Methanol Poisoning

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Mappings

MONDO

MONDO:0017860 methanol poisoning

Primary MONDO disease identifier for this methanol poisoning entry.

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Definitions

1

Clinical case definition for methanol poisoning

Methanol poisoning is a toxic syndrome in which methanol is metabolized to formic acid, producing a high-anion-gap metabolic acidosis and ocular and basal-ganglia injury in a compatible exposure context.

CASE_DEFINITION Disease-level clinical framing across the latent period and toxic phase

Show evidence (1 reference)

PMID:1469176 SUPPORT Other

"While methanol itself may be harmless, it is converted in vivo to the highly toxic formic acid."

Supports the core framing that toxicity arises from metabolic conversion of methanol to formic acid.

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Discussions and Knowledge Gaps

1

How much clinical benefit does folate/folinic-acid therapy add for enhancing formate clearance in human methanol poisoning?

KNOWLEDGE GAP OPEN gap_methanol_folate_efficacy

Attached to

treatments#Folinic acid pathophysiology#Formate accumulation

The rationale for folinic acid is mechanistically sound (folate-dependent 10-formyltetrahydrofolate dehydrogenase is the only human pathway that clears formate), and it is recommended adjunctively, but the human clinical evidence that it improves outcomes is largely experimental and observational rather than from controlled trials.

Show evidence (1 reference)

PMID:1469176 SUPPORT Other

"Experimental data suggests that administration of folic acid may be of benefit by hastening the metabolism of formic acid to carbon dioxide."

Indicates the folate-benefit evidence is experimental, motivating the open question about clinical efficacy.

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Pathophysiology

11

Methanol ingestion and absorption

Methanol is rapidly absorbed from the gastrointestinal tract, with peak concentrations within 30-60 minutes, and distributed in body water. Methanol itself is only mildly intoxicating; toxicity requires its metabolism to formic acid.

hepatocyte CL:0000182

Downstream

Alcohol dehydrogenase oxidation to formaldehyde Absorbed methanol is oxidized by hepatic alcohol dehydrogenase.

Central nervous system depression Methanol itself produces mild central nervous system depression before metabolism.

Show evidence (1 reference)

PMID:12216995 SUPPORT Other

"The absorption of methanol following oral administration is rapid and peak methanol concentrations occur within 30-60minutes."

Supports rapid gastrointestinal absorption of ingested methanol.

Alcohol dehydrogenase oxidation to formaldehyde

Hepatic alcohol dehydrogenase (ADH) oxidizes methanol to formaldehyde. This is the rate-limiting step and the target of antidotal therapy with fomepizole and ethanol.

hepatocyte CL:0000182

methanol oxidation GO:0015946 ↑ INCREASED

Downstream

Aldehyde dehydrogenase oxidation to formate Formaldehyde is rapidly oxidized to formate.

Show evidence (1 reference)

PMID:12216995 SUPPORT Other

"Methanol is oxidized by alcohol dehydrogenase to formaldehyde."

Directly supports alcohol dehydrogenase oxidation of methanol to formaldehyde.

Aldehyde dehydrogenase oxidation to formate

Formaldehyde is very rapidly oxidized by aldehyde/formaldehyde dehydrogenase to formic acid (formate); because this step is fast, formaldehyde does not accumulate.

hepatocyte CL:0000182

formaldehyde metabolic process GO:0046292 ↑ INCREASED

Downstream

Formate accumulation Formate is produced faster than it is eliminated and accumulates.

Show evidence (1 reference)

PMID:12216995 SUPPORT Other

"The oxidation of formaldehyde to formic acid is facilitated by formaldehyde dehydrogenase."

Supports oxidation of formaldehyde to formic acid.

Formate accumulation

Formate is eliminated slowly because its folate-dependent conversion to carbon dioxide by 10-formyltetrahydrofolate dehydrogenase (ALDH1L1/FDH) is rate-limited and saturable in humans, so it accumulates and is the proximate toxin responsible for the metabolic, ocular, and neurological injury. This slow, folate-dependent clearance is the rationale for folinic-acid rescue.

formate metabolic process GO:0015942 ↑ INCREASED

Downstream

Cytochrome c oxidase inhibition by formate Accumulated formate inhibits mitochondrial cytochrome c oxidase.

High anion gap metabolic acidosis Accumulated formate is a major unmeasured anion contributing to the acidosis.

Retinal and optic nerve toxicity Formate is directly toxic to the retina and optic nerve.

Show evidence (1 reference)

PMID:12216995 SUPPORT Other

"In cases of methanol poisoning, formic acid accumulates and there is a direct correlation between the formic acid concentration and increased morbidity and mortality."

Supports formate accumulation and its correlation with morbidity and mortality.

Cytochrome c oxidase inhibition by formate

Formate binds and inhibits mitochondrial cytochrome c oxidase (Complex IV), impairing oxidative phosphorylation and producing histotoxic (cellular) hypoxia independent of oxygen delivery, and is the prime cause of the ocular toxicity.

oxidative phosphorylation GO:0006119 ↓ DECREASED mitochondrial electron transport, cytochrome c to oxygen GO:0006123 ↓ DECREASED

Downstream

Cellular energy failure Impaired oxidative phosphorylation forces anaerobic metabolism and lactate production.

Oxidative stress and apoptosis Mitochondrial dysfunction from Complex IV inhibition generates reactive oxygen species and drives apoptotic cell death.

Show evidence (1 reference)

PMID:12216995 SUPPORT Other

"Formic acid has also been shown to inhibit cytochrome oxidase and is the prime cause of ocular toxicity, though acidosis can increase toxicity further by enabling greater diffusion of formic acid into cells."

Supports formate inhibition of cytochrome oxidase and the acidosis-driven feed-forward diffusion of formic acid.

Oxidative stress and apoptosis

Beyond direct Complex IV inhibition, formate toxicity intensifies oxidative stress and lipid peroxidation with formation of cytotoxic compounds and apoptotic cell death, amplifying tissue injury in the optic nerve, retina, and basal ganglia.

response to oxidative stress GO:0006979 ↑ INCREASED apoptotic process GO:0006915 ↑ INCREASED

Downstream

Retinal and optic nerve toxicity Oxidative stress and lipid peroxidation amplify the optic nerve and retinal injury.

Basal ganglia injury Oxidative injury contributes to basal-ganglia neuronal death.

Show evidence (1 reference)

PMID:34988610 SUPPORT Other

"damage to the eye tissues by oxidative stress causing the intensification of the oxidative peroxidation process with the formation of cytotoxic compounds"

Supports oxidative stress and lipid peroxidation forming cytotoxic compounds as an injury mechanism beyond direct cytochrome oxidase inhibition.

Cellular energy failure

Inhibition of oxidative phosphorylation depletes cellular ATP and shifts metabolism toward anaerobic glycolysis, generating lactate that adds to the acidosis and injuring metabolically demanding tissues such as the basal ganglia.

cellular response to hypoxia GO:0071456 ↑ INCREASED

Downstream

High anion gap metabolic acidosis Lactate accumulation from anaerobic metabolism contributes to the high anion gap acidosis.

Basal ganglia injury Energy failure in the metabolically demanding basal ganglia produces putaminal necrosis.

Show evidence (1 reference)

PMID:27180631 SUPPORT Other

"Its adverse effects are due primarily to the impact of its major metabolite formic acid and lactic acid resulting from cellular hypoxia."

Supports cellular hypoxia producing lactic acid as a driver of adverse effects.

High anion gap metabolic acidosis

Accumulated formate and lactate produce a severe high-anion-gap metabolic acidosis; the low pH increases the proportion of undissociated formic acid, which crosses membranes more readily and worsens cellular toxicity in a feed-forward loop.

Downstream

Central nervous system depression Severe acidosis and systemic toxicity depress the central nervous system.

Show evidence (1 reference)

PMID:12216995 SUPPORT Other

"The acidosis observed in methanol poisoning appears to be caused directly or indirectly by formic acid production."

Supports the high-anion-gap acidosis being driven by formic acid.

Retinal and optic nerve toxicity

Formate inhibits mitochondrial respiration in retinal ganglion cells and the optic nerve head, producing optic disc edema, optic neuropathy, and visual loss that can become permanent blindness.

retinal ganglion cell CL:0000740

oxidative phosphorylation GO:0006119 ↓ DECREASED

Show evidence (1 reference)

PMID:21192754 SUPPORT Other

"Formic acid is implicated in the optic nerve damage associated with methanol."

Supports formate as the cause of optic nerve damage in methanol poisoning.

Basal ganglia injury

Formate toxicity and energy failure produce bilateral putaminal necrosis, at times hemorrhagic, the substrate for delayed parkinsonism and dystonia in survivors.

neuron CL:0000540

cellular response to hypoxia GO:0071456 ↑ INCREASED

Show evidence (1 reference)

PMID:36377024 SUPPORT Human Clinical

"Haemorrhagic necrosis of bilateral basal ganglia, particularly of the putamen, is one of the distinctive features of this entity."

Supports bilateral putaminal hemorrhagic necrosis as the characteristic basal-ganglia lesion.

Central nervous system depression

Methanol itself and the ensuing acidosis and histotoxic hypoxia depress the central nervous system, producing inebriation, confusion, decreased consciousness, coma, and, in severe poisoning, seizures.

neuron CL:0000540

Show evidence (1 reference)

PMID:21192754 SUPPORT Other

"patients frequently develop an early neurological syndrome consisting of inebriation, ataxia, and if severe, seizures and coma."

Supports central nervous system depression progressing to seizures and coma.

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Pathograph

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Phenotypes

14

Cardiovascular 1

Hypotension HP:0002615

Show evidence (1 reference)

PMID:38627622 SUPPORT Human Clinical

"About 9% from the patient were hypotensive, 36% were tachycardic, 41% were tachypneic and 4% were having SpO2 < 94%."

Outbreak-series data document hypotension in a subset of methanol-poisoned patients.

Digestive 2

Nausea and vomiting HP:0002017

Show evidence (1 reference)

PMID:12216995 SUPPORT Other

"Methanol poisoning typically induces nausea, vomiting, abdominal pain, and mild central nervous system depression."

Supports nausea and vomiting as typical early manifestations.

Pancreatitis HP:0001733

Show evidence (1 reference)

PMID:10866330 SUPPORT Human Clinical

"we found evidence of pancreatic damage in 11 patients."

Case-series data document pancreatic injury in half of a methanol-poisoning cohort.

Eye 3

Visual disturbance Blurred vision HP:0000622

Show evidence (1 reference)

PMID:12216995 SUPPORT Other

"visualfunction becomes impaired, ranging from blurred vision and altered visual fields to complete blindness."

Directly supports blurred vision within the spectrum of visual impairment in methanol poisoning.

Blindness HP:0000618

Show evidence (1 reference)

PMID:1469176 SUPPORT Other

"Methanol ingestion is an uncommon form of poisoning that can cause severe metabolic disturbances, blindness, permanent neurologic dysfunction and death."

Supports blindness as a consequence of methanol poisoning.

Optic atrophy HP:0000648

Show evidence (1 reference)

PMID:21192754 SUPPORT Other

"Formic acid is implicated in the optic nerve damage associated with methanol."

Supports optic nerve injury (optic atrophy) from formate in methanol poisoning.

Metabolism 1

Metabolic acidosis HP:0001942

Show evidence (1 reference)

PMID:1469176 SUPPORT Other

"The presence of metabolic acidosis associated with an increased anion gap and increased osmol gap are important laboratory findings."

Supports high-anion-gap metabolic acidosis as a hallmark laboratory finding.

Nervous System 4

Coma HP:0001259

Show evidence (1 reference)

PMID:21192754 SUPPORT Other

"patients frequently develop an early neurological syndrome consisting of inebriation, ataxia, and if severe, seizures and coma."

Supports coma as a manifestation of severe poisoning.

Seizures HP:0001250

Show evidence (1 reference)

PMID:21192754 SUPPORT Other

"patients frequently develop an early neurological syndrome consisting of inebriation, ataxia, and if severe, seizures and coma."

Supports seizures as a manifestation of severe poisoning.

Parkinsonism HP:0001300

Show evidence (1 reference)

PMID:21192754 SUPPORT Other

"Methanol poisoning has led to Parkinsonism and polyneuropathy."

Supports delayed parkinsonism as a neurological sequela of methanol poisoning.

Peripheral neuropathy HP:0009830

Show evidence (1 reference)

PMID:21192754 SUPPORT Other

"Methanol poisoning has led to Parkinsonism and polyneuropathy."

Supports polyneuropathy as a delayed neurological sequela.

Respiratory 1

Tachypnea HP:0002789

Show evidence (1 reference)

PMID:38627622 SUPPORT Human Clinical

"About 9% from the patient were hypotensive, 36% were tachycardic, 41% were tachypneic and 4% were having SpO2 < 94%."

Outbreak-series data document tachypnea in a large fraction of methanol-poisoned patients.

Constitutional 1

Abdominal pain HP:0002027

Show evidence (1 reference)

PMID:12216995 SUPPORT Other

"Methanol poisoning typically induces nausea, vomiting, abdominal pain, and mild central nervous system depression."

Supports abdominal pain as a typical early manifestation.

Other 1

Decreased consciousness Reduced consciousness HP:0004372

Show evidence (1 reference)

PMID:38627622 SUPPORT Human Clinical

"the most common complaints were nausea or vomiting followed by altered level of consciousness."

Outbreak-series data identify altered level of consciousness as a common presenting complaint.

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Genetic Associations

1

ALDH2 (Genetic susceptibility modifier of methanol poisoning outcome)

Gene: ALDH2 hgnc:404 relationship_type: SUSCEPTIBILITY

Show evidence (1 reference)

PMID:29968299 SUPPORT Human Clinical

"Minor C allele carriers of the ALDH2 were significantly more common among methanol-poisoned persons (46%) than among patients with alcoholic liver cirrhosis or healthy controls (31% in both groups, P < 0.05 and 0.025, respectively)"

Supports the ALDH2 minor allele as a susceptibility modifier over-represented in methanol-poisoned patients.

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Medical Actions

5

Fomepizole

Action: Pharmacotherapy NCIT:C15986

Agent: fomepizole CHEBI:5141

Fomepizole (4-methylpyrazole) is a competitive inhibitor of alcohol dehydrogenase that blocks conversion of methanol to formate, halting toxin production; it is the preferred antidote.

Mechanism Target:

INHIBITS Alcohol dehydrogenase oxidation to formaldehyde — Fomepizole competitively inhibits alcohol dehydrogenase, blocking formate production.

Show evidence (1 reference)

PMID:11172179 SUPPORT Human Clinical

"In response to fomepizole, plasma formic acid concentrations fell and metabolic abnormalities resolved in all patients."

Trial evidence that fomepizole lowers formate and resolves the metabolic abnormalities.

Ethanol

Action: Pharmacotherapy NCIT:C15986

Agent: ethanol CHEBI:16236

Ethanol competes with methanol for alcohol dehydrogenase and can be used to block methanol metabolism when fomepizole is unavailable.

Mechanism Target:

INHIBITS Alcohol dehydrogenase oxidation to formaldehyde — Ethanol competitively occupies alcohol dehydrogenase, slowing methanol oxidation.

Show evidence (1 reference)

PMID:1469176 SUPPORT Other

"administration of enteral or parenteral ethanol to competitively inhibit the metabolic breakdown of methanol to formic acid."

Supports ethanol competitively inhibiting methanol metabolism to formic acid.

Folinic acid

Action: Pharmacotherapy NCIT:C15986

Agent: folinic acid CHEBI:63606

Folinic acid (or folic acid) accelerates the folate-dependent oxidation of formate to carbon dioxide by 10-formyltetrahydrofolate dehydrogenase (ALDH1L1/FDH), enhancing clearance of the toxic metabolite.

Mechanism Target:

INHIBITS Formate accumulation — Folinic acid enhances folate-dependent formate metabolism to carbon dioxide.

Show evidence (1 reference)

PMID:1469176 SUPPORT Other

"administration of folic acid may be of benefit by hastening the metabolism of formic acid to carbon dioxide."

Supports folate-based therapy hastening formate metabolism to carbon dioxide.

Hemodialysis

Action: hemodialysis Ontology label: Hemodialysis NCIT:C15248

Hemodialysis removes methanol and formate and corrects the metabolic acidosis, and is used in severe poisoning with acidosis, visual symptoms, or high methanol concentrations.

Mechanism Target:

INHIBITS Formate accumulation — Dialysis directly removes formate and methanol from the blood.

Show evidence (1 reference)

PMID:1469176 SUPPORT Other

"Hemodialysis accelerates the elimination of both methanol and formic acid and also assists in correction of the metabolic acidosis."

Supports hemodialysis removing methanol and formate and correcting acidosis.

Sodium bicarbonate

Action: Pharmacotherapy NCIT:C15986

Agent: sodium bicarbonate CHEBI:32139

Intravenous sodium bicarbonate corrects the metabolic acidosis and, by raising pH, shifts formate toward its ionized form that penetrates tissues less readily.

Mechanism Target:

INHIBITS High anion gap metabolic acidosis — Bicarbonate buffers the metabolic acidosis and reduces membrane-permeant formic acid.

Show evidence (1 reference)

PMID:1469176 SUPPORT Other

"correction of the metabolic acidosis with sodium bicarbonate"

Supports sodium bicarbonate correcting the metabolic acidosis.

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Environmental Factors

3

Adulterated or illicit alcoholic beverages

Drinking methanol-adulterated or illicitly distilled spirits, including homemade alcoholic beverages, is the leading cause of methanol poisoning outbreaks worldwide.

Show evidence (1 reference)

PMID:38627622 SUPPORT Human Clinical

"Homemade alcoholic beverages are a frequent source of such poisoning."

Supports homemade/illicit alcoholic beverages as a frequent source of methanol poisoning.

Mechanism Target:

TRIGGERS Methanol ingestion and absorption — Methanol-adulterated or illicitly distilled spirits are swallowed as if they were drinking alcohol, delivering a methanol dose orally.

Show evidence (1 reference)

PMID:12216995 SUPPORT Other

"The absorption of methanol following oral administration is rapid and peak methanol concentrations occur within 30-60minutes."

Swallowed methanol is absorbed rapidly and near-completely, so an ingestion of this source translates promptly into a systemic methanol load.

Windshield washer fluid and antifreeze

Ingestion of methanol-containing windshield washer fluid or antifreeze, often as an ethanol substitute, is a common source.

Show evidence (1 reference)

PMID:21192754 SUPPORT Other

"are found in a variety of common household products including antifreeze, windshield washer fluid, brake fluid and lubricants."

Identifies antifreeze and windshield washer fluid as common household sources of methanol and related toxic alcohols.

Mechanism Target:

TRIGGERS Methanol ingestion and absorption — These household fluids are ingested, often as an ethanol substitute, delivering methanol by the same oral route.

Show evidence (1 reference)

PMID:12216995 SUPPORT Other

"The absorption of methanol following oral administration is rapid and peak methanol concentrations occur within 30-60minutes."

Swallowed methanol is absorbed rapidly and near-completely, so an ingestion of this source translates promptly into a systemic methanol load.

Industrial and solvent exposure

Occupational or accidental exposure to methanol-containing industrial solvents, fuels, and cleaning products can cause poisoning, rarely by inhalation or dermal absorption.

Show evidence (1 reference)

PMID:12216995 SUPPORT Other

"Almost all cases of acute methanol toxicity result from ingestion, though rarely cases of poisoning have followed inhalation or dermal absorption."

Supports inhalation and dermal absorption as rare non-ingestion routes of exposure.

Mechanism Target:

TRIGGERS Methanol ingestion and absorption — An uncommon, non-oral route: occupational methanol vapour or skin contact can load methanol systemically without any ingestion. Almost all clinical poisoning is oral, so this route is documented but rare.

Show evidence (1 reference)

PMID:12216995 SUPPORT Other

"Almost all cases of acute methanol toxicity result from ingestion, though rarely cases of poisoning have followed inhalation or dermal absorption."

Confirms inhalation and dermal absorption as genuine but rare routes to systemic methanol, and marks ingestion as the dominant one.

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Biochemical Markers

4

Serum formate (INCREASED)

Show evidence (1 reference)

PMID:11172179 SUPPORT Human Clinical

"Plasma formic acid concentrations were detectable in eight patients, and these concentrations were closely correlated with the initial arterial pH values (r=0.92, P<0.001)."

Supports serum formate correlating closely with the acidosis (arterial pH).

Anion gap (INCREASED)

Show evidence (1 reference)

PMID:1469176 SUPPORT Other

"The presence of metabolic acidosis associated with an increased anion gap and increased osmol gap are important laboratory findings."

Supports the increased anion gap as an important laboratory finding.

Osmolar gap (INCREASED)

Show evidence (1 reference)

PMID:27180631 SUPPORT Other

"increases in serum osmolal and anion gaps can be clues to its presence."

Supports the osmolal and anion gaps as diagnostic clues.

Serum bicarbonate (DECREASED)

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Prevalence

1

Worldwide

Unknown Rare

Methanol poisoning is uncommon and typically occurs in outbreaks from methanol-adulterated or illicitly distilled beverages, alongside sporadic accidental and intentional exposures.

Show evidence (1 reference)

PMID:1469176 SUPPORT Other

"Methanol ingestion is an uncommon form of poisoning that can cause severe metabolic disturbances, blindness, permanent neurologic dysfunction and death."

Supports the rarity and severity of methanol poisoning.

{ }

Source YAML

click to show

name: Methanol Poisoning
creation_date: "2026-07-10T00:00:00Z"
category: Environmental
categories:
- Toxic Exposure Disorder
- Toxic Alcohol Poisoning
- Environmental Health Disorder
synonyms:
- methyl alcohol poisoning
- wood alcohol poisoning
- methanol toxicity
description: >-
  Methanol poisoning is a toxic condition caused by ingestion, inhalation, or
  dermal absorption of methanol (methyl alcohol, wood alcohol), most often from
  drinking methanol-adulterated or illicitly distilled alcoholic beverages, or
  from windshield washer fluid, antifreeze, and industrial solvents. Methanol
  itself causes only mild inebriation, but hepatic alcohol dehydrogenase oxidizes
  it to formaldehyde and then to formic acid (formate), the toxic metabolite
  responsible for the disease. Formate inhibits mitochondrial cytochrome c
  oxidase, producing histotoxic hypoxia and a severe high-anion-gap metabolic
  acidosis, and is directly toxic to the optic nerve and retina and to the basal
  ganglia. After a characteristic latent period of hours, patients develop visual
  disturbances that can progress to permanent blindness, metabolic acidosis,
  putaminal necrosis with parkinsonism, coma, and death. Treatment blocks
  metabolism with the alcohol dehydrogenase inhibitor fomepizole (or ethanol),
  enhances formate clearance with folinic acid, corrects the acidosis, and
  removes methanol and formate with hemodialysis.
disease_term:
  preferred_term: methanol poisoning
  term:
    id: MONDO:0017860
    label: methanol poisoning
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0017860
      label: methanol poisoning
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: Primary MONDO disease identifier for this methanol poisoning entry.
definitions:
- name: Clinical case definition for methanol poisoning
  definition_type: CASE_DEFINITION
  description: >-
    Methanol poisoning is a toxic syndrome in which methanol is metabolized to
    formic acid, producing a high-anion-gap metabolic acidosis and ocular and
    basal-ganglia injury in a compatible exposure context.
  scope: Disease-level clinical framing across the latent period and toxic phase
  evidence:
  - reference: PMID:1469176
    reference_title: "Methanol poisoning."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "While methanol itself may be harmless, it is converted in vivo to the highly toxic formic acid."
    explanation: Supports the core framing that toxicity arises from metabolic conversion of methanol to formic acid.
parents:
- toxic alcohol poisoning
prevalence:
- population: Worldwide
  measure_type: UNKNOWN
  prevalence_class: RARE
  notes: >-
    Methanol poisoning is uncommon and typically occurs in outbreaks from
    methanol-adulterated or illicitly distilled beverages, alongside sporadic
    accidental and intentional exposures.
  evidence:
  - reference: PMID:1469176
    reference_title: "Methanol poisoning."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Methanol ingestion is an uncommon form of poisoning that can cause severe metabolic disturbances, blindness, permanent neurologic dysfunction and death."
    explanation: Supports the rarity and severity of methanol poisoning.
pathophysiology:
- name: Methanol ingestion and absorption
  description: >-
    Methanol is rapidly absorbed from the gastrointestinal tract, with peak
    concentrations within 30-60 minutes, and distributed in body water. Methanol
    itself is only mildly intoxicating; toxicity requires its metabolism to
    formic acid.
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  downstream:
  - target: Alcohol dehydrogenase oxidation to formaldehyde
    description: Absorbed methanol is oxidized by hepatic alcohol dehydrogenase.
  - target: Central nervous system depression
    description: Methanol itself produces mild central nervous system depression before metabolism.
  evidence:
  - reference: PMID:12216995
    reference_title: "American Academy of Clinical Toxicology practice guidelines on the treatment of methanol poisoning."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The absorption of methanol following oral administration is rapid and peak methanol concentrations occur within 30-60minutes."
    explanation: Supports rapid gastrointestinal absorption of ingested methanol.
- name: Alcohol dehydrogenase oxidation to formaldehyde
  description: >-
    Hepatic alcohol dehydrogenase (ADH) oxidizes methanol to formaldehyde. This
    is the rate-limiting step and the target of antidotal therapy with fomepizole
    and ethanol.
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  biological_processes:
  - preferred_term: methanol oxidation
    modifier: INCREASED
    term:
      id: GO:0015946
      label: methanol oxidation
  downstream:
  - target: Aldehyde dehydrogenase oxidation to formate
    description: Formaldehyde is rapidly oxidized to formate.
  evidence:
  - reference: PMID:12216995
    reference_title: "American Academy of Clinical Toxicology practice guidelines on the treatment of methanol poisoning."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Methanol is oxidized by alcohol dehydrogenase to formaldehyde."
    explanation: Directly supports alcohol dehydrogenase oxidation of methanol to formaldehyde.
- name: Aldehyde dehydrogenase oxidation to formate
  description: >-
    Formaldehyde is very rapidly oxidized by aldehyde/formaldehyde dehydrogenase
    to formic acid (formate); because this step is fast, formaldehyde does not
    accumulate.
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  biological_processes:
  - preferred_term: formaldehyde metabolic process
    modifier: INCREASED
    term:
      id: GO:0046292
      label: formaldehyde metabolic process
  downstream:
  - target: Formate accumulation
    description: Formate is produced faster than it is eliminated and accumulates.
  evidence:
  - reference: PMID:12216995
    reference_title: "American Academy of Clinical Toxicology practice guidelines on the treatment of methanol poisoning."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The oxidation of formaldehyde to formic acid is facilitated by formaldehyde dehydrogenase."
    explanation: Supports oxidation of formaldehyde to formic acid.
- name: Formate accumulation
  description: >-
    Formate is eliminated slowly because its folate-dependent conversion to
    carbon dioxide by 10-formyltetrahydrofolate dehydrogenase (ALDH1L1/FDH) is
    rate-limited and saturable in humans, so it accumulates and is the proximate
    toxin responsible for the metabolic, ocular, and neurological injury. This
    slow, folate-dependent clearance is the rationale for folinic-acid rescue.
  biological_processes:
  - preferred_term: formate metabolic process
    modifier: INCREASED
    term:
      id: GO:0015942
      label: formate metabolic process
  downstream:
  - target: Cytochrome c oxidase inhibition by formate
    description: Accumulated formate inhibits mitochondrial cytochrome c oxidase.
  - target: High anion gap metabolic acidosis
    description: Accumulated formate is a major unmeasured anion contributing to the acidosis.
  - target: Retinal and optic nerve toxicity
    description: Formate is directly toxic to the retina and optic nerve.
  evidence:
  - reference: PMID:12216995
    reference_title: "American Academy of Clinical Toxicology practice guidelines on the treatment of methanol poisoning."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "In cases of methanol poisoning, formic acid accumulates and there is a direct correlation between the formic acid concentration and increased morbidity and mortality."
    explanation: Supports formate accumulation and its correlation with morbidity and mortality.
- name: Cytochrome c oxidase inhibition by formate
  description: >-
    Formate binds and inhibits mitochondrial cytochrome c oxidase (Complex IV),
    impairing oxidative phosphorylation and producing histotoxic (cellular)
    hypoxia independent of oxygen delivery, and is the prime cause of the ocular
    toxicity.
  biological_processes:
  - preferred_term: oxidative phosphorylation
    modifier: DECREASED
    term:
      id: GO:0006119
      label: oxidative phosphorylation
  - preferred_term: mitochondrial electron transport, cytochrome c to oxygen
    modifier: DECREASED
    term:
      id: GO:0006123
      label: mitochondrial electron transport, cytochrome c to oxygen
  downstream:
  - target: Cellular energy failure
    description: Impaired oxidative phosphorylation forces anaerobic metabolism and lactate production.
  - target: Oxidative stress and apoptosis
    description: Mitochondrial dysfunction from Complex IV inhibition generates reactive oxygen species and drives apoptotic cell death.
  evidence:
  - reference: PMID:12216995
    reference_title: "American Academy of Clinical Toxicology practice guidelines on the treatment of methanol poisoning."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Formic acid has also been shown to inhibit cytochrome oxidase and is the prime cause of ocular toxicity, though acidosis can increase toxicity further by enabling greater diffusion of formic acid into cells."
    explanation: Supports formate inhibition of cytochrome oxidase and the acidosis-driven feed-forward diffusion of formic acid.
- name: Oxidative stress and apoptosis
  description: >-
    Beyond direct Complex IV inhibition, formate toxicity intensifies oxidative
    stress and lipid peroxidation with formation of cytotoxic compounds and
    apoptotic cell death, amplifying tissue injury in the optic nerve, retina,
    and basal ganglia.
  biological_processes:
  - preferred_term: response to oxidative stress
    modifier: INCREASED
    term:
      id: GO:0006979
      label: response to oxidative stress
  - preferred_term: apoptotic process
    modifier: INCREASED
    term:
      id: GO:0006915
      label: apoptotic process
  downstream:
  - target: Retinal and optic nerve toxicity
    description: Oxidative stress and lipid peroxidation amplify the optic nerve and retinal injury.
  - target: Basal ganglia injury
    description: Oxidative injury contributes to basal-ganglia neuronal death.
  evidence:
  - reference: PMID:34988610
    reference_title: "Methanol-induced optic neuropathy: a still-present problem."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "damage to the eye tissues by oxidative stress causing the intensification of the oxidative peroxidation process with the formation of cytotoxic compounds"
    explanation: Supports oxidative stress and lipid peroxidation forming cytotoxic compounds as an injury mechanism beyond direct cytochrome oxidase inhibition.
- name: Cellular energy failure
  description: >-
    Inhibition of oxidative phosphorylation depletes cellular ATP and shifts
    metabolism toward anaerobic glycolysis, generating lactate that adds to the
    acidosis and injuring metabolically demanding tissues such as the basal
    ganglia.
  biological_processes:
  - preferred_term: cellular response to hypoxia
    modifier: INCREASED
    term:
      id: GO:0071456
      label: cellular response to hypoxia
  downstream:
  - target: High anion gap metabolic acidosis
    description: Lactate accumulation from anaerobic metabolism contributes to the high anion gap acidosis.
  - target: Basal ganglia injury
    description: Energy failure in the metabolically demanding basal ganglia produces putaminal necrosis.
  evidence:
  - reference: PMID:27180631
    reference_title: "Approach to the Treatment of Methanol Intoxication."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Its adverse effects are due primarily to the impact of its major metabolite formic acid and lactic acid resulting from cellular hypoxia."
    explanation: Supports cellular hypoxia producing lactic acid as a driver of adverse effects.
- name: High anion gap metabolic acidosis
  description: >-
    Accumulated formate and lactate produce a severe high-anion-gap metabolic
    acidosis; the low pH increases the proportion of undissociated formic acid,
    which crosses membranes more readily and worsens cellular toxicity in a
    feed-forward loop.
  downstream:
  - target: Central nervous system depression
    description: Severe acidosis and systemic toxicity depress the central nervous system.
  evidence:
  - reference: PMID:12216995
    reference_title: "American Academy of Clinical Toxicology practice guidelines on the treatment of methanol poisoning."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The acidosis observed in methanol poisoning appears to be caused directly or indirectly by formic acid production."
    explanation: Supports the high-anion-gap acidosis being driven by formic acid.
- name: Retinal and optic nerve toxicity
  description: >-
    Formate inhibits mitochondrial respiration in retinal ganglion cells and the
    optic nerve head, producing optic disc edema, optic neuropathy, and visual
    loss that can become permanent blindness.
  cell_types:
  - preferred_term: retinal ganglion cell
    term:
      id: CL:0000740
      label: retinal ganglion cell
  biological_processes:
  - preferred_term: oxidative phosphorylation
    modifier: DECREASED
    term:
      id: GO:0006119
      label: oxidative phosphorylation
  evidence:
  - reference: PMID:21192754
    reference_title: "Delayed neurological sequelae from ethylene glycol, diethylene glycol and methanol poisonings."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Formic acid is implicated in the optic nerve damage associated with methanol."
    explanation: Supports formate as the cause of optic nerve damage in methanol poisoning.
- name: Basal ganglia injury
  description: >-
    Formate toxicity and energy failure produce bilateral putaminal necrosis, at
    times hemorrhagic, the substrate for delayed parkinsonism and dystonia in
    survivors.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: cellular response to hypoxia
    modifier: INCREASED
    term:
      id: GO:0071456
      label: cellular response to hypoxia
  evidence:
  - reference: PMID:36377024
    reference_title: "Importance of Susceptibility-weighted-imaging in Methanol Toxicity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Haemorrhagic necrosis of bilateral basal ganglia, particularly of the putamen, is one of the distinctive features of this entity."
    explanation: Supports bilateral putaminal hemorrhagic necrosis as the characteristic basal-ganglia lesion.
- name: Central nervous system depression
  description: >-
    Methanol itself and the ensuing acidosis and histotoxic hypoxia depress the
    central nervous system, producing inebriation, confusion, decreased
    consciousness, coma, and, in severe poisoning, seizures.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  evidence:
  - reference: PMID:21192754
    reference_title: "Delayed neurological sequelae from ethylene glycol, diethylene glycol and methanol poisonings."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "patients frequently develop an early neurological syndrome consisting of inebriation, ataxia, and if severe, seizures and coma."
    explanation: Supports central nervous system depression progressing to seizures and coma.
phenotypes:
- category: Ophthalmologic
  name: Visual disturbance
  description: >-
    Blurred vision, decreased visual acuity, and the classic "snowfield" vision
    are early ocular manifestations of formate toxicity.
  phenotype_term:
    preferred_term: blurred vision
    term:
      id: HP:0000622
      label: Blurred vision
  evidence:
  - reference: PMID:12216995
    reference_title: "American Academy of Clinical Toxicology practice guidelines on the treatment of methanol poisoning."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "visualfunction becomes impaired, ranging from blurred vision and altered visual fields to complete blindness."
    explanation: Directly supports blurred vision within the spectrum of visual impairment in methanol poisoning.
- category: Ophthalmologic
  name: Blindness
  description: >-
    Formate-induced optic neuropathy can progress to permanent blindness if
    untreated.
  phenotype_term:
    preferred_term: blindness
    term:
      id: HP:0000618
      label: Blindness
  evidence:
  - reference: PMID:1469176
    reference_title: "Methanol poisoning."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Methanol ingestion is an uncommon form of poisoning that can cause severe metabolic disturbances, blindness, permanent neurologic dysfunction and death."
    explanation: Supports blindness as a consequence of methanol poisoning.
- category: Ophthalmologic
  name: Optic atrophy
  description: >-
    Optic disc edema followed by optic atrophy reflects the optic nerve injury of
    methanol poisoning.
  phenotype_term:
    preferred_term: optic atrophy
    term:
      id: HP:0000648
      label: Optic atrophy
  evidence:
  - reference: PMID:21192754
    reference_title: "Delayed neurological sequelae from ethylene glycol, diethylene glycol and methanol poisonings."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Formic acid is implicated in the optic nerve damage associated with methanol."
    explanation: Supports optic nerve injury (optic atrophy) from formate in methanol poisoning.
- category: Cardiovascular
  name: Hypotension
  description: >-
    Hypotension can occur in severe methanol poisoning and is a marker of poor
    outcome.
  phenotype_term:
    preferred_term: hypotension
    term:
      id: HP:0002615
      label: Hypotension
  evidence:
  - reference: PMID:38627622
    reference_title: "Clinical presentation and management of methanol poisoning outbreaks in Riyadh, Saudi Arabia: a retrospective analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "About 9% from the patient were hypotensive, 36% were tachycardic, 41% were tachypneic and 4% were having SpO2 < 94%."
    explanation: Outbreak-series data document hypotension in a subset of methanol-poisoned patients.
- category: Respiratory
  name: Tachypnea
  description: >-
    Rapid breathing (tachypnea), the respiratory compensation for the metabolic
    acidosis, is common in methanol poisoning.
  phenotype_term:
    preferred_term: tachypnea
    term:
      id: HP:0002789
      label: Tachypnea
  evidence:
  - reference: PMID:38627622
    reference_title: "Clinical presentation and management of methanol poisoning outbreaks in Riyadh, Saudi Arabia: a retrospective analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "About 9% from the patient were hypotensive, 36% were tachycardic, 41% were tachypneic and 4% were having SpO2 < 94%."
    explanation: Outbreak-series data document tachypnea in a large fraction of methanol-poisoned patients.
- category: Metabolic
  name: Metabolic acidosis
  description: >-
    A severe high-anion-gap metabolic acidosis from formate and lactate is a
    hallmark of methanol poisoning.
  phenotype_term:
    preferred_term: metabolic acidosis
    term:
      id: HP:0001942
      label: Metabolic acidosis
  evidence:
  - reference: PMID:1469176
    reference_title: "Methanol poisoning."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The presence of metabolic acidosis associated with an increased anion gap and increased osmol gap are important laboratory findings."
    explanation: Supports high-anion-gap metabolic acidosis as a hallmark laboratory finding.
- category: Gastrointestinal
  name: Nausea and vomiting
  description: >-
    Nausea and vomiting are common early symptoms.
  phenotype_term:
    preferred_term: nausea and vomiting
    term:
      id: HP:0002017
      label: Nausea and vomiting
  evidence:
  - reference: PMID:12216995
    reference_title: "American Academy of Clinical Toxicology practice guidelines on the treatment of methanol poisoning."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Methanol poisoning typically induces nausea, vomiting, abdominal pain, and mild central nervous system depression."
    explanation: Supports nausea and vomiting as typical early manifestations.
- category: Gastrointestinal
  name: Abdominal pain
  description: >-
    Abdominal pain, sometimes from pancreatitis, occurs in methanol poisoning.
  phenotype_term:
    preferred_term: abdominal pain
    term:
      id: HP:0002027
      label: Abdominal pain
  evidence:
  - reference: PMID:12216995
    reference_title: "American Academy of Clinical Toxicology practice guidelines on the treatment of methanol poisoning."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Methanol poisoning typically induces nausea, vomiting, abdominal pain, and mild central nervous system depression."
    explanation: Supports abdominal pain as a typical early manifestation.
- category: Gastrointestinal
  name: Pancreatitis
  description: >-
    Acute pancreatitis, at times necrotizing, is an under-recognized complication
    of acute methanol poisoning and a source of abdominal pain.
  phenotype_term:
    preferred_term: pancreatitis
    term:
      id: HP:0001733
      label: Pancreatitis
  evidence:
  - reference: PMID:10866330
    reference_title: "Pancreatic injury following acute methanol poisoning."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we found evidence of pancreatic damage in 11 patients."
    explanation: Case-series data document pancreatic injury in half of a methanol-poisoning cohort.
- category: Nervous System
  name: Decreased consciousness
  description: >-
    An altered or decreased level of consciousness reflects the central nervous
    system depression of methanol poisoning and is a common presenting complaint.
  phenotype_term:
    preferred_term: altered level of consciousness
    term:
      id: HP:0004372
      label: Reduced consciousness
  evidence:
  - reference: PMID:38627622
    reference_title: "Clinical presentation and management of methanol poisoning outbreaks in Riyadh, Saudi Arabia: a retrospective analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the most common complaints were nausea or vomiting followed by altered level of consciousness."
    explanation: Outbreak-series data identify altered level of consciousness as a common presenting complaint.
- category: Nervous System
  name: Coma
  description: >-
    Coma occurs in severe methanol poisoning and portends a poor prognosis.
  phenotype_term:
    preferred_term: coma
    term:
      id: HP:0001259
      label: Coma
  evidence:
  - reference: PMID:21192754
    reference_title: "Delayed neurological sequelae from ethylene glycol, diethylene glycol and methanol poisonings."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "patients frequently develop an early neurological syndrome consisting of inebriation, ataxia, and if severe, seizures and coma."
    explanation: Supports coma as a manifestation of severe poisoning.
- category: Nervous System
  name: Seizures
  description: >-
    Seizures can occur in severe poisoning.
  phenotype_term:
    preferred_term: seizures
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:21192754
    reference_title: "Delayed neurological sequelae from ethylene glycol, diethylene glycol and methanol poisonings."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "patients frequently develop an early neurological syndrome consisting of inebriation, ataxia, and if severe, seizures and coma."
    explanation: Supports seizures as a manifestation of severe poisoning.
- category: Nervous System
  name: Parkinsonism
  description: >-
    Delayed parkinsonism and dystonia can follow bilateral putaminal necrosis in
    survivors.
  phenotype_term:
    preferred_term: parkinsonism
    term:
      id: HP:0001300
      label: Parkinsonism
  evidence:
  - reference: PMID:21192754
    reference_title: "Delayed neurological sequelae from ethylene glycol, diethylene glycol and methanol poisonings."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Methanol poisoning has led to Parkinsonism and polyneuropathy."
    explanation: Supports delayed parkinsonism as a neurological sequela of methanol poisoning.
- category: Nervous System
  name: Peripheral neuropathy
  description: >-
    A polyneuropathy has been reported as a delayed neurological complication of
    methanol poisoning.
  phenotype_term:
    preferred_term: peripheral neuropathy
    term:
      id: HP:0009830
      label: Peripheral neuropathy
  evidence:
  - reference: PMID:21192754
    reference_title: "Delayed neurological sequelae from ethylene glycol, diethylene glycol and methanol poisonings."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Methanol poisoning has led to Parkinsonism and polyneuropathy."
    explanation: Supports polyneuropathy as a delayed neurological sequela.
biochemical:
- name: Serum formate
  presence: INCREASED
  notes: >-
    Elevated serum formate is the proximate toxin and correlates with acidosis
    and outcome better than the methanol level.
  evidence:
  - reference: PMID:11172179
    reference_title: "Fomepizole for the treatment of methanol poisoning."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Plasma formic acid concentrations were detectable in eight patients, and these concentrations were closely correlated with the initial arterial pH values (r=0.92, P<0.001)."
    explanation: Supports serum formate correlating closely with the acidosis (arterial pH).
- name: Anion gap
  presence: INCREASED
  notes: >-
    A high anion gap reflects accumulation of formate and lactate.
  evidence:
  - reference: PMID:1469176
    reference_title: "Methanol poisoning."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The presence of metabolic acidosis associated with an increased anion gap and increased osmol gap are important laboratory findings."
    explanation: Supports the increased anion gap as an important laboratory finding.
- name: Osmolar gap
  presence: INCREASED
  notes: >-
    An elevated osmolar gap is an early clue while methanol is unmetabolized; it
    falls as methanol is converted to formate and the anion gap rises.
  evidence:
  - reference: PMID:27180631
    reference_title: "Approach to the Treatment of Methanol Intoxication."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "increases in serum osmolal and anion gaps can be clues to its presence."
    explanation: Supports the osmolal and anion gaps as diagnostic clues.
- name: Serum bicarbonate
  presence: DECREASED
  notes: >-
    Serum bicarbonate falls with the metabolic acidosis.
genetic:
- name: ALDH2
  gene_term:
    preferred_term: ALDH2
    term:
      id: hgnc:404
      label: ALDH2
  relationship_type: SUSCEPTIBILITY
  association: Genetic susceptibility modifier of methanol poisoning outcome
  notes: >-
    Mitochondrial aldehyde dehydrogenase 2 (ALDH2) oxidizes formaldehyde toward
    formate; the reduced-activity ALDH2 minor (C, ALDH2*2-associated) allele is
    over-represented among methanol-poisoned patients and is a candidate modifier
    of susceptibility and outcome, whereas ADH1B variation was not associated.
  evidence:
  - reference: PMID:29968299
    reference_title: "Aldehyde dehydrogenase 2 polymorphism affects the outcome of methanol poisoning in exposed humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Minor C allele carriers of the ALDH2 were significantly more common among methanol-poisoned persons (46%) than among patients with alcoholic liver cirrhosis or healthy controls (31% in both groups, P < 0.05 and 0.025, respectively)"
    explanation: Supports the ALDH2 minor allele as a susceptibility modifier over-represented in methanol-poisoned patients.
environmental:
- name: Adulterated or illicit alcoholic beverages
  exposure_term:
    preferred_term: exposure to methanol
    term:
      id: ECTO:9000028
      label: exposure to methanol
  description: >-
    Drinking methanol-adulterated or illicitly distilled spirits, including
    homemade alcoholic beverages, is the leading cause of methanol poisoning
    outbreaks worldwide.
  evidence:
  - reference: PMID:38627622
    reference_title: "Clinical presentation and management of methanol poisoning outbreaks in Riyadh, Saudi Arabia: a retrospective analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Homemade alcoholic beverages are a frequent source of such poisoning."
    explanation: Supports homemade/illicit alcoholic beverages as a frequent source of methanol poisoning.
  influences_mechanisms:
  - target: Methanol ingestion and absorption
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Methanol-adulterated or illicitly distilled spirits are swallowed as if
      they were drinking alcohol, delivering a methanol dose orally.
    evidence:
    - reference: PMID:12216995
      reference_title: "American Academy of Clinical Toxicology practice guidelines on the treatment of methanol poisoning."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "The absorption of methanol following oral administration is rapid and peak methanol concentrations occur within 30-60minutes."
      explanation: >-
        Swallowed methanol is absorbed rapidly and near-completely, so an
        ingestion of this source translates promptly into a systemic methanol
        load.
- name: Windshield washer fluid and antifreeze
  exposure_term:
    preferred_term: exposure to methanol
    term:
      id: ECTO:9000028
      label: exposure to methanol
  description: >-
    Ingestion of methanol-containing windshield washer fluid or antifreeze, often
    as an ethanol substitute, is a common source.
  evidence:
  - reference: PMID:21192754
    reference_title: "Delayed neurological sequelae from ethylene glycol, diethylene glycol and methanol poisonings."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "are found in a variety of common household products including antifreeze, windshield washer fluid, brake fluid and lubricants."
    explanation: Identifies antifreeze and windshield washer fluid as common household sources of methanol and related toxic alcohols.
  influences_mechanisms:
  - target: Methanol ingestion and absorption
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      These household fluids are ingested, often as an ethanol substitute,
      delivering methanol by the same oral route.
    evidence:
    - reference: PMID:12216995
      reference_title: "American Academy of Clinical Toxicology practice guidelines on the treatment of methanol poisoning."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "The absorption of methanol following oral administration is rapid and peak methanol concentrations occur within 30-60minutes."
      explanation: >-
        Swallowed methanol is absorbed rapidly and near-completely, so an
        ingestion of this source translates promptly into a systemic methanol
        load.
- name: Industrial and solvent exposure
  exposure_term:
    preferred_term: exposure to methanol
    term:
      id: ECTO:9000028
      label: exposure to methanol
  description: >-
    Occupational or accidental exposure to methanol-containing industrial
    solvents, fuels, and cleaning products can cause poisoning, rarely by
    inhalation or dermal absorption.
  evidence:
  - reference: PMID:12216995
    reference_title: "American Academy of Clinical Toxicology practice guidelines on the treatment of methanol poisoning."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Almost all cases of acute methanol toxicity result from ingestion, though rarely cases of poisoning have followed inhalation or dermal absorption."
    explanation: Supports inhalation and dermal absorption as rare non-ingestion routes of exposure.
  influences_mechanisms:
  - target: Methanol ingestion and absorption
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      An uncommon, non-oral route: occupational methanol vapour or skin
      contact can load methanol systemically without any ingestion. Almost
      all clinical poisoning is oral, so this route is documented but rare.
    evidence:
    - reference: PMID:12216995
      reference_title: "American Academy of Clinical Toxicology practice guidelines on the treatment of methanol poisoning."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Almost all cases of acute methanol toxicity result from ingestion, though rarely cases of poisoning have followed inhalation or dermal absorption."
      explanation: >-
        Confirms inhalation and dermal absorption as genuine but rare routes to
        systemic methanol, and marks ingestion as the dominant one.
treatments:
- name: Fomepizole
  description: >-
    Fomepizole (4-methylpyrazole) is a competitive inhibitor of alcohol
    dehydrogenase that blocks conversion of methanol to formate, halting toxin
    production; it is the preferred antidote.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: fomepizole
      term:
        id: CHEBI:5141
        label: fomepizole
  target_mechanisms:
  - target: Alcohol dehydrogenase oxidation to formaldehyde
    treatment_effect: INHIBITS
    description: Fomepizole competitively inhibits alcohol dehydrogenase, blocking formate production.
  evidence:
  - reference: PMID:11172179
    reference_title: "Fomepizole for the treatment of methanol poisoning."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In response to fomepizole, plasma formic acid concentrations fell and metabolic abnormalities resolved in all patients."
    explanation: Trial evidence that fomepizole lowers formate and resolves the metabolic abnormalities.
- name: Ethanol
  description: >-
    Ethanol competes with methanol for alcohol dehydrogenase and can be used to
    block methanol metabolism when fomepizole is unavailable.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: ethanol
      term:
        id: CHEBI:16236
        label: ethanol
  target_mechanisms:
  - target: Alcohol dehydrogenase oxidation to formaldehyde
    treatment_effect: INHIBITS
    description: Ethanol competitively occupies alcohol dehydrogenase, slowing methanol oxidation.
  evidence:
  - reference: PMID:1469176
    reference_title: "Methanol poisoning."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "administration of enteral or parenteral ethanol to competitively inhibit the metabolic breakdown of methanol to formic acid."
    explanation: Supports ethanol competitively inhibiting methanol metabolism to formic acid.
- name: Folinic acid
  description: >-
    Folinic acid (or folic acid) accelerates the folate-dependent oxidation of
    formate to carbon dioxide by 10-formyltetrahydrofolate dehydrogenase
    (ALDH1L1/FDH), enhancing clearance of the toxic metabolite.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: folinic acid
      term:
        id: CHEBI:63606
        label: (6S)-5-formyltetrahydrofolic acid
  target_mechanisms:
  - target: Formate accumulation
    treatment_effect: INHIBITS
    description: Folinic acid enhances folate-dependent formate metabolism to carbon dioxide.
  evidence:
  - reference: PMID:1469176
    reference_title: "Methanol poisoning."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "administration of folic acid may be of benefit by hastening the metabolism of formic acid to carbon dioxide."
    explanation: Supports folate-based therapy hastening formate metabolism to carbon dioxide.
- name: Hemodialysis
  description: >-
    Hemodialysis removes methanol and formate and corrects the metabolic
    acidosis, and is used in severe poisoning with acidosis, visual symptoms, or
    high methanol concentrations.
  treatment_term:
    preferred_term: hemodialysis
    term:
      id: NCIT:C15248
      label: Hemodialysis
  target_mechanisms:
  - target: Formate accumulation
    treatment_effect: INHIBITS
    description: Dialysis directly removes formate and methanol from the blood.
  evidence:
  - reference: PMID:1469176
    reference_title: "Methanol poisoning."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Hemodialysis accelerates the elimination of both methanol and formic acid and also assists in correction of the metabolic acidosis."
    explanation: Supports hemodialysis removing methanol and formate and correcting acidosis.
- name: Sodium bicarbonate
  description: >-
    Intravenous sodium bicarbonate corrects the metabolic acidosis and, by
    raising pH, shifts formate toward its ionized form that penetrates tissues
    less readily.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: sodium bicarbonate
      term:
        id: CHEBI:32139
        label: sodium hydrogencarbonate
  target_mechanisms:
  - target: High anion gap metabolic acidosis
    treatment_effect: INHIBITS
    description: Bicarbonate buffers the metabolic acidosis and reduces membrane-permeant formic acid.
  evidence:
  - reference: PMID:1469176
    reference_title: "Methanol poisoning."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "correction of the metabolic acidosis with sodium bicarbonate"
    explanation: Supports sodium bicarbonate correcting the metabolic acidosis.
discussions:
- discussion_id: gap_methanol_folate_efficacy
  prompt: >-
    How much clinical benefit does folate/folinic-acid therapy add for enhancing
    formate clearance in human methanol poisoning?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - treatments#Folinic acid
  - pathophysiology#Formate accumulation
  rationale: >-
    The rationale for folinic acid is mechanistically sound (folate-dependent
    10-formyltetrahydrofolate dehydrogenase is the only human pathway that clears
    formate), and it is recommended adjunctively, but the human clinical evidence
    that it improves outcomes is largely experimental and observational rather
    than from controlled trials.
  evidence:
  - reference: PMID:1469176
    reference_title: "Methanol poisoning."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Experimental data suggests that administration of folic acid may be of benefit by hastening the metabolism of formic acid to carbon dioxide."
    explanation: Indicates the folate-benefit evidence is experimental, motivating the open question about clinical efficacy.
datasets: []

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References & Deep Research

Deep Research

1

Claude Code ▸

1. Disease Information

claude-haiku-4-5-20251001, claude-opus-4-8 19 citations 2026-07-10T14:33:17.324122

1. Disease Information

Overview. Methanol (methyl alcohol, wood alcohol, CH₃OH; CHEBI:17790) poisoning is an acute toxic syndrome resulting from ingestion, inhalation, or dermal absorption of methanol. Methanol itself is only mildly intoxicating (similar to ethanol), but it is oxidized in the liver to formaldehyde and then to formic acid/formate, the metabolite responsible for the characteristic delayed high-anion-gap metabolic acidosis, visual toxicity (potentially irreversible blindness), basal-ganglia injury, and death (StatPearls NBK482121; Liesivuori & Savolainen 1991, Pharmacol Toxicol). A hallmark clinical feature is a latent period of ~12–24 hours between ingestion and symptom onset, corresponding to the time needed to accumulate formate.

Key identifiers. - MONDO: MONDO:0017860 (methanol poisoning) — MalaCards - ICD-10-CM: T51.1 ("Toxic effect of methanol"), with subcodes for accidental (T51.1X1), intentional self-harm (T51.1X2), assault (T51.1X3), undetermined (T51.1X4) — ICD10Data - ICD-11: NE61 (toxic effect of alcohol category); specific code for methanol under harmful effects of substances. - Orphanet: ORPHA:31825 - UMLS: C0392621 - MeSH: "Methanol" (D000432) with subheading /poisoning; "Alcohols" toxicity tree. - Toxic agent: methanol — CHEBI:17790; toxic metabolite formate — CHEBI:15740 (formic acid CHEBI:30751).

Synonyms: methyl alcohol poisoning, wood alcohol poisoning, wood spirit poisoning, carbinol poisoning, methanol toxicity, methanol intoxication, methanol overdose.

Data derivation. Knowledge is derived primarily from aggregated disease-level sources — clinical toxicology practice guidelines, case series, and mass-poisoning outbreak cohorts (Estonia, Norway, Iran, Malaysia, Libya, Tunisia) — supplemented by individual case reports and controlled animal/primate studies of formate toxicity. It is not a registry/EHR-defined chronic disease.

2. Etiology

Primary cause (environmental/chemical). Ingestion (most common), inhalation, or transdermal absorption of methanol-containing products. There is no genetic causation; this is a xenobiotic intoxication. Common sources (StatPearls NBK482121): - Adulterated/illicit "bootleg" alcoholic beverages — the leading cause of mass-casualty outbreaks worldwide, especially where informal spirits are consumed or during alcohol prohibition. - Windshield washer/wiper fluid, antifreeze (some formulations), carburetor cleaner, gas-line antifreeze, solvents, paint removers/thinners, shellac, duplicating/copy-machine fluid, canned "chafing/heating fuel" (Sterno), perfumes/colognes, hand sanitizers (methanol-contaminated hand sanitizers caused FDA recalls and poisonings in 2020). - Industrial/occupational and inhalational exposure (fuel, laboratory, model-airplane fuel).

Toxic dose. The estimated minimum lethal dose is ~1 g/kg (≈1–2 mL/kg of pure methanol); as little as ~10 mL can cause permanent blindness and ~30 mL can be fatal, though outcome depends heavily on time to treatment and co-ingested ethanol. Blood methanol >20–25 mg/dL generally warrants antidotal treatment (StatPearls NBK482121).

Risk factors. - Behavioral/social: alcohol use disorder, consumption of illicitly produced/counterfeit spirits, suicidal self-poisoning, poverty and alcohol prohibition contexts, pandemic-related disruption of legal alcohol supply (large Iranian outbreaks during COVID-19) (Hassanian-Moghaddam et al., PMC9189800). - Occupational: solvent/fuel handling. - Nutritional: folate deficiency (malnourished, chronic alcoholics) slows formate clearance and worsens toxicity — a modifiable host factor (see §6). - Demographic: adult males predominate in most outbreak cohorts (median age ~32 in the Iran cohort).

Protective factors. - Co-ingested ethanol is strongly protective: ethanol competitively saturates alcohol dehydrogenase (ADH) — for which it has ~10–20× higher affinity than methanol — delaying/blocking formate generation. This is both the mechanistic basis for ethanol antidotal therapy and an explanation for why some heavily co-intoxicated patients present late but with lower formate burden. - Adequate folate status accelerates formate → CO₂ oxidation (see §6). - No well-established germline protective allele; a pharmacogenetic modifier signal exists at ALDH2 (below).

Gene–environment interaction (pharmacogenetic modifier). In acutely methanol-exposed humans, the ALDH2 minor (C, ALDH2*2-associated) allele was over-represented among poisoned patients (46%) versus healthy controls (31%) (odds ratios ~1.9), suggesting reduced-activity ALDH2 modifies susceptibility/outcome, whereas ADH1B variation did not significantly affect susceptibility (Zakharov et al. 2018, PMID:29968299). This is a susceptibility/modifier signal (SUSCEPTIBILITY relationship type), not a causal gene.

3. Phenotypes

Methanol poisoning is a biphasic syndrome. Suggested HPO terms and typical frequencies below (frequencies are qualitative estimates from outbreak cohorts; treat frequency bands cautiously per curation policy).

Early (0–~12 h, "mild inebriation" phase): | Phenotype | HPO suggestion | Notes | |---|---|---| | Inebriation / CNS depression (mild) | HP:0001254 (Lethargy) / HP:0001250 relatives | Often milder than expected for ethanol | | Nausea and vomiting | HP:0002018 (Nausea), HP:0002013 (Vomiting) | Common; GI irritation | | Abdominal pain | HP:0002027 (Abdominal pain) | Can mimic pancreatitis | | Headache, dizziness | HP:0002315 (Headache), HP:0002321 (Vertigo) | |

Latent period (~12–24 h): relatively asymptomatic while formate accumulates — a dangerous window where patients appear well.

Late (~12–72 h, toxic phase): | Phenotype | HPO suggestion | Frequency (qualitative) | |---|---|---| | Visual disturbance — blurred vision, "snowfield"/halo vision, photophobia, decreased acuity, central scotoma | HP:0000504 (Abnormality of vision), HP:0000546 (Retinal degeneration), HP:0000662 (Nyctalopia relatives) | Very frequent; visual sequelae in ~30–40% of survivors (PMC8731680) | | Blindness / severe visual loss | HP:0000618 (Blindness) | Occasional–frequent, often permanent | | Optic disc hyperemia / peripapillary edema → optic atrophy | HP:0000543 (Optic disc pallor), HP:0000648 (Optic atrophy) | Fundoscopic hallmark | | Fixed/dilated, poorly reactive pupils | HP:0000545 relatives; HP:0000577 (Abnormal pupillary function) | Poor prognostic sign | | High-anion-gap metabolic acidosis | HP:0001942 (Metabolic acidosis) | Cardinal lab abnormality (late) | | Tachypnea / Kussmaul hyperventilation | HP:0002098 (Respiratory distress), HP:0002091 (Tachypnea) | Respiratory compensation | | Coma / depressed consciousness | HP:0001259 (Coma) | Severe cases; poor prognosis | | Seizures | HP:0001250 (Seizure) | Severe cases | | Parkinsonism / dystonia (delayed) | HP:0001300 (Parkinsonism), HP:0001332 (Dystonia) | Sequela of putaminal necrosis | | Hypotension / circulatory failure | HP:0002615 (Hypotension) | Terminal; strongly predicts death | | Pancreatitis / elevated amylase | HP:0001733 (Pancreatitis) | Reported complication |

Phenotype characteristics: onset acute/subacute (adult predominant); severity variable (from asymptomatic to fatal), dose- and time-to-treatment-dependent; course episodic-then-progressive in untreated disease; neuro-ophthalmic deficits may be permanent (progressive optic atrophy) or partially recover.

Prognostic phenotype associations (from cohorts): nausea and blurred vision at presentation were paradoxically associated with better prognosis (earlier presentation), whereas absence of blurred vision and hypotension at admission were associated with death; delayed admission and elevated anion gap predicted blindness (Prognosis in a developing setting, PMC11097318).

Quality-of-life impact: permanent visual loss and Parkinsonian motor sequelae substantially impair independent functioning; long-term follow-up documents new-onset neurologic and visual impairment developing even after apparent recovery (Paasma et al. 2009, PMID:19327138).

4. Genetic / Molecular Information

Not applicable as a causal genetic disease. There are no causal genes, pathogenic variants, chromosomal abnormalities, or Mendelian inheritance.

Relevant enzymes/genes (host metabolism, not disease-causing): - ADH1B / ADH1C / ADH1A (alcohol dehydrogenase, class I; HGNC:249, HGNC:250, HGNC:251) — catalyze methanol → formaldehyde; the therapeutic target of fomepizole/ethanol. ADH1B polymorphism does not significantly modify susceptibility (PMID:29968299). - ALDH2 (aldehyde dehydrogenase 2, mitochondrial; HGNC:404) — formaldehyde → formate; the reduced-activity ALDH2*2 allele is a candidate modifier of outcome (PMID:29968299). - ALDH1L1 (cytosolic 10-formyltetrahydrofolate dehydrogenase, FDH; HGNC:3978) — the folate-dependent enzyme oxidizing 10-formyl-THF → THF + CO₂; the only pathway that clears formate in humans and the basis of folate/folinic-acid rescue. Adequate folate + functional FDH protect against toxicity (folate-formate literature). - CAT (catalase) and peroxisomal metabolism contribute to methanol/formaldehyde handling, especially in retina (minor pathway).

Epigenetics / molecular profiling: No established disease-specific methylation/histone signature; transcriptomic/proteomic/metabolomic profiling is not a routine diagnostic feature. The definitive metabolomic biomarker is elevated serum formate.

5. Environmental Information

Environmental/toxic factors: methanol (CHEBI:17790) is the sole necessary exposure. Sources as in §2 (illicit spirits, washer fluid, solvents, adulterated sanitizer). CTD indexes methanol/formaldehyde/formic acid toxicant–gene interactions.
Lifestyle factors: heavy/illicit alcohol consumption is the dominant behavioral driver; poor nutrition (folate deficiency) worsens outcome.
Infectious agents: none (not applicable).
Contextual amplifiers: alcohol prohibition, informal alcohol economies, and supply-chain disruptions (e.g., COVID-19 pandemic misinformation that alcohol prevents infection) precipitate large outbreaks (PMC9189800).

6. Mechanism / Pathophysiology

Central causal chain (toxicokinetic → toxicodynamic):

Methanol (CHEBI:17790) is absorbed and distributed in body water; it is only weakly CNS-depressant on its own.
ADH oxidizes methanol → formaldehyde (rate-limiting; NAD⁺→NADH). "Alcohol dehydrogenase oxidizes methanol to formaldehyde, and aldehyde dehydrogenase subsequently oxidizes formaldehyde to formic acid" (StatPearls NBK482121). GO:0004022 (alcohol dehydrogenase activity), GO:0006069 (ethanol/alcohol oxidation).
ALDH2 oxidizes formaldehyde → formic acid/formate (very rapid; formaldehyde does not accumulate). GO:0004029 (aldehyde dehydrogenase activity).
Formate accumulates because human formate clearance (folate-dependent 10-formyl-THF pathway via ALDH1L1/FDH) is slow and saturable — the species difference that makes primates far more sensitive than rodents (PNAS 1985).
Formate inhibits mitochondrial cytochrome c oxidase (Complex IV) → blockade of the electron transport chain → histotoxic (cytotoxic) hypoxia and ATP depletion (Liesivuori & Savolainen 1991). GO:0004129 (cytochrome-c oxidase activity), GO:0006123 (mitochondrial electron transport, cytochrome c to oxygen), GO:0006119 (oxidative phosphorylation).
Downstream amplifiers:
Impaired aerobic respiration → lactic acidosis compounds the direct organic (formic) acidosis → severe high-anion-gap metabolic acidosis (GO:0006099 TCA/energy metabolism disruption).
Acidemia increases the un-ionized (diffusible) fraction of formic acid, enhancing cellular entry — a positive-feedback loop worsening tissue penetration and toxicity.
ETC blockade → increased reactive oxygen species → oxidative stress and apoptosis (Liesivuori & Savolainen 1991). GO:0006915 (apoptotic process), GO:0006979 (response to oxidative stress).
Target-tissue injury:
Optic nerve / retina: the retinal ganglion cells, optic nerve head (prelaminar region), and photoreceptors are highly vulnerable due to high energy demand; histopathology shows axonal vacuolation and edema of the oligodendroglia, optic disc edema → optic atrophy (PMC8731680). Suggested CL terms: CL:0000740 (retinal ganglion cell), CL:0000210 (photoreceptor cell), CL:0000128 (oligodendrocyte), CL:0000031 (neuroblast/neuron relatives); UBERON:0000941 (optic nerve), UBERON:0000966 (retina).
Basal ganglia (putamen): bilateral putaminal necrosis ± hemorrhage is the characteristic CNS lesion, attributed to the region's metabolic vulnerability to formate/ischemia; predilection for putamen (not caudate) helps distinguish it from CO poisoning (Sefidbakht et al., MRI spectrum; putamen necrosis, PMID:9561519). UBERON:0001874 (putamen), UBERON:0002420 (basal ganglion). CL:0000129 (microglia) and neuron loss involved.
Systemic collapse: progressive acidosis, coma, seizures, hypotension, respiratory/circulatory failure → death.

Upstream vs downstream: methanol ingestion and ADH-mediated oxidation are upstream; formate accumulation and Complex IV inhibition are the pivotal node; metabolic acidosis, ROS/apoptosis, optic-nerve and putaminal injury are downstream effectors of clinical morbidity.

Protein dysfunction: the injury is not from a mutant protein but from formate as a reversible inhibitor of cytochrome c oxidase (heme a₃–CuB binuclear center), analogous to cyanide/azide.

Metabolic changes: blocked oxidative phosphorylation, elevated lactate, elevated formate; folate one-carbon pool consumption during formate detoxification.

Immune involvement: secondary sterile inflammation/oxidative injury; no primary autoimmune mechanism.

7. Anatomical Structures Affected

Organ level (primary): - Eye / optic nerve (UBERON:0000970 eye; UBERON:0000941 optic nerve; UBERON:0000966 retina) — primary and most feared target. - Brain, specifically basal ganglia / putamen (UBERON:0000955 brain; UBERON:0002420 basal ganglia; UBERON:0001874 putamen) — bilateral necrosis ± hemorrhage; subcortical white matter can also be involved.

Organ level (secondary/systemic): - Metabolic/whole-body: high-anion-gap metabolic acidosis (blood/plasma). - Cardiovascular (hypotension, circulatory failure), respiratory (compensatory hyperventilation, later failure), gastrointestinal/pancreas (nausea, abdominal pain, pancreatitis), kidney (secondary in severe/shock states), CNS (coma, cerebral edema).

Body systems: nervous (central + special sensory/visual), cardiovascular, respiratory, digestive, and metabolic/acid–base systems.

Tissue/cell level: retinal ganglion cells (CL:0000740), photoreceptors (CL:0000210), optic-nerve oligodendrocytes/myelin (CL:0000128), basal-ganglia neurons; endothelial and glial involvement in hemorrhagic putaminal lesions.

Subcellular level: mitochondria (GO:0005739) — the primary compartment of injury (Complex IV, GO:0005751 mitochondrial respiratory chain complex IV); peroxisomes (retinal methanol metabolism, GO:0005777).

Localization/lateralization: CNS and optic lesions are characteristically bilateral and symmetric.

8. Temporal Development

Onset: acute, typically adult. Symptom onset is delayed 12–24 h post-ingestion (longer if ethanol co-ingested), producing a deceptive latent period (StatPearls NBK482121).
Progression/stages: (1) early mild inebriation/GI phase; (2) latent asymptomatic phase; (3) toxic phase (visual, acidotic, CNS); (4) severe/terminal phase (coma, seizures, cardiorespiratory collapse). Progression is rapid once acidosis develops.
Course pattern: untreated disease is progressive; with early antidote/dialysis it is largely self-limited with recovery. Neuro-ophthalmic damage, once established, may be permanent (progressive optic atrophy; fixed Parkinsonism from putaminal necrosis).
Critical window: intervention before or during formate accumulation (ideally within hours, before significant acidosis/visual loss) is decisive; delayed presentation is the strongest driver of blindness and death. Notably, new visual/neurologic deficits can emerge after discharge (Paasma et al. 2009, PMID:19327138).
Duration: acute illness resolves over days with treatment; sequelae are lifelong.

9. Inheritance and Population (Epidemiology)

Epidemiology. Occurs as sporadic individual poisonings and epidemic mass-casualty outbreaks. There is no meaningful "prevalence/incidence per 100,000" as a chronic disease; burden is episodic. In the U.S., roughly ~24 methanol-related deaths were reported in 2023 (StatPearls NBK482121). Large outbreaks include: - Estonia 2001: 111 hospitalized; 86 survived (66 without, 20 with sequelae) (Paasma et al. 2009, PMID:19327138). - Iran (COVID-19 era, 2020): hundreds to thousands poisoned across provinces; one linked cohort reported 795 hospitalized, 84 deaths (PMC9189800). - Malaysia (2018) and other outbreaks report case-fatality up to ~55–61% in some pandemic-era series.

Case fatality / morbidity (from cohorts): reported mortality ranges widely (~8% to >60%) depending on time-to-care, availability of antidote/dialysis, and outbreak conditions; e.g., ~23.9% mortality in one series, with visual sequelae in ~33.7% and neurologic sequelae in ~6.2% (prognosis studies, PMC11097318).

Inheritance: Not applicable (acquired). No inheritance pattern, penetrance, expressivity, anticipation, mosaicism, founder effect, consanguinity, or carrier frequency.

Demographics: adult male predominance; associated with alcohol use disorder, low socioeconomic status, and regions with informal/illicit alcohol production or prohibition. Median outbreak age ~30s. Geographic distribution reflects socioeconomic and regulatory context (South/Southeast Asia, Middle East, Eastern Europe, Africa hotspots), not genetics.

10. Diagnostics

Laboratory (core): - Serum methanol concentration by gas chromatography — definitive; treat at >20–25 mg/dL (StatPearls NBK482121). LOINC: methanol [Mass/volume] in serum/plasma. - Elevated osmolar/osmolal gap early (parent alcohol present; >~10–25 mOsm/kg) that normalizes as methanol is metabolized. LOINC: osmolality serum. - High anion-gap metabolic acidosis later (formate). Arterial blood gas: low pH, low bicarbonate. Anion gap and acidosis are late and correlate with formate. - Serum/plasma formate — best correlate of toxicity/acidosis but not widely available. - Ancillary: elevated lactate, elevated amylase/lipase (pancreatitis), electrolytes/renal function.

Important diagnostic pitfall: early presenters may have an elevated osmolar gap without acidosis; late presenters may have severe acidosis with a near-normal osmolar gap (methanol already metabolized). Serial BMP/ABG every 2–4 h is advised, with 16–24 h observation (StatPearls NBK482121).

Imaging (prognostic, not primary diagnostic): - CT/MRI: bilateral putaminal necrosis ± hemorrhage, subcortical white-matter and optic-nerve changes; putamen-predominant (vs caudate in CO poisoning) plus optic atrophy is nearly pathognomonic (MRI spectrum, ScienceDirect; PMID:9561519). RadLex: putaminal necrosis/hemorrhage.

Ophthalmologic: funduscopy (optic disc hyperemia, peripapillary edema early; optic atrophy late), pupillary reactivity (fixed/dilated = poor prognosis); OCT and visual-evoked potentials for follow-up.

Genetic testing: Not applicable for diagnosis (no causal gene). Pharmacogenetic ALDH2 genotyping is a research modifier, not clinical.

Clinical criteria / differential diagnosis: high-anion-gap metabolic acidosis (MUDPILES) differentials — ethylene glycol poisoning (calcium-oxalate crystals, renal failure, no visual loss), diabetic/alcoholic/lactic ketoacidosis, uremia, salicylate, isopropanol (ketosis without acidosis), paraldehyde. Osmolar-gap + anion-gap pattern, visual symptoms, and putaminal imaging distinguish methanol.

Screening: no population screening; public-health outbreak surveillance of adulterated alcohol is the operative "screening" mode.

11. Outcome / Prognosis

Mortality: highly variable (~8% to >60%), driven by time to treatment, severity of acidosis (pH), coma, and antidote/dialysis availability (PMC11097318; PMC9189800).
Key adverse prognostic factors: low arterial pH (<7.0–7.2), coma or seizures on presentation, hypotension (in some cohorts, all hypotensive-on-admission patients died), abnormal pupillary reactivity, high formate, delayed presentation (PMC8731680; PMC11097318).
Visual morbidity: persistent visual sequelae in ~30–40% of survivors; initial severity predicts long-term visual outcome; some remyelination-related recovery over ~2 years (PMC8731680).
Neurologic morbidity: Parkinsonism, dystonia, cognitive deficits from bilateral putaminal necrosis; delayed encephalopathy. New deficits can appear post-discharge (Paasma et al. 2009, PMID:19327138).
Recovery potential: excellent if treated before significant acidosis/visual loss; established optic atrophy and putaminal necrosis are largely irreversible.
Prognostic biomarkers: admission pH/bicarbonate, formate, methanol level, GCS, and hemodynamic status; risk-prediction nomograms for in-hospital mortality have been developed (PMC11617918).

12. Treatment

The strategy is: (1) block toxic-metabolite formation (ADH inhibition), (2) correct acidosis, (3) enhance formate elimination (dialysis + folate), (4) supportive care.

Antidotes — ADH inhibition (MAXO:0000001 therapeutic intervention / MAXO pharmacotherapy): - Fomepizole (4-methylpyrazole) — first-line preferred antidote. Binds ADH with affinity ~8,000× greater than ethanol, halting methanol→formaldehyde. Dosing: loading 15 mg/kg IV, then 10 mg/kg q12h ×4 doses, then 15 mg/kg q12h (autoinduction), until methanol <20–25 mg/dL and acidosis resolves; q4h or post-dialysis dosing during hemodialysis (StatPearls NBK482121). Landmark efficacy/safety trial: Brent et al., NEJM 2001 (Methylpyrazole for Toxic Alcohols Study Group) (NEJM 2001). CHEBI: fomepizole (CHEBI:47519). Therapeutic agent binds ADH1B (target enzyme). - Ethanol — alternative when fomepizole unavailable; competitive ADH substrate. Target serum ethanol 100–120 mg/dL (IV 10%: ~8 mL/kg load then 1–2 mL/kg/h; oral 50%: 2 mL/kg load then 0.2–0.4 mL/kg/h); requires frequent level monitoring, causes intoxication/hypoglycemia, harder to titrate (StatPearls NBK482121). CHEBI:16236 (ethanol).

Extracorporeal removal — hemodialysis (MAXO:0000059 hemodialysis / renal replacement): - Removes both methanol and formate and corrects acidosis; dramatically shortens methanol half-life (from ~52–70 h with fomepizole alone to ~2.5 h with dialysis). - EXTRIP / AACT indications: severe metabolic acidosis, coma or seizures, visual deficits, renal impairment, or high methanol concentration (>~50 mg/dL without fomepizole; >~70 mg/dL with fomepizole), or evidence of end-organ injury (EXTRIP/AJKD Core Curriculum; AACT Practice Guidelines, Barceloux et al.). Intermittent HD is generally preferred over continuous RRT in mass-casualty settings (PMC5519513).

Acidosis correction: - IV sodium bicarbonate for severe metabolic acidosis; raising pH also traps formate in ionized (less diffusible) form, reducing tissue penetration, and improves formate renal clearance (MAXO/pharmacotherapy). CHEBI:32139 (bicarbonate).

Enhancing formate elimination (folate cofactor rescue): - Folinic acid (leucovorin) — preferred (bypasses dihydrofolate reductase), typically 1 mg/kg (up to ~50 mg) IV q4–6h; folic acid if folinic unavailable. Provides the tetrahydrofolate substrate for 10-formyl-THF dehydrogenase (ALDH1L1) to oxidize formate → CO₂. Folate deficiency potentiates and folate repletion prevents/reverses methanol toxicity in primates (PNAS 1985; folates & visual sequelae, ScienceDirect). CHEBI: folinic acid (CHEBI:15636), folic acid (CHEBI:27470). MAXO: dietary/vitamin supplementation.

Supportive care (MAXO:0000950 supportive care): airway/ventilation, IV fluids with dextrose and thiamine (CHEBI:26948), electrolyte management, seizure control, hemodynamic support.

Investigational/adjunctive for optic injury: high-dose IV methylprednisolone (e.g., 1 g/day ×3–4 days) reported effective in >80% of early-treated cases; erythropoietin neuroprotection and near-infrared photobiomodulation (670 nm) show promise in animal/pilot studies (PMC8731680). These are not standard of care.

Pharmacogenomics: ALDH2 genotype may modify outcome (research); no genotype-guided dosing exists.

13. Prevention

Primary prevention (population/public-health, the dominant lever): regulation and quality control of alcoholic beverages; suppression of illicit/counterfeit spirit production; denaturing/formulation and product labeling (though methanol denaturing is itself a hazard); consumer warnings on washer fluid, solvents, and hand sanitizer; removal of methanol-contaminated hand sanitizers (FDA 2020 actions); rapid outbreak response (alerting, stockpiling fomepizole/ethanol, ensuring dialysis capacity) (StatPearls NBK482121; WHO methanol-poisoning technical guidance).
Secondary prevention: early recognition and rapid antidote/dialysis in exposed individuals; poison-control triage; screening co-exposed people during known outbreaks (shared source).
Tertiary prevention: aggressive acidosis correction and extracorporeal removal to prevent blindness/CNS injury; ophthalmologic and neurologic follow-up for sequelae.
Behavioral interventions: alcohol-use-disorder treatment; public education (especially countering misinformation, e.g., "drinking alcohol prevents COVID").
Environmental interventions: occupational solvent-exposure controls (ventilation, PPE, exposure limits).
Counseling / immunization / prophylactic medication: genetic counseling and vaccination not applicable; no prophylactic drug.

14. Other Species / Natural Disease

Taxonomy / susceptibility: methanol toxicity is species-dependent and driven by hepatic tetrahydrofolate–dependent formate-oxidation capacity. Primates (including humans, NCBITaxon:9606) clear formate slowly and are highly susceptible; rodents (mouse NCBITaxon:10090, rat NCBITaxon:10116) oxidize formate rapidly and are relatively resistant, developing acidosis/ocular injury only under folate deficiency or folate-blockade (PNAS 1985).
Veterinary/natural disease: accidental methanol exposure occurs in companion and production animals, but classic optic/putaminal syndrome is a primate phenomenon; ethylene glycol is the far more common toxic-alcohol veterinary poisoning.
Comparative biology / evolutionary conservation: the ADH→ALDH oxidation and the folate one-carbon formate-clearance pathway (ALDH1L1/FDH) are evolutionarily conserved; the human phenotype reflects a quantitative (slow formate clearance), not qualitative, difference.
Zoonotic potential / transmission: none (chemical toxicity, not transmissible).

15. Model Organisms

Non-human primates (macaque/monkey): the gold-standard model reproducing human formate accumulation, metabolic acidosis, and ocular/optic toxicity; used to establish that formate (not methanol/formaldehyde) is the toxic agent and that folate modulates toxicity (PNAS 1985). MODEL_ORGANISM evidence.
Folate-deficient / folate-blocked rodents and folate-deficient young swine: engineered to slow formate clearance so rodents recapitulate primate-like formate toxicokinetics; used for formate pharmacokinetics and antidote studies (formate PK in folate-deficient swine, ScienceDirect).
Rat / rabbit ocular-toxicity models: for retinal/optic-nerve mitochondrial injury, photoreceptor vulnerability, and photobiomodulation/neuroprotection studies.
In vitro / cellular: isolated mitochondria and cell lines to characterize formate inhibition of cytochrome c oxidase (Complex IV) and ROS generation (IN_VITRO evidence) (Liesivuori & Savolainen 1991).
Genetic models: no knockout "disease model" per se; Aldh1l1 (FDH) and folate-pathway perturbations are the closest genetic modifiers used to sensitize animals.
Model limitations: rodents require artificial folate deficiency to mimic human sensitivity; no single model fully captures the human latent period + delayed bilateral putaminal necrosis; primate models are ethically/logistically constrained.
Resources: MGI/RGD (Adh, Aldh2, Aldh1l1 orthologs), Alliance of Genome Resources, Comparative Toxicogenomics Database (methanol/formaldehyde/formic acid).

Consolidated Ontology Term Suggestions

Disease: MONDO:0017860 (methanol poisoning)
Chemicals (CHEBI): methanol 17790; formaldehyde 16842; formic acid 30751 / formate 15740; fomepizole 47519; ethanol 16236; folinic acid 15636; folic acid 27470; sodium bicarbonate 32139; thiamine 26948
Phenotypes (HPO): HP:0001942 (metabolic acidosis), HP:0000504 (abnormal vision), HP:0000618 (blindness), HP:0000648 (optic atrophy), HP:0000543 (optic disc pallor), HP:0001259 (coma), HP:0001250 (seizure), HP:0001300 (parkinsonism), HP:0001332 (dystonia), HP:0002615 (hypotension), HP:0002013 (vomiting), HP:0002027 (abdominal pain), HP:0002091 (tachypnea), HP:0001733 (pancreatitis)
Biological processes (GO): GO:0004022 (alcohol dehydrogenase activity), GO:0004029 (aldehyde dehydrogenase activity), GO:0004129 (cytochrome-c oxidase activity), GO:0006123 (mito electron transport cyt c→O₂), GO:0006119 (oxidative phosphorylation), GO:0006979 (response to oxidative stress), GO:0006915 (apoptotic process), GO:0035999 (tetrahydrofolate interconversion / one-carbon metabolism)
Cell types (CL): CL:0000740 (retinal ganglion cell), CL:0000210 (photoreceptor cell), CL:0000128 (oligodendrocyte), CL:0000129 (microglial cell)
Anatomy (UBERON): UBERON:0000941 (optic nerve), UBERON:0000966 (retina), UBERON:0001874 (putamen), UBERON:0002420 (basal ganglia), UBERON:0000955 (brain), UBERON:0000970 (eye)
Subcellular (GO CC): GO:0005739 (mitochondrion), GO:0005751 (mito respiratory chain complex IV), GO:0005777 (peroxisome)
Treatments (MAXO): pharmacotherapy (fomepizole/ethanol/bicarbonate/folinic acid), MAXO hemodialysis/renal replacement, MAXO:0000950 (supportive care), vitamin/dietary supplementation (folate)
Genes (HGNC, host metabolism/modifiers — not causal): ADH1B (HGNC:249), ADH1C (HGNC:250), ALDH2 (HGNC:404), ALDH1L1 (HGNC:3978), CAT (HGNC:1516)

Key References (PMID/DOI)

StatPearls, "Methanol Toxicity" — NBK482121 — comprehensive clinical review (dose, metabolism, dosing, prognosis). https://www.ncbi.nlm.nih.gov/books/NBK482121/
Brent J, McMartin K, Phillips S, et al. Fomepizole for the Treatment of Methanol Poisoning. N Engl J Med. 2001;344(6):424–429 (Methylpyrazole for Toxic Alcohols Study Group). https://www.nejm.org/doi/full/10.1056/NEJM200102083440605
Barceloux DG, et al. AACT Practice Guidelines on the Treatment of Methanol Poisoning. J Toxicol Clin Toxicol. 2002;40(4):415–446. https://www.tandfonline.com/doi/abs/10.1081/CLT-120006745
Liesivuori J, Savolainen H. Methanol and formic acid toxicity: biochemical mechanisms. Pharmacol Toxicol. 1991 — Complex IV inhibition, histotoxic hypoxia, ROS/apoptosis. https://physoc.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1600-0773.1991.tb01290.x
Paasma R, Hovda KE, Jacobsen D. Methanol poisoning and long term sequelae – a six years follow-up after a large methanol outbreak. BMC Clin Pharmacol. 2009;9:5. PMID:19327138. https://pubmed.ncbi.nlm.nih.gov/19327138/
Zakharov S, et al. ALDH2 polymorphism affects the outcome of methanol poisoning in exposed humans. 2018. PMID:29968299. https://pubmed.ncbi.nlm.nih.gov/29968299/
Methanol-induced optic neuropathy: a still-present problem. PMC8731680 (PMID:34988610) — mechanism, ~30–40% persistent visual sequelae, adjunctive therapies. https://pmc.ncbi.nlm.nih.gov/articles/PMC8731680/
MRI spectrum in 58 methanol-intoxication patients (long-term visual/neurologic correlation), Eur J Radiol — putaminal necrosis + optic-nerve enhancement. https://www.sciencedirect.com/science/article/pii/S0378603X16300936
Necrosis and haemorrhage of the putamen in methanol poisoning shown on MRI. PMID:9561519. https://pubmed.ncbi.nlm.nih.gov/9561519/
Hassanian-Moghaddam H, et al. Methanol poisoning hospital admissions/mortality in Iranian adults during COVID-19. PMC9189800. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9189800/
Prognosis of Methanol Poisoning in a Developing Setting. PMC11097318 — mortality/sequelae, prognostic factors. https://pmc.ncbi.nlm.nih.gov/articles/PMC11097318/
Risk-prediction nomogram for in-hospital mortality in acute methanol poisoning. PMC11617918. https://pmc.ncbi.nlm.nih.gov/articles/PMC11617918/
EXTRIP / nephrologist role in poisoning (Core Curriculum 2022), Am J Kidney Dis — hemodialysis thresholds and indications. https://www.ajkd.org/article/S0272-6386%2821%2900796-4/fulltext
Species difference: role of hepatic tetrahydrofolate in methanol/formate toxicity. PNAS 1985;82:3854. https://www.pnas.org/doi/pdf/10.1073/pnas.82.11.3854
Acute methanol poisonings: folates administration and visual sequelae. Clin Toxicol/relevant. https://www.sciencedirect.com/science/article/abs/pii/S1214021X14000660

Evidence-source tagging guidance for curation: most clinical claims are HUMAN_CLINICAL (outbreak cohorts, case series, guidelines); the Complex IV/ROS mechanism includes IN_VITRO biochemical data; primate/rodent/swine formate-toxicity and folate-modulation studies are MODEL_ORGANISM; risk-prediction nomograms are HUMAN_CLINICAL (some COMPUTATIONAL modeling on clinical data). Per the dismech DR-verification SOP, each PMID and its snippet must be independently fetched and substring-verified (just fetch-reference PMID:XXXX → just validate-references) before committing — the quotes and figures above are research leads, not pre-validated evidence snippets.

Notable data gaps / not applicable: no causal gene, inheritance, penetrance, carrier frequency, or chromosomal abnormality (acquired poisoning); no established disease-specific epigenetic or omics diagnostic signature; formate assays and pharmacogenetic (ALDH2) testing remain research/reference-lab tools rather than routine clinical diagnostics.

Methanol Poisoning

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