This paper was prepared from the key points that were presented in a workshop entitled, ‘Chemical-induced autoimmunity’’ at Eurotox, 2001, the 39th Congress of the European Societies of Toxicology. One could reasonably question why a focus on pesticides was included in a workshop devoted to chemicals and autoimmunity. A search of the literature by this author using PubMed and the keywords, ‘pesticides’ and ‘autoimmunity’, turned up a total of only 18 citations, many of which will be highlighted below.
Moreover, previous reviews and/or books devoted to the topics of autoimmunity or autoimmune disease have rarely addressed the role played by pesticides. For example, a review by Kosuda and Bigazzi (1996) in Experimental Immunotoxicology entitled, ‘Chemical-induced Autoimmunity’, never used the word, ‘pesticide’, and included only two examples of pesticides (i.e. paraquat and pentachlorophenol (PCP)) in a table listing well over a hundred xenobiotics that have been associated with autoimmune diseases.
The converse was also true in a review by Rodgers (1996) in Experimental Immunotoxicology entitled, ‘Immunotoxicity of Pesticides’, in that the terms, ‘autoimmunity’ or ‘autoimmune disease’, were never used. However, it is important to note that a few studies were described by Rodgers which indicated that exposure to pesticides caused an enhancement of some immune parameters. This type of observation will be discussed further below.
Finally, over a hundred immunologists, clinicians, epidemiologists, molecular biologists and toxicologists came together in a workshop in September of 1998 to review the current knowledge about environmental links to autoimmune disease, and to identify data gaps and future research needs. That workshop was entitled, ‘Linking Environmental Agents and Autoimmune Diseases’, and was sponsored by several branches of the U.S. National Institutes of Health, by the U.S. Environmental Protection Agency (EPA), by the American Autoimmune Related Diseases Association, Inc. and by the Juvenile Diabetes Foundation International.
Pesticides and animal studies using standard immunotoxicological parameters
A number of studies have set out to characterize the immunotoxic potential of a variety of pesticides using standard immunotoxicological parameters. A review by Rodgers (1996) indicated that a few studies showed that exposure to pesticides enhanced some immune parameters. More recently, an extensive review of the literature by Barnett (1997) was captured in a table that illustrated the effects of a variety of pesticides and a multitude of immune parameters.
Depending on the specific chemical, the exposure conditions, the species being tested and the immune parameter being measured, the outcomes were decreases, increases or no effects. A few examples of increased effects by pesticides will be provided below. Rodgers et al. (1986) reported that exposure to malathion caused an increase in the antibody response to sheep erythrocytes (SRBC).
The significance of this observation becomes a little clearer in light of the fact that this same laboratory subsequently showed that malathion had a positive effect on a spontaneous autoimmune mouse model (Rodgers, 1997), as described below in the next section. Interestingly, other pesticides have been shown to be capable of increasing the antibody response to SRBC including carbaryl (Andre et al., 1983), lindane (Meera et al., 1992) and aminocarb (Bernier et al., 1988). The significance of these results is difficult to ascertain.
However, in the case of aminocarb, subsequent results indicated that exposure caused an increased expression of MHC class II antigens (i.e. one of the putative mechanisms for xenobiotic-induced autoimmunity presented above) and the authors speculated that aminocarb may represent an autoimmunity-inducing agent (Bernier et al., 1995). There is no consensus regarding the correct way to interpret an enhanced antibody response to SRBC.
Pesticides and animal studies using specialized models of autoimmunity
To date, there have been few, if any well-documented observations of autoimmunity induced specifically by chemical exposure in laboratory animals. House (1997) speculated that the basis for this paucity of observations is because the induction of autoimmunity requires a long-term exposure to the inducing material and the limited life-span of rodents may preclude observation of these types of reactions. House (1997) and others (i.e. the U.S. National Toxicology Program) have recommended that a more efficient approach may be the use of animals that are predisposed toward autoimmune disease.
A number of experimental autoimmune animal models were described in the review by Kosuda and Bigazzi (1996), and two spontaneous autoimmune models were highlighted in the review by House (1997). In these specialized models, the animals are treated with a control substance or test materials prior to the anticipated appearance of the disease. The time to onset of the disease or a change in the severity or duration of the disease would then provide information on the autoimmunogenic potential of the test material.
Clearly, these models can provide some insight into the role for a xenobiotic in a specific type of autoimmune disease. Because these models are as unique as the human diseases they are intended to mimic, it is difficult to imagine how they can be used as a general screen for autoimmunogenic potential. More importantly, in the context of the topic of pesticides and autoimmunity, only a few studies were identified, including the aforementioned results with HCB in two induced models of encephalomyelitis and arthritis (Michielsen et al., 1999).
In the only study with a pesticide in a spontaneous autoimmune model, Rodgers (1997) administered malathion at noncholinergic doses to MRL-lpr mice and their MRL-+/+ littermates. Treatment of MRL-lpr mice with malathion accelerated the appearance of the urinary protein indicative of the onset of autoimmune disease. At later time points, malathion treatment also increased the level of antinuclear antibodies and the number of inflamed glomeruli.
Pesticides and human studies after environmental or occupational exposure
Descotes et al. (1995) noted that autoimmune reactions associated with exposure to xenobiotics are uncommon, and that while many pharmaceutical drugs are reportedly involved, few chemicals are suspected. A workgroup from the U.S. Agency for Toxic Substances and Disease Registry (ATSDR) recommended a strategy for evaluating the presence of autoimmunity or autoimmune diseases in communities located near hazardous waste sites (Ozonoff et al., 1994).
The proposed strategy included measuring the levels of C-reactive protein (i.e. an acute phase reactive protein whose levels rise in response to tissue damage and infection), anti-nuclear antibody (i.e. ANA, a commonly occurring autoantibody), antithyroglobulin antibody (i.e. an autoantibody associated with a variety of thyroid disorders) and rheumatoid factor (i.e. an autoantibody to immunoglobulin M) as well as a complete blood count including a five-part differential and a total lymphocyte count.
At the time this workgroup made their recommendations, no studies had been done to try to establish a causal relationship between autoimmunity or autoimmune disease and the kinds of exposures found in communities located near hazardous waste sites (Ozonoff et al., 1994). Nonetheless, these types of studies were inevitable because it has been noted that there is a general impression that the incidence of autoimmune diseases, such as systemic lupus erythematosus and rheumatoid arthritis, may be increasing for reasons not understood (Luster, 1996).
Therefore, a few investigators have applied components of the strategy proposed by the ATSDR workgroup in human studies with pesticides. Thrasher et al. (1993) reported a significantly higher number of patients had one or more autoantibodies following exposure to the organophosphate pesticide, chlorpyrifos, compared to healthy controls, and two of 12 exposed patients were reportedly diagnosed with lupus-like syndrome.
Pesticides and human studies after accidental poisoning
In the context of pesticides and autoimmunity, the single most important incident of human poisoning occurred from 1955 to 1959 when approximately 3000–5000 people in southeastern Turkey ingested seed grain contaminated with the fungicide, HCB. Patients developed a disease characterized by hepatic porphyria called porphyria turcica (Cam, 1958), which was manifested as bullous skin lesions, mainly in sun-exposed skin that ultimately healed with severe scars. The skin lesions have been attributed to the phototoxicity associated with the elevated level of porphyrins.
Porphyria turcica primarily affected children aged 6–16 years (Dogramaci et al., 1962a). In addition to the dermatological changes, other clinical manifestations included neurologic symptoms, hepatomegaly, enlarged thyroid, splenomegaly, hyperpigmentation, hirsutism, enlarged lymph nodes and painless arthritis of the hands (Dogramaci et al., 1962b).
In follow-up studies among 204 victims 25–30 years after the poisoning incident, the dermatologic abnormalities, neurologic symptoms, enlarged thyroid and painless arthritis of the hands still persisted (Cripps et al., 1984). For many of the clinical symptoms exhibited by the victims of the HCB poisoning incident in Turkey, an immune etiology was considered. In fact, the autoimmunogenic potential of HCB has been characterized in a number of laboratory studies described above.
Interestingly, additional supportive evidence for the ability of HCB to trigger autoimmunity in humans was recently provided when serum IgM and IgG levels increased in workers occupationally exposed to HCB (Queiroz et al., 1998). However, it is important to note that in spite of extensive mechanistic work, the mechanism by which HCB affects the skin, immune systems and other organs is still unclear (Michielsen et al., 1999).
Author: Michael P Holsapple