Toxicology of Industrial Compounds

fraction of tumour-bearing animals is then plotted against the dose, and
lowdose effects are estimated from some model curve fitted to the data
points.
The shape of the dose-response curve at the low-dose end is strongly
debated, especially for nongenotoxic carcinogens. For DNA-reactive
carcinogens, it is widely accepted that there is no dose without effect, and a
linear extrapolation is used (Lutz, 1990b). This is based on the idea that 1
molecule of a DNA-reactive carcinogen could form a dangerous DNA
adduct in a critical gene and activate an oncogene or inactivate a tumour
suppressor gene by mutation, if the adduct is not repaired before DNA
replication.
Table 25.1 shows the consequences of linear interpolation between the
tumour incidence in the controls and in a dosed group of a bioassay for
carcinogenicity. An organ-specific tumour incidence of 4 per cent in the
control group (2/50) and 14 per cent (7/50) after treatment for 2 years at
10 mg kg −1 per day is assumed. With linear interpolation, a treatmentrelated
increment in tumour incidence of 1 per cent would be calculated
per mg kg −1 per day so that at 1 mg kg −1 per day, a 5 per cent total tumour
incidence would be expected.
In humans, increments in cancer risk in the per cent range would not be
acceptable. A risk of 1 in 1 million lives might be considered negligible and
the respective exposure could be regarded as ‘virtually safe.’ With the
example given in Table 25.1 and upon linear interpolation, this ‘virtually
safe’ dose would be calculated as 0.0001 mg kg −1 per day.
What does it mean: ‘1 additional tumour in 1000 000
lives’?
The fact that a cancer risk is only 10 −6 cannot be a consolation for the
affected individual. For this person, the cancer risk was 1. In the public
opinion, therefore, an increase by one tumour case per one million lives is
often interpreted to mean that one additional individual has got cancer
who could otherwise have lived a much longer tumour-free life. For
reasons explained below, this fear appears unfounded.
Endogenous DNA damage; individual susceptibility
W.K.LUTZ 357
Carcinogenesis is a multi-stage process based on the accumulation of a
number of critical DNA-related changes, due to, for example, DNAcarcinogen
adducts. Evidence of background DNA damage from
endogenous and unavoidable substances is accumulating (Ames, 1989;
Loeb, 1989; Lutz, 1990a). It is due to, for instance, electrophiles such as
S-adenosylmethionine, epoxides, quinones, or aldehydes, or to reactive
oxygen species. In addition, DNA is not a chemically stable molecule, it