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TETRODOTOXIN

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Tetrodotoxin (TTX) is a potent neurotoxin which blocks sodium ion channels responsible for nerve and muscle excitability. It is found in various marine organisms, most commonly including the puffer fish, and causes paralytic poisoning following ingestions.

Specific Substances

    A) COMMON NAMES ASSOCIATED WITH TETRODOTOXIN
    1) Balloon fish
    2) Balloon fish toxin
    3) Blowfish
    4) Blow-fish toxin
    5) Blue-ringed octopus (common name for Hapalochlaena spp.)
    6) Fish poisoning, tetrodotoxin
    7) Frog shell Tutufa lissostoma
    8) Fugu
    9) Globefish
    10) Globefish toxin
    11) Goby fish (Gobius criniger)
    12) Horseshoe crab
    13) Japanese ivory shell
    14) Japanese ivory shell (Babylonia japonica)
    15) Maculotoxin
    16) MTX (maculotoxin)
    17) Porcupine fish
    18) Potka fish
    19) Puffer fish toxin
    20) Swellfish
    21) Swellfish toxin
    22) Starfish Astropecten latespinosus
    23) Toadfish
    24) Toad fish toxin
    25) Tarichatoxin
    26) Triturus embryonic toxin
    27) Trumpet shell
    28) TTX
    SPECIES ASSOCIATED WITH TETRODOTOXIN
    1) Aleromonas species
    2) Alexandrium tamarense
    3) Astropecten latespinosus
    4) Astropecten scoparius
    5) Astropecten polyacanthus
    6) Atelopus species
    7) Atergatis floridus
    8) Babylonia japonica
    9) Carcinoscorpius rotundicaudia
    10) Cephalothrix linearis
    11) Charonia sauliae
    12) Charonia lampas sauliae
    13) Cynops pyrrhogaster
    14) Cynops ensicaudus
    15) Frog shell Tutufa lissostoma
    16) Gastropod mollusks
    17) Gobius criniger
    18) Hapalochlaena fasciata
    19) Hapalochlaena lunulata
    20) Hapalochlaena maculosa
    21) Lepidonotus helotypus
    22) Lagocephalus lunaris
    23) Lagocephalus sceleratus
    24) Lineus fuscoviridis
    25) Nassarius castus
    26) Nassarius conoidalis
    27) Notophthalmus viridescens
    28) Paramesotriton hongkongensis
    29) Parasagitta elegans
    30) Planocera multite taculata
    31) Planocera reticulata
    32) Pseudomonas species
    33) Red calcareous alga
    34) Speroides porphyrus
    35) Speroides vermicularis
    36) Speroides rubripes
    37) T. Pivularis
    38) T. granulosa
    39) Takifugu oblongus
    40) Tarichatorosa
    41) Tetractenos hamiltoni
    42) Tetraodon leiurus
    43) Tetraodon steindachneri
    44) Triturus vulgaris
    45) Triturus cristatus
    46) Triturus alpestris
    47) Triturus marmoratus
    48) Tubulanus punctatus
    49) V. alginolyticus
    50) Vibrio species
    51) Yongeichtyyc criniger
    52) Zeuxis samiplicutus
    53) Zeuxis siguinjorensis
    54) Zeuxis variciterus
    55) Zeuxis succinctus

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) WITH POISONING/EXPOSURE
    1) CDC CASE DEFINITIONS
    a) BACKGROUND
    1) Harmful algal blooms (HABs) are fast growing algae that are found worldwide, which can have a negative impact on the environment, as well as the health and safety of humans and animals. As part of the ongoing efforts of the Centers for Disease Control and Prevention (CDC), the Harmful Algal Bloom-related Illness Surveillance System (HABISS) collects data on the effects to human and animal health due to the potential environmental impact of HABs. The CDC has developed case definitions for HABs toxin-related disease as part of their national surveillance efforts to support public health decision-making. The following information has been created to identify pertinent information related to a potential exposure to HABs. For further information regarding the reporting of suspected human illness due to HABs, please contact: Lorraine C. Backer, PhD, MPH, Senior Scientist and Team Lead, National Center for Environmental Health, CDC, Atlanta, GA at lfb9@cdc.gov or Rebecca LePrell, MPH, HABISS Coordinator, National Center for Environmental Health, CDC, at gla7@cdc.gov.
    b) ACUTE SYMPTOMS
    1) Hypothermia, hypotension due to vasodilation, bradycardia, dysrhythmias, and asystole can occur. Hypertension has also been reported. Nausea, vomiting, diarrhea, salvation and diaphoresis may occur. Death is typically caused by respiratory depression and respiratory muscle paralysis. Cyanosis and depression of the cough reflex can also occur. Vertigo, dizziness, headache and blurred vision are common. Generalized weakness in the limbs with ascending onset, paresthesias (particularly perio-oral), ataxia, and areflexia may occur. Seizures are rare. Victims may appear comatose with pinpoint or dilated fixed pupils, but they are actually completely aware as long as ventilation is provided.
    c) CHRONIC SYMPTOMS
    1) At present time, no data available regarding chronic symptoms.
    d) FATALITY RATE
    1) Fatality rates can vary and are dependent on the correct diagnosis and treatment (including life support and ICU facilities availability). The reported fatality rates have varied from 13% to 60%.
    e) ONSET OF SYMPTOMS
    1) Symptoms can present in minutes to hours. Death may occur within the first 6 to 24 hours, and prognosis is good if patient survives the first 24 hours.
    f) DURATION
    1) Recovery is usually seen within days, but there has been no formal follow-up beyond days to weeks.
    g) ROUTE OF EXPOSURE
    1) Consumption of the flesh, viscera, ovaries, or skin of contaminated fish. The musculature is usually free of toxin.
    h) CAUSATIVE ORGANISMS
    1) Recent evidence suggests that the tetrodotoxin may be produced by bacteria in the implicated fish, rather than by the fish themselves. The following organisms have been implicated: Epiphytic bacteria (Aleromonas spp.), Vibrio spp., Psuedomonas spp., and Dinoflagellate Alexandrium tamarense.
    i) TOXIN
    1) Tetrodotoxin
    2) Pufferfish poisoning with saxitoxins, not tetrodotoxins, have been reported; therefore although the clinical presentation and symptoms are similar, confirmatory laboratory testing must be performed for both saxitoxins and tetrodotoxins.
    j) DOSE
    1) A dose of approximately 10 mcg/kg is thought to be a serious toxic dose for humans based on extrapolated mouse data. Oral LD50 for mice is 334 mcg/kg.
    k) VECTOR
    1) Tetradontiformes: balloon fish, blow-fish, globe fish, swellfish, toad fish, "fugu" in Japan (Speroides vermicularis, Speroides rubripes, Takifugu oblongus), and other pufferfish varieties from the coasts of Japan, Thailand, Bangladesh, the Phillipines and southeastern US Atlantic coast.
    2) Levels of tetrodotoxin are particularly high in the gonads and viscera of the pufferfish. In Japan, licensed chefs with special training prepare the "fugu" as a soup or sashimi to avoid tetrodotoxin contamination of the muscle by the viscera and gonads.
    3) Tetrodotoxins can be accumulated in the following: blue-ringed octopus (Haplochlaena maculosa), salamanders and newts (Tarichatorosa), crab (Xanthid), starfish (Astropecten latespinosus, A. Scoparius, A. polyacanthus), flatworms, ribbonworms, arrowworms, annelids, red calcareous alga (Jania spp.), gastropod mollusks and Gobius criniger.
    l) MECHANISM
    1) Tetrodotoxin is a potent neurotoxin which blocks sodium ion channels in nerves, particularly skeletal muscles, causing paralytic poisoning through blockade of both action potential generation and impulse conduction.
    m) LIKELY GEOGRAPHIC DISTRIBUTION
    1) It is most common in subtropical and tropical marine waters, although tetrodotoxins have been reported in freshwater pufferfish as well.
    n) DIFFERENTIAL DIAGNOSIS
    1) Other marine toxin poisonings (primarily neurotoxic shellfish poisoning), brevetoxicosis in the food web, scombroid fish poisoning, ciguatera fish poisoning, pesticide poisoning including organophosphate poisoning, cholinesterase inhibitor poisoning, microbial food poisonings, botulism, guillain-barre.
    o) DIAGNOSIS
    1) May be based on all of the following: history of consuming pufferfish and subsequent onset of gastrointestinal and neurologic symptoms or detection of tetrodotoxin in meal remnant or clinical specimen (urine or blood) by HPLC. Urine HPLC can be utilized up to 5 days after exposure.
    p) SUSPECT CASE
    1) History of consuming pufferfish and very rapid onset of symptoms.
    2) Victims can present much like victims of PSP and may even be suffering from saxitoxin contaminated pufferfish poisoning; therefore both toxins must be tested for in any specimens.
    q) CONFIRMED CASE
    1) Suspect cases along with laboratory confirmation of toxin in meal remnants or clinical specimen.
    r) REFERENCES
    1) (HABISS Work-Group et al, Jan 12, 2009).
    0.2.3) VITAL SIGNS
    A) WITH POISONING/EXPOSURE
    1) Hypothermia may develop following exposure .
    0.2.5) CARDIOVASCULAR
    A) WITH POISONING/EXPOSURE
    1) Hypotension due to vasodilatation commonly occurs. The heart rate usually remains normal, but bradycardia is common and asystole has occurred.
    0.2.6) RESPIRATORY
    A) WITH POISONING/EXPOSURE
    1) Death is usually caused by respiratory depression and respiratory muscle paralysis. Cyanosis and depression of the cough reflex may also occur.
    0.2.7) NEUROLOGIC
    A) WITH POISONING/EXPOSURE
    1) All voluntary muscles, including the respiratory muscles, are rapidly weakened. Weakness develops first in the hands and arms and then in the legs. Paresthesias, dizziness, ataxia, and areflexia may occur. Seizures are rare, but have been reported.
    0.2.8) GASTROINTESTINAL
    A) WITH POISONING/EXPOSURE
    1) Vomiting is a common sign; diarrhea and salivation may also occur.
    0.2.12) FLUID-ELECTROLYTE
    A) WITH POISONING/EXPOSURE
    1) Diabetes insipidus has been described in a patient following a blow-fish ingestion.
    0.2.13) HEMATOLOGIC
    A) WITH POISONING/EXPOSURE
    1) Petechial hemorrhages and hematemesis may occur in a patient with severe vomiting secondary to increased intrathoracic and intraabdominal pressure. Leukocytosis has been reported.
    0.2.14) DERMATOLOGIC
    A) WITH POISONING/EXPOSURE
    1) Pallor and diaphoresis may be seen early. Blistering and desquamation have been occasionally reported.

Laboratory Monitoring

    A) Laboratory determination of tetrodotoxin is not commonly available or clinically useful. Bioassay, chromatographic methods, and monoclonal antibodies are available to detect tetrodotoxin for research purposes, to confirm exposure, and for food safety monitoring.
    B) Frequent vital signs, ECG and continuous cardiac monitoring.
    C) Monitor continuous pulse oximetry, evaluate for evidence of respiratory depression; serial measurements of negative inspiratory force may be useful to anticipate the need for endotracheal intubation.
    D) Monitor serial neurologic exam for evidence of progressive weakness.
    E) Monitor fluid and electrolytes as indicated.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) SUPPORT
    1) Treatment is supportive, with special attention towards maintaining ventilation, monitoring blood pressure, and maintaining hydration.
    B) DECONTAMINATION
    1) PREHOSPITAL: Because of the potential for the rapid onset of respiratory paralysis, prehospital decontamination is not recommended.
    2) HOSPITAL: Tetrodotoxin is a fast acting agent which may cause respiratory paralysis. If a patient presents early after exposure without evidence of neuromuscular compromise, activated charcoal is preferred. In patients with clinical evidence of toxicity, activated charcoal should not be administered unless the airway is protected.
    C) AIRWAY MANAGEMENT
    1) Monitor respiratory function. Serial measurements of negative inspiratory force may be useful. Perform endotracheal intubation and provide mechanical ventilation in patients with evidence of respiratory muscle weakness or respiratory compromise.
    D) HYPOTENSION
    1) Administer IV 0.9% saline, add vasopressors if hypotension persists.
    E) SEIZURES
    1) Ensure adequate oxygenation and ventilation. Administer benzodiazepines, add propofol or barbiturates, if seizures persist.
    F) CHOLINESTERASE INHIBITOR
    1) Neostigmine (0.5 mg IV in adults; 0.02 mg/kg IV in children) edrophonium (10 mg IV in adults) may be used for the treatment of muscle weakness.

Range Of Toxicity

    A) Toxic tetrodotoxin (TTX) levels have not been established. Ingestion of 1 newt in a 29-year-old has resulted in death.
    B) A woman ingested an estimated 3 mg of tetrodotoxin (a potentially lethal dose) and developed sensory deficits, which resolved within 24 hours, along with persistent motor weakness requiring intensive physical therapy.
    C) As little as 10 mcg/kg has been estimated as a serious toxic dose in humans, but this is based on mouse data.
    D) A MLD50 of TTX is reported to be 10,000 mouse units, which is approximately 2 mg of TTX.
    E) Prognosis for recovery is generally good if timely endotracheal intubation and mechanical ventilation are provided.

Clinical Effects

Summary Of Exposure

    A) WITH POISONING/EXPOSURE
    1) CDC CASE DEFINITIONS
    a) BACKGROUND
    1) Harmful algal blooms (HABs) are fast growing algae that are found worldwide, which can have a negative impact on the environment, as well as the health and safety of humans and animals. As part of the ongoing efforts of the Centers for Disease Control and Prevention (CDC), the Harmful Algal Bloom-related Illness Surveillance System (HABISS) collects data on the effects to human and animal health due to the potential environmental impact of HABs. The CDC has developed case definitions for HABs toxin-related disease as part of their national surveillance efforts to support public health decision-making. The following information has been created to identify pertinent information related to a potential exposure to HABs. For further information regarding the reporting of suspected human illness due to HABs, please contact: Lorraine C. Backer, PhD, MPH, Senior Scientist and Team Lead, National Center for Environmental Health, CDC, Atlanta, GA at lfb9@cdc.gov or Rebecca LePrell, MPH, HABISS Coordinator, National Center for Environmental Health, CDC, at gla7@cdc.gov.
    b) ACUTE SYMPTOMS
    1) Hypothermia, hypotension due to vasodilation, bradycardia, dysrhythmias, and asystole can occur. Hypertension has also been reported. Nausea, vomiting, diarrhea, salvation and diaphoresis may occur. Death is typically caused by respiratory depression and respiratory muscle paralysis. Cyanosis and depression of the cough reflex can also occur. Vertigo, dizziness, headache and blurred vision are common. Generalized weakness in the limbs with ascending onset, paresthesias (particularly perio-oral), ataxia, and areflexia may occur. Seizures are rare. Victims may appear comatose with pinpoint or dilated fixed pupils, but they are actually completely aware as long as ventilation is provided.
    c) CHRONIC SYMPTOMS
    1) At present time, no data available regarding chronic symptoms.
    d) FATALITY RATE
    1) Fatality rates can vary and are dependent on the correct diagnosis and treatment (including life support and ICU facilities availability). The reported fatality rates have varied from 13% to 60%.
    e) ONSET OF SYMPTOMS
    1) Symptoms can present in minutes to hours. Death may occur within the first 6 to 24 hours, and prognosis is good if patient survives the first 24 hours.
    f) DURATION
    1) Recovery is usually seen within days, but there has been no formal follow-up beyond days to weeks.
    g) ROUTE OF EXPOSURE
    1) Consumption of the flesh, viscera, ovaries, or skin of contaminated fish. The musculature is usually free of toxin.
    h) CAUSATIVE ORGANISMS
    1) Recent evidence suggests that the tetrodotoxin may be produced by bacteria in the implicated fish, rather than by the fish themselves. The following organisms have been implicated: Epiphytic bacteria (Aleromonas spp.), Vibrio spp., Psuedomonas spp., and Dinoflagellate Alexandrium tamarense.
    i) TOXIN
    1) Tetrodotoxin
    2) Pufferfish poisoning with saxitoxins, not tetrodotoxins, have been reported; therefore although the clinical presentation and symptoms are similar, confirmatory laboratory testing must be performed for both saxitoxins and tetrodotoxins.
    j) DOSE
    1) A dose of approximately 10 mcg/kg is thought to be a serious toxic dose for humans based on extrapolated mouse data. Oral LD50 for mice is 334 mcg/kg.
    k) VECTOR
    1) Tetradontiformes: balloon fish, blow-fish, globe fish, swellfish, toad fish, "fugu" in Japan (Speroides vermicularis, Speroides rubripes, Takifugu oblongus), and other pufferfish varieties from the coasts of Japan, Thailand, Bangladesh, the Phillipines and southeastern US Atlantic coast.
    2) Levels of tetrodotoxin are particularly high in the gonads and viscera of the pufferfish. In Japan, licensed chefs with special training prepare the "fugu" as a soup or sashimi to avoid tetrodotoxin contamination of the muscle by the viscera and gonads.
    3) Tetrodotoxins can be accumulated in the following: blue-ringed octopus (Haplochlaena maculosa), salamanders and newts (Tarichatorosa), crab (Xanthid), starfish (Astropecten latespinosus, A. Scoparius, A. polyacanthus), flatworms, ribbonworms, arrowworms, annelids, red calcareous alga (Jania spp.), gastropod mollusks and Gobius criniger.
    l) MECHANISM
    1) Tetrodotoxin is a potent neurotoxin which blocks sodium ion channels in nerves, particularly skeletal muscles, causing paralytic poisoning through blockade of both action potential generation and impulse conduction.
    m) LIKELY GEOGRAPHIC DISTRIBUTION
    1) It is most common in subtropical and tropical marine waters, although tetrodotoxins have been reported in freshwater pufferfish as well.
    n) DIFFERENTIAL DIAGNOSIS
    1) Other marine toxin poisonings (primarily neurotoxic shellfish poisoning), brevetoxicosis in the food web, scombroid fish poisoning, ciguatera fish poisoning, pesticide poisoning including organophosphate poisoning, cholinesterase inhibitor poisoning, microbial food poisonings, botulism, guillain-barre.
    o) DIAGNOSIS
    1) May be based on all of the following: history of consuming pufferfish and subsequent onset of gastrointestinal and neurologic symptoms or detection of tetrodotoxin in meal remnant or clinical specimen (urine or blood) by HPLC. Urine HPLC can be utilized up to 5 days after exposure.
    p) SUSPECT CASE
    1) History of consuming pufferfish and very rapid onset of symptoms.
    2) Victims can present much like victims of PSP and may even be suffering from saxitoxin contaminated pufferfish poisoning; therefore both toxins must be tested for in any specimens.
    q) CONFIRMED CASE
    1) Suspect cases along with laboratory confirmation of toxin in meal remnants or clinical specimen.
    r) REFERENCES
    1) (HABISS Work-Group et al, Jan 12, 2009).

Vital Signs

    3.3.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Hypothermia may develop following exposure .
    3.3.3) TEMPERATURE
    A) WITH POISONING/EXPOSURE
    1) HYPOTHERMIA may be noted (Kao, 1966; Oda et al, 1989; Tambyah et al, 1994).

Heent

    3.4.2) HEAD
    A) WITH POISONING/EXPOSURE
    1) LIP TINGLING was seen within 10 minutes of swallowing a 20 cm Taricha newt (Bradley & Klika, 1981). Circumoral tingling may include the tongue and inner surface of the mouth and generally occurs within 10 to 45 minutes of ingestion (Eisenman et al, 2008; Kiernan et al, 2005; Fuhrman, 1967; Oda et al, 1989; Sun et al, 1994; CDC, 1996; Lan et al, 1999; Mahmud et al, 1999a; Fenner, 2000). Oral paresthesia is usually the initial symptom of pufferfish poisoning (Eisenman et al, 2008; Noguchi & Ebesu, 2001). In a series of 37 patients with tetrodotoxin poisoning, 24 (65%) developed perioral paresthesias (Ahasan et al, 2004; How et al, 2003).
    2) In one case, possible circumoral tingling was reported in a 2-year-old girl who bit the tail off the family's pet newt (King et al, 2000). Highest toxin concentrations have been reported in the skin and muscle of the newt (Miyazawa & Noguchi, 2001).
    3) APHONIA as well as dysphagia and aphagia may be seen as muscle paralysis progresses (Halstead, 1978).
    3.4.3) EYES
    A) WITH POISONING/EXPOSURE
    1) OPHTHALMOPARESIS with reduced ocular movement has been reported (Isbister et al, 2002; Kanchanapongkul, 2001; Chew et al, 1983).
    2) BLURRED VISION may occur (Cavazzoni et al, 2008; Chowdhury et al, 2007; Chowdhury et al, 2007a; Gage & Dulhunty, 1973; Oda et al, 1989).
    3) MYDRIASIS is common in later stages of severe poisoning (Noguchi & Ebesu, 2001). Mydriasis which persisted for over 44 hours has been reported (Tibballs, 1988). Fixed and dilated pupils have been reported following pufferfish and blowfish ingestions (Kanchanapongkul, 2001; Sun et al, 1994; Tambyah et al, 1994; Noguchi & Ebesu, 2001) and has been observed following the ingestion of the eggs of horseshoe crab (Kanchanapongkul, 2008). Eight cases of mydriasis were reported from a survey of 52 TTX poisonings (Yang et al, 1996).
    4) MIOSIS is an early effect of TTX poisoning (Noguchi & Ebesu, 2001). Miosis occurred in 4% of 52 patients in Taiwan during the period July 1988 to December 1995 (Yang et al, 1996). Field (1998) reports an adult with constricted pupils following pufferfish ingestion.
    5) PUPILLARY LIGHT REFLEX may be absent (Lan et al, 1999).
    3.4.6) THROAT
    A) WITH POISONING/EXPOSURE
    1) LARYNGOSPASM with difficulty in speaking and chest tightening was reported 10 to 15 minutes following ingestion of pufferfish (P Tanner , 1996).
    2) TASTE DISTURBANCE is a common early symptom of TTX poisoning (Noguchi & Ebesu, 2001).
    3) DYSPHAGIA was reported in a 47-year-old man who had consumed two bowls of soup that was made from approximately 30 pufferfish (Kiernan et al, 2005).

Cardiovascular

    3.5.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Hypotension due to vasodilatation commonly occurs. The heart rate usually remains normal, but bradycardia is common and asystole has occurred.
    3.5.2) CLINICAL EFFECTS
    A) HYPOTENSIVE EPISODE
    1) WITH POISONING/EXPOSURE
    a) Hypotension due to vasodilation commonly occurs. Patients with severe tetrodotoxin intoxication may develop cyanosis and hypotension (How et al, 2003; Bradley & Klika, 1981; Sims & Ostman, 1986; Sun et al, 1994; Yang et al, 1996; CDC, 1996; Noguchi & Ebesu, 2001).
    B) BRADYCARDIA
    1) WITH POISONING/EXPOSURE
    a) Heart rate is usually normal (Bradley & Klika, 1981; Kao, 1966), but dysrhythmias and bradycardia may occur (How et al, 2003; Chew et al, 1983; Flachsenberger, 1987). Severe poisoning is characterized by hypotension, sinus bradycardia and AV node conduction abnormalities (Noguchi & Ebesu, 2001; CDC, 1996). Asystole may occur (Noguchi & Ebesu, 2001; Walker, 1983).
    C) CHEST PAIN
    1) WITH POISONING/EXPOSURE
    a) Precordial pain has been noted in some cases (Halstead, 1978; Yang et al, 1996; P Tanner , 1996).
    D) CARDIAC ARREST
    1) WITH POISONING/EXPOSURE
    a) Cardiac arrest has been seen as a complication in some cases, and is likely secondary to respiratory failure (Noguchi & Ebesu, 2001; Laobhripatr et al, 1990).
    b) CASE REPORT: A 45-year-old man developed coma, apnea and pulselessness 3 hours after ingesting 80 grams of pufferfish (Lagocephalus lunaris). He presented to an ED 30 minutes later and was initially resuscitated, but then died 26 hours after ingestion of intractable bradycardia (complete atrioventricular block) and multiple organ failure (How et al, 2003).
    E) HYPERTENSIVE EPISODE
    1) WITH POISONING/EXPOSURE
    a) Hypertension may occur, but is not as common as hypotension. Generally, patients who exhibit hypertension have preexisting hypertension or sensitivity to sympathetic stimulation (Noguchi & Ebesu, 2001).
    b) CASE SERIES: Hypertension has been reported in 8 of 30 patients exposed to tetrodotoxin evidenced by retinopathy and elevated blood pressure (average BP 192/110 mm Hg). It has been suggested that these patients had preexisting hypertensive disease and atherosclerotic disease which was a predisposing feature (Deng et al, 1991).
    1) One of the 8 patients, a 63-year-old woman died of hypertensive congestive heart failure with acute pulmonary edema 2 hours after exposure to tetrodotoxin (Deng et al, 1991).
    c) INCIDENCE: An outbreak of tetrodotoxin poisoning was reported following ingestion of gastropod mollusks shown to contain varying amounts of tetrodotoxin. Eight out of 17 cases (47%) were reported to have hypertension (Yang et al, 1995). In another case series of pufferfish exposure, 9 out of 25 patients (36%) developed transient hypertension (Kanchanapongkul, 2001).
    d) In a series of 280 cases of tetrodotoxin poisoning from the toxic eggs of the horseshoe crab, 97 cases (39.6%) of transient hypertension occurred (Kanchanapongkul, 2008).
    1) In a retrospective survey between July 1988 and December 1995 in Taiwan, 24% of 52 patients with TTX poisoning were reported to have hypertension (Yang et al, 1996).
    e) CASE REPORT: Tanner et al (1996) reported a case of hypertension (BP 167/125 mm Hg) with heart rate of 112 beats/min in a 32-year-old man shortly after ingesting approximately 1.5 ounces pufferfish (P Tanner , 1996).
    3.5.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) HYPOTENSION
    a) ANIMAL STUDIES: When TTX was given intraarterially in rats, hypotension was both profound and rapid (Flachsenberger, 1987). In this experiment hypotension started within 1 to 2 minutes and became lethal in 6 minutes.
    2) CARDIOMYOPATHY
    a) In animal models large doses cause slowing in intracardiac conduction, atrioventricular dissociation and failure of myocardial contractility (Torda et al, 1973).

Respiratory

    3.6.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Death is usually caused by respiratory depression and respiratory muscle paralysis. Cyanosis and depression of the cough reflex may also occur.
    3.6.2) CLINICAL EFFECTS
    A) DYSPNEA
    1) WITH POISONING/EXPOSURE
    a) Dyspnea is common following ingestion of a TTX-containing marine fish or amphibian (Chowdhury et al, 2007a; Lan et al, 1999a; Noguchi & Ebesu, 2001; Fenner, 2000; Mahmud et al, 1999a).
    b) BLUE RINGED OCTOPUS ENVENOMATION
    1) Dyspnea may be an early manifestation of blue ringed octopus envenomation. Out of 12 patients with blue ringed octopus bites, 4 reported dyspnea (White, 1995).
    B) ACUTE RESPIRATORY INSUFFICIENCY
    1) WITH POISONING/EXPOSURE
    a) Death from tetrodotoxin may be caused from respiratory depression leading to failure (Chowdhury et al, 2007a; Ahasan et al, 2004; How et al, 2003; Fenner, 2000; Flachsenberger, 1987). Apnea has been reported within the first 2 hours (Noguchi & Ebesu, 2001; Tibballs, 1988).
    b) RESPIRATORY MUSCLE PARALYSIS: TTX is a neurotoxin blocking transmission in skeletal muscles. Ascending paralysis may develop and death can occur within 24 hours, generally as a result of respiratory muscle paralysis. Several cases of respiratory paralysis have been reported in patients with pufferfish poisoning (Kanchanapongkul, 2008; Chowdhury et al, 2007; Isbister et al, 2002; Kanchanapongkul, 2001; Sun et al, 1994; Lan et al, 1999).
    c) Sun et al (1994) reported a case of a 24-year-old man requiring endotracheal intubation and mechanical ventilation 2 hours following ingestion of a pufferfish due to respiratory muscle weakness (Sun et al, 1994).
    d) CASE REPORT: A 52-year-old woman required mechanical ventilation 4 hours after ingestion of a fish soup (Lan et al, 1999).
    e) CASE SERIES: Six family members (4 to 35-years-old) developed tingling and numbness throughout the body (particularly perioral tingling sensation), weakness of limbs, vomiting, and vertigo after ingesting 15 to 35 grams of pufferfish (Potka) liver. Two of the patients who ingested the highest amount of fish (approximately 35 grams) experienced blurring of vision and severe respiratory paralysis, and were treated with neostigmine and atropine. Following supportive care, all patients recovered completely within 2 days (Chowdhury et al, 2007).
    f) INCIDENCE: In a retrospective survey in Taiwan of 52 patients with TTX poisoning, 17 (32.6%) cases of respiratory paralysis were reported (Yang et al, 1996). Similar findings were reported in a series of 53 (30.1%) cases reported in Bangladesh where 16 patients developed clinical features of respiratory failure (Chowdhury et al, 2007a).
    1) In a series of 280 cases of tetrodotoxin poisoning from the toxic eggs of the horseshoe crab, 68 (27.7%) cases of respiratory paralysis occurred (Kanchanapongkul, 2008).
    g) BLUE RINGED OCTOPUS ENVENOMATION
    1) Out of 12 patients with blue ringed octopus bites, 6 developed respiratory failure (White, 1995).
    C) COUGH
    1) WITH POISONING/EXPOSURE
    a) Depression of the cough reflex may occur (Bradley & Klika, 1981; Kao, 1966).
    D) ACUTE PULMONARY EDEMA
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Acute pulmonary edema secondary to hypertensive congestive heart failure resulted in the death of a 63-year-old woman 2 hours after exposure to tetrodotoxin (Deng et al, 1991).
    E) PULMONARY ASPIRATION
    1) WITH POISONING/EXPOSURE
    a) CASE SERIES: Fatal aspiration pneumonia was reported in 3 patients in a retrospective survey of 52 patients with TTX poisoning (Yang et al, 1996).

Neurologic

    3.7.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) All voluntary muscles, including the respiratory muscles, are rapidly weakened. Weakness develops first in the hands and arms and then in the legs. Paresthesias, dizziness, ataxia, and areflexia may occur. Seizures are rare, but have been reported.
    3.7.2) CLINICAL EFFECTS
    A) PARALYSIS
    1) WITH POISONING/EXPOSURE
    a) Paralysis is rapid (within 2 hours); weakening of all voluntary muscles including the respiratory muscles may lead to ataxia (Halstead, 1978; Oda et al, 1989). Tetrodotoxin blocks sodium conductance and neuronal transmission in skeletal muscles. Weakness develops first in the hands and arms and then in the legs (Bradley & Klika, 1981; CDC, 1996; Noguchi & Ebesu, 2001). Ascending paralysis may follow (Gage & Dulhunty, 1973; CDC, 1996), as may areflexia, with absent Babinski signs (Chew et al, 1984; Field, 1998; Lan et al, 1999; Mahmud et al, 1999a; Hwang et al, 2002).
    1) CASE REPORTS/PUFFER FISH: Two adults developed puffer fish poisoning after eating fish bought from an Asian market that was sold as monkfish. One patient developed tingling of the perioral region and extremities, lower extremity weakness, headache and chest pain within 30 minutes of exposure. Her sensory deficits resolved within 24 hours, but she required 3 weeks of inpatient therapy for persistent motor weakness followed by long-term rehabilitative care. An investigation by the USFDA led to the voluntary recall of the fish in three states. Fish obtained from the implicated lot was found to belong to the family Tetraodontidae, with high concentrations of tetrodotoxin found in remnants of the fish meal as well as the lot which was marketed as "monk fish, gutted and head-off, product of China". It was estimated that the patient consumed as much as 3 mg of tetrodotoxin (a potentially lethal dose) (Cohen et al, 2009).
    2) CASE REPORT: Sun et al (1994) reported a case of a 24-year-old man who presented to the ED 2 hours following ingestion of a pufferfish exhibiting generalized weakness with symmetrically diminished motor power of grade 3/5. He was obtunded and had a protruding tongue, and pupils were dilated and nonreactive to light. Endotracheal intubation and mechanical ventilation were required (Sun et al, 1994).
    3) CASE REPORT: A 36-year-old man developed symmetrically flaccid limbs and absent deep tendon reflexes approximately 6 hours following ingestion of a pufferfish. Six hours after hospital admission his symptoms improved, with tingling around his mouth and fingers. By the next day he was able to walk, but had a wide based, high stepping gait and positive Romberg's sign (Field, 1998).
    b) BLUE RINGED OCTOPUS
    1) Weakness generally occurs soon after blue ringed octopus envenomation and may progress to paralysis. Early manifestations can include limb weakness, blurred or double vision, difficulty swallowing, dyspnea, difficulty speaking or ataxia (Sutherland & Lane, 1969). Out of 12 patients with blue ringed octopus bites, 3 developed weakness that did not progress and 6 had weakness that progressed to complete paralysis and respiratory failure (White, 1995).
    2) CASE REPORT: A 4-year-old boy was bitten by a blue-ringed octopus (Hapalochlaena sp.) and initially developed vomiting followed by the inability to stand and blurred vision. He was intubated and ventilated for approximately 17 hours with spontaneous return of muscular activity about 15 hours after envenomation. No long-term sequelae was observed (Cavazzoni et al, 2008).
    B) NUMBNESS
    1) WITH POISONING/EXPOSURE
    a) In a series of 280 cases of tetrodotoxin poisoning from the toxic eggs of the horseshoe crab, 232 (94.7%) cases of hands and feet numbness were reported, with 146 (59.6%) cases of weakness (Kanchanapongkul, 2008).
    C) ELECTROENCEPHALOGRAM ABNORMAL
    1) WITH POISONING/EXPOSURE
    a) Lan et al (1999) reported a poisoning case in which a patient lost reflexes in all 4 limbs. An EEG reading, 18 hours after onset of symptoms, showed posterior dominant alpha waves intermixing with trains of short duration and diffuse theta waves. Theta waves were replaced transiently with beta activities following brief noxious stimuli to the sternum, suggesting peripheral neurological dysfunction (Lan et al, 1999).
    D) NEUROPATHY
    1) WITH POISONING/EXPOSURE
    a) CRANIAL NERVE INVOLVEMENT may be manifested by blurred vision, ophthalmoplegia, dysphagia, and dysphonia (Halstead, 1978; Chew et al, 1983).
    E) COMA
    1) WITH POISONING/EXPOSURE
    a) Coma may occur following severe TTX poisoning, but is not common (Lan et al, 1999a; Mahmud et al, 1999a; Hwang et al, 2002). Most patients remain fully conscious until immediately prior to death (Noguchi & Ebesu, 2001).
    b) CASE REPORT: A 24-year-old man became unresponsive with a Glasgow Coma Scale score of 3 following ingestion of a blow-fish (Arothron reticularis). Coma followed syncope and apnea, with successful resuscitation. Pupils were fixed and dilated and brainstem areflexia and hypothermia were present. Full recovery ensued following symptomatic treatment, and he was discharged on day 7 (Tambyah et al, 1994).
    F) PARESTHESIA
    1) WITH POISONING/EXPOSURE
    a) Tingling of the lips, perioral paraesthesia, and extremities may be seen as early as 10 to 30 minutes postingestion of newts or other tetrodotoxic fish (e.g., puffer fish) (Cohen et al, 2009; Eisenman et al, 2008; Chowdhury et al, 2007; Kanchanapongkul, 2001; Chowdhury et al, 2007a; How et al, 2003; Shui et al, 2003; Isbister et al, 2002; Laobhripatr et al, 1990; Sun et al, 1994; P Tanner , 1996; Field, 1998; Noguchi & Ebesu, 2001). This may progress to severe numbness of the extremities (Cohen et al, 2009; Halstead, 1978; Oda et al, 1989).
    b) INCIDENCE: In a review of 53 cases of pufferfish poisoning, perioral paraesthesia was the most common complaint, with 38 (71%) patients reporting symptoms. Weakness of the upper and lower extremities occurred in 33 (62%) patients and paraesthesia over the entire body developed in 34 (64%) patients (Chowdhury et al, 2007a).
    1) Yang et al (1996) reported 28 cases of hand numbness, 25 cases of circumoral numbness and 20 cases of leg numbness out of a total of 52 patients in a retrospective survey of TTX poisonings in Taiwan (Yang et al, 1996). In another series of 37 patients with tetrodotoxin poisoning 24 (65%) developed perioral paresthesias and 18 (49%) developed paresthesias all over the body (Ahasan et al, 2004).
    c) CASE SERIES: Four patients experienced circumoral numbness and numbness of hands and feet within 2 hours after consuming a soup made from approximately 30 pufferfish. Nausea, vomiting, dysphagia, light-headedness, and ataxia also occurred. Reflexes were absent in 2 of the patients. With supportive care, all 4 patients completely recovered within a week (Kiernan et al, 2005).
    d) CASE SERIES: Six family members (4 to 35 years old) developed tingling and numbness throughout the body (particularly perioral tingling sensation), weakness of limbs, vomiting, and vertigo after ingesting 15 to 35 grams of pufferfish (Potka) liver. Two of the patients who ingested the highest amount of fish (approximately 35 grams) experienced blurring of vision and severe respiratory paralysis, and were treated with neostigmine and atropine. Following supportive care, all patients recovered completely within 2 days (Chowdhury et al, 2007).
    e) BLUE RINGED OCTOPUS
    1) Paresthesias are a common early manifestation of blue ringed octopus envenomation (White, 1995).
    G) DIZZINESS
    1) WITH POISONING/EXPOSURE
    a) Dizziness and malaise have been reported in several cases of poisoning by TTX (Chowdhury et al, 2007; Kanchanapongkul, 2001; How et al, 2003; Isbister et al, 2002; Tsunenari et al, 1980; P Tanner , 1996). Onset may be as soon as 15 to 30 minutes postingestion (Tibballs, 1988).
    b) INCIDENCE: Nineteen cases of dizziness were reported in a survey of 52 patients with documented TTX poisonings in Taiwan (Yang et al, 1996). In a series of 280 cases of tetrodotoxin poisoning from the toxic eggs of the horseshoe crab, 133 cases (54.3%) of dizziness and vertigo occurred (Kanchanapongkul, 2008).
    H) HEADACHE
    1) WITH POISONING/EXPOSURE
    a) Headache may develop in the early stages of poisoning (Chowdhury et al, 2007; Halstead, 1978; Sun et al, 1994; P Tanner , 1996).
    b) INCIDENCE: In a total of 52 cases of documented TTX poisoning in Taiwan, 13 patients developed headaches (Yang et al, 1996). In another series of 37 patients with tetrodotoxin poisoning, 15 (41%) developed headache (Ahasan et al, 2004).
    I) DIABETES INSIPIDUS
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Diabetes insipidus has been described in a patient in grade 3 coma following ingestion of a blowfish (Arothron reticularis) (Tambyah et al, 1994).
    J) SEIZURE
    1) WITH POISONING/EXPOSURE
    a) Several cases of seizures have been reported in documented TTX poisonings (CDC, 1996). Seizures generally occur later in the course of severe TTX poisonings (Noguchi & Ebesu, 2001).
    b) CASE SERIES: One case of seizures was reported out of a total of 52 cases of documented TTX poisonings in Taiwan (Yang et al, 1996).
    K) ATAXIA
    1) WITH POISONING/EXPOSURE
    a) Ataxia has been reported in patients with pufferfish poisoning (Kiernan et al, 2005; Isbister et al, 2002).
    b) CASE SERIES: Ataxia was reported in 4 patients within 2 hours of consuming soup that was made from approximately 30 pufferfish. The patients completely recovered with supportive care (Kiernan et al, 2005).
    L) ABSENT REFLEX
    1) WITH POISONING/EXPOSURE
    a) Reflexes were absent in two patients within 2 hours of consuming soup that was made from approximately 30 pufferfish. The patients completely recovered with supportive care (Kiernan et al, 2005).
    M) MYOCLONUS
    1) WITH POISONING/EXPOSURE
    a) Spasmodic jerking of the limbs that lasted several hours developed in a child with blue ringed octopus envenomation; he recovered fully (White, 1995). An adult bitten by a blue ringed octopus developed spasmodic jerking of the body that lasted 6 hours; he recovered (White, 1995)
    3.7.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) SEIZURES
    a) Seizures have been reported in some cases of exposure (Torda et al, 1973; Walker, 1983).

Gastrointestinal

    3.8.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Vomiting is a common sign; diarrhea and salivation may also occur.
    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH POISONING/EXPOSURE
    a) Nausea, vomiting and epigastric pain are common signs of TTX poisoning. Vomiting may be profuse and prolonged (Cohen et al, 2009; Cavazzoni et al, 2008; Chowdhury et al, 2007; Chowdhury et al, 2007a; Kiernan et al, 2005; How et al, 2003; Isbister et al, 2002; Kanchanapongkul, 2001; Kao, 1966; Halstead, 1978; Bradley & Klika, 1981; CDC, 1996; Field, 1998; Mahmud et al, 1999a; Hwang et al, 2002).
    b) INCIDENCE: Twenty-one cases of vomiting were reported out of a total of 52 reported cases of TTX poisonings in Taiwan (Yang et al, 1996). Gastrointestinal symptoms are not present in all cases.
    1) In a series of 280 cases of tetrodotoxin poisoning from the toxic eggs of the horseshoe crab, 129 (52.6%) cases of nausea and vomiting occurred (Kanchanapongkul, 2008).
    c) CASE REPORT: A 24-year-old man complained of weakness, nausea and vomiting one hour after ingestion of a pufferfish (Sun et al, 1994).
    d) BLUE RINGED OCTOPUS
    1) Nausea and vomiting are common early manifestations of blue ringed octopus envenomation. Out of 12 patients with blue ringed octopus bites, 6 patients developed vomiting (White, 1995).
    B) EXCESSIVE SALIVATION
    1) WITH POISONING/EXPOSURE
    a) Excessive salivation may be seen early in poisoning (Noguchi & Ebesu, 2001; Torda et al, 1973).
    C) DIARRHEA
    1) WITH POISONING/EXPOSURE
    a) Diarrhea may be present in the early stages of poisoning (Noguchi & Ebesu, 2001; Torda et al, 1973).

Hematologic

    3.13.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Petechial hemorrhages and hematemesis may occur in a patient with severe vomiting secondary to increased intrathoracic and intraabdominal pressure. Leukocytosis has been reported.
    3.13.2) CLINICAL EFFECTS
    A) HEMORRHAGE
    1) WITH POISONING/EXPOSURE
    a) Petechial hemorrhages and hematemesis are possible signs (Noguchi & Ebesu, 2001; Chew et al, 1983), which may occur in patients with severe vomiting secondary to increased intrathoracic and intraabdominal pressure.
    B) LEUKOCYTOSIS
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Leukocytosis has been reported in a 24-year-old man following ingestion of a pufferfish (Sun et al, 1994).

Dermatologic

    3.14.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Pallor and diaphoresis may be seen early. Blistering and desquamation have been occasionally reported.
    3.14.2) CLINICAL EFFECTS
    A) PALE COMPLEXION
    1) WITH POISONING/EXPOSURE
    a) Pallor may be seen within 10 to 45 minutes of ingestion (Halstead, 1978).
    B) BULLOUS ERUPTION
    1) WITH POISONING/EXPOSURE
    a) Blistering, petechiae, and desquamation have been reported in later stages of TTX poisoning (Noguchi & Ebesu, 2001; Leber, 1972).
    C) EXCESSIVE SWEATING
    1) WITH POISONING/EXPOSURE
    a) Diaphoresis is a common early symptom of TTX poisoning (Noguchi & Ebesu, 2001; Torda et al, 1973).
    b) CASE SERIES: Sweating was reported in 5 cases of TTX poisonings out of a total of 52 patients (Yang et al, 1996).
    D) ANIMAL BITE WOUND
    1) WITH POISONING/EXPOSURE
    a) BLUE RINGED OCTOPUS
    1) In cases of blue ringed octopus envenomation, the bite is generally not very painful and may not be noticed (Sutherland & Lane, 1969; Flecker & Cotton, 1955). Out of 12 cases of suspected blue ringed octopus bite, 5 patients did not feel the initial bite (White, 1995). Minor bleeding may be noted at the bite site.

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS4368-28-9 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Laboratory determination of tetrodotoxin is not commonly available or clinically useful. Bioassay, chromatographic methods, and monoclonal antibodies are available to detect tetrodotoxin for research purposes, to confirm exposure, and for food safety monitoring.
    B) Frequent vital signs, ECG and continuous cardiac monitoring.
    C) Monitor continuous pulse oximetry, evaluate for evidence of respiratory depression; serial measurements of negative inspiratory force may be useful to anticipate the need for endotracheal intubation.
    D) Monitor serial neurologic exam for evidence of progressive weakness.
    E) Monitor fluid and electrolytes as indicated.

Methods

    A) MULTIPLE ANALYTICAL METHODS
    1) Laboratory determination of tetrodotoxin (TTX) is not commonly available. Potency of TTX must be done by bioassay; identification may be done with thin layer chromatography (Shui et al, 2003; Brodie, 1968; Ritchie & Rogart, 1977), or high performance liquid chromatography (HPLC) (Yotsu et al, 1987; (Nagashima et al, 1987). Use of electrophoresis, HPLC, LC/MS and H-NMR analyses of fish samples for determination of TTX have been described (Shui et al, 2003; Mahmud et al, 1999; Tanu & Noguchi, 1999).
    2) A relatively new immunoassay method, using a highly specific monoclonal antibody (MAb) and immunoaffinity column chromatography, has been developed for the isolation and identification of TTX from urine samples of poisoned patients. This method is performed in combination with fluorometric HPLC and has a maximum recovery rate of TTX of 88%, with a detection limit of TTX of 2 ng/mL of the urine (Noguchi & Mahmud, 2001).
    B) CHROMATOGRAPHY
    1) Kawatsu et al (1999) reported a high performance liquid chromatography (HPLC) method for detection of tetrodotoxin in urine for the diagnosis of TTX-food poisoning. The HPLC method appears to have a high sensitivity to TTX. Immunoaffinity chromatography is first used for isolation of TTX prior to HPLC analysis.
    2) A reversed-phase ion-pairing HPLC method appears to be a fast and efficient means for the analysis of TTX and its analogues in poisoned marine samples. Another alternative method if HPLC is unavailable is thin-layer chromatography (TLC), which has a detection limit of about 2 mcg of TTX (10 mouse units) (Noguchi & Mahmud, 2001).
    3) Lin et al (1998) reported a HPLC and GC-MS methodology for the determination and quantitation of TTX in fish samples.
    C) BIOASSAY
    1) Historically, the mouse bioassay has been the most widely applied tool for determining toxicity levels in monitoring foods known to cause TTX poisonings. Ingestion of fish containing 10,000 mouse units (MU) of TTX is approximately equivalent to 2 mg of TTX (Noguchi & Ebesu, 2001; Noguchi & Mahmud, 2001). One MU is defined as the amount of TTX required to kill a 20 g male mouse of ddY strain in 30 minutes. Due to low precision and requirements of a continuous supply of a specific size of mouse, new methods, such as HPLC, are replacing the traditional mouse assay test.
    2) Kawatsu et al (1997) have developed a monoclonal antibody against tetrodotoxin (TTX) which is highly specific for TTX with no cross-reaction to tetrodonic acid. From this monoclonal antibody, a rapid and highly sensitive competitive enzyme immunoassay (EIA) was developed for quantitative analysis of TTX within 30 minutes. Range for quantitative analysis was 2-100 ng/ml.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Because of the potential difference in susceptibility and unpredictability of an individual's course, at least 24 hours of intensive monitoring of respiratory status is recommended in patients without immediate, prominent respiratory insufficiency (How et al, 2003).

Monitoring

    A) Laboratory determination of tetrodotoxin is not commonly available or clinically useful. Bioassay, chromatographic methods, and monoclonal antibodies are available to detect tetrodotoxin for research purposes, to confirm exposure, and for food safety monitoring.
    B) Frequent vital signs, ECG and continuous cardiac monitoring.
    C) Monitor continuous pulse oximetry, evaluate for evidence of respiratory depression; serial measurements of negative inspiratory force may be useful to anticipate the need for endotracheal intubation.
    D) Monitor serial neurologic exam for evidence of progressive weakness.
    E) Monitor fluid and electrolytes as indicated.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Because of the potential for the rapid onset of respiratory paralysis, prehospital decontamination is not recommended.
    6.5.2) PREVENTION OF ABSORPTION
    A) SUMMARY
    1) Tetrodotoxin is a fast acting agent which may cause respiratory paralysis; the risk of aspiration probably outweighs any potential benefit. GI decontamination is generally not recommended.
    6.5.3) TREATMENT
    A) SUPPORT
    1) There is no specific antidote or treatment for TTX toxicity. Good supportive care of blood pressure and respiration is critical (Torda et al, 1973).
    2) Prognosis should be good if medical aid is sought early and supportive measures undertaken (Chew et al, 1983; Torda et al, 1973).
    B) MONITORING OF PATIENT
    1) Frequent vital signs, ECG and continuous cardiac monitoring.
    2) Monitor continuous pulse oximetry and evaluate respiratory function. Serial measurements of negative inspiratory force may help anticipate the need for endotracheal intubation and mechanical ventilation.
    3) Monitor serial neurologic exam for evidence of progressive weakness.
    4) Monitor fluid and electrolytes as indicated.
    C) AIRWAY MANAGEMENT
    1) Monitor respiratory function. Serial measurements of negative inspiratory force may be useful. Perform endotracheal intubation and provide mechanical ventilation in patients with evidence of respiratory muscle weakness or respiratory compromise.
    2) Assisted ventilation may be necessary for 12 to 24 hours. It is noteworthy that the patient is generally aware and conscious during the time ventilation is needed (Fenner, 2000).
    D) HYPOTENSIVE EPISODE
    1) SUMMARY
    a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.
    2) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).
    3) DOPAMINE
    a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    4) ANIMAL DATA: Epinephrine and norepinephrine proved useful in reversing the hypotension in rat and rabbit models (Freeman & Turner, 1970).
    E) BRADYCARDIA
    1) Evaluate for hypoxia. Administer oxygen and manage airway as necessary.
    2) ATROPINE/DOSE
    a) ADULT BRADYCARDIA: BOLUS: Give 0.5 milligram IV, repeat every 3 to 5 minutes, if bradycardia persists. Maximum: 3 milligrams (0.04 milligram/kilogram) intravenously is a fully vagolytic dose in most adults. Doses less than 0.5 milligram may cause paradoxical bradycardia in adults (Neumar et al, 2010).
    b) PEDIATRIC DOSE: As premedication for emergency intubation in specific situations (eg, giving succinylchoine to facilitate intubation), give 0.02 milligram/kilogram intravenously or intraosseously (0.04 to 0.06 mg/kg via endotracheal tube followed by several positive pressure breaths) repeat once, if needed (de Caen et al, 2015; Kleinman et al, 2010). MAXIMUM SINGLE DOSE: Children: 0.5 milligram; adolescent: 1 mg.
    1) There is no minimum dose (de Caen et al, 2015).
    2) MAXIMUM TOTAL DOSE: Children: 1 milligram; adolescents: 2 milligrams (Kleinman et al, 2010).
    F) FLUID/ELECTROLYTE BALANCE REGULATION
    1) Hydration may be necessary (Sims & Ostman, 1986), and should be regulated according to arterial blood pressure, central venous pressure, and urinary output (Halstead, 1978).
    G) CHOLINESTERASE INHIBITOR
    1) Cholinesterase inhibitors have been used for the treatment of muscle weakness. There is no proven role for their use in tetrodotoxin poisoning. They have been used primarily in developing countries where ventilatory support was not available.
    2) CASE SERIES/NEOSTIGMINE: In a series of 53 cases of puffer fish poisoning in Bangladesh, 5 patients died immediately after admission. Of the remaining 48 patients, 16 developed severe respiratory failure (ie, tachypnea, labored breathing, bounding peripheral pulse, difficulty speaking, cyanosis, and exhaustion) and were administered 0.05 mL/kg of IV neostigmine every 6 hours for a 24 hour period, along with atropine (0.025 mL/kg) to dry secretions. Thirteen patients improved within 24 to 48 hours with normal respiratory function; 3 patients died. A total of 45 patients were discharged and well at follow-up. Its suggested that tetrodotoxin-induced respiratory muscle paralysis is the predominant cause of death, neostigmine can antagonize the paralyzing effects of the toxin by restoring the neuronal transmission to skeletal muscles (Chowdhury et al, 2007a).
    3) CASE SERIES: In a series of 37 cases of puffer fish poisoning which was purchased from a local market, 22 patients developed ascending paralysis of the limbs which ascended to involve the respiratory muscles in 17 patients. Of these 17 patients, 8 died due to respiratory failure secondary to respiratory paralysis within 1 to 5 hours of ingestion. The 14 remaining patients (9 with respiratory muscle paralysis; 5 without respiratory symptoms) were administered neostigmine (adults 0.5 mg IV; children 0.02 mg/kg IV), and all of the cases improved (Ahasan et al, 2005).
    4) Six family members (4 to 35 years old) developed tingling and numbness throughout the body (particularly perioral tingling sensation), weakness of limbs, vomiting, and vertigo after ingesting 15 to 35 g of puffer fish (Potka) liver. Three of them also developed abdominal pain and headache. Two of the patients who ingested the highest amount of fish (approximately 35 g) experienced blurring of vision and severe respiratory paralysis, and were treated with neostigmine and atropine. Following supportive care, all patients recovered completely within 2 days (Chowdhury et al, 2007).
    5) There are cases in the literature where slow administration of 10 milligrams edrophonium intravenously or 0.5 milligram of neostigmine intramuscularly were associated with clinical improvement (Chew et al, 1983; Chew et al, 1984).
    H) EXPERIMENTAL THERAPY
    1) IMMUNIZATION: Active and passive immunization was created in the murine model. Tetrodotoxin was conjugated with keyhole limpet hemocyanin and used as an immunogen. The process is experimental and has not been tested in humans (Fukiya & Matusmura, 1992).
    2) CONTRAINDICATED
    a) High concentrations of adrenergic antagonists may prolong neuromuscular blockade of tetrodotoxin and are not recommended in these patients (Kohane et al, 2001).
    I) SEIZURE
    1) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    2) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    3) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    4) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2010; Chin et al, 2008).
    5) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    6) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).

Enhanced Elimination

    A) HEMODIALYSIS
    1) A uremic woman who was receiving regular hemodialysis, developed severe symptoms of tetrodotoxin intoxication after eating fish soup (her husband ate the same soup and remained asymptomatic). One hour after she was treated with hemodialysis (approximately 21 hours after the onset of the symptoms), her condition improved dramatically. The authors concluded that hemodialysis might be effective for the treatment of tetrodotoxin intoxication because it has a low molecular weight, is water soluble and is not significantly bound to protein (Lan et al, 1999a).

Abstracts

Case Reports

    A) ADULT
    1) ACUTE EFFECTS
    a) A 24-year-old man presented to the ED after ingestion of a blowfish (Arothron reticularis). Initial symptoms included nausea and abdominal pain with sudden onset of apnea and loss of consciousness. Following successful CPR he became comatose with fixed and dilated pupils, brainstem areflexia, hypothermia and no spontaneous respirations. The patient developed diabetes insipidus 5 hours later, with these corresponding laboratory values: serum sodium 164 mmol/L, serum osmolality 334 mmol/Kg, and urine osmolality 157 mmol/Kg. A therapeutic response to 4 mcg desmopressin IV was obtained. He remained in a comatose state for 36 hours, with subsequent rapid improvements and spontaneous respirations following. He was discharged after 7 days fully recovered (Tambyah et al, 1994).
    2) A 57-year-old man ate 9 Tetraodon fangi (freshwater puffer) for breakfast. Within 25 minutes he developed vomiting, vertigo, and both extremity and perioral numbness. Muscle weakness was noted soon afterwards. He was transferred to a hospital where he experienced a 3 minute cardiac arrest, 2 hours postingestion. He was then intubated. Four hours postingestion he became comatose and 12 after ingestion he regained consciousness, had no difficulty with breathing or with muscle weakness. He was discharged 4 days after ingestion (Laobhripatr et al, 1990).
    3) A 33-year-old woman presented with nausea and vomiting, perioral paraesthesia, dysarthria, ataxia, limb weakness, hyporeflexia, ophthalmoplegia, decreased FEV1 with respiratory failure several hours after ingesting seven pufferfish. Following supportive care, she recovered completely and was discharged home on day 5. Another patient, a 40-year-old man developed perioral and extremity paresthesia and dizziness after ingesting 10 small toadfish and drinking a significant quantity of alcohol. Following an overnight observation, he was discharged the next day (Isbister et al, 2002).

Range Of Toxicity

Summary

    A) Toxic tetrodotoxin (TTX) levels have not been established. Ingestion of 1 newt in a 29-year-old has resulted in death.
    B) A woman ingested an estimated 3 mg of tetrodotoxin (a potentially lethal dose) and developed sensory deficits, which resolved within 24 hours, along with persistent motor weakness requiring intensive physical therapy.
    C) As little as 10 mcg/kg has been estimated as a serious toxic dose in humans, but this is based on mouse data.
    D) A MLD50 of TTX is reported to be 10,000 mouse units, which is approximately 2 mg of TTX.
    E) Prognosis for recovery is generally good if timely endotracheal intubation and mechanical ventilation are provided.

Minimum Lethal Exposure

    A) ACUTE
    1) A minimum lethal dose in 50% of adults of TTX is reported to be 10,000 mouse units, which is approximately 2 milligrams of TTX. The minimum dose for developing toxic symptoms is close to the MLD50 (Shui et al, 2003; Noguchi & Ebesu, 2001). Death is due to progressive ascending paralysis involving the respiratory muscles. Prognosis for recovery is generally good if timely, appropriate respiratory support is provided.
    2) Cornish (1973) has suggested an oral dose of as little as 10 micrograms/kilogram may be fatal.
    3) The fatality rate for puffer fish ingestion in Japan is 61.5% with about 50 cases annually (Torda et al, 1973). The overall fatality rate over the last 78 years is 59% (Sims & Ostman, 1986).
    4) The reported estimated minimum lethal dose of tetrodotoxin for humans is 200,000 mouse units. One mouse unit is the amount of tetrodotoxin that will kill a mouse in a standard period of time (Tsunenari et al, 1980; Deng et al, 1991).
    5) Ingestion of one newt in a 29-year-old has resulted in death (Bradley & Klika, 1981).
    6) CASE REPORT - Following the ingestion of 4 partially cooked puffer fish livers along with some skin of the puffer, a 48-year-old male died of respiratory failure within about 2 hours of the ingestion. After bioassay of the fish remains, it was determined that the victim ingested about 10,000 mouse units of TTX (approximately 2 milligrams of TTX) (Noguchi & Ebesu, 2001).
    7) CASE REPORT - A 45-year-old man developed coma, apnea and pulselessness 3 hours after ingesting 80 grams of puffer fish (Lagocephalus lunaris). He presented to an ED 30 minutes later and was initially resuscitated, but then died 26 hours after ingestion of intractable bradycardia (complete atrioventricular block) and multiple organ failure (How et al, 2003).
    8) In a study of 42 outbreaks of tetrodotoxin-associated snail poisoning (309 cases) in Zhoushan City, China, 16 (5.2%) deaths (toxin levels of the snail ranged from 50 to 300 mcg of tetrodotoxin per gram of tissue) were reported. The authors reported that approximately 0.3 gram of snail tissue is edible, and that the patients who died probably consumed more than 7 to 40 grams of edible snail tissue, or more than 23 to 133 snails (Shui et al, 2003).

Maximum Tolerated Exposure

    A) ACUTE
    1) GENERAL: Eating as little as 1/4 ounce of TTX poisoned fish has resulted in signs and symptoms of TTX poisoning (CDC, 1996).
    2) CASE SERIES - Six family members (4 to 35 years old) experienced tetrodotoxin poisoning approximately 30 minutes to 210 minutes after ingesting 15 g to 35 g of puffer fish (Potka) liver. Two of the patients who ingested the highest amount of fish (approximately 35 g) developed blurring of vision and severe respiratory paralysis, and were treated with neostigmine and atropine. Following supportive care, all patients recovered completely within 2 days (Chowdhury et al, 2007).
    3) CASE REPORT - A 4-year-old boy was bitten by a blue-ringed octopus (Hapalochlaena sp.) and developed vomiting within 10 minutes of exposure followed by the inability to stand and blurred vision. He was intubated and ventilated for approximately 17 hours with spontaneous return of muscular activity about 15 hours after envenomation. No long-term sequelae was observed (Cavazzoni et al, 2008).
    4) CASE REPORTS/PUFFER FISH: Two adults developed puffer fish poisoning after eating fish bought from an Asian market that was sold as monkfish. One patient developed tingling of the perioral region and extremities, lower extremity weakness, headache and chest pain within 30 minutes of exposure. Her sensory deficits resolved within 24 hours, but she required 3 weeks of inpatient therapy for persistent motor weakness followed by long-term rehabilitative care. It was estimated that the patient consumed as much as 3 mg of tetrodotoxin (a potentially lethal dose). Fish obtained from the implicated lot was found to belong to the family Tetraodontidae, with high concentrations of tetrodotoxin found in remnants of the fish meal as well as the lot which was marketed as "monk fish, gutted and head-off, product of China". An investigation by the USFDA led to the voluntary recall of the fish in three states (Cohen et al, 2009).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) Toxic tetrodotoxin levels have not been established.
    2) URINE - Tetrodotoxin in urine samples from six poisoned victims ranged from 6 to 102 nanograms/milliliter (Kawatsu et al, 1999).
    3) Four patients developed circumoral numbness, numbness of the hands and feet, and ataxia within two hours after consuming a soup made from approximately 30 puffer fish. Tetrodotoxin concentrations, detected in the urine samples of all four patients, ranged from 28 to 258 ng/mL (Kiernan et al, 2005).

Workplace Standards

    A) ACGIH TLV Values for CAS4368-28-9 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) NIOSH REL and IDLH Values for CAS4368-28-9 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    C) Carcinogenicity Ratings for CAS4368-28-9 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    D) OSHA PEL Values for CAS4368-28-9 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) LD50- (INTRAPERITONEAL)MOUSE:
    1) 10 mcg/kg (Kao & Fuhrman, 1967)

Pharmacology Toxicology

Toxicologic Mechanism

    A) This is a non-protein toxin, a perhydroquinazoline derivative, that in an acid solution has both a negative and positive charge -- a zwitterion (Fuhrman, 1967; Wakely et al, 1966).
    B) Tetrodotoxin is 160,000 times more potent than cocaine on isolated nerves. Neuromuscular transmission is interrupted by tetrodotoxin not at the end plates but on the motor axons (Cheymol et al, 1962; Kao & Fuhrman, 1963), and on the muscle membrane (Kao & Fuhrman, 1963; Matsumoto & Yamamoto, 1954; Narahashi et al, 1960). It interferes with production of action potentials in common excitable cells (Kao & Fuhrman, 1967).
    C) Tetrodotoxin has a direct blocking action on skeletal muscle fibers (Hagiwara, 1960; Katagi, 1927). It is a selective and potent sodium channel blocker. TTX blocks the action potential without any effect on resting membrane potential or the resting membrane resistance. It blocks nerve and muscle conduction. Its action is thought to interfere with the increase in sodium permeability associated with nerve excitation with changing potassium permeability, but the action may not be ion specific but rather is specifically localized to the early transiently open channels in the excitable membrane (Kiernan et al, 2005; Narahashi, 2001; Kao & Fuhrman, 1967).
    D) Oda et al (1989) suggested that human tetrodotoxication is the result of a reversible effect on myelinated nerve fibers along the entire length of the axon by lowering the conductance of sodium currents at nodes of Ranvier (Oda et al, 1989).
    E) ELECTRODIAGNOSTIC FEATURES - One study examined the electrodiagnostic features in a man with severe puffer fish poisoning (eg; coma, severe respiratory failure, hypotension). Conduction studies and EMG examinations performed one day after ingestion revealed complete conduction block with no compound muscle action potentials (CMAPS) or sensory nerve action potentials (SNAPs). Although insertional activity was normal, no motor unit action potentials (MUAPs) were observed. An EEG revealed posterior dominant alpha waves which were replaced transiently by beta activities with light stimulation. The authors concluded that tetrodotoxin has a complete conduction block effect on myelinated nerve fibers and spares axons (Cong & TuanLe, 2006). In another study, neurological examination of 4 patients with puffer fish poisoning (within 24 hours postingestion), showed a reduction in sodium conductance in the nerves of affected patients, consistent with direct blockade of axonal sodium channels by tetrodotoxins (Isbister et al, 2002).
    F) EMESIS - is produced because TTX acts directly on the brainstem medulla at or near the chemoreceptor trigger zone (Sims & Ostman, 1986).
    G) Controversy exists on how respiratory depression is produced. Some believe tetrodotoxin has a specific inhibitory action on respiratory center, while others are of the opinion that paralysis of respiratory nerves and muscle occurs (Sims & Ostman, 1986; Chew et al, 1983).

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