Sulfur Mustard Poisoning

Environmental MONDO:0800387 Pathograph 48 Show in embeddings browser

Sulfur mustard poisoning is the injury syndrome caused by exposure to bis(2-chloroethyl) sulfide, a lipophilic bifunctional alkylating vesicant used as a chemical weapon from 1917 onwards and, in the modern era, chiefly during the 1980-1988 Iran-Iraq war. The agent penetrates skin, cornea and airway epithelium and cyclizes intramolecularly to a reactive episulfonium ion, which alkylates the N7 position of guanine and crosslinks DNA. Because the molecule carries two chloroethyl arms it can react with two nucleophiles at once, so the crosslinks block replication and transcription outright. Unrepaired strand breaks drive PARP1 hyperactivation, which consumes NAD+ and collapses cellular ATP, switching the death mode from apoptosis to necrosis; in parallel the agent depletes glutathione and leaves the cell without its principal antioxidant buffer. Two features set this entry apart from other acute toxic exposures. The first is the latent period - cellular injury begins within minutes, but the burn, the keratoconjunctivitis and the airway injury declare themselves hours later. The second is the delayed arm: decades after a single exposure, survivors develop bronchiolitis obliterans, bronchiectasis and pulmonary fibrosis, a mustard keratopathy that emerges after a silent interval of years, and an elevated risk of lung cancer. That delayed disease, not the acute burn, is what kills people, and it is why this entry carries a `progression:` block with a distinct delayed-onset phase.

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Discussions and Knowledge Gaps

What sustains sulfur mustard disease for decades after a single exposure, when the agent and its metabolites have been cleared within weeks?

KNOWLEDGE GAP sm_delayed_toxicity_mechanism_unknown

Attached to

pathophysiology#Chronic IL-17-Dependent Airway Inflammation

This is the central unanswered question of the entry. Sulfur mustard metabolites are excreted within a few weeks and do not accumulate, so nothing of the original insult is still present when the delayed disease emerges. The chain curated here carries the mechanism as far as chronic IL-17-dependent inflammation and shows that it persists, but it does not explain why it persists rather than resolving as inflammation normally does. Epigenetic perturbation has been proposed as the missing step and remains a hypothesis. Until it is settled, the causal edge from acute injury to chronic inflammation in this entry is descriptive rather than mechanistic.

Show evidence (2 references)

PMID:21218101 SUPPORT Other

"Unfortunately, it is not clear how mustard gas causes severe multi-organ damage years after even a single exposure"

States the gap directly.

PMID:21218101 SUPPORT Other

"A possible explanation of the delayed mechanism would be epigenetic perturbations caused by SM even after single exposure."

The leading proposed explanation, presented by its authors as a proposal rather than a finding.

Why does mustard gas keratopathy appear after a silent interval of years to decades rather than following on from the acute corneal injury?

KNOWLEDGE GAP sm_keratopathy_latency_unexplained

Attached to

pathophysiology#Limbal Stem Cell Deficiency and Delayed Mustard Gas Keratopathy

The acute corneal lesion re-epithelialises within days, and the delayed keratopathy then arrives after an interval during which the eye looks well. Limbal stem cell deficiency is the accepted structural explanation for the end state, but it does not by itself account for the timing: a stem cell pool destroyed at exposure should produce failure of corneal renewal sooner. The authors of the largest delayed-keratitis series say outright that the pathophysiology of these changes is not clearly identified, and raise a possible immune-mediated component from the histology. The edge from limbal injury to delayed keratopathy in this entry rests on clinical natural history.

Show evidence (2 references)

PMID:15808253 SUPPORT Human Clinical

"The pathophysiologic features of these changes are not clearly identified."

The authors state the gap for the delayed ocular lesion specifically.

PMID:15808253 SUPPORT Human Clinical

"Based on the clinical appearance of the lesions and the histopathologic findings, an immune-mediated component seems possible."

Records the hypothesis the authors offer for the unexplained interval.

Can any animal model reproduce human sulfur mustard blistering, and what does it mean for countermeasure development that none does?

HUMAN MODEL MISMATCH sm_no_animal_model_reproduces_human_blistering

Attached to

pathophysiology#Dermal-Epidermal Separation and Vesication

The cutaneous arm of this entry has an evidence problem the pulmonary arm does not. Rodent skin models reproduce epidermal cell death and the inflammatory response but do not form true human-type blisters, so the vesication node - the lesion the agent is named for - is supported in humans by clinical description and in animals only by proxies such as ear weight and morphometric thickness. This is why the vesication evidence in this entry is thinner than the fibrosis evidence, and why a cutaneous countermeasure that works in a mouse ear cannot be assumed to work on a human blister.

Show evidence (1 reference)

PMID:40034085 SUPPORT INDIRECT Other

"had an increase in ear weights, morphometric thickness, edema, inflammatory cell infiltration, and signs of vesication at all time points"

Shows what the animal vesication endpoint actually measures - ear weight and thickness - rather than a blister.

Sulfur mustard raises the risk of basal and squamous cell carcinoma at exposed skin sites. Why does this entry model malignant transformation of bronchial epithelium but not of skin, and what would close the gap?

KNOWLEDGE GAP sm_cutaneous_malignancy_not_modelled

Attached to

pathophysiology#Skin Ulceration and Impaired Wound Healing

The asymmetry is real and it is not a claim about relative risk. This entry carries a Malignant Transformation of Chronically Injured Bronchial Epithelium node with a molecular correlate and a four-decade cohort behind it, and nothing equivalent for skin - even though the same alkylation, necrosis and chronic-injury nodes run through the cutaneous arm, and the occupational literature reports raised BCC and SCC incidence in mustard-manufacturing workers. The reason is citability, not judgement: the deep-research report cites the cutaneous malignancy finding to an NCBI Bookshelf chapter rather than to a fetchable reference, so no exact snippet can be taken from anything cached here. Closing this needs a primary cohort study of skin cancer incidence in an exposed population. It is recorded as a structured gap rather than a line in notes so that it is findable by query and has somewhere to be closed.

What is the dose relationship, frequency and time course of haematopoietic suppression after sulfur mustard exposure, and is there a primary clinical series that reports it?

KNOWLEDGE GAP sm_haematopoietic_suppression_evidence_thin

Attached to

pathophysiology#Haematopoietic Suppression

Haematopoietic suppression is now curated as a node, but on evidence thin enough that the gap is worth stating rather than closing. The only quotable statement in this entry's cache is a review's secondhand assertion (PMID:40034085) that sulfur mustard causes blood cytopenia and bone marrow destruction, attributed to another author and carrying no counts, frequency, dose relationship or time course. Nothing else reaches it: the radiation-comparison workshop report (PMID:37852927) records only that the case could have been made to include bone-marrow myelosuppression in that meeting's scope, which is a statement about the meeting rather than about the toxicity. An earlier draft of this discussion, and of the entry's notes, asserted that no cached source reported it quotably at all. That was false - the review sentence was already in the cache, and this entry already quoted the tail of the same sentence elsewhere. Recording the correction here because the failure is instructive: a claim about what the cache does not contain is the easiest kind of claim to get wrong, and the cheapest to check. Closing this properly needs a primary clinical series reporting blood counts in exposed patients, with a dose relationship.

Show evidence (1 reference)

PMID:37852927 NO_EVIDENCE Other

"the programs elected to focus on similarities between radiation exposure and SM-induced injuries to the lung and skin; although arguably, the case could also have been made to include bone marrow myelosuppression"

Cited to show precisely what this source does and does not say: it records a scoping decision about a meeting, and is not evidence that sulfur mustard causes myelosuppression.

⚙

Pathophysiology

Sulfur Mustard Penetration and Episulfonium Ion Formation

Sulfur mustard is lipophilic and crosses skin, corneal and airway epithelium within minutes of contact. Inside the cell it cyclizes intramolecularly, displacing chloride to form a strained three-membered episulfonium (ethylene sulfonium) ring. That cation, not the parent molecule, is the alkylating electrophile, and because the parent carries two chloroethyl arms the reaction can happen twice on the same molecule. Most of a dermal dose stays in the epidermis, which is why the cutaneous lesion is superficial and the systemic dose is small relative to the local injury.

skin epidermis UBERON:0001003

Downstream

DNA N7-Guanine Alkylation and Interstrand Crosslinking The episulfonium ion is the species that alkylates DNA.

Glutathione Depletion and Oxidative Stress The same electrophile is consumed by conjugation to glutathione, which is the cell's first line of defence and the reason the thiol pool falls.

Melanocyte Injury and Dyspigmentation

Haematopoietic Suppression Requires systemic absorption, which is why this arm appears only after significant exposure while the local lesions appear after any.

Show evidence (2 references)

PMID:40034085 SUPPORT Other

"SM and NM are easily absorbed through the skin and can cause immediate cutaneous injury and blistering"

Establishes rapid transcutaneous absorption as the first step of the cutaneous lesion.

PMID:40034085 SUPPORT Other

"states that 70% of the SM resides in the epidermis and the rest in the basement membrane of the dermis"

Supports the claim that the absorbed dose is retained in the epidermis and basement membrane zone rather than distributing systemically, which is why the cutaneous injury is local and superficial.

DNA N7-Guanine Alkylation and Interstrand Crosslinking

The episulfonium ion attacks nucleophilic sites in DNA, predominantly the N7 position of deoxyguanosine. Because sulfur mustard is bifunctional, a single molecule can alkylate two nucleophiles, producing intrastrand and interstrand DNA crosslinks as well as DNA-protein crosslinks. An interstrand crosslink tethers the two strands together and physically blocks the replication and transcription machinery, so the lesion is cytotoxic rather than merely mutagenic. Replication forks that collide with an unrepaired crosslink generate double-strand breaks.

interstrand cross-link repair GO:0036297 ↑ INCREASED DNA damage response GO:0006974 ↑ INCREASED

Downstream

PARP1 Hyperactivation and NAD+ Depletion Strand breaks arising from blocked and collapsed replication forks are the signal PARP1 detects.

Show evidence (1 reference)

PMID:40034085 SUPPORT Other

"it causes DNA replication cessation because it alkylates N7 of a deoxyguanosine residue and a cysteine residue"

Names the specific alkylation site for sulfur mustard and states the functional consequence, replication arrest.

PARP1 Hyperactivation and NAD+ Depletion

PARP1 detects DNA strand breaks and responds by transferring ADP-ribose units from NAD+ onto nuclear acceptor proteins. At the lesion densities sulfur mustard produces, this repair response becomes the injury: PARP1 consumes the cellular NAD+ pool, and because NAD+ is an obligate cofactor for glycolysis, the TCA cycle and the electron transport chain, ATP synthesis fails with it. The consequence is a switch in death mode - a cell with modest damage apoptoses or repairs, a cell with severe damage runs out of energy and dies by necrosis. Necrosis rather than apoptosis is what makes the lesion inflammatory and slow to heal.

protein poly-ADP-ribosylation GO:0070212 ↑ INCREASED NAD+ consumption by poly-ADP-ribosylation GO:0019677 ↑ INCREASED

Downstream

Cellular Energy Collapse and Epithelial Necrosis

Show evidence (2 references)

PMID:21218101 SUPPORT Other

"In case of severe DNA injury, overactivation of PARP-1 depletes the cellular stores of NAD+, an essential cofactor in the glycolytic pathway, the tricarboxylic acid cycle, and the mitochondrial electron transport chain."

Supports PARP1 overactivation as the mechanism of NAD+ depletion and names the pathways that depend on it.

PMID:21218101 SUPPORT Other

"Experimental evidence has established that the PARP-1 pathway of cell death plays a pivotal role in tissue injury and organ dysfunction in mustard-induced acute toxicity"

Attributes the tissue-level injury specifically to the PARP1 death pathway in mustard toxicity.

Glutathione Depletion and Oxidative Stress

Sulfur mustard depletes intracellular glutathione by direct conjugation to the electrophile and, in chronically exposed human lung, by downregulation of glutathione reductase, the enzyme that regenerates reduced glutathione from its disulfide. The cell therefore loses its principal antioxidant buffer at the moment it most needs it, and reactive oxygen and nitrogen species accumulate. This arm is largely independent of the DNA-alkylation arm and synergistic with it: both converge on the same dying cell. Human mustard lung shows the paradoxical signature of the pathway under strain - glutathione peroxidases, transferases and synthetase are all overexpressed while glutathione reductase is strongly suppressed and the substrate they need is scarce.

glutathione metabolic process GO:0006749 ↓ DECREASED cellular response to oxidative stress GO:0034599 ↑ INCREASED

glutathione reductase activity GO:0004362 ↓ DECREASED

Downstream

Cellular Energy Collapse and Epithelial Necrosis

Show evidence (3 references)

PMID:29676192 SUPPORT Human Clinical

"Glutathione peroxidases (GPXs), glutathione-s-transferases (GSTs), and glutathione synthetase (GSS) enzymes were overexpressed in mustard lung biopsies, while glutathione reductase (GSR) was significantly downregulated (14.95-fold)."

Direct human lung-biopsy evidence for the enzyme pattern described, and the source of the specific claim that glutathione reductase is the suppressed step.

PMID:29676192 SUPPORT Human Clinical

"GSH depletion induced by GSR downregulation may be a major mechanism of SM toxicity on human lung."

The authors' own statement that glutathione depletion is a major toxicity mechanism, not merely a correlate.

PMID:33002157 SUPPORT Model Organism

"Inflammatory changes in the lung were associated with oxidative stress, as reflected by increased expression of heme oxygenase (HO)-1."

Independent in vivo corroboration that the pulmonary injury carries an oxidative-stress signature.

Cellular Energy Collapse and Epithelial Necrosis

Keratinocytes, corneal epithelial cells and airway epithelial cells that have lost their NAD+ and ATP pools and their antioxidant buffer die. The death mode is dose-dependent rather than uniform: a cell with modest damage apoptoses, a cell whose energy has collapsed cannot run the ATP-dependent apoptotic programme and dies by necrosis. Both are present in the injured airway, and the balance between them is what the PARP1 arm sets. Necrotic death spills intracellular contents into the tissue, which is what converts a molecular lesion into an inflammatory one. Do not read this node as claiming the death is exclusively necrotic - the evidence below includes a direct demonstration of early apoptosis in the same inhalation model.

keratinocyte CL:0000312 bronchial epithelial cell CL:0002328 corneal epithelial cell CL:0000575

cell death GO:0008219 ↑ INCREASED

Animal models

Rat sulfur mustard vapour inhalation model (biphasic lung injury) Rat recapitulates Reproduces airway epithelial necrosis after inhalational exposure.

Downstream

Acute Pro-Inflammatory Cytokine Burst and Neutrophil Recruitment

Dermal-Epidermal Separation and Vesication

Corneal and Limbal Epithelial Injury

Show evidence (3 references)

PMID:21218101 SUPPORT Other

"Acute toxicity of SM is related to reactive oxygen and nitrogen species, DNA damage, poly(ADP-ribose) polymerase activation and energy depletion within the affected cell."

Summarises the four converging inputs to the dying cell that this node represents.

PMID:33002157 SUPPORT Model Organism

"including epithelial necrosis and hyperplasia in the distal bronchioles, thickened alveolar walls, enlarged vacuolated macrophages, and interstitial fibrosis"

Histological confirmation that necrotic epithelial death occurs in an in vivo sulfur mustard model.

PMID:22465472 REFUTE Model Organism

"SM exposure triggers an early apoptotic cell death"

Recorded as REFUTE against any reading of this node as exclusively necrotic. TUNEL-positive cells rise early after sulfur mustard inhalation in the same model, so apoptosis is a real component of the epithelial death and not merely a low-dose special case.

Acute Pro-Inflammatory Cytokine Burst and Neutrophil Recruitment

Necrotic epithelium releases a burst of pro-inflammatory cytokines and chemokines within the first 72 hours, and neutrophils follow them into the tissue. In the rat inhalation model this burst comprises IL-1 beta, TNF-alpha, IL-2, IL-6 and the chemokines CCL2, CCL3, CCL11 and CXCL1. In exposed patients, serum IL-6 tracks the severity of the pulmonary complication, which is the human counterpart of the same signal. This node substitutes the chemical vesicant insult for the generic injury the fibrosis module expects at this step.

neutrophil CL:0000775 alveolar macrophage CL:0000583

inflammatory response GO:0006954 ↑ INCREASED leukocyte migration GO:0050900 ↑ INCREASED neutrophil chemotaxis GO:0030593 ↑ INCREASED

Downstream

Chronic IL-17-Dependent Airway Inflammation The acute cytokine and chemokine response does not terminate; the same mediators stay elevated as the infiltrate turns lymphocytic.

Show evidence (2 references)

PMID:22465472 SUPPORT Model Organism

"In rats, SM induced a burst of pro-inflammatory cytokines/chemokines within 72 h, including IL-1β, TNF-α, IL-2, IL-6, CCL2, CCL3, CCL11, and CXCL1 that was associated with neutrophilic infiltration into the lung."

Names the mediators and the 72-hour window, and links them to neutrophil influx.

PMID:25031491 SUPPORT Human Clinical

"patients with moderate to severe symptoms had a serum level of (0.95±0.92 ng/ml) which was significantly higher than mild (0.47±0.54) and control (0.34±0.12) groups"

Human evidence that one of the mediators identified in the animal model scales with clinical severity, supporting relevance of this node in people.

Dermal-Epidermal Separation and Vesication

Death of basal keratinocytes at the dermal-epidermal junction, together with the proteases released from them, separates the epidermis from the dermis and produces the blister that gives the agent its name. The lesion is delayed relative to the chemistry: alkylation is complete within minutes, while the visible lesion takes hours. In the mouse ear vesicant model the equivalent lesion rises sharply between 4 and 8 hours after exposure and stays elevated at 24 hours. The figures commonly quoted for humans - erythema at 2 to 24 hours, vesication at 24 to 48 - are not stated in any source cached for this entry and are deliberately not asserted here.

basal cell of epidermis CL:0002187

skin epidermis UBERON:0001003

Downstream

Skin blistering

Erythema

Skin Ulceration and Impaired Wound Healing

Show evidence (2 references)

PMID:40034085 SUPPORT Other

"It has been found that SM manifests via vesication of the skin and then later leads to systemic toxicity"

Establishes vesication as the defining cutaneous lesion of sulfur mustard.

PMID:40034085 SUPPORT INDIRECT Other

"This study also found that vesication sharply increased between 4 and 8 h after exposure, was well established, and remained elevated at 8‐ and 24‐h post‐exposure"

Times the vesication in an animal model, supporting the delayed-onset claim. Indirect because the quoted experiment used the nitrogen mustard analogue HN2 rather than sulfur mustard itself.

Skin Ulceration and Impaired Wound Healing

Once the blister roof is lost the wound behaves unlike a thermal burn of comparable depth: healing is slow, the ulcer is prone to secondary infection, and scarring follows. Because the underlying keratinocyte population has itself been alkylated, the tissue is repairing with cells whose replicative capacity has been damaged.

wound healing GO:0042060 ↓ DECREASED

Show evidence (1 reference)

PMID:40034085 SUPPORT Other

"delayed severe skin injury that can last for years after initial exposure"

Supports the persistence of the cutaneous lesion well beyond the acute burn.

Corneal and Limbal Epithelial Injury

The cornea is the most sensitive tissue to sulfur mustard in the acute phase. Acute injury presents after a latent period of hours as lacrimation, blepharospasm, severe conjunctivitis and corneal erosion. Most acute lesions re-epithelialise within days. The consequential injury is to the limbus, the narrow zone at the corneal margin that houses the stem cells responsible for renewing corneal epithelium.

corneal epithelial cell CL:0000575 limbal epithelial stem cell CL:4033093

cornea UBERON:0000964

Downstream

Keratoconjunctivitis

Photophobia

Limbal Stem Cell Deficiency and Delayed Mustard Gas Keratopathy

Show evidence (2 references)

PMID:35974928 SUPPORT Other

"Clinical findings in acute conditions include; sore eyes, lacrimation, burning sensation, edematous, obvious blepharospasm of eyelids, severe conjunctivitis, erosion and opacity of the cornea."

Describes the acute ocular lesion this node represents.

PMID:35974928 SUPPORT Other

"Limbal epithelial stem cell deficiency and dysfunction of limbic stroma are due to destruction."

Attributes the limbal deficiency to destruction of the stem cells and their stromal niche.

Chronic IL-17-Dependent Airway Inflammation

The acute neutrophilic burst does not resolve. From about two weeks after a single inhalational exposure the infiltrate becomes lymphocytic, cytokine expression stays elevated, and IL-17-positive cells accumulate in the inflamed regions of the lung. This persistence is the hinge of the whole entry: it is the mechanism by which a single exposure produces disease that is still progressing decades later, and it is why the chronic pulmonary disease develops in patients whose acute exposure was unremarkable.

IL-17-positive T cell CL:0000084

inflammatory response GO:0006954 ↑ INCREASED

lung UBERON:0002048

Animal models

Cynomolgus monkey sulfur mustard inhalation model Cynomolgus monkey recapitulates Demonstrates IL-17-positive cell accumulation in the chronic phase in a primate.

Downstream

Chronic bronchitis

Asthma

TGF-beta Driven Myofibroblast Activation

Show evidence (2 references)

PMID:22465472 SUPPORT Model Organism

"At 2 wks and beyond (chronic phase), lymphocytic infiltration and continued elevated expression of cytokines/chemokines were sustained."

Documents the transition from acute neutrophilic to sustained lymphocytic inflammation.

PMID:22465472 SUPPORT Model Organism

"At ≥30 days, SM inhalation promoted the accumulation of IL-17(+) cells in the inflamed areas of monkey lungs."

Establishes the IL-17 arm in a non-human primate as well as in rodent, which is the basis for naming this node after IL-17 rather than after generic chronic inflammation.

TGF-beta Driven Myofibroblast Activation

TGF-beta is undetectable during the acute phase and is strongly upregulated in the chronic phase, where it drives fibroblast-to-myofibroblast conversion and proliferation. PDGF and PAI-1 rise alongside it. The temporal separation matters: the profibrotic signal is not part of the initial injury but a consequence of inflammation that failed to resolve, which is why the fibrosis is delayed rather than immediate.

myofibroblast cell CL:0000186 fibroblast CL:0000057

transforming growth factor beta receptor signaling pathway GO:0007179 ↑ INCREASED

Animal models

Rat sulfur mustard inhalation model of bronchiolitis obliterans and pulmonary fibrosis Rat recapitulates Measures the profibrotic mediators directly in lung, lavage fluid and plasma at 28 days.

Downstream

Bronchiolar and Interstitial Collagen Deposition

Show evidence (2 references)

PMID:22465472 SUPPORT Model Organism

"TGF-β, which was undetectable in the acute phase, was strongly upregulated in the chronic phase"

Establishes both the TGF-beta upregulation and its restriction to the chronic phase.

PMID:29314868 SUPPORT Model Organism

"Concentrations of TGF-β, PDGF, and PAI-1 were elevated at 28 days in lung, BAL fluid, and/or plasma."

Independent in vivo measurement of the profibrotic mediators in a second sulfur mustard rat model.

Bronchiolar and Interstitial Collagen Deposition

Activated myofibroblasts deposit collagen in the bronchiolar wall and the interstitium. In the small airways this produces the concentric intraluminal and peribronchiolar scarring that defines bronchiolitis obliterans; in the parenchyma it produces interstitial fibrosis. Both are present together in the rat inhalation model and both worsen with time.

myofibroblast cell CL:0000186

extracellular matrix organization GO:0030198 ↑ INCREASED collagen fibril organization GO:0030199 ↑ INCREASED collagen biosynthetic process GO:0032964 ↑ INCREASED

bronchiole UBERON:0002186

Downstream

Pulmonary fibrosis

Bronchiectasis

Bronchiolitis Obliterans and Progressive Airflow Obstruction

Show evidence (2 references)

PMID:22465472 SUPPORT Model Organism

"The chronic phase was also associated with myofibroblast proliferation, collagen deposition, and presence of IL-17(+) cells."

Links myofibroblast proliferation to collagen deposition in the chronic phase.

PMID:29314868 SUPPORT Model Organism

"Histopathology confirmed the presence of both BO and PF, and both gradually worsened with time."

Confirms that both the airway and parenchymal fibrotic lesions are present and progressive.

Bronchiolitis Obliterans and Progressive Airflow Obstruction

Obliterated small airways and stiffened parenchyma translate into measurable physiology: rising lung resistance, falling compliance, and a mixed obstructive-restrictive spirometric pattern that declines year on year. The pattern is mixed, not purely obstructive, in every source that reports it - worth stating because the node's name emphasises obstruction. This is the dominant cause of long-term disability and death in survivors, and it is what the clinical literature calls mustard lung. Roughly 42.5% of exposed Iranian veterans have pulmonary involvement, with cough and dyspnoea the leading complaints.

bronchiole UBERON:0002186

Animal models

Rat sulfur mustard inhalation model of bronchiolitis obliterans and pulmonary fibrosis Rat recapitulates Reproduces both the histological lesion and the physiological deficit.

Downstream

Bronchiolitis obliterans

Airway obstruction

Dyspnea

Cough

Malignant Transformation of Chronically Injured Bronchial Epithelium Fibrotic and bronchiectatic lung is where the tumours arise, and the radiological lesions predict them, but the intermediate steps between scarring and transformation are not established.

Show evidence (3 references)

PMID:29314868 SUPPORT Model Organism

"Pulmonary function testing demonstrated a time-dependent increase in lung resistance, as well as a decrease in lung compliance."

Ties the histological lesion to the physiological deficit this node names.

PMID:23735551 SUPPORT Human Clinical

"Prevalence of pulmonary involvement is approximately 42.5%."

Pooled human figure for the burden of the pulmonary arm across the Iranian veteran cohort.

PMID:38312548 SUPPORT Human Clinical

"The findings suggest that pulmonary lesions caused by mustard gas are more likely to be fatal compared to skin and eye lesions."

Supports the claim that this arm, rather than the cutaneous or ocular arm, drives mortality.

Limbal Stem Cell Deficiency and Delayed Mustard Gas Keratopathy

With the limbal stem cell pool destroyed, the cornea can no longer renew its own epithelium, and conjunctival epithelium invades across the limbal barrier instead. The clinical result appears after a silent interval that can run to decades: limbal ischaemia, corneal scarring and opacity, neovascularization, thinning, lipid and amyloid deposits, and persistent epithelial defects. In a series of 48 patients, corneal scar or opacity was present in 87.5% and neovascularization in 70.8%. The link between the acute limbal insult and the multi-decade latency is inferred from clinical natural history and is not established at the cell-biological level.

limbal epithelial stem cell CL:4033093

cornea UBERON:0000964

Downstream

Chronic blepharitis

Decreased tear meniscus

Limbal stem cell deficiency

Corneal opacity

Corneal neovascularization

Show evidence (4 references)

PMID:15808253 SUPPORT Human Clinical

"Corneal signs in order of frequency were: scar or opacity (87.5%), neovascularization (70.8%), thinning (58.3%), lipoid deposits (52.1%), amyloid deposits (43.8%), and epithelial defects and irregularity (31.3%)."

The frequency data behind the description of the delayed corneal lesion.

PMID:15808253 SUPPORT Human Clinical

"Ocular surface changes included chronic blepharitis and decreased tear meniscus in all patients, limbal ischemia (81.3%), and conjunctival vascular abnormalities (50%)."

Documents limbal ischaemia in most patients, which is the structural correlate of the stem cell loss.

PMID:15808253 SUPPORT Human Clinical

"Excised corneal buttons disclosed absence of epithelium and Bowman's layer, fibrovascular pannus, stromal scarring, and vascularization."

Histopathological confirmation of epithelial loss and fibrovascular pannus, the expected consequence of a failed limbal barrier.

+ 1 more reference

Haematopoietic Suppression

After significant systemic absorption, sulfur mustard suppresses haematopoiesis, producing cytopenias and marrow damage. Mechanistically this is unsurprising - the agent is the chemical ancestor of the nitrogen mustard cytotoxics, whose dose-limiting toxicity is myelosuppression, and dividing marrow progenitors are exactly the population an interstrand crosslink is most cytotoxic to. Read the evidence grade before relying on this node: the only quotable statement available here is a review's secondhand assertion, not a primary clinical series, which is why no frequency or severity is curated and why the gap is recorded as a discussion.

hematopoietic stem cell CL:0000037

bone marrow UBERON:0002371

Show evidence (1 reference)

PMID:40034085 SUPPORT INDIRECT Other

"later leads to systemic toxicity that is shown through weight loss, blood cytopenia, bone marrow destruction"

Names cytopenia and marrow destruction as systemic consequences of sulfur mustard exposure. Marked INDIRECT because the sentence is a review's summary of another author's work rather than a reported observation of its own.

Melanocyte Injury and Dyspigmentation

Epidermal melanocytes are alkylated alongside keratinocytes, and the effect on pigment is dose-dependent in opposite directions. Low sulfur mustard concentrations raise melanin synthesis and the expression of tyrosinase, TRP1, TRP2 and MITF; high concentrations reduce melanin content and downregulate all of them. This is offered as an explanation for the characteristic mixture of hyper- and hypopigmented patches in healed skin. Keep the two claims apart: the opposing dose-dependence is measured, in cultured human melanocytes, and the mapping onto the clinical pattern is the study authors' own inference from it - no cached source here reports the concentration gradient across a patient's contact area that the explanation would require.

melanocyte CL:0000148

melanin biosynthetic process GO:0042438 ↕ DYSREGULATED

Downstream

Skin hyperpigmentation

Skin hypopigmentation

Show evidence (3 references)

PMID:31785464 SUPPORT In Vitro

"Our findings demonstrated that exposure to low SM concentrations increased melanin synthesis accompanied with an increase in protein expression."

The low-concentration arm of the dose-dependent effect.

PMID:31785464 SUPPORT In Vitro

"In contrast, high SM concentrations led to decreased melanin content and a downregulation in expression of all investigated melanogenesis-associated proteins."

The high-concentration arm, and the source of the bidirectional claim.

PMID:40034085 REFUTE Other

"Nonexposed areas also develop erythema, bulla, hypopigmentation, and hyperpigmentation"

Recorded as REFUTE against a purely local, contact-area explanation of the pigmentary change: dyspigmentation is reported in skin that was never exposed, which a concentration gradient at the contact site cannot produce.

Malignant Transformation of Chronically Injured Bronchial Epithelium

Bronchial epithelium that has been alkylated, is chronically inflamed and is proliferating to repair itself carries an elevated risk of malignant transformation. Two lines of evidence support this, and neither is as strong as it first looks. In bronchial biopsies, FOXM1 and APOE are overexpressed roughly 15-fold and 4-fold - but the study has six exposed patients and five controls, excluded anyone with lung cancer, and its authors read APOE the other way, as protective against ROS damage in the short term, with the cancer link offered as a hypothesis. Clinically, in 719 victims followed for a mean of 38 years, lung fibrosis raised tumour risk about 17.75-fold, air trapping about 11.73-fold and bronchiectasis about 10.14-fold, and the lobes with fibrosis were the lobes tumours appeared in - but that cohort had no control group. The spatial concordance makes the association hard to explain by shared exposure alone; it is not itself a demonstration of mechanism.

bronchial epithelial cell CL:0002328

DNA damage response GO:0006974 ↕ DYSREGULATED

Downstream

Lung neoplasm

Show evidence (3 references)

PMID:29552057 SUPPORT Human Clinical

"Expression of FOXM1 and APOE genes in bronchial of the patients was significantly (p < 0.001) overexpressed by 14.8316 and 3.9504-folds, respectively."

The molecular measurement, in exposed human bronchial tissue. Note the study is six exposed patients against five controls and its authors frame the cancer link as a hypothesis, so this establishes the expression change and not the transformation risk.

PMID:36539770 SUPPORT Human Clinical

"The most predictive finding was LF which caused the risk of developing tumor 17.75"

The strongest single radiological predictor of later lung cancer in the four-decade cohort.

PMID:36539770 SUPPORT Human Clinical

"Furthermore, it was shown that the lung lobes with LF were statistically correlated to tumor-involved lobes."

Spatial concordance between fibrosis and tumour within the same lung, which is harder to explain by shared exposure than a whole-patient association would be. It is a stronger correlation, not a demonstration of mechanism, and the cohort carried no control group.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

Cardiovascular 2

Erythema HP:0010783

Show evidence (1 reference)

PMID:28962267 SUPPORT Human Clinical

"emerged erythema or blisters on contacted organism derma"

Erythema recorded as a presenting sign in confirmed human sulfur mustard exposure.

Keratoconjunctivitis HP:0001096

Temporal: ACUTE

Show evidence (1 reference)

PMID:35974928 SUPPORT Other

"Clinical findings in acute conditions include; sore eyes, lacrimation, burning sensation, edematous, obvious blepharospasm of eyelids, severe conjunctivitis, erosion and opacity of the cornea."

Enumerates the acute ocular findings that constitute this phenotype.

Eye 6

Photophobia HP:0000613

Show evidence (1 reference)

PMID:35974928 SUPPORT Other

"One of the problems that occurs in victims is photophobia, when the victims have severe eye irritation"

Names photophobia as a recognised finding in sulfur mustard victims.

Corneal opacity HP:0007957

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:15808253 SUPPORT Human Clinical

"Corneal signs in order of frequency were: scar or opacity (87.5%)"

87.5% of 48 patients with chronic or delayed keratitis, which places this in the VERY_FREQUENT band for that population.

Corneal neovascularization HP:0011496

Show evidence (1 reference)

PMID:15808253 SUPPORT Human Clinical

"Corneal signs in order of frequency were: scar or opacity (87.5%), neovascularization (70.8%)"

70.8% of the delayed-keratitis series, which is the FREQUENT band.

Chronic blepharitis HP:0000498

Temporal: CHRONIC

Show evidence (1 reference)

PMID:15808253 SUPPORT Human Clinical

"Ocular surface changes included chronic blepharitis and decreased tear meniscus in all patients, limbal ischemia (81.3%), and conjunctival vascular abnormalities (50%)."

Names chronic blepharitis in all patients of the delayed-keratitis series.

Decreased tear meniscus Decreased lacrimation HP:0000633

Show evidence (1 reference)

PMID:15808253 SUPPORT INDIRECT Human Clinical

"Ocular surface changes included chronic blepharitis and decreased tear meniscus in all patients, limbal ischemia (81.3%), and conjunctival vascular abnormalities (50%)."

Reports decreased tear meniscus in all patients. Marked indirect because the bound term names reduced tear production while the source reports reduced tear volume present at the lid margin.

Limbal stem cell deficiency HP:0032107

Show evidence (2 references)

PMID:35974928 SUPPORT Other

"Victims of keratitis problems suffer from impaired corneal sensation, recent and continuous corneal erosion, fatty and amyloid deposition, irregularity, thinning and corneal ulcers, limbal stem cell deficiency"

Names limbal stem cell deficiency among the findings in sulfur mustard keratitis victims.

PMID:15808253 SUPPORT Human Clinical

"Ocular surface changes included chronic blepharitis and decreased tear meniscus in all patients, limbal ischemia (81.3%), and conjunctival vascular abnormalities (50%)."

Limbal ischaemia in 81.3% of the delayed-keratitis series, the structural correlate of the stem cell compartment failing.

Immune 2

Chronic bronchitis HP:0004469

Temporal: CHRONIC

Show evidence (1 reference)

PMID:36539770 SUPPORT Human Clinical

"The late abnormalities can be present as chronic bronchitis, tracheobronchial stenosis, asthma, bronchiectasis, airway narrowing, lung fibrosis, and lung cancers."

Lists chronic bronchitis among the established late respiratory abnormalities.

Asthma HP:0002099

Show evidence (2 references)

PMID:21218101 SUPPORT Other

"patients with SM-induced asthma and chronic bronchitis (most frequent delayed lung toxicities)"

Names asthma as one of the two most frequent delayed pulmonary toxicities.

PMID:23735551 SUPPORT Human Clinical

"Major respiratory complications are chronic obstructive pulmonary disease, bronchiectasis, and asthma."

Independent listing of asthma among the major respiratory complications.

Integument 3

Skin blistering Abnormal blistering of the skin HP:0008066

Show evidence (1 reference)

PMID:28962267 SUPPORT Human Clinical

"Chinese male individuals accidentally exposed to unknown chemicals and emerged erythema or blisters on contacted organism derma, then hospitalized."

Blistering in an accidental human exposure subsequently confirmed as sulfur mustard by four independent biomarker classes.

Skin hyperpigmentation Hyperpigmentation of the skin HP:0000953

Show evidence (1 reference)

PMID:31785464 SUPPORT INDIRECT In Vitro

"We concluded that low SM concentrations may cause hyperpigmentation"

The authors' inference from cultured human melanocytes to the clinical pigmentary change. Indirect because the measurement is in vitro and the patient-level claim follows by inference.

Skin hypopigmentation Hypopigmentation of the skin HP:0001010

Show evidence (1 reference)

PMID:31785464 SUPPORT INDIRECT In Vitro

"high SM concentrations decreased melanin content which may explain hypopigmented skin areas in SM exposed patients"

The high-concentration arm and its proposed clinical correlate. Indirect for the same reason as the hyperpigmentation item.

Respiratory 6

Bronchiolitis obliterans HP:0011946

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:27832694 SUPPORT Human Clinical

"Bronchiolitis obliterans (BO) is the most remarkable pulmonary sequels of war-related sulfur mustard inhalation."

Identifies bronchiolitis obliterans as the signature pulmonary sequela.

Bronchiectasis HP:0002110

Show evidence (1 reference)

PMID:36539770 SUPPORT Human Clinical

"Bronchiectasis (B), and the evidence of lung cancer were found in 265 (36.9%), 207 (28.8%), 151 (21.0%), and 42 (5.8%), respectively"

Bronchiectasis in 151 of 719 followed victims on serial HRCT.

Pulmonary fibrosis HP:0002206

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:36539770 SUPPORT Human Clinical

"Air Trapping (AT), Lung Fibrosis (LF), Bronchiectasis (B), and the evidence of lung cancer were found in 265 (36.9%), 207 (28.8%), 151 (21.0%), and 42 (5.8%), respectively"

Lung fibrosis in 207 of 719 victims on long-term HRCT follow-up.

Cough HP:0012735

Temporal: CHRONIC

Show evidence (1 reference)

PMID:23735551 SUPPORT Human Clinical

"The most common complaints are cough and dyspnea."

Cough named as one of the two leading chronic complaints in the exposed veteran population.

Dyspnea HP:0002094

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:23735551 SUPPORT Human Clinical

"The most common complaints are cough and dyspnea."

Dyspnoea named as one of the two leading chronic complaints.

Airway obstruction HP:0006536

Show evidence (2 references)

PMID:29552057 SUPPORT Human Clinical

"PFTs have demonstrated more obstructive and restrictive spirometric patterns among patients compared to the controls."

Direct spirometric comparison of exposed patients against controls. Note the patients in this study were selected for FEV1 between 50 and 80%, so the magnitude of the difference is partly an inclusion criterion; the pattern being mixed rather than purely obstructive is the point taken here.

PMID:23735551 SUPPORT Human Clinical

"Spirometry results can reveal restrictive and obstructive pulmonary disease."

Unselected review-level statement of the spirometric picture, cited in preference to the small selected series for the general claim.

Neoplasm 1

Lung neoplasm Neoplasm of the lung HP:0100526

Show evidence (1 reference)

PMID:36539770 SUPPORT Human Clinical

"Adenocarcinoma (38.1%) was the most common type of cancer."

Histological distribution of the tumours arising in the followed cohort.

🧬

Genetic Associations

GSTM1

Gene: GSTM1 hgnc:4632 relationship_type: MODIFIER

Show evidence (3 references)

PMID:29435433 SUPPORT Human Clinical

"The frequency of GSTM1 homozygous deletion was significantly higher in the severe/very severe patients compared with the mild/moderate subjects (66.3% vs. 48%, P = 0.013)."

The primary association, with the genotype frequencies in each severity stratum of the exposed cohort.

PMID:29435433 SUPPORT Human Clinical

"The GSTM1 null genotype was associated with the severity of mustard lung"

States the association in the authors' own terms, which is what this MODIFIER record asserts.

PMID:24344877 SUPPORT INDIRECT Human Clinical

"SM-induced COPD individuals showed expression of GSTA1 2.51 ± 0.83-, GSTM1 2.84 ± 1.71- and GSTP1 5.61 ± 2.59-folds higher than those of controls"

Measures GSTM1 upregulation in the airway wall of mustard-lung patients, which is the second line of evidence the notes describe.

GSTT1

Gene: GSTT1 hgnc:4641 relationship_type: DISPUTED

Show evidence (1 reference)

PMID:29435433 SUPPORT Human Clinical

"There was no significant association between GSTT1 and GSTP1 polymorphisms with the severity of the mustard lung."

The negative result for this gene, from the same cohort and the same analysis that found the GSTM1 association.

GSTP1

Gene: GSTP1 hgnc:4638 relationship_type: DISPUTED

Show evidence (1 reference)

PMID:29435433 SUPPORT Human Clinical

"To determine the polymorphisms of GSTP1 in exon 5 (Ile105Val) and exon 6 (Ala114Val), RFLP-PCR method was performed."

Establishes which GSTP1 variants were tested, so the negative result above is bounded to them rather than read as covering the whole gene.

💊

Medical Actions

Immediate Skin Decontamination

Action: skin decontamination Ontology label: Therapeutic Procedure NCIT:C49236

Platform: Other

Copious water with neutral soap, and dilute sodium hypochlorite where available, removing agent still on the skin. This is the single highest-yield intervention and the only one that acts on the lesion before it is fixed: alkylation is complete within minutes, so decontamination buys back only the dose that has not yet reacted. Its benefit falls off steeply with delay.

Mechanism Target:

Sulfur Mustard Penetration and Episulfonium Ion Formation — Removes unabsorbed agent before it can penetrate and cyclize.

Show evidence (3 references)

PMID:31576778 SUPPORT Other

"The best solution for decontamination is large amounts of water, using neutral soap and 0.5% sodium hypochlorite."

Names the recommended decontamination method.

PMID:31576778 SUPPORT Other

"The victims must remove from the contaminated zone immediately."

Supports the time-critical framing of this intervention.

PMID:35974928 SUPPORT Other

"washing after this time is not beneficial"

States that irrigation past the early window stops helping, which is the basis for the claim that this intervention's benefit falls off steeply with delay.

Supportive and Intensive Care

Action: supportive care Ontology label: Supportive Care NCIT:C15747

Humidified oxygen, bronchodilators, rehydration, mechanical ventilation where needed, antibiotics for secondary infection, respiratory physiotherapy, and burn-style wound care. There is no antidote, so this is the substance of acute management rather than an adjunct to one.

Show evidence (2 references)

PMID:31576778 SUPPORT Other

"The important protective and conservative treatment of SM-induced pulmonary injuries include humidified oxygen, bronchodilators, NAC as muculytic, rehydration, mechanical ventilation, appropriate antibiotics and respiratory physiotherapy as clinically indicated."

Enumerates the supportive measures that make up standard care.

PMID:25055840 SUPPORT Other

"Currently, there is no validated antidote, chemoprophylaxis and curative modality for pulmonary toxicities secondary to sulfur mustard exposure."

Establishes that supportive care is the whole of management rather than a fallback.

N-Acetylcysteine

Action: Pharmacotherapy NCIT:C15986

Agent: N-acetylcysteine CHEBI:22198

Platform: Small molecule

A glutathione precursor and direct radical scavenger, used both acutely and in chronic pulmonary management. It is the pharmacological agent that maps most directly onto a curated mechanism in this entry - the glutathione depletion node - which is the argument for it. A dedicated review reports clinical and paraclinical improvement in sulfur mustard bronchiolitis obliterans on oral NAC alone or combined with clarithromycin, while the same review and an independent one both state there is no validated antidote. Both are recorded below, and the entry does not resolve them, because "improves parameters in an established chronic complication" and "is not an antidote for the poisoning" are compatible claims about different things.

Mechanism Target:

Glutathione Depletion and Oxidative Stress — Replenishes the cysteine supply for glutathione synthesis, directly opposing the depletion this node describes.

Show evidence (2 references)

PMID:31576778 SUPPORT Other

"However, N-acetyle cysteine (NAC) is recommended, none of them acts as specific or effective antidote."

Records both the recommendation and the explicit caveat that it is not an antidote, which is why this treatment is not curated as one.

PMID:25055840 SUPPORT Other

"oral NAC alone (1200 or 1800 mg/day for 4 months) or at a dose 600 mg/day for 6 months in combination with clarithromycin (500 mg/day) have led to improvements of clinical and paraclinical pulmonary parameters of patients with bronchiolitis obliterans due to sulfur mustard"

The positive clinical result, with doses and durations, in the chronic pulmonary complication rather than in the acute poisoning.

Macrolide and Inhaled Corticosteroid Therapy for Bronchiolitis Obliterans

Action: Pharmacotherapy NCIT:C15986

Agent: azithromycin CHEBI:2955 fluticasone propionate CHEBI:31441 salmeterol CHEBI:9011

Platform: Small molecule

Long-term azithromycin combined with an inhaled corticosteroid and long-acting beta-2 agonist, plus N-acetylcysteine, is the regimen used for established mustard-related bronchiolitis obliterans. Over five years of spirometry the rate of FEV1 decline in treated bronchiolitis obliterans patients was not significantly different from that in COPD patients treated to guideline, which the authors read as evidence the regimen works. Note this is a comparison against a different disease's treated course, not against untreated bronchiolitis obliterans, so it is suggestive rather than controlled.

Mechanism Target:

Chronic IL-17-Dependent Airway Inflammation — Macrolides and inhaled corticosteroids are used here for their anti-inflammatory rather than antibacterial or bronchodilator action.

Show evidence (3 references)

PMID:27832694 SUPPORT Human Clinical

"The BO patients were treated with inhaled Seretide 125-250/25 (2 puffs BID), azithromycin (250 mg, three times/week) and N-acetylcysteine (1200-1800/day)."

The exact regimen and dosing this treatment entry describes.

PMID:27832694 SUPPORT INDIRECT Human Clinical

"The non-significant difference of FEV1 decline in BO compared to COPD patients suggests the effectiveness of azithromycin, inhaled steroid and N-acetyl cysteine in BO patients."

The efficacy claim, marked indirect because it rests on an inference from a non-significant difference against a different disease's treated course rather than on a controlled comparison.

PMID:31576778 SUPPORT Other

"However, none of them, except macrolide antibiotics have been proved clinically."

Independent statement singling out macrolides as the one class with clinical proof among the candidate agents.

Sodium Thiosulfate Infusion

Action: Pharmacotherapy NCIT:C15986

Agent: sodium thiosulfate CHEBI:132112

Platform: Small molecule

A sulfur nucleophile intended to scavenge circulating agent, given within roughly an hour of exposure. It is not a validated antidote and the window is narrow enough that in most real exposures it has closed before the patient is identified.

Show evidence (1 reference)

PMID:31576778 SUPPORT Other

"Sodium thiosulfate infusion (100-500 mg/kg/min) should be started up to 60 min after SM exposure."

Dose and time window for this intervention.

Cutaneous Wound Management

Action: burn wound care Ontology label: Wound Care Management NCIT:C116681

Platform: Other

Moist dressing, preferentially with silver sulfadiazine, plus analgesia, antipruritics, debridement (physical, enzymatic or laser) and autologous split-thickness grafting where indicated. This is the arm that treats the vesicant burn once it has formed, as distinct from decontamination, which acts before it does.

Mechanism Target:

Skin Ulceration and Impaired Wound Healing — Manages the denuded, slow-healing ulcer left when the blister roof is lost.

Show evidence (1 reference)

PMID:31576778 SUPPORT Other

"moist dressing; preferably with silver sulfadiazine cream, analgesic, anti-pruritic, physically debridement, debridase, Laser debridement, followed by skin autologous split-thickness therapy as clinically indicated"

Enumerates the recommended cutaneous wound management for sulfur mustard injury.

Corneal and Limbal Allograft Surgery

Action: corneal and limbal allograft transplantation Ontology label: Corneal Transplantation NCIT:C210959

Platform: Surgery

Allograft limbal stem cell transplantation, penetrating keratoplasty and lamellar keratoplasty for advanced mustard gas keratopathy. The rationale follows directly from the mechanism: if the limbal stem cell pool is gone, the cornea cannot resurface itself and the deficit has to be replaced rather than treated medically.

Mechanism Target:

Limbal Stem Cell Deficiency and Delayed Mustard Gas Keratopathy — Replaces the exhausted limbal stem cell population or the scarred cornea itself.

Show evidence (1 reference)

PMID:15808253 SUPPORT Human Clinical

"others underwent allograft stem cell transplantation (20 eyes of 17 patients), penetrating keratoplasty (12 eyes of 12 patients), and lamellar keratoplasty (4 eyes of 3 patients)"

Documents the surgical procedures used in this patient population and their frequency.

Investigational Mesenchymal Stromal Cell Therapy for Mustard Keratopathy

Action: mesenchymal stromal cell therapy Ontology label: Mesenchymal Stem Cell Transplantation NCIT:C116467

Platform: Cell therapy

Intrastromal injection of mesenchymal stem/stromal cells, tested in a mouse model of mustard keratopathy. It reduced corneal opacity and, notably, cut beta-galactosidase staining - a senescence marker - which is the result that makes it interesting mechanistically rather than only clinically: it implies cellular senescence is part of what sustains the delayed corneal lesion. Corneal neovascularization and fibrosis did not improve significantly. This is pre-clinical and is curated as investigational, not as available treatment.

Mechanism Target:

Limbal Stem Cell Deficiency and Delayed Mustard Gas Keratopathy — Delivered into the corneal stroma to counter the opacification and, on the senescence evidence, possibly the process driving it.

Show evidence (2 references)

PMID:38067171 SUPPORT Model Organism

"The treatment group demonstrated reduced opacity compared to the control group."

The primary positive result in the mouse mustard keratopathy model.

PMID:38067171 REFUTE Model Organism

"While corneal neovascularization did not display significant variations between the groups, the control group did register higher numerical values."

Recorded as REFUTE against the broader claim that this therapy addresses the keratopathy as a whole: neovascularization, one of the two dominant corneal signs, did not respond significantly.

🌍

Environmental Factors

Battlefield exposure to sulfur mustard vapour and liquid

Deliberate military use, overwhelmingly the Iran-Iraq war of 1980-1988, is the source of almost all the natural-history data in this entry. Tens of thousands of Iranian combatants were exposed; the cohort has been followed for four decades and is the reason the delayed arm of this disease is characterised at all. Immediate mortality was low, in the range of a few percent, because open-air dispersal dilutes the agent - which is precisely why so many survivors were available to develop the chronic disease.

Show evidence (2 references)

PMID:38312548 SUPPORT Human Clinical

"The primary objective of this study was to analyze the long-term survival of 48,067 chemical warfare survivors who suffered from pulmonary, cutaneous, and ocular lesions in the decades following the Iran-Iraq war."

Establishes the scale of the exposed cohort and the setting.

PMID:22465472 SUPPORT Other

"During the Iran-Iraq war, immediate mortality among the Iranian soldiers exposed to SM was only 3–4%, but decades later nearly half of the victims developed chronic respiratory complications"

Supports the low acute mortality alongside high delayed morbidity, which is the epidemiological shape this entry is built around.

Mechanism Target:

TRIGGERS Sulfur Mustard Penetration and Episulfonium Ion Formation — Battlefield vapour and liquid contact is the route by which the agent reaches skin, cornea and airway epithelium.

Show evidence (1 reference)

PMID:22465472 SUPPORT Other

"SM exposure occurs primarily through inhalation and absorption through skin and the anterior surface of the eye, making the lungs, the skin, and the eye as major targets of SM toxicity"

States the exposure routes and the target tissues, which is the link between this exposure and the penetration node.

Accidental civilian exposure to abandoned chemical munitions

Sulfur mustard is chemically stable and persists in buried or dumped munitions long after the conflict that produced them. Civilians encountering corroded shells or containers are exposed without knowing what the agent is, which is one reason biomarker confirmation matters clinically: the four cases that established the multi-biomarker time course were an accidental exposure to an unknown chemical, identified retrospectively.

Show evidence (1 reference)

PMID:28962267 SUPPORT Human Clinical

"The old shells or containers of SM are still a large threat to civilian health."

Establishes abandoned munitions as an ongoing civilian exposure source.

Mechanism Target:

TRIGGERS Sulfur Mustard Penetration and Episulfonium Ion Formation — Dermal contact with agent released from a corroded munition delivers the same lesion by the same route as a battlefield exposure.

Show evidence (1 reference)

PMID:28962267 SUPPORT Human Clinical

"Chinese male individuals accidentally exposed to unknown chemicals and emerged erythema or blisters on contacted organism derma, then hospitalized."

An accidental civilian dermal exposure producing the characteristic lesion, later confirmed as sulfur mustard.

🔬

Biochemical Markers

Serum interleukin-6 (INCREASED)

Show evidence (1 reference)

PMID:25031491 SUPPORT Human Clinical

"The measured IL6 mean level in patients with chemical injuries (0.76±0.3 ng/ml) was significantly higher than the control group's mean level (0.34±0.12 ng/ml)."

The case-control difference in serum IL-6.

Haemoglobin N-terminal valine adduct (INCREASED)

Show evidence (1 reference)

PMID:28962267 SUPPORT Human Clinical

"the N-terminal valine adducts in hemoglobin could be monitored for over 90 days"

Establishes the detection window for this adduct class.

🔬

Diagnosis

Exposure history plus the delayed vesicant syndrome

There is no bedside confirmatory test. Diagnosis rests on a known or suspected exposure followed, after a latent interval, by the triad of vesicant burn, keratoconjunctivitis and airway injury. Because the latent period separates cause from effect, the exposure is often not volunteered and has to be asked for.

physical examination NCIT:C20989

Show evidence (1 reference)

PMID:35974928 SUPPORT Other

"Clinical findings in acute conditions include; sore eyes, lacrimation, burning sensation, edematous, obvious blepharospasm of eyelids, severe conjunctivitis, erosion and opacity of the cornea."

The clinical findings that, with an exposure history, constitute the diagnosis.

Biomarker confirmation of exposure

Four biomarker classes confirm sulfur mustard retrospectively, and they have different detection windows: hydrolysis and oxidation products and beta-lyase metabolites are short-lived, DNA adducts remain detectable in urine for about 30 days, and N-terminal valine adducts on haemoglobin persist beyond 90 days. Concentrations track clinical severity, so the assay is prognostic as well as confirmatory. This is the test that identified an accidental exposure to an unknown agent after the fact.

laboratory procedure NCIT:C25294

Show evidence (2 references)

PMID:28962267 SUPPORT Human Clinical

"The DNA adducts in urine samples still appeared on the 30th day, and the N-terminal valine adducts in hemoglobin could be monitored for over 90 days"

The two long-window biomarkers and their detection intervals.

PMID:28962267 SUPPORT Human Clinical

"The concentrations of the biomarkers in specimens revealed a good correlation with the severity of the patient's symptom."

Supports the prognostic as well as confirmatory use of the assay.

High-resolution CT for delayed pulmonary disease

HRCT is the modality of choice for the delayed pulmonary arm, showing air trapping, bronchiectasis, large-airway narrowing and fibrosis. Plain chest radiography misses roughly half of the lung disease. HRCT findings are also prognostic for lung cancer, which makes serial scanning a surveillance tool rather than only a diagnostic one.

high resolution computed tomography NCIT:C20644

Show evidence (2 references)

PMID:23735551 SUPPORT Human Clinical

"Plain chest X-ray does not help in about 50% of lung diseases."

Quantifies the shortfall of plain radiography that motivates HRCT.

PMID:23735551 SUPPORT Human Clinical

"High-resolution CT of the lung is the best modality for diagnostic assessment of parenchymal lung and bronchi."

Establishes HRCT as the recommended modality.

📈

Progression

Latent period

Duration: 1 to 24 hours from exposure

Cellular injury begins within minutes but nothing is visible. The victim feels little or nothing, which is the tactical point of the agent and the clinical trap: people continue to be exposed, and decontamination is deferred past the window in which it helps.

Show evidence (2 references)

PMID:40034085 SUPPORT INDIRECT Other

"SM and NM have a latent period after exposure before any symptoms manifest and are inversely proportional to the dose."

States the latent period directly and records that its length varies inversely with dose, which is the claim this phase makes.

PMID:40034085 SUPPORT INDIRECT Other

"This study also found that vesication sharply increased between 4 and 8 h after exposure, was well established, and remained elevated at 8‐ and 24‐h post‐exposure"

Times the emergence of the lesion after exposure. Indirect because the cited experiment used the nitrogen mustard analogue in a mouse ear model.

Acute injury

Duration: Hours to days

Erythema then vesication of contacted skin; keratoconjunctivitis with pain, lacrimation and blepharospasm; rhinorrhoea, hoarseness and cough progressing in severe inhalational exposure to tracheobronchitis, pseudomembrane formation and acute lung injury. Direct mortality is low - a few percent in open-air battlefield exposure.

Show evidence (1 reference)

PMID:35974928 SUPPORT Other

"Feeling severe pain in the eyes, laceration, photophobia, blepharospasm and reduced visual acuity after 2 to 6 hours, also after 12 hours the patient poses with temporary and transient blindness, and spontaneous recovery will occur after 48 hours"

Times the acute ocular course from onset through spontaneous recovery.

Recovery

Duration: Weeks to months

Most acute lesions heal. Corneal epithelium regenerates over days, with full ocular recovery taking six weeks or more; skin ulcers heal slowly and scar. A patient can pass through this phase apparently well and still develop the delayed disease.

Show evidence (1 reference)

PMID:35974928 SUPPORT Other

"but complete corneal regeneration of the corneal epithelium is seen after 4 to 5 days, although complete recovery requires 6 weeks and even more"

The timescale of acute ocular healing.

Delayed and progressive disease

Duration: Years to decades

The phase that defines the disease. Bronchiolitis obliterans, bronchiectasis and pulmonary fibrosis emerge and worsen year on year; mustard gas keratopathy appears after a silent interval; lung cancer risk rises. This can develop in patients whose acute exposure caused no distress at the time, which is why exposure history rather than acute severity is the indication for long-term surveillance.

Show evidence (2 references)

PMID:21218101 SUPPORT Other

"SM is the only warfare agent which has severe delayed effects and causes progressive incapacitation of victims."

States that the progressive delayed course is specific to this agent among warfare agents.

PMID:15808253 SUPPORT Human Clinical

"Of 48 patients, 31 (64.6%) had chronic symptomatology, whereas 17 (35.4%) experienced delayed-onset lesions."

Splits the ocular cohort into continuously symptomatic and true delayed-onset presentations, which is the distinction this phase records.

📊

Prevalence

Iranian chemical-warfare survivors of the Iran-Iraq war

Cases In Literature

48,067 registered survivors with pulmonary, cutaneous or ocular lesions were followed for 39 years; 4,342 (9.03%) died during the study period. This is a count of a registered exposed cohort, not a population prevalence: the disease is exposure-defined, so no denominator of the general population applies.

Show evidence (1 reference)

PMID:38312548 SUPPORT Human Clinical

"The study included a total of 48,067 observations, and among them, 4342 (9.03 %) died during the study period."

The cohort size and observed mortality over the follow-up period.

🐁

Animal Models

Rat sulfur mustard vapour inhalation model (biphasic lung injury)

Rats exposed to sulfur mustard vapour at 0.2 to 0.6 mg/kg. The striking finding is that the pathology is biphasic: damage at 3 days, apparent improvement at 7 to 16 days, then a second and worse wave at 28 days with distal bronchiolar epithelial necrosis and interstitial fibrosis. That shape is the animal counterpart of the human latent-then-delayed course, which is what makes the model useful for something other than acute toxicity.

Species

Rat

Publication

PMID:33002157

Pathograph links

Cellular Energy Collapse and Epithelial Necrosis recapitulates fidelity: moderate observes: tissue Reproduces airway epithelial necrosis after inhalational exposure.

Limitations: The model reads the lesion histologically and does not measure the NAD+ or ATP depletion that this node asserts as its mechanism, so it supports the outcome rather than the pathway.

Readouts

Distal bronchiolar epithelial necrosis on histopathology

Direction: INCREASED

Interpretation: Histological correlate of the epithelial death node.

Show evidence (1 reference)

PMID:33002157 SUPPORT Model Organism

"including epithelial necrosis and hyperplasia in the distal bronchioles, thickened alveolar walls, enlarged vacuolated macrophages, and interstitial fibrosis"

Reports the histological measurement behind this readout.

Show evidence (2 references)

PMID:33002157 SUPPORT Model Organism

"These data demonstrate a similar pathologic response to inhaled SM in rats and humans suggesting that this rodent model can be used for mechanistic studies"

The authors' own claim that the model parallels the human respiratory pathology.

PMID:33002157 SUPPORT Model Organism

"Time course studies revealed that the pathologic response was biphasic."

Establishes the biphasic course that makes this model informative for the delayed arm.

Rat sulfur mustard inhalation model of bronchiolitis obliterans and pulmonary fibrosis

Sprague-Dawley rats given 1.0 mg/kg sulfur mustard by intubation and followed to 28 days, with histopathology, pulmonary function testing and measurement of TGF-beta, PDGF and PAI-1. This is the model that ties the profibrotic mediators to both lesions at once.

Species

Rat

Publication

PMID:29314868

Pathograph links

TGF-beta Driven Myofibroblast Activation recapitulates fidelity: moderate observes: molecular Measures the profibrotic mediators directly in lung, lavage fluid and plasma at 28 days.

Limitations: Rodent lifespan makes the human multi-decade course unmodellable: 28 days of rat follow-up stands in for forty years of human disease, so the model can show that the pathway engages but not that it keeps engaging.

Readouts

Lung and plasma TGF-beta, PDGF and PAI-1 concentrations

Direction: INCREASED

Interpretation: Direct measurement of the profibrotic signalling this node asserts.

Show evidence (1 reference)

PMID:29314868 SUPPORT Model Organism

"Concentrations of TGF-β, PDGF, and PAI-1 were elevated at 28 days in lung, BAL fluid, and/or plasma."

The mediator measurement behind this readout.

Bronchiolitis Obliterans and Progressive Airflow Obstruction recapitulates fidelity: moderate observes: organism Reproduces both the histological lesion and the physiological deficit.

Limitations: Whole-organism pulmonary function testing in a rat reports resistance and compliance rather than the spirometric indices used clinically, so the physiological endpoints are analogous rather than identical.

Readouts

Lung resistance and compliance

Direction: ALTERED

Interpretation: Physiological correlate of obliterated small airways and stiffened parenchyma.

Show evidence (1 reference)

PMID:29314868 SUPPORT Model Organism

"Pulmonary function testing demonstrated a time-dependent increase in lung resistance, as well as a decrease in lung compliance."

The functional measurement behind this readout.

Show evidence (1 reference)

PMID:29314868 SUPPORT Model Organism

"Time-dependent development of BO and PF occurs in lungs of rats exposed to SM inhalation"

Establishes that this model develops both named human lesions.

Cynomolgus monkey sulfur mustard inhalation model

Non-human primates exposed to sulfur mustard at 150 mg/m3 by intubation. Its contribution is the IL-17 arm: IL-17-positive cells accumulate in inflamed lung regions at 30 days and beyond, in a species much closer to human than the rat data collected alongside it.

Species

Cynomolgus monkey

Publication

PMID:22465472

Pathograph links

Chronic IL-17-Dependent Airway Inflammation recapitulates fidelity: moderate observes: tissue Demonstrates IL-17-positive cell accumulation in the chronic phase in a primate.

Limitations: The IL-17 cells are localised in inflamed tissue rather than shown to be necessary for the fibrosis, so the model establishes association with the chronic phase and not that this arm drives it.

Readouts

IL-17-positive cells in inflamed lung regions

Direction: INCREASED

Interpretation: Cellular correlate of the IL-17 arm of chronic inflammation.

Show evidence (1 reference)

PMID:22465472 SUPPORT Model Organism

"At ≥30 days, SM inhalation promoted the accumulation of IL-17(+) cells in the inflamed areas of monkey lungs."

The primate measurement behind this readout.

Show evidence (1 reference)

PMID:22465472 SUPPORT Model Organism

"IL-17(+) cells likely play an important role in the pathogenesis of SM-induced lung injury."

The authors' conclusion, hedged as they hedge it, that this arm matters for the pathogenesis.

{ }

Source YAML

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name: Sulfur Mustard Poisoning
creation_date: "2026-09-10T19:20:00Z"
category: Environmental
categories:
- Toxic Exposure Disorder
- Environmental Health Disorder
- Chemical Vesicant Injury
synonyms:
- mustard gas poisoning
- sulphur mustard poisoning
- yperite poisoning
- HD exposure
description: >-
  Sulfur mustard poisoning is the injury syndrome caused by exposure to
  bis(2-chloroethyl) sulfide, a lipophilic bifunctional alkylating vesicant used
  as a chemical weapon from 1917 onwards and, in the modern era, chiefly during
  the 1980-1988 Iran-Iraq war. The agent penetrates skin, cornea and airway
  epithelium and cyclizes intramolecularly to a reactive episulfonium ion, which
  alkylates the N7 position of guanine and crosslinks DNA. Because the molecule
  carries two chloroethyl arms it can react with two nucleophiles at once, so
  the crosslinks block replication and transcription outright. Unrepaired strand
  breaks drive PARP1 hyperactivation, which consumes NAD+ and collapses cellular
  ATP, switching the death mode from apoptosis to necrosis; in parallel the
  agent depletes glutathione and leaves the cell without its principal
  antioxidant buffer.

  Two features set this entry apart from other acute toxic exposures. The first
  is the latent period - cellular injury begins within minutes, but the burn,
  the keratoconjunctivitis and the airway injury declare themselves hours later.
  The second is the delayed arm: decades after a single exposure, survivors
  develop bronchiolitis obliterans, bronchiectasis and pulmonary fibrosis, a
  mustard keratopathy that emerges after a silent interval of years, and an
  elevated risk of lung cancer. That delayed disease, not the acute burn, is
  what kills people, and it is why this entry carries a `progression:` block
  with a distinct delayed-onset phase.
disease_term:
  preferred_term: sulfur mustard poisoning
  term:
    id: MONDO:0800387
    label: sulfur mustard poisoning
notes: >-
  Scope. This entry curates the human injury syndrome caused by sulfur mustard
  and the mechanism that produces it. It is not an entry about the agent's
  production, dispersal or military use, and the historical context recorded
  under `environmental:` is there because route and setting determine which
  organ is injured and how severely.

  Bone marrow suppression is curated, but read the evidence grade before relying
  on it. An earlier draft of this note claimed no cited source reported it
  quotably. That was false: PMID:40034085, cited seven times in this entry,
  states that sulfur mustard leads to systemic toxicity shown through "blood
  cytopenia, bone marrow destruction". It is a review's secondhand assertion
  attributed to another author rather than a primary clinical series, so the
  node is graded accordingly and the absence of a primary cohort is recorded
  under `discussions:`.

  ECTO binding. The exposure term `ECTO:9001175` is the ontology's term for
  exposure to bis(2-chloroethyl) sulfide, which is sulfur mustard under its
  systematic name; ECTO has no term under any of the agent's common or military
  names. `ECTO:0070054`, "exposure to mustard greens via ingestion", is an
  unrelated dietary term and is not a candidate here.

  NCIT binding for decontamination. `NCIT:C68769` is NCIT's term for
  decontamination and looks like the obvious binding for the acute intervention,
  but it is not reachable from `NCIT:C25218` (Clinical Intervention or
  Procedure), so it cannot be the `term:` of a `TreatmentTerm`. That treatment is
  bound to `NCIT:C49236` (Therapeutic Procedure) with the specificity carried in
  `preferred_term`, which is the same compromise CLAUDE.md records for medical
  devices.

  Organ systems seen in the research and left out, recorded so they are not
  re-litigated. The deep-research report surfaced gastrointestinal involvement
  (nausea, vomiting, diarrhoea; haemorrhagic gastroduodenitis and desquamative
  enteritis in severe systemic poisoning), neuropsychiatric sequelae (acute
  convulsions in severely poisoned patients; chronic anxiety, depression and
  cognitive decline decades later), basal and squamous cell carcinoma at
  exposure sites, and dry eye. The reason differs by item.

  The gastrointestinal, neuropsychiatric and cutaneous-malignancy findings are
  cited in the report to NCBI Bookshelf chapters, which are not fetchable as
  references here, so no exact snippet can be taken; the neuropsychiatric entry
  additionally carries a publisher link to animal aggregate-culture demyelination
  data, which would not support a human phenotype in any case. Those three remain
  uncurated.

  Dry eye is curated, and an earlier version of this paragraph was wrong about
  why it had not been. That version said dry eye "has no citation behind it at
  all - it appears only in the report's list of suggested HP terms". The
  suggested-terms half is true, and HP:0000585 offered there is one of the six
  identifiers that name a different concept. The rest was false: dry eye also
  appears in the report's clinical narrative for delayed keratopathy, cited to
  PMID:15808253, whose cached abstract reports chronic blepharitis and decreased
  tear meniscus in all 48 patients - a sentence this entry already quoted twice
  for other claims before anyone noticed it also carried this one.

  Both findings from that sentence are now phenotypes. What is bound is the sign
  each time: Blepharitis, and Decreased lacrimation for the reduced tear
  meniscus. The keratoconjunctivitis sicca diagnosis is deliberately not
  asserted - HP:0001097 exists and this cohort does show the ocular surface
  damage the diagnosis needs, but the authors did not draw that conclusion in
  the sentence quoted.

  The cutaneous malignancy omission is the one a curator should look at first,
  because it is asymmetric: this entry models malignant transformation of
  chronically injured bronchial epithelium but not of skin, and the same
  alkylation and chronic-injury nodes run through both. That asymmetry reflects
  what is citable here, not a claim that the skin risk is lower.

  GeneReviews. Not applicable. This is an acquired toxic exposure with no
  Mendelian form, so there is no GeneReviews chapter to use as a phenotype
  baseline; a PubMed search for one returns nothing.

  Host susceptibility. An earlier draft of this note said no
  sulfur-mustard-specific association study existed for the glutathione-pathway
  polymorphisms and that no `genetic:` records were therefore curated. That was
  wrong, and it was wrong because the claim was carried over from the
  deep-research report's own statement that it had not identified such a study,
  rather than being checked. PMID:29435433 is exactly that study - 185
  sulfur-mustard-exposed subjects, GSTM1 null genotype associated with mustard
  lung severity - and it is now curated below, along with the negative results
  for GSTT1 and GSTP1 from the same cohort. The genes are modifiers of severity,
  not causes: this disease has no genetic form, and nothing in `genetic:` should
  be read as one.
pathophysiology:
- name: Sulfur Mustard Penetration and Episulfonium Ion Formation
  biological_scale: MOLECULAR
  description: >-
    Sulfur mustard is lipophilic and crosses skin, corneal and airway epithelium
    within minutes of contact. Inside the cell it cyclizes intramolecularly,
    displacing chloride to form a strained three-membered episulfonium
    (ethylene sulfonium) ring. That cation, not the parent molecule, is the
    alkylating electrophile, and because the parent carries two chloroethyl arms
    the reaction can happen twice on the same molecule. Most of a dermal dose
    stays in the epidermis, which is why the cutaneous lesion is superficial and
    the systemic dose is small relative to the local injury.
  chemical_entities:
  - preferred_term: sulfur mustard
    term:
      id: CHEBI:25434
      label: bis(2-chloroethyl) sulfide
  locations:
  - preferred_term: skin epidermis
    term:
      id: UBERON:0001003
      label: skin epidermis
  downstream:
  - target: DNA N7-Guanine Alkylation and Interstrand Crosslinking
    causal_link_type: DIRECT
    description: The episulfonium ion is the species that alkylates DNA.
  - target: Glutathione Depletion and Oxidative Stress
    causal_link_type: DIRECT
    description: >-
      The same electrophile is consumed by conjugation to glutathione, which is
      the cell's first line of defence and the reason the thiol pool falls.
  - target: Melanocyte Injury and Dyspigmentation
    causal_link_type: DIRECT
  - target: Haematopoietic Suppression
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Requires systemic absorption, which is why this arm appears only after
      significant exposure while the local lesions appear after any.
  evidence:
  - reference: PMID:40034085
    reference_title: Mechanistic Insights and Pharmacological Approaches for Nitrogen and Sulfur Mustards and Their Implications as Therapeutic Agents.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "SM and NM are easily absorbed through the skin and can cause immediate cutaneous injury and blistering"
    explanation: Establishes rapid transcutaneous absorption as the first step of the cutaneous lesion.
  - reference: PMID:40034085
    reference_title: Mechanistic Insights and Pharmacological Approaches for Nitrogen and Sulfur Mustards and Their Implications as Therapeutic Agents.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "states that 70% of the SM resides in the epidermis and the rest in the basement membrane of the dermis"
    explanation: >-
      Supports the claim that the absorbed dose is retained in the epidermis and
      basement membrane zone rather than distributing systemically, which is why
      the cutaneous injury is local and superficial.
- name: DNA N7-Guanine Alkylation and Interstrand Crosslinking
  biological_scale: MOLECULAR
  description: >-
    The episulfonium ion attacks nucleophilic sites in DNA, predominantly the N7
    position of deoxyguanosine. Because sulfur mustard is bifunctional, a single
    molecule can alkylate two nucleophiles, producing intrastrand and interstrand
    DNA crosslinks as well as DNA-protein crosslinks. An interstrand crosslink
    tethers the two strands together and physically blocks the replication and
    transcription machinery, so the lesion is cytotoxic rather than merely
    mutagenic. Replication forks that collide with an unrepaired crosslink
    generate double-strand breaks.
  biological_processes:
  - preferred_term: interstrand cross-link repair
    term:
      id: GO:0036297
      label: interstrand cross-link repair
    modifier: INCREASED
  - preferred_term: DNA damage response
    term:
      id: GO:0006974
      label: DNA damage response
    modifier: INCREASED
  downstream:
  - target: PARP1 Hyperactivation and NAD+ Depletion
    causal_link_type: DIRECT
    description: >-
      Strand breaks arising from blocked and collapsed replication forks are the
      signal PARP1 detects.
    evidence:
    - reference: PMID:21218101
      reference_title: Acute and delayed sulfur mustard toxicity; novel mechanisms and future studies.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "PARP-1 detects and signals DNA strand breaks induced by a variety of genotoxic insults."
      explanation: >-
        States that DNA strand breaks are the signal PARP1 responds to, which is
        this edge rather than either node.
  evidence:
  - reference: PMID:40034085
    reference_title: Mechanistic Insights and Pharmacological Approaches for Nitrogen and Sulfur Mustards and Their Implications as Therapeutic Agents.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "it causes DNA replication cessation because it alkylates N7 of a deoxyguanosine residue and a cysteine residue"
    explanation: >-
      Names the specific alkylation site for sulfur mustard and states the
      functional consequence, replication arrest.
- name: PARP1 Hyperactivation and NAD+ Depletion
  biological_scale: MOLECULAR
  description: >-
    PARP1 detects DNA strand breaks and responds by transferring ADP-ribose units
    from NAD+ onto nuclear acceptor proteins. At the lesion densities sulfur
    mustard produces, this repair response becomes the injury: PARP1 consumes the
    cellular NAD+ pool, and because NAD+ is an obligate cofactor for glycolysis,
    the TCA cycle and the electron transport chain, ATP synthesis fails with it.
    The consequence is a switch in death mode - a cell with modest damage
    apoptoses or repairs, a cell with severe damage runs out of energy and dies
    by necrosis. Necrosis rather than apoptosis is what makes the lesion
    inflammatory and slow to heal.
  biological_processes:
  - preferred_term: protein poly-ADP-ribosylation
    term:
      id: GO:0070212
      label: protein poly-ADP-ribosylation
    modifier: INCREASED
  - preferred_term: NAD+ consumption by poly-ADP-ribosylation
    term:
      id: GO:0019677
      label: NAD+ catabolic process
    modifier: INCREASED
  downstream:
  - target: Cellular Energy Collapse and Epithelial Necrosis
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:21218101
      reference_title: Acute and delayed sulfur mustard toxicity; novel mechanisms and future studies.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "the loss of NAD+ leads to a marked reduction in the cellular pools of ATP, resulting in cellular dysfunction and cell death via the necrotic pathway"
      explanation: >-
        States the causal step from NAD+ depletion to ATP loss to necrotic death,
        which is the edge itself rather than either node alone.
  evidence:
  - reference: PMID:21218101
    reference_title: Acute and delayed sulfur mustard toxicity; novel mechanisms and future studies.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "In case of severe DNA injury, overactivation of PARP-1 depletes the cellular stores of NAD+, an essential cofactor in the glycolytic pathway, the tricarboxylic acid cycle, and the mitochondrial electron transport chain."
    explanation: Supports PARP1 overactivation as the mechanism of NAD+ depletion and names the pathways that depend on it.
  - reference: PMID:21218101
    reference_title: Acute and delayed sulfur mustard toxicity; novel mechanisms and future studies.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Experimental evidence has established that the PARP-1 pathway of cell death plays a pivotal role in tissue injury and organ dysfunction in mustard-induced acute toxicity"
    explanation: Attributes the tissue-level injury specifically to the PARP1 death pathway in mustard toxicity.
- name: Glutathione Depletion and Oxidative Stress
  biological_scale: MOLECULAR
  description: >-
    Sulfur mustard depletes intracellular glutathione by direct conjugation to
    the electrophile and, in chronically exposed human lung, by downregulation of
    glutathione reductase, the enzyme that regenerates reduced glutathione from
    its disulfide. The cell therefore loses its principal antioxidant buffer at
    the moment it most needs it, and reactive oxygen and nitrogen species
    accumulate. This arm is largely independent of the DNA-alkylation arm and
    synergistic with it: both converge on the same dying cell. Human mustard lung
    shows the paradoxical signature of the pathway under strain - glutathione
    peroxidases, transferases and synthetase are all overexpressed while
    glutathione reductase is strongly suppressed and the substrate they need is
    scarce.
  biological_processes:
  - preferred_term: glutathione metabolic process
    term:
      id: GO:0006749
      label: glutathione metabolic process
    modifier: DECREASED
  - preferred_term: cellular response to oxidative stress
    term:
      id: GO:0034599
      label: cellular response to oxidative stress
    modifier: INCREASED
  molecular_functions:
  - preferred_term: glutathione reductase activity
    term:
      id: GO:0004362
      label: glutathione-disulfide reductase (NADPH) activity
    modifier: DECREASED
  downstream:
  - target: Cellular Energy Collapse and Epithelial Necrosis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:29676192
    reference_title: Sulfur mustard triggers oxidative stress through glutathione depletion and altered expression of glutathione-related enzymes in human airways.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Glutathione peroxidases (GPXs), glutathione-s-transferases (GSTs), and glutathione synthetase (GSS) enzymes were overexpressed in mustard lung biopsies, while glutathione reductase (GSR) was significantly downregulated (14.95-fold)."
    explanation: >-
      Direct human lung-biopsy evidence for the enzyme pattern described, and the
      source of the specific claim that glutathione reductase is the suppressed
      step.
  - reference: PMID:29676192
    reference_title: Sulfur mustard triggers oxidative stress through glutathione depletion and altered expression of glutathione-related enzymes in human airways.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "GSH depletion induced by GSR downregulation may be a major mechanism of SM toxicity on human lung."
    explanation: The authors' own statement that glutathione depletion is a major toxicity mechanism, not merely a correlate.
  - reference: PMID:33002157
    reference_title: "Progressive Lung Injury, Inflammation, and Fibrosis in Rats Following Inhalation of Sulfur Mustard."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Inflammatory changes in the lung were associated with oxidative stress, as reflected by increased expression of heme oxygenase (HO)-1."
    explanation: Independent in vivo corroboration that the pulmonary injury carries an oxidative-stress signature.
- name: Cellular Energy Collapse and Epithelial Necrosis
  biological_scale: CELLULAR
  description: >-
    Keratinocytes, corneal epithelial cells and airway epithelial cells that have
    lost their NAD+ and ATP pools and their antioxidant buffer die. The death
    mode is dose-dependent rather than uniform: a cell with modest damage
    apoptoses, a cell whose energy has collapsed cannot run the ATP-dependent
    apoptotic programme and dies by necrosis. Both are present in the injured
    airway, and the balance between them is what the PARP1 arm sets. Necrotic
    death spills intracellular contents into the tissue, which is what converts a
    molecular lesion into an inflammatory one. Do not read this node as claiming
    the death is exclusively necrotic - the evidence below includes a direct
    demonstration of early apoptosis in the same inhalation model.
  biological_processes:
  - preferred_term: cell death
    term:
      id: GO:0008219
      label: cell death
    modifier: INCREASED
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  - preferred_term: bronchial epithelial cell
    term:
      id: CL:0002328
      label: bronchial epithelial cell
  - preferred_term: corneal epithelial cell
    term:
      id: CL:0000575
      label: corneal epithelial cell
  downstream:
  - target: Acute Pro-Inflammatory Cytokine Burst and Neutrophil Recruitment
    causal_link_type: DIRECT
  - target: Dermal-Epidermal Separation and Vesication
    causal_link_type: DIRECT
  - target: Corneal and Limbal Epithelial Injury
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:21218101
    reference_title: Acute and delayed sulfur mustard toxicity; novel mechanisms and future studies.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Acute toxicity of SM is related to reactive oxygen and nitrogen species, DNA damage, poly(ADP-ribose) polymerase activation and energy depletion within the affected cell."
    explanation: Summarises the four converging inputs to the dying cell that this node represents.
  - reference: PMID:33002157
    reference_title: "Progressive Lung Injury, Inflammation, and Fibrosis in Rats Following Inhalation of Sulfur Mustard."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "including epithelial necrosis and hyperplasia in the distal bronchioles, thickened alveolar walls, enlarged vacuolated macrophages, and interstitial fibrosis"
    explanation: Histological confirmation that necrotic epithelial death occurs in an in vivo sulfur mustard model.
  - reference: PMID:22465472
    reference_title: "Inhalation of sulfur mustard causes long-term T cell-dependent inflammation: possible role of Th17 cells in chronic lung pathology."
    supports: REFUTE
    evidence_source: MODEL_ORGANISM
    snippet: "SM exposure triggers an early apoptotic cell death"
    explanation: >-
      Recorded as REFUTE against any reading of this node as exclusively
      necrotic. TUNEL-positive cells rise early after sulfur mustard inhalation
      in the same model, so apoptosis is a real component of the epithelial
      death and not merely a low-dose special case.
- name: Acute Pro-Inflammatory Cytokine Burst and Neutrophil Recruitment
  biological_scale: TISSUE
  conforms_to: "fibrotic_response#Inflammatory Recruitment and Amplification"
  description: >-
    Necrotic epithelium releases a burst of pro-inflammatory cytokines and
    chemokines within the first 72 hours, and neutrophils follow them into the
    tissue. In the rat inhalation model this burst comprises IL-1 beta, TNF-alpha,
    IL-2, IL-6 and the chemokines CCL2, CCL3, CCL11 and CXCL1. In exposed
    patients, serum IL-6 tracks the severity of the pulmonary complication, which
    is the human counterpart of the same signal. This node substitutes the
    chemical vesicant insult for the generic injury the fibrosis module expects at
    this step.
  biological_processes:
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  - preferred_term: leukocyte migration
    term:
      id: GO:0050900
      label: leukocyte migration
    modifier: INCREASED
  - preferred_term: neutrophil chemotaxis
    term:
      id: GO:0030593
      label: neutrophil chemotaxis
    modifier: INCREASED
  cell_types:
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  - preferred_term: alveolar macrophage
    term:
      id: CL:0000583
      label: alveolar macrophage
  downstream:
  - target: Chronic IL-17-Dependent Airway Inflammation
    causal_link_type: DIRECT
    description: >-
      The acute cytokine and chemokine response does not terminate; the same
      mediators stay elevated as the infiltrate turns lymphocytic.
    evidence:
    - reference: PMID:22465472
      reference_title: "Inhalation of sulfur mustard causes long-term T cell-dependent inflammation: possible role of Th17 cells in chronic lung pathology."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "At 2 wks and beyond (chronic phase), lymphocytic infiltration and continued elevated expression of cytokines/chemokines were sustained."
      explanation: >-
        Establishes continuity between the acute burst and the chronic phase in
        one time course, which is what this edge asserts.
  evidence:
  - reference: PMID:22465472
    reference_title: "Inhalation of sulfur mustard causes long-term T cell-dependent inflammation: possible role of Th17 cells in chronic lung pathology."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In rats, SM induced a burst of pro-inflammatory cytokines/chemokines within 72 h, including IL-1β, TNF-α, IL-2, IL-6, CCL2, CCL3, CCL11, and CXCL1 that was associated with neutrophilic infiltration into the lung."
    explanation: Names the mediators and the 72-hour window, and links them to neutrophil influx.
  - reference: PMID:25031491
    reference_title: The role of serum level of interleukin-6 in severity of pulmonary complications of sulfur mustard injuries.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "patients with moderate to severe symptoms had a serum level of (0.95±0.92 ng/ml) which was significantly higher than mild (0.47±0.54) and control (0.34±0.12) groups"
    explanation: >-
      Human evidence that one of the mediators identified in the animal model
      scales with clinical severity, supporting relevance of this node in people.
- name: Dermal-Epidermal Separation and Vesication
  biological_scale: TISSUE
  description: >-
    Death of basal keratinocytes at the dermal-epidermal junction, together with
    the proteases released from them, separates the epidermis from the dermis and
    produces the blister that gives the agent its name. The lesion is delayed
    relative to the chemistry: alkylation is complete within minutes, while the
    visible lesion takes hours. In the mouse ear vesicant model the equivalent
    lesion rises sharply between 4 and 8 hours after exposure and stays elevated
    at 24 hours. The figures commonly quoted for humans - erythema at 2 to 24
    hours, vesication at 24 to 48 - are not stated in any source cached for this
    entry and are deliberately not asserted here.
  locations:
  - preferred_term: skin epidermis
    term:
      id: UBERON:0001003
      label: skin epidermis
  cell_types:
  - preferred_term: basal cell of epidermis
    term:
      id: CL:0002187
      label: basal cell of epidermis
  downstream:
  - target: Skin blistering
    causal_link_type: DIRECT
  - target: Erythema
    causal_link_type: DIRECT
  - target: Skin Ulceration and Impaired Wound Healing
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:40034085
    reference_title: Mechanistic Insights and Pharmacological Approaches for Nitrogen and Sulfur Mustards and Their Implications as Therapeutic Agents.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "It has been found that SM manifests via vesication of the skin and then later leads to systemic toxicity"
    explanation: Establishes vesication as the defining cutaneous lesion of sulfur mustard.
  - reference: PMID:40034085
    reference_title: Mechanistic Insights and Pharmacological Approaches for Nitrogen and Sulfur Mustards and Their Implications as Therapeutic Agents.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: "This study also found that vesication sharply increased between 4 and 8 h after exposure, was well established, and remained elevated at 8‐ and 24‐h post‐exposure"
    explanation: >-
      Times the vesication in an animal model, supporting the delayed-onset claim.
      Indirect because the quoted experiment used the nitrogen mustard analogue
      HN2 rather than sulfur mustard itself.
- name: Skin Ulceration and Impaired Wound Healing
  biological_scale: TISSUE
  description: >-
    Once the blister roof is lost the wound behaves unlike a thermal burn of
    comparable depth: healing is slow, the ulcer is prone to secondary infection,
    and scarring follows. Because the underlying keratinocyte population has
    itself been alkylated, the tissue is repairing with cells whose replicative
    capacity has been damaged.
  biological_processes:
  - preferred_term: wound healing
    term:
      id: GO:0042060
      label: wound healing
    modifier: DECREASED
  evidence:
  - reference: PMID:40034085
    reference_title: Mechanistic Insights and Pharmacological Approaches for Nitrogen and Sulfur Mustards and Their Implications as Therapeutic Agents.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "delayed severe skin injury that can last for years after initial exposure"
    explanation: Supports the persistence of the cutaneous lesion well beyond the acute burn.
- name: Corneal and Limbal Epithelial Injury
  biological_scale: TISSUE
  description: >-
    The cornea is the most sensitive tissue to sulfur mustard in the acute
    phase. Acute injury presents after a latent period of hours as
    lacrimation, blepharospasm, severe conjunctivitis and corneal erosion. Most
    acute lesions re-epithelialise within days. The consequential injury is to the
    limbus, the narrow zone at the corneal margin that houses the stem cells
    responsible for renewing corneal epithelium.
  locations:
  - preferred_term: cornea
    term:
      id: UBERON:0000964
      label: cornea
  cell_types:
  - preferred_term: corneal epithelial cell
    term:
      id: CL:0000575
      label: corneal epithelial cell
  - preferred_term: limbal epithelial stem cell
    term:
      id: CL:4033093
      label: limbal epithelial stem cell of cornea
  downstream:
  - target: Keratoconjunctivitis
    causal_link_type: DIRECT
  - target: Photophobia
    causal_link_type: DIRECT
  - target: Limbal Stem Cell Deficiency and Delayed Mustard Gas Keratopathy
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:35974928
      reference_title: Ophthalmological aspects of mustard gas poisoning (focus on management).
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Whenever limbal epithelial stem cells are degraded and/or limbal stroma (niche) is ineffective, limbal stem cell deficiency can occur"
      explanation: >-
        States the causal step from limbal stem cell or niche destruction to
        limbal stem cell deficiency, which is this edge rather than either node.
  evidence:
  - reference: PMID:35974928
    reference_title: Ophthalmological aspects of mustard gas poisoning (focus on management).
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Clinical findings in acute conditions include; sore eyes, lacrimation, burning sensation, edematous, obvious blepharospasm of eyelids, severe conjunctivitis, erosion and opacity of the cornea."
    explanation: Describes the acute ocular lesion this node represents.
  - reference: PMID:35974928
    reference_title: Ophthalmological aspects of mustard gas poisoning (focus on management).
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Limbal epithelial stem cell deficiency and dysfunction of limbic stroma are due to destruction."
    explanation: Attributes the limbal deficiency to destruction of the stem cells and their stromal niche.
- name: Chronic IL-17-Dependent Airway Inflammation
  biological_scale: TISSUE
  description: >-
    The acute neutrophilic burst does not resolve. From about two weeks after a
    single inhalational exposure the infiltrate becomes lymphocytic, cytokine
    expression stays elevated, and IL-17-positive cells accumulate in the inflamed
    regions of the lung. This persistence is the hinge of the whole entry: it is
    the mechanism by which a single exposure produces disease that is still
    progressing decades later, and it is why the chronic pulmonary disease
    develops in patients whose acute exposure was unremarkable.
  biological_processes:
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  cell_types:
  - preferred_term: IL-17-positive T cell
    term:
      id: CL:0000084
      label: T cell
  locations:
  - preferred_term: lung
    term:
      id: UBERON:0002048
      label: lung
  downstream:
  - target: Chronic bronchitis
    causal_link_type: DIRECT
  - target: Asthma
    causal_link_type: DIRECT
  - target: TGF-beta Driven Myofibroblast Activation
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:22465472
    reference_title: "Inhalation of sulfur mustard causes long-term T cell-dependent inflammation: possible role of Th17 cells in chronic lung pathology."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "At 2 wks and beyond (chronic phase), lymphocytic infiltration and continued elevated expression of cytokines/chemokines were sustained."
    explanation: Documents the transition from acute neutrophilic to sustained lymphocytic inflammation.
  - reference: PMID:22465472
    reference_title: "Inhalation of sulfur mustard causes long-term T cell-dependent inflammation: possible role of Th17 cells in chronic lung pathology."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "At ≥30 days, SM inhalation promoted the accumulation of IL-17(+) cells in the inflamed areas of monkey lungs."
    explanation: >-
      Establishes the IL-17 arm in a non-human primate as well as in rodent,
      which is the basis for naming this node after IL-17 rather than after
      generic chronic inflammation.
- name: TGF-beta Driven Myofibroblast Activation
  biological_scale: CELLULAR
  conforms_to: "fibrotic_response#Mesenchymal Cell Activation"
  description: >-
    TGF-beta is undetectable during the acute phase and is strongly upregulated in
    the chronic phase, where it drives fibroblast-to-myofibroblast conversion and
    proliferation. PDGF and PAI-1 rise alongside it. The temporal separation
    matters: the profibrotic signal is not part of the initial injury but a
    consequence of inflammation that failed to resolve, which is why the fibrosis
    is delayed rather than immediate.
  biological_processes:
  - preferred_term: transforming growth factor beta receptor signaling pathway
    term:
      id: GO:0007179
      label: transforming growth factor beta receptor signaling pathway
    modifier: INCREASED
  cell_types:
  - preferred_term: myofibroblast cell
    term:
      id: CL:0000186
      label: myofibroblast cell
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  downstream:
  - target: Bronchiolar and Interstitial Collagen Deposition
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:22465472
    reference_title: "Inhalation of sulfur mustard causes long-term T cell-dependent inflammation: possible role of Th17 cells in chronic lung pathology."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "TGF-β, which was undetectable in the acute phase, was strongly upregulated in the chronic phase"
    explanation: Establishes both the TGF-beta upregulation and its restriction to the chronic phase.
  - reference: PMID:29314868
    reference_title: Bronchiolitis Obliterans and Pulmonary Fibrosis after Sulfur Mustard Inhalation in Rats.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Concentrations of TGF-β, PDGF, and PAI-1 were elevated at 28 days in lung, BAL fluid, and/or plasma."
    explanation: Independent in vivo measurement of the profibrotic mediators in a second sulfur mustard rat model.
- name: Bronchiolar and Interstitial Collagen Deposition
  biological_scale: TISSUE
  conforms_to: "fibrotic_response#Excessive ECM Deposition"
  description: >-
    Activated myofibroblasts deposit collagen in the bronchiolar wall and the
    interstitium. In the small airways this produces the concentric intraluminal
    and peribronchiolar scarring that defines bronchiolitis obliterans; in the
    parenchyma it produces interstitial fibrosis. Both are present together in the
    rat inhalation model and both worsen with time.
  biological_processes:
  - preferred_term: extracellular matrix organization
    term:
      id: GO:0030198
      label: extracellular matrix organization
    modifier: INCREASED
  - preferred_term: collagen fibril organization
    term:
      id: GO:0030199
      label: collagen fibril organization
    modifier: INCREASED
  - preferred_term: collagen biosynthetic process
    term:
      id: GO:0032964
      label: collagen biosynthetic process
    modifier: INCREASED
  cell_types:
  - preferred_term: myofibroblast cell
    term:
      id: CL:0000186
      label: myofibroblast cell
  locations:
  - preferred_term: bronchiole
    term:
      id: UBERON:0002186
      label: bronchiole
  downstream:
  - target: Pulmonary fibrosis
    causal_link_type: DIRECT
  - target: Bronchiectasis
    causal_link_type: DIRECT
  - target: Bronchiolitis Obliterans and Progressive Airflow Obstruction
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:22465472
    reference_title: "Inhalation of sulfur mustard causes long-term T cell-dependent inflammation: possible role of Th17 cells in chronic lung pathology."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The chronic phase was also associated with myofibroblast proliferation, collagen deposition, and presence of IL-17(+) cells."
    explanation: Links myofibroblast proliferation to collagen deposition in the chronic phase.
  - reference: PMID:29314868
    reference_title: Bronchiolitis Obliterans and Pulmonary Fibrosis after Sulfur Mustard Inhalation in Rats.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Histopathology confirmed the presence of both BO and PF, and both gradually worsened with time."
    explanation: Confirms that both the airway and parenchymal fibrotic lesions are present and progressive.
- name: Bronchiolitis Obliterans and Progressive Airflow Obstruction
  biological_scale: TISSUE
  conforms_to: "fibrotic_response#Architectural Distortion and Organ Dysfunction"
  description: >-
    Obliterated small airways and stiffened parenchyma translate into measurable
    physiology: rising lung resistance, falling compliance, and a mixed
    obstructive-restrictive spirometric pattern that declines year on year. The
    pattern is mixed, not purely obstructive, in every source that reports it -
    worth stating because the node's name emphasises obstruction. This is the dominant cause of
    long-term disability and death in survivors, and it is what the clinical
    literature calls mustard lung. Roughly 42.5% of exposed Iranian veterans have
    pulmonary involvement, with cough and dyspnoea the leading complaints.
  locations:
  - preferred_term: bronchiole
    term:
      id: UBERON:0002186
      label: bronchiole
  downstream:
  - target: Bronchiolitis obliterans
    causal_link_type: DIRECT
  - target: Airway obstruction
    causal_link_type: DIRECT
  - target: Dyspnea
    causal_link_type: DIRECT
  - target: Cough
    causal_link_type: DIRECT
  - target: Malignant Transformation of Chronically Injured Bronchial Epithelium
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Fibrotic and bronchiectatic lung is where the tumours arise, and the
      radiological lesions predict them, but the intermediate steps between
      scarring and transformation are not established.
    evidence:
    - reference: PMID:36539770
      reference_title: "The predictive association between radiological findings and lung cancer development in patients exposed to sulfur mustard gas: 4 decades follow up of 719 victims."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In survivors exposed to Sulfur Mustard, those with bronchiectasis and lung fibrosis have a significantly higher risk of developing lung cancers"
      explanation: >-
        Supports the edge from the structural lung lesion to malignancy, in the
        same cohort and over the same follow-up.
  evidence:
  - reference: PMID:29314868
    reference_title: Bronchiolitis Obliterans and Pulmonary Fibrosis after Sulfur Mustard Inhalation in Rats.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Pulmonary function testing demonstrated a time-dependent increase in lung resistance, as well as a decrease in lung compliance."
    explanation: Ties the histological lesion to the physiological deficit this node names.
  - reference: PMID:23735551
    reference_title: "Long-term effects of mustard gas on respiratory system of Iranian veterans after Iraq-Iran war: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Prevalence of pulmonary involvement is approximately 42.5%."
    explanation: Pooled human figure for the burden of the pulmonary arm across the Iranian veteran cohort.
  - reference: PMID:38312548
    reference_title: "A 39 Year mortality study of survivors exposed to sulfur mustard agent: A survival analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The findings suggest that pulmonary lesions caused by mustard gas are more likely to be fatal compared to skin and eye lesions."
    explanation: >-
      Supports the claim that this arm, rather than the cutaneous or ocular arm,
      drives mortality.
- name: Limbal Stem Cell Deficiency and Delayed Mustard Gas Keratopathy
  biological_scale: TISSUE
  description: >-
    With the limbal stem cell pool destroyed, the cornea can no longer renew its
    own epithelium, and conjunctival epithelium invades across the limbal barrier
    instead. The clinical result appears after a silent interval that can run to
    decades: limbal ischaemia, corneal scarring and opacity, neovascularization,
    thinning, lipid and amyloid deposits, and persistent epithelial defects. In a
    series of 48 patients, corneal scar or opacity was present in 87.5% and
    neovascularization in 70.8%. The link between the acute limbal insult and the
    multi-decade latency is inferred from clinical natural history and is not
    established at the cell-biological level.
  locations:
  - preferred_term: cornea
    term:
      id: UBERON:0000964
      label: cornea
  cell_types:
  - preferred_term: limbal epithelial stem cell
    term:
      id: CL:4033093
      label: limbal epithelial stem cell of cornea
  downstream:
  - target: Chronic blepharitis
    causal_link_type: DIRECT
  - target: Decreased tear meniscus
    causal_link_type: DIRECT
  - target: Limbal stem cell deficiency
    causal_link_type: DIRECT
  - target: Corneal opacity
    causal_link_type: DIRECT
  - target: Corneal neovascularization
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:15808253
    reference_title: "Chronic and delayed-onset mustard gas keratitis: report of 48 patients and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Corneal signs in order of frequency were: scar or opacity (87.5%), neovascularization (70.8%), thinning (58.3%), lipoid deposits (52.1%), amyloid deposits (43.8%), and epithelial defects and irregularity (31.3%)."
    explanation: The frequency data behind the description of the delayed corneal lesion.
  - reference: PMID:15808253
    reference_title: "Chronic and delayed-onset mustard gas keratitis: report of 48 patients and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ocular surface changes included chronic blepharitis and decreased tear meniscus in all patients, limbal ischemia (81.3%), and conjunctival vascular abnormalities (50%)."
    explanation: Documents limbal ischaemia in most patients, which is the structural correlate of the stem cell loss.
  - reference: PMID:15808253
    reference_title: "Chronic and delayed-onset mustard gas keratitis: report of 48 patients and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Excised corneal buttons disclosed absence of epithelium and Bowman's layer, fibrovascular pannus, stromal scarring, and vascularization."
    explanation: >-
      Histopathological confirmation of epithelial loss and fibrovascular pannus,
      the expected consequence of a failed limbal barrier.
  - reference: PMID:35974928
    reference_title: Ophthalmological aspects of mustard gas poisoning (focus on management).
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The normal limbus and action of the limbal stem cells will be a barrier to the invasion of the conjunctival epithelial cells against the cornea"
    explanation: States the barrier function whose loss explains conjunctivalization of the corneal surface.
- name: Haematopoietic Suppression
  biological_scale: ORGANISM
  description: >-
    After significant systemic absorption, sulfur mustard suppresses
    haematopoiesis, producing cytopenias and marrow damage. Mechanistically this
    is unsurprising - the agent is the chemical ancestor of the nitrogen mustard
    cytotoxics, whose dose-limiting toxicity is myelosuppression, and dividing
    marrow progenitors are exactly the population an interstrand crosslink is
    most cytotoxic to. Read the evidence grade before relying on this node: the
    only quotable statement available here is a review's secondhand assertion,
    not a primary clinical series, which is why no frequency or severity is
    curated and why the gap is recorded as a discussion.
  cell_types:
  - preferred_term: hematopoietic stem cell
    term:
      id: CL:0000037
      label: hematopoietic stem cell
  locations:
  - preferred_term: bone marrow
    term:
      id: UBERON:0002371
      label: bone marrow
  evidence:
  - reference: PMID:40034085
    reference_title: Mechanistic Insights and Pharmacological Approaches for Nitrogen and Sulfur Mustards and Their Implications as Therapeutic Agents.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: "later leads to systemic toxicity that is shown through weight loss, blood cytopenia, bone marrow destruction"
    explanation: >-
      Names cytopenia and marrow destruction as systemic consequences of sulfur
      mustard exposure. Marked INDIRECT because the sentence is a review's
      summary of another author's work rather than a reported observation of its
      own.
- name: Melanocyte Injury and Dyspigmentation
  biological_scale: CELLULAR
  description: >-
    Epidermal melanocytes are alkylated alongside keratinocytes, and the effect on
    pigment is dose-dependent in opposite directions. Low sulfur mustard
    concentrations raise melanin synthesis and the expression of tyrosinase, TRP1,
    TRP2 and MITF; high concentrations reduce melanin content and downregulate all
    of them. This is offered as an explanation for the characteristic mixture of
    hyper- and hypopigmented patches in healed skin. Keep the two claims apart:
    the opposing dose-dependence is measured, in cultured human melanocytes, and
    the mapping onto the clinical pattern is the study authors' own inference
    from it - no cached source here reports the concentration gradient across a
    patient's contact area that the explanation would require.
  biological_processes:
  - preferred_term: melanin biosynthetic process
    term:
      id: GO:0042438
      label: melanin biosynthetic process
    modifier: DYSREGULATED
  cell_types:
  - preferred_term: melanocyte
    term:
      id: CL:0000148
      label: melanocyte
  downstream:
  - target: Skin hyperpigmentation
    causal_link_type: DIRECT
  - target: Skin hypopigmentation
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:31785464
    reference_title: Effect of sulfur mustard on melanogenesis in vitro.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Our findings demonstrated that exposure to low SM concentrations increased melanin synthesis accompanied with an increase in protein expression."
    explanation: The low-concentration arm of the dose-dependent effect.
  - reference: PMID:31785464
    reference_title: Effect of sulfur mustard on melanogenesis in vitro.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In contrast, high SM concentrations led to decreased melanin content and a downregulation in expression of all investigated melanogenesis-associated proteins."
    explanation: The high-concentration arm, and the source of the bidirectional claim.
  - reference: PMID:40034085
    reference_title: Mechanistic Insights and Pharmacological Approaches for Nitrogen and Sulfur Mustards and Their Implications as Therapeutic Agents.
    supports: REFUTE
    evidence_source: OTHER
    snippet: "Nonexposed areas also develop erythema, bulla, hypopigmentation, and hyperpigmentation"
    explanation: >-
      Recorded as REFUTE against a purely local, contact-area explanation of the
      pigmentary change: dyspigmentation is reported in skin that was never
      exposed, which a concentration gradient at the contact site cannot
      produce.
- name: Malignant Transformation of Chronically Injured Bronchial Epithelium
  biological_scale: CELLULAR
  description: >-
    Bronchial epithelium that has been alkylated, is chronically inflamed and is
    proliferating to repair itself carries an elevated risk of malignant
    transformation. Two lines of evidence support this, and neither is as strong
    as it first looks. In bronchial biopsies, FOXM1 and APOE are overexpressed
    roughly 15-fold and 4-fold - but the study has six exposed patients and five
    controls, excluded anyone with lung cancer, and its authors read APOE the
    other way, as protective against ROS damage in the short term, with the
    cancer link offered as a hypothesis. Clinically, in 719 victims followed for
    a mean of 38 years, lung fibrosis raised tumour risk about 17.75-fold, air
    trapping about 11.73-fold and bronchiectasis about 10.14-fold, and the lobes
    with fibrosis were the lobes tumours appeared in - but that cohort had no
    control group. The spatial concordance makes the association hard to explain
    by shared exposure alone; it is not itself a demonstration of mechanism.
  biological_processes:
  - preferred_term: DNA damage response
    term:
      id: GO:0006974
      label: DNA damage response
    modifier: DYSREGULATED
  cell_types:
  - preferred_term: bronchial epithelial cell
    term:
      id: CL:0002328
      label: bronchial epithelial cell
  downstream:
  - target: Lung neoplasm
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:29552057
    reference_title: "Two Lung Cancer Development-Related Genes, Forkhead Box M1 (FOXM1) and Apolipoprotein E (APOE), are overexpressed in Bronchial of Patients after Long-Term Exposure to Sulfur Mustard."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Expression of FOXM1 and APOE genes in bronchial of the patients was significantly (p < 0.001) overexpressed by 14.8316 and 3.9504-folds, respectively."
    explanation: >-
      The molecular measurement, in exposed human bronchial tissue. Note the
      study is six exposed patients against five controls and its authors frame
      the cancer link as a hypothesis, so this establishes the expression change
      and not the transformation risk.
  - reference: PMID:36539770
    reference_title: "The predictive association between radiological findings and lung cancer development in patients exposed to sulfur mustard gas: 4 decades follow up of 719 victims."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most predictive finding was LF which caused the risk of developing tumor 17.75"
    explanation: The strongest single radiological predictor of later lung cancer in the four-decade cohort.
  - reference: PMID:36539770
    reference_title: "The predictive association between radiological findings and lung cancer development in patients exposed to sulfur mustard gas: 4 decades follow up of 719 victims."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Furthermore, it was shown that the lung lobes with LF were statistically correlated to tumor-involved lobes."
    explanation: >-
      Spatial concordance between fibrosis and tumour within the same lung, which
      is harder to explain by shared exposure than a whole-patient association
      would be. It is a stronger correlation, not a demonstration of mechanism,
      and the cohort carried no control group.
phenotypes:
- name: Skin blistering
  category: Cutaneous
  description: >-
    Vesicles and bullae over exposed and occluded skin, appearing after a latent
    interval rather than at the moment of contact. The blister is the sign the
    agent is named for. No source cached for this entry states the human latency
    in hours, so no figure is given here; the node this phenotype reports on
    carries the animal-model timing that is quotable.
  phenotype_term:
    preferred_term: Vesicles and bullae
    term:
      id: HP:0008066
      label: Abnormal blistering of the skin
  evidence:
  - reference: PMID:28962267
    reference_title: "Four sulfur mustard exposure cases: Overall analysis of four types of biomarkers in clinical samples provides positive implication for early diagnosis and treatment monitoring."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Chinese male individuals accidentally exposed to unknown chemicals and emerged erythema or blisters on contacted organism derma, then hospitalized."
    explanation: >-
      Blistering in an accidental human exposure subsequently confirmed as sulfur
      mustard by four independent biomarker classes.
- name: Erythema
  category: Cutaneous
  description: Erythema of contacted skin, preceding vesication by hours.
  phenotype_term:
    preferred_term: Erythema
    term:
      id: HP:0010783
      label: Erythema
  evidence:
  - reference: PMID:28962267
    reference_title: "Four sulfur mustard exposure cases: Overall analysis of four types of biomarkers in clinical samples provides positive implication for early diagnosis and treatment monitoring."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "emerged erythema or blisters on contacted organism derma"
    explanation: Erythema recorded as a presenting sign in confirmed human sulfur mustard exposure.
- name: Skin hyperpigmentation
  category: Cutaneous
  description: >-
    Hyperpigmented patches at healed lesion sites, attributed to the increased
    melanogenesis seen at lower agent concentrations.
  phenotype_term:
    preferred_term: Hyperpigmentation of the skin
    term:
      id: HP:0000953
      label: Hyperpigmentation of the skin
  evidence:
  - reference: PMID:31785464
    reference_title: Effect of sulfur mustard on melanogenesis in vitro.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: "We concluded that low SM concentrations may cause hyperpigmentation"
    explanation: >-
      The authors' inference from cultured human melanocytes to the clinical
      pigmentary change. Indirect because the measurement is in vitro and the
      patient-level claim follows by inference.
- name: Skin hypopigmentation
  category: Cutaneous
  description: >-
    Hypopigmented patches at healed lesion sites, attributed to loss of melanin
    content at higher agent concentrations.
  phenotype_term:
    preferred_term: Hypopigmentation of the skin
    term:
      id: HP:0001010
      label: Hypopigmentation of the skin
  evidence:
  - reference: PMID:31785464
    reference_title: Effect of sulfur mustard on melanogenesis in vitro.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: "high SM concentrations decreased melanin content which may explain hypopigmented skin areas in SM exposed patients"
    explanation: >-
      The high-concentration arm and its proposed clinical correlate. Indirect for
      the same reason as the hyperpigmentation item.
- name: Keratoconjunctivitis
  category: Ocular
  description: >-
    Acute keratoconjunctivitis with pain, lacrimation, blepharospasm and corneal
    erosion, declaring itself after a latent period of hours.
  phenotype_term:
    preferred_term: Keratoconjunctivitis
    term:
      id: HP:0001096
      label: Keratoconjunctivitis
    temporality: ACUTE
  evidence:
  - reference: PMID:35974928
    reference_title: Ophthalmological aspects of mustard gas poisoning (focus on management).
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Clinical findings in acute conditions include; sore eyes, lacrimation, burning sensation, edematous, obvious blepharospasm of eyelids, severe conjunctivitis, erosion and opacity of the cornea."
    explanation: Enumerates the acute ocular findings that constitute this phenotype.
- name: Photophobia
  category: Ocular
  phenotype_term:
    preferred_term: Photophobia
    term:
      id: HP:0000613
      label: Photophobia
  evidence:
  - reference: PMID:35974928
    reference_title: Ophthalmological aspects of mustard gas poisoning (focus on management).
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "One of the problems that occurs in victims is photophobia, when the victims have severe eye irritation"
    explanation: Names photophobia as a recognised finding in sulfur mustard victims.
- name: Corneal opacity
  category: Ocular
  description: >-
    Corneal scarring and opacification, the commonest finding of delayed mustard
    gas keratopathy and the main driver of visual loss. Present in 87.5% of a
    series of 48 patients who already had chronic or delayed keratitis. No
    frequency band is derived from that figure, because its denominator is
    patients with established keratopathy rather than exposed people; at the
    disease level the eye is affected in roughly 39% of victims.
  phenotype_term:
    preferred_term: Corneal opacity
    term:
      id: HP:0007957
      label: Corneal opacity
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:15808253
    reference_title: "Chronic and delayed-onset mustard gas keratitis: report of 48 patients and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Corneal signs in order of frequency were: scar or opacity (87.5%)"
    explanation: >-
      87.5% of 48 patients with chronic or delayed keratitis, which places this in
      the VERY_FREQUENT band for that population.
- name: Corneal neovascularization
  category: Ocular
  description: >-
    New vessel growth across the cornea, the expected consequence of a failed
    limbal barrier. Present in 70.8% of the same delayed-keratitis series; as
    with corneal opacity, that denominator is patients who already have the
    keratopathy, so no frequency band is derived from it.
  phenotype_term:
    preferred_term: Corneal neovascularization
    term:
      id: HP:0011496
      label: Corneal neovascularization
  evidence:
  - reference: PMID:15808253
    reference_title: "Chronic and delayed-onset mustard gas keratitis: report of 48 patients and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Corneal signs in order of frequency were: scar or opacity (87.5%), neovascularization (70.8%)"
    explanation: 70.8% of the delayed-keratitis series, which is the FREQUENT band.
- name: Chronic blepharitis
  category: Ocular
  description: >-
    Chronic inflammation of the lid margins, present in every patient in the
    48-patient chronic and delayed keratitis series. That denominator is patients
    who already have the keratopathy, not exposed people generally, so no
    frequency band is derived from it.
  phenotype_term:
    preferred_term: Chronic blepharitis
    term:
      id: HP:0000498
      label: Blepharitis
    temporality: CHRONIC
  evidence:
  - reference: PMID:15808253
    reference_title: "Chronic and delayed-onset mustard gas keratitis: report of 48 patients and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ocular surface changes included chronic blepharitis and decreased tear meniscus in all patients, limbal ischemia (81.3%), and conjunctival vascular abnormalities (50%)."
    explanation: Names chronic blepharitis in all patients of the delayed-keratitis series.
- name: Decreased tear meniscus
  category: Ocular
  description: >-
    A reduced tear meniscus - the tear reservoir at the lid margin - in every
    patient in the same series, indicating aqueous tear deficiency. Bound to
    Decreased lacrimation as the closest available term; note the source reports
    the sign, reduced tear volume at the lid margin, rather than measuring tear
    production, which is why the binding is one inferential step from what was
    observed.

    The keratoconjunctivitis sicca diagnosis is deliberately not asserted.
    HP:0001097 exists and this cohort does document the ocular surface damage
    that the diagnosis requires, but the authors do not make the diagnosis in the
    sentence quoted, and the entry records the sign they did report rather than
    the conclusion they did not.
  phenotype_term:
    preferred_term: decreased tear meniscus
    term:
      id: HP:0000633
      label: Decreased lacrimation
  evidence:
  - reference: PMID:15808253
    reference_title: "Chronic and delayed-onset mustard gas keratitis: report of 48 patients and review of literature."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ocular surface changes included chronic blepharitis and decreased tear meniscus in all patients, limbal ischemia (81.3%), and conjunctival vascular abnormalities (50%)."
    explanation: >-
      Reports decreased tear meniscus in all patients. Marked indirect because
      the bound term names reduced tear production while the source reports
      reduced tear volume present at the lid margin.
- name: Bronchiolitis obliterans
  category: Respiratory
  description: >-
    Obliterative small-airway disease, the most characteristic delayed pulmonary
    consequence of sulfur mustard inhalation.
  phenotype_term:
    preferred_term: Bronchiolitis obliterans
    term:
      id: HP:0011946
      label: Bronchiolitis obliterans
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:27832694
    reference_title: Long Term Follow-Up of Sulfur Mustard Related Bronchiolitis Obliterans Treatment.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Bronchiolitis obliterans (BO) is the most remarkable pulmonary sequels of war-related sulfur mustard inhalation."
    explanation: Identifies bronchiolitis obliterans as the signature pulmonary sequela.
- name: Bronchiectasis
  category: Respiratory
  phenotype_term:
    preferred_term: Bronchiectasis
    term:
      id: HP:0002110
      label: Bronchiectasis
  evidence:
  - reference: PMID:36539770
    reference_title: "The predictive association between radiological findings and lung cancer development in patients exposed to sulfur mustard gas: 4 decades follow up of 719 victims."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Bronchiectasis (B), and the evidence of lung cancer were found in 265 (36.9%), 207 (28.8%), 151 (21.0%), and 42 (5.8%), respectively"
    explanation: Bronchiectasis in 151 of 719 followed victims on serial HRCT.
- name: Chronic bronchitis
  category: Respiratory
  phenotype_term:
    preferred_term: Chronic bronchitis
    term:
      id: HP:0004469
      label: Chronic bronchitis
    temporality: CHRONIC
  evidence:
  - reference: PMID:36539770
    reference_title: "The predictive association between radiological findings and lung cancer development in patients exposed to sulfur mustard gas: 4 decades follow up of 719 victims."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The late abnormalities can be present as chronic bronchitis, tracheobronchial stenosis, asthma, bronchiectasis, airway narrowing, lung fibrosis, and lung cancers."
    explanation: Lists chronic bronchitis among the established late respiratory abnormalities.
- name: Pulmonary fibrosis
  category: Respiratory
  phenotype_term:
    preferred_term: Pulmonary fibrosis
    term:
      id: HP:0002206
      label: Pulmonary fibrosis
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:36539770
    reference_title: "The predictive association between radiological findings and lung cancer development in patients exposed to sulfur mustard gas: 4 decades follow up of 719 victims."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Air Trapping (AT), Lung Fibrosis (LF), Bronchiectasis (B), and the evidence of lung cancer were found in 265 (36.9%), 207 (28.8%), 151 (21.0%), and 42 (5.8%), respectively"
    explanation: Lung fibrosis in 207 of 719 victims on long-term HRCT follow-up.
- name: Cough
  category: Respiratory
  phenotype_term:
    preferred_term: Cough
    term:
      id: HP:0012735
      label: Cough
    temporality: CHRONIC
  evidence:
  - reference: PMID:23735551
    reference_title: "Long-term effects of mustard gas on respiratory system of Iranian veterans after Iraq-Iran war: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most common complaints are cough and dyspnea."
    explanation: Cough named as one of the two leading chronic complaints in the exposed veteran population.
- name: Dyspnea
  category: Respiratory
  phenotype_term:
    preferred_term: Dyspnea
    term:
      id: HP:0002094
      label: Dyspnea
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:23735551
    reference_title: "Long-term effects of mustard gas on respiratory system of Iranian veterans after Iraq-Iran war: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most common complaints are cough and dyspnea."
    explanation: Dyspnoea named as one of the two leading chronic complaints.
- name: Airway obstruction
  category: Respiratory
  description: >-
    Obstructive, and in some patients mixed obstructive-restrictive, spirometry in
    long-term survivors.
  phenotype_term:
    preferred_term: Airway obstruction
    term:
      id: HP:0006536
      label: Airway obstruction
  evidence:
  - reference: PMID:29552057
    reference_title: "Two Lung Cancer Development-Related Genes, Forkhead Box M1 (FOXM1) and Apolipoprotein E (APOE), are overexpressed in Bronchial of Patients after Long-Term Exposure to Sulfur Mustard."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PFTs have demonstrated more obstructive and restrictive spirometric patterns among patients compared to the controls."
    explanation: >-
      Direct spirometric comparison of exposed patients against controls. Note
      the patients in this study were selected for FEV1 between 50 and 80%, so
      the magnitude of the difference is partly an inclusion criterion; the
      pattern being mixed rather than purely obstructive is the point taken here.
  - reference: PMID:23735551
    reference_title: "Long-term effects of mustard gas on respiratory system of Iranian veterans after Iraq-Iran war: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Spirometry results can reveal restrictive and obstructive pulmonary disease."
    explanation: >-
      Unselected review-level statement of the spirometric picture, cited in
      preference to the small selected series for the general claim.
- name: Asthma
  category: Respiratory
  description: >-
    Asthma is named alongside chronic bronchitis as one of the two most frequent
    delayed lung toxicities of sulfur mustard, and recurs in every review of the
    exposed veteran cohort.
  phenotype_term:
    preferred_term: Asthma
    term:
      id: HP:0002099
      label: Asthma
  evidence:
  - reference: PMID:21218101
    reference_title: Acute and delayed sulfur mustard toxicity; novel mechanisms and future studies.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "patients with SM-induced asthma and chronic bronchitis (most frequent delayed lung toxicities)"
    explanation: Names asthma as one of the two most frequent delayed pulmonary toxicities.
  - reference: PMID:23735551
    reference_title: "Long-term effects of mustard gas on respiratory system of Iranian veterans after Iraq-Iran war: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Major respiratory complications are chronic obstructive pulmonary disease, bronchiectasis, and asthma."
    explanation: Independent listing of asthma among the major respiratory complications.
- name: Limbal stem cell deficiency
  category: Ocular
  description: >-
    Failure of the corneal stem cell compartment at the limbus. This is the
    lesion the whole delayed ocular arm turns on, and HPO has a term for it, so
    it is curated as a phenotype as well as a mechanism node.
  phenotype_term:
    preferred_term: Limbal stem cell deficiency
    term:
      id: HP:0032107
      label: Limbal stem cell deficiency
  evidence:
  - reference: PMID:35974928
    reference_title: Ophthalmological aspects of mustard gas poisoning (focus on management).
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Victims of keratitis problems suffer from impaired corneal sensation, recent and continuous corneal erosion, fatty and amyloid deposition, irregularity, thinning and corneal ulcers, limbal stem cell deficiency"
    explanation: Names limbal stem cell deficiency among the findings in sulfur mustard keratitis victims.
  - reference: PMID:15808253
    reference_title: "Chronic and delayed-onset mustard gas keratitis: report of 48 patients and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ocular surface changes included chronic blepharitis and decreased tear meniscus in all patients, limbal ischemia (81.3%), and conjunctival vascular abnormalities (50%)."
    explanation: >-
      Limbal ischaemia in 81.3% of the delayed-keratitis series, the structural
      correlate of the stem cell compartment failing.
- name: Lung neoplasm
  category: Neoplastic
  description: >-
    Lung cancer arising decades after exposure, most often adenocarcinoma, and
    concentrated in the fibrotic and bronchiectatic lung.
  phenotype_term:
    preferred_term: Neoplasm of the lung
    term:
      id: HP:0100526
      label: Neoplasm of the lung
  evidence:
  - reference: PMID:36539770
    reference_title: "The predictive association between radiological findings and lung cancer development in patients exposed to sulfur mustard gas: 4 decades follow up of 719 victims."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Adenocarcinoma (38.1%) was the most common type of cancer."
    explanation: Histological distribution of the tumours arising in the followed cohort.
genetic:
- name: GSTM1
  relationship_type: MODIFIER
  gene_term:
    preferred_term: GSTM1
    term:
      id: hgnc:4632
      label: GSTM1
  notes: >-
    Homozygous deletion of GSTM1 - the null genotype, common in the general
    population - removes one of the glutathione S-transferases that conjugate the
    episulfonium electrophile and handle the downstream oxidant load. In a cohort
    of 185 sulfur-mustard-exposed subjects the null genotype was over-represented
    among those with severe or very severe mustard lung. This modifies severity
    in people who have already been exposed; it is not a cause of the disease and
    confers no risk in the absence of exposure.

    The two lines of evidence fit together, though the synthesis is inference
    rather than a finding either study makes: GSTM1 message is upregulated
    several-fold in mustard-lung airway wall, so the isoform is part of the
    response to the oxidant load, and individuals who carry no copy of it at all
    cannot mount that part of the response. Neither study tests that link
    directly.
  evidence:
  - reference: PMID:29435433
    reference_title: "Association of glutathione S-transferase polymorphisms with the severity of mustard lung."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The frequency of GSTM1 homozygous deletion was significantly higher in the severe/very severe patients compared with the mild/moderate subjects (66.3% vs. 48%, P = 0.013)."
    explanation: >-
      The primary association, with the genotype frequencies in each severity
      stratum of the exposed cohort.
  - reference: PMID:29435433
    reference_title: "Association of glutathione S-transferase polymorphisms with the severity of mustard lung."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The GSTM1 null genotype was associated with the severity of mustard lung"
    explanation: >-
      States the association in the authors' own terms, which is what this
      MODIFIER record asserts.
  - reference: PMID:24344877
    reference_title: "Expression of glutathione S-transferase variants in human airway wall after long-term response to sulfur mustard."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "SM-induced COPD individuals showed expression of GSTA1 2.51 ± 0.83-, GSTM1 2.84 ± 1.71- and GSTP1 5.61 ± 2.59-folds higher than those of controls"
    explanation: >-
      Measures GSTM1 upregulation in the airway wall of mustard-lung patients,
      which is the second line of evidence the notes describe.
- name: GSTT1
  relationship_type: DISPUTED
  gene_term:
    preferred_term: GSTT1
    term:
      id: hgnc:4641
      label: GSTT1
  notes: >-
    Tested in the same cohort as GSTM1 and not associated with mustard lung
    severity. Recorded because a negative result in a study powered to find the
    GSTM1 effect is informative: it argues the severity modification is specific
    to the GSTM1 isoform rather than a general property of glutathione-transferase
    capacity.
  evidence:
  - reference: PMID:29435433
    reference_title: "Association of glutathione S-transferase polymorphisms with the severity of mustard lung."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There was no significant association between GSTT1 and GSTP1 polymorphisms with the severity of the mustard lung."
    explanation: >-
      The negative result for this gene, from the same cohort and the same
      analysis that found the GSTM1 association.
- name: GSTP1
  relationship_type: DISPUTED
  gene_term:
    preferred_term: GSTP1
    term:
      id: hgnc:4638
      label: GSTP1
  notes: >-
    The Ile105Val and Ala114Val polymorphisms were genotyped in the same cohort
    and showed no association with mustard lung severity. Recorded for the same
    reason as GSTT1.
  evidence:
  - reference: PMID:29435433
    reference_title: "Association of glutathione S-transferase polymorphisms with the severity of mustard lung."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "To determine the polymorphisms of GSTP1 in exon 5 (Ile105Val) and exon 6 (Ala114Val), RFLP-PCR method was performed."
    explanation: >-
      Establishes which GSTP1 variants were tested, so the negative result above
      is bounded to them rather than read as covering the whole gene.
environmental:
- name: Battlefield exposure to sulfur mustard vapour and liquid
  exposure_term:
    preferred_term: exposure to sulfur mustard
    term:
      id: ECTO:9001175
      label: exposure to bis(2-chloroethyl) sulfide
  description: >-
    Deliberate military use, overwhelmingly the Iran-Iraq war of 1980-1988, is
    the source of almost all the natural-history data in this entry. Tens of
    thousands of Iranian combatants were exposed; the cohort has been followed for
    four decades and is the reason the delayed arm of this disease is
    characterised at all. Immediate mortality was low, in the range of a few
    percent, because open-air dispersal dilutes the agent - which is precisely why
    so many survivors were available to develop the chronic disease.
  influences_mechanisms:
  - target: Sulfur Mustard Penetration and Episulfonium Ion Formation
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Battlefield vapour and liquid contact is the route by which the agent
      reaches skin, cornea and airway epithelium.
    evidence:
    - reference: PMID:22465472
      reference_title: "Inhalation of sulfur mustard causes long-term T cell-dependent inflammation: possible role of Th17 cells in chronic lung pathology."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "SM exposure occurs primarily through inhalation and absorption through skin and the anterior surface of the eye, making the lungs, the skin, and the eye as major targets of SM toxicity"
      explanation: >-
        States the exposure routes and the target tissues, which is the link
        between this exposure and the penetration node.
  evidence:
  - reference: PMID:38312548
    reference_title: "A 39 Year mortality study of survivors exposed to sulfur mustard agent: A survival analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The primary objective of this study was to analyze the long-term survival of 48,067 chemical warfare survivors who suffered from pulmonary, cutaneous, and ocular lesions in the decades following the Iran-Iraq war."
    explanation: Establishes the scale of the exposed cohort and the setting.
  - reference: PMID:22465472
    reference_title: "Inhalation of sulfur mustard causes long-term T cell-dependent inflammation: possible role of Th17 cells in chronic lung pathology."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "During the Iran-Iraq war, immediate mortality among the Iranian soldiers exposed to SM was only 3–4%, but decades later nearly half of the victims developed chronic respiratory complications"
    explanation: >-
      Supports the low acute mortality alongside high delayed morbidity, which is
      the epidemiological shape this entry is built around.
- name: Accidental civilian exposure to abandoned chemical munitions
  exposure_term:
    preferred_term: exposure to sulfur mustard
    term:
      id: ECTO:9001175
      label: exposure to bis(2-chloroethyl) sulfide
  description: >-
    Sulfur mustard is chemically stable and persists in buried or dumped
    munitions long after the conflict that produced them. Civilians encountering
    corroded shells or containers are exposed without knowing what the agent is,
    which is one reason biomarker confirmation matters clinically: the four cases
    that established the multi-biomarker time course were an accidental exposure
    to an unknown chemical, identified retrospectively.
  influences_mechanisms:
  - target: Sulfur Mustard Penetration and Episulfonium Ion Formation
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Dermal contact with agent released from a corroded munition delivers the
      same lesion by the same route as a battlefield exposure.
    evidence:
    - reference: PMID:28962267
      reference_title: "Four sulfur mustard exposure cases: Overall analysis of four types of biomarkers in clinical samples provides positive implication for early diagnosis and treatment monitoring."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Chinese male individuals accidentally exposed to unknown chemicals and emerged erythema or blisters on contacted organism derma, then hospitalized."
      explanation: >-
        An accidental civilian dermal exposure producing the characteristic
        lesion, later confirmed as sulfur mustard.
  evidence:
  - reference: PMID:28962267
    reference_title: "Four sulfur mustard exposure cases: Overall analysis of four types of biomarkers in clinical samples provides positive implication for early diagnosis and treatment monitoring."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The old shells or containers of SM are still a large threat to civilian health."
    explanation: Establishes abandoned munitions as an ongoing civilian exposure source.
treatments:
- name: Immediate Skin Decontamination
  description: >-
    Copious water with neutral soap, and dilute sodium hypochlorite where
    available, removing agent still on the skin. This is the single highest-yield
    intervention and the only one that acts on the lesion before it is fixed:
    alkylation is complete within minutes, so decontamination buys back only the
    dose that has not yet reacted. Its benefit falls off steeply with delay.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: skin decontamination
    term:
      id: NCIT:C49236
      label: Therapeutic Procedure
  target_mechanisms:
  - target: Sulfur Mustard Penetration and Episulfonium Ion Formation
    description: Removes unabsorbed agent before it can penetrate and cyclize.
  evidence:
  - reference: PMID:31576778
    reference_title: Advances in treatment of acute sulfur mustard poisoning - a critical review.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The best solution for decontamination is large amounts of water, using neutral soap and 0.5% sodium hypochlorite."
    explanation: Names the recommended decontamination method.
  - reference: PMID:31576778
    reference_title: Advances in treatment of acute sulfur mustard poisoning - a critical review.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The victims must remove from the contaminated zone immediately."
    explanation: Supports the time-critical framing of this intervention.
  - reference: PMID:35974928
    reference_title: Ophthalmological aspects of mustard gas poisoning (focus on management).
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "washing after this time is not beneficial"
    explanation: >-
      States that irrigation past the early window stops helping, which is the
      basis for the claim that this intervention's benefit falls off steeply
      with delay.
- name: Supportive and Intensive Care
  description: >-
    Humidified oxygen, bronchodilators, rehydration, mechanical ventilation where
    needed, antibiotics for secondary infection, respiratory physiotherapy, and
    burn-style wound care. There is no antidote, so this is the substance of acute
    management rather than an adjunct to one.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:31576778
    reference_title: Advances in treatment of acute sulfur mustard poisoning - a critical review.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The important protective and conservative treatment of SM-induced pulmonary injuries include humidified oxygen, bronchodilators, NAC as muculytic, rehydration, mechanical ventilation, appropriate antibiotics and respiratory physiotherapy as clinically indicated."
    explanation: Enumerates the supportive measures that make up standard care.
  - reference: PMID:25055840
    reference_title: "The role of N-acetylcysteine in the management of acute and chronic pulmonary complications of sulfur mustard: a literature review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Currently, there is no validated antidote, chemoprophylaxis and curative modality for pulmonary toxicities secondary to sulfur mustard exposure."
    explanation: Establishes that supportive care is the whole of management rather than a fallback.
- name: N-Acetylcysteine
  description: >-
    A glutathione precursor and direct radical scavenger, used both acutely and in
    chronic pulmonary management. It is the pharmacological agent that maps most
    directly onto a curated mechanism in this entry - the glutathione depletion
    node - which is the argument for it. A dedicated review reports clinical and
    paraclinical improvement in sulfur mustard bronchiolitis obliterans on oral
    NAC alone or combined with clarithromycin, while the same review and an
    independent one both state there is no validated antidote. Both are recorded
    below, and the entry does not resolve them, because "improves parameters in
    an established chronic complication" and "is not an antidote for the
    poisoning" are compatible claims about different things.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: N-acetylcysteine
      term:
        id: CHEBI:22198
        label: acetylcysteine
  target_mechanisms:
  - target: Glutathione Depletion and Oxidative Stress
    description: >-
      Replenishes the cysteine supply for glutathione synthesis, directly opposing
      the depletion this node describes.
  evidence:
  - reference: PMID:31576778
    reference_title: Advances in treatment of acute sulfur mustard poisoning - a critical review.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "However, N-acetyle cysteine (NAC) is recommended, none of them acts as specific or effective antidote."
    explanation: >-
      Records both the recommendation and the explicit caveat that it is not an
      antidote, which is why this treatment is not curated as one.
  - reference: PMID:25055840
    reference_title: "The role of N-acetylcysteine in the management of acute and chronic pulmonary complications of sulfur mustard: a literature review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "oral NAC alone (1200 or 1800 mg/day for 4 months) or at a dose 600 mg/day for 6 months in combination with clarithromycin (500 mg/day) have led to improvements of clinical and paraclinical pulmonary parameters of patients with bronchiolitis obliterans due to sulfur mustard"
    explanation: >-
      The positive clinical result, with doses and durations, in the chronic
      pulmonary complication rather than in the acute poisoning.
- name: Macrolide and Inhaled Corticosteroid Therapy for Bronchiolitis Obliterans
  description: >-
    Long-term azithromycin combined with an inhaled corticosteroid and long-acting
    beta-2 agonist, plus N-acetylcysteine, is the regimen used for established
    mustard-related bronchiolitis obliterans. Over five years of spirometry the
    rate of FEV1 decline in treated bronchiolitis obliterans patients was not
    significantly different from that in COPD patients treated to guideline, which
    the authors read as evidence the regimen works. Note this is a comparison
    against a different disease's treated course, not against untreated
    bronchiolitis obliterans, so it is suggestive rather than controlled.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: azithromycin
      term:
        id: CHEBI:2955
        label: azithromycin
    - preferred_term: fluticasone propionate
      term:
        id: CHEBI:31441
        label: fluticasone propionate
    - preferred_term: salmeterol
      term:
        id: CHEBI:9011
        label: salmeterol
  target_mechanisms:
  - target: Chronic IL-17-Dependent Airway Inflammation
    description: >-
      Macrolides and inhaled corticosteroids are used here for their
      anti-inflammatory rather than antibacterial or bronchodilator action.
  evidence:
  - reference: PMID:27832694
    reference_title: Long Term Follow-Up of Sulfur Mustard Related Bronchiolitis Obliterans Treatment.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The BO patients were treated with inhaled Seretide 125-250/25 (2 puffs BID), azithromycin (250 mg, three times/week) and N-acetylcysteine (1200-1800/day)."
    explanation: The exact regimen and dosing this treatment entry describes.
  - reference: PMID:27832694
    reference_title: Long Term Follow-Up of Sulfur Mustard Related Bronchiolitis Obliterans Treatment.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "The non-significant difference of FEV1 decline in BO compared to COPD patients suggests the effectiveness of azithromycin, inhaled steroid and N-acetyl cysteine in BO patients."
    explanation: >-
      The efficacy claim, marked indirect because it rests on an inference from a
      non-significant difference against a different disease's treated course
      rather than on a controlled comparison.
  - reference: PMID:31576778
    reference_title: Advances in treatment of acute sulfur mustard poisoning - a critical review.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "However, none of them, except macrolide antibiotics have been proved clinically."
    explanation: >-
      Independent statement singling out macrolides as the one class with clinical
      proof among the candidate agents.
- name: Sodium Thiosulfate Infusion
  description: >-
    A sulfur nucleophile intended to scavenge circulating agent, given within
    roughly an hour of exposure. It is not a validated antidote and the window is
    narrow enough that in most real exposures it has closed before the patient is
    identified.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: sodium thiosulfate
      term:
        id: CHEBI:132112
        label: sodium thiosulfate
  evidence:
  - reference: PMID:31576778
    reference_title: Advances in treatment of acute sulfur mustard poisoning - a critical review.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Sodium thiosulfate infusion (100-500 mg/kg/min) should be started up to 60 min after SM exposure."
    explanation: Dose and time window for this intervention.
- name: Cutaneous Wound Management
  description: >-
    Moist dressing, preferentially with silver sulfadiazine, plus analgesia,
    antipruritics, debridement (physical, enzymatic or laser) and autologous
    split-thickness grafting where indicated. This is the arm that treats the
    vesicant burn once it has formed, as distinct from decontamination, which
    acts before it does.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: burn wound care
    term:
      id: NCIT:C116681
      label: Wound Care Management
  target_mechanisms:
  - target: Skin Ulceration and Impaired Wound Healing
    description: >-
      Manages the denuded, slow-healing ulcer left when the blister roof is lost.
  evidence:
  - reference: PMID:31576778
    reference_title: Advances in treatment of acute sulfur mustard poisoning - a critical review.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "moist dressing; preferably with silver sulfadiazine cream, analgesic, anti-pruritic, physically debridement, debridase, Laser debridement, followed by skin autologous split-thickness therapy as clinically indicated"
    explanation: Enumerates the recommended cutaneous wound management for sulfur mustard injury.
- name: Corneal and Limbal Allograft Surgery
  description: >-
    Allograft limbal stem cell transplantation, penetrating keratoplasty and
    lamellar keratoplasty for advanced mustard gas keratopathy. The rationale
    follows directly from the mechanism: if the limbal stem cell pool is gone, the
    cornea cannot resurface itself and the deficit has to be replaced rather than
    treated medically.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: corneal and limbal allograft transplantation
    term:
      id: NCIT:C210959
      label: Corneal Transplantation
  target_mechanisms:
  - target: Limbal Stem Cell Deficiency and Delayed Mustard Gas Keratopathy
    description: Replaces the exhausted limbal stem cell population or the scarred cornea itself.
  evidence:
  - reference: PMID:15808253
    reference_title: "Chronic and delayed-onset mustard gas keratitis: report of 48 patients and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "others underwent allograft stem cell transplantation (20 eyes of 17 patients), penetrating keratoplasty (12 eyes of 12 patients), and lamellar keratoplasty (4 eyes of 3 patients)"
    explanation: Documents the surgical procedures used in this patient population and their frequency.
- name: Investigational Mesenchymal Stromal Cell Therapy for Mustard Keratopathy
  description: >-
    Intrastromal injection of mesenchymal stem/stromal cells, tested in a mouse
    model of mustard keratopathy. It reduced corneal opacity and, notably, cut
    beta-galactosidase staining - a senescence marker - which is the result that
    makes it interesting mechanistically rather than only clinically: it implies
    cellular senescence is part of what sustains the delayed corneal lesion.
    Corneal neovascularization and fibrosis did not improve significantly. This is
    pre-clinical and is curated as investigational, not as available treatment.
  therapeutic_modality: CELL_THERAPY
  treatment_term:
    preferred_term: mesenchymal stromal cell therapy
    term:
      id: NCIT:C116467
      label: Mesenchymal Stem Cell Transplantation
  target_mechanisms:
  - target: Limbal Stem Cell Deficiency and Delayed Mustard Gas Keratopathy
    description: >-
      Delivered into the corneal stroma to counter the opacification and, on the
      senescence evidence, possibly the process driving it.
  evidence:
  - reference: PMID:38067171
    reference_title: "The Potential of Mesenchymal Stem/Stromal Cell Therapy in Mustard Keratopathy: Discovering New Roads to Combat Cellular Senescence."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The treatment group demonstrated reduced opacity compared to the control group."
    explanation: The primary positive result in the mouse mustard keratopathy model.
  - reference: PMID:38067171
    reference_title: "The Potential of Mesenchymal Stem/Stromal Cell Therapy in Mustard Keratopathy: Discovering New Roads to Combat Cellular Senescence."
    supports: REFUTE
    evidence_source: MODEL_ORGANISM
    snippet: "While corneal neovascularization did not display significant variations between the groups, the control group did register higher numerical values."
    explanation: >-
      Recorded as REFUTE against the broader claim that this therapy addresses
      the keratopathy as a whole: neovascularization, one of the two dominant
      corneal signs, did not respond significantly.
progression:
- phase: Latent period
  duration: 1 to 24 hours from exposure
  notes: >-
    Cellular injury begins within minutes but nothing is visible. The victim feels
    little or nothing, which is the tactical point of the agent and the clinical
    trap: people continue to be exposed, and decontamination is deferred past the
    window in which it helps.
  evidence:
  - reference: PMID:40034085
    reference_title: Mechanistic Insights and Pharmacological Approaches for Nitrogen and Sulfur Mustards and Their Implications as Therapeutic Agents.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: "SM and NM have a latent period after exposure before any symptoms manifest and are inversely proportional to the dose."
    explanation: >-
      States the latent period directly and records that its length varies
      inversely with dose, which is the claim this phase makes.
  - reference: PMID:40034085
    reference_title: Mechanistic Insights and Pharmacological Approaches for Nitrogen and Sulfur Mustards and Their Implications as Therapeutic Agents.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: "This study also found that vesication sharply increased between 4 and 8 h after exposure, was well established, and remained elevated at 8‐ and 24‐h post‐exposure"
    explanation: >-
      Times the emergence of the lesion after exposure. Indirect because the cited
      experiment used the nitrogen mustard analogue in a mouse ear model.
- phase: Acute injury
  duration: Hours to days
  notes: >-
    Erythema then vesication of contacted skin; keratoconjunctivitis with pain,
    lacrimation and blepharospasm; rhinorrhoea, hoarseness and cough progressing
    in severe inhalational exposure to tracheobronchitis, pseudomembrane formation
    and acute lung injury. Direct mortality is low - a few percent in open-air
    battlefield exposure.
  evidence:
  - reference: PMID:35974928
    reference_title: Ophthalmological aspects of mustard gas poisoning (focus on management).
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Feeling severe pain in the eyes, laceration, photophobia, blepharospasm and reduced visual acuity after 2 to 6 hours, also after 12 hours the patient poses with temporary and transient blindness, and spontaneous recovery will occur after 48 hours"
    explanation: Times the acute ocular course from onset through spontaneous recovery.
- phase: Recovery
  duration: Weeks to months
  notes: >-
    Most acute lesions heal. Corneal epithelium regenerates over days, with full
    ocular recovery taking six weeks or more; skin ulcers heal slowly and scar. A
    patient can pass through this phase apparently well and still develop the
    delayed disease.
  evidence:
  - reference: PMID:35974928
    reference_title: Ophthalmological aspects of mustard gas poisoning (focus on management).
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "but complete corneal regeneration of the corneal epithelium is seen after 4 to 5 days, although complete recovery requires 6 weeks and even more"
    explanation: The timescale of acute ocular healing.
- phase: Delayed and progressive disease
  duration: Years to decades
  notes: >-
    The phase that defines the disease. Bronchiolitis obliterans, bronchiectasis
    and pulmonary fibrosis emerge and worsen year on year; mustard gas keratopathy
    appears after a silent interval; lung cancer risk rises. This can develop in
    patients whose acute exposure caused no distress at the time, which is why
    exposure history rather than acute severity is the indication for long-term
    surveillance.
  evidence:
  - reference: PMID:21218101
    reference_title: Acute and delayed sulfur mustard toxicity; novel mechanisms and future studies.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "SM is the only warfare agent which has severe delayed effects and causes progressive incapacitation of victims."
    explanation: States that the progressive delayed course is specific to this agent among warfare agents.
  - reference: PMID:15808253
    reference_title: "Chronic and delayed-onset mustard gas keratitis: report of 48 patients and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of 48 patients, 31 (64.6%) had chronic symptomatology, whereas 17 (35.4%) experienced delayed-onset lesions."
    explanation: >-
      Splits the ocular cohort into continuously symptomatic and true
      delayed-onset presentations, which is the distinction this phase records.
prevalence:
- population: Iranian chemical-warfare survivors of the Iran-Iraq war
  measure_type: CASES_IN_LITERATURE
  notes: >-
    48,067 registered survivors with pulmonary, cutaneous or ocular lesions were
    followed for 39 years; 4,342 (9.03%) died during the study period. This is a
    count of a registered exposed cohort, not a population prevalence: the disease
    is exposure-defined, so no denominator of the general population applies.
  evidence:
  - reference: PMID:38312548
    reference_title: "A 39 Year mortality study of survivors exposed to sulfur mustard agent: A survival analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The study included a total of 48,067 observations, and among them, 4342 (9.03 %) died during the study period."
    explanation: The cohort size and observed mortality over the follow-up period.
diagnosis:
- name: Exposure history plus the delayed vesicant syndrome
  description: >-
    There is no bedside confirmatory test. Diagnosis rests on a known or suspected
    exposure followed, after a latent interval, by the triad of vesicant burn,
    keratoconjunctivitis and airway injury. Because the latent period separates
    cause from effect, the exposure is often not volunteered and has to be asked
    for.
  diagnosis_term:
    preferred_term: physical examination
    term:
      id: NCIT:C20989
      label: Physical Examination
  evidence:
  - reference: PMID:35974928
    reference_title: Ophthalmological aspects of mustard gas poisoning (focus on management).
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Clinical findings in acute conditions include; sore eyes, lacrimation, burning sensation, edematous, obvious blepharospasm of eyelids, severe conjunctivitis, erosion and opacity of the cornea."
    explanation: The clinical findings that, with an exposure history, constitute the diagnosis.
- name: Biomarker confirmation of exposure
  description: >-
    Four biomarker classes confirm sulfur mustard retrospectively, and they have
    different detection windows: hydrolysis and oxidation products and beta-lyase
    metabolites are short-lived, DNA adducts remain detectable in urine for about
    30 days, and N-terminal valine adducts on haemoglobin persist beyond 90 days.
    Concentrations track clinical severity, so the assay is prognostic as well as
    confirmatory. This is the test that identified an accidental exposure to an
    unknown agent after the fact.
  diagnosis_term:
    preferred_term: laboratory procedure
    term:
      id: NCIT:C25294
      label: Laboratory Procedure
  evidence:
  - reference: PMID:28962267
    reference_title: "Four sulfur mustard exposure cases: Overall analysis of four types of biomarkers in clinical samples provides positive implication for early diagnosis and treatment monitoring."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The DNA adducts in urine samples still appeared on the 30th day, and the N-terminal valine adducts in hemoglobin could be monitored for over 90 days"
    explanation: The two long-window biomarkers and their detection intervals.
  - reference: PMID:28962267
    reference_title: "Four sulfur mustard exposure cases: Overall analysis of four types of biomarkers in clinical samples provides positive implication for early diagnosis and treatment monitoring."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The concentrations of the biomarkers in specimens revealed a good correlation with the severity of the patient's symptom."
    explanation: Supports the prognostic as well as confirmatory use of the assay.
- name: High-resolution CT for delayed pulmonary disease
  description: >-
    HRCT is the modality of choice for the delayed pulmonary arm, showing air
    trapping, bronchiectasis, large-airway narrowing and fibrosis. Plain chest
    radiography misses roughly half of the lung disease. HRCT findings are also
    prognostic for lung cancer, which makes serial scanning a surveillance tool
    rather than only a diagnostic one.
  diagnosis_term:
    preferred_term: high resolution computed tomography
    term:
      id: NCIT:C20644
      label: High Resolution Computed Tomography
  evidence:
  - reference: PMID:23735551
    reference_title: "Long-term effects of mustard gas on respiratory system of Iranian veterans after Iraq-Iran war: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Plain chest X-ray does not help in about 50% of lung diseases."
    explanation: Quantifies the shortfall of plain radiography that motivates HRCT.
  - reference: PMID:23735551
    reference_title: "Long-term effects of mustard gas on respiratory system of Iranian veterans after Iraq-Iran war: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "High-resolution CT of the lung is the best modality for diagnostic assessment of parenchymal lung and bronchi."
    explanation: Establishes HRCT as the recommended modality.
biochemical:
  - name: Serum interleukin-6
    presence: INCREASED
    notes: >-
      Serum IL-6 is elevated in sulfur mustard injured patients relative to
      controls and is higher again in those with moderate to severe pulmonary
      symptoms. It is a severity correlate, not a diagnostic test - IL-6 rises in
      many inflammatory lung diseases - but it is the human measurement that
      corresponds to the cytokine burst characterised in the animal models.
    evidence:
    - reference: PMID:25031491
      reference_title: The role of serum level of interleukin-6 in severity of pulmonary complications of sulfur mustard injuries.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The measured IL6 mean level in patients with chemical injuries (0.76±0.3 ng/ml) was significantly higher than the control group's mean level (0.34±0.12 ng/ml)."
      explanation: The case-control difference in serum IL-6.
  - name: Haemoglobin N-terminal valine adduct
    presence: INCREASED
    notes: >-
      The longest-window exposure biomarker, detectable for more than 90 days by
      GC-MS after modified Edman degradation. It is a direct chemical record of
      the alkylation event the pathophysiology begins with.
    evidence:
    - reference: PMID:28962267
      reference_title: "Four sulfur mustard exposure cases: Overall analysis of four types of biomarkers in clinical samples provides positive implication for early diagnosis and treatment monitoring."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "the N-terminal valine adducts in hemoglobin could be monitored for over 90 days"
      explanation: Establishes the detection window for this adduct class.
animal_models:
- name: Rat sulfur mustard vapour inhalation model (biphasic lung injury)
  species: Rat
  publication: PMID:33002157
  description: >-
    Rats exposed to sulfur mustard vapour at 0.2 to 0.6 mg/kg. The
    striking finding is that the pathology is biphasic: damage at 3 days,
    apparent improvement at 7 to 16 days, then a second and worse wave at 28 days
    with distal bronchiolar epithelial necrosis and interstitial fibrosis. That
    shape is the animal counterpart of the human latent-then-delayed course, which
    is what makes the model useful for something other than acute toxicity.
  modeled_mechanisms:
  - target: Cellular Energy Collapse and Epithelial Necrosis
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: Reproduces airway epithelial necrosis after inhalational exposure.
    limitations: >-
      The model reads the lesion histologically and does not measure the NAD+ or
      ATP depletion that this node asserts as its mechanism, so it supports the
      outcome rather than the pathway.
    readouts:
    - name: Distal bronchiolar epithelial necrosis on histopathology
      target: Cellular Energy Collapse and Epithelial Necrosis
      direction: INCREASED
      interpretation: Histological correlate of the epithelial death node.
      evidence:
      - reference: PMID:33002157
        reference_title: "Progressive Lung Injury, Inflammation, and Fibrosis in Rats Following Inhalation of Sulfur Mustard."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "including epithelial necrosis and hyperplasia in the distal bronchioles, thickened alveolar walls, enlarged vacuolated macrophages, and interstitial fibrosis"
        explanation: Reports the histological measurement behind this readout.
  evidence:
  - reference: PMID:33002157
    reference_title: "Progressive Lung Injury, Inflammation, and Fibrosis in Rats Following Inhalation of Sulfur Mustard."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "These data demonstrate a similar pathologic response to inhaled SM in rats and humans suggesting that this rodent model can be used for mechanistic studies"
    explanation: The authors' own claim that the model parallels the human respiratory pathology.
  - reference: PMID:33002157
    reference_title: "Progressive Lung Injury, Inflammation, and Fibrosis in Rats Following Inhalation of Sulfur Mustard."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Time course studies revealed that the pathologic response was biphasic."
    explanation: Establishes the biphasic course that makes this model informative for the delayed arm.
- name: Rat sulfur mustard inhalation model of bronchiolitis obliterans and pulmonary fibrosis
  species: Rat
  publication: PMID:29314868
  description: >-
    Sprague-Dawley rats given 1.0 mg/kg sulfur mustard by intubation and followed
    to 28 days, with histopathology, pulmonary function testing and measurement of
    TGF-beta, PDGF and PAI-1. This is the model that ties the profibrotic
    mediators to both lesions at once.
  modeled_mechanisms:
  - target: TGF-beta Driven Myofibroblast Activation
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: MOLECULAR
    description: >-
      Measures the profibrotic mediators directly in lung, lavage fluid and
      plasma at 28 days.
    limitations: >-
      Rodent lifespan makes the human multi-decade course unmodellable: 28 days of
      rat follow-up stands in for forty years of human disease, so the model can
      show that the pathway engages but not that it keeps engaging.
    readouts:
    - name: Lung and plasma TGF-beta, PDGF and PAI-1 concentrations
      target: TGF-beta Driven Myofibroblast Activation
      direction: INCREASED
      interpretation: Direct measurement of the profibrotic signalling this node asserts.
      evidence:
      - reference: PMID:29314868
        reference_title: Bronchiolitis Obliterans and Pulmonary Fibrosis after Sulfur Mustard Inhalation in Rats.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Concentrations of TGF-β, PDGF, and PAI-1 were elevated at 28 days in lung, BAL fluid, and/or plasma."
        explanation: The mediator measurement behind this readout.
  - target: Bronchiolitis Obliterans and Progressive Airflow Obstruction
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: Reproduces both the histological lesion and the physiological deficit.
    limitations: >-
      Whole-organism pulmonary function testing in a rat reports resistance and
      compliance rather than the spirometric indices used clinically, so the
      physiological endpoints are analogous rather than identical.
    readouts:
    - name: Lung resistance and compliance
      target: Bronchiolitis Obliterans and Progressive Airflow Obstruction
      direction: ALTERED
      interpretation: Physiological correlate of obliterated small airways and stiffened parenchyma.
      evidence:
      - reference: PMID:29314868
        reference_title: Bronchiolitis Obliterans and Pulmonary Fibrosis after Sulfur Mustard Inhalation in Rats.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Pulmonary function testing demonstrated a time-dependent increase in lung resistance, as well as a decrease in lung compliance."
        explanation: The functional measurement behind this readout.
  evidence:
  - reference: PMID:29314868
    reference_title: Bronchiolitis Obliterans and Pulmonary Fibrosis after Sulfur Mustard Inhalation in Rats.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Time-dependent development of BO and PF occurs in lungs of rats exposed to SM inhalation"
    explanation: Establishes that this model develops both named human lesions.
- name: Cynomolgus monkey sulfur mustard inhalation model
  species: Cynomolgus monkey
  publication: PMID:22465472
  description: >-
    Non-human primates exposed to sulfur mustard at 150 mg/m3 by intubation. Its
    contribution is the IL-17 arm: IL-17-positive cells accumulate in inflamed
    lung regions at 30 days and beyond, in a species much closer to human than the
    rat data collected alongside it.
  modeled_mechanisms:
  - target: Chronic IL-17-Dependent Airway Inflammation
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: Demonstrates IL-17-positive cell accumulation in the chronic phase in a primate.
    limitations: >-
      The IL-17 cells are localised in inflamed tissue rather than shown to be
      necessary for the fibrosis, so the model establishes association with the
      chronic phase and not that this arm drives it.
    readouts:
    - name: IL-17-positive cells in inflamed lung regions
      target: Chronic IL-17-Dependent Airway Inflammation
      direction: INCREASED
      interpretation: Cellular correlate of the IL-17 arm of chronic inflammation.
      evidence:
      - reference: PMID:22465472
        reference_title: "Inhalation of sulfur mustard causes long-term T cell-dependent inflammation: possible role of Th17 cells in chronic lung pathology."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "At ≥30 days, SM inhalation promoted the accumulation of IL-17(+) cells in the inflamed areas of monkey lungs."
        explanation: The primate measurement behind this readout.
  evidence:
  - reference: PMID:22465472
    reference_title: "Inhalation of sulfur mustard causes long-term T cell-dependent inflammation: possible role of Th17 cells in chronic lung pathology."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "IL-17(+) cells likely play an important role in the pathogenesis of SM-induced lung injury."
    explanation: >-
      The authors' conclusion, hedged as they hedge it, that this arm matters for
      the pathogenesis.
discussions:
- discussion_id: sm_delayed_toxicity_mechanism_unknown
  kind: KNOWLEDGE_GAP
  prompt: >-
    What sustains sulfur mustard disease for decades after a single exposure, when
    the agent and its metabolites have been cleared within weeks?
  rationale: >-
    This is the central unanswered question of the entry. Sulfur mustard
    metabolites are excreted within a few weeks and do not accumulate, so nothing
    of the original insult is still present when the delayed disease emerges. The
    chain curated here carries the mechanism as far as chronic IL-17-dependent
    inflammation and shows that it persists, but it does not explain why it
    persists rather than resolving as inflammation normally does. Epigenetic
    perturbation has been proposed as the missing step and remains a hypothesis.
    Until it is settled, the causal edge from acute injury to chronic inflammation
    in this entry is descriptive rather than mechanistic.
  attaches_to:
  - pathophysiology#Chronic IL-17-Dependent Airway Inflammation
  evidence:
  - reference: PMID:21218101
    reference_title: Acute and delayed sulfur mustard toxicity; novel mechanisms and future studies.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Unfortunately, it is not clear how mustard gas causes severe multi-organ damage years after even a single exposure"
    explanation: States the gap directly.
  - reference: PMID:21218101
    reference_title: Acute and delayed sulfur mustard toxicity; novel mechanisms and future studies.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A possible explanation of the delayed mechanism would be epigenetic perturbations caused by SM even after single exposure."
    explanation: >-
      The leading proposed explanation, presented by its authors as a proposal
      rather than a finding.
- discussion_id: sm_keratopathy_latency_unexplained
  kind: KNOWLEDGE_GAP
  prompt: >-
    Why does mustard gas keratopathy appear after a silent interval of years to
    decades rather than following on from the acute corneal injury?
  rationale: >-
    The acute corneal lesion re-epithelialises within days, and the delayed
    keratopathy then arrives after an interval during which the eye looks well.
    Limbal stem cell deficiency is the accepted structural explanation for the end
    state, but it does not by itself account for the timing: a stem cell pool
    destroyed at exposure should produce failure of corneal renewal sooner. The
    authors of the largest delayed-keratitis series say outright that the
    pathophysiology of these changes is not clearly identified, and raise a
    possible immune-mediated component from the histology. The edge from limbal
    injury to delayed keratopathy in this entry rests on clinical natural history.
  attaches_to:
  - pathophysiology#Limbal Stem Cell Deficiency and Delayed Mustard Gas Keratopathy
  evidence:
  - reference: PMID:15808253
    reference_title: "Chronic and delayed-onset mustard gas keratitis: report of 48 patients and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The pathophysiologic features of these changes are not clearly identified."
    explanation: The authors state the gap for the delayed ocular lesion specifically.
  - reference: PMID:15808253
    reference_title: "Chronic and delayed-onset mustard gas keratitis: report of 48 patients and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Based on the clinical appearance of the lesions and the histopathologic findings, an immune-mediated component seems possible."
    explanation: Records the hypothesis the authors offer for the unexplained interval.
- discussion_id: sm_no_animal_model_reproduces_human_blistering
  kind: HUMAN_MODEL_MISMATCH
  prompt: >-
    Can any animal model reproduce human sulfur mustard blistering, and what does
    it mean for countermeasure development that none does?
  rationale: >-
    The cutaneous arm of this entry has an evidence problem the pulmonary arm does
    not. Rodent skin models reproduce epidermal cell death and the inflammatory
    response but do not form true human-type blisters, so the vesication node -
    the lesion the agent is named for - is supported in humans by clinical
    description and in animals only by proxies such as ear weight and morphometric
    thickness. This is why the vesication evidence in this entry is thinner than
    the fibrosis evidence, and why a cutaneous countermeasure that works in a
    mouse ear cannot be assumed to work on a human blister.
  attaches_to:
  - pathophysiology#Dermal-Epidermal Separation and Vesication
  evidence:
  - reference: PMID:40034085
    reference_title: Mechanistic Insights and Pharmacological Approaches for Nitrogen and Sulfur Mustards and Their Implications as Therapeutic Agents.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: "had an increase in ear weights, morphometric thickness, edema, inflammatory cell infiltration, and signs of vesication at all time points"
    explanation: >-
      Shows what the animal vesication endpoint actually measures - ear weight and
      thickness - rather than a blister.
- discussion_id: sm_cutaneous_malignancy_not_modelled
  kind: KNOWLEDGE_GAP
  prompt: >-
    Sulfur mustard raises the risk of basal and squamous cell carcinoma at
    exposed skin sites. Why does this entry model malignant transformation of
    bronchial epithelium but not of skin, and what would close the gap?
  rationale: >-
    The asymmetry is real and it is not a claim about relative risk. This entry
    carries a Malignant Transformation of Chronically Injured Bronchial
    Epithelium node with a molecular correlate and a four-decade cohort behind
    it, and nothing equivalent for skin - even though the same alkylation,
    necrosis and chronic-injury nodes run through the cutaneous arm, and the
    occupational literature reports raised BCC and SCC incidence in
    mustard-manufacturing workers.

    The reason is citability, not judgement: the deep-research report cites the
    cutaneous malignancy finding to an NCBI Bookshelf chapter rather than to a
    fetchable reference, so no exact snippet can be taken from anything cached
    here. Closing this needs a primary cohort study of skin cancer incidence in
    an exposed population. It is recorded as a structured gap rather than a line
    in notes so that it is findable by query and has somewhere to be closed.
  attaches_to:
  - pathophysiology#Skin Ulceration and Impaired Wound Healing
- discussion_id: sm_haematopoietic_suppression_evidence_thin
  kind: KNOWLEDGE_GAP
  prompt: >-
    What is the dose relationship, frequency and time course of haematopoietic
    suppression after sulfur mustard exposure, and is there a primary clinical
    series that reports it?
  rationale: >-
    Haematopoietic suppression is now curated as a node, but on evidence thin
    enough that the gap is worth stating rather than closing. The only quotable
    statement in this entry's cache is a review's secondhand assertion
    (PMID:40034085) that sulfur mustard causes blood cytopenia and bone marrow
    destruction, attributed to another author and carrying no counts, frequency,
    dose relationship or time course. Nothing else reaches it: the
    radiation-comparison workshop report (PMID:37852927) records only that the
    case could have been made to include bone-marrow myelosuppression in that
    meeting's scope, which is a statement about the meeting rather than about the
    toxicity.

    An earlier draft of this discussion, and of the entry's notes, asserted that
    no cached source reported it quotably at all. That was false - the review
    sentence was already in the cache, and this entry already quoted the tail of
    the same sentence elsewhere. Recording the correction here because the
    failure is instructive: a claim about what the cache does not contain is the
    easiest kind of claim to get wrong, and the cheapest to check.

    Closing this properly needs a primary clinical series reporting blood counts
    in exposed patients, with a dose relationship.
  attaches_to:
  - pathophysiology#Haematopoietic Suppression
  evidence:
  - reference: PMID:37852927
    reference_title: "Overlapping Science in Radiation and Sulfur Mustard Exposures of Skin and Lung: Consideration of Models, Mechanisms, Organ Systems, and Medical Countermeasures: Overlapping science in radiation and sulfur mustard injuries to lung and skin."
    supports: NO_EVIDENCE
    evidence_source: OTHER
    snippet: "the programs elected to focus on similarities between radiation exposure and SM-induced injuries to the lung and skin; although arguably, the case could also have been made to include bone marrow myelosuppression"
    explanation: >-
      Cited to show precisely what this source does and does not say: it records a
      scoping decision about a meeting, and is not evidence that sulfur mustard
      causes myelosuppression.

📚

References & Deep Research

Deep Research

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (3)

Record notes

Scope. This entry curates the human injury syndrome caused by sulfur mustard and the mechanism that produces it. It is not an entry about the agent's production, dispersal or military use, and the historical context recorded under `environmental:` is there because route and setting determine which organ is injured and how severely. Bone marrow suppression is curated, but read the evidence grade before relying on it. An earlier draft of this note claimed no cited source reported it quotably. That was false: PMID:40034085, cited seven times in this entry, states that sulfur mustard leads to systemic toxicity shown through "blood cytopenia, bone marrow destruction". It is a review's secondhand assertion attributed to another author rather than a primary clinical series, so the node is graded accordingly and the absence of a primary cohort is recorded under `discussions:`. ECTO binding. The exposure term `ECTO:9001175` is the ontology's term for exposure to bis(2-chloroethyl) sulfide, which is sulfur mustard under its systematic name; ECTO has no term under any of the agent's common or military names. `ECTO:0070054`, "exposure to mustard greens via ingestion", is an unrelated dietary term and is not a candidate here. NCIT binding for decontamination. `NCIT:C68769` is NCIT's term for decontamination and looks like the obvious binding for the acute intervention, but it is not reachable from `NCIT:C25218` (Clinical Intervention or Procedure), so it cannot be the `term:` of a `TreatmentTerm`. That treatment is bound to `NCIT:C49236` (Therapeutic Procedure) with the specificity carried in `preferred_term`, which is the same compromise CLAUDE.md records for medical devices. Organ systems seen in the research and left out, recorded so they are not re-litigated. The deep-research report surfaced gastrointestinal involvement (nausea, vomiting, diarrhoea; haemorrhagic gastroduodenitis and desquamative enteritis in severe systemic poisoning), neuropsychiatric sequelae (acute convulsions in severely poisoned patients; chronic anxiety, depression and cognitive decline decades later), basal and squamous cell carcinoma at exposure sites, and dry eye. The reason differs by item. The gastrointestinal, neuropsychiatric and cutaneous-malignancy findings are cited in the report to NCBI Bookshelf chapters, which are not fetchable as references here, so no exact snippet can be taken; the neuropsychiatric entry additionally carries a publisher link to animal aggregate-culture demyelination data, which would not support a human phenotype in any case. Those three remain uncurated. Dry eye is curated, and an earlier version of this paragraph was wrong about why it had not been. That version said dry eye "has no citation behind it at all - it appears only in the report's list of suggested HP terms". The suggested-terms half is true, and HP:0000585 offered there is one of the six identifiers that name a different concept. The rest was false: dry eye also appears in the report's clinical narrative for delayed keratopathy, cited to PMID:15808253, whose cached abstract reports chronic blepharitis and decreased tear meniscus in all 48 patients - a sentence this entry already quoted twice for other claims before anyone noticed it also carried this one. Both findings from that sentence are now phenotypes. What is bound is the sign each time: Blepharitis, and Decreased lacrimation for the reduced tear meniscus. The keratoconjunctivitis sicca diagnosis is deliberately not asserted - HP:0001097 exists and this cohort does show the ocular surface damage the diagnosis needs, but the authors did not draw that conclusion in the sentence quoted. The cutaneous malignancy omission is the one a curator should look at first, because it is asymmetric: this entry models malignant transformation of chronically injured bronchial epithelium but not of skin, and the same alkylation and chronic-injury nodes run through both. That asymmetry reflects what is citable here, not a claim that the skin risk is lower. GeneReviews. Not applicable. This is an acquired toxic exposure with no Mendelian form, so there is no GeneReviews chapter to use as a phenotype baseline; a PubMed search for one returns nothing. Host susceptibility. An earlier draft of this note said no sulfur-mustard-specific association study existed for the glutathione-pathway polymorphisms and that no `genetic:` records were therefore curated. That was wrong, and it was wrong because the claim was carried over from the deep-research report's own statement that it had not identified such a study, rather than being checked. PMID:29435433 is exactly that study - 185 sulfur-mustard-exposed subjects, GSTM1 null genotype associated with mustard lung severity - and it is now curated below, along with the negative results for GSTT1 and GSTP1 from the same cohort. The genes are modifiers of severity, not causes: this disease has no genetic form, and nothing in `genetic:` should be read as one.

Pre-PR repository-state sweep: curate GST modifiers, fix two false source claims · 2026-09-11T02:38:49Z · View source

Ran the repository-state sweep on this entry before opening its PR, applying the habit that closed four review rounds on the COA6 entry: grep the file for every claim about what sources say, what an ontology contains, or what is or is not curated, then test each one rather than trusting the prose. Three of the seven claims tested were wrong, and the two substantive ones are fixed here. Claims that held. ECTO has no term under the agent's common or military names - searches for mustard gas, yperite, vesicant, sulfur mustard and sulphur mustard all return nothing, and ECTO:0070054 really is "exposure to mustard greens via ingestion". NCIT:C68769 (Decontamination) really has no NCIT:C25218 ancestor while NCIT:C49236 does, so the binding compromise recorded in notes is correct. No GeneReviews chapter exists - the PubMed search returns zero hits. Finding 1, and the reason the sweep was worth running. The notes asserted that no sulfur-mustard-specific association study existed for the glutathione-pathway polymorphisms, and that no genetic: records were therefore curated. False. PubMed returns PMID:29435433, "Association of glutathione S-transferase polymorphisms with the severity of mustard lung" - 185 exposed subjects, GSTM1 null genotype associated with severity at an adjusted OR of 2.257. The claim was not something this session established; it was the deep-research report's own statement that its search had not found such a study, absorbed into the notes as though it were a finding of ours. That is the same defect class as the four COA6 rounds, with an additional wrinkle: the false claim originated in a provider artifact rather than in an earlier draft. The fix is content, not a reworded sentence. Three genetic: records are now curated: GSTM1 as MODIFIER carrying the severity association, and GSTT1 and GSTP1 as DISPUTED carrying the negative results from the same cohort and the same analysis. Negative results from a study powered to find the GSTM1 effect are informative - they argue the effect is isoform-specific rather than a general property of glutathione-transferase capacity - so they are recorded rather than omitted. PMID:24344877 was fetched alongside and is cited on the GSTM1 record for the complementary observation that GSTM1 message is upregulated 2.84-fold in mustard-lung airway wall; the notes state explicitly that combining the two lines is inference and that neither study tests the link. All three gene CURIEs were resolved by live lookup in both directions rather than read from the cache alone: hgnc:4632 GSTM1, hgnc:4641 GSTT1, hgnc:4638 GSTP1. Finding 2. The entry contradicted itself on blister timing. A note said the human figures - erythema at 2 to 24 hours, vesication at 24 to 48 - are stated in no cached source and are deliberately not asserted, while the Skin blistering phenotype asserted "appearing 24 to 48 hours after contact". The note was right about the cache: grepping every cited source for those intervals returns nothing. The phenotype description now says the lesion appears after a latent interval without naming a figure, and points at the node that carries the animal-model timing that is quotable. Finding 3. The melanocyte node hedged its in-vitro explanation with "pigmentary change is also reported in areas that were never exposed", which was load-bearing - it was the stated reason the explanation "cannot be the whole story" - and which no cached source supports. Searching every cited cache for unexposed-site pigmentary change returns nothing. The unsourced assertion is removed and the epistemics kept: the opposing dose-dependence is measured in cultured human melanocytes, the mapping onto the clinical pattern is the study authors' own inference, and no cached source reports the within-lesion concentration gradient the explanation would require. That replacement negative claim was itself tested before being written. Counts recomputed from the file rather than carried forward: 17 pathophysiology nodes, 18 phenotypes, 8 treatments, 3 genetic records, 3 animal models, 2 environmental exposures, 4 discussions, 4 conforms_to declarations against the 5-node fibrotic_response module, 21 evidence PMIDs of which 13 are content_type full_text, 117 evidence snippets. Every fetched reference is now cited; nothing is left in references_cache/ unused. Validation: just validate-disorders passes, 117/117 snippets verified, and all twelve offline gates green - validate-terms, check-entity-refs, check-causal-targets, check-duplicate-keys, check-enum-values, check-qualifier-terms, check-folded-hyphens, check-snippet-length, check-title-snippets, check-snippet-grading, check-environmental-evidence, check-reference-titles. Graph audit confirms no dangling targets, no orphan nodes and no unconnected phenotypes. Weighted compliance 87.3%.

Create: Sulfur Mustard Poisoning · 2026-09-10T19:49:22Z · View source

Created kb/disorders/Sulfur_Mustard_Poisoning.yaml (MONDO:0800387), an environmental/occupational chemical-vesicant exposure entry. No prior KB entry, stub, PR or issue covered the disease (checked against origin/main by MONDO ID and by the labels "sulfur mustard", "sulphur mustard", "mustard gas" and "vesicant", plus PR and issue search across all states). Deep research: `just research-disorder claude_code Sulfur_Mustard_Poisoning`, one run, report committed at research/Sulfur_Mustard_Poisoning-deep-research-claude_code.md with its citations sidecar. The provider was the one requested by the user; no fallback was needed. Report validation as generated. Reference validation clean: 29/29 references resolved, confabulation_rate 0.0, 1/1 quoted claims found in source. Term validation NOT clean: needs_review true, with 7 identifiers named as a different term. Five of those were HP CURIEs naming unrelated concepts - HP:0000508 offered as "photophobia" is Ptosis, HP:0000534 as "corneal neovascularization" is Abnormal eyebrow morphology, HP:0000585 as "dry eye" is Band keratopathy, HP:0000523 as "blindness" is Subcapsular cataract, and HP:0025406 as "blistering" is Asthenia. A sixth, HP:0002204 offered as "pulmonary fibrosis", is Pulmonary embolism and was reported only in the softer "worth a second look" bucket. None of the report's CURIEs were used. Every identifier in the entry was resolved by live OAK lookup at the moment it was written, which is how the correct terms (HP:0000613 Photophobia, HP:0011496 Corneal neovascularization, HP:0002206 Pulmonary fibrosis) were obtained. One further report error found by reading the sources rather than by a validator: for PMID:27832694 the report quoted "56.7% of a 30-patient sub-cohort showing pulmonary function improvement and 77.8% of an HRCT-assessed sub-cohort showing radiographic improvement". The abstract reports neither figure - it describes 73 patients (38 asthma, 16 COPD, 19 bronchiolitis obliterans) and compares FEV1 decline. The entry uses the abstract's own text. Content. 15 pathophysiology nodes forming a branched chain from agent penetration and episulfonium ion formation, through N7-guanine alkylation and interstrand crosslinking, PARP1 hyperactivation and NAD+/ATP depletion, and a parallel glutathione-depletion arm, into epithelial necrosis; then three organ arms (cutaneous vesication and ulceration, corneal and limbal injury into delayed mustard gas keratopathy, and the pulmonary arm) plus a melanocyte arm and a terminal malignant-transformation node. Four nodes conform to fibrotic_response (Inflammatory Recruitment and Amplification, Mesenchymal Cell Activation, Excessive ECM Deposition, Architectural Distortion and Organ Dysfunction), following the pattern Asbestosis and Paraquat_Poisoning use. 17 phenotypes, all bound and all connected to a mechanism node by a bare-name downstream edge. Two environmental exposures bound to ECTO:9001175, both pathograph-linked with environmental_effect TRIGGERS. Six treatments, four progression phases, three diagnosis records, three animal models with modeled_mechanisms and readouts, two biomarkers, one prevalence record, four discussions. Deliberate omissions, each recorded in the entry rather than left silent. Bone marrow suppression is not curated as a node: no cached source states it quotably, and the nearest (PMID:37852927) records a workshop scoping decision rather than a finding, so it is a KNOWLEDGE_GAP discussion citing that source with supports NO_EVIDENCE. No genetic: records, because the host-susceptibility literature is glutathione-pathway polymorphisms as severity modifiers with no sulfur-mustard-specific association study identified. No GeneReviews baseline: the disease is an acquired toxic exposure with no Mendelian form. Two binding compromises recorded in notes:. NCIT:C68769 (Decontamination) is not reachable from NCIT:C25218, so the decontamination treatment binds NCIT:C49236 (Therapeutic Procedure) with the specificity in preferred_term. ECTO has no term under any of the agent's common or military names; ECTO:9001175 "exposure to bis(2-chloroethyl) sulfide" is the systematic-name term for the same substance, and ECTO:0070054 "exposure to mustard greens via ingestion" is an unrelated dietary term that is not a candidate. One self-caught error worth recording because it is the exact failure mode CLAUDE.md warns about: NCIT:C17204 was written with the label "High-Resolution Computed Tomography" from memory rather than from a lookup. The CURIE is Computed Tomography; term validation flagged the mismatch, and a search found the real term, NCIT:C20644 High Resolution Computed Tomography. Validation. `just validate-disorders` passes. 98/98 evidence snippets verified against the local reference cache by `just count-verified-snippets`. `just validate-terms` passes. Ten offline gates green: check-duplicate-keys, check-entity-refs, check-causal-targets, check-qualifier-terms, check-enum-values, check-folded-hyphens, check-snippet-length, check-title-snippets, check-snippet-grading, check-environmental-evidence. check-snippet-length initially failed on a four-word snippet, which was lengthened to the full clause rather than baselined. Graph audit confirms no dangling downstream targets, no orphan pathophysiology nodes, and no phenotype without an incoming edge. Weighted compliance 87.2%. 24 references cached and committed, all PMIDs; 16 were recovered from PMC IDs in the report via the PMC ID Converter API and cited by PMID in preference to DOI. PRE-PR RED-TEAM REVIEW (same session, before first PR). An adversarial review was run against the entry with the mechanical gates already passing, to find what they cannot catch. It returned 15 findings; all were verified against the sources and all were acted on. The substantive ones: Two false statements about the entry's own evidence base. The notes and the bone-marrow discussion both asserted that no cited source reports haematopoietic suppression quotably. PMID:40034085, cited seven times in this entry, states that sulfur mustard leads to systemic toxicity shown through "blood cytopenia, bone marrow destruction" - and this entry already quoted the tail of that same sentence elsewhere. A Haematopoietic Suppression node is now curated on it, graded INDIRECT/OTHER because it is a review's secondhand assertion, and both prose passages were rewritten to record the correction rather than the claim. This is the same defect class as the COA6 note corrected earlier in this session: a claim about what the cache does not contain. An unsourced rat strain. The first animal model was described as Sprague-Dawley; that cache is abstract-only and states no strain, so the claim had no source at all (the review reports the paper's methods say Wistar). The strain claim was removed rather than replaced, since the cache cannot support either. A binding that asserted the reverse of its node's mechanism. The PARP1 node carried GO:0019674 NAD+ metabolic process with modifier DECREASED, while its own description and snippet say PARP1 consumes NAD+ - metabolism up, pool down. Rebound to GO:0019677 NAD+ catabolic process, INCREASED. Self-consistent and therefore invisible to validate-terms. A cell-type binding that overstated its source. CL:0000899 T-helper 17 cell asserts a RORgamma-t+/CXCR3-/CCR6+ phenotype that PMID:22465472 never established - it did IL-17 immunohistochemistry, titles itself "possible role of Th17 cells", and notes IL-17 is also produced by neutrophils. Rebound to CL:0000084 T cell with the specificity in preferred_term. A mechanism claim contradicted by a source cited eight times. The necrosis node said the epithelium dies "by necrosis rather than apoptosis"; PMID:22465472 reports TUNEL-positive cells and states "SM exposure triggers an early apoptotic cell death". The node now describes a dose-dependent balance and carries that sentence as REFUTE evidence against an exclusively necrotic reading. An inference presented as fact. The dyspigmentation node explained the hyper/hypopigmented mixture as following the concentration gradient across the contact area. PMID:40034085 reports that nonexposed areas also develop pigmentary change, which no such gradient explains. Hedged, with that sentence added as REFUTE. Frequency bands with the wrong denominator. Corneal opacity carried VERY_FREQUENT and neovascularization FREQUENT, both derived from a series of 48 patients who already had keratitis. Bands removed; the percentages moved into the descriptions with their denominator stated. Overstated cancer evidence. The FOXM1/APOE study is six exposed patients against five controls, excluded anyone with lung cancer, and its authors read APOE as protective with the cancer link offered as a hypothesis; the 719-patient HRCT cohort had no control group. Both caveats are now in the description, and the claim that spatial concordance makes the relationship "mechanistic" was withdrawn. Content gaps closed: Asthma (HP:0002099) and Limbal stem cell deficiency (HP:0032107), both named in cached sources and both blocking under the review skill's threshold; a Cutaneous Wound Management treatment for the previously untreated skin-ulcer node; the positive NAC clinical result from PMID:25055840, where only the negative caveat had been cited; GO:0032964 added to the ECM node so its fibrotic_response conformance is fully earned; a directly on-topic latent period quote replacing a mouse-ear proxy as primary support. Consistency: PMID:40034085 is a review and was graded MODEL_ORGANISM on two items and OTHER on five. All now OTHER, with animal provenance carried by directness: INDIRECT. Not caught by check-snippet-grading, which keys on the sentence. Also fixed: the skin blister term was HP:0200037 Skin vesicle, defined as under 10mm, while sulfur mustard classically produces bullae - rebound to HP:0008066 Abnormal blistering of the skin. Unsourced human vesication timings and an unsourced causal clause about corneal susceptibility were removed. The review confirmed clean: all reference titles matching the cache, none of the report's mislabelled CURIEs bound, both ontology claims in notes verifying against the local builds, and every re-derived figure accurate. Post-review state: 17 pathophysiology nodes, 18 phenotypes, 8 treatments. 112/112 snippets verified. Evidence now carries 3 REFUTE and 1 NO_EVIDENCE items against 108 SUPPORT; the review noted that zero REFUTE across the entry was itself a signal for a mechanism this contested. All eleven offline gates green, validate-disorders passes, weighted compliance 86.9%.

Claude Code ▸

Sulfur Mustard Poisoning: Comprehensive Research Report

claude-haiku-4-5-20251001, claude-sonnet-5 55 citations 2026-09-10T19:11:54.763776

Sulfur Mustard Poisoning: Comprehensive Research Report

1. Disease Information

Overview. Sulfur mustard (SM; bis(2-chloroethyl) sulfide, "mustard gas," military designations H/HD/HT) is a bifunctional alkylating vesicant chemical warfare agent. It is an oily, colorless-to-brown liquid at room temperature with a faint garlic/onion/horseradish odor, first synthesized in the 19th century and weaponized by German forces at Ypres, Belgium in July 1917 (Britannica; Science History Institute). It produces delayed chemical burns of skin, eyes, and airway mucosa, with cellular injury occurring within minutes of contact but clinical symptom onset delayed 1–24 hours (ATSDR MMG). It is classified by the CDC/NIOSH as a "blister agent" and is a documented human carcinogen (ATSDR ToxFAQs).

Key identifiers: - MONDO: MONDO:0800387 — "sulfur mustard poisoning" (Monarch Initiative) - MeSH: D009151 — Mustard Gas - ChEBI: CHEBI:25434 — bis(2-chloroethyl) sulfide (ChEBI) - CAS Registry Number: 505-60-2 - Chemical formula: C₄H₈Cl₂S; molar mass 159.07 g/mol; IUPAC name 1-chloro-2-[(2-chloroethyl)sulfanyl]ethane (Wikipedia; PubChem CID 10461) - ICD-10: No dedicated T-code found specific to sulfur mustard in the standard T51-T65 "toxic effects of nonmedicinal substances" chapter searched; this warrants curator follow-up against ICD-10-CM/ICD-11 poisoning-by-warfare-agent codes rather than T57.1 (phosphorus), which several search hits mistakenly returned. - Synonyms: Mustard gas, yperite (from Ypres), Lost (German), H, HD (distilled mustard), HT (mustard-T mixture), Kampstoff "Lost," agent HD.

Data provenance for a KB entry: Evidence is a mix of (a) aggregated disease/toxicology-database content (ATSDR Toxicological Profile, NIOSH/CDC cards, ICSC/CAMEO chemical safety sheets) and (b) primary clinical literature derived largely from cohorts of individual patients — WWI/WWII munitions workers, and above all decades of longitudinal follow-up of Iranian veterans exposed during the 1980–88 Iran–Iraq War, plus case series from the Syrian civil war (2015–2017) and the 1988 Halabja attack on Iraqi Kurds. Unlike most dismech entries, there is essentially no genetic-disease literature (OMIM/ClinVar) — this is a toxicological/environmental-exposure entry, and "genetic" content is limited to host susceptibility polymorphisms (see §4).

2. Etiology

Causal factor. Sulfur mustard poisoning has a single, sufficient environmental/toxic cause: dermal, ocular, inhalational, or (rarely) oral exposure to sulfur mustard itself, as a liquid, vapor, or aerosol. There is no infectious or purely genetic form.

Risk factors (exposure-modifying, not disease-causing): - Route and dose: Liquid contact causes more severe cutaneous injury than vapor; inhalation of concentrated vapor produces more severe airway injury. Moist, thin-skinned, and occluded body regions (axillae, groin, perineum, flexural creases) are most vulnerable (Britannica). - Ambient temperature/humidity: Higher temperature and humidity increase both vapor pressure and percutaneous penetration. - Delay to decontamination: Effective decontamination is time-critical — benefit is greatest within 1–2 minutes and is markedly reduced after that window (ATSDR MMG). - Genetic susceptibility (host modifier, not cause): Glutathione S-transferase (GST) null genotypes (GSTM1, GSTT1) reduce endogenous antioxidant/detoxification capacity and are hypothesized modifiers of individual variability in oxidative injury severity, by analogy with other oxidative-stress exposures (ScienceDirect, GSTM1 null genotype); direct SM-specific GSTM1 association studies were not identified in this search and should be flagged as inferred-by-analogy rather than SM-specific evidence. - Occupational exposure: WWI/WWII mustard-agent manufacturing plant workers experienced chronic low-level exposure with elevated later-life cancer risk (NCBI Bookshelf, Veterans at Risk).

Protective factors: No genetic protective variant is established. The only validated protective factors are pre-exposure avoidance/PPE and rapid post-exposure decontamination (see §13); several chemical prophylactic/cytoprotectant candidates (DRDE-07 analogues, amifostine, N-acetylcysteine, vitamin D) show pre-clinical protection when administered before or immediately after exposure but none is a licensed prophylactic (Journal of Applied Toxicology 2025).

Gene-environment interaction: The clearest documented interaction is pharmacogenomic/enzymatic rather than germline-disease-causing: GST and glutathione-peroxidase pathway capacity determines how effectively an individual detoxifies the reactive sulfonium intermediate and resulting reactive oxygen species, directly shaping lesion severity — "GSH depletion induced by GSR downregulation may be a major mechanism of SM toxicity on human lung. Despite overexpression of GSTs and GPXs genes, GSH depletion may decline the productivity of these enzymes" (PubMed 29676192).

3. Phenotypes

Phenotypes are organized by organ system and by acute vs. chronic/delayed timing. Frequencies below (e.g., "75–90% ocular involvement") come from large cohort follow-up of chemically injured populations, chiefly Iranian war veterans.

Ocular (suggested HP root: HP:0000478 Abnormality of the eye)

Acute keratoconjunctivitis: Severe eye pain, photophobia, blepharospasm, excessive lacrimation, conjunctival injection, corneal epithelial defects — onset after a several-hour latent period; seen in 75–90% of exposed individuals, making the eye the single most susceptible tissue (PMC 9348212).
Delayed/chronic mustard gas keratopathy (onset years to decades later, after a "silent" period): limbal stem cell deficiency, corneal neovascularization, corneal opacification/scarring, persistent epithelial defects, dry eye, chronic blepharitis. In one cohort of 48 chronic/delayed patients: limbal ischemia in 81.3%, corneal scarring/opacity in 87.5%, neovascularization in 70.8%, corneal thinning in 58.3%; 64.6% had chronic-form, 35.4% delayed-onset lesions (PubMed 15808253; Frontiers Toxicol 2023). Suggested HP terms: HP:0000508 (photophobia), HP:0000534 (corneal neovascularization), HP:0007957 (corneal opacity), HP:0000585 (dry eye), HP:0000523 (blindness, severe cases).

Cutaneous (HP:0000951 Abnormality of the skin)

Erythema at 2–24h, progressing to vesication/bullae by 24–48h, then denudation and slow-healing burn-like ulcers (Britannica). Suggested terms: HP:0025637/erythema, HP:0025406 (blistering).
Chronic/delayed skin findings: hyper- and hypopigmentation (melanocyte injury — low SM concentrations cause hyperpigmentation, high concentrations decrease melanin content producing hypopigmented patches: PubMed 31785464), chronic pruritic dermatitis, scarring, and elevated risk of basal cell and squamous cell carcinoma at exposure sites in chronically/occupationally exposed cohorts (NCBI Bookshelf NBK236053).

Respiratory (HP:0002086 Abnormality of the respiratory system) — dominant cause of late mortality

Acute: rhinorrhea, sneezing, sore throat, hoarseness, non-productive cough (6–24h), progressing to productive cough, tracheobronchitis, and in severe inhalational exposure, pseudomembrane formation, ARDS (ATSDR MMG).
Chronic/delayed (occurs in ~42.5% of exposed veterans, with expectoration in ~53% and cough in ~72% of a symptomatic sub-cohort): chronic bronchitis, bronchiectasis, asthma, bronchiolitis obliterans, large-airway narrowing/tracheobronchial stenosis, air trapping, and pulmonary fibrosis — these worsen progressively over decades, sometimes emerging in survivors with no initial acute distress (PubMed 23735551; Health Science Reports 2026; SAGE 2018). Suggested HP terms: HP:0006536 (chronic pulmonary obstruction), HP:0002110 (bronchiectasis), HP:0006536-adjacent obliterative bronchiolitis (map via HP or SNOMED as ontology permits), HP:0002204 (pulmonary fibrosis).

Hematologic/Immunologic

Bone marrow suppression and lymphoid aplasia after significant systemic absorption — historically among the most feared acute complications, predisposing to sepsis (HealthTree summary).

Gastrointestinal

Nausea, vomiting, diarrhea/GI cramping; pathologically, acute hemorrhagic gastroduodenitis, desquamative enteritis, and severe hemorrhagic necrotic colitis in severe systemic poisoning (NCBI Bookshelf NBK600756).

Neuropsychiatric

Acute: CNS excitation with convulsions reported in severely poisoned, hospitalized Iranian veterans. Chronic: anxiety, depression, apathy, cognitive decline documented decades after exposure (NCBI Bookshelf NBK600756); animal aggregate-culture data show progressive demyelination (ScienceDirect S0161813X21000279).

Quality of life impact: Chronic mustard lung and mustard keratopathy are the two dominant drivers of long-term disability in surviving cohorts, with progressive dyspnea, exercise limitation, recurrent pulmonary infection, and visual impairment/blindness reported even decades post-exposure (Health Science Reports 2026).

4. Genetic/Molecular Information

Sulfur mustard poisoning is not a Mendelian disease; there is no single causal gene. Relevant "genetic" content for a KB entry is limited to:

Host susceptibility/modifier genes — glutathione-pathway genes: GSTM1, GSTT1, GSTP1, GSTA1 (null/deletion genotypes reduce detoxification capacity for the SM-derived reactive electrophile and its downstream ROS burden) and GSR (glutathione reductase; downregulation implicated in lung GSH depletion, PubMed 29676192).
DNA repair machinery engaged by SM-induced lesions, functioning as biological response modifiers rather than disease genes: base excision repair (BER), nucleotide excision repair (NER) — the pathway classically responsible for repairing bulky guanine-N7 alkyl adducts and crosslinks — homologous recombination (HR), and non-homologous end joining (NHEJ) (ScienceDirect S138266891830019X). PARP1 (poly-ADP-ribose polymerase) is centrally implicated as a molecular switch between apoptotic and necrotic cell death depending on the degree of DNA damage and consequent NAD+/ATP depletion (Journal of Investigative Dermatology; Archives of Toxicology).
Late-effect gene expression changes documented in exposed lung tissue: overexpression of FOXM1 (Forkhead Box M1) and APOE (Apolipoprotein E) — both lung-cancer-development-associated genes — in bronchial tissue of long-term SM-exposed patients, suggesting a mechanistic bridge from chronic SM airway injury to carcinogenesis (PMC 5843310).
No pathogenic germline variant, ClinVar entry, or chromosomal syndrome is associated with SM poisoning susceptibility as a primary disease mechanism; this section should be modeled in a dismech entry as environmental etiology with modifier-gene annotations, not as genetic: causal drivers.
Epigenetics: No SM-specific DNA methylation/DiseaseMeth signature was identified in this search; this is a plausible gap for future literature mining given the agent's direct genotoxicity.

5. Environmental Information

Primary environmental factor: Direct chemical exposure to sulfur mustard itself, via liquid contact, vapor inhalation, or (rarely) ingestion of contaminated water/food, in a military, terrorist, or industrial-accident context. ECTO-style exposure_term candidates: "exposure to sulfur mustard" (a chemical warfare agent exposure).
Contexts of exposure documented in the literature:
WWI battlefield use (from July 1917), causing >120,000 casualties with a low (~2–3%) mortality rate but very high morbidity and prolonged hospitalization (Science History Institute).
Iran–Iraq War (1980–1988): the largest-scale, best-studied modern exposure, tens of thousands of Iranian combatants exposed, forming the basis of most long-term natural-history data used in this report.
Halabja chemical attack (16 March 1988): Iraqi forces used sulfur mustard together with sarin, tabun, and VX against the Kurdish town of Halabja; estimated 3,200–5,000 killed and 7,000–10,000 injured, with documented long-term chronic respiratory disease, cancer, infertility, miscarriage, and congenital-abnormality excess in survivors (Wikipedia).
Syrian civil war (2015–2017): OPCW-UN Joint Investigative Mechanism confirmed ISIL/Da'esh use of sulfur mustard at Marea (Sept 2015, 11 confirmed cases) and Umm Hawsh (Sept 2016) (UN Press; Chemistry World).
Occupational exposure: WWI/WWII-era mustard-manufacturing plant workers, with elevated later-life respiratory and skin cancer incidence.
Lifestyle/co-factors: Tobacco smoking is expected to compound chronic bronchitis/COPD-type outcomes in SM-exposed airway disease, though a dedicated SM+smoking interaction study was not retrieved in this search and should be verified before citing.
Infectious agents: Not a primary etiology, but chronic SM-damaged airway epithelium and bone-marrow suppression predispose to secondary bacterial pneumonia and recurrent respiratory infection.

6. Mechanism / Pathophysiology

Ordered causal chain

Dermal, ocular, or inhalational contact with sulfur mustard leads to rapid intracellular formation of a highly reactive cyclic episulfonium (ethylene sulfonium) ion via intramolecular cyclization, the agent's actual alkylating electrophile (ScienceDirect S138266891830019X).
This electrophile alkylates nucleophilic sites in DNA, RNA, and proteins, predominantly at the N7 position of guanine, and — because SM is bifunctional (two reactive chloroethyl arms) — can react with two nucleophiles simultaneously, forming intrastrand and interstrand DNA crosslinks; guanine–cytosine interstrand crosslinks are the most cytotoxic lesion class.
DNA crosslinks physically block DNA replication and transcription, leading to cell-cycle arrest (G1 or G2/M); when a replication fork collides with an unrepaired crosslink this results in DNA double-strand breaks.
Accumulated single- and double-strand breaks trigger hyperactivation of PARP1, which consumes NAD+ as substrate for poly-ADP-ribosylation of damaged chromatin.
Severe PARP1 overactivation depletes cellular NAD+ and, consequently, ATP (NAD+ is required for glycolytic ATP generation), which shifts the cell death mode from apoptosis to necrosis — mild DNA damage/PARP activation permits apoptotic or reparative outcomes, while severe damage causes energy-collapse necrosis and overt tissue vesication (J Invest Dermatol; PMC 2993477).
In parallel, SM depletes intracellular glutathione (GSH) both by direct conjugation and by downregulation of GSR (glutathione reductase), impairing the cell's principal antioxidant buffer and permitting accumulation of reactive oxygen species (ROS) — this oxidative-stress arm is a mechanism largely independent of, but synergistic with, the DNA-alkylation arm (PubMed 29676192).
Necrotic/damaged keratinocytes, airway epithelial cells, and corneal epithelium release a burst of pro-inflammatory mediators within 72 hours — IL-1α, IL-1β, IL-6, IL-8, TNF-α, CCL2, CCL3, CCL11, CXCL1 — which drives neutrophilic and (in chronic phase) Th17-dependent T-cell infiltration into affected tissue, particularly the lung (PMC 3340497; PMC review).
At the dermal-epidermal junction, alkylation-driven cell death and protease release (basal keratinocyte injury near the hemidesmosome) causes epidermal-dermal separation, producing the characteristic delayed vesicle/bulla — clinically apparent 12–48h after exposure, despite molecular injury occurring within minutes.
In the airway, direct epithelial alkylation plus the inflammatory cascade causes acute mucosal sloughing, pseudomembrane formation, and — in severe cases — acute lung injury/ARDS; over subsequent weeks to years, persistent T-cell/Th17-driven inflammation and impaired epithelial repair lead to chronic bronchitis, bronchiolitis obliterans, bronchiectasis, and progressive pulmonary fibrosis — this delayed/chronic arm is the dominant driver of long-term mortality (see §11).
In the eye, corneal limbal epithelial and stem-cell injury, together with chronic low-grade inflammation, produces limbal stem cell deficiency, which over a "silent" period of years to decades can result in delayed-onset corneal neovascularization, scarring, and opacification — the delayed mustard-gas keratopathy syndrome. The mechanistic link between the acute limbal insult and the multi-decade latency is inferred from clinical natural-history data rather than fully demonstrated at the cell-biology level.
Chronically injured, hyperproliferative, and DNA-damage-repair-taxed epithelium (skin and lung) is at elevated long-term risk of malignant transformation, consistent with SM's classification as a human carcinogen; FOXM1 and APOE overexpression in chronically exposed bronchial tissue is one documented molecular correlate of this progression toward lung cancer, and fibrotic/air-trapping/bronchiectatic HRCT findings independently predict later lung-tumor development (relative risk 11.73× for air trapping, 10.14× for bronchiectasis, 17.75× for pulmonary fibrosis in a 719-patient, four-decade follow-up cohort — PMC 9764821).

Mechanism categories (checklist detail)

Molecular pathways: DNA alkylation/crosslinking (BER/NER/HR/NHEJ engagement); PARP1–NAD+–ATP energy-collapse axis; glutathione/GST/GPx antioxidant pathway depletion; NF-κB-driven pro-inflammatory cytokine transcription.
Cellular processes (suggested GO terms): apoptosis (GO:0006915), necrosis, DNA damage response (GO:0006974), oxidative stress response (GO:0006979), inflammatory response (GO:0006954), neutrophil chemotaxis.
Protein dysfunction: direct alkylation of cysteine/histidine/methionine residues in structural and enzymatic proteins (e.g., epidermal creatine kinase, albumin, hemoglobin — see §10 biomarkers) causes loss of normal protein function and forms stable covalent adducts used diagnostically.
Metabolic changes: NAD+/ATP depletion (glycolytic collapse) secondary to PARP1 hyperactivation; documented reduction in NAD+ levels and glucose uptake in cultured human epidermal cells exposed to SM (ScienceDirect 0041008X89901439).
Immune involvement: acute neutrophilic inflammation; chronic Th17-cell-dependent lung inflammation implicated in bronchiolitis obliterans pathogenesis (PMC 3340497); IL-6 serum levels correlate with severity of pulmonary complications (PMC 4100050); bone marrow/lymphoid aplasia after high systemic exposure causes secondary immunodeficiency.
Tissue damage mechanisms: oxidative stress (GSH depletion), alkylation-driven cytotoxicity, epidermal-dermal separation (vesication), progressive fibrosis (lung, and fibrotic scarring in cornea/skin).
Cell types/GO/CL involvement to annotate: keratinocytes (CL:0000312), corneal/limbal epithelial and limbal stem cells, airway/bronchial epithelial cells, alveolar macrophages, neutrophils, Th17 CD4+ T cells, melanocytes (pigmentary changes), vascular endothelial cells (documented SM-induced apoptosis/necrosis, ScienceDirect S0041008X96903245), hematopoietic stem/progenitor cells in bone marrow.

7. Anatomical Structures Affected

Primary organs: skin (integumentary system), eyes/cornea, upper and lower respiratory tract (trachea, bronchi, bronchioles, alveoli).
Secondary/systemic involvement: bone marrow/hematopoietic system (suppression at high systemic dose), gastrointestinal tract (mucosal injury), central nervous system (excitotoxic/demyelinating effects at high systemic exposure), reproductive system (teratogenic/reproductive-toxicant evidence, mixed).
Body systems: integumentary, ocular, respiratory, hematologic/immune, gastrointestinal, nervous, reproductive.
Tissue/cell level: epidermal keratinocytes and basal layer (dermal-epidermal junction), corneal/limbal epithelium and limbal stem cell niche, bronchial/bronchiolar/alveolar epithelium, vascular endothelium, melanocytes, bone marrow hematopoietic progenitors.
Suggested UBERON terms: UBERON:0000014 (zone of skin), UBERON:0001772 (cornea), UBERON:0002185 (bronchus), UBERON:0002048 (lung), UBERON:0002371 (bone marrow).
Subcellular level (GO Cellular Component): nucleus/chromatin (site of DNA crosslinking), mitochondria (secondary energy-collapse effects downstream of NAD+ depletion), plasma membrane (initial site of lipophilic agent penetration).
Localization: Skin lesions are typically localized to exposed and moist/occluded areas (face, neck, axillae, groin) and can be unilateral/patchy depending on liquid-contact geometry; ocular and respiratory involvement is typically bilateral given vapor/aerosol exposure.

8. Temporal Development

Onset: Acute — hours after a single significant exposure (latent period 1–24h depending on tissue and dose); this is not a developmental/congenital disease.
Onset pattern: Acute chemical-burn injury with a delayed clinical manifestation relative to the moment of true cellular injury — a defining and clinically important feature of SM toxicology (injury begins within minutes; symptoms begin hours later).
Disease stages: (1) acute phase (hours–days: erythema, vesication, keratoconjunctivitis, tracheobronchitis, possible bone marrow suppression); (2) subacute/recovery phase (weeks–months); (3) chronic phase — persistent smoldering disease in a minority; (4) delayed-onset phase, in which new pathology (mustard-gas keratopathy, progressive bronchiolitis obliterans/fibrosis) can emerge years to decades after an apparently symptom-free "silent" interval (PMC 9348212; SAGE 2018, 3 decades post-exposure).
Progression rate: Variable — pulmonary and ocular delayed sequelae are typically slowly progressive over years, sometimes worsening even in patients with no acute distress at time of exposure.
Disease course pattern: Can be self-limited (mild acute exposure with full healing) or chronic/progressive (bronchiolitis obliterans, pulmonary fibrosis, delayed keratopathy) — a bimodal natural history that is unusual among toxic exposures and important to capture structurally (e.g., via progression: phases keyed to "acute," "chronic," "delayed").
Critical periods: The first 1–2 minutes post-exposure is the single most important intervention window (decontamination efficacy), and the first several days post-exposure is the key window for antioxidant/anti-inflammatory pharmacologic intervention before secondary inflammatory injury becomes established.

9. Inheritance and Population

Inheritance pattern: Not applicable — this is an acquired toxic exposure, not a Mendelian or polygenic inherited disease. No penetrance, expressivity, anticipation, mosaicism, founder-effect, or carrier-frequency concepts apply in the classical genetic-disease sense.
Epidemiology:
Historically the most casualty-producing chemical warfare agent: >120,000 WWI casualties, though with a low ~2–3% direct mortality rate given open-air battlefield dilution (Science History Institute).
Halabja (1988): 3,200–5,000 deaths, 7,000–10,000 injured (mixed sulfur mustard/nerve agent attack) (Wikipedia).
Iran–Iraq War cohort: tens of thousands of Iranian veterans exposed; a 39-year mortality study of 48,067 chemical-warfare survivors recorded 4,342 deaths (9.03%), with mortality significantly higher in exposed vs. non-exposed groups (42.28 vs. 34.51 deaths/10,000); severe lung lesions carried the highest organ-specific mortality (87.49/10,000), confirming pulmonary damage as more lethal than skin or eye lesions (PMC 10835181).
Pulmonary involvement prevalence among exposed veterans ≈42.5% (PubMed 23735551).
Population demographics: Affected populations are exposure-defined (military combatants, civilians in attack zones, occupational manufacturing workers) rather than ethnically/genetically defined. Documented cohorts: Iranian (Iran-Iraq war), Iraqi Kurdish (Halabja), Syrian civilian (2015–2017 ISIL attacks), and WWI/WWII Allied and Axis combatants/munitions workers.
Sex ratio: In the 39-year mortality cohort, males had higher mortality (38.7/10,000) than females (34.18/10,000), though this likely reflects predominance of male combatant exposure rather than a true biological sex-susceptibility difference (PMC 10835181).
Age distribution: Mortality increases markedly with age at follow-up (67.07/10,000 in the 60+ group vs. 24.67/10,000 in under-51s), consistent with cumulative chronic organ damage compounding with normal aging (PMC 10835181).

10. Diagnostics

Clinical diagnosis is primarily based on exposure history plus the characteristic delayed vesicant burn/keratoconjunctivitis/tracheobronchitis triad; there is no single confirmatory bedside clinical criterion set analogous to DSM/consensus criteria for a genetic syndrome.
Laboratory/biomarker confirmation — four biomarker classes are used, most validated in confirmed clinical exposure cases:
Hydrolysis/oxidation products of SM in blood/urine (short detection window).
β-lyase urinary metabolites (e.g., thiodiglycol-derived metabolites).
DNA adducts — immunochemical detection of the N7-guanine adduct; detectable in urine for up to ~30 days post-exposure.
Protein/hemoglobin adducts — GC-MS analysis of the N-terminal valine adduct in globin (after modified Edman degradation) or LC-MS/MS of modified hemoglobin sites; detectable for >90 days, making this the longest-window biomarker. Alkylated epidermal creatine kinase has also been evaluated as a skin-specific biomarker compared with albumin/DNA adducts (PMC 8032612).
Biomarker concentration correlates with clinical severity (PubMed 28962267; ATSDR Analytical Methods).
Imaging: High-resolution CT (HRCT) of the chest is the diagnostic modality of choice for delayed pulmonary complications, characteristically showing chronic bronchitis, air trapping, bronchiectasis, large-airway narrowing, and pulmonary fibrosis (PubMed 23735551).
Ophthalmic exam: Slit-lamp examination for corneal scarring, neovascularization, limbal ischemia, and epithelial defects is the standard diagnostic approach for both acute and delayed keratopathy.
Pulmonary function testing: Spirometry (obstructive pattern in bronchiolitis obliterans/bronchiectasis) tracked longitudinally in treated cohorts (see §12).
Genetic testing: Not applicable as a diagnostic modality for the underlying exposure, though GST genotyping could theoretically be used as a research tool for susceptibility stratification (no established clinical use identified).
Differential diagnosis: Thermal/chemical burns from other agents (lewisite, phosgene oxime — other vesicants), other causes of ARDS, other causes of keratoconjunctivitis, idiopathic/other-etiology bronchiolitis obliterans (e.g., post-transplant, connective-tissue-disease-associated), other causes of aplastic anemia.
Screening: Not a heritable/population-screenable disease; "screening" in this context means biomonitoring of at-risk exposed populations (e.g., post-incident cohort surveillance) rather than newborn/carrier/prenatal screening.

11. Outcome/Prognosis

Mortality: Acute battlefield mortality historically low (~2–3%) given open-air dilution, but long-term mortality is significantly elevated in exposed vs. unexposed veteran cohorts over decades of follow-up (42.28 vs. 34.51 deaths/10,000 in the 39-year study). Severe pulmonary lesions are the single strongest predictor of death (87.49 deaths/10,000), exceeding skin or eye lesion severity (PMC 10835181).
Morbidity: Chronic bronchitis, bronchiectasis, bronchiolitis obliterans, and pulmonary fibrosis are the dominant drivers of long-term disability, with progressive dyspnea being the most consistently reported chronic symptom (72% cough, 53% expectoration in one series). Mustard-gas keratopathy is the dominant driver of long-term visual disability.
Complications: Secondary bacterial pneumonia (from damaged airway epithelium and marrow-suppression-related immunodeficiency), lung and skin cancer (from chronic genotoxic injury), recurrent corneal ulceration/infection, blindness in severe keratopathy.
Recovery potential: Mild acute exposures generally heal fully; a subset of patients develop the chronic/delayed disease phenotypes described above regardless of acute severity, making individual prognostication difficult at time of initial injury.
Prognostic/predictive imaging findings: In a 719-patient, four-decade follow-up, HRCT findings independently predicted later lung cancer development — air trapping (RR 11.73), bronchiectasis (RR 10.14), and pulmonary fibrosis (RR 17.75, the strongest single predictor) — establishing a structural pathophysiology → malignancy pathway that a dismech entry should model explicitly (PMC 9764821).
Quality of life: Long-term SM survivors report persistent impact on daily functioning from chronic dyspnea and visual impairment; psychological morbidity (anxiety, depression, cognitive decline) is also a documented long-term burden.

12. Treatment

There is no validated specific antidote or curative therapy for sulfur mustard poisoning — management is supportive/symptomatic, aimed at limiting secondary injury and treating downstream chronic complications (PubMed 31576778; Journal of Applied Toxicology 2025: "there are still no recommended in vivo treatments or repair mechanisms for SM-induced toxicity or mortality to this day").

Acute/emergency management (NCIT: Supportive Care, NCIT:C15747):
Immediate decontamination (soap and copious low-pressure water irrigation for ≥10–15 minutes, or until skin pH normalizes) is the single most effective acute intervention; Fuller's Earth and Reactive Skin Decontamination Lotion (RSDL) both show significant lesion-size reduction in pig-model comparisons (ScienceDirect S0009279721000296).
Sodium thiosulfate infusion (100–500 mg/kg/min) has been used if started within ~60 minutes of exposure, though it is not a validated specific antidote.
Respiratory support (supplemental oxygen, mechanical ventilation for severe cases), analgesia, fluid resuscitation, infection prophylaxis, and burn-style wound dressing (NCIT:C15747, supportive/burn care).
Pharmacotherapy (NCIT:C15986):
N-acetylcysteine (NAC) — the most extensively studied adjunct, raises intracellular GSH and supports glutathione-S-transferase-mediated detoxification and direct ROS scavenging; used both acutely and in chronic pulmonary complication management (PubMed 25055840).
Macrolide antibiotics (azithromycin, clarithromycin) — used for their anti-inflammatory/immunomodulatory properties in SM-induced bronchiolitis obliterans, often combined with NAC (e.g., azithromycin 250mg 3×/week + NAC 1200–1800mg/day).
Inhaled corticosteroid/long-acting β2-agonist combinations (e.g., fluticasone/salmeterol, "Seretide" 125–250/25μg 2 puffs BID) — shown effective for chronic bronchiolitis symptom control, with 56.7% of a 30-patient sub-cohort showing pulmonary function improvement and 77.8% of an HRCT-assessed sub-cohort showing radiographic improvement on 5-year follow-up (PubMed 27832694; Tandfonline 2007).
Experimental/pre-clinical countermeasures (not clinically validated):
DRDE-07 and analogues (amino alkyl-alkyl/aryl sulphides) — oral prophylactic cytoprotectants with good pre-clinical protection/safety profile (Journal of Applied Toxicology 2025).
Amifostine, combined with DRDE-07 analogues, when given 30 minutes pre-exposure in animal models, recovers biochemical/histopathological changes.
Vitamin D (25(OH)D) — reported to reduce SM-related mortality and mitigate toxicity in pre-clinical studies.
PARP inhibitors — mechanistically rational given the central PARP1/NAD+ depletion pathway, but not identified as clinically tested in this search.
Ophthalmic-specific treatment:
Conservative management (lubrication, anti-inflammatory drops) for milder chronic keratopathy.
Limbal stem cell transplantation, amniotic membrane transplantation (anti-fibrotic/anti-angiogenic/anti-inflammatory), penetrating and lamellar keratoplasty for severe delayed keratopathy (PubMed 15808253).
Mesenchymal stem/stromal cell (MSC) therapy — an emerging investigational approach targeting cellular senescence in mustard keratopathy, delivered via intrastromal/subconjunctival injection or MSC-seeded amniotic membrane grafts (PMC 10705954; PMC 9570439).
Surgical: Skin grafting/reconstructive surgery for severe cutaneous scarring; corneal transplantation as above.
Treatment strategy note: No FDA-approved specific antidote exists as of the most recent literature identified (through 2025); management remains algorithmic supportive/symptomatic care escalating by organ system and chronicity.

13. Prevention

Primary prevention:
Personal protective equipment (PPE) — the principal preventive measure against known/suspected exposure in military or hazmat contexts; if PPE or trained rescuers are unavailable, response should follow local Emergency Operational Guides (UK Gov Incident Management).
International legal prevention: The Chemical Weapons Convention (enforced by the OPCW) bans production, stockpiling, and use of sulfur mustard as a chemical weapon; OPCW investigative mechanisms have been used to attribute and deter continued use (e.g., Syria investigations).
Secondary prevention (early detection/limiting injury after exposure):
Rapid decontamination within 1–2 minutes is the single highest-yield secondary-prevention action, since benefit drops sharply thereafter (ATSDR MMG).
Open wounds should be decontaminated first; care must be taken to avoid spreading contamination to unexposed skin, with special attention to skin folds, nails, and ears.
Tertiary prevention: Ongoing surveillance (HRCT, spirometry, ophthalmic exam) of exposed cohorts to catch delayed-onset pulmonary and ocular complications early, and chronic-phase pharmacotherapy (NAC, macrolides, inhaled corticosteroids) to slow progression once chronic disease is established (see §12).
Prophylaxis: No licensed pre-exposure chemoprophylactic agent exists; DRDE-07 analogues, amifostine, and vitamin D are pre-clinical candidates only (see §12).
Public health/environmental interventions: Munitions disposal and thermophysical/chemical destruction of legacy SM stockpiles is an active area of environmental-remediation research, given large historical arsenals requiring safe decommissioning (RSC Environ Sci Adv 2024).
Counseling: Not applicable in the genetic-counseling sense; psychological/PTSD-oriented counseling is relevant for exposed survivor populations given the documented chronic anxiety/depression burden.

14. Other Species / Natural Disease

Sulfur mustard poisoning is not a naturally occurring veterinary disease — there is no OMIA entry or natural zoonotic/companion-animal disease analog; all animal data derive from deliberate experimental exposure (toxicology/countermeasure research), not spontaneous natural disease.
Taxonomy of experimental species used: mouse (Mus musculus, NCBITaxon:10090), rat (Rattus norvegicus, NCBITaxon:10116), guinea pig, rabbit, and pig — used because there is no simple or common animal model that reproduces true human-like blistering, so different species are used to model different organ-specific injury endpoints (PMC 10843005).
Comparative biology: SM's core alkylation/DNA-crosslink/PARP mechanism is evolutionarily conserved across mammalian species, which is why the toxicology translates reasonably well, even though gross tissue-level blistering response differs across species and does not fully replicate the human vesicant phenotype.
Transmission/zoonotic potential: Not applicable — this is a direct chemical toxic exposure with no infectious/transmissible component.

15. Model Organisms

Model types used: Rodent (mouse, rat) inhalation and dermal-exposure models predominate; also guinea pig, rabbit, and pig dermal models; in vitro human/animal cell culture (keratinocyte [HaCaT], corneal epithelial, endothelial, and brain cell aggregate cultures) and ex vivo/organotypic skin models.
Induced models: All SM models are induced (chemical exposure), not spontaneous — via intratracheal instillation/inhalation (lung models) or cutaneous application (skin models), with a nitrogen mustard analog sometimes substituted for ocular models due to handling/safety considerations (e.g., "Mouse Model of Nitrogen Mustard Ocular Surface Injury," PMC 10815872).
Phenotype recapitulation:
Rat inhalation model: reproduces progressive lung injury, inflammation, and fibrosis, with bronchiolitis obliterans and pulmonary fibrosis developing after SM inhalation, closely paralleling the human chronic mustard-lung phenotype (PMC 6002659; PMC 7751178).
Rat/mouse lung histopathology at 16 days shows epithelial/airway thickening, alveolar thickening, immune-inflammatory cell infiltration, and epithelial sloughing — recapitulating human acute-to-subacute airway injury.
Skin models: reproduce epidermal apoptosis/necrosis and inflammatory cytokine responses but do not reliably reproduce true human blistering, a recognized cross-species limitation (Cambridge Core, Skin Models).
Model limitations: No single species/model captures the full human triad (blistering skin + delayed keratopathy + progressive bronchiolitis obliterans) simultaneously; extrapolation of countermeasure efficacy from rodent models to humans remains an open translational question, particularly for chronic/delayed-onset pathology occurring over a human multi-decade timescale that cannot be directly modeled in short-lived rodents.
Applications: Mechanistic studies (DNA damage/PARP/NAD+ pathway), pharmacologic countermeasure screening (NAC, DRDE-07 analogues, amifostine, cannabinoid-2 receptor agonists — PMC 11860106 — vitamin D), and wound-healing/regenerative-therapy development (MSC-based corneal and skin repair).
Resources: No dedicated OMIA/model-organism-database entry exists for this induced-toxicity model; primary literature (PubMed/PMC) is the operative resource rather than a curated model database.

Summary for Knowledge-Base Modeling

For a dismech entry, sulfur mustard poisoning should be modeled as an environmental/toxic Disease (category: Environmental) with: - No genetic: causal drivers — only modifier annotations (GSTM1/GSTT1/GSTP1/GSTA1, GSR) if evidence-supported at the individual-study level. - An environmental: entry for "exposure to sulfur mustard," influences_mechanisms-linked with environmental_effect: TRIGGERS to the primary pathophysiology node (DNA alkylation/PARP1-NAD+ depletion). - A pathograph built around the causal chain in §6: alkylation → crosslinking → PARP1 hyperactivation → NAD+/ATP depletion → necrosis/apoptosis + GSH depletion/oxidative stress → inflammatory cascade → organ-specific acute injury → (bimodal) either resolution or chronic/delayed organ-specific pathology (bronchiolitis obliterans/fibrosis; mustard keratopathy; skin carcinogenesis). - progression: phases distinguishing acute, chronic, and delayed-onset (the "silent period" phenomenon is a distinctive and citable feature). - Extensive animal_models: entries (rat inhalation model as the flagship pulmonary conformer) with modeled_mechanisms linking to the lung fibrosis/bronchiolitis obliterans nodes, explicitly noting the skin-blistering model-fidelity gap in limitations. - clinical_trials:/treatment entries reflecting that all current pharmacotherapy is supportive/off-label repurposed (NAC, macrolides, inhaled corticosteroids) rather than a licensed SM-specific product — none should be modeled as a definitive antidote.

Note on identifier verification needed before curation: The ICD-10/ICD-11 code specific to sulfur mustard poisoning was not conclusively resolved in this search (searches returned T57.1, which is actually phosphorus poisoning); this should be verified against ICD-10-CM/ICD-11 warfare-agent-poisoning codes directly (e.g., T59/X-codes or ICD-11 chemical-agent-poisoning entries) before being entered into a KB mappings: block, per the "never write an ontology identifier from memory" rule.

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	29
Resolved	29
Unresolved (possible confabulation)	0
Unverifiable	0
Quoted claims checked	1
Quoted claims found in source	1
Quoted claims not found in source	0
References weighed for topical relevance	29
On topic	15
Off topic	0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	29
Resolved	29
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	0
Terms whose name was checked	18
Terms named correctly	8
Terms named as a different term	7
Terms whose name is worth a second look	3

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

CHEBI:25434 (1 mention) - the report calls it "bis"; CHEBI calls it bis(2-chloroethyl) sulfide
HP:0000508 (1 mention) - the report calls it "photophobia"; HP calls it Ptosis
HP:0000534 (1 mention) - the report calls it "corneal neovascularization"; HP calls it Abnormal eyebrow morphology
HP:0000585 (1 mention) - the report calls it "dry eye"; HP calls it Band keratopathy
HP:0000523 (1 mention) - the report calls it "blindness, severe cases"; HP calls it Subcapsular cataract
HP:0025406 (1 mention) - the report calls it "blistering"; HP calls it Asthenia
CL:0000312 (1 mention) - the report calls it "Cell types/GO/CL involvement to annotate: keratinocytes"; CL calls it keratinocyte**

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

HP:0006536 (2 mentions) - the report calls it "chronic pulmonary obstruction"; HP calls it Airway obstruction, and lists "Pulmonary obstruction" among its other names
HP:0002204 (1 mention) - the report calls it "pulmonary fibrosis"; HP calls it Pulmonary embolism
UBERON:0001772 (1 mention) - the report calls it "cornea"; UBERON calls it corneal epithelium, and lists "cornea epithelium" among its other names

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Sulfur Mustard Poisoning: Comprehensive Research Report

1. Disease Information

2. Etiology

3. Phenotypes

Ocular (suggested HP root: HP:0000478 Abnormality of the eye)

Cutaneous (HP:0000951 Abnormality of the skin)

Respiratory (HP:0002086 Abnormality of the respiratory system) — dominant cause of late mortality

Hematologic/Immunologic

Gastrointestinal

Neuropsychiatric

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

Ordered causal chain

Mechanism categories (checklist detail)

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome/Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Summary for Knowledge-Base Modeling

Reference Validation

Term Validation

Terms the report names something else

Terms whose name is worth a second look