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Veterans
and Agent
Orange
Length of Presumptive Period for
Association Between Exposure
and Respiratory Cancer
Committee to Review the Health Effects in
Vietnam Veterans of Exposure to Herbicides
Board on Health Promotion and Disease Prevention
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THE NATIONAL ACADEMIES PRESS 500 Fifth Street, NW Washington, DC 20001
NOTICE: 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 Insti-
tute of Medicine. The members of the committee responsible for the report were chosen
for their special competences and with regard for appropriate balance.
Support for this project was provided by the US Department of Veterans Affairs. The
project was supported by Cooperative Agreement V101(93)P-1637 between the National
Academy of Sciences and the US Department of Veterans Affairs. The views presented in
this report are those of the Institute of Medicine Committee to Review the Health Effects
in Vietnam Veterans of Exposure to Herbicides and are not necessarily those of the
funding agency.
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Copyright 2004 by the National Academy of Sciences. All rights reserved.
Printed in the United States of America.
The serpent has been a symbol of long life, healing, and knowledge among almost all
cultures and religions since the beginning of recorded history. The serpent adopted as a
logotype by the Institute of Medicine is a relief carving from ancient Greece, now held by
the Staatliche Museen in Berlin.
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"Knowing is not enough; we must apply.
Willing is not enough; we must do."
--Goethe
Adviser to the Nation to Improve Health
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The National Academy of Sciences is a private, nonprofit, self-perpetuating society of
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furtherance of science and technology and to their use for the general welfare. Upon the
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Bruce M. Alberts is president of the National Academy of Sciences.
The National Academy of Engineering was established in 1964, under the charter of the
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The Institute of Medicine was established in 1970 by the National Academy of Sciences
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The National Research Council was organized by the National Academy of Sciences in
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chair and vice chair, respectively, of the National Research Council.
www.national-academies.org
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COMMITTEE TO REVIEW THE HEALTH EFFECTS IN
VIETNAM VETERANS OF EXPOSURE TO HERBICIDES
Irva Hertz-Picciotto, PhD (Chair), Professor, Department of Epidemiology
and Preventive Medicine, University of California, Davis, California
Kiros T. Berhane, PhD, Assistant Professor, Department of Preventive
Medicine, University of Southern California, Los Angeles, California
Margit L. Bleecker, MD, PhD, Director, Center for Occupational and
Environmental Neurology, Baltimore, Maryland
Paul F. Engstrom, MD, Senior Vice President and Medical Director, Fox
Chase Network, Philadelphia, Pennsylvania
Richard A. Fenske, PhD, MPH, Professor, Environmental Health, Industrial
Hygiene and Safety Program, University of Washington, Seattle,
Washington
Thomas A. Gasiewicz, PhD, Professor and Chair of Environmental Medicine
and Director of the Environmental Health Sciences Center, University of
Rochester, Rochester, New York
Tee L. Guidotti, MD, MPH, Professor and Chair of the Department of
Environmental and Occupational Health, The George Washington
University School of Public Health and Health Services, Washington, DC
Loren D. Koller, DVM, PhD, Consultant, Environmental Health and
Toxicology, Corvallis, Oregon
John J. Stegeman, PhD, Senior Scientist and Chair of the Biology
Department, Woods Hole Oceanographic Institution, Woods Hole,
Massachusetts
David S. Strogatz, PhD, MSPH, Associate Professor and Chair of
Epidemiology, School of Public Health, State University of New York at
Albany, New York
Staff
Michelle C. Catlin, Study Director
Jennifer A. Cohen, Research Associate
Elizabeth J. Albrigo, Project Assistant
Joe A. Esparza, Senior Project Assistant
Norman Grossblatt, Senior Editor
Rose Marie Martinez, Director, Board on Health Promotion and Disease
Prevention
v
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Reviewers
T his report has been reviewed in draft form by persons chosen for their
diverse perspectives and technical expertise, in accordance with proce-
dures approved by the National Research Council's Report Review Com-
mittee. The purpose of this independent review is to provide candid and critical
comments that will assist the institution in making its published report as sound
as possible and to ensure that the report meets institutional standards of objectiv-
ity, 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 review of this
report:
Michael Bates, PhD, MPH, School of Public Health, University of Califor-
nia, Berkeley
Mark D. Eisner, MD, MPH, Department of Medicine, University of Califor-
nia, San Francisco
Philip C. Nasca, PhD, School of Public Health and Health Sciences, Univer-
sity of Massachusetts, Amherst
Tim Ramsay, PhD, Institute of Population Health, University of Ottawa
Andrew Salmon, MA, DPhil, Office of Environmental Health Hazard As-
sessment, California Environmental Protection Agency
Judith T. Zelikoff, PhD, Institute of Environmental Medicine, New York
University School of Medicine
Although the reviewers listed above have provided many constructive com-
ments and suggestions, they were not asked to endorse the conclusions or recom-
vii
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viii REVIEWERS
mendations, nor did they see the final draft of the report before its release. The
review of this report was overseen by David J. Tollerud, MD, MPH, of the
Institute of Public Health Research at the University of Louisville. Appointed by
the Institute of Medicine, he was responsible for making certain that an indepen-
dent examination of this report was carried out in accordance with institutional
procedures and that all review comments were carefully considered. Responsi-
bility for the final content of this report rests entirely with the author committee
and the institution.
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Preface
I n 1991, because of continuing uncertainty about the long-term health effects
on Vietnam veterans who where exposed to herbicides during their service
in Vietnam (mixtures of 2,4-dichlorophenoxyacetic acid [2,4-D], 2,4,5-tri-
chlorophenoxyacetic acid [2,4,5-T], picloram, and cacodylic acid), Congress
passed Public Law 102-4, the Agent Orange Act of 1991. That legislation di-
rected the secretary of veterans affairs to ask the National Academy of Sciences
(NAS) to perform a comprehensive evaluation of scientific and medical informa-
tion regarding the health effects of exposure to Agent Orange, other herbicides
used in Vietnam, and the various chemical components of those herbicides, in-
cluding 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The secretary was also to
ask NAS to conduct updates at least every 2 years for 10 years from the date of
the first report to review newly available literature and draw conclusions from
the overall evidence.
In response to the request, the Institute of Medicine (IOM) of NAS con-
vened a committee, whose conclusions IOM published in 1994 in Veterans and
Agent Orange: Health Effects of Herbicides Used in Vietnam (hereafter referred
to as VAO). The work of later committees resulted in the publication of biennial
updates (Update 1996, Update 1998, Update 2000, and Update 2002) and of
focused reports reviewing the scientific evidence regarding type 2 (non-insulin-
dependent) diabetes (Type 2 Diabetes) and acute myelogenous leukemia in chil-
dren (Acute Myelogenous Leukemia).
VAO concluded that there is "limited/suggestive" evidence of an association
between exposure to at least one of the chemicals of interest (2,4-D, 2,4,5-T and
its contaminant TCDD, picloram, and cacodylic acid) and respiratory cancer.
ix
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x PREFACE
That conclusion was reaffirmed in Update 1996, Update 1998, Update 2000, and
Update 2002.
The Department of Veterans Affairs (VA), on the basis of the findings of
VAO and its own review of the available literature, published a notice in the
Federal Register on February 3, 1994, stating that there is "a positive association
between exposure to herbicides used in the Republic of Vietnam and the subse-
quent development of respiratory cancers." The VA further found that "the
weight of the available evidence indicates that chemically-induced respiratory
cancers manifest within a definitive period following exposure, after which there
is little effect from the exposure," and proposed, as part of its rule, that respira-
tory cancer will be presumed service connected only if it is manifest within 30
years after exposure.
In the Veterans Education and Benefits Expansion Act of 2001, Public Law
107-103, Congress removed the 30-year presumptive period for respiratory can-
cer and mandated that the secretary of veterans affairs ask NAS to conduct a
study. That study was to review "available scientific literature on the effects of
exposure to an herbicide agent containing dioxin on the development of respira-
tory cancers in humans." And to review "whether it is possible to identify a
period of time after exposure to herbicides after which a presumption of service-
connection" of respiratory cancer would not be warranted.
To complete this task, the IOM called upon the Update 2002 committee to
extend its service and address this issue. This committee consists of members
who 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 TCDD exposure. Biographical sketches of committee members and
staff appear in the appendix.
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 closed sessions and working group meetings
in which members could freely examine, characterize, and weigh the strengths
and limitations of the evidence.
The committee is grateful to Michelle Catlin who skillfully served as the
study director for this project. The committee would also like to acknowledge
the excellent work of IOM staff members Jennifer Cohen, Joe Esparza, and
Elizabeth Albrigo. Thanks are also extended to Jim Banihashemi, who handled
the finances for the project; Norman Grossblatt, who provided excellent editorial
skills; and William McLeod, who conducted database searches.
Irva Hertz-Picciotto, Chair
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Contents
EXECUTIVE SUMMARY 1
Charge to the Committee, 2
Committee's Approach to the Charge, 3
Epidemiologic Evidence, 3
Other Evidence, 5
Uncertainty, 6
Committee's Conclusions on Presumptive Period, 7
1 INTRODUCTION 9
Charge to the Committee, 10
Committee's Approach to the Charge, 11
Previous Conclusion Regarding Respiratory Cancer, 11
Evaluations of Latency by Previous Committees, 11
Organization of This Report, 12
References, 12
2 EVALUATION OF LATENT AND PRESUMPTIVE PERIODS 14
Latent Period vs Presumptive Period, 14
Factors That Affect Time Course of Disease, 18
Carcinogenicity of TCDD, 23
Analysis of Latent Period and Presumptive Period, 25
Latency and Respiratory Cancer, 33
Summary and Conclusions, 36
References, 37
xi
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xii CONTENTS
3 EPIDEMIOLOGIC STUDIES 40
Review of Studies, 41
Summary, 47
References, 49
4 CONCLUSIONS 51
Data for Estimation of Presumptive Period, 51
Uncertainty, 53
Committee's Conclusions on Latent Period and Presumptive Period, 55
References, 55
APPENDIX COMMITTEE AND STAFF BIOGRAPHIES 57
