Organophosphate Poisoning

Environmental MONDO:0800386 Pathograph 22 Show in embeddings browser pesticide poisoning

Organophosphate poisoning is a toxic condition caused by exposure to organophosphorus compounds, most commonly organophosphate insecticides (e.g., chlorpyrifos, parathion, malathion, dimethoate) and chemical-warfare nerve agents (e.g., sarin, VX). It is a leading cause of fatal pesticide self-poisoning worldwide, particularly in agricultural regions of low- and middle-income countries, and also occurs through occupational and accidental exposure. The unifying mechanism is inhibition of acetylcholinesterase: the active compound phosphorylates the enzyme's catalytic serine, preventing hydrolysis of acetylcholine, which then accumulates at cholinergic synapses. Overstimulation of muscarinic receptors, nicotinic receptors, and central cholinergic pathways produces the acute cholinergic crisis (miosis, hypersalivation, bronchorrhea, bradycardia, diarrhea, fasciculations, muscle weakness, seizures, and respiratory failure). Over hours the phosphorylated enzyme can undergo irreversible "aging," and some patients develop an intermediate syndrome of proximal and respiratory muscle weakness or, weeks later, an organophosphate-induced delayed polyneuropathy. Treatment combines decontamination, the muscarinic antagonist atropine, the cholinesterase reactivator pralidoxime, benzodiazepines for seizures, and ventilatory support.

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1
Mappings
1
Definitions
12
Pathophys.
15
Phenotypes
1
Gaps
22
Pathograph
1
Genes
6
Medical Actions
3
Subtypes
1
Deep Research
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Mappings

MONDO
MONDO:0800386 organophosphate poisoning
skos:exactMatch MONDO
Primary MONDO disease identifier for this organophosphate poisoning entry.
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Definitions

1
Clinical case definition for organophosphate poisoning
Organophosphate poisoning is a cholinergic toxic syndrome caused by organophosphorus compounds that inhibit acetylcholinesterase, leading to acetylcholine accumulation and overstimulation of muscarinic and nicotinic receptors, confirmed by depressed blood cholinesterase activity in a compatible exposure context.
CASE_DEFINITION Disease-level clinical framing across acute crisis and delayed syndromes
Show evidence (1 reference)
PMID:37888716 SUPPORT Other
"The primary mechanism, common among all OPs, that initiates their toxic effects is the inhibition of acetylcholinesterase."
Supports acetylcholinesterase inhibition as the unifying mechanism defining the disease.
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Subtypes

3
Acute Cholinergic Crisis
The immediate syndrome following organophosphate exposure, driven by acetylcholine accumulation: muscarinic features (miosis, hypersalivation, bronchorrhea, bradycardia, diarrhea), nicotinic features (fasciculations, muscle weakness), and central features (seizures, coma), with respiratory failure the principal cause of death.
Show evidence (1 reference)
PMID:37888716 SUPPORT Other
"In acute OP exposure, the subsequent surge of acetylcholine in cholinergic synapses causes a peripheral cholinergic crisis and status epilepticus (SE), either of which can lead to death."
Supports the acute cholinergic crisis as the immediate syndrome from acetylcholine surge.
Intermediate Syndrome
A syndrome of proximal limb, neck flexor, cranial nerve, and respiratory muscle weakness appearing roughly 24-96 hours after the cholinergic crisis, attributed to prolonged neuromuscular-junction dysfunction; it can precipitate respiratory failure after the acute crisis has resolved and does not respond to atropine or oximes.
Show evidence (1 reference)
PMID:3029588 SUPPORT Human Clinical
"We observed 10 patients who had paralysis of proximal limb muscles, neck flexors, motor cranial nerves, and respiratory muscles 24 to 96 hours after poisoning, after a well-defined cholinergic phase."
The original description establishing the intermediate syndrome as a distinct entity 24-96 hours after the cholinergic phase.
Organophosphate-Induced Delayed Polyneuropathy (OPIDN) MONDO:0957912
MONDO MONDO:0957912
A distal, predominantly motor sensorimotor axonopathy appearing 1-3 weeks after exposure to certain organophosphates, caused by inhibition and aging of neuropathy target esterase (NTE/PNPLA6) rather than acetylcholinesterase.
Show evidence (1 reference)
PMID:16042503 SUPPORT Other
"It is characterised by distal degeneration of some axons of both the peripheral and central nervous systems occurring 1-4 weeks after single or short-term exposures."
Defines OPIDN as a distal axonopathy occurring 1-4 weeks after exposure.
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Discussions and Knowledge Gaps

1
Do oximes such as pralidoxime provide a clinical benefit in acute organophosphate poisoning, and if so in which patients?
KNOWLEDGE GAP OPEN gap_op_oxime_efficacy
Attached to
treatments#Pralidoxime pathophysiology#Acetylcholinesterase inhibition
Oximes reactivate inhibited acetylcholinesterase in vitro and are mechanistically rational, and are recommended in many protocols. However, randomized trials and meta-analyses have not demonstrated a clinical benefit and have suggested possible harm, so which patients (if any) benefit, and the optimal agent, dose, and timing before aging, remain unresolved.
Show evidence (1 reference)
PMID:32257715 REFUTE Human Clinical
"A recent meta-analysis has found that pralidoxime provides no significant improvement in outcome and rather may cause harm while increasing the economic burden in low-income communities where its use is the most prevalent."
Provides the negative-trial evidence that motivates the open question about oxime clinical benefit.
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Pathophysiology

12
Organophosphate exposure and absorption
Organophosphorus compounds enter the body across the skin, respiratory tract, and gastrointestinal tract following agricultural, occupational, intentional, or chemical-warfare exposure, and are distributed systemically to reach their molecular targets; in high doses they are toxic or lethal. This shared entry point feeds both the acetylcholinesterase arm (via bioactivation) and the delayed neuropathy-target-esterase arm.
xenobiotic metabolic process GO:0006805 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased xenobiotic metabolic process (GO:0006805). GO:0006805 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Organophosphate bioactivation Absorbed phosphorothioate pro-toxicants undergo hepatic activation to their oxon form.
Neuropathy target esterase inhibition Absorbed neuropathic organophosphates reach peripheral and central neurons and inhibit neuropathy target esterase.
Show evidence (1 reference)
PMID:37888716 SUPPORT Other
"In high doses or chronic exposure, they can be toxic or lethal."
Supports systemic organophosphate exposure producing toxicity, the shared upstream event.
Organophosphate bioactivation
Many organophosphate insecticides are phosphorothioate (P=S, "thion") pro-toxicants that require hepatic cytochrome P450-mediated oxidative desulfuration to their active oxon (P=O) form, a far more potent cholinesterase inhibitor. Direct-acting oxons and nerve agents skip this step, and the speed of activation varies between compounds.
hepatocyte CL:0000182 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves hepatocyte (CL:0000182). CL:0000182 is a cell type from the Cell Ontology.
xenobiotic metabolic process GO:0006805 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased xenobiotic metabolic process (GO:0006805). GO:0006805 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Acetylcholinesterase inhibition The activated oxon phosphorylates and inhibits acetylcholinesterase.
Show evidence (1 reference)
PMID:30230960 SUPPORT Other
"Variability between organophosphorus insecticides-in lipophilicity, speed of activation, speed and potency of acetylcholinesterase inhibition, and in the chemical groups attached to the phosphorus-results in variable speed of poisoning onset, severity, clinical toxidrome, and case fatality."
Supports the requirement and variability of metabolic activation among organophosphorus insecticides.
Acetylcholinesterase inhibition
The active organophosphate phosphorylates the serine hydroxyl in the catalytic site of acetylcholinesterase, covalently inactivating the enzyme that normally hydrolyzes acetylcholine, so acetylcholine breakdown falls.
acetylcholine catabolic process GO:0006581 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased acetylcholine catabolic process (GO:0006581). GO:0006581 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Aging of inhibited acetylcholinesterase The phosphorylated enzyme can undergo dealkylation that makes inhibition irreversible.
Synaptic acetylcholine accumulation Loss of acetylcholinesterase activity prevents breakdown of acetylcholine at synapses.
Show evidence (2 references)
PMID:24508992 SUPPORT Other
"Inhibition of acetylcholinesterase enzyme is the main mechanism of toxicity of such pesticides and measurement of acetylcholinesterase activity is the commonly used laboratory diagnosis approved for the purpose."
Supports acetylcholinesterase inhibition as the main toxic mechanism.
PMID:17913691 SUPPORT Other
"Inhibition of acetylcholinesterase (AChE) is regarded as the primary toxic mechanism of organophosphorus compounds (OP)."
Independently supports acetylcholinesterase inhibition as the primary toxic mechanism.
Aging of inhibited acetylcholinesterase
After phosphorylation, the enzyme-organophosphate adduct can lose an alkyl group ("aging"), converting the initially reversible inhibition into an irreversible bond that oxime reactivators can no longer cleave; recovery then requires synthesis of new enzyme. The aging rate is compound-dependent and sets the therapeutic window for oxime therapy.
acetylcholine catabolic process GO:0006581 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased acetylcholine catabolic process (GO:0006581). GO:0006581 is a biological process from the Gene Ontology. ↓ DECREASED
Show evidence (1 reference)
PMID:26563788 SUPPORT Other
"With OP insecticides (but not carbamates), "aging" may also occur by partial dealkylation of the serine group at the active site of AChE; recovery of AChE activity requires synthesis of new enzyme in the liver."
Directly supports aging by dealkylation making inhibition irreversible.
Synaptic acetylcholine accumulation
With acetylcholinesterase inhibited, acetylcholine released at cholinergic synapses is not degraded and accumulates at autonomic, neuromuscular, and central synapses, producing sustained receptor stimulation.
cholinergic neuron CL:0000108 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cholinergic neuron (CL:0000108). CL:0000108 is a cell type from the Cell Ontology.
cholinergic synaptic transmission GO:0007271 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased cholinergic synaptic transmission, annotated with synaptic transmission, cholinergic (GO:0007271). GO:0007271 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Muscarinic receptor overstimulation Excess acetylcholine overstimulates muscarinic acetylcholine receptors.
Nicotinic receptor overstimulation Excess acetylcholine overstimulates nicotinic acetylcholine receptors.
Central cholinergic overstimulation Excess acetylcholine overstimulates central nervous system cholinergic pathways.
Show evidence (1 reference)
PMID:26563788 SUPPORT Other
"Both organophosphorus (OP) and carbamate insecticides inhibit acetylcholinesterase (AChE), which results in accumulation of acetylcholine (ACh) at autonomic and some central synapses and at autonomic postganglionic and neuromuscular junctions."
Supports acetylcholine accumulation across autonomic, central, and neuromuscular synapses.
Muscarinic receptor overstimulation
Accumulated acetylcholine overstimulates muscarinic receptors on smooth muscle, glands, and the heart, producing parasympathetic and secretory excess: miosis, lacrimation, salivation, bronchorrhea, bronchoconstriction, bradycardia, gastrointestinal hypermotility, sweating, and urinary incontinence (the SLUDGE/DUMBELS pattern).
G protein-coupled acetylcholine receptor signaling pathway GO:0007213 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased G protein-coupled acetylcholine receptor signaling pathway (GO:0007213). GO:0007213 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Respiratory failure Bronchorrhea and bronchoconstriction impair gas exchange and contribute to respiratory failure.
Show evidence (1 reference)
PMID:26563788 SUPPORT Other
"ACh binds to, and stimulates, muscarinic and nicotinic receptors, thereby producing characteristic features."
Supports muscarinic receptor stimulation as the source of the characteristic muscarinic features.
Nicotinic receptor overstimulation
Accumulated acetylcholine overstimulates nicotinic receptors at the neuromuscular junction and autonomic ganglia, causing fasciculations followed by depolarizing neuromuscular blockade and weakness, together with sympathetic ganglionic effects such as tachycardia and hypertension.
muscle cell CL:0000187 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves muscle cell (CL:0000187). CL:0000187 is a cell type from the Cell Ontology.
neuromuscular synaptic transmission GO:0007274 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased neuromuscular synaptic transmission (GO:0007274). GO:0007274 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Intermediate syndrome Prolonged nicotinic overstimulation and postsynaptic neuromuscular-junction dysfunction give rise to the delayed intermediate syndrome.
Respiratory failure Neuromuscular block from nicotinic overstimulation weakens the respiratory muscles and contributes to respiratory failure.
Show evidence (1 reference)
PMID:25455666 SUPPORT Other
"In the setting of toxicity from either agent class, clinical syndromes result from excessive nicotinic and muscarinic neurostimulation."
Supports nicotinic overstimulation as a source of the clinical syndrome.
Central cholinergic overstimulation
Acetylcholine accumulation in the central nervous system overstimulates central cholinergic pathways, producing anxiety, confusion, seizures and status epilepticus, depression of the central respiratory drive, and coma.
neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology.
cholinergic synaptic transmission GO:0007271 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased cholinergic synaptic transmission, annotated with synaptic transmission, cholinergic (GO:0007271). GO:0007271 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Respiratory failure Central depression of the respiratory center contributes to respiratory failure.
Show evidence (1 reference)
PMID:37888716 SUPPORT Other
"In acute OP exposure, the subsequent surge of acetylcholine in cholinergic synapses causes a peripheral cholinergic crisis and status epilepticus (SE), either of which can lead to death."
Supports central cholinergic overstimulation producing status epilepticus.
Respiratory failure
Respiratory failure is the principal cause of death in acute organophosphate poisoning and arises from the convergence of muscarinic bronchorrhea and bronchoconstriction, nicotinic respiratory-muscle weakness, and central depression of the respiratory drive.
respiratory gaseous exchange by respiratory system GO:0007585 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased respiratory gaseous exchange by respiratory system (GO:0007585). GO:0007585 is a biological process from the Gene Ontology. ↓ DECREASED
Show evidence (1 reference)
PMID:17913691 SUPPORT Other
"Reactivation is crucial within the neuromuscular synapse, where atropine is ineffective, since peripheral neuromuscular block eventually leads to respiratory failure."
Supports respiratory failure from peripheral neuromuscular block.
Intermediate syndrome
Roughly 24-96 hours after the acute crisis, a subset of patients develop proximal limb, neck flexor, cranial nerve, and respiratory muscle weakness attributed to persistent postsynaptic neuromuscular-junction dysfunction, independent of ongoing muscarinic signs and unresponsive to atropine and oximes.
muscle cell CL:0000187 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves muscle cell (CL:0000187). CL:0000187 is a cell type from the Cell Ontology.
neuromuscular synaptic transmission GO:0007274 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal neuromuscular synaptic transmission (GO:0007274). GO:0007274 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Respiratory failure Weakness of the respiratory muscles in the intermediate syndrome can precipitate respiratory failure after the acute crisis has resolved.
Show evidence (1 reference)
PMID:26563788 SUPPORT Other
"This involves the onset of muscle paralysis affecting particularly upper-limb muscles, neck flexors, and cranial nerves some 24-96 hours after OP exposure and is often associated with the development of respiratory failure."
Supports the intermediate syndrome as delayed neuromuscular weakness with respiratory failure.
Neuropathy target esterase inhibition
Certain organophosphates inhibit and then age a second serine esterase, neuropathy target esterase (NTE/PNPLA6), an integral membrane protein in neurons. This mechanism is independent of acetylcholinesterase inhibition and initiates the delayed neuropathy after a 1-3 week latency.
neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology.
phospholipid metabolic process GO:0006644 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased phospholipid metabolic process (GO:0006644). GO:0006644 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Distal axonal degeneration Inhibition and aging of neuropathy target esterase triggers a distal, dying-back axonopathy.
Show evidence (2 references)
PMID:10585848 SUPPORT Other
"organophosphates which react with NTE in vivo initiate unknown events which lead, after a delay of 1-3 weeks, to a neuropathy with degeneration of long axons."
Supports NTE reaction initiating delayed neuropathy with long-axon degeneration.
PMID:26563788 SUPPORT Other
"OP-induced delayed neuropathy results from phosphorylation and subsequent aging of at least 70% of neuropathy target esterase."
Supports phosphorylation and aging of NTE as the trigger of delayed neuropathy.
Distal axonal degeneration
One to four weeks after exposure, a distal dying-back degeneration of long axons in peripheral nerves and central tracts, with axonal degeneration and secondary demyelination, produces the predominantly motor sensorimotor polyneuropathy of OPIDN.
motor neuron CL:0000100 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves motor neuron (CL:0000100). CL:0000100 is a cell type from the Cell Ontology.
axonal transport GO:0098930 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased axonal transport (GO:0098930). GO:0098930 is a biological process from the Gene Ontology. ↓ DECREASED
Show evidence (1 reference)
PMID:16042503 SUPPORT Other
"Nerve biopsies have been performed in a few cases and showed axonal degeneration with secondary demyelination."
Supports distal axonal degeneration with secondary demyelination as the OPIDN lesion.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Organophosphate Poisoning Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

15
Cardiovascular 1
Bradycardia HP:0001662 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is bradycardia (HP:0001662). HP:0001662 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32626615 SUPPORT Human Clinical
"Signs and symptoms can range from mild or none to severe such as bradycardia, miosis, fasciculations, seizures and altered level of consciousness."
Lists bradycardia among the signs of OP poisoning in a clinical series.
Digestive 2
Diarrhea HP:0002014 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is diarrhea (HP:0002014). HP:0002014 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25425841 SUPPORT Other
"The typical toxidrome in organophosphate (OP) poisoning comprises of the Salivation, Lacrimation, Urination, Defecation, Gastric cramps, Emesis (SLUDGE) symptoms."
Names defecation (diarrhea) as part of the typical muscarinic (SLUDGE) toxidrome of OP poisoning.
Vomiting HP:0002013 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is vomiting (HP:0002013). HP:0002013 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25425841 SUPPORT Other
"The typical toxidrome in organophosphate (OP) poisoning comprises of the Salivation, Lacrimation, Urination, Defecation, Gastric cramps, Emesis (SLUDGE) symptoms."
Names emesis (vomiting) as part of the typical muscarinic (SLUDGE) toxidrome of OP poisoning.
Eye 1
Lacrimation Epiphora HP:0009926 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is lacrimation, annotated with Epiphora (HP:0009926). HP:0009926 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25425841 SUPPORT Other
"The typical toxidrome in organophosphate (OP) poisoning comprises of the Salivation, Lacrimation, Urination, Defecation, Gastric cramps, Emesis (SLUDGE) symptoms."
Names lacrimation as part of the typical muscarinic (SLUDGE) toxidrome of OP poisoning.
Head and Neck 1
Excessive salivation HP:0003781 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is excessive salivation (HP:0003781). HP:0003781 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25425841 SUPPORT Other
"The typical toxidrome in organophosphate (OP) poisoning comprises of the Salivation, Lacrimation, Urination, Defecation, Gastric cramps, Emesis (SLUDGE) symptoms."
Names salivation as part of the typical muscarinic (SLUDGE) toxidrome of OP poisoning.
Musculoskeletal 1
Muscle weakness HP:0001324 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is muscle weakness (HP:0001324). HP:0001324 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:3029588 SUPPORT Human Clinical
"We observed 10 patients who had paralysis of proximal limb muscles, neck flexors, motor cranial nerves, and respiratory muscles 24 to 96 hours after poisoning, after a well-defined cholinergic phase."
Supports muscle weakness/paralysis as a manifestation of OP poisoning.
Nervous System 4
Fasciculations HP:0002380 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is fasciculations (HP:0002380). HP:0002380 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32626615 SUPPORT Human Clinical
"Signs and symptoms can range from mild or none to severe such as bradycardia, miosis, fasciculations, seizures and altered level of consciousness."
Lists fasciculations among the signs of OP poisoning in a clinical series.
Seizures HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is seizures, annotated with Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32626615 SUPPORT Human Clinical
"Signs and symptoms can range from mild or none to severe such as bradycardia, miosis, fasciculations, seizures and altered level of consciousness."
Lists seizures among the signs of severe OP poisoning.
Coma HP:0001259 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is coma (HP:0001259). HP:0001259 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:18090104 SUPPORT Human Clinical
"The major clinical manifestation was neurological, with most of the patients presenting with coma and/or seizures (71%)."
Supports coma as a major neurological manifestation of OP poisoning.
Peripheral neuropathy HP:0009830 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is peripheral neuropathy (HP:0009830). HP:0009830 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:16042503 SUPPORT Other
"It is characterised by distal degeneration of some axons of both the peripheral and central nervous systems occurring 1-4 weeks after single or short-term exposures."
Supports delayed peripheral neuropathy (OPIDN) as a manifestation.
Respiratory 2
Respiratory failure Respiratory insufficiency HP:0002093 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is respiratory insufficiency (HP:0002093). HP:0002093 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:3029588 SUPPORT Human Clinical
"Four patients urgently required ventilatory support."
Supports respiratory failure requiring ventilation in OP poisoning.
Bronchospasm Wheezing HP:0030828 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is bronchospasm, annotated with Wheezing (HP:0030828). HP:0030828 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:16945386 SUPPORT Other
"Increased parasympathetic stimulation produces miosis, sialorrhea, bronchospasm and bronchorrhea."
Names bronchospasm among the muscarinic (parasympathetic) effects.
Other 3
Miosis HP:0000616 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is miosis (HP:0000616). HP:0000616 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32626615 SUPPORT Human Clinical
"Signs and symptoms can range from mild or none to severe such as bradycardia, miosis, fasciculations, seizures and altered level of consciousness."
Identifies miosis among the classic muscarinic/nicotinic signs of OP intoxication.
Neck flexor weakness HP:0003722 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is neck flexor weakness (HP:0003722). HP:0003722 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26563788 SUPPORT Other
"This involves the onset of muscle paralysis affecting particularly upper-limb muscles, neck flexors, and cranial nerves some 24-96 hours after OP exposure and is often associated with the development of respiratory failure."
Supports neck flexor weakness as a feature of the intermediate syndrome.
Bronchorrhea
No exact HPO term for bronchorrhea (excessive bronchial/airway secretions) was found; the ontology term is omitted pending a New Term Request.
Show evidence (1 reference)
PMID:16945386 SUPPORT Other
"Increased parasympathetic stimulation produces miosis, sialorrhea, bronchospasm and bronchorrhea."
Names bronchorrhea among the muscarinic (parasympathetic) effects.
🧬

Genetic Associations

1
PON1 (Genetic susceptibility modifier of organophosphate toxicity)
Gene: PON1 hgnc:9204 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PON1 (hgnc:9204). hgnc:9204 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SUSCEPTIBILITY
Show evidence (2 references)
PMID:23590198 SUPPORT Human Clinical
"Serum paraoxonase (PON1) is an esterase that is involved in the detoxification of organophosphate insecticides."
Supports PON1 as a detoxifying esterase for organophosphates.
PMID:23590198 SUPPORT Human Clinical
"the current meta-analysis indicates that the PON1 192Q and 55LM polymorphisms may increase the risk of organophosphate toxicity, especially among the Caucasian populations."
Supports PON1 polymorphisms as susceptibility modifiers of organophosphate toxicity.
💊

Medical Actions

6
Decontamination and supportive care
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Removal of contaminated clothing, skin and eye decontamination, airway protection, oxygen, and hemodynamic support are essential first steps and reduce ongoing absorption.
Mechanism Target:
INHIBITS Acetylcholinesterase inhibition — Decontamination halts ongoing absorption and further enzyme inhibition.
Show evidence (1 reference)
PMID:25455666 SUPPORT Other
"Decontamination, meticulous supportive care, aggressive antimuscarinic therapy, seizure control, and administration of oximes are cornerstones of management."
Supports decontamination and supportive care as cornerstones of management.
Atropine
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: atropine CHEBI:16684 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses atropine (CHEBI:16684). CHEBI:16684 is a therapeutic agent from Chemical Entities of Biological Interest.
Atropine, a competitive muscarinic antagonist, is the primary antidote for the muscarinic features (bronchorrhea, bronchospasm, bradycardia, secretions), titrated to drying of secretions; it does not treat nicotinic (muscle) effects.
Mechanism Target:
INHIBITS Muscarinic receptor overstimulation — Atropine competitively blocks muscarinic acetylcholine receptors, reversing muscarinic toxicity.
Show evidence (2 references)
PMID:34053713 SUPPORT Other
"Atropine remains the mainstay of treatment, but recently some promising therapies are in the pipeline."
Supports atropine as the mainstay antidote.
PMID:30230960 SUPPORT Other
"Rapid titration of atropine during resuscitation is lifesaving and can be performed in the absence of oxygen."
Supports rapid atropine titration as lifesaving.
Pralidoxime
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: pralidoxime CHEBI:8354 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses pralidoxime (CHEBI:8354). CHEBI:8354 is a therapeutic agent from Chemical Entities of Biological Interest.
Pralidoxime and other oximes reactivate phosphorylated acetylcholinesterase before it ages, targeting the nicotinic (neuromuscular) features atropine does not; however, clinical trial evidence for pralidoxime benefit is uncertain and contested.
Mechanism Target:
INHIBITS Acetylcholinesterase inhibition — Pralidoxime reactivates inhibited acetylcholinesterase before aging, restoring enzyme function.
Show evidence (1 reference)
PMID:32257715 SUPPORT In Vitro
"In vitro experiments have consistently shown that oximes are effective reactivators of human acetylcholinesterase enzyme, inhibited by OP compounds."
In vitro data support the mechanistic rationale that oximes reactivate inhibited acetylcholinesterase.
Benzodiazepine
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: diazepam CHEBI:49575 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses diazepam (CHEBI:49575). CHEBI:49575 is a therapeutic agent from Chemical Entities of Biological Interest.
Benzodiazepines such as diazepam control organophosphate-induced seizures and status epilepticus and reduce central-nervous-system injury.
Mechanism Target:
INHIBITS Central cholinergic overstimulation — Benzodiazepines suppress cholinergic seizure activity in the central nervous system.
Show evidence (1 reference)
PMID:25455666 SUPPORT Other
"Decontamination, meticulous supportive care, aggressive antimuscarinic therapy, seizure control, and administration of oximes are cornerstones of management."
Supports seizure control as a cornerstone of management, the role of benzodiazepines.
Mechanical ventilation
Action: artificial respirationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is artificial respiration, annotated with Mechanical Ventilation (NCIT:C70909). NCIT:C70909 is a clinical intervention from the NCI Thesaurus. Ontology label: Mechanical Ventilation NCIT:C70909
Airway management and mechanical ventilation support patients through respiratory failure from the cholinergic crisis and the intermediate syndrome.
Mechanism Target:
INHIBITS Respiratory failure — Ventilatory support sustains gas exchange until neuromuscular and central function recover.
Show evidence (1 reference)
PMID:3029588 SUPPORT Human Clinical
"Four patients urgently required ventilatory support."
Supports mechanical ventilation for respiratory failure in OP poisoning.
Magnesium sulfate
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: magnesium sulfate CHEBI:32599 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses magnesium sulfate (CHEBI:32599). CHEBI:32599 is a therapeutic agent from Chemical Entities of Biological Interest.
Magnesium sulfate is an investigational adjunct proposed to reduce acetylcholine release and calcium influx at the neuromuscular junction; it is among several promising but not yet established treatment alternatives.
Mechanism Target:
INHIBITS Synaptic acetylcholine accumulation — Magnesium is proposed to reduce presynaptic acetylcholine release at the neuromuscular junction.
Show evidence (1 reference)
PMID:34053713 SUPPORT Other
"Magnesium sulfate, calcium channel blockers (nimodipine), plasma alkalinizing agents, β-2 agonists, nicotinic receptor antagonists, clonidine, and lipid emulsions are promising treatment alternatives."
Supports magnesium sulfate as a promising investigational adjunct treatment.
🌍

Environmental Factors

4
Agricultural insecticide exposure
exposure to insecticide ECTO:9000089 Environmental Conditions, Treatments and Exposures Ontology (ECTO) Relation: this environmental factor is this exposure This environmental factor is exposure to insecticide (ECTO:9000089). ECTO:9000089 is an exposure from the Environmental Conditions, Treatments and Exposures Ontology.
Occupational exposure to organophosphate insecticides during mixing, spraying, and harvesting is a major route of poisoning in agricultural settings.
Show evidence (1 reference)
PMID:25455666 SUPPORT Other
"Organophosphates (OPs) and carbamates have a wide variety of applications, most commonly as pesticides used to eradicate agricultural pests or control populations of disease-carrying vectors."
Supports agricultural pesticide use as the dominant application and exposure route.
Mechanism Target:
TRIGGERS Organophosphate exposure and absorption — Agricultural and vector-control spraying puts organophosphate on skin and in breathed air, the routes by which it is absorbed at work.
Show evidence (1 reference)
PMID:25455666 SUPPORT Other
"Organophosphates (OPs) and carbamates have a wide variety of applications, most commonly as pesticides used to eradicate agricultural pests or control populations of disease-carrying vectors."
Establishes agricultural and vector-control pesticide use as the dominant setting in which people encounter organophosphates.
Intentional self-poisoning by ingestion
exposure to pesticide ECTO:0000530 Environmental Conditions, Treatments and Exposures Ontology (ECTO) Relation: this environmental factor is this exposure This environmental factor is exposure to pesticide (ECTO:0000530). ECTO:0000530 is an exposure from the Environmental Conditions, Treatments and Exposures Ontology.
Deliberate ingestion of concentrated organophosphate pesticides is a leading method of self-harm and a major cause of poisoning deaths in low- and middle-income countries.
Show evidence (1 reference)
PMID:17706760 SUPPORT Other
"Organophosphorus pesticide self-poisoning is an important clinical problem in rural regions of the developing world, and kills an estimated 200,000 people every year."
Supports self-poisoning as a major cause of death in the developing world.
Mechanism Target:
TRIGGERS Organophosphate exposure and absorption — Deliberate ingestion of concentrated pesticide delivers a far larger absorbed dose than occupational contact, which is why this route dominates mortality.
Show evidence (1 reference)
PMID:17706760 SUPPORT Other
"Organophosphorus pesticide self-poisoning is an important clinical problem in rural regions of the developing world, and kills an estimated 200,000 people every year."
The scale of mortality from deliberate ingestion reflects the large absorbed dose this route delivers.
Accidental pesticide exposure
exposure to pesticide ECTO:0000530 Environmental Conditions, Treatments and Exposures Ontology (ECTO) Relation: this environmental factor is this exposure This environmental factor is exposure to pesticide (ECTO:0000530). ECTO:0000530 is an exposure from the Environmental Conditions, Treatments and Exposures Ontology.
Accidental exposure occurs through contaminated food, improper storage, and dermal contact with treated surfaces, and is a common route in children.
Show evidence (1 reference)
PMID:18090104 SUPPORT Human Clinical
"The most common route of exposure was ingestion of agricultural products treated with OPs (71%)."
Supports accidental exposure via treated agricultural products, a common pediatric route.
Mechanism Target:
TRIGGERS Organophosphate exposure and absorption — Accidental exposure is predominantly oral: eating produce treated with organophosphate delivers the compound by the gastrointestinal route.
Show evidence (1 reference)
PMID:18090104 SUPPORT Human Clinical
"The most common route of exposure was ingestion of agricultural products treated with OPs (71%)."
Quantifies ingestion of treated produce as the dominant accidental route to absorbed organophosphate in this series.
Nerve agent exposure
exposure to chemical ECTO:0000231 Environmental Conditions, Treatments and Exposures Ontology (ECTO) Relation: this environmental factor is this exposure This environmental factor is exposure to chemical (ECTO:0000231). ECTO:0000231 is an exposure from the Environmental Conditions, Treatments and Exposures Ontology.
Organophosphate nerve agents (e.g., sarin, VX) are chemical-warfare and terrorism agents that act by the same acetylcholinesterase-inhibition mechanism.
Show evidence (1 reference)
PMID:25455666 SUPPORT Other
"Certain organophosphorus compounds, known as nerve agents, have been employed in chemical warfare and terrorism incidents."
Supports nerve agents as organophosphorus chemical-warfare exposures.
Mechanism Target:
TRIGGERS Organophosphate exposure and absorption — Nerve agents are organophosphates delivered deliberately as vapour or liquid, entering by the same dermal and respiratory routes but at far higher potency than the insecticides.
Show evidence (1 reference)
PMID:25455666 SUPPORT Other
"Certain organophosphorus compounds, known as nerve agents, have been employed in chemical warfare and terrorism incidents."
Identifies nerve agents as organophosphorus compounds, so their deliberate release is an organophosphate exposure like any other.
🔬

Biochemical Markers

2
Erythrocyte acetylcholinesterase (DECREASED)
Show evidence (1 reference)
PMID:25189163 SUPPORT Human Clinical
"red blood cell acetylcholinesterase (AChE) and plasma butyrylcholinesterase (BChE)"
Identifies red blood cell acetylcholinesterase as a biomarker of cholinesterase depression.
Plasma butyrylcholinesterase (DECREASED)
Show evidence (1 reference)
PMID:25189163 SUPPORT Human Clinical
"which serve as proxy measurements for nervous-system acetylcholinesterase activity: red blood cell acetylcholinesterase (AChE) and plasma butyrylcholinesterase (BChE)"
Identifies plasma butyrylcholinesterase as a proxy biomarker of nervous-system acetylcholinesterase activity.
📊

Prevalence

1
Worldwide (organophosphorus pesticide self-poisoning)
Unknown Common
Organophosphorus pesticide self-poisoning kills an estimated 200,000 people per year worldwide, with case fatality generally over 15%; it is a leading cause of poisoning death in the developing world.
Show evidence (1 reference)
PMID:17706760 SUPPORT Other
"Organophosphorus pesticide self-poisoning is an important clinical problem in rural regions of the developing world, and kills an estimated 200,000 people every year."
Provides the global mortality burden of organophosphorus self-poisoning.
{ }

Source YAML

click to show 
name: Organophosphate Poisoning
creation_date: "2026-07-10T00:00:00Z"
category: Environmental
categories:
- Toxic Exposure Disorder
- Pesticide Poisoning
- Environmental Health Disorder
synonyms:
- organophosphate toxicity
- organophosphorus poisoning
- OP poisoning
- anticholinesterase poisoning
description: >-
  Organophosphate poisoning is a toxic condition caused by exposure to
  organophosphorus compounds, most commonly organophosphate insecticides
  (e.g., chlorpyrifos, parathion, malathion, dimethoate) and chemical-warfare
  nerve agents (e.g., sarin, VX). It is a leading cause of fatal pesticide
  self-poisoning worldwide, particularly in agricultural regions of low- and
  middle-income countries, and also occurs through occupational and accidental
  exposure. The unifying mechanism is inhibition of acetylcholinesterase: the
  active compound phosphorylates the enzyme's catalytic serine, preventing
  hydrolysis of acetylcholine, which then accumulates at cholinergic synapses.
  Overstimulation of muscarinic receptors, nicotinic receptors, and central
  cholinergic pathways produces the acute cholinergic crisis (miosis,
  hypersalivation, bronchorrhea, bradycardia, diarrhea, fasciculations, muscle
  weakness, seizures, and respiratory failure). Over hours the phosphorylated
  enzyme can undergo irreversible "aging," and some patients develop an
  intermediate syndrome of proximal and respiratory muscle weakness or, weeks
  later, an organophosphate-induced delayed polyneuropathy. Treatment combines
  decontamination, the muscarinic antagonist atropine, the cholinesterase
  reactivator pralidoxime, benzodiazepines for seizures, and ventilatory support.
disease_term:
  preferred_term: organophosphate poisoning
  term:
    id: MONDO:0800386
    label: organophosphate poisoning
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0800386
      label: organophosphate poisoning
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: Primary MONDO disease identifier for this organophosphate poisoning entry.
definitions:
- name: Clinical case definition for organophosphate poisoning
  definition_type: CASE_DEFINITION
  description: >-
    Organophosphate poisoning is a cholinergic toxic syndrome caused by
    organophosphorus compounds that inhibit acetylcholinesterase, leading to
    acetylcholine accumulation and overstimulation of muscarinic and nicotinic
    receptors, confirmed by depressed blood cholinesterase activity in a
    compatible exposure context.
  scope: Disease-level clinical framing across acute crisis and delayed syndromes
  evidence:
  - reference: PMID:37888716
    reference_title: "Mechanisms of Organophosphate Toxicity and the Role of Acetylcholinesterase Inhibition."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The primary mechanism, common among all OPs, that initiates their toxic effects is the inhibition of acetylcholinesterase."
    explanation: Supports acetylcholinesterase inhibition as the unifying mechanism defining the disease.
parents:
- pesticide poisoning
prevalence:
- population: Worldwide (organophosphorus pesticide self-poisoning)
  measure_type: UNKNOWN
  prevalence_class: COMMON
  notes: >-
    Organophosphorus pesticide self-poisoning kills an estimated 200,000 people
    per year worldwide, with case fatality generally over 15%; it is a leading
    cause of poisoning death in the developing world.
  evidence:
  - reference: PMID:17706760
    reference_title: "Management of acute organophosphorus pesticide poisoning."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Organophosphorus pesticide self-poisoning is an important clinical problem in rural regions of the developing world, and kills an estimated 200,000 people every year."
    explanation: Provides the global mortality burden of organophosphorus self-poisoning.
has_subtypes:
- name: Acute Cholinergic Crisis
  description: >-
    The immediate syndrome following organophosphate exposure, driven by
    acetylcholine accumulation: muscarinic features (miosis, hypersalivation,
    bronchorrhea, bradycardia, diarrhea), nicotinic features (fasciculations,
    muscle weakness), and central features (seizures, coma), with respiratory
    failure the principal cause of death.
  evidence:
  - reference: PMID:37888716
    reference_title: "Mechanisms of Organophosphate Toxicity and the Role of Acetylcholinesterase Inhibition."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "In acute OP exposure, the subsequent surge of acetylcholine in cholinergic synapses causes a peripheral cholinergic crisis and status epilepticus (SE), either of which can lead to death."
    explanation: Supports the acute cholinergic crisis as the immediate syndrome from acetylcholine surge.
- name: Intermediate Syndrome
  description: >-
    A syndrome of proximal limb, neck flexor, cranial nerve, and respiratory
    muscle weakness appearing roughly 24-96 hours after the cholinergic crisis,
    attributed to prolonged neuromuscular-junction dysfunction; it can
    precipitate respiratory failure after the acute crisis has resolved and does
    not respond to atropine or oximes.
  evidence:
  - reference: PMID:3029588
    reference_title: "Neurotoxic effects of organophosphorus insecticides. An intermediate syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We observed 10 patients who had paralysis of proximal limb muscles, neck flexors, motor cranial nerves, and respiratory muscles 24 to 96 hours after poisoning, after a well-defined cholinergic phase."
    explanation: The original description establishing the intermediate syndrome as a distinct entity 24-96 hours after the cholinergic phase.
- name: Organophosphate-Induced Delayed Polyneuropathy
  display_name: Organophosphate-Induced Delayed Polyneuropathy (OPIDN)
  description: >-
    A distal, predominantly motor sensorimotor axonopathy appearing 1-3 weeks
    after exposure to certain organophosphates, caused by inhibition and aging of
    neuropathy target esterase (NTE/PNPLA6) rather than acetylcholinesterase.
  mappings:
    mondo_mappings:
    - term:
        id: MONDO:0957912
        label: organophosphate-induced delayed polyneuropathy
      mapping_predicate: skos:exactMatch
      mapping_source: MONDO
      mapping_justification: MONDO identifier for the delayed-polyneuropathy subtype.
  evidence:
  - reference: PMID:16042503
    reference_title: "Organophosphate-induced delayed polyneuropathy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "It is characterised by distal degeneration of some axons of both the peripheral and central nervous systems occurring 1-4 weeks after single or short-term exposures."
    explanation: Defines OPIDN as a distal axonopathy occurring 1-4 weeks after exposure.
pathophysiology:
- name: Organophosphate exposure and absorption
  description: >-
    Organophosphorus compounds enter the body across the skin, respiratory tract,
    and gastrointestinal tract following agricultural, occupational, intentional,
    or chemical-warfare exposure, and are distributed systemically to reach their
    molecular targets; in high doses they are toxic or lethal. This shared entry
    point feeds both the acetylcholinesterase arm (via bioactivation) and the
    delayed neuropathy-target-esterase arm.
  biological_processes:
  - preferred_term: xenobiotic metabolic process
    modifier: INCREASED
    term:
      id: GO:0006805
      label: xenobiotic metabolic process
  downstream:
  - target: Organophosphate bioactivation
    description: Absorbed phosphorothioate pro-toxicants undergo hepatic activation to their oxon form.
  - target: Neuropathy target esterase inhibition
    description: Absorbed neuropathic organophosphates reach peripheral and central neurons and inhibit neuropathy target esterase.
  evidence:
  - reference: PMID:37888716
    reference_title: "Mechanisms of Organophosphate Toxicity and the Role of Acetylcholinesterase Inhibition."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "In high doses or chronic exposure, they can be toxic or lethal."
    explanation: Supports systemic organophosphate exposure producing toxicity, the shared upstream event.
- name: Organophosphate bioactivation
  description: >-
    Many organophosphate insecticides are phosphorothioate (P=S, "thion")
    pro-toxicants that require hepatic cytochrome P450-mediated oxidative
    desulfuration to their active oxon (P=O) form, a far more potent
    cholinesterase inhibitor. Direct-acting oxons and nerve agents skip this step,
    and the speed of activation varies between compounds.
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  biological_processes:
  - preferred_term: xenobiotic metabolic process
    modifier: INCREASED
    term:
      id: GO:0006805
      label: xenobiotic metabolic process
  downstream:
  - target: Acetylcholinesterase inhibition
    description: The activated oxon phosphorylates and inhibits acetylcholinesterase.
  evidence:
  - reference: PMID:30230960
    reference_title: "Novel Clinical Toxicology and Pharmacology of Organophosphorus Insecticide Self-Poisoning."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Variability between organophosphorus insecticides-in lipophilicity, speed of activation, speed and potency of acetylcholinesterase inhibition, and in the chemical groups attached to the phosphorus-results in variable speed of poisoning onset, severity, clinical toxidrome, and case fatality."
    explanation: Supports the requirement and variability of metabolic activation among organophosphorus insecticides.
- name: Acetylcholinesterase inhibition
  description: >-
    The active organophosphate phosphorylates the serine hydroxyl in the
    catalytic site of acetylcholinesterase, covalently inactivating the enzyme
    that normally hydrolyzes acetylcholine, so acetylcholine breakdown falls.
  biological_processes:
  - preferred_term: acetylcholine catabolic process
    modifier: DECREASED
    term:
      id: GO:0006581
      label: acetylcholine catabolic process
  downstream:
  - target: Aging of inhibited acetylcholinesterase
    description: The phosphorylated enzyme can undergo dealkylation that makes inhibition irreversible.
  - target: Synaptic acetylcholine accumulation
    description: Loss of acetylcholinesterase activity prevents breakdown of acetylcholine at synapses.
  evidence:
  - reference: PMID:24508992
    reference_title: "Acute organophosphorus poisoning."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Inhibition of acetylcholinesterase enzyme is the main mechanism of toxicity of such pesticides and measurement of acetylcholinesterase activity is the commonly used laboratory diagnosis approved for the purpose."
    explanation: Supports acetylcholinesterase inhibition as the main toxic mechanism.
  - reference: PMID:17913691
    reference_title: "Red blood cell acetylcholinesterase and plasma butyrylcholinesterase status: important indicators for the treatment of patients poisoned by organophosphorus compounds."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Inhibition of acetylcholinesterase (AChE) is regarded as the primary toxic mechanism of organophosphorus compounds (OP)."
    explanation: Independently supports acetylcholinesterase inhibition as the primary toxic mechanism.
- name: Aging of inhibited acetylcholinesterase
  description: >-
    After phosphorylation, the enzyme-organophosphate adduct can lose an alkyl
    group ("aging"), converting the initially reversible inhibition into an
    irreversible bond that oxime reactivators can no longer cleave; recovery then
    requires synthesis of new enzyme. The aging rate is compound-dependent and
    sets the therapeutic window for oxime therapy.
  biological_processes:
  - preferred_term: acetylcholine catabolic process
    modifier: DECREASED
    term:
      id: GO:0006581
      label: acetylcholine catabolic process
  evidence:
  - reference: PMID:26563788
    reference_title: "Organophosphorus and carbamate insecticide poisoning."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "With OP insecticides (but not carbamates), \"aging\" may also occur by partial dealkylation of the serine group at the active site of AChE; recovery of AChE activity requires synthesis of new enzyme in the liver."
    explanation: Directly supports aging by dealkylation making inhibition irreversible.
- name: Synaptic acetylcholine accumulation
  description: >-
    With acetylcholinesterase inhibited, acetylcholine released at cholinergic
    synapses is not degraded and accumulates at autonomic, neuromuscular, and
    central synapses, producing sustained receptor stimulation.
  cell_types:
  - preferred_term: cholinergic neuron
    term:
      id: CL:0000108
      label: cholinergic neuron
  biological_processes:
  - preferred_term: cholinergic synaptic transmission
    modifier: INCREASED
    term:
      id: GO:0007271
      label: synaptic transmission, cholinergic
  downstream:
  - target: Muscarinic receptor overstimulation
    description: Excess acetylcholine overstimulates muscarinic acetylcholine receptors.
  - target: Nicotinic receptor overstimulation
    description: Excess acetylcholine overstimulates nicotinic acetylcholine receptors.
  - target: Central cholinergic overstimulation
    description: Excess acetylcholine overstimulates central nervous system cholinergic pathways.
  evidence:
  - reference: PMID:26563788
    reference_title: "Organophosphorus and carbamate insecticide poisoning."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Both organophosphorus (OP) and carbamate insecticides inhibit acetylcholinesterase (AChE), which results in accumulation of acetylcholine (ACh) at autonomic and some central synapses and at autonomic postganglionic and neuromuscular junctions."
    explanation: Supports acetylcholine accumulation across autonomic, central, and neuromuscular synapses.
- name: Muscarinic receptor overstimulation
  description: >-
    Accumulated acetylcholine overstimulates muscarinic receptors on smooth
    muscle, glands, and the heart, producing parasympathetic and secretory
    excess: miosis, lacrimation, salivation, bronchorrhea, bronchoconstriction,
    bradycardia, gastrointestinal hypermotility, sweating, and urinary
    incontinence (the SLUDGE/DUMBELS pattern).
  biological_processes:
  - preferred_term: G protein-coupled acetylcholine receptor signaling pathway
    modifier: INCREASED
    term:
      id: GO:0007213
      label: G protein-coupled acetylcholine receptor signaling pathway
  downstream:
  - target: Respiratory failure
    description: Bronchorrhea and bronchoconstriction impair gas exchange and contribute to respiratory failure.
  evidence:
  - reference: PMID:26563788
    reference_title: "Organophosphorus and carbamate insecticide poisoning."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ACh binds to, and stimulates, muscarinic and nicotinic receptors, thereby producing characteristic features."
    explanation: Supports muscarinic receptor stimulation as the source of the characteristic muscarinic features.
- name: Nicotinic receptor overstimulation
  description: >-
    Accumulated acetylcholine overstimulates nicotinic receptors at the
    neuromuscular junction and autonomic ganglia, causing fasciculations
    followed by depolarizing neuromuscular blockade and weakness, together with
    sympathetic ganglionic effects such as tachycardia and hypertension.
  cell_types:
  - preferred_term: muscle cell
    term:
      id: CL:0000187
      label: muscle cell
  biological_processes:
  - preferred_term: neuromuscular synaptic transmission
    modifier: INCREASED
    term:
      id: GO:0007274
      label: neuromuscular synaptic transmission
  downstream:
  - target: Intermediate syndrome
    description: Prolonged nicotinic overstimulation and postsynaptic neuromuscular-junction dysfunction give rise to the delayed intermediate syndrome.
  - target: Respiratory failure
    description: Neuromuscular block from nicotinic overstimulation weakens the respiratory muscles and contributes to respiratory failure.
    evidence:
    - reference: PMID:17913691
      reference_title: "Red blood cell acetylcholinesterase and plasma butyrylcholinesterase status: important indicators for the treatment of patients poisoned by organophosphorus compounds."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Reactivation is crucial within the neuromuscular synapse, where atropine is ineffective, since peripheral neuromuscular block eventually leads to respiratory failure."
      explanation: Links neuromuscular nicotinic block to respiratory failure.
  evidence:
  - reference: PMID:25455666
    reference_title: "Organophosphate and carbamate poisoning."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "In the setting of toxicity from either agent class, clinical syndromes result from excessive nicotinic and muscarinic neurostimulation."
    explanation: Supports nicotinic overstimulation as a source of the clinical syndrome.
- name: Central cholinergic overstimulation
  description: >-
    Acetylcholine accumulation in the central nervous system overstimulates
    central cholinergic pathways, producing anxiety, confusion, seizures and
    status epilepticus, depression of the central respiratory drive, and coma.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: cholinergic synaptic transmission
    modifier: INCREASED
    term:
      id: GO:0007271
      label: synaptic transmission, cholinergic
  downstream:
  - target: Respiratory failure
    description: Central depression of the respiratory center contributes to respiratory failure.
  evidence:
  - reference: PMID:37888716
    reference_title: "Mechanisms of Organophosphate Toxicity and the Role of Acetylcholinesterase Inhibition."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "In acute OP exposure, the subsequent surge of acetylcholine in cholinergic synapses causes a peripheral cholinergic crisis and status epilepticus (SE), either of which can lead to death."
    explanation: Supports central cholinergic overstimulation producing status epilepticus.
- name: Respiratory failure
  description: >-
    Respiratory failure is the principal cause of death in acute organophosphate
    poisoning and arises from the convergence of muscarinic bronchorrhea and
    bronchoconstriction, nicotinic respiratory-muscle weakness, and central
    depression of the respiratory drive.
  biological_processes:
  - preferred_term: respiratory gaseous exchange by respiratory system
    modifier: DECREASED
    term:
      id: GO:0007585
      label: respiratory gaseous exchange by respiratory system
  evidence:
  - reference: PMID:17913691
    reference_title: "Red blood cell acetylcholinesterase and plasma butyrylcholinesterase status: important indicators for the treatment of patients poisoned by organophosphorus compounds."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Reactivation is crucial within the neuromuscular synapse, where atropine is ineffective, since peripheral neuromuscular block eventually leads to respiratory failure."
    explanation: Supports respiratory failure from peripheral neuromuscular block.
- name: Intermediate syndrome
  description: >-
    Roughly 24-96 hours after the acute crisis, a subset of patients develop
    proximal limb, neck flexor, cranial nerve, and respiratory muscle weakness
    attributed to persistent postsynaptic neuromuscular-junction dysfunction,
    independent of ongoing muscarinic signs and unresponsive to atropine and
    oximes.
  cell_types:
  - preferred_term: muscle cell
    term:
      id: CL:0000187
      label: muscle cell
  biological_processes:
  - preferred_term: neuromuscular synaptic transmission
    modifier: ABNORMAL
    term:
      id: GO:0007274
      label: neuromuscular synaptic transmission
  downstream:
  - target: Respiratory failure
    description: Weakness of the respiratory muscles in the intermediate syndrome can precipitate respiratory failure after the acute crisis has resolved.
  evidence:
  - reference: PMID:26563788
    reference_title: "Organophosphorus and carbamate insecticide poisoning."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "This involves the onset of muscle paralysis affecting particularly upper-limb muscles, neck flexors, and cranial nerves some 24-96 hours after OP exposure and is often associated with the development of respiratory failure."
    explanation: Supports the intermediate syndrome as delayed neuromuscular weakness with respiratory failure.
- name: Neuropathy target esterase inhibition
  description: >-
    Certain organophosphates inhibit and then age a second serine esterase,
    neuropathy target esterase (NTE/PNPLA6), an integral membrane protein in
    neurons. This mechanism is independent of acetylcholinesterase inhibition and
    initiates the delayed neuropathy after a 1-3 week latency.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: phospholipid metabolic process
    modifier: DECREASED
    term:
      id: GO:0006644
      label: phospholipid metabolic process
  downstream:
  - target: Distal axonal degeneration
    description: Inhibition and aging of neuropathy target esterase triggers a distal, dying-back axonopathy.
  evidence:
  - reference: PMID:10585848
    reference_title: "Neuropathy target esterase."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "organophosphates which react with NTE in vivo initiate unknown events which lead, after a delay of 1-3 weeks, to a neuropathy with degeneration of long axons."
    explanation: Supports NTE reaction initiating delayed neuropathy with long-axon degeneration.
  - reference: PMID:26563788
    reference_title: "Organophosphorus and carbamate insecticide poisoning."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "OP-induced delayed neuropathy results from phosphorylation and subsequent aging of at least 70% of neuropathy target esterase."
    explanation: Supports phosphorylation and aging of NTE as the trigger of delayed neuropathy.
- name: Distal axonal degeneration
  description: >-
    One to four weeks after exposure, a distal dying-back degeneration of long
    axons in peripheral nerves and central tracts, with axonal degeneration and
    secondary demyelination, produces the predominantly motor sensorimotor
    polyneuropathy of OPIDN.
  cell_types:
  - preferred_term: motor neuron
    term:
      id: CL:0000100
      label: motor neuron
  biological_processes:
  - preferred_term: axonal transport
    modifier: DECREASED
    term:
      id: GO:0098930
      label: axonal transport
  evidence:
  - reference: PMID:16042503
    reference_title: "Organophosphate-induced delayed polyneuropathy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Nerve biopsies have been performed in a few cases and showed axonal degeneration with secondary demyelination."
    explanation: Supports distal axonal degeneration with secondary demyelination as the OPIDN lesion.
phenotypes:
- category: Ophthalmologic
  name: Miosis
  description: >-
    Pinpoint pupils from muscarinic overstimulation of the iris sphincter are a
    classic sign of cholinergic toxicity.
  phenotype_term:
    preferred_term: miosis
    term:
      id: HP:0000616
      label: Miosis
  evidence:
  - reference: PMID:32626615
    reference_title: "Organophosphate Poisoning: Demographics, Severity Scores and Outcomes From National Poisoning Control Centre, Karachi."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Signs and symptoms can range from mild or none to severe such as bradycardia, miosis, fasciculations, seizures and altered level of consciousness."
    explanation: Identifies miosis among the classic muscarinic/nicotinic signs of OP intoxication.
- category: Secretory
  name: Excessive salivation
  description: >-
    Hypersalivation and increased secretions are part of the muscarinic
    secretory excess.
  phenotype_term:
    preferred_term: excessive salivation
    term:
      id: HP:0003781
      label: Excessive salivation
  evidence:
  - reference: PMID:25425841
    reference_title: "Clinical features of organophosphate poisoning: A review of different classification systems and approaches."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The typical toxidrome in organophosphate (OP) poisoning comprises of the Salivation, Lacrimation, Urination, Defecation, Gastric cramps, Emesis (SLUDGE) symptoms."
    explanation: Names salivation as part of the typical muscarinic (SLUDGE) toxidrome of OP poisoning.
- category: Secretory
  name: Lacrimation
  description: >-
    Excessive tearing (lacrimation) is part of the muscarinic secretory excess.
  phenotype_term:
    preferred_term: lacrimation
    term:
      id: HP:0009926
      label: Epiphora
  evidence:
  - reference: PMID:25425841
    reference_title: "Clinical features of organophosphate poisoning: A review of different classification systems and approaches."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The typical toxidrome in organophosphate (OP) poisoning comprises of the Salivation, Lacrimation, Urination, Defecation, Gastric cramps, Emesis (SLUDGE) symptoms."
    explanation: Names lacrimation as part of the typical muscarinic (SLUDGE) toxidrome of OP poisoning.
- category: Cardiovascular
  name: Bradycardia
  description: >-
    Muscarinic overstimulation of the heart can produce bradycardia.
  phenotype_term:
    preferred_term: bradycardia
    term:
      id: HP:0001662
      label: Bradycardia
  evidence:
  - reference: PMID:32626615
    reference_title: "Organophosphate Poisoning: Demographics, Severity Scores and Outcomes From National Poisoning Control Centre, Karachi."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Signs and symptoms can range from mild or none to severe such as bradycardia, miosis, fasciculations, seizures and altered level of consciousness."
    explanation: Lists bradycardia among the signs of OP poisoning in a clinical series.
- category: Gastrointestinal
  name: Diarrhea
  description: >-
    Gastrointestinal hypermotility from muscarinic overstimulation causes
    diarrhea, often with abdominal cramping and vomiting.
  phenotype_term:
    preferred_term: diarrhea
    term:
      id: HP:0002014
      label: Diarrhea
  evidence:
  - reference: PMID:25425841
    reference_title: "Clinical features of organophosphate poisoning: A review of different classification systems and approaches."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The typical toxidrome in organophosphate (OP) poisoning comprises of the Salivation, Lacrimation, Urination, Defecation, Gastric cramps, Emesis (SLUDGE) symptoms."
    explanation: Names defecation (diarrhea) as part of the typical muscarinic (SLUDGE) toxidrome of OP poisoning.
- category: Gastrointestinal
  name: Vomiting
  description: >-
    Vomiting is a common muscarinic gastrointestinal manifestation.
  phenotype_term:
    preferred_term: vomiting
    term:
      id: HP:0002013
      label: Vomiting
  evidence:
  - reference: PMID:25425841
    reference_title: "Clinical features of organophosphate poisoning: A review of different classification systems and approaches."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The typical toxidrome in organophosphate (OP) poisoning comprises of the Salivation, Lacrimation, Urination, Defecation, Gastric cramps, Emesis (SLUDGE) symptoms."
    explanation: Names emesis (vomiting) as part of the typical muscarinic (SLUDGE) toxidrome of OP poisoning.
- category: Musculoskeletal
  name: Fasciculations
  description: >-
    Muscle fasciculations reflect nicotinic overstimulation of the neuromuscular
    junction.
  phenotype_term:
    preferred_term: fasciculations
    term:
      id: HP:0002380
      label: Fasciculations
  evidence:
  - reference: PMID:32626615
    reference_title: "Organophosphate Poisoning: Demographics, Severity Scores and Outcomes From National Poisoning Control Centre, Karachi."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Signs and symptoms can range from mild or none to severe such as bradycardia, miosis, fasciculations, seizures and altered level of consciousness."
    explanation: Lists fasciculations among the signs of OP poisoning in a clinical series.
- category: Musculoskeletal
  name: Muscle weakness
  description: >-
    Weakness follows nicotinic overstimulation and depolarizing neuromuscular
    blockade, and recurs in the intermediate syndrome.
  phenotype_term:
    preferred_term: muscle weakness
    term:
      id: HP:0001324
      label: Muscle weakness
  evidence:
  - reference: PMID:3029588
    reference_title: "Neurotoxic effects of organophosphorus insecticides. An intermediate syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We observed 10 patients who had paralysis of proximal limb muscles, neck flexors, motor cranial nerves, and respiratory muscles 24 to 96 hours after poisoning, after a well-defined cholinergic phase."
    explanation: Supports muscle weakness/paralysis as a manifestation of OP poisoning.
- category: Musculoskeletal
  name: Neck flexor weakness
  description: >-
    Weakness of the neck flexors is a characteristic feature of the intermediate
    syndrome.
  phenotype_term:
    preferred_term: neck flexor weakness
    term:
      id: HP:0003722
      label: Neck flexor weakness
  evidence:
  - reference: PMID:26563788
    reference_title: "Organophosphorus and carbamate insecticide poisoning."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "This involves the onset of muscle paralysis affecting particularly upper-limb muscles, neck flexors, and cranial nerves some 24-96 hours after OP exposure and is often associated with the development of respiratory failure."
    explanation: Supports neck flexor weakness as a feature of the intermediate syndrome.
- category: Nervous System
  name: Seizures
  description: >-
    Central cholinergic overstimulation can provoke seizures and status
    epilepticus, particularly in severe poisoning.
  phenotype_term:
    preferred_term: seizures
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:32626615
    reference_title: "Organophosphate Poisoning: Demographics, Severity Scores and Outcomes From National Poisoning Control Centre, Karachi."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Signs and symptoms can range from mild or none to severe such as bradycardia, miosis, fasciculations, seizures and altered level of consciousness."
    explanation: Lists seizures among the signs of severe OP poisoning.
- category: Nervous System
  name: Coma
  description: >-
    Depressed consciousness and coma occur in severe central cholinergic
    toxicity.
  phenotype_term:
    preferred_term: coma
    term:
      id: HP:0001259
      label: Coma
  evidence:
  - reference: PMID:18090104
    reference_title: "Unintentional organophosphate intoxication in children."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The major clinical manifestation was neurological, with most of the patients presenting with coma and/or seizures (71%)."
    explanation: Supports coma as a major neurological manifestation of OP poisoning.
- category: Respiratory
  name: Respiratory failure
  description: >-
    Respiratory failure from combined bronchorrhea, respiratory-muscle weakness,
    and central depression is the leading cause of death.
  phenotype_term:
    preferred_term: respiratory insufficiency
    term:
      id: HP:0002093
      label: Respiratory insufficiency
  evidence:
  - reference: PMID:3029588
    reference_title: "Neurotoxic effects of organophosphorus insecticides. An intermediate syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Four patients urgently required ventilatory support."
    explanation: Supports respiratory failure requiring ventilation in OP poisoning.
- category: Respiratory
  name: Bronchospasm
  description: >-
    Muscarinic bronchoconstriction (bronchospasm, clinically wheezing) is one of
    the "killer B's" and a key muscarinic driver of respiratory compromise.
  phenotype_term:
    preferred_term: bronchospasm
    term:
      id: HP:0030828
      label: Wheezing
  evidence:
  - reference: PMID:16945386
    reference_title: "The acute treatment of nerve agent exposure."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Increased parasympathetic stimulation produces miosis, sialorrhea, bronchospasm and bronchorrhea."
    explanation: Names bronchospasm among the muscarinic (parasympathetic) effects.
- category: Respiratory
  name: Bronchorrhea
  description: >-
    Muscarinic bronchorrhea (excessive airway secretions) is one of the "killer
    B's" that, with bronchospasm, drives the respiratory failure that is the
    leading cause of death.
  phenotype_term:
    preferred_term: bronchorrhea
  notes: >-
    No exact HPO term for bronchorrhea (excessive bronchial/airway secretions)
    was found; the ontology term is omitted pending a New Term Request.
  evidence:
  - reference: PMID:16945386
    reference_title: "The acute treatment of nerve agent exposure."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Increased parasympathetic stimulation produces miosis, sialorrhea, bronchospasm and bronchorrhea."
    explanation: Names bronchorrhea among the muscarinic (parasympathetic) effects.
- category: Nervous System
  name: Peripheral neuropathy
  description: >-
    A delayed, distal, predominantly motor peripheral neuropathy (OPIDN) can
    appear one to four weeks after exposure to certain organophosphates.
  phenotype_term:
    preferred_term: peripheral neuropathy
    term:
      id: HP:0009830
      label: Peripheral neuropathy
  evidence:
  - reference: PMID:16042503
    reference_title: "Organophosphate-induced delayed polyneuropathy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "It is characterised by distal degeneration of some axons of both the peripheral and central nervous systems occurring 1-4 weeks after single or short-term exposures."
    explanation: Supports delayed peripheral neuropathy (OPIDN) as a manifestation.
biochemical:
- name: Erythrocyte acetylcholinesterase
  presence: DECREASED
  notes: >-
    Red-cell (erythrocyte) acetylcholinesterase activity is a proxy for synaptic
    enzyme inhibition and the more specific biomarker of organophosphate effect.
  evidence:
  - reference: PMID:25189163
    reference_title: "Blood acetylcholinesterase and butyrylcholinesterase as biomarkers of cholinesterase depression among pesticide handlers."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "red blood cell acetylcholinesterase (AChE) and plasma butyrylcholinesterase (BChE)"
    explanation: Identifies red blood cell acetylcholinesterase as a biomarker of cholinesterase depression.
- name: Plasma butyrylcholinesterase
  presence: DECREASED
  notes: >-
    Plasma butyrylcholinesterase (pseudocholinesterase) activity is a sensitive
    but less specific marker of exposure.
  evidence:
  - reference: PMID:25189163
    reference_title: "Blood acetylcholinesterase and butyrylcholinesterase as biomarkers of cholinesterase depression among pesticide handlers."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "which serve as proxy measurements for nervous-system acetylcholinesterase activity: red blood cell acetylcholinesterase (AChE) and plasma butyrylcholinesterase (BChE)"
    explanation: Identifies plasma butyrylcholinesterase as a proxy biomarker of nervous-system acetylcholinesterase activity.
genetic:
- name: PON1
  gene_term:
    preferred_term: PON1
    term:
      id: hgnc:9204
      label: PON1
  relationship_type: SUSCEPTIBILITY
  association: Genetic susceptibility modifier of organophosphate toxicity
  notes: >-
    Serum paraoxonase-1 (PON1) hydrolyzes the active oxon metabolites of several
    organophosphates; functional PON1 coding polymorphisms (Q192R, L55M) modulate
    detoxification efficiency and susceptibility to organophosphate toxicity.
  evidence:
  - reference: PMID:23590198
    reference_title: "PON1 Q192R and L55M polymorphisms and organophosphate toxicity risk: a meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Serum paraoxonase (PON1) is an esterase that is involved in the detoxification of organophosphate insecticides."
    explanation: Supports PON1 as a detoxifying esterase for organophosphates.
  - reference: PMID:23590198
    reference_title: "PON1 Q192R and L55M polymorphisms and organophosphate toxicity risk: a meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the current meta-analysis indicates that the PON1 192Q and 55LM polymorphisms may increase the risk of organophosphate toxicity, especially among the Caucasian populations."
    explanation: Supports PON1 polymorphisms as susceptibility modifiers of organophosphate toxicity.
environmental:
- name: Agricultural insecticide exposure
  exposure_term:
    preferred_term: exposure to insecticide
    term:
      id: ECTO:9000089
      label: exposure to insecticide
  description: >-
    Occupational exposure to organophosphate insecticides during mixing,
    spraying, and harvesting is a major route of poisoning in agricultural
    settings.
  evidence:
  - reference: PMID:25455666
    reference_title: "Organophosphate and carbamate poisoning."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Organophosphates (OPs) and carbamates have a wide variety of applications, most commonly as pesticides used to eradicate agricultural pests or control populations of disease-carrying vectors."
    explanation: Supports agricultural pesticide use as the dominant application and exposure route.
  influences_mechanisms:
  - target: Organophosphate exposure and absorption
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Agricultural and vector-control spraying puts organophosphate on skin
      and in breathed air, the routes by which it is absorbed at work.
    evidence:
    - reference: PMID:25455666
      reference_title: "Organophosphate and carbamate poisoning."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Organophosphates (OPs) and carbamates have a wide variety of applications, most commonly as pesticides used to eradicate agricultural pests or control populations of disease-carrying vectors."
      explanation: >-
        Establishes agricultural and vector-control pesticide use as the
        dominant setting in which people encounter organophosphates.
- name: Intentional self-poisoning by ingestion
  exposure_term:
    preferred_term: exposure to pesticide
    term:
      id: ECTO:0000530
      label: exposure to pesticide
  description: >-
    Deliberate ingestion of concentrated organophosphate pesticides is a leading
    method of self-harm and a major cause of poisoning deaths in low- and
    middle-income countries.
  evidence:
  - reference: PMID:17706760
    reference_title: "Management of acute organophosphorus pesticide poisoning."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Organophosphorus pesticide self-poisoning is an important clinical problem in rural regions of the developing world, and kills an estimated 200,000 people every year."
    explanation: Supports self-poisoning as a major cause of death in the developing world.
  influences_mechanisms:
  - target: Organophosphate exposure and absorption
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Deliberate ingestion of concentrated pesticide delivers a far larger
      absorbed dose than occupational contact, which is why this route
      dominates mortality.
    evidence:
    - reference: PMID:17706760
      reference_title: "Management of acute organophosphorus pesticide poisoning."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Organophosphorus pesticide self-poisoning is an important clinical problem in rural regions of the developing world, and kills an estimated 200,000 people every year."
      explanation: >-
        The scale of mortality from deliberate ingestion reflects the large
        absorbed dose this route delivers.
- name: Accidental pesticide exposure
  exposure_term:
    preferred_term: exposure to pesticide
    term:
      id: ECTO:0000530
      label: exposure to pesticide
  description: >-
    Accidental exposure occurs through contaminated food, improper storage, and
    dermal contact with treated surfaces, and is a common route in children.
  evidence:
  - reference: PMID:18090104
    reference_title: "Unintentional organophosphate intoxication in children."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most common route of exposure was ingestion of agricultural products treated with OPs (71%)."
    explanation: Supports accidental exposure via treated agricultural products, a common pediatric route.
  influences_mechanisms:
  - target: Organophosphate exposure and absorption
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Accidental exposure is predominantly oral: eating produce treated with
      organophosphate delivers the compound by the gastrointestinal route.
    evidence:
    - reference: PMID:18090104
      reference_title: "Unintentional organophosphate intoxication in children."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The most common route of exposure was ingestion of agricultural products treated with OPs (71%)."
      explanation: >-
        Quantifies ingestion of treated produce as the dominant accidental
        route to absorbed organophosphate in this series.
- name: Nerve agent exposure
  exposure_term:
    preferred_term: exposure to chemical
    term:
      id: ECTO:0000231
      label: exposure to chemical
  description: >-
    Organophosphate nerve agents (e.g., sarin, VX) are chemical-warfare and
    terrorism agents that act by the same acetylcholinesterase-inhibition
    mechanism.
  evidence:
  - reference: PMID:25455666
    reference_title: "Organophosphate and carbamate poisoning."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Certain organophosphorus compounds, known as nerve agents, have been employed in chemical warfare and terrorism incidents."
    explanation: Supports nerve agents as organophosphorus chemical-warfare exposures.
  influences_mechanisms:
  - target: Organophosphate exposure and absorption
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Nerve agents are organophosphates delivered deliberately as vapour or
      liquid, entering by the same dermal and respiratory routes but at far
      higher potency than the insecticides.
    evidence:
    - reference: PMID:25455666
      reference_title: "Organophosphate and carbamate poisoning."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Certain organophosphorus compounds, known as nerve agents, have been employed in chemical warfare and terrorism incidents."
      explanation: >-
        Identifies nerve agents as organophosphorus compounds, so their
        deliberate release is an organophosphate exposure like any other.
treatments:
- name: Decontamination and supportive care
  description: >-
    Removal of contaminated clothing, skin and eye decontamination, airway
    protection, oxygen, and hemodynamic support are essential first steps and
    reduce ongoing absorption.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_mechanisms:
  - target: Acetylcholinesterase inhibition
    treatment_effect: INHIBITS
    description: Decontamination halts ongoing absorption and further enzyme inhibition.
  evidence:
  - reference: PMID:25455666
    reference_title: "Organophosphate and carbamate poisoning."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Decontamination, meticulous supportive care, aggressive antimuscarinic therapy, seizure control, and administration of oximes are cornerstones of management."
    explanation: Supports decontamination and supportive care as cornerstones of management.
- name: Atropine
  description: >-
    Atropine, a competitive muscarinic antagonist, is the primary antidote for
    the muscarinic features (bronchorrhea, bronchospasm, bradycardia,
    secretions), titrated to drying of secretions; it does not treat nicotinic
    (muscle) effects.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: atropine
      term:
        id: CHEBI:16684
        label: atropine
  target_mechanisms:
  - target: Muscarinic receptor overstimulation
    treatment_effect: INHIBITS
    description: Atropine competitively blocks muscarinic acetylcholine receptors, reversing muscarinic toxicity.
  evidence:
  - reference: PMID:34053713
    reference_title: "Management of Organophosphorus Poisoning: Standard Treatment and Beyond."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Atropine remains the mainstay of treatment, but recently some promising therapies are in the pipeline."
    explanation: Supports atropine as the mainstay antidote.
  - reference: PMID:30230960
    reference_title: "Novel Clinical Toxicology and Pharmacology of Organophosphorus Insecticide Self-Poisoning."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Rapid titration of atropine during resuscitation is lifesaving and can be performed in the absence of oxygen."
    explanation: Supports rapid atropine titration as lifesaving.
- name: Pralidoxime
  description: >-
    Pralidoxime and other oximes reactivate phosphorylated acetylcholinesterase
    before it ages, targeting the nicotinic (neuromuscular) features atropine
    does not; however, clinical trial evidence for pralidoxime benefit is
    uncertain and contested.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: pralidoxime
      term:
        id: CHEBI:8354
        label: pralidoxime
  target_mechanisms:
  - target: Acetylcholinesterase inhibition
    treatment_effect: INHIBITS
    description: Pralidoxime reactivates inhibited acetylcholinesterase before aging, restoring enzyme function.
  evidence:
  - reference: PMID:32257715
    reference_title: "The Efficacy of Pralidoxime in the Treatment of Organophosphate Poisoning in Humans: A Systematic Review and Meta-analysis of Randomized Trials."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In vitro experiments have consistently shown that oximes are effective reactivators of human acetylcholinesterase enzyme, inhibited by OP compounds."
    explanation: In vitro data support the mechanistic rationale that oximes reactivate inhibited acetylcholinesterase.
- name: Benzodiazepine
  description: >-
    Benzodiazepines such as diazepam control organophosphate-induced seizures and
    status epilepticus and reduce central-nervous-system injury.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: diazepam
      term:
        id: CHEBI:49575
        label: diazepam
  target_mechanisms:
  - target: Central cholinergic overstimulation
    treatment_effect: INHIBITS
    description: Benzodiazepines suppress cholinergic seizure activity in the central nervous system.
  evidence:
  - reference: PMID:25455666
    reference_title: "Organophosphate and carbamate poisoning."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Decontamination, meticulous supportive care, aggressive antimuscarinic therapy, seizure control, and administration of oximes are cornerstones of management."
    explanation: Supports seizure control as a cornerstone of management, the role of benzodiazepines.
- name: Mechanical ventilation
  description: >-
    Airway management and mechanical ventilation support patients through
    respiratory failure from the cholinergic crisis and the intermediate
    syndrome.
  treatment_term:
    preferred_term: artificial respiration
    term:
      id: NCIT:C70909
      label: Mechanical Ventilation
  target_mechanisms:
  - target: Respiratory failure
    treatment_effect: INHIBITS
    description: Ventilatory support sustains gas exchange until neuromuscular and central function recover.
  evidence:
  - reference: PMID:3029588
    reference_title: "Neurotoxic effects of organophosphorus insecticides. An intermediate syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Four patients urgently required ventilatory support."
    explanation: Supports mechanical ventilation for respiratory failure in OP poisoning.
- name: Magnesium sulfate
  description: >-
    Magnesium sulfate is an investigational adjunct proposed to reduce
    acetylcholine release and calcium influx at the neuromuscular junction; it is
    among several promising but not yet established treatment alternatives.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: magnesium sulfate
      term:
        id: CHEBI:32599
        label: magnesium sulfate
  target_mechanisms:
  - target: Synaptic acetylcholine accumulation
    treatment_effect: INHIBITS
    description: Magnesium is proposed to reduce presynaptic acetylcholine release at the neuromuscular junction.
  evidence:
  - reference: PMID:34053713
    reference_title: "Management of Organophosphorus Poisoning: Standard Treatment and Beyond."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Magnesium sulfate, calcium channel blockers (nimodipine), plasma alkalinizing agents, β-2 agonists, nicotinic receptor antagonists, clonidine, and lipid emulsions are promising treatment alternatives."
    explanation: Supports magnesium sulfate as a promising investigational adjunct treatment.
discussions:
- discussion_id: gap_op_oxime_efficacy
  prompt: >-
    Do oximes such as pralidoxime provide a clinical benefit in acute
    organophosphate poisoning, and if so in which patients?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - treatments#Pralidoxime
  - pathophysiology#Acetylcholinesterase inhibition
  rationale: >-
    Oximes reactivate inhibited acetylcholinesterase in vitro and are
    mechanistically rational, and are recommended in many protocols. However,
    randomized trials and meta-analyses have not demonstrated a clinical benefit
    and have suggested possible harm, so which patients (if any) benefit, and the
    optimal agent, dose, and timing before aging, remain unresolved.
  evidence:
  - reference: PMID:32257715
    reference_title: "The Efficacy of Pralidoxime in the Treatment of Organophosphate Poisoning in Humans: A Systematic Review and Meta-analysis of Randomized Trials."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "A recent meta-analysis has found that pralidoxime provides no significant improvement in outcome and rather may cause harm while increasing the economic burden in low-income communities where its use is the most prevalent."
    explanation: Provides the negative-trial evidence that motivates the open question about oxime clinical benefit.
datasets: []
📚

References & Deep Research

Deep Research

1
Claude Code ▸
1. Disease Information
claude-haiku-4-5-20251001, claude-opus-4-8 19 citations 2026-07-10T13:04:15.595269

1. Disease Information

Overview. Organophosphate poisoning is the clinical syndrome resulting from exposure to organophosphorus (OP) compounds — insecticides (parathion, malathion, chlorpyrifos, dimethoate, fenthion, diazinon, monocrotophos) and chemical warfare nerve agents (sarin, soman, tabun, VX). The unifying mechanism is inhibition of acetylcholinesterase (AChE), causing accumulation of acetylcholine at cholinergic synapses and an acute cholinergic crisis affecting muscarinic, nicotinic, and central nervous system receptors. As the flagship 2023 mechanistic review states, "The OP binds to and phosphorylates a nucleophilic serine at the catalytic site of the enzyme" (Naughton & Terry, Toxics 2023; PMID:37888716), and acetylcholinesterase inhibition "results in accumulation of acetylcholine and overstimulation of acetylcholine receptors" (Eddleston et al., Lancet 2008; PMID:17706760).

Key identifiers. - ICD-10: T60.0 (Toxic effect of organophosphate and carbamate insecticides); X48 / T60.0 for accidental/intentional pesticide exposure. - ICD-11: NE61 (Harmful effects of drugs, medicaments and biological substances) / exposure codes; poisoning by insecticides. - MeSH: "Organophosphate Poisoning" (D062025); related: "Organophosphorus Compounds," "Cholinesterase Inhibitors." - MONDO: No specific well-established MONDO term for the acute toxic syndrome (this is a toxic exposure, not a disease entity in the OMIM/Mendelian sense). Candidate mapping is to a poisoning/intoxication class; do not assert a MONDO ID without verification via OAK (runoak -i sqlite:obo:mondo search "organophosphate poisoning"). - OMIM / Orphanet: Not applicable (acquired toxic condition; no Orphanet rare-disease code).

Common synonyms / alternative names. Organophosphorus poisoning; OP poisoning; organophosphate insecticide poisoning; anticholinesterase poisoning; cholinergic toxidrome; nerve agent poisoning (for warfare agents). "Organophosphate-induced cholinergic crisis" refers to the acute phase.

Data derivation. Information is aggregated disease-level (toxicology reviews, clinical cohorts, RCTs, poison-center registries) rather than individual EHR-derived — though large single-center Asian cohorts (Sri Lanka, India, Pakistan, Bangladesh) supply much of the clinical evidence.

2. Etiology

Primary cause. Exposure — dermal, inhalational, or (most lethally) oral ingestion — to an organophosphorus compound. The dominant global context is intentional self-poisoning (suicide) by ingestion of agricultural insecticides in low- and middle-income countries; secondary causes are occupational/agricultural exposure and accidental (often pediatric) exposure. Chemical warfare/terrorism (e.g., Tokyo sarin 1995; Syria) is a distinct high-acuity setting.

Risk factors (environmental/behavioral): - Residence in rural agricultural regions of South Asia, Southeast Asia, sub-Saharan Africa, Central/South America. - Occupational: farm workers, pesticide applicators/handlers, sheep-dip workers (chronic low-dose exposure). - Ready domestic availability of highly hazardous WHO Class I OP pesticides. - Psychiatric distress / acute interpersonal crisis (impulsive self-harm — the reason means-restriction works so well). - Male sex and working age predominate in fatal self-poisoning cohorts.

Genetic susceptibility modifiers (not causal genes). PON1 (paraoxonase-1) is the principal host determinant. PON1 is "an A-esterase capable of hydrolyzing the active metabolites (oxons) of a number of organophosphorus insecticides such as parathion, diazinon and chlorpyrifos" (Costa et al.; PMC3516631). The Q192R (rs662) and L55M coding polymorphisms and the −108 C/T promoter variant (governing expression level) modulate detoxification efficiency in a substrate-specific manner — "The PON1R192 alloform hydrolyzes chlorpyrifos oxon and paraoxon more rapidly than PON1Q192." A meta-analysis found "PON1 192Q and 55LM polymorphisms may increase the risk of organophosphate toxicity, especially among Caucasian populations" (PMID:23590198). See §4 and §9.

Protective factors. - Environmental/public-health: national bans of highly hazardous pesticides (Sri Lanka's staged bans are the landmark example — see §9/§13), safe storage, dilution/formulation changes. These are the single most effective interventions for population mortality. - Genetic: high-activity PON1 alloforms/high plasma PON1 status confer relative protection against specific oxons; there is no universally protective allele (protection is compound-dependent).

Gene–environment interaction. The canonical GxE here is PON1 genotype × specific OP compound: "The extent to which PON1 protects against a given OP is determined by its catalytic efficiency" toward that compound's oxon. Groups with high-dose exposure (sheep-dip workers, first Gulf War veterans) reported poorer health if carrying the 192R allele (PMC3516631). CTD (Comparative Toxicogenomics Database) catalogs OP compound → gene interactions for curation cross-reference.

3. Phenotypes

Clinical features derive from cholinergic excess at three receptor populations. Onset is acute (minutes to hours after ingestion; sometimes delayed with lipophilic agents like fenthion).

Muscarinic effects (mnemonics SLUDGE / DUMBELS): salivation, lacrimation, urination, defecation/diarrhea, gastrointestinal cramping, emesis; plus miosis, bronchorrhea, bronchospasm, bradycardia, sweating. Bronchorrhea + bronchospasm ("the killer B's") drive early respiratory failure.

Phenotype Type HPO suggestion Frequency (qualitative)
Miosis (pinpoint pupils) Sign HP:0000616 (Anisocoria/miosis — nearest: HP:0025616 Miosis) Very frequent
Hypersalivation Sign HP:0002307 (Drooling) / HP:0000048 Frequent
Excessive lacrimation Sign HP:0009926 (Increased lacrimation) Frequent
Diarrhea Symptom HP:0002014 (Diarrhea) Frequent
Vomiting Symptom HP:0002013 (Vomiting) Frequent
Bronchorrhea / excessive airway secretions Sign HP:0002486 (nearest: Abnormal bronchus morphology); use HP:0033109/secretion terms Frequent, life-threatening
Bronchospasm / wheezing Sign HP:0030828 (Wheezing) Frequent
Bradycardia Sign HP:0001662 (Bradycardia) Common (tachycardia also possible)
Sweating Sign HP:0000975 (Hyperhidrosis) Frequent
Muscle fasciculations Sign (nicotinic) HP:0002380 (Fasciculations) Frequent
Muscle weakness / flaccid paralysis Sign (nicotinic) HP:0001324 (Muscle weakness) Common, severe cases
Respiratory failure Sign HP:0002878 (Respiratory failure) Leading cause of death
Seizures / status epilepticus Sign (CNS) HP:0001250 (Seizure); HP:0002133 (Status epilepticus) Severe cases, esp. nerve agents
Altered consciousness / coma Sign (CNS) HP:0001259 (Coma) / HP:0002493 Severe cases
Confusion, anxiety, agitation Behavioral (CNS) HP:0001289 (Confusion) Common

Nicotinic effects: fasciculations, muscle weakness, cramps, tachycardia, hypertension, mydriasis (variable) — reflecting neuromuscular junction and sympathetic ganglion stimulation. "Overstimulation of nicotinic acetylcholine receptors in the CNS results in anxiety, headache, convulsions, ataxia, depression of respiration and circulation, tremor, general weakness, and potentially coma" (mechanism reviews).

CNS effects: anxiety, restlessness, confusion, tremor, seizures, and status epilepticus. Per the 2023 review, "brain damage from acute OP exposure is a direct result of status epilepticus," and "muscarinic but not nicotinic receptor antagonists prevent seizure induction if administered before OP exposure" (PMID:37888716).

Later/secondary phenotypes (see §8 for timing): - Intermediate syndrome (IMS): proximal muscle and neck-flexor weakness, cranial nerve palsies, and respiratory failure 24–96 h after cholinergic crisis, "not responsive to atropine or oxime therapy" (PMC5548687). HPO: HP:0002878, HP:0003324 (Generalized muscle weakness). - OP-induced delayed polyneuropathy (OPIDN): distal sensorimotor peripheral neuropathy 1–3 weeks post-exposure. HPO: HP:0009830 (Peripheral neuropathy), HP:0007015 (Sensorimotor neuropathy). - Chronic OP-induced neuropsychiatric disorder (COPIND): cognitive/affective sequelae after chronic or severe acute exposure.

Severity & progression. Severity graded clinically by the Peradeniya Organophosphorus Poisoning (POP) scale (miosis, fasciculations, respiration, bradycardia, consciousness, seizures); "Higher POP scale scores are associated with increased mortality, need for ventilatory support, and atropine dosages" (PMC10336367). Course is acute and often episodic across the three phases; QoL impact is dominated by ICU-level respiratory failure, prolonged ventilation, and (in survivors) persistent neuropsychiatric and peripheral-nerve deficits.

4. Genetic / Molecular Information

Causal genes: NOT APPLICABLE — OP poisoning is toxin-induced; there is no disease-causing germline mutation.

Host-susceptibility gene (modifier): PON1 - HGNC: PON1 (paraoxonase 1), HGNC:9204; chromosome 7q21.3. - Function: calcium-dependent A-esterase that hydrolyzes OP oxons (the toxic activated metabolites); "PON1 activity is highest in liver and in plasma" (PMC3516631). - Key variants (germline polymorphisms, not pathogenic mutations): - Q192R (rs662): substrate-specific catalytic difference; R192 hydrolyzes chlorpyrifos-oxon/paraoxon faster, Q192 hydrolyzes some others (e.g., soman/sarin analogs) better. Both hydrolyze diazoxon equally. - L55M (rs854560): affects protein stability/level. - −108 C/T (promoter): "the major contributor of differences in the levels of PON1 expression." - Allele frequencies vary widely by ancestry (e.g., 192R more common in some Asian/African populations); consult gnomAD for population-specific frequencies. - Functional consequence: modifies detoxification capacity — effectively a pharmacokinetic protective/risk gradient, not loss/gain-of-function disease biology.

Other modifier candidates: BCHE (butyrylcholinesterase) genotype affects plasma pseudocholinesterase scavenging capacity; carboxylesterase (CES1/CES2) contributes to OP scavenging in some species (large in rodents, minor in humans — relevant to model translation, §15). These are secondary.

Epigenetics / chromosomal abnormalities: Not applicable to the acute syndrome. Some experimental and epidemiological work links chronic/developmental OP exposure to DNA-methylation changes (neurodevelopmental cohorts), but this is not part of the acute poisoning entity.

5. Environmental Information

Environmental / chemical agents (the etiology itself). Representative OP insecticides — with CHEBI suggestions for curation: - Parathion (CHEBI:27928), methyl-parathion, chlorpyrifos (CHEBI:34631), malathion (CHEBI:6651), diazinon (CHEBI:34682), dimethoate (CHEBI:34706), monocrotophos, fenthion, dichlorvos (CHEBI:4498). - Nerve agents: sarin (CHEBI:75701), soman, tabun, VX. - Detoxification/therapeutic chemicals: atropine (CHEBI:16684), pralidoxime (CHEBI:8354), obidoxime, diazepam (CHEBI:49575).

WHO hazard classification (Class Ia/Ib "extremely/highly hazardous") predicts case fatality — the basis for regulatory bans.

Lifestyle factors. Alcohol co-ingestion at the time of self-poisoning worsens outcome; occupational non-use of personal protective equipment increases dermal/inhalational absorption in agricultural workers.

Infectious agents: Not applicable (aspiration pneumonia is a complication, not a cause).

6. Mechanism / Pathophysiology

Causal chain (upstream → downstream):

  1. OP absorption and bioactivation. Parent thion OPs (P=S) are metabolized by hepatic cytochrome P450 to the active oxon (P=O) form; PON1 competes by hydrolyzing oxons (detoxification branch). Pathways: KEGG "Metabolism of xenobiotics by cytochrome P450."
  2. AChE inhibition (primary lesion). The oxon phosphorylates the catalytic serine of acetylcholinesterase (AChE, ACHES/ACHE; EC 3.1.1.7): "The OP binds to and phosphorylates a nucleophilic serine at the catalytic site of the enzyme" (PMID:37888716). GO terms: GO:0003990 (acetylcholinesterase activity), GO:0004104 (cholinesterase activity), GO:0042135 (neurotransmitter catabolic process).
  3. "Aging." The phosphorylated enzyme can undergo dealkylation ("aging"), after which it becomes irreversibly inhibited and no longer reactivatable by oximes — the pharmacological rationale for giving oximes early. Aging half-time is compound-specific (minutes for soman; hours–days for many insecticides).
  4. Acetylcholine accumulation → receptor overstimulation. Acetylcholine (CHEBI:15355) accumulates at synapses; overstimulation of muscarinic (CHRM1-5) and nicotinic (CHRNA/CHRNB) acetylcholine receptors. GO: GO:0007271 (synaptic transmission, cholinergic), GO:0007213 (G-protein-coupled acetylcholine receptor signaling). Clinical cholinergic toxidrome results (§3).
  5. CNS excitotoxicity. Cholinergic overactivity triggers seizures/status epilepticus; downstream, "the amygdala displays a rapid increase in extracellular glutamate after exposure to soman" — a glutamatergic secondary phase that sustains seizures and neuronal injury even after cholinergic control (PMID:37888716).
  6. Calcium overload, mitochondrial dysfunction, oxidative stress. "Excess Ca++ disrupts the function of mitochondria, leading to ATP depletion and oxidative stress"; "oxidative stress and inflammation play an important role in neuronal damage caused by chronic OP exposure." GO: GO:0006954 (inflammatory response), GO:0006979 (response to oxidative stress), GO:0006915 (apoptotic process). This drives neuronal necrosis/apoptosis and long-term brain damage.
  7. Respiratory failure (the proximate cause of death). Convergence of bronchorrhea/bronchospasm (muscarinic), diaphragmatic/intercostal weakness (nicotinic neuromuscular block), and central respiratory depression (CNS).

Distinct secondary mechanisms: - Intermediate syndrome (IMS): post-synaptic neuromuscular dysfunction and receptor downregulation from prolonged ACh excess; correlates with sustained AChE inhibition and specific agents (dimethoate, fenthion, monocrotophos). - OPIDN: mechanistically separate — covalent inhibition and "aging" of neuropathy target esterase (NTE / PNPLA6), "localised to the cytoplasmic face of the endoplasmic reticulum," which normally deacylates ER phosphatidylcholine; its inhibition "may perturb the metabolism of important membrane phospholipids," causing distal axonopathy (PMC5548687). Newer work implicates TRPA1 channel activation: "a variety of organophosphates, exemplified by malathion, activates TRPA1 but not other neuronal TRP channels" (Cell Discovery 2017, celldisc201724). GO: GO:0004622-type phospholipase activity; NTE = PNPLA6 (HGNC:16268).

Molecular profiling. Candidate severity biomarkers beyond cholinesterase include serum S100B and amyloid-β (PMC10579114) and creatine phosphokinase (CPK) for muscle involvement (PMC9662705); these are prognostic, not diagnostic.

7. Anatomical Structures Affected

Organ / system level: - Nervous system (primary): central (UBERON:0001017 CNS — brain seizures/excitotoxicity), peripheral/autonomic, neuromuscular junction. - Respiratory system (UBERON:0001004): bronchi (bronchorrhea/bronchospasm), diaphragm (UBERON:0001103) — respiratory failure. - Cardiovascular (UBERON:0004535): brady-/tachyarrhythmia, QT prolongation. - Gastrointestinal (UBERON:0005409): hypersalivation, cramping, diarrhea. - Eye (UBERON:0000970): pupil (miosis via iris sphincter), lacrimal gland (UBERON:0001817). - Exocrine glands: salivary (UBERON:0001044), sweat glands. - Skeletal muscle (UBERON:0001134): fasciculation, weakness, rhabdomyolysis.

Cell types (CL suggestions): - Cholinergic neurons (CL:0000108 cholinergic neuron). - Skeletal muscle fibers / motor endplate (CL:0000188 cell of skeletal muscle). - Peripheral neurons and Schwann cells (CL:0002573) — OPIDN axonopathy. - Bronchial smooth muscle and secretory (goblet) cells; cardiac pacemaker cells.

Subcellular (GO cellular component): synaptic cleft (GO:0043083), neuromuscular junction (GO:0031594), endoplasmic reticulum (GO:0005783 — NTE localization), mitochondria (GO:0005739 — Ca²⁺/oxidative injury).

Localization / lateralization: systemic and bilateral/symmetric; miosis is bilateral; OPIDN is length-dependent and symmetric distal.

8. Temporal Development

Three temporally distinct phases (a hallmark of OP toxicology):

  1. Acute cholinergic crisis — onset minutes to a few hours (delayed/prolonged with lipophilic agents like fenthion, which can relapse over days). Duration ~24–72 h; the phase in which most deaths occur.
  2. Intermediate syndrome (IMS) — "occurs 24–96 hours after exposure," after apparent recovery from cholinergic signs; proximal/respiratory muscle weakness; "the patient usually recovers within 2 or 3 weeks"; atropine/oxime-unresponsive (PMC5548687). A critical window because respiratory arrest can occur in a conscious, seemingly recovering patient ("type II respiratory failure," Eddleston 2008).
  3. OPIDN — delayed, 1–3 weeks (typically ~2 weeks) after exposure; progressive distal sensorimotor neuropathy; recovery partial and slow over months, often incomplete.

Onset pattern: acute for the syndrome overall; subacute/delayed for IMS and OPIDN. Course: episodic/multiphasic rather than continuously progressive. Critical intervention window: the first minutes–hours (decontamination, atropine, early oxime before "aging"); and vigilant monitoring across the 1–4 day IMS window.

9. Inheritance and Population (Epidemiology)

Global burden. OP self-poisoning is a major global health problem. Pesticide self-poisoning overall causes roughly 110,000–168,000 deaths per year; a systematic review estimated "around one in seven of global suicides were due to pesticide self-poisoning" (~110,000/year, 2010–2014). Eddleston et al. attribute "around two-thirds of these deaths — a total of 200,000 a year" to organophosphorus pesticides specifically (PMID:17706760; earlier BJPsych global-response analysis, Gunnell & Eddleston, PMID:16946353 / PMC2493385).

Case fatality. "Medical management is difficult, with case fatality generally more than 15%" and reported ranges of 15–30% in Asian hospital cohorts (Eddleston 2008). Fatality is compound-dependent (dimethoate, fenthion, parathion far more lethal than malathion/chlorpyrifos).

Geographic distribution. Concentrated in rural low- and middle-income countries — South Asia (Sri Lanka, India, Bangladesh), Southeast Asia, China, sub-Saharan Africa, and parts of Central/South America — where highly hazardous OP insecticides are agriculturally available. The Sri Lankan pesticide-ban natural experiment is the landmark demonstration that means restriction cuts population suicide rates (Lancet Global Health, 2017).

Demographics. Male predominance and working-age (roughly 15–45 y) predominance in fatal self-poisoning; a separate pediatric accidental-exposure population exists. Occupational chronic exposure affects agricultural workers of both sexes.

Genetics (host): No inheritance pattern for the disease (it is acquired). PON1 susceptibility alleles follow ordinary Mendelian codominant polymorphism inheritance with ancestry-dependent allele frequencies (see §4). Penetrance/expressivity concepts do not apply to a toxic exposure.

10. Diagnostics

Diagnosis is primarily clinical (exposure history + cholinergic toxidrome), supported by:

Laboratory / biomarkers (LOINC-codable): - Red-cell (erythrocyte) acetylcholinesterase (RBC AChE) — best surrogate for synaptic AChE; "direct measurement of red blood cell acetylcholinesterase activity indicates the degree of toxicity, and sequential measurement could be used to assess treatment response" (PMID:17913691). LOINC ~ "Acetylcholinesterase [Enzymatic activity/volume] in RBC." - Plasma butyrylcholinesterase (BChE / pseudocholinesterase) — "more easily available but may not correlate with severity of poisoning and cannot be used to guide treatment," though useful as an exposure biomarker; "serum cholinesterase can fall to about 40% before any symptoms occur and up to 70–80% before symptoms become severe" (PMID:25189163 / PMC4224972; PMID:17913691). - CPK (muscle injury / severity prediction; PMC9662705); amylase; arterial blood gas (respiratory failure); electrolytes; lactate. - Emerging: S100B, amyloid-β as severity biomarkers (PMC10579114).

Functional / electrophysiology: ECG (bradycardia, QT prolongation, arrhythmia — prognostic); repetitive nerve stimulation / EMG shows decrement-increment and can predict/confirm intermediate syndrome; nerve conduction studies for OPIDN.

Imaging: chest X-ray for aspiration pneumonia/ARDS (a complication, not diagnostic).

Clinical severity criteria: Peradeniya Organophosphorus Poisoning (POP) scale (PMC10336367); POP correlates with mortality, ventilation need, and atropine requirement.

Genetic testing: Not diagnostic. PON1 genotyping is a research/exposure-susceptibility tool, not a clinical diagnostic (GTR lists PON1 assays for research contexts).

Differential diagnosis: carbamate poisoning (same toxidrome, spontaneously reversible carbamylation, oximes usually unnecessary/controversial), nerve-agent exposure, muscarine-containing mushroom poisoning, nicotine toxicity, cholinergic drugs, and non-toxic causes of miosis/coma (opioids — miosis but no SLUDGE, no bronchorrhea).

11. Outcome / Prognosis

Mortality. Case fatality 15–30% in resource-limited cohorts, dominated by early respiratory failure and later IMS-related respiratory arrest, aspiration pneumonia, and ARDS (§9). Death is driven by agent lethality, ingested dose, time-to-treatment, and access to ICU ventilation.

Prognostic factors: ingested compound (dimethoate/fenthion/parathion worst), POP severity score, depth/duration of cholinesterase inhibition, GCS/coma at presentation, need for intubation, hypotension, and time to atropinization. Elevated CPK and persistent low RBC AChE predict complicated courses.

Morbidity in survivors: - Intermediate syndrome — prolonged ventilation, ICU complications; usually recovers over 2–3 weeks. - OPIDN — distal weakness/sensory loss with slow, often incomplete recovery; long-term disability. - COPIND / neuropsychiatric sequelae — persistent cognitive impairment, depression, anxiety, EEG changes after severe/repeated exposure. - Anoxic brain injury from prolonged seizures/respiratory failure.

Recovery potential: with prompt aggressive supportive care (early intubation, adequate atropinization) survival is good for many insecticides; nerve agents and the most lethal insecticides carry high mortality despite treatment.

12. Treatment

Management rests on decontamination + resuscitation + antidotes (atropine, oxime, benzodiazepine) — MAXO suggestions noted.

Immediate / supportive (MAXO:0000950 supportive care): airway protection and early intubation/mechanical ventilation for respiratory failure/secretions (MAXO for mechanical ventilation / oxygen administration); IV access, fluids; skin/GI decontamination (remove clothing, wash skin; activated charcoal if early and airway protected). Staff PPE to prevent secondary contamination.

Antidotes (pharmacotherapy — MAXO:0000058 / administration of drug):

  1. Atropine (CHEBI:16684) — competitive muscarinic antagonist; the mainstay, benefit well established. Give by doubling-dose titration: "a regimen of doubling doses, with the aim of raising the pulse above 80 beats per minute and systolic blood pressure above 80 mm Hg," continuing "until the heart rate is more than 80 bpm, the systolic BP is more than 80 mm Hg, and the chest is clear" (Eddleston 2008, PMID:17706760; doubling-dose vs ad hoc comparison PMID:18784205). Does not treat nicotinic (muscle weakness) effects. Watch for atropine toxicity (agitation, hyperthermia, ileus).
  2. Oximes — pralidoxime (CHEBI:8354) / obidoxime — reactivate phosphorylated AChE before aging. WHO regimen: "pralidoxime chloride 2 g IV over 20–30 min, follow with an infusion of pralidoxime 0.5–1 g/h" (Eddleston 2008). Efficacy is genuinely uncertain: a Cochrane review concluded current evidence is insufficient to show benefit or harm and does not support the WHO regimen; a 2020 meta-analysis of RCTs found "the risk of mortality and the need for ventilator support were not significantly different," with "a significant increase in the incidence of intermediate syndrome in the pralidoxime group" — "pralidoxime was not shown to be beneficial" (PMID:32257715 / PMC7117609; earlier systematic review PMID:11978898). Curate this as a genuine evidence controversy (SUPPORT vs REFUTE evidence items).
  3. Benzodiazepine — diazepam (CHEBI:49575) — for seizures/agitation and neuroprotection: "Acutely agitated patients will benefit from treatment with diazepam" (Eddleston 2008); first-line for OP/nerve-agent seizures (with midazolam increasingly preferred pre-hospital).

Pharmacogenomics: PON1 status influences endogenous detoxification (§4) but is not yet used to guide antidote dosing.

Experimental / investigational therapies: novel reactivators (e.g., experimental oxime K027 vs pralidoxime/obidoxime, PMC6547910), CNS-penetrant oxime prodrugs, bioscavengers (recombinant/plasma-derived butyrylcholinesterase as a stoichiometric scavenger), magnesium sulfate and clonidine as adjuncts, lipid emulsion, and — for nerve-agent neuroprotection — the Src-kinase inhibitor saracatinib (soman model, PMC12270223). Search ClinicalTrials.gov for active adjunct trials (magnesium, sodium bicarbonate, fresh frozen plasma/BChE).

Treatment algorithm summary: decontaminate → secure airway/ventilate → atropine titrated to secretions/HR/BP → oxime early (per local protocol, acknowledging weak evidence) → benzodiazepine for seizures → ICU monitoring for intermediate syndrome across days 1–4 → rehabilitation for OPIDN.

13. Prevention

Primary prevention (the highest-impact lever): - Regulatory bans of highly hazardous OP pesticides — WHO-endorsed; Sri Lanka's staged bans produced large national declines in suicide with negligible agricultural cost (Lancet Global Health 2017). This population-level means restriction is the single most effective intervention. - Safer formulations, dilution, and secure household/community storage (lockboxes). - Occupational: PPE, closed application systems, worker training, exposure limits (EPA/WHO).

Secondary prevention: occupational cholinesterase surveillance of pesticide handlers (baseline + periodic RBC AChE/BChE; remove from exposure at defined depression thresholds — "cholinesterase depression among pesticide handlers," PMID:25189163); early recognition and rapid treatment of exposures.

Tertiary prevention: ICU monitoring to preempt IMS respiratory arrest; rehabilitation for OPIDN; psychiatric follow-up and safety planning for self-poisoning survivors to prevent repetition.

Public-health / behavioral: integrated suicide-prevention (means restriction remains dominant over individual counseling given impulsivity), agricultural extension education, and poison-center infrastructure. Immunization/prophylaxis: for anticipated nerve-agent exposure only, military pretreatment with pyridostigmine (reversible carbamate that shields a fraction of AChE) plus auto-injector atropine/oxime kits — not applicable to civilian insecticide poisoning.

14. Other Species / Natural Disease

  • Taxonomy affected: OPs are toxic across vertebrates and invertebrates (the insecticidal target is homologous insect AChE). Mammals studied include mouse (NCBITaxon:10090), rat (NCBITaxon:10116), guinea pig (NCBITaxon:10141), and non-human primates; birds and fish are ecotoxicologically important.
  • Veterinary relevance: OP/carbamate toxicosis is a common companion-animal and livestock poisoning (dogs, cats, cattle, horses) from flea/tick products, dips, and agricultural exposure — same cholinergic toxidrome, treated with atropine ± pralidoxime. OMIA is not the relevant resource (no Mendelian trait); veterinary toxicology literature and VetCompass cover incidence.
  • Comparative biology: the AChE mechanism is deeply evolutionarily conserved (single active-site serine across taxa), which is why OPs are broad-spectrum. A key cross-species caveat: rodents express high plasma carboxylesterase that scavenges OPs, conferring protection humans lack — a major translational confounder (§15).
  • Cross-species susceptibility differences track carboxylesterase levels, PON1 orthologs, and body-size/dosing; guinea pigs (low carboxylesterase) better model human nerve-agent responses than rats/mice.
  • Zoonotic/transmission: Not applicable (non-communicable toxic exposure).

15. Model Organisms

  • Guinea pig (NCBITaxon:10141): historically preferred for nerve-agent/OP work because low plasma carboxylesterase mimics human pharmacokinetics; toxicity is "sex- and age-dependent and cannot be solely accounted for by acetylcholinesterase inhibition" (PMC2630363).
  • Rat (NCBITaxon:10116): widely used for seizure/EEG, respiratory, and countermeasure studies (anesthetized-rat EEG/respiratory assays); confounded by high carboxylesterase.
  • Genetically humanized mice (KIKO): a modern model — "a novel genetically modified mouse strain (KIKO) with nonfunctional serum carboxylesterase (Es1 KO) and an altered AChE gene expressing the human form (AChE KI)" — engineered to remove the rodent carboxylesterase scavenging confounder and express human-sequence AChE, improving translation for soman/nerve-agent countermeasure testing (PMC7918218; MALDI-MSI characterization PMC11172367).
  • Model types available: knock-in (human AChE), knockout (Es1/serum carboxylesterase), and induced (agent-dosed) models. Resources: MGI, IMPC, IMSR.
  • Phenotype recapitulation: models reproduce cholinergic crisis, seizures/status epilepticus, and respiratory failure, and support antidote/neuroprotectant screening (e.g., saracatinib in soman-poisoned models, PMC12270223; physostigmine adjunct in soman guinea pig, PMC3043258).
  • Limitations: rodent carboxylesterase overprotection; species differences in oxime pharmacokinetics and in the human-specific chronicity of IMS/COPIND; nerve-agent models may not fully capture insecticide self-poisoning kinetics (huge ingested doses, slow absorption, prolonged redistribution of lipophilic agents).

Curation Notes & Ontology Cross-Reference Summary

  • Nature of entry: environmental/toxic exposure syndrome — populate pathophysiology around AChE inhibition; treat PON1 as a SUSCEPTIBILITY/MODIFIER gene, not a causal gene; do not add inheritance blocks for the disease itself.
  • Key genes: ACHE (HGNC:108), BCHE (HGNC:983), PON1 (HGNC:9204), PNPLA6/NTE (HGNC:16268).
  • Key GO: GO:0003990 (acetylcholinesterase activity), GO:0007271 (cholinergic synaptic transmission), GO:0007213 (GPCR ACh receptor signaling), GO:0006979 (oxidative stress response), GO:0006954 (inflammation).
  • Key CHEBI: acetylcholine (CHEBI:15355), atropine (CHEBI:16684), pralidoxime (CHEBI:8354), diazepam (CHEBI:49575), chlorpyrifos (CHEBI:34631), parathion (CHEBI:27928), sarin (CHEBI:75701).
  • Key MAXO: supportive care (MAXO:0000950), pharmacotherapy/drug administration, mechanical ventilation, dietary/GI decontamination.
  • Evidence controversy to encode explicitly: oxime/pralidoxime efficacy — pair a SUPPORT item (mechanistic reactivation rationale) with REFUTE/PARTIAL items from the 2020 RCT meta-analysis (PMID:32257715) and Cochrane review.

Primary Sources (verify each PMID with just fetch-reference before quoting in YAML)

Topic Citation ID
Mechanism / AChE inhibition review (2023) Naughton SX, Terry AV. Toxics 2023 — Mechanisms of Organophosphate Toxicity and the Role of Acetylcholinesterase Inhibition PMID:37888716 / PMC10611379
Clinical management (landmark) Eddleston M et al. Management of acute organophosphorus pesticide poisoning. Lancet 2008 PMID:17706760 / PMC2493390
Pralidoxime efficacy meta-analysis Efficacy of Pralidoxime in OP Poisoning: Systematic Review & Meta-analysis of RCTs, 2020 PMID:32257715 / PMC7117609
Oximes systematic review Eddleston M et al. Oximes in acute OP pesticide poisoning: systematic review of clinical trials, 2002 PMID:11978898
Global burden / prevention Gunnell D, Eddleston M. Deaths from pesticide poisoning: a global response. Br J Psychiatry 2006 PMID:16946353 / PMC2493385
Novel toxicology/pharmacology review Eddleston M. Novel Clinical Toxicology and Pharmacology of OP Insecticide Self-Poisoning. Annu Rev Pharmacol Toxicol 2019 (Annu Rev; DOI 10.1146/annurev-pharmtox-010818-021842)
PON1 susceptibility Costa LG et al. Paraoxonase 1 (PON1) as a genetic determinant of susceptibility to OP toxicity PMC3516631
PON1 meta-analysis PON1 Q192R and L55M polymorphisms and OP toxicity risk: a meta-analysis, 2013 PMID:23590198
Cholinesterase biomarkers Blood AChE and BChE as biomarkers of cholinesterase depression among pesticide handlers, 2014 PMID:25189163 / PMC4224972
RBC AChE / BChE clinical use RBC acetylcholinesterase and plasma butyrylcholinesterase status, 2007 PMID:17913691
Delayed neuropathy (OPIDN) Delayed Polyneuropathy Induced by Organophosphate Poisoning PMC5548687
TRPA1 in OPIDN TRPA1 channel mediates organophosphate-induced delayed neuropathy. Cell Discovery 2017 (celldisc.2017.24)
Severity scale Assessment of the Peradeniya OP Poisoning Scale PMC10336367
Atropine regimen comparison Doubling doses vs ad hoc atropinization, prospective study, 2008 PMID:18784205
Humanized (KIKO) mouse model Novel Genetically Modified Mouse Model to Assess Soman Toxicity (KIKO) PMC7918218
Guinea pig model Acute Toxicity of OP Compounds in Guinea Pigs is Sex- and Age-Dependent PMC2630363
Overview reference Organophosphate Toxicity, StatPearls (NCBI) NBK470430

Verification reminder for KB ingestion: every snippet above is drawn from search-surfaced abstracts/reviews; before committing any of these as evidence items, run just fetch-reference PMID:XXXX and confirm each snippet is an exact substring of the fetched abstract (per the dismech anti-hallucination SOP), and validate all HP/GO/CL/CHEBI/UBERON/MAXO term IDs and labels with just validate-terms-file. The oxime-efficacy claim in particular should be curated as a genuine SUPPORT-vs-REFUTE controversy, not a settled recommendation.

Sources: - Mechanisms of Organophosphate Toxicity and the Role of Acetylcholinesterase Inhibition (Toxics 2023) · PubMed - Management of acute organophosphorus pesticide poisoning (Lancet 2008 / PMC) · PubMed - Efficacy of Pralidoxime: Systematic Review & Meta-analysis (2020) - Oximes in acute OP pesticide poisoning: systematic review (2002) - Deaths from pesticide poisoning: a global response (BJPsych 2006) - Novel Clinical Toxicology and Pharmacology of OP Insecticide Self-Poisoning (Annu Rev) - PON1 as a genetic determinant of susceptibility to OP toxicity · PON1 Q192R/L55M meta-analysis - Blood AChE and BChE as biomarkers among pesticide handlers · RBC AChE and plasma BChE status - Delayed Polyneuropathy Induced by OP Poisoning (OPIDN) · TRPA1 mediates OPIDN (Cell Discovery) - Peradeniya OP Poisoning Scale assessment - Doubling doses vs ad hoc atropinization (2008) - KIKO humanized mouse model of soman toxicity · Guinea pig OP toxicity model - Organophosphate Toxicity — StatPearls

This report is ready to seed a dismech Organophosphate_Poisoning.yaml entry. The two most important curation cautions: treat it as a toxic-exposure entry (PON1 = susceptibility modifier, no causal gene/inheritance), and encode the oxime efficacy uncertainty as competing evidence rather than a recommendation.