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2 Evaluating the Evidence
Pages 37-64

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From page 37...
... DEFINE THE EVALUATION PARAMETERS This section describes the primary evaluation parameters used by the committee. This includes the choice and measurement of health outcomes of concern, 1  Despite loose usage of "Agent Orange" by many people, in numerous publications, and even in the title of this series, this committee uses "herbicides" to refer to the full range of herbicide exposures experienced in Vietnam, while "Agent Orange" is reserved for a specific one of the mixtures sprayed in Vietnam.
From page 38...
... However, Public Law 102-4, which mandated the committee's work, did not specify any particular health outcomes suspected of being associated with herbicide exposure. Such a list of outcomes was developed on the basis of diseases and conditions addressed in the scientific literature identified through the original VAO committee's extensive literature searches.
From page 39...
... , a range of other chronic health outcomes, and fertility and gestational effects. The primary focus of the evaluation was on adverse outcomes in the veterans themselves, but a targeted evaluation was also conducted to look for potential adverse health effects in offspring of Vietnam veterans.
From page 40...
... 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. Death-certificate diagnoses are notoriously inaccurate if the certificates are completed by medical officers who are not familiar with the decedents' medical history (Smith Sehdev and Hutchins, 2001)
From page 41...
... For nonmalignant conditions, the diversity of disease processes involved makes the use of broad ICD ranges less useful, but, because VAO committees could not possibly address every rare nonmalignant disease, they do not draw explicit conclusions about diseases that are not discussed. Thus, the category of "inadequate or insufficient evidence to determine an association" is the default or starting point for any health outcome; if a condition or outcome is not addressed specifically, then it will be in this category.
From page 42...
... , are responsible for some of the adverse effects of inorganic arsenic. This committee considered the available toxicologic information on DMA very carefully in assessing its contribution to the biologic plausibility of an association of various health outcomes with exposure to the herbicides used in Vietnam.
From page 43...
... 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 above, inorganic arsenic and benzene were not considered as relevant servicerelated exposures among Vietnam veterans and thus were not evaluated in relation to their potential risk of adverse health outcomes.
From page 44...
... Cacodylic Acid [75-60-5] CI NH 2 O HO CI As O N OH CI FIGURE 2-2  Chemical structures and CAS numbers for specific chemicals of interest.
From page 45...
... The quality of exposure information in the scientific literature reviewed by this and previous VAO committees varies widely. Some studies relied on interviews or questionnaires to determine the extent and frequency of exposure.
From page 46...
... The committee for Update 2006 decided that doing exhaustive searches on job titles, occupations, or industries in order to identify additional study populations that had possible, but not specifically characterized, exposure to the COIs was no longer an efficient means of augmenting the evidence database in that the citations such searches would yield were more likely to be those with information about a health outcome at the expense of considerable uncertainty about exposure. The previous and current committees followed the Update 2006 committee's practice of performing more circumscribed searching.
From page 47...
... Mechanistic and toxicology studies of the COIs are not core evidence in the overall evaluation of the potential associations between the COIs and health outcomes specific to Vietnam veterans, but they are considered for the potential insight they may provide into biologic plausibility. COMPILATION OF EVIDENCE FOR EVALUATION This section describes the manner in which potentially relevant literature was identified, how such literature was screened and processed, and how the new information that was identified has been integrated with previous information evaluated by the committee.
From page 48...
... The specific search terms used by the committee directly parallel the target COIs defined above, but they were also purposely broad so as to be exhaustive in terms of identifying all relevant literature. The search strategy included the chemical names, synonyms, and CAS numbers of the specific COIs -- 2,4D, 2,4,5-T, TCDD, cacodylic acid, and picloram (see Figure 2-2 for chemical structures and CAS numbers)
From page 49...
... Because dioxin-like and non–dioxin-like PCB congeners are found together in environmental mixtures and are known to mediate toxicity by various mechanisms, the relative contribution of dioxin-like PCBs to an individual health outcome can be difficult to determine. Therefore, evidence from epidemiologic studies of PCB exposure has been retained only for results that concerned specific dioxin-like congeners or that were reported in terms of TEQs.
From page 50...
... In a considerable number of instances over the course of the VAO reports, single study populations have generated multiple entries for a given health outcome. Before Update 2010, the procedure had been to enter new results into the summary results tables in groups corresponding to the VAO update in which the study first appeared, so it has been difficult to recognize which findings are based on the experience of the same set of people.
From page 51...
... The committee had three specific tasks: to determine whether there is a statistical association between exposure to the herbicides used in Vietnam and health outcomes, to determine the increase in risk of effects among Vietnam veterans, and to determine whether plausible biologic mechanisms provide support for a causal relationship with a given health outcome. Scientifically relevant associations between exposures to the COIs and specific health outcomes are determined through an analysis of available epidemiologic studies that is informed by an understanding of the toxicology of the chemicals and their exposure pathways.
From page 52...
... Because studies of Vietnam veterans address the very population of concern to the legislation that mandated the present review, any demonstrations of increased incidence of particular health outcomes among them are of unquestionable pertinence in drawing conclusions. It is difficult to quantify risk when exposures of a population have not been accurately measured.
From page 53...
... Some of the studies provide stronger evidence about health outcomes than do studies of veterans because the exposures were measured sooner after occurrence and were more thoroughly characterized than has been the case in most studies of veterans. Furthermore, in the studies of workers in chemical-production plants, the magnitude and duration of exposure to the chemicals were generally greater, so the likelihood that any possible health consequence would be manifested was greater.
From page 54...
... DEFINE THE EVALUATION APPROACH This section describes the manner in which the committee reviewed all of the evidence it compiled and synthesized in rendering its conclusions on the relationships between the COIs and health outcomes among Vietnam veterans. This includes the overarching evaluation principles that the committee employed and the role of judgment, the use of statistical association as the primary evaluation ­ etric, and the methodological factors that were considered, such as mul m tiple publications on the same study cohort, plausible biological mechanisms, and publication bias.
From page 55...
... However, for many conditions, particularly uncommon ones, associations with the COIs have remained unaddressed in the medical research literature; for these, the committee remains neutral, understanding that "absence of evidence is not evidence of absence." An issue related to evidence evaluation that was of concern for the Update 2006 committee was the evidence category of "no association." That committee determined that a conclusion of no association would require substantive evidence of such a lack of effect for all of the COIs. Given the paucity of available information on cacodylic acid and picloram, either positive or negative for virtually all health outcomes, such a conclusion would seem suspect even if substantial evidence uniformly supported a finding of no association both with exposure to the phenoxy herbicides and with exposure to TCDD.
From page 56...
... These aspects of the committee's review required thoughtful consideration of alternative approaches at several points and could not be accomplished by adherence to a narrowly prescribed formula. The realized approach, as described here, has been determined to a large extent by the nature of the exposures, of the health outcomes, and of the resulting evidence available for examination; for that reason, it has evolved during the course of the work of this and previous VAO committees.
From page 57...
... For those reasons, the committee for Update 2010 did not adopt the suggestion to perform what in effect would be a checklist approach to distilling the evidence concerning underlying causality for any observed statistical association between a human health effect and exposure to the components of the herbicides sprayed in Vietnam. The current committee also interprets its charge to be to summarize the scientific evidence for consideration by the Secretary, whose role is to make the policy decision of whether a contribution of herbicide exposure to the occurrence of an adverse health effect is likely enough to merit recognition as a presumptive condition.
From page 58...
... For example, if the rate in an exposed population is twice the rate in a non-exposed population, then the relative risk is 2. Similarly, if the odds of a health outcome are 1:20 in an exposed population but 1:100 in a nonexposed population, the odds ratio is 5.
From page 59...
... as having "suggestive evidence of no association" with "exposure to herbicides" into this default category of inadequate or insufficient evidence for any conclusion about association to be drawn for a specific health outcome. Define Factors to Consider in Weighing the Evidence Totality of Evidence and Multiple Publications VAO committees wanted to be clear in indicating what evidence is factored into their conclusions.
From page 60...
... The main categorization of veteran, occupational, and environmental cohort studies and case-control studies has been retained in both instances. In an effort to provide a coherent picture of the occurrence over time of a specific health outcome in a given study population, the current committee has shifted its emphasis away from individual publications by moving the citation that was the source of a particular finding to the rightmost column in the results tables.
From page 61...
... 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. Animal studies and in vitro studies with human cells and cell lines provide links that are important for understanding the underlying biochemical mechanisms associated with toxicity induced by xenobiotics (exogenous chemicals)
From page 62...
... criteria for causality (previously discussed) , but also insights about biologic processes inform whether an observed pattern of statistical association might be interpreted as the product of more than error, bias, confounding, and chance.
From page 63...
... Thus, conclusions about the associations between exposure and outcome that are based solely on published results could be subject to bias. Despite that, the committee does not believe that its conclusions have been unduly affected by publication bias, for two reasons: The extensive publicity surrounding the possibility of health effects associated with the herbicides used in Vietnam has created considerable pressure to publish all findings on the subject, and the many published studies assembled and reviewed contain among their results the full range of possible statistical associations, from convincingly negative through indeterminate to strongly positive.


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