The skin sensitization adverse outcome pathway: exploring the role of mechanistic understanding for higher tier risk assessment

Abstract

For over a decade, the skin sensitization Adverse Outcome Pathway (AOP) has served as a useful framework for development of novel in chemico and in vitro assays for use in skin sensitization hazard and risk assessment. Since its establishment, the AOP framework further fueled the existing efforts in new assay development and stimulated a plethora of activities with particular focus on validation, reproducibility and interpretation of individual assays and combination of assay outputs for use in hazard/risk assessment. In parallel, research efforts have also accelerated in pace, providing new molecular and dynamic insight into key events leading to sensitization. In light of novel hypotheses emerging from over a decade of focused research effort, mechanistic evidence relating to the key events in the skin sensitization AOP may complement the tools currently used in risk assessment. We reviewed the recent advances unraveling the complexity of molecular events in sensitization and signpost the most promising avenues for further exploration and development of useful assays.

Keywords:

• Skin sensitization
• allergy
• hapten
• reactivity
• antigen
• risk assessment
• new approach methodologies
• mechanistic insights

Acknowledgments

The authors wish to thank Gavin Maxwell of Safety and Environmental Assurance Centre, Unilever for helpful suggestions and encouragement during the early stages of the manuscript preparation. Our thanks also go to Georgia Reynolds, Maria Baltazar and Carl Westmoreland (all of Safety and Environmental Assurance Centre, Unilever) for their thorough critical review of the manuscript and helpful suggestions ahead of submission. We are very grateful to Eoin Winston and Frank Munnelly of NEXU Creative for their detailed and masterful effort on the images for Figures 1 and 3. We would also like to express our gratitude for their thoughtful and detailed comments and suggestions to the reviewers of the manuscript who were selected by the Editor and whose identity is unknown to the authors.

Declaration of interest

The submitted manuscript was inspired by the publication by Natsch and Emter in 2017 (Natsch and Emter 2017). MA conceived the original idea, which was further developed in many discussions with RR, NG, SS and RA with a view to review the most up to date mechanistic insights into induction of sensitization in humans. Our motivation is to emphasize the most promising areas of research suitable for development of novel assays with capacity to determine sensitizing potency and aid risk assessment decisions. The authors are employees of Safety and Environmental Assurance Centre, Unilever and no external funds were used in the preparation of this manuscript. The authors do not imply competing financial interests or personal relationships that could have appeared to influence the work reported in this manuscript.