Toxicology of Industrial Compounds

25
Low Dose of a Genotoxic Carcinogen does not
‘Cause’ Cancer; it Accelerates Spontaneous
Carcinogenesis
WERNER K.LUTZ
University of Würzburg, Würzburg
Definitions of cancer risk
The risk of cancer is normally expressed as a fraction of a population
diagnosed with cancer within a specified period of time. In an animal
bioassay for carcinogenicity, this period usually is 2 years; in cancer
epidemiology, a life span of 65 years (0–64) is often used. The two periods
can be considered equivalent with respect to the process of carcinogenesis:
its rate in different species is inversely correlated with the natural life span
and basal metabolism and the background cancer incidence in 2-year old
rats or mice is very similar to the one seen in 65-year-old humans
(Anisimov, 1989; Raabe, 1989; Tennant, 1993).
For an individual, a cancer risk can only be 0 or 1, depending on
whether the situation is analysed before or after the diagnosis of the
tumour. The population-based expression of a cancer risk therefore is not
easily visualized and does not take into account interindividual differences
in susceptibility.
In the following discussion, the dose-response relationship in chemical
carcinogenesis is analysed in terms of an effect of a carcinogen on the
individual tumour latency time (Kodell et al., 1980; Littlefield et al., 1980;
Day, 1983; Gaylor, 1992). Together with the idea of background DNA
damage responsible for what is considered ‘spontaneous’ tumour formation
and including individual variability for the rate of this process, it will be
shown that low doses of genotoxic carcinogens might accelerate the
spontaneous process of carcinogenesis but are not expected to induce
cancer ‘out of the blue’.
Linear dose response for a DNA-reactive carcinogen
The effect of a carcinogen at low dose is normally extrapolated from data
obtained in 2-year bioassays. At the end of the 2-year treatment period, the
surviving animals are killed and analysed for the presence of tumours. The