Toxicology of Industrial Compounds

A.S.WRIGHT ET AL. 191
intrinsic promoter activity of the chemical arising, for example as a
consequence of cell injury, would be negligible at low exposures—
particularly when viewed in the context of the overall promoter pressure
exerted on the populations at risk. Thus, it is unlikely that the added
cancer risk would be greater than and may approximate to the increment in
critical mutations caused by the specific exposure (Figure 14.1).
Experimental studies indicate that all known categories of genotoxic
agents ranging from methylating agents to polycyclic aromatic compounds
can induce the critical mutations leading to malignancy (Figure 14.1).
Furthermore, at low doses, the possibility that exposure to a particular
genotoxic chemical would induce more than one of the critical mutations in
any particular cell is extremely remote. Indeed it is probable that each
critical mutation is induced by a different agent or mechanism, i.e.
chemical, radiation or ‘spontaneous’. In this sense, each critical mutation
would have equal status, i.e. no single event would be any more or any less
critical than any other to the final outcome. Accordingly, the increment in
cancer risk would equate with the increment in any decisive, e.g. oncogeneactivating,
mutation in any critical gene. The induction of such mutations
is almost certainly a direct function of overall mutagenic activity of the
chemical, i.e. linked to the number of mutational events rather than the type
of mutations induced by a given dose of the chemical. At low exposures,
therefore, the increment in cancer incidence due to a specific genotoxic
agent would approximate to the small increase in the total mutational load
caused by the exposure, i.e. relative to the overall background level of
mutations due to all causes, multiplied by the overall cancer incidence in
the population at risk. (The latter function introduces a measure of the net
impact of promoter and anti-promoter pressure acting on initiated cells in
the population at risk.) Of course risks may also be calculated on the basis
of specific tumours and specific tissues.
The determination of small increments in mutation associated with lowlevel
exposures to genotoxic chemicals in human populations presents
enormous technical problems not least due to the much larger and variable
background of mutations due to all causes. Increasing the sensitivity of
mutation assays per se (vide supra) is unlikely to improve the situation.
High resolving power is also needed to discriminate between effects due to
different contributory factors. Nevertheless, while direct approaches to
assess absolute cancer risks posed by such low-level exposures may elude
us we can nevertheless begin to determine relative cancer risks and
prioritise genotoxic chemicals on the basis of experimental determinations
of mutagenic potency and estimates of target doses resulting from
environmental or occupational exposures. Thus, according to the foregoing
the relative cancer risk posed by a low exposure to a genotoxic agent
would approximate to the number of mutations induced per unit target
dose×estimated human target dose. Once relative cancer risks have been