Abstract
Hundreds of chemicals have been identified as skin sensitizers. These are chemicals that possess the ability to induce hypersensitivity reactions in humans, giving rise to a condition termed allergic contact dermatitis. The capacity to limit hazardous exposure to such chemicals depends upon the ability to accurately identify and characterize their skin sensitizing potency. This has traditionally been accomplished using animal models, but their widespread use offers challenges from both an ethical and a scientific perspective. Comprehensive efforts have been made by the scientific community to develop new approach methodologies (NAMs) capable of replacing in vivo assays, which have successfully yielded several methods that can identify skin sensitizers. However, there is still a lack of new approaches that can effectively measure skin sensitizing potency. We present a novel methodology for quantitative assessment of skin sensitizing potency, which is founded on the already established protocols of the GARDskin assay. This approach analyses dose–response relationships in the GARDskin assay to identify chemical-specific concentrations that are sufficient to induce a positive response in the assay. We here compare results for 22 skin sensitizers analyzed using this method with both human and LLNA potency reference data and show that the results correlate strongly and significantly with both metrics (rLLNA = 0.81, p = 9.1 × 10–5; rHuman = 0.74, p = 1.5 × 10–3). In conclusion, the results suggest that the proposed GARDskin dose–response methodology provides a novel non-animal approach for quantitative potency assessment, which could represent an important step towards reducing the need for in vivo experiments.
Highlights
Hundreds of chemicals have been identified as skin sensitizers
The proposed dose–response measurements would be aligned with common toxicological principles for potency assessments, where the response value (DV), the binary threshold (DV ≥ 0), and the derived c DV0 concentrations may be viewed as an analogue to the response value (stimulation index (SI)), the binary threshold (SI ≥ 3), and the EC3 concentrations in the LLNA assay, respectively
The first step in this procedure is to derive a continuous prediction of skin sensitizing potency to define a concentration below which no reactions are expected to occur, a so-called No Expected Sensitization Induction Level (NESIL) value[35], for use as a point-of-departure (POD) in the quantitative risk assessments (QRA)
Summary
Hundreds of chemicals have been identified as skin sensitizers. These are chemicals that possess the ability to induce hypersensitivity reactions in humans, giving rise to a condition termed allergic contact dermatitis. We present a novel methodology for quantitative assessment of skin sensitizing potency, which is founded on the already established protocols of the GARDskin assay This approach analyses dose–response relationships in the GARDskin assay to identify chemical-specific concentrations that are sufficient to induce a positive response in the assay. A modified version of the Direct Peptide Reactivity Assay (DPRA, OECD TG 442 C14, the kinetic DPRA (kDPRA)[18], has been described in a series of publications and has initially shown promising results for GHS potency subcategorization[19,20,21], but it still remains to be determined how well this approach performs on external data with an a priori defined classification threshold To this end, development and regulatory implementation of NAM based strategies capable of providing continuous potency data beyond the discrete GHS subcategories remain a topic of high priority
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