Germolec, in Encyclopedia of Immunology Second Edition , Immunotoxicology has been defined as the study of adverse effects on the immune system resulting directly or indirectly from occupational, environmental or therapeutic exposure to chemicals including drugs , biologic materials and, in certain instances, physiological factors, collectively referred to as agents. It encompasses studies of altered immunologic events associated with exposure of humans and wildlife species including immune regulation suppression or enhancement , allergy and autoimmunity Figure 1. In the former case, the systemic or local e.
In allergy, the immune system responds to chemical hapten —host protein conjugates or high molecular weight compounds. The most likely health consequences of the latter include respiratory tract allergies e. Autoimmunity may occur either as a result of an agent-induced alteration in host tissue, endocrine function or immune regulation.
Immunotoxicology , the science of poisons to the immune system, is devoted to the study of adverse effects of pharmaceuticals and all other chemicals on the immune responsiveness of treated or exposed living hosts immunosuppression and immunostimulation as well as the induction of hypersensitivity and autoimmunity. Although immunotoxicology is an active area of toxicology, this is still a relatively small area. Therefore, an extensive list of all books devoted to immunotoxicology published since is provided below.
Because immunotoxicology is a cornerstone between toxicology and immunology, key immunology textbooks potentially useful for toxicologists with limited immunological background in immunology are listed as well.
Over the past 30 years, the main focus of immunotoxicologists has been on non-clinical aspects of immunotoxicity, especially from a mechanistic or regulatory perspective. A lot of efforts have been paid to designing and validating animal models and in vitro assays useful for the non-clinical evaluation of immunotoxicity and risk assessment. This is reflected in the selection of journal articles among the most relevant review articles on immunotoxicology published since Immunotoxicity may be exhibited as either a suppression of the immune response, leading to decreased host resistance to infectious agents or tumor cells, or an enhancement of the immune response, which can exaggerate autoimmune diseases or confer hypersensitivity.
Drug product immunotoxicity should initially be assessed as a part of the general toxicology study Table If different aspects of the immune system appear to be affected, such as the spleen, thymus, bone marrow, lymph nodes and hematology parameters, additional parameters may be added to a repeated-dose study to further define the level of immunosuppression or stimulation . Similarly to other assessments for biopharmaceuticals, immunotoxicity evaluation should also take place using a relevant species to make the assessment as predictive to humans as possible.
Transgenic models may be more predictive, but standardized and validated methods will be required . Volger, in Toxicogenomics-Based Cellular Models , Immunotoxicity is defined as deleterious effects of a xenobiotic on the functioning of the immune system. Immunotoxic xenobiotics can be natural toxins, chemicals, or pharmaceuticals. Immunotoxicants are considered to be a high risk to human health, because immunotoxicity may be associated with high morbidity and mortality, and humans are continuously exposed to a range of immunotoxic substances, a considerable proportion of which are man-made industrial chemicals or pharmaceuticals.
A response against an antigen that requires the local accumulation of lymphocytes is termed cell-mediated immunity and the lymphocytes involved are called T cells. Responses involving antibodies made at a distant site are referred to as humoral immunity and the lymphocytes producing the antibodies are called B cells. A generalized reduction in the capacity for either type of response is known as immunosuppression and may result in an increased susceptibility to infection by micro-organisms or to the development of tumors, as seen, for example, in acquired immune deficiency syndrome AIDS.
A generalized increase in immune responsiveness is known as immunopotentiation. One manifestation is hypersensitivity allergy. When the immune system responds to and attacks the proteins of its own tissue, autoimmune disease may occur. In Chapter 2 , the function of the immune system is given with greater detail along with an explanation for how disease may evolve from disregulation of the immune system.
Immunology is primarily a science that began in the late nineteenth century. Special interest in chemicals from nonbiologic sources—xenobiotics—is of recent origin. Immunotoxicology formally emerged as a distinct discipline within toxicology during the s Descotes, , prompted by animal studies that demonstrated the researcher's ability to measure the effects of chemicals on the immune system Koller, ; Vos, ; Dean et al. Landsteiner in the mid's demonstrated that the guinea pig could be used to determine the sensitization potential of chemicals Landsteiner and Jacobs, , , and these techniques have been used over the years in the determination of the potential to produce hypersensitivity responses, particularly with cosmetics ingredients, consumer products, and drugs.
The ''new" field was fully recognized in when an immunotoxicology program was established within the National Toxicology Program.
The goal of the immunotoxicology program was to select, develop, and validate animal models for use in assessing immunomodulation induced by xenobiotic substances. The initial focus of investigations was the potential of nonbiologic chemicals to cause immunosuppression. More recently, active sensitization and hypersensitivity reactions to xenobiotics have received attention.
Immune responses are many and varied, and they produce markers that can indicate environmental exposure. Such markers include increases in specific antibodies, increases or decreases in total immunoglobulin, changes in the absolute or relative numbers of lymphocytes, and changes in the in vitro or in vivo reaction to antigens or mitogens.
It can be difficult to distinguish responses that indicate toxicity, and are thus markers of effect, from those that are normal physiologic adaptations to the environment. Continued integration of the work of toxicologists, pharmacologists, and other researchers has led to the use of a diversity of biologic markers. For this study, the committee, for the most part, deals with the potential of xenobiotics to produce an adverse effect on the immune system manifested by hypersensitivity, autoimmunity, or suppression of the immune system. The suppression of the immune system can lead to the development of an increased rate of infection or cancer.
Humans are often and unavoidably exposed to many hazardous environmental chemicals. The immune system functions to neutralize foreign materials and infectious agents by specifically responding to varied macromolecular factors in the environment.
In addition to its response to molecules derived from bacteria and viruses, the immune system may respond to varied macromolecular components in ingested food, inhaled air, and anything that touches the skin. Immune responses can be specific or nonspecific. Specific responses usually involve a small fraction of highly specific lymphocytes, and the degree of response to different antigens can vary widely within an individual. Animal experiments can demonstrate which substances are potential antigens in humans. However, animal results do not always predict the occurrence of hypersensitivity reactions in humans.
For example, exposure to ragweed pollen induces a normal antibody response in mice, but it can cause severe allergy in some humans. Many persons are afflicted with diseases, such as skin allergies and asthma, that are related to immune hypersensitivity. Immunologic allergic asthma is defined as variable airway obstruction that results from exposure to generally low-level concentrations of immune-reactive substances in the environment.
Between 50, and , workers in the United States are regularly exposed to highly reactive compounds, such as diisocynates Musk et al. Five to ten percent of exposed workers have become hypersensitive to TDI. In such situations, the presence of specific antibody is a definitive marker of exposure , although not all workers hypersensitive to TDI have detectable TDI antibodies, nor do all workers with antibodies develop symptoms of hypersensitivity. The Spanish toxic oil syndrome developed in approximately 20, people in Madrid in after they had ingested adulterated rapeseed cooking oil.
Affected persons had symptoms of fever, rash, dyspnea, malaise, and gastrointestinal symptoms. Nonspecific effects of xenobiotics on the immune system can involve a variety of cells and similar actions are observed between individual and species. For example, exposure to whole-body radiation or cyclosporin A depresses the immune systems of mice and humans; each modality affects different cells, but they act in a similar immunosuppressive manner in both species. Organ-transplant patients are treated with drugs that suppress the immune response to prevent organ rejection, but because their immune system is deficient, these patients frequently develop infections and some types of neoplasm.
The relationship between the immune system and the development of cancer has been recognized for years. In adopting standards on 13 occupational carcinogens in , the Occupational Safety and Health Administration required that "in all physical examinations, the examining physician shall consider whether there exist conditions of increased risk including reduced immunological competence.
Recent animal immunotoxicity studies suggest that some environmental substances induce immune-system suppression. Trichloroethylene TCE in the drinking water of mice has been found to suppress humoral and cell-mediated immunity. Neither the period of TCE exposure nor dose-response correlations have been established in human studies, but leukemia and increased infections have developed in some populations exposed to TCE as a result of contaminants in their drinking water.
In addition, registries for benzene and dioxin have also been established. These chemicals also suppress the immune system as part of their spectrum of toxicity. In the broadest sense, biologic markers are measurements on biologic specimens that will elucidate the relationship between environmental exposures and human diseases, so that such exposures and diseases can be prevented. Early detection that leads to prevention of disease and of disability is the ultimate goal and promise of the use of biologic markers.
The term "marker" is commonly used by immunologists for membrane proteins that "mark" different kinds of cells.
Interest is growing in the use of biologic markers by researchers in clinical medicine, epidemiology, toxicology, and related biomedical fields to study the health effects of exposure to environmental toxicants. Clinicians can use markers for early detection of disease. Epidemiologists can use them as indicators of exposure to determine internal dose or health effects. Toxicologists can use them to develop estimates of dose-response relationships and to facilitate assessment of risk associated with small exposures. Biologic markers also can be helpful in clarifying the underlying mechanisms of chemically induced diseases.
Recently, selected immune-system markers have been measured in epidemiologic studies of exposed populations to detect associations between exposure and disease. However, the complexity of the test populations and uncertainties in the measurement of markers of immunotoxicity have prevented meaningful evaluation.
New developments in molecular biology and biochemical approaches to medicine have elucidated sensitive markers for assessing exposure NRC, They have also increased our knowledge of disease, improved our ability to predict the outcome of disease, and helped direct courses of treatment. There has been an explosive expansion in interest and increased activity in immunologic markers because of AIDS. Many diseases are defined not only by clinical signs and symptoms but also by the assessment of biologic markers at the subcellular and molecular levels.
Diseases of the liver and kidney, for example, are often detected by measurement of enzymes in blood or proteins in urine; diabetes can be suspected if glucose is found in urine; and inborn errors of metabolism, such as phenylketonuria, are found by early biochemical analysis, rather than later as a result of clinical dysfunction. The Committee on Biologic Markers of the National Research Council defined biologic markers as indicators of events or conditions in biologic systems or samples. As such, they are indicators of exposure, effect , or susceptibility.
This classification is a useful theoretical scheme by which to characterize biologic markers of any organ system; however, it must be qualified somewhat for practical application. First, classification with respect to any of the three categories will depend on the particular definition of that event. Second, the three categories often are related and can be seen as descriptors of a continuum from environmental exposure to clinical disease Figure The measurement of a chemical in a biologic specimen is a marker of exposure, and it could be more useful than measurements on air samples at a potential exposure site.
Cellular or molecular changes associated with disease are biologic markers of adverse health effects. Biologic markers often are elucidated by clinical laboratory measurements or clinical tests used in the differential diagnosis of various diseases. The markers can serve as surrogates for other methods of detection in determining the molecular and cellular events in the development of health problems.
If such markers could be detected before exposed persons became obviously ill, the disease process might be reversed in those affected or prevented in others. In addition, some cellular or molecular measurements can identify people who are more vulnerable to the effects of toxic exposure; these are markers of susceptibility. There also might be biologic markers that would indicate individual susceptibility to environmentally induced disease. A biologic marker of exposure is a xenobiotic chemical or its metabolite or the product of an interaction between the chemical and some target cell or biomolecule.
Most commonly, the indicators of exposure are the concentration of the material in urine, blood, or other body tissue, including the hair or nails. The most definitive immune-system markers of exposure are antigen-specific antibodies or cellular responses to a particular xenobiotic. Immune-specific biologic markers of exposure include antibodies to toxicants Pezzini et al.
Several problems limit the usefulness of antigen-specific markers of exposure. First, many environmental xenobiotics are small molecules that must act as haptens to elicit an immune response. Haptens alone cannot evoke an immune response; they must be covalently linked or strongly bound to "carrier" proteins in the tissues. For instance, isocyanates react chemically with tissue proteins, and nickel forms very strong tissue chelates. Antigen -specific immune markers can be detected for both of these agents.
However, many environmental toxicants do not trigger antigen-recognition pathways and will not produce specific immune markers. Even if a xenobiotic can elicit a specific immune-system response, the dose and route of exposure must be appropriate. Very small or very large doses of a substance can induce tolerance and even paralyze the immune system, ablating any indicators of exposure.
The route of administration also can be critical. A third problem with specific immune-system markers of exposure is that they decay with time after exposure ceases. This decay of responsiveness is the reason re-immunization is often required for maximum protection. A false-negative result can therefore be obtained if specific immune markers are sought long after exposure. The persistence of immune markers varies widely among the different humoral mediators and cellular components, and it can depend on conditions within the organism.
Highly reactive humoral mediators that act locally such as prostaglandin are often inactivated within minutes of their formation, even though their inactivation products can circulate in the system much longer. Serum IgE is cleared more quickly than is serum IgG, but IgE bound to mast cells or basophils persists much longer than any serum protein does.
A marker of effect is a measurable cellular or biochemical alteration within an organism that, depending on magnitude, can be recognized as an established or potential health impairment or disease. A marker of susceptibility is an indicator of an inherent or acquired limitation of an organism's ability to respond to the challenge of exposure to a specific xenobiotic substance.
Immunologic markers of effect include changes in the components of the immune system itself such as shifts in the distribution of lymphocyte subpopulations and changes in other tissues caused by immune-mediated dysfunction such as signs of kidney failure caused by autoimmune kidney disease. As with all organ systems, the most critical aspect of defining immune-system markers of effect is to define the criteria for determining whether the effects have occurred Radford, This point is especially important because changes in the immune system can reflect an extremely broad spectrum of biologic effects ranging from normal variation to sudden death Table Therefore, immune-system markers of effect must be defined in terms of the specific health effects for which they might serve as indicators.
When there are clinically apparent health effects caused by immune-system dysfunction, changes in immune-system markers are often evident and serve as helpful indicators of pathogenesis. Biologic markers of effect are usually less obvious during the inactive phases of immune-mediated disease. If immune-related effects occur below the clinical disease level, the altered state of the immune system cannot necessarily be "recognized as impairment or disease" Committee on Biological Markers of the National Research Council, Description Table of Contents.
Summary This text provides a concise and comprehensive introduction to key immunotoxicological issues for all those interested in, but with no prior knowledge of, this area of toxicology. The first section explores the health consequences of immunotoxicity, namely the adverse effects related to chemically-induced immunosuppression and immunostimulation, hypersensitivity reactions and autoimmune diseases, with an overview of major immunotoxicants. The second part describes the latest methods used to detect and evaluate, preclinically and clinically, the unexpected immunotoxic effects of xenobiotics.
Trends in implementing strategies and recent changes to the regulatory aspects are also considered. The third section examines possible future developments, including In Vitro methods, biomarkers of immunotixicity and risk assessment. Definition of Immunotoxicology 2. Overview of the Immune System. Assays of Humoral Immunity. Assays of Cell-Mediated Immunity. Assays of Non-Specific Defences.