2
Evaluating the Evidence

This chapter outlines the approach used by the Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides: Sixth Biennial Update and its predecessors to evaluate the available scientific evidence. A more complete description is found in Chapter 5 of Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam, hereafter referred to as VAO (IOM, 1994).

CHOICE OF HEALTH OUTCOMES

As discussed in Chapter 1, the committee was charged with summarizing the strength of the scientific evidence of an association between herbicide exposure during service in the Vietnam War and individual diseases or health outcomes. 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. 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.

IDENTIFICATION OF RELEVANT LITERATURE

Mixtures of 2,4-dichlorophenoxyacetic acid (2,4-D), 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), picloram, and cacodylic acid made up the bulk of the



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2 Evaluating the Evidence This chapter outlines the approach used by the Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides: Sixth Biennial Update and its predecessors to evaluate the available scientific evidence. A more complete description is found in Chapter 5 of Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam, hereafter referred to as VAO (IOM, 1994). CHOICE OF HEALTH OUTCOMES As discussed in Chapter 1, the committee was charged with summarizing the strength of the scientific evidence of an association between herbicide exposure during service in the Vietnam War and individual diseases or health outcomes. Public Law 102-4, which mandated the committee’s work, however, did not spec- ify 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. 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. IDENTIFICATION OF RELEVANT LITERATURE Mixtures of 2,4-dichlorophenoxyacetic acid (2,4-D), 2,4,5-trichlorophen- oxyacetic acid (2,4,5-T), picloram, and cacodylic acid made up the bulk of the 29

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30 VETERANS AND AGENT ORANGE: UPDATE 2006 herbicides sprayed in Vietnam. At the time of the spraying, 2,3,7,8-tetrachloro- dibenzo-p-dioxin (TCDD, one form of dioxin) was an unintended contaminant from the production of 2,4,5-T and was present in Agent Orange and some other herbicide formulations sprayed in Vietnam; thus, it should be noted that TCDD and Agent Orange are not synonymous. Therefore, databases have been searched for the names of those compounds, their synonyms and abbreviations, and their Chemical Abstracts Service (CAS) numbers. The evidence indicates that a tissue protein, the aryl hydrocarbon receptor (AhR), mediates most of the toxicity of TCDD, so “AhR” also was used as a keyword, as were “dioxin,” “Agent Orange,” and “Vietnam veteran.” As discussed in Chapter 3, one of the herbicides used in Vietnam, cacodylic acid, is dimethylarsinic acid (DMA), an organic form of arsenic. In addition to being synthesized as an herbicide, DMA is a metabolite of inorganic arsenic in humans. DMA was long thought to be a biologically inactive metabolite of inor- ganic arsenic, but recent evidence suggests that one form —DMA III—might be responsible for some of the adverse effects of inorganic arsenic. That evidence, however, is not sufficient to support a conclusion that exposure to cacodylic acid results in the same adverse health effects as would exposure to toxic con- centrations of inorganic arsenic. Therefore, the literature on the health effects of inorganic arsenic was not considered in this report. Further details on the effects of inorganic arsenic can be found in Arsenic in Drinking Water (NRC, 1999) and Arsenic in Drinking Water: 2001 Update (NRC, 2001). For cacodylic acid and picloram, the search terms were the chemical names, synonyms, and CAS numbers of the herbicides. This report concentrates on the evidence published after the completion of work on Veterans and Agent Orange: Update 2004 (IOM, 2005). Relevant new contributions to the literature made during the period June 1, 2004, through Sep- tember 30, 2006, were sought. The information the committee used was compiled from a comprehensive electronic search of public and commercial databases— biologic, medical, toxicologic, chemical, historical, and regulatory—that provide citations from the scientific literature. In addition, the reference lists of some review and research articles, books, and reports were examined for potentially relevant articles. 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”). By analogy, results on other specific phenoxy herbicides are also of interest: 2-methyl, 4-chlorophenoxyacetic acid (MCPA) and 2-(2-methyl-4- chlorophenoxy) propionic acid (MCPP or Mecoprop) for 2,4-D; 2-(2,4,5-tri- chlorophenoxy) propionic acid (2,4,5-TP or Silvex) for 2,4,5-T (see Figure 2-1 for chemical structures and CAS numbers). Findings only related to exposure to the diverse chemical families of pesticides were considered too nonspecific for

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31 EVALUATING THE EVIDENCE Phenoxy Herbicides 2,4-Dichlorophenoxyacetic acid [94-75-7] 2,4,5-T [93-76-5] MCPA [94-74-6] Silvex [93-72-1] MCPP [93-65-2] 2,3,7,8-Tetrachlorodibenzo-p-Dioxin [1746-01-6] Picloram [1918-02-1] Cacodylic Acid [75-60-5] FIGURE 2-1 The chemical structures and CAS numbers for specific chemicals of interest.

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32 VETERANS AND AGENT ORANGE: UPDATE 2006 inclusion in the evidentiary database for drawing conclusions about association. However, “pesticide” was included among the search terms to ensure that all pos- sible articles on herbicides (for which our specific targets were only the phenoxy herbicides, cacodylic acid, and picloram) would be identified and subjected to the next phase of screening. Because they are the target population of the VAO charge, studies of Viet- nam veterans (American or otherwise) have always been accorded considerable weight in the committees’ deliberations, whether or not estimation of exposure to herbicide-related substances has been attempted. Characterization of exposure in studies of the veterans was extremely uncommon at the time of the original VAO, and the Vietnam veterans’ own ages were still below the ages at which many chronic illnesses are manifested. Consequently, the original committee made extensive efforts to consider several groups known or thought to have poten- tially higher and better-characterized exposure to TCDD or phenoxy herbicides than Vietnam veterans themselves—both occupational exposure (as of chemical production, paper and pulp, sawmill, tannery, waste-incinerator, railroad, agri- cultural, and forestry workers) and environmental exposure (as of residents of Seveso, Times Beach, Quail Run, and Vietnam). Successive committees have chosen to concentrate more on studies that explicitly addressed the exposures specified in the charge. 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 consti- tuted an efficacious tool for realizing its intention to improve scientific reliability by focusing on better-characterized information. Searches based solely on job titles, occupations, or industries assumed to be related to one of the substances of interest were not done, because they are more likely to retrieve citations with information about a health outcome at the expense of considerable uncertainty about exposure. In general, an article did not merit review in VAO updates if its own authors had not thought that exposure to one of the substances of concern was prominent enough to mention it as a keyword that would be picked up by searches based on chemical names, synonyms, or CAS numbers. It is well accepted that any TCDD effect may be diluted somewhat in studies of Vietnam veterans because some of the veterans may not have been exposed or may have been exposed only at low levels. The problem is exacerbated in studies in which exposure is defined in terms of occupation (even on the basis of a full job history). Exploratory studies based on linking to a one-time statement of oc- cupation (for example, on a death certificate or in a census) are thought to be of little usefulness, even when a job-exposure matrix is used to “convert” standard- ized job codes to specific exposures. Not only is there uncertainty about whether all members of the sample have been exposed to one of the chemicals of interest

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33 EVALUATING THE EVIDENCE unless detailed personal monitoring and industrial-hygiene work have been per- formed, but for most occupational categories there is considerable certainty that the workers have been exposed to myriad other potentially toxic agents. Thus, such studies may well minimize the effects of dioxin exposure while yielding misleading indications of health problems resulting from other exposures. The search strategy was devised to ensure that abstracts of all potentially relevant articles were subjected to closer screening, but it also resulted in the iden- tification of a large number of non-relevant studies. The searches produced 5,800 “hits,” including some studies that were identified more than once. For most of the citations, it was evident from the abstract that the articles did not address health effects in association with exposure to the chemicals of interest; for example, many of the identified citations investigated the efficacy of herbicides in killing weeds and searching for “AhR” systematically also retrieved numerous investigations of “airway hyper-responsiveness.” All studies that discussed health effects were con- sidered if the search-related information (title, abstract, and keywords) indicated that any of the herbicides of interest (or any of their components) may have been investigated. For the more than 1,200 potentially relevant citations thus identified, a copy of the entire article was obtained online or retrieved from library sources and reviewed more thoroughly by the committee for inclusion in the report. In large part, included reports are peer-reviewed journal articles, but gener- ally available and formally published government studies (particularly those investigating health effects in Vietnam veterans) are also included under the presumption that they have been carefully reviewed. In practice, the articles are generally in English, but the committee would obtain translations for crucial studies, as was done for a study of Korean veterans of the Vietnam War (Kim HA et al., 2003; Kim JS et al., 2003) when Update 2004 was produced. TCDD, the 2,3,7,8-chlorinated congener of dioxin, is the most potent of the polychlorinated dibenzo-p-dioxins, dibenzofurans, and biphenyls (PCBs), so it is presumed to be most problematic. However, our concern is not limited to this single congener. In non-laboratory settings—that is, epidemiologic studies—ex- posures occur not only to TCDD, but to mixtures of dioxins, dibenzofurans, and PCBs, which vary in their degree of chlorination. Toxic equivalency factors, which express the toxicity of an individual congener relative to the toxicity of TCDD, are available and often used to estimate the cumulative toxic potency of such mixtures in terms of an equivalent concentration of TCDD. That approach is often taken in epidemiologic studies focusing on PCBs. 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. Thus, epidemiologic studies that included analyses of PCBs were retained only if they reported data on the contri- bution of polychlorinated dioxins to the health outcome of interest.

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34 VETERANS AND AGENT ORANGE: UPDATE 2006 Roughly 350 citations contributed new information to this update. For each health outcome, new evidence was reviewed in detail. The conclusions, however, are based on the accumulated evidence, not just on recently published studies. If statistics have been generated on the same study population over time (as noted in Chapter 4), multiple entries correspond to successive updates in the summary ta- bles of Chapters 6–9, but only the most comprehensive version of the information on a given population is factored into the committee’s conclusion on any health outcome. Primary findings are the components of the evidence the committee endeavors to integrate; reanalyses, pooled analyses, reviews, and so on, may be discussed in conjunction with primary results or in synthesis sections for a given health outcome, but they are not themselves part of the evidentiary data set. COMMITTEE’S APPROACH The committee’s general approach to the evaluation of scientific evidence is presented here. It corresponds very closely with the approached developed by the original committee, as delineated in detail in Chapter 5 of VAO (IOM, 1994). The committee had three specific tasks: to determine whether there is a statisti- cal association between exposure to the herbicides used in Vietnam and health outcomes, to determine the degree of increased risk of effects among Vietnam veterans, and to determine whether plausible biologic mechanisms provide sup- port for a causal relationship with a given health outcome. This section discusses the committee’s approach to each task. 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. Epidemiologists estimate as- sociations between exposure and outcome in a specific population or group by using such measures as relative risk, standardized mortality ratio, and odds ratio. Those measures indicate the magnitude of a difference in the rate of an outcome between two populations. For example, if the rate in an exposed population is twice the rate in a non-exposed population, the relative risk, or rate ratio, is 2. Similarly, if the odds of a health outcome are 1:20 in an exposed population but 1:100 in a non-exposed population, the odds ratio is 5. In this report relative risk refers to the results of cohort studies; odds ratio (an estimate of relative risk) usually refers to the results of case–control studies. (The results of cohort stud- ies sometimes are reported with odds ratios, again to estimate relative risk.) An estimated relative risk greater than 1 indicates a positive association (that is, it is more likely that the outcome will be seen with exposure than with non-exposure),

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35 EVALUATING THE EVIDENCE whereas a relative risk between zero and 1 indicates a negative or inverse associa- tion (that is, the outcome is less likely with exposure). A ratio of 1 suggests the absence of association. A statistically significant association is one that would be unlikely to occur by chance if there were truly no association (that is, if the null hypothesis is true). Determining whether an estimated association between an exposure and an outcome represents a real relationship requires careful scrutiny because there can be more than one explanation for the estimate. Bias is a distortion of the measure of association that results from flawed selection in the assembly of the study population or from error in measurement of the characteristics studied. Confounding is the distortion of the measure of association that results from the failure to recognize or account for some other factor related both to expo- sure and to outcome. Chance is the degree to which the estimated association might vary randomly among different samples of the population studied. The width of the confidence interval is used to quantify the likely variability of the exposure–disease association. Even when a relative risk or standardized mortality ratio exceeds 1, a conclusion regarding increased risk must be qualified when the confidence interval is broad. In drawing its conclusions, the committee examined the quantitative estimates of association and evaluated the potential influences of bias, confounding, and chance. When integrating the findings from various studies, the committee considered the degree of statistical significance associated with every estimated risk (a reflection of the magnitude of the observed effect and the power of the study designs), rather than simply tallying the “significant” and “non-significant” outcomes as dichotomous items of evidence. 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. Any instrument of observation, even the most excellent epidemiologic study, is limited in its resolving power. In a strict technical sense, therefore, the commit- tee could not prove the absence of an association between a health outcome and exposure to any of the compounds of interest. That contributed to the current committee’s decision to re-evaluate findings on the health endpoints classified in Update 2004 as having “suggestive evidence of no association.” Such factors as consistency of evidence, biologic plausibility, temporality, dose–response relationships, and strength of association may be considered when deciding whether an observed statistical association is causal. The committee’s charge, however, did not extend to making determinations of causality, so it drew no conclusions regarding cause-and-effect relationships. Interaction or synergism among the chemicals of interest, or with other agents, is another theoretical concern. The committee was not charged with attrib- uting effects to specific chemicals of interest; joint effects among them should be adequately identified by the committee’s approach. The number of combinations

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36 VETERANS AND AGENT ORANGE: UPDATE 2006 of these chemicals with other agents that might be problematic is virtually infi- nite. Real-life experience, as investigated with epidemiologic studies, effectively integrates any results of exposure to a target substance over all other possibly detrimental or mitigating exposures that a population might have. It may not be possible quantitatively to partition contributions of the chemicals of interest from those of all other factors, 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 out- come if there is evidence of a positive association between one or more of the chemicals of interest 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 non-exposed veterans, adjusted for the degree to which any other factors that differ between exposed and non- exposed veterans might influence those rates. A dose–response relationship established in another human population suitably adjusted for such factors would be similarly suitable. It is difficult, however, to quantify risk when exposures in a population have not been measured accurately. Fairly accurate exposure data for Vietnam veterans in terms of recent serum TCDD concentrations are available only for subgroups enrolled in the Air Force Health Study (the Ranch Hand and comparison subjects) and in VA’s study for deployed and non-deployed members of the Army Chemical Corps. Therefore, the absence of reliable measures of exposure to the chemicals of interest among Vietnam veterans limits the committee’s ability to quantify risk of specific diseases in this population. 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 quan- titatively 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 plausi- bility or the extent to which an observed statistical association in epidemiologic studies is consistent with other biologic or medical knowledge. In other words, would causation of the particular health effect observed make sense based on 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. In this report,

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37 EVALUATING THE EVIDENCE the committee reviews toxicology studies that were published after Update 2004 (IOM, 2005) and considers them in combination with earlier studies in comment- ing on the biologic plausibility of individual health outcomes. A positive statistical association between an exposure and an outcome does not necessarily mean that the exposure is the cause of the outcome. Data from toxicology studies may support or refute a hypothesis that a specific compound can cause a particular disease. Many toxicology studies are conducted with laboratory animals so that variables, including the amount and duration of ex- posure, can be controlled precisely. Studies that use isolated cells in culture also can elucidate how a compound alters cellular processes. The objectives of those toxicology studies are to determine what toxic effects are observed at different exposure concentrations and to identify the mechanisms by which the effects are produced. Ultimately, the results of the toxicology studies should be consistent with what is known about the human disease process to support a conclusion that the development of the disease was caused by exposure. That approach is not without shortcomings; for example, the dose of a chemi- cal required to produce an effect in experimental animals is often many times higher than human exposures. (For TCDD, however, effects have been observed in animals whose body burdens are no more than 10-fold higher than those at the high end of the general population in the industrialized world.) Furthermore, animal and cell-culture models do not always accurately mimic human responses. When the epidemiologic evidence is strong, the absence of evidence for biologic plausibility from toxicology studies does not rule out the possibility that a causal relationship exists. In fact, such cases often drive new toxicology research. As noted in VAO (IOM, 1994), not only is information on biologic plausi- bility one of the primary elements in the widely accepted Bradford Hill (1965) criteria for causality, but insights about biologic processes also provide informa- tion as to whether an observed pattern of statistical association ought to be ques- tioned as being attributable to error, bias, confounding, or chance, as is the task of this committee. 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 as- sociation; 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. In reaching conclusions, VAO committees consider the nature of the exposures, the nature of the health outcomes, the populations

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38 VETERANS AND AGENT ORANGE: UPDATE 2006 exposed, and the quality of the evidence examined. Some specific issues that this and prior committees have considered are addressed below. Human Studies The committee reviewed studies of Vietnam veterans and of other popula- tions that might have been exposed to the chemicals of interest. Those studies included cohorts of workers in chemical production and agriculture, populations that reside near sites of environmental contamination, and residents of Vietnam. The committee believes that studies of such non-veteran subjects can help in the assessment of whether the chemicals of interest are associated with particular health outcomes, although (as mentioned above in describing the literature search) these studies were identified on the basis of the agents considered by the original researchers to be possible toxic exposures rather than by occupational definitions. Some of the studies, especially those of workers in chemical-production plants, provide stronger evidence about health outcomes than do studies of veterans, because the industrial exposures were measured sooner after occurrence and were more thoroughly characterized than has been the case in most studies of Vietnam veterans. Furthermore, in the studies of workers at chemical-production plants, the magnitude and duration of exposure to the chemicals were generally greater, increasing the likelihood that any possible health consequence would be manifested. The studies were often large enough to examine health risks among groups of people with different levels of exposure, so dose–response relation- ships could be investigated. The general practice of VAO committees has been to evaluate all studies, whether or not their subjects are Vietnam veterans, according to the same criteria when determining the strength and validity of the findings. Because the subjects of studies of Vietnam veterans are the concern of the legisla- tion 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 quan- titative 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. The appropriate use of meta-analysis requires more methodologic consistency across studies, especially in the definition of exposure, than is present in the literature reviewed by the committee (Egger et al., 2002; Petitti, 2000). It is more infor- mative to include a detailed discussion of the results from individual studies in appropriate categories (occupational, environmental, and Vietnam veterans) with a thorough examination of each study’s strengths and weaknesses. In general, the committee did not consider case reports, case series, or other

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39 EVALUATING THE EVIDENCE published studies that lacked control or comparison groups. An exception was made, however, for early-onset transient peripheral neuropathy. Individual case reports were reviewed because the rapid appearance and transient nature of that condition imposes methodologic constraints that might have precluded the ap- plication 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 related to a par- ticular endpoint from various investigations before integrating the information. The researchers conducting the studies reviewed by the committee faced the same challenge in interpreting the available documentation when assigning a diagnostic label to a given subject and then grouping the labels for analysis. Pathologists, clinicians, and epidemiologists use several classification sys- tems, including the International Classification of Diseases (ICD), the Inter- national Classification of Diseases—Clinical Modification (ICD-CM), and the International Classification of Diseases for Oncology (ICD-O). The International Classification of Diseases, 10th Edition (ICD-10) is currently used to classify mortality information. Most of subjects investigated in the studies cited in this up- date were diagnosed under earlier systems and most of the articles report results in accordance with the ICD-9, if they use ICD codes at all, so the committee has also employed ICD-9. ICD codes are a hierarchic system for indicating type of disease and site (for example, ICD-9 162 specifies cancers of the lung, trachea, or bronchus; 162.2 specifies cancer of the main bronchus; 162.3, cancer of the upper lobe of the lung; and 162.4, cancer of the middle lobe of the lung). For a patient to be correctly diagnosed, careful staging of the extent of disease is necessary and a biopsy of the tissue must be analyzed by microscopy, often with special immunohistochemical stains, to confirm a clinical impression. 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). Self-reported diagnoses, which are obtained from survey questionnaires, often are partially or completely inaccurate; for instance, a patient may state that he was treated for stomach cancer when the correct diagnosis was gastric adenocarcinoma, gastric lymphoma, pancreatic cancer, large bowel cancer, or peritoneal cancer. Many epidemiologic studies report disease outcome by organ system. For instance, the term “digestive system” may be used for conditions that are be- nign or malignant and that affect the esophagus, stomach, liver, pancreas, small bowel, large bowel, or rectum. Therefore, if a report indicated that a cohort has an increased incidence of digestive system cancer, it would be unclear whether the association was attributable to excess cases of esophageal, gastric, hepatic, pancreatic, or intestinal cancers or to some combination. Such generalization is

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40 VETERANS AND AGENT ORANGE: UPDATE 2006 complicated by the fact that the cause of cancer may differ at various anatomic sites; for instance, there are strong associations between gastric cancer and Heli- cobacter pylori infection, between smoking and squamous cell carcinoma of the esophagus, and between chronic hepatitis B infection and hepatic cancer. Further- more, a single site may experience a carcinogenic response to multiple agents. The committee recognizes that outcome misclassification is a possibility when recording of a diagnosis with a specific ICD code is used as the means to enter an observation into an analysis, but this system has been refined over many decades and is virtually universally used and understood, in addition to being exhaustive and explicit. Therefore, this and previous VAO committees have opted to use the ICD system as an organizing tool. Although the groupings of cancer sites for which conclusions about association have been presented may corre- spond more closely to National Institute for Occupational Safety and Health or National Cancer Institute Surveillance Epidemiology and End Results categories (see Appendix B), the underlying ICD codes provide the most exactitude. 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. (See Appendix B for cancer groupings with corresponding ICD-9 and ICD-10 codes.) For Update 2006, VA requested two refinements in the system used in previ- ous VAO reports for presenting conclusions about the adequacy of evidence con- cerning associations between cancer types and exposure to the herbicides sprayed in Vietnam. First, conclusions should be provided for the full range of cancer types; that is, the cancer groupings for which conclusions are drawn should be exhaustive. Second, it should be apparent into which of these groupings any spe- cific cancer diagnosis falls. Table B-1 in Appendix B delineates the groups used in reporting conclusions through Update 2004 and points out the ICD-9 codes that had not been expressly addressed and so could be considered “gaps.” The opening section of Chapter 6 explains how this committee addressed each of those gaps with prescriptions for how they ought to be handled in future updates. Rare diseases are difficult to study because it is hard to accumulate enough cases to permit analysis. Often, the result is that whatever cases are observed are included in a broader, less specific category. Thus, epidemiologic data may not be available for assessing whether a particular rare disease is associated with Agent Orange exposure. In some instances, as for chronic lymphocytic leukemia, VAO committees have reached conclusions on the basis of the data available and the etiology of the disease. Through more systematic application of the hierarchic nature of the ICD coding system, this and future VAO committees will offer an explicit conclusion about the adequacy of available evidence to support an asso- ciation. For nonmalignant conditions, however, the diversity of disease processes involved makes the use of broad ICD ranges less meaningful, but, because VAO

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41 EVALUATING THE EVIDENCE committees could not possibly address every rare nonmalignant disease, no ex- plicit conclusion is drawn about a disease that has not been 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. The committee is aware of the concerns of some veterans about the role of herbicide exposure in the occurrence of multiple health outcomes, such as mul- tiple cancers, in a given person. Little research has been done to address whether the rate of concurrence is greater than would be expected by chance. Simultane- ous 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. The ongoing practice in this series has been to augment the results table for a given health outcome with any additional publications considered in the current update in the categories of occupational, environmental, or Vietnam-veteran studies; the 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 exists. The cumulative set of reports noted for each endpoint was reviewed to identify the ones that represent multiple longitudinal reports derived from a given study population. In this update, tables have been revised to indicate a report that has been superseded by italicizing its citation. Another issue related to evidence evaluation that was of concern for this update was the evidence category of no association. It is the current committee’s judgment that a conclusion of no association would require substantive evidence of such a lack of effect for each of the chemicals of interest. 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. Accordingly, the entire evidentiary sets for brain and gastrointestinal cancers, which had been classified as showing “no association,” were reviewed in this respect. Exposure Assessment Much of the evidence that VAO committees have considered is drawn from studies of populations that were not in Vietnam during the period when Agent Orange and other herbicides were used as defoliants. The most informative studies have been well-documented investigations of occupational exposures to TCDD or specific herbicides, such as 2,4-D or 2,4,5-T. In many studies, TCDD

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42 VETERANS AND AGENT ORANGE: UPDATE 2006 exposure is combined with exposures to an array of “dioxin-like” compounds, and the herbicides are often analyzed as members of a functional class; this is less informative for the committee’s purpose than individual results for each specific compound. In the real-world situations investigated in epidemiology studies, ex- posure to multiple possibly toxic chemicals is the rule rather than the exception; for example, farmers or other agricultural populations are likely to be exposed to insecticides and fungicides as well as to herbicides. In such studies, the com- mittee looked for evidence of health effects that are associated with the specific compounds in the defoliants used in Vietnam and also sought consideration of and adjustment for other possibly confounding exposures. The quality of exposure information in the scientific literature reviewed by this and previous committees spans a broad range. Some studies relied on inter- views or questionnaires to determine the extent and frequency of exposure. Such self-reported information generally carries less weight than would more objective measures of exposure. To the extent that questionnaire-based information can be corroborated or validated by other sources, its strength as evidence of exposure is enhanced. Written records of chemical purchase or production can provide one type of objective information. Even more useful are scientific measurements of exposure. In some occupational studies, for example, workers wear air-sampling instruments that measure the concentration of a contaminant in each worker’s breathing zone. Measurement of chemicals or their products in biologic speci- mens, such as blood or urine, also can provide reliable indications of exposure for specific periods. Studies that categorize exposure from well-documented environ- mental sources of contaminants can be important in the identification of exposed populations, but their results may be inaccurate when people with different levels of exposure are assigned to the same general category of exposure. Studies that explore environmental exposure and disease frequency in populations (such as states and counties) are known as ecologic studies. 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 ex- posure assessment for a population, such as Vietnam veterans, in which few measurements were made during the period of exposure. Much work has relied on records of herbicide production and use and on military records of troop locations. A recent effort overseen by the Institute of Medicine developed a new algorithm for application to Vietnam veterans (the “Stellman model”) by using records of herbicide applications in Vietnam and revised data on troop move- ments (IOM, 2003). The new information holds promise for use in the estimation of what is called exposure opportunity for individual veterans, that is, estimates of the amount of herbicides (with characteristic TCDD contamination) applied at particular places over particular periods. Recent studies of veterans known to

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43 EVALUATING THE EVIDENCE have been exposed to herbicides in Vietnam have included collection of blood samples and analysis of TCDD in them. The readings from those contemporary samples have been used to identify groups of Vietnam veterans with relatively high exposures and to validate estimates from the Stellman model extrapolated to the present. Although such analysis clearly is valuable, it must be viewed with caution. In most cases, the measurement of compounds in blood has taken place many years after exposure. 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 single- compartment elimination (Aylward et al., 2005a,b; Cheng et al., 2006). Previous uncertainty about back-extrapolated estimates arising from questions about the appropriate value for the biologic half-life of TCDD in humans is augmented by those modeling insights. Chapter 5 of this update addresses issues of exposure estimation in more detail and discusses the presumed hierarchy in quality for various types of expo- sure information. The agent of interest may be assessed with various degrees of specificity. For instance, TCDD concentrations may be estimated exactly as the most potent congener, 2,3,7,8-TCDD; as dioxin; as dioxin-like toxic equivalents in a mixture of dioxins, furans, and PCBs; or, more vaguely, as nonvolatile chlori- nated hydrocarbons. Any of the four herbicides in question could be individually measured and phenoxy herbicides would be a meaningful broader category for 2,4,5-T and 2,4-D; but a report of findings in terms simply of “herbicides” is on the margin of being informative, whereas results stated in terms of “pesticides” are too vague to be useful. For a given chemical of interest, the measure of expo- sure may be increasingly imprecise—for example, concentrations in target tissue, serum concentrations, cumulative exposure, possible exposure, and so on down to merely a report of service in a job or industry category. Those approaches can address complexities in specificity, duration, and intensity of exposure with vari- ous degrees of success. All may provide some information about association with a chemical of interest, but this committee has determined that investigation of associations between most health outcomes and the exposures of concern has ad- vanced to the stage where some characterizations of exposure are too nonspecific to advance insight. 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 re- produce, with some degree of fidelity, the manifestations of the disease in humans. However, a given effect of herbicide exposure in an animal species cannot always be used to establish its occurrence in humans. In addition to possible species

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44 VETERANS AND AGENT ORANGE: UPDATE 2006 differences, many factors affect the ability to extrapolate from results of animal studies to health effects in humans. Animals used in experimental studies are most often exposed to purified chemicals, not to mixtures. Even if herbicide for- mulations or mixtures are used, the conditions of exposure might not realistically reproduce exposures that occur in the field. Furthermore, Vietnam veterans were probably exposed to other agents—such as tobacco smoke, therapeutics, drugs, diesel fumes, and alcohol—that may increase or decrease the ability of chemicals in herbicides to produce a particular adverse health outcome. Few, if any, studies either in humans or in experimental animals have examined those interactions. As discussed in Chapter 3, TCDD, a contaminant of 2,4,5-T, is thought to be responsible for many of the toxic effects of the herbicides used in Vietnam. Attempts to establish correlations in the effects of TCDD between experimental systems and humans are particularly problematic because of known species-, sex-, and endpoint-specific differences in susceptibility to TCDD toxicity. Some data indicate that humans might be more resistant than are other species to TCDD’s toxic effects (Ema et al., 1994; Moriguchi et al., 2003); other data suggest that, for some endpoints, human sensitivity could be the same as or greater than that of some experimental animals (DeVito et al., 1995). Differences in susceptibility may also be affected by variations in the rate at which TCDD is eliminated from the body (see Chapter 3 for details on the toxicokinetics of TCDD). It also is important to account for TCDD’s mode of action when considering species and strain differences. There is a consensus that most of or all the toxic effects of TCDD involve interaction with the AhR, a protein that binds TCDD and other aromatic hydrocarbons with high affinity. Formation of an active complex involving the intracellular receptor, the ligand (the TCDD molecule), and other proteins is followed by interaction of the activated complex with specific sites on DNA. That interaction can alter the expression of genes involved in the regulation of cellular processes. The development of mice that lack the AhR has helped to establish a definitive association between the AhR and TCDD-mediated toxicity. The affinity of TCDD for the AhR is species- and strain-specific, and responses to binding of the receptor vary among cell types and developmental stages. 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 exer- cised because it is still not clear to what extent toxicity is affected by the trans- formation itself or by the conditions under which cell lines are cultured in vitro. Publication Bias Some studies are more likely to be published than others. That is the concept of publication bias, which has been documented in biomedical research (Song

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45 EVALUATING THE EVIDENCE et al., 2000; Stern and Simes, 1997). Most commonly, bias can be introduced when studies whose hypotheses are supported by statistically significant results or that are otherwise deemed favorable by their authors are selectively submitted for publication. Conversely, “negative” studies, in which the hypotheses being tested are not supported by the study findings, often go unpublished. Therefore, conclusions about 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. 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. First, the committee had to assess the relevance and validity of individual reports. Then, it had to evaluate the possible influences of mea- surement error, selection bias, confounding, and chance on the reported results. Next, the committee integrated all the evidence within and across diverse fields of research. Finally, the conclusions drawn were based on consensus within the committee. 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. 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. The committee has endeavored to express its judgments as clearly and precisely as the data allowed.

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46 VETERANS AND AGENT ORANGE: UPDATE 2006 REFERENCES1 Aylward LL, Brunet RC, Carrier G, Hays SM, Cushing CA, Needham LL, Patterson DG Jr, Gerthoux PM, Brambilla P, Mocarelli P. 2005a. Concentration-dependent TCDD elimination kinetics in humans: Toxicokinetic modeling for moderately to highly exposed adults from Seveso, Italy, and Vienna, Austria, and impact on dose estimates for the NIOSH cohort. Journal of Exposure Analysis and Environment Epidemiology 15(1):51–65. Aylward LL, Brunet RC, Starr TB, Carrier G, Delzell E, Cheng H, Beall C. 2005b. Exposure recon- struction for the TCDD-exposed NIOSH cohort using a concentration- and age-dependent model of elimination. Risk Analysis 25(4):945–956. Cheng H, Aylward L, Beall C, Starr TB, Brunet RC, Carrier G, Delzell E. 2006. TCDD exposure- response analysis and risk assessment. Risk Analysis 26(4):1059–1071. DeVito MJ, Birnbaum LS, Farland WH, Gasiewicz TA. 1995. Comparisons of estimated human body burdens of dioxin-like chemicals and TCDD body burdens in experimentally exposed animals. Environmental Health Perspectives 103(9):820–831. Egger M, Ebrahim S, Smith GD. 2002. Where now for meta-analysis? International Journal of Epidemiology 31(1):1–5. Ema M, Ohe N, Suzuki M, Mimura J, Sogawa K, Ikawa S, Fujii-Kuriyama Y. 1994. Dioxin binding activities of polymorphic forms of mouse and human arylhydrocarbon receptors. Journal of Biological Chemistry 269(44):27337–27343. Hill AB. 1965. The environment and disease: Association or causation? Proceedings of the Royal Society of Medicine 58:295–300. IOM (Institute of Medicine). 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: National Academy Press. IOM. 2003. Characterizing Exposure of Veterans to Agent Orange and Other Herbicides Used in Vietnam: Final Report. Washington, DC: The National Academies Press. IOM. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. Kim HA, Kim EM, Park YC, Yu JY, Hong SK, Jeon SH, Park KL, Hur SJ, Heo Y. 2003a. Immuno- toxicological effects of Agent Orange exposure to the Vietnam War Korean veterans. Industrial Health 41(3):158−166. Kim JS, Lim HS, Cho SI, Cheong HK, Lim MK. 2003b. Impact of Agent Orange exposure among Korean Vietnam veterans. Industrial Health 41(3):149−157. Moriguchi T, Motohashi H, Hosoya T, Nakajima O, Takahashi S, Ohsako S, Aoki Y, Nishimura N, Tohyama C, Fujii-Kuriyama Y, Yamamoto M. 2003. Distinct response to dioxin in an arylhydro- carbon receptor (AHR)-humanized mouse. Proceedings of the National Academy of Sciences of the United States of America 100(10):5652–5657. NRC (National Research Council). 1999. Arsenic in Drinking Water. Washington, DC: National Academy Press. NRC. 2001. Arsenic in Drinking Water: 2001 Update. Washington, DC: National Academy Press. Petitti DB. 2000. Meta-Analysis, Decision Analysis, and Cost-Effectiveness Analysis: Methods for Quantitative Synthesis in Medicine. New York: Oxford Press. Smith Sehdev AE, Hutchins GM. 2001. Problems with proper completion and accuracy of the cause- of-death statement. Archives of Internal Medicine 161(2):277−284. Song F, Eastwood AJ, Gilbody S, Duley L, Sutton AJ. 2000. Publication and related biases. Health Technology Assessment 4(10):1–115. Stern JM, Simes RJ. 1997. Publication bias: Evidence of delayed publication in a cohort study of clinical research projects. British Medical Journal 315(7109):640–645. 1Throughout the report the same alphabetic indicator following year of publication is used consistently for the same article when there were multiple citations by the same first author in a given year. The convention of assigning the alphabetic indicator in order of citation in a given chapter is not followed.