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. 1997 Sep;105(Suppl 5):1235–1240. doi: 10.1289/ehp.97105s51235

Short-term inhalation and in vitro tests as predictors of fiber pathogenicity.

R T Cullen 1, B G Miller 1, J M Davis 1, D M Brown 1, K Donaldson 1
PMCID: PMC1470121  PMID: 9400730

Abstract

A wide range of fiber types was tested in two in vitro assays: toxicity to A549 epithelial cells, as detachment from substrate, and the production of the proinflammatory cytokine tumor necrosis factor (TNF) by rat alveolar macrophages. Three of the fibers were also studied in vivo, using short-term inhalation followed by a) bronchoalveolar lavage to assess the inflammatory response and b) measurement of cell proliferation in terminal bronchioles and alveolar ducts, using incorporation of bromodeoxyuridine (BrdU). The amount of TNF produced by macrophages in vitro depended on the fiber type, with the man-made vitreous fibers, and refractory ceramic fibers being least stimulatory and silicon carbide (SiC) whiskers providing the greatest stimulation. In the epithelial detachment assay there were dose-dependent differences in the toxicity of the various fibers, with long amosite being the most toxic. However, there was no clear relationship to known chronic pathogenicity. Fibers studied by short-term inhalation produced some inflammation, but there was no clear discrimination between the responses to code 100/475 glass fibers and the more pathogenic amosite and SiC. However, measurements of BrdU uptake into lung cells showed that amosite and SiC produced a greater reaction than code 100/475, which itself caused no more proliferation than that seen in untreated lungs. These results mirror the pathogenicity ranking of the fibers in long-term experiments. In conclusion, the only test to show potential as a predictive measure of pathogenicity was that of cell proliferation in lungs after brief inhalation exposure (BrdU assay). We believe that this assay should be validated with a wider range of fibers, doses, and time points.

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Selected References

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  1. Barrett J. C. Cellular and molecular mechanisms of asbestos carcinogenicity: implications for biopersistence. Environ Health Perspect. 1994 Oct;102 (Suppl 5):19–23. doi: 10.1289/ehp.94102s519. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bissonnette E., Rola-Pleszczynski M. Pulmonary inflammation and fibrosis in a murine model of asbestosis and silicosis. Possible role of tumor necrosis factor. Inflammation. 1989 Jun;13(3):329–339. doi: 10.1007/BF00914399. [DOI] [PubMed] [Google Scholar]
  3. Brody A. R., Overby L. H. Incorporation of tritiated thymidine by epithelial and interstitial cells in bronchiolar-alveolar regions of asbestos-exposed rats. Am J Pathol. 1989 Jan;134(1):133–140. [PMC free article] [PubMed] [Google Scholar]
  4. Bunn W. B., 3rd, Bender J. R., Hesterberg T. W., Chase G. R., Konzen J. L. Recent studies of man-made vitreous fibers. Chronic animal inhalation studies. J Occup Med. 1993 Feb;35(2):101–113. doi: 10.1097/00043764-199302000-00009. [DOI] [PubMed] [Google Scholar]
  5. Chang L. Y., Overby L. H., Brody A. R., Crapo J. D. Progressive lung cell reactions and extracellular matrix production after a brief exposure to asbestos. Am J Pathol. 1988 Apr;131(1):156–170. [PMC free article] [PubMed] [Google Scholar]
  6. Davis J. M., Addison J., Bolton R. E., Donaldson K., Jones A. D., Smith T. The pathogenicity of long versus short fibre samples of amosite asbestos administered to rats by inhalation and intraperitoneal injection. Br J Exp Pathol. 1986 Jun;67(3):415–430. [PMC free article] [PubMed] [Google Scholar]
  7. Donaldson K., Addison J., Miller B. G., Cullen R. T., Davis J. M. Use of the short-term inflammatory response in the mouse peritoneal cavity to assess the biological activity of leached vitreous fibers. Environ Health Perspect. 1994 Oct;102 (Suppl 5):159–162. doi: 10.1289/ehp.94102s5159. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Donaldson K., Brown D. M., Miller B. G., Brody A. R. Bromo-deoxyuridine (BRDU) uptake in the lungs of rats inhaling amosite asbestos or vitreous fibres at equal airborne fibre concentrations. Exp Toxicol Pathol. 1995 May;47(2-3):207–211. doi: 10.1016/S0940-2993(11)80316-7. [DOI] [PubMed] [Google Scholar]
  9. Donaldson K., Miller B. G., Sara E., Slight J., Brown R. C. Asbestos fibre length-dependent detachment injury to alveolar epithelial cells in vitro: role of a fibronectin-binding receptor. Int J Exp Pathol. 1993 Jun;74(3):243–250. [PMC free article] [PubMed] [Google Scholar]
  10. Donaldson K., Slight J., Brown G. M., Bolton R. E. The ability of inflammatory bronchoalveolar leucocyte populations elicited with microbes or mineral dust to injure alveolar epithelial cells and degrade extracellular matrix in vitro. Br J Exp Pathol. 1988 Jun;69(3):327–338. [PMC free article] [PubMed] [Google Scholar]
  11. Flick D. A., Gifford G. E. Comparison of in vitro cell cytotoxic assays for tumor necrosis factor. J Immunol Methods. 1984 Mar 30;68(1-2):167–175. doi: 10.1016/0022-1759(84)90147-9. [DOI] [PubMed] [Google Scholar]
  12. Goodglick L. A., Kane A. B. Cytotoxicity of long and short crocidolite asbestos fibers in vitro and in vivo. Cancer Res. 1990 Aug 15;50(16):5153–5163. [PubMed] [Google Scholar]
  13. Hart G. A., Kathman L. M., Hesterberg T. W. In vitro cytotoxicity of asbestos and man-made vitreous fibers: roles of fiber length, diameter and composition. Carcinogenesis. 1994 May;15(5):971–977. doi: 10.1093/carcin/15.5.971. [DOI] [PubMed] [Google Scholar]
  14. Hesterberg T. W., Miiller W. C., McConnell E. E., Chevalier J., Hadley J. G., Bernstein D. M., Thevenaz P., Anderson R. Chronic inhalation toxicity of size-separated glass fibers in Fischer 344 rats. Fundam Appl Toxicol. 1993 May;20(4):464–476. doi: 10.1006/faat.1993.1057. [DOI] [PubMed] [Google Scholar]
  15. Infante P. F., Schuman L. D., Dement J., Huff J. Fibrous glass and cancer. Am J Ind Med. 1994 Oct;26(4):559–584. doi: 10.1002/ajim.4700260413. [DOI] [PubMed] [Google Scholar]
  16. Johnson N. F., Hoover M. D., Thomassen D. G., Cheng Y. S., Dalley A., Brooks A. L. In vitro activity of silicon carbide whiskers in comparison to other industrial fibers using four cell culture systems. Am J Ind Med. 1992;21(6):807–823. doi: 10.1002/ajim.4700210604. [DOI] [PubMed] [Google Scholar]
  17. Li X. Y., Donaldson K., Brown D., MacNee W. The role of tumor necrosis factor in increased airspace epithelial permeability in acute lung inflammation. Am J Respir Cell Mol Biol. 1995 Aug;13(2):185–195. doi: 10.1165/ajrcmb.13.2.7626286. [DOI] [PubMed] [Google Scholar]
  18. McGavran P. D., Brody A. R. Chrysotile asbestos inhalation induces tritiated thymidine incorporation by epithelial cells of distal bronchioles. Am J Respir Cell Mol Biol. 1989 Sep;1(3):231–235. doi: 10.1165/ajrcmb/1.3.231. [DOI] [PubMed] [Google Scholar]
  19. Piguet P. F., Collart M. A., Grau G. E., Sappino A. P., Vassalli P. Requirement of tumour necrosis factor for development of silica-induced pulmonary fibrosis. Nature. 1990 Mar 15;344(6263):245–247. doi: 10.1038/344245a0. [DOI] [PubMed] [Google Scholar]
  20. Rom W. N., Travis W. D., Brody A. R. Cellular and molecular basis of the asbestos-related diseases. Am Rev Respir Dis. 1991 Feb;143(2):408–422. doi: 10.1164/ajrccm/143.2.408. [DOI] [PubMed] [Google Scholar]
  21. Vaughan G. L., Jordan J., Karr S. The toxicity, in vitro, of silicon carbide whiskers. Environ Res. 1991 Oct;56(1):57–67. doi: 10.1016/s0013-9351(05)80109-4. [DOI] [PubMed] [Google Scholar]
  22. Vaughan G. L., Trently S. A., Wilson R. B. Pulmonary response, in vivo, to silicon carbide whiskers. Environ Res. 1993 Nov;63(2):191–201. doi: 10.1006/enrs.1993.1140. [DOI] [PubMed] [Google Scholar]
  23. Warheit D. B., Kellar K. A., Hartsky M. A. Pulmonary cellular effects in rats following aerosol exposures to ultrafine Kevlar aramid fibrils: evidence for biodegradability of inhaled fibrils. Toxicol Appl Pharmacol. 1992 Oct;116(2):225–239. doi: 10.1016/0041-008x(92)90302-9. [DOI] [PubMed] [Google Scholar]

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