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Event: 827

Key Event Title

The KE title should describe a discrete biological change that can be measured. It should generally define the biological object or process being measured and whether it is increased, decreased, or otherwise definably altered relative to a control state. For example “enzyme activity, decreased”, “hormone concentration, increased”, or “growth rate, decreased”, where the specific enzyme or hormone being measured is defined. More help

sensitisation, skin

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. The short name should be less than 80 characters in length. More help
sensitisation, skin

Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. Note, KEs should be defined within a particular level of biological organization. Only KERs should be used to transition from one level of organization to another. Selection of the level of biological organization defines which structured terms will be available to select when defining the Event Components (below). More help

Organ term

Further information on Event Components and Biological Context may be viewed on the attached pdf.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. More help

Key Event Components

Further information on Event Components and Biological Context may be viewed on the attached pdf.Because one of the aims of the AOP-KB is to facilitate de facto construction of AOP networks through the use of shared KE and KER elements, authors are also asked to define their KEs using a set of structured ontology terms (Event Components). In the absence of structured terms, the same KE can readily be defined using a number of synonymous titles (read by a computer as character strings). In order to make these synonymous KEs more machine-readable, KEs should also be defined by one or more “event components” consisting of a biological process, object, and action with each term originating from one of 22 biological ontologies (Ives, et al., 2017; See List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling). 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 signalling 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. More help

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
Skin Sensitisation AOP AdverseOutcome Agnes Aggy (send email) Open for citation & comment TFHA/WNT Endorsed

Stressors

This is a structured field used to identify specific agents (generally chemicals) that can trigger the KE. Stressors identified in this field will be linked to the KE in a machine-readable manner, such that, for example, a stressor search would identify this as an event the stressor can trigger. NOTE: intermediate or downstream KEs in one AOP may function as MIEs in other AOPs, meaning that stressor information may be added to the KE description, even if it is a downstream KE in the pathway currently under development.Information concerning the stressors that may trigger an MIE can be defined using a combination of structured and unstructured (free-text) fields. For example, structured fields may be used to indicate specific chemicals for which there is evidence of an interaction relevant to this MIE. By linking the KE description to a structured chemical name, it will be increasingly possible to link the MIE to other sources of chemical data and information, enhancing searchability and inter-operability among different data-sources and knowledgebases. The free-text section “Evidence for perturbation of this MIE by stressor” can be used both to identify the supporting evidence for specific stressors triggering the MIE as well as to define broad chemical categories or other properties that classify the stressors able to trigger the MIE for which specific structured terms may not exist. More help

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected from an ontology. 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
mouse Mus musculus High NCBI
guinea pig Cavia porcellus High NCBI

Life Stages

The structured ontology terms for life-stage are more comprehensive than those for taxa, but may still require further description/development and explanation in the free text section. More help

Sex Applicability

The authors must select from one of the following: Male, female, mixed, asexual, third gender, hermaphrodite, or unspecific. More help

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. For example, the biological state being measured could be the activity of an enzyme, the expression of a gene or abundance of an mRNA transcript, the concentration of a hormone or protein, neuronal activity, heart rate, etc. The biological compartment may be a particular cell type, tissue, organ, fluid (e.g., plasma, cerebrospinal fluid), etc. The role in the biology could describe the reaction that an enzyme catalyses and the role of that reaction within a given metabolic pathway; the protein that a gene or mRNA transcript codes for and the function of that protein; the function of a hormone in a given target tissue, physiological function of an organ, etc. Careful attention should be taken to avoid reference to other KEs, KERs or AOPs. Only describe this KE as a single isolated measurable event/state. This will ensure that the KE is modular and can be used by other AOPs, thereby facilitating construction of AOP networks. More help

Skin sensitisation is an immunological process that is described in two phases: the induction of sensitisation and the subsequent elicitation of the immune reaction. A sensitised subject has the capacity to mount a more accelerated secondary response to the same chemical. Upon reaching an unknown threshold number of hapten-specific T cells an individual will be said to be sensitised and will elicit a T cell-mediated eczematous skin reaction (termed allergic contact dermatitis, ACD) at the site of sensitiser re-exposure. Above the threshold, the severity of the adverse effect is assumed to increase proportionally to the dose, so the total dose per area of skin (e.g. μg/cm2) is the critical exposure determinant. In this regard, animal data is consistent with human clinical data[1]. The allergic reaction causes inflammation of the skin manifested by varying degrees of erythema, oedema, and vesiculation. It takes up to one week or more for individuals to develop specific sensitivity to a new allergen following exposure. An individual who never has been sensitised to a substance may develop only a mild dermatitis 2 weeks following the initial exposure but typically develops severe dermatitis within 1-2 days of the second and subsequent exposures[2].

How It Is Measured or Detected

One of the primary considerations in evaluating AOPs is the relevance and reliability of the methods with which the KEs can be measured. The aim of this section of the KE description is not to provide detailed protocols, but rather to capture, in a sentence or two, per method, the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements. Methods that can be used to detect or measure the biological state represented in the KE should be briefly described and/or cited. 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).Key considerations regarding scientific confidence in the measurement approach include whether the assay is fit for purpose, whether it provides a direct or indirect measure of the biological state in question, whether it is repeatable and reproducible, and the extent to which it is accepted in the scientific and/or regulatory community. Information can be obtained from the OECD Test Guidelines website and the EURL ECVAM Database Service on Alternative Methods to Animal Experimentation (DB-ALM). ?

[3]Human sensitisation testing is conducted with the Human Repeat Insult Patch Test (HRIPT), as described by McNamee et al.[4];[5]. Skin biopsy may help to confirm the diagnosis and exclude other disorders.

Animal models have been developed to assess the sensitisation potential of chemicals. Adler et al. (2011) have reviewed animal test methods for skin sensitisation[6]. Briefly, among these in vivo assays are the guinea-pig occluded patch test[7];[8], the Magnusson-Kligman guinea pig maximization test[7];[9];[10], and the murine Local Lymph Node Assay[11];[12];[13]. Using LLNA data, sensitisers can be grouped into potency groups (e.g. extreme, strong, moderate, weak and non-sensitisers). However, as noted by Basketter et al. [14], the LLNA is not without limitations.

Domain of Applicability

This free text section should be used to elaborate on the scientific basis for the indicated domains of applicability and the WoE calls (if provided). While structured terms may be selected to define the taxonomic, life stage and sex applicability (see structured applicability terms, above) of the KE, the structured terms may not adequately reflect or capture the overall biological applicability domain (particularly with regard to taxa). Likewise, the structured terms do not provide an explanation or rationale for the selection. The free-text section on evidence for taxonomic, life stage, and sex applicability can be used to elaborate on why the specific structured terms were selected, and provide supporting references and background information.  More help

In vivo studies remain the basis of assessing the sensitisation potential of chemicals (see [6]). As previously noted, human sensitisation testing is conducted with the HRIPT[4]. Other in vivo methods include the guinea-pig occluded patch test[6];[15], the Magnusson- Kligman guinea-pig maximization test [16] and the mouse LLNA[11];[12];[13].

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. For KEs that are designated as an AO, one additional field of information (regulatory significance of the AO) should be completed, to the extent feasible. If the KE is being described is not an AO, simply indicate “not an AO” in this section.A key criterion for defining an AO is its relevance for regulatory decision-making (i.e., it corresponds to an accepted protection goal or common apical endpoint in an established regulatory guideline study). For example, in humans this may constitute increased risk of disease-related pathology in a particular organ or organ system in an individual or in either the entire or a specified subset of the population. In wildlife, this will most often be an outcome of demographic significance that has meaning in terms of estimates of population sustainability. Given this consideration, in addition to describing the biological state associated with the AO, how it can be measured, and its taxonomic, life stage, and sex applicability, it is useful to describe regulatory examples using this AO. More help

Skin sensitisation is an endpoint that needs to be assessed within:

- CLP Regulation (EC) No1272/2008 for "Classification, Labelling and Packaging of substances and Mixtures",

- REACH Regulation (EC) No1907/2006 concerning the Registration, Evaluation, Authorization and Restriction of Chemicals,

- PPP Regulation (EC) No1107/2009 concerning the placing of plant protection products on the market,

- Biocidal Products Regulation (BPR) (EU) No528/2012 concerning the making available on the market and use of biocidal products,

- Cosmetics Regulation (EC) No1223/2009.

References

List of the literature that was cited for this KE description. Ideally, the list of references, should conform, to the extent possible, with the OECD Style Guide (https://www.oecd.org/about/publishing/OECD-Style-Guide-Third-Edition.pdf) (OECD, 2015). More help
  1. Api AM, Basketter DA, Cadby PA, Cano MF, Ellis G, Gerberick GF, Griem P, McNamee PM, Ryan CA, Safford B. 2008. Dermal sensitisation quantitative risk assessment (QRA) for fragrance ingredients. Regul Toxicol Pharmacol. 52(1):3-23.
  2. Hogan DJ and James WD.2015. Allergic Contact Dermatitis Workup Updated: Apr 22, 2015. Available on: http://emedicine.medscape.com/article/1049216-overview accessed 17.9.2015
  3. Bernstein IL, Li JT, Bernstein DI et al.2008. Allergy diagnostic testing: an updated practice parameter. Ann Allergy Asthma Immunol. 100(3 Suppl 3):S1-148.
  4. 4.0 4.1 McNamee PM, Api AM, Basketter DA, Frank Gerberick G, Gilpin DA, Hall BM, Jowsey I, Robinson MK.2008. A review of critical factors in the conduct and interpretation of the human repeat insult patch test. Regul Toxicol Pharmacol. 52(1):24-34.
  5. Larkin A and Rietschel RL.1998. The utility of patch tests using larger screening series of allergens. Am. J. Contact Dermat. 9(3):142-5.
  6. 6.0 6.1 6.2 Adler S, Basketter D, Creton S, Pelkonen O, van Benthem J, Zuang V, Ejner-Andersen K, Angers- Loustau A, Aptula A, Bal-Price A, Benfenati E, Bernauer U, Bessems J, Bois FY, Boobis A, Brandon E, Bremer S, Broschard T, Casati S, Coecke S, Corvi R, Cronin M, Daston G, Dekant W, Felter S, Grignard E, Gundert-Remy U, Heinonen T, Kimber I, Kleinjans J, Komulainen H, Kreiling R, Kreysa J, Batista Leite S, Loizou G, Maxwell G, Mazzatorta P, Munn S, Pfuhler S, Phrakonkham P, Piersma A, Poth A, Prieto P, Repetto G, Rogiers V, Schoeters G, Schwarz M, Serafimova R, Tahti H, Testai E, van Delft J, van Loveren H, Vinken M, Worth A, Zaldivar JM. 2011. Alternative (non-animal) methods for cosmetics testing: current status and future prospects-2010. Arch. Toxicol. 85: 367-485.
  7. 7.0 7.1 OECD 1992. Test No. 406: Skin Sensitisation, OECD Guidelines for the Testing of Chemicals, Section 4: Health Effects, OECD Publishing. doi: 10.1787/9789264070660-en.
  8. Buehler EV. 1965. Delayed hypersensitivity in the guinea pig. Arch. Dermatol. 91: 171-177.
  9. Magnusson B and Kligman AM. 1970. Allergic Contact Dermatitis in the Guinea Pig. Identification of Contact Allergens. Charles C Thomas; Springfield, IL USA.
  10. Maurer T, Arthur A and Bentley P. 1994. Guinea-pig contact sensitisation assays. Toxicology 93: 47-54.
  11. 11.0 11.1 OECD 2010. Test No429: Skin Sensitisation: Local Lymph Node Assay, OECD Guidelines for the Testing of Chemicals, Section 4: Health Effects, OECD Publishing. doi: 10.1787/9789264071100-en
  12. 12.0 12.1 OECD 2010b. Test No442A: Skin Sensitisation: Local Lymph Node Assay: DA, OECD Guidelines for the Testing of Chemicals, Section 4: Health Effects, OECD Publishing. doi: 10.1787/9789264090972- en.
  13. 13.0 13.1 OECD 2010c. Test No442B: Skin Sensitisation: Local Lymph Node Assay: BrdU-ELISA, OECD Guidelines for the Testing of Chemicals, Section 4: Health Effects, OECD Publishing. doi: 10.1787/9789264090996-en
  14. Basketter DA, McFadden JF, Gerberick F, Cochshott A and Kimber I. 2009. Nothing is perfect, not even the local lymph node assay: a commentary and the implications for REACH. Contact Dermat. 60: 65-69.
  15. OECD 1992. Test No 406: Skin Sensitisation, OECD Guidelines for the Testing of Chemicals, Section 4: Health Effects, OECD Publishing. doi: 10.1787/9789264070660-en
  16. Magnusson B, Kligman AM. The identification of contact allergens by animal assay.1969. The guinea pig maximization test. J. Invest. Dermatol. 52(3):268-76.