Long-term toxicity of naturally occurring asbestos in male Fischer 344 rats

Our plain-English summary of Long-term toxicity of naturally occurring asbestos in male Fischer 344 rats, by J.M. Cyphert, M.A. McGee, A. Nyska, et al (Journal of Toxicology and Environmental Health. Part a, 2016).

The study

• Authors: J.M. Cyphert, M.A. McGee, A. Nyska, M.C. Schladweiler, U.P. Kodavanti, S.H. Gavett
• Journal: Journal of Toxicology and Environmental Health. Part a
• Published: 2016;79(2):49-60
• Cited by: 17 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Naturally occurring asbestos (NOA) fibers are found in geologic deposits that may be disturbed by mining, earthworks, or natural processes, resulting in adverse health risks to exposed individuals. The toxicities of Libby amphibole and NOA samples including Sumas Mountain chrysotile (SM), El Dorado tremolite (ED), and Ontario ferroactinolite cleavage fragments (ON) were compared in male Fischer 344 (F344) rats 15 mo after exposure. Rat-respirable fractions of LA and SM displayed greater mean lengths and aspect ratios than ED and ON. After a single intratracheal (IT) instillation (0.5 or 1.5 mg/rat), persistent changes in ventilatory parameters and a significant increase in lung resistance at baseline and after methacholine aerosol dosing were found only in rats exposed to 1.5 mg SM. High-dose ED significantly elevated bronchoalveolar lavage lactate dehydrogenase (LDH) activity and protein levels, while high-dose SM increased γ-glutamyl transferase and LDH activities. A moderate degree of lung interstitial fibrosis after exposure to 1.5 mg SM persisted 15 mo after exposure, unchanged from previous findings at 3 mo. LA induced mild fibrosis, while ED and ON produced minimal and no apparent fibrosis, respectively. Bronchioloalveolar carcinoma was observed 15 mo after exposure to LA or ED. Data demonstrated that SM, given by bolus IT dosing on an equivalent mass basis, induced greater pulmonary function deficits, airway hyperresponsiveness, and interstitial fibrosis than other NOA, although unlike LA and ED, no apparent evidence for carcinogenicity was found. All NOA samples except ON cleavage fragments produced some degree of long-term toxicity.

In plain English

In this animal experiment, male Fischer 344 rats were placed in nine groups of 24. Each of eight groups received one dose, 0.5 or 1.5 mg per rat, of one of four mineral samples placed directly into the windpipe: Libby amphibole, Sumas Mountain chrysotile, El Dorado tremolite, or Ontario ferroactinolite cleavage fragments. A ninth, control group received only the liquid the fibers were suspended in. The rats were examined 15 months later. Only the 1.5 mg Sumas Mountain chrysotile group showed lasting breathing changes and significantly raised lung resistance. Sumas Mountain chrysotile caused the most lung scarring (interstitial fibrosis), graded moderate at the high dose. Libby amphibole and El Dorado tremolite caused less, and the Ontario fragments caused no apparent fibrosis. One lung cancer (bronchioloalveolar carcinoma) was found after 0.5 mg Libby amphibole, and it had spread. One more was found after 0.5 mg El Dorado tremolite. None were found in the control, chrysotile or Ontario groups. The authors concluded that all samples except the Ontario cleavage fragments showed some degree of long-term toxicity. They noted that windpipe delivery bypasses the nose and gives a high dose rate.

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: single intratracheal instillation in rats, followed up for 15 months
• Who was studied: Male Fischer 344 rats, 6 to 8 weeks old, 24 per group in 9 groups: a control group given dispersion medium, and two dose groups for each of four mineral samples
• Exposure: Rat-respirable fractions of four rock samples: Libby amphibole, Ontario ferroactinolite (cleavage fragments), Sumas Mountain chrysotile and El Dorado tremolite. Each was given once by intratracheal instillation at 0.5 or 1.5 mg per rat. The control group received dispersion medium only (0 mg per rat).
• Main results:
  • Minute volume (air breathed per minute) was significantly increased in the 1.5 mg Sumas Mountain chrysotile group compared with controls at 1 week. The authors report this persisted at 3, 9 and 15 months. No other high-dose sample produced significant changes in minute volume.
  • At 15 months, rats given 1.5 mg Sumas Mountain chrysotile had significantly higher lung resistance than controls, both at baseline and after every methacholine dose (8 rats per group). The other groups showed no marked change.
  • In lung wash fluid at 15 months, GGT and LDH activity (markers of membrane damage and cytotoxicity) were significantly elevated in the 1.5 mg Sumas Mountain chrysotile group.
  • In the 1.5 mg El Dorado tremolite group, albumin, total protein and LDH in lung wash fluid were significantly increased compared with controls at 15 months.
  • Sumas Mountain chrysotile produced the greatest interstitial lung fibrosis at both doses. At the high dose it was graded moderate (grade 3), and all 24 high-dose rats had fibrosis. At the high dose, Libby amphibole averaged grade 2 and El Dorado tremolite grade 1. The Ontario cleavage fragments produced no apparent fibrosis.
  • One bronchioloalveolar carcinoma was found in the 0.5 mg Libby amphibole group (1 of 24 rats). It had spread to the pericardium, diaphragm and thymus.
  • One bronchioloalveolar carcinoma, without spread, was found in the 0.5 mg El Dorado tremolite group (1 of 24 rats).
  • No lung tumors were found in the control, Sumas Mountain chrysotile or Ontario groups.
  • No changes were found in the parietal pleura of the ribs with any sample. Two cases of minimal focal fibrosis of the diaphragm were seen in the 1.5 mg Libby amphibole group, and diaphragm fibrosis was also seen in single El Dorado tremolite rats.
  • Between 0 and 4 of 24 rats per group died before 15 months. Survival time showed no relationship to dose or asbestos type.
• The authors' conclusion: The authors concluded that all the naturally occurring asbestos samples except the Ontario ferroactinolite cleavage fragments showed some degree of chronic toxicity in this rat model.
• Limitations the authors state:
  • Intratracheal dosing bypasses the nose and delivers material to the lung at a high dose rate, which may distribute it unevenly and alter normal responses.
  • The authors could not rule out that clumped fibers caused focal inflammation and granulomas.
  • Pleural and diaphragm changes may need more time after exposure than 15 months to develop.
  • The processing used to make the El Dorado sample respirable for rats likely removed large or long fibers, so it differed from field samples analyzed by the USGS.
  • There was no clear dose-response relationship for the carcinoma seen after Libby amphibole.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Actinolite, Chrysotile, Tremolite.

Medical terms in this study, explained in our Lexicon: naturally occurring asbestos (NOA), Libby amphiboles, Chrysotile, Tremolite, Ferro-actinolite, Cleavage Fragment, Respirable Fraction, Aspect Ratio (Length-to-diameter ratio).

Related studies

• 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)
• Early and delayed effects of naturally occurring asbestos on serum biomarkers of inflammation and metabolism — U.P. Kodavanti, D. Andrews, et al. (2014)
• 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)
• Long-term response of rats to single intratracheal exposure of Libby amphibole or amosite — J.M. Cyphert, D.J. Padilla-Carlin, et al. (2012)
• Carcinogenic effect of potassium octatitanate (POT) fibers in the lung and pleura of male Fischer 344 rats after intrapulmonary administration — M. Abdelgied, A.M. El-Gazzar, et al. (2019)
• Pulmonary and pleural toxicity of potassium octatitanate fibers, rutile titanium dioxide nanoparticles, and MWCNT-7 in male Fischer 344 rats — M. Abdelgied, A.M. El-Gazzar, et al. (2019)

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