Studies on the chronic toxicity (inhalation) of four types of refractory ceramic fiber in male Fischer 344 rats

Our plain-English summary of Studies on the chronic toxicity (inhalation) of four types of refractory ceramic fiber in male Fischer 344 rats, by R.W. Mast, E.E. McConnell, R. Anderson, et al (Inhalation Toxicology, 1995).

The study

• Authors: R.W. Mast, E.E. McConnell, R. Anderson, J. Chevalier, P. Kotin, D.M. Bernstein, P. Thevenaz, L.R. Glass, W.C. Miiller, T.W. Hesterberg
• Journal: Inhalation Toxicology
• Published: 1995;7(4):425-67
• Cited by: 89 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Abstract Refractory ceramic fibers (RCF) are man-made vitreous fibers used primarily in industrial high-temperature applications, especially for insulation of furnaces and kilns. Because of their increasing use and potential for human exposure, a chronic toxicity/carcinogenicity inhalation study was conducted in Fischer 344 (F344) rats. Five groups of 140 weanling male F344 rats were exposed via noseonly inhalation to either HEPA-filtered air (chamber controls) or 30 mg/m(3) (approximately 220 fibers/cm(3)) of three types [kaolin-based, high-purity, and aluminum zirconia silica (AZS)] of "size-selected" RCF fibers (approximately 1µ in diameter and approximately 20 um in length) and an "after-service" heat-treated (2400°F for 24 h) kaolin-based fiber for 6 h/day, 5 days/wk for 24 mo. They were then held unexposed until approximately 20% survival and then sacrificed at 30 mo. A positive control group of 80 F344 rats was exposed to 10 mg/m(3) chrysotile asbestos. Croups of 3-6 animals were sacrificed at 3, 6, 9, 12, 15, 18, and 24 mo to follow the progression of lesions and to determine fiber lung burdens. Additional groups of 3 rats were removed from exposure at 3, 6, 9, 12, and 18 mo and were held until sacrificed at 24 mo (recovery groups) for similar determinations. Lung burdens increased rapidly for all RCFs, appearing to plateau by about 12 mo. By 24 mo, lung burdens ranged from 2.6 to 9.6 × 10(5) fiberslmg of dry lung tissue for the RCFs tested. Treatment-related lesions were restricted to the lungs. To some extent all types of RCF resulted in macrophage infiltration, bronchiolization of proximal alveoli, and microgranuloma formation by 3 mo of exposure. Interstitial fibrosis was observed at 6 mo for all types of RCF, except the "after-service" fiber where fibrosis was not seen until 12 mo. The lesions progressed in severity until 12-15 mo, after which they plateaued. A minimal amount of focal pleural fibrosis was first observed at 9 mo and progressed to a mild severity by the end of the study. Fxposure-related pulmonary neoplasms (bronchoalveolar adenomas and carcinomas combined) were observed with all 4 types of RCF [kaolin, 16 of 123 (13%); AZS, 9 of 121 (7.4%); high-purity, 19 of 121 (15.7%); and "after-service,"4 of 118 (3.4%)], compared to 2 of 120 (1.5%) in the untreated air controls. Pleural mesotheliomas were observed in two kaolin, three AZS, two high-purity, and one "after-service" exposed rats. A comparable but slightly greater amount of fibrosis was observed in the lungs of the positive (chrysotile asbestos) controls. The incidence of bronchoalveolar neoplasms in the chrysotile exposed rats was 13 of 69 (18.8%), and a mesothelioma occurred in 1 (1.4%) animal. The results of this study showed that the four types of RCF studied had carcinogenic activity in rats at the maximum tolerated dose.

In plain English

Groups of 140 male Fischer 344 rats breathed filtered air or 30 mg/m3 of one of four refractory ceramic fibers (RCF). These were kaolin-based, aluminum zirconia silica (AZS), high-purity, and a heat-treated "after-service" kaolin fiber. Another 80 rats breathed 10 mg/m3 chrysotile asbestos. Exposure lasted 24 months; small groups were killed at set intervals, and surviving rats were held unexposed until final sacrifice at about 30 months. Lung tumors (benign and malignant combined) occurred in 16 of 123 kaolin, 9 of 121 AZS, 19 of 121 high-purity and 4 of 118 after-service rats. Air controls had 2 tumors (1.5%; denominator 120 in the abstract, 130 in Table 8), and chrysotile rats had 13 of 69. The increase was statistically significant in every fiber group except after-service. Mesotheliomas occurred in 2, 3, 2 and 1 RCF-group rats and 1 chrysotile rat. All RCF types produced lung fibrosis; mortality was unaffected. The authors concluded that the four RCF types had carcinogenic activity in rats at the maximum tolerated dose. They noted the exposure was 400-600 times typical RCF manufacturing levels.

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: Chronic (lifetime) inhalation experiment in rats. Exposure was nose-only for 24 months, followed by unexposed observation until about 20% survival (30 months), with interim and recovery-group sacrifices.
• Who was studied: Weanling male Fischer 344 rats from Charles River Laboratories, Kingston, NY: 140 in each of four RCF groups and in a filtered-air control group, plus 80 in a chrysotile asbestos positive-control group
• Exposure: Rats breathed 30 mg/m3 (approximately 200-260 fibers/cm3) of size-selected RCF, about 1 micrometer in diameter and about 20 micrometers long. The fibers were kaolin (RCF 1), aluminum zirconia silica (RCF 2), high-purity (RCF 3), and 'after-service' RCF 4 (kaolin fiber heated at 2400°F for 24 h, containing about 27% cristobalite). The positive control was 10 mg/m3 chrysotile asbestos. Exposure was 6 h/day, 5 days/wk for 24 months.
• Main results:
  • Lung tumors (bronchoalveolar adenomas and carcinomas combined): kaolin, 16 of 123 (13%); AZS, 9 of 121 (7.4%); high-purity, 19 of 121 (15.7%)
  • Lung tumors (combined) in the after-service group: 4 of 118 (3.4%). In the air controls there were 2 (1.5%). The abstract gives the control denominator as 120, while Table 8 lists 130 animals at risk.
  • The increase in total lung tumors compared with control was statistically significant in all fiber-exposed groups except RCF 4 (after-service). The authors stated that the RCF 4 rate was within reported background rates for F344 rats.
  • Chrysotile asbestos group: bronchoalveolar neoplasms in 13 of 69 (18.8%), and mesothelioma in 1 (1.4%) rat
  • Pleural mesotheliomas occurred in two kaolin, three AZS, two high-purity and one after-service rat. The authors also noted an occasional mesothelioma in the abdominal cavity near the epididymis.
  • All mesotheliomas occurred between 24 months and the end of the study at 30 months
  • Interstitial lung fibrosis appeared at 6 months for all RCF types except the after-service fiber, which first showed fibrosis at 12 months. Lesions plateaued after 12-15 months.
  • Focal pleural fibrosis was first seen at 9 months and reached mild severity by the end of the study
  • The chrysotile-exposed rats had comparable but slightly greater lung fibrosis than the RCF groups
  • Silicotic-like nodules were found only in the after-service (RCF 4) group, at all time points except 3 months
  • After 24 months of exposure, total lung fiber burden was 3.70, 9.58, 2.57 and 5.95 × 10^5 fibers per mg dry lung tissue for RCF 1, 2, 3 and 4 respectively
  • In rats exposed for 3 or 6 months and then held 18 or 21 months without exposure, roughly 80% of lung fiber was cleared
  • Mortality was not affected by RCF or chrysotile exposure
• The authors' conclusion: The authors concluded that the four types of RCF studied had carcinogenic activity in rats at the maximum tolerated dose
• Limitations the authors state:
  • The exposure concentration was 400-600 times higher than levels typically seen in RCF manufacturing facilities
  • The size-separated test fibers represent a very small fraction of commercial product. The authors said relevance to humans must be weighed against much lower workplace exposures.
  • A high incidence (more than 75%) of mononuclear cell leukemia confounded evaluation of subtle lung changes. The authors said it did not cause a major problem in diagnosing lung tumors.
  • The grading system used does not take pleural lesions into account
  • Studies at lower doses would be needed to understand the dose-response relationship and whether a no-effect level exists

Mines named here

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

• Jeffrey mine, Asbestos, Quebec

All asbestos mines

Topics

Medical terms in this study, explained in our Lexicon: Vitreous, Chrysotile, Macrophage, Alveoli, Interstitial Fibrosis, Fibrosis, Neoplasm, Carcinoma.

Related studies

• Chronic inhalation toxicity of size-separated glass fibers in Fischer 344 rats — T.W. Hesterberg, W.C. Miiller, et al. (1993)
• Relationship between lung biopersistence and biological effects of man-made vitreous fibers after chronic inhalation in rats — T.W. Hesterberg, W.C. Miiller, et al. (1994)
• 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)
• Pulmonary and pleural leukocytes from F344 rats produce elevated levels of fibronectin following inhalation of refractory ceramic fibers — T.R. Gelzleichter, J.B. Mangum, et al. (1996)
• The importance of fiber biopersistence and lung dose in determining the chronic inhalation effects of X607, RCF1, and chrysotile asbestos in rats — T.W. Hesterberg, G.A. Hart, et al. (1998)
• Long-term toxicity of naturally occurring asbestos in male Fischer 344 rats — J.M. Cyphert, M.A. McGee, et al. (2016)

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