Anchoring molecular mechanisms to the adverse outcome pathway for skin sensitization: Analysis of existing data

Abstract

Allergic contact dermatitis (ACD) is a hypersensitivity immune response induced by small protein-reactive chemicals. Currently, the murine local lymph node assay (LLNA) provides hazard identification and quantitative estimation of sensitizing potency. Given the complexity of ACD, a single alternative method cannot replace the LLNA, but it is necessary to combine methods through an integrated testing strategy (ITS). In the development of an ITS, information regarding mechanisms and molecular processes involved in skin sensitization is crucial. The recently published adverse outcome pathway (AOP) for skin sensitization captures mechanistic knowledge into key events that lead to ACD. To understand the molecular processes in ACD, a systematic review of murine in vivo studies was performed and an ACD molecular map was constructed. In addition, comparing the molecular map to the limited human in vivo toxicogenomic data available suggests that certain processes are similarly triggered in mice and humans, but additional human data will be needed to confirm these findings and identify differences. To gain insight in the molecular mechanisms represented by various human in vitro systems, the map was compared to in vitro toxicogenomic data. This analysis allows for comparison of emerging in vitro methods on a molecular basis, in addition to mathematical predictive value. Finally, a survey of the current in silico, in chemico, and in vitro methods was used to indicate which AOP key event is modeled by each method. By anchoring emerging classification methods to the AOP and the ACD molecular map, complementing methods can be identified, which provides a cornerstone for the development of a testing strategy that accurately reflects the key events in skin sensitization.

Keywords:

• allergic contact dermatitis
• adverse outcome pathway
• human in vitro systems
• mechanisms of toxicity
• molecular map
• skin sensitization

Acknowledgments

Dr. T Rustemeyer (VU Medical Centre, Amsterdam), Dr. J. Pennings (RIVM) and E. Rorije (RIVM) are acknowledged for critically assessing the quality of our work.

Declaration of interest

The author's affiliation is as shown on the cover page. The authors have sole responsibility for the writing and content of the paper. This work was funded by the Netherlands Organisation for Health research and development (ZonMW) through the ‘Data lntegration & Mining Towards Risk Assessment (project number: 165600002)’ project. TNO internal funding was provided from Enabling Technology Systems Biology and 3R research programs.