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 request that the National Academy of Sciences (NAS) 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 well as the most well-known of the formulations, Agent Orange (a 50:50 mixture of the herbicides 2,4-dichlorophenoxyacetic acid [2,4-D] and 2,4,5-trichlorophenoxyacetic acid [2,4,5-T], which contained a contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin [TCDD]). The legislation also called for biennial reviews of newly available information for a period of 10 years, which was extended until 2014 by the Veterans Education and Benefits Expansion Act of 2001. 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 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 were formed to fulfill the requirement for updated reviews. Those committees produced Veterans and Agent Orange: Update 1996 (IOM, 1996), Update 1998 (IOM, 1999), Update 2000 (IOM, 2001), and Update 2002 (IOM, 2003). In 1999, VA requested that IOM convene a com-



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Veterans and Agent Orange: Update 2004 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 request that the National Academy of Sciences (NAS) 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 well as the most well-known of the formulations, Agent Orange (a 50:50 mixture of the herbicides 2,4-dichlorophenoxyacetic acid [2,4-D] and 2,4,5-trichlorophenoxyacetic acid [2,4,5-T], which contained a contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin [TCDD]). The legislation also called for biennial reviews of newly available information for a period of 10 years, which was extended until 2014 by the Veterans Education and Benefits Expansion Act of 2001. 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 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 were formed to fulfill the requirement for updated reviews. Those committees produced Veterans and Agent Orange: Update 1996 (IOM, 1996), Update 1998 (IOM, 1999), Update 2000 (IOM, 2001), and Update 2002 (IOM, 2003). In 1999, VA requested that IOM convene a com-

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Veterans and Agent Orange: Update 2004 mittee 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, Type 2 Diabetes; IOM, 2000). In 2001, VA requested that IOM convene a committee to conduct an interim review of acute myelogenous leukemia (AML) in children associated with parental exposure. Its review of the literature, including literature available since its review for Update 2000, is published in Veterans and Agent Orange: Herbicide/Dioxin Exposure and Acute Myelogenous Leukemia in the Children of Vietnam Veterans (hereafter, Acute Myelogenous Leukemia; IOM, 2002). In 2001, Congress (PL 107-103) directed the Secretary of Veterans Affairs to request that NAS 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” for the disease would not be warranted. Veterans and Agent Orange: Length of Presumptive Period for Association Between Exposure and Respiratory Cancer (hereafter, Respiratory Cancer; IOM, 2004) is the result of that effort. In conducting their work, the committees responsible for those reports 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 have claimed injury from herbicide exposure. The reports are 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. Details of the committee’s approach to its charge and the methods it used in reaching conclusions are provided in Chapter 2.

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Veterans and Agent Orange: Update 2004 CONCLUSIONS OF PREVIOUS VETERANS AND AGENT ORANGE REPORTS Health Outcomes VAO, Update 1996, Update 1998, Update 2000, Update 2002, 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 exposure by assigning each of the health outcomes under study to one of four categories 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 have adopted the same categories. 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 Update 2002 (IOM, 2003) for 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 prior to 2002 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 exposures; they do not consider the likelihood that any individual’s health problem is associated with or caused by the herbicides 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

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Veterans and Agent Orange: Update 2004 TABLE 1-1 Summary of Conclusions from Update 2002 on Specific Health Outcomes and Exposure to Herbicidesa Sufficient Evidence of an Association Chronic lymphocytic leukemia (CLL) Soft-tissue sarcoma Non-Hodgkin’s lymphoma Hodgkin’s disease Chloracne Limited or Suggestive Evidence of an Association Respiratory cancers (lung/bronchus, larynx, and trachea) Prostate cancer Multiple myeloma Acute and subacute (or early-onset) transient peripheral neuropathy Porphyria cutanea tarda Type 2 diabetes (mellitis) Spina bifida in offspring of exposed individuals Inadequate or Insufficient Evidence to Determine Whether an Association Exists Hepatobiliary cancers Nasal or nasopharyngeal cancer Bone cancer Breast cancer Female reproductive cancers (cervix, uterus, and ovary) Urinary bladder cancer Renal cancer Testicular cancer Leukemia (other than CLL) Skin cancers Abnormal sperm characteristics and infertility Spontaneous abortion Neonatal or infant death and stillbirth in offspring of exposed individuals Low birthweight in offspring of exposed individuals Birth defects (other than spina bifida) in offspring of exposed individuals Childhood cancer (including acute myelogenous leukemia) in offspring of exposed individuals Cognitive and neuropsychiatric disorders Motor or coordination dysfunction Chronic peripheral nervous system disorders Metabolic and digestive disorders (changes in liver enzymes, lipid abnormalities, ulcers) Immune system disorders (immune suppression, autoimmunity) Circulatory disorders Respiratory disorders AL-type primary amyloidosis Limited/Suggestive Evidence of No Association Gastrointestinal tumors (stomach, pancreas, colon, rectum) Brain tumors 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 veterans studies in which individuals were exposed the herbicides used in Vietnam, their components, or to their contaminants.

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Veterans and Agent Orange: Update 2004 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 they evaluate whether chronic lymphocytic leukemia (CLL) should be considered separately from other leukemias. The committee concluded that CLL could be considered separately and, on the basis of the given epidemiology literature and the etiology of the disease, placed CLL in the sufficient category. Limited or Suggestive Evidence of 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 confidently rule out chance, bias, or confounding. Typically, at least one high-quality study indicates a positive association, but the results of other studies could be inconsistent. The committee responsible for VAO found limited or suggestive evidence of an association between exposure to herbicides and three categories of cancer: respiratory cancers, prostatic cancer, and multiple myeloma. The Update 1996 committee added three health outcomes to this list: PCT, acute and subacute transient peripheral neuropathy (henceforth called “early-onset transient 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 committee responsible for Update 1996 reviewed those neuropathies and based its determination on case histories (Chapter 10, Update 1996). A 1995 analysis of birth defects among the offspring of veterans of 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 classify it in the limited or suggestive-evidence category (Chapter 9, Update 1996). No changes were made in this category in Update 1998. After the publication of Update 1998, and based on 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 acute myelogenous leukemia in the chil-

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Veterans and Agent Orange: Update 2004 dren of Vietnam veterans. After release of that report, researchers on one of the studies reviewed in Update 2000 discovered an error in the published data. After reconvening to reevaluate the previously reviewed and new literature regarding that illness, the Acute Myelogenous Leukemia report was produced; it reclassified AML in children from “limited or suggestive evidence of an association” to “inadequate evidence to determine whether an association exists.” Inadequate or Insufficient Evidence to Determine Association By default, any health outcome considered falls into this category prior to accumulation of enough reliable scientific data to promote it to the categories of sufficient or limited-suggestive evidence of an association or to the category of suggestive evidence of no association. In this category, available studies may have inconsistent findings or are of insufficient quality or statistical power to support a conclusion regarding the presence or absence of an association. Such studies might fail to control for confounding or might have inadequate assessment of exposure. The cancers and other health effects so categorized as of Update 2002 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 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 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 acute myelogenous leukemia in the offspring of Vietnam veterans from other childhood cancers and put it in the classification with 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, chronic lymphocytic leukemia was moved from this category to join Hodgkin’s and non-Hodgkins lymphomas in the category with sufficient evidence of an association. Limited or Suggestive Evidence of No Association In this category, several adequate studies covering the full range of human exposure are consistent in not showing a positive association between exposure to herbicides and the outcome, at any exposure. Those studies have relatively narrow confidence intervals. A conclusion of “no association” is inevitably limited to the conditions, exposures, and length of observation covered by the

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Veterans and Agent Orange: Update 2004 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–insufficient evidence to limited–suggestive evidence of no association would require new studies that correct for the problems in methodology in previous studies and that have sample sizes that are large enough to limit the range of possible study results attributable to chance. The original VAO committee found a sufficient number and variety of well-designed studies to conclude that there is limited or suggestive evidence of no association between the exposures of interest and a small group of cancers: gastrointestinal tumors (colon, rectum, stomach, pancreas), skin cancer, brain tumors, and bladder cancer. The Update 1996 committee removed skin cancer and the Update 1998 committee removed urinary bladder cancer from this category because the evidence no longer supported a no-association classification. No further changes in this category were made in Update 2000 or Update 2002. 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 although there have been many health studies of Vietnam veterans, most are hampered by relatively poor measures of exposure to herbicides or TCDD and by other problems in methodology. 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 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. Estimating the magnitude of risk of a particular health outcome among herbicide-exposed Vietnam veterans requires quantitative information about the dose–time–response relationship for each health outcome in humans, information on the extent of herbicide exposure among Vietnam veterans, and estimates of individual exposure. The persisting large uncertainties about the magnitude of risk posed by exposure to herbicides as defined by the studies reviewed and about the nature and magnitude of exposure to herbicides in Vietnam make quantitative risk assessments difficult. The 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. 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) had lower exposure to herbicides and

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Veterans and Agent Orange: Update 2004 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. 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, and Update 2002. Specific findings on each health outcome are also given in the chapters that review the epidemiologic literature. ORGANIZATION OF THIS REPORT The remainder of this report is organized into 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 potential health effects in human populations. Chapter 4 provides an overview of populations repeatedly studied in an effort to understand the chemicals of interest in this report; it also gives design information on those epidemiologic studies new to 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 epidemiologic 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, respectively. The committee’s research recommendations are presented in Chapter 10. REFERENCES 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. 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.

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Veterans and Agent Orange: Update 2004 IOM. 2000. Veterans and Agent Orange: Herbicide/Dioxin Exposure and Type 2 Diabetes. Washington, 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: National Academy Press. IOM. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. IOM. 2004. Veterans and Agent Orange: Veterans and Agent Orange: Length of Presumptive Period for Association Between Exposure and Respiratory Cancer. Washington, DC: The National Academies Press.