Ricin Toxicity

Michael Hayoun; Erwin Kong; Matthew Smith; Kevin King

Ricin Toxicity

Earn CME/CE in your profession:

Free Review Questions

Continuing Education Activity

Ricin is a naturally occurring carbohydrate-binding protein produced in the seeds of ricinus communis, the plant that produces castor oil. It is toxic when inhaled, ingested, or injected. As few as five to ten micrograms per kilogram can be lethal. This activity reviews the evaluation and management of patients effected by ricin toxicity, and highlights the role of the interprofessional team in caring for these patients.

Objectives:

Explain the pathophysiology of ricin.
Outline the symptoms and presentation of patients exposed to ricin.
Summarize appropriate diagnostic testing and medical management of patients exposed to ricin.
Explain the importance of collaboration and communication amongst the interprofessional team as well as public health officials, law enforcement agencies, members of the media, and elected officials to ensure appropriate treatment of patients exposed to ricin and management of incidents involving ricin.

Introduction

Ricin is a naturally occurring carbohydrate-binding protein produced in the seeds of Ricinus communis, the castor oil plant. It is toxic when inhaled, ingested, or injected. As few as five to ten micrograms per kilogram can be lethal.

Etiology

Ricin is a lectin (carbohydrate-binding protein) produced in the endosperm of the seeds of the castor oil plant. Ingestion of as few as two castor oil plant seeds has been shown to be toxic, although patients have survived ingesting as many as 30. Ricin is also toxic by inhalation or injection, and as little as five to ten micrograms per kilogram by inhalation can be lethal. Ricin was developed as a biological weapon by both the United States and the Soviet Union. The castor oil plant grows in the wild in tropical climates. Approximately two million tons of castor seeds are produced yearly around the globe. Castor seeds can be crushed to extract castor oil, which has industrial applications in lubricants, dyes, preservatives, and pharmaceuticals. The waste mash of castor seeds after the oil extraction process is approximately 5% ricin by weight. This waste can be detoxified and used as a fertilizer or as a supplement in animal feed. [1] [2]

Epidemiology

If a group was targeted as part of a ricin attack, the presentation of some patients with a history of being at a particular place at the same time and complaining of similar symptoms consistent with the route of exposure would likely be the first epidemiologic red flag. Sudden onset of respiratory distress among several people in one place would evidence of aerosol exposure. Nausea, vomiting, and gastrointestinal hemorrhage would common in an ingestion exposure. [1]

Pathophysiology

Ricin is a globular glycoprotein that is composed of different protein chains connected by a disulfide bond. It is classified as a Type II ribosome-inactivating protein (RIP). The ricin toxin A chain inactivates ribosomes by hydrolyzing the N-glycosidic bond of an adenosine residue in the 28 S ribosomal RNA of eukaryotic cells; this inhibits protein synthesis by blocking the binding of elongation factors. This inhibition of protein synthesis by the ricin toxin A chain is a mechanism of ricin toxicity. The ricin toxin B chain binds to carbohydrates on the surface of eukaryotic cells and facilitates entry of the toxin into the cell. Ricin can enter the cell by numerous mechanisms including both receptor-mediated and adsorptive-mediated endocytosis. After endocytosis, ricin is transferred by vesicular transport from early endosomes to the trans-Golgi network, then undergoes retrograde vesicular transport through the Golgi apparatus. Ricin has been shown to be transported from the Golgi apparatus to the endoplasmic reticulum by the chaperone protein calreticulin. Once ricin reaches the endoplasmic reticulum, the disulfide bond between the A chain and the B chain is reduced by protein disulfide isomerase. The A chain then undergoes partial unfolding, after which it crosses the endoplasmic reticulum membrane via the Sec61p translocon. The unfolded A chain avoids ubiquitination because of its low lysine content, thus enabling the A chain to evade degradation by proteasomes and refold into its biologically active conformation, after which it resumes catalytic activity. [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20]

Toxicokinetics

Ricin toxin A chain can inactivate approximately 1500 ribosomes per minute. There are reports that a single molecule of ricin reaching the cytosol can be lethal to a cell. The lethal oral dose by ingestion in humans is estimated to be one to twenty milligrams per kilogram. As little as five to ten micrograms per kilogram by inhalation can be lethal. [21] [22] [23] [7] [8] [9] [10] [15]

History and Physical

Symptoms of ricin ingestion include nausea, vomiting, diarrhea, hematemesis, and melena. Necrosis of the spleen, liver, and kidneys may occur. Inhalation exposure symptoms include a cough, wheezing, dyspnea, sore throat, and congestion. Exposed patients may go on to develop pulmonary edema and pneumonia. Symptoms of injection exposure include erythema, induration, blisters, capillary leak syndrome, and localized necrosis surrounding the injection site. These symptoms may progress to seizures, shock, organ failure, pulmonary edema, and respiratory failure. Symptoms may begin within a few hours if ingested; however, symptoms may start almost immediately or may not be apparent for several hours in cases of ingestion or inhalation. [4]

Evaluation

Laboratory testing for ricin includes liquid chromatography-mass spectrometry and immunoassays. Laboratory studies may show leukocytosis, electrolyte abnormalities, liver failure, renal failure, and coagulopathy. Chest radiography may be normal or may show pulmonary edema or pneumonia in people with inhalational exposure. [24] [25] [26] [27] [28] [29] [30]

Treatment / Management

All symptomatic patients with suspected ricin exposure should be admitted. The treatment of ricin toxicity is supportive and includes management of shock, correction of electrolyte abnormalities, respiratory support, and treatment of seizures. Patients exposed to ricin by inhalation may require airway management and positive-pressure ventilation. Activated charcoal can be given to patients who have ingested ricin if vomiting has not yet occurred and the patient's airway has been secured. Gastric lavage can be used if the patient ingested ricin within the past hour. Electrolytes, coagulation studies, renal function, and liver function should be monitored; coagulopathies and electrolyte abnormalities should be corrected. There is no ricin antidote available for humans. [31] [32] [33] [34]

Differential Diagnosis

Cellulitis

Chemotherapeutic drugs

Capillary leak syndrome

CBRNE-Staphylococcal enterotoxin B

Myocardial infarction

Pneumonia

Plagues

Phosgene toxicity

Q fever

Salmonella infection

Shigella infection

Streptococcus aurea infection

Tularemia

Undifferentiated sepsis

Pearls and Other Issues

Ricin was used in the assassination of Bulgarian dissident Georgi Markov in London in 1978; a pellet containing ricin was found in his leg during an autopsy. A Bulgarian defector, Vladimir Kostov, survived a similar assassination attempt in Paris involving the injection of a pellet containing ricin under his skin ten days prior. In August 1981, double-agent Boris Korczak survived being shot by an air gun with a pellet containing ricin while at a grocery store in Virginia. In 2003, ricin was detected in a facility that handled mail for the White House. However, no one was harmed. In April 2013, envelopes addressed to President Barack Obama, Mississippi Senator Roger Wicker, and Lee County, Mississippi Judge Sadie Holland tested positive for ricin; Tupelo, Mississippi, resident Everett Dutschke was arrested later that month and plead guilty in May 2014. In May 2013, actress Shannon Richardson mailed letters containing ricin to President Barack Obama, New York City Mayor Michael Bloomberg, and Mark Glaze, who at that time was executive director of Mayors Against Illegal Guns. All suspected cases of ricin exposure should be reported to poison control and the health department. Ricin is included on the United States Department of Health and Human Services Select Agents and Toxins List under 42 CFR 73.3. [35] [36] [34]

Enhancing Healthcare Team Outcomes

Recent use of ricin demonstrates how incidents involving ricin will quickly become international news. Once a patient has been poisoned with ricin, healthcare providers will be responsible for communicating not only numerous colleagues and staff but also with public health officials, law enforcement agencies, members of the media, and elected officials. In attacks involving numerous numbers of casualties or high-profile targets such as elected officials, the marshaling of resources to respond will almost certainly reach the national level. (Level V)

Important interprofessional communication points early in the care of the patient among physicians, nurses, and pharmacists will include adequate decontamination of the patient and appropriate precautions for first responders and hospital staff to avoid additional casualties. Training and education prior to such an event will be more effective than just-in-time training after an event has occurred when emotions run high and resources may run low. In large-scale events, it will be essential for healthcare staff to have a clear understanding of their available resources as well as the anticipated demands on those resources, and continuously communicating with government officials to access medical supply stockpiles and resources for the capacity to treat large numbers of patients will be vital. (Level V)

Details

References

[1]

From S, Płusa T. [Today's threat of ricin toxin]. Polski merkuriusz lekarski : organ Polskiego Towarzystwa Lekarskiego. 2015 Sep:39(231):162-4 [PubMed PMID: 26449579]

[2]

Pita R, Romero A. Toxins as Weapons: A Historical Review. Forensic science review. 2014 Jul:26(2):85-96 [PubMed PMID: 26227025]

[3]

Tyagi N, Tyagi M, Pachauri M, Ghosh PC. Potential therapeutic applications of plant toxin-ricin in cancer: challenges and advances. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine. 2015 Nov:36(11):8239-46. doi: 10.1007/s13277-015-4028-4. Epub 2015 Sep 9 [PubMed PMID: 26349746]

Level 3 (low-level) evidence

[4]

Pincus SH, Bhaskaran M, Brey RN 3rd, Didier PJ, Doyle-Meyers LA, Roy CJ. Clinical and Pathological Findings Associated with Aerosol Exposure of Macaques to Ricin Toxin. Toxins. 2015 Jun 9:7(6):2121-33. doi: 10.3390/toxins7062121. Epub 2015 Jun 9 [PubMed PMID: 26067369]

[5]

Acosta W, Ayala J, Dolan MC, Cramer CL. RTB Lectin: a novel receptor-independent delivery system for lysosomal enzyme replacement therapies. Scientific reports. 2015 Sep 18:5():14144. doi: 10.1038/srep14144. Epub 2015 Sep 18 [PubMed PMID: 26382970]

[6]

O'Hara JM, Mantis NJ. Neutralizing monoclonal antibodies against ricin's enzymatic subunit interfere with protein disulfide isomerase-mediated reduction of ricin holotoxin in vitro. Journal of immunological methods. 2013 Sep 30:395(1-2):71-8. doi: 10.1016/j.jim.2013.06.004. Epub 2013 Jun 15 [PubMed PMID: 23774033]

[7]

Yermakova A, Klokk TI, O'Hara JM, Cole R, Sandvig K, Mantis NJ. Neutralizing Monoclonal Antibodies against Disparate Epitopes on Ricin Toxin's Enzymatic Subunit Interfere with Intracellular Toxin Transport. Scientific reports. 2016 Mar 7:6():22721. doi: 10.1038/srep22721. Epub 2016 Mar 7 [PubMed PMID: 26949061]

[8]

Wesche J. Retrograde transport of ricin. International journal of medical microbiology : IJMM. 2002 Feb:291(6-7):517-21 [PubMed PMID: 11890552]

[9]

Day PJ, Owens SR, Wesche J, Olsnes S, Roberts LM, Lord JM. An interaction between ricin and calreticulin that may have implications for toxin trafficking. The Journal of biological chemistry. 2001 Mar 9:276(10):7202-8 [PubMed PMID: 11113144]

[10]

Pasetto M, Barison E, Castagna M, Della Cristina P, Anselmi C, Colombatti M. Reductive activation of type 2 ribosome-inactivating proteins is promoted by transmembrane thioredoxin-related protein. The Journal of biological chemistry. 2012 Mar 2:287(10):7367-73. doi: 10.1074/jbc.M111.316828. Epub 2012 Jan 6 [PubMed PMID: 22228764]

[11]

Spooner RA, Watson PD, Marsden CJ, Smith DC, Moore KA, Cook JP, Lord JM, Roberts LM. Protein disulphide-isomerase reduces ricin to its A and B chains in the endoplasmic reticulum. The Biochemical journal. 2004 Oct 15:383(Pt 2):285-93 [PubMed PMID: 15225124]

[12]

Bellisola G, Fracasso G, Ippoliti R, Menestrina G, Rosén A, Soldà S, Udali S, Tomazzolli R, Tridente G, Colombatti M. Reductive activation of ricin and ricin A-chain immunotoxins by protein disulfide isomerase and thioredoxin reductase. Biochemical pharmacology. 2004 May 1:67(9):1721-31 [PubMed PMID: 15081871]

[13]

Allen SC, Moore KA, Marsden CJ, Fülöp V, Moffat KG, Lord JM, Ladds G, Roberts LM. The isolation and characterization of temperature-dependent ricin A chain molecules in Saccharomyces cerevisiae. The FEBS journal. 2007 Nov:274(21):5586-99 [PubMed PMID: 17916187]

[14]

Jolliffe NA, Di Cola A, Marsden CJ, Lord JM, Ceriotti A, Frigerio L, Roberts LM. The N-terminal ricin propeptide influences the fate of ricin A-chain in tobacco protoplasts. The Journal of biological chemistry. 2006 Aug 18:281(33):23377-85 [PubMed PMID: 16774920]

[15]

Vago R, Marsden CJ, Lord JM, Ippoliti R, Flavell DJ, Flavell SU, Ceriotti A, Fabbrini MS. Saporin and ricin A chain follow different intracellular routes to enter the cytosol of intoxicated cells. The FEBS journal. 2005 Oct:272(19):4983-95 [PubMed PMID: 16176271]

[16]

Lord MJ, Jolliffe NA, Marsden CJ, Pateman CS, Smith DC, Spooner RA, Watson PD, Roberts LM. Ricin. Mechanisms of cytotoxicity. Toxicological reviews. 2003:22(1):53-64 [PubMed PMID: 14579547]

[17]

Spooner RA, Lord JM. Ricin trafficking in cells. Toxins. 2015 Jan 9:7(1):49-65. doi: 10.3390/toxins7010049. Epub 2015 Jan 9 [PubMed PMID: 25584427]

[18]

Endo Y, Mitsui K, Motizuki M, Tsurugi K. The mechanism of action of ricin and related toxic lectins on eukaryotic ribosomes. The site and the characteristics of the modification in 28 S ribosomal RNA caused by the toxins. The Journal of biological chemistry. 1987 Apr 25:262(12):5908-12 [PubMed PMID: 3571242]

[19]

Endo Y, Tsurugi K. The RNA N-glycosidase activity of ricin A-chain. The characteristics of the enzymatic activity of ricin A-chain with ribosomes and with rRNA. The Journal of biological chemistry. 1988 Jun 25:263(18):8735-9 [PubMed PMID: 3288622]

[20]

Deeks ED, Cook JP, Day PJ, Smith DC, Roberts LM, Lord JM. The low lysine content of ricin A chain reduces the risk of proteolytic degradation after translocation from the endoplasmic reticulum to the cytosol. Biochemistry. 2002 Mar 12:41(10):3405-13 [PubMed PMID: 11876649]

[21]

Jetzt AE, Li XP, Tumer NE, Cohick WS. Toxicity of ricin A chain is reduced in mammalian cells by inhibiting its interaction with the ribosome. Toxicology and applied pharmacology. 2016 Nov 1:310():120-128. doi: 10.1016/j.taap.2016.09.004. Epub 2016 Sep 15 [PubMed PMID: 27639428]

[22]

Meneguelli de Souza LC, Carvalho LP, Araújo JS, Melo EJT, Machado OLT. Cell toxicity by ricin and elucidation of mechanism of Ricin inactivation. International journal of biological macromolecules. 2018 Jul 1:113():821-828. doi: 10.1016/j.ijbiomac.2018.03.024. Epub 2018 Mar 6 [PubMed PMID: 29522821]

[23]

Liu WY. Research on ribosome-inactivating proteins from angiospermae to gymnospermae and cryptogamia. American journal of translational research. 2017:9(12):5719-5742 [PubMed PMID: 29312524]

[24]

Simon S, Worbs S, Avondet MA, Tracz DM, Dano J, Schmidt L, Volland H, Dorner BG, Corbett CR. Recommended Immunological Assays to Screen for Ricin-Containing Samples. Toxins. 2015 Nov 26:7(12):4967-86. doi: 10.3390/toxins7124858. Epub 2015 Nov 26 [PubMed PMID: 26703725]

[25]

Worbs S, Skiba M, Söderström M, Rapinoja ML, Zeleny R, Russmann H, Schimmel H, Vanninen P, Fredriksson SÅ, Dorner BG. Characterization of Ricin and R. communis Agglutinin Reference Materials. Toxins. 2015 Nov 26:7(12):4906-34. doi: 10.3390/toxins7124856. Epub 2015 Nov 26 [PubMed PMID: 26703723]

[26]

Diakite ML, Rollin J, Jary D, Berthier J, Mourton-Gilles C, Sauvaire D, Philippe C, Delapierre G, Gidrol X. Point-of-care diagnostics for ricin exposure. Lab on a chip. 2015 May 21:15(10):2308-17. doi: 10.1039/c5lc00178a. Epub [PubMed PMID: 25892365]

[27]

Bozza WP, Tolleson WH, Rivera Rosado LA, Zhang B. Ricin detection: tracking active toxin. Biotechnology advances. 2015 Jan-Feb:33(1):117-123. doi: 10.1016/j.biotechadv.2014.11.012. Epub 2014 Dec 4 [PubMed PMID: 25481398]

Level 3 (low-level) evidence

[28]

Slotved HC, Sparding N, Tanassi JT, Steenhard NR, Heegaard NH. Evaluating 6 ricin field detection assays. Biosecurity and bioterrorism : biodefense strategy, practice, and science. 2014 Jul-Aug:12(4):186-9. doi: 10.1089/bsp.2014.0015. Epub 2014 Jun 30 [PubMed PMID: 24978020]

[29]

Tevell Åberg A, Björnstad K, Hedeland M. Mass spectrometric detection of protein-based toxins. Biosecurity and bioterrorism : biodefense strategy, practice, and science. 2013 Sep:11 Suppl 1():S215-26. doi: 10.1089/bsp.2012.0072. Epub [PubMed PMID: 23971809]

[30]

Becker B, Schnöder T, Schmitt MJ. Yeast Reporter Assay to Identify Cellular Components of Ricin Toxin A Chain Trafficking. Toxins. 2016 Dec 6:8(12): [PubMed PMID: 27929418]

[31]

Ricin: current understanding and prospects for an antiricin vaccine., Marsden CJ,Smith DC,Roberts LM,Lord JM,, Expert review of vaccines, 2005 Apr [PubMed PMID: 15889996]

Level 3 (low-level) evidence

[32]

Marsden CJ, Knight S, Smith DC, Day PJ, Roberts LM, Phillips GJ, Lord JM. Insertional mutagenesis of ricin A chain: a novel route to an anti-ricin vaccine. Vaccine. 2004 Jul 29:22(21-22):2800-5 [PubMed PMID: 15246614]

[33]

Coopman V, De Leeuw M, Cordonnier J, Jacobs W. Suicidal death after injection of a castor bean extract (Ricinus communis L.). Forensic science international. 2009 Aug 10:189(1-3):e13-20. doi: 10.1016/j.forsciint.2009.04.019. Epub 2009 May 23 [PubMed PMID: 19477090]

[34]

Schep LJ, Temple WA, Butt GA, Beasley MD. Ricin as a weapon of mass terror--separating fact from fiction. Environment international. 2009 Nov:35(8):1267-71. doi: 10.1016/j.envint.2009.08.004. Epub 2009 Sep 19 [PubMed PMID: 19767104]

[35]

Centers for Disease Control and Prevention (CDC). Investigation of a ricin-containing envelope at a postal facility--South Carolina, 2003. MMWR. Morbidity and mortality weekly report. 2003 Nov 21:52(46):1129-31 [PubMed PMID: 14627953]

[36]

Gaillard Y, Regenstreif P, Fanton L. Modern toxic antipersonnel projectiles. The American journal of forensic medicine and pathology. 2014 Dec:35(4):258-64. doi: 10.1097/PAF.0b013e318288abe8. Epub [PubMed PMID: 25354227]