enzymes for AChE inhibitors may be susceptibility factors for the development of myltisumptom illness.

Human studies of Gulf War veterans have consistently shown increased symptom reports among a portion of the deployed veterans compared with nondeployed veterans (see Chapter 4). Unfortunately, objective exposure information is generally lacking, and most studies have depended upon self-reports of both exposure and illness and symptoms. No consistent relationship is apparent between specific exposures and symptoms across these studies. Studies of genetic differences in metabolizing or buffering toxins and their relationship to multisymptom illness may hold promise for understanding multisymptom illness given that genes represent an unbiased measure of susceptibility.

THE ROLE OF CHOLINESTERASE INHIBITORS AND PESTICIDES IN MULTISYMPTOM ILLNESS

While pesticide and PB use appear to have been widespread during the Gulf War, there is no evidence that Gulf War veterans suffered acute toxicity from either nerve gas or pesticides on a wide scale during and after the conflict. Except for an association with Parkinsonism, there remains substantial doubt as to whether long-term illness results from low-level chronic exposure to pesticides, including cholinesterase inhibitors. The Agricultural Health Study, the largest study of a pesticide-exposed cohort to date, has confirmed what had been reported from smaller studies of acute pesticide exposures, that is, CNS disorders may persist after acute exposures cease. Two groups of people with chronic, nonintoxicating pesticide exposures have been studied. Studies of UK sheep dippers with organophosphate exposures and one study of pesticide applicators in Iowa and North Carolina have found persistent long-term CNS effects from chronic exposure to high levels of pesticides (Beseler et al., 2008). In the latter study, no dose-response relationship was seen, and pesticides were not restricted to cholinesterase inhibitors. Low-level chronic pesticide exposure has been implicated in Parkinsonism in multiple studies and a causal association with a specific mixture of pesticides (herbicides and fungicides, neither of which are cholinesterase inhibitors) during a vulnerable period of life may explain why stronger associations with pesticide use were not found earlier and more frequently (Costello et al., 2009).

Animal studies have provided mixed results in terms of central and persistent effects of exposure to cholinesterase inhibitors and pesticides, and many questions remain. These questions include: whether the blood-brain barrier can be breached by PB during stress and whether persistent changes in peripheral or CNS function can be induced by exposure to cholinesterase inhibitors at levels comparable to those experienced by Gulf War veterans.

Studies of Gulf War veterans have not used uniform descriptions of possible exposures in theater and the exposures assessments are based almost exclusively on self-reports by veterans, often years after deployment, making it difficult to compare studies. The same is true for symptom reporting by the veterans. The terminology used by the researchers for the veterans’ symptoms can differ markedly as is evident from the factor analysis studies described in the section on “Multisymptom Illnesses” in Chapter 4.

There have been several studies that have found associations between self-reported exposures to pesticides, nerve gas, PB, and mixtures thereof, and self-reported symptoms and multisymptom illness. However, several well-designed studies have concluded that no association exists for such exposures, and other stress-related and environmental factors appear to be more important. Due to the publicity surrounding multisymptom illness and its possible



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