New Publication: An Adverse Outcome Pathway for Sensitization of the Respiratory Tract by Low-Molecular-Weight Chemicals: Building Evidence to Support the Utility of In Vitro and In Silico Methods in a Regulatory Context

Share

Sensitization of the respiratory tract is an important occupational health challenge, and understanding the mechanistic basis of this effect is necessary to support the development of toxicological tools to detect chemicals which may cause it. Here, we use the Adverse Outcome Pathway framework to organize information which may better inform our understanding of sensitization of the respiratory tract, building upon a skin sensitization AOP published in 2012. We rely on literature evidence linked to low molecular weight organic chemicals to the exclusion of other known respiratory sensitizers acting via different molecular initiating events. The established key events are:

1) Covalent binding of chemicals to proteins,

2) Activation of cellular danger signals (inflammatory cytokines and chemokines and cytoprotective gene pathways),

3) Dendritic cell activation and migration,

4) Activation and proliferation of T cells, and

5) Sensitization of the respiratory tract.

These events mirror the skin sensitization AOP but with specific differences. For example, there is some evidence that respiratory sensitizers bind preferentially to lysine moieties, whereas skin sensitizers bind to both cysteine and lysine. Furthermore, exposure to respiratory sensitizers seems to result in cell behaviour for key events 2 and 3, as well as the effector T cell response, in general skewing towards cytokine secretions predominantly associated with T helper 2 response. Knowledge gaps include the precise relationship between common respiratory sensitizers and the Th2 response. The construction of this AOP may provide insight into predictive tests which would support the discrimination of respiratory-sensitizing from skin-sensitizing chemicals, a clear regulatory need.

View the publication.

Comments are closed.