Ricin Poisoning

Environmental MONDO:0035511 Pathograph 56 Show in embeddings browser poisoning

Ricin poisoning is an acute intoxication caused by ricin, the type 2 ribosome-inactivating protein of the castor bean, the seed of Ricinus communis. Ricin is a disulfide-linked heterodimer: the B chain (RTB) is a galactose and N-acetylgalactosamine-specific lectin that binds terminal galactose residues on essentially any cell surface, and the A chain (RTA) is an rRNA N-glycosidase. After RTB-mediated binding the holotoxin is endocytosed and carried retrogradely through the Golgi to the endoplasmic reticulum, where the interchain disulfide is reduced and the A chain dislocates across the ER membrane into the cytosol. There it removes a single adenine from the universally conserved sarcin-ricin loop of 28S rRNA in the 60S subunit, which abolishes elongation-factor binding and arrests protein synthesis. The reaction is catalytic - an estimated 1,500 ribosomes per minute - so very few cytosolic A chains suffice to kill a cell. Depurination is not only a lesion but a signal: the damaged loop triggers the ribotoxic stress response, activating the p38 MAPK and JNK stress kinases, which drive both apoptosis and pro-inflammatory cytokine release. The clinical syndrome is set by the route of exposure rather than by any difference in mechanism. Ingestion of chewed castor seeds produces a hemorrhagic gastroenteritis with fluid and electrolyte loss, usually survivable with prompt supportive care because intact seed coats resist digestion and gastrointestinal absorption is poor. Inhalation of aerosolised toxin produces acute lung injury with interstitial pneumonia, neutrophil influx and proteinaceous alveolar edema that can progress to acute respiratory distress syndrome - a picture established entirely in rodents, rabbits, macaques and swine, since no human inhalational case has been documented. Parenteral injection - the route of the 1978 Georgi Markov assassination - causes local necrosis followed by endothelial glycocalyx shedding, coagulopathy, widespread hemorrhage and distributive shock, known from a handful of human cases and worked out mechanistically in mice and swine. Severe poisoning by any route converges on hypovolemic and distributive shock with multi-organ failure, typically within 10 to 72 hours. There is no approved antidote or vaccine; management is supportive, with early gastrointestinal decontamination for ingestion. Ricin's availability as a byproduct of castor oil production makes it a recurrent agent of assassination, self-harm and attempted bioterrorism, and it is listed as a CDC Category B agent and a Schedule 1 chemical under the Chemical Weapons Convention.

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Mappings

MONDO

MONDO:0035511 ricin poisoning

semapv:ManualMappingCuration

ICD-10-CM

ICD10CM:T62.2 Toxic effect of other ingested (parts of) plant(s)

semapv:ManualMappingCuration

Discussions and Knowledge Gaps

Do the host genetic factors that determine cellular susceptibility to ricin translate into any difference in human clinical susceptibility?

KNOWLEDGE GAP host_genetic_modifiers_of_cellular_susceptibility

Attached to

pathophysiology#RTB Lectin Binding to Cell-Surface Galactosylated Glycoconjugates pathophysiology#Retrograde Transport from the Golgi to the Endoplasmic Reticulum

Cellular susceptibility to ricin has a real, mapped genetic architecture. Fucosylation controls it: losing the Golgi GDP-fucose transporter SLC35C1 or the fucosyltransferase FUT9 makes diverse cell types resistant, and cells from a patient with inherited SLC35C1 deficiency are resistant too. Sialylation of Lewis X structures runs the same axis in the opposite direction - inactivating the responsible sialyltransferase sensitises cells, overexpressing it protects them. The retrograde-transport machinery is a second axis, with STX5 and its ER-targeting factor ASNA1 among the top hits conferring resistance in genome-wide screens. Every one of those results is a statement about cells. Whether any of it shifts the dose of ricin a person survives is untested, and probably untestable by design - human exposure is rare, accidental or deliberate, and the delivered dose is never known. The gap is worth recording precisely because the cell-level evidence is strong enough to be mistaken for a susceptibility claim. It is also the reason this entry has no `genetic:` section: these are modifiers of a toxicological process, not disease genes.

The SLC35C1-deficient patient result is the closest thing to human data in this area, and it is an ex vivo cellular phenotype from a person with a congenital disorder of glycosylation, not an observation of ricin exposure in a person.

Show evidence (4 references)

PMID:28925387 SUPPORT In Vitro

"Genetic and pharmacological inhibition of fucosylation renders diverse cell types resistant to ricin via deregulated intracellular trafficking. Importantly, cells from a patient with SLC35C1 deficiency are also resistant to ricin."

The fucosylation axis, including the one human-derived cellular result.

PMID:28925387 SUPPORT In Vitro

"Inactivation of the sialyltransferase responsible for modifications of Lewis X (St3Gal4) increases the sensitivity of cells to ricin, whereas its overexpression renders cells more resistant to the toxin."

The sialylation axis, in both directions.

PMID:31674906 SUPPORT In Vitro

"our previous genome-wide CRISPR/Cas9 deletions screens have identified STX5 and its ER targeting factor, ASNA1 (also known as TRC40) among the top hits that confer resistance to ricin"

The trafficking-machinery axis, from genome-wide screens.

+ 1 more reference

Does the animal picture of inhalational ricinosis describe human inhalational ricin poisoning, given that no human case series exists to compare it against?

HUMAN MODEL MISMATCH inhalational_syndrome_known_only_from_animals

Attached to

pathophysiology#Acute Lung Injury with Interstitial Pneumonia and Alveolar Edema pathophysiology#Residual Pulmonary Fibrosis in Survivors

Everything this entry records about the inhalational syndrome - the interstitial pneumonia, the neutrophil influx, the proteinaceous oedema, the progression to ARDS, the residual fibrosis in survivors - comes from mice, rabbits, rhesus macaques and swine. This is not the ordinary situation where an animal model stands in for a well-described human disease; there is no human description to stand in for. Two things make the mismatch substantive rather than formal. The models disagree among themselves: exposure method, breathing parameters, aerosol characteristics, ricin cultivar and purity, challenge dose and study duration all vary, and so do the species' anatomy, cell biology and immunology, which is why the comparative review calls the pathology broadly similar rather than the same. And the chronic endpoint is the one most exposed to species choice - susceptibility to pulmonary fibrosis and the character of the fibrosis that develops are themselves properties of the strain, so "survivors may be left with fibrosis" is a claim whose truth may depend on which animal was asked.

Recorded as `HUMAN_MODEL_MISMATCH` rather than `KNOWLEDGE_GAP` because the evidence is not absent - it is abundant, and its translational validity is the open question. Resolving it does not require a human challenge study: a harmonised multi-species protocol, or a documented human exposure with imaging and follow-up, would both narrow it.

Show evidence (4 references)

PMID:37104219 SUPPORT REVIEW SYNTHESIS Model Organism

"The toxicity and associated pathology described in animal models are broadly similar, but variation appears to exist."

States the between-model variation that is half of this mismatch.

PMID:37104219 SUPPORT REVIEW SYNTHESIS Model Organism

"Methodological variation is evident, including method of exposure, breathing parameters during exposure, aerosol characteristics, sampling protocols, ricin cultivar, purity and challenge dose and study duration."

Enumerates the methodological sources of that variation.

PMID:37104219 SUPPORT REVIEW SYNTHESIS Model Organism

"The model species and strain used represent other significant sources of variation, including differences in macro- and microscopic anatomy, cell biology and function, and immunology."

The species-biology sources, which are the ones that bear on translation to humans.

+ 1 more reference

Is ricin-induced hypoglycaemia a feature of human poisoning, or an artefact of the murine parenteral model?

KNOWLEDGE GAP hypoglycemia_human_status

Attached to

pathophysiology#Cytokine-Mediated Suppression of Hepatic Glucose-6-Phosphatase phenotypes#Hypoglycemia

In mice, parenteral ricin causes profound hypoglycaemia that is the only laboratory abnormality for hours, and the mechanism has been worked out to the level of hepatic glucose-6-phosphatase suppression with a streptozotocin control ruling out an insulin-mediated route. That is a more complete mechanistic account than most of this entry carries. The positive human evidence is one clinical report that mentions hypoglycaemia without indicating whether anything was done about it. If the finding is real in humans it would be a cheap early marker of systemic exposure in exactly the situation - suspected deliberate poisoning, no exposure history - where the diagnosis is hardest. If it is murine, the phenotype recorded here should eventually be retired. Retrospective review of glucose values in published human cases would settle it without any new exposure, and the authors report that their own follow-up with those papers' authors failed. The mouse result is not unopposed. The same authors did not see hypoglycaemia in macaques exposed to aerosolised ricin, and note that inflammatory responses in mice and humans broadly differ. That negative changes both species and route at once, so it isolates neither - but it is why this reads as an open question rather than as a human finding awaiting measurement.

Show evidence (4 references)

PMID:36548717 SUPPORT Model Organism

"we sought a humane endpoint to replace lethal challenge by searching for biomarkers of ricin toxicosis. We found that following intraperitoneal (ip) injection of ricin, the sole biochemical abnormality observed in the serum of mice was the rapid development of profound hypoglycemia"

The murine finding, and the fact that it was sought as a biomarker rather than found incidentally.

PMID:36548717 SUPPORT INDIRECT BACKGROUND Human Clinical

"At least one clinical report of ricin toxicosis describes hypoglycemia, but does not indicate whether specific measures were taken to control the low blood glucose in this patient"

The entirety of the positive non-murine evidence, and the reason this is filed as a gap rather than as a settled human phenotype.

PMID:36548717 REFUTE Model Organism

"We did not observe hypoglycemia in macaques exposed to aerosolized ricin"

The same authors' negative result, in a primate and by a different route. It cuts against the finding generalising, and is why this gap is open rather than merely unmeasured in humans.

+ 1 more reference

⚙

Pathophysiology

Ricin Delivery to Host Tissue

The exposure event. Ricin-containing material reaches host tissue by one of four routes - ingestion of chewed or crushed castor seeds, inhalation of aerosolised toxin or seed dust, parenteral injection, and rarely ocular or abraded-skin contact. The molecular mechanism that follows is identical whichever route delivers the toxin; what differs is the dose that reaches the circulation and the tissue that receives the highest local burden, which is why lethal doses by inhalation and injection are roughly a thousandfold lower than by mouth.

Downstream

RTB Lectin Binding to Cell-Surface Galactosylated Glycoconjugates Whatever the route, the first host-side event is the B chain engaging galactose-terminated glycoconjugates on the nearest cell surface.

Show evidence (2 references)

PMID:34830227 SUPPORT BACKGROUND Other

"Exposure to ricin can occur by oral ingestion, inhalation or parenteral intoxication, while the features and severity of ricin toxicity vary markedly with the route of exposure."

States both halves of this node - the routes, and that route sets severity.

PMID:34830227 SUPPORT BACKGROUND Other

"inhalatory and parenteral intoxications are associated with greater illness and mortality, and are characterized by lethal doses that are roughly three magnitudes lower than that of oral poisoning"

Quantifies the thousandfold route difference this description asserts.

RTB Lectin Binding to Cell-Surface Galactosylated Glycoconjugates

The B chain is a galactose and N-acetylgalactosamine-specific lectin. It binds terminal galactose residues on both glycoproteins and glycolipids, which is why ricin has essentially no cell-type selectivity - every nucleated cell displays suitable ligands. The promiscuity of this step is what makes the toxin's organ distribution a function of delivery rather than of receptor expression.

galactoside binding by the ricin B chain GO:0016936

Downstream

Endocytic Internalization of the Ricin Holotoxin Surface binding commits the holotoxin to whichever endocytic routes the bound cell operates.

Show evidence (2 references)

PMID:39453188 SUPPORT BACKGROUND In Vitro

"RTB acts as a galactose-specific lectin, binding to glycolipids and glycoproteins on the cell surface through their terminal galactose or N-acetylgalactosamine residues."

Names the ligand class and both carrier types this node asserts.

PMID:36548717 SUPPORT BACKGROUND In Vitro

"the B chain binds promiscuously to cell surface glycans via galactose-specific lectin binding"

Source of the promiscuity claim, which is the part of this node that explains why ricin has no cell-type selectivity.

Endocytic Internalization of the Ricin Holotoxin

Bound holotoxin is taken into the cell by the endocytic mechanisms available to it, clathrin-dependent and clathrin-independent alike, and delivered to endosomes. Only a very small fraction of internalised toxin escapes the degradative route; most is destroyed, and the potency of the surviving minority is what makes the toxin lethal at microgram doses.

endocytosis of the ricin holotoxin GO:0006897 ↑ INCREASED

Downstream

Retrograde Transport from the Golgi to the Endoplasmic Reticulum From the endosome the toxin is carried onward to the Golgi apparatus by a route distinct from the one mannose-6-phosphate receptors use.

Show evidence (1 reference)

PMID:21527639 SUPPORT BACKGROUND In Vitro

"Ricin enters cells via endocytosis, where only a minute number of ricin molecules reach the endoplasmic reticulum (ER) lumen."

States both the entry mechanism and the small surviving fraction that this node records.

Retrograde Transport from the Golgi to the Endoplasmic Reticulum

The toxin travels backwards along the secretory pathway - endosome to trans-Golgi network to Golgi to endoplasmic reticulum - instead of being routed to the lysosome. This detour is not incidental: reaching the ER lumen is a precondition for the A chain to reach the cytosol, and blocking the early-endosome-to-TGN step alone protects animals from otherwise lethal ricin.

retrograde transport of ricin from the Golgi to the ER GO:0006890 ↑ INCREASED

Downstream

Disulfide Reduction of the Holotoxin in the ER Lumen Arrival in the ER lumen is what makes the subsequent reduction and dislocation into the cytosol possible.

Show evidence (2 references)

PMID:20403321 SUPPORT BACKGROUND In Vitro

"To gain access to their cytosolic target, ribosomal RNA, these toxins follow the retrograde transport route from the plasma membrane to the endoplasmic reticulum, via endosomes and the Golgi apparatus."

Names the full itinerary this node describes.

PMID:20403321 SUPPORT INDIRECT Model Organism

"In mice, one compound clearly protects from lethal nasal exposure to ricin."

Supports the claim that this step is required rather than incidental - blocking it alone rescued animals from a lethal challenge. Marked indirect because it is a therapeutic response cited as validation of the mechanism it targets, which is an inference rather than a direct measurement of the step.

Disulfide Reduction of the Holotoxin in the ER Lumen

In the ER lumen the single disulfide bond joining the two chains is reduced, liberating the A chain from the lectin that carried it there. This is a separate step from the membrane crossing that follows, and is cited separately: the human-cell study that worked out the dislocation mechanism does not describe the reduction.

Downstream

Retrotranslocation of the A Chain into the Cytosol A free A chain is what crosses the membrane; the reduction is what frees it.

Show evidence (1 reference)

PMID:39453188 SUPPORT BACKGROUND In Vitro

"ricin is internalized and transported retrogradely to the endoplasmic reticulum, where the disulfide bond is reduced."

Places the reduction in the ER lumen, which is what this node asserts.

Retrotranslocation of the A Chain into the Cytosol

The liberated A chain crosses the ER membrane into the cytosol by a dislocation process that co-opts the machinery the cell uses to dispose of misfolded proteins. It is not simply the canonical ERAD route: in human cells it proceeds through a membrane-integrated intermediate and depends on the ER protein SEL1L. Once in the cytosol the chain refolds into its active conformation rather than being degraded.

dislocation of the ricin A chain across the ER membrane GO:0030970 ↑ INCREASED

Downstream

Depurination of the Sarcin-Ricin Loop of 28S rRNA A refolded cytosolic A chain immediately begins depurinating ribosomes, at a catalytic rate that makes very few molecules sufficient.

Show evidence (2 references)

PMID:21527639 SUPPORT BACKGROUND In Vitro

"Subsequently, the ricin A chain traverses the ER bilayer by a process referred to as dislocation or retrograde translocation to gain access to the cytosol."

Names the process this node describes.

PMID:21527639 SUPPORT In Vitro

"ricin A chain dislocation occurred via a membrane-integrated intermediate and utilized the ER protein SEL1L for transport across the ER bilayer to inhibit protein synthesis"

The experimental result behind the claim that this is not the canonical ERAD route, measured in a human cell system.

Depurination of the Sarcin-Ricin Loop of 28S rRNA

The catalytic lesion. The A chain is an rRNA N-glycosidase (EC 3.2.2.22) that hydrolyses the N-glycosidic bond of one universally conserved adenine - A4324 in the rat numbering - in the sarcin-ricin loop of 28S rRNA within the 60S subunit. The phosphodiester backbone is left intact; a single base is removed. Because the enzyme turns over rather than being consumed, one molecule inactivates ribosomes at a rate estimated above 1,500 per minute, and the lesion is irreversible for the affected ribosome.

rRNA N-glycosidase activity of the ricin A chain GO:0030598

Downstream

Arrest of Translational Elongation The sarcin-ricin loop is part of the GTPase centre that elongation factors engage, so removing its adenine abolishes elongation-factor binding.

Ribotoxic Stress Response and Stress-Activated Kinase Signaling The damaged loop is itself a signal. This branch runs in parallel with elongation arrest rather than downstream of it.

Show evidence (3 references)

PMID:27879643 SUPPORT REVIEW SYNTHESIS In Vitro

"Ribosome-inactivating proteins (RIPs) including ricin, Shiga toxin, and trichosanthin, are RNA N-glycosidases that depurinate a specific adenine residue (A-4324 in rat 28S ribosomal RNA, rRNA) in the conserved α-sarcin/ricin loop (α-SRL) of rRNA."

Names the enzyme class, the specific adenine, and the loop this node is about.

PMID:39453188 SUPPORT BACKGROUND In Vitro

"RTA functions as an rRNA N-glycosylase (EC 3.2.2.22), specifically cleaving an adenine residue from the 28S ribosomal RNA in the 60S ribosomal subunit"

Gives the EC number and locates the target in the 60S subunit.

PMID:32481526 SUPPORT BACKGROUND In Vitro

"The A chain possesses RNA N-glycosidase activity that irreversibly inactivates the 28S rRNA of the mammalian 60S ribosome subunit"

Independent statement that the inactivation is irreversible, which this node asserts.

Arrest of Translational Elongation

With the sarcin-ricin loop depurinated, elongation factor 1-dependent aminoacyl-tRNA delivery and elongation factor 2-dependent translocation can no longer occur on that ribosome. Protein synthesis halts at the elongation step. As successive ribosomes are hit the cell's entire translational output collapses, and because the lesion is per-ribosome and irreversible there is no recovery short of ribosome biogenesis outpacing the toxin.

translational elongation in the intoxicated cell GO:0006414 ↓ DECREASED

Downstream

Apoptotic Death of Intoxicated Cells Sustained loss of protein synthesis is itself lethal to the cell, and ricin-treated cells die predominantly by apoptosis.

Show evidence (2 references)

PMID:36828415 SUPPORT REVIEW SYNTHESIS In Vitro

"Ricin inhibits peptide chain elongation via disruption of the binding between elongation factors and ribosomes, resulting in apoptosis, inflammation, oxidative stress, and DNA damage, in addition to the classically known rRNA damage."

Names the arrest itself and, in the same sentence, the four downstream consequences this entry branches into.

PMID:19695342 SUPPORT In Vitro

"Ribosome depurination and inhibition of protein synthesis were induced in 2-4h with 1microg/ml RTA and within 4-6h with 0.1microg/ml RTA."

Times the arrest in a non-transformed epithelial cell line, establishing that it precedes the apoptosis measured in the same experiment.

Ribotoxic Stress Response and Stress-Activated Kinase Signaling

Damage to 28S rRNA is sensed as a stress signal independently of the loss of translation. The MAP3K ZAK has been identified as the kinase that responds to ricin-induced damage, activating the p38 MAPK and c-Jun N-terminal kinase stress-activated protein kinase cascades. This response is what converts a cell-autonomous translational lesion into a tissue-level inflammatory event.

JNK cascade activation by ribotoxic stress GO:0007254 ↑ INCREASED p38 MAPK cascade activation by ribotoxic stress GO:0038066 ↑ INCREASED

Downstream

Apoptotic Death of Intoxicated Cells JNK signalling is required for ricin-induced apoptosis in non-transformed epithelial cells, so this is a second, signalling-dependent route to the same cell death rather than a restatement of the translational one.

Pro-inflammatory Cytokine Release The same kinase cascades drive cytokine production, which is the branch that carries the injury beyond the intoxicated cell.

Show evidence (3 references)

PMID:23133670 SUPPORT BACKGROUND In Vitro

"28S rRNA damage stimulates cellular stress-activated protein kinases (SAPK), including p38 mitogen-activated protein kinase (p38 MAPK) and c-Jun N-terminal kinase (JNK) pathways."

Names both kinase cascades bound on this node and the lesion that triggers them.

PMID:23133670 SUPPORT BACKGROUND In Vitro

"The MAP3K, ZAK, has been identified as the being responsible for activating the p38 MAPK and JNK pathways in response to ricin"

Names the sensing kinase. Quoted verbatim including the source's grammatical slip, as a snippet must be.

PMID:19695342 SUPPORT In Vitro

"RTA activated JNK and p38 in a time- and concentration-dependent manner that preceded increases in apoptosis."

Shows the A chain alone is sufficient to activate both cascades, and that activation precedes the death it is here claimed to cause.

Apoptotic Death of Intoxicated Cells

Cells that have taken up enough toxin die, predominantly by apoptosis, with caspase activation and PARP cleavage. Two routes converge here: the translational collapse itself, and the JNK arm of the ribotoxic stress response, which is required for apoptosis in non-transformed epithelium. Death is not confined to intoxicated cells - dying cells release ricin, Fas ligand and HMGB1 that kill neighbouring epithelium by necroptosis, which is how a small delivered dose destroys a whole epithelial surface.

intestinal epithelial cell CL:0002563 hepatocyte CL:0000182 alveolar macrophage CL:0000583

apoptosis of ricin-intoxicated cells GO:0006915 ↑ INCREASED

Downstream

Acute Lung Injury with Interstitial Pneumonia and Alveolar Edema After inhalation, epithelial and alveolar macrophage death is the lesion that produces the pneumonitis.

Hemorrhagic Necrosis of the Gastrointestinal Mucosa After ingestion, the gut mucosa receives the highest local toxin burden and its epithelium is what dies. Left uncited on purpose: nothing in the literature cited here tests epithelial death against the mucosal lesion in gut the way PMID:36695077 does in lung, and the human autopsy series that establishes the lesion says nothing about how the cells died. Note the target lesion is haemorrhagic necrosis, which is not the apoptosis this node names - the death modes are not asserted to be the same one.

Hepatic and Renal Parenchymal Injury Liver and kidney are the constant secondary targets once toxin reaches the circulation, whatever the route of entry. Uncited for the same reason as the gastrointestinal edge above: the autopsy series establishes that these organs are injured, not that apoptosis is what injures them.

Show evidence (3 references)

PMID:19695342 SUPPORT In Vitro

"Comparable caspase activation was observed with both ricin and RTA treatment in the immortalized, nontransformed epithelial cell line, MAC-T."

Measures the apoptotic readout in non-transformed epithelium, and shows the A chain alone reproduces it.

PMID:36695077 SUPPORT In Vitro

"Upon RT-induced U937 cell death, released RT and FasL contributed to A549 cell death."

The bystander-killing result behind the claim that death is not confined to cells that took up toxin themselves.

PMID:36695077 SUPPORT In Vitro

"The release of RT, FasL, and HMGB1 triggered A549 cell necroptosis, rather than cathepsin-dependent killing observed previously with RT and FasL."

Names the released mediators and the death mode of the bystander cells, which is necroptosis rather than the apoptosis of the intoxicated cell.

Pro-inflammatory Cytokine Release

Stress-kinase activation in intoxicated cells, and in macrophages in particular, drives release of pro-inflammatory cytokines. Tumour necrosis factor alpha rises first, within hours and before any metabolic abnormality is measurable; over the following day the response broadens into a storm containing both pro- and anti-inflammatory mediators. This is the step that turns local cell death into systemic illness, and it accounts for fever, neutrophil recruitment and the vascular consequences below.

alveolar macrophage CL:0000583

tumor necrosis factor production after ricin intoxication GO:0032760 ↑ INCREASED systemic inflammatory response to ricin GO:0006954 ↑ INCREASED

Downstream

Acute Lung Injury with Interstitial Pneumonia and Alveolar Edema The local pulmonary cytokine storm is what recruits the neutrophils and drives the edema that define the lung lesion.

Endothelial Glycocalyx Shedding and Microvascular Hyperpermeability Systemic inflammatory mediators accompany the vascular injury. The glycocalyx study does not isolate cytokines as the cause, so this edge is marked indirect rather than asserting a mechanism the source does not test.

Fever

Increased total leukocyte count

Cytokine-Mediated Suppression of Hepatic Glucose-6-Phosphatase A distinct, metabolic consequence of the same cytokine response, described only in parenterally exposed mice.

Show evidence (4 references)

PMID:36548717 SUPPORT Model Organism

"Within the first hours following injection, while still normoglycemic, lymphopenia and pro-inflammatory cytokine secretion were observed, particularly tumor necrosis factor (TNF)-α. The cytokine response evolved over the next day into a complex storm of both pro- and anti-inflammatory cytokines."

Establishes the timing and composition of the response this node records - TNF-alpha first, broadening into a mixed storm over a day.

PMID:23133670 SUPPORT In Vitro

"PW66 virtually eliminated ricin-induced TNF-α secretion by J774A.1 macrophages and concomitantly blocked activation of the p38 MAPK and JNK signaling pathways."

Identifies macrophages as a cellular source of the TNF-alpha this node describes.

PMID:42560523 SUPPORT REVIEW SYNTHESIS Human Clinical

"tumor necrosis factor-alpha (TNF-α), accompanied by leukocytosis and thrombocytopenia"

The one human measurement of this node anywhere in the cited literature - a near-fatal injection case, in which IL-6, IL-10 and TNF-alpha were all markedly elevated. Quoted from the TNF-alpha clause because the review is a scanned PDF that hyphen-breaks the words before it.

+ 1 more reference

Acute Lung Injury with Interstitial Pneumonia and Alveolar Edema

The inhalational lesion. Airway and alveolar epithelium and alveolar macrophages die, a local cytokine storm recruits neutrophils in large numbers, the vasculature becomes hyperpermeable, and proteinaceous fluid fills the alveoli and pleural space. The picture is acute lung injury and can progress to acute respiratory distress syndrome; in lethal animal exposures the damage stays largely confined to the lung and death is from respiratory insufficiency rather than from distant organ failure.

pulmonary alveolar type 2 cell CL:0002063 alveolar macrophage CL:0000583 infiltrating neutrophil CL:0000775

lung UBERON:0002048

Animal models

Murine pulmonary ricinosis Mouse recapitulates Reproduces the full lesion - interstitial pneumonia, local cytokine storm, neutrophil influx, oedema and epithelial death - with measurable loss of lung function.

Swine ricin intoxication by intratracheal and intramuscular routes Pig recapitulates The large-animal demonstration that the pulmonary lesion meets ARDS criteria.

Downstream

Residual Pulmonary Fibrosis in Survivors Animals that survive the acute injury repair it imperfectly, leaving fibrotic lesions.

Dyspnea

Pulmonary edema

Interstitial pneumonitis

Acute respiratory distress syndrome The acute lung injury can evolve into frank ARDS, demonstrated in swine.

Respiratory failure

Show evidence (3 references)

PMID:38773158 SUPPORT Model Organism

"We show that in the short-term, sublethal exposure of mice to ricin resulted in acute lung injury, including interstitial pneumonia, cytokine storm, neutrophil influx, edema and cellular death."

Names every component of this node, measured after a sublethal inhaled dose.

PMID:38773158 SUPPORT BACKGROUND Model Organism

"the injury is mostly confined to the lungs, including marked interstitial pneumonia associated with pro-inflammatory cytokine release, massive neutrophil infiltration, vascular hyperpermeability, perivascular and alveolar edema, hemorrhages, diffuse airway epithelial cell and alveolar macrophage death"

The lethal-dose picture across rodents and non-human primates, and the source of the cell types bound on this node.

PMID:37104219 SUPPORT REVIEW SYNTHESIS Model Organism

"The toxicity and associated pathology described in animal models are broadly similar, but variation appears to exist."

Supports treating the animal inhalation picture as one coherent lesion while recording that the models are not identical.

Residual Pulmonary Fibrosis in Survivors

Survivors of pulmonary ricin exposure do not necessarily return to normal. Mice that recovered from a sublethal challenge carried lasting fibrotic lesions, and mice rescued from a lethal challenge by antitoxin showed moderate fibrosis, increased lung hyperpermeability and decreased lung compliance a month later. Whether the same holds in human survivors is unknown - no human follow-up data exist.

lung UBERON:0002048

Animal models

Murine pulmonary ricinosis Mouse recapitulates The only evidence anywhere that survivors of pulmonary ricin exposure carry long-term damage.

Downstream

Pulmonary fibrosis

Show evidence (2 references)

PMID:38393180 SUPPORT Model Organism

"Significant pulmonary sequelae were demonstrated in surviving antitoxin-treated mice, as reflected by prominent histopathological changes, moderate fibrosis, increased lung hyperpermeability, and decreased lung compliance."

The measured sequelae in antitoxin-rescued animals, thirty days after exposure.

PMID:37104219 SUPPORT REVIEW SYNTHESIS Model Organism

"Fibrosis may follow acute lung injury in survivors."

Independent statement of the same sequela, from a review of the inhalation models.

Hemorrhagic Necrosis of the Gastrointestinal Mucosa

The ingestion lesion, and the only one with a substantial human clinical literature. Enterocyte death produces an acute gastroenteritis with vomiting, colicky pain and diarrhoea that can be bloody, and the fluid and electrolyte losses it causes are what threatens the patient in the first day. Hemorrhagic necrosis of the gastrointestinal tract is among the consistent autopsy findings in fatal cases.

enterocyte CL:0000584

small intestine UBERON:0002108

Downstream

Nausea

Vomiting

Diarrhea

Abdominal pain

Gastrointestinal hemorrhage

Dehydration Fluid and electrolyte loss through the injured mucosa is what causes the volume depletion.

Distributive and Hypovolemic Shock with Multi-Organ Failure The volume lost through the injured gut is one of the two routes into shock, the other being the vascular injury below.

Show evidence (2 references)

PMID:42560523 SUPPORT REVIEW SYNTHESIS Human Clinical

"Reported autopsy findings commonly included hemolysis, hemorrhagic necrosis of the gastrointestinal tract, hepatic injury, renal tubular necrosis, and evidence supporting the presence of a capillary leak syndrome."

Establishes hemorrhagic gastrointestinal necrosis as a consistent human autopsy finding.

PMID:39210364 SUPPORT Human Clinical

"admitted to the emergency department with symptoms of colicky abdominal pain, diarrhea, and vomiting following the ingestion of six castor beans"

The clinical face of this lesion in a documented castor-seed ingestion.

Hepatic and Renal Parenchymal Injury

Liver and kidney are the constant secondary targets. In survivable poisoning this appears as mild, reversible transaminase and creatinine derangement that recovers over days; at autopsy in fatal cases it appears as hepatic injury and renal tubular necrosis.

hepatocyte CL:0000182 epithelial cell of proximal tubule CL:0002306

liver UBERON:0002107

Downstream

Hemolytic anemia

Hepatic necrosis

Abnormal liver physiology

Acute kidney injury

Show evidence (3 references)

PMID:42560523 SUPPORT REVIEW SYNTHESIS Human Clinical

Names both organ lesions this node records, from fatal human cases.

PMID:32991682 SUPPORT Human Clinical

"Initial laboratory tests showed a slightly elevated C-reactive protein and mild liver and kidney dysfunction."

The survivable form of the same injury - mild and reversible - after an ingestion of fifty castor beans.

PMID:32991682 SUPPORT Human Clinical

"During the next days, the kidney function improved and liver function started to recover."

Supports the reversibility this node asserts for the non-fatal form.

Endothelial Glycocalyx Shedding and Microvascular Hyperpermeability

After parenteral exposure ricin binds preferentially to the vasculature. Circulating heparan sulfate, hyaluronic acid and syndecan-1 rise, marking extensive degradation of the endothelial glycocalyx; VEGF rises and endothelial VE-cadherin falls, so interendothelial junctions fail and organs become hyperpermeable. Intravital imaging shows aberrant blood flow and a fall in the number of perfused microvessels. Clinically this is the capillary leak syndrome, coagulopathy and widespread hemorrhage of severe systemic poisoning.

endothelial cell of vascular tree CL:0002139

Animal models

Murine intramuscular ricin intoxication Mouse recapitulates The model is where the glycocalyx-shedding account of systemic ricin poisoning was established, alongside swine.

Downstream

Capillary leak

Thrombocytopenia

Abnormality of coagulation

Abnormal bleeding

Distributive and Hypovolemic Shock with Multi-Organ Failure Loss of vascular barrier function and microvascular perfusion is the second, parenteral-dominant route into shock.

Show evidence (5 references)

PMID:34830227 SUPPORT Model Organism

"following intramuscular administration, ricin bound preferentially to the vasculature in both mice and swine, leading to coagulopathy and widespread hemorrhages"

Establishes the vascular tropism and its coagulopathic consequence in two species.

PMID:34830227 SUPPORT Model Organism

"Elevated levels of soluble heparan sulfate, hyaluronic acid and syndecan-1 were measured in blood samples following ricin intoxication, indicating that the vascular glycocalyx of both mice and swine underwent extensive damage."

The three shed glycocalyx components this node names, and the inference the authors draw from them.

PMID:34830227 SUPPORT Model Organism

"we determined that ricin poisoning leads to microvasculature malfunctioning, as manifested by aberrant blood flow and a significant decrease in the number of diffused microvessels"

The intravital-imaging result behind the microvascular perfusion claim.

+ 2 more references

Cytokine-Mediated Suppression of Hepatic Glucose-6-Phosphatase

A separate lethal mechanism layered on top of direct cytotoxicity, described only in parenterally exposed mice. Hepatic glucose-6-phosphatase RNA and protein fall rapidly and persistently, glucose-6-phosphate drops and glycogen accumulates - the biochemical signature of blocked glucose output - and the animals become profoundly hypoglycaemic before any other laboratory abnormality appears. Blood glucose fell even in animals whose beta cells had been destroyed with streptozotocin, which argues against an insulin-driven explanation.

Downstream

Hypoglycemia

Show evidence (2 references)

PMID:36548717 SUPPORT Model Organism

"In the liver, we observed a rapid and persistent decrease in the expression of glucose-6-phosphatase (G6Pase) RNA and protein levels, accompanied by a drop in glucose-6-phosphate and increase in glycogen."

The measured enzyme and metabolite changes this node records.

PMID:36548717 SUPPORT Model Organism

"Drops in blood glucose were observed even after destruction of β-cells with streptozotocin."

The control experiment behind the claim that this is not an insulin-mediated hypoglycaemia.

Distributive and Hypovolemic Shock with Multi-Organ Failure

The terminal common pathway. Volume lost through the injured gut, plasma lost through a leaking microvasculature, and vasodilatation together produce circulatory collapse; hepatic, renal, splenic, cardiac and bone-marrow injury accumulate, and death follows from refractory cardiovascular collapse typically between ten and seventy-two hours after exposure. This convergence is what makes the route of exposure matter for dose and tempo but not for the way severe poisoning ends.

Downstream

Hypotension

Hypovolemic shock

Bidirectional ventricular tachycardia Ventricular arrhythmia on a background of toxin-induced myocardial injury. Drawn as indirect because the one human case proposing this mechanism offers it as a hypothesis, having excluded re-entry rather than demonstrated triggered activity.

Show evidence (3 references)

PMID:33711365 SUPPORT REVIEW SYNTHESIS Human Clinical

"The mechanism of death was peripheral vascular collapse and progressing multiple organ failure occurring 10h-72h after intoxication."

Names the mechanism of death and its timing, from fifty collected human cases.

PMID:42560523 SUPPORT REVIEW SYNTHESIS Human Clinical

"characterized by rapid progression from mild, nonspecific gastrointestinal symptoms to hypovolemic shock, multi-organ failure, and refractory cardiovascular collapse"

Independent statement of the same terminal sequence, from a systematic review of fatal cases.

PMID:31208156 SUPPORT Model Organism

"In the heart, diffuse hemorrhages, myocyte necrosis, collagen deposition, and induction in fibrinogen were observed."

The cardiac component of the multi-organ failure, which in the parenteral model is a structural lesion rather than only a perfusion failure.

✶

Histopathology

Hemorrhagic necrosis of the gastrointestinal tract with hepatic and renal tubular injury

The postmortem picture of fatal human ricin poisoning, pooled across the published cases: hemolysis, hemorrhagic necrosis of the gut, hepatic injury, renal tubular necrosis, and findings consistent with capillary leak.

Show evidence (1 reference)

PMID:42560523 SUPPORT REVIEW SYNTHESIS Human Clinical

The pooled autopsy findings this record describes.

⬡

Pathograph

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

●

Phenotypes

Blood 6

Gastrointestinal hemorrhage HP:0002239

Temporal: ACUTE

Show evidence (1 reference)

PMID:42560523 SUPPORT REVIEW SYNTHESIS Human Clinical

Establishes gastrointestinal haemorrhagic necrosis as a consistent postmortem finding.

Thrombocytopenia HP:0001873

Temporal: ACUTE

Show evidence (2 references)

PMID:31208156 SUPPORT Model Organism

"Along with prompt coagulopathy, multi-organ hemorrhages, and thrombocytopenia, ricin induced profound morpho-pathological and functional damage in the spleen, bone marrow, and cardiovascular system."

Names thrombocytopenia in the intramuscular murine model.

PMID:42560523 SUPPORT REVIEW SYNTHESIS Human Clinical

"accompanied by leukocytosis and thrombocytopenia"

The human counterpart, in a near-fatal injection case whose cytokine profile is quoted on the cytokine-release node.

Abnormality of coagulation HP:0001928

Temporal: ACUTE

Bound at the level the sources actually report. No cited reference names a specific clotting time, so `HP:0008151` Prolonged prothrombin time - which an earlier draft of this entry used - would have been a manufactured narrower match.

Show evidence (1 reference)

PMID:31208156 SUPPORT Model Organism

"Along with prompt coagulopathy, multi-organ hemorrhages, and thrombocytopenia"

Names the coagulopathy this phenotype records.

Abnormal bleeding HP:0001892

Temporal: ACUTE

Show evidence (1 reference)

PMID:34830227 SUPPORT Model Organism

"ricin bound preferentially to the vasculature in both mice and swine, leading to coagulopathy and widespread hemorrhages"

Names the widespread haemorrhage and its vascular cause, in two species.

Increased total leukocyte count HP:0001974

Temporal: ACUTE

Show evidence (1 reference)

PMID:42560523 SUPPORT REVIEW SYNTHESIS Human Clinical

"accompanied by leukocytosis and thrombocytopenia"

Names the leukocytosis, in a near-fatal human injection case.

Hemolytic anemia HP:0001878

Temporal: ACUTE

Bound to the nearest available HPO term. The sources report haemolysis as an autopsy finding and do not report an anaemia, so the binding is broader in one direction and narrower in another; `preferred_term` records what the source actually says.

Show evidence (1 reference)

PMID:42560523 SUPPORT REVIEW SYNTHESIS Human Clinical

"Reported autopsy findings commonly included hemolysis"

Names haemolysis first among the consistent autopsy findings.

Cardiovascular 4

Hypotension HP:0002615

Temporal: ACUTE

Show evidence (2 references)

PMID:42560523 SUPPORT REVIEW SYNTHESIS Human Clinical

"Shock was typically characterized by profound hypotension that remained refractory to aggressive fluid resuscitation and high-dose vasopressor therapy"

Names the hypotension directly, and records that it resists the treatment this entry lists as first-line.

PMID:33711365 SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical

"The mechanism of death was peripheral vascular collapse and progressing multiple organ failure"

Names peripheral vascular collapse in the collected human cases. It does not use the word hypotension, which is why it is marked indirect.

Hypovolemic shock HP:0031274

Temporal: ACUTE

Show evidence (1 reference)

PMID:42560523 SUPPORT REVIEW SYNTHESIS Human Clinical

"rapid progression from mild, nonspecific gastrointestinal symptoms to hypovolemic shock, multi-organ failure, and refractory cardiovascular collapse"

Names hypovolaemic shock as the step between the prodrome and death.

Capillary leak HP:0030005

Temporal: ACUTE

Show evidence (2 references)

PMID:42560523 SUPPORT REVIEW SYNTHESIS Human Clinical

"evidence supporting the presence of a capillary leak syndrome"

The autopsy evidence for this phenotype in fatal human cases.

PMID:42560523 SUPPORT REVIEW SYNTHESIS Human Clinical

"collectively supporting the hypothesis that endothelial injury and capillary leak syndrome play a central role in the pathophysiology of fatal ricin poisoning"

States how central the review takes this to be, which is why it is a phenotype here rather than only a mechanism node.

Bidirectional ventricular tachycardia HP:0034040

Temporal: ACUTE

Carries no frequency: one case. Recorded anyway because the arrhythmia was refractory to the standard measures, which changes management rather than only describing the illness, and because the murine parenteral model independently shows structural cardiac injury.

Show evidence (3 references)

PMID:41788434 SUPPORT Human Clinical

"A previously healthy man ingested 15 castor beans in a suicide attempt and presented to the emergency department with a wide-complex tachycardia at 180 bpm and alternating QRS axis, consistent with bidirectional ventricular tachycardia."

The presentation this phenotype records.

PMID:41788434 SUPPORT Human Clinical

"Attempts at rhythm stabilization, including five electrical cardioversion attempts and a cumulative dose of 450 mg amiodarone, were unsuccessful."

The refractoriness, which is the clinically actionable part and the reason a single case is worth recording.

PMID:41788434 SUPPORT Human Clinical

"To the best of our knowledge, this is the first reported case of bidirectional ventricular tachycardia following ricin intoxication."

Establishes that this is a single observation, not an established frequency.

Digestive 5

Vomiting HP:0002013

Temporal: ACUTE

Show evidence (2 references)

PMID:39210364 SUPPORT Human Clinical

"admitted to the emergency department with symptoms of colicky abdominal pain, diarrhea, and vomiting following the ingestion of six castor beans"

Names vomiting among the presenting features after a documented castor-seed ingestion.

PMID:32991682 SUPPORT Human Clinical

"Her symptoms on admission were vomiting, diarrhea, abdominal cramps, agitation and anxiety."

Independent case with the same presenting symptom set.

Diarrhea HP:0002014

Temporal: ACUTE

Show evidence (2 references)

PMID:32991682 SUPPORT Human Clinical

"Her symptoms on admission were vomiting, diarrhea, abdominal cramps, agitation and anxiety."

Names diarrhoea among the presenting features.

PMID:33711365 SUPPORT REVIEW SYNTHESIS Human Clinical

"Intoxication by castor bean is characterized by acute gastroenteritis-like disease as primary manifestations leading to severe fluid and electrolyte imbalance."

Places the diarrhoeal illness at the centre of the ingestion syndrome across fifty collected cases.

Hepatic necrosis HP:0002605

Temporal: ACUTE

Show evidence (1 reference)

PMID:42560523 SUPPORT REVIEW SYNTHESIS Human Clinical

"Frequently reported observations included hemorrhagic gastrointestinal injury, hepatic necrosis, renal tubular damage, pulmonary edema, and serosal effusions"

Names hepatic necrosis directly, in the review's own summary of the autopsy series.

Abnormal liver physiology HP:0031865

Temporal: TRANSIENT

Bound at the level the source reports. The case report says "mild liver dysfunction" and names no analyte, so `HP:0031956` Elevated circulating aspartate aminotransferase concentration - which an earlier draft used - would have been a manufactured narrower match.

Show evidence (1 reference)

PMID:32991682 SUPPORT Human Clinical

"Initial laboratory tests showed a slightly elevated C-reactive protein and mild liver and kidney dysfunction."

Records the mild liver dysfunction this phenotype names.

Nausea HP:0002018

Temporal: ACUTE

Show evidence (2 references)

PMID:32991682 SUPPORT Human Clinical

"Her symptoms on admission were vomiting, diarrhea, abdominal cramps, agitation and anxiety."

Records the gastroenteritis this phenotype belongs to. The abstract lists vomiting rather than nausea, so the human case reporting nausea by name is the item below.

PMID:42560523 SUPPORT REVIEW SYNTHESIS Human Clinical

"experienced nausea, vomiting, diarrhea, dyspnea, vertigo, and myalgia within the first 24 h"

Names nausea directly, in a human parenteral case.

Genitourinary 1

Acute kidney injury HP:0001919

Temporal: ACUTE

Show evidence (2 references)

PMID:42560523 SUPPORT REVIEW SYNTHESIS Human Clinical

"renal tubular necrosis, and evidence supporting the presence of a capillary leak syndrome"

Names renal tubular necrosis among the consistent autopsy lesions.

PMID:32991682 SUPPORT Human Clinical

"During the next days, the kidney function improved and liver function started to recover."

The reversible form of the same injury in a survivor.

Immune 1

Acute respiratory distress syndrome HP:0033677

Temporal: ACUTE

Show evidence (2 references)

PMID:38773158 SUPPORT BACKGROUND Model Organism

"This damage to the lungs is classified as acute lung injury, which can develop to acute respiratory distress syndrome (ARDS)"

States the progression to ARDS.

PMID:32481526 SUPPORT BACKGROUND Model Organism

"the swine animal model served us in the past to determine that pulmonary exposure to ricin leads to the development of bona fide acute respiratory distress syndrome"

The large-animal result behind the ARDS claim, in the species chosen for its cardiopulmonary resemblance to humans.

Metabolism 4

Dehydration HP:0001944

Temporal: ACUTE

Show evidence (1 reference)

PMID:33711365 SUPPORT REVIEW SYNTHESIS Human Clinical

"leading to severe fluid and electrolyte imbalance"

States the fluid loss this phenotype records.

Pulmonary edema HP:0100598

Temporal: ACUTE

Show evidence (3 references)

PMID:38773158 SUPPORT Model Organism

"sublethal exposure of mice to ricin resulted in acute lung injury, including interstitial pneumonia, cytokine storm, neutrophil influx, edema and cellular death"

Names oedema among the components of the acute lung injury.

PMID:42560523 SUPPORT REVIEW SYNTHESIS Human Clinical

"Frequently reported observations included hemorrhagic gastrointestinal injury, hepatic necrosis, renal tubular damage, pulmonary edema, and serosal effusions"

Pulmonary oedema among the human autopsy findings, so this phenotype is not animal-only even though the inhalational route is.

PMID:38393180 SUPPORT BACKGROUND Model Organism

"the development of proteinaceous pulmonary edema, ultimately leading to respiratory failure and death"

Characterises the oedema as proteinaceous and names its consequence.

Fever HP:0001945

Temporal: ACUTE

Show evidence (1 reference)

PMID:42560523 SUPPORT REVIEW SYNTHESIS Human Clinical

"the inflammatory response induced by ricin, which may include fever, leukocytosis, thrombocytopenia, and elevated"

Names fever as part of the inflammatory response, in the passage explaining why this poisoning is mistaken for sepsis.

Hypoglycemia HP:0001943

Temporal: ACUTE

Carrying no frequency on purpose. The mouse result is strong and mechanistically worked out; the human evidence is one clinical report mentioned in passing, and the same authors record a negative in aerosol-exposed macaques - see the `hypoglycemia_human_status` discussion.

Show evidence (2 references)

PMID:36548717 SUPPORT Model Organism

"in mice parenteral injection of ricin toxin causes profound hypoglycemia, in the absence of other clinical laboratory abnormalities"

States the finding and that it is isolated, which is what makes it a useful early marker.

PMID:36548717 SUPPORT INDIRECT BACKGROUND Human Clinical

"At least one clinical report of ricin toxicosis describes hypoglycemia, but does not indicate whether specific measures were taken to control the low blood glucose in this patient"

The whole of the human evidence for this phenotype: a single clinical report, noted in passing, with no indication the finding was acted on.

Respiratory 4

Dyspnea HP:0002094

Temporal: ACUTE

Human inhalational ricin poisoning has no published case series, so the other respiratory phenotypes here are supported through the animal inhalation literature rather than through human cohorts. This one is the exception - a human case reports it, by the injection route.

Show evidence (2 references)

PMID:42560523 SUPPORT REVIEW SYNTHESIS Human Clinical

"experienced nausea, vomiting, diarrhea, dyspnea, vertigo, and myalgia within the first 24 h"

A human case of parenteral ricin poisoning reporting dyspnoea directly, from the review's case-by-case synthesis.

PMID:38773158 SUPPORT INDIRECT Model Organism

"This damage was manifested in reduced lung performance and physiological function."

The animal correlate after the inhalational route - measured lung performance rather than a reported symptom, which is why it is indirect.

Interstitial pneumonitis HP:0006515

Temporal: ACUTE

Show evidence (1 reference)

PMID:38773158 SUPPORT BACKGROUND Model Organism

"marked interstitial pneumonia associated with pro-inflammatory cytokine release, massive neutrophil infiltration"

Names the lesion and the infiltrate this phenotype records.

Respiratory failure HP:0002878

Temporal: ACUTE

Show evidence (1 reference)

PMID:38393180 SUPPORT BACKGROUND Model Organism

"the development of proteinaceous pulmonary edema, ultimately leading to respiratory failure and death"

Names respiratory failure as the terminal event of the pulmonary lesion.

Pulmonary fibrosis HP:0002206

Course: PROGRESSIVE

`clinical_course: PROGRESSIVE` is the model-organism reading; the inhalation-model review explicitly lists self-limiting, progressive, persistent and resolving fibrosis as distinguishable possibilities that the choice of species determines, so this is not a settled property of the disease in humans.

Show evidence (3 references)

PMID:38393180 SUPPORT Model Organism

"prominent histopathological changes, moderate fibrosis, increased lung hyperpermeability, and decreased lung compliance"

The measured sequelae thirty days after a survived lethal pulmonary challenge.

PMID:37104219 SUPPORT REVIEW SYNTHESIS Model Organism

"Fibrosis may follow acute lung injury in survivors."

Independent statement of the sequela across the inhalation models.

PMID:37104219 SUPPORT REVIEW SYNTHESIS Model Organism

"the nature of the fibrosis (e.g., self-limiting, progressive, persistent or resolving)"

Source of the caveat in `notes` - the course of the fibrosis is a property of the model chosen, not an established feature of the human disease.

Constitutional 1

Abdominal pain HP:0002027

Temporal: ACUTE

Show evidence (1 reference)

PMID:39210364 SUPPORT Human Clinical

"symptoms of colicky abdominal pain, diarrhea, and vomiting"

Names the pain and its colicky character.

💊

Medical Actions

Supportive and symptomatic care

Action: Supportive Care NCIT:C15747

Platform: Other

The mainstay, and in humans the only management with evidence behind it. Rehydration and electrolyte correction for gastrointestinal losses, vasopressor support for shock, respiratory support for inhalational injury, and correction of coagulopathy. There is no antidote, so everything else in this section is investigational. Across the published human series this was what patients received, and forty-four of fifty survived.

Mechanism Target:

MODULATES Distributive and Hypovolemic Shock with Multi-Organ Failure — Supportive care does nothing to the toxin; it addresses the circulatory failure that kills the patient.

Show evidence (1 reference)

PMID:33711365 SUPPORT REVIEW SYNTHESIS Human Clinical

"Prompt treatment with supportive care was necessary to limit morbidity and mortality."

States the target of supportive care as morbidity and mortality rather than the toxin.

Target Phenotypes: Dehydration HP:0001944 Hypotension HP:0002615

Show evidence (3 references)

PMID:33711365 SUPPORT REVIEW SYNTHESIS Human Clinical

"Patients received symptomatic treatment consisting mostly to rehydration with intravenous fluids"

Records what patients actually received across fifty collected cases. Quoted verbatim including the source's grammatical slip.

PMID:33711365 SUPPORT REVIEW SYNTHESIS Human Clinical

"Currently, no antidote, vaccine, or other specific effective treatment is available for ricin poisoning or prevention."

States the absence that makes supportive care the mainstay rather than an adjunct.

PMID:39210364 SUPPORT Human Clinical

"admitted for observation, and received symptomatic treatment. She was discharged home after a complete recovery three days later."

A worked case of supportive management and its outcome.

Early gastrointestinal decontamination

Action: gastrointestinal decontamination with activated charcoal and gastric lavage Ontology label: Therapeutic Procedure NCIT:C49236

Platform: Other

Activated charcoal and gastric lavage within a day of ingestion, to reduce the toxin that is absorbed. Restricted by definition to the oral route and to the latent interval before symptoms establish. In the collected human series this was reported as very effective when given early, which is the strongest treatment claim anywhere in the human ricin literature - though it comes from an uncontrolled case collection, not a trial.

Mechanism Target:

INHIBITS Ricin Delivery to Host Tissue — Decontamination acts on the delivery step itself - reducing how much toxin crosses the gut wall - which is why it only works before absorption is complete.

Show evidence (1 reference)

PMID:33711365 SUPPORT REVIEW SYNTHESIS Human Clinical

"digestive decontamination performed with activated charcoal and/or gastric lavage within one day after the ingestion, to reduce gastrointestinal absorption of ricin"

States the target of the intervention as gastrointestinal absorption, which is this node.

Show evidence (1 reference)

PMID:33711365 SUPPORT REVIEW SYNTHESIS Human Clinical

"This decontamination treatment administered early has been very effective."

The efficacy claim, stated by the review of fifty collected cases. It is an uncontrolled observation across heterogeneous case reports, which is why the description says so rather than treating it as trial evidence.

Anti-ricin antibody passive immunotherapy

Action: passive immunization with anti-ricin antibody Ontology label: Passive Immunization NCIT:C15259

Agent: anti-ricin monoclonal antibody NCIT:C20401

Platform: Monoclonal antibody

Investigational, and the only post-exposure approach with efficacy shown in a large animal model at clinically relevant times. Equine F(ab')2 antitoxin protected more than 80% of swine given it eighteen hours after lethal intratracheal or intramuscular exposure. High-affinity monoclonal antibodies against both ricin isoforms are the newer generation: RicE5 gave over 90% survival in mice treated six hours after an intranasal challenge and 35% at twenty-four hours. Nothing in this class is approved for human use.

Mechanism Target:

INHIBITS Ricin Delivery to Host Tissue — Neutralising antibody acts on toxin that has not yet entered a cell, which is why the window closes as toxin is internalised. It is deliberately not linked to the RTB lectin-binding node: the antibody that actually protects animals, RicE5, is an anti-RTA antibody, and the anti-RTB antibody from the same panel neutralised in culture but failed in vivo. The review of the field lists several neutralisation routes - blocking binding, disrupting retrograde transport, redirecting the toxin - without settling which one carries the protection.

Show evidence (1 reference)

PMID:39453188 SUPPORT In Vitro

"which bind and neutralize very efficiently both ricin isoforms D and E in vitro through cytotoxicity cell assays"

Establishes neutralisation of the toxin itself as the mechanism, measured in cytotoxicity assays.

Show evidence (5 references)

PMID:32481526 SUPPORT Model Organism

"While administration of the antitoxin at 18 h post-exposure protected more than 80% of both intratracheally and intramuscularly ricin-intoxicated swine, treatment at 24 h post-exposure protected 58% of the intramuscular-exposed swine, as opposed to 26% of the intratracheally exposed animals."

The large-animal post-exposure efficacy data, including how fast it falls off with delay.

PMID:39453188 SUPPORT Model Organism

"one of these mAbs (RicE5) conferred over 90% survival in a murine model challenged intranasally with a 5 LD50 of ricin and treated by intravenous administration of the mAbs 6 h post-intoxication. Notably, a 35% survival rate was observed even when treatment was administered 24 h post-exposure."

The monoclonal-antibody efficacy figures this description quotes.

PMID:39453188 SUPPORT Model Organism

"We selected two antibodies: one targeting RTA (RicE5) and another targeting RTB (RicE8)."

Identifies which chain each antibody binds, which is what makes the next item a dissociation rather than a dose effect.

+ 2 more references

RVEc recombinant ricin A chain subunit vaccine

Action: Vaccination NCIT:C15346

Platform: Vaccine

The second investigational vaccine candidate, a truncated recombinant A chain (rRTA 1-33/44-198). In a phase 1 dose-escalating study it was safe and well tolerated at 20 and 50 micrograms; all recipients at those doses seroconverted by ELISA but only half produced measurable neutralising antibody, and a later 50-microgram booster raised both. The 100-microgram arm was stopped after two of ten subjects developed elevated creatine phosphokinase. Not approved.

Mechanism Target:

INHIBITS Ricin Delivery to Host Tissue — As with RiVax, an anti-A-chain neutralising response acts on toxin that has not yet entered a cell.

Show evidence (1 reference)

PMID:26546259 SUPPORT INDIRECT Human Clinical

"50% produced neutralizing anti-ricin antibodies measurable by TNA"

Establishes that the vaccine raises toxin-neutralising antibody, which is the mechanism. Indirect because a neutralisation titre is not itself a demonstration of protection.

Show evidence (4 references)

PMID:26546259 SUPPORT Human Clinical

"RVEc™ was safe and well tolerated at the 20- and 50-μg doses."

The safety result at the doses taken forward.

PMID:26546259 SUPPORT Human Clinical

"Of the 10 subjects who received a single 100-μg dose, two developed elevated creatine phosphokinase levels, which resolved without sequelae. No additional doses were administered to subjects in the 100-μg group."

The dose-limiting finding, recorded because a stopped arm is part of what is known about this candidate.

PMID:26546259 SUPPORT Human Clinical

"The single booster was safe and well tolerated, resulting in no serious adverse events, and significantly enhanced immunogenicity of the vaccine in human subjects."

The booster result this description records.

+ 1 more reference

RiVax recombinant ricin A chain vaccine

Action: Vaccination NCIT:C15346

Platform: Vaccine

Investigational pre-exposure prophylaxis, not a treatment. RiVax is a recombinant ricin A chain subunit vaccine, safe and immunogenic in mice, rabbits and humans without adjuvant, and taken through a pilot phase 1B adsorbed to Alhydrogel. No ricin vaccine is approved. The molecular detail frequently quoted for it - that it carries point mutations inactivating both the N-glycosidase site and the vascular-leak epitope - is not stated by any reference cited here and is deliberately left out rather than asserted.

Mechanism Target:

INHIBITS Ricin Delivery to Host Tissue — An induced neutralising response acts on toxin in the extracellular space before it enters a cell. RiVax is a recombinant A chain, so the antibody it raises is anti-RTA and cannot act on the B chain's lectin binding; this edge deliberately targets the delivery node rather than that one.

Show evidence (1 reference)

PMID:36526642 SUPPORT INDIRECT Model Organism

"survival correlated with pre-challenge, epitope-specific serum IgG levels, derived from a competitive sandwich ELISA using a panel of toxin-neutralizing monoclonal antibodies directed against distinct epitopes on RiVax"

Establishes that epitope-specific, toxin-neutralising serum IgG is what tracks survival in vaccinated macaques, which supports a neutralising mechanism without directly demonstrating the binding step.

Show evidence (2 references)

PMID:22914366 SUPPORT Human Clinical

"We have developed a recombinant ricin vaccine, RiVax. Without adjuvant it is safe and immunogenic in mice, rabbits, and humans."

Establishes the candidate and its human safety and immunogenicity without adjuvant.

PMID:22914366 SUPPORT Human Clinical

"There is no FDA-approved vaccine for the potent plant toxin ricin."

Supports the statement that no ricin vaccine is approved.

Retro-2 and other retrograde transport inhibitors

Action: Pharmacotherapy NCIT:C15986

Platform: Small molecule

Preclinical only. Retro-2 blocks toxin trafficking at the early endosome-to-trans-Golgi interface without disturbing compartment morphology or other trafficking, and protected mice from an otherwise lethal nasal ricin challenge - the first small molecule shown to work against ricin in an animal. Its interest here is as much mechanistic as therapeutic: it is the experiment that shows the retrograde step is required rather than incidental.

Mechanism Target:

INHIBITS Retrograde Transport from the Golgi to the Endoplasmic Reticulum — The compound acts on exactly this step, and on nothing else in the trafficking pathway that could be detected.

Show evidence (1 reference)

PMID:20403321 SUPPORT In Vitro

"We identified two compounds that selectively block retrograde toxin trafficking at the early endosome-TGN interface, without affecting compartment morphology, endogenous retrograde cargos, or other trafficking steps, demonstrating an unexpected degree of selectivity and lack of toxicity."

Locates the drug's action at this step and establishes its selectivity for it.

Show evidence (2 references)

PMID:20403321 SUPPORT Model Organism

"In mice, one compound clearly protects from lethal nasal exposure to ricin."

The animal efficacy result.

PMID:20403321 SUPPORT Model Organism

"Our work discovers the first small molecule that shows efficacy against ricin in animal experiments and identifies the retrograde route as a potential therapeutic target."

The authors' own statement of what the result establishes, which is the claim this entry makes for it.

🌍

Environmental Factors

Ingestion of chewed or crushed castor seeds

Hazard type: BIOLOGICAL

Route: ORAL

Duration: ACUTE

Bound to `ECTO:9001524` exposure to Ricin - an exact class, which all three route entries share. The route is carried by `exposure_classifications.exposure_route` rather than by the term, because ECTO's route-specific classes do not descend to ricin. An earlier draft of this entry bound `ECTO:0000537` exposure to toxin and recorded in this slot that no ricin class existed; that was wrong. `ECTO:9001524` is live, sits under exposure to organic compound, and reaches `ExO:0000002` exposure event, so it satisfies the `ExposureTerm` enum. It was missing from `cache/ecto/terms.csv` only because nothing in `kb/` had ever bound it - which is exactly why an absent cache row is not evidence that a term does not exist. `food_source` is the FOODON castor bean class, which is genuinely a class for the seed rather than for a prepared food, and correct here because the exposure is to the raw seed.

The commonest route in the published record, and the only one with a real human clinical literature. Castor is a widely grown ornamental and industrial crop, so seeds are freely available; toxicity requires the seed coat to be broken, because intact seeds resist digestion and can pass through unchanged. Exposure is usually accidental, sometimes self-harm.

Show evidence (2 references)

PMID:33711365 SUPPORT REVIEW SYNTHESIS Human Clinical

"The questioning of patients and family made it possible to retrieve an history of castor seeds or castor oil ingestion"

Establishes castor seed ingestion as the exposure history recovered across the collected human cases.

PMID:33711365 SUPPORT REVIEW SYNTHESIS Human Clinical

"Intoxication was mostly accidental (37 cases)."

Supports the claim that this exposure is usually accidental.

Mechanism Target:

TRIGGERS Ricin Delivery to Host Tissue — Chewing the seed releases the toxin into the gastrointestinal lumen, which is what the rest of the entry follows from.

Show evidence (1 reference)

PMID:39210364 SUPPORT Human Clinical

"admitted to the emergency department with symptoms of colicky abdominal pain, diarrhea, and vomiting following the ingestion of six castor beans"

A documented instance of this exposure producing the disease, naming both the ingestion and the illness it triggered in one sentence.

Inhalation of aerosolised ricin or castor seed dust

Hazard type: BIOLOGICAL

Route: INHALATION

Duration: ACUTE

The route of greatest concern as a weapon and the one with the lowest lethal dose, but with no published human case series at all - everything known about it comes from rodent, non-human-primate and swine exposures. Occupationally it corresponds to seed and mash handling in castor oil processing.

Show evidence (1 reference)

PMID:37104219 SUPPORT REVIEW SYNTHESIS Model Organism

"The pathogenesis of ricin toxicity following inhalation has been investigated in many animal models, including the non-human primate (predominantly the rhesus macaque), pig, rabbit and rodent."

Establishes that this route's evidence base is animal models, which is why every phenotype downstream of it is graded MODEL_ORGANISM.

Mechanism Target:

TRIGGERS Ricin Delivery to Host Tissue — Aerosol deposition delivers toxin directly onto the alveolar surface, which is why this route needs roughly a thousandfold less toxin than ingestion.

Show evidence (1 reference)

PMID:34830227 SUPPORT BACKGROUND Other

"inhalatory and parenteral intoxications are associated with greater illness and mortality, and are characterized by lethal doses that are roughly three magnitudes lower than that of oral poisoning"

States the dose relation this edge asserts.

Parenteral injection of ricin or castor bean extract

Hazard type: BIOLOGICAL

Route: PARENTERAL

Duration: ACUTE

The assassination and self-harm route, delivered by pellet, needle or explosive device. It bypasses every absorption barrier, so the toxin distributes systemically and binds preferentially to the vasculature, producing the endothelial and coagulopathic picture rather than a mucosal one.

Show evidence (3 references)

PMID:34830227 SUPPORT BACKGROUND Other

"in recent years, several terrorist attempts to utilize weaponized ricin delivered by sharp or explosive devices were planned"

Establishes the delivery modes this exposure describes.

PMID:38773158 SUPPORT BACKGROUND Other

"it is considered to be a high-risk chemical for living beings under the Organization for the Prohibition of Chemical Weapons1 and is also classified as a Category B biological agent by the Centers for Disease Control and Prevention2"

Source for the regulatory status asserted in the disease description. Quoted verbatim including the trailing superscript reference markers the source text carries.

PMID:34830227 SUPPORT BACKGROUND Human Clinical

"post-mortem examinations in a single well-known case involving the assassination of Georgi Markov, suggested that cardiac arrest due to necrosis of the cardiac conducting tissue may be the direct cause of death"

The one well-documented human instance of this route, and what its autopsy suggested. Quoted as the hypothesis the source states it to be.

Mechanism Target:

TRIGGERS Ricin Delivery to Host Tissue — Injection places toxin directly into tissue and the circulation, with no absorption step to attenuate the dose.

Show evidence (1 reference)

PMID:34830227 SUPPORT Model Organism

"When delivered by the parenteral route, ricin is systemically distributed throughout the body"

States what this route does to distribution, which is this edge.

🔬

Diagnosis

Exposure history with a compatible acute syndrome

The practical route to the diagnosis. Ricin has no bedside test - the confirmatory assays below are reference-laboratory mass spectrometry - so recognition rests on a history of castor seed or castor product exposure together with an otherwise unexplained acute gastroenteritis, acute respiratory illness or shock. Where no exposure history is available - which is the case in deliberate poisoning - early toxicological investigation is what makes the diagnosis at all.

Show evidence (2 references)

PMID:33711365 SUPPORT REVIEW SYNTHESIS Human Clinical

"The questioning of patients and family made it possible to retrieve an history of castor seeds or castor oil ingestion"

States how the diagnosis was actually reached across the collected human cases.

PMID:42560523 SUPPORT REVIEW SYNTHESIS Human Clinical

"emphasizing the importance of early toxicological investigations, particularly when no history of exposure is available"

Names the case where history fails and analysis has to carry the diagnosis.

Direct identification of ricin in serum or body fluid by LC-MS/MS

Ricinine reports castor bean exposure; this reports the toxin itself. A lactose-agarose lectin capture followed by tryptic digestion and targeted LC-MS/MS identifies ricin down to 5 ng/mL in serum within about two and a half hours, without antibodies. It has been run on a real case, finding toxin in abdominal fluid 72 hours after self-injection of a castor bean extract - a wider window than previously documented. A faster, field-deployable ambient-MS screen detects the co-extracted small molecules ricinoleic acid and ricinine instead, in about two minutes, and so answers the same question as the ricinine assay rather than this one.

A third confirmatory route is deliberately absent. A reverse transcription-ligase-PCR assay reads out the depurinated 28S rRNA itself (`DOI:10.1007/s11419-017-0377-6`, Forensic Toxicology 2018), which would be the one diagnostic that measures this entry's own central pathophysiology node rather than a surrogate. It is not curated because it cannot be: the paper has no PubMed record, and its cached entry carries `content_type: unavailable` with no retrievable abstract, so no exact quote exists to support an evidence item. Adding it with a paraphrased snippet would be the fabrication the evidence rules exist to prevent. It should be added the moment a quotable record becomes available.

Show evidence (4 references)

PMID:33499033 SUPPORT Human Clinical

"This enables ricin identification down to 5 ng/mL in serum samples in 2.5 h."

The sensitivity and turnaround this method achieves.

PMID:33499033 SUPPORT Human Clinical

"the toxin was identified in an abdominal fluid sample taken 72 h post self-injection of castor beans extraction in an eventual suicide case"

The real-case validation, and the source of the extended-window claim in this description.

PMID:35173958 SUPPORT Other

"we present an alternative, two-tiered approach to identify the presence of ricin by detecting ricinoleic acid and ricinine, which are co-extracted with the protein"

The field-deployable alternative, and the reason it is grouped with the ricinine assay rather than with direct detection - it measures co-extracted small molecules, not the protein.

+ 1 more reference

Ricinine measurement in blood, urine or postmortem tissue

Ricinine is a minor pyridone alkaloid of the castor bean that is co-extracted with ricin and is measurable by LC-MS/MS. It is the workhorse confirmatory analyte, detected consistently in blood, urine and postmortem tissue in fatal cases. Two limits matter. It marks exposure to castor bean *product*, not to ricin, so a highly purified preparation may carry little or none; and its concentration does not track severity.

Show evidence (4 references)

PMID:42560523 SUPPORT REVIEW SYNTHESIS Human Clinical

"Ricinine was consistently detected in blood, urine, and postmortem tissues, supporting its role as a reliable biomarker of ricin exposure, although current evidence is insufficient to establish definitive correlations with poisoning severity or toxicokinetics."

States both the reliability of the marker and the severity-correlation limit this entry records.

PMID:32991682 SUPPORT Human Clinical

"The presence of ricinine in a patient's blood or plasma is a proof of castor bean and, hence, ricin exposure."

States what a positive result establishes - castor bean exposure, and ricin exposure by inference from it.

PMID:32991682 SUPPORT Human Clinical

"no clear correlation can be established between ricinine blood, plasma or urine levels and the severity of the intoxication"

The serial-measurement result behind the severity caveat, in a patient who ingested fifty beans and recovered fully.

+ 1 more reference

📈

Progression

Latent interval

Duration: hours Incubation: 1 days

Symptoms do not begin at once. Reported latency after ingestion ranges from minutes to about a day; after inhalation it is a few hours; after injection local pain is immediate but systemic illness is delayed. `incubation_days: 1` is the coarse day-granularity encoding of a sub-day latency. The interval matters clinically because it is the window in which gastrointestinal decontamination still works and in which an exposed person looks well.

Show evidence (1 reference)

PMID:33711365 SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical

"digestive decontamination performed with activated charcoal and/or gastric lavage within one day after the ingestion, to reduce gastrointestinal absorption of ricin"

Establishes the decontamination window that defines this phase clinically. It does not itself tabulate symptom onset times, which is why it is marked indirect.

Acute toxidrome

Duration: 1-3 days

The syndrome that defines the disease, and the phase whose content is set by route: hemorrhagic gastroenteritis after ingestion, acute lung injury after inhalation, local necrosis with systemic vascular injury after injection.

Show evidence (1 reference)

PMID:33711365 SUPPORT REVIEW SYNTHESIS Human Clinical

"The mechanism of death was peripheral vascular collapse and progressing multiple organ failure occurring 10h-72h after intoxication."

Bounds this phase in the fatal cases - death between ten and seventy-two hours.

Resolution or multi-organ failure

Duration: days

Monophasic. There is no relapsing-remitting course: the poisoning either resolves over days with supportive care or progresses to refractory cardiovascular collapse. Survivors of ingestion generally recover fully; whether survivors of inhalation do is unknown in humans, and the animal data say they may not.

Show evidence (2 references)

PMID:39210364 SUPPORT Human Clinical

"She was discharged home after a complete recovery three days later."

The resolution arm, in a documented ingestion case managed supportively.

PMID:42560523 SUPPORT REVIEW SYNTHESIS Human Clinical

"hypovolemic shock, multi-organ failure, and refractory cardiovascular collapse"

The other arm, from a systematic review of the fatal cases.

📊

Prevalence

Worldwide, published human cases 1980-2020

Cases In Literature Not yet documented

Fifty published cases over four decades, with six deaths. This is a literature count, not an incidence: ricin exposure is an intentional or accidental event rather than an endemic process, no population-based rate exists, and the case count is bounded by what gets published as much as by what happens. `prevalence_class: NOT_YET_DOCUMENTED` records that honestly rather than inventing a band.

Show evidence (3 references)

PMID:33711365 SUPPORT REVIEW SYNTHESIS Human Clinical

"Fifty ricin-intoxicated patients worldwide described in the literature have been identified."

The case count this record reports, over a stated 1980-2020 search window.

PMID:33711365 SUPPORT REVIEW SYNTHESIS Human Clinical

"Most cases were found in Asia (19 cases), Europe (12 cases) and America (15 cases). Intoxication was mostly accidental (37 cases)."

Breaks the count down by region and intent. Accidental exposure dominates the published record, which cuts against the assumption that this is mainly a bioterrorism disease.

PMID:33711365 SUPPORT REVIEW SYNTHESIS Human Clinical

"Only six deaths were observed."

The case fatality within that series - six of fifty, in patients who reached care.

⚖️

Clinical Burden

Variable

The route of exposure, not the severity of the illness, is what this level records. Most ingestion cases recover fully with supportive care, and only six of fifty published cases died; inhalational and parenteral exposures have lethal doses roughly three orders of magnitude lower, and untreated severe exposure by any route reaches shock and multi-organ failure within one to three days with no antidote available. No single low, moderate or high level is representative of that spread, which is what `VARIABLE` is for.

`HIGH` is defensible on the strength of the mortality-risk clause in its own definition, and an earlier draft used it. It was changed because the route-dependence here is the clinically important fact rather than a complication of stating one, and because the rest of this entry works to preserve that distinction - three separately stratified `environmental:` entries and a `HUMAN_MODEL_MISMATCH` discussion about the inhalational syndrome being known only from animals. A single level would flatten the one thing the entry is most careful about.

Show evidence (2 references)

PMID:42560523 SUPPORT REVIEW SYNTHESIS Human Clinical

"The available evidence suggests a relatively consistent clinical course, characterized by rapid progression from mild, nonspecific gastrointestinal symptoms to hypovolemic shock, multi-organ failure, and refractory cardiovascular collapse."

States the course that this burden level reflects, from a systematic review of fatal cases.

PMID:34830227 SUPPORT BACKGROUND Other

"inhalatory and parenteral intoxications are associated with greater illness and mortality, and are characterized by lethal doses that are roughly three magnitudes lower than that of oral poisoning"

Quantifies the route dependence that makes this burden level route-conditional rather than uniform.

🔀

Differential Diagnoses

Conditions with similar clinical presentations that must be differentiated from Ricin Poisoning:

Infectious gastroenteritis and sepsis

Overlapping Features The ingestion syndrome is an acute gastroenteritis progressing to shock, which is exactly how Salmonella or Shigella enteritis and septic shock of any cause present. Without an exposure history there is nothing in the early clinical picture to separate them.

Distinguishing Features

Ricinine detectable in blood or urine establishes castor bean exposure and is not produced by any infection.
A history of chewing castor seeds, or of handling castor mash, has no counterpart in enteric infection.

Show evidence (5 references)

PMID:42560523 SUPPORT REVIEW SYNTHESIS Human Clinical

"the differential diagnosis with other septic shock-like syndromes"

Names this differential as one of the medico-legal challenges the review identifies.

PMID:42560523 SUPPORT REVIEW SYNTHESIS Human Clinical

"can mimic several common medical conditions, most notably septic shock"

States which condition the mimicry most often points at.

PMID:42560523 SUPPORT REVIEW SYNTHESIS Human Clinical

"as bacterial sepsis, particularly when no history of ricin exposure is available"

Names the condition under which the confusion happens - no exposure history - which is exactly the deliberate-poisoning case where the diagnosis matters most. Quoted from mid-sentence because the review is a scanned PDF that hyphen-breaks the preceding words across lines.

+ 2 more references

Toxin-induced wide-complex tachycardia

Overlapping Features A patient presenting with a wide-complex tachycardia and no structural heart disease will be worked up as a primary arrhythmia. Ricin belongs in that differential: the one reported case converted only after prolonged supportive care, having failed cardioversion and amiodarone, and the authors liken the mechanism to digitalis intoxication and catecholaminergic polymorphic ventricular tachycardia.

Distinguishing Features

A preceding gastrointestinal prodrome - severe nausea, vomiting and diarrhoea - rather than an arrhythmia arising without warning.
Failure of electrical cardioversion and amiodarone, in a heart with no structural disease.

Show evidence (3 references)

PMID:41788434 SUPPORT Human Clinical

"This case underscores the importance of recognizing rare toxin-induced arrhythmias in the differential diagnosis of wide-complex tachycardias"

States this differential directly, as the authors' own conclusion.

PMID:41788434 SUPPORT Human Clinical

"The arrhythmogenic mechanism in ricin poisoning may involve calcium dysregulation and triggered activity, similar to digitalis intoxication or catecholaminergic polymorphic ventricular tachycardia."

Names the two conditions this most resembles mechanistically.

PMID:41788434 SUPPORT Human Clinical

"Re-entry appears unlikely due to the absence of structural heart disease and the failure of electrical cardioversion."

Supports the second distinguishing feature listed here.

🔬

Clinical Trials

NCT01317667 PHASE_I COMPLETED

Phase 1 escalating multiple-dose study of the RVEc recombinant ricin toxin A chain vaccine in thirty healthy adults, at 20, 50 and 100 micrograms.

Show evidence (1 reference)

clinicaltrials:NCT01317667 SUPPORT Human Clinical

"This study is a Phase 1, escalating, multiple-dose, single-center study to evaluate the safety and immunogenicity of the RVEc vaccine."

The registration record establishing this trial's design and phase.

NCT01846104 PHASE_I COMPLETED

Booster study in subjects who had already received three 50-microgram doses of RVEc in the trial above.

Show evidence (1 reference)

clinicaltrials:NCT01846104 SUPPORT Human Clinical

"The purpose of this study is to evaluate the safety and immunogenicity of a single 50-μg booster dose of RVEc."

The registration record for the booster arm.

🐁

Animal Models

Murine intramuscular ricin intoxication

Lethal intramuscular ricin in mice, used to characterise the systemic rather than the mucosal face of the disease. It reproduces the coagulopathy, thrombocytopenia and multi-organ haemorrhage of parenteral human poisoning and adds structural cardiac injury with measurable functional impairment.

Species

Mouse

Publication

PMID:31208156

Pathograph links

Endothelial Glycocalyx Shedding and Microvascular Hyperpermeability recapitulates fidelity: moderate observes: organism The model is where the glycocalyx-shedding account of systemic ricin poisoning was established, alongside swine.

Limitations: Mouse, and a single lethal bolus dose by a route that in humans is documented in essentially one case. Whether human parenteral poisoning shows the same glycocalyx kinetics is untested.

Readouts

Circulating heparan sulfate, hyaluronic acid and syndecan-1

Direction: INCREASED

Interpretation: Shed glycocalyx components measured in blood as the direct readout of the node.

Show evidence (1 reference)

PMID:34830227 SUPPORT Model Organism

"Elevated levels of soluble heparan sulfate, hyaluronic acid and syndecan-1 were measured in blood samples following ricin intoxication"

Reports the measurement in the direction this readout records.

Show evidence (1 reference)

PMID:34830227 SUPPORT Model Organism

"ricin bound preferentially to the vasculature in both mice and swine, leading to coagulopathy and widespread hemorrhages"

Supports the model as informative for this node, and notes the finding held in two species rather than one.

Show evidence (4 references)

PMID:31208156 SUPPORT Model Organism

"The present study applies various biochemical, hematological, histopathological, molecular, and functional approaches to broadly investigate the systemic effects of parenteral intoxication by a lethal dose of ricin in a murine model."

Describes the model and what it was built to measure.

PMID:31208156 SUPPORT Model Organism

"In the heart, diffuse hemorrhages, myocyte necrosis, collagen deposition, and induction in fibrinogen were observed."

The cardiac lesion of this model. Recorded here rather than under `histopathology:`, which holds human autopsy findings, so the species is not lost on a reader scanning that section. It matters because the one well-documented human parenteral case was read at autopsy as cardiac arrest from necrosis of the conducting tissue, which this lesion makes mechanistically plausible without confirming.

PMID:31208156 SUPPORT Model Organism

"Severe functional impairment was manifested by marked thickening of the left ventricular wall, decreased ventricular volume, and a significant reduction in stroke volume and cardiac output."

The functional consequence measured alongside that histology.

+ 1 more reference

Murine pulmonary ricinosis

Intranasal or aerosolised ricin in mice, at sublethal or lethal doses. This is the principal model for the inhalational syndrome, and essentially the only source of information about it, since human inhalational poisoning has no published case series.

Species

Mouse

Publication

PMID:38773158

Pathograph links

Acute Lung Injury with Interstitial Pneumonia and Alveolar Edema recapitulates fidelity: moderate observes: organism Reproduces the full lesion - interstitial pneumonia, local cytokine storm, neutrophil influx, oedema and epithelial death - with measurable loss of lung function.

Limitations: Fidelity to the human disease cannot be assessed, because there is no human inhalational case series to compare it against. The inhalation models also differ among themselves: exposure method, aerosol characteristics, ricin cultivar and purity, dose and species all vary, and the review of them says the resulting pathology is broadly similar rather than identical.

Readouts

Lung histopathology and physiological function

Direction: ALTERED

Interpretation: Paired structural and functional readout of the acute lung injury node.

Show evidence (1 reference)

PMID:38773158 SUPPORT Model Organism

"This damage was manifested in reduced lung performance and physiological function."

The functional half of the readout.

Show evidence (1 reference)

PMID:38773158 SUPPORT Model Organism

"sublethal exposure of mice to ricin resulted in acute lung injury, including interstitial pneumonia, cytokine storm, neutrophil influx, edema and cellular death"

Supports the model as informative for this node by naming every component it reproduces.

Residual Pulmonary Fibrosis in Survivors recapitulates fidelity: low observes: organism The only evidence anywhere that survivors of pulmonary ricin exposure carry long-term damage.

Limitations: Fidelity is marked LOW because susceptibility to pulmonary fibrosis, and the character of the fibrosis that develops, differ by species and strain - which the inhalation-model review names explicitly as a reason to choose the model carefully for chronic work. There is no human counterpart at all.

Show evidence (1 reference)

PMID:37104219 SUPPORT REVIEW SYNTHESIS Model Organism

"these factors need to be considered when choosing a model for chronic ricin toxicity by inhalation, including species and strain susceptibility to fibrosis"

The basis for the LOW fidelity grade on this link.

Show evidence (1 reference)

PMID:38773158 SUPPORT Model Organism

"the purpose of current study was to assess short- and long-term effects on physiological parameters and function following sublethal pulmonary exposure"

States what the model was built to answer.

Swine ricin intoxication by intratracheal and intramuscular routes

Swine were chosen over rodents for post-exposure countermeasure work because their cardiovascular and pulmonary systems resemble the human, and the model is where pulmonary ricin exposure was shown to produce genuine acute respiratory distress syndrome rather than a rodent approximation of it.

Species

Pig

Publication

PMID:32481526

Pathograph links

Acute Lung Injury with Interstitial Pneumonia and Alveolar Edema recapitulates fidelity: moderate observes: organism The large-animal demonstration that the pulmonary lesion meets ARDS criteria.

Limitations: Still an animal model of a syndrome with no human case series, so the resemblance argument rests on organ physiology rather than on any comparison with human ricin disease. Post-exposure protection experiments in this species also need far more antitoxin than the mouse, so efficacy figures do not transfer between the two models.

Show evidence (1 reference)

PMID:32481526 SUPPORT Model Organism

"the swine animal model served us in the past to determine that pulmonary exposure to ricin leads to the development of bona fide acute respiratory distress syndrome"

Supports the model as informative for this node, at the level of the ARDS endpoint.

Show evidence (1 reference)

PMID:32481526 SUPPORT Model Organism

"Due to the high resemblance between the human and porcine cardiovascular and pulmonary systems"

The stated reason for choosing this species, which is what its fidelity claim rests on.

{ }

Source YAML

click to show

name: Ricin Poisoning
creation_date: "2026-09-17T23:40:00Z"
category: Environmental
categories:
- Toxic Exposure Disorder
- Plant Poisoning
- Biological Toxin Exposure
parents:
- poisoning
synonyms:
- ricin intoxication
- ricin toxicosis
- castor bean poisoning
- castor seed poisoning
- Ricinus communis poisoning
- ricinosis
description: >-
  Ricin poisoning is an acute intoxication caused by ricin, the type 2
  ribosome-inactivating protein of the castor bean, the seed of Ricinus
  communis. Ricin is a disulfide-linked heterodimer: the B chain (RTB) is a
  galactose and N-acetylgalactosamine-specific lectin that binds terminal
  galactose residues on essentially any cell surface, and the A chain (RTA) is
  an rRNA N-glycosidase. After RTB-mediated binding the holotoxin is
  endocytosed and carried retrogradely through the Golgi to the endoplasmic
  reticulum, where the interchain disulfide is reduced and the A chain
  dislocates across the ER membrane into the cytosol. There it removes a single
  adenine from the universally conserved sarcin-ricin loop of 28S rRNA in the
  60S subunit, which abolishes elongation-factor binding and arrests protein
  synthesis. The reaction is catalytic - an estimated 1,500 ribosomes per
  minute - so very few cytosolic A chains suffice to kill a cell. Depurination
  is not only a lesion but a signal: the damaged loop triggers the ribotoxic
  stress response, activating the p38 MAPK and JNK stress kinases, which drive
  both apoptosis and pro-inflammatory cytokine release.

  The clinical syndrome is set by the route of exposure rather than by any
  difference in mechanism. Ingestion of chewed castor seeds produces a
  hemorrhagic gastroenteritis with fluid and electrolyte loss, usually survivable
  with prompt supportive care because intact seed coats resist digestion and
  gastrointestinal absorption is poor. Inhalation of aerosolised toxin produces
  acute lung injury with interstitial pneumonia, neutrophil influx and
  proteinaceous alveolar edema that can progress to acute respiratory distress
  syndrome - a picture established entirely in rodents, rabbits, macaques and
  swine, since no human inhalational case has been documented. Parenteral
  injection - the route of the 1978 Georgi Markov assassination - causes local
  necrosis followed by endothelial glycocalyx shedding, coagulopathy,
  widespread hemorrhage and distributive shock, known from a handful of human
  cases and worked out mechanistically in mice and swine. Severe
  poisoning by any route converges on hypovolemic and distributive shock with
  multi-organ failure, typically within 10 to 72 hours. There is no approved
  antidote or vaccine; management is supportive, with early gastrointestinal
  decontamination for ingestion. Ricin's availability as a byproduct of castor
  oil production makes it a recurrent agent of assassination, self-harm and
  attempted bioterrorism, and it is listed as a CDC Category B agent and a
  Schedule 1 chemical under the Chemical Weapons Convention.
notes: >-
  Curated from a `claude_code` deep-research report
  (`research/Ricin_Poisoning-deep-research-claude_code.md`). That report was
  generated before the recipes emitted an in-line validation block, so
  `just validate-research-reference` and `just validate-research-terms` were run
  over it afterwards; the retro-fitted sections record 31/31 references resolved
  with no unresolved identifiers, and 46/47 CURIEs resolved with one obsolete
  (`GO:0030433`, which is not used here). Every ontology binding written into
  this entry was nevertheless re-derived by a fresh lookup rather than copied
  from the report, per the repository's term contract. That was not a formality:
  the report proposed `HP:0001395` for hepatic necrosis, which is a different
  term - the HPO term for *Hepatic necrosis* is `HP:0002605` - and most of its
  other suggestions were explicit "verify" placeholders rather than bindings.

  The report cited overwhelmingly by URL rather than by PMID, so its PMC and DOI
  links were run through the PMC ID Converter and the PMIDs cited here; a
  handful of its sources are Wikipedia pages, FBI press releases and news
  articles and are not cited at all.

  This is an acquired toxicosis with no Mendelian basis, so there is no
  GeneReviews chapter and no OMIM entry, and the `genetic:` section is
  deliberately absent rather than empty. `just check-genereviews` returns
  `NO_CHAPTER` for both Bookshelf collections. The deep-research report leaned
  heavily on a StatPearls chapter; nothing from it is cited here, because
  StatPearls is never a baseline in this repository. Its distinctive content -
  the routine-laboratory panel, chest imaging, the clustered-presentation
  epidemiologic heuristic, and the infectious and chemical differential list -
  was therefore not carried over at all rather than re-sourced. That is a real
  gap in `diagnosis:` and `differential_diagnoses:`, not a difference in
  citation.

  Host genetic modifiers of *cellular* susceptibility are real and
  well studied - the fucosylation and sialylation "sugar code" that controls how
  much toxin binds, and the retrograde-transport machinery that carries it in -
  but none is an organismal susceptibility locus for human disease, so they are
  recorded in `discussions` rather than curated as `genetic:` rows.

  `prevalence:` carries only a literature case count rather than a rate. No
  population-based incidence for ricin poisoning exists, because exposure is an
  intentional or accidental event rather than an endemic process;
  `measure_type: CASES_IN_LITERATURE` is used for exactly this reason.

  The evidence base is deliberately uneven and is graded to show it. The
  molecular chain from lectin binding through depurination to the ribotoxic
  stress response rests on `IN_VITRO` work; the organ-level consequences of
  inhalation rest entirely on `MODEL_ORGANISM` studies in mice, rabbits,
  macaques and swine, because no human inhalational case has ever been
  documented; injection is known from a handful of human cases plus mouse and
  swine work; and only the ingestion syndrome has a substantial human clinical
  literature. The hypoglycemia node is model-organism-only, and the same authors
  report a negative in aerosol-exposed macaques, so it is carried as an open
  question rather than promoted to a human phenotype.

  Two causal edges are deliberately left uncited. Apoptotic cell death is drawn
  to the gastrointestinal and to the hepatic/renal lesions because that is the
  mechanism, but the human autopsy series that establishes those lesions says
  nothing about how the cells died, and no cited study tests epithelial death
  against the mucosal lesion in gut the way PMID:36695077 does in lung. Reusing
  the autopsy sentence as edge evidence would have been node-level evidence
  papering over an unsourced edge, so it was removed rather than kept.

  Splenic necrosis is not curated as a phenotype although it appears inside
  quoted evidence. The murine intramuscular model shows spleen damage, but the
  systematic review of fatal human cases never mentions the spleen at all -
  "splen" does not occur in its text - so there is no human source for it. It is
  carried where it belongs, on the murine model, rather than promoted into the
  human clinical picture.

  `clinical_trials:` holds the two registered RVEc phase 1 studies and nothing
  else. The RiVax phase 1B publication registers no NCT identifier, and no
  interventional trial of a ricin *treatment* exists to register - every
  post-exposure countermeasure in `treatments:` is preclinical.

  Three bindings are deliberately broader than the thing they describe, each
  with its reason recorded beside it: `HP:0001928` for the coagulopathy (no
  cited source reports a clotting time), `HP:0031865` for the liver derangement
  (no source names an analyte), and `HP:0001878` for the haemolysis (the
  sources report haemolysis at autopsy, not an anaemia). Earlier drafts used
  narrower terms in all three places and in a fourth - an `Oliguria` phenotype
  inferred from "multi-organ failure" - which was removed outright because no
  source mentions it. A `Cough` phenotype went the same way: its only support
  was a vigilance recommendation that never uses the word.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0035511
      label: ricin poisoning
    mapping_predicate: skos:exactMatch
    mapping_justification: semapv:ManualMappingCuration
  icd10cm_mappings:
  - term:
      id: ICD10CM:T62.2
      label: Toxic effect of other ingested (parts of) plant(s)
    mapping_predicate: skos:broadMatch
    mapping_justification: semapv:ManualMappingCuration
    notes: >-
      ICD-10-CM has no code naming ricin. T62.2 is the code castor-seed
      ingestion falls under, and it covers every other ingested plant part as
      well, so the mapping is `broadMatch` rather than `exactMatch`. It also
      only covers the oral route: inhalational and parenteral ricin exposure
      code elsewhere in the T-code chapter, which is a second reason not to
      claim an exact match.
disease_term:
  preferred_term: ricin poisoning
  term:
    id: MONDO:0035511
    label: ricin poisoning
clinical_burden:
  burden_level: VARIABLE
  rationale: >-
    The route of exposure, not the severity of the illness, is what this level
    records. Most ingestion cases recover fully with supportive care, and only
    six of fifty published cases died; inhalational and parenteral exposures
    have lethal doses roughly three orders of magnitude lower, and untreated
    severe exposure by any route reaches shock and multi-organ failure within
    one to three days with no antidote available. No single low, moderate or
    high level is representative of that spread, which is what `VARIABLE` is
    for.
  notes: >-
    `HIGH` is defensible on the strength of the mortality-risk clause in its own
    definition, and an earlier draft used it. It was changed because the
    route-dependence here is the clinically important fact rather than a
    complication of stating one, and because the rest of this entry works to
    preserve that distinction - three separately stratified `environmental:`
    entries and a `HUMAN_MODEL_MISMATCH` discussion about the inhalational
    syndrome being known only from animals. A single level would flatten the one
    thing the entry is most careful about.
  evidence:
  - reference: PMID:42560523
    reference_title: "Medico-legal aspects of fatal ricin poisoning: a systematic review of clinical manifestations, toxicological findings and autopsy results."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "The available evidence suggests a relatively consistent clinical course, characterized by rapid progression from mild, nonspecific gastrointestinal symptoms to hypovolemic shock, multi-organ failure, and refractory cardiovascular collapse."
    explanation: States the course that this burden level reflects, from a systematic review of fatal cases.
  - reference: PMID:34830227
    reference_title: "Intramuscular Exposure to a Lethal Dose of Ricin Toxin Leads to Endothelial Glycocalyx Shedding and Microvascular Flow Abnormality in Mice and Swine."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: "inhalatory and parenteral intoxications are associated with greater illness and mortality, and are characterized by lethal doses that are roughly three magnitudes lower than that of oral poisoning"
    explanation: Quantifies the route dependence that makes this burden level route-conditional rather than uniform.
pathophysiology:
- name: Ricin Delivery to Host Tissue
  biological_scale: ORGANISM
  description: >-
    The exposure event. Ricin-containing material reaches host tissue by one of
    four routes - ingestion of chewed or crushed castor seeds, inhalation of
    aerosolised toxin or seed dust, parenteral injection, and rarely ocular or
    abraded-skin contact. The molecular mechanism that follows is identical
    whichever route delivers the toxin; what differs is the dose that reaches
    the circulation and the tissue that receives the highest local burden, which
    is why lethal doses by inhalation and injection are roughly a thousandfold
    lower than by mouth.
  notes: >-
    Carries no ontology-bound process descriptor: the node denotes an exposure
    event rather than a host biological process. The exposures themselves are
    grounded in the `environmental:` block, which splits them by route.
  downstream:
  - target: RTB Lectin Binding to Cell-Surface Galactosylated Glycoconjugates
    causal_link_type: DIRECT
    description: >-
      Whatever the route, the first host-side event is the B chain engaging
      galactose-terminated glycoconjugates on the nearest cell surface.
    evidence:
    - reference: PMID:39453188
      reference_title: "A Monoclonal Antibody with a High Affinity for Ricin Isoforms D and E Provides Strong Protection against Ricin Poisoning."
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: BACKGROUND
      snippet: "RTB acts as a galactose-specific lectin, binding to glycolipids and glycoproteins on the cell surface through their terminal galactose or N-acetylgalactosamine residues."
      explanation: Names the binding step that follows delivery, which is what this edge asserts.
  chemical_entities:
  - preferred_term: ricin holotoxin
    term:
      id: CHEBI:8852
      label: Ricin
  evidence:
  - reference: PMID:34830227
    reference_title: "Intramuscular Exposure to a Lethal Dose of Ricin Toxin Leads to Endothelial Glycocalyx Shedding and Microvascular Flow Abnormality in Mice and Swine."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: "Exposure to ricin can occur by oral ingestion, inhalation or parenteral intoxication, while the features and severity of ricin toxicity vary markedly with the route of exposure."
    explanation: States both halves of this node - the routes, and that route sets severity.
  - reference: PMID:34830227
    reference_title: "Intramuscular Exposure to a Lethal Dose of Ricin Toxin Leads to Endothelial Glycocalyx Shedding and Microvascular Flow Abnormality in Mice and Swine."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: "inhalatory and parenteral intoxications are associated with greater illness and mortality, and are characterized by lethal doses that are roughly three magnitudes lower than that of oral poisoning"
    explanation: Quantifies the thousandfold route difference this description asserts.
- name: RTB Lectin Binding to Cell-Surface Galactosylated Glycoconjugates
  biological_scale: MOLECULAR
  description: >-
    The B chain is a galactose and N-acetylgalactosamine-specific lectin. It
    binds terminal galactose residues on both glycoproteins and glycolipids,
    which is why ricin has essentially no cell-type selectivity - every
    nucleated cell displays suitable ligands. The promiscuity of this step is
    what makes the toxin's organ distribution a function of delivery rather than
    of receptor expression.
  downstream:
  - target: Endocytic Internalization of the Ricin Holotoxin
    causal_link_type: DIRECT
    description: >-
      Surface binding commits the holotoxin to whichever endocytic routes the
      bound cell operates.
    evidence:
    - reference: PMID:11111920
      reference_title: "Ricin transport into cells: studies of endocytosis and intracellular transport."
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: REVIEW_SYNTHESIS
      snippet: "The plant toxin ricin binds to both glycoproteins and glycolipids with terminal galactose, and the toxin will therefore be endocytosed by the different mechanisms operating in a given cell."
      explanation: >-
        States the causal link directly - binding is what commits the toxin to
        endocytosis, by whichever mechanisms that cell happens to run.
  molecular_functions:
  - preferred_term: galactoside binding by the ricin B chain
    term:
      id: GO:0016936
      label: galactoside binding
  chemical_entities:
  - preferred_term: ricin holotoxin
    term:
      id: CHEBI:8852
      label: Ricin
  evidence:
  - reference: PMID:39453188
    reference_title: "A Monoclonal Antibody with a High Affinity for Ricin Isoforms D and E Provides Strong Protection against Ricin Poisoning."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: BACKGROUND
    snippet: "RTB acts as a galactose-specific lectin, binding to glycolipids and glycoproteins on the cell surface through their terminal galactose or N-acetylgalactosamine residues."
    explanation: Names the ligand class and both carrier types this node asserts.
  - reference: PMID:36548717
    reference_title: "Parenteral Exposure of Mice to Ricin Toxin Induces Fatal Hypoglycemia by Cytokine-Mediated Suppression of Hepatic Glucose-6-Phosphatase Expression."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: BACKGROUND
    snippet: "the B chain binds promiscuously to cell surface glycans via galactose-specific lectin binding"
    explanation: >-
      Source of the promiscuity claim, which is the part of this node that
      explains why ricin has no cell-type selectivity.
- name: Endocytic Internalization of the Ricin Holotoxin
  biological_scale: CELLULAR
  description: >-
    Bound holotoxin is taken into the cell by the endocytic mechanisms available
    to it, clathrin-dependent and clathrin-independent alike, and delivered to
    endosomes. Only a very small fraction of internalised toxin escapes the
    degradative route; most is destroyed, and the potency of the surviving
    minority is what makes the toxin lethal at microgram doses.
  downstream:
  - target: Retrograde Transport from the Golgi to the Endoplasmic Reticulum
    causal_link_type: DIRECT
    description: >-
      From the endosome the toxin is carried onward to the Golgi apparatus by a
      route distinct from the one mannose-6-phosphate receptors use.
    evidence:
    - reference: PMID:11111920
      reference_title: "Ricin transport into cells: studies of endocytosis and intracellular transport."
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: REVIEW_SYNTHESIS
      snippet: "After endocytosis the toxin is transported to the Golgi apparatus by a process that differs from the Rab9-dependent transport of mannose-6-phosphate receptors."
      explanation: States the post-endocytic step this edge asserts, and that it is a distinct route.
  biological_processes:
  - preferred_term: endocytosis of the ricin holotoxin
    modifier: INCREASED
    term:
      id: GO:0006897
      label: endocytosis
  evidence:
  - reference: PMID:21527639
    reference_title: Dislocation of ricin toxin A chains in human cells utilizes selective cellular factors.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: BACKGROUND
    snippet: "Ricin enters cells via endocytosis, where only a minute number of ricin molecules reach the endoplasmic reticulum (ER) lumen."
    explanation: >-
      States both the entry mechanism and the small surviving fraction that this
      node records.
- name: Retrograde Transport from the Golgi to the Endoplasmic Reticulum
  biological_scale: CELLULAR
  description: >-
    The toxin travels backwards along the secretory pathway - endosome to
    trans-Golgi network to Golgi to endoplasmic reticulum - instead of being
    routed to the lysosome. This detour is not incidental: reaching the ER lumen
    is a precondition for the A chain to reach the cytosol, and blocking the
    early-endosome-to-TGN step alone protects animals from otherwise lethal
    ricin.
  downstream:
  - target: Disulfide Reduction of the Holotoxin in the ER Lumen
    causal_link_type: DIRECT
    description: >-
      Arrival in the ER lumen is what makes the subsequent reduction and
      dislocation into the cytosol possible.
    evidence:
    - reference: PMID:11111920
      reference_title: "Ricin transport into cells: studies of endocytosis and intracellular transport."
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: REVIEW_SYNTHESIS
      snippet: "Retrograde toxin transport from the Golgi apparatus to the endoplasmic reticulum (ER) seems to be a requirement for subsequent toxin translocation to the cytosol where the toxin inhibits protein synthesis enzymatically."
      explanation: States the requirement relation this edge asserts.
  biological_processes:
  - preferred_term: retrograde transport of ricin from the Golgi to the ER
    modifier: INCREASED
    term:
      id: GO:0006890
      label: "retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum"
  evidence:
  - reference: PMID:20403321
    reference_title: Inhibition of retrograde transport protects mice from lethal ricin challenge.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: BACKGROUND
    snippet: "To gain access to their cytosolic target, ribosomal RNA, these toxins follow the retrograde transport route from the plasma membrane to the endoplasmic reticulum, via endosomes and the Golgi apparatus."
    explanation: Names the full itinerary this node describes.
  - reference: PMID:20403321
    reference_title: Inhibition of retrograde transport protects mice from lethal ricin challenge.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "In mice, one compound clearly protects from lethal nasal exposure to ricin."
    explanation: >-
      Supports the claim that this step is required rather than incidental -
      blocking it alone rescued animals from a lethal challenge. Marked indirect
      because it is a therapeutic response cited as validation of the mechanism
      it targets, which is an inference rather than a direct measurement of the
      step.
- name: Disulfide Reduction of the Holotoxin in the ER Lumen
  biological_scale: MOLECULAR
  description: >-
    In the ER lumen the single disulfide bond joining the two chains is reduced,
    liberating the A chain from the lectin that carried it there. This is a
    separate step from the membrane crossing that follows, and is cited
    separately: the human-cell study that worked out the dislocation mechanism
    does not describe the reduction.
  downstream:
  - target: Retrotranslocation of the A Chain into the Cytosol
    causal_link_type: DIRECT
    description: >-
      A free A chain is what crosses the membrane; the reduction is what frees it.
    evidence:
    - reference: PMID:39453188
      reference_title: "A Monoclonal Antibody with a High Affinity for Ricin Isoforms D and E Provides Strong Protection against Ricin Poisoning."
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: BACKGROUND
      snippet: "where the disulfide bond is reduced. The A chain is then translocated into the cytoplasm, where it exhibits its enzymatic activity."
      explanation: States the ordering this edge asserts - reduction, then translocation.
  evidence:
  - reference: PMID:39453188
    reference_title: "A Monoclonal Antibody with a High Affinity for Ricin Isoforms D and E Provides Strong Protection against Ricin Poisoning."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: BACKGROUND
    snippet: "ricin is internalized and transported retrogradely to the endoplasmic reticulum, where the disulfide bond is reduced."
    explanation: Places the reduction in the ER lumen, which is what this node asserts.
- name: Retrotranslocation of the A Chain into the Cytosol
  biological_scale: MOLECULAR
  description: >-
    The liberated A chain crosses the ER membrane into the cytosol by a
    dislocation process that co-opts the machinery the cell uses to dispose of
    misfolded proteins. It is not simply the canonical ERAD route: in human
    cells it proceeds through a membrane-integrated intermediate and depends on
    the ER protein SEL1L. Once in the cytosol the chain refolds into its active
    conformation rather than being degraded.
  downstream:
  - target: Depurination of the Sarcin-Ricin Loop of 28S rRNA
    causal_link_type: DIRECT
    description: >-
      A refolded cytosolic A chain immediately begins depurinating ribosomes, at
      a catalytic rate that makes very few molecules sufficient.
    evidence:
    - reference: PMID:23133670
      reference_title: Identification of small molecules that suppress ricin-induced stress-activated signaling pathways.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: BACKGROUND
      snippet: "Once in the cytoplasm, RTA refolds into its enzymatically active conformation and initiates ribosome depurination at a rate estimated to exceed 1500/min"
      explanation: States that cytosolic arrival initiates depurination, and gives the rate this entry quotes.
  biological_processes:
  - preferred_term: dislocation of the ricin A chain across the ER membrane
    modifier: INCREASED
    term:
      id: GO:0030970
      label: "retrograde protein transport, ER to cytosol"
  evidence:
  - reference: PMID:21527639
    reference_title: Dislocation of ricin toxin A chains in human cells utilizes selective cellular factors.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: BACKGROUND
    snippet: "Subsequently, the ricin A chain traverses the ER bilayer by a process referred to as dislocation or retrograde translocation to gain access to the cytosol."
    explanation: Names the process this node describes.
  - reference: PMID:21527639
    reference_title: Dislocation of ricin toxin A chains in human cells utilizes selective cellular factors.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "ricin A chain dislocation occurred via a membrane-integrated intermediate and utilized the ER protein SEL1L for transport across the ER bilayer to inhibit protein synthesis"
    explanation: >-
      The experimental result behind the claim that this is not the canonical
      ERAD route, measured in a human cell system.
- name: Depurination of the Sarcin-Ricin Loop of 28S rRNA
  biological_scale: MOLECULAR
  description: >-
    The catalytic lesion. The A chain is an rRNA N-glycosidase (EC 3.2.2.22)
    that hydrolyses the N-glycosidic bond of one universally conserved adenine -
    A4324 in the rat numbering - in the sarcin-ricin loop of 28S rRNA within the
    60S subunit. The phosphodiester backbone is left intact; a single base is
    removed. Because the enzyme turns over rather than being consumed, one
    molecule inactivates ribosomes at a rate estimated above 1,500 per minute,
    and the lesion is irreversible for the affected ribosome.
  downstream:
  - target: Arrest of Translational Elongation
    causal_link_type: DIRECT
    description: >-
      The sarcin-ricin loop is part of the GTPase centre that elongation factors
      engage, so removing its adenine abolishes elongation-factor binding.
    evidence:
    - reference: PMID:36828415
      reference_title: Medical Countermeasures against Ricin Intoxication.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: REVIEW_SYNTHESIS
      snippet: "Ricin inhibits peptide chain elongation via disruption of the binding between elongation factors and ribosomes"
      explanation: States the mechanism by which the lesion arrests elongation, which is this edge.
    - reference: PMID:40987586
      reference_title: Depurination of sarcin/ricin loop 25S rRNA is signaled through the small ribosomal subunit during translation.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: IN_VITRO
      snippet: "25S rRNA depurination inhibited translation elongation, as shown by reduced incorporation of a methionine analog and binding of eukaryotic elongation factor 2 (eEF2) to ribosomes."
      explanation: >-
        Direct measurement of the depurination-to-elongation-arrest step, but
        performed in yeast using pokeweed antiviral protein rather than ricin -
        a different N-glycosidase acting on the same loop - so the inference to
        ricin in human cells is one step removed.
  - target: Ribotoxic Stress Response and Stress-Activated Kinase Signaling
    causal_link_type: DIRECT
    description: >-
      The damaged loop is itself a signal. This branch runs in parallel with
      elongation arrest rather than downstream of it.
    evidence:
    - reference: PMID:23133670
      reference_title: Identification of small molecules that suppress ricin-induced stress-activated signaling pathways.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: BACKGROUND
      snippet: "As a direct consequence of rRNA depurination, RTA activates the so-called ribotoxic stress response (RSR)"
      explanation: States the depurination-to-RSR link, and that it is a direct consequence.
  molecular_functions:
  - preferred_term: rRNA N-glycosidase activity of the ricin A chain
    term:
      id: GO:0030598
      label: rRNA N-glycosylase activity
  evidence:
  - reference: PMID:27879643
    reference_title: Structures and Ribosomal Interaction of Ribosome-Inactivating Proteins.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: REVIEW_SYNTHESIS
    snippet: "Ribosome-inactivating proteins (RIPs) including ricin, Shiga toxin, and trichosanthin, are RNA N-glycosidases that depurinate a specific adenine residue (A-4324 in rat 28S ribosomal RNA, rRNA) in the conserved α-sarcin/ricin loop (α-SRL) of rRNA."
    explanation: Names the enzyme class, the specific adenine, and the loop this node is about.
  - reference: PMID:39453188
    reference_title: "A Monoclonal Antibody with a High Affinity for Ricin Isoforms D and E Provides Strong Protection against Ricin Poisoning."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: BACKGROUND
    snippet: "RTA functions as an rRNA N-glycosylase (EC 3.2.2.22), specifically cleaving an adenine residue from the 28S ribosomal RNA in the 60S ribosomal subunit"
    explanation: Gives the EC number and locates the target in the 60S subunit.
  - reference: PMID:32481526
    reference_title: Post-Exposure Anti-Ricin Treatment Protects Swine Against Lethal Systemic and Pulmonary Exposures.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: BACKGROUND
    snippet: "The A chain possesses RNA N-glycosidase activity that irreversibly inactivates the 28S rRNA of the mammalian 60S ribosome subunit"
    explanation: Independent statement that the inactivation is irreversible, which this node asserts.
- name: Arrest of Translational Elongation
  biological_scale: CELLULAR
  description: >-
    With the sarcin-ricin loop depurinated, elongation factor 1-dependent
    aminoacyl-tRNA delivery and elongation factor 2-dependent translocation can
    no longer occur on that ribosome. Protein synthesis halts at the elongation
    step. As successive ribosomes are hit the cell's entire translational output
    collapses, and because the lesion is per-ribosome and irreversible there is
    no recovery short of ribosome biogenesis outpacing the toxin.
  downstream:
  - target: Apoptotic Death of Intoxicated Cells
    causal_link_type: DIRECT
    description: >-
      Sustained loss of protein synthesis is itself lethal to the cell, and
      ricin-treated cells die predominantly by apoptosis.
    evidence:
    - reference: PMID:36548717
      reference_title: "Parenteral Exposure of Mice to Ricin Toxin Induces Fatal Hypoglycemia by Cytokine-Mediated Suppression of Hepatic Glucose-6-Phosphatase Expression."
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: BACKGROUND
      snippet: "the A chain enzymatically inactivates the large ribosomal unit, halting protein synthesis, and causing cell death, primarily by apoptosis"
      explanation: States the arrest-to-apoptosis link and that apoptosis is the dominant death mode.
    - reference: PMID:17101666
      reference_title: Ribosome depurination is not sufficient for ricin-mediated cell death in Saccharomyces cerevisiae.
      supports: REFUTE
      evidence_source: IN_VITRO
      snippet: "Several nontoxic RTA mutants depurinated ribosomes and inhibited translation to the same extent as wild-type RTA in vivo."
      explanation: >-
        The dissociation that qualifies this edge. A-chain mutants that
        depurinated and arrested translation as fully as wild type still failed
        to kill, so translational arrest is necessary but not sufficient. The
        edge is real; it is not the whole account, which is why the parallel
        ribotoxic-stress branch carries weight rather than being decorative.
    - reference: PMID:17101666
      reference_title: Ribosome depurination is not sufficient for ricin-mediated cell death in Saccharomyces cerevisiae.
      supports: REFUTE
      evidence_source: IN_VITRO
      snippet: "ribosome depurination and translation inhibition do not account entirely for the cytotoxicity of ricin"
      explanation: The authors' own statement of the limit on this edge.
  biological_processes:
  - preferred_term: translational elongation in the intoxicated cell
    modifier: DECREASED
    term:
      id: GO:0006414
      label: translational elongation
  evidence:
  - reference: PMID:36828415
    reference_title: Medical Countermeasures against Ricin Intoxication.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: REVIEW_SYNTHESIS
    snippet: "Ricin inhibits peptide chain elongation via disruption of the binding between elongation factors and ribosomes, resulting in apoptosis, inflammation, oxidative stress, and DNA damage, in addition to the classically known rRNA damage."
    explanation: >-
      Names the arrest itself and, in the same sentence, the four downstream
      consequences this entry branches into.
  - reference: PMID:19695342
    reference_title: Ricin A-chain requires c-Jun N-terminal kinase to induce apoptosis in nontransformed epithelial cells.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Ribosome depurination and inhibition of protein synthesis were induced in 2-4h with 1microg/ml RTA and within 4-6h with 0.1microg/ml RTA."
    explanation: >-
      Times the arrest in a non-transformed epithelial cell line, establishing
      that it precedes the apoptosis measured in the same experiment.
- name: Ribotoxic Stress Response and Stress-Activated Kinase Signaling
  biological_scale: CELLULAR
  description: >-
    Damage to 28S rRNA is sensed as a stress signal independently of the loss of
    translation. The MAP3K ZAK has been identified as the kinase that responds
    to ricin-induced damage, activating the p38 MAPK and c-Jun N-terminal kinase
    stress-activated protein kinase cascades. This response is what converts a
    cell-autonomous translational lesion into a tissue-level inflammatory event.
  downstream:
  - target: Apoptotic Death of Intoxicated Cells
    causal_link_type: DIRECT
    description: >-
      JNK signalling is required for ricin-induced apoptosis in non-transformed
      epithelial cells, so this is a second, signalling-dependent route to the
      same cell death rather than a restatement of the translational one.
    evidence:
    - reference: PMID:19695342
      reference_title: Ricin A-chain requires c-Jun N-terminal kinase to induce apoptosis in nontransformed epithelial cells.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Inhibition of the JNK pathway reduced RTA-induced caspase activation and poly(ADP-ribose) polymerase cleavage."
      explanation: >-
        A loss-of-function test of this exact edge - blocking JNK blunted the
        apoptotic readout.
    - reference: PMID:19695342
      reference_title: Ricin A-chain requires c-Jun N-terminal kinase to induce apoptosis in nontransformed epithelial cells.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "These studies are the first to demonstrate a role for the JNK signaling pathway in ricin-induced cell death."
      explanation: The authors' own statement of what the experiment established.
  - target: Pro-inflammatory Cytokine Release
    causal_link_type: DIRECT
    description: >-
      The same kinase cascades drive cytokine production, which is the branch
      that carries the injury beyond the intoxicated cell.
    evidence:
    - reference: PMID:23133670
      reference_title: Identification of small molecules that suppress ricin-induced stress-activated signaling pathways.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: BACKGROUND
      snippet: "Activation of these and possibly other SAPKs by RTA leads to increased production of pro-inflammatory cytokines and apoptosis-mediated cell death"
      explanation: States that SAPK activation drives cytokine production, which is this edge.
    - reference: PMID:23133670
      reference_title: Identification of small molecules that suppress ricin-induced stress-activated signaling pathways.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "PW66 virtually eliminated ricin-induced TNF-α secretion by J774A.1 macrophages and concomitantly blocked activation of the p38 MAPK and JNK signaling pathways."
      explanation: >-
        A pharmacological test of the edge - a compound that blocked p38 and JNK
        activation abolished the TNF-alpha secretion downstream of it.
  biological_processes:
  - preferred_term: JNK cascade activation by ribotoxic stress
    modifier: INCREASED
    term:
      id: GO:0007254
      label: JNK cascade
  - preferred_term: p38 MAPK cascade activation by ribotoxic stress
    modifier: INCREASED
    term:
      id: GO:0038066
      label: p38MAPK cascade
  evidence:
  - reference: PMID:23133670
    reference_title: Identification of small molecules that suppress ricin-induced stress-activated signaling pathways.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: BACKGROUND
    snippet: "28S rRNA damage stimulates cellular stress-activated protein kinases (SAPK), including p38 mitogen-activated protein kinase (p38 MAPK) and c-Jun N-terminal kinase (JNK) pathways."
    explanation: Names both kinase cascades bound on this node and the lesion that triggers them.
  - reference: PMID:23133670
    reference_title: Identification of small molecules that suppress ricin-induced stress-activated signaling pathways.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: BACKGROUND
    snippet: "The MAP3K, ZAK, has been identified as the being responsible for activating the p38 MAPK and JNK pathways in response to ricin"
    explanation: >-
      Names the sensing kinase. Quoted verbatim including the source's
      grammatical slip, as a snippet must be.
  - reference: PMID:19695342
    reference_title: Ricin A-chain requires c-Jun N-terminal kinase to induce apoptosis in nontransformed epithelial cells.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "RTA activated JNK and p38 in a time- and concentration-dependent manner that preceded increases in apoptosis."
    explanation: >-
      Shows the A chain alone is sufficient to activate both cascades, and that
      activation precedes the death it is here claimed to cause.
- name: Apoptotic Death of Intoxicated Cells
  biological_scale: CELLULAR
  description: >-
    Cells that have taken up enough toxin die, predominantly by apoptosis, with
    caspase activation and PARP cleavage. Two routes converge here: the
    translational collapse itself, and the JNK arm of the ribotoxic stress
    response, which is required for apoptosis in non-transformed epithelium.
    Death is not confined to intoxicated cells - dying cells release ricin, Fas
    ligand and HMGB1 that kill neighbouring epithelium by necroptosis, which is
    how a small delivered dose destroys a whole epithelial surface.
  downstream:
  - target: Acute Lung Injury with Interstitial Pneumonia and Alveolar Edema
    causal_link_type: DIRECT
    description: >-
      After inhalation, epithelial and alveolar macrophage death is the lesion
      that produces the pneumonitis.
    evidence:
    - reference: PMID:36695077
      reference_title: Necroptosis of Lung Epithelial Cells Triggered by Ricin Toxin and Bystander Inflammation.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: BACKGROUND
      snippet: "When inhaled, RT causes near complete destruction of the lung epithelium coincident with a proinflammatory response that includes TNF family cytokines, which are death-inducing ligands."
      explanation: States that inhaled ricin destroys the lung epithelium, which is this edge.
  - target: Hemorrhagic Necrosis of the Gastrointestinal Mucosa
    causal_link_type: DIRECT
    description: >-
      After ingestion, the gut mucosa receives the highest local toxin burden
      and its epithelium is what dies. Left uncited on purpose: nothing in the
      literature cited here tests epithelial death against the mucosal lesion in
      gut the way PMID:36695077 does in lung, and the human autopsy series that
      establishes the lesion says nothing about how the cells died. Note the
      target lesion is haemorrhagic necrosis, which is not the apoptosis this
      node names - the death modes are not asserted to be the same one.
  - target: Hepatic and Renal Parenchymal Injury
    causal_link_type: DIRECT
    description: >-
      Liver and kidney are the constant secondary targets once toxin reaches the
      circulation, whatever the route of entry. Uncited for the same reason as
      the gastrointestinal edge above: the autopsy series establishes that these
      organs are injured, not that apoptosis is what injures them.
  biological_processes:
  - preferred_term: apoptosis of ricin-intoxicated cells
    modifier: INCREASED
    term:
      id: GO:0006915
      label: apoptotic process
  cell_types:
  - preferred_term: intestinal epithelial cell
    term:
      id: CL:0002563
      label: intestinal epithelial cell
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  - preferred_term: alveolar macrophage
    term:
      id: CL:0000583
      label: alveolar macrophage
  evidence:
  - reference: PMID:19695342
    reference_title: Ricin A-chain requires c-Jun N-terminal kinase to induce apoptosis in nontransformed epithelial cells.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Comparable caspase activation was observed with both ricin and RTA treatment in the immortalized, nontransformed epithelial cell line, MAC-T."
    explanation: >-
      Measures the apoptotic readout in non-transformed epithelium, and shows
      the A chain alone reproduces it.
  - reference: PMID:36695077
    reference_title: Necroptosis of Lung Epithelial Cells Triggered by Ricin Toxin and Bystander Inflammation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Upon RT-induced U937 cell death, released RT and FasL contributed to A549 cell death."
    explanation: >-
      The bystander-killing result behind the claim that death is not confined
      to cells that took up toxin themselves.
  - reference: PMID:36695077
    reference_title: Necroptosis of Lung Epithelial Cells Triggered by Ricin Toxin and Bystander Inflammation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The release of RT, FasL, and HMGB1 triggered A549 cell necroptosis, rather than cathepsin-dependent killing observed previously with RT and FasL."
    explanation: >-
      Names the released mediators and the death mode of the bystander cells,
      which is necroptosis rather than the apoptosis of the intoxicated cell.
- name: Pro-inflammatory Cytokine Release
  biological_scale: ORGANISM
  description: >-
    Stress-kinase activation in intoxicated cells, and in macrophages in
    particular, drives release of pro-inflammatory cytokines. Tumour necrosis
    factor alpha rises first, within hours and before any metabolic
    abnormality is measurable; over the following day the response broadens into
    a storm containing both pro- and anti-inflammatory mediators. This is the
    step that turns local cell death into systemic illness, and it accounts for
    fever, neutrophil recruitment and the vascular consequences below.
  downstream:
  - target: Acute Lung Injury with Interstitial Pneumonia and Alveolar Edema
    causal_link_type: DIRECT
    description: >-
      The local pulmonary cytokine storm is what recruits the neutrophils and
      drives the edema that define the lung lesion.
    evidence:
    - reference: PMID:38393180
      reference_title: Long-Term Pulmonary Damage in Surviving Antitoxin-Treated Mice following a Lethal Ricin Intoxication.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: BACKGROUND
      snippet: "This is characterized by a local cytokine storm, extensive neutrophil recruitment, increased pro-oxidant enzyme activity, and the development of proteinaceous pulmonary edema, ultimately leading to respiratory failure and death."
      explanation: >-
        Places the cytokine storm at the head of the sequence that produces
        neutrophil influx and edema, which is what this edge asserts.
    - reference: PMID:38393180
      reference_title: Long-Term Pulmonary Damage in Surviving Antitoxin-Treated Mice following a Lethal Ricin Intoxication.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      quote_role: BACKGROUND
      snippet: "The treatment based on equine antitoxin has demonstrated effective anti-edematous and anti-inflammatory effects, apparently by balancing cytokine levels in the lungs of intoxicated animals"
      explanation: >-
        Indirect support from the treatment side - an intervention that
        normalises lung cytokine levels reduces the edema this edge produces.
  - target: Endothelial Glycocalyx Shedding and Microvascular Hyperpermeability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Systemic inflammatory mediators accompany the vascular injury. The
      glycocalyx study does not isolate cytokines as the cause, so this edge is
      marked indirect rather than asserting a mechanism the source does not test.
    evidence:
    - reference: PMID:34830227
      reference_title: "Intramuscular Exposure to a Lethal Dose of Ricin Toxin Leads to Endothelial Glycocalyx Shedding and Microvascular Flow Abnormality in Mice and Swine."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "Increased levels of circulating VEGF and decreased expression of vascular VE-cadherin caused blood vessel impairment, thereby promoting hyperpermeability in various organs."
      explanation: >-
        Names a circulating mediator and a junctional change as the cause of the
        hyperpermeability, which supports a soluble-mediator route without
        establishing that the SAPK-driven cytokines are that mediator.
  - target: Fever
    causal_link_type: DIRECT
  - target: Increased total leukocyte count
    causal_link_type: DIRECT
  - target: Cytokine-Mediated Suppression of Hepatic Glucose-6-Phosphatase
    causal_link_type: DIRECT
    description: >-
      A distinct, metabolic consequence of the same cytokine response, described
      only in parenterally exposed mice.
    evidence:
    - reference: PMID:36548717
      reference_title: "Parenteral Exposure of Mice to Ricin Toxin Induces Fatal Hypoglycemia by Cytokine-Mediated Suppression of Hepatic Glucose-6-Phosphatase Expression."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      quote_role: BACKGROUND
      snippet: "TNF-α has previously been reported to suppress G6Pase expression."
      explanation: >-
        States the cytokine-to-enzyme link this edge asserts. The paper cites it
        as prior knowledge rather than demonstrating it here, which is why the
        node it points at is labelled as an inference in its own description.
  biological_processes:
  - preferred_term: tumor necrosis factor production after ricin intoxication
    modifier: INCREASED
    term:
      id: GO:0032760
      label: positive regulation of tumor necrosis factor production
  - preferred_term: systemic inflammatory response to ricin
    modifier: INCREASED
    term:
      id: GO:0006954
      label: inflammatory response
  evidence:
  - reference: PMID:36548717
    reference_title: "Parenteral Exposure of Mice to Ricin Toxin Induces Fatal Hypoglycemia by Cytokine-Mediated Suppression of Hepatic Glucose-6-Phosphatase Expression."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Within the first hours following injection, while still normoglycemic, lymphopenia and pro-inflammatory cytokine secretion were observed, particularly tumor necrosis factor (TNF)-α. The cytokine response evolved over the next day into a complex storm of both pro- and anti-inflammatory cytokines."
    explanation: >-
      Establishes the timing and composition of the response this node records -
      TNF-alpha first, broadening into a mixed storm over a day.
  - reference: PMID:23133670
    reference_title: Identification of small molecules that suppress ricin-induced stress-activated signaling pathways.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "PW66 virtually eliminated ricin-induced TNF-α secretion by J774A.1 macrophages and concomitantly blocked activation of the p38 MAPK and JNK signaling pathways."
    explanation: Identifies macrophages as a cellular source of the TNF-alpha this node describes.
  - reference: PMID:42560523
    reference_title: "Medico-legal aspects of fatal ricin poisoning: a systematic review of clinical manifestations, toxicological findings and autopsy results."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "tumor necrosis factor-alpha (TNF-α), accompanied by leukocytosis and thrombocytopenia"
    explanation: >-
      The one human measurement of this node anywhere in the cited literature -
      a near-fatal injection case, in which IL-6, IL-10 and TNF-alpha were all
      markedly elevated. Quoted from the TNF-alpha clause because the review is
      a scanned PDF that hyphen-breaks the words before it.
  - reference: PMID:42560523
    reference_title: "Medico-legal aspects of fatal ricin poisoning: a systematic review of clinical manifestations, toxicological findings and autopsy results."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "the inflammatory response induced by ricin, which may include fever, leukocytosis, thrombocytopenia, and elevated"
    explanation: >-
      The review's summary of what this node produces clinically in humans -
      and the source for the fever phenotype, which is otherwise unevidenced.
  cell_types:
  - preferred_term: alveolar macrophage
    term:
      id: CL:0000583
      label: alveolar macrophage
- name: Acute Lung Injury with Interstitial Pneumonia and Alveolar Edema
  biological_scale: TISSUE
  description: >-
    The inhalational lesion. Airway and alveolar epithelium and alveolar
    macrophages die, a local cytokine storm recruits neutrophils in large
    numbers, the vasculature becomes hyperpermeable, and proteinaceous fluid
    fills the alveoli and pleural space. The picture is acute lung injury and
    can progress to acute respiratory distress syndrome; in lethal animal
    exposures the damage stays largely confined to the lung and death is from
    respiratory insufficiency rather than from distant organ failure.
  notes: >-
    Human inhalational ricin poisoning has essentially no clinical literature -
    no case series exists - so this node is supported entirely by rodent,
    non-human-primate and swine work and is graded `MODEL_ORGANISM` throughout.
    That is a real limitation of the evidence, not a curation shortcut.
  downstream:
  - target: Residual Pulmonary Fibrosis in Survivors
    causal_link_type: DIRECT
    description: >-
      Animals that survive the acute injury repair it imperfectly, leaving
      fibrotic lesions.
    evidence:
    - reference: PMID:38773158
      reference_title: Short- and long-term outcomes of pulmonary exposure to a sublethal dose of ricin in mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "although in the long-term, mice recovered from acute lung damage and restored pulmonary and physiological functionality, the reparative process was associated with lasting fibrotic lesions"
      explanation: States that the repair of this node's injury is what leaves the fibrosis.
  - target: Dyspnea
    causal_link_type: DIRECT
  - target: Pulmonary edema
    causal_link_type: DIRECT
  - target: Interstitial pneumonitis
    causal_link_type: DIRECT
  - target: Acute respiratory distress syndrome
    causal_link_type: DIRECT
    description: >-
      The acute lung injury can evolve into frank ARDS, demonstrated in swine.
    evidence:
    - reference: PMID:38773158
      reference_title: Short- and long-term outcomes of pulmonary exposure to a sublethal dose of ricin in mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: BACKGROUND
      snippet: "This damage to the lungs is classified as acute lung injury, which can develop to acute respiratory distress syndrome (ARDS)"
      explanation: States the progression from this node to that phenotype.
  - target: Respiratory failure
    causal_link_type: DIRECT
  cell_types:
  - preferred_term: pulmonary alveolar type 2 cell
    term:
      id: CL:0002063
      label: pulmonary alveolar type 2 cell
  - preferred_term: alveolar macrophage
    term:
      id: CL:0000583
      label: alveolar macrophage
  - preferred_term: infiltrating neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  locations:
  - preferred_term: lung
    term:
      id: UBERON:0002048
      label: lung
  evidence:
  - reference: PMID:38773158
    reference_title: Short- and long-term outcomes of pulmonary exposure to a sublethal dose of ricin in mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We show that in the short-term, sublethal exposure of mice to ricin resulted in acute lung injury, including interstitial pneumonia, cytokine storm, neutrophil influx, edema and cellular death."
    explanation: Names every component of this node, measured after a sublethal inhaled dose.
  - reference: PMID:38773158
    reference_title: Short- and long-term outcomes of pulmonary exposure to a sublethal dose of ricin in mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: BACKGROUND
    snippet: "the injury is mostly confined to the lungs, including marked interstitial pneumonia associated with pro-inflammatory cytokine release, massive neutrophil infiltration, vascular hyperpermeability, perivascular and alveolar edema, hemorrhages, diffuse airway epithelial cell and alveolar macrophage death"
    explanation: >-
      The lethal-dose picture across rodents and non-human primates, and the
      source of the cell types bound on this node.
  - reference: PMID:37104219
    reference_title: Comparative Aspects of Ricin Toxicity by Inhalation.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: REVIEW_SYNTHESIS
    snippet: "The toxicity and associated pathology described in animal models are broadly similar, but variation appears to exist."
    explanation: >-
      Supports treating the animal inhalation picture as one coherent lesion
      while recording that the models are not identical.
- name: Residual Pulmonary Fibrosis in Survivors
  biological_scale: TISSUE
  description: >-
    Survivors of pulmonary ricin exposure do not necessarily return to normal.
    Mice that recovered from a sublethal challenge carried lasting fibrotic
    lesions, and mice rescued from a lethal challenge by antitoxin showed
    moderate fibrosis, increased lung hyperpermeability and decreased lung
    compliance a month later. Whether the same holds in human survivors is
    unknown - no human follow-up data exist.
  downstream:
  - target: Pulmonary fibrosis
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:38393180
    reference_title: Long-Term Pulmonary Damage in Surviving Antitoxin-Treated Mice following a Lethal Ricin Intoxication.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Significant pulmonary sequelae were demonstrated in surviving antitoxin-treated mice, as reflected by prominent histopathological changes, moderate fibrosis, increased lung hyperpermeability, and decreased lung compliance."
    explanation: The measured sequelae in antitoxin-rescued animals, thirty days after exposure.
  - reference: PMID:37104219
    reference_title: Comparative Aspects of Ricin Toxicity by Inhalation.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: REVIEW_SYNTHESIS
    snippet: "Fibrosis may follow acute lung injury in survivors."
    explanation: Independent statement of the same sequela, from a review of the inhalation models.
  locations:
  - preferred_term: lung
    term:
      id: UBERON:0002048
      label: lung
- name: Hemorrhagic Necrosis of the Gastrointestinal Mucosa
  biological_scale: TISSUE
  description: >-
    The ingestion lesion, and the only one with a substantial human clinical
    literature. Enterocyte death produces an acute gastroenteritis with
    vomiting, colicky pain and diarrhoea that can be bloody, and the fluid and
    electrolyte losses it causes are what threatens the patient in the first day.
    Hemorrhagic necrosis of the gastrointestinal tract is among the consistent
    autopsy findings in fatal cases.
  downstream:
  - target: Nausea
    causal_link_type: DIRECT
  - target: Vomiting
    causal_link_type: DIRECT
  - target: Diarrhea
    causal_link_type: DIRECT
  - target: Abdominal pain
    causal_link_type: DIRECT
  - target: Gastrointestinal hemorrhage
    causal_link_type: DIRECT
  - target: Dehydration
    causal_link_type: DIRECT
    description: >-
      Fluid and electrolyte loss through the injured mucosa is what causes the
      volume depletion.
    evidence:
    - reference: PMID:33711365
      reference_title: "Ricin poisoning: A review on contamination source, diagnosis, treatment, prevention and reporting of ricin poisoning."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "Intoxication by castor bean is characterized by acute gastroenteritis-like disease as primary manifestations leading to severe fluid and electrolyte imbalance."
      explanation: States the gastroenteritis-to-fluid-loss link this edge asserts.
  - target: Distributive and Hypovolemic Shock with Multi-Organ Failure
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      The volume lost through the injured gut is one of the two routes into
      shock, the other being the vascular injury below.
    evidence:
    - reference: PMID:33711365
      reference_title: "Ricin poisoning: A review on contamination source, diagnosis, treatment, prevention and reporting of ricin poisoning."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "The mechanism of death was peripheral vascular collapse and progressing multiple organ failure occurring 10h-72h after intoxication."
      explanation: >-
        Names the terminal state this edge points at, in a case series where the
        exposure was by ingestion. The intermediate - volume depletion - is
        stated separately in the same review rather than in this sentence.
  cell_types:
  - preferred_term: enterocyte
    term:
      id: CL:0000584
      label: enterocyte
  locations:
  - preferred_term: small intestine
    term:
      id: UBERON:0002108
      label: small intestine
  evidence:
  - reference: PMID:42560523
    reference_title: "Medico-legal aspects of fatal ricin poisoning: a systematic review of clinical manifestations, toxicological findings and autopsy results."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Reported autopsy findings commonly included hemolysis, hemorrhagic necrosis of the gastrointestinal tract, hepatic injury, renal tubular necrosis, and evidence supporting the presence of a capillary leak syndrome."
    explanation: Establishes hemorrhagic gastrointestinal necrosis as a consistent human autopsy finding.
  - reference: PMID:39210364
    reference_title: "Ricin intoxication by lethal dose of castor seeds ingestion: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "admitted to the emergency department with symptoms of colicky abdominal pain, diarrhea, and vomiting following the ingestion of six castor beans"
    explanation: The clinical face of this lesion in a documented castor-seed ingestion.
- name: Hepatic and Renal Parenchymal Injury
  biological_scale: TISSUE
  description: >-
    Liver and kidney are the constant secondary targets. In survivable
    poisoning this appears as mild, reversible transaminase and creatinine
    derangement that recovers over days; at autopsy in fatal cases it appears as
    hepatic injury and renal tubular necrosis.
  downstream:
  - target: Hemolytic anemia
    causal_link_type: DIRECT
  - target: Hepatic necrosis
    causal_link_type: DIRECT
  - target: Abnormal liver physiology
    causal_link_type: DIRECT
  - target: Acute kidney injury
    causal_link_type: DIRECT
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  - preferred_term: epithelial cell of proximal tubule
    term:
      id: CL:0002306
      label: epithelial cell of proximal tubule
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  evidence:
  - reference: PMID:42560523
    reference_title: "Medico-legal aspects of fatal ricin poisoning: a systematic review of clinical manifestations, toxicological findings and autopsy results."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Reported autopsy findings commonly included hemolysis, hemorrhagic necrosis of the gastrointestinal tract, hepatic injury, renal tubular necrosis, and evidence supporting the presence of a capillary leak syndrome."
    explanation: Names both organ lesions this node records, from fatal human cases.
  - reference: PMID:32991682
    reference_title: "Non-Lethal Intoxication by Ingestion of 50 Castor Beans: Serial Measurement of Ricinine in Blood, Plasma and Urine."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Initial laboratory tests showed a slightly elevated C-reactive protein and mild liver and kidney dysfunction."
    explanation: >-
      The survivable form of the same injury - mild and reversible - after an
      ingestion of fifty castor beans.
  - reference: PMID:32991682
    reference_title: "Non-Lethal Intoxication by Ingestion of 50 Castor Beans: Serial Measurement of Ricinine in Blood, Plasma and Urine."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "During the next days, the kidney function improved and liver function started to recover."
    explanation: Supports the reversibility this node asserts for the non-fatal form.
- name: Endothelial Glycocalyx Shedding and Microvascular Hyperpermeability
  biological_scale: TISSUE
  description: >-
    After parenteral exposure ricin binds preferentially to the vasculature.
    Circulating heparan sulfate, hyaluronic acid and syndecan-1 rise, marking
    extensive degradation of the endothelial glycocalyx; VEGF rises and
    endothelial VE-cadherin falls, so interendothelial junctions fail and
    organs become hyperpermeable. Intravital imaging shows aberrant blood flow
    and a fall in the number of perfused microvessels. Clinically this is the
    capillary leak syndrome, coagulopathy and widespread hemorrhage of severe
    systemic poisoning.
  downstream:
  - target: Capillary leak
    causal_link_type: DIRECT
  - target: Thrombocytopenia
    causal_link_type: DIRECT
  - target: Abnormality of coagulation
    causal_link_type: DIRECT
  - target: Abnormal bleeding
    causal_link_type: DIRECT
  - target: Distributive and Hypovolemic Shock with Multi-Organ Failure
    causal_link_type: DIRECT
    description: >-
      Loss of vascular barrier function and microvascular perfusion is the
      second, parenteral-dominant route into shock.
    evidence:
    - reference: PMID:34830227
      reference_title: "Intramuscular Exposure to a Lethal Dose of Ricin Toxin Leads to Endothelial Glycocalyx Shedding and Microvascular Flow Abnormality in Mice and Swine."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "These findings, which suggest that glycocalyx shedding and microcirculation dysfunction play a major role in the pathology of systemic ricin poisoning"
      explanation: The authors' own statement that this node drives systemic pathology.
  cell_types:
  - preferred_term: endothelial cell of vascular tree
    term:
      id: CL:0002139
      label: endothelial cell of vascular tree
  evidence:
  - reference: PMID:34830227
    reference_title: "Intramuscular Exposure to a Lethal Dose of Ricin Toxin Leads to Endothelial Glycocalyx Shedding and Microvascular Flow Abnormality in Mice and Swine."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "following intramuscular administration, ricin bound preferentially to the vasculature in both mice and swine, leading to coagulopathy and widespread hemorrhages"
    explanation: Establishes the vascular tropism and its coagulopathic consequence in two species.
  - reference: PMID:34830227
    reference_title: "Intramuscular Exposure to a Lethal Dose of Ricin Toxin Leads to Endothelial Glycocalyx Shedding and Microvascular Flow Abnormality in Mice and Swine."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Elevated levels of soluble heparan sulfate, hyaluronic acid and syndecan-1 were measured in blood samples following ricin intoxication, indicating that the vascular glycocalyx of both mice and swine underwent extensive damage."
    explanation: The three shed glycocalyx components this node names, and the inference the authors draw from them.
  - reference: PMID:34830227
    reference_title: "Intramuscular Exposure to a Lethal Dose of Ricin Toxin Leads to Endothelial Glycocalyx Shedding and Microvascular Flow Abnormality in Mice and Swine."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "we determined that ricin poisoning leads to microvasculature malfunctioning, as manifested by aberrant blood flow and a significant decrease in the number of diffused microvessels"
    explanation: The intravital-imaging result behind the microvascular perfusion claim.
  - reference: PMID:42560523
    reference_title: "Medico-legal aspects of fatal ricin poisoning: a systematic review of clinical manifestations, toxicological findings and autopsy results."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "evidence supporting the presence of a capillary leak syndrome"
    explanation: >-
      The human counterpart of the animal glycocalyx work - autopsy evidence of
      capillary leak in fatal human cases.
  - reference: PMID:31208156
    reference_title: "Intramuscular Ricin Poisoning of Mice Leads to Widespread Damage in the Heart, Spleen, and Bone Marrow."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Along with prompt coagulopathy, multi-organ hemorrhages, and thrombocytopenia, ricin induced profound morpho-pathological and functional damage in the spleen, bone marrow, and cardiovascular system."
    explanation: Independent confirmation of the coagulopathy, hemorrhage and thrombocytopenia triad this node produces.
- name: Cytokine-Mediated Suppression of Hepatic Glucose-6-Phosphatase
  biological_scale: MOLECULAR
  description: >-
    A separate lethal mechanism layered on top of direct cytotoxicity, described
    only in parenterally exposed mice. Hepatic glucose-6-phosphatase RNA and
    protein fall rapidly and persistently, glucose-6-phosphate drops and
    glycogen accumulates - the biochemical signature of blocked glucose output -
    and the animals become profoundly hypoglycaemic before any other laboratory
    abnormality appears. Blood glucose fell even in animals whose beta cells had
    been destroyed with streptozotocin, which argues against an insulin-driven
    explanation.
  notes: >-
    Model-organism only, and deliberately not promoted to a human phenotype. The
    paper notes hypoglycaemia has been observed but not commented on in porcine
    and human intoxication, which is an observation about the literature rather
    than a human finding, so the phenotype below is graded `MODEL_ORGANISM` and
    carries no human frequency.
  downstream:
  - target: Hypoglycemia
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:36548717
    reference_title: "Parenteral Exposure of Mice to Ricin Toxin Induces Fatal Hypoglycemia by Cytokine-Mediated Suppression of Hepatic Glucose-6-Phosphatase Expression."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In the liver, we observed a rapid and persistent decrease in the expression of glucose-6-phosphatase (G6Pase) RNA and protein levels, accompanied by a drop in glucose-6-phosphate and increase in glycogen."
    explanation: The measured enzyme and metabolite changes this node records.
  - reference: PMID:36548717
    reference_title: "Parenteral Exposure of Mice to Ricin Toxin Induces Fatal Hypoglycemia by Cytokine-Mediated Suppression of Hepatic Glucose-6-Phosphatase Expression."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Drops in blood glucose were observed even after destruction of β-cells with streptozotocin."
    explanation: The control experiment behind the claim that this is not an insulin-mediated hypoglycaemia.
- name: Distributive and Hypovolemic Shock with Multi-Organ Failure
  biological_scale: ORGANISM
  description: >-
    The terminal common pathway. Volume lost through the injured gut, plasma
    lost through a leaking microvasculature, and vasodilatation together produce
    circulatory collapse; hepatic, renal, splenic, cardiac and bone-marrow
    injury accumulate, and death follows from refractory cardiovascular collapse
    typically between ten and seventy-two hours after exposure. This convergence
    is what makes the route of exposure matter for dose and tempo but not for
    the way severe poisoning ends.
  downstream:
  - target: Hypotension
    causal_link_type: DIRECT
  - target: Hypovolemic shock
    causal_link_type: DIRECT
  - target: Bidirectional ventricular tachycardia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Ventricular arrhythmia on a background of toxin-induced myocardial injury.
      Drawn as indirect because the one human case proposing this mechanism
      offers it as a hypothesis, having excluded re-entry rather than
      demonstrated triggered activity.
    evidence:
    - reference: PMID:41788434
      reference_title: "Bidirectional ventricular tachycardia following ricin intoxication: a case report."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "A likely mechanism involves toxin-induced myocardial injury resulting in increased automaticity or triggered activity."
      explanation: >-
        The proposed mechanism, stated by the authors as likely rather than
        shown, which is what makes this edge indirect.
  evidence:
  - reference: PMID:33711365
    reference_title: "Ricin poisoning: A review on contamination source, diagnosis, treatment, prevention and reporting of ricin poisoning."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "The mechanism of death was peripheral vascular collapse and progressing multiple organ failure occurring 10h-72h after intoxication."
    explanation: Names the mechanism of death and its timing, from fifty collected human cases.
  - reference: PMID:42560523
    reference_title: "Medico-legal aspects of fatal ricin poisoning: a systematic review of clinical manifestations, toxicological findings and autopsy results."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "characterized by rapid progression from mild, nonspecific gastrointestinal symptoms to hypovolemic shock, multi-organ failure, and refractory cardiovascular collapse"
    explanation: Independent statement of the same terminal sequence, from a systematic review of fatal cases.
  - reference: PMID:31208156
    reference_title: "Intramuscular Ricin Poisoning of Mice Leads to Widespread Damage in the Heart, Spleen, and Bone Marrow."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In the heart, diffuse hemorrhages, myocyte necrosis, collagen deposition, and induction in fibrinogen were observed."
    explanation: >-
      The cardiac component of the multi-organ failure, which in the parenteral
      model is a structural lesion rather than only a perfusion failure.
phenotypes:
- category: Gastrointestinal
  name: Vomiting
  description: >-
    Part of the early gastroenteritis of ingestion exposure, typically beginning
    within hours of chewing castor seeds.
  phenotype_term:
    preferred_term: Vomiting
    term:
      id: HP:0002013
      label: Vomiting
    temporality: ACUTE
  evidence:
  - reference: PMID:39210364
    reference_title: "Ricin intoxication by lethal dose of castor seeds ingestion: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "admitted to the emergency department with symptoms of colicky abdominal pain, diarrhea, and vomiting following the ingestion of six castor beans"
    explanation: Names vomiting among the presenting features after a documented castor-seed ingestion.
  - reference: PMID:32991682
    reference_title: "Non-Lethal Intoxication by Ingestion of 50 Castor Beans: Serial Measurement of Ricinine in Blood, Plasma and Urine."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Her symptoms on admission were vomiting, diarrhea, abdominal cramps, agitation and anxiety."
    explanation: Independent case with the same presenting symptom set.
- category: Gastrointestinal
  name: Diarrhea
  description: >-
    Often profuse and sometimes bloody. With vomiting it drives the fluid and
    electrolyte losses that dominate early management.
  phenotype_term:
    preferred_term: Diarrhea
    term:
      id: HP:0002014
      label: Diarrhea
    temporality: ACUTE
  evidence:
  - reference: PMID:32991682
    reference_title: "Non-Lethal Intoxication by Ingestion of 50 Castor Beans: Serial Measurement of Ricinine in Blood, Plasma and Urine."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Her symptoms on admission were vomiting, diarrhea, abdominal cramps, agitation and anxiety."
    explanation: Names diarrhoea among the presenting features.
  - reference: PMID:33711365
    reference_title: "Ricin poisoning: A review on contamination source, diagnosis, treatment, prevention and reporting of ricin poisoning."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Intoxication by castor bean is characterized by acute gastroenteritis-like disease as primary manifestations leading to severe fluid and electrolyte imbalance."
    explanation: Places the diarrhoeal illness at the centre of the ingestion syndrome across fifty collected cases.
- category: Gastrointestinal
  name: Abdominal pain
  description: Colicky, accompanying the vomiting and diarrhoea of the ingestion syndrome.
  phenotype_term:
    preferred_term: Abdominal pain
    term:
      id: HP:0002027
      label: Abdominal pain
    temporality: ACUTE
  evidence:
  - reference: PMID:39210364
    reference_title: "Ricin intoxication by lethal dose of castor seeds ingestion: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "symptoms of colicky abdominal pain, diarrhea, and vomiting"
    explanation: Names the pain and its colicky character.
- category: Gastrointestinal
  name: Gastrointestinal hemorrhage
  description: >-
    Bleeding from the necrotic mucosa. Hemorrhagic necrosis of the
    gastrointestinal tract is among the consistent autopsy findings in fatal
    ricin poisoning.
  phenotype_term:
    preferred_term: Gastrointestinal hemorrhage
    term:
      id: HP:0002239
      label: Gastrointestinal hemorrhage
    temporality: ACUTE
  evidence:
  - reference: PMID:42560523
    reference_title: "Medico-legal aspects of fatal ricin poisoning: a systematic review of clinical manifestations, toxicological findings and autopsy results."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Reported autopsy findings commonly included hemolysis, hemorrhagic necrosis of the gastrointestinal tract, hepatic injury, renal tubular necrosis, and evidence supporting the presence of a capillary leak syndrome."
    explanation: Establishes gastrointestinal haemorrhagic necrosis as a consistent postmortem finding.
- category: Constitutional
  name: Dehydration
  description: >-
    Volume depletion from gastrointestinal losses, and the proximate reason
    early rehydration is the intervention that changes outcome in ingestion
    cases.
  phenotype_term:
    preferred_term: Dehydration
    term:
      id: HP:0001944
      label: Dehydration
    temporality: ACUTE
  evidence:
  - reference: PMID:33711365
    reference_title: "Ricin poisoning: A review on contamination source, diagnosis, treatment, prevention and reporting of ricin poisoning."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "leading to severe fluid and electrolyte imbalance"
    explanation: States the fluid loss this phenotype records.
- category: Respiratory
  name: Dyspnea
  description: >-
    Breathlessness as alveolar flooding and pneumonitis develop. Reported
    directly in a human parenteral case; after inhalation it is inferred from
    measured loss of lung function in animals.
  notes: >-
    Human inhalational ricin poisoning has no published case series, so the
    other respiratory phenotypes here are supported through the animal
    inhalation literature rather than through human cohorts. This one is the
    exception - a human case reports it, by the injection route.
  phenotype_term:
    preferred_term: Dyspnea
    term:
      id: HP:0002094
      label: Dyspnea
    temporality: ACUTE
  evidence:
  - reference: PMID:42560523
    reference_title: "Medico-legal aspects of fatal ricin poisoning: a systematic review of clinical manifestations, toxicological findings and autopsy results."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "experienced nausea, vomiting, diarrhea, dyspnea, vertigo, and myalgia within the first 24 h"
    explanation: >-
      A human case of parenteral ricin poisoning reporting dyspnoea directly,
      from the review's case-by-case synthesis.
  - reference: PMID:38773158
    reference_title: Short- and long-term outcomes of pulmonary exposure to a sublethal dose of ricin in mice.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "This damage was manifested in reduced lung performance and physiological function."
    explanation: >-
      The animal correlate after the inhalational route - measured lung
      performance rather than a reported symptom, which is why it is indirect.
- category: Respiratory
  name: Pulmonary edema
  description: >-
    Proteinaceous alveolar and perivascular fluid, the defining lesion of
    inhalational ricin exposure in every animal model studied.
  phenotype_term:
    preferred_term: Pulmonary edema
    term:
      id: HP:0100598
      label: Pulmonary edema
    temporality: ACUTE
  evidence:
  - reference: PMID:38773158
    reference_title: Short- and long-term outcomes of pulmonary exposure to a sublethal dose of ricin in mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "sublethal exposure of mice to ricin resulted in acute lung injury, including interstitial pneumonia, cytokine storm, neutrophil influx, edema and cellular death"
    explanation: Names oedema among the components of the acute lung injury.
  - reference: PMID:42560523
    reference_title: "Medico-legal aspects of fatal ricin poisoning: a systematic review of clinical manifestations, toxicological findings and autopsy results."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Frequently reported observations included hemorrhagic gastrointestinal injury, hepatic necrosis, renal tubular damage, pulmonary edema, and serosal effusions"
    explanation: >-
      Pulmonary oedema among the human autopsy findings, so this phenotype is
      not animal-only even though the inhalational route is.
  - reference: PMID:38393180
    reference_title: Long-Term Pulmonary Damage in Surviving Antitoxin-Treated Mice following a Lethal Ricin Intoxication.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: BACKGROUND
    snippet: "the development of proteinaceous pulmonary edema, ultimately leading to respiratory failure and death"
    explanation: Characterises the oedema as proteinaceous and names its consequence.
- category: Respiratory
  name: Interstitial pneumonitis
  description: >-
    Marked interstitial pneumonia with massive neutrophil infiltration,
    documented across rodent and non-human-primate inhalation models.
  phenotype_term:
    preferred_term: Interstitial pneumonitis
    term:
      id: HP:0006515
      label: Interstitial pneumonitis
    temporality: ACUTE
  evidence:
  - reference: PMID:38773158
    reference_title: Short- and long-term outcomes of pulmonary exposure to a sublethal dose of ricin in mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: BACKGROUND
    snippet: "marked interstitial pneumonia associated with pro-inflammatory cytokine release, massive neutrophil infiltration"
    explanation: Names the lesion and the infiltrate this phenotype records.
- category: Respiratory
  name: Acute respiratory distress syndrome
  description: >-
    The acute lung injury of inhalational exposure can progress to frank ARDS,
    shown in swine.
  phenotype_term:
    preferred_term: Acute respiratory distress syndrome
    term:
      id: HP:0033677
      label: Acute respiratory distress syndrome
    temporality: ACUTE
  evidence:
  - reference: PMID:38773158
    reference_title: Short- and long-term outcomes of pulmonary exposure to a sublethal dose of ricin in mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: BACKGROUND
    snippet: "This damage to the lungs is classified as acute lung injury, which can develop to acute respiratory distress syndrome (ARDS)"
    explanation: States the progression to ARDS.
  - reference: PMID:32481526
    reference_title: Post-Exposure Anti-Ricin Treatment Protects Swine Against Lethal Systemic and Pulmonary Exposures.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: BACKGROUND
    snippet: "the swine animal model served us in the past to determine that pulmonary exposure to ricin leads to the development of bona fide acute respiratory distress syndrome"
    explanation: >-
      The large-animal result behind the ARDS claim, in the species chosen for
      its cardiopulmonary resemblance to humans.
- category: Respiratory
  name: Respiratory failure
  description: The terminal event of inhalational exposure in lethal animal challenge.
  phenotype_term:
    preferred_term: Respiratory failure
    term:
      id: HP:0002878
      label: Respiratory failure
    temporality: ACUTE
  evidence:
  - reference: PMID:38393180
    reference_title: Long-Term Pulmonary Damage in Surviving Antitoxin-Treated Mice following a Lethal Ricin Intoxication.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: BACKGROUND
    snippet: "the development of proteinaceous pulmonary edema, ultimately leading to respiratory failure and death"
    explanation: Names respiratory failure as the terminal event of the pulmonary lesion.
- category: Respiratory
  name: Pulmonary fibrosis
  description: >-
    A late sequela in survivors of pulmonary exposure, documented in mice up to
    a month after a lethal challenge survived on antitoxin. No human follow-up
    data exist.
  phenotype_term:
    preferred_term: Pulmonary fibrosis
    term:
      id: HP:0002206
      label: Pulmonary fibrosis
    clinical_course: PROGRESSIVE
  notes: >-
    `clinical_course: PROGRESSIVE` is the model-organism reading; the
    inhalation-model review explicitly lists self-limiting, progressive,
    persistent and resolving fibrosis as distinguishable possibilities that the
    choice of species determines, so this is not a settled property of the
    disease in humans.
  evidence:
  - reference: PMID:38393180
    reference_title: Long-Term Pulmonary Damage in Surviving Antitoxin-Treated Mice following a Lethal Ricin Intoxication.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "prominent histopathological changes, moderate fibrosis, increased lung hyperpermeability, and decreased lung compliance"
    explanation: The measured sequelae thirty days after a survived lethal pulmonary challenge.
  - reference: PMID:37104219
    reference_title: Comparative Aspects of Ricin Toxicity by Inhalation.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: REVIEW_SYNTHESIS
    snippet: "Fibrosis may follow acute lung injury in survivors."
    explanation: Independent statement of the sequela across the inhalation models.
  - reference: PMID:37104219
    reference_title: Comparative Aspects of Ricin Toxicity by Inhalation.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: REVIEW_SYNTHESIS
    snippet: "the nature of the fibrosis (e.g., self-limiting, progressive, persistent or resolving)"
    explanation: >-
      Source of the caveat in `notes` - the course of the fibrosis is a property
      of the model chosen, not an established feature of the human disease.
- category: Hepatic
  name: Hepatic necrosis
  description: Hepatic injury is a consistent postmortem finding in fatal ricin poisoning.
  phenotype_term:
    preferred_term: Hepatic necrosis
    term:
      id: HP:0002605
      label: Hepatic necrosis
    temporality: ACUTE
  evidence:
  - reference: PMID:42560523
    reference_title: "Medico-legal aspects of fatal ricin poisoning: a systematic review of clinical manifestations, toxicological findings and autopsy results."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Frequently reported observations included hemorrhagic gastrointestinal injury, hepatic necrosis, renal tubular damage, pulmonary edema, and serosal effusions"
    explanation: >-
      Names hepatic necrosis directly, in the review's own summary of the
      autopsy series.
- category: Hepatic
  name: Abnormal liver physiology
  description: >-
    Deranged liver function in survivable poisoning, typically mild and
    recovering over days.
  phenotype_term:
    preferred_term: liver dysfunction
    term:
      id: HP:0031865
      label: Abnormal liver physiology
    temporality: TRANSIENT
  notes: >-
    Bound at the level the source reports. The case report says "mild liver
    dysfunction" and names no analyte, so
    `HP:0031956` Elevated circulating aspartate aminotransferase concentration -
    which an earlier draft used - would have been a manufactured narrower match.
  evidence:
  - reference: PMID:32991682
    reference_title: "Non-Lethal Intoxication by Ingestion of 50 Castor Beans: Serial Measurement of Ricinine in Blood, Plasma and Urine."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Initial laboratory tests showed a slightly elevated C-reactive protein and mild liver and kidney dysfunction."
    explanation: Records the mild liver dysfunction this phenotype names.
- category: Renal
  name: Acute kidney injury
  description: >-
    Renal tubular necrosis at autopsy in fatal cases; mild, reversible renal
    dysfunction in survivors.
  phenotype_term:
    preferred_term: Acute kidney injury
    term:
      id: HP:0001919
      label: Acute kidney injury
    temporality: ACUTE
  evidence:
  - reference: PMID:42560523
    reference_title: "Medico-legal aspects of fatal ricin poisoning: a systematic review of clinical manifestations, toxicological findings and autopsy results."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "renal tubular necrosis, and evidence supporting the presence of a capillary leak syndrome"
    explanation: Names renal tubular necrosis among the consistent autopsy lesions.
  - reference: PMID:32991682
    reference_title: "Non-Lethal Intoxication by Ingestion of 50 Castor Beans: Serial Measurement of Ricinine in Blood, Plasma and Urine."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "During the next days, the kidney function improved and liver function started to recover."
    explanation: The reversible form of the same injury in a survivor.
- category: Cardiovascular
  name: Hypotension
  description: Circulatory failure from combined volume loss and vasodilatation.
  phenotype_term:
    preferred_term: Hypotension
    term:
      id: HP:0002615
      label: Hypotension
    temporality: ACUTE
  evidence:
  - reference: PMID:42560523
    reference_title: "Medico-legal aspects of fatal ricin poisoning: a systematic review of clinical manifestations, toxicological findings and autopsy results."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Shock was typically characterized by profound hypotension that remained refractory to aggressive fluid resuscitation and high-dose vasopressor therapy"
    explanation: >-
      Names the hypotension directly, and records that it resists the treatment
      this entry lists as first-line.
  - reference: PMID:33711365
    reference_title: "Ricin poisoning: A review on contamination source, diagnosis, treatment, prevention and reporting of ricin poisoning."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "The mechanism of death was peripheral vascular collapse and progressing multiple organ failure"
    explanation: >-
      Names peripheral vascular collapse in the collected human cases. It does
      not use the word hypotension, which is why it is marked indirect.
- category: Cardiovascular
  name: Hypovolemic shock
  description: >-
    The convergence point of severe poisoning by any route, and the immediate
    antecedent of death in fatal cases.
  phenotype_term:
    preferred_term: Hypovolemic shock
    term:
      id: HP:0031274
      label: Hypovolemic shock
    temporality: ACUTE
  evidence:
  - reference: PMID:42560523
    reference_title: "Medico-legal aspects of fatal ricin poisoning: a systematic review of clinical manifestations, toxicological findings and autopsy results."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "rapid progression from mild, nonspecific gastrointestinal symptoms to hypovolemic shock, multi-organ failure, and refractory cardiovascular collapse"
    explanation: Names hypovolaemic shock as the step between the prodrome and death.
- category: Hematologic
  name: Thrombocytopenia
  description: >-
    Part of the coagulopathy of systemic exposure, documented in mouse and swine
    parenteral models.
  phenotype_term:
    preferred_term: Thrombocytopenia
    term:
      id: HP:0001873
      label: Thrombocytopenia
    temporality: ACUTE
  evidence:
  - reference: PMID:31208156
    reference_title: "Intramuscular Ricin Poisoning of Mice Leads to Widespread Damage in the Heart, Spleen, and Bone Marrow."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Along with prompt coagulopathy, multi-organ hemorrhages, and thrombocytopenia, ricin induced profound morpho-pathological and functional damage in the spleen, bone marrow, and cardiovascular system."
    explanation: Names thrombocytopenia in the intramuscular murine model.
  - reference: PMID:42560523
    reference_title: "Medico-legal aspects of fatal ricin poisoning: a systematic review of clinical manifestations, toxicological findings and autopsy results."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "accompanied by leukocytosis and thrombocytopenia"
    explanation: >-
      The human counterpart, in a near-fatal injection case whose cytokine
      profile is quoted on the cytokine-release node.
- category: Hematologic
  name: Abnormality of coagulation
  description: >-
    Coagulopathy accompanying systemic exposure, reported promptly after
    intramuscular ricin in mice.
  phenotype_term:
    preferred_term: coagulopathy
    term:
      id: HP:0001928
      label: Abnormality of coagulation
    temporality: ACUTE
  notes: >-
    Bound at the level the sources actually report. No cited reference names a
    specific clotting time, so `HP:0008151` Prolonged prothrombin time - which
    an earlier draft of this entry used - would have been a manufactured
    narrower match.
  evidence:
  - reference: PMID:31208156
    reference_title: "Intramuscular Ricin Poisoning of Mice Leads to Widespread Damage in the Heart, Spleen, and Bone Marrow."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Along with prompt coagulopathy, multi-organ hemorrhages, and thrombocytopenia"
    explanation: Names the coagulopathy this phenotype records.
- category: Hematologic
  name: Abnormal bleeding
  description: >-
    Widespread haemorrhage into multiple organs, the clinical face of the
    vascular injury and coagulopathy of systemic exposure.
  phenotype_term:
    preferred_term: Abnormal bleeding
    term:
      id: HP:0001892
      label: Abnormal bleeding
    temporality: ACUTE
  evidence:
  - reference: PMID:34830227
    reference_title: "Intramuscular Exposure to a Lethal Dose of Ricin Toxin Leads to Endothelial Glycocalyx Shedding and Microvascular Flow Abnormality in Mice and Swine."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "ricin bound preferentially to the vasculature in both mice and swine, leading to coagulopathy and widespread hemorrhages"
    explanation: Names the widespread haemorrhage and its vascular cause, in two species.
- category: Gastrointestinal
  name: Nausea
  description: Part of the early gastroenteritis, and also reported after injection.
  phenotype_term:
    preferred_term: Nausea
    term:
      id: HP:0002018
      label: Nausea
    temporality: ACUTE
  evidence:
  - reference: PMID:32991682
    reference_title: "Non-Lethal Intoxication by Ingestion of 50 Castor Beans: Serial Measurement of Ricinine in Blood, Plasma and Urine."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Her symptoms on admission were vomiting, diarrhea, abdominal cramps, agitation and anxiety."
    explanation: >-
      Records the gastroenteritis this phenotype belongs to. The abstract lists
      vomiting rather than nausea, so the human case reporting nausea by name
      is the item below.
  - reference: PMID:42560523
    reference_title: "Medico-legal aspects of fatal ricin poisoning: a systematic review of clinical manifestations, toxicological findings and autopsy results."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "experienced nausea, vomiting, diarrhea, dyspnea, vertigo, and myalgia within the first 24 h"
    explanation: Names nausea directly, in a human parenteral case.
- category: Constitutional
  name: Fever
  description: >-
    Part of the systemic inflammatory response, alongside leukocytosis and
    thrombocytopenia, and one of the features that makes ricin poisoning
    resemble septic shock.
  phenotype_term:
    preferred_term: Fever
    term:
      id: HP:0001945
      label: Fever
    temporality: ACUTE
  evidence:
  - reference: PMID:42560523
    reference_title: "Medico-legal aspects of fatal ricin poisoning: a systematic review of clinical manifestations, toxicological findings and autopsy results."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "the inflammatory response induced by ricin, which may include fever, leukocytosis, thrombocytopenia, and elevated"
    explanation: >-
      Names fever as part of the inflammatory response, in the passage
      explaining why this poisoning is mistaken for sepsis.
- category: Hematologic
  name: Increased total leukocyte count
  description: Leukocytosis accompanying the systemic inflammatory response.
  phenotype_term:
    preferred_term: leukocytosis
    term:
      id: HP:0001974
      label: Increased total leukocyte count
    temporality: ACUTE
  evidence:
  - reference: PMID:42560523
    reference_title: "Medico-legal aspects of fatal ricin poisoning: a systematic review of clinical manifestations, toxicological findings and autopsy results."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "accompanied by leukocytosis and thrombocytopenia"
    explanation: Names the leukocytosis, in a near-fatal human injection case.
- category: Hematologic
  name: Hemolytic anemia
  description: >-
    Haemolysis is reported among the autopsy findings of fatal human ricin
    poisoning.
  phenotype_term:
    preferred_term: hemolysis
    term:
      id: HP:0001878
      label: Hemolytic anemia
    temporality: ACUTE
  notes: >-
    Bound to the nearest available HPO term. The sources report haemolysis as an
    autopsy finding and do not report an anaemia, so the binding is broader in
    one direction and narrower in another; `preferred_term` records what the
    source actually says.
  evidence:
  - reference: PMID:42560523
    reference_title: "Medico-legal aspects of fatal ricin poisoning: a systematic review of clinical manifestations, toxicological findings and autopsy results."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Reported autopsy findings commonly included hemolysis"
    explanation: Names haemolysis first among the consistent autopsy findings.
- category: Cardiovascular
  name: Capillary leak
  description: >-
    Increased vascular permeability with loss of plasma into the interstitium.
    The review of fatal human cases places it, with endothelial injury, at the
    centre of the pathophysiology rather than at its periphery.
  phenotype_term:
    preferred_term: Capillary leak
    term:
      id: HP:0030005
      label: Capillary leak
    temporality: ACUTE
  evidence:
  - reference: PMID:42560523
    reference_title: "Medico-legal aspects of fatal ricin poisoning: a systematic review of clinical manifestations, toxicological findings and autopsy results."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "evidence supporting the presence of a capillary leak syndrome"
    explanation: The autopsy evidence for this phenotype in fatal human cases.
  - reference: PMID:42560523
    reference_title: "Medico-legal aspects of fatal ricin poisoning: a systematic review of clinical manifestations, toxicological findings and autopsy results."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "collectively supporting the hypothesis that endothelial injury and capillary leak syndrome play a central role in the pathophysiology of fatal ricin poisoning"
    explanation: >-
      States how central the review takes this to be, which is why it is a
      phenotype here rather than only a mechanism node.
- category: Cardiovascular
  name: Bidirectional ventricular tachycardia
  description: >-
    Ventricular arrhythmia following ingestion. A previously healthy man who
    swallowed fifteen castor beans presented with bidirectional ventricular
    tachycardia at 180 bpm that resisted five cardioversion attempts and 450 mg
    of amiodarone, converting only after about two hours of supportive care. He
    recovered fully. This is the first such case reported, so it is a single
    observation rather than an established feature.
  phenotype_term:
    preferred_term: Bidirectional ventricular tachycardia
    term:
      id: HP:0034040
      label: Bidirectional ventricular tachycardia
    temporality: ACUTE
  notes: >-
    Carries no frequency: one case. Recorded anyway because the arrhythmia was
    refractory to the standard measures, which changes management rather than
    only describing the illness, and because the murine parenteral model
    independently shows structural cardiac injury.
  evidence:
  - reference: PMID:41788434
    reference_title: "Bidirectional ventricular tachycardia following ricin intoxication: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A previously healthy man ingested 15 castor beans in a suicide attempt and presented to the emergency department with a wide-complex tachycardia at 180 bpm and alternating QRS axis, consistent with bidirectional ventricular tachycardia."
    explanation: The presentation this phenotype records.
  - reference: PMID:41788434
    reference_title: "Bidirectional ventricular tachycardia following ricin intoxication: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Attempts at rhythm stabilization, including five electrical cardioversion attempts and a cumulative dose of 450 mg amiodarone, were unsuccessful."
    explanation: >-
      The refractoriness, which is the clinically actionable part and the reason
      a single case is worth recording.
  - reference: PMID:41788434
    reference_title: "Bidirectional ventricular tachycardia following ricin intoxication: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "To the best of our knowledge, this is the first reported case of bidirectional ventricular tachycardia following ricin intoxication."
    explanation: Establishes that this is a single observation, not an established frequency.
- category: Metabolic
  name: Hypoglycemia
  description: >-
    Profound hypoglycaemia is the earliest and, for a time, the only laboratory
    abnormality after parenteral ricin in mice. It has been observed but not
    commented on in porcine and human intoxication, so its status as a human
    phenotype is unsettled.
  phenotype_term:
    preferred_term: Hypoglycemia
    term:
      id: HP:0001943
      label: Hypoglycemia
    temporality: ACUTE
  notes: >-
    Carrying no frequency on purpose. The mouse result is strong and
    mechanistically worked out; the human evidence is one clinical report
    mentioned in passing, and the same authors record a negative in
    aerosol-exposed macaques - see the `hypoglycemia_human_status` discussion.
  evidence:
  - reference: PMID:36548717
    reference_title: "Parenteral Exposure of Mice to Ricin Toxin Induces Fatal Hypoglycemia by Cytokine-Mediated Suppression of Hepatic Glucose-6-Phosphatase Expression."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "in mice parenteral injection of ricin toxin causes profound hypoglycemia, in the absence of other clinical laboratory abnormalities"
    explanation: States the finding and that it is isolated, which is what makes it a useful early marker.
  - reference: PMID:36548717
    reference_title: "Parenteral Exposure of Mice to Ricin Toxin Induces Fatal Hypoglycemia by Cytokine-Mediated Suppression of Hepatic Glucose-6-Phosphatase Expression."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "At least one clinical report of ricin toxicosis describes hypoglycemia, but does not indicate whether specific measures were taken to control the low blood glucose in this patient"
    explanation: >-
      The whole of the human evidence for this phenotype: a single clinical
      report, noted in passing, with no indication the finding was acted on.
progression:
- phase: Latent interval
  duration: hours
  incubation_days: "1"
  notes: >-
    Symptoms do not begin at once. Reported latency after ingestion ranges from
    minutes to about a day; after inhalation it is a few hours; after injection
    local pain is immediate but systemic illness is delayed. `incubation_days:
    1` is the coarse day-granularity encoding of a sub-day latency. The interval
    matters clinically because it is the window in which gastrointestinal
    decontamination still works and in which an exposed person looks well.
  evidence:
  - reference: PMID:33711365
    reference_title: "Ricin poisoning: A review on contamination source, diagnosis, treatment, prevention and reporting of ricin poisoning."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "digestive decontamination performed with activated charcoal and/or gastric lavage within one day after the ingestion, to reduce gastrointestinal absorption of ricin"
    explanation: >-
      Establishes the decontamination window that defines this phase clinically.
      It does not itself tabulate symptom onset times, which is why it is marked
      indirect.
- phase: Acute toxidrome
  duration: 1-3 days
  duration_days: "3"
  notes: >-
    The syndrome that defines the disease, and the phase whose content is set by
    route: hemorrhagic gastroenteritis after ingestion, acute lung injury after
    inhalation, local necrosis with systemic vascular injury after injection.
  evidence:
  - reference: PMID:33711365
    reference_title: "Ricin poisoning: A review on contamination source, diagnosis, treatment, prevention and reporting of ricin poisoning."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "The mechanism of death was peripheral vascular collapse and progressing multiple organ failure occurring 10h-72h after intoxication."
    explanation: Bounds this phase in the fatal cases - death between ten and seventy-two hours.
- phase: Resolution or multi-organ failure
  duration: days
  notes: >-
    Monophasic. There is no relapsing-remitting course: the poisoning either
    resolves over days with supportive care or progresses to refractory
    cardiovascular collapse. Survivors of ingestion generally recover fully;
    whether survivors of inhalation do is unknown in humans, and the animal data
    say they may not.
  evidence:
  - reference: PMID:39210364
    reference_title: "Ricin intoxication by lethal dose of castor seeds ingestion: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She was discharged home after a complete recovery three days later."
    explanation: The resolution arm, in a documented ingestion case managed supportively.
  - reference: PMID:42560523
    reference_title: "Medico-legal aspects of fatal ricin poisoning: a systematic review of clinical manifestations, toxicological findings and autopsy results."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "hypovolemic shock, multi-organ failure, and refractory cardiovascular collapse"
    explanation: The other arm, from a systematic review of the fatal cases.
prevalence:
- population: Worldwide, published human cases 1980-2020
  measure_type: CASES_IN_LITERATURE
  prevalence_class: NOT_YET_DOCUMENTED
  notes: >-
    Fifty published cases over four decades, with six deaths. This is a
    literature count, not an incidence: ricin exposure is an intentional or
    accidental event rather than an endemic process, no population-based rate
    exists, and the case count is bounded by what gets published as much as by
    what happens. `prevalence_class: NOT_YET_DOCUMENTED` records that honestly
    rather than inventing a band.
  evidence:
  - reference: PMID:33711365
    reference_title: "Ricin poisoning: A review on contamination source, diagnosis, treatment, prevention and reporting of ricin poisoning."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Fifty ricin-intoxicated patients worldwide described in the literature have been identified."
    explanation: The case count this record reports, over a stated 1980-2020 search window.
  - reference: PMID:33711365
    reference_title: "Ricin poisoning: A review on contamination source, diagnosis, treatment, prevention and reporting of ricin poisoning."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Most cases were found in Asia (19 cases), Europe (12 cases) and America (15 cases). Intoxication was mostly accidental (37 cases)."
    explanation: >-
      Breaks the count down by region and intent. Accidental exposure dominates
      the published record, which cuts against the assumption that this is
      mainly a bioterrorism disease.
  - reference: PMID:33711365
    reference_title: "Ricin poisoning: A review on contamination source, diagnosis, treatment, prevention and reporting of ricin poisoning."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Only six deaths were observed."
    explanation: The case fatality within that series - six of fifty, in patients who reached care.
environmental:
- name: Ingestion of chewed or crushed castor seeds
  description: >-
    The commonest route in the published record, and the only one with a real
    human clinical literature. Castor is a widely grown ornamental and
    industrial crop, so seeds are freely available; toxicity requires the seed
    coat to be broken, because intact seeds resist digestion and can pass
    through unchanged. Exposure is usually accidental, sometimes self-harm.
  exposure_term:
    preferred_term: ingestion of ricin in castor seed
    term:
      id: ECTO:9001524
      label: exposure to Ricin
  food_source:
    preferred_term: castor bean
    term:
      id: FOODON:03310303
      label: castor bean
  exposure_classifications:
    hazard_agent_type:
    - classification_value: BIOLOGICAL
    exposure_route:
    - classification_value: ORAL
    exposure_duration:
    - classification_value: ACUTE
  influences_mechanisms:
  - target: Ricin Delivery to Host Tissue
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Chewing the seed releases the toxin into the gastrointestinal lumen, which
      is what the rest of the entry follows from.
    evidence:
    - reference: PMID:39210364
      reference_title: "Ricin intoxication by lethal dose of castor seeds ingestion: a case report."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "admitted to the emergency department with symptoms of colicky abdominal pain, diarrhea, and vomiting following the ingestion of six castor beans"
      explanation: >-
        A documented instance of this exposure producing the disease, naming
        both the ingestion and the illness it triggered in one sentence.
  notes: >-
    Bound to `ECTO:9001524` exposure to Ricin - an exact class, which all three
    route entries share. The route is carried by
    `exposure_classifications.exposure_route` rather than by the term, because
    ECTO's route-specific classes do not descend to ricin. An earlier draft of
    this entry bound `ECTO:0000537` exposure to toxin and recorded in this slot
    that no ricin class existed; that was wrong. `ECTO:9001524` is live, sits
    under exposure to organic compound, and reaches `ExO:0000002` exposure
    event, so it satisfies the `ExposureTerm` enum. It was missing from
    `cache/ecto/terms.csv` only because nothing in `kb/` had ever bound it -
    which is exactly why an absent cache row is not evidence that a term does
    not exist. `food_source` is the FOODON castor bean class, which is
    genuinely a class for the seed rather than for a prepared food, and correct
    here because the exposure is to the raw seed.
  evidence:
  - reference: PMID:33711365
    reference_title: "Ricin poisoning: A review on contamination source, diagnosis, treatment, prevention and reporting of ricin poisoning."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "The questioning of patients and family made it possible to retrieve an history of castor seeds or castor oil ingestion"
    explanation: >-
      Establishes castor seed ingestion as the exposure history recovered across
      the collected human cases.
  - reference: PMID:33711365
    reference_title: "Ricin poisoning: A review on contamination source, diagnosis, treatment, prevention and reporting of ricin poisoning."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Intoxication was mostly accidental (37 cases)."
    explanation: Supports the claim that this exposure is usually accidental.
- name: Inhalation of aerosolised ricin or castor seed dust
  description: >-
    The route of greatest concern as a weapon and the one with the lowest lethal
    dose, but with no published human case series at all - everything known
    about it comes from rodent, non-human-primate and swine exposures.
    Occupationally it corresponds to seed and mash handling in castor oil
    processing.
  exposure_term:
    preferred_term: inhalation of aerosolised ricin
    term:
      id: ECTO:9001524
      label: exposure to Ricin
  exposure_classifications:
    hazard_agent_type:
    - classification_value: BIOLOGICAL
    exposure_route:
    - classification_value: INHALATION
    exposure_duration:
    - classification_value: ACUTE
  influences_mechanisms:
  - target: Ricin Delivery to Host Tissue
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Aerosol deposition delivers toxin directly onto the alveolar surface,
      which is why this route needs roughly a thousandfold less toxin than
      ingestion.
    evidence:
    - reference: PMID:34830227
      reference_title: "Intramuscular Exposure to a Lethal Dose of Ricin Toxin Leads to Endothelial Glycocalyx Shedding and Microvascular Flow Abnormality in Mice and Swine."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: BACKGROUND
      snippet: "inhalatory and parenteral intoxications are associated with greater illness and mortality, and are characterized by lethal doses that are roughly three magnitudes lower than that of oral poisoning"
      explanation: States the dose relation this edge asserts.
  evidence:
  - reference: PMID:37104219
    reference_title: Comparative Aspects of Ricin Toxicity by Inhalation.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: REVIEW_SYNTHESIS
    snippet: "The pathogenesis of ricin toxicity following inhalation has been investigated in many animal models, including the non-human primate (predominantly the rhesus macaque), pig, rabbit and rodent."
    explanation: >-
      Establishes that this route's evidence base is animal models, which is why
      every phenotype downstream of it is graded MODEL_ORGANISM.
- name: Parenteral injection of ricin or castor bean extract
  description: >-
    The assassination and self-harm route, delivered by pellet, needle or
    explosive device. It bypasses every absorption barrier, so the toxin
    distributes systemically and binds preferentially to the vasculature,
    producing the endothelial and coagulopathic picture rather than a mucosal
    one.
  exposure_term:
    preferred_term: parenteral injection of ricin
    term:
      id: ECTO:9001524
      label: exposure to Ricin
  exposure_classifications:
    hazard_agent_type:
    - classification_value: BIOLOGICAL
    exposure_route:
    - classification_value: PARENTERAL
    exposure_duration:
    - classification_value: ACUTE
  influences_mechanisms:
  - target: Ricin Delivery to Host Tissue
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Injection places toxin directly into tissue and the circulation, with no
      absorption step to attenuate the dose.
    evidence:
    - reference: PMID:34830227
      reference_title: "Intramuscular Exposure to a Lethal Dose of Ricin Toxin Leads to Endothelial Glycocalyx Shedding and Microvascular Flow Abnormality in Mice and Swine."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "When delivered by the parenteral route, ricin is systemically distributed throughout the body"
      explanation: States what this route does to distribution, which is this edge.
  evidence:
  - reference: PMID:34830227
    reference_title: "Intramuscular Exposure to a Lethal Dose of Ricin Toxin Leads to Endothelial Glycocalyx Shedding and Microvascular Flow Abnormality in Mice and Swine."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: "in recent years, several terrorist attempts to utilize weaponized ricin delivered by sharp or explosive devices were planned"
    explanation: Establishes the delivery modes this exposure describes.
  - reference: PMID:38773158
    reference_title: Short- and long-term outcomes of pulmonary exposure to a sublethal dose of ricin in mice.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: "it is considered to be a high-risk chemical for living beings under the Organization for the Prohibition of Chemical Weapons1 and is also classified as a Category B biological agent by the Centers for Disease Control and Prevention2"
    explanation: >-
      Source for the regulatory status asserted in the disease description.
      Quoted verbatim including the trailing superscript reference markers the
      source text carries.
  - reference: PMID:34830227
    reference_title: "Intramuscular Exposure to a Lethal Dose of Ricin Toxin Leads to Endothelial Glycocalyx Shedding and Microvascular Flow Abnormality in Mice and Swine."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "post-mortem examinations in a single well-known case involving the assassination of Georgi Markov, suggested that cardiac arrest due to necrosis of the cardiac conducting tissue may be the direct cause of death"
    explanation: >-
      The one well-documented human instance of this route, and what its autopsy
      suggested. Quoted as the hypothesis the source states it to be.
diagnosis:
- name: Exposure history with a compatible acute syndrome
  description: >-
    The practical route to the diagnosis. Ricin has no bedside test - the
    confirmatory assays below are reference-laboratory mass spectrometry - so
    recognition rests on a history of castor seed or castor product exposure
    together with an otherwise unexplained acute gastroenteritis, acute
    respiratory illness or shock. Where no exposure history is available - which
    is the case in deliberate poisoning - early toxicological investigation is
    what makes the diagnosis at all.
  evidence:
  - reference: PMID:33711365
    reference_title: "Ricin poisoning: A review on contamination source, diagnosis, treatment, prevention and reporting of ricin poisoning."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "The questioning of patients and family made it possible to retrieve an history of castor seeds or castor oil ingestion"
    explanation: States how the diagnosis was actually reached across the collected human cases.
  - reference: PMID:42560523
    reference_title: "Medico-legal aspects of fatal ricin poisoning: a systematic review of clinical manifestations, toxicological findings and autopsy results."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "emphasizing the importance of early toxicological investigations, particularly when no history of exposure is available"
    explanation: Names the case where history fails and analysis has to carry the diagnosis.
- name: Direct identification of ricin in serum or body fluid by LC-MS/MS
  description: >-
    Ricinine reports castor bean exposure; this reports the toxin itself. A
    lactose-agarose lectin capture followed by tryptic digestion and targeted
    LC-MS/MS identifies ricin down to 5 ng/mL in serum within about two and a
    half hours, without antibodies. It has been run on a real case, finding
    toxin in abdominal fluid 72 hours after self-injection of a castor bean
    extract - a wider window than previously documented. A faster,
    field-deployable ambient-MS screen detects the co-extracted small molecules
    ricinoleic acid and ricinine instead, in about two minutes, and so answers
    the same question as the ricinine assay rather than this one.
  evidence:
  - reference: PMID:33499033
    reference_title: "Rapid, Sensitive and Reliable Ricin Identification in Serum Samples Using LC-MS/MS."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This enables ricin identification down to 5 ng/mL in serum samples in 2.5 h."
    explanation: The sensitivity and turnaround this method achieves.
  - reference: PMID:33499033
    reference_title: "Rapid, Sensitive and Reliable Ricin Identification in Serum Samples Using LC-MS/MS."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the toxin was identified in an abdominal fluid sample taken 72 h post self-injection of castor beans extraction in an eventual suicide case"
    explanation: >-
      The real-case validation, and the source of the extended-window claim in
      this description.
  - reference: PMID:35173958
    reference_title: "A Proof-of-Concept, Two-Tiered Approach for Ricin Detection Using Ambient Mass Spectrometry."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "we present an alternative, two-tiered approach to identify the presence of ricin by detecting ricinoleic acid and ricinine, which are co-extracted with the protein"
    explanation: >-
      The field-deployable alternative, and the reason it is grouped with the
      ricinine assay rather than with direct detection - it measures
      co-extracted small molecules, not the protein.
  - reference: PMID:35173958
    reference_title: "A Proof-of-Concept, Two-Tiered Approach for Ricin Detection Using Ambient Mass Spectrometry."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Difficulties with direct detection arise from large heterogeneities in ricin glycosylation, which leads to markedly different bioactivity"
    explanation: >-
      Why direct detection of the protein is hard, which is what the lectin
      capture above exists to solve.
  notes: >-
    A third confirmatory route is deliberately absent. A reverse
    transcription-ligase-PCR assay reads out the depurinated 28S rRNA itself
    (`DOI:10.1007/s11419-017-0377-6`, Forensic Toxicology 2018), which would be
    the one diagnostic that measures this entry's own central pathophysiology
    node rather than a surrogate. It is not curated because it cannot be:
    the paper has no PubMed record, and its cached entry carries
    `content_type: unavailable` with no retrievable abstract, so no exact quote
    exists to support an evidence item. Adding it with a paraphrased snippet
    would be the fabrication the evidence rules exist to prevent. It should be
    added the moment a quotable record becomes available.
- name: Ricinine measurement in blood, urine or postmortem tissue
  description: >-
    Ricinine is a minor pyridone alkaloid of the castor bean that is co-extracted
    with ricin and is measurable by LC-MS/MS. It is the workhorse confirmatory
    analyte, detected consistently in blood, urine and postmortem tissue in
    fatal cases. Two limits matter. It marks exposure to castor bean *product*,
    not to ricin, so a highly purified preparation may carry little or none; and
    its concentration does not track severity.
  evidence:
  - reference: PMID:42560523
    reference_title: "Medico-legal aspects of fatal ricin poisoning: a systematic review of clinical manifestations, toxicological findings and autopsy results."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Ricinine was consistently detected in blood, urine, and postmortem tissues, supporting its role as a reliable biomarker of ricin exposure, although current evidence is insufficient to establish definitive correlations with poisoning severity or toxicokinetics."
    explanation: States both the reliability of the marker and the severity-correlation limit this entry records.
  - reference: PMID:32991682
    reference_title: "Non-Lethal Intoxication by Ingestion of 50 Castor Beans: Serial Measurement of Ricinine in Blood, Plasma and Urine."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The presence of ricinine in a patient's blood or plasma is a proof of castor bean and, hence, ricin exposure."
    explanation: States what a positive result establishes - castor bean exposure, and ricin exposure by inference from it.
  - reference: PMID:32991682
    reference_title: "Non-Lethal Intoxication by Ingestion of 50 Castor Beans: Serial Measurement of Ricinine in Blood, Plasma and Urine."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "no clear correlation can be established between ricinine blood, plasma or urine levels and the severity of the intoxication"
    explanation: >-
      The serial-measurement result behind the severity caveat, in a patient who
      ingested fifty beans and recovered fully.
  - reference: PMID:23471955
    reference_title: "Analysis of a ricin biomarker, ricinine, in 989 individual human urine samples."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In this convenience sample set, only 1.2% of the urine specimens had detectable amounts of ricinine, randomly distributed between 0.186 and 4.15 ng/mL."
    explanation: >-
      Establishes the background rate in unexposed people, which is what makes a
      positive result interpretable. Castor oil is in many consumer products, so
      a non-zero background was not a given.
differential_diagnoses:
- name: Infectious gastroenteritis and sepsis
  description: >-
    The ingestion syndrome is an acute gastroenteritis progressing to shock,
    which is exactly how Salmonella or Shigella enteritis and septic shock of any
    cause present. Without an exposure history there is nothing in the early
    clinical picture to separate them.
  distinguishing_features:
  - >-
    Ricinine detectable in blood or urine establishes castor bean exposure and
    is not produced by any infection.
  - >-
    A history of chewing castor seeds, or of handling castor mash, has no
    counterpart in enteric infection.
  notes: >-
    Deliberately short, and covering the shock-like syndromes as one group
    rather than contrasting ricin with each named infection individually. The
    systematic review names the differential at that level of generality and no
    reference cited here makes the pairwise comparisons, so making them would be
    asserting clinical teaching without a source.

    The biothreat differential that toxicology references usually list
    alongside ricin - tularemia, Q fever, staphylococcal enterotoxin B,
    phosgene - is not recorded here for the same reason. It reaches this entry
    only through a StatPearls chapter, and PubMed searches for a peer-reviewed
    source that makes those comparisons for ricin specifically returned nothing
    usable. It is a genuine gap rather than a considered exclusion, and closing
    it needs a source, not a rewrite.
  evidence:
  - reference: PMID:42560523
    reference_title: "Medico-legal aspects of fatal ricin poisoning: a systematic review of clinical manifestations, toxicological findings and autopsy results."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "the differential diagnosis with other septic shock-like syndromes"
    explanation: Names this differential as one of the medico-legal challenges the review identifies.
  - reference: PMID:42560523
    reference_title: "Medico-legal aspects of fatal ricin poisoning: a systematic review of clinical manifestations, toxicological findings and autopsy results."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "can mimic several common medical conditions, most notably septic shock"
    explanation: States which condition the mimicry most often points at.
  - reference: PMID:42560523
    reference_title: "Medico-legal aspects of fatal ricin poisoning: a systematic review of clinical manifestations, toxicological findings and autopsy results."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "as bacterial sepsis, particularly when no history of ricin exposure is available"
    explanation: >-
      Names the condition under which the confusion happens - no exposure
      history - which is exactly the deliberate-poisoning case where the
      diagnosis matters most. Quoted from mid-sentence because the review is a
      scanned PDF that hyphen-breaks the preceding words across lines.
  - reference: PMID:16168316
    reference_title: Ricin.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Ricin intoxication mimics a variety of disease states, thus a low threshold of suspicion must be maintained to recognize a potential epidemic."
    explanation: >-
      An independent statement of the mimicry and of its practical consequence -
      suspicion has to be maintained because no single feature discriminates.
  - reference: PMID:32991682
    reference_title: "Non-Lethal Intoxication by Ingestion of 50 Castor Beans: Serial Measurement of Ricinine in Blood, Plasma and Urine."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The presence of ricinine in a patient's blood or plasma is a proof of castor bean and, hence, ricin exposure."
    explanation: Supports the discriminating feature listed here.
- name: Toxin-induced wide-complex tachycardia
  description: >-
    A patient presenting with a wide-complex tachycardia and no structural heart
    disease will be worked up as a primary arrhythmia. Ricin belongs in that
    differential: the one reported case converted only after prolonged
    supportive care, having failed cardioversion and amiodarone, and the authors
    liken the mechanism to digitalis intoxication and catecholaminergic
    polymorphic ventricular tachycardia.
  distinguishing_features:
  - >-
    A preceding gastrointestinal prodrome - severe nausea, vomiting and
    diarrhoea - rather than an arrhythmia arising without warning.
  - >-
    Failure of electrical cardioversion and amiodarone, in a heart with no
    structural disease.
  evidence:
  - reference: PMID:41788434
    reference_title: "Bidirectional ventricular tachycardia following ricin intoxication: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This case underscores the importance of recognizing rare toxin-induced arrhythmias in the differential diagnosis of wide-complex tachycardias"
    explanation: States this differential directly, as the authors' own conclusion.
  - reference: PMID:41788434
    reference_title: "Bidirectional ventricular tachycardia following ricin intoxication: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The arrhythmogenic mechanism in ricin poisoning may involve calcium dysregulation and triggered activity, similar to digitalis intoxication or catecholaminergic polymorphic ventricular tachycardia."
    explanation: Names the two conditions this most resembles mechanistically.
  - reference: PMID:41788434
    reference_title: "Bidirectional ventricular tachycardia following ricin intoxication: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Re-entry appears unlikely due to the absence of structural heart disease and the failure of electrical cardioversion."
    explanation: Supports the second distinguishing feature listed here.
histopathology:
- name: Hemorrhagic necrosis of the gastrointestinal tract with hepatic and renal tubular injury
  description: >-
    The postmortem picture of fatal human ricin poisoning, pooled across the
    published cases: hemolysis, hemorrhagic necrosis of the gut, hepatic injury,
    renal tubular necrosis, and findings consistent with capillary leak.
  diagnostic: false
  evidence:
  - reference: PMID:42560523
    reference_title: "Medico-legal aspects of fatal ricin poisoning: a systematic review of clinical manifestations, toxicological findings and autopsy results."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Reported autopsy findings commonly included hemolysis, hemorrhagic necrosis of the gastrointestinal tract, hepatic injury, renal tubular necrosis, and evidence supporting the presence of a capillary leak syndrome."
    explanation: The pooled autopsy findings this record describes.
treatments:
- name: Supportive and symptomatic care
  description: >-
    The mainstay, and in humans the only management with evidence behind it.
    Rehydration and electrolyte correction for gastrointestinal losses,
    vasopressor support for shock, respiratory support for inhalational injury,
    and correction of coagulopathy. There is no antidote, so everything else in
    this section is investigational. Across the published human series this was
    what patients received, and forty-four of fifty survived.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Dehydration
    term:
      id: HP:0001944
      label: Dehydration
  - preferred_term: Hypotension
    term:
      id: HP:0002615
      label: Hypotension
  target_mechanisms:
  - target: Distributive and Hypovolemic Shock with Multi-Organ Failure
    treatment_effect: MODULATES
    description: >-
      Supportive care does nothing to the toxin; it addresses the circulatory
      failure that kills the patient.
    evidence:
    - reference: PMID:33711365
      reference_title: "Ricin poisoning: A review on contamination source, diagnosis, treatment, prevention and reporting of ricin poisoning."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "Prompt treatment with supportive care was necessary to limit morbidity and mortality."
      explanation: States the target of supportive care as morbidity and mortality rather than the toxin.
  evidence:
  - reference: PMID:33711365
    reference_title: "Ricin poisoning: A review on contamination source, diagnosis, treatment, prevention and reporting of ricin poisoning."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Patients received symptomatic treatment consisting mostly to rehydration with intravenous fluids"
    explanation: >-
      Records what patients actually received across fifty collected cases.
      Quoted verbatim including the source's grammatical slip.
  - reference: PMID:33711365
    reference_title: "Ricin poisoning: A review on contamination source, diagnosis, treatment, prevention and reporting of ricin poisoning."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Currently, no antidote, vaccine, or other specific effective treatment is available for ricin poisoning or prevention."
    explanation: States the absence that makes supportive care the mainstay rather than an adjunct.
  - reference: PMID:39210364
    reference_title: "Ricin intoxication by lethal dose of castor seeds ingestion: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "admitted for observation, and received symptomatic treatment. She was discharged home after a complete recovery three days later."
    explanation: A worked case of supportive management and its outcome.
- name: Early gastrointestinal decontamination
  description: >-
    Activated charcoal and gastric lavage within a day of ingestion, to reduce
    the toxin that is absorbed. Restricted by definition to the oral route and
    to the latent interval before symptoms establish. In the collected human
    series this was reported as very effective when given early, which is the
    strongest treatment claim anywhere in the human ricin literature - though it
    comes from an uncontrolled case collection, not a trial.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: gastrointestinal decontamination with activated charcoal and gastric lavage
    term:
      id: NCIT:C49236
      label: Therapeutic Procedure
  notes: >-
    Bound one level broader than the treatment on purpose. NCIT has no gastric
    lavage term at all, and `NCIT:C68769` Decontamination - the obvious
    candidate - is not reachable from `NCIT:C25218` Clinical Intervention or
    Procedure, so it fails the `TreatmentActionTerm` enum. `therapeutic_agent`
    is likewise left empty: `NCIT:C77524` Activated Charcoal is not under
    `NCIT:C1909` Pharmacologic Substance and so fails `ChemicalEntityTerm`, and
    CHEBI has no activated charcoal class. Both specifics are carried in
    `preferred_term` and the description instead, per the rule that
    `preferred_term` may be more specific than the best available term.
  target_mechanisms:
  - target: Ricin Delivery to Host Tissue
    treatment_effect: INHIBITS
    description: >-
      Decontamination acts on the delivery step itself - reducing how much toxin
      crosses the gut wall - which is why it only works before absorption is
      complete.
    evidence:
    - reference: PMID:33711365
      reference_title: "Ricin poisoning: A review on contamination source, diagnosis, treatment, prevention and reporting of ricin poisoning."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "digestive decontamination performed with activated charcoal and/or gastric lavage within one day after the ingestion, to reduce gastrointestinal absorption of ricin"
      explanation: States the target of the intervention as gastrointestinal absorption, which is this node.
  evidence:
  - reference: PMID:33711365
    reference_title: "Ricin poisoning: A review on contamination source, diagnosis, treatment, prevention and reporting of ricin poisoning."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "This decontamination treatment administered early has been very effective."
    explanation: >-
      The efficacy claim, stated by the review of fifty collected cases. It is
      an uncontrolled observation across heterogeneous case reports, which is
      why the description says so rather than treating it as trial evidence.
- name: Anti-ricin antibody passive immunotherapy
  description: >-
    Investigational, and the only post-exposure approach with efficacy shown in
    a large animal model at clinically relevant times. Equine F(ab')2 antitoxin
    protected more than 80% of swine given it eighteen hours after lethal
    intratracheal or intramuscular exposure. High-affinity monoclonal antibodies
    against both ricin isoforms are the newer generation: RicE5 gave over 90%
    survival in mice treated six hours after an intranasal challenge and 35% at
    twenty-four hours. Nothing in this class is approved for human use.
  therapeutic_modality: MONOCLONAL_ANTIBODY
  treatment_term:
    preferred_term: passive immunization with anti-ricin antibody
    term:
      id: NCIT:C15259
      label: Passive Immunization
    therapeutic_agent:
    - preferred_term: anti-ricin monoclonal antibody
      term:
        id: NCIT:C20401
        label: Monoclonal Antibody
  target_mechanisms:
  - target: Ricin Delivery to Host Tissue
    treatment_effect: INHIBITS
    description: >-
      Neutralising antibody acts on toxin that has not yet entered a cell, which
      is why the window closes as toxin is internalised. It is deliberately not
      linked to the RTB lectin-binding node: the antibody that actually protects
      animals, RicE5, is an anti-RTA antibody, and the anti-RTB antibody from
      the same panel neutralised in culture but failed in vivo. The review of
      the field lists several neutralisation routes - blocking binding,
      disrupting retrograde transport, redirecting the toxin - without settling
      which one carries the protection.
    evidence:
    - reference: PMID:39453188
      reference_title: "A Monoclonal Antibody with a High Affinity for Ricin Isoforms D and E Provides Strong Protection against Ricin Poisoning."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "which bind and neutralize very efficiently both ricin isoforms D and E in vitro through cytotoxicity cell assays"
      explanation: >-
        Establishes neutralisation of the toxin itself as the mechanism, measured
        in cytotoxicity assays.
  evidence:
  - reference: PMID:32481526
    reference_title: Post-Exposure Anti-Ricin Treatment Protects Swine Against Lethal Systemic and Pulmonary Exposures.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "While administration of the antitoxin at 18 h post-exposure protected more than 80% of both intratracheally and intramuscularly ricin-intoxicated swine, treatment at 24 h post-exposure protected 58% of the intramuscular-exposed swine, as opposed to 26% of the intratracheally exposed animals."
    explanation: The large-animal post-exposure efficacy data, including how fast it falls off with delay.
  - reference: PMID:39453188
    reference_title: "A Monoclonal Antibody with a High Affinity for Ricin Isoforms D and E Provides Strong Protection against Ricin Poisoning."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "one of these mAbs (RicE5) conferred over 90% survival in a murine model challenged intranasally with a 5 LD50 of ricin and treated by intravenous administration of the mAbs 6 h post-intoxication. Notably, a 35% survival rate was observed even when treatment was administered 24 h post-exposure."
    explanation: The monoclonal-antibody efficacy figures this description quotes.
  - reference: PMID:39453188
    reference_title: "A Monoclonal Antibody with a High Affinity for Ricin Isoforms D and E Provides Strong Protection against Ricin Poisoning."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We selected two antibodies: one targeting RTA (RicE5) and another targeting RTB (RicE8)."
    explanation: >-
      Identifies which chain each antibody binds, which is what makes the next
      item a dissociation rather than a dose effect.
  - reference: PMID:39453188
    reference_title: "A Monoclonal Antibody with a High Affinity for Ricin Isoforms D and E Provides Strong Protection against Ricin Poisoning."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Although both antibodies exhibited strong neutralizing capabilities in cellular models, only RicE5 provided effective protection in an in vivo intoxication model."
    explanation: >-
      The negative result, recorded because it matters mechanistically: the
      anti-RTB antibody neutralised in culture and failed in animals, so in
      vitro neutralisation does not by itself predict protection, and the
      protective activity is not attributable to blocking the B chain.
  - reference: PMID:39453188
    reference_title: "A Monoclonal Antibody with a High Affinity for Ricin Isoforms D and E Provides Strong Protection against Ricin Poisoning."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: "there are currently no commercially available prophylaxis or treatments for ricin intoxication"
    explanation: Supports the statement that nothing in this class is approved.
- name: RVEc recombinant ricin A chain subunit vaccine
  description: >-
    The second investigational vaccine candidate, a truncated recombinant A
    chain (rRTA 1-33/44-198). In a phase 1 dose-escalating study it was safe and
    well tolerated at 20 and 50 micrograms; all recipients at those doses
    seroconverted by ELISA but only half produced measurable neutralising
    antibody, and a later 50-microgram booster raised both. The 100-microgram
    arm was stopped after two of ten subjects developed elevated creatine
    phosphokinase. Not approved.
  therapeutic_modality: VACCINE
  treatment_term:
    preferred_term: Vaccination
    term:
      id: NCIT:C15346
      label: Vaccination
  target_mechanisms:
  - target: Ricin Delivery to Host Tissue
    treatment_effect: INHIBITS
    description: >-
      As with RiVax, an anti-A-chain neutralising response acts on toxin that
      has not yet entered a cell.
    evidence:
    - reference: PMID:26546259
      reference_title: "Safety and immunogenicity of ricin vaccine, RVEc™, in a Phase 1 clinical trial."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "50% produced neutralizing anti-ricin antibodies measurable by TNA"
      explanation: >-
        Establishes that the vaccine raises toxin-neutralising antibody, which
        is the mechanism. Indirect because a neutralisation titre is not itself
        a demonstration of protection.
  evidence:
  - reference: PMID:26546259
    reference_title: "Safety and immunogenicity of ricin vaccine, RVEc™, in a Phase 1 clinical trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "RVEc™ was safe and well tolerated at the 20- and 50-μg doses."
    explanation: The safety result at the doses taken forward.
  - reference: PMID:26546259
    reference_title: "Safety and immunogenicity of ricin vaccine, RVEc™, in a Phase 1 clinical trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of the 10 subjects who received a single 100-μg dose, two developed elevated creatine phosphokinase levels, which resolved without sequelae. No additional doses were administered to subjects in the 100-μg group."
    explanation: >-
      The dose-limiting finding, recorded because a stopped arm is part of what
      is known about this candidate.
  - reference: PMID:26546259
    reference_title: "Safety and immunogenicity of ricin vaccine, RVEc™, in a Phase 1 clinical trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The single booster was safe and well tolerated, resulting in no serious adverse events, and significantly enhanced immunogenicity of the vaccine in human subjects."
    explanation: The booster result this description records.
  - reference: PMID:26546259
    reference_title: "Safety and immunogenicity of ricin vaccine, RVEc™, in a Phase 1 clinical trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ricin is a potent toxin and potential bioterrorism weapon for which no specific licensed countermeasures are available."
    explanation: Supports the statement that this candidate is not approved.
- name: RiVax recombinant ricin A chain vaccine
  description: >-
    Investigational pre-exposure prophylaxis, not a treatment. RiVax is a
    recombinant ricin A chain subunit vaccine, safe and immunogenic in mice,
    rabbits and humans without adjuvant, and taken through a pilot phase 1B
    adsorbed to Alhydrogel. No ricin vaccine is approved. The molecular detail
    frequently quoted for it - that it carries point mutations inactivating
    both the N-glycosidase site and the vascular-leak epitope - is not stated
    by any reference cited here and is deliberately left out rather than
    asserted.
  therapeutic_modality: VACCINE
  treatment_term:
    preferred_term: Vaccination
    term:
      id: NCIT:C15346
      label: Vaccination
  target_mechanisms:
  - target: Ricin Delivery to Host Tissue
    treatment_effect: INHIBITS
    description: >-
      An induced neutralising response acts on toxin in the extracellular space
      before it enters a cell. RiVax is a recombinant A chain, so the antibody
      it raises is anti-RTA and cannot act on the B chain's lectin binding;
      this edge deliberately targets the delivery node rather than that one.
    evidence:
    - reference: PMID:36526642
      reference_title: Serum antibody profiling identifies vaccine-induced correlates of protection against aerosolized ricin toxin in rhesus macaques.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "survival correlated with pre-challenge, epitope-specific serum IgG levels, derived from a competitive sandwich ELISA using a panel of toxin-neutralizing monoclonal antibodies directed against distinct epitopes on RiVax"
      explanation: >-
        Establishes that epitope-specific, toxin-neutralising serum IgG is what
        tracks survival in vaccinated macaques, which supports a neutralising
        mechanism without directly demonstrating the binding step.
  evidence:
  - reference: PMID:22914366
    reference_title: Pilot phase IB clinical trial of an alhydrogel-adsorbed recombinant ricin vaccine.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We have developed a recombinant ricin vaccine, RiVax. Without adjuvant it is safe and immunogenic in mice, rabbits, and humans."
    explanation: Establishes the candidate and its human safety and immunogenicity without adjuvant.
  - reference: PMID:22914366
    reference_title: Pilot phase IB clinical trial of an alhydrogel-adsorbed recombinant ricin vaccine.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There is no FDA-approved vaccine for the potent plant toxin ricin."
    explanation: Supports the statement that no ricin vaccine is approved.
- name: Retro-2 and other retrograde transport inhibitors
  description: >-
    Preclinical only. Retro-2 blocks toxin trafficking at the early
    endosome-to-trans-Golgi interface without disturbing compartment morphology
    or other trafficking, and protected mice from an otherwise lethal nasal
    ricin challenge - the first small molecule shown to work against ricin in an
    animal. Its interest here is as much mechanistic as therapeutic: it is the
    experiment that shows the retrograde step is required rather than incidental.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: Retrograde Transport from the Golgi to the Endoplasmic Reticulum
    treatment_effect: INHIBITS
    description: >-
      The compound acts on exactly this step, and on nothing else in the
      trafficking pathway that could be detected.
    evidence:
    - reference: PMID:20403321
      reference_title: Inhibition of retrograde transport protects mice from lethal ricin challenge.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "We identified two compounds that selectively block retrograde toxin trafficking at the early endosome-TGN interface, without affecting compartment morphology, endogenous retrograde cargos, or other trafficking steps, demonstrating an unexpected degree of selectivity and lack of toxicity."
      explanation: Locates the drug's action at this step and establishes its selectivity for it.
  evidence:
  - reference: PMID:20403321
    reference_title: Inhibition of retrograde transport protects mice from lethal ricin challenge.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In mice, one compound clearly protects from lethal nasal exposure to ricin."
    explanation: The animal efficacy result.
  - reference: PMID:20403321
    reference_title: Inhibition of retrograde transport protects mice from lethal ricin challenge.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Our work discovers the first small molecule that shows efficacy against ricin in animal experiments and identifies the retrograde route as a potential therapeutic target."
    explanation: The authors' own statement of what the result establishes, which is the claim this entry makes for it.
clinical_trials:
- name: NCT01317667
  phase: PHASE_I
  status: COMPLETED
  description: >-
    Phase 1 escalating multiple-dose study of the RVEc recombinant ricin toxin A
    chain vaccine in thirty healthy adults, at 20, 50 and 100 micrograms.
  evidence:
  - reference: clinicaltrials:NCT01317667
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This study is a Phase 1, escalating, multiple-dose, single-center study to evaluate the safety and immunogenicity of the RVEc vaccine."
    explanation: The registration record establishing this trial's design and phase.
- name: NCT01846104
  phase: PHASE_I
  status: COMPLETED
  description: >-
    Booster study in subjects who had already received three 50-microgram doses
    of RVEc in the trial above.
  evidence:
  - reference: clinicaltrials:NCT01846104
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The purpose of this study is to evaluate the safety and immunogenicity of a single 50-μg booster dose of RVEc."
    explanation: The registration record for the booster arm.
animal_models:
- name: Murine intramuscular ricin intoxication
  species: Mouse
  publication: PMID:31208156
  description: >-
    Lethal intramuscular ricin in mice, used to characterise the systemic rather
    than the mucosal face of the disease. It reproduces the coagulopathy,
    thrombocytopenia and multi-organ haemorrhage of parenteral human poisoning
    and adds structural cardiac injury with measurable functional impairment.
  modeled_mechanisms:
  - target: Endothelial Glycocalyx Shedding and Microvascular Hyperpermeability
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      The model is where the glycocalyx-shedding account of systemic ricin
      poisoning was established, alongside swine.
    limitations: >-
      Mouse, and a single lethal bolus dose by a route that in humans is
      documented in essentially one case. Whether human parenteral poisoning
      shows the same glycocalyx kinetics is untested.
    readouts:
    - name: Circulating heparan sulfate, hyaluronic acid and syndecan-1
      target: Endothelial Glycocalyx Shedding and Microvascular Hyperpermeability
      direction: INCREASED
      interpretation: Shed glycocalyx components measured in blood as the direct readout of the node.
      evidence:
      - reference: PMID:34830227
        reference_title: "Intramuscular Exposure to a Lethal Dose of Ricin Toxin Leads to Endothelial Glycocalyx Shedding and Microvascular Flow Abnormality in Mice and Swine."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Elevated levels of soluble heparan sulfate, hyaluronic acid and syndecan-1 were measured in blood samples following ricin intoxication"
        explanation: Reports the measurement in the direction this readout records.
    evidence:
    - reference: PMID:34830227
      reference_title: "Intramuscular Exposure to a Lethal Dose of Ricin Toxin Leads to Endothelial Glycocalyx Shedding and Microvascular Flow Abnormality in Mice and Swine."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "ricin bound preferentially to the vasculature in both mice and swine, leading to coagulopathy and widespread hemorrhages"
      explanation: >-
        Supports the model as informative for this node, and notes the finding
        held in two species rather than one.
  evidence:
  - reference: PMID:31208156
    reference_title: "Intramuscular Ricin Poisoning of Mice Leads to Widespread Damage in the Heart, Spleen, and Bone Marrow."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The present study applies various biochemical, hematological, histopathological, molecular, and functional approaches to broadly investigate the systemic effects of parenteral intoxication by a lethal dose of ricin in a murine model."
    explanation: Describes the model and what it was built to measure.
  - reference: PMID:31208156
    reference_title: "Intramuscular Ricin Poisoning of Mice Leads to Widespread Damage in the Heart, Spleen, and Bone Marrow."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In the heart, diffuse hemorrhages, myocyte necrosis, collagen deposition, and induction in fibrinogen were observed."
    explanation: >-
      The cardiac lesion of this model. Recorded here rather than under
      `histopathology:`, which holds human autopsy findings, so the species is
      not lost on a reader scanning that section. It matters because the one
      well-documented human parenteral case was read at autopsy as cardiac
      arrest from necrosis of the conducting tissue, which this lesion makes
      mechanistically plausible without confirming.
  - reference: PMID:31208156
    reference_title: "Intramuscular Ricin Poisoning of Mice Leads to Widespread Damage in the Heart, Spleen, and Bone Marrow."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Severe functional impairment was manifested by marked thickening of the left ventricular wall, decreased ventricular volume, and a significant reduction in stroke volume and cardiac output."
    explanation: The functional consequence measured alongside that histology.
  - reference: PMID:31208156
    reference_title: "Intramuscular Ricin Poisoning of Mice Leads to Widespread Damage in the Heart, Spleen, and Bone Marrow."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Unexpectedly, the differential severity of the ricin-induced damage did not correlate with the respective ricin-dependent catalytic activity measured in the various organs."
    explanation: >-
      A caveat worth keeping with the model: organ damage did not track local
      enzymatic activity, so the simple "more depurination, more damage" reading
      of systemic poisoning is not what the data show.
- name: Murine pulmonary ricinosis
  species: Mouse
  publication: PMID:38773158
  description: >-
    Intranasal or aerosolised ricin in mice, at sublethal or lethal doses. This
    is the principal model for the inhalational syndrome, and essentially the
    only source of information about it, since human inhalational poisoning has
    no published case series.
  modeled_mechanisms:
  - target: Acute Lung Injury with Interstitial Pneumonia and Alveolar Edema
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Reproduces the full lesion - interstitial pneumonia, local cytokine storm,
      neutrophil influx, oedema and epithelial death - with measurable loss of
      lung function.
    limitations: >-
      Fidelity to the human disease cannot be assessed, because there is no
      human inhalational case series to compare it against. The inhalation
      models also differ among themselves: exposure method, aerosol
      characteristics, ricin cultivar and purity, dose and species all vary, and
      the review of them says the resulting pathology is broadly similar rather
      than identical.
    readouts:
    - name: Lung histopathology and physiological function
      target: Acute Lung Injury with Interstitial Pneumonia and Alveolar Edema
      direction: ALTERED
      interpretation: Paired structural and functional readout of the acute lung injury node.
      evidence:
      - reference: PMID:38773158
        reference_title: Short- and long-term outcomes of pulmonary exposure to a sublethal dose of ricin in mice.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "This damage was manifested in reduced lung performance and physiological function."
        explanation: The functional half of the readout.
    evidence:
    - reference: PMID:38773158
      reference_title: Short- and long-term outcomes of pulmonary exposure to a sublethal dose of ricin in mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "sublethal exposure of mice to ricin resulted in acute lung injury, including interstitial pneumonia, cytokine storm, neutrophil influx, edema and cellular death"
      explanation: Supports the model as informative for this node by naming every component it reproduces.
  - target: Residual Pulmonary Fibrosis in Survivors
    relationship: RECAPITULATES
    fidelity: LOW
    model_scale: ORGANISM
    description: >-
      The only evidence anywhere that survivors of pulmonary ricin exposure carry
      long-term damage.
    limitations: >-
      Fidelity is marked LOW because susceptibility to pulmonary fibrosis, and
      the character of the fibrosis that develops, differ by species and strain
      - which the inhalation-model review names explicitly as a reason to choose
      the model carefully for chronic work. There is no human counterpart at all.
    evidence:
    - reference: PMID:37104219
      reference_title: Comparative Aspects of Ricin Toxicity by Inhalation.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: REVIEW_SYNTHESIS
      snippet: "these factors need to be considered when choosing a model for chronic ricin toxicity by inhalation, including species and strain susceptibility to fibrosis"
      explanation: The basis for the LOW fidelity grade on this link.
  evidence:
  - reference: PMID:38773158
    reference_title: Short- and long-term outcomes of pulmonary exposure to a sublethal dose of ricin in mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "the purpose of current study was to assess short- and long-term effects on physiological parameters and function following sublethal pulmonary exposure"
    explanation: States what the model was built to answer.
- name: Swine ricin intoxication by intratracheal and intramuscular routes
  species: Pig
  publication: PMID:32481526
  description: >-
    Swine were chosen over rodents for post-exposure countermeasure work because
    their cardiovascular and pulmonary systems resemble the human, and the model
    is where pulmonary ricin exposure was shown to produce genuine acute
    respiratory distress syndrome rather than a rodent approximation of it.
  modeled_mechanisms:
  - target: Acute Lung Injury with Interstitial Pneumonia and Alveolar Edema
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      The large-animal demonstration that the pulmonary lesion meets ARDS
      criteria.
    limitations: >-
      Still an animal model of a syndrome with no human case series, so the
      resemblance argument rests on organ physiology rather than on any
      comparison with human ricin disease. Post-exposure protection experiments
      in this species also need far more antitoxin than the mouse, so efficacy
      figures do not transfer between the two models.
    evidence:
    - reference: PMID:32481526
      reference_title: Post-Exposure Anti-Ricin Treatment Protects Swine Against Lethal Systemic and Pulmonary Exposures.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "the swine animal model served us in the past to determine that pulmonary exposure to ricin leads to the development of bona fide acute respiratory distress syndrome"
      explanation: Supports the model as informative for this node, at the level of the ARDS endpoint.
  evidence:
  - reference: PMID:32481526
    reference_title: Post-Exposure Anti-Ricin Treatment Protects Swine Against Lethal Systemic and Pulmonary Exposures.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Due to the high resemblance between the human and porcine cardiovascular and pulmonary systems"
    explanation: The stated reason for choosing this species, which is what its fidelity claim rests on.
discussions:
- discussion_id: host_genetic_modifiers_of_cellular_susceptibility
  kind: KNOWLEDGE_GAP
  prompt: >-
    Do the host genetic factors that determine cellular susceptibility to ricin
    translate into any difference in human clinical susceptibility?
  attaches_to:
  - pathophysiology#RTB Lectin Binding to Cell-Surface Galactosylated Glycoconjugates
  - pathophysiology#Retrograde Transport from the Golgi to the Endoplasmic Reticulum
  rationale: >-
    Cellular susceptibility to ricin has a real, mapped genetic architecture.
    Fucosylation controls it: losing the Golgi GDP-fucose transporter SLC35C1 or
    the fucosyltransferase FUT9 makes diverse cell types resistant, and cells
    from a patient with inherited SLC35C1 deficiency are resistant too.
    Sialylation of Lewis X structures runs the same axis in the opposite
    direction - inactivating the responsible sialyltransferase sensitises cells,
    overexpressing it protects them. The retrograde-transport machinery is a
    second axis, with STX5 and its ER-targeting factor ASNA1 among the top hits
    conferring resistance in genome-wide screens.

    Every one of those results is a statement about cells. Whether any of it
    shifts the dose of ricin a person survives is untested, and probably
    untestable by design - human exposure is rare, accidental or deliberate, and
    the delivered dose is never known. The gap is worth recording precisely
    because the cell-level evidence is strong enough to be mistaken for a
    susceptibility claim. It is also the reason this entry has no `genetic:`
    section: these are modifiers of a toxicological process, not disease genes.
  notes: >-
    The SLC35C1-deficient patient result is the closest thing to human data in
    this area, and it is an ex vivo cellular phenotype from a person with a
    congenital disorder of glycosylation, not an observation of ricin exposure
    in a person.
  evidence:
  - reference: PMID:28925387
    reference_title: A vital sugar code for ricin toxicity.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Genetic and pharmacological inhibition of fucosylation renders diverse cell types resistant to ricin via deregulated intracellular trafficking. Importantly, cells from a patient with SLC35C1 deficiency are also resistant to ricin."
    explanation: The fucosylation axis, including the one human-derived cellular result.
  - reference: PMID:28925387
    reference_title: A vital sugar code for ricin toxicity.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Inactivation of the sialyltransferase responsible for modifications of Lewis X (St3Gal4) increases the sensitivity of cells to ricin, whereas its overexpression renders cells more resistant to the toxin."
    explanation: The sialylation axis, in both directions.
  - reference: PMID:31674906
    reference_title: Retro-2 protects cells from ricin toxicity by inhibiting ASNA1-mediated ER targeting and insertion of tail-anchored proteins.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "our previous genome-wide CRISPR/Cas9 deletions screens have identified STX5 and its ER targeting factor, ASNA1 (also known as TRC40) among the top hits that confer resistance to ricin"
    explanation: The trafficking-machinery axis, from genome-wide screens.
  - reference: PMID:28925387
    reference_title: A vital sugar code for ricin toxicity.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: BACKGROUND
    snippet: "Although multiple cellular factors that are required for ricin toxicity have been identified, they often depend on cell type and organism of origin, as well as duration and amount of ricin exposure"
    explanation: >-
      Supports the caution in this gap - the host factors identified are
      themselves context-dependent, which is a further step away from an
      organismal susceptibility claim.
- discussion_id: inhalational_syndrome_known_only_from_animals
  kind: HUMAN_MODEL_MISMATCH
  prompt: >-
    Does the animal picture of inhalational ricinosis describe human
    inhalational ricin poisoning, given that no human case series exists to
    compare it against?
  attaches_to:
  - pathophysiology#Acute Lung Injury with Interstitial Pneumonia and Alveolar Edema
  - pathophysiology#Residual Pulmonary Fibrosis in Survivors
  rationale: >-
    Everything this entry records about the inhalational syndrome - the
    interstitial pneumonia, the neutrophil influx, the proteinaceous oedema, the
    progression to ARDS, the residual fibrosis in survivors - comes from mice,
    rabbits, rhesus macaques and swine. This is not the ordinary situation where
    an animal model stands in for a well-described human disease; there is no
    human description to stand in for.

    Two things make the mismatch substantive rather than formal. The models
    disagree among themselves: exposure method, breathing parameters, aerosol
    characteristics, ricin cultivar and purity, challenge dose and study
    duration all vary, and so do the species' anatomy, cell biology and
    immunology, which is why the comparative review calls the pathology broadly
    similar rather than the same. And the chronic endpoint is the one most
    exposed to species choice - susceptibility to pulmonary fibrosis and the
    character of the fibrosis that develops are themselves properties of the
    strain, so "survivors may be left with fibrosis" is a claim whose truth may
    depend on which animal was asked.
  notes: >-
    Recorded as `HUMAN_MODEL_MISMATCH` rather than `KNOWLEDGE_GAP` because the
    evidence is not absent - it is abundant, and its translational validity is
    the open question. Resolving it does not require a human challenge study:
    a harmonised multi-species protocol, or a documented human exposure with
    imaging and follow-up, would both narrow it.
  evidence:
  - reference: PMID:37104219
    reference_title: Comparative Aspects of Ricin Toxicity by Inhalation.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: REVIEW_SYNTHESIS
    snippet: "The toxicity and associated pathology described in animal models are broadly similar, but variation appears to exist."
    explanation: States the between-model variation that is half of this mismatch.
  - reference: PMID:37104219
    reference_title: Comparative Aspects of Ricin Toxicity by Inhalation.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: REVIEW_SYNTHESIS
    snippet: "Methodological variation is evident, including method of exposure, breathing parameters during exposure, aerosol characteristics, sampling protocols, ricin cultivar, purity and challenge dose and study duration."
    explanation: Enumerates the methodological sources of that variation.
  - reference: PMID:37104219
    reference_title: Comparative Aspects of Ricin Toxicity by Inhalation.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: REVIEW_SYNTHESIS
    snippet: "The model species and strain used represent other significant sources of variation, including differences in macro- and microscopic anatomy, cell biology and function, and immunology."
    explanation: The species-biology sources, which are the ones that bear on translation to humans.
  - reference: PMID:37104219
    reference_title: Comparative Aspects of Ricin Toxicity by Inhalation.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: REVIEW_SYNTHESIS
    snippet: "Chronic pathology of ricin toxicity by inhalation, associated with sublethal challenge or lethal challenge and treatment with medical countermeasures, has received less attention in the literature."
    explanation: >-
      Supports singling out the chronic endpoint as the weakest link, which is
      why the fibrosis node carries a LOW-fidelity model link.
- discussion_id: hypoglycemia_human_status
  kind: KNOWLEDGE_GAP
  prompt: >-
    Is ricin-induced hypoglycaemia a feature of human poisoning, or an artefact
    of the murine parenteral model?
  attaches_to:
  - pathophysiology#Cytokine-Mediated Suppression of Hepatic Glucose-6-Phosphatase
  - phenotypes#Hypoglycemia
  rationale: >-
    In mice, parenteral ricin causes profound hypoglycaemia that is the only
    laboratory abnormality for hours, and the mechanism has been worked out to
    the level of hepatic glucose-6-phosphatase suppression with a
    streptozotocin control ruling out an insulin-mediated route. That is a more
    complete mechanistic account than most of this entry carries.

    The positive human evidence is one clinical report that mentions
    hypoglycaemia without indicating whether anything was done about it. If the
    finding is real in humans it would be a cheap early marker of systemic
    exposure in exactly the situation - suspected deliberate poisoning, no
    exposure history - where the diagnosis is hardest. If it is murine, the
    phenotype recorded here should eventually be retired. Retrospective review
    of glucose values in published human cases would settle it without any new
    exposure, and the authors report that their own follow-up with those
    papers' authors failed.

    The mouse result is not unopposed. The same authors did not see
    hypoglycaemia in macaques exposed to aerosolised ricin, and note that
    inflammatory responses in mice and humans broadly differ. That negative
    changes both species and route at once, so it isolates neither - but it is
    why this reads as an open question rather than as a human finding awaiting
    measurement.
  evidence:
  - reference: PMID:36548717
    reference_title: "Parenteral Exposure of Mice to Ricin Toxin Induces Fatal Hypoglycemia by Cytokine-Mediated Suppression of Hepatic Glucose-6-Phosphatase Expression."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "we sought a humane endpoint to replace lethal challenge by searching for biomarkers of ricin toxicosis. We found that following intraperitoneal (ip) injection of ricin, the sole biochemical abnormality observed in the serum of mice was the rapid development of profound hypoglycemia"
    explanation: The murine finding, and the fact that it was sought as a biomarker rather than found incidentally.
  - reference: PMID:36548717
    reference_title: "Parenteral Exposure of Mice to Ricin Toxin Induces Fatal Hypoglycemia by Cytokine-Mediated Suppression of Hepatic Glucose-6-Phosphatase Expression."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "At least one clinical report of ricin toxicosis describes hypoglycemia, but does not indicate whether specific measures were taken to control the low blood glucose in this patient"
    explanation: >-
      The entirety of the positive non-murine evidence, and the reason this is
      filed as a gap rather than as a settled human phenotype.
  - reference: PMID:36548717
    reference_title: "Parenteral Exposure of Mice to Ricin Toxin Induces Fatal Hypoglycemia by Cytokine-Mediated Suppression of Hepatic Glucose-6-Phosphatase Expression."
    supports: REFUTE
    evidence_source: MODEL_ORGANISM
    snippet: "We did not observe hypoglycemia in macaques exposed to aerosolized ricin"
    explanation: >-
      The same authors' negative result, in a primate and by a different route.
      It cuts against the finding generalising, and is why this gap is open
      rather than merely unmeasured in humans.
  - reference: PMID:36548717
    reference_title: "Parenteral Exposure of Mice to Ricin Toxin Induces Fatal Hypoglycemia by Cytokine-Mediated Suppression of Hepatic Glucose-6-Phosphatase Expression."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Whether this path would occur in humans is not known. Inflammatory responses in mice and humans are known to broadly differ"
    explanation: >-
      The authors state the translational uncertainty themselves, and name the
      species difference that drives it.

📚

References & Deep Research

Deep Research

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

Evaluations and curation notes (3)

Record notes

Curated from a `claude_code` deep-research report (`research/Ricin_Poisoning-deep-research-claude_code.md`). That report was generated before the recipes emitted an in-line validation block, so `just validate-research-reference` and `just validate-research-terms` were run over it afterwards; the retro-fitted sections record 31/31 references resolved with no unresolved identifiers, and 46/47 CURIEs resolved with one obsolete (`GO:0030433`, which is not used here). Every ontology binding written into this entry was nevertheless re-derived by a fresh lookup rather than copied from the report, per the repository's term contract. That was not a formality: the report proposed `HP:0001395` for hepatic necrosis, which is a different term - the HPO term for *Hepatic necrosis* is `HP:0002605` - and most of its other suggestions were explicit "verify" placeholders rather than bindings. The report cited overwhelmingly by URL rather than by PMID, so its PMC and DOI links were run through the PMC ID Converter and the PMIDs cited here; a handful of its sources are Wikipedia pages, FBI press releases and news articles and are not cited at all. This is an acquired toxicosis with no Mendelian basis, so there is no GeneReviews chapter and no OMIM entry, and the `genetic:` section is deliberately absent rather than empty. `just check-genereviews` returns `NO_CHAPTER` for both Bookshelf collections. The deep-research report leaned heavily on a StatPearls chapter; nothing from it is cited here, because StatPearls is never a baseline in this repository. Its distinctive content - the routine-laboratory panel, chest imaging, the clustered-presentation epidemiologic heuristic, and the infectious and chemical differential list - was therefore not carried over at all rather than re-sourced. That is a real gap in `diagnosis:` and `differential_diagnoses:`, not a difference in citation. Host genetic modifiers of *cellular* susceptibility are real and well studied - the fucosylation and sialylation "sugar code" that controls how much toxin binds, and the retrograde-transport machinery that carries it in - but none is an organismal susceptibility locus for human disease, so they are recorded in `discussions` rather than curated as `genetic:` rows. `prevalence:` carries only a literature case count rather than a rate. No population-based incidence for ricin poisoning exists, because exposure is an intentional or accidental event rather than an endemic process; `measure_type: CASES_IN_LITERATURE` is used for exactly this reason. The evidence base is deliberately uneven and is graded to show it. The molecular chain from lectin binding through depurination to the ribotoxic stress response rests on `IN_VITRO` work; the organ-level consequences of inhalation rest entirely on `MODEL_ORGANISM` studies in mice, rabbits, macaques and swine, because no human inhalational case has ever been documented; injection is known from a handful of human cases plus mouse and swine work; and only the ingestion syndrome has a substantial human clinical literature. The hypoglycemia node is model-organism-only, and the same authors report a negative in aerosol-exposed macaques, so it is carried as an open question rather than promoted to a human phenotype. Two causal edges are deliberately left uncited. Apoptotic cell death is drawn to the gastrointestinal and to the hepatic/renal lesions because that is the mechanism, but the human autopsy series that establishes those lesions says nothing about how the cells died, and no cited study tests epithelial death against the mucosal lesion in gut the way PMID:36695077 does in lung. Reusing the autopsy sentence as edge evidence would have been node-level evidence papering over an unsourced edge, so it was removed rather than kept. Splenic necrosis is not curated as a phenotype although it appears inside quoted evidence. The murine intramuscular model shows spleen damage, but the systematic review of fatal human cases never mentions the spleen at all - "splen" does not occur in its text - so there is no human source for it. It is carried where it belongs, on the murine model, rather than promoted into the human clinical picture. `clinical_trials:` holds the two registered RVEc phase 1 studies and nothing else. The RiVax phase 1B publication registers no NCT identifier, and no interventional trial of a ricin *treatment* exists to register - every post-exposure countermeasure in `treatments:` is preclinical. Three bindings are deliberately broader than the thing they describe, each with its reason recorded beside it: `HP:0001928` for the coagulopathy (no cited source reports a clotting time), `HP:0031865` for the liver derangement (no source names an analyte), and `HP:0001878` for the haemolysis (the sources report haemolysis at autopsy, not an anaemia). Earlier drafts used narrower terms in all three places and in a fourth - an `Oliguria` phenotype inferred from "multi-organ failure" - which was removed outright because no source mentions it. A `Cough` phenotype went the same way: its only support was a vigilance recommendation that never uses the word.

Address PR #12109 review suggestions · 2026-09-18T03:02:36Z · View source

Round two on PR #12109. The automated review approved with zero critical and zero important findings; these are the five optional suggestions plus its second opinion on clinical_burden, all acted on at the user's request. clinical_burden HIGH to VARIABLE. The reviewer's argument is the one the entry's own rationale was already making - burden depends on the route, and the schema's VARIABLE description covers variation across contexts explicitly. A three-orders-of-magnitude spread in lethal dose between ingestion and inhalation is about as wide as context-dependence gets, and HIGH was the one place this entry flattened a distinction it works hard everywhere else to preserve. The reason for the change, and the fact that HIGH remains defensible on its mortality-risk clause, are recorded in a notes field beside the level. Differential diagnoses. The sepsis entry gained three quotes that were sitting unused in an already-committed cache - the review's 'can mimic several common medical conditions, most notably septic shock' and its 'as bacterial sepsis, particularly when no history of ricin exposure is available' - plus PMID:16168316 for the mimicry claim from a peer-reviewed source rather than StatPearls. A second differential entry was added for toxin-induced wide-complex tachycardia, from PMID:41788434, a 2026 case report that also produced a new phenotype. The reviewer suggested adding the biothreat differential (tularemia, Q fever, staphylococcal enterotoxin B, phosgene) from primary biodefense literature. PubMed searches for a peer-reviewed source making those comparisons for ricin specifically returned nothing usable; that list reaches this entry only through StatPearls. Recorded as a genuine gap in the differential's notes rather than filled with an invented citation. Depurination RT-PCR assay - suggestion accepted in principle, not actionable. It would be the one diagnostic reading out this entry's own central node, but the paper has no PubMed record and its cached entry carries content_type: unavailable with no retrievable abstract, so no exact quote exists. Recorded in the diagnosis notes with the reason and a standing instruction to add it once a quotable record appears. Adding it with a paraphrase would be the fabrication the evidence rules exist to prevent. Yeast necessary-but-not-sufficient result. Added PMID:17101666 as two REFUTE items on the translational-arrest to apoptosis edge: A-chain mutants that depurinated and arrested translation as fully as wild type still failed to kill. Note the reviewer placed this on 'the depurination to apoptosis edges, which are currently the two uncited ones' - that is a misreading. The uncited edges are apoptosis to the gastrointestinal and hepatic/renal lesions; the depurination path runs through translational arrest and the ribotoxic stress response, both of which were already cited. The result qualifies the arrest edge, which is where it now sits, and it makes the parallel stress-kinase branch load-bearing rather than decorative. Splenic necrosis - declined, with the reason recorded. HP:6000232 exists, but the systematic review of fatal human cases never mentions the spleen; the finding is murine only and is carried on the murine model rather than promoted into the human clinical picture. RVEc added as a second vaccine treatment (PMID:26546259), including the stopped 100-microgram arm, since a dose-limiting finding is part of what is known about a candidate. That paper registers two NCT identifiers, which the deep-research report had not surfaced, so a clinical_trials block was added for NCT01317667 and NCT01846104 - closing the one checklist dimension the reviewer marked as having a gap for a reason other than absent literature. New phenotype: Bidirectional ventricular tachycardia (HP:0034040), wired from the shock node with an INDIRECT_UNKNOWN_INTERMEDIATES edge because the case report offers its mechanism as a hypothesis, having excluded re-entry rather than shown triggered activity. Two snippets from the systematic review were rejected by linkml-reference-validator after passing count-verified-snippets, because they crossed words the scanned PDF hyphen-breaks across lines. Worth knowing the two tools differ here: the fast counter normalizes cache defects and reports it, the gating validator does not. Both were re-quoted from clean spans. Post-round state: 200/200 snippets verified offline, 26/26 phenotypes causally connected, validate-disorders passing, all offline gates green.

Create: Ricin Poisoning · 2026-09-18T00:20:14Z · View source

New Disease entry for ricin poisoning (MONDO:0035511), an acute toxin-exposure intoxication with no prior coverage in kb/disorders/. Duplicate preflight was clean on all three surfaces: git grep over origin/main for the MONDO ID and for 'ricin' returned only amphotericin/griseofulvin substring hits, and GitHub PR and issue searches returned zero results. Deep research: one run with the claude_code provider (just research-disorder claude_code Ricin_Poisoning), producing research/Ricin_Poisoning-deep-research-claude_code.md plus its citations sidecar. The report predates the in-line validation blocks, so just validate-research-reference and just validate-research-terms were run over it afterwards; the retro-fitted sections record 31/31 references resolved with zero unresolved, and 46/47 CURIEs resolved with one obsolete (GO:0030433, not used here). The report cites almost entirely by URL rather than by PMID, so its PMC and DOI links were converted through the PMC ID Converter and the resulting PMIDs cited; its Wikipedia, FBI and news-article sources were not used at all. Every ontology binding in the entry was re-derived by a fresh OLS lookup rather than copied from the report - which mattered, because the report proposed HP:0001395 for hepatic necrosis where the correct HPO term is HP:0002605. Content: a fifteen-node causal chain from route-dependent delivery through RTB lectin binding, endocytosis, retrograde transport to the ER, A-chain retrotranslocation, sarcin-ricin loop depurination, and then branching into translational arrest and the ribotoxic stress response, converging on apoptosis and cytokine release and then on the three route-specific organ lesions and shock. 22 phenotypes, all causally connected (just list-disconnected-phenotypes reports 22/22). Three environmental exposures, one per route, each pathograph-linked. Five treatments including the investigational antibody, vaccine and Retro-2 arms. Three animal models with typed modeled_mechanisms links. Three discussions: a KNOWLEDGE_GAP on host genetic modifiers of cellular susceptibility (which is also why there is no genetic: section), a HUMAN_MODEL_MISMATCH on the inhalational syndrome being known only from animals, and a KNOWLEDGE_GAP on whether ricin hypoglycaemia is a human finding or murine. Validation: just validate-disorders passed (schema, terms, references batched), 162/162 snippets verified against the local cache with no network fetches; just validate-terms passed; just compliance reports 91.8% weighted. Offline gates run and passing: check-folded-hyphens (one finding introduced and fixed by reflowing 'route-dependent'), check-snippet-length, check-title-snippets, check-snippet-grading, check-environmental-evidence, check-enum-values, check-duplicate-keys, check-qualifier-terms, check-entity-refs, check-causal-targets, check-case-collisions. just check-genereviews --online returns NO_CHAPTER for both Bookshelf collections, which the entry's notes record. Two bindings were deliberately left broader than the treatment they describe and the reason recorded in notes: NCIT has no gastric lavage term and NCIT:C68769 Decontamination is not reachable from NCIT:C25218, so gastrointestinal decontamination binds NCIT:C49236 Therapeutic Procedure; and NCIT:C77524 Activated Charcoal is not under NCIT:C1909 Pharmacologic Substance while CHEBI has no activated charcoal class, so therapeutic_agent is left empty there. Reference cache hygiene: 11 references fetched during research but cited by neither the entry nor the committed report were removed before commit. The cited-identifier list was re-derived from the entry immediately before pruning, and just count-verified-snippets was re-run on the pruned tree and still reports 162/162 verified offline. The eight DOI_* cache files and the report-cited PMIDs were kept deliberately, so the report's own retro-fitted "## Reference Validation" section stays reproducible without network access.

Claude Code ▸

Ricin Poisoning: Comprehensive Research Report

claude-haiku-4-5-20251001, claude-sonnet-5 62 citations 2026-09-17T23:46:04.512541

Ricin Poisoning: Comprehensive Research Report

1. Disease Information

Overview

Ricin poisoning is an acute, potentially life-threatening toxidrome caused by exposure — via ingestion, inhalation, injection, or (rarely) ocular/dermal contact — to ricin, a highly potent ribosome-inactivating protein (RIP) lectin found in the seeds ("castor beans") of Ricinus communis L. (family Euphorbiaceae), the castor oil plant. The condition is not a genetic disease but an environmentally/intentionally acquired toxin-mediated cellular injury syndrome: a single ricin molecule reaching the cytosol can inactivate ribosomes at a rate of ~1,500 per minute and is considered potentially lethal to that cell StatPearls NBK441948. Clinical severity and organ pattern depend heavily on the route of exposure, with inhalation being the most toxic route per unit dose, followed by parenteral injection, then ingestion StatPearls; NORD.

Ricin is produced as a defensive protein in the endosperm of castor seeds; the waste "mash" remaining after industrial extraction of castor oil (used for lubricants, biodiesel, and pharmaceutical excipients) contains approximately 5% ricin by weight, making it a large-scale, low-cost byproduct with genuine dual-use/bioterrorism concern StatPearls; CDC. Ricin is one of the most acutely toxic substances known — reported to be roughly 400× more toxic than cobra venom, 1,000× more toxic than cyanide, and 4,000× more toxic than arsenic on a molar/weight basis [WebSearch synthesis of toxicology reviews].

Key Identifiers

MONDO: MONDO:0035511 (ricin poisoning) — as provided in the task; cross-referenced by NORD/rarediseases.org MONDO page and MalaCards (Ricin Poisoning – MalaCards).
ICD-10-CM: T62.2X– series ("Toxic effect of other ingested (parts of) plant(s)"), with 5th/6th/7th-character modifiers for intent (accidental T62.2X1–, intentional self-harm T62.2X2–, assault T62.2X3–, undetermined T62.2X4–) and encounter type (initial A, subsequent D, sequela S) ICD List. No dedicated ICD-10 code exists specifically for "ricin" as distinct from generic plant-toxin ingestion; inhalational/parenteral ricin exposure would code under the corresponding T-code sections for those routes (curators should verify per current ICD-10-CM/ICD-11 tabular index rather than relying on T62.2 alone for non-oral routes).
CDC Select Agent status: Ricin toxin is a CDC Category B bioterrorism agent and is listed as a Schedule 1 toxic chemical under the Chemical Weapons Convention [WebSearch synthesis; CDC/NIOSH].
CHEBI: A specific curator-verified CHEBI accession for ricin (the ~65 kDa heterodimeric holotoxin) was not confirmed through available web search in this session — ChEBI is queryable at ebi.ac.uk/chebi, but no authoritative ID could be extracted from search snippets alone. This should be verified directly via OAK/ChEBI lookup before binding any CHEBI CURIE (per the project's "never write an ontology identifier from memory" rule).
NCIT: Not confirmed from search results; verify via runoak -i sqlite:obo:ncit search "ricin" for the correct term prior to binding.
Structural biology: Ricin is a ~65 kDa disulfide-linked AB-toxin glycoprotein: the A chain (RTA, ~32 kDa) is the catalytic N-glycosidase; the B chain (RTB, ~34 kDa) is a galactose/N-acetylgalactosamine-specific lectin. Isoforms D and E have been characterized Medical Countermeasures against Ricin Intoxication, Toxins 2023, doi:10.3390/toxins15020100; A Monoclonal Antibody with High Affinity for Ricin Isoforms D and E, Toxins 2024.

Synonyms / Alternative Names

Ricin toxin; castor bean toxin; Ricinus communis agglutinin II (RCA-II, to distinguish the toxic lectin from the non-toxic agglutinin RCA-I); "the perfect poison" (media/forensic shorthand); castor bean poisoning; ricinus toxicosis (veterinary usage).

Data Provenance

Information here derives from aggregated disease-level literature — case reports/series, systematic reviews, toxicology textbooks (StatPearls), CDC/NIOSH/OSHA fact sheets, and mechanistic bench-science publications — rather than a single large EHR cohort. No dedicated disease registry or large aggregated-EHR cohort for ricin poisoning was identified; most epidemiological and clinical-course data come from individual case reports, small case series, forensic/medico-legal case compilations, and animal-model extrapolation.

2. Etiology

Disease Causal Factor

Ricin poisoning has a single, well-defined toxicological (non-genetic, non-infectious) etiology: exposure to ricin protein, either from crude castor-seed material (chewed/crushed seeds, seed mash, homemade extracts) or from purified/semi-purified ricin preparations (forensic/bioterrorism scenarios). As few as two chewed castor seeds can cause toxicity in a child, although some adult patients have survived ingesting up to 30 seeds because intact (unchewed) seed coats resist digestion and pass through the GI tract without releasing ricin StatPearls NBK441948.

Risk Factors

Environmental/exposure risk factors (the dominant causal axis for this entry): - Occupational exposure in castor-oil processing facilities (seed handling, mash disposal) - Deliberate/criminal exposure (bioterrorism, assassination, self-harm) — historically documented incidents include the 1978 Georgi Markov assassination (injected ricin-laden pellet), the 2003/2004 White House and Senate mail incidents, and the 2013 letters mailed to President Obama and others Wikipedia: List of incidents involving ricin; FBI press releases - Accidental pediatric ingestion of ornamental castor bean plant seeds (castor bean is a common ornamental/landscaping plant) - Ingestion of adulterated herbal remedies containing castor bean material - Route of exposure itself strongly modifies risk: inhalation LD (5–10 µg/kg) << injection << ingestion (1–20 mg/kg) [StatPearls] - Age: pediatric patients are at higher risk from smaller absolute seed quantities due to lower body weight and greater likelihood of exploratory ingestion

Genetic/host risk and modifying factors (mechanistic, not classic Mendelian susceptibility): - A genome-wide mammalian genetic-interaction screen identified ~200 host factors that sensitize or protect cells from ricin, clustering around the retrograde-transport pathway, ribosome biogenesis, and cholesterol biosynthesis (HMG-CoA reductase inhibitors dose-dependently protect ricin-exposed cells) A Systematic Mammalian Genetic Interaction Map Reveals Pathways Underlying Ricin Susceptibility, Cell 2013 - Cell-surface glycosylation state modulates susceptibility: inactivation of the sialyltransferase responsible for Lewis X modification increases ricin sensitivity, while its overexpression confers relative resistance — i.e., host glycan "sugar code" is a documented modifier of cellular vulnerability A vital sugar code for ricin toxicity, Cell Research 2017 - No human Mendelian susceptibility locus or population-level genetic risk variant for ricin poisoning has been established in the literature surveyed; this is fundamentally an acute environmental exposure, not a heritable disease.

Protective factors: - Active immunization (RiVax/RVEc vaccines — see Treatment/Prevention) confers antibody-mediated protection in vaccinated individuals - Passive immunization with neutralizing anti-ricin monoclonal antibodies administered pre- or shortly post-exposure - Small-molecule retrograde-transport inhibitors (Retro-2) in preclinical models - HMGCR inhibitors (statins) show in vitro protective effects against ricin cytotoxicity, an unconfirmed but mechanistically plausible protective lead - Unbroken/unchewed seed coat (intact castor seeds largely resist gastric digestion, limiting toxin release)

Gene-Environment Interaction

There is no established classical gene-environment interaction for human disease susceptibility to ricin analogous to pharmacogenomic drug-metabolism variability. The closest documented analog is the cell-intrinsic host-factor network above (glycosylation machinery, retrograde-transport genes, cholesterol biosynthesis genes) that determines cellular — not organismal — susceptibility in experimental systems, which is a mechanistic rather than epidemiological GxE finding.

3. Phenotypes

Ricin poisoning phenotypes are strongly route-dependent. All are acute-onset (minutes to ~24 hours), non-progressive in a chronic sense (the condition either resolves with supportive care or evolves to multi-organ failure/death over days), and none currently have HPO frequency data (this is an acute toxidrome, not a chronic Mendelian phenotype set, so classic HPO frequency percentages from cohort studies are largely unavailable — most frequency information below is qualitative/case-series-derived).

A. Ingestion (oral) route

Phenotype	Suggested HP term	Onset/Notes
Nausea	HP:0002018 Nausea	Onset 15 min–20 h post-ingestion
Vomiting	HP:0002013 Vomiting	Early, prominent
Diarrhea (often hemorrhagic)	HP:0002014 Diarrhea	—
Abdominal pain / colic	HP:0002027 Abdominal pain	—
Hematemesis	HP:0002248 Hematemesis (or closest available HPO term)	Indicates GI mucosal necrosis
Melena	(search for closest HP GI-bleeding term)	—
Hepatic necrosis	HP:0001395 Hepatic necrosis (verify exact term)	Multi-organ target
Renal tubular necrosis / acute kidney injury	HP:0000083 Renal insufficiency / acute tubular necrosis term	—
Splenic necrosis	(verify HPO term)	Reported at autopsy in fatal cases
Hypovolemic shock	HP:0032263 or closest shock term	Late-stage

StatPersk; Ricin intoxication by lethal dose of castor seeds ingestion: a case report, PMC 2024

B. Inhalation route

Phenotype	Suggested HP term	Notes
Cough	HP:0012735 Cough	—
Wheezing	HP:0030828 Wheezing	—
Dyspnea	HP:0002094 Dyspnea	—
Sore throat / pharyngeal congestion	(verify HP term)	—
Fever	HP:0001945 Fever	—
Chest tightness	(verify HP term)	—
Diaphoresis	HP:0000975 (verify)	—
Pulmonary edema	HP:0100598 Pulmonary edema	Onset within hours
Interstitial pneumonia / necrotizing pneumonia	HP:0006515 (verify)	Documented in animal inhalation models and human case reports
Respiratory failure	HP:0002878 Respiratory failure	Terminal event in severe cases

Animal inhalation-model pathology corroborates the human picture: mice exposed to sublethal inhaled ricin show "marked interstitial pneumonia, neutrophil infiltration, pro-inflammatory cytokine response, alveolar macrophage and alveolar epithelial type II cell death and edema" over days 1–7, with residual peribronchial/perivascular inflammation, alveolar wall thickening, and possible mild fibrosis of respiratory bronchioles by day 34–96 Short- and long-term outcomes of pulmonary exposure to a sublethal dose of ricin in mice, Scientific Reports 2024; Comparative Aspects of Ricin Toxicity by Inhalation, Toxins 2023.

C. Injection/parenteral route

Phenotype	Suggested HP term	Notes
Localized erythema/induration at injection site	(verify HP term)	Immediate
Blistering	HP:0008066 Bullous skin lesions (verify closest)	—
Capillary leak syndrome	(search HP; may need free text)	Systemic vascular injury
Localized tissue necrosis	HP:0031630 or verify	—
Coagulopathy / prolonged PT-APTT	HP:0001928 Abnormal coagulation	Documented in mouse/swine IM models
Thrombocytopenia	HP:0001873 Thrombocytopenia	4–5-fold platelet decrease by 48–72h in mouse IM models
Shock	—	—
Multi-organ failure	HP:0001626 (cardiac) plus organ-specific terms	—

The classic Markov-case clinical course: "pain developed immediately at the injection site, weakness developed within 5 hours, fever and vomiting developed within 24 hours, followed by shock and multi-organ failure, and death within 3 days" Ricin and the Assassination of Georgi Markov.

D. Systemic / laboratory phenotypes (multiple routes)

Hypoglycemia: parenteral ricin exposure in mice induces fatal hypoglycemia via cytokine-mediated suppression of hepatic glucose-6-phosphatase expression Parenteral Exposure of Mice to Ricin Toxin Induces Fatal Hypoglycemia by Cytokine-Mediated Suppression of Hepatic Glucose-6-Phosphatase Expression, PMC 2022 — a plausible-but-model-organism-only finding (evidence_source: MODEL_ORGANISM)
Cytokine storm: sudden acute rise in circulating pro-inflammatory cytokines (TNF-α rises early/rapidly; IL-6, IL-1, IFN-γ, IL-17 rise later, if at all) Frontiers in Immunology 2022
Endothelial glycocalyx shedding: elevated soluble heparan sulfate, hyaluronic acid, and syndecan-1 in blood, with microvascular flow abnormality Intramuscular Exposure to a Lethal Dose of Ricin Toxin Leads to Endothelial Glycocalyx Shedding, PMC 2021
Leukocytosis, electrolyte abnormalities, hepatic/renal failure markers on routine labs [StatPearls]

Quality of Life Impact

Acute survivors generally recover fully with no long-term sequelae if supportive care is prompt (see Prognosis); however, animal inhalation models show residual pulmonary fibrosis and inflammatory changes persisting for weeks to months after sublethal exposure, raising the possibility of long-term respiratory impairment in inhalation survivors — no dedicated human quality-of-life instrument data (EQ-5D/SF-36) for ricin-poisoning survivors were identified in this search.

4. Genetic/Molecular Information

Ricin poisoning has no causal human gene — it is a toxin-exposure syndrome, not an inherited disease. This section is therefore reframed around the toxin's own molecular biology and the host genes it acts on/through, rather than a human disease-gene table.

The toxin's own molecular identity (source organism: Ricinus communis, not human)

Ricin is encoded by a gene family in castor bean; the mature protein is ~65 kDa, two chains (RTA ~32 kDa, RTB ~34 kDa) joined by a single disulfide bond ScienceDirect Topics: Ricin overview
RTA is a type II ribosome-inactivating protein (RIP) N-glycosidase (EC 3.2.2.22)
Isoforms D and E have been distinguished serologically, with isoform-specific monoclonal antibodies now characterized Toxins 2024

Host genes/targets relevant to mechanism (for `genetic:` or `biological_processes` annotation purposes, not as causal disease genes)

Ricin's molecular target: a single, universally conserved adenine (A4324 in humans) within the sarcin-ricin loop (SRL) of 28S rRNA, in the GAGA tetraloop motif — this is an RNA target, not a protein-coding gene, but is essential to describing mechanism
ASNA1/TRC40: mediates ER-targeting/insertion of tail-anchored proteins; required for ricin's translocation route and is the target of the protective small molecule Retro-2 Retro-2 protects cells from ricin toxicity by inhibiting ASNA1-mediated ER targeting, eLife 2019
HMGCR (HMG-CoA reductase): cholesterol-biosynthesis pathway gene whose inhibition (statins) protects cells from ricin in vitro [Cell 2013 genetic interaction map]
Sialyltransferase genes controlling Lewis X modification: loss increases ricin sensitivity in cellular models [Cell Research 2017]
ASGR1 (asialoglycoprotein receptor 1, hgnc-bound gene): plays a well-established role in hepatocyte receptor-mediated endocytosis of galactose/GalNAc-terminal glycoproteins generally, and ricin's B chain binds β-1,4-linked galactose residues on cell-surface glycoproteins/glycolipids broadly — however, a specific literature link establishing ASGR1 as ricin's primary hepatocyte entry receptor was not confirmed in this search; ricin's B-chain lectin binding is generally described as promiscuous across galactose/GalNAc-bearing surface receptors rather than ASGR1-specific, and this claim should not be curated without a direct primary-literature citation.

Variant classification / population frequency

Not applicable — there is no ClinVar/gnomAD-relevant human germline variant catalog for this toxin-exposure condition.

Epigenetics

No disease-specific epigenetic (DNA methylation/histone) literature for ricin poisoning was identified; this is outside scope for an acute-toxicity condition without chronic epigenetic reprogramming data in the literature surveyed.

Chromosomal abnormalities

Not applicable.

5. Environmental Information

Environmental/Toxicological Factor

The entry's entire "genetic/environmental" causal weight sits on the environmental side: ricin exposure from Ricinus communis is the sole documented cause. Key environmental-curation points:

Source material: castor bean seed, castor-oil-extraction waste mash (~5% ricin by weight)
Routes: ingestion (seeds, contaminated food/herbal products), inhalation (aerosolized powder — the highest bioterrorism/military concern route), injection (targeted assassination/self-harm), and rarely ocular or transdermal (with abraded skin) contact
Toxin stability: ricin is heat-labile above ~80°C but stable at room temperature for extended periods in dried/powdered form, relevant to environmental persistence and forensic sample handling

Occupational/Lifestyle Factors

Castor-oil industry workers handling seed mash
Home gardeners/ornamental-plant exposure (castor bean is a popular landscaping plant with visually distinctive but attractive spiny seed capsules, posing accidental pediatric ingestion risk)
Illicit drug/extraction-kit exposure (do-it-yourself extraction from online "recipes," as documented in the 2013 Dutschke case, where beans were purchased on eBay and processed with a coffee grinder FBI press release)

Infectious Agents

Not applicable — ricin poisoning is a non-infectious toxin exposure.

6. Mechanism / Pathophysiology

Ordered Causal Chain

Exposure to ricin-containing material (chewed/crushed castor seeds, extracted toxin powder, or purified ricin) leads to systemic or local absorption of the ricin heterodimer, depending on route (GI mucosa for ingestion; alveolar epithelium for inhalation; direct tissue/vascular deposition for injection).
The RTB lectin domain binds cell-surface glycoproteins/glycolipids bearing terminal β-1,4-linked galactose or N-acetylgalactosamine residues, which leads to receptor-mediated (clathrin-dependent or -independent, depending on the specific surface ligand engaged) endocytosis of the ricin holotoxin Ricin transport into cells: studies of endocytosis and intracellular transport, PMID:11111920.
Internalized ricin traffics retrogradely — early endosome → trans-Golgi network → Golgi → endoplasmic reticulum — bypassing lysosomal degradation via this non-canonical retrograde route, which is required for cytotoxicity (this retrograde step is the target of the experimental inhibitor Retro-2) Inhibition of Retrograde Transport Protects Mice from Lethal Ricin Challenge, Cell 2010.
In the ER, protein disulfide isomerase reduces the single A-chain/B-chain disulfide bond, and the partially unfolded RTA is translocated across the ER membrane into the cytosol via the Sec61 translocon (co-opting the ER-associated degradation/ERAD pathway meant for misfolded host proteins) — this dislocation step utilizes host ER-targeting/tail-anchored-protein machinery including ASNA1/TRC40 Dislocation of Ricin Toxin A Chains in Human Cells Utilizes Selective Cellular Factors, PMC 2011; Retro-2 mechanism, eLife 2019.
Cytosolic, catalytically active RTA hydrolyzes the N-glycosidic bond of a single, universally conserved adenine (A4324) within the sarcin-ricin loop (SRL) of the 28S ribosomal RNA in the 60S large ribosomal subunit, irreversibly depurinating this residue while leaving the RNA phosphodiester backbone intact Structures and Ribosomal Interaction of Ribosome-Inactivating Proteins, PMC 2018.
SRL depurination abolishes elongation-factor-1-dependent aminoacyl-tRNA binding and elongation-factor-2-dependent GTP hydrolysis at the ribosome, arresting protein synthesis at the elongation step — one RTA molecule can inactivate ~1,500 ribosomes/minute, so a very small number of cytosolic RTA molecules is sufficient to shut down a cell's entire translational output.
In parallel to (and partly downstream of) direct ribosome inactivation, the damaged sarcin-ricin loop itself acts as a stress signal, activating the ribotoxic stress response (RSR): the MAP3K ZAK senses SRL damage and activates p38 MAPK and JNK stress-activated protein kinase (SAPK) cascades Structures and Ribosomal Interaction of RIPs; Identification of Small Molecules That Suppress Ricin-Induced Stress-Activated Signaling Pathways, PLOS ONE.
SAPK/RSR activation drives two convergent downstream branches:
(8a) Apoptotic branch: ricin/RTA activates both the extrinsic (death-receptor) and intrinsic (mitochondrial) apoptosis pathways, with JNK signaling required for apoptosis in nontransformed epithelial cells Ricin A-chain requires JNK to induce apoptosis, PMC.
(8b) Pro-inflammatory branch: SAPK activation increases production of pro-inflammatory cytokines (TNF-α rising early; IL-6, IL-1, IFN-γ, IL-17 rising later in a delayed "cytokine storm" pattern), with airway epithelial NF-κB activation documented after inhalational exposure Frontiers Immunology 2022.
The combined loss of protein synthesis (step 6), apoptotic cell death (8a), and cytokine-driven inflammation (8b) leads to organ-specific tissue injury whose pattern tracks the exposure route: alveolar epithelial/macrophage death, neutrophil infiltration and pulmonary edema after inhalation; enterocyte/hepatocyte/splenocyte necrosis and hemorrhagic GI mucosal injury after ingestion; and local tissue necrosis with systemic vascular injury after injection.
Systemically, ricin binds preferentially to vascular endothelium, causing endothelial glycocalyx shedding (elevated circulating heparan sulfate, hyaluronic acid, syndecan-1) and microvascular flow abnormality, which leads to capillary leak syndrome, coagulopathy (prolonged PT/APTT, thrombocytopenia), and widespread hemorrhage Intramuscular Exposure to a Lethal Dose of Ricin Toxin Leads to Endothelial Glycocalyx Shedding, PMC 2021; Intramuscular Ricin Poisoning of Mice Leads to Widespread Damage in the Heart, Spleen, and Bone Marrow, Toxins 2019.
A cytokine-mediated suppression of hepatic glucose-6-phosphatase expression contributes to fatal hypoglycemia in parenteral-exposure mouse models — an additional, partially independent lethal mechanism layered on top of direct cytotoxicity (evidence: MODEL_ORGANISM only) PMC 2022, PMID search.
The cumulative effect of (9)–(11) — hypovolemic/distributive shock, multi-organ (hepatic, renal, splenic, cardiac, bone-marrow, pulmonary) failure, and refractory cardiovascular collapse — is the proximate cause of death in fatal cases, typically within 36–72 hours of severe untreated exposure.

Molecular Pathways (GO/pathway suggestions)

Ribosome inactivation / translational elongation arrest: GO:0017148 (negative regulation of translation), GO:0006414 (translational elongation)
rRNA N-glycosidase activity: GO:0030598 (rRNA N-glycosylase activity)
Ribotoxic stress response / SAPK activation: GO:0007254 (JNK cascade), GO:0038066 (p38MAPK cascade)
Apoptotic signaling, extrinsic and intrinsic: GO:0097191 (extrinsic apoptotic signaling pathway), GO:0097193 (intrinsic apoptotic signaling pathway)
Retrograde vesicle-mediated transport, Golgi to ER: GO:0042147 (retrograde transport, endosome to Golgi)
Endoplasmic-reticulum-associated protein catabolic process (ERAD, co-opted for translocation): GO:0030433
Cytokine-mediated inflammatory response: GO:0002526 (acute inflammatory response), GO:0032640 (TNF production)

Cell Types Involved (CL term suggestions — verify via OAK before binding)

Alveolar type I/II pneumocytes (CL:0002062, CL:0002063) and alveolar macrophages (CL:0000583) — inhalation route
Enterocytes / intestinal epithelial cells (CL:0000584) — ingestion route
Hepatocytes (CL:0000182), splenocytes, renal tubular epithelial cells (CL:1001318 or nearest), vascular endothelial cells (CL:0000115), cardiomyocytes (CL:0000746), bone marrow hematopoietic cells
Neutrophils (CL:0000775) — prominent infiltrating effector cell in pulmonary injury

Anatomical structures targeted (UBERON — verify via OAK)

Lung/respiratory epithelium (inhalation), small/large intestine mucosa (ingestion), liver, spleen, kidney (particularly renal tubules), bone marrow, heart, and systemic vasculature/microvasculature (all routes, secondary to endothelial tropism).

Molecular profiling

No large-scale human transcriptomic/proteomic/metabolomic dataset specific to ricin poisoning was identified; mouse pulmonary gene-expression profiling after inhaled ricin has been reported Pulmonary gene expression profiling of inhaled ricin, Toxicology 2003, and serum peptide/MALDI-TOF profiling has been explored as a murine diagnostic approach Detection of Ricin Intoxication in Mice Using Serum Peptide Profiling by MALDI-TOF/MS, PMC.

7. Anatomical Structures Affected

Organ level (primary): Route-dependent — lungs (inhalation), gastrointestinal tract (ingestion), skin/soft tissue at injection site (parenteral)
Organ level (secondary/systemic, all severe cases): liver (hepatic necrosis/failure), kidney (acute tubular necrosis), spleen (necrosis, reported at autopsy), heart (myocyte necrosis, collagen deposition in mouse IM models), bone marrow (widespread damage documented in mouse IM studies)
Body systems: respiratory, gastrointestinal, hepatic, renal, cardiovascular (via endothelial/coagulation injury), hematologic (thrombocytopenia, coagulopathy), immune (cytokine storm)
Tissue level: alveolar epithelium and interstitium, intestinal mucosa (hemorrhagic necrosis), vascular endothelium/glycocalyx (a specific, mechanistically central tissue target), skeletal/cardiac muscle at injection sites
Subcellular level: ribosome (60S large subunit, specifically the sarcin-ricin loop of 28S rRNA — GO Cellular Component: cytosolic large ribosomal subunit, GO:0022625), endoplasmic reticulum (site of A-chain translocation), Golgi/trans-Golgi network (retrograde transport waypoint), mitochondria (intrinsic apoptosis)
Localization: generally systemic/bilateral once absorbed; injection-site findings are unilateral/localized initially before systemic spread

8. Temporal Development

Onset

Acute onset in all routes; this is not a congenital/developmental-onset condition
Ingestion: symptom onset from as early as 15 minutes up to 20 hours post-exposure [WebSearch synthesis of case reports]
Inhalation: symptoms typically within a few hours
Injection: pain immediate at site; systemic symptoms (weakness, fever, vomiting) within 5–24 hours in the Markov case

Progression

Rapid progression pattern: mild, nonspecific prodromal GI or respiratory symptoms → hypovolemic/distributive shock → multi-organ failure → refractory cardiovascular collapse in severe/fatal cases Medico-legal aspects of fatal ricin poisoning systematic review, Int J Legal Med 2026, PMID:42560523
Time to death in severe, untreated exposure: typically 36–72 hours
No chronic/relapsing-remitting course — the condition is monophasic: either resolves with supportive care within days, or progresses to death within roughly 3–5 days
Long-term pulmonary sequelae (peribronchial/perivascular inflammation, mild fibrosis) can persist for weeks to months in inhalation-exposure survivors based on animal-model long-term follow-up Scientific Reports 2024; Long-Term Pulmonary Damage in Surviving Antitoxin-Treated Mice, Toxins 2024

Patterns

No spontaneous remission pattern reported beyond simple resolution of acute intoxication with supportive care in survivors
Critical intervention window: earliest possible decontamination/supportive care (within the first hour for GI decontamination) is repeatedly emphasized as the dominant modifiable prognostic factor

9. Inheritance and Population

Epidemiology

Ricin poisoning is rare as a clinical presentation; there is no formal population-based prevalence or incidence rate (cases per 100,000) reported in the literature, consistent with its status as an intentional/accidental toxin-exposure event rather than an endemic disease
Multiple discrete, well-documented bioterrorism/forensic incidents in the US and UK from 1978–2013 constitute the bulk of "epidemiological" data: Georgi Markov (1978, fatal), Vladimir Kostov (1978, survived), Boris Korczak (1981), 2003/2004 White House/Senate mail incidents, 2013 letters to President Obama and others (James Everett Dutschke case, and the 2013 Spokane, WA mailings) Wikipedia: List of incidents involving ricin; April 2013 ricin letters; 2003 ricin letters
The FBI has noted a possible increase in ricin-related copycat incidents attributed to the relative accessibility of extraction methods online Seattle Times coverage of 2013 cases

Inheritance Pattern

Not applicable — ricin poisoning is not a heritable Mendelian, X-linked, mitochondrial, or polygenic condition. There is no penetrance, expressivity, genetic anticipation, germline mosaicism, founder effect, consanguinity role, or carrier frequency to report, as this is an acquired toxic exposure.

Population Demographics

No specific ethnic/demographic predisposition documented (would be expected to track exposure opportunity rather than biological susceptibility)
Castor bean cultivation and endemic accidental-exposure risk is geographically concentrated where Ricinus communis is grown commercially or ornamentally (tropical/subtropical regions for cultivation; globally for ornamental garden use)
Age distribution: pediatric accidental ingestion cases (ornamental seed exposure) and adult intentional/forensic cases are the two dominant demographic clusters reported in case literature
No consistent sex ratio has been established from the sparse case-report literature

10. Diagnostics

Clinical/Laboratory Tests

Routine labs: leukocytosis, electrolyte abnormalities, elevated liver enzymes/renal function markers, coagulation panel abnormalities (prolonged PT/APTT), thrombocytopenia [StatPearls NBK441948]
Imaging: chest radiography (may be normal early, or show pulmonary edema/infiltrates/pneumonia pattern in inhalational exposure)
Histopathology (post-mortem or biopsy): hemorrhagic necrosis of GI tract, hepatic injury, renal tubular necrosis, cerebral/pulmonary edema, hepatic steatosis — from the 2026 medico-legal systematic review of fatal cases PMID:42560523

Specific/Confirmatory Diagnostic Methods

Ricinine biomarker (urine/serum): Ricinine (3-cyano-4-methoxy-N-methyl-2-pyridone), a minor castor-bean alkaloid co-extracted with ricin, is measurable by LC-MS/MS (including dried urine/blood spot methods) as a biomarker of castor-bean-product exposure. Reported urine concentrations 12–41 hours post-intoxication: 20–58 ng/mL, versus background population detection in only 1.2% of urine specimens (range 0.186–4.15 ng/mL) Analysis of a Ricin Biomarker, Ricinine, in 989 Individual Human Urine Samples, PMID:23471955; Serial ricinine levels in serum and urine after ricin intoxication, PMID:23592744. Important limitation: ricinine is a marker of castor-bean-product exposure, not of purified ricin — it "may be absent or present only in negligible amounts" in highly purified/criminal ricin preparations, so a negative ricinine result does not exclude purified-ricin poisoning.
Direct ricin detection: LC-MS/MS-based rapid serum ricin identification methods Rapid, Sensitive and Reliable Ricin Identification in Serum Samples Using LC–MS/MS, doi:10.3390/toxins13020079; immunoassays (ELISA-type); ambient mass spectrometry two-tiered screening approaches A Proof-of-Concept, Two-Tiered Approach for Ricin Detection Using Ambient Mass Spectrometry, PMID:35173958
Molecular/forensic depurination assay: RT-PCR-based (reverse transcription-ligase-PCR) detection of the specific depurinated adenine signature left in 28S rRNA after ricin action, usable on biological samples as a functional/mechanistic confirmatory test rather than direct toxin immunodetection Determination of ricin intoxication in biological samples by monitoring depurinated 28S rRNA, Forensic Toxicology 2018, doi:10.1007/s11419-017-0377-6
Nanopore direct RNA sequencing to identify depurination events induced by ricin and other RIPs — an emerging research-grade method bioRxiv 2021

Genetic Testing

Not applicable — no genetic test is diagnostic for this acquired toxin exposure.

Clinical Criteria / Epidemiologic Diagnostic Pattern

Per StatPearls, recognition often depends on exposure-pattern epidemiology rather than a single confirmatory bedside test: simultaneous presentation of multiple patients at one location with consistent symptoms (e.g., "sudden onset of respiratory distress among several people in one place") should raise suspicion for aerosolized/inhalational exposure; multi-patient GI-symptom clusters suggest ingestion exposure StatPearls NBK441948.

Differential Diagnosis

Cellulitis, pneumonia, sepsis, Salmonella/Shigella enteric infection, tularemia, Q fever, phosgene toxicity, staphylococcal enterotoxin B exposure, and myocardial infarction (for the shock/cardiovascular-collapse presentation) [StatPearls NBK441948].

Veterinary diagnosis (comparative)

In livestock, diagnosis "is based primarily on exposure history, compatible clinical signs, and identification of castor bean plants or seeds within the environment," since "bloodwork results are usually not specific to ricin poisoning" [castor bean toxicosis review, various veterinary sources].

11. Outcome/Prognosis

Survival and Mortality

With prompt supportive care, approximately 98% of people who ingest ricin survive, reflecting the relatively high oral LD (1–20 mg/kg) and the buffering effect of intact seed coats limiting toxin release [WebSearch synthesis of clinical toxicology sources]
Very limited human outcome data exist for inhalation or injection routes, given their rarity; these routes are associated with substantially lower LD (5–10 µg/kg inhalation) and historically higher lethality in documented forensic cases (e.g., Markov, fatal within days)
Severe/untreated exposure: progression to fatality within 36–72 hours, characterized by rapid evolution from nonspecific GI/respiratory prodrome to hypovolemic shock, multi-organ failure, and refractory cardiovascular collapse [Systematic review, Int J Legal Med 2026, PMID:42560523]

Morbidity/Function

Full recovery is typical in survivors of mild-to-moderate exposure managed supportively — e.g., a documented case of a 47-year-old woman who ingested six castor beans, received symptomatic treatment, and was "discharged home after a complete recovery three days later" [case report, ScienceDirect/PubMed synthesis]
Long-term pulmonary impairment is a plausible but human-data-sparse concern for inhalation survivors, based on residual fibrotic/inflammatory changes documented in mouse models up to day 96 post-exposure

Complications

Hypovolemic/distributive shock, disseminated coagulopathy and thrombocytopenia, capillary leak syndrome, hepatic and renal failure, hypoglycemia (model-organism evidence), and respiratory failure/ARDS-like picture in inhalation cases.

Prognostic Factors

Dose and route of exposure are the two dominant prognostic determinants
Time to initiation of supportive care is repeatedly emphasized in clinical sources as the single most important modifiable survival factor ("the single most important factor in survival is how quickly someone gets to emergency care after exposure")
No validated ricin-specific prognostic biomarker/severity score was identified in this search.

12. Treatment

No Approved Antidote

There is currently no FDA-approved antidote or specific antitoxin for human ricin poisoning. Management is exclusively supportive care, and this is the single most important treatment-section fact to encode [StatPearls NBK441948; multiple corroborating sources].

Supportive Care (by route) — suggested NCIT terms

Intervention	Route context	Suggested NCIT
Gastric lavage (within ~1 hour of ingestion)	Ingestion	NCIT:C15329 (Surgical/procedural) or nearest procedure term — verify
Activated charcoal administration	Ingestion (after airway secured)	verify NCIT term
Fluid resuscitation / IV fluids	All routes	NCIT:C15986 Pharmacotherapy (supportive)
Vasopressor support for shock	All routes, severe	NCIT:C15986 Pharmacotherapy
Mechanical ventilation / respiratory support	Inhalation	verify device/procedure term
Wound/skin decontamination (soap and water)	Dermal/injection-site	NCIT:C15747 Supportive Care
Correction of electrolyte/coagulopathy abnormalities	All routes, severe	NCIT:C15747 Supportive Care
Seizure management	Severe systemic cases	NCIT:C15986 Pharmacotherapy
ICU admission and monitoring	All symptomatic suspected exposures	NCIT:C15747 Supportive Care

"All symptomatic patients with suspected ricin exposure should be admitted" for monitoring [StatPearls NBK441948].

Experimental / Investigational Countermeasures

Passive immunotherapy — anti-ricin monoclonal antibodies: e.g., monoclonal antibody RicE5 conferred >90% survival in a murine model when given 6 hours post-intoxication, with 35% survival even at 24 hours post-exposure treatment; other monoclonal antibodies target isoforms D and E specifically PMC 2024, Toxins
Active immunization / vaccines:
RiVax: a recombinant RTA-based vaccine with two point mutations that genetically inactivate both the ribotoxic (N-glycosidase) active site and the vascular-leak-syndrome-inducing epitope; advanced through Phase 1A (dose-escalation, no adjuvant, 20/50/100 µg doses) and Phase 1B (alum-adjuvanted, safe/well-tolerated, improved neutralizing-antibody titers) human clinical trials Pilot Phase IB Clinical Trial of an Alhydrogel-Adsorbed Recombinant Ricin Vaccine, Clin Vaccine Immunol, doi:10.1128/cvi.00381-12; FDA granted Soligenix "Fast Track" designation for RiVax Global Biodefense
RVEc™: another recombinant ricin-toxin vaccine candidate with reported Phase 1 safety/immunogenicity data ScienceDirect, Vaccine 2015
Thermostable lyophilized subunit vaccine formulations have been shown to elicit durable immunity in preclinical models PMC 2021
Vaccine-induced serum antibody correlates of protection against aerosolized ricin have been profiled in rhesus macaques npj Vaccines 2022
Small-molecule retrograde-transport inhibitors: Retro-2 blocks ricin's retrograde trafficking at the early-endosome/TGN interface by inhibiting ASNA1/TRC40-mediated ER-targeting of tail-anchored proteins; "rescued mice from lethal doses of ricin" and was "tolerated at high doses" in preclinical studies — "the first small molecule that shows efficacy against ricin in animal experiments" Cell 2010; eLife 2019. A related "novel small molecule retrograde transport blocker" has shown post-exposure protection in preclinical models PMID:32140395.
Immunomodulatory/anti-inflammatory approaches: activation of the cholinergic anti-inflammatory pathway reduced ricin-induced mortality and organ failure in mice Molecular Medicine, doi:10.2119/molmed.2008.00105; small molecules suppressing ricin-induced SAPK stress signaling have been identified in screens PLOS ONE
Post-exposure antitoxin in large-animal models: post-exposure anti-ricin treatment protected swine against lethal systemic and pulmonary exposures PMC 2020

Treatment Strategy Notes for Curation

For a dismech Treatment entry, the mainstay entry should be treatment_term: NCIT:C15747 Supportive Care (verify exact NCIT code via OAK) with description covering airway/fluid/electrolyte management, and a separate experimental-treatment cluster for RiVax (therapeutic_modality: VACCINE) and anti-ricin monoclonal antibodies (therapeutic_modality: MONOCLONAL_ANTIBODY), each carrying its own PMID evidence and clearly marked as investigational/not FDA-approved.

13. Prevention

Primary Prevention

Occupational controls: PPE and engineering controls in castor-oil processing facilities to limit dust/mash exposure (OSHA hazard guidance exists: OSHA Ricin Hazard Recognition)
Restriction of access to purified ricin: Schedule 1 Chemical Weapons Convention controls and CDC Select Agent Program registration requirements for laboratories handling ricin toxin
Public/consumer safety: awareness messaging about ornamental castor bean plant seed toxicity, particularly for households with young children
Active immunization (RiVax/RVEc) is being developed specifically as a pre-exposure primary-prevention countermeasure for at-risk populations (military personnel, laboratory workers), not yet in general public use

Secondary Prevention / Early Detection

Rapid clinical recognition using the exposure-pattern heuristics above (clustered presentations)
Rapid decontamination protocols: GI decontamination (gastric lavage/activated charcoal) within the first hour of suspected ingestion; skin decontamination with soap and water for dermal exposure
Forensic/public-health mail-screening programs (developed in response to the 2003/2013 mail incidents) for early interception of intentional exposures

Tertiary Prevention

Aggressive ICU-level supportive care to prevent progression to multi-organ failure once poisoning is confirmed or strongly suspected.

Genetic Counseling / Screening

Not applicable — no heritable component to counsel on.

Public Health / Biodefense

Ricin's CDC Category B and CWC Schedule 1 status drive a public-health/biodefense prevention framework (select-agent regulation, law-enforcement interdiction, mail-screening infrastructure) distinct from the individual clinical-prevention measures above.

14. Other Species / Natural Disease

Taxonomy

Source organism: Ricinus communis L. (NCBITaxon:3988), family Euphorbiaceae
Affected species: broadly mammalian (and likely other vertebrate) susceptibility, given the conserved eukaryotic ribosomal sarcin-ricin loop target

Natural/Accidental Veterinary Disease

Castor bean toxicosis is a well-documented naturally occurring accidental poisoning in livestock and companion animals:

Relative species susceptibility: "Horses are the most susceptible of the farm animals; sheep, cattle and pigs are intermediate; and poultry are the most resistant" [Mad Barn veterinary summary; academic castor-bean-toxicosis reviews]
Toxic dose thresholds: seeds ingested at ~0.2% of body weight caused toxicosis in cattle; ~0.01% of body weight was toxic in horses
Onset/course: clinical signs appear 6–30 hours after seed ingestion; clinical evolution to death ranges from 4–56 hours across species
Clinical signs: predominantly gastrointestinal — diarrhea, vomiting, and colic (notably prominent in horses) — mirroring the human ingestion phenotype
Mechanistic prerequisite: "chewing of the beans is vital in releasing the ricin, as the seed coat is very hard and the seed will pass harmlessly through the digestive tract unless the seed coat is broken" — the same intact-seed-coat protective mechanism documented in human cases
Documented case reports/series: castor bean toxicosis in a sheep flock ScienceDirect; accidental poisoning by castor bean cake in horses in Brazil SciELO

Comparative Biology

The core molecular mechanism (RTA-mediated depurination of the conserved sarcin-ricin loop) is expected to be conserved across all eukaryotic species studied, since the SRL is a near-universally conserved rRNA element — this underlies both the broad mammalian veterinary susceptibility pattern and the utility of non-mammalian/cell-based systems (including yeast, Saccharomyces cerevisiae) for mechanistic dissection Ribosome Depurination Is Not Sufficient for Ricin-Mediated Cell Death in Saccharomyces cerevisiae, PMC — notably, this yeast study demonstrates that depurination alone is not sufficient for ricin-mediated cell death, implying additional downstream cytotoxic mechanisms beyond simple translational arrest, an important nuance for the mechanism-chain description above.

Transmission / Zoonotic Potential

Not applicable — ricin poisoning is a direct toxin exposure, not a transmissible infectious disease; there is no zoonotic transmission concept relevant here, only shared plant-source exposure risk across species.

15. Model Organisms

Mouse Models

Intranasal instillation: LD50 in rodents 3.5–4.8 µg/kg
Aerosolized inhalation: LD50 in mice 10–20 µg/kg (higher than intranasal instillation, attributed to nasal turbinate filtering of inhaled aerosol particles) Comparative Aspects of Ricin Toxicity by Inhalation, Toxins 2023
Intramuscular/parenteral models: demonstrate widespread damage to heart, spleen, and bone marrow, with diffuse hemorrhages, myocyte necrosis, collagen deposition, coagulopathy, and severe thrombocytopenia — closely recapitulating human injection-route pathology Toxins 2019, PMID:31208156
Pulmonary/inhalation models: recapitulate acute interstitial pneumonia, neutrophilic infiltration, pro-inflammatory cytokine response, and alveolar epithelial cell death (days 1–7), with residual inflammatory/fibrotic changes at days 21–96, closely tracking presumed human inhalation-injury biology (fidelity: HIGH to MODERATE for acute-phase pulmonary injury; long-term fibrosis correlation to humans is UNCONFIRMED due to sparse human inhalation-survivor data) Scientific Reports 2024
Hypoglycemia model: parenteral mouse exposure reveals a cytokine-mediated hepatic glucose-6-phosphatase suppression mechanism not yet confirmed in human cases — a clear candidate for HUMAN_MODEL_MISMATCH/translational-uncertainty flagging if curated PMC:9786807
Antitoxin/vaccine efficacy models: RiVax, RVEc, monoclonal antibody (RicE5 and others), and Retro-2 efficacy have all been established primarily in mouse lethal-challenge models, with confirmatory work extending to rhesus macaques (vaccine correlate-of-protection studies) and swine (post-exposure antitoxin efficacy for both systemic and pulmonary exposure, and endothelial glycocalyx/microvascular-flow pathology) npj Vaccines 2022; PMC 2020 swine antitoxin; PMC 2021 swine glycocalyx

Cellular/Genetic Screening Models

Genome-wide mammalian cell (haploid/CRISPR) genetic-interaction screens have identified ~200 sensitizing/protective host factors, clustering in retrograde transport, ribosome biogenesis, and cholesterol biosynthesis pathways — providing a systems-level map of cellular ricin susceptibility determinants usable for mechanistic annotation Cell 2013
Yeast (S. cerevisiae) models have been used to dissect depurination-vs-cytotoxicity relationships, showing depurination is necessary but not sufficient for cell death PMC, PMID search

Model Limitations

Nasal-anatomy differences between rodents and humans (turbinate filtering) complicate direct LD50 extrapolation for inhalation exposure
Most severe systemic pathophysiology data (coagulopathy, glycocalyx shedding, cytokine storm kinetics) derive from parenteral (IM/IV) rodent/swine models rather than the clinically more common ingestion route in humans — a route-mismatch worth flagging in any model-to-mechanism link (model_scale/divergences per dismech's ModelMechanismLink conventions)
No engineered genetic (knockout/transgenic) mouse model of "ricin poisoning" exists in the conventional sense, since this is an induced-exposure rather than genetic model; genetic screens instead identify modifier genes in cultured cells

Resources

No dedicated ricin-poisoning model repository/database catalog (comparable to IMPC/MGI for genetic disease models) was identified — model access is via individual published studies (MGI/RGD apply only incidentally, for strain-background documentation of the mice used in the cited studies).

Summary of Curation-Relevant Gaps and Cautions

No confirmed CHEBI or NCIT CURIE for ricin was extracted from this search — these must be looked up directly via OAK/ChEBI before binding, per dismech's ontology-term contract.
ASGR1-specific ricin hepatocyte-entry claim is unconfirmed — do not curate this link without a direct primary citation; ricin's B-chain lectin binding is generally described as broadly galactose/GalNAc-receptor-promiscuous rather than ASGR1-specific in the sources found.
Most severe-pathophysiology mechanistic detail (hypoglycemia, glycocalyx shedding, cytokine kinetics, coagulopathy) is MODEL_ORGANISM evidence (mouse/swine), not confirmed in human case series — grade evidence_source accordingly and consider HUMAN_MODEL_MISMATCH discussion entries where translational fidelity to human ricin poisoning is untested.
HPO term suggestions above are illustrative and unverified — every HP CURIE must be confirmed via OAK lookup (just validate-terms) before use; several suggested terms are marked "(verify exact term)" because exact-match searches were not run against the live HPO in this session.
This is fundamentally a toxicology/environmental entry with minimal true "genetic" content — Sections 4/9 genetic subsections are appropriately sparse and should not be padded to fit a template designed primarily for Mendelian disease.

Sources

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	31
Resolved	31
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	31
On topic	18
Off topic	0

All extracted references resolved successfully.

Term Validation

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

Outcome	Count
Terms checked	47
Resolved	46
Unresolved (possible confabulation)	0
Obsolete	1
Unverifiable	0
Terms whose name was checked	8
Terms named correctly	3
Terms named as a different term	4
Terms whose name is worth a second look	1

Terms the report names something else

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

HP:0000975 (1 mention) - the report calls it "verify"; HP calls it Hyperhidrosis
HP:0006515 (1 mention) - the report calls it "verify"; HP calls it Interstitial pneumonitis
HP:0001626 (1 mention) - the report calls it "cardiac"; HP calls it Abnormality of the cardiovascular system
CL:0000584 (1 mention) - the report calls it "Enterocytes / intestinal epithelial cells"; CL calls it enterocyte

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

GO:0030433 (obsolete ubiquitin-dependent ERAD pathway) (1 mention) - replaced by GO:0036503

Terms whose name is worth a second look

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

NCIT:C15329 (1 mention) - the report calls it "Surgical/procedural"; NCIT calls it Surgical Procedure

Ask OpenScientist

OpenScientist Report

Mappings

Discussions and Knowledge Gaps

Pathophysiology

Histopathology

Pathograph

Phenotypes

Medical Actions

Environmental Factors

Diagnosis

Progression

Prevalence

Clinical Burden

Differential Diagnoses

Clinical Trials

Animal Models

Source YAML

References & Deep Research

Deep Research

Ricin Poisoning: Comprehensive Research Report

1. Disease Information

Overview

Key Identifiers

Synonyms / Alternative Names

Data Provenance

2. Etiology

Disease Causal Factor

Risk Factors

Gene-Environment Interaction

3. Phenotypes

A. Ingestion (oral) route

B. Inhalation route

C. Injection/parenteral route

D. Systemic / laboratory phenotypes (multiple routes)

Quality of Life Impact

4. Genetic/Molecular Information

The toxin's own molecular identity (source organism: Ricinus communis, not human)

Host genes/targets relevant to mechanism (for genetic: or biological_processes annotation purposes, not as causal disease genes)

Variant classification / population frequency

Epigenetics

Chromosomal abnormalities

5. Environmental Information

Environmental/Toxicological Factor

Occupational/Lifestyle Factors

Infectious Agents

6. Mechanism / Pathophysiology

Ordered Causal Chain

Molecular Pathways (GO/pathway suggestions)

Cell Types Involved (CL term suggestions — verify via OAK before binding)

Anatomical structures targeted (UBERON — verify via OAK)

Molecular profiling

7. Anatomical Structures Affected

8. Temporal Development

Onset

Progression

Patterns

9. Inheritance and Population

Epidemiology

Inheritance Pattern

Population Demographics

10. Diagnostics

Clinical/Laboratory Tests

Specific/Confirmatory Diagnostic Methods

Genetic Testing

Clinical Criteria / Epidemiologic Diagnostic Pattern

Differential Diagnosis

Veterinary diagnosis (comparative)

11. Outcome/Prognosis

Survival and Mortality

Morbidity/Function

Complications

Prognostic Factors

12. Treatment

No Approved Antidote

Supportive Care (by route) — suggested NCIT terms

Experimental / Investigational Countermeasures

Treatment Strategy Notes for Curation

13. Prevention

Primary Prevention

Host genes/targets relevant to mechanism (for `genetic:` or `biological_processes` annotation purposes, not as causal disease genes)