Evaluation of the global performance of eight in silico skin sensitization models using human data_suppl

Emily Golden

doi:10.14573/altex.1911261s

Abstract

Allergic contact dermatitis, or the clinical manifestation of skin sensitization, is a leading occupational hazard. Several testing approaches exist to assess skin sensitization, but in silico models are perhaps the most advantageous due to their high speed and low-cost results. Many in silico skin sensitization models exist, though many have only been tested against results from animal studies (e.g., LLNA); this creates uncertainty in human skin sensitization assessments in both a screening and regulatory context. This project’s aim was to evaluate the accuracy of eight in silico skin sensitization models against two human data sets: one highly curated (Basketter et al., 2014) and one screening level (HSDB). The binary skin sensitization status of each chemical in each of the two data sets was compared to the prediction from eight in silico skin sensitization tools (Toxtree, PredSkin, OECD’s QSAR Toolbox, UL’s REACHAcross™, Danish QSAR Database, TIMES-SS, and Lhasa Limited’s Derek Nexus). Models were assessed for coverage, accuracy, sensitivity, and specificity, as well as optimization features (e.g., probability of accuracy, applicability domain, etc.), if available. While there was a wide range of sensitivity and specificity, the models generally performed comparably to the LLNA in predicting human skin sensitization status (i.e., approximately 70-80% accuracy). Additionally, the models did not mispredict the same compounds, suggesting there might be an advantage in combining models. In silico skin sensitization models offer accurate and useful insights in a screening context; however, further improvements are necessary so these models may be considered fully reliable for regulatory applications.

Highlights

Skin sensitization is defined as an allergic response that follows chemical contact with the skin (UN, 2017)
Data sets A set of 131 chemicals and their corresponding human skin sensitization statuses compiled by Basketter et al (2014) were used in this assessment
Chemical summaries in the final Hazardous Substances Data Bank (HSDB) data set were drawn from roughly 16 source types; 80% of the skin sensitization summaries were extracted from only three source types: Human Exposure Studies, Human Toxicity Excerpts, and Signs and Symptoms

Summary

Introduction

Skin sensitization is defined as an allergic response that follows chemical contact with the skin (UN, 2017). An electrophilic chemical must penetrate the skin and bind to proteins, which activates cellular immune responses and results in immunological priming. Upon re-exposure to the chemical, an allergic response can follow (Kimber et al, 2002). These events and responses have collectively been identified as the adverse outcome pathway (AOP) for skin sensitization (OECD, 2012). The skin sensitization potential of chemicals has been assessed using animal methods, such as the guinea pig maximization test (GPMT) and the Buehler assay. The mouse local lymph node assay (LLNA) has been validated as a refined animal model to evaluate skin sensitization (Sailstad et al, 2001)

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Conclusion