Executive Summary



Veterans and Agent Orange

Update 1998



Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides


Division of Health Promotion and Disease Prevention




National Academy Press

Washington, D.C. 1999



Preface | Table of Contents | Executive Summary


National Academy Press - 2101 Constitution Avenue, N.W. Washington, D.C. 20418


Note: The project that is the subject of this report was approved by the Governing Board of the National Research Council, whose members are drawn from the councils of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. The members of the committee responsible for the report were chosen for their special competences and with regard for appropriate balance.

The Institute of Medicine was chartered in 1970 by the National Academy of Sciences to enlist distinguished members of the appropriate professions in the examination of policy matters pertaining to the health of the public. In this, the Institute acts under the Academy's 1863 congressional charter responsibility to be an adviser to the federal government and its own initiative in identifying issues of medical care, research, and education. Dr. Kenneth I. Shine is president of the Institute of Medicine.

Support for this study was provided by the Department of Veterans Affairs (contract no. V101(93)P-1331).

This Executive Summary is available in limited quantities from the Institute of Medicine, Division of Health Promotion and Disease Prevention, 2101 Constitution Avenue, N.W., Washington, DC 20418.

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Committee to Review the Health Effects in Vietnam
Veterans of Exposure to Herbicides (Second Biennial Update)



DAVID TOLLERUD, MD, MPH (Chair),*,** Professor, School of Public Health, MCP Hahnemann University, Philadelphia

MICHAEL AMINOFF, MD,** Professor, Department of Neurology, University of California at San Francisco School of Medicine

STEVEN GOODMAN, MD, MHS, PhD, Associate Professor, Department of Oncology, Division of Biostatistics, Johns Hopkins University School of Medicine

ROBERT HERRICK, PhD, CIH, Lecturer on Industrial Hygiene, Department of Environmental Health, Harvard School of Public Health

IRVA HERTZ-PICCIOTTO, PhD, Associate Professor, Department of Epidemiology, University of North Carolina, Chapel Hill

DAVID HOEL, PhD, Distinguished University Professor, Medical University of South Carolina

ANDREW OLSHAN, PhD,*,** Associate Professor, Department of Epidemiology, University of North Carolina, Chapel Hill

TREVOR ORCHARD, MBBCh, MMSc, Professor, Rangos Research Center, University of Pittsburgh

HOWARD OZER, MD, PhD, Professor, Department of Medicine, MCP Hahnemann University, Philadelphia

KENNETH RAMOS, PhD,** Professor, Department of Physiology and Pharmacology, Texas A&M University College of Veterinary Medicine

NOEL ROSE, MD, PhD,** Professor, Department of Molecular Microbiology and Immunology, Johns Hopkins University School of Hygiene and Public Health

SUSAN WOSKIE, PhD, CIH, Associate Professor, Department of Work Environment, University of Massachusetts, Lowell


Project Staff

DAVID A. BUTLER, Study Director SANJAY S. BALIGA, Research Associate JAMES BOWERS, Research/Project Assistant KATHLEEN R. STRATTON, Director, Division of Health Promotion and Disease Prevention DONNA D. DUNCAN, Division Assistant SHARON GALLOWAY, Financial Associate


Staff Consultants

JANE DURCH, Senior Program Officer, Institute of Medicine CAROL MACZKA, Director of Toxicology and Risk Assessment, National Research Council FLORENCE POILLON, Contract Editor



 *Member of the committee responsible for Veterans and Agent Orange (1994)
**Member of the committee responsible for Veterans and Agent Orange: Update 1996.


Preface



In response to the concerns voiced by Vietnam veterans and their families, Congress called upon the National Academy of Sciences (NAS) to review the scientific evidence on the possible health effects of exposure to Agent Orange and other herbicides (Public Law 102-4, enacted on February 6, 1991). The creation of the first NAS Institute of Medicine committee, in 1992, underscored the critical importance of approaching these questions from a nonpartisan scientific standpoint. The original Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides realized from the beginning that it could not conduct a credible scientific review without a full understanding of the experiences and perspectives of veterans. Thus, to supplement its standard scientific process, the committee opened several of its meetings to the public in order to allow veterans and other interested individuals to voice their concerns and opinions, to provide personal information about individual exposure to herbicides and associated health effects, and to educate committee members on recent research results and studies still under way. This information provided a meaningful backdrop for the numerous scientific articles that the committee considered.

Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam (abbreviated as VAO in this report) reviewed and evaluated the available scientific evidence regarding the association between exposure to dioxin or other chemical compounds contained in herbicides used in Vietnam and a wide range of health effects. The report provided information for the Secretary of Veterans Affairs to consider as the Department of Veterans Affairs carried out its responsibilities to Vietnam veterans. It also described areas in which the available scientific data were insufficient to determine whether an association exists and provided the committee's recommendations for future research.

Public Law 102-4 also tasked the NAS to conduct biennial updates that would review newly published scientific literature regarding statistical associations between health outcomes and exposure to dioxin and other chemical compounds in these herbicides. The first of these, Veterans and Agent Orange: Update 1996 (Update 1996) was published in March of that year. The focus of this second updated review is on scientific studies published since the release of Update 1996. To conduct the review, the IOM established a committee of 12 members representing a wide range of expertise to take a fresh look at the studies reviewed in VAO and Update 1996 along with the newest scientific evidence. In order to provide a link to the experience and expertise developed by the previous committees, five of the members of the committee responsible for this report were recruited from the committee responsible for Update 1996; two of these individuals also served on the VAO committee. All committee members were selected because they are leading experts in their fields, have no conflicts of interest with regard to the matter under study, and have taken no public positions concerning the potential health effects of herbicides in Vietnam veterans or related aspects of herbicide or dioxin exposure. Biographical sketches of committee members and staff appear in Appendix B.

The committee worked on several fronts in conducting this updated review, always with the goal of seeking the most accurate information and advice from the widest possible range of knowledgeable sources. Consistent with procedures of the NAS, the committee met in a series of closed sessions and working group meetings in which members could freely examine, characterize, and weigh the strengths and limitations of the evidence. It also convened two open meetings to provide the opportunity for veterans and veterans service organizations, researchers, policymakers, and other interested parties to present their concerns, review their research, and exchange information directly with committee members. The first of these was held in conjunction with the committee's second meeting in June 1997 in Washington, D.C; the second in Irvine, California in October 1997. To solicit broad participation, the committee sent announcements to individuals, organizations and listserves known to have an interest in this issue. The oral presentations and written statements submitted to the committee are described in detail in Appendix A. In order to address one area of interest identified by the Department of Veterans Affairs, the committee convened a workshop on the combination and reanalysis of existing data on the health effects of herbicide and dioxin exposure. The workshop, which took place in August 1997, brought together experts in these methodologies with researchers who have developed and analyzed datasets evaluating the health of Vietnam veterans and individuals exposed to herbicides or dioxin. The results of this effort will be addressed in a separate report published in 1998.

In addition to its formal meetings, the committee actively and continuously sought information from, and explained its mission to, a broad array of individuals and organizations with interest or expertise in assessing the effects of exposure to herbicides. The committee also heard from the public through telephone calls, letters and e-mails.

This report has been reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise, in accordance with procedures approved by the NRC's Report Review Committee. The purpose of this independent review is to provide candid and critical comments that will assist the institution in making the published report as sound as possible and to ensure that the report meets institutional standards for objectivity, evidence, and responsiveness to the study charge. The review comments and draft manuscript remain confidential to protect the integrity of the deliberative process. We wish to thank the following individuals for their participation in the review of this report: Patricia Buffler, University of California, Berkeley; Graham Colditz, Harvard University; John Doull, University of Kansas; Kristine Gebbie, Columbia University; David Kriebel, University of Massachusetts, Lowell; Gilbert Omenn, University of Michigan; Jonathan Samet, Johns Hopkins University; David Strogatz, University of Albany, SUNY. While the individuals listed above have provided constructive comments and suggestions, it must be emphasized that responsibility for the final content of this report rests entirely with the authoring committee and the institution.

David A. Butler served as the study director for this project and deserves credit for drafting sections of the report. The committee would also like to acknowledge the excellent work of IOM staff members Sanjay Baliga and James Bowers. Carol Maczka of the Academy's National Research Council provided invaluable help on the toxicology chapter of the report. Thanks are also extended to Sharon Galloway, who handled the finances for the project; Florence Poillon and Jane Durch, who provided excellent editorial skills; Susan Fourt, who conducted database searches; Michael Edington, who supervised the report through the editorial and publication phases; and Donna Duncan, who provided administrative support to the project. The knowledge and experience of Michael Stoto and Catharyn Liverman, who served as staff members on the original committee, was helpful in this effort.

The committee also benefited from the assistance of several scientists and researchers who generously lent their time and expertise to help give committee members insight on particular issues, provide copies of newly released research, or answer queries concerning their work. Special thanks are extended to Drs. Bruce Armstrong (New South Wales Cancer Council, Australia), Michael DeVito (U.S. EPA), Keith Horsley (Commonwealth Department of Veterans' Affairs, Australia), Han Kang (U.S. Department of Veterans Affairs), Stephen Katz (National Institutes of Health, DHHS), Edward McCarthy (Johns Hopkins University), Joel Michalek (Armstrong Laboratory, USAF), and Jerry Rice (International Agency for Research on Cancer).



David Tollerud, Chairman




Contents



EXECUTIVE SUMMARY, 1

Organization and Framework, 2

Toxicology Summary, 3

Exposure Assessment, 4

Conclusions About Health Outcomes, 5


The contents of the entire report, from which this Executive Summary has been extracted, are listed below.


2VETERANS AND AGENT ORANGE: PREVIOUS IOM REPORTS

Background

Impact of the Reports

Federal Government's Response to Concerns Over the Military Use of Herbicides in Vietnam


3TOXICOLOGY

Summary

VAO and Update 1996--Overview

Update of the Scientific Literature--Overview

Toxicity Profiles Updates

Issues in Evaluating the Evidence


4METHODOLOGIC CONSIDERATIONS IN EVALUATING THE EVIDENCE

Questions to Be Addressed

Issues in Evaluating the Evidence

Summary of the Evidence


5EXPOSURE ASSESSMENT

Military Use of Herbicides in Vietnam

Occupational and Environmental Exposures to Herbicides and Dioxin

Exposure Assessment for Epidemiology

Exposure Assessment in Studies of Vietnam Veterans

Exposure Assessment in Occupational and Environmental Studies

Review of the Scientific Literature


6EPIDEMIOLOGIC STUDIES

Occupational Studies

Environmental Studies

Vietnam Veterans Studies


7CANCER

Introduction

Gastrointestinal Tract Tumors

Hepatobiliary Cancers

Nasal/Nasopharyngeal Cancer

Laryngeal Cancer

Lung Cancer

Bone Cancer

Soft-Tissue Sarcomas

Skin Cancers

Melanoma

Basal and Squamous Cell (Nonmelanoma) Skin Cancer

Breast Cancer

Cancers of the Female Reproductive System

Prostate Cancer

Testicular Cancer

Urinary Bladder Cancer

Renal Cancer

Brain Tumors

Non-Hodgkin's Lymphoma

Hodgkin's Disease

Multiple Myeloma

Leukemia

Summary


8LATENCY AND CANCER RISK

Analysis of Latency in Epidemiologic Studies

Four Questions Addressed by the Committee

Review of the Scientific Literature

Respiratory Cancer

Prostate Cancer

Non-Hodgkin's Lymphoma

Relevance of Latency in Assessing the Effect of Herbicides on Cancer Risk in

Vietnam Veterans


9REPRODUCTIVE EFFECTS

Introduction

Birth Defects

Fertility

Stillbirth, Neonatal Death, and Infant Death

Low Birthweight and Preterm Birth

Conclusions for Reproductive Effects


10NEUROBEHAVIORAL DISORDERS

Background

Cognitive and Neuropsychiatric Effects

Motor/Coordination Dysfunction

Chronic Persistent Peripheral Neuropathy

Acute and Subacute Transient Peripheral Neuropathy

Conclusions for Neurobehavioral Disorders


11OTHER HEALTH EFFECTS

Introduction

Chloracne

Porphyria Cutanea Tarda

Respiratory Disorders

Immune System Disorders

Diabetes

Lipid and Lipoprotein Disorders

Gastrointestinal and Digestive Disease, Including Liver Toxicity

Circulatory Disorders

Summary



APPENDIXES

A Information Gathering

BICD 9 Codes for Cancer Outcomes

CCommittee and Staff Biographies


INDEX




Executive Summary



Because of continuing uncertainty about the long-term health effects of exposure to the herbicides used in Vietnam, Congress passed Public Law 102-4, the "Agent Orange Act of 1991." This legislation directed the Secretary of Veterans Affairs to request the National Academy of Sciences (NAS) to conduct a comprehensive review and evaluation of scientific and medical information regarding the health effects of exposure to Agent Orange, other herbicides used in Vietnam, and the various chemical components of these herbicides, including dioxin. A committee convened by the Institute of Medicine (IOM) of the NAS conducted this review and in 1994 published a comprehensive report, entitled Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam (henceforth called VAO) (IOM, 1994).

Public Law 102-4 also called for the NAS to conduct subsequent reviews at least every two years for a period of ten years from the date of the first report. The NAS was instructed to conduct a comprehensive review of the evidence that has become available since the previous IOM committee report and to reassess its determinations and estimates of statistical association, risk, and biological plausibility. On completion of VAO, a successor committee was formed that produced Veterans and Agent Orange: Update 1996 (henceforth called Update 1996) (IOM, 1996).

The present IOM report is the second updated review and evaluation of the newly published scientific evidence regarding associations between diseases and exposure to dioxin and other chemical compounds in herbicides used in Vietnam. For each disease, the IOM was asked to determine, to the extent that available data permitted meaningful determinations; (1) whether a statistical association with herbicide exposure exists, taking into account the strength of the scientific evidence and the appropriateness of the statistical and epidemiologic methods used to detect the association; (2) the increased risk of the disease among those exposed to herbicides during Vietnam service; and (3) whether there is a plausible biological mechanism or other evidence of a causal relationship between herbicide exposure and the disease.

In addition to bringing the earlier scientific evidence up to date, the committee has addressed five specific areas of interest identified by the Department of Veterans Affairs (DVA). These are: (1) the relationship between exposure to herbicides and the subsequent development of diabetes; (2) the issue of the latency between exposure to herbicides and development of adverse health outcomes; (3) the classification of chondrosarcomas of the skull; (4) herbicide exposure assessment for Vietnam veterans; and (5) the potential for using data combination methodologies to informatively reexamine existing data on the health effects of herbicide or dioxin exposure..

In conducting its study, the IOM committee operated independently of the DVA and other government agencies. The committee was not asked to and did not make judgments regarding specific cases in which individual Vietnam veterans have claimed injury from herbicide exposure. Rather, the study provides scientific information for the Secretary of Veterans Affairs to consider as the DVA exercises its responsibilities to Vietnam veterans.



ORGANIZATION AND FRAMEWORK


The conclusions in this updated report are based on cumulative evidence from the scientific literature reviewed in VAO and Update 1996. This present update is intended to supplement rather than replace the two previous reports; therefore, much of the information on studies reviewed in those reports has not been repeated. Most chapter begin with brief summaries of the scientific data in VAO and Update 1996, followed by a more thorough discussion of the newly published data and their interpretation. The reader is referred to relevant sections of the previous reports for additional detail and explanation.

Chapter 2 provides an overview of the methods and conclusions of VAO and Update 1996. In addition, it provides a summary of the recent activities of several federal government agencies that are relevant to the health effects of Agent Orange and other herbicides used in Vietnam. Chapter 3 provides an update of the recent experimental toxicology data on the effects of the herbicides and of 2,3,7,8-TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin, commonly referred to as TCDD or "dioxin"), a compound found as a contaminant in the herbicide 2,4,5-trichlorophenoxyacetic acid (2,4,5-T). These data serve as the basis for the biological plausibility of potential health effects in human populations. Chapter 4 describes the methodological considerations that guided the committee's review and its of evaluation. Chapter 5 addresses exposure assessment issues. Chapter 6 provides a general review of the epidemiologic studies used to assess the potential association between herbicides and specific health outcomes. The chapter is organized to reflect similarities and differences in the nature of exposure among three types of study populations: occupationally exposed, environmentally exposed, and Vietnam veterans. Chapter 8 reviews the methods used to study latency, or time-related effects--a topic of special interest to the DVA--and evaluates the evidence on latency for the cancers under study.

Health outcomes are addressed in the remaining chapters: Chapter 7 focuses on cancer outcomes; Chapter 9, on reproductive effects; Chapter 10, on neurobehavioral disorders; and Chapter 11, on other (noncancer) health effects including respiratory, immune system, metabolic, digestive, and circulatory disorders. Many of the same epidemiologic studies were used to assess different types of health outcomes (see Chapter 6).

The committee focused most of its efforts on reviewing and interpreting epidemiologic studies, in order to evaluate the extent to which the scientific literature does or does not suggest that particular human health effects are associated with exposure to herbicides or dioxin. The committee weighed the strengths and limitations of the scientific data in VAO and Update 1996, as well as the newly published scientific data, and reached its conclusions by interpreting the new evidence in the context of the whole of the literature. Each disease has been placed into one of four categories, depending on the strength of evidence for an association (see "Conclusions About Health Outcomes," below). The committee used the same criteria to categorize health outcomes as used in the two previous reports.



TOXICOLOGY SUMMARY


The results of cellular and animal studies published since the release of Update 1996 that investigated the toxicokinetics, mechanism of action, and disease outcomes of TCDD, plus the herbicides themselves are reviewed in Chapter 3.

TCDD elicits a diverse spectrum of biological sex-, strain-, age-, and species-specific effects, including carcinogenicity, immunotoxicity, reproductive or developmental toxicity, hepatotoxicity, neurotoxicity, chloracne, and loss of body weight. These effects vary according to the age, sex, species, and strain of the animals involved. To date, the scientific consensus is that TCDD is not genotoxic and that its ability to influence the carcinogenic process is mediated via epigenetic events such as enzyme induction, cell proliferation, apoptosis, and intracellular communication.

There is evidence that the mechanism by which TCDD induces tumor promotion may involve oxygen radicals. In support of this, other studies have shown that TCDD induction of cancer-causing processes appears to result in a release of oxygen radicals and subsequent oxidative DNA damage that could lead to mutation and cancer. This is also evidence that TCDD tumor promotion may be due to its ability to interfere with intercellular communications.

Low doses of TCDD administered to experimental animals alter the reproductive development and fertility of the progeny. Studies in male rats and hamsters have shown that decreased daily sperm production and cauda epididymal sperm number are some of the most sensitive effects of in utero and lactational TCDD exposure. However, in utero and lactational TCDD exposure does not appear to alter sperm transit time through the whole epididymis. Studies have been conducted to determine whether in utero and lactational TCDD exposure decreases male rat accessory sex organ weights during postnatal development and whether this effect involved decreases in hormone production or metabolism. Results suggest that in utero and lactational TCDD exposure selectively impairs rat prostate growth and development. TCDD exposure in gestating animals results in malformations of the external genitalia, including complete to partial clefting of the phallus. Additionally, functional reproductive alterations in female progeny are observed after TCDD exposure. Moreover, TCDD-mediated inhibition of angiogenesis has been suggested as an important contributor to the embryotoxicity of TCDD.

Animal studies and test-tube studies continue to emphasize the importance of alterations in neurotransmitter systems as underlying mechanisms of TCDD induced behavioral dysfunction. TCDD can affect the metabolism of serotonin, a neurotransmitter in the brain able to modulate food intake. This biochemical change is consistent with observations of progressive weight loss and anorexia in experimental animals exposed to TCDD. In certain brain cells, there is evidence that TCDD may increase the uptake of calcium.

TCDD exposure causes a broad range of immunologic effects in experimental animals. Recent studies support earlier data that TCDD decreases innate immunity and host resistance to pathogenic microorganisms; impairs cell-mediated immune responses, such as the generation and lytic activity of cytotoxic T cells; and suppresses humoral immunity by inhibiting B-lymphocyte differentiation into antibody-producing cells. Despite considerable laboratory research, the mechanisms underlying the immunotoxic effects of TCDD are still unclear. TCDD immunotoxicity appears to be mediated primarily through aryl hydrocarbon receptor (AhR) dependent processes, but some components of immunosuppression have been shown to act independently of the Ah receptor.

Several recent studies have examined the effects of TCDD on specific disease outcomes in animals. Liver enlargement has, for example, been shown to occur following high subchronic doses. The mechanism by which TCDD affects the liver is still under investigation. Recently, TCDD has been shown to inhibit DNA synthesis of liver cells, decrease certain receptors in liver cell membranes, and inhibit liver enzymatic activity. TCDD has also been shown to affect blood serum hormone levels, an outcome thought to be partially due to the action of TCDD on the pituitary gland. TCDD has also been shown to affect the development of skin cells by binding to the AhR. This effect is antagonized by retinoids. Several reports published during the reference period describe developmental deficits in the cardiovascular system of TCDD-treated animals. Evidence suggests that the endothelial lining of blood vessels is a primary target site of TCDD-induced cardiovascular toxicity.

Much research over the past two years has focused on the elucidation of the molecular mechanism of TCDD toxicity. Recent studies confirm earlier findings that the toxic effects of TCDD are caused by the binding of TCDD to the aryl hydrocarbon receptor. TCDD binding to this receptor triggers other effects that result in a toxic sequelae. Structural and functional studies of AhR and its partner protein Arnt indicate that similar protein receptors exist in a number of different species and interact with a number of other proteins to influence receptor function. TCDD may influence the ways in which genes are expressed by binding to the AhR. Researchers have recently bred mice that lack the AhR protein, and it is anticipated that these mice will allow more informative studies of TCDD effects in the future.

The toxicity of the herbicides used in Vietnam remains poorly studied. In general, the herbicides 2,4-D (2,4-dichlorophenoxyacetic acid), 2,4,5-T, cacodylic acid, and picloram have not been identified as particularly toxic substances since high concentrations are often required to modulate cellular and biochemical processes. New reports suggest that 2,4-D may affect the membrane sheath around nerve cells. Other studies support the view that 2,4-D may disrupt cellular processes in the liver, and reports of kidney and muscle damage have been published. A case-control study of dogs exposed to 2,4-D, in addition to other pesticides used in yard work, reported an increase in lymphomas associated with exposure. Some animal studies suggest that 2,4,5-T may alter nerve and muscle function. 2,4,5-T may also induce mutations at different stages of cell development and hinder a cellular process that is involved in the elimination of harmful carcinogens. Limited evidence published during the past two years suggest that cacodylic acid may promote urinary, bladder, kidney, liver, and thyroid gland cancer in some species of animals.



EXPOSURE ASSESSMENT


Assessment of individual exposure to herbicides and dioxin is a key element in determining whether specific health outcomes are linked to these compounds. The committee responsible for producing VAO found, however, that the definition and quantification of exposure are the weakest methodologic aspects of the epidemiologic studies. Although different approaches have been used to estimate exposure among Vietnam veterans, each approach is limited in its ability to determine precisely the intensity and duration of individual exposure.

A separate effort by another Institute of Medicine committee is facilitating the development and evaluation of models of herbicide exposure for use in studies of Vietnam veterans. That committee authored and disseminated a Request for Proposals for exposure assessment research in 1997 (IOM, 1997) and has begun to carry out scientific oversight of the research.

Although definitive data are presently lacking, the available evidence suggests that Vietnam veterans as a group had substantially lower exposure to herbicides and dioxin than did the subjects in many occupational studies. Participants in Operation Ranch Hand and members of the Army Chemical Corps are exceptions to this pattern, and it is likely that there are others who served in Vietnam who had exposures comparable in intensity to members of the occupationally exposed cohorts. Although it is currently not possible to identify this heavily exposed fraction of Vietnam veterans, the exposure assessment research effort presently underway may allow progress to be made on this important question.



CONCLUSIONS ABOUT HEALTH OUTCOMES


Chapters 7, 9, 10, and 11 provide a detailed evaluation of the epidemiologic studies reviewed by the committee and their implications for cancer, reproductive effects, neurobehavioral effects, and other health effects. As detailed in Chapter 4, the committee used the epidemiologic evidence it reviewed to assign each of the health outcomes being studied to one of the four categories listed in Table 1. The definitions of the categories and the criteria for assigning a particular health outcome to them are described in the table, and the specific rationale for each of the findings is detailed in the appropriate health outcomes chapter (Chapters 7, 9, 10, and 11).

Consistent with the mandate of Public Law 102-4, the distinctions between categories are based on "statistical association," not on causality, as is common in scientific reviews. Thus, standard criteria used in epidemiology for assessing causality (Hill, 1971) do not strictly apply. The committee was charged with reviewing the scientific evidence rather than making recommendations regarding DVA policy, and Table 1 is not intended to imply or suggest any policy decisions; these must rest with the Secretary of Veterans Affairs.



Health Outcomes with Sufficient Evidence of an Association


In Update 1996, the committee found sufficient evidence of an association between exposure to herbicides and/or TCDD and four diseases: soft-tissue sarcoma, non-Hodgkin's lymphoma, Hodgkin's disease, and chloracne. The recent scientific literature continues to support the classification of these diseases in the category of sufficient evidence. Based on the recent literature, there are no additional diseases that satisfy this category's criteria--that 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 regards evidence from several small studies that are free from bias and confounding, and that show an association that is consistent in magnitude and direction, as sufficient evidence for an association. The evidence that supports the committee's conclusions for the three cancers is detailed in Chapter 7 and for chloracne in Chapter 11.



TABLE 1 Updated (1998) Summary of Findings in Occupational, Environmental, and Veterans Studies Regarding the Association Between Specific Health Outcomes and Exposure to Herbicides


Sufficient Evidence of an Association

Evidence is sufficient to conclude that there is a positive association. That is, a positive association has been observed between herbicides and the outcome in studies in which chance, bias, and confounding could be ruled out with reasonable confidence. For example, if several small studies that are free from bias and confounding show an association that is consistent in magnitude and direction, there may be sufficient evidence for an association. There is sufficient evidence of an association between exposure to herbicides and the following health outcomes:


Soft-tissue sarcoma Non-Hodgkin's lymphoma Hodgkin's disease Chloracne


Limited/Suggestive Evidence of an AssociationEvidence is suggestive of an association between herbicides and the outcome but is limited because chance, bias, and confounding could not be ruled out with confidence. For example, at least one high-quality study shows a positive association, but the results of other studies are inconsistent. There is limited/suggestive evidence of an association between exposure to herbicides and the following health outcomes:


Respiratory cancers (lung, larynx, trachea) Prostate cancerMultiple myelomaAcute and subacute transient peripheral neuropathySpina bifida in the children of veteransPorphyria cutanea tarda


Inadequate/Insufficient Evidence to Determine Whether an Association ExistsThe available studies are of insufficient quality, consistency, or statistical power to permit a conclusion regarding the presence or absence of an association. For example, studies fail to control for confounding, have inadequate exposure assessment, or fail to address latency. There is inadequate or insufficient evidence to determine whether an association exists between exposure to herbicides and the following health outcomes:


Hepatobiliary cancersNasal/nasopharyngeal cancerBone cancerBreast cancerFemale reproductive cancers (cervical, uterine, ovarian) Urinary bladder cancer (category change in 1998)Testicular cancerLeukemiaSpontaneous abortionBirth defects (other than spina bifida) Neonatal/infant death and stillbirthsLow birthweightChildhood cancer in offspringAbnormal sperm parameters and infertilityMotor/coordination dysfunctionChronic peripheral nervous system disordersMetabolic and digestive disorders (diabetes, changes in liver enzymes, lipid abnormalities, ulcers) Immune system disorders (immune suppression and autoimmunity) Circulatory disordersRespiratory disordersSkin cancers


Limited/Suggestive Evidence of No AssociationSeveral adequate studies, covering the full range of levels of exposure that human beings are known to encounter, are mutually consistent in not showing a positive association between exposure to herbicides and the outcome at any level of exposure. A conclusion of "no association" is inevitably limited to the conditions, level of exposure, and length of observation covered by the available studies. In addition, the possibility of a very small elevation in risk at the levels of exposure studied can never be excluded. There is limited/suggestive evidence of no association between exposure to herbicides and the following health outcomes:


Gastrointestinal tumors (stomach cancer, pancreatic cancer, colon cancer, rectal cancer) Brain tumors


NOTE: "Herbicides" refers to the major herbicides used in Vietnam: 2,4-D (2,4-dichlorophenoxyacetic acid); 2,4,5-T (2,4,5-trichlorophenoxyacetic acid) and its contaminant TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin); cacodylic acid; and picloram. The evidence regarding association is drawn from occupational and other studies in which subjects were exposed to a variety of herbicides and herbicide components.



Health Outcomes with Limited/Suggestive Evidence of Association


In Update 1996, the committee found limited/suggestive evidence of an association for six classes of diseases, three cancers--respiratory (larynx, lung, and trachea) cancer, prostate cancer, and multiple myeloma--and three other health outcomes-- spina bifida in the children of veterans, acute and subacute (transient) peripheral neuropathy, and porphyria cutanea tarda. The recent scientific literature continues to support the classification of these diseases in the limited/suggestive category of sufficient evidence. Based on the recent literature, there are no additional diseases that satisfy this category's criteria.

For outcomes in this category, the evidence must be suggestive of an association with herbicides, but the association may be limited because chance, bias, or confounding could not be ruled out with confidence. Typically, at least one high-quality study indicates a positive association, but the results of other studies may be inconsistent.

Since the last update, there have been several studies of respiratory cancer among occupationally exposed groups and Vietnam veterans. Newly published studies of phenoxy herbicide production workers (Kogevinas et al., 1997) and workers exposed as a result of an industrial accident (Ott and Zober, 1996) show small but statistically significant excesses of lung cancer mortality. Results in both studies indicate higher estimated risk for individuals with higher estimated exposure. One other occupational study (Ramlow et al., 1996) reports a relative risk indistinguishable from 1. A study of rice farmers in Italy (Gambini et al., 1997) found lower lung cancer incidence than observed in the general population, a result similar to that found in studies of U.S. farmers, which may reflect lower incidence of smoking in this occupational group. New data from the Seveso accident (Bertazzi et al., 1997) do not indicate any increase in lung cancer mortality in this environmentally exposed group, but an insufficient number of years have passed since exposure to draw conclusions about any effect that the accidental exposure may have had. Increases in respiratory cancers were seen in new studies of U.S. and Australian Vietnam veterans, although there is evidence that cigarette smoking was more prevalent among Vietnam veterans than among non-Vietnam veterans or the general public. In summary, the most recently published studies continue to support placing respiratory cancers in the category of limited/suggestive evidence. Although smoking undoubtedly plays a role in these cancers, the consistency of the finding across several studies argues against the notion that it is the sole explanatory factor.

New studies of production workers continue to show weak but consistent evidence of effects on prostate cancer mortality, whereas new research on agricultural workers shows no indication of increased risk. A detailed and well-conducted analysis of Australian male Vietnam veterans' mortality (Crane et al., 1997) found a statistically significant relationship between Vietnam service and prostate cancer. The committee's summary evaluation, based on all of the epidemiologic evidence, was that the data continue to support the classification of prostate cancer in the limited/suggestive category.

The evidence that supports the committee's conclusions for multiple myeloma is detailed in Chapter 7 and is not substantially changed from Update 1996.

In Update 1996 the committee identified three studies of the offspring of Vietnam veterans that were suggestive of an association between exposure to the herbicides considered in this report and spina bifida, although a number of methodologic issues limited the interpretation of these results. Since the publication of that report, occupational studies of the offspring of fathers employed in British Columbia sawmills (Dimich-Ward et al., 1996) and the offspring of Norwegian farmers (Kristensen et al., 1997), and a multicenter case-control study of paternal occupation and risk of spina bifida conducted in the Netherlands (Blatter et al., 1997), have provided some additional support for the association with this specific birth defect, although concerns remain including control of confounding, exposure determination, and isolation of exposure to specific herbicides and TCDD.

No additional evidence has been published since Update 1996 regarding acute and subacute transient peripheral neuropathy or porphyria cutanea tarda.



Health Outcomes with Inadequate/Insufficient Evidence to Determine
Whether an Association Exists


The scientific data for the many of the cancers and other diseases reviewed by the committee were inadequate or insufficient to determine whether an association exists. For cancers in this category, the available 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 or have inadequate exposure assessment. This group includes hepatobiliary cancers (cancers of the liver and intrahepatic bile duct), nasal and nasopharyngeal cancer, bone cancer, skin cancers (including basal cell carcinoma, squamous cell carcinoma, and non-melanocytic skin cancers), breast cancer, cancers of the female reproductive system (including cervix, endometrium, and ovaries), testicular cancer, urinary bladder cancer, renal cancer (cancers of the kidney and renal pelvis), and leukemias. The scientific evidence regarding each of these cancers is detailed in Chapter 7.

Based on an evaluation of all the epidemiologic evidence, including studies published since the release of Update 1996, the committee felt that urinary bladder cancer should be added to this category. Although there is no evidence that exposure to herbicides or dioxin is related to this cancer, relative risks in some of the largest cohorts tended to be greater than one, weakening the committee's prior conclusion that there was positive evidence of no relationship. The co-exposure to TCDD and a variety of known bladder carcinogens makes it very difficult to isolate any possible additional effect of herbicides, although little total effect was seen.

A recent community based case-control study examining herbicide exposure and skin cancers drew the attention of the committee (Gallagher et al, 1996). This study, which controlled for a number of factors known to influence skin cancer rates, found increasing risk of squamous cell carcinoma with increasing lifetime exposure to herbicides. Although there are concerns regarding the study's control of confounding and the adequacy of the exposure assessment, the committee concluded that the study was the best of its kind to date. The available evidence is insufficient to determine whether an association exists between herbicide exposure and any of the forms of skin cancer. However, the committee encourages further study of basal and squamous cell skin cancer incidence among working and Vietnam veteran populations. In any future studies, careful attention should be paid to exposure assessment, as well as to controlling for confounding from UV exposures. Efforts to examine the carcinogenicity of organic arsenicals are also encouraged.

Several reproductive effects are classified in this category, including spontaneous abortion, birth defects other than spina bifida, neonatal or infant death and stillbirths, low birthweight, childhood cancer in offspring, and abnormal sperm parameters and infertility. The scientific evidence for reproductive effects is detailed in Chapter 9. Neurobehavioral effects that are classified in this category include cognitive and neuropsychiatric disorders, motor or coordination dysfunction, and chronic peripheral nervous system disorders. The scientific evidence for these effects is detailed in Chapter 10.

Other health effects that are classified in this category include metabolic and digestive disorders, immune system disorders, circulatory disorders, and respiratory disorders. The scientific evidence for these effects is detailed in Chapter 11. Diabetes is a health outcome of special interest to the DVA. When viewed in the context of the total literature the committee concludes that, at this time, there is inadequate/insufficient evidence to determine whether an association exists between herbicide or dioxin exposure and increased risk of diabetes. Further analyses and full publication of existing studies may justify a reevaluation of this conclusion.

Many animal studies provide potential biological mechanisms for an association between herbicide exposure and diabetes risk. Although the majority of earlier reports on humans suggest little association, the potentially more definitive 1997 report from the Ranch Hand study (Henriksen et al., 1997) raises the possibility that the highest-exposure group (highest TCDD level) may have an increased risk. Such a conclusion may be supported by the currently unpublished NIOSH study of exposed workers. It is important to note that both these studies used serum TCDD levels as the measure of exposure. At this time, questions concerning case definition and full control for obesity, or other confounders (in the Ranch Hand study) preclude determining whether or not an association exists between herbicide exposure and diabetes in these studies. The committee strongly urges that the NIOSH study be documented more completely and published in the peer-reviewed literature, so that its potentially important findings can be evaluated fully. It strongly recommends that the Ranch Hand study develop a fully adjusted multivariate model (e.g., Cox Proportional Hazard with time to diabetes as the outcome), fully controlling for baseline age and obesity (BMI) and, if possible, for family history of diabetes, central fat distribution, diabetogenic drug exposure, and a measure of obesity at the time of Vietnam service. The committee recommends consideration given to a combined analysis of the Ranch Hand and NIOSH studies to further examine the possibility that herbicide exposure leads to an increased risk of diabetes.



Health Outcomes with Limited/Suggestive Evidence of No Association


In VAO, the committee found a sufficient number and variety of well-designed studies to conclude that there is limited/suggestive evidence of no association between a small group of cancers and exposure to TCDD or herbicides. This group includes gastrointestinal tumors (colon, rectal, stomach, and pancreatic) and brain tumors. Recent scientific evidence continues to support the classification of such cancers in this category and is detailed in Chapter 7. Based on the recent literature, there are no additional diseases that satisfy the criteria necessary for this category.

For outcomes in this category, several adequate studies covering the full range of levels of herbicide exposure that human beings are known to encounter are mutually consistent in not showing a positive association between exposure and health risk at any level of exposure. These studies have relatively narrow confidence intervals. A conclusion of "no association" is inevitably limited to the conditions, level of exposure, and length of observation covered by the available studies. In addition, the possibility of a very small elevation in risk at the levels of exposure studied can never be excluded.



The Relationship Between the Length of Time Since Exposure and the
Possible Risk of Cancer Development


The importance of latency effects and other time-related factors in determining cancer risk has long been recognized, and statistical methodologies have been developed to study this issue. A variety of practical difficulties relating to exposure assessment and other data requirements, however, have limited the use of these methods in epidemiologic studies of environmental carcinogens. In response to the request from the DVA to explore latency issues related to herbicides used in Vietnam, the committee attempts in Chapter 8 to establish a methodology to address the timing of herbicide exposure and the risk of cancer. This chapter also reviews the literature on herbicide exposure and some cancers for results that describe how the timing of exposure affects the relative risk due to exposure.

One of the committee's tasks was to assess the likelihood that exposure to herbicides used in Vietnam resulted in or will result in increased risk of disease in Vietnam veterans. Currently, any such inference would have to be based on extrapolation from the findings about disease experience of other groups exposed to TCDD or herbicides generally. Given that we know when the potential exposure to TCDD and other herbicides used in Vietnam began and ended, it would appear reasonable to examine time-related factors for those who served in Vietnam, but to date, no adequate analysis of time-related factors for cancer occurrence in Vietnam veterans has been published. Extrapolation from other types of studies is problematic for several reasons. Brief exposures, such as occurred in Seveso, and chronic occupational exposures may not apply to Vietnam veterans because of the different exposure situation. For example, there is evidence in the literature (e.g., for respiratory cancer) that latency can vary not only among individuals, but also according to other aspects of the exposure scenario, such as the magnitude of exposure. Thus, if high exposures in an occupational setting result in a certain pattern of relative risks for a given time since first exposure, this pattern may not hold for lower level exposures such as occurred in Vietnam. Similarly, direct evidence was not presented to evaluate the impact of age at exposure to herbicides. It is possible that the age at which exposure was received could influence the pattern of latency that would be observed (e.g., exposures incurred at younger ages could be more potent, but the impact might not be seen for a longer time period; conversely, exposures at older ages might be more harmful, particularly in the short run). Unfortunately, the data are not available to evaluate the hypothesis that age at exposure is important. A major limitation of the analyses discussed in this chapter is the failure of most studies to conduct analyses of latency that also controlled for factors such as duration of exposure, age, and calendar time of exposure (or analyses of age at exposure that controlled for time since exposure), particularly for occupational cohorts with protracted exposure periods.

Another consideration is the long retention time of TCDD and other highly chlorinated herbicides. Since body burdens from any exposure, no matter how brief, result in continuing exposures to internal organs, the concept of time since exposure ended has a different meaning than for chemical agents that are eliminated quickly.

A third issue concerns the distinction between morbidity and mortality. As discussed in this chapter, the latency between exposure and death is composed of two parts: (1) latency until disease appears and (2) time between disease occurrence and death. For diseases with low survival rates, such as respiratory cancer, the time between disease occurrence and death is generally short; therefore, a study focusing on mortality will give a good approximation of the latency period. However, for diseases that are not always fatal or that have a long survival time such as prostate cancer, it is preferable to examine incidence rather than mortality. Thus, further data on prostate cancer incidence would be of great help, since relatively few men with prostate cancer die from it.

Overall, the data on latency do not alter the committee's conclusions with regard to the categories of evidence for individual cancer sites, but they do provide some information on how long the effects of herbicide exposures last. The evidence suggests that if respiratory cancer does result from exposure to herbicides used in Vietnam, the greatest relative risk for lung cancer may be in the first decade after exposure, but until further follow-up has been carried out for some of the cohorts, it will not be possible to put an upper limit on the length of time these herbicides could exert their effect. For prostate cancer, the published data are largely uninformative, and conclusions must await more definitive studies, preferably using incidence rather than mortality. For non-Hodgkin's lymphoma, effects are seen in the second decade after exposure begins and continue to be observed more than 20 years after external exposure ends. Because of the long retention times of TCDD, internal exposures can continue long after external exposures cease.



Increased Risk of Disease Among Vietnam Veterans


One of the three primary charges contained in the Agent Orange Act of 1991 (Public Law 102-4, subsequently codified as 38 USC Sec. 1116) states:


For each disease reviewed, the Academy shall determine (to the extent that available scientific data permit meaningful determinations) . . . the increased risk of the disease among those exposed to herbicides during service in the Republic of Vietnam during the Vietnam era. . . .


Although there have been numerous health studies of Vietnam veterans, most have been hampered by relatively poor measures of exposure to herbicides or TCDD, in addition to other methodological problems. Most of the evidence on which the findings regarding disease association are based comes from studies of people exposed to dioxin or herbicides in occupational and environmental settings, rather than from studies of Vietnam veterans. The committee found this body of evidence sufficient for reaching the conclusions about statistical associations between herbicides and the health outcomes. However, the lack of adequate data on Vietnam veterans per se complicates the quantification of any increased risk of disease among individuals exposed to herbicides during service in Vietnam. Given the large uncertainties that remain about the magnitude of potential risk from exposure to herbicides in the epidemiologic studies that have been reviewed (Chapters 7, 9, 10, and 11), the inadequate control for other important risk factors, and the uncertainty about the nature and magnitude of exposure to herbicides in Vietnam (Chapter 5), the necessary information to undertake a quantitative risk assessment is lacking.

Thus, the committee cannot quantify the degree of risk likely to be experienced by those exposed to herbicides during service in the Republic of Vietnam during the Vietnam era. For those outcomes in the "Sufficient" and "Limited/Suggestive" categories, what can be said is that too little is known about the herbicide exposure of veterans to make a meaningful determination of the increased risk, if any, of these outcomes among Vietnam veterans. As discussed above, the epidemiologic analyses to date have many limitations which prevent a more quantitative exposure-response analysis. Where there is inadequate/insufficient evidence to determine whether an association exists between herbicide exposure and a particular health outcome, there is also inadequate/insufficient information to assess the increased risk, if any, of that outcome. Finally, a finding of "limited/suggestive evidence of no association" between herbicide exposure and a health outcome means that the evidence suggests there is no increased risk of that outcome among Vietnam veterans. These conclusions are inevitably limited to the conditions, level of exposure, and length of observation covered by the studies reviewed by the committee. There are certain diseases where the committee can draw more specific conclusions, and this information is related in the discussion of those diseases.



References


Blatter BM, Hermens R, Bakker M, Roeleveld N, Verbeek AL, Zielhuis GA. 1997. Paternal occupational exposure around conception and spina bifida in offspring. American Journal of Industrial Medicine 32(3):283-291.

Bertazzi PA, Zochetti C, Guercilena S, Consonni D, Tironi A, Landi MT, Pesatori AC. 1997. Dioxin exposure and cancer risk: A 15-year mortality study after the "Seveso Accident." Epidemiology 8(6):646-652.

Crane PJ, KD Horsley, Adena MA. 1997. Mortality of Vietnam veterans: the veteran cohort study: A report of the 1996 retrospective cohort study of Australian Vietnam veterans. Canberra: Department of Veterans Affairs.

Dimich-Ward H, Hertzman C, Teschke K, Hershler R, Marion SA, Ostry A, Kelly S. 1996. Reproductive effects of paternal exposure to chlorophenate wood preservatives in the sawmill industry. Scandinavian Journal of Work, Environment and Health 22:267-273.

Gallagher RP, Bajdik CD, Fincham S, Hill GB, Keefe AR, Coldman A, McLean DI. 1996. Chemical exposures, medical history, and risk of squamous and basal cell carcinoma of the skin. Cancer Epidemiology, Biomarkers and Prevention 5(6):419-424.

Gambini GF, Mantovani C, Pira E, Piolatto PG, Negri E. 1997. Cancer mortality among rice growers in Novara Province, Northern Italy. American Journal of Industrial Medicine 31:435-441.

Henriksen GL, Ketchum NS, Michalek JE, Swaby JA. 1997. Serum dioxin and diabetes mellitus in veterans of operation ranchhand. Epidemiology 8:252-258.

Hill, AB. 1971. Principles of Medical Statistics, 9th ed. New York: Oxford University Press.

Institute of Medicine (IOM). 1994. Veterans and Agent Orange Health Effects of Herbicides Used in Vietnam. Washington, DC: National Academy Press.

Institute of Medicine. 1996. Veterans and Agent Orange: Update 1996. Washington, DC: National Academy Press.

Institute of Medicine. 1997. Characterizing Exposure of Veterans to Agent Orange and Other Herbicides Used in Vietnam: Scientific Considerations Regarding a Request for Proposals for Research. Washington, DC: National Academy Press.

Kogevinas M, Becher H, Benn T, Bertazzi PA, Boffetta P, Bueno-de-Mesquita HB, Coggon D, Colin D, Flesch-Janys D, Fingerhut M, Green L, Kauppinen T, Littorin M, Lynge E, Mathews JD, Neuberger M, Pearce N, Saracci R. 1997. Cancer mortality in workers exposed to phenoxy herbicides, chlorophenols, and dioxins. An expanded and updated international cohort study. American Journal of Epidemiology 145(12):1061-1075.

Kristensen P, Irgens LM, Andersen A, Bye AS, Sundheim L. 1997. Birth defects among offspring of Norwegian farmers, 1967-1991. Epidemiology 8(5):537-544.

Ott MG, and Zober A. 1996. Cause specific mortality and cancer incidence among employees exposed to 2,3,7,8-TCDD after a 1953 reactor accident. Occuptional and Environmental Medicine 53:606-612.

Ramlow JM, Spadacene NW, Hoag SR, Stafford BA, Cartmill JB, Lerner PJ. 1996. Mortality in a cohort of pentachlorophenol manufacturing workers, 1940-1989. American Journal of Industrial Medicine 30:180-194.


Update: June 6, 2012

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