Regulatory recognition of indirect genotoxicity mechanisms in the European Union.

The European Union (EU) system for the regulation of chemicals includes approval systems for pharmaceuticals, pesticides and biocides, requirements for hazard classification and for risk assessment of industrial chemicals. Regulators have traditionally used the commonly accepted categorisation of chemicals into genotoxic (DNA-reactive) or non-genotoxic agents in their decision-making processes, and have generally considered that there is no threshold level for the former group. The recognition that a number of genotoxic agents operate by indirect genotoxicity mechanisms such as induction of aneuploidy, oxidative stress, inhibition of DNA synthesis or cytotoxicity presents new problems for the regulator. The dose-response relationship for a number of such agents is generally accepted to show a threshold, however, the degree of acceptance of the threshold effect differs in different EU regulatory systems. The classification system for mutagens is based primarily on intrinsic hazard rather than risk, and the classification criteria do not allow for a less stringent classification for chemicals operating by a threshold mechanism. In contrast, regulatory approval systems for plant protection products and therapeutic agents are based on a risk assessment approach, in which a demonstrated threshold effect for a genotoxic agent is likely to be an important factor in reaching a decision concerning authorisation of the product.