Fiber Dimensions and Mesothelioma: A Reappraisal of the Stanton Hypothesis

  • Agnes B. Kane
Part of the NATO ASI Series book series (NSSA, volume 223)


Fiber dimensions are postulated to be critical factors in the toxicity, fibrogenicity, and carcinogenicity of asbestos fibers. Recent in vitro experiments have provided evidence that the chemical composition of mineral fibers, especially surface iron content, is important in catalyzing the formation of highly reactive hydroxyl radicals that may cause acute toxicity, lipid peroxidation, and DNA damage. We have reexamined the roles of fiber length in the acute toxicity of crocidolite asbestos fibers in vitro and in vivo and in the induction of mesotheliomas in mice. Native UICC crocidolite asbestos fibers were separated into long and short fiber preparations by differential centrifugation. Both long and short fiber preparations stimulated the production of reactive oxygen species by elicited mouse peritoneal macrophages. Whether compared on the basis of equal mass, fiber number, or surface area, both long and short fiber preparations were toxic to macrophages. In vitro toxicity was prevented by the iron chelator, deferoxamine, or by exogenous superoxide dismutase or catalase. A single intraperitoneal injection of long crocidolite asbestos fibers caused deposition of fibers on the mesothelial surface at sites of lymphatic stomata, while short fibers were cleared to regional lymph nodes. Only the long fiber preparation caused an intense inflammatory reaction, local production of superoxide anions, and mesothelial cell injury. Similar to in vitro toxicity, mesothelial cell injury in vivo was ameliorated by deferoxamine or PEG-conjugated superoxide dismutase or catalase. If lymphatic clearance was prevented by daily repeated injections, short crocidolite asbestos fibers (but not titanium dioxide particles) accumulated at the mesothelial surface and stimulated an inflammatory reaction with local production of superoxide anions and injury to adjacent mesothelial cells. We tested whether repeated injections of short crocidolite asbestos fibers would prevent lymphatic clearance and produce mesotheliomas. Mice were injected weekly with equal numbers of native, long, or short crocidolite asbestos fiber preparations. After 22–60 weekly injections, 37.5% of mice injected with native crocidolite asbestos fibers developed malignant mesotheliomas. In contrast, 50.0% of mice injected with short fibers and 23.5% of mice injected with long fibers developed tumors. In summary, both long and short crocidolite asbestos fibers are toxic in vitro via an oxidant-dependent mechanism. In vivo, short fibers are also toxic and carcinogenic if lymphatic clearance is prevented.


Mesothelial Cell Malignant Mesothelioma Trypan Blue Staining Asbestos Fiber Fiber Preparation 
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  1. Antman, K. and Aisner, J. (1987) “Asbestos-Related Malignancy”, Grune & Stratton, Orlando, FL.Google Scholar
  2. Bey, E. and Harington, J.S. (1971) Cytotoxic effects of some mineral dusts on Syrian hamster peritoneal macrophages. J. Exp. Med. 133: 1149–1169.PubMedCrossRefGoogle Scholar
  3. Bolton, R.E., Vincent, J.H., Jones, A.D., Addison, J. and Beckett, S.T. (1983) An overload hypothesis for pulmonary clearance of UICC amosite fibres inhaled by rats. Br. J. Indust. Med. 40: 264–272.Google Scholar
  4. Bonneau, L., Marlard, C. and Pezerat, H. (1986) Studies on surface properties of asbestos. Environ. Res. 41: 268–275.PubMedCrossRefGoogle Scholar
  5. Chamberlain, M. and Brown, R.C. (1978) The cytotoxic effects of asbestos and other mineral dust in tissue culture cell lines. Br. J. Exp. Pathol. 59: 183–189.PubMedGoogle Scholar
  6. Churg, A. and Green, F.H.Y., eds. (1988) “Pathology of Occupational Lung Disease”, IgakuShoin, N.Y.Google Scholar
  7. Churg, A. and Wiggs, B. (1984) Fiber size and number in asbestos-induced mesothelioma. Am. J. Pathol. 115: 437–442.PubMedGoogle Scholar
  8. Craighead, J.E. (1987) Current pathogenetic concepts of diffuse malignant mesothelioma. Human Pathol. 18: 544–577.CrossRefGoogle Scholar
  9. Courtice, F.C. and Simmonds, W.J. (1954) Physiological significance of lymph drainage of the serosal cavities and lungs. Physiol. Rev. 34: 419–448.PubMedGoogle Scholar
  10. Davis, J.M.G., Addison, J., Bolton, R.E., Donaldson, K., Jones, A.D. and Smith, T. (1986) The pathogenicity of long versus short fibre samples of amosite asbestos administered to rats by inhalation and intraperitoneal injection. Br. J. Exp. Pathol. 67: 415–430.PubMedGoogle Scholar
  11. Donaldson, K., Brown, G.M., Brown, D.M., Bolton, R.E. and Davis, J.M.G. (1989) Inflammation generating potential of long and short fibre amosite asbestos samples. Br. J. Indust. Med. 46: 271–276.Google Scholar
  12. Dunnigan, J. (1984) Biological effects of fibers: Stanton’s hypothesis revisited. Environ. Hlth Perspect. 57: 333–337.CrossRefGoogle Scholar
  13. Dunnigan, J. (1984) Biological effects of fibers: Stanton’s hypothesis revisited. Environ. Hlth Perspect. 57: 333–337.CrossRefGoogle Scholar
  14. Goodglick, L.A. and Kane, A.B. (1990) Cytotoxicity of long and short crocidolite asbestos fibers in vitroand in vivo. Cancer Res. 50: 5153–5163.Google Scholar
  15. Goodglick, L.A. and Kane, A.B. (1986) The role of reactive oxygen metabolites in crocidolite asbestos toxicity to macrophages. Cancer Res. 46: 5558–5566.PubMedGoogle Scholar
  16. Gulumian, M. and Van Wyk, J.A. (1987) Hydroxyl radical production in the presence of fibres by a Fenton-type reaction. Chem. Biol. Inter. 62: 89–97.CrossRefGoogle Scholar
  17. Harington, J.S. (1981) Fiber carcinogenesis: epidemiologic observations and the Stanton hypothesis. J. Nall. Canc. Inst. 67: 977–989.Google Scholar
  18. Hesterberg, T.W. and Barrett, J.C. (1985) Induction by asbestos fibers of anaphase abnormalities. Carcinogenesis 6: 473–475.PubMedCrossRefGoogle Scholar
  19. Hesterberg, T.W. and Barrett, J.C. (1984) Dependence of asbestos-and mineral dust-induced transformation of mammalian cells in culture on fiber dimension. Cancer Res. 44: 2170–2180.PubMedGoogle Scholar
  20. Kaw, J.L., Tilkes, F. and Beck, E.G. (1982) Reaction of cells cultured in vitroto different asbestos dusts of equal surface area but different fibre length. Br. J. Exp. Pathol. 63: 109–115.PubMedGoogle Scholar
  21. Kolev, K. (1982) Experimentally induced mesothelioma in white rats in response to intraperitoneal administration of amorphous crocidolite asbestos. Environ. Res. 29: 123–133.PubMedCrossRefGoogle Scholar
  22. Macdonald, J.L. and Kane, A.B. (1986) Identification of asbestos fibers within single cells. Lab. Invest. 55: 177–185.PubMedGoogle Scholar
  23. Moalli, P.A., Macdonald, J.L., Goodglick, L.A. and Kane, A.B. (1987) Acute injury and regenera- tion of the mesothelium in response to asbestos fibers. Am. J. Pathol. 128: 425–445.Google Scholar
  24. Monchaux, G., Bignon, J., Jaurand, M.-C., Lafuma, J., Sebastien, P., Masse, R., Hirsch, A. and Goni, J. (1981) Mesotheliomas in rats following inoculation with acid-leached chrysotile asbestos and other mineral fibers. Carcinogenesis 2: 229–236.PubMedCrossRefGoogle Scholar
  25. Mossman, B.T. and Marsh, J.P. (1989) Evidence supporting a role for active oxygen species in asbestos-induced toxicity and lung disease. Environ. Hlth Perspect. 81: 91–4.CrossRefGoogle Scholar
  26. Pott, F. (1987) Problems in defining carcinogenic fibers. Ann. Occup. Hyg. 31: 799–802.PubMedCrossRefGoogle Scholar
  27. Shatos, M.A., Doherty, J.M., Marsh, J.P. and Mossman, B.T. (1987) Prevention of asbestos-in-duced cell death in rat lung fibroblasts and alveolar macrophages by scavengers of active oxygen species. Environ. Res. 44: 103–116.PubMedCrossRefGoogle Scholar
  28. Stanton, M.F., Layard, M., Tegeris, A., Miller, E., May, M., Morgan, E. and Smith, A. (1981) Relation of particle dimensions to carcinogenicity in amphibole asbestoses and other fibrous minerals. J. Natl. Canc. Inst. 67: 965–975.Google Scholar
  29. Wagner, J.C., Berry, G. and Timbrell, V. (1973) Mesotheliomata in rats after inoculation with asbestos and other minerals. Br. J. Cancer 28: 173–185.PubMedCrossRefGoogle Scholar
  30. Wagner, J.C., Griffiths, D.M. and Hill, R.J. (1984) The effect of fibre size on the in vivoactivity of UICC crocidolite. Br. J. Cancer 49: 453–458.PubMedCrossRefGoogle Scholar
  31. Weitzman, S.A. and Graceffa, P. (1984) Asbestos catalyzes hydroxyl and superoxide radical release from hydrogen peroxide. Arch. Biochem. Biophys. 228: 373–376.PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1991

Authors and Affiliations

  • Agnes B. Kane
    • 1
  1. 1.Department of Pathology and Laboratory MedicineBrown UniversityProvidenceUSA

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