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3
Exposure to the Herbicides Used in Vietnam
Assessment of human exposure is a key element in addressing two of the
charges that guide the work of this committee. This chapter first presents back-
ground information on the military use of herbicides in Vietnam from 1961 to
1971 with a review of our knowledge of exposures of those who served in Viet-
nam and of the Vietnamese population to the herbicides and to the contaminant
2,3,7,8-tetrachlorodibenzo-p-dioxin (referred to in this report as TCDD, the most
toxic congener of the tetrachlorodibenzo-p-dioxins [tetraCDDs], also commonly
referred to as dioxin). It then reviews several key methodologic issues in human
population studies, namely, disease latency, possible misclassification based on
exposure, and exposure specificity required for scientific evaluation of studies.
Exposure of human populations can be assessed in a number of ways, includ-
ing use of historical information, questionnaires and interviews, measurements
in environmental media, and measurements in biologic specimens. Researchers
often rely on a mixture of qualitative and quantitative information to derive esti-
mates (Armstrong et al., 1994; Checkoway et al., 2004). The most basic approach
compares members of a presumably exposed group with the general population or
with a nonexposed group. That method of classification offers simplicity and ease
of interpretation. A more refined method assigns each study subject to an expo-
sure category, such as high, medium, or low exposure. Disease risk for each group
is calculated separately and compared with a reference or nonexposed group.
That method can identify the presence or absence of an exposure–response trend.
In some cases, more detailed information is available for quantitative exposure
estimates, and these can be used to construct what are sometimes called exposure
metrics. The metrics integrate quantitative estimates of exposure intensity (such
as chemical concentration in air or extent of skin contact) with exposure duration
46
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4
EXPOSURE TO THE HERBICIDES USED IN VIETNAM
to produce an estimate of cumulative exposure. Exposure also can be assessed
by measuring chemicals and their metabolites in human tissues. Such biologic
markers of exposure integrate absorption from all routes, and their interpretation
requires knowledge of pharmacokinetic processes. All those approaches have
been used in studies of Vietnam veterans.
MILITARY USE OF HERBICIDES IN VIETNAM
Military use of herbicides in Vietnam took place from 1962 through 1971.
Selection of the specific herbicides to be used was based on tests conducted in
the United States and elsewhere that were designed to evaluate their defoliation
efficacy (IOM, 1994; Young and Newton, 2004). Four compounds were used in
the herbicide formulations in Vietnam: 2,4-dichlorophenoxyacetic acid (2,4-D),
2,4,5-trichlorophenoxyacetic acid (2,4,5-T), 4-amino-3,5,6-trichloropicolinic acid
(picloram), and dimethylarsinic acid (cacodylic acid). The chemical structures of
those compounds are presented in Chapter 2 (Figure 2-1). The herbicides were
used to defoliate inland hardwood forests, coastal mangrove forests, cultivated
land, and zones around military bases. In 1974, a National Academy of Sciences
committee estimated the amount of herbicides sprayed from helicopters and other
aircraft by using records gathered from August 1965 through February 1971
(NAS, 1974). That committee calculated that about 18 million gallons (about
68 million liters) of herbicide were sprayed over about 3.6 million acres (about
1.5 million hectares) in Vietnam in that period. The amount of herbicides sprayed
on the ground to defoliate the perimeters of base camps and fire bases and the
amount sprayed by Navy boats along river banks were not estimated.
A new analysis of spray activities and exposure potential of troops emerged
from a recent study overseen by a committee of the Institute of Medicine (IOM)
(IOM, 1997, 2003a,b). That work yielded new estimates of the use of military
herbicides in Vietnam from 1961 through 1971 (Stellman et al., 2003a). The
investigators reanalyzed the original data sources that were used to develop
herbicide-use estimates in the 1970s and identified errors that inappropriately
removed spraying missions from the dataset. They also added new data on spray-
ing missions that took place before 1965. Finally, a comparison of procurement
records with spraying records indicated errors in both types and suggested that
additional spraying had taken place but gone unrecorded at the time.
The new analyses led to a revision in estimates of the amounts of the agents
applied, as indicated in Table 3-1. The new research effort estimated that about
77 million liters were applied, about 9 million liters more than the previous
estimate.
Herbicides were identified by the color of a band on 55-gal containers and
were called Agents Pink, Green, Purple, Orange, White, and Blue. Agent Green
and Agent Pink were used in 1961 and 1965, and Agent Purple in 1962–1965.
Agent Orange was used in 1965–1970, and a slightly different formulation (Agent
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TABLE 3-1 Military Use of Herbicides in Vietnam (1961–1971)
48
Amount Sprayed
Concentration of Active
Code Name Chemical Constituentsa Ingredienta Years Useda VAO Estimateb Revised Estimatea
Pink 60% n-butyl: 40% isobutyl ester of 2,4,5-T 961–1,081 g/L acid 1961, 1965 464,817 L 50,312 L sprayed;
equivalent (122,792 gal) 413,852 L additional on
procurement records
Green n-butyl ester of 2,4,5-T — 1961, 1965 31,071 L 31,026 L on procurement
(8,208 gal) records
Purple 50% n-butyl ester of 2,4-D, 30% n-butyl ester 1,033 g/L acid equivalent 1962–1965 548,883 L 1,892,733 L
of 2,4,5-T, 20% isobutyl ester of 2,4,5-T (145,000 gal)
Orange 50% n-butyl ester of 2,4-D, 50% n-butyl ester 1,033 g/L acid equivalent 1965–1970 42,629,013 L 45,677,937 L (could
of 2,4,5-T (11,261,429 gal) include Agent Orange II)
Orange II 50% n-butyl ester of 2,4-D, 50% isooctyl ester 910 g/L acid equivalent After 1968 — Unknown; at least
of 2,4,5-T 3,591,000 L shipped
White Acid weight basis: 21.2% triisopropanolamine By acid weight, 240 g/L 1966–1971 19,860,108 L 20,556,525 L
salts of 2,4-D, 5.7% picloram 2,4-D, 65 g/L picloram (5,246,502 gal)
Blue powder Cacodylic acid (dimethylarsinic acid) sodium Acid, 65% active ingredient; 1962–1964 — 25,650 L
cacodylate salt, 70% active ingredient
Blue aqueous 21% sodium cacodylate + cacodylic acid to Acid weight, 360 g/L 1964–1971 4,255,952 L 4,715,731 L
solution yield at least 26% total acid equivalent by (1,124,307 gal)
weight
Total, all 67,789,844 L 76,954,766 L (including
formulations (17,908,238 gal) procured)
a Based on Stellman et al. (2003a).
b Based on data from MRI (1967), NAS (1974), and Young and Reggiani (1988).
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49
EXPOSURE TO THE HERBICIDES USED IN VIETNAM
Orange II) probably was used after 1968. Agent White was used in 1966–1971.
Agent Blue was used in powder form in 1962–1964 and as a liquid in 1964–1971.
Agents Pink, Green, Purple, Orange, and Orange II all contained 2,4,5-T and
were contaminated to some extent with TCDD. Agent White contained 2,4-D
and picloram. Agent Blue (powder and liquid) contained cacodylic acid. The
chlorinated phenoxy acids 2,4-D and 2,4,5-T persist in soil for only a few weeks;
picloram is much more stable, persisting in soil for years; and cacodylic acid is
nonvolatile and stable in sunlight (NAS, 1974). More details on the herbicides
used are presented in the initial National Academy of Sciences report (NAS,
1974) and the initial VAO report (IOM, 1994).
TCDD IN HERBICIDES USED IN VIETNAM
TCDD is formed during the manufacture of 2,4,5-T in the following manner:
trichlorophenol (2,4,5-TCP), the precursor for the synthesis of 2,4,5-T, is formed
by the reaction of tetrachlorobenzene and sodium hydroxide (Figure 3-1a);
2,4,5-T is formed when 2,4,5-TCP reacts with chloroacetic acid (Figure 3-1b);
small amounts of TCDD are formed as a byproduct of the intended main reaction
(Figure 3-1b) when a molecule of 2,4,5-TCP reacts with the tetrachlorobenzene
stock (Figure 3-1c) instead of with chloroacetic acid. For each step in the reaction,
a chlorine atom is replaced with an oxygen atom, and this leads to the final TCDD
molecule (NAS, 1974). In the class of compounds known as polychlorinated
dibenzo-p-dioxins (PCDDs), 75 congeners can occur, depending on the number
and placement of the chlorines. Cochrane et al. (1982) noted that TCDD had been
found in pre-1970 samples of 2,4,5-TCP. Other PCDDs—2,7-dichloro-dibenzo-
p-dioxin and 1,3,6,8-tetrachloro-dibenzo-p-dioxin—were measured in the same
samples. The concentration of TCDD in any given lot of 2,4,5-T depended on the
manufacturing process (FAO/UNEP, 2009; Young et al., 1976).
The manufacture of 2,4-D is based on a different process. Its synthesis
is based on dichlorophenol, a molecule formed from the reaction of phenol
with chlorine (NZIC, 2009). Neither tetrachlorobenzene nor trichlorophenol is
formed during this reaction, so TCDD is not normally a byproduct of the syn-
thetic process. However, other, less toxic PCDDs have been detected in pre-1970
commercial-grade 2,4-D (Cochrane et al., 1982; Rappe et al., 1978; Tosine,
1983). Cochrane et al. (1982) found multiple PCDDs in isooctyl ester, mixed
butyl ester, and dimethylamine salt samples of 2,4-D. It has also been noted that
cross-contamination of 2,4-D by 2,3,7,8-TCDD occurred in the operations of at
least one major manufacturer (Lilienfeld and Gallo, 1989).
TCDD concentrations in individual herbicide shipments were not recorded
but were known to vary from batch to batch and between manufacturers. TCDD
concentrations in stocks of Agent Orange remaining after the conflict, which ei-
ther had been returned from South Vietnam or had been procured but not shipped,
ranged from less than 0.05 ppm to almost 50 ppm and averaged 2–3 ppm in two
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0 VETERANS AND AGENT ORANGE: UPDATE 2008
a. Trichlorophenol, the precursor for the synthesis of 2,4,5-T, is formed by the reaction of
tetrachlorobenzene and sodium hydroxide (NaOH).
b. The herbicide 2,4,5-T is formed when a reactive form of trichlorophenol (2,4,5-tri-
chlorophenoxide) reacts with chloroacetic acid.
c. TCDD is formed when a molecule of trichlorophenol reacts with its own precursor,
tetrachlorobenzene. Two intermediate steps are shown in this diagram. At each step, an
oxygen–carbon bond forms as a chlorine atom is released. This reaction does not occur
in the synthesis of 2,4-D, because these precursors with adjacent chlorines are not used
in its production.
FIGURE 3-1 TCDD formation during 2,4,5-T production.
Figure 3-1abc.eps
sets of samples (NAS, 1974; Young et al., 1978). Comparable manufacturing
standards for the domestic use of 2,4,5-T in 1974 required that TCDD not be
present at over 0.05 ppm (NAS, 1974).
Until recently, data from Young and Gough have been used to estimate the
amount of TCDD in the various herbicide formulations (Gough, 1986; Young,
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1
EXPOSURE TO THE HERBICIDES USED IN VIETNAM
1992; Young et al., 1978). Young et al. (1978) estimated that Agents Green,
Pink, and Purple—used early in the program (through 1965)—contained 16
times the mean TCDD content of the formulations used in 1965–1970, whereas
mean TCDD concentrations in Agents Pink and Green were estimated at 66 ppm.
Gough (1986) estimated that about 167 kg of TCDD was sprayed in Vietnam
over a 6-year period.
A new analysis by researchers at Columbia University benefited from access
to military spray records that had not been available earlier and has resulted in
substantial revisions of the estimates (Stellman et al., 2003a). The investigators
were able to incorporate newly found data on spraying in the early period of
the war (1961–1965) and to document that larger volumes of TCDD-containing
herbicides were used in Vietnam than had been estimated previously. They also
found that the earlier estimates of TCDD contamination in the herbicide formula-
tions were too low, noting that the original estimates were based on samples at the
lower end of the distribution of concentration values. They concluded that mean
TCDD concentrations in Agent Orange were closer to 13 ppm than to the earlier
estimates of 3 ppm. They therefore proposed 366 kg of TCDD as a plausible
estimate of the total amount of TCDD applied in Vietnam during 1961–1971.
EXPOSURE OF VIETNAM VETERANS
Determination of exposure among US military personnel who served in
Vietnam has been a great challenge in the study of health effects associated with
herbicides and TCDD. Some military personnel stationed in cities or on large
bases may have received little or no herbicide exposures, whereas troops who
moved through defoliated areas soon after treatment may have been exposed
through soil contact, drinking water, or bathing. Reliable estimates of the magni-
tude and duration of such exposures are not possible in most cases, given the lack
of contemporaneous chemical measurements and the lack of records of individual
behaviors. In accord with Congress’s mandated presumption of herbicide expo-
sure for all Vietnam veterans, VAO committees have treated Vietnam-veteran
status as a proxy for some herbicide exposure when no more specific exposure
information is available.
Exposure of Herbicide Handlers
Military personnel who came into direct contact with the herbicidal com-
pounds through mixing, loading, spraying, and clean-up activities had relatively
high exposures to herbicides. The US Environmental Protection Agency refers to
such personnel as pesticide handlers and provides special guidance for prevent-
ing or minimizing their exposure during those activities in its worker protection
standard for pesticides (EPA, 1992). The number of US military personnel who
handled herbicides directly is not known precisely, but two groups have been
identified as high-risk subpopulations among veterans: Air Force personnel in-
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2 VETERANS AND AGENT ORANGE: UPDATE 2008
volved in fixed-wing aircraft spraying activities (often referred to as Operation
Ranch Hand), and members of the US Army Chemical Corps (ACC) who used
hand-operated equipment and helicopters to conduct smaller-scale operations,
including defoliation around special-forces camps; clearing of the perimeters of
airfields, depots, and other bases; and small-scale crop destruction (NRC, 1980;
Thomas and Kang, 1990; Warren, 1968). Additional units and individuals handled
or sprayed herbicides around bases or lines of communication; for example, Navy
river patrols were reported to have used herbicides to clear inland waterways, and
engineering personnel used herbicides to remove underbrush and dense growth
in constructing fire-support bases. However, they have not been the subject of
epidemiologic studies. The herbicides used in Vietnam were not considered to
present an important human health hazard at that time, so few precautions were
taken to prevent exposure of personnel (GAO, 1978, 1979); that is, military per-
sonnel did not typically use chemical-protective gloves, coveralls, or protective
aprons, so substantial skin exposure almost certainly occurred in these popula-
tions in addition to exposure by inhalation and incidental ingestion (such as by
hand-to-mouth contact).
The Air Force personnel who participated in Operation Ranch Hand were
the first Vietnam-veteran subpopulation to receive special attention with regard
to herbicide exposure. In the Air Force Health Study (AFHS), the members
of this Ranch Hand cohort were contrasted with Air Force personnel who had
served elsewhere in Southeast Asia during the Vietnam era. The AFHS began in
1979 (IOM, 2006). The exposure index initially proposed in it relied on military
spray records for the TCDD-containing herbicides (Agents Orange, Purple, Pink,
Green) and helped to identify the members of the cohort. The subjects were fur-
ther characterized by military occupation, and exposure in the cohort and com-
parison group was evaluated through measurement of TCDD in blood (serum)
samples drawn in 1987 or later. A general increase in serum TCDD was detected
in people whose jobs involved more frequent handling of herbicides, but there
was no clear demarcation between the distributions of serum concentrations in
the Ranch Hand subjects and in the comparison group (AFHS, 1991). Several
methods for estimating herbicide exposure of members of the cohort were de-
veloped on the basis of questionnaires and focused on such factors as number of
days of skin exposure, percentage of skin area exposed, and the concentration
of TCDD in the different herbicidal formulations (Michalek et al., 1995). Most
recent analyses of the AFHS data have relied on serum TCDD concentration as
the primary exposure metric for epidemiologic classification (Kern et al., 2004;
Michalek et al., 2001, 2003; Pavuk et al., 2003). The IOM has issued a compre-
hensive review of the AFHS with recommendations for the use of the extensive
data collected in the project (IOM, 2006).
Members of the ACC performed chemical operations on the ground and by
helicopter and were thereby involved in the direct handling and distribution of
herbicides in Vietnam. They were identified for detailed study of health effects
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EXPOSURE TO THE HERBICIDES USED IN VIETNAM
related to herbicide exposure only in the late 1980s (Thomas and Kang, 1990).
An initial feasibility study recruited Vietnam veterans and nondeployed Vietnam-
era veterans from within the ACC (Kang et al., 2001). Blood samples collected
in 1996 from 50 Vietnam veterans showed an association between those who
reported spraying herbicides and higher TCDD concentrations; this finding was
confirmed in a follow-up study of a larger fraction of the cohort (Kang et al.,
2006).
Exposure of Ground Troops
In light of the widespread use of herbicides in Vietnam for many years, it is
reasonable to assume that many military personnel were inadvertently exposed to
the chemicals of concern. Surveys of Vietnam veterans who were not part of the
Ranch Hand or ACC groups have indicated that 25–55% believe that they were
exposed to herbicides (CDC, 1989a). That view has been supported by govern-
ment reports (GAO, 1979) and reiterated by veterans and their representatives in
testimony to the VAO committees over the last several years.
Numerous attempts were made in the 1980s to characterize herbicide expo-
sures of people who served as ground troops in Vietnam (CDC, 1988; Erickson
et al., 1984; NRC, 1982; Stellman and Stellman, 1986; Stellman et al., 1988).
The efforts combined self-reported contact with herbicides or military service
records with aerial-spray data to produce an “exposure opportunity” index. For
example, Erickson et al. (1984) created five exposure categories based on military
records to examine the risks of birth defects among the offspring of veterans.
Those studies were conducted carefully and provided reasonable estimates based
on available data, but no means of testing the validity of the estimates were avail-
able at the time.
The search for a validation method led to the development of exposure bio-
markers in veterans. Initial studies measured concentrations of dioxin in adipose
tissue of veterans (Gross et al., 1984; Schecter et al., 1987). A study sponsored
by the New Jersey Agent Orange Commission was the first to link dioxin con-
centrations in adipose tissue to dioxin concentrations in blood (Kahn et al.,
1988). At the same time, the Center for Disease Control undertook what came
to be called the Agent Orange Validation Study, measuring TCDD in the serum
portion of blood from a relatively large sample of Vietnam veterans and veterans
who served elsewhere during the Vietnam era (CDC, 1989b). The study did not
find a significant difference in TCDD serum concentrations among the groups.
A review of a preliminary report of the work by an advisory panel established
through the IOM concluded that the long lag between exposure and the serum
measurements (about 20 years) called into question the accuracy of exposure
classification based on serum concentrations. The panel concluded that estimates
based on troop locations and herbicide-spraying activities might be more reliable
indicators of exposure serum measurements (IOM, 1987).
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4 VETERANS AND AGENT ORANGE: UPDATE 2008
The report of the VAO committee (IOM, 1994) proposed further work on
exposure reconstruction and development of a model that could be used to
categorize exposures of ground troops. The committee cautioned that serum
TCDD measurements not be regarded as a “gold standard” for exposure, that
is, as a fully accurate measure of herbicide exposure. Recent efforts to develop
exposure-reconstruction models for US Vietnam veterans are discussed later in
this chapter.
One other effort to reconstruct exposure has been reported by researchers
in the Republic of Korea (Kim et al., 2001, 2003). They developed an exposure
index for Korean military personnel who served in Vietnam. The exposure in-
dex was based on herbicide-spray patterns in military regions in which Korean
personnel served during 1964–1973, time–location data on the military units
stationed in Vietnam, and an exposure score derived from self-reported activities
during service. The researchers were not successful in an attempt to validate their
exposure index with serum dioxin measurements.
Exposure of Personnel Who Had Offshore Vietnam Service
US Navy riverine units are known to have used herbicides while patrolling
inland waterways (IOM, 1994; Zumwalt, 1993), and it is generally acknowledged
that estuarine waters became contaminated with herbicides and dioxin as a result
of shoreline spraying and runoff from spraying on land. Thus, military personnel
who did not serve on land were among those exposed to the chemicals during
the Vietnam conflict. A particular concern for the personnel has been possible
contamination of drinking water. Most vessels serving offshore but within the
territorial limits of the Republic of Vietnam converted seawater to drinking water
through distillation.
Higher than expected mortality among Royal Australian Navy Vietnam vet-
erans prompted a study of potable-water contamination on ships offshore dur-
ing the Vietnam conflict (Mueller et al., 2001, 2002). Specifically, the study
investigated the potential for naval personnel to ingest TCDD and cacodylic
acid in drinking water. The study focused on the evaporative distillation process
that was used to produce potable water from surrounding estuarine waters. The
study found that codistillation of dioxins was observable in all experiments con-
ducted and that distillation increased the concentration of dioxins in the distillate
compared with the concentration in the source water. The study also found that
dimethylarsenic acid did not codistill to a great extent during evaporation and
concluded that drinking water on ships was unlikely to have been contaminated
with this herbicide. In a follow-up discussion of the study with its authors, it
was noted that vessels would take up water for distillation as close to shore as
possible to minimize salt content (Wells, 2006). On the basis of that study and
other evidence, the Australian Department of Veterans Affairs determined that
Royal Australian Navy personnel who served offshore were exposed to dioxins
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EXPOSURE TO THE HERBICIDES USED IN VIETNAM
that resulted from herbicide spraying in Vietnam even if they did not go ashore
during their tour of duty (ADVA, 2005).
The current committee engaged Steven Hawthorne as a consultant to review
the Mueller et al. (2002) publication and to comment generally on the abil-
ity of organic compounds to codistill during the production of potable water.
Hawthorne is an environmental chemist at the University of North Dakota’s
Energy and Environmental Research Center and has specific expertise in the
study of organic emissions from water (Hawthorne et al., 1985). He affirmed the
findings of the Australian study, citing Henry’s law for an explanation of how
contaminants with low water solubility would evaporate from water and not-
ing that the distillation process would enhance the process by adding heat and
reducing pressure (SB Hawthorne, University of North Dakota Energy Research
Center, personal communication on October 23, 2008). No measurements of
dioxin concentrations in seawater were collected during the Vietnam conflict, so
it is not possible to ascertain the extent to which drinking water on US vessels
may have been contaminated through distillation processes. However, it seems
likely that vessels with such distillation processes that traveled near land or even
at some distance from river deltas would periodically collect water that contained
dioxin. Thus, a presumption of exposure of military personnel serving on those
vessels is not unreasonable.
In its charge to the original VAO committee, the Department of Veterans
Affairs asked the committee to include military personnel who served in inland
waterways, offshore of the Republic of Vietnam, and in the airspace above the
Republic of Vietnam. A presumption of exposure to Agent Orange and other
herbicides used as defoliants applied to each of those groups as well as to those
who served on land. In light of the findings of the Australian study regarding
potential drinking-water contamination and those serving offshore, the presump-
tion seems well founded.
EXPOSURE OF THE VIETNAMESE POPULATION
Studies of exposure to herbicides among the residents of South Vietnam
have compared nonexposed residents of the South with residents of the North
(Constable and Hatch, 1985). Other studies have attempted to identify wives of
veterans of North Vietnam who served in South Vietnam. Records of herbicide
spraying have been used to refine exposure measurements, comparing people who
lived in sprayed villages in the South with those living in unsprayed villages. In
some studies, village residents were considered exposed if a herbicide mission
had passed within 10 km of the village center (Dai et al., 1990). Other criteria
for classifying exposure included length of residence in a sprayed area and the
number of times the area reportedly had been sprayed.
A small number of studies have provided information on TCDD concentra-
tions in Vietnamese civilians exposed during the war (Schecter et al., 1986, 2002,
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6 VETERANS AND AGENT ORANGE: UPDATE 2008
2006). Dwernychuk et al. (2002) have emphasized the need to evaluate dioxin
contamination around former air bases in Vietnam. They collected environmen-
tal and food samples, human blood, and breast milk from residents of the Aluoi
Valley of central Vietnam. The investigators identified locations where relatively
high dioxin concentrations remained in soil or water systems. Soil dioxin concen-
trations were particularly high around former air fields and military bases where
herbicides were handled. Fish harvested from ponds in those areas were found
to contain high dioxin concentrations. More recently, Dwernychuk (2005) elabo-
rated on the importance of “hot spots” as important locations for future studies
and argued that herbicide use at former US military installations was the most
likely cause of the hot spots. The above studies are not directly relevant to this
committee’s task, but they may prove useful in future epidemiologic studies of
the Vietnamese population and in the development of risk-mitigation policies.
The only new study of dioxin in Vietnam reviewed by the committee ex-
amined dioxin contamination in soils (Mai et al., 2007). The study focused on
the Bien Hoa Air Base, considered a hot spot because of the use of chemical
defoliants around the base, and found high dioxin concentrations. The study did
not involve estimates of exposure of the population living in the vicinity of the
bases.
NEW MODELS FOR CHARACTERIZING HERBICIDE EXPOSURE
IOM, following up on the recommendations contained in the original VAO
report (IOM, 1994), issued a request for proposals seeking individuals and or-
ganizations to develop historical exposure-reconstruction approaches suitable
for epidemiologic studies of herbicide exposure among US veterans during the
Vietnam War (IOM, 1997). The request resulted in the project Characterizing Ex-
posure of Veterans to Agent Orange and Other Herbicides in Vietnam. The project
was carried out under contract by a team of researchers in Columbia University’s
Mailman School of Public Health. The Columbia University project integrated
various sources of information concerning spray activities to generate individual-
ized estimates of the exposure potential of troops serving in Vietnam (Stellman
and Stellman, 2003). Location data on military units assigned to Vietnam were
compiled into a database.
“Mobility-factor” analysis, a new concept for studying troop movement, was
developed for use in reconstructing herbicide-exposure histories. The analysis is
a three-part classification system for characterizing the location and movement of
military units in Vietnam. It comprises a mobility designation (stable or mobile),
a distance designation (usually in a range of kilometers) to indicate how far a unit
might travel in a day, and a notation of the modes of travel available to the unit
(air; ground by truck, tank, or armored personnel carrier; or water). A mobility
factor was assigned to every unit that served in Vietnam.
The data were combined into a geographic information system (GIS) for
Vietnam. Herbicide-spraying records were integrated into the GIS and linked
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EXPOSURE TO THE HERBICIDES USED IN VIETNAM
with data on military-unit locations to permit estimation of individual exposure-
opportunity scores. The results are the subject of reports by the contractor
(Stellman and Stellman, 2003) and the Committee on the Assessment of War-
time Exposure to Herbicides in Vietnam (IOM, 2003a,b). A summary of the
findings regarding the extent and pattern of herbicide spraying (Stellman et al.,
2003a), a description of the GIS for characterizing exposure to Agent Orange and
other herbicides in Vietnam (Stellman et al., 2003b), and an explanation of the
exposure-opportunity models based on that work (Stellman and Stellman, 2004)
have been published in peer-reviewed journals. The publications have argued that
it is now feasible to conduct epidemiologic investigations of veterans who served
as ground troops during the Vietnam War.
A different perspective has been put forth by Young and colleagues in a series
of papers (Young et al., 2004a,b). They have argued that ground troops had little
direct contact with herbicide sprays and that TCDD residues in Vietnam had low
bioavailability. Those conclusions were based on analyses of previously unpub-
lished military records and environmental-fate studies. They have also argued that
ground-troop exposures were relatively low because herbicide-spraying missions
were carefully planned, and spraying occurred only when friendly forces were
not in the target area.
Since Update 2006, IOM has issued a report that examined the feasibil-
ity of using the Agent Orange Reconstruction Model developed by Columbia
University (IOM, 2008). The report concluded that “despite the shortcomings of
the exposure assessment model in its current form and the inherent limitations
in the approach, the committee agreed that the model holds promise for support-
ing informative epidemiologic studies of herbicides and health among Vietnam
veterans and that it should be used to conduct studies.”
METHODOLOGIC ISSUES IN EXPOSURE ASSESSMENT
Analyses of Vietnam-veteran studies have been an important source of in-
formation for understanding associations between the herbicides used in Vietnam
and specific health outcomes, but, as discussed in Chapter 2, the committee has
extended its review of the scientific literature to other populations in which ex-
posure could be estimated with greater accuracy. Those populations are discussed
in detail in Chapter 5. We focus here on several key methodologic issues that
complicate development of accurate exposure estimates in the Vietnam-veteran
population and in the other study populations discussed in this report: the latent
period between exposure and disease, exposure misclassification, and exposure
specificity.
Latency
The temporal relationship between exposure and disease is complex and
often difficult to define in studies of human populations. Many diseases do not
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8 VETERANS AND AGENT ORANGE: UPDATE 2008
appear immediately after exposure. In the case of cancer, for example, the disease
may not appear for many years after exposure. The time between a defined expo-
sure period and the occurrence of disease is often referred to as a latency period
(IOM, 2004). Exposures can be brief (sometimes referred to as acute exposures)
or protracted (sometimes referred to as chronic exposures). At one extreme, an
exposure can be the result of a single event, as in an accidental poisoning. At
the other extreme, a person exposed to a chemical that is stored in the body may
continue to experience “internal exposure” for years even if exposure from the
environment has ceased. The definition of the proper timeframe for duration of
exposure constitutes a challenge to exposure scientists.
Misclassification
Exposure misclassification in epidemiologic studies can affect estimates of
risk. A typical situation is in a case–control study in which the reported mea-
surement of exposure of either group or both groups can be misclassified. The
simplest situation to consider is one in which the exposure is classified into just
two levels, for example, ever vs never exposed. If the probability of exposure
misclassification is the same in cases and controls (that is, non-differential), then
it can be shown that the estimated association between disease and exposure is
biased toward the null value; in other words, one would expect the true associa-
tion to be stronger than the association observed. However, if the probability of
misclassification is different between cases and controls, bias in the estimated
association can occur in either direction; in this case, the true association might
be stronger or weaker than the association observed.
The situation in which exposure is classified into more than two levels is
somewhat more complicated. Dosemeci et al. (1990) have demonstrated that in
that situation the slope of a dose–response trend is not necessarily attenuated
toward the null value even if the probability of misclassification is the same in
the two groups of subjects being compared; in other words, the observed trend in
disease risk across the several levels of exposure may be either an overestimate or
an underestimate of the true trend in risk. Greenland and Gustafson (2006) have
discussed the effect of exposure misclassification on the statistical significance of
the result, demonstrating that if one adjusts for exposure misclassification when
the exposure is represented as binary (for example, ever vs never exposed), the
resulting association is not necessarily more significant than in the unadjusted
estimate. That result remains true even though the observed magnitude of the
association (for example, the relative risk) might be increased.
Specificity
Only a few herbicidal compounds were used as defoliants during the Vietnam
conflict: esters and salts of 2,4-D and 2,4,5-T, cacodylic acid, and picloram in
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9
EXPOSURE TO THE HERBICIDES USED IN VIETNAM
various formulations. Many scientific studies reviewed by the committee have
reported exposures to broad categories of chemicals rather than to those specific
compounds. The categories are presented in Table 3-2, with their relevance to
the committee’s charge. The information in Table 3-2 represents the current
committee’s thinking and has helped to guide our evaluation of epidemiologic
studies. Previous VAO committees did not necessarily address the issue of expo-
sure specificity in this manner.
Many studies have examined the relationship between exposure to “pesti-
cides” and adverse health outcomes, and others have used the category of “her-
bicides” without identifying specific compounds. A careful reading of a scientific
report often reveals that none of the compounds of interest (those used in Viet-
nam, as delineated above) contributed to the exposures of the study population, so
such studies could be excluded from consideration. But in many cases, the situ-
ation is more ambiguous. For example, reports that define exposure in the broad
category of “pesticides” with no further information have little relevance to the
committee’s charge to determine associations between exposures to herbicides
used in Vietnam and adverse health outcomes. Reports that define exposure in the
more restricted category of “herbicides” are of greater relevance but are of little
value unless it is clear from additional information that exposure to one or more
of the herbicides used in Vietnam occurred in the study population, for example,
TABLE 3-2 Current Committee Guidance for the Classification of Exposure
Information in Epidemiologic Studies That Focus on the Use of Pesticides
or Herbicides, and Relevance of the Information to the Committee’s Charge
to Evaluate Exposures to 2,4-D and 2,4,5-T (phenoxy herbicides), Cacodylic
Acid, and Picloram
Relevance to
Specificity of Exposure Committee’s
Reported in Study Additional Information Charge
Pesticides Chemicals of interest were not used or no Not relevant
additional information
Chemicals of interest were used Limited relevance
Herbicides Chemicals of interest were not used Not relevant
No additional information Limited relevance
Chemicals of interest were used Relevant
Phenoxy herbicides Highly relevant
2,4-D or 2,4,5-T Highly relevant
Cacodylic acida Highly relevant
Picloram Highly relevant
aNone of the epidemiologic studies reviewed by the committee to date have specified exposure to
cacodylic acid.
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60 VETERANS AND AGENT ORANGE: UPDATE 2008
if the published report indicates that the chemicals of interest were among the
pesticides or herbicides used by the study population, the lead author of a pub-
lished report has been contacted and has indicated that the chemicals of interest
were among the chemicals used, the chemicals of interest are used commonly for
the crops identified in the study, or the chemicals of interest are used commonly
for a specific purpose, such as removal of weeds and shrubs along highways.
Among the various chemical classes of herbicides that have been identified
in published studies reviewed by the committee, phenoxy herbicides, particularly
2,4-D and 2,4,5-T, are directly relevant to the exposures experienced by US
military forces in Vietnam. On the basis of the assumption that compounds with
similar chemical structure may have analogous biologic activity, information on
the effects of other chemicals in the phenoxy herbicide class—such as Silvex,
2-methyl-4-chlorophenoxyacetic acid (MCPA), 2-(2-methyl-4-chlorophenoxy)
propionic acid (MCPP, Mecoprop), and dicamba—has been factored into the
committee’s deliberations with somewhat less weight. The very few epidemio-
logic findings on exposure to picloram or cacodylic acid have been regarded as
highly relevant. The committee has decided to include many studies that report on
unspecified herbicides in the discussions in the health-effects sections, and their
results have been entered into the health-outcome–specific tables. However, these
studies tend to contribute little to the evidence considered by the committee. The
many studies that provide chemical-specific exposure information are believed
to be far more informative for the committee’s purposes.
A similar issue arises in the evaluation of studies that document exposure to
dioxin-like compounds. Most “dioxin” studies reviewed by the committee have
focused on TCDD, but TCDD is only one of a number of PCDDs. The commit-
tee recognizes that in real-world conditions exposure to TCDD virtually never
occurs in isolation and that there are hundreds of similar compounds to which
humans might be exposed, including other PCDDs, polychlorinated dibenzofu-
rans, and polychlorinated biphenyls (PCBs). Exposure to TCDD is almost always
accompanied by exposure to one or more of the other compounds. The literature
on the other compounds, particularly PCBs, was not reviewed systematically by
the committee unless TCDD was identified as an important component of the
exposure or the risks of health effects were expressed in terms of toxicity equiva-
lent quotients, which are the sums of toxicity equivalency factors for individual
dioxin-like compounds as measured by activity with the aryl hydrocarbon recep-
tor (AHR). We took that approach for two reasons. First, exposure of Vietnam
veterans to substantial amounts of the other compounds, relative to exposure to
TCDD, has not been documented. Second, the most important mechanism for
TCDD toxicity involves its ability to bind to and activate the AHR. Many of the
other compounds act by different or multiple mechanisms, so it is difficult to at-
tribute toxic effects after such exposures to TCDD.
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EXPOSURE TO THE HERBICIDES USED IN VIETNAM
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