Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter.
Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.
Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.
OCR for page 54
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, which is referred to in this report as TCDD
(and commonly referred to as dioxin) and is the most toxic congener of the
tetrachlorodibenzo-p-dioxins. It then reviews several key methodologic issues in
human population studies; disease latency, possible misclassification based on
exposure, and exposure specificity required for scientific evaluation of studies.
Further discussion is presented to underscore the difficulties of assessing expo -
sure in the complex environment that characterized Vietnam during the period
of interest.
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 such
estimates (Armstrong et al., 1994; Checkoway et al., 2004). The most basic ap-
proach compares members of a presumably exposed group with the general popu-
lation or with a nonexposed group; this method of classification offers simplicity
and ease of interpretation. A more refined method assigns each study subject to
an exposure category—such as high, medium, or low exposure—and calculates
disease risk for each group separately and compares it with the risk for a refer-
ence or nonexposed group; this method can identify the presence or absence of
an exposure–response trend. In some cases, more detailed information is avail -
54
OCR for page 55
55
EXPOSURE TO THE HERBICIDES USED IN VIETNAM
able for quantitative exposure estimates that 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 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
exposure routes, but their interpretation requires knowledge of pharmacokinetic
processes. All those exposure-assessment 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.
Tests conducted in the United States and elsewhere designed to evaluate defo -
liation efficacy were used to select specific herbicides (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 dimethyl -
arsinic 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 lands, and zones around
military bases. In 1974, a National Resource Council committee estimated the
amount of herbicides sprayed from helicopters and other aircraft by using records
gathered from August 1965 through February 1971 (NRC, 1974). That commit -
tee calculated that about 18 million gallons (about 68 million liters) of herbicide
was 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 revised analysis of spray activities and exposure potential of troops
emerged from a study overseen by a committee of the Institute of Medicine
(IOM, 1997, 2003a,b). That work yielded new estimates of the amounts of mili-
tary herbicides used 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 found errors that suggested that additional spraying
had taken place but gone unrecorded at the time. The new analyses led to revision
of 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.
OCR for page 56
TABLE 3-1 Military Use of Herbicides in Vietnam (1961–1971)
56
Amount Sprayed
Concentration of Years
Code Name Chemical Constituentsa Active Ingredienta Useda VAO Estimateb Revised Estimatea
Pink 60% n-butyl ester 40% isobutyl ester of 1961, 1965 464,817 L 50,312 L sprayed; 413,852 L
961-1,081 g/L acid
2,4,5-T equivalent (122,792 gal) additional on procurement records
Green n-butyl ester of 2,4,5-T — 1961, 1965 31,071 L 31,026 L on procurement records
(8,208 gal)
Purple 50% n-butyl ester of 2,4-D, 30% n-butyl ester 1,033 g/L acid 548,883 L 1,892,733 L
1962-1965
of 2,4,5-T, 20% isobutyl ester of 2,4,5-T equivalent (145,000 gal)
Orange 50% n-butyl ester of 2,4-D, 50% n-butyl ester 1,033 g/L acid 42,629,013 L 45,677,937 L (could include
1965-1970
of 2,4,5-T equivalent (11,261,429 gal) Agent Orange II)
Orange II 50% n-butyl ester of 2,4-D, 50% isooctyl 910 g/L acid After 1968 — Unknown; at least 3,591,000 L
ester of 2,4,5-T equivalent shipped
White Acid weight basis: 21.2% triisopropanolamine By acid weight, 240 19,860,108 L 20,556,525 L
1966-1971
salts of 2,4-D, 5.7% picloram g/L 2,4-D, 65 g/L (5,246,502 gal)
picloram
Blue powder Cacodylic acid (dimethylarsinic acid) sodium Acid, 65% active — 25,650 L
1962-1964
cacodylate ingredient; salt, 70%
active ingredient
Blue aqueous 21% sodium cacodylate + cacodylic acid to Acid weight, 360 g/L 4,255,952 L 4,715,731 L
1964-1971
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)
aBased on Stellman et al. (2003a).
bBased on data from MRI (1967), NRC (1974), and Young and Reggiani (1988).
OCR for page 57
57
EXPOSURE TO THE HERBICIDES USED IN VIETNAM
Herbicides were identified by the color of a band on 55-gal shipping contain-
ers and were called Agent Pink, Agent Green, Agent Purple, Agent Orange, Agent
White, and Agent 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 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. Agent Pink, Agent Green,
Agent Purple, Agent Orange, and Agent 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 (NRC, 1974). More details on the herbicides
used are presented in the initial IOM report, Veterans and Agent Orange: Health
Effects of Herbicides Used in Vietnam (VAO; 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 reac -
tion, a chlorine atom is replaced with an oxygen atom, and this leads to the final
TCDD molecule (NRC, 1974). In the class of compounds known as polychlo-
rinated dibenzo-p-dioxins (PCDDs), 75 congeners can occur, depending on the
number and placement of the chlorine atoms. 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 mea-
sured 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 a different process: its synthesis is based
on dichlorophenol, a molecule formed from the reaction of phenol with chlo-
rine (NZIC, 2009). Neither tetrachlorobenzene nor trichlorophenol is formed
during this reaction, so TCDD is not normally a byproduct of the manufactur-
ing 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).
OCR for page 58
58 VETERANS AND AGENT ORANGE: UPDATE 2010
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-trichlo -
rophenoxide) 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 the 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
OCR for page 59
59
EXPOSURE TO THE HERBICIDES USED IN VIETNAM
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
sets of samples (NRC, 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 (NRC, 1974).
Data from Young and Gough were originally used to estimate the amount of
TCDD in the various herbicide formulations (Gough, 1986; Young, 1992; Young
et al., 1978). Young et al. (1978) estimated that Agent Green, Agent Pink, and
Agent 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 Agent Pink and Agent Green were estimated at 66 ppm.
Gough (1986) estimated that about 167 kg of TCDD was sprayed in Vietnam
over a 6-year period.
Later 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 the earlier estimates of TCDD contamination in the herbicide formulations
to be low, noting that the original estimates were based on samples at the lower
end of the distribution of concentration. They concluded that the mean TCDD
concentration in Agent Orange was closer to 13 ppm than to the earlier estimate
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 exposures of US military personnel who served in Vietnam
has been perhaps the greatest 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 exposure, 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, the lack of a full understanding of
the movement and behavior of the defoliants in the environment, and the lack of
records of individual behaviors and locations. Consequently, most studies have
focused on populations that had well-defined tasks that brought them into contact
with the agents. It is believed that the subjects of those studies, primarily Air
OCR for page 60
60 VETERANS AND AGENT ORANGE: UPDATE 2010
Force personnel involved in fixed-wing aircraft spraying activities (often referred
to as Operation Ranch Hand) and members of the US Army Chemical Corps
(ACC), may have also had among the highest exposures. As described below,
exposures of ground troops are difficult to define, so this group has not been as
intensely studied. In accord with Congress’s mandated presumption of herbicide
exposure of 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 chemi -
cals through mixing, loading, spraying, and clean-up activities had relatively high
exposures to them. The US Environmental Protection Agency refers to such per-
sonnel as pesticide handlers and provides special guidance for preventing or mini -
mizing 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 involved in Opera-
tion Ranch Hand and members of the ACC who used hand-operated equipment
and helicopters to conduct smaller-scale operations, including defoliation around
special-forces camps; clearing 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. The latter groups 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 personnel did not typically use
chemical-protective gloves, coveralls, or protective aprons, so substantial skin
exposure almost certainly occurred in these populations 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 population to receive special attention with regard to
herbicide exposure. In the Air Force Health Study (AFHS), job and work history,
biomarkers, and health outcomes of 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 relied on military spray records for the TCDD-containing
herbicides (Agent Orange, Agent Purple, Agent Pink, and Agent Green), which
also helped to identify the members of the cohort. The subjects were further char-
OCR for page 61
61
EXPOSURE TO THE HERBICIDES USED IN VIETNAM
acterized by military occupation, and exposure in the cohort and the comparison
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 TCDD concentrations
in the Ranch Hand subjects and those in the comparison group (AFHS, 1991).
Several methods for estimating herbicide exposure of members of the cohort were
developed 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). IOM has issued a comprehensive
review of the AFHS with recommendations for the use of the extensive data col-
lected in the project (IOM, 2006).
Members of the ACC performed herbicide-spraying operations on the ground
and by helicopter and were thereby involved in the direct handling and distribu -
tion of Agent Orange and other herbicides in Vietnam. They were identified for
detailed study of health effects 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 from 50 Vietnam veterans in 1996 showed
an association between those who reported spraying herbicides and higher serum
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 past 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-reports of contact with herbicides or military service
records with aerial-spray data to produce an “exposure opportunity index” (EOI).
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 vet -
erans. Those studies were conducted carefully and provided reasonable estimates
OCR for page 62
62 VETERANS AND AGENT ORANGE: UPDATE 2010
based on available data, but no means of testing the validity of the estimates were
available 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 concen-
trations in adipose tissue to dioxin concentrations in blood (Kahn et al., 1988).
At the same time, the Centers for Disease Control (now the Centers for Disease
Control and Prevention) undertook what came to be called the Agent Orange Vali-
dation 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 statistically significant
difference in mean serum TCDD concentrations between the groups. A review
of a preliminary report of the work by an advisory panel established through
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 than serum measurements (IOM, 1987).
The report of the first 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. 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 who developed an exposure index for Korean military per-
sonnel who served in Vietnam (Kim et al., 2001, 2003). The exposure index 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 ser-
vice. 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. In recent years, concern about dioxin exposure via drinking
water has arisen among personnel who served offshore but within the territorial
OCR for page 63
63
EXPOSURE TO THE HERBICIDES USED IN VIETNAM
limits of the Republic of Vietnam on ships that converted seawater to drinking
water through distillation. Since the last VAO update, NAS convened the Blue
Water Navy Vietnam Veterans and Agent Orange Exposure Committee to address
that specific issue; its recently released report (IOM, 2011) found that information
to determine the extent of exposure experienced by Blue Water Navy personnel
was inadequate, but that there were possible routes of exposure.
EXPOSURE OF THE VIETNAMESE POPULATION
As summarized by Constable and Hatch (1985), Vietnamese researchers
have made a number of attempts to characterize the herbicide exposure of resi-
dents of Vietnam in the process of trying to assess adverse reproductive out -
comes. Some compared residents of the South with residents of the unsprayed
North, and others endeavored to compare South Vietnamese people who lived
in sprayed and unsprayed villages, as determined by observed defoliation. For
evaluating reproductive outcomes, pregnancy outcomes of North Vietnamese
women married to veterans who served in South Vietnam were compared with
those of women whose husbands had not. In some cases, records of herbicide
spraying have been used to refine exposure measurements. In assessing infant
mortality, Dai et al. (1990) considered village residents to have been exposed if
a herbicide mission had passed within 10 km of the village center and further
classified exposure by length of residence in a sprayed area and the number of
times that 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,
2006). Dwernychuk et al. (2002) emphasized the need to evaluate dioxin con-
tamination around former air bases in Vietnam. They collected environmental 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 concentra -
tions were particularly high around former airfields 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 Bien Hoa Air Base, considered a hot spot be -
cause of the use of chemical defoliants around the base, was the focus of a study
examining dioxin contamination in soils in Vietnam (Mai et al., 2007). The study
found high soil concentrations but did not involve estimation of the exposure of
people who lived in the vicinity of the bases.
Since Update 2008, there has been an increase in the number of publi-
cations reporting mostly environmental concentrations of dioxins in various
areas throughout Vietnam (Brodsky et al., 2009; Feshin et al., 2008; Hatfield
OCR for page 64
64 VETERANS AND AGENT ORANGE: UPDATE 2010
Consultants, 2009a,b,c; Nhu et al., 2009; Saito et al., 2010). Taken as a whole,
those studies suggest a pervasive exposure to dioxins—not limited to hot spots—
through environmental media throughout the country more than a half-century
after they were initially deposited.
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.
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 orga -
nizations to develop historical exposure-reconstruction approaches suitable for
epidemiologic studies of herbicide exposure of US veterans during the Vietnam
War (IOM, 1997). The request resulted in the project Characterizing Exposure
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 and information on
location of military units assigned to Vietnam, all compiled into a database, to
generate individualized estimates of the exposure potential of troops serving in
Vietnam (Stellman and Stellman, 2003).
“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 kilometers) to indicate how far a unit might
travel in a day, and a notation of the modes of travel available to the unit (by
air, by water, or on the ground by truck, tank, or armored personnel carrier). 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
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 Wartime
Exposure to Herbicides in Vietnam (IOM, 2003a,b). A summary of the findings on
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 feasible to
conduct epidemiologic investigations of veterans who served as ground troops
during the Vietnam War. IOM later issued a report that examined the feasibility
OCR for page 65
65
EXPOSURE TO THE HERBICIDES USED IN VIETNAM
of using the Agent Orange Reconstruction Model developed by Columbia Uni-
versity (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.”
A different perspective has been put forth by Young and colleagues in a se -
ries 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 previ -
ously unpublished military records and environmental-fate studies. They have
also argued that direct exposures of ground troops 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 2008, a pair of industry-sponsored papers that used a math-
ematical model of herbicide dispersion and deposition from aerial spraying
concluded that actual ground deposition of Agent Orange was many orders of
magnitude lower than that predicted by previous exposure estimations proposed
for use in evaluating ground-troop health effects (Ginevan et al., 2009a,b). The
new papers first undertook a quantitative evaluation of the Stellman EOI model
(Stellman and Stellman, 2004; Stellman et al., 2003a,b) recommended for pos -
sible use in an epidemiologic evaluation of ground troops by IOM (2008). The
new evaluation revealed frequent and substantial inconsistencies in the calculated
EOI based in part on the use of a central equation “contrary to a large body of
pesticide exposure assessment practice,” the general imprecision of spray-flight
path records, the use of 1.2-km2 exposure cells in the model, and “unknown
computational errors” in the model. The analyses demonstrated unexpected and
unexplained 1,000-fold differences in model output for sample flight paths that
appear to be in all respects equivalent. The authors propose the use of the
AgDRIFT Tier III model as a more accurate and appropriate estimator of ground-
troop potential exposures. That model uses a combination of standard Lagrangian
and Gaussian techniques in combination with empirically derived information,
such as aerosol penetration through a forest canopy, to estimate ground-level
exposure. The AgDRIFT Tier III model is purportedly validated and used by
the US Forest Service to plan aerial application of various agents to forests. The
AgDRIFT model predicts a much smaller area of impact under the spray path
and Agent Orange concentrations lower by several orders of magnitude than the
EOI estimates for the same set of sample flight paths. That effect is particularly
pronounced at points distant from the spray path; the AgDRIFT model predicts
Agent Orange exposures up to 20 orders of magnitude lower than the EOI model
at a point 4 km away from the flight-path centerline. Finally, the authors point out
that the use of any exposure model for ground troops will be severely limited by
the imprecision of spatial and temporal measures of troop movements.
OCR for page 66
66 VETERANS AND AGENT ORANGE: UPDATE 2010
Exposure assessment of human populations is difficult. It is most reliable
in situations in which there is a single or predominant source of contamination
or a single route of exposure that occurs over a short period, such as the atomic
bomb studies used to assess the health effects of radiation exposure. Accurate and
reliable assessment is far more problematic in situations with multiple dispersed
sources of contamination or multiple routes of exposure that occur over an ex-
tended period many years in the past. Exposure-assessment studies for the Ranch
Hand and ACC cohort studies approach the former scenario in their relative
simplicity and ease. Nonetheless, attempts to quantify exposures to date, even
at the level of serum biomarkers of exposure, have been less than satisfactory.
In the case of ground troops, which more nearly approaches the latter scenario,
few studies have characterized exposure beyond “in-theater” vs “not-in-theater”
comparisons. Considerable work has been done by National Academies commit -
tees and others to develop ground-troop exposure assessments based on num -
bers, patterns, and timing of aerial spray missions combined with troop-location
information.
Although previously recommended by earlier VAO committees, the Stellman
model has not yet been applied in a study evaluating the health of ground troops.
The focus on aerial spraying as the primary exposure, however, may be misplaced.
To ascribe a health effect to an exposure in an epidemiologic study accurately, one
must account for all sources and routes of exposure—a concept now popularly
termed total exposure assessment. In the Vietnam theater, there were undoubtedly
multiple sources and routes of TCDD exposure of ground troops other than being
directly under an aerial-spray mission. The relative magnitudes of those sources
and whether the aerial spray route predominated are unknown and now prob-
ably unknowable. For instance, troops in the field commonly collected drinking
water from streams. Some of those streams are still highly polluted with TCDD.
Although the ultimate source of the TCDD in the streams may have been aerial
spraying, the concentration of TCDD in the water would not necessarily be cor-
related with spray mission exposure estimates and could conceivably far exceed
the “direct exposure” estimates, depending on the terrain, rainfall, timing of water
collection, and other unknown factors. The dynamic nature of TCDD released into
the environment is largely unknown quantitatively, so an exposure assessment that
accounts for all sources of TCDD exposure is impossible. In addition, an assess -
ment of total exposure must include an understanding of coexposures that could
confound TCDD exposure analyses or otherwise directly account for an observed
health effect. Studies have not factored coexposures into health risk estimates.
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
OCR for page 67
67
EXPOSURE TO THE HERBICIDES USED IN VIETNAM
extended its review of the scientific literature to other populations in which expo -
sure could be estimated with greater accuracy. Those populations are discussed in
detail in Chapter 5. We focus here on several key methodologic issues that com -
plicate development of accurate estimates of exposure of the Vietnam-veteran
population and 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 ap-
pear immediately after exposure. Cancer, for example, might not appear for many
years after exposure. The time between a defined exposure period and the occur-
rence of disease is often referred to as a latent 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, nondifferential), 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 association to
be stronger than the observed association. However, if the probability of misclas -
sification is different between cases and controls, bias in the estimated association
can occur in either direction, and the true association might be stronger or weaker
than the observed association.
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 to -
ward the null value even if the probability of misclassification is the same in the
two groups of subjects being compared; the observed trend in disease risk across
the several levels of exposure may be either an overestimate or an underestimate
OCR for page 68
68 VETERANS AND AGENT ORANGE: UPDATE 2010
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 expo -
sure 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
Incorporation of findings of studies of persons exposed to components of
the herbicides sprayed in Vietnam requires some decisions about their relative
contributions to the VAO project’s evidentiary database. Only a few herbicidal
chemicals 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 various formulations. Many
scientific studies reviewed by the committee report exposures to broad categories
of chemicals rather than to those specific chemicals. The categories are presented
in Table 3-2 with their relevance to the committee’s charge. The information in
Tables 3-2 and 3-3 represents the committee’s current thinking with respect to
their relevance and has helped to guide its evaluation of epidemiologic studies.
Earlier VAO committees did not address the issue of exposure specificity in
exactly this manner. The committee for VAO and the first several updates gave
more weight to results based solely on job title (for example, “farmer” with
no additional information) than have the committees for the last three updates
but entirely excluded findings from the Yusho and Yucheng polychlorinated
biphenyl (PCB) poisonings, whereas recent committees have factored in results
that are now more commonly expressed in terms of individual dioxin-like PCB
congeners.
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 chemicals. A careful reading of a scientific
report often reveals that none of the chemicals of interest (those used in Vietnam,
as delineated above) contributed to the exposures of the study population, so such
studies could be excluded from consideration. But in many cases, the situation is
more ambiguous. For example, reports that define exposure in the broad category
of “pesticides” with no further information have little relevance to the commit -
tee’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, if the
published report indicates that the chemicals of interest were among the pesti -
cides or herbicides used by the study population, the lead author of a published
OCR for page 69
69
EXPOSURE TO THE HERBICIDES USED IN VIETNAM
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
Specificity of Exposure Relevance to
Reported in Study Additional Information Committee’s Charge
Pesticides Chemicals of interest were not used, or there was Not relevant
no additional information
Chemicals of interest were used Limited relevance
Herbicides Chemicals of interest were not used Not relevant
There was 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
acida
Cacodylic — Highly relevant
Picloram — Highly relevant
aNone of the epidemiologic studies reviewed by the committee to date has specified exposure to
cacodylic acid.
TABLE 3-3 Current Committee Guidance for the Classification of Exposure
Information in Epidemiologic Studies That Focus on Exposure to Dioxin-like
Chemicals and Relevance of the Information to the Committee’s Charge
Specificity of Exposure Relevance to
Reported in Study Additional Information Committee’s Charge
Dioxin-like chemicals Exposure to PCBs or polychlorinated Limited relevance
dibenzofuron (PCDF)
Dioxin-like chemicals Results expressed in terms of (total) toxic Highly relevant
equivalents (TEQs) or concentrations of
individual congeners recognized as having dioxin-
like activitya
TCDD or mixture of Established on the basis of environmental Highly relevant
PCDDs sampling or work histories
TCDD or mixture of Concentrations in tissues of a subset of Very highly relevant
PCDDs participants (preferably soon after exposure)
TCDD or mixture of Concentrations in tissues of individual Most informative
PCDDs participants (preferably soon after exposure)
aThe values of toxic equivalency factors for individual dioxin-like chemicals, which are weighted
by concentration and summed to derive TEQs are presented in Table 4-2.
OCR for page 70
70 VETERANS AND AGENT ORANGE: UPDATE 2010
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, 2-(2-methyl-4-chlorophenoxy) propionic
acid (Mecoprop), and dicamba—has been factored into the committee’s delib-
erations with somewhat less weight. The very few epidemiologic 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 their 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
committee recognizes that in real-world conditions exposure to TCDD virtu -
ally never occurs in isolation and that there are hundreds of similar compounds
to which humans might be exposed, including other PCDDs, polychlorinated
dibenzofurans (PCDFs), and PCBs. Exposure to TCDD is almost always ac-
companied by exposure to one or more of the other compounds. The literature
on the other compounds, particularly PCBs, has not been reviewed systemati-
cally 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
equivalent quotients (TEQs), which are the sums of toxicity equivalency fac -
tors for individual dioxin-like compounds as measured by activity with the aryl
hydrocarbon receptor (AHR). The committee took that approach for two reasons.
First, exposure of Vietnam veterans to substantial amounts of the other chemicals,
relative to exposure to TCDD has not been documented. Second, the most impor-
tant mechanism for TCDD toxicity involves its ability to bind to and activate the
AHR. Many of the other chemicals act by different or multiple mechanisms, so
it is difficult to attribute toxic effects after such exposures specifically to TCDD.
Furthermore, people’s environmental exposures to dioxin-like chemicals and their
non–dioxin-like counterparts are to mixtures of components that tend to be corre-
lated, so it is not surprising that specific chemicals measured in a person’s serum
also tend to be correlated; this means that it will be difficult for epidemiologic
OCR for page 71
71
EXPOSURE TO THE HERBICIDES USED IN VIETNAM
studies to attribute any observed association to a particular chemical configuration
(Longnecker and Michalek, 2000). Analyses in terms of TEQs circumvent that
problem to some extent.
REFERENCES1
AFHS (Air Force Health Study). 1991. An Epidemiologic Investigation of Health Effects in Air Force
Personnel Following Exposure to Herbicides. Serum Dioxin Analysis of 1987 Examination Re -
sults. Air Force Health Study. Brooks AFB, TX: USAF School of Aerospace Medicine. 9 vols.
Armstrong BK, White E, Saracci R. 1994. Principles of Exposure Assessment in Epidemiology. New
York: Oxford University Press.
Brodsky ES, Shelepchikov AA, Feshin DB, Roumak VS, Umnova NV, Kuznetsov AN, Sau TK,
Truong NX, Pavlov DS. 2009. The current level of dioxin pollution in the area of large-scale
spraying of Agent Orange in Vietnam. Doklady Biological Sciences 429:526–530.
CDC (Centers for Disease Control). 1988. Serum 2,3,7,8-tetrachlorodibenzo- p-dioxin levels in US
Army Vietnam era veterans. Journal of the American Medical Association 260:1249–1254.
CDC. 1989a. Health Status of Vietnam Veterans. Vietnam Experience Study. Atlanta: US Department
of Health and Human Services. Vols. I–V, Supplements A–C.
CDC. 1989b. Comparison of Serum Levels of 2,3,7,8-Tetrachlorodibenzo-p-Dioxin with Indirect Es-
timates of Agent Orange Exposure Among Vietnam Veterans: Final Report. Centers for Disease
Control. Atlanta: US Department of Health and Human Services.
Checkoway H, Pearce NE, Kriebel D. 2004. Research Methods in Occupational Epidemiology (2nd
Edition). New York: Oxford University Press.
Cochrane WP, Sirgh J, Miles W, Wakeford B, Scott J. 1982. Analysis of technical and formulated
products of 2,4-dichlorophenoxyacetic acid for the presence of chlorinated dibenzo- p-dioxins.
In: Hutzinger O, Frei RW, Merian E, Pocchiari F, eds. Chlorinated Dioxins and Related Com-
pounds: Impact on the Environment. Oxford: Pergamon Press, pp. 209–213.
Constable JD, Hatch MC. 1985. Reproductive effects of herbicide exposure in Vietnam: Recent stud -
ies by the Vietnamese and others. Teratogenesis, Carcinogenesis, and Mutagenesis 5:231–250.
Dai LC, Phuong NTN, Thom LH, Thuy TT, Van NTT, Cam LH, Chi HTK, Thuy LB. 1990. A com -
parison of infant mortality rates between two Vietnamese villages sprayed by defoliants in
wartime and one unsprayed village. Chemosphere 20:1005–1012.
Dosemeci M, Wacholder S, Lubin JH. 1990. Does nondifferential misclassification of exposure always
bias a true effect toward the null value? American Journal of Epidemiology 132(4):746–748.
Dwernychuk LW. 2005. Dioxin hot spots in Vietnam. Chemosphere 60(7):998–999.
Dwernychuk LW, Cau HD, Hatfield CT, Boivin TG, Hung TM, Dung PT, Thai ND. 2002. Dioxin
reservoirs in southern Viet Nam–A legacy of Agent Orange. Chemosphere 47(2):117–137.
EPA (US Environmental Protection Agency). 1992. Worker Protection Standard. Washington, DC:
US Environmental Protection Agency,.
Erickson JD, Mulinare J, Mcclain PW. 1984. Vietnam veterans’ risks for fathering babies with birth
defects. Journal of the American Medical Association 252:903–912.
FAO/UNEP (Food and Agriculture Organization, United Nations Environment Programme). 2009.
2,4,5-T and Its Salts and Esters. Decision Guidance Documents. Secretariat for the Rotterdam
Convention on the Prior Informed Consent Procedure for Certain Hazardous Chemicals and
Pesticides in International Trade. Joint FAO/UNEP Programme for the Operation of the Prior
Informed Consent. Accessed March 9, 2009, at http://www.pic.int/en/DGDs/2,4,5-TEN.doc.
1 Throughout this report the same alphabetic indicator after year of publication is used consistently
for a given reference when there are multiple citations by the same first author in a given year. The
convention of assigning the alphabetic indicator in order of citation in a given chapter is not followed.
OCR for page 72
72 VETERANS AND AGENT ORANGE: UPDATE 2010
Feshin DB, Shelepchikov AA, Brodskii ES, Kalinkevich GA, Mir-Kadyrova EY, Rumak VS, Pavlov
DS. 2008. Current levels of PCDDs and PCDFs in the placenta and breast milk of the population
of Vietnam. Doklady Biological Sciences 423:443–446.
GAO (General Accounting Office). 1978. Use of Agent Orange in Vietnam. Washington, DC: GAO.
CED-78-158.
GAO. 1979. US Ground Troops in South Vietnam Were in Areas Sprayed with Herbicide Orange.
Report by the Comptroller General of the United States. Washington, DC: GAO. FPCD 80-23.
Ginevan ME, Ross JH, Watkins DK. 2009a. Assessing exposure to allied ground troops in the Vietnam
War: A comparison of AgDRIFT and exposure opportunity index models. Journal of Exposure
Science and Environmental Epidemiology 19(2):187–200.
Ginevan ME, Watkins DK, Ross JH, O’Boyle RA. 2009b. Assessing exposure to allied ground troops
in the Vietnam War: A quantitative evaluation of the Stellman exposure opportunity index
model. Chemosphere 75(11):1512–1518.
Gough M. 1986. Dioxin, Agent Orange: The Facts. New York: Plenum Press.
Greenland P, Gustafson S. 2006. The performance of random coefficient regression in accounting for
residual confounding. Biometrics 62(3):760–768.
Gross ML, Lay JO, Lippstreu D, Lyon PA, Kangas N, Harless RL, Taylor SE. 1984. 2,3,7,8-tetra -
chlorodibenzo-p-dioxin levels in adipose tissue of Vietnam veterans. Environmental Research
33:261.
Hatfield Consultants. 2009a. Comprehensive Assessment of Dioxin Contamination in Da Nang Air-
port, Vietnam: Environmental Levels, Human Exposure and Options for Mitigating Impacts—
Final Report. North Vancouver, British Columbia, Canada: Ford Foundation Special Initiative
on Agent Orange/Dioxin.
Hatfield Consultants. 2009b. Appendices. North Vancouver, British Columbia, Canada: Ford Founda-
tion Special Initiative on Agent Orange/Dioxin.
Hatfield Consultants. 2009c. Comprehensive Assessment of Dioxin Contamination in Da Nang Air-
port, Vietnam: Environmental Levels, Human Exposure and Options for Mitigating Impacts—
Final Summary of Findings. North Vancouver, British Columbia, Canada: Ford Foundation
Special Initiative on Agent Orange/Dioxin.
IOM (Institute of Medicine). 1987. Review of Comparison of Serum Levels of 2,3,7,8-TCDD with
Indirect Estimates of Agent Orange Exposure in Vietnam Veterans. Fifth Letter Report. Wash-
ington DC: National Academy Press.
IOM. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington,
DC: National Academy Press.
IOM. 1997. Characterizing Exposure of Veterans to Agent Orange and Other Herbicides Used in
Vietnam: Scientific Considerations Regarding a Request for Proposals for Research. Washing-
ton, DC: National Academy Press.
IOM. 2003a. Characterizing Exposure of Veterans to Agent Orange and Other Herbicides Used in
Vietnam: Interim Findings and Recommendations. Washington, DC: The National Academies
Press.
IOM. 2003b. Characterizing Exposure of Veterans to Agent Orange and Other Herbicides Used in
Vietnam: Final Report. Washington, DC: The National Academies Press.
IOM. 2004. Veterans and Agent Orange: Length of Presumptive Period for Association Between
Exposure and Respiratory Cancer. Washington, DC: The National Academies Press.
IOM. 2006. Disposition of the Air Force Health Study. Washington, DC: The National Academies
Press.
IOM. 2008. The Utility of Proximity-Based Herbicide Exposure Assessment in Epidemiologic Studies
of Vietnam Veterans. Washington DC: The National Academies Press.
IOM. 2011. Blue Water Navy Vietnam Veterans and Agent Orange Exposure. Washington DC: The
National Academies Press.
OCR for page 73
73
EXPOSURE TO THE HERBICIDES USED IN VIETNAM
Kahn PC, Gochfeld M, Nygren M, Hansson M, Rappe C, Velez H, Ghent-Guenther T, Wilson WP.
1988. Dioxins and dibenzofurans in blood and adipose tissue of Agent Orange-exposed Vietnam
veterans and matched controls. Journal of the American Medical Association 259:1661–1667.
Kang HK, Dalager NA, Needham LL, Patterson DG, Matanoski GM, Kanchanaraksa S, Lees PSJ.
2001. US Army Chemical Corps Vietnam Veterans Health Study: Preliminary results. Chemo-
sphere 43:943–949.
Kang HK, Dalager NA, Needham LL, Patterson DG, Lees PSJ, Yates K, Matanoski GM. 2006. Health
status of Army Chemical Corps Vietnam veterans who sprayed defoliant in Vietnam. American
Journal of Industrial Medicine 49(11):875–884.
Kern PA, Said S, Jackson WG Jr, Michalek JE. 2004. Insulin sensitivity following agent orange
exposure in Vietnam veterans with high blood levels of 2,3,7,8-tetrachlorodibenzo- p-dioxin.
Journal of Clinical Endocrinology and Metabolism 89(9):4665–4672.
Kim JS, Kang HK, Lim HS, Cheong HK, Lim MK. 2001. A study on the correlation between catego -
rizations of the individual exposure levels to Agent Orange and serum dioxin levels among the
Korean Vietnam veterans. Korean Journal of Preventive Medicine 34(1):80–88.
Kim JS, Lim HS, Cho SI, Cheong HK, Lim MK. 2003. Impact of Agent Orange exposure among
Korean Vietnam veterans. Industrial Health 41:149–157.
Lilienfeld DE, Gallo MA. 1989. 2,4-D, 2,4,5-T and 2,3,7,8-TCDD: An overview. Epidemiological
Review 11:28–58.
Longnecker MP, Michalek JE. 2000. Serum dioxin level in relation to diabetes mellitus among Air
Force veterans with background levels of exposure. Epidemiology 11(1):44–48.
Mai TA, Doan TV, Tarradellas J, de Alencastro LF, Grandjean D. 2007. Dioxin contamination in soils
in Southern Vietnam. Chemosphere 67(9):1802–1807.
Michalek JE, Wolfe WH, Miner JC, Papa TM, Pirkle JL. 1995. Indices of TCDD exposure and TCDD
body burden in veterans of Operation Ranch Hand. Journal of Exposure Analysis and Environ-
mental Epidemiology 5(2):209–223.
Michalek JE, Akhtar FZ, Longnecker MP, Burton JE. 2001. Relation of serum 2,3,7,8-tetrachloro-
dibenzo-p-dioxin (TCDD) level to hematological examination results in veterans of Operation
Ranch Hand. Archives of Environmental Health 56(5):396–405.
Michalek JE, Ketchum NS, Tripathi RC. 2003. Diabetes mellitus and 2,3,7,8-tetrachlorodibenzo- p-
dioxin elimination in veterans of Operation Ranch Hand. Journal of Toxicology and Environ-
mental Health, Part A 66(3):211–221.
MRI (Midwest Research Institute). 1967. Assessment of Ecological Effects of Extensive or Repeated
Use of Herbicides. MRI Project No. 3103-B. Kansas City, MO: MRI. NTIS AD-824-314.
Nhu DD, Kido T, Naganuma R, Sawano N, Tawara K, Nishijo M, Nakagawa H, Hung NN, Thom
LTH. 2009. A GIS study of dioxin contamination in a Vietnamese region sprayed with herbicide.
Environmental Health and Preventive Medicine 14(6):353–360.
NRC (National Research Council). 1974. The Effects of Herbicides in South Vietnam. Washington,
DC: National Academy Press.
NRC. 1980. Review of US Air Force Protocol: Epidemiological Investigation of Health Effects in
Air Force Personnel Following Exposure to Herbicide Orange. Washington, DC: National
Academy Press.
NRC. 1982. The Effects of Exposure to Agent Orange on Ground Troops in Vietnam: A Report of
the Subcommittee Appointed to Review a Protocol. Washington, DC: National Academy Press.
NZIC (New Zealand Institute of Chemistry). 2009. The Production of Phenoxy Herbicides. New
Zealand Institute of Chemistry. Accessed March 9, 2009, at http://nzic.org.nz/ChemProcesses/
production/index.html
Pavuk M, Schecter AJ, Akhtar FZ, Michalek JE. 2003. Serum 2,3,7,8-tetrachlorodibenzo- p-dioxin
(TCDD) levels and thyroid function in Air Force veterans of the Vietnam War. Annals of Epi-
demiology 13(5):335–343.
OCR for page 74
74 VETERANS AND AGENT ORANGE: UPDATE 2010
Rappe C, Buser HR, Bosshardt HP. 1978. Identification and quantitation of polychlorinated dibenzo-
p-dioxins (PCDDs) and dibenzofurans (PCDFs) in 2,4,5-T ester formulations and herbicide
orange. Chemosphere 5:431–438.
Saito K, Nhu DD, Suzuki H, Kido T, Naganuma R, Sakakibara C, Tawara K, Nishijo M, Nakagawa
H, Kusama K, Dung PT, Thom LH, Hung NN. 2010. Association between dioxin concentra -
tions in breast milk and food group intake in Vietnam. Environmental Health and Preventive
Medicine 15(1):48–56.
Schecter A, Ryan JJ, Constable JD. 1986. Chlorinated dibenzo-p-dioxin and dibenzofuran levels in
human adipose tissue and milk samples from the north and south of Vietnam. Chemosphere
15:1613–1620.
Schecter A, Constable JD, Arghestani S, Tong H, Gross ML. 1987. Elevated levels 2,3,7,8-tetra-
chlorodibenzodioxin in adipose tissue of certain US veterans of the Vietnam war. Chemosphere
16:1997–2002.
Schecter A, Pavuk M, Constable JD, Dai LC, Papke O. 2002. A follow-up: High level of dioxin con-
tamination in Vietnamese from Agent Orange, three decades after the end of spraying [letter].
Journal of Occupational and Environmental Medicine 44(3):218–220.
Schecter A, Quynh HT, Papke O, Tung KC, Constable JD. 2006. Agent Orange, dioxins, and other
chemicals of concern in Vietnam: Update 2006. Journal of Occupational and Environmental
Medicine 48(4):408–413.
Stellman JM, Stellman SD. 2003. Contractor’s Final Report: Characterizing Exposure of Veterans
to Agent Orange and Other Herbicides in Vietnam. Submitted to the National Academy of
Sciences, Institute of Medicine in fulfillment of Subcontract VA-5124-98-0019, June 30, 2003.
Stellman JM, Stellman SD, Christian R, Weber T, Tomasallo C. 2003a. The extent and patterns of
usage of Agent Orange and other herbicides in Vietnam. Nature 422:681–687.
Stellman JM, Stellman SD, Weber T, Tomasallo C, Stellman AB, Christian R. 2003b. A geographic
information system for characterizing exposure to Agent Orange and other herbicides in Viet -
nam. Environmental Health Perspectives 111:321–328.
Stellman SD, Stellman JM. 1986. Estimation of exposure to Agent Orange and other defoliants among
American troops in Vietnam: A methodological approach. American Journal of Industrial
Medicine 9:305–321.
Stellman SD, Stellman JM. 2004. Exposure opportunity models for Agent Orange, dioxin, and other
military herbicides used in Vietnam, 1961–1971. Journal of Exposure Analysis and Environ-
mental Epidemiology 14:354–362.
Stellman SD, Mager-Stellman J, Sommer JF Jr. 1988. Combat and herbicide exposures in Vietnam
among a sample of American Legionnaires. Environmental Research 47:112–128.
Thomas TL, Kang HK. 1990. Mortality and morbidity among Army Chemical Corps Vietnam veter-
ans: A preliminary report. American Journal of Industrial Medicine 18:665–673.
Tosine H. 1983. Dioxins: A Canadian perspective. In: Chlorinated Dioxins and Dibenzofurans in the
Total Environment, Choudhary G, Keith LH, Rappe C, eds. Woburn, MA: Butterworth Publish -
ers, pp. 3–14.
Warren WF. 1968. A Review of the Herbicide Program in South Vietnam. San Francisco: Scientific
Advisory Group. Working Paper No. 10-68. NTIS AD-779-797.
Young AL. 1992. The Military Use of Herbicides in Vietnam. Presentation to the Institute of Medi-
cine Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides.
December 8, 1992. Washington, DC.
Young AL, Reggiani GM, eds. 1988. Agent Orange and Its Associated Dioxin: Assessment of a Con-
troversy. Amsterdam: Elsevier.
Young AL, Newton M. 2004. Long overlooked historical information on Agent Orange and TCDD
following massive applications of 2,4,5-T-containing herbicides, Eglin Air Force Base, Florida.
Environmental Science and Pollution Research 11(4):209–221.
OCR for page 75
75
EXPOSURE TO THE HERBICIDES USED IN VIETNAM
Young AL, Thalken CE, Arnold EL, Cupello JM, Cockerham LG. 1976. Fate of 2,3,7,8 Tetrachloro-
dibenzo-p-dioxin (TCDD) in the Environment: Summary and Decontamination Recommenda -
tions. Colorado Springs: US Air Force Academy. USAFA TR 76 18.
Young AL, Calcagni JA, Thalken CE, Tremblay JW. 1978. The Toxicology, Environmental Fate, and
Human Risk of Herbicide Orange and Its Associated Dioxin. Brooks AFB, TX: Air Force Oc-
cupational and Environmental Health Lab. USAF OEHL TR 78 92.
Young AL, Cecil PF Sr, Guilmartin JF Jr. 2004a. Assessing possible exposures of ground troops to
Agent Orange during the Vietnam War: The use of contemporary military records. Environmen-
tal Science and Pollution Research 11(6):349–358.
Young AL, Giesy JP, Jones P, Newton M, Guilmartin JF Jr, Cecil PF Sr. 2004b. Assessment of poten-
tial exposure to Agent Orange and its associated TCDD. Environmental Science and Pollution
Research 11(6):347–348.
Zumwalt ER Jr. 1993. Letter to the Institute of Medicine Committee to Review the Health Effects in
Vietnam Veterans of Exposure to Herbicides regarding draft version of the IOM chapter on the
US military and the herbicide program in Vietnam, May 20.
