Thresholds for Genotoxins and Their Application in Risk Assessment – Editorial

Authors : Carmichael P, Kirsch-Volders M, Vrihof, H
Publisher : Mutation Research/Mutation Research/Genetic Toxicology and Environmental Mutagenesis, vol. 678, n°2, p 71

Abstract

This special issue of Mutation Research presents discussion of, and new data establishing thresholds for genotoxic agents. The papers herein help to further challenge the common view that hazard equals risk for genotoxic chemicals, even at low exposure concentrations. In other words, it is generally assumed that genotoxic agents follow linear models when extrapolating low-dose effects from experimental data. As a consequence, safe exposure levels for humans cannot be established. However, as explored in this special issue, if a threshold-dose or concentration can be determined below which a substance does not induce a specific genotoxic effect (although it has the potential to induce it), this level can be used as a basis for a human risk assessment. This is demonstrated for particular genotoxins in this special issue, whereby a safe level may be established. The manuscripts were collated following a successful symposium organised by the European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC) and held on the last day of the 2008 annual general meeting of the European Environmental Mutagen Society (EEMS) in Cavtat, Croatia (25 September 2008).

The Symposium was well attended by over 300 registered conference participants, mostly from academia, government, contract research organisations and the pharmaceutical industry. Participants of a subsequent ECETOC workshop on DNA adducts (Cavtat, 25?26 September) were also in attendance and a report from that satellite meeting is also within this special issue. Building upon the success of the main symposium, this special issue contains manuscripts produced by the majority of the speakers, plus additional work from authors involved in the ?thresholds? area of research. Furthermore, the inclusion of papers from speakers with a regulatory role, contribute to a more complete consideration of the field.

As the reader will see, expert judgement on a case-by-case basis is necessary at this stage of our knowledge of the biological basis of genotoxicity thresholds. If the underlying biological mechanism can be explained satisfactorily, the genotoxic threshold might be extrapolated to estimate a safe dose for humans. Clearly this is contrary to the paradigm that, in the absence of repair and assuming the genotoxic agent reaches its intracellular target (DNA), one single ?hit? (DNA base change) can lead to a mutation and cancer. A key feature, illustrated in this special issue, is the need for adequate low-dose evaluations to be conducted and the application of sound statistical modelling to establish non-linear dose response relationships. However, for some compounds there may be no clear threshold, or none which will be relevant for risk assessment. Although there is clear progress in using thresholds in risk assessment, and growing acceptance of the principle by regulatory authorities, more research is needed to develop a more complete understanding of the underlying mechanisms.