Evaluation of the dose-response and fate in the lung and pleura of chrysotile-containing brake dust compared to chrysotile or crocidolite asbestos in a 28-day quantitative inhalation toxicology study

Our plain-English summary of Evaluation of the dose-response and fate in the lung and pleura of chrysotile-containing brake dust compared to chrysotile or crocidolite asbestos in a 28-day quantitative inhalation toxicology study, by D.M. Bernstein, B. Toth, R.A. Rogers, et al (Toxicology and Applied Pharmacology, 2018).

The study

• Authors: D.M. Bernstein, B. Toth, R.A. Rogers, R. Sepulveda, P. Kunzendorf, J.I. Phillips, H. Ernst
• Journal: Toxicology and Applied Pharmacology
• Published: 2018;351:74-92
• Cited by: 12 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

This study provides an understanding of the biokinetics and potential toxicology in the lung and pleura following inhalation of brake-dust (brakes manufactured with chrysotile). The design included a 28-day repeated multi-dose inhalation exposure (6 h/d, 5 d/wk, 4 wks) followed by 28-days without exposure. Fiber control groups included a similar grade chrysotile as used in the brakes and a commercial crocidolite asbestos. Aerosol fiber distributions of the chrysotile and crocidolite were similar (fiber-length > 20 μm/cm3: Chrysotile-low/high 42/62; Crocidolite-low/high 36/55; WHO-fibers/cm3: Chrysotile-low/high 192/219; Crocidolite-low/high 211/255). The total number of aerosol particles/cm3 in the brake-dust was similar to that in the chrysotile (Brake-dust 710-1065; Chrysotile 532-1442). Brake-dust at particle exposure levels equal to or greater than chrysotile or crocidolite caused no indication of microgranulomas, epithelial hyperplasia, or fibrosis (Wagner score < 1.7) or changes in bronchoalveolar lavage (BAL) indices from the air control. Chrysotile BAL indices did not differ from the air control. Pathologically, there was low level of inflammation and epithelial hyperplasia, but no fibrosis (Wagner score ≤ 3). Crocidolite induced elevated neutrophils and cell damage (BAL), persistent inflammation, microgranulomas, and fibrosis (Wagner scores 4) which persisted through the post exposure period. Confocal microscopy of snap-frozen chestwalls showed no difference between control, brake-dust and chrysotile-HD groups or in thickness of visceral or parietal pleural. The crocidolite exposure resulted in extensive inflammatory response, collagen development and adhesions between the visceral and parietal surfaces with double the surface thickness. These results provide essential information for the design of a subsequent subchronic study.

Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

In plain English

This was an animal inhalation experiment in young adult male Wistar rats. It was run as a range-finding study for a later 90-day study. Through the nose only, rats breathed filtered air, dust from grinding chrysotile-containing drum brake shoes (three dose levels), Canadian chrysotile (two levels) or South African crocidolite (two levels). Exposure lasted 6 hours a day, 5 days a week, for 4 weeks, followed by 4 weeks without exposure. Brake dust caused no adverse lung changes. The only exposure-related findings in those groups were small numbers of particle-laden macrophages and very slight changes in a few rats. Chrysotile caused mild cellular changes but no fibrosis. Crocidolite fibers built up in the lung with little or no clearance. Crocidolite caused interstitial fibrosis (Wagner grade 4 in all animals during recovery) and raised neutrophils and a marker of cell damage in lung washings. In the high-dose group it also caused pleural thickening of 1.9 to 2.5 times the control and pleural adhesions. The authors concluded that brake dust caused no significant pathological response at concentrations well above those at which humans have been exposed.

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: 28-day multi-dose, nose-only inhalation toxicology study with a 28-day recovery period, run as a range-finding study for a later 90-day study
• Who was studied: Young adult male Wistar rats, 8 weeks old at the start, in 8 groups. Subsets of 4 rats per group were used for lavage, histopathology and lung burden, and 3 per group for confocal microscopy of the chest wall. Exposures were done at CiToxLAB Hungary. The total number of rats and the study dates are not given.
• Exposure: Filtered air (control) was compared with three test materials:
• Brake dust made by grinding drum brake shoes containing about 30% chrysotile by area, at low, mid and high doses (mean 7, 15 and 24 WHO fibers/cm3).
• Chrysotile grade 7H19 from the Jeffery mine, Canada, at low and high doses.
• Crocidolite from the Voorspoed mine, South Africa, at low and high doses.
  The chrysotile and crocidolite groups had WHO fiber concentrations ranging from 193 to 255 fibers/cm3.
• Main results:
  • Brake dust groups (all three doses): no adverse histopathological effect at any examination time point.
  • Brake dust and chrysotile groups: no fibrosis was observed. Wagner grades were 1 to 2 for brake dust and 1 to 3 for chrysotile.
  • Crocidolite groups: Wagner grade rose from 3 to 4 (fibrosis) in a dose-related way during exposure, and all animals were grade 4 during the recovery period.
  • Neutrophils in lung lavage, crocidolite low and high dose versus control:
• Day 28: 210% (not significant) and 341% (p less than 0.05).
• Day 56: 561% and 416% (p less than 0.05).
  • Brake dust and chrysotile groups: no statistically significant increase in lavage neutrophils compared with controls at any dose or time point.
  • Crocidolite low and high dose groups: lactate dehydrogenase (a cell-damage marker) in lavage fluid was increased at each time point (p less than 0.01).
  • No group showed statistically significant exposure-related changes in the lavage cytokines IL-1, TNF-alpha or TGF-beta.
  • Crocidolite groups: lung burdens of fibers stayed similar after exposure ended, showing little or no clearance.
  • High-dose chrysotile group: about an order of magnitude fewer fibers longer than 20 µm accumulated in the lung than with crocidolite, despite similar aerosol concentrations. Their estimated half-time after exposure was about 5 days.
  • High-dose crocidolite group, pleural thickness compared with control (p less than 0.05):
• Visceral pleura: 1.9 times at day 28 and 2.2 times at day 56.
• Parietal pleura: 2.5 times at day 28 and 2.1 times at day 56.
  • High-dose brake dust and high-dose chrysotile groups: at day 56, the pleura looked similar to the air control under confocal microscopy.
  • Crocidolite group: adhesions between the visceral and parietal pleural surfaces were seen at day 28.
  • Fibers longer than 20 µm were found in the visceral pleura only in crocidolite-exposed animals.
• The authors' conclusion: The authors concluded that the brake dust groups showed no significant pathological response at any time, at concentrations well above those at which humans have been exposed. They concluded that crocidolite produced persistent fibrosis and pleural changes, and that the results inform the design of the later subchronic study.
• Limitations the authors state:
  • Confocal analysis of the pleura was done only at day 28 (end of exposure) and day 56 (end of recovery).
  • In the brake dust groups, the SEM lung analysis did not systematically tell chrysotile fibers apart from other elongated objects. The authors estimated more than half were residue from the lung digestion procedure.
  • Impactor particle-size measurements did not give meaningful results for the chrysotile and crocidolite groups because fiber concentrations were low.

Topics

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

Medical terms in this study, explained in our Lexicon: Dose-response relationship, Pleura, Chrysotile, Crocidolite, Fibrosis, Bronchoalveolar Lavage (BAL), Inflammation, Collagen.

Related studies

• Evaluation of the exposure, dose-response and fate in the lung and pleura of chrysotile-containing brake dust compared to TiO2, chrysotile, crocidolite or amosite asbestos in a 90-day quantitative inhalation toxicology study - Interim results Part 1: Experimental design, aerosol exposure, lung burdens and BAL — D.M. Bernstein, B. Toth, et al. (2020)
• Evaluation of the dose-response and fate in the lung and pleura of chrysotile-containing brake dust compared to TiO2, chrysotile, crocidolite or amosite asbestos in a 90-day quantitative inhalation toxicology study - Interim results Part 2: Histopathological examination, Confocal microscopy and collagen quantification of the lung and pleural cavity — D.M. Bernstein, B. Toth, et al. (2020)
• Final results from a 90-day quantitative inhalation toxicology study evaluating the dose-response and fate in the lung and pleura of chrysotile-containing brake dust compared to TiO2, chrysotile, crocidolite or amosite asbestos: Histopathological examination, confocal microscopy and collagen quantification of the lung and pleural cavity — D.M. Bernstein, B. Toth, et al. (2021)
• Evaluation of the fate and pathological response in the lung and pleura of brake dust alone and in combination with added chrysotile compared to crocidolite asbestos following short-term inhalation exposure — D.M. Bernstein, R.A. Rogers, et al. (2015)
• Evaluation of the deposition, translocation and pathological response of brake dust with and without added chrysotile in comparison to crocidolite asbestos following short-term inhalation: interim results — D.M. Bernstein, R. Rogers, et al. (2014)
• 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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