Toward regulatory acceptance and improving the prediction confidence of in silico approaches: a case study of genotoxicity

Introduction: Genotoxicity is an imperative component of the human health safety assessment of chemicals. Its secure forecast is of the utmost importance for all health prevention strategies and regulations. Areas covered: We surveyed several types of alternative, animal-free approaches ((quantitative) structure-activity relationship (Q)SAR, read-across, Adverse Outcome Pathway, Integrated Approaches to Testing and Assessment) for genotoxicity prediction within the needs of regulatory frameworks, putting special emphasis on data quality and uncertainties issues. Expert opinion: (Q)SAR models and read-across approaches for in vitro bacterial mutagenicity have sufficient reliability for use in prioritization processes, and as support in regulatory decisions in combination with other types of evidence. (Q)SARs and read-across methodologies for other genotoxicity endpoints need further improvements and should be applied with caution. It appears that there is still large room for improvement of genotoxicity prediction methods. Availability of well-curated high-quality databases, covering a broader chemical space, is one of the most important needs. Integration of in silico predictions with expert knowledge, weight-of-evidence-based assessment, and mechanistic understanding of genotoxicity pathways are other key points to be addressed for the generation of more accurate and trustable results.