Toxicology of Industrial Compounds

192 MOLECULAR APPROACHES TO ASSESS CANCER RISKS
established, the determination of the ‘absolute’ risks for one genotoxic
chemical would permit calculation of the ‘absolute’ risks for the others.
Such ‘absolute’ risks will nevertheless vary from population to population
dependent upon variations in promoter pressure.
Determination of ‘absolute’ cancer risks
Increments in human mutation caused by low-level exposures to genotoxic
chemicals are essential for risk estimation but cannot be determined
directly (vide supra). Such increments may be estimated using experimental
models. However, unless the variations in background are of a very low
order, it is unlikely that even the most sensitive of the emerging mutation
assays will permit the measurement of small increments of mutation at
low, e.g. environmental, exposures. Extrapolation to low doses will be
required and must necessarily be conservative, i.e. linear extrapolation to
the origin.
In addition to ‘high’ dose-low dose extrapolation, it will be necessary to
apply corrections for differences between the model and humans in the
operation of systemic factors that govern the relationships between
exposure and mutagenic effect. Estimates of target dose in the human
population at risk and in the experimental model compensate for
differences in metabolic and biokinetic factors that determine the
relationships between exposure and the critical dose. In effect, the
determination of target dose provides a measure of the rates of formation of
the key (primary and critical) chemical lesions leading to mutation. The
final stage in translating the experimentally-determined risk data to
humans is to apply corrections for systemic factors that determine the
progression of the key lesions into mutations.
The equivalent radiation dose concept
The principal systemic factors determining the progression of key chemical
lesions in DNA into mutations are the rates and fidelities of DNA repair
and replication (Wright et al., 1988). Ehrenberg and co-workers have
suggested that the repair of primary DNA damage induced by low doses of
radiation may be proportionate to that induced by low doses of genotoxic
chemicals. They have further suggested that the determination of the
relative mutagenic effectiveness or potencies of radiation and any
particular genotoxic chemical may be of value in correcting for species
differences in factors determining the progression of primary DNA damage
into mutations. The model proposed by Ehrenberg (1980) is based on the
determination of the dose-response curves for the induction of the same
mutation in the same experimental system by low target doses of the test
chemical and acute -radiation. A consistent ratio between the two curves,