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2
Evaluating the Evidence
This chapter outlines the approach used by the Committee to Review the
Health Effects in Vietnam Veterans of Exposure to Herbicides (Eighth Biennial
Update) and its predecessors to evaluate the available scientific evidence. A more
complete description is found in Chapter 5 of Veterans and Agent Orange: Health
Effects of Herbicides Used in Vietnam, hereafter referred to as VAO (IOM, 1994).
CHOICE OF HEALTH OUTCOMES
As discussed in Chapter 1, the committee was charged with summarizing the
strength of the scientific evidence of associations between exposure to various
herbicides and contaminants during service in the Vietnam War and individual
diseases or other health outcomes. Public Law 102-4, which mandated the com -
mittee’s work, however, did not specify particular health outcomes suspected of
being associated with herbicide exposure. Such a list of outcomes was developed
on the basis of diseases and conditions addressed in the scientific literature identi-
fied through the original VAO’s extensive literature searches. The list has been
amended in the VAO updates in response to new publications, to requests from
the Department of Veterans Affairs (VA) and various veterans’ service organiza-
tions, and to concerns of Vietnam veterans and their families. Comments received
at public hearings and in written submissions from veterans and other interested
persons have been valuable in identifying issues to be pursued in greater depth
in the scientific literature.
The VAO committees began their evaluation by presuming neither the pres-
ence nor the absence of an association between exposure and any particular health
outcome. Over the series of reviews, evidence of various degrees of association,
31
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32 VETERANS AND AGENT ORANGE: UPDATE 2010
lack of association, or persistent indeterminacy with respect to a wide array of
disease states has accrued. For many conditions, however, particularly ones that
are very uncommon, associations with the chemicals of interest have remained
unaddressed in the medical research literature; for these, the committee remains
neutral on the basis of the understanding that “absence of evidence is not evi-
dence of absence.”
IDENTIFICATION OF RELEVANT LITERATURE
Mixtures of 2,4-dichlorophenoxyacetic acid (2,4-D), 2,4,5-trichlorophen-
oxyacetic acid (2,4,5-T), picloram, and cacodylic acid made up the bulk of the
herbicides sprayed in Vietnam. At the time of the spraying, 2,3,7,8-tetrachloro -
dibenzo-p-dioxin (TCDD, one form of dioxin) was an unintended contaminant
from the production of 2,4,5-T and so was present in Agent Pink, Agent Green,
Agent Purple, Agent Orange, and Agent Orange II, which all contained 2,4,5-T.
It is important to note that TCDD and Agent Orange are not the same. Databases
have been searched for the names of those compounds, their synonyms and ab -
breviations, and their Chemical Abstracts Service (CAS) numbers. The evidence
indicates that a single protein, the aryl hydrocarbon receptor (AHR), mediates
essentially all the toxicity of TCDD, so aryl hydrocarbon receptor also was used
as a keyword, as were dioxin, Agent Orange, and Vietnam veteran.
One of the herbicides used in Vietnam was cacodylic acid, or dimethylar-
sinic acid of valency 5 (DMAV), an organic form of arsenic. In addition to being
synthesized as a herbicide, DMAV is a metabolite of inorganic arsenic exposure
in humans. DMAV was long thought to be a biologically inactive metabolite, but
evidence suggests that methylated forms such as MMAIII (Aposhian et al., 2000),
and perhaps DMAIII and DMAV (Cohen et al., 2006), might be responsible for
some of the adverse effects of inorganic arsenic. The committee carefully recon -
sidered that evidence but again determined that it does not support a conclusion
that exposure to cacodylic acid (DMAV) would be expected to result in the same
adverse health effects as would exposure to toxic concentrations of inorganic
arsenic. Therefore, as in prior VAO reports, the literature on the health effects
of inorganic arsenic was not considered here. Further details on the effects of
inorganic arsenic can be found in Arsenic in Drinking Water (NRC, 1999) and
Arsenic in Drinking Water: 2001 Update (NRC, 2001). For cacodylic acid and
picloram, the search terms were the chemical names, synonyms, and CAS num -
bers of the herbicides.
This report concentrates on the evidence published after the completion of
work on Veterans and Agent Orange: Update 2008 (IOM, 2009). Relevant new
contributions to the literature made during the period October 1, 2008–September
30, 2010, were sought. The information that the committee used was compiled
from a comprehensive electronic search of public and commercial databases—
biologic, medical, toxicologic, chemical, historical, and regulatory—that pro -
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EVALUATING THE EVIDENCE
vide citations of the scientific literature. In addition, the reference lists of some
review and research articles, books, and reports were examined for potentially
relevant articles. As noted above, the terms used in the search strategy included
the chemical names, synonyms, and CAS numbers of the specific chemicals of
interest—2,4-D, 2,4,5-T, TCDD, cacocylic acid, and picloram (see Figure 2-1 for
chemical structures and CAS numbers)—and the more generic terms involved
with this project: Vietnam veteran, Agent Orange, aryl hydrocarbon receptor,
dioxin, herbicide, and phenoxy. Results on other specific phenoxy herbicides are
also of interest: 2-methyl-4-chlorophenoxyacetic acid (MCPA) and 2-(2-methyl-4
-chlorophenoxy) propionic acid (MCPP or Mecoprop) for 2,4-D and 2-(2,4,5-tri -
chlorophenoxy) propionic acid (2,4,5-TP or Silvex) for 2,4,5-T (see Figure 2-1);
although the benzoate herbicide dicamba (2-methoxy-3,6-dichlorobenzoic acid)
is not always categorized with the phenoxy herbicides, it has structural similari -
ties with this class, and measures of its association with various adverse health
outcomes have been factored into the evidence. Because some polychlorinated
biphenyls (PCBs) and polychlorodibenzofurans (PCDFs) have dioxin-like bio-
logic activity, studies of populations exposed to PCBs or PCDFs were reviewed
when results were presented in terms of TOTSL toxic equivalents (TEQs). Find -
ings related only to exposure to the diverse chemical families of pesticides were
considered too nonspecific for inclusion in the evidence database used to draw
conclusions about associations. (An ancillary analysis conducted during prepa -
ration of Update 2008 determined that the term pesticide did not identify any
relevant citation that was not picked up by more specific terms, and so it was
eliminated from the searches conducted for the current update, and this reduced
the number of extraneous hits to be culled.)
(With the structural representation at hand in Figure 2-1, the committee
will respond to an assertion it has heard repeatedly from individual Vietnam
veterans that “benzene is contained in TCDD.” Indeed, the two rings at the ends
of the three-ring structure constituting the basic structure of dioxin compounds,
to which chlorine molecules or other chemical radicals can be attached, do have
the molecular structure of a single benzene molecule and “dibenzo-dioxin” in
TCDD’s chemical name does mean the molecule is indeed a benzene-substituted
dioxane. The benzene ring structure is a basic building block of a vast number of
organic compounds, both industrial [such as polyaromatic hydrocarbons, the phe-
noxy herbicides, picloram, and PCBs] and natural [such as estradiol, a hormone
present in both men and women]. However, the biologically active compound
benzene does not emerge from dioxin, whose three-ring structure is extremely
stable and very resistant to metabolism.)
Because they are the target population of the charge to the VAO commit-
tees, studies of Vietnam veterans (serving in any of the armed forces, American
or otherwise) have always been accorded considerable weight in the commit-
tees’ deliberations, whether or not estimation of exposure to herbicide-related
substances has been attempted. Characterization of exposure in studies of the
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34 VETERANS AND AGENT ORANGE: UPDATE 2010
Phenoxy Herbicides
2,4-D [ 94-75-7] 2,4,5-T [ 93-76-5]
CI
O
CI O
O
CI O
CI OH
CI OH
MCPA [ 94-74-6] Silvex [ 93-72-1]
CI
O
CI O
O
CI O
OH
OH
CI
MCPP [ 93-65-2] Dicamba [1918-00-9]
CI O
O
O
CI O
OH
OH
CI
2,3,7,8-TCDD [1746-01-6]
CI CI
O
O
IC IC
Picloram [1918-02-1] Cacodylic Acid [75-60-5]
CI NH 2
O
HO
As
CI
N
O
OH
CI
FIGURE 2-1 Chemical structures and CAS numbers for specific chemicals of interest.
Figure 2-1.eps
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35
EVALUATING THE EVIDENCE
veterans was extremely uncommon at the time of the original VAO report, and
the Vietnam veterans’ own ages were still below the ages at which many chronic
illnesses are manifested. Consequently, the original committee made extensive
efforts to consider several groups known or thought to have potentially higher
and better-characterized exposure to TCDD or phenoxy herbicides than Vietnam
veterans themselves—both occupational exposure (as of chemical-production,
paper and pulp, sawmill, tannery, waste-incinerator, railroad, agricultural, and
forestry workers) and environmental exposure (as of residents of Seveso, Times
Beach, Quail Run, and Vietnam).
Successive committees have been able to concentrate more on studies that
explicitly addressed the exposures specified in the charge. Some occupational and
environmental cohorts that received exceptionally high exposures (such as the
International Agency for Research on Cancer and Seveso cohorts) are now well
characterized and producing a stream of informative results. The Agricultural
Health Study, a continuing prospective cohort study of agricultural populations
with specific information on the chemicals of interest, is also now contributing a
steady stream of information to the database. Most important, the Vietnam vet -
erans themselves are advancing in age and when studied are capable of directly
providing substantial information on chronic health conditions and, in some study
populations, information related to serum TCDD concentrations. The committee
for Update 2006 decided that exhaustive searches on job titles, occupations, or
industries to identify additional study populations with possible, but not specifi -
cally characterized, exposure to the chemicals of interest were no longer an ef -
ficient means of augmenting the evidence database, in that they are more likely
to retrieve citations with information about a health outcome at the expense of
considerable uncertainty about exposure.
The previous and current committees followed the Update 2006 committee’s
practice of more circumscribed searching. As the information in the database on
populations that had established exposure to the chemicals of interest has grown,
VAO committees have become less dependent on data from studies with non-
specific exposure information and have been able to focus more on findings of
studies with refined exposure specificity. In recognition of the more pivotal role
that findings drawn directly from Vietnam veterans were able to play in its deci-
sions, the committee for Update 2008 reordered its consideration of populations.
For each health outcome, studies of Vietnam veterans, the target population of the
VAO series, are addressed first and then occupational and environmental studies.
It is well accepted that any TCDD or herbicide effect may be diluted some-
what in studies of Vietnam veterans because some of the veterans may not have
been exposed or may have been exposed only at low concentrations. The problem
is exacerbated in studies in which exposure is defined in terms of occupation
(even on the basis of a full job history). Exploratory studies based on linking
to a one-time statement of occupation (for example, on a death certificate or
in a census) are thought to be of little use even when a job–exposure matrix is
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36 VETERANS AND AGENT ORANGE: UPDATE 2010
used to “convert” standardized job codes to specific exposures. Not only is there
uncertainty about whether all members of the sample have been exposed to one
of the chemicals of interest unless detailed personal monitoring and industrial-
hygiene work have been performed but for most occupational categories there is
considerable certainty that the workers were exposed to many other potentially
toxic agents. Thus, such studies may well minimize the effects of exposure to
TCDD or the herbicides of interest while yielding misleading indications of
health problems resulting from other exposures.
The search strategy was devised to ensure that abstracts of all potentially
relevant articles were subjected to closer screening, but it also resulted in the
identification of a large number of nonrelevant studies. The searches produced
in excess of 6,600 “hits,” including some studies that were identified more than
once. It was evident from the abstracts of most of the cited articles that they did
not address health effects in association with exposure to the chemicals of inter-
est; for example, many of the cited studies investigated the efficacy of herbicides
in killing weeds. All studies that discussed health effects were considered if the
search-related information (title, abstract, and keywords) indicated that any of the
herbicides of interest (or any of their components) may have been investigated.
For each of the more than 1,300 potentially relevant citations ultimately identi -
fied, a copy of the entire article was obtained online and reviewed more thor-
oughly by the committee for inclusion in its report. For the present update, very
few documents of interest had to be retrieved as hard copies from library sources.
In large part, included reports are peer-reviewed journal articles, but gener-
ally available and formally published government studies (particularly those
investigating health effects in Vietnam veterans) are also included under the
presumption that they have been carefully reviewed. In practice, the articles are
generally in English, but the committee obtained translations for crucial ones that
were not in English, as in the case of reports of a study of Korean veterans of the
Vietnam War (Kim HA et al., 2003; Kim JS et al., 2003) when Update 2004 was
produced. For the present update, in an effort to determine whether the results
of epidemiologic studies of the Vietnamese population had been published in
foreign-language publications, a search of non-English journals was conducted
on this topic; no additional literature of this sort was identified.
TCDD, the 2,3,7,8-chlorinated congener of dioxin, is the most potent of the
polychlorinated dibenzo-p-dioxins (PCDDs), dibenzofurans, and biphenyls, so it
is presumed to be most problematic of the dioxin-like chemicals contaminating
the phenoxy herbicides used in Vietnam. However, our concern is not limited to
that congener. In nonlaboratory settings—for example, epidemiologic studies—
exposures occur not only to TCDD but to mixtures of dioxins, dibenzofurans, and
PCBs, which vary in their degree of chlorination. The concept of toxic equiva -
lency has been developed primarily to permit overarching estimation of oral ex -
posure and risk from certain environmentally persistent chemicals with structural
similarities to PCDDs and PCDFs that bind the AHR, induce the same spectrum
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EVALUATING THE EVIDENCE
of effects, and bioacumulate in the food chain (van den Berg et al., 2006). A
toxicity equivalency factor (TEF) is an estimate of the dioxin-like potency of
an individual congener relative to the toxicity of TCDD. TEQs are often used to
estimate the cumulative toxic potency of mixtures as the sum of TEFs weighted
by the concentrations of the corresponding congeners in the mixture; this total
is denoted as the mixture’s TEQ in terms of dioxin-like activity. That approach is
often taken in epidemiologic studies that focus on PCBs. Many epidemiologic
studies of PCBs were recovered in the literature search although they were not
specifically sought. Because dioxin-like and non–dioxin-like PCB congeners are
found together in environmental mixtures and are known to mediate toxicity by
various mechanisms, the relative contribution of dioxin-like PCBs to an indi-
vidual health outcome can be difficult to determine. Therefore, evidence from
epidemiologic studies of PCB exposure was retained only for results reported for
specific dioxin-like congeners or in terms of TEQs.
The committee for Update 2008 investigated what pesticides are used in
greenhouses and determined that greenhouse workers are not likely to be exposed
to herbicides, particularly those of interest for VAO committee deliberations
(Czarnota, 2004; Neal, 2006; University of Connecticut, 2006). Results on such
populations (Abell et al., 2000, on fertility; Hansen et al., 1992, on cancer in
female workers) were retroactively excluded from the evidence database con-
sidered in Update 2008, and no new citations for studies of such workers have
been retained.
More than 60 articles on epidemiologic studies and several score of toxicol -
ogy studies contributed new information to the present update. New evidence
on each health outcome was reviewed in detail. The committee’s conclusions,
however, are based on the accumulated evidence, not just on recently published
studies. In a considerable number of instances over the course of the VAO reports,
single study populations have generated multiple entries for a given health out-
come. The past procedure has been to enter new results into the summary results
tables in groups corresponding to successive updates, so it has been difficult to
recognize which findings are based on the experience of the same set of people.
For the present update, the committee adopted a major change in the for-
matting of the tables of cumulative results for the health outcomes in an effort
to make the interrelationships more evident for its own deliberations and for the
reader. The practice followed in previous VAO updates of inserting the findings
from new publications at the beginning of the sections on veteran, occupational,
and environmental studies, thereby creating chronologic bands of studies re-
viewed in an individual update, has been replaced with a presentation of results
by study population. The reported findings on a given condition from a particular
study population have been gathered and presented in reverse chronologic order
so that the most mature set of statistics appears first. In many instances, this will
represent the most informative set of data, the set that has the greatest power
to demonstrate an adverse effect in this population. For some health problems,
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38 VETERANS AND AGENT ORANGE: UPDATE 2010
particularly those common in old age, the toxic effect associated with an external
factor may be to make a disease manifest itself sooner. In such situations, the
evidence of an association with an exposure may consist of a wave of diagnoses
in younger people, and the prevalence will equalize with that of the control group
as the populations age. The committee therefore decided that it could not retain
only the most recent findings when considering the experience of a given study
population.
The cohorts themselves have been ordered in the tables to reflect the over-
arching cohorts of which they are a subgroup. And, the exposure of interest for
each cohort is explicitly noted in the tables to facilitate judgments about when
consistency might be expected among populations that experience the same ex -
posure. That should minimize misapprehensions that there are inconsistencies if
two excellent studies of groups exposed to different chemicals of interest have
incongruent findings.
Primary findings are the components of the evidence that the committee
endeavors to integrate in drawing its conclusions; reanalyses (without the incor-
poration of additional information), pooled analyses, reviews, and so on, may be
discussed in conjunction with primary results or in synthesis sections for a given
health outcome, but they are not themselves part of the evidence dataset.
COMMITTEE’S APPROACH
The committee’s general approach to the evaluation of scientific evidence
corresponds closely with the approach developed by the original VAO committee
as delineated in detail in Chapter 5 of VAO. The committee had three specific
tasks: to determine whether there is a statistical association between exposure to
the herbicides used in Vietnam and health outcomes, to determine the increase
in risk of effects among Vietnam veterans, and to determine whether plausible
biologic mechanisms provide support for a causal relationship with a given health
outcome.
Statistical Association
The issues in determining whether a statistical association exists are detailed
in Chapter 5 of VAO. The committee found that the most relevant evidence came
from epidemiologic studies—investigations in which large groups of people are
studied to identify an association between exposure to a chemical of interest and
the occurrence of particular health outcomes.
Epidemiologists estimate associations between exposure and outcome in a
specific population or group by using such measures as relative risk, standardized
mortality ratio, and odds ratio. Those measures indicate the magnitude of a dif -
ference in the rate of an outcome between two populations. For example, if the
rate in an exposed population is twice the rate in a nonexposed population, the
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EVALUATING THE EVIDENCE
relative risk, or rate ratio, is 2. Similarly, if the odds of a health outcome are 1:20
in an exposed population but 1:100 in a nonexposed population, the odds ratio
is 5. In this report, both relative risk (also called risk ratio) and odds ratio are
used to represent the association between exposure and adverse outcome. Both
measures are often reported in prospective cohort studies. Case–control studies
usually report odds ratios, and cannot report relative risk because the base rate in
the control group is usually not available in these studies. However, it is possible
for case–control studies to provide estimates for relative risk if ancillary informa-
tion on the base rate is available (Hsieh et al., 1985; Langholz, 2010). For rare
diseases with low rates for both the exposed group and the control group, odds is
approximately identical to risk, therefore an odds ratio is approximately identical
to a relative risk (that is,
odds = risk / [1 − risk],
so that when risk is close to zero, [1 − risk] is close to one, and therefore odds will
be close to risk). An estimated relative risk or odds ratio greater than 1 indicates
a positive association (that is, it is more likely that the outcome will be seen in
exposed people than in nonexposed people), whereas a relative risk or odds ratio
between 0 and 1 indicates a negative or inverse association (that is, the outcome
is less likely in exposed people). A relative risk or odds ratio of 1 suggests the
absence of association, which is usually the null hypothesis to be tested. A sta -
tistically significant association is one that would be unlikely to occur by chance
(that is, if the null hypothesis is true). (Chapters 6–11 contain tables of results
abstracted from the studies providing evidence about individual health outcomes.
Because the distinction between risk and odds is of little consequence in the
deliberations of VAO committees, the column labeled “Estimated Risk” presents
these findings without specifying the precise nature of the reported statistic.)
Determining whether an estimated association between an exposure and an
outcome represents a real relationship requires careful scrutiny because there can
be more than one explanation for an estimate. Bias is a distortion of the measure
of association that results from flawed selection in the assembly of the study
population or from error in measurement of studied characteristics. Confounding
is a distortion of the measure of association that results from failure to recognize
or account for some factor related both to exposure and to outcome. Chance is
the degree to which an estimated association might vary randomly among differ-
ent samples of the population studied. The width of a confidence interval is used
to quantify the likely statistical variability of an exposure–disease association,
but it does not incorporate quantification of distortions that may arise from the
systematic problems mentioned above. Even when a relative risk or standardized
mortality ratio substantially exceeds 1, a conclusion regarding increased risk must
be qualified when the confidence interval is wide. In drawing its conclusions, the
committee examined the quantitative estimates of association and evaluated the
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40 VETERANS AND AGENT ORANGE: UPDATE 2010
potential influences of bias, confounding, and chance. In integrating the findings
of various studies, the committee considered the degree of statistical significance
associated with every estimated risk (a reflection of the magnitude of the ob -
served effect and the power of the study designs) rather than simply tallying the
“significant” and “nonsignificant” outcomes as dichotomous items of evidence.
The committee also considered whether controlled laboratory investigations pro -
vide information consistent with the chemicals’ of interest being associated with
a given effect and perhaps causally linked to it.
In pursuing the question of statistical association, the committee recognized
that an absolute conclusion about the absence of association is unattainable. As
in science generally, studies of health effects associated with herbicide exposure
cannot demonstrate that a purported effect is impossible or could never occur,
only that it is statistically improbable. Any instrument of observation, even an
excellent epidemiologic study, is limited in its resolving power. In a strict tech -
nical sense, therefore, the absence of an association between even one chemical
and a health outcome cannot be proved. Convincingly demonstrating the lack of
a particular effect of all five of the compounds of interest simultaneously would
be a daunting effort, especially in light of the paucity of information concern -
ing picloram and cacodylic acid. The present committee therefore endorses the
decision by the committee for Update 2006 to reclassify several types of cancer
that had been classified since VAO (1994) as having “suggestive evidence of no
association” with “exposure to herbicides.”
Interaction or synergism among the chemicals of interest or with other agents
is another theoretical concern. The committee was not charged with attributing
effects to specific chemicals of interest, and joint effects among them should be
adequately identified by the committee’s approach. The number of combinations
of the chemicals with other agents that might be problematic is virtually infi -
nite. Real-life experience, as investigated with epidemiologic studies, effectively
integrates any results of exposure to a target substance over all other possibly
detrimental or mitigating exposures that a population might have. It may not be
possible to partition contributions of the chemicals of interest from those of all
other factors quantitatively, but, to the extent that the possibility of confounding
influences can be appraised, the committee will have achieved its objective.
Increased Risk in Vietnam Veterans
When all the available epidemiologic evidence has been evaluated, it is pre -
sumed that Vietnam veterans are at increased risk for a specific health outcome if
there is evidence of a positive association between one or more of the chemicals
of interest and the outcome. The best measure of potency for the quantification
of risk to veterans would be the rate of the outcome in exposed Vietnam veterans
compared with the rate in nonexposed veterans, adjusted for the degree to which
any other factors that differ between exposed and nonexposed veterans might
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EVALUATING THE EVIDENCE
influence those rates. A dose–response relationship established in another human
population suitably adjusted for such factors would be similarly suitable.
It is difficult to quantify risk when exposures of a population have not been
measured accurately. Recent serum TCDD concentrations are available only
on subgroups enrolled in the Air Force Health Study (AFHS) (the Ranch Hand
and Southeast Asia comparison subjects) and from VA’s study of deployed and
nondeployed members of the Army Chemical Corps. Pharmacokinetic models,
with their own set of assumptions, must be applied to extrapolate from contem -
porary readings to obtain presumably accurate estimates of original exposure of
Vietnam-era veterans. The absence of reliable measures of exposure of Vietnam
veterans to the chemicals of interest limits the committee’s ability to quantify
risks of specific diseases in this population.
Although serum TCDD measurements in only a small portion of Vietnam-era
veterans are available, the observed distributions of these most reliable measures
of exposure make it clear that they cannot be used as a standard to partition vet -
erans into discrete exposure groups, such as service on Vietnamese soil, service
in the Blue Water Navy, and service elsewhere in Southeast Asia. For example,
many TCDD values observed in the comparison group from the AFHS exceeded
US background levels and overlapped considerably with those of the Ranch Hand
subjects.
As explained in Chapter 1, the committee for Update 2006 decided to make a
general statement about its continuing inability to address that aspect of its charge
quantitatively rather than to reiterate a disclaimer in the concluding section for
every health outcome, and the present committee has retained that approach.
Plausible Biologic Mechanisms
Chapter 4, “Information Related to Biologic Plausibility” and previously
denoted as “Toxicology,” details the experimental basis of assessment of biologic
plausibility or the extent to which an observed statistical association in epidemio -
logic studies is consistent with other biologic or medical knowledge. Does the
observation of a particular health effect make sense on the basis of what is known
about how the chemicals in question act at the tissue, cellular, or molecular level?
The relationship between a particular exposure and a specific human health out -
come is addressed in the context of research on the effects of the chemicals on
biologic systems and of evidence from animal studies.
Chapter 4 presents an integrated toxicity profile of each of the chemicals of
interest without providing detailed commentary on each possibly relevant toxicol-
ogy article published in the update period. Experimental information pertinent to
a particular health outcome is now presented immediately after the epidemiologic
evidence on that outcome in the “Biologic Plausibility” sections of the individual
health outcomes (Chapters 6–11).
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EVALUATING THE EVIDENCE
xenobiotic exposures between male and female animals, some of which
are modified by sex steroids; there are probably other reasons for sex
differences.
• Prior and recurring exposures to multiple sources. Humans are ex-
posed to xenobiotics from multiple sources throughout their lifetime.
• Complex mixtures. Most xenobiotic exposures occur in complex mix-
tures; the makeup of these mixtures can greatly influence the ultimate
toxic effects; in addition to dietary modulation of response to other expo -
sures in both humans and animals, human metabolism is further perturbed
by dietary supplements, prescription and over-the-counter pharmaceuti-
cals, and other factors (such as cigarette-smoking or ambient pollution).
• Stress. Stress of known or unknown origin is a well-known modifier of
human disease responses (such as immune responses); stress is an ever-
present variable that is difficult to assess or control for in epidemiologic
studies because there is substantial individual variation in response to
stress (Cohen et al., 2007).
The absence of evidence of biologic plausibility from toxicology studies, how-
ever, does not rule out the possibility of a biologic relationship. In fact, cases in
which the epidemiologic evidence is strong but toxicologic support is lacking
often drive new toxicology research.
As noted in VAO, not only is information on biologic plausibility one of
the primary elements in the oft-cited list of factors that has rather imprecisely
become known as the Bradford Hill (1965) “criteria” for causality (discussed
in more detail at the end of this chapter) but insights about biologic processes
inform whether an observed pattern of statistical association might be interpreted
as the product of more than error, bias, confounding, and chance. The committee
used toxicologic information in that fashion and placed the information before its
synthesis and conclusion to provide readers with a more coherent argument for
its ultimate conclusion about the adequacy of the available evidence to support
the existence of a particular association.
EVALUATION OF THE EVIDENCE
Associations between exposures to the chemicals of interest and specific
health outcomes are determined through an analysis of available epidemiologic
studies that is informed by an understanding of the toxicology of the chemicals
and their exposure pathways. In reaching conclusions, VAO committees consider
the nature of the exposures, the nature of the health outcomes, the populations
exposed, and the quality of the evidence examined. Some specific issues that this
and prior committees have considered are addressed below.
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44 VETERANS AND AGENT ORANGE: UPDATE 2010
Human Studies
The committee reviewed studies of Vietnam veterans and of other popu-
lations that might have been exposed to the chemicals of interest. The other
populations factored into the committee’s evaluation included cohorts of work-
ers in chemical production and agriculture and populations residing near sites of
environmental contamination. The committee believes that studies of such non -
veteran subjects can help in the assessment of whether the chemicals of interest
are associated with particular health outcomes. As noted above in describing the
literature search, studies of nonveteran subjects were identified because one of
the chemicals of interest was specified by the original researchers as presenting a
possible toxic exposure rather than on the basis of occupational definitions. Some
of the studies provide stronger evidence about health outcomes than do studies
of veterans because exposures were measured sooner after occurrence and were
more thoroughly characterized than has been the case in most studies of veterans.
Furthermore, in the studies of workers in chemical-production plants, the mag -
nitude and duration of exposure to the chemicals were generally greater, so the
likelihood that any possible health consequence would be manifested was greater.
The studies were often large enough to examine health risks among groups of
people with different levels of exposure, so dose–response relationships could
be investigated. The general practice of VAO committees has been to evaluate
all studies, whether or not their subjects were Vietnam veterans, according to
the same criteria in determining the strength and validity of findings. Because
the subjects of studies of Vietnam veterans are the concern of the legislation that
mandated the present review, however, demonstrations of increased incidence
of particular health outcomes among them are of unquestionable pertinence in
drawing conclusions.
The committee has concluded that it would be inappropriate to use quan-
titative techniques, such as meta-analysis, to combine individual study results
into a single summary measure of statistical association. The committee reached
that conclusion because of the many differences among studies in definitions of
exposure, health outcomes considered, criteria for defining study populations,
correction for confounding factors, and degree of detail in reporting results. The
appropriate use of meta-analysis requires more methodologic consistency among
studies, especially in the definition of exposure, than is present in the literature
reviewed by the committee (Egger et al., 2002; Petitti, 2000). A detailed dis -
cussion of the results of individual studies in appropriate categories (Vietnam-
veteran, occupational, or environmental exposure; and exposure to Agent Orange
or equivalent dioxin-contaminated phenoxy herbicides, to dioxin, to phenoxy
herbicides without dioxin contamination, to cacodylic acid, or to picloram) with a
thorough examination of each study’s strengths and weaknesses is fully informa -
tive without making unfounded assumptions of homogeneity.
In general, VAO committees have not considered case reports, case series, or
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other published studies that lacked control or comparison groups. An exception
was made, however, for early-onset peripheral neuropathy. Individual case re -
ports were reviewed because the rapid appearance and frequently transient nature
of the condition impose methodologic constraints that might have precluded the
application of standard epidemiologic techniques.
Because any effect of Agent Orange in individuals or groups of veterans is
evaluated in terms of disease or medical outcome, attention to disease classifica -
tion was important to the committee in assembling pertinent data from various
investigations related to a particular outcome before integrating the information.
The researchers who conducted the studies reviewed by the committee faced the
same challenge in interpreting the available documentation when assigning diag -
nostic labels to given subjects and then grouping the labels for analysis.
Pathologists, clinicians, and epidemiologists use several classification sys -
tems, including the International Classification of Diseases (ICD); the Interna-
tional Classification of Diseases, 9th Revision (ICD-9), Clinical Modification
(ICD-9-CM), and the International Classification of Diseases for Oncology. The
10th revision of ICD (ICD-10) is currently used to classify mortality information.
Most of the subjects investigated in the studies cited in this update were diag-
nosed under earlier systems, and most of the articles report results in accordance
with ICD-9 if they use ICD codes at all, so the committee has also used ICD-9.
ICD codes are a hierarchic system for indicating type of disease and site. For
example, ICD-9 162 specifies cancers of the lung, trachea, or bronchus; 162.2,
cancer of a main bronchus; 162.3, cancer of an upper lobe; 162.4, cancer of a
middle lobe, and 162.5, cancer of a lower lobe.
For a patient to receive a correct cancer diagnosis, careful staging of the
extent of disease is necessary, and a biopsy of the tissue must be analyzed with
microscopy, often with special immunohistochemical stains, to confirm a clini -
cal impression. Many of the epidemiologic studies reviewed by this committee
did not use the ICD approach to classification of disease and relied instead on
clinical impression alone. Death-certificate diagnoses are notoriously inaccurate
if the certificates are completed by medical officers who are not familiar with the
decedents’ medical history (Smith Sehdev and Hutchins, 2001). Self-reported
diagnoses, which are obtained from survey questionnaires, often are partially
or completely inaccurate; for instance, a patient may report having been treated
for stomach cancer although the correct diagnosis was gastric adenocarcinoma,
gastric lymphoma, pancreatic cancer, large bowel cancer, or peritoneal cancer.
Many epidemiologic studies report disease outcome by organ system. For
instance, the term digestive system may be used for conditions that are benign or
malignant and that affect the esophagus, stomach, liver, pancreas, small bowel,
large bowel, or rectum. Therefore, if a report indicated that a cohort has an in -
creased incidence of digestive system cancer, it would be unclear whether the
association was attributable to excess cases of esophageal, gastric, hepatic, pan -
creatic, or intestinal cancers or to some combination thereof. Such generalization
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46 VETERANS AND AGENT ORANGE: UPDATE 2010
is complicated by the fact that the cause of cancer may differ between anatomic
sites. For instance, there are strong associations between gastric cancer and Heli-
cobacter pylori infection, between smoking and squamous cell carcinoma of the
esophagus, and between chronic hepatitis B infection and hepatic cancer. Further-
more, a single site may experience a carcinogenic response to multiple agents.
The committee recognizes that outcome misclassification is a possibility
when recording of a diagnosis with a specific ICD code is used as the means of
entering an observation into an analysis, but this system has been refined over
many decades and is virtually universally used and understood, in addition to
being exhaustive and explicit. Therefore, this and previous VAO committees
have opted to use the ICD system as an organizing tool. Although the groupings
of cancer sites for which conclusions about association have been presented may
correspond more closely to National Institute for Occupational Safety and Health
or National Cancer Institute Surveillance Epidemiology and End Results catego -
ries (see Appendix B), the underlying ICD codes provide the most exactitude. In
this report, ICD codes appear almost exclusively in the introductory sections of
health-outcome discussions (particularly for cancers) to specify precisely what
outcome the committee is addressing and, when possible, in the results table to
indicate exactly what the primary researchers believed that they were investi -
gating. (See Appendix B for cancer groupings with corresponding ICD-9 and
ICD-10 codes.)
Rare diseases, such as hairy cell leukemia and tonsil cancer, are difficult to
study because it is hard to accumulate enough cases to permit analysis. Often,
the result is that observed cases are included in a broader, less specific category.
Thus, epidemiologic data may not be available for assessing whether a particu -
lar rare disease is associated with Agent Orange exposure. In some instances,
such as chronic lymphocytic leukemia and AL amyloidosis, VAO committees
have reached conclusions on the basis of the data available and the etiology of
the disease. Through systematic application of the hierarchic nature of the ICD
coding system, committees intend to draw, for every type of cancer, an explicit
conclusion about the adequacy of available evidence to support an association
between herbicide exposure and that type of cancer. For nonmalignant condi -
tions, however, the diversity of disease processes involved makes the use of
broad ICD ranges less useful, but, because VAO committees could not possibly
address every rare nonmalignant disease, they do not draw explicit conclusions
about diseases that are not discussed. Thus, the category of “inadequate or insuf -
ficient evidence to determine an association” is the default or starting point for
any health outcome; if a condition or outcome is not addressed specifically, it
will be in this category.
The committee is aware of the concerns of some veterans about the role
of herbicide exposure in the occurrence of multiple health outcomes, such as
multiple cancers, in a given person. Little research has been done to address
whether the rate of concurrence is greater than would be expected by chance.
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Simultaneous analysis of multiple health outcomes could potentially provide
more insight into whether the chemicals of interest cause multiple health effects,
into competing risks between various health outcomes, and into the interactive
effects of health outcomes; but addressing health conditions individually has
remained challenging.
VAO committees wanted to be clear in indicating what evidence is factored
into their conclusions. The practice in the VAO reports has been to augment the
results table for a given health outcome with any additional publications consid -
ered in the current update in the categories of Vietnam-veteran, occupational, or
environmental studies. Inclusion of sequential sets of results from follow-ups of
a study population has the potential to create the appearance of a greater weight
of evidence than is warranted, so Update 2006 and Update 2008 used italicized
citations in results tables to indicate that results had been superseded. The cur-
rent committee did not want to convey the notion that earlier findings were of
no importance. In an effort to get a comprehensive and comprehensible picture
of the history of each study population, the current committee decided to abandon
the sequential entries by update that had been the format for the result tables since
Update 1996. The new format adopted for the results tables is a refinement of the
cohort-based approach introduced in Update 2006 for cardiovascular diseases. To
facilitate the reader’s locating the discussion of the characteristics of particular
study populations and the attributes of the publications based on them, the order
of studies in the results tables corresponds to their presentation in Chapter 5. The
main categorization of veteran, occupational, and environmental studies has been
retained in both instances.
An issue related to evidence evaluation that was of concern for the Update
2006 committee was the evidence category of “no association.” That commit-
tee determined that a conclusion of no association would require substantive
evidence of such a lack of effect of each of the chemicals of interest. Given the
paucity of information that exists for cacodylic acid and picloram, that conclusion
would seem suspect even if substantial evidence uniformly supported a finding of
no association both with exposure to the phenoxy herbicides and with exposure
to TCDD. The Update 2008 and current committees concurred in that determina-
tion and adopted a similar approach to the placement of health outcomes in this
category.
Exposure Assessment
Much of the evidence that VAO committees have considered has been drawn
from studies of populations that were not in Vietnam during the period when
Agent Orange and other herbicides were used as defoliants. The most informative
of those studies were well-documented investigations of occupational exposures
to TCDD or specific herbicides, such as 2,4-D and 2,4,5-T. In many other stud-
ies, TCDD exposure was combined with exposures to an array of “dioxin-like”
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48 VETERANS AND AGENT ORANGE: UPDATE 2010
compounds, and the herbicides were often analyzed as members of a functional
class; this is less informative for the committee’s purpose than individual results
on a specific compound. In the real-world situations investigated in epidemio -
logic studies, exposure to multiple possibly toxic chemicals is the rule rather
than the exception; for example, farmers and other agricultural populations are
likely to be exposed to insecticides, fungicides, and herbicides. In such studies,
the committee looked for evidence of health effects that are associated with the
specific compounds in the defoliants used in Vietnam and sought consideration
of and adjustment for other possibly confounding exposures.
The quality of exposure information in the scientific literature reviewed by
this and previous VAO committees spans a broad range. Some studies relied on
interviews or questionnaires to determine the extent and frequency of exposure.
Such self-reported information generally carries less weight than would more
objective measures of exposure. The strength of questionnaire-based information
as evidence of exposure is enhanced to the extent that the information can be cor-
roborated or validated by other sources. Written records of chemical purchase or
production can provide one type of objective information. Even more useful are
scientific measurements of exposure. In some occupational studies, for example,
workers wear air-sampling instruments that measure the concentration of a con -
taminant in each worker’s breathing zone. Measurement of chemicals or their
products in biologic specimens, such as blood and urine, can provide reliable in -
dications of exposure for specific periods. Studies that categorize exposure from
well-documented environmental sources of contaminants can be useful in the
identification of exposed populations, but their results may be inaccurate if people
with different magnitudes of exposure are assigned to the same general category
of exposure. Studies that explore environmental exposure and disease frequency
in regional populations (such as states and counties) are known as ecologic stud -
ies. Most ecologic studies are considered preliminary or “hypothesis-generating”
studies because they lack information on exposure and disease on an individual
basis and are unable to address potential confounding factors.
Chapter 3 of this update addresses issues of exposure estimation in more
detail. The agent of interest may be assessed with various degrees of specificity.
For instance, any of the four herbicides in question could be individually mea -
sured, and phenoxy herbicides would be a useful broader category for 2,4,5-T
and 2,4-D; but a report of findings in terms simply of “herbicides” is only on the
margin of being informative, and results stated in terms of “pesticides” are too
vague to be useful. For a given chemical of interest, the measure of exposure
may be increasingly imprecise—for example, concentrations in target tissue,
serum concentrations, cumulative exposure, possible exposure, and so on down
to merely a report of service in a job or industry category. Those approaches
can address complexities in specificity, duration, and intensity of exposure with
various degrees of success. All may provide some information about association
with a chemical of interest, but this committee has determined that investigation
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EVALUATING THE EVIDENCE
of associations between an exposure of concern and most health outcomes has
reached the stage where some characterizations of exposure are too nonspecific
to promote insight. For health outcomes with very little evidence, a somewhat
looser criterion would apply so that no possible signal of an association would
be overlooked.
Animal and Mechanistic Studies
Animal models used as surrogates for the study of a human disease must
reproduce, with some degree of fidelity, the manifestations of the disease in
humans. However, a given effect of herbicide exposure in an animal species
does not necessarily establish its occurrence in humans. In addition to possible
species differences, many factors affect the ability to extrapolate from results of
animal studies to health effects in humans. Animals used in experimental studies
are most often exposed to purified chemicals, not to mixtures. Even if herbicide
formulations or mixtures are used, the conditions of exposure might not realisti -
cally reproduce human exposures that occur in the field. Furthermore, Vietnam
veterans were exposed to other agents—such as tobacco smoke, insecticides,
therapeutics, drugs, diesel fumes, and alcohol—that may increase or decrease the
ability of chemicals in herbicides to produce a particular adverse health outcome.
Few, if any, studies either in humans or in experimental animals have examined
those interactions.
As discussed in Chapter 4, TCDD is thought to be responsible for many of
the toxic effects of the herbicides used in Vietnam. Attempts to establish cor-
relations in the effects of TCDD between experimental systems and humans are
particularly problematic because of known species-, sex-, and outcome-specific
differences in susceptibility to TCDD toxicity. Some data indicate that humans
might be more resistant than are other species to TCDD’s toxic effects (Ema
et al., 1994; Moriguchi et al., 2003); other data suggest that, for some outcomes,
human sensitivity could be the same as or greater than that of some experimental
animals (DeVito et al., 1995). Differences in vulnerability may also be affected
by variations in the rate at which TCDD is eliminated from the body (see Chapter
4 for details on the toxicokinetics of TCDD), although susceptibility is generally
thought be an inherent biological response.
It is important to account for TCDD’s mode of action in considering species
and strain differences. There is a consensus that most of or all the toxic effects of
TCDD involve interaction with the AHR, a protein that binds TCDD and certain
other aromatic hydrocarbons with high affinity. Formation of an active complex
involving the intracellular receptor, the ligand (the TCDD molecule), and other
proteins is followed by interaction of the activated complex with specific sites on
DNA. That interaction can alter the expression of genes involved in the regulation
of cellular processes. The development of mice that lack the AHR has helped to
establish a definitive association between the AHR and TCDD-mediated toxicity.
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50 VETERANS AND AGENT ORANGE: UPDATE 2010
The affinity of TCDD for the AHR is species- and strain-specific, and responses
to binding of the receptor vary among cell types and developmental stages. In
addition, genetic differences in the properties of the AHR are known in human
populations, as they are in laboratory animals, so some people are at intrinsically
greater or less risk for the toxic effects of TCDD.
Although studying AHR biology in transformed human cell lines mini-
mizes the inherent error associated with species extrapolations, caution must be
exercised because it is still not clear to what extent toxicity is affected by the
transformation itself or by the conditions under which cell lines are cultured in
vitro. Furthermore, humans have AHR with differing affinities for dioxin, and
thus a single transformed human cell line will not accurately reflect the responses
observed across the entire human population.
Publication Bias
Some studies are more likely to be published than others. That is the concept
of publication bias, which has been documented in biomedical research (Song
et al., 2000; Stern and Simes, 1997). Most commonly, bias can be introduced
when studies whose hypotheses are supported by statistically significant results
or that are otherwise deemed favorable by their authors are selectively submitted
for publication. In addition, papers with “interesting findings” may be of more
interest to journal editors and reviewers and thus be more likely to be accepted
for publication after submission. Conversely, “negative” studies, in which the
hypotheses being tested are not supported by the study findings, often go un-
published. Investigators employed by industry may be inhibited from submitting
findings that have potential legal or economic ramifications.
Thus, conclusions about associations between exposure and outcome that
are based solely on published results could be subject to bias. Despite that, the
committee does not believe that its conclusions have been unduly affected by
publication bias, for two reasons: the extensive publicity surrounding the pos -
sibility of health effects associated with the herbicides used in Vietnam has cre -
ated considerable pressure to publish all findings on the subject, and the many
published studies assembled and reviewed contain among their results the full
range of possible statistical associations, from convincingly negative through
indeterminate to strongly positive.
Role of Judgment
This committee’s process of reaching conclusions about statistical associa -
tions involved more than a formulaic application of quantitative procedures to the
assembled evidence. First, the committee had to assess the relevance and validity
of individual reports. Then, it had to evaluate the possible influences of mea -
surement error, selection bias, confounding, and chance on the reported results.
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Next, the committee integrated all the evidence within and among diverse fields
of research. Finally, the conclusions drawn were based on consensus within the
committee. Those aspects of the committee’s review required thoughtful consid -
eration of alternative approaches at several points and could not be accomplished
by adherence to a narrowly prescribed formula.
The realized approach, as described here, has been determined to a large
extent by the nature of the exposures, of the health outcomes, and of the result -
ing evidence available for examination; therefore, it has evolved in the course of
the work of this and previous VAO committees. The quantitative and qualitative
procedures underlying this review have been made as explicit as possible, but
ultimately the conclusions about association expressed in this report are based on
the committee’s collective judgment. The committee has endeavored to express
its judgments as clearly and precisely as the data allowed.
In delivering the committee its charge for this update, VA’s representative
requested that the committee delineate, for health outcomes found to have some
evidence supporting statistical association, how well each of the factors that have
rather imprecisely become known as the Hill (1965) “criteria” for causality have
been satisfied. Having a scientific perspective on the extent to which these factors,
in addition to biologic plausibility, were met would help facilitate the Secretary
in making a policy decision concerning a presumptive relationship of any new
health outcome to exposure to the herbicides used by the military in Vietnam.
The committee is uniformly and strongly of the opinion that execution of a
checklist of the Hill criteria would not be an appropriate approach for fulfilling
its charge. The list of issues that Hill discussed are not a definitive set of factors
to be addressed in evaluating whether a collection of evidence supports causal -
ity. The nine aspects of a statistical association noted by Hill (1965)—strength,
consistency, specificity, temporality, biologic gradient, plausibility, coherence,
experiment, and analogy—as contributing to a finding of causality vary in the
importance that might be assigned to them, but none is sufficient, and only
temporality (that the cause precede the effect) is necessary. Philosophers of sci -
ence have established that a set of sufficient criteria for causality does not exist
(Rothman and Greenland, 1998). Citing Weed and Gorelick (1996) and Holman
et al. (2001), Rothman et al. (2008) noted that “epidemiologists have not agreed
on a set of causal criteria or on how to apply them [emphasis in orginal]. . . .
The typical use of causal criteria is to make a case for a position for or against
causality that has been arrived at by other, unstated means.” The establishment
of causality is not an absolute or discrete (or necessarily permanent) state. The
Hill criteria have often been used as a point of reference in addressing the subject
of causation in evaluating possible environmental harms, but even in theoreti -
cal and optimal circumstances scientists have not derived a definitive algorithm
for recognizing causality. The extent to which a relationship is judged to be
causal entails many subjective elements involving the universe of information
considered and the weight accorded to each evidentiary component considered.
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52 VETERANS AND AGENT ORANGE: UPDATE 2010
Furthermore, with regard to chronic diseases, causality is rarely limited to a
single factor.
For those reasons, the present VAO committee has not adopted the suggestion
to perform what would be in effect a checklist approach to distilling evidence
concerning underlying causality for any observed statistical association between
a human health effect and exposure to the components of the herbicides sprayed
in Vietnam. The committee interprets its charge to be to summarize the scientific
evidence for consideration by the Secretary, whose role is to make the policy
decision of whether a contribution by herbicide exposure to the occurrence of
an adverse health effect is likely enough to merit recognition as a presumptive
condition.
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