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Covalent Binding, Protein leads to Increase, Allergic Respiratory Hypersensitivity Response
Key Event Relationship Overview
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|
Life Stage Applicability
|All life stages||High|
Key Event Relationship Description
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
Evidence Supporting this KER
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).
Uncertainties and Inconsistencies
Known modulating factors
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).
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
Domain of Applicability
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.