Comparative long-term toxicity of Libby amphibole and amosite asbestos in rats after single or multiple intratracheal exposures

Our plain-English summary of Comparative long-term toxicity of Libby amphibole and amosite asbestos in rats after single or multiple intratracheal exposures, by J.M. Cyphert, D.J. Carlin, A. Nyska, et al (Journal of Toxicology and Environmental Health. Part a, 2015).

The study

• Authors: J.M. Cyphert, D.J. Carlin, A. Nyska, M.C. Schladweiler, A.D. Ledbetter, J.H. Shannahan, U.P. Kodavanti, S.H. Gavett
• Journal: Journal of Toxicology and Environmental Health. Part a
• Published: 2015;78(3):151-65
• Cited by: 13 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

In former mine workers of Libby, MT, exposure to amphibole-containing vermiculite was linked to increased rates of asbestosis, lung cancer, and mesothelioma. Although many studies showed adverse effects following exposure to Libby amphibole (LA; a mixture of winchite, richterite, and tremolite), little is known regarding the relative toxicity of LA compared to regulated asbestos, or regarding the risks associated with acute high-dose exposures relative to repeated low-dose exposures. In this study, pulmonary function, inflammation, and pathology were assessed after single or multiple intratracheal (IT) exposures of LA or a well-characterized amosite (AM) control fiber with equivalent fiber characteristics. Male F344 rats were exposed to an equivalent total mass dose (0.15, 0.5, 1.5, or 5 mg/rat) of LA or AM administered either as a single IT instillation, or as multiple IT instillations given every other week over a 13-wk period, and necropsied up to 20 mo after the initial IT. When comparing the two fiber types, in both studies LA resulted in greater acute neutrophilic inflammation and cellular toxicity than equal doses of AM, but long-term histopathological changes were approximately equivalent between fibers, suggesting that LA is at least as toxic as AM. In addition, although no dose-response relationship was discerned, mesothelioma or lung carcinomas were found after exposure to low and high dose levels of LA or AM in both studies. Conversely, when comparing studies, an equal mass dose given over multiple exposures instead of a single bolus resulted in greater chronic pathological changes in lung at lower doses, despite the initially weaker acute inflammatory response. Overall, these results suggest that there is a possibility of greater long-term pathological changes with repeated lower LA dose exposures, which more accurately simulates chronic environmental exposures.

In plain English

This animal experiment used 504 male Fischer 344 rats. The authors placed respirable Libby amphibole (winchite, richterite and tremolite) or UICC amosite of similar fiber size into the windpipe. In Study S rats received one dose; in Study M each rat's total dose was split into 7 equal doses given every other week over 13 weeks. Libby amphibole totals were 0.15 to 5 mg per rat in both studies; amosite doses differed, with only 0.5 mg shared. Rats were followed up to 20 months. One day after dosing, Libby amphibole caused significantly more neutrophil inflammation than an equal amosite dose. By 20 months inflammation had subsided. Lung scarring (interstitial fibrosis) was comparable between fibers at equal doses in Study M and, at lower Libby amphibole doses, greater after multiple than single dosing; at 0.5 mg amosite it was equal. Three Libby amphibole rats developed mesothelioma (two benign, one malignant on the pericardium); two amosite rats developed lung tumors. The authors said tumors were too few for inferences about fiber type or dose, and concluded Libby amphibole was at least as toxic as amosite.

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 received asbestos by intratracheal instillation, meaning the material was placed directly into the windpipe. There were two parallel studies: a single-dose study (Study S) and a multiple-dose study (Study M) in which each total dose was given as seven equal instillations.
• Who was studied: 504 healthy male F344 rats aged 6 to 8 weeks, from Charles River Laboratories, Raleigh, NC: 224 in Study M and 280 in Study S. The procedures were approved by the animal care committee of the U.S. EPA National Health and Environmental Effects Research Laboratory. Study dates are not given.
• Exposure: Two fiber samples were compared:
• Libby amphibole (LA), collected in 2007 from the Rainy Creek Complex near Libby, MT, and water-elutriated to a rat-respirable fraction (PM2.5).
• UICC amosite (AM), used as a reference sample with similar fiber length, width and aspect ratio.

Total doses:

• Libby amphibole: 0.15, 0.5, 1.5 or 5 mg per rat in both studies.
• Amosite in Study M: 0.5 or 1.5 mg.
• Amosite in Study S: 0.15 or 0.5 mg.
• Controls: dispersion media only.

In Study M each instillation was one-seventh of the total dose.

• Main results:
  • In both studies, one day after dosing, both fibers caused dose-dependent neutrophil inflammation in lung lavage fluid. This inflammation was significantly greater in Libby amphibole-exposed rats than in rats given an equal dose of amosite.
  • In both studies, at 20 months after first exposure, macrophage and neutrophil levels in all asbestos-exposed groups matched those of controls.
  • In both studies, the macrophage lysosomal marker NAG was significantly raised after high doses of Libby amphibole, and this persisted to 20 months.
  • In Study M, one week after the final dose:
• Rats given the highest Libby amphibole dose (5 mg per rat) had significantly lower body weight.
• Enhanced pause (Penh), a breathing measure often linked to airflow obstruction, rose with dose after Libby amphibole or amosite.
  • At 20 months, interstitial fibrosis at lower Libby amphibole doses was greater after multiple exposures than after a single dose. At higher Libby amphibole doses the response was equal in both studies.
  • At the one amosite dose used in both studies (0.5 mg), the degree of fibrosis was equal after multiple and single exposure.
  • In Study M, interstitial fibrosis was comparable between rats given the same mass dose of Libby amphibole or amosite.
  • After multiple Libby amphibole exposures (Study M), two benign mesotheliomas were found: one on the diaphragm in the 0.15 mg group and one on the parietal pleura in the 5 mg group.
  • After a single 5 mg dose of Libby amphibole (Study S), one rat developed a malignant mesothelioma on the pericardium that had invaded the underlying heart muscle.
  • No mesothelioma was seen after amosite in either study.
  • In Study S, two amosite-exposed rats had bronchiolo-alveolar tumors: a malignant carcinoma in the 0.15 mg group and a benign adenoma in the 0.5 mg group.
  • All 20-month groups had early deaths, ranging from 4 to 12 of 24 rats per group. Survival was not related to dose or asbestos type.
• The authors' conclusion: The authors concluded that Libby amphibole is at least as toxic as amosite. It caused greater short-term inflammation and cellular toxicity, while long-term lung changes were approximately equivalent between the two fibers. They also concluded that repeated lower-dose exposures may produce greater long-term lung changes than a single dose.
• Limitations the authors state:
  • Few tumors occurred, so no significant inferences could be made about fiber type or dose.
  • The Libby amphibole sample had a greater surface area than the amosite sample, which may confound the comparison. Surface chemistry and chemical composition were not assessed.
  • Doses were measured by mass; other dose measures, such as fiber length or surface area, may be more appropriate.
  • Instillation into the windpipe bypasses the nasal passages in an animal that breathes through its nose.
  • Some of the higher minute volumes seen at 20 months in Study S were partly due to unusually low values in the control group.

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: Amosite.

Medical terms in this study, explained in our Lexicon: Libby amphiboles, Amosite, Amphibole Group, vermiculite, Lung Cancer, Mesothelioma, winchite, richterite.

Related studies

• Long-term response of rats to single intratracheal exposure of Libby amphibole or amosite — J.M. Cyphert, D.J. Padilla-Carlin, et al. (2012)
• 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)
• Persistent effects of Libby amphibole and amosite asbestos following subchronic inhalation in rats — S.H. Gavett, C.U. Parkinson, et al. (2016)
• Sumas Mountain chrysotile induces greater lung fibrosis in Fischer344 rats than Libby amphibole, El Dorado tremolite, and Ontario ferroactinolite — J.M. Cyphert, A. Nyska, et al. (2012)
• Long-term toxicity of naturally occurring asbestos in male Fischer 344 rats — J.M. Cyphert, M.A. McGee, et al. (2016)
• Vascular and thrombogenic effects of pulmonary exposure to Libby amphibole — J.H. Shannahan, M.C. Schladweiler, et al. (2012)

Browse more research in Journal of Toxicology and Environmental Health. Part a, or return to medical research.