Veterans and Agent Orange Update 2008 (2009) / Chapter Skim
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2 Evaluating the Evidence
2 Evaluating the Evidence
Pages 27-45
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From page 27... ...
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 was developed on the basis of diseases and conditions addressed in the scientific literature identified through the original VAO's extensive literature searches.
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From page 28... ...
The committee carefully reconsidered that evidence but again determined that it does not support a conclusion that exposure to cacodylic acid would be expected to result in the same adverse health effects as would exposure to toxic concentrations of inorganic arsenic. Therefore, as in prior VAO reports, the literature on the health effects of inorganic arsenic was not considered here.
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From page 29... ...
(An ancillary analysis of the search results by this committee determined that the term "pesticide" did not identify any relevant citation that was not picked up by more specific terms, and so it will be eliminated from searches in future VAO updates, thereby reducing the number of extraneous hits to be culled.) Because they are the target population of the charge to the VAO committees, studies of Vietnam veterans (serving in any of the armed forces, American or otherwise)
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From page 30... ...
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 chemical of interest.
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From page 31... ...
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 veterans themselves are advancing in age and, when studied, capable of directly providing substantial information on chronic health conditions, often as related to serum TCDD concentrations.
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From page 32... ...
Many epidemiologic studies of PCBs 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 33... ...
Statistical Association The issues in determining whether a statistical association exists are detailed in Chapter 5 of VAO. 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.
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From page 34... ...
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, only that it is statistically improbable.
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From page 35... ...
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 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 chemicals of interest and the outcome.
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From page 36... ...
In other words, does the observation of a particular health effect make sense on the basis of what is known about how the chemicals in question act at the tissue, cellular, or molecular level? The relationship between a particular exposure and a specific human health outcome is addressed in the context of research on the effects of the chemicals on biologic systems and of evidence from animal studies.
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From page 37... ...
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 38... ...
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 39... ...
Many of the epidemiologic studies reviewed by this committee did not use the ICD approach to classification of disease and 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 40... ...
Simultaneous analysis of multiple health outcomes could potentially provide more insight into whether the chemicals of interest cause multiple health effects, into competing risks between various health outcomes, and into the interactive effects of some health outcomes on others; but addressing health conditions individually has remained challenging.
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From page 41... ...
Given the paucity of information that has ever been found on cacodylic acid and picloram, that 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. The current committee concurs with that determination and has adopted a similar approach to the placement of health outcomes in this category.
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From page 42... ...
For health outcomes with very little evidence, a somewhat looser criterion would apply so that no possible signal of an association would be overlooked. Animal and Mechanistic Studies Animal models used as surrogates for the study of a human disease must reproduce, with some degree of fidelity, the manifestations of the disease in humans.
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From page 43... ...
There is a consensus that most of or all the toxic effects of TCDD involve interaction with the aryl hydrocarbon receptor (AHR) , a protein that binds TCDD and other aromatic hydrocarbons with high affinity.
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From page 44... ...
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 this 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 45... ...
2003a. Immuno toxicological effects of Agent Orange exposure to the Vietnam War Korean veterans.
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