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Constructing an adverse outcome pathway for sensitization of the respiratory tract: Network thinking meets regulatory utility

: Sullivan, K.; Cochrane, S.; Enoch, S.J.; Ezendam, J.; Patlewicz, G.; Roggen, E.L.; Sewald, Katherina

The Toxicologist 54 (2015), No.1, pp.142, Abstract PS 666
ISSN: 0731-9193
Society of Toxicology (Annual Meeting) <54, 2015, San Diego/Calif.>
Fraunhofer ITEM ()

Concerted international efforts are underway to build networks of AOPs with shared key events (KEs) to enable the database of known AOPs to eventually serve as a framework for contextualizing results of predictive test methods across varied biological mechanisms. The development of an AOP for sensitization of the respiratory tract by low-molecular-weight (LMW) organic chemicals was envisioned to build upon a skin sensitization AOP published by OECD in 2012, since KEs may be common to both pathways. Indeed, the established KEs, which are 1) Covalent binding of LMW chemicals to proteins, 2) Cellular Danger Signals: Activation of inflammatory cytokines and chemokines and cytoprotective gene pathways, 3) Dendritic cell activation and migration, 4) Activation and proliferation of T cells, and 5) B Cell activation and class switching, are very similar. However, there are differences. For example, though the Molecular Initiating Event (MIE), covalent binding to proteins, is common to the two AOPs, there is some evidence that respiratory sensitizers bind preferentially to lysine, whereas skin sensitizers bind to both cysteine and lysine. In some cases this preference may be consequential enough to the respiratory sensitization pathway that it warrants separate description from the MIE for skin sensitization. Other events that may be similarly discriminatory include KEs 2 and 5; in fact, there has been some success separating skin and respiratory sensitizers by assessing specific profiles of inflammatory mediators expressed after in vitro exposure to sensitizers. The construction of this AOP highlights knowledge gaps and may provide insight into which predictive tests would be most useful to develop further to support the discrimination of respiratory-sensitizing from skin-sensitizing chemicals, a clear regulatory need.