Integrated decision strategies for skin sensitization hazard

Abstract

One of the top priorities of the Interagency Coordinating Committee for the Validation of Alternative Methods (ICCVAM) is the identification and evaluation of non-animal alternatives for skin sensitization testing. Although skin sensitization is a complex process, the key biological events of the process have been well characterized in an adverse outcome pathway (AOP) proposed by the Organisation for Economic Co-operation and Development (OECD). Accordingly, ICCVAM is working to develop integrated decision strategies based on the AOP using in vitro, in chemico and in silico information. Data were compiled for 120 substances tested in the murine local lymph node assay (LLNA), direct peptide reactivity assay (DPRA), human cell line activation test (h-CLAT) and KeratinoSens assay. Data for six physicochemical properties, which may affect skin penetration, were also collected, and skin sensitization read-across predictions were performed using OECD QSAR Toolbox. All data were combined into a variety of potential integrated decision strategies to predict LLNA outcomes using a training set of 94 substances and an external test set of 26 substances. Fifty-four models were built using multiple combinations of machine learning approaches and predictor variables. The seven models with the highest accuracy (89-96% for the test set and 96-99% for the training set) for predicting LLNA outcomes used a support vector machine (SVM) approach with different combinations of predictor variables. The performance statistics of the SVM models were higher than any of the non-animal tests alone and higher than simple test battery approaches using these methods. These data suggest that computational approaches are promising tools to effectively integrate data sources to identify potential skin sensitizers without animal testing. Published 2016. This article has been contributed to by US Government employees and their work is in the public domain in the USA.

Keywords: DPRA; KeratinoSens; LLNA; allergic contact dermatitis; h-CLAT; integrated decision strategy; machine learning; skin sensitization; support vector machine.

Figure 1. Adverse Outcome Pathway for Skin Sensitization Initiated by Covalent Binding to Proteins

Abbreviations: DPRA = direct peptide reactivity assay; h-CLAT = human cell line activation test; LLNA = murine local lymph node assay. Note: Although KeratinoSens, h-CLAT, and LLNA are aligned with single key events, these assays also recapitulate the prior key events.

Figure 2. Product Uses for 120 Substances

Total number of substances exceeds 120 because most substances were associated with more than one product use.

Figure 3. Frequency of Appearance of 192 Chemotypes in the 120 Substance Set

Bars show the number of substances with each of 192 chemotypes.