Veterans and Agent Orange Update 2012 (2014) / Chapter Skim
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2 Evaluating the Evidence
2 Evaluating the Evidence
Pages 30-53
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From page 30... ...
Public Law 102-4, which mandated the committee's work, however, did not specify 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.
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From page 31... ...
, can be responsible for some of the adverse effects of inorganic arsenic. VAO committees have carefully reconsidered that evidence repeatedly but have continued to conclude that it does not support a conclusion that exposure to DMAV would be expected to result in the same adverse health effects as would exposure to toxic concentrations of inorganic arsenic.
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From page 32... ...
-- and the more generic terms involved with this project: Vietnam veteran, Agent Orange, aryl hydrocarbon receptor, dioxin, herbicide, and phenoxy. Results on other specific phenoxy herbicides are also of interest: 2-methyl-4-chlorophenoxyacetic acid (MCPA)
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From page 33... ...
Cacodylic Acid [75-60-5] CI NH 2 O HO CI As O N OH CI FIGURE 2-1 Chemical structures and CAS numbers for specific chemicals of interest.
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From page 34... ...
Most important, the Vietnam veterans 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. The committee for Update 2006 decided that exhaustive searches on job titles, occupations, or industries to identify additional study populations that had possible, but not specifically characterized, exposure to the COIs were no longer an efficient means of augmenting the evidence database in that they are more likely to yield citations with information about a health outcome at the expense of considerable uncertainty about exposure.
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From page 35... ...
are also included under the presumption that they have been carefully reviewed. In practice, the articles are generally in English, but VAO committees have obtained translations for crucial ones that were not in English, as in the case of reports of a study of Korean veterans of the Vietnam War (Kim HA et al., 2003; Kim JS et al., 2003)
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From page 36... ...
Because dioxin-like and non–dioxinlike PCB congeners are found together in environmental mixtures and are known to mediate toxicity by various mechanisms, the relative contribution of dioxinlike PCBs to an individual health outcome can be difficult to determine. Therefore, evidence from epidemiologic studies of PCB exposure has been retained only for reported results on specific dioxin-like congeners or in terms of TEQs.
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From page 37... ...
The committee's conclusions, however, are based on the accumulated evidence, not just on recently published studies. 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.
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From page 38... ...
The current committee has not modified the criteria used by previous VAO committees to assign categories of association to particular health outcomes but will henceforth state the object of its evaluation to be "scientifically relevant association" in order to clarify that the strength of evidence evaluated, based on the quality of the scientific studies reviewed, was a fundamental component of the committee's deliberations to address the imprecisely defined legislative target of "statistical association." Epidemiologists estimate associations between exposure and outcome in a specific population or group in terms of relative risk by using such measures as standardized mortality ratio, odds ratio, rate ratio, or hazard ratio. Those measures indicate the magnitude of a difference in the rate of an outcome between two populations.
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From page 39... ...
is close to 1; therefore, odds will be close to risk. An estimated relative risk or odds ratio greater than 1 indicates a positive association; it is more likely that the outcome will be seen in exposed people than in nonexposed people.
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From page 40... ...
Increased Risk in Vietnam Veterans When all the available epidemiologic evidence has been evaluated, it is presumed 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 COIs and the outcome. The best measure of potency for the quantification of risk to veterans would be the rate of the outcome in exposed Vietnam veterans compared with the rate in nonexposed veterans, adjusted for the degree to which any other factors that differ between exposed and nonexposed veterans might influence those rates.
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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," previously called "Toxicology," details the experimental basis of assessment of biologic plausibility or the extent to which an observed statistical association in epidemiologic 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 links that are important for 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 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.
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From page 44... ...
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. The committee reached that conclusion because of the many differences among studies in definitions of exposure, health outcomes considered, criteria for defining study populations, correction for confounding factors, and degree of detail in reporting results.
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From page 45... ...
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)
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From page 46... ...
For nonmalignant conditions, however, 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, it will be in this category.
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From page 47... ...
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 right-most column in the results tables. 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 of each of the chemicals of interest.
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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 varies widely.
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From page 49... ...
Even if herbicide formulations or mixtures are used, the conditions of exposure might not realistically 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 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. Role of Judgment This committee's process of reaching conclusions about statistical associations involved more than a formulaic application of quantitative procedures to the assembled evidence.
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From page 51... ...
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; therefore, it has evolved in the course of the work of this and previous VAO committees. The quantitative and qualitative procedures underlying the present review have been made as explicit as possible, but ultimately the conclusions about association expressed in this report are based on the committee's collective judgment.
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From page 52... ...
For those reasons, the committee for Update 2010 did not adopt the suggestion to perform what would be in effect a checklist approach to distilling 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.
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From page 53... ...
2003. Immuno toxicological effects of Agent Orange exposure to the Vietnam War Korean veterans.
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