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Classifications

Harrison's Part

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Mappings

MONDO

MONDO:0005480 contact dermatitis

Primary MONDO disease identifier for this contact dermatitis entry.

ICD-10-CM

ICD10CM:L23 Allergic contact dermatitis

Contact dermatitis includes allergic contact dermatitis as a major clinical subtype.

ICD10CM:L24 Irritant contact dermatitis

Contact dermatitis includes irritant contact dermatitis as a major clinical subtype.

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Definitions

2

Clinical syndrome definition for contact dermatitis

Contact dermatitis is an exogenous eczematous inflammatory disorder caused by direct skin contact with an external substance, most commonly expressed as irritant contact dermatitis or allergic contact dermatitis at sites of exposure.

CASE_DEFINITION General clinical framing of contact dermatitis in dermatology and occupational medicine

Show evidence (2 references)

PMID:25102574 SUPPORT Human clinical

"Contact dermatitis results from skin contact with an exogenous substance."

This supports the core disease definition as dermatitis caused by external cutaneous exposure.

PMID:25102574 SUPPORT Human clinical

"The two most common variants are irritant contact dermatitis (ICD) and allergic contact dermatitis (ACD)."

This supports the umbrella disease definition encompassing irritant and allergic forms as the principal variants.

Practical diagnostic definition for suspected allergic contact dermatitis

In routine practice, suspected allergic contact dermatitis is defined by a compatible exposure-linked dermatitis pattern evaluated through focused history and physical examination, with patch testing used to confirm relevant sensitization and distinguish allergic from irritant disease.

DIAGNOSTIC_CRITERIA Clinical diagnosis of recurrent, persistent, or exposure-pattern dermatitis suspicious for allergic contact dermatitis

Show evidence (2 references)

PMID:31757238 SUPPORT Human clinical

"Diagnosis is based on a thorough history, physical examination, and patch testing."

This supports the practical diagnostic framework of history, examination, and patch testing.

PMID:25102574 SUPPORT Human clinical

"If ACD is suspected the patient should be referred to secondary care for patch testing."

This supports patch testing as the confirmatory step when allergic contact dermatitis is suspected clinically.

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Subtypes

2

Allergic Contact Dermatitis

Delayed type IV hypersensitivity dermatitis caused by prior sensitization to a contact allergen.

Show evidence (2 references)

PMID:25102574 SUPPORT Human clinical

"Classical ACD is mediated by type 4 cell-mediated immunity."

This review explicitly defines allergic contact dermatitis as a type IV cell-mediated immune process.

PMID:19839974 SUPPORT REVIEW SYNTHESIS Human clinical

"Allergic contact dermatitis (ACD), one of the commonest occupational diseases, is a T-cell-mediated skin inflammation caused by repeated skin exposure to contact allergens, i.e. nonprotein chemicals called haptens."

This supports allergic contact dermatitis as a hapten-driven T-cell-mediated subtype of contact dermatitis.

Irritant Contact Dermatitis

Non-sensitization-dependent dermatitis caused by direct toxic or barrier-disrupting effects of an exposure.

Show evidence (2 references)

PMID:25274939 SUPPORT Human clinical

"Irritant contact dermatitis (ICD) is the most common form of contact dermatitis."

This supports irritant contact dermatitis as a principal subtype within the broader contact dermatitis category.

PMID:25102574 SUPPORT Human clinical

"ICD is a form of eczema and is induced by direct inflammatory pathways without prior sensitisation."

This supports the non-sensitization-dependent inflammatory mechanism of irritant contact dermatitis.

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Discussions and Knowledge Gaps

6

The only keratinocyte activation node sits in the irritant arm, downstream of barrier disruption. Should the sensitization arm carry its own keratinocyte activation step, driven by hapten electrophilicity rather than by barrier injury?

KNOWLEDGE GAP RESOLVED no_node_for_hapten_driven_keratinocyte_activation

Attached to

pathophysiology#Hapten-driven keratinocyte electrophile sensing pathophysiology#Keratinocyte inflammasome danger signalling

The OECD TG 442D methods and the reconstructed-epidermis assays that extend them measure keratinocyte activation under hapten exposure with no barrier injury, and they separate a sensitizer from an irritant on exactly that readout. The existing node is curated as the consequence of irritant barrier failure, so mapping those methods onto it imports a cause the methods do not use. Two arms of keratinocyte activation are described in this literature — electrophile sensing through Keap1-Nrf2-ARE, and inflammasome-dependent IL-1 family danger signalling — and the sensitization arm of this entry currently passes straight from hapten exposure to innate immune activation without either.

Resolved 2026-11-01T00:00:00Z

Resolution: Resolved by curating the step as two nodes rather than one. The sensitization arm now runs from Covalent hapten-protein adduct formation to Hapten-driven keratinocyte electrophile sensing and to Keratinocyte inflammasome danger signalling, and from each of those to Skin innate immune activation during sensitization. Both are the arms this discussion named, and together they cover AOP 40 Key Event 826. They were kept apart rather than merged into one Key-Event-wide node because the two models in this entry read different arms: the Keap1-Nrf2-ARE systems moved onto the sensing node, where the CAUSE_UNREPRESENTED divergence they carried no longer applies and has been removed, and the NALP3- and ASC-deficient mouse moved onto the danger-signalling node. The cost of that choice is that each node is narrower than Key Event 826, so a consumer mapping the Key Event onto this entry aggregates both. The adduct node keeps its direct edge to innate immune activation, which is AOP 40's separate branch from Key Event 396 to Key Event 398. What is not resolved is which epidermal protein has to be modified for either arm to follow, recorded in the adduct node's own description.

Show evidence (1 reference)

PMID:24794257 SUPPORT DIRECT In vitro / ex vivo

"Results show that the Keap1-Nrf2-ARE pathway is activated by the sensitizer DNCB in monolayer keratinocytes and as well as the LEMs and NEMs and not by the irritant SDS."

Shows the keratinocyte response discriminating sensitizer from irritant, which is what makes hapten-driven keratinocyte activation a distinct step from the irritant-driven node it would otherwise be mapped to.

The entry's computational models predict sensitization hazard and potency for the whole outcome, not any single step. The entry's pathograph ends in mechanism nodes with no adverse-outcome node, so none of them has anything to attach to. Should the entry carry a sensitization-outcome node?

KNOWLEDGE GAP no_node_for_integrated_outcome_prediction

Attached to

pathophysiology#Allergen-specific T-cell priming

The SARA model, SARA-ICE, the decision-tree defined approach, and the Skin Sensitization Prediction Model (SSPM) each take readouts spanning several key events, or a formulation-level patch-test history, and return one statement about the human outcome. That is a claim about the outcome, so linking any of them to a mechanism node would assert it measures a step it does not measure, and all four are recorded with no mechanism link for that reason. The regulatory framing has the same shape: OECD Guideline No. 497 exists to turn the per-key-event assays into a single classification, so an entry that curates the methods but has no node for what they jointly predict cannot represent the integration step at all. This discussion is attached to the most downstream sensitization node for want of an outcome node, which is the gap itself. The human predictive patch test (HPPT) reference database (PMID:37615678, in this entry's references catalog) is a different case and is not part of this gap: it is the reference truth these predictions are benchmarked against rather than a prediction itself, so it carries no outcome claim to attach and is not modelled as an experimental_models record.

Show evidence (2 references)

PMID:35311660 SUPPORT DIRECT Computational

"The SARA model utilises a Bayesian statistical approach to infer a human-relevant metric of sensitiser potency and a measure of risk associated with a given consumer exposure based upon any combination of human repeat insult patch test, local lymph node, direct peptide reactivity assay,..."

The inferred quantity is a potency and risk metric for the outcome, which is what no node in this entry represents.

PMID:40953631 SUPPORT DIRECT Human clinical

"The SSPM sets modifiable thresholds for each individual ingredient of a proposed formulation and for the formulation as a whole, applying risk calculations based on dosage density, potential for skin occlusion, potential for skin barrier impairment, and potential effects on immune-primed skin."

The output is a formulation-level risk call rather than a measurement of any mechanism step in this entry, which is why this model is also recorded with no mechanism link.

Nickel and cobalt initiate sensitization by coordinating human TLR4 rather than by binding protein covalently. Should the entry carry that route separately, given that nickel is the most frequent cause of contact hypersensitivity?

KNOWLEDGE GAP no_node_for_non_covalent_metal_initiation

Attached to

pathophysiology#Hapten exposure

The entry's sensitization arm begins with hapten exposure understood as exposure to reactive chemicals that bind protein. Metals reach the same adverse outcome by a different initiating mechanism: direct, non-covalent coordination of two non-conserved histidines of human TLR4, which produces the proinflammatory signal. The route is also human-specific, which is the mechanistic explanation for nickel appearing as a false negative in the mouse local lymph node assay, and so it bears directly on how that assay's output should be read for metals.

Show evidence (1 reference)

PMID:20711192 SUPPORT DIRECT In vitro / ex vivo

"Ni(2+)-induced TLR4 activation was species-specific, as mouse TLR4 could not generate this response."

Establishes the species specificity of the metal route, which is what makes it both a distinct initiating mechanism and the explanation for the animal assay's blind spot. The quoted comparison is receptor-level rather than in vivo: it sits between the human TLR4 activation result and the mutant-TLR4 studies, and the paper's animal arm is the separate transgenic experiment, which is not what is quoted here.

This node lists Langerhans cell and dendritic cell together as the antigen-presenting cells of allergen-specific T-cell priming. Which of them, or which other skin-resident or migratory antigen-presenting cell, actually primes the human sensitization response?

KNOWLEDGE GAP unresolved_human_priming_antigen_presenting_cell

Attached to

pathophysiology#Allergen-specific T-cell priming

The Langerin-DTA mouse model in this entry's animal_models already establishes that Langerhans cells are dispensable for priming and can be regulatory rather than required, which rules out the historically assumed answer without supplying a replacement. The question of which dendritic cell subset does prime the response in vivo is stated as explicitly unresolved in the literature, so this entry's two-cell-type listing records what has been ruled in and out rather than an identified answer.

Show evidence (1 reference)

PMID:18460878 SUPPORT DIRECT REVIEW SYNTHESIS Human clinical

"The identity of the antigen presenting cells that complement Langerhans cells has yet to be identified."

States directly that the priming antigen-presenting cell is unresolved, which is the gap this discussion records.

HLA class II associations are an established determinant of individual susceptibility to sensitization by a protein allergen. Is there a reproducible HLA basis for susceptibility to a low-molecular-weight contact hapten specifically?

KNOWLEDGE GAP no_reproducible_hla_basis_for_hapten_susceptibility

Attached to

pathophysiology#Allergen-specific T-cell priming

HLA-DR7 is associated with occupational sensitization to a protein respiratory allergen (rat urinary lipocalin), with amino acid analyses of the associated molecules offering a biologically plausible explanation. That demonstrates HLA class II restriction can govern susceptibility to an allergen in principle, but the allergen there is a whole protein presented without the covalent hapten-protein adduct chemistry this entry's sensitization arm runs on, and the association is for sensitization without symptoms as well as with them. No comparably reproduced HLA association for a low-molecular-weight contact hapten is curated in this entry, so whether contact-hapten susceptibility has an HLA basis at all remains open rather than answered by extension from the protein-allergen literature.

Show evidence (1 reference)

PMID:12704360 SUPPORT INDIRECT PRIMARY RESULT Human clinical

"HLA-DR7 was associated with sensitization (odds ratio [OR], 1.82; CI, 1.12-2.97), respiratory symptoms at work (OR, 2.96; CI, 1.64-5.37) and, most strongly, sensitization with symptoms (OR, 3.81; CI, 1.90-7.65)."

Establishes an HLA class II association with sensitization for a protein allergen, which is the contrast case this discussion uses: the allergen is a protein presented without covalent haptenation, so the association does not itself establish an HLA basis for a contact hapten's T-cell priming step.

A contact hapten activates the keratinocyte NLRP3 inflammasome, but the proximal cellular event that triggers assembly is not identified here. Which route does a hapten use: potassium efflux, lysosomal rupture, mitochondrial damage with reactive oxygen species, or another?

KNOWLEDGE GAP unidentified_proximal_route_to_hapten_inflammasome_activation

Attached to

pathophysiology#Keratinocyte inflammasome danger signalling

The evidence curated on this node establishes an assembled, caspase-1-activating NLRP3 complex in hapten-exposed keratinocytes, which is what the nlrp3_inflammasome_activation module's assembly node asks for. It identifies none of the proximal routes that define that module's upstream Activating Danger Signal node, which is why conformance is anchored on assembly rather than on the danger signal. The route is not a curation omission that reading one more paper would close: the candidate routes are interrelated and mutually causative, the general NLRP3 literature has not reached consensus on a unifying route, and none of the candidate routes has been curated for a contact hapten specifically. Answering this would add a new upstream pathophysiology node conforming to Activating Danger Signal; until then the step is recorded as assembly alone.

Show evidence (1 reference)

PMID:23809161 SUPPORT INDIRECT BACKGROUND Other

"Several events have been proposed to explain the activation of the NLRP3 inflammasome including the production of reactive oxygen species (ROS), mitochondrial damage, lysosomal damage, formation of large non-specific pore in the cell membrane, and cytosolic K+ efflux"

Enumerates the candidate proximal routes and so defines the set this gap is a choice within. The quote is the paper's introduction restating proposals established elsewhere rather than its own result, hence BACKGROUND; it describes a field of competing proposals rather than one study's evidence, hence OTHER. The paper's own result, that potassium efflux is the common trigger, is curated on the module's Activating Danger Signal node and is not extended to haptens by this entry.

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Pathophysiology

18

Irritant exposure and toxic insult

In irritant contact dermatitis, direct exposure to chemical or physical irritants causes the initiating toxic cutaneous insult.

Downstream

Epidermal barrier disruption Toxic or physical irritants injure the epidermis and precipitate barrier failure.

Show evidence (1 reference)

PMID:25274939 SUPPORT Human clinical

"It represents the cutaneous response to the toxic/physical effects of a wide variety of environmental agents."

This supports direct toxic or physical exposure as the initiating event in irritant contact dermatitis.

Epidermal barrier disruption

Irritant injury disrupts epidermal barrier integrity and creates the tissue context for downstream inflammatory activation.

keratinocyte CL:0000312

Downstream

Keratinocyte activation and proinflammatory mediator release Barrier failure activates keratinocytes and promotes local proinflammatory signaling.

Show evidence (1 reference)

PMID:25274939 SUPPORT Human clinical

"involves skin barrier disruption"

This identifies barrier disruption as a distinct mechanistic step in irritant contact dermatitis.

Keratinocyte activation and proinflammatory mediator release

Barrier-injured keratinocytes enter an activated inflammatory state and release mediators that propagate local cutaneous inflammation.

keratinocyte CL:0000312

keratinocyte activation GO:0032980 inflammatory response GO:0006954

Downstream

Inflammatory cell recruitment Keratinocyte-derived inflammatory mediators recruit and activate additional inflammatory cells in skin.

Show evidence (2 references)

PMID:25274939 SUPPORT Human clinical

"involves skin barrier disruption, cellular changes, and release of proinflammatory mediators."

This supports proinflammatory mediator release as a distinct ICD mechanism.

DOI:10.1155/2013/916497 SUPPORT Human clinical

"Irritant contact dermatitis is a result of activated innate immune response to various external stimuli and consists of complex interplay which involves skin barrier disruption, cellular changes, and release of proinflammatory mediators."

This corroborates activated innate immune signaling and mediator release as central mechanisms in irritant contact dermatitis.

Inflammatory cell recruitment

Irritant-induced mediators recruit and activate inflammatory cells in skin after barrier injury, including T lymphocytes. Previously named "Innate inflammatory cell recruitment"; the "innate" qualifier was dropped because the supporting evidence describes recruitment and activation of T lymphocytes, which are adaptive effectors.

dendritic cell CL:0000451

inflammatory response GO:0006954

Downstream

Contact dermatitis Inflammatory cell recruitment culminates in the clinically visible dermatitis lesion.

Show evidence (1 reference)

PMID:25274939 SUPPORT Human clinical

"release of proinflammatory mediators that directly recruit and activate T lymphocytes."

This supports recruitment and activation of inflammatory cells as a separate downstream ICD mechanism.

Hapten exposure

In allergic contact dermatitis, repeated skin contact with small reactive chemicals exposes the immune system to haptens and initiates sensitization.

Downstream

Covalent hapten-protein adduct formation Contact with a reactive small chemical leads directly to covalent modification of skin protein, the chemical reaction that converts an exposure into an immunologically visible antigen.

Abiotic pre-hapten autoxidation to a reactive electrophile A chemical that is not itself protein-reactive can be converted to a reactive electrophile by nonenzymatic oxidation occurring independently of the skin.

Keratinocyte pro-hapten bioactivation to a reactive electrophile A chemical that is not itself protein-reactive can instead require enzymatic metabolism by skin keratinocytes to become a reactive electrophile.

Show evidence (1 reference)

PMID:19839974 SUPPORT REVIEW SYNTHESIS Human clinical

"Allergic contact dermatitis (ACD), one of the commonest occupational diseases, is a T-cell-mediated skin inflammation caused by repeated skin exposure to contact allergens, i.e. nonprotein chemicals called haptens."

This supports hapten exposure as the initiating event in allergic contact dermatitis.

Abiotic pre-hapten autoxidation to a reactive electrophile

A pre-hapten is a contact allergen that is not itself protein-reactive but is converted to a reactive electrophile by abiotic, nonenzymatic oxidation that can occur independently of the skin (on air exposure, for example). This route sits upstream of the covalent-binding step rather than around it, so the protein-reactive species a sensitized person actually generates can differ from the parent chemical applied to the skin.

Downstream

Covalent hapten-protein adduct formation The abiotically oxidized pre-hapten species goes on to form the covalent hapten-protein adduct.

Show evidence (2 references)

PMID:21742781 SUPPORT DIRECT In vitro / ex vivo

"In agreement with the hapten concept, responses to 2,4-dinitrochlorobenzene, Bandrowski's base, and the prehapten isoeugenol were not significantly modified."

Shows the contrast case: a direct hapten and a prehapten are unaffected by keratinocyte coculture, consistent with prehapten activation occurring abiotically rather than depending on keratinocyte metabolism -- unlike the sibling pro-hapten node, where coculture raises the response.

PMID:23510343 SUPPORT DIRECT Human clinical

"Geraniol is a pro-hapten and a pre-hapten, and sensitizers are formed in the autoxidation and skin metabolism of geraniol."

Names a specific, clinically relevant contact allergen for which the abiotic (pre-hapten) autoxidation route this node describes has been documented; the same sentence's skin-metabolism half supports the sibling pro-hapten node.

Keratinocyte pro-hapten bioactivation to a reactive electrophile

A pro-hapten is a contact allergen that is not itself protein-reactive but requires enzymatic metabolism in skin, chiefly by cytochrome P450 and NAD(P)H:quinone oxidoreductase 1 (NQO1) in keratinocytes, to become a reactive electrophile. This route sits upstream of the covalent-binding step rather than around it, so the protein-reactive species a sensitized person actually generates can differ from the parent chemical applied to the skin.

keratinocyte CL:0000312

xenobiotic metabolic process GO:0006805

Downstream

Covalent hapten-protein adduct formation The enzymatically activated pro-hapten species goes on to form the covalent hapten-protein adduct.

Show evidence (2 references)

PMID:21742781 SUPPORT DIRECT In vitro / ex vivo

"Under coculture conditions, the prohaptens eugenol, 2-methoxy-4-methylphenol, and benzo ... pyrene induced a significantly higher upregulation of CD86 expression on THP-1."

Demonstrates that keratinocyte coculture, which supplies the metabolic activation keratinocytes provide, is required for these named chemicals to raise a dendritic-cell-surrogate activation marker, supporting enzymatic bioactivation as the operative mechanism for the pro-hapten class -- unlike the sibling pre-hapten node, where coculture makes no difference.

PMID:23510343 SUPPORT DIRECT Human clinical

"Reactions to pure geraniol in patients not reacting to oxidized geraniol indicated metabolic activation of geraniol."

Shows a subset of patients reacting only to the unoxidized parent chemical, which the authors attribute to skin metabolism generating the reactive species directly from pure geraniol -- the pro-hapten route this node describes, distinct from the sibling node's abiotic oxidation route.

Covalent hapten-protein adduct formation

A reactive small chemical forms a covalent bond with a skin protein, generating the hapten-protein adduct that downstream innate and adaptive responses recognize. This is the molecular initiating event of skin sensitization and is rate-limiting for sensitizer potency. The step itself is well established, but its molecular target in skin is not: the available evidence is in chemico and in vitro, using synthetic peptides, albumin in solution and cultured human cells, and the assays of this field measure bulk cysteine-peptide depletion as a surrogate. Which specific epidermal protein has to be modified for the downstream steps to follow remains unresolved.

Downstream

Hapten-driven keratinocyte electrophile sensing The adduct-forming electrophile is sensed by keratinocytes through the Keap1-Nrf2-ARE pathway. This is AOP 40 KER 833, Key Event 396 to Key Event 826, read as its electrophile-sensing arm.

Keratinocyte inflammasome danger signalling The hapten is read as a danger signal by the keratinocyte inflammasome. This is the second arm of AOP 40 KER 833, Key Event 396 to Key Event 826.

Skin innate immune activation during sensitization Hapten-modified skin protein activates innate cutaneous immune pathways during the sensitization phase.

Show evidence (5 references)

PMID:20631061 SUPPORT DIRECT In vitro / ex vivo

"Modification of proteins by reactive small chemicals is a key step in the activation of chemical-specific T cells in allergic contact dermatitis (ACD)."

States the step this node represents, and places it within allergic contact dermatitis specifically.

PMID:32840629 SUPPORT DIRECT In vitro / ex vivo

"The reaction of sensitizing molecules with skin proteins is the molecular initiating event and appears to be rate-limiting, as chemical reactivity strongly correlates with sensitizer potency."

Supports treating this reaction as the molecular initiating event of the pathway and as the rate-limiting step for potency.

PMID:28882705 SUPPORT DIRECT In vitro / ex vivo

"since the protein-adduct formation is determining the dose of the allergen in the skin, peptide reactivity was used to assess the potency"

Supports the framing of this node as the step that sets the effective dose of allergen in skin.

+ 2 more references

Hapten-driven keratinocyte electrophile sensing

Keratinocytes read the hapten as an electrophile and mount a Keap1-Nrf2-ARE antioxidant-response programme: Nrf2 protein accumulates, translocates to the nucleus, and activates its transcriptional targets. This is the electrophile-sensing arm of the sensitization-phase keratinocyte step corresponding to AOP 40 Key Event 826 (Activation, Keratinocytes), and the cause is the chemistry of the hapten rather than barrier injury: the response separates a sensitizer from an irritant at non-toxic concentrations, which is the biology the OECD TG 442D methods measure. It is curated apart from the inflammasome danger-signalling arm of the same Key Event, which runs through IL-1 family cytokines and carries its own node, because the two are read by different models.

keratinocyte CL:0000312

keratinocyte activation GO:0032980 ↑ INCREASED Keap1-Nrf2-ARE electrophile sensing GO:0062197 ↑ INCREASED

Experimental models

Keratinocyte Keap1-Nrf2-ARE sensitizer-response models OTHER Measures this node's own quantity, Keap1-Nrf2-ARE pathway activation in keratinocytes under hapten exposure, and separates sensitizer-driven from irritant-driven activation on that readout.

KeratinoSens CELL LINE Measures this node's own quantity, Nrf2-dependent transcriptional activation in keratinocytes under exposure to an electrophilic sensitizer, read as induction of the AKR1C2 ARE luciferase reporter.

LuSens CELL LINE Measures this node's own quantity, ARE-driven transcriptional activation in keratinocytes under exposure to an electrophilic sensitizer, read as induction of the rat NQO1 ARE luciferase reporter.

EpiSensA OTHER Reads the cytoprotective arm of hapten-driven keratinocyte activation as Nrf2-dependent GCLM induction, alongside ATF3 and IL-8 as a separate P2X7-dependent inflammatory readout this entry has no node for.

Downstream

Skin innate immune activation during sensitization Keratinocytes responding to the hapten contribute to the innate cutaneous response that supports dendritic-cell-mediated priming.

Show evidence (2 references)

PMID:24794257 SUPPORT DIRECT BACKGROUND In vitro / ex vivo

"One of the pathways that has been shown to be induced by sensitizers is the Keap1-Nrf2-ARE pathway."

Names the pathway this node represents and attributes its induction to sensitizers. The sentence restates prior in vitro sensitizer work rather than reporting this study's own result.

PMID:24794257 SUPPORT DIRECT In vitro / ex vivo

"Results show that the Keap1-Nrf2-ARE pathway is activated by the sensitizer DNCB in monolayer keratinocytes and as well as the LEMs and NEMs and not by the irritant SDS."

Measures the node's own quantity in keratinocytes, across monolayer and reconstructed epidermal models, and shows it responding to a sensitizer and not to an irritant. That contrast is what makes this a distinct step from the irritant arm's keratinocyte node.

Keratinocyte inflammasome danger signalling

The hapten acts as a danger signal in keratinocytes: the NLRP3 and ASC inflammasome assembles and activates caspase-1, which processes pro-IL-1beta and pro-IL-18 to their mature forms and releases them. This is the danger-signalling arm of the sensitization-phase keratinocyte step corresponding to AOP 40 Key Event 826, running in parallel with Keap1-Nrf2-ARE electrophile sensing rather than downstream of it, and it supplies the proinflammatory cytokines the innate and adaptive steps below require. Like the sensing arm it is driven by the hapten and not by barrier disruption, which is what separates it from the irritant arm's keratinocyte node.

keratinocyte CL:0000312

keratinocyte activation GO:0032980 ↑ INCREASED NLRP3 inflammasome complex assembly GO:0044546 ↑ INCREASED NLRP3 inflammasome-mediated signalling GO:0141084 ↑ INCREASED caspase-1-dependent IL-1beta maturation and release GO:0032611 ↑ INCREASED caspase-1-dependent IL-18 maturation and release GO:0032621 ↑ INCREASED

Experimental models

Reconstructed human skin organ-on-chip with neopapillae (RhS-NP) ORGAN ON CHIP Reads the inflammasome-dependent danger-signalling arm of keratinocyte activation as secreted IL-18 and IL-1beta from a topically dosed tissue construct under perfusion, rather than from a monolayer.

Animal models

NALP3- and ASC-deficient contact hypersensitivity mouse Mus musculus perturbs Shows that loss of NALP3 or ASC impairs the response to contact sensitizers, establishing the caspase-1-dependent IL-1beta and IL-18 processing this node asserts as a required part of the sensitization response rather than an incidental accompaniment of it.

Downstream

Skin innate immune activation during sensitization Keratinocyte-derived mature IL-1beta and IL-18 are the danger signals that the innate cutaneous response during sensitization runs on.

Show evidence (2 references)

PMID:17429439 SUPPORT DIRECT In vitro / ex vivo

"We show here that key components of the inflammasome are present in human keratinocytes and that CS like trinitro-chlorobenzene induce caspase-1/ASC dependent IL-1beta and IL-18 processing and secretion."

Establishes every component of this node in human keratinocytes: the inflammasome is present, a contact sensitizer drives it, and the output is caspase-1-dependent processing and release of both IL-1 family cytokines.

PMID:17632566 SUPPORT INDIRECT REVIEW SYNTHESIS Other

"The study documents a regulatory effect of innate immunity in a T-cell-mediated delayed-type hypersensitivity reaction."

An accompanying commentary's reading of the keratinocyte inflammasome result, placing it as a regulator of innate immunity within a T-cell-mediated delayed-type hypersensitivity response, which is where this node sits in the sensitization arm. It is an editorial synthesis of the companion paper and reports no data of its own.

Skin innate immune activation during sensitization

Early innate immune signaling in allergen-exposed skin shapes the sensitization phase and supports subsequent adaptive immune priming.

Langerhans cell CL:0000453 dendritic cell CL:0000451

Experimental models

Human Cell Line Activation Test (h-CLAT) CELL LINE Reads the dendritic-cell activation step of sensitization as two costimulatory and adhesion markers on a monocytic line.

GARDskin CELL LINE Reads the dendritic-cell activation step as induced transcriptional change across co-stimulatory, stress and xenobiotic-response programs.

Full-thickness skin equivalent with MUTZ-3-derived Langerhans cells CO CULTURE Reproduces allergen-driven Langerhans cell maturation together with migration out of the epidermis toward the dermal compartment, which the monolayer dendritic-cell assays cannot show.

U-SENS (Myeloid U937 Skin Sensitization Test) CELL LINE Reads the dendritic-cell activation step of sensitization as CD86 upregulation on a myeloid line.

IL-8 Luc assay CELL LINE Reads the dendritic-cell activation step of sensitization as IL-8-promoter luciferase induction in a monocytic reporter line.

SENS-IS OTHER Reads sensitization hazard and potency from induced expression across a large gene panel in reconstructed epidermis, rather than from a single pathway readout.

Endothelialised skin-on-chip with flowing immune cells (MMA-6MWP) ORGAN ON CHIP Reads dendritic-cell-surrogate activation (CD83 and CD86 upregulation on MUTZ-3) occurring when immune cells flow past an endothelialised skin construct topically exposed to a sensitizer, adding circulation and a vascular interface that static monolayer and reconstructed-tissue assays lack.

Animal models

Langerin-DTA Langerhans-cell-deficient mouse Mus musculus perturbs Removes Langerhans cells and shows contact hypersensitivity is amplified rather than abolished, so Langerhans cells are dispensable for priming and act to restrain it. This revises the antigen-presenting-cell assumption this node inherits.

Downstream

Allergen-specific T-cell priming Innate activation in skin supports dendritic-cell-mediated priming of allergen-specific T cells.

Show evidence (1 reference)

PMID:19839974 SUPPORT REVIEW SYNTHESIS Human clinical

"Recent advances in the pathophysiology of ACD have demonstrated the important role of skin innate immunity in the sensitization process"

This supports skin innate immune activation as a distinct mechanistic stage in allergic contact dermatitis sensitization.

Breakdown of regulatory T-cell-mediated hapten tolerance

Allergic contact dermatitis reflects failure of suppressive CD4-positive regulatory T-cell programs that normally prevent hapten priming and dampen eczema in sensitized individuals.

regulatory T cell CL:0000815

Animal models

DNFB contact hypersensitivity regulatory T-cell model Mus musculus measures Measures the regulatory arm whose failure this node asserts, rather than reproducing that failure. Hapten immunization of wild-type mice induces a CD4+CD25+ regulatory T-cell population that suppresses hapten-reactive CD8+ effectors in a hapten-specific manner, so the model shows the suppression intact and characterizes the population whose loss the node records.

Downstream

Allergen-specific T-cell priming Loss of regulatory control permits priming to haptens in susceptible individuals.

Contact dermatitis Loss of suppressive T-cell control permits persistence and amplification of eczema in allergic patients.

Show evidence (1 reference)

PMID:19839974 SUPPORT REVIEW SYNTHESIS Human clinical

"Subsets of CD4+ T cells endowed with suppressive activity are responsible for both the down-regulation of eczema in allergic patients and the prevention of priming to haptens in nonallergic individuals."

This review identifies suppressive CD4-positive regulatory T-cell activity as a core counter-regulatory axis in allergic contact dermatitis.

Allergen-specific T-cell priming

During sensitization, antigen-presenting cells prime allergen-specific T cells, establishing the adaptive immune memory required for later flares.

Langerhans cell CL:0000453 dendritic cell CL:0000451 CD8-positive, alpha-beta T cell CL:0000625

dendritic cell antigen processing and presentation GO:0002468 T cell activation GO:0042110

Experimental models

Human T-cell priming assay CO CULTURE Primes an allergen-specific human T-cell response in vitro, which is the step this node asserts, using primary human cells on both sides of the interaction.

Animal models

Mouse local lymph node assay Mus musculus measures Reads draining-lymph-node T-cell proliferation after dermal exposure, so it integrates penetration, metabolism, antigen-presenting-cell migration and clonal expansion in one whole-organism readout.

Downstream

Re-exposure-driven effector T-cell recruitment Sensitized allergen-specific T cells are recruited back to skin after hapten re-exposure.

Show evidence (1 reference)

PMID:19839974 SUPPORT REVIEW SYNTHESIS Human clinical

"Allergic contact dermatitis, also referred to as contact hypersensitivity, is mediated by CD8+ T cells, which are primed in lymphoid organs during the sensitization phase and are recruited in the skin upon re-exposure to the hapten."

This supports sensitization and T-cell priming as a discrete adaptive immune stage in allergic contact dermatitis.

Re-exposure-driven effector T-cell recruitment

Upon renewed hapten exposure, primed effector T cells re-enter skin and initiate the elicitation phase of allergic contact dermatitis.

CD8-positive effector T cell CL:0000625

type IV hypersensitivity GO:0001806

Animal models

Guinea pig maximization test Cavia porcellus measures The scored endpoint is the challenge-patch reaction in an animal already induced with the test chemical, so what the assay reads is the elicitation response to re-exposure rather than the priming that produced it. Priming is inferred from the presence of that reaction.

Buehler occluded patch test Cavia porcellus measures Reads the same challenge-patch reaction as the maximization test, under a milder induction regimen. Fidelity is graded LOW because the method returns negative results for chemicals that are strong sensitizers in the parallel test, so a negative here does not constrain whether the mechanism occurred.

Downstream

Resident memory T-cell flare activation Re-exposure activates epidermal resident memory T cells and intensifies the flare response.

Show evidence (1 reference)

PMID:19839974 SUPPORT REVIEW SYNTHESIS Human clinical

"Allergic contact dermatitis, also referred to as contact hypersensitivity, is mediated by CD8+ T cells, which are primed in lymphoid organs during the sensitization phase and are recruited in the skin upon re-exposure to the hapten."

This supports effector T-cell recruitment to skin on hapten re-exposure as a separate mechanism node.

Resident memory T-cell flare activation

Epidermal resident memory CD8-positive T cells are activated in allergen-experienced skin and intensify local flare responses.

resident memory CD8-positive T cell CL:0000625

Downstream

Mixed type 1 and type 3 cytokine and chemokine amplification Activated resident memory T cells drive a broader inflammatory cytokine and chemokine program.

Show evidence (1 reference)

PMID:37700557 SUPPORT Model organism

"BACKGROUND: Allergic contact dermatitis (ACD) is an inflammatory disease with a complex pathophysiology in which epidermal-resident memory CD8+ T (TRM ) cells play a key role."

This supports resident memory CD8-positive T cells as a distinct driver of allergic contact dermatitis flares.

Mixed type 1 and type 3 cytokine and chemokine amplification

Activated effector and resident memory T cells amplify IFNg-, IL-17A-, IL-1beta-, and chemokine-rich inflammatory programs, with predominant type 1 and type 3 effector responses and lesser type 2 contributions.

T cell CL:0000084 neutrophil CL:0000775

chemokine production GO:0032602

Downstream

Fibroblast CXCL9/CXCL10 reinforcement Type 1 lymphocyte-derived IFNg reprograms dermal fibroblasts into chemokine-producing inflammatory stromal cells.

Show evidence (2 references)

PMID:37700557 SUPPORT Model organism

"We show that loss of CD100 results in a reduced inflammatory response to DNFB with impaired production of IFNγ, IL-17A, CXCL1, CXCL2, CXCL5, and IL-1β and decreased recruitment of neutrophils to the epidermis."

This supports amplification of inflammatory cytokines, chemokines, and neutrophil recruitment as a discrete downstream mechanism in allergic contact dermatitis.

DOI:10.1111/all.16642 SUPPORT Human clinical

"All allergens exhibited mixed effector immune responses, mainly type 1 and 3 immunity, and, to a lesser extent, type 2 immunity."

This human transcriptomic study supports mixed type 1 and type 3 cytokine programs, with lesser type 2 contributions, during allergic contact dermatitis elicitation.

Fibroblast CXCL9/CXCL10 reinforcement

Dermal fibroblasts adopt a chemokine-producing inflammatory phenotype that reinforces type 1 lymphocyte polarization and sustains cutaneous inflammation.

fibroblast CL:0000057 T cell CL:0000084

chemokine production GO:0032602

Downstream

Contact dermatitis Fibroblast chemokine reinforcement sustains the inflammatory dermatitis lesion in affected skin.

Show evidence (1 reference)

PMID:39213029 SUPPORT Model organism

"IFNγ treatment shifted dermal fibroblasts from collagen-producing to CXCL9/10-producing, which promoted T cell polarization toward the type-1 phenotype through a CXCR3-dependent mechanism."

This supports inflammatory fibroblast reprogramming as a distinct amplifying mechanism in allergic contact dermatitis.

Complement-associated sensory neuron activation

In allergic contact dermatitis, complement-associated neuroimmune signaling activates peripheral sensory pathways and contributes to itch generation.

sensory neuron CL:0000101

Downstream

Pruritus Sensory neuron activation contributes to the itching phenotype in allergic contact dermatitis.

Show evidence (1 reference)

PMID:34417985 SUPPORT Model organism

"The complement system in sensory ganglion might play an essential role in forming pruritic and nociceptive sensations in ACD."

This supports complement-linked sensory pathway activation as a distinct neuroimmune mechanism in allergic contact dermatitis.

✶

Histopathology

2

Spongiotic dermatitis pattern

Allergic contact dermatitis falls within the broader histopathologic pattern of spongiotic or eczematous dermatitis, so biopsy findings require clinicopathologic correlation and exposure assessment rather than stand alone as a definitive discriminator.

Show evidence (1 reference)

PMID:39709083 SUPPORT Human clinical

"BACKGROUND: Allergic contact dermatitis cannot be reliably differentiated from other forms of spongiotic/eczematous dermatitis by histology alone."

This supports spongiotic/eczematous dermatitis as the core histopathologic pattern of allergic contact dermatitis while emphasizing its limited specificity.

Epidermal spongiotic Langerhans cell collections

Within allergic contact dermatitis biopsies, epidermal collections of Langerhans cells are a supportive microscopic clue that can favor the diagnosis over other spongiotic dermatoses.

Show evidence (1 reference)

PMID:39709083 SUPPORT Human clinical

"CONCLUSION: This largest study to date is the first to independently confirm Langerhans cell collections as the single histopathologic feature most closely associated with allergic contact dermatitis."

This supports epidermal spongiotic Langerhans cell collections as a biopsy feature that favors allergic contact dermatitis.

⬡

Pathograph

Use Group by to collapse related nodes into one box. Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

4

Cardiovascular 1

Erythema FREQUENT HP:0010783

Erythematous patches or plaques are common at exposed or directly contacted skin sites.

Show evidence (1 reference)

PMID:9590995 SUPPORT Human clinical

"Clinical signs include vesicles, papules, bullae, erythema, edema, scaling, and lichenification."

This review supports erythema as a common clinical sign of contact dermatitis, particularly irritant presentations.

Immune 1

Contact dermatitis OBLIGATE HP:0032282

Localized eczematous inflammation at sites of irritant or allergen exposure.

Show evidence (1 reference)

PMID:25102574 SUPPORT Human clinical

"The two most common variants are irritant contact dermatitis (ICD) and allergic contact dermatitis (ACD)."

This supports the broad clinical entity of contact dermatitis comprising allergic and irritant forms.

Integument 2

Pruritus FREQUENT HP:0000989

Itching is a common symptom, especially in allergic forms and on thin skin sites such as the eyelids.

Show evidence (1 reference)

PMID:39941494 SUPPORT Human clinical

"Background/Objectives: Eyelid dermatitis is an inflammatory disease affecting the palpebral skin characterized by itching, edema, and scaling of the periorbital area."

This human clinical series supports itching as a characteristic manifestation of contact dermatitis.

Scaling skin FREQUENT HP:0040189

Scaling commonly accompanies eczematous plaques and chronic hand or eyelid dermatitis.

Show evidence (1 reference)

PMID:39941494 SUPPORT Human clinical

"Background/Objectives: Eyelid dermatitis is an inflammatory disease affecting the palpebral skin characterized by itching, edema, and scaling of the periorbital area."

This human clinical study supports scaling as a characteristic manifestation of contact dermatitis.

🧬

Genetic Associations

2

FLG loss-of-function variants and allergic sensitization susceptibility (Risk Factor)

Gene: FLG hgnc:3748 gene page

Show evidence (2 references)

PMID:23343419 SUPPORT PRIMARY RESULT Human clinical

"FLG mutation carriers with self-reported dermatitis have an increased risk of contact sensitization to substances other than nickel"

This human population study supports FLG loss-of-function variants as a genetic risk factor for contact sensitization relevant to allergic contact dermatitis.

PMID:18049447 SUPPORT DIRECT PRIMARY RESULT Human clinical

"an association with contact sensitization to nickel and contact sensitization to nickel combined with intolerance to fashion jewelry, but not with other contact allergens, was observed."

A separate general-population cohort (KORA) reports the converse allergen pattern from the self-reported-dermatitis cohort quoted above: here the FLG association is specific to nickel and does not extend to other contact allergens. The two studies agree that FLG deficiency raises contact sensitization risk and disagree on which allergens the effect covers, which is recorded rather than resolved. The same finding is also cited from Atopic_Dermatitis.yaml's barrier-dysfunction node, where this comorbid outcome originates mechanistically.

FLG loss-of-function variants and irritant contact dermatitis susceptibility (Risk Factor)

Gene: FLG hgnc:3748 gene page

Show evidence (1 reference)

PMID:23039796 SUPPORT PRIMARY RESULT Human clinical

"Our results indicate that both FLG mutations and AD increase the risk of ICD."

This occupational case-control study supports FLG variants as an independent genetic susceptibility factor for irritant contact dermatitis.

💊

Medical Actions

4

Allergen and irritant avoidance

Action: medical action avoidance Ontology label: Lifestyle Therapy NCIT:C15900

Identification and avoidance of the offending allergen or irritant is the central management strategy for both allergic and irritant contact dermatitis.

Show evidence (2 references)

PMID:25102574 SUPPORT Human clinical

"Accurate diagnosis, avoidance of identified allergens and protection from irritants are the key to successful treatment."

This supports avoidance of sensitizers and irritants as first-line disease management.

PMID:9590995 SUPPORT Human clinical

"Elimination of the offending agent and protection from further exposure are important in both diagnosis and management."

This independently supports exposure elimination and barrier protection as core treatment measures.

Topical corticosteroids

Action: topical corticosteroid therapy Ontology label: Topical Corticosteroid Therapy NCIT:C122078

Topical corticosteroids are used to treat inflammatory flares, especially in allergic contact dermatitis, while avoidance remains essential for long-term control.

Show evidence (1 reference)

PMID:31757238 SUPPORT Human clinical

"Topical corticosteroids can be used to treat exacerbations, but should be avoided in long-term treatment."

This supports topical corticosteroids for short-term treatment of inflammatory exacerbations.

Topical calcineurin inhibitors

Action: topical calcineurin inhibitor therapy Ontology label: Pharmacotherapy NCIT:C15986

Agent: tacrolimus CHEBI:61049 pimecrolimus CHEBI:135888

Topical calcineurin inhibitors can be used as steroid-sparing topical therapy in selected allergic contact dermatitis settings, although evidence is mixed across allergens and agents. Tacrolimus improved chronic nickel-induced allergic contact dermatitis in a randomized trial, whereas pimecrolimus was ineffective for established Toxicodendron-induced allergic contact dermatitis in a small placebo-controlled study.

Show evidence (2 references)

PMID:16781290 SUPPORT Human clinical

"CONCLUSIONS: Tacrolimus ointment 0.1% is well tolerated and significantly more effective than vehicle in treating chronically exposed, nickel-induced ACD."

This randomized clinical trial supports topical tacrolimus as an effective steroid-sparing option for chronic nickel-induced allergic contact dermatitis.

PMID:14700441 REFUTE Human clinical

"CONCLUSIONS: The application of topical pimecrolimus is ineffective in the treatment of ongoing Toxicodendron-induced ACD."

This placebo-controlled human study refutes efficacy of pimecrolimus for established Toxicodendron-induced allergic contact dermatitis.

Systemic corticosteroids

Action: systemic corticosteroid therapy Ontology label: Systemic Corticosteroid Therapy NCIT:C122080

Systemic corticosteroids are used for more severe or widespread flares of allergic contact dermatitis when topical treatment alone is insufficient, while culprit avoidance remains the core intervention.

Show evidence (1 reference)

DOI:10.3389/fmed.2023.1184289 SUPPORT Human clinical

"The treatment goal is to avoid contact with the culprit agent and use topical and/or systemic corticosteroid therapy."

This review supports systemic corticosteroid therapy as a treatment option for allergic contact dermatitis alongside trigger avoidance.

🌍

Environmental Factors

13

Wet work and detergent exposure

Repetitive wet work and exposure to soaps and detergents are common environmental drivers of irritant contact dermatitis, especially on the hands.

Show evidence (1 reference)

PMID:25102574 SUPPORT Human clinical

"Cumulative effects of water, soaps and detergents are the most common cause of ICD which affects the hands more often than any other site."

This supports wet work and detergent exposure as major environmental triggers of irritant contact dermatitis.

Mechanism Target:

TRIGGERS Irritant exposure and toxic insult — Water, soap and detergent strip stratum corneum lipids and damage keratinocytes directly, with no immune sensitization required. This is the irritant arm of the entry, which is why it targets the toxic-insult node rather than the hapten node the sensitizers use.

Show evidence (1 reference)

PMID:25102574 SUPPORT Human clinical

"Cumulative effects of water, soaps and detergents are the most common cause of ICD which affects the hands more often than any other site."

Identifies cumulative water, soap and detergent exposure as the most common cause of irritant contact dermatitis, the non-immunological insult this node describes.

Nickel exposure

Exposure to nickel-containing jewelry, tools, and occupational metal sources is a common environmental trigger of allergic contact dermatitis.

Show evidence (1 reference)

DOI:10.3389/fmed.2023.1184289 SUPPORT Human clinical

"Metals, especially nickel, fragrance mix, isothiazolinones, and para-phenylenediamine, are the most commonly positive allergens in patients patch tested for suspected ACD."

This review identifies nickel as one of the most common sensitizing exposures in allergic contact dermatitis.

Mechanism Target:

TRIGGERS Hapten exposure — Nickel ions released from metal in prolonged skin contact bind self-protein to form the hapten-protein complex this node represents. It is consistently the single most frequent contact allergen.

Show evidence (1 reference)

DOI:10.3389/fmed.2023.1184289 SUPPORT Human clinical

"Metals, especially nickel, fragrance mix, isothiazolinones, and para-phenylenediamine, are the most commonly positive allergens in patients patch tested for suspected ACD."

Identifies nickel first among the most commonly positive allergens on patch testing, the sensitizers that supply the hapten at this node.

Fragrance exposure

Fragrance-containing cosmetics, personal care products, and topical agents are common environmental triggers of allergic contact dermatitis.

Show evidence (1 reference)

DOI:10.3389/fmed.2023.1184289 SUPPORT Human clinical

"Metals, especially nickel, fragrance mix, isothiazolinones, and para-phenylenediamine, are the most commonly positive allergens in patients patch tested for suspected ACD."

This review identifies fragrance mix as a common sensitizer in patients patch tested for allergic contact dermatitis.

Mechanism Target:

TRIGGERS Hapten exposure — Fragrance chemicals are a mixture rather than a single molecule, several members of which are haptens; patch testing uses a fragrance mix for that reason.

Show evidence (1 reference)

DOI:10.3389/fmed.2023.1184289 SUPPORT Human clinical

"Metals, especially nickel, fragrance mix, isothiazolinones, and para-phenylenediamine, are the most commonly positive allergens in patients patch tested for suspected ACD."

Identifies fragrance mix among the most commonly positive allergens on patch testing.

Isothiazolinone exposure

Exposure to isothiazolinone preservatives in personal care, household, and industrial products is a recognized environmental trigger of allergic contact dermatitis.

Show evidence (2 references)

DOI:10.3389/fmed.2023.1184289 SUPPORT Human clinical

"Metals, especially nickel, fragrance mix, isothiazolinones, and para-phenylenediamine, are the most commonly positive allergens in patients patch tested for suspected ACD."

This review identifies isothiazolinones as common sensitizing preservatives in allergic contact dermatitis.

PMID:41804652 SUPPORT Human clinical

"The prevalence of CA to methylchloroisothiazolinone/methylisothiazolinone (MCI/MI) was 4.58%, methylisothiazolinone (MI) was 5.48%, and benzisothiazolinone (BIT) was 2.09%."

This meta-analysis adds current human prevalence data showing multiple isothiazolinone preservatives are established sensitizers among dermatitis patients.

Mechanism Target:

TRIGGERS Hapten exposure — Preservatives in cosmetics and household products, and the sensitizer behind a documented epidemic of contact allergy after their concentration in leave-on products rose.

Show evidence (1 reference)

PMID:41804652 SUPPORT Human clinical

"The prevalence of CA to methylchloroisothiazolinone/methylisothiazolinone (MCI/MI) was 4.58%, methylisothiazolinone (MI) was 5.48%, and benzisothiazolinone (BIT) was 2.09%."

Quantifies contact allergy prevalence to methylchloroisothiazolinone and methylisothiazolinone in a tested population, establishing them as active sensitizers rather than merely present chemicals.

Mastisol adhesive exposure

Exposure to Mastisol liquid adhesive used for wound closure is a reported trigger of allergic contact dermatitis after surgical procedures.

Show evidence (1 reference)

PMID:30465037 SUPPORT Human clinical

"We report on a rare case of allergic contact dermatitis (ACD) from Mastisol liquid adhesive."

This case report supports Mastisol as a specific adhesive trigger of allergic contact dermatitis.

Mechanism Target:

TRIGGERS Hapten exposure — A liquid surgical adhesive whose gum-resin constituents can sensitize; reported rarely, so this link records a documented rather than a frequent hapten source.

Show evidence (1 reference)

PMID:30465037 SUPPORT Human clinical

"We report on a rare case of allergic contact dermatitis (ACD) from Mastisol liquid adhesive."

Reports a case of allergic contact dermatitis attributed to this liquid adhesive, a documented but uncommon hapten source.

2-octyl cyanoacrylate adhesive exposure

Exposure to 2-octyl cyanoacrylate topical skin adhesives used for surgical wound closure is an increasingly recognized trigger of allergic contact dermatitis, especially after repeat exposure.

Show evidence (2 references)

PMID:41784277 SUPPORT BACKGROUND Human clinical

"2-octyl cyanoacrylate (2-OCA) topical skin adhesives are widely used for surgical wound closure but are increasingly associated with allergic contact dermatitis (ACD)."

This systematic review supports 2-octyl cyanoacrylate as a specific surgical adhesive trigger of allergic contact dermatitis.

PMID:41784277 SUPPORT Human clinical

"Re-exposure markedly increased risk, with reaction rates rising from 1-3% after initial exposure to >20% in staged or repeat procedures in several cohorts."

This supports repeat exposure as an important risk amplifier for cyanoacrylate-triggered allergic contact dermatitis.

Mechanism Target:

TRIGGERS Hapten exposure — A surgical skin adhesive increasingly implicated as a sensitizer, notable because the exposure is iatrogenic and occurs on a wound that is already breached.

Show evidence (1 reference)

PMID:41784277 SUPPORT BACKGROUND Human clinical

"2-octyl cyanoacrylate (2-OCA) topical skin adhesives are widely used for surgical wound closure but are increasingly associated with allergic contact dermatitis (ACD)."

Reports that these topical skin adhesives, widely used for surgical wound closure, are increasingly associated with allergic contact dermatitis.

TRIGGERS Re-exposure-driven effector T-cell recruitment — A second, later encounter with the same adhesive is what recruits primed effector T cells to the skin, which is why staged or repeat surgical procedures carry an order-of-magnitude higher reaction rate than a first exposure. Sensitization and elicitation are separate events, and this link records the second.

Show evidence (1 reference)

PMID:41784277 SUPPORT Human clinical

"Re-exposure markedly increased risk, with reaction rates rising from 1-3% after initial exposure to >20% in staged or repeat procedures in several cohorts."

Reaction rates rise from a few percent after initial exposure to over twenty percent on staged or repeat exposure, quantifying elicitation on re-encounter rather than sensitization at first contact.

Para-phenylenediamine exposure

Exposure to para-phenylenediamine, particularly in hair dyes and related products, is a common environmental trigger of allergic contact dermatitis.

Show evidence (1 reference)

DOI:10.3389/fmed.2023.1184289 SUPPORT Human clinical

"Metals, especially nickel, fragrance mix, isothiazolinones, and para-phenylenediamine, are the most commonly positive allergens in patients patch tested for suspected ACD."

This review identifies para-phenylenediamine as a common sensitizer in allergic contact dermatitis.

Mechanism Target:

TRIGGERS Hapten exposure — The principal sensitizer in permanent hair dye and in black henna tattoos, where the unregulated concentrations make sensitization more likely.

Show evidence (1 reference)

DOI:10.3389/fmed.2023.1184289 SUPPORT Human clinical

"Metals, especially nickel, fragrance mix, isothiazolinones, and para-phenylenediamine, are the most commonly positive allergens in patients patch tested for suspected ACD."

Identifies para-phenylenediamine among the most commonly positive allergens on patch testing.

Rubber accelerator exposure

Exposure to rubber accelerators in gloves, footwear, and occupational materials is a common environmental trigger of allergic contact dermatitis.

Show evidence (1 reference)

PMID:25102574 SUPPORT Human clinical

"Nickel, fragrances, rubber accelerators and biocides are the most common sensitisers in ACD."

This review identifies rubber accelerators as common sensitizers in allergic contact dermatitis.

Mechanism Target:

TRIGGERS Hapten exposure — Thiurams and carbamates added during rubber vulcanisation remain in the finished product, which is why gloves intended as protection are themselves a common source of occupational sensitization.

Show evidence (1 reference)

PMID:25102574 SUPPORT Human clinical

"Nickel, fragrances, rubber accelerators and biocides are the most common sensitisers in ACD."

Names rubber accelerators among the most common sensitizers in allergic contact dermatitis.

Biocide exposure

Exposure to biocides and preservative chemicals in occupational and consumer products is a common environmental trigger of allergic contact dermatitis.

Show evidence (1 reference)

PMID:25102574 SUPPORT Human clinical

"Nickel, fragrances, rubber accelerators and biocides are the most common sensitisers in ACD."

This review identifies biocides as common sensitizers in allergic contact dermatitis.

Mechanism Target:

TRIGGERS Hapten exposure — Preservatives and antimicrobials added to cosmetics, cutting fluids and paints, encountered in both occupational and consumer settings.

Show evidence (1 reference)

PMID:25102574 SUPPORT Human clinical

"Nickel, fragrances, rubber accelerators and biocides are the most common sensitisers in ACD."

Names biocides among the most common sensitizers in allergic contact dermatitis.

Repeated and high-concentration allergen exposure

Repeated contact and higher local concentrations of potential allergens increase the probability of sensitization and later allergic flares.

Show evidence (1 reference)

PMID:25102574 SUPPORT Human clinical

"Frequent exposure and high concentrations of potential allergens increase the risk of sensitisation."

This supports repeated or intense exposure as an environmental risk factor for allergic sensitization.

Mechanism Target:

PREDISPOSES Allergen-specific T-cell priming — Not a hapten itself but a property of the encounter. Sensitization is dose- and frequency-dependent, so the same chemical is more likely to prime a T-cell response when met often or at high concentration.

Show evidence (1 reference)

PMID:25102574 SUPPORT Human clinical

"Frequent exposure and high concentrations of potential allergens increase the risk of sensitisation."

States that frequent exposure and high allergen concentrations increase the risk of sensitisation, which is the priming step this node describes.

Toxicodendron exposure

Exposure to Toxicodendron plants such as poison ivy, poison oak, and poison sumac is a common environmental trigger of allergic contact dermatitis.

Show evidence (2 references)

PMID:14700441 SUPPORT BACKGROUND Human clinical

"Plants of the Toxicodendron species cause allergic contact dermatitis (ACD) in 50% to 70% of the population."

This supports Toxicodendron plant exposure as a common and clinically important trigger of allergic contact dermatitis.

PMID:27548435 SUPPORT Human clinical

"Among various urushiol congeners, we identified diunsaturated pentadecylcatechol (C15:2) as the dominant antigen for CD1a-restricted T cells."

This supports urushiol III, the diunsaturated pentadecylcatechol congener, as a specific Toxicodendron allergen linked to poison ivy dermatitis.

Mechanism Target:

TRIGGERS Hapten exposure — Poison ivy, oak and sumac deliver urushiol, a catechol that penetrates skin and binds protein to form the hapten. Unusually for a contact allergen, it sensitizes a majority of the population.

Show evidence (1 reference)

PMID:27548435 SUPPORT Human clinical

"Human subjects with poison-ivy dermatitis had a similar cytokine signature following CD1a-mediated recognition of urushiol."

Shows CD1a-mediated recognition of urushiol in patients with poison-ivy dermatitis, evidencing the hapten being presented in actual disease rather than in a clone assay.

Lime and other psoralen-rich citrus exposure with ultraviolet light

Contact with lime juice or peel followed by ultraviolet exposure can trigger phytophotodermatitis, a phototoxic contact reaction that may be mistaken for allergic dermatitis.

Show evidence (1 reference)

PMID:41064302 SUPPORT BACKGROUND Human clinical

"Lime-induced phytophotodermatitis, sometimes called "lime disease" or "margarita photodermatitis," is one of the most common forms, caused by furocoumarins in lime juice or peel."

This case report supports lime-derived psoralen exposure with UV light as a specific trigger of photocontact dermatitis.

Mechanism Target:

TRIGGERS Irritant exposure and toxic insult — Phytophotodermatitis needs both halves and is neither allergic nor idiosyncratic: furocoumarins on the skin absorb ultraviolet A and become directly cytotoxic, so the reaction is a phototoxic irritant insult rather than a hapten-driven sensitization.

Show evidence (1 reference)

PMID:41064302 SUPPORT BACKGROUND Human clinical

"Lime-induced phytophotodermatitis, sometimes called "lime disease" or "margarita photodermatitis," is one of the most common forms, caused by furocoumarins in lime juice or peel."

Identifies lime-induced phytophotodermatitis as caused by furocoumarins, the phototoxic irritant insult this node describes.

Mare's milk soap exposure

Soap products containing mare's milk have been reported as a specific trigger of allergic contact dermatitis in sensitized individuals. Weight accordingly - this is an n-of-1 allergen report, not an established trigger class.

🔬

Diagnosis

2

Exposure history and lesion-pattern assessment

Diagnosis begins with careful review of exposures, timing, occupational and personal products, and the anatomic distribution of dermatitis.

clinical history and physical examination NCIT:C18020

Show evidence (2 references)

PMID:31757238 SUPPORT Human clinical

"Diagnosis is based on a thorough history, physical examination, and patch testing."

This supports exposure-focused clinical history and examination as the foundation of diagnosis.

DOI:10.1073/pnas.2009192117 SUPPORT Human clinical

"Current diagnostic regimes rely on allergy testing, exposure specification, and follow-up visits."

This supports exposure specification and serial clinical assessment as standard parts of the diagnostic workflow for contact dermatitis.

Patch testing for suspected allergic contact dermatitis

Patch testing is used when allergic contact dermatitis is suspected, especially in recurrent or persistent disease, to identify relevant sensitizers and distinguish allergic from irritant dermatitis; common positive allergens include metals, fragrance mixes, isothiazolinones, and para-phenylenediamine.

patch testing NCIT:C18020

Show evidence (3 references)

PMID:31757238 SUPPORT Human clinical

"Diagnosis is based on a thorough history, physical examination, and patch testing."

This supports patch testing as a core diagnostic modality for allergic contact dermatitis.

PMID:25102574 SUPPORT Human clinical

"If ACD is suspected the patient should be referred to secondary care for patch testing."

This supports referral for patch testing when allergic contact dermatitis is clinically suspected.

DOI:10.3389/fmed.2023.1184289 SUPPORT Human clinical

"Patch testing with suspected allergens is required for a diagnosis."

This review reinforces patch testing as the defining diagnostic procedure for allergic contact dermatitis.

📊

Prevalence

2

Adults from five European countries

Lifetime prevalence 15000.0 per 100,000 >1 in 1,000

Questionnaire-based lifetime occurrence estimate in a representative cross-sectional sample of adults aged 18-74 years from Germany, Italy, the Netherlands, Portugal, and Sweden. A related European population study of contact allergy reported a nearly identical age-standardized lifetime contact dermatitis estimate of 15.1%.

Show evidence (2 references)

PMID:29247509 SUPPORT Human clinical

"The most common skin disease was warts (41·3%), followed by acne (19·2%) and contact dermatitis (15·0%)."

This provides a direct population-based lifetime prevalence estimate for contact dermatitis in adults from five European countries.

PMID:26370659 SUPPORT PRIMARY RESULT Human clinical

"Subjects reporting contact dermatitis in their lifetime (age-standardized prevalence 15·1%, 95% CI 13·8-16·3)"

This independent European population study closely replicates the approximately 15% lifetime contact dermatitis prevalence estimate.

General population over a lifetime

Lifetime prevalence 15000.0 per 100,000 >1 in 1,000

Approximate lifetime burden cited in a U.S. population-based epidemiology study background; consistent with the directly measured European population-based estimates above, but not itself a pooled global meta-analytic prevalence estimate.

Show evidence (1 reference)

PMID:39403761 SUPPORT Human clinical

"Background: Contact dermatitis (CD) affects ∼15% of the general population over a lifetime."

This U.S. population-based study cites an approximately 15% lifetime general-population burden, supporting the broader prevalence context.

🌍

Epidemiology

1

Predominant occupational skin disease burden

Contact dermatitis is the dominant occupational skin disorder and accounts for most cases of occupational skin disease in industrialized settings.

occupation

Show evidence (2 references)

PMID:19580930 SUPPORT Human clinical

"Contact dermatitis is the most common occupational skin disorder, responsible for up to 30% of all cases of occupational disease in industrialized nations."

This review supports contact dermatitis as a leading occupational disease burden.

PMID:19580930 SUPPORT Human clinical

"Epidemiologic data suggest that contact dermatitis accounts for 90% to 95% of all cases of occupational skin disease"

This review supports contact dermatitis as the major contributor to occupational skin disease cases.

🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Contact Dermatitis:

Atopic dermatitis MONDO:0004980

Overlapping Features Atopic dermatitis can overlap with contact dermatitis when patients present with chronic pruritic eczema, and the two disorders may coexist in the same patient.

Distinguishing Features

Atopic dermatitis more often shows a chronic relapsing endogenous eczema pattern with broader flexural involvement and an atopic background.
Contact dermatitis is more tightly linked to external exposures and tends to localize to the area of contact with the exogenous trigger.

Show evidence (2 references)

PMID:38713001 SUPPORT Human clinical

"Furthermore, other conditions, with different pathogenesis and treatment, may clinically simulate contact dermatitis."

This task-force review supports atopic dermatitis as part of the clinical differential diagnosis for contact dermatitis.

PMID:38713001 SUPPORT Human clinical

"Although irritant and allergic contact dermatitis have a different pathogenesis, both are characterized by a rather typical morphology, are triggered by external factors and tend to occur primarily in the area of contact with the exogenous agent."

This supports exposure-linked localization as a key feature that helps distinguish contact dermatitis from broader endogenous eczema such as atopic dermatitis.

Psoriasis MONDO:0005083

Overlapping Features Psoriasis can mimic chronic scaly dermatitis, especially on the hands or scalp, but it is a distinct immune-mediated papulosquamous disorder rather than an exposure-driven eczema.

Distinguishing Features

Psoriasis more often produces sharply demarcated plaques with thick adherent scale and characteristic extensor, scalp, or nail involvement.
Contact dermatitis is usually linked to a relevant irritant or allergen exposure history and improves when the offending exposure is removed.

Show evidence (2 references)

PMID:38713001 SUPPORT Human clinical

"Furthermore, other conditions, with different pathogenesis and treatment, may clinically simulate contact dermatitis."

This practical review supports psoriasis as a plausible simulator within the differential diagnosis of contact dermatitis.

PMID:25102574 SUPPORT Human clinical

"Contact dermatitis results from skin contact with an exogenous substance."

This supports exogenous exposure as a distinguishing feature of contact dermatitis relative to psoriasis.

Tinea corporis Not Yet Curated MONDO:0001461

Overlapping Features Dermatophyte infection can resemble localized eczematous dermatitis when lesions are annular and scaly, particularly if exposure history is unclear.

Distinguishing Features

Tinea corporis typically shows an annular advancing border with central clearing and is confirmed by fungal testing when needed.
Contact dermatitis is evaluated through exposure history and, for allergic disease, patch testing rather than mycologic testing.

Show evidence (2 references)

PMID:38713001 SUPPORT Human clinical

"Furthermore, other conditions, with different pathogenesis and treatment, may clinically simulate contact dermatitis."

This supports superficial fungal infection as part of the broader mimic set that must be separated from contact dermatitis.

PMID:31757238 SUPPORT Human clinical

"Diagnosis is based on a thorough history, physical examination, and patch testing."

This supports patch testing and exposure-based evaluation as distinguishing elements for allergic contact dermatitis.

📊

Related Datasets

2

Genome-Wide Profiling of Lesional and Non-Lesional Skin from Atopic Dermatitis, Psoriasis, and Contact Dermatitis Skin geo:GSE153007

Comparative human skin transcriptomic dataset spanning lesional and non-lesional samples from contact dermatitis alongside atopic dermatitis and psoriasis, enabling cross-disease comparison of inflammatory programs.

Homo sapiens MICROARRAY

Conditions: contact dermatitis skin non-lesional skin atopic dermatitis skin psoriasis skin

Dataset record: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE153007 Carries no evidence block: the GEO record has no summary (its summary field repeats the title) and no linked publication, so there is no abstract sentence to quote. The title, conditions and organism above are GEO's own values.

Inhibition of DYRK1B suppresses inflammation in allergic contact dermatitis model and Th1/Th17 immune response geo:GSE215457

Transcriptomic dataset associated with DYRK1B inhibition experiments used to interrogate T-cell inflammatory programs relevant to allergic contact dermatitis and Th1/Th17 polarization.

Homo sapiens BULK RNA SEQ

Dataset record: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE215457

Show evidence (1 reference)

GEO:GSE215457 SUPPORT In vitro / ex vivo

"To investigate the inhibition effect of DYRK1B kinase function on human naïve CD4+ T cell differetionation which stimulated under Treg polarizing condition for 24 hours."

This GEO record supports a human T-cell transcriptomic dataset tied to mechanistic allergic contact dermatitis work on inflammatory T-cell polarization.

🔬

Clinical Trials

2

NCT05535738 PHASE_II RECRUITING

Recruiting combined phase 2/3 mechanistic interventional study using a controlled contact dermatitis model with biologic pretreatment and suction blister-based skin sampling to dissect cutaneous inflammatory pathways.

Target Phenotypes: Contact dermatitis HP:0032282

Show evidence (1 reference)

clinicaltrials:NCT05535738 SUPPORT Human clinical

"The purpose of this study is to answer: how do inflammation and anti-inflammatory skin therapies work in the skin?"

This official study record supports a currently recruiting interventional trial that uses a contact dermatitis model to study inflammatory skin responses.

NCT02778711 PHASE_III UNKNOWN

Registered phase 3 interventional study evaluating secukinumab as a targeted treatment strategy for severe allergic contact dermatitis.

Target Phenotypes: Pruritus HP:0000989 Erythema HP:0010783

Show evidence (1 reference)

clinicaltrials:NCT02778711 SUPPORT Human clinical

"The purpose of this study is to assess the efficacy of anti-IL 17 treatment (secukinumab) in patients with known severe allergic contact dermatitis (ACD)."

This official study record supports a registered interventional trial directly focused on severe allergic contact dermatitis.

🧫

Experimental Models

13

Human Cell Line Activation Test (h-CLAT) CELL_LINE

An OECD TG 442E method that reads sensitizer-induced activation of a dendritic-cell surrogate as CD86 and CD54 surface expression on the THP-1 human monocytic leukemia line after 24 hours of chemical exposure.

Publication

PMID:20510347

Pathograph links

Skin innate immune activation during sensitization measures fidelity: moderate observes: cellular Reads the dendritic-cell activation step of sensitization as two costimulatory and adhesion markers on a monocytic line.

Limitations: THP-1 is a monocytic leukemia line, not a dendritic cell, so marker upregulation stands in for antigen-presenting-cell activation rather than demonstrating it. About 15% of outcomes were misclassified in the COLIPA ring trials, with weak allergens and poorly soluble chemicals named as the failure classes. The assay reads a hazard call and carries little potency information, and being cell-only it cannot activate pro-haptens.

Divergences from the human mechanism

proxy quantity qualifying

CD86 and CD54 are the measured quantity; dendritic-cell activation in skin is the quantity of interest.

scale extrapolation qualifying

The assay observes single cells in suspension; the node is tissue-scale innate activation in skin. Nothing in the readout reports the tissue context — no keratinocyte crosstalk, no migration, no barrier — so the step from marker induction to skin-level activation is inferred.

Show evidence (1 reference)

PMID:20510347 SUPPORT DIRECT In vitro / ex vivo

"The human Cell Line Activation Test (h-CLAT) examines the level of CD86 and CD54 expression on the surface of THP-1 cells, a human monocytic leukemia cell line, following 24h of chemical exposure."

States the measured readout and the cell provenance, which is what fixes this model to the dendritic-cell activation step and bounds what it can show.

Show evidence (1 reference)

PMID:20510347 SUPPORT In vitro / ex vivo

"From the RT data, the feasibility of utilizing cell lines as surrogate DC in development of in vitro skin sensitization methods shows promise."

States what the ring trials establish about the model itself: that a cell line can serve as a dendritic-cell surrogate for this purpose. The assay's 15% misclassification rate is the counterweight, and it is recorded in the link's limitations rather than here, because model-level evidence attests that the model is informative.

GARDskin CELL_LINE

An OECD TG 442E method that reads sensitizer-induced activation of a dendritic-cell-like line as a multi-gene transcriptional signature rather than as individual surface markers.

Publication

PMID:31099396

Pathograph links

Skin innate immune activation during sensitization measures fidelity: moderate observes: cellular Reads the dendritic-cell activation step as induced transcriptional change across co-stimulatory, stress and xenobiotic-response programs.

Limitations: The readout is a trained signature in the MUTZ-3 dendritic-cell-like myeloid line, so the prediction is model-dependent and the cell is a surrogate rather than a primary dendritic cell. Reported accuracy is tied to the 28-chemical blinded ring-trial set.

Divergences from the human mechanism

scale extrapolation qualifying

The signature is measured in a single cultured cell type; the node is tissue-scale innate activation in skin. The transcriptional programs read out are cell-intrinsic, so the tissue-level claim is inferred rather than observed.

Show evidence (1 reference)

PMID:31099396 SUPPORT DIRECT In vitro / ex vivo

"The methodology is based on a dendritic cell (DC)-like cell line, thus mimicking the mechanistic events leading to initiation and modulation of downstream immunological responses."

States the biological basis the method claims, which is what maps it to the dendritic-cell activation step of sensitization.

Human T-cell priming assay CO_CULTURE

A co-culture of sorted naive human T cells with monocyte-derived dendritic cells pulsed with the test chemical, reading antigen-specific priming as IFN-gamma and TNF-alpha production at single-cell level.

Publication

PMID:22906571

Pathograph links

Allergen-specific T-cell priming recapitulates fidelity: moderate observes: cellular Primes an allergen-specific human T-cell response in vitro, which is the step this node asserts, using primary human cells on both sides of the interaction.

Limitations: The assay is not regulatory-validated and is low-throughput, and donor-to-donor variability is not yet well defined. It establishes that priming occurs in human cells but cannot establish the whole-organism adverse outcome.

Show evidence (1 reference)

PMID:22906571 SUPPORT DIRECT In vitro / ex vivo

"Using sorted naïve T cells and monocyte-derived dendritic cells pulsed with the test chemical or with chemical-protein conjugates, the successful priming of an antigen-specific T cell response is controlled after antigen-specific restimulation by cytokine readout."

Describes priming of a chemical-specific naive human T-cell response, which is the mechanism this pathograph node records.

Full-thickness skin equivalent with MUTZ-3-derived Langerhans cells CO_CULTURE

An immunocompetent full-thickness skin equivalent whose epidermis carries keratinocytes, melanocytes and CD1a+ Langerin+ HLA-DR+ Langerhans cells derived from the MUTZ-3 line, over a fibroblast-populated dermis.

Publication

PMID:21697260

Pathograph links

Skin innate immune activation during sensitization partially recapitulates fidelity: moderate observes: tissue Reproduces allergen-driven Langerhans cell maturation together with migration out of the epidermis toward the dermal compartment, which the monolayer dendritic-cell assays cannot show.

Limitations: The Langerhans cells are MUTZ-3-derived surrogates rather than primary cells, and the system is a research model without regulatory validation.

Show evidence (1 reference)

PMID:21697260 SUPPORT DIRECT In vitro / ex vivo

"Exposure of the SE to subtoxic concentrations of the allergens NiSO(4) and resorcinol resulted in LC migration out of the epidermis toward the fibroblast-populated dermal compartment."

Demonstrates allergen-driven migration of epidermal Langerhans cells, the physical step of innate activation during sensitization that monolayer assays omit.

Keratinocyte Keap1-Nrf2-ARE sensitizer-response models OTHER

Four keratinocyte-based systems — primary human keratinocytes, N/TERT monolayers, and the Leiden and N/TERT reconstructed epidermal models — read for Nrf2 protein, nuclear translocation and Nrf2 target activation after exposure to a sensitizer versus an irritant. This is the biology OECD TG 442D methods (KeratinoSens, LuSens) measure.

Publication

PMID:24794257

Pathograph links

Hapten-driven keratinocyte electrophile sensing measures fidelity: moderate observes: cellular Measures this node's own quantity, Keap1-Nrf2-ARE pathway activation in keratinocytes under hapten exposure, and separates sensitizer-driven from irritant-driven activation on that readout.

Limitations: Keratinocytes alone, in monolayer or reconstructed epidermis, so nothing downstream of the sensing step is represented: no Langerhans cells, no dendritic cells, no draining lymph node. The monolayer arms also have no stratum corneum, so they are dosed in medium rather than per unit area of skin surface. These are research systems reading the biology the validated TG 442D methods measure, not those methods themselves.

Show evidence (1 reference)

PMID:24794257 SUPPORT DIRECT In vitro / ex vivo

"Results show that the Keap1-Nrf2-ARE pathway is activated by the sensitizer DNCB in monolayer keratinocytes and as well as the LEMs and NEMs and not by the irritant SDS."

Establishes that this keratinocyte readout responds to a sensitizer and not to an irritant, which is what makes it a measurement of this node's hapten-driven step rather than of the irritant arm's keratinocyte node.

KeratinoSens CELL_LINE

An OECD TG 442D method that reads sensitizer-induced keratinocyte activation as luciferase induction from a reporter under the control of the antioxidant response element of the aldoketoreductase gene AKR1C2, in an immortalised human keratinocyte line. The first cell-based in vitro skin sensitisation test to carry an OECD Test Guideline.

Publication

PMID:27805827

Pathograph links

Hapten-driven keratinocyte electrophile sensing measures fidelity: moderate observes: cellular Measures this node's own quantity, Nrf2-dependent transcriptional activation in keratinocytes under exposure to an electrophilic sensitizer, read as induction of the AKR1C2 ARE luciferase reporter.

Limitations: The reporter reads the Nrf2-dependent arm only. Sensitizer-induced heat shock and cellular stress markers in this same cell line were shown to be Nrf2-independent, so they do not reach the luciferase readout, and a non-sensitizer (Tween 80) induces the reporter through Nrf2 as a documented false positive. Being a keratinocyte monolayer, nothing downstream of keratinocyte activation is represented: no Langerhans cells, no dendritic cells, no draining lymph node, and the monolayer lacks the stratum corneum and metabolic competence a reconstructed epidermis uses to activate a pre- or pro-hapten, so a chemical needing conversion may not be converted here. The EURL ECVAM review of 127 substances found that sensitizers requiring activation were still identified by one or more methods of the non-animal battery, which is a statement about the battery rather than about this assay alone.

Divergences from the human mechanism

proxy quantity qualifying

Induction of a transfected AKR1C2 ARE luciferase reporter is the measured quantity; endogenous Keap1-Nrf2-ARE pathway activation in keratinocytes is the quantity this node carries.

Show evidence (1 reference)

PMID:24055896 SUPPORT DIRECT In vitro / ex vivo

"These results confirm that the KeratinoSens™ cell line is a rapid and adequate screening tool to assess the sensitizer-induced Nrf2-response in keratinocytes."

Supports treating this assay as a measurement of the sensitizer-driven Nrf2 response in keratinocytes, which is the biology this node carries.

Show evidence (2 references)

PMID:24055896 SUPPORT DIRECT In vitro / ex vivo

"The KeratinoSens™ assay is an in vitro screen for the skin sensitization potential of chemicals. It is based on a luciferase reporter gene under the control of the antioxidant response element of the aldoketoreductase gene AKR1C2."

States what the assay is and which reporter construct carries its readout, which is what this model entry records.

PMID:26796489 SUPPORT DIRECT BACKGROUND Other

"The KeratinoSens assay addresses the cellular event of keratinocyte activation and is a method accepted under OECD TG 442D."

Names the guideline this method is accepted under. Quoted from the background of the LuSens inter-laboratory study, which is restating a regulatory decision rather than reporting its own result.

LuSens CELL_LINE

The second OECD TG 442D method, a human keratinocyte line carrying a reporter gene construct built from the antioxidant response element of the rat NADPH:quinone oxidoreductase 1 gene and the luciferase gene, read as sensitizer-induced keratinocyte activation.

Publication

PMID:25172300

Pathograph links

Hapten-driven keratinocyte electrophile sensing measures fidelity: moderate observes: cellular Measures this node's own quantity, ARE-driven transcriptional activation in keratinocytes under exposure to an electrophilic sensitizer, read as induction of the rat NQO1 ARE luciferase reporter.

Limitations: A keratinocyte monolayer reporter line, so nothing downstream of keratinocyte activation is represented: no Langerhans cells, no dendritic cells, no draining lymph node. The readout is a single ARE-driven reporter, so a sensitizer acting on keratinocytes through a pathway that does not converge on the ARE is not read, and the reporter element is of rat origin in a human cell line. As a monolayer it lacks the stratum corneum and metabolic competence a reconstructed epidermis uses to activate a pre- or pro-hapten, so a chemical needing conversion may not be converted here; the EURL ECVAM review of 127 substances found that sensitizers requiring activation were still identified by one or more methods of the non-animal battery, which is a statement about the battery rather than about this assay alone.

Divergences from the human mechanism

proxy quantity qualifying

Induction of a transfected rat NQO1 ARE luciferase reporter is the measured quantity; endogenous Keap1-Nrf2-ARE pathway activation in keratinocytes is the quantity this node carries.

Show evidence (1 reference)

PMID:25172300 SUPPORT DIRECT In vitro / ex vivo

"the LuSens assay, that uses a human keratinocyte cell line harbouring a reporter gene construct composed of the antioxidant response element (ARE) of the rat NADPH:quinone oxidoreductase 1 gene and the luciferase gene"

Establishes that the assay reads ARE-driven activation in a human keratinocyte line, which is the measurement this link claims.

Show evidence (1 reference)

PMID:26796489 SUPPORT DIRECT In vitro / ex vivo

"The data demonstrate a remarkable reproducibility of 100% and an accuracy of over 80% in identifying skin sensitizers, indicating a good concordance with in vivo data."

Reports the inter-laboratory reproducibility and accuracy behind this method's regulatory acceptance.

U-SENS (Myeloid U937 Skin Sensitization Test) CELL_LINE

An OECD TG 442E method that reads sensitizer-induced activation of a dendritic-cell surrogate as CD86 surface expression on the U937 human myeloid cell line, measured by flow cytometry.

Publication

PMID:25820135

Pathograph links

Skin innate immune activation during sensitization measures fidelity: moderate observes: cellular Reads the dendritic-cell activation step of sensitization as CD86 upregulation on a myeloid line.

Limitations: U937 is a myeloid leukemia line, not a dendritic cell, so CD86 upregulation stands in for antigen-presenting-cell activation rather than demonstrating it directly. Between-laboratory reproducibility in the ring study was lower than within-laboratory reproducibility (79% versus 95%), and being cell-only it cannot activate pro-haptens.

Divergences from the human mechanism

proxy quantity qualifying

CD86 is the measured quantity; dendritic-cell activation in skin is the quantity of interest.

scale extrapolation qualifying

The assay observes single cells in suspension; the node is tissue-scale innate activation in skin. Nothing in the readout reports the tissue context.

Show evidence (1 reference)

PMID:25820135 SUPPORT DIRECT In vitro / ex vivo

"Dendritic cell activation following exposure to sensitizers was modelled in the U937 human myeloid cell line by measuring the induction of the expression of CD86 by flow cytometry."

States the measured readout and cell provenance, which is what fixes this model to the dendritic-cell activation step and bounds what it can show.

The human comparator data for this kind of assay-validation analysis is the sort compiled in the HPPT reference database (PMID:37615678, in this entry's references catalog): a database of 2,277 human predictive patch tests across 1,366 substances assembled to serve as the human standard non-animal methods are benchmarked against.

Show evidence (1 reference)

PMID:25820135 SUPPORT In vitro / ex vivo

"U-SENS™ showed 79% specificity, 90% sensitivity and 88% accuracy."

States what the comparison analysis against human and LLNA data establishes about the model's predictive performance.

IL-8 Luc assay CELL_LINE

An OECD TG 442E method that reads sensitizer-induced activation of a dendritic-cell surrogate as IL-8 promoter-driven luciferase induction in the THP-G8 human monocytic reporter line, with a parallel GAPDH-promoter luciferase reporter used to flag cytotoxicity.

Publication

PMID:33068120

Pathograph links

Skin innate immune activation during sensitization measures fidelity: moderate observes: cellular Reads the dendritic-cell activation step of sensitization as IL-8-promoter luciferase induction in a monocytic reporter line.

Limitations: THP-G8 is a monocytic reporter line, not a dendritic cell, so the luciferase readout stands in for antigen-presenting-cell activation rather than demonstrating it directly. The unmodified assay returns an indeterminate call for a chemical that will not dissolve at 20 mg/mL in medium, a documented false-negative route for lipophilic sensitizers with logKow above 3.5; being cell-only it also cannot activate pro-haptens.

Divergences from the human mechanism

proxy quantity qualifying

IL-8 promoter-driven luciferase activity is the measured quantity; dendritic-cell activation in skin is the quantity of interest.

scale extrapolation qualifying

The assay observes single cells in suspension; the node is tissue-scale innate activation in skin.

Show evidence (1 reference)

PMID:33068120 SUPPORT DIRECT In vitro / ex vivo

"The IL-8 Luc assay (OECD442E) is unique in that if chemicals do not dissolve at 20 mg/mL in medium and have no effect on IL-8 luciferase activity (IL8LA), they are classified as indeterminate."

States the assay's OECD classification and readout, and names the solubility-driven indeterminate call this entry's limitations records as a false-negative route for lipophilic chemicals.

Show evidence (1 reference)

PMID:33068120 SUPPORT In vitro / ex vivo

"This modification reduced the number of indeterminate chemicals and increased specificity, highlighting the unique advantage of the IL-8 Luc assay."

States what this study establishes about the model: a solubility-aware modification improves on a documented false-negative route of the base assay.

EpiSensA OTHER

A reconstructed human epidermis (RhE) gene-expression assay that reads hapten-driven keratinocyte activation as induced expression of ATF3, IL-8, DNAJB4 and GCLM, spanning an inflammatory (P2X7-dependent) and a cytoprotective (Nrf2-dependent) keratinocyte response. Because the RhE model retains a stratified stratum corneum and metabolic competence, it can be dosed topically and can activate lipophilic chemicals and pre-/pro-haptens that monolayer cell-line assays miss.

Publication

PMID:27965148

Pathograph links

Hapten-driven keratinocyte electrophile sensing measures fidelity: moderate observes: tissue Reads the cytoprotective arm of hapten-driven keratinocyte activation as Nrf2-dependent GCLM induction, alongside ATF3 and IL-8 as a separate P2X7-dependent inflammatory readout this entry has no node for.

Limitations: The marker genes are a trained signature rather than the Keap1-Nrf2-ARE pathway itself, and the inter-laboratory validation reports a lower specificity (63.0%) than sensitivity (92.6%) against LLNA results. Reported accuracy depends on the LLNA and human comparator datasets used to build it.

Divergences from the human mechanism

proxy quantity qualifying

Induced expression of ATF3, IL-8, DNAJB4 and GCLM is the measured quantity; Keap1-Nrf2-ARE pathway activation is the quantity the GCLM arm is read as representing.

Show evidence (1 reference)

PMID:27965148 SUPPORT DIRECT In vitro / ex vivo

"The up-regulation of ATF3 and IL-8, or DNAJB4 and GCLM induced by the representative sensitizer 2,4-dinitrochlorobenzene in human keratinocytes was significantly suppressed by a P2X7 specific antagonist KN-62, or by Nrf2 siRNA, respectively, which supported mechanistic relevance of marker genes."

Establishes that the GCLM/DNAJB4 arm of the signature runs through Nrf2, which is what maps it onto this entry's Keap1-Nrf2-ARE-driven node; the ATF3/IL-8 arm runs through P2X7 instead, a separate mechanism this entry does not yet have a node for.

Show evidence (3 references)

PMID:27965148 SUPPORT In vitro / ex vivo

"the EpiSensA had sensitivity, specificity and accuracy of 93%, 100% and 93% for 29 lipophilic chemicals (logKow≥3.5), and of 96%, 75% and 88% for 43 hydrophilic chemicals including 11 pre/pro-haptens, compared with the LLNA."

States the assay's performance specifically on the lipophilic and pre-/pro-hapten chemical classes that motivate this model, as distinct from its overall performance.

PMID:37897225 SUPPORT In vitro / ex vivo

"the predictive capacity among the three laboratories showed 92.6% sensitivity, 63.0% specificity, 82.7% accuracy, and 77.8% balanced accuracy based on murine local lymph node assay (LLNA) results."

Gives the formal inter-laboratory validation figures for transferability and reproducibility, which is the model-level evidence that the assay performs consistently across laboratories.

PMID:37846211 SUPPORT In vitro / ex vivo

"The EpiSensA could detect 76 out of 88 sensitizers at lower concentrations than the LLNA, indicating that the EpiSensA has higher sensitivity for the detection of minor sensitizing constituents."

Supports the assay's applicability-domain advantage over the animal reference method for weak or minor sensitizing constituents.

SENS-IS OTHER

A reconstructed human epidermis (Episkin) gene-expression assay that quantifies sensitization hazard and potency from a large transcriptional panel, the same stratum-corneum-intact, metabolically competent format EpiSensA also uses.

Publication

PMID:26795242

Pathograph links

Skin innate immune activation during sensitization measures fidelity: moderate observes: tissue Reads sensitization hazard and potency from induced expression across a large gene panel in reconstructed epidermis, rather than from a single pathway readout.

Limitations: The panel is a trained signature over many genes rather than a mechanistic readout of one step, so which genes drive a given call is not individually interpretable from the model record alone. Reported predictivity figures come from the ring-study and 150-chemical test sets used to validate it.

Divergences from the human mechanism

proxy quantity qualifying

A multi-gene transcriptional signature is the measured quantity; dendritic-cell and keratinocyte activation in skin are the quantities of interest.

Show evidence (1 reference)

PMID:26795242 SUPPORT DIRECT In vitro / ex vivo

"The SENS-IS test protocol for the in vitro detection of sensitizers is based on a reconstructed human skin model (Episkin) as the test system and on the analysis of the expression of a large panel of genes."

States the test system and readout, which is what fixes this model to a tissue-scale transcriptional measurement rather than a single pathway reporter.

Show evidence (1 reference)

PMID:26795242 SUPPORT In vitro / ex vivo

"data analysis confirmed the excellent capacity of the SENS-IS assay for predicting both hazard and potency characteristics, confirming that this assay should be considered as a serious alternative to the available in vivo sensitization tests."

States what the comprehensive 150-chemical test set establishes about the model's predictive performance for both hazard and potency.

Reconstructed human skin organ-on-chip with neopapillae (RhS-NP) ORGAN_ON_CHIP

A next-generation skin-on-chip combining a stratified, differentiated epidermis on a fibroblast-populated hydrogel containing dermal-papilla spheroids (neopapillae), cultured air-exposed under dynamic flow and dosed topically with a sensitizer.

Publication

PMID:35893784

Pathograph links

Keratinocyte inflammasome danger signalling measures fidelity: moderate observes: tissue Reads the inflammasome-dependent danger-signalling arm of keratinocyte activation as secreted IL-18 and IL-1beta from a topically dosed tissue construct under perfusion, rather than from a monolayer.

Limitations: This is a proof-of-concept study with one sensitizer (cinnamaldehyde) and no irritant or non-sensitizer comparator, so sensitizer specificity of the cytokine panel is not established from this report alone.

Divergences from the human mechanism

proxy quantity qualifying

Secreted IL-18 and IL-1beta in culture medium are the measured quantity; keratinocyte inflammasome activation in skin is the quantity of interest.

Show evidence (1 reference)

PMID:35893784 SUPPORT DIRECT In vitro / ex vivo

"Topical cinnamaldehyde exposure to RhS-NP resulted in dose-dependent cytotoxicity (increased LDH release) and elevated cytokine secretion of contact sensitizer specific IL-18, pro-inflammatory IL-1β, inflammatory IL-23 and IFN-γ, as well as anti-inflammatory IL-10 and IL-12p70."

Reports the inflammasome-associated cytokines IL-18 and IL-1beta induced by a topically dosed sensitizer in this tissue-scale system, which is what maps the measurement onto this node.

Show evidence (1 reference)

PMID:35893784 SUPPORT In vitro / ex vivo

"This study demonstrates the robustness and feasibility of complex next generation skin models for investigating skin immunotoxicity."

States what the study establishes about the model system itself: the multi-day, dynamic-flow culture is robust and feasible across replicates.

Endothelialised skin-on-chip with flowing immune cells (MMA-6MWP) ORGAN_ON_CHIP

A reusable multi-well microfluidic adaptor combining reconstructed human skin with an endothelial layer and flowing monocyte-like MUTZ-3 cells, reading dendritic-cell-surrogate activation under perfusion rather than in static culture.

Publication

PMID:39370595

Pathograph links

Skin innate immune activation during sensitization measures fidelity: moderate observes: tissue Reads dendritic-cell-surrogate activation (CD83 and CD86 upregulation on MUTZ-3) occurring when immune cells flow past an endothelialised skin construct topically exposed to a sensitizer, adding circulation and a vascular interface that static monolayer and reconstructed-tissue assays lack.

Limitations: This is a proof-of-concept demonstration with one sensitizer and no comparator irritant or non-sensitizer, so specificity is not established from this report alone. MUTZ-3 is a dendritic-cell-like line rather than a primary dendritic cell.

Divergences from the human mechanism

proxy quantity qualifying

CD83 and CD86 on a dendritic-cell-like line are the measured quantity; dendritic-cell activation in skin is the quantity of interest.

Show evidence (1 reference)

PMID:39370595 SUPPORT DIRECT In vitro / ex vivo

"This dynamic setting activates the monocyte-like MUTZ-3 cells (CD83 and CD86 upregulation) upon topical exposure of RhS to a sensitizer, revealing the MMA-6MWP's unique capabilities compared to static culturing, where such activation is absent."

Shows that this model detects dendritic-cell-surrogate activation that a static culture of the same cells and tissue does not, which is the specific capability perfusion adds over the monolayer and reconstructed-tissue models already in this entry.

Show evidence (1 reference)

PMID:39370595 SUPPORT In vitro / ex vivo

"RhS viability is maintained under flow for three days and their morphology closely resembles that of native human skin."

States what this study establishes about the model system itself: it keeps reconstructed skin viable with native-like morphology under flow for the duration of the proof-of-concept experiment.

🐁

Animal Models

6

Langerin-DTA Langerhans-cell-deficient mouse

A BAC transgenic mouse with constitutive, durable absence of epidermal Langerhans cells and otherwise intact immunity, used to test whether Langerhans cells are required to prime contact hypersensitivity.

Species

Mus musculus

Genotype

human Langerin promoter-driven diphtheria toxin A BAC transgenic

Publication

PMID:16356859

Pathograph links

Skin innate immune activation during sensitization perturbs fidelity: moderate observes: organism Removes Langerhans cells and shows contact hypersensitivity is amplified rather than abolished, so Langerhans cells are dispensable for priming and act to restrain it. This revises the antigen-presenting-cell assumption this node inherits.

Limitations: Mouse genetic ablation; the dendritic-cell subset that primes the response in the absence of Langerhans cells is not identified, in this work or since, and the human priming antigen-presenting cell remains unresolved.

Divergences from the human mechanism

species mismatch qualifying

The requirement was tested in mouse contact hypersensitivity; no equivalent human ablation experiment exists.

Show evidence (1 reference)

PMID:16356859 SUPPORT DIRECT Model organism

"Unexpectedly, we found that contact hypersensitivity (CHS) was amplified rather than abrogated in the absence of LCs."

Establishes what this model is informative for: ablating Langerhans cells changes contact hypersensitivity, and in the direction opposite to an obligatory priming role, which is what makes the model a usable probe of this node rather than a confirmation of it.

NALP3- and ASC-deficient contact hypersensitivity mouse

Inflammasome-component knockouts exposed to contact sensitizers, used to test whether keratinocyte inflammasome signaling is required for the innate arm of contact hypersensitivity.

Species

Mus musculus

Genotype

Nlrp3-deficient or Pycard (ASC)-deficient

Publication

PMID:17429439

Pathograph links

Keratinocyte inflammasome danger signalling perturbs fidelity: moderate observes: organism Shows that loss of NALP3 or ASC impairs the response to contact sensitizers, establishing the caspase-1-dependent IL-1beta and IL-18 processing this node asserts as a required part of the sensitization response rather than an incidental accompaniment of it.

Limitations: Mouse knockouts; the companion human evidence is in keratinocytes in vitro rather than in human skin.

Show evidence (1 reference)

PMID:17429439 SUPPORT DIRECT Model organism

"We also show that ASC- and NALP3-deficient mice display an impaired response to CS."

Establishes the inflammasome as required for the contact-sensitizer response, which is what links this genotype to the keratinocyte inflammasome danger-signalling step this model is attached to.

DNFB contact hypersensitivity regulatory T-cell model

A 2,4-dinitrofluorobenzene contact hypersensitivity model used to characterize the regulatory T-cell population that restrains priming of effector CD8+ T cells.

Species

Mus musculus

Genotype

wild type, with FoxP3 reporter strains for Treg origin

Publication

PMID:20624644

Pathograph links

Breakdown of regulatory T-cell-mediated hapten tolerance measures fidelity: moderate observes: organism Measures the regulatory arm whose failure this node asserts, rather than reproducing that failure. Hapten immunization of wild-type mice induces a CD4+CD25+ regulatory T-cell population that suppresses hapten-reactive CD8+ effectors in a hapten-specific manner, so the model shows the suppression intact and characterizes the population whose loss the node records.

Limitations: Mouse contact hypersensitivity; the human counterpart evidence for hapten tolerance is in vitro nickel-responsiveness in healthy donors rather than in vivo.

Show evidence (1 reference)

PMID:20624644 SUPPORT DIRECT Model organism

"2,4-Dinitrofluorobenzene immunization induced a population of CD4(+)CD25(+) Treg cells that controlled CD8(+) T-cell effector responses in a hapten-specific manner in vivo."

Establishes hapten-specific regulatory T-cell control of the effector arm, the mechanism whose breakdown this node asserts.

Mouse local lymph node assay

The regulatory animal method (OECD TG 429, 442A, 442B) that reads sensitization as proliferation of T cells in the lymph node draining the site of dermal exposure.

Species

Mus musculus

Genotype

wild type

Publication

PMID:24532485

Pathograph links

Allergen-specific T-cell priming measures fidelity: moderate observes: organism Reads draining-lymph-node T-cell proliferation after dermal exposure, so it integrates penetration, metabolism, antigen-presenting-cell migration and clonal expansion in one whole-organism readout.

Limitations: Mouse; it misses metal sensitizers, with nickel sulfate hexahydrate recorded as a false negative, which is consistent with metals initiating through human TLR4 rather than covalent binding. Potency estimates are also vehicle-dependent.

Divergences from the human mechanism

species mismatch qualifying

The nickel false negative is mechanistically explained by human-specific TLR4 coordination that mouse TLR4 cannot reproduce.

Show evidence (2 references)

PMID:24532485 SUPPORT DIRECT Model organism

"Exposure to a dermal sensitizer results in proliferation of local lymph node T cells"

States what the assay measures, which is the lymph-node priming step this node records. Cut before the isotope label, whose bracketed form the snippet validator normalizes away.

+ 1 more reference

Guinea pig maximization test

The more sensitive of the two guinea pig methods recommended by OECD TG 406. Induction combines intradermal injection with adjuvant and a topical application; after a rest interval the animal is challenged with a patch at a non-irritant concentration and the dermal reaction is graded by eye.

Species

Cavia porcellus

Genotype

wild type

Publication

PMID:11028857

Pathograph links

Re-exposure-driven effector T-cell recruitment measures fidelity: moderate observes: organism The scored endpoint is the challenge-patch reaction in an animal already induced with the test chemical, so what the assay reads is the elicitation response to re-exposure rather than the priming that produced it. Priming is inferred from the presence of that reaction.

Limitations: Guinea pig rather than human, and the endpoint is a visually graded skin reaction rather than an antigen-specific cellular measurement. The adjuvant and intradermal induction are more aggressive than any topical human exposure, which is what makes this the sensitive member of the pair and also what makes a positive result an upper bound on potency. Chlorhexidine is negative in this test, and the guinea pig methods as a class have recorded false positives for vanillin and sulfanilic acid and a false negative for abietic acid.

Divergences from the human mechanism

proxy quantity qualifying

Erythema and swelling graded on a four-point scale stand in for effector T-cell recruitment. Nothing in the readout is antigen-specific or cellular, so an irritant reaction and an allergic one are separated by the choice of a non-irritant challenge dose rather than by the measurement itself.

Show evidence (4 references)

PMID:11028857 SUPPORT DIRECT BACKGROUND Other

"International test guidelines, such as the Organisation for Economic Cooperation and Development (OECD) guideline #406, recommend 2 guinea pig methods for testing of the contact allergenic potential of chemicals"

Establishes this as one of the two methods the guideline recommends, which is the regulatory standing the record asserts. Graded OTHER because the quoted sentence describes a guideline rather than reporting any study, and BACKGROUND because it is the abstract's opening framing rather than a result this paper produced.

+ 3 more references

Buehler occluded patch test

The second guinea pig method recommended by OECD TG 406. Induction is by repeated topical occluded patch without adjuvant, so exposure resembles topical human contact more closely than the maximization test does, and the challenge is read the same way. It is the less sensitive of the pair.

Species

Cavia porcellus

Genotype

wild type

Publication

PMID:11028857

Pathograph links

Re-exposure-driven effector T-cell recruitment measures fidelity: low observes: organism Reads the same challenge-patch reaction as the maximization test, under a milder induction regimen. Fidelity is graded LOW because the method returns negative results for chemicals that are strong sensitizers in the parallel test, so a negative here does not constrain whether the mechanism occurred.

Limitations: Guinea pig, and the readout is a visually graded skin reaction. Eugenol and mercaptobenzothiazole are negative in this test while scoring as strong sensitizers in the maximization test under identical conditions, and higher induction concentrations are needed before allergenicity shows at all. For some allergens the protocol is not sensitive enough to demonstrate the potential, so negative results carry little weight.

Divergences from the human mechanism

proxy quantity qualifying

As in the maximization test, a graded erythema score stands in for effector T-cell recruitment, with no antigen-specific or cellular measurement behind it.

boundary omission invalidating

The induction regimen is mild enough that known strong sensitizers fail to induce a detectable response, so the model's negative range does not correspond to absence of the mechanism. This invalidates negative results specifically, not positive ones.

Show evidence (3 references)

PMID:11028857 SUPPORT DIRECT Model organism

"eugenol and mercaptobenzothiazole were negative in the Buehler test"

The head-to-head result behind the LOW fidelity grade: both chemicals are strong sensitizers in the maximization test run under identical conditions in the same study.

+ 2 more references

🧮

Computational Models

4

Skin Allergy Risk Assessment (SARA) model MACHINE_LEARNING

A Bayesian model that infers a human-relevant sensitizer potency metric and a risk measure for a given consumer exposure from any combination of human patch test, local lymph node assay, DPRA, KeratinoSens, h-CLAT or U-SENS data.

PMID:35311660

Variable	Model ID	Unit	Ontology Mappings	Phenotype Thresholds
Human repeat insult patch test result Human in vivo reference input. The model takes any combination of its six input types rather than a fixed set.
Local lymph node assay result Murine in vivo reference input, curated in this entry as its own animal model.
Direct peptide reactivity assay result Peptide reactivity input.
KeratinoSens result Keratinocyte reporter input.
Human cell line activation test result Dendritic-cell-surrogate activation input, curated in this entry as its own experimental model, which records CD86 and CD54 as the measured quantity.
U-SENS result A second dendritic-cell-surrogate activation input, measured in the U937 line.
Sensitiser potency metric The model's inferred human-relevant potency estimate, carrying explicit quantification of uncertainty. Neither source states the unit, so none is recorded here.
Margin of exposure The ratio of the potency estimate to the consumer exposure level, which is the quantity regressed against the clinical benchmark classifications.		{ratio}
Probability that an exposure is low risk The risk metric the model reports for a given consumer exposure. Deriving it by regression against benchmark risk classifications is what lets the model avoid applying safety assessment factors to a non-animal point of departure.		{probability}

Notes

Carries no mechanism link, because what it predicts is the sensitization outcome and this entry has no adverse-outcome node to attach that to; see the no_node_for_integrated_outcome_prediction discussion. The potency metric is inferred statistically rather than measured, and the model is anchored on human patch test and local lymph node assay reference data, so it inherits those reference sets' domains. Whether the safety assessment factors used with animal data suit a non-animal point of departure is unresolved.

Show evidence (4 references)

PMID:35311660 SUPPORT DIRECT Computational

"The SARA model utilises a Bayesian statistical approach to infer a human-relevant metric of sensitiser potency and a measure of risk associated with a given consumer exposure based upon any combination of human repeat insult patch test, local lymph node, direct peptide reactivity assay,..."

States the inputs and the inferred quantity: the model's output is a statement about the human outcome, not a measurement of any single mechanism step in this entry.

PMID:35835397 SUPPORT DIRECT BACKGROUND Computational

"Our skin allergy risk assessment model Defined Approach uses Bayesian statistics to infer a human-relevant metric of sensitiser potency with explicit quantification of uncertainty, using any combination of human repeat insult patch test, local lymph node assay, direct peptide reactivity assay,..."

Enumerates the six input types the model accepts and states that it takes any combination of them, which is what the input variables above record. Graded BACKGROUND because the model and its input set were established in the authors' earlier work and this paper restates them before extending the approach.

PMID:35835397 SUPPORT DIRECT PRIMARY RESULT Computational

"Margins-of-exposure (potency estimate to consumer exposure level ratio) are regressed against the benchmark risk classifications, enabling derivation of a risk metric defined as the probability that an exposure is low risk."

Names the model's two reported output quantities and defines each one: the margin of exposure as a ratio, and the risk metric as a probability. This is the quantity the entry previously described only as a measure of risk.

+ 1 more reference

Decision-tree defined approach with Derek Nexus and a k-nearest-neighbours potency model MACHINE_LEARNING

A defined approach that applies exclusion criteria to prioritise in chemico and in vitro sources covering key events 1 to 3, combines them in a two out of three hazard call, and assigns a potency category using a k-nearest-neighbours model built on human and local lymph node assay data.

PMID:30439387

Notes

Carries no mechanism link for the same reason as the SARA model: it integrates the per-key-event assay readouts into a hazard and potency prediction for the outcome, and this entry has no adverse-outcome node. Its inputs cover key events 1 to 3, so no single node corresponds to it either. Hazard accuracy is about 85 to 86 percent against local lymph node assay and human reference data, but the correct potency category is reached for only 59 to 68 percent of chemicals. The structural component rests on chemical structure and statistical association rather than on the molecular processes of sensitization.

Show evidence (3 references)

PMID:30439387 SUPPORT DIRECT Computational

"The DA correctly identified the hazard (sensitiser/non-sensitiser) for 85% and 86% of a dataset with reference LLNA and human data."

Gives the hazard performance against both reference sets, which bounds what the integrated prediction supports.

PMID:42797696 SUPPORT INDIRECT Computational

"Although NAMs have achieved substantial regulatory maturity for this endpoint, most computational approaches-including structural alerts, read-across, and quantitative structure-activity relationship models-rely predominantly on chemical structure and statistical associations, with limited..."

States the general limitation this entry's own notes already record for this defined approach's structural component: a structural-alerts and statistical-association method represents chemical structure rather than the molecular processes of sensitization, which this review treats as a property of the whole class of such methods rather than of this one defined approach specifically.

PMID:42797696 SUPPORT INDIRECT Computational

"Rather than replacing established experimental NAMs or DAs, the proposed workflow is intended as a complementary, tiered evidence layer for the early prioritization of structurally characterized cosmetic ingredients and for guiding subsequent experimental testing."

Supports reading a structural-alert and read-across method, such as the Derek Nexus component of this defined approach, as a complementary prioritization tier rather than a replacement for the assay-based key event methods this entry curates.

Skin Sensitization Prediction Model (SSPM)

An algorithm that compares a proposed cosmetic or personal-care formulation against a database of more than 20 years of human repeat insult patch test (HRIPT) results on 1274 product formulations and 1226 common ingredients, tested on 203,640 human subjects, to set per-ingredient and per-formulation risk thresholds from dosage density, occlusion potential, skin-barrier-impairment potential, and potential effects on immune-primed skin.

PMID:40953631

Notes

Carries no mechanism link for the same reason as the SARA model: it predicts a formulation-level sensitization risk call rather than measuring any single mechanism step, and this entry has no adverse-outcome node to attach that to; see the no_node_for_integrated_outcome_prediction discussion. It is a rule-based risk-threshold calculator over historical human test data rather than a trained statistical or machine-learning model, so no ComputationalModelTypeEnum value is a good fit and model_type is left unset. Its reference data is a separate, proprietary HRIPT database rather than the published HPPT database (PMID:37615678, in this entry's references catalog) that the other assay-validation records cite.

Show evidence (2 references)

PMID:40953631 SUPPORT DIRECT Human clinical

"The novel Skin Sensitization Prediction Model (SSPM) is a methodology that draws upon a database consisting of more than 20 years of historical HRIPT data pertaining to 1274 unique product formulations, comprising 1226 common ingredients, for which HRIPT testing has been performed on 203,640..."

States the scale and composition of the reference database this algorithm is built on.

PMID:40953631 SUPPORT Human clinical

"The SSPM sets modifiable thresholds for each individual ingredient of a proposed formulation and for the formulation as a whole, applying risk calculations based on dosage density, potential for skin occlusion, potential for skin barrier impairment, and potential effects on immune-primed skin."

States the risk factors the algorithm calculates over, which is what distinguishes it from a single-assay prediction and from a trained classifier.

Skin Allergy Risk Assessment - Integrated Chemical Environment (SARA-ICE) MACHINE_LEARNING

A Bayesian framework for quantitative skin sensitization hazard and potency assessment, developed by NICEATM and Unilever, that estimates the ED01: the dermal dose associated with a 1 percent sensitization probability in humans. It integrates in chemico and in vitro assay results and can also take historical human and murine data. Two implementations share the one model. SARA-ICE DA is a fixed defined approach accepted into OECD Guideline 497 for deriving a point of departure and usable under Mutual Acceptance of Data; it reports the point of departure as the geometric mean of the ED01 distribution. SARA-ICE Extended returns the full ED01 distribution, a prediction uncertainty ratio, and probabilities for the GHS subcategories.

PMID:41816003

Variable	Model ID	Unit	Ontology Mappings	Phenotype Thresholds
Direct peptide reactivity assay result Peptide reactivity input. The curated SARA-ICE training database holds 650 direct peptide reactivity assay results.
Kinetic direct peptide reactivity assay result Rate-based peptide reactivity input, and the one input class the earlier SARA model did not take. The training database holds 361 results.
KeratinoSens result Keratinocyte reporter input. The training database holds 972 results, the largest of the non-animal input sets.
Human cell line activation test result Dendritic-cell-surrogate activation input, curated in this entry as its own experimental model. The training database holds 431 results.
U937 cell line activation test result A second dendritic-cell-surrogate activation input, measured in the U937 line. The training database holds 164 results, the smallest input set.
Human predictive patch test result Human in vivo reference input, comprising human maximization test and human repeat-insult patch test data. The training database holds 871 results, 506 maximization and 365 repeat-insult.
Local lymph node assay result Murine in vivo reference input, curated in this entry as its own animal model. The training database holds 536 results.
ED01 The model's estimated quantity: the dermal dose associated with a 1 percent sensitization probability in a theoretical human predictive patch test population. Reported as a distribution whose variance measures the uncertainty in the estimate, summarised as the interval between the 5th and 95th percentiles.		ug/cm2
SARA-ICE DA point of departure The point of departure the fixed defined approach reports, calculated as the geometric mean of the ED01 distribution on the assumption that the chemical is a sensitizer. The distribution is bounded above at 60000 ug/cm2, the GHS Category 1 boundary.		ug/cm2
SARA-ICE prediction uncertainty ratio The Extended implementation's summary measure of estimate uncertainty, the ratio between the 5th and 50th percentiles of the ED01 distribution.		{ratio}
GHS subcategory probability The Extended implementation's probability of assignment to GHS Subcategory 1A, Subcategory 1B, or Not Categorized, taken as the probability mass either side of the 500 and 60000 ug/cm2 thresholds.		{probability}

Notes

Carries no mechanism link for the same reason as the SARA model above: it predicts the sensitization outcome from inputs spanning several key events, and this entry has no adverse-outcome node to attach that to; see the no_node_for_integrated_outcome_prediction discussion. A separate record from the SARA model rather than a re-curation of it, because SARA-ICE was built on the Unilever SARA model with an expanded training set drawn from the NICEATM Integrated Chemical Environment database and a curated human predictive patch test set, names the ED01 as its output quantity, and takes kinetic direct peptide reactivity assay results, which SARA does not. The two implementations are recorded as one model because the source presents them as two implementations of one Bayesian framework, differing in output and in whether a user can change them: the defined approach is fixed and cannot be altered outside a guideline update, while Extended is versioned and may gain input types. The human input is the same quantity the SARA record calls human repeat insult patch test; the later paper uses the umbrella term human predictive patch test for the maximization and repeat-insult tests together. The defined approach requires at least two key event inputs to be acceptable under Mutual Acceptance of Data. Two limits on what the evaluation supports. Specificity for non-sensitizers was lower than sensitivity, so the model is more reliable at identifying a sensitizer than at clearing a non-sensitizer; and GHS subcategorization accuracy of 33 to 77 percent means the potency category is considerably weaker than the hazard call, as it is for the defined approach recorded above. The input enumeration and every per-assay count in this record come from the source's Methods section 2.1.1, which describes a database of 434 distinct chemicals and nearly 5000 data points; that section is not in the cached abstract, so no snippet here covers those figures. Two further statements in this record are beyond the cached abstract in the same way, and no snippet covers them either: the abstract records acceptance by the OECD and use under Mutual Acceptance of Data without naming Guideline 497, which the source identifies in its introduction, and the defined approach's two-key-event input requirement, which is in Methods section 2.1.2. The 180 substances in the evidence below are the evaluation set, tested in the direct peptide reactivity assay, KeratinoSens and the human cell line activation test only, and are not the training database. What this source does not give is each input's measured endpoint and unit as the model consumes it: it states the assay names and defers the model's internals to Reinke et al. 2025 and Reynolds et al. 2019 and 2022. The endpoints are therefore recorded here only where this entry already curates the assay as its own model.

Show evidence (6 references)

PMID:41816003 SUPPORT DIRECT BACKGROUND Computational

"The Skin Allergy Risk Assessment - Integrated Chemical Environment (SARA-ICE) is a Bayesian framework for quantitative skin sensitization hazard and potency assessment and estimates an ED01, the dermal dose associated with a 1% sensitization probability in humans."

Defines the model's output quantity, which is the ED01 variable recorded above: a dose at a stated sensitization probability, not a hazard call. Graded BACKGROUND because the model was published separately and this evaluation paper restates what it estimates.

PMID:41816003 SUPPORT DIRECT BACKGROUND Computational

"SARA-ICE has two implementations: (i) SARA-ICE DA, a fixed defined approach (DA) for point-of-departure derivation (PoD), accepted by the Organisation for Economic Co-operation and Development and usable under Mutual Acceptance of Data"

Establishes that the two implementations belong to one model, which is why they are curated as a single record, and gives the defined approach its regulatory standing. Graded BACKGROUND because acceptance into Guideline 497 is prior fact this paper restates.

PMID:41816003 SUPPORT DIRECT BACKGROUND Computational

"SARA-ICE Extended, which returns ED01 distributions, a prediction uncertainty ratio, and probabilities for assignments to Globally Harmonized System of Classification and Labeling of Chemicals (GHS) categories."

Names the three quantities the Extended implementation reports, which are the remaining output variables recorded above and the reason the two implementations are distinguishable within one record.

+ 3 more references

{ }

Source YAML

click to show

name: Contact Dermatitis
creation_date: '2026-03-13T18:40:33Z'
category: Complex
description: >-
  Contact dermatitis is an exogenous inflammatory eczema triggered by direct
  skin exposure to irritants or sensitizing allergens. The umbrella disorder
  includes irritant contact dermatitis, driven by barrier injury and innate
  inflammation, and allergic contact dermatitis, driven by hapten-specific type
  IV T-cell immunity after sensitization.
definitions:
- name: Clinical syndrome definition for contact dermatitis
  definition_type: CASE_DEFINITION
  description: >-
    Contact dermatitis is an exogenous eczematous inflammatory disorder caused
    by direct skin contact with an external substance, most commonly expressed
    as irritant contact dermatitis or allergic contact dermatitis at sites of
    exposure.
  scope: General clinical framing of contact dermatitis in dermatology and occupational medicine
  evidence:
  - reference: PMID:25102574
    reference_title: "Identifying the causes of contact dermatitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Contact dermatitis results from skin contact with an exogenous substance."
    explanation: This supports the core disease definition as dermatitis caused by external cutaneous exposure.
  - reference: PMID:25102574
    reference_title: "Identifying the causes of contact dermatitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The two most common variants are irritant contact dermatitis (ICD) and allergic contact dermatitis (ACD)."
    explanation: This supports the umbrella disease definition encompassing irritant and allergic forms as the principal variants.
- name: Practical diagnostic definition for suspected allergic contact dermatitis
  definition_type: DIAGNOSTIC_CRITERIA
  description: >-
    In routine practice, suspected allergic contact dermatitis is defined by a
    compatible exposure-linked dermatitis pattern evaluated through focused
    history and physical examination, with patch testing used to confirm
    relevant sensitization and distinguish allergic from irritant disease.
  scope: Clinical diagnosis of recurrent, persistent, or exposure-pattern dermatitis suspicious for allergic contact dermatitis
  evidence:
  - reference: PMID:31757238
    reference_title: "Allergic Contact Dermatitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Diagnosis is based on a thorough history, physical examination, and patch testing."
    explanation: This supports the practical diagnostic framework of history, examination, and patch testing.
  - reference: PMID:25102574
    reference_title: "Identifying the causes of contact dermatitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "If ACD is suspected the patient should be referred to secondary care for patch testing."
    explanation: This supports patch testing as the confirmatory step when allergic contact dermatitis is suspected clinically.
synonyms:
- contact dermatitis/eczema
- dermatitis venenata
- contact eczema
disease_term:
  preferred_term: contact dermatitis
  term:
    id: MONDO:0005480
    label: contact dermatitis
mappings:
  icd10cm_mappings:
  - term:
      id: ICD10CM:L23
      label: Allergic contact dermatitis
    mapping_predicate: skos:closeMatch
    mapping_source: ICD-10-CM
    mapping_justification: Contact dermatitis includes allergic contact dermatitis as a major clinical subtype.
  - term:
      id: ICD10CM:L24
      label: Irritant contact dermatitis
    mapping_predicate: skos:closeMatch
    mapping_source: ICD-10-CM
    mapping_justification: Contact dermatitis includes irritant contact dermatitis as a major clinical subtype.
  mondo_mappings:
  - term:
      id: MONDO:0005480
      label: contact dermatitis
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: Primary MONDO disease identifier for this contact dermatitis entry.
classifications:
  harrisons_chapter:
  - classification_value: DERMATOLOGY
parents:
- Dermatological Disease
- Inflammatory Disease
has_subtypes:
- name: Allergic Contact Dermatitis
  description: Delayed type IV hypersensitivity dermatitis caused by prior sensitization to a contact allergen.
  evidence:
  - reference: PMID:25102574
    reference_title: "Identifying the causes of contact dermatitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Classical ACD is mediated by type 4 cell-mediated immunity."
    explanation: This review explicitly defines allergic contact dermatitis as a type IV cell-mediated immune process.
  - reference: PMID:19839974
    reference_title: "Effector and regulatory mechanisms in allergic contact dermatitis."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Allergic contact dermatitis (ACD), one of the commonest occupational diseases, is a T-cell-mediated skin inflammation caused by repeated skin exposure to contact allergens, i.e. nonprotein chemicals called haptens."
    explanation: This supports allergic contact dermatitis as a hapten-driven T-cell-mediated subtype of contact dermatitis.
- name: Irritant Contact Dermatitis
  description: Non-sensitization-dependent dermatitis caused by direct toxic or barrier-disrupting effects of an exposure.
  evidence:
  - reference: PMID:25274939
    reference_title: "Irritant contact dermatitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Irritant contact dermatitis (ICD) is the most common form of contact dermatitis."
    explanation: This supports irritant contact dermatitis as a principal subtype within the broader contact dermatitis category.
  - reference: PMID:25102574
    reference_title: "Identifying the causes of contact dermatitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ICD is a form of eczema and is induced by direct inflammatory pathways without prior sensitisation."
    explanation: This supports the non-sensitization-dependent inflammatory mechanism of irritant contact dermatitis.
pathophysiology:
- name: Irritant exposure and toxic insult
  description: >-
    In irritant contact dermatitis, direct exposure to chemical or physical
    irritants causes the initiating toxic cutaneous insult.
  downstream:
  - target: Epidermal barrier disruption
    description: Toxic or physical irritants injure the epidermis and precipitate barrier failure.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:25274939
      reference_title: "Irritant contact dermatitis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The pathophysiological mechanism depends on activation of the innate immune system and involves skin barrier disruption"
      explanation: This supports a direct transition from irritant exposure to epidermal barrier injury in irritant contact dermatitis.
  evidence:
  - reference: PMID:25274939
    reference_title: "Irritant contact dermatitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It represents the cutaneous response to the toxic/physical effects of a wide variety of environmental agents."
    explanation: This supports direct toxic or physical exposure as the initiating event in irritant contact dermatitis.
- name: Epidermal barrier disruption
  description: >-
    Irritant injury disrupts epidermal barrier integrity and creates the tissue
    context for downstream inflammatory activation.
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  downstream:
  - target: Keratinocyte activation and proinflammatory mediator release
    description: Barrier failure activates keratinocytes and promotes local proinflammatory signaling.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:25274939
      reference_title: "Irritant contact dermatitis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "involves skin barrier disruption, cellular changes"
      explanation: This supports barrier disruption as the immediate precursor to keratinocyte and mediator activation.
  evidence:
  - reference: PMID:25274939
    reference_title: "Irritant contact dermatitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "involves skin barrier disruption"
    explanation: This identifies barrier disruption as a distinct mechanistic step in irritant contact dermatitis.
- name: Keratinocyte activation and proinflammatory mediator release
  biological_scale: CELLULAR
  description: >-
    Barrier-injured keratinocytes enter an activated inflammatory state and
    release mediators that propagate local cutaneous inflammation.
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  biological_processes:
  - preferred_term: keratinocyte activation
    term:
      id: GO:0032980
      label: keratinocyte activation
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
  downstream:
  - target: Inflammatory cell recruitment
    description: Keratinocyte-derived inflammatory mediators recruit and activate additional inflammatory cells in skin.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:25274939
      reference_title: "Irritant contact dermatitis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "release of proinflammatory mediators that directly recruit and activate T lymphocytes."
      explanation: This supports mediator-driven recruitment of inflammatory cells as the next step after keratinocyte activation.
  evidence:
  - reference: PMID:25274939
    reference_title: "Irritant contact dermatitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "involves skin barrier disruption, cellular changes, and release of proinflammatory mediators."
    explanation: This supports proinflammatory mediator release as a distinct ICD mechanism.
  - reference: DOI:10.1155/2013/916497
    reference_title: "Cytokines and Chemokines in Irritant Contact Dermatitis"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Irritant contact dermatitis is a result of activated innate immune response to various external stimuli and consists of complex interplay which involves skin barrier disruption, cellular changes, and release of proinflammatory mediators."
    explanation: This corroborates activated innate immune signaling and mediator release as central mechanisms in irritant contact dermatitis.
- name: Inflammatory cell recruitment
  description: >-
    Irritant-induced mediators recruit and activate inflammatory cells in skin
    after barrier injury, including T lymphocytes. Previously named "Innate
    inflammatory cell recruitment"; the "innate" qualifier was dropped because
    the supporting evidence describes recruitment and activation of T
    lymphocytes, which are adaptive effectors.
  cell_types:
  - preferred_term: dendritic cell
    term:
      id: CL:0000451
      label: dendritic cell
  biological_processes:
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
  downstream:
  - target: Contact dermatitis
    description: Inflammatory cell recruitment culminates in the clinically visible dermatitis lesion.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:9590995
      reference_title: "Irritant contact dermatitis. Clues to causes, clinical characteristics, and control."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Clinical signs include vesicles, papules, bullae, erythema, edema, scaling, and lichenification."
      explanation: This supports progression from inflammatory recruitment to clinically evident contact dermatitis.
  evidence:
  - reference: PMID:25274939
    reference_title: "Irritant contact dermatitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "release of proinflammatory mediators that directly recruit and activate T lymphocytes."
    explanation: This supports recruitment and activation of inflammatory cells as a separate downstream ICD mechanism.
- name: Hapten exposure
  description: >-
    In allergic contact dermatitis, repeated skin contact with small reactive
    chemicals exposes the immune system to haptens and initiates sensitization.
  downstream:
  - target: Covalent hapten-protein adduct formation
    description: >-
      Contact with a reactive small chemical leads directly to covalent
      modification of skin protein, the chemical reaction that converts an
      exposure into an immunologically visible antigen.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20631061
      reference_title: "Tracking human contact allergens: from mass spectrometric identification of peptide-bound reactive small chemicals to chemical-specific naive human T-cell priming."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: IN_VITRO
      snippet: "Mass spectrometric detection and quantification revealed thiol-dependent peptide adduct formation at all pH values found in human skin layers."
      explanation: >-
        Shows that a strong human contact sensitizer forms protein adducts under
        the pH conditions of human skin, which is the step hapten exposure leads
        into.
  - target: Abiotic pre-hapten autoxidation to a reactive electrophile
    description: >-
      A chemical that is not itself protein-reactive can be converted to a
      reactive electrophile by nonenzymatic oxidation occurring independently
      of the skin.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:21742781
      reference_title: "Cross talk between keratinocytes and dendritic cells: impact on the prediction of sensitization."
      supports: SUPPORT
      directness: DIRECT
      quote_role: BACKGROUND
      evidence_source: IN_VITRO
      snippet: >-
        Many potential sensitizers are not directly immunogenic but require
        activation outside or inside the skin by nonenzymatic oxidation
        (prehaptens) or metabolic transformation (prohaptens) prior to being
        able to induce an immune response.
      explanation: >-
        States that this subset of hapten exposures requires an activation step
        before it can enter the sensitization pathway; the prehapten half of
        this framing sentence is what the downstream node represents.
  - target: Keratinocyte pro-hapten bioactivation to a reactive electrophile
    description: >-
      A chemical that is not itself protein-reactive can instead require
      enzymatic metabolism by skin keratinocytes to become a reactive
      electrophile.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:21742781
      reference_title: "Cross talk between keratinocytes and dendritic cells: impact on the prediction of sensitization."
      supports: SUPPORT
      directness: DIRECT
      quote_role: BACKGROUND
      evidence_source: IN_VITRO
      snippet: >-
        Many potential sensitizers are not directly immunogenic but require
        activation outside or inside the skin by nonenzymatic oxidation
        (prehaptens) or metabolic transformation (prohaptens) prior to being
        able to induce an immune response.
      explanation: >-
        States that this subset of hapten exposures requires an activation step
        before it can enter the sensitization pathway; the prohapten half of
        this framing sentence is what the downstream node represents.
  evidence:
  - reference: PMID:19839974
    reference_title: "Effector and regulatory mechanisms in allergic contact dermatitis."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Allergic contact dermatitis (ACD), one of the commonest occupational diseases, is a T-cell-mediated skin inflammation caused by repeated skin exposure to contact allergens, i.e. nonprotein chemicals called haptens."
    explanation: This supports hapten exposure as the initiating event in allergic contact dermatitis.
- name: Abiotic pre-hapten autoxidation to a reactive electrophile
  biological_scale: MOLECULAR
  description: >-
    A pre-hapten is a contact allergen that is not itself protein-reactive but
    is converted to a reactive electrophile by abiotic, nonenzymatic oxidation
    that can occur independently of the skin (on air exposure, for example).
    This route sits upstream of the covalent-binding step rather than around
    it, so the protein-reactive species a sensitized person actually generates
    can differ from the parent chemical applied to the skin.
  notes: >-
    Left without a biological_processes binding. OLS searches of GO for
    "autoxidation", "nonenzymatic oxidation", "chemical oxidation" and
    "abiotic oxidation" (via `runoak -i ols:go search`) all return nothing.
    Abiotic, nonenzymatic oxidation outside the organism is not a GO
    biological process to begin with, so no term fits this route the way
    GO:0006805 fits the enzymatic pro-hapten route at the sibling node.
  downstream:
  - target: Covalent hapten-protein adduct formation
    description: >-
      The abiotically oxidized pre-hapten species goes on to form the covalent
      hapten-protein adduct.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:23510343
      reference_title: Finding the optimal patch test material and test concentration to detect contact allergy to geraniol.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "oxidized geraniol detected positive reactions in 0.92-4.6% of the patients"
      explanation: >-
        Shows the air-oxidized (pre-hapten-activated) form of a named contact
        allergen detecting more positive patch-test reactions than the
        unoxidized parent chemical, consistent with autoxidation generating the
        protein-reactive species that goes on to form the adduct. The patch
        test reads a positive allergic reaction rather than the adduct itself,
        so the adduct step is inferred rather than measured here.
  evidence:
  - reference: PMID:21742781
    reference_title: "Cross talk between keratinocytes and dendritic cells: impact on the prediction of sensitization."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: >-
      In agreement with the hapten concept, responses to
      2,4-dinitrochlorobenzene, Bandrowski's base, and the prehapten isoeugenol
      were not significantly modified.
    explanation: >-
      Shows the contrast case: a direct hapten and a prehapten are unaffected by
      keratinocyte coculture, consistent with prehapten activation occurring
      abiotically rather than depending on keratinocyte metabolism -- unlike
      the sibling pro-hapten node, where coculture raises the response.
  - reference: PMID:23510343
    reference_title: Finding the optimal patch test material and test concentration to detect contact allergy to geraniol.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Geraniol is a pro-hapten and a pre-hapten, and sensitizers are formed in the autoxidation and skin metabolism of geraniol."
    explanation: >-
      Names a specific, clinically relevant contact allergen for which the
      abiotic (pre-hapten) autoxidation route this node describes has been
      documented; the same sentence's skin-metabolism half supports the
      sibling pro-hapten node.
- name: Keratinocyte pro-hapten bioactivation to a reactive electrophile
  biological_scale: MOLECULAR
  description: >-
    A pro-hapten is a contact allergen that is not itself protein-reactive but
    requires enzymatic metabolism in skin, chiefly by cytochrome P450 and
    NAD(P)H:quinone oxidoreductase 1 (NQO1) in keratinocytes, to become a
    reactive electrophile. This route sits upstream of the covalent-binding
    step rather than around it, so the protein-reactive species a sensitized
    person actually generates can differ from the parent chemical applied to
    the skin.
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  biological_processes:
  - preferred_term: xenobiotic metabolic process
    term:
      id: GO:0006805
      label: xenobiotic metabolic process
  downstream:
  - target: Covalent hapten-protein adduct formation
    description: >-
      The enzymatically activated pro-hapten species goes on to form the
      covalent hapten-protein adduct.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:21742781
      reference_title: "Cross talk between keratinocytes and dendritic cells: impact on the prediction of sensitization."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: IN_VITRO
      snippet: >-
        Inhibition of cytochrome P450 or NAD(P)H:quinone oxidoreductase (NQO1)
        activity reduced the prohapten-mediated upregulation of CD86 on
        cocultured THP-1 cells.
      explanation: >-
        Shows that blocking keratinocyte CYP450/NQO1 metabolism blocks the
        downstream dendritic-cell-surrogate activation that a pro-hapten
        otherwise drives, placing this metabolic step causally upstream of the
        response the adduct is understood to trigger. The readout is CD86 on a
        cocultured cell line rather than the adduct itself, so the adduct step
        is inferred rather than measured here.
  evidence:
  - reference: PMID:21742781
    reference_title: "Cross talk between keratinocytes and dendritic cells: impact on the prediction of sensitization."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: >-
      Under coculture conditions, the prohaptens eugenol, 2-methoxy-4-methylphenol,
      and benzo ... pyrene induced a significantly higher upregulation of CD86
      expression on THP-1.
    explanation: >-
      Demonstrates that keratinocyte coculture, which supplies the metabolic
      activation keratinocytes provide, is required for these named chemicals to
      raise a dendritic-cell-surrogate activation marker, supporting enzymatic
      bioactivation as the operative mechanism for the pro-hapten class --
      unlike the sibling pre-hapten node, where coculture makes no difference.
  - reference: PMID:23510343
    reference_title: Finding the optimal patch test material and test concentration to detect contact allergy to geraniol.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Reactions to pure geraniol in patients not reacting to oxidized geraniol indicated metabolic activation of geraniol."
    explanation: >-
      Shows a subset of patients reacting only to the unoxidized parent
      chemical, which the authors attribute to skin metabolism generating the
      reactive species directly from pure geraniol -- the pro-hapten route this
      node describes, distinct from the sibling node's abiotic oxidation route.
- name: Covalent hapten-protein adduct formation
  biological_scale: MOLECULAR
  description: >-
    A reactive small chemical forms a covalent bond with a skin protein,
    generating the hapten-protein adduct that downstream innate and adaptive
    responses recognize. This is the molecular initiating event of skin
    sensitization and is rate-limiting for sensitizer potency. The step itself is
    well established, but its molecular target in skin is not: the available
    evidence is in chemico and in vitro, using synthetic peptides, albumin in
    solution and cultured human cells, and the assays of this field measure bulk
    cysteine-peptide depletion as a surrogate. Which specific epidermal protein
    has to be modified for the downstream steps to follow remains unresolved.
  notes: >-
    Left without a biological_processes or chemical_entities binding. GO has no
    term for non-enzymatic covalent modification of protein by a xenobiotic
    electrophile: OLS searches of GO for "protein adduct", "haptenation",
    "protein arylation" and "covalent modification" return nothing relevant, and
    the one near candidate, GO:0008213 protein alkylation, is defined as "the
    addition of an alkyl group to a protein amino acid", which does not cover
    the arylating SNAr electrophiles (DNCB, DNBS) that the cited evidence uses.
    CHEBI:59174 hapten is the right concept for the reactive chemical, but CHEBI
    files it as a role rather than under CHEBI:24431 chemical entity, so it is
    outside the ChemicalEntityTerm enum and not bindable here; the hapten
    identity is carried by the upstream Hapten exposure node instead.
  downstream:
  - target: Hapten-driven keratinocyte electrophile sensing
    description: >-
      The adduct-forming electrophile is sensed by keratinocytes through the
      Keap1-Nrf2-ARE pathway. This is AOP 40 KER 833, Key Event 396 to Key
      Event 826, read as its electrophile-sensing arm.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:24794257
      reference_title: "Performance of the N/TERT epidermal model for skin sensitizer identification via Nrf2-Keap1-ARE pathway activation."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: IN_VITRO
      snippet: >-
        Results show that the Keap1-Nrf2-ARE pathway is activated by the
        sensitizer DNCB in monolayer keratinocytes and as well as the LEMs and
        NEMs and not by the irritant SDS.
      explanation: >-
        The keratinocyte response follows exposure to an arylating sensitizer and
        not to a membrane-damaging irritant, which is what places it downstream
        of this node's adduct-forming chemistry rather than downstream of barrier
        injury. The experiment doses the parent chemical and reads pathway
        activation, so adduct formation is the inference and not the measurement,
        and the intervening Keap1 cysteine modification is omitted from the graph.
  - target: Keratinocyte inflammasome danger signalling
    description: >-
      The hapten is read as a danger signal by the keratinocyte inflammasome.
      This is the second arm of AOP 40 KER 833, Key Event 396 to Key Event 826.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:17429439
      reference_title: "Activation of the IL-1beta-processing inflammasome is involved in contact hypersensitivity."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: IN_VITRO
      snippet: >-
        We show here that key components of the inflammasome are present in human
        keratinocytes and that CS like trinitro-chlorobenzene induce
        caspase-1/ASC dependent IL-1beta and IL-18 processing and secretion.
      explanation: >-
        Gives the causal direction this edge asserts, from contact sensitizer to
        keratinocyte inflammasome output. As with the sensing arm, the sensitizer
        is applied as the parent chemical, so the adduct step this node
        represents is inferred from the chemistry rather than measured.
  - target: Skin innate immune activation during sensitization
    description: Hapten-modified skin protein activates innate cutaneous immune pathways during the sensitization phase.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:19839974
      reference_title: "Effector and regulatory mechanisms in allergic contact dermatitis."
      supports: SUPPORT
      quote_role: REVIEW_SYNTHESIS
      evidence_source: HUMAN_CLINICAL
      snippet: "Recent advances in the pathophysiology of ACD have demonstrated the important role of skin innate immunity in the sensitization process"
      explanation: This supports hapten-modified skin protein feeding into innate skin immune activation during sensitization.
    - reference: PMID:20631061
      reference_title: "Tracking human contact allergens: from mass spectrometric identification of peptide-bound reactive small chemicals to chemical-specific naive human T-cell priming."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: IN_VITRO
      snippet: "Moreover, DNP-modified HSA protein effectively induced primary T-cell responses when processed by iDC."
      explanation: >-
        Shows that it is the adduct, once taken up and processed by human
        dendritic cells, that drives the immune response, which is the causal
        step out of this node.
  evidence:
  - reference: PMID:20631061
    reference_title: "Tracking human contact allergens: from mass spectrometric identification of peptide-bound reactive small chemicals to chemical-specific naive human T-cell priming."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: "Modification of proteins by reactive small chemicals is a key step in the activation of chemical-specific T cells in allergic contact dermatitis (ACD)."
    explanation: >-
      States the step this node represents, and places it within allergic
      contact dermatitis specifically.
  - reference: PMID:32840629
    reference_title: "Predictivity of the kinetic direct peptide reactivity assay (kDPRA) for sensitizer potency assessment and GHS subclassification."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: >-
      The reaction of sensitizing molecules with skin proteins is the molecular
      initiating event and appears to be rate-limiting, as chemical reactivity
      strongly correlates with sensitizer potency.
    explanation: >-
      Supports treating this reaction as the molecular initiating event of the
      pathway and as the rate-limiting step for potency.
  - reference: PMID:28882705
    reference_title: "Prediction of skin sensitization potency sub-categories using peptide reactivity data."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: "since the protein-adduct formation is determining the dose of the allergen in the skin, peptide reactivity was used to assess the potency"
    explanation: >-
      Supports the framing of this node as the step that sets the effective dose
      of allergen in skin.
  - reference: PMID:28882705
    reference_title: "Prediction of skin sensitization potency sub-categories using peptide reactivity data."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: "The analysis of the Cys-adducts was already sufficient; additional analysis of Lys-adducts did not improve the predictivity."
    explanation: >-
      Supports cysteine as the preferred nucleophile for this reaction, since
      adding lysine adducts does not improve prediction of potency.
  - reference: PMID:24397518
    reference_title: "Electrophilic reactivity and skin sensitization potency of SNAr electrophiles."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: COMPUTATIONAL
    snippet: "With these two compounds excluded, sensitization potency is well correlated with the experimental rate constants for the DNXB compounds (X = SO3(-), I, Br, Cl) together with 2,4-dichloro-1-nitrobenzene and 1,3,4,5-tetrachloro-2,6-dicyanobenzene. The regression equation is pEC3 = 0.88 log k + 4.03, R(2) = 0.966."
    explanation: >-
      Gives the quantitative form of the potency-reactivity relationship, derived
      by regression over published rate constants and mouse assay potencies
      rather than measured in human skin. The relation holds for the named
      compound set and only once two more reactive outliers (X = F and X = SCN)
      are excluded, so it is evidence that potency tracks reactivity within a
      congeneric series, not a general law.
- name: Hapten-driven keratinocyte electrophile sensing
  biological_scale: CELLULAR
  description: >-
    Keratinocytes read the hapten as an electrophile and mount a Keap1-Nrf2-ARE
    antioxidant-response programme: Nrf2 protein accumulates, translocates to
    the nucleus, and activates its transcriptional targets. This is the
    electrophile-sensing arm of the sensitization-phase keratinocyte step
    corresponding to AOP 40 Key Event 826 (Activation, Keratinocytes), and the
    cause is the chemistry of the hapten rather than barrier injury: the
    response separates a sensitizer from an irritant at non-toxic
    concentrations, which is the biology the OECD TG 442D methods measure. It is
    curated apart from the inflammasome danger-signalling arm of the same Key
    Event, which runs through IL-1 family cytokines and carries its own node,
    because the two are read by different models.
  notes: >-
    Curated as the keratinocyte sensor readout, not as an established driver of
    the steps below it. Nrf2 induction is what the TG 442D tier measures and
    what discriminates sensitizer from irritant, but the cited work doses the
    parent chemical and follows pathway activation; none of it measures the step
    from adduct to Nrf2, or from Nrf2 to innate immune activation. The outbound
    edge is typed and explained accordingly.
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  biological_processes:
  - preferred_term: keratinocyte activation
    term:
      id: GO:0032980
      label: keratinocyte activation
    modifier: INCREASED
  - preferred_term: Keap1-Nrf2-ARE electrophile sensing
    term:
      id: GO:0062197
      label: cellular response to chemical stress
    modifier: INCREASED
  downstream:
  - target: Skin innate immune activation during sensitization
    description: >-
      Keratinocytes responding to the hapten contribute to the innate cutaneous
      response that supports dendritic-cell-mediated priming.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:24794257
      reference_title: "Performance of the N/TERT epidermal model for skin sensitizer identification via Nrf2-Keap1-ARE pathway activation."
      supports: SUPPORT
      directness: INDIRECT
      quote_role: BACKGROUND
      evidence_source: OTHER
      snippet: "In human skin, keratinocytes (KCs) are abundantly present and are key players in initiation of allergic contact dermatitis."
      explanation: >-
        Places the keratinocyte among the initiators of allergic contact
        dermatitis, which is the ground for drawing this edge at all. It is an
        introductory framing of established skin biology rather than a result of
        this study, and it does not identify the intermediates between Nrf2
        pathway activation and innate immune activation, which is why the edge is
        typed with unknown intermediates. Graded OTHER rather than
        HUMAN_CLINICAL because the sentence is a mechanistic generalisation about
        what keratinocytes do in this disease, not a clinical observation or
        measurement in patients: this paper reports no human clinical data, and
        the claim rests on a mixed human and in vitro literature it does not
        cite here, so no single study type stands behind the quoted words.
  evidence:
  - reference: PMID:24794257
    reference_title: "Performance of the N/TERT epidermal model for skin sensitizer identification via Nrf2-Keap1-ARE pathway activation."
    supports: SUPPORT
    directness: DIRECT
    quote_role: BACKGROUND
    evidence_source: IN_VITRO
    snippet: "One of the pathways that has been shown to be induced by sensitizers is the Keap1-Nrf2-ARE pathway."
    explanation: >-
      Names the pathway this node represents and attributes its induction to
      sensitizers. The sentence restates prior in vitro sensitizer work rather
      than reporting this study's own result.
  - reference: PMID:24794257
    reference_title: "Performance of the N/TERT epidermal model for skin sensitizer identification via Nrf2-Keap1-ARE pathway activation."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: >-
      Results show that the Keap1-Nrf2-ARE pathway is activated by the
      sensitizer DNCB in monolayer keratinocytes and as well as the LEMs and
      NEMs and not by the irritant SDS.
    explanation: >-
      Measures the node's own quantity in keratinocytes, across monolayer and
      reconstructed epidermal models, and shows it responding to a sensitizer and
      not to an irritant. That contrast is what makes this a distinct step from
      the irritant arm's keratinocyte node.
- name: Keratinocyte inflammasome danger signalling
  conforms_to: "nlrp3_inflammasome_activation#NLRP3 Inflammasome Assembly and Caspase-1 Activation"
  biological_scale: CELLULAR
  notes: >-
    Conformance anchored on the module's assembly and caspase-1 node, not on its
    Activating Danger Signal node, although this node's own name uses that
    phrase. Activating Danger Signal is the module's Signal 2 and is defined by
    three proximal routes, potassium efflux, lysosomal rupture after
    phagocytosis, and mitochondrial damage with reactive oxygen species; the
    evidence here identifies none of them, so conforming there would assert a
    route this entry cannot support. The assembly node instead asks for an
    assembled, caspase-1-activating NLRP3 complex in the causal chain, and
    states that elevated IL-1beta alone does not satisfy it: PMID:17429439
    supplies ASC-dependent and caspase-1-dependent processing in human
    keratinocytes together with the Nlrp3- and Pycard-deficient mice, which
    meets that bar. Which proximal route a hapten uses is the open lead; if it
    is ever curated it belongs on a new upstream node conforming to Activating
    Danger Signal, not on this one.

    This node also binds GO:0032611 and GO:0032621, which belong to the
    module's next node, IL-1 Family Cytokine Maturation and Gasdermin
    D-Mediated Pyroptosis. It is deliberately not split to match the module
    chain. The cited evidence covers assembly and cytokine output in one
    sentence, so two nodes would carry the same quote with no claim
    distinguishing them, and the step is this entry's reading of AOP 40 Key
    Event 826, which a further split would fragment. No pyroptosis or gasdermin
    D evidence is curated here, so that arm of the module's next node is not
    claimed at all.
  description: >-
    The hapten acts as a danger signal in keratinocytes: the NLRP3 and ASC
    inflammasome assembles and activates caspase-1, which processes pro-IL-1beta
    and pro-IL-18 to their mature forms and releases them. This is the
    danger-signalling arm of the sensitization-phase keratinocyte step
    corresponding to AOP 40 Key Event 826, running in parallel with
    Keap1-Nrf2-ARE electrophile sensing rather than downstream of it, and it
    supplies the proinflammatory cytokines the innate and adaptive steps below
    require. Like the sensing arm it is driven by the hapten and not by barrier
    disruption, which is what separates it from the irritant arm's keratinocyte
    node.
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  biological_processes:
  - preferred_term: keratinocyte activation
    term:
      id: GO:0032980
      label: keratinocyte activation
    modifier: INCREASED
  - preferred_term: NLRP3 inflammasome complex assembly
    term:
      id: GO:0044546
      label: NLRP3 inflammasome complex assembly
    modifier: INCREASED
  - preferred_term: NLRP3 inflammasome-mediated signalling
    term:
      id: GO:0141084
      label: inflammasome-mediated signaling pathway
    modifier: INCREASED
  - preferred_term: caspase-1-dependent IL-1beta maturation and release
    term:
      id: GO:0032611
      label: interleukin-1 beta production
    modifier: INCREASED
  - preferred_term: caspase-1-dependent IL-18 maturation and release
    term:
      id: GO:0032621
      label: interleukin-18 production
    modifier: INCREASED
  downstream:
  - target: Skin innate immune activation during sensitization
    description: >-
      Keratinocyte-derived mature IL-1beta and IL-18 are the danger signals that
      the innate cutaneous response during sensitization runs on.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:17429439
      reference_title: "Activation of the IL-1beta-processing inflammasome is involved in contact hypersensitivity."
      supports: SUPPORT
      directness: DIRECT
      quote_role: BACKGROUND
      evidence_source: OTHER
      snippet: >-
        In this delayed-type hypersensitivity response, efficient priming of the
        adaptive immunity depends on the concomitant activation of the innate
        immune system, including IL-1beta/IL-18 activation in the skin.
      explanation: >-
        States the dependency this edge records, naming the same two cytokines
        this node produces. It is the study's framing of established biology
        rather than its own measurement, so it is graded as background rather
        than as the paper's result. Graded OTHER rather than MODEL_ORGANISM
        because the sentence asserts the dependency for delayed-type
        hypersensitivity in general and names neither a species nor a study
        design; this paper's own mouse work is quoted separately on the
        NALP3- and ASC-deficient model, where MODEL_ORGANISM is the accurate
        grade.
  evidence:
  - reference: PMID:17429439
    reference_title: "Activation of the IL-1beta-processing inflammasome is involved in contact hypersensitivity."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: >-
      We show here that key components of the inflammasome are present in human
      keratinocytes and that CS like trinitro-chlorobenzene induce
      caspase-1/ASC dependent IL-1beta and IL-18 processing and secretion.
    explanation: >-
      Establishes every component of this node in human keratinocytes: the
      inflammasome is present, a contact sensitizer drives it, and the output is
      caspase-1-dependent processing and release of both IL-1 family cytokines.
  - reference: PMID:17632566
    reference_title: "Inflammasome activation in delayed-type hypersensitivity reactions."
    supports: SUPPORT
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: OTHER
    snippet: "The study documents a regulatory effect of innate immunity in a T-cell-mediated delayed-type hypersensitivity reaction."
    explanation: >-
      An accompanying commentary's reading of the keratinocyte inflammasome
      result, placing it as a regulator of innate immunity within a
      T-cell-mediated delayed-type hypersensitivity response, which is where this
      node sits in the sensitization arm. It is an editorial synthesis of the
      companion paper and reports no data of its own.
- name: Skin innate immune activation during sensitization
  biological_scale: TISSUE
  description: >-
    Early innate immune signaling in allergen-exposed skin shapes the
    sensitization phase and supports subsequent adaptive immune priming.
  cell_types:
  - preferred_term: Langerhans cell
    term:
      id: CL:0000453
      label: Langerhans cell
  - preferred_term: dendritic cell
    term:
      id: CL:0000451
      label: dendritic cell
  downstream:
  - target: Allergen-specific T-cell priming
    description: Innate activation in skin supports dendritic-cell-mediated priming of allergen-specific T cells.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:19839974
      reference_title: "Effector and regulatory mechanisms in allergic contact dermatitis."
      supports: SUPPORT
      quote_role: REVIEW_SYNTHESIS
      evidence_source: HUMAN_CLINICAL
      snippet: "Recent advances in the pathophysiology of ACD have demonstrated the important role of skin innate immunity in the sensitization process and have revisited the dogma that Langerhans cells are mandatory for CD8+ T-cell priming."
      explanation: This supports innate skin immune activation as an upstream component of adaptive immune priming in allergic contact dermatitis.
  evidence:
  - reference: PMID:19839974
    reference_title: "Effector and regulatory mechanisms in allergic contact dermatitis."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Recent advances in the pathophysiology of ACD have demonstrated the important role of skin innate immunity in the sensitization process"
    explanation: This supports skin innate immune activation as a distinct mechanistic stage in allergic contact dermatitis sensitization.
- name: Breakdown of regulatory T-cell-mediated hapten tolerance
  biological_scale: CELLULAR
  description: >-
    Allergic contact dermatitis reflects failure of suppressive CD4-positive
    regulatory T-cell programs that normally prevent hapten priming and dampen
    eczema in sensitized individuals.
  cell_types:
  - preferred_term: regulatory T cell
    term:
      id: CL:0000815
      label: regulatory T cell
  downstream:
  - target: Allergen-specific T-cell priming
    description: Loss of regulatory control permits priming to haptens in susceptible individuals.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:19839974
      reference_title: "Effector and regulatory mechanisms in allergic contact dermatitis."
      supports: SUPPORT
      quote_role: REVIEW_SYNTHESIS
      evidence_source: HUMAN_CLINICAL
      snippet: "Subsets of CD4+ T cells endowed with suppressive activity are responsible for both the down-regulation of eczema in allergic patients and the prevention of priming to haptens in nonallergic individuals."
      explanation: This supports a direct role for failed regulatory T-cell suppression in permitting allergen-specific T-cell priming.
  - target: Contact dermatitis
    description: Loss of suppressive T-cell control permits persistence and amplification of eczema in allergic patients.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:19839974
      reference_title: "Effector and regulatory mechanisms in allergic contact dermatitis."
      supports: SUPPORT
      quote_role: REVIEW_SYNTHESIS
      evidence_source: HUMAN_CLINICAL
      snippet: "Therefore, ACD should be considered as a breakdown of the skin immune tolerance to haptens."
      explanation: This supports failed immune tolerance as a causal contributor to allergic contact dermatitis lesions.
  evidence:
  - reference: PMID:19839974
    reference_title: "Effector and regulatory mechanisms in allergic contact dermatitis."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Subsets of CD4+ T cells endowed with suppressive activity are responsible for both the down-regulation of eczema in allergic patients and the prevention of priming to haptens in nonallergic individuals."
    explanation: This review identifies suppressive CD4-positive regulatory T-cell activity as a core counter-regulatory axis in allergic contact dermatitis.
- name: Allergen-specific T-cell priming
  biological_scale: CELLULAR
  description: >-
    During sensitization, antigen-presenting cells prime allergen-specific T
    cells, establishing the adaptive immune memory required for later flares.
  cell_types:
  - preferred_term: Langerhans cell
    term:
      id: CL:0000453
      label: Langerhans cell
  - preferred_term: dendritic cell
    term:
      id: CL:0000451
      label: dendritic cell
  - preferred_term: CD8-positive, alpha-beta T cell
    term:
      id: CL:0000625
      label: CD8-positive, alpha-beta T cell
  biological_processes:
  - preferred_term: dendritic cell antigen processing and presentation
    term:
      id: GO:0002468
      label: dendritic cell antigen processing and presentation
  - preferred_term: T cell activation
    term:
      id: GO:0042110
      label: T cell activation
  downstream:
  - target: Re-exposure-driven effector T-cell recruitment
    description: Sensitized allergen-specific T cells are recruited back to skin after hapten re-exposure.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:19839974
      reference_title: "Effector and regulatory mechanisms in allergic contact dermatitis."
      supports: SUPPORT
      quote_role: REVIEW_SYNTHESIS
      evidence_source: HUMAN_CLINICAL
      snippet: "Allergic contact dermatitis, also referred to as contact hypersensitivity, is mediated by CD8+ T cells, which are primed in lymphoid organs during the sensitization phase and are recruited in the skin upon re-exposure to the hapten."
      explanation: This directly supports progression from sensitization-phase priming to re-exposure-driven effector T-cell recruitment.
  evidence:
  - reference: PMID:19839974
    reference_title: "Effector and regulatory mechanisms in allergic contact dermatitis."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Allergic contact dermatitis, also referred to as contact hypersensitivity, is mediated by CD8+ T cells, which are primed in lymphoid organs during the sensitization phase and are recruited in the skin upon re-exposure to the hapten."
    explanation: This supports sensitization and T-cell priming as a discrete adaptive immune stage in allergic contact dermatitis.
- name: Re-exposure-driven effector T-cell recruitment
  biological_scale: TISSUE
  description: >-
    Upon renewed hapten exposure, primed effector T cells re-enter skin and
    initiate the elicitation phase of allergic contact dermatitis.
  cell_types:
  - preferred_term: CD8-positive effector T cell
    term:
      id: CL:0000625
      label: CD8-positive, alpha-beta T cell
  biological_processes:
  - preferred_term: type IV hypersensitivity
    term:
      id: GO:0001806
      label: type IV hypersensitivity
  downstream:
  - target: Resident memory T-cell flare activation
    description: Re-exposure activates epidermal resident memory T cells and intensifies the flare response.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:37700557
      reference_title: "CD100 boosts the inflammatory response in the challenge phase of allergic contact dermatitis in mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We show that CD8+ TRM cells express CD100 during homeostatic conditions and up-regulate it following re-exposure of allergen-experienced skin to the experimental contact allergen 1-fluoro-2,4-dinitrobenzene (DNFB)."
      explanation: This supports activation of resident memory T cells after allergen re-exposure during the elicitation phase.
  evidence:
  - reference: PMID:19839974
    reference_title: "Effector and regulatory mechanisms in allergic contact dermatitis."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Allergic contact dermatitis, also referred to as contact hypersensitivity, is mediated by CD8+ T cells, which are primed in lymphoid organs during the sensitization phase and are recruited in the skin upon re-exposure to the hapten."
    explanation: This supports effector T-cell recruitment to skin on hapten re-exposure as a separate mechanism node.
- name: Resident memory T-cell flare activation
  description: >-
    Epidermal resident memory CD8-positive T cells are activated in
    allergen-experienced skin and intensify local flare responses.
  cell_types:
  - preferred_term: resident memory CD8-positive T cell
    term:
      id: CL:0000625
      label: CD8-positive, alpha-beta T cell
  downstream:
  - target: Mixed type 1 and type 3 cytokine and chemokine amplification
    description: Activated resident memory T cells drive a broader inflammatory cytokine and chemokine program.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:37700557
      reference_title: "CD100 boosts the inflammatory response in the challenge phase of allergic contact dermatitis in mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We show that loss of CD100 results in a reduced inflammatory response to DNFB with impaired production of IFNγ, IL-17A, CXCL1, CXCL2, CXCL5, and IL-1β and decreased recruitment of neutrophils to the epidermis."
      explanation: This supports resident memory T-cell-dependent amplification of cytokine and chemokine production during allergic flare responses.
  evidence:
  - reference: PMID:37700557
    reference_title: "CD100 boosts the inflammatory response in the challenge phase of allergic contact dermatitis in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "BACKGROUND: Allergic contact dermatitis (ACD) is an inflammatory disease with a complex pathophysiology in which epidermal-resident memory CD8+ T (TRM ) cells play a key role."
    explanation: This supports resident memory CD8-positive T cells as a distinct driver of allergic contact dermatitis flares.
- name: Mixed type 1 and type 3 cytokine and chemokine amplification
  description: >-
    Activated effector and resident memory T cells amplify IFNg-, IL-17A-,
    IL-1beta-, and chemokine-rich inflammatory programs, with predominant type
    1 and type 3 effector responses and lesser type 2 contributions.
  cell_types:
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T cell
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  biological_processes:
  - preferred_term: chemokine production
    term:
      id: GO:0032602
      label: chemokine production
  downstream:
  - target: Fibroblast CXCL9/CXCL10 reinforcement
    description: Type 1 lymphocyte-derived IFNg reprograms dermal fibroblasts into chemokine-producing inflammatory stromal cells.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39213029
      reference_title: "Defining cell type-specific immune responses in a mouse model of allergic contact dermatitis by single-cell transcriptomics."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "IFNγ treatment shifted dermal fibroblasts from collagen-producing to CXCL9/10-producing, which promoted T cell polarization toward the type-1 phenotype through a CXCR3-dependent mechanism."
      explanation: This supports a direct edge from type 1 inflammatory cytokine signaling to fibroblast chemokine reinforcement.
  evidence:
  - reference: PMID:37700557
    reference_title: "CD100 boosts the inflammatory response in the challenge phase of allergic contact dermatitis in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We show that loss of CD100 results in a reduced inflammatory response to DNFB with impaired production of IFNγ, IL-17A, CXCL1, CXCL2, CXCL5, and IL-1β and decreased recruitment of neutrophils to the epidermis."
    explanation: This supports amplification of inflammatory cytokines, chemokines, and neutrophil recruitment as a discrete downstream mechanism in allergic contact dermatitis.
  - reference: DOI:10.1111/all.16642
    reference_title: "Transcriptomic Analysis of Allergic Patch Test Reactions in Non‐Atopic Patients: A Comparative Study Across Multiple Allergens"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All allergens exhibited mixed effector immune responses, mainly type 1 and 3 immunity, and, to a lesser extent, type 2 immunity."
    explanation: This human transcriptomic study supports mixed type 1 and type 3 cytokine programs, with lesser type 2 contributions, during allergic contact dermatitis elicitation.
- name: Fibroblast CXCL9/CXCL10 reinforcement
  description: >-
    Dermal fibroblasts adopt a chemokine-producing inflammatory phenotype that
    reinforces type 1 lymphocyte polarization and sustains cutaneous
    inflammation.
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T cell
  biological_processes:
  - preferred_term: chemokine production
    term:
      id: GO:0032602
      label: chemokine production
  downstream:
  - target: Contact dermatitis
    description: Fibroblast chemokine reinforcement sustains the inflammatory dermatitis lesion in affected skin.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39213029
      reference_title: "Defining cell type-specific immune responses in a mouse model of allergic contact dermatitis by single-cell transcriptomics."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Together, our results define the cell type-specific immune responses in ACD, and recognize an indispensable role of dermal fibroblasts in shaping the development of type-1 skin inflammation through the IFNGR-CXCR3 signaling circuit during ACD pathogenesis."
      explanation: This supports fibroblast chemokine reinforcement as a direct contributor to sustained allergic contact dermatitis lesions.
  evidence:
  - reference: PMID:39213029
    reference_title: "Defining cell type-specific immune responses in a mouse model of allergic contact dermatitis by single-cell transcriptomics."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "IFNγ treatment shifted dermal fibroblasts from collagen-producing to CXCL9/10-producing, which promoted T cell polarization toward the type-1 phenotype through a CXCR3-dependent mechanism."
    explanation: This supports inflammatory fibroblast reprogramming as a distinct amplifying mechanism in allergic contact dermatitis.
- name: Complement-associated sensory neuron activation
  description: >-
    In allergic contact dermatitis, complement-associated neuroimmune signaling
    activates peripheral sensory pathways and contributes to itch generation.
  cell_types:
  - preferred_term: sensory neuron
    term:
      id: CL:0000101
      label: sensory neuron
  downstream:
  - target: Pruritus
    description: Sensory neuron activation contributes to the itching phenotype in allergic contact dermatitis.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:34417985
      reference_title: "Proteome Profile of Trigeminal Ganglion in Murine Model of Allergic Contact Dermatitis: Complement 3 Pathway Contributes to Itch and Pain Sensation."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "The complement system in sensory ganglion might play an essential role in forming pruritic and nociceptive sensations in ACD."
      explanation: This supports complement-associated sensory neuron activation as a direct contributor to pruritus in allergic contact dermatitis.
  evidence:
  - reference: PMID:34417985
    reference_title: "Proteome Profile of Trigeminal Ganglion in Murine Model of Allergic Contact Dermatitis: Complement 3 Pathway Contributes to Itch and Pain Sensation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The complement system in sensory ganglion might play an essential role in forming pruritic and nociceptive sensations in ACD."
    explanation: This supports complement-linked sensory pathway activation as a distinct neuroimmune mechanism in allergic contact dermatitis.
phenotypes:
- name: Contact dermatitis
  category: Dermatological
  diagnostic: true
  frequency: OBLIGATE
  notes: Localized eczematous inflammation at sites of irritant or allergen exposure.
  phenotype_term:
    preferred_term: Contact dermatitis
    term:
      id: HP:0032282
      label: Contact dermatitis
  evidence:
  - reference: PMID:25102574
    reference_title: "Identifying the causes of contact dermatitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The two most common variants are irritant contact dermatitis (ICD) and allergic contact dermatitis (ACD)."
    explanation: This supports the broad clinical entity of contact dermatitis comprising allergic and irritant forms.
- name: Pruritus
  category: Dermatological
  diagnostic: true
  frequency: FREQUENT
  notes: Itching is a common symptom, especially in allergic forms and on thin skin sites such as the eyelids.
  phenotype_term:
    preferred_term: Pruritus
    term:
      id: HP:0000989
      label: Pruritus
  evidence:
  - reference: PMID:39941494
    reference_title: "Eyelid Contact Dermatitis: 25-Year Single-Center Retrospective Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Background/Objectives: Eyelid dermatitis is an inflammatory disease affecting the palpebral skin characterized by itching, edema, and scaling of the periorbital area."
    explanation: This human clinical series supports itching as a characteristic manifestation of contact dermatitis.
- name: Erythema
  category: Dermatological
  frequency: FREQUENT
  notes: Erythematous patches or plaques are common at exposed or directly contacted skin sites.
  phenotype_term:
    preferred_term: Erythema
    term:
      id: HP:0010783
      label: Erythema
  evidence:
  - reference: PMID:9590995
    reference_title: "Irritant contact dermatitis. Clues to causes, clinical characteristics, and control."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical signs include vesicles, papules, bullae, erythema, edema, scaling, and lichenification."
    explanation: This review supports erythema as a common clinical sign of contact dermatitis, particularly irritant presentations.
- name: Scaling skin
  category: Dermatological
  frequency: FREQUENT
  notes: Scaling commonly accompanies eczematous plaques and chronic hand or eyelid dermatitis.
  phenotype_term:
    preferred_term: Scaling skin
    term:
      id: HP:0040189
      label: Scaling skin
  evidence:
  - reference: PMID:39941494
    reference_title: "Eyelid Contact Dermatitis: 25-Year Single-Center Retrospective Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Background/Objectives: Eyelid dermatitis is an inflammatory disease affecting the palpebral skin characterized by itching, edema, and scaling of the periorbital area."
    explanation: This human clinical study supports scaling as a characteristic manifestation of contact dermatitis.
histopathology:
- name: Spongiotic dermatitis pattern
  finding_term:
    preferred_term: Spongiotic dermatitis
    term:
      id: NCIT:C96291
      label: Spongiosis
  description: >-
    Allergic contact dermatitis falls within the broader histopathologic pattern
    of spongiotic or eczematous dermatitis, so biopsy findings require
    clinicopathologic correlation and exposure assessment rather than stand
    alone as a definitive discriminator.
  subtype: Allergic Contact Dermatitis
  evidence:
  - reference: PMID:39709083
    reference_title: "Epidermal spongiotic Langerhans cell collections, but not eosinophils, are a clue to the diagnosis of allergic contact dermatitis: A series of 170 clinically- and patch test-confirmed cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "BACKGROUND: Allergic contact dermatitis cannot be reliably differentiated from other forms of spongiotic/eczematous dermatitis by histology alone."
    explanation: This supports spongiotic/eczematous dermatitis as the core histopathologic pattern of allergic contact dermatitis while emphasizing its limited specificity.
- name: Epidermal spongiotic Langerhans cell collections
  description: >-
    Within allergic contact dermatitis biopsies, epidermal collections of
    Langerhans cells are a supportive microscopic clue that can favor the
    diagnosis over other spongiotic dermatoses.
  subtype: Allergic Contact Dermatitis
  evidence:
  - reference: PMID:39709083
    reference_title: "Epidermal spongiotic Langerhans cell collections, but not eosinophils, are a clue to the diagnosis of allergic contact dermatitis: A series of 170 clinically- and patch test-confirmed cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CONCLUSION: This largest study to date is the first to independently confirm Langerhans cell collections as the single histopathologic feature most closely associated with allergic contact dermatitis."
    explanation: This supports epidermal spongiotic Langerhans cell collections as a biopsy feature that favors allergic contact dermatitis.
prevalence:
- population: Adults from five European countries
  measure_type: LIFETIME_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 15000.0
  percentage: 15.0
  notes: >-
    Questionnaire-based lifetime occurrence estimate in a representative
    cross-sectional sample of adults aged 18-74 years from Germany, Italy, the
    Netherlands, Portugal, and Sweden. A related European population study of
    contact allergy reported a nearly identical age-standardized lifetime
    contact dermatitis estimate of 15.1%.
  evidence:
  - reference: PMID:29247509
    reference_title: "Prevalence of skin disease in a population-based sample of adults from five European countries."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most common skin disease was warts (41·3%), followed by acne (19·2%) and contact dermatitis (15·0%)."
    explanation: This provides a direct population-based lifetime prevalence estimate for contact dermatitis in adults from five European countries.
  - reference: PMID:26370659
    reference_title: "Prevalence of contact allergy in the general population in different European regions."
    supports: SUPPORT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Subjects reporting contact dermatitis in their lifetime (age-standardized prevalence 15·1%, 95% CI 13·8-16·3)"
    explanation: This independent European population study closely replicates the approximately 15% lifetime contact dermatitis prevalence estimate.
- population: General population over a lifetime
  measure_type: LIFETIME_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 15000.0
  percentage: 15.0
  notes: >-
    Approximate lifetime burden cited in a U.S. population-based epidemiology
    study background; consistent with the directly measured European
    population-based estimates above, but not itself a pooled global
    meta-analytic prevalence estimate.
  evidence:
  - reference: PMID:39403761
    reference_title: "Contact Dermatitis in the United States: A Population-Based Study on Patient Visit Characteristics and Treatment Prescription Patterns."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Background: Contact dermatitis (CD) affects ∼15% of the general population over a lifetime."
    explanation: This U.S. population-based study cites an approximately 15% lifetime general-population burden, supporting the broader prevalence context.
epidemiology:
- name: Predominant occupational skin disease burden
  description: Contact dermatitis is the dominant occupational skin disorder and accounts for most cases of occupational skin disease in industrialized settings.
  factors:
  - occupation
  evidence:
  - reference: PMID:19580930
    reference_title: "Management of occupational dermatitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Contact dermatitis is the most common occupational skin disorder, responsible for up to 30% of all cases of occupational disease in industrialized nations."
    explanation: This review supports contact dermatitis as a leading occupational disease burden.
  - reference: PMID:19580930
    reference_title: "Management of occupational dermatitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Epidemiologic data suggest that contact dermatitis accounts for 90% to 95% of all cases of occupational skin disease"
    explanation: This review supports contact dermatitis as the major contributor to occupational skin disease cases.
genetic:
- name: FLG loss-of-function variants and allergic sensitization susceptibility
  association: Risk Factor
  subtype: Allergic Contact Dermatitis
  notes: Barrier-impaired filaggrin deficiency increases penetrance of contact allergens and raises the risk of sensitization in people with dermatitis.
  gene_term:
    preferred_term: FLG
    term:
      id: hgnc:3748
      label: FLG
  evidence:
  - reference: PMID:23343419
    reference_title: "Filaggrin mutations are strongly associated with contact sensitization in individuals with dermatitis."
    supports: SUPPORT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "FLG mutation carriers with self-reported dermatitis have an increased risk of contact sensitization to substances other than nickel"
    explanation: This human population study supports FLG loss-of-function variants as a genetic risk factor for contact sensitization relevant to allergic contact dermatitis.
  - reference: PMID:18049447
    reference_title: "Loss-of-function mutations in the filaggrin gene and allergic contact sensitization to nickel."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      an association with contact sensitization to nickel and contact
      sensitization to nickel combined with intolerance to fashion jewelry,
      but not with other contact allergens, was observed.
    explanation: >-
      A separate general-population cohort (KORA) reports the converse
      allergen pattern from the self-reported-dermatitis cohort quoted above:
      here the FLG association is specific to nickel and does not extend to
      other contact allergens. The two studies agree that FLG deficiency
      raises contact sensitization risk and disagree on which allergens the
      effect covers, which is recorded rather than resolved. The same finding
      is also cited from Atopic_Dermatitis.yaml's barrier-dysfunction node,
      where this comorbid outcome originates mechanistically.
- name: FLG loss-of-function variants and irritant contact dermatitis susceptibility
  association: Risk Factor
  subtype: Irritant Contact Dermatitis
  notes: Filaggrin deficiency contributes to barrier vulnerability and independently increases occupational irritant contact dermatitis risk.
  gene_term:
    preferred_term: FLG
    term:
      id: hgnc:3748
      label: FLG
  evidence:
  - reference: PMID:23039796
    reference_title: "Impact of atopic dermatitis and loss-of-function mutations in the filaggrin gene on the development of occupational irritant contact dermatitis."
    supports: SUPPORT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our results indicate that both FLG mutations and AD increase the risk of ICD."
    explanation: This occupational case-control study supports FLG variants as an independent genetic susceptibility factor for irritant contact dermatitis.
environmental:
- name: Wet work and detergent exposure
  influences_mechanisms:
  - target: Irritant exposure and toxic insult
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Water, soap and detergent strip stratum corneum lipids and damage
      keratinocytes directly, with no immune sensitization required. This is
      the irritant arm of the entry, which is why it targets the toxic-insult
      node rather than the hapten node the sensitizers use.
    evidence:
    - reference: PMID:25102574
      reference_title: "Identifying the causes of contact dermatitis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Cumulative effects of water, soaps and detergents are the most common cause of ICD which affects the hands more often than any other site."
      explanation: >-
        Identifies cumulative water, soap and detergent exposure as the most
        common cause of irritant contact dermatitis, the non-immunological
        insult this node describes.
  exposure_term:
    preferred_term: exposure to detergent
    term:
      id: ECTO:9001690
      label: exposure to detergent
    qualifiers:
    - predicate:
        preferred_term: has participant
        term:
          id: RO:0000057
          label: has participant
      value:
        preferred_term: skin of manus
        term:
          id: UBERON:0001519
          label: skin of manus
  description: >-
    Repetitive wet work and exposure to soaps and detergents are common
    environmental drivers of irritant contact dermatitis, especially on the
    hands.
  effect: TRIGGERS
  evidence:
  - reference: PMID:25102574
    reference_title: "Identifying the causes of contact dermatitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cumulative effects of water, soaps and detergents are the most common cause of ICD which affects the hands more often than any other site."
    explanation: This supports wet work and detergent exposure as major environmental triggers of irritant contact dermatitis.
- name: Nickel exposure
  influences_mechanisms:
  - target: Hapten exposure
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Nickel ions released from metal in prolonged skin contact bind
      self-protein to form the hapten-protein complex this node represents. It
      is consistently the single most frequent contact allergen.
    evidence:
    - reference: DOI:10.3389/fmed.2023.1184289
      reference_title: "Advancing the understanding of allergic contact dermatitis: from pathophysiology to novel therapeutic approaches"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Metals, especially nickel, fragrance mix, isothiazolinones, and para-phenylenediamine, are the most commonly positive allergens in patients patch tested for suspected ACD."
      explanation: >-
        Identifies nickel first among the most commonly positive allergens on
        patch testing, the sensitizers that supply the hapten at this node.
  exposure_term:
    preferred_term: exposure to nickel
    term:
      id: ECTO:9000063
      label: exposure to nickel
  description: >-
    Exposure to nickel-containing jewelry, tools, and occupational metal
    sources is a common environmental trigger of allergic contact dermatitis.
  effect: TRIGGERS
  evidence:
  - reference: DOI:10.3389/fmed.2023.1184289
    reference_title: "Advancing the understanding of allergic contact dermatitis: from pathophysiology to novel therapeutic approaches"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Metals, especially nickel, fragrance mix, isothiazolinones, and para-phenylenediamine, are the most commonly positive allergens in patients patch tested for suspected ACD."
    explanation: This review identifies nickel as one of the most common sensitizing exposures in allergic contact dermatitis.
- name: Fragrance exposure
  influences_mechanisms:
  - target: Hapten exposure
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Fragrance chemicals are a mixture rather than a single molecule, several
      members of which are haptens; patch testing uses a fragrance mix for
      that reason.
    evidence:
    - reference: DOI:10.3389/fmed.2023.1184289
      reference_title: "Advancing the understanding of allergic contact dermatitis: from pathophysiology to novel therapeutic approaches"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Metals, especially nickel, fragrance mix, isothiazolinones, and para-phenylenediamine, are the most commonly positive allergens in patients patch tested for suspected ACD."
      explanation: >-
        Identifies fragrance mix among the most commonly positive allergens on
        patch testing.
  exposure_term:
    preferred_term: exposure to fragrance
    term:
      id: ECTO:9001808
      label: exposure to fragrance
  description: >-
    Fragrance-containing cosmetics, personal care products, and topical agents
    are common environmental triggers of allergic contact dermatitis.
  effect: TRIGGERS
  evidence:
  - reference: DOI:10.3389/fmed.2023.1184289
    reference_title: "Advancing the understanding of allergic contact dermatitis: from pathophysiology to novel therapeutic approaches"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Metals, especially nickel, fragrance mix, isothiazolinones, and para-phenylenediamine, are the most commonly positive allergens in patients patch tested for suspected ACD."
    explanation: This review identifies fragrance mix as a common sensitizer in patients patch tested for allergic contact dermatitis.
- name: Isothiazolinone exposure
  influences_mechanisms:
  - target: Hapten exposure
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Preservatives in cosmetics and household products, and the sensitizer
      behind a documented epidemic of contact allergy after their
      concentration in leave-on products rose.
    evidence:
    - reference: PMID:41804652
      reference_title: "Prevalence of Contact Allergy to Isothiazolinones in Dermatitis Patients From 2000 to 2025: A Systematic Review and Meta-Analysis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The prevalence of CA to methylchloroisothiazolinone/methylisothiazolinone (MCI/MI) was 4.58%, methylisothiazolinone (MI) was 5.48%, and benzisothiazolinone (BIT) was 2.09%."
      explanation: >-
        Quantifies contact allergy prevalence to methylchloroisothiazolinone
        and methylisothiazolinone in a tested population, establishing them as
        active sensitizers rather than merely present chemicals.
  description: >-
    Exposure to isothiazolinone preservatives in personal care, household, and
    industrial products is a recognized environmental trigger of allergic
    contact dermatitis.
  effect: TRIGGERS
  evidence:
  - reference: DOI:10.3389/fmed.2023.1184289
    reference_title: "Advancing the understanding of allergic contact dermatitis: from pathophysiology to novel therapeutic approaches"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Metals, especially nickel, fragrance mix, isothiazolinones, and para-phenylenediamine, are the most commonly positive allergens in patients patch tested for suspected ACD."
    explanation: This review identifies isothiazolinones as common sensitizing preservatives in allergic contact dermatitis.
  - reference: PMID:41804652
    reference_title: "Prevalence of Contact Allergy to Isothiazolinones in Dermatitis Patients From 2000 to 2025: A Systematic Review and Meta-Analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The prevalence of CA to methylchloroisothiazolinone/methylisothiazolinone (MCI/MI) was 4.58%, methylisothiazolinone (MI) was 5.48%, and benzisothiazolinone (BIT) was 2.09%."
    explanation: This meta-analysis adds current human prevalence data showing multiple isothiazolinone preservatives are established sensitizers among dermatitis patients.
- name: Mastisol adhesive exposure
  influences_mechanisms:
  - target: Hapten exposure
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      A liquid surgical adhesive whose gum-resin constituents can sensitize;
      reported rarely, so this link records a documented rather than a
      frequent hapten source.
    evidence:
    - reference: PMID:30465037
      reference_title: "Allergic Contact Dermatitis to Mastisol Adhesive Used for Skin Closure in Orthopedic Surgery: A Case Report."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We report on a rare case of allergic contact dermatitis (ACD) from Mastisol liquid adhesive."
      explanation: >-
        Reports a case of allergic contact dermatitis attributed to this
        liquid adhesive, a documented but uncommon hapten source.
  exposure_term:
    preferred_term: exposure to glue
    term:
      id: ECTO:7000130
      label: exposure to glue
  description: >-
    Exposure to Mastisol liquid adhesive used for wound closure is a reported
    trigger of allergic contact dermatitis after surgical procedures.
  effect: TRIGGERS
  evidence:
  - reference: PMID:30465037
    reference_title: "Allergic Contact Dermatitis to Mastisol Adhesive Used for Skin Closure in Orthopedic Surgery: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report on a rare case of allergic contact dermatitis (ACD) from Mastisol liquid adhesive."
    explanation: This case report supports Mastisol as a specific adhesive trigger of allergic contact dermatitis.
- name: 2-octyl cyanoacrylate adhesive exposure
  influences_mechanisms:
  - target: Hapten exposure
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      A surgical skin adhesive increasingly implicated as a sensitizer,
      notable because the exposure is iatrogenic and occurs on a wound that is
      already breached.
    evidence:
    - reference: PMID:41784277
      reference_title: "Systematic Review and Meta Analysis of Allergic Contact Dermatitis from 2-Octyl Cyanoacrylate Adhesives."
      supports: SUPPORT
      quote_role: BACKGROUND
      evidence_source: HUMAN_CLINICAL
      snippet: "2-octyl cyanoacrylate (2-OCA) topical skin adhesives are widely used for surgical wound closure but are increasingly associated with allergic contact dermatitis (ACD)."
      explanation: >-
        Reports that these topical skin adhesives, widely used for surgical
        wound closure, are increasingly associated with allergic contact
        dermatitis.
  - target: Re-exposure-driven effector T-cell recruitment
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      A second, later encounter with the same adhesive is what recruits primed
      effector T cells to the skin, which is why staged or repeat surgical
      procedures carry an order-of-magnitude higher reaction rate than a first
      exposure. Sensitization and elicitation are separate events, and this
      link records the second.
    evidence:
    - reference: PMID:41784277
      reference_title: "Systematic Review and Meta Analysis of Allergic Contact Dermatitis from 2-Octyl Cyanoacrylate Adhesives."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Re-exposure markedly increased risk, with reaction rates rising from 1-3% after initial exposure to >20% in staged or repeat procedures in several cohorts."
      explanation: >-
        Reaction rates rise from a few percent after initial exposure to over
        twenty percent on staged or repeat exposure, quantifying elicitation on
        re-encounter rather than sensitization at first contact.
  exposure_term:
    preferred_term: exposure to glue
    term:
      id: ECTO:7000130
      label: exposure to glue
    qualifiers:
    - predicate:
        preferred_term: has input
        term:
          id: RO:0002233
          label: has input
      value:
        preferred_term: acrylate
        term:
          id: CHEBI:37080
          label: acrylate
  description: >-
    Exposure to 2-octyl cyanoacrylate topical skin adhesives used for surgical
    wound closure is an increasingly recognized trigger of allergic contact
    dermatitis, especially after repeat exposure.
  effect: TRIGGERS
  evidence:
  - reference: PMID:41784277
    reference_title: "Systematic Review and Meta Analysis of Allergic Contact Dermatitis from 2-Octyl Cyanoacrylate Adhesives."
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "2-octyl cyanoacrylate (2-OCA) topical skin adhesives are widely used for surgical wound closure but are increasingly associated with allergic contact dermatitis (ACD)."
    explanation: This systematic review supports 2-octyl cyanoacrylate as a specific surgical adhesive trigger of allergic contact dermatitis.
  - reference: PMID:41784277
    reference_title: "Systematic Review and Meta Analysis of Allergic Contact Dermatitis from 2-Octyl Cyanoacrylate Adhesives."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Re-exposure markedly increased risk, with reaction rates rising from 1-3% after initial exposure to >20% in staged or repeat procedures in several cohorts."
    explanation: This supports repeat exposure as an important risk amplifier for cyanoacrylate-triggered allergic contact dermatitis.
- name: Para-phenylenediamine exposure
  exposure_term:
    preferred_term: exposure to para-phenylenediamine
    term:
      id: ECTO:9001223
      label: exposure to 1,4-phenylenediamine
  influences_mechanisms:
  - target: Hapten exposure
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      The principal sensitizer in permanent hair dye and in black henna
      tattoos, where the unregulated concentrations make sensitization more
      likely.
    evidence:
    - reference: DOI:10.3389/fmed.2023.1184289
      reference_title: "Advancing the understanding of allergic contact dermatitis: from pathophysiology to novel therapeutic approaches"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Metals, especially nickel, fragrance mix, isothiazolinones, and para-phenylenediamine, are the most commonly positive allergens in patients patch tested for suspected ACD."
      explanation: >-
        Identifies para-phenylenediamine among the most commonly positive
        allergens on patch testing.
  description: >-
    Exposure to para-phenylenediamine, particularly in hair dyes and related
    products, is a common environmental trigger of allergic contact dermatitis.
  effect: TRIGGERS
  evidence:
  - reference: DOI:10.3389/fmed.2023.1184289
    reference_title: "Advancing the understanding of allergic contact dermatitis: from pathophysiology to novel therapeutic approaches"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Metals, especially nickel, fragrance mix, isothiazolinones, and para-phenylenediamine, are the most commonly positive allergens in patients patch tested for suspected ACD."
    explanation: This review identifies para-phenylenediamine as a common sensitizer in allergic contact dermatitis.
- name: Rubber accelerator exposure
  influences_mechanisms:
  - target: Hapten exposure
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Thiurams and carbamates added during rubber vulcanisation remain in the
      finished product, which is why gloves intended as protection are
      themselves a common source of occupational sensitization.
    evidence:
    - reference: PMID:25102574
      reference_title: "Identifying the causes of contact dermatitis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Nickel, fragrances, rubber accelerators and biocides are the most common sensitisers in ACD."
      explanation: >-
        Names rubber accelerators among the most common sensitizers in
        allergic contact dermatitis.
  description: >-
    Exposure to rubber accelerators in gloves, footwear, and occupational
    materials is a common environmental trigger of allergic contact dermatitis.
  effect: TRIGGERS
  evidence:
  - reference: PMID:25102574
    reference_title: "Identifying the causes of contact dermatitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Nickel, fragrances, rubber accelerators and biocides are the most common sensitisers in ACD."
    explanation: This review identifies rubber accelerators as common sensitizers in allergic contact dermatitis.
- name: Biocide exposure
  influences_mechanisms:
  - target: Hapten exposure
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Preservatives and antimicrobials added to cosmetics, cutting fluids and
      paints, encountered in both occupational and consumer settings.
    evidence:
    - reference: PMID:25102574
      reference_title: "Identifying the causes of contact dermatitis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Nickel, fragrances, rubber accelerators and biocides are the most common sensitisers in ACD."
      explanation: >-
        Names biocides among the most common sensitizers in allergic contact
        dermatitis.
  description: >-
    Exposure to biocides and preservative chemicals in occupational and consumer
    products is a common environmental trigger of allergic contact dermatitis.
  effect: TRIGGERS
  evidence:
  - reference: PMID:25102574
    reference_title: "Identifying the causes of contact dermatitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Nickel, fragrances, rubber accelerators and biocides are the most common sensitisers in ACD."
    explanation: This review identifies biocides as common sensitizers in allergic contact dermatitis.
- name: Repeated and high-concentration allergen exposure
  exposure_term:
    preferred_term: exposure to allergen
    term:
      id: ECTO:0000726
      label: exposure to allergen
  influences_mechanisms:
  - target: Allergen-specific T-cell priming
    environmental_effect: PREDISPOSES
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Not a hapten itself but a property of the encounter. Sensitization is
      dose- and frequency-dependent, so the same chemical is more likely to
      prime a T-cell response when met often or at high concentration.
    evidence:
    - reference: PMID:25102574
      reference_title: "Identifying the causes of contact dermatitis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Frequent exposure and high concentrations of potential allergens increase the risk of sensitisation."
      explanation: >-
        States that frequent exposure and high allergen concentrations
        increase the risk of sensitisation, which is the priming step this
        node describes.
  description: >-
    Repeated contact and higher local concentrations of potential allergens
    increase the probability of sensitization and later allergic flares.
  effect: Increases sensitization risk
  evidence:
  - reference: PMID:25102574
    reference_title: "Identifying the causes of contact dermatitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Frequent exposure and high concentrations of potential allergens increase the risk of sensitisation."
    explanation: This supports repeated or intense exposure as an environmental risk factor for allergic sensitization.
- name: Toxicodendron exposure
  influences_mechanisms:
  - target: Hapten exposure
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Poison ivy, oak and sumac deliver urushiol, a catechol that penetrates
      skin and binds protein to form the hapten. Unusually for a contact
      allergen, it sensitizes a majority of the population.
    evidence:
    - reference: PMID:27548435
      reference_title: "CD1a on Langerhans cells controls inflammatory skin disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Human subjects with poison-ivy dermatitis had a similar cytokine signature following CD1a-mediated recognition of urushiol."
      explanation: >-
        Shows CD1a-mediated recognition of urushiol in patients with poison-ivy
        dermatitis, evidencing the hapten being presented in actual disease
        rather than in a clone assay.
  exposure_term:
    preferred_term: exposure to allergen
    term:
      id: ECTO:0000726
      label: exposure to allergen
    qualifiers:
    - predicate:
        preferred_term: has input
        term:
          id: RO:0002233
          label: has input
      value:
        preferred_term: urushiol III
        term:
          id: CHEBI:9909
          label: urushiol III
  description: >-
    Exposure to Toxicodendron plants such as poison ivy, poison oak, and poison
    sumac is a common environmental trigger of allergic contact dermatitis.
  effect: TRIGGERS
  evidence:
  - reference: PMID:14700441
    reference_title: "Topical pimecrolimus in the treatment of human allergic contact dermatitis."
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "Plants of the Toxicodendron species cause allergic contact dermatitis (ACD) in 50% to 70% of the population."
    explanation: This supports Toxicodendron plant exposure as a common and clinically important trigger of allergic contact dermatitis.
  - reference: PMID:27548435
    reference_title: "CD1a on Langerhans cells controls inflammatory skin disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among various urushiol congeners, we identified diunsaturated pentadecylcatechol (C15:2) as the dominant antigen for CD1a-restricted T cells."
    explanation: This supports urushiol III, the diunsaturated pentadecylcatechol congener, as a specific Toxicodendron allergen linked to poison ivy dermatitis.
- name: Lime and other psoralen-rich citrus exposure with ultraviolet light
  influences_mechanisms:
  - target: Irritant exposure and toxic insult
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Phytophotodermatitis needs both halves and is neither allergic nor
      idiosyncratic: furocoumarins on the skin absorb ultraviolet A and become
      directly cytotoxic, so the reaction is a phototoxic irritant insult
      rather than a hapten-driven sensitization.
    evidence:
    - reference: PMID:41064302
      reference_title: "Mojito-Induced Phytophotodermatitis: A Case of Lime-Triggered Skin Reaction."
      supports: SUPPORT
      quote_role: BACKGROUND
      evidence_source: HUMAN_CLINICAL
      snippet: 'Lime-induced phytophotodermatitis, sometimes called "lime disease" or "margarita photodermatitis," is one of the most common forms, caused by furocoumarins in lime juice or peel.'
      explanation: >-
        Identifies lime-induced phytophotodermatitis as caused by
        furocoumarins, the phototoxic irritant insult this node describes.
  description: >-
    Contact with lime juice or peel followed by ultraviolet exposure can trigger
    phytophotodermatitis, a phototoxic contact reaction that may be mistaken for
    allergic dermatitis.
  effect: TRIGGERS
  evidence:
  - reference: PMID:41064302
    reference_title: "Mojito-Induced Phytophotodermatitis: A Case of Lime-Triggered Skin Reaction."
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "Lime-induced phytophotodermatitis, sometimes called \"lime disease\" or \"margarita photodermatitis,\" is one of the most common forms, caused by furocoumarins in lime juice or peel."
    explanation: This case report supports lime-derived psoralen exposure with UV light as a specific trigger of photocontact dermatitis.
- name: Mare's milk soap exposure
  description: >-
    Soap products containing mare's milk have been reported as a specific
    trigger of allergic contact dermatitis in sensitized individuals. Weight
    accordingly - this is an n-of-1 allergen report, not an established trigger
    class.
  review_notes: >-
    Left deliberately uncited. The claim comes from a single case report,
    PMID:40921440, which is indexed in PubMed without an abstract, so no
    quotable excerpt exists to validate against. Per the evidence SOP the claim
    is recorded here rather than backed by a title-as-snippet evidence item.
    This text was previously in the description; it was moved so the
    disposition is machine-detectable by
    scripts/check_environmental_evidence.py rather than reading as an
    unexamined gap.
  effect: TRIGGERS
experimental_models:
- name: Human Cell Line Activation Test (h-CLAT)
  description: >-
    An OECD TG 442E method that reads sensitizer-induced activation of a
    dendritic-cell surrogate as CD86 and CD54 surface expression on the THP-1
    human monocytic leukemia line after 24 hours of chemical exposure.
  experimental_model_type: CELL_LINE
  publication: PMID:20510347
  modeled_mechanisms:
  - target: Skin innate immune activation during sensitization
    relationship: MEASURES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      Reads the dendritic-cell activation step of sensitization as two
      costimulatory and adhesion markers on a monocytic line.
    limitations: >-
      THP-1 is a monocytic leukemia line, not a dendritic cell, so marker
      upregulation stands in for antigen-presenting-cell activation rather than
      demonstrating it. About 15% of outcomes were misclassified in the COLIPA
      ring trials, with weak allergens and poorly soluble chemicals named as the
      failure classes. The assay reads a hazard call and carries little potency
      information, and being cell-only it cannot activate pro-haptens.
    divergences:
    - divergence_type: PROXY_QUANTITY
      materiality: QUALIFYING
      description: >-
        CD86 and CD54 are the measured quantity; dendritic-cell activation in
        skin is the quantity of interest.
    - divergence_type: SCALE_EXTRAPOLATION
      materiality: QUALIFYING
      description: >-
        The assay observes single cells in suspension; the node is tissue-scale
        innate activation in skin. Nothing in the readout reports the tissue
        context — no keratinocyte crosstalk, no migration, no barrier — so the
        step from marker induction to skin-level activation is inferred.
    evidence:
    - reference: PMID:20510347
      reference_title: "Predicting skin sensitization potential and inter-laboratory reproducibility of a human Cell Line Activation Test (h-CLAT) in the European Cosmetics Association (COLIPA) ring trials."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: IN_VITRO
      snippet: >-
        The human Cell Line Activation Test (h-CLAT) examines the level of CD86
        and CD54 expression on the surface of THP-1 cells, a human monocytic
        leukemia cell line, following 24h of chemical exposure.
      explanation: >-
        States the measured readout and the cell provenance, which is what fixes
        this model to the dendritic-cell activation step and bounds what it can
        show.
  evidence:
  - reference: PMID:20510347
    reference_title: "Predicting skin sensitization potential and inter-laboratory reproducibility of a human Cell Line Activation Test (h-CLAT) in the European Cosmetics Association (COLIPA) ring trials."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      From the RT data, the feasibility of utilizing cell lines as surrogate DC
      in development of in vitro skin sensitization methods shows promise.
    explanation: >-
      States what the ring trials establish about the model itself: that a cell
      line can serve as a dendritic-cell surrogate for this purpose. The assay's
      15% misclassification rate is the counterweight, and it is recorded in the
      link's limitations rather than here, because model-level evidence attests
      that the model is informative.
- name: GARDskin
  description: >-
    An OECD TG 442E method that reads sensitizer-induced activation of a
    dendritic-cell-like line as a multi-gene transcriptional signature rather
    than as individual surface markers.
  experimental_model_type: CELL_LINE
  publication: PMID:31099396
  modeled_mechanisms:
  - target: Skin innate immune activation during sensitization
    relationship: MEASURES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      Reads the dendritic-cell activation step as induced transcriptional change
      across co-stimulatory, stress and xenobiotic-response programs.
    limitations: >-
      The readout is a trained signature in the MUTZ-3 dendritic-cell-like
      myeloid line, so the prediction is model-dependent and the cell is a
      surrogate rather than a primary dendritic cell. Reported accuracy is tied
      to the 28-chemical blinded ring-trial set.
    divergences:
    - divergence_type: SCALE_EXTRAPOLATION
      materiality: QUALIFYING
      description: >-
        The signature is measured in a single cultured cell type; the node is
        tissue-scale innate activation in skin. The transcriptional programs read
        out are cell-intrinsic, so the tissue-level claim is inferred rather than
        observed.
    evidence:
    - reference: PMID:31099396
      reference_title: "Validation of the GARD™skin Assay for Assessment of Chemical Skin Sensitizers: Ring Trial Results of Predictive Performance and Reproducibility."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: IN_VITRO
      snippet: >-
        The methodology is based on a dendritic cell (DC)-like cell line, thus
        mimicking the mechanistic events leading to initiation and modulation of
        downstream immunological responses.
      explanation: >-
        States the biological basis the method claims, which is what maps it to
        the dendritic-cell activation step of sensitization.
- name: Human T-cell priming assay
  description: >-
    A co-culture of sorted naive human T cells with monocyte-derived dendritic
    cells pulsed with the test chemical, reading antigen-specific priming as
    IFN-gamma and TNF-alpha production at single-cell level.
  experimental_model_type: CO_CULTURE
  publication: PMID:22906571
  modeled_mechanisms:
  - target: Allergen-specific T-cell priming
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      Primes an allergen-specific human T-cell response in vitro, which is the
      step this node asserts, using primary human cells on both sides of the
      interaction.
    limitations: >-
      The assay is not regulatory-validated and is low-throughput, and
      donor-to-donor variability is not yet well defined. It establishes that
      priming occurs in human cells but cannot establish the whole-organism
      adverse outcome.
    evidence:
    - reference: PMID:22906571
      reference_title: "Human T cell priming assay (hTCPA) for the identification of contact allergens based on naive T cells and DC--IFN-γ and TNF-α readout."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: IN_VITRO
      snippet: >-
        Using sorted naïve T cells and monocyte-derived dendritic cells pulsed
        with the test chemical or with chemical-protein conjugates, the
        successful priming of an antigen-specific T cell response is controlled
        after antigen-specific restimulation by cytokine readout.
      explanation: >-
        Describes priming of a chemical-specific naive human T-cell response,
        which is the mechanism this pathograph node records.
- name: Full-thickness skin equivalent with MUTZ-3-derived Langerhans cells
  description: >-
    An immunocompetent full-thickness skin equivalent whose epidermis carries
    keratinocytes, melanocytes and CD1a+ Langerin+ HLA-DR+ Langerhans cells
    derived from the MUTZ-3 line, over a fibroblast-populated dermis.
  experimental_model_type: CO_CULTURE
  publication: PMID:21697260
  modeled_mechanisms:
  - target: Skin innate immune activation during sensitization
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: >-
      Reproduces allergen-driven Langerhans cell maturation together with
      migration out of the epidermis toward the dermal compartment, which the
      monolayer dendritic-cell assays cannot show.
    limitations: >-
      The Langerhans cells are MUTZ-3-derived surrogates rather than primary
      cells, and the system is a research model without regulatory validation.
    evidence:
    - reference: PMID:21697260
      reference_title: "Technical advance: Langerhans cells derived from a human cell line in a full-thickness skin equivalent undergo allergen-induced maturation and migration."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: IN_VITRO
      snippet: >-
        Exposure of the SE to subtoxic concentrations of the allergens NiSO(4)
        and resorcinol resulted in LC migration out of the epidermis toward the
        fibroblast-populated dermal compartment.
      explanation: >-
        Demonstrates allergen-driven migration of epidermal Langerhans cells,
        the physical step of innate activation during sensitization that
        monolayer assays omit.
- name: Keratinocyte Keap1-Nrf2-ARE sensitizer-response models
  description: >-
    Four keratinocyte-based systems — primary human keratinocytes, N/TERT
    monolayers, and the Leiden and N/TERT reconstructed epidermal models — read
    for Nrf2 protein, nuclear translocation and Nrf2 target activation after
    exposure to a sensitizer versus an irritant. This is the biology OECD TG
    442D methods (KeratinoSens, LuSens) measure.
  experimental_model_type: OTHER
  publication: PMID:24794257
  modeled_mechanisms:
  - target: Hapten-driven keratinocyte electrophile sensing
    relationship: MEASURES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      Measures this node's own quantity, Keap1-Nrf2-ARE pathway activation in
      keratinocytes under hapten exposure, and separates sensitizer-driven from
      irritant-driven activation on that readout.
    limitations: >-
      Keratinocytes alone, in monolayer or reconstructed epidermis, so nothing
      downstream of the sensing step is represented: no Langerhans cells, no
      dendritic cells, no draining lymph node. The monolayer arms also have no
      stratum corneum, so they are dosed in medium rather than per unit area of
      skin surface. These are research systems reading the biology the validated
      TG 442D methods measure, not those methods themselves.
    evidence:
    - reference: PMID:24794257
      reference_title: "Performance of the N/TERT epidermal model for skin sensitizer identification via Nrf2-Keap1-ARE pathway activation."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: IN_VITRO
      snippet: >-
        Results show that the Keap1-Nrf2-ARE pathway is activated by the
        sensitizer DNCB in monolayer keratinocytes and as well as the LEMs and
        NEMs and not by the irritant SDS.
      explanation: >-
        Establishes that this keratinocyte readout responds to a sensitizer and
        not to an irritant, which is what makes it a measurement of this node's
        hapten-driven step rather than of the irritant arm's keratinocyte node.
- name: KeratinoSens
  description: >-
    An OECD TG 442D method that reads sensitizer-induced keratinocyte
    activation as luciferase induction from a reporter under the control of
    the antioxidant response element of the aldoketoreductase gene AKR1C2, in
    an immortalised human keratinocyte line. The first cell-based in vitro
    skin sensitisation test to carry an OECD Test Guideline.
  experimental_model_type: CELL_LINE
  publication: PMID:27805827
  evidence:
  - reference: PMID:24055896
    reference_title: "Gene expression changes induced by skin sensitizers in the KeratinoSens™ cell line: Discriminating Nrf2-dependent and Nrf2-independent events."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: >-
      The KeratinoSens™ assay is an in vitro screen for the skin sensitization
      potential of chemicals. It is based on a luciferase reporter gene under
      the control of the antioxidant response element of the aldoketoreductase
      gene AKR1C2.
    explanation: >-
      States what the assay is and which reporter construct carries its
      readout, which is what this model entry records.
  - reference: PMID:26796489
    reference_title: "Intra- and inter-laboratory reproducibility and accuracy of the LuSens assay: A reporter gene-cell line to detect keratinocyte activation by skin sensitizers."
    supports: SUPPORT
    quote_role: BACKGROUND
    directness: DIRECT
    evidence_source: OTHER
    snippet: >-
      The KeratinoSens assay addresses the cellular event of keratinocyte
      activation and is a method accepted under OECD TG 442D.
    explanation: >-
      Names the guideline this method is accepted under. Quoted from the
      background of the LuSens inter-laboratory study, which is restating a
      regulatory decision rather than reporting its own result.
  modeled_mechanisms:
  - target: Hapten-driven keratinocyte electrophile sensing
    relationship: MEASURES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      Measures this node's own quantity, Nrf2-dependent transcriptional
      activation in keratinocytes under exposure to an electrophilic
      sensitizer, read as induction of the AKR1C2 ARE luciferase reporter.
    limitations: >-
      The reporter reads the Nrf2-dependent arm only. Sensitizer-induced heat
      shock and cellular stress markers in this same cell line were shown to
      be Nrf2-independent, so they do not reach the luciferase readout, and a
      non-sensitizer (Tween 80) induces the reporter through Nrf2 as a
      documented false positive. Being a keratinocyte monolayer, nothing
      downstream of keratinocyte activation is represented: no Langerhans
      cells, no dendritic cells, no draining lymph node, and the monolayer
      lacks the stratum corneum and metabolic competence a reconstructed
      epidermis uses to activate a pre- or pro-hapten, so a chemical needing
      conversion may not be converted here. The EURL ECVAM review of 127
      substances found that sensitizers requiring activation were still
      identified by one or more methods of the non-animal battery, which is a
      statement about the battery rather than about this assay alone.
    divergences:
    - divergence_type: PROXY_QUANTITY
      materiality: QUALIFYING
      description: >-
        Induction of a transfected AKR1C2 ARE luciferase reporter is the
        measured quantity; endogenous Keap1-Nrf2-ARE pathway activation in
        keratinocytes is the quantity this node carries.
    evidence:
    - reference: PMID:24055896
      reference_title: "Gene expression changes induced by skin sensitizers in the KeratinoSens™ cell line: Discriminating Nrf2-dependent and Nrf2-independent events."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: IN_VITRO
      snippet: >-
        These results confirm that the KeratinoSens™ cell line is a rapid and
        adequate screening tool to assess the sensitizer-induced Nrf2-response
        in keratinocytes.
      explanation: >-
        Supports treating this assay as a measurement of the sensitizer-driven
        Nrf2 response in keratinocytes, which is the biology this node carries.
- name: LuSens
  description: >-
    The second OECD TG 442D method, a human keratinocyte line carrying a
    reporter gene construct built from the antioxidant response element of the
    rat NADPH:quinone oxidoreductase 1 gene and the luciferase gene, read as
    sensitizer-induced keratinocyte activation.
  experimental_model_type: CELL_LINE
  publication: PMID:25172300
  evidence:
  - reference: PMID:26796489
    reference_title: "Intra- and inter-laboratory reproducibility and accuracy of the LuSens assay: A reporter gene-cell line to detect keratinocyte activation by skin sensitizers."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: >-
      The data demonstrate a remarkable reproducibility of 100% and an
      accuracy of over 80% in identifying skin sensitizers, indicating a good
      concordance with in vivo data.
    explanation: >-
      Reports the inter-laboratory reproducibility and accuracy behind this
      method's regulatory acceptance.
  modeled_mechanisms:
  - target: Hapten-driven keratinocyte electrophile sensing
    relationship: MEASURES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      Measures this node's own quantity, ARE-driven transcriptional activation
      in keratinocytes under exposure to an electrophilic sensitizer, read as
      induction of the rat NQO1 ARE luciferase reporter.
    limitations: >-
      A keratinocyte monolayer reporter line, so nothing downstream of
      keratinocyte activation is represented: no Langerhans cells, no
      dendritic cells, no draining lymph node. The readout is a single
      ARE-driven reporter, so a sensitizer acting on keratinocytes through a
      pathway that does not converge on the ARE is not read, and the reporter
      element is of rat origin in a human cell line. As a monolayer it lacks
      the stratum corneum and metabolic competence a reconstructed epidermis
      uses to activate a pre- or pro-hapten, so a chemical needing conversion
      may not be converted here; the EURL ECVAM review of 127 substances found
      that sensitizers requiring activation were still identified by one or
      more methods of the non-animal battery, which is a statement about the
      battery rather than about this assay alone.
    divergences:
    - divergence_type: PROXY_QUANTITY
      materiality: QUALIFYING
      description: >-
        Induction of a transfected rat NQO1 ARE luciferase reporter is the
        measured quantity; endogenous Keap1-Nrf2-ARE pathway activation in
        keratinocytes is the quantity this node carries.
    evidence:
    - reference: PMID:25172300
      reference_title: "LuSens: a keratinocyte based ARE reporter gene assay for use in integrated testing strategies for skin sensitization hazard identification."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: IN_VITRO
      snippet: >-
        the LuSens assay, that uses a human keratinocyte cell line harbouring
        a reporter gene construct composed of the antioxidant response element
        (ARE) of the rat NADPH:quinone oxidoreductase 1 gene and the
        luciferase gene
      explanation: >-
        Establishes that the assay reads ARE-driven activation in a human
        keratinocyte line, which is the measurement this link claims.
- name: U-SENS (Myeloid U937 Skin Sensitization Test)
  description: >-
    An OECD TG 442E method that reads sensitizer-induced activation of a
    dendritic-cell surrogate as CD86 surface expression on the U937 human
    myeloid cell line, measured by flow cytometry.
  experimental_model_type: CELL_LINE
  publication: PMID:25820135
  notes: >-
    The human comparator data for this kind of assay-validation analysis is
    the sort compiled in the HPPT reference database (PMID:37615678, in this
    entry's references catalog): a database of 2,277 human predictive patch
    tests across 1,366 substances assembled to serve as the human standard
    non-animal methods are benchmarked against.
  modeled_mechanisms:
  - target: Skin innate immune activation during sensitization
    relationship: MEASURES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      Reads the dendritic-cell activation step of sensitization as CD86
      upregulation on a myeloid line.
    limitations: >-
      U937 is a myeloid leukemia line, not a dendritic cell, so CD86
      upregulation stands in for antigen-presenting-cell activation rather
      than demonstrating it directly. Between-laboratory reproducibility in
      the ring study was lower than within-laboratory reproducibility (79%
      versus 95%), and being cell-only it cannot activate pro-haptens.
    divergences:
    - divergence_type: PROXY_QUANTITY
      materiality: QUALIFYING
      description: >-
        CD86 is the measured quantity; dendritic-cell activation in skin is
        the quantity of interest.
    - divergence_type: SCALE_EXTRAPOLATION
      materiality: QUALIFYING
      description: >-
        The assay observes single cells in suspension; the node is
        tissue-scale innate activation in skin. Nothing in the readout reports
        the tissue context.
    evidence:
    - reference: PMID:25820135
      reference_title: "The Myeloid U937 Skin Sensitization Test (U-SENS) addresses the activation of dendritic cell event in the adverse outcome pathway for skin sensitization."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: IN_VITRO
      snippet: >-
        Dendritic cell activation following exposure to sensitizers was
        modelled in the U937 human myeloid cell line by measuring the
        induction of the expression of CD86 by flow cytometry.
      explanation: >-
        States the measured readout and cell provenance, which is what fixes
        this model to the dendritic-cell activation step and bounds what it
        can show.
  evidence:
  - reference: PMID:25820135
    reference_title: "The Myeloid U937 Skin Sensitization Test (U-SENS) addresses the activation of dendritic cell event in the adverse outcome pathway for skin sensitization."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "U-SENS™ showed 79% specificity, 90% sensitivity and 88% accuracy."
    explanation: >-
      States what the comparison analysis against human and LLNA data
      establishes about the model's predictive performance.
- name: IL-8 Luc assay
  description: >-
    An OECD TG 442E method that reads sensitizer-induced activation of a
    dendritic-cell surrogate as IL-8 promoter-driven luciferase induction in
    the THP-G8 human monocytic reporter line, with a parallel GAPDH-promoter
    luciferase reporter used to flag cytotoxicity.
  experimental_model_type: CELL_LINE
  publication: PMID:33068120
  modeled_mechanisms:
  - target: Skin innate immune activation during sensitization
    relationship: MEASURES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      Reads the dendritic-cell activation step of sensitization as
      IL-8-promoter luciferase induction in a monocytic reporter line.
    limitations: >-
      THP-G8 is a monocytic reporter line, not a dendritic cell, so the
      luciferase readout stands in for antigen-presenting-cell activation
      rather than demonstrating it directly. The unmodified assay returns an
      indeterminate call for a chemical that will not dissolve at 20 mg/mL in
      medium, a documented false-negative route for lipophilic sensitizers
      with logKow above 3.5; being cell-only it also cannot activate
      pro-haptens.
    divergences:
    - divergence_type: PROXY_QUANTITY
      materiality: QUALIFYING
      description: >-
        IL-8 promoter-driven luciferase activity is the measured quantity;
        dendritic-cell activation in skin is the quantity of interest.
    - divergence_type: SCALE_EXTRAPOLATION
      materiality: QUALIFYING
      description: >-
        The assay observes single cells in suspension; the node is
        tissue-scale innate activation in skin.
    evidence:
    - reference: PMID:33068120
      reference_title: "The modified IL-8 Luc assay, an in vitro skin sensitisation test, can significantly improve the false-negative judgment of lipophilic sensitizers with logK(ow) values > 3.5."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: IN_VITRO
      snippet: >-
        The IL-8 Luc assay (OECD442E) is unique in that if chemicals do not
        dissolve at 20 mg/mL in medium and have no effect on IL-8 luciferase
        activity (IL8LA), they are classified as indeterminate.
      explanation: >-
        States the assay's OECD classification and readout, and names the
        solubility-driven indeterminate call this entry's limitations records
        as a false-negative route for lipophilic chemicals.
  evidence:
  - reference: PMID:33068120
    reference_title: "The modified IL-8 Luc assay, an in vitro skin sensitisation test, can significantly improve the false-negative judgment of lipophilic sensitizers with logK(ow) values > 3.5."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      This modification reduced the number of indeterminate chemicals and
      increased specificity, highlighting the unique advantage of the IL-8
      Luc assay.
    explanation: >-
      States what this study establishes about the model: a solubility-aware
      modification improves on a documented false-negative route of the base
      assay.
- name: EpiSensA
  description: >-
    A reconstructed human epidermis (RhE) gene-expression assay that reads
    hapten-driven keratinocyte activation as induced expression of ATF3, IL-8,
    DNAJB4 and GCLM, spanning an inflammatory (P2X7-dependent) and a
    cytoprotective (Nrf2-dependent) keratinocyte response. Because the RhE
    model retains a stratified stratum corneum and metabolic competence, it
    can be dosed topically and can activate lipophilic chemicals and
    pre-/pro-haptens that monolayer cell-line assays miss.
  experimental_model_type: OTHER
  publication: PMID:27965148
  modeled_mechanisms:
  - target: Hapten-driven keratinocyte electrophile sensing
    relationship: MEASURES
    fidelity: MODERATE
    model_scale: TISSUE
    description: >-
      Reads the cytoprotective arm of hapten-driven keratinocyte activation as
      Nrf2-dependent GCLM induction, alongside ATF3 and IL-8 as a separate
      P2X7-dependent inflammatory readout this entry has no node for.
    limitations: >-
      The marker genes are a trained signature rather than the Keap1-Nrf2-ARE
      pathway itself, and the inter-laboratory validation reports a lower
      specificity (63.0%) than sensitivity (92.6%) against LLNA results.
      Reported accuracy depends on the LLNA and human comparator datasets used
      to build it.
    divergences:
    - divergence_type: PROXY_QUANTITY
      materiality: QUALIFYING
      description: >-
        Induced expression of ATF3, IL-8, DNAJB4 and GCLM is the measured
        quantity; Keap1-Nrf2-ARE pathway activation is the quantity the GCLM
        arm is read as representing.
    evidence:
    - reference: PMID:27965148
      reference_title: "An in vitro skin sensitization assay termed EpiSensA for broad sets of chemicals including lipophilic chemicals and pre/pro-haptens."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: IN_VITRO
      snippet: >-
        The up-regulation of ATF3 and IL-8, or DNAJB4 and GCLM induced by the
        representative sensitizer 2,4-dinitrochlorobenzene in human
        keratinocytes was significantly suppressed by a P2X7 specific
        antagonist KN-62, or by Nrf2 siRNA, respectively, which supported
        mechanistic relevance of marker genes.
      explanation: >-
        Establishes that the GCLM/DNAJB4 arm of the signature runs through
        Nrf2, which is what maps it onto this entry's Keap1-Nrf2-ARE-driven
        node; the ATF3/IL-8 arm runs through P2X7 instead, a separate
        mechanism this entry does not yet have a node for.
  evidence:
  - reference: PMID:27965148
    reference_title: "An in vitro skin sensitization assay termed EpiSensA for broad sets of chemicals including lipophilic chemicals and pre/pro-haptens."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      the EpiSensA had sensitivity, specificity and accuracy of 93%, 100% and
      93% for 29 lipophilic chemicals (logKow≥3.5), and of 96%, 75% and 88%
      for 43 hydrophilic chemicals including 11 pre/pro-haptens, compared with
      the LLNA.
    explanation: >-
      States the assay's performance specifically on the lipophilic and
      pre-/pro-hapten chemical classes that motivate this model, as distinct
      from its overall performance.
  - reference: PMID:37897225
    reference_title: "The inter-laboratory validation study of EpiSensA for predicting skin sensitization potential."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      the predictive capacity among the three laboratories showed 92.6%
      sensitivity, 63.0% specificity, 82.7% accuracy, and 77.8% balanced
      accuracy based on murine local lymph node assay (LLNA) results.
    explanation: >-
      Gives the formal inter-laboratory validation figures for
      transferability and reproducibility, which is the model-level evidence
      that the assay performs consistently across laboratories.
  - reference: PMID:37846211
    reference_title: "Reconstructed human epidermis-based testing strategy of skin sensitization potential and potency classification using epidermal sensitization assay and in silico data."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The EpiSensA could detect 76 out of 88 sensitizers at lower
      concentrations than the LLNA, indicating that the EpiSensA has higher
      sensitivity for the detection of minor sensitizing constituents.
    explanation: >-
      Supports the assay's applicability-domain advantage over the animal
      reference method for weak or minor sensitizing constituents.
- name: SENS-IS
  description: >-
    A reconstructed human epidermis (Episkin) gene-expression assay that
    quantifies sensitization hazard and potency from a large transcriptional
    panel, the same stratum-corneum-intact, metabolically competent format
    EpiSensA also uses.
  experimental_model_type: OTHER
  publication: PMID:26795242
  modeled_mechanisms:
  - target: Skin innate immune activation during sensitization
    relationship: MEASURES
    fidelity: MODERATE
    model_scale: TISSUE
    description: >-
      Reads sensitization hazard and potency from induced expression across a
      large gene panel in reconstructed epidermis, rather than from a single
      pathway readout.
    limitations: >-
      The panel is a trained signature over many genes rather than a
      mechanistic readout of one step, so which genes drive a given call is
      not individually interpretable from the model record alone. Reported
      predictivity figures come from the ring-study and 150-chemical test sets
      used to validate it.
    divergences:
    - divergence_type: PROXY_QUANTITY
      materiality: QUALIFYING
      description: >-
        A multi-gene transcriptional signature is the measured quantity;
        dendritic-cell and keratinocyte activation in skin are the quantities
        of interest.
    evidence:
    - reference: PMID:26795242
      reference_title: "SENS-IS, a 3D reconstituted epidermis based model for quantifying chemical sensitization potency: Reproducibility and predictivity results from an inter-laboratory study."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: IN_VITRO
      snippet: >-
        The SENS-IS test protocol for the in vitro detection of sensitizers is
        based on a reconstructed human skin model (Episkin) as the test
        system and on the analysis of the expression of a large panel of
        genes.
      explanation: >-
        States the test system and readout, which is what fixes this model to
        a tissue-scale transcriptional measurement rather than a single
        pathway reporter.
  evidence:
  - reference: PMID:26795242
    reference_title: "SENS-IS, a 3D reconstituted epidermis based model for quantifying chemical sensitization potency: Reproducibility and predictivity results from an inter-laboratory study."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      data analysis confirmed the excellent capacity of the SENS-IS assay for
      predicting both hazard and potency characteristics, confirming that
      this assay should be considered as a serious alternative to the
      available in vivo sensitization tests.
    explanation: >-
      States what the comprehensive 150-chemical test set establishes about
      the model's predictive performance for both hazard and potency.
- name: Reconstructed human skin organ-on-chip with neopapillae (RhS-NP)
  description: >-
    A next-generation skin-on-chip combining a stratified, differentiated
    epidermis on a fibroblast-populated hydrogel containing dermal-papilla
    spheroids (neopapillae), cultured air-exposed under dynamic flow and dosed
    topically with a sensitizer.
  experimental_model_type: ORGAN_ON_CHIP
  publication: PMID:35893784
  modeled_mechanisms:
  - target: Keratinocyte inflammasome danger signalling
    relationship: MEASURES
    fidelity: MODERATE
    model_scale: TISSUE
    description: >-
      Reads the inflammasome-dependent danger-signalling arm of keratinocyte
      activation as secreted IL-18 and IL-1beta from a topically dosed tissue
      construct under perfusion, rather than from a monolayer.
    limitations: >-
      This is a proof-of-concept study with one sensitizer (cinnamaldehyde)
      and no irritant or non-sensitizer comparator, so sensitizer specificity
      of the cytokine panel is not established from this report alone.
    divergences:
    - divergence_type: PROXY_QUANTITY
      materiality: QUALIFYING
      description: >-
        Secreted IL-18 and IL-1beta in culture medium are the measured
        quantity; keratinocyte inflammasome activation in skin is the
        quantity of interest.
    evidence:
    - reference: PMID:35893784
      reference_title: "Proof-of-Concept Organ-on-Chip Study: Topical Cinnamaldehyde Exposure of Reconstructed Human Skin with Integrated Neopapillae Cultured under Dynamic Flow."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: IN_VITRO
      snippet: >-
        Topical cinnamaldehyde exposure to RhS-NP resulted in dose-dependent
        cytotoxicity (increased LDH release) and elevated cytokine secretion
        of contact sensitizer specific IL-18, pro-inflammatory IL-1β,
        inflammatory IL-23 and IFN-γ, as well as anti-inflammatory IL-10 and
        IL-12p70.
      explanation: >-
        Reports the inflammasome-associated cytokines IL-18 and IL-1beta
        induced by a topically dosed sensitizer in this tissue-scale system,
        which is what maps the measurement onto this node.
  evidence:
  - reference: PMID:35893784
    reference_title: "Proof-of-Concept Organ-on-Chip Study: Topical Cinnamaldehyde Exposure of Reconstructed Human Skin with Integrated Neopapillae Cultured under Dynamic Flow."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      This study demonstrates the robustness and feasibility of complex next
      generation skin models for investigating skin immunotoxicity.
    explanation: >-
      States what the study establishes about the model system itself: the
      multi-day, dynamic-flow culture is robust and feasible across
      replicates.
- name: Endothelialised skin-on-chip with flowing immune cells (MMA-6MWP)
  description: >-
    A reusable multi-well microfluidic adaptor combining reconstructed human
    skin with an endothelial layer and flowing monocyte-like MUTZ-3 cells,
    reading dendritic-cell-surrogate activation under perfusion rather than in
    static culture.
  experimental_model_type: ORGAN_ON_CHIP
  publication: PMID:39370595
  modeled_mechanisms:
  - target: Skin innate immune activation during sensitization
    relationship: MEASURES
    fidelity: MODERATE
    model_scale: TISSUE
    description: >-
      Reads dendritic-cell-surrogate activation (CD83 and CD86 upregulation on
      MUTZ-3) occurring when immune cells flow past an endothelialised skin
      construct topically exposed to a sensitizer, adding circulation and a
      vascular interface that static monolayer and reconstructed-tissue
      assays lack.
    limitations: >-
      This is a proof-of-concept demonstration with one sensitizer and no
      comparator irritant or non-sensitizer, so specificity is not established
      from this report alone. MUTZ-3 is a dendritic-cell-like line rather than
      a primary dendritic cell.
    divergences:
    - divergence_type: PROXY_QUANTITY
      materiality: QUALIFYING
      description: >-
        CD83 and CD86 on a dendritic-cell-like line are the measured
        quantity; dendritic-cell activation in skin is the quantity of
        interest.
    evidence:
    - reference: PMID:39370595
      reference_title: "Environmentally Controlled Microfluidic System Enabling Immune Cell Flow and Activation in an Endothelialised Skin-On-Chip."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: IN_VITRO
      snippet: >-
        This dynamic setting activates the monocyte-like MUTZ-3 cells (CD83
        and CD86 upregulation) upon topical exposure of RhS to a sensitizer,
        revealing the MMA-6MWP's unique capabilities compared to static
        culturing, where such activation is absent.
      explanation: >-
        Shows that this model detects dendritic-cell-surrogate activation
        that a static culture of the same cells and tissue does not, which is
        the specific capability perfusion adds over the monolayer and
        reconstructed-tissue models already in this entry.
  evidence:
  - reference: PMID:39370595
    reference_title: "Environmentally Controlled Microfluidic System Enabling Immune Cell Flow and Activation in an Endothelialised Skin-On-Chip."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      RhS viability is maintained under flow for three days and their
      morphology closely resembles that of native human skin.
    explanation: >-
      States what this study establishes about the model system itself: it
      keeps reconstructed skin viable with native-like morphology under flow
      for the duration of the proof-of-concept experiment.
animal_models:
- name: Langerin-DTA Langerhans-cell-deficient mouse
  species: Mus musculus
  genotype: human Langerin promoter-driven diphtheria toxin A BAC transgenic
  description: >-
    A BAC transgenic mouse with constitutive, durable absence of epidermal
    Langerhans cells and otherwise intact immunity, used to test whether
    Langerhans cells are required to prime contact hypersensitivity.
  publication: PMID:16356859
  modeled_mechanisms:
  - target: Skin innate immune activation during sensitization
    relationship: PERTURBS
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Removes Langerhans cells and shows contact hypersensitivity is amplified
      rather than abolished, so Langerhans cells are dispensable for priming and
      act to restrain it. This revises the antigen-presenting-cell assumption
      this node inherits.
    limitations: >-
      Mouse genetic ablation; the dendritic-cell subset that primes the response
      in the absence of Langerhans cells is not identified, in this work or
      since, and the human priming antigen-presenting cell remains unresolved.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: >-
        The requirement was tested in mouse contact hypersensitivity; no
        equivalent human ablation experiment exists.
    evidence:
    - reference: PMID:16356859
      reference_title: "Epidermal langerhans cell-deficient mice develop enhanced contact hypersensitivity."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Unexpectedly, we found that contact hypersensitivity (CHS) was amplified
        rather than abrogated in the absence of LCs.
      explanation: >-
        Establishes what this model is informative for: ablating Langerhans cells
        changes contact hypersensitivity, and in the direction opposite to an
        obligatory priming role, which is what makes the model a usable probe of
        this node rather than a confirmation of it.
- name: NALP3- and ASC-deficient contact hypersensitivity mouse
  species: Mus musculus
  genotype: Nlrp3-deficient or Pycard (ASC)-deficient
  description: >-
    Inflammasome-component knockouts exposed to contact sensitizers, used to test
    whether keratinocyte inflammasome signaling is required for the innate arm of
    contact hypersensitivity.
  publication: PMID:17429439
  modeled_mechanisms:
  - target: Keratinocyte inflammasome danger signalling
    relationship: PERTURBS
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Shows that loss of NALP3 or ASC impairs the response to contact
      sensitizers, establishing the caspase-1-dependent IL-1beta and IL-18
      processing this node asserts as a required part of the sensitization
      response rather than an incidental accompaniment of it.
    limitations: >-
      Mouse knockouts; the companion human evidence is in keratinocytes in
      vitro rather than in human skin.
    evidence:
    - reference: PMID:17429439
      reference_title: "Activation of the IL-1beta-processing inflammasome is involved in contact hypersensitivity."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        We also show that ASC- and NALP3-deficient mice display an impaired
        response to CS.
      explanation: >-
        Establishes the inflammasome as required for the contact-sensitizer
        response, which is what links this genotype to the keratinocyte
        inflammasome danger-signalling step this model is attached to.
- name: DNFB contact hypersensitivity regulatory T-cell model
  species: Mus musculus
  genotype: wild type, with FoxP3 reporter strains for Treg origin
  description: >-
    A 2,4-dinitrofluorobenzene contact hypersensitivity model used to
    characterize the regulatory T-cell population that restrains priming of
    effector CD8+ T cells.
  publication: PMID:20624644
  modeled_mechanisms:
  - target: Breakdown of regulatory T-cell-mediated hapten tolerance
    relationship: MEASURES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Measures the regulatory arm whose failure this node asserts, rather than
      reproducing that failure. Hapten immunization of wild-type mice induces a
      CD4+CD25+ regulatory T-cell population that suppresses hapten-reactive
      CD8+ effectors in a hapten-specific manner, so the model shows the
      suppression intact and characterizes the population whose loss the node
      records.
    limitations: >-
      Mouse contact hypersensitivity; the human counterpart evidence for
      hapten tolerance is in vitro nickel-responsiveness in healthy donors
      rather than in vivo.
    evidence:
    - reference: PMID:20624644
      reference_title: "Inducible costimulator (ICOS) is a marker for highly suppressive antigen-specific T cells sharing features of TH17/TH1 and regulatory T cells."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        2,4-Dinitrofluorobenzene immunization induced a population of
        CD4(+)CD25(+) Treg cells that controlled CD8(+) T-cell effector
        responses in a hapten-specific manner in vivo.
      explanation: >-
        Establishes hapten-specific regulatory T-cell control of the effector
        arm, the mechanism whose breakdown this node asserts.
- name: Mouse local lymph node assay
  species: Mus musculus
  genotype: wild type
  description: >-
    The regulatory animal method (OECD TG 429, 442A, 442B) that reads
    sensitization as proliferation of T cells in the lymph node draining the
    site of dermal exposure.
  publication: PMID:24532485
  modeled_mechanisms:
  - target: Allergen-specific T-cell priming
    relationship: MEASURES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Reads draining-lymph-node T-cell proliferation after dermal exposure, so
      it integrates penetration, metabolism, antigen-presenting-cell migration
      and clonal expansion in one whole-organism readout.
    limitations: >-
      Mouse; it misses metal sensitizers, with nickel sulfate hexahydrate
      recorded as a false negative, which is consistent with metals initiating
      through human TLR4 rather than covalent binding. Potency estimates are
      also vehicle-dependent.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: >-
        The nickel false negative is mechanistically explained by human-specific
        TLR4 coordination that mouse TLR4 cannot reproduce.
    evidence:
    - reference: PMID:24532485
      reference_title: "Development and utilization of an ex vivo bromodeoxyuridine local lymph node assay protocol for assessing potential chemical sensitizers."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Exposure to a dermal sensitizer results in proliferation of local lymph
        node T cells
      explanation: >-
        States what the assay measures, which is the lymph-node priming step
        this node records. Cut before the isotope label, whose bracketed form
        the snippet validator normalizes away.
    - reference: PMID:24532485
      reference_title: "Development and utilization of an ex vivo bromodeoxyuridine local lymph node assay protocol for assessing potential chemical sensitizers."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        As anticipated, neither non-sensitizers isopropanol and lactic acid nor
        the false negative chemical nickel II sulfate hexahydrate induced a
        positive threshold response in the assay.
      explanation: >-
        Records nickel as a known false negative of the assay, treated by the
        authors as expected behaviour rather than an anomaly.
- name: Guinea pig maximization test
  species: Cavia porcellus
  genotype: wild type
  description: >-
    The more sensitive of the two guinea pig methods recommended by OECD TG 406.
    Induction combines intradermal injection with adjuvant and a topical
    application; after a rest interval the animal is challenged with a patch at
    a non-irritant concentration and the dermal reaction is graded by eye.
  publication: PMID:11028857
  modeled_mechanisms:
  - target: Re-exposure-driven effector T-cell recruitment
    relationship: MEASURES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      The scored endpoint is the challenge-patch reaction in an animal already
      induced with the test chemical, so what the assay reads is the elicitation
      response to re-exposure rather than the priming that produced it. Priming
      is inferred from the presence of that reaction.
    limitations: >-
      Guinea pig rather than human, and the endpoint is a visually graded skin
      reaction rather than an antigen-specific cellular measurement. The
      adjuvant and intradermal induction are more aggressive than any topical
      human exposure, which is what makes this the sensitive member of the pair
      and also what makes a positive result an upper bound on potency.
      Chlorhexidine is negative in this test, and the guinea pig methods as a
      class have recorded false positives for vanillin and sulfanilic acid and
      a false negative for abietic acid.
    divergences:
    - divergence_type: PROXY_QUANTITY
      materiality: QUALIFYING
      description: >-
        Erythema and swelling graded on a four-point scale stand in for
        effector T-cell recruitment. Nothing in the readout is
        antigen-specific or cellular, so an irritant reaction and an allergic
        one are separated by the choice of a non-irritant challenge dose rather
        than by the measurement itself.
    evidence:
    - reference: PMID:11028857
      reference_title: "Comparison of the sensitivities of the Buehler test and the guinea pig maximization test for predictive testing of contact allergy."
      supports: SUPPORT
      directness: DIRECT
      quote_role: BACKGROUND
      evidence_source: OTHER
      snippet: "International test guidelines, such as the Organisation for Economic Cooperation and Development (OECD) guideline #406, recommend 2 guinea pig methods for testing of the contact allergenic potential of chemicals"
      explanation: >-
        Establishes this as one of the two methods the guideline recommends,
        which is the regulatory standing the record asserts. Graded OTHER
        because the quoted sentence describes a guideline rather than reporting
        any study, and BACKGROUND because it is the abstract's opening framing
        rather than a result this paper produced.
    - reference: PMID:32799435
      reference_title: "Trichloroethylene and trichloroethanol induce skin sensitization with focal hepatic necrosis in guinea pigs."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Allergenic reactions were scored using the Magnusson-Kligman grading
        scale to evaluate challenge patch test reactions as follows: 0, no
        visible change; 1, discrete or patchy erythema; 2, moderate, confluent
        erythema; and 3, intense erythema and swelling
      explanation: >-
        States the readout this link turns on: a graded dermal reaction at
        challenge, scored on the Magnusson-Kligman scale, which is the proxy
        the divergence records.
    - reference: PMID:11028857
      reference_title: "Comparison of the sensitivities of the Buehler test and the guinea pig maximization test for predictive testing of contact allergy."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Mercaptobenzothiazole, eugenol and chloraniline were all strong
        sensitizers in the GPMT
      explanation: >-
        Shows the test detecting three sensitizers that the Buehler method
        called negative or equivocal, which is the sensitivity difference
        separating the two records.
    - reference: PMID:20583317
      reference_title: "Skin sensitization, false positives and false negatives: experience with guinea pig assays."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        well-characterized examples of instances where both false negatives
        (including abietic acid and eugenol) or false positives (including
        vanillin and sulfanilic acid) have been recorded in guinea pig tests
      explanation: >-
        Supports the discordance in limitations, but graded INDIRECT because
        the review attributes these cases to guinea pig tests as a class and
        does not say which method produced each one. PMID:11028857 shows the
        eugenol case belongs to the Buehler test, not this one.
- name: Buehler occluded patch test
  species: Cavia porcellus
  genotype: wild type
  description: >-
    The second guinea pig method recommended by OECD TG 406. Induction is by
    repeated topical occluded patch without adjuvant, so exposure resembles
    topical human contact more closely than the maximization test does, and
    the challenge is read the same way. It is the less sensitive of the pair.
  publication: PMID:11028857
  modeled_mechanisms:
  - target: Re-exposure-driven effector T-cell recruitment
    relationship: MEASURES
    fidelity: LOW
    model_scale: ORGANISM
    description: >-
      Reads the same challenge-patch reaction as the maximization test, under a
      milder induction regimen. Fidelity is graded LOW because the method
      returns negative results for chemicals that are strong sensitizers in the
      parallel test, so a negative here does not constrain whether the
      mechanism occurred.
    limitations: >-
      Guinea pig, and the readout is a visually graded skin reaction. Eugenol
      and mercaptobenzothiazole are negative in this test while scoring as
      strong sensitizers in the maximization test under identical conditions,
      and higher induction concentrations are needed before allergenicity shows
      at all. For some allergens the protocol is not sensitive enough to
      demonstrate the potential, so negative results carry little weight.
    divergences:
    - divergence_type: PROXY_QUANTITY
      materiality: QUALIFYING
      description: >-
        As in the maximization test, a graded erythema score stands in for
        effector T-cell recruitment, with no antigen-specific or cellular
        measurement behind it.
    - divergence_type: BOUNDARY_OMISSION
      materiality: INVALIDATING
      description: >-
        The induction regimen is mild enough that known strong sensitizers fail
        to induce a detectable response, so the model's negative range does not
        correspond to absence of the mechanism. This invalidates negative
        results specifically, not positive ones.
    evidence:
    - reference: PMID:11028857
      reference_title: "Comparison of the sensitivities of the Buehler test and the guinea pig maximization test for predictive testing of contact allergy."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        eugenol and mercaptobenzothiazole were negative in the Buehler test
      explanation: >-
        The head-to-head result behind the LOW fidelity grade: both chemicals
        are strong sensitizers in the maximization test run under identical
        conditions in the same study.
    - reference: PMID:11028857
      reference_title: "Comparison of the sensitivities of the Buehler test and the guinea pig maximization test for predictive testing of contact allergy."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Higher induction concentrations were needed to show allergenicity in
        the Buehler test and for some allergens the Buehler test protocol was
        not sensitive enough to demonstrate allergenic potential
      explanation: >-
        States the sensitivity shortfall directly, which is what the
        BOUNDARY_OMISSION divergence records.
    - reference: PMID:11028857
      reference_title: "Comparison of the sensitivities of the Buehler test and the guinea pig maximization test for predictive testing of contact allergy."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "Parallel GPMT and Buehler tests were conducted according to OECD guideline #406 using a multiple-dose design"
      explanation: >-
        Stands in for the challenge-reaction readout, which no cached source
        describes for this method specifically. It establishes that the method
        was run to the same guideline as the maximization test, whose readout
        PMID:32799435 does describe.
computational_models:
- name: Skin Allergy Risk Assessment (SARA) model
  description: >-
    A Bayesian model that infers a human-relevant sensitizer potency metric and a
    risk measure for a given consumer exposure from any combination of human
    patch test, local lymph node assay, DPRA, KeratinoSens, h-CLAT or U-SENS
    data.
  model_type: MACHINE_LEARNING
  publication: PMID:35311660
  variables:
  - name: Human repeat insult patch test result
    description: >-
      Human in vivo reference input. The model takes any combination of its six
      input types rather than a fixed set.
  - name: Local lymph node assay result
    description: >-
      Murine in vivo reference input, curated in this entry as its own animal
      model.
  - name: Direct peptide reactivity assay result
    description: Peptide reactivity input.
  - name: KeratinoSens result
    description: Keratinocyte reporter input.
  - name: Human cell line activation test result
    description: >-
      Dendritic-cell-surrogate activation input, curated in this entry as its
      own experimental model, which records CD86 and CD54 as the measured
      quantity.
  - name: U-SENS result
    description: >-
      A second dendritic-cell-surrogate activation input, measured in the U937
      line.
  - name: Sensitiser potency metric
    description: >-
      The model's inferred human-relevant potency estimate, carrying explicit
      quantification of uncertainty. Neither source states the unit, so none is
      recorded here.
  - name: Margin of exposure
    description: >-
      The ratio of the potency estimate to the consumer exposure level, which is
      the quantity regressed against the clinical benchmark classifications.
    unit: '{ratio}'
  - name: Probability that an exposure is low risk
    description: >-
      The risk metric the model reports for a given consumer exposure. Deriving
      it by regression against benchmark risk classifications is what lets the
      model avoid applying safety assessment factors to a non-animal point of
      departure.
    unit: '{probability}'
  notes: >-
    Carries no mechanism link, because what it predicts is the sensitization
    outcome and this entry has no adverse-outcome node to attach that to; see the
    no_node_for_integrated_outcome_prediction discussion. The potency metric is
    inferred statistically rather than measured, and the model is anchored on
    human patch test and local lymph node assay reference data, so it inherits
    those reference sets' domains. Whether the safety assessment factors used
    with animal data suit a non-animal point of departure is unresolved.
  evidence:
  - reference: PMID:35311660
    reference_title: "Next generation risk assessment for skin allergy: Decision making using new approach methodologies."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: COMPUTATIONAL
    snippet: >-
      The SARA model utilises a Bayesian statistical approach to infer a
      human-relevant metric of sensitiser potency and a measure of risk
      associated with a given consumer exposure based upon any combination of
      human repeat insult patch test, local lymph node, direct peptide
      reactivity assay, KeratinoSens™, h-CLAT or U-SENS™ data.
    explanation: >-
      States the inputs and the inferred quantity: the model's output is a
      statement about the human outcome, not a measurement of any single
      mechanism step in this entry.
  - reference: PMID:35835397
    reference_title: "Decision making in next generation risk assessment for skin allergy: Using historical clinical experience to benchmark risk."
    supports: SUPPORT
    directness: DIRECT
    quote_role: BACKGROUND
    evidence_source: COMPUTATIONAL
    snippet: >-
      Our skin allergy risk assessment model Defined Approach uses Bayesian
      statistics to infer a human-relevant metric of sensitiser potency with
      explicit quantification of uncertainty, using any combination of human
      repeat insult patch test, local lymph node assay, direct peptide
      reactivity assay, KeratinoSens™, h-CLAT or U-SENS™ data.
    explanation: >-
      Enumerates the six input types the model accepts and states that it takes
      any combination of them, which is what the input variables above record.
      Graded BACKGROUND because the model and its input set were established in
      the authors' earlier work and this paper restates them before extending
      the approach.
  - reference: PMID:35835397
    reference_title: "Decision making in next generation risk assessment for skin allergy: Using historical clinical experience to benchmark risk."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: COMPUTATIONAL
    snippet: >-
      Margins-of-exposure (potency estimate to consumer exposure level ratio)
      are regressed against the benchmark risk classifications, enabling
      derivation of a risk metric defined as the probability that an exposure is
      low risk.
    explanation: >-
      Names the model's two reported output quantities and defines each one: the
      margin of exposure as a ratio, and the risk metric as a probability. This
      is the quantity the entry previously described only as a measure of risk.
  - reference: PMID:35835397
    reference_title: "Decision making in next generation risk assessment for skin allergy: Using historical clinical experience to benchmark risk."
    supports: SUPPORT
    directness: DIRECT
    quote_role: BACKGROUND
    evidence_source: OTHER
    snippet: >-
      It is currently unclear whether these safety assessment factors are
      appropriate when using non-animal test data to derive a point-of
      departure.
    explanation: >-
      Sources the open question recorded in this model's notes. Graded OTHER
      because the sentence states the authors' assessment of current regulatory
      extrapolation practice rather than reporting a study result, and
      BACKGROUND because it is the motivation the paper opens with rather than
      something it measured.
- name: Decision-tree defined approach with Derek Nexus and a k-nearest-neighbours potency model
  description: >-
    A defined approach that applies exclusion criteria to prioritise in chemico
    and in vitro sources covering key events 1 to 3, combines them in a two out
    of three hazard call, and assigns a potency category using a
    k-nearest-neighbours model built on human and local lymph node assay data.
  model_type: MACHINE_LEARNING
  publication: PMID:30439387
  notes: >-
    Carries no mechanism link for the same reason as the SARA model: it
    integrates the per-key-event assay readouts into a hazard and potency
    prediction for the outcome, and this entry has no adverse-outcome node. Its
    inputs cover key events 1 to 3, so no single node corresponds to it either.
    Hazard accuracy is about 85 to 86 percent against local lymph node assay and
    human reference data, but the correct potency category is reached for only 59
    to 68 percent of chemicals. The structural component rests on chemical
    structure and statistical association rather than on the molecular processes
    of sensitization.
  evidence:
  - reference: PMID:30439387
    reference_title: "A defined approach for predicting skin sensitisation hazard and potency based on the guided integration of in silico, in chemico and in vitro data using exclusion criteria."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: COMPUTATIONAL
    snippet: >-
      The DA correctly identified the hazard (sensitiser/non-sensitiser) for
      85% and 86% of a dataset with reference LLNA and human data.
    explanation: >-
      Gives the hazard performance against both reference sets, which bounds
      what the integrated prediction supports.
  - reference: PMID:42797696
    reference_title: "Accelerating Cosmetic Innovation Through Next-Generation Computational Toxicology: From Structural Alerts to Molecular Dynamics and Artificial Intelligence for Skin Sensitization Assessment."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: COMPUTATIONAL
    snippet: >-
      Although NAMs have achieved substantial regulatory maturity for this
      endpoint, most computational approaches-including structural alerts,
      read-across, and quantitative structure-activity relationship
      models-rely predominantly on chemical structure and statistical
      associations, with limited representation of the molecular processes
      underlying sensitization.
    explanation: >-
      States the general limitation this entry's own notes already record for
      this defined approach's structural component: a structural-alerts and
      statistical-association method represents chemical structure rather than
      the molecular processes of sensitization, which this review treats as a
      property of the whole class of such methods rather than of this one
      defined approach specifically.
  - reference: PMID:42797696
    reference_title: "Accelerating Cosmetic Innovation Through Next-Generation Computational Toxicology: From Structural Alerts to Molecular Dynamics and Artificial Intelligence for Skin Sensitization Assessment."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: COMPUTATIONAL
    snippet: >-
      Rather than replacing established experimental NAMs or DAs, the proposed
      workflow is intended as a complementary, tiered evidence layer for the
      early prioritization of structurally characterized cosmetic ingredients
      and for guiding subsequent experimental testing.
    explanation: >-
      Supports reading a structural-alert and read-across method, such as the
      Derek Nexus component of this defined approach, as a complementary
      prioritization tier rather than a replacement for the assay-based key
      event methods this entry curates.
- name: Skin Sensitization Prediction Model (SSPM)
  description: >-
    An algorithm that compares a proposed cosmetic or personal-care
    formulation against a database of more than 20 years of human repeat
    insult patch test (HRIPT) results on 1274 product formulations and 1226
    common ingredients, tested on 203,640 human subjects, to set
    per-ingredient and per-formulation risk thresholds from dosage density,
    occlusion potential, skin-barrier-impairment potential, and potential
    effects on immune-primed skin.
  publication: PMID:40953631
  notes: >-
    Carries no mechanism link for the same reason as the SARA model: it
    predicts a formulation-level sensitization risk call rather than
    measuring any single mechanism step, and this entry has no
    adverse-outcome node to attach that to; see the
    no_node_for_integrated_outcome_prediction discussion. It is a rule-based
    risk-threshold calculator over historical human test data rather than a
    trained statistical or machine-learning model, so no
    ComputationalModelTypeEnum value is a good fit and model_type is left
    unset. Its reference data is a separate, proprietary HRIPT database
    rather than the published HPPT database (PMID:37615678, in this entry's
    references catalog) that the other assay-validation records cite.
  evidence:
  - reference: PMID:40953631
    reference_title: "The skin sensitization prediction model: an algorithm for real-world prediction of skin sensitization risk and minimization of human sensitization testing."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The novel Skin Sensitization Prediction Model (SSPM) is a methodology
      that draws upon a database consisting of more than 20 years of
      historical HRIPT data pertaining to 1274 unique product formulations,
      comprising 1226 common ingredients, for which HRIPT testing has been
      performed on 203,640 human subjects.
    explanation: >-
      States the scale and composition of the reference database this
      algorithm is built on.
  - reference: PMID:40953631
    reference_title: "The skin sensitization prediction model: an algorithm for real-world prediction of skin sensitization risk and minimization of human sensitization testing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The SSPM sets modifiable thresholds for each individual ingredient of a
      proposed formulation and for the formulation as a whole, applying risk
      calculations based on dosage density, potential for skin occlusion,
      potential for skin barrier impairment, and potential effects on
      immune-primed skin.
    explanation: >-
      States the risk factors the algorithm calculates over, which is what
      distinguishes it from a single-assay prediction and from a trained
      classifier.
- name: Skin Allergy Risk Assessment - Integrated Chemical Environment (SARA-ICE)
  description: >-
    A Bayesian framework for quantitative skin sensitization hazard and potency
    assessment, developed by NICEATM and Unilever, that estimates the ED01: the
    dermal dose associated with a 1 percent sensitization probability in humans.
    It integrates in chemico and in vitro assay results and can also take
    historical human and murine data. Two implementations share the one model.
    SARA-ICE DA is a fixed defined approach accepted into OECD Guideline 497 for
    deriving a point of departure and usable under Mutual Acceptance of Data; it
    reports the point of departure as the geometric mean of the ED01
    distribution. SARA-ICE Extended returns the full ED01 distribution, a
    prediction uncertainty ratio, and probabilities for the GHS subcategories.
  model_type: MACHINE_LEARNING
  publication: PMID:41816003
  variables:
  - name: Direct peptide reactivity assay result
    description: >-
      Peptide reactivity input. The curated SARA-ICE training database holds 650
      direct peptide reactivity assay results.
  - name: Kinetic direct peptide reactivity assay result
    description: >-
      Rate-based peptide reactivity input, and the one input class the earlier
      SARA model did not take. The training database holds 361 results.
  - name: KeratinoSens result
    description: >-
      Keratinocyte reporter input. The training database holds 972 results, the
      largest of the non-animal input sets.
  - name: Human cell line activation test result
    description: >-
      Dendritic-cell-surrogate activation input, curated in this entry as its
      own experimental model. The training database holds 431 results.
  - name: U937 cell line activation test result
    description: >-
      A second dendritic-cell-surrogate activation input, measured in the U937
      line. The training database holds 164 results, the smallest input set.
  - name: Human predictive patch test result
    description: >-
      Human in vivo reference input, comprising human maximization test and
      human repeat-insult patch test data. The training database holds 871
      results, 506 maximization and 365 repeat-insult.
  - name: Local lymph node assay result
    description: >-
      Murine in vivo reference input, curated in this entry as its own animal
      model. The training database holds 536 results.
  - name: ED01
    description: >-
      The model's estimated quantity: the dermal dose associated with a 1
      percent sensitization probability in a theoretical human predictive patch
      test population. Reported as a distribution whose variance measures the
      uncertainty in the estimate, summarised as the interval between the 5th
      and 95th percentiles.
    unit: ug/cm2
  - name: SARA-ICE DA point of departure
    description: >-
      The point of departure the fixed defined approach reports, calculated as
      the geometric mean of the ED01 distribution on the assumption that the
      chemical is a sensitizer. The distribution is bounded above at 60000
      ug/cm2, the GHS Category 1 boundary.
    unit: ug/cm2
  - name: SARA-ICE prediction uncertainty ratio
    description: >-
      The Extended implementation's summary measure of estimate uncertainty, the
      ratio between the 5th and 50th percentiles of the ED01 distribution.
    unit: '{ratio}'
  - name: GHS subcategory probability
    description: >-
      The Extended implementation's probability of assignment to GHS Subcategory
      1A, Subcategory 1B, or Not Categorized, taken as the probability mass
      either side of the 500 and 60000 ug/cm2 thresholds.
    unit: '{probability}'
  notes: >-
    Carries no mechanism link for the same reason as the SARA model above: it
    predicts the sensitization outcome from inputs spanning several key events,
    and this entry has no adverse-outcome node to attach that to; see the
    no_node_for_integrated_outcome_prediction discussion. A separate record from
    the SARA model rather than a re-curation of it, because SARA-ICE was built
    on the Unilever SARA model with an expanded training set drawn from the
    NICEATM Integrated Chemical Environment database and a curated human
    predictive patch test set, names the ED01 as its output quantity, and takes
    kinetic direct peptide reactivity assay results, which SARA does not. The
    two implementations are recorded as one model because the source presents
    them as two implementations of one Bayesian framework, differing in output
    and in whether a user can change them: the defined approach is fixed and
    cannot be altered outside a guideline update, while Extended is versioned
    and may gain input types. The human input is the same quantity the SARA
    record calls human repeat insult patch test; the later paper uses the
    umbrella term human predictive patch test for the maximization and
    repeat-insult tests together. The defined approach requires at least two key
    event inputs to be acceptable under Mutual Acceptance of Data. Two limits on
    what the evaluation supports. Specificity for non-sensitizers was lower than
    sensitivity, so the model is more reliable at identifying a sensitizer than
    at clearing a non-sensitizer; and GHS subcategorization accuracy of 33 to 77
    percent means the potency category is considerably weaker than the hazard
    call, as it is for the defined approach recorded above. The input
    enumeration and every per-assay count in this record come from the source's
    Methods section 2.1.1, which describes a database of 434 distinct chemicals
    and nearly 5000 data points; that section is not in the cached abstract, so
    no snippet here covers those figures. Two further statements in this record
    are beyond the cached abstract in the same way, and no snippet covers them
    either: the abstract records acceptance by the OECD and use under Mutual
    Acceptance of Data without naming Guideline 497, which the source identifies
    in its introduction, and the defined approach's two-key-event input
    requirement, which is in Methods section 2.1.2. The 180 substances in the evidence
    below are the evaluation set, tested in the direct peptide reactivity assay,
    KeratinoSens and the human cell line activation test only, and are not the
    training database. What this source does not give is each input's measured
    endpoint and unit as the model consumes it: it states the assay names and
    defers the model's internals to Reinke et al. 2025 and Reynolds et al. 2019
    and 2022. The endpoints are therefore recorded here only where this entry
    already curates the assay as its own model.
  evidence:
  - reference: PMID:41816003
    reference_title: "Deriving a point-of-departure for skin sensitization risk assessments, application of the SARA-ICE tool to a diverse set of chemicals."
    supports: SUPPORT
    directness: DIRECT
    quote_role: BACKGROUND
    evidence_source: COMPUTATIONAL
    snippet: >-
      The Skin Allergy Risk Assessment - Integrated Chemical Environment
      (SARA-ICE) is a Bayesian framework for quantitative skin sensitization
      hazard and potency assessment and estimates an ED01, the dermal dose
      associated with a 1% sensitization probability in humans.
    explanation: >-
      Defines the model's output quantity, which is the ED01 variable recorded
      above: a dose at a stated sensitization probability, not a hazard call.
      Graded BACKGROUND because the model was published separately and this
      evaluation paper restates what it estimates.
  - reference: PMID:41816003
    reference_title: "Deriving a point-of-departure for skin sensitization risk assessments, application of the SARA-ICE tool to a diverse set of chemicals."
    supports: SUPPORT
    directness: DIRECT
    quote_role: BACKGROUND
    evidence_source: COMPUTATIONAL
    snippet: >-
      SARA-ICE has two implementations: (i) SARA-ICE DA, a fixed defined
      approach (DA) for point-of-departure derivation (PoD), accepted by the
      Organisation for Economic Co-operation and Development and usable under
      Mutual Acceptance of Data
    explanation: >-
      Establishes that the two implementations belong to one model, which is why
      they are curated as a single record, and gives the defined approach its
      regulatory standing. Graded BACKGROUND because acceptance into Guideline
      497 is prior fact this paper restates.
  - reference: PMID:41816003
    reference_title: "Deriving a point-of-departure for skin sensitization risk assessments, application of the SARA-ICE tool to a diverse set of chemicals."
    supports: SUPPORT
    directness: DIRECT
    quote_role: BACKGROUND
    evidence_source: COMPUTATIONAL
    snippet: >-
      SARA-ICE Extended, which returns ED01 distributions, a prediction
      uncertainty ratio, and probabilities for assignments to Globally
      Harmonized System of Classification and Labeling of Chemicals (GHS)
      categories.
    explanation: >-
      Names the three quantities the Extended implementation reports, which are
      the remaining output variables recorded above and the reason the two
      implementations are distinguishable within one record.
  - reference: PMID:41816003
    reference_title: "Deriving a point-of-departure for skin sensitization risk assessments, application of the SARA-ICE tool to a diverse set of chemicals."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: COMPUTATIONAL
    snippet: >-
      Using in chemico and in vitro skin sensitization data on 180 substances of
      interest to U.S. federal agencies, we evaluated the performance of both
      SARA-ICE versions against human and murine data and OECD Guideline 497
      DAs
    explanation: >-
      States the classes of assay data the model takes and the size of the
      evaluation set, and names the human, murine and defined-approach
      comparators the performance figures are measured against. The per-assay
      input list is in the paper's methods rather than this sentence, as the
      notes record.
  - reference: PMID:41816003
    reference_title: "Deriving a point-of-departure for skin sensitization risk assessments, application of the SARA-ICE tool to a diverse set of chemicals."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: COMPUTATIONAL
    snippet: >-
      For GHS subcategorization, accuracy ranged from 33-77% with low
      underprediction (8-21%), with concordance highest with the Guideline 497
      DAs
    explanation: >-
      Bounds the potency output: the subcategory assignment is considerably
      weaker than the hazard call, which is the limit a safety assessment
      reading this model has to carry.
  - reference: PMID:41816003
    reference_title: "Deriving a point-of-departure for skin sensitization risk assessments, application of the SARA-ICE tool to a diverse set of chemicals."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: COMPUTATIONAL
    snippet: >-
      risk calls from SARA-ICE were broadly comparable to HPPT-derived metrics
      and generally more protective than LLNA-derived PoDs
    explanation: >-
      Compares the non-animal point of departure against the human and murine
      reference metrics it is meant to replace, which is what makes the model
      usable for an exposure-led safety assessment.
treatments:
- name: Allergen and irritant avoidance
  description: >-
    Identification and avoidance of the offending allergen or irritant is the
    central management strategy for both allergic and irritant contact
    dermatitis.
  treatment_term:
    preferred_term: medical action avoidance
    term:
      id: NCIT:C15900
      label: Lifestyle Therapy
  evidence:
  - reference: PMID:25102574
    reference_title: "Identifying the causes of contact dermatitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Accurate diagnosis, avoidance of identified allergens and protection from irritants are the key to successful treatment."
    explanation: This supports avoidance of sensitizers and irritants as first-line disease management.
  - reference: PMID:9590995
    reference_title: "Irritant contact dermatitis. Clues to causes, clinical characteristics, and control."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Elimination of the offending agent and protection from further exposure are important in both diagnosis and management."
    explanation: This independently supports exposure elimination and barrier protection as core treatment measures.
- name: Topical corticosteroids
  description: >-
    Topical corticosteroids are used to treat inflammatory flares, especially in
    allergic contact dermatitis, while avoidance remains essential for long-term
    control.
  treatment_term:
    preferred_term: topical corticosteroid therapy
    term:
      id: NCIT:C122078
      label: Topical Corticosteroid Therapy
    qualifiers:
    - predicate:
        preferred_term: therapeutic agent
        term:
          id: NCIT:C1909
          label: Pharmacologic Substance
      value:
        preferred_term: therapeutic corticosteroid
        term:
          id: NCIT:C211
          label: Therapeutic Corticosteroid
    - predicate:
        preferred_term: route of administration
        term:
          id: NCIT:C38114
          label: Route of Administration
      value:
        preferred_term: topical route of administration
        term:
          id: NCIT:C38304
          label: Topical Route of Administration
  evidence:
  - reference: PMID:31757238
    reference_title: "Allergic Contact Dermatitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Topical corticosteroids can be used to treat exacerbations, but should be avoided in long-term treatment."
    explanation: This supports topical corticosteroids for short-term treatment of inflammatory exacerbations.
- name: Topical calcineurin inhibitors
  description: >-
    Topical calcineurin inhibitors can be used as steroid-sparing topical
    therapy in selected allergic contact dermatitis settings, although evidence
    is mixed across allergens and agents. Tacrolimus improved chronic
    nickel-induced allergic contact dermatitis in a randomized trial, whereas
    pimecrolimus was ineffective for established Toxicodendron-induced allergic
    contact dermatitis in a small placebo-controlled study.
  treatment_term:
    preferred_term: topical calcineurin inhibitor therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: tacrolimus
      term:
        id: CHEBI:61049
        label: tacrolimus (anhydrous)
    - preferred_term: pimecrolimus
      term:
        id: CHEBI:135888
        label: pimecrolimus
    qualifiers:
    - predicate:
        preferred_term: therapeutic agent
        term:
          id: NCIT:C1909
          label: Pharmacologic Substance
      value:
        preferred_term: tacrolimus
        term:
          id: CHEBI:61049
          label: tacrolimus (anhydrous)
    - predicate:
        preferred_term: therapeutic agent
        term:
          id: NCIT:C1909
          label: Pharmacologic Substance
      value:
        preferred_term: pimecrolimus
        term:
          id: CHEBI:135888
          label: pimecrolimus
    - predicate:
        preferred_term: route of administration
        term:
          id: NCIT:C38114
          label: Route of Administration
      value:
        preferred_term: topical route of administration
        term:
          id: NCIT:C38304
          label: Topical Route of Administration
  evidence:
  - reference: PMID:16781290
    reference_title: "A prospective randomized clinical trial of 0.1% tacrolimus ointment in a model of chronic allergic contact dermatitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CONCLUSIONS: Tacrolimus ointment 0.1% is well tolerated and significantly more effective than vehicle in treating chronically exposed, nickel-induced ACD."
    explanation: This randomized clinical trial supports topical tacrolimus as an effective steroid-sparing option for chronic nickel-induced allergic contact dermatitis.
  - reference: PMID:14700441
    reference_title: "Topical pimecrolimus in the treatment of human allergic contact dermatitis."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "CONCLUSIONS: The application of topical pimecrolimus is ineffective in the treatment of ongoing Toxicodendron-induced ACD."
    explanation: This placebo-controlled human study refutes efficacy of pimecrolimus for established Toxicodendron-induced allergic contact dermatitis.
- name: Systemic corticosteroids
  description: >-
    Systemic corticosteroids are used for more severe or widespread flares of
    allergic contact dermatitis when topical treatment alone is insufficient,
    while culprit avoidance remains the core intervention.
  treatment_term:
    preferred_term: systemic corticosteroid therapy
    term:
      id: NCIT:C122080
      label: Systemic Corticosteroid Therapy
    qualifiers:
    - predicate:
        preferred_term: therapeutic agent
        term:
          id: NCIT:C1909
          label: Pharmacologic Substance
      value:
        preferred_term: therapeutic corticosteroid
        term:
          id: NCIT:C211
          label: Therapeutic Corticosteroid
  evidence:
  - reference: DOI:10.3389/fmed.2023.1184289
    reference_title: "Advancing the understanding of allergic contact dermatitis: from pathophysiology to novel therapeutic approaches"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The treatment goal is to avoid contact with the culprit agent and use topical and/or systemic corticosteroid therapy."
    explanation: This review supports systemic corticosteroid therapy as a treatment option for allergic contact dermatitis alongside trigger avoidance.
diagnosis:
- name: Exposure history and lesion-pattern assessment
  description: >-
    Diagnosis begins with careful review of exposures, timing, occupational and
    personal products, and the anatomic distribution of dermatitis.
  diagnosis_term:
    preferred_term: clinical history and physical examination
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
  evidence:
  - reference: PMID:31757238
    reference_title: "Allergic Contact Dermatitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Diagnosis is based on a thorough history, physical examination, and patch testing."
    explanation: This supports exposure-focused clinical history and examination as the foundation of diagnosis.
  - reference: DOI:10.1073/pnas.2009192117
    reference_title: "Machine-learning–driven biomarker discovery for the discrimination between allergic and irritant contact dermatitis"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Current diagnostic regimes rely on allergy testing, exposure specification, and follow-up visits."
    explanation: This supports exposure specification and serial clinical assessment as standard parts of the diagnostic workflow for contact dermatitis.
- name: Patch testing for suspected allergic contact dermatitis
  description: >-
    Patch testing is used when allergic contact dermatitis is suspected,
    especially in recurrent or persistent disease, to identify relevant
    sensitizers and distinguish allergic from irritant dermatitis; common
    positive allergens include metals, fragrance mixes, isothiazolinones, and
    para-phenylenediamine.
  diagnosis_term:
    preferred_term: patch testing
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
    qualifiers:
    - predicate:
        preferred_term: has participant
        term:
          id: RO:0000057
          label: has participant
      value:
        preferred_term: skin of body
        term:
          id: UBERON:0002097
          label: skin of body
  evidence:
  - reference: PMID:31757238
    reference_title: "Allergic Contact Dermatitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Diagnosis is based on a thorough history, physical examination, and patch testing."
    explanation: This supports patch testing as a core diagnostic modality for allergic contact dermatitis.
  - reference: PMID:25102574
    reference_title: "Identifying the causes of contact dermatitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "If ACD is suspected the patient should be referred to secondary care for patch testing."
    explanation: This supports referral for patch testing when allergic contact dermatitis is clinically suspected.
  - reference: DOI:10.3389/fmed.2023.1184289
    reference_title: "Advancing the understanding of allergic contact dermatitis: from pathophysiology to novel therapeutic approaches"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patch testing with suspected allergens is required for a diagnosis."
    explanation: This review reinforces patch testing as the defining diagnostic procedure for allergic contact dermatitis.
differential_diagnoses:
- name: Atopic dermatitis
  disease_term:
    preferred_term: atopic dermatitis
    term:
      id: MONDO:0004980
      label: atopic eczema
  description: >-
    Atopic dermatitis can overlap with contact dermatitis when patients present
    with chronic pruritic eczema, and the two disorders may coexist in the same
    patient.
  distinguishing_features:
  - Atopic dermatitis more often shows a chronic relapsing endogenous eczema pattern with broader flexural involvement and an atopic background.
  - Contact dermatitis is more tightly linked to external exposures and tends to localize to the area of contact with the exogenous trigger.
  evidence:
  - reference: PMID:38713001
    reference_title: "Differential diagnosis of contact dermatitis: A practical-approach review by the EADV Task Force on contact dermatitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Furthermore, other conditions, with different pathogenesis and treatment, may clinically simulate contact dermatitis."
    explanation: This task-force review supports atopic dermatitis as part of the clinical differential diagnosis for contact dermatitis.
  - reference: PMID:38713001
    reference_title: "Differential diagnosis of contact dermatitis: A practical-approach review by the EADV Task Force on contact dermatitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although irritant and allergic contact dermatitis have a different pathogenesis, both are characterized by a rather typical morphology, are triggered by external factors and tend to occur primarily in the area of contact with the exogenous agent."
    explanation: This supports exposure-linked localization as a key feature that helps distinguish contact dermatitis from broader endogenous eczema such as atopic dermatitis.
- name: Psoriasis
  disease_term:
    preferred_term: psoriasis
    term:
      id: MONDO:0005083
      label: psoriasis
  description: >-
    Psoriasis can mimic chronic scaly dermatitis, especially on the hands or
    scalp, but it is a distinct immune-mediated papulosquamous disorder rather
    than an exposure-driven eczema.
  distinguishing_features:
  - Psoriasis more often produces sharply demarcated plaques with thick adherent scale and characteristic extensor, scalp, or nail involvement.
  - Contact dermatitis is usually linked to a relevant irritant or allergen exposure history and improves when the offending exposure is removed.
  evidence:
  - reference: PMID:38713001
    reference_title: "Differential diagnosis of contact dermatitis: A practical-approach review by the EADV Task Force on contact dermatitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Furthermore, other conditions, with different pathogenesis and treatment, may clinically simulate contact dermatitis."
    explanation: This practical review supports psoriasis as a plausible simulator within the differential diagnosis of contact dermatitis.
  - reference: PMID:25102574
    reference_title: "Identifying the causes of contact dermatitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Contact dermatitis results from skin contact with an exogenous substance."
    explanation: This supports exogenous exposure as a distinguishing feature of contact dermatitis relative to psoriasis.
- name: Tinea corporis
  disease_term:
    preferred_term: tinea corporis
    term:
      id: MONDO:0001461
      label: tinea corporis
  description: >-
    Dermatophyte infection can resemble localized eczematous dermatitis when
    lesions are annular and scaly, particularly if exposure history is unclear.
  distinguishing_features:
  - Tinea corporis typically shows an annular advancing border with central clearing and is confirmed by fungal testing when needed.
  - Contact dermatitis is evaluated through exposure history and, for allergic disease, patch testing rather than mycologic testing.
  evidence:
  - reference: PMID:38713001
    reference_title: "Differential diagnosis of contact dermatitis: A practical-approach review by the EADV Task Force on contact dermatitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Furthermore, other conditions, with different pathogenesis and treatment, may clinically simulate contact dermatitis."
    explanation: This supports superficial fungal infection as part of the broader mimic set that must be separated from contact dermatitis.
  - reference: PMID:31757238
    reference_title: "Allergic Contact Dermatitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Diagnosis is based on a thorough history, physical examination, and patch testing."
    explanation: This supports patch testing and exposure-based evaluation as distinguishing elements for allergic contact dermatitis.
clinical_trials:
- name: NCT05535738
  phase: PHASE_II
  status: RECRUITING
  description: >-
    Recruiting combined phase 2/3 mechanistic interventional study using a
    controlled contact dermatitis model with biologic pretreatment and suction
    blister-based skin sampling to dissect cutaneous inflammatory pathways.
  target_phenotypes:
  - preferred_term: Contact dermatitis
    term:
      id: HP:0032282
      label: Contact dermatitis
  evidence:
  - reference: clinicaltrials:NCT05535738
    reference_title: "Biologics and Blistering - Using a Contact Dermatitis Model With Biologic Medications to Study Skin Inflammation Through Suction Blistering"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The purpose of this study is to answer: how do inflammation and anti-inflammatory skin therapies work in the skin?"
    explanation: This official study record supports a currently recruiting interventional trial that uses a contact dermatitis model to study inflammatory skin responses.
  notes: ClinicalTrials.gov lists this as a combined phase 2/3 study; mapped to PHASE_II because the schema accepts a single phase value.
- name: NCT02778711
  phase: PHASE_III
  status: UNKNOWN
  description: >-
    Registered phase 3 interventional study evaluating secukinumab as a
    targeted treatment strategy for severe allergic contact dermatitis.
  target_phenotypes:
  - preferred_term: Pruritus
    term:
      id: HP:0000989
      label: Pruritus
  - preferred_term: Erythema
    term:
      id: HP:0010783
      label: Erythema
  evidence:
  - reference: clinicaltrials:NCT02778711
    reference_title: "Anti-IL-17 a New Treatment for Contact Dermatititis"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The purpose of this study is to assess the efficacy of anti-IL 17 treatment (secukinumab) in patients with known severe allergic contact dermatitis (ACD)."
    explanation: This official study record supports a registered interventional trial directly focused on severe allergic contact dermatitis.
datasets:
- accession: geo:GSE153007
  title: Genome-Wide Profiling of Lesional and Non-Lesional Skin from Atopic Dermatitis, Psoriasis, and Contact Dermatitis Skin
  description: >-
    Comparative human skin transcriptomic dataset spanning lesional and
    non-lesional samples from contact dermatitis alongside atopic dermatitis and
    psoriasis, enabling cross-disease comparison of inflammatory programs.
  organism:
    preferred_term: Homo sapiens
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: MICROARRAY
  conditions:
  - contact dermatitis skin
  - non-lesional skin
  - atopic dermatitis skin
  - psoriasis skin
  notes: >-
    Dataset record: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE153007
    Carries no evidence block: the GEO record has no summary (its summary field
    repeats the title) and no linked publication, so there is no abstract
    sentence to quote. The title, conditions and organism above are GEO's own
    values.
- accession: geo:GSE215457
  title: Inhibition of DYRK1B suppresses inflammation in allergic contact dermatitis model and Th1/Th17 immune response
  description: >-
    Transcriptomic dataset associated with DYRK1B inhibition experiments used to
    interrogate T-cell inflammatory programs relevant to allergic contact
    dermatitis and Th1/Th17 polarization.
  organism:
    preferred_term: Homo sapiens
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  evidence:
  - reference: GEO:GSE215457
    reference_title: "Inhibition of DYRK1B suppresses inflammation in allergic contact dermatitis model and Th1/Th17 immune response"
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "To investigate the inhibition effect of DYRK1B kinase function on human naïve CD4+ T cell differetionation which stimulated under Treg polarizing condition for 24 hours."
    explanation: This GEO record supports a human T-cell transcriptomic dataset tied to mechanistic allergic contact dermatitis work on inflammatory T-cell polarization.
  notes: "Dataset record: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE215457"
discussions:
- discussion_id: no_node_for_hapten_driven_keratinocyte_activation
  kind: KNOWLEDGE_GAP
  status: RESOLVED
  attaches_to:
  - pathophysiology#Hapten-driven keratinocyte electrophile sensing
  - pathophysiology#Keratinocyte inflammasome danger signalling
  prompt: >-
    The only keratinocyte activation node sits in the irritant arm, downstream of
    barrier disruption. Should the sensitization arm carry its own keratinocyte
    activation step, driven by hapten electrophilicity rather than by barrier
    injury?
  rationale: >-
    The OECD TG 442D methods and the reconstructed-epidermis assays that extend
    them measure keratinocyte activation under hapten exposure with no barrier
    injury, and they separate a sensitizer from an irritant on exactly that
    readout. The existing node is curated as the consequence of irritant barrier
    failure, so mapping those methods onto it imports a cause the methods do not
    use. Two arms of keratinocyte activation are described in this literature —
    electrophile sensing through Keap1-Nrf2-ARE, and inflammasome-dependent IL-1
    family danger signalling — and the sensitization arm of this entry currently
    passes straight from hapten exposure to innate immune activation without
    either.
  evidence:
  - reference: PMID:24794257
    reference_title: "Performance of the N/TERT epidermal model for skin sensitizer identification via Nrf2-Keap1-ARE pathway activation."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: >-
      Results show that the Keap1-Nrf2-ARE pathway is activated by the sensitizer
      DNCB in monolayer keratinocytes and as well as the LEMs and NEMs and not by
      the irritant SDS.
    explanation: >-
      Shows the keratinocyte response discriminating sensitizer from irritant,
      which is what makes hapten-driven keratinocyte activation a distinct step
      from the irritant-driven node it would otherwise be mapped to.
  resolved_date: '2026-11-01T00:00:00Z'
  resolution_note: >-
    Resolved by curating the step as two nodes rather than one. The
    sensitization arm now runs from Covalent hapten-protein adduct formation to
    Hapten-driven keratinocyte electrophile sensing and to Keratinocyte
    inflammasome danger signalling, and from each of those to Skin innate immune
    activation during sensitization. Both are the arms this discussion named, and
    together they cover AOP 40 Key Event 826. They were kept apart rather than
    merged into one Key-Event-wide node because the two models in this entry read
    different arms: the Keap1-Nrf2-ARE systems moved onto the sensing node, where
    the CAUSE_UNREPRESENTED divergence they carried no longer applies and has
    been removed, and the NALP3- and ASC-deficient mouse moved onto the
    danger-signalling node. The cost of that choice is that each node is narrower
    than Key Event 826, so a consumer mapping the Key Event onto this entry
    aggregates both. The adduct node keeps its direct edge to innate immune
    activation, which is AOP 40's separate branch from Key Event 396 to Key Event
    398. What is not resolved is which epidermal protein has to be modified for
    either arm to follow, recorded in the adduct node's own description.
- discussion_id: no_node_for_integrated_outcome_prediction
  kind: KNOWLEDGE_GAP
  attaches_to:
  - pathophysiology#Allergen-specific T-cell priming
  prompt: >-
    The entry's computational models predict sensitization hazard and potency
    for the whole outcome, not any single step. The entry's pathograph ends in
    mechanism nodes with no adverse-outcome node, so none of them has anything
    to attach to. Should the entry carry a sensitization-outcome node?
  rationale: >-
    The SARA model, SARA-ICE, the decision-tree defined approach, and the Skin
    Sensitization Prediction Model (SSPM) each take readouts spanning several
    key events, or a formulation-level patch-test history, and return one
    statement about the human outcome. That is a claim about the outcome, so
    linking any of them to a mechanism node would assert it measures a step it
    does not measure, and all four are recorded with no mechanism link for
    that reason. The regulatory framing has the same shape: OECD Guideline No.
    497 exists to turn the per-key-event assays into a single classification,
    so an entry that curates the methods but has no node for what they jointly
    predict cannot represent the integration step at all. This discussion is
    attached to the most downstream sensitization node for want of an outcome
    node, which is the gap itself. The human predictive patch test (HPPT)
    reference database (PMID:37615678, in this entry's references catalog)
    is a different case and is not part of this gap: it is the reference
    truth these predictions are benchmarked against rather than a prediction
    itself, so it carries no outcome claim to attach and is not modelled as
    an experimental_models record.
  evidence:
  - reference: PMID:35311660
    reference_title: "Next generation risk assessment for skin allergy: Decision making using new approach methodologies."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: COMPUTATIONAL
    snippet: >-
      The SARA model utilises a Bayesian statistical approach to infer a
      human-relevant metric of sensitiser potency and a measure of risk
      associated with a given consumer exposure based upon any combination of
      human repeat insult patch test, local lymph node, direct peptide
      reactivity assay, KeratinoSens™, h-CLAT or U-SENS™ data.
    explanation: >-
      The inferred quantity is a potency and risk metric for the outcome, which
      is what no node in this entry represents.
  - reference: PMID:40953631
    reference_title: "The skin sensitization prediction model: an algorithm for real-world prediction of skin sensitization risk and minimization of human sensitization testing."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The SSPM sets modifiable thresholds for each individual ingredient of a
      proposed formulation and for the formulation as a whole, applying risk
      calculations based on dosage density, potential for skin occlusion,
      potential for skin barrier impairment, and potential effects on
      immune-primed skin.
    explanation: >-
      The output is a formulation-level risk call rather than a measurement of
      any mechanism step in this entry, which is why this model is also
      recorded with no mechanism link.
- discussion_id: no_node_for_non_covalent_metal_initiation
  kind: KNOWLEDGE_GAP
  attaches_to:
  - pathophysiology#Hapten exposure
  prompt: >-
    Nickel and cobalt initiate sensitization by coordinating human TLR4 rather
    than by binding protein covalently. Should the entry carry that route
    separately, given that nickel is the most frequent cause of contact
    hypersensitivity?
  rationale: >-
    The entry's sensitization arm begins with hapten exposure understood as
    exposure to reactive chemicals that bind protein. Metals reach the same
    adverse outcome by a different initiating mechanism: direct, non-covalent
    coordination of two non-conserved histidines of human TLR4, which produces the
    proinflammatory signal. The route is also human-specific, which is the
    mechanistic explanation for nickel appearing as a false negative in the mouse
    local lymph node assay, and so it bears directly on how that assay's output
    should be read for metals.
  evidence:
  - reference: PMID:20711192
    reference_title: "Crucial role for human Toll-like receptor 4 in the development of contact allergy to nickel."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: >-
      Ni(2+)-induced TLR4 activation was species-specific, as mouse TLR4 could
      not generate this response.
    explanation: >-
      Establishes the species specificity of the metal route, which is what makes
      it both a distinct initiating mechanism and the explanation for the animal
      assay's blind spot. The quoted comparison is receptor-level rather than in
      vivo: it sits between the human TLR4 activation result and the mutant-TLR4
      studies, and the paper's animal arm is the separate transgenic experiment,
      which is not what is quoted here.
- discussion_id: unresolved_human_priming_antigen_presenting_cell
  kind: KNOWLEDGE_GAP
  attaches_to:
  - pathophysiology#Allergen-specific T-cell priming
  prompt: >-
    This node lists Langerhans cell and dendritic cell together as the
    antigen-presenting cells of allergen-specific T-cell priming. Which of
    them, or which other skin-resident or migratory antigen-presenting cell,
    actually primes the human sensitization response?
  rationale: >-
    The Langerin-DTA mouse model in this entry's animal_models already
    establishes that Langerhans cells are dispensable for priming and can be
    regulatory rather than required, which rules out the historically assumed
    answer without supplying a replacement. The question of which dendritic
    cell subset does prime the response in vivo is stated as explicitly
    unresolved in the literature, so this entry's two-cell-type listing
    records what has been ruled in and out rather than an identified answer.
  evidence:
  - reference: PMID:18460878
    reference_title: "Allergic contact dermatitis."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "The identity of the antigen presenting cells that complement Langerhans cells has yet to be identified."
    explanation: >-
      States directly that the priming antigen-presenting cell is unresolved,
      which is the gap this discussion records.
- discussion_id: no_reproducible_hla_basis_for_hapten_susceptibility
  kind: KNOWLEDGE_GAP
  attaches_to:
  - pathophysiology#Allergen-specific T-cell priming
  prompt: >-
    HLA class II associations are an established determinant of individual
    susceptibility to sensitization by a protein allergen. Is there a
    reproducible HLA basis for susceptibility to a low-molecular-weight
    contact hapten specifically?
  rationale: >-
    HLA-DR7 is associated with occupational sensitization to a protein
    respiratory allergen (rat urinary lipocalin), with amino acid analyses of
    the associated molecules offering a biologically plausible explanation.
    That demonstrates HLA class II restriction can govern susceptibility to an
    allergen in principle, but the allergen there is a whole protein presented
    without the covalent hapten-protein adduct chemistry this entry's
    sensitization arm runs on, and the association is for sensitization
    without symptoms as well as with them. No comparably reproduced HLA
    association for a low-molecular-weight contact hapten is curated in this
    entry, so whether contact-hapten susceptibility has an HLA basis at all
    remains open rather than answered by extension from the protein-allergen
    literature.
  evidence:
  - reference: PMID:12704360
    reference_title: "HLA associations with occupational sensitization to rat lipocalin allergens: a model for other animal allergies?"
    supports: SUPPORT
    directness: INDIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      HLA-DR7 was associated with sensitization (odds ratio [OR], 1.82; CI,
      1.12-2.97), respiratory symptoms at work (OR, 2.96; CI, 1.64-5.37) and,
      most strongly, sensitization with symptoms (OR, 3.81; CI, 1.90-7.65).
    explanation: >-
      Establishes an HLA class II association with sensitization for a
      protein allergen, which is the contrast case this discussion uses: the
      allergen is a protein presented without covalent haptenation, so the
      association does not itself establish an HLA basis for a contact
      hapten's T-cell priming step.
- discussion_id: unidentified_proximal_route_to_hapten_inflammasome_activation
  kind: KNOWLEDGE_GAP
  attaches_to:
  - pathophysiology#Keratinocyte inflammasome danger signalling
  prompt: >-
    A contact hapten activates the keratinocyte NLRP3 inflammasome, but the
    proximal cellular event that triggers assembly is not identified here.
    Which route does a hapten use: potassium efflux, lysosomal rupture,
    mitochondrial damage with reactive oxygen species, or another?
  rationale: >-
    The evidence curated on this node establishes an assembled,
    caspase-1-activating NLRP3 complex in hapten-exposed keratinocytes, which
    is what the nlrp3_inflammasome_activation module's assembly node asks for.
    It identifies none of the proximal routes that define that module's
    upstream Activating Danger Signal node, which is why conformance is
    anchored on assembly rather than on the danger signal. The route is not a
    curation omission that reading one more paper would close: the candidate
    routes are interrelated and mutually causative, the general NLRP3
    literature has not reached consensus on a unifying route, and none of the
    candidate routes has been curated for a contact hapten specifically.
    Answering this would add a new upstream pathophysiology node conforming to
    Activating Danger Signal; until then the step is recorded as assembly
    alone.
  evidence:
  - reference: PMID:23809161
    reference_title: "K⁺ efflux is the common trigger of NLRP3 inflammasome activation by bacterial toxins and particulate matter."
    supports: SUPPORT
    directness: INDIRECT
    quote_role: BACKGROUND
    evidence_source: OTHER
    snippet: >-
      Several events have been proposed to explain the activation of the NLRP3
      inflammasome including the production of reactive oxygen species (ROS),
      mitochondrial damage, lysosomal damage, formation of large non-specific
      pore in the cell membrane, and cytosolic K+ efflux
    explanation: >-
      Enumerates the candidate proximal routes and so defines the set this gap
      is a choice within. The quote is the paper's introduction restating
      proposals established elsewhere rather than its own result, hence
      BACKGROUND; it describes a field of competing proposals rather than one
      study's evidence, hence OTHER. The paper's own result, that potassium
      efflux is the common trigger, is curated on the module's Activating
      Danger Signal node and is not extended to haptens by this entry.
references:
- reference: PMID:37615678
  title: A database of human predictive patch test data for skin sensitization.
  findings: []
- reference: PMID:19839974
  title: Effector and regulatory mechanisms in allergic contact dermatitis.
  findings: []
- reference: PMID:25102574
  title: Identifying the causes of contact dermatitis.
  findings: []
- reference: PMID:25274939
  title: Irritant contact dermatitis.
  findings: []
- reference: PMID:31757238
  title: Allergic Contact Dermatitis.
  findings: []
- reference: PMID:38713001
  title: "Differential diagnosis of contact dermatitis: A practical-approach review by the EADV Task Force on contact dermatitis."
  findings: []
- reference: PMID:39709083
  title: "Epidermal spongiotic Langerhans cell collections, but not eosinophils, are a clue to the diagnosis of allergic contact dermatitis: A series of 170 clinically- and patch test-confirmed cases."
  findings: []
- reference: PMID:26370659
  title: Prevalence of contact allergy in the general population in different European regions.
  findings: []
- reference: PMID:23343419
  title: Filaggrin mutations are strongly associated with contact sensitization in individuals with dermatitis.
  findings: []
- reference: PMID:23039796
  title: Impact of atopic dermatitis and loss-of-function mutations in the filaggrin gene on the development of occupational irritant contact dermatitis.
  findings: []
- reference: PMID:19580930
  title: Management of occupational dermatitis.
  findings: []
- reference: PMID:30465037
  title: "Allergic Contact Dermatitis to Mastisol Adhesive Used for Skin Closure in Orthopedic Surgery: A Case Report."
  findings: []
- reference: PMID:41804652
  title: "Prevalence of Contact Allergy to Isothiazolinones in Dermatitis Patients From 2000 to 2025: A Systematic Review and Meta-Analysis."
  findings: []
- reference: PMID:41784277
  title: Systematic Review and Meta Analysis of Allergic Contact Dermatitis from 2-Octyl Cyanoacrylate Adhesives.
  findings: []
- reference: PMID:41064302
  title: "Mojito-Induced Phytophotodermatitis: A Case of Lime-Triggered Skin Reaction."
  findings: []
- reference: PMID:40921440
  title: "Allergic Contact Dermatitis Triggered by a Mare's Milk-Based Soap."
  findings: []
- reference: DOI:10.1073/pnas.2009192117
  title: Machine-learning–driven biomarker discovery for the discrimination between allergic and irritant contact dermatitis
  findings: []
- reference: DOI:10.1155/2013/916497
  title: Cytokines and Chemokines in Irritant Contact Dermatitis
  findings: []
- reference: DOI:10.3389/fmed.2023.1184289
  title: "Advancing the understanding of allergic contact dermatitis: from pathophysiology to novel therapeutic approaches"
  findings: []
- reference: DOI:10.1111/all.16642
  title: "Transcriptomic Analysis of Allergic Patch Test Reactions in Non‐Atopic Patients: A Comparative Study Across Multiple Allergens"
  findings: []
- reference: PMID:38385441
  title: "The skin sensitization adverse outcome pathway: exploring the role of mechanistic understanding for higher tier risk assessment."
  findings: []

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References & Deep Research