Categorization of the Associations Between Exposure to the Herbicides Used in Vietnam or Their Conta

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Categorization of the Associations Between
Exposure to the Herbicides Used in Vietnam or
Their Contaminants and Health Outcomes J. Cohen,
M. B. Paxton Institute of Medicine, The National
Academies, Washington DC, USA
VETERANS AND AGENT ORANGE UPDATE 2004 COMMITTEE
MEMBERS JOHN J. STEGEMAN, (Chair), Senior
Scientist and Chair of the Biology Department,
Woods Hole Oceanographic Institution, Woods Hole,
Massachusetts KIROS T. BERHANE, Assistant
Professor, Department of Preventive Medicine,
University of Southern California, Los Angeles,
California PAUL F. ENGSTROM, Senior Vice
President and Medical Director, Fox Chase
Network, Philadelphia, Pennsylvania RICHARD A.
FENSKE, Professor, Environmental Health,
Industrial Hygiene and Safety Program, University
of Washington, Seattle, Washington JORDAN
FIRESTONE, Assistant Professor of Neurology,
Clinic Director of Occupational and Environmental
Medicine, University of Washington, Seattle,
Washington THOMAS A. GASIEWICZ, Professor and
Chair of Environmental Medicine and Director of
the Environmental Health Sciences Center,
University of Rochester, Rochester, New
York CLAUDIA HOPENHAYN, Assistant Professor,
College of Public Health, University of Kentucky,
Lexington, Kentucky LOREN D. KOLLER, Consultant,
Environmental Health and Toxicology, Corvallis,
Oregon NANCY I. KERKVLIET, Professor, Department
of Environmental and Molecular Toxicology, Oregon
State University, Corvallis, Oregon JOEL
MCCULLOUGH, Medical Director of Environmental
Health, Chicago Department of Health, Chicago,
Illinois DAVID S. STROGATZ, Associate Professor
and Chair of Epidemiology, School of Public
Health, State University of New York at Albany,
New York
ABSTRACT Between 1962 and 1971, United States
military forces sprayed herbicides over Vietnam.
Because of ongoing uncertainty about the
long-term health effects on Vietnam veterans of
the herbicides sprayed, Congress passed the Agent
Orange Act of 1991. That legislation directed the
Secretary of Veterans Affairs to request the
National Academy of Sciences, a non-profit
organization that provides independent, objective
advice on scientific issues, to perform 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 those herbicides,
including dioxin. The first comprehensive review
was published in 1994 and biennial updates have
integrated all subsequent and relevant
peer-reviewed information. In assessing the
evidence for an association of a health outcome
with exposure to the herbicides or their
components with a health outcome, the committee
responsible for the report reviews the available
literature and categorize the evidence as 1)
sufficient for an association 2) suggestive of
an association 3) inadequate or insufficient to
determine whether an association exists or 4)
suggestive of NO association. In addition,
conclusions regarding the biological plausibility
of the health effects and the risk to Vietnam
veterans are made. The latest reports, Veterans
and Agent Orange Update 2006, will be released
in the Spring of 2007. The assessments in the
reports are used by the Department of Veterans
Affairs to make policy decisions regarding
compensation to veterans for service-related
illnesses.
VETERANS AND AGENT ORANGE UPDATE 2004
COMMITTEES CONCLUSIONS Sufficient Evidence of
an Association Chronic lymphocytic leukemia (CLL)
Soft-tissue sarcoma Non-Hodgkins
lymphoma Hodgkins disease Chloracne Limited or
Suggestive Evidence of an Association Respiratory
cancer (lung or bronchus, larynx, and
trachea) Prostate cancer Multiple
myeloma 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 Oral, nasal, and
pharyngeal cancer Bone and joint cancer Skin
cancers (melanoma, basal, and squamous
cell) Breast cancer Female reproductive cancer
(cervix, uterus, ovary) Testicular cancer Urinary
bladder cancer Renal cancer Leukemia (other than
CLL) 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 Neurobehavioral disorders (cognitive
and neuropsychiatric) Movement disorders,
including Parkinsons disease and amyotrophic
lateral sclerosis (ALS) Chronic peripheral
nervous system disorders Respiratory
disorders Gastrointestinal, metabolic, and
digestive disorders (changes in liver enzymes,
lipid abnormalities, ulcers) Immune system
disorders (immune suppression, autoimmunity) Circu
latory disorders AL amyloidosis Endometriosis Effe
cts on thyroid homeostasis Limited or
Suggestive Evidence of No Association Gastrointest
inal tumors (stomach, pancreas, colon,
rectum) Brain tumors

• GENERAL BACKGROUND
• The National Academy of Sciences (The National
  Academies) was chartered by the US Congress in
  1863 as an independent non-governmental
  institution
• ... the Academy shall, whenever called upon by
  any department of the Government, investigate,
  examine, experiment, and report upon any subject
  of science or art .
• The Institute of Medicine is a component of The
  National Academies, chartered in 1970
• ...to enlist distinguished members of the
  medical and other professions in the study of
  problems that affect the publics health.
• The institution works with committees comprised
  of experts who volunteer to prepare consensus
  reports that provide scientific background for
  decisions made by government agencies and others.
  The reports are subject to peer review prior to
  release and are released as final reports.

VETERANS AND AGENT ORANGE UPDATE 2006 COMMITTEE
MEMBERS JOHN J. STEGEMAN, (Chair), Senior
Scientist and Chair of the Biology Department,
Woods Hole Oceanographic Institution, Woods Hole,
Massachusetts RICHARD A. FENSKE, Professor,
Environmental Health, Industrial Hygiene and
Safety Program, University of Washington,
Seattle, Washington PETER GANN, Professor,
University of Illinois, Chicago, Illinois JORDAN
FIRESTONE, Clinic Director of Occupational and
Environmental Medicine, University of Washington,
Seattle, Washington MARK GOLDBERG, Associate
Professor, McGill University, Montreal,
Quebec CLAUDIA HOPENHAYN, Professor, College of
Public Health, University of Kentucky, Lexington,
Kentucky NANCY I. KERKVLIET, Professor,
Department of Environmental and Molecular
Toxicology, Oregon State University, Corvallis,
Oregon LINDA A. MCCAULEY, Professor, School of
Nursing, University of Pennsylvania,
Philadelphia, Pennsylvania DEJURAN RICHARDSON,
Professor, Mathematics and Computer Science, Lake
Forest College, Lake Forest, Illinois HOLLIE I.
SWANSON, Associate Professor, Pharmacology,
University of Kentucky College of Medicine,
Lexington, Kentucky MARY K. WALKER, Associate
Professor, Pharmacology and Toxicology,
University of New Mexico, Albuquerque, New
Mexico STEPHEN D. WALTER, Professor, Clinical
Epidemiology and Biostatistics, McMaster
University, Hamilton, Ontario

• VETERANS AND AGENT ORANGE SERIES BACKGROUND
• From 1962 to 1971, US military forces sprayed
  herbicides over Vietnam to strip the thick jungle
  canopy that helped conceal opposition forces, to
  destroy crops that enemy forces might depend on,
  and to clear tall grasses and bushes from the
  perimeters of US base camps and outlying
  fire-support bases.
• Mixtures of 2,4-dichlorophenoxyacetic acid
  (2,4-D), 2,4,5-trichlorophenoxyacetic acid
  (2,4,5-T), picloram, and cacodylic acid made up
  the majority of the herbicides sprayed. At the
  time of the spraying, 2,3,7,8-tetrachlorodibenzo-p
  -dioxin (TCDD, one form of dioxin) was an
  unintended contaminant from the production of
  2,4,5-T.
• In 1991, because of continuing uncertainty about
  the long-term health effects on Vietnam veterans
  of the herbicides sprayed, Congress passed Public
  Law 102-4 (PL 102-4), the Agent Orange Act of
  1991. That legislation directed the Secretary of
  Veterans Affairs to ask the National Academy of
  Sciences (NAS) to perform a comprehensive
  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 those herbicides,
  including TCDD. The secretary was also to ask
  that NAS 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. The
  Veterans Education and Benefits Expansion Act of
  2001 extended the updates until 2014.
• In response to the request, the Institute of
  Medicine (IOM) of NAS convened 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, Update 2002, and Update
  2004) and focused reports reviewing the
  scientific evidence regarding type 2 (non-insulin
  dependent) diabetes (Type 2 Diabetes), and acute
  myelogenous leukemia in children (Acute
  Myelogenous Leukemia). Veterans and Agent Orange
  Update 2004 was the fifth review of published
  scientific evidence regarding associations
  between health outcomes and exposure to TCDD and
  other chemical compounds in herbicides used in
  Vietnam. Veterans and Agent Orange Update 2006
  will be the sixth review.

CATEGORIES OF EVIDENCE 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 of an association.
Limited or Suggestive Evidence of an
Association Evidence 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. Inadequate or Insufficient
Evidence To Determine Whether an Association
Exists 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, have inadequate
exposure assessment, or fail to address latency.
Limited or Suggestive Evidence of No
Association Several adequate studies, covering
the full range of levels of exposure that human
beings are known to encounter, are consistent in
not showing a positive association between any
magnitude of exposure to herbicides and the
outcome. A conclusion of no association is
inevitably limited to the conditions, exposure,
and length of observation covered by the
available studies. In addition, the possibility
of a very small increase in risk at the exposure
studied can never be excluded.

• VETERANS AND AGENT ORANGE UPDATE 2006
• METHOD FOR APPROACHING THE CHARGE
• Extensive review of literature published since
  previous update (reviewed over 550 studies)
• Submissions from interested individuals from
  public meetings and written testimony
• Focused on 2,4-D, 2,4,5-T and its contaminant
  TCDD, picloram, and cacodylic acid
• Categorized health outcomes into one of four
  categories, adapted from IARC classification
  scheme, based on evidence of a statistical
  association in new and previously reviewed
  literature
• Focus is on epidemiologic literature with
  toxicologic literature used for biological
  mechanism
• Epidemiologic data comes from military
  populations (Air Force Health Study CDC Vietnam
  Experience Study U.S. and Australian DVA
  research), industrially exposed populations
  (NIOSH IARC analyses BASF other production
  worker cohorts pulp and paper workers)
  agricultural workers (National Cancer Institute
  research Canadian and European cohorts), and
  environmentally exposed populations (Seveso,
  Italy Vertac/Hercules Superfund site)

• COMMITTEE CHARGE FOR THE VETERANS AND AGENT
  ORANGE
• SERIES OF REPORTS
• The committee was asked to determine (to the
  extent that available 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.

• REPORT AVAILABILITY
• A full text version of the Veterans and Agent
  Update 2004 report is available for viewing at
  the website of the National Academy Press at
  http//www.nap.edu