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Last updated January 1, 2014

Although scientists have known since the early 1900s that occupational exposure to certain chemicals can induce severe immune effects, recent chemical disasters of national and international prominence have renewed interest in the subject. It is generally agreed that human health is influenced by the environment and that many diseases are caused or enhanced by environmental factors, but effects on the immune system have been difficult to delineate. Researchers in the field of immunotoxicology, who study the adverse effects to immune function that result from occupational, inadvertant, or therapeutic exposure to environmental chemicals, biological materials, and drugs, debate if toxicants damage the immune system and to what extent. Some researchers contend that certain chemicals can affect immunity, significantly increasing an individual's susceptibility to disease, in some cases causing hypersensitivity reactions, autoimmunity, or immunosuppression. Others dispute this view, arguing that the evidence for immunotoxicity in humans is greatly overstated.

To Serve and Protect
The immune system is the body's complex surveillance network whose mission is to recognize and destroy disease-causing or "foreign" agents. It contains millions of highly specialized cells in the bloodstream and various tissues designed for this purpose. When the body is invaded by foreign substances such as viruses and bacteria, the appropriate immune cells respond by destroying the foreign matter or rendering it harmless. When parts of the immune system are damaged, the body cannot fight its adversaries and conditions and diseases ranging from allergies to AIDS may result.

In order to perform its safeguarding duties, the immune system has developed a number of important attributes. Each individual's immune system is distinctive, causing enemy agents and immune cells to interact differently from person to person, thanks to a unique set of molecules on the surface of immune cells called antigens. The healthy immune system can discriminate the body's own antigens, known as self, from foreign antigens, known as nonself. Not only can the immune system detect millions of nonself antigens, it can produce armies of cellular and chemical mediators to launch an initial attack against a foreign substance and manufacture great numbers of specialized cells in the process. The immune system is able to "remember" foreign antigens once the attack is over so that immune responses are activated more rapidly if exposure to a particular antigen reoccurs. This rapid recall is the basis for protection against antigens by vaccination.

Cells designed to develop into immune cells are produced in the bone marrow in a process called lymphopoiesis. These immune cells, called leukocytes or white blood cells, include a variety of specialized cells: macrophages, eosinophils, natural killer (NK) cells, plasma cells, and T- and B-lymphocytes. The development of these various cell types is directed by chemicals called cytokines. Some lymphocytes cluster in immune organs including the thymus, spleen, lymph nodes, tonsils, and adenoids, while others flow continuously throughout the body in the blood and through a network of lymphatic vessels. The vessels carry lymph to the lymph nodes, the small bean-shaped organs that store lymphocytes and other immune cells. In the lymph nodes, antigens are filtered out and handed over to immune cells and lymph flows back into the bloodstream to monitor organs and tissue for foreign antigens. Lymphoid tissues are also present in local groups known as bronchus-, gut-, and skin-associated lymphoid tissue.

Immune cells manufacture a wide variety of chemical messengers that can instruct and control other immune cells or help to attack and destroy foreign antigens. These chemicals include antibodies, which are protein molecules capable of combining with a foreign subtance, cytokines such as interferon and interleukins, and complement, which consists of proteins that act in concert with antibodies.

The responses of the immune system to the presence of foreign agents are divided into innate and acquired responses. Innate immune responses can be thought of as the first line of defense against foreign bodies carried out by all-purpose immune cells such as particle-eating cells like macrophages and neutrophils. NK cells are also part of the innate response, destroying any cells containing tumor or viral antigens. Acquired immune responses develop to attack specific infectious agents, tumor cells, or allergens. Macrophages also play a role in acquired immunity when they process and present antigens to T-lymphocytes, or T-cells, that work to destroy specific antigens. There are different types of T-cells that play different roles when the body is under attack. For example, cytotoxic T-cells recognize and kill cells containing viral or tumor antigens, and suppressor T-cells decrease the immune response when needed.

B-lymphocytes, or B-cells, also multiply in the presence of a specific antigen, often with the assistance of T-cells. B-cells differentiate into plasma cells that produce antibodies that specifically bind to the antigen of the invading foreign body. These antibodies may also assist macrophages in engulfing foreign bodies, rupture bacterial cells, neutralize viruses, and facilitate the cytotoxic activities of NK cells.

Who's Susceptible?
According to Michael Luster, head of the Environmental Immunology and Neurobiology Section of the NIEHS, age, genetics, preexisting disease, lifestyle, diet, drugs, or stress may compound the effects of chemical exposures to further compromise immune function and increase the chance of disease. Most of the evidence for this interaction comes from animal studies, but there is evidence from human observations as well. About 10% of the U.S. population has a genetic tendency to develop allergies. Studies have shown that parents with allergies have a higher proportion of children with allergies. In one study, children born to allergic parents had a 50% chance of being allergic; with only one allergic parent, the chances were still 30%. Normal immune response depends on the collaboration of more than 60 genes.

It is thought that some immunologic disorders surface even under ordinary environmental conditions, while others appear only after toxic challenges from the environment that act to invoke a previously undetected genetic condition. Genetic studies have demonstrated the existence of a receptor, called the Ah receptor for aromatic hydrocarbon responsiveness, in some animals and humans that binds to halogenated aromatic hydrocarbons, or HAH. This binding of an HAH may cause toxicity to immune cells, the liver, and DNA and increase cancer risk.

Children and the elderly may be especially susceptible to reductions in immune function. It is well known that the developing immune system is vulnerable to chemical injury. Infants are born with only passive immunity; that is, they are protected for a short period by maternal antibodies that they receive through the placenta and later from breast milk. Although studies of long-term, low-level exposures to environmental toxicants have not been done in the elderly, it is probable that some of the health problems in this population may be associated with reductions in immune function.

Certain therapeutic drugs may also damage immunity. Vitamins, antibiotics, antifungal agents, replacement hormones, diphenylhydantoin, and lithium are a few of the drugs associated with immunologic changes. Abused substances, including alcohol, cocaine, and opioids, may be immunotoxic as well.

Do Chemicals Injure Immunity?
Many immunotoxicologists say that exposures to certain chemicals can have a significant effect on immune function. Studies have shown that chemical exposures can affect immunity in two major ways: by causing hypersensitivity reactions, including allergy, which can be harmful to organs and tissues, and autoimmunity, in which immune cells attack self; or by causing immunosuppression, a reduction in the responses and activities of the immune system.

Hypersensitivity. Luster has written that 35 million Americans suffer from allergies, of which 2-5% are due to occupational chemical exposure. In some individuals, certain substances can aggravate the immune system and cause it to overreact. The first time that an allergy-prone person is exposed to an allergy-causing antigen (an allergen), the matching B-cells generate the class of antibody called immunoglobulin E (IgE). These IgE antibodies attach to the surfaces of other immune cells known as mast cells and basophils, which are found in the lungs, skin, tongue, nose, and intestinal tract. Upon second exposure to the allergen, IgE antibodies on mast cells or basophils signal the release of chemicals such as histamine, which is largely responsible for the intense itching, watery eyes, and runny noses that are commonly associated with allergies.

Immune platoon. Specialized cells in the immune system fight off toxic agents.
Double-click on image to see larger version. Source: Mary Jane Selgrade

Some people have more severe allergic reactions than others. Many chemicals cause serious allergic responses beyond the ordinary mild reactions. For example, exposure to toluene diisocyanate (TDI), used in the production of plastics and resins, can result in both contact dermatitis and asthma. Workers in the paint and plastic industries exposed to trimetalic anhydrides had antigen-mediated asthma and rhinitis, late respiratory systemic syndrome, and pulmonary disease anemia.

Other agents induce different types of hypersensitivities. Metals can cause the development of autoimmunity, in which the immune system identifies self as nonself, and mounts an aberrant assault. The result can be an autoimmune disease of the joints and kidneys, such as rheumatoid arthritis, glomerulonephritis, and interstitial nephritis, all of which have been associated with exposures to mercury, gold, or lead. Other organ systems such as the gastrointestinal tract, blood and blood vessels, the central nervous system, and the thyroid, may be targeted for chemically induced autoimmunity.

Exposure to beryllium, a metal used in the manufacture of copper alloys and in the aerospace, nuclear, and electronics industries, is associated with delayed hypersensitivity, in which the immune system reacts to antigen in an immune cell that cannot be cleared or digested. T-cells are then activated to release substances called lymphokines, which cause inflammation due to the influx of immune cells and lymphocytes to the site. With repeated exposures, cells gather at the site of the metal and form masses known as granulomas. When granulomas collect in the lungs, the chronic lung disease known as berylliosis sets in. Short-term, high-concentration beryllium exposure can also lead to dermatitis and sensitization to beryllium.

Immunosuppression. Immunosuppression is normally associated with drugs used to treat autoimmune diseases and increase the survivability of an organ transplant. No matter how closely an organ donor matches an organ recipient, the new organ will have some different antigens that may be perceived by the immune system as foreign bodies. Because the activities of the immune system have been reduced, immunosuppressed patients are more susceptible to infections and cancers.

A number of human studies cite evidence that immunosuppression also occurs in individuals exposed to environmental agents. In the late 1970s, a group of dairy farmers living in a small town in Michigan who were affected by Hodgkin's disease were also found to have been exposed to polybrominated biphenyls. Children exposed to industrial chemical-contaminated drinking water in the 1980s were reported to have a higher incidence of leukemia and recurrent infections, and their family members had increased levels of T-cells, antibodies directed against self antigens, and repeated rashes. Taiwanese individuals who ingested rice oil contaminated with polychlorinated biphenyls (PCBs) and dibenzofurans exhibited increased sinopulmonary infections and altered T-cell functions. Other researchers have reported incidence of "toxic oil syndrome," an immunosuppressive disease that appears to also involve autoimmunity, in Spanish residents who consumed rapeseed oil containing imidazolidethion. Evidence also shows that exposure to ultraviolet radiation and ozone suppresses immune responses in humans.

While the mechanism of chemically induced immunosuppresion is not completely understood, it appears that in some cases hemotoxicity, direct damage to the organs and progenitor immune cells, is partially responsible. Specifically, environmental chemicals can affect the process of hematopoeisis, the production and maturation of blood cells, including immune cells. Environmental agents can target stem cells, reducing the number of cells available for maturation; affect the marrow itself, rendering it nonfunctional; or damage specific types of immune cells, causing imbalances among cell types.

War plans. Immune cells launch an attack on target cells through a variety of mechanisms.
Double-click on image to see larger version. Source: Michael Luster

Organic solvents are well known for their destructive effect on hematopoiesis. Used in the paint and other industries, benzene exposure can lead to abnormalities in the numbers of blood cell types, including leukopenia, and bone marrow hyperplasia. In the past, exposures to heavy metals, in particular lead, was thought to only affect red blood cells. Recently, studies have shown that lead accumulates in the bone marrow, reducing the number of stem and other types of cells. Another chemical, dimethylnitrosamine, is a potent inhibitor of antibody production.

HAHs such as 2,4-dichlorophenoxyacetic acid (2,4-D) and 2,4,5-trichlorophenoxylacetic acid, the active ingredients in Agent Orange, have multiple effects on immune functions. TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) is an HAH considered to be the prototype dioxin. Dioxins affect antibody production and immune cell activities. They may also cause immunosuppression and decreased resistance to disease.

The Debate
The controversy over immunity focuses mainly on the questions of whether environmental and chemical agents can suppress the immune system in the general population and, if so, if this reduction in immune function can result in clinical disease. While animal toxicology data clearly demonstrate such effects, many researchers and clinicians in the field of immunotoxicology believe that current evidence is not sufficient to support the notion that immunologic damage to humans occurs as the result of chemical exposures. Epidemiologic studies demonstrating such immunotoxic effects have come under fire from researchers who criticize, among other things, lack of a complete or firm immunodeficiency diagnosis, small patient group sizes, and the inability to establish actual exposure levels. These are problems that have plagued epidemiology and toxicology for decades, making it difficult to evaluate the magnitude of health problems associated with occupational exposures or the effects on the population at large.

Some point out that the immune system, like every physiological system, probably has "reserve capacity," that is, enough overlap in functions that small amounts of injury are anticipated and absorbed. While the possibility exists that high-dose toxin exposures could cause significant changes, "the immune system is resilient," says Jack Dean, president of the research division of Sanofi-Winthrop. "You need a lot of injury before you can see an effect. There are very few cases where the two can be linked," says Dean. In a number of studies, immune function was normal in individuals exposed to high levels of immunotoxic chemicals, including heavy metals and TCDD. Another example is the Bhopal disaster, in which individuals exposed to methyl isocyanate, an intermediate chemical produced in the manufacture of carbamate pesticides, were found to have increases in numbers of T-cells and decreases in cell activity following exposure to methyl isocyanate, but no clinical immunologic diseases were reported. Neighbors of the Michigan dairy farmers who were exposed to polybrominated biphenyls had no immune changes at all. Even in factory workers exposed to benzene and other organic solvents, the clinical relevance of immune system changes is unclear.

Luster admits that the question of whether environmental agents can decrease immune function is difficult to answer because the types of immunologic effects one might expect in the general population are probably subtle. "There is a lot of immunologic variability between individuals; it would be hard to establish a 10 to 15 percent reduction in immune function," he says. To sort out the effects of environmental agents, researchers agree that further clinical studies using well-defined subpopulations and the development of sensitive tests are needed. But opinions on what the best approaches might be vary widely.

The value of animal models for collecting data on immunotoxicity is even questioned, despite the fact that the majority of data on immunotoxic chemicals comes from such studies. In the past, some animal studies were criticized because the doses used were well beyond what humans might be exposed to except in cases of accidents, but most researchers have recognized this problem and adjusted their studies. The problem of how to extrapolate animal results to humans still remains an issue. "The challenge for risk assessment is to extrapolate from immunotoxicity testing, which is usually a measure of cellular effects in animals, to human health effects at the population level," says Mary Jane Selgrade, Chief, Health Effects Research Laboratory of the EPA Immunotoxicology Branch. "We can do this qualitatively but not quantitatively."

Research in animals has confirmed the results of accidental exposures. The immune systems of several laboratory animals are similar to that of humans in organization, function, and responsiveness, including those of mice and rats. Monkeys chronically exposed to a mixture of PCBs equivalent to that found in the environment became immunosuppressed: they had aberrant ratios of T-cell types and lowered antibody responses. Moreover, immunosuppression was seen in the offspring that were exposed perinatally. These immunological effects were similar to those reported in individuals from Taiwan who were exposed to PCB-contaminated rice oil.

Selgrade has developed a mouse model to examine the relationship between chemical suppression of natural killer cells (which are nonspecific) and susceptibility to cytomegalovirus infection. She administered eight chemicals in various doses and found that a significant correlation was observed between chemical suppression of natural killer cell activity against the virus and an increased number of deaths due to viral infection. Selgrade and others have done similar studies with bacterial infections and their effect on lung immune cells, specifically suppression of alveolar macrophages in which phagocytosis correlates with susceptibility to streptococcus infection in the lung. In situations where comparisons are possible between effect of environmental agents on human and mouse immune responses, she has found that, "the mouse has predicted pretty well what happens in humans."

Nancy Kerkvliet, associate professor in the Department of Agricultural Chemistry at Oregon State University, cites another problem with animal studies: most examine the spleen after exposure, whereas in humans, blood tests are used to measure immune impairment. "We need more comparable models," says Kerkvliet. Measurements of toxic effects to immunity in humans rely on the use of standard clinical tests, which include measures of antibody levels, the ability of lymphocytes to proliferate, and responses of immune cells to antigens. In a few cases, such assays are accepted as indicative of exposure. Clinical evidence of beryllium exposure is strongly associated with immune activity against the metal by T-lymphocytes obtained from bronchoalveolar lavage or peripheral blood, for example. However, these types of tests may not be sensitive enough to assess immunotoxic problems due to most low-level chemical exposures. "You expect these effects to be more subtle; we really can't depend on the standard tests," says Michael Holsapple, Research Associate of Dow Chemical, who conducted a number of TCDD studies in animals. Others would go one step further in questioning the validity of such tests for immunotoxicology. Says Dean, "It is not clear how much of a change in functional assay signals a difference in the immune system."

It may be that the small changes observed in the laboratory are often blown out of proportion, according to Kerkvliet. In addition, she says, little attention is paid to the chemical exposures that appear to increase immune system activity. "Except in cases of autoimmunity and allergy, the negative interpretations for this boost in immunity may not necessarily be valid." But immunotoxic damage in both humans and animals happens "against a background of other factors," says Selgrade. "Immunocompetence in the general population probably is a bell-shaped curve. The concern in immunotoxicity is most likely those individuals that fall on the lower end of the curve," she says.

Most immunotoxicologists would agree that there is a need for more well-controlled epidemiology studies in humans. Holsapple suggests that better ways to assess risk might be to look more closely at chemical-exposed populations. For instance, the administration of a flu vaccine to a dioxin-exposed population would give direct information on how these individuals handle direct antigenic challenge. Selgrade is involved in collaborative research in which humans are exposed to ozone by inhalation in order to quantify alveolar macrophage responses and compare them to the animal responses she has studied. Similarly, following controlled human exposures to ultraviolet radiation, EPA studies have demonstrated immune suppression that is similar to that observed in mice. Says Holsapple: "We need to ask more and more analogous questions in humans to take advantage of what we've learned in animals." Immunologists continue to struggle with these issues in attempts to aid the risk assessment process in a way that is meaningful for human health.

Glover-Kerkvliet, Janet. 1995. Environmental Assault on Immunity. Environmental Health Perspectives 103:3, March 1995, http://ehpnet1.niehs.nih.gov/docs/1995/103-3/focus.html. Glover-Kerkvliet is a freelance journalist from Cockeysville, Maryland.

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