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Ricin and abrin
Chemical terrorism
Ricin and abrin Sally Bradberry
Abstract Ricin is derived from the beans of the castor oil plant Ricinus communis. Many of the features seen in poisoning can be explained by ricin-induced endothelial cell damage, which leads to fluid and protein leakage and tissue oedema, causing so-called ‘vascular leak syndrome’. Immunization against ricin exposure using inactivated ricin toxoid or genetically engineered ricin A chain are realistic future therapeutic options. Abrin is a plant toxin obtained from the seeds of Abrus precatorius, which is closely related to ricin in terms of its structure and chemical properties.
Keywords abrin; mechanisms of toxicity; poisoning; ricin; vascular leak syndrome
Figure 1 Structure of ricin. The α carbon backbone of ricin toxin B chain (RTB) is shown in green whilst that of ricin toxin A chain (RTA) is coloured according to its structure with α-helices in pink, β-strands in yellow and coil in white. The site of the single interchain disulphide bond is shown in blue.1 Courtesy of Professor Mike Lord.
Ricin Source, structure and potential use as a chemical weapon Ricin is a globular glycoprotein derived from the beans of the castor oil plant Ricinus communis. It can be extracted easily from whole beans or from the waste ‘mash’ remaining after castor oil extraction. The toxin is inactivated by heating for 10 minutes at 80°C. Ricin toxin comprises an A chain (or RTA) and a B chain (or RTB), linked by a single disulphide bond (Figure 1). The A chain confers cellular toxicity while the B chain is essential for cell binding.1 Use of ricin to cause mass casualties would require either aerosolization by means of a dispersal device or its addition to food or beverages as a contaminant. By inhalation or injection, the lethal dose is about 5–10 μg/kg but it is approximately one thousand-fold less toxic by ingestion.2 Ricin is not absorbed through intact skin.
by ricin- induced endothelial cell damage, which leads to fluid and protein leakage and tissue oedema, causing so-called ‘vascular leak syndrome’. Subsequent to protein synthesis termination a process of programmed cell death, apoptosis, ensues.3 The details of this process remain to be clarified but there is evidence that ricin A and B chains are involved and that the mechanism is independent of that which inhibits protein synthesis.4 Features Ingestion Most cases involve eating castor beans. Beans swallowed whole may pass through the gastrointestinal tract intact, whereas chewing facilitates ricin release. Vomiting, diarrhoea and abdominal pain ensue. Gastrointestinal fluid and electrolyte loss may be substantial and complicated by haematemesis or melaena, hypovolaemic shock and multiorgan failure.
Mechanisms of toxicity Ricin binds to cell surface carbohydrates containing terminal N-acetyl galactosamine or β-1,4-linked galactose residues.1 In addition, ricin contains a large number of mannose residues by which it can bind to the limited number of cell lines that bear mannose receptors. Among these are cells of the reticulo-endothelial system which are therefore particularly susceptible to ricin toxicity. Once internalized, the A chain inhibits protein synthesis by cleaving a specific glycosidic bond within the 60S subunit of ribosomal RNA.1 Many of the features seen in poisoning can be explained
Inhalation Non-human primates exposed to ricin by inhalation develop a fibrinopurulent necrotizing pneumonia, typically after a dose-dependent delay of 8–24 hours. Non-pulmonary effects do not occur.5 Parenteral administration Among the small number of reports of parenteral ricin administration, the most well-known is the assassination of the Bulgarian refugee Georgi Markov who died three days after being stabbed with an umbrella believed to be loaded with a ricin-containing pellet. Fatigue, nausea, vomiting and fever developed over 24 hours followed by necrotic lymphadenopathy at the injection
Sally Bradberry BSc MRCP is Assistant Director of the National Poisons Information Service (Birmingham Unit) at City Hospital, Birmingham, UK. Competing interests: none declared.
MEDICINE 35:10
576
© 2007 Elsevier Ltd. All rights reserved.
Chemical terrorism
site. Pre-terminal complications included gastrointestinal haemorrhage, hypovolaemic shock and renal failure.6
References 1 Lord MJ, Jolliffe NA, Marsden CJ, et al. Ricin: mechanisms of cytotoxicity. Toxicol Rev 2003; 22: 53–64. 2 Franz DR, Jaax NK. Ricin toxin. In: Zajtchuk R, Bellamy RF, eds. Textbook of military medicine. Part I. Warfare, weaponry, and the casualty. Washington DC: Office of the Surgeon General at TMM Publications, 1997. 3 Hughes JN, Lindsay CD, Griffiths GD. Morphology of ricin and abrin exposed endothelial cells is consistent with apoptotic cell death. Hum Exp Toxicol 1996; 15: 443–51. 4 Battelli MG. Cytotoxicity and toxicity to animals and humans of ribosome-inactivating proteins. Mini Rev Med Chem 2004; 4: 513–21. 5 Wilhelmsen C, Pitt L. Lesions of acute inhaled lethal ricin intoxication in rhesus monkeys. Vet Pathol 1993; 30: 482. 6 Crompton R, Gall D. Georgi Markov – death in a pellet. Med Leg J 1980; 48: 51–62. 7 Leith AG, Griffiths GD, Green MA. Quantification of ricin toxin using a highly sensitive avidin/biotin enzyme-linked immunosorbent assay. J Forensic Sci Soc 1988; 28: 227–36. 8 Shyu H-F, Chiao D-J, Liu H-W, Tang S-S. Monoclonal antibody-based enzyme immunoassay for detection of ricin. Hybrid Hybridomics 2002; 21: 69–73. 9 Bradberry SM, Lord JM, Rice P, Vale JA. Ricin and abrin poisoning. In: Marrs TC, Maynard RL, Sidell FR, eds. Chemical warfare agents: toxicology and treatment. 2nd edn. Chichester: John Wiley & Sons, 2007: 613–31. 10 Bradberry SM, Dickers KJ, Rice P, et al. Ricin poisoning. Toxicol Rev 2003; 22: 65–70. 11 Marsden CJ, Smith DC, Roberts LM, Lord JM. Ricin: current understanding and prospects for an antiricin vaccine. Expert Rev Vaccines 2005; 4: 229–37. 12 Griffiths GD, Lindsay CD, Upshall DG. Examination of the toxicity of several protein toxins of plant origin using bovine pulmonary endothelial cells. Toxicology 1994; 90: 11–27. 13 Davis JH. Abrus precatorius (rosary pea). The most common lethal plant poison. J Fla Med Assoc 1978; 65: 188–91. 14 Guggisberg M. A propos d’une curieuse intoxication par des grains de chapelet (Abrus precatorius). Rev Med Suisse Romande 1968; 88: 206–8. 15 Fernando C. Poisoning due to Abrus precatorius (jequirity bean). Anaesthesia 2001; 56: 1178–80. 16 Pillay VV, Bhagyanathan PV, Krishnaprasad R, et al. Poisoning due to white seed variety of Abrus precatorius. J Assoc Physicians India 2005; 53: 317–19.
Diagnosis Ricin or its constituent A or B chains can be detected by immunoabsorbant assay for up to 48 hours after exposure.7,8 Detection of antiricin antibodies could aid diagnosis in those who survive for 2–3 weeks but will not be detected in those who die soon after exposure. Management Management is symptomatic and supportive.9,10 Immunization against ricin exposure using inactivated ricin toxoid or genetically engineered ricin A chain are realistic future therapeutic options.11
Abrin Source, structure and potential use as a chemical weapon Abrin is a plant toxin, which is closely related to ricin in terms of its structure and chemical properties. It is obtained from the seeds of Abrus precatorius (commonly known as jequirity bean or rosary pea), a tropical vine cultivated as an ornamental plant in many locations. Jequirity beans are usually scarlet in colour with a black spot at one end (though less common different coloured varieties exist) and are approximately 3 × 8 mm in size. Like ricin, abrin is a type 2 ribosome inactivating protein with A and B chains linked by a disulphide bond. At least theoretically, the similarity of abrin to ricin gives it a similar potential as a chemical weapon. Mechanisms of toxicity The mechanism of ribosome inactivation by abrin is essentially identical to ricin, except that in vitro studies suggest abrin is an even more potent toxin than ricin in this regard.12 Features Features following substantial abrin ingestion have usually been very similar in nature and time course to those described for ricin, with initial gastrointestinal manifestations13–16 followed in severe cases by neurological features and organ failure.16 Management The principles of management of abrin poisoning are similar to those for ricin. ◆
MEDICINE 35:10
577
© 2007 Elsevier Ltd. All rights reserved.
Ricin and abrin Sally Bradberry
Abstract Ricin is derived from the beans of the castor oil plant Ricinus communis. Many of the features seen in poisoning can be explained by ricin-induced endothelial cell damage, which leads to fluid and protein leakage and tissue oedema, causing so-called ‘vascular leak syndrome’. Immunization against ricin exposure using inactivated ricin toxoid or genetically engineered ricin A chain are realistic future therapeutic options. Abrin is a plant toxin obtained from the seeds of Abrus precatorius, which is closely related to ricin in terms of its structure and chemical properties.
Keywords abrin; mechanisms of toxicity; poisoning; ricin; vascular leak syndrome
Figure 1 Structure of ricin. The α carbon backbone of ricin toxin B chain (RTB) is shown in green whilst that of ricin toxin A chain (RTA) is coloured according to its structure with α-helices in pink, β-strands in yellow and coil in white. The site of the single interchain disulphide bond is shown in blue.1 Courtesy of Professor Mike Lord.
Ricin Source, structure and potential use as a chemical weapon Ricin is a globular glycoprotein derived from the beans of the castor oil plant Ricinus communis. It can be extracted easily from whole beans or from the waste ‘mash’ remaining after castor oil extraction. The toxin is inactivated by heating for 10 minutes at 80°C. Ricin toxin comprises an A chain (or RTA) and a B chain (or RTB), linked by a single disulphide bond (Figure 1). The A chain confers cellular toxicity while the B chain is essential for cell binding.1 Use of ricin to cause mass casualties would require either aerosolization by means of a dispersal device or its addition to food or beverages as a contaminant. By inhalation or injection, the lethal dose is about 5–10 μg/kg but it is approximately one thousand-fold less toxic by ingestion.2 Ricin is not absorbed through intact skin.
by ricin- induced endothelial cell damage, which leads to fluid and protein leakage and tissue oedema, causing so-called ‘vascular leak syndrome’. Subsequent to protein synthesis termination a process of programmed cell death, apoptosis, ensues.3 The details of this process remain to be clarified but there is evidence that ricin A and B chains are involved and that the mechanism is independent of that which inhibits protein synthesis.4 Features Ingestion Most cases involve eating castor beans. Beans swallowed whole may pass through the gastrointestinal tract intact, whereas chewing facilitates ricin release. Vomiting, diarrhoea and abdominal pain ensue. Gastrointestinal fluid and electrolyte loss may be substantial and complicated by haematemesis or melaena, hypovolaemic shock and multiorgan failure.
Mechanisms of toxicity Ricin binds to cell surface carbohydrates containing terminal N-acetyl galactosamine or β-1,4-linked galactose residues.1 In addition, ricin contains a large number of mannose residues by which it can bind to the limited number of cell lines that bear mannose receptors. Among these are cells of the reticulo-endothelial system which are therefore particularly susceptible to ricin toxicity. Once internalized, the A chain inhibits protein synthesis by cleaving a specific glycosidic bond within the 60S subunit of ribosomal RNA.1 Many of the features seen in poisoning can be explained
Inhalation Non-human primates exposed to ricin by inhalation develop a fibrinopurulent necrotizing pneumonia, typically after a dose-dependent delay of 8–24 hours. Non-pulmonary effects do not occur.5 Parenteral administration Among the small number of reports of parenteral ricin administration, the most well-known is the assassination of the Bulgarian refugee Georgi Markov who died three days after being stabbed with an umbrella believed to be loaded with a ricin-containing pellet. Fatigue, nausea, vomiting and fever developed over 24 hours followed by necrotic lymphadenopathy at the injection
Sally Bradberry BSc MRCP is Assistant Director of the National Poisons Information Service (Birmingham Unit) at City Hospital, Birmingham, UK. Competing interests: none declared.
MEDICINE 35:10
576
© 2007 Elsevier Ltd. All rights reserved.
Chemical terrorism
site. Pre-terminal complications included gastrointestinal haemorrhage, hypovolaemic shock and renal failure.6
References 1 Lord MJ, Jolliffe NA, Marsden CJ, et al. Ricin: mechanisms of cytotoxicity. Toxicol Rev 2003; 22: 53–64. 2 Franz DR, Jaax NK. Ricin toxin. In: Zajtchuk R, Bellamy RF, eds. Textbook of military medicine. Part I. Warfare, weaponry, and the casualty. Washington DC: Office of the Surgeon General at TMM Publications, 1997. 3 Hughes JN, Lindsay CD, Griffiths GD. Morphology of ricin and abrin exposed endothelial cells is consistent with apoptotic cell death. Hum Exp Toxicol 1996; 15: 443–51. 4 Battelli MG. Cytotoxicity and toxicity to animals and humans of ribosome-inactivating proteins. Mini Rev Med Chem 2004; 4: 513–21. 5 Wilhelmsen C, Pitt L. Lesions of acute inhaled lethal ricin intoxication in rhesus monkeys. Vet Pathol 1993; 30: 482. 6 Crompton R, Gall D. Georgi Markov – death in a pellet. Med Leg J 1980; 48: 51–62. 7 Leith AG, Griffiths GD, Green MA. Quantification of ricin toxin using a highly sensitive avidin/biotin enzyme-linked immunosorbent assay. J Forensic Sci Soc 1988; 28: 227–36. 8 Shyu H-F, Chiao D-J, Liu H-W, Tang S-S. Monoclonal antibody-based enzyme immunoassay for detection of ricin. Hybrid Hybridomics 2002; 21: 69–73. 9 Bradberry SM, Lord JM, Rice P, Vale JA. Ricin and abrin poisoning. In: Marrs TC, Maynard RL, Sidell FR, eds. Chemical warfare agents: toxicology and treatment. 2nd edn. Chichester: John Wiley & Sons, 2007: 613–31. 10 Bradberry SM, Dickers KJ, Rice P, et al. Ricin poisoning. Toxicol Rev 2003; 22: 65–70. 11 Marsden CJ, Smith DC, Roberts LM, Lord JM. Ricin: current understanding and prospects for an antiricin vaccine. Expert Rev Vaccines 2005; 4: 229–37. 12 Griffiths GD, Lindsay CD, Upshall DG. Examination of the toxicity of several protein toxins of plant origin using bovine pulmonary endothelial cells. Toxicology 1994; 90: 11–27. 13 Davis JH. Abrus precatorius (rosary pea). The most common lethal plant poison. J Fla Med Assoc 1978; 65: 188–91. 14 Guggisberg M. A propos d’une curieuse intoxication par des grains de chapelet (Abrus precatorius). Rev Med Suisse Romande 1968; 88: 206–8. 15 Fernando C. Poisoning due to Abrus precatorius (jequirity bean). Anaesthesia 2001; 56: 1178–80. 16 Pillay VV, Bhagyanathan PV, Krishnaprasad R, et al. Poisoning due to white seed variety of Abrus precatorius. J Assoc Physicians India 2005; 53: 317–19.
Diagnosis Ricin or its constituent A or B chains can be detected by immunoabsorbant assay for up to 48 hours after exposure.7,8 Detection of antiricin antibodies could aid diagnosis in those who survive for 2–3 weeks but will not be detected in those who die soon after exposure. Management Management is symptomatic and supportive.9,10 Immunization against ricin exposure using inactivated ricin toxoid or genetically engineered ricin A chain are realistic future therapeutic options.11
Abrin Source, structure and potential use as a chemical weapon Abrin is a plant toxin, which is closely related to ricin in terms of its structure and chemical properties. It is obtained from the seeds of Abrus precatorius (commonly known as jequirity bean or rosary pea), a tropical vine cultivated as an ornamental plant in many locations. Jequirity beans are usually scarlet in colour with a black spot at one end (though less common different coloured varieties exist) and are approximately 3 × 8 mm in size. Like ricin, abrin is a type 2 ribosome inactivating protein with A and B chains linked by a disulphide bond. At least theoretically, the similarity of abrin to ricin gives it a similar potential as a chemical weapon. Mechanisms of toxicity The mechanism of ribosome inactivation by abrin is essentially identical to ricin, except that in vitro studies suggest abrin is an even more potent toxin than ricin in this regard.12 Features Features following substantial abrin ingestion have usually been very similar in nature and time course to those described for ricin, with initial gastrointestinal manifestations13–16 followed in severe cases by neurological features and organ failure.16 Management The principles of management of abrin poisoning are similar to those for ricin. ◆
MEDICINE 35:10
577
© 2007 Elsevier Ltd. All rights reserved.