National Academies Press: OpenBook

Issues in Risk Assessment (1993)

Chapter: THE TWO-STAGE MODEL OF CARCINOGENESIS

« Previous: USE OF THE MAXIMUM TOLERATED DOSE IN ANIMAL BIOASSAYS FOR CARCINOGENICITY
Suggested Citation:"THE TWO-STAGE MODEL OF CARCINOGENESIS." National Research Council. 1993. Issues in Risk Assessment. Washington, DC: The National Academies Press. doi: 10.17226/2078.
×

carcinogenicity testing would be most effective in providing information to assist risk managers, given the incomplete scientific understanding of chemical carcinogenesis in rodents and humans.

The Two-Stage Model of Carcinogenesis

Efforts to improve cancer risk assessment have resulted in the development of a mathematical dose-response model, called the two-stage model, that is based on a two-stage paradigm for the biologic phenomena thought to be associated with carcinogenesis. This paradigm is based on the relationship between tumor incidence and age, which suggests that at least two critical cellular changes are necessary for the development of many nonhereditary tumors. Current evidence suggests that some tumors might require more than two critical events to be expressed as human cancer. More complex models might be needed to describe multistage carcinogenesis accurately; however, it is hoped that the two-stage model will provide more accurate estimates of the cancer potency of chemicals that the multistage models currently in use by regulatory agencies.

Applying the two-stage model requires more extensive biologic data than current procedures; and because its feasibility as a tool for routine regulatory use has been questioned CRAM chose as its second task to evaluate the data needs and regulatory applicability of two-stage models of carcinogenesis. The committee considered several applications of the two-stage model to rodent carcinogens with different mechanisms of action and different quantities of available data. The committee noted that numerous assumptions were required to apply the model in each case. Assumptions must be made about mechanisms of action, appropriate target cells, time dependence, and the shape of the dose-response relationship. Extensive data would have to be obtained to reduce the current uncertainty in these assumptions. In fact, for very few chemicals are data sufficient to support the use of this model.

By studying specific application of the two-stage model, the committee determined that when different forms of the model are consistent with a particular data set, risk estimates can differ by several orders of magnitude. Therefore, the committee concluded that even if an agent's

Suggested Citation:"THE TWO-STAGE MODEL OF CARCINOGENESIS." National Research Council. 1993. Issues in Risk Assessment. Washington, DC: The National Academies Press. doi: 10.17226/2078.
×
Page 9
Next: A PARADIGM FOR ECOLOGIC RISK ASSESSMENT »
Issues in Risk Assessment Get This Book
×
Buy Paperback | $65.00
MyNAP members save 10% online.
Login or Register to save!
Download Free PDF

The scientific basis, inference assumptions, regulatory uses, and research needs in risk assessment are considered in this two-part volume.

The first part, Use of Maximum Tolerated Dose in Animal Bioassays for Carcinogenicity, focuses on whether the maximum tolerated dose should continue to be used in carcinogenesis bioassays. The committee considers several options for modifying current bioassay procedures.

The second part, Two-Stage Models of Carcinogenesis, stems from efforts to identify improved means of cancer risk assessment that have resulted in the development of a mathematical dose-response model based on a paradigm for the biologic phenomena thought to be associated with carcinogenesis.

  1. ×

    Welcome to OpenBook!

    You're looking at OpenBook, NAP.edu's online reading room since 1999. Based on feedback from you, our users, we've made some improvements that make it easier than ever to read thousands of publications on our website.

    Do you want to take a quick tour of the OpenBook's features?

    No Thanks Take a Tour »
  2. ×

    Show this book's table of contents, where you can jump to any chapter by name.

    « Back Next »
  3. ×

    ...or use these buttons to go back to the previous chapter or skip to the next one.

    « Back Next »
  4. ×

    Jump up to the previous page or down to the next one. Also, you can type in a page number and press Enter to go directly to that page in the book.

    « Back Next »
  5. ×

    Switch between the Original Pages, where you can read the report as it appeared in print, and Text Pages for the web version, where you can highlight and search the text.

    « Back Next »
  6. ×

    To search the entire text of this book, type in your search term here and press Enter.

    « Back Next »
  7. ×

    Share a link to this book page on your preferred social network or via email.

    « Back Next »
  8. ×

    View our suggested citation for this chapter.

    « Back Next »
  9. ×

    Ready to take your reading offline? Click here to buy this book in print or download it as a free PDF, if available.

    « Back Next »
Stay Connected!