Protein–Hapten Binding: Challenges and Limitations for In Vitro Skin Sensitization Assays

In the search for practical alternatives to the use of animals in the predictive identification of chemicals which possess the intrinsic potential to cause sensitization of the skin, for 2 decades attention has been paid to structure–activity relationships. The work has delivered many valuable insights and has even led to the development of useful computer-based systems (e.g., DEREK). However, these efforts have been predicated very largely on an interrogation of how the chemical itself may be reactive (or may become so after metabolic intervention). Scant attention has been paid to the “substrate” with which the chemical must interact, i.e., skin protein. In this review, we consider in detail those actual protein substructures, examining what is known chemically, what may be predicted to occur, and how they can be investigated. Ultimately, understanding of the protein–hapten binding mechanisms in vitro will increase the confidence in sensitization hazard predictions using in silico tools. It could also permit development of a simple in vitro sensitization screen.