Page 180 - 20dynamics of cancer

9 Carcinogens

Carcinogens shift age-incidence curves. Such shifts provide clues about
the nature of cancer progression. For example, a carcinogen that influ-
enced only a late stage in progression would have little effect if applied
early in life, whereas a carcinogen that influenced only an early stage
would have little effect if applied late in life. By various combinations of
treatments, one can test hypotheses about the causes of different stages
in progression.
The first section begins with the observation that incidence rises more
rapidly with the duration of exposure to a carcinogen than with the
dosage. Cigarette smoking provides the classic example, in which inci-
dence rises with about the fifth power of duration and the second power
of dosage.
The standard explanation for the relatively weaker effect of dosage
compared with duration assumes that a carcinogen affects only a subset
of stages. I contrast that standard theory with a variety of alternative
explanations. For example, a model in which a carcinogen affects equally
all stages also fits the data well. Overall, fitting different models to the
data provides little insight.
The second section begins with the observation that lung cancer in-
cidence changes little after the cessation of smoking but increases in
continuing smokers. The standard explanation assumes that smoking
does not affect the final transition in the sequence of stages of cancer
progression. Among those who quit, nearly all subsequent cases arise
from individuals who progressed to the penultimate stage while smok-
ing, and await only the final transition. With one stage to go, incidence
remains nearly constant over time.
I show once again that a model in which a carcinogen affects equally
all stages also fits the data well. Although the data do not distinguish
between theories, the various theories do set a basis for connecting how
carcinogens influence mechanisms of cellular and tissue change, how
those changes affect rates of transition in the stages of tumorigenesis,
and how those rates of progression affect incidence curves.
The third section links different mechanistic hypotheses about car-
cinogen action to predicted shifts in age-incidence patterns. Those links