Relevance to Humans of Experimentally Induced Pulmonary Tumors in Rats and Hamsters

  • U. Mohr
  • D. L. Dungworth
Part of the ILSI Monographs book series (ILSI MONOGRAPHS)


Extrapolation of data from animal experiments to the human situation is a necessary part of risk assessment. Because both qualitative and quantitative results of carcinogenicity studies vary widely from one animal species to another, it is well recognized that there is a need to use data from several species in extrapolating to possible human effects. Accurate extrapolation requires an understanding of why there are large interspecies differences, and this understanding is beginning to be developed. Two important aspects, namely, interspecies differences in dosimetry of inhaled materials and in epithelial cell biology, are covered elsewhere in this book, and only a few specific examples will be considered here. This article concentrates on lesions observed in lungs of rats and hamsters during in vivo carcinogenicity trials (1) and on comparative information being derived from in vitro studies.


Diesel Exhaust Pulmonary Tumor Tracheal Epithelial Cell Hamster Tracheal Epithelium Squamous Cell Tumor 
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  1. 1.
    Mohr U, Takenaka S, Dung worth DL (1986) Morphologic effects of inhaled diesel engine exhaust on lungs of rats: comparison with effects of coal oven flue gas mixed with pyrolyzed pitch. In: Ishinishi N, Koizumi A, McClellan RO, Stöber W (eds) Carcinogenic and mutagenic effects of diesel engine exhaust. Elsevier, Amsterdam, pp 459–470 (Developments in toxicology and environmental science, vol 13)Google Scholar
  2. 2.
    Raabe OG, Yeh H-C, Newton GJ, Phalen RF, Velasquez DJ (1977) Deposition of inhaled monodisperse aerosols in small rodents. In: Walton WH (ed) Inhaled particles IV. Pergamon, Oxford, pp 3–20Google Scholar
  3. 3.
    Schreiber H, Martin DH, Pazmino N (1975) Species differences in the effect of benzo(a)pyrene-ferric oxide on the respiratory tract of rats and hamsters. Cancer Res 35:1654–1661PubMedGoogle Scholar
  4. 4.
    Brain JD, Mensah GA (1983) Comparative toxicology of the respiratory tract. Am Rev Respir Dis 128:s87–s90PubMedGoogle Scholar
  5. 5.
    Plopper CG, Mariassy AT, Wilson DW, Alley JL, Nishio SJ, Nettesheim P (1983) Comparison of nonciliated tracheal epithelial cells in six mammalian species: ultrastructure and population densities. Exp Lung Res 5:281–294PubMedCrossRefGoogle Scholar
  6. 6.
    Abramson FP, Robinson D, Bai SA (1983) Relationships between propranolol plasma protein binding, glycoprotein concentration, and enzyme induction following phenobarbital administration in the dog. Biochem Pharmacol 32:2618–2620PubMedCrossRefGoogle Scholar
  7. 7.
    Prough RA, Patrizi VW, Okita RT, Masters BSS, Jakobsson SW (1979) Characteristics of benzo(a)pyrene metabolism by kidney, liver, and lung microsomal fractions from rodents and humans. Cancer Res 39:1199–1206Google Scholar
  8. 8.
    Mass M J, Kaufman DG (1983) Species differences in the activation of benzo(a)pyrene in the tracheal epithelium of rats and hamsters. Basic Life Sci 24:331–351PubMedGoogle Scholar
  9. 9.
    Schreiber H, Nettesheim P, Martin DH (1972) Rapid development of bronchioloalveolar squamous cell tumors in rats after intratracheal injection of 3-methylchol-anthrene. J Nat Cancer Inst 49:541–554PubMedGoogle Scholar
  10. 10.
    Nettesheim P, Marchok A (1983) Neoplastic development in airway epithelium. Adv Cancer Res 39:1–69PubMedCrossRefGoogle Scholar
  11. 11.
    Mäher VM, Ouellette LM, Curren RD, McCormick JJ (1976) Frequency of ultraviolet light-induced mutations is higher in xeroderma pigmentosum variant cells than in normal human cells. Nature 261:593–595PubMedCrossRefGoogle Scholar
  12. 12.
    DiPaolo JA (1983) Relative difficulties in transforming human and animal cells in vitro. J Nat Cancer Inst 70:3–8PubMedGoogle Scholar
  13. 13.
    Yuspa SH (1984) Mechanisms of initiation and promotion in mouse epidermis. IARC Sci Pub 56:191–204Google Scholar
  14. 14.
    Thomassen DG (1986) Role of spontaneous transformation in carcinogenesis: development of preneoplastic rat tracheal epithelial cells at a constant rate. Cancer Res 46:2344–2348PubMedGoogle Scholar
  15. 15.
    Brand KG, Buoen LC, Johnson KH, Brand I (1975) Etiological factors, stages, and the role of the foreign body in foreign body tumorigenesis: a review. Cancer Res 35:279–286PubMedGoogle Scholar
  16. 16.
    Schuller HM, Witschi HP (1987) A novel in vivo model for the induction of carcinoids and small cell cancer of the lung (meeting abstract). Toxicologist 7:19Google Scholar
  17. 17.
    Rhoads K, Mahassey JA, Sanders CL (1981) A morphometric study of rat and hamster lung following inhalation of 239PuO2. Rad Res 88:266–279CrossRefGoogle Scholar
  18. 18.
    Carney DN (1986) Recent advances in the biology of small cell lung cancer. Chest 89:253S–257SPubMedGoogle Scholar
  19. 19.
    Barbacid M (1986) Oncogenes and human cancer: cause or consequence. Carcinogenesis 7:1037–1042PubMedCrossRefGoogle Scholar
  20. 20.
    Alitalo K, Schwab M (1986) Oncogene amplification in tumor cells. Adv Cancer Res 47:235–281PubMedCrossRefGoogle Scholar
  21. 21.
    Yamamoto F, Nakano H, Neville C, Perucho M (1985) Structure and mechanisms of activation of c-K-ras oncogenes in human lung cancer. Prog Med Virol 32:101–114PubMedGoogle Scholar
  22. 22.
    Milici A, Blick M, Murphy E, Gutterman JU (1986) c-K-ras Codon 12 GGT-CGT point mutation: an infrequent event in human lung cancer. Biochem Biophys Res Comm 140:699–705PubMedCrossRefGoogle Scholar
  23. 23.
    Chan SYT, Evan GI, Ritson A, Watson J, Wraight P, Sikora K (1986) Localisation of lung cancer by a radiolabeled monoclonal antibody against the c-myc oncogene product. Br J Cancer 5:761–769CrossRefGoogle Scholar
  24. 24.
    Nau MM, Brooks BJ Jr, Carney DN, Gazdar AF, Battey JF, Sausville EA, Minna JD (1986) Human small-cell lung cancers show amplification and expression of the N-myc gene. Proc Nat Acad Sci USA 83:1092–1096PubMedCrossRefGoogle Scholar
  25. 25.
    Saksela K, Bergh J, Nilsson K (1986) Amplification of the N-myc oncogene in an adenocarcinoma of the lung. J Cell Biochem 31:297–304PubMedCrossRefGoogle Scholar
  26. 26.
    Wong AJ, Ruppert JM, Eggleston J, Hamilton SR, Baylin SB, Vogelstein B (1986) Gene amplification of c-myc and N-myc in small cell carcinoma of the lung. Science 233:461–464PubMedCrossRefGoogle Scholar
  27. 27.
    Stowers SJ, Glover PL, Reynolds SH, Boone LR, Maronpot RR, Anderson MW (1987) Activation of the K-ras oncogene in lung tumors from rats and mice chronically exposed to tetranitromethane. Cancer Res, in pressGoogle Scholar
  28. 28.
    Harris CC (1987) Human tissues and cells in carcinogenesis research. Cancer Res 47:1–10PubMedGoogle Scholar
  29. 29.
    Lechner JF, Tokiwa T, McClendon IA, Haugen A (1984) Effects of nickel sulfate on growth and differentiation of normal human bronchial epithelial cells. Carcinogenesis 5:1697–1703PubMedCrossRefGoogle Scholar
  30. 30.
    Lechner JF, Haugen A, Trump BF, Tokiwa T, Harris CC (1983) Effects of asbestos and carcinogenic metals on cultured human bronchial epithelium. In: Harris CC, Autrup H (eds) Human carcinogenesis. Academic, New York, pp 561–588Google Scholar
  31. 31.
    Lechner JF, Tokiwa T, LaVeck M, Benedict WF, Banks-Schlegel S, Yeager H Jr, Banerjee A, Harris CC (1985) Asbestos-associated chromosomal changes in human mesothelial cells. Proc Natl Acad Sci USA 82:3884–3888PubMedCrossRefGoogle Scholar
  32. 32.
    Emura M, Mohr U, Kakunaga T, Hilfrich J (1985) Growth inhibition and transformation of a human fetal tracheal epithelial cell line by long-term exposure to diethyl-nitrosamine. Carcinogenesis 6:1079–1085PubMedCrossRefGoogle Scholar
  33. 33.
    Yoshida Y, Hattori A, Mori M (1983) Transformation of human lung cells by 3-methylcholanthrene in vitro. Gann 74:615–618PubMedGoogle Scholar
  34. 34.
    Steele VE, Marchok AC, Nettesheim P (1979) Oncogenic transformation in epithelial cell lines derived from tracheal expiants exposed in vitro to N-methyl-N’-nitro-N-nitrosoguanidine. Cancer Res 39:3805–3811PubMedGoogle Scholar
  35. 35.
    Pai SB, Steele VE, Nettesheim P (1983) Neoplastic transformation of primary tracheal epithelial cell cultures. Carcinogenesis 4:369–374PubMedCrossRefGoogle Scholar
  36. 36.
    Thomassen DG, Gray TE, Mass M J, Barrett JC (1983) High frequency of carcinogen-induced early, preneoplastic changes in rat tracheal epithelial cells in culture. Cancer Res 43:5956–5963PubMedGoogle Scholar
  37. 37.
    Emura M, Richter-Reichhelm H-B, Böning W, Eichinger R, Schoch C, Althoff J, Mohr U (1982) A fetal respiratory epithelial cell line for studying some problems of transplacental carcinogenesis in Syrian golden hamsters. J Cancer Res Clin Oncol 104:133–144PubMedCrossRefGoogle Scholar
  38. 38.
    Emura M, Mohr U, Riebe M, Aufderheide M, Dungworth DL (1987) Predisposition of cloned fetal hamster lung epithelial cells to transformation by a precarcinogen, benzo(a)pyrene, using growth hormone supplementation and collagen gel substratum. Cancer Res 47:1155–1160PubMedGoogle Scholar
  39. 39.
    Mossmann BT, Craighead JE (1979) Use of hamster tracheal organ cultures for assessing the cocarcinogenic effects of inorganic particulates on the respiratory epithelium. Prog Exp Tumor Res 24:37–47Google Scholar
  40. 40.
    Rasmussen RE, Crocker TT (1981) A culture system for the direct exposure of mammalian cells to airborne pollutants. In: Waters MD, Sandhu SS, Huisingh JL, Claxton L, Nesnow S (eds) Short-term bioassays in the analysis of complex environmental mixtures II. Plenum, New York, pp 119–131Google Scholar
  41. 41.
    Acosta D, Anuforo DC, McMillin R, Soine WH, Smith RV (1979) Comparison of cytochrome P-450 levels in adult rat liver, postnatal rat liver, and primary cultures of postnatal rat hepatocytes. Life Sci 25:1413–1418PubMedCrossRefGoogle Scholar
  42. 42.
    Lake BG, Paine AJ (1982) The effect of hepatocyte culture conditions on cytochrome P-450 linked drug metabolising enzymes. Biochem Pharmacol 31:2141–2144PubMedCrossRefGoogle Scholar
  43. 43.
    Trump BF, McDowell EM, Glavin F, Barrett LA, Becci PJ, Schürch W, Kaiser HE, Harris CC (1978) The respiratory epithelium. III. Histogenesis of epidermoid metaplasia and carcinoma in situ in the human. J Nat Cancer Inst 61:565–575Google Scholar
  44. 44.
    McDowell EM, Trump BF (1983) Histogenesis of preneoplastic and neoplastic lesions in tracheobronchial epithelium. Surv Synth Pathol Res 2:235–279Google Scholar
  45. 45.
    Keenan KP, Wilson TS, McDowell EM (1983) Regeneration of hamster tracheal epithelium after mechanical injury. IV. Histochemical, immunocytochemical and ultrastructural studies. Virchows Arch Cell Path 43:213–240CrossRefGoogle Scholar
  46. 46.
    Yagi T, Nikaido O, Takebe H (1984) Excision repair of mouse and human fibroblast cells, and a factor affecting the amount of UV-induced unscheduled DNA synthesis. Mut Res 132:101–112Google Scholar
  47. 47.
    Warren W, Grathorn AR, Shooter KV (1979) The stability of methylated purines and of methylphosphotriesters in the DNA of V79 cells after treatment with N-methyl-N-nitrosourea. Biochim Biophys Acta 563:82–88PubMedGoogle Scholar
  48. 48.
    Goth-Goldstein R (1980) Inability of Chinese hamster ovary cells to excise O 6-alkylguanine. Cancer Res 40:2623–2624PubMedGoogle Scholar
  49. 49.
    Gerson SL, Trey JE, Miller K, Benjamin E (1987) Repair of O 6-alkylguanine during DNA synthesis in murine bone marrow hematopoietic precursors. Cancer Res 47:89–95PubMedGoogle Scholar
  50. 50.
    Bodell WJ, Singer B, Thomas GH, Cleaver JE (1979) Evidence for removal at different rates of O-ethyl pyrimidines and ethylphosphotriesters in two human fibroblast cell lines. Nucleic Acid Res 6:2819–2829PubMedCrossRefGoogle Scholar
  51. 51.
    Hahn FF (1985) Radiation-induced squamous cell carcinoma, lung of rodents. In: Jones TC, Mohr U, Hunt RD (eds) Respiratory system. Springer, Berlin Heidelberg New York, pp 127–133Google Scholar
  52. 52.
    Heinrich U, Muhle H, Koch W, Mohr U (1985) Long-term inhalation studies with rodents. In: Homburger F (ed) Safety evaluation and regulation of chemicals 2. Karger, Basel, pp 241–250Google Scholar
  53. 53.
    Wilbourn J, Haroun L, Heseltine E, Kaldor J, Partensky C, Vainio H (1986) Response of experimental animals to human carcinogens: an analysis based upon the IARC monographs programme. Carcinogenesis 7:1853–1863PubMedCrossRefGoogle Scholar
  54. 54.
    Liemen RA, Lee JS, Wagoner JK, Blejer HP (1976) Cancer mortality among cadmium production workers. Ann NY Acad Sci 271:273–279CrossRefGoogle Scholar
  55. 55.
    Takenaka S, Oldiges M, König H, Hochrainer D, Oberdörster G (1983) Carcinogenicity of cadmium chloride aerosols in W rats. J Nat Cancer Inst 70:367–373PubMedGoogle Scholar
  56. 56.
    Thun MJ, Schnorr TM, Smith AB, Halperin WE, Lernen RA (1985) Mortality among a cohort of US cadmium production workers—an update. J Nat Cancer Inst /4:325–333Google Scholar
  57. 57.
    Goldsmith DF, Winn DM, Shy CM (eds) (1986) Silica, silicosis, and cancer. Praeger, New YorkGoogle Scholar
  58. 58.
    Heinrich U, Muhle H, Takenaka S, Ernst H, Fuhst R, Mohr U, Pott F, Stöber W (1986) Chronic effects on the respiratory tract of hamsters, mice and rats after long-term inhalation of high concentrations of filtered and unfiltered diesel engine emissions. J Appl Toxicol 6:383–395PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag New York Inc. 1988

Authors and Affiliations

  • U. Mohr
    • 1
  • D. L. Dungworth
    • 2
  1. 1.Institut für Experimentelle PathologieMedizinische Hochschule HannoverHannover 61Germany
  2. 2.Department of Veterinary PathologyUniversity of CaliforniaDavisUSA

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