Threshold effects in genetic toxicity: perspective of chemicals regulationin Germany

In the regulation of chemical substances, it is generally agreed that there are no thresholds for genotoxic effects of chemicals, i.e., that there are no doses without genotoxic effects. When classifying and labelling chemica ls, dangerous properties of chemicals are to be identified. In this context , in general, the mode of action (threshold or not) is not considered for g enotoxic substances. In the process of quantitative risk assessment, howeve r, determination of the type of dose-effect relationships is decisive for t he outcome and the type of risk management. The presence of a threshold mus t be justified specifically in each individual case. Inter alia, the follow ing aspects may be discussed in this respect: aneugenic activity, indirect modes of action, extremely steep dose-effect relationships in combination w ith strong toxicity, specific toxicokinetic conditions which may lead to 'm etabolic protection' prior to an attack of DNA. In the practice of the regu lation of chemical substances with respect to their genotoxic effects, the discussion of thresholds has played a minor role. For notified new substanc es, there are, in general, no data available that would allow a reasonable discussion. Concerning substances out of the European programme on existing substances, so far 29 have been assessed in our institute with respect to genetic toxicity. Eight out of these have shown considerable evidence for g enotoxicity. Far two of them, a possible threshold is discussed: one substa nce is an aneugen, the other one is metabolised to an endogenic compound wi th genotoxic potential. In the practice of risk assessment of genotoxic sub stances, the discussion of the mode of action for genotoxicity is frequentl y associated with the evaluation of potential carcinogenic effects. Here, t issue-specific genotoxic effects in target organs for carcinogenicity are t o be discussed. Moreover, the contribution of genotoxicity to the multifact orial process of tumour development should be assessed. (C) 2000 Elsevier S cience B.V. All rights reserved.