1

Introduction

The Agent Orange Act of 1991—Public Law (PL) 102-4, enacted February 6, 1991, and codified as Section 1116 of Title 38 of the United States Code—directed the Secretary of Veterans Affairs to ask the National Academy of Sciences (NAS) to conduct an independent comprehensive review and evaluation of scientific and medical information regarding the health effects of exposure to herbicides used during military operations in Vietnam. The herbicides picloram and cacodylic acid were to be addressed, as were chemicals in various formulations containing the herbicides 2,4-dichlorophenoxyacetic acid (2,4-D) and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T). 2,4,5-T contained the contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (referred to in this report as TCDD to represent a single—and the most toxic—congener of the tetrachlorodibenzo-p-dioxins [tetraCDDs], also commonly referred to as dioxin). It should be noted that TCDD and Agent Orange are not the same. NAS also was asked to recommend, as appropriate, additional studies to resolve continuing scientific uncertainties and to comment on particular programs mandated in the law. In addition, the legislation called for biennial reviews of newly available information for a period of 10 years; the period was extended to 2014 by the Veterans Education and Benefits Expansion Act of 2001 (PL 107-103).

In response to the request from the Department of Veterans Affairs (VA), the Institute of Medicine (IOM) of the National Academies convened the Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides. The results of the original committee’s work were published in 1994 as Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam, hereafter referred to as VAO (IOM, 1994). Successor committees formed to fulfill the requirement for updated reviews produced Veterans and Agent Orange: Update 1996 (IOM,



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1 Introduction The Agent Orange Act of 1991—Public Law (PL) 102-4, enacted February 6, 1991, and codified as Section 1116 of Title 38 of the United States Code— directed the Secretary of Veterans Affairs to ask the National Academy of Sci- ences (NAS) to conduct an independent comprehensive review and evaluation of scientific and medical information regarding the health effects of exposure to herbicides used during military operations in Vietnam. The herbicides picloram and cacodylic acid were to be addressed, as were chemicals in various formu - lations containing the herbicides 2,4-dichlorophenoxyacetic acid (2,4-D) and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T). 2,4,5-T contained the contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (referred to in this report as TCDD to repre- sent a single—and the most toxic—congener of the tetrachlorodibenzo- p-dioxins [tetraCDDs], also commonly referred to as dioxin). It should be noted that TCDD and Agent Orange are not the same. NAS also was asked to recommend, as ap - propriate, additional studies to resolve continuing scientific uncertainties and to comment on particular programs mandated in the law. In addition, the legislation called for biennial reviews of newly available information for a period of 10 years; the period was extended to 2014 by the Veterans Education and Benefits Expansion Act of 2001 (PL 107-103). In response to the request from the Department of Veterans Affairs (VA), the Institute of Medicine (IOM) of the National Academies convened the Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides. The results of the original committee’s work were published in 1994 as Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam, hereafter referred to as VAO (IOM, 1994). Successor committees formed to fulfill the requirement for updated reviews produced Veterans and Agent Orange: Update 1996 (IOM, 14

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15 INTRODUCTION 1996), Update 1998 (IOM, 1999), Update 2000 (IOM, 2001), Update 2002 (IOM, 2003a), Update 2004 (IOM, 2005a), Update 2006 (IOM, 2007), and Up- date 2008 (IOM, 2009). In 1999, VA asked IOM to convene a committee to conduct an interim review of type 2 diabetes; that effort resulted in the report Veterans and Agent Orange: Herbicide/Dioxin Exposure and Type 2 Diabetes, hereafter referred to as Type 2 Diabetes (IOM, 2000). In 2001, VA asked IOM to convene a committee to conduct an interim review of childhood acute myelogenous leukemia (AML, now preferably referred to as acute myeloid leukemia) associated with parental exposure to any of the chemicals of interest; its review of the literature, including literature available since the review for Update 2000, was published as Veterans and Agent Orange: Herbicide/Dioxin Exposure and Acute Myelogenous Leuke- mia in the Children of Vietnam Veterans, hereafter referred to as Acute Myelog- enous Leukemia (IOM, 2002). In PL 107-103, passed in 2001, Congress directed the Secretary of Veterans Affairs to ask NAS to review “available scientific literature on the effects of exposure to an herbicide agent containing dioxin on the development of respiratory cancers in humans” and to address “whether it is possible to identify a period of time after exposure to herbicides after which a presumption of service-connection” of the disease would not be warranted; the re- sult of that effort was Veterans and Agent Orange: Length of Presumptive Period for Association Between Exposure and Respiratory Cancer, hereafter referred to as Respiratory Cancer (IOM, 2004). In conducting their work, the committees responsible for those reports oper- ated independently of VA and other government agencies. They were not asked to and did not make judgments regarding specific cases in which individual Vietnam veterans have claimed injury from herbicide exposure. The reports were intended to provide scientific information for the Secretary of Veterans Affairs to consider as VA exercises its responsibilities to Vietnam veterans. This VAO update and all previous VAO reports are freely accessible on line at the National Academies Press’s Website (http://www.nap.edu). CHARGE TO THE COMMITTEE In accordance with PL 102-4, the committee was asked to “determine (to the extent that available scientific data permit meaningful determinations)” the following regarding associations between specific health outcomes and exposure to TCDD and other chemicals in the herbicides used by the military in Vietnam: A) whether a statistical association with herbicide exposure exists, taking into account the strength of the scientific evidence and the appropriate- ness of the statistical and epidemiological methods used to detect the association;

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16 VETERANS AND AGENT ORANGE: UPDATE 2010 B) the increased risk of the disease among those exposed to herbicides dur- ing service in the Republic of Vietnam during the Vietnam era; and C) whether there exists a plausible biological mechanism or other evidence of a causal relationship between herbicide exposure and the disease. The committee notes that, as a consequence of congressional and judicial history, both its congressional mandate and the statement of task are phrased with the target of evaluation being “association” between exposure and health out - comes, although biologic mechanism and causal relationship are also mentioned as part of the evaluation in Article C. As used technically and as thoroughly ad - dressed in a recent report on decision-making (IOM, 2008), the criteria for causa- tion are somewhat more stringent than those for association. The unique mandate of VAO committees to evaluate association, rather than causation, means that the approach delineated in that report is not entirely applicable here. The rigor of the evidentiary database needed to support a finding of statistical association is weaker than that to support causality; however, positive findings for any of the indicators for causality would enhance conviction that an observed statistical association was reliable. In accord with its charge, the committee examined a variety of indicators appropriate for the task, including factors commonly used to evaluate statistical associations, such as the adequacy of control for bias and confounding and the likelihood that an observed association could be explained by chance; and it assessed evidence concerning biologic plausibility derived from laboratory findings in cell-culture or animal models. The full array of indicators examined was used to categorize the strength of the evidence. In particular, as- sociations that manifest multiple indicators were interpreted as having stronger scientific support. Table 1-1 below presents the cumulative findings through Update 2008 of VAO committees using this approach. In delivering the charge to the current committee, VA made an additional request arising from the decision-making at VA necessitated by the findings of Update 2008. The sponsor asked that the committee, when summarizing the evidence available to support the association of a health effect with exposure to the components of the herbicides used by the military in Vietnam, address whether all the points that have rather imprecisely become known as the “Hill criteria for causality” (Hill, 1965) had been satisfied by the information available. The committee’s response to that request can be found Chapter 2 in the section “Evaluation of the Evidence.” Chapter 2 provides details of the committee’s approach to its charge and the methods that it used in reaching conclusions. ISSUES RAISED IN PUBLIC SESSIONS It has been the practice of VAO committees to conduct open sessions, not only to gather additional information from people who have particular expertise

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17 INTRODUCTION TABLE 1-1 Summary from Update 2008 (Seventh Biennial Update) of Findings in Occupational, Environmental, and Veterans Studies Regarding the Association Between Specific Health Outcomes and Exposure to Herbicides a Sufficient Evidence of Association Epidemiologic evidence is sufficient to conclude that there is a positive association. That is, a positive association has been observed between exposure to herbicides and the outcome in studies in which chance, bias, and confounding could be ruled out with reasonable confidence. b For example, if several small studies that are free of bias and confounding show an association that is consistent in magnitude and direction, there could be sufficient evidence of an association. There is sufficient evidence of an association between exposure to the chemicals of interest and the following health outcomes: Soft-tissue sarcoma (including heart) Non-Hodgkin’s lymphoma Chronic lymphocytic leukemia (CLL) (including hairy cell leukemia and other chronic B-cell leukemias) (category clarification since Update 2006) Hodgkin’s disease Chloracne Limited or Suggestive Evidence of Association Epidemiologic evidence suggests an association between exposure to herbicides and the outcome, but a firm conclusion is limited because chance, bias, and confounding could not be ruled out with confidence.b For example, a well-conducted study with strong findings in accord with less compelling results from studies of populations with similar exposures could constitute such evidence. There is limited or suggestive evidence of an association between exposure to the chemicals of interest and the following health outcomes: Laryngeal cancer Cancer of the lung, bronchus, or trachea Prostate cancer Multiple myeloma AL amyloidosis Early-onset transient peripheral neuropathy Porphyria cutanea tarda Parkinson’s disease (category change from Update 2006) Hypertension Ischemic heart disease (category change from Update 2006) Type 2 diabetes (mellitus) Spina bifida in offspring of exposed people Inadequate or Insufficient Evidence to Determine Association The available epidemiologic studies are of insufficient quality, consistency, or statistical power to permit a conclusion regarding the presence or absence of an association. For example, studies fail to control for confounding, have inadequate exposure assessment, or fail to address latency. There is inadequate or insufficient evidence to determine association between exposure to the chemicals of interest and the following health outcomes that were explicitly reviewed: Cancers of the oral cavity (including lips and tongue), pharynx (including tonsils), or nasal cavity (including ears and sinuses) Cancers of the pleura, mediastinum, and other unspecified sites within the respiratory system and intrathoracic organs Esophageal cancer Stomach cancer

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18 VETERANS AND AGENT ORANGE: UPDATE 2010 TABLE 1-1 Continued Colorectal cancer (including small intestine and anus) Hepatobiliary cancers (liver, gallbladder, and bile ducts) Pancreatic cancer Bone and joint cancer Melanoma Nonmelanoma skin cancer (basal-cell and squamous-cell) Breast cancer Cancers of reproductive organs (cervix, uterus, ovary, testes, and penis; excluding prostate) Urinary bladder cancer Renal cancer (kidney and renal pelvis) Cancers of brain and nervous system (including eye) Endocrine cancers (thyroid, thymus, and other endocrine) Leukemia (other than all chronic B-cell leukemias, including CLL and hairy-cell leukemia) Cancers at other and unspecified sites Infertility Spontaneous abortion (other than for paternal exposure to TCDD, which appears not to be associated)b Neonatal or infant death and stillbirth in offspring of exposed people Low birth weight in offspring of exposed people Birth defects (other than spina bifida) in offspring of exposed people Childhood cancer (including acute myeloid leukemia) in offspring of exposed people Neurobehavioral disorders (cognitive and neuropsychiatric) Neurodegenerative diseases, excluding Parkinson’s disease Chronic peripheral nervous system disorders Respiratory disorders (wheeze or asthma, chronic obstructive pulmonary disease, and farmer’s lung) Gastrointestinal, metabolic, and digestive disorders (changes in liver enzymes, lipid abnormalities, and ulcers) Immune system disorders (immune suppression, allergy, and autoimmunity) Circulatory disorders (other than hypertension and ischemic heart disease) Endometriosis Effects on thyroid homeostasis This committee used a classification that spans the full array of cancers. However, reviews for nonmalignant conditions were conducted only if they were found to have been the subjects of epidemiologic investigation or at the request of the Department of Veterans Affairs. By default, any health outcome on which no epidemiologic information has been found falls into this category. Limited or Suggestive Evidence of No Association Several adequate studies, which cover the full range of human exposure, are consistent in not showing a positive association between any magnitude of exposure to the chemicals of interest and the outcome. A conclusion of “no association” is inevitably limited to the conditions, exposures, and length of observation covered by the available studies. In addition, the possibility of a very small increase in risk at the exposure studied can never be excluded. There is limited or suggestive evidence of no association between exposure to the chemicals of interest and the following health outcome: continued

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19 INTRODUCTION TABLE 1-1 Continued Spontaneous abortion and paternal exposure to TCDD aHerbicides indicates the following chemicals of interest: 2,4-dichlorophenoxyacetic acid (2,4-D), 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) and its contaminant 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD, or dioxin), cacodylic acid, and picloram. The evidence regarding association was drawn from occupational, environmental, and veteran studies in which people were exposed to the herbicides used in Vietnam, to their components, or to their contaminants. bEvidence of an association can be strengthened by experimental data supporting biologic plausibil- ity, but its absence would not detract from the epidemiologic evidence. on points that arise during deliberations but especially to hear from individual Vietnam veterans and others concerned about aspects of their health experience that may be service-related. The present committee was pleased by the response to its invitation, which had been circulated by VA, to the primary such session held in Chicago. Open sessions were held at the first four of the committee’s five meetings, and the agendas are presented in Appendix A. A summary of the topics raised at the open sessions and the committee’s responses to them follows. First Meeting, Washington, DC Autoimmune conditions, particularly mixed connective tissue disease: • There is a paucity of evidence from human studies on herbicide exposure and immunologic responses, and what little there is evaluates biomarkers rather than disease states that have an immunologic etiology. The present committee conducted a comprehensive review of the available information, which is addressed in Chapter 6 on immune effects. Exposure to Agent Orange during Vietnam-era service on Guam: Evaluat- • ing where herbicide exposure may have occurred is not within the scope of this committee’s charge. Second Meeting, Chicago Coverage of all forms of parkinsonism in VA’s recognition of Parkinson • disease as a condition presumptively associated with service in Vietnam. Health problems in children and grandchildren of Vietnam veterans: Chap- • ter 8 addresses evidence related to the possibility that the exposure of Viet- nam veterans has adverse consequences for their progeny. Thyroid disease: The existing evidence on disruption of thyroid homeostasis • is discussed in Chapter 11. As is the case for immune effects, the available information focuses on biomarkers of perturbation rather than on clinical

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20 VETERANS AND AGENT ORANGE: UPDATE 2010 conditions. A considerable amount of research has addressed exposure dur- ing gestation and nursing, which is not relevant to the experience of Vietnam veterans themselves; the possible consequences of maternal exposure are discussed in Chapter 8. Myelodysplastic syndromes as forms of leukemia: The International Clas- • sification of Diseases has regarded these myeloid neoplasms as having uncer- tain or unknown behavior, so they cannot be defined as malignant or benign. No epidemiologic studies have looked at this end point with exposure speci- ficity that meets VAO criteria for inclusion, although recently some work has been done on exposure to the broad classification of pesticides in general. In any event, when myelodysplastic syndromes progress into unquestionable malignancies, they become AML, on which there is inadequate or insuf- ficient evidence of association with herbicides (see Chapter 7). Vietnam veterans may have experienced multiple potentially harmful ex- • posures in addition to herbicide exposure (particularly, exposure to the benzene-containing petroleum products used as dispersants for the herbi- cides and the extensively used insecticides): Addressing interactions or syn- ergies of other substances with the several components of these herbicides is beyond the scope of the committee’s charge. People are continually exposed to many chemicals, whose possible adverse effects might be exacerbated by exposure to other agents. The number of pairs that could be addressed is enormous, and the number would rise exponentially if triads and larger com - binations were considered. There is a vast toxicologic literature on petroleum products and their constituents (for example, see Gulf War and Health: Vol- ume 3—Fuel, Combustion Products, and Propellants [IOM, 2005b]) and on the various chemical families of insecticides (see also, Gulf War and Health: Volume 2—Insecticides and Solvents [IOM, 2003b]). Third Meeting, Albuquerque Glioblastomas: The available evidence concerning cancers of the brain and • herbicide exposure is discussed in Chapter 7. Evidence from the Vietnamese population: After a thorough search of • the literature and consultation with US scientists who have attempted to establish collaborative relationships with Vietnamese scientists, the com - mittee concludes that there has been virtually no epidemiologic study of the Vietnamese population that followed the standards of Western protocols. In the interest of increasing scientific understanding, such research would be de- sirable. Investigations of reproductive outcomes associated with the chronic environmental exposure of men and women occurring now, however, would not be particularly informative about the time-limited exposure experience of predominantly male US veterans.

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21 INTRODUCTION Fifth Meeting, Phoenix Alzheimer disease, especially of early onset: The limited available evidence • on an association of Alzheimer disease and herbicide exposure is discussed in Chapter 9. CONCLUSIONS OF PREVIOUS VETERANS AND AGENT ORANGE REPORTS Health Outcomes VAO, Update 1996, Update 1998, Update 2000, Update 2002, Update 2004, Type 2 Diabetes, Acute Myelogenous Leukemia, Respiratory Cancer, Update 2006, and Update 2008 contain detailed reviews of the scientific studies evalu- ated by the committees and their implications for cancer, reproductive and devel- opmental effects, neurologic disorders, and other health effects. The original VAO committee addressed the statutory mandate to evaluate the association between herbicide exposure and a given health effect by assigning each of the health outcomes under study to one of four categories on the basis of the epidemiologic evidence reviewed. The categories were adapted from the ones used by the International Agency for Research on Cancer in evaluating evidence of the carcinogenicity of various substances (IARC, 1977). Successor VAO com - mittees adopted the same categories. The question of whether the committee should be considering statistical as- sociation rather than causality has been controversial. In legal proceedings that predate passage of the legislation mandating the VAO series of reviews, Nehmer v United States Veterans Administration (712 F. Supp. 1404, 1989) found that the legislative history, and prior VA and congressional practice, support our finding that Congress intended that the Administrator predicate service con - nection upon a finding of a significant statistical association between dioxin exposure and various diseases. We hold that the VA erred by requiring proof of a causal relationship. The committee believes that the categorization of strength of evidence as shown in Table 1-1 is consistent with that court ruling. In particular, the ruling does not preclude the consideration of the factors usually assessed in determin - ing a causal relationship (Hill, 1965; IOM, 2008) as indicators of the strength of scientific evidence of an association. In accord with the court ruling, the com - mittee was not seeking proof of a causal relationship, but any information that supports a causal relationship, such as a plausible biologic mechanism as speci - fied in Article C of the charge to the committee, would also lend credence to the reliability of an observed association. Understanding of causal relationships is the ultimate objective of science, while the committee’s goal of assessing statistical

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22 VETERANS AND AGENT ORANGE: UPDATE 2010 association is an intermediate (less well-defined) point along a continuum that culminates in causality. The categories, the criteria for assigning a particular health outcome to a category, and the health outcomes that have been assigned to the categories in past updates are discussed below. Table 1-1 summarizes the conclusions of Up- date 2008 regarding associations between health outcomes and exposure to the herbicides used in Vietnam or to any of their components or contaminants. That integration of the literature through September 2008 served as the starting point for the current committee’s deliberations. It should be noted that the categories of association concern the occurrence of health outcomes in human populations in relation to chemical exposure; they do not address the likelihood that any indi- vidual’s health problem is associated with or caused by the chemicals in question. Health Outcomes with Sufficient Evidence of an Association In this category, a positive association between herbicides and the outcome must be observed in epidemiologic studies in which chance, bias, and confound - ing can be ruled out with reasonable confidence. The committee regarded evi- dence from several studies that satisfactorily addressed bias and confounding and that show an association that is consistent in magnitude and direction as sufficient evidence of an association. Experimental data supporting biologic plausibility strengthen evidence for an association, but are not a prerequisite. The original VAO committee found sufficient evidence of an association between exposure to herbicides and three cancers—soft-tissue sarcoma, non- Hodgkin lymphoma, and Hodgkin lymphoma—and two other health outcomes, chloracne and porphyria cutanea tarda (PCT). After reviewing all the literature available in 1995, the committee responsible for Update 1996 concluded that the statistical evidence still supported that classification for the three cancers and chloracne but that the evidence of an association with PCT warranted its being placed in the category of limited or suggestive evidence of an association with ex- posure. No changes were made in this category in Update 1998 or Update 2000. As the committee responsible for Update 2002 began its work, VA requested that it evaluate whether chronic lymphocytic leukemia (CLL) should be consid- ered separately from other leukemias. That committee concluded that CLL could be considered separately and, on the basis of the epidemiologic literature and the etiology of the disease, placed CLL in the “sufficient” category. In response to a request from VA, the committee for Update 2008 affirmed that hairy-cell leukemia belonged in the category of sufficient evidence of an association with the related conditions CLL and the lymphomas. Health Outcomes with Limited or Suggestive Evidence of an Association In this category, the evidence must suggest an association between exposure to herbicides and the outcome considered, but the evidence can be limited by

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23 INTRODUCTION the inability to rule out chance, bias, or confounding confidently. The coherence of the full body of epidemiologic information, in light of biologic plausibility, is considered when the committee reaches a judgment about association for a given outcome. Because the VAO series has four herbicides and TCDD as agents of concern whose profiles of toxicity are not expected to be uniform, apparent inconsistencies can be expected among study populations that have experienced different exposures. Even for a single exposure, a spectrum of results would be expected, depending on the power of the studies and other design factors. The committee responsible for VAO found limited or suggestive evidence of an association between exposure to herbicides and three categories of cancer: respiratory cancer (after individual evaluations of laryngeal cancer and of can - cers of the trachea, lung, or bronchus), prostate cancer, and multiple myeloma. The Update 1996 committee added three health outcomes to the list: PCT, acute and subacute peripheral neuropathy (after Update 2004 called early-onset tran- sient peripheral neuropathy), and spina bifida in children of veterans. Transient peripheral neuropathies had not been addressed in VAO, because they are not amenable to epidemiologic study. In response to a VA request, however, the Up- date 1996 committee reviewed those neuropathies and based its determination on case histories. A combination of a 1995 analysis of birth defects among the offspring of veterans who served in Operation Ranch Hand and results of earlier studies of neural-tube defects in the children of Vietnam veterans (published by the Centers for Disease Control and Prevention) led the Update 1996 commit- tee to distinguish spina bifida from other reproductive outcomes and to place it in the “limited or suggestive evidence” category. No changes were made in this category in Update 1998. After the publication of Update 1998, the committee responsible for Type 2 Diabetes, on the basis of its evaluation of newly available scientific evidence and the cumulative findings of research reviewed in previous VAO reports, concluded that there was limited or suggestive evidence of an association between exposure to the herbicides used in Vietnam or the contaminant TCDD and type 2 diabetes (mellitus). The evidence reviewed in Update 2000 supported that finding. The committee responsible for Update 2000 reviewed the material in earlier reports and the newly published literature and determined that there was limited or suggestive evidence of an association between exposure to herbicides used in Vietnam or the contaminant TCDD and AML in the children of Vietnam veterans. After release of Update 2000, researchers in one of the studies that it reviewed discovered an error in the published data. The committee for Update 2000 was reconvened to re-evaluate the previously reviewed and new literature regarding AML, and it produced Acute Myelogenous Leukemia, which reclassified AML in children from “limited or suggestive evidence of an association” to “inadequate or insufficient evidence to determine an association.” After reviewing the data reviewed in previous VAO reports and recently pub- lished scientific literature, the committee responsible for Update 2006 determined

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24 VETERANS AND AGENT ORANGE: UPDATE 2010 that there was limited or suggestive evidence of an association between exposure to the herbicides used in Vietnam or the contaminant TCDD and hypertension. AL amyloidosis was also moved to the category of “limited or suggestive evi - dence of an association” primarily on the basis of its close biologic relationship with multiple myeloma. With a bit more consistent epidemiologic data augmented by increased understanding of mechanisms arising from new toxicologic research, the com - mittee for Update 2008 was able to resolve the Update 2006 committee’s lack of consensus and moved ischemic heart disease into this category, joining another cardiovascular condition, hypertension. New studies of Parkinson disease with positive findings for association with the specific herbicides of interest were deemed to move the evidence to the category of limited or suggestive. Health Outcomes with Inadequate or Insufficient Evidence to Determine an Association By default, any health outcome is in this category before enough reliable scientific data accumulate to promote it to the category of sufficient evidence or limited or suggestive evidence of an association or to move it to the category of limited or suggestive evidence of no association. In this category, available stud- ies may have inconsistent findings or be of insufficient quality or statistical power to support a conclusion regarding the presence of an association. Such studies might have failed to control for confounding or might have had inadequate as- sessment of exposure. The cancers and other health effects so categorized in Update 2004 are listed in Table 1-1, but several health effects have been moved into or out of this cat - egory since the original VAO committee reviewed the evidence then available. Skin cancer was moved into this category in Update 1996 when inclusion of new evidence no longer supported its classification as a condition with limited or suggestive evidence of no association. Similarly, the Update 1998 committee moved urinary bladder cancer from the category of limited or suggestive evidence of no association to this category; although there was no evidence that exposure to herbicides or TCDD is related to urinary bladder cancer, newly available evi - dence weakened the evidence of no association. The committee for Update 2000 had partitioned AML in the offspring of Vietnam veterans from other childhood cancers and put it into the category of suggestive evidence; but a separate review, as reported in Acute Myelogenous Leukemia, found errors in the published infor- mation and returned it to this category with other childhood cancers. In Update 2002, CLL was moved from this category to join Hodgkin and non-Hodgkin lymphomas in the category of sufficient evidence of an association. The committee responsible for Update 2006 removed several cancers (of the brain, stomach, colon, rectum, and pancreas) from the category of limited or suggestive evidence of no association into this category because of some changes

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25 INTRODUCTION in evidence since they were originally placed in the “no association” category but primarily because that committee had concerns about the lack of information on all five chemicals of interest and each of these cancers. Health Outcomes with Limited or Suggestive Evidence of No Association The original VAO committee defined this category for health outcomes for which several adequate studies covering the “full range of human exposure” were consistent in showing no association with exposure to herbicides at any concentration and had relatively narrow confidence intervals. A conclusion of “no association” is inevitably limited to the conditions, exposures, and observation periods covered by the available studies, and the possibility of a small increase in risk related to the magnitude of exposure studied can never be excluded. However, a change in classification from inadequate or insufficient evidence of an association to limited or suggestive evidence of no association would require new studies that correct for the methodologic problems of previous studies and that have samples large enough to limit the possible study results attributable to chance. The original VAO committee found a sufficient number and variety of well- designed studies to conclude that there was limited or suggestive evidence of no association between the exposures of interest and a small group of cancers: gas - trointestinal tumors (colon, rectum, stomach, and pancreas), skin cancers, brain tumors, and urinary bladder cancer. The Update 1996 committee removed skin cancers and the Update 1998 committee removed urinary bladder cancer from this category because the evidence no longer supported a conclusion of no asso- ciation. The Update 2002 committee concluded that there was adequate evidence to determine that spontaneous abortion is not associated with paternal exposure specifically to TCDD; the evidence on this outcome was deemed inadequate for drawing a conclusion about an association with maternal exposure to any of the chemicals of interest or with paternal exposure to any of the chemicals of inter- est other than TCDD. No changes in this category were made in Update 2000 or Update 2004. The Update 2006 committee removed brain cancer and several digestive cancers from this category because of concern that the overall paucity of information on picloram and cacodylic acid made it inappropriate for those outcomes to remain in this category. Determining Increased Risk in Vietnam Veterans The second part of the committee’s charge is to determine, to the extent permitted by available scientific data, the increased risk of disease among people exposed to herbicides or the contaminant TCDD during service in Vietnam. Previous reports pointed out that most of the many health studies of Vietnam veterans were hampered by relatively poor measures of exposure to herbicides

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26 VETERANS AND AGENT ORANGE: UPDATE 2010 or TCDD and by other methodologic problems. Most of the evidence on which the findings regarding associations are based, therefore, comes from studies of people exposed to TCDD or herbicides in occupational and environmental set - tings rather than from studies of Vietnam veterans. The committees that produced VAO and the updates found that the body of evidence was sufficient for reaching conclusions about statistical associations between herbicide exposures and health outcomes but that the lack of adequate data on Vietnam veterans themselves complicated consideration of the second part of the charge. The evidence of herbicide exposure among various groups studied suggests that although some had documented high exposures (such as participants in Op - eration Ranch Hand and Army Chemical Corps personnel), most Vietnam veter- ans had lower exposures to herbicides and TCDD than did the subjects of many occupational and environmental studies. Individual veterans who had very high exposures to herbicides, however, could have risks approaching those described in the occupational and environmental studies. Estimating the magnitude of risk of each particular health outcome among herbicide-exposed Vietnam veterans requires quantitative information about the dose–time–response relationship for the health outcome in humans, information on the extent of herbicide exposure among Vietnam veterans, and estimates of individual exposure. Committees responsible for VAO and the updates have con- cluded that in general it is impossible to quantify the risk to veterans posed by their exposure to herbicides in Vietnam. Statements to that effect were made for each health outcome in VAO (IOM, 1994) and in every update through Update 2004. The committee responsible for Update 2006 chose to eliminate the repeti- tive restatements in favor of the following general conclusion: “At least for the present, it is not possible to derive quantitative estimates of the increase in risk of various adverse health effects that Vietnam veterans may have experienced in association with exposure to the herbicides sprayed in Vietnam.” The committee responsible for Update 2008 and the current committee have opted to retain the modification in the formatting of the health-outcomes sections. After decades of research, the challenge of estimating the magnitude of po - tential risk posed by exposure to the compounds of interest remains intractable. The requisite information is still absent despite concerted efforts to reconstruct likely exposure by modeling on the basis of records of troop movements and spraying missions (Stellman and Stellman, 2003, 2004; Stellman et al., 2003a,b), to measure serum TCDD in individual veterans (Kang et al., 2006; Michalek et al., 1995), and to model the pharmacokinetics of TCDD clearance (Aylward et al., 2005a,b; Cheng et al., 2006b; Emond et al., 2004, 2005, 2006). There is still uncertainty about the specific agents that may be responsible for a particular health effect. Even if one accepts an individual veteran’s serum TCDD concentra- tion as the optimal surrogate for overall exposure to Agent Orange and the other herbicide mixtures sprayed in Vietnam, not only is the measurement nontrivial but the hurdle of accounting for biologic clearance and extrapolating to the proper

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27 INTRODUCTION timeframe remains. The committee therefore believes that it is very unlikely that additional information or more sophisticated methods are going to become avail - able that would permit any sort of quantitative assessment of Vietnam veterans’ increased risks of particular adverse health outcomes attributable to exposure to the compounds associated with herbicide spraying in Vietnam. Existence of a Plausible Biologic Mechanism or Other Evidence of a Causal Relationship Toxicologic data form the basis of the committee’s response to the third part of its charge—to determine whether there is a plausible biologic mechanism or other evidence of a causal relationship between herbicide exposure and a health effect. A separate chapter summarizes toxicologic findings on the chemicals of concern. In updates before Update 2008, a considerable amount of detail had been provided about individual newly published toxicology studies; the current committee concurs with the decision made by the last committee that it would be more informative for the general reader to provide integrated toxicologic profiles for the chemicals of interest by interpreting the underlying experimental findings. When there are specific toxicologic findings pertinent to a particular health out- come, they are discussed in the chapter reviewing the epidemiologic literature on that condition. The current committee has endeavored to refine this approach to make the chapter on toxicologic information more accessible to lay readers and more illuminating about its relevance to epidemiologic findings. In VAO and updates before Update 2006, this topic has been discussed in the conclusions section for each health outcome after a statement of the committee’s judgment about the adequacy of the epidemiologic evidence of an association of that outcome with exposure to the chemicals of interest. As Update 2006 noted, the degree of biologic plausibility itself influences whether the committee per- ceives positive findings to be indicative of a pattern or the product of statistical fluctuations. To provide the reader with a more logical sequence, the committee responsible for Update 2006 placed the biologic-plausibility sections between the presentation of new epidemiologic evidence and the synthesis of all the evidence, which in turn leads to the ultimate statement of the committee’s conclusion. The current committee supports that change and has continued to group the sections that way. ORGANIZATION OF THIS REPORT The remainder of this report is organized in 11 chapters. Chapter 2 briefly describes the considerations that guided the committee’s review and evalua- tion of the scientific evidence. Chapter 3 addresses exposure-assessment issues. Chapter 4 summarizes the toxicology data on the effects of 2,4-D, 2,4,5-T and

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28 VETERANS AND AGENT ORANGE: UPDATE 2010 its contaminant TCDD, cacodylic acid, and picloram; the data contribute to the biologic plausibility of health effects in human populations. Chapter 5 has two roles with respect to the epidemiologic information that constitutes the core of the committee’s deliberations. First, the tables in the opening section identify the relevant new epidemiologic literature published in this update period, indicating the health outcomes reported upon and whether a previously study population has been revisited. The second portion of Chapter 5 provides a cumulative overview of the study populations that have generated findings (in some instances, in the form of dozens of separate publications) reviewed in the VAO report series. In addition to showing where the new literature fits into this compendium of pub - lications on Vietnam veterans, occupational cohorts, environmentally exposed groups, and case–control study populations, the latter part of this chapter includes description and critical appraisal of the design, exposure assessment, and analysis approaches used. The committee’s evaluation of the epidemiologic literature and its conclu - sions regarding associations between the exposures of interest and particular health outcomes are presented in the several subsequent chapters. In this update, the committee has broken out two new chapters from the chapter on “other health effects.” A chapter on immunologic effects (Chapter 6) now precedes the chapter on cancer (Chapter 7). The new chapter addresses reasons for what might be perceived as a discrepancy between clear immunotoxicity in animal studies and a paucity of epidemiologic studies with such findings. Its placement reflects the committee’s belief that immunologic changes may constitute an intermediary mechanism in the generation of more distinct clinical conditions discussed in the following chapters. As in Update 2008, Chapter 8, on reproduc- tive and developmental effects, places more emphasis on problems that might be manifested later in the lives of veterans’ children or even in later generations. Chapter 9 addresses neurologic disorders. Early-onset peripheral neuropathy is a condition long recognized as a response to herbicide exposure that is manifested shortly after exposure but unlikely to be a response that arises for the first time decades after exposed people leave Vietnam; the discussion of evidence on this short-term response has been taken from Chapter 9 and placed in Appendix B, with the information on chloracne and porphyria cutanea tarda, which are also short-term responses presumptively associated with herbicide exposure. Chapter 10 consists of a set of conditions related to cardiovascular and metabolic effects that have also been excised from the “other health outcomes” chapter. Chapter 11 now contains the residual “other health outcomes”: respiratory disorders, gastro - intestinal problems, thyroid homeostasis and other endocrine disorders, and new sections on eye problems and bone conditions. A summary of the committee’s findings and its research recommendations are presented in Chapter 12.

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29 INTRODUCTION 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 Environmental 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. 2006b. TCDD exposure- response analysis and risk assessment. Risk Analysis 26(4):1059−1071. Emond C, Birnbaum LS, DeVito MJ. 2004. Physiologically based pharmacokinetic model for devel - opmental exposures to TCDD in the rat. Toxicological Sciences 80(1):115−133. Emond C, Michalek JE, Birnbaum LS, DeVito MJ. 2005. Comparison of the use of physiologically based pharmacokinetic model and a classical pharmacokinetic model for dioxin exposure as - sessments. Environmental Health Perspectives 113(12):1666−1668. Emond C, Birnbaum LS, DeVito MJ. 2006. Use of a physiologically based pharmacokinetic model for rats to study the influence of body fat mass and induction of CYP1A2 on the pharmacokinetics of TCDD. Environmental Health Perspectives 114(9):1394−1400. Hill AB. 1965. The environment and disease: Association or causation? Proceedings of the Royal Society of Medicine 58:295–300. IARC (International Agency for Research on Cancer). 1977. Some Fumigants, the Herbicides 2,4-D and 2,4,5-T, Chlorinated Dibenzodioxins and Miscellaneous Industrial Chemicals. IARC Mono- graphs on the Evaluation of the Carcinogenic Risk of Chemicals to Man, Vol. 15. Lyon, France: World Health Organization, IARC. IOM (Institute of Medicine). 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: National Academy Press. IOM. 1996. Veterans and Agent Orange: Update 1996. Washington, DC: National Academy Press. IOM. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: National Academy Press. IOM. 2000. Veterans and Agent Orange: Herbicide/Dioxin Exposure and Type 2 Diabetes. Washing- ton, DC: National Academy Press. IOM. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: National Academy Press. IOM. 2002. Veterans and Agent Orange: Herbicide/Dioxin Exposure and Acute Myelogenous Leu - kemia in the Children of Vietnam Veterans. Washington, DC: The National Academies Press. IOM. 2003a. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. IOM. 2003b. Gulf War and Health: Volume 2—Insecticides and Solvents. Washington, DC: The National Academies Press. IOM. 2004. Veterans and Agent Orange: Length of Presumptive Period for Association Between Exposure and Respiratory Cancer. Washington, DC: The National Academies Press. IOM. 2005a. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. IOM. 2005b. Gulf War and Health: Volume 3—Fuel, Combustion Products, and Propellants. Wash- ington, DC: The National Academies Press. 1 Throughout the report the same alphabetic indicator following year of publication is used con - sistently 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.

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30 VETERANS AND AGENT ORANGE: UPDATE 2010 IOM. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. IOM. 2008. Improving the Presumptive Disability Decision-making Process for Veterans. Washing- ton, DC: The National Academies Press. IOM. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press. Kang HK, Dalager NA, Needham LL, Patterson DG, Lees PSJ, Yates K, Matanoski GM. 2006. Health status of Army Chemical Corps Vietnam veterans who sprayed defoliant in Vietnam. American Journal of Industrial Medicine 49(11):875–884. Michalek J, Wolfe W, Miner J, Papa T, Pirkle J. 1995. Indices of TCDD exposure and TCDD body burden in veterans of Operation Ranch Hand. Journal of Exposure Analysis and Environmental Epidemiology 5(2):209−223. Stellman JM, Stellman SD. 2003. Contractor’s Final Report: Characterizing Exposure of Veterans to Agent Orange and Other Herbicides in Vietnam. Submitted to the National Academy of Sciences, Institute of Medicine in fulfillment of Subcontract VA-5124-98-0019, June 30, 2003. Stellman SD, Stellman JM. 2004. Exposure opportunity models for Agent Orange, dioxin, and other military herbicides used in Vietnam, 1961–1971. Journal of Exposure Analysis and Environ- mental Epidemiology 14(4):354–362. Stellman J, Stellman S, Christians R, Weber T, Tomasallo C. 2003a. The extent and patterns of usage of Agent Orange and other herbicides in Vietnam. Nature 422:681−687. Stellman J, Stellman S, Weber T, Tomasallo C, Stellman A, Christian R Jr. 2003b. A geographic in - formation system for characterizing exposure to Agent Orange and other herbicides in Vietnam. Environmental Health Perspectives 111(3):321−328.