paradigms of stress (swimming and cold), a result that directly contradicts the conclusions of the Friedman report. While Grauer et al. did not explicitly evaluate properties of the blood-brain barrier, they inferred that it must have remained intact in the absence of any effect of peripheral pyridostigmine on brain AChE levels. This view is in alignment with a report from Telang et al. (1999) that radiolabeled pyridostigmine failed to permeate the brains of FVB/N mice, even after swim-induced stress.

A second important question that animal studies might help answer is whether short-term exposures to intoxicants can lead to long-term consequences for the CNS. Of interest in this context is the report by van Helden that a 5-hour exposure to sarin induces changes in the power spectrum of electroencephalograms (EEGs; plots of the intensity of EEG activity as a function of EEG frequency) that can be detected 1 year after exposure. Moreover, the change in the EEG occurs at a much lower dose than the appearance of miosis, which is among the most subtle clinical manifestations of sarin exposure (van Helden et al., 2004).

These findings are broadly consistent with earlier reports from Burchfiel and Duffy (1982) who found long-term changes in the EEGs of rhesus monkeys after a single high dose of sarin. High doses of sarin have been shown to result in derangements of the EEG, visual-evoked potentials, and event-related potentials as seen in human following the sarin incidents in Japan (Yanagisawa et al., 2006). What is less clear is whether the severity and intensity of putative sarin exposures of Gulf War veterans approaches those of the Japanese cases or the animal studies.

The Update committee finds that these animal studies address but do not resolve the questions about whether in the context of stress, low-level intoxicants that are otherwise well tolerated may exert adverse effects on the CNS; and whether brief exposures to some intoxicants can exert long-lasting (albeit subtle) neurotoxic effects on the brain. Because the animal data on these points are inconsistent or contradictory, the greatest need is for further investigation of these issues in the context of the symptoms of some Gulf War veterans. Specifically, investigations can focus on whether there are factors that confer heightened sensitivity to stress and intoxicants on some veterans such that they experience an increased adverse response to the brief exposures? Are there clinical tools that help define objective findings that correlate with peripheral and central Gulf War symptom complexes? Will subtle but quantitative measures of cortical function, brain oscillators, or central autonomic parameters—using techniques such as functional MRI, polysomnography, event-evoked potentials—reveal persistent abnormalities that have thus far eluded definition? In the committee’s view, these questions are among the set of issues that merit further analysis in the effort to understand and treat Gulf War illness.

GENETIC SUSCEPTIBILITY TO CHOLINESTERASE INHIBITORS

Multisymptom illness is striking for the lack of uniformity of symptoms among deployed veterans and that only a minority of the deployed cohort is symptomatic. To the extent that multisymptom illness in Gulf War veterans might be a consequence of exposure to toxins such as cholinesterase inhibitors, a potential explanation for this nonuniformity is the high degree of polymorphism in the proteins that detoxify a wide range of intoxicants. Foremost among these are the paroxonases, three esterases that metabolize oxidized lipids (PON1, 2, and 3). PON1 also metabolizes the highly toxic oxon forms of organophosphate insecticides, such as chlorpyrifos and diazinon (Aldridge, 1953; Furlong et al., 1989). Naturally occurring genetic variations in the genes encoding the paroxonases determine the expression levels and functions of the PON



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