Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter.
Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.
Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.
OCR for page 1
Summary
From 1962 to 1971, the US military sprayed herbicides over Vietnam to
strip the thick jungle canopy that could conceal opposition forces, to destroy
crops that those 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 bulk of the herbicides
sprayed. The herbicide mixtures used were named according to the colors of
identification bands painted on the storage drums; the main chemical mixture
sprayed was Agent Orange (a 50:50 mixture of 2,4-D and 2,4,5-T). At the time of
the spraying, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the most toxic form
of dioxin, was an unintended contaminant generated during the production of
2,4,5-T and so was present in Agent Orange and some other formulations sprayed
in Vietnam; it is important to remember that Agent Orange is not synonymous
with TCDD or dioxin.
Complaints from returning Vietnam veterans about their own health and
that of their children combined with emerging toxicologic evidence of adverse
effects of phenoxy herbicides and TCDD in animal studies and some positive
epidemiologic studies resulted in sustained controversy. In 1991, because of
continuing uncertainty about long-term health effects of the sprayed herbicides
in Vietnam veterans, Congress passed Public Law (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 components of
those herbicides, including TCDD. The legislation also instructed the Secretary
1
OCR for page 2
2 VETERANS AND AGENT ORANGE: UPDATE 2010
to ask NAS to conduct updates 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 first request, the Institute of Medicine (IOM) convened
a committee, whose conclusions IOM published in 1994 in Veterans and Agent
Orange: Health Effects of Herbicides Used in Vietnam (VAO). The work of later
committees resulted in the publication of biennial updates (Update 1996, Update
1998, Update 2000, Update 2002, Update 2004, Update 2006, and Update 2008)
and of focused reports on the scientific evidence regarding type 2 diabetes, acute
myeloid leukemia in children, and the latent period for respiratory cancer.
Enacted in 2002, PL 107-103, the Veterans Education and Benefits Expan -
sion Act of 2001, mandated that the VAO biennial updates continue through
2014. Update 2006 was the first report published under that legislation. The cur-
rent update presents this committee’s review of peer-reviewed scientific reports
concerning associations between health outcomes and exposure to TCDD and
other chemicals in the herbicides used in Vietnam that were published in October
2008–September 2010 and the committee’s integration of this information with
the previously established evidence database.
CHARGE TO THE COMMITTEE
In accordance with PL 102-4 and PL 107-103, the Committee to Review
the Health Effects in Vietnam Veterans of Exposure to Herbicides (Eighth Bi -
ennial Update) 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
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;
B) the increased risk of 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.
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
outcomes. The rigor of the evidentiary database needed to support a finding of
statistical association is weaker than that needed to establish causality, but posi -
OCR for page 3
3
SUMMARY
tive findings for any of the aspects of scientific evidence supportive of causality
enhance conviction that an observed statistical association is reliable. Such scien-
tific evidence, of course, would include any information assembled in relation to
plausible biologic mechanisms as directed in Article C. In accord with its charge,
the committee examined outcome measures commonly used to evaluate statistical
associations, while assessing the adequacy of control for bias and confounding
and the likelihood that an observed association could be explained by chance.
Additionally, the committee assessed evidence concerning biologic plausibility
derived from laboratory findings in cell-culture or animal models. In particular,
associations found to have multiple supportive lines of evidence were interpreted
as having stronger scientific support.
In conducting its study, the present committee operated independently of
the Department of Veterans Affairs (VA) and other government agencies. The
committee was not asked to make and did not make judgments regarding specific
cases in which individual Vietnam veterans have claimed injury from herbicide
exposure. This report provides scientific information for the Secretary of Veterans
Affairs to consider as VA exercises its responsibilities to Vietnam veterans. The
committee was not charged to focus on broader issues, such as the potential costs
of compensation for veterans or policies regarding such compensation.
In addition to the above charge, the VA made an additional request arising
from the decision-making at VA necessitated by the findings of Update 2008.
The sponsor asked that, 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, the committee address whether or not all the
points that have rather imprecisely become known as the Bradford Hill (1965)
“criteria” for causality (strength, consistency, specificity, temporality, biologic
gradient, plausibility, coherence, experiment, and analogy) had been satisfied by
the information available
COMMITTEE’S APPROACH TO ITS CHARGE
Following the pattern established by prior VAO committees, the present
committee concentrated its review on epidemiologic studies to fulfill its charge
of assessing whether specific human health effects are associated with exposure
to at least one of the herbicides sprayed in Vietnam or to TCDD. The committee
also considered controlled laboratory investigations that provided information
on whether association between the chemicals of interest and a given effect is
biologically plausible.
The VAO committees began their evaluation presuming neither the pres-
ence nor the absence of association for any particular health outcome. Over
the sequence of reviews, evidence of various degrees of association, lack of
association, or persisting indeterminacy with respect to a wide array of disease
OCR for page 4
4 VETERANS AND AGENT ORANGE: UPDATE 2010
states has accrued. For many conditions, however, particularly ones that are
very uncommon, any association with the chemicals of interest has remained
unaddressed in the medical research literature; for these (unless the condition is
logically subsumed under a broader disease category that has been evaluated),
the committee remains neutral, abiding by the maxim that “absence of evidence
is not evidence of absence.”
In accord with Congress’s mandated presumption of herbicide exposure for
all Vietnam veterans, VAO committees have treated Vietnam-veteran status as
a proxy for some herbicide exposure when no more specific exposure informa-
tion is available. To obtain information potentially relevant to the evaluation of
health effects related to herbicide exposure in addition to that available from
studies of Vietnam veterans, the committee reviewed studies of other groups
potentially exposed to the constituents of the herbicide mixtures used in Vietnam
(2,4-D, 2,4,5-T, TCDD, cacodylic acid, and picloram). In addition to retriev -
ing articles identified on the basis of keywords specifying the compounds and
chemical classes of interest, literature searches for the earliest reports in the VAO
series had been structured to retrieve all studies of several occupational groups,
including chemical, agricultural, pulp and paper, sawmill, and forestry workers.
To the extent that studies of those workforces were recovered in new searches
directed at particular agents of exposure, they were incorporated into the data -
base. Some occupational and environmental cohorts that received exceptionally
high exposures (such as the International Agency for Research on Cancer [IARC]
and Seveso cohorts discussed in this report) are now well characterized and are
producing a stream of informative results. A continuing prospective cohort study
of agricultural populations with specific information on the chemicals of interest
is also steadily contributing new findings to the database. Most important, the
Vietnam veterans themselves are advancing in age and, when studied, are capable
of providing substantial information on chronic health conditions directly. As
the information in the database on populations with established exposures to the
chemicals of interest has grown, the committee has come to depend less on data
from studies with nonspecific exposure information and has been able to focus
more on findings of studies with refined exposure specificity.
In this update, the committee endeavored to emphasize and clarify the rela -
tionship among the succession of publications that have provided ever increasing
insight into the health responses of particular exposed populations that have been
studied for many years. The information in the results tables for individual health
outcomes has grown over eight cycles of revision, but this committee found that
the presentation of new findings in update-specific clusters obscured the interde -
pendent nature of many of the studies on a given cohort. Therefore, the findings
in the results tables have been rearranged and grouped by study population. In
addition, the cohorts themselves have been ordered on these tables to reflect the
hierarchical nature of many of these study populations (for example, workers at
the Dow plant in Midland, Michigan, are one of several cohorts composing the
OCR for page 5
5
SUMMARY
National Institute for Occupational Safety and Health cohort, which in turn is
one of the many international cohorts making up the IARC cohort). Lastly, the
exposure of interest for each cohort has been explicitly noted on the tables to fa-
cilitate judgments about when consistency might be expected among populations
experiencing the same exposure.
The original legislation, PL 102-4, did not provide a list of specific diseases
and conditions suspected of being associated with herbicide exposure. Such a list
was developed on the basis of diseases and conditions that had been mentioned in
the scientific literature or in other documents identified through the original VAO’s
extensive literature searches. The VAO list has been augmented in response to
developments in the literature, requests by VA, and concerns of Vietnam veterans.
The information that the present committee reviewed was identified through
a comprehensive search of relevant databases, including databases covering bio -
logic, medical, toxicologic, chemical, historical, and regulatory information. The
search of literature published through September 30, 2010, identified more than
6,600 potentially relevant citations. Screening of those retained about 1,300 for
closer consideration, and about 65 papers on epidemiologic studies and several
score of toxicology studies ultimately contributed new information to this review.
Additional information came from veterans and other interested people who testi-
fied at public hearings and offered written submissions.
To determine whether there is an association between exposure and a health
outcome, epidemiologists estimate the magnitude of an appropriate measure
(such as the relative risk or the odds ratio) that describes the relationship between
exposure and disease in a defined population or group. In evaluating the strength
of the evidence linking herbicide exposure with a particular outcome, the com -
mittee considered whether such estimates of risk might be incorrect (because of
confounding, chance, or bias related to errors in selection and measurement) or
might accurately represent true associations; although they are not required, data
supporting biologic plausibility serve to strengthen confidence that an associa -
tion is not spurious. It has been the practice of all VAO committees to evaluate
all studies according to the same criteria and then to weight findings of similar
strength and validity equivalently, whether or not the study subjects are Vietnam
veterans, when drawing conclusions. The committee recognizes that an absolute
conclusion about the absence of association might never be attained, because,
as is generally the case in science, studies of health outcomes after herbicide
exposure cannot demonstrate that a purported effect is impossible, only that it is
statistically improbable.
EVIDENCE REVIEWED BY THE COMMITTEE
The sections below summarize new epidemiologic information evaluated
in this update and integrated with that previously assembled. The epidemiologic
studies have been divided, both here and in the health-outcome chapters, into
OCR for page 6
6 VETERANS AND AGENT ORANGE: UPDATE 2010
three categories—Vietnam-veteran, occupational, and environmental—depend -
ing on the population addressed.
Vietnam-Veterans Studies
Three studies of Vietnam veterans published since Update 2008 were re-
viewed by the committee. One study on Army Chemical Corp personnel pro-
duced findings related to all cause mortality, while another study on Australian
Vietnam veterans evaluated the prevalence of a multitude of self-reported health
outcomes, including cancers, circulatory diseases, respiratory diseases, diabetes,
and digestive disorders. A third study examined the progression of prostate cancer
in a case–control study of veterans with previous Agent Orange exposure.
Occupational Studies
Several occupational studies have been published since Update 2008. Recent
reports from the Agricultural Health Study examined the incidence of pancreatic
cancer, hearing loss, melanoma, thyroid disease, adult onset asthma, myocardial
infarction, and rhinitis in private pesticide applicators (farmers), their spouses,
and commercial pesticide applicators. The incidence of Parkinson disease (PD)
was investigated in an expanded cohort of farmers occupationally exposed to
2,4-D from Washington State and in three newly defined case–control studies
assembled from Texas, France, and eight clinics in North America. All cause
mortality incidence was reported from two different subcohorts of the IARC
cohort. Circulatory diseases and neurologic outcomes were studied in a 40-year
follow-up of Czech production workers who were exposed to TCDD during the
production of 2,4,5-T.
Environmental Studies
Numerous studies from environmental exposures to the chemicals of interest
have been published since Update 2008. Reproductive outcomes, including birth
weight, birth defects, childhood cancer, neonatal thyroid function, and develop -
ment of childhood obesity were studied in offspring of mothers exposed to TCDD
and other chemicals with dioxin-like biologic activity from incinerator emissions
in France, the industrial accident at Seveso, Italy, and dietary intake in Taiwan,
Italy, Belgium, the Netherlands, and Japan. Cancer outcomes were evaluated in
follow-up studies of residents of Seveso, Italy, farmers and pesticide applicators/
users in Canada and the US. Diabetes and conditions associated with meta-
bolic syndrome were assessed in Great Lakes sport-fish consumers, Taiwanese
residents near a pentachlorophenol factory, Finnish fisherman, Japanese men and
women, and the general US population via the National Health and Nutrition Ex-
OCR for page 7
7
SUMMARY
amination Survey. New case–control studies examined environmental exposures
to the chemicals of interest and endometriosis and Parkinson disease.
THE COMMITTEE’S CONCLUSIONS
Health Outcomes
The present committee weighed the strengths and limitations of the epide -
miologic evidence reviewed in this report and in previous VAO reports. Although
the studies published since Update 2008 are the subject of detailed evaluation in
this report, the committee drew its conclusions in the context of the entire body
of literature. The contribution of recent publications to the evidence database was
substantial, but the committee did not weigh them more heavily merely because
they were new. Epidemiologic methods and analytic capabilities have improved,
but many of the recent studies were also particularly useful for this committee’s
purpose because they produced results in terms of serum TCDD concentrations or
the total amount of exposure from all dioxin-like chemicals. Of course, observa -
tions on the health of our population of primary concern, Vietnam veterans, are
increasingly informative as they age.
Table S-1 defines four categories of association and gives criteria for as-
signing health outcomes to them. On the basis of its evaluation of veteran, oc -
cupational, and environmental studies, the committee allocated particular health
outcomes to categories of relative certainty of association with exposure to the
herbicides that were used in Vietnam or to any of their components or contami -
nants (with no intention of specifying particular chemicals). The committee notes
that experimental data related to biologic plausibility of conditions statistically
associated with exposure to Agent Orange have gradually emerged since the
beginning of this series of VAO reports and that these findings can inform the
decisions about how to categorize the degree of association for individual condi -
tions; a footnote to this effect has been added to Table S-1.
The terminology of “early-onset transient peripheral neuropathy” was ad -
opted in Update 2004 as a replacement for the terminology of “acute and sub-
acute peripheral neuropathy” used in Update 1996. Update 1996, the first VAO
report to find “limited or suggestive evidence of association” with exposure to
the chemicals of interest for this health outcome, also noted in the body of the
report that this was a “transient” effect. When VA declared this outcome to be
presumptively associated with service in Vietnam, its definition included the
temporal constraints that symptoms develop shortly after herbicide exposure and
that recovery from those symptoms occurs within 2 years of their initial devel -
opment. Thus, currently qualifying cases are contingent upon when symptoms
arise relative to when exposure occurred and that the symptoms are transitory in
nature. A thorough review of the existing literature in populations with members
OCR for page 8
8 VETERANS AND AGENT ORANGE: UPDATE 2010
TABLE S-1 Summary of Eighth Biennial Update of Findings of Veterans,
Occupational, and Environmental Studies Regarding Associations Between
Exposure to Herbicides and Specific Health Outcomesa
Sufficient Evidence of an 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 lymphoma
* Chronic lymphocytic leukemia (including hairy cell leukemia and other chronic B-cell
leukemias)
* Hodgkin lymphoma
Chloracne
Limited or Suggestive Evidence of an 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 peripheral neuropathy (category clarification from Update 2008)
Parkinson disease
Porphyria cutanea tarda
Hypertension
Ischemic heart disease
Type 2 diabetes (mellitus)
Spina bifida in offspring of exposed people
Inadequate or Insufficient Evidence to Determine an 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 in the respiratory system
and intrathoracic organs
Esophageal cancer
Stomach cancer
OCR for page 9
9
SUMMARY
TABLE S-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 organs)
Leukemia (other than all chronic B-cell leukemias, including chronic lymphocytic
leukemia and hairy cell leukemia)
Cancers at other and unspecified sites
Infertility
Spontaneous abortion (other than after paternal exposure to TCDD, which appears not
to be associated)
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 disease
Chronic peripheral nervous system disorders
Hearing loss (newly addressed health outcome)
Respiratory disorders (wheeze or asthma, chronic obstructive pulmonary disease, and
farmer’s lung)
Gastrointestinal, metabolic, and digestive disorders (changes in hepatic 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
Eye problems (newly addressed health outcome)
Bone conditions (newly addressed health outcome)
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 a component of the
herbicides 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
continued
OCR for page 10
10 VETERANS AND AGENT ORANGE: UPDATE 2010
TABLE S-1 Continued
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 herbicide component of
interest and the following health outcomes:
Spontaneous abortion after 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 for an association is strengthened by experimental data supporting biologic plausibility,
but its absence would not detract from the epidemiologic evidence.
*The committee notes the consistency of these findings with the biologic understanding of the
clonal derivation of lymphohematopoietic cancers that is the basis of the World Health Organization
classification system.
experiencing early-onset peripheral neuropathy, however, indicated that some
individuals continue to manifest neuropathy symptoms long after external ex -
posure has ceased, demonstrating that early-onset peripheral neuropathy is not
necessarily a transient condition. Based on this literature, the committee chose
to delete the word transient to recognize that symptoms of early-onset periph-
eral neuropathy may be protracted and recovery from those symptoms may be
incomplete. This change to the classifications made since the previous update is
bolded in Table S-1.
As mandated by PL 102-4, the distinctions among categories are based on
statistical association, not on strict causality. The committee was directed to
review the scientific data, not to recommend VA policy; therefore, conclusions
reported in Table S-1 are not intended to imply or suggest policy decisions. The
conclusions are related to associations between exposure and outcomes in human
populations, not to the likelihood that any individual’s health problem is associ -
ated with or caused by the herbicides in question.
This committee gave careful consideration to the request from VA that, in
addition to its usual discussion of biologic plausibility, the committee should
state the degree to which each of the other “Hill criteria for causality” are satis -
fied by the existing scientific information. As well known as these standards
or those developed by the US Surgeon General when first assessing the health
consequences of smoking are, there is in fact no sufficient set of criteria for de-
claring that causality has been established. In accord with the current thinking
of epidemiologists, the committee concluded that adopting a checklist approach
would be inappropriate.
OCR for page 11
11
SUMMARY
Risk in Vietnam Veterans
There have been numerous health studies of Vietnam veterans, but most have
been hampered by relatively poor measures of exposure to herbicides or TCDD
and by other methodologic problems. In light of those problems, many conclu -
sions regarding associations between exposure to the chemicals of interest and
disease have been based on studies of people exposed in various occupational
and environmental settings rather than on studies of Vietnam veterans, although
studies of health consequences in the maturing veterans themselves have now
begun to generate more informative findings. The committee believes that there
is sufficient evidence to reach general or qualitative conclusions about associa -
tions between herbicide exposure and health outcomes, but the lack of adequate
exposure data on Vietnam veterans themselves makes it difficult to estimate the
degree of increased risk of disease in Vietnam veterans as a group or individu -
ally. Without information on the extent of herbicide exposure of Vietnam veterans
and quantitative information about the dose–time–response relationship for each
health outcome in humans, estimation of the risks experienced by veterans ex-
posed to the chemicals of interest during the Vietnam War is not possible.
Because of those limitations, only general assertions can be made about risks
to Vietnam veterans, depending on the category of association into which a given
health outcome has been placed. If there were “limited or suggestive evidence of
no association” between herbicide exposure and a health outcome, the evidence
would suggest no increased risk of the outcome in Vietnam veterans attributable
to exposure to the chemicals of interest (at least for the conditions, exposures,
and lengths of observation covered by the studies reviewed). Even qualitative es -
timates are not possible when there is “inadequate or insufficient” evidence of an
association. For outcomes categorized as having “sufficient” or “limited or sug -
gestive” evidence of an association with herbicide exposure, the lack of exposure
information on Vietnam veterans prevents calculation of precise risk estimates.
The information needed for assigning risk estimates continues to be absent
despite concerted efforts to model the exposure of the troops in Vietnam, to mea -
sure the serum TCDD concentrations of individual veterans, and to model the
dynamics of retention and clearance of TCDD in the human body. Accordingly,
several successive VAO committees have stated as a general conclusion that, at
least for the present, it was not possible to derive quantitative estimates of any
increased risks of various adverse health effects that Vietnam veterans may have
experienced in association with exposure to the herbicides sprayed in Vietnam.
Given the amount of time that has passed since the Vietnam era, the current com -
mittee has concluded that the necessary information to perform such estimation
for Vietnam veterans is extremely unlikely ever to become available.
OCR for page 12
12 VETERANS AND AGENT ORANGE: UPDATE 2010
COMMITTEE RECOMMENDATIONS
IOM has been asked to make recommendations concerning the need, if any,
for additional scientific studies to resolve continuing scientific uncertainties about
the health effects of the herbicides used in Vietnam and their contaminants. Great
strides have been made over the past several years in understanding the health
effects of exposure to the herbicides used in Vietnam and to TCDD and in elu-
cidating the mechanisms that underlie the effects, but there are still subjects on
which increased knowledge could be very useful.
This committee recommends that VA should more actively query its own
medical databases to identify potential associations between Vietnam service and
specific health outcomes, particularly for those outcomes that are less common.
Moreover, if a perceived conflict of interest exists in surveying its own databases,
it is recommended that an external advisory group be formed to determine the
best mechanism for mining this information so that these medical databases could
be available for external study.
The committee for Update 2008 concluded that it was plausible that exposure
to the herbicides sprayed in Vietnam could cause paternally mediated effects in
offspring as a result of epigenetic changes, and such potential would most likely
be attributable to the TCDD contaminant in Agent Orange. There is a growing
body of evidence that TCDD, and also arsenicals, can induce epigenetic changes
in animal models, but there remains extremely limited data on the risk of paternal
exposure to xenobiotics in general, and the VAO chemicals of interest in particu -
lar, resulting in adverse effects on their offspring. Consequently, this committee
continues to recommend that laboratory research be conducted to characterize
TCDD’s potential for inducing epigenetic modifications. Further, the committee
recommends development of epidemiologic protocols to address the logistical
challenge of determining whether adverse effects are being manifested in the
adult children and grandchildren of Vietnam veterans as a result of paternal ex -
posure. The best cohorts for revealing potential associations would be those with
known, well-characterized exposure information. Another alternative would be to
adopt a case–control approach and explore whether information about Vietnam
exposure or specific herbicide exposure could be ascertained in any of the many
birth cohorts that have been established in the past several decades. To hone in on
a paternal effect, however, it will be necessary to establish that the mothers did
not have the opportunity for exposure above background levels to the chemicals
of interest.
As in previous years, this committee recommends the pursuit of additional
research in toxicology. The development of animal models of various chronic
health conditions and their progression would be useful for understanding the
possible contributions of the chemicals of interest to compromise the health
of aging Vietnam veterans. Specifically, determining the mechanism by which
dioxin-like chemicals induce B cell cancers and how this exposure alters the sus -
OCR for page 13
13
SUMMARY
ceptibility to developing obesity and components of metabolic syndrome would
fill important knowledge gaps. Health problems, such as metabolic syndrome,
chronic obstructive pulmonary disease (COPD), and measuring meaningful bio -
markers of immune/inflammatory disease merit study in human populations.
The committee notes that the earlier investment in studying several exposed
populations is now producing useful findings; the National Institute for Occupa -
tional Safety and Health, Seveso, Air Force Health Study, and Army Chemical
Corps cohorts all merit continuing follow-up or more comprehensive analysis.
It is especially important that longitudinal analyses be conducted on cancer,
cardiovascular, and reproductive outcomes represented in the complete database
assembled in the course of the Air Force Health Study. The committee endorses
VA’s actions toward restarting the congressionally mandated National Vietnam
Veterans Longitudinal Study, derived from the cohort originally studied in the
National Vietnam Veterans Readjustment Study.
The committee notes that its recommendations are similar to those offered
in previous updates and that there has been little activity in several critical areas.
The fate of the assemblage of data and biologic samples from the Air Force
Health Study remains unsettled; in the interim, critical integrative analyses such
as longitudinal evaluation of the cancer data have not yet been made public, and
the unique potential of this resource languishes. It is the committee’s conviction
that work needs to be undertaken promptly to resolve questions regarding sev -
eral health outcomes, importantly COPD, tonsil cancer, melanoma, Alzheimer
disease, and paternally transmitted effects to their offspring. Creative analysis
of VA’s own data resources and further work on cohorts that have already been
established may well be the most effective way to address those outcomes and
to gain a better understanding of the role of herbicide exposure in development
of PD in Vietnam veterans.
