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The interchangeability of in vitro key event-based skin sensitisation assays - impact on defined approaches

pdf fileChilton ML; Macmillan DS;

This poster was presented by Principal Scientist Donna Macmillan at the 15th International Congress of Toxicology in July 2019. 

There are a growing number of in chemico/in vitro assays which measure skin sensitisation, driven by a global move away from animal testing. These assays are linked to particular key events in the skin sensitisation Adverse Outcome Pathway. Currently there are OECD test guidelines covering the Direct Peptide Reactivity Assay (DPRA) which measures the molecular initiating event (covalent binding to proteins), the KeratinoSens™ and LuSens assays which measure key event 2 (keratinocyte activation), and the h-CLAT, U-SENS™ and IL-8 Luc assays which measure key event 3 (dendritic cell activation). Each assay has an intrinsic reproducibility, which are reported to range between 75% and 100%. Where multiple assays cover the same key event there is also the question of how interchangeable the different tests are. It is important to gauge the magnitude of the interchangeability as it will impact the uncertainty of both the individual assay predictions as well as any predictions resulting from defined approaches that are based on these test results. 

This research aimed to collect publicly available in chemico/in vitro skin sensitisation data for chemicals tested in the 6 assays which currently feature in OECD guidelines, and to analyse the interchangeability between different assays covering the same key event. To this end data was collected for 394 unique chemicals variously tested in the DPRA, KeratinoSens™, LuSens, h-CLAT, U-SENS™ and IL-8 Luc assays. The interchangeability between assays covering key event was calculated to be 85%, and the interchangeability between assays covering key event 3 was found to range between 74% and 92%. In a worst-case scenario, these figures could lead to hazard classifications differing for approximately one third of compounds evaluated in several published defined approaches. 

Assay interchangeability will have an impact on key-event based hazard predictions and any uncertainty will be propagated when assay results are combined within a defined approachThis analysis could be useful when characterising the uncertainty remaining in skin sensitisation predictions using non-animal approaches, which is an important part of the process to gaining acceptance in these emerging methods. 


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