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11
Other Health Effects
This chapter discusses data on the possible association between exposure
to the herbicides used in Vietnam—2,4-dichlorophenoxyacetic acid (2,4-D),
2,4,5-trichlorophenoxyacetic acid (2,4,5-T), picloram, and cacodylic acid—and
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a contaminant of 2,4,5-T, and sev-
eral noncancer health outcomes: respiratory disorders, immune-system disorders,
diabetes, lipid and lipoprotein disorders, gastrointestinal and digestive disease
(including liver toxicity), circulatory disorders, and adverse effects on thyroid
homeostasis. The committee also considers studies of exposure to polychlorinated
biphenyls (PCBs) and other dioxin-like chemicals informative if their results
were reported in terms of TCDD toxic equivalents (TEQs) or concentrations of
specific congeners.
In previous updates, chloracne and porphyria cutanea tarda (PCT) were
considered along with these chronic noncancer conditions. These are conditions
that are quite well accepted to be associated with dioxin exposure, but when they
occur this happens within a matter of months of the exposure. In this update these
two health outcomes have been moved to an appendix on short-term effects along
with transient early-onset peripheral neuropathy, which had previously been dis -
cussed in the chapter on neurologic disorder.
For each type of health outcome, background information is followed by
a brief summary of the findings described in earlier reports by the Institute of
Medicine (IOM) Committee to Review the Health Effects in Vietnam Veterans of
Exposure to Herbicides. In the discussion of the most recent scientific literature,
studies are grouped by exposure type (Vietnam veteran, occupational, or envi-
ronmental). For articles that report on only a single health outcome and that are
not revisiting a previously studied population, design information is summarized
708
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OTHER HEALTH EFFECTS
with the results; design information on other studies can be found in Chapter 5. A
synopsis of toxicologic and clinical information related to the biologic plausibil -
ity that the chemicals of interest can influence the occurrence of a health outcome
is presented next and followed by a synthesis of all the material reviewed. Each
health-outcome section ends with the present committee’s conclusions regarding
the strength of the evidence that supports an association with the chemicals of
interest. The categories of association and the committee’s approach to categoriz -
ing the health outcomes are discussed in Chapters 1 and 2.
RESPIRATORY DISORDERS
For the purposes of this report, noncancerous respiratory disorders comprise
acute and chronic lung diseases other than cancer. Acute noncancerous respira -
tory disorders include pneumonia and other respiratory infections; they can
increase in frequency and severity when the normal defense mechanisms of the
lower respiratory tract are compromised. Chronic noncancerous respiratory disor-
ders generally take two forms: airways disease and parenchymal disease. Airways
disease encompasses disorders, among them asthma and chronic obstructive pul -
monary disease (COPD), characterized by obstruction of the flow of air out of the
lungs. COPD is also known as chronic obstructive airways disease and includes
emphysema and chronic bronchitis. Parenchymal disease, or interstitial disease,
generally includes disorders that cause inflammation and scarring of the deep
lung tissue, including the air sacs and supporting structures; parenchymal disease
is less common than airways disease and is characterized by reductions in lung
capacity, although it can include a component of airway obstruction. Some severe
chronic lung disorders, such as cystic fibrosis, are hereditary. Because Vietnam
veterans received health screenings before entering military service, few severe
hereditary chronic lung disorders are expected in that population.
The most important risk factor for many noncancerous respiratory disorders
is inhalation of cigarette smoke. Although exposure to cigarette smoke is not
associated with all diseases of the lungs, it is the major cause of many airways
disorders, especially COPD; it contributes to some interstitial disease; and it
compromises host defenses in such a way that people who smoke are generally
more susceptible to some types of pneumonia. Cigarette-smoking also makes
almost every respiratory disorder more severe and symptomatic than it would
otherwise be. The frequency of habitual cigarette-smoking varies with occupa -
tion, socioeconomic status, and generation. For those reasons, cigarette-smoking
can be a major confounding factor in interpreting the literature on risk factors for
respiratory disease. Vietnam veterans are reported to smoke more heavily than are
non-Vietnam veterans (Kang et al., 2006; McKinney et al., 1997).
It is well known that causes of death from respiratory diseases, especially
chronic diseases, are frequently misclassified on death certificates. Grouping vari-
ous respiratory diseases for analysis, unless they all are associated with a given
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710 VETERANS AND AGENT ORANGE: UPDATE 2010
exposure, will lead to attenuation of the estimates of relative risk (RR) and to a
diminution of statistical power. Moreover, diagnosis of the primary cause of death
from respiratory and cardiovascular diseases (CVDs) is often inconsistent. In
particular, when persons have both conditions concurrently and both contributed
to death, there may be some uncertainty about which cause should be selected
as the primary underlying cause. In other instances, errors may arise in selecting
one underlying cause in a complex chain of health events (for example, if COPD
leads to congestive heart failure and then to respiratory failure).
Many study populations are small, so investigators group deaths from all
noncancerous respiratory diseases into one category that combined pneumonia,
influenza, and other diseases with COPD and asthma. The committee notes that
an association for the grouping of all noncancerous respiratory diseases with any
of the chemicals of interest would be too nonspecific to be clinically meaningful;
at most, such a pattern would be an indication that within this broad classifica -
tion some particular disease entity might be impacted by an exposure of interest.
Conclusions from VAO and Previous Updates
The committee responsible for Veterans and Agent Orange: Health Effects of
Herbicides Used in Vietnam, hereafter referred to as VAO (IOM, 1994) concluded
that there was inadequate or insufficient information to determine whether there is
an association between exposure to the chemicals of interest and the respiratory
disorders specified above. Additional information available to the committees re -
sponsible for Veterans and Agent Orange: Update 1996 (IOM, 1996) and Update
1998 (IOM, 1999) did not change that finding.
Veterans and Agent Orange: Update 2000 (IOM, 2001) drew attention to
findings on the Seveso cohort that suggested a higher mortality from noncancer-
ous respiratory disorders in study subjects, particularly males, who were more
heavily exposed to TCDD. Those findings were not replicated in several other
relevant studies, although one showed an increase that did not attain statistical
significance. The committee responsible for Update 2000 concluded that although
new evidence suggested an increased risk of noncancerous respiratory disorders,
particularly COPD, in people exposed to TCDD, the observation was tentative
and the information insufficient to determine whether there is an association
between exposures to the chemicals of interest and respiratory disorders. Addi -
tional information available to the committee responsible for Veterans and Agent
Orange: Update 2002 (IOM, 2003) did not change that finding.
Veterans and Agent Orange: Update 2004 (IOM, 2005) included a new
cross-sectional study of residents near a wood-treatment plant (Dahlgren et al.,
2003). Soil and sediment samples from a ditch in the neighborhood contained
dioxins and furans. Although exposed residents reported a greater frequency of
chronic bronchitis by history (17.8% vs 5.7%; p < 0.0001) and asthma by history
(40.5% vs 11.0%; p < 0.0001) than a “nonexposed” control group, the committee
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OTHER HEALTH EFFECTS
concluded that selection bias and recall bias limited the utility of the results and
that there was a possibility of confounding in that history of tobacco use was not
accounted for adequately.
Veterans and Agent Orange: Update 2006 (IOM, 2007) reviewed a number
of studies of veterans of the Vietnam War. Mortality from respiratory diseases
was not found to be higher than expected in the Centers for Disease Control and
Prevention Vietnam Experience Study (Boehmer et al., 2004), in the Air Force
Health Study (Ketchum and Michalek, 2005), and in two Australian studies
of Vietnam veterans (ADVA, 2005b,c). In contrast, in the US Army Chemical
Corps cohort of Vietnam veterans, Kang et al. (2006) found that the prevalence
of self-reported noncancerous respiratory problems diagnosed by a doctor was
significantly increased by about 40–60%, although no differences in the preva -
lence of respiratory problems was found in the subset of veterans whose serum
TCDD was above 2.5 ppt.
In addition, Update 2006 addressed new studies of potentially exposed oc-
cupational cohorts. No associations with respiratory mortality were found in a
small subcohort of New Zealand phenoxy-herbicide sprayers included in the
International Agency for Research on Cancer (IARC) cohort (’t Mannetje et al.,
2005). In the Agricultural Health Study (AHS), no associations between the
herbicide and mortality from COPD were found in private applicators or their
spouses (Blair et al., 2005). There was also an AHS analysis (Hoppin et al.,
2006a) of specific pesticide exposures and the self-reported prevalence of wheeze
that showed an association with “current” exposure to 2,4-D.
Several additional new AHS publications were reviewed in Veterans and
Agent Orange: Update 2008 (IOM, 2009) concerning morbidity from particular
self-reported respiratory health problems: another analysis concerning wheeze
(Hoppin et al., 2006b), asthma (Hoppin et al., 2008), “farmer’s lung” or hypersen-
sitivity pneumonitis (Hoppin et al., 2007a), and chronic bronchitis (Hoppin et al.,
2007b; Valcin et al., 2007). The 25-year follow-up of the mortality of the Seveso
population through 2001 (Consonni et al., 2008) was also considered in Update
2008; again there was some elevation in mortality from COPD as had been seen
in the earlier mortality follow-up reviewed in Update 2000.
Table 11-1 summarizes the results of the relevant studies.
Update of the Epidemiologic Literature
Vietnam-Veteran Studies
The Army Chemical Corps (ACC) cohort is of particular interest because
the members deployed to Vietnam had potential exposure to the chemicals of
interest second only to that of the Ranch Hand veterans. Cypel and Kang (2010)
reported the cause-specific mortality through 2005 in ACC veterans who served
in Vietnam between July 1, 1965–March 28, 1973 (n = 2,872) and ACC veterans
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712 VETERANS AND AGENT ORANGE: UPDATE 2010
TABLE 11-1 Selected Epidemiologic Studies—Noncancerous Respiratory
Disease
Exposure of Interest/
Exposed Estimated Risk
Casesa (95% CI)a
Reference Study Population
VIETNAM VETERANS
US Air Force Health Study—Ranch Hand veterans vs SEA veterans All COIs
Ketchum and Rand Hand personnel (n = 1,262) vs SEA
Michalek, veterans (19,078)—respiratory disease (ICD-9
2005 460–519)
Mortality through 1999 8 1.2 (0.6–2.5)
AFHS, 1996 Mortality through 1993 2 0.5 (0.1–1.6)
US VA Cohort of Army Chemical Corps All COIs
Cypel and Deployed veterans (2,872) vs nondeployed
Kang, 2010 (2,737)—mortality through 2005
Respiratory system disease 32 vs 8 2.2 (1.0–4.9)
Pneumonia and influenza 12 vs 6 1.3 (0.5–3.6)
COPD 20 vs 2 4.8 (1.1–21.2)
ACC deployed men in Kang et al. (2006)
reported sprayed herbicide vs did not spray
Respiratory system disease 8 2.2 (0.4–11.8)
Pulmonary disease (COPD) 6 3.6 (0.4–32.1)
Kang et al., Self-reported morbidity 1999—noncancerous
2006 respiratory problems diagnosed by doctor
Deployed (n = 1,499) vs nondeployed (n = 267 1.4 (1.1–1.8)
1,428)
Sprayed herbicides in Vietnam vs never 140 1.6 (1.2–2.1)
Dalager and Mortality through 1991
Kang, 1997 Respiratory system disease 11 vs 2 2.6 (0.5–12.2)
US CDC Vietnam Experience Study All COIs
Boehmer Vietnam Experience Cohort
et al., 2004 Noncancerous respiratory mortality (ICD-9 20 0.8 (0.5–1.5)
460–519)
CDC, 1988 Cross-sectional study, with medical
examinations, of US Army Vietnam veterans vs
nondeployed US Army veterans
Odds ratios from pulmonary-function tests
(case definition: ≥ 80% predicted value)
FEV1 254 0.9 (0.7–1.1)
FVC 177 1.0 (0.8–1.3)
FEV1/FVC 152 1.0 (0.8–1.3)
US VA Mortality Study of Army and Marine Veterans (ground troops All COIs
serving July 4, 1965–March 1, 1973)
Watanabe Mortality of US Vietnam veterans who
and Kang, died during 1965–1988, PMR analysis of
1996 noncancerous respiratory mortality (ICD-8
460–519)
0.8 (p < 0.05)
Army 648
0.7 (p < 0.05)
Marine Corps 111
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OTHER HEALTH EFFECTS
TABLE 11-1 Noncancerous Respiratory Disease, continued
Exposure of Interest/
Exposed Estimated Risk
Casesa (95% CI)a
Reference Study Population
US VA Cohort of Monozygotic Twins All COIs
Eisen et al., Incidence in deployed vs nondeployed
1991 monozygotic twins who served in US military
during Vietnam era
Respiratory conditions
Present at time of survey nr 1.4 (0.8–2.4)
At any time since service nr 1.4 (0.9–2.0)
Required hospitalization nr 1.8 (0.7–4.2)
Other US VA Vietnam Veteran Studies All COIs
Bullman and Male Vietnam veterans who were wounded in
Kang, 1996 combat vs US population
Noncancerous respiratory mortality (ICD 9 43 0.9 (0.7–1.2)
460–519)
State Studies of US Vietnam Veterans All COIs
Anderson White males with Wisconsin death certificate
et al., 1986 (1968–1978), mortality from noncancerous
respiratory disease (ICD-8 460–519)
Vietnam veterans vs expected deaths
calculated from proportions for: 10
Nonveterans 0.5 (0.3–0.8)
All veterans 0.8 (0.4–1.5)
Vietnam-era veterans 1.0 (0.5–1.8)
Australian Vietnam Veterans vs Australian Population All COIs
ADVA, Third Australian Vietnam Veterans Mortality
2005b Study
Deployed veterans vs Australian population
All branches
Respiratory system diseases 239 0.8 (0.7–0.9)
COPD 128 0.9 (0.7–1.0)
Navy
Respiratory system diseases 50 0.8 (0.6–1.0)
COPD 28 0.9 (0.6–1.3)
Army
Respiratory system diseases 162 0.8 (0.7–0.9)
COPD 81 0.9 (0.7–1.0)
Air Force
Respiratory system diseases 28 0.6 (0.4–0.9)
COPD 18 0.8 (0.4–1.2)
CDVA, Mortality of male Australian Vietnam veterans
1997a vs Australian population
Noncancerous respiratory mortality (ICD-9
460–519)
1964–1979 3 0.1 (0.0–0.3)
1980–1994 92 0.9 (0.7–1.1)
Chronic obstructive airways disease
(ICD-9 490–496) 47 0.9 (0.7–1.2)
continued
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714 VETERANS AND AGENT ORANGE: UPDATE 2010
TABLE 11-1 Noncancerous Respiratory Disease, continued
Exposure of Interest/
Exposed Estimated Risk
Casesa (95% CI)a
Reference Study Population
Australian Conscripted Army National Service (deployed vs All COIs
nondeployed)
ADVA, Mortality 1966–2001
2005c Respiratory diseases 18 1.1 (0.6–2.2)
COPD 8 1.0 (0.3–2.8)
CDVA, Mortality from noncancer respiratory disease
1997b 1965–1982 2 2.6 (0.2–30.0)
1982–1994 6 0.9 (0.3–2.7)
Australian Army Vietnam Veterans—sample of 1,000 vs Australian All COIs
National Health Survey—self-reported chronic conditions Relative Prevalence
O’Toole Veterans interviewed 2005–2006 (n = 450) vs
et al., 2009 2004–2005 National Survey results
Chronic lower respiratory disease nr
Bronchitis nr 2.9 (2.2–3.6)
Emphysema nr 2.0 (1.3–2.7)
Asthma nr 1.3 (1.0–1.6)
Hay fever and allergic rhinitis nr 1.2 (0.96–1.4)
Chronic sinusitis nr 1.7 (1.5–2.0)
Other diseases of the respiratory system nr 15.4 (11.7–19.1)
O’Toole Veterans interviewed 1990–1993 (n = 641) vs
et al., 1996 1989–1990 National Survey results
Asthma nr 0.9 (0.5–1.4)
Bronchitis, emphysema nr 4.1 (2.8–5.5)
Other nr 4.0 (2.2–5.9)
OCCUPATIONAL
IARC Phenoxy Herbicides Cohort (mortality vs national mortality Dioxin, phenoxy
rates) herbicides
Kogevinas Mortality in international workers producing
et al., 1997 or applying phenoxy herbicides, noncancerous
respiratory mortality (ICD-9 460–519),
1939–1992
Men 252 0.8 (0.7–0.9)
Women 7 1.1 (0.4–2.2)
NIOSH Mortality Cohort (12 US plants, production 1942–1984) Dioxin, phenoxy
(included in IARC cohort) herbicides
Steenland NIOSH mortality study of chemical workers at
et al., 1999 12 plants in US exposed to TCDD
Noncancerous respiratory mortality (ICD-9
460–519) 86 0.9 (0.7–1.1)
Preliminary NIOSH Cross-Sectional Medical Study—workers in Dioxin, phenoxy
herbicides
production of sodium trichlorophenol, 2,4,5-T ester contaminated with
TCDD—morbidity
Sweeney Chronic bronchitis and COPD 2 nr
et al.,
1997/98
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OTHER HEALTH EFFECTS
TABLE 11-1 Noncancerous Respiratory Disease, continued
Exposure of Interest/
Exposed Estimated Risk
Casesa (95% CI)a
Reference Study Population
Calvert Odds ratios for increase in 1 ppt of serum
et al., 1991TCDD compared to unexposed workers
Chronic bronchitis nr 0.5 (0.1–2.6)
COPD nr 1.2 (0.5–2.8)
Monsanto Production Workers—Nitro, WV, 2,4,5-T plant Dioxin, phenoxy
herbicides
Suskind and Cross-sectional study, 1979, comparing exposed
Hertzberg, with nonexposed workers for “abnormal”
1984 outcome on pulmonary-functions tests:
FEV1 (< 80% predicted) 2.81 (p = 0.02)
FVC (< 80% predicted) 2.25 (p = 0.03)
FEV1/FVC (< 70%) 2.97 (p = 0.01)
FEF25-75 (< 80% predicted) 1.86 (p = 0.05)
Dow Chemical Company—Midland, MI (included in IARC and Dioxin, phenoxy
NIOSH cohorts) herbicides
Collins Mortality 1942–2003—noncancerous
et al., 2009a respiratory disease (ICD-10 J00–J99)
TCP workers 44 0.8 (0.6–1.0)
Collins Mortality 1942–2003—noncancerous
et al., 2009b respiratory disease (ICD-10 J00–J99)
PCP workers without TCP exposure 19 0.7 (0.4–1.2)
Burns et al., Mortality of 2,4-D workers, 1945–1994
2001 Noncancerous respiratory (ICD-8 460–519) 8 0.4 (0.2–0.7)
Pneumonia 4 0.6 (0.2–1.4)
Ramlow Mortality of PCP workers, 1940–1989
et al., 1996 Noncancerous respiratory mortality (ICD-8
460–519) 14 0.9 (0.5–1.5)
Cumulative PCP exposure
< 1 unit 3 0.6 (0.2–1.9)
≥ 1 unit 11 1.4 (0.8–2.5)
Pneumonia (ICD-8 480–486) 6 1.1 (0.4–2.4)
Emphysema (ICD-8 492) 4 1.3 (0.4–3.3)
BASF Production Workers—German workers exposed to trichlorophenol Dioxin, phenoxy
herbicides
contaminated with TCDD from 1953 accident (included in IARC cohort)
Ott and Noncancerous respiratory mortality through 1 0.1 (0.0–0.8)
Zober, 1996 1993 vs West German rates (n = 243 men)
Zober et al., Prevalence—cohort (n = 158), reference (n =
1994 161) (illness episodes per 100 person–years,
1953–1989)
All noncancerous respiratory diseases (ICD-9
460–519) nr 33.7/31.0 (p = 0.22)
Upper respiratory tract infections (ICD-9
460–478) nr 12.0/9.0 (p = 0.00)
Pneumonia or influenza (ICD-9 480–487) nr 17.4/18.8 (p = 0.08)
COPD (ICD-9 490–496) nr 8.0/7.5 (p = 0.31)
continued
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716 VETERANS AND AGENT ORANGE: UPDATE 2010
TABLE 11-1 Noncancerous Respiratory Disease, continued
Exposure of Interest/
Exposed Estimated Risk
Casesa (95% CI)a
Reference Study Population
Dutch Production Workers (included in IARC cohort) Dioxin, phenoxy
herbicides
Boers et al.,
Dutch chlorophenoxy workers
2010 Diseases of the respiratory system
Factory A (HR for exposed vs unexposed) 19 vs 12 1.0 (0.4–2.3)
Factory B (HR for exposed vs unexposed) 6 vs 15 0.5 (0.2–1.2)
German Production Workers (included in IARC cohort) Dioxin, phenoxy
herbicides
Becher et al., Four German facilites for production
1996 of phenoxy herbicides, chlorophenols,
noncancerous respiratory mortality (ICD-9
460–519)
Boehringer Ingelheim 10 0.5 (0.3–1.0)
Bayer Uerdingen 2 0.9 (0.1–3.1)
Bayer Dormagen 0 0.0
BASF Ludwigshafen 4 0.6 (0.2–1.6)
New Zealand Production Workers—Dow plant in Plymouth, NZ Dioxin, phenoxy
(included in IARC cohort) herbicides
McBride Dow trichlorophenol workers in Plymouth, NZ
et al., 2009a Ever-exposed workers 12 0.8 (0.4–1.4)
’t Mannetje New Zealand phenoxy herbicide workers,
et al., 2005 noncancerous respiratory mortality (ICD-9
480–519)
Producers 9 0.9 (0.4–1.8)
Sprayers 6 0.7 (0.2–1.2)
United Kingdom Production Workers (included in IARC cohort) Dioxin, phenoxy
herbicides
Coggon Production of phenoxy herbicides, 8 0.7 (0.3–1.3)
et al., 1991 chlorophenols in four British plants, mortality
from noncancerous respiratory diseases,
1963–1985
Coggon British plant manufacturing MCPA, mortality 93 0.6 (0.5–0.8)
et al., 1986 from noncancerous respiratory diseases (ICD-9
460–519), 1947–1983
Agricultural Health Study Herbicides
Hoppin US AHS—prevalence at enrollment among
et al., 2009 male agricultural workers of:
Allergic asthma
2,4,5-T 38 1.4 (1.0–2.2)
2,4-D 110 1.6 (0.9–2.7)
Nonallergic asthma
2,4,5-T 88 1.2 (0.9–1.6)
2,4-D 264 1.2 (0.9–1.6)
Slager et al., US AHS—commercial pesticide applicators 1,664
2009 Current rhinitis and exposure to:
2,4-D 750 1.3 (1.1–1.6)
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OTHER HEALTH EFFECTS
TABLE 11-1 Noncancerous Respiratory Disease, continued
Exposure of Interest/
Exposed Estimated Risk
Casesa (95% CI)a
Reference Study Population
Hoppin US AHS—prevalence at enrollment among
et al., 2008 farm women of:
Atopic asthma having exposure to:
2,4-D 52 1.5 (1.1–2.1)
Dicamba 11 1.1 (0.6–2.1)
Nonatopic asthma having exposure to:
2,4-D 66 1.1 (0.8–1.4)
Dicamba 13 0.7 (0.4–1.3)
Hoppin US AHS—prevalence at enrollment of
et al., 2007a self-reported farmer’s lung (hypersensitivity
pneumonitis)
Private applicators exposed to phenoxy 392 1.2 (0.8–1.7)
herbicides
Spouses exposed to phenoxy herbicides 16 1.4 (0.7–2.7)
Hoppin US AHS—prevalence at enrollment of chronic
et al., 2007b bronchitis in private applicators exposed to:
2,4-D 78 1.1 (0.9–1.4)
2,4,5-T (lifetime days) 28 1.5 (1.3–1.8)
None 74 1.0
1–14 16 1.4 (1.1–1.8)
15–55 6 1.3 (0.9–1.8)
> 55 4 1.0 (0.6–1.5)
2,4,5-TP (lifetime days) 9 1.7 (1.3–1.3)
None 92 1.0
1–14 3 1.1 (0.7–1.8)
15–55 3 1.6 (1.0–2.8)
> 55 2 1.4 (0.8–2.5)
Dicamba 48 1.0 (0.8–1.2)
Valcin et al., US AHS—prevalence at enrollment of chronic
2007 bronchitis in nonsmoking farm women exposed 0.9 (0.7–1.1)
to:
2,4-D 16 1.2 (0.9–1.6)
2,4,5-T 1 1.0 (0.4–2.5)
Dicamba 5 1.1 (0.6–2.0)
Hoppin US AHS—cross-sectional study of wheeze in
et al., 2006a commercial applicators with current use of:
2,4-D 225 1.3 (1.0–1.7)
Dicamba 167 1.1 (0.9–1.4)
continued
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718 VETERANS AND AGENT ORANGE: UPDATE 2010
TABLE 11-1 Noncancerous Respiratory Disease, continued
Exposure of Interest/
Exposed Estimated Risk
Casesa (95% CI)a
Reference Study Population
Hoppin US AHS—prevalence at enrollment of wheeze
et al., 2006b (added adjustment for exposure to herbicide
chlorimuron-ethyl)
Private applicators with current use of:
2,4-D nr 1.0 (0.9–1.1)
Dicamba nr 1.1 (0.9–1.2)
Commercial applicators with current use of:
2,4-D nr 1.0 (0.7–1.3)
Dicamba nr 0.8 (0.6–1.1)
Blair et al., US AHS—COPD mortality
2005 Private applicators 50 0.2 (0.2–0.3)
Spouses 15 0.3 (0.2–0.7)
Other Agricultural Studies Herbicides
Senthilselvan Cross-sectional study of self-reported
et al., 1992 prevalence of self-reported asthma (n = 83) Asthmatics vs
in male farmers (n = 1,939) in Saskatchewan nonasthmatics
(1982–1983)
Phenoxyacetic herbicide use 71 85.5% vs 88.5%
Herbicide and Pesticide Applicators Herbicides
Blair et al., Licensed pesticide applicators, Florida,
1983 noncancerous respiratory diseases, (ICD-8 2 0.9 (nr)
460–519)
Analyses by length of licensure
≥ 10 yrs 8 0.6 (nr)
10–19 yrs 8 1.5 (nr)
≥ 20 yrs 4 1.7 (nr)
Forestry Workers Herbicides
Alavanja PMR study of US Department of Agriculture 80 0.8 (0.6–1.0)
et al., 1989 soil, forest conservationists, mortality 1970–
1979 from noncancerous respiratory diseases
(ICD-9 460–519)
ENVIRONMENTAL
Seveso, Italy Residential Cohort TCDD
Consonni 25-yr follow-up of Seveso residents—mortality
et al., 2008 Respiratory disease (ICD-9 460–519)
Zone A 9 1.4 (0.7–2.7)
Zone B 48 1.0 (0.8–1.4)
Zone R 341 1.0 (0.9–1.1)
COPD (ICD-9 490–493)
Zone A 7 2.5 (1.2–5.3)
Zone B 26 1.3 (0.9–1.9)
Zone R 175 1.2 (1.0–1.4)
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748 VETERANS AND AGENT ORANGE: UPDATE 2010
the osteoporosis disease process can be without symptoms for decades. It is well
known that hormones, vitamins, and pharmaceuticals can have adverse effects on
bone. Drug-induced osteoporosis occurs primarily in postmenopausal women, but
premenopausal women and men are also significantly affected. Glucocorticoids
are the most common cause of drug-induced osteoporosis (Mazziotti et al., 2010).
Other risk factors for loss of bone density include long-acting benzodiazepine or
anticonvulsant drug use, previous hyperthyroidism, excessive caffeine intake, and
standing 4 or fewer hours per day (Lash, 2009).
Several studies have described a link between organochlorine exposure and
effects on bone growth, most notably reports of infants exposed in utero to high
concentration of PCBs and polychlorinated dibenzofurans developing irregular
calcifications of their skull bones (Miller, 1985) and reports of accidental or-
ganochlorine poisonings resulting in osteoporosis (Cripps et al., 1984; Gocmen
et al., 1989). However; the epidemiological studies of the association between
bone disorders and environmental exposures to organochlorine compounds have
been inconsistent.
Summary of Previous Updates
Previous VAO updates have not examined bone density or osteoporosis as
a health outcome. This is the first VAO update in which studies examining the
association between exposures to the chemicals of interest and decrease in bone
density are reviewed.
Update of the Scientific Literature
No Vietnam-veteran or occupational studies concerning the chemicals of
interest and bone density or osteoporosis have been published.
Environmental Studies
Hodgson et al. (2008) studied the relationship between organochlorine ex-
posure and BMD in a subset of 325 members of the Osteoporosis Cadmium as a
Risk Factor (OSCAR) cohort who were at least 60 years old. Many of the cohort
members lived close to the Baltic coast and may have had PCB exposure from
fish consumption and potentially from exposure from a PCB-contaminated river.
The cohort contains 1,021 individuals who provided information on employment,
residence, smoking, diet, and medical history. Forearm BMD was measured on
the distal site of the nondominant forearm with an osteometer using dual energy
x-ray absorptiometry. Blood samples were analyzed for total TEQs for five mono-
ortho chlorine substituted congeners (PCB 105, 118, 156, 157, and 167) and for
the concentration of PCB 118 alone. TEQs for the mono-ortho PCBs ranged from
0.002 to 0.067 pg/mL in men and from 0.003 to 0.053 pg/mL in women. In males,
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OTHER HEALTH EFFECTS
stepwise multivariate analyses adjusted for age, BMI, and milk consumption
found PCB 118 to have a marginally significant negative association with BMD
(β = –0.00011, p = 0.079), but TEQ for all five dioxin-like PCBs did not show
an association (β = 0.225, p = 0.846). In females, stepwise multivariate analyses
adjusted for age, BMI, age at menstruation, and ever-pregnant found PCB 118
alone and TEQ for all five dioxin-like PCBs were positively associated with BMD
(β = 0.00008, p = 0.045; β = 1.652, p = 0.057, respectively). When the risk of
low BMD (more than 1 standard deviation below the mean value) was treated as
a binary variable in a similarly adjusted logistic model, there was a significant
association with PCB 118 in men (OR = 1.06, 95% CI 1.01–1.12, p = 0.027), but
none of the measured organochlorine compounds (also including non-dioxin-like
PCB 138, 153, and 180) were predictive for the women.
Biological Plausibility
Animal studies suggest that TCDD may have some influence on bone forma-
tion and maintenance. For instance, TCDD exposure via the dam’s milk impaired
bone mineralization during postnatal development in mice due to a reduction of
the osteoblastic activity, which is caused by TCDD-induced up-regulation in the
active form of vitamin D in serum (Nishimura et al., 2009). TCDD altered osteo -
genesis (bone formation) in an in vitro osteoblast model, producing alterations in
proteins associated with cytoskeleton organization and biogenesis and a decrease
in the expression of calcium-binding proteins, which decreases osteoblast calcium
deposition (Carpi et al., 2009).
Synthesis
The small amount of epidemiologic information available concerning pos -
sible adverse effects on bone structure in association with exposure to the chemi -
cals of interest is based almost entirely on a single dioxin-like PCB. The findings
of Hodgson et al. (2008) do not constitute a strong or consistent pattern.
Conclusion
There is inadequate or insufficient evidence of an association between expo -
sure to the chemicals of interest and clinical or overt adverse effects of osteopo-
rosis or loss of bone mineral density.
SUMMARY
On the basis of the occupational, environmental, and veterans studies re-
viewed and in light of information concerning biologic plausibility, the commit -
tee reached one of four conclusions about the strength of the evidence regarding
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750 VETERANS AND AGENT ORANGE: UPDATE 2010
an association between exposure to the chemicals of interest and each of the
health outcomes discussed in this chapter. In categorizing diseases according to
the strength of the evidence, the committee applied the same criteria (discussed
in Chapter 2) that were used in VAO, Update 1996, Update 1998, Update 2000,
Update 2002, Update 2004, Update 2006, and Update 2008. To be consistent
with the charge to the committee by the Secretary of Veterans Affairs in Public
Law 102-4 and with accepted standards of scientific reviews, the distinctions
between conclusions are based on statistical association.
Health Outcomes with Sufficient Evidence of an Association
For diseases in this category, a positive association between exposure and
outcome must be observed in studies in which chance, bias, and confounding
can be ruled out with reasonable confidence. On the basis of the literature, none
of the health effects discussed in this chapter satisfy the criteria necessary for
inclusion in this category.
Health Outcomes with Limited or Suggestive Evidence of an Association
For this category, the evidence must suggest an association between exposure
and outcome, although it can be limited because chance, bias, or confounding
could not be ruled out with confidence. On the basis of the literature, none of the
health effects discussed in this chapter satisfy the criteria necessary for inclusion
in this category.
Health Outcomes with Inadequate or Insufficient Evidence
to Determine Whether There Is an Association
The scientific data on many of the health outcomes reviewed by the present
committee were inadequate or insufficient to determine whether there is an asso-
ciation between exposure to the chemicals of interest and the outcomes. For the
health outcomes in this category, the available studies are of insufficient quality,
consistency, or statistical power to permit a conclusion regarding the presence or
absence of an association. Some studies failed to control for confounding or used
inadequate exposure assessment. This category includes noncancerous respiratory
disorders, such as COPD, asthma in isolation, pleurisy, pneumonia, and tuber-
culosis; gastrointestinal diseases; digestive diseases; liver toxicity; disorders of
thyroid homeostasis; and disorders of the eyes and bones.
Health Outcomes with Limited or Suggestive Evidence of No Association
To classify outcomes in this category, several adequate studies covering the
full range of known human exposure must be consistent in not showing a positive
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751
OTHER HEALTH EFFECTS
association between exposure and outcome at any magnitude of exposure. The
studies also must have relatively narrow confidence intervals. A conclusion of “no
association” is inevitably limited to the conditions, magnitudes of exposure, and
periods of observation covered by the available studies. The possibility of a very
small increase in risk at the exposure studied can never be excluded.
The committees responsible for VAO, Update 1996, Update 1998, Update
2000, Update 2002, Update 2004, and Update 2006 concluded that none of the
health outcomes discussed in this chapter had limited or suggestive evidence of
no association with exposure to the chemicals of interest. The most recent scien -
tific evidence continues to support that conclusion.
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