1
Introduction

The Agent Orange Act of 1991 (Public Law [PL] 102-4, enacted February 6, 1991, and codified as 38 USC Sec. 1116) 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). The most well known of the formulations, Agent Orange, was a 50:50 mixture of the herbicides 2,4-D and 2,4,5-T, which contained the contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD); thus, it should be noted that TCDD and Agent Orange are not synonymous. 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 NAS 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, 1996), Up-



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1 Introduction The Agent Orange Act of 1991 (Public Law [PL] 102-4, enacted February 6, 1991, and codified as 38 USC Sec. 1116) directed the Secretary of Veterans Affairs to ask the National Academy of Sciences (NAS) to conduct an indepen- dent comprehensive review and evaluation of scientific and medical informa- tion 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). The most well known of the formulations, Agent Orange, was a 50:50 mixture of the herbicides 2,4-D and 2,4,5-T, which contained the contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD); thus, it should be noted that TCDD and Agent Orange are not synonymous. 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 legisla- tion 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 NAS 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 Or- ange: 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, 1996), Up- 17

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18 VETERANS AND AGENT ORANGE: UPDATE 2006 date 1998 (IOM, 1999), Update 2000 (IOM, 2001), Update 2002 (IOM, 2003), and Update 2004 (IOM, 2005). 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 my- elogenous leukemia (AML) associated with parental exposure; 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). Also in 2001, Congress (PL 107- 103) 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 result 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. 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 chemical compounds in herbicides: 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 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 both its congressional mandate and the statement of task are phrased with the target of evaluation being “association,” not “causal-

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19 INTRODUCTION ity,” between exposure and health outcomes. As used technically, the criteria for causation are somewhat more stringent than those for association. The standard of association was not the choice of VAO committees, but the consequence of congressional and judicial history. IOM has recently convened a separate com- mittee to evaluate VA’s methods of determining whether medical conditions are service-related; that committee will address this and other issues. In delivering the above charge to the current committee, the VA project officer made two additional specific requests. First, he asked the committee to examine the evidence related to whether the occurrence of AML, tonsil cancer, AL amyloidosis, and lupus may be associated with exposure to the components of herbicides used by the military in Vietnam. Second, he made the more general request that the appropriate category of association be explicitly indicated for all forms of cancer, leaving no gaps in the exhaustive range of codes for malignant neoplasms (ICD-9 140–208, according to the International Classification of Diseases, Ninth Edition). Details of the committee’s approach to its charge and the methods it used in reaching conclusions are provided in Chapter 2 and elaborated on in the health-outcome chapters, particularly Chapter 6, on evidence concerning specific cancers. 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, and Respiratory Cancer provide detailed reviews of the scientific studies evaluated by the committees and their implications for cancer, reproductive and developmental effects, neurobehavioral disorders, and other health effects. The original committee addressed the statutory mandate to determine whether there is a statistical association between a given health effect and herbicide expo- sure by assigning each of the health outcomes under study to one of four catego- ries on the basis of the epidemiologic evidence reviewed. Those categories were adapted from the ones used by the International Agency for Research on Cancer (IARC) in evaluating evidence of the carcinogenicity of various substances (IARC, 1977). Successor committees adopted the same categories. The establishment of categories regarding the evidence for “statistical asso- ciation,” rather than “causality,” has been controversial. It should be noted, how- ever, that this principle was established in legal proceedings that predate passage of the legislation mandating the VAO series of reviews. Nehmer vs United States Veterans Administration (712 F. Supp. 1404, 1989) found that:

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20 VETERANS AND AGENT ORANGE: UPDATE 2006 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 categories, the criteria for assigning a particular health outcome to a cat- egory, and the health outcomes that have been assigned to the categories in past updates are discussed below. Table 1-1 summarizes the conclusions of Update 2004 (IOM, 2005) regarding associations between health outcomes and exposure to the herbicides used in Vietnam or to any of their components or contaminants. This integration of the literature to 2004 served as the starting point for the cur- rent committee’s deliberations. It should be noted that the categories of associa- tion concern the occurrence of health outcomes in human populations in relation to chemical exposures; they do not address the likelihood that any individual’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 studies in which chance, bias, and confounding can be ruled out with reasonable confidence. The committee regarded evidence from several small 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. 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) (IOM, 1994). 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; Chapter 11 of Update 1996 details the decision. 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 given epidemiologic literature and the etiology of the disease, placed CLL in the “sufficient” category.

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21 INTRODUCTION TABLE 1-1 Summary of Conclusions from Update 2004 on Specific Health Outcomes and Exposure to Herbicidesa Sufficient Evidence of Association Chronic lymphocytic leukemia (CLL) Soft-tissue sarcoma Non-Hodgkin’s lymphoma Hodgkin’s disease Chloracne Limited or Suggestive Evidence of Association Cancer of the lung, bronchus, or trachea Cancer of the larynx Prostate cancer Multiple myeloma Early-onset transient peripheral neuropathy Porphyria cutanea tarda Type 2 diabetes (mellitus) Spina bifida in offspring of exposed people Inadequate or Insufficient Evidence to Determine Association Hepatobiliary cancers Oral, nasal, and pharyngeal cancer Bone and joint cancer Skin cancers (melanoma, basal cell, and squamous cell) Breast cancer Female reproductive cancer (cervix, uterus, and ovary) Testicular cancer Urinary bladder cancer Renal cancer Leukemia (other than CLL) Abnormal sperm characteristics and 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 myelogenous leukemia) in offspring of exposed people Neurobehavioral disorders (cognitive and neuropsychiatric) Movement disorders, 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 and autoimmunity) Circulatory disorders continued

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22 VETERANS AND AGENT ORANGE: UPDATE 2006 TABLE 1-1 Continued AL amyloidosis Endometriosis Effects on thyroid homeostasis Limited or Suggestive Evidence of No Association Gastrointestinal tumors (stomach, pancreas, colon, and rectum) Brain tumors Spontaneous abortion and paternal exposure to TCDDb 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 New finding from Update 2002, which had not been listed in previous summary tables. 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 wording “For example, at least one high-quality study shows a positive association, but the results of other studies are inconsistent” has appeared in prior VAO reports. The present committee interpreted that statement as an example of one particular situation. 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 endpoint. 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. If the committee encountered a high-quality study showing an association for a given health outcome in a body of evidence that also contained a high-quality study showing strong negative findings on exposure to the same agent, it would not automatically adopt a classification of limited or suggestive evidence of an association. 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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23 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 his- tories (Update 1996, Chapter 10). A 1995 analysis of birth defects among the off- spring 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 evidence” category (Update 1996, Chapter 9). No changes were made in this category in Update 1998. After the publication of Update 1998, on the basis of its evaluation of newly available scientific evidence and the cumulative findings of research reviewed in previous VAO reports, the committee responsible for Type 2 Diabetes 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 that report, researchers on one of the studies reviewed in Up- date 2000 discovered an error in the published data. The committee for Update 2000 was reconvened to re-evaluate the previously reviewed and new literature regarding that illness. It produced the Acute Myelogenous Leukemia report, which reclassified AML in children from “limited or suggestive evidence of an associa- tion” to “inadequate evidence to determine an association.” 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 the category of limited or suggestive evidence of no association. In this category, available studies may have inconsistent findings or be of insufficient quality or statistical power to sup- port a conclusion regarding the presence of an association. Such studies might have failed to control for confounding or might have had inadequate assessment 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 VAO committee reviewed the evidence then available. Skin cancer was moved into this category in Update 1996 when inclusion of

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24 VETERANS AND AGENT ORANGE: UPDATE 2006 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 (IOM, 2002), found errors in the published information and returned it to the category of inadequate or insufficient evidence 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. Health Outcomes with Limited or Suggestive Evidence of No Association The original VAO committee defined this category for health outcomes for which there were several adequate studies covering the “full range of human exposure” that were consistent in showing no association between exposure to herbicides at any level and the outcome and that had relatively narrow confidence intervals. A conclusion of “no association” is inevitably limited to the condi- tions, exposures, and observation period covered by the available studies. 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 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: gastrointestinal 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 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 for this endpoint was deemed inad- equate for drawing a conclusion about association for maternal exposure overall or for paternal exposure to any other of the chemicals of interest. No changes in this category were made in Update 2000, or Update 2004. As will be discussed in greater detail in this volume, the current committee was concerned that the overall paucity of information on picloram and cacodylic acid make this asser-

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25 INTRODUCTION tion questionable for the endpoints (brain cancer and several digestive cancers) remaining 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 during service in Vietnam. Previous 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 most Vietnam veterans (except those with documented high exposures, such as participants in Operation Ranch Hand or the Army Chemical Corps) 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 occu- pational 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. Previous committees have concluded that in general it is impossible to quantify the degree of risk likely to be experienced by veterans because of their exposure to herbicides in Vietnam. Overall statements to that effect were made in VAO (IOM, 1994) and in every update, but uniformity in the set explanations about the unavailability of the necessary information for performance of quantitative risk assessment for Vietnam veterans in the conclud- ing section for each health outcome or in chapter summaries became somewhat idiosyncratic over the course of the updates. In an effort to streamline the presen- tation for the individual health outcomes, the point will no longer be reiterated in each instance. The present committee has chosen to eliminate the repetitive 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.

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26 VETERANS AND AGENT ORANGE: UPDATE 2006 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 based on records of troop movements and spray- ing missions (Stellman et al., 2003a,b; Stellman and Stellman, 2003, 2004), 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). Uncertainty re- mains about the specific agent that may be responsible for a particular health ef- fect. Even if one accepts an individual veteran’s serum TCDD level as the optimal surrogate for his overall exposure to Agent Orange and the other herbicide mix- tures 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 compounds associ- ated 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. That information is summarized in general terms in separate toxicology chapters in previous reports: Chapter 4 of VAO and Chapter 3 of Update 1996, Update 1998, Update 2000, Update 2002, and Update 2004. An analogous chapter in this update summarizes recent toxicologic findings on the chemicals of concern, and specific findings on each health outcome are also given in the chapters that review the epidemiologic literature. In previous updates, 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. In fact, the degree of biologic plausibility itself influences whether the committee perceives positive findings to be indica- tive of a pattern or the product of statistical fluctuations. To provide the reader with a more logical sequence, biologic-plausibility sections have been placed 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.

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27 INTRODUCTION 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 updates the toxicology data on the effects of 2,4-D, 2,4,5-T and its contaminant TCDD, cacodylic acid, and picloram; those data contribute to the biologic plausibility of health effects in human populations. Chapter 4 provides an overview of populations repeatedly studied in the course of investigating the toxic potential of the chemicals of interest in this report; it also gives design information on the epidemiologic studies new in this update that investigated those populations or that report multiple health outcomes. Chapter 5 addresses exposure-assessment issues and the exposure assessments conducted in the studies of the major cohorts. The committee’s evaluation of the epidemio- logic literature and its conclusions regarding associations between the exposures of interest and cancer, reproductive and developmental effects, neurobehavioral disorders, and other health effects are discussed in Chapters 6, 7, 8, and 9, respec- tively. 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 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. 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 Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man, Vol. 15. Lyon, France: World Health Organization, IARC. 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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28 VETERANS AND AGENT ORANGE: UPDATE 2006 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 Leukemia in the Children of Vietnam Veterans. Washington, DC: The National Academies Press. IOM. 2003. Veterans and Agent Orange: Update 2002. 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. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. 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. 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. 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. 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 Sci- ences, 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.