Advertisement

Assessment of Low-Exposure Risk from Carcinogens: Implications of the Knudson-Moolgavkar Two-Critical Mutation Theory

  • James D. Wilson

Abstract

The two-critical-mutation carcinogenesis theory of Knudson and Moolgavkar seems to provide solutions to some of the most contentious problems in cancer risk assessment. It describes a class of agents which increase tumor incidence without being reactive toward DNA: these nongenotoxic agents act through increases in cell birth rate. Because mutations occur when DNA lesions are not repaired before mitosis, increasing the mitotic rate increases the probability that a critical mutation will occur. Agents which affect mitotic rate can act either on normal cells or on those which have undergone one of the two critical mutations (“initiated”). Those acting on initiated cells are identified with the class called “promoters” by experimentalists. No unequivocal examples of agents acting solely on normal cells have yet been reported, although some are postulated.

Exposure limits for nongenotoxic agents should be set based on the dose-response for mitotic rate increase, since this is the determining step in the process.

Genotoxic agents act directly on DNA; their hazard is proportional to cumulative exposure when acting in this mode. However, all such agents will also increase mitotic rate under some conditions and, in addition, many are believed also to act as promoters. The two kinds of activity are synergistic; where both occur, the dose-response curve is much steeper than would otherwise be expected. Incidence data from this regime (i.e., high dose or dose-rate experiments) cannot be used to estimate low-exposure hazard through the conventional “linearized multistage” technique, because effect cannot be taken to be simply proportional to dose. A mathematically correct version of this method would be appropriate for estimation of low-dose hazard, if applied to data from experiments where mitotic rate is not elevated. Unfortunately, conventional lifetime bioassays do not provide the information needed to ascertain if their output can be so used; additional experiments must be done.

Also discussed are recommendations for improving oxicity testing so that better low-exposure hazard estimates can be made.

Keywords

Maximum Tolerate Dose Critical Path Mitotic Rate Cancer Risk Assessment Genotoxic Agent 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Alexander, P., 1988. In: “Theories of Carcinogenesis”, O. H. Iversen, ed., Hemisphere Publishing Co., Washington, DC, 293–294.Google Scholar
  2. Ames, B., 1983, Science, 221: 1256–1264.PubMedCrossRefGoogle Scholar
  3. Ames, B. and R. L. Saul, 1988. In: “Theories of Carcinogenesis”, O. H. Iversen, ed.; Hemisphere Pub. Corp.; Washington; 203–220.Google Scholar
  4. Anderson, R. L., 1987. In Banbury Report 25: Nongenotoxic Mechanisms in Carcinogenesis, Cold Spring Harbor Laboratory, 277–283. Also R. L. Anderson, C. L. Alden, manuscript submitted for publication.Google Scholar
  5. Armitage, P. and R. Doll, 1954. Brit. J. CancerGoogle Scholar
  6. Barrett, J. C. and R. W. Wiseman, 1987. Environ. Health Perspect., 76:65–70.Google Scholar
  7. Bayard, S. and T. W. Thorslund, 1987. Paper given at “Dioxin 87”, Las Vegas, NV; Chemosphere, 17 (in press).Google Scholar
  8. Bois, F., 1985. Private communication (poster presented at symposium, “Human Risk Assessment The Role of Animal Selection and Extrapolation”, St. Louis, MO; October 28–31, 1985.Google Scholar
  9. Bradshaw, R. A. and S. Prentis, eds., 1987. “Oncogenes and Growth Factors”, Elsevier, Amsterdam.Google Scholar
  10. Cohen, S. M., and L. B. Ellwein, 1988. Tox. Letters (in press).Google Scholar
  11. Conolly, R. B., R. H. Reitz, and M. E. Andersen, 1987. In: “Pharmacokinetics in Risk Assessment”, National Academy Press, Washington, DC; 273–285.Google Scholar
  12. Den Otter, W., 1985. Cancer Immunol. Immunother., 19: 159–162.CrossRefGoogle Scholar
  13. Driver, H. E., I. N. H. White, W. H. Butler, 1987. Br. J. Exp. Path., 68: 133–143.Google Scholar
  14. Ellwein, L. B., and S. M. Cohen, 1988. Risk Analysis, 8: 215–221.PubMedCrossRefGoogle Scholar
  15. Greenfield, R. E., L. B. Ellwein, and S. M. Cohen, 1984. Carcinogenesis, 5: 437–445.PubMedCrossRefGoogle Scholar
  16. Hasegawa, R., S. M. Cohen, M. St. John, M. Cano, and L. B. Ellwein, 1986. Carcinogenesis, 7: 633–636.PubMedCrossRefGoogle Scholar
  17. Hudson, L. G., W. A. Toscano, Jr., and W. F. Greenlee, 1986. Tox. Appl. Pharm., 82: 481–492.Google Scholar
  18. Iannaccone, P. M., W. C. Weinberg, and F. D. Deamant, 1987. Int. J. Cancer 39: 778–784.PubMedCrossRefGoogle Scholar
  19. Inman, W. H. and S. P. Colowick, 1985. Proc. Natl. Acad. Sci. USA, 82: 1246–1349.CrossRefGoogle Scholar
  20. Isaacs, J. T., 1985. Cancer Res., 45: 4827–4832.PubMedGoogle Scholar
  21. Kimchi, A., X. -F. Wang, R. A. Weinberg, S. Cheiftez, and J. Massague, 1988. Science, 240: 196–199.PubMedCrossRefGoogle Scholar
  22. Klein, G. and E. Klein, 1984. Carcinogenesis, 5: 429–435.PubMedCrossRefGoogle Scholar
  23. Klein, G., 1987. Science, 238: 1539–1545.PubMedCrossRefGoogle Scholar
  24. Knudson, A. G., 1985. Cancer Research, 45: 1437–1443.PubMedGoogle Scholar
  25. Knudson, A. G., 1987. Adv. Viral Oncology, 7: 1–17.Google Scholar
  26. Littlefield, N. A. and D. W. Gaylor, 1985. J. Tox. Env. Health, 15:545–550.CrossRefGoogle Scholar
  27. Mauskopf, J., 1986. Paper given at the annual meeting of the Society for Risk Analysis; Boston, MA. Proceedings (in press).Google Scholar
  28. Metzger, B., E. A. C. Crouch, and R. Wilson, 1987. Manuscript submitted for publication.Google Scholar
  29. Miller, J. A. and E. C. Miller, 1977. In: “Origins of Human Cancer”, H. H. Hiatt, J. D. Watson, and J. A. Winsten, eds., Cold Spring Harbor Laboratory, 605–627.Google Scholar
  30. Moolgavkar, S. H., 1979. J. Nat. Cancer Inst., 61: 49–52.Google Scholar
  31. Moolgavkar, S. H., 1983. Env. Health Perspectives, 50: 285–291.CrossRefGoogle Scholar
  32. Moolgavkar, S. H., 1986. Ann. Rev. Pub. Health, 7: 151–169.Google Scholar
  33. Moolgavkar, S. H. and A. Dewanji, 1988. Risk Analysis, 8: 5–7.PubMedCrossRefGoogle Scholar
  34. Moolgavkar, S. H. and A. G. Knudson, 1981. J. Nat. Cancer Inst., 66: 1037–1052.PubMedGoogle Scholar
  35. Moolgavkar, S. H. and D. J. Venzon, 1979. Math. Biosci., 47:55–77.CrossRefGoogle Scholar
  36. Parkinson, E. K., P. Grabham, A. Emmerson, 1983. Carcinogenesis, 4: 857–861.CrossRefGoogle Scholar
  37. Pitot, H. C., T. L. Goldsworthy, S. Moran, W. Kennan, H. P. Glauert, R. R. Maronpot, and H. A. Campbell, 1987. Carcinogenesis, 8: 1491–1499.PubMedCrossRefGoogle Scholar
  38. Potter, V. R., 1981. Carcinogenesis, 2: 1375–1379.PubMedCrossRefGoogle Scholar
  39. Potter, V. R., 1988. Advan. Oncology, 4 (1): 3–8.Google Scholar
  40. Saul, R. L., Ames, B. N., 1985. Paper given at the International Conference “Mechanisms of DNA Damage and Repair”, Gaithersburg, Maryland. Proceedings (in press).Google Scholar
  41. Simic, M., and M. Karel, eds., 1980. “Autoxidation in Food and Biological Systems”, Plenum Press, New York.Google Scholar
  42. Takehara, K., E. C. LeRoy, and G. R. Grotendorst, 1987. Cell, 49: 415–422.PubMedCrossRefGoogle Scholar
  43. Thorslund, T. W., C. C. Brown, and G. Charnley, 1987. Risk Analysis, 7: 109–119.PubMedCrossRefGoogle Scholar
  44. Travis, C., 1988. This volume.Google Scholar
  45. Trosko, J. E., 1988. Mutagenesis, 3: 363–364.PubMedCrossRefGoogle Scholar
  46. Trosko, J. E. and C. -C. Chang, 1978. Quart. Rev. Biology, 53: 115CrossRefGoogle Scholar
  47. Trosko, J. E. and C. -C. Chang, 1980. Med. Hypotheses, 6: 455–468.PubMedCrossRefGoogle Scholar
  48. Trosko, J. E., C. -C. Chang, and A. Medcalf, 1983. Cancer Investigation. 1: 511–526.PubMedCrossRefGoogle Scholar
  49. Whittemore, A., and J. B. Keller, 1978. SIAM Rev., 20: 1–30.CrossRefGoogle Scholar
  50. Zeise, L., E. A. C. Crouch, and R. Wilson, 1984. Risk Anal., 4:187–199. Also, Risk Anal., 5:265–270 (1985) and J. Tox. Environ. Health, 20: 1–10 (1987).Google Scholar
  51. Zeise, L. and E. A. C. Crouch, 1985. Private communication (unpublished manuscript).Google Scholar

Copyright information

© Plenum Press, New York 1989

Authors and Affiliations

  • James D. Wilson
    • 1
  1. 1.Monsanto CompanySt. LouisUSA

Personalised recommendations