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6
Immune-System Disorders
For the first time in the Veterans and Agent Orange series, immune-system
disorders are being addressed in a separate chapter preceding those on other types
of adverse health outcomes. In previous Veterans and Agent Orange reports—Vet-
erans and Agent Orange: Health Effects of Herbicides Used in Vietnam, hereafter
referred to as VAO (IOM, 1994), Veterans and Agent Orange: Update 1996 (IOM,
1996), Update 1998 (IOM, 1999), Update 2000 (IOM, 2001), Update 2002 (IOM,
2003), Update 2004 (IOM, 2005), Update 2006 (IOM, 2007), and Update 2008
(IOM, 2009)—possible adverse health outcomes arising from disruptions of the
immune system were included in the Other Health Outcomes chapter. The current
committee elected to comprehensively revisit the limited epidemiologic evidence
concerning association of immune disease with herbicide exposure in light of
the substantial volume of toxicologic evidence of 2,3,7,8-tetrachlorodibenzo- p-
dioxin’s (TCDD’s) impairment of the immune systems of laboratory animals.
The chapter opens with an overview of the various types of health problems that
can arise from malfunctioning of the human immune system. The standard VAO
sections leading to the committee’s assignment of a health outcome to a category
of association follow and include a new tabulation of all the immune-related epi-
demiologic information that has been considered in this series, plus a synopsis of
the information new to this update. The next section discusses a series of factors
that may contribute to the immune responses of animals exposed to the chemi-
cals of interest being considerably more pronounced than any observed to date
in humans. The chapter closes with the committee’s thoughts for research on the
possibility that immune perturbations in humans may function as a mechanistic
step in the development of disease processes in other organ systems.
240
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241
IMMUNE-SYSTEM DISORDERS
The immune system plays three important roles in the body:
• It defends the body against infection by viruses, bacteria, and other
disease-producing microorganisms, known as pathogens.
• It defends against cancer by destroying mutated cells that might otherwise
develop into tumors and by providing immunity against tumors.
• It provides resident immune cells that are specially adapted for different
tissues and organs (such as microglia in the central nervous system and
Kupffer cells in the liver) that help to regulate the functional activity and
integrity of those tissues.
To recognize the wide array of pathogens in the environment, the immune
system relies on many cell types that operate together to generate immune re -
sponses. Those cells arise from stem cells in the bone marrow, they are found in
lymphoid tissues throughout the body, and they circulate in the blood as white
blood cells (WBCs). The main types of WBCs are granulocytes, monocytes,
and lymphocytes. Each category has many specialized cell populations that are
responsible for specific functions connected to the production of specific immune
hormones (generically known as cytokines). Imbalances in these specialized
populations or in their level of functional activity can result in inadequate or im -
proper immune responses that may lead to pathologic outcomes. Diseases arising
from immune dysfunction may be apparent immediately or observed only after
an organism encounters an environmental challenge that causes immune cells to
respond (such as an infection). Immune dysfunctions are in four major categories
that need not be mutually exclusive: immune suppression, allergy, autoimmunity,
and inflammatory dysfunction (inappropriate and/or misdirected inflammation).
Although immune suppression usually is seen as an increased incidence of in -
fections or an increased risk of cancer, allergic, autoimmune, and inflammatory
disorders can be manifested as diseases affecting virtually any tissue. It is often
difficult to diagnose such diseases, so they may or may not be medically catego -
rized as immune disorders.
Immune Suppression
Suppression of immune responses can reduce resistance to infectious disease
and increase the risk of cancer. Infection with the human immunodeficiency virus
(HIV) is a well-recognized example of an acquired immune deficiency in which a
specific type of lymphocyte (CD4+ T cells) is the target of the virus. The decline
in the number of CD4+ T cells after HIV infection correlates with an increased
incidence of infectious diseases, including fatal opportunistic infections, and with
an increased incidence of several types of cancer. Treatment of cancer patients
with toxic chemotherapeutic drugs suppresses the immune system by inhibiting
the generation of new WBCs by the bone marrow and by blocking proliferation
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242 VETERANS AND AGENT ORANGE: UPDATE 2010
of lymphocytes during an immune response. Both those examples represent se -
vere immune suppression in which the adverse outcome is easily detected with
clinical measurements.
Immune suppression can also result from exposure to chemicals in the
workplace or in the environment and be manifested as recurrent infections, op -
portunistic infections, a higher incidence of a specific category of infections, or a
higher incidence of cancer. However, unless the immune suppression is severe, it
is often difficult to obtain clinical evidence that directly links chemically induced
changes in immune function to increased infectious disease or cancer, because
many confounding factors can influence a person’s ability to combat infection.
Such confounders include age, vaccination status, the virulence of the pathogen,
the presence of other diseases (such as diabetes), stress, smoking, and the use of
drugs or alcohol. Therefore, immunotoxicology studies are often conducted in
laboratory animals to understand the scope and mechanism of chemical-induced
immune suppression. Results of such studies can be used to develop biomarkers
to assess effects in human populations. Infectious-disease models in animals can
also be used to determine whether the pattern of disease changes with chemical
exposure.
Allergic Diseases
The immune system sometimes responds to a foreign substance that is
not pathogenic. Such immunogenic substances are called allergens. Like most
immune-based diseases, allergic diseases have both environmental and genetic
risk factors. Their prevalence has increased in many countries in recent decades
(CDC, 2004; Linneberg et al., 2000; Simpson et al., 2008; Sly, 1999). Major
forms of allergic diseases are asthma, allergic rhinitis, atopic dermatitis, and food
allergy. The response to some allergens, such as pollen and bee venom, results
in the production of immunoglobulin E (IgE) antibodies. Once produced, IgE
antibodies bind to mast cells, specialized cells that occur in tissues throughout the
body, including lung airways, the intestinal wall, and blood-vessel walls. When a
person is exposed to the allergen again, it binds to the antibodies on the mast cells
and caused them to release histamine and leukotrienes, which produce the symp -
toms associated with an allergic response. Other allergens, such as poison ivy and
nickel, activate allergen-specific lymphocytes at the site of contact (usually the
skin) that release substances that cause inflammation and tissue damage. Some
allergic responses, such as those to food allergens, may involve a combination
of allergen-specific lymphocyte–driven and IgE–driven inflammation. Allergic
responses may be manifested in specific tissues (such as skin, eye, airways, and
gastrointestinal tract) or result in a system-wide response called anaphylaxis.
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243
IMMUNE-SYSTEM DISORDERS
Autoimmune Diseases
At least 60 recognized diseases and conditions affecting the cardiovascular,
respiratory, nervous, endocrine, dermal, gastrointestinal, hepatic, and excretory
systems are classified as autoimmune diseases (WHO, 2006). They affect both
men and women. Most of the autoimmune diseases affect more women than
men (Fairweather et al., 2008). Genetic predisposition, age, hormone status, and
environmental factors, such as infectious diseases and stress, are known to affect
the risk of developing autoimmune diseases. The existence of some autoimmune
diseases is also a risk factor for the development of other immune-related dis -
eases, such as some types of cancer (Landgren et al., 2010).
Autoimmune disease is an example of the immune system’s causing rather
than preventing disease: the immune system attacks the body’s own cells and
tissues as though they are foreign. Inappropriate immune responses that result
in autoimmune disease can be promoted by different components of the immune
system (such as antibodies and lymphocytes) and can be directed against a wide
variety of tissues or organs. For example, the autoimmune reaction in multiple
sclerosis is directed against the myelin sheath of the nervous system; in Crohn
disease, the intestine is the target of attack; in type 1 diabetes mellitus, the
insulin-producing cells of the pancreas are destroyed by the immune response;
rheumatoid arthritis arises from immune attack on the joints.
More generalized forms of autoimmune diseases also occur. Systemic lupus
erythematosus (SLE) is an autoimmune disease that has no specific target organ
of immune attack. Instead, patients have a variety of symptoms that often occur in
other diseases, and this makes diagnosis difficult. A characteristic rash across the
cheeks and nose and sensitivity to sunlight are common symptoms; oral ulcers,
arthritis, pleurisy, proteinuria, and neurologic disorders may be present. Almost
all people who have SLE test positive for antinuclear antibodies in the absence
of drugs known to induce them. The causes of SLE are unknown, but environ-
mental and genetic factors have been implicated. Some of the environmental
factors that may trigger it are infections, antibiotics (especially those in the sulfa
and penicillin groups) and some other drugs, ultraviolet radiation, extreme stress,
and hormones. Occupational exposures to such chemicals as crystalline silica,
solvents, and pesticides have also been associated with SLE (Cooper and Parks,
2004; Parks and Cooper, 2005).
Inflammatory Diseases
Inflammatory diseases make up a more recently identified category of
immune-related disorders characterized by dysfunctional inflammatory responses
(usually involving immune cells) that are exaggerated, excessively prolonged,
or misdirected. Tissue disease can result from this inappropriate inflammation,
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244 VETERANS AND AGENT ORANGE: UPDATE 2010
which can affect virtually any organ. Examples of diseases and other conditions
that are most often included in other disease categories but are also considered to
be inflammatory diseases are coronary arterial disease, asthma, eczema, chronic
sinusitis, hepatic steatosis, psoriasis, celiac disease, and prostatitis. Inflammatory
diseases often occur with one another, and this has resulted in the categorizing
of different but linked inflammatory diseases together as a single chronic in -
flammatory disorder (Borensztajn et al., 2011); among these are atherosclerosis
and chronic pulmonary obstructive disease. Inappropriate inflammation also ap -
pears to play a role in promoting the growth of cancer (Bornschein et al., 2010;
Hillegass et al., 2010; Landgren et al., 2010; Porta et al., 2010; Winans et al.,
2010). Examples of this can be seen in the higher prevalence of specific cancers
in patients who have such inflammatory diseases as inflammatory bowel disease
(Lucas et al., 2010; Viennot et al., 2009; Westbrook et al., 2010), prostatitis
(Sandhu, 2008; Wang et al., 2009) and psoriasis (Ji et al., 2009).
Ordinarily, inflammation can be advantageous in fighting infectious diseases.
It is one component of the normal host response to infection and is mediated by
innate immune cells. Inflammatory responses have evolved to speed the traffick -
ing of macrophages, granulocytes, and some lymphocytes to the area of infection,
where they produce toxic metabolites that kill pathogens. Interactions among
innate immune cells and epithelial and endothelial cells are important in regulat -
ing the level of inflammation. However, improperly regulated inflammation can
contribute to diseases that arise in nonlymphoid tissues such as the lungs, skin,
nervous system, endocrine system, and reproductive system.
CONCLUSIONS FROM VAO AND PREVIOUS UPDATES
The following comments are restricted to findings on the immune system
after adult human exposure. For a discussion of potential effects on the immune
system arising from early-life (such as perinatal) exposures (which would not be
directly applicable to the Vietnam veterans who are the target of this report), see
Chapters 4 and 8. Studies that served as the basis of prior updates of VAO and
one 2009 study are shown in Table 6-1.
Vietnam Veterans
A handful of the direct studies of veterans listed in Table 6-1 reported a
statistical difference in a single immune measure (Kim et al., 2003; Michalek
et al., 1999a). But invariably the same effect was not found in other studies of
Vietnam veterans, nor was support found in epidemiologic studies of other popu -
lations. Thus, there were no consistent findings indicative of immunosuppression,
increased risk of autoimmunity (usually as measured with autoantibodies), or
biomarkers of atopy or allergy (such as increased IgE concentrations). Much of
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245
IMMUNE-SYSTEM DISORDERS
TABLE 6-1 Selected Epidemiologic Studies—Immune Effects in Adult
Humans
Reference Study Population Exposure/Results
VIETNAM VETERANS
US Air Force Health Study (AFHS)—Ranch All COIs
Hand veterans vs SEA veterans
AFHS, 2000 Participants in 1987 A small dose-related increase in T-cell
examination cycle, counts and a high-dose increase in NK
Ranch Hands vs markers, neither considered by authors to
comparisons—mortality be biologically important; no dose–response
relationship for TCCD exposure associated
with T-cell activation markers (CD25),
serum Ig, or autoantibodies
Michalek et al., Participants in 1997 No change in surface markers for B and
1999a examination cycle, T cells, no change in serum Ig, no change
Ranch Hands vs in autoantibodies (antinuclear antibody,
comparisons—incidence smooth muscle autoantibody, parietal
cell autoantibody, rheumatoid factor, and
monoclonal immunoglobulins) and no dose-
related change in DTH response
Wolfe et al., 1990 Participants in 1987 No change in surface markers for B and T
examination cycle, cells
Ranch Hands vs
comparisons—morbidity
Wolfe et al., 1985 Participants in 1985 No change in surface markers for B and T
examination cycle, Ranch cells
Hands vs comparisons—
morbidity and mortality
US CDC Vietnam Experience Study (VES) All COIs
Boehmer et al., 2004 Mortality (1965–2000) No increase in infectious or parasitic
diseases
CDC, 1988b Deployed vs No differences in infections, no changes in
nondeployed—morbidity B and T cell-surface markers, WBC counts,
or circulating serum Ig
US VA Cohort of Monozygotic Twins All COIs
Eisen et al., 1991 Physical health—morbidity Increase in skin conditions of unknown
etiology, no increase in blood disorders
American Legion Cohort All COIs
Stellman et al., 1988 Physical health and Increase in skin conditions and arthritis
reproductive outcomes
continued
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246 VETERANS AND AGENT ORANGE: UPDATE 2010
TABLE 6-1 Continued
Reference Study Population Exposure/Results
State Studies of US Vietnam Veterans All COIs
Visintainer et al., Michigan Vietnam Veterans Increased mortality from infectious
1995 (deployed vs nondeployed) (including parasitic) diseases
Kahn et al., 1992 New Jersey Agent Orange Depressed response to tetanus in DTH tests,
Commission decrease in CD4 and SmIg+ B cells
Newell, 1984 Agent Orange Advisory Increase in percentage of active T rosette-
Committee of Texas forming cells
Australian Vietnam Veterans All COIs
O’Toole et al., 2009 Australian Vietnam Increase in hay fever, increases in infectious
Veterans—longitudinal and parasitic diseases, increase in arthritis
cohort study of 67
conditions in randomly
selected Vietnam veterans
vs general population
CDVA, 1997b National Service Vietnam No change in mortality from infectious
Veterans—mortality (including parasitic) diseases
Korean Vietnam Veterans All COIs
Kim et al., 2003 Immunotoxicologic study Increase in IgE and IL-4, decrease in IgG1
and IFN-gamma, no change in lymphocyte
counts
Vietnamese Vietnam Veterans All COIs
Chinh et al., 1996 Antinuclear and sperm No change in autoantibodies to sperm,
autoantibodies antinuclear bodies
OCCUPATIONAL STUDIES
Chemical or Industrial Workers
Pesticide factories (not specifically
Baranska et al., 2008 A prospective multicenter
cohort study of 238 TCDD): Reduced antibody responses to
pesticide-exposed workers hepatitis B vaccination among exposed
vs 138 unexposed workers workers carrying a specific IL-1 allele
TCDD (or “TCDD toxic equivalents” from
Neubert et al., 2000 Updated and expanded
evaluation of 158 workers PCDD/PCDF): No differences in serum Ig
in a German chemical plant or cytokine (IL1, IL6, TNF-alpha)
with differing exposure
studied in two trials
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247
IMMUNE-SYSTEM DISORDERS
TABLE 6-1 Continued
Reference Study Population Exposure/Results
TCDD (in chemical plant): In subset of
Ernst et al., 1998 19 highly exposed chemical
workers vs 28 unexposed leukocytes, increase in CD8+ memory
controls in two chemical T cells and decrease in naïve T cells
plants in Hamburg, (CD45RA+) after TCDD exposure, as was
Germany stimulated IFN-gamma production from
whole blood cultures associated with TCDD
exposure
TCDD (exposure in a chemical plant): No
Halperin et al., 1998 Cross-sectional study
of 259 TCDD-exposed significant changes in serum Ig or major
2,4,5-trichlorophenate (and leukocyte categories; TCDD associated with
its derivatives) workers decreased circulating CD26 cells (activated
(mean serum TCDD, 223 T cells)
ppt) and 243 unexposed
residential controls (mean
serum TCDD, 6 ppt)
TCDD (or TEQs from PCDD/PCDF
Jung et al., 1998 192 workers in a German
pesticide plant, including exposure): No significant changes in TCDD
29 highly exposed and and lymphocyte subsets, antibody responses
28 controls compared for to vaccination, lymphocyte proliferation,
immune functional tests or autoantibody production; decrease in
chromate resistance of PHA-stimulated
lymphocytes in highest exposure group
TCDD (as a contaminant in chemical
Sweeney et al., 1987 cross-sectional study
1997/1998 of 281 chemical-plant production): Increase in TCDD associated
workers in NJ and MO with a decrease in CD3/Ta1 (helper
at least 15 years after lymphocytes) cells
exposure vs 260 unexposed
controls
TCDD: No differences in any lymphoid
Tonn et al., 1996 Comparison of 11
2,4,5-trichlorophenol subset or in mitogen-induced proliferation;
production workers 20 TCDD exposure was associated with
years after exposure vs 10 decreases in MLR response and in
unexposed age-matched stimulation with IL-2 in vitro
workers in the same
company
TCDD: Reduced gamma globulins in
Jansing and Korff, Examination of eight
1994 trichlorophenol production the most-exposed workers; no significant
workers who developed effects on T4, T8 ratios
chloracne and were re-
examined 15–25 years after
initial exposure
continued
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248 VETERANS AND AGENT ORANGE: UPDATE 2010
TABLE 6-1 Continued
Reference Study Population Exposure/Results
TCDD (during production of TCP): DTH
Benner et al., 1994 Cross-sectional study of
153 male workers in six responses not correlated with dioxin
chemical plants in Germany concentration; slight decrease in IgM was
reported with increasing dioxin exposure;
overall lymphoid counts not different
TCDD: Among 14 immune measures;
Ott et al., 1994 138 surviving workers
from a larger cohort of 254 regression analysis of TCDD concentration
exposed workers after an suggested marginal positive associations
accident in a BASF TCP with IgG, IgA, C3, and C4; marginal
production facility reductions in some lymphocyte population
were also reported
TCDD (or equivalents via PCDD/PCDF
Neubert et al., 1993, 89 volunteers involved in
1994 decontamination work at a exposure): Potentially complicated by age
chemical plant in Hamburg, differences among the compared groups;
German; no control only subtle, clinically nonsignificant
population changes were seen among immune-cell
surface markers in a comparison of higher
exposed vs low-exposed to moderately
exposed workers
TCDD: No changes in serum Ig classes,
Jennings et al., 1988 18 chemical workers in a
2,4,5-T factory exposed increases in antinuclear antibodies and
as a result of an industrial immune complexes, and increase in
accident 17 years before circulating NK cells (Leu7+) in exposed
study vs 15 matched workers
controls
Waste Incinerator Workers
TCDD (via waste incineration): Lymphoid
Oh et al., 2005 Comparison of immune
measures in 31 waste- subsets, IFN-gamma, and Ig not statistically
incineration workers vs 84 different; decrease in IL-4 and increase in
controls T-cell activation (measured as combined
CD3 and CD69 markers) associated with
TCDD exposure
Agricultural Health Study (AHS) Various categories of agricultural
pesticides
Beseler et al., 2008 Comparison from the Both high-level acute pesticide exposure
AHS of 534 cases of (OR = 2.57, 95% CI 1.74–3.79) and
self-reported physician- cumulative pesticide exposure (OR =
diagnosed depression vs 1.54, 95% CI 1.16–2.04) were positively
17,051 controls associated with increase in depression
Beseler et al., 2006 29,074 female spouses of Depression was significantly associated
pesticide applicators in the with pesticide poisoning (OR = 3.26,
AHS 95% CI 1.72–6.19) but not with lower
cumulative exposure
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249
IMMUNE-SYSTEM DISORDERS
TABLE 6-1 Continued
Reference Study Population Exposure/Results
De Roos et al., 2005b Nested case–control study No strong risk factors were identified for
of rheumatoid arthritis in pesticide mixing or application or for any
agricultural families (57,000 specific class of pesticides in the AHS of
pesticide applicators and rheumatoid arthritis.
their spouses).
Other Agricultural Studies
2,4-D and MCPA formulations:
Faustini et al., 1996 Longitudinal study of 10
farmers during 1994 within Decreases in percentages of CD4, CD8,
7 days before and 1–12 CTL, CD8-DR, and NK cells and in
days and 50–70 days after NK activity and mitogen-stimulated
exposure lymphoproliferation; CD4:CD8 ratio was
unaltered; CD3 and CD8 percentages had
recovered by the second assessment period;
no significant correlations between immune
changes and amount of pesticides applied
ENVIRONMENTAL STUDIES
Seveso Cleanup Workers TCDD
Ghezzi et al., 1982 Prospective study using No differences in WBC counts and platelet
analysis of samples from counts
36 cleanup workers
(divided into three groups
based on time spent in
the contamination area);
pre-employment samples
and samples after 9
months were analyzed for
comparison with samples
from 31 nonexposed
workers
Seveso Residential Population TCDD
Baccarelli et al., Study of 101 chloracne Persistent increase in TCDD in chloracne
2005b cases vs 211 controls 20 cases; younger people seemed to be more
years after the accident; susceptible; no major trends in disease
relatively low statistical occurrence
power was available
because the study examined
the occurrence of individual
diseases
Baccarelli et al., 2002 Study of 62 people from a Plasma concentration of TCDD was
highly exposed zone and 53 determined; multivariate regression analysis
from noncontaminated areas showed significant decrease in plasma IgG
20 years after the accident with increasing TCDD concentration and no
changes in IgM, IgA, or C3
continued
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250 VETERANS AND AGENT ORANGE: UPDATE 2010
TABLE 6-1 Continued
Reference Study Population Exposure/Results
Pocchiari et al., 1979 45 children (3–7 yrs of age) No differences in serum IG, mitogen
living in exposed areas vs responses of lymphocytes (PHA and
45 nonexposed children as pokeweed), or percentage of rosette-
controls forming lymphocytes
Times Beach (MO) Cohort TCDD
Webb et al., 1987 82 people in more highly No differences in DTH response or T-cell
contaminated areas vs 40 in subsets (T4/T8)
low-risk exposure areas as
controls
Stehr et al., 1986 80 people in highly No differences in DTH induration or T-cell
contaminated areas vs 40 subset analysis (T4/T8)
controls in lower-risk areas
Knutsen, 1984 Pilot study of small Multitest DTH evaluation to seven recall
numbers of people; for antigens was performed, no statistical
comparisons, people differences were reported, and only trends
were assigned to two were noted; no statistical differences
environmental-exposure were reported for T-cell markers (T3, T4,
groups: those in high-risk and T8) or mitogen-induced lymphocyte
areas (27 men, 23 women, proliferation (PHA, Con A, and pokeweed
and 15 children) and those mitogen), and only trends were noted
in low-risk areas (12 men,
10 women, and 8 children)
Quail Run Mobile Home Park (MO) Cohort TCDD
Evans et al., 1988 A subset of the previously Retesting of DTH failed to produce the
anergic persons in the differences observed initially
Stehr-Green et al. (1987)
study were re-evaluated in
the DTH test with a higher
DTH test dose and highly
trained, blinded readers
Knutsen et al., 1987 Small (ill-defined) samples DTH suppression in the exposed group
were used; comparisons of was reported, but data from two of four
residents of the Quail Run readers were discarded; no differences in
Mobile Home Park with T-cell mitogen stimulation; decreases in
residents of St. Louis–area percentages of T3, T4, and T11 cells in the
trailer parks as controls exposed group
Stehr-Green et al., 154 people in highly Increase in anergy and decrease in
1987 contaminated area vs 155 in induration for DTH in exposed group; data
three low–environmental- from some readers were excluded; decrease
contamination areas as in percentages of T3, T4, and T11 cells, but
controls no difference in cell number of T4/T8 ratio.
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254 VETERANS AND AGENT ORANGE: UPDATE 2010
self-reported arthritis (Lee et al., 2007a), but De Roos et al. (2005b) had found
no such association in their study.
Prior VAO updates concluded that human data were either insufficient or
inconsistent with respect to an increased risk of immunosuppression, allergic
disease, or autoimmune disease.
UPDATE OF THE EPIDEMIOLOGIC
LITERATURE AND HUMAN STUDIES
For this update, the committee revisited the entire literature of herbicide–
human immune findings from studies of Vietnam veterans, occupationally ex -
posed people, and environmentally exposed people (Table 6-1), including studies
reviewed in prior VAO updates and one study published since Update 2008.
Among the previously considered human studies, only two stand out for
special consideration on the basis of their analysis of actual immune-based dis -
ease or clinically relevant human immune responses. Zober et al. (1994) studied
three categories of occupationally exposed workers based on chloracne status
(chloracne not evident, moderate, or severe) and nonexposed workers. They found
that the frequencies of episodes of parasitic diseases, respiratory infections, and
skin diseases were elevated with respect to the nonexposed workers (p = 0.067,
p = 0.003, and p = 0.001, respectively), and each of these outcomes showed in-
creasing trends over the three chloracne categories (an indicator of higher dioxin
exposure). Baccarrelli et al. (2002) reported that higher TCDD exposure was
associated with lower serum IgG in the exposed Seveso populations.
Only one new epidemiologic study addressed exposure to the chemicals of
interest and outcomes in which immune function may play a prominent role.
Infectious and parasitic diseases, respiratory disorders, and skin disorders were
among the many conditions that O’Toole et al. (2009) found to be significantly
more prevalent in Australian Vietnam veterans, on the basis of self-reports, than
in the general population. The confidence that can be placed in this new study
is substantially hampered by a poor response rate, its reliance on self-reported
diagnoses, the questionable suitability of the general population as a control
group, and the fact that the veterans and the controls were interviewed under quite
different circumstances. Reporting bias and a “healthy-warrior” effect might be
expected to bias the findings in opposite directions, but the near uniformity of sig-
nificant findings on these self-reported health problems in the deployed veterans
suggests that problems associated with reporting bias may have been dominant.
In combination, the studies raise the question of whether high TCDD ex -
posure may contribute to a reduced ability to fend off or to clear some types of
infections.
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255
IMMUNE-SYSTEM DISORDERS
BIOLOGIC PLAUSIBILITY
There is an extensive body of evidence from experimental studies in animal-
model systems that TCDD, other dioxins, and several dioxin-like chemicals
(DLCs) are immunotoxic (Kerkvliet, 2009). Immunotoxicity is due primarily
to changes in adaptive immune responses that result in suppression of both
antibody and cell-mediated immunity and a reduction in the ability to clear
pathogenic infections and prevent tumor growth. Studies in laboratory mice
have shown that the immunotoxicity of TCDD and DLCs depends on activation
of the arylhydrocarbon receptor (AHR). Most of the cell types involved in the
immune system express the AHR, so there are many potential pathways to im -
munotoxicity. TCDD has also been shown to alter macrophages and neutrophils
in a manner that exacerbates some forms of inflammation during infections and
may contribute to the development of chronic inflammatory lung disease (Teske
et al., 2005; Wong et al., 2010).
TCDD is a potent immunosuppressive chemical in laboratory animals. The
relative potencies of given DLCs based on induction hepatic enzymes (their
toxicity equivalency factors [TEFs]) appear to predict the degree of immunosup -
pression induced (Smialowicz et al., 2008). Exposure of animals to dioxin not
only suppresses some adaptive immune responses but also has been shown to
increase the incidence and severity of various infectious diseases and to increase
the development of cancer (Choi et al., 2003; Head and Lawrence, 2009; Jin et al.,
2010). It is consistent with its immunosuppressive effects that TCDD exposure
suppresses the allergic immune response of rodents, and this in turn results
in decreased allergen-associated pathologic lung conditions and has recently
been shown to suppress the development of experimental autoimmune disease
(Quintana et al., 2008). Thus, depending on the disease, TCDD exposure could
result in exacerbation or amelioration of symptoms.
Recent attention has focused on the ability of the AHR to induce regulatory T
cells (Marshall and Kerkvliet, 2010). These so-called Tregs have potent suppres-
sive activity in the immune system, and their inappropriate induction by TCDD
could account for much of the immune suppression. AHR activation in dendritic
cells has also been shown to promote the development of Tregs by inducing
tryptophan metabolism. AHR activation in B cells can directly disrupt the produc-
tion of antibodies (Sulentic and Kaminski, 2011). The recent demonstration that
AHR activation by TCDD leads to the development of regulatory T cells helps
to explain the diversity of effects seen after exposure to TCDD (Funatake et al.,
2008; Marshall et al., 2008; Quintana et al., 2008).
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256 VETERANS AND AGENT ORANGE: UPDATE 2010
SYNTHESIS
Immune Suppression
One would expect exposure to substantial doses of TCDD to result in immune
suppression in Vietnam veterans. However, several studies of various measures
of human immune function failed to reveal consistent correlations with TCDD
exposure, probably because the exposures were inadequate to produce immune
suppression or the characteristics measured were not among those most relevant
with respect to biological plausibility. No clear pattern of an increase in infec -
tious disease has been documented in the studies of veterans exposed to TCDD
or to the herbicides used in Vietnam. However, one occupational-exposure study
and one environmental-exposure study do support the possibility that sufficiently
high exposure to TCDD may result in an increased frequency of infections. It was
also supported by the self-reporting study by O’Toole et al. (2009). As a result,
frequency and duration of specific types of infections should be a focus of future
studies. Suppression of the immune response by TCDD might increase the risk
of some kinds of cancer in Vietnam veterans, but there is no evidence to support
that connection.
Allergic and Autoimmune Diseases
Epidemiologic studies have been inconsistent with regard to TCDD’s influ -
ence on IgE production in humans. No human studies have specifically addressed
the influence of TCDD on autoimmune disease, but several animal studies have
shown that TCDD suppresses the development of autoimmune diseases. In study-
ing postservice mortality, Boehmer et al. (2004) found no increase in deaths
of Vietnam veterans that could be attributed to immune-system disorders. The
present committee’s review included a study that found a significant association
between concentrations of dioxin-like PCBs and the prevalence of arthritis in
women but not in men (Lee et al., 2007a). There is no experimental evidence to
support that finding, but increased inflammatory responses could be involved.
Future studies are needed to determine a potential mechanism of TCDD-induced
rheumatoid arthritis.
Few effects of phenoxy herbicide or cacodylic acid exposure on the im-
mune system have been reported in animals or humans, and no clear association
between such exposure and autoimmune or allergic disease has been found.
Exposure of laboratory animals to phenoxy herbicides or cacodylic acid has not
been associated with immunotoxicity.
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Inflammatory Diseases
There are no human data on the potential for dioxin or the herbicides of inter-
est to induce dysregulation of inflammation that could contribute to an increased
risk of inflammation-associated diseases.
Possible associations involving infectious or inflammation-related diseases
should be a focus for the future. Examples of studies that would add support for
these potential adverse outcomes are Baccarelli et al. (2002), Baranska et al.
(2008), Beseler et al. (2008), Oh et al. (2005), O’Toole et al. (2009), Tonn et al.
(1996), and Visintainer et al. (1995).
Conclusions
On the basis of the evidence reviewed here and in previous VAO reports, the
present committee concludes that there is inadequate or insufficient evidence to
determine whether there is an association between exposure to the chemicals of
interest and specific infectious, allergic, or autoimmune diseases.
TRANSLATION BETWEEN ANIMAL AND HUMAN STUDIES
Animal studies and in vitro studies with human cells and cell lines are
important ways of trying to understand underlying biologic mechanisms associ -
ated with immunotoxic and other responses to xenobiotics, which are “foreign”
substances that do not normally occur in biologic systems. However, as discussed
above, despite the vast array of data supporting the immunotoxicity of TCDD in
laboratory animals, there is little evidence from studies of Vietnam veterans or
other human populations that suggests that TCDD or the herbicides of concern
produce immune alterations. Many factors must be considered in examining the
relevance of animal and in vitro studies to human disease and disease progression,
and they are discussed Chapter 4. Here, we present the factors that are probably
most important in considering differences between the results of laboratory stud -
ies and the findings of observational epidemiologic studies.
Magnitude and Timing of Exposure
In general, the TCDD exposures used in animal studies have been orders
of magnitude higher than Vietnam veterans are likely to have received during
military service. It is well known that the immune system is highly susceptible
to xenobiotic exposure during critical stages of development, such as gestation.
It is also well known that primary immune responses are easier to alter than sec -
ondary immune responses. In vivo studies show that exposure to antigens may
be important, so the timing of antigen exposure relative to TCDD exposure may
be an important variable.
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258 VETERANS AND AGENT ORANGE: UPDATE 2010
Genetic Susceptibilities
Human immune diseases are likely to have complex etiologies and to be
under the influence of numerous genes and gene-by-environment interactions
(Dietert et al., 2010). Differences in AHR affinity between species may be a fac-
tor in animal-to-human extrapolation. For example, many strains of mice (AHRb)
are known to exhibit greater susceptibility of CYP1A1 induction and immune
suppression than other strains (AHRd). In contrast, a simple single-haplotype dif-
ference in susceptibility to TCDD has not been observed in humans. Rats appear
to be more similar to the resistant AHRd phenotype of mice in their sensitivity to
TCDD. Indeed, it is difficult to produce immune suppression in rats with TCDD
because of that, and there probably are other genetic reasons as well.
Sex Differences
There are well-known differences in the susceptibility to xenobiotic expo-
sures between male and female animals. There are probably multiple reasons
for the differences, some of which may pertain to immunomodulation by sex
steroids. Similarly, evidence suggests that specific immune-based health risks in
humans have important sex differences. For example, women generally are much
more susceptible to the development of several autoimmune diseases than men;
such differences in humans may result from a combination of genetic factors and
environmental exposures. That has ramifications for future studies. In consider-
ing the potential impact of Agent Orange on the immune system and the risk of
disease, sex-based differences in chemically induced adverse immune outcomes
need to be investigated. Future studies should ensure that, whether in animal
models or in direct human studies, gene- or sex-specific immune effects are able
to be evaluated with sufficient statistical power to support distinctions.
Stress
Stress produced is a well known modifier of human immune responses. It is
an ever-present variable that is difficult to assess or control for in epidemiologic
studies.
SUBJECTS FOR FUTURE RESEARCH
Immune biomarkers (such as cytokines, antibodies, antitumor activity, popu-
lations of specialized cells, and inflammatory metabolites) can be used to examine
the risks of such specific health problems as heightened allergic responses, defi -
ciency in cell-mediated immunity, and susceptibility to autoimmune responses. In
addition, there may be more generalized biomarkers; for example, a recent human
study reported that the concentrations of a specific cytokine produced by macro -
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IMMUNE-SYSTEM DISORDERS
phages (macrophage inhibitory cytokine-1) was a useful biomarker for predicting
all-causes mortality (in subjects who already had particular chronic diseases) over
a span of 14 years (Wiklund et al., 2010). In the absence of clearly defined im -
mune diseases, combinations of immune measures may be used as biomarkers of
altered immune responses associated with risks of specific diseases. As a result,
antibody concentrations, recall antigen tests, lymphoid subpopulation sizes, and
cytokine, receptor, and metabolite concentrations are often used in combina -
tion for the prediction of immune-associated health risks. Immune biomarkers,
when appropriately selected, could provide useful information regarding potential
immune-associated health risk connected with TCDD. However, it is critical that
the biomarkers used in such studies be those most predictive for risk of disease,
and not just those most readily measured.
On the basis of extensive animal studies involving TCDD, the most plausible
immune alterations expected in dioxin-exposed human adults are suppression
of selected adaptive immune responses and misregulated inflammation. Several
human studies (Baccarelli et al., 2002; Halperin et al., 1998; Jung et al., 1998;
Michalek et al., 1999a) have examined measures that could reflect functional im -
mune suppression (for example the DTH recall antigen test and concentrations
of various antibodies). However, most studies have failed to show a significant
effect of dioxin exposure on those measures. Regulation of inflammation is best
assessed under the conditions of vaccination or infectious challenge rather than
in a resting state. Biomarkers of inflammation would normally include the cyto-
kines TNF-a, TGF-b, IL-6, IL-8, IL-10; receptors for TNF-a and IL-6, VCAM-
1, ICAM-1, PGE2 and thromboxane; and C-reactive protein–reactive oxygen
species production and nitric oxide production. Although a handful of studies
included resting (unchallenged) measures for one or two of those biomarkers,
no comprehensive testing or challenge-associated analysis has been performed.
That constitutes a data gap. Finally, additional studies should focus on novel im-
mune subpopulations, such as Fox p3+ T regulatory cells, Th17 cells, and den -
dritic cells, on which dioxin has reportedly exerted effects in laboratory animals
(Chmill et al., 2010; Jin et al., 2010; Marshall and Kerkvliet, 2010).
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