Veterans and Agent Orange Update 2006 (2007) / Chapter Skim
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2 Evaluating the Evidence
2 Evaluating the Evidence
Pages 29-46
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From page 29... ...
Public Law 102-4, which mandated the committee's work, however, did not specify particular health outcomes of interest. VAO listed health outcomes addressed in the scientific literature, and the list has been amended in the VAO updates in response to new publications, to requests from the Department of Veterans Affairs and various veterans' service organizations, and to concerns of Vietnam veterans and their families.
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From page 30... ...
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," "AhR," "dioxin," "herbicide," "phenoxy")
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From page 31... ...
Picloram [1918-02-1] Cacodylic Acid [75-60-5]
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From page 32... ...
It is now known which highly exposed, non-veteran occupational and environmental cohorts are under continuing study and they are monitored for new publications, while ever more relevant results are becoming available on the maturing cohort of Vietnam veterans. The committee, therefore, decided that global searches for additional occupational and environmental study populations possibly highly exposed to the chemicals of interest no longer constituted an efficacious tool for realizing its intention to improve scientific reliability by focusing on better-characterized information.
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From page 33... ...
Many epidemiologic studies of PCB were recovered in the literature search, although they were not specifically sought. Because dioxin-like and non-dioxin-like PCB congeners are found together in environmental mixtures and are known to mediate toxicity by unique mechanisms, the relative contribution of dioxin-like PCBs to an individual health outcome can be difficult to determine.
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From page 34... ...
The committee found that the most relevant evidence came from epidemiologic studies -- investigations in which large groups of people are studied to identify an association between exposure to a chemical of interest and the occurrence of particular health outcomes. Epidemiologists estimate associations between exposure and outcome in a specific population or group by using such measures as relative risk, standardized mortality ratio, and odds ratio.
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From page 35... ...
In pursuing the question of statistical association, the committee recognized that an absolute conclusion about the absence of association is unattainable. As in science generally, studies of health effects associated with herbicide exposure cannot demonstrate that a purported effect is impossible or could never occur.
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From page 36... ...
As explained in Chapter 1, the committee has decided to make a general statement about its continuing inability to address this aspect of its charge quantitatively rather than reiterate a disclaimer in the concluding section for every health outcome. Plausible Biologic Mechanisms Chapter 3 details the experimental basis for 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 37... ...
The committee used toxicologic information in this fashion and believes that placing this information before its conclusion presents readers of its report with a more coherent argument for its ultimate conclusion about the adequacy of the available evidence to support the existence of a particular association; therefore, this section has been moved from the final section for each health outcome to precede the synthesis section. 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 38... ...
Because the subjects of studies of Vietnam veterans are the concern of the legislation that mandated this review, however, demonstrations of increased incidence of particular health outcomes among them are of unquestionable pertinence when 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 39... ...
Individual case reports were reviewed because the rapid appearance and transient nature of that condition imposes 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 classification was important to the committee in assembling pertinent data related to a particular endpoint from various investigations before integrating the information.
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From page 40... ...
In this report, ICD codes appear almost exclusively in the introductory sections of health-outcome discussions (particularly for cancers) to specify precisely what endpoint the committee is addressing and, when available, on the results table to indicate exactly what the primary researchers believed they were investigating.
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From page 41... ...
Simultaneous analysis of multiple health outcomes could potentially provide more insight into the effect of the chemicals of interest in causing multiple health effects, competing risks between various health outcomes, and the interactive effects of some health endpoints on others, but addressing health conditions individually has remained challenging. For this and future updates, the committee wanted to be more transparent about indicating what evidence is factored into its conclusions.
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From page 42... ...
Although ecologic studies vary in their ability to link an exposure to a health outcome specifically, most are considered preliminary or "hypothesis-generating" studies because they lack information on exposure and disease on an individual basis and are unable to address potential confounding factors. Exposure or dose reconstruction is a particularly challenging aspect of exposure assessment for a population, such as Vietnam veterans, in which few measurements were made during the period of exposure.
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From page 43... ...
The recognized difficulty of extrapolating back from contemporaneous tissue TCDD concentrations to estimate TCDD (and indirectly herbicide) doses at the time of first exposure or to estimate maximal exposure was highlighted in this update by recent work supporting biphasic, rather than singlecompartment elimination (Aylward et al., 2005a,b; Cheng et al., 2006)
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From page 44... ...
In addition, genetic differences in the properties of the AhR are known in human populations, as they are in laboratory animals, so some people are at intrinsically greater or less risk for the toxic effects of TCDD. Although studying AhR biology in transformed human cell lines minimizes the inherent error associated with species extrapolations, caution must be exercised because it is still not clear to what extent toxicity is affected by the transformation itself or by the conditions under which cell lines are cultured in vitro.
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From page 45... ...
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 46... ...
2003a. Immuno toxicological effects of Agent Orange exposure to the Vietnam War Korean veterans.
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