Next Generation of Adaptive Integrated Testing Strategies for Skin Sensitization

Joanna Jaworska, Procter & Gamble, Belgium

Bayesian Network Integrated Testing Strategy (ITS-1) pilot phase showed potential to be a useful tool for decision making with alternative test information and offered novel insights. In a next generation ITS, ITS-2, the aim was to confirm findings from the pilot phase using a significantly enlarged data set and develop practical, optimal testing strategy for skin sensitization hazard testing. To this end we continue to combine in silico, in chemico and in vitro data related to skin penetration, peptide reactivity, activation of Nrf2-dependent gene activity and dendritic cell activation. However, we introduce several changes. We extend the number/modify input tests as they evolved over time. For example we evaluate value of the newly developed peroxidase peptide reactivity assays that consider metabolic activation and report result based on dose response with one of the existing direct peptide reactivity assays. We replace the AREc32 assay with the more standardized KeratinoSens assay. In addition, we include cytotoxicity as a co-factor that may be an indicator of effects related to danger signal formation / local trauma thought to affect sensitizer potency. We also include mechanistic evidence, like reactivity domain characterization, not directly related to potency yet an important co-factor in potency determination. This way we start the evolution from an integrated testing strategy towards an intelligent testing strategy that will relay on an increasing number of mechanistic evidence generated with systems biology data.