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have a no-effect threshold with re- spect to tumorigenesis. This is par- ticularly true for nongenotoxic chemicals that act through a mech- anism nol: directly involving a cell receptor. Substantial difficulties arise in interpreting the carcinogenic po- tential of many chemicals, exem- plified by asbestos (83). For exam- ple, controversy continues as to whether asbestos itself is geno- toxic, since it has clastogenic activ- ity in sozzie cell culture systems. Also of significance, exposure of limited duration to asbestos is ac- tually lifetime exposure, since it re- mains within the mesothelial cells. Thus, it provides a chronic prolif- erative stimulus even if the actual environmer.ital exposure was rela- tively brief, The challenge remains to ascertain whether there is a min- imal level of chronic proliferation that determines whether there is a no-effect threshold exposure level with respect to asbestos-induced carcinogenesis in humans. CONCLUSIONS We have presented a two-event model of carcinogenesis, wherein agents increase the likelihood of developing cancer by increasing the probability o:F genetic damage dur- ing each cell mitosis or by increas- ing the number of cell divisions subject to spontaneous genetic damage probabilities (i.e., cell pro- liferation), or by doing both. Whether cancer occurs by two, or more, critic~tl genetic events, these two general mechanisms remain as the only ones by which an agent can increase cancer risk. Agents causing direct genetic damage dur- ing cell division, such as radiation and genotoxic chemicals, are not likely to have a threshold for car- cinogenic re;st onse. Further, the dose-response can be significantly influenced by the cytoxicity and regenerative hyperplasia that fol- low exposure to these agents at high doses. For agents that act only by in- creasing cell proliferation, whether nongenotoxic chemicals, infectious organisms, or chronic inflamma- tory processes, the magnitude and duration of the increased prolifer- ative processes are integral to car- cinogenesis. Brief responses will probably not be associated with a detectable increased risk of cancer, since any increased proliferation will be of short duration and con- tribute little to the total number of cell divisions during which spon- taneous genetic damage might oc- cur. Both genetic damage and in- creased cell proliferation act in hu- man and in animal carcinogenesis. Study of the complex of biochemi- cal and physiologic adaptive and maladaptive tissue processes offers numerous opportunities for en- hancing our understanding of the carcinogenic process and for de- signing preventive intervention strategies. Acknowledgments: The authors grate- fully acknowledge the numerous individuals that have contributed to their research, par- ticularly the late Dr. Robert E. Greenfield for his many contributions to the develop- ment of the concepts presented in this pa- per. They thank Ginni Philbrick for her valuable assistance with the preparation of this manuscript. Laboratory work has been supported by Grants CA32513, CA44886, CA30196, and CA36727 from the National Cancer Insti- tute; grants from the Department of Health, State of Nebraska; funding from the Inter- national Life Sciences Institute; and gifts to the Lymphoproliferative Research Fund. Date of acceptance: December 20, 1990. Address reprint requests to: Dr. Samuel M. Cohen, Department of Pathology and Microbiology, University of Nebraska Med- ical Center, 600 South 42nd Street, Omaha, NE 68198-3135. ® REFERENCES 1. Cancer Facts and Figures. New York, Ameri- can Cancer Society, 1989. 2. Loeb LA, Ernster VL, Warner KE, Abbotts J, Laszio J: Smoking and lung cancer: an over- view. Cancer Res 44:5940, 1984 3. Tomatis L, Aitio A, Wilbourn J, Shuker L: Human carcinogens so far identified. Jpn J Cancer Res 80:795, 1989 4. Rubin E, Farber JL: Neoplasia. In Pathology, edited by Rubin E, Farber JL. Philadelphia, JB Lippincott Company, 1988 5. Boveri T: Zur Trage der Entstehung maligner Tumoren, edited by Jena, Fischer, 1914 6. Berenblum I, Shubik P: A new quantitative approach to the study of the stages of chemical carcinogenesis in the mouse's skin. Br J Can- cer 1:383, 1947 7. Knudson AG: Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci USA 68:820, 1971 8. Nordling CO: A new theory on the cancer- inducing mechanism. Br J Cancer 7:68, 1953 9. Moolgavkar SH, Knudson AG Jr. Mutation and cancer. a model for human carcinogenesis. JNCI 66:1037, 1981 10. Moolgavkar SH, Luebeck G, deGunst M: Two mutation model for carcinogenesis: relative roles of somatic mutations and cell prolifera- tion in determining risk. In Scientific Issues in Quantitative Risk Assessment, edited by Moolgavkar SH, p 136. Boston, Birkhauser, 1990 11. Greenfield RE, Ellwein LB, Cohen SM: A general probabilistic model of carcinogenesis: analysis of experimental urinary bladder can- cer. Carcinogenesis 5:437, 1984 12. Cohen SM, Ellwein LB: Cell proliferation in carcinogenesis. Science 249:1007, 1990 13. Knudson AG Jr: Two-event carcinogenesis; roles of oncogenes and antioncogenes. In Sci- entific Issues in Quantitative Risk Assess- ment, edited by Moolgavkar SH, p 32. Boston, Birkhauser, 1990 14. Sager R: Tumor suppressor genes: the puzzle and the promise. Science 246:1406, 1989 15. Knudson AG Jr: Hereditary cancers: clues to mechanisms of carcinogenesis. Br J Cancer 59:661, 1989 16. Purtilo DT, Pacquin LA, Gindhart T: Ge- netics of neoplasia: impact of ecogenetics on oncogenesis. Am J Patho191:609, 1978 17. Fearon ER, Vogelstein B: A genetic model for colorectal tumorigenesis. Cell 61:759, 1990 18. Furth J: Conditioned and autonomous neo- plasms: a review. Cancer Res 13:477, 1953 19. Ziel HK, Finkle WD: Increased risk of endo- metrial carcinoma among users of conjugated estrogens. N Engl J Med 293:1167, 1975 20. Russo J, Gusterson BA, Rogers AE, Russo IH, Wellings SR, van Zwieten M: Biology of dis- ease: comparative study of human and rat mammary tumorigenesis. Lab Invest 62:244, 1990 21. Hill RN, Erdreich LS, Paynter OE, Roberts PA, Rosenthal SL, Wilkinson CF: Thyroid follicular cell carcinogenesis. Fundam Appl Toxicol 12:697, 1989 22. Bosland MC: The etiopathogenesis of pros- tatic cancer with special reference to environ- mental factors. Adv Cancer Res 51:1, 1988 23. Key TJA, Pike MC: The dose-effect relation- ship between "unopposed" oestrogens and en- dometrial mitotic rate: its central role in ex- plaining and predicting endometrial cancer risk. Br J Cancer 57:205, 1988 24. Bolt HM, Gobel P: Formation of estrogens from androgens by human subcutaneous adi- pose tissue in vitro. Horm Metab Res 4:312, 1976 25. Coulam CB, Annegers JF, Kranz JS: Chronic anovulation syndrome and associated neopla- sia. Obstet Gynecol 61:403, 1983 26. Some naturally occuring substances. IARC Monogr Eval Carcinog Risk Chem Man 10:153,1975 27. Herbst AL: The effects in the human of dieth- ylstilbestrol (DES) use during pregnancy. In Proceedings of the 18th International Sym- posium of the Princess Takamatsu Cancer Research Fund, p 67. Tokyo, Japan Scientific Societies Press, 1988 28. Liehr JG, Randerath K, Randerath E: Target organ-specific covalent DNA damage preced- ing diethylstilbesterol-induced carcinogenesis. Carcinogenesis 6:1067, 1985 29. Henderson BE, Ross RK, Pike MC, Casa- grande JT: Endogenous hormones as a major factor in human cancer. Cancer Res 42:3232, 1982 30. Barrows GH, Mays ET, Christopherson WM: Steroid related neoplasia in human liver. In Proceedings of the 18th International Sym- posium of the Princess Takamatsu Cancer Research Fund, p 47. Tokyo, Japan Scientific Societies Press, 1988 31. Pimental E: Oncogenes. Boca Raton, FL, CRC Press, 1986 32. Miller EC, Miller JA: Carcinogens and muta- gens that may occur in foods. Cancer 58:1795, 1986 33. Hirono 1: Natural carcinogeneic products of plant origin. Crit Rev Toxicol 8:235, 2981 34. Khojasteh A, Haghighi P: Immunoprotifera- CELL PROLIFERATION AND CANCER 381

tive small intestinal disease: portrait of a po- tcntially preventable cancer from the third world. Am J Med 89:483, 1990 35. El-Bolkainy MN: Schistosomiasis and bladder cancer. In The Pathology of Bladder Cancer, edited by Bryan GT, Cohen SM, Vol I, p 57. Boca Raton, FL, CRC Press, 1983 36. Purtilo DT: Clonorchiasis and hepatic neo- plasms. Trop Geogr Med 28:21, 1976 37. Gutierrez Y: The trematodes of blood vessels: the schistosomes-schistosomiasis. In Diagnos- tic Pathology of Parasite Infections with Clin- ical Correlations, p 393. Philadelphia, Lea and Febiger, 1990 38. Ktirathong S, Lerdverasirikul P, Wongpaitoon V, Pramoolsinsap C, Kanjanapitak A, Varav- ithya W, Phuapradit P, Bunyaratvej S, Upa- tham ES, Brockelman WY: Opisthorchis uiv- errini infection and cholangiocarcinoma. Gas- troenterology 89:151, 1985 39. Varrrus H: Retroviruses. Science 10:1427, 1988 40. To maisi TB: Retroviruses, oncogenes, and can- cer. Adv Pathol 1:229, 1988 41. Purtilo DT: Lymphotropic viruses, Epstein- Barr virus (EBV), and human T-lymphotropic vinis-I (HTLV-I), adult T-cell leukemia virus (ATLV), and HTLV-III/human immune de- fici?nzy virus (HIV) as etiological agents of malignant lymphoma and immune deficiency. AIDS Res 2S177, 1986 42. Purtilo DT, Manolov G, Manolova Y, Harada S, Grierson H: Squamous cell carcinoma. Ka- posz s sarcoma, and Burkitt's lymphoma are conseluences of impaired immune surveil- lance of ubiquitous viruses in acquired im- mune deficiency syndrome, allograft recipi- ents, end tropical African patients. In \'iruces and Tumors in Africans, edited by William. AO, O'Connor GT, DeThe G, Johnson CA. p 749. New York, Oxford University Press. 1984 43. Fenoglio CM, Galloway DA, Crum CP: Herpes simplex virus and cervical neoplasia. In Pro- gress in Surgical Pathology, edited by Fenoglio CM, M7o1ff M, p 45. New York, Masson, 1981 44. Biscegie AM, Rustgi VK, Hoofnagle JH. Dusheiko GM, Lotze MT: Hepatocellular car- cinoma. Ann Intern Med 108:390, 1988 45. Beaslev RP: Hepatitis B virus. Cancer 61:1942,1987 46. Tiollais P, Pourcel C, Dejean A: The hepatitis B viuv,. Nature 317:489,1985 47. Dunsfard HA, Sell S, Chisari FV: Hepatocar- cinogenesis due to chronic liver cell injury in hepatitis B virus transgenic mice. Cancer Res 50:3400, 1990 48. zur Hausen H: Papillomaviruses as carcinoma viruses. In Advances in Viral Oncology, edited by Ii:lein G, Vol 8, p 1. New York, Raven Press, 1989 49. Friedell GH, Hertig AT, Younge PA: Carci- noma ia Situ of the Uterine Cervix. Spring- field, IL, CC Thomas, 1960 50. Clarke EA, Morgan RW, Newman AM: Smok- ing as a risk factor in cancer of the cervix: additional evidence from a case-control study. Am J Epidemiol 115:59, 1982 51. Thorley-Lawson DA: Immunological re- sponses to Epstein-Barr virus infection and the pathogenesis of EBV-induced diseases. Biochim Biophys Acta 948:263, 1988 52. Klein G, Klein E: Conditioned tumorigenicity of activated oncogenes. Cancer Res 46:3211, 1986 53. Yukawa K, Kikutani H, Inomoto T, Uehira M, Bin SH, Akagi K, Yamamura KI, Kishi- moto T: Strain dependency of B- and T-lym- phoma development in immunoglobulin heavy chain enhancer (Eg)-myc transgenic mice. J Exp Med 170:711, 1989 54. Knutson JC, Sugden B: Immortalization of lymphocytes by Epstein-Barr virus: what does the virus contribute to the cell? In Advances in Viral Oncology, edited by Klein G, Vol 8, p 151. New York, Raven Press, 1989 55. Kripke ML, Borsos T: Immune surveillance revisited. JNCI 52:1393, 1974 56. Elliott BE, Carlow DA, Rodricks AM, Wade A: Perspectives on the role of MHC antigens in normal and malignant cell development. Adv Cancer Res 53:181, 1989 57. Schwartz RW: Another look at immunologic surveillance. N Engl J Med 293:181, 1975 58. Baldwin RW: Immunological aspects of chem- ical carcinogenesis. Cancer Res 33:1, 1973 59. Purtilo DT: Defective immune surveillance in viral oncogenesis. Lab Invest 51:373, 1984 60. Purtilo DT, Linder J: Oncological conse- quences of impaired immune surveillance against ubiquitous viruses. J Clin Immunol 3:197, 1983 61. Ensoli B, Barillari G, Salahuddin SZ, Galo RC, Wong-Staal F: Tat protein of HIV-1 stim- ulates growth of cells derived from Kaposi's sarcoma lesions of AIDS patients. Nature 345:84,1990 62. Gopas J, Rager-Zisman B, Bar-Eli M, Ham- erling GJ, Segal S: The relationship between MHC antigen expression and metastasis. Adv Cancer Res 53:89, 1989 63. Mirvish SS: The etiology of gastric cancer. intragastric nitrosamide formation and other theories. JNCI 71:631, 1983 64. Riddell RH, Goldman H, Ransohoff DF, Ap- pelman HD, Fenoglio CM, Haggitt RC, Ahren C, Correa P, Hamilton SR, Morson BC, Som- mers SC, Jardley JH: Dysplasia in inflamma- tory bowel disease: standardized classification with provisional clinical applications. Hum Pathol 14:931, 1983 65. Dooley CP, Cohen H, Fitzgibbons PL, Bauer M, Appleman MD, Perez-Perez GI, Blaser MJ: Prevalence of Helicobacter pylori infection and histologic gastritis in asymptomatic per- sons. N EngI J Med 321:1562, 1989 66. Lipkin M: Biomarkers of increased suscepti- bility to gastrointestinal cancer- new applica- tion to studies of cancer prevention in human subjects. Cancer Res 48:235, 1988 67. Reshef R, Rozen P, Fireman Z, Fine N, Bar- zilai M, Shasha SM, Shkolkik T: Effect of a calcium-enriched diet on the colonic epithelial hyperproliferation induced by N-methyl-N'- nitro-N-nitrosoguanidine in rats on a low cal- cium and fat diet. Cancer Res 50:1764, 1990 68. Kato I, Kato K, Akai S, Tominaga S: A case- control study of gallstones: a major risk factor for biliary tract cancer. Jpn J Cancer Res 81:578, 1990 69. Connor DH: Tropical phagedenic ulcer. In The Skin, International Academy of Pathology Monograph 10, p 448. Baltimore, Williams & Wilkins, 1971 70. Potet F, Duchatelle V: Barrett's oesophagus. Curr Top Pathol 81:43, 1990 71. Price CHG: Primary bone-forming tumors and their relationship to skeletal growth. J Bone Joint Surg [Br] 40:574, 1958 72. Spjut HJ, Dorfman HD, Fechner RE, Acker- man LV: Tumors of bone and cartilage. In AFIP-Atlas of Tumor Pathology, p 174. Wash- ington, DC, AFIP, 1971 73. Committee on Biological Effects of Ionizing Radiations: Health Effects of Exposure to Low Levels of Ionizing Radiation. Washington, DC, National Academy Press, 1990 74. MacMahon HE, Murphy AS, Bates MI: Endo- thelial-cell sarcoma of liver following thoro- trast injections. Am J Pathol 23:585, 1947 75. Hale KA, Ewing SL, Gosnell BA, Niewoehner DE: Lung disease in long-term cigarette smok- ers with and without chronic air-flow obstruc- tion. Am Rev Respir Dis 130:716, 1984 76. Auerbach 0, Garfinkel L: Histologic changes in the urinary bladder in relation to cigarette smoking and use of artificial sweeteners. Can- cer 64:984, 1989 77. Johansson SL, Hirsch JM, Larsson P-A, Saidi J, Osterdahl B-G: Snuff-induced carcinogen- esis: effect of snuff in rats initiated with 4- nitroquinoline N-oxide. Cancer Res 49:3063, 1989 78. Tennant RW, Margolin BH, Shelby MD, Zeiger E, Haseman JK, Spalding J, Caspary W, Resnick M, Stasiewicz S, Anderson B, Minor R: Prediction of chemical carcinogen- icity in rodents from in vitro genetic toxicity assays. Science 236:933, 1987 79. Melnick RL, Boorman GA, Haseman JK, Montali RJ, Huff J: Urolithiasis and bladder carcinogenicity of melamine in rodents. Tox- icol Appl Pharmacol 72:292, 1984 80. Heck HD'A, Tyl RW: The induction of blad- der stones by terephthalic acid, dimethyl ter- ephthalate, melamine (2,4,6-triamino-S-tria- zine), and its relevance to risk assessment. Regul Toxicol Pharmacol 5:294, 1985 81. Environmental Protection Agency. Melamine: toxic chemical release reporting: community right-to-know. In Federal Register, Vol 53, p 23128. Washington, DC, GPO, 1988 82. Ellwein LB, Cohen SM: The health risks of saccharin revisited. Crit Rev Toxicology 20:311,1990 83. Mossman BT, Gee JBL: Asbestos-related dis- eases. N Engl J Med 320:1721, 1989 382 MODERN PATHOLOGY