Evaluation of the GARD assay in a blind Cosmetics Europe study_suppl

Henrik Johansson

doi:10.14573/altex.1701121s

Abstract

Chemical hypersensitivity is an immunological response towards foreign substances, commonly referred to as sensitizers, which gives rise primarily to the clinical symptoms known as allergic contact dermatitis. For the purpose of mitigating risks associated with consumer products, chemicals are screened for sensitizing effects. Historically, such predictive screenings have been performed using animal models. However, due to industrial and regulatory demand, animal models for the purpose of sensitization assessment are being replaced by non-animal testing methods, a global trend that is spreading across industries and market segments. To meet this demand, the Genomic Allergen Rapid Detection (GARD) assay was developed. GARD is a novel, cell-based assay that utilizes the innate recognition of xenobiotic substances by dendritic cells, as measured by a multivariate readout of genomic biomarkers. Following cellular stimulation, chemicals are classified as sensitizers or non-sensitizers based on induced transcriptional profiles. Recently, a number of non-animal methods were comparatively evaluated by Cosmetics Europe, using a coherent and blinded test panel of reference chemicals with human and local lymph node assay data, comprising a wide range of sensitizers and non-sensitizers. The outcome of the GARD assay is presented in this paper. It was demonstrated that GARD is a highly functional assay with a predictive performance of 83% in this Cosmetics Europe dataset. The average accumulated predictive accuracy of GARD across independent datasets was 86% for skin sensitization hazard.

Highlights

Chemical hypersensitivity is a disease state induced by the human immune system in response to chemical sensitizers, which most frequently gives rise to the clinical symptoms of allergic contact dermatitis (ACD)
Observations of the receiver operating characteristic (ROC) (Lasko et al, 2005) allowed the identification of the prediction model cutoff that achieves the highest accuracy of predictions of the benchmark control dataset, which was subsequently subtracted from all decision values (DVs) generated from samples of the test dataset
For the purpose of binary predictions, a composite reference was defined to classify a sensitizer as a compound that is categorized as having a human potency (HP) (Basketter et al, 2014) of 1-4, or being categorized as HP 5, if it is predicted as a sensitizer by the Local Lymph Node Assay (LLNA)

Summary

Introduction

Chemical hypersensitivity is a disease state induced by the human immune system in response to chemical sensitizers, which most frequently gives rise to the clinical symptoms of allergic contact dermatitis (ACD). The molecular and cellular mechanisms of sensitization have been reviewed extensively (Ainscough et al, 2013; Martin, 2015; Martin et al, 2011). Protein-hapten complexes are taken up by resident dendritic cells (DCs), which upon maturation migrate to local lymph nodes where antigen presentation to naïve T cells occurs. This results in the induction of an immunologic memory towards the specific sensitizer. A sensitized individual will suffer from ACD-associated symptoms following the elicitation of specific Th1 and cytotoxic CD8+ T-cells

Methods

Results

Discussion

Conclusion