Ricin Poisoning

Abstract

Ricin is a naturally occurring toxin derived from the beans of the castor oil plant Ricinus communis. It is considered a potential chemical weapon. Ricin binds to cell surface carbohydrates, is internalised then causes cell death by inhibiting protein synthesis. Oral absorption is poor and absorption through intact skin most unlikely; the most hazardous routes of exposure being inhalation and injection. Features of toxicity mainly reflect damage to cells of the reticuloendothelial system, with fluid and protein loss, bleeding, oedema and impaired cellular defence against endogenous toxins. It has been estimated that in man, the lethal dose by inhalation (breathing in solid or liquid particles) and injection (into muscle or vein) is approximately 5-10 micrograms/kg, that is 350-700 micrograms for a 70 kg adult. Death has ensued within hours of deliberate subcutaneous injection. Management is supportive. Prophylactic immunisation against ricin toxicity is a developing research initiative, although presently not a realistic option in a civilian context.

Full text

Toxicol Rev 2003; 22 (1): 65-70
R
EVIEW
A
RTICLE
1176-2551/03/0001-0065/$30.00/0
 Adis Data Information BV 2003. All rights reserved.
Ricin Poisoning
Sally M. Bradberry,
1,2
Kirsten J. Dickers,
1
Paul Rice,
3
Gareth D. Griffiths
3
and J. Allister Vale
1,2
1 National Poisons Information Service (Birmingham Centre), City Hospital, Birmingham, UK
2 West Midlands Poisons Unit, City Hospital, Birmingham, UK
3 Dstl Porton Down, Salisbury, UK
Contents
Abstract ................................................................................................................65
1. The Potential Use of Ricin as a Chemical Weapon .......................................................................66
2. Mechanisms of Toxicity ...............................................................................................66
3. Toxicokinetics ........................................................................................................66
4. Clinical Features .....................................................................................................66
4.1 Ingestion ........................................................................................................66
4.2 Intramuscular and Subcutaneous Administration ....................................................................67
4.3 Intravenous Administration ........................................................................................67
4.4 Inhalation .......................................................................................................68
4.5 Topical .........................................................................................................68
5. Diagnosis ............................................................................................................68
6. Management .......................................................................................................68
6.1 Ingestion ........................................................................................................68
6.2 Parenteral Exposure ..............................................................................................68
6.3 Aerosol Inhalation ................................................................................................68
6.4 Prophylaxis ......................................................................................................69
7. Conclusion ..........................................................................................................69
Ricin is a naturally occurring toxin derived from the beans of the castor oil plant Ricinus communis. It is
Abstract
considered a potential chemical weapon. Ricin binds to cell surface carbohydrates, is internalised then causes
cell death by inhibiting protein synthesis. Oral absorption is poor and absorption through intact skin most
unlikely; the most hazardous routes of exposure being inhalation and injection. Features of toxicity mainly
reflect damage to cells of the reticuloendothelial system, with fluid and protein loss, bleeding, oedema and
impaired cellular defence against endogenous toxins. It has been estimated that in man, the lethal dose by
inhalation (breathing in solid or liquid particles) and injection (into muscle or vein) is approximately 5–10 µg/kg,
that is 350–700µg for a 70kg adult. Death has ensued within hours of deliberate subcutaneous injection.
Management is supportive. Prophylactic immunisation against ricin toxicity is a developing research initiative,
although presently not a realistic option in a civilian context.
Ricin is a globular glycoprotein, which makes up 1–5% by length. Castor oil is obtained from the beans by cold pressing and
weight of the beans of the castor oil plant Ricinus communis, an is used as a purgative and laxative. Hot pressing of the beans,
annual shrub common in warm climates. The beans are 0.5–2cm in followed by solvent extraction, is used to produce specialist oils

66 Bradberry et al.
and lubricants. The residue is used as a cattle feed or as a induced hepatotoxicity. Kupffer cell destruction impairs the liver’s
fertiliser
[1]
after ricin has been destroyed by heating. Ricin, a capacity to detoxify endogenous toxins, which may contribute to
soluble white powder, is stable under ambient conditions, but can further damage.
[4]
Mice administered intraperitoneal ricin show
be detoxified by heating for 10 minutes at 80ºC or for 1 hour at evidence of oxidative stress in the liver and kidneys, with accumu-
50ºC.
[2]
lation of lipid peroxidation products that may also arise from
damaged Kupffer cells.
[5]
Ricin consists of an A chain and a B chain, linked by disulphide
bonds. The A chain confers ricin’s cellular toxicity, while the B
3. Toxicokinetics
chain gives ricin the properties of a lectin, that is a plant molecule
with a high affinity for glycoproteins on cell surface receptors. The
As a relatively large protein, ricin is unlikely to be extensively
term ‘toxalbumin’ is also sometimes applied to ricin and refers to
absorbed from the gastrointestinal tract. In animal studies, most
those larger lectin molecules that have a molecular weight similar
orally administered ricin was found in the large intestine after 24
to albumin.
hours, with only limited systemic uptake.
[6]
Dermal absorption of
ricin through intact skin is most unlikely to occur, unless there are
1. The Potential Use of Ricin as a Chemical Weapon
open cuts. In mice, intravenously administered ricin was distribut-
ed predominantly to the spleen, kidneys, heart and liver.
[7]
Ricin
The use of ricin to cause mass casualties would require either its
administered intramuscularly was found to localise in draining
aerosolisation by means of a dispersal device, or its addition to
lymph nodes.
[8]
Ricin was eliminated as degraded proteins, pre-
food and beverages as a contaminant. It should be noted that by the
dominantly in the urine, in other studies in rats.
[9]
oral route, ricin is approximately three orders of magnitude less
toxic than by either the inhalation or parenteral routes. Generating
4. Clinical Features
a large-scale aerosol would be best achieved with a dry powder
consisting of very small particles. By inhalation (breathing in solid
Ricin is toxic via all routes, although the features of poisoning
or liquid particles) and injection (into muscle or a vein), the lethal
and severity of toxicity vary markedly with the dose and route of
dose is approximately 5–10 µg/kg bodyweight, that is for an
exposure. The estimated dose of ricin which is lethal to 50% of
average male weighing 70kg, the lethal dose would be 350–700µg.
mice tested (LD
50
) by intragastric administration was 20 mg/kg
bodyweight,
[10]
although the frequently cited human fatal oral dose
2. Mechanisms of Toxicity
of 1 mg/kg bodyweight
[11-13]
remains unconfirmed. In mice, the
LD
50
by intravenous injection was 5 µg/kg bodyweight.
[10]
The
Ricin binds to cell surface carbohydrates; cells of the
fatal dose by injection in humans has been suggested to be in the
reticuloendothelial system are particularly susceptible since they
order of 1–10 µg/kg bodyweight;
[14]
however, there are no reliable
are one of a limited number of cell lines to bear mannose receptors
data to support this.
to which ricin can bind avidly. Once internalised, the ricin A chain
attacks ribosomes and so inhibits protein synthesis, leading to cell
4.1 Ingestion
death. These aspects are covered more extensively by Marsden et
al. in the accompanying review.
[3]
Many of the features observed Most cases of ingestion involve eating castor beans. The degree
in poisoning can therefore be explained by ricin-induced endothe- of seed mastication is important since beans swallowed whole may
lial cell damage, with fluid and protein leakage and tissue oedema, pass through the gastrointestinal tract intact, whereas the chewing
causing a so-called ‘vascular leak syndrome’. Disseminated in- of seeds facilitates ricin release.
travascular coagulation has been observed in experimental animals
In cases of substantial ingestion of castor beans, the onset of
following intravenous ricin administration and this is also likely to
gastrointestinal features occurred typically within a few hours with
reflect endothelial cell damage.
oropharyngeal irritation,
[15,16]
vomiting,
[11-13,15-19]
abdominal
Hepatocellular and renal damage is at least partly secondary to pain
[11,12,15,16,18,20-23]
and diarrhoea.
[11,12,15,16,19,21,23,24]
Hae-
vascular damage and impaired tissue perfusion, rather than a direct matemesis,
[22]
bloody diarrhoea
[19,21]
or melaena
[25]
may occur.
effect of the toxin itself. Animal studies have suggested that Subsequent features reflect fluid and electrolyte loss with hypoten-
Kupffer cells (liver macrophages) are the primary targets in ricin- sion,
[25]
tachycardia,
[11,12,15,23]
tachypnoea,
[11,17]
sweating,
[22]
dehy-
 Adis Data Information BV 2003. All rights reserved. Toxicol Rev 2003; 22 (1)

Ricin Poisoning 67
dration
[12,15,21,23]
and peripheral cyanosis.
[12,25,26]
Pre-renal impair- Ricin was allegedly used in the assassination of the Bulgarian
ment secondary to hypovolaemia is common in patients with defector Georgi Markov. Those investigating the case estimated
substantial gastrointestinal fluid loss
[12]
and may progress to renal the injected dose of ricin to be some 500µg, although ricin was
failure.
[25]
In more severe cases, hypovolaemic shock, with never isolated analytically.
[14]
There was immediate pain at the site
oliguria or anuria, may ensue.
[12,17,22]
Proteinuria,
[15,21,24]
haema- of injection (the thigh), with fatigue, nausea, vomiting and fever
turia
[15,21,24]
and hyaline casts on urine microscopy
[21]
have also developing over the next 24 hours. At admission, some 36 hours
been reported. after the incident, local necrotic lymphadenopathy was present and
gastrointestinal haemorrhage ensued with hypovolaemic shock
Some degree of transient liver damage is likely in all but the
and renal failure; death occurred on the third day. At autopsy there
mildest cases, with increased hepatic transaminase and lactate
was evidence of pulmonary oedema and haemorrhagic necrosis of
dehydrogenase activities,
[15,27]
and less commonly hyperbilirubi-
the small bowel; haemorrhages were observed in the lymph nodes
naemia.
[13]
Occasionally, liver function tests remain normal until
local to the injection site, in the myocardium, testicles and pancre-
several days after exposure.
[13]
as.
Other reported features include disorientation,
[16,18,21,27]
drowsi-
A 36-year-old chemist self-administered two intramuscular in-
ness,
[26]
confusion,
[11,26]
light-headedness,
[15]
muscle
jections of ricin prepared from a single castor bean.
[31]
Although it
cramps,
[12,17,25]
convulsions,
[16]
intravascular haemolysis,
[21]
was calculated that he had injected 150mg ricin, this would be
bradycardia,
[15]
hypertonia,
[16,25]
miosis,
[21]
mydriasis
[19,28]
and
impossible from a single bean. The maximum amount of ricin that
blurred vision.
[12]
is extractable from a single bean is about 10mg, which would
Investigations may show a metabolic acidosis,
[15,27]
leucocyto-
equate to a maximum dose of no more than 140 µg/kg bodyweight.
sis,
[12,15,21]
hyperglycaemia
[15,27]
or hypoglycaemia,
[15]
hypo-
Ten hours after the injections, he complained of headache and
phosphataemia
[15]
and increased creatine kinase activity.
[15]
rigors. He developed anorexia and nausea, a sinus tachycardia,
In a series of ten paediatric castor bean ingestions, seven had
erythematous areas around the puncture wounds and local
transient ECG abnormalities, including QT interval prolongation
lymphadenopathy at the sites of injection. Investigation showed
(in five cases), intraventricular conduction disturbance and repo-
mildly increased hepatic transaminase activities. He was dis-
larisation changes. The authors suggested that these changes were
charged well after 10 days.
probably secondary to metabolic disturbances.
[18]
It is possible that
A 20-year-old man was admitted to hospital 36 hours after
these abnormalities may have resulted from ricin-induced apopto-
injecting castor bean extract subcutaneously.
[32]
He complained of
sis of key elements of the cardiac conduction system. Such an
nausea, weakness, dizziness, chest and abdominal pain and myal-
effect of ricin has been noted in vivo in rats.
[29]
gia with paraesthesiae of the extremities. Hypotension, anuria and
In fatal cases, death usually occurs on the third day or later and
a metabolic acidosis were noted on examination and fresh blood
is due to multi-organ failure.
[10]
The most common findings at
was present in the rectum, possibly related to the development of a
autopsy are ulceration of the mucosa of the stomach and small
bleeding diathesis. Hepatorenal and cardiorespiratory failure then
intestine, necrosis of mesenteric lymph nodes, hepatic necrosis
developed and the patient died 18 hours after admission following
and nephritis.
[10]
an asystolic arrest.
4.2 Intramuscular and Subcutaneous Administration
4.3 Intravenous Administration
When intravenous ricin 18–20 µg/m
2
(approximately 0.5 µg/kg
Rats administered ricin 5µg (33–50µg/kg bodyweight) intra-
bodyweight) was investigated as a potential chemotherapeutic
muscularly survived a maximum of 35 hours. Post-mortem exam-
agent it caused flu-like symptoms with marked fatigue and myal-
ination of the intestinal tract demonstrated severe haemorrhage
gia, and sometimes nausea and vomiting.
[33]
with apoptosis of cells lining the small intestine, particularly the
ileum, which showed marked lymphoid cell and macrophage In studies using ricin A chain linked to a monoclonal antibody
infiltration of villi. The stomach and colon were largely unaffect- for anti-tumour immunotherapy, the principal dose-limiting ad-
ed.
[30]
verse effect was ‘vascular leak syndrome’. This was characterised
 Adis Data Information BV 2003. All rights reserved. Toxicol Rev 2003; 22 (1)

68 Bradberry et al.
by hypoalbuminaemia,
[34,35]
oedema-associated weight gain,
[34,35]
Ricin is severely irritating to the eye. In animal studies, pseudo-
pulmonary function abnormalities including reduced forced vital membranous conjunctivitis occurred following application of ricin
capacity, pleural effusion,
[35]
pulmonary oedema,
[35]
renal insuffi- solutions in concentrations of 1 : 1000–1 : 10 000.
[46]
ciency (with oliguria and impaired creatinine clearance),
[35]
cardi-
5. Diagnosis
ac failure and hypotension,
[34,35]
sometimes in association with a
pericardial effusion.
[35]
Other common features included weak-
Detection of anti-ricin antibodies could aid the diagnosis in
ness,
[34]
nausea and vomiting,
[34]
myalgia, associated in some cases
those individuals exposed to ricin who survive for 2–3 weeks.
with increased total creatine kinase activity,
[34]
joint discomfort,
[34]
However, humoral immunoglobulin M responses would likely be
thrombocytopenia
[34]
and occasionally ‘allergic reactions’ during
of short duration only. No immunological memory would be
the infusion.
[34]
anticipated without boosting. Anti-ricin antibodies would not be
In a study of 56 patients treated with ricin A chain immunotox-
detected in those dying soon after exposure. In these circum-
in, 12 required interruption or termination of treatment due to the
stances, the use of a ribosome inactivation test
[47]
would be more
severity of adverse effects, and two patients died as a result of
useful. A sensitive enzyme-linked immunosorbent assay was de-
vascular leak syndrome.
[35]
Vascular leak syndrome was more
veloped by Leith et al.
[48]
that could detect ricin in selected tissues
common in patients who had received radiotherapy prior to im-
up to 48 hours following its intramuscular administration. Beyond
munotherapy.
[36]
this timeframe, toxin detection would be unlikely, although it may
well be possible to extend the sensitivity of this assay and hence,
4.4 Inhalation
perhaps, the window for retrospective identification.
Non-human primates exposed to ricin by inhalation, developed
6. Management
necrotising interstitial and alveolar inflammation with oedema and
fibrinopurulent pneumonia. These manifestations typically oc-
6.1 Ingestion
curred after a dose-dependent delay of 8–24 hours.
[37]
Similar
findings have been observed in rodents.
[38-40]
The benefit of gastric lavage or the administration of activated
An allergic syndrome has been observed in workers occupa-
charcoal is uncertain but may be considered if patients present
tionally exposed to castor bean dust.
[41,42]
Susceptible patients
within the first hour following ingestion of ricin. Gastrointestinal
presented with acute onset conjunctivitis,
[41]
rhinitis,
[41,43]
sneez-
fluid losses should be replaced. Cardiopulmonary, hepatic and
ing, urticaria and wheeze,
[41]
which responded to conventional
renal function should be monitored. Organ dysfunction should be
measures and removal from exposure. Historically, castor bean
managed conventionally.
dust has been the cause of endemic asthma in the locality of a
castor oil mill.
[42]
The allergen identified as being responsible for
6.2 Parenteral Exposure
this effect is now known not to be ricin itself but a separate protein.
Symptomatic and supportive measures are the mainstay of
management of this highly toxic route of exposure. There is some
4.5 Topical
evidence that the intravenous administration of ricin antibody
shortly (within 1–2 hours) after ricin exposure may improve
Both type I and type IV allergic responses have been reported
survival,
[49]
although this has to be confirmed and probably has no
following dermal exposure to castor bean dust.
[43,44]
A 21-year-old
utility in a civilian population where there would be no near real-
female had an anaphylactic-type response after a castor bean from
time detection of ricin exposure.
her necklace disintegrated in her fingers. She immediately devel-
oped sneezing, rhinitis and periorbital oedema, with facial urticar-
6.3 Aerosol Inhalation
ia and erythema, requiring subcutaneous adrenaline (epineph-
rine).
[45]
However, as suggested in section 4.4, ricin is only one of Removal from exposure and airway support with adequate
several allergenic proteins in castor beans. ventilation are the priorities. Pulmonary oedema should be treated
 Adis Data Information BV 2003. All rights reserved. Toxicol Rev 2003; 22 (1)

Ricin Poisoning 69
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No sources of funding were used to assist in the preparation of this
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to the content of this manuscript.
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