Genotoxicity testing: moving beyond qualitative "screen and bin" approach towards characterization of dose-response and thresholds.
For more than 40+ years, genotoxicity data have been interpreted in a qualitative, binary mode; a chemical is considered either positive or negative for a response in the test system. Although dose-response information is sometimes used in this decision, it is not routine to obtain the amount of information needed to inform risk assessment, for example to determine no-observed-genotoxic-effect-levels, primarily due to the historical view of genotoxic responses as "linear, no-threshold." Only recently have researchers begun to address this issue through robust experimental designs and application of statistical models. A growing body-of-evidence supports the existence of response thresholds for a number of mutagenic agents, in vitro and in vivo. Clearly, simple observation of a "hockey-stick" dose-response curve is not sufficient to establish a threshold. Collection of robust empirical data must be supported with an analysis of biological plausibility for the observed threshold. In this context, a chemical-specific mode-of-action (MOA) approach, which identifies key events responsible for the observed mutagenic effect, is extremely valuable. Biomarkers of key events, providing qualitative and quantitative information, can be integrated in a weight-of-evidence-based assessment of genotoxicity data from multiple test systems and used to identify data gaps to resolve/reduce uncertainties during the risk assessment process. To this end, specific recommendations on study design and data analysis are proposed. As the Environmental Mutagen Society celebrates its 40th anniversary, the field of genetic toxicology is marking a milestone on the path to a new paradigm, using a MOA, data-driven approach to answer questions about thresholds for genotoxic agents.
Pottenger
Lynn H
LH
Toxicology and Environmental Research and Consulting (TERC), The Dow Chemical Company, 1803 Bldg Washington St, Midland, Michigan 48674, USA. Lpottenger@dow.com
Gollapudi
B Bhaskar
BB
D004305:Dose-Response Relationship, Drug; D049673:History, 20th Century; D049674:History, 21st Century; D009152:Mutagenicity Tests; D009153:Mutagens / Q000633:toxicity; D012958:Societies, Scientific / Q000266:history*
D009153:Mutagens