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Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides (Ninth Biennial Update); Board on the Health of Select Populations; Institute of Medicine. Veterans and Agent Orange: Update 2012. Washington (DC): National Academies Press (US); 2014 Mar 6.

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Veterans and Agent Orange: Update 2012.

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7Immune-System Disorders

As in Veterans and Agent Orange: Update 2010 (IOM, 2012, hereafter referred to as Update 2010), immune-system disorders are being addressed in a separate chapter preceding those on other adverse health outcomes. In Veterans and Agent Orange (VAO) reports prior to Update 2010—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 Effects” chapter. The current committee elected to revisit comprehensively 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 (TCDD) impairment of the immune systems of laboratory animals.

This 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 they include a new tabulation of all the immune-related epidemiologic information that has been considered in this series and a synopsis of the information new in this update. The next section discusses factors that may lead the immune responses of animals exposed to the chemicals of interest (COIs) to be much more pronounced than any observed to date in humans. The chapter closes with the committee's thoughts regarding research on the possibility that immune perturbations in humans function as a mechanistic step in the development of disease processes in other organ systems.

The immune system plays three important roles in the body:

1.

It defends the body against infection by viruses, bacteria, and other disease-producing microorganisms, known as pathogens.

2.

It defends against cancer by destroying mutated cells that might otherwise develop into tumors and by providing immunity against tumors.

3.

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 responses. 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 type has many specialized cell populations that are responsible for specific functions connected to the production of specific mediators, such as immune hormones, cytokines, and other secreted factors. Imbalances in those specialized populations or in their level of functional activity can result in inadequate or improper immune responses, which 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).

CATEGORIES OF IMMUNE DYSFUNCTION

Immune dysfunctions are in four major categories that need not be mutually exclusive: immune suppression, allergy, autoimmunity, and inflammatory dysfunction (inappropriate or misdirected inflammation). Although immune suppression usually is seen as an increased incidence of infections or an increased risk of cancer, allergic, autoimmune, and inflammatory disorders can be manifested as diseases that affect virtually any tissue. It is often difficult to diagnose such diseases, so they may or may not be medically categorized 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 cell) 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 of lymphocytes during an immune response. Both those examples represent severe 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, opportunistic 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. In immediate hypersensitivity, 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 causes them to release histamine and leukotrienes, which produce the symptoms associated with an allergic response. In delayed-type hypersensitivity (DTH) reactions, also known as cell-mediated immunity, other allergens, such as poison ivy and nickel, activate allergen-specific lymphocytes at the site of contact (usually the skin) that (memory T cells) 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, eyes, airways, and gastrointestinal tract) or may result in a system-wide response called anaphylaxis.

Autoimmune Diseases

The National Institutes of Health Autoimmune Disease Coordinating Committee recognizes 80 diseases and conditions that affect the cardiovascular, respiratory, nervous, endocrine, dermal, gastrointestinal, hepatic, and excretory systems and are classified as autoimmune diseases (NIH Autoimmune Diseases Coordinating Committee, 2005). They affect both men and women, but most affect more women than men (Fairweather et al., 2008). Genetic predisposition, age, hormone status, and such environmental factors as infectious diseases and stress are known to affect the risk of developing autoimmune diseases, and different autoimmune diseases tend to occur in the same person and to cluster in families. The existence of some autoimmune diseases is also a risk factor for the development of other immune-related diseases, 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's 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; and rheumatoid arthritis arises from immune attack on the joints, but can also involve the lung, heart, and additional organs.

More generalized forms of autoimmune diseases also occur. Systemic lupus erythematosus (SLE) is an autoimmune disease that has multiple target organs 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 environmental 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 (also referred to as auto-inflammatory diseases) make up a more recently identified category of immune-related disorders that are characterized by exaggerated, excessively prolonged, or misdirected dysfunctional inflammatory responses (usually involving immune cells). Tissue disease can result from this inappropriate inflammation, 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 inflammatory disorder (Borensztajn et al., 2011); among these are atherosclerosis and chronic pulmonary obstructive disease. Inappropriate inflammation also appears 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 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 trafficking 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 regulating the magnitude 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 related to the immune system that occur 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 9. Studies that served as the basis of prior updates of VAO are shown in Table 7-1.

TABLE 7-1. Selected Epidemiologic Studies—Immune Effects in Adult Humans (Shaded Entries Are New Information for This Update).

TABLE 7-1

Selected Epidemiologic Studies—Immune Effects in Adult Humans (Shaded Entries Are New Information for This Update).

Vietnam Veterans

A handful of the direct studies of veterans listed in Table 7-1 reported a statistically significant 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 populations. 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 the focus of the studies was on measuring T4:T8 ratios. The T4:T8 ratio is an effective biomarker of the progression of HIV-induced AIDS, but, on the basis of the TCDD-exposure animal data, it is not an immunologic index that is expected to be altered. The results of a survey of Australian Vietnam veterans (O'Toole et al., 2009) included purportedly significant increases in the prevalence of a number of conditions in which immune function may play a prominent role, but the study's methods were deemed unreliable.

Occupational Exposures

Occupational-exposure studies shown in Table 7-1 evaluated concentrations of lymphoid populations in circulation, such as CD4, CD8 (and the ratio of the two), and natural killer (NK) cells; cell-mediated immunity (the delayed-hyper-sensitivity response); serum concentrations of immunoglobulins, such as IgM, IgG, and IgA; concentrations of complement, such as C3 and C4; and concentrations of cytokines, such as IL-1, IL-2, interferon-gamma, IL-4, IL-6, and tumor necrosis factor (TNF)-alpha. A few studies also included disease or condition endpoints, such as rheumatoid arthritis, SLE, and depression. Ex vivo analyses included measures of NK activity, lymphoid mitogen-induced proliferation, and the mixed lymphocyte response (MLR) against allogeneic cells. Some studies identified one or more dioxin-related shifts in immune measures, but many reported no significant differences in the same measures. That is particularly true of the study by Neubert et al. (2000), which measured toxicity equivalents (TEQs) for dioxin but found no immunoglobulin or cytokine alterations. In general, the spectrum of occupational-exposure findings does not provide a consistent or clear picture of alterations in immune measures that could be extrapolated to an increased risk of a single disease or even a broader category of diseases. The exception may be observations of pesticide-associated autoimmunity and depression. Immune depression was rather consistently associated with very high pesticide exposures or pesticide poisonings. However, because the studies generally concerned broad categories of pesticide exposure, their relevance to herbicide exposures in Vietnam is not clear.

Environmental Exposures

Several environmental-exposure studies reported alterations, but findings were inconsistent among the studies (see Table 7-1). Some studies reported alterations in immune measures associated with TEQs for dioxin. For example, Van den Heuvel et al. (2002) reported that IgE, positive radioallergosorbent (RAST) tests in response to specific allergens, eosinophil counts, and NK-cell counts correlated negatively with dioxin TEQs but that IgA increased; these alterations, however, were not seen consistently in other studies. Baccarelli et al. (2002) found no changes in IgA but saw changes in IgG in the Seveso population. Svensson et al. (1994) found that NK-cell numbers were reduced with increasing concentrations of persistent organic chemicals, but Lovik et al. (1996) found no difference in NK numbers or activity. Similarly, the occupational-exposure studies (see Table 7-1) that examined NK concentrations reported the full spectrum of results: no alterations (Halperin et al., 1998), a decrease (Faustini et al., 1996), and even an increase in NK numbers (Jennings et al., 1988) in dioxin-exposed people.

As seen in Table 7-1, some early studies of the Quail Run Mobile Home Park population exposures reported that dioxin exposure was associated with a reduced cell-mediated immune response, the delayed-type hypersensitivity (DTH) response (Andrews et al., 1986; Hoffman et al., 1986; Knutsen et al., 1987; Stehr-Green et al., 1987). But some of those studies had technical problems in assessment and in followup analyses. Dioxin-associated changes were not confirmed (Evans et al., 1988; Webb et al., 1989). In addition, several studies of the Times Beach population did not find any alteration of the DTH response in dioxin-exposed populations (Knutsen, 1984; Stehr et al., 1986; Webb et al., 1987).

Analysis of National Health and Nutrition Examination Survey (NHANES) data found that exposure to dioxin-like polychlorinated biphenyls was associated with an increase in self-reported arthritis (Lee et al., 2007a), but De Roos et al. (2005b) had found no such association in their study.

Prior VAO updates have 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

Vietnam-Veteran and Case-Control Studies

No new case-control studies or studies of Vietnam veterans exposed to the COIs and adverse immunologic conditions have been published since Update 2010.

Occupational Studies

There were several small new studies of occupational cohorts. Endres et al. (2012) studied fungal sensitization in the Agricultural Health Study and reported that farmers had levels of fungal sensitization lower than the national levels found in the NHANES studies. It is difficult to interpret those data, although they do suggest that farmers as a group have a lower reactivity to fungal antigens.

Saberi Hosnijeh et al. (2011) studied Dutch phenoxy-herbicide workers, assessing their humoral immunity. The 45 TCDD-exposed workers had decreased concentrations of complement factor 4 but no other apparent changes in humoral immunity as measured by other complement factors or immunoglobulins. The same authors (Saberi Hosnijeh et al., 2012) reported that plasma TCDD concentrations were associated with decreases in cytokines, chemokines, and growth factors. The authors conclude that this work provided evidence of immunologic effects of TCDD.

Environmental Studies

No environmental studies of adverse immunologic conditions have been published since the 2010 review. However, a report of an investigation of the immune response of a single highly exposed person (Brembilla et al., 2011) reported some clearly TCDD-associated immune changes (such as IL-22 production by CD4+ T cells), confirming some TCDD-associated changes in immune measures. It is interesting that there was no measured effect of TCDD exposure on the person's T regulatory cells. Earlier publications cited indicate that this patient was Victor Yuchenko, whose poisoning in 2004 has provided insight into human response to and biotransformation of an extremely high dose of TCDD, exceeding by orders of magnitude the exposures experienced by Vietnam veterans.

The literature searches for the current update found two epidemiologic studies (Jusko et al., 2011; Miyashita et al., 2011) that addressed immune-related outcomes in the children of mothers potentially exposed to the COIs (the topic of Chapter 10) that are not relevant to assessing immune consequences in Vietnam veterans of their own exposure.

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, 2012). Immunotoxicity is due primarily to changes in adaptive immune responses that result in suppression of both antibody-mediated and cell-mediated immunity. A new endogenous pathway, the tryptophan metabolic pathway, has recently been identified as affecting the aryl hydrocarbon receptor (AHR) and immune biology (Opitz et al., 2011). Dioxin and related chemicals with dioxin-like activity may induce a reduction in the ability to clear pathogenic infections and prevent tumor growth in a fashion that is mediated by endogenous pathways. Studies in laboratory mice have shown that the immunotoxicity of TCDD and DLCs depends on activation of the AHR. Most of the cell types involved in the immune system express the AHR, so there are many potential pathways to immunotoxicity. 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). Other recent work shows that the AHR is involved in hematopoiesis at multiple stages (Baba et al., 2012; Sibilano et al., 2012; Simones and Shepherd, 2011; Singh et al., 2011). Working with human B cells in vitro, Allan and Sherr (2010) demonstrated a new AHR-dependent mechanism by which exposure to environmental polycyclic aromatic hydrocarbons could suppress humoral immunity by blocking differentiation of B cells into plasma cells.

TCDD is a potent immunosuppressive chemical in laboratory animals. The relative potencies of given DLCs based on induction hepatic enzymes—their toxicity equivalence factors (TEFs)—appear to predict the degree of immunosuppression induced (Smialowicz et al., 2008). TCDD has also been shown to induce apoptosis in rabbit chondrocytes, and this supports a potential role of TCDD in contributing in a novel way to arthritis (Yang and Lee, 2010). 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; Elizondo et al., 2011; Fiorito et al., 2010, 2011; Head and Lawrence, 2009; Jin et al., 2010; Sanchez et al., 2010). It is consistent with its immunosuppressive effects that TCDD exposure suppresses the allergic immune response of rodents; 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), to induce the suppression of autoimmune uveoretinitis (Zhang et al., 2010), and to affect colitis (Takamura et al., 2011), arthritis (Nakahama et al., 2011), and inflammatory lung diseases, such as silicosis (Beamer et al., 2012). A recent study of 18 people who had allergic asthma, 17 people whose asthma was controlled, and 12 controls showed that the plasma concentrations of IL-22 and the expression of the AHR in peripheral blood mononuclear cells was associated with the severity of allergic asthma; this finding strengthened the possibility that the AHR is involved in allergic asthma, thereby implying a role for dioxin exposure in this condition (Zhu et al., 2011). Thus, depending on the disease, TCDD exposure could exacerbate or ameliorate symptoms.

Recent attention has focused on the ability of the AHR to induce regulatory T cells, or Tregs (Kerkvliet, 2012; Marshall and Kerkvliet, 2010). Tregs have potent suppressive 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 production of antibodies (Sulentic and Kaminski, 2011). The recent demonstration that AHR activation by TCDD leads to the development of Tregs helps to explain the diversity of effects seen after exposure to TCDD (Funatake et al., 2008; Kerkvliet, 2012; Marshall et al., 2008; Quintana et al., 2008; Stockinger et al., 2011; Yamamoto and Shlomchik, 2010).

Recent data indicate that the AHR pathway plays an integral role in B-cell maturation, and that TCDD and DLC exposure may alter the function of these cells and result in critical changes in the immune response. Suppression of the immune response by TCDD and similar compounds in mice has been known for over 30 years, but the effect on human cells is less clear. Some recent reports indicate that TCDD and DLC elicit similar effects in humans. Activation of non-transformed human B cells results in an increase in expression of the AHR, indicating that this pathway has a role in normal B-cell function (Allan and Sherr, 2010). Furthermore, treatment of those cells with B[a]P suppresses B-cell differentiation. Lu et al. (2010) demonstrated that although human B cells appeared less responsive to TCDD in increasing expression of AHR battery genes, the ability of TCDD to decrease IgM production was similar in both mouse and human B cells. In addition, data from human hemopoietic stem cells (HSCs) and knockout AHR mouse models show that the AHR is critical in HSC maturation and differentiation (Fracchiolla et al., 2011; Singh et al., 2011). TCDD not only alters HSC maturation but also alters proliferation and migration in vivo and in vitro (Casado et al., 2011), and this indicates that exposure may have multiple effects on immune-cell function.

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 because the characteristics measured were not among those most relevant with respect to biologic plausibility. No clear pattern of an increase in infectious disease has been documented in the studies of veterans exposed to TCDD or to the herbicides used in Vietnam. However, three occupational-exposure studies provide some support for the idea that exposure to TCDD may result in an altered immune response to some exposures and an increased frequency of infections. The study of a single highly exposed person (Brembilla et al., 2011) confirmed TCDD-associated changes in immune measures that may not be applicable to people whose exposure was considerably lower. Immune alteration and the frequency and duration of specific types of infections should therefore 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 the connection.

Allergic and Autoimmune Diseases

Epidemiologic studies have been inconsistent with regard to TCDD's influence 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 studying postservice mortality, Boehmer et al. (2004) found no increase in deaths of Vietnam veterans that could be attributed to immune-system disorders. There is no experimental evidence to support that finding, but increased inflammatory responses could be involved. The study of people who had allergic asthma or controlled asthma strengthened the data and suggested that the AHR (and thus dioxin exposure) is involved in the disease (Zhu et al., 2011). Future studies are needed to determine a potential mechanism of TCDD-induced allergic and autoimmune disease, including rheumatoid arthritis.

Few effects of phenoxy herbicide or cacodylic acid exposure on the immune 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.

Inflammatory Diseases

There are no human data on the potential for dioxin or the herbicides of interest 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 earlier studies whose results support the occurrence of such 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 COIs 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 associated 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, little evidence from studies of Vietnam veterans or other human populations 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 in Chapter 4. Here, we present the factors that are probably most important in considering differences between the results of laboratory studies 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 exposures that 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, and that primary immune responses are easier to alter than are secondary 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.

Genetic Susceptibilities

Human immune diseases are likely to have complex etiologies and to be under the influence of numerous genes and gene–environment interactions (Dietert et al., 2010). Differences in AHR affinity between species may be a factor 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 are other strains (AHRd). In contrast, a simple single-haplotype difference 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 susceptibility to xenobiotic exposures 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 than are men to the development of several autoimmune diseases; such differences in humans may result from a combination of genetic factors and environmental exposures. That has ramifications for future studies. In considering the potential effects 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 human studies—gene-specific or sex-specific immune effects are able to be evaluated with sufficient statistical power to support distinctions.

Stress

Stress is a well-known modifier of human immune responses. It is an everpresent variable that is difficult to assess or control for in epidemiologic studies.

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Footnotes

1

Throughout this report, the same alphabetic indicator after year of publication is used consistently for a given reference when there are multiple citations by the same first author in a given year. The convention of assigning the alphabetic indicators in order of citation in a given chapter is not followed.

Copyright 2014 by the National Academy of Sciences. All rights reserved.
Bookshelf ID: NBK195098

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