3
Background

Since the Persian Gulf War, the VA and DoD have undertaken various activities to address potential health consequences of service in the Persian Gulf theater, including activities involving the cooperation of several federal agencies. At the time of this writing (September 1994), the committee had learned of and evaluated the activities listed in Appendix E.

The committee sought to determine what is currently known about the health status of PGW veterans, and about their opportunities for exposures to various agents present in their environment and through their occupations in the Persian Gulf. We requested, received, and reviewed information from researchers involved in the activities listed in Appendix E. In addition, persons involved in some of these activities presented their work to the IOM committee in January and August 1994 (see Appendix B). The quantity and quality of supporting materials the committee received about the activities varied widely. Initially, the federal government lacked any overall strategy by means of which to evaluate a range of potential health effects. There is a need to develop a strategy that will promote a better capacity for the government to deal with these problems in future situations.

In an attempt to characterize and evaluate the various research activities as a response to the health concerns of PG veterans, the committee offers the comments in this chapter. We derived our findings and recommendations from the background information we present here.

In this chapter we discuss activities completed and underway in four major categories, boards and committees; population-based activities; activities



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Health Consequences of Service During the Persian Gulf War: Initial Findings and Recommendations for Immediate Action 3 Background Since the Persian Gulf War, the VA and DoD have undertaken various activities to address potential health consequences of service in the Persian Gulf theater, including activities involving the cooperation of several federal agencies. At the time of this writing (September 1994), the committee had learned of and evaluated the activities listed in Appendix E. The committee sought to determine what is currently known about the health status of PGW veterans, and about their opportunities for exposures to various agents present in their environment and through their occupations in the Persian Gulf. We requested, received, and reviewed information from researchers involved in the activities listed in Appendix E. In addition, persons involved in some of these activities presented their work to the IOM committee in January and August 1994 (see Appendix B). The quantity and quality of supporting materials the committee received about the activities varied widely. Initially, the federal government lacked any overall strategy by means of which to evaluate a range of potential health effects. There is a need to develop a strategy that will promote a better capacity for the government to deal with these problems in future situations. In an attempt to characterize and evaluate the various research activities as a response to the health concerns of PG veterans, the committee offers the comments in this chapter. We derived our findings and recommendations from the background information we present here. In this chapter we discuss activities completed and underway in four major categories, boards and committees; population-based activities; activities

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Health Consequences of Service During the Persian Gulf War: Initial Findings and Recommendations for Immediate Action based on health outcomes, both completed or well underway, and new or just beginning; and exposure assessment activities. BOARDS AND COMMITTEES The work of this IOM committee, as mentioned in the introduction, was specified under PL 102-585, with the original charge focusing on possible health effects of the oil well fires. Because concerns about adverse health consequences of the PGW have broadened since the law was passed, the IOM committee has considered the full range of potential health effects. Since PL 102-585 was passed in November 1992, the federal government has conducted and sponsored research activities under the auspices of several agencies, including the Department of Veterans Affairs, Department of Defense, Environmental Protection Agency, and Department of Health and Human Services. The earliest research on potential health consequences included some evaluation of the possible occurrence of post-traumatic stress disorder (PTSD) and the development of models to predict cancer risk from airborne products of the oil well fires. Initially, there were few panels, boards, committees, individuals, or councils to oversee, coordinate, direct, supervise, or advise those conducting the various federal activities. In May 1993, the VA held the first meeting of an informal "blue ribbon panel" of experts in response to a growing concern that PG veterans were experiencing unexplained illnesses. The group was chartered (October 8, 1993) as the Persian Gulf Expert Scientific Committee to advise the VA Assistant Chief Medical Director for Environmental Medicine and Public Health, and subsequently the VA Undersecretary for Health about medical findings affecting Persian Gulf veterans. The committee is charged to review all aspects of patient care and medical diagnoses, and will provide professional consultation as needed. This VA committee may advise on other areas involving research and development, veteran benefits, and training for patients and staff. The newly chartered committee met in February 1994, and again in April and July 1994. This is an ongoing advisory committee, with no set termination date. The Department of Defense also assembled a group of experts to examine reports of illnesses that could not be diagnosed. As requested by the Undersecretary of Defense in December 1993, a Task Force of the Defense Science Board (DSB) of the DoD was charged to review scientific and medical evidence relating to long-term health effects of exposure to low levels of neuro-toxic agents. The Task Force on Persian Gulf War Health Effects of the DSB first met in December 1993. Dr. Joshua Lederberg, the Rockefeller University, chaired the proceedings. Following the first meeting, the Task Force requested that the charge be changed to focus deliberations on the cause and effect of the

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Health Consequences of Service During the Persian Gulf War: Initial Findings and Recommendations for Immediate Action full range of exposure to low levels of chemicals, and also to environmental pollutants, endemic biologics, and other health hazards that might affect veterans of the Gulf War. An interim report was released March 15, 1994; the final report was released in June 1994 (DSB, 1994). The final report by the DSB task force does not provide evidence for any specific cause-effect relationships between putative exposures and an undefined illness. The medical nature and the cause or causes of GWS remained undefined by the Task Force. However, several hypotheses were considered, including some comparisons between chronic fatigue syndrome (CFS) and GWS. The DSB task force is convinced that GWS is not due to chemical or biological warfare agents. This Task Force has completed its work. During this same time, as concern about unexplained illness among Persian Gulf veterans continued to grow, the Secretaries of Defense, Veterans Affairs, and Health and Human Services established a Persian Gulf Veterans Coordinating Board on January 21, 1994, to ensure interagency coordination of all efforts, separate and joint, in research, clinical care, and disability determination and compensation for post-Operation Desert Shield/Desert Storm illnesses (PGVCB, 1994). The board released an interim report of activities April 1994, and an updated report in May 1994. PL 102-585 also requires that the President of the United States designate an appropriate department or agency of the federal government to coordinate all research activities undertaken or funded by the Executive branch on the health consequences of military service in the Persian Gulf theater of operations during the Persian Gulf War (see Appendix C). On August 31, 1993, President William Clinton designated the VA as the lead agency for this effort, which also includes the DoD, HHS, and EPA. This Persian Gulf Interagency Research Coordinating Council serves as the "Research Working Group" of the PG Veterans Coordinating Board mentioned above. Representatives of the Persian Gulf Interagency Research Coordinating Council sponsored a National Institutes of Health (NIH) Technology Assessment Workshop entitled The Persian Gulf Experience and Health, held April 27–29, 1994 (NIH Technology Assessment Workshop Panel, 1994). The workshop initially was expected to be a Consensus Development Conference on the issue of multiple chemical sensitivities (MCS), which some persons believe is linked to GWS. However, the Director of NIH determined that this issue would not fit the guidelines for Consensus Development, as not enough is known or generally accepted on the issue of MCS. Therefore, he assigned members of his staff to assist the Persian Gulf Interagency Research Coordinating Council in planning an appropriate workshop to evaluate PG-related health issues. The two-and-a-half-day workshop considered the following four questions: 1) What is the evidence for an increased incidence of unexpected illnesses

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Health Consequences of Service During the Persian Gulf War: Initial Findings and Recommendations for Immediate Action attributable to service in the Persian Gulf War? 2) If unexpected illnesses have occurred, what are the components of the most practical working case definition(s) based on existing data? 3) If unexpected illnesses have occurred, what are the plausible etiologies and biological explanations for these unexpected illnesses? 4) What future research is necessary? The panel was unable to develop a definition of the GWS that could be used to determine whether there is an association between exposures (plausible etiologies) and outcomes (otherwise unexplained illnesses). The panel criticized the lack of research and data available to date, and focused its recommendations on the following: 1) a short health questionnaire aimed at all 700,000 people who served in the PGW; 2) a focused hospital/clinical protocol for DoD and VA to use in their research on CFS; 3) designs for cohort and case-control studies of health effects of the Persian Gulf War; 4) a retrospective cohort study of pulmonary function in veterans; 5) retrospective simulation of exposures of possible health interest; 6) research into potential stressors; 7) development of effective responses to diagnosis and treatment of stress-related conditions; 8) planning for prospective data collection; and 9) further research on leishmaniasis, which has been mentioned as a possible cause of illness in PG veterans (NIH Technology Assessment Workshop Panel, 1994). Reports of a complex of signs and symptoms among PG veterans that could not be attributed to a known diagnosis have led to concerns about a "mystery illness" or "Gulf War Syndrome." Even though these reports remain controversial, veterans, their families, and veteran service organizations have organized support for persons reporting such signs and symptoms. Although the clinical assessment of PG veterans with undefined illnesses has benefited from some coordination of efforts between the VA, DoD, HHS, and EPA, the responses of various branches of the government have not been fully coordinated, and are not organized around clear clinical and scientific goals. Through its discussions with the various organizations and groups of investigators charged with investigating the health effects of Persian Gulf War service, the IOM Committee has become aware of the very significant barriers to effective coordination of activities among the various government agencies whose participation in such activities will be essential to their success. It has appeared to the committee that the responsibility of these groups has not been translated into effective action and that the impact on epidemiologic research studies appears to be nil. Large numbers of studies that are too small will not provide answers; if actively coordinated, the joint effort may be more effective in approaching a meaningful study size. The current coordination of many of the activities is on paper only. In fact, when several investigators were contacted regarding their work, they were surprised that other federal agencies had been listed as being involved in the coordination of their research. Addition-

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Health Consequences of Service During the Persian Gulf War: Initial Findings and Recommendations for Immediate Action ally, it has appeared to the committee that the term "coordination," means that information is simply shared between federal agencies (VA, 1994), but does not usually mean that efforts are made to reduce duplication of similar research activities. Therefore, the IOM committee believes that the authority of coordinating bodies to implement changes in programs and procedures within each of these agencies must be increased substantially. In particular, the committee believes that the leadership of the Vice President of the United States will be needed to achieve the coordination required for this effort. Given the necessary authority, the Persian Gulf Veterans Coordinating Board and the Persian Gulf Interagency Research Coordinating Council can play an important role in this effort. The Persian Gulf Veterans Coordinating Board, while serving many useful functions, does not appear to be taking the lead in coordinating research activities. This role should be filled by some group, somewhere. Coordinating bodies also can increase the ability of different agencies to link and to establish compatibility among databases. This will require doing detailed work on eligibility criteria, identifying information for individual records, and defining the variables to be linked. Finally, these coordinating bodies can support efforts to synthesize completed studies and to identify gaps in current knowledge. GENERAL COMMENTS ON STUDY DESIGN Although addressing public and individual concerns about long-term health effects of service in the Persian Gulf War were prominent in the initial charge to this committee, this issue has been largely displaced in public discussion by the growing concern that veterans and their families already are experiencing a variety of health effects of Gulf War service, including those known collectively as the Gulf War Syndrome. Groups of veterans and their families were the first to focus public attention on the possible adverse health consequences of service in the Persian Gulf. Their concerns have elicited a variety of institutional responses and investigations, as described in subsequent sections of this chapter. Some of these investigations can be characterized as "hot pursuit" or "cluster" studies of groups of apparently affected veterans. Other responses, especially the creation of the VA Persian Gulf Health Registry, represent efforts to identify and provide care to those self-identified as experiencing health problems consequential to Gulf War service. Though these efforts may be seen as responsive to community concerns and may also provide care to those who are ill, the methods used to select participants and collect data make these undertakings intrinsically unsuitable for systematic study of the health effects of the Gulf War.

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Health Consequences of Service During the Persian Gulf War: Initial Findings and Recommendations for Immediate Action Because "hot pursuit" studies and the Persian Gulf Health Registry represent samples of self-identified respondents, the data they provide are not representative of the collective experience of the entire cohort of Gulf War veterans. In the absence of data about the population at risk, these studies provide no information about the frequency of specific illnesses or syndromes in that population. Because no control populations are studied, no attributions of health outcomes to Gulf War service or specific exposures can be made. Moreover, although studies of groups of individuals reporting illness sometimes can yield insight about either the characteristics of the illness or the exposures shared by those affected, these early studies of Gulf War veterans have not achieved either of these objectives. Given the level of public concern about health effects of service in the Persian Gulf War, it is vital that future studies of Gulf War veterans be based on more rigorous epidemiological methods. Defining the population at risk is the priority task in order to assess the health effects of the Gulf War. Therefore, the Department of Defense must complete its Registry of Unit Locations as soon as possible, and also must request a review of that database by scientists competent to assess its sufficiency for future epidemiological investigations. Developing this population registry will create the potential for several investigations that can define the scope of health effects related to Persian Gulf service. First, it will be possible to perform a population-based survey of the current health status of Gulf War veterans. Second, it will be possible to create a cohort of veterans who can be followed to assess long-term health effects. Third, it will provide a context for the conduct of population-based case-control studies of specific illnesses or syndromes. The merits of each of these approaches to further study the health effects of Gulf War service are discussed in subsequent sections. We emphasize, however, that each of these studies will require the creation of a valid population registry. Finally, the committee believes that every proposal to study Gulf War veterans must be subjected to rigorous scientific review and must be evaluated in the context of other research. POPULATION-BASED ACTIVITIES The Department of Defense is assembling a "Registry of Unit Locations" as required originally by PL 102-190 and modified by PL 102-585. The committee concludes that the Registry of Unit Locations has the potential to be an essential data source for epidemiological investigation because it will be the single best source of data about service members discovered to date, and because it will attempt to define the entire population at risk. Designed to include basic demographic and personnel data for every member of the military

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Health Consequences of Service During the Persian Gulf War: Initial Findings and Recommendations for Immediate Action who served in the Gulf War between January 1, 1991, and the withdrawal of the last troops, also to be included is information on the day-by-day location of all troops at the unit level. This database is designed to interface with a similar computer-based registry of oil well fire exposure data such that individual exposure matrices can be developed. This registry will include procedures both to verify which veteran units served in the Gulf War, and to standardize quality control of the database. Nevertheless, not enough information was available to the IOM committee to determine whether the data will be of a quality suitable for research purposes. Accordingly, this committee has considered ways to improve completeness and accuracy in data acquisition and extraction. The usefulness of this registry in studies of possible cause-effect relations will depend heavily on the quality of the exposure data. HEALTH-OUTCOME-BASED ACTIVITIES-COMPLETED OR WELL UNDERWAY Constructing a Case Definition During and since the Persian Gulf War, a proportion of returned American service personnel have reported conditions that they attribute to their assignment to the Arabian peninsula and its environs, including their experiences during and after the military campaign continuum called Operation Desert Shield and Desert Storm. Most of these medical problems have been diagnosed and treated in the usual way. However some have been misdiagnosed, have defied diagnosis, or have failed to respond to treatment as expected. Of these, some began in the theater of operations before, during, or after the brief period of combat; others followed the service member's return to the U.S., after a time that ranged from days to many months or even years. Furthermore, some of these men and women subsequently became parents, and some of their offspring have suffered birth defects or other ailments. Over time the symptoms of these persons (some still on active duty, but most returned to civilian life) became increasingly publicized. Networking of various types, inquiries and reports by the media, and responses by politicians to complaints from constituents have coalesced into a broad public perception that there is or may be some type of "mystery illness" resulting from service in the Persian Gulf. Manifestations have been varied from person to person, but often include arthralgia, weakness, fatigue, headache, memory loss, and other mental impairment. Skin rashes and hair loss have also been mentioned frequently. Problems reported in offspring ranged from miscarriage to Down's syndrome to failure to thrive.

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Health Consequences of Service During the Persian Gulf War: Initial Findings and Recommendations for Immediate Action No known etiology could account for this collective picture, although descriptive diagnoses could be used for general symptoms (such as alopecia areata versus toxic alopecia versus male-pattern baldness; or adjustment reaction versus neurotic depression versus post-traumatic stress disorder versus malingering). Several hard-to-verify or obscure diseases have been invoked as causes of these reported symptoms, ranging from leishmaniasis to oxidative phosphorylation disorder. The very legitimacy of some mentioned causes has been questioned, such as multiple chemical sensitivity disorder. A variety of toxins have been suspected, including agents of chemical and biological warfare, fumes of both leaded and unleaded fuels, components of smoke from burning oil wells, illicit substitutes for alcohol, and recreational drugs. Differences in reported rates of the "mystery illness" among different population segments appear to be both substantial and unexplained. For example, there appears to be no similar condition in the indigenous population, which must have been exposed to local environmental hazards, including products of the oil fires, earlier more intensively, and later than the U.S. military forces (Blanck, 1994; DSB, 1994). Similarly, there seems to be no corresponding problem with the "mystery illness" in members of the Allied Armed Forces. At this time, data are not adequate to determine whether substantial differences exist between men and women, regular and reserve troops, and officers and enlisted personnel. These matters also must be considered in framing research questions. Mystery illnesses are observed from time to time in every population. Approximately 700,000 U.S. military personnel served in the Persian Gulf. Study of a random sample of that number of persons from the U.S. population, of similar age and sex distribution and similar good health at the start of a period of observation, surely would show that some proportion of them would become ill with some kind of "mystery illness" that causes considerable distress and that has not been fully explained and understood within the U.S. medical system. The question thus is not whether there are any "mystery illnesses" among the returning service personnel, but whether the number or characteristics of such conditions exceeds what one might expect if the same persons had not served in the Gulf War. In short, it is not enough to point to a small number of fully confirmed ''mystery illnesses;" a control population is needed to provide U.S.-based background rates of such conditions. Unusual psychological stress has been promoted as a possible cause or contributing factor to the "mystery illness," but there appears to have been no direct comparison of levels of stress with stress levels reported in other conflicts, such as those in Vietnam, Korea, and World War II. The committee notes that many of the military personnel in the Gulf were older reservists, not new recruits. On the other hand, the committee has heard from several secondary sources that persons in the regular military services do not want to complain about health problems that are less than intolerable, because of possible adverse repercussions on their military careers.

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Health Consequences of Service During the Persian Gulf War: Initial Findings and Recommendations for Immediate Action One of the major obstacles to doing studies of unexplained illnesses is the lack of a case definition. Several attempts have been made to form such a definition for the purposes of identifying people to include in an epidemiological study. The committee agrees with the report of the NIH panel that ''it is impossible at this time to establish a single case definition" (NIH Technology Assessment Workshop Panel, 1994). The Gulf War illness phenomenon may prove to be a mixture of several illnesses, or may prove not to be associated with a specific exposure or disease. Without understanding the nature and etiology of the phenomenon, investigators must be prepared to adapt their case definition to new information as it emerges. Still, a provisional case definition is required for certain types of scientific research. For example, a provisional case definition could provide a basis for a case-control study comparing the Gulf War experience of veterans with symptoms meeting the case criterion with veterans without such symptoms. If such a study is undertaken, it should meet usual standards for size, rigor, and clarity of purpose as case-control studies conducted in other settings. In particular, a study should be large enough to identify patterns of exposure or Gulf War experience among those complaining of Gulf War illness. A provisional case definition also may have a role in clinical management of Gulf War veterans. Such a definition might be used to identify veterans eligible for care for these symptoms at VA hospitals. It should be recognized, however, that any such case definition would not have a firm scientific basis. We concur in the recommendations of the NIH panel that eligibility for medical care not be based on case definition. The proposals for a case definition developed to date have several elements in common, including service in the Persian Gulf theater (proposed to be the time span of August 8, 1990, to late July 1991 (Sanford, 1994)); a requirement that the person report a combination of several symptoms from a list that includes fatigue; arthralgia; headache; diarrhea; neuropsychiatric complaints (forgetfulness, difficulty concentrating, depression, memory loss, irritability); difficulty sleeping; fever; weight loss; dyspnea; rash; and myalgia; and that the diagnosis be made only when known clinical conditions with similar symptoms have been excluded. Case definition is, at the moment, handicapped by the lack of any generally recognized pathognomonic physical signs or laboratory findings, and by uncertainty about whether a specific syndrome exists and, if it does exist, its prevalence among Gulf War veterans. The subjectivity of many of the complaints associated with the Gulf War illness creates serious problems for those seeking to investigate the validity and origins of the illness. The symptoms have been widely publicized, and any attempt to estimate the prevalence of the problem from self-reports could be contaminated by well-known problems of

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Health Consequences of Service During the Persian Gulf War: Initial Findings and Recommendations for Immediate Action self-reporting. Restrictive policies regarding treatment at VA hospitals could create incentives for veterans to report symptoms now as insurance against a future need to seek medical care. Outbreak Investigations In response to reports of outbreaks of unexplained signs and symptoms in Gulf War veterans, the DoD conducted two outbreak investigations to determine whether further study of these groups was necessary, or whether these particular "clusters" showed any indicators of common exposures that could be pursued as a connection to the presenting signs and symptoms. These "hot pursuit" studies, in which investigators focused on reported clusters of symptoms or illnesses among Persian Gulf War veterans, are similar in many respects to the frequent "cluster studies" of illness in the United States with a possible environmental cause (Caldwell, 1990). This analogy is instructive, because many of the investigators who have participated in such cluster studies have become skeptical about their scientific value (Rothman, 1990). The typical cluster study is characterized by small sample size, an implicit multiple comparisons problem (in that many other groups of people could have been studied but were not, because the individuals did not report a cluster), a poorly identified exposure, and a significant potential for information bias resulting from respondent awareness of the underlying concern. In the environmental domain, these studies rarely have been fruitful (Cutler et al., 1986; Bender et al., 1990). A few of these studies, especially if they are done well, can be useful at the early stages of an investigation by helping to define the problem and by ruling out both some statistical flukes that have been misinterpreted and some possible etiologies. That phase of research on the reported "Gulf War Syndrome" has been completed. The exploratory studies failed to generate useful leads about either the condition or the exposures that might cause it. Proposals for future studies of this type should be scrutinized very carefully. Additional studies of this type are unlikely to be useful, and they may divert attention and resources away from studies that could be useful. The first "hot pursuit" investigation was reported by Major Robert F. DeFraites, MC, and colleagues (DeFraites et al., 1992) who investigated reports of symptomatic complaints among reservists belonging to the 123d Army Reserve Command (ARCOM), Lafayette, Indiana. Early in 1992, staff of the 123d ARCOM Surgeon's Office became aware of these complaints, which were subsequently reported by members of the 417th Quartermaster Company, Scottsburg, Indiana.

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Health Consequences of Service During the Persian Gulf War: Initial Findings and Recommendations for Immediate Action In response to growing concern about these complaints, Major DeFraites visited Fort Benjamin Harrison and neighboring facilities in April 1992. During this visit, 79 reservists were evaluated. All 79 study participants completed a medical questionnaire, and 78 were interviewed using a short symptom inventory. Each reservist interviewed completed a brief psychiatric intake-type interview, and had vital signs measured. All but one of the reservists received a dental examination. All 78 who participated in the interviews also had blood drawn for complete blood count, white blood cell differential, platelet count, erythrocyte sedimentation rate, and liver function studies. All sera were tested for antibody to Leishmania tropica. Sera from selected individuals were tested for antibody for brucellosis. Limited comparative data were available from other groups of veterans. Fatigue was the most common symptom (70 percent). Other systemic symptoms, including fever, abdominal pain, and diarrhea were much less common. The onset of fatigue and associated symptoms tended to occur after redeployment from SWA, except that the onset of diarrhea was more frequent during deployment. No cases of leishmaniasis, brucellosis, or Lyme disease were detected. The objective findings did not suggest a common pattern of illness among the study group members. Review of potential exposures during ODS/S provided no evidence that the respondents had been exposed to microwaves, chemicals, radiation, or any other environmental hazard. These reservists did report high levels of stress, which may explain some of the symptoms. The investigators noted that the rapid deployment and subsequent redeployment was stressful for many reservists and their families. The investigators believed, however, that PTSD was present in few, if any, of these reservists. The investigators concluded that this study provided no objective evidence of an outbreak of any disease in this group. They thought that the documentable medical problems and illnesses found were typical of a general population with similar demographic characteristics. When it is not possible to define a population at risk, as in this case, the investigation does not provide a statistical basis for determining whether rates of symptoms or illnesses depart from expected rates by more than ordinary chance variation. Because of the need to contend with the operations of chance, "hot pursuit" is most effective when it focuses on a cluster of a typically rare disease, or when it uncovers a common pattern of exposure. Thus, as noted above, a "hot pursuit" investigation, in which a small group of apparent cases of disease are studied intensely, can on rare occasions be very useful, but it has important limitations. The problem here is that the group coming to clinical evaluation is a small subset of a larger deployed force, and its representativeness to the larger deployed unit is unclear.

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Health Consequences of Service During the Persian Gulf War: Initial Findings and Recommendations for Immediate Action Battery Repair: Corrosive liquids, particularly sulfuric acid, lead. Cleaning/Degreasing: Degreasing solvents generally including a range of chlorinated hydrocarbons such as trichloroethylene. Electronic/Radio Repair: Soldering fumes and cleaning solvents. Generator Repair: Carbon monoxide. Grinding/Sanding: Abrasive particulate. Sand blasting: Abrasive (possibly crystalline silica) particulates in the respirable range. Lathing/Milling: Metal working fluids. Vehicle Painting: Paint solvent vapors and mists. During primary and repair painting operations there was a potential for overexposure to isocyanate paints, which can cause primary sensitization and asthma as well as exacerbation of existing asthma. The chemical agent resistant coating (CARC) paint system was directly used by an estimated 1,000 troops (PGVCB, 1994). The number of vehicles painted each day varied between 10 and 100 at the major work site in Al Jabayl. At least one episode of overexposure was reported (December, 1990) (Riley, 1992). Refrigeration servicing: Lead fumes and exposure to refrigerant such as fluorocarbons. Vehicle Repair: Asbestos from brake repair, carbon monoxide, organic solvents. Weapons Repair: Lead particulate. Welding/Cutting: Chromates, ozone, nitrogen dioxides, heated metal fumes. USAEHA industrial hygiene sampling showed increases in personal or general air monitoring results of outdoor occupational environment from selected locations, but these increased levels still did not exceed recommended standards. Threat of Chemical and Biological Warfare Agents Direct and indirect statements to this committee by several Gulf War veterans and groups speaking on their behalf have ranged from worried concern to firm statements that troops were exposed to unspecified war agents, chemical, biological, or both. The strong suspicions seem to be that exposures were to nerve agents stockpiled by the Iraqis for use against Iran and the Kurdish population. Such stockpiling and use would have preceded Operation Desert Storm. Some claims have also been made that U.S. CDC Type-Cultures (anthrax and botulism) supplied by the United States to Iraq in the 1980's for research and vaccine production could have been fashioned into weapons and

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Health Consequences of Service During the Persian Gulf War: Initial Findings and Recommendations for Immediate Action used, overtly or covertly, against U.S. forces. Testimony before several Congressional committees has carried into the press strong assertions that members of Congress or their staffs actually have concluded that self-reported signs and symptoms said to be associated with soviet-designed surface-to-surface missiles (SCUD) attacks and concomitant chemical and biological warfare (CBW) alarms were sufficiently convincing to make a prime facie case for CBW use. These assertions have been amply reported elsewhere in the public domain and will not be repeated here. The committee could find absolutely no reliable intelligence, and no medical or biological justification for any of these purported claims. Furthermore, analysis of the attacks indicated that the alarms were false positives generated by dust particulates. When analysis of the alarms was followed by more sophisticated tests, the results were confirmed to be negative. This information speaks convincingly against the claims of CBW. Official analyses by the Central Intelligence Agency (CIA) Directorate of Intelligence, the CIA Non-Proliferation Center, the Defense Intelligence Agency, and a high-level all-source DoD committee, the Task Force of the Defense Science Board have concluded, independently and based on all-source/codeword access, that no use by intention or by accident occurred, and that bombing of storage areas both in theater and to the rear also did not cause CBW exposure. These reports are also in the public domain and will not be further referenced here. One member of the IOM committee obtained classified briefings on known Iraqi capabilities, believed intentions, and prior use of weapons of mass destruction. The committee as a whole obtained briefings on theater operations and CBW suspicions. This material was obtained and reviewed prior to and after disclosure and declassification of most of the same material and the committee found no inconsistencies. This material is now in the public domain and will not be further referenced here. The committee is not aware of any other actual data, complete or incomplete, that are inconsistent with the above conclusions and is not aware of any reports or studies, classified or unclassified that are inconsistent with the above. Therefore, the committee believes that the illnesses that have been reported are not the result of chemical, biological, or toxin warfare, or accidental exposures to stored weapons or research material. The committee believes further that, in light of this negative evidence from highly placed sources, claims of exposure to chemical or biological warfare agents should not be made or given credence in the absence of reliable data to the contrary.

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Health Consequences of Service During the Persian Gulf War: Initial Findings and Recommendations for Immediate Action Vaccines and Prophylactic Treatment Anthrax and Botulinum Toxoid The threat of CBW was quite real, as mentioned above, when troops were deployed. Threats of chemical and biological warfare were anticipated. DoD vaccinated some troops against anthrax and botulism, which were considered the biological warfare agents most likely to be encountered. These vaccines were not administered together. Individuals receiving vaccines signed their consent to a list. Prophylactic treatment against possible chemical warfare agents was provided in the form of self-administered pills. Respiratory-acquired anthrax is a fatal disease unless the diagnosis is made and appropriate antibiotic treatment is begun within hours of exposure. Botulism is a fatal disease caused by potent neurotoxins released by Clostridium botulinum that must be promptly neutralized by antitoxin therapy. There was concern that the Iraqi forces could use one or both of these agents against U.S. forces during ODS. Vaccines against them were made available to selected groups. Several factors have created questions about these vaccines: they were unique in the military immunization program; the botulism toxoid was distributed to the Army as an investigational new drug (IND) by the Food and Drug Administration (FDA) and was to be given on a voluntary basis with informed consent; the anthrax program was involuntary; many persons believed that these vaccines were not properly tested; the program was classified as secret; and each vaccine was intended to prevent serious disease induced by these potential biological weapons. These concerns have raised further questions about a possible role of these vaccines in the long-term health effects reported by some recipients. Anthrax vaccine contains the known protective antigen of a killed avirulent strain of Bacillus anthracis. In order to enhance its immunogenicity, it is absorbed onto an adjuvant, aluminum hydroxide. The vaccine has been produced by the Michigan State Department of Public Health and licensed since 1972. The primary nonmilitary use has been for persons with occupational risks—those workers who process wool, goat hair, animal hides, and bone and bone products. It has also been administered to laboratory workers. Over 7,900 doses have been given in the past 22 years to employees at the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID). The recommended dosage schedule of anthrax vaccine is 6 injections over an 18-month period. Few service members in ODS received more than the first 2 doses, given 2 weeks apart. The program was discontinued when the war was over. It is estimated that about 150,000 service members received at least one dose. The known side-effects of the vaccine include tenderness, erythema, and swelling at the injection site. These have been reported in about

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Health Consequences of Service During the Persian Gulf War: Initial Findings and Recommendations for Immediate Action 6 percent of recipients. Less that 1 percent have more severe local reactions, which may limit the use of the arm for 1 to 2 days. Systemic reactions rarely have been reported, and no chronic sequelae have been noted. The reaction rates among those receiving the vaccine in ODS were unmeasured. One person was hospitalized because of an infection at the injection site. Botulinum toxoid vaccine consists of five of the most common types of toxins (A, B, C, D, E) that have been toxoided by use of formalin. It is also manufactured by the Michigan State Department of Public Health. Alum is used as an adjuvant. Botulinum toxoid vaccine has status as an IND with the FDA, as mentioned, and has been used as an investigational vaccine for over 20 years. More than 3,600 doses have been administered at USAMRIID. This experience has permitted an estimate of the reaction rate. There have been more mild local reactions (up to 10 percent) than noted with anthrax vaccine, and about 3 percent experienced mild systemic reactions, such as headache, myalgia, fever, and malaise for 48 to 72 hours. No chronic sequelae have been reported. The vaccine is to be given in 3 injections: an initial dose, followed by other injections at 2 and 12 weeks, with a booster at 1 year. About 8,000 service members received at least 1 dose. The recipients were primarily members of the U.S. Marine Corps, First Marine Division, and the U.S. Army VII Corps. None of those troops received the anthrax vaccine. All members of these units were to have had the opportunity to volunteer and to give informed consent before receiving the vaccine. No reaction data were collected. A retrospective postcard survey was conducted at Camp Pendleton for the Marines who received the vaccine. Of the 123 cards mailed, 121 responded. Of respondents, 96 percent had received 2 doses; 12 percent reported mild local reactions; 14 percent reported pain that limited use of the arm temporarily; and 2.5 percent reported systemic symptoms that did not limit activity. There was no evidence of long-term effects. The military has had long experience with vaccine administration. There are 7 vaccines administered during basic training to Army recruits. All active duty Army personnel receive one additional vaccine, as well as boosters to two of the basic training immunizations. Seven other vaccines, excluding anthrax and botulinum toxoids, are given for deployment to high-risk areas, to alert forces, as required by host country, or as directed by the surgeon general. Each of these 15 vaccines can produce local or systemic reactions in recipients. The reactions noted with the anthrax and botulinum vaccines are not unique. The tetanus-diphtheria vaccine is a toxoid vaccine, and is employed worldwide without evidence of inducing chronic medical conditions. The ''antigenic load'' injected into service members is considerable; an even larger volume of antigens was given (up to 75 cc) to employees at Fort Detrick, Maryland. These people were studied over a period of 15 years and no evidence of im-

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Health Consequences of Service During the Persian Gulf War: Initial Findings and Recommendations for Immediate Action mune-associated illness was identified. No other chronic disease has been attributed to vaccine use. The swine flu episode of the mid-seventies caused large numbers of Americans to receive a new antigenic strain of influenza virus. Over 40 million people received the vaccine. Many of these recipients claimed that the vaccine initiated rheumatoid arthritis or exacerbated their arthritis. Others claimed to have developed neurological complications from the vaccine. However, several prospective studies demonstrated that there was no association between the vaccine administration and the claimants' arthritic conditions (Herron et al., 1979; Kurland et al., 1984). Conflicting data have been presented regarding neurological complications, but the best epidemiological data, from military records, show no increase in the incidence of Guillain-Barré syndrome. Most or all of the claims for both rheumatic diseases and Guillain-Barré syndrome seem to have been a result of coincidences that were wrongly interpreted to be causal. The U.S. Government did establish a fund to settle claims, but this was done in order to avoid legal expenses rather than because of a confirmed association between exposure and complications. The introduction of other vaccines in the last 30 years has been associated with similar examples of coincidences, such as a concern about neurological disease after use of a measles vaccine. One striking exception to this was the polio vaccine. The attenuated living strains have caused paralytic disease in a few recipients or persons infected from a vaccine recipient. Also, a "killed" polio vaccine that had been incompletely treated caused a form of polio. These are examples of disease that clearly can be attributed to the vaccine. We have no evidence that vaccines in general cause the non-specific complaints associated with service during Operation Desert Storm. Pyridostigmine Bromide Pyridostigmine bromide (PB) is a drug that belongs to the group of agents classified as anticholinesterases (AChE) that bind reversibly with acetylcholinesterase. This allows the temporary and partial buildup of acetylcholine, which may allow continuous stimulation of cholinergic receptors throughout the central and peripheral nervous system. This pharmacological action has been taken advantage of in the protection of military personnel from the effects of organophosphate toxic gases; these agents bind irreversibly with AChE causing life-threatening complications. PB can compete for binding sites and allow escape of AChE to permit more controlled transmission of nerve impulses. Anti-AChE agents are not new drugs. The first drug in this group, Physostigmine, was isolated in 1864. PB has been used for decades to treat patients with myasthenia gravis. (The dose employed is 360 mg to 6,000 mg

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Health Consequences of Service During the Persian Gulf War: Initial Findings and Recommendations for Immediate Action daily.) There is a great deal of pharmacological data, therefore, about the use of this drug. Some persons have claimed, however, that the dose recommended for use in military personnel in the war against Iraq (30 mg three times a day) had not been adequately tested in persons who have no diseases such as myasthenia gravis. Certain medical conditions can be made worse by anti-AChE agents. Thus, persons with asthma, coronary artery disease, or cardiac dysrhythmias (especially bradycardia) may have a worsening of their condition, and those who are sensitive to the drug may develop anaphylactic shock. These conditions occur promptly after an overdose of the drug; discontinuation of the drug and the administration of atropine lead to rapid recovery in most people. PB is poorly absorbed from the gastrointestinal tract. The bioavailability is 8 percent to 29 percent of ingested dose. It is 70 percent to 90 percent eliminated unchanged in the urine with the half-life of 3.7 hours. The maximum plasma concentration is reached in 1.7 hours. There is minimal penetration of the blood-brain barrier by this drug. The side effects of PB include those expected from stimulation of the peripheral parasympathetic nervous system, including nausea, vomiting, diarrhea, abdominal cramps, increased peristalsis, increased salivation, bronchial secretions, miosis, and diaphoresis. Skeletal neuromuscular junctions also are stimulated; the effects involve striated muscle groups—muscle cramps, fasciculation, and weakness. The bromide radical can cause skin rashes which subside when the drug is stopped. There have been no documented long-term side effects of the drug. No effects on pregnancy are known, but there is no evidence to suggest any adverse effects. All of the side effects noted above have been reported in PG military personnel taking PB for varying periods, including up to 50 percent in the U.S. Army Medical Research Institute of Chemical Defense (USAMRICD) study, 38 percent in flight crews, and 48 percent of those seen in health care facilities in the theater of operation. Gastrointestinal symptoms were the most common complaint. The frequency of these complaints was surprising in light of the few complaints among volunteers who took the same dose, but under more controlled experimental conditions. A possible explanation of these effects was the Stress of being in a hot desert environment and under the threats common to battle-grounds. A study of a small number of volunteers in a desert environment failed to show any difference in symptoms while taking PB versus a placebo (Cook et al., 1992). PB does raise body temperature slightly because it decreases blood flow to the skin, thus limiting heat loss by convection. Offsetting this effect is the increased sweating that occurs as a consequence of PB. In the volunteer study, the slight increase in temperature did not affect exercise tolerance in the heated chamber.

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Health Consequences of Service During the Persian Gulf War: Initial Findings and Recommendations for Immediate Action Other explanations for a possible increase in symptoms following PB ingestion have been raised by staff of the Senate Committee on Veterans Affairs. First, the reactions of women may differ from those of men, especially if they are on birth control pills; the effects of PB on women have not been studied. Second, the troops were not screened for those conditions that are contraindications to use of PB, including asthma, peptic ulcer disease, liver disease, kidney disease, or hypersensitivity to PB, though predeployment medical examinations should assume that these conditions, other than sensitivity, were present in few of the troops on active duty. A third hypothesis is a possible synergistic reaction between PB, the pesticides, the insect repellent-impregnated clothing used by the troops, or all of these. It has been known for many years that the simultaneous or sequential administration of two anti-AChE drugs would have an additive or even a synergistic effect. The staff of the Senate Committee cited recent studies in cockroaches, in which a combination of the "pesticide" DEET (actually an insect repellent) and PB was reported to be 10 times as toxic as DEET alone. Several pesticides in low doses are not toxic to most humans, but are effective against insects. Robbins and Cherniack (1986) have reported that DEET is only partially absorbed through the skin of humans and is rapidly but not completely excreted. DEET impairs mammalian biochemical pathways (reversibly inhibiting the urea cycle) and can block lactate-dependent synthesis of glucose (Heick et al., 1988; Brini and Tremblay, 1991). Pesticides such as permethrin (i.e., synthetic pyrethoids) modify the ionic permeability of nerve membranes and produce a neuroexcitatory toxic response (Casida et al., 1983; Vijverberg and van den Berchen, 1990). They have been shown to act in a stereospecific fashion, that is, in a fashion directly dependent upon the structural conformation of the pesticides, on sodium channels in nerve membranes (Eells et al., 1992). Permethrin has also been found to inhibit calcium-dependent ATP-ase enzyme activity in cells from the central nervous system (Kodavanti et al., 1993). Inhaled pesticides plus PB conceivably could have synergistic effects, but such effects would be immediately obvious, as was true for the combination that killed the cockroaches. The drugs do not persist in the body, and the IOM committee knows of no pharmacological reason why they should have any long-term effect. Other medications could possibly increase the risk of side effects of PB. Those drugs would include the beta-blockers used for treating hypertension. This combination could cause a further reduction in cardiac output and blood pressure. In rare persons, there could be bronchial constriction. A combination of PB with medications that cause vasodilation, for example calcium channel blockers, or direct-acting vasodilators in circumstances of poor hydration, could lead to lightheaded feelings or syncope. Antimalarial medications

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Health Consequences of Service During the Persian Gulf War: Initial Findings and Recommendations for Immediate Action in combination with PB could lead to diarrhea. Quinidine and PB could induce heart block, but the former is not used routinely for malaria prophylaxis or treatment. All these possible drug interactions (and others not mentioned) cause acute and short-lived problems. There is no evidence of any chronic effect. In summary, PB is a well-studied medication belonging to a class of drugs about which extensive knowledge exists. The DSB Task Force recommended doing a study of the effects of the drug and its metabolites to determine whether they cause long-term effects. The DSB Task Force believed that this was necessary because PB can prevent or ameliorate serious consequences of chemical warfare and must therefore be kept in the military's pharmacopoeia. It seems unlikely that these studies will be revealing, because so much information is available already, and the drug is excreted essentially unchanged. Depleted Uranium Daxon (1994) has reported that: Natural uranium is composed of three radioactive isotopes: U-238 (99.3 percent by weight), U-235 (0.7 percent), and U-234 (0.006 percent). The depleted uranium (DU) used by DoD is a by-product of the uranium enrichment process that increases the concentration of U-235 to levels suitable for nuclear power and nuclear weapons. The uranium that remains is "depleted" in both U-235 and U-234 and typically contains 0.2 percent of U-235 and 0.001 percent of U-234. Because the radioactive decay rate of U-235 and especially of U-234 is so much higher than U-238, this decrease reduces the radioactivity of DU by approximately 50 percent when compared to natural uranium. The specific activity of natural uranium is 0.7 µCi/g while DU is 0.4 µCi/g. DU is used by DoD in antitank munitions and in tank armor because of its high density and pyrophoric properties. Intact DU munitions and armor radiation exposure is minimal and within accepted standards. A series of studies conducted by the DoD quantified the radiation exposure received by personnel during the transportation, storage, and use of DU-containing systems. Studies have shown that, with the exception of warehouses where large quantities of DU munitions were stored, the estimated annual exposure did not exceed the current standard of 100 mrem/year for the general population. Where this limit might be exceeded, standard radiation protection programs are in place (Daxon, 1994). DU can enter the body on the battle field as a result of fires involving DU munitions, use of DU munitions, or working in a vehicle or other space con-

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Health Consequences of Service During the Persian Gulf War: Initial Findings and Recommendations for Immediate Action taminated with DU. Daxon (1994) continues: "In general, only a small fraction (less than 1 percent) of DU particulates from storage or tanks fires were respirable, and more than 90 percent of the respirable particulates were insoluble. When a DU munition strikes an armored target, the fraction of particulates generated that are respirable ranges from 50 percent to 90 percent. Approximately 17 percent to 48 percent of the respirable particles are soluble in lung fluid." The potential for inhaled DU particles to exceed current safety standards exists only inside vehicles when they are penetrated by DU munitions. This was shown from estimates of simulated bulk storage fires, test fires involving vehicles with DU munitions, and tests in which DU munitions struck armored vehicles. The Persian Gulf experience showed that DU can reach internal body sites through wound contamination and the injection of DU fragments. DU inside the body presents both radiological and toxicological risks. Irreparable kidney damage has been shown in studies of injected or inhaled uranium salts. The toxic level for uranium in the kidney for single exposures is 1–3 µg of uranium per gram of kidney (Kearsley and Daxon, 1993). However, there is considerable uncertainty regarding the toxicity of long-term exposure to uranium. The toxicological hazards of DU inhalation and ingestion are probably more significant than the radiological hazards if the uranium compounds internalized are soluble. For insoluble compounds, the ingestion hazards (both radiological and toxicological) are minimal because the majority of the ingested compounds are rapidly eliminated from the body. The risks associated with the inhalation of insoluble compounds are primarily radiological and are determined by the total radiation exposure to the body. The radiological and toxicological hazards associated with long-term exposure to imbedded fragments are uncertain. There are no known studies of the long-term effects of uranium metal implanted in tissues. During the Persian Gulf War, few personnel were exposed to DU. A friendly fire incident wounded 35 U.S. soldiers, of whom 22 were suspected to have retained DU fragments (Daxon, 1993). Soldiers (27) from the 144th Supply and Service Company involved in fighting fires, vehicle recovery, and cleaning of the 29 tanks damaged by DU munitions were potentially exposed. There were 32 others that had a chance of exposure. DU rounds were left on the battlefield. A five-year follow-up policy has been developed for the 22 soldiers suspected of having retained DU particles and for all others suspected of being exposed to DU (Keogh, 1993). The Armed Forces Radiobiology Research Institute (AFRRI) reviewed this policy and found that there were sufficient uncertainties with the potential chronic effects to warrant long-term follow-up of veterans with fragments and to conduct research. The Department of De-

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Health Consequences of Service During the Persian Gulf War: Initial Findings and Recommendations for Immediate Action fense and the Department of Veterans Affairs are conducting the recommended patient review and the Department of Defense is initiating AFRRI-recommended research. Environmental Research Centers In January 1994 the VA announced a program to establish centers for basic and clinical science studies of environmental hazards. Up to $500,000 per year would be provided for up to five years of support for centers to engage in basic research on environmental health effects, with special emphasis on the diagnosis and treatment of medical problems currently being reported by the PGW veterans. An additional $100,000 will be available for equipment in the first year. The VA is especially interested in new initiatives that complement current activities, and has suggested that interorganizational agreements and scientific affiliations are encouraged if they are justified and set up properly. Links with non-VA researchers are allowed. As of May 13, 1994, the VA Central Office reported that a group of six "distinguished and internationally renowned scientists was selected to be the ad hoc Scientific Review Committee for the proposals." They were selected on their reputation as "outstanding in the field of environmental science." The committee was to operate much like an NIH study section group; it was to "exclusively make judgment on the scientific quality of each proposal." These environmental research centers were established in July 1994, in the Veterans Affairs Medical Centers in Boston, Massachusetts; East Orange, New Jersey; and Portland, Oregon. The environmental centers are expected to be fully funded by October 1, 1994. The grants are for five years and there will be a mid-point review conducted by a panel of experts other than the ad hoc committee. Constituting the ad hoc committee to review proposals and having a mid-term review are excellent ideas; however, the halfway point for a review may come too late. This committee recommends a review by an advisory committee at six months and then every year. The VA should examine how the entire problem can be investigated, and should provide a sufficient degree of central evaluation and advice. Possibly, an external advisory committee could be established, and collaboration with qualified investigators and other federal and non-federal agencies more strongly encouraged. Review should ensure that appropriate infrastructures will be in place and that funding will support new initiatives and not simply fund current projects. Limiting the non-recurring instrumentation expenditures to $100,000 will surely lead to core laboratories with limited or out-moded testing capabilities.

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Health Consequences of Service During the Persian Gulf War: Initial Findings and Recommendations for Immediate Action There is a concern about funding levels for these studies and whether there is going to be sufficient funding to keep these studies going.