Effects of Libby amphibole asbestos exposure on two models of arthritis in the Lewis rat

Our plain-English summary of Effects of Libby amphibole asbestos exposure on two models of arthritis in the Lewis rat, by K.D. Salazar, C.B. Copeland, R.W. Luebke (Journal of Toxicology and Environmental Health. Part a, 2012).

The study

• Authors: K.D. Salazar, C.B. Copeland, R.W. Luebke
• Journal: Journal of Toxicology and Environmental Health. Part a
• Published: 2012;75(6):351-65
• Cited by: 14 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Epidemiological data suggest that occupational exposure to the amphibole-containing vermiculite in Libby, MT, was associated with increased risk for developing autoimmune diseases and had an odds ratio of 3.23 for developing rheumatoid arthritis (RA). The collagen-induced arthritis (CIA) and the peptidoglycan-polysaccharide (PG-PS) models of RA were employed to determine whether exposure to Libby amphibole (LA) induced a more rapid onset, increased expression, or prolonged course of RA. Female Lewis rats were intratracheally instilled with total doses of 0.15, 0.5, 1.5, or 5 mg LA or 0.5 or 1.5 mg amosite asbestos, and arthritis was induced with either the PG-PS or CIA model. Neither LA nor amosite exposure affected the disease course in the CIA model, or the production of rheumatoid factor (RF) or anti-cyclic citrullinated peptide (CCP) antibodies. LA exposure reduced swelling in the PG-PS model and decreased anti-PG-PS and total immunoglobulin M (IgM) antibody titers. Both amosite and LA exposure increased the number of rats with circulating anti-nuclear antibodies (ANA), the majority of which presented a speckled staining pattern. However, this ANA enhancement was not dose responsive. These results failed to show a positive correlation between LA exposure and RA disease in two animal models, although upregulated ANA suggest an altered immunological profile consistent with other systemic autoimmune diseases.

In plain English

This U.S. EPA study tested whether Libby amphibole asbestos (LA) would make rheumatoid arthritis start sooner, become more severe, or last longer in female Lewis rats. Rats received LA (total 0.15, 0.5, 1.5 or 5 mg) or amosite (0.5 or 1.5 mg) into the windpipe seven times over 13 weeks. Arthritis was induced with collagen (CIA model) or bacterial cell-wall material (PG-PS model). Both fibers raised markers of lung injury. In the CIA model, neither fiber changed joint swelling or arthritis-related antibodies. In the optimal PG-PS model, 5 mg LA reduced peak second-phase swelling by 3.7%, which the authors judged unlikely to be biologically relevant as an explanation for increased rheumatoid arthritis in Libby; some doses also lowered certain antibodies there. Lower LA doses and amosite increased the share of rats with anti-nuclear antibodies (ANA), which the authors called nonspecific, in PG-PS-treated and adjuvant-only rats but not significantly in collagen-treated rats; this did not rise with dose. The authors concluded that their results failed to show a relationship between LA exposure and rheumatoid arthritis in these two models, noting other models might.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Animal experiment (rats given asbestos into the windpipe, then two laboratory models of rheumatoid arthritis)
• Who was studied: Female Lewis rats, 8–9 weeks old at the start, bought from Charles River Laboratories (Raleigh, NC) and housed at U.S. EPA animal facilities. Each group had eight animals. Experiments were repeated: three times for the CIA model, two for the suboptimal PG-PS model and five for the optimal PG-PS model. The total number of rats is not stated.
• Exposure: Libby amphibole (LA), collected in 2007 from the Rainy Creek Complex near Libby, MT, by the U.S. Geological Survey, or a UICC reference sample of amosite. Fibers were given by intratracheal instillation every two weeks for 13 weeks (7 instillations), at total doses of 0, 0.15, 0.5, 1.5 or 5 mg LA, or 0.5 or 1.5 mg amosite. Arthritis was induced 1 week after the last instillation.
• Main results:
  • Lung injury: LA raised LDH activity and total protein in lung lavage fluid in a dose-dependent way. Amosite also raised both. At 1.5 mg, LA caused a greater increase than amosite.
  • CIA model: no dose of LA or amosite changed the onset of swelling or the size of hind ankle inflammation.
  • CIA model: LA and amosite did not change the levels of the rheumatoid arthritis biomarkers (RF-IgG, RF-IgM, anti-CCP IgG) in collagen-treated or adjuvant-only (IFA) rats.
  • PG-PS model: LA and amosite did not change the acute or chronic swelling phases in the suboptimal or optimal models. The one exception came in the optimal model (Figure 5), where 5 mg LA reduced peak swelling by 3.7% compared with vehicle during the second phase.
  • The authors judged this swelling reduction, although statistically significant, unlikely to be biologically relevant as an explanation for increased rheumatoid arthritis in the Libby population. Their reasons were that it was limited in duration and magnitude, and was the opposite of what would be expected.
  • Optimal PG-PS model: anti-PG-PS antibodies were significantly reduced in rats given 5 mg LA and 1.5 mg amosite (by 45% compared to vehicle, per the discussion). Total IgM was reduced by 1.5 mg and 5 mg LA and by both amosite doses (approximately 20%).
  • ANA in optimal PG-PS rats: 0.15 and 0.5 mg LA and both amosite doses significantly increased the number of high-titer ANA-positive rats. The LA 1.5 mg and 5 mg groups were 50% and 47% ANA positive, against 23% in the vehicle group, which was not significant (p = .1 for both).
  • ANA in adjuvant-only (IFA) rats: 0.15 and 0.5 mg LA and 1.5 mg amosite significantly increased ANA. The LA 1.5 mg and 5 mg groups were 47% and 62.5% positive, not statistically different from 32% in the vehicle group (p = .47 and .16).
  • ANA in collagen-injected (CIA) rats: no fiber treatment significantly changed ANA compared with vehicle. The authors attributed this to increased ANA in the collagen-injected vehicle rats.
  • More than 98% of ANA-positive samples showed a speckled staining pattern. Neither LA nor amosite produced a dose-dependent ANA effect.
  • The authors noted that ANA are considered nonspecific, because many people with ANA do not have any disease.
• The authors' conclusion: The authors concluded that their results failed to show a relationship between rheumatoid arthritis and LA exposure in two animal models, though other models might show a positive association. They also said that the lack of dose-responsive effects prevented a conclusion about the toxicity of LA relative to amosite.
• Limitations the authors state:
  • No animal model of rheumatoid arthritis perfectly mimics the human disease.
  • The negative CIA results could reflect an ineffective dose range, poor timing of arthritis induction relative to asbestos-induced inflammation, or an unsuitable model.
  • The dose range may have been too high to show a dose response for ANA.
  • It is unknown whether the PG-PS or IFA treatments themselves altered ANA production.
  • The biological significance of the reduced anti-PG-PS and total IgM levels could not be determined.

Mines named here

Asbestos mines this study is about. Each mine's page says who ran it, when it worked, and what it produced.

• Libby vermiculite mine, Montana

All asbestos mines

Topics

The National Library of Medicine indexes this study under subjects our site covers: Talc and vermiculite.

Medical terms in this study, explained in our Lexicon: Libby amphiboles, Asbestos Exposure, Occupational Exposure, Amphibole Group, vermiculite, Odds Ratio, Collagen, Amosite.

Related studies

• Evaluation of anti-nuclear antibodies and kidney pathology in Lewis rats following exposure to Libby amphibole asbestos — K.D. Salazar, C.B. Copeland, et al. (2013)
• Pulmonary inflammatory and fibrotic responses in Fischer 344 rats after intratracheal instillation exposure to Libby amphibole — D.J. Padilla-Carlin, M.C. Schladweiler, et al. (2011)
• Vermiculite worker mortality: estimated effects of occupational exposure to Libby amphibole — T.C. Larson, V.C. Antao, et al. (2010)
• Long-term response of rats to single intratracheal exposure of Libby amphibole or amosite — J.M. Cyphert, D.J. Padilla-Carlin, et al. (2012)
• Vascular and thrombogenic effects of pulmonary exposure to Libby amphibole — J.H. Shannahan, M.C. Schladweiler, et al. (2012)
• Mortality in a cohort of vermiculite miners exposed to fibrous amphibole in Libby, Montana — J.C. McDonald, J. Harris, et al. (2004)

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