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FIRE TOAD

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) The fire toads are Bombina species which are natives of Eastern Europe and Western Asia. They may also be raised in various aquariums as pets (Alderton, 1986).
    B) SPECIFIC TERMS
    1) BOMBESIN: A tetradecapeptide with cardiovascular activity (Fregnan & Glasser, 1975).
    2) BOMBININE: A low molecular weight tetracosane peptide with hemolytic activity (Csordas & Michl, 1970).

Specific Substances

    A) CONSTITUENTS OF THE GROUP
    1) Bombina bombina (Common Fire Toad)
    2) Bombina variegata variegata
    3) Bombina orientalis (Oriental Fire Toad)
    4) Bombina variegata pachypus (Yellow-bellied Toad)

Overview

Life Support

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

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Fire toads of the Bombina species are native to Eastern Europe and Western Asia. Fire toads are frequently kept as pets.
    B) TOXICOLOGY: The Bombina species have 2 different skin serous or "venom" gland types; one with small granules (2 to 3 micrometers) and one with large (10 to 20 micrometers) granules. These glands manufacture, store, and release the granular venom, which has many biologic functions. The "venom" glands generally contain 2 types of agents, the peptides (proteins and polypeptides) and indolealkyl amines.
    C) EPIDEMIOLOGY: There are no reports of life-threatening toxicity to humans from fire toads.
    D) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Human exposure has caused eye irritation, miosis, eyelid edema, transient visual changes, oral irritation, lethargy, and hives.
    2) SEVERE TOXICITY: No human cases of severe toxicity have been reported. In animal studies, increased blood pressure, arterial changes, stimulation of intestinal smooth muscle as well as stimulation of gastric and pancreatic secretions have been reported. Hemolysis has also been reported.

Laboratory Monitoring

    A) Monitor vital signs.
    B) No specific laboratory measures are indicated.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Casual contact with fire toads kept as pets has caused eye and mouth irritation. Wash exposed skin, irrigate exposed eyes and mucous membranes. There is no specific treatment or antidote.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) If the toad is ingested, patients may need to be monitored for hypertension, heart rate changes (bradycardia may be more prevalent), gastrointestinal irritation, or hemolysis. If significant bradycardia occurs, atropine may be administered as follows. BRADYCARDIA: ADULT DOSE: BOLUS: 0.5 mg IV; may repeat every 3 to 5 minutes; MAXIMUM: 3 mg. PEDIATRIC DOSE: 0.02 mg/kg IV/IO (0.04 to 0.06 mg/kt ET). Repeat once if needed. Minimum dose is 0.1 mg. MAXIMUM SINGLE DOSE: CHILD: 0.5 mg: ADOLESCENT: 1 mg. MAXIMUM TOTAL DOSE: CHILD: 1 mg. ADOLESCENT: 2 mg.
    C) DECONTAMINATION
    1) PREHOSPITAL: DERMAL: Remove contaminated clothing and wash exposed area thoroughly with soap and water. OCULAR: Irrigate exposed eyes with copious amounts of room temperature water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist, the patient should be seen in a health care facility. INGESTION: In the event of ingestion, immediately dilute with 4 to 8 ounces (120 to 240 mL) of water or milk (not to exceed 4 ounces (120 mL) in a child).
    2) HOSPITAL: DERMAL: Remove contaminated clothing and wash exposed area thoroughly with soap and water. OCULAR: Irrigate exposed eyes with copious amounts of room temperature water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist, perform a careful eye exam including slit lamp exam. INGESTION: In the event of ingestion, immediately dilute with 4 to 8 ounces (120 to 240 mL) of water or milk (not to exceed 4 ounces (120 mL) in a child).
    D) BRADYCARDIA
    1) Usually does not require treatment. If significant bradycardia occurs, atropine may be administered as follows. BRADYCARDIA: ADULT DOSE: BOLUS: 0.5 mg IV; may repeat every 3 to 5 minutes; MAXIMUM: 3 mg. PEDIATRIC DOSE: 0.02 mg/kg IV/IO (0.04 to 0.06 mg/kt ET). Repeat once if needed. Minimum dose is 0.1 mg. MAXIMUM SINGLE DOSE: CHILD: 0.5 mg: ADOLESCENT: 1 mg. MAXIMUM TOTAL DOSE: CHILD: 1 mg. ADOLESCENT: 2 mg.
    E) AIRWAY MANAGEMENT
    1) Airway management is unlikely to be required.
    F) ANTIDOTE
    1) No antidote is available.
    G) ENHANCED ELIMINATION
    1) Hemodialysis is not useful in fire toad exposure.
    H) PATIENT DISPOSITION
    1) HOME CRITERIA: Patients who are asymptomatic or who have only mild eye, skin, or mucous membrane irritation and who did not ingest the toad may be observed at home.
    2) OBSERVATION CRITERIA: In cases of eye or skin exposure, if irritation, pain, swelling, lacrimation, or photophobia persist after irrigation, the patient should be seen in a health care facility. Any patients who have ingested the toad or toad skin should be seen in a health care facility and observed for 6 hours.
    3) ADMISSION CRITERIA: Admit all patients with systemic symptoms lasting greater than 6 hours.
    4) CONSULT CRITERIA: A toxicologist should be consulted on patients who have ingested the toad, have persistent symptoms, or if the diagnosis is unclear.
    I) PITFALLS
    1) Significant toxicity is not expected; do not overtreat. Accurate identification of the toad may be difficult.
    J) TOXICOKINETICS
    1) The toxicokinetics of fire toad toxins are unknown.
    K) DIFFERENTIAL DIAGNOSIS
    1) Any substance which may cause skin/eye irritation including acids, bases, chlorine, ammonia, and capsaicin.

Range Of Toxicity

    A) TOXICITY: Mild local irritation has been described after casual contact with pets. No human cases of severe toxicity have been reported.

Clinical Effects

Summary Of Exposure

    A) USES: Fire toads of the Bombina species are native to Eastern Europe and Western Asia. Fire toads are frequently kept as pets.
    B) TOXICOLOGY: The Bombina species have 2 different skin serous or "venom" gland types; one with small granules (2 to 3 micrometers) and one with large (10 to 20 micrometers) granules. These glands manufacture, store, and release the granular venom, which has many biologic functions. The "venom" glands generally contain 2 types of agents, the peptides (proteins and polypeptides) and indolealkyl amines.
    C) EPIDEMIOLOGY: There are no reports of life-threatening toxicity to humans from fire toads.
    D) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Human exposure has caused eye irritation, miosis, eyelid edema, transient visual changes, oral irritation, lethargy, and hives.
    2) SEVERE TOXICITY: No human cases of severe toxicity have been reported. In animal studies, increased blood pressure, arterial changes, stimulation of intestinal smooth muscle as well as stimulation of gastric and pancreatic secretions have been reported. Hemolysis has also been reported.

Vital Signs

    3.3.3) TEMPERATURE
    A) ANIMAL STUDY: HYPOTHERMIA: Bombesin had a potent hypothermic effect when given to rats, being 10,000 times more potent than neurotensin. These effects were noted when given into the cisterna magna, but not when given intravenously (Brown et al, 1977).

Heent

    3.4.3) EYES
    A) WITH POISONING/EXPOSURE
    1) EYE IRRITATION: Casual contact with fire toads kept as pets has caused eye irritation, infected sclera and eyelid edema (Dahl & Crouch, 1996; Henricksen, 1999). Transient visual loss and miosis have also been described (Dahl & Crouch, 1996).
    2) CASE REPORT: A 6-year-old boy developed reddening of the conjunctiva, intense pain, and corneal abrasion after ocular exposure to the toxins secreted from a European fire-bellied toad (Bombina bombina); however, no systemic toxicity was observed (Scaglione et al, 2002).

Cardiovascular

    3.5.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) HYPERTENSION
    a) HYPERTENSION was seen in dogs given the tetradecapeptide bomesin (Fregnan & Glasser, 1975).
    2) BRADYCARDIA
    a) BRADYCARDIA was seen in dogs given bomesin (Fregnan & Glasser, 1975).
    3) VASOSPASM
    a) ARTERIAL CONSTRICTION: Of the renal, mesenteric and coeliac arteries was seen in anesthetized dogs given bomesin (Fregnan & Glasser, 1975).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) GASTROINTESTINAL IRRITATION
    1) WITH POISONING/EXPOSURE
    a) Casual contact with fire toads kept as pets has caused oral irritation and erythema of the mouth and lips (Henricksen, 1999; Dahl & Crouch, 1996).
    3.8.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) GASTROINTESTINAL DISORDER
    a) GASTROINTESTINAL STIMULATION: Bombesin was noted to have a stimulant action both on the rat and the guinea-pig colon as well as the cat ileum. It also has a stimulant effect on gastric acid secretion in the chicken and dog (Anastasi et al, 1971). Bombesin is a potent gastric and pancreatic secretion stimulant in mammals (Windholz, 1983).

Genitourinary

    3.10.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) UTERINE DISORDER
    a) UTERINE STIMULATION: Potent uterine stimulation was noted as an action of bombesin in the rat (Anastasi et al, 1971).

Hematologic

    3.13.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) HEMOLYSIS
    a) Both a high molecular and low molecular weight hemolysin have been isolated from the skin "venom" of Bombina species (Mar & Michl, 1976; Kiss & Michl, 1962; Bachmayer et al, 1967). The activity of the high molecular weight hemolysin is dependent on the calcium ion concentration (Mar & Michl, 1976). Bombina skin trypsin/thrombin inhibitor (BSTI) inhibits thrombin and trypsin in vitro (Mignogna et al, 1996).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) URTICARIA
    1) WITH POISONING/EXPOSURE
    a) Casual contact with fire toads kept as pets has caused hives (Dahl & Crouch, 1996).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs.
    B) No specific laboratory measures are indicated.
    4.1.2) SERUM/BLOOD
    A) No specific laboratory measures are indicated.
    4.1.4) OTHER
    A) OTHER
    1) MONITORING
    a) Monitor vital signs.

Methods

    A) CHROMATOGRAPHY
    1) The "venom" may be isolated on SDS-polyacrylamide slab gels by electrophoresis or by column chromotography (Laemmli, 1970; Swank & Munkres, 1971).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Admit all patients with systemic symptoms lasting greater than 6 hours.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Patients who are asymptomatic or who have only mild eye, skin, or mucous membrane irritation and who did not ingest the toad may be observed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) A toxicologist should be consulted on patients who have ingested the toad, have persistent symptoms, or if the diagnosis is unclear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) In cases of eye or skin exposure, if irritation, pain, swelling, lacrimation, or photophobia persist after irrigation, the patient should be seen in a health care facility. Any patients who have ingested the toad or toad skin should be seen in a health care facility and observed for 6 hours.

Monitoring

    A) Monitor vital signs.
    B) No specific laboratory measures are indicated.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) SUMMARY
    1) INGESTION: Immediately flush the oral mucous membranes to decrease absorption. Do not swallow the rinse water.
    2) DERMAL: Remove contaminated clothing and wash exposed area extremely thoroughly with soap and water.
    3) OCULAR: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature water for at least 15 minutes.
    6.5.2) PREVENTION OF ABSORPTION
    A) DILUTION: Immediately dilute with 4 to 8 ounces (120 to 240 mL) of water or milk (not to exceed 4 ounces/120 mL in a child).
    6.5.3) TREATMENT
    A) MONITORING OF PATIENT
    1) Monitor vital signs.
    2) No specific laboratory measures are indicated.
    B) BRADYCARDIA
    1) Atropine is useful in the management of bradycardia, varying degrees of heart block, and other cardiac irregularities due to the digitalis-like induced effects of enhanced vagal tone on the SA node rhythm and on conduction through the AV node (Chern et al, 1991).
    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).
    C) HYPERTENSIVE EPISODE
    1) Monitor vital signs regularly. For mild/moderate hypertension without evidence of end organ damage, pharmacologic intervention is generally not necessary. Sedative agents such as benzodiazepines may be helpful in treating hypertension and tachycardia in agitated patients, especially if a sympathomimetic agent is involved in the poisoning.
    2) For hypertensive emergencies (severe hypertension with evidence of end organ injury (CNS, cardiac, renal), or emergent need to lower mean arterial pressure 20% to 25% within one hour), sodium nitroprusside is preferred. Nitroglycerin and phentolamine are possible alternatives.
    3) SODIUM NITROPRUSSIDE/INDICATIONS
    a) Useful for emergent treatment of severe hypertension secondary to poisonings. Sodium nitroprusside has a rapid onset of action, a short duration of action and a half-life of about 2 minutes (Prod Info NITROPRESS(R) injection for IV infusion, 2007) that can allow accurate titration of blood pressure, as the hypertensive effects of drug overdoses are often short lived.
    4) SODIUM NITROPRUSSIDE/DOSE
    a) ADULT: Begin intravenous infusion at 0.1 microgram/kilogram/minute and titrate to desired effect; up to 10 micrograms/kilogram/minute may be required (American Heart Association, 2005). Frequent hemodynamic monitoring and administration by an infusion pump that ensures a precise flow rate is mandatory (Prod Info NITROPRESS(R) injection for IV infusion, 2007). PEDIATRIC: Initial: 0.5 to 1 microgram/kilogram/minute; titrate to effect up to 8 micrograms/kilogram/minute (Kleinman et al, 2010).
    5) SODIUM NITROPRUSSIDE/SOLUTION PREPARATION
    a) The reconstituted 50 mg solution must be further diluted in 250 to 1000 mL D5W to desired concentration (recommended 50 to 200 mcg/mL) (Prod Info NITROPRESS(R) injection, 2004). Prepare fresh every 24 hours; wrap in aluminum foil. Discard discolored solution (Prod Info NITROPRESS(R) injection for IV infusion, 2007).
    6) SODIUM NITROPRUSSIDE/MAJOR ADVERSE REACTIONS
    a) Severe hypotension; headaches, nausea, vomiting, abdominal cramps; thiocyanate or cyanide toxicity (generally from prolonged, high dose infusion); methemoglobinemia; lactic acidosis; chest pain or dysrhythmias (high doses) (Prod Info NITROPRESS(R) injection for IV infusion, 2007). The addition of 1 gram of sodium thiosulfate to each 100 milligrams of sodium nitroprusside for infusion may help to prevent cyanide toxicity in patients receiving prolonged or high dose infusions (Prod Info NITROPRESS(R) injection for IV infusion, 2007).
    7) SODIUM NITROPRUSSIDE/MONITORING PARAMETERS
    a) Monitor blood pressure every 30 to 60 seconds at onset of infusion; once stabilized, monitor every 5 minutes. Continuous blood pressure monitoring with an intra-arterial catheter is advised (Prod Info NITROPRESS(R) injection for IV infusion, 2007).
    8) PHENTOLAMINE/INDICATIONS
    a) Useful for severe hypertension, particularly if caused by agents with alpha adrenergic agonist effects usually induced by catecholamine excess (Rhoney & Peacock, 2009).
    9) PHENTOLAMINE/ADULT DOSE
    a) BOLUS DOSE: 5 to 15 mg IV bolus repeated as needed (U.S. Departement of Health and Human Services, National Institutes of Health, and National Heart, Lung, and Blood Institute, 2004). Onset of action is 1 to 2 minutes with a duration of 10 to 30 minutes (Rhoney & Peacock, 2009).
    b) CONTINUOUS INFUSION: 1 mg/hr, adjusted hourly to stabilize blood pressure. Prepared by adding 60 mg of phentolamine mesylate to 100 mL of 0.9% sodium chloride injection; continuous infusion ranging from 12 to 52 mg/hr over 4 days has been used in case reports (McMillian et al, 2011).
    10) PHENTOLAMINE/PEDIATRIC DOSE
    a) 0.05 to 0.1 mg/kg/dose (maximum of 5 mg per dose) intravenously every 5 minutes until hypertension is controlled, then every 2 to 4 hours as needed (Singh et al, 2012; Koch-Weser, 1974).
    11) PHENTOLAMINE/ADVERSE EFFECTS
    a) Adverse events can include orthostatic or prolonged hypotension, tachycardia, dysrhythmias, angina, flushing, headache, nasal congestion, nausea, vomiting, abdominal pain and diarrhea (Rhoney & Peacock, 2009; Prod Info Phentolamine Mesylate IM, IV injection Sandoz Standard, 2005).
    12) CAUTION
    a) Phentolamine should be used with caution in patients with coronary artery disease because it may induce angina or myocardial infarction (Rhoney & Peacock, 2009).
    13) NITROGLYCERIN/INDICATIONS
    a) May be used to control hypertension, and is particularly useful in patients with acute coronary syndromes or acute pulmonary edema (Rhoney & Peacock, 2009).
    14) NITROGLYCERIN/ADULT DOSE
    a) Begin infusion at 10 to 20 mcg/min and increase by 5 or 10 mcg/min every 5 to 10 minutes until the desired hemodynamic response is achieved (American Heart Association, 2005). Maximum rate 200 mcg/min (Rhoney & Peacock, 2009).
    15) NITROGLYCERIN/PEDIATRIC DOSE
    a) Usual Dose: 29 days or Older: 1 to 5 mcg/kg/min continuous IV infusion. Maximum 60 mcg/kg/min (Laitinen et al, 1997; Nam et al, 1989; Rasch & Lancaster, 1987; Ilbawi et al, 1985; Friedman & George, 1985).

Eye Exposure

    6.8.1) DECONTAMINATION
    A) Irrigate exposed eyes with copious amounts of room temperature water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist, perform a careful eye exam including a slit lamp exam

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) Remove contaminated clothing and wash exposed area thoroughly with soap and water.

Enhanced Elimination

    A) HEMODIALYSIS
    1) Hemodialysis is NOT useful in fire toad exposure.

Range Of Toxicity

Summary

    A) TOXICITY: Mild local irritation has been described after casual contact with pets. No human cases of severe toxicity have been reported.

Minimum Lethal Exposure

    A) There are no reports of life-threatening toxicity to humans from fire toads. The minimum lethal human exposure is not known.

Maximum Tolerated Exposure

    A) The maximum tolerated human exposure to fire toads has not been described.
    B) CYTOTOXICITY: The skin secretions from the serous glands of these toads are known to be cytotoxic (Kiss & Michl, 1962) Kaiser & Kramer, 1967).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) SUMMARY -
    1) In general, the "venom" glands of these toads contain two types of biologically active substances, peptides (proteins and polypeptides) and indolealkyl amines (Barerio et al, 1987).
    2) The serous glands which produce and store the grandular "venoms" contain primarily two types of biologically active substances, the indoalkyl aminies and the peptides. The two main agents are 5-hydroxytryptamine (5-HT) and bombesin (Anastasi et al, 1971; Anastasi et al, 1972; Erspamer & Vialli, 1952).
    3) The release of the toxin from the skin of the toad is controlled via an adrenergic mechanism. It is stimulated via alpha adrenoceptor stimulation and inhibited by beta adrenoceptor stimulation (Delfino et al, 1982).
    4) These "venoms" have also exhibited cytotoxic and antimicrobial properties (Barberio et al, 1987; Balboni et al, 1992; Gibson et al, 1991; Simmaco et al, 1991).
    5) Skin secretions from Bombina bombina have yielded large amounts of serotonin, free amino acids, and basic peptides. Bombina varigata yields 12 alpha amino acids, gamma amino butyric acid and serotonin, two nonapeptides, and a hemolytic polypeptide (Amdur et al, 1991).
    6) Bombina skin trypsin/thrombin inhibitor (BSTI) has been isolated from the skin secretions of Bombina bombina. It inhibits trypsin and thrombin in vitro (Mignogna et al, 1996).
    B) BOMBESIN -
    1) The amino acid sequence of bombesin is: 
    pyroglutamic acid/glutamine/arginine/leucine/glycine/
asparagine/glutamine/tryptophan/alanine/valine/
glycine/histidine/leucine/methionine/NH2 (Brown et al,
1977; Anastasi et al,1972).

    2) The skin of Bombina species contains a tetradecapeptide called bombesin which constricts renal, mesenteric, and coeliac arterial vessels.

Physicochemical

Molecular Weight

    A) BOMBESIN: 1619.82 (Windholz, 1983)

References

General Bibliography

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    4) Anastasi A, Erspamer V, & Bucci M: Isolation and amino-acid sequences of alytesin and bombesin, two analogous active tetradecapeptides from the skin of European discoglossid frogs. Archs Biochem Biophys 1972; 148:443.
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