Veterans and Agent Orange Update 2010 (2012) / Chapter Skim
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2 Evaluating the Evidence
2 Evaluating the Evidence
Pages 31-53
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From page 31... ...
Comments received at public hearings and in written submissions from veterans and other interested persons have been valuable in identifying issues to be pursued in greater depth in the scientific literature. The VAO committees began their evaluation by presuming neither the presence nor the absence of an association between exposure and any particular health outcome.
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From page 32... ...
, mediates essentially all the toxicity of TCDD, so aryl hydrocarbon receptor also was used as a keyword, as were dioxin, Agent Orange, and Vietnam veteran. One of the herbicides used in Vietnam was cacodylic acid, or dimethylarsinic acid of valency 5 (DMAV)
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From page 33... ...
As noted above, the terms used in the search strategy included the chemical names, synonyms, and CAS numbers of the specific chemicals of interest -- 2,4-D, 2,4,5-T, TCDD, cacocylic acid, and picloram (see Figure 2-1 for chemical structures and CAS numbers) -- and the more generic terms involved with this project: Vietnam veteran, Agent Orange, aryl hydrocarbon receptor, dioxin, herbicide, and phenoxy.
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From page 34... ...
Cacodylic Acid [75-60-5] CI NH 2 O HO As CI N O OH CI FIGURE 2-1 Chemical structures and CAS numbers for specific chemicals of interest.
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From page 35... ...
The Agricultural Health Study, a continuing prospective cohort study of agricultural populations with specific information on the chemicals of interest, is also now contributing a steady stream of information to the database. Most important, the Vietnam vet erans themselves are advancing in age and when studied are capable of directly providing substantial information on chronic health conditions and, in some study populations, information related to serum TCDD concentrations.
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From page 36... ...
For the present update, very few documents of interest had to be retrieved as hard copies from library sources. In large part, included reports are peer-reviewed journal articles, but generally available and formally published government studies (particularly those investigating health effects in Vietnam veterans)
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From page 37... ...
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. The past procedure has been to enter new results into the summary results tables in groups corresponding to successive updates, so it has been difficult to recognize which findings are based on the experience of the same set of people.
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From page 38... ...
COMMITTEE'S APPROACH The committee's general approach to the evaluation of scientific evidence corresponds closely with the approach developed by the original VAO committee as delineated in detail in Chapter 5 of VAO. 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.
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From page 39... ...
. (Chapters 6–11 contain tables of results abstracted from the studies providing evidence about individual health outcomes.
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From page 40... ...
It may not be possible to partition contributions of the chemicals of interest from those of all other factors quantitatively, but, to the extent that the possibility of confounding influences can be appraised, the committee will have achieved its objective. Increased Risk in Vietnam Veterans When all the available epidemiologic evidence has been evaluated, it is pre sumed that Vietnam veterans are at increased risk for a specific health outcome if there is evidence of a positive association between one or more of the chemicals of interest and the outcome.
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From page 41... ...
As explained in Chapter 1, the committee for Update 2006 decided to make a general statement about its continuing inability to address that aspect of its charge quantitatively rather than to reiterate a disclaimer in the concluding section for every health outcome, and the present committee has retained that approach. Plausible Biologic Mechanisms Chapter 4, "Information Related to Biologic Plausibility" and previously denoted as "Toxicology," details the experimental basis of assessment of biologic plausibility or the extent to which an observed statistical association in epidemio logic studies is consistent with other biologic or medical knowledge.
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From page 42... ...
Animal studies and in vitro studies with human cells and cell lines do provide important links to understanding underlying biochemical mechanisms associated with toxicity induced by xenobiotics (exogenous chemicals)
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From page 43... ...
The committee used toxicologic information in that fashion and placed the information before its synthesis and conclusion to provide readers with a more coherent argument for its ultimate conclusion about the adequacy of the available evidence to support the existence of a particular association. EVALUATION OF THE EVIDENCE Associations between exposures to the chemicals of interest 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.
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From page 44... ...
Because the subjects of studies of Vietnam veterans are the concern of the legislation that mandated the present review, however, demonstrations of increased incidence of particular health outcomes among them are of unquestionable pertinence in drawing conclusions. The committee has concluded that it would be inappropriate to use quantitative techniques, such as meta-analysis, to combine individual study results into a single summary measure of statistical association.
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From page 45... ...
Individual case re ports were reviewed because the rapid appearance and frequently transient nature of the condition impose methodologic constraints that might have precluded the application of standard epidemiologic techniques. Because any effect of Agent Orange in individuals or groups of veterans is evaluated in terms of disease or medical outcome, attention to disease classifica tion was important to the committee in assembling pertinent data from various investigations related to a particular outcome before integrating the information.
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From page 46... ...
Thus, epidemiologic data may not be available for assessing whether a particu lar rare disease is associated with Agent Orange exposure. In some instances, such as chronic lymphocytic leukemia and AL amyloidosis, VAO committees have reached conclusions on the basis of the data available and the etiology of the disease.
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From page 47... ...
The practice in the VAO reports has been to augment the results table for a given health outcome with any additional publications consid ered in the current update in the categories of Vietnam-veteran, occupational, or environmental studies. Inclusion of sequential sets of results from follow-ups of a study population has the potential to create the appearance of a greater weight of evidence than is warranted, so Update 2006 and Update 2008 used italicized citations in results tables to indicate that results had been superseded.
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From page 48... ...
In such studies, the committee looked for evidence of health effects that are associated with the specific compounds in the defoliants used in Vietnam and sought consideration of and adjustment for other possibly confounding exposures. The quality of exposure information in the scientific literature reviewed by this and previous VAO committees spans a broad range.
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From page 49... ...
Even if herbicide formulations or mixtures are used, the conditions of exposure might not realisti cally reproduce human exposures that occur in the field. Furthermore, Vietnam veterans were exposed to other agents -- such as tobacco smoke, insecticides, therapeutics, drugs, diesel fumes, and alcohol -- that may increase or decrease the ability of chemicals in herbicides to produce a particular adverse health outcome.
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From page 50... ...
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 pos sibility of health effects associated with the herbicides used in Vietnam has cre ated 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. Role of Judgment This committee's process of reaching conclusions about statistical associa tions involved more than a formulaic application of quantitative procedures to the assembled evidence.
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From page 51... ...
Those aspects of the committee's review required thoughtful consid eration 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 result ing evidence available for examination; therefore, it has evolved in the course of the work of this and previous VAO committees.
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From page 52... ...
The committee 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 by herbicide exposure to the occurrence of an adverse health effect is likely enough to merit recognition as a presumptive condition. REFERENCES1 Abell A, Juul S, Bonde JP.
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From page 53... ...
2003. Impact of Agent Orange exposure among Korean Vietnam veterans.
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