In silico modelling of hazard endpoints: current problems and perspectives

Major scientific hurdles in the acceptance of quantitative structure-activity relationships (QSAR) for regulatory purposes have been identified. First, when quantifying important features of chemical structure complexities of molecular structure have often been ignored. More mechanistic modelling of chemical structure should proceed on two fronts: by developing a more in-depth understanding and representation of the multiple states possible for a single chemical by achieving greater rigor in understanding of conformational flexibility of chemicals; and, by considering families of activated metabolites that are derived in biological systems from an initial chemical substrate. Second, QSAR research is severely limited by the lack of systematic databases for important risk assessment endpoints, and despite many decades of research, the ability to cluster reactive chemicals by common toxicity pathways is in its infancy. Finally, computational tools are lacking for defining where a specific QSAR is applicable within the domain (universe) of chemical structures that are to be regulated. This paper describes some of the approaches being taken to address these needs. Applications of some of these new approaches are demonstrated for the prediction of chemical mutagenicity, where considerations of both molecular flexibility and metabolic activation improved the QSAR predictability and interpretations. Lastly, the applicability domain for a specific QSAR predicting estrogen receptor binding is presented in the context of a mechanistically-defined chemical structure space for large heterogeneous chemical datasets of regulatory concern. A strategic approach is discussed to selecting chemicals for model improvement and validation until regulatory acceptance criteria for risk assessment applications are met.