Tetrodotoxin (anhydrotetrodotoxin 4-epitetrodotoxin, tetrodonic acid, TTX) is a potent neurotoxin, which shuts down electrical signalling in nerves by binding to the pores of voltage-gated sodium channel proteins in nerve cell membranes. In essence, this toxin will selectively block voltage-gated Na+ channels. Its name derives from Tetraodontidae, the scientific family name of the puffer fishes, some species of which carry the toxin. Although tetrodotoxin was discovered in these fish and found in several other animals, it is actually thought to be a product of bacteria such as Pseudoalteromonas tetraodonis, certain Pseudomonas and Vibrio species, as well as some others.
Fish poisoning by consumption of members of the order Tetraodontiformes is one of the most violent intoxications from marine species. The gonads, liver, intestines, and skin of pufferfish can contain levels of tetrodotoxin sufficient to produce rapid and violent death. The flesh of many pufferfish may not usually be dangerously toxic.
Tetrodotoxin has also been isolated from widely differing animal species, including the California newt, parrotfish, frogs of the genus Atelopus, the blue-ringed octopus, starfish, angelfish, and xanthid crabs.
Common causes of tetrodotoxin poisoning include the eating of the puffer fish known as fugu, which is a popular but rare delicacy in Japan and often contains significant amounts of toxin in its liver and other viscera. Cone snail stings represent another common source, which most often affect divers. Blue-ringed octopus, which inhabit tidepools, also sometimes contain the toxin, and people have died from their bites. Lethal dose is about .01 mg/kg, less than ricin but more than botulism toxin.
Symptoms and diagnosis
The diagnosis of pufferfish poisoning is based on the observed symptomology and recent dietary history.
The effects of tetrodotoxin poisoning include shortness of breath, numbness, tingling, lightheadedness, paralysis and irregular heartbeat. Symptoms typically onset quickly, minor ones instantaneously. Death is the usual outcome. Although the toxin unbinds from channels as its concentration around nerves diminishes, its molecules are exceptionally potent and unbind only very slowly. Treatment usually consists of respiratory assistance. Nothing equivalent to an antivenin has been developed--presumably because the toxin acts quickly and binds with an affinity that isn't easily overcome.
Course of disease and complications
The first symptom of intoxication is a slight numbness of the lips and tongue, appearing between 20 minutes to three hours after eating poisonous pufferfish. The next symptom is increasing paresthesia 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 stage 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 within 4 to 6 hours, with a known range of about 20 minutes to 8 hours.
Areas where tetrodotoxin poisoning is most common
Poisonings from tetrodotoxin have been almost exclusively associated with the consumption of pufferfish from waters of the Indo-Pacific ocean regions. Several reported cases of poisonings, including fatalities, involved pufferfish from the Atlantic Ocean, Gulf of Mexico, and Gulf of California. There have been no confirmed cases of poisoning from the Atlantic pufferfish, Spheroides maculatus. However, in one study, extracts from fish of this species were highly toxic in mice. The trumpet shell Charonia sauliae has been implicated in food poisonings, and evidence suggests that it contains a tetrodotoxin derivative. There have been several reported poisonings from mislabelled pufferfish and at least one report of a fatal episode when an individual swallowed a California newt.
Relative frequency of disease
From 1974 through 1983 there were 646 reported cases of pufferfish poisoning in Japan, with 179 fatalities. Estimates as high as 200 cases per year with mortality approaching 50% have been reported. Only a few cases have been reported in the United States, and outbreaks in countries outside the Indo-Pacific area are rare.
All humans are susceptible to tetrodotoxin poisoning. This toxicosis may be avoided by not consuming pufferfish or other animal species containing tetrodotoxin. Most other animal species known to contain tetrodotoxin are not usually consumed by humans. Poisoning from tetrodotoxin is of major public health concern primarily in Japan, where "fugu" is a traditional delicacy. It is prepared and sold in special restaurants where trained and licensed individuals carefully remove the viscera to reduce the danger of poisoning. Importation of pufferfish into the United States is not generally permitted, although special exceptions may be granted. There is potential for misidentification and/or mislabelling, particularly of prepared, frozen fish products.
The mouse bioassay developed for paralytic shellfish poisoning (PSP) can be used to monitor tetrodotoxin in pufferfish and is the current method of choice. An HPLC method with post-column reaction with alkali and fluorescence has been developed to determine tetrodotoxin and its associated toxins. The alkali degradation products can be confirmed as their trimethylsilyl derivatives by gas chromatography/mass spectrometry. These chromatographic methods have not yet been validated.