Ricin

RICIN

SUMMARY

Signs and Symptoms: Weakness, fever, cough and pulmonary edema occur 18-24 hours after inhalation exposure, followed by severe respiratory distress and death from hypoxemia in 36-72 hours.

Diagnosis: Signs and symptoms noted above in large numbers of geographically clustered patients could suggest an exposure to aerosolized ricin. The rapid time course to severe symptoms and death would be unusual for infectious agents. Laboratory findings are nonspecific but similar to other pulmonary irritants which cause pulmonary edema. Specific serum ELISA is available. Acute and convalescent sera should be collected.

Treatment: Management is supportive and should include treatment for pulmonary edema. Gastric decontamination measures should be used if ingested.

Prophylaxis: There is currently no vaccine or prophylactic antitoxin available for human use, although immunization appears promising in animal models. Use of the protective mask is currently the best protection against inhalation.

Isolation and Decontamination: Standard Precautions for healthcare workers. Secondary aerosols should generally not be a danger to health care providers. Weak hypochlorite solutions (0.1% sodium hypochlorite) and/or soap and water can decontaminate skin surfaces.

OVERVIEW

Ricin is a potent protein toxin derived from the beans of the castor plant (Ricinus communis). Castor beans are ubiquitous worldwide, and the toxin is fairly easily produced. Ricin is therefore a potentially widely available toxin. When inhaled as a small particle aerosol, this toxin may produce pathologic changes within 8 hours and severe respiratory symptoms followed by acute hypoxic respiratory failure in 36-72 hours. When ingested, ricin causes severe gastrointestinal symptoms followed by vascular collapse and death. This toxin may also cause disseminated intravascular coagulation, microcirculatory failure and multiple organ failure if given intravenously in laboratory animals.

HISTORY AND SIGNIFICANCE

Ricin’s significance as a potential biological warfare toxin relates in part to its wide availability. Worldwide, one million tons of castor beans are processed annually in the production of castor oil; the waste mash from this process is five percent ricin by weight. The toxin is also quite stable and extremely toxic by several routes of exposure, including the respiratory route. Ricin is said to have been used in the assassination of Bulgarian exile Georgi Markov in London in 1978. Markov was attacked with a specially engineered weapon disguised as an umbrella which implanted a ricin-containing pellet into his body.

TOXIN CHARACTERISTICS

Ricin is actually made up of two hemagglutinins and two toxins. The toxins, RCL III and RCL IV, are dimers of about 66,000 daltons molecular weight. The toxins are made up of two polypeptide chains, an A chain and a B chain, which are joined by a disulfide bond. Ricin can be produced relatively easily and inexpensively in large quantities in a fairly low technology setting. It is of marginal toxicity in terms of its LED50 in comparison to toxins such as botulinum and SEB (incapacitating dose), so an enemy would have to produce it in larger quantities to cover a significant area on the battlefield. This might limit large-scale use of ricin by an adversary. Ricin can be prepared in liquid or crystalline form, or it can be lyophilized to make it a dry powder. It could be disseminated by an enemy as an aerosol, or it could be used as a sabotage, assassination, or terrorist weapon.

MECHANISM OF TOXICITY

Ricin is very toxic to cells. It acts by inhibiting protein synthesis. The B chain binds to cell surface receptors and the toxin-receptor complex is taken into the cell; the A chain has endonuclease activity and extremely low concentrations will inhibit protein synthesis. In rodents, the histopathology of aerosol exposure is characterized by necrotizing airway lesions causing tracheitis, bronchitis, bronchiolitis, and interstitial pneumonia with perivascular and alveolar edema. There is a latent period of 8 hours post-inhalation exposure before histologic lesions are observed in animal models. In rodents, ricin is more toxic by the aerosol route than by other routes of exposure.

There is little toxicity data in humans. The exact cause of morbidity and mortality would be dependent upon the route of exposure. Aerosol exposure in man would be expected to cause acute lung injury, pulmonary edema secondary to increased capillary permeability, and eventual acute hypoxic respiratory failure.

CLINICAL FEATURES

The clinical picture in intoxicated victims would depend on the route of exposure. After aerosol exposure, signs and symptoms would depend on the dose inhaled. Accidental sublethal aerosol exposures which occurred in humans in the 1940’s were characterized by onset of the following symptoms in four to eight hours: fever, chest tightness, cough, dyspnea, nausea, and arthralgias. The onset of profuse sweating some hours later was commonly the sign of termination of most of the symptoms. Although lethal human aerosol exposures have not been described, the severe pathophysiologic changes seen in the animal respiratory tract, including necrosis and severe alveolar flooding, are probably sufficient to cause death if enough toxin is inhaled. Time to death in experimental animals is dose dependent, occurring 36-72 hours post inhalation exposure. Humans would be expected to develop severe lung inflammation with progressive cough, dyspnea, cyanosis and pulmonary edema.

By other routes of exposure, ricin is not a direct lung irritant; however, intravascular injection can cause minimal pulmonary perivascular edema due to vascular endothelial injury. Ingestion causes gastrointestinal hemorrhage with hepatic, splenic, and renal necrosis. Intramuscular administration causes severe local necrosis of muscle and regional lymph nodes with moderate visceral organ involvement.

DIAGNOSIS

An attack with aerosolized ricin would be, as with many biological warfare agents, primarily diagnosed by the clinical and epidemiological setting. Acute lung injury affecting a large number of cases in a war zone (where a BW attack could occur) should raise suspicion of an attack with a pulmonary irritant such as ricin, although other pulmonary pathogens could present with similar signs and symptoms. Other biological threats, such as SEB, Q fever, tularemia, plague, and some chemical warfare agents like phosgene, need to be included in a differential diagnosis. Ricin intoxication would be expected to progress despite treatment with antibiotics, as opposed to an infectious process. There would be no mediastinitis as seen with inhalation anthrax. SEB would be different in that most patients would not progress to a life-threatening syndrome but would tend to plateau clinically. Phosgene-induced acute lung injury would progress much faster than that caused by ricin.

Additional supportive clinical or diagnostic features after aerosol exposure to ricin may include the following: bilateral infiltrates on chest radiographs, arterial hypoxemia, neutrophilic leukocytosis, and a bronchial aspirate rich in protein compared to plasma which is characteristic of high permeability pulmonary edema. Specific ELISA testing on serum or immunohistochemical techniques for direct tissue analysis may be used where available to confirm the diagnosis. Ricin is an extremely immunogenic toxin, and acute as well as convalescent sera should be obtained from survivors for measurement of antibody response.

MEDICAL MANAGEMENT

Management of ricin-intoxicated patients again depends on the route of exposure. Patients with pulmonary intoxication are managed by appropriate treatment for pulmonary edema and respiratory support as indicated. Gastrointestinal intoxication is best managed by vigorous gastric decontamination with superactivated charcoal, followed by use of cathartics such as magnesium citrate. Volume replacement of GI fluid losses is important. In percutaneous exposures, treatment would be primarily supportive.

PROPHYLAXIS

The protective mask is effective in preventing aerosol exposure. Although a vaccine is not currently available, candidate vaccines are under development which are immunogenic and confer protection against lethal aerosol exposures in animals. Prophylaxis with such a vaccine is the most promising defense against a biological warfare attack with ricin.