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Relationship: 376

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Covalent Binding, Protein leads to Response, Keratinocytes

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Covalent Binding, Protein
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help
Response, Keratinocytes

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes. Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

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 KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER.  More help

Sex Applicability

An indication of the the relevant sex for this KER. More help

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

Haptens can also react with cell surface proteins and activate response pathways in keratinocytes (see [1]). Uptake of the hapten by keratinocytes activates multiple events, including the release of pro-inflammatory cytokines and the induction of cyto-protective cellular pathways. Activation of the pro-inflammatory cytokine IL-18 results from cleavage of inactive IL-18 precursor protein by inflammasome-associated caspase-1[2]. Sensitizers can activate the inflammasome ([3];[4]) and in so doing induce IL-18 production. Intracellular Nodlike receptors (NLR) contain sensors for a number of cellular insults. Upon activation (by a currently unknown mechanism), NLRs oligomerise form molecular complexes (i.e. inflammasomes) that are involved in the activation of inflammatory-associated caspases, including caspase-1. Inductions of intracellular levels of IL-18 exhibit responses upon exposure to sensitizers which can be used to establish potency[5].

Keratinocyte exposure to sensitizers also results in induction of antioxidant/electrophile response element ARE/EpRE-dependent pathways[6]. Briefly, reactive chemicals bind to Keap1 (Kelch-like ECH-associates protein 1) that normally inhibit the nuclear erythroid 2-related factor 2 (Nrf2). Released Nrf2 interacts with other nuclear proteins and binds to and activates ARE/EpREdependent pathways, including the cytoprotective genes NADPH-quinone oxidoreductase 1 (NQ01) and glutathione S-transferase (GSHST), among others ([6];[7]).

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER.  For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings.  Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help
Biological Plausibility
Addresses the biological rationale for a connection between KEupstream and KEdownstream.  This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured.   More help

The in chemico, in vitro, and in vivo experimental evidence is logical and consistent with the mechanistic plausibility proposed by covalent reactions based on the protein binding theory ([8]; [9]; [10]). In selected cases, (e.g. 1-chloro-2,4-dinitrobenzenes) where the same compound has been examined in a variety of assays (see Annex 1 of [11]), the coherence and consistency of the experimental data is excellent. Alternative mechanism that logically present themselves and the extent to which they may distract from the postulated AOP. It should be noted that alternative mechanisms of action, if supported, require a separate AOP. While covalent reactions with thiol groups and to a lesser extent amino groups, are clearly supported by the proposed AOP, reactions targeting other nucleophiles may or may not be supported by the proposed AOP. Limited data on chemical reactivity shows that two competing reactions are possible, the faster reaction dominates. However, this has yet to be proven in vitro or in vivo.

Uncertainties and Inconsistencies
Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

Uncertainties include the structural and physicochemical cut-offs between theoretical and measured reactivity ([12]), the significance of the preferred amino acid target (e.g., cysteine versus lysine) (OECD, 2011b), the significance of Th1 or type 1 (IFN-γ) versus Th2 or type 2 (IL-2, IL-4, IL-13) cytokine secretion profiles ([13]), and sensitisation measurements in different in vivo models.

Inconsistencies within the reported data are seen. There are differences between in vitro responses for highly similar chemicals (see[6];[14]). There are differences within and between in vivo test results for highly similar chemicals (see Annex C of the European Centre for Ecotoxicological and Toxicological Chemicals, 2010). Highly hydrophobic chemicals, which are in vivo sensitizers, are not active in aquatic-based in chemico or in vitro assays. The specific nature of the relationship between irritation and sensitisation has yet to be elucidated.

Data gaps: Based on the more than 50 chemical reactions associated with covalent binding to thiol or primary amine moieties[15] in vitro data for keratinocyte, dendritic cell, and T-cell assays, as well as in vivo sensitisation data, is incomplete in that it does not cover the chemical spaces associated with many of these chemical reactions; in chemico data is also incomplete, especially for reactions that favour amino acid targets other than cysteine.

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references.  More help
Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  More help
Time-scale
Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help
Known Feedforward/Feedback loops influencing this KER
Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

While in vivo testing focuses on selected mammals including man, the key events for this AOP appear to be conserved across mammals. With exceptions, there is agreement between sensitizers initiated by covalent binding to proteins and non-sensitizers tested in mice, guinea-pigs, and humans; this is especially the case for extreme and strong sensitizers but lesser so for weak and non-sensitizers. One problem is that earlier results, especially with the guinea-pig, were not dose-response experiments. Chemical reactivity data show very good concordance of dose-response relationships regardless of the method. In general, available data from in vitro assays are fragmentary and often qualitative (i.e., yes/no).

References

List of the literature that was cited for this KER description. More help
  1. ↑ Weltzien H, Corsini E, Gibbs S, Lindstedt M, Borrebaeck C, Budde P, Schulz-Knappe P, Thierse HJ, Martin S, Roggen, E. 2009. Safe cosmetics without animal testing? Contributions of the EU Project Sens-it-iv. J. für Verbraucherschutz und Lebensmittelsicherheit. 4: 41-48.
  2. ↑ Martinon F, Mayor A, Tschopp J. 2009. The inflammasomes: guardians of the body. Ann. Rev. Immunol. 27: 229-265.
  3. ↑ Sutterwala FS, Ogura Y, Szczepanik M, Lara-Tejero M, Lichtenberger GS, Grant EP, Bertin J, Coyle AJ, Galán JE, Askenase PW, Flavell RA. 2006. Critical role for NALP3/CIAS1/Cryopyrin in innate and adaptive immunity through its regulation of caspase-1. Immunity 24: 317-327.
  4. ↑ Watanabe H, Gaide O, Pétrilli V, Martinon F, Contassot E, Roques S, Kummer JA, Tschopp J, French LE. 2007. Activation of the IL-1beta-processing inflammasome is involved in contact hypersensitivity. J. Invest. Dermatol. 127: 1956-1963.
  5. ↑ Van Och FMM, Van Loveren H, Van Wolfswinkel JC, Machielsen AJC, Vandebriel RJ. 2005. Assessment of potency of allergenic activity of low molecular weight compounds based on IL-1α and IL-18 production by a murine and human keratinocyte cell line. Toxicology 210: 95-109.
  6. ↑ 6.0 6.1 6.2 Natsch A and Emter R. 2008. Skin sensitizers induce antioxidant response element dependent genes: Application to the in vitro testing of the sensitisation potential of chemicals. Toxicol. Sci. 102: 110-119
  7. ↑ Ade N, Leon F, Pallardy M, Pfeiffer JL, Kerdine-Romer S, Tissier MH, Bonnet PA, Fabre I Ourlin JC. 2009. HMOX1 and NQO1 genes are upregulated in response to contact sensitizers in dendritic cells and THP-1 cell line: role of the Keap1/Nrf2 pathway. Toxicol. Sci. 107: 451-460.
  8. ↑ Gerberick F, Aleksic M, Basketter D, Casati S, Karlberg AT, Kern P, Kimber I, Lepoittevin JP, Natsch A, Ovigne JM, Rovida C, Sakaguchi H and Schultz T 2008. Chemical reactivity measurement and the predictive identification of skin sensitisers. Altern. Lab. Anim.36: 215-242.
  9. ↑ Karlberg AT, Bergström MA, Börje A, Luthman, K, Nilsson JL. 2008. Allergic contact dermatitis- formation, structural requirements, and reactivity of skin sensitizers. Chem. Res. Toxicol. 21: 53-69.
  10. ↑ 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.
  11. ↑ OECD (2012a) The Adverse Outcome Pathway for Skin Sensitisation Initiated by Covalent Binding to Proteins. Part 1: Scientific Evidence. Series on Testing and Assessment No. 168.
  12. ↑ Schwöbel JAH, Koleva YK, Bajot F, Enoch SJ, Hewitt M, Madden JC, Roberts DW, Schultz TW, Cronin MTD. 2011. Measurement and estimation of electrophilic reactivity for predictive toxicology. Chem. Rev. 111: 2562-2596
  13. ↑ Hopkins JE, Naisbitt DJ, Kitteringham NR, Dearman RJ, Kimber I, Park BK. 2005. Selective haptenation of cellular or extracellular proteins by chemical allergens: Association with cytokine polarization. Chem. Res. Toxicol. 18: 375-381
  14. ↑ 14.0 14.1 McKim JM Jr, Keller DJ III, Gorski JR. 2010. A new in vitro method for identifying chemical sensitizers combining peptide binding with ARE/EpRE-mediated gene expression in human skin cells. Cutan. Ocul. Toxicol. 29: 171-192.
  15. ↑ OECD 2011b. Report of the Expert Consultation on Scientific and Regulatory Evaluation of Organic Chemistry-based Structural Alerts for the Identification of Protein-binding Chemicals. OECD Environment, Health and Safety Publications Series on Testing and Assessment No. 139. ENV/JM/MONO(2011)9.
  16. ↑ Emter R, Ellis G, Natsch A. 2010. Performance of a novel keratinocyte-based reporter cell line in screen skin sensitizers in vitro. Toxicol. Appl. Pharmacol. 245: 281-290.