10
Summary and Recommendations

The field of immunotoxicology has undergone considerable growth and expansion since its inception in the early 1970s. The discipline was founded by combining knowledge from the areas of immunology and toxicology to study the effects that xenobiotics exert on the immune system. It has progressed from the initial identification of immunotoxic chemicals to the development of sensitive, quantitative assays that assess chemically induced alterations of the immune system and that determine the mechanisms by which xenobiotic substances compromise immune function. These immunoassays and other more conventional tests may well serve as the key to identifying biologic markers of immunotoxicity. Immunotoxicology now plays a role in developing health standards and permissible levels of human exposure to xenobiotics.

This document was prepared by scientists with diverse backgrounds in and knowledge of immunology, toxicology, immunotoxicology, risk analysis, and other disciplines. Its purpose is to assess the past and current status of immunotoxicology and to identify areas for future research. The field of immunotoxicology is expanding rapidly, and there is interest not only in the traditional immunotoxic effects of drugs and environmentally dispersed chemicals on hypersensitivity, autoimmunity, systemic immunity, and carcinogenesis, but also investigations related to risk assessment, food safety, water quality, and indoor air. Some of these features have been addressed in this document.

Immunotoxicology is a scientific discipline that explores the effects of physical, biologic and chemical agents on the immune system, which is extremely sophisticated and is self-regulated as well as being influenced by other systems. Immunocytes, orchestrated by their receptors and secretory products, act as a network. Although the immune system was long considered autonomous in both regulation and action, recent data strongly suggest that a significant reciprocal interaction occurs between the nervous, endocrine, and immune systems to maintain homeostasis. These interregulatory patterns confirm the existence of a nervous-endocrine-immune axis, which complicates attempts to study and model whole-body responses in vitro. Although sophisticated in vitro systems have specific applications, intact animal systems are essential for accurate investigations of the immunotoxic potential of xenobiotics.

This document presents a brief history and review of immunology, immunotoxicology,



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Biologic Markers in Immunotoxicology 10 Summary and Recommendations The field of immunotoxicology has undergone considerable growth and expansion since its inception in the early 1970s. The discipline was founded by combining knowledge from the areas of immunology and toxicology to study the effects that xenobiotics exert on the immune system. It has progressed from the initial identification of immunotoxic chemicals to the development of sensitive, quantitative assays that assess chemically induced alterations of the immune system and that determine the mechanisms by which xenobiotic substances compromise immune function. These immunoassays and other more conventional tests may well serve as the key to identifying biologic markers of immunotoxicity. Immunotoxicology now plays a role in developing health standards and permissible levels of human exposure to xenobiotics. This document was prepared by scientists with diverse backgrounds in and knowledge of immunology, toxicology, immunotoxicology, risk analysis, and other disciplines. Its purpose is to assess the past and current status of immunotoxicology and to identify areas for future research. The field of immunotoxicology is expanding rapidly, and there is interest not only in the traditional immunotoxic effects of drugs and environmentally dispersed chemicals on hypersensitivity, autoimmunity, systemic immunity, and carcinogenesis, but also investigations related to risk assessment, food safety, water quality, and indoor air. Some of these features have been addressed in this document. Immunotoxicology is a scientific discipline that explores the effects of physical, biologic and chemical agents on the immune system, which is extremely sophisticated and is self-regulated as well as being influenced by other systems. Immunocytes, orchestrated by their receptors and secretory products, act as a network. Although the immune system was long considered autonomous in both regulation and action, recent data strongly suggest that a significant reciprocal interaction occurs between the nervous, endocrine, and immune systems to maintain homeostasis. These interregulatory patterns confirm the existence of a nervous-endocrine-immune axis, which complicates attempts to study and model whole-body responses in vitro. Although sophisticated in vitro systems have specific applications, intact animal systems are essential for accurate investigations of the immunotoxic potential of xenobiotics. This document presents a brief history and review of immunology, immunotoxicology,

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Biologic Markers in Immunotoxicology and biologic markers (Chapters 1 and 2). These chapters provide supportive information for the remainder of the document. The immune system can be expressed bidirectionally; excessive stimulation can result in hypersensitivity, autoimmunity, or both. Suppression can increase the susceptibility of the host to infectious and neoplastic agents. Hypersensitivity (Chapter 3) has become an important human health problem in industrialized societies. Inhalation of a variety of chemicals can cause individuals to develop asthma, rhinitis, pneumonitis, or chronic granulomatous pulmonary disorders, among others. Hypersensitivity is an immunologically based host response to a compound or its metabolic products (as distinguished from the purported ''hypersensitivity syndrome," which has not been shown to have an immunologic basis (Chapter 9). Hypersensitivity reactions, including autoimmunity, are frequently influenced by heredity. IgE is an important mediator and biologic marker of hypersensitivity, as this immunoglobulin binds to basophils and mast cells and initiates release of the inflammatory mediators responsible for the symptoms on re-exposure to the allergen. Validated tests are available to assess hypersensitivity in animals and humans. Autoimmune disease occurs when an individual's immune system attacks the body's own tissues or organs, resulting in functional impairment, inflammation, and occasionally permanent tissue damage (Chapter 4). Autoimmune disease is an infrequent occurrence in humans that can result in considerable discomfort and even death. Certain xenobiotics are known to induce autoimmune disorder, but there is a paucity of information concerning the relationship of autoimmunity to environmental exposure. The immune system provides the primary defense against invasion by pathogens and neoplastic agents. Exposure to drugs and chemicals can impair this natural host defense mechanism, which can lead to an increased incidence of infectious disease or cancer. Xenobiotic-induced immune dysfunction has been well established in animals for several chemicals. In some cases, the immune system has been identified as the most sensitive target organ for the minimum toxic dose of a xenobiotic. Although one or more of the many compartments of the immune system can be suppressed significantly, this suppression might not be expressed as an immune-mediated disease. Rather, suppression can be viewed as a potential risk because of the reduced ability of the host to resist natural and acquired diseases. There is limited information to suggest that humans exposed to environmental pollutants are immunologically compromised. However, it has been well established that treatment of humans with immunosuppressive therapeutic agents can result in an increased incidence of infectious disease and neoplasia. Animal immunologic bioassays are useful to identify possible hazards associated with human exposure to xenobiotics. It is accepted that the immune systems of many animals and humans are comparable, that animal models are available to assess immune dysfunction objectively, that positive immunosuppressants, such as cyclophosphamide and cyclosporin A, are used to validate assays, and that data obtained from animal studies can sometimes be verified in humans. Although the principles and phenomena in humans and animals are basically similar and comparable, it is recognized that different responses can occur. Animal models have been used to identify immunotoxic agents, to develop immune-system profiles, to identify mechanisms of action, and to alert researchers and regulators to potential health risks associated with exposure to specific xenobiotics, either consumed as drugs or through environmental exposure (Chapter 6). Several immunotoxicity bioassays have been validated in animals to detect drug-and chemical-induced immunomodulation. Some of these bioassays are sensitive and predictive of immune dysfunction. Many others that either are in development or have not been used extensively will have application in

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Biologic Markers in Immunotoxicology immunotoxicology, once they have been validated. Although many tests are available to screen for immunotoxicants, the choice of an initial test that evaluates the T-cell-dependent antibody response permits assessment of several compartments of the immune system simultaneously. These procedures are easily performed, quantitative, sensitive, and economical, and they detect a large percentage of known immunosuppressive agents. In animal models, data are obtained from cells, tissues, and organs that are collected on death at the end of an experiment; this practice obviously cannot be duplicated in humans. However, use of animal data, coupled with information gained from limited human biologic and epidemiologic studies, has proved of value in human risk assessment. Several tests assess humoral and cellular immunity, as well as nonspecific resistance in humans (Chapter 7). This report suggests a series of tests to assess immune-system competence in persons who have been exposed to a known or suspected immunotoxicant. Some of these procedures parallel animal studies and require prospective validation in exposed populations and in control groups to ascertain their predictive value. This aggressive approach will permit use of sensitive procedures for detection of immunomodulation in humans. The limits on experimentation in humans predicate the use of epidemiologic methods to obtain health information after accidental or occupational exposure. Epidemiologic research can involve an experimental study in which the conditions are controlled and the effects are subsequently observed in a test population, or it can use cohorts or cases in which the test population is observed without altering the circumstances (Chapter 8). Epidemiologic procedures frequently permit long-term monitoring of the health effects in large numbers of persons exposed to defined levels of a given environmental xenobiotic. Data obtained in such investigations can provide valuable and relevant information on the immunotoxic properties of numerous xenobiotics in humans that supports or disputes animal data that cannot be obtained otherwise (experimentally) in normal human populations. Are some individuals genetically predisposed or innately hypersensitive to harm caused by given xenobiotics? It is well known that some individuals experience skin or pulmonary disorders in reaction to contact allergens. However, although it has been suggested, it is not known whether the systemic arm of the immune system in a given individual is uniquely sensitive to immunomodulation by several chemicals (Chapter 9). Current evidence does not indicate that "sick-building syndrome" originates in or involves the immune system. Many other factors could be involved in the etiology of such conditions and, should the immune system be involved, it could be in secondary or indirect responses to conditions, rather than as a directly contributing factor in the etiology of these syndromes. The survival of humans and animals in their natural environment depends on a functional immune system. It is clear that drugs and other chemicals can induce serious immune dysfunction in animals and humans. Although the discipline of immunotoxicology is relatively young, there has been considerable progress in demonstrating that some xenobiotics can in fact modulate immunity and that, in some instances, the immune system is a primary target organ. Nevertheless, progress has been slow and the level of knowledge needs to be expanded, both in depth and in breadth, to elucidate fully the effect of xenobiotics on the functioning immune system and human health. This document has reviewed the past and evaluated the current state of immunotoxicology. CHEMICAL-INDUCED IMMUNOSUPPRESSION IN HUMANS Conclusions There is increasing awareness and concern

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Biologic Markers in Immunotoxicology within the scientific and public communities that chemical pollutants can suppress immune processes and thus result in an increase of neoplastic and infectious diseases. Adverse effects in humans treated with immunosuppressive drugs, numerous studies employing experimental animals, and, to a lesser extent, isolated cases of altered immune function in humans inadvertently or occupationally exposed to xenobiotic substances support these concerns. Evidence is weak that individuals who are putatively exposed because they live in the vicinity of contaminated sites or near chemical manufacturing plants have been immunologically compromised to the extent that they have an increased risk of disease. Nevertheless, examples of chemically induced disease and our knowledge of the pathogenesis of disease support the likelihood that damage to the human immune system is associated with adverse health effects, some of which could become apparent only after a long latency. Furthermore, exposure to immunotoxic xenobiotics can present additional risk to individuals whose immune systems are already compromised, for example, because of malnutrition, infancy, or old age. Finally, the value of incorporating immunologic data for toxicologic assessment of drugs, chemicals, and biologics for human hazard evaluation is increasingly recognized. However, it is often difficult to extrapolate changes in a given area of immune function in experimental animals to the incidence of clinical or pathologic effects in humans. Some biologic markers have been useful in identifying increased susceptibility to immune-related diseases or susceptibility to some substances. In general, however, the use of markers of immunotoxicity to identify increased susceptibility to environmental hazards has received little attention. Although immune-system markers offer promise in assessing the effect of environmental toxicants on human health, many of these markers are inadequately characterized with respect to their association with toxicant exposure, long-term health effects, and individual susceptibility to chemical injury. Recommendations Clinical studies in humans are needed to determine the relationship between chemical exposures and immune-mediated diseases. Of particular concern are the contributions of xenobiotic exposure to the increased frequency or severity of infectious or neoplastic diseases. Does the known ability of ultraviolet light to suppress immune function play a role in the increased incidence of skin cancer detected after prolonged exposure to sunlight? Is there a causal relationship between chemical-induced immunosuppression and non-Hodgkin's lymphoma? Carefully designed clinical and epidemiologic studies should be undertaken with well-defined populations. Consideration should be given to groups for which exposure levels to immunotoxicants, including duration and dose, can be confirmed. Clinical examinations should include the most advanced immunodiagnostic techniques. The use of these techniques should be preceded by validation of the assays such that they are known to be sensitive to modulation by immunotoxicants and the normal ranges are established. Clinical evaluations should include the use of sensitive, validated immunodiagnostic techniques, standardized case definitions, and information derived from the detection of validated biologic markers of immune-system changes. In addition, factors that contribute additional risk, such as age, genetic predisposition, stress, and malnutrition should be examined. One or more environmental health centers that focus on immunologic disorders should be developed and staffed with experts in immunotoxicology, clinical immunology, occupational medicine, and epidemiology. Within such centers, response plans would

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Biologic Markers in Immunotoxicology be developed and a team of scientists would be available to collect appropriate specimens promptly when accidental exposures occur. ROLE OF ENVIRONMENTAL CHEMICAL EXPOSURE IN HYPERSENSITIVITY AND AUTOIMMUNE DISEASES Conclusions There is evidence that environmental exposure to toxic chemicals plays a role in the induction of autoimmune diseases and hypersensitivity responses, either by acting as direct causative agents or by increasing the severity of pre-existing hypersensitivity disease. For example, 2-5% of all cases of asthma in the United States are induced by workplace exposure to toxicants. Prospective studies have suggested that about 6% of research-animal handlers become sensitized to animal serum, urine, or dander; that 10-20% of bakers develop asthma associated with flour dust; and that almost all workers in the platinum-salt industry develop at least mild allergic respiratory symptoms. In the United States alone, approximately 5% of persons exposed to toluene diisocyanate fumes in the polyurethane foam and plastic manufacturing industries develop severe asthmatic symptoms. Evidence also exists that asthma, the incidence of which has increased by 58% since 1970, can be exacerbated by air pollutants, such as ozone and nitrogen dioxide. Likewise, the influence of environmental chemical exposures on autoimmune diseases, such as rheumatoid arthritis, which afflicts thousands of persons, has never been systematically examined. Recommendations Studies of human markers of immunotoxicology should be designed and tested to document their analytic accuracy and precision and to evaluate their predictive value for identifying toxicant exposure and predicting adverse health outcomes. The use of immunotoxicity markers in longitudinal studies of short duration (months) and long duration (years) will be required. Additional studies could be warranted to determine the prevalence of hypersensitivity and autoimmune diseases influenced by exposure to environmental chemicals. Because instances of autoimmune disease are not reportable to local public-health departments, some effort should be made to establish a national registry for persons with such diseases. Until this is done, no reliable estimates of prevalence can be established. Immune and genetic biologic markers, particularly those which would be practical for wide-scale use, also should be explored for use in identifying individuals who are highly susceptible to environmental hazards. Special attention should be focused on markers of susceptibility that aid in diagnosis and reveal the mechanistic aspects of environmental disease. Moreover, factors that predispose individuals to disease caused by immunotoxic chemicals should be determined. This research should address the roles of age, genetics, nutrition, and concurrent disease in the pathogenesis of chemical-induced immune-system dysfunction. ANIMAL AND IN VITRO MODELS Conclusions The development and use of animal models and in vitro models to find markers of immunotoxicity are essential for the continued growth of this discipline. Results from the model systems are needed to engage appropriate decision-making processes on chemical use and to predict the risk to human health as it pertains to immune-mediated diseases. Such studies should

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Biologic Markers in Immunotoxicology establish immune-system profiles for xenobiotics in animals and provide the foundation for understanding structure-activity relationships, mechanisms of chemical-induced injury, and, if required, means of therapeutic intervention. Recommendations The National Toxicology Program, the Environmental Protection Agency, other federal agencies, and groups in the private sector have developed protocols for evaluating the potential of chemical toxins to suppress the immune systems of rodents. Abnormalities in these tests often precede overt evidence of immunopathology. Such tests should continue and be developed further to allow accurate assessment and prediction of adverse effects on the immune and host defense systems of humans. Of special importance could be the temporal relationship between suppression of the immune system and the development of clinical disease. Sequences of standard tests for natural and acquired immunity should be used to screen for chemicals that alter immune function. More specific and sensitive tests should be adopted after they are validated and compared with established but less desirable tests. The application of newer biotechnical methods could provide better insight into the action of immunotoxicants and their significance in the development of diseases of immune dysfunction. Immune-system profiles developed for chemicals in animals could provide information of predictive value for humans. The ability of chemicals to depress immune responsiveness should be compared with their corresponding ability to depress the capacity of experimental animals to resist infectious agents or neoplasia. It is anticipated that there will not always be a detectable positive correlation, and in-depth analyses will be required to identify the molecular basis of decreased immune responsiveness and the underlying mechanisms (including intermediate stages) responsible for altered host resistance to disease. A positive correlation between chemical exposure and altered immune function must be established. Animal studies usually involve short-term, high-dose exposure; human exposure is generally chronic and at low levels. Methods need to be developed to provide more accurate extrapolation from animals to humans, particularly as it pertains to development of clinical diseases. Procedures have been established to predict chemical-induced hypersensitivity and autoimmunity in laboratory animals. These methods need to be applied to ascertain their predictive value in humans. In some cases, such as hypersensitivity induced by inhalation and ingestion of allergens, additional tests that more closely reflect human experiences might need to be developed. The use of such predictive tests should be encouraged to provide sensitive markers for assessing immunotoxicity of xenobiotics and for setting acceptable levels of exposure. Markers of susceptibility that could reveal the diagnostic and mechanistic aspects of environmental disease should be studied in laboratory models. Biologic markers from noninvasive techniques in humans should be an emphasis of these studies. Because autoimmune diseases appear to develop from immune dysregulation, the ability of xenobiotics to interfere with normal immune regulation that could predispose persons to autoimmune and chronic inflammatory diseases should be studied. Better animal models should be developed to evaluate the influence of xenobiotics on autoimmune disease and to describe the underlying mechanisms of regulatory dysfunction, with the ultimate goals of prevention and therapy. There also is a need to ascertain the extent to which chemicals modify inflammatory responses, as measured by increases or decreases in the number and function of leukocytes at sites of inflammation. Experimental guidelines are not available

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Biologic Markers in Immunotoxicology to investigate the multiple-chemical-sensitivity syndrome adequately. Development of such guidelines should be developed for the investigation of the etiology, symptomatology, and pathogenesis of this syndrome. This putative disorder must be defined and carefully characterized, because there is no definite evidence to associate it with immune-system dysfunction. MARKERS OF SKIN AND MUCOSAL RESPONSES Conclusions The skin and mucosal surfaces of the respiratory and gastrointestinal tracts are generally the first tissues of contact by environmental agents. The immune components of these surface tissues are especially adapted for their recognition and response functions. Although the contribution of these tissues to host defense mechanisms is still unclear, evidence exists that some environmental chemicals can enhance neoplastic diseases after exposure to the skin, the gastrointestinal tract, and particularly the lung. It is known, for example, that many inhaled gases (such as nitrogen dioxide and ozone) and particles (such as asbestos and silica) alter local immunity and thus result in increased susceptibility to lung infection. In addition, exposure of the skin to ultraviolet light suppresses immune-system responses that could prevent the development of skin tumors caused by exposure to sunlight. More recently, such chemicals as dimethyl-benzanthracene and cyclosporin A have been shown to inhibit immune-system responses in the skin and thus to lead to systemic immunosuppression. Recommendations Studies need to be conducted to determine whether enhanced susceptibility to or severity of viral, bacterial, and neoplastic diseases is related to, or a direct consequence of, impaired local immune function. Biologic markers need to be identified in humans and animals to detect potentially dangerous changes in local immune function. Markers chosen for development should meet several criteria. They should be sensitive; be derived from noninvasive techniques; be meaningful with respect to susceptibility, severity, and recovery from disease; detect injury to specific and nonspecific immunity of the humoral and cell-mediated immune systems; evaluate local versus systemic immunity; and provide data that can be used to compare adverse effects across species. EDUCATION AND TRAINING Conclusions Education of scientists to investigate the many environmental problems must have high priority. There are few opportunities for students to pursue graduate education and training in immunotoxicology. Physicians and scientists trained in immunotoxicology and environmental health research are needed in the private and academic sectors to help develop expertise in this area. The public needs to be better informed of the risk to the immune system associated with chemical exposure. Recommendations More information about immunotoxicology needs to be incorporated into graduate and postgraduate medical education. New postdoctoral fellowships should be made available to cross-train scientists from other disciplines. Public understanding and perception of risk associated with chemical exposure, especially as related to the immune system, should be fostered through various mechanisms, including the mass media.

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Biologic Markers in Immunotoxicology The Subcommittee on Immunotoxicology supports establishment of federally funded research centers, program grants, competitive grant programs, and training grants in immunotoxicology. The subcommittee's members advocate a fostering of communication and dissemination of information within and between government agencies, academe, and industry. The availability of data, both published and proprietary, should be improved to permit realistic assessment of adverse health effects of environmental chemicals. ENVIRONMENTAL EXPOSURES AND SENSITIVITY SYNDROMES Conclusions There has arisen considerable public concern regarding "sick-building syndrome" (SBS) and multiple-chemical-sensitivity (MCS) syndrome. SBS is a better-defined entity, consisting mainly of irritation of mucous membranes that occurs in occupants of new, airtight buildings. These effects are believed to be associated with exposure to irritants, chemical or biologic immunogens, or mixtures of chemical pollutants. Individuals who develop adverse reactions to numerous chemicals at doses below presumed toxic levels are said to have MCS. The agents said to cause these symptoms include many environmental contaminants, chemical additives, synthetic drugs, and cosmetics. The existence of MCS has been challenged in the scientific and medical communities. Although all areas of environmental medicine have issues to resolve (such as extrapolation of animal data to humans and development of more predictive or clinically relevant tests), there are numerous basic scientific facts and data gaps that clearly distinguish MCS from other areas of immunology and toxicology. The causative environmental or other agents are unknown (they are assumed to be almost any synthetic or natural environmental contaminant, rather than a chemical of specific structure or a class of chemicals). Rather than having a specific disease symptomatology, MCS often is characterized by diverse subjective symptoms that potentially affect one or several organ systems. The etiology, pathogenesis, and prevalences of MCS have not been established, although many conflicting theories and various clinical presentations have been reported. This paucity of solid scientific data has severely clouded objective scientific understanding of this syndrome, including its clinical diagnosis and effective treatment. Recommendations A case-comparison study of patients claiming unique susceptibility to chemicals in the environmental workplace should be undertaken. Because sick building syndrome appears to be a real phenomenon caused by contamination of indoor air that cause discomfort to a substantial number of workers, indoor air pollution standards for homes, schools, and workplaces should be established. These standards should restrict offending agents including volatile organic compounds to levels below those at which significant numbers of occupants develop symptoms. There is a need to establish a multidisciplinary team of experts in lung physiology, immunotoxicology, clinical immunology, psychiatry, toxicology, occupational medicine, and industrial hygiene to study patients with these purported syndromes. A standard, comprehensive panel of clinical procedures should be applied to aid their diagnosis. Blind-challenge studies, using well-defined cohorts with established exposures, might need to be conducted.