Tetrodotoxin

319.27

319.27

224-458-8

Crystals

30029090

187.75000

2.16

white powder

2.8±0.1 g/cm3

280 °C (decomp)

702.6±70.0 °C at 760 mmHg

378.7±35.7 °C

2.087

H2O: stable at pH 4-5 if stored frozensoluble

2-8°C

Oral-Mouse LD50: 0.334 mg/kg; Intravenous-Mouse LD50: 0.007 mg/kg

Flammable, decomposes toxic nitrogen oxide gas when burning

D25 -8.64° (c = 8.55 in dil acetic acid)

pKa: 8.76 (water), 9.4 (50% alcohol)

Darkens above 220 °C without decomposition ... toxin /is/ destroyed in strong acids and in alkaline solutions.|... heat-stable (except in alkaline milieu), water-soluble ... unstable when heated to 100 °C (212 °F) in acid ... can be fatal when ingested|Hydroxyl radical reaction rate constant = 3.71X10-10 cu cm/molec-sec at 25 °C (est)

I

6.1(a)

UN 3462 6.1/PG 1

3

26/27/28

22-36/37/39-45-36/37-28

IO1450000

T+

Treasury low temperature (below 4℃), ventilated, dry; stored separately from food raw materials

Stable to boiling except in an alkaline solution.

SRP: Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air quality; potential migration in air, soil or water; effects on animal, aquatic and plant life; and conformance with environmental and public health regulations. If it is possible or reasonable use an alternative chemical product with less inherent propensity for occupational harm/injury/toxicity or environmental contamination.

Tetrodotoxin (TTX) is one of the most potent and oldest known neurotoxins. The poisoning cases due to ingestion of TTX-containing marine animals, especially for puffer, have frequently occurred in Asia since a long time ago. This chapter describes various topics on TTX poisoning including the tendency of poisoning incidents, typical case report, treatment and prevention, biology distribution, original source, infestation mechanism, detection methods, characteristics of chemistry and pharmacology, and therapeutic application. Furthermore, the protocols for how to make puffer safe to eat and how to prevent puffer products made from toxic puffers have been suggested. Finally, the biological significance and neurophysiological role of TTX have been elucidated and TTX may act as an important drug like anesthetic in future.[Hwang DF, Noguchi T; Adv Food Nutr Res 52: 141-236 (2007)]

|Danger|H300 (100%): Fatal if swallowed [Danger Acute toxicity, oral]|P260, P262, P264, P270, P271, P280, P284, P301+P310, P302+P350, P304+P340, P310, P320, P321, P322, P330, P361, P363, P403+P233, P405, and P501|Aggregated GHS information provided by 41 companies from 3 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

GENERAL INFORMATION: The following are general recommendations for hazardous material exposure. However, it is unlikely that tetrodotoxin will require this amount of protection.First Responders should use a NIOSH-certified Chemical, Biological, Radiological, Nuclear (CBRN) Self Contained Breathing Apparatus (SCBA) with a Level A protective suit when entering an area with an unknown contaminant or when entering an area where the concentration of the contaminant is unknown. Level A protection should be used until monitoring results confirm the contaminant and the concentration of the contaminant.NOTE:Safe use of protective clothing and equipment requires specific skills developed through training and experience.

Information is unavailable about the carcinogenicity, developmental toxicity, or reproductive toxicity from chronic or repeated exposure to tetrodotoxin.

most toxic

IDENTIFICATION AND USE: Tetrodotoxin (TTX) is a solid. TTX contained in puffer, has become an extremely popular chemical tool in the physiological and pharmacological laboratories since discovery of its channel blocking action in the early 1960s. More recently, the TTX-resistant sodium channels have been discovered in the nervous system and received much attention because of their role in pain sensation. TTX is now known to be produced not by puffer but by bacteria, and reaches various species of animals via food chain. HUMAN STUDIES: TTX is a deadly neurotoxin which selectively inhibits Na(+) activation mechanism of nerve impulse, without affecting the permeability of K(+) ions. TTX interferes with the transmission of signals from nerves to muscles by blocking sodium channels. This results in rapid weakening and paralysis of muscles, including those of the respiratory tract, which can lead to respiratory arrest and death. TTX poisoning may either have rapid onset (10 to 45 minutes) or delayed onset (generally within 3 to 6 hours but rarely longer). Death may occur as early as 20 minutes, or as late as 24 hours, after exposure; but it usually occurs within the first 4 to 8 hours. Patient/victims who live through the acute intoxication in the first 24 hours usually recover without residual deficits. Symptoms may last for several days and recovery takes days to occur. Upon ingestion, at first stage TTX producing numbness and sensation of prickling and tingling (paresthesia) of the lips and tongue, followed by facial and extremity paresthesias and numbness, headache, sensations of lightness or floating, profuse sweating (diaphoresis), dizziness, salivation (ptyalism), nausea, vomiting (emesis), diarrhea, abdominal (epigastric) pain, difficulty moving (motor dysfunction), weakness (malaise), and speech difficulties. At the second stage there is increasing paralysis, first in the extremities, then in the rest of the body, and finally in the respiratory muscles; difficulty breathing or shortness of breath (dyspnea); abnormal heart rhythms (cardiac dysrhythmias or arrhythmia); abnormally low blood pressure (hypotension); fixed and dilated pupils (mydriasis); coma; seizures; respiratory arrest; and death. A number of case reports describe food poisoning with TTX. Most of these poisoning episodes occur from home preparation and consumption and not from commercial sources of the pufferfish. TTX was shown to lack genotoxic activity in vitro in human lymphocytes with or without metabolic activation. ANIMAL STUDIES: The clinical symptoms and signs of TTX poisoning in dogs treated with TTX by iv infusion were similar to those of anticholinesterase poisoning. TTX was found to be about fifty times less toxic and to have more delayed death occurrence to mice via oral route than that via i.p. injection. In rats brain serotonin level was significantly increased and reached its peak level after 4 hours of TTX administration. Brain acetylcholine, histamine, and norepinephrine levels were also significantly increased but reached peak level after 6 hours. The effect of the gonad extract from pufferfish was more significantly profound and of longer duration than the skin extract. On the other hand, brain epinephrine did not show any significant change during the experimental period. TTX administered iv in male rabbits at sublethal levels produced shock due to perfusion failure with lactacidemia, hypoproteinemia, increased bleeding time, decreased red cell mass, and decreased platelet count. The severity of poisoning was proportional to the magnitude of tetrodotoxin given. Hemorrhages in brain, liver, lung, and diaphragm were observed in necropsy study. Significant differences in susceptibility to TTX were found among five mouse strains tested. TTX was clearly shown to lack in vitro or in vivo genotoxic activity. ECOTOXICITY STUDIES: TTX and its analogs (TTXs), widely distributed among marine as well as terrestrial animals, induce dangerous intoxications. Besides helping to deter predators, TTX resistance enables pufferfishes to selectively feed on TTX-bearing organisms. However TTXs do not protect flatworms from Guam from their predators but instead are used to capture mobile prey.

The ability of a tetrodotoxin (TTX)-specific monoclonal antibody to confer passive protection against lethal TTX challenge was investigated. The monoclonal antibody, T20G10, has an estimated affinity for TTX of approximately 10-9 M and is about 50-fold less reactive with anhydrotetrodotoxin and unreactive with tetrodonic acid by competitive immunoassay. T20G10 specifically inhibited TTX binding in an in vitro radioligand receptor binding assay, but had no effect on the binding of saxitoxin to the sodium channel on rat brain membranes. In prophylaxis studies, mice were administered T20G10 via the tail vein 30 min prior to i.p. TTX challenge (10 ug/kg). Under these conditions, 100 micrograms T20G10 protected 6/6 mice, whereas 3/6 mice were protected with 50 micrograms T20G10. Non-specific control monoclonal antibody did not protect against lethality. Therapy studies simulating oral intoxication were performed with mice given a lethal dose of TTX by gavage in a suspension of non-fat dry milk in phosphate-buffered saline. Death occurred within 25-35 min in 6/6 mice not treated with T20G10. However, 500 ug T20G10 administered via the tail vein 10-15 min after oral TTX exposure prevented death in 6/6 mice. Lower doses of mAb conferred less protection.|At 24 hours after coronary artery occlusion in dogs, lidocaine (4 mg/kg, iv) and tetrodotoxin (2 ug/kg, iv) showed marked antiarrhythmic activity. At 2-fold lower doses, neither substance alone had an effect on arrhythmias, but when administered together, they induced almost complete restoration of cardiac rhythm.|Batrachotoxin increased sodium uptake by synaptosomes. Veratridine also increased the sodium uptake. Tetrodotoxin blocked the effects of the above toxins.|Denervated muscle of mice was excised after 5-6 days and incubated in 0.5% papain at 28-9 °C for 5-8 minutes. The proteolytic treatment abolished the shielding of sodium ion channel by labile surface proteins by partial removal which restored the sensitivity of receptors to tetrodotoxin after impairment by denervation.|For more Interactions (Complete) data for Tetrodotoxin (8 total), please visit the HSDB record page.

... the minimum lethal dose in an adult human is estimated to be 2-3 mg.

LD50 Mouse oral 0.435 mg/kg|LD50 Mouse ip 0.008 mg/kg|LD50 Mouse sc 0.008 mg/kg|LD50 Mouse iv 0.009 mg/kg

/AQUATIC SPECIES/ ...Puffer fish contain tetrodotoxin (TTX) at a high concentration mainly in liver ... Uptake of TTX into the liver tissue slices of puffer fish (Takifugu rubripes) was investigated by in vitro incubation experiment. When T. rubripes liver slices were incubated with 0-2000 uM TTX at 20 °C for 60 min, the uptake rates exhibited non-linearity, suggesting that the TTX uptake into T. rubripes liver is carrier-mediated. The TTX uptake was composed of a saturable component (V(max) 47.7+/-5.9 pmol/min/mg protein and K(m) 249+/-47 uM) and a non-saturable component (P(dif) 0.0335+/-0.0041uL/min/mg protein). The uptake of TTX was significantly decreased to 0.4 and 0.6 fold by the incubation at 5 °C and the replacement of sodium-ion by choline in the buffer, respectively, while it was not affected by the presence of 1 mM l-carnitine, p-aminohippurate, taurocholate or tetraethylammonium. The TTX uptake by black scraper (Thamnaconus modestus) liver slices was much lower than that of T. rubripes and independent of the incubation temperature, unlike T. rubripes. ...|/AQUATIC SPECIES/...Elliptio /camplanatus/ were more sensitive to...tetrodotoxin than several marine bivalves...|/AQUATIC SPECIES/ Tetrodotoxin (TTX) is a highly potent neurotoxin that selectively binds to the outer vestibule of voltage-gated sodium channels. Pufferfishes accumulate extremely high concentrations of TTX without any adverse effect. A nonaromatic amino acid (Asn) residue present in domain I of the pufferfish, Takifugu pardalis, Na v1.4 channel has been implicated in the TTX resistance of pufferfishes. However, the effect of this residue on TTX sensitivity has not been investigated, and it is not known if this residue is conserved in all pufferfishes. /The authors/... investigated the genetic basis of TTX resistance in pufferfishes by comparing the sodium channels from two pufferfishes (Takifugu rubripes [fugu] and Tetraodon nigroviridis) and the TTX-sensitive zebrafish. Although all three fishes contain duplicate copies of Na v1.4 channels (Na v1.4a and Na v1.4b), several substitutions were found in the TTX binding outer vestibule of the two pufferfish channels. Electrophysiological studies showed that the nonaromatic residue (Asn in fugu and Cys in Tetraodon) in domain I of Na v1.4a channels confers TTX resistance. The Glu-to-Asp mutation in domain II of Tetraodon channel Na v1.4b is similar to that in the saxitoxin- and TTX-resistant Na+ channels of softshell clams . Besides helping to deter predators, TTX resistance enables pufferfishes to selectively feed on TTX-bearing organisms.|/OTHER TERRESTRIAL SPECIES/ The activation of the hypothalamic pituitary adrenal (HPA) axis is one of the most important physiological processes in coping with any deviation in an organism's homeostasis. This activation and the secretion of glucocorticoids, such as corticosterone, allow organisms to cope with perturbations and return to optimal physiological functioning as quickly as possible. In this study, we examined the HPA axis activation in common gartersnakes (Thamnophis sirtalis) as a response to a natural toxin, tetrodotoxin (TTX). This neurotoxin is found in high levels in the Rough-skinned Newt (Taricha granulosa), which is a prey item for these snakes. To consume this toxic prey, these snakes have evolved variable resistance. We hypothesized that the more resistant individuals would show a lower HPA axis response than less resistant individuals, as measured by corticosterone (CORT) and bactericidal ability, which is a functional downstream measurement of CORT's activity. We determined "resistance level" for tetrodotoxin from each individual snake by determining the dose which reduced race speed by 50%. Individuals were injected them with an increasing amount of tetrodotoxin (10, 25, and 50 MAMUs) to determine this value. Thirty minutes after every injection, we gathered blood samples from each snake. Our results show that, while there were no significant differences among individual CORT levels in a dose-dependent manner, female snakes did have a larger stress response when compared to both males and juveniles. Different life-histories could explain why females were able to mount a higher HPA axis response. However, TTX had no downstream effects on bactericidal ability, although juveniles had consistently lower values than adults. Our research shows a possible dichotomy between how each sex manages tetrodotoxin and gives way for a more comprehensive analysis of tetrodotoxin in an ecological context.|/FIELD STUDIES/ The deadly neurotoxin tetrodotoxin (TTX) is found in a variety of animal phyla and, because of its toxicity, is most often assumed to deter predation. On the tropical Pacific island of Guam, ... an undescribed flatworm (planocerid sp. 1) /was found/ that contains high levels of TTX and its analogs. Through ecological experiments, /it was found/ that TTXs do not protect these flatworms from some predators but instead are used to capture mobile prey. TTX is known to have multiple ecological functions, which has probably led to its widespread presence among prokaryotes and at least 10 metazoan phyla.

Tetrodotoxin is a nonprotein, aminoperhydroquanizole found mainly in the skin, liver, ovary, intestine, and possibly muscle /of certain fish/. The ovary has the highest concentration of the toxin, and is most poisonous if eaten during the spawning season(1). The ovaries and liver of many species of tetraodontidae, especially the globe fish (Spheroides rubripes) contain tetrodotoxin(2). The gonads, liver, intestines, and skin of pufferfish can contain levels of tetrodotoxin sufficient to produce rapid and violent death. ... 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(3).|Tetrodotoxin (TTX) and its analogs (TTXs), widely distributed among marine as well as terrestrial animals, induce dangerous intoxications. These highly potential toxins are also known as the causative agent of puffer fish poisoning. ... TTX, anhydrotetrodotoxin, 11-deoxytetrodotoxin and trideoxytetrodotoxin were determined in separated tissues of Bangladeshi marine puffers, Takifugu oblongus. TTX was predominant in skin, muscle and liver, whereas trideoxytetrodotoxin preponderated in the ovary.|... Puffer fish contain tetrodotoxin (TTX) at a high concentration mainly in liver ..|/in puffer fish/ tetrodotoxin is widely distributed in organelles in liver cells, though predominantly in the cytosol fraction.|For more Natural Pollution Sources (Complete) data for Tetrodotoxin (7 total), please visit the HSDB record page.

The Food and Drug Administration (FDA) is warning restaurants and fish markets that serve or sell puffer fish (also known as puffer, fugu, bok, blowfish, globefish, swellfish, balloonfish, or sea squab) not to buy or sell this product unless it is obtained from a known safe source. Due to the potential health hazard, commercial importation of puffer fish into the United States is heavily restricted. Personal importation is prohibited. The liver, gonads (ovaries and testes), intestines and skin of puffer fish typically contain the toxin. Unless puffer fish is cleaned and prepared in a special manner to carefully remove the organs containing toxin, the flesh of the fish will become contaminated with the toxin. The toxin cannot be destroyed by cooking or freezing. In fact, freezing and thawing of the product prior to removal of the toxic organs may result in the migration of toxin into the flesh of the fish. The State of Florida currently has a ban on both commercial and recreational harvesting of puffer fish from the waters of Volusia, Brevard, Indian River, St. Lucie, and Martin counties on the east coast of Florida due to persistent toxicity. Puffer fish harvested from these Florida counties have been found to contain significant amounts of toxin in the flesh regardless of the preparation technique. The Northern Puffer fish from the mid-Atlantic coastal waters of the United States, typically between Virginia and New York, has not been found to contain toxin, but without routine toxin screening there still is a potential risk(1).|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 mislabeling, particularly of prepared, frozen fish products. Three deaths were reported in Italy in 1977 following the consumption of frozen pufferfish imported from Taiwan and mislabeled as angler fish(1).|FDA is warning consumers not to buy or eat imported fish labeled as monkfish, which actually may be puffer fish, containing a potentially deadly toxin called tetrodotoxin. Monkfish do not contain tetrodotoxin. 282 22-pound boxes labeled as monkfish were distributed to wholesalers in Illinois, California, and Hawaii beginning in September 2006. These fish were then sold to restaurants or in stores. In one instance, the retailer labeled the fish as "bok," the Korean name for puffer fish(1).|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(1).

/EXPL THER/ Corneal injury can produce photophobia, an aversive sensitivity to light. Using topical application of lidocaine, a local anesthetic, and tetrodotoxin (TTX), a selective voltage-sensitive sodium channel blocker, we assessed whether enhanced aversiveness to light induced by corneal injury in rats was caused by enhanced activity in corneal afferents. Eye closure induced by 30 seconds of exposure to bright light (460-485 nm) was increased 24 hours after corneal injury induced by de-epithelialization. Although the topical application of lidocaine did not affect the baseline eye closure response to bright light in control rats, it eliminated the enhancement of the response to the light stimulus after corneal injury (photophobia). Similarly, topical application of TTX had no effect on the eye closure response to bright light in rats with intact corneas, but it markedly attenuated photophobia in rats with corneal injury. Given the well-established corneal toxicity of local anesthetics, we suggest TTX as a therapeutic option to treat photophobia and possibly other symptoms that occur in clinical diseases that involve corneal nociceptor sensitization. PERSPECTIVE: We show that lidocaine and TTX attenuate photophobia induced by corneal injury. Although corneal toxicity limits use of local anesthetics, TTX may be a safer therapeutic option to reduce the symptom of photophobia associated with corneal injury.|/EXPL THER/ Burn injuries have been identified as the primary cause of injury in 5% of U.S. military personnel evacuated from Operations Iraqi Freedom and Enduring Freedom. Severe burn-associated pain is typically treated with opioids such as fentanyl, morphine, and methadone. Side effects of opioids include respiratory depression, cardiac depression, decrease in motor and cognitive function, as well as the development of hyperalgesia, tolerance and dependence. These effects have led us to search for novel analgesics for the treatment of burn-associated pain in wounded combat service members. Tetrodotoxin (TTX) is a selective voltage-gated sodium channel blocker currently in clinical trials as an analgesic. A phase 3 clinical trial for cancer-related pain has been completed and phase 3 clinical trials on chemotherapy-induced neuropathic pain are planned. It has also been shown in mice to inhibit the development of chemotherapy-induced neuropathic pain. TTX was originally identified as a neurotoxin in marine animals but has now been shown to be safe in humans at therapeutic doses. The antinociceptive effects of TTX are thought to be due to inhibition of Na(+) ion influx required for initiation and conduction of nociceptive impulses. One TTX sensitive sodium channel, Nav1.7, has been shown to be essential in lowering the heat pain threshold after burn injuries. To date, the analgesic effect of TTX has not been tested in burn-associated pain. Male Sprague-Dawley rats were subjected to a full thickness thermal injury on the right hind paw. TTX (8 ug/kg) was administered once a day systemically by subcutaneous injection beginning 3 days post thermal injury and continued through 7 days post thermal injury. Thermal hyperalgesia and mechanical allodynia were assessed 60 and 120 min post injection on each day of TTX treatment. TTX significantly reduced thermal hyperalgesia at all days tested and had a less robust, but statistically significant suppressive effect on mechanical allodynia. These results suggest that systemic TTX may be an effective, rapidly acting analgesic for battlefield burn injuries and has the potential for replacing or reducing the need for opioid analgesics.|/EXPL THER/ Persistent muscle pain is a common and disabling symptom for which available treatments have limited efficacy. Since tetrodotoxin (TTX) displays a marked antinociceptive effect in models of persistent cutaneous pain, we tested its local antinociceptive effect in rat models of muscle pain induced by inflammation, ergonomic injury and chemotherapy-induced neuropathy. While local injection of TTX (0.03-1 ug) into the gastrocnemius muscle did not affect the mechanical nociceptive threshold in naive rats, exposure to the inflammogen carrageenan produced a marked muscle mechanical hyperalgesia, which was dose-dependently inhibited by TTX. This antihyperalgesic effect was still significant at 24 hr. TTX also displayed a robust antinociceptive effect on eccentric exercise-induced mechanical hyperalgesia in the gastrocnemius muscle, a model of ergonomic pain. Finally, TTX produced a small but significant inhibition of neuropathic muscle pain induced by systemic administration of the cancer chemotherapeutic agent oxaliplatin. These results indicate that TTX-sensitive sodium currents in nociceptors play a central role in diverse states of skeletal muscle nociceptive sensitization, supporting the suggestion that therapeutic interventions based on TTX may prove useful in the treatment of muscle pain.|/EXPL THER/ OBJECTIVE: This study evaluated subcutaneous injections of tetrodotoxin (TTX) for the treatment of moderate to severe, inadequately controlled cancer-related pain. METHODS: Eligible patients were randomized to receive TTX (30 ug) or placebo subcutaneously twice daily for four consecutive days. Efficacy was assessed using pain and composite endpoints (including pain and quality of life measures), and safety was evaluated using standard measures. RESULTS: 165 patients were enrolled at 19 sites in Canada, Australia, and New Zealand, with 149 patients in the primary analysis "intent-to-treat" population. The primary analysis supports a clinical benefit of TTX over placebo based on the pain endpoint alone with a clinically significant estimated effect size of 16.2% (p = 0.0460). The p value was nominally statistically significant after prespecified (Bonferroni Holm) adjustment for the two primary endpoints but not at the prespecified two-sided 5% level. The mean duration of analgesic response was 56.7 days (TTX) and 9.9 days (placebo). Most common adverse events were nausea, dizziness, and oral numbness or tingling and were generally mild to moderate and transient. CONCLUSIONS: Although underpowered, this study demonstrates a clinically important analgesic signal. TTX may provide clinically meaningful analgesia for patients who have persistent moderate to severe cancer pain despite best analgesic care.|For more Therapeutic Uses (Complete) data for Tetrodotoxin (6 total), please visit the HSDB record page.

A fatal dose may be as little as 1 to 4 mg per person.|... the minimum lethal dose in an adult human is estimated to be 2-3 mg.

Drugs that block nerve conduction when applied locally to nerve tissue in appropriate concentrations. They act on any part of the nervous system and on every type of nerve fiber. In contact with a nerve trunk, these anesthetics can cause both sensory and motor paralysis in the innervated area. Their action is completely reversible. (From Gilman AG, et. al., Goodman and Gilman's The Pharmacological Basis of Therapeutics, 8th ed) Nearly all local anesthetics act by reducing the tendency of voltage-dependent sodium channels to activate. (See all compounds classified as Anesthetics, Local.)|Substances which, when ingested, inhaled, or absorbed, or when applied to, injected into, or developed within the body in relatively small amounts may, by their chemical action, cause damage to structure or disturbance of function. (From Dorland, 27th ed) (See all compounds classified as Poisons.)|A class of drugs that act by inhibition of sodium influx through cell membranes. Blockade of sodium channels slows the rate and amplitude of initial rapid depolarization, reduces cell excitability, and reduces conduction velocity. (See all compounds classified as Sodium Channel Blockers.)

Twenty-three specimens of a tree-frog Polypedates sp. were collected from two locations (Mymensingh and Barisal) of Bangladesh in 1999, and assayed for their toxicity scores and toxin principle. Among the tissues, only the skin of the Mymensingh specimens was found to be toxic in mouse test, with the toxicity scores of 31-923 ug/g. The toxin isolated from the skin was analyzed by high-performance liquid chromatography, electrospray ionization-time of flight mass spectrometry and proton nuclear magnetic resonance, and characterized as tetrodotoxin, a toxin principle.|Tetrodotoxin (TTX) and its analogs (TTXs), widely distributed among marine as well as terrestrial animals, induce dangerous intoxications. These highly potential toxins are also known as the causative agent of puffer fish poisoning. ... TTX, anhydrotetrodotoxin, 11-deoxytetrodotoxin and trideoxytetrodotoxin were determined in separated tissues of Bangladeshi marine puffers, Takifugu oblongus. TTX was predominant in skin, muscle and liver, whereas trideoxytetrodotoxin preponderated in the ovary. The toxicity of the various tissues was determined by a mouse bioassay.|To investigate the relationship between the toxicity of puffer fish and the distribution of tetrodotoxin-producing bacteria in puffer fish Fugu rubripes collected from the Bohai Sea of China, bacteria were isolated from each organ (ovaries, livers, intestines and gallbladders) and screened for tetrodotoxin (TTX) production. 20 out of 36 isolated strains were found to produce TTX in vitro. In the organs of ovaries and livers whose toxicity is more potent than other organs, the number and toxicity of TTX-producing strains was greater than that of others. Most TTX-producing bacterial strains were identified as Bacillus spp. (19 strains) and Actinomycete spp. (1 strain) based on the morphological observation, physiological and biochemical characteristics and G+C content of DNA. The purified toxin was identified to be TTX by high performance liquid chromatography assay, thin-layer chromatography assay and electrospray ionization mass spectrometry analysis. Our results suggested that TTX-producing bacteria are closely related to the toxification of the puffer fish. More research is needed to elucidate the mechanism of TTX synthesis and the role of TTX in bacteria.|The liver homogenate of puffer fish was fractionated into blood cell, nuclear, mitochondrial, microsomal and cytosol fractions by the differential centrifugation method. ... Analyses by HPLC and LC-FABMS demonstrated that tetrodotoxin is the major toxic principle in each fraction. These results reveal that tetrodotoxin is widely distributed in organelles in liver cells, though predominantly in the cytosol fraction.|For more Absorption, Distribution and Excretion (Complete) data for Tetrodotoxin (9 total), please visit the HSDB record page.

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.|To investigate the genes related to the biosynthesis or accumulation of tetrodotoxin (TTX) in pufferfish, mRNA expression patterns in the liver from pufferfish, akamefugu Takifugu chrysops and kusafugu Takifugu niphobles, were compared by mRNA arbitrarily primed reverse transcription-polymerase chain reaction (RAP RT-PCR) with fish bearing different concentrations of TTX and its derivatives. RAP RT-PCR provided a 383 bp cDNA fragment and its transcripts were higher in toxic than non-toxic pufferfish liver. Its deduced amino acid sequence was similar to those of fibrinogen-like proteins reported for other vertebrates. Northern blot analysis and rapid amplification of cDNA ends (RACE) revealed that the cDNA fragment of 383 bp was composed of at least three fibrinogen-like protein (flp) genes, flp-1, flp-2 and flp-3. Relative mRNA levels of flp-1, flp-2 and flp-3 showed a linear correlation with toxicity of the liver for two pufferfish species.

Sodium current (I(Na)) of the mammalian heart is resistant to tetrodotoxin (TTX) due to low TTX affinity of the cardiac sodium channel (Na(v)) isoform Na(v)1.5. To test applicability of this finding to other vertebrates, TTX sensitivity of the fish cardiac I(Na) and its molecular identity were examined. METHODS: Molecular cloning and whole-cell patch-clamp were used to examine alpha-subunit composition and TTX inhibition of the rainbow trout (Oncorhynchus mykiss) cardiac Na(v) respectively. ...: I(Na) of the trout heart is about 1000 times more sensitive to TTX (IC50 = 1.8-2 nm) than the mammalian cardiac I(Na) and it is produced by three Na(v)alpha-subunits which are orthologs to mammalian skeletal muscle Na(v)1.4, cardiac Na(v)1.5 and peripheral nervous system Na(v)1.6 isoforms respectively. Oncorhynchus mykiss (om) omNa(v)1.4a is the predominant isoform of the trout heart accounting for over 80% of the Na(v) transcripts, while omNa(v)1.5a forms about 18% and omNa(v)1.6a only 0.1% of the transcripts. OmNa(v)1.4a and omNa(v)1.6a have aromatic amino acids, phenylalanine and tyrosine, respectively, in the critical position 401 of the TTX binding site of the domain I, which confers their high TTX sensitivity. More surprisingly, omNa(v)1.5a also has an aromatic tyrosine in this position, instead of the cysteine of the mammalian TTX-resistant Na(v)1.5. CONCLUSIONS: The ortholog of the mammalian skeletal muscle isoform, omNa(v)1.4a, is the predominant Na(v)alpha-subunit in the trout heart, and all trout cardiac isoforms have an aromatic residue in position 401 rendering the fish cardiac I(Na) highly sensitive to TTX.|... TTX inhibits voltage-gated sodium channels in a highly potent and selective manner without effects on any other receptor and ion channel systems. TTX blocks the sodium channel only from outside of the nerve membrane, and is due to binding to the selectivity filter resulting in prevention of sodium ion flow. It does not impair the channel gating mechanism. More recently, the TTX-resistant sodium channels have been discovered in the nervous system and received much attention because of their role in pain sensation. TTX is now known to be produced not by puffer but by bacteria, and reaches various species of animals via food chain.

GENERAL INFORMATION: Initial treatment is primarily supportive.

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/|/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam (Valium) or lorazepam (Ativan) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/|On April 17, 2001, an outbreak of TTX poisoning occurred among Mainland Chinese fishermen who shared puffer fish on their boat in the Taiwan Strait. All six cases were middle-aged men (aged 32-49 yr). Onset of symptoms began approximately 2 to 3 hours after ingestion; symptoms included orolingual numbness, acroparesthesia, and breathlessness. As a result of delayed transportation and initial resuscitation, one patient presented in full cardiac arrest, with recovery of spontaneous circulation after successful cardiopulmonary resuscitation. With the exception of this patient, the initial acid-base abnormalities were inconsistent with severity of illness and mild hypercapnia was common (4 out of 5). The patient who presented in full arrest died 1 day after admission as a result of intractable bradycardia (complete atrioventricular block), a finding rarely mentioned in the literature, despite intravenous atropine and dopamine infusion. The remaining patients survived without significant sequelae and were discharged after short-term observation and supportive care, although some had neurologic and cardiopulmonary manifestations (muscle weakness, hypotension, hypoxemia, and hypercapnia). Some mildly hypoventilated patients recovered well without endotracheal intubation and ventilatory support. Favorable outcomes in most patients can be obtained if aggressive supportive treatment is provided in time. Thus, appropriate prehospital and ED ventilatory support (the implementation of a bag-valve mask or endotracheal intubation with good ventilatory support) is mandatory for those patients with respiratory failure. Most patients experience onset of symptoms within 6 hours of ingestion, but a few have a delayed onset up to 20 hours. Therefore, for those TTX-intoxicated patients without immediate prominent respiratory insufficiency, at least 24 hours of intensive monitoring of their respiratory state is necessary because of the different susceptibility and unpredictability of an individual course.|For more Antidote and Emergency Treatment (Complete) data for Tetrodotoxin (9 total), please visit the HSDB record page.

/HUMAN EXPOSURE STUDIES/ ... This study evaluates the analgesic activity of tetrodotoxin, a highly selective sodium channel blocker, in cancer pain. A Phase IIa, open-label, multicenter, dose-escalation study of intramuscular tetrodotoxin was conducted in patients with severe, unrelieved cancer pain. The study design called for six ascending dose levels of intramuscular tetrodotoxin, administered over a four-day treatment period in hospitalized patients, with six patients to be enrolled within each successive dose level. Twenty-four patients underwent 31 courses of treatment at doses ranging from 15 to 90 ug daily, administered in divided doses, over four days. Most patients described transient perioral tingling or other mild sensory phenomena within about an hour of each treatment. Nausea and other toxicities were generally mild, but two patients experienced a serious adverse event, truncal and gait ataxia, that resolved over days. Seventeen of 31 treatments resulted in clinically meaningful reductions in pain intensity, and relief of pain persisted for up to two weeks or longer. Two patients had opioids held due to /CNS depression/ concurrent with relief of pain. Somatic, visceral, or neuropathic pain could all respond, but it was not possible to predict which patients were more likely to have an analgesic effect. ... Tetrodotoxin ... effectively relieved severe, treatment-resistant cancer pain in the majority of patients and often for prolonged periods after treatment. It may have a novel mechanism of analgesic effect. ...|/SIGNS AND SYMPTOMS/ Tetrodotoxin interferes with the transmission of signals from nerves to muscles by blocking sodium channels. This results in rapid weakening and paralysis of muscles, including those of the respiratory tract, which can lead to respiratory arrest and death.|/SIGNS AND SYMPTOMS/ Tetrodotoxin poisoning may either have rapid onset (10 to 45 minutes) or delayed onset (generally within 3 to 6 hours but rarely longer). Death may occur as early as 20 minutes, or as late as 24 hours, after exposure; but it usually occurs within the first 4 to 8 hours. Patient/victims who live through the acute intoxication in the first 24 hours usually recover without residual deficits. Symptoms may last for several days and recovery takes days to occur.|/SIGNS AND SYMPTOMS/ The consumption of toxic amounts of tetrodotoxin results primarily in neurologic and gastrointestinal signs and symptoms. In severe poisoning, dysrhythmias, hypotension, and even death might occur. If a rapid onset of one of the following neurologic and gastrointestinal signs or symptoms occurs, the clinical description for tetrodotoxin poisoning has been met: 1) oral paresthesias (might progress to include the arms and legs), 2) cranial nerve dysfunction, 3) weakness (might progress to paralysis), or 4) nausea or vomiting.|For more Human Toxicity Excerpts (Complete) data for Tetrodotoxin (24 total), please visit the HSDB record page.

Fugu Toxin

Exposure occurs due to ingestion of fish or other food containing tetrodotoxin.

Decontamination

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.|Determination of puffer fish tetrodotoxin by capillary isotachophoresis.|Separation of tetrodotoxin and paralytic shellfish (puffer and scallop) poisons by HPLC with a fluorometric detection using o-phthalaldehyde.|Tetrodotoxin (TTX) is a potent, low molecular weight analyte that can lead to fatal poisoning and requires a sensitive, rapid detection method. Here, we have developed a competitive, lateral-flow immunochromatographic strip combined with quantum dot nanobeads (QDNBs) and gold nanoflowers (AuNFs). This approach is called turn-on C-LFICS and it meets all testing requirements. Subsequent analysis revealed that this turn-on C-LFICS was rapid (8 min), sensitive (LOD = 0.2 ng/mL), and quantitative (DLR = 1.56-100 ng/mL), and had a positive signal readout (based on fluorescence quenching effects) for TTX detection. Moreover, it had superior signal brightness and a low background interference signal when compared with previous methods. Finally, it can function free of interference from the sample matrix and has a demonstrated recovery range of 85.5% to 119.7% in spiked samples. Taken together, these results show that our turn-on C-LFICS is an effective detection tool for TTX or other small molecules.|For more Analytic Laboratory Methods (Complete) data for Tetrodotoxin (16 total), please visit the HSDB record page.

Six fishermen were victims (including one death) of food poisoning from unknown fish on their boat in central Taiwan Strait, in April 2001. The symptoms were like those of tetrodotoxin (TTX) poisoning. As there was no remaining fish, a new protocol was developed to determine TTX in the urine and blood of the victims. The urine and blood samples were cleansed using a C18 Sep-Pak cartridge column, and the toxin was extracted by methanol. The eluate was filtered through a microcentrifuge filter. The filtrate was freeze-dried, dissolved in distilled water, and determined by LC-MS. The recovery was more than 88.9%. The detection limit was 15.6 nM. A linear relationship between response and concentration was obtained between 93.75 and 9375 nM of TTX. It was shown that the urine and blood of the victims contained TTX. The range of TTX was 4.5-40.6 nM in blood and 47-344 nM in urine. ...|...The purified toxin was identified to be /tetrodotoxin/ (TTX) by high performance liquid chromatography assay, thin-layer chromatography assay and electrospray ionization mass spectrometry analysis. Our results suggested that TTX-producing bacteria are closely related to the toxification of the puffer fish. More research is needed to elucidate the mechanism of TTX synthesis and the role of TTX in bacteria.|...The toxin isolated from the /tree-frog Polypedates sp./ skin was analyzed by high-performance liquid chromatography, electrospray ionization-time of flight mass spectrometry and proton nuclear magnetic resonance, and characterized as tetrodotoxin, a toxin principle.|In November 2015, a patient presented with symptoms of toxicity after eating whole boiled samples of the scavenging gastropod Nassarius (Alectrion) glans "Kinshibai" in Nagasaki. This food poisoning case was the third recorded in Japan. The case was investigated by evaluation of the toxin profile of the gastropod, and monitoring of tetrodotoxin (TTX) levels in serum and urine sampled from the affected individual. One gastropod contained a harmful dose of TTX (2.5 mg/ individual in food residue sample 2). In biological samples, maximum TTX concentrations were 42.8 ng/mL in serum on the day after onset of symptoms. TTX urinary excretion was calculated to be 2.4 mg. From the measured TTX concentrations, it was estimated that a lethal dose had been ingested in this case. Moreover, it was found by LC-QqQ-MS/MS analysis and mouse bioassay that the toxicity of "Kinshibai" was not solely due to TTX. The remaining toxicity was thought to be due to 11-oxoTTX. As in previous poisoning cases, it was concluded that ingestion of this gastropod poses a high risk of food poisoning.|For more Clinical Laboratory Methods (Complete) data for Tetrodotoxin (7 total), please visit the HSDB record page.

Biotoxins -> NIOSH Emergency Response Categories