Environment International 35 (2009) 1267–1271
Contents lists available at ScienceDirect
Environment International
j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / e n v i n t
Review article
Ricin as a weapon of mass terror — Separating fact from fiction
Leo J. Schep a,⁎, Wayne A. Temple a, Grant A. Butt b, Michael D. Beasley a
a
b
National Poisons Centre, University of Otago, Dunedin, New Zealand
Department of Physiology, University of Otago, Dunedin, New Zealand
a r t i c l e
i n f o
a b s t r a c t
Article history:
Received 18 April 2009
Accepted 30 August 2009
Available online 19 September 2009
In recent years there has been an increased concern regarding the potential use of chemical and biological
weapons for mass urban terror. In particular, there are concerns that ricin could be employed as such an agent.
This has been reinforced by recent high profile cases involving ricin, and its use during the cold war to assassinate
a high profile communist dissident. Nevertheless, despite these events, does it deserve such a reputation? Ricin is
clearly toxic, though its level of risk depends on the route of entry. By ingestion, the pathology of ricin is largely
restricted to the gastrointestinal tract where it may cause mucosal injuries; with appropriate treatment, most
patients will make a full recovery. As an agent of terror, it could be used to contaminate an urban water supply,
with the intent of causing lethality in a large urban population. However, a substantial mass of pure ricin powder
would be required. Such an exercise would be impossible to achieve covertly and would not guarantee success
due to variables such as reticulation management, chlorination, mixing, bacterial degradation and ultra-violet
light. By injection, ricin is lethal; however, while parenteral delivery is an ideal route for assassination, it is not
realistic for an urban population. Dermal absorption of ricin has not been demonstrated. Ricin is also lethal by
inhalation. Low doses can lead to progressive and diffuse pulmonary oedema with associated inflammation and
necrosis of the alveolar pneumocytes. However, the risk of toxicity is dependent on the aerodynamic equivalent
diameter (AED) of the ricin particles. The AED, which is an indicator of the aerodynamic behaviour of a particle,
must be of sufficiently low micron size as to target the human alveoli and thereby cause major toxic effects. To
target a large population would also necessitate a quantity of powder in excess of several metric tons. The technical and logistical skills required to formulate such a mass of powder to the required size is beyond the ability of
terrorists who typically operate out of a kitchen in a small urban dwelling or in a small ill-equipped laboratory.
Ricin as a toxin is deadly but as an agent of bioterror it is unsuitable and therefore does not deserve the press
attention and subsequent public alarm that has been created.
© 2009 Elsevier Ltd. All rights reserved.
Keywords:
Ricin
Toxin
Ingestion
Inhalation
Dermal
Parenteral
Risk
Aerodynamic equivalent diameter
Terror
Contents
1.
Introduction . . . . . . . . .
2.
Methods . . . . . . . . . .
3.
Mechanism of toxicity . . . .
4.
Toxicity by ingestion . . . . .
5.
Toxicity by parenteral delivery
6.
Toxicity by dermal contact . .
7.
Toxicity by inhalation . . . .
8.
Conclusion . . . . . . . . .
References . . . . . . . . . . . .
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1267
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1. Introduction
⁎ Corresponding author. National Poisons Centre, University of Otago, P.O. Box 913,
Dunedin, New Zealand. Tel.: +64 3 479 7250; fax: +64 3 477 0509.
E-mail address: [email protected] (L.J. Schep).
0160-4120/$ – see front matter © 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.envint.2009.08.004
In recent years, there has been heightened concern regarding the
potential of various chemical and biological weapons as agents for urban
terrorism (Gosden and Gardener, 2005). These concerns have been
reinforced by the recent attempted uses of ricin by various groups in the
United States and United Kingdom (Gibson et al., 2003; Mayor, 2003).
1268
L.J. Schep et al. / Environment International 35 (2009) 1267–1271
Ricin is regarded as an ideal agent for terrorism (Franz and Jaax, 1997),
partly because of its notoriety arising from the high profile assassination of a leading communist dissident in London during the late 1970s
(Crompton and Gall, 1980). Furthermore, it is readily accessible, and
its relative ease of extraction from the castor bean plant, as well as its
stability in both hot and cold conditions (CDC, 2004), seem to make it a
weapon of choice. It has been regarded as one of the most potent poisons
in the plant kingdom (Lee and Wang, 2005) and has been described as a
toxin that can cause death within minutes of exposure (Marshall, 1997).
However, despite these assertions, does ricin ultimately warrant this
reputation as an ideal weapon of mass terror?
2. Methods
We searched OVID MEDLINE (January 1950 to March 2009) and ISI
Web of Science (http://www.isiknowledge.com) (1900 to March 2009)
to identify all studies associated with the toxicity of ricin, the routes of
exposure and mechanisms of toxicity; no restrictions were placed on
year of publication. To identify the expected toxicity following exposure
to ricin we used the terms ricin, Ricinus communis, toxalbumin, castor
beans and ricinine which were combined with either poisoning, toxicology, pharmacology, routes of exposure, diagnosis, treatment or terrorism. Bibliographies of identified articles were screened for additional
relevant studies including non-indexed reports. Non peer-reviewed
sources were also included: books, relevant newspaper reports and applicable web material.
3. Mechanism of toxicity
Ricin is a toxic glycoprotein (toxalbumin) derived from the castor oil
plant Ricinus communis; it consists of a neutral A-Chain (32 kDa) bound
by a disulfide bond to an acidic B-Chain (34 kDa) (Lord et al., 1994). The
B-subunit binds to glycoproteins on the surface of epithelial cells,
enabling the A-subunit to enter the cell via receptor-mediated endocytosis. This subunit inactivates ribosomal RNA by depurinating a specific ribosomal residue, thereby inhibiting protein synthesis. One ricin
molecule can inactivate 2000 ribosomes per minute, which ultimately
leads to the death of the cell.
4. Toxicity by ingestion
Ricin is clearly toxic to humans, but the risk will vary depending on
the route (and source) of exposure. The dose of ricin required to produce
death in 50% of mice (LD50) can be as small as 1–10 µg/kg, when
delivered by injection or inhalation (Table 1); lethal doses by ingestion
are, however, several orders of magnitude greater. This dramatic difference could in part arise from gastrointestinal digestion and/or relatively low gut absorption of intact ricin. The latter seems a more
important factor, as in vitro data suggests that ricin is resistant to acidic
and proteolytic enzyme degradation (Olsnes et al., 1975) but is poorly
absorbed across the intestine (Cook et al., 2006; Ishiguro et al., 1983).
This is further supported by the finding that most of the pathology
associated with human ingestion relates to local injury predominantly
within the gastrointestinal tract, with minimal internal organ injury
(Audi et al., 2005; Balint, 1974; Challoner and McCarron, 1990; Lim et al.,
2009; Meldrum, 1900; Mouser et al., 2007). Histological studies in rats
reveal significant erosion to the intestinal mucosa and evidence of apoptotic cell death (Leek et al., 1989; Sekine et al., 1986). Patients
ingesting ricin are susceptible to fluid losses as a direct result of these
mucosal injuries; in severe cases, such losses can progress to fatal hypovolemic shock. However, the majority of patients are successfully
treated, with a good recovery. Indeed, an exhaustive review of the literature spanning back to the nineteenth century concluded that from a
total of 751 cases of ricin toxicity, only 14 deaths were reported (1.9%)
(Rauber and Heard, 1985). Of these deaths, 12 occurred prior to 1930,
when management of the patient may not necessarily have been as
effective.
Nevertheless, the potential exists that ricin could be employed to
poison a large urban population. Such a scenario could involve contaminating a regional water supply. To estimate human risks, it is not unreasonable to assume that a dose as low as one hundredth of the mouse
oral LD50 estimate (of 20 mg/kg) (Bradberry et al., 2003) may be fatal to
some susceptible humans. Such an overall “uncertainty factor” of 100
takes into consideration likely inter-species and intra-species variations
in humans (IPCS, 1994), and the result equates to a dose of 0.2 mg/kg, or
12 mg in a 60 kg adult for example.
Assuming then that at least 12 mg ricin would be required to achieve
lethality in some humans (adults of 60 kg) via the oral route, then, on
the basis of an estimated daily water consumption of around 2 l per day,
a concentration of 6 mg/l would be required to deliver the necessary
dose (at least within a 24 hour period). As an example, the Weir Wood
reservoir, which supplies water to approximately 60,000 residents in
Sussex, England, has a capacity of 1237 million litres. To achieve the
required lethal concentration, approximately 7422 kg of pure ricin powder would need to be introduced to the reservoir. Furthermore, this
calculation does not consider the effect of water treatment with hypochlorite, which has been shown to be effective against ricin (Mackinnon
and Alderton, 2000). Further variables such as mixing, bacterial degradation, ultra-violet light and other reticulation management practices
may also reduce the deliverable concentrations of ricin. Such an exercise, therefore, would be impossible to achieve covertly. Moreover, in
the unlikely event of mass poisoning most patients would, with appropriate supportive care, make a full recovery. Lack of mortality in this type
of scenario severely limits the feasibility of oral ricin as an agent of mass
poisoning.
Terrorists may, however, seek to contaminate water to strategic
targets such as houses of parliament or military facilities. These institutions most likely access their water from local government resources
and therefore any contamination would be required at points of supply,
where security would most likely be greater given their recognised high
profile risks, especially since September 11 2001.
To achieve mild morbidity without mortality, such as causing mild
gastrointestinal distress within a given population, the amount of ricin
necessary to poison a city water supply would be substantially lower.
Such estimates are often based on extrapolation from the “no-observed
(adverse) effect level” (NOAEL) found from animal studies. To the
knowledge of the authors, there are no reported NOAELs for ricin.
Nevertheless, it has been proposed, on the basis of theoretical considerations and empirical observations, that the (sub-chronic) NOAEL (at
least of biological agents) can be roughly predicted from their acute LD50
values (Burrows and Renner, 1999):
Sub chronic ðoralÞ NOAEL = ð0:004=dayÞ × ðoralÞ LD50 :
Table 1
Ricin LD50 values for mouse via different routes.
Route of entry
Dose to achieve
LD50 (µg/kg)
Reference
Ingestion
Injection
Inhalation
20,000
2.8–3.3
1–10
Bradberry et al. (2003)
Fodstad et al. (1976), Olsnes and Pihl (1973)
Roy et al. (2003)
For ricin, with an oral LD50 of 20 mg/kg, this equates to 0.08 mg/kg/
day. This value can then be used to estimate the likely human no
observable adverse effect level (using the same inter- and intra-species
safety factors as above), and thence to the likely safe water level,
depending on volumes consumed (2l) and chosen body weight (60 kg).
Though there is some degree of imprecision with this model, the
L.J. Schep et al. / Environment International 35 (2009) 1267–1271
approximate level in a city reservoir which would need to be exceeded
for toxicity to occur can be roughly estimated:
ðLD50 × 0:004Þ = 100 × 60 = 2 = 24 μ g=L:
To so contaminate a water supply, such as the Weir reservoir, may
require a mass in excess of 30 kg. Although the manufacture of this
amount of ricin appears achievable, such an exercise would not have the
same impact on society as an incident involving death. The dissemination of lesser amounts of ricin could still result in mild morbidity in a
population and the perceived risk of serious toxicity may still result in
mass panic leading to a serious drain on healthcare, emergency and
other local governmental resources.
Previous threats of terrorism utilising ricin have involved amounts
that have been measured in grams, or in some cases only the alleged
traces of ricin (BBC, 2005; Friess, 2008; Johnston and Hulse, 2004). These
incidents caused disproportionate outcries in the media, unrealistic in
relation to the actual threat posed on that society, though such incidents
can raise the awareness of a given terrorist's cause.
5. Toxicity by parenteral delivery
In contrast to ingestion, parenteral delivery of ricin can be associated
with a greater mortality rate, as indicated by the limited number of case
reports in humans, with five of seven cited incidents resulting in death
(Crompton and Gall, 1980; De Paepe et al., 2005; Fine et al., 1992;
Passeron et al., 2004; Targosz et al., 2002; Watson et al., 2004). A summary of these case reports is presented in Table 2. When delivered by the
parenteral route, ricin distributes rapidly to the liver, spleen, and muscle
(Fodstad et al., 1976). While the bulk of the toxalbumin is eliminated
within 24 h (Ramsden et al., 1989), damage can still be sufficient to
cause death within days of exposure (Knight, 1979). Post-mortem examination suggests that heart block, due to necrosis of the cardiac
conducting tissue, may be a leading cause of death (Crompton and Gall,
1980). The high mortality rate from these incidents is not surprising,
given the very high acute toxicity of ricin via the parenteral route, as
determined experimentally (Table 1). By injection, ricin is a suitable
weapon for assassination (Knight, 1979); however, a scenario involving
parenteral administration to a large urban population is clearly not
feasible.
6. Toxicity by dermal contact
Dermal application of ricin has been considered an alternate route of
ricin toxicity. Members of the “Minnesota Patriots Council” mixed ricin
extract with dimethylsulfoxide (DMSO) and planed to smear doorknobs
or items of clothing to assassinate unspecified individuals (Tucker,
1999). However, evidence in animal models suggests that ricin is poorly
absorbed across intact skin. Topological application of 50 µg ricin resulted in no indication of toxicity in mice (Franz and Jaax, 1997). There is
evidence that some members of the population may be susceptible to
type I and type IV allergic responses following dermal exposure to ricin
dust; cited case reports describe such responses following workplace
exposures (Kanerva et al., 1990; Metz et al., 2001). These allergies, however, are thought to be due to one of several proteins that do not include
ricin itself (Bradberry et al., 2003). There is no evidence to suggest that
ricin is successfully absorbed across skin and therefore toxicity by this
route is most likely unachievable.
7. Toxicity by inhalation
Of all the routes of exposure, the airborne dissemination of biological
toxins has the most potential as a threat to urban populations (Wiener,
1996). As the toxicity of ricin by inhalation is high, as determined by
animal studies (Table 1), the formulation and delivery of such a powder
could lead to a substantial number of casualties (Bradberry et al., 2003).
1269
Table 2
Summary of case reports following parenteral administration of ricin.
Age and
gender
Administration of
ricin
Male,
Malicious
49 years intramuscular
injection of a pellet
containing ricin into
the leg of the victim
Female,
Injection of ricin
59 years extract in the leg by
partner
Clinical effects
Outcome Reference
Hyperthermia,
abdominal pain,
diarrhoea, elevated
leucocytes, coma
Crompton
Death
and Gall
3 days
(1980)
post
exposure
Hyperthermia,
inflammation at site
of exposure,
leucocytosis,
hypokalemia, later
developed necrotising
fasciitis with
rhabdomyolysis, renal
failure, diffuse
intravascular
coagulopathy and
ARDS
Male,
Self injection of ricin
Similar effects as his
56 years extract in the arm
partner, arm
amputation and
resulting multiple
organ failure
Evidence of
Male,
Self intramuscular
erythematous areas at
36 years injection of a single
ricin bean extract into wound site.
Developed headache,
leg
rigors, anorexia,
nausea and sinus
tachycardia plus
evidence of mild
increase in
transaminase activity.
Discharged after
10 days.
Evidence of
Male,
Self masticated bean
developing cellulitis
53 years extract, injected into
at wound site,
inner thigh
attributed to
Enterococcus faecalis
and ricin. Patient
recovered following
antibiotic
administration and
surgery
Weakness, nausea,
Male,
Self subcutaneous
dizziness, headache
20 years injection of ricin
and compressed
extract
chest, abdominal and
muscular pain, with
oedema at site of
injection. Later
developed
haemorrhagic
diathesis with
subsequent multiorgan failure. Death
due to asystolic arrest
Infection at site of
Male,
Self antecubital vein
wound, developed
61 years injection of ricin
extracted into acetone vomiting,
haematemesis,
acidosis,
hypoglycaemia, renal
failure and
hypotension
Death
De Paepe
6 days
et al.
post
(2005)
exposure
Death
De Paepe
et al.
(2005)
Survived
Fine et al.
(1992)
Survived
Passeron
et al.
(2004)
Targosz
Death,
et al.
2 days
(2002)
post
exposure
Watson
Death,
36 h post et al.
exposure (2004)
Indeed, in experimental animals, extremely low doses can be lethal
when administered via this route. In mice, evidence suggests that the
inhalation of ricin powder can lead to progressive and diffuse
pulmonary oedema with associated inflammation and necrosis of the
alveolar pneumocytes (Brown and White, 1997; DaSilva et al., 2003;
Griffiths et al., 1995). Such injuries are predominantly localised to the
organ of exposure (Doebler et al., 1995; Wilhelmsen and Pitt, 1996).
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L.J. Schep et al. / Environment International 35 (2009) 1267–1271
mass is necessary to generate an effective cloud that would expose
individuals to a lethal dose. Variabilities in this model, however, may
include dispersion of the powder to smaller volumes and variations in
rates of respiration; increased rates of breathing due to exercise, for example, will enhance the potential for increased inhalation uptake.
Nevertheless, to achieve this critical AED size range, particles must
first be extracted, formulated and milled to the appropriate dimensions
(Wiener, 1996). Preparing ricin to attain the necessary aerodynamic
parameters and amounts necessary to inflict injury and death requires
technical skills, and access to adequately equipped laboratories (Bigalke
and Rummel, 2005). Technical and logistical skills necessary to produce
ricin powder in a sufficiently hazardous form and quantity are beyond
the reach of most terrorists, who, with the exception of resources
available to rogue states, are devoid of state funding and resources, and
who typically operate only from either a kitchen in a small urban
dwelling or a small ill-equipped laboratory. While potentially more devastating than other scenarios, the inhalation of ricin powder resulting
in mortality, sufficient to generate urban terror still seems somewhat
infeasible.
8. Conclusion
Fig. 1. The deposition of particles in various regions of the lung, as a function of particle
size during moderate workload at 30 respirations per minute, 750 cm3 tidal volume.
The solid lines are the calculated values of head (H), tracheobronchial (TB), alveolar (A)
and total (T) deposition. Used with permission (Yu and Diu, 1983).
Nevertheless, this research does suggest that toxicity by inhalation is
dependent on the aerodynamic equivalent diameter (AED) of ricin
powder (Roy et al., 2003). The AED is an indicator of the aerodynamic
behaviour of a particle, which depends not only on its size but also on
other parameters such as shape and density (Bates et al., 1966); it has
been defined as the diameter of a unit density sphere having the same
settling velocity as the particle itself. Depending on their AEDs, particles
generally distribute to specific regions of the lung (Fig. 1) (Yu and Diu,
1983). In healthy humans, for example, evidence suggest that particles
with AEDs over 10 µm will impact on the nasal and pharyngeal mucosae
(the extrathoracic fraction) whereas those between 5 and 10 µm will
largely settle in the bronchi and proximal bronchioles by sedimentation,
where they will be cleared by the goblet and ciliated cells (Emmett et al.,
1982); expulsion from the respiratory tract is either by coughing
or swallowing where they will be available for gastrointestinal uptake.
Those particles with AEDs below about 3–5 µm constitute the
“respirable fraction”, settling predominantly in the respiratory bronchioles and alveolar regions (Emmett et al., 1982). Minimal alveoli deposition of particles occurs with AED values from 0.1 to 2 µm, though
below 0.1 µm diameter there is some evidence of increasing deposition
(Parkes, 1994).
In mice, administered particles of ricin clustered closely around a
mass median aerodynamic diameter (MMAD) of ~1 µm (55 µg/kg)
proved to be lethal, whereas those receiving particles all near their
MMAD of 5 µm (36 µg/kg) all survived (Roy et al., 2003). The relatively
small particles of lower aerodynamic diameter had access to and were
deposited within the alveoli, where they caused localised damage to the
pneumocytes, leading to the rapid death of the animals within that
group.
While the hazardous AED range for toxic particle may differ between
rodents and humans, there is sufficient evidence to suggest that the
same principle applies (Schlesinger, 1985). To be effective as an agent of
terrorism, the AED of ricin powder must be of sufficiently low micron
size to target the human alveoli and thereby cause toxicity. If particles
are any larger, they will be cleared (either expelled or swallowed),
substantially decreasing the risk of lethality. Furthermore, mathematical
modelling, based on robust field tests, has predicted the mass of ricin
required for effective aerosol toxicity in a 100 km2 area to be in excess of
several metric tons (Darling et al., 2004). The authors suggest that such a
Ricin is clearly toxic. As a weapon of terror, it has gained popularity
because of its notoriety as an agent of assassination, ease of access,
relative ease of extraction and its stability. By ingestion, ricin acts to
erode the intestinal mucosa; this may then lead to massive fluid loss and
hypovolemic shock, both of which, however, are manageable with appropriate medical care. To contaminate a city water supply with lethal
concentrations of ricin would require impossibly large amounts of
powder, making this approach unfeasible. By injection, ricin is ideally
suited as a weapon of assassination, but not for causing mass mortality.
There is no evidence of dermal absorption of ricin. Delivery by inhalation, however, shows the greatest promise, but utilising this route
would also be fraught with problems. To target a large urban population,
a substantial mass of powder needs to be extracted, formulated and
milled down to a sufficient size to target the region of the lung where
fatal consequences are probable; covertly manufacturing this amount of
“specialised” powder is beyond the reach of most terrorists. Ricin as a
toxin is deadly but as an agent of bioterror is unsuitable and therefore
does not warrant the press attention and subsequent public alarm that
has been created.
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