8
Research Recommendations

The committee’s charge was to review the scientific literature on the potential health effects of the agents to which Gulf War veterans may have been exposed. Of the many stressors and biological and chemical agents in the Gulf War theater, this report has reviewed the literature on the agents that were of most concern to the veterans and their representatives. Subsequent IOM studies will examine the literature on the remaining Gulf War-related agents.

The committee considered the evidence for each of the agents in turn, as if each one was the only risk factor for adverse health effects. It did so because the committee sought to learn how each agent, in the absence of all of the others, might affect human health. The committee realized through the course of this study, however, that there may also be a need to examine the impact of the total experience of deployment and war on veterans’ health. Such an approach may help elucidate the nature of the illnesses in Gulf War veterans in a way that is not possible by examining single agents. Unfortunately, most of the studies conducted to date focus on single agents. Yet integrating the various stressors, biological and chemical exposures, the complexities faced by military personnel during all phases of deployment, and the issues surrounding war may provide a more realistic approach toward understanding veterans’ health and may provide insights for preventing illnesses in future deployments.

The committee recommends research on the interactions among the multiple stressors, and biological and chemical agents to which military personnel were exposed as a result of the Gulf War conflict.



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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines 8 Research Recommendations The committee’s charge was to review the scientific literature on the potential health effects of the agents to which Gulf War veterans may have been exposed. Of the many stressors and biological and chemical agents in the Gulf War theater, this report has reviewed the literature on the agents that were of most concern to the veterans and their representatives. Subsequent IOM studies will examine the literature on the remaining Gulf War-related agents. The committee considered the evidence for each of the agents in turn, as if each one was the only risk factor for adverse health effects. It did so because the committee sought to learn how each agent, in the absence of all of the others, might affect human health. The committee realized through the course of this study, however, that there may also be a need to examine the impact of the total experience of deployment and war on veterans’ health. Such an approach may help elucidate the nature of the illnesses in Gulf War veterans in a way that is not possible by examining single agents. Unfortunately, most of the studies conducted to date focus on single agents. Yet integrating the various stressors, biological and chemical exposures, the complexities faced by military personnel during all phases of deployment, and the issues surrounding war may provide a more realistic approach toward understanding veterans’ health and may provide insights for preventing illnesses in future deployments. The committee recommends research on the interactions among the multiple stressors, and biological and chemical agents to which military personnel were exposed as a result of the Gulf War conflict.

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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines The committee has developed the following additional recommendations for research based on its review of the literature on each of the putative agents (Chapters 4–7). These recommendations highlight areas of scientific uncertainty and gaps in research. DEPLETED URANIUM While a group of veterans exist with depleted uranium in their tissues, the majority of veterans’ exposure to DU is unknown. The committee urges the continuation and expansion of efforts to model potential exposures to DU in various military settings (e.g., inside and outside vehicles damaged by DU munitions, other areas potentially contaminated by the dispersion of DU particles). Such efforts may result in a quantitative assessment of Gulf War veterans’ exposure to depleted uranium. Further, the committee urges publication of the results in the peer-reviewed literature so that the studies may receive broad review. The committee recommends the following avenues of research to complement our current knowledge of the health effects of depleted uranium. The committee recommends long-term follow-up of veterans exposed to depleted uranium, including the Baltimore cohort and other veterans potentially exposed to depleted uranium (e.g., those involved in cleanup operations or radiation control units). Long-term follow-up of the cohort of veterans who have undergone evaluation at the Baltimore Veterans Administration (VA) Medical Center since 1993 will continue to improve our understanding of the health effects of exposure to depleted uranium. The committee recommends expanding the cohort of DU-exposed veterans and including control cohorts of non-DU-exposed Gulf War-deployed veterans in this study. Additionally, controlled, long-term morbidity and mortality studies of additional cohorts of Gulf War veterans, particularly those that may have been exposed to DU through different routes of exposure (e.g., those involved in cleanup operations and in radiation control units), would further the knowledge on health effects related to DU exposure. The committee recommends continued follow-up of the cohorts of uranium processing workers, particularly studies that will incorporate more sophisticated analyses of the data. The majority of the evidence on the human health effects of exposure to uranium is from studies of workers in uranium processing mills and other facilities. These cohorts are a valuable information resource, as they are, in many cases, large groups that have been studied for many years. Additionally, researchers have analyzed data across several of these cohorts to enable comparisons between the cohorts and to increase the possibility of observing rare health outcomes. The

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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines committee encourages studies that will provide continued long-term follow-up of uranium processing workers, particularly those that incorporate new methods of measuring dose and utilize sophisticated statistical analyses. The committee recommends additional studies in experimental animals to investigate specific effects of depleted uranium. Animal studies provide the opportunity to carefully study the effects of depleted uranium in isolation from other exposures. Controlled experimental conditions provide a contrast with studies of veterans or workers in industrial settings as both populations have concomitant exposures to many other potential hazards. Of particular importance are studies of cognitive function, neurophysiological responses, brain DU concentrations, and the transport kinetics of DU. SARIN The committee recommends the following avenues of research to augment our understanding of long-term effects of exposure to sarin. The committee recommends careful long-term follow-up of populations exposed to sarin in the Matsumoto and Tokyo terrorist attacks. The Matsumoto experience shows that direct exposure to sarin, particularly in intermediate to high doses, is associated with the acute cholinergic syndrome. Further, follow-up studies of Matsumoto demonstrate that significant chronic symptoms from sarin exposure persist and include visual disturbances, fatigue or asthenia, and headache. These chronic symptoms appear to be dose dependent. Follow-up studies, with well-defined control populations, will provide information related to possible long-term health effects. The Tokyo sarin experience also confirms that intermediate doses of sarin leads to the acute cholinergic syndrome. Visual disturbances are frequent sequelae of acute exposure. Neurophysiological testing of a small group of asymptomatic people exposed to sarin shows chronic changes in visual and event-related evoked potentials and vestibulocerebellar function months after the acute syndrome had subsided. While these neurophysiological data are suggestive of subtle, persistent central nervous system (CNS) effects from sarin, long-term follow-up studies are required. Of particular importance is a study that would include a group of individuals that presented symptoms of acute sarin poisoning at the time of exposure, as well as a group that was involved in the incidents but did not experience acute illness. These two groups, together with an unexposed matched control group, would provide important information on whether the long-term sequelae already reported occur in those who have been exposed to subsymptomatic levels of sarin. Studies should include neuropsychological testing, electroencephalogram (EEG), evoked potentials, and vestibular testing.

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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines The committee recommends studies in experimental animals to investigate the long-term effects of acute, short-term sarin exposure at doses that do not cause overt cholinergic effects and cause only minimal acetylcholinesterase inhibition. Massive acute doses of sarin, through inhibition of neuropathy target esterase (NTE), can induce delayed neurotoxicity in some, but not all, animal species. Lower doses over long periods may also exert this effect, but more research is needed to substantiate this finding. Long-term alterations in the EEG of nonhuman primates occur after sarin administration at high doses, as well as at doses that do not produce acute signs of toxicity. The clinical and long-term significance of these EEG changes is unclear. Studies should describe concomitant changes at the behavioral, electrophysiological, and biochemical levels. Studies should test the hypothesis that repeated exposure to sarin—alone and in combination with other organophosphate (OP) pesticides or nerve agents—at doses that do not cause overt cholinergic toxicity can produce delayed polyneuropathy. The committee recommends research on genetic factors that may alter susceptibility to sarin toxicity. The enzyme paraoxonase inactivates sarin by hydrolysis. The human PON1 gene has various polymorphisms. The corresponding genotypes determine the catalytic properties of an enzyme that hydrolyzes certain organophosphates at two different rates depending on which polymorphism is present. Studies have suggested a relationship between these genetic polymorphisms and neurological impairment in Gulf War veterans. However, because of their small size the findings require confirmation in a larger population. Studies on genetic polymorphisms, particularly of PON1, may elucidate the nature of human susceptibility to sarin toxicity. PYRIDOSTIGMINE BROMIDE The committee recommends studies on chemical interactions between pyridostigmine bromide (PB) and other agents, such as stress, and insecticides. Studies have suggested the possibility that combinations of chemicals (particularly insecticides) and stress result in greater toxic consequences than when each of these exposures is present alone. Possible synergistic interactions of PB with chemicals and stressors (environmental and psychological) require replication and confirmation, particularly studies exploring the possibility of toxic interactions resulting from exposure to chemicals at low doses and over long periods of time. Such studies may also shed light on whether or not PB (which is unlikely to initiate organophosphate-induced delayed neuropathy [OPIDN]) may promote other chemically induced neuropathies.

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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines The committee recommends research on genetic factors (e.g., genetic polymorphisms of butyrylcholinesterase [BuChE] and paraoxonase [PON1]) that may alter susceptibility to the effects of PB. Differences in genetic susceptibility are proving important in many disease conditions and will likely emerge as a major determinant of neurotoxicity in humans. The observation that a small percentage of troops taking PB has more severe acute side-effects than the majority, which experienced little or no discomfort, suggests a spectrum of vulnerabilities in sensitive individuals, where genetic differences may contribute to their ability to absorb and metabolize PB. Polymorphisms in BuChE have long been recognized, but whether they play a role in determining the outcome of PB exposure is unknown. The potential relevance of genetic polymorphisms of paraoxonase to PB toxicity is also unclear since PB is not a substrate for these enzymes. However, the role of genetic variations influencing the toxicology of PB is an attractive target for research. The committee recommends epidemiologic studies on the possible long-term health effects of PB. As previously noted in this report, there has been little attention given to studying long-term health effects of PB. However, preliminary clinical findings suggesting effects of PB on cognitive function, cardiovascular disease, and visual function warrant future study. Epidemiologic studies that observe long-term adverse effects in patients with myasthenia gravis might be a first step. Although patients with myasthenia gravis may provide an opportunity to study the long-term health effects of PB, the higher doses of PB prescribed to these patients and the characteristics of their disease may make it difficult to draw comparisons from myasthenics to a group of healthy individuals. VACCINES As noted throughout this report, medical record keeping for Gulf War veterans was extremely poor. It is difficult, if not impossible, to understand the effect of vaccinations without adequate records documenting individual vaccination histories. The committee urges the Department of Defense (DoD) to implement proper practices for medical record keeping and systematic collection of baseline and follow-up health data related to vaccination. The committee is aware of efforts by the DoD to collect data on health outcomes of the recipients of the anthrax vaccination and to conduct a long-term study of this cohort. The DoD has an opportunity to properly monitor recipients of this vaccine and to provide invaluable information about potential long-term health effects. This research should be a priority for the DoD.

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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines The committee recommends a long-term longitudinal study of participants in the Anthrax Vaccine Immunization Program. The committee urges DoD to actively monitor the participants of this program and systematically collect and analyze data about symptoms, and functional and disease status. Further, the committee strongly urges investigators conducting studies on the safety of anthrax and botulinum toxoid vaccines to submit their results to peer-reviewed scientific journals for publication. The process of peer review by fellow professionals, one of the hallmarks of modern science, ensures high standards of quality and will enable broad review of results. Finally, the committee hopes that the following recommendations will complement areas of ongoing vaccine research. The committee recommends long-term, systematic research to examine potential adverse effects of anthrax and botulinum toxoid vaccination in multiple species and strains of animals. To date, animal studies have focused largely on the efficacy of the anthrax and botulinum toxoid vaccines, rather than on possible adverse effects of vaccination. Future research should consider issues related to potential long-term adverse effects of anthrax and botulinum toxoid vaccines; potential health effects of the combinations of these and other vaccines routinely given to armed forces personnel; and potential health effects of combinations of these vaccines and pyridostigmine bromide, exposure to organophosphate compounds, and stress. The committee recommends a careful study of current symptoms, functional status, and disease status in cohorts of Gulf War veterans and Gulf War era veterans for whom vaccination records exist. Although vaccination records are not available for most Gulf War veterans, cohorts might be identified for whom such records exist. It would be important to assemble several groups to study long-term adverse health outcomes of anthrax and botulinum toxoid vaccines; these cohorts should include: nonimmunized, deployed and nondeployed Gulf War veterans; and immunized, deployed and nondeployed Gulf War veterans. This report takes its place alongside several other recent IOM reports on the health of Gulf War veterans. Although the conclusions and recommendations presented here will not end the controversy surrounding Gulf War veterans’ illnesses, this report will provide a scientific basis for consideration by the Department of Veterans Affairs as they develop a compensation program for veterans. The committee hopes that its deliberations, along with the work of many others, will add to the body of accumulating knowledge about the health of Gulf War veterans.

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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines Appendixes

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