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This is a legacy representation of this AOP. Please see the current version here:

AOP Title

Sensitisation of the Respiratory Tract induced by Covalent Binding of Low Molecular Weight Organic Chemicals to Proteins
Short name: Respiratory Sensitisation/Allergy induced by covalent binding to proteins


Kristie Sullivan, Physicians Committee for Responsible Medicine/ICAPO,

Darrell Boverhof, Dow Chemical Company

Stella Cochrane, Unilever

Steven Enoch, Liverpool John Moores University

Janine Ezendam, RIVM

Ian Kimber, University of Manchester

Joanna Matheson & Kent Carlson, US CPSC

Grace Patlewicz, DuPont

Erwin Roggen, Novozymes

Katherina Sewald, Fraunhofer ITEM


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Alert: The Weight of Evidence column in the Molecular Initiating Event and Key Event tables has changed to Essentiality. Consider re-evaluating the columns in these tables.

OECD Project 1.20: The Adverse Outcome Pathway for Sensitisation of the Respiratory Tract Induced by Covalent Binding to Proteins

Under development: Do not distribute or cite.

This AOP page was last modified on 12/11/2016.

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The assessment of xenobiotics for potential to induce an allergenic response in the respiratory tract is of great regulatory and industrial interest. Currently, however, there are not standardized, validated and accepted regulatory models for detecting these materials, potentially due to remaining uncertainty within the literature as to the exact mechanistic pathway leading to respiratory allergy.

Ongoing work in this area has hypothesized some differences between the dermal and respiratory sensitisation pathways; however in some cases a lack of strong empirical evidence on a variety of chemistries to test these hypothesis. This AOP represents the currently available data with the aim of identifying knowledge gaps which may be filled with directed research.

Summary of the AOP

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Molecular Initiating Event

Molecular Initiating Event Support for Essentiality
Covalent binding to protein, possibly lysine residue, N/A Strong

Key Events

Event Support for Essentiality
Inflammatory cytokines, chemokines, cytoprotective gene pathways, Activation Moderate

Adverse Outcome

Adverse Outcome
Allergic Respiratory Hypersensitivity Response, Increase

Relationships Among Key Events and the Adverse Outcome

Event Description Triggers Weight of Evidence Quantitative Understanding
Covalent binding to protein, possibly lysine residue, N/A Directly Leads to Inflammatory cytokines, chemokines, cytoprotective gene pathways, Activation Moderate Weak

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Life Stage Applicability

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Taxonomic Applicability

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Sex Applicability

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Graphical Representation

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Overall Assessment of the AOP

Consider the following criteria (may include references to KE Relationship pages): 1. concordance of dose-response relationships; 2. temporal concordance among the key events and adverse effect; 3. strength, consistency, and specificity of association of adverse effect and initiating event; 4. biological plausibility, coherence, and consistency of the experimental evidence; 5. alternative mechanisms that logically present themselves and the extent to which they may distract from the postulated AOP. It should be noted that alternative mechanisms of action, if supported, require a separate AOP; 6. uncertainties, inconsistencies and data gaps.

Weight of Evidence Summary

Summary Table
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Essentiality of the Key Events

Molecular Initiating Event Summary, Key Event Summary
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Quantitative Considerations

Summary Table
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Applicability of the AOP

Life Stage Applicability, Taxonomic Applicability, Sex Applicability
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Considerations for Potential Applications of the AOP (optional)


Chipenda I, Hettick JM, Siegal PD (2011) Haptenation: Chemical Reactivity and Protein Binding, Journal of Allergy, vol. 2011, Article ID 839682, 11 pages. doi:10.1155/2011/839682.

Templeton D (2004) Mechanisms of Immunosensitisation to Metals, Pure and Applied Chemistry, 76:1255-1268.

Confidence in the AOP

Information from this section should be moved to the Key Event Relationship pages!

Elaborate on the domains of applicability listed in the summary section above. Specifically, provide the literature supporting, or excluding, certain domains.

Sensitizers which do not fit into this AOP:

There have been a number of studies into the sensitisation (and toxicity) of transition metal complexes; key amongst these is a recent study outlining the evidence for these complexes initiating sensitisation via the formation of co-ordination complexes rather than covalent bond formation (Chipenda et al 2011). The authors of this study present the evidence that these co-ordination complexes are not stable enough to survive the antigen processing that a covalent hapten undergoes, thus cannot sensitise via this MIE. Instead an alternative MIE is outlined in which these complexes bind to cell surface proteins like MHC, bypassing the intracellular antigen process. This MIE fits in with the observed cross-reactivity that appears to transcend the trends one would expect based on the periodic table (for example, complexes of Cr, a group 6 metal, cross sensitising with complexes of Co, a group 9 metal) (Templeton et al 2004). It is thought that the surface protein chelates the metal complex and presents it to T-cells directly. Therefore transition metals would require a separate AOP from chemicals acting via covalent binding to proteins.