Skip to main content
SpringerLink
Log in

Evaluation of the Carcinogenic Potential of Pharmaceuticals

Opportunities Arising from the International Conference on Harmonisation

  • Current Opinion
  • Published:
Drug Safety Aims and scope Submit manuscript

Summary

The evaluation of the carcinogenic potential of pharmaceuticals is currently undergoing dramatic changes. For the past 25 years the regulatory expectation for agents intended for long term use has been that lifespan studies (usually lasting 2 years) in 2 rodent species be conducted. These studies take at least 3 years to plan, execute and interpret, and use over 1200 animals. It is now recognised that the quality of the information obtained from these studies is unreliable for prediction of carcinogenic risk to humans.

Over the past 4 years, the International Conference on Harmonisation (ICH) has recommended changes in approaches to assessing the carcinogenic potential of pharmaceuticals. In future, only one long term rodent study will be routinely required (usually in rats), provided this is complemented with a short or medium term test in one of the emerging new models for carcinogenicity, such as transgenic mice or newborn mice. However, the relevance of these new models to human cancer and their use in risk assessment is still largely unknown and this situation must be kept under review as knowledge accumulates. Along term study in a second rodent species is still an option.

Dose selection has also been improved inasmuch as there are now several alternatives to the use of the maximum tolerated dose (MTD). In the past, the use of the MTD, when the normal homeostasis of the test animals is disturbed, has been considered one of the major problems with the rodent carcinogenicity bio-assay. However, one of the alternative end-points to the use of the MTD, i.e. the comparison of plasma concentrations in rodents and humans, must be viewed with caution. While this may contribute to limiting the high dose level for agents of very low toxicity, the concept should not be interpreted as signifying that plasma concentrations provide a sound basis for comparing the carcinogenic activity of agents in different species.

Recognition of the 4 properties (genotoxicity, immunosuppression, steroid hormonal activity and long term tissue damage), at least one of which is associated with each of the pharmaceuticals known to be carcinogenic to humans, should focus more attention on a search for these properties in patients. Absence of these properties at clinically relevant dose levels indicates that a pharmaceutical is highly unlikely to be carcinogenic to humans.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. D’Arcy PF, Harron DWG, editors. Proceedings of the Third International Conference on Harmonisation; Nov 1995: Yokohama, Japan. Belfast: Queen’s University Press, 1996

    Google Scholar 

  2. Ashby J, Tennant RW. Definitive relationships among chemical structure, carcinogenicity and mutagenicity for 301 chemicals tested by the US NTP. Mutat Res 1991; 257: 229–306

    Article  PubMed  CAS  Google Scholar 

  3. Gold LS, Bernstein L, Magaw R, et al. Inter-species extrapolation in carcinogenesis: prediction between rats and mice. Environ Health Perspect 1989: 81: 211–9

    Article  PubMed  CAS  Google Scholar 

  4. Monro AM. Testing for carcinogenic potential. In: D’Arcy PF, Harron DWG, editors. Proceedings of the Third International Conference on Harmonisation: Nov 1995: Yokohama, Japan. Belfast: Queen’s University Press, 1996: 261–8

    Google Scholar 

  5. van Oosterhout JPJ, van der Laan JW, de Waal EJ, et al. The utility of two rodent species in carcinogenic risk assessment of pharmaceuticals in Europe. Regul Pharmacol Toxicol 1997: 25: 6–17

    Article  Google Scholar 

  6. Contrera JF, Jacobs AC, DeGeorge JJ. Carcinogenicity testing and the evaluation of the regulatory requirements for pharmaceuticals. Regul Pharmacol Toxicol 1997: 25: 130–45

    Article  CAS  Google Scholar 

  7. Ames BN, Gold LS, Willett WC. The causes and prevention of cancer. Proc Natl Acad Sci USA 1995: 92: 5258–65

    Article  PubMed  CAS  Google Scholar 

  8. Monro AM. Are lifespan rodent carcinogenicity studies defensible for pharmaceutical agents? Exp Toxicol Pathol 1996: 48: 155–66

    Article  PubMed  CAS  Google Scholar 

  9. Cancer facts and figures. Atlanta (GA): American Cancer Society, 1995

  10. Davies TS, Monro AM. Marketed human pharmaceuticals reported to be tumorigenic in rodents. J Am Coll Toxicol 1995: 14: 90–107

    Article  CAS  Google Scholar 

  11. Haseman JK. Patterns of tumor incidence in two-year cancer bioassay feeding studies in Fischer 344 rats. Fundam Appl Toxicol 1983: 3: 1–9

    Article  PubMed  CAS  Google Scholar 

  12. Davies TS, Monro AM. The rodent carcinogenicity bioassay produces a similar frequency of tumor increases and decreases: implications for risk assessment. Regul Toxicol Pharmacol 1994: 20: 281–301

    Article  PubMed  CAS  Google Scholar 

  13. Ames BN, Gold LW. Too many rodent carcinogens: mitogenesis increases carcinogenesis. Science 1990: 249: 970–1

    Article  PubMed  CAS  Google Scholar 

  14. Cohen SM, Ellwein LB. Cell proliferation in carcinogenesis. Science 1990: 249: 1007–11

    Article  PubMed  CAS  Google Scholar 

  15. Clayson DB, Iverson F, Mueller R. An appreciation of the maximum tolerated dose: an inadequately precise decision point in designing a carcinogenesis bioassay? Teratog Carcinog Mutagen 1991: 11: 279–96

    Article  PubMed  CAS  Google Scholar 

  16. Grasso P, Sharrat M, Cohen AJ. Role of persistent, non-genotoxictissue damage in rodent cancer and relevance to humans. Annu Rev Pharmacol Toxicol 1991: 31: 253–87

    Article  PubMed  CAS  Google Scholar 

  17. Monro AM. How useful are chronic (life-span) toxicology studies in rodents in identifying pharmaceuticals that pose a carcinogenic risk to humans. Adverse Drug React Toxicol Rev 1993: 12: 5–34

    PubMed  CAS  Google Scholar 

  18. Cohen SM. Human relevance of animal carcinogenicity studies. Regul Toxicol Pharmacol 1995: 21: 75–80

    Article  PubMed  CAS  Google Scholar 

  19. Goodman JI. A rational approach to risk assessment requires the use of biological information: an analysis of the National Toxicology Program (NTP), final report of the advisory review by the NTP Board of Scientific Counsellors. Regul Toxicol Pharmacol 1994: 19: 51–9

    Article  PubMed  CAS  Google Scholar 

  20. Gori GB, Flamm WG. How sick a patient? Report of a workshop on cancer risk assessment. Regul Toxicol Pharmacol 1991: 14: 215–22

    Article  PubMed  CAS  Google Scholar 

  21. Marselos M, Vainio H. Carcinogenic properties of pharmaceutical agents evaluated in the IARC Monographs programme. Carcinogenesis 1991: 12: 1751–6

    Article  PubMed  CAS  Google Scholar 

  22. Ashby J, Paton D. The influence of chemical structure on the extent and sites of carcinogenesis for 522 rodent carcinogens and 55 different human carcinogen exposures. Mutat Res 1993: 286: 3–74

    Article  PubMed  CAS  Google Scholar 

  23. Monographs on the evaluation of the carcinogenic risk to humans. International Agency for Research on Cancer, Lyon: 64: 1996

  24. Williams GM, Weisburger JH. Chemical carcinogenesis. In: Amdur MO, Doull J, Klaassen CD, editors. Casarett and Doull’s toxicology. 4th ed. New York: Pergamon Press, 1991: 127–200

    Google Scholar 

  25. Henderson BE, Ross RK, Pike MC. Toward the primary prevention of cancer. Science 1995: 254: 1131–8

    Article  Google Scholar 

  26. Key TJA, Beral V. Sex hormones and cancer. In: Vainio H, Magee PN, McGregor DB, et al., editors. Mechanisms of carcinogenesis in risk identification. Lyon: IARC, 1992: 255–69

    Google Scholar 

  27. Preston-Martin S, Pike MC, Ross RK, et al. Increased cell division as a cause of human cancer. Cancer Res 1990: 50: 7415–21

    PubMed  CAS  Google Scholar 

  28. Ashby J, Tennant RW. Prediction of rodent carcinogenicity for 44 chemicals: results. Mutagenesis 1994: 9: 7–15

    Article  PubMed  CAS  Google Scholar 

  29. Usui T, Griffiths S, Lumley CE. Industry viewpoint: the utility of the mouse for the assessment of the carcinogenic potential of pharmaceuticals. In: D’Arcy PF, Harron DWG, editors. Proceedings of the Third International Conference on Harmonisation; Nov 1995: Yokohama, Japan. Belfast: Queen’s University Press, 1996: 279–84

    Google Scholar 

  30. Goldsworthy TL, Reuo L, Brown K, et al. Transgenic animals in toxicology. Fundam Appl Toxicol 1994: 22: 8–19

    Article  PubMed  CAS  Google Scholar 

  31. Gonzalez F. Use of transgenic animals in carcinogenesis studies. Molec Carcinogen 1996: 16: 63–7

    Article  CAS  Google Scholar 

  32. Tennant RW, French JE, Spalding JW. Identifying chemical carcinogens and assessing potential risk in short-term bioassays using transgenic mouse models. Environ Health Perspect 1995: 103: 942–50

    Article  PubMed  CAS  Google Scholar 

  33. Robinson D. ILSF’s role in the evaluation of alternative methodologies for the assessment of carcinogenic risk. Toxicol Pathol 1998. In press

  34. Ashton GA, Griffiths SA, McAuslane JAN, et al. High dose selection for carcinogenicity studies — implementation of ICH guidelines during 1995 and 1996 [abstract no. 286]. Toxicol Sci 1998; 42S

  35. Monro AM. The paradoxical lack of interspecies correlations between plasma concentrations and chemical carcinogenicity. Regul Toxicol Pharmacol 1993; 18: 115–35

    Article  PubMed  CAS  Google Scholar 

  36. Newman TB, Hulley SB. Carcinogenicity of lipid-lowering drugs. JAMA 1996; 275: 55–60

    Article  PubMed  CAS  Google Scholar 

  37. Contrera JF, Jacobs AC, Prasanna HR, et al. A systemic exposure-based alternative to maximum tolerated dose for carcinogenicity studies of human therapeutics. J Am Coll Toxicol 1995; 14: 1–10

    Article  CAS  Google Scholar 

  38. Monro AM, Davies TS. High dose levels are not necessary in rodent studies to detect human carcinogens. Cancer Fett 1993; 75: 183–94

    Article  CAS  Google Scholar 

  39. Davies TS, Monro AM. The case for an upper dose limit of 1000 mg/kg in rodent carcinogenicity tests. Cancer Lett 1995; 95: 69–77

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Pfizer Central Research, Pfizer Ltd, Sandwich, Kent, CT13 9NJ, England

    Alastair M. Monro

  2. Schering-Plough Research Institute, Kenilworth, New Jersey, USA

    James S. MacDonald

Authors
  1. Alastair M. Monro
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. James S. MacDonald
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Monro, A.M., MacDonald, J.S. Evaluation of the Carcinogenic Potential of Pharmaceuticals. Drug-Safety 18, 309–319 (1998). https://doi.org/10.2165/00002018-199818050-00001

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00002018-199818050-00001

Keywords

Search

Navigation