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CARCINOGENS 197

themselves rather than risking repair of damage (supporting evidence
in Bach et al. 2000; Potten 1998).
If these processes reduce stem cell mutation rates, then carcinogens
or other accidents that kill stem cells may have a large effect on the accu-
mulation of mutations (Cairns 2002). In particular, lost stem cells must
be replaced by normal, symmetric cell division with typical mutation
rates that may be much higher than stem cell mutation rates. Thus, re-
generation of stem cells following carcinogen exposure or during wound
healing may cause increased mutation.
Clonal expansion of predisposed cell lineages.—Once a mutation occurs, a
mitogen may stimulate clonal expansion. An expanding clone increases
the number of target cells for the next transition (Muller 1951). This
increase in transition rate between stages does not require a rise in mu-
tation rate per cell division, only an increase in the number of cells avail-
able for progressing to the next stage.

TESTS
The mechanistic details of mitogenesis may be studied directly at the
biochemical and cellular levels. However, I am particularly interested
in the different ways in which mitogenesis shifts age-incidence curves.
To study shifts in age incidence, one must analyze how mechanistic
consequences of mitogenesis affect rates at which carcinogenic changes
accumulate in cells.
The first two mechanistic hypotheses in the previous section focus on
an increase in the mutation rate per cell; the third hypothesis focuses
on an increase in the number of target cells susceptible for transition
to the next stage. The two processes have different consequences for
age-incidence curves.

Increase in mutation rate per cell.—In this case, the mitogen acts like a
mutagen. The particular hypotheses and tests from the section on direct
mutagenesis apply.
Increase in number of target cells for next transition.—More target cells
cause a higher transition rate per unit time. The main difference from
mutagenic agents arises from the time course over which the mutation
rate increases. When a chemical agent causes an increased rate of mu-
tation per cell, the rise in the mutation rate most likely occurs over a
short period of time. By contrast, an increase in the number of target