Paraquat Poisoning

Environmental MONDO:0017862 Pathograph 34 Show in embeddings browser

Paraquat poisoning is intoxication by the non-selective bipyridylium herbicide paraquat (methyl viologen), most often after deliberate ingestion of a concentrated formulation. Two properties make it exceptionally lethal. First, paraquat is accumulated against a concentration gradient into lung epithelium by the polyamine transport system, reaching pulmonary concentrations six to ten times those in plasma and being retained there as blood levels fall - which is why the lung is the principal target organ despite the exposure being systemic. Second, once inside the cell it undergoes redox cycling: one-electron reduction to a cation radical followed by reoxidation by molecular oxygen, which regenerates the parent compound and so generates superoxide catalytically rather than stoichiometrically, consuming reducing equivalents as it goes. The illness is biphasic - caustic oropharyngeal and gastrointestinal injury with acute kidney and liver failure in the first days, then a delayed fibroproliferative phase in which survivors develop progressive pulmonary fibrosis and die of respiratory failure over two to three weeks. There is no antidote, and reported case fatality reaches 90%.

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Discussions and Knowledge Gaps

Does glucocorticoid plus cyclophosphamide immunosuppression reduce mortality in acute paraquat poisoning, and if so in which severity stratum?

KNOWLEDGE GAP OPEN gap_paraquat_immunosuppression_efficacy

Attached to

pathophysiology#Alveolar Epithelial Injury and Cell Death pathophysiology#Progressive Pulmonary Fibrosis

The evidence points both ways and this entry records both rather than choosing. A systematic search of human studies concluded that the efficacy of immunosuppression and antioxidants was anecdotal; three randomised controlled trials of dexamethasone, methylprednisolone and cyclophosphamide each reported a mortality benefit over standard treatment. That is a real contradiction, not a gradient of confidence, and there are two candidate explanations that lead to opposite clinical conclusions. Either the trials are right and the earlier reviews were diluted by heterogeneous, late-presenting cohorts; or the trials are small and conducted where severity assessment is limited, so apparent benefit reflects imbalance in ingested dose - the single strongest determinant of outcome - rather than treatment. The distinction matters because the intervention is not free: cyclophosphamide in a patient with acute kidney injury and impaired elimination carries real harm, and paraquat's case fatality is high enough that an ineffective therapy is not a neutral default. Note this entry's evidence for both positions is second-hand, drawn from an editorial summarising the primary literature rather than from the trials themselves; closing this gap starts with reading them.

Proposed experiments

Dose-stratified randomised trial of immunosuppression in acute paraquat poisoning

exp_paraquat_immunosuppression_dose_stratified

Multicentre randomised trial of glucocorticoid plus cyclophosphamide versus supportive care, with randomisation stratified on an objective measure of ingested dose (plasma paraquat concentration on a validated time-versus-concentration nomogram, or urine dithionite grade where plasma assay is unavailable), and with time from ingestion to presentation recorded as a prespecified covariate rather than an exclusion.

Decision criterion

Whether a mortality difference survives adjustment for measured ingested dose and presentation delay, and whether any benefit is confined to a definable severity stratum rather than being uniform.

Supporting outcome

A mortality benefit that persists after adjustment for plasma paraquat concentration and presentation delay.
A benefit concentrated in an intermediate-dose stratum, which would explain why unstratified cohorts disagree.

Refuting outcome

A benefit that disappears once ingested dose is adjusted for, indicating confounding by severity.
Excess harm in the immunosuppressed arm among patients with acute kidney injury.

Can any intervention reduce the pulmonary paraquat burden once uptake has occurred, or is the therapeutic window closed as soon as the lung has concentrated the dose?

KNOWLEDGE GAP OPEN gap_paraquat_therapeutic_window_vs_lung_retention

Attached to

pathophysiology#Polyamine-Transporter-Mediated Pulmonary Accumulation

Two curated facts, taken together, predict the clinical observation and suggest the field is optimising the wrong variable. Paraquat is concentrated six- to ten-fold above plasma in lung and retained there as blood levels fall; and haemoperfusion helps within four to six hours and largely stops helping later. Extracorporeal elimination clears the compartment paraquat is leaving, not the one it has entered - which would explain why removing more drug, later, does not translate into survival. If that reading is right, the tractable target is not clearance but the polyamine transporter itself: competitive inhibition of uptake, plausible in principle since the transporter is a known and characterised system, would have to be given inside the same few hours to matter. What is missing is a direct measurement: no evidence consulted here reports lung paraquat burden as a function of time and of extracorporeal treatment in humans, so the causal claim that late clearance fails *because* of lung retention remains an inference from two separate observations.

Proposed experiments

Serial lung-versus-plasma paraquat kinetics under extracorporeal treatment

exp_paraquat_lung_burden_kinetics

Paired plasma and lung paraquat measurement over time in a large-animal model of ingestion, with and without haemoperfusion started at staggered intervals after dosing; complemented in humans by post-mortem lung paraquat concentration in treated and untreated fatalities with recorded ingestion and treatment times.

Decision criterion

Whether extracorporeal clearance started after the early window lowers the lung concentration at all, or lowers plasma only while lung burden is unchanged.

Supporting outcome

Lung concentration unchanged by late haemoperfusion despite a fall in plasma.
A lung-to-plasma ratio that rises over time irrespective of treatment.

Refuting outcome

Lung burden falling proportionally with plasma under late clearance, which would relocate the reason for treatment failure elsewhere.

What are the haemodynamic and electrophysiological effects of acute paraquat poisoning in humans, and does cardiac depression contribute materially to death in fulminant high-dose ingestion?

KNOWLEDGE GAP OPEN gap_paraquat_cardiac_effects_uncharacterised

Attached to

pathophysiology#Cardiac Involvement

This gap is recorded because a plausible claim was available and declined. The deep-research report generated for this entry states that cardiogenic or circulatory collapse is the dominant fatal mechanism in fulminant poisoning. It is mechanistically plausible - rodents show dose-dependent falls in heart rate, blood pressure and contractility, and the >40 mg/kg course kills in two to three days, faster than fibrosis can develop, so something other than the lung must be killing those patients. But no source located for this entry supports it, and the one human source that addresses the question states that little to no evidence exists on the haemodynamic and cardiac electromechanical effects of acute paraquat poisoning. So the mechanism of death in the fulminant form is, on this entry's evidence, unaccounted for - which is a more useful thing to record than a borrowed assertion. Resolving it would also settle whether the bradycardia reported as unusual is genuinely rare or merely rarely looked for.

Proposed experiments

Prospective cardiac phenotyping in acute paraquat poisoning

exp_paraquat_cardiac_phenotyping_prospective

Serial ECG, echocardiography and high-sensitivity troponin in consecutive patients admitted with acute paraquat poisoning, stratified by SIPP, with cause of death adjudicated against the cardiac, respiratory and renal arms rather than recorded as multiorgan failure.

Decision criterion

Whether patients in the fulminant high-dose stratum show cardiac depression or arrhythmia preceding death, and whether adjudicated cause of death in that stratum is cardiac rather than respiratory.

Supporting outcome

Falling contractility or conduction abnormality preceding death in the high-SIPP stratum.
Troponin release out of proportion to resuscitation received.

Refuting outcome

Preserved cardiac function up to death, locating the fulminant fatal mechanism elsewhere.
Bradycardia occurring at the same low rate across severity strata, making it incidental.

Is the epidemiological association between chronic low-dose paraquat exposure and Parkinson disease causal, and does it share a mechanism with the acute poisoning curated here?

CONTROVERSY OPEN controversy_paraquat_parkinson_association

Attached to

pathophysiology#Redox Cycling and Catalytic Superoxide Generation

This entry curates acute high-dose poisoning; the paraquat-Parkinson question concerns chronic low-dose exposure and is a different exposure regime with a different target organ. They are linked here rather than merged because they share the redox-cycling node: paraquat is structurally similar to MPP+, is taken up by cation transporters, and is used experimentally to model nigrostriatal degeneration - and this knowledge base already treats paraquat as an environmental complex I toxin in `Parkinsons_Disease` and in the `parkinsonism_dopaminergic_degeneration` module. The association is meta-analytically supported but is not curated as established causation here, because the acute-poisoning literature cannot speak to it and this entry has not assessed the chronic-exposure evidence. Recorded so the relationship between these entries is explicit rather than implied by a shared substance name.

Show evidence (1 reference)

PMID:30474499 SUPPORT Human Clinical

"There is a statistically significant association between paraquat exposure and PD."

PARTIAL - the meta-analysis (13 case-control studies, OR 1.64, 95% CI 1.27-2.13) establishes a statistically significant association, which is not the same as causation and says nothing about whether it shares a mechanism with the acute poisoning curated here. That is precisely the open question this discussion records.

⚙

Pathophysiology

Ingestion of Concentrated Paraquat

The exposure event. Deaths follow accidental or deliberate ingestion of concentrated herbicide formulations; cutaneous and mucosal contact are also reported routes. Dose sets the tempo rather than merely the severity: fulminant poisoning above roughly 40 mg/kg kills within two to three days, while lower doses produce the slower fibrotic course. Paraquat is a leading agent in the wider problem of fatal pesticide self-poisoning, which the global literature places at roughly a third of all suicides worldwide.

Downstream

Caustic Oropharyngeal and Gastrointestinal Injury Direct contact of concentrated herbicide with mucosal surfaces on the way down.

Polyamine-Transporter-Mediated Pulmonary Accumulation Absorbed paraquat is delivered systemically and concentrated by lung epithelium.

Show evidence (3 references)

PMID:18161502 SUPPORT Other

"However, over the last decades, there have been numerous fatalities, mainly caused by accidental or voluntary ingestion."

Establishes ingestion as the route producing fatal poisoning.

PMID:39239177 SUPPORT Other

"Self-ingestion or cutaneous/mucosal contact can rapidly lead to multiorgan failure involving the respiratory, liver, and renal systems."

Names the routes of exposure and the organ systems they reach.

PMID:39239177 SUPPORT Other

"However, patients with fulminant poisoning (more than 40 mg per kg body weight) can develop complications within hours and die in 2-3 days."

Supports the dose-dependent tempo: above roughly 40 mg/kg the illness is fulminant rather than fibrotic.

Caustic Oropharyngeal and Gastrointestinal Injury

Direct corrosive injury where concentrated herbicide contacts mucosa. It begins focally, most often on the tongue, and with delay becomes multifocal and diffuse, involving buccal mucosa and then oropharynx and oesophagus. Lesions ulcerate and bleed, and can perforate the tract with consequent mediastinitis and pneumomediastinum. This arm is not merely cosmetic - severe mucositis is associated with systemic complications including acute kidney injury, which is what makes the oral findings prognostically informative.

mucosal ulceration and necrosis following caustic contact GO:0008219 ↑ INCREASED

Downstream

Paraquat-Associated Stomatitis The oral expression of caustic mucosal injury.

Pneumomediastinum Perforation of the ulcerated tract allows air into the mediastinum.

Subcutaneous Emphysema Air tracking from the mediastinum reaches the cervical and thoracic soft tissues.

Proximal Tubular Injury and Acute Kidney Injury Severe mucosal disease travels with acute kidney injury. Marked INDIRECT because the cited evidence is an association across pooled cases, not a demonstrated causal route - the shared driver is most likely ingested dose.

Severe Mucositis The higher-grade expression of the same mucosal lesion.

Vomiting Mucosal irritation drives early emesis.

Diarrhea Mucosal injury extends through the gastrointestinal tract.

Show evidence (3 references)

PMID:39239177 SUPPORT Other

"Gastrointestinal toxicity occurs in the form of mucosal lesions which can ulcerate and bleed, sometimes resulting in perforation of the tract and associated mediastinitis and pneumomediastinum."

States the ulceration, bleeding and perforation this node asserts.

PMID:42048945 SUPPORT Human Clinical

"With increasing treatment delay, lesions progressed to a multifocal and diffuse pattern, significantly involving the buccal mucosa (Absolute Risk Difference, ARD: 55.6%; p = 0.049) and oropharynx/oesophagus."

Supports the focal-to-diffuse anatomical progression described here, from a pooled individual-patient analysis of 170 cases.

PMID:42048945 SUPPORT Human Clinical

"A strong association existed between severe PAS and systemic complications like acute kidney injury."

Supports the claim that the mucosal arm tracks systemic toxicity rather than being an isolated local effect.

Polyamine-Transporter-Mediated Pulmonary Accumulation

The reason the lung is the target organ. Paraquat is a substrate of the polyamine transport system, which is abundantly expressed in the membranes of alveolar type I and type II cells and Clara (club) cells. Transport is against the concentration gradient, so pulmonary concentrations reach six to ten times plasma levels, and - critically for treatment timing - paraquat is retained in lung even once blood levels begin to fall. This is why measures that lower the plasma level late have limited effect on the lung burden already established.

alveolar type I cell CL:0002062 alveolar type II cell CL:0002063 Clara (club) cell CL:0000158

polyamine transport system-mediated uptake of paraquat GO:1902047 ↑ INCREASED

polyamine transporter accepting paraquat as a substrate GO:0015203

Downstream

Redox Cycling and Catalytic Superoxide Generation Intracellular paraquat becomes the substrate for catalytic redox cycling.

Show evidence (2 references)

PMID:18161502 SUPPORT Other

"PQ mainly accumulates in the lung (pulmonary concentrations can be 6 to 10 times higher than those in the plasma), where it is retained even when blood levels start to decrease."

Quantifies the pulmonary accumulation and states the retention that persists as plasma levels fall.

PMID:18161502 SUPPORT Other

"The pulmonary effects can be explained by the participation of the polyamine transport system abundantly expressed in the membrane of alveolar cells type I, II, and Clara cells."

Names the transporter and the three cell types, which is what the cell_type bindings on this node encode.

Redox Cycling and Catalytic Superoxide Generation

The rate-limiting molecular lesion. Paraquat undergoes one-electron reduction to a cation radical, which is reoxidised by molecular oxygen; the reoxidation regenerates the parent paraquat cation and releases superoxide. Because the toxicant is regenerated, one paraquat molecule generates reactive oxygen species catalytically rather than being consumed, which is why very small intracellular quantities are lethal and why no stoichiometric scavenger has succeeded as an antidote. The cycle also consumes reducing equivalents, compounding oxidative injury with a loss of antioxidant reserve. The reduction is localised: paraquat is carried into the mitochondrial matrix in a membrane-potential-dependent manner as the dication rather than the radical, and is there reduced principally by complex I in mammalian mitochondria.

catalytic superoxide generation by paraquat redox cycling GO:0042554 ↑ INCREASED overwhelmed cellular oxidative stress response GO:0006979 ↑ INCREASED

Downstream

Alveolar Epithelial Injury and Cell Death Sustained radical generation inside lung epithelium exceeds antioxidant capacity.

Proximal Tubular Injury and Acute Kidney Injury The same redox chemistry operates in the proximal tubule, where paraquat also distributes highly.

Cardiac Involvement Paraquat causes multiorgan injury including the heart, and the same redox chemistry is the presumed route. Marked INDIRECT_UNKNOWN_INTERMEDIATES deliberately: no human study localises cardiac injury to redox cycling, so this connects the node to the graph without asserting the mechanism the accompanying KNOWLEDGE_GAP says is unestablished.

Hepatocellular Injury And in hepatocytes, damaging smooth endoplasmic reticulum and mitochondria.

Show evidence (4 references)

PMID:18161502 SUPPORT Other

"Further downstream at the toxicodynamic level, the main molecular mechanism of PQ toxicity is based on redox cycling and intracellular oxidative stress generation."

Identifies redox cycling as the principal molecular mechanism.

PMID:39239177 SUPPORT Other

"Paraquat exerts its toxic and lethal effects by forming cation radicals post-metabolism, subsequently generating free oxygen radicals, leading to mitochondrial damage and apoptosis."

States the cation radical intermediate and the downstream radical generation, mitochondrial damage and apoptosis.

PMID:18039652 SUPPORT In Vitro

"Experiments with disrupted mitochondria showed that once in the matrix paraquat was principally reduced by complex I (mammals) or by NADPH dehydrogenases (yeast) to form the paraquat radical cation that then reacted with oxygen to form superoxide."

Localises the one-electron reduction to mitochondrial complex I in mammals and states the radical-then-superoxide sequence this node asserts.

+ 1 more reference

Alveolar Epithelial Injury and Cell Death

Oxidative injury to the alveolar epithelium, expressed as alveolitis and alveolar damage with mitochondrial injury and cell death. Cell death here is not apoptosis alone: rat work implicates ferroptosis - iron-dependent lipid peroxidative death - driven by Keap1 upregulation and Nrf2 degradation, which connects the redox arm to the fibrotic one through a distinct death programme. This is the destructive phase that precedes and licenses the fibrotic one.

pulmonary alveolar epithelial cell CL:0000322

oxidative-stress-driven apoptosis of alveolar epithelium GO:0008631 ↑ INCREASED iron-dependent lipid peroxidative cell death (ferroptosis) GO:0097707 ↑ INCREASED

Downstream

TGF-beta-Driven Mesenchymal Transition of Alveolar Epithelium Surviving epithelium at sublethal exposure transforms rather than dies.

Acute Respiratory Distress Syndrome Diffuse alveolar injury presents clinically as ARDS, days before the fibrotic phase.

Show evidence (3 references)

PMID:39239177 SUPPORT Other

"Lungs are affected the most as the chemical is sequestrated here due to the concentration gradient, and alveolitis, alveolar damage, and fibrosis set in."

States the alveolitis and alveolar damage of this node and its progression to fibrosis.

PMID:39239177 SUPPORT Other

"Paraquat exerts its toxic and lethal effects by forming cation radicals post-metabolism, subsequently generating free oxygen radicals, leading to mitochondrial damage and apoptosis."

Carries the mitochondrial-damage and apoptosis claim this node's description and its `GO:0008631` binding rest on. The same sentence also evidences the upstream redox node; it is repeated here rather than left one node away from the claim it supports.

PMID:37812357 SUPPORT Model Organism

"Our results suggest that PQ can regulate Keap1/Nrf2 signaling pathway, leading to increased lipid peroxidation and abnormal iron uptake, thereby inducing iron death and exacerbating the progression of pulmonary fibrosis."

Rat evidence for ferroptosis as a second death programme linking oxidative injury to fibrosis, and the basis for the `GO:0097707` binding. Tagged MODEL_ORGANISM: no human data establish this arm.

TGF-beta-Driven Mesenchymal Transition of Alveolar Epithelium

The step that converts injury into fibrosis, and it is dose-dependent in a way that matters clinically. In alveolar epithelial cells, short high-dose paraquat causes apoptotic death, whereas prolonged low-dose exposure instead drives transformation into spindle-shaped mesenchymal-like cells that lose E-cadherin, gain alpha-smooth muscle actin and secrete fibronectin. The transformation is TGF-beta1-dependent - a receptor antagonist abolishes it - and it confers resistance to cell death, so the cells that survive are precisely the ones that make matrix. This is why subacute, lower-dose poisoning produces the delayed fibrotic course rather than simply a milder version of the fulminant one.

alveolar epithelial cell undergoing mesenchymal transition CL:0000322 myofibroblast-like cell CL:0000186

EMT-like transformation of alveolar epithelium GO:0001837 ↑ INCREASED TGF-beta1 signalling driving the transition GO:0007179 ↑ INCREASED

Downstream

Progressive Pulmonary Fibrosis Mesenchymal-like cells secrete the extracellular matrix that becomes fibrosis.

Show evidence (2 references)

PMID:25799450 SUPPORT In Vitro

"In contrast, long-term (6-12 days) low-dose (30 μM) treatments with PQ resulted in a transformation into spindle-shaped mesenchymal-like cells with a decrease of E-cadherin as well as an increase of α-smooth muscle actin"

States the mesenchymal transformation and its marker shift, and pins it to the low-dose long-duration condition rather than to high-dose exposure.

PMID:25799450 SUPPORT In Vitro

"The administration of a TGF-β1 receptor antagonist, SB431542, almost completely attenuated the mesenchymal transformation as well as fibronectin secretion, suggesting a crucial role of TGF-β1 in EMT-like cellular response and subsequent fibrogenesis."

Establishes TGF-beta1 dependence by antagonist rescue, which is what licenses the GO:0007179 binding on this node.

Progressive Pulmonary Fibrosis

The delayed fibroproliferative phase, and the characteristic cause of death in patients who survive the acute multiorgan insult. Fibrosis obliterates the gas-exchange surface over two to three weeks, producing progressive respiratory failure. Its delayed onset is what makes paraquat poisoning unusual among acute toxidromes: a patient can appear to stabilise and still die of the exposure a fortnight later.

fibrotic extracellular matrix deposition in the alveolar wall GO:0030198 ↑ INCREASED collagen fibril deposition GO:0030199 ↑ INCREASED

Downstream

Multiorgan Failure and Death Loss of gas-exchange surface produces terminal respiratory failure.

Pulmonary Fibrosis The radiological and histological expression of this node.

Respiratory Failure Loss of gas-exchange surface produces respiratory failure.

Dyspnea Falling compliance and gas exchange are felt as breathlessness.

Show evidence (1 reference)

PMID:39239177 SUPPORT Other

"In contrast, severe poisoning can lead to acute kidney failure, acute lung injury, and lung fibrosis resulting in death over 2-3 weeks."

Establishes lung fibrosis as the delayed cause of death and gives the two-to-three-week interval.

Proximal Tubular Injury and Acute Kidney Injury

Necrosis of the proximal convoluted tubule, where paraquat distribution is high. The kidney concentrates paraquat by an active transport route of its own, distinct from the lung's: the organic cation transporter hOCT2 (SLC22A2) and the extrusion transporter hMATE1 both carry paraquat, and expressing either in cells raises both uptake and cytotoxicity by an order of magnitude. Renal failure therefore matters three times over - as organ injury, as the route by which most of an absorbed dose leaves the body, and because the very transporters that clear paraquat are what load the tubular cell with it.

proximal convoluted tubule epithelial cell CL:1000838

hOCT2- and hMATE1-mediated tubular transport of paraquat GO:0055085 ↑ INCREASED

Downstream

Multiorgan Failure and Death Renal failure contributes to the multiorgan course.

Acute Kidney Injury The clinical expression of tubular necrosis.

Oliguria Falling urine output accompanies the fall in filtration.

Show evidence (4 references)

PMID:39239177 SUPPORT Other

"Kidney failure occurs due to necrosis in the proximal convoluted tubule whereas acute liver injury occurs due to damage to the smooth endoplasmic reticulum and mitochondria, the distribution being high in these two organs."

States the proximal tubular necrosis mechanism and the high renal and hepatic distribution.

PMID:39239177 SUPPORT Other

"Though 90% of the compound is excreted in the urine unchanged within 12-24 hours post-exposure, it is the absorbed chemical that manifests the complications, and treatment interventions are aimed at it."

PARTIAL - establishes that urinary excretion is the dominant elimination route, which is the premise for the claim that tubular injury impairs clearance; the source does not itself state that renal injury slows elimination.

PMID:17495125 SUPPORT In Vitro

"We found that overexpression of hOCT2 but not hOCT1 and hOCT3 in HEK-293 cells significantly enhanced the accumulation and cytotoxicity of PQ"

Identifies hOCT2 specifically - and excludes hOCT1 and hOCT3 - as the transporter whose expression raises both paraquat accumulation and cytotoxicity.

+ 1 more reference

Hepatocellular Injury

Acute liver injury from damage to the smooth endoplasmic reticulum and mitochondria of hepatocytes, in which paraquat also distributes highly.

Downstream

Multiorgan Failure and Death Hepatic failure contributes to the multiorgan course.

Acute Liver Injury The clinical expression of hepatocyte injury.

Jaundice Impaired bilirubin handling produces jaundice.

Show evidence (1 reference)

PMID:39239177 SUPPORT Other

States the subcellular targets of hepatic injury and the high hepatic distribution.

Cardiac Involvement

A real but poorly characterised arm, curated at the strength the evidence actually supports. Paraquat causes multiorgan injury including the heart, and dose-dependent falls in heart rate, blood pressure and cardiac contractility are documented in anaesthetised rodents. In humans the picture is thin: the source curated here states plainly that little to no evidence exists on the haemodynamic and cardiac electromechanical effects of acute poisoning, and reports severe bradycardia refractory to anticholinergics as an unusual manifestation.

Downstream

Bradycardia Reported as an unusual manifestation, refractory to chronotropic agents.

Show evidence (2 references)

PMID:38204158 SUPPORT Other

"However, little to no evidence exists on the hemodynamic and cardiac electromechanical effects of acute paraquat poisoning [7]."

PARTIAL by its own content: this is the source establishing that the human cardiac evidence base is close to empty, which is what bounds this node.

PMID:38204158 SUPPORT Model Organism

"Decreases in heart rate, blood pressure, and cardiac contractility have been noted in a dose-dependent manner in anesthetized rodents [7]."

Rodent evidence for dose-dependent cardiac depression - the only mechanistic support this node has, and tagged MODEL_ORGANISM accordingly.

Multiorgan Failure and Death

The convergent outcome. Reported case fatality reaches 90%, and can follow even low doses. There is no antidote with specific effects, so the case fatality reflects the toxicology rather than any failure of supportive care.

Show evidence (1 reference)

PMID:39239177 SUPPORT Other

"In the absence of an antidote, and with a fatality rate as high as 90%, which can occur even with low doses, it continues to be a potential hazard and challenge for clinicians."

Establishes the case fatality and the absence of an antidote.

⬡

Pathograph

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●

Phenotypes

Digestive 4

Acute Liver Injury Acute hepatic failure HP:0006554

Temporal: ACUTE

Bound to `HP:0006554` Acute hepatic failure, which is more severe than the "acute liver injury" the source names. The preferred_term is kept at the source's wording so the entry does not silently upgrade injury to failure; HPO has no acute-liver-injury term short of failure.

Show evidence (1 reference)

PMID:39239177 SUPPORT Other

States acute liver injury and its subcellular mechanism.

Vomiting HP:0002013

Temporal: ACUTE

Show evidence (2 references)

PMID:42266604 SUPPORT Human Clinical

"A 42-year-old male with a history of hypertension and diabetes was admitted to the ICU on December 8, presenting with a 4-day history of vomiting and diarrhea, and a 2-day history of dyspnea and oliguria."

Documents vomiting and diarrhoea as the presenting features.

PMID:42266604 SUPPORT Human Clinical

"Notably, the increasing prevalence of atypical exposure patterns, combined with early nonspecific manifestations such as gastrointestinal and respiratory symptoms, often results in a high misdiagnosis rate during the initial evaluation of occult poisoning."

Supports the claim that the non-specificity of these symptoms drives misdiagnosis, which is why they are curated rather than omitted as generic.

Diarrhea HP:0002014

Temporal: ACUTE

Show evidence (1 reference)

PMID:42266604 SUPPORT Human Clinical

Documents diarrhoea among the presenting features.

Jaundice HP:0000952

Temporal: ACUTE Severity: SEVERE

Show evidence (2 references)

PMID:42266604 SUPPORT Human Clinical

"On examination, he was febrile (37.7 C) with oxygen desaturation (SpO2 79%) and severe jaundice."

Documents severe jaundice on examination.

PMID:42266604 SUPPORT Human Clinical

"Laboratory findings showed acute kidney injury (Cr 1011 μmol/L), hyperbilirubinemia (TBil 203 μmol/L), and hypoxemia (PaO2 65 mmHg)."

Gives the biochemical correlate, and in the same sentence the concurrent acute kidney injury and hypoxaemia of the multiorgan picture.

Genitourinary 2

Acute Kidney Injury HP:0001919

Temporal: ACUTE

Show evidence (2 references)

PMID:39239177 SUPPORT Other

States renal failure and its tubular mechanism.

PMID:42048945 SUPPORT Human Clinical

"A strong association existed between severe PAS and systemic complications like acute kidney injury."

Independent support for acute kidney injury as a systemic complication, and for its co-occurrence with severe mucosal disease.

Oliguria HP:0100520

Temporal: ACUTE

Show evidence (1 reference)

PMID:42266604 SUPPORT Human Clinical

Documents oliguria among the presenting features.

Head and Neck 1

Severe Mucositis Oral ulcer HP:0000155

Temporal: ACUTE Severity: SEVERE

Show evidence (1 reference)

PMID:42048945 SUPPORT Human Clinical

"Severe mucositis (WHO Grade 3-4) increased from 13.9% in patients presenting within 6 h to 58.3% in those presenting at 1-3 days (p = 0.027)."

Quantifies the time dependence. No frequency band is asserted for this phenotype precisely because the figure depends on presentation delay rather than being a fixed property of the poisoning.

Respiratory 4

Pulmonary Fibrosis HP:0002206

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:39239177 SUPPORT Other

"In contrast, severe poisoning can lead to acute kidney failure, acute lung injury, and lung fibrosis resulting in death over 2-3 weeks."

Names lung fibrosis and its two-to-three-week fatal course.

Respiratory Failure HP:0002878

Temporal: ACUTE

Show evidence (1 reference)

PMID:42266604 SUPPORT Human Clinical

"This rapid development of fatal progressive respiratory failure was deduced based on the severe clinical status of the patient at the time of discharge and the established toxicological mechanisms of paraquat‐induced lung injury."

Documents fatal progressive respiratory failure as the terminal event in a poisoned patient. Replaces an earlier snippet that spoke only to overall mortality and, by its own explanation, did not evidence this phenotype.

Acute Respiratory Distress Syndrome HP:0033677

Temporal: ACUTE

Show evidence (1 reference)

PMID:42266604 SUPPORT Human Clinical

"He progressed to severe ARDS within 48 h (PaO2/FiO2 ratio < 100 mmHg, radiographic involvement > 85%), failing lung-protective ventilation."

Documents severe ARDS with its physiological and radiographic criteria.

Dyspnea HP:0002094

Temporal: ACUTE Course: PROGRESSIVE

Show evidence (1 reference)

PMID:42266604 SUPPORT Human Clinical

"A 22-year-old male presented to the emergency department with a 6-day history of progressive chest pain and dyspnea, leading to admission on February 10, 2024."

Documents progressive dyspnoea and chest pain at presentation.

Other 4

Paraquat-Associated Stomatitis FREQUENT HP:0010280

Temporal: ACUTE

Show evidence (2 references)

PMID:42048945 SUPPORT Human Clinical

"Analysis of 170 cases revealed PAS in 78.8% of patients."

Supports the FREQUENT band directly: 78.8% falls inside the 30-79% range, close to its upper edge. From a pooled individual-patient analysis of 170 published cases, so the denominator is a case literature rather than a population - the band is an estimate, not an incidence.

PMID:42048945 SUPPORT Human Clinical

"Anatomically, early presentations (<=6 h) were characterized by focal involvement, predominantly on the tongue (35.8%)."

Supports the early focal, predominantly lingual distribution.

Pneumomediastinum HP:0025421

Temporal: ACUTE

Show evidence (1 reference)

PMID:39239177 SUPPORT Other

"Gastrointestinal toxicity occurs in the form of mucosal lesions which can ulcerate and bleed, sometimes resulting in perforation of the tract and associated mediastinitis and pneumomediastinum."

Names pneumomediastinum as a consequence of tract perforation.

Subcutaneous Emphysema HP:6001021

Temporal: ACUTE

Show evidence (1 reference)

PMID:42266604 SUPPORT Human Clinical

"Physical examination revealed severe respiratory distress and extensive subcutaneous crepitus across the neck and chest."

Documents the clinical sign of subcutaneous emphysema.

Bradycardia Sinus bradycardia HP:0001688

Temporal: ACUTE

Show evidence (3 references)

PMID:38204158 SUPPORT Human Clinical

"On day 3 of hospitalization, the patient developed severe bradycardia, with his heart rate dropping to 35 beats/min."

Case-level documentation of severe bradycardia. Single case, so no frequency is asserted.

PMID:38204158 SUPPORT Human Clinical

"We report a case of bradycardia that was refractory to anticholinergics, which is an unusual clinical manifestation of acute paraquat poisoning."

States both the refractoriness and, explicitly, that this is unusual - which is why no frequency band is given.

PMID:38204158 SUPPORT Human Clinical

"A 12-lead electrocardiogram suggested sinus bradycardia, and the echocardiogram was normal."

Licenses the narrower `HP:0001688` Sinus bradycardia rather than the parent `HP:0001662`: the rhythm was characterised on ECG. The normal echocardiogram in the same sentence is also why this entry does not claim structural cardiac injury.

💊

Medical Actions

Supportive Care Without an Antidote

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

The baseline, and an honest statement of the position: there is no antidote with specific effects for acute paraquat poisoning. Everything else in this section is an attempt to reduce absorbed dose or blunt oxidative injury, and none of it is guideline-backed.

Show evidence (2 references)

PMID:39239177 SUPPORT Other

"There is currently no antidote with specific effects, for acute paraquat poisoning."

States the absence of an antidote directly.

PMID:39239177 SUPPORT Other

"These modalities though, are not based on guidelines or recommendations, and the supporting evidence is also weak, as it has been extrapolated from animal studies and case series in resource-limited settings, which lack information on the severity of the disease."

States that the treatment modalities in this section rest on weak, extrapolated evidence rather than guidelines.

Extracorporeal Elimination (Haemoperfusion and Renal Replacement Therapy)

Action: haemoperfusion and continuous renal replacement therapy Ontology label: Therapeutic Procedure NCIT:C49236

Removal of absorbed paraquat by haemoperfusion, alone or combined with continuous renal replacement therapy. Timing dominates: benefit is reported when performed within four to six hours of ingestion and largely disappears with later presentation, which fits the toxicokinetics - paraquat is taken up into lung against a gradient and retained there as plasma levels fall, so lowering the plasma level late does not retrieve the lung burden already established.

Mechanism Target:

INHIBITS Polyamine-Transporter-Mediated Pulmonary Accumulation — Lowering the circulating concentration early limits how much paraquat the lung can concentrate. The link is to the uptake node rather than to the exposure node because that is the step extracorporeal clearance actually competes with, and it is why the therapeutic window is measured in hours.

Show evidence (1 reference)

PMID:39239177 SUPPORT Other

"Majority of the studies emphasized that hemoperfusion should be performed within 4 hours of ingestion of paraquat, for best results."

PARTIAL - establishes the narrow timing window, which is the observable consequence of competing with pulmonary uptake, but does not itself demonstrate the mechanistic link asserted here.

Show evidence (3 references)

PMID:39239177 SUPPORT Other

"They emphasized the use of hemoperfusion within 6 hours for improved outcome."

Reports better outcome with early haemoperfusion in a 101-patient series.

PMID:39239177 SUPPORT Other

"A systematic review and meta-analysis in Iran in 2022, studied 44 patients where all required mechanical ventilation, and despite hemodialysis, there was no reduction in mortality."

PARTIAL, and deliberately included as a counterweight - a pooled analysis showing no mortality reduction, attributed to delayed presentation. The evidence for extracorporeal elimination is not uniformly positive.

PMID:33050540 REFUTE Human Clinical

"Among acute PQ-poisoned patients, this study found that HP was not associated with increased 60-day survival. Furthermore, neither early HP nor multiple secessions of HP were associated with survival."

REFUTE, and it refutes the specific claim this treatment is built on. A multi-centre study of 213 SIPP-stratified patients found no survival benefit from haemoperfusion, AND no benefit from EARLY haemoperfusion - which contradicts the four-to-six-hour window quoted above from the editorial. Read directly rather than second-hand. The treatment is retained because it remains in use, not because the evidence supports it.

Immunosuppressive Therapy

Action: Pharmacotherapy NCIT:C15986

Agent: methylprednisolone NCIT:C647 cyclophosphamide NCIT:C405

Glucocorticoids (methylprednisolone, dexamethasone) and cyclophosphamide, directed at the inflammatory and fibroproliferative arm rather than at redox cycling - which is why this link targets the alveolar-injury and fibrosis nodes, the same nodes the KNOWLEDGE_GAP on its efficacy attaches to. The evidence is genuinely contested rather than merely thin, and this entry does not record it as effective.

Mechanism Target:

MODULATES Alveolar Epithelial Injury and Cell Death — Aimed at suppressing the inflammatory amplification of alveolar injury. MODULATES because the direction and size of the effect are exactly what is disputed.

Show evidence (1 reference)

PMID:39239177 SUPPORT Other

"Measures for treatment include reducing poison absorption and eliminating absorbed poison, use of antioxidants, anti-inflammatory agents, and immunosuppressants, hemodialysis, and hemoperfusion, along with other supportive care."

PARTIAL - establishes that immunosuppressants are used in this role, without evidencing that they work.

Show evidence (3 references)

PMID:39239177 SUPPORT Other

"However, another three randomized controlled trials compared dexamethasone, methylprednisolone, and cyclophosphamide with standard treatment, and all three showed mortality benefit in the treatment arm compared to the standard treatment."

PARTIAL - randomised evidence of mortality benefit, reported second-hand in an editorial rather than read here in the primary trials. Retained alongside the primary registry evidence below rather than replaced, since it is the entry's record of what the trial literature claims.

PMID:24475310 SUPPORT Human Clinical

"IST significantly increases survival rate (from 24.3% to 29.3%, P<0.001). The combined IST with methylprednisolone, cyclophosphamide and dexamethasone associates with the highest survival rate (48%, P<0.001)."

Primary evidence, read directly rather than through the editorial: a nationwide retrospective cohort of 1811 hemoperfused patients. Note the absolute effect is modest (24.3% to 29.3%) against an overall survival of 26.4%, so this supports use without supporting optimism.

PMID:39239177 REFUTE Other

"They suggested that the efficacy of immunosuppression and antioxidants was anecdotal."

REFUTE - a systematic search of human studies concluding the efficacy is anecdotal, directly contradicting the trial evidence above. Both are recorded so the disagreement is visible in the entry rather than resolved by selection.

Antioxidant Therapy

Action: Pharmacotherapy NCIT:C15986

Vitamin C, vitamin E, N-acetylcysteine and reduced glutathione, directed at the oxidative output of redox cycling. Curated separately from immunosuppression because the two act on different nodes and their evidence is assessed together only by accident of being administered together.

Mechanism Target:

MODULATES Redox Cycling and Catalytic Superoxide Generation — Scavenges the radical output of redox cycling. MODULATES rather than INHIBITS deliberately: because paraquat is regenerated each cycle it produces radicals catalytically, so a stoichiometric scavenger cannot stop the source - only buffer the product.

Show evidence (1 reference)

PMID:39239177 SUPPORT Other

PARTIAL - establishes that antioxidants are used against this mechanism, without evidencing that they work.

Show evidence (1 reference)

PMID:42266604 SUPPORT Human Clinical

"Antioxidants included intravenous reduced glutathione at 2400 mg daily, intravenous vitamin C at 2 g every 12 h, and gastric N-acetylcysteine at 0.6 g every 12 h"

PARTIAL - documents the specific antioxidant regimen given in a case that nonetheless ended fatally, so it evidences use rather than benefit.

Reduction of Absorption

Action: Pharmacotherapy NCIT:C15986

Agent: activated charcoal CHEBI:91090

Gastric lavage and adsorbents to limit the absorbed dose. Rational given the dose dependence of outcome, but subject to the same narrow time window as extracorporeal elimination.

Mechanism Target:

INHIBITS Ingestion of Concentrated Paraquat — Limits how much of an ingested dose reaches the systemic circulation.

Show evidence (1 reference)

PMID:39239177 SUPPORT Other

PARTIAL - names reducing absorption as a treatment aim without quantifying its effect.

Show evidence (1 reference)

PMID:39239177 SUPPORT Other

"It included 109 patients in a tertiary hospital, where all treatment modalities were provided, including gastric lavage, mechanical ventilation, immunosuppression, antioxidants, hemoperfusion, and renal replacement therapy."

PARTIAL - documents gastric lavage as part of the standard bundle in a 109-patient series whose mortality was nonetheless 88%.

Lung Transplantation

Action: lung transplantation Ontology label: Organ Transplantation NCIT:C15289

The only intervention that addresses the lesion that kills survivors. Once fibrosis is established it is irreversible, so transplantation is the definitive rather than the supportive option, with ECMO as a bridge to a donor lung. Reported successfully after paraquat poisoning, including a double-lung transplant on ECMO support 34 days after ingestion with a good outcome. Its limiting factors in the cited cases were not medical: one patient reached transplantation only through publicly raised funds, and in another it was abandoned for want of money.

Mechanism Target:

BYPASSES Progressive Pulmonary Fibrosis — Replaces the fibrotic organ rather than modifying the fibrotic process - the one place in this entry where BYPASSES is the accurate enum, since the graft supplies gas exchange by an entirely different route while the injured lung is removed.

Show evidence (1 reference)

PMID:36626514 SUPPORT Human Clinical

"Lung transplantation is currently the most effective treatment for pulmonary fibrosis, and mass media campaigns can provide economic support, influence potential organ donation, and provide such patients more chances to survive."

States transplantation as the most effective treatment for the fibrotic endpoint this node represents.

Show evidence (3 references)

PMID:36626514 SUPPORT Human Clinical

"The patient received financial assistance; thus, she could receive a double-lung transplant with extracorporeal membrane oxygenation (ECMO) support on the 34th day after the poisoning."

Documents a completed double-lung transplant on ECMO support after paraquat poisoning, and - notably - that access turned on funding rather than on medical eligibility.

PMID:42266604 SUPPORT Human Clinical

"However, lung transplantation was abandoned due to financial constraints experienced by the family, resulting in the voluntary discharge of the patient against medical advice."

PARTIAL - a negative instance rather than evidence of efficacy: it documents transplantation being considered and forgone, which is why the cost barrier is curated in the description rather than left implicit.

PMID:41647033 SUPPORT Human Clinical

"Lung transplantation (LT) remains a rare but life-saving option for end-stage pulmonary fibrosis secondary to paraquat poisoning."

PARTIAL, and included for what it qualifies rather than what it confirms: the same report documents failed extubation from respiratory muscle weakness after successful transplantation, so graft function is not the whole outcome. It also notes a review of 15 previously reported paraquat-related transplant cases, which bounds how much experience exists.

Restrictive Oxygen Strategy

Action: restrictive inspired-oxygen strategy Ontology label: Therapeutic Procedure NCIT:C49236

The counterintuitive one, and the clearest clinical corollary of this entry's redox node: supplemental oxygen is the substrate that reoxidises the paraquat radical, so high inspired oxygen fuels the cycle that is doing the damage. Oxygen is therefore restricted rather than given liberally. It is a genuine trade-off rather than a rule - withholding oxygen delays radical generation at the cost of tissue hypoxia - and the cited source frames it as a ventilator-setting judgement in patients already on ECMO, not as a blanket prohibition.

Mechanism Target:

INHIBITS Redox Cycling and Catalytic Superoxide Generation — Limiting inspired oxygen limits the substrate for reoxidation of the paraquat radical, and so the rate of the cycle itself. This is the only intervention curated here that acts on the redox mechanism rather than on its consequences.

Show evidence (1 reference)

PMID:42266604 SUPPORT Human Clinical

"Although both patients received ECMO support, mechanical ventilation parameter settings need to be carefully weighed: high‐concentration oxygen therapy may exacerbate oxidative stress injury, whereas hypoxic strategies, while delaying ROS generation, may exacerbate tissue hypoxia."

States both halves of the trade-off: high-concentration oxygen worsens oxidative injury, and hypoxic strategies delay radical generation but worsen tissue hypoxia.

Show evidence (1 reference)

PMID:42266604 SUPPORT Human Clinical

The source's own statement of the oxygen trade-off in paraquat poisoning.

🌍

Environmental Factors

Ingestion of concentrated paraquat herbicide

`ECTO:9000395` is route-agnostic and is chosen over the route-specific siblings `ECTO:0090011` (in air), `ECTO:0090012` (in soil) and `ECTO:0090013` (in water), none of which describes ingestion. A full label scan of ECTO for `paraquat` returned exactly these four plus `ECTO:9001210` exposure to paraquat dichloride; there is no ingestion-route paraquat term.

The dominant exposure route in fatal cases. Paraquat is cheap, widely available in agricultural communities, and highly toxic, which is the combination that makes it a leading agent of fatal pesticide self-poisoning. Cutaneous and mucosal contact are also reported routes.

Show evidence (2 references)

PMID:18161502 SUPPORT Other

"However, over the last decades, there have been numerous fatalities, mainly caused by accidental or voluntary ingestion."

Establishes ingestion as the route producing fatalities.

PMID:18154668 SUPPORT Human Clinical

"it is the pattern of pesticide use and the toxicity of the products, not the quantity used, that influences the likelihood they will be used in acts of fatal self-harm."

PARTIAL - this systematic review is about pesticide self-poisoning as a class rather than paraquat specifically, but it establishes product toxicity and availability, not volume sold, as what drives fatal use, which is the rationale for paraquat's prominence and for the bans described here.

Mechanism Target:

TRIGGERS Ingestion of Concentrated Paraquat — Ingesting a concentrated formulation is the route by which a lethal systemic dose is delivered.

Show evidence (1 reference)

PMID:39239177 SUPPORT Other

"Self-ingestion or cutaneous/mucosal contact can rapidly lead to multiorgan failure involving the respiratory, liver, and renal systems."

Links the exposure routes directly to the multiorgan failure this entry curates.

Occult inhalational exposure by nebulisation

Bound to the same route-agnostic `ECTO:9000395` as the ingestion entry, since ECTO has no inhalational paraquat term either; `ECTO:0090011` exposure to paraquat in air denotes ambient air, not deliberate nebulisation, and would misdescribe this route.

A rare and diagnostically treacherous route: paraquat solution delivered by a personal nebulisation device. It is curated because it breaks the assumptions the usual diagnostic pathway rests on - there is no caustic oral injury to see, the exposure history is denied or absent, and an initial urine paraquat test can be negative. The diagnosis in the cited case was made only by analysing residue from the device itself.

Show evidence (2 references)

PMID:42266604 SUPPORT Human Clinical

"Analysis of the residual solution from his nebulization device confirmed the presence of methyl viologen, the active component of paraquat, establishing the diagnosis of inhaled paraquat poisoning via nebulization."

Documents the nebulised inhalational route and how the diagnosis was finally established.

PMID:42266604 SUPPORT Human Clinical

"Although an initial urine paraquat test yielded a negative result, a subsequent targeted investigation of the patient's personal items revealed a video documenting inhalation of an unknown substance."

Supports the specific diagnostic trap recorded here - a negative initial urine screen in a genuinely poisoned patient.

Mechanism Target:

TRIGGERS Alveolar Epithelial Injury and Cell Death — Aerosol deposition reaches the terminal bronchioles and alveolar lumen directly and destroys alveolar epithelium at the site of deposition, without the systemic distribution step that ingestion requires. Note this is a shortcut in DELIVERY, not a bypass of transport: the same source says absorption then proceeds through epithelial active transport mechanisms, so the uptake machinery is still involved and the link is not curated as circumventing it.

Show evidence (2 references)

PMID:42266604 SUPPORT Human Clinical

"During aerosolized inhalation, the aerodynamic deposition of toxic fine particles allows them to reach the terminal bronchioles and alveolar lumen directly."

States the direct aerodynamic deposition at the alveolar lumen.

PMID:42266604 SUPPORT Human Clinical

"This localized deposition causes immediate alveolar epithelial cell destruction and massive pulmonary accumulation while bypassing hepatic first pass metabolism."

States immediate alveolar epithelial destruction, which is what justifies targeting the injury node rather than the systemic-accumulation node.

🔬

Diagnosis

Severity Index of Paraquat Poisoning (SIPP)

Plasma paraquat concentration multiplied by hours since ingestion. It is the most-used prognostic index in this poisoning, and its two inputs are exactly the two variables this entry's mechanism section says govern outcome - dose and time - which is why it earns a place here rather than being left to a guideline. It predicts acute kidney injury independently of other admission variables.

Show evidence (2 references)

PMID:28881652 SUPPORT Human Clinical

"Multivariate logistic regression indicated that acute hepatitis (P < 0.001), a longer time to hospital arrival (P < 0.001), higher SIPP score (P = 0.026) and higher PaO2 at admission (P = 0.014) were predictors of AKI."

Establishes SIPP as an independent predictor of acute kidney injury in 222 patients, alongside time to arrival - both dose-and-time proxies.

PMID:33050540 SUPPORT Human Clinical

"We used the Severity Index of Paraquat Poisoning (SIPP) to stratify the severity of PQ-poisoned patients."

Independent confirmation that SIPP is the working severity stratifier in clinical studies of this poisoning.

Semiquantitative urine paraquat (dithionite) test

A bedside colorimetric screen used to confirm exposure and to gate treatment decisions. Its limitation is curated deliberately: it can be negative early in a genuinely poisoned patient, which is one of the traps recorded on the occult inhalational exposure route in this entry.

Show evidence (2 references)

PMID:33050540 SUPPORT Human Clinical

"The indication to start HP was a positive result for the semiquantitative urine PQ test and presentation to the hospital was within 24 h."

Documents the urine test being used as the operational gate for starting extracorporeal treatment.

PMID:42266604 SUPPORT Human Clinical

PARTIAL and included as the counterweight: a false-negative urine screen in a patient who was in fact poisoned.

Admission mortality-prediction nomogram

A multivariable model built on 724 patients, using variables available within 24 hours of admission. Notable for what it selects: alongside plasma paraquat concentration it picks creatinine and alanine aminotransferase - the renal and hepatic arms this entry curates - and conscious level, so the model is effectively scoring the multiorgan chain rather than the toxin alone.

Curated as a prognostic tool, not a validated one. The authors state it needs further external validation, and that qualification is preserved here rather than dropped.

Show evidence (1 reference)

DOI:10.1038/s41598-023-50722-z SUPPORT Human Clinical

"In the training cohort, decreased level of consciousness (Glasgow Coma Scale score < 15), neutrophil-to-lymphocyte ratio, alanine aminotransferase, creatinine, carbon dioxide combining power, and paraquat plasma concentrations at admission were identified as independent predictors of in-hospital..."

PARTIAL - names the selected predictors, but the same paper states the model requires further external validation before clinical use, so this supports the variables rather than the tool's readiness.

{ }

Source YAML

click to show

name: Paraquat Poisoning
creation_date: "2026-08-22T18:00:00Z"
category: Environmental
categories:
- Toxic Exposure Disorder
- Pesticide Poisoning
- Environmental Health Disorder
synonyms:
- paraquat intoxication
- paraquat dichloride poisoning
- methyl viologen poisoning
description: >-
  Paraquat poisoning is intoxication by the non-selective bipyridylium herbicide
  paraquat (methyl viologen), most often after deliberate ingestion of a
  concentrated formulation. Two properties make it exceptionally lethal. First,
  paraquat is accumulated against a concentration gradient into lung epithelium
  by the polyamine transport system, reaching pulmonary concentrations six to ten
  times those in plasma and being retained there as blood levels fall - which is
  why the lung is the principal target organ despite the exposure being systemic.
  Second, once inside the cell it undergoes redox cycling: one-electron reduction
  to a cation radical followed by reoxidation by molecular oxygen, which
  regenerates the parent compound and so generates superoxide catalytically
  rather than stoichiometrically, consuming reducing equivalents as it goes. The
  illness is biphasic - caustic oropharyngeal and gastrointestinal injury with
  acute kidney and liver failure in the first days, then a delayed
  fibroproliferative phase in which survivors develop progressive pulmonary
  fibrosis and die of respiratory failure over two to three weeks. There is no
  antidote, and reported case fatality reaches 90%.
disease_term:
  preferred_term: paraquat poisoning
  term:
    id: MONDO:0017862
    label: paraquat poisoning
notes: >-
  MONDO records the causative chemical directly on this term as
  `RO:0004028 CHEBI:34905 ! paraquat`, so the agent is already machine-queryable
  from the disease term and is not duplicated into a `mappings` block - the
  `DiseaseMappings` class has no chemical slot in any case.

  No `prevalence:` record is curated. The only occurrence figure located is a
  systematic-review estimate of 258,234 deaths per year from pesticide
  self-poisoning worldwide, about 30% of global suicides (PMID:18154668) - but
  that counts ALL pesticides, of which paraquat is one prominent agent, so
  recording it as this disease's prevalence would misattribute it. An earlier
  draft did record it with the scope written into the `population` field, which
  CLAUDE.md reserves for cohort and geography; that was a category error dressed
  up as a caveat. The class-level figure is kept here as context instead.
  Orphanet (`Orphanet:31827`, xrefed from MONDO:0017862) would be the right
  source for a paraquat-specific prevalence class, but no `ORPHA_31827.md` is
  present in `references_cache/`; `just structured-rebuild-orphanet --id 31827`
  is the way to obtain one.
pathophysiology:
- name: Ingestion of Concentrated Paraquat
  biological_scale: ORGANISM
  description: >-
    The exposure event. Deaths follow accidental or deliberate ingestion of
    concentrated herbicide formulations; cutaneous and mucosal contact are also
    reported routes. Dose sets the tempo rather than merely the severity:
    fulminant poisoning above roughly 40 mg/kg kills within two to three days,
    while lower doses produce the slower fibrotic course. Paraquat is a leading
    agent in the wider problem of fatal pesticide self-poisoning, which the
    global literature places at roughly a third of all suicides worldwide.
  notes: >-
    Carries no ontology-bound process descriptor by design - this node denotes an
    exposure event rather than a host biological process, and no GO term
    describes it. The exposure is grounded through ECTO in the `environmental:`
    block instead.
  downstream:
  - target: Caustic Oropharyngeal and Gastrointestinal Injury
    description: >-
      Direct contact of concentrated herbicide with mucosal surfaces on the way
      down.
  - target: Polyamine-Transporter-Mediated Pulmonary Accumulation
    description: >-
      Absorbed paraquat is delivered systemically and concentrated by lung
      epithelium.
  evidence:
  - reference: PMID:18161502
    reference_title: "Paraquat poisonings: mechanisms of lung toxicity, clinical features, and treatment."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "However, over the last decades, there have been numerous fatalities, mainly caused by accidental or voluntary ingestion."
    explanation: Establishes ingestion as the route producing fatal poisoning.
  - reference: PMID:39239177
    reference_title: "Management of Paraquat Poisoning-The Way Forward."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Self-ingestion or cutaneous/mucosal contact can rapidly lead to multiorgan failure involving the respiratory, liver, and renal systems."
    explanation: Names the routes of exposure and the organ systems they reach.
  - reference: PMID:39239177
    reference_title: "Management of Paraquat Poisoning-The Way Forward."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "However, patients with fulminant poisoning (more than 40 mg per kg body weight) can develop complications within hours and die in 2-3 days."
    explanation: >-
      Supports the dose-dependent tempo: above roughly 40 mg/kg the illness is
      fulminant rather than fibrotic.
- name: Caustic Oropharyngeal and Gastrointestinal Injury
  biological_scale: TISSUE
  description: >-
    Direct corrosive injury where concentrated herbicide contacts mucosa. It
    begins focally, most often on the tongue, and with delay becomes multifocal
    and diffuse, involving buccal mucosa and then oropharynx and oesophagus.
    Lesions ulcerate and bleed, and can perforate the tract with consequent
    mediastinitis and pneumomediastinum. This arm is not merely cosmetic - severe
    mucositis is associated with systemic complications including acute kidney
    injury, which is what makes the oral findings prognostically informative.
  biological_processes:
  - preferred_term: mucosal ulceration and necrosis following caustic contact
    modifier: INCREASED
    term:
      id: GO:0008219
      label: cell death
  downstream:
  - target: Paraquat-Associated Stomatitis
    description: The oral expression of caustic mucosal injury.
  - target: Pneumomediastinum
    description: >-
      Perforation of the ulcerated tract allows air into the mediastinum.
  - target: Subcutaneous Emphysema
    description: >-
      Air tracking from the mediastinum reaches the cervical and thoracic soft
      tissues.
  - target: Proximal Tubular Injury and Acute Kidney Injury
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Severe mucosal disease travels with acute kidney injury. Marked INDIRECT
      because the cited evidence is an association across pooled cases, not a
      demonstrated causal route - the shared driver is most likely ingested dose.
  - target: Severe Mucositis
    description: The higher-grade expression of the same mucosal lesion.
  - target: Vomiting
    description: Mucosal irritation drives early emesis.
  - target: Diarrhea
    description: Mucosal injury extends through the gastrointestinal tract.
  evidence:
  - reference: PMID:39239177
    reference_title: "Management of Paraquat Poisoning-The Way Forward."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Gastrointestinal toxicity occurs in the form of mucosal lesions which can ulcerate and bleed, sometimes resulting in perforation of the tract and associated mediastinitis and pneumomediastinum."
    explanation: States the ulceration, bleeding and perforation this node asserts.
  - reference: PMID:42048945
    reference_title: "The natural history of paraquat-associated stomatitis: A four-stage model."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "With increasing treatment delay, lesions progressed to a multifocal and diffuse pattern, significantly involving the buccal mucosa (Absolute Risk Difference, ARD: 55.6%; p = 0.049) and oropharynx/oesophagus."
    explanation: >-
      Supports the focal-to-diffuse anatomical progression described here, from a
      pooled individual-patient analysis of 170 cases.
  - reference: PMID:42048945
    reference_title: "The natural history of paraquat-associated stomatitis: A four-stage model."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A strong association existed between severe PAS and systemic complications like acute kidney injury."
    explanation: >-
      Supports the claim that the mucosal arm tracks systemic toxicity rather
      than being an isolated local effect.
- name: Polyamine-Transporter-Mediated Pulmonary Accumulation
  biological_scale: CELLULAR
  description: >-
    The reason the lung is the target organ. Paraquat is a substrate of the
    polyamine transport system, which is abundantly expressed in the membranes of
    alveolar type I and type II cells and Clara (club) cells. Transport is
    against the concentration gradient, so pulmonary concentrations reach six to
    ten times plasma levels, and - critically for treatment timing - paraquat is
    retained in lung even once blood levels begin to fall. This is why measures
    that lower the plasma level late have limited effect on the lung burden
    already established.
  cell_types:
  - preferred_term: alveolar type I cell
    term:
      id: CL:0002062
      label: pulmonary alveolar type 1 cell
  - preferred_term: alveolar type II cell
    term:
      id: CL:0002063
      label: pulmonary alveolar type 2 cell
  - preferred_term: Clara (club) cell
    term:
      id: CL:0000158
      label: club cell
  biological_processes:
  - preferred_term: polyamine transport system-mediated uptake of paraquat
    modifier: INCREASED
    term:
      id: GO:1902047
      label: polyamine transmembrane transport
  molecular_functions:
  - preferred_term: polyamine transporter accepting paraquat as a substrate
    term:
      id: GO:0015203
      label: polyamine transmembrane transporter activity
  downstream:
  - target: Redox Cycling and Catalytic Superoxide Generation
    description: >-
      Intracellular paraquat becomes the substrate for catalytic redox cycling.
  evidence:
  - reference: PMID:18161502
    reference_title: "Paraquat poisonings: mechanisms of lung toxicity, clinical features, and treatment."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "PQ mainly accumulates in the lung (pulmonary concentrations can be 6 to 10 times higher than those in the plasma), where it is retained even when blood levels start to decrease."
    explanation: >-
      Quantifies the pulmonary accumulation and states the retention that
      persists as plasma levels fall.
  - reference: PMID:18161502
    reference_title: "Paraquat poisonings: mechanisms of lung toxicity, clinical features, and treatment."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The pulmonary effects can be explained by the participation of the polyamine transport system abundantly expressed in the membrane of alveolar cells type I, II, and Clara cells."
    explanation: >-
      Names the transporter and the three cell types, which is what the cell_type
      bindings on this node encode.
- name: Redox Cycling and Catalytic Superoxide Generation
  biological_scale: MOLECULAR
  description: >-
    The rate-limiting molecular lesion. Paraquat undergoes one-electron reduction
    to a cation radical, which is reoxidised by molecular oxygen; the reoxidation
    regenerates the parent paraquat cation and releases superoxide. Because the
    toxicant is regenerated, one paraquat molecule generates reactive oxygen
    species catalytically rather than being consumed, which is why very small
    intracellular quantities are lethal and why no stoichiometric scavenger has
    succeeded as an antidote. The cycle also consumes reducing equivalents,
    compounding oxidative injury with a loss of antioxidant reserve. The reduction is
    localised: paraquat is carried into the mitochondrial matrix in a
    membrane-potential-dependent manner as the dication rather than the radical,
    and is there reduced principally by complex I in mammalian mitochondria.
  notes: >-
    The node name is deliberately cofactor-agnostic. An earlier draft called it
    "NADPH-Dependent", which was wrong twice over: mammalian complex I is
    NADH:ubiquinone oxidoreductase (`GO:0008137` NADH dehydrogenase (ubiquinone)
    activity), and the cited abstract puts NADPH on the *yeast* side of the same
    sentence - "reduced by complex I (mammals) or by NADPH dehydrogenases
    (yeast)". The name therefore asserted the one cofactor this entry declines to
    curate and mislabelled the one it does. Two reduction sites are reported and
    they are complementary rather than competing: mitochondrial complex I, localised experimentally in isolated
    mitochondria, and NADPH oxidase, emphasised in the clinical literature. This
    entry curates complex I on the node because that is where the direct
    experimental evidence sits, and records the NADPH oxidase claim here rather
    than binding it, since the source asserting it is a two-patient case report
    citing secondary literature.
  biological_processes:
  - preferred_term: catalytic superoxide generation by paraquat redox cycling
    modifier: INCREASED
    term:
      id: GO:0042554
      label: superoxide anion generation
  - preferred_term: overwhelmed cellular oxidative stress response
    modifier: INCREASED
    term:
      id: GO:0006979
      label: response to oxidative stress
  downstream:
  - target: Alveolar Epithelial Injury and Cell Death
    description: >-
      Sustained radical generation inside lung epithelium exceeds antioxidant
      capacity.
  - target: Proximal Tubular Injury and Acute Kidney Injury
    description: >-
      The same redox chemistry operates in the proximal tubule, where paraquat
      also distributes highly.
  - target: Cardiac Involvement
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Paraquat causes multiorgan injury including the heart, and the same redox
      chemistry is the presumed route. Marked INDIRECT_UNKNOWN_INTERMEDIATES
      deliberately: no human study localises cardiac injury to redox cycling, so
      this connects the node to the graph without asserting the mechanism the
      accompanying KNOWLEDGE_GAP says is unestablished.
  - target: Hepatocellular Injury
    description: >-
      And in hepatocytes, damaging smooth endoplasmic reticulum and mitochondria.
  evidence:
  - reference: PMID:18161502
    reference_title: "Paraquat poisonings: mechanisms of lung toxicity, clinical features, and treatment."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Further downstream at the toxicodynamic level, the main molecular mechanism of PQ toxicity is based on redox cycling and intracellular oxidative stress generation."
    explanation: Identifies redox cycling as the principal molecular mechanism.
  - reference: PMID:39239177
    reference_title: "Management of Paraquat Poisoning-The Way Forward."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Paraquat exerts its toxic and lethal effects by forming cation radicals post-metabolism, subsequently generating free oxygen radicals, leading to mitochondrial damage and apoptosis."
    explanation: >-
      States the cation radical intermediate and the downstream radical
      generation, mitochondrial damage and apoptosis.
  - reference: PMID:18039652
    reference_title: "Complex I is the major site of mitochondrial superoxide production by paraquat."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Experiments with disrupted mitochondria showed that once in the matrix paraquat was principally reduced by complex I (mammals) or by NADPH dehydrogenases (yeast) to form the paraquat radical cation that then reacted with oxygen to form superoxide."
    explanation: >-
      Localises the one-electron reduction to mitochondrial complex I in mammals
      and states the radical-then-superoxide sequence this node asserts.
  - reference: PMID:18039652
    reference_title: "Complex I is the major site of mitochondrial superoxide production by paraquat."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "This paraquat-induced superoxide production in the mitochondrial matrix required a membrane potential that was essential for paraquat uptake into mitochondria."
    explanation: >-
      Establishes a second, membrane-potential-dependent transport step that
      concentrates paraquat inside mitochondria before reduction, so the
      selectivity story has two tiers - cellular, then subcellular.
- name: Alveolar Epithelial Injury and Cell Death
  biological_scale: CELLULAR
  description: >-
    Oxidative injury to the alveolar epithelium, expressed as alveolitis and
    alveolar damage with mitochondrial injury and cell death. Cell death here is
    not apoptosis alone: rat work implicates ferroptosis - iron-dependent lipid
    peroxidative death - driven by Keap1 upregulation and Nrf2 degradation, which
    connects the redox arm to the fibrotic one through a distinct death
    programme. This is the destructive phase that precedes and licenses the
    fibrotic one.
  cell_types:
  - preferred_term: pulmonary alveolar epithelial cell
    term:
      id: CL:0000322
      label: pulmonary alveolar epithelial cell
  biological_processes:
  - preferred_term: oxidative-stress-driven apoptosis of alveolar epithelium
    modifier: INCREASED
    term:
      id: GO:0008631
      label: intrinsic apoptotic signaling pathway in response to oxidative stress
  - preferred_term: iron-dependent lipid peroxidative cell death (ferroptosis)
    modifier: INCREASED
    term:
      id: GO:0097707
      label: ferroptosis
  downstream:
  - target: TGF-beta-Driven Mesenchymal Transition of Alveolar Epithelium
    description: >-
      Surviving epithelium at sublethal exposure transforms rather than dies.
  - target: Acute Respiratory Distress Syndrome
    description: >-
      Diffuse alveolar injury presents clinically as ARDS, days before the
      fibrotic phase.
  evidence:
  - reference: PMID:39239177
    reference_title: "Management of Paraquat Poisoning-The Way Forward."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Lungs are affected the most as the chemical is sequestrated here due to the concentration gradient, and alveolitis, alveolar damage, and fibrosis set in."
    explanation: >-
      States the alveolitis and alveolar damage of this node and its progression
      to fibrosis.
  - reference: PMID:39239177
    reference_title: "Management of Paraquat Poisoning-The Way Forward."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Paraquat exerts its toxic and lethal effects by forming cation radicals post-metabolism, subsequently generating free oxygen radicals, leading to mitochondrial damage and apoptosis."
    explanation: >-
      Carries the mitochondrial-damage and apoptosis claim this node's
      description and its `GO:0008631` binding rest on. The same sentence also
      evidences the upstream redox node; it is repeated here rather than left
      one node away from the claim it supports.
  - reference: PMID:37812357
    reference_title: "Molecular mechanism of paraquat-induced ferroptosis leading to pulmonary fibrosis mediated by Keap1/Nrf2 signaling pathway."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Our results suggest that PQ can regulate Keap1/Nrf2 signaling pathway, leading to increased lipid peroxidation and abnormal iron uptake, thereby inducing iron death and exacerbating the progression of pulmonary fibrosis."
    explanation: >-
      Rat evidence for ferroptosis as a second death programme linking oxidative
      injury to fibrosis, and the basis for the `GO:0097707` binding. Tagged
      MODEL_ORGANISM: no human data establish this arm.
- name: TGF-beta-Driven Mesenchymal Transition of Alveolar Epithelium
  biological_scale: CELLULAR
  description: >-
    The step that converts injury into fibrosis, and it is dose-dependent in a
    way that matters clinically. In alveolar epithelial cells, short high-dose
    paraquat causes apoptotic death, whereas prolonged low-dose exposure instead
    drives transformation into spindle-shaped mesenchymal-like cells that lose
    E-cadherin, gain alpha-smooth muscle actin and secrete fibronectin. The
    transformation is TGF-beta1-dependent - a receptor antagonist abolishes it -
    and it confers resistance to cell death, so the cells that survive are
    precisely the ones that make matrix. This is why subacute, lower-dose
    poisoning produces the delayed fibrotic course rather than simply a milder
    version of the fulminant one.
  conforms_to: "fibrotic_response#Mesenchymal Cell Activation"
  cell_types:
  - preferred_term: alveolar epithelial cell undergoing mesenchymal transition
    term:
      id: CL:0000322
      label: pulmonary alveolar epithelial cell
  - preferred_term: myofibroblast-like cell
    term:
      id: CL:0000186
      label: myofibroblast cell
  biological_processes:
  - preferred_term: EMT-like transformation of alveolar epithelium
    modifier: INCREASED
    term:
      id: GO:0001837
      label: epithelial to mesenchymal transition
  - preferred_term: TGF-beta1 signalling driving the transition
    modifier: INCREASED
    term:
      id: GO:0007179
      label: transforming growth factor beta receptor signaling pathway
  notes: >-
    Entirely in-vitro: A549 and normal human bronchial epithelial cells. It is
    wired into the human causal chain nonetheless - unlike the rodent arms
    declined in other entries - because the dose-and-duration dependence it
    demonstrates is what explains the biphasic clinical course this entry curates,
    and the authors state the model reflects the etiology of human poisoning.
    A curator who disagrees with that judgement should detach the edge rather
    than delete the node.
  downstream:
  - target: Progressive Pulmonary Fibrosis
    description: >-
      Mesenchymal-like cells secrete the extracellular matrix that becomes
      fibrosis.
  evidence:
  - reference: PMID:25799450
    reference_title: "Paraquat induces epithelial-mesenchymal transition-like cellular response resulting in fibrogenesis and the prevention of apoptosis in human pulmonary epithelial cells."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In contrast, long-term (6-12 days) low-dose (30 μM) treatments with PQ resulted in a transformation into spindle-shaped mesenchymal-like cells with a decrease of E-cadherin as well as an increase of α-smooth muscle actin"
    explanation: >-
      States the mesenchymal transformation and its marker shift, and pins it to
      the low-dose long-duration condition rather than to high-dose exposure.
  - reference: PMID:25799450
    reference_title: "Paraquat induces epithelial-mesenchymal transition-like cellular response resulting in fibrogenesis and the prevention of apoptosis in human pulmonary epithelial cells."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The administration of a TGF-β1 receptor antagonist, SB431542, almost completely attenuated the mesenchymal transformation as well as fibronectin secretion, suggesting a crucial role of TGF-β1 in EMT-like cellular response and subsequent fibrogenesis."
    explanation: >-
      Establishes TGF-beta1 dependence by antagonist rescue, which is what
      licenses the GO:0007179 binding on this node.
- name: Progressive Pulmonary Fibrosis
  biological_scale: TISSUE
  conforms_to: "fibrotic_response#Excessive ECM Deposition"
  description: >-
    The delayed fibroproliferative phase, and the characteristic cause of death
    in patients who survive the acute multiorgan insult. Fibrosis obliterates the
    gas-exchange surface over two to three weeks, producing progressive
    respiratory failure. Its delayed onset is what makes paraquat poisoning
    unusual among acute toxidromes: a patient can appear to stabilise and still
    die of the exposure a fortnight later.
  biological_processes:
  - preferred_term: fibrotic extracellular matrix deposition in the alveolar wall
    modifier: INCREASED
    term:
      id: GO:0030198
      label: extracellular matrix organization
  - preferred_term: collagen fibril deposition
    modifier: INCREASED
    term:
      id: GO:0030199
      label: collagen fibril organization
  downstream:
  - target: Multiorgan Failure and Death
    description: >-
      Loss of gas-exchange surface produces terminal respiratory failure.
  - target: Pulmonary Fibrosis
    description: The radiological and histological expression of this node.
  - target: Respiratory Failure
    description: Loss of gas-exchange surface produces respiratory failure.
  - target: Dyspnea
    description: Falling compliance and gas exchange are felt as breathlessness.
  evidence:
  - reference: PMID:39239177
    reference_title: "Management of Paraquat Poisoning-The Way Forward."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "In contrast, severe poisoning can lead to acute kidney failure, acute lung injury, and lung fibrosis resulting in death over 2-3 weeks."
    explanation: >-
      Establishes lung fibrosis as the delayed cause of death and gives the
      two-to-three-week interval.
- name: Proximal Tubular Injury and Acute Kidney Injury
  biological_scale: TISSUE
  description: >-
    Necrosis of the proximal convoluted tubule, where paraquat distribution is
    high. The kidney concentrates paraquat by an active transport route of its
    own, distinct from the lung's: the organic cation transporter hOCT2 (SLC22A2)
    and the extrusion transporter hMATE1 both carry paraquat, and expressing
    either in cells raises both uptake and cytotoxicity by an order of magnitude.
    Renal failure therefore matters three times over - as organ injury, as the
    route by which most of an absorbed dose leaves the body, and because the very
    transporters that clear paraquat are what load the tubular cell with it.
  cell_types:
  - preferred_term: proximal convoluted tubule epithelial cell
    term:
      id: CL:1000838
      label: kidney proximal convoluted tubule epithelial cell
  biological_processes:
  - preferred_term: hOCT2- and hMATE1-mediated tubular transport of paraquat
    modifier: INCREASED
    term:
      id: GO:0055085
      label: transmembrane transport
  notes: >-
    Two ontology limitations, both recorded so a later curator does not read them
    as oversights. First, no molecular_function descriptor is bound for the
    transporter itself: every GO organic-cation-transmembrane-transporter-activity
    term is obsolete (`GO:0015101`, `GO:0008513`). Second, the natural process
    term `GO:0015695` organic cation transport is ALSO obsolete in current GO -
    OLS returns its label as `obsolete organic cation transport` - so the dynamic
    enum was right to reject it, and `GO:0055085` transmembrane transport is
    bound instead with a specific preferred_term. Recorded because the local
    `sqlite:obo:go` build used for lookups here is stale: it still reports
    `GO:0015695` as live, with an `is_a GO:0006810` parent and no deprecation
    axiom. An earlier draft of this note trusted that build and wrongly blamed a
    gap in the enum's membership cache. One local OAK build is not sufficient
    evidence that a term is live - cross-check obsoletion against OLS or against
    the label the term validator itself writes into `cache/`, which is what
    caught this.
  downstream:
  - target: Multiorgan Failure and Death
    description: Renal failure contributes to the multiorgan course.
  - target: Acute Kidney Injury
    description: The clinical expression of tubular necrosis.
  - target: Oliguria
    description: Falling urine output accompanies the fall in filtration.
  evidence:
  - reference: PMID:39239177
    reference_title: "Management of Paraquat Poisoning-The Way Forward."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Kidney failure occurs due to necrosis in the proximal convoluted tubule whereas acute liver injury occurs due to damage to the smooth endoplasmic reticulum and mitochondria, the distribution being high in these two organs."
    explanation: >-
      States the proximal tubular necrosis mechanism and the high renal and
      hepatic distribution.
  - reference: PMID:39239177
    reference_title: "Management of Paraquat Poisoning-The Way Forward."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Though 90% of the compound is excreted in the urine unchanged within 12-24 hours post-exposure, it is the absorbed chemical that manifests the complications, and treatment interventions are aimed at it."
    explanation: >-
      PARTIAL - establishes that urinary excretion is the dominant elimination
      route, which is the premise for the claim that tubular injury impairs
      clearance; the source does not itself state that renal injury slows
      elimination.
  - reference: PMID:17495125
    reference_title: "Transport of paraquat by human organic cation transporters and multidrug and toxic compound extrusion family."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We found that overexpression of hOCT2 but not hOCT1 and hOCT3 in HEK-293 cells significantly enhanced the accumulation and cytotoxicity of PQ"
    explanation: >-
      Identifies hOCT2 specifically - and excludes hOCT1 and hOCT3 - as the
      transporter whose expression raises both paraquat accumulation and
      cytotoxicity.
  - reference: PMID:17495125
    reference_title: "Transport of paraquat by human organic cation transporters and multidrug and toxic compound extrusion family."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Because PQ is primarily eliminated in the kidney, renal elimination, including tubular transport, plays a critical role in controlling systemic exposure to the herbicide."
    explanation: >-
      Supports the dual role of renal tubular transport in both eliminating
      paraquat and exposing the tubular cell to it.
- name: Hepatocellular Injury
  biological_scale: TISSUE
  description: >-
    Acute liver injury from damage to the smooth endoplasmic reticulum and
    mitochondria of hepatocytes, in which paraquat also distributes highly.
  downstream:
  - target: Multiorgan Failure and Death
    description: Hepatic failure contributes to the multiorgan course.
  - target: Acute Liver Injury
    description: The clinical expression of hepatocyte injury.
  - target: Jaundice
    description: Impaired bilirubin handling produces jaundice.
  evidence:
  - reference: PMID:39239177
    reference_title: "Management of Paraquat Poisoning-The Way Forward."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Kidney failure occurs due to necrosis in the proximal convoluted tubule whereas acute liver injury occurs due to damage to the smooth endoplasmic reticulum and mitochondria, the distribution being high in these two organs."
    explanation: >-
      States the subcellular targets of hepatic injury and the high hepatic
      distribution.
- name: Cardiac Involvement
  biological_scale: TISSUE
  description: >-
    A real but poorly characterised arm, curated at the strength the evidence
    actually supports. Paraquat causes multiorgan injury including the heart, and
    dose-dependent falls in heart rate, blood pressure and cardiac contractility
    are documented in anaesthetised rodents. In humans the picture is thin: the
    source curated here states plainly that little to no evidence exists on the
    haemodynamic and cardiac electromechanical effects of acute poisoning, and
    reports severe bradycardia refractory to anticholinergics as an unusual
    manifestation.
  notes: >-
    The deep-research report for this entry asserts that cardiogenic or
    circulatory collapse is "the dominant fatal mechanism in the fulminant form".
    That claim is NOT curated, and the node is deliberately not placed on a fatal
    path. No source located for this entry supports it, and the one human source
    that addresses the question directly says the opposite - that the cardiac
    effects of acute paraquat poisoning are close to uncharacterised. Treating a
    deep-research assertion as evidence is exactly what the DR SOP warns against;
    see the accompanying KNOWLEDGE_GAP.
  downstream:
  - target: Bradycardia
    description: >-
      Reported as an unusual manifestation, refractory to chronotropic agents.
  evidence:
  - reference: PMID:38204158
    reference_title: "Unraveling the link between severe bradycardia and paraquat poisoning."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "However, little to no evidence exists on the hemodynamic and cardiac electromechanical effects of acute paraquat poisoning [7]."
    explanation: >-
      PARTIAL by its own content: this is the source establishing that the human
      cardiac evidence base is close to empty, which is what bounds this node.
  - reference: PMID:38204158
    reference_title: "Unraveling the link between severe bradycardia and paraquat poisoning."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Decreases in heart rate, blood pressure, and cardiac contractility have been noted in a dose-dependent manner in anesthetized rodents [7]."
    explanation: >-
      Rodent evidence for dose-dependent cardiac depression - the only
      mechanistic support this node has, and tagged MODEL_ORGANISM accordingly.
- name: Multiorgan Failure and Death
  biological_scale: ORGANISM
  description: >-
    The convergent outcome. Reported case fatality reaches 90%, and can follow
    even low doses. There is no antidote with specific effects, so the case
    fatality reflects the toxicology rather than any failure of supportive care.
  evidence:
  - reference: PMID:39239177
    reference_title: "Management of Paraquat Poisoning-The Way Forward."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "In the absence of an antidote, and with a fatality rate as high as 90%, which can occur even with low doses, it continues to be a potential hazard and challenge for clinicians."
    explanation: Establishes the case fatality and the absence of an antidote.
phenotypes:
- category: Oral
  name: Paraquat-Associated Stomatitis
  description: >-
    Oral mucosal ulceration ("paraquat tongue"), the most consistent early
    physical sign. It begins focally, usually on the tongue, and becomes
    multifocal and diffuse with delay to presentation.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Paraquat-associated stomatitis
    term:
      id: HP:0010280
      label: Stomatitis
    temporality: ACUTE
  evidence:
  - reference: PMID:42048945
    reference_title: "The natural history of paraquat-associated stomatitis: A four-stage model."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Analysis of 170 cases revealed PAS in 78.8% of patients."
    explanation: >-
      Supports the FREQUENT band directly: 78.8% falls inside the 30-79% range,
      close to its upper edge. From a pooled individual-patient analysis of 170
      published cases, so the denominator is a case literature rather than a
      population - the band is an estimate, not an incidence.
  - reference: PMID:42048945
    reference_title: "The natural history of paraquat-associated stomatitis: A four-stage model."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Anatomically, early presentations (<=6 h) were characterized by focal involvement, predominantly on the tongue (35.8%)."
    explanation: Supports the early focal, predominantly lingual distribution.
- category: Oral
  name: Severe Mucositis
  description: >-
    WHO Grade 3-4 mucositis, whose prevalence rises steeply with delay from
    exposure to presentation - a time dependence that makes the finding useful
    for forensic timing as well as prognosis.
  phenotype_term:
    preferred_term: Severe oral mucosal ulceration
    term:
      id: HP:0000155
      label: Oral ulcer
    severity: SEVERE
    temporality: ACUTE
  evidence:
  - reference: PMID:42048945
    reference_title: "The natural history of paraquat-associated stomatitis: A four-stage model."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Severe mucositis (WHO Grade 3-4) increased from 13.9% in patients presenting within 6 h to 58.3% in those presenting at 1-3 days (p = 0.027)."
    explanation: >-
      Quantifies the time dependence. No frequency band is asserted for this
      phenotype precisely because the figure depends on presentation delay rather
      than being a fixed property of the poisoning.
- category: Respiratory
  name: Pulmonary Fibrosis
  description: >-
    Progressive interstitial fibrosis developing over two to three weeks, the
    characteristic delayed cause of death.
  phenotype_term:
    preferred_term: Progressive pulmonary fibrosis
    term:
      id: HP:0002206
      label: Pulmonary fibrosis
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:39239177
    reference_title: "Management of Paraquat Poisoning-The Way Forward."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "In contrast, severe poisoning can lead to acute kidney failure, acute lung injury, and lung fibrosis resulting in death over 2-3 weeks."
    explanation: Names lung fibrosis and its two-to-three-week fatal course.
- category: Respiratory
  name: Respiratory Failure
  description: >-
    Terminal respiratory failure from loss of gas-exchange surface, the usual
    mode of death in patients surviving the acute phase.
  phenotype_term:
    preferred_term: Respiratory failure
    term:
      id: HP:0002878
      label: Respiratory failure
    temporality: ACUTE
  evidence:
  - reference: PMID:42266604
    reference_title: "Clinical Profiles and Therapeutic Interventions in Occult Paraquat Poisoning: A Comparative Report of Two Cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This rapid development of fatal progressive respiratory failure was deduced based on the severe clinical status of the patient at the time of discharge and the established toxicological mechanisms of paraquat‐induced lung injury."
    explanation: >-
      Documents fatal progressive respiratory failure as the terminal event in a
      poisoned patient. Replaces an earlier snippet that spoke only to overall
      mortality and, by its own explanation, did not evidence this phenotype.
- category: Renal
  name: Acute Kidney Injury
  description: >-
    Acute kidney injury from proximal tubular necrosis, appearing early and
    associated with severe mucosal disease.
  phenotype_term:
    preferred_term: Acute kidney injury
    term:
      id: HP:0001919
      label: Acute kidney injury
    temporality: ACUTE
  evidence:
  - reference: PMID:39239177
    reference_title: "Management of Paraquat Poisoning-The Way Forward."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Kidney failure occurs due to necrosis in the proximal convoluted tubule whereas acute liver injury occurs due to damage to the smooth endoplasmic reticulum and mitochondria, the distribution being high in these two organs."
    explanation: States renal failure and its tubular mechanism.
  - reference: PMID:42048945
    reference_title: "The natural history of paraquat-associated stomatitis: A four-stage model."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A strong association existed between severe PAS and systemic complications like acute kidney injury."
    explanation: >-
      Independent support for acute kidney injury as a systemic complication,
      and for its co-occurrence with severe mucosal disease.
- category: Hepatic
  name: Acute Liver Injury
  description: Acute hepatocellular injury from damage to smooth ER and mitochondria.
  phenotype_term:
    preferred_term: Acute liver injury
    term:
      id: HP:0006554
      label: Acute hepatic failure
    temporality: ACUTE
  notes: >-
    Bound to `HP:0006554` Acute hepatic failure, which is more severe than the
    "acute liver injury" the source names. The preferred_term is kept at the
    source's wording so the entry does not silently upgrade injury to failure;
    HPO has no acute-liver-injury term short of failure.
  evidence:
  - reference: PMID:39239177
    reference_title: "Management of Paraquat Poisoning-The Way Forward."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Kidney failure occurs due to necrosis in the proximal convoluted tubule whereas acute liver injury occurs due to damage to the smooth endoplasmic reticulum and mitochondria, the distribution being high in these two organs."
    explanation: States acute liver injury and its subcellular mechanism.
- category: Gastrointestinal
  name: Pneumomediastinum
  description: >-
    Pneumomediastinum following perforation of the ulcerated gastrointestinal
    tract, with associated mediastinitis.
  phenotype_term:
    preferred_term: Pneumomediastinum
    term:
      id: HP:0025421
      label: Pneumomediastinum
    temporality: ACUTE
  evidence:
  - reference: PMID:39239177
    reference_title: "Management of Paraquat Poisoning-The Way Forward."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Gastrointestinal toxicity occurs in the form of mucosal lesions which can ulcerate and bleed, sometimes resulting in perforation of the tract and associated mediastinitis and pneumomediastinum."
    explanation: Names pneumomediastinum as a consequence of tract perforation.
- category: Gastrointestinal
  name: Vomiting
  description: >-
    Vomiting as an early, non-specific gastrointestinal symptom. Its
    non-specificity is clinically consequential rather than incidental: in occult
    poisoning such symptoms are a recognised cause of initial misdiagnosis.
    Curated separately from diarrhoea, which has its own HPO term, rather than
    bundling two findings under one binding.
  phenotype_term:
    preferred_term: Vomiting
    term:
      id: HP:0002013
      label: Vomiting
    temporality: ACUTE
  evidence:
  - reference: PMID:42266604
    reference_title: "Clinical Profiles and Therapeutic Interventions in Occult Paraquat Poisoning: A Comparative Report of Two Cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A 42-year-old male with a history of hypertension and diabetes was admitted to the ICU on December 8, presenting with a 4-day history of vomiting and diarrhea, and a 2-day history of dyspnea and oliguria."
    explanation: Documents vomiting and diarrhoea as the presenting features.
  - reference: PMID:42266604
    reference_title: "Clinical Profiles and Therapeutic Interventions in Occult Paraquat Poisoning: A Comparative Report of Two Cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Notably, the increasing prevalence of atypical exposure patterns, combined with early nonspecific manifestations such as gastrointestinal and respiratory symptoms, often results in a high misdiagnosis rate during the initial evaluation of occult poisoning."
    explanation: >-
      Supports the claim that the non-specificity of these symptoms drives
      misdiagnosis, which is why they are curated rather than omitted as generic.
- category: Gastrointestinal
  name: Diarrhea
  description: Diarrhoea accompanying vomiting in the early gastrointestinal phase.
  phenotype_term:
    preferred_term: Diarrhea
    term:
      id: HP:0002014
      label: Diarrhea
    temporality: ACUTE
  evidence:
  - reference: PMID:42266604
    reference_title: "Clinical Profiles and Therapeutic Interventions in Occult Paraquat Poisoning: A Comparative Report of Two Cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A 42-year-old male with a history of hypertension and diabetes was admitted to the ICU on December 8, presenting with a 4-day history of vomiting and diarrhea, and a 2-day history of dyspnea and oliguria."
    explanation: Documents diarrhoea among the presenting features.
- category: Respiratory
  name: Acute Respiratory Distress Syndrome
  description: >-
    Severe ARDS developing within days, preceding and distinct from the delayed
    fibrotic phase.
  phenotype_term:
    preferred_term: Acute respiratory distress syndrome
    term:
      id: HP:0033677
      label: Acute respiratory distress syndrome
    temporality: ACUTE
  evidence:
  - reference: PMID:42266604
    reference_title: "Clinical Profiles and Therapeutic Interventions in Occult Paraquat Poisoning: A Comparative Report of Two Cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He progressed to severe ARDS within 48 h (PaO2/FiO2 ratio < 100 mmHg, radiographic involvement > 85%), failing lung-protective ventilation."
    explanation: Documents severe ARDS with its physiological and radiographic criteria.
- category: Respiratory
  name: Subcutaneous Emphysema
  description: >-
    Cervical and thoracic subcutaneous emphysema accompanying pneumomediastinum,
    reflecting air tracking from ruptured alveoli or a perforated tract.
  phenotype_term:
    preferred_term: Cervical and thoracic subcutaneous emphysema
    term:
      id: HP:6001021
      label: Subcutaneous emphysema
    temporality: ACUTE
  evidence:
  - reference: PMID:42266604
    reference_title: "Clinical Profiles and Therapeutic Interventions in Occult Paraquat Poisoning: A Comparative Report of Two Cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Physical examination revealed severe respiratory distress and extensive subcutaneous crepitus across the neck and chest."
    explanation: Documents the clinical sign of subcutaneous emphysema.
- category: Hepatic
  name: Jaundice
  description: >-
    Severe jaundice with hyperbilirubinaemia, part of the hepatic arm of
    multiorgan involvement.
  phenotype_term:
    preferred_term: Jaundice
    term:
      id: HP:0000952
      label: Jaundice
    severity: SEVERE
    temporality: ACUTE
  evidence:
  - reference: PMID:42266604
    reference_title: "Clinical Profiles and Therapeutic Interventions in Occult Paraquat Poisoning: A Comparative Report of Two Cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "On examination, he was febrile (37.7 C) with oxygen desaturation (SpO2 79%) and severe jaundice."
    explanation: Documents severe jaundice on examination.
  - reference: PMID:42266604
    reference_title: "Clinical Profiles and Therapeutic Interventions in Occult Paraquat Poisoning: A Comparative Report of Two Cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Laboratory findings showed acute kidney injury (Cr 1011 μmol/L), hyperbilirubinemia (TBil 203 μmol/L), and hypoxemia (PaO2 65 mmHg)."
    explanation: >-
      Gives the biochemical correlate, and in the same sentence the concurrent
      acute kidney injury and hypoxaemia of the multiorgan picture.
- category: Cardiovascular
  name: Bradycardia
  description: >-
    Severe sinus bradycardia refractory to anticholinergics, reported as an
    unusual manifestation of acute poisoning.
  phenotype_term:
    preferred_term: Severe sinus bradycardia
    term:
      id: HP:0001688
      label: Sinus bradycardia
    temporality: ACUTE
  evidence:
  - reference: PMID:38204158
    reference_title: "Unraveling the link between severe bradycardia and paraquat poisoning."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "On day 3 of hospitalization, the patient developed severe bradycardia, with his heart rate dropping to 35 beats/min."
    explanation: >-
      Case-level documentation of severe bradycardia. Single case, so no
      frequency is asserted.
  - reference: PMID:38204158
    reference_title: "Unraveling the link between severe bradycardia and paraquat poisoning."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report a case of bradycardia that was refractory to anticholinergics, which is an unusual clinical manifestation of acute paraquat poisoning."
    explanation: >-
      States both the refractoriness and, explicitly, that this is unusual - which
      is why no frequency band is given.
  - reference: PMID:38204158
    reference_title: "Unraveling the link between severe bradycardia and paraquat poisoning."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A 12-lead electrocardiogram suggested sinus bradycardia, and the echocardiogram was normal."
    explanation: >-
      Licenses the narrower `HP:0001688` Sinus bradycardia rather than the parent
      `HP:0001662`: the rhythm was characterised on ECG. The normal echocardiogram
      in the same sentence is also why this entry does not claim structural
      cardiac injury.
- category: Renal
  name: Oliguria
  description: Reduced urine output accompanying acute kidney injury.
  phenotype_term:
    preferred_term: Oliguria
    term:
      id: HP:0100520
      label: Oliguria
    temporality: ACUTE
  evidence:
  - reference: PMID:42266604
    reference_title: "Clinical Profiles and Therapeutic Interventions in Occult Paraquat Poisoning: A Comparative Report of Two Cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A 42-year-old male with a history of hypertension and diabetes was admitted to the ICU on December 8, presenting with a 4-day history of vomiting and diarrhea, and a 2-day history of dyspnea and oliguria."
    explanation: Documents oliguria among the presenting features.
- category: Respiratory
  name: Dyspnea
  description: Breathlessness, an early and progressive respiratory symptom.
  phenotype_term:
    preferred_term: Dyspnea
    term:
      id: HP:0002094
      label: Dyspnea
    clinical_course: PROGRESSIVE
    temporality: ACUTE
  evidence:
  - reference: PMID:42266604
    reference_title: "Clinical Profiles and Therapeutic Interventions in Occult Paraquat Poisoning: A Comparative Report of Two Cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A 22-year-old male presented to the emergency department with a 6-day history of progressive chest pain and dyspnea, leading to admission on February 10, 2024."
    explanation: Documents progressive dyspnoea and chest pain at presentation.
environmental:
- name: Ingestion of concentrated paraquat herbicide
  exposure_term:
    preferred_term: ingestion of concentrated paraquat herbicide formulation
    term:
      id: ECTO:9000395
      label: exposure to paraquat
  description: >-
    The dominant exposure route in fatal cases. Paraquat is cheap, widely
    available in agricultural communities, and highly toxic, which is the
    combination that makes it a leading agent of fatal pesticide self-poisoning.
    Cutaneous and mucosal contact are also reported routes.
  notes: >-
    `ECTO:9000395` is route-agnostic and is chosen over the route-specific
    siblings `ECTO:0090011` (in air), `ECTO:0090012` (in soil) and
    `ECTO:0090013` (in water), none of which describes ingestion. A full label
    scan of ECTO for `paraquat` returned exactly these four plus
    `ECTO:9001210` exposure to paraquat dichloride; there is no ingestion-route
    paraquat term.
  evidence:
  - reference: PMID:18161502
    reference_title: "Paraquat poisonings: mechanisms of lung toxicity, clinical features, and treatment."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "However, over the last decades, there have been numerous fatalities, mainly caused by accidental or voluntary ingestion."
    explanation: Establishes ingestion as the route producing fatalities.
  - reference: PMID:18154668
    reference_title: "The global distribution of fatal pesticide self-poisoning: systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "it is the pattern of pesticide use and the toxicity of the products, not the quantity used, that influences the likelihood they will be used in acts of fatal self-harm."
    explanation: >-
      PARTIAL - this systematic review is about pesticide self-poisoning as a
      class rather than paraquat specifically, but it establishes product
      toxicity and availability, not volume sold, as what drives fatal use, which
      is the rationale for paraquat's prominence and for the bans described here.
  influences_mechanisms:
  - target: Ingestion of Concentrated Paraquat
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Ingesting a concentrated formulation is the route by which a lethal
      systemic dose is delivered.
    evidence:
    - reference: PMID:39239177
      reference_title: "Management of Paraquat Poisoning-The Way Forward."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Self-ingestion or cutaneous/mucosal contact can rapidly lead to multiorgan failure involving the respiratory, liver, and renal systems."
      explanation: >-
        Links the exposure routes directly to the multiorgan failure this entry
        curates.
- name: Occult inhalational exposure by nebulisation
  exposure_term:
    preferred_term: inhalation of nebulised paraquat solution
    term:
      id: ECTO:9000395
      label: exposure to paraquat
  description: >-
    A rare and diagnostically treacherous route: paraquat solution delivered by a
    personal nebulisation device. It is curated because it breaks the assumptions
    the usual diagnostic pathway rests on - there is no caustic oral injury to
    see, the exposure history is denied or absent, and an initial urine paraquat
    test can be negative. The diagnosis in the cited case was made only by
    analysing residue from the device itself.
  notes: >-
    Bound to the same route-agnostic `ECTO:9000395` as the ingestion entry, since
    ECTO has no inhalational paraquat term either; `ECTO:0090011` exposure to
    paraquat in air denotes ambient air, not deliberate nebulisation, and would
    misdescribe this route.
  evidence:
  - reference: PMID:42266604
    reference_title: "Clinical Profiles and Therapeutic Interventions in Occult Paraquat Poisoning: A Comparative Report of Two Cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Analysis of the residual solution from his nebulization device confirmed the presence of methyl viologen, the active component of paraquat, establishing the diagnosis of inhaled paraquat poisoning via nebulization."
    explanation: >-
      Documents the nebulised inhalational route and how the diagnosis was
      finally established.
  - reference: PMID:42266604
    reference_title: "Clinical Profiles and Therapeutic Interventions in Occult Paraquat Poisoning: A Comparative Report of Two Cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although an initial urine paraquat test yielded a negative result, a subsequent targeted investigation of the patient's personal items revealed a video documenting inhalation of an unknown substance."
    explanation: >-
      Supports the specific diagnostic trap recorded here - a negative initial
      urine screen in a genuinely poisoned patient.
  influences_mechanisms:
  - target: Alveolar Epithelial Injury and Cell Death
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Aerosol deposition reaches the terminal bronchioles and alveolar lumen
      directly and destroys alveolar epithelium at the site of deposition,
      without the systemic distribution step that ingestion requires. Note this
      is a shortcut in DELIVERY, not a bypass of transport: the same source says
      absorption then proceeds through epithelial active transport mechanisms,
      so the uptake machinery is still involved and the link is not curated as
      circumventing it.
    evidence:
    - reference: PMID:42266604
      reference_title: "Clinical Profiles and Therapeutic Interventions in Occult Paraquat Poisoning: A Comparative Report of Two Cases."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "During aerosolized inhalation, the aerodynamic deposition of toxic fine particles allows them to reach the terminal bronchioles and alveolar lumen directly."
      explanation: States the direct aerodynamic deposition at the alveolar lumen.
    - reference: PMID:42266604
      reference_title: "Clinical Profiles and Therapeutic Interventions in Occult Paraquat Poisoning: A Comparative Report of Two Cases."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "This localized deposition causes immediate alveolar epithelial cell destruction and massive pulmonary accumulation while bypassing hepatic first pass metabolism."
      explanation: >-
        States immediate alveolar epithelial destruction, which is what justifies
        targeting the injury node rather than the systemic-accumulation node.
diagnosis:
- name: Severity Index of Paraquat Poisoning (SIPP)
  description: >-
    Plasma paraquat concentration multiplied by hours since ingestion. It is the
    most-used prognostic index in this poisoning, and its two inputs are exactly
    the two variables this entry's mechanism section says govern outcome - dose
    and time - which is why it earns a place here rather than being left to a
    guideline. It predicts acute kidney injury independently of other admission
    variables.
  evidence:
  - reference: PMID:28881652
    reference_title: "Predictors of acute kidney injury after paraquat intoxication."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Multivariate logistic regression indicated that acute hepatitis (P < 0.001), a longer time to hospital arrival (P < 0.001), higher SIPP score (P = 0.026) and higher PaO2 at admission (P = 0.014) were predictors of AKI."
    explanation: >-
      Establishes SIPP as an independent predictor of acute kidney injury in 222
      patients, alongside time to arrival - both dose-and-time proxies.
  - reference: PMID:33050540
    reference_title: "Does Hemoperfusion Increase Survival in Acute Paraquat Poisoning? A Retrospective Multicenter Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We used the Severity Index of Paraquat Poisoning (SIPP) to stratify the severity of PQ-poisoned patients."
    explanation: >-
      Independent confirmation that SIPP is the working severity stratifier in
      clinical studies of this poisoning.
- name: Semiquantitative urine paraquat (dithionite) test
  description: >-
    A bedside colorimetric screen used to confirm exposure and to gate treatment
    decisions. Its limitation is curated deliberately: it can be negative early
    in a genuinely poisoned patient, which is one of the traps recorded on the
    occult inhalational exposure route in this entry.
  evidence:
  - reference: PMID:33050540
    reference_title: "Does Hemoperfusion Increase Survival in Acute Paraquat Poisoning? A Retrospective Multicenter Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The indication to start HP was a positive result for the semiquantitative urine PQ test and presentation to the hospital was within 24 h."
    explanation: >-
      Documents the urine test being used as the operational gate for starting
      extracorporeal treatment.
  - reference: PMID:42266604
    reference_title: "Clinical Profiles and Therapeutic Interventions in Occult Paraquat Poisoning: A Comparative Report of Two Cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although an initial urine paraquat test yielded a negative result, a subsequent targeted investigation of the patient's personal items revealed a video documenting inhalation of an unknown substance."
    explanation: >-
      PARTIAL and included as the counterweight: a false-negative urine screen in
      a patient who was in fact poisoned.
- name: Admission mortality-prediction nomogram
  description: >-
    A multivariable model built on 724 patients, using variables available within
    24 hours of admission. Notable for what it selects: alongside plasma paraquat
    concentration it picks creatinine and alanine aminotransferase - the renal
    and hepatic arms this entry curates - and conscious level, so the model is
    effectively scoring the multiorgan chain rather than the toxin alone.
  notes: >-
    Curated as a prognostic tool, not a validated one. The authors state it needs
    further external validation, and that qualification is preserved here rather
    than dropped.
  evidence:
  - reference: DOI:10.1038/s41598-023-50722-z
    reference_title: "Development and validation of a prognostic nomogram for predicting in-hospital mortality of patients with acute paraquat poisoning"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the training cohort, decreased level of consciousness (Glasgow Coma Scale score < 15), neutrophil-to-lymphocyte ratio, alanine aminotransferase, creatinine, carbon dioxide combining power, and paraquat plasma concentrations at admission were identified as independent predictors of in-hospital mortality in patients with acute paraquat poisoning."
    explanation: >-
      PARTIAL - names the selected predictors, but the same paper states the
      model requires further external validation before clinical use, so this
      supports the variables rather than the tool's readiness.

treatments:
- name: Supportive Care Without an Antidote
  description: >-
    The baseline, and an honest statement of the position: there is no antidote
    with specific effects for acute paraquat poisoning. Everything else in this
    section is an attempt to reduce absorbed dose or blunt oxidative injury, and
    none of it is guideline-backed.
  notes: >-
    No `therapeutic_modality` is set. CLAUDE.md scopes `BEHAVIORAL` to
    behavioural, physical, dietary or lifestyle intervention and places
    `NCIT:C15747` Supportive Care outside the mechanical-inference table, because
    it is not a platform-classifiable action; ICU organ support is neither a
    lifestyle intervention nor a single modality.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:39239177
    reference_title: "Management of Paraquat Poisoning-The Way Forward."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "There is currently no antidote with specific effects, for acute paraquat poisoning."
    explanation: States the absence of an antidote directly.
  - reference: PMID:39239177
    reference_title: "Management of Paraquat Poisoning-The Way Forward."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "These modalities though, are not based on guidelines or recommendations, and the supporting evidence is also weak, as it has been extrapolated from animal studies and case series in resource-limited settings, which lack information on the severity of the disease."
    explanation: >-
      States that the treatment modalities in this section rest on weak,
      extrapolated evidence rather than guidelines.
- name: Extracorporeal Elimination (Haemoperfusion and Renal Replacement Therapy)
  description: >-
    Removal of absorbed paraquat by haemoperfusion, alone or combined with
    continuous renal replacement therapy. Timing dominates: benefit is reported
    when performed within four to six hours of ingestion and largely disappears
    with later presentation, which fits the toxicokinetics - paraquat is taken up
    into lung against a gradient and retained there as plasma levels fall, so
    lowering the plasma level late does not retrieve the lung burden already
    established.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: haemoperfusion and continuous renal replacement therapy
    term:
      id: NCIT:C49236
      label: Therapeutic Procedure
  notes: >-
    Bound to the generic `NCIT:C49236` because NCIT has no haemoperfusion term -
    a direct label scan of the release used here returns zero matches for both
    `hemoperfusion` and `haemoperfusion`. The hemodialysis family exists but is a
    different modality.
  target_mechanisms:
  - target: Polyamine-Transporter-Mediated Pulmonary Accumulation
    treatment_effect: INHIBITS
    description: >-
      Lowering the circulating concentration early limits how much paraquat the
      lung can concentrate. The link is to the uptake node rather than to the
      exposure node because that is the step extracorporeal clearance actually
      competes with, and it is why the therapeutic window is measured in hours.
    evidence:
    - reference: PMID:39239177
      reference_title: "Management of Paraquat Poisoning-The Way Forward."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Majority of the studies emphasized that hemoperfusion should be performed within 4 hours of ingestion of paraquat, for best results."
      explanation: >-
        PARTIAL - establishes the narrow timing window, which is the observable
        consequence of competing with pulmonary uptake, but does not itself
        demonstrate the mechanistic link asserted here.
  evidence:
  - reference: PMID:39239177
    reference_title: "Management of Paraquat Poisoning-The Way Forward."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "They emphasized the use of hemoperfusion within 6 hours for improved outcome."
    explanation: >-
      Reports better outcome with early haemoperfusion in a 101-patient series.
  - reference: PMID:39239177
    reference_title: "Management of Paraquat Poisoning-The Way Forward."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A systematic review and meta-analysis in Iran in 2022, studied 44 patients where all required mechanical ventilation, and despite hemodialysis, there was no reduction in mortality."
    explanation: >-
      PARTIAL, and deliberately included as a counterweight - a pooled analysis
      showing no mortality reduction, attributed to delayed presentation. The
      evidence for extracorporeal elimination is not uniformly positive.
  - reference: PMID:33050540
    reference_title: "Does Hemoperfusion Increase Survival in Acute Paraquat Poisoning? A Retrospective Multicenter Study."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Among acute PQ-poisoned patients, this study found that HP was not associated with increased 60-day survival. Furthermore, neither early HP nor multiple secessions of HP were associated with survival."
    explanation: >-
      REFUTE, and it refutes the specific claim this treatment is built on. A
      multi-centre study of 213 SIPP-stratified patients found no survival
      benefit from haemoperfusion, AND no benefit from EARLY haemoperfusion -
      which contradicts the four-to-six-hour window quoted above from the
      editorial. Read directly rather than second-hand. The treatment is retained
      because it remains in use, not because the evidence supports it.
- name: Immunosuppressive Therapy
  description: >-
    Glucocorticoids (methylprednisolone, dexamethasone) and cyclophosphamide,
    directed at the inflammatory and fibroproliferative arm rather than at redox
    cycling - which is why this link targets the alveolar-injury and fibrosis
    nodes, the same nodes the KNOWLEDGE_GAP on its efficacy attaches to. The
    evidence is genuinely contested rather than merely thin, and this entry does
    not record it as effective.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: methylprednisolone
      term:
        id: NCIT:C647
        label: Methylprednisolone
    - preferred_term: cyclophosphamide
      term:
        id: NCIT:C405
        label: Cyclophosphamide
  target_mechanisms:
  - target: Alveolar Epithelial Injury and Cell Death
    treatment_effect: MODULATES
    description: >-
      Aimed at suppressing the inflammatory amplification of alveolar injury.
      MODULATES because the direction and size of the effect are exactly what is
      disputed.
    evidence:
    - reference: PMID:39239177
      reference_title: "Management of Paraquat Poisoning-The Way Forward."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Measures for treatment include reducing poison absorption and eliminating absorbed poison, use of antioxidants, anti-inflammatory agents, and immunosuppressants, hemodialysis, and hemoperfusion, along with other supportive care."
      explanation: >-
        PARTIAL - establishes that immunosuppressants are used in this role,
        without evidencing that they work.
  evidence:
  - reference: PMID:39239177
    reference_title: "Management of Paraquat Poisoning-The Way Forward."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "However, another three randomized controlled trials compared dexamethasone, methylprednisolone, and cyclophosphamide with standard treatment, and all three showed mortality benefit in the treatment arm compared to the standard treatment."
    explanation: >-
      PARTIAL - randomised evidence of mortality benefit, reported second-hand in
      an editorial rather than read here in the primary trials. Retained
      alongside the primary registry evidence below rather than replaced, since
      it is the entry's record of what the trial literature claims.
  - reference: PMID:24475310
    reference_title: "Addition of immunosuppressive treatment to hemoperfusion is associated with improved survival after paraquat poisoning: a nationwide study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "IST significantly increases survival rate (from 24.3% to 29.3%, P<0.001). The combined IST with methylprednisolone, cyclophosphamide and dexamethasone associates with the highest survival rate (48%, P<0.001)."
    explanation: >-
      Primary evidence, read directly rather than through the editorial: a
      nationwide retrospective cohort of 1811 hemoperfused patients. Note the
      absolute effect is modest (24.3% to 29.3%) against an overall survival of
      26.4%, so this supports use without supporting optimism.
  - reference: PMID:39239177
    reference_title: "Management of Paraquat Poisoning-The Way Forward."
    supports: REFUTE
    evidence_source: OTHER
    snippet: "They suggested that the efficacy of immunosuppression and antioxidants was anecdotal."
    explanation: >-
      REFUTE - a systematic search of human studies concluding the efficacy is
      anecdotal, directly contradicting the trial evidence above. Both are
      recorded so the disagreement is visible in the entry rather than resolved
      by selection.
- name: Antioxidant Therapy
  description: >-
    Vitamin C, vitamin E, N-acetylcysteine and reduced glutathione, directed at
    the oxidative output of redox cycling. Curated separately from
    immunosuppression because the two act on different nodes and their evidence
    is assessed together only by accident of being administered together.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  notes: >-
    No `therapeutic_agent` is bound. Ascorbate, tocopherol, N-acetylcysteine and
    glutathione all have CHEBI terms, but the sources here name them only as a
    bundle administered alongside immunosuppression, with no per-agent evidence;
    binding them individually would imply a specificity the evidence does not
    have. Worth revisiting if a per-agent study is curated.
  target_mechanisms:
  - target: Redox Cycling and Catalytic Superoxide Generation
    treatment_effect: MODULATES
    description: >-
      Scavenges the radical output of redox cycling. MODULATES rather than
      INHIBITS deliberately: because paraquat is regenerated each cycle it
      produces radicals catalytically, so a stoichiometric scavenger cannot stop
      the source - only buffer the product.
    evidence:
    - reference: PMID:39239177
      reference_title: "Management of Paraquat Poisoning-The Way Forward."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Measures for treatment include reducing poison absorption and eliminating absorbed poison, use of antioxidants, anti-inflammatory agents, and immunosuppressants, hemodialysis, and hemoperfusion, along with other supportive care."
      explanation: >-
        PARTIAL - establishes that antioxidants are used against this mechanism,
        without evidencing that they work.
  evidence:
  - reference: PMID:42266604
    reference_title: "Clinical Profiles and Therapeutic Interventions in Occult Paraquat Poisoning: A Comparative Report of Two Cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Antioxidants included intravenous reduced glutathione at 2400 mg daily, intravenous vitamin C at 2 g every 12 h, and gastric N-acetylcysteine at 0.6 g every 12 h"
    explanation: >-
      PARTIAL - documents the specific antioxidant regimen given in a case that
      nonetheless ended fatally, so it evidences use rather than benefit.

- name: Reduction of Absorption
  description: >-
    Gastric lavage and adsorbents to limit the absorbed dose. Rational given the
    dose dependence of outcome, but subject to the same narrow time window as
    extracorporeal elimination.
  notes: >-
    The agent is bound to `CHEBI:91090` charcoal rather than `NCIT:C77524`
    Activated Charcoal: the NCIT term is not a member of the schema's
    `ChemicalEntityTerm` dynamic enum and is rejected by term validation. CHEBI
    has no separate activated-charcoal term, so `preferred_term` carries the
    "activated" qualifier that the bound label lacks.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: activated charcoal
      term:
        id: CHEBI:91090
        label: charcoal
  target_mechanisms:
  - target: Ingestion of Concentrated Paraquat
    treatment_effect: INHIBITS
    description: >-
      Limits how much of an ingested dose reaches the systemic circulation.
    evidence:
    - reference: PMID:39239177
      reference_title: "Management of Paraquat Poisoning-The Way Forward."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Measures for treatment include reducing poison absorption and eliminating absorbed poison, use of antioxidants, anti-inflammatory agents, and immunosuppressants, hemodialysis, and hemoperfusion, along with other supportive care."
      explanation: >-
        PARTIAL - names reducing absorption as a treatment aim without
        quantifying its effect.
  evidence:
  - reference: PMID:39239177
    reference_title: "Management of Paraquat Poisoning-The Way Forward."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "It included 109 patients in a tertiary hospital, where all treatment modalities were provided, including gastric lavage, mechanical ventilation, immunosuppression, antioxidants, hemoperfusion, and renal replacement therapy."
    explanation: >-
      PARTIAL - documents gastric lavage as part of the standard bundle in a
      109-patient series whose mortality was nonetheless 88%.
- name: Lung Transplantation
  description: >-
    The only intervention that addresses the lesion that kills survivors. Once
    fibrosis is established it is irreversible, so transplantation is the
    definitive rather than the supportive option, with ECMO as a bridge to a
    donor lung. Reported successfully after paraquat poisoning, including a
    double-lung transplant on ECMO support 34 days after ingestion with a good
    outcome. Its limiting factors in the cited cases were not medical: one
    patient reached transplantation only through publicly raised funds, and in
    another it was abandoned for want of money.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: lung transplantation
    term:
      id: NCIT:C15289
      label: Organ Transplantation
  target_mechanisms:
  - target: Progressive Pulmonary Fibrosis
    treatment_effect: BYPASSES
    description: >-
      Replaces the fibrotic organ rather than modifying the fibrotic process -
      the one place in this entry where BYPASSES is the accurate enum, since the
      graft supplies gas exchange by an entirely different route while the
      injured lung is removed.
    evidence:
    - reference: PMID:36626514
      reference_title: "Lung transplantation in a woman with paraquat poisoning that led to pulmonary fibrosis-Widely reported by the media: A case report."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Lung transplantation is currently the most effective treatment for pulmonary fibrosis, and mass media campaigns can provide economic support, influence potential organ donation, and provide such patients more chances to survive."
      explanation: >-
        States transplantation as the most effective treatment for the fibrotic
        endpoint this node represents.
  evidence:
  - reference: PMID:36626514
    reference_title: "Lung transplantation in a woman with paraquat poisoning that led to pulmonary fibrosis-Widely reported by the media: A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient received financial assistance; thus, she could receive a double-lung transplant with extracorporeal membrane oxygenation (ECMO) support on the 34th day after the poisoning."
    explanation: >-
      Documents a completed double-lung transplant on ECMO support after paraquat
      poisoning, and - notably - that access turned on funding rather than on
      medical eligibility.
  - reference: PMID:42266604
    reference_title: "Clinical Profiles and Therapeutic Interventions in Occult Paraquat Poisoning: A Comparative Report of Two Cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, lung transplantation was abandoned due to financial constraints experienced by the family, resulting in the voluntary discharge of the patient against medical advice."
    explanation: >-
      PARTIAL - a negative instance rather than evidence of efficacy: it
      documents transplantation being considered and forgone, which is why the
      cost barrier is curated in the description rather than left implicit.
  - reference: PMID:41647033
    reference_title: "Case Report: Multifactorial weaning failure after lung transplantation in paraquat-induced pulmonary fibrosis: a case-based clinical review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Lung transplantation (LT) remains a rare but life-saving option for end-stage pulmonary fibrosis secondary to paraquat poisoning."
    explanation: >-
      PARTIAL, and included for what it qualifies rather than what it confirms:
      the same report documents failed extubation from respiratory muscle
      weakness after successful transplantation, so graft function is not the
      whole outcome. It also notes a review of 15 previously reported
      paraquat-related transplant cases, which bounds how much experience exists.
- name: Restrictive Oxygen Strategy
  description: >-
    The counterintuitive one, and the clearest clinical corollary of this entry's
    redox node: supplemental oxygen is the substrate that reoxidises the paraquat
    radical, so high inspired oxygen fuels the cycle that is doing the damage.
    Oxygen is therefore restricted rather than given liberally. It is a genuine
    trade-off rather than a rule - withholding oxygen delays radical generation
    at the cost of tissue hypoxia - and the cited source frames it as a
    ventilator-setting judgement in patients already on ECMO, not as a blanket
    prohibition.
  treatment_term:
    preferred_term: restrictive inspired-oxygen strategy
    term:
      id: NCIT:C49236
      label: Therapeutic Procedure
  target_mechanisms:
  - target: Redox Cycling and Catalytic Superoxide Generation
    treatment_effect: INHIBITS
    description: >-
      Limiting inspired oxygen limits the substrate for reoxidation of the
      paraquat radical, and so the rate of the cycle itself. This is the only
      intervention curated here that acts on the redox mechanism rather than on
      its consequences.
    evidence:
    - reference: PMID:42266604
      reference_title: "Clinical Profiles and Therapeutic Interventions in Occult Paraquat Poisoning: A Comparative Report of Two Cases."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Although both patients received ECMO support, mechanical ventilation parameter settings need to be carefully weighed: high‐concentration oxygen therapy may exacerbate oxidative stress injury, whereas hypoxic strategies, while delaying ROS generation, may exacerbate tissue hypoxia."
      explanation: >-
        States both halves of the trade-off: high-concentration oxygen worsens
        oxidative injury, and hypoxic strategies delay radical generation but
        worsen tissue hypoxia.
  notes: >-
    Bound to the generic `NCIT:C49236` - NCIT has no restrictive-oxygen or
    permissive-hypoxaemia term, and `NCIT:C171507` Extracorporeal Membrane
    Oxygenation names a different intervention. No `therapeutic_modality` is set
    for the same reason it is omitted on supportive care: a ventilator-setting
    strategy is not a platform.
  evidence:
  - reference: PMID:42266604
    reference_title: "Clinical Profiles and Therapeutic Interventions in Occult Paraquat Poisoning: A Comparative Report of Two Cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although both patients received ECMO support, mechanical ventilation parameter settings need to be carefully weighed: high‐concentration oxygen therapy may exacerbate oxidative stress injury, whereas hypoxic strategies, while delaying ROS generation, may exacerbate tissue hypoxia."
    explanation: >-
      The source's own statement of the oxygen trade-off in paraquat poisoning.
discussions:
- discussion_id: gap_paraquat_immunosuppression_efficacy
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - "pathophysiology#Alveolar Epithelial Injury and Cell Death"
  - "pathophysiology#Progressive Pulmonary Fibrosis"
  prompt: >-
    Does glucocorticoid plus cyclophosphamide immunosuppression reduce mortality
    in acute paraquat poisoning, and if so in which severity stratum?
  rationale: >-
    The evidence points both ways and this entry records both rather than
    choosing. A systematic search of human studies concluded that the efficacy of
    immunosuppression and antioxidants was anecdotal; three randomised controlled
    trials of dexamethasone, methylprednisolone and cyclophosphamide each reported
    a mortality benefit over standard treatment. That is a real contradiction, not
    a gradient of confidence, and there are two candidate explanations that lead
    to opposite clinical conclusions. Either the trials are right and the earlier
    reviews were diluted by heterogeneous, late-presenting cohorts; or the trials
    are small and conducted where severity assessment is limited, so apparent
    benefit reflects imbalance in ingested dose - the single strongest determinant
    of outcome - rather than treatment. The distinction matters because the
    intervention is not free: cyclophosphamide in a patient with acute kidney
    injury and impaired elimination carries real harm, and paraquat's case
    fatality is high enough that an ineffective therapy is not a neutral default.
    Note this entry's evidence for both positions is second-hand, drawn from an
    editorial summarising the primary literature rather than from the trials
    themselves; closing this gap starts with reading them.
  proposed_experiments:
  - experiment_id: exp_paraquat_immunosuppression_dose_stratified
    name: Dose-stratified randomised trial of immunosuppression in acute paraquat poisoning
    description: >-
      Multicentre randomised trial of glucocorticoid plus cyclophosphamide versus
      supportive care, with randomisation stratified on an objective measure of
      ingested dose (plasma paraquat concentration on a validated
      time-versus-concentration nomogram, or urine dithionite grade where plasma
      assay is unavailable), and with time from ingestion to presentation recorded
      as a prespecified covariate rather than an exclusion.
    decision_criterion: >-
      Whether a mortality difference survives adjustment for measured ingested
      dose and presentation delay, and whether any benefit is confined to a
      definable severity stratum rather than being uniform.
    supporting_outcome:
    - A mortality benefit that persists after adjustment for plasma paraquat concentration and presentation delay.
    - A benefit concentrated in an intermediate-dose stratum, which would explain why unstratified cohorts disagree.
    refuting_outcome:
    - A benefit that disappears once ingested dose is adjusted for, indicating confounding by severity.
    - Excess harm in the immunosuppressed arm among patients with acute kidney injury.
- discussion_id: gap_paraquat_therapeutic_window_vs_lung_retention
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - "pathophysiology#Polyamine-Transporter-Mediated Pulmonary Accumulation"
  prompt: >-
    Can any intervention reduce the pulmonary paraquat burden once uptake has
    occurred, or is the therapeutic window closed as soon as the lung has
    concentrated the dose?
  rationale: >-
    Two curated facts, taken together, predict the clinical observation and
    suggest the field is optimising the wrong variable. Paraquat is concentrated
    six- to ten-fold above plasma in lung and retained there as blood levels
    fall; and haemoperfusion helps within four to six hours and largely stops
    helping later. Extracorporeal elimination clears the compartment paraquat is
    leaving, not the one it has entered - which would explain why removing more
    drug, later, does not translate into survival. If that reading is right, the
    tractable target is not clearance but the polyamine transporter itself:
    competitive inhibition of uptake, plausible in principle since the transporter
    is a known and characterised system, would have to be given inside the same
    few hours to matter. What is missing is a direct measurement: no evidence
    consulted here reports lung paraquat burden as a function of time and of
    extracorporeal treatment in humans, so the causal claim that late clearance
    fails *because* of lung retention remains an inference from two separate
    observations.
  proposed_experiments:
  - experiment_id: exp_paraquat_lung_burden_kinetics
    name: Serial lung-versus-plasma paraquat kinetics under extracorporeal treatment
    description: >-
      Paired plasma and lung paraquat measurement over time in a large-animal
      model of ingestion, with and without haemoperfusion started at staggered
      intervals after dosing; complemented in humans by post-mortem lung paraquat
      concentration in treated and untreated fatalities with recorded ingestion
      and treatment times.
    decision_criterion: >-
      Whether extracorporeal clearance started after the early window lowers the
      lung concentration at all, or lowers plasma only while lung burden is
      unchanged.
    supporting_outcome:
    - Lung concentration unchanged by late haemoperfusion despite a fall in plasma.
    - A lung-to-plasma ratio that rises over time irrespective of treatment.
    refuting_outcome:
    - Lung burden falling proportionally with plasma under late clearance, which would relocate the reason for treatment failure elsewhere.
- discussion_id: gap_paraquat_cardiac_effects_uncharacterised
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - "pathophysiology#Cardiac Involvement"
  prompt: >-
    What are the haemodynamic and electrophysiological effects of acute paraquat
    poisoning in humans, and does cardiac depression contribute materially to
    death in fulminant high-dose ingestion?
  rationale: >-
    This gap is recorded because a plausible claim was available and declined.
    The deep-research report generated for this entry states that cardiogenic or
    circulatory collapse is the dominant fatal mechanism in fulminant poisoning.
    It is mechanistically plausible - rodents show dose-dependent falls in heart
    rate, blood pressure and contractility, and the >40 mg/kg course kills in two
    to three days, faster than fibrosis can develop, so something other than the
    lung must be killing those patients. But no source located for this entry
    supports it, and the one human source that addresses the question states that
    little to no evidence exists on the haemodynamic and cardiac
    electromechanical effects of acute paraquat poisoning. So the mechanism of
    death in the fulminant form is, on this entry's evidence, unaccounted for -
    which is a more useful thing to record than a borrowed assertion. Resolving it
    would also settle whether the bradycardia reported as unusual is genuinely
    rare or merely rarely looked for.
  proposed_experiments:
  - experiment_id: exp_paraquat_cardiac_phenotyping_prospective
    name: Prospective cardiac phenotyping in acute paraquat poisoning
    description: >-
      Serial ECG, echocardiography and high-sensitivity troponin in consecutive
      patients admitted with acute paraquat poisoning, stratified by SIPP, with
      cause of death adjudicated against the cardiac, respiratory and renal arms
      rather than recorded as multiorgan failure.
    decision_criterion: >-
      Whether patients in the fulminant high-dose stratum show cardiac depression
      or arrhythmia preceding death, and whether adjudicated cause of death in
      that stratum is cardiac rather than respiratory.
    supporting_outcome:
    - Falling contractility or conduction abnormality preceding death in the high-SIPP stratum.
    - Troponin release out of proportion to resuscitation received.
    refuting_outcome:
    - Preserved cardiac function up to death, locating the fulminant fatal mechanism elsewhere.
    - Bradycardia occurring at the same low rate across severity strata, making it incidental.
- discussion_id: controversy_paraquat_parkinson_association
  kind: CONTROVERSY
  status: OPEN
  attaches_to:
  - "pathophysiology#Redox Cycling and Catalytic Superoxide Generation"
  prompt: >-
    Is the epidemiological association between chronic low-dose paraquat exposure
    and Parkinson disease causal, and does it share a mechanism with the acute
    poisoning curated here?
  rationale: >-
    This entry curates acute high-dose poisoning; the paraquat-Parkinson question
    concerns chronic low-dose exposure and is a different exposure regime with a
    different target organ. They are linked here rather than merged because they
    share the redox-cycling node: paraquat is structurally similar to MPP+, is
    taken up by cation transporters, and is used experimentally to model
    nigrostriatal degeneration - and this knowledge base already treats paraquat
    as an environmental complex I toxin in `Parkinsons_Disease` and in the
    `parkinsonism_dopaminergic_degeneration` module. The association is
    meta-analytically supported but is not curated as established causation here,
    because the acute-poisoning literature cannot speak to it and this entry has
    not assessed the chronic-exposure evidence. Recorded so the relationship
    between these entries is explicit rather than implied by a shared substance
    name.
  evidence:
  - reference: PMID:30474499
    reference_title: "Paraquat exposure and Parkinson's disease: A systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There is a statistically significant association between paraquat exposure and PD."
    explanation: >-
      PARTIAL - the meta-analysis (13 case-control studies, OR 1.64, 95% CI
      1.27-2.13) establishes a statistically significant association, which is
      not the same as causation and says nothing about whether it shares a
      mechanism with the acute poisoning curated here. That is precisely the
      open question this discussion records.

📚

References & Deep Research

Deep Research

Claude Code ▸

Paraquat Poisoning — Comprehensive Research Report

claude-haiku-4-5-20251001, claude-sonnet-5 2026-08-22T21:08:16.353349

Paraquat Poisoning — Comprehensive Research Report

1. Disease Information

Overview. Paraquat poisoning is acute (and occasionally chronic/occupational) toxicity caused by exposure to paraquat (1,1′-dimethyl-4,4′-bipyridinium dichloride), a fast-acting, non-selective bipyridyl contact herbicide. The overwhelming majority of severe, fatal poisonings result from deliberate ingestion (self-harm) of concentrated commercial formulations (typically 20% w/v solutions), though occupational dermal/inhalational exposure and rare accidental ingestions also occur. Ingested paraquat is corrosive to mucosa, is concentrated in the lung by an active pulmonary uptake system, undergoes redox cycling that generates reactive oxygen species (ROS), and causes multi-organ toxicity — acute kidney injury, hepatic injury, and (in survivors of the acute phase) progressive, often fatal pulmonary fibrosis. There is no specific antidote, and case-fatality remains among the highest of any acute poisoning.

Key identifiers: - MeSH: Paraquat (D010297) - ICD-10-CM: T60.3 (Toxic effect of herbicides and fungicides), with 5th/7th character for intent (accidental T60.3X1A, intentional self-harm T60.3X2A, assault T60.3X3A) and Y-code E-codes historically (ICD-9 E863.5) - ICD-11: NE61 / PJ21 (Toxic effect of pesticides) — herbicide-specific subcode under the poisoning chapter - CAS Registry Number: 1910-42-5 (paraquat dichloride); 4685-14-7 (paraquat cation) - CHEBI: CHEBI:34905 (paraquat dichloride); CHEBI:34922 (paraquat) — verify canonical labels via OAK before binding - MONDO: No dedicated, well-populated MONDO term for "paraquat poisoning" specifically was identified in this pass; poisoning-by-substance concepts in MONDO are generally sparse compared to genetic disease — this should be confirmed directly against the MONDO release before curation (candidate parent: a general "poisoning by pesticide/herbicide" grouping term). - Synonyms: Methyl viologen; PQ; Gramoxone (trade name); N,N′-dimethyl-4,4′-bipyridinium dichloride; 1,1′-dimethyl-4,4′-bipyridylium dichloride.

Evidence source note: Information below is drawn from aggregated disease-level literature (toxicology reviews, case series, cohort/registry studies, national mortality statistics) rather than individual patient-level EHR data, with individual case reports cited where they illustrate a specific clinical course (e.g., lung transplantation).

2. Etiology

Disease causal factor: Direct chemical/toxicological — absorption of a threshold dose of paraquat (principally by ingestion; also possible by inhalation of concentrated spray/mist or extensive dermal contact through broken skin) initiates redox-cycling oxidative injury. This is not a genetic or infectious disease; it is a single-agent environmental/toxicological exposure disorder.

Risk factors: - Dose: The single strongest determinant of outcome. Ingestion of >40–50 mg/kg body weight (of paraquat ion; roughly >20–40 mL of 20% solution) is usually fatal within hours to days; 20–40 mg/kg causes a subacute, often-fatal multi-organ/pulmonary-fibrotic course over days-to-weeks; <20 mg/kg is frequently survivable with supportive care (Dinis-Oliveira et al., Crit Rev Toxicol 2008, PMID:18161502). - Occupational exposure: Agricultural workers/applicators in countries where paraquat remains registered, particularly with inadequate protective equipment, backpack sprayer leaks, or contaminated storage containers (accidental ingestion from re-used drink bottles is a well-documented accidental-poisoning pattern). - Access to concentrated formulations / means availability: In agrarian, low- and middle-income settings, ready household access to concentrated paraquat is the dominant modifiable risk factor for suicidal ingestion (Gunnell & Eddleston, PLOS Medicine/related pesticide-suicide literature). - Delayed presentation: Delayed hospital arrival (rural distance, stigma, lack of recognition of severity) worsens prognosis because early gastrointestinal decontamination and hemoperfusion lose efficacy after paraquat has distributed into tissue (within ~12–24 h). - Psychiatric comorbidity: Documented as an important covariate of mortality among intentional-ingestion cohorts (e.g., psychiatric comorbidity and mortality analysis, PMC4227688). - Renal impairment at presentation: Pre-existing or evolving acute kidney injury (AKI) — since renal clearance is the principal excretory route and its failure both raises systemic exposure and independently predicts death (mortality 70.1% with AKI vs 40.0% without; Oncotarget, PMC5584253/PMC5584253).

Protective factors: - Regulatory restriction / means restriction: Withdrawal or reformulation (e.g., addition of an emetic, stenching agent, dye, and reduced concentration) of paraquat products, and outright bans, have measurably reduced pesticide-suicide mortality without simple substitution to other lethal methods in several national studies (South Korea ban analysis, Cha et al., PLOS ONE 2015; Sri Lanka pesticide-restriction natural experiments). - Early, repeated hemoperfusion (within 12 h of ingestion) is associated with reduced 90-day mortality in some cohort analyses, though evidence quality is limited (retrospective multicenter study, PMC7711471). - Combined immunosuppressive therapy (methylprednisolone + cyclophosphamide ± dexamethasone) added to hemoperfusion was associated with improved survival (48% vs comparator) in a nationwide Taiwanese registry study (Lin et al., PLOS ONE 2014, PMID:24475310), and case series report favorable outcomes (Afzali & Gholyaf; PMC3348234) — though the overall evidence base remains weak and randomized-trial confirmation is lacking. - Genetic/molecular: No validated human protective genetic variant has been established; efflux-transporter (e.g., MDR1/P-glycoprotein) activity has been shown in vitro to reduce paraquat cytotoxicity in proximal tubule cells (Toxicol Sci, "MDR1 Transporter Protects Against Paraquat-Induced Toxicity in Human and Mouse Proximal Tubule Cells"), suggesting a plausible but unproven modifier locus.

Gene-environment interactions: The best-characterized gene-environment axis for paraquat is not the acute-poisoning phenotype but paraquat as an environmental risk modifier for idiopathic Parkinson's disease — where genetic background (e.g., variants affecting dopaminergic handling, mitochondrial quality control, or xenobiotic transport) is hypothesized to modulate individual susceptibility to paraquat-induced dopaminergic neurodegeneration (see Section 6/Section 2 crosslink below); this is an epidemiological association layer distinct from acute toxicity.

3. Phenotypes

Paraquat poisoning presents as a dose- and time-dependent, multi-organ symptom complex. Three broadly recognized clinical syndromes are described by ingested dose:

Syndrome	Approx. ingested dose	Course
Mild-moderate	<20 mg/kg	GI symptoms only; usually full recovery, occasional mild transient renal/hepatic changes
Moderate-severe	20–40 mg/kg	Multi-organ (renal, hepatic, cardiac) injury over days, followed by progressive pulmonary fibrosis over 1–4 weeks; often fatal
Fulminant	>40 mg/kg	Rapid multi-organ failure, refractory shock, death within 24–72 h ("hyperacute" form)

Symptoms / clinical signs (local, corrosive — onset minutes to hours): - Oropharyngeal, esophageal, and gastric ulceration and burning pain (HP:0000164 mouth ulcer / esophageal ulceration is not separately coded in HPO but is captured under "gastrointestinal ulceration") - Vomiting (HP:0002013 Vomiting), abdominal pain (HP:0002027 Abdominal pain), diarrhea (HP:0002014 Diarrhea) — frequent, near-universal after significant ingestion - Dysphagia/odynophagia from caustic esophagitis; rare esophageal perforation and mediastinitis with very concentrated/large ingestions

Systemic/organ-specific manifestations: - Renal: Acute kidney injury (HP:0001919 Acute kidney injury) from proximal tubular necrosis — often the earliest laboratory abnormality (creatinine rise within 24 h), and the single strongest early predictor of mortality - Hepatic: Elevated transaminases, hepatocellular injury, occasionally jaundice/liver failure (HP:0001392-type hepatic dysfunction) - Cardiovascular: Myocarditis, arrhythmia, and refractory hypotension/circulatory shock in severe poisoning (cardiogenic/circulatory collapse is the dominant fatal mechanism in the fulminant form) — HP:0001635 Congestive heart failure / cardiogenic shock phenotype - Pulmonary — the defining and most characteristic feature: - Early: hypoxemia, tachypnea - Delayed (days to weeks): progressive, often irreversible pulmonary fibrosis (HP:0002206 Pulmonary fibrosis) driven by alveolar epithelial injury, epithelial-mesenchymal transition-like fibrogenesis, and impaired reepithelialization ("paraquat lung"). Paradoxically, supplemental oxygen can worsen pulmonary injury in the acute phase by fueling further ROS generation via redox cycling, so oxygen is withheld unless the patient is significantly hypoxemic — an important, counter-intuitive clinical management point. - Radiographic pattern: initially patchy alveolar infiltrates progressing to diffuse ground-glass/honeycombing consistent with acute respiratory distress syndrome (ARDS)-like injury evolving into fibrosis - Metabolic: Metabolic acidosis (HP:0001942 Metabolic acidosis), hypoxemia (HP:0012418 Hypoxemia) - Neurological (rare, less characterized): Peripheral neuropathy and case reports of CNS demyelination following paraquat self-poisoning (systematic review, PMC11590890) — an emerging, still limited literature. - Cutaneous/local (occupational exposure): Contact dermatitis, chemical burns, nail changes with repeated dermal contact; corneal injury with ocular splash.

Age of onset / progression / frequency: Onset is acute (minutes–hours for local GI effects; hours–days for renal/hepatic failure; days–weeks for pulmonary fibrosis). Course is progressive in survivors of the acute phase who go on to develop fibrosis, and pulmonary fibrosis is the dominant determinant of subacute/delayed mortality in the moderate-severe group. GI symptoms are near-universal (approaching 100% after a substantial ingestion); AKI incidence is high in moderate-to-severe poisoning (studies report roughly one-third to over half of hospitalized cases, varying by cohort); pulmonary fibrosis develops in a substantial proportion of patients who survive the first several days after moderate-to-large ingestions.

Quality of life impact: Survivors with established pulmonary fibrosis face chronic dyspnea, oxygen dependence, and in the most severe cases require lung transplantation — itself associated with a complex, high-morbidity post-transplant course (see Section 12).

Suggested HPO terms: HP:0002013 (Vomiting), HP:0002027 (Abdominal pain), HP:0002014 (Diarrhea), HP:0001919 (Acute kidney injury), HP:0002206 (Pulmonary fibrosis), HP:0002094 (Dyspnea), HP:0012418 (Hypoxemia), HP:0001942 (Metabolic acidosis), HP:0001635 (Congestive heart failure / circulatory collapse phenotype), HP:0001392 (Abnormality of liver physiology).

4. Genetic/Molecular Information

Paraquat poisoning is not a Mendelian genetic disease — it is an acute toxicological exposure. There is no causal gene, pathogenic variant, or chromosomal abnormality that produces the disease; instead, "genetic/molecular information" for this entry is best modeled as host susceptibility/transporter genes that modulate uptake, distribution, and excretion, and (separately) the molecular targets of paraquat's toxic mechanism (covered fully in Section 6).

Transporter genes implicated in tissue uptake/handling (host susceptibility, not causal mutations): - SLC22A2 (OCT2, hgnc:11005): The principal transporter mediating renal tubular secretion/uptake of paraquat; overexpression of human OCT2 (but not OCT1 or OCT3) in HEK-293 cells markedly enhanced paraquat accumulation and cytotoxicity (Chen et al., "Transport of paraquat by human organic cation transporters and multidrug and toxic compound extrusion family," PMID:17495125). At toxic plasma concentrations, OCT2-mediated proximal tubular secretion itself becomes a route of self-injury: the transporter concentrates paraquat inside tubular cells, which then poisons the very secretory mechanism, and ultimately destroys the cells (renal AKI mechanism reviews, PMC4376530 / PMC5584253). - SLC22A3 (OCT3, hgnc:11043): Transports the monovalent paraquat radical cation and contributes to distribution into brain and other extra-renal tissues; implicated together with the dopamine transporter (SLC6A3/DAT) in paraquat neurotoxicity to dopaminergic neurons (Rappold et al., PNAS, "Paraquat neurotoxicity is mediated by the dopamine transporter and organic cation transporter-3," PMC3251116). - ABCB1 (MDR1/P-glycoprotein, hgnc:40): An efflux transporter shown in vitro to be protective against paraquat-induced cytotoxicity in human and mouse proximal tubule cells (Toxicological Sciences 2014), suggesting reduced MDR1 activity/expression could be a modifier of individual susceptibility to nephrotoxicity — not established in human epidemiology. - Pulmonary "polyamine uptake system": The lung's active, saturable uptake of paraquat (yielding 6–10× plasma concentration in lung tissue) has classically been attributed to a polyamine-transport-like carrier system; the precise molecular transporter(s) responsible for this pulmonary-selective concentration are still incompletely characterized at the single-gene level in the literature reviewed here and would need targeted confirmation before ontology binding.

Somatic vs. germline: Not applicable — no somatic mutational driver is implicated; this is a pharmacokinetic/toxicodynamic host-modifier question, not a mutation-driven disease.

Epigenetics: No paraquat-poisoning-specific human epigenetic signature was identified in this pass; epigenetic mechanisms (histone modification, DNA methylation) are, however, an active research area in the separate paraquat–Parkinson's-disease epidemiological literature (e.g., "Linking environmental risk factors with epigenetic mechanisms in Parkinson's disease," npj Parkinson's Disease 2023, PMC10457362), which is a distinct chronic-exposure/neurodegeneration question rather than the acute-poisoning phenotype.

Chromosomal abnormalities: Not applicable.

5. Environmental Information

Environmental/chemical factor (the disease-defining exposure): Paraquat dichloride, a quaternary-nitrogen bipyridyl herbicide formulated commercially (e.g., as Gramoxone) typically at 20% w/v concentration. Suggested exposure-term binding: ECTO term for "exposure to paraquat" (verify exact CURIE via OAK against ECTO; a general herbicide-exposure ECTO branch exists and should be searched for the paraquat-specific leaf term).

Routes of exposure: - Ingestion (dominant route for severe/fatal poisoning; deliberate self-poisoning is responsible for the great majority — cited as ~93% of fatalities in some series — of deaths) - Inhalation of spray mist during agricultural application (low systemic absorption via this route under normal use conditions, but relevant with heavy/prolonged occupational exposure or misuse) - Dermal absorption (minimal through intact skin; significant through abraded/broken skin or prolonged saturated-clothing contact) - Ocular splash exposure (local corneal/conjunctival injury)

Occupational/lifestyle factors: Agricultural work involving herbicide application without adequate personal protective equipment; storage/transfer of concentrated paraquat in unlabeled beverage containers (a recurrent, well-documented cause of accidental fatal ingestion, especially of children); rural/agrarian residence in regions where paraquat remains legally available.

Infectious agents: Not applicable — paraquat poisoning is a purely chemical/toxicological disease with no infectious component (though secondary infection, e.g., ventilator-associated pneumonia or catheter-related sepsis, is a recognized complication of prolonged critical illness in survivors).

6. Mechanism / Pathophysiology

Causal chain overview: ingestion → mucosal/GI corrosive injury → systemic absorption (variable, generally poor oral bioavailability, ~5–10% but sufficient at high doses to be lethal) → selective, active, saturable pulmonary and renal tissue concentration → intracellular redox cycling and reactive-oxygen-species generation → lipid peroxidation, NADPH depletion, mitochondrial dysfunction, and direct cytotoxicity → acute organ injury (kidney, liver, heart) in the near term and progressive fibrogenic remodeling (lung) in the medium term → multi-organ failure and/or respiratory failure as terminal common pathways.

Molecular mechanism — redox cycling (the central, defining mechanism): Paraquat is a redox-active dication (PQ²⁺). Intracellularly it is reduced by one electron — chiefly via mitochondrial Complex I (NADH:ubiquinone oxidoreductase) — to the paraquat radical monocation (PQ•⁺), which then reacts non-enzymatically with molecular oxygen to regenerate PQ²⁺ while producing superoxide anion (O₂•⁻). This cycle repeats catalytically, consuming NADPH/NADH and continuously generating ROS. Complex I was identified as the major site of mitochondrial superoxide production by paraquat (Cochemé & Murphy, J Biol Chem; "Complex I Is the Major Site of Mitochondrial Superoxide Production by Paraquat"). NADPH oxidase (NOX) is a second major site of redox cycling, particularly in phagocytic/microglial cells, generating extracellular superoxide (search results on NADPH-oxidase–mediated paraquat/maneb oxidative stress). Superoxide is dismutated to hydrogen peroxide and, via Fenton-type chemistry, to the highly reactive hydroxyl radical, which attacks polyunsaturated fatty acids in membrane phospholipids, initiating lipid peroxidation and membrane destruction. This ROS burden also depletes cellular NADPH reserves needed for glutathione regeneration, compounding oxidative injury (GO:0006979 response to oxidative stress; GO:0055114 oxidation-reduction process; GO:0006749 glutathione metabolic process).

Structural analogy to MPP+/Parkinsonian toxins: Paraquat (PQ²⁺) is structurally similar to 1-methyl-4-phenylpyridinium (MPP⁺), the active dopaminergic neurotoxic metabolite of MPTP; both are taken up via cation transporters (dopamine transporter, OCT3) into dopaminergic neurons, generate ROS, and have been used experimentally to model nigrostriatal degeneration in Parkinson's disease research (PMC5082881; PNAS PMC3251116). This mechanistic parallel underlies the long-standing epidemiological hypothesis linking chronic low-dose paraquat exposure to Parkinson's disease risk (Section 2).

Ferroptosis and Nrf2/Keap1 signaling: Recent mechanistic work implicates ferroptosis — iron-dependent lipid peroxidative cell death — as a specific contributor to paraquat-induced pulmonary fibrosis, mediated through Keap1/Nrf2 signaling dysregulation ("Molecular mechanism of paraquat-induced ferroptosis leading to pulmonary fibrosis mediated by Keap1/Nrf2 signaling pathway," PMC10635988). GO:0097707 (ferroptosis) is a candidate process term.

Fibrogenic cascade in the lung (the disease-defining subacute mechanism): 1. Selective, active pulmonary uptake concentrates paraquat 6–10-fold above plasma in alveolar type I and type II epithelial cells and Clara (club) cells (via the classical "polyamine uptake system"). 2. Redox-cycling ROS generation causes diffuse alveolar epithelial injury and death, producing an early alveolitis/ARDS-like picture. 3. Surviving/regenerating alveolar epithelial cells undergo an epithelial-mesenchymal transition (EMT)-like fibrogenic response, with resistance to apoptosis and acquisition of a pro-fibrotic phenotype (PMC4370722, "Paraquat Induces Epithelial-Mesenchymal Transition-Like Cellular Response..."). 4. NF-κB and JNK/p38 MAPK signaling pathways are activated, driving pro-inflammatory and pro-fibrotic gene programs (PMC5396433, liver X receptor agonist attenuation study). 5. Excess extracellular matrix deposition (GO:0030198 extracellular matrix organization) by activated (myo)fibroblasts (CL:0000186) produces progressive interstitial fibrosis, culminating in restrictive lung physiology and, in the most severe cases, respiratory failure over 1–4 weeks — the classical "delayed progressive pulmonary fibrosis" of subacute paraquat poisoning.

Renal mechanism: Active tubular secretion of paraquat by OCT2 concentrates the compound within proximal tubular epithelial cells (CL:0002306/CL candidate: proximal tubule epithelial cell), where redox cycling drives tubular necrosis; this is compounded by systemic oxidative stress from other organs. Early creatinine rise reflects both true tubular injury and a component of systemic oxidative-stress-driven renal dysfunction (PLOS ONE, "Mechanisms Underlying Early Rapid Increases in Creatinine in Paraquat Poisoning," PMC4376530). AKI is a strong independent mortality predictor.

Cardiac and hepatic injury: Direct oxidative myocardial and hepatocellular injury via the same redox-cycling mechanism, contributing to circulatory collapse (dominant fatal mechanism in fulminant, high-dose poisoning) and hepatic dysfunction/failure in severe cases.

Cell types involved (candidate CL terms): CL:0002063 (type I pneumocyte), CL:0002062 (type II pneumocyte), CL:0000158 (Clara/club cell), CL:0000186 (myofibroblast), proximal tubule epithelial cell (CL candidate), CL:0000700 (dopaminergic neuron, relevant to the PD-association literature), CL:0000129 (microglial cell, implicated in NOX-mediated CNS oxidative injury).

Candidate GO biological process terms: GO:0006979 (response to oxidative stress), GO:0034599 (cellular response to oxidative stress), GO:0055114 (oxidation-reduction process), GO:0006749 (glutathione metabolic process), GO:0097707 (ferroptosis), GO:0030198 (extracellular matrix organization), GO:0097237 (cellular response to toxic substance), GO:0006915 (apoptotic process).

Molecular profiling: An iTRAQ quantitative proteomic study has identified candidate serum biomarkers of acute paraquat poisoning in humans (PMC9078879), an early step toward systems-level (proteomic) characterization; comprehensive transcriptomic/metabolomic paraquat-poisoning-specific human datasets were not identified in this pass (much of the -omics literature instead concerns paraquat as an experimental oxidative-stress or Parkinson's-model tool rather than clinical poisoning cohorts).

7. Anatomical Structures Affected

Organ level: - Primary target organs: Lung (the organ most characteristically and often fatally affected — UBERON:0002048), kidney (UBERON:0002113, especially the proximal tubule), and the gastrointestinal tract (oropharynx, esophagus, stomach — direct corrosive contact site; UBERON:0001043 esophagus) - Secondary/complication organs: Liver (UBERON:0002107, hepatocellular injury), heart (UBERON:0000948, myocarditis/circulatory collapse), and less consistently the central and peripheral nervous system (rare demyelination/neuropathy reports) - Body systems involved: Respiratory, renal, gastrointestinal, hepatic, cardiovascular, and (uncommonly) nervous systems — i.e., a multi-system toxidrome.

Tissue and cell level: - Respiratory epithelium — alveolar type I/II pneumocytes and club (Clara) cells (the selective site of pulmonary paraquat concentration) - Renal proximal tubular epithelium (the selective site of tubular secretion/reabsorption-mediated concentration) - Gastrointestinal squamous/columnar mucosa (direct corrosive contact injury) - Hepatocytes - Cardiac myocytes - In the chronic/PD-association literature: nigrostriatal dopaminergic neurons of the substantia nigra pars compacta (UBERON:0002038) and associated microglia

Subcellular level: Mitochondria (Complex I as the principal intracellular site of paraquat-driven superoxide generation; GO Cellular Component: GO:0005743 mitochondrial inner membrane), plasma membrane/lipid bilayer (site of lipid peroxidation), and — via NADPH oxidase — the cell membrane-associated NOX complex.

Localization: Bilateral, diffuse pulmonary involvement (not focal/unilateral); bilateral renal involvement; systemic (not lateralized) disease overall.

8. Temporal Development

Onset: Acute, occurring within minutes to hours of ingestion for local corrosive/GI effects, within 24–72 hours for renal/hepatic/cardiac injury, and over days to 1–4 weeks for the defining delayed pulmonary fibrosis.

Progression / disease course pattern (dose-stratified, as in Section 3): - Mild-moderate poisoning: Self-limited, typically resolving GI symptoms with supportive care; may have transient, reversible organ dysfunction. - Moderate-severe poisoning: A biphasic/triphasic course — initial GI/corrosive phase, followed by an organ-failure phase (renal/hepatic/cardiac, days 1–4), followed by a progressive pulmonary-fibrotic phase (days–weeks) that is frequently the ultimate cause of death. - Fulminant (massive-dose) poisoning: Rapid, unremitting multi-organ failure and refractory circulatory shock, typically fatal within 24–72 hours, often before pulmonary fibrosis has time to develop.

Critical period for intervention: The first ~12–24 hours after ingestion is the critical window for gastrointestinal decontamination and hemoperfusion, since paraquat distributes irreversibly into tissue compartments after this window, sharply reducing the efficacy of extracorporeal removal.

Disease duration: Ranges from self-limited (days, in mild ingestions) to a protracted, weeks-to-months critical illness culminating in death or, in a minority of survivors, chronic pulmonary fibrosis requiring long-term oxygen support or lung transplantation.

Remission: Full recovery is possible after low-dose ingestion; there is no described spontaneous remission pattern once significant pulmonary fibrosis is established — the mechanism is progressive rather than fluctuating.

9. Inheritance and Population

Paraquat poisoning is not a heritable genetic disease; inheritance-pattern fields (AD/AR/X-linked, penetrance, expressivity, anticipation, mosaicism, founder effect, consanguinity, carrier frequency) are not applicable.

Epidemiology: - Pesticide self-poisoning as a whole is estimated to account for a substantial share of global suicide deaths, disproportionately concentrated in rural areas of low- and middle-income countries in Asia and the Pacific. - Paraquat specifically has historically been one of the most lethal agents used, with an estimated ~20 deaths per million persons worldwide attributable to paraquat as a suicide method in earlier global estimates, and it has been described as the most frequently used self-poisoning agent in some national settings (e.g., historically in South Korea and Trinidad). - ~93% of fatalities from paraquat intoxication are reported as suicides, occurring predominantly in developing/agrarian countries (search-derived synthesis of pesticide-suicide epidemiology literature; see also "Suicide by intentional ingestion of pesticides: A continuing tragedy in developing countries").

Mortality: Global case-fatality estimates are consistently high, generally cited in the 35–70%+ range across cohorts, with some sources citing an overall mortality around 60% and others up to 70–90% depending on dose distribution and access to care; mortality is strongly right-shifted toward the lethal end because ingestion is so often deliberate and at high concentration.

Geographic distribution: Historically concentrated in agrarian regions of East/Southeast Asia (China, South Korea historically before its ban, other parts of Asia-Pacific), parts of Latin America and the Caribbean (e.g., Trinidad), and Sub-Saharan Africa where paraquat has remained available; incidence has fallen sharply in jurisdictions that banned or restricted paraquat sale (see Section 13 and regulatory notes below).

Age/sex distribution: Case series generally show a predominance of working-age adults with agricultural access; sex distribution varies by setting/study, reflecting local patterns of self-harm method choice rather than a biological sex-specific susceptibility.

Regulatory/geographic status as of 2024–2026 (relevant population-exposure context): Paraquat is banned or severely restricted in more than 70 countries, including the European Union, China, Brazil, Canada, and — as of 2024 — Nigeria. It remains registered and in agricultural use in the United States (subject to restricted-use/certified-applicator rules tightened in 2016 after fatal accidental exposures), with U.S. EPA regulatory review ongoing (the EPA removed a 2021 interim risk-mitigation decision in January 2025) and state-level actions underway (e.g., a 2026 voluntary registration cancellation by Syngenta in California, and California legislative proposals to phase out paraquat by end of 2025). It also remains registered in India, Japan, and Australia among other countries.

10. Diagnostics

Clinical/laboratory tests: - Urine dithionite (sodium hydrosulfite) colorimetric test: A rapid, low-cost bedside qualitative screening test — a blue/blue-green color change on adding alkaline sodium dithionite to urine indicates the presence of paraquat and roughly correlates with severity (used widely in resource-limited settings for triage). - Plasma/serum paraquat concentration (measured by spectrophotometry historically, and by LC-MS/MS in modern laboratories) — the single most validated quantitative prognostic test, plotted against time-since-ingestion on validated nomograms (see below). - Routine chemistry: serum creatinine (early rise is a key marker of renal injury and independent mortality predictor), liver enzymes, arterial blood gas/lactate, and inflammatory markers. - Novel/investigational biomarkers: urinary NGAL (neutrophil gelatinase-associated lipocalin, elevated in AKI but not independently predictive of death), urinary cystatin C (reflecting altered proximal-tubular reuptake/degradation and confirming tubular injury), and serum proteomic panels under investigation (PMC9078879).

Prognostic/severity scoring tools: - Proudfoot nomogram (1979): Relates outcome to plasma paraquat concentration at a given time post-ingestion (valid for samples drawn 4–24 h post-ingestion). - Scherrmann extension (1987): Extends the nomogram's applicability beyond 24 hours post-ingestion. - Severity Index for Paraquat Poisoning (SIPP), Sawada et al.: SIPP = elapsed time from ingestion to arrival (hours) × serum paraquat concentration (µg/mL). SIPP <10 → good prognosis; SIPP 10–50 → high risk of death from progressive pulmonary fibrosis/organ failure; SIPP >50 → typically rapid death from circulatory collapse. - APACHE II score and serum lactate have also been evaluated (sometimes in combination with SIPP) as prognostic tools in Chinese cohorts. - More recent prognostic nomograms integrating multiple clinical variables for predicting in-hospital mortality have been developed and validated (Scientific Reports 2023, doi:10.1038/s41598-023-50722-z).

Imaging: Chest radiography/CT showing progression from patchy alveolar infiltrates (early) to diffuse ground-glass and honeycomb fibrotic change (late) tracks the pulmonary phase.

Differential diagnosis: Other causes of acute corrosive ingestion (other herbicides/pesticides, especially diquat — a related bipyridyl compound with a similar corrosive/multi-organ-failure profile but without paraquat's selective pulmonary accumulation and characteristic fibrosis), ARDS from other etiologies, and other causes of rapidly progressive interstitial lung disease in a patient without a clear ingestion history.

Genetic testing: Not applicable/not indicated — this is not a heritable disease and there is no clinically validated genetic test for paraquat susceptibility.

Screening: No population screening program exists; the principal "screening" intervention at the population level is public-health means restriction (regulatory withdrawal, reformulation with deterrents, or licensing controls) rather than individual biomarker screening.

11. Outcome/Prognosis

Survival/mortality: Case-fatality is high across the literature, commonly cited in the range of ~35–70%, with some series (particularly those enriched for intentional, high-dose ingestion) reporting up to 70–90% mortality. Death from progressive pulmonary fibrosis typically occurs over 1–4 weeks after ingestion in the moderate-dose group; death from circulatory collapse/multi-organ failure typically occurs within 24 hours to a few days in the high-dose group.

Key prognostic factors: Ingested dose/plasma paraquat concentration (the dominant factor, formalized in the Proudfoot/Scherrmann nomograms and SIPP), time from ingestion to treatment (earlier decontamination/hemoperfusion improves outcome), development of AKI (strongly associated with mortality — 70.1% vs 40.0% in AKI vs non-AKI patients), and age (younger patients, e.g., <45 years, have shown better survival in some immunosuppressive-therapy cohorts).

Morbidity in survivors: The principal long-term morbidity is chronic restrictive lung disease from established pulmonary fibrosis, which can progress to end-stage respiratory failure requiring long-term oxygen or lung transplantation. Renal recovery is variable; some patients develop chronic kidney disease after severe AKI. Case reports also describe delayed neurological sequelae (demyelination, peripheral neuropathy) though this is not well quantified epidemiologically.

Complications: Esophageal stricture/perforation and mediastinitis (from corrosive injury), secondary nosocomial infection during prolonged critical illness, and — in the small subset undergoing lung transplantation — the full range of transplant-related complications (graft dysfunction, rejection, infection, weaning failure from mechanical ventilation) (case-based reviews, PMC12868150; PMC10387547).

Recovery potential: Full recovery is achievable after low-dose ingestion with prompt supportive care; recovery after moderate-severe poisoning is possible but guarded and dependent on whether pulmonary fibrosis becomes established; recovery after fulminant, massive-dose poisoning is exceedingly rare.

12. Treatment

There is no specific antidote for paraquat poisoning; management is supportive, decontamination-focused, and — for the fibrotic/organ-failure phase — largely investigational, with a generally weak evidence base for any single intervention.

Gastrointestinal decontamination (early, time-critical): - Activated charcoal or Fuller's earth/bentonite clay administered as soon as possible after ingestion to adsorb unabsorbed paraquat and limit systemic exposure — NCIT candidate term: NCIT:C1445 (Activated Charcoal) as a therapeutic agent under a general decontamination/pharmacotherapy treatment_term. - Gastric lavage may be considered very early after ingestion in some protocols, though evidence and practice vary.

Extracorporeal removal: - Hemoperfusion (charcoal or resin cartridge) — theoretically attractive because it removes paraquat directly from blood, but overall trial evidence for a survival benefit is weak/mixed; some retrospective analyses suggest benefit only when performed early (within ~12 h) and repeatedly (PMC7711471), reflecting the narrow window before tissue redistribution. - Hemodialysis — similarly limited by rapid tissue distribution and reduced efficacy after the first ~24 hours, further diminished once tubular necrosis reduces renal clearance. - Continuous renal replacement therapy (CRRT) for established AKI, primarily as supportive renal-failure management rather than a paraquat-elimination strategy per se.

Immunosuppressive therapy (targeting the inflammatory/fibrogenic cascade): - Combination pulse methylprednisolone + cyclophosphamide ± dexamethasone is the most widely studied regimen; a nationwide Taiwanese registry analysis found immunosuppressive therapy added to hemoperfusion associated with improved survival (48% vs lower in comparator groups, p<0.001), with the greatest benefit in patients under 45 (Lin et al., PLOS ONE 2014, PMID:24475310). A small case series (n=9) using pulse cyclophosphamide/methylprednisolone reported 100% survival, though this is a very small, likely selected sample. Overall the evidence remains "very weak" per multiple reviews, and randomized controlled trial data are lacking. NCIT candidate terms: NCIT:C15632 (Chemotherapy) treatment_term with therapeutic_agent cyclophosphamide (CHEBI candidate) and corticosteroids.

Antioxidant therapy (adjunctive, mechanistically motivated but weakly evidenced): - N-acetylcysteine (NAC), vitamin C, and vitamin E have been used to scavenge ROS and support glutathione regeneration, consistent with the redox-cycling mechanism, though clinical efficacy data are limited and mostly derived from small studies/case series.

Oxygen therapy — a critical caveat, not a straightforward supportive measure: - Supplemental oxygen is generally withheld unless the patient is significantly hypoxemic, because hyperoxia can potentiate paraquat's redox-cycling ROS generation and worsen pulmonary injury — a distinctive, mechanism-driven deviation from standard critical-care oxygen practice.

Definitive/last-resort therapy: - Lung transplantation has been performed in selected survivors with progressive, irreversible pulmonary fibrosis after systemic paraquat clearance, sometimes bridged with ECMO. Case reports and small reviews (8 reports/11 patients; a more recent review of 15 cases) describe generally encouraging but heterogeneous outcomes, with careful timing (waiting for hepatorenal recovery), infection prevention, and multidisciplinary perioperative management identified as key to success (PMID:36626514; PMC10387547; PMC12868150; PMC8660696). NCIT candidate term: NCIT:C15289 (Organ Transplantation).

Experimental/investigational directions: Preclinical work targeting Nrf2/Keap1 signaling, ferroptosis inhibition, NF-κB/JNK–p38 MAPK pathway modulation (e.g., liver X receptor agonist TO901317 in mouse models, PMC5396433), and pirfenidone (an antifibrotic approved for idiopathic pulmonary fibrosis) has shown protective effects against paraquat-induced lung injury/fibrosis in animal models, representing candidate translational targets not yet established in human treatment guidelines.

Treatment algorithm summary: (1) Immediate GI decontamination if within the window; (2) supportive/organ-support care (fluid resuscitation, renal replacement as needed, cautious oxygen use); (3) consider early, repeated hemoperfusion if very early presentation; (4) consider pulse immunosuppressive therapy in moderate-severe poisoning, weighing infection risk; (5) antioxidant adjuncts; (6) evaluate for lung transplantation in survivors with established, progressive, irreversible fibrosis once systemic toxicity has cleared.

13. Prevention

Primary prevention — means restriction (the dominant, best-evidenced strategy): Because the great majority of severe/fatal paraquat poisoning is intentional self-poisoning enabled by ready access to a highly lethal concentrated agent, regulatory restriction of paraquat availability is the single most impactful and best-documented prevention strategy at a population level: - National bans or severe restrictions (now covering 70+ countries, including the EU, China, Brazil, Canada, and — as of 2024 — Nigeria) have been followed by measurable declines in pesticide-suicide mortality in several jurisdictions, without simple full substitution to other lethal methods (South Korea paraquat-prohibition analysis, Cha et al., PLOS ONE 2015). - Reformulation strategies short of outright bans — reduced concentration, addition of an emetic, a stenching/warning agent, and a blue dye to discourage confusion with beverages — have also been used to reduce lethality of accidental/impulsive ingestions. - U.S. regulatory status remains under active review (restricted-use/certified-applicator requirements since 2016; EPA's 2025 removal of a 2021 interim decision; ongoing state-level legislative and voluntary-registrant actions such as California's 2026 cancellation).

Occupational/behavioral prevention: - Personal protective equipment, restricted/certified-applicator licensing, and safe storage/labeling practices (never storing paraquat in unlabeled drink bottles) to reduce accidental occupational and household exposure.

Secondary prevention: - Rapid recognition and immediate decontamination (activated charcoal/Fuller's earth) at first medical contact is the most time-critical secondary-prevention measure, given the narrow window before irreversible tissue distribution. - Rural health-worker and community education to shorten time-to-presentation after ingestion.

Public health / suicide-prevention framing: - Paraquat restriction is a widely cited exemplar of the "means restriction" approach to suicide prevention (paralleling the broader evidence base from Sri Lanka's WHO Class I/II pesticide restrictions), on the rationale that highly lethal, impulsively accessible methods disproportionately convert a suicide attempt into a death, and restricting access reduces population suicide mortality even without addressing underlying psychiatric drivers directly.

Prophylaxis: No pharmacological prophylaxis exists; prevention is exposure-control based, not medication-based.

14. Other Species / Natural Disease

Paraquat poisoning is not a naturally occurring disease of non-human species in the sense of a spontaneous veterinary condition, but accidental and occasionally deliberate paraquat poisoning is a recognized veterinary and wildlife toxicology entity:

Companion and farm animals (dogs, cats, livestock — NCBITaxon:9615 Canis lupus familiaris, NCBITaxon:9685 Felis catus, NCBITaxon:9913 Bos taurus, etc.) can be accidentally poisoned via contaminated feed, water, or direct ingestion of herbicide, presenting with the same core toxidrome (GI corrosive injury, renal injury, and progressive pulmonary fibrosis), and this is documented in the veterinary toxicology literature (search for veterinary paraquat case reports/OMIA was not exhaustively pursued in this pass; recommend a targeted OMIA/veterinary-toxicology literature search if this section needs deeper sourcing).
Wildlife exposure (birds, in particular) via contaminated agricultural runoff or direct ingestion of treated vegetation is documented in environmental-toxicology literature, though this is an ecotoxicology question distinct from clinical veterinary poisoning.
Comparative pathology: The core mechanism — selective pulmonary uptake, redox cycling, and progressive fibrosis — appears broadly conserved across mammalian species, which is precisely what underlies the extensive use of rodent models (Section 15).
Zoonotic potential: Not applicable — paraquat poisoning is a toxicological, not infectious, condition, so there is no zoonotic transmission dimension; however, cross-species susceptibility to the same chemical mechanism is expected wherever the relevant transporters (OCT-family) and mitochondrial Complex I are conserved.

15. Model Organisms

Paraquat is one of the most widely used experimental toxicants precisely because it reliably reproduces two distinct human disease phenotypes in model systems: pulmonary fibrosis and dopaminergic neurodegeneration (Parkinsonian) phenotypes.

Rodent models (pulmonary fibrosis): - Mouse (Mus musculus, NCBITaxon:10090): Intraperitoneal injection (a commonly used protocol reports paraquat 40 mg/kg IP producing optimal pulmonary fibrosis by 2 weeks post-injection, with diffuse alveolar thickening and interstitial fibrosis on histology) and intratracheal aerosolized delivery (e.g., 0.02 mg/mouse) are both used, with intratracheal delivery cited as producing more homogeneous lesion distribution across the lung. There is no single standardized dosing protocol across the field — gastric gavage, intraperitoneal injection, and intratracheal instillation are all used, with intraperitoneal injection most common (search synthesis of multiple mouse-model papers, including PMC9011139/"Paraquat Induces Lung Injury via miR-199-Mediated SET in a Mouse Model"). - Rat (Rattus norvegicus, NCBITaxon:10116): Also used for paraquat-induced lung-injury/fibrosis modeling, often compared against the bleomycin model (the other classical chemical-induction model for pulmonary fibrosis). - Fidelity/limitations: These models recapitulate the redox-cycling, alveolar-epithelial-injury, and fibrogenic-remodeling cascade reasonably well and are used to test antifibrotic/antioxidant candidate therapies (e.g., pirfenidone, LXR agonists), but do not fully reproduce the human multi-organ (renal/hepatic/cardiac) failure syndrome seen after oral ingestion, since dosing routes differ from the human ingestion route and dose selection is optimized for the pulmonary endpoint specifically.

Rodent and invertebrate models (Parkinsonian/dopaminergic neurodegeneration): - Mouse: Systemic paraquat administration (often combined with the fungicide maneb for synergistic effect) is a standard chemical model of nigrostriatal dopaminergic neuron loss and microglial activation in the substantia nigra pars compacta, used to probe Parkinson's-disease-relevant mechanisms (PMC5082881, "Assessment of the Effects of MPTP and Paraquat on Dopaminergic Neurons and Microglia in the Substantia Nigra Pars Compacta of C57BL/6 Mice"). - Drosophila melanogaster (NCBITaxon:7227): Paraquat feeding is a classical oxidative-stress/Parkinsonian-phenotype assay in flies; a 2025 genome-wide screen identified genes mediating resistance to paraquat-induced neurodegeneration in Drosophila, offering candidate modifier loci for translational follow-up (bioRxiv preprint, 2025.04.02.646829). - C. elegans: Also used as a rapid, genetically tractable oxidative-stress/paraquat-exposure model system, though not detailed in the sources retrieved here.

Model limitations (general): No single model captures the full human clinical picture (GI corrosive injury + renal + hepatic + cardiac + delayed pulmonary fibrosis, in a dose- and time-dependent cascade following oral ingestion). Pulmonary-fibrosis rodent models typically bypass the GI/systemic-absorption step (via IP or intratracheal dosing) and so are best understood as models of the downstream fibrogenic mechanism rather than the complete ingestion-poisoning syndrome; Parkinsonian models use chronic low-dose systemic exposure distinct from the acute high-dose ingestion scenario that defines clinical "paraquat poisoning."

Applications: Rodent lung models are used to test candidate antifibrotic/antioxidant therapeutics and to dissect the Nrf2/Keap1-ferroptosis and NF-κB/MAPK signaling pathways; Drosophila/mouse Parkinsonian models are used to study gene-environment interaction and neurodegeneration mechanism, informing (but not proving) the human paraquat-Parkinson's-disease epidemiological association.

Ontology Term Suggestions Summary (for curator verification via OAK)

Category	Candidate terms (verify before binding)
HPO	HP:0002013 Vomiting; HP:0002027 Abdominal pain; HP:0002014 Diarrhea; HP:0001919 Acute kidney injury; HP:0002206 Pulmonary fibrosis; HP:0002094 Dyspnea; HP:0012418 Hypoxemia; HP:0001942 Metabolic acidosis
GO (biological process)	GO:0006979 response to oxidative stress; GO:0034599 cellular response to oxidative stress; GO:0055114 oxidation-reduction process; GO:0006749 glutathione metabolic process; GO:0097707 ferroptosis; GO:0030198 extracellular matrix organization; GO:0006915 apoptotic process
CL	type I pneumocyte; type II pneumocyte; club (Clara) cell; myofibroblast; proximal tubule epithelial cell; dopaminergic neuron; microglial cell
UBERON	UBERON:0002048 lung; UBERON:0002113 kidney; UBERON:0002107 liver; UBERON:0000948 heart; UBERON:0001043 esophagus; UBERON:0002038 substantia nigra
CHEBI	CHEBI:34905 paraquat dichloride (verify canonical form)
NCIT (treatment)	NCIT:C1445 Activated Charcoal; NCIT:C15632 Chemotherapy (cyclophosphamide regimen); NCIT:C15289 Organ Transplantation; NCIT:C15986 Pharmacotherapy
HGNC (transporter genes)	SLC22A2 (OCT2, hgnc:11005); SLC22A3 (OCT3, hgnc:11043); ABCB1 (MDR1, hgnc:40)

Key Citations

Dinis-Oliveira RJ et al. Paraquat poisonings: mechanisms of lung toxicity, clinical features, and treatment. Crit Rev Toxicol. 2008. PMID:18161502
Paraquat poisoning: an overview of the current status. PMID:2198050
Chen Y et al. Transport of paraquat by human organic cation transporters and multidrug and toxic compound extrusion family. PMID:17495125
Lin JL et al. Addition of immunosuppressive treatment to hemoperfusion is associated with improved survival after paraquat poisoning: a nationwide study. PLOS ONE. 2014. PMID:24475310
Cochemé HM, Murphy MP. Complex I is the major site of mitochondrial superoxide production by paraquat. J Biol Chem.
Rappold PM et al. Paraquat neurotoxicity is mediated by the dopamine transporter and organic cation transporter-3. PNAS. PMC3251116
Molecular mechanism of paraquat-induced ferroptosis leading to pulmonary fibrosis mediated by Keap1/Nrf2 signaling pathway. PMC10635988
Paraquat Induces Epithelial-Mesenchymal Transition-Like Cellular Response Resulting in Fibrogenesis... PMC4370722
Predictors of acute kidney injury after paraquat intoxication. Oncotarget. PMC5584253
Mechanisms Underlying Early Rapid Increases in Creatinine in Paraquat Poisoning. PLOS ONE. PMC4376530
Development and validation of a prognostic nomogram for predicting in-hospital mortality of patients with acute paraquat poisoning. Sci Rep. 2023. doi:10.1038/s41598-023-50722-z
Cha ES et al. Paraquat Prohibition and Change in the Suicide Rate and Methods in South Korea. PLOS ONE. 2015.
Lung transplantation in a woman with paraquat poisoning that led to pulmonary fibrosis: A case report. PMID:36626514
Case Report: Multifactorial weaning failure after lung transplantation in paraquat-induced pulmonary fibrosis. PMC12868150
The Link Between Paraquat and Demyelination: A Review of Current Evidence. PMC11590890
Van Maele-Fabry G, meta-analysis of pesticide exposure and Parkinson's disease risk (summary risk ratio ~1.6, referenced via secondary sources)
Genome-wide analysis reveals genes mediating resistance to paraquat neurodegeneration in Drosophila. bioRxiv 2025.04.02.646829

Note on evidence completeness: This report synthesizes disease-level literature (toxicology reviews, cohort/registry studies, case reports, mechanistic and animal-model papers, and regulatory-status sources) retrieved via targeted web/PubMed-indexed searches conducted August 2026. Several sections (precise MONDO ID, exhaustive gene-frequency/variant data — not applicable given the non-genetic etiology, and comprehensive veterinary/wildlife case literature) would benefit from direct database queries (MONDO release browser, OMIA, PubMed full-text search) beyond what a search-engine-mediated pass can confirm, and all PMIDs and ontology term candidates listed above should be independently re-verified (e.g., via OAK runoak info lookups) before being bound into a curated knowledge-base entry, consistent with standard anti-hallucination practice for AI-assisted curation.

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	23
Resolved	23
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	23
On topic	14
Off topic	0

All extracted references resolved successfully.

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Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Medical Actions

Environmental Factors

Diagnosis

Source YAML

References & Deep Research

Deep Research

Paraquat Poisoning — Comprehensive Research Report

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

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

Ontology Term Suggestions Summary (for curator verification via OAK)

Key Citations

Reference Validation