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Escher, S.E.; Aguayo-Orozco, A.; Benfenati, E.; Bitsch, A.; Braunbeck, T.; Brotzmann, K.; ... ; Fisher, C. (2021)

Integrate mechanistic evidence from new approach methodologies (NAMs) into a read-across assessment to characterise trends in shared mode of action

Article / Letter to editor
This read-across case study characterises thirteen, structurally similar carboxylic acids demonstrating the application of in vitro and in silico human-based new approach methods, to determine biological similarity. Based on data from in vivo animal studies, the read-across hypothesis is that all analogues are steatotic and so should be considered hazardous. Transcriptomic analysis to determine differentially expressed genes (DEGs) in hepatocytes served as first tier testing to confirm a common mode-of-action and identify differences in the potency of the analogues. An adverse outcome pathway (AOP) network for hepatic steatosis, informed the design of an in vitro testing battery, targeting AOP relevant MIEs and KEs, and Dempster-Shafer decision theory was used to systematically quantify uncertainty and to define the minimal testing scope. The case study shows that the read-across hypothesis is the critical core to designing a robust, NAM-based testing strategy. By summarising the...Show moreThis read-across case study characterises thirteen, structurally similar carboxylic acids demonstrating the application of in vitro and in silico human-based new approach methods, to determine biological similarity. Based on data from in vivo animal studies, the read-across hypothesis is that all analogues are steatotic and so should be considered hazardous. Transcriptomic analysis to determine differentially expressed genes (DEGs) in hepatocytes served as first tier testing to confirm a common mode-of-action and identify differences in the potency of the analogues. An adverse outcome pathway (AOP) network for hepatic steatosis, informed the design of an in vitro testing battery, targeting AOP relevant MIEs and KEs, and Dempster-Shafer decision theory was used to systematically quantify uncertainty and to define the minimal testing scope. The case study shows that the read-across hypothesis is the critical core to designing a robust, NAM-based testing strategy. By summarising the current mechanistic understanding, an AOP enables the selection of NAMs covering MIEs, early KEs, and late KEs. Experimental coverage of the AOP in this way is vital since MIEs and early KEs alone are not confirmatory of progression to the AO. This strategy exemplifies the workflow previously published by the EUTOXRISK project driving a paradigm shift towards NAM-based NGRA.Show less
Read-across
NAM
Mechanistic hazard assessment
AOP-network
Liver steatosis
All authors
Escher, S.E.; Aguayo-Orozco, A.; Benfenati, E.; Bitsch, A.; Braunbeck, T.; Brotzmann, K.; Bois, F.; Burg, B. van der; Castel, J.; Exner, T.; Gadaleta, D.; Gardner, I.; Goldmann, D.; Hatley, O.; Golbamaki, N.; Graepel, R.; Jennings, P.; Limonciel, A.; Long, A.; Maclennan, R.; Mombelli, E.; Norinder, U.; Jain, S.; Capinha, L.S.; Taboureau, O.T.; Tolosa, L.; Vrijenhoek, N.G.; Vugt-Lussenburg, B.M.A. van; Walker, P.; Water, B. van de; Wehr, M.; White, A.; Zdrazil, B.; Fisher, C.
Date
2021-10-29
Journal
Toxicology In Vitro
Volume
79
DOI
doi:10.1016/j.tiv.2021.105269
Link
http://dx.doi.org/10.1016/j.tiv.2021.105269