1
INTRODUCTION

The 1991 Persian Gulf War was considered a brief and successful military operation with few injuries and deaths among coalition forces. The returning veterans, however, soon began reporting numerous health problems that they believed to be associated with their service in the gulf. Many Gulf War veterans returned to normal activities, but a large number have had a wide array of unexplained illnesses.

In response to the growing concerns of ill Gulf War veterans, Congress passed two laws in 1998: PL 105–277, the Persian Gulf War Veterans Act, and PL 105–368, the Veterans Programs Enhancement Act. Those laws directed the secretary of veterans affairs to enter into a contract with the National Academy of Sciences (NAS) to review and evaluate the scientific and medical literature regarding associations between illness and exposure to toxic agents, environmental or wartime hazards, or preventive medicines or vaccines associated with Gulf War service and to consider the NAS conclusions when making decisions about compensation. The study was assigned to the Institute of Medicine (IOM).

The Persian Gulf War legislation directs IOM to study a wide array of diverse biologic, chemical, and physical agents (Box 1.1). Exposures to most of the Gulf War agents have been extensively studied and characterized, primarily in occupational settings (for example, exposure to pesticides, solvents, and fuels) but others have not been as well studied and characterized in human populations (for example, exposure to nerve agents and vaccines).

Given the large number of agents to study, IOM divided the task into several reviews. It has completed two reviews: Gulf War and Health, Volume 1: Depleted Uranium, Pyridostigmine Bromide, Sarin, Vaccines (IOM 2000) and Gulf War and Health, Volume 2: Insecticides and Solvents (IOM 2003). The conclusions of the first two reports are presented in Appendix A. The current volume examines the health effects of fuels, combustion products, hydrazines, and nitric acid. Those broad categories include the agents listed in the legislation (for example, hydrogen sulfide, oil-fire byproducts, and diesel-heater fumes).



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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 1 INTRODUCTION The 1991 Persian Gulf War was considered a brief and successful military operation with few injuries and deaths among coalition forces. The returning veterans, however, soon began reporting numerous health problems that they believed to be associated with their service in the gulf. Many Gulf War veterans returned to normal activities, but a large number have had a wide array of unexplained illnesses. In response to the growing concerns of ill Gulf War veterans, Congress passed two laws in 1998: PL 105–277, the Persian Gulf War Veterans Act, and PL 105–368, the Veterans Programs Enhancement Act. Those laws directed the secretary of veterans affairs to enter into a contract with the National Academy of Sciences (NAS) to review and evaluate the scientific and medical literature regarding associations between illness and exposure to toxic agents, environmental or wartime hazards, or preventive medicines or vaccines associated with Gulf War service and to consider the NAS conclusions when making decisions about compensation. The study was assigned to the Institute of Medicine (IOM). The Persian Gulf War legislation directs IOM to study a wide array of diverse biologic, chemical, and physical agents (Box 1.1). Exposures to most of the Gulf War agents have been extensively studied and characterized, primarily in occupational settings (for example, exposure to pesticides, solvents, and fuels) but others have not been as well studied and characterized in human populations (for example, exposure to nerve agents and vaccines). Given the large number of agents to study, IOM divided the task into several reviews. It has completed two reviews: Gulf War and Health, Volume 1: Depleted Uranium, Pyridostigmine Bromide, Sarin, Vaccines (IOM 2000) and Gulf War and Health, Volume 2: Insecticides and Solvents (IOM 2003). The conclusions of the first two reports are presented in Appendix A. The current volume examines the health effects of fuels, combustion products, hydrazines, and nitric acid. Those broad categories include the agents listed in the legislation (for example, hydrogen sulfide, oil-fire byproducts, and diesel-heater fumes).

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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 BOX 1.1 Agents Specified in PL 105–368 and PL 105–277 The following organophosphorous pesticides: Chlorpyrifos. Diazinon. Dichlorvos. Malathion. The following carbamate pesticides: Proxpur. Carbaryl. Methomyl. The carbamate pyridostigmine bromide used as nerve agent prophylaxis. The following chlorinated hydrocarbons and other pesticides and repellents: Lindane. Pyrethrins. Permethrins. Rodenticides (bait). Repellent (DEBT). The following low-level nerve agents and precursor compounds at exposure levels below those which produce immediately apparent incapacitating symptoms: Sarin. Tabun. The following synthetic chemical compounds: Mustard agents at levels below those which cause immediate blistering. Volatile organic compounds. Hydrazine. Red fuming nitric acid. Solvents. The following sources of radiation: Depleted uranium. Microwave radiation. Radio frequency radiation. The following environmental particulates and pollutants: Hydrogen sulfide. Oil fire byproducts. Diesel heater fumes. Sand micro-particles. Diseases endemic to the region (including the following): Leishmaniasis. Sandfly fever. Pathogenic escherichia coli. Shigellosis. Time compressed administration of multiple live, “attenuated,” and toxoid vaccines. SCOPE OF THIS VOLUME After the 1991 Gulf War, deployed veterans began to report more symptoms than their nondeployed counterparts according to numerous population-based studies from the United States (Iowa Persian Gulf Study Group 1997; Kang et al. 2000), United Kingdom (Cherry et al.

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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 2001; Unwin et al. 1999), Canada (Goss Gilroy Inc. 1998), and Denmark (Suadicani et al. 1999). Among the most common symptoms were fatigue, rash, headache, pain, and memory complaints. Symptoms often grouped together into clusters, which were characterized as “unexplained illnesses” because they did not fit any established medical diagnoses. Some 20–25% of deployed veterans reported symptom clusters—a rate 2 or 3 times that in nondeployed military personnel. The symptom clusters were associated with disability and poorer quality of life. But the deployed veterans did not appear to have higher rates of hospitalization or mortality, than veterans not deployed to the Persian Gulf. The search for causes of veterans’ symptoms has produced a large body of published studies. Exposures to numerous agents during the Gulf War (see Box 1.1) have been analyzed in relation to veterans’ symptoms. This volume, however, will examine health outcomes only as related to exposure to fuels, combustion products, hydrazines, and nitric acid. The various ways that the veterans might have been exposed to those agents are discussed briefly below and described in more detail in Chapters 3 and 9. During the 1991 Persian Gulf War, the Iraqis used Scud missiles that contained inhibited red fuming nitric acid (IRFNA), a highly corrosive oxidizing agent in liquid rocket fuel. It is believed that veterans might have been exposed to IRFNA when they disarmed or disposed of weapons or were downwind of the breakup, impact, or interception of a Scud. Hydrazine was probably not used in the Scuds, but it remains an agent of interest (Chapter 9). The most visually dramatic environmental event of the Gulf War was the smoke from more than 600 oil-well fires. Veterans were probably exposed through air pollution as smoke plumes rose and combined to form giant plumes that could be seen for hundreds of kilometers. There were other potential sources of exposure to petroleum-based products, such as gasoline, kerosene, and diesel fuels used in unvented tent heaters, cooking stoves, and portable generators. Petroleum products, including diesel fuels, were used to suppress sand and dust, and petroleum fuels were used for burning waste and trash. In light of those conditions, the committee used its collective judgment in choosing studies and occupations that it believed were most representative of the environmental exposures experienced by veterans in the Persian Gulf. The committee reviewed hundreds of studies to arrive at its conclusions about association between exposures and specific health outcomes. The committee reviewed epidemiologic studies of fuels and combustion products rather than the numerous components of those agents. Its review included all relevant experimental and epidemiologic studies. As noted above, because only a few studies were related directly to veterans’ exposures, the committee reviewed occupational, environmental, and clinical studies of populations that had been exposed to the agents of interest. Those studies often included people whose exposure was over a lifetime (such as in community air pollution studies) or included workers employed in a particular industry over many years. In contrast, the exposures experienced by veterans in the Persian Gulf were relatively short although the intensity might vary from occupational exposures. Therefore, the exposures experienced in the gulf might only approximate exposures described in the occupational literature used in this report. CHARGE TO THE COMMITTEE In accordance with PL 105–368 and PL 105–277, IOM appointed the Committee on Gulf War and Health: Literature Review of Selected Environmental Particulates, Pollutants, and Synthetic Chemical Compounds, which was asked to assess the following for associations

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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 between illness and each agent, hazard, or medicine or vaccine to the extent that available scientific data permit meaningful determinations: whether a statistical association exists between exposure to the agent, hazard, or medicine or vaccine and the illness, taking into account the strength of the scientific evidence and the appropriateness of the scientific methodology used to detect the association; the increased risk of the illness among human or animal populations exposed to the agent, hazard, or medicine or vaccine; and whether a plausible biological mechanism or other evidence of a causal relationship exists between exposure to the agent, hazard, or medicine or vaccine and the illness. The legislation did not provide the IOM committee with a list of illnesses suspected to be associated with exposure to the numerous agents in the Persian Gulf. The IOM staff and committee members developed such a list on the basis of the diseases and conditions that had been mentioned in the scientific literature that came to their attention through extensive literature searches, as described in Chapter 2. It should be noted that the charge to IOM was not to determine whether a unique Gulf War syndrome exists or to make judgments regarding whether veterans were exposed to the putative agents. Nor was the charge to focus on broader issues, such as the potential costs of compensation for veterans or policy regarding such compensation; such decisions are the responsibility of the secretary of veterans affairs. COMMITTEE’S APPROACH TO ITS CHARGE Specific details of how the committee approached its charge and the methods it used in reaching conclusions are discussed in Chapter 2. However, a brief overview is presented here. Evidence of Statistical Association The committee reviewed the available scientific evidence in the peer-reviewed literature to draw conclusions about associations between the agents of interest and adverse health effects. The committee placed its conclusions in categories that reflect the strength of the evidence of an association. In an effort to determine whether a statistical association between the putative agent and a health outcome exists, the committee adapted categories of association used by the International Agency for Research on Cancer in evaluating evidence of the carcinogenicity of various agents and categories used by numerous other IOM committees. The categories and the criteria for assigning a particular health outcome to a category are described in Chapter 2. It should be noted that the categories described are related to associations between exposure to agents and health outcomes in human populations, primarily from occupational studies, not to the likelihood that any individual’s illnesses are associated with a given agent. Determining Increased Risk in Gulf War Veterans The second part of the committee’s charge is to determine, to the extent permitted by available scientific data, the increased risk of illness among people exposed to the putative agents during service in the Persian Gulf. Generally, to accomplish that task, the committee

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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 would have reviewed studies of Gulf War veterans. However, many of the Gulf War veteran studies were hampered by poor measures of exposure to the putative agents, used questionnaires to identify illnesses and exposure to the agents of concern, or did not include outcomes measured with actual clinical examinations or laboratory tests. The committee therefore based its conclusions primarily on evidence from studies of people exposed to the putative agents in occupational or clinical settings rather than from studies of Persian Gulf veterans. The committee found the evidence from occupational studies sufficient for drawing conclusions about associations between the putative agents and health outcomes, but the lack of adequate data on the veterans themselves complicated its consideration of the second part of the charge—determination of increased risk in Gulf War veterans. To estimate the magnitude of risk of a particular health outcome among Gulf War veterans, the committee would need to compare the rates of health effects or disease in veterans exposed to the putative agents with the rates in those who were not exposed. That would require information about the specific agents to which individual veterans were exposed and about their doses. However, there is a paucity of data regarding the agents and doses to which individual Gulf War veterans were exposed. Furthermore, to answer questions about increased risk of illnesses in Gulf War veterans, it would be important to know the degree to which any other differences between exposed and nonexposed veterans could influence the rates of health outcomes or diseases; such information in the Gulf War veteran population is lacking. Because of the lack of various kinds of data on veterans, the committee could not extrapolate from the exposures in the studies that it reviewed to the exposures of Gulf War veterans. Therefore, it could not determine the likelihood of increased risk of adverse health outcomes among Gulf War veterans due to exposure to the agents examined in this report. Existence of a Plausible Biologic Mechanism or Other Evidence of a Causal Relationship Toxicologic data form the basis of the committee’s response to the third part of its charge—to determine whether there is a plausible biologic mechanism or other evidence of a causal relationship between exposure to a particular agent and a health effect. That information is summarized in general terms in Chapter 3. Specific toxicologic findings related to each health outcome are also given in the chapters that review the epidemiologic literature (Chapters 4–9). ORGANIZATION OF THE REPORT Chapter 2 discusses the considerations that guided the committee’s review and evaluation of the scientific evidence and the criteria that it established to draw conclusions of association. Chapter 3 provides background information on fuels and combustion products, discusses how the veterans might have been exposed to those agents, and provides an overview of their toxicology. In Chapters 4 through 8 the committee presents its review of epidemiologic studies that identify health outcomes related to exposure to the putative agents and provide conclusions about those associations. Specifically, Chapter 4 discusses cancer; Chapter 5 examines respiratory outcomes; Chapter 6 presents the committee’s findings with respect to cardiovascular outcomes; Chapter 7 reviews reproductive and developmental outcomes, including childhood cancers; and Chapter 8 presents remaining health outcomes, such as neurologic and dermatologic findings. Finally, Chapter 9 is organized differently from the previous five chapters in that all the health outcomes related to exposure to missile propellants—hydrazines and red fuming nitric acid—are presented.

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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 Additionally, Chapter 9 discusses how veterans might have been exposed to those propellants and presents an overview of the their toxicology. Appendix A provides the conclusions from the first two Gulf War reports. Appendix B provides details of the committee’s search strategy of the peer-reviewed medical and scientific literature. The types of studies reviewed by the committee and comments about the nature of the Gulf War studies are discussed in Appendix C. Descriptive tables of the cohort and case-control studies included in the cancer chapter may be found in Appendix D. REFERENCES Cherry N, Creed F, Silman A, Dunn G, Baxter D, Smedley J, Taylor S, Macfarlane GJ. 2001. 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. Goss Gilroy Inc. 1998. Health Study of Canadian Forces Personnel Involved in the 1991 Conflict in the Persian Gulf. Ottawa, Canada: Goss Gilroy Inc., Department of National Defence. IOM (Institute of Medicine). 2000. Gulf War and Health, Volume 1: Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines. Washington, DC: National Academy Press. IOM. 2003. Gulf War and Health, Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. Iowa Persian Gulf Study Group. 1997. Self-reported illness and health status among Gulf War veterans. A population-based study. The Iowa Persian Gulf Study Group. Journal of the American Medical Association 277(3):238–245. 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. Suadicani P, Ishoy T, Guldager B, Appleyard M, Gyntelberg F. 1999. Determinants of long-term neuropsychological symptoms: The Danish Gulf War Study. Danish Medical Bulletin 46(5):423–427. Unwin C, Blatchley N, Coker W, Ferry S, Hotopf M, Hull L, Ismail K, Palmer I, David A, Wessely S. 1999. Health of UK servicemen who served in Persian Gulf War. Lancet 353:169–178.