Nested Case-Control Study of Autoimmune Disease in an Asbestos-Exposed Population

An association between occupational exposures of inhaled particulates and autoimmunity was postulated as early as 1914, when Bramwell (1914) reported increased frequency of diffuse scleroderma (SSc) in stone masons. Although genetic factors undoubtedly exist that affect the development of systemic autoimmune diseases (SAIDs) in certain individuals, the concordance of SAIDs among identical twins is only 25–40%, suggesting that environmental factors play a substantial role (Powell et al. 1999). Indeed, several environmental agents are implicated in triggering or accelerating SAIDs, including mercury, iodine, vinyl chloride, certain pharmaceuticals, and crystalline silica. However, much more research is needed to determine the mechanisms and epidemiology linking exposures to development of SAIDs. There is considerable epidemiologic evidence supporting the hypothesis that occupational silica exposure is associated with a variety of SAIDs, including SSc, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), glomerulonephritis, and small vessel vasculitis (Koeger et al. 1995; Parks et al. 1999, 2002; Powell et al. 1999; Steenland and Goldsmith 1995). Research regarding asbestos exposure and SAIDs has been much more limited. Asbestos-related lung disease continues to be a serious and significant problem worldwide despite increasing awareness of health hazards of asbestos inhalation. Asbestos exposure is associated with various lung conditions, including fibrosis, pleural plaques, and cancer. Although the exact mechanisms leading to the progression of these conditions have not been fully explained, there is evidence that some of the lung abnormalities seen with both asbestos and silica exposures are immunologically mediated (Hamilton et al. 1996; Holian et al. 1997; Perkins et al. 1993). Nevertheless, it is unclear how these innate immune responses might translate to specific humoral responses. Increased serum immunoglobulins (Ig), positive antinuclear antibody (ANA) tests, and immune complexes have been reported in small cohorts of individuals exposed to asbestos (Lange 1980; Nigam et al. 1993; Pfau et al. 2005; Zerva et al. 1989), but no comprehensive study has been undertaken to assess the association between asbestos exposure and autoimmune disease. Our major objective, therefore, is to establish whether such an association exists, and the community of Libby, Montana, provides a unique opportunity to investigate this question. Individuals in this population experienced significant exposures that occurred as a result of asbestos-contaminated vermiculite mining near the community. From the early 1920s to 1990, the world’s largest vermiculite deposits, located near Libby, were mined and processed. Vermiculite is a silicate mineral with unique properties and numerous commercial applications (Lockey 1984). The fibrous minerals contaminating Libby vermiculite have been characterized as both regulated asbestos fibers (e.g., tremolite and other amphibole forms) and unregulated fibers (e.g., winchite and richterite) (Meeker et al. 2003). The various mining, transportation, and processing activities as well as the personal and commercial use of vermiculite in the community have led to widespread environmental exposures in the Libby area with this asbestos-contaminated vermiculite. Potential asbestos exposures in this community have been documented not only in the miners but also in their family members as well as anyone who used the vermiculite or played near the mine tailings (Dixon et al. 1985). A mortality study in this community found more than 40-fold increases in standardized mortality ratios for asbestosis, and elevated mortality also was observed for malignant neoplasm of respiratory and intrathoracic organs (Horton et al., in press). Recently, the Agency for Toxic Substances and Disease Registry (ATSDR) conducted an extensive screening program of > 7,300 individuals from this community (Peipins et al. 2003). The initial results of this screening program identified various routes of exposure in the community and how those routes of exposure were associated with abnormalities on chest radiographs (Peipins et al. 2003). In addition, when the ATSDR performed its screening in Libby during 2000–2001, 494 (6.7%) participants indicated that they had been diagnosed with SLE, SSc, or RA (Noonan et al. 2005). By comparison, a prevalence of < 1% for these three conditions combined would be expected based on pooled estimates from 43 prevalence studies (Jacobson et al. 1997). In the present study, we take these data a step further by exploring the association of these systemic autoimmune conditions with various parameters of asbestos and/or vermiculite exposure using a nested case–control approach.