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—Veterans 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 immunerelated 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 chemicals 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.



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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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257 IMMUNE-SYSTEM DISORDERS 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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259 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). REFERENCES1 AFHS (Air Force Health Study). 2000. An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. 1997 Follow-up Examination Results. Brooks AFB, TX: Epidemiologic Research Division, Armstrong Laboratory. AFRL-HE-BR-TR-2000-02. Andrews JS, Stehr-Green PA, Hoffman RE, Needham LL, Patterson DG Jr, Bagby JR Jr, Roberts DW, Webb KB, Evans RG. 1986. Missouri dioxin studies: Some thoughts on their implications. Proceedings of the 7th National Conference on Management of Uncontrolled Hazardous Waste Sites. December 1–3, 1986. Washington, DC. 78–83. 1Throughout the report the same alphabetic indicator following year of publication is used consistently for the same article when there were 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.

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