Prediction of skin sensitization potency sub-categories using peptide reactivity data

Area of Science:

• Toxicology
• Dermatology
• Chemical Safety

Background:

• Non-animal methods can identify skin sensitization hazards but struggle with potency sub-classification (GHS 1A/1B).
• Skin sensitization potency is linked to allergen dose, determined by protein-adduct formation.
• Peptide reactivity assays measure protein-adduct formation to assess sensitization potency.

Purpose of the Study:

• To evaluate and improve non-animal methods for classifying skin sensitization potency sub-categories.
• To assess the performance of different Direct Peptide Reactivity Assay (DPRA) protocols against existing data.
• To determine the suitability of the kinetic DPRA for replacing in vivo testing for sensitization potency.

Main Methods:

• Compared standard DPRA (one concentration/time) with quantitative DPRA (three concentrations/one time) and kinetic DPRA (multiple concentrations/times).
• Assessed predictivity using cysteine (Cys) and lysine (Lys) adducts.
• Validated assay performance against Local Lymph Node Assay (LLNA) and human data.

Main Results:

• Standard DPRA showed low accuracy (56%) for GHS 1A/1B classification compared to LLNA data.
• Quantitative DPRA improved accuracy to 81% (LLNA) and 57% (human data).
• Kinetic DPRA achieved high accuracy (35/38 substances) for GHS 1A/1B classification against LLNA and human data, with Cys-adduct analysis being sufficient.

Conclusions:

• The kinetic DPRA protocol demonstrates high accuracy in classifying skin sensitization potency sub-categories.
• Analysis of Cys-adducts is sufficient for potency assessment; Lys-adducts do not improve predictivity.
• Kinetic DPRA shows promise for replacing in vivo testing for comprehensive skin sensitization assessment, including potency.