterans (Doyle et al., 1999). Studies of Stress-Related Disorders Two population-based epidemiologic studies of Gulf War veterans described earlier detected a significant increase in the self-reported prevalence of symptoms of PTSD and depression (Goss Gilroy Inc., 1998; Iowa Persian Gulf Study Group, 1997).22 In the Iowa study, 17% of Gulf War veterans reported symptoms of depression and 1.9% reported symptoms of PTSD.23 Those figures were significantly higher than those for nondeployed controls, whose prevalences were 11% and 0.8%, respectively (Table A.4). The third population-based study found that UK Gulf War veterans were about 2.5 times more likely than controls to have symptoms of PTSD; there were no significant differences in the levels of depression between deployed veterans and controls (Unwin et al., 1999). The large, population-based VA study did not survey veterans for PTSD or depression (either symptoms or diagnoses). The rates of PTSD and depression in less-representative military units also have been studied. In a study of military personnel (n=16,167) from Pennsylvania and Hawaii (described earlier), 8–9% of deployed veterans met criteria for PTSD symptoms on the basis of self-reported symptom checklists compared with 1–2% of nondeployed veterans (Stretch et al., 1996). Similarly, a small study found higher PTSD scores in deployed than in nondeployed veterans (Perconte et al., 1993a). Sutker and colleagues (1993) compared 215 National Guard and Army reserve veterans who were deployed to the Gulf War with 60 veterans from the same unit who were activated but not deployed overseas. None had sought mental health treatment. The investigators found that 16–24% of war zone-exposed troops had symptoms of distress that suggested depression or PTSD. Those who reported higher levels of stress had greater severity of PTSD and more health complaints than veterans who had low self-reported stress or no war-zone stress. Similarly, PTSD symptoms or diagnoses were more likely in groups of Gulf War veterans who had combat exposure or injury (Baker et al., 1997; Labbate et al., 1998; Wolfe et al., 1998), in women (Wolfe et al., 1993), in veterans who had been exposed to missile attack (Perconte et al., 1993b), and in those who had grave-registration duties (Sutker et al., 1994). A study by Engel and colleagues (1999) is one of the few that used a clinician-administered diagnostic instrument rather than self-reported symptom scales to assess the presence of psychiatric disorders. Researchers compiled diagnoses from among all Gulf War veterans (n=13,161) who sought health examinations through the DOD registry during its first year of operation (1994–1995). The authors used the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, Third Edition (DSM-III-R [SCID-NP]) to explore a range of possible psychiatric disorders and the Clinician- 22   Most epidemiologic studies of veterans have assessed the prevalence of self-reported symptoms of PTSD by asking subjects to fill out validated psychometric scales, such as the Mississippi Scale for Combat-Related PTSD and the PTSD Checklist—Military. Psychometric scales of PTSD, useful as screening tools for approximating a PTSD diagnosis, are not deemed to be diagnostic by themselves (Keane et al., 1988; Kulka et al., 1991). 23   A recent reanalysis of PTSD-symptom prevalence in the Iowa cohort found an adjusted OR of 2.02 for deployed versus nondeployed veterans, but the finding was of borderline significance (confidence interval, 0.97–4.23) (Barrett et al., 2002).

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Gulf War and Health: Insecticides and Solvents, Volume 2 Administered PTSD Scale to explore PTSD. Both measures have been psychometrically validated on combat veterans, so this study is methodologically stronger than many of the previous investigations. However, the study did not use a control or comparison group and, in using a treatment-seeking population, was not, by design, representative of the Gulf War veteran population. The authors found that 37% of the veterans met criteria for at least one psychiatric disorder. About 13% of the entire sample met diagnostic criteria for mood disorders, 14% for somatoform disorders,24 and 6% for current PTSD. A study of a subset of this cohort (n=131) referred for specialty evaluation found that PTSD and somatoform disorders were associated with the reporting of traumatic events (such as handling dead bodies) (Labbate et al., 1998). The authors of the smaller study concluded that at least some veterans with unexplained physical symptoms might be suffering the consequences of combat trauma. There is only one longitudinal study of PTSD in Gulf War veterans. The rates of PTSD symptoms, measured with a validated symptom questionnaire known as the Mississippi Scale for Combat-Related PTSD, showed an increase from 3% of deployed veterans immediately after the war to 8% in 1993–1994 (Wolfe et al., 1999). Women and veterans with the highest levels of combat exposure were at greatest risk for PTSD. Two years later, in 1994–1996, the same research team conducted an even more methodologically rigorous study via structured clinical interviews (in addition to PTSD questionnaires). They found a current diagnosis of PTSD in 5–7% of deployed veterans (n=206) compared with none in a control group deployed to Germany (n=48) (Wolfe et al., 1999). Regarding depression, the 1994–1996 wave of the study found similarly increased rates of current major depressive disorder and dysthymia (two distinct types of depression) but did not find increased rates of somatoform disorders. Yet nearly two-thirds of veterans who reported health symptoms in the moderate to high range had no current psychiatric diagnosis, such as PTSD or major depressive disorder.25 The authors concluded that although psychiatric diagnosis is associated with some Gulf War health complaints, such diagnoses do not account entirely for the full range and extent of Gulf War veterans’ symptom reporting. Studies of Infectious Disease, Gastrointestinal Symptoms, and Testicular Cancer During the Gulf War, the occurrence of infectious diseases was lower than expected (Hyams et al., 1995). The most common infectious disease among US troops was diarrheal disease caused by the bacterial pathogens Escherichia coli and Shigella sonnei, as detected by stool cultures (Hyams et al., 1991). Almost 60% of troops who responded to a questionnaire reported at least one episode of diarrheal disease within an average of 2 months in Saudi Arabia (Hyams et al., 1991). Upper respiratory infections also were frequent (Hyams et al., 1995). Finally, 19 cases of cutaneous leishmaniasis and 12 cases of a variant of visceral leishmaniasis have been reported among US Gulf War veterans.26 The latter is an unusual finding because the etiologic agent found in veterans’ tissue samples— 24   This term encompasses a variety of disorders in which patients have multiple physical symptoms that are not explained by a known medical disease or condition, by the effects of a substance, or by another mental disorder. The symptoms cause clinically significant distress or impaired functioning (APA, 1994). 25   About 40% also had no lifetime history of these disorders (Wolfe et al., 1999). 26   Leishmaniasis is a variety of diseases affecting the skin (cutaneous leishmaniasis), mucous membranes, and internal organs (visceral leishmaniasis), caused by infection with single-celled parasites of the genus Leishmania. It is transmitted from infected animals or people to new hosts by the bites of sand flies (Clayman, 1989).

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Gulf War and Health: Insecticides and Solvents, Volume 2 the protozoan parasite Leishmania tropica, transmitted by sand flies—is not endemic to the Persian Gulf area and is usually associated with cutaneous leishmaniasis (CDC, 1992; Hyams et al., 1995; Magill et al., 1993). Because veterans’ symptoms (such as fever, lymphadenopathy, and hepatosplenomegaly) were milder than symptoms of classic visceral leishmaniasis, the condition was given the name viscerotropic leishmaniasis. Even though visceral leishmaniasis and its variants are chronic infectious diseases, the cases were considered too few and classic signs and symptoms too readily detectable at physical examination to account for the much more frequent occurrence of unexplained illnesses in veterans (Hyams et al., 1995; PAC, 1996). Furthermore, in the controlled study of Gulf War veterans by Fukuda and colleagues (1998), none of the eight participants who seroreacted to leishmanial antigens met the study’s case definition of a severe case of unexplained illness; that suggests that viscerotropic leishmaniasis is distinct from veterans’ unexplained illnesses. However, some people with visceral or viscerotropic leishmaniasis can present with nonspecific symptoms (fatigue, low-grade fever, and gastrointestinal symptoms) that are consistent with those seen in veterans who have unexplained illnesses. Further research is required (NIH, 1994). Gastrointestinal complaints, as noted earlier, are somewhat common among veterans in the DOD and VA registries (Joseph, 1997; Murphy et al., 1999, Table A.2). In the study noted earlier by Proctor and colleagues (1998), gastrointestinal symptoms were among the symptoms with greatest prevalence differences between deployed and nondeployed veterans. One study investigated a host of gastrointestinal symptoms in a National Guard unit (n=136). Excessive gas, loose stool, incomplete rectal evacuation, and abdominal pain were more prevalent during and after the war in deployed than in nondeployed veterans from the same unit (Sostek et al., 1996). The results were based on a 64-item questionnaire administered after the war. Subjects reported that their gastrointestinal complaints began while in the Persian Gulf area and persisted after return to the United States. A population-based study of Danish peacekeeping troops who were sent to the Persian Gulf after the war had significantly higher prevalence of gastrointestinal symptoms among deployed (9.1%) than nondeployed (1.7%) veterans (Ishoy et al., 1999a). The population-based study of US veterans found up to 25% of veterans reporting medical conditions of gastritis and frequent diarrhea (Kang et al., 2000, Table A.6). Over the last 5 months of 1991, hospitalizations for testicular cancer were slightly increased in a large study of active-duty deployed versus nondeployed veterans (Gray et al., 1996). In a followup study, the investigators extended their analysis through 1996. They replicated their earlier finding but found that by 4 years after the war the cumulative risk of testicular cancer was similar in the two groups of veterans (Knoke et al., 1998). They attributed the transient increase in testicular cancer immediately after the war to regression to the mean because of the healthy-soldier effect and to deferral of care during deployment (during which time they would not have had the opportunity for diagnosis and treatment). LIMITATIONS OF PAST AND CURRENT STUDIES The epidemiologic studies of Gulf War veterans summarized above have contributed greatly to our understanding of veterans’ symptoms, but they are beset by limitations commonly encountered in epidemiologic studies. A major limitation is representativeness;

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Gulf War and Health: Insecticides and Solvents, Volume 2 most studies focus on groups that are not representative of all Gulf War veterans with respect to their military duties and location during deployment, their military status during the war (active duty, reserves, or National Guard), their military status after the war (active duty, reserves, or discharged), their branch of service (Army, Navy, Air Force, or Marines), or ease of ascertainment (IOM, 1999a). The VA study, with its population-based design, is the most representative of US veterans. The findings of population-based studies in Canada (Goss Gilroy Inc., 1998) and the UK (Unwin et al., 1999; Cherry et al., 2001a) are generally consistent with the VA and other large US studies. Other limitations of epidemiologic studies include small samples, low participation rates that could result in selection bias in some studies, and recall bias.27 The potential for recall bias is particularly important because most studies rely on self-reporting of symptoms and exposures years after the event rather than on biologic measures (Joellenbeck et al., 1998). Veterans with more symptoms are more likely to report more exposures (Unwin et al., 1999). Outcome misclassification is also a concern. One study found disparities between veterans’ symptom reporting on questionnaires and later clinical examination (McCauley et al., 1999). Studies might also be too narrow in their assessment of health status. The measurement instruments might have been too insensitive to detect abnormalities that affect deployed veterans. Finally, the period of investigation has, of necessity, been too brief to detect health outcomes that have a long latency or require many years to progress to the point where disability, hospitalization, or death occurs. Virtually all US studies are cross-sectional, and this limits the opportunity to learn about symptom duration and chronicity, latency of onset (especially for health conditions with a long latency, such as cancer), and prognosis. A major problem for most epidemiologic studies of Gulf War veterans is the lack of biologic measures of exposure to potentially harmful agents. Reliance on self-reported exposures, which often took place years earlier, lacks external verification and is subject to recall bias, a problem that potentially affects many retrospective epidemiologic studies. Furthermore, self-reports of exposure may be complicated by recall of perceived—rather than actual—exposures (for example, because of the sensitivity of the monitors, many false alarms may have been perceived as chemical-warfare agent exposure). Enhanced record keeping and monitoring of the environment during and after the Gulf War would have averted this problem. Indeed, many expert panels have recommended efforts to improve record-keeping and environmental monitoring in future deployments (e.g., IOM, 1999b; NRC, 2000a,b,c). CONCLUSION This appendix provides an overview of the body of published studies on the health of Gulf War veterans. Gulf War veterans report more symptoms than do their nondeployed counterparts, according to methodologically robust studies from several countries (Goss Gilroy Inc., 1998; Kang et al., 2000; Iowa Persian Gulf Study Group, 1997; Unwin et al., 1999). Symptoms related to cognition, the musculoskeletal system, and fatigue are more prevalent among Gulf War veterans than controls. Many symptoms and their clustering do 27   Selection bias would occur if Gulf War veterans who were symptomatic chose to participate in a study more frequently than those who were not symptomatic. Recall bias would occur if Gulf War veterans who were symptomatic tended to overestimate their exposures compared with veterans who were not symptomatic.

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Gulf War and Health: Insecticides and Solvents, Volume 2 not appear to fit conventional diagnoses. The question is whether these unexplained symptoms constitute a syndrome and, if so, whether they are best studied and treated as a unique new syndrome or as a variant form of an existing syndrome (IOM, 2000). Although one uncontrolled study reported several unique new syndromes through factor analysis (Haley et al., 1997), four controlled studies did not uncover a unique syndrome (Doebbeling et al., 2000; Fukuda et al., 1998; Ismail et al., 1999; Knoke et al., 2000). Since then, a new factor analysis study has been reported by the VA on a population-based sample of Gulf War deployed versus nondeployed veterans (Kang et al., 2002). The authors found a unique neurologic factor marked by dizziness/balance-related symptoms. They interpreted their findings as suggesting a possible syndrome related to Gulf War deployment that requires objective supporting clinical evidence. The very lack of definition or classification of veterans’ unexplained symptoms and illnesses has made it difficult to diagnose and treat many Gulf War veterans (IOM, 2001). The commonality of the symptoms in the general population (Kroenke and Mangelsdorff, 1989), coupled with their nonspecific nature and lack of biologic markers, has made it difficult to determine which, if any, exposures or sets of exposures during the Gulf War are responsible. The health studies reviewed in this appendix have found little or no excess mortality, hospitalizations, or birth defects in the children of veterans, although the studies have some limitations. Deployment to the Gulf War is associated with stress-related disorders, such as PTSD and depression, but a sizable number of veterans with unexplained symptoms do not have any psychiatric diagnoses. REFERENCES Amato AA, McVey A, Cha C, Matthews EC, Jackson CE, Kleingunther R, Worley L, Cornman E, Kagan-Hallet K. 1997. Evaluation of neuromuscular symptoms in veterans of the Persian Gulf War. Neurology 48(1):4–12. APA (American Psychiatric Association). 1994. Diagnostic and Statistical Manual of Mental Disorders, DSM-IV. 4th ed. Washington, DC: APA. Araneta MR, Moore CA, Olney RS, Edmonds LD, Karcher JA, McDonough C, Hiliopoulos KM, Schlangen KM, Gray GC. 1997. Goldenhar syndrome among infants born in military hospitals to Gulf War veterans. Teratology 56(4):244–251. Araneta MRG, Destiche DA, Schlangen KM, Merz RD, Forrester MB, Gray GC. 1999. Birth defects prevalence among infants of Gulf War veterans born in Hawaii, 1989–1993 [abstract]. Proceedings of the Conference on Federally Sponsored Gulf War Veterans’ Illnesses Research. Pentagon City, VA: Research Working Group, Persian Gulf Veterans Coordinating Board. Aronowitz RA. 1991. Lyme disease: The social construction of a new disease and its social consequences. Milbank Quarterly 69(1):79–112. Axelrod BN, Milner IB. 1997. Neuropsychological findings in a sample of Operation Desert Storm veterans. Journal of Neuropsychiatry and Clinical Neurosciences 9(1):23–28. Baker DG, Mendenhall CL, Simbartl LA, Magan LK, Steinberg JL. 1997. Relationship between posttraumatic stress disorder and self-reported physical symptoms in Persian Gulf War veterans. Archives of Internal Medicine 157(18):2076–2078. Barrett DH, Doebbeling CC, Schwartz DA Voelker MD, Falter KH, Woolson RF, Doebbeling BN. 2002. Posttraumatic stress disorder in self-reported physical health status among U.S. military personnel serving during the Gulf War period: A population-based study. Psychosomatics 43(3):195–205. CDC (Centers for Disease Control and Prevention). 1992. Viscerotropic leishmaniasis in persons returning from Operation Desert Storm, 1990–1991. Morbidity and Mortality Weekly Report 41(8):131–134.

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Gulf War and Health: Insecticides and Solvents, Volume 2 CDC (Centers for Disease Control and Prevention). 1999. Background Document on Gulf War-Related Research. The Health Impact of Chemical Exposures During the Gulf War: A Research Planning Conference. Atlanta, GA: CDC. Cecchine G, Golomb BA, Hilborne LH, Spektor DM, Anthony RA. 2000. A Review of the Scientific Literature As It Pertains to Gulf War Illnesses. Volume 8: Pesticides. Santa Monica, CA: National Defense Research Institute, RAND. Chalder T, Hotopf M, Unwin C, Hull L, Ismail K, David A, Wessely S. 2001. Prevalence of Gulf war veterans who believe they have Gulf war syndrome: questionnaire study. British Medical Journal 323(7311):473–476. Cherry N, Creed F, Silman A, Dunn G, Baxter D, Smedley J, Taylor S, Macfarlane GJ. 2001a. Health and exposures of United Kingdom Gulf war veterans. Part I: The pattern and extent of ill health. Occupational and Environmental Medicine 58(5)291–298. Cherry N, Creed F, Silman A, Dunn G, Baxter D, Smedley J, Taylor S, Macfarlane GJ. 2001b. Health and exposures of United Kingdom Gulf war veterans. Part II: The relation of health to exposure. Occupational and Environmental Medicine 58(5)299–306. Clayman CB, ed. 1989. The American Medical Association Encyclopedia of Medicine. New York: Random House. Coker WJ, Bhatt BM, Blatchley NF, Graham JT. 1999. Clinical findings for the first 1000 Gulf war veterans in the Ministry of Defence’s medical assessment programme. British Medical Journal 318(7179):290–294. Cowan DN, DeFraites RF, Gray GC, Goldenbaum MB, Wishik SM. 1997. The risk of birth defects among children of Persian Gulf War veterans. New England Journal of Medicine 336(23):1650–1656. Doebbeling BN, Clarke WR, Watson D, Torner JC, Woolson RF, Voelker MD, Barrett DH, Schwartz DA. 2000. Is there a Persian Gulf War syndrome? Evidence from a large population-based survey of veterans and nondeployed controls. American Journal of Medicine 108(9):695–704. Doyle P, Maconochie N, Roman E, McMichael A. 1999. Study of the reproductive health of UK Gulf War veterans and the health of their children: An update [abstract]. Proceedings of the Conference on Federally Sponsored Gulf War Veterans’ Illnesses Research. Pentagon City, VA: Research Working Group, Persian Gulf Veterans Coordinating Board. Engel CC Jr, Ursano R, Magruder C, Tartaglione R, Jing Z, Labbate LA, Debakey S. 1999. Psychological conditions diagnosed among veterans seeking Department of Defense care for Gulf War-related health concerns. Journal of Occupational and Environmental Medicine 41(5):384–392. Fukuda K, Nisenbaum R, Stewart G, Thompson WW, Robin L, Washko RM, Noah DL, Barrett DH, Randall B, Herwaldt BL, Mawle AC, Reeves WC. 1998. Chronic multisymptom illness affecting Air Force veterans of the Gulf War. Journal of the American Medical Association 280(11):981–988. Goldstein G, Beers SR, Morrow LA, Shemansky WJ, Steinhauer SR. 1996. A preliminary neuropsychological study of Persian Gulf veterans. Journal of the International Neuropsychological Society 2(4):368–371. Goss Gilroy Inc. 1998. Health Study of Canadian Forces Personnel Involved in the 1991 Conflict in the Persian Gulf, Vol. 1. Ottawa, Ontario: Goss Gilroy Inc. Prepared for the Department of National Defence. Gray GC, Coate BD, Anderson CM, Kang HK, Berg SW, Wignall FS, Knoke JD, Barrett-Connor E. 1996. The postwar hospitalization experience of U.S. veterans of the Persian Gulf War. New England Journal of Medicine 335(20):1505–1513. Haley RW. 1998. Point: Bias from the “healthy-warrior effect” and unequal follow-up in three government studies of health effects of the Gulf War. American Journal of Epidemiology 148(4):315–323. Haley RW, Kurt TL. 1997. Self-reported exposure to neurotoxic chemical combinations in the Gulf War. A cross-sectional epidemiologic study. Journal of the American Medical Association 277(3):231–237. Haley RW, Horn J, Roland PS, Bryan WW, Van Ness PC, Bonte FJ, Devous MDS, Mathews D, Fleckenstein JL, Wians FH Jr, Wolfe GI, Kurt TL. 1997a. Evaluation of neurologic function in Gulf War veterans. A blinded case-control study. Journal of the American Medical Association 277(3):223–230. Haley RW, Kurt TL, Horn J. 1997b. Is there a Gulf War syndrome? Searching for syndromes by factor analysis of symptoms. Journal of the American Medical Association 277(3):215–222. Haley RW, Billecke S, La Du BN. 1999. Association of low PON1 type Q (type A) arylesterase activity with neurologic symptom complexes in Gulf War veterans. Toxicology and Applied Pharmacology 157(3):227–233. Haley RW, Fleckenstein JL, Marshall WW, McDonald GG, Kramer GL, Petty F. 2000. Effect of basal ganglia injury on central dopamine activity in Gulf War syndrome: Correlation of proton magnetic resonance spectroscopy and plasma homovanillic acid levels. Archives of Neurology 57(9):1280–1285.

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Gulf War and Health: Insecticides and Solvents, Volume 2 Hotopf M, David A, Hull L, Ismail K, Unwin C, Wessely S. 2000. Role of vaccinations as risk factors for ill health in veterans of the Gulf War: Cross sectional study. British Medical Journal 320:1363–1367. Hyams KC, Bourgeois AL, Merrell BR, Rozmajzl P, Escamilla J, Thorton SA, Wasserman GM, Burke A, Echeverria P, Green KY, Kapikian AZ, Woody JN. 1991. Diarrheal disease during Operation Desert Shield. New England Journal of Medicine 325(20):1423–1428. Hyams KC, Hanson K, Wignall FS, Escamilla J, Oldfield EC III. 1995. The impact of infectious diseases on the health of U.S. troops deployed to the Persian Gulf during Operations Desert Shield and Desert Storm. Clinical Infectious Diseases 20(6):1497–1504. IOM (Institute of Medicine). 1995. Health Consequences of Service During the Persion Gulf War: Initial Findings and Recommendations for Immediate Action. Washington, DC: National Academy Press. IOM (Institute of Medicine). 1996. Health Consequences of Service During the Persion Gulf War: Recommendations for Research and Information Systems. Washington, DC: National Academy Press. IOM (Institute of Medicine). 1997. Adequacy of the Comprehensive Clinical Evaluation Program: Nerve Agents. Washington, DC: National Academy Press. IOM (Institute of Medicine). 1998. Adequacy of the VA Persian Gulf Registry and Uniform Case Assessment Protocl. Washington, DC: National Academy Press. IOM (Institute of Medicine). 1999a. Gulf War Veterans: Measuring Health. Washington, DC: National Academy Press. IOM (Institute of Medicine). 1999b. Strategies to Protect the Health of Deployed U.S. Forces: Medical Surveillance, Record Keeping, and Risk Reduction. Washington, DC: National Academy Press. IOM (Institute of Medicine). 2000. Gulf War and Health. Vol 1. Depleted Uranium, Pyridostigmine Bromide, Sarin, Vaccines. Washington, DC: National Academy Press. IOM (Institute of Medicine). 2001. Gulf War Veterans: Treating Symptoms and Syndromes. Washington, DC: National Academy Press. Ishoy T, Suadicani P, Guldager B, Appleyard M, Gyntelberg F. 1999a. Risk factors for gastrointestinal symptoms. Danish Medical Bulletin 46(5):420–423. Ishoy T, Suadicani P, Guldager B, Appleyard M, Hein HO, Gyntelberg F. 1999b. State of health after deployment in the Persian Gulf. Danish Medical Bulletin 46(5):416–419. Iowa Persian Gulf Study Group. 1997. Self-reported illness and health status among Gulf War veterans: A population-based study. Journal of the American Medical Association 277(3):238–245. Ismail K, Everitt B, Blatchley N, Hull L, Unwin C, David A, Wessely S. 1999. Is there a Gulf War syndrome? Lancet 353(9148):179–182. Jamal GA, Hansen S, Apartopoulos F, Peden A. 1996. The “Gulf War syndrome.” Is there evidence of dysfunction in the nervous system? Journal of Neurology Neurosurgery and Psychiatry 60(4):449–451. Joellenbeck LM, Landrigan PJ, Larson EL. 1998. Gulf War veterans’ illnesses: A case study in causal inference. Environmental Research 79(2):71–81. Joseph SC. 1997. A comprehensive clinical evaluation of 20,000 Persian Gulf War veterans. Military Medicine 162(3):149–155. Kang HK, Bullman TA. 1996. Mortality among U.S. veterans of the Persian Gulf War. New England Journal of Medicine 335(20):1498–1504. Kang HK, Bullman TA. 1998. Counterpoint: Negligible “healthy-warrior effect” on Gulf War veterans’ mortality. American Journal of Epidemiology 148(4):324–325; discussion 334–338. Kang HK, Bullman TA. 2001. Mortality among US veterans of the Persian Gulf War: 7-year follow-up. American Journal of Epidemiology 154(5):399–405. Kang HK, Mahan CM, Lee KY, Magee CA, Murphy FM. 2000. Illnesses among United States veterans of the Gulf war: A population-based survey of 30,000 veterans. Journal of Occupational and Environmental Medicine 42(5):491–501. Kang H, Magee C, Mahan C, Lee K, Murphy F, Jackson L, Matanoski G. 2001. Pregnancy outcomes among U.S. Gulf War veterans: A population-based survey of 30,000 veterans. Annals of Epidemiology 11(7):504–511. Kang HK, Mahan CM, Lee KY, Murphy FM, Simmens SJ, Young HA, Levine PH. 2002. Evidence for a deployment-related Gulf War syndrome by factor analysis. Archives of Environmental Health 57(1):61–68. Keane TM, Caddell JM, Taylor KL. 1988. Mississippi Scale for combat-related posttraumatic stress disorder: Three studies in reliability and validity. Journal of Consulting and Clinical Psychology 56(1):85–90.

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