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Relationship: 2650


A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Covalent Binding, Protein leads to Increase, Allergic Respiratory Hypersensitivity Response

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes. Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name Adjacency Weight of Evidence Quantitative Understanding Point of Contact Author Status OECD Status
Covalent Binding of Low Molecular Weight Organic Chemicals to Proteins leads to Sensitisation (Sensitization) of the Respiratory Tract non-adjacent High Low Kristie Sullivan (send email) Under Development: Contributions and Comments Welcome Under Development

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER.  More help
Term Scientific Term Evidence Link
human Homo sapiens High NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help
Sex Evidence
Unspecific High

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help
Term Evidence
All life stages High

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

Consistent epidemiologic evidence shows that allergic respiratory hypersensitivity is caused by exposure to electophilic low molecular weight chemicals, which are too small to activate the immune system without first generating hapten-protein conjugates. 

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER.  For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings.  Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

The ability of certain chemicals to cause allergic respiratory hypersensitivity (respiratory sensitization) is a chemical health hazard, that has high levels of morbidity in occupational settings that has been known sin. (Kimber et al., 2011; Kimber et al., 2018). 

Biological Plausibility
Addresses the biological rationale for a connection between KEupstream and KEdownstream.  This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured.   More help
Uncertainties and Inconsistencies
Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references.  More help
Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  More help

Mounting evidence supports a threshhold relationship between hapten exposure and airway hypersensitivity. While average exposures to toluene diisocyanate have decreased significantly from the 1970s and 1980s, asthma incidence rates have stayed the same. A pair of studies (Plehiers et al., 2020a and 2020b) found that gross cumulative exposure does not correlate with asthma incidence. Instead, frequency of unprotected exposurse over a certain threshold was positively associated with incidence. A recent review highlighted the evidence that sensitization is threshold-based, but noted practical difficulties in definining accurate numerical threshold exposure values (Cochrane, SA et al., 2015).

Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help

The rapid onset of symptoms (within 1 hour and often within minutes of chemical exposure) of respiratory allergic symptoms in sensitized individuals is indicative of an antibody-mediated (type I hypersensitivity) mechanism.

Known Feedforward/Feedback loops influencing this KER
Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help


List of the literature that was cited for this KER description. More help

Cochrane SA, Arts JHE, Ehnes C, et al. 2015. Thresholds in chemical respiratory sensitisation. Toxicology. 333:179-194.

Kimber I, Basketter DA, Gerberick GF, Ryan CA, Dearman RJ. 2011. Chemical allergy: translating biology into hazard characterization. Toxicol Sci. 120 Suppl 1:S238-S268.

Kimber I, Poole A, Basketter DA. 2018. Skin and respiratory chemical allergy: confluence and divergence in a hybrid adverse outcome pathway. Toxicol Res (Camb). 2018;7(4):586-605. 

PLEHIERS, P. M., CHAPPELLE, A. H. & SPENCE, M. W. 2020a. Practical learnings from an epidemiology study on TDI-related occupational asthma: Part I-Cumulative exposure is not a good indicator of risk. Toxicol Ind Health, 36, 876-884. PLEHIERS, P. M., CHAPPELLE, A. H. & SPENCE, M. W. 2020b. Practical learnings from an epidemiology study on TDI-related occupational asthma: Part II-Exposure without respiratory protection to TWA-8 values indicative of peak events is a good indicator of risk. Toxicol Ind Health, 36, 885-891.