4
HEALTH OUTCOMES

Veterans who were deployed to the Persian Gulf War have reported a constellation of symptoms and medical conditions during their deployment and since their return home. Epidemiologic studies comparing veterans who were deployed to the Gulf War with veterans who were in the military during the Gulf War but were not deployed have confirmed that deployed veterans have a greater prevalence of a number of medical conditions, illnesses, and symptoms. This increased reporting of symptoms and prevalence of medical conditions has also been seen in deployed veterans from many of the countries that formed the coalition forces, including the United States, the United Kingdom (UK), Australia, Canada, and Denmark. Recently, French forces deployed to the Gulf War have also been under study, but as yet few results have been published on this cohort.

In this chapter, the studies that have examined the health outcomes that have been reported or diagnosed in Gulf War veterans are presented. In the majority of studies, the prevalence of each medical condition or symptom seen in the deployed veterans is compared with the prevalence seen in nondeployed veterans. Where the prevalence of a symptom or condition has been linked by the study authors to any specific exposures experienced during deployment such as vaccines, oil-well fire smoke, anti-nerve-gas agents, or combat, the committee reviewed those associations as well.

ORGANIZATION OF THE CHAPTER

The committee presents the health outcomes in the order they appear in the International Statistical Classification of Diseases and Related Health Problems, 10th Edition (ICD-10),1 except for the last section, which examines the health status of female Gulf War veterans. The committee considered all possible health effects identified in the studies it reviewed, regardless of the potential cause of the health effect, with the exception of health effects related to or resulting from infectious and parasitic diseases as those outcomes were examined in Gulf War and Health, Volume 5: Infectious Diseases (IOM, 2007). The committee considered studies that attempted to link health effects seen in Gulf War veterans to specific deployment exposures such as nerve gas and oil-well fire smoke, but an exhaustive search of the toxicologic and

1

The International Statistical Classification of Diseases and Related Health Problems (ICD) provides a detailed description of known diseases and injuries. Every disease (or group of related diseases) is given a unique code. ICD is periodically revised and is currently in its 10th edition (ICD-10) and available at http://www.who.int/classifications/apps/icd/icd10online/.



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4 HEALTH OUTCOMES Veterans who were deployed to the Persian Gulf War have reported a constellation of symptoms and medical conditions during their deployment and since their return home. Epidemiologic studies comparing veterans who were deployed to the Gulf War with veterans who were in the military during the Gulf War but were not deployed have confirmed that deployed veterans have a greater prevalence of a number of medical conditions, illnesses, and symptoms. This increased reporting of symptoms and prevalence of medical conditions has also been seen in deployed veterans from many of the countries that formed the coalition forces, including the United States, the United Kingdom (UK), Australia, Canada, and Denmark. Recently, French forces deployed to the Gulf War have also been under study, but as yet few results have been published on this cohort. In this chapter, the studies that have examined the health outcomes that have been reported or diagnosed in Gulf War veterans are presented. In the majority of studies, the prevalence of each medical condition or symptom seen in the deployed veterans is compared with the prevalence seen in nondeployed veterans. Where the prevalence of a symptom or condition has been linked by the study authors to any specific exposures experienced during deployment such as vaccines, oil-well fire smoke, anti-nerve-gas agents, or combat, the committee reviewed those associations as well. ORGANIZATION OF THE CHAPTER The committee presents the health outcomes in the order they appear in the International Statistical Classification of Diseases and Related Health Problems, 10th Edition (ICD-10),1 except for the last section, which examines the health status of female Gulf War veterans. The committee considered all possible health effects identified in the studies it reviewed, regardless of the potential cause of the health effect, with the exception of health effects related to or resulting from infectious and parasitic diseases as those outcomes were examined in Gulf War and Health, Volume 5: Infectious Diseases (IOM, 2007). The committee considered studies that attempted to link health effects seen in Gulf War veterans to specific deployment exposures such as nerve gas and oil-well fire smoke, but an exhaustive search of the toxicologic and 1 The International Statistical Classification of Diseases and Related Health Problems (ICD) provides a detailed description of known diseases and injuries. Every disease (or group of related diseases) is given a unique code. ICD is periodically revised and is currently in its 10th edition (ICD-10) and available at http://www.who.int/classifications/apps/icd/icd10online/. 71

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72 GULF WAR AND HEALTH epidemiologic literature on all the possible environmental agents to which Gulf War veterans might have been exposed was not conducted. For each health effect presented in this chapter, the committee first summarizes the primary studies and secondary or supporting studies that were included in Gulf War and Health, Volume 4: Health Effects of Serving in the Gulf War (referred to as Volume 4). The committee then identifies additional primary and secondary studies from its updated literature searches and reconsiders the studies described in Volume 4 taking into account these updates. Although many of the studies are new and were published after Volume 4 was completed in 2006, some of the additional studies cited by the Update committee were published before or during 2006 but were not discussed in Volume 4. Because the Volume 4 committee was tasked with identifying those health effects seen at greater prevalence in deployed versus nondeployed Gulf War veterans and not with determining the strength of the association between deployment and the development of a particular health effect, not every study that examined an association between a health effect and Gulf War exposures was included in Volume 4. Therefore, the Update committee reviewed the categorization (primary or secondary) of all of the studies considered for Volume 4 as well as any new studies identified from an updated literature search. All studies for each health outcome, including those originally cited in Volume 4, were reviewed and categorized as primary or secondary by the entire committee in plenary session, before it came to a consensus on the appropriate category of association to be assigned to each health outcome. Consistent with previous volumes of the Gulf War and Health series, the primary studies on which the committee based its conclusions are detailed in the evidence table at the end of each health outcome section. Using this weight-of-the-evidence approach required that the Update committee be more rigorous in its review of the studies in Volume 4; as a result some studies considered to be primary in Volume 4 were recategorized as secondary for this report and vice versa. Thus, the Update committee summarizes de novo the information from both Volume 4 and any new literature to arrive at its conclusions on the strength of the association between deployment to the Gulf War and a health outcome. As described in Chapter 2, a primary study had to include information about the putative exposure (generally deployment) and specific health outcomes, demonstrate rigorous methods, include adequate details of its methods to allow a thorough assessment, include an appropriate control or reference group, and provide appropriate adjustment for confounders. It is of note that many of the large cohort studies examined multiple outcomes and so might be referred to in more than one place in this report. A given study might be deemed a primary study for one or more health outcome and be a secondary study for another outcome, based on how each health outcome was defined and measured. For example, a particular study might be well designed for assessing diabetes because the authors used a strong indicator such as blood glucose levels to identify this disorder, but the same study might not be well designed for assessing a psychiatric disorder because the authors used only a screening instrument to identify the disorder. In general, only primary studies appear in the evidence tables that accompany the discussion of each health outcome. A secondary study typically had methodological limitations, such as not including a rigorous or well-defined method of diagnosis, or a lack of an appropriate control group. The secondary studies were reviewed and included in the discussion because they evaluated the same health outcomes and in some cases provided useful information on veteran populations from the same conflicts as the primary studies. For this reason it was felt that secondary studies add information that might modify (increase or decrease) confidence in the conclusions, which are

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HEALTH OUTCOMES 73 made based on review of primary studies. Confidence in a secondary study is substantially reduced if the statistical analysis did not include adjustment for confounders, if the data were obtained from self-reported cross-sectional surveys or from screening instruments that relied solely on self-reports of diagnoses, or if response rates were unacceptably low. Without supportive evidence from primary studies, the potential for unreliable findings due to bias, chance, or multiple comparisons may outweigh the extent to which secondary studies may contribute, even collectively, to the overall conclusion of the committee about an association between deployment and any specific health outcome. Understanding the relationship between a health outcome and deployment may also be hampered by attempts to identify specific harmful exposures based on recall many years after the war. Virtually none of the studies verified veterans’ reported exposures against military records. This chapter excludes studies of participants in Gulf War registries established by the Department of Veterans Affairs (VA) or the Department of Defense (DoD), which were not intended to be representative of the population of Gulf War veterans. Registry participants cannot be considered representative of all Gulf War veterans in that they are self-selected, and many may have joined the registries because they believed that they have symptoms of a new medical syndrome; they were not a random sample of Gulf War military personnel, and there is no nondeployed comparison group. CANCER Cancer can develop at any age but about 77% of cancers are diagnosed in people aged 55 and older. Furthermore, cancer is a disease of long latency, meaning that often the diagnosis of a cancer does not occur until 15 to 20 years or longer after the exposure that caused it (Cogliano et al., 2004). Therefore, many veterans are still young for cancer diagnoses (the mean age of military personnel during the Gulf War was 28), and for most cancers, the time since the Gulf War is probably too short to expect to observe the onset of cancer. Cancers with younger average age at onset, and also possible shorter latency periods, can include testicular cancer, skin cancer, leukemias and lymphomas, and brain cancer. The majority of observations on the association of overall and cause-specific cancers (that is, malignant neoplasms) with Gulf War deployment are discussed in studies of general mortality and hospitalizations, rather than in reports focused specifically on cancer. However, a few studies on brain and testicular cancer in Gulf War veterans have been published. All studies in which malignant neoplasms, as a group or at particular sites, are specifically identified are reviewed here and summarized in Table 4-1. Summary of Volume 4 Brain Cancer The Volume 4 committee identified one cohort mortality study assessing the relationship between nerve-agent exposure caused by weapons demolition at Khamisiyah with brain cancer deaths in US Gulf War veterans. Bullman et al. (2005) explored the relationship between estimated exposure to chemical munitions destruction (sarin gas) at Khamisiyah in 1991 with cause-specific mortality of Gulf War veterans through December 31, 2000. Using the DoD’s 2000 sarin plume exposure model (Rostker, 2000), 100,487 military personnel were identified as potentially exposed and 224,980 similarly deployed military personnel were considered 73

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74 GULF WAR AND HEALTH unexposed. The study reported an increased risk of brain cancer deaths in the exposed population (relative risk [RR] 1.94, 95% confidence interval [CI] 1.12-3.34; 25 exposed cases vs 27 unexposed cases) and there was a suggestion of a dose-response relationship with increased risk among those who were considered exposed for 2 days (6 cases) relative to 1 day (19 cases) (RR 3.26, 95% CI 1.33-7.96 and RR 1.72, 95% CI 0.95-3.10, respectively). The authors also discussed modeling exposure to smoke from oil-well fires as a confounder, and the effect estimates for exposure to Khamisiyah nerve agents remained elevated. There was no significant elevation in risk associated with exposure to oil-well fires as a main effect. Because brain cancer likely has a latent period of 10-20 years and Bullman et al. (2005) had fewer than 9 years of follow-up, the Volume 4 committee concluded that additional follow-up is needed to draw any definitive conclusions concerning the association between deployment to the Gulf War and the development of brain cancer. Testicular Cancer The Volume 4 committee identified two studies that specifically examined testicular cancer among US servicemen during the Gulf War: Knoke et al. (1998) and Levine et al. (2005), and one study of military hospitalizations where a positive association for testicular cancer was observed (Gray et al., 1996). Gray and colleagues (1996) examined all-cause hospitalizations in DoD hospitals from August 1, 1991, through September 30, 1993, for 517,223 deployed and 1,291,323 nondeployed Gulf War servicemen. They observed an increased risk of hospitalization for testicular cancer among the deployed (standardized rate ratio 2.12, 95% CI 1.11-4.02) in the last 5 months of 1991, the period immediately after the end of deployment. However, the increased risk did not carry over into 1992 or into the first 9 months of 1993. Knoke et al. (1998) focused on the cases of first diagnosis of testicular cancer in this cohort, continuing follow-up until March 31, 1996. They observed no association with deployment status (standardized rate ratio 1.05, 95% CI 0.86-1.29). This pattern of increased incidence immediately after the war with a tapering off with time likely demonstrates a healthy warrior effect. In other words, the peak probably represented a regression to the mean after healthier people were selected for deployment and there was deferment of care during deployment. The limitations of these studies are that they were restricted to active-duty military personnel and did not include veterans who may have left the service because of poor health or those who sought treatment elsewhere. Levine et al. (2005) conducted a pilot study matching data from the District of Columbia and New Jersey cancer-registry cases with the records of 621,902 deployed Gulf War veterans and 746,248 veterans serving at the same time as the Gulf War but not deployed. Testicular cancer cases yielded a crude proportional incidence rate (PIR) of 3.05 (95% CI 1.47-6.35) that was attenuated after adjustment for state of residence, deployment status, race, and age (PIR 2.33; 95% CI 0.95-5.70). No definitive conclusions could be made until additional registries are added. All Cancers The Volume 4 committee included results from two primary mortality studies. Kang and Bullman (2001) compared cause-specific mortality rates in the same database of Gulf War deployed veterans and nondeployed veterans used for the Levine et al. (2005) study described above. Vital status was determined using databases of the VA and the Social Security Administration (SSA). Over the follow-up period of 1991 to 1997, there were no significant excesses of overall cancer deaths or deaths from cancer at any specific site among deployed

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HEALTH OUTCOMES 75 veterans compared with the controls (total cancers: males, OR 0.90, 95% CI 0.81-1.01; females, OR 1.11, 95% CI 0.78-1.57). Macfarlane et al. (2003) conducted a cohort study among 51,721 UK servicemembers deployed to the Persian Gulf and 50,755 nondeployed servicemembers using the National Health Service Cancer Register to identify first diagnoses of malignant cancer through July 31, 2002. The rate ratio for unspecified cancer was 0.99 (95% CI 0.83-1.17), after adjusting for sex, age, service branch, and rank. In subgroups of the cohort who participated in morbidity surveys and provided information on smoking and alcohol use, the adjusted rate ratio for all cancers was 1.12 (95% CI 0.86-1.45). Updated and Supplemental Literature Primary Studies The Update committee identified one new primary study of brain cancer mortality. It also identified three studies of hospitalization or incidence, one mortality study, and one combined study where cancer was specifically assessed. Brain Cancer In continued mortality follow-up through 2004 of the 621,902 Gulf War deployed veterans and 746,248 nondeployed veterans originally studied by Kang and Bullman (2001), Barth et al. (2009) focused on mortality from neurological causes, that is, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Parkinson’s disease, and primary brain cancer. The cases included in the Bullman et al. study (2005) described above, also were identified from this cohort and were included in the Barth et al. study. A total of 144 cases of brain cancer were identified among the deployed veterans and 228 among the nondeployed for a mortality rate ratio (RR) of 0.90 (95% CI 0.73-1.11), adjusted for race, branch of service, type of unit, age, marital status at entry to follow-up, and sex. Within the Gulf War cohort, exposure to nerve agents from the Khamisiyah explosion for 2 or more days (Winkenwerder, 2002) and exposure to oil-well fire smoke (Rostker, 2000) were both positively associated with risk of brain cancer mortality when modeled simultaneously (adjusted rate ratios 2.71, 95% CI 1.25-5.87 and 1.81, 95% CI 1.00-3.27, respectively). Of the 43 brain cancer cases exposed to oil-well fires, 20 were also exposed for at least 1 day at Khamisiyah (S. Barth, Department of Veterans Affairs, personal communication, November 30, 2009). Medical records were obtained for 236 of the 372 cases of brain cancer (63%). The record review resulted in 204 confirmed cases, 13 probable cases, and 19 misclassified cancers. The risk of dying from brain cancer did not change with the removal of the 19 misclassified cancers. Hospitalization Studies Gray et al. (2000) conducted an expanded analysis of their original 1996 study of hospitalizations to include US Gulf War veterans (n = 652,979) and nondeployed veterans (random selection of n = 652,922 from 2,912,737 total) who had separated from the armed services and those who served in the National Guard or reserve. Hospitalization data from the DoD, the VA, and California Office of Statewide Health Planning and Development over the period August 1, 1991, through December 31, 1994, were assessed separately. There was no evidence of increased hospitalization from neoplasms among the Gulf War veterans compared to the nondeployed veterans in any of the three hospital systems. 75

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76 GULF WAR AND HEALTH Smith et al. (2006) compared cause-specific postdeployment hospitalization in DoD military treatment facilities during the period October 1, 1988, through December 31, 2000, among US active-duty servicemembers who served in the Gulf War (n = 455,465), Southwest Asia following the Gulf War (n = 249,047), or Bosnia, also following the Gulf War (n = 44,341). After adjusting for age, sex, marital status, pay grade, race/ethnicity, service branch, occupation, and predeployment hospitalization, the hazard ratio (HR) for nondefined neoplasms was 1.03 (95% CI 0.93-1.15) for the Gulf War deployed veterans compared to the Southwest Asia cohort and 0.61 (95% CI 0.50-0.76) compared to the Bosnia group. The adjusted HR for testicular cancer in Gulf War veterans was 0.64 (95% CI 0.32-1.28) and 0.80 (95% CI 0.27-2.39) compared to the Southwest Asia and Bosnia groups, respectively. Mortality Studies The UK Defence Analytical Service Agency (DASA, 2009) published summary statistics comparing mortality rates of 53,409 UK Gulf War veterans with those of 53,143 UK armed forces personnel of similar age, sex, service status, and rank who were in service at the same time, but not deployed to the gulf (era cohort). It reported 209 and 228 malignant neoplasms among the gulf and era cohorts, respectively (age-adjusted mortality RR 0.97, 95% CI 0.81- 1.18). They did not observe any significant associations for specific neoplasms. The Canadian Department of National Defense used the national mortality database and the national cancer registry to examine mortality rates and cancer incidence among Canadian Gulf War veterans from 1991 through 1999 (Statistics Canada, 2005). Two cohorts were established—the deployed cohort consisting of 5117 servicemembers sent to the gulf between August 1990 and October 1991, and the nondeployed cohort of 6093 servicemembers who were eligible for deployment but were not deployed. During the follow-up period, 10 deaths from cancer were identified in the deployed cohort and 15 in the nondeployed. The age-adjusted HR was 0.85 (95% CI 0.38-1.90). Among the deployed and nondeployed cohorts 29 and 42 incident cancers, respectively, were identified (age-adjusted HR 0.86, 95% CI 0.54-1.39). The largest number of the cases were cancers of the digestive tract (n = 15). There were also 8 testicular cancers and 4 brain cancers (all among the nondeployed). There was no evidence of an association between deployment and these specific cancers. In continued follow-up of the study by Macfarlane et al. (2003) (discussed above), there was still no excess risk of mortality from malignant neoplasms with 2 more years of data (RR 1.01, 95% CI 0.79-1.30) (Macfarlane et al., 2005). Secondary Studies The Update committee identified eight secondary studies of multiple outcomes that had been included in Volume 4, but had not been considered in that review of malignant neoplasms (Goss Gilroy, 1998; Iowa Persian Gulf Study Group, 1997; Ishoy et al., 1999a; Kang et al., 2000; Kelsall et al., 2004a; McCauley et al., 2002; Simmons et al., 2004; Steele, 2000). Because there is specific mention of cancer in these studies, they are described here in chronological order. From September 1995 through May 1996, the Iowa Persian Gulf Study Group (1997) performed a cross-sectional telephone survey to solicit self-reported illness in Iowan military personnel active during the Gulf War (n = 4886). Members of the National Guard who had been deployed (n = 911) were more likely to report any cancer than nondeployed National Guards members (n = 831) (prevalence difference [PD] 1.3, 95% CI 0.6-2.0), but the prevalence was similar compared with the deployed (n = 985) and nondeployed regular military (n = 968) (PD 0.3, 95% CI −0.6-1.2). Specific reports of skin cancer followed a similar pattern.

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HEALTH OUTCOMES 77 The Canadian Department of National Defense commissioned Goss Gilroy, Inc., to assess the prevalence of health outcomes in Canadian forces deployed to the Gulf War (Goss Gilroy, 1998). In 1997, a questionnaire was administered to 3113 Gulf War deployed veterans and 3439 active but nondeployed Canadian veterans. Among the respondents 20-44 years of age, 0.8% of the deployed veterans and 0.5% of the nondeployed reported any cancer, and among the 45-65 year olds, the prevalence of any cancer was 4.2% in the deployed veterans and 2.5% in the nondeployed veterans. Ishoy et al. (1999a) conducted a cross-sectional clinical examination study during 1997. Participants included Danish servicemembers deployed to the Gulf (n = 686) and eligible but nondeployed Danish servicemembers (n = 231). Skin cancer was assessed; however, results were not presented since the p-value comparing the two groups was greater than 0.05. Kang et al. (2000) conducted a health survey comparing self-reported health outcomes for a population based sample of 15,000 deployed and 15,000 nondeployed US Gulf War veterans. Based on the responses from 11,441 deployed and 9476 nondeployed veterans, they estimated the population prevalence rates of various medical conditions. The estimated population prevalence for skin cancer was 1.5% for the deployed and 1.4% for the nondeployed veterans, with a significant difference (rate difference 0.15, 95% CI 0.11-0.19). A population based survey of Kansas veterans deployed to the gulf (n = 1548) and nondeployed (n = 482) examined the health outcomes of deployment through automated telephone interviews to define and establish prevalence of “Gulf War illness” symptom complex (Steele, 2000). The incidence of disease diagnosed or treated by a physician was tracked through 1998. The OR for cancers, not including skin cancer (n = 18) was 1.21 (95% CI 0.40-3.69), and the OR for skin cancer (n = 23) was 1.17 (95% CI 0.47-2.90), adjusting for sex, age, income, and level of education. In 1999, McCauley et al. (2002) conducted a telephone survey of 2918 active or reserve Army or National Guard veterans resident in Oregon, Washington, California, Georgia, or North Carolina. Among the 1263 deployed subjects, 21 incident cancers were reported, compared to 3 among the 516 nondeployed comparison group (OR 3.0, 95% CI 1.0-13.1). Details on year of diagnosis and type of cancer were obtained for 20 of the 24 cases. When all skin cancers (n = 7) and cases that were not confirmed at the time of telephone follow-up (n = 4) were excluded, the OR was 4.94 (95% CI 0.6-38.1) and there was no apparent trend for any specific type of cancer. Among the Gulf War veterans, there was no indication of an association of cancer risk with exposure to nerve agents at Khamisiyah, defined as being within a 50-km radius of Khamisiyah between March 4, 1991, and March 13, 1991 (OR for exposed vs unexposed 0.4, 95% CI 0.1- 1.4). A cohort study of Australian service personnel who had (n = 1456) or had not (n = 1588) been deployed to the gulf was designed to investigate the association of symptoms and medical conditions with immunizations and other Gulf War exposures (Kelsall et al., 2004a). This study was included in Volume 4 as a major cohort study and specifically in the reviews of diseases of the circulatory system, diseases of the respiratory system, and symptoms in general. However, skin cancer, other than malignant melanoma, was also one of the 15 most frequently doctor- diagnosed medical conditions reported by the participants. After medical record review, 92 deployed veterans and 110 nondeployed veterans had a possible or probable diagnosis of the malignancy. The OR, adjusted for service type, rank, age, education, and marital status was 1.0 (95% CI 0.7-1.3). 77

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78 GULF WAR AND HEALTH Simmons et al. (2004) conducted a retrospective cohort study of male UK Gulf War deployed veterans (n = 23,358) and a comparable cohort of nondeployed veterans (n = 17,730) for self-reported health outcomes. Among the deployed veterans, 127 cancer cases, including malignant neoplasms and brain tumors were reported, compared to 88 among the nondeployed veterans (OR 1.1, 95% CI 0.9-1.5). Finally, the Update committee identified two new secondary studies with information on cancer outcomes. From 1994 to 1996, Proctor et al. (2001a) evaluated health-related quality of life among 141 Gulf War deployed veterans and 46 veterans deployed to Germany, selected from active-duty, reserve and National Guard troops deployed through Fort Devens, Massachusetts. Among the Gulf War deployed veterans and the Germany deployed participants, 2.1% and 4.4% respectively, reported cancer, excluding skin cancer. In 2005, Kang and colleagues published a follow-up survey of the sample (15,000 deployed and 15,000 nondeployed US Gulf War veterans) described in the earlier study (Kang et al., 2000, 2009). Among the 6111 deployed and 3859 era veterans who responded, 1160 reported skin cancer diagnoses and 990 reported “other cancer.” The risk ratios, adjusted for age, sex, race, body mass index, current cigarette smoking, rank, branch of service, and unit component, for skin cancer and other cancer were 1.09 (95% CI 0.97-1.22) and 1.09 (95% CI 0.96-1.24), respectively. Summary and Conclusions There is no consistent evidence of a higher overall incidence of cancer in veterans who were deployed to the Gulf War than in nondeployed veterans. An association of brain-cancer mortality with possible nerve-agent exposure (based on the 2000 DoD exposure model) was observed in one study discussed in Volume 4 (Bullman et al., 2005), and the association holds up with an additional 4 years of follow-up in the same cohort (Barth et al., 2009). The association with exposure to smoke from oil-well fires became stronger with further follow-up. However, the numbers of cases of brain cancer who had possibly been exposed to nerve agents as a result of the Khamisiyah explosion was small, and there is little previous evidence of an association of sarin or organophosphate pesticides with brain cancer. Therefore, the committee concluded that there was insufficient/inadequate evidence of an association between Gulf War exposures and brain cancer. Mixed results for testicular cancer were reported by the Volume 4 committee; however, the Update committee did not identify any new studies of this cancer site. In general, many veterans are still too young for cancer diagnoses, and for most cancers the follow-up period after the Gulf War is probably too short to expect the onset of cancer. Therefore, the committee believes that further follow-up is necessary to be able to make a conclusion about whether there is an association between deployment during the Gulf War and cancer outcomes. The committee concludes that there is insufficient/inadequate evidence of an association between deployment to the Gulf War and any cancer. Recommendation: Due to the long latency period for cancer, there needs to be continued follow-up of Gulf War veterans and an appropriate comparison group to adequately determine any association.

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TABLE 4-1 Cancer Study Design Population Outcomes Results Adjustments Comments Brain cancer Bullman et Cohort 100,487 US Army Brain cancer Exposed (25 cases) vs Age at entry, 9-year follow-up likely al., 2005 mortality study GWVs exposed to mortality unexposed (27 cases) race, sex, unit too short to examine (Vol. 4) (population chemical warfare through RR 1.94 (95% CI 1.12-3.34); component, and brain cancer risk from same agents at December 2000 Exposed 1 day: RR 1.72 rank (increases with time source as Kang Khamisiyah; 224,980 ascertained from (95% CI 0.95-3.10) since exposure); and Bullman, nonexposed Army BIRLS and NDI Exposed 2+ days: RR 3.26 multiple comparisons; 1996, 2001) GWVs; exposure (95% CI 1.33-7.96) death certificate determined from the diagnosis DoD plume model Barth et al., Mortality 621,902 US GWVs Brain cancer GWVs (144 cases) compared Race, service Similar results after 19 2009 cohort study, and 746,248 mortality to era veterans (228 cases) branch, type of misclassified cancers (Update) follow-up nondeployed era MRR 0.90 (95% CI 0.73- unit, age, marital were removed from through 2004 of veterans; 1.11) status, and sex analysis same cohort as 98,406 GWVs Khamisiyah exposed: Kang and exposed to MRR 2.71 (95% CI 1.25- Bullman (2001) Khamisiyah nerve 5.87) agents; 123,478 Oil-well fire smoke exposed: GWVs exposed to MRR 1.81 (95% CI 1.00- oil-well fire smoke 3.27) Testicular cancer Knoke et al., Cohort study US, all regular, First diagnosis of GWVs (134 cases) vs NDVs Race or Short follow-up time, 1998 (follow-up of active-duty male testicular cancer (371 cases) ethnicity, age, but right age range; (Vol. 4) Gray et al., servicemembers at US military RR 1.05 (95% CI 0.86-1.29) occupation no specific exposures 1996) GWVs (n = 517,223) hospitals evaluated; NDVs (n = worldwide military hospitals only 1,291,323) (7/31/1991- 3/31/1996) Testicular GWVs (cases = 17) vs NDVs Age, state of Levine et al., Population- US, all personnel cancers (cases = 11) (358 males with residence, 2005 based survey— (including reserves) deployed to Gulf War diagnosed 1991- cancer) deployment (Vol. 4) pilot study (GWVs) and random 1999 and PIR 2.33 (95% CI 0.95-5.70) status, race sample of NDVs; registered by DC GWVs (n = 621,902) or NJ Cancer NDVs (n = 746,248) Registries 79

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Study Design Population Outcomes Results Adjustments Comments 80 Gray et al., Hospitalizations 547,076 active-duty Hospital- GWVs vs nondeployed Prewar Limitations: 1996 from August GWVs, 618,335 non- discharge Last 5 months of 1991: 29 hospitalization, restricted to persons (Vol. 4) 1991 through GWVs diagnoses of cases vs 14 cases, SRR 2.12 sex, age, race, remaining on active September 1993 testicular cancer (95% CI 1.11-4.02) service branch, duty after the war, and (ICD-9-CM 1992: SRR 1.39 (95% CI marital status, thus does not include Code 186) 0.91-2.11) rank, length of veterans who may have 1993: SRR 0.89 (95% CI service, salary, left the service due to 0.54-1.44) occupation poor health; no adjustment for other potential confounders All cancers Kang and Cohort Deployed GWVs (n = Overall cancer Males: Age, race, Short latency; Bullman, mortality study; 621,902) compared to mortality GWVs (cases = 477) vs branch of low age range; 2001 follow-up from random sample of ascertained from controls (cases = 860): RR service, unit death certificates (Vol. 4) 1991 through nondeployed era BIRLS, death 0.90 (95% CI 0.81-1.01) component, 1997 veterans (n = certificates, and Females: marital status 746,248) NDI GWVs (cases = 49) vs controls (cases = 103): RR 1.11 (95% CI 0.78-1.57) Macfarlane et Cohort 51,721 UK GWVs, Cancers GWVs (cases = 270) vs Main analysis: Follow-up period al., 2003 (follow-up of 50,755 NDVs; identified from NDVs (cases = 269) sex, age group, shorter than expected (Vol. 4) Macfarlane et random samples National Health Main study: RR 0.99 (95% service branch, latency for most al., 2000) Subgroup of 28,518 Service Central CI 0.83-1.17) rank cancers; GWVs and 20,829 Register; first Subgroup: RR 1.12 (95% CI Subgroup: low age; era veterans with diagnosis 0.86-1.45) smoking, grouped all cancer sites records of smoking 4/1/1991- alcohol use due to low numbers of and alcohol use 7/31/2002 occurrences Gray et al., Retrospective 652,979 GWVs, Hospital- DoD PMR 0.98 (95% CI Age, sex, race Able to assess only 2000 cohort, 652,922 randomly discharge 0.94-1.01) illnesses that resulted in (Update) hospitalizations selected NDVs diagnoses of VA PMR 0.88 (95% CI 0.78- hospitalization; from August 182,164 DoD neoplasms in 0.98) possible undetected 1991 through hospitalizations; DoD, VA, and COSHPD PMR 0.86 (95% confounders December 1994 16,030 VA COSHPD CI 0.61-1.1) hospitalizations; hospital systems 5,185 COSHPD hospitalizations

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Study Design Population Outcomes Results Adjustments Comments Smith et al., Hospitalizations Active-duty Postdeployment Veterans of Bosnia and Sex, age, marital Active-duty personnel 2006 cohort study personnel with a hospitalization veterans of SW Asia status, pay only; hospitalizations at (Update) (cohort data single deployment to: events (1991- compared to GW veterans grade, DoD facilities only from DMDC) Gulf War theatre (n = 2000) for an Any neoplasm: race/ethnicity, 455,465); Southwest ICD-9-CM Bosnia HR 0.61 (95% CI service branch, Asia peacekeeping diagnosis of 0.50-0.76) occupation, and mission, 1991-1998 malignant SW Asia HR 1.03 (95% CI predeployment (n = 249,047); neoplasm (140- 0.93-1.15) hospitalization; Bosnia, 1995-1998 (n 208), and for Testicular cancer: time-dependent = 44,341) testicular cancer Bosnia HR 0.80 (95% CI covariate to specifically 0.27-2.39) account for SW Asia HR 0.64 (95% CI changing 0.32-1.28) hospitalization methods, diagnostic criteria, and procedures DASA, 2009 Summary UK GWVs (n = Mortality due to GWVs (209 cases) compared Single years of (Update) statistics of 53,409) vs era malignant to era veterans (228 cases) age structure of causes of death veterans (n = 53,143) neoplasms MMR 0.97 (95% CI 0.81- the Gulf cohort from April 1, 1.18) at January 1, 1991 to No significant difference in 1991 December 31, mortality rate was found for 2007 any of the specific classes of malignant neoplasm included in the study Statistics Retrospective 5117 Canadian Mortality and Cancer mortality, HR 0.85 Age, rank Limitations: Small Canada, 2005 cohort study GWVs; 6093 cancer (95% CI 0.38-1.09) sample size with low (Update) (based on Goss Canadian era incidences Incidence of any cancer (HR statistical power; young Gilroy, 1998) veterans, frequency determined from 0.86, 95% CI 0.54-1.39); age of cohort; short Approximately matched for age, sex, the CMD and cancer of the digestive follow-up period; no 2200 members and military duty CCD through system (HR 2.00, 95% CI information on of the deployed status 1999 0.62-6.12); testicular cancer confounding factors cohort were in (HR 0.76, 95% CI 0.18- the gulf region 3.24); cancer of the lymph during combat nodes (HR 0.65, 95% CI period 0.16-2.62) 81

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246 GULF WAR AND HEALTH Lang, K. A., and J. Saylor. 1995. Gastrointestinal symptoms and the Gulf War syndrome. Gastroenterology 108(4):A23. Lange, G., L. A. Tiersky, J. B. Scharer, T. Policastro, N. Fiedler, T. E. Morgan, and B. H. Natelson. 2001. Cognitive functioning in Gulf War illness. Journal of Clinical and Experimental Neuropsychology 23(2):240-249. Lange, J. L., D. A. Schwartz, B. N. Doebbeling, J. M. Heller, and P. S. Thorne. 2002. Exposures to the Kuwait oil fires and their association with asthma and bronchitis among gulf war veterans. Environmental Health Perspectives 110(11):1141-1146. Levine, P. H., H. A. Young, S. J. Simmens, D. Rentz, V. E. Kofie, C. M. Mahan, and H. K. Kang. 2005. Is testicular cancer related to Gulf War deployment? Evidence from a pilot population-based study of Gulf War era veterans and cancer registries. Military Medicine 170(2):149-153. Levy, R. L., W. E. Whitehead, M. R. Von Korff, and A. D. Feld. 2000. Intergenerational transmission of gastrointestinal illness behavior. American Journal of Gastroenterology 95(2):451-456. Levy, R. L., K. W. Olden, B. D. Naliboff, L. A. Bradley, C. F. Francisconi, D. A. Drossman, and F. Creed. 2006. Psychosocial aspects of the functional gastrointestinal disorder. Gastroenterology 130:1447-1458. Lincoln, A. E., T. I. Hooper, H. K. Kang, S. F. Debakey, D. N. Cowan, and G. D. Gackstetter. 2006. Motor vehicle fatalities among Gulf War era veterans: Characteristics, mechanisms, and circumstances. Traffic Injury Prevention 7(1):31-37. Lindem, K., T. Heeren, R. F. White, S. P. Proctor, M. Krengel, J. Vasterling, P. B. Sutker, J. Wolfe, and T. M. Keane. 2003a. Neuropsychological performance in Gulf War era veterans: Traumatic stress symptomatology and exposure to chemical-biological warfare agents. Journal of Psychopathology and Behavioral Assessment. 25(2):105-119. Lindem, K., S. P. Proctor, T. Heeren, M. Krengel, J. Vasterling, P. B. Sutker, J. Wolfe, T. M. Keane, and R. F. White. 2003b. Neuropsychological performance in Gulf War era veterans: Neuropsychological symptom reporting. Journal of Psychopathology and Behavioral Assessment.(2):121-127. Lindem, K., R. F. White, T. Heeren, S. P. Proctor, M. Krengel, J. Vasterling, J. Wolfe, P. B. Sutker, S. Kirkley, and T. M. Keane. 2003c. Neuropsychological performance in Gulf War era veterans: Motivational factors and effort. Journal of Psychopathology and Behavioral Assessment. 25(2):129-138. Longstreth, G. F. 2006. Functional dyspepsia—Managing the conundrum. New England Journal of Medicine 354(8):791-793. Longstreth, G. F., W. G. Thompson, W. D. Chey, L. A. Houghton, F. Mearin, and R. C. Spiller. 2006. Functional bowel disorders. Gastroenterology 130(5):1480-1491. Lucas, K. E., P. C. Rowe, and H. K. Armenian. 2007. Latency and exposure-health associations in Gulf War veterans with early fatigue onsets: A case-control study. Annals of Epidemiology 17(10):799-806. Macfarlane, G. J., E. Thomas, and N. Cherry. 2000. Mortality among UK Gulf War veterans. Lancet 356(9223):17-21.

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