Quantitative evaluation of genotoxicity data for risk assessment and regulatory decision-making: Time for a paradigm shift.

Genotoxicity plays an important role in chemical safety assessment, as genetic alterations can lead to severe and irreversible health consequences. To date, the assessment of genotoxicity has mostly been limited to hazard identification, followed by rigorous risk mitigation measures if a substance is found to be mutagenic, regardless of potency, the underlying mechanism, and cellular biology. While this regulatory hazard-based approach is straightforward, it is unsatisfactory when exposure to genotoxic substances cannot be completely avoided and/or regulatory measures lead to misperceptions of risk and undesirable socioeconomic side effects. The latter becomes particularly obvious in light of natural genotoxicants, e.g. occurring in plant-based food, and for substances that are difficult to replace but come with a high socioeconomic value but little potency and exposure. Hence, there is an increasing demand for a paradigm shift towards a quantitative interpretation of genotoxicity data in regulatory risk assessment. However, moving away from the traditional hazard-based assessment and doing so safely requires a collective effort of all relevant stakeholders. To this end, the German Federal Institute for Risk Assessment (BfR) organised an international symposium, at which experts from regulatory authorities, academia and industry discussed the opportunities and challenges involved. Here, we present key issues to be considered for a successful implementation of quantitative approaches. In situations where exposure to genotoxic substances cannot be completely avoided, e.g. occurrence of contaminants, quantitative approaches offer the opportunity to better characterise the associated risks and thus enable risk managers to make more informed decisions.