WHO task group on environmental health criteria on principles and methods for assessing autoimmunity associated with exposure to chemicals

Autoimmunity is characterized by the reaction of cells (autoreactive T lymphocytes) or products (autoantibodies) of the immune system against the organism's own antigens (autoantigens). It may be part of the physiological immune response ("natural autoimmunity") or pathologically induced, which may eventually lead to development of clinical abnormalities ("autoimmune diseases"). Many different autoimmune diseases can occur, but all are characterized by the inappropriate or excessive immune response against autoantigens, leading to chronic inflammation, tissue destruction, and/or dysfunction. To date, more than 60 diseases have a proven or strongly suspected autoimmune etiology. Generally, autoimmune diseases are perceived to be relatively uncommon. However, when all autoimmune diseases are combined, the estimated prevalence is high (3-5% of the general population), which underlines their importance to public health. Because of difficulties in diagnosis and in designing and standardizing epidemiological studies, limited data are available, and the prevalence may actually be underestimated. Nonetheless, there is epidemiological evidence of increasing prevalence of certain autoimmune diseases in highly industrialized countries, which cannot be attributed to better diagnosis alone. Furthermore, there is growing evidence that autoimmune mechanisms may play a role in many other diseases (atherosclerosis, for instance). Autoimmune diseases are multifactorial. Both intrinsic factors (e.g. genetics, hormones, age) and environmental factors (e.g. infections, diet, drugs, environmental chemicals) may contribute to the induction, development, and progression of autoimmune diseases. Environmental factors are believed to be a major factor responsible for their increased prevalence. Environmental factors operating in a genetically susceptible host may directly initiate, facilitate, or exacerbate the pathological immune process, induce mutations in genes coding for immunoregulatory factors, or modify immune tolerance or regulatory and immune effector pathways. Drug-induced autoimmune or autoimmune-like disorders and hypersensitivity are of major concern and often the reason for withdrawing drugs from the market or restricting their use. Systemic allergy is not well understood and is often considered idiosyncratic, but it may be of an allergic or autoimmune nature. We have learned much about the mechanisms of idiosyncratic autoimmune diseases by studying the autoimmune phenomena that result from exposure to therapeutics. In addition, there have been several "point source" outbreaks of autoimmune diseases due to environmental exposures to chemicals such as Spanish toxic oil and L-tryptophan that have advanced our knowledge substantially. There is now considerable epidemiological evidence pertaining to the association between occupational exposure to crystalline silica dust (quartz) and the risk of several systemic autoimmune diseases (specifically, systemic sclerosis, systemic lupus erythematosus, rheumatoid arthritis, and systemic small vessel vasculitis). Epidemiological studies also support a role of occupational exposure to solvents in the development of systemic sclerosis, but a clear consensus has not developed on the specific exposures or classes of chemicals involved and whether this association extends to other diseases. Some autoimmune diseases (e.g. Graves disease, rheumatoid arthritis) have been associated with tobacco use, particularly among current smokers, but only weak or no associations have been seen with other diseases. Additional experimental research examining the effects of these and other chemical and physical agents, using exposure routes relevant to the human experience in occupational settings or in environmental contamination, is needed to advance our understanding of the pathogenesis of autoimmune diseases. In contrast to the available studies concerning silica, solvents, and smoking, there are relatively few epidemiological data pertaining to the effect of dioxins, pesticides, or heavy metals on the development or progression of autoimmune diseases. There is also some research on the influence of dietary factors on autoimmune diseases. This is a broad area that includes caloric intake, specific nutrients and foods, and dietary supplements. Coeliac disease is an example of an autoimmune disease with a clear dietary link in which an immunological response to specific proteins in wheat, barley, and rye produces autoantibodies directed against tissue transglutaminase, causing mucosal damage in the small intestine. It is highly likely that infection plays a role in many autoimmune disorders, although the infectious agent and mechanism by which it causes disease may differ from one disorder to another. Most hypotheses relating infection to autoimmunity have assumed that infection plays a direct causal role, although it may simply serve as a predisposing factor. Infectious agents may play a role due to sequence homology with endogenous proteins, resulting in "molecular mimicry", and also may act as "priming" agents due to non-specific/polyclonal stimulation of immune factors such as cytokines and co-stimulatory molecules. Hygienic status, resulting in a lack of infectious stimuli, may have an impact on autoimmunity. Chemical agents may play an important role in interacting with infections, an area that has been poorly studied. There exist a variety of methods to detect enhanced antibody formation and autoantibodies in humans and experimental animals following environmental exposure. In contrast, tests available for measuring the potential of chemicals or environmental factors to produce autoimmune disease or augment existing autoimmune disease are not readily available. A large number of animal models exist that have been used primarily to explore basic mechanisms and therapeutic possibilities for certain autoimmune diseases. Etiology in the various models is based on genetic predisposition, induction with specific antigens (mostly in combination with an adjuvant), or challenge with infectious agents. Chemical-induced autoimmune disease models are less common. In addition, autoimmunogenic and allergenic effects of compounds are usually not identified in routine toxicity studies, in part because outbred animals are used and relevant parameters are not studied. In addition, outliers are usually discarded from the experiment, whereas in fact outliers may indicate unexpected and idiosyncratic immune effects. A general strategy to assess the autoimmunogenic potential of chemicals is lacking. One promising approach is the popliteal lymph node assay. This represents a straightforward and robust animal test model that may be used to link direct lymphocyte node reactions to local application of potentially immunoactive chemicals. However, these assays may be predictive of the sensitizing potential, but not necessarily of the autoimmunogenic potential, of agents and do not represent a systemic route of exposure. The burden on health and heavy costs of autoimmune diseases highlight their importance with regard to risk assessment. Risk assessment of autoimmunity associated with chemical or physical agents should consider available epidemiological data, hazard identification and dose-response data derived from animal and human studies, data related to mode of action, and susceptibility factors. The risk assessment process may eventually help to calculate the cost of autoimmune disease associated with exposure to chemical and physical agents. Currently, the risk assessment for agents that are suspected of inducing or exacerbating autoimmunity or autoimmune diseases is hampered by the fact that appropriate information is not available, particularly validated animal models. Because of the individual- and population-level burden of autoimmune disease, risk assessment with respect to this group of diseases assumes special importance.