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

Chemical mutagens are currently regulated and labelled on the basis of their hazardous properties defined in hazard classification schemes. The strength and type of experimental evidence is used as the only criterion for classification 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 consideration is given to potency, nor to the mechanism of action. The rationale of such hazard based classification is that the hazardous property of a chemical is an intrinsic feature, which is expressed independently of dosing. Changing of dose level results in a mere change in the probability to observe an adverse effect, but not in its potential occurrence. The lack of theoretical threshold underlying this approach can be envisaged, in principle, for stochastic processes such as DNA damage, which can be triggered by single molecular interactions. On the other hand, indirect mechanisms of genotoxicity, involving multiple interactions with non-DNA targets, are expected to show a threshold. At variance to DNA reactive agents, chemicals acting with threshold-mediated mechanism do change also qualitatively their toxic properties depending on the dose level. Possible problems arising in the application of hazard based schemes for the evaluation of chemicals with threshold-mediated mechanism of action are discussed, using the spindle poisons benzimidazole fungicides as an example.