The importance of fiber biopersistence and lung dose in determining the chronic inhalation effects of X607, RCF1, and chrysotile asbestos in rats

Our plain-English summary of The importance of fiber biopersistence and lung dose in determining the chronic inhalation effects of X607, RCF1, and chrysotile asbestos in rats, by T.W. Hesterberg, G.A. Hart, J. Chevalier, et al (Toxicology and Applied Pharmacology, 1998).

The study

• Authors: T.W. Hesterberg, G.A. Hart, J. Chevalier, W.C. Miiller, R.D. Hamilton, J. Bauer, P. Thevenaz
• Journal: Toxicology and Applied Pharmacology
• Published: 1998;153(1):68-82
• Cited by: 49 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

The chronic inhalation effects in rats of X607 (a rapidly dissolving synthetic vitreous fiber) were compared with those previously reported for RCF1 (a refractory ceramic synthetic vitreous fiber) and chrysotile asbestos. Of primary concern was the importance of biopersistence as a mechanism of fiber toxicity. Fischer rats were exposed to fiber aerosol by nose-only inhalation for 6 h/day, 5 days/week for 2 years. X607 and RCF1 aerosols were similar in concentration (approximately 200 fibers/cc) and average dimensions (approximately 20 x 1 microns). Chrysotile aerosol was higher in concentration (10,600 fibers/cc) and an order of magnitude smaller in average dimensions. Lung fiber deposition after 6 h inhalation was greater for X607 than for RCF1. However, at later time points, fibers/lung (especially long fibers) were much lower for X607 than for RCF1, suggesting less biopersistence for X607. X607 was neither fibrogenic nor tumorigenic and induced only minimal lung cellularity that reversed after exposure was terminated. In contrast, RCF1 and chrysotile asbestos induced pulmonary fibrosis and thoracic neoplasms (chrysotile induced 32% more pulmonary neoplasms than RCF1). Lung deposition and fiber lengths did not explain the toxicologic differences between the three fibers. Fiber biodurability, including chemical and physical parameters, appears to be a major toxicologic determinant here. Chemical analysis of lung fibers revealed rapid leaching of X607 compared to RCF1. In in vitro dissolution tests, X607 underwent rapid dissolution (kdis = 990 ng/cm2/h) and transverse fragmentation, RCF1 dissolved slowly (kdis = 6 ng/cm2/h) and did not fragment, and chrysotile dissolution was negligible (< 0.1 ng/cm2/h).

In plain English

This was an animal experiment in male Fischer 344 rats. The rats breathed, nose-only, X607 (a fast-dissolving synthetic vitreous fiber), RCF1 (a refractory ceramic fiber), chrysotile asbestos, or filtered air. Exposure ran 6 hours a day, 5 days a week, for up to 2 years, and some rats were then kept unexposed for periods of 23 to 91 weeks. The authors reported new results for X607 and compared them with earlier reports on RCF1 and chrysotile. X607 caused only mild cell changes and no fibrosis, and tumor rates in X607 rats were comparable to air controls. RCF1 and chrysotile caused fibrosis and chest tumors. Among rats that survived at least 12 months (118 RCF1 and 69 chrysotile rats), lung adenomas and carcinomas occurred in 12.4% (RCF1) and 17.4% (chrysotile), and pleural mesotheliomas in 1.7% and 1.4%. Far fewer long X607 fibers than RCF1 fibers stayed in the lungs. In laboratory fluid, X607 dissolved quickly and broke apart, RCF1 dissolved slowly, and chrysotile barely dissolved. The authors concluded that a high lung dose over time, from heavy loading and long-lasting fibers, appeared to drive disease.

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 2-year chronic nose-only inhalation study in rats, with post-exposure recovery groups, plus a 6-hour lung deposition study and an in vitro fiber dissolution study. New data were reported for X607. The RCF1 and chrysotile pathology was summarized from an earlier report (Mast et al., 1995b). The chrysotile dissolution rate was based on data reported by Law et al. (1990).
• Who was studied: Male Fischer 344 rats from Charles River (Raleigh, NC). Initial group sizes were 140 rats each for filtered air, X607 and RCF1, and 80 rats for chrysotile. Animals at risk for tumors (surviving at least 12 months) numbered 130 (air), 121 (X607), 118 (RCF1) and 69 (chrysotile). A separate 6-hour deposition study used rats exposed to X607 or RCF1. Study dates are not given.
• Exposure: Nose-only inhalation for 6 hours a day, 5 days a week, for 104 weeks, followed by a 23-week exposure-free recovery period. Interim recovery rats from the X607 and RCF1 groups only stopped exposure at 13, 26, 52 or 78 weeks and were kept without further treatment until week 104. X607 is a high-silica synthetic vitreous fiber developed by Johns Manville Corporation. The target concentration for X607 and RCF1 was 30 mg/m3, with measured averages of 174 (X607) and 187 (RCF1) WHO fibers/ml. The chrysotile was intermediate-length NIEHS chrysotile from the Jeffrey Mine, Quebec, at a target of 10 mg/m3. It averaged 10,600 WHO fibers/ml, with no fibers longer than 20 micrometers in the aerosol.
• Main results:
  • Among animals at risk for tumors (those surviving at least 12 months), pulmonary adenomas and carcinomas occurred in 12.4% of RCF1-exposed rats and 17.4% of chrysotile-exposed rats. Pleural mesotheliomas occurred in 1.7% of RCF1-exposed rats and 1.4% of chrysotile-exposed rats. The at-risk groups were 118 RCF1 rats and 69 chrysotile rats.
  • The tumor percentages are based on animals at risk, defined as those surviving until at least the 12-month time point.
  • The incidences of adenomas, carcinomas and mesotheliomas were significantly elevated in RCF1- and chrysotile-exposed rats compared with air controls.
  • X607 did not induce fibrosis or neoplasms, and no mesotheliomas were seen in X607-exposed rats. The neoplastic lesions that did occur in X607 rats appeared late in life, at incidences comparable to air controls.
  • After 104 weeks of exposure, the mean Wagner lung grade was 2.8 for X607 and 4.0 for both RCF1 and chrysotile. On this scale, 3 means cellularity and 4 means irreversible fibrosis.
  • From 13 weeks on, lung weights in RCF1- and chrysotile-exposed rats were significantly elevated, by as much as 60% over air-control and X607-exposed rats. Chrysotile-exposed rats had significantly lower survival at several time points in the second half of the study.
  • After 6 hours of inhalation, the number of WHO fibers per mg of dry lung was about 2.6-fold greater for X607 than for RCF1.
  • After 104 weeks of exposure plus 23 weeks of recovery, long fibers (longer than 20 micrometers) per lung numbered 0.1 million for X607 and 6.7 million for RCF1. No chrysotile fibers that long were found in the lung.
  • After 104 weeks of exposure plus 23 weeks of recovery, the share of WHO fibers retained was 26% for X607, 43% for RCF1 and 14% for chrysotile. In absolute numbers, retained WHO fibers per lung were 15 million for X607, 61 million for RCF1 and 216 million for chrysotile.
  • In simulated lung fluid, the dissolution rate constant was 990 ng per cm2 per hour for X607 and 6 for RCF1. X607 fragmented after 500 hours, while RCF1 did not fragment over 700 hours.
  • The chrysotile dissolution rate constant was 0.08 ng per cm2 per hour, calculated from silica dissolution data reported by Law et al. (1990).
• The authors' conclusion: The authors concluded that the data suggest fiber-induced lung disease arises from a high lung dose over time, resulting from high lung loading and prolonged biopersistence of fibers. They added that the data do not rule out other mechanisms, such as the bioreactivity of fiber surface chemistry. They also said that toxic potential cannot be predicted solely from the dimensions of fibers retained in the lung.
• Limitations the authors state:
  • No X607 lung fiber burden data were available for the 13- and 26-week time points, because the samples were stored in Formalin, which apparently dissolved the fibers.
  • X607 aerosol fiber and particle counts may have been slightly reduced because the counting samples were stored in aqueous solution for about a week before processing.
  • With the limited data, the rate of calcium loss from X607 in the lung could not be accurately determined.
  • The lung effects, if any, of the greater number of non-fibrous particles in RCF1 compared with X607 could not be determined.
  • Lung deposition after 6 hours of inhalation was not determined for chrysotile.
  • The data do not rule out that other mechanisms are involved in disease caused by some fiber types.

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

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

Medical terms in this study, explained in our Lexicon: biopersistence, Chrysotile, Vitreous, Deposition, Fibrogenic, Pulmonary Fibrosis, Neoplasm, Fiber Length.

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