API

Aop: 39

AOP Title

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Sensitisation of the Respiratory Tract induced by Covalent Binding of Low Molecular Weight Organic Chemicals to Proteins

Short name:

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Respiratory Sensitisation/Allergy induced by covalent binding to proteins

Authors

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Kristie Sullivan, Physicians Committee for Responsible Medicine/ICAPO, Ksullivan@pcrm.org

Stella Cochrane, Unilever

Steven Enoch, Liverpool John Moores University

Janine Ezendam, RIVM

Joanna Matheson & Kent Carlson, US CPSC

Grace Patlewicz, US EPA

Erwin Roggen, 3RsMC ApS

Katherina Sewald, Fraunhofer ITEM

Point of Contact

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Kristie Sullivan

Contributors

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  • Kristie Sullivan

Status

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Author status OECD status OECD project SAAOP status
Under development: Not open for comment. Do not cite Under Development 1.20 Included in OECD Work Plan


This AOP was last modified on September 25, 2017 13:50

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Revision dates for related pages

Page Revision Date/Time
N/A, Covalent binding to protein, possibly lysine residue September 16, 2017 10:14
Activation, Inflammatory cytokines, chemokines, cytoprotective gene pathways September 16, 2017 10:14
Increase, Allergic Respiratory Hypersensitivity Response September 16, 2017 10:14
N/A, Covalent binding to protein, possibly lysine residue leads to Activation, Inflammatory cytokines, chemokines, cytoprotective gene pathways December 03, 2016 16:37

Abstract

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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.


Background (optional)

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Summary of the AOP

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Stressors

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Molecular Initiating Event

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Title Short name
N/A, Covalent binding to protein, possibly lysine residue N/A, Covalent binding to protein, possibly lysine residue

Key Events

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Title Short name
Activation, Inflammatory cytokines, chemokines, cytoprotective gene pathways Activation, Inflammatory cytokines, chemokines, cytoprotective gene pathways

Adverse Outcome

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Title Short name
Increase, Allergic Respiratory Hypersensitivity Response Increase, Allergic Respiratory Hypersensitivity Response

Relationships Between Two Key Events (Including MIEs and AOs)

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Network View

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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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Click to download graphical representation template

Overall Assessment of the AOP

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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.

Domain of Applicability

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Essentiality of the Key Events

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Weight of Evidence Summary

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Quantitative Considerations

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Considerations for Potential Applications of the AOP (optional)

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References

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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.