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Non‐animal assessment of skin sensitization hazard: Is an integrated testing strategy needed, and if so what should be integrated?
Citation:
Roberts, D. AND G. Patlewicz. Non‐animal assessment of skin sensitization hazard: Is an integrated testing strategy needed, and if so what should be integrated? JOURNAL OF APPLIED TOXICOLOGY. John Wiley & Sons, Ltd., Indianapolis, IN, 38(1):41-50, (2017). https://doi.org/10.1002/jat.3479
Impact/Purpose:
To meet the regulatory requirements to assess the potential of chemicals to cause skin sensitization, there is a strong push to apply non‐animal test methods. As stated in the OECD test guidelines of the new non‐animal methods, the expectation is that a combination of assays will be needed, each of which represents a KE in the associated AOP for skin sensitization. Here a data set of 271 chemicals with LLNA, human sensitization data and one or more outcomes from three non‐animal test methods was evaluated to assess the performance characteristics of the non‐animal test methods individually and as binary combinations in comparison with that of the “two out of three” approach. The analysis here highlights the need for flexibility in the approach taken for a specific substance, paying close attention to the relevance and validity of all existing sensitization information, in particular the reaction chemistry of the substance under evaluation and its physicochemical characteristics, to conduct the most targeted testing necessary to address the specific decision context under consideration.
Description:
There is an expectation that to meet regulatory requirements, and avoid or minimise animal testing, integrated testing and assessment approaches (IATA) will be needed that rely on assays representing key events (KEs) in the adverse outcome pathway (AOP). Three non-animal assays have been formally validated and regulatory adopted: the direct peptide reactivity assay (DPRA), the KeratinoSensTM assay and the human Cell Line Activation Test (h-CLAT). There have been many efforts to develop IATA with the ‘2 out of 3’ approach attracting much attention. Here a set of 271 chemicals with mouse, human and non-animal sensitisation test data was evaluated to compare the predictive performances of the 3 individual non-animal assays, their binary combinations and the ‘2 out of 3’ approach. The most predictive approach was to use both the DPRA and h-CLAT as follows: 1. Perform DPRA – if positive, classify as sensitising; 2. If negative, perform h-CLAT – a positive outcome denotes a sensitiser, a negative, a non-sensitiser. With this approach, 83% (LLNA) and 93% (human) of non-sensitiser predictions were correct, compared with the ‘2 out of 3’ approach which had 69% (LLNA) and 79% (human) of non-sensitiser predictions correct. The findings are consistent with the argument, supported by published quantitative mechanistic models (QMMs) that only the first KE needs to be modelled. The three assays all model this KE to an extent. The value of using more than one assay depends on how the different assays compensate for each other’s technical deficiencies.
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DOI: Non‐animal assessment of skin sensitization hazard: Is an integrated testing strategy needed, and if so what should be integrated?