Persistent effects of Libby amphibole and amosite asbestos following subchronic inhalation in rats

Our plain-English summary of Persistent effects of Libby amphibole and amosite asbestos following subchronic inhalation in rats, by S.H. Gavett, C.U. Parkinson, G.A. Willson, et al (Particle and Fibre Toxicology, 2016).

The study

• Authors: S.H. Gavett, C.U. Parkinson, G.A. Willson, C.E. Wood, A.M. Jarabek, K.C. Roberts, U.P. Kodavanti, D.E. Dodd
• Journal: Particle and Fibre Toxicology
• Published: 2016;13:17
• Cited by: 9 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Human exposure to Libby amphibole (LA) asbestos increases risk of lung cancer, mesothelioma, and non-malignant respiratory disease. This study evaluated potency and time-course effects of LA and positive control amosite (AM) asbestos fibers in male F344 rats following nose-only inhalation exposure.

Methods: Rats were exposed to air, LA (0.5, 3.5, or 25.0 mg/m(3) targets), or AM (3.5 mg/m(3) target) for 10 days and assessed for markers of lung inflammation, injury, and cell proliferation. Short-term results guided concentration levels for a stop-exposure study in which rats were exposed to air, LA (1.0, 3.3, or 10.0 mg/m(3)), or AM (3.3 mg/m(3)) 6 h/day, 5 days/week for 13 weeks, and assessed 1 day, 1, 3, and 18 months post-exposure. Fibers were relatively short; for 10 mg/m(3) LA, mean length of all structures was 3.7 μm and 1% were longer than 20 μm.

Results: Ten days exposure to 25.0 mg/m(3) LA resulted in significantly increased lung inflammation, fibrosis, bronchiolar epithelial cell proliferation and hyperplasia, and inflammatory cytokine gene expression compared to air. Exposure to 3.5 mg/m(3) LA resulted in modestly higher markers of acute lung injury and inflammation compared to AM. Following 13 weeks exposure, lung fiber burdens correlated with exposure mass concentrations, declining gradually over 18 months. LA (3.3 and 10.0 mg/m(3)) and AM produced significantly higher bronchoalveolar lavage markers of inflammation and lung tissue cytokines, Akt, and MAPK/ERK pathway components compared to air control from 1 day to 3 months post-exposure. Histopathology showed alveolar inflammation and interstitial fibrosis in all fiber-exposed groups up to 18 months post-exposure. Positive dose trends for incidence of alveolar epithelial hyperplasia and bronchiolar/alveolar adenoma or carcinoma were observed among LA groups.

Conclusions: Inhalation of relatively short LA fibers produced inflammatory, fibrogenic, and tumorigenic effects in rats which replicate essential attributes of asbestos-related disease in exposed humans. Fiber burden, inflammation, and activation of growth factor pathways may persist and contribute to lung tumorigenesis long after initial LA exposure. Fiber burden data are being used to develop a dosimetry model for LA fibers, which may provide insights on mode of action for hazard assessment.

In plain English

This animal experiment exposed male F344 rats to clean air, Libby amphibole (LA) asbestos from near Libby, Montana, or amosite asbestos. A 10-day study set the doses for a 13-week study (LA 1.0, 3.3 or 10.0 mg/m3; amosite 3.3 mg/m3), with follow-up up to 18 months. After 10 days, LA produced more lung injury markers than the same mass of amosite. After 13 weeks, effects were comparable at the same mass concentration (3.3 mg/m3). Fibers cleared slowly from the lungs. Eighteen months after exposure, all fiber-exposed groups showed lung inflammation and fibrosis, including pleural and subpleural fibrosis. Lung tumors (bronchiolar/alveolar adenomas or carcinomas) occurred in 2 amosite rats, 2 rats at 3.3 mg/m3 LA (4 % each), 4 at 10.0 mg/m3 LA (8 %) and no air-control rats. Group-by-group differences were not statistically significant, but the trend with LA dose was. No pleural mesotheliomas were seen. The authors concluded that lasting inflammation from relatively short LA fibers may contribute to lung tumors long after exposure. They noted that only the left lung was examined microscopically, sampling less tissue than protocols examining both lungs.

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: a 10-day (2-week) range-finding nose-only inhalation study, followed by a 13-week stop-exposure inhalation study with follow-up up to 18 months after exposure
• Who was studied: Male F344 rats. In the 10-day study there were 7 per group. In the 13-week study there were 8 per group at 1 day, 1 month and 3 months after exposure, and 50 per group at 18 months after exposure, plus extra rats used for fiber-burden measurements.
• Exposure: Libby amphibole (LA) collected from the Rainy Creek Complex near Libby, Montana, in 2007, and UICC amosite (AM) as a reference fiber. In the 13-week study, rats were exposed nose-only for 6 h/day, 5 days/week to filtered air, LA at 1.0, 3.3 or 10.0 mg/m3, or AM at 3.3 mg/m3. In the 10-day study the targets were LA 0.5, 3.5 or 25.0 mg/m3 and AM 3.5 mg/m3. The fibers were relatively short: very long fibers (20 micrometers or more) were about 1 % or less of all structures.
• Main results:
  • After 10 days of exposure, neutrophils as a share of lung-wash cells were significantly higher than in air controls in the 3.5 mg/m3 LA group (10 %) and the 25.0 mg/m3 LA group (47 %), but not in the 3.5 mg/m3 AM group (7 %).
  • In the 10-day study, LA showed greater lung toxicity than AM at the same mass concentration. In the 13-week study, LA's potency was comparable to that of AM on a mass basis.
  • After the 13-week exposure, lung fiber counts declined slowly. They were significantly greater in the 10.0 mg/m3 LA group than in all other groups at every time point.
  • Neutrophil and lung-injury responses in lung-wash fluid had abated by 18 months after exposure.
  • At 18 months after the 13-week exposure, all fiber-exposed groups (AM and all LA groups) showed alveolar inflammation and interstitial, pleural and subpleural fibrosis.
  • Alveolar epithelial hyperplasia at 18 months showed a positive dose trend among the LA groups (P = 0.0099).
  • Bronchiolar/alveolar tumors (adenoma and carcinoma) occurred in 8 rats: 2 in the AM group and 2 in the 3.3 mg/m3 LA group (4 % incidence each), and 4 in the 10.0 mg/m3 LA group (8 % incidence). None occurred in the air control or 1.0 mg/m3 LA groups.
  • Pairwise differences in lung adenoma and/or carcinoma incidence between groups were not statistically significant (unadjusted P = 0.058). The trend in combined tumor incidence across LA groups was statistically significant (P = 0.0064 for all 18-month animals with pathology data).
  • Tumor incidence in the AM and 3.3 mg/m3 LA groups (4 %) was similar to historical control estimates in aged male F344 rats.
  • No pleural mesotheliomas were observed in any group.
  • Exposure did not significantly affect early deaths before the scheduled necropsy, which ranged from 9 to 19 rats per group of 50.
• The authors' conclusion: The authors concluded that inhaling relatively short LA fibers produced persistent inflammatory and fibrotic responses in rats. In their view these responses may drive proliferative effects and contribute to lung tumor formation long after exposure ends.
• Limitations the authors state:
  • Only the left lung was examined under the microscope (histopathology), which gives lower sampling intensity than protocols that examine both left and right lungs.
  • Historical control tumor rates vary by institution and sectioning protocol, so comparisons with them should be treated with caution.
  • The authors cautioned against ranking the relative toxicity of the fiber types until dose-response relationships are explored further.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Amosite, Lung cancer.

Medical terms in this study, explained in our Lexicon: Libby amphiboles, Amosite, Lung Cancer, Mesothelioma, Inflammation, Fibrosis, Cytokine, Fiber Burden.

Related studies

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• Long-term response of rats to single intratracheal exposure of Libby amphibole or amosite — J.M. Cyphert, D.J. Padilla-Carlin, et al. (2012)
• Comparative long-term toxicity of Libby amphibole and amosite asbestos in rats after single or multiple intratracheal exposures — J.M. Cyphert, D.J. Carlin, et al. (2015)
• Studies on the inhalation toxicology of two fiberglasses and amosite asbestos in the syrian golden hamster. Part I. Results of a subchronic study and dose selection for a chronic study — T.W. Hesterberg, C. Axten, et al. (1999)
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• Quantification of the pathological response and fate in the lung and pleura of chrysotile in combination with fine particles compared to amosite-asbestos following short-term inhalation exposure — D.M. Bernstein, R.A. Rogers, et al. (2011)

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