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100-465: Fugu possesses a potentially fatal poison known as tetrodotoxin , therefore necessitating meticulous preparation to eliminate poisonous components and prevent the fish meat from being contaminated. The restaurant preparation of fugu is strictly controlled by law in Japan , Korea and several other countries, and only chefs who have qualified after three or more years of rigorous training are allowed to prepare

200-399: A coma . If the patient survives 24 hours, recovery without any aftereffects will usually occur over a few days. Therapy is supportive and based on symptoms, with aggressive early airway management. If consumed, treatment can consist of emptying the stomach, feeding the victim activated charcoal to bind the toxin, and taking standard life-support measures to keep the victim alive until

300-526: A Rover . But this theory has been questioned by the scientific community since the 1990s based on analytical chemistry -based tests of multiple preparations and review of earlier reports (see above). Shell midden A midden is an old dump for domestic waste . It may consist of animal bones , human excrement , botanical material, mollusc shells , potsherds , lithics (especially debitage ), and other artifacts and ecofacts associated with past human occupation. These features provide

400-583: A biochemical probe has elucidated two distinct types of voltage-gated sodium channels (VGSCs) present in mammals: tetrodotoxin-sensitive voltage-gated sodium channels (TTX-s Na channels) and tetrodotoxin-resistant voltage-gated sodium channels (TTX-r Na channels). Tetrodotoxin inhibits TTX-s Na channels at concentrations of around 1–10 nM, whereas micromolar concentrations of tetrodotoxin are required to inhibit TTX-r Na channels. Nerve cells containing TTX-r Na channels are located primarily in cardiac tissue, while nerve cells containing TTX-s Na channels dominate

500-623: A chef at two- Michelin star "Fugu Fukuji" in Tokyo was suspended from his post. The chef served fugu liver to a customer who, despite being warned of the risks, specifically asked that it be provided. The 35-year-old customer subsequently required hospital treatment for mild symptoms of tetrodotoxin paralysis, but made a full recovery. Five men were poisoned at a restaurant in Wakayama in March 2015 after specifically asking for liver. In December 2020, 3 people in

600-466: A clear central area. Many are known from Japan and the southeastern United States, and at least one from South America. The word is of Scandinavian via Middle English derivation (from early Scandinavian; Danish: mødding , Swedish regional: mödding ). The word "midden" is still in everyday use in Scotland and has come by extension to refer to anything that is a mess, a muddle, or chaos. The word

700-585: A diagnosis of poisoning in hospitalized patients or to assist in the forensic investigation of a case of fatal overdosage. Most analytical techniques involve mass spectrometric detection following gas or liquid chromatographic separation. Tetrodotoxin has been investigated as a possible treatment for cancer-associated pain. Early clinical trials demonstrate significant pain relief in some patients. It has also been studied in relation to migraine headaches. Mutations in one particular TTX-sensitive Na channel are associated with some migraine headaches, although it

800-610: A highly renowned delicacy, garnering widespread acclaim in establishing itself as one of the most celebrated dishes in Japanese and Korean cuisine. Fugu has also been gradually emerging as a prized seafood delicacy in the Chinese culinary landscape as well. There are close to 200 species in the family Tetraodontidae (pufferfish), a family of primarily marine and estuarine fish of the order Tetraodontiformes . However, only some of them are eaten and traded as "fugu". Fugu contains lethal amounts of

900-453: A house in the village. Each household would dump its garbage directly outside the house. In all cases, shell middens are extremely complex and very difficult to excavate fully and exactly. The fact that they contain a detailed record of what food was eaten or processed and many fragments of stone tools and household goods makes them invaluable objects of archaeological study. Shells have a high calcium carbonate content, which tends to make

1000-489: A list that shows which species' body parts can be consumed. The list names safe genera including pufferfish of the Lagocephalus and Sphoeroides genera and the related porcupinefish ( Harisenbon ) of the family Diodontidae . Strict fishing regulations are now in place to protect fugu populations from depletion. Most fugu is now harvested in the spring during the spawning season and then farmed in floating cages in

1100-656: A long period between the 6th millennium BCE and the beginning of European colonisation. European shell middens are primarily found along the Atlantic seaboard and in Denmark and primarily date to the 5th millennium BCE ( Ertebølle and Early Funnel Beaker cultures), containing the remains of the earliest Neolithisation process (pottery, cereals and domestic animals). Younger shell middens are found in Latvia (associated with Comb Ware ceramics), Sweden (associated with Pitted Ware ceramics),

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1200-670: A plot device for characters to fake death, as in the films Hello Again (1987), The Serpent and the Rainbow (1988), The A-Team (2010) and Captain America: The Winter Soldier (2014), War (2019), and in episodes of " Jane the Virgin ", Miami Vice (1985), Nikita , MacGyver Season 7, Episode 6, where the antidote is Datura stramonium leaf, CSI: NY (Season 4, episode 9 "Boo") and Chuck . In Law Abiding Citizen (2009) and Alex Cross (2012), its paralysis

1300-708: A restaurant, while the others all involved fishermen eating their catch. From 2006 through 2009 in Japan there were 119 incidents involving 183 people but only seven people died. Only a few cases have been reported in the United States, and outbreaks in countries outside the Indo-Pacific area are rare. In Haiti, tetrodotoxin was thought to have been used in voodoo preparations, in so-called zombie poisons. Subsequent careful analysis has however repeatedly called early studies into question on technical grounds, and failed to identify

1400-450: A role in TTX biosynthesis" – although the correlation has been extended to most but not all animals in which the toxin has been identified. To the contrary, there has been a failure in a single case, that of newts ( Taricha granulosa ), to detect TTX-producing bacteria in the tissues with highest toxin levels ( skin , ovaries , muscle ), using PCR methods, although technical concerns about

1500-651: A seafood delicacy, sometimes resulting in poisoning incidents. Japanese restaurateur Nobuyoshi Kuraoka waged a five-year legal battle with the U.S. Food and Drug Administration to allow the exclusive import of the Japanese Tiger puffer into his Manhattan restaurant, with the license finally being granted to him in 1989. By 2003, only seventeen restaurants in the United States were licensed to serve fugu; fourteen in New York State , twelve of which are in New York City . In

1600-517: A service each year at the height of the fugu season, releasing hundreds of caught fugu into the Sumida River . A similar ceremony is also held at another large market in Shimonoseki. A rakugo , or humorous short story, tells of three men who prepared a fugu stew but were unsure whether it was safe to eat. To test the stew, they gave some to a beggar. When it did not seem to do him any harm, they ate

1700-550: A small domestic luxury market that has been operating under license since 2003. Tetrodotoxin Tetrodotoxin ( TTX ) is a potent neurotoxin . Its name derives from Tetraodontiformes , an order that includes pufferfish , porcupinefish , ocean sunfish , and triggerfish ; several of these species carry the toxin. Although tetrodotoxin was discovered in these fish, it is found in several other animals (e.g., in blue-ringed octopi , rough-skinned newts , and moon snails ). It

1800-517: A strong case is made for ingestion of TTX and/or TTX-producing bacteria, with accumulation and possible subsequent colonization and production. Nevertheless, without clear biosynthetic pathways (not yet found in animals, but shown for bacteria), it remains uncertain whether it is simply via bacteria that each animal accumulates TTX; the question remains as to whether the quantities can be sufficiently explained by ingestion, ingestion plus colonization, or some other mechanism. Tetrodotoxin binds to what

1900-483: A style of pottery described as "cord-marked", translated as " Jōmon ", which came to be used to refer to the early period of Japanese history when this style of pottery was produced. Shell middens were studied in Denmark in the latter half of the 19th century. The Danish word køkkenmødding (kitchen mound) is now used internationally. The English word "midden" (waste mound) derives from the same Old Norse word that produced

2000-599: A tetrodotoxin derivative. There have been several reported poisonings from mislabelled pufferfish, and at least one report of a fatal episode in Oregon when an individual swallowed a rough-skinned newt Taricha granulosa on a dare. In 2009, a major scare in the Auckland Region of New Zealand was sparked after several dogs died eating Pleurobranchaea maculata (grey side-gilled seaslug) on beaches. Children and pet owners were asked to avoid beaches, and recreational fishing

2100-540: A tonic effect when used at the correct dose. The principal use was "to arrest convulsive diseases". In the Pen-T’so Kang Mu (Index Herbacea or The Great Herbal by Li Shih-Chen, 1596) some types of the fish Ho-Tun (the current Chinese name for tetraodon ) were also recognized as both toxic yet, at the right dose, useful as part of a tonic. Increased toxicity in Ho-Tun was noted in fish caught at sea (rather than river) after

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2200-452: A toxicity inspection, and other tests." In Korean cuisine , edible pufferfish are prepared in various ways including gui (grilling), jorim (simmering), jjim , Bulgogi , Hoe (raw fish) and guk (soup). Despite the comparatively lower consumption rate of the fish in comparison to other East Asian nations, the prevalence of fugu restaurants has experienced a significant surge across Chinese urban areas since 2016. The fish

2300-425: A useful resource for archaeologists who wish to study the diets and habits of past societies. Middens with damp, anaerobic conditions can even preserve organic remains in deposits as the debris of daily life are tossed on the pile. Each individual toss will contribute a different mix of materials depending upon the activity associated with that particular toss. During the course of deposition sedimentary material

2400-637: Is Takefuku , in the upscale Ginza district in Tokyo with Zuboraya being another popular restaurant chain in Osaka that both offer the celebrated seafood delicacy. The fugu is cleaned of its most toxic parts in Japan and freeze-flown to the United States under license in clearly customized plastic containers. Fugu chefs who cook in American restaurants are trained under the same rigorous and stringent specifications as in Japan. Pufferfish native to American waters, particularly

2500-472: Is a sodium channel blocker . It inhibits the firing of action potentials in neurons by binding to the voltage-gated sodium channels in nerve cell membranes and blocking the passage of sodium ions (responsible for the rising phase of an action potential) into the neuron. This prevents the nervous system from carrying messages and thus muscles from contracting in response to nervous stimulation. Its mechanism of action – selective blocking of

2600-410: Is also made into everyday objects like wallets or waterproof boxes. Scientists at Nagasaki University have succeeded in culturing non-toxic torafugu by restricting the fish's diet. The experiment included raising over 5,000 fish between the years 2001–2004, and analyzing the toxicity of muscle, skin, gonads, livers, and other organs. The team concluded that the amount of tetrodotoxin in all those parts

2700-405: Is also produced by certain infectious or symbiotic bacteria like Pseudoalteromonas , Pseudomonas , and Vibrio as well as other species found in symbiotic relationships with animals and plants. Although it produces thousands of intoxications annually and several deaths, it has shown efficacy for the treatment of cancer-related pain in phase II and III clinical trials. Tetrodotoxin

2800-537: Is deposited as well. Different mechanisms, from wind and water to animal digs, create a matrix which can also be analysed to provide seasonal and climatic information. In some middens individual dumps of material can be discerned and analysed. A shell midden or shell mound is an archaeological feature consisting mainly of mollusc shells. The Danish term køkkenmøddinger (plural) was first used by Japetus Steenstrup to describe shell heaps and continues to be used by some researchers. A midden, by definition, contains

2900-455: Is forbidden altogether in the European Union . In Switzerland , the importation of fugu is legal, but only as long as it is purchased exclusively for private consumption. Fugu chefs who cook in American restaurants are trained under the same rigorous and stringent specifications as in Japan. Pufferfish native to American waters, particularly the genus Spheroides , have also been consumed as

3000-522: Is in development by USAMRIID that was effective, in the one study, for reducing toxin lethality in tests on mice. Poisonings from tetrodotoxin have been almost exclusively associated with the consumption of pufferfish from waters of the Indo-Pacific Ocean regions, primarily because equally toxic pufferfishes from other regions are much less commonly eaten. Several reported cases of poisonings, including fatalities, nonetheless involved pufferfish from

3100-507: Is increasing respiratory distress , speech is affected, and the victim usually exhibits shortness of breath , excess pupil dilation , and abnormally low blood pressure . Paralysis increases, and convulsions , mental impairment, and irregular heartbeats may occur. The victim, although completely paralysed, may be conscious and in some cases completely understandable until shortly before death, which generally occurs within 4 to 6 hours (range ~20 minutes to ~8 hours). However, some victims enter

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3200-412: Is known as site 1 of the fast voltage-gated sodium channel . Site 1 is located at the extracellular pore opening of the ion channel. Any molecule bound to this site will block sodium ions from going into the nerve cell through this channel (which is ultimately necessary for nerve conduction). Saxitoxin , neosaxitoxin , and several of the conotoxins also bind the same site. The use of this toxin as

3300-615: Is no known antidote , and treatment consists of emptying the stomach, administering activated charcoal to bind the toxin, and putting the person on life support until the poison has worn off. Toxicologists have been working on developing an antidote for tetrodotoxin. Between 1996 and 2006, statistics from the Tokyo Bureau of Social Welfare and Public Health indicate 20–44 annual incidents of fugu poisoning in Japan, some affecting multiple diners. Annually, 34–64 people were hospitalized and 0–6 died, with an average fatality rate of 6.8%. Of

3400-460: Is not a factor in susceptibility to tetrodotoxin poisoning. This toxicosis may be avoided by not consuming animal species known to contain tetrodotoxin, principally pufferfish; other tetrodotoxic species are not usually consumed by humans. Poisoning from tetrodotoxin is of particular public health concern in Japan, where fugu is a traditional delicacy. It is prepared and sold in special restaurants where trained and licensed chefs carefully remove

3500-408: Is only made in specific regions of Ishikawa Prefecture ( Mikawa district , Ono district, Kanaiwa district, and Wajima ), and only the traditional method is permitted. Non-professionals are warned against attempting the process. After one year of pickling, about 10% of the toxin is suggested to remain, and after the full three years the product is "only sold after having been checked for safety through

3600-403: Is only partially understood. It is long known that the molecule is related to saxitoxin , and as of 2011 it is believed that there are separate routes for aquatic (bacterial) and terrestrial (newt) TTX. In 2020, new intermediates found in newts suggest that the synthesis starts with geranyl guanidine in the amphibian; these intermediates were not found in aquatic TTX-containing animals, supporting

3700-478: Is only sold in a processed form (without organs) with a test certificate from the fishery. In 2023, processed raw farmed fugu across China is sold to ordinary customers online. Most Japanese cities have one or more fugu restaurants, perhaps in clusters because of earlier restrictions, as proximity made it easier when transporting the seafood delicacy so as to preserve its long-term freshness upon being served to potential patrons. A famous restaurant specializing in fugu

3800-477: Is over 9 metres (30 ft) deep and spans over 10,000 years of continuous occupation. Shell middens created in coastal regions of Australia by Indigenous Australians exist in Australia today. Middens provide evidence of prior occupation and are generally protected from mining and other developments. One must exercise caution in deciding whether one is examining a midden or a beach mound. There are good examples on

3900-648: Is presented as a method of assisting torture. The toxin was also referenced in "synthetic form" in the S1E2 of the series " FBI ". The toxin is used as a weapon in both the second season of Archer , in Covert Affairs and in the Inside No. 9 episode " The Riddle of the Sphinx ". In Columbo, Episode 2 of Season 7, fugu is used to kill the antagonists victim. Columbo (season 7) In The Apothecary Diaries light novel, as well as

4000-551: Is unclear as to whether this has any therapeutic relevance for most people with migraine. Tetrodotoxin has been used clinically to relieve negative affects associated with heroin withdrawal . In the U.S., tetrodotoxin appears on the select agents list of the Department of Health and Human Services , and scientists must register with HHS to use tetrodotoxin in their research. However, investigators possessing less than 500 mg are exempt from regulation. Tetrodotoxin serves as

4100-638: Is used by farmers in Britain to describe the place where farm yard manure from cows or other animals is collected. Grants are sometimes available to protect these from rain to avoid runoff and pollution . In the animal kingdom, some species establish ground burrows , also known as middens, that are used mostly for food storage. For example, the North American red squirrel ( Tamiasciurus hudsonicus ) usually has one large active midden in each territory with perhaps an inactive or auxiliary midden. A midden may be

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4200-758: The Dreamtime , such as those of the Anbarra group of the Burarra people of Arnhem Land . The Ohlone and Coast Miwok peoples built over 425 shell mounds in the San Francisco Bay Area. These mounds were used as: The mounds were constructed over thousands of years. They were often discovered by accident during construction, mining, or farming. Some of the largest mounds in the Bay Area include: Emeryville Shellmound Located between Oakland and Berkeley, this mound

4300-660: The Freycinet Peninsula in Tasmania where wave action currently is combining charcoal from forest fire debris with a mix of shells into masses that storms deposit above high-water mark. Shell mounds near Weipa in far north Queensland that are mostly less than 2 metres (6.6 ft) high (although ranging up to 10 metres (33 ft) high) and a few tens of metres long are claimed to be middens, but are in fact shell cheniers (beach ridges) re-worked by nest mound-building birds. Some shell middens are regarded as sacred sites, linked to

4400-542: The Jōmon period that date back more than 2,300 years. The Tokugawa shogunate (1603–1868) prohibited the consumption of fugu in Edo and its area of influence. It became common again as the power of the Shōgunate weakened. In western regions of Japan, where the government's influence was weaker and fugu was easier to obtain, various cooking methods were developed to safely eat them. During

4500-504: The Kansai region of Japan, the slang word teppō , ( 鉄砲 ) meaning musket, rifle or gun , is used for the fish. This is a play of words on the verb ataru ( 当たる ), which can mean to be poisoned or shot. In Shimonoseki region, the ancient pronunciation fuku is more common instead of the modern fugu . The former is also a homonym for good fortune whereas the latter is one for disabled. The Tsukiji fish market fugu association holds

4600-622: The Meiji Era (1867–1912), fugu was again banned in many areas. According to one fugu chef in Tokyo, the Emperor of Japan has never eaten fugu due to an unspecified "centuries old ban". In China, the use of the pufferfish for culinary purposes was already well-established by the Song dynasty as one of the "three delicacies of the Yangtze" ( Chinese : 長江三鮮 ), alongside saury and Reeve's shad , and appears in

4700-525: The Pacific Ocean . The largest wholesale fugu market in Japan is in Shimonoseki . Fugu prices rise in autumn and peak in winter, the best season, because they fatten to survive the cold. Live fish arrive at a restaurant, surviving in a large tank, usually prominently displayed. Prepared fugu is also often available in grocery stores, which must display official license documents. Whole fish may not be sold to

4800-537: The cell membranes of those cells. Its ability to cross the blood–brain barrier is uncertain. In the case of the pufferfish host, at least (see below), their insusceptibility to the poison is thought to result from cysteine asperagine amino acid substitutions in the sequence of their specific types of sodium channel proteins. TTX is not produced by pufferfish and the other aquatic animals from which it has been isolated. Rather, bacteria such as Alteromonas , Shewanella , and Vibrio species infect or cohabit with

4900-664: The viscera to reduce the danger of poisoning. There is potential for misidentification and 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. Tetrodotoxin may be quantified in serum, whole blood or urine to confirm

5000-654: The 1938 non-fiction book Tell My Horse by Zora Neale Hurston in which there were multiple accounts of purported tetrodotoxin poisoning in Haiti by a voodoo sorcerer called the bokor . These stories were later popularized by Harvard -trained ethnobotanist Wade Davis in his 1985 book and Wes Craven 's 1988 film, both titled The Serpent and the Rainbow . James Ellroy includes "blowfish toxin" as an ingredient in Haitian Vodou preparations to produce zombieism and poisoning deaths in his dark, disturbing, violent novel Blood's

5100-451: The 23 incidents reported in Tokyo from 1993 through 2006, only one took place in a restaurant; all others involved people catching and eating the fish. Poisonings through amateur preparation can result from confusion between types of puffer, as well as improper methods. Some may also represent deliberate suicide attempts; Engelbert Kaempfer , a German physician who resided in Japan in the 1690s, reported that an unusually toxic variety of puffer

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5200-692: The Atlantic Ocean, Gulf of Mexico , and Gulf of California . There have been no confirmed cases of tetrodotoxicity from the Atlantic pufferfish, Sphoeroides maculatus , but three studies found extracts from fish of this species highly toxic in mice. Several recent intoxications from these fishes in Florida were due to saxitoxin , which causes paralytic shellfish poisoning with very similar symptoms and signs. The trumpet shell Charonia sauliae has been implicated in food poisonings, and evidence suggests it contains

5300-406: The Chinese culinary sphere, fugu is generally prepared as a soup or braised whole. The fish may also be prepared using traditional Japanese culinary techniques. In the cuisine of Hakusan, Ishikawa , ovaries are served after reducing the toxin level by salting and pickling for three years, in a dish named "blowfish ovaries pickled in rice-bran paste " ( 河豚の卵巣の糠漬け, ふぐのらんそうのぬかづけ ) . The dish

5400-534: The Food Safety Commission of Japan three times to reconsider its ban on fugu liver, stating that its farmed fugu is non-toxic. The FSCJ has rejected the proposals thrice due to "data insufficient to prove safety". NYT reported in 2008 that there is a well-known underground fugu-kimo scene in another Japanese town, Usuki, Ōita . In the case of torafugu , the most common fugu, the cost is between JP¥1000–JP¥4000 (US$ 7–29) per kilogram, depending on

5500-500: The Netherlands (associated with Corded Ware ceramics) and Schleswig-Holstein ( Late Neolithic and Iron Age ). All these are examples where communities practised a mixed farming and hunting/gathering economy. On Canada 's west coast, there are shell middens that run for more than 1 kilometre (0.6 mi) along the coast and are several meters deep. The midden in Namu, British Columbia

5600-600: The Philippines died, while 4 more were hospitalized after eating pufferfish. In March 2023, an elderly woman and her husband in Malaysia died after consuming pufferfish purchased from a fishmonger. In January 2024, a Brazilian man, 46, died after eating pufferfish gifted to him by a friend. Although not as frequently consumed as in Japan and Korea, fugu is still considered a delicacy and served across restaurants in Beijing . Within

5700-412: The amount needed to reach a lethal dose by injection is 8 μg per kg in mice. The toxin can enter the body of a victim by ingestion , injection, or inhalation , or through abraded skin. Poisoning occurring as a consequence of consumption of fish from the order Tetraodontiformes is extremely serious. The organs (e.g., liver) of the pufferfish can contain levels of tetrodotoxin sufficient to produce

5800-785: The animal species from which TTX is isolated, and a bacterial biosynthetic pathway for its production has been rationalized. In animal studies with mice, the median lethal dose of TTX was found to be 232 μg per kg body weight. Tetrodotoxin levels are affected by preparation (removal of most toxic materials, treatments such as curing and pickling, see below); it is, however, reportedly not significantly affected by cooking. Despite its toxicity, TTX has clinical therapeutic applications, being evaluated in phase II and III clinical trials to be effective for treating cancer-related pain without increasing serious adverse events. The inhabitants of Japan have eaten fugu for centuries. Fugu bones have been found in several shell middens , called kaizuka , from

5900-423: The approach have been raised. Critically for the general argument, Takifugu rubripes puffers captured and raised in laboratory on controlled, TTX-free diets "lose toxicity over time", while cultured, TTX-free Takifugu niphobles puffers fed on TTX-containing diets saw TTX in the livers of the fishes increase to toxic levels. Hence, as bacterial species that produce TTX are broadly present in aquatic sediments,

6000-459: The body and brain. As a result, TTX causes loss of sensation, and paralysis of voluntary muscles including the diaphragm and intercostal muscles, stopping breathing. The therapeutic uses of puffer fish ( tetraodon ) eggs were mentioned in the first Chinese pharmacopoeia Pen-T’so Ching (The Book of Herbs, allegedly 2838–2698 BC by Shennong ; but a later date is more likely ), where they were classified as having "medium" toxicity, but could have

6100-606: The creation of tropical hardwood hammocks , one example being the Otter Mound Preserve in Florida , where shell deposits from Calusa natives provided flood free high areas in otherwise large watered areas. There are instances in which shell middens may have doubled as areas of ceremonial construction or ritual significance. The Woodland period Crystal River site provides an example of this phenomenon. Some shell mounds, known as shell rings , are circular or open arcs with

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6200-429: The deaths. In March 2008, a fisherman in the Philippines died and members of his family became ill from pufferfish. The previous year, four people in the same town died and five others had fallen ill after eating the same variety of pufferfish. In February 2009, a Malaysian fisherman died and four others were hospitalised after they consumed a meal of pufferfish when they ran out of food while at sea. In November 2011,

6300-413: The debris of human activity, and should not be confused with wind- or tide-created beach mounds. Some shell middens are processing remains: areas where aquatic resources were processed directly after harvest and prior to use or storage in a distant location. Some shell middens are directly associated with villages, as a designated village dump site. In other middens, the material is directly associated with

6400-404: The described paralysis of the diaphragm and corresponding death due to respiratory failure . Toxicity varies between species and at different seasons and geographic localities, and the flesh of many pufferfish may not be dangerously toxic. The mechanism of toxicity is through the blockage of fast voltage-gated sodium channels, which are required for the normal transmission of signals between

6500-436: The effect of the poison has worn off. Alpha adrenergic agonists are recommended in addition to intravenous fluids to increase the blood pressure; anticholinesterase agents "have been proposed as a treatment option but have not been tested adequately". No antidote has been developed and approved for human use, but a primary research report (preliminary result) indicates that a monoclonal antibody specific to tetrodotoxin

6600-491: The effects of TTX. Mutations in the VGSC genes, especially the genes for Na v 1.4 (skeletal muscle VGSC, "TTX-s" ), are found in many such animals. These mutations have independently arisen several times, even multiple times in different populations of the same species as seen in the garter snake. They consist of different amino acid substitutions in similar positions, a weak example of convergent evolution caused by how TTX binds to

6700-405: The fish away from the bacteria – see § Aquaculture below. Tetrodotoxin (TTX) is a natural product that has been isolated not only from pufferfish, but also octopuses, crabs, shellfish, frogs, newts, and other aquatic animals (see below). It is a potent neurotoxin that shuts down electrical signaling in nerves ; it acts via interaction with components of the sodium channels in

6800-649: The fish away from the bacteria that makes them poisonous. Since October 2012, restaurants in Japan have been permitted to sell fugu that has been prepared and packaged by a licensed practitioner elsewhere. China began issuing trial permits for serving fugu to restaurants in 2003. In 2016, the Chinese government abolished the permit system and allowed all restaurants to buy and serve farmed fish (without organs), now widely available. By 2019, such restaurants have become commonplace. China also allowed ordinary households to buy processed (organ-removed) whole fish online starting in 2017. The Saga Prefecture in Japan has petitioned

6900-603: The fish were, to the extent that it would be used for suicide and that the Emperor specifically decreed that soldiers were not permitted to eat it. There is also evidence from other sources that knowledge of such toxicity was widespread throughout southeast Asia and India. The first recorded cases of TTX poisoning affecting Westerners are from the logs of Captain James Cook from 7 September 1774. On that date Cook recorded his crew eating some local tropic fish (pufferfish), then feeding

7000-412: The fish. Domestic preparation occasionally leads to accidental death. Throughout Japan, fugu is served as sashimi and nabemono . The liver was served as a traditional dish named fugu-kimo , being widely thought to be a tasty part, but it is also the most poisonous, and serving this organ in restaurants was banned in Japan in 1984. In the gastronomic domains of East Asian cuisine, fugu has emerged as

7100-472: The following animals, specific bacterial species have been implicated: The association of bacterial species with the production of the toxin is unequivocal – Lago and coworkers state, "[e]ndocellular symbiotic bacteria have been proposed as a possible source of eukaryotic TTX by means of an exogenous pathway", and Chau and coworkers note that the "widespread occurrence of TTX in phylogenetically distinct organisms... strongly suggests that symbiotic bacteria play

7200-555: The general public. Since 1958, fugu chefs must earn a license to prepare and sell fugu to the public. This involves a two- or three-year apprenticeship. The licensing examination process consists of a written test, a fish-identification test, and a practical test, preparing and eating the fish. Only about 35 percent of the applicants pass. Small miscalculations result in failure or, in rare cases, death. Consumers believe that this training process makes it safer to eat fugu in restaurants or markets. Non-poisonous fugu can be produced by keeping

7300-562: The genus Spheroides , have also been consumed as a seafood delicacy, sometimes resulting in poisoning incidents. In South Korea , fugu is known as bok-eo (복어), the seafood delicacy is very popular in southern port cities such as Busan and Changwon . It is prepared in a number of ways resulting in a variety of dishes ranging from soups, raw fish and salads, all of which command a high price. Fugu Bulgogi and Jorim are popular in Daegu . Sale of fish belonging to this family (Tetraodontidae)

7400-520: The identity of maculotoxin and TTX was reported in Science in 1978, and the synonymity of these two toxins is supported in modern reports (e.g., at Pubchem and in modern toxicology textbooks ) though historic monographs questioning this continue in reprint. The toxin is variously used by animals as a defensive biotoxin to ward off predation , or as both a defensive and predatory venom (e.g., in octopuses, chaetognaths , and ribbon worms ). Even though

7500-418: The lips and tongue is followed by developing it in the extremities, hypersalivation , sweating , headache, weakness, lethargy, incoordination , tremor , paralysis, bluish skin , loss of voice , difficulty swallowing , and seizures . The gastrointestinal symptoms are often severe and include nausea , vomiting , diarrhoea , and abdominal pain ; death is usually secondary to respiratory failure . There

7600-461: The middens alkaline . This slows the normal rate of decay caused by soil acidity, leaving a relatively high proportion of organic material (food remnants, organic tools, clothing, human remains) available for archaeologists to find. Edward Sylvester Morse conducted one of the first archaeological excavations of the Omori Shell Mounds in Tokyo, Japan in 1877, which led to the discovery of

7700-472: The modern Danish one. Shell middens are found in coastal or lakeshore zones all over the world. Consisting mostly of mollusc shells, they are interpreted as being the waste products of meals eaten by nomadic groups or hunting parties. Some are small examples relating to meals had by a handful of individuals, others are many metres in length and width and represent centuries of shell deposition. In Brazil , they are known as sambaquis , having been created over

7800-466: The month of March. It was recognized that the most poisonous parts were the liver and eggs, but that toxicity could be reduced by soaking the eggs. (Tetrodotoxin is slightly water-soluble, and soluble at 1 mg/ml in slightly acidic solutions.) The German physician Engelbert Kaempfer , in his "A History of Japan" (translated and published in English in 1727), described how well known the toxic effects of

7900-410: The poison tetrodotoxin in its organs, especially the liver , ovaries , eyes, and skin. The poison, a sodium channel blocker , paralyzes the muscles while the victim stays fully conscious; the poisoned victim is unable to breathe and eventually dies from asphyxiation . There is no known antidote for fugu poison. The standard treatment is to support the respiratory and circulatory systems until

8000-490: The poison is metabolized and excreted by the victim's body. Researchers have determined that a fugu's tetrodotoxin comes from eating other animals infested with tetrodotoxin-laden bacteria , to which the fish develops insensitivity over time. Whether tetrodotoxin is sequestered from or produced by symbiotic bacteria is still debated. As such, efforts have been made in research and aquaculture to allow farmers to produce safe fugu. Farmers now produce poison-free fugu by keeping

8100-477: The presence of the toxin by chemical analysis, and the association of the bacteria with TTX production by toxicity assay of media in which suspected bacteria are grown. As Lago et al. note, "there is good evidence that uptake of bacteria producing TTX is an important element of TTX toxicity in marine animals that present this toxin." TTX-producing bacteria include Actinomyces , Aeromonas , Alteromonas , Bacillus , Pseudomonas , and Vibrio species; in

8200-429: The remains to the pigs kept on board. The crew experienced numbness and shortness of breath, while the pigs were all found dead the next morning. In hindsight, it is clear that the crew survived a mild dose of tetrodotoxin, while the pigs ate the pufferfish body parts that contain most of the toxin, thus being fatally poisoned. The toxin was first isolated and named in 1909 by Japanese scientist Dr. Yoshizumi Tahara. It

8300-426: The respective manga and anime adaptations, fugu toxin is encountered across multiple mystery arcs. Based on the presumption that tetrodotoxin is not always fatal, but at near-lethal doses can leave a person extremely unwell with the person remaining conscious, tetrodotoxin has been alleged to result in zombieism , and has been suggested as an ingredient in Haitian Vodou preparations. This idea first appeared in

8400-406: The rest of the body. TTX and its analogs have historically been important agents for use as chemical tool compounds, for use in channel characterization and in fundamental studies of channel function. The prevalence of TTX-s Na channels in the central nervous system makes tetrodotoxin a valuable agent for the silencing of neural activity within a cell culture . The biosynthetic route to TTX

8500-488: The sale of which was prohibited by local ordinances at the time. Bandō claimed to be able to resist the poison, but died several hours after returning to his hotel. On August 23, 2007, a doctor in Thailand reported that unscrupulous fish sellers sold puffer meat disguised as salmon, which caused fifteen deaths over three years. About 115 people were taken to different hospitals. Fugu had been banned in Thailand five years prior to

8600-560: The season and quality, as of 2022. The expense encourages chefs to slice the fish very carefully to obtain the largest possible amount of meat. A special knife, called fugu hiki , is usually stored separately from other knives. In China, packaged farmed fugu cost CN¥330 (US$ 50) per kilogram as of February 2023. The symptoms of tetrodotoxin poisoning include dizziness, exhaustion, headache, nausea, or difficulty breathing. The person remains conscious but cannot speak or move. In high doses, breathing stops and asphyxiation follows. There

8700-424: The separate-route theory. In 2021, the first genome of a TTX-producing bacterium was produced. This " Bacillus sp. 1839" was identified as Cytobacillus gottheilii using its rRNA sequence. The researcher responsible for this study has not yet identified a coherent pathway but hopes to do so in the future. Animals that accumulate TTX as a defense mechanism as well as their predators must evolve to be resistant to

8800-439: The sodium channel – was shown definitively in 1964 by Toshio Narahashi and John W. Moore at Duke University , using the sucrose gap voltage clamp technique. Apart from their bacterial species of most likely ultimate biosynthetic origin (see below), tetrodotoxin has been isolated from widely differing animal species, including: Tarichatoxin was shown to be identical to TTX in 1964 by Mosher et al., and

8900-452: The stew. Later, they met the beggar again and were delighted to see that he was still in good health. After that encounter, the beggar, who had hidden the stew instead of eating it, knew that it was safe and he could eat it. The three men had been fooled by the wise beggar. Lanterns can be made from the bodies of preserved fugu. These are occasionally seen outside of fugu restaurants, as children's toys, as folk art, or as souvenirs. Fugu skin

9000-540: The structure of tetrodotoxin. The structure was confirmed by X-ray crystallography in 1970. Yoshito Kishi and coworkers reported the first total synthesis of racemic tetrodotoxin in 1972. M. Isobe and coworkers and J. Du Bois reported the asymmetric total synthesis of tetrodotoxin in 2003. The two 2003 syntheses used very different strategies, with Isobe's route based on a Diels-Alder approach and Du Bois's work using C–H bond activation . Since then, methods have rapidly advanced, with several new strategies for

9100-425: The synthesis of tetrodotoxin having been developed. TTX is extremely toxic. The material safety data sheet for TTX lists the oral median lethal dose ( LD 50 ) for mice as 334  μg per kg. For comparison, the oral LD 50 of potassium cyanide for mice is 8,500 μg per kg, demonstrating that even orally, TTX is more poisonous than cyanide . TTX is even more dangerous if administered intravenously;

9200-432: The toxin acts as a defense mechanism, some predators such as the common garter snake have developed insensitivity to TTX, which allows them to prey upon toxic newts . The association of TTX with consumed, infecting, or symbiotic bacterial populations within the animal species from which it is isolated is relatively clear; presence of TTX-producing bacteria within an animal's microbiome is determined by culture methods,

9300-401: The toxin in any preparation. Discussion of the matter has therefore all but disappeared from the primary literature since the early 1990s. Kao and Yasumoto concluded in the first of their papers in 1986 that "the widely circulated claim in the lay press to the effect that tetrodotoxin is the causal agent in the initial zombification process is without factual foundation." Genetic background

9400-407: The unmutated VGSC. Another path to TTX resistance is toxin-binding proteins that hold onto TTX tightly enough to prevent it reaching the vulnerable VGSCs. Various proteins that bind TTX have been found in pufferfish, crabs, and gastropods. There are also proteins that bind saxitoxin (STX), a toxin with a similar mode of action. In 1964, a team of scientists led by Robert B. Woodward elucidated

9500-531: The writings of the polymath Shen Kuo as well as in the encyclopedic work Taiping Guangji . The scholar-statesman Su Shi famously remarked that the taste is worthy of death ( 值那一死 ). The torafugu , or tiger pufferfish ( Takifugu rubripes ), is the most prestigious edible species and the most poisonous. Other species are also eaten; for example, Higanfugu ( T. pardalis ), Shōsaifugu ( T. vermicularis syn. snyderi ), and Mafugu ( T. porphyreus ). The Ministry of Health, Labour and Welfare of Japan provides

9600-481: Was also interrupted for a time. After exhaustive analysis, it was found that the sea slugs must have ingested tetrodotoxin. Statistics from the Tokyo Bureau of Social Welfare and Public Health indicate 20–44 incidents of fugu poisoning per year between 1996 and 2006 in the entire country, leading to 34–64 hospitalizations and 0–6 deaths per year, for an average fatality rate of 6.8%. Of the 23 incidents recorded within Tokyo between 1993 and 2006, only one took place in

9700-504: Was estimated to be 60 feet high and 350 feet in diameter. It was demolished in 1924. Huichuin Located in Berkeley, this mound was 20 feet high and was the site of the first human settlement on the shores of San Francisco Bay. West Berkeley and Ellis Landing These mounds measured almost 200 meters in diameter and rose 9 meters above the shoreline. Shell mounds are also credited with

9800-447: Was non-toxic, and it would allow for the safe preparation of fugu-kimo (puffer liver). Usuki , a town in Ōita Prefecture , has become known for selling non-poisonous fugu by 2008. Blowfish, specifically the obscure pufferfish and the torafugu, has been farmed in China since 1993 under the state-owned Tianzheng company. As of 2012, most such fish is exported to Japan and South Korea, with

9900-452: Was one of the agents studied by Japan's Unit 731 , which evaluated biological weapons on human subjects in the 1930s. The diagnosis of pufferfish poisoning is based on the observed symptomatology and recent dietary history. Symptoms typically develop within 30 minutes of ingestion, but may be delayed by up to four hours; however, if the dose is fatal, symptoms are usually present within 17 minutes of ingestion. Having pins and needles of

10000-654: Was sometimes sought out by individuals who wished to take their own lives. Much higher figures were reported in earlier years, peaking in 1958 when 176 people died from eating fugu in a single year. According to the Fugu Research Institute , 50% of the victims were poisoned by eating the liver, 43% from eating the ovaries, and 7% from eating the skin. One of the most famous victims was the Kabuki actor and " Living National Treasure " Bandō Mitsugorō VIII , who in 1975 died after eating four servings of fugu kimo (fugu liver),

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