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Event: 313

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Increase, Allergic Respiratory Hypersensitivity Response

Short name
The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. More help
Increase, Allergic Respiratory Hypersensitivity Response
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Biological Context

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Level of Biological Organization

Organ term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help
Organ term

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling).  The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor).  Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description.  To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons.  If a desired term does not exist, a new term request may be made via Term Requests.  Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help
Process Object Action
Respiratory Hypersensitivity increased

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE.Clicking on the name of the AOP will bring you to the individual page for that AOP. More help
AOP Name Role of event in AOP Point of Contact Author Status OECD Status
Covalent binding to proteins leads to Respiratory Sensitisation/Sensitization/Allergy AdverseOutcome Jessica Ponder (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 KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help
Term Scientific Term Evidence Link
human Homo sapiens High NCBI
guinea pig Cavia porcellus Low NCBI
rat Rattus norvegicus Low NCBI

Life Stages

An indication of the the relevant life stage(s) for this KE. More help
Life stage Evidence
During development and at adulthood High

Sex Applicability

An indication of the the relevant sex for this KE. More help
Term Evidence
Unspecific High

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

The development of an allergic hypersensitivity reaction in the respiratory tract is a two-step process, first requiring induction of the immune response (Boverhof et al, 2008). Subsequent single or multiple exposures to the same substance result in elicitation of an allergic hypersensitivity reaction, characterized by breathlessness and wheezing, airflow obstruction, bronchoconstriction, and tightness of the chest (Lauenstein et al, 2014). Reactions can be acutely life threatening or lead to chronic occupational asthma (Boverhof et al, 2008).

How It Is Measured or Detected

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

Clinical signs described above can be objectively assessed in humans to confirm diagnosis of respiratory hypersensitivity. Airflow obstruction and bronchoconstriction are measured using serial measures of airflow (usually FEV1) about 12 hours after exposure to test for immediate or delayed bronchoconstriction (Beckett, 2008). However, to differentiate between irritant and allergic asthma, additional testing to confirm immune involvement must also be conducted.

Allergen-specific IgE detection and measurement techniques include skin tests (intradermal and subcutaneous skin prick testing) and blood testing using immune assays such as ELISAs and commercially available tests such as ImmunoCAP™. For example, Bernstein et al. investigated the ability of TMA skin testing to identify sensitized workers and found that skin prick testing was positive in 8 of 11 workers with serum-specific IgE and intradermal testing in a further two (Bernstein et al., 2011). It is important to note, however, that there are technical challenges associated with detection and measurement of specific IgE and IgG to chemical respiratory allergens, including production of the correct protein conjugate and timing of measurement (Kimber et al., 2014, Quirce, 2014). Immune assays such as ELISA or ImmunoCAP are also used to investigate allergen-specific antibody isotype profiles (Movérare et al., 2017). Investigations into direct and indirect class switching involve transcriptomic analyses of IgE heavy chain transcripts and are challenging due to the scarcity of IgE-switched B cells in human blood (Davies et al., 2013).

In cases where specific IgE cannot be identified, the Basophil Activation Test (BAT) can identify allergic response in patients within a year of the last allergen exposure. Basophils degranulate in response to IgE cross-links bound to the high-affinity IgE receptor, much like mast cells. In fresh blood samples (less than 24 hours old) this can be measured by the translocation of CD63 to the membrane using flow cytometry. A review of the use of BAT in diagnosing occupational asthma shows that BAT is a functional readout that works for a variety of allergens, including dust, latex, and small molecules such as ammonium persulfate, chlorhexidine, and beta-lactam antibiotics. However, 10 - 20% of people are estimated to be BAT non-responders in which this response is not detected (Vera-Berrios et al., 2019).

In vivo, alterations in breathing parameters such as respiratory rate, minute volume, tidal volume, peak expiratory flow, inspiratory and expiratory times and a flow-derived estimation of airflow restriction (enhanced pause, Penh) have been used for quantitative assessment of allergen induced airway hyperreactivity (Boverhof et al. 2008).

In rats, respiratory exposure to diisocyanites leads to immediate and delayed airway response. Elicitation is confirmed measuring PMN in bronchoalveolar lavage fluid (BAL) one day after inhalation challenge and exhaled NO (Pauluhn 2014).

Domain of Applicability

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided).  More help

The domain of applicability for respiratory sensitisation is primarily limited to humans. Guinea pigs, and to a lesser degree rats, are the only rodent species that exhibit respiratory hypersensitivity, but in guinea pigs, IgG1 is the driver antibody (Boverhof et al 2008). In mice, vascular hypersensitivity is observed rather than respiratory response (Boverhof et al 2008). Therefore investigations in mice are limited to the study of earlier key events, or elicitation of vascular hypersensitivity.

Regulatory Significance of the Adverse Outcome

An AO is a specialised KE that represents the end (an adverse outcome of regulatory significance) of an AOP. More help

This adverse outcome is of high regulatory interest and relevance, though no test guideline is available. Regulatory agencies and industrial producers are interested in preventing the first step--induction of immune response. Importantly, induction of respiratory sensitisation can be obtained via skin exposure, which is consequential for potential exposure restrictions.


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

Beckett, W.S., 2005. Revised protocol: criteria for designating substances as occupational asthmagens on the AOEC List of Exposure Codes.

Boverhof DR, Billington R, Bhaskar Gollapudi B, Hotchkiss JA, Krieger SM, Poole A, Wiescinski CM, and Woolhiser MR. 2008. Respiratory sensitization and allergy: Current research approaches and needs. Tox Appl Pharm 226:1-13.

Dearman RJ, Betts CJ, Humphreys N, Flanagan BF, Gilmour NJ, Basketter DA, Kimber I. 2003. Chemical allergy: considerations for the practical application of cytokine profiling. Toxicol. Sci. 71, 137–145.

Lauenstein L, Switalla S, Prenzler F, Seehase S, Pfennig O, Förster C, Fieguth H, Braun A and Sewald K. 2014. Assessment of immunotoxicity induced by chemicals in human precision-cut lung slices (PCLS). Tox in Vitro 28:588–599.

OECD (2010) Test No. 429: Skin Sensitisation: Local Lymph Node Assay, OECD Guidelines for the Testing of Chemicals, Section 4, OECD Publishing. doi: 10.1787/9789264071100-en.

Pauluhn J. 2014. Development of a respiratory sensitization/elicitation protocol of toluene diisocyanate (TDI) in Brown Norway rats to derive an elicitation-based occupational exposure level. Toxicology 319: 10–22.

BERNSTEIN, J. A., GHOSH, D., SUBLETT, W. J., WELLS, H. & LEVIN, L. 2011. Is trimellitic anhydride skin testing a sufficient screening tool for selectively identifying TMA-exposed workers with TMA-specific serum IgE antibodies? J Occup Environ Med, 53, 1122-7.

DAVIES, J. M., PLATTS-MILLS, T. A. & AALBERSE, R. C. 2013. The enigma of IgE+ B-cell memory in human subjects. J Allergy Clin Immunol, 131, 972-6.

KIMBER, I., DEARMAN, R. J. & BASKETTER, D. A. 2014. Diisocyanates, occupational asthma and IgE antibody: implications for hazard characterization. J Appl Toxicol, 34, 1073-7.

MOVÉRARE, R., BLUME, K., LIND, P., CREVEL, R., MARKNELL DEWITT, Å. & COCHRANE, S. 2017. Human Allergen-Specific IgG Subclass Antibodies Measured Using ImmunoCAP Technology. Int Arch Allergy Immunol, 172, 1-10.

QUIRCE, S. 2014. IgE antibodies in occupational asthma: are they causative or an associated phenomenon? Curr Opin Allergy Clin Immunol, 14, 100-5.

VERA-BERRIOS, R. N., FEARY, J. & CULLINAN, P. 2019. Basophil activation testing in occupational respiratory allergy to low molecular weight compounds. Curr Opin Allergy Clin Immunol, 19, 92-97.