U.S. troops were reportedly exposed before, during, and after the Gulf War to a variety of potentially hazardous substances. These substances include decontaminating and protective compounds used without proper safeguards (particularly decontaminating solution 2, or DS2, and chemical agent resistant coating); diesel fuel used as a sand suppressant in and around encampments, fuel oil used to burn human waste; fuel in shower water; and leaded vehicle exhaust used to dry sleeping bags. Other potential hazards included infectious diseases (most prominently leishmaniasis, a parasitic infection); pyridostigmine bromide and vaccines (to protect against chemical and biological weapons); depleted uranium (contained in certain ammunition and in residues from the use of this ammunition); pesticides and insect repellents, chemical and biological warfare agents; and compounds and particulate matter contained in the extensive smoke from the oil-well fires at the end of the war. Over 100,000 of the approximately 700,000 Gulf War veterans have participated in health examination programs that the Department of Defense (DOD) and the Department of Veterans Affairs (VA) 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. The federal government, primarily through DOD and VA, has sponsored a variety of research on Gulf War veterans’ illnesses. DOD’s research is one component of a broader agenda coordinated under the aegis of the Persian Gulf Veterans’ Coordinating Board (PGVCB), which comprises the Secretaries of the Department of Health and Human Services, VA, and DOD. The details of this agenda are described in the PGVCB publication entitled A Working Plan for Research on Persian Gulf Veterans’ Illnesses. This agenda was developed in response to an Institute of Medicine conclusion that the DOD and VA should determine specific research questions that need to be answered and design epidemiologic research to these questions. Accordingly, most of the research sponsored under this agenda is characterized by PGVCB as epidemiological. The objectives of epidemiologic research are to determine the extent of diseases and illness in the population or subpopulations, the causes of disease and its modes of transmission, the natural history of disease, and the basis for developing preventive strategies or interventions. To conduct such research, investigators must follow a few basic generally accepted principles. First, they 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, the investigators must have valid and reliable methods of collecting data on the past exposure(s) of those in the study and 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. To the extent that the actual exposure of individuals is misclassified, it is difficult to detect any effects of the exposure. Another means of linking environmental factors to disease is to determine whether or not evidence shows that as the exposure increases, the risk of disease also increases. However, this dose-response pattern can be detected only if the degree of exposure among different groups can be determined. Finally, in addition to specific case definition and dose-specific exposure information with known accuracy, it is important that a sufficient number of persons be studied to have a reasonable likelihood of detecting any relationship between exposures and disease. To the extent that this relationship is subtle or obscured in particular investigations by “loose” case definition (that is, a case definition that is too broad and encompasses different types of illnesses) or problems in measuring exposure, larger samples would be required. For example, the Institute of Medicine noted that “very large groups must be studied in order to identify the small risks associated with low levels of exposure, whereas a relatively small study may be able to detect the effect of heavy or sustained exposure to a toxic substance. In this way, a study’s precision or statistical power is also linked to the extent of the exposure and the accuracy of its measurement. Inaccurate assessment of exposure can obscure the existence of such a trend and thus make it less likely that a true risk will be identified.” Similarly, if an exposure had an effect only on a particular birth defect for example, this effect might be missed by studying all birth defects as a group. Although Gulf War 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 research responded to legislative requirements or external reviewers’ recommendations. As noted by external reviewers, since federal research goals and objectives were not identified until 1995, after most research activities had been initiated, the research reflects a rationalization of ongoing activity rather than a research management strategy. The government’s 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. By the time research was accelerated and broadened, opportunities had been missed to collect critical data that researchers cannot accurately reconstruct. Even efforts to measure the chemical content of the oil-fire smoke, begun only 2 months after the fires began burning, were initiated after most troops had left the affected areas and the climatological dynamics were different. Consequently, researchers had to use statistical models of the behavior of smoke plumes in order to infer the ground-level exposures experienced by the large numbers of troops who had departed by the time they began collecting data. Even if such models could accurately explain the behavior of the smoke plumes, they had not been validated as measures of individual exposure, and their accuracy for this purpose could not be presumed. Similar and even more serious problems were caused in the measurement of other exposures by the failure to collect data promptly and maintain adequate records. The delay in starting research has also hindered accurate reporting of exposures by Gulf War veterans. At the time of our review, 6 years after the war ended, questionnaires were being distributed requesting information from veterans on their exposures to certain agents during the war. Early federal research appeared to emphasize risks associated with psychological factors such as stress. To support this emphasis, DOD pointed out that the psychological state of mind can influence physical well-being. DOD also pointed to a recent argument that from the American Civil War onward (and perhaps even earlier), a small number of veterans have reacted to the stress of war by suffering symptoms similar to those reported by some Gulf War veterans. Of the 19 studies initiated before 1994, roughly half focused on exposures to stress or the potential for posttraumatic stress disorder (PTSD) among returning troops. As late as December 1996, the Presidential Advisory Committee noted that “stress is the risk factor funded for the greatest fraction of total - 32 studies (30 percent).” While research on exposures to stress received early emphasis, other hypotheses have received scant support. In its Final Report, the Institute of Medicine discusses the evidence for a number of disease hypotheses, including multiple chemical sensitivity, fibromyalgia, and organophosphate-induced delayed neuropathy. However, the federal research program has supported only one study of the relationship between symptoms reported by veterans and fibromyalgia. In addition, prior to October 1996, only one of the studies initiated in response to Gulf War veterans’ illnesses focused on the health effects of potential exposures to chemical warfare agents. While multiple studies of the role of stress in the veterans’ illnesses have been supported with federal research dollars, other hypotheses have been pursued largely outside the federal research program. Although veterans raised concerns about potential chemical exposures soon after the war, the federal research plan was not modified to include an investigation of these concerns until 1996, when DOD acknowledged potential exposures to chemical agents at Khamisiyah, Iraq. The failure to fund such research cannot be traced to an absence of investigator-initiated submissions. According to DOD officials, three recently funded proposals on low-level chemical exposure had previously been rejected. A substantial body of research suggests that low-level exposures to chemical warfare agents or chemically related compounds, such as certain pesticides, are associated with delayed or long-term health effects. For example, abundant evidence from animal experiments, studies of accidental human exposures, and epidemiologic studies of humans shows that low-level exposures to certain organophosphorus compounds, including sarin nerve agents to which our troops may have been exposed, can cause delayed, chronic neurotoxic effects. This syndrome is characterized by clinical signs and symptoms manifested 4 to 21 days after exposure to organophosphate compounds. The symptoms of delayed neurotoxicity can take at least two forms: (1) a single large dose may cause nerve damage with paralysis and later spastic movement and (2) repetitive low doses may damage the brain, causing impaired concentration and memory, depression, fatigue, and irritability. These delayed symptoms may be permanent. As early as the 1950s, studies demonstrated that repeated oral and subcutaneous exposures to neurotoxic organophosphates produced delayed neurotoxic effects in rats and mice. In addition, German personnel who were exposed to nerve agents during World War II displayed signs and symptoms of neurological problems even 5 to 10 years after their last exposure. Long-term abnormal neurological and psychiatric symptoms as well as disturbed brain wave patterns have also been seen in workers exposed to sarin in sarin manufacturing plants. The same abnormal brain wave disturbances were produced experimentally in primates by exposing them to low doses of sarin.