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

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 that may cause it. Here we use the adverse outcome pathway (AOP) framework to organize information that may better inform our understanding of sensitization of the respiratory tract, building on a previously published skin sensitization AOP, relying on literature evidence linked to low-molecular-weight organic chemicals and excluding other known respiratory sensitizers acting via different molecular initiating events. The established key events (KEs) are as follows: (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, proliferation, and polarization 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 behavior for KEs 2 and 3, as well as the effector T cell response, in general skewing toward cytokine secretions predominantly associated with T helper 2 (Th2) response. Knowledge gaps include the lack of understanding of which KE(s) drive the Th2 polarization. The construction of this AOP may provide insight into predictive tests that would in combination support the discrimination of respiratory-sensitizing from non- and skin-sensitizing chemicals, a clear regulatory need

Additional file 1: of Determinants of first-time utilization of long-term care services in the Netherlands: an observational record linkage study

Selection and definition of chronic diseases used in study. Diseases are defined using the ICPC-1 classification for primary care. (XLSX 12Â kb

Additional file 4: of Determinants of first-time utilization of long-term care services in the Netherlands: an observational record linkage study

Extended versions of Tables 5 and 6, including outcomes for 10-K cross-validation of the models. For each model sensitivity, specificity, threshold, accuracy, precision and negative predictive value are specified. (XLSX 12 kb

Additional file 3: of Determinants of first-time utilization of long-term care services in the Netherlands: an observational record linkage study

Statistical parameters final models. Statistical addendum for models in Tables 5, 6 and 7. Contains coefficients, confidence intervals and p-values for all determinants. (XLSX 27 kb

Additional file 2: of Determinants of first-time utilization of long-term care services in the Netherlands: an observational record linkage study

Model selection. Statistical information and description of the model selection process. (XLSX 20Â kb