Thresholds in genotoxicity responses

It has been commonly accepted that risk assessments of genotoxic chemicals are based on linear extrapolation methods. However, there is substantial ev idence that some chemicals may be genotoxic only at high doses by mechanism s that do not occur at low doses, or only under specific conditions in geno toxicity assays, but are inactive at concentrations within the range of hum an exposure levels. There are a variety of possible mechanisms of threshold ed genotoxicity, including disruption of cell division and chromosome segre gation, inhibition of DNA synthesis, overloading of oxidative defence mecha nisms, metabolism or plasma binding capacity, disturbances of metal homeost asis, cytotoxicity and physiological perturbations in in vivo assays. The d egrees of evidence supporting the proposed mechanisms are variable and not all are sufficiently robust to be universally accepted as yet by the scient ific community. However, a survey of industrial companies indicated that da ta have been accepted by some regulatory authorities indicating thresholds contributing to genotoxicity responses. (C) 2000 Elsevier Science B.V. All rights reserved.