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Event: 312

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

N/A, Allergic contact dermatitis on challenge

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
N/A, Allergic contact dermatitis on challenge

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

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

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

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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

In vivo studies, including ones with human subjects, have been critical in the evolution of the science of skin sensitisation. Human sensitisation testing is conducted with the human repeat insult patch test (HRIPT), as described by McNamee et al.[1]. The experimental endpoint of this type of study can be considered the adverse outcome described as allergic contact dermatitis. Dermal sensitizers are assumed to elicit an adverse effect only after a threshold dose is reached. Above this 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 ([2]). These observations are consistent with the immunological mechanism presented with this AOP, where it is assumed that for an adverse outcome to commence, a certain number of dendritic cells is required to be activated and to migrate to the nearest lymph node in order to instigate the further cascade of biological events (see [2]).

Today the generation of sensitisation data in animal models remains the basis of assessing the sensitisation potential of chemicals. Adler et al.[3] have reviewed animal test methods for skin sensitisation. Briefly, among these in vivo assays are the guinea-pig occluded patch test ([4];[5];[5]), the Magnusson-Kligman guinea-pig maximization test [6]; [5];[7]), and the murine LLNA ([8];[9]; [10],[11],[12]). Positive results in the occluded patch test or the guinea-pig maximization test can be considered the adverse outcome described as contact hypersensitivity.

The similarities and differences between results, with the guinea-pig test, the LLNA and where available human evidence, is important in the IPCS MOA Framework[13] and addressed through the Bradford Hill criteria. While it will have implication in human risk assessment and classification and labelling under existing standards, it has less of an impact on the acceptance of an AOP and its use in forming chemical categories and integrated assessment and testing approaches.

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). ?

In vivo studies, including ones with human subjects, have been critical in the evolution of the science of skin sensitisation. Human sensitisation testing is conducted with the human repeat insult patch test (HRIPT), as described by McNamee et al[1].

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[3]) As previously noted, human sensitisation testing is conducted with the HRIPT ([1]). Other in vivo methods include the guinea-pig occluded patch test[5], the Magnusson- Kligman guinea-pig maximization test ([5]), and the mouse LLNA ([10];[11];[12]). While quantitative models have been developed with guinea-pig data, the LLNA assay was designed to allow for a direct quantitative assessment of skin sensitisation potency. Briefly, the relative potency of a skin-sensitizing chemical is measured by derivation of an ECx value, which is the concentration of a test chemical necessary to produce a X-fold increase in lymph node cell proliferation compared with concurrent vehicle controls (i.e. a threshold positive response) ([14]). Since the LLNA does not include the challenge phase of sensitisation, it may be considered an incomplete in vivo sensitisation assay. Using LLNA data, sensitizers can be grouped into potency groups (e.g. extreme, strong, moderate, weak, and non-sensitizers). However, as noted by Basketter et al. ([15]), the LLNA is not without limitations, including variability between EC3 values or any other value (i.e. ECx) within isoreactive mechanistic classes. There are increased efforts to look at in vivo skin sensitisation potential or lack of potential as concordance between LLNA and guinea-pig data, and human evidence.

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. 1.0 1.1 1.2 McNamee PM, Api AM, Basketter DA, Gerberick GF, 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. Reg. Toxicol. Pharmacol. 52: 24-34.
  2. 2.0 2.1 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. Reg. Toxicol. Pharmcol. 52: 3-23.
  3. 3.0 3.1 3.2 3.3 Adler S, BasketterD, 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.
  4. Buehler EV. 1965. Delayed hypersensitivity in the guinea pig. Arch. Dermatol. 91: 171-177.
  5. 5.0 5.1 5.2 5.3 5.4 Organization for Economic Co-operation and Development (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
  6. Magnusson B and Kligman AM. 1970. Allergic Contact Dermatitis in the Guinea Pig. Identification of Contact Allergens. Charles C Thomas, ; Springfield, IL USA.
  7. Maurer T, Arthur A, Bentley P. 1994. Guinea-pig contact sensitisation assays. Toxicology 93: 47- 54.
  8. 8.0 8.1 Basketter DA, Gerberick GF, Kimber I, Loveless SE. 1996. The local lymph node assay: a viable alternative to currently accepted skin sensitisation tests. Food Chem. Toxicol. 34: 985-997.
  9. Kimber I, Basketter DA, Gerberick GF, Dearman RJ. 2002a. Allergic contact dermatitis. Int.Immunopharmacol. 2: 201-211.
  10. 10.0 10.1 OECD 2010a. Test No. 429: Skin Sensitisation: Local Lymph Node Assay, OECD Guidelines for the Testing of Chemicals, Section 4: Health Effects, OECD Publishing. doi: 10.1787/9789264071100- en
  11. 11.0 11.1 OECD 2010b. Test No. 442A: 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
  12. 12.0 12.1 OECD 2010c. Test No. 442B: 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
  13. Boobis AR, Doe JE, Heinrich-Hirsch B, Meek ME, Munn S, Ruchirawat M, Schlatter J, Seed J, Vickers C. 2008. IPCS framework for analyzing the relevance of the non-cancer mode of action for humans. Crit. Rev. Toxicol. 38: 87-96.
  14. Basketter DA, Lea LJ, Cooper KJ, Dickens A, Stocks J, Pate I. 1999. Thresholds for classification as a skin sensitiser in the local lymph node assay: a statistical evaluation. Food Chem. Toxicol. 37:1167-1174.
  15. Basketter DA, McFadden JF, Gerberick F, Cochshott A, Kimber I. 2009. Nothing is perfect, not even the local lymph node assay: a commentary and the implications for REACH. Contact Dermatitis 60: 65-69.
  16. Aeby P, Ashikaga T, Bessou-Touya S, Schapky A, Geberick F, Kern P, Marrec-Fairley M, Maxwell G, Ovigne J-M, Sakaguchi H, Reisinger K, Tailhardat M, Martinozzi-Teisser S, Winkler P 2010. Identifying and characterizing chemical skin sensitizers without animal testing; Colipa’s research and methods development program. Toxicol. In Vitro 24: 1465-1473.
  17. Basketter DA and Kimber I. 2010. Contact hypersensitivity. In: McQueen, CA (ed) Comparative Toxicology Vol. 5, 2nd Ed. Elsevier, Kidlington, UK, pp. 397-411.
  18. Kimber I, Dearman RJ, Basketter DA, Ryan CA, Gerberick GF. 2002b. The local lymph node assay: past, present and future. Contact Dermatitis 47: 315-328.
  19. Basketter DA, Lea LJ, Cooper KJ, Dickens A, Stocks J, Pate I. 1999. Thresholds for classification as a skin sensitiser in the local lymph node assay: a statistical evaluation. Food Chem. Toxicol. 37:1167-1174.
  20. Basketter DA, McFadden JF, Gerberick F, Cochshott A, Kimber I. 2009. Nothing is perfect, not even the local lymph node assay: a commentary and the implications for REACH. Contact Dermatitis 60: 65-69.
  21. Ball N, Cagen S, Carrillo JC, Certa H, Eigler D, Emter R, Faulhammer F, Garcia C, Graham C, Haux C, Kolle SN, Kreiling R, Natsch A, Mehling A. 2011. Evaluating the sensitisation potential of surfactants: Integrating data from the local lymph node assay, guinea pig maximization test, and in vitro methods in a weight-of-evidence approach, Reg. Toxicol. Pharmacol., doi:10.1016/j.yrtph.2011.05.007