A case for a new paradigm in genetic toxicology testing

Abstract

The field of genetic toxicology is in need of a transformational change in experimental approaches and data interpretation so that genotoxicity data can better inform risk assessment. The historical approach of the one-hit theory for DNA-reactive chemicals and the view of genotoxicity as an inherent property of a chemical are being challenged, based on a better understanding of the complexity of molecular mechanisms of mutation. A seemingly simple, but hitherto rarely practiced, approach that could help catapult the field forward is the application of the fundamental tenet of toxicology, a better understanding of the dose–response. There is a growing body of evidence to support the existence of thresholds/NOAELs for genotoxic effects, even from DNA-reactive chemicals. It is also suggested that a better understanding of the internal and/or effective dose to the critical target, for both in vitro and in vivo experiments, can significantly help to improve characterization of the shape of the dose–response curve and serve to support cross-species extrapolation. These experimental design and data interpretation approaches will render genetic toxicology data more useful to inform the mode-of-action-based risk assessment process, and provide the paradigm shift necessary to help bring the field into the 21st century.