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

  • James D. Wilson


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.


Maximum Tolerate Dose Critical Path Mitotic Rate Cancer Risk Assessment Genotoxic Agent 
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Copyright information

© Plenum Press, New York 1989

Authors and Affiliations

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

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