Threshold-mediated mechanisms in mutagenesis: implications in the classification and regulation of chemical mutagens

Chemical mutagens are currently regulated and labelled an the basis of thei r hazardous properties defined in hazard classification schemes. The streng th and type of experimental evidence is used as the only criterion for clas sification in categories which express different levels of concern for the possibility of adverse effects - notably transmissible genetic alterations - in humans. Differently from the classification of carcinogens, no conside ration is given to potency, nor to the mechanism of action. The rationale o f such hazard based classification is that the hazardous property of a chem ical is an intrinsic feature, which is expressed independently of dosing. C hanging of dose level results in a mere change in the probability to observ e an adverse effect, but not in its potential occurrence. The lack of theor etical threshold underlying this approach can be envisaged, in principle, f or stochastic processes :such as DNA damage, which can be triggered by sing le molecular interactions. On the other hand, indirect mechanisms of genoto xicity, involving multiple interactions with non-DNA targets, are expected to show a threshold. At variance to DNA reactive agents, chemicals acting w ith threshold-mediated mechanism do change also qualitatively their toxic p roperties depending on the dose level. Possible problems arising in the app lication of hazard based schemes for the evaluation of chemicals with thres hold-mediated mechanism of action are discussed, using the spindle poisons benzimidazole fungicides as an example. (C) 2000 Elsevier Science B.V. All rights reserved.