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CARCINOGENS 201

system has already been mutated in the germline. The knockout should
also be insensitive to clonal expansion, because in the knockout all cells
share the loss of repair function and so there should be no selective
advantage for relative loss of repair function. The knockout should be
affected mainly by the tertiary mutagenesis.
Quantitative predictions could be developed for the relative incidence
patterns in wild-type and knockout genotypes, using the methods of the
earlier theory chapters. Those predictions could be tested in labora-
tory animals. Although such tests may not be easily accomplished, it is
worthwhile to consider how to connect carcinogenic effects to mecha-
nism, and mechanism to incidence. Ultimate understanding of cancer
can only be achieved by understanding how factors influence the rates
of progression, and how rates of progression affect incidence.

9.4 Summary

This chapter analyzed classical explanations for chemical carcinogen-
esis. Those explanations focused on how dosage and duration of chem-
ical exposure may alter incidence. The classical explanations are not as
compelling as they originally appeared. The problem arises from the
ease with which alternative models can be fit to the data. To avoid the
problems of fitting models to the data, I showed how one may frame
quantitative hypotheses about chemical carcinogenesis as comparative
predictions—the most powerful method for testing causal interpreta-
tions of cancer progression.
The next chapter turns to mortality patterns for the leading causes
of death. I show that the quantitative tools I have developed to study
cancer may help to understand the dynamics of progression for other
age-specific diseases and the processes of aging.