Prospective detection and assessment of genotoxic hazards: a critical appreciation of the contribution of L. Ehrenberg.

Advances in our understanding of the mechanisms of chemical carcinogenesis are now being applied to improve the quality of prospective risk assessment. The contribution of Ehrenberg and his colleagues (at the University of Stockholm) probably represents the most comprehensive application of mechanistic knowledge to this field during the past 20 years. The strategic approach developed by the Swedish group was based on the identification of differences between man and experimental risk models in factors that determine the relationships between exposure and biological response and the development of methods to compensate for these differences. Many of the critical stages in chemical carcinogenesis and the cellular determinants of these stages have now been identified. As a first step in seeking to improve risk assessment, Ehrenberg introduced the target dose concept, in which the doses of carcinogens penetrating to the cellular target (DNA) are determined. This approach provides an improved basis for determining exposures to carcinogenic agents and also for compensating for species differences in factors such as metabolism that determine the relationships between exposure dose and the dose at the critical target. The target dose concept is now widely accepted and has led to the development of new biomedical monitoring techniques, based, for example, on the measurement of haemoglobin adducts, which are now being applied to detect and identify genotoxic hazards. The introduction of the target dose concept has led to significant improvements in the quality of prospective risk assessment. Further improvements necessitate procedures to compensate for differences between man and prospective risk models in factors that determine subsequent stages of the carcinogenic process. Ehrenberg has proposed that the rad-equivalence approach may be of value in this respect. Its application has accurately predicted the incidence of leukaemias in occupational cohorts which had exposures to ethylene oxide in common. The possible general applicability of this approach is discussed.