Toxicology of Industrial Compounds

182 MOLECULAR APPROACHES TO ASSESS CANCER RISKS
Management of cancer risks (key requirements)
The management of toxicological risks implies a capacity to control
exposures within acceptable safety limits. Effective control is, therefore,
dependent not only on the qualitative detection and identification of
hazardous chemicals but also on a capacity to determine human exposure
and to evaluate the health risks. This last requirement necessitates a
knowledge of potency, i.e. quantitative human dose-response relationships.
In the case of genotoxic chemicals, the relevant data reside in the very low
region of the dose-response curve.
The concept of acceptable risk is readily accepted when applied to the
many classes of toxic chemicals operating by a thresholded mechanism
indicative of the virtual absence of risk at sub-threshold doses. Absolute
safety margins for genotoxic chemicals cannot be guaranteed (vide supra)
leading to the adoption of conservative safety measures. Indeed, cursory
analysis might suggest that quantitative risk data are not required for the
effective management of cancer risks associated with genotoxic chemicals.
Thus, it is generally accepted that human contact with carcinogens should
be minimised. Purely qualitative identification of the hazard would permit
the design of measures to limit human exposure and minimise carcinogenic
impact. Indeed, a purely qualitative indication of genotoxicity can be an
absolute deterrent to the development of new products. Nevertheless,
certain exposures, e.g. to indigenous genotoxic chemicals and natural food
components, are unavoidable. Furthermore, measures to reduce exposures
to ‘avoidable’ genotoxic hazards, e.g. certain combustion products, key
industrial base chemicals and intermediates, are often difficult and costly.
Quantitative risk assessment is needed to prioritise these hazards and, most
importantly, to determine safety margins. Certainly a failure to determine
carcinogenic potency would lead to uncertainty about the adequacy of
safety margins and, probably, to unnecessary measures to further reduce
exposures. Thus, despite their additive and cumulative actions, even
genotoxic chemicals can pose a negligible health risk. Of course, the
definition of a negligible, i.e. acceptable, risk is a socio-political judgement
which nevertheless has to be realistic in the case of unavoidable hazards
and achievable in the case of avoidable hazards.
Detection of genotoxic carcinogens
Concerns about genotoxic hazards have provided an incentive for the
development of a broad range of rapid tests to detect intrinsic genotoxic
activity or potential. The principal aim of these approaches is to predict
carcinogenic activity or, more accurately, cancer initiating activity. The
most widely used tests are the coupled microsomal-microbial mutation
assays developed by Ames et al. (1973). However, such approaches are