Biologic Markers in Immunotoxicology (1992)

The field of immunology has progressed rapidly over the past decade, as demonstrated by the rapid elucidation of the mechanisms of acquired immune deficiency syndrome (AIDS). In the general population, increasing numbers of people suffer from disorders of the immune system, such as allergies, asthma, and AIDS. The incidence of asthma has increased 58% since 1970, and it is well known that nitrogen dioxide and ozone, common air pollutants, interact with allergens to increase the frequency and severity of asthma attacks. Some prolonged periods of air pollution have caused deaths among asthmatics in the United States and abroad. Some drugs have been linked with the induction of autoimmune diseases, in which the body's immune system destroys its other tissues. People living near chemical waste sites have complained of symptoms that might be related to immune dysregulation. Experimental animal studies suggest that mixtures of chemical pollutants found in groundwater can produce suppression of the immune system. Recently, the U.S. Office of Technology Assessment issued a background paper on the identification and control of immunotoxic substances.

With the sponsorship of the U.S. Environmental Protection Agency (EPA), the National Institute of Environmental Health Sciences (NIEHS), and the Agency for Toxic Substances and Disease Registry (ATSDR), the National Research Council's Committee on Biologic Markers undertook to study the interrelationship of toxic exposure and immune-system response. The Subcommittee on Immunotoxicology, comprising scientists with diverse backgrounds in and knowledge of immunology, toxicology, immunotoxicology, risk analysis, and other disciplines, prepared this document. As two previous subcommittees on reproductive and developmental toxicity and pulmonary toxicity had done, the Subcommittee on Immunotoxicology reviewed research on currently known markers, and it identified and evaluated promising new technologies to find new markers, important research opportunities in the field, and areas where interdisciplinary research in environmental health is needed. Although the discipline of immunotoxicology is relatively young, considerable progress has been made in demonstrating that some xenobiotic substances can modulate immunity and that, in some instances, the immune system is a primary target of these materials. Progress has been slow, however, and more

information is needed about how xenobiotics affect immune-system function and human health.

The immune system is a complex intra-and interregulated mechanism. Immunocytes, directed by their receptors and secretory products, act as a network. Although the immune system often is considered autonomous in regulation and action, there is strong evidence that a significant reciprocal interaction among the nervous, endocrine, and immune systems maintains homeostasis. 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, the use of intact animal systems is essential for accurate investigation of the immunotoxic potential of xenobiotics.

This document presents a brief history and review of immunology, immunotoxicology, and biologic markers (Chapters 1 and 2). The effects of toxicants on the immune system can be expressed in two ways. Excessive stimulation can result in hypersensitivity or autoimmunity; suppression can result in the increased susceptibility of the host to infectious and neoplastic agents. In addition, the immune system is affected by genetics, age, and life style, factors that often make it difficult to interpret research results. Tests for an agent's potential to induce hypersensitivity are widely used in the cosmetics industry and in development of some other consumer products.

There has been only limited application of immunotoxicology in the management of risks to human health from xenobiotic substances and in occupational medical surveillance to determine increased risk as a result of reduced immune-system competence. Knowledge of immunotoxicity is not often applied in the management of risk from dietary or environmental exposures.

The committee recommends that educational programs be developed to inform the public of risks from exposure to immunotoxic agents and to develop expertise among environmental health researchers in immunotoxicology.

Hypersensitivity (Chapter 3) has become an important human health problem in industrialized societies. Inhalation of a variety of chemicals can cause asthma, rhinitis, pneumonitis, or chronic granulomatous pulmonary disorders. Hypersensitivity is an immunologically based host response to a compound or its metabolic products. This is distinguished from multiple chemical sensitivity (MCS) syndrome, which has not been shown to have an immunologic basis. Hypersensitivity reactions are frequently influenced by heredity. Immunoglobulin E is an important mediator and biologic marker of hypersensitivity. Procedures are available to assess hypersensitivity in animals and humans.

The committee recommends that research be devoted to testing the analytic accuracy of biologic markers discussed in this report to facilitate their use in predicting adverse health effects and in identifying causative agents. Markers of immunotoxicity could be useful in epidemiology to confirm causal relationships between environmental exposures and prevalence of hypersensitivity.

Autoimmune disease occurs when an immune system attacks the body's own tissues or organs, resulting in functional impairment, inflammation, and occasionally, permanent tissue damage (Chapter 4). Some xenobiotics are known to induce autoimmunity, but there is little information about the relationship of autoimmunity to environmental exposure, and only a few

animal models have been developed to study autoimmune diseases. This lack of information and the strong genetic factors of autoimmunity make it difficult to decipher the relationship between exposure and autoimmune diseases.

The committee recommends the establishment of a national registry for autoimmune diseases to determine the prevalence of these diseases. The use of genetic and immune-system markers to identify persons who are susceptible to autoimmune diseases should be explored. Animal models of autoimmunity suitable for testing the induction of these diseases by chemicals are required for further research. The surveillance of pharmaceutical workers who are exposed to drugs that induce autoimmunity offers a good opportunity to advance knowledge about the possible induction of autoimmune diseases by chemicals.

The immune system provides protection against invasion by pathogens and the growth of neoplastic cells. Exposure to some drugs and chemicals can impair this natural host defense mechanism, and this can lead to an increased incidence of infectious disease or cancer (Chapter 5). Several xenobiotics have been identified as causing immune-system dysfunction. In some cases, the immune system has been identified as the most sensitive target 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. It is universally 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. For immunosuppressants, the plasma concentration of an agent is an adequate marker of exposure that also serves as the effective biologic dose. Markers of effect suggesting changes in the immune system are indicated by alterations in subpopulations of cell type, such as the helper-to-suppressor cell ratio. Although the principles and phenomena in humans and animals are basically similar and comparable, it is recognized that different responses can occur.

The committee recommends that occupational exposures and accidental exposures to high concentrations of immunotoxicants be studied by research teams familiar with techniques used in immunotoxicology. Research that uses animal models should quantify the effects of factors such as age, stress, malnutrition, and pregnancy on the induction of immune-system suppression. The degree of suppression necessary to produce an increase in disease needs to be determined. Mechanistic and metabolic information on immunosuppressants require further exploration to reduce the uncertainties in the assessment of risk of immunosuppressive chemicals.

Animal bioassays for toxicity (Chapter 6) are useful for identifying possible hazards that could attend human exposure to xenobiotics. Researchers have used animal models

to identify immunotoxic agents, to develop immune-system profiles, to identify mechanisms of action, and to identify potential health risks associated with exposure to specific xenobiotics, either consumed as drugs or through environmental exposure. The results of animal studies are useful for determining chemical hazards, managing risk, and determining relatively safe conditions of exposure. A series of animal bioassays has been developed to detect changes in the immune system caused by low oral doses of immunosuppressants. These bioassays give consistent results in different laboratories. Assays for pulmonary immunocompetence have been developed but require broader use. There is a need for additional mechanistic studies, particularly those that relate the immune system to the development of cancer.

The committee recommends that biologic markers be identified in humans and animals to allow detection of potentially dangerous changes in local immune function in lung and skin tissues, because these tissues are often the tissues of first contact. Studies of the interaction of the immune system and ultraviolet light might be particularly rewarding.

The use of animal data, coupled with information gained from limited human clinical and epidemiologic studies, has been valuable in human risk assessment and hazard evaluation. Several tests assess humoral and cellular immunity, as well as nonspecific resistance in humans (Chapter 7). Some of these procedures parallel those used in animal studies and require prospective evaluation in exposed populations and in control groups to ascertain the tests' usefulness.

The committee recommends a series of tests to assess immune-system competence in persons who have been exposed to known or suspected immunotoxicants. An aggressive approach will permit use of sensitive procedures for detection of chemically induced modulation of the human immune system. The use of case studies arising from such a program could be useful in identifying xenobiotics that are likely to cause damage to human health and a reduced ability to function normally.

The limits on experimentation in humans restrict the use of epidemiologic methods to obtain health information after accidental or occupational exposure to toxic substances. Epidemiologic research (Chapter 8) can involve experimental studies in which conditions are controlled and effects are subsequently observed in a test population, or it can use cohorts or cases in which the test population is observed without the circumstances being altered. Epidemiologic procedures frequently permit long-term monitoring of health effects in large numbers of persons exposed to undefined quantities of a given environmental xenobiotic. Data obtained in such investigations, which cannot be obtained otherwise for normal human populations, can provide information about immunotoxic effects. However, a review of the literature reveals no epidemiologic studies that have made full use of markers of exposure, markers of adverse immunologic effect, or markers indicating susceptibility because of variation in the capacity of the immune system.

The committee recommends that greater use be made of markers of exposure, effect, and susceptibility in epidemiologic studies to identify the influence of the immune system on diseases.

Considerable public concern has arisen regarding sick building syndrome (SBS), a condition that causes discomfort brought on by mucous membrane irritation in a substantial number of occupants of air-tight buildings (Chapter 9). The resulting symptoms could be associated with exposure to irritants, chemical or biologic allergens, or mixtures of chemical pollutants, including volatile organic compounds.

The committee recommends that studies be conducted on potential methods and guidelines for reducing harmful exposures and adverse consequences of indoor air pollution in homes, schools, and the workplace.

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 immune system in a given individual is uniquely sensitive to modulation by several chemicals. Current evidence does not indicate that multiple chemical sensitivity (MCS) originates in or involves the immune system. Many confounding factors could be involved in the etiology of such conditions and, should the immune system be involved, it could be through secondary or indirect responses to conditions rather than as a directly contributing factor in the etiology of MCS.

A workshop held in the spring of 1991 aided the committee in its deliberations on the problems associated with MCS; the committee considered the proceedings of the workshop in completing this report. The proceedings of the workshop will be published under separate cover.

The committee recommends that epidemiologic research focus on the prevalence of MCS. Patients with MCS could be studied under controlled environmental conditions. A multidisciplinary team of experts in lung physiology, immunotoxicology, clinical immunology, psychiatry, toxicology, occupational medicine, and industrial hygiene is required in the evaluation of these cases. A standard comprehensive panel of clinical procedures should be applied to aid in diagnosis. Biologic markers could be useful in confirming or eliminating immune-system dysfunction as a cause of MCS.

Biological Makers in Immunotoxicology