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3 Evaluation of the Evidence Base
Pages 45-68

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From page 45...
... The committee also describes some of the issues it encountered when reviewing the literature on Vietnam War exposures and health outcomes, such as multiple exposures and individual variability. Because the current committee closely followed the approach used by prior Veterans and Agent Orange (VAO)
From page 46...
... Search terms included full and abbreviated chemical names, common and manufacturer trade names, the Chemical Abstracts Service numbers, and MeSH1 descriptors for each of the COIs and other similar chemicals on an assumption that compounds with similar chemical structure may have analogous biologic activity. The aryl hydrocarbon receptor (AHR)
From page 47...
... TCDD Toxicity Mediator Aryl hydrocarbon receptor (AHR) and related MeSH descriptors Generic Terms Vietnam, veteran, Vietnam veteran, Agent Orange, dioxin, herbicide, and phenoxy SEARCH TERMS FOR CONDITIONS SPECIFIED IN THE STATEMENT OF TASK Generational Health Effects Reproductive OR Reproduction OR Gonads OR Fertility OR Infertility OR Fertilization OR Sperm*
From page 48...
... In addition, potentially relevant articles were also identified by searching the reference lists of relevant review and research articles, books, and reports. Exact duplicate articles and those that had been summarized and referenced in Update 2014 were deleted.
From page 49...
... While, as past VAO committees have noted, the increased risks of these types of mental health conditions among veterans of all U.S. conflicts are of scientific and public health concern, military service alone, including deployment and service in Vietnam, is known to confer a range of exposures to potentially traumatic events that may be expected to increase the risk of developing PTSD and related psychologic conditions.
From page 50...
... VAO committees have considered and reviewed toxicologic studies in which animals were directly exposed to dimethylarsinic acid (DMA) , but the extensive literature on the health effects of exposure to inorganic arsenic (including the epidemiologic research, animal experiments, and mecha nistic studies)
From page 51...
... Thus, at this time the committee was not able to determine whether the COIs might magnify the impact of traumatic events. Although exposure to 2,4-D, 2,4,5-T, TCDD, cacodylic acid, and picloram are most germane to the committee's charge and given the most weight in the review of the evidence on a particular health outcome, chemicals that are structurally similar to the herbicides and contaminants found in the tactical herbicides used in Vietnam are assumed to have similar biologic activity and thus were also included in the committee's review of the literature, consistent with prior VAO Update committees.
From page 52...
... Thus, in aggregate, the primary COIs evaluated by the committee with respect to potential associations with adverse health outcomes among Vietnam veterans are 2,4-D, 2,4,5-T, picloram, cacodylic acid, and TCDD. As explained, inorganic arsenic and benzene were not considered as relevant service-related exposures among Vietnam veterans and thus were not evaluated in terms of their risk for adverse health outcomes.
From page 53...
... Because the use of the general search terms "pesticides" or "pesticide," "defoliants," "defoliant agent," and "herbicide" or "herbicides" resulted in more than 57,000 "hits," the committee focused its search on the specific COIs as well as related chemical classes. Even using the more targeted terms for the COI identified many studies that examined the relationship between exposure to "pesticides" or "herbicides" and adverse health outcomes without identifying specific chemicals.
From page 54...
... Articles using the generic term "herbicide" were kept if a published report specified that the COIs were among the pesticides or herbicides used by the study population or the COIs are used commonly for the crops identified in the study or the COIs are used commonly for a specific purpose, such as the removal of weeds and shrubs along highways. For instance, this rubric would apply to any published articles from the Agricultural Health Study because 2,4-D was one of the most frequently used pesticides in this large prospective cohort, but some results have lumped all herbicide exposure together.
From page 55...
... As with all VAO committees, the committee began its assessment of the literature by assuming neither the presence nor the absence of an association between exposure and any particular health outcome. Because of the variability in the descriptions and diagnoses of the health conditions considered in this report, the committee made no a priori assumptions about the usefulness of any article or report for a health outcome.
From page 56...
... were revised to include only the new primary epidemiologic studies; secondary studies, including mechanistic and toxicologic studies, were not included in the compendium evidence tables for each outcome. If no new primary studies for a health outcome were identified, the evidence table from Update 2014 was included.
From page 57...
... Toxicologic studies, particularly in animal models, are included to inform the understanding of biologic plausibility through the toxicology of the chemicals and their exposure pathways. Vietnam Veterans Because Vietnam veterans are the target population of the charge to the VAO committees, studies of these veterans (whether American or otherwise)
From page 58...
... to TCDD and the other COIs provide evidence of exposure and health outcomes to supplement the studies of Vietnam veterans. Some occupational and environmental cohorts that received exceptionally high exposures have produced many informative results and provide stronger evidence about health outcomes than studies of Vietnam veterans because the exposures were better characterized and measured sooner relative to the exposure.
From page 59...
... Ultimately, the results of the toxicology studies should be consistent with what is known about the human disease process if they are to support a conclusion that the development of the disease was influenced by an exposure. Aryl Hydrocarbon Receptor  Many of the available toxicologic and mechanistic studies involve the AHR because it has been found that essentially all of the toxic effects of TCDD involve interaction with this protein (receptor)
From page 60...
... The objectives of those toxicology studies are to determine what toxic effects are observed at different exposure levels and to identify the mechanisms by which the effects are produced. To be considered an acceptable surrogate for the study of a human disease, an animal model must reproduce, with some degree of fidelity, the manifestations of the disease in humans.
From page 61...
... Stress -- of known or unknown origin -- is a well-known modifier of human disease responses (such as immune responses) ; stress is an ever present variable that is difficult to assess or control for in epidemiologic studies because there is substantial individual variation in response to it.
From page 62...
... Generational effects were specifically included in the committee's charge and are addressed along with reproductive outcomes in a combined chapter. Although for most health outcomes the primary focus of the evaluation was on adverse outcomes in the veterans themselves, to examine potential effects, the children of Vietnam veterans and also later generations were included in the evaluation of the literature.
From page 63...
... Therefore, this and previous VAO committees have opted to use the ICD system as an organizing tool. Many of the epidemiologic studies reviewed by VAO committees have not used the ICD approach to classification of disease and have relied instead on clinical impression alone.
From page 64...
... For example, misclassification bias may result in exaggerated or underestimated estimates, whereas self-selection bias affects the representativeness of the study population and can limit the applicability of the results to the larger population of interest. Another type of bias that may potentially affect studies of Vietnam veterans is detection bias, in which veterans who are encouraged to and who choose to participate in screening programs or registries, such as the Agent Orange Registry (discussed in Chapter 5)
From page 65...
... Detection bias may lead to an overestimate or underestimate of the true effect size. Confounding is a common type of bias in epidemiologic studies that occurs when a risk factor for the disease is also related to the exposure and creates a spurious exposure–disease association.
From page 66...
... In its examination of these epidemiologic studies, the committee looked for evidence of health effects that are associated with the specific compounds in the herbicides used in Vietnam and sought consideration of and adjustment for other possibly confounding exposures. When all the available epidemiologic evidence has been evaluated, Vietnam veterans are presumed to be at increased risk for a specific health outcome if there is evidence of a positive association between one or more of the COIs and the outcome.
From page 67...
... The coherence of the full body of epidemiologic information, including biologic plausibility, is considered when the committee reaches a judgment about association for a given outcome. As was the case with the past three update committees, this committee did not use the Bradford Hill criteria for causality (Hill, 1965)
From page 68...
... Limited or Suggestive Evidence of No Association The original VAO committee defined the category "limited or suggestive evidence of no association" for health outcomes for which several adequate studies covering the "full range of human exposure" were consistent in showing no association with exposure to herbicides at any concentration and had relatively narrow confidence intervals. A conclusion of "no association" is inevitably limited to the conditions, exposures, and observation periods covered by the available studies, and the possibility of a small increase in risk related to the magnitude of exposure studied can never be excluded.


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