[Citation in PubMed] [Related Articles]

Linking Environmental Agents and Autoimmune Diseases

Glinda S. Cooper,¹ Dori Germolec,² Jerry Heindel,³ and MaryJane Selgrade⁴

¹Epidemiology Branch, ²Laboratory of Toxicology, ³Division of Extramural Research and Training, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina USA; ⁴Immunotoxicology Branch, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina USA

This monograph is based on the workshop "Linking Environmental Agents and Autoimmune Diseases" held at the National Institute of Environmental Health Sciences held 1-3 September 1998. The workshop brought together immunologists, clinicians, epidemiologists, molecular biologists, and toxicologists to review current knowledge about environmental links to autoimmune disease and to identify data gaps and future research needs. (Environmental agents were defined as xenobiotic chemicals in the environment; viruses and infectious agents were not considered in this particular workshop.)

The impetus for the workshop was the question of whether environmental agents affect the development or progression of autoimmune disease. If so, the ultimate goal is to understand the role of environmental agents and the underlying mechanisms through which these agents act so that the potential risks of exposure to these agents can be assessed and reduced. The workshop's objectives were to assemble experts from a variety of fields and provide a forum where they could interact; review what is known about links between environmental exposures and autoimmune disease; identify and prioritize research needs; and develop an integrated, multidisciplinary research agenda. The following critical questions framed the workshop's program:

a) Is there an increased risk for autoimmune disease as a result of environmental exposures? If so, what is the magnitude of that risk? Most autoimmune diseases are relatively rare and hence risk may appear to be low when based on a specific disease. The risk would be greater if several autoimmune diseases were affected by a chemical exposure, possibly via common mechanisms. For the population at large, the risk is probably smaller than it is for certain sensitive populations. For any individual chemical the risk may be small, but if a number of (possibly structurally similar) chemicals have similar effects, the magnitude of risk increases. Finally, the dose response, prevalence, and persistence of the chemical(s) in question all affect the magnitude of risk. Information with respect to these issues is needed to understand the importance of environmental agents in the development or expression of autoimmune disease.

b) What are the underlying mechanisms? Because many autoimmune diseases involve different organ systems, pathogenesis is likely to involve multiple mechanisms. There are several potential targets for chemicals, including the immune system, the affected organ(s) (particularly with respect to alteration of antigenic expression), and the neuroendocrine system. If common mechanisms can be identified, it may be possible to group certain diseases or chemicals together. Understanding the underlying mechanisms(s) also is critical for developing biomarkers of effect that can be used in testing strategies. It would also be useful to know whether there are common mechanisms across the varied forms of immune response (immune suppression, allergy, and autoimmune disease). Finally, mechanistic data would help determine structure-activity relationships, which frequently are the first consideration in hazard identification.

c) How should we evaluate the role of environmental agents using animal testing methods? Chemicals that suppress immune responses may enhance susceptibility to infectious and neoplastic disease, and inappropriate stimulation of the immune system may result in allergic or autoimmune disease. To date, toxicologists have primarily focused their research on immune suppression and allergy. So much progress has been made in the area of immune suppression that the U.S. Environmental Protection Agency recently drafted and approved test guidelines to be used in assessing chemicals for immunosuppressive effects (1). In the area of allergy there are tests to assess for contact sensitizers (2), and a number of laboratories are working on tests for chemicals that might elicit respiratory hypersensitivity (3). However, there are no well-validated methods for assessing autoimmunity. The workshop was to determine the research necessary to either support the development and recommendation of test guidelines or provide a scientific basis for not recommending testing. Development of a panel of assays depends on the identification of appropriate animal models. Again the issue of common mechanisms is important because it is not feasible to have different tests for every type of autoimmune disease. Ideally, biomarkers need to be identified that are indicative of risk of more than one type of autoimmune disease and can be assessed in humans as well as experimental animal models, providing a bridge between animal research and human effects.

d) How should we evaluate the role of environmental agents using epidemiologic studies? There are few human studies examining environmental exposures and autoimmune disease. Another purpose of the workshop was to help prioritize hypotheses that could be evaluated in epidemiologic studies and to stimulate development of exposure assessment techniques (as well as biologic markers of exposure or response) needed for large-scale studies.

The National Research Council of the National Academy of Sciences has defined risk assessment as comprising some or all of the following components: hazard identification, dose response, exposure assessment, and risk characterization (4). Hazard identification is a qualitative assessment that addresses the question, "What types of effects occur as a result of chemical exposure?" In this case, the question would be "Does a chemical have the potential to induce or exacerbate autoimmune disease?" Dose response is a quantitative assessment and broadly interpreted addresses the question, "Under what conditions does a chemical cause these effects in humans?" Exposure assessment is an analysis of the level of exposure in the environment and the numbers and types of individuals that are likely to be exposed. Finally, all of this information is integrated to develop a risk characterization. It is clear from the foregoing that the state of the science with respect to environmental agents and autoimmune disease is in the early stages of hazard identification.

The peer-reviewed papers in this monograph are divided into six sections on the basis of workshop sessions: the first section includes an introduction to the immunology of autoimmunity and autoimmune diseases and articles on the evidence for the role of environmental agents in the initiation or progression of autoimmune conditions, available screening tests, and considerations for risk assessment; the second section covers several different issues regarding susceptibility and susceptible populations; the third section focuses on clinical, experimental animal models, and epidemiologic studies of systemic autoimmune diseases (scleroderma and systemic lupus erythematosus); the fourth section includes some examples of what are considered more organ-specific diseases (e.g., thyroiditis); the fifth section contains articles about specific exposures and mechanisms (e.g., hexachlorobenzene, silica); and the final section consists of the consensus of research needs and priorities developed by workshop participants. This monograph is intended to provide a resource for developing a research strategy to address potential links between environmental agents and autoimmune disease, including the important issue of the interaction between genetic, hormonal, and environmental factors involved in the etiology and progression of autoimmune diseases.

REFERENCES AND NOTES

1. U.S. EPA. Health Effects Test Guidelines. EPA 712-C-98-351. Washington, DC:U.S. Environmental Protection Agency, 1998.

2. U.S. EPA. Health Effects Test Guidelines. EPA 712-C-96-197. Washington, DC:U.S. Environmental Protection Agency, 1996.

3. Kimber I, Bernstein IL, Karol MH, Robinson MK, Sarlo K, Selgrade MJK. Workshop overview: identification of respiratory allergens. Fundam Appl Toxicol 33:1-10 (1996).

4. National Research Council. Risk Assessment in the Federal Government: Managing the Process. Washington, DC:National Academy Press, 1983;17-83.

Last Updated: September 20, 1999