Gulf War and Health Volume 1: Depleted Uranium, Sarin, Pyridostigmine Bromide, and Vaccines (2000) / Chapter Skim
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Methodology
Methodology
Pages 69-88
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From page 69... ...
, Saran and cyclosarin, and the anthrax and botulinum toxoid vaccines to determine whether they might be associated with adverse health effects. A1though many chemical and biological agents were present during and after the Gulf War conflict, the committee chose these agents because they were of particular concern to the veterans (see Chapter 1~.2 For each agent, the committee determined to the extent that available published scientific data permitted meaningful determinations the strength of the evidence for associations between exposure to the putative agent and adverse health effects.
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. As noted, the committee did not limit its review to health effects reported by Gulf War veterans but studied all health outcomes reported in populations exposed to the agents of concern.
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Animal and Other Nonhuman Studies Studies of laboratory animals and other nonhuman systems are essential to understanding mechanisms of action, biologic plausibility, and providing information about possible health effects when experimental research in humans is not ethically or practically possible (Cohrssen and Covello, 1989; NRC, 1991~. Such studies permit a potentially toxic agent to be introduced under conditions controlled by the researcher—such as dose,3 duration, and route of exposure to probe health effects on many body systems.
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For its evaluation and categorization of the degree of association between each exposure and a human health effect, however, the committee only used evidence from human studies. Nevertheless, the committee did use nonhuman studies as the basis for judgments about biologic plausibility, which is one of the criteria for establishing causation (see below)
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A retrospective (or historical) cohort study differs from a prospective study in terms of temporal direction; the 4A confounding factor is a variable that is independently associated with the health outcome and may affect the results of the study because it is distributed differently in the study and control groups.
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Further, as discussed below many cohort studies refine their measures of health outcomes by using an internal comparison group, which may differ in exposure level but may otherwise be more similar to the cohort than the general population. Many of the studies of uranium workers are retrospective cohort studies (see Chapter 4~.
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When health outcomes are infrequent or rare, longitudinal or cross-sectional studies must be large enough and of sufficiently long duration to accumulate enough adverse events to accurately estimate the risk of a particular agent. In casecontrol studies, subjects (or cases)
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Cross-sectional studies seek to uncover potential associations between exposure to specific agents and development of disease. They may compare disease or symptom rates between groups with and without the exposure to the specific agent or may compare exposure to the specific agent between groups with and without the disease.
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Neither case reports nor case series are formal epidemiologic studies, but both are means for generating hypotheses about exposure and disease relationships. For Gulf War veterans, registry programs established by the VA and the Department of Defense (DoD)
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to help evaluate the strength of the evidence for or against an association between exposure to the agent under study and adverse health outcomes. The committee assessed the evidence by considering the six general criteria (strength of association, dose-response relationship, consistency of association, temporal relationship, specificity of association, and biological plausibility)
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Establishing a temporal relationship is often difficult, especially with health outcomes that have long induction periods, such as cancer. The committee interpreted the lack of an appropriate time sequence as evidence against association, but recognized that insufficient knowledge of the natural history and pathogenesis of many of the health outcomes under review limited the utility of this criterion (IOM, 1994b)
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An apparent effect of an agent on a health outcome may be the result of random variation due to sampling when assembling the study populations, rather than to the agent under study. Standard methods using confidence intervals or tests of statistical significance allow one to assess the role of chance variation due to sampling.
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SUMMARY OF THE EVIDENCE As seen below in the discussion of categories of association, the committee distinguishes between "sufficient evidence of a causal relationship" and "sufficient evidence of an association." Thus, before describing the categories used to summarize its findings, the committee provides a brief discussion of the concepts of causation and association.
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Epidemiologic studies can establish statistical associations between exposure to specific agents and health effects. In the types of epidemiologic studies described earlier in this chapter, the degree of an association is often measured by relative risks, odds ratios, and SMRs.
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· Sufficient Evidence of a Causal Relationship. Evidence is sufficient to conclude that a causal relationship exists between the exposure to a specific agent and a health outcome in humans.
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To infer a causal relationship from a body of evidence, the committee relied on long-standing criteria for assessing causation in epidemiology (Hill, 1971; Evans, 1976~. COMMENTS ON INCREASED RISK OF ADVERSE HEALTH OUTCOMES AMONG GULF WAR VETERANS As discussed in the beginning of this chapter, the committee reviewed the available scientific evidence in the peer-reviewed literature in order to draw conclusions about associations between the agents of interest and adverse health effects in all populations.
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Thus, the committee could not determine the likelihood of increased risk of adverse health outcomes among Gulf War veterans due to exposure to the agents examined in this report. REFERENCES Ballantyne B
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1999. Randomized controlled trials mark a golden anniversary.
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The studies in this cohort have limited relevance to the depleted uranium exposures of Gulf War veterans because, as described below, the primary disease-causing exposures for the miners were not to uranium, but to radon. The remainder of the section provides detailed descriptions of studies on workers occupationally exposed to uranium in uranium-processing plants.
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CONTENTS TOXICOLOGY................................................. Pharmacokinetics and Toxicokinetics, 94 Animal and In Vitro Studies, 99 94 EPIDEMIOLOGIC STUDIES: DESCRIPTION OF THE STUDIES 106 General Considerations, 106 Studies of Uranium Miners, 107 Studies of Uranium Processing Workers, 110 HUMAN HEALTH EFFECTS OF URANIUM 121 Assessing the Evidence: Factors Influencing the Quality of Studies, 123 All Cancer Deaths, 128 Lung Cancer, 128 Lymphatic Cancer, 142 Bone Cancer, 143 Nonmalignant Renal Disease, 147 Nonmalignant Neurological Disease, 151 Nonmalignant Respiratory Disease, 153 Other Health Outcomes, 156 CONCLUSIONS REFERENCES 159 160
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