organophosphate-induced delayed polyneuropathy) may contribute to the unexplained illnesses of the gulf war veterans. organophosphate pesticides the use of organophosphate pesticides and insect repellents during the first gulf war is credited with keeping rates of pest-borne diseases low. pesticide use is one of only two exposures consistently identified by gulf war epidemiologic studies to be significantly associated with gulf war illness. multisymptom illness profiles similar to gulf war illness have been associated with low-level pesticide exposures in other human populations. in addition, gulf war studies have identified dose-response effects, indicating that greater pesticide use is more strongly associated with gulf war illness than more limited use. pesticide use during the gulf war has also been associated with neurocognitive deficits and neuroendocrine alterations in gulf war veterans in clinical studies conducted following the end of the war. the 2008 report concluded that "all available sources of evidence combine to support a consistent and compelling case that pesticide use during the gulf war is causally associated with gulf war illness." sarin nerve agent many of the symptoms of gulf war illness are similar to the symptoms of organophosphate, mustard gas, and nerve gas poisoning. gulf war veterans were exposed to a number of sources of these compounds, including nerve gas and pesticides. chemical detection units from czechoslovakia, france, and britain confirmed chemical agents. french detection units detected chemical agents. both czech and french forces reported detections immediately to u.s. forces. u.s. forces detected, confirmed, and reported chemical agents; and u.s. soldiers were awarded medals for detecting chemical agents. the riegle report said that chemical alarms went off 18,000 times during the gulf war. after the air war started on january 16, 1991, coalition forces were chronically exposed to low, nonlethal levels of chemical and biological agents released primarily by direct iraqi attack via missiles, rockets, artillery, or aircraft munitions and by fallout from allied bombings of iraqi chemical warfare munitions facilities. in 1997, the us government released an unclassified report that stated: "the us intelligence community (ic) has assessed that iraq did not use chemical weapons during the gulf war. however, based on a comprehensive review of intelligence information and relevant information made available by the united nations special commission (unscom), we conclude that chemical warfare (cw) agent was released as a result of us postwar demolition of rockets with chemical warheads in a bunker (called bunker 73 by iraq) and a pit in an area known as khamisiyah." over 125,000 u.s. troops and 9,000 u.k. troops were exposed to nerve gas and mustard gas when the iraqi depot in khamisiyah was destroyed. recent studies have confirmed earlier suspicions that exposure to sarin, in combination with other contaminants such as pesticides and pb were related to reports of veteran illness. estimates range from 100,000 to 300,000 individuals exposed to nerve agents. while low-level exposure to nerve agents has been suggested as the cause of gwi, the 2008 report by the u.s. department of veterans affairs (va) research advisory committee on gulf war illnesses (rac) stated that "evidence is inconsistent or limited in important ways." the va's 2014 rac report concluded that, "exposure to the nerve gas agents sarin/cyclosarin has been linked in two more studies to changes in structural magnetic resonance imaging findings that are associated with cognitive decrements, further supporting the conclusion from evidence reviewed in the 2008 report that exposure to these agents is etiologically important to the central nervous system dysfunction that occurs in some subsets of gulf war veterans." a 2022 study by dr. robert w. haley of the university of texas southwestern medical center, et al., of 1,016 u.s. gulf war veterans found evidence of a causal link between gwi and exposure to low levels of sarin, which was released into the air by coalition bombing of iraqi chemical weapons facilities. significantly, the study found an increased incidence of gwi not only among veterans who recounted hearing nerve agent alarms, but also among veterans with the rr or qr (as opposed to the qq) forms of the pon1 gene, which produces an enzyme that deactivates organophosphates (including sarin) through hydrolysis. by contrast, gwi was inversely associated with higher levels of the type q isozyme, which is more efficient at breaking down sarin than its type r counterpart. the authors "found that the pon1 genotype and hearing nerve agent alarms were independent and the findings robust to both measured and unmeasured confounding, supporting a mechanistic interaction. ... moreover, the change in the combined effect from one category to the next was significantly greater than the sum of the independent effects of the environmental exposure and the genotype". although organophosphate pesticides could have triggered the nerve agent alarms in use at the time and contributed to neurotoxic symptoms similar to gwi, haley et al. ruled out pesticides as a primary cause of gwi, citing that pesticide use was "ubiquitous long before the approximately 10,000 alarms began sounding at the start of the air campaign when coalition bombing of iraqi chemical weapon facilities released the fallout cloud that reached u.s. troop concentrations just as sarin was detected at multiple sites," while "the pon1 r isoenzyme is the more efficient detoxifier of most pesticides." less likely causes according to the va's 2008 rac report, "for several gulf war exposures, an association with gulf war illness cannot be ruled out. these include low-level exposure to nerve agents, close proximity to oil well fires, receipt of multiple vaccines, and effects of combinations of gulf war exposures." however, several potential causes of gwi were deemed, "not likely to have caused gulf war illness for the majority of ill veterans," including "depleted uranium, anthrax vaccine, fuels, solvents, sand and particulates, infectious diseases, and chemical agent resistant coating (carc)," for which "there is little evidence supporting an association with gulf war illness or a major role is unlikely based on what is known about exposure patterns during the gulf war and more recent deployments." the va's 2014 rac report reinforced its 2008 report findings: "the research reviewed in this report supports and reinforces the conclusion in the 2008 racgwvi report that exposures to pesticides and pyridostigmine bromide are causally associated with gulf war illness. evidence also continues to demonstrate that gulf war illness is not the result of psychological stressors during the war." it also found additional evidence since the 2008 report for the role of sarin in gwi, but inadequate evidence regarding exposures to oil well fires, vaccines, and depleted uranium to make new conclusions about them. oil well fires during the war, many oil wells were set on fire in kuwait by the retreating iraqi army, and the smoke from those fires was inhaled by large numbers of soldiers, many of whom had acute pulmonary and other chronic effects, including asthma and bronchitis. however, firefighters who were assigned to the oil well fires and encountered the smoke, but who did not take part in combat, have not had gwi symptoms.: 148, 154, 156 the 2008 rac report states that "evidence is inconsistent or limited in important ways." anthrax vaccine iraq had loaded anthrax, botulinum toxin, and aflatoxin into missiles and artillery shells in preparing for the gulf war and these munitions were deployed to four locations in iraq. during operation desert storm, 41% of u.s. combat soldiers and 75% of uk combat soldiers were vaccinated against anthrax.: 73 reactions included local skin irritation, some lasting for weeks or months. while the food and drug administration (fda) approved the vaccine, it never went through large-scale clinical trials. while recent studies have demonstrated the vaccine is highly reactogenic, there is no clear evidence or epidemiological studies on gulf war veterans linking the vaccine to gulf war illness. combining this with the lack of symptoms from current deployments of individuals who have received the vaccine led the committee on gulf war veterans' illnesses to conclude that the vaccine is not a likely cause of gulf war illness for most ill veterans. however, the committee report does point out that veterans who received a larger number of various vaccines in advance of deployment have shown higher rates of persistent symptoms since the war. however, research was done by pb asa, y cao, and rf garry on serum antibodies to squalene in gulf war syndrome patients. the results showed "the substantial majority (95%) of overtly ill deployed gws patients had antibodies to squalene. all (100%) gws patients immunized for service in desert shield/desert storm who did not deploy, but had the same signs and symptoms as those who did deploy, had antibodies to squalene. in contrast, none (0%) of the deployed persian gulf veterans not showing signs and symptoms of gws have antibodies to squalene. neither patients with idiopathic autoimmune disease nor healthy controls had detectable serum antibodies to squalene." their work of the researchers was profiled by gary matsumoto in "vaccine a". this research and theory was later criticized, and further research has leaned heavily against squalene in vaccinations causing gws; perhaps the most important points against this theory include that squalene antibodies have been detected in populations not exposed to squalene containing vaccinations, and that the anthrax vaccines used in the gulf war did not actually contain squalene in any form. combat stress research studies conducted since the war have consistently indicated that psychiatric illness, combat experience or other deployment-related stressors do not explain gulf war veterans illnesses in the large majority of ill veterans, according to a u.s. department of veterans affairs (va) review committee. an april 2010 institute of medicine review found, "the excess of unexplained medical symptoms reported by deployed gulf war veterans cannot be reliably ascribed to any known psychiatric disorder", although they also concluded that "the constellation of unexplained symptoms associated with the gulf war illness complex could result from interplay between both biological and psychological factors." pathobiology chronic inflammation the 2008 va report on gulf war illness and the health of gulf war veterans suggested a possible link between gwi and chronic, nonspecific inflammation of the central nervous system that cause pain, fatigue and memory issues, possibly due to pathologically persistent increases in cytokines and suggested further research be conducted on this issue. diagnosis clinical diagnosis of gulf war illness has been complicated by multiple case definitions. in 2014, the national academy of sciences institute of medicine (iom)—contracted by the u.s. department of veterans affairs for the task—released a report concluding that the creation of a new case definition for chronic multisymptom illness in gulf war veterans was not possible because of insufficient evidence in published studies regarding its onset, duration, severity, frequency of symptoms, exclusionary criteria, and laboratory findings. instead, the report recommended the use of two case definitions, the "kansas" definition and the "centers for disease control and prevention (cdc)" definition, noting: "there is a set of symptoms (fatigue, pain, neurocognitive) that are reported in all the studies that have been reviewed. the cdc definition captures those three symptoms; the kansas definition also captures them, but it also includes the symptoms reported most frequently by gulf war veterans." the kansas case definition is more specific and may be more applicable for research settings, while the cdc case definition is more broad and may be more applicable for clinical settings. classification medical ailments associated with service in the 1990–1991 gulf war have been recognized by both the u.s. department of defense and the u.s. department of veterans affairs. before 1998, the terms gulf war syndrome, gulf war veterans' illness, unexplained illness, and undiagnosed illness were used interchangeably to describe chronic unexplained symptoms in veterans of the 1991 gulf war. the term chronic multisymptom illness (cmi) was first used following publication of a 1998 study describing chronic unexplained symptoms in air force veterans of the 1991 gulf war. in a 2014 report contracted by the u.s. department of veterans affairs, the national academy of sciences institute of medicine recommended the use the term gulf war illness rather than chronic multisymptom illness. since that time, relevant publications by the national academy of science and the u.s. department of defense have used only the term gulf war illness (gwi). the u.s. department of veterans affairs (va) confusingly still uses an array of both old and new terminology for gulf war illness. va's specialty clinical evaluation war related illness and injury study