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 Academies of Sciences, Engineering, and Medicine (“the National Academies”) 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 act specified that the herbicides picloram and cacodylic acid were to be addressed, as were chemicals in various formulations that contain the herbicides 2,4-dichlorophenoxyacetic acid (2,4-D) and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T).
Agent Orange refers specifically to a 50:50 formulation of 2,4-D and 2,4,5-T, which was stored in barrels identified by an orange band, but the term has come to often be used more generically to refer to all the herbicides sprayed by the U.S. military in Vietnam.1 2,4,5-T contained the contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin, commonly referred to as “dioxin,” which is referred to in this report as TCDD, to represent a single—and the most toxic—congener of the tetrachlorodibenzo-p-dioxins. It should be noted that TCDD and Agent Orange are not synonymous. The National Academies was also asked to recommend, as appropriate, additional studies needed to resolve continuing scientific uncertainties related to health effects and herbicide exposures and to comment
1 Despite loose usage of “Agent Orange” by many people, in numerous publications, and even in the title of this series, this committee uses “herbicides” to refer to the full range of herbicide exposures experienced in Vietnam, while “Agent Orange” is reserved for a specific one of the mixtures sprayed in Vietnam.
on particular programs mandated in the law. The original legislation called for biennial reviews of newly available information for a period of 10 years, which was subsequently extended to October 1, 2014, by the Veterans Education and Benefits Expansion Act of 2001 (PL 107-103). Subsequently, through the Department of Veterans Affairs Expiring Authorities Act, the Agent Orange Act of 1991 was extended annually for 4 years (PL 113-175, PL 114-58, PL 114-228, and PL 115-62), with a final termination date of September 30, 2018. Although the previous Veterans and Agent Orange (VAO) update was thought to be the final update in the series mandated by PL 107-103, the Department of Veterans Affairs (VA) interpreted the extension act to require an additional study.
In response to the request from VA, the Institute of Medicine (IOM)2 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 fulfil the requirement for updated reviews produced Veterans and Agent Orange: Update 1996 (IOM, 1996), Update 1998 (IOM, 1999), Update 2000 (IOM, 2001), Update 2002 (IOM, 2003c), Update 2004 (IOM, 2005), Update 2006 (, 2007), Update 2008 (IOM, 2009), Update 2010 (IOM, 2011a), Update 2012 (IOM, 2014), and Update 2014 (NASEM, 2016a).
Intermittently between biennial updates, VA has requested targeted reviews of specific health outcomes to determine whether they are associated with exposure to any of the chemicals of interest (COIs). These separate and focused topics have included type 2 diabetes (IOM, 2000b), childhood acute myelogenous leukemia (now generally referred to as acute myeloid leukemia) associated with parental exposure to any of the COIs (IOM, 2002), and respiratory cancers (IOM, 2004). The respiratory cancer review was included in PL 107-103, which was passed by Congress in 2001 and which directed the Secretary of Veterans Affairs to ask the National Academies 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.
Each report in the VAO series contains detailed reviews of the scientific studies evaluated by the committees and their implications for cancers, reproductive and developmental effects, neurologic disorders, and other health effects. VA has specified particular areas of focus for each update, for example, the Update
2 Since March 2016, the Health and Medicine Division of the National Academies has continued the consensus studies and convening activities previously undertaken by the Institute of Medicine (IOM).
2014 committee was asked to specifically address whether all neurodegenerative diseases with Parkinson-like symptoms should be considered service-related under the association identified between Parkinson disease and herbicide exposure by the committee for Update 2006. Each committee used the compilation of evidence presented in the previous reports as a starting point for updating the evidence base concerning the associations of health outcomes with exposure to any of the COIs. As such, each committee operated independently of prior committees, chose how to present the new and existing information, and determined its own conclusions regarding the strength of the evidence and each health outcome.
In conducting their work, the committees responsible for the updates and the targeted reviews operated 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 claimed injury from herbicide exposure. The reports are intended to provide evidence-based assessments of the scientific information available for the Secretary of Veterans Affairs to consider as VA exercises its responsibilities to Vietnam veterans. This report and all previous VAO reports are freely accessible online at the National Academies Press’s website (http://www.nap.edu).
Box 1-1 shows the committee’s Statement of Task. A VA representative delivered the charge to the committee during the open session of the committee’s first meeting. In addition to the standard language of assessing associations between health outcomes and exposures to chemicals present in the herbicides used by the military in Vietnam that all VAO update committees are charged with reviewing, the committee for this final update was asked to assess three health outcomes in particular: possible generational effects on the descendants of male Vietnam veterans that may be the result of exposure to any of the COIs, myeloproliferative neoplasms, and glioblastoma multiforme. In addition, the committee was asked to offer recommendations as appropriate, such as which areas to prioritize for future research, a request that has been made of each of the VAO committees.
Both the committee’s congressional mandate and the Statement of Task instruct that the evaluation be focused on the “association” between exposure and health outcomes, although biologic mechanisms and causal relationships are also mentioned as part of the evaluation in Article C. The criteria for causation do not themselves constitute a set checklist, but they are more stringent than those for association. The unique mandate of VAO committees to evaluate association rather than causation means that the rigor of the evidence required to support a finding of statistical association is weaker than what is required to support causality. Positive findings on any of the indicators for causality would strengthen a conclusion that an observed statistical association is valid. In accordance 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 model systems. As such, a full array of indicators was used to categorize the strength of the evidence. In particular, associations supported by multiple indicators were interpreted as having stronger scientific support.
The committee convened by the National Academies included experts in epidemiology, biostatistics, environmental health, exposure assessment, military and veteran’s health, genetics and epigenetics, toxicology, oncology, and reproductive health. It comprised 12 members who met in person 7 times over 14 months. Between in-person meetings, small groups of committee members would
hold conference calls related to reviewing the specific studies or to discuss the evidence base on a particular topic.
Several activities were undertaken to develop the scientific foundation for the report’s findings, conclusions, and recommendations. As has been the practice of previous VAO committees, the committee held three open sessions not only to gather additional information from people who have particular expertise on topics and subjects that arise during deliberations (such as VA researchers, experts in glioblastoma multiforme, and specialists in environmental exposures and heritable health effects), but also especially to listen to individual Vietnam veterans and others, such as spouses and other family members and veterans service organization advocates, who are concerned about aspects of health that may be service-related. Open sessions were held during meetings 1, 3, and 4, the agendas and presentation topics of which are presented in Appendix A. The comments and information provided by the public at the open meetings and over the course of the study were used to identify information gaps in the literature regarding specific health outcomes of concern to Vietnam veterans.
In addition to information provided from invited speakers and public attendees at open sessions, the committee made information requests to VA to follow up on issues raised during presentations and on sources of data on Vietnam veterans who use VA health care. All presentations, responses to information requests, and written comments are available in the public access file for the project.
The principal source of information on health effects from potential exposure to the COIs for the committee to consider and deliberate on came from detailed searches of the peer-reviewed literature published since VAO: Update 2014 (NASEM, 2016a). The literature search strategy and process for reviewing all results is discussed in detail in Chapter 3: Evaluating the Evidence Base. This was supplemented by examining other pertinent published literature, government documents and reports, and testimony presented to Congress; attending professional meetings and educational events; and consulting relevant National Academies reports. The committee also received data from VA, veterans’ advocacy organizations, and other sources including the Sierra Valley Cancer Registry.
The remainder of this report is organized into 11 chapters, 2 appendixes, and an online supplement of studies reviewed in the course of the VAO series for each health outcome that has an associated conclusion. Chapter 2 presents background information about the population of Vietnam veterans and the military herbicides used in the conflict and addresses exposure-assessment issues. Chapter 3 briefly describes the considerations that guided the committee’s review and evaluation of the scientific evidence. Chapter 4 summarizes the toxicology data on the effects of 2,4-D, 2,4,5-T and its contaminant TCDD, cacodylic acid, and picloram; these data contribute to the committee’s consideration of the
biologic plausibility of health effects in human populations. Chapter 5 offers a selected overview of the study populations that have generated findings (in some instances presented in dozens of separate publications) reviewed in the VAO report series as well as those studies that have presented multiple health outcomes, which are presented and discussed in several chapters. In addition to showing where the new literature fits into the compendium of previous publications on Vietnam veterans, occupational cohorts, environmentally exposed groups, and case-control study populations, that chapter includes a description and critical appraisal of the approaches used in the design, exposure assessment, and analysis in these studies.
The committee’s evaluation of the epidemiologic literature and its conclusions regarding the associations between exposures and the particular health outcomes that might be manifested long after exposure to the COIs are presented in Chapters 6–11. Because many individual outcomes are included in each chapter, a summary of the findings for each health outcome reviewed in a particular chapter is presented at the beginning of the chapter.
Chapter 6, the first of the chapters evaluating epidemiologic evidence concerning particular health outcomes, addresses immunologic effects and discusses the reasons for what might be perceived as a discrepancy between a clear demonstration of immunotoxicity in animal studies and a paucity of human epidemiologic studies with similar findings. Its placement in the report reflects the committee’s belief that immunologic changes may constitute an intermediate step in the generation of distinct clinical conditions, as discussed in subsequent chapters.
Chapter 7 discusses issues related to the possible overall carcinogenic potential of the COIs, particularly TCDD, and then assesses, in order of their codes in the International Classification of Diseases, the available epidemiologic evidence on specific types of cancer, which are regarded as individual disease states that might be found to be service-related. Two of the conditions specified in the committee’s charge—glioblastoma multiforme and myeloproliferative neoplasms—are covered in this chapter.
Chapter 8 addresses reproductive outcomes that may have been manifested in the veterans themselves, such as reduced fertility and pregnancy loss. It then covers gestational issues, including low birth weight and preterm delivery. This is followed by problems that might be manifested in veterans’ children at birth (traditionally defined as birth defects) or later in their lives (childhood cancers, plus a broad spectrum of conditions for which impacts from parental exposures have been posited) or even in later generations.
Chapter 9 addresses neurologic disorders and diseases of the nervous system. Chapter 10 covers conditions related to cardiovascular and metabolic effects (including diabetes) on the basis of their apparent interrelationship in the emerging medical phenomenon known as “metabolic syndrome.” Chapter 11 contains information covering the residual “other chronic health outcomes” about which
epidemiologic results related to the COIs have been encountered in the course of this series of VAO reports and in the current literature search: respiratory disorders, gastrointestinal problems and liver toxicity, kidney and urinary bladder disease, thyroid homeostasis and other endocrine disorders, chronic skin conditions (new to this report), eye problems, and bone conditions.
A summary of the committee’s findings and its research recommendations are presented in Chapter 12. In the previous report, which was intended to be the final report of the series as mandated by PL 102-4 and PL 107-103 (and extended by PL 113-175, PL 114-58, PL 114-228, and PL 115-62), the committee reported on the status of recommendations made throughout the VAO series.
In the interest of minimizing unnecessary repetition, the citations for all chapters have been merged into a single reference list that follows all of the chapters. Appendix A provides a list of open meeting agendas and invited presentation topics. Committee and staff biographies can be found in Appendix B. Compendium tables summarizing new results identified for this current update as well as those reviewed by prior committees are available in digital form only and can be accessed from www.nap.edu/catalog/25137.