U.S. Food & Drug Administration Center for Food Safety & Applied Nutrition Foodborne Pathogenic Microorganisms and Natural Toxins Handbook

1. Name of the Organism:	Tetrodotoxin (anhydrotetrodotoxin 4-epitetrodotoxin, tetrodonic acid)
2. Nature of Acute Disease:	Pufferfish Poisoning, Tetradon Poisoning, Fugu Poisoning
3. Nature of Disease:	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. The metabolic source of tetrodotoxin is uncertain. No algal source has been identified, and until recently tetrodotoxin was assumed to be a metabolic product of the host. However, recent reports of the production of tetrodotoxin/anhydrotetrodotoxin by several bacterial species, including strains of the family Vibrionaceae, Pseudomonas sp., and Photobacterium phosphoreum, point toward a bacterial origin of this family of toxins. These are relatively common marine bacteria that are often associated with marine animals. If confirmed, these findings may have some significance in toxicoses that have been more directly related to these bacterial species.
4. Diagnosis of Human Illness:	The diagnosis of pufferfish poisoning is based on the observed symptomology and recent dietary history.
5. Associated Foods:	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.
6. 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.
7. 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 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 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.
8. Target Populations:	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.
9. Food Analysis:	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.
10. Selected Outbreaks:	Literature references can be found at the links below.
MMWR 45(19):1996	On April 29, 1996, three cases of tetrodotoxin poisoning occurred among chefs in California who shared contaminated fugu (puffer fish) brought from Japan by a co-worker as a prepackaged, ready-to-eat product. The quantity eaten by each person was minimal, ranging from approximately 1/4 to 1 1/2 oz. Onset of symptoms began approximately 3-20 minutes after ingestion, and all three persons were transported by ambulance to a local emergency department.
	Pufferfish poisoning is a continuing problem in Japan, affecting 30 - 100 persons/year. Most of these poisoning episodes occur from home preparation and consumption and not from commercial sources of the pufferfish. Three deaths were reported in Italy in 1977 following the consumption of frozen pufferfish imported from Taiwan and mislabelled as angler fish.
Morbidity and Mortality Weekly Reports	For more information on recent outbreaks see the CDC.
11. Education and Background Resources:	Literature references can be found at the links below.
Loci index for genome Tetraodontidae (Pufferfish family)	Available from the GenBank Taxonomy database, which contains the names of all organisms that are represented in the genetic databases with at least one nucleotide or protein sequence.
12. Molecular Structural Data:	This structure was created by Fred Fry, Ph.D, CFSAN.
	Tetrodotoxin

CDC/MMWR

The CDC/MMWR link will provide a list of Morbidity and Mortality Weekly Reports at CDC relating to this organism or toxin. The date shown is the date the item was posted on the Web, not the date of the MMWR. The summary statement shown are the initial words of the overall document. The specific article of interest may be just one article or item within the overall report.

NIH/PubMed

The NIH/PubMed button at the top of the page will provide a list of research abstracts contained in the National Library of Medicine's MEDLINE database for this organism or toxin.

AGRICOLA

The AGRICOLA button will provide a list of research abstracts contained in the National Agricultural Library database for this organism or toxin.

mow@cfsan.fda.gov
January 1992 with periodic updates