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1
Introduction
The Agent Orange Act of 1991—Public Law (PL) 102-4, enacted February
6, 1991, and codified as Section 1116 of Title 38 of the United States Code—
directed the Secretary of Veterans Affairs to ask the National Academy of Sci-
ences (NAS) to conduct an independent comprehensive review and evaluation
of scientific and medical information regarding the health effects of exposure to
herbicides used during military operations in Vietnam. The herbicides picloram
and cacodylic acid were to be addressed, as were chemicals in various formu -
lations containing the herbicides 2,4-dichlorophenoxyacetic acid (2,4-D) and
2,4,5-trichlorophenoxyacetic acid (2,4,5-T). 2,4,5-T contained the contaminant
2,3,7,8-tetrachlorodibenzo-p-dioxin (referred to in this report as TCDD to repre-
sent a single—and the most toxic—congener of the tetrachlorodibenzo- p-dioxins
[tetraCDDs], also commonly referred to as dioxin). It should be noted that TCDD
and Agent Orange are not the same. NAS also was asked to recommend, as ap -
propriate, additional studies to resolve continuing scientific uncertainties and to
comment on particular programs mandated in the law. In addition, the legislation
called for biennial reviews of newly available information for a period of 10
years; the period was extended to 2014 by the Veterans Education and Benefits
Expansion Act of 2001 (PL 107-103).
In response to the request from the Department of Veterans Affairs (VA), the
Institute of Medicine (IOM) of the National Academies convened the Committee
to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides. The
results of the original committee’s work were published in 1994 as Veterans and
Agent Orange: Health Effects of Herbicides Used in Vietnam, hereafter referred
to as VAO (IOM, 1994). Successor committees formed to fulfill the requirement
for updated reviews produced Veterans and Agent Orange: Update 1996 (IOM,
14
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15
INTRODUCTION
1996), Update 1998 (IOM, 1999), Update 2000 (IOM, 2001), Update 2002
(IOM, 2003a), Update 2004 (IOM, 2005a), Update 2006 (IOM, 2007), and Up-
date 2008 (IOM, 2009).
In 1999, VA asked IOM to convene a committee 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 referred to as Type
2 Diabetes (IOM, 2000). In 2001, VA asked IOM to convene a committee to
conduct an interim review of childhood acute myelogenous leukemia (AML,
now preferably referred to as acute myeloid leukemia) associated with parental
exposure to any of the chemicals of interest; its review of the literature, including
literature available since the review for Update 2000, was published as Veterans
and Agent Orange: Herbicide/Dioxin Exposure and Acute Myelogenous Leuke-
mia in the Children of Vietnam Veterans, hereafter referred to as Acute Myelog-
enous Leukemia (IOM, 2002). In PL 107-103, passed in 2001, Congress directed
the Secretary of Veterans Affairs to ask NAS to review “available scientific
literature on the effects of exposure to an herbicide agent containing dioxin on
the development of respiratory cancers in humans” and to address “whether it is
possible to identify a period of time after exposure to herbicides after which a
presumption of service-connection” of the disease would not be warranted; the re-
sult of that effort was Veterans and Agent Orange: Length of Presumptive Period
for Association Between Exposure and Respiratory Cancer, hereafter referred to
as Respiratory Cancer (IOM, 2004).
In conducting their work, the committees responsible for those reports oper-
ated 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 were intended
to provide scientific information for the Secretary of Veterans Affairs to consider
as VA exercises its responsibilities to Vietnam veterans. This VAO update and
all previous VAO reports are freely accessible on line at the National Academies
Press’s Website (http://www.nap.edu).
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 chemicals in the herbicides used by the military in Vietnam:
A) whether a statistical association with herbicide exposure exists, taking
into account the strength of the scientific evidence and the appropriate-
ness of the statistical and epidemiological methods used to detect the
association;
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16 VETERANS AND AGENT ORANGE: UPDATE 2010
B) the increased risk of the disease among those exposed to herbicides dur-
ing 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.
The committee notes that, as a consequence of congressional and judicial
history, both its congressional mandate and the statement of task are phrased with
the target of evaluation being “association” between exposure and health out -
comes, although biologic mechanism and causal relationship are also mentioned
as part of the evaluation in Article C. As used technically and as thoroughly ad -
dressed in a recent report on decision-making (IOM, 2008), the criteria for causa-
tion are somewhat more stringent than those for association. The unique mandate
of VAO committees to evaluate association, rather than causation, means that
the approach delineated in that report is not entirely applicable here. The rigor
of the evidentiary database needed to support a finding of statistical association
is weaker than that to support causality; however, positive findings for any of
the indicators for causality would enhance conviction that an observed statistical
association was reliable. In accord with its charge, the committee examined a
variety of indicators appropriate for the task, including factors commonly used
to evaluate statistical associations, such as the adequacy of control for bias and
confounding and the likelihood that an observed association could be explained
by chance; and it assessed evidence concerning biologic plausibility derived from
laboratory findings in cell-culture or animal models. The full array of indicators
examined was used to categorize the strength of the evidence. In particular, as-
sociations that manifest multiple indicators were interpreted as having stronger
scientific support. Table 1-1 below presents the cumulative findings through
Update 2008 of VAO committees using this approach.
In delivering the charge to the current committee, VA made an additional
request arising from the decision-making at VA necessitated by the findings of
Update 2008. The sponsor asked that the committee, when summarizing the
evidence available to support the association of a health effect with exposure
to the components of the herbicides used by the military in Vietnam, address
whether all the points that have rather imprecisely become known as the “Hill
criteria for causality” (Hill, 1965) had been satisfied by the information available.
The committee’s response to that request can be found Chapter 2 in the section
“Evaluation of the Evidence.”
Chapter 2 provides details of the committee’s approach to its charge and the
methods that it used in reaching conclusions.
ISSUES RAISED IN PUBLIC SESSIONS
It has been the practice of VAO committees to conduct open sessions, not
only to gather additional information from people who have particular expertise
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INTRODUCTION
TABLE 1-1 Summary from Update 2008 (Seventh Biennial Update) of
Findings in Occupational, Environmental, and Veterans Studies Regarding the
Association Between Specific Health Outcomes and Exposure to Herbicides a
Sufficient Evidence of Association
Epidemiologic evidence is sufficient to conclude that there is a positive association. That is, a
positive association has been observed between exposure to herbicides and the outcome in studies
in which chance, bias, and confounding could be ruled out with reasonable confidence. b For
example, if several small studies that are free of bias and confounding show an association that is
consistent in magnitude and direction, there could be sufficient evidence of an association. There
is sufficient evidence of an association between exposure to the chemicals of interest and the
following health outcomes:
Soft-tissue sarcoma (including heart)
Non-Hodgkin’s lymphoma
Chronic lymphocytic leukemia (CLL) (including hairy cell leukemia and other
chronic B-cell leukemias) (category clarification since Update 2006)
Hodgkin’s disease
Chloracne
Limited or Suggestive Evidence of Association
Epidemiologic evidence suggests an association between exposure to herbicides and the outcome,
but a firm conclusion is limited because chance, bias, and confounding could not be ruled out
with confidence.b For example, a well-conducted study with strong findings in accord with less
compelling results from studies of populations with similar exposures could constitute such
evidence. There is limited or suggestive evidence of an association between exposure to the
chemicals of interest and the following health outcomes:
Laryngeal cancer
Cancer of the lung, bronchus, or trachea
Prostate cancer
Multiple myeloma
AL amyloidosis
Early-onset transient peripheral neuropathy
Porphyria cutanea tarda
Parkinson’s disease (category change from Update 2006)
Hypertension
Ischemic heart disease (category change from Update 2006)
Type 2 diabetes (mellitus)
Spina bifida in offspring of exposed people
Inadequate or Insufficient Evidence to Determine Association
The available epidemiologic 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 association between exposure to the chemicals
of interest and the following health outcomes that were explicitly reviewed:
Cancers of the oral cavity (including lips and tongue), pharynx (including tonsils), or
nasal cavity (including ears and sinuses)
Cancers of the pleura, mediastinum, and other unspecified sites within the respiratory
system and intrathoracic organs
Esophageal cancer
Stomach cancer
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18 VETERANS AND AGENT ORANGE: UPDATE 2010
TABLE 1-1 Continued
Colorectal cancer (including small intestine and anus)
Hepatobiliary cancers (liver, gallbladder, and bile ducts)
Pancreatic cancer
Bone and joint cancer
Melanoma
Nonmelanoma skin cancer (basal-cell and squamous-cell)
Breast cancer
Cancers of reproductive organs (cervix, uterus, ovary, testes, and penis; excluding
prostate)
Urinary bladder cancer
Renal cancer (kidney and renal pelvis)
Cancers of brain and nervous system (including eye)
Endocrine cancers (thyroid, thymus, and other endocrine)
Leukemia (other than all chronic B-cell leukemias, including CLL and hairy-cell
leukemia)
Cancers at other and unspecified sites
Infertility
Spontaneous abortion (other than for paternal exposure to TCDD, which appears not to
be associated)b
Neonatal or infant death and stillbirth in offspring of exposed people
Low birth weight in offspring of exposed people
Birth defects (other than spina bifida) in offspring of exposed people
Childhood cancer (including acute myeloid leukemia) in offspring of exposed people
Neurobehavioral disorders (cognitive and neuropsychiatric)
Neurodegenerative diseases, excluding Parkinson’s disease
Chronic peripheral nervous system disorders
Respiratory disorders (wheeze or asthma, chronic obstructive pulmonary disease, and
farmer’s lung)
Gastrointestinal, metabolic, and digestive disorders (changes in liver enzymes, lipid
abnormalities, and ulcers)
Immune system disorders (immune suppression, allergy, and autoimmunity)
Circulatory disorders (other than hypertension and ischemic heart disease)
Endometriosis
Effects on thyroid homeostasis
This committee used a classification that spans the full array of cancers. However, reviews for
nonmalignant conditions were conducted only if they were found to have been the subjects of
epidemiologic investigation or at the request of the Department of Veterans Affairs. By default, any
health outcome on which no epidemiologic information has been found falls into this category.
Limited or Suggestive Evidence of No Association
Several adequate studies, which cover the full range of human exposure, are consistent in not
showing a positive association between any magnitude of exposure to the chemicals of interest and
the outcome. A conclusion of “no association” is inevitably limited to the conditions, exposures,
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. There is limited or suggestive
evidence of no association between exposure to the chemicals of interest and the following health
outcome:
continued
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19
INTRODUCTION
TABLE 1-1 Continued
Spontaneous abortion and paternal exposure to TCDD
aHerbicides 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 veteran studies in which people were exposed to the herbicides used
in Vietnam, to their components, or to their contaminants.
bEvidence of an association can be strengthened by experimental data supporting biologic plausibil-
ity, but its absence would not detract from the epidemiologic evidence.
on points that arise during deliberations but especially to hear from individual
Vietnam veterans and others concerned about aspects of their health experience
that may be service-related. The present committee was pleased by the response
to its invitation, which had been circulated by VA, to the primary such session
held in Chicago. Open sessions were held at the first four of the committee’s five
meetings, and the agendas are presented in Appendix A.
A summary of the topics raised at the open sessions and the committee’s
responses to them follows.
First Meeting, Washington, DC
Autoimmune conditions, particularly mixed connective tissue disease:
•
There is a paucity of evidence from human studies on herbicide exposure
and immunologic responses, and what little there is evaluates biomarkers
rather than disease states that have an immunologic etiology. The present
committee conducted a comprehensive review of the available information,
which is addressed in Chapter 6 on immune effects.
Exposure to Agent Orange during Vietnam-era service on Guam: Evaluat-
•
ing where herbicide exposure may have occurred is not within the scope of
this committee’s charge.
Second Meeting, Chicago
Coverage of all forms of parkinsonism in VA’s recognition of Parkinson
•
disease as a condition presumptively associated with service in Vietnam.
Health problems in children and grandchildren of Vietnam veterans: Chap-
•
ter 8 addresses evidence related to the possibility that the exposure of Viet-
nam veterans has adverse consequences for their progeny.
Thyroid disease: The existing evidence on disruption of thyroid homeostasis
•
is discussed in Chapter 11. As is the case for immune effects, the available
information focuses on biomarkers of perturbation rather than on clinical
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20 VETERANS AND AGENT ORANGE: UPDATE 2010
conditions. A considerable amount of research has addressed exposure dur-
ing gestation and nursing, which is not relevant to the experience of Vietnam
veterans themselves; the possible consequences of maternal exposure are
discussed in Chapter 8.
Myelodysplastic syndromes as forms of leukemia: The International Clas-
•
sification of Diseases has regarded these myeloid neoplasms as having uncer-
tain or unknown behavior, so they cannot be defined as malignant or benign.
No epidemiologic studies have looked at this end point with exposure speci-
ficity that meets VAO criteria for inclusion, although recently some work has
been done on exposure to the broad classification of pesticides in general. In
any event, when myelodysplastic syndromes progress into unquestionable
malignancies, they become AML, on which there is inadequate or insuf-
ficient evidence of association with herbicides (see Chapter 7).
Vietnam veterans may have experienced multiple potentially harmful ex-
•
posures in addition to herbicide exposure (particularly, exposure to the
benzene-containing petroleum products used as dispersants for the herbi-
cides and the extensively used insecticides): Addressing interactions or syn-
ergies of other substances with the several components of these herbicides is
beyond the scope of the committee’s charge. People are continually exposed
to many chemicals, whose possible adverse effects might be exacerbated
by exposure to other agents. The number of pairs that could be addressed is
enormous, and the number would rise exponentially if triads and larger com -
binations were considered. There is a vast toxicologic literature on petroleum
products and their constituents (for example, see Gulf War and Health: Vol-
ume 3—Fuel, Combustion Products, and Propellants [IOM, 2005b]) and on
the various chemical families of insecticides (see also, Gulf War and Health:
Volume 2—Insecticides and Solvents [IOM, 2003b]).
Third Meeting, Albuquerque
Glioblastomas: The available evidence concerning cancers of the brain and
•
herbicide exposure is discussed in Chapter 7.
Evidence from the Vietnamese population: After a thorough search of
•
the literature and consultation with US scientists who have attempted to
establish collaborative relationships with Vietnamese scientists, the com -
mittee concludes that there has been virtually no epidemiologic study of the
Vietnamese population that followed the standards of Western protocols. In
the interest of increasing scientific understanding, such research would be de-
sirable. Investigations of reproductive outcomes associated with the chronic
environmental exposure of men and women occurring now, however, would
not be particularly informative about the time-limited exposure experience
of predominantly male US veterans.
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INTRODUCTION
Fifth Meeting, Phoenix
Alzheimer disease, especially of early onset: The limited available evidence
•
on an association of Alzheimer disease and herbicide exposure is discussed
in Chapter 9.
CONCLUSIONS OF PREVIOUS VETERANS
AND AGENT ORANGE REPORTS
Health Outcomes
VAO, Update 1996, Update 1998, Update 2000, Update 2002, Update 2004,
Type 2 Diabetes, Acute Myelogenous Leukemia, Respiratory Cancer, Update
2006, and Update 2008 contain detailed reviews of the scientific studies evalu-
ated by the committees and their implications for cancer, reproductive and devel-
opmental effects, neurologic disorders, and other health effects.
The original VAO committee addressed the statutory mandate to evaluate the
association between herbicide exposure and a given health effect by assigning
each of the health outcomes under study to one of four categories on the basis of
the epidemiologic evidence reviewed. The categories were adapted from the ones
used by the International Agency for Research on Cancer in evaluating evidence
of the carcinogenicity of various substances (IARC, 1977). Successor VAO com -
mittees adopted the same categories.
The question of whether the committee should be considering statistical as-
sociation rather than causality has been controversial. In legal proceedings that
predate passage of the legislation mandating the VAO series of reviews, Nehmer
v United States Veterans Administration (712 F. Supp. 1404, 1989) found that
the legislative history, and prior VA and congressional practice, support our
finding that Congress intended that the Administrator predicate service con -
nection upon a finding of a significant statistical association between dioxin
exposure and various diseases. We hold that the VA erred by requiring proof of
a causal relationship.
The committee believes that the categorization of strength of evidence as
shown in Table 1-1 is consistent with that court ruling. In particular, the ruling
does not preclude the consideration of the factors usually assessed in determin -
ing a causal relationship (Hill, 1965; IOM, 2008) as indicators of the strength of
scientific evidence of an association. In accord with the court ruling, the com -
mittee was not seeking proof of a causal relationship, but any information that
supports a causal relationship, such as a plausible biologic mechanism as speci -
fied in Article C of the charge to the committee, would also lend credence to the
reliability of an observed association. Understanding of causal relationships is the
ultimate objective of science, while the committee’s goal of assessing statistical
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22 VETERANS AND AGENT ORANGE: UPDATE 2010
association is an intermediate (less well-defined) point along a continuum that
culminates in causality.
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 Up-
date 2008 regarding associations between health outcomes and exposure to the
herbicides used in Vietnam or to any of their components or contaminants. That
integration of the literature through September 2008 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 exposure; they do not address the likelihood that any indi-
vidual’s health problem is associated with or caused by the chemicals 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 epidemiologic studies in which chance, bias, and confound -
ing can be ruled out with reasonable confidence. The committee regarded evi-
dence from several studies that satisfactorily addressed bias and confounding and
that show an association that is consistent in magnitude and direction as sufficient
evidence of an association. Experimental data supporting biologic plausibility
strengthen evidence for an association, but are not a prerequisite.
The original VAO committee found sufficient evidence of an association
between exposure to herbicides and three cancers—soft-tissue sarcoma, non-
Hodgkin lymphoma, and Hodgkin lymphoma—and two other health outcomes,
chloracne and porphyria cutanea tarda (PCT). 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
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 ex-
posure. 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 it evaluate whether chronic lymphocytic leukemia (CLL) should be consid-
ered separately from other leukemias. That committee concluded that CLL could
be considered separately and, on the basis of the epidemiologic literature and
the etiology of the disease, placed CLL in the “sufficient” category. In response
to a request from VA, the committee for Update 2008 affirmed that hairy-cell
leukemia belonged in the category of sufficient evidence of an association with
the related conditions CLL and the lymphomas.
Health Outcomes with Limited or Suggestive Evidence of an 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
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23
INTRODUCTION
the inability to rule out chance, bias, or confounding confidently. The coherence
of the full body of epidemiologic information, in light of biologic plausibility,
is considered when the committee reaches a judgment about association for a
given outcome. Because the VAO series has four herbicides and TCDD as agents
of concern whose profiles of toxicity are not expected to be uniform, apparent
inconsistencies can be expected among study populations that have experienced
different exposures. Even for a single exposure, a spectrum of results would be
expected, depending on the power of the studies and other design factors.
The committee responsible for VAO found limited or suggestive evidence
of an association between exposure to herbicides and three categories of cancer:
respiratory cancer (after individual evaluations of laryngeal cancer and of can -
cers of the trachea, lung, or bronchus), prostate cancer, and multiple myeloma.
The Update 1996 committee added three health outcomes to the list: PCT, acute
and subacute peripheral neuropathy (after Update 2004 called early-onset tran-
sient 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 Up-
date 1996 committee reviewed those neuropathies and based its determination
on case histories. A combination of a 1995 analysis of birth defects among the
offspring of veterans who served in Operation Ranch Hand and results of 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 commit-
tee to distinguish spina bifida from other reproductive outcomes and to place it
in the “limited or suggestive evidence” category. No changes were made in this
category in Update 1998.
After the publication of Update 1998, the committee responsible for Type 2
Diabetes, on the basis of its evaluation of newly available scientific evidence and
the cumulative findings of research reviewed in previous VAO reports, 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 AML in the children of Vietnam veterans.
After release of Update 2000, researchers in one of the studies that it reviewed
discovered an error in the published data. The committee for Update 2000 was
reconvened to re-evaluate the previously reviewed and new literature regarding
AML, and it produced Acute Myelogenous Leukemia, which reclassified AML in
children from “limited or suggestive evidence of an association” to “inadequate
or insufficient evidence to determine an association.”
After reviewing the data reviewed in previous VAO reports and recently pub-
lished scientific literature, the committee responsible for Update 2006 determined
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24 VETERANS AND AGENT ORANGE: UPDATE 2010
that there was limited or suggestive evidence of an association between exposure
to the herbicides used in Vietnam or the contaminant TCDD and hypertension.
AL amyloidosis was also moved to the category of “limited or suggestive evi -
dence of an association” primarily on the basis of its close biologic relationship
with multiple myeloma.
With a bit more consistent epidemiologic data augmented by increased
understanding of mechanisms arising from new toxicologic research, the com -
mittee for Update 2008 was able to resolve the Update 2006 committee’s lack of
consensus and moved ischemic heart disease into this category, joining another
cardiovascular condition, hypertension. New studies of Parkinson disease with
positive findings for association with the specific herbicides of interest were
deemed to move the evidence to the category of limited or suggestive.
Health Outcomes with Inadequate or Insufficient
Evidence to Determine an Association
By default, any health outcome is in this category before enough reliable
scientific data accumulate to promote it to the category of sufficient evidence or
limited or suggestive evidence of an association or to move it to the category of
limited or suggestive evidence of no association. In this category, available stud-
ies may have inconsistent findings or be of insufficient quality or statistical power
to support a conclusion regarding the presence of an association. Such studies
might have failed to control for confounding or might have had inadequate as-
sessment of exposure.
The cancers and other health effects so categorized in Update 2004 are listed
in Table 1-1, but several health effects have been moved into or out of this cat -
egory 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 limited or 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 evi -
dence weakened the evidence of no association. The committee for Update 2000
had partitioned AML in the offspring of Vietnam veterans from other childhood
cancers and put it into the category of suggestive evidence; but a separate review,
as reported in Acute Myelogenous Leukemia, found errors in the published infor-
mation and returned it to this category with other childhood cancers. In Update
2002, CLL was moved from this category to join Hodgkin and non-Hodgkin
lymphomas in the category of sufficient evidence of an association.
The committee responsible for Update 2006 removed several cancers (of
the brain, stomach, colon, rectum, and pancreas) from the category of limited or
suggestive evidence of no association into this category because of some changes
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25
INTRODUCTION
in evidence since they were originally placed in the “no association” category but
primarily because that committee had concerns about the lack of information on
all five chemicals of interest and each of these cancers.
Health Outcomes with Limited or Suggestive Evidence of No Association
The original VAO committee defined this category for health outcomes for
which several adequate studies covering the “full range of human exposure”
were consistent in showing no association with exposure to herbicides at any
concentration and had relatively narrow confidence intervals. A conclusion of “no
association” is inevitably limited to the conditions, exposures, and observation
periods covered by the available studies, and the possibility of a small increase
in risk related to the magnitude of exposure studied can never be excluded.
However, a change in classification from inadequate or insufficient evidence of
an association to limited or suggestive evidence of no association would require
new studies that correct for the methodologic problems of previous studies and
that have samples large enough to limit the possible study results attributable to
chance.
The original VAO committee found a sufficient number and variety of well-
designed studies to conclude that there was limited or suggestive evidence of no
association between the exposures of interest and a small group of cancers: gas -
trointestinal tumors (colon, rectum, stomach, and pancreas), skin cancers, brain
tumors, and urinary bladder cancer. The Update 1996 committee removed skin
cancers and the Update 1998 committee removed urinary bladder cancer from
this category because the evidence no longer supported a conclusion of no asso-
ciation. The Update 2002 committee concluded that there was adequate evidence
to determine that spontaneous abortion is not associated with paternal exposure
specifically to TCDD; the evidence on this outcome was deemed inadequate for
drawing a conclusion about an association with maternal exposure to any of the
chemicals of interest or with paternal exposure to any of the chemicals of inter-
est other than TCDD. No changes in this category were made in Update 2000
or Update 2004. The Update 2006 committee removed brain cancer and several
digestive cancers from this category because of concern that the overall paucity
of information on picloram and cacodylic acid made it inappropriate for those
outcomes to remain in this category.
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 or the contaminant TCDD during service in Vietnam.
Previous reports pointed out that most of the many health studies of Vietnam
veterans were hampered by relatively poor measures of exposure to herbicides
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26 VETERANS AND AGENT ORANGE: UPDATE 2010
or TCDD and by other methodologic problems. 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 set -
tings rather than from studies of Vietnam veterans. The committees that produced
VAO and the updates found that the 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.
The evidence of herbicide exposure among various groups studied suggests
that although some had documented high exposures (such as participants in Op -
eration Ranch Hand and Army Chemical Corps personnel), most Vietnam veter-
ans had lower exposures to herbicides and 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.
Estimating the magnitude of risk of each particular health outcome among
herbicide-exposed Vietnam veterans requires quantitative information about the
dose–time–response relationship for the health outcome in humans, information
on the extent of herbicide exposure among Vietnam veterans, and estimates of
individual exposure. Committees responsible for VAO and the updates have con-
cluded that in general it is impossible to quantify the risk to veterans posed by
their exposure to herbicides in Vietnam. Statements to that effect were made for
each health outcome in VAO (IOM, 1994) and in every update through Update
2004. The committee responsible for Update 2006 chose to eliminate the repeti-
tive restatements in favor of the following general conclusion: “At least for the
present, it is not possible to derive quantitative estimates of the increase in risk
of various adverse health effects that Vietnam veterans may have experienced in
association with exposure to the herbicides sprayed in Vietnam.” The committee
responsible for Update 2008 and the current committee have opted to retain the
modification in the formatting of the health-outcomes sections.
After decades of research, the challenge of estimating the magnitude of po -
tential risk posed by exposure to the compounds of interest remains intractable.
The requisite information is still absent despite concerted efforts to reconstruct
likely exposure by modeling on the basis of records of troop movements and
spraying missions (Stellman and Stellman, 2003, 2004; Stellman et al., 2003a,b),
to measure serum TCDD in individual veterans (Kang et al., 2006; Michalek
et al., 1995), and to model the pharmacokinetics of TCDD clearance (Aylward
et al., 2005a,b; Cheng et al., 2006b; Emond et al., 2004, 2005, 2006). There is
still uncertainty about the specific agents that may be responsible for a particular
health effect. Even if one accepts an individual veteran’s serum TCDD concentra-
tion as the optimal surrogate for overall exposure to Agent Orange and the other
herbicide mixtures sprayed in Vietnam, not only is the measurement nontrivial
but the hurdle of accounting for biologic clearance and extrapolating to the proper
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27
INTRODUCTION
timeframe remains. The committee therefore believes that it is very unlikely that
additional information or more sophisticated methods are going to become avail -
able that would permit any sort of quantitative assessment of Vietnam veterans’
increased risks of particular adverse health outcomes attributable to exposure to
the compounds associated with herbicide spraying in Vietnam.
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. A separate chapter summarizes toxicologic findings on the chemicals of
concern. In updates before Update 2008, a considerable amount of detail had
been provided about individual newly published toxicology studies; the current
committee concurs with the decision made by the last committee that it would be
more informative for the general reader to provide integrated toxicologic profiles
for the chemicals of interest by interpreting the underlying experimental findings.
When there are specific toxicologic findings pertinent to a particular health out-
come, they are discussed in the chapter reviewing the epidemiologic literature on
that condition. The current committee has endeavored to refine this approach to
make the chapter on toxicologic information more accessible to lay readers and
more illuminating about its relevance to epidemiologic findings.
In VAO and updates before Update 2006, this topic has been discussed in the
conclusions section for each health outcome after a statement of the committee’s
judgment about the adequacy of the epidemiologic evidence of an association of
that outcome with exposure to the chemicals of interest. As Update 2006 noted,
the degree of biologic plausibility itself influences whether the committee per-
ceives positive findings to be indicative of a pattern or the product of statistical
fluctuations. To provide the reader with a more logical sequence, the committee
responsible for Update 2006 placed the biologic-plausibility sections between the
presentation of new epidemiologic evidence and the synthesis of all the evidence,
which in turn leads to the ultimate statement of the committee’s conclusion. The
current committee supports that change and has continued to group the sections
that way.
ORGANIZATION OF THIS REPORT
The remainder of this report is organized in 11 chapters. Chapter 2 briefly
describes the considerations that guided the committee’s review and evalua-
tion of the scientific evidence. Chapter 3 addresses exposure-assessment issues.
Chapter 4 summarizes the toxicology data on the effects of 2,4-D, 2,4,5-T and
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28 VETERANS AND AGENT ORANGE: UPDATE 2010
its contaminant TCDD, cacodylic acid, and picloram; the data contribute to the
biologic plausibility of health effects in human populations. Chapter 5 has two
roles with respect to the epidemiologic information that constitutes the core of
the committee’s deliberations. First, the tables in the opening section identify the
relevant new epidemiologic literature published in this update period, indicating
the health outcomes reported upon and whether a previously study population has
been revisited. The second portion of Chapter 5 provides a cumulative overview
of the study populations that have generated findings (in some instances, in the
form of dozens of separate publications) reviewed in the VAO report series. In
addition to showing where the new literature fits into this compendium of pub -
lications on Vietnam veterans, occupational cohorts, environmentally exposed
groups, and case–control study populations, the latter part of this chapter includes
description and critical appraisal of the design, exposure assessment, and analysis
approaches used.
The committee’s evaluation of the epidemiologic literature and its conclu -
sions regarding associations between the exposures of interest and particular
health outcomes are presented in the several subsequent chapters. In this update,
the committee has broken out two new chapters from the chapter on “other
health effects.” A chapter on immunologic effects (Chapter 6) now precedes
the chapter on cancer (Chapter 7). The new chapter addresses reasons for what
might be perceived as a discrepancy between clear immunotoxicity in animal
studies and a paucity of epidemiologic studies with such findings. Its placement
reflects the committee’s belief that immunologic changes may constitute an
intermediary mechanism in the generation of more distinct clinical conditions
discussed in the following chapters. As in Update 2008, Chapter 8, on reproduc-
tive and developmental effects, places more emphasis on problems that might
be manifested later in the lives of veterans’ children or even in later generations.
Chapter 9 addresses neurologic disorders. Early-onset peripheral neuropathy is a
condition long recognized as a response to herbicide exposure that is manifested
shortly after exposure but unlikely to be a response that arises for the first time
decades after exposed people leave Vietnam; the discussion of evidence on this
short-term response has been taken from Chapter 9 and placed in Appendix B,
with the information on chloracne and porphyria cutanea tarda, which are also
short-term responses presumptively associated with herbicide exposure. Chapter
10 consists of a set of conditions related to cardiovascular and metabolic effects
that have also been excised from the “other health outcomes” chapter. Chapter 11
now contains the residual “other health outcomes”: respiratory disorders, gastro -
intestinal problems, thyroid homeostasis and other endocrine disorders, and new
sections on eye problems and bone conditions.
A summary of the committee’s findings and its research recommendations
are presented in Chapter 12.
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29
INTRODUCTION
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