Quantitative next generation risk assessment for skin sensitization - application of regression models based on in vitro data to estimate point of departure.

Summary

This methods paper integrates in vitro regression models into NGRA to derive quantitative points of departure for skin sensitization, enabling QRA2 without animal data. Case studies showed AEL/CEL ratios based on NAM-NESILs align with historically human-derived NESILs, supporting reliability and regulatory applicability.

Key Findings

• Introduces an NGRA framework that uses OECD TG 497 in vitro assays and regression models to derive quantitative PoDs for skin sensitizers.
• Applies the approach to two sensitizers (p-mentha-1,8-dien-7-al and 3-propylidenephthalide), calculating product-specific AELs (e.g., deodorants, bar soaps) and AEL/CEL ratios.
• NAM-NESIL-based QRA outcomes were consistent with historically human-derived NESILs, supporting the reliability of in vitro models.
• The approach can reduce or potentially eliminate dependence on in vivo data for PoD derivation in cosmetic safety assessment.

Clinical Implications

Dermatologists and safety assessors can reference NAM-derived NESILs when evaluating fragrance and cosmetic formulations, supporting safer concentrations and informed counseling for patients with contact dermatitis risk.

Limitations

• Demonstration limited to two sensitizer case studies, requiring broader chemical coverage
• Regression-based PoDs depend on model assumptions and input variability; external validation across datasets is needed

Future Directions

Expand to larger chemical sets, harmonize regression models across consortia, publish reference NAM-NESIL libraries, and integrate consumer exposure variability and skin condition modifiers into QRA.