The toxicological response of Brazilian chrysotile asbestos: a multidose subchronic 90-day inhalation toxicology study with 92-day recovery to assess cellular and pathological response

Our plain-English summary of The toxicological response of Brazilian chrysotile asbestos: a multidose subchronic 90-day inhalation toxicology study with 92-day recovery to assess cellular and pathological response, by D.M. Bernstein, R. Rogers, P. Smith, et al (Inhalation Toxicology, 2006).

The study

• Authors: D.M. Bernstein, R. Rogers, P. Smith, J. Chevalier
• Journal: Inhalation Toxicology
• Published: 2006;18(5):313-32
• Cited by: 15 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Inhalation toxicology studies with chrysotile asbestos have in the past been performed at exceedingly high doses without consideration of fiber number or dimensions. As such, the exposures have exceeded lung overload levels, making quantitative assessment of these studies difficult if not impossible. To assess the cellular and pathological response in the rat lung to a well-characterized aerosol of chrysotile asbestos, a 90-day subchronic inhalation toxicology study was performed using a commercial Brazilian chrysotile (CA 300). The protocol was based on that established by the European Commission for the evaluation of synthetic vitreous fibers. The study was also designed to assess the potential for reversibility of any such changes and to permit association of responses with fiber dose in the lung and the influence of fiber length. Wistar male rats were randomly assigned to an air control group and to 2 CA 300 exposure groups at mean fiber aerosol concentrations of 76 fibers L > 20 microm/cm3 (3413 total fibers/cm3; 536 WHO fibers/cm3) or 207 fibers L > 20 microm/cm3 (8941 total fibers/cm3; 1429 WHO fibers/cm3). The animals were exposed using a flow-past, nose-only exposure system for 5 days/wk, 6 h/day, during 13 consecutive weeks (65 exposures), followed by a subsequent nonexposure period lasting for 92 days. Animals were sacrificed after cessation of exposure and after 50 and 92 days of nonexposure recovery. At each sacrifice, subgroups of rats were assessed for the determination of the lung burden; histopathological examination; cell proliferation response; bronchoalveolar lavage with the determination of inflammatory cells; clinical biochemistry; and for analysis by confocal microscopy. Through 90 days of exposure and 92 days of recovery, chrysotile at a mean exposure of 76 fibers L > 20 microm/cm3 (3413 total fibers/cm3) resulted in no fibrosis (Wagner score 1.8 to 2.6) at any time point. The long chrysotile fibers were observed to break apart into small particles and smaller fibers. In vitro modeling has indicated that these particles are essentially amorphous silica. At an exposure concentration of 207 fibers L > 20 microm/cm3 (8941 total fibers/cm3) slight fibrosis was observed. In comparison with other studies, chrysotile produced less inflammatory response than the biosoluble synthetic vitreous fiber CMS. As predicted by the recent biopersistence studies on chrysotile, this study clearly shows that at that at an exposure concentration 5000 times greater than the U.S. threshold limit value of 0.1 f(WHO)/cm3, chrysotile produces no significant pathological response.

In plain English

In this animal experiment, male Wistar rats breathed a commercial Brazilian chrysotile asbestos nose-only for 6 hours a day, 5 days a week, for 13 weeks. They were examined after exposure and after 50 and 92 recovery days. A control group breathed filtered air. The medium dose averaged 76 fibers longer than 20 µm per cm3 (3413 total fibers/cm3) and the high dose 207 (8941 total fibers/cm3). In the medium-dose group, the authors described average Wagner scores of 1.8 to 2.6 as no fibrosis, although minimal focal fibrosis was seen in microgranulomas of some rats and one rat had slight fibrosis at 92 days. All high-dose rats examined under the microscope had slight fibrosis (Wagner grade 4). In lung washings from subgroups of five rats, the high-dose group's neutrophils rose after exposure, then declined but stayed at twice the control level. Some long fibers remained in the lungs at 92 days. The authors concluded that at 5000 times the U.S. threshold limit value, chrysotile produced no significant pathological response. They judged that the high dose very likely approached or exceeded lung overload.

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: multidose, subchronic 90-day inhalation toxicology study in rats with up to 92 days of exposure-free recovery, following a European Commission protocol for synthetic mineral fibers
• Who was studied: Male Wistar Han-Ibm rats, 9 weeks old, in groups of 39 per chrysotile dose, plus an air control group. Subgroups (generally 5 rats) were examined at each time point, with separate subgroups for lavage, lung burden and histopathology. Exposures were done at Research and Consulting Company Ltd., Füllinsdorf, Switzerland.
• Exposure: Commercial Brazilian chrysotile (CA 300) from the Cana Brava Mine, Minasu, Goias, Brazil, inhaled nose-only at mean concentrations of 76 (medium dose) and 207 (high dose) fibers longer than 20 µm per cm3, 6 hours a day, 5 days a week, for 13 weeks (65 exposures)
• Main results:
  • Measured exposure for all fiber lengths was 3413 fibers/cm3 in the medium-dose group and 8941 fibers/cm3 in the high-dose group (536 and 1429 WHO fibers/cm3; 1.32 and 3.56 mg/m3 achieved, per Table 3)
  • Medium-dose group: total fibers per lung were 147.1 million after the 90-day exposure, 25.6 million after 50 days of recovery and 21.5 million after 92 days of recovery
  • High-dose group: total fibers per lung were 273.4 million after exposure, 50.4 million after 50 days and 42.8 million after 92 days of recovery
  • Some long fibers remained through 92 days after exposure (high dose). The authors said these represented about 0.4% of the total number of fibers.
  • Lung weights increased with dose after exposure and after 50 days of recovery. By 92 days the difference from controls was no longer statistically significant.
  • Lung lavage was performed on subgroups of five rats per dose group at each time point
  • Lung lavage, medium-dose group: no statistically significant difference in neutrophils compared with controls at any time point
  • Lung lavage, high-dose group: statistically significant increase in neutrophils and lymphocytes immediately after exposure
  • High-dose group: neutrophils were reduced at 50 and 92 days but remained at twice the control level
  • High-dose group: LDH (a marker of cell injury) in lavage fluid was 2.8 times control at the end of exposure
  • LDH did not differ significantly from control at 50 days. At 92 days it was 1.6 times control in the high-dose group and 1.7 times control in the medium-dose group.
  • Cell proliferation (BrdU) at 92 days of recovery, measured in 3 high-dose and 3 control rats, was nearly identical between the two groups
  • Medium-dose group: mean Wagner scores of 1.8 to 2.6, which the authors described as no fibrosis at any time point
  • Medium-dose group, right after the 90-day exposure: 4 rats had minimal focal fibrosis in microgranulomas. Because it was restricted to one or two foci, the lesion was scored as Wagner grade 3.
  • Medium-dose group after 92 days of recovery: 1 rat had minimal focal fibrosis in microgranulomas, which was not considered sufficient for Wagner grade 4
  • Medium-dose group at 92 days of recovery: a different rat was scored Wagner grade 4, with slight fibrosis at the bronchiolar-alveolar junction
  • High-dose group: Wagner grade 4 (slight fibrosis at the bronchiolar-alveolar junction) was diagnosed in all rats examined histologically at each time point
  • The fibrotic response affected less than 0.2% of the lung in the medium-dose group and less than 1.4% in the high-dose group
  • The authors compared their results with a separate earlier study (Bellmann et al., 2003). They reported that medium-dose chrysotile produced less inflammatory response than a similar exposure to the synthetic fiber CMS.
• The authors' conclusion: The authors concluded that, at an exposure concentration 5000 times greater than the U.S. threshold limit value of 0.1 WHO fibers/cm3, chrysotile produced no significant pathological response in this subchronic inhalation study
• Limitations the authors state:
  • Cell proliferation was measured in only 3 of the 5 rats per group and only at 92 days after exposure ended
  • Macrophage clearance rates were not measured, and the authors judged the high dose very likely approached or exceeded lung overload
  • The much higher weight-based concentration of CMS in the comparison study confounds a direct comparison with chrysotile
  • Comparable results were not available for amphibole asbestos

Mines named here

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

• Cana Brava mine, Uruaçu, Goiás

All asbestos mines

Topics

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

Medical terms in this study, explained in our Lexicon: Chrysotile, Vitreous, Fiber Length, Bronchoalveolar Lavage (BAL), Fibrosis, biopersistence, Threshold Limit Value (TLV).

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