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1
Introduction
F rom 1962 to 1971, US military forces sprayed herbicides over Vietnam to
strip the thick jungle canopy that helped to conceal opposition forces, to
destroy crops that enemy forces might depend on, and to clear tall grasses
and bushes from the perimeters of US base camps and outlying fire-support
bases. Mixtures of 2,4-dichlorophenoxyacetic acid (2,4-D), 2,4,5-trichlorophen-
oxyacetic acid (2,4,5-T), picloram, and cacodylic acid made up the bulk of the
herbicides sprayed. The herbicide mixtures used were named according to the
colors of identification bands painted on the storage drums; one of the main
chemical mixtures sprayed was Agent Orange (a 50:50 mixture of 2,4-D and
2,4,5-T). At the time of the spraying, 2,3,7,8-tetrachlorodibenzo-p-dioxin
(TCDD, one form of dioxin) was an unintended contaminant formed in the pro-
duction of 2,4,5-T and was present in Agent Orange and some other formula-
tions sprayed in Vietnam.
In 1991, because of continuing uncertainty about the long-term health ef-
fects on Vietnam veterans of the herbicides sprayed, Congress passed Public
Law (PL) 102-4, the Agent Orange Act of 1991. That legislation directed the
secretary of veterans affairs to ask the National Academy of Sciences (NAS) to
perform a comprehensive evaluation of scientific and medical information re-
garding the health effects of exposure to Agent Orange, other herbicides used in
Vietnam, and the various chemical components of those herbicides, including
TCDD. The secretary was also to ask NAS to conduct an update at least every 2
years for 10 years from the date of the first report to review newly available
literature and draw conclusions from the overall evidence.
In response to the request, the Institute of Medicine (IOM) convened a
committee, whose conclusions were published in 1994 in Veterans and Agent
9
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10 VETERANS AND AGENT ORANGE
Orange: Health Effects of Herbicides Used in Vietnam (hereafter referred to as
VAO). The work of later committees resulted in the publication of biennial
updates (Update 1996, Update 1998, Update 2000, and Update 2002) and
focused reports reviewing the scientific evidence regarding type 2 (non-insulin-
dependent) diabetes (Type 2 Diabetes) and acute myelogenous leukemia in chil-
dren (Acute Myelogenous Leukemia).
VAO (IOM, 1994) concluded that there is "limited/suggestive" evidence of
an association between exposure to at least one of the chemicals of interest (2,4-
D, 2,4,5-T and its contaminant TCDD, picloram, and cacodylic acid) and respi-
ratory cancer (of lung and bronchus, larynx, and trachea). That conclusion was
reaffirmed in Update 1996 (IOM, 1996), Update 1998 (IOM, 1999), Update
2000 (IOM, 2001), and Update 2002 (IOM, 2003).
The Department of Veterans Affairs (VA), on the basis of the findings of
VAO and its own review of the literature, published a notice in the Federal
Register in February 1994, stating that there is "a positive association between
exposure to herbicides used in the Republic of Vietnam and the subsequent
development of respiratory cancers" (Federal Register, 1994). The VA further
found that "the weight of the available evidence indicates that chemically-
induced respiratory cancers manifest within a definitive period following expo-
sure, after which there is little effect from the exposure" (Federal Register, 1994).
That Federal Register notice discusses data on chemically-induced respiratory
cancers in Ontario steel-plant workers (Finkelstein et al., 1991), people exposed
as a result of a trichlorophenol-process accident in West Virginia (Zack and
Suskind, 1980), and workers exposed to TCDD after a 1953 accident in a factory
in Germany (Zober et al., 1990). The VA therefore proposed, as part of its rule,
that respiratory cancer "be presumed service connected only if it is manifest
within 30 years after exposure" (Federal Register, 1994).
The Veterans Education and Benefits Expansion Act of 2001, PL 107-103,
removed the 30-year presumptive period for respiratory cancer and mandated
that the secretary of veterans affairs ask the National Academy of Sciences (NAS)
to review "available scientific literature on the effects of exposure to an herbi-
cide agent containing dioxin on the development of respiratory cancers in hu-
mans." And to review "whether it is possible to identify a period of time after
exposure to herbicides after which a presumption of service-connection" for the
disease would not be warranted.
CHARGE TO THE COMMITTEE
In response to the VA request, IOM extended the service of the Committee
to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides
that was responsible for Update 2002 to address the question of presumptive
period and respiratory cancer. The charge to the committee was to review and
evaluate the evidence regarding the period between cessation of exposure to the
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INTRODUCTION 11
chemicals used in Vietnam (2,4-D, 2,4,5-T and its contaminant TCDD, cacodylic
acid, and picloram) and the occurrence of respiratory cancer.
COMMITTEE'S APPROACH TO THE CHARGE
To meet its charge, the committee conducted literature searches to identify
relevant research. As discussed earlier, the committee had concluded in Update
2002 that there is "limited/suggestive" evidence of an association between at
least one of the chemicals of interest and respiratory cancer. For the current
report, the committee did not reevaluate that conclusion; rather, it focused on
articles that provide information on the time course of exposure and develop-
ment of disease. In addition to the data on the chemicals of interest, the commit-
tee briefly reviewed what is known regarding the latent period of respiratory
cancer after exposure to other physical and chemical agents. And, although it is
not possible to extrapolate directly from animal bioassays to human cancers with
respect to the timing of carcinogenesis, the committee reviewed data from ex-
perimental animal and in vitro studies that could provide insight into the mecha-
nisms by which the chemicals might lead to cancer.
PREVIOUS CONCLUSION REGARDING RESPIRATORY CANCER
Update 2002 (IOM, 2003) concluded that evidence remained "limited/sug-
gestive" regarding an association between exposure to at least one of the chemi-
cals of interest (2,4-D, 2,4,5-T and its contaminant TCDD, picloram, or ca-
codylic acid) and respiratory cancer (of the lung and bronchus, larynx, and
trachea). A health outcome is classified as being "limited/suggestive" if the evi-
dence is suggestive of an association between herbicides and the outcome but is
limited because chance, bias, and confounding could not be ruled out with confi-
dence. For example, at least one high-quality study shows a positive association,
but the results of other studies are inconsistent. Uncertainty is introduced by the
absence of data on smoking, occupational exposures, and other confounding
factors in available studies. Animal studies support the plausibility of the asso-
ciation and a role of TCDD as a promoter.
EVALUATIONS OF LATENCY BY PREVIOUS COMMITTEES
The question of the latent period between exposure to the chemicals of
interest and respiratory cancer was first addressed by the IOM committee in
Update 1996. That report reviewed results on the timing of exposure in relation
to respiratory cancer and prostate cancer. For respiratory cancer (as well as pros-
tate cancer), the reports of some potentially informative studies did not include
latency, and no latent period could be estimated.
Update 1998 reviewed the literature relevant to latency that was published
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12 VETERANS AND AGENT ORANGE
after Update 1996. With respect to respiratory cancer, it discussed evidence from
the National Institute for Occupational Safety and Health study of chemical work-
ers (Fingerhut et al., 1991), studies of environmental exposures after an indus-
trial accident in Seveso, Italy (Bertazzi et al., 1989a,b; 1997), a study of Finnish
herbicide appliers (Asp et al., 1994), occupational studies on a cohort compiled
by the International Agency for Research on Cancer (Kogevinas et al., 1997) and
a study on a subset of the cohort (Becher et al., 1996), studies of Vietnam veter-
ans who were involved in the aerial spraying of the herbicides (the Ranch Hands)
(Michalek et al., 1998), and studies of Australian Vietnam veterans (Crane et al.,
1997). The Update 1998 committee's conclusion was that "the evidence sug-
gests that if respiratory cancer does result from exposure to the herbicides used
in Vietnam, the greatest relative risk for lung cancer may be in the first decade
after exposure, but until further follow-up has been carried out for some of the
cohorts, it will not be possible to put an upper limit on the length of time these
herbicides could exert their effect" (IOM, 1999).
When Update 2000 was being prepared, the new data on latency were not
sufficient to warrant a reexamination of the latent period. In light of the request
for the present report, the Update 2002 committee did not review latency.
ORGANIZATION OF THIS REPORT
The remainder of this report is organized into three chapters. Chapter 2
discusses the committee's use of the terms latency and presumptive period and
the factors that can affect those periods, and briefly discusses chemicals that are
known to be associated with respiratory cancer and confounders and cofactors
that are especially pertinent to respiratory cancer. Epidemiology studies of the
chemicals of interest that provide information on latency are discussed in Chap-
ter 3. Chapter 4 presents the committee's overall conclusions on the period be-
tween exposure to the chemicals of interest and the development of respiratory
cancer. It also describes how those conclusions are related to the period during
which a respiratory cancer could be presumed to have been caused by exposures
incurred during service in Vietnam.
REFERENCES
Asp S, Riihimaki V, Hernberg S, Pukkala E. 1994. Mortality and cancer morbidity of Finnish chlo-
rophenoxy herbicide applicators: an 18-year prospective follow-up. American Journal of Indus-
trial Medicine 26:243253.
Becher H, Flesch-Janys D, Kauppinen T, Kogevinas M, Steindorf K, Manz A, Wahrendorf J. 1996.
Cancer mortality in German male workers exposed to phenoxy herbicides and dioxins. Cancer
Causes and Control 7(3):312321.
Bertazzi PA, Zocchetti C, Pesatori AC, Guercilena S, Sanarico M, Radice L. 1989a. Mortality in an
area contaminated by TCDD following an industrial incident. Medicina Del Lavoro 80:316
329.
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INTRODUCTION 13
Bertazzi PA, Zocchetti C, Pesatori AC, Guercilena S, Sanarico M, Radice L. 1989b. Ten-year mor-
tality study of the population involved in the Seveso incident in 1976. American Journal of
Epidemiology 129:11871200.
Bertazzi PA, Zochetti C, Guercilena S, Consonni D, Tironi A, Landi MT, Pesatori AC. 1997. Dioxin
exposure and cancer risk: a 15-year mortality study after the "Seveso accident." Epidemiology
8(6):646652.
Crane PJ, Barnard DL, Horsley KW, Adena MA. 1997. Mortality of Vietnam veterans: the veteran
cohort study. A report of the 1996 retrospective cohort study of Australian Vietnam veterans.
Canberra: Department of Veterans' Affairs.
Federal Register. 1994. Disease Associated with Exposure to Certain Herbicide Agents (Multiple
Myeloma and Respiratory Cancers). Proposed Rule (38 CFR Part 3, RIN 2900-AG73), Febru-
ary 3.
Fingerhut MA, Halperin WE, Marlow DA, Piacitelli LA, Honchar PA, Sweeney MH, Greife AL,
Dill PA, Steenland K, Suruda AJ. 1991. Cancer mortality in workers exposed to 2,3,7,8-tetra-
chlorodibenzo-p-dioxin. New England Journal of Medicine 324:212218.
Finkelstein MM, Boulard M, Wilk N. 1991. Increased risk of lung cancer in the melting department
of a second Ontario steel manufacturer. American Journal of Industrial Medicine 19(2):183
194.
IOM (Institute of Medicine). 1994. Veterans and Agent Orange: Health Effects of Herbicides Used
in Vietnam. Washington, DC: National Academy Press.
IOM. 1996. Veterans and Agent Orange: Update 1996. Washington, DC: National Academy Press.
IOM. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: National Academy Press.
IOM. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: National Academy Press.
IOM. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies
Press.
Kogevinas M, Becher H, Benn T, Bertazzi PA, Boffetta P, Bueno-de-Mesquita HB, Coggon D, Colin
D, Flesch-Janys D, Fingerhut M, Green L, Kauppinen T, Littorin M, Lynge E, Mathews JD,
Neuberger M, Pearce N, Saracci R. 1997. Cancer mortality in workers exposed to phenoxy
herbicides, chlorophenols, and dioxins. An expanded and updated international cohort study.
American Journal of Epidemiology 145(12):10611075.
Michalek JE, Ketchum NS, Akhtar FZ. 1998. Postservice mortality of U.S. Air Force veterans
occupationally exposed to herbicides in Vietnam: 15-year follow-up. American Journal of Epi-
demiology 148(8):786792.
Zack JA, Suskind RR. 1980. The mortality experience of workers exposed to tetrachlorodibenzo-
dioxin in a trichlorophenol process accident. Journal of Occupational Medicine 22:1114.
Zober A, Messerer P, Huber P. 1990. Thirty-four-year mortality follow-up of BASF employees
exposed to 2,3,7,8-TCDD after the 1953 accident. International Archives of Occupational and
Environmental Health 62:139157.
Representative terms from entire chapter:
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