Key Event Title
|Level of Biological Organization|
Key Event Components
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP|
|Respiratory Sensitisation/Allergy induced by covalent binding to proteins||AdverseOutcome|
Key Event Description
The development of an allergic hypersensitivity reaction in the respiratory tract is a two-step process, first requiring induction of the immune response, here as a result of exposure to a low-molecular-weight chemical (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
Clinical signs described above can be objectively assessed in humans to confirm diagnosis of respiratory hypersensitivity.
Boverhof et al (2008) reviews various in vivo methods to detect respiratory hypersensitivity.
In rats, respiratory exposure to diisocyanites leads to immediate and delayed airway response (i.e. lung function). Elicitation is confirmed measuring PMN in bronchoalveolar lavage fluid (BAL) one day after inhalation challenge and exhaled NO (Pauluhn 2014).
In mice, induction of immune response, measured by T-lymphocyte maturation and proliferation in local lymph nodes, can often be detected using a Local Lymph Node Assay protocol (OECD 2010) with subsequent cytokine fingerprinting or IgE testing (Dearman et al 2003; Boverhof et al 2008).
Domain of Applicability
Regulatory Significance of the Adverse Outcome
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.
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.