Before providing you details on the results of our work, let me briefly provide some background information. During service associated with the Gulf War, many of the approximately 700,000 veterans might have been exposed to a variety of potentially hazardous substances. These substances include compounds used to decontaminate equipment and protect it against chemical agents, pesticides, vaccines, and drugs to protect against chemical warfare agents (for example, pyridostigmine bromide). Following the postwar demolition of Iraqi ammunition facilities, some veterans might also have been exposed to the nerve agent sarin. Over 100,000 of the approximately 700,000 Gulf War veterans have participated in DOD and VA health examination programs established between 1992 and 1994. Of those veterans examined by DOD and VA, nearly 90 percent have reported a wide array of health complaints and disabling conditions, including fatigue, muscle and joint pain, gastrointestinal complaints, headaches, depression, neurologic and neurocognitive impairments, memory loss, shortness of breath, and sleep disturbances. Some of the veterans fear that they are suffering from chronic disabling conditions because of exposure during the war to substances with known or suspected health effects. In 1992, VA established a program through which Gulf War veterans could receive medical examinations and diagnostic services. Participants received a regular physical examination with basic laboratory tests. In 1994, VA established a standardized examination to obtain information about exposures and symptoms related to diseases endemic to the Gulf region and to order specific tests to detect the “biochemical fingerprints” of certain diseases. If a diagnosis was not apparent, veterans could receive up to 22 additional tests and additional specialty consultations. In addition, if the illness defied diagnosis, the veterans could be referred to one of four VA Persian Gulf referral centers. In 1994, DOD initiated its Comprehensive Clinical Evaluation Program, through which it used a clinical protocol and provided diagnostic services similar to those of the VA program. In examining the causes of Gulf War veterans’ illnesses, the Presidential Advisory Committee on Gulf War Veterans’ Illnesses and the Institute of Medicine confirmed the need for effective medical surveillance capabilities. They found that research efforts to determine the causes of the veterans’ illnesses were hampered by incomplete data on (1) the names and locations of deployed personnel, (2) the exposure of personnel to environmental health hazards, (3) changes in the health status of personnel while deployed, and (4) immunizations and other health services for personnel while deployed. Subsequently, in May 1997, we reviewed the actions DOD had taken since the Gulf War to improve its medical surveillance capabilities. Specifically, we determined what medical surveillance procedures DOD had used in Operation Joint Endeavor, which was conducted in the countries of Bosnia-Herzegovina, Croatia, and Hungary, and whether DOD had corrected the problems that surfaced during the Gulf War. DOD and VA officials claimed that regardless of the cause of Gulf War veterans’ illnesses, the veterans had received appropriate and effective symptomatic treatment. Both agencies tried to measure or ensure the quality of veterans’ initial examinations by training health care specialists and maintaining standards for physicians’ qualifications. However, these mechanisms did not ensure a given level of effectiveness for the care provided or help to identify the most effective treatments. Beyond the initial examination, neither DOD nor VA had mechanisms for monitoring the quality, appropriateness, or effectiveness of these veterans’ care or clinical progress, and they had no plans to establish such mechanisms. VA officials told us that they regarded monitoring the clinical progress of registry participants as a separate research project, and officials from DOD’s Clinical Care and Evaluation Program made similar comments. We noted that such monitoring was important because (1) undiagnosed conditions were not uncommon among ill veterans, (2) treatment for veterans with undiagnosed conditions was based on their symptoms, (3) veterans with undiagnosed conditions or multiple diagnoses might see multiple providers, (4) follow-up could provide a better understanding of the clinical progression of the illnesses over time, and (5) the success or failure of physicians’ treatments of Gulf War veterans could be identified. Without follow-up of their treatment, DOD and VA cannot say whether these ill veterans are any better or worse today than when they were first examined. Federal research on Gulf War veterans’ illnesses and factors that might have caused their problems was not pursued proactively. Although these veterans’ health problems began surfacing in the early 1990s, the vast majority of research was not initiated until 1994 or later, and much of that responded to legislative requirements or external reviewers’ recommendations. This 3-year delay complicated the researchers’ tasks and limited the amount of completed research available. Of the 91 studies receiving federal funding, over 70 had not been completed at the time of our review. The results of some studies will not be available until after 2000. While research on exposure to stress was emphasized in earlier studies, research on low-level chemical exposure was not pursued until legislated in 1996. The failure to fund such research could not be traced to an absence of proposals. According to DOD officials, three recently funded proposals on low-level chemical exposure had previously been denied funds because, at the time, DOD did not believe that U.S. troops had been exposed to chemical warfare agents. We found that additional hypotheses were pursued in the private sector. A substantial body of this research suggests that low-level exposure to chemical warfare agents or chemically related compounds, such as certain pesticides, is associated with delayed or long-term health effects. For example, animal experiments, studies of accidental human exposures, and epidemiological studies of humans offer evidence that low-level exposures to certain organophosphorus compounds, including sarin nerve agents to which some of our troops may have been exposed, can cause delayed, chronic neurotoxic effects. It was suggested that the ill-defined symptoms experienced by Gulf War veterans might be due in part to organophosphate-induced delayed neurotoxicity. This hypothesis was tested in a privately supported epidemiological study of Gulf War veterans. The study clarified the patterns among veterans’ symptoms through the use of statistical factor analyses and demonstrated that vague symptoms of the ill veterans were associated with brain and nerve damage compatible with the known chronic effects of exposures to low levels of organophosphates. It further linked the veterans’ illnesses to exposure to combinations of chemicals, including nerve agents, insect repellents, and pyridostigmine bromide tablets. Toxicological research indicates that pyridostigmine bromide, which Gulf War veterans took to protect themselves against the immediate, life-threatening effects of nerve agents, may alter the metabolism of organophosphates in ways that activate their delayed, chronic effects on the brain. Moreover, exposure to combinations of organophosphates and related chemicals like pyridostigmine bromide has been shown in animal studies to be far more likely to cause morbidity and mortality than any of the chemicals acting alone. Aside from the hypotheses being emphasized in the research being done, we found that the bulk of ongoing federal research on Gulf War veterans’ illnesses was focused on the epidemiological study of the prevalence and cause of the illnesses. It is important to note that to conduct such studies, investigators must adhere to basic, generally accepted principles. First, investigators must specify diagnostic criteria to (1) reliably determine who has the disease or condition being studied and who does not and (2) select appropriate controls (people who do not have the disease or condition). Second, they must have valid and reliable methods of collecting and relating data on past exposure(s) of those in the study to possible factors that may have caused the symptoms. The need for accurate, dose-specific exposure information is particularly critical when low-level or intermittent exposure to drugs, chemicals, or air pollutants is possible. It is important not only to assess the presence or absence of exposure but also to characterize the intensity and duration of exposure. The epidemiological federal research we examined had two methodological problems: the lack of a case definition (that is, a reliable way to identify individuals with a specific disease) and the absence of accurate exposure data. Without valid and reliable data on exposures and the multiplicity of agents to which the veterans were exposed, researchers will likely continue to find it difficult to detect relatively subtle effects and to eliminate alternative explanations for Gulf War veterans’ illnesses. Prevalence data can be useful, but it requires careful interpretation in the absence of better information on the factors to which veterans were exposed. While multiple federally funded studies on the role of stress in the veterans’ illnesses have been done, basic toxicological questions regarding the substances to which they were exposed remain unanswered. The ongoing epidemiological research cannot provide precise, accurate, and conclusive answers regarding the causes of veterans’ illnesses because of these methodological problems as well as the following: Researchers have found it extremely difficult to gather information about exposures to such things as oil-well fire smoke and insects carrying infection. Medical records of the use of pyridostigmine bromide tablets and vaccinations to protect against chemical/biological warfare exposures were inadequate. Gulf War veterans were typically exposed to a wide array of agents, making it difficult to isolate and characterize the effects of individual agents or to study their combined effects. Most of the epidemiological studies on Gulf War veterans’ illnesses have relied only on self-reports for measuring most of the agents to which veterans might have been exposed. The information gathered from Gulf War veterans years after the war may be inaccurate or biased. There is often no straightforward way to test the validity of self-reported exposure information, making it impossible to separate bias in recalled information from actual differences in the frequency of exposures. As a result, findings from these studies may be spurious or equivocal. Classifying the symptoms and identifying veterans’ illnesses have been difficult. From the outset, the symptoms reported have been varied and difficult to classify into one or more distinct illnesses. Moreover, several different diagnoses might provide plausible explanations for some of the specific health complaints. It has thus been difficult to develop a case definition. Six years after the war, little was conclusively known about the causes of Gulf War veterans’ illnesses.