A case for a new paradigm in genetic toxicology testing.
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.
Pottenger
Lynn H
LH
Toxicology & Environmental Research and Consulting, The Dow Chemical Company, Midland, MI 48674, USA. lpottenger@dow.com
Gollapudi
B Bhaskar
BB
D004305:Dose-Response Relationship, Drug; D008957:Models, Genetic; D009152:Mutagenicity Tests / Q000379:methods; D009153:Mutagens / Q000633:toxicity*; D019055:No-Observed-Adverse-Effect Level; D018570:Risk Assessment; D020711:Threshold Limit Values
D009153:Mutagens