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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 formula- tions containing the herbicides 2,4-dichlorophenoxyacetic acid (2,4-D) and 2,4,5- trichlorophenoxyacetic acid (2,4,5-T). The most well known of the formulations, Agent Orange, was a 50:50 mixture of 2,4-D and 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 tetrachloro- dibenzo-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 ad- dition, 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 Educa- tion 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 1

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14 VETERANS AND AGENT ORANGE: UPDATE 2008 for updated reviews produced Veterans and Agent Orange: Update 1996 (IOM, 1996), Update 1998 (IOM, 1999), Update 2000 (IOM, 2001), Update 2002 (IOM, 2003), Update 2004 (IOM, 2005), and Update 2006 (IOM, 2007). 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) as- sociated 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 in Veterans and Agent Orange: Herbicide/Dioxin Exposure and Acute Myelogenous Leukemia in the Children of Vietnam Veterans, hereafter referred to as Acute Myelogenous Leukemia (IOM, 2002). In PL 107-103, passed in 2001, Congress directed the Secretary of Veterans Affairs to ask NAS to review “avail- able scientific literature on the effects of exposure to an herbicide agent contain - ing 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 result of that effort was Veterans and Agent Orange: Length of Presumptie 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’ website (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 fol- lowing 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 appropriateness of the statistical and epidemiological methods used to detect the association; B) the increased risk of the disease among those exposed to herbicides during service in the Republic of Vietnam during the Vietnam era; and

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1 INTRODUCTION 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 (IOM, 2008) is not entirely applicable here. The rigor of the evidentiary database needed to support a finding of statistical association is weaker than that for 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 additionally assessed evidence concerning biologic plausibility derived from laboratory findings in cell-culture or animal models. The full ar- ray of indicators examined was used to categorize the strength of the evidence, as shown in Table 1-1 below. In particular, associations that manifest multiple indicators were interpreted as having stronger scientific support. In delivering the charge to the current committee, the VA made two addi- tional requests. First, the committee was asked to consider whether the occur- rence of hairy cell leukemia should be regarded as associated with exposure to the components of herbicides used by the military in Vietnam. Second, the com- mittee was asked to comment on whether effects of herbicide exposure might be manifested in veterans’ children at later stages of their development than have been systematically evaluated to date or in later generations and on the feasibility of assessing such effects. When the first Veterans and Agent Orange committee received its charge from VA, service in the Republic of Vietnam was defined in Subsections a and f of Section 1116 of Title 38 of the United States Code as including military per- sonnel who served in “the inland waterways of such Republic, the waters offshore of such Republic, and the airspace above such Republic.” Using that definition, the original and later Veterans and Agent Orange committees routinely considered any research material pertaining to veterans from any of the armed forces who served in the Vietnam theater as relevant to its charge. It has recently come to the committee’s attention that the definition of a qualifying exposure in VA’s manual for processing veterans’ applications was modified in 2002 and now limits presumption of exposure to Vietnam veterans

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16 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 1-1 Summary from Update 2006 of Findings in Occupational, Environmental, and Veterans Studies Regarding the Association Between Specific Health Outcomes and Exposure to Herbicidesa 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) 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 (category change from Update 2004) Early-onset transient peripheral neuropathy Porphyria cutanea tarda Hypertension (category change from Update 2004) 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. b There is inadequate or insufficient evidence to determine association between exposure to the chemicals of interest and the following health outcomes that were explicitly reiewed: 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 (category change from Update 2004) Stomach cancer (category change from Update 2004) Colorectal cancer (including small intestine and anus) (category change from Update 2004)

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1 INTRODUCTION TABLE 1-1 Continued Hepatobiliary cancers (liver, gallbladder, and bile ducts) Pancreatic cancer (category change from Update 2004) Bone and joint cancer * Melanoma Non-melanoma 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 Cancers of brain and nervous system (including eye) (category change from Update 2004) Endocrine cancers (thyroid, thymus, and other endocrine) Leukemia (other than CLL) Cancers at other and unspecified sites Infertility Spontaneous abortion (other than for paternal exposure to TCDD, which appears not to be associated)c 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 myelogenous leukemia) in offspring of exposed people Neurobehavioral disorders (cognitive and neuropsychiatric) Neurodegenerative diseases, including Parkinson’s disease and amyotrophic lateral sclerosis (ALS) Chronic peripheral nervous system disorders Respiratory disorders Gastrointestinal, metabolic, and digestive disorders (changes in liver enzymes, lipid abnormalities, and ulcers) Immune system disorders (immune suppression, allergy, and autoimmunity) * Ischemic heart disease Circulatory disorders (other than hypertension and perhaps 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 herbicides 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 ery small increase in risk at the exposure studied can neer be excluded. There is limited or suggestive continued

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18 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 1-1 Continued evidence of no association between exposure to the herbicides of interest and the following health outcomes: Spontaneous abortion and paternal exposure to TCDDc a Herbicides 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. b The criteria for these categories of association as stated in the current update have added the phrase “Evidence for an association can be strengthened by experimental data supporting biologic plausi- bility, but it is not required.” to clarify the role toxiciologic information has played throughout the history of the VAO series. c This conclusion appropriately constrained by specific chemical and exposed parent was drawn in Update 2002, but was not carried into the summary table. * The committee responsible for Update 2006 was unable to reach consensus as to whether these health outcomes had Limited or Suggestive Evidence of an Association or had Inadequate or Insufficient Evidence to Determine an Association, and so left them in the lower category. whose service involved duty or visitation on land in the Republic of Vietnam. That motivated the legal challenge in Haas . Nicholson and appeals by VA. For consistency, the committee has chosen to maintain the original definition of exposure for its determinations and to consider any veterans who served in the Vietnam theater as included in populations of interest for the committee’s find- ings. This statement is not a change in the committee’s procedures but rather is intended to clarify its characterization of populations that it deems relevant for making determinations about possible health effects related to exposure to herbicides during the Vietnam conflict; adopting VA’s new definition would have entailed eliminating some data points on naval subpopulations from the evidence database, such as some of the strongest findings on an association with non-Hodgkin’s lymphoma. Thus, the Veterans and Agent Orange committee continues to consider studies of and research on all populations that served in the Vietnam theater—the Air Force, the Army, and the Blue Water Navy—to be germane to its work. Chapter 2 provides details of the committee’s approach to its charge and the methods it used in reaching conclusions. 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, and Update

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19 INTRODUCTION 2006 contain detailed reviews of the scientific studies evaluated by the commit- tees and their implications for cancer, reproductive and developmental effects, neurologic disorders, and other health effects. The original Veterans and Agent Orange 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 Veterans and Agent Orange committees adopted the same categories. The question as to whether the committee should be considering “statistical association” rather than “causality,” has been controversial. In legal proceedings that predate passage of the legislation mandating this Veterans and Agent Orange (VAO) series of reviews, Nehmer . 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 determining whether a causal relationship exists (Hill, 1965; IOM, 2008) as indicators of the strength of scientific evidence for an association. In accord with the court ruling, the committee was not seeking proof of a causal relationship, but any informa- tion that supports a causal relationship, such as a plausible biologic mechanism as specified in Article C of the charge to the committee, would also lend credence to the reliability of an observed association. Science is principally concerned with causal relationships, and the committee’s objective of statistical association is an intermediate (less well-defined) point along a continuum culminating 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 2006 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 2006 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 indiid- ual’s health problem is associated with or caused by the chemicals in question.

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20 VETERANS AND AGENT ORANGE: UPDATE 2008 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 confounding can be ruled out with reasonable confidence. The committee regarded evidence from several studies that have 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 strengthens evidence for an association, but is not a prerequisite. The original committee found sufficient evidence of an association between exposure to herbicides and three cancers—soft-tissue sarcoma, non-Hodgkin’s lymphoma, and Hodgkin’s disease—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 exposure. 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. The 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. No additional changes to this category have been made since Update 2002. 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 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 cancers 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 transient peripheral neuropathy (hereafter called early-onset transient

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21 INTRODUCTION peripheral neuropathy), and spina bifida in children of veterans. Transient periph- eral neuropathies had not been addressed in VAO, because they are not amenable to epidemiologic study. In response to a VA request, however, the Update 1996 committee reviewed those neuropathies and based its determination on case histo- ries. A 1995 analysis of birth defects among the offspring of veterans who served in Operation Ranch Hand, combined with 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 committee to distinguish spina bifida from other reproductive outcomes and to classify it in the “limited or suggestive evi- dence” 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 on one of the studies reviewed in it 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 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. 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

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22 VETERANS AND AGENT ORANGE: UPDATE 2008 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 category since the original Veterans and Agent Orange 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 lim- ited 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 evidence 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 information and returned it to this category with other childhood cancers. In Update 2002, CLL was moved from this category to join Hodgkin’s and non-Hodgkin’s lymphomas in the category of sufficient evidence of an association. The committee responsible for Update 2006 moved 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 changes in evidence since they were originally placed in the “no association” category and 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 Veterans and Agent Orange committee defined this category for health outcomes on which several adequate studies covering the “full range of human exposure” were consistent in showing no association with exposure to herbicides at any level and had relatively narrow confidence intervals. A conclu- sion 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 at the levels 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 Veterans and Agent Orange committee found a sufficient num- ber and variety of well-designed studies to conclude that there was limited or sug- gestive evidence of no association between the exposures of interest and a small

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2 INTRODUCTION group of cancers: gastrointestinal tumors (colon, rectum, stomach, and pancreas), skin cancers, brain tumors, and urinary bladder cancer. The Update 1996 com- mittee 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 association. 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 interest 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 they were concerned 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. Pre- vious reports point out that most of the many health studies of Vietnam veterans are hampered by relatively poor measures of exposure to herbicides 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 settings 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 Operation Ranch Hand or the Army Chemical Corps personnel), most Vietnam veterans 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 de- scribed 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

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24 VETERANS AND AGENT ORANGE: UPDATE 2008 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 current committee retains that approach. 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 timeframe remains. The committee therefore believes that it cannot accurately estimate the risk to Vietnam veterans that is attributable to exposure to the com- pounds 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 previous updates, a considerable amount of detail had been provided about individual newly published toxicology studies; the current committee de- cided it would be more informative for the general reader to provide an integrated profile by interpreting the underlying experimental findings. Specific toxicologic findings pertinent to each health outcome are given in the chapters that review the epidemiologic literature. 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-

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2 INTRODUCTION 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 nine chapters. Chapter 2 briefly describes the considerations that guided the committee’s review and evaluation 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 its con- taminant TCDD, cacodylic acid, and picloram; the data contribute to the biologic plausibility of health effects in human populations. Chapter 5 presents the rel- evant new epidemiologic literature identified in this update period, an overview of populations repeatedly studied by publications reviewed in the series of VAO reports with discussion of the exposure assessments conducted on the major co- horts, and design information on the epidemiologic studies that are newly covered in this update and investigated those populations or that report multiple health outcomes. The committee’s evaluation of the epidemiologic literature and its conclusions regarding associations between the exposures of interest and cancer, reproductive and developmental effects, neurologic disorders, and other health effects are discussed in Chapters 6, 7, 8, and 9, respectively. The committee’s research recommendations are presented in Chapter 10. 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 Enironmental 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. 1Throughout 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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