1
INTRODUCTION

The Gulf War was considered a brief and successful military operation, with few injuries and deaths of US troops. The war began in August 1990, and the last US ground troops returned home by June 1991. Although most Gulf War veterans resumed their normal activities, many soon began reporting a variety of unexplained health problems that they attributed to their participation in the Gulf War, including chronic fatigue, muscle and joint pain, loss of concentration, forgetfulness, headache, and rash (see Appendix A).

One response to concerns about the veterans’ health problems was a request by the Department of Veterans Affairs (VA) that the Institute of Medicine (IOM) review the scientific and medical literature on the long-term adverse health effects of agents to which the Gulf War veterans may have been exposed. In 1998, the IOM and the VA entered into a contract for a series of studies that would provide conclusions about the strength of the association between exposure to the agents of concern and health outcomes as observed in the epidemiologic literature.

Congress, also responding to the growing concerns of ill veterans, passed legislation in 19981 for a similar study to that previously requested by the VA. The legislation directed the secretary of veterans affairs to enter into an agreement with IOM to review the literature on 33 agents related to service in the Gulf War and to assess the strength of associations between exposure to those agents and long-term adverse health effects as noted in the published literature. The legislation directs the secretary to consider the IOM conclusions when making decisions about compensation.

The following agents are listed in PL 105–277 and PL 105–368:

Pyridostigmine bromide.

Nerve agents and precursor compounds: Sarin and tabun.

Pesticides: Organophosphorous pesticides (chlorpyrifos, diazinon, dichlorvos, and malathion), carbamate pesticides (proxpur2, carbaryl, and methomyl), and chlorinated-hydrocarbon and other pesticides and repellents (lindane, pyrethrins, permethrins3, rodenticides [bait], and the repellent DEET [N,N-diethyl-3-methylbenzamide]).

Synthetic chemical compounds: Mustard agents, volatile organic compounds, hydrazine, red fuming nitric acid, and solvents.

Environmental particles and pollutants: Hydrogen sulfide, oil-fire byproducts, diesel heater fumes, and sand microparticles.

Sources of radiation: Uranium, depleted uranium, microwave radiation, and radiofrequency radiation.

1  

The two laws passed by Congress are the Persian Gulf War Veterans Act of 1998, PL 105–277, and the Veterans Programs Enhancement Act of 1998, PL 105–368.

2  

The committee searched and examined the literature on the insecticide propoxur.

3  

Permethrin is the name of a specific pyrethroid insecticide.



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Gulf War and Health: Insecticides and Solvents, Volume 2 1 INTRODUCTION The Gulf War was considered a brief and successful military operation, with few injuries and deaths of US troops. The war began in August 1990, and the last US ground troops returned home by June 1991. Although most Gulf War veterans resumed their normal activities, many soon began reporting a variety of unexplained health problems that they attributed to their participation in the Gulf War, including chronic fatigue, muscle and joint pain, loss of concentration, forgetfulness, headache, and rash (see Appendix A). One response to concerns about the veterans’ health problems was a request by the Department of Veterans Affairs (VA) that the Institute of Medicine (IOM) review the scientific and medical literature on the long-term adverse health effects of agents to which the Gulf War veterans may have been exposed. In 1998, the IOM and the VA entered into a contract for a series of studies that would provide conclusions about the strength of the association between exposure to the agents of concern and health outcomes as observed in the epidemiologic literature. Congress, also responding to the growing concerns of ill veterans, passed legislation in 19981 for a similar study to that previously requested by the VA. The legislation directed the secretary of veterans affairs to enter into an agreement with IOM to review the literature on 33 agents related to service in the Gulf War and to assess the strength of associations between exposure to those agents and long-term adverse health effects as noted in the published literature. The legislation directs the secretary to consider the IOM conclusions when making decisions about compensation. The following agents are listed in PL 105–277 and PL 105–368: Pyridostigmine bromide. Nerve agents and precursor compounds: Sarin and tabun. Pesticides: Organophosphorous pesticides (chlorpyrifos, diazinon, dichlorvos, and malathion), carbamate pesticides (proxpur2, carbaryl, and methomyl), and chlorinated-hydrocarbon and other pesticides and repellents (lindane, pyrethrins, permethrins3, rodenticides [bait], and the repellent DEET [N,N-diethyl-3-methylbenzamide]). Synthetic chemical compounds: Mustard agents, volatile organic compounds, hydrazine, red fuming nitric acid, and solvents. Environmental particles and pollutants: Hydrogen sulfide, oil-fire byproducts, diesel heater fumes, and sand microparticles. Sources of radiation: Uranium, depleted uranium, microwave radiation, and radiofrequency radiation. 1   The two laws passed by Congress are the Persian Gulf War Veterans Act of 1998, PL 105–277, and the Veterans Programs Enhancement Act of 1998, PL 105–368. 2   The committee searched and examined the literature on the insecticide propoxur. 3   Permethrin is the name of a specific pyrethroid insecticide.

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Gulf War and Health: Insecticides and Solvents, Volume 2 Diseases endemic to the region: Leishmaniasis, sandfly fever, pathogenic Escherichia coli, and shigellosis. Administration of live, “attenuated,” and toxoid vaccines. In response to VA and Congress, IOM determined that the study would be conducted in phases and that the initial phase would include review of the agents that were of most concern to the veterans. After meetings with Gulf War veterans, the first IOM Gulf War committee (The Committee on Health Effects Associated with Exposure During the Gulf War) decided that its study would focus on depleted uranium, pyridostigmine bromide, sarin, and vaccines (anthrax and botulinum toxoid). After reviewing IOM’s Gulf War and Health, Volume I (IOM, 2000) the secretary of veterans affairs determined that there was no basis to establish a presumption of a connection between Gulf War exposure to sarin, pyridostigmine bromide, depleted uranium, or anthrax and botulinum toxoid vaccines and various health outcomes (Department of Veterans Affairs, 2001). The conclusions and recommendations from the first report are presented in Appendix B. SCOPE OF VOLUME 2 This second volume focuses on long-term adverse health outcomes associated with exposure to insecticides and solvents. The IOM committee that was formed to conduct the second study (Gulf War and Health: Literature Review of Pesticides and Solvents) began its work by overseeing extensive searches of the peer-reviewed medical and scientific literature, described in Appendix C and Chapter 2. The searches retrieved about 30,000 potentially relevant references that were considered by the committee and staff. All searches were completed by August 2001; relevant studies published after that date will be reviewed by future IOM committees. After an assessment of those references, the committee focused on approximately 3000 epidemiologic studies that analyzed associations between the relevant insecticides and solvents and long-term adverse health effects in humans. Although the committee also examined the experimental evidence, animal studies had a limited role in its assessment of association between exposure and health outcome. The animal data were used to make assessments of biologic plausibility for adverse health outcomes. The animal data were not used as part of the weight-of-evidence to determine the likelihood that an exposure to a specific agent might cause a long-term outcome. The animal studies, however, were used as evidence to support the human epidemiologic data. Information on the specific insecticides and solvents used during the Gulf War was obtained from a variety of sources, including veterans, the Department of Defense (DOD), VA, the RAND Corporation, the Presidential Advisory Commission (Cecchine et al., 2000; PAC, 1996, 1997) and PL 105–277 and PL 105–368. On the basis of those sources, this IOM committee reviewed the literature on the long-term adverse health effects of “insecticides,” the classes of insecticides (such as organophosphorous compounds), and 12 specific insecticides and one insect repellent identified as having been used in the Persian Gulf. Although the committee also reviewed the literature on exposure to pesticides, it did not make conclusions of association on this broad category because it includes herbicides, fungicides, and other agents, known not to have been used during the Gulf War. Similarly,

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Gulf War and Health: Insecticides and Solvents, Volume 2 the committee reviewed the literature on the broad category of “solvents,” the classes of solvents, and 53 specific solvents (Appendix D). Although DOD sent rodenticides to the Persian Gulf, the committee did not review the health effects of rodenticide exposure. Inasmuch as those products were sent to the Persian Gulf in pellet form (Cecchine et al., 2000), exposure would have required ingestion. Because there were no accounts of military personnel consuming rodenticides, the committee did not believe it necessary to review their adverse health effects. 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 the 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. The committee’s charge was to assess the scientific evidence regarding long-term health effects associated with exposure to specific agents that were potentially present during the Gulf War. The secretary may consider the committee’s assessment as a compensation program for Gulf War veterans continues to be developed. USE OF INSECTICIDES IN THE GULF WAR Military personnel in the Gulf War were exposed to insecticides through field or personal use. Most used insecticides to control insects that could serve as vectors for infectious diseases, such as leishmaniasis, sand fly fever, and malaria. In addition to the list of insecticides congressionally mandated for study, the committee learned about insecticide use during the Gulf War from reports from DOD, the Office of the Special Assistant for Gulf War Illnesses (OSAGWI), surveys and self-reports from Gulf War veterans, and RAND (Cecchine et al., 2000; Fricker et al., 2000; OSAGWI, 2001; Spektor et al., 2000). The specific insecticides and quantities shipped to the Persian Gulf can be documented, but how they were used and the amount each person was exposed to are unknown. Under contract with DOD, RAND conducted interviews with 2005 service members regarding specific insecticides and their use in the Persian Gulf. On the basis of reports of those interviews, the committee added azamethiphos, bendiocarb, and d-phenothrin to the list of insecticides congressionally mandated for study. The entire list of insecticides under review may be found in Appendix D. According to DOD, most US service members had access primarily to two insecticides: permethrin and DEET. Permethrin was provided in spray cans for treating uniforms, and DEET in liquid or stick form was used as a personal mosquito and fly repellent. According to DOD, US service members were not provided with permethrin-pretreated uniforms. All other insecticides sent to the Gulf War were intended for use only by specifically trained people or for special applications (PAC, 1996). However, some service members reportedly used other, unapproved insecticides obtained on the local market, and pet tick and flea collars apparently were used by some US service members (OSAGWI, 2001). All insecticides shipped to the Gulf War had been approved by the US Environmental Protection Agency (EPA) or the US Food and Drug Administration for

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Gulf War and Health: Insecticides and Solvents, Volume 2 general use in the United States (PAC, 1996) at that time. However, EPA has since placed restrictions on some of the insecticides used during the Gulf War. USE OF SOLVENTS IN THE GULF WAR To determine the specific solvents used in the Gulf War the committee gathered information from several sources, including veterans, OSAGWI (2000), and DOD’s Defense Logistics Agency. As a result of its research, the committee ultimately identified 53 solvents for review (Appendix D). There is little information to characterize the use of solvents in the Gulf War. Wartime uses of solvents (such as vehicle maintenance and repair, cleaning, and degreasing) probably paralleled stateside military or civilian uses of solvents, but operating conditions in the Gulf War (such as ventilation and the use of masks) may have varied widely from stateside working conditions. The most thoroughly documented solvent exposure involved spray-painting with chemical-agent-resistant coating (CARC) (OSAGWI, 2000). Thousands of military vehicles deployed to the Gulf War were painted with tan CARC to provide camouflage protection for the desert environment and a surface that was easily decontaminated. Not all military personnel involved in CARC painting were trained in spray-painting operations, and some might not have had all the necessary personal protective equipment (OSAGWI, 2000). Personnel engaged in CARC painting were exposed to solvents in the CARC formulations, paint thinners, and cleaning products. As noted in the OSAGWI report, some of the solvents used to clean painting equipment might have been purchased locally and therefore not identified. COMPLEXITIES IN ADDRESSING GULF WAR HEALTH ISSUES Investigations of the health effects of past wars often focused on narrowly defined hazards or health outcomes, such as infectious diseases (for example, typhoid and malaria) during the Civil War, specific chemical hazards (for example, mustard gas and Agent Orange) in World War I and Vietnam, and combat injuries. Discussion of the possible health effects of the Gulf War, however, involves many complex issues, such as exposure to multiple agents, lack of exposure information, nonspecific illnesses that lack defined diagnoses or treatment protocols, and the experience of war itself. The committee was not charged with addressing those issues, but it presents them here to acknowledge the difficulties faced by veterans and their families, researchers, policy-makers, and others in trying to understand Gulf War veterans’ health. Multiple Exposures and Chemical Interactions Military personnel were potentially exposed to numerous agents during the Gulf War. The number of agents and the combination of agents to which the veterans may have been exposed make it difficult to determine whether any one agent or combination of agents is the cause of the veterans’ illnesses. These include preventive measures (such as use of pyridostigmine bromide, vaccines, and insecticides), hazards of the natural environment

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Gulf War and Health: Insecticides and Solvents, Volume 2 (such as sand and endemic diseases) job-specific exposures (such as paints, solvents, and diesel fumes), war-related exposures (such as smoke from oil-well fires, depleted uranium, and stress), and hazards associated with cleanup operations (such as sarin and cyclosarin). Thus, Gulf War military personnel may have been exposed to a variety of agents concurrently. That most epidemiologic studies analyze single agents, not combinations of agents, makes it difficult to determine the effects of multiple wartime exposures and stressors. Lack of Exposure Information Determining whether Gulf War veterans face an increased risk of illness because of their exposures during the war would require extensive information about each exposure (for example, the agents, duration of exposure, route of exposure, internal dose, and adverse reactions). But very little is known about most Gulf War veterans’ exposures and about their susceptibility to adverse effects. After the ground war, an environmental-monitoring effort was initiated primarily because of concerns related to smoke from oil-well fires4, and modeling efforts related to sarin exposure continue; however, there is sparse information on other agents to which the troops may have been exposed. Consequently, exposure data on most of the chemical agents are lacking or incomplete. Various exposure-assessment tools (such as global positioning systems) are being used to fill gaps in exposure information, but reconstruction of exposure events can never be completely accurate. Unexplained Symptoms Many Gulf War veterans suffer from an array of health problems and symptoms that are not disease-specific and are not easily classified with standard diagnostic coding systems. Population-based studies have found a higher prevalence of self-reported symptoms in Gulf War veterans than in nondeployed Gulf War-era veterans or other comparison groups (see Appendix A; Goss Gilroy Inc., 1998; Iowa Persian Gulf Study Group, 1997; Unwin et al., 1999). Gulf War veterans do not all experience the same symptoms, and that has complicated efforts to determine whether there is a unique Gulf War syndrome. The symptoms suffered by many Gulf War veterans do not point to an obvious diagnosis, etiology, or standard treatment. The War Experience It has been documented from the Civil War to the Gulf War that the experience of war, with its many physical and psychologic stressors, places military personnel at high risk for adverse health effects. Some of the effects that have been reported are poorly understood multisymptom clusters, including fatigue, shortness of breath, headache, sleep disturbance, forgetfulness, and impaired concentration (Hyams et al., 1996). In World War II veterans, exposure to combat was associated with physical decline or death during the postwar period 1945–1960 (Elder et al., 1997). Similarly, combat exposure in Australian Vietnam veterans was related to reports of chronic mental disorders, ulcers, rashes, back disorders, and ill- 4   Health effects of oil-well fires will be examined in Gulf War and Health, Volume 3, expected to be completed in the fall of 2004.

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Gulf War and Health: Insecticides and Solvents, Volume 2 defined conditions (O’Toole et al., 1996). Various labels have been used to describe such symptom clusters, including shell shock, combat fatigue, and irritable heart; but no single etiology has been determined (Hyams et al., 1996). In addition to the threat or experience of combat, the Gulf War involved rapid and unexpected deployment, harsh living conditions, and continuous anticipation of exposure to chemical and biologic agents, environmental pollution from oil-well fires, and family disruption and financial strain. Each of those stressors—let alone all of them combined—may have had adverse effects on the health of many Gulf War veterans (IOM, 2001). The committee, in responding to its charge, reviewed the literature on the agents associated with service in the Gulf War; it did not review the totality of the war experience (including pre- and post-deployment). The committee looked exclusively at the putative agents as though each one were the only risk factor for adverse health effects. The committee recognizes, however, that it might be important to look at the totality of the experience of war and its stressors, as well as at specific biologic, chemical, and radiologic exposures. ORGANIZATION OF THE REPORT Chapter 2 discusses the steps taken to identify and evaluate the literature and the criteria established by the committee to make conclusions of association. It also highlights many of the complex issues considered by the committee as the literature was reviewed. Chapters 3 and 4 are overviews of the toxicology of the relevant insecticides and solvents, respectively, and provide information on their short-term health effects in humans. Chapters 5–9 provide the committee’s in-depth review of the epidemiologic studies of exposure to insecticides and solvents with regard to long-term adverse health effects. They present the committee’s conclusions about the strength of the association between the putative agents and cancer (Chapters 5 and 6), neurologic effects (Chapter 7), reproductive effects (Chapter 8), and other health effects, such as dermatologic, renal, and hepatic outcomes (Chapter 9). There are several appendices in the report: Appendix A provides a discussion of the numerous studies of Gulf War veterans; the information offers background for the reader and provides a context for members of the IOM committee. Appendix B provides the conclusions and recommendations from Gulf War and Health, Volume 1. Appendix C provides a discussion of the methods used in searching the literature, while Appendix D includes a list of all insecticides and solvents identified as having been sent to the Persian Gulf. Appendix E provides a discussion and table of expected relative risks for lung cancer due solely to smoking for selected scenarios regarding the prevalence of smoking in the occupational cohort and in the general population. Appendix F describes the numerous neurologic tests that are used to diagnose neurologic health outcomes. Appendix G presents the committee’s conclusions organized by health outcome rather than by category of association.

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Gulf War and Health: Insecticides and Solvents, Volume 2 REFERENCES Cecchine G, Golomb BA, Hilborne LH, Spektor DM, Anthony CR. 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. DVA (Department of Veterans Affairs). 2001. Illnesses not associated with service in the Gulf during the Gulf War. Federal Register 66(130):35702–35710. Elder GH Jr, Shanahan MJ, Clipp EC. 1997. Linking combat and physical health: The legacy of World War II in men’s lives. American Journal of Psychiatry 154(3):330–336. Fricker RD Jr, Reardon E, Spektor DM, Cotton SK, Hawes-Dawson J, Pace JE, Hosek SD. 2000. Pesticide Use During the Gulf War: A Survey of Gulf War Veterans. Santa Monica, CA: National Defense Research Institute, RAND. Goss Gilroy Inc. 1998. Health Study of Canadian Forces Personnel Involved in the 1991 Conflict in the Persian Gulf. Volume 1. Ottawa, Canada: Goss Gilroy Inc. Prepared for the Department of National Defence. Hyams KC, Wignall S, Roswell R. 1996. War syndromes and their evaluation: From the U.S. Civil War to the Persian Gulf War. Annals of Internal Medicine 125(5):398–405. IOM (Institute of Medicine). 2000. Gulf War and Health: Depleted Uranium, Pyridostigmine Bromide, Sarin, Vaccines. Vol. 1. Washington, DC: National Academy Press. IOM. 2001. Gulf War Veterans: Treating Symptoms and Syndromes. Washington, DC: National Academy Press. 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. OSAGWI (Office of the Special Assistant for Gulf War Illnesses). 2000. Environmental Exposure Report: Chemical Agent Resistant Coating. Final Report. Washington, DC: US Department of Defense, OSAGWI. OSAGWI. 2001. Environmental Exposure Report-Pesticides. Washington, DC: US Department of Defense, OSAGWI. O’Toole BI, Marshall RP, Grayson DA, Schureck RJ, Dobson M, French M, Pulvertaft B, Meldrum L, Bolton J, Vennard J. 1996. The Australian Vietnam Veterans Health Study: II. Self-reported health of veterans compared with the Australian population. International Journal of Epidemiology 25(2):319–330. PAC (Presidential Advisory Committee on Gulf War Veterans’ Illnesses). 1996. Presidential Advisory Committee on Gulf War Veterans’ Illnesses: Final Report. Washington, DC: US Government Printing Office. PAC. 1997. Special Report. Washington, DC: US Government Printing Office. Spektor DM, Reardon E, Cotton SK. 2000. Documentation for the Survey of Pesticide Use During the Gulf War: The Survey Instrument. Santa Monica, CA: National Defense Research Institute, RAND. Unwin C, Blatchley N, Coker W, Ferry S, Hotopf M, Hull L, Ismail K, Palmer I, David A, Wessely S. 1999. Health of UK servicemen who served in the Persian Gulf War. Lancet 353(9148):169–17.