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The threat of bioterrorism remains a reality worldwide, although of low probability, an attack would be a high-consequence event. Microbes are available to individuals with appropriate contacts and even many low-grade bacterial pathogens can severely affect health. Toxins provide bacteria with a system of defense that is often detrimental to humans and their versatility makes them potential tools of bioterrorism. It should be remembered that the aim of terrorism is not always to kill but rather to strike fear into people's lives. Importantly, no state can ever be fully prepared for a response and it is probable that no state ever could be. It is for this reason that biological agents are so attractive as weapons. (British Journal of Biomedical Science, 2005)
Deserving of a closer look as a potential weapon of bioterrorism and as a threat to public health and safety is tetrodotoxin. Tetrodotoxin (TTX) is a potent marine neurotoxin, named after the order of fish from which it is most commonly associated, the Tetrodoniformes (tetras - four and odontos-tooth), or the tetraodon puffer fish. The tetraodon puffers are equipped with four large teeth which are nearly fused, forming a beak-like structure used for cracking mollusks and other invertebrates, as well as for scraping corals and general reef grazing. (Florida State University, January, 2002)
According to the New York Times, first isolated from the puffer fish, tetrodotoxin is among the most potent toxins known. It is 100 times as toxic by weight as potassium cyanide - two milligrams can kill an adult human - and it is not destroyed by cooking. Tetrodotoxin is found in more than just marine creatures. It is present in high concentrations in the skin of certain newts in North American and Japan, and in several kinds of frogs in Central and South America and Banglaesh. (New York Times - Science, December, 2009)
The flesh of the puffer fish (i.e. fugu) is considered a delicacy in Japan. It is prepared by chefs specially trained and certified by the government to prepare the flesh free of the toxic liver, gonads and skin. Despite these precautions, many cases of tetrodotoxin poisoning are reported each year in patients ingesting fugu. (Medscape CDC Commentary Series, October, 2009) "From 1974 through 1983 there 646 reported cases of fugu (puffer fish) poisoning in Japan, with 179 fatalities. Estimates as high as 200 cases per year with mortality approaching 50% have been reported." (Florida State University, January, 2002)
Interestingly while tetrodotoxin is found in several different branches of the animal kingdom, the tetrodotoxin found in each of these creatures is identical - unlike the venoms produced by snakes and scorpions which are made up of different kinds of toxins particular to that species. The evidence suggests that these animals do make the toxin themselves. (New York Times - Science, December, 2009)
The toxin itself appears to be made by relatively common marine bacteria, specifically Pseudoalteromonas haloplanktis tetraodonis, which associates with these animals. Validating this theory when puffer fish are raised in aquariums with filtered, bacteria-free water, they are non-toxic and the same results are achieved when Japanese newts or Panamanian frogs are raised on special diets - they lose their toxicity. These experiments validate the theory that these toxic animals obtain the toxin from the food chain. Several species of tetrodotoxin-producing bacteria have been found in puffer fish, the blue-ringed octopus, and certain small and other animals. It appears that the animals become toxic by sequestering the bacterially produced toxin in their tissues. (New York Times - Science, December, 2009)
The exact origin of tetrodotoxin in the food chain remains unclear. The only common dominator seems to be that tetrodotoxin producing animals are closely related to an aquatic system and the bacteria that commonly inhabit the aquatic system. (MDPI Marine Drugs, May 2008)
"The toxic dose is not clear because puffer fish have different concentrations of tetrodotoxin. A dose of 1-2 mg of purified toxin can be lethal. Reported cases from the Centers for Disease Control and Prevention (CDC) have documented toxicity with ingestion as little as 1.4 ounces of puffer fish." (Medscape CDC Commentary Series, October, 2009)
In contrast, the botulinum toxin (Clostridium botulinum) "is reported to be the most toxic substance known. If evenly dispersed for inhalation, 1 gram of pure (botulinum) toxin is sufficient to kill 1 million people." (Ryan & Glarum, 2008, p. 65)
Tetrodotoxin is a neurotoxin. Neurotoxin is a toxin that acts specifically on nerve cells of the nervous system, typically by interacting with membrane proteins and especially ion channels. (Knowledgerush, n.d.) Tetrodotoxin binds to the sodium channel of the nerve preventing the passage of sodium ions through the cell membrane and therefore (passage) of the nerve impulse. (CBWinfo.com, 1999) Many of the venoms and other toxins that organisms use in defense against vertebrates are neurotoxins. A common effect is paralysis, which typically onsets extremely rapidly. (Knowledgerush)
"The first symptom of (tetrodotoxin) intoxication is a slight numbness of the lips and tongue, appearing between 20 minutes to three hours after eating poisonous puffer fish,. The next symptom is increasing paraesthesia in the face and extremities, which may be followed by sensations of lightness or floating. Headache, epigastric pain, nausea, diarrhea, and/or vomiting may occur. Occasionally, some reeling or difficulty in walking may occur.
The second state of the intoxication is increasing paralysis. Many victims are unable to move; even sitting may be difficult. There is increasing respiratory distress. Speech is affected, and the victim usually exhibits dyspnea, cyanosis, and hypotension. Paralysis increases and convulsions, mental impairment, and cardiac arrhythmia may occur. The victim, although completely paralyzed, may be conscious and in some cases completely lucid until shortly before death. Death usually occurs with in 4 to 6 hours, with a known range of about 20 minutes to 8 hours." (U.S. Department of Health and Human Services; FDA U.S. Food & Drug Administration, n.d.)
No specific antidote has been tested in humans. No drug has been shown to reverse the effects of tetrodotoxin poisoning. Treatment is symptomatic. Specific drug efficacy has only been documented anecdotally. (Medscape CDC Commentary Series, October 2009)
Animal studies using monoclonal antibodies against TTX have been done. Monoclonal antibodies were shown to e life saving in mice treated both before and after the ingestion of a lethal dose of TTX. Further studies are needed to document the efficacy in humans. In another study using guinea pigs intoxicated with tetrodotoxin, 4-aminopyridine (a potassium channel blocker) showed dramatic improvement in respiratory, cardiac, and CNS status occurred after administration of the drug. No human studies of this drug for use in tetrodotoxin poisoning are in progress. (Medscape CDC Commentary Series, October 2009)
No specific laboratory test confirms tetrodotoxin ingestion exits; thus dietary history is key for diagnosis. Tetrodotoxin poisoning can be misdiagnosed as one of many differential diagnoses including: gastroenteritis, Guillain-Barre Syndrome, 1st, 2nd and 3rd degree heart blockage, hypocalcemia, Lambert-Eaton Myasthenic Syndrome, myasthenia gravis, octopus envenomations, and ciguatera, scombroid and shellfish toxicity.
Since tetrodotoxin is produced from bacteria, there is a risk that the toxin could be manufactured on a significant scale by fermentation. (CBWinfo.com, 1999) Tetrodotoxin is a colorless crystalline solid that darkens when heated about 428° F or 220° C. (CDC National Institute for Occupational Safety and Health, n.d.)
Relatively is little is known about tetrodotoxin as a possible toxin weapon although the Japanese did some work its weaponization in Unite 731 during World war II. It is included on the Australia Group lists by reason of its toxicity. It is not known to be made in large quantities that could be used in weapons and little or nothing is know about its inhalation toxicity. (CBWinfo.com, 1999)
( NOTE: The Australia Group (AG) is an informal forum of countries which, through the harmonization of export controls, seeks to ensure that exports do not contribute to the development of chemical or biological weapons. Coordination of national export control measures assists Australia Group participants to fulfill their obligations under the Chemical Weapons Convention and the Biological and Toxin Weapons Convention to the fullest extent possible.) (The Australia Group, n.d.)
The National Institute for Occupational Safety and Health (NIOSH) offers insight into the various methods tetrodotoxin could be disseminated and the feasibility of each method. For example, dissemination through indoor air, outdoor air or water is extremely unlikely because the source of the toxin is living organisms and to manufacture tetrodotoxin in appreciable quantities is extremely difficult. And, since tetrodotoxin is unlikely to be disseminated in the air, it is also unlikely to be disseminated through agricultural products. Ingestion does seem the most likely source of dissemination. Exposure to tetrodotoxin usually occurs through eating improperly prepared fish or possibly through contamination of other food products. (CDC National Institute for Occupational Safety and Health, n.d.) According to NIOSH, there is no antidote for tetrodotoxin toxicity and initial treatment is primarily supportive.
In 2007 two individuals developed symptoms consistent with tetrodotoxin poisoning after ingesting home-cooked puffer fish purchased in Chicago. Both the retailer and supplier claimed the product was monkfish. High levels of tetrodotoxin were detected in the remains of the ingested meal and fish retrieved from the contaminated shipment. This case of tetrodotoxin poisoning highlights the need for continued stringent regulation of puffer fish importation by the U.S. Food and Drug Administration, education of the public regarding the dangers of puffer fish consumption, and raising awareness among medical providers of the diagnosis and management of foodborne toxin ingestions and the need for reporting to public health agencies. (PubMed U.S. National Library of Medicine National Institute of Health, 2009)
Currently tetrodotoxin is manufactured by several specialized biotech companies. CHEMTE Biotech Company, LTD located in Nanjing, Jiangsu, China specializes in the manufacture of tetrodotoxin. According to CHEMTE Biotech's website, "after ten years' research and development, we have achieved extensive isolation and purification of TTX based on the abundant resource in our area. We founded the TTX production base in the world with annual product (sic) is more than 1000g. (CHEMTE Biotech Company, Ltd., n.d.)
Through the use of their technology process CHEMTE has raised production rate and product quality of TTX up to the world's highest level. CHEMTE boasts that their customers in many countries find their purity is higher than their own pure products. Currently in the European market, TTX from CHEMTE is sold as the standard product. (CHEMTE Biotech Company, Ltd., n.d.)
The China Kantte Bio-Chemical company located in Shanghai, China produces tetrodotoxin extracted from puffer fish in large scale, and purified close to 100% by high-performance liquid chromatograph (HPLC) and capillary electrophoresis. (China Kantte Bio-Chemical, n.d.)
While it is possible to procure TTX for research as a potential pain therapeutic and medicine for opium withdrawal symptoms, its purchase is limited to researchers and scientistsâ€¦.just ask Edward F. Bachner IV of Lake Hills, Illinois. On August 26, 2008 a federal grand jury in Rockford, Illinois returned a ten-count indictment charging him with unlawfully acquiring and possessing tetrodotoxin, on five separate occasions between November 7, 2006 and June 30, 2008. Five of the counts allege that on five separate occasions, Bachner acquired tetrodotoxin in order to use it as a weapon. Bachner possessed tetrodotoxin in a quantity that was not reasonable justified by a prophylactic, protective, bona fide research, or other peaceful purpose. If convicted of acquiring TTX to use as a weapon, Bachner could be sentenced to a maximum penalty of life imprisonment. (U.S. Department of Justice, 2008)
As a fun aside, during my research I came across an interesting article about the use of tetrodotoxin and folklore surrounding creation of zombies. In eight samples of "zombie powder" collected from four regions of Haiti all appeared to have four ingredients in common: 1) one or more species of puffer fish which contained tetrodotoxin, 2) a toxic marine frog, 3) a hyla tree frog which secretes an irritating substance, and 4) human remains. (Strayer University, n.d.) According to some theories a person poisoned with Haitian zombie powder regains consciousness either while in the coffin or shortly after being removed from it and therefore, think they have died and are now a zombie. (How Stuff Works, n.d.)
When analyzing an agent as a potential biological agent for use as a weapon of bioterrorism one must examine certain attributes as they apply to that specific agent. Some of these attributes include ease of dissemination, route of entry, morbidity, mortality, infectivity, potential for contagion, potential for panic and social disturbance, and the impact on public health and public health preparedness.
The most efficient route of entry for tetrodotoxin would be ingestion - either through consumption of the toxin itself or the consumption of other food products tainted with tetrodotoxin. Because ingestion is the favored route of entry, tetrodotoxin does not lend itself for use as a weapon that is easily disseminated or for use as a bioterrorism weapon.
Tetrodotoxin does have some potential use as a target specific biological weapon. Bioterrorists could use tetrodotoxin for targeted victims, such as political figures, world leaders or small contingents of military forces. Even for use on targeted specific victims tetrodotoxin is not be easily disseminated. Tetrodotoxin poisoning would require the introduction of the toxin directly into a food or liquid source ingested by the target. Ingestion as a route of entry makes tetrodotoxin not easily disseminated.
Morbidity rates are 100% for tetrodotoxin poisoning; rarely will ingestion of tetrodotoxin contaminated food leave the victim unscathed as evidenced by the number of fugu poisoning cases recorded in Japan each year. Tetrodotoxin with its high morbidity rate could be considered as a weapon for bioterrorism. Infectivity rates for tetrodotoxin are 100%.
Another fact influencing the high morbidity rate of tetrodotoxin poisoning is the possibility it can easily be mistaken for one of many differential diagnoses. Patients presenting with tetrodotoxin poisoning could easily be misdiagnosed especially if a valid dietary history is unavailable or overlooked.
Mortality rates for tetrodotoxin are difficult to establish; anecdotal reports suggest 50-60% mortality, even with good supportive care. One report suggests that prognosis is good if the patient survives the first 24 hours. (Medscape CDC Commentary Series, October 2009) The same cannot be said for biological agents like plague. In the pneumonic form plague is almost 100% fatal without immediate medical attention. (Ryan & Glarum, 2008) A biological weapon with only a possible 50-60% mortality rate would probably not be perceived as an effective weapon of bioterrorism.
Unlike some other biological agents that lend themselves to inhalation or person-to-person transmission, tetrodotoxin poisoning is transmitted only through ingestion of the toxin. It does not have the potential as a weapon of bioterrorism because transmission is limited to persons ingesting the toxin.
Tetrodotoxin poisoning offers no potential threat for contagion in terms of an epidemic or pandemic. The bacteria are contained within the host organism.
Tetrodotoxin poisoning could certainly create panic and social disturbance, especially if the targeted victims were persons of political or military importance. There could also be public panic caused by the concern as to the nature, origin and location of the toxin.
To be considered as a potential weapon of bioterrorism the biological agent would need to: 1) be easily disseminated or transmitted, 2) cause high mortality, 3) severely affect the public health, 4) cause public panic and social disruption, and 5) require special action for public health preparedness.
Overall, while tetrodotoxin is a lethal neurotoxin with: 1) a high level of morbidity, 2) moderate level of mortality, 3) a difficult dissemination method, 4) ingestion as the route of entry, 5) no transmission qualities, 6) no likelihood of contagion and 7) unlikely to cause panic or social disruption, in my opinion it would not be useful as a biological weapon of mass destruction.
In my opinion tetrodotoxin has some modest potential as a limited bioterrorism agent in special circumstances. Tetrodotoxin does not meet all the necessary criteria to be considered as a biological agent capable of causing severe damage to the health and safety of the public.