Aop:39

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Authors

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

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

Status

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.

Under development: Do not distribute or cite.

Abstract

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

Molecular Initiating Event

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Molecular Initiating Event Support for Essentiality
Covalent binding to protein, possibly lysine residue, N/A Strong <html><button id="edit" name="Molecular Initiating Event"></button><button id="del" name="Molecular Initiating Event"></button></html>

Key Events

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Event Support for Essentiality
Inflammatory cytokines, chemokines, cytoprotective gene pathways, Activation Moderate <html><button id="edit" name="Key Events"></button><button id="del" name="Key Events"></button></html>

Adverse Outcome

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Adverse Outcome
Allergic Respiratory Hypersensitivity Response <html><button id="edit" name="Adverse Outcome"></button><button id="del" name="Adverse Outcome"></button></html>

Relationships Among Key Events and the Adverse Outcome

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Step Event Description Triggers Weight of Evidence Quantitative Understanding
1 Covalent binding to protein, possibly lysine residue, N/A Directly Leads to Inflammatory cytokines, chemokines, cytoprotective gene pathways, Activation Moderate Weak <html><button id="edit" name="Relationships Among Key Events and the Adverse Outcome"></button><button id="del" name="Relationships Among Key Events and the Adverse Outcome"></button></html>

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Life Stage Applicability

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Life Stage Evidence Links

Taxonomic Applicability

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Name Scientific Name Evidence Links

Sex Applicability

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Sex Evidence Links

Graphical Representation

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Confidence in the AOP

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.

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
Provide an overall summary of the weight of evidence based on the evaluations of the individual linkages from the Key Event Relationship pages.

Essentiality of the Key Events

Molecular Initiating Event Summary, Key Event Summary
Provide an overall assessment of the essentiality for the key events in the AOP. Support calls for individual key events can be included in the molecular initiating event, key event, and adverse outcome tables above.

Quantitative Considerations

Summary Table
Provide an overall discussion of the quantitative information available for this AOP. Support calls for the individual relationships can be included in the Key Event Relationship table above.

Applicability of the AOP

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

References

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.