Toxicology of Industrial Compounds

358 CARCINOGENESIS AT LOW DOSE
Table 25.1 Linear low-dose interpolation of a cancer risk based on a hypothetical 2year
bioassay for carcinogenicity
Notes:
Data in boldface; extrapolations in italics.
depurinates and deaminates spontaneously. Finally, DNA replication is not
100 per cent correct so that mutations cannot be avoided completely. The
resulting background DNA damage is responsible for spontaneous
mutations and for what is called spontaneous tumour formation. The
process of carcinogenesis therefore has a non-zero rate even if exposure to
exogenous DNA-reactive carcinogens could be avoided.
The level of the background mutation rate is expected to show
interindividual variability. It depends both upon genetic and life-style
factors which govern, for instance, enzyme activities responsible for
carcinogen metabolism or DNA repair (Harris, 1989). The rate of
spontaneous carcinogenesis is further governed by the inherited and
acquired presence of activated oncogenes or absence of tumour suppressor
genes (Scrable et al., 1990). Therefore, each individual in a heterogeneous
population is expected to have its own endogenous cancer risk expressed as
an individual time-to-tumour or tumourfree lifetime.
Exogenous DNA damage; acceleration of spontaneous
carcinogenesis
Exposure to an additional, exogenous DNA-reactive molecule adds to the
background DNA damage, increases the probability of a mutation and
accelerates the multi-stage process of carcinogenesis. At low doses of the
exogenous carcinogen, the rate of the process is expected to be dominated
by the background damage so that the exogenous factor cannot constitute
a cancer risk independent of the spontaneous process. The acceleration
must be dose dependent and might be related to the background rate
operating in each individual.
It is true, therefore, that even a few molecules of a DNA-reactive
carcinogen can have an effect. However, this effect cannot be a tumour