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BISMUTH

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Bismuth and a large number of trivalent bismuth salts have been used both industrially and medically for centuries. Pentavalent salts oxidize readily and are not useful medicinal agents. Therefore, all medicinal salts are bismuthyl (BiO) rather than bismuthos compounds.
    B) Medically, some salts have been used for their astringent action on the gastrointestinal tract (eg, bismuth subsalicylate, bismuth subcarbonate, bismuth subnitrate), while other insoluble salts were thought to be surface protectants for various skin conditions (eg, bismuth subgallate, bismuth subnitrate) (Winship, 1983).

Specific Substances

    A) Bismuth
    1) CAS 7440-69-9
    BISMUTH ALUMINATE
    1) Aluminum bismuth oxide
    BISMUTH BUTYLTHIOLAURATE
    1) 2-(butylthio) dodecanoic acid
    2) bismuth basic salt
    BISMUTH CHLORIDE OXIDE
    1) Basic bismuth chloride
    2) Bismuth oxychloride
    3) Bismuthyl chloride
    4) Bismuthyl subchloride
    BISMUTH ETHYL CAMPHORATE
    1) D-camphoric acid
    2) Ethylester bismuth salt
    BISMUTH IODIDE OXIDE
    1) Basic bismuth iodide
    2) Bismuth oxyiodide
    3) Bismuthyl iodide
    4) Bismuth subiodide
    BISMUTH SUBCARBONATE
    1) Bismuthcarbonate, basic
    2) Bismuthine
    3) Bismuthoxycarbonate
    4) CAS 5892-10-4
    BISMUTH SUBCITRATE
    1) Tripotassium dicitratobismuthate
    2) CAS 57644-54-9
    BISMUTH SUBGALLATE
    1) Bismuth gallate, basic salt
    2) BSG
    3) Gallic acid bismuth, basic
    4) CAS 22650-86-8
    BISMUTH SUBNITRATE
    1) Bismuth hydroxide nitrate oxide
    2) Bismuth nitrate, basic
    3) Bismuth oxynitrate
    4) Bismuth subnitricum
    5) Bismuth white
    6) Bismuthyl nitrate
    7) Magistery of bismuth
    8) Novismuth
    9) Paint white
    10) Spanish white
    11) CAS 1036-44-1
    BISMUTH SUBSALICYLATE
    1) Basic bismuth salicylate
    2) Bismuth salicylate, basic
    3) Oxo(salicylato) bismuth
    4) Salicylic Acid, basic bismuthyl salt
    5) CAS 14882-18-9

    1.2.1) MOLECULAR FORMULA
    1) Bi

Available Forms Sources

    A) FORMS
    1) The percentages of bismuth in various salts are listed below (Winship, 1983; Windholz & Budavari, 1983):
    COMPOUNDAPPROXIMATE %
    Bismuth aluminate54.5
    Bismuth and ammonium citrate41.5
    Bismuth chloride oxide80.2
    Bismuth citrate52.5
    Bismuth iodide oxide59.4
    Bismuth oxide anhydrous89.7
    Bismuth potassium tartrate60 to 64
    Bismuth sodium tartrate70 to 75
    Bismuth subacetate74
    Bismuth subcarbonate81
    Bismuth subgallate52
    Bismuth subnitrate72
    Bismuth subsalicylate58
    Bismuth sulfate59
    Bismuth valerate64
    Tripotassium dicitratobismuthate29

    B) SOURCES
    1) DeNol is a bismuth chelate of tripotassium dicitro bismuthate; BIPP is ribbon gauze impregnated with bismuth iodoform paraffin paste.
    2) NORMAL LEVELS
    a) Bismuth is normally in our environment. The normal daily intake in untreated people is 5 to 20 mcg/day (Hamilton et al, 1972, 1973; (Woolrich, 1973).
    b) A "normal" background blood level in untreated subjects is 1 to 15 (+/-12) mcg/L (Conso et al, 1975; Dekker et al, 1986; pp 293-296).
    c) "Normal" background urinary excretion of bismuth in non-treated subjects is 8.2 to 22 mcg/L (Conso et al, 1975; Dekker & Reisma, 1979).
    C) USES
    1) INDUSTRIAL - Bismuth is used in fusible alloys, boiler plugs, electrical fuses, solders, "silvering" of mirrors, and dental techniques.
    2) MEDICAL - Various bismuth salts have been used as dusting powders for open lesions in animals, gastrointestinal lining protectants, x-ray contrast medium, and treatment of buccal warts in dogs. It was once used as an antacid, GI astringent, skin protectant for various eczemas and rashes, and for yaws and syphilis. Because of concern for toxicity, these uses are now infrequent.
    a) Bismuth-containing drugs are used in the treatment of Heliobacter-pylori-associated peptic ulcers (Pedersen et al, 2003).

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: Bismuth is a metal that is formulated into a salt used in medications for the treatment of nausea, vomiting, and diarrhea, in surgical paste for ileostomies and colostomies, and as an adjunct in the treatment of ulcers.
    B) PHARMACOLOGY: The pharmacological mechanism of bismuth is not clear. It may have protective effects in the gastric mucosa and it inhibits the growth of H. pylori.
    C) TOXICOLOGY: Bismuth toxicity varies regarding both onset and type of toxicity due to the solubility of the salt form administered. Binds sulfhydryl groups, especially in the CNS, resulting in loss of white matter and specifically Purkinje cells and encephalopathy. Also causes degeneration of proximal tubules in the kidney, resulting in nephrotoxicity.
    D) EPIDEMIOLOGY: Ingestion of bismuth products is common, but toxicity from bismuth is rare and deaths have not been reported.
    E) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE POISONING: Can cause oral mucosal lesions, nausea, vomiting, and diarrhea. Chronic use can cause discoloration of the skin, oral, or vaginal mucosa.
    2) SEVERE POISONING: Chronic intoxication can cause encephalopathy which can manifest as mental status changes, such as memory loss, confusion, delirium, psychosis, depression, insomnia, difficulty in concentration, ataxia, tremors, myoclonus, and seizures. Acute renal failure has been reported after large ingestions.
    0.2.20) REPRODUCTIVE
    A) There are two reported cases of pregnant women with acute bismuth poisoning who had normal pregnancies and children.
    B) At the time of this review, few reproductive studies were available for bismuth. It is known to cross the placenta. It did not cause birth defects in chickens, but did apparently produce a stunted lamb with other birth defects when given to a pregnant ewe.
    C) Bismuth subnitrate was found to a toxic effect on rat Leydig cells.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, no studies were found on the possible carcinogenic activity of bismuth in humans.

Laboratory Monitoring

    A) Monitor liver enzymes and kidney function due to potential for hepatic and renal damage. Renal failure may not develop for several days after large ingestions.
    B) Monitor urine output and urinalysis after large overdose, as proteinuria, glycosuria, hematuria, and oliguria may develop in patients with renal injury.
    C) Blood or urine bismuth concentrations are not routinely available from most clinical laboratories and they are not clinically useful in the acute setting.
    D) Blood bismuth concentrations less than 5 mcg/dL are seldom associated with symptoms. Normal background levels are approximately 1 to 5 mcg/dL.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TOXICITY
    1) Treat nausea and vomiting with antiemetics and fluids.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Severe toxicity is rare after acute ingestion. Chronic toxicity may produce seizures and encephalopathy. Treat seizures with IV benzodiazepines; DIAZEPAM (ADULT: 5 to 10 mg, repeat every 10 to 15 min as needed; CHILD: 0.2 to 0.5 mg/kg, repeat every 5 min as needed) or LORAZEPAM (ADULT: 2 to 4 mg; CHILD: 0.05 to 0.1 mg/kg).
    C) DECONTAMINATION
    1) PREHOSPITAL: No pre-hospital decontamination is needed.
    2) HOSPITAL: Gastrointestinal decontamination is generally not needed.
    D) AIRWAY MANAGEMENT
    1) Not generally required.
    E) ANTIDOTE
    1) None
    F) ENHANCED ELIMINATION
    1) There is no evidence that diuresis or hemodialysis is effective. Case reports suggest that chelation with unithiol combined with hemodialysis may increase bismuth elimination. In animal studies, succimer, D-penicillamine, and unithiol (DMPS) accelerated bismuth elimination. However, the efficacy of chelator treatment in humans has not been clearly demonstrated, and it is not routinely recommended.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: Small, single ingestions of bismuth are unlikely to cause systemic toxicity. Asymptomatic patients may be observed at home.
    2) OBSERVATION CRITERIA: Patients with large, acute overdoses and those with self-harm attempts should be evaluated in a healthcare facility. Patients with symptoms of chronic intoxication should be referred to a healthcare facility.
    3) ADMISSION CRITERIA: Those with persistent vomiting or evidence of systemic toxicity should be admitted for observation and supportive care.
    4) CONSULT CRITERIA: Consult a medical toxicologist or your local poison control center for any patient who develops systemic toxicity from bismuth.
    H) PITFALLS
    1) Making the diagnosis of bismuth toxicity can be difficult without a clear history of exposure. Renal failure may not manifest for several days after large overdose, outpatient monitoring of renal function may be necessary in these patients.
    I) PHARMACOKINETICS
    1) Only approximately 0.2% of orally administered bismuth is absorbed systemically from the gastrointestinal tract. The time to peak concentration is typically within one hour. The volume of distribution is unknown. The distribution half-life is approximately 1 to 4 hours, and the elimination half-life is 5 to 11 days. Urinary bismuth is detectable 3 months after the last dose.
    J) DIFFERENTIAL DIAGNOSIS
    1) Ethanol withdrawal, neurodegenerative disease, nonketotic hyperosmolar coma, viral encephalopathy, lithium toxicity, progressive multifocal ataxia.

Range Of Toxicity

    A) TOXICITY: Blood levels less than 5 mcg/dL are rarely associated with symptoms. ADULT: In 6 patients who ingested 227 g/day for 3 weeks, there were no detectable blood levels 24 hours after cessation of therapy and no symptoms. An adult developed acute renal failure, Fanconi's syndrome, and oral ulcerations after ingesting 5.4 g colloidal bismuth subcitrate. PEDIATRIC: Acute toxic symptoms have occurred with as little as 5.2 mg IM over 26 hours in a 21-month-old to 30 g over 8 days in a 7.5-year-old. A 17-year-old developed acute renal failure but recovered after ingesting 7.5 g bismuth subcitrate.
    B) THERAPEUTIC DOSE: BISMUTH SUBSALICYLATE: 12 yrs and older: 524 mg orally every 0.5 to 1 hour, up to a maximum of 8 doses/day (4192 mg/day).

Clinical Effects

Summary Of Exposure

    A) USES: Bismuth is a metal that is formulated into a salt used in medications for the treatment of nausea, vomiting, and diarrhea, in surgical paste for ileostomies and colostomies, and as an adjunct in the treatment of ulcers.
    B) PHARMACOLOGY: The pharmacological mechanism of bismuth is not clear. It may have protective effects in the gastric mucosa and it inhibits the growth of H. pylori.
    C) TOXICOLOGY: Bismuth toxicity varies regarding both onset and type of toxicity due to the solubility of the salt form administered. Binds sulfhydryl groups, especially in the CNS, resulting in loss of white matter and specifically Purkinje cells and encephalopathy. Also causes degeneration of proximal tubules in the kidney, resulting in nephrotoxicity.
    D) EPIDEMIOLOGY: Ingestion of bismuth products is common, but toxicity from bismuth is rare and deaths have not been reported.
    E) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE POISONING: Can cause oral mucosal lesions, nausea, vomiting, and diarrhea. Chronic use can cause discoloration of the skin, oral, or vaginal mucosa.
    2) SEVERE POISONING: Chronic intoxication can cause encephalopathy which can manifest as mental status changes, such as memory loss, confusion, delirium, psychosis, depression, insomnia, difficulty in concentration, ataxia, tremors, myoclonus, and seizures. Acute renal failure has been reported after large ingestions.

Heent

    3.4.2) HEAD
    A) BUCCAL IRRITATION: Swelling of the buccal mucous membranes and vesication of the tongue has occurred with oral administration (Winship, 1983).
    B) SALIVATION: Increased salivation is often one of the initial symptoms (Winship, 1983).
    C) BISMUTH LINE: A bluish or brownish discoloration of the gums, a bismuth line, is caused by deposition of bismuth sulfide in fibrous tissues of the gums (Mayer & Baehr, 1912; Bradley et al, 1989).
    D) PYORRHOEA: Pyorrhoea with loss of teeth is a possible reaction (Winship, 1983).
    E) STOMATITIS: Ulcerative stomatitis and/or cheilitis may be seen as a result of exposure to various bismuth salts (Dowds, 1936; Maurice, 1988).
    F) TONSIL ULCERATION: Bilateral tonsil ulceration and stomatitis occurred in a 22-year-old woman 8 days after she intentionally ingested 5.4 grams of colloidal bismuth subcitrate. The ulcerations and stomatitis resolved following treatment with an oral lidocaine solution (Hruz et al, 2002).
    3.4.5) NOSE
    A) GUSTATORY/OLFACTORY DYSFUNCTION: A patient on bismuth subgallate tablets was reported after one year to experience ageusia, dysgeusia and olfactory dysfunctions (Friedland et al, 1993).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) VENTRICULAR ARRHYTHMIA
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Cardiovascular damage is uncommon, but in one case PVCs and myocardial damage were reported. The dose the patient received was 2.4 g IM over 6 months (Wachstein, 1944).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) SECONDARY PERIPHERAL NEUROPATHY
    1) Peripheral neuritis has been reported (Winship, 1983).
    B) TOXIC ENCEPHALOPATHY
    1) WITH THERAPEUTIC USE
    a) Bismuth toxicity typically presents with gradual subacute progressive encephalopathy which includes mental status changes (memory loss, confusion, delirium, psychosis, depression), ataxia, tremors, myoclonus, and seizures. These symptoms are usually reversible over several weeks or months after bismuth is discontinued (Winship, 1983; Jones, 1990).
    b) A typical case would involve a patient taking chronic oral bismuth subgallate. Symptoms might start with malaise and lethargy with later occurrence of deteriorating mental abilities, memory loss, reading and writing ability loss, muscle twitching, sleeplessness, and ataxia. Eventually the patient becomes bedridden (Burns et al, 1974; Mendelowitz et al, 1990; Jones, 1990). Coma and seizures may occur.
    c) The dose necessary and the time to onset varies considerably. Usually 5 to 25 g/day were taken for approximately a year before symptoms arose, but a few patients have developed symptoms in as short a period as weeks or months (Winship, 1983).
    d) Impairment of renal function may contribute to the development of bismuth-induced encephalopathy (Playford et al, 1990).
    e) The characteristic EEG and bismuth encephalopathy includes bihemispheric slowing, low voltage, and diffuse beta frequencies bilaterally, maximal in the frontal and central areas and accentuated by hyperventilation (Haskings & Duggan, 1982).
    f) Human case reports suggest that recovery from bismuth toxicity usually varies from 2 to 10 weeks following cessation of bismuth intake. In animal studies, chelators have accelerated bismuth elimination. However, the efficacy of chelation in humans has not been clearly demonstrated (Basinger et al, 1983).
    g) Paranoid behavior is an uncommon effect associated with encephalopathy. A case is reported of a 74-year-old man developing paranoid ideation after ingesting bismuth for one year (Friedland et al, 1993).
    h) CASE REPORT: A 67-year-old man with a sacral chondroma became acutely confused, disorientated, delusional, and verbally aggressive 5 days after bismuth iodoform paraffin paste (BIPP) packing was used postoperatively for his surgical wound breakdown. He also developed abdominal discomfort, nausea, tremor, myoclonic jerks, and intermittent episodes of drowsiness and worsening confusion. He was diagnosed with bismuth toxicity (blood and urine bismuth concentrations, 340 mcg/L and 2800 mcg/L, respectively) and BIPP packing was removed. Following DMPS chelation therapy for 51 days, his blood bismuth concentration declined to 5 mcg/L and his condition gradually improved. On 6-month follow-up, he remained well and his sacral wound was healing well (Ovaska et al, 2008).
    i) CASE REPORT: A 54-year-old man presented with a 6 week history of progressive confusion and memory difficulty and a 2 to 3 week history of involuntary movements and gait impairment. His encephalopathy was further characterized by marked multifocal myoclonic jerks, coarse postural tremors, and postural instability. The patient gradually improved (Gordon et al, 1995).
    1) Spinal tap and brain MRI scan were normal. Extensive toxic, metabolic, and infectious workup demonstrated bismuth toxicity.
    2) As the patient's encephalopathy cleared, he reported chronic bismuth subsalicylate use (between 1,040 to 4,160 mg/day). Bismuth levels 5 weeks after cessation were 3.6 micrograms/dL (typical level up to 2 micrograms/dL) in serum and 42 micrograms/L (typical level up to 20 micrograms/L) in urine.
    j) CASE REPORT: A 72-year-old woman developed extrapyramidal symptoms after four weeks of consuming bismuth salts. The patient was initially considered permanently disabled by brain stem infarction (Baudisch et al, 1995). Blood bismuth was 380 micrograms/L (normal level less than 1 micrograms/L, bismuth treated patients less than 10 micrograms/L). The patient was treated with IV unithiol (DMPS) which resulted in reversal of neurologic symptoms and a striking improvement of her mental status within 24 hours.
    k) CASE REPORT: A 56-year-old woman developed hypertension (165/94 mmHg), tachycardia (117 bpm), progressive confusion, myoclonus, muscle rigidity, tremors, ataxia, and visual hallucinations after chronically ingesting Pepto Bismuth 45 mL three times daily for several weeks for treatment of chronic gastrointestinal symptoms. Her bismuth blood concentration was 397 mcg/L (normal range 0 to 9 mcg/L). Following cessation of bismuth, the patient showed improvement in cognitive function, with resolution of her myoclonus, rigidity, and visual hallucinations, and was discharged on hospital day 10; however, fine residual tremors continued to persist at the 4 month follow-up post discharge (Masannat & Nazer, 2013).
    2) WITH POISONING/EXPOSURE
    a) Bismuth toxicity typically presents with gradual subacute progressive encephalopathy which includes mental status changes such as memory loss, confusion, delirium, psychosis, depression, insomnia, and difficulty in concentration (Weller, 1988).
    b) CASE REPORT: A 27-year-old man developed anorexia, nausea, vomiting, general malaise, weakness of his legs, blurring of vision, thirst, and poor urinary output 10 days after ingesting 100 De-Nol tablets containing 120 milligrams bismuth subcitrate per tablet. Blood bismuth was 260 micrograms/liter on the eleventh day after ingestion. Hemodialysis was performed daily on days 12 through 16 for renal failure. Bismuth blood concentrations decreased slightly after hemodialysis. Renal function and neurologic signs resolved after the fifth day of dialysis. At 96 days postingestion blood bismuth concentration was still detectable at 8 micrograms/liter (Hudson & Mowat, 1989).
    C) HEADACHE
    1) Headache may also occur.

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH POISONING/EXPOSURE
    a) Nausea and vomiting have been seen in both chronic and acute bismuth poisoning cases (Sarikaya et al, 2002; Mayer & Baehr, 1912).
    B) DIARRHEA
    1) WITH POISONING/EXPOSURE
    a) Diarrhea and abdominal cramping has also been reported in acute and chronic cases (Gryboski & Gotoff, 1961).
    C) CONSTIPATION
    1) WITH THERAPEUTIC USE
    a) FECAL IMPACTION: A stercolith-like stercoroma was reported in a 72-year-old woman after receiving bismuth subnitrate 2 grams/day. It was associated with a paralytic ileus-like syndrome, but resolved upon enema administration and discontinuation of the bismuth (Umeki, 1988).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) TOXIC HEPATITIS
    1) Hepatic degeneration may be seen (Winship, 1983), including fatty changes (Dowd, 1936), jaundice, and central necrosis (animals).
    2) Ten percent of prisoners treated for syphilis with injectable bismuth salts developed hepatitis. Predisposing factors included diet, previous alcohol use, and previous arsphenamine therapy (Kulchar & Reynolds, 1942).
    3) Hepatotoxicity is associated with degeneration and necrosis of peripheral and midlobular parenchymal cells which, upon close examination, appear as cloudy swelling and granular degeneration (Beaver & Burr, 1963).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) NEPHRITIS
    1) WITH THERAPEUTIC USE
    a) Urizar & Vernier (1966) reported over 30 cases of nephritis in children (Urizar & Vernier, 1966). Vacuolation of the cytoplasm of the convoluted tubules and inclusion bodies in the nuclei of epithelial cells have been reported (Pappenheimer & Maechling, 1934). Fanconi's syndrome may be seen.
    b) Incomplete recovery might result even after discontinuation of bismuth use (Winship, 1983), but full recovery has also been reported (Czerwinski & Ginn, 1964).
    B) ACUTE TUBULAR NECROSIS
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 17-year-old girl presented to the emergency department with nausea, vomiting and anuria, 7 days after intentionally ingesting 25 tablets of 300 mg (7.5 g) bismuth subcitrate. Lab findings included: blood urea nitrogen (BUN) 71 mg/dL, serum creatinine 12.3 mg/dL, uric acid 8.5 mg/dL, serum glutamic-oxaloacetic transaminase (SGOT) 85 units/L and lactic dehydrogenase 2,371 units/L. Renal biopsy revealed signs of acute tubular necrosis in the proximal tubule epithelium. Hemodialysis was performed 6 times. The patient recovered and was discharged with normal BUN and creatinine levels (Sarikaya et al, 2002).
    b) CASE REPORT: A 16-year-old girl presented to the hospital with a 4- to 5-day history of nausea, vomiting, dizziness, and a 2-day history of oliguria. The patient had ingested 10 to 15 tablets of tripotassium dicitrato bismuthate (3 to 4.5 g) 1 week prior to presentation. Laboratory data, obtained at admission, revealed a BUN of 146 mg/dL and a serum creatinine of 17.9 mg/dL. A renal biopsy showed necrosis and prominent regeneration primarily in the proximal tubule epithelium and moderate cell infiltration in the interstitium, minimal edema, congestion, and narrowing of the Bowman's capsular space in the glomeruli, leading to a diagnosis of acute tubular necrosis. With supportive care, including hemodialysis, the patient gradually recovered (Akpolat et al, 1996).
    C) RENAL FAILURE SYNDROME
    1) WITH POISONING/EXPOSURE
    a) SUMMARY
    1) Renal failure has occurred in several cases following overdose ingestions of bismuth subcitrate, bismuth sodium triglycollamate and tripotassium dicitratobismuthate.
    b) CASE REPORTS
    1) Renal failure occurred in a 14-year-old who, over a few hours, ingested a small number of bismuth sodium triglycollamate tablets (James, 1968).
    2) A 76-year-old man developed renal failure after ingestion of 80 tablets of tripotassium dicitratobismuthate (Taylor & Klenerman, 1990).
    3) A 21-year-old man developed renal failure within 48 hours of ingestion of 39 tablets of bismuth subcitrate (Huwez et al, 1992).
    4) A 22-year-old woman developed renal failure and proximal tubular dysfunction (Fanconi's syndrome) after intentionally ingesting 5.4 grams of colloidal bismuth subcitrate. On presentation, the patient was oliguric (<500 mL/24 hours) progressing to anuria. Over the next 48 hours, laboratory data indicated serum creatinine and BUN levels of 7.8 mg/dL and 38.4 mg/dL, respectively, metabolic acidosis, hypophosphatemia, hypouricemia, microscopic hematuria, and proteinuria. Treatment included intravenous chelation therapy with unithiol (DMPS) and 9 hemodialysis sessions. The patient gradually recovered with diuresis occurring 10 days post-admission, and serum creatinine levels continuously decreasing from hospital day 18. The patient's renal function normalized with no signs of tubular dysfunction on follow-up 6 and 12 weeks post-intoxication (Hruz et al, 2002).
    5) A 16-year-old girl intentionally ingested 60 tablets (18 g) of colloidal bismuth subcitrate and, 6 hours later, presented to a hospital and underwent gastric lavage, received IV fluids, and was discharged 24 hours later. Following discharge, she continued to vomit 3 or 4 times daily at home and, 9 days later, she presented to another hospital with nausea, vomiting, and facial paresthesia. Laboratory data revealed a serum BUN of 102 mg/dL and serum creatinine of 19.9 mg/dL. Urinalysis indicated glucosuria, proteinuria, and microscopic hematuria. With hemodialysis and oral penicillamine therapy, the patient gradually recovered and was discharged 16 days later, with normalization of renal function reported approximately 7 weeks post-discharge (Cengiz et al, 2005).
    6) CHILD: A 2-year-old boy developed acute renal failure after ingesting 28 tablets (8.4 g) of colloidal bismuth subcitrate. Two days post-ingestion, the patient was somnolent and lethargic and had developed oliguria (urine output 140 mL/day). Laboratory data revealed a plasma BUN concentration of 36 mg/dL and a serum creatinine concentration of 1.5 mg/dL. Despite administration of IV fluids and furosemide, urine output continued to decrease to 50 mL/day and his BUN and creatinine concentrations increased to a peak of 75 mg/dL and 4 mg/dL, respectively, by day 4. Peritoneal dialysis was initiated and continued for a total of 16 days (automated peritoneal dialysis for 6 days and daytime ambulatory peritoneal dialysis for 10 days), resulting in a decrease in BUN and serum creatinine concentrations of 14 mg/dL and 0.7 mg/dL, respectively. The patient continued to improve clinically and was discharged approximately 20 days post-ingestion (Islek et al, 2001).
    D) ALBUMINURIA
    1) Albuminuria as well as mild hematuria has been reported (Wachstein, 1944).
    E) MELANOSIS
    1) WITH THERAPEUTIC USE
    a) Melanosis of the vagina due to formation of bismuth sulfide, has been reported. It is generally considered benign, but has been associated with bleeding and desquamation of vaginal tissues (Bradley et al, 1989).
    F) FANCONI SYNDROME
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 22-year-old woman developed renal failure and proximal tubular dysfunction (Fanconi's syndrome) after intentionally ingesting 5.4 grams of colloidal bismuth subcitrate. On presentation, the patient was oliguric (<500 mL/24 hours) progressing to anuria. Over the next 48 hours, laboratory data indicated serum creatinine and BUN levels of 7.8 mg/dL and 38.4 mg/dL, respectively. Prior to the development of anuria, proximal tubular dysfunction with tubular proteinuria was observed, with alpha1-microglobulin and retinol binding protein 22-fold (normal <1.58 mg/mmol of creatinine) and 120-fold (normal <0.11 mg/mmol of creatinine) greater than the norm, respectively, as well as hyperuricosuria, hyperphosphaturia, aminoaciduria, metabolic acidosis (due to bicarbonate loss), and glucosuria. Treatment included intravenous chelation therapy with unithiol (DMPS) and 9 hemodialysis sessions. The patient gradually recovered with diuresis occurring 10 days post-admission, and serum creatinine levels continuously decreasing from hospital day 18. The patient's renal function normalized with no signs of tubular dysfunction on follow-up 6 and 12 weeks post-intoxication (Hruz et al, 2002).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) METHEMOGLOBINEMIA
    1) If large amounts of bismuth subnitrate are ingested, intestinal bacteria MAY reduce the subnitrate to nitrate and cause nitrate poisoning and methemoglobinemia (Winship, 1983; Bradley et al, 1989).
    B) THROMBOCYTOPENIC DISORDER
    1) CASE REPORT: Thrombocytopenia was reported in a 72-year-old who used tripotassium dicitrobimuthate as needed. The platelet count was less than 10 x 10(9)/L. The thrombocytopenia was thought to be an idiosyncratic reaction due to bismuth absorption via multiple oral ulcers (Beckingham et al, 1989).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) CONTACT DERMATITIS
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Allergic contact dermatitis was seen in a patient due to bismuth subnitrate in addition to iodoform. Upon rechallenge with bismuth subnitrate alone, he redeveloped symptoms (Goh & Ng, 1987).
    B) ERUPTION
    1) WITH THERAPEUTIC USE
    a) When bismuth compounds were used for syphilis, erythema and rash was seen on the head, trunk, and extremities. This rash occurred after about 9 days of therapy (Bradley et al, 1989).
    C) SKIN FINDING
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Small, black particles (size range, 0.2 to 0.5 mm) were noted in the follicular orifices of a 42-year-old man who reported taking 2 bismuth subsalicylate tablets once or twice a month over the last 4 years after eating. Qualitative analysis was positive for bismuth. Biopsy showed a follicular orifice containing black particles and spores of P.ovale. The black granules disappeared a few months after the patient stopped taking bismuth (Ruiz-Maldonado et al, 1997).
    b) Other skin findings reported after intramuscular or oral administration of bismuth include: blue linear pigmentation of the soft palate, oral mucosa or vagina; ulcerative stomatitis; generalized cutaneous pigmentation simulating argyria; dermatitis; and erythroderma (Ruiz-Maldonado et al, 1997).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) OSTEOPOROSIS
    1) Osteoporosis and osteomalacia, usually, but not always, occurring in conjunction with encephalopathy, has been seen as a rare complication. Bismuth inclusion into the bones was observed in children treated with bismuth compounds for syphilis (Bradley et al, 1989). Gluteal injection granulomas have been seen on radiographs in elderly patients undergoing hip and pelvic x-rays. Bismuth injections were used around the time of World War I as a treatment for syphilis and appear as radiopaque deposits on x-ray (Tamai & Shaw, 2002).
    2) Bismuth is stored in bone, and levels of 1470 to 6770 mcg/kg were found in these patients ("normal" less than 10 mcg/kg).
    3) Other bone toxicity seen includes necrosis of the humeral head and osteolytic and deforming glenohumeral arthropathy (Winship, 1983; Gaucher et al, 1979).

Reproductive

    3.20.1) SUMMARY
    A) There are two reported cases of pregnant women with acute bismuth poisoning who had normal pregnancies and children.
    B) At the time of this review, few reproductive studies were available for bismuth. It is known to cross the placenta. It did not cause birth defects in chickens, but did apparently produce a stunted lamb with other birth defects when given to a pregnant ewe.
    C) Bismuth subnitrate was found to a toxic effect on rat Leydig cells.
    3.20.3) EFFECTS IN PREGNANCY
    A) PLACENTAL BARRIER
    1) Soluble bismuth salts rapidly diffuse through the fetal blood, insoluble salts accumulate in the placenta (Thompson et al, 1941)It is known to cross the placenta (Leonard & Love, 1928). Babies of mothers who have bismuth encephalopathy appear to be normal at birth (Winship, 1983). Use of bismuth subsalicylate is recommended to be restricted to the first half of pregnancy in amounts not exceeding recommended doses, due to significant fetal adverse effects reported after chronic exposure to salicylates (Briggs et al, 1998).
    B) PREGNANCY CATEGORY
    BISMUTH SUBSALICYLATEC
    Reference: Briggs et al, 1998
    C) LACK OF EFFECT
    1) There are two reported cases of pregnant women with acute bismuth poisoning who had normal pregnancies and children (Cambier, 1975; Hervet, 1975).
    D) ANIMAL STUDIES
    1) At the time of this review, few reproductive studies were available for bismuth. It did not cause birth defects in chickens (Ridgway & Karnofsky, 1952), but did apparently produce a stunted lamb with other birth defects when given to a pregnant ewe (James, 1966).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS7440-69-9 (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
    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, no studies were found on the possible carcinogenic activity of bismuth in humans.

Genotoxicity

    A) Bismuth trioxide was clastogenic in mice when given oral doses up to 1000 mg/kg per day for up to 21 days. Frequencies of chromosome aberrations in bone marrow cells were proportional to both dose and duration of exposure.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor liver enzymes and kidney function due to potential for hepatic and renal damage. Renal failure may not develop for several days after large ingestions.
    B) Monitor urine output and urinalysis after large overdose, as proteinuria, glycosuria, hematuria, and oliguria may develop in patients with renal injury.
    C) Blood or urine bismuth concentrations are not routinely available from most clinical laboratories and they are not clinically useful in the acute setting.
    D) Blood bismuth concentrations less than 5 mcg/dL are seldom associated with symptoms. Normal background levels are approximately 1 to 5 mcg/dL.
    4.1.2) SERUM/BLOOD
    A) TOXICITY
    1) Levels under 5 mcg/dL are seldom toxic, but there are exceptions.
    2) "Normal", background levels are approximately 1 to 5 mcg/dL (Winship, 1983; Haskings & Duggan, 1982).
    3) Blood bismuth measurements do not correlate well with symptoms of toxicity in individual persons. Bismuth is sequestered in tissues and has a large volume of distribution, which may result in accumulation during prolonged therapy or exposure (Friedland et al, 1993).
    B) BLOOD/SERUM CHEMISTRY
    1) Monitor liver enzymes and kidney function due to potential for hepatic and renal damage. Renal function may not develop for several days after large ingestions (Islek et al, 2001; Cengiz et al, 2005).
    4.1.3) URINE
    A) URINARY LEVELS
    1) Twenty-four-hour urine bismuth concentrations may be measured. A reported case noted a 24-hour bismuth urine concentration of 889 mcg/Liter in a patient taking oral bismuth for one year and exhibiting signs of bismuth encephalopathy (Friedland et al, 1993).

Methods

    A) SPECTROSCOPY/SPECTROMETRY
    1) Both flame and flameless atomic absorption spectrophotometry may be used, the latter being preferable. Quantities found in biological specimens are in mcg/dL (Winship, 1983).
    B) OTHER
    1) Another method used for biological samples in anodic stripping voltammetry. The current method of choice for quantification of bismuth in blood, serum or urine is either electrothermal atomic absorption spectrophotometry (AAS) or AAS with hydride generation (Slikkerveer & de Wolff, 1989).

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) Those with persistent vomiting or evidence of systemic toxicity should be admitted for observation and supportive care.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Small, single ingestions of bismuth are unlikely to cause systemic toxicity. Asymptomatic patients may be observed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a medical toxicologist or your local poison control center for any patient who develops systemic toxicity from bismuth.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with large, acute overdoses and those with self-harm attempts should be evaluated in a healthcare facility. Patients with symptoms of chronic intoxication should be referred to a healthcare facility.

Monitoring

    A) Monitor liver enzymes and kidney function due to potential for hepatic and renal damage. Renal failure may not develop for several days after large ingestions.
    B) Monitor urine output and urinalysis after large overdose, as proteinuria, glycosuria, hematuria, and oliguria may develop in patients with renal injury.
    C) Blood or urine bismuth concentrations are not routinely available from most clinical laboratories and they are not clinically useful in the acute setting.
    D) Blood bismuth concentrations less than 5 mcg/dL are seldom associated with symptoms. Normal background levels are approximately 1 to 5 mcg/dL.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) PREHOSPITAL: No pre-hospital decontamination is needed.
    6.5.2) PREVENTION OF ABSORPTION
    A) Gastrointestinal decontamination is generally not needed.
    6.5.3) TREATMENT
    A) SUPPORT
    1) Recovery from bismuth encephalopathy and nephropathy is a slow process. Good supportive care is necessary for these patients. There is no evidence that diuresis or hemodialysis is effective, although hemodialysis may be necessary for those in renal failure. Seizures are a rare complication.
    B) MONITORING OF PATIENT
    1) Monitor liver enzymes and kidney function due to potential for hepatic and renal damage.
    2) Monitor urine output and urinalysis after large overdose.
    3) Blood or urine bismuth concentrations are not routinely available from most clinical laboratories and they are not clinically useful in the acute setting.
    4) Blood bismuth concentrations less than 5 mcg/dL are seldom associated with symptoms. Normal background levels are approximately 1 to 5 mcg/dL.
    C) CHELATION THERAPY
    1) Human case reports suggest that recovery from bismuth toxicity usually varies from 2 to 10 weeks following cessation of bismuth intake. Case reports suggest that chelation with unithiol combined with hemodialysis may increase bismuth elimination; however, the efficacy of chelator treatment in humans has not been carefully studied or clearly demonstrated and is not routinely recommended.
    2) Basinger et al (1983) tested 9 different chelators in an animal model for bismuth poisoning (Basinger et al, 1983). The most effective available agents were succimer , unithiol (DMPS), and D-penicillamine. However, in the United States, unithiol is not currently approved for clinical use by the FDA (it may be obtained from some compounding pharmacies). In Europe, IV unithiol has been used to treat bismuth toxicity with reported success (Hruz et al, 2002; Baudisch et al, 1995). D-penicillamine has been used in human bismuth overdoses (Mendelowitz et al, 1990).
    D) SUCCIMER
    1) SUMMARY
    a) Efficacy of succimer treatment in humans has not been carefully studied or clearly demonstrated and is not routinely recommended.
    2) SUCCIMER/DOSE/ADMINISTRATION
    a) PEDIATRIC: Initial dose is 10 mg/kg or 350 mg/m(2) orally every 8 hours for 5 days (Prod Info CHEMET(R) oral capsules, 2011).
    1) The dosing interval is then increased to every 12 hours for the next 14 days. A repeat course may be given if indicated by elevated blood levels. A minimum of 2 weeks between courses is recommended, unless blood lead concentrations indicate the need for prompt retreatment.
    2) Succimer capsule contents may be administered mixed in a small amount of food (Prod Info CHEMET(R) oral capsules, 2011).
    b) ADULT: Succimer is not FDA approved for use in adults, however it has been shown to be safe and effective when used to treat adults with poisoning from a variety of heavy metals (Fournier et al, 1988). Initial dose is 10 mg/kg or 350 mg/m(2) orally every 8 hours for 5 days (Prod Info CHEMET(R) oral capsules, 2011).
    1) The dosing interval then is increased to every 12 hours for the next 14 days. A repeat course may be given if indicated by elevated blood levels. A minimum of 2 weeks between courses is recommended, unless the patient's symptoms or blood concentrations indicate a need for more prompt treatment (Prod Info CHEMET(R) oral capsules, 2011).
    3) MONITORING PARAMETERS
    a) The manufacturer recommends monitoring liver enzymes and complete blood count with differential and platelet count prior to the start of therapy and at least weekly during therapy (Prod Info CHEMET(R) oral capsules, 2011).
    b) Succimer therapy did not worsen preexisting borderline abnormal liver enzyme levels in a prospective evaluation of 15 children with lead poisoning (Kuntzelman & Angle, 1992).
    4) SUCCIMER/ADVERSE EFFECTS: The following adverse events have occurred in children and adults during clinical trials: nausea, vomiting and diarrhea; transient liver enzyme elevations; rash, pruritus; drowsiness and paresthesia. Events reported infrequently include: sore throat, rhinorrhea, mucosal vesicular eruption, thrombocytosis, eosinophilia, and mild to moderate neutropenia (Prod Info CHEMET(R) oral capsules, 2011).
    5) ODOR: Succimer has a sulfurous odor that may be evident in the patient's breath or urine (Prod Info CHEMET(R) oral capsules, 2005).
    6) HYPERTHERMIA: One adult developed acute severe hyperthermia associated with hypotension; rechallenge resulted in hyperthermia with shaking chills and hypertension (Marcus et al, 1991a).
    7) AVAILABLE FORMS: Succimer (Chemet (R)), 100 mg capsules (Prod Info CHEMET(R) oral capsules, 2011).
    8) In a retrospective review of 41 children and 22 adults, most side effects of succimer were benign. One adult developed acute severe hyperthermia associated with hypotension. On rechallenge, he developed hyperthermia with shaking chills and hypertension (Marcus et al, 1991). Hemolytic anemia was reported in a man with G6PD deficiency during treatment with succimer (Gerr et al, 1994).
    E) PENICILLAMINE
    1) SUMMARY
    a) Efficacy of penicillamine treatment in humans has not been carefully studied or clearly demonstrated and is not routinely recommended.
    2) PRECAUTIONS
    a) Patients allergic to penicillin products may have cross-sensitivity to penicillamine (Prod Info DEPEN(R) titratable oral tablets, 2009).
    b) Monitor for proteinuria and hematuria; heavy metals may also cause renal toxicity (Prod Info DEPEN(R) titratable oral tablets, 2009).
    c) Monitor CBC with differential, platelet count, and hepatic enzymes (Prod Info DEPEN(R) titratable oral tablets, 2009).
    3) DOSE
    a) USUAL ADULT DOSE
    1) 1 to 1.5 g/day given orally in 4 divided doses (Nelson, 2011).
    b) USUAL PEDIATRIC DOSE
    1) 15 to 30 mg/kg/day in 3 to 4 divided doses. Initially, a small dose may be given to minimize side effects and then increased gradually (eg, 25% of the desired dose in week 1, 50% in week 2, and the full dose by week 3) (Caravati, 2004; Prod Info DEPEN(R) titratable oral tablets, 2009).
    4) PREGNANCY
    a) Penicillamine is considered FDA pregnancy category D(Prod Info CUPRIMINE(R) oral capsules, 2004); it should be avoided if possible in pregnant patients.
    b) Use of penicillamine throughout pregnancy has been associated with connective tissue abnormalities, hydrocephalus, cerebral palsy, cardiac and great vessel anomalies, webbing of fingers and toes, and arthrogryposis multipex (Linares et al, 1979; Solomon et al, 1977; Anon, 1981; Beck et al, 1981; Rosa, 1986). However, the teratogenic effect when used in low doses or for short periods of time, as in metal chelation, has yet to be determined.
    5) A 16-year-old girl intentionally ingested 60 tablets (18 g) of colloidal bismuth subcitrate and, 6 hours later, presented to a hospital and underwent gastric lavage, received IV fluids, and was discharged 24 hours later. Following discharge, she continued to vomit 3 or 4 times daily at home and, 9 days later, she presented to another hospital with nausea, vomiting, and facial paresthesia. Laboratory data revealed a serum BUN of 102 mg/dL and serum creatinine of 19.9 mg/dL. Urinalysis indicated glucosuria, proteinuria, and microscopic hematuria. With hemodialysis and oral penicillamine therapy (20 mg/kg/day), the patient gradually recovered and was discharged 16 days later, with normalization of renal function reported approximately 7 weeks post-discharge (Cengiz et al, 2005).
    F) DIMERCAPROL
    1) SUMMARY
    a) Efficacy of dimercaprol treatment in humans has not been carefully studied or clearly demonstrated and is not routinely recommended.
    2) DOSE
    a) 3 milligrams/kilogram may be tried within 8 to 12 hours of a bismuth poisoning.
    3) EFFICACY
    a) Later administration may be ineffective due to rapid absorption (Czerwinski & Ginn, 1964).
    b) One study showed BAL to be ineffective in humans (Goule et al, 1975). After 48 hours of 720 mg/day, no increase in elimination was seen in one patient.
    c) Liessens et al (1978) saw a slight increase in excretion when BAL, 800 mcg/day was given (Liessens et al, 1978).
    d) Another patient given BAL for 8 days had a 60-fold increase in excretion (Nogue et al, 1985).
    G) UNITHIOL
    1) SUMMARY
    a) Efficacy of unithiol treatment in humans has not been carefully studied or clearly demonstrated and is not routinely recommended.
    2) AVAILABILITY
    a) Unithiol is available outside the US from Heyl Chem-pharm Fabrik (Germany). It is not approved for human use by the US FDA, but may be obtained from some compounding pharmacies. Unithiol is available as ampoules containing 250 mg unithiol in 5 mL for injection (Prod Info DIMAVAL(R) IV, IM injection, 2004), and as 100 mg hard capsules available in packages of 3, 9 and 20 capsules (Prod Info DIMAVAL(R) oral capsules, 2004).
    3) DOSE
    1) FIRST DAY: 250 mg (one ampule) by intravenous infusion every 3 to 4 hours.
    2) SECOND DAY: 250 mg (one ampule) by intravenous infusion every 4 to 6 hours.
    3) THIRD DAY: 250 mg (one ampule) by intravenous infusion every 6 to 8 hours.
    4) FOURTH DAY: 250 mg (one ampule) by intravenous infusion every 8 to 12 hours.
    5) SUBSEQUENT DAYS: Depending on the patient's clinical condition, administer 250 mg (one ampule) by intravenous infusion one to three times daily.
    a) INTRAVENOUS: The dosing regimen depends on the severity of poisoning. For adults with acute heavy metal poisoning the following dosing is recommended (Prod Info DIMAVAL(R) IV, IM injection, 2004).
    4) EFFICACY
    a) Unithiol has been used to treat patients with acute bismuth intoxication; it induces a small increase in renal elimination, but allows removal of bismuth by hemodialysis (Hruz et al, 2002).
    b) In a patient with bismuth intoxication, unithiol increased urinary bismuth clearance (from a baseline of 2.2 L/min to 8.2 to 9.7 mL/min) and increased the amount of bismuth removed by hemodialysis (from none without unithiol to 10 to 52 mL/min with unithiol) (Stevens et al, 1995).
    c) CASE REPORT: A 67-year-old man with a sacral chondroma developed neurological features of bismuth toxicity (blood and urine bismuth concentrations, 340 mcg/L and 2800 mcg/L, respectively) 5 days after bismuth iodoform paraffin paste (BIPP) packing was used postoperatively for his surgical wound breakdown. Following the removal of BIPP packing and 51 days of unithiol chelation therapy (27 days of IV unithiol, 5 mg/kg 4 times daily for 5 days, 5 mg/kg three times daily for 5 days followed by 5 mg/kg twice a day for 17 days) followed by 24 days of oral unithiol (200 mg three times a day for 10 days, followed 200 mg twice daily for 14 days), his blood bismuth concentration declined to 5 mcg/L and his condition gradually improved. At the start of intravenous unithiol, urinary bismuth concentration increased to 540 mcg/L from a baseline of 340 mcg/L (Ovaska et al, 2008).
    d) CASE REPORT: A 22-year-old woman developed acute renal failure and proximal tubular dysfunction (Fanconi's syndrome) after intentionally ingesting 5.4 grams of colloidal bismuth subcitrate. On presentation, the patient was oliguric (<500 mL/24 hours) progressing to anuria. Over the next 48 hours, her serum creatinine level increased from 0.73 mg/dL to 7.8 mg/dL and her BUN level increased from 10.9 mg/dL to 38.4 mg/dL. Sixty hours post-ingestion, chelation therapy with intravenous unithiol (DMPS) was initiated at a dosage regimen of 250 milligrams every 4 hours for 48 hours, followed by 250 milligrams every 6 hours for 48 hours, then 250 milligrams every 12 hours for another 4 days (total amount of unithiol administered 7 grams). Hemodialysis was also started after administration of the first dose of unithiol, and continued over the next 12 days (approximately 14 days post-ingestion). Within 6 days following initiation of therapy with unithiol and hemodialysis, the patient's serum bismuth concentration decreased from 640 mcg/L to 15 mcg/L. The patient gradually recovered with diuresis occurring 10 days post-admission, and serum creatinine levels continuously decreasing from hospital day 18. The patient's renal function normalized with no signs of tubular dysfunction on follow-up 6 and 12 weeks post-intoxication (Hruz et al, 2002).
    H) FLUID/ELECTROLYTE BALANCE REGULATION
    1) Diuresis may occur, therefore, fluid and electrolyte monitoring may be necessary (Karelitz & Freedman, 1951).
    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, 2009; 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).
    J) GENERAL TREATMENT
    1) AMMONIUM CHLORIDE
    a) Mobilization and excretion of bismuth may be enhanced by ammonium chloride (Czerwinski & Ginn, 1964; Goodman & Gilman, 1965).
    2) INTESTINAL LAVAGE
    a) Intestinal lavage to remove retained bismuth has NOT been shown to be of value (Buge et al, 1974).

Enhanced Elimination

    A) DIURESIS
    1) Forced diuresis has NOT been shown to be of value (Buge et al, 1974).
    B) HEMODIALYSIS
    1) Hemodialysis does not increase bismuth elimination, but is used to treat acute renal failure after overdose. The combination of unithiol and hemodialysis may increase bismuth elimination but is not routinely recommended.
    2) Hemodialysis was performed on a 17-year-old girl 7 days after ingesting 25 tablets containing 300 mg bismuth subcitrate (total 7.5 g). She initially presented to the emergency department with anuria and elevated blood urea nitrogen (BUN) and creatinine. Renal biopsy found acute tubular necrosis. After 6 hemodialysis sessions, the patient was discharged home with normal BUN and creatinine levels. The authors concluded that hemodialysis may be necessary in acute renal failure, but has little effect on the rate of elimination from the intracellular compartment in which bismuth has a long half-life (Sarikaya et al, 2002).
    3) A 22-year-old woman developed acute renal failure and proximal tubular dysfunction (Fanconi's syndrome) after intentionally ingesting 5.4 grams of colloidal bismuth subcitrate. On presentation, the patient was oliguric (<500 mL/24 hours) progressing to anuria. Over the next 48 hours, her serum creatinine level increased from 0.73 mg/dL to 7.8 mg/dL and her BUN level increased from 10.9 mg/dL to 38.4 mg/dL. Treatment was initiated with intravenous unithiol as chelation therapy and hemodialysis. A total of 9 hemodialysis sessions were performed over a 12-day period. Within 6 days after initiation of therapy, her serum bismuth concentration decreased from 640 mcg/L to 15 mcg/L. The patient gradually recovered with diuresis occurring 10 days post-admission, and serum creatinine levels continuously decreasing from hospital day 18. The patient's renal function normalized with no signs of tubular dysfunction on follow-up 6 and 12 weeks post-intoxication (Hruz et al, 2002).
    C) PERITONEAL DIALYSIS
    1) CHILD: A 2-year-old boy developed acute renal failure after ingesting 28 tablets (8.4 g) of colloidal bismuth subcitrate. Two days post-ingestion, the patient was somnolent and lethargic and had developed oliguria (urine output 140 mL/day). Laboratory data revealed a plasma BUN concentration of 36 mg/dL and a serum creatinine concentration of 1.5 mg/dL. Despite administration of IV fluids and furosemide, urine output continued to decrease to 50 mL/day and his BUN and creatinine concentrations increased to a peak of 75 mg/dL and 4 mg/dL, respectively, by day 4. Peritoneal dialysis was initiated and continued for a total of 16 days (automated peritoneal dialysis (APD) for 6 days and daytime ambulatory peritoneal dialysis (DAPD) for 10 days), resulting in a decrease in BUN and serum creatinine concentrations of 14 mg/dL and 0.7 mg/dL, respectively. The patient continued to improve clinically and was discharged approximately 20 days post-ingestion (Islek et al, 2001).
    a) Bismuth concentrations on hospital day 10 (day 1 of DAPD) were 739 mcg/L, 693 mcg/L, and 498 mcg/L in the blood, urine, and nighttime dialysate, respectively. On hospital day 15 (day 5 of DAPD), the bismuth concentrations were 614 mcg/L, 554 mcg/L, and 372 mcg/L in the blood, urine, and dialysate, respectively. indicating that bismuth removal using peritoneal dialysis is a slow process (Islek et al, 2001)

Abstracts

Case Reports

    A) ADULT
    1) A 27-year-old man developed anorexia, nausea, vomiting, general malaise, weakness of his legs, blurring of vision, thirst, and poor urinary output 10 days after ingesting 100 De-Nol tablets containing 120 mg bismuth subcitrate per tablet. Blood bismuth was 260 micrograms/liter on the eleventh day after ingestion. Hemodialysis was performed daily on days 12 through 16 for renal failure. Bismuth blood concentrations decreased slightly after hemodialysis. Renal function and neurologic signs resolved after the fifth day of dialysis. At 96 days postingestion blood bismuth concentration was still detectable at 8 micrograms/liter (Hudson & Mowat, 1989).
    2) A 54-year-old man presented with a 6 week history of progressive confusion and memory difficulty and a 2 to 3 week history of involuntary movements and gait impairment. His encephalopathy was further characterized by marked multifocal myoclonic jerks, coarse postural tremors, and postural instability. The patient gradually improved. Spinal tap and brain MRI scan were normal. Extensive toxic, metabolic, and infectious workup demonstrated bismuth toxicity. As the patient's encephalopathy cleared, he reported chronic bismuth subsalicylate use (between 1,040 to 4,160 mg/day). Bismuth levels 5 weeks after cessation were 3.6 micrograms/dL (typical level up to 2 micrograms/dL) in serum and 42 micrograms/L (typical level up to 20 micrograms/L) in urine (Gordon et al, 1995).
    3) A 72-year-old woman developed extrapyramidal symptoms after four weeks of consuming bismuth salts. The patient was initially considered permanently disabled by brain stem infarction. Blood bismuth was 380 micrograms/L (normal level less than 1 micrograms/L, bismuth treated patients less than 10 micrograms/L). The patient was treated with IV unithiol (DMPS) which resulted in reversal of neurologic symptoms and a striking improvement of her mental status within 24 hours (Baudisch et al, 1995).

Range Of Toxicity

Summary

    A) TOXICITY: Blood levels less than 5 mcg/dL are rarely associated with symptoms. ADULT: In 6 patients who ingested 227 g/day for 3 weeks, there were no detectable blood levels 24 hours after cessation of therapy and no symptoms. An adult developed acute renal failure, Fanconi's syndrome, and oral ulcerations after ingesting 5.4 g colloidal bismuth subcitrate. PEDIATRIC: Acute toxic symptoms have occurred with as little as 5.2 mg IM over 26 hours in a 21-month-old to 30 g over 8 days in a 7.5-year-old. A 17-year-old developed acute renal failure but recovered after ingesting 7.5 g bismuth subcitrate.
    B) THERAPEUTIC DOSE: BISMUTH SUBSALICYLATE: 12 yrs and older: 524 mg orally every 0.5 to 1 hour, up to a maximum of 8 doses/day (4192 mg/day).

Therapeutic Dose

    7.2.1) ADULT
    A) BISMUTH SUBSALICYLATE
    1) DIARRHEA, NAUSEA, DYSPEPSIA, HEARTBURN: 524 mg orally every 0.5 to 1 hour, up to a maximum of 8 doses/day (4192 mg/day) (OTC Product Information, as posted to the DailyMed site 8/2013; Prod Info Peptic Relief Liquid oral suspension, 2012; OTC Product Information, as posted to the DailyMed site 07/2012).
    B) BISMUTH SUBSALICYLATE METRONIDAZOLE TETRACYCLINE HYDROCHLORIDE
    1) HELIOBACTOR PYLORI INFECTION AND DUODENAL ULCER DISEASE: 524.8 mg orally 4 times a day, in combination with metronidazole 250 mg orally 4 times a day and tetracycline hydrochloride 500 mg orally 4 times a day (Prod Info HELIDAC(R) Therapy oral chewable tablets, tablets, capsule, 2012), plus an H2 antagonist or standard-dose proton pump inhibitor for 10 to 14 days (Chey et al, 2007).
    7.2.2) PEDIATRIC
    A) BISMUTH SUBSALICYLATE
    1) DIARRHEA, NAUSEA, DYSPEPSIA, HEARTBURN, AGED 12 YEARS AND OLDER: 524 mg orally every 0.5 to 1 hour, up to a maximum of 8 doses/day (4192 mg/day) (OTC Product Information, as posted to the DailyMed site 8/2013; Prod Info Peptic Relief Liquid oral suspension, 2012; OTC Product Information, as posted to the DailyMed site 07/2012).
    2) DIARRHEA, NAUSEA, DYSPEPSIA, UP TO 12 YEARS OF AGE: Safety and efficacy have not been established (OTC Product Information, as posted to the DailyMed site 8/2013; Prod Info Peptic Relief Liquid oral suspension, 2012; OTC Product Information, as posted to the DailyMed site 07/2012).
    B) BISMUTH SUBSALICYLATE METRONIDAZOLE TETRACYCLINE HYDROCHLORIDE
    1) HELIOBACTOR PYLORI INFECTION AND DUODENAL ULCER DISEASE: Safety and efficacy have not been established (Prod Info HELIDAC(R) Therapy oral chewable tablets, tablets, capsule, 2012).

Maximum Tolerated Exposure

    A) GENERAL/SUMMARY
    1) Toxicity of the various bismuth salts is somewhat determined by the solubility, and may be divided into 4 main types (Serfontein & Mekel, 1979).
    2) TYPE A: Composed of inorganic salts and subsalts which are water insoluble and have minor absorption and produce almost no bismuth toxicity. Examples: bismuth subcarbonate, bismuth subnitrate, and bismuth subsalicylate.
    3) TYPE B: Composed of lipid-soluble salts and complexes which are absorbed and may result in significant blood levels and potential neurotoxicity and hepatotoxicity. Example: bismuth subgallate.
    4) TYPE C: Composed of water soluble compounds and complexes which stay stable long enough for absorption and result in blood levels. Renal damage is a primary human toxicity from these compounds. Example: bismuth triglycollamate.
    5) TYPE D: Decompose to unstable bismuth compounds or complexes which hydrolyze into the gastrointestinal tract to produce simple, poorly soluble or insoluble compounds such as bismuth subchloride or sulfide. Because of poor solubility, there is minimal absorption and minimal toxicity. Example - bicitropeptide.
    B) SPECIFIC SUBSTANCE
    1) BISMUTH SUBSALICYLATE
    a) One study of 6 patients who ingested 227 grams/day for 3 weeks showed no detectable blood levels 24 hours after cessation of therapy and no symptoms (Ericsson et al, 1980). Plasma levels of salicylate approximating those following an analgesic dose were found in 6 volunteers given a dose of an OTC product containing bismuth subsalicylate (Anon, 1980; Pickering et al, 1981).
    b) A 45-year-old man with AIDS was found lethargic and dysarthric, with myoclonic jerks of his facial and axial muscles on the seventh day after beginning acyclovir and bismuth subsalicylate 5.2 to 9.4 grams daily in divided doses for treatment of severe diarrhea.
    1) Over the next 2 days his mental status progressed to coma. He had a salicylate concentration of 2 milligrams/deciliter and bismuth concentrations in blood of 200 micrograms/liter and in urine of 2960 micrograms/liter.
    2) No other causes could be found for his mental status change (Hoffman et al, 1989).
    2) BISMUTH SUBCITRATE
    a) CASE REPORT: A 17-year-old girl presented to the emergency department with nausea, vomiting and anuria, 7 days after intentionally ingesting 25 tablets of 300 mg (7.5 g) bismuth subcitrate. Lab findings included: blood urea nitrogen (BUN) 71 mg/dL, serum creatinine 12.3 mg/dL, uric acid 8.5 mg/dL, serum glutamic-oxaloacetic transaminase (SGOT) 85 U/L and lactic dehydrogenase 2,371 U/L. Renal biopsy revealed signs of acute tubular necrosis in the proximal tubule epithelium. Hemodialysis was performed 6 times. The patient recovered and was discharged with normal BUN and creatinine levels (Sarikaya et al, 2002).
    b) CASE REPORT: A 22-year-old woman developed renal failure and proximal tubular dysfunction (Fanconi's syndrome) after intentionally ingesting 5.4 grams of colloidal bismuth subcitrate. On presentation, the patient was oliguric (<500 mL/24 hours) progressing to anuria. Over the next 48 hours, laboratory data indicated serum creatinine and BUN levels of 7.8 mg/dL and 38.4 mg/dL, respectively. Treatment included intravenous chelation therapy with unithiol and 9 hemodialysis sessions. The patient gradually recovered with diuresis occurring 10 days post-admission, and serum creatinine levels continuously decreasing from hospital day 18. The patient's renal function normalized with no signs of tubular dysfunction on follow-up 6 and 12 weeks post-intoxication (Hruz et al, 2002).
    c) CASE REPORT/CHILD: A 2-year-old boy developed acute renal failure after ingesting 28 tablets (8.4 g) of colloidal bismuth subcitrate. Two days post-ingestion, the patient was somnolent and lethargic and had developed oliguria (urine output 140 mL/day). Laboratory data revealed a plasma BUN concentration of 36 mg/dL and a serum creatinine concentration of 1.5 mg/dL. Despite administration of IV fluids and furosemide, urine output continued to decrease to 50 mL/day and his BUN and creatinine concentrations increased to a peak of 75 mg/dL and 4 mg/dL, respectively, by day 4. Peritoneal dialysis was initiated and continued for a total of 16 days (automated peritoneal dialysis for 6 days and daytime ambulatory peritoneal dialysis for 10 days), resulting in a decrease in BUN and serum creatinine concentrations of 14 mg/dL and 0.7 mg/dL, respectively. The patient continued to improve clinically and was discharged approximately 20 days post-ingestion (Islek et al, 2001).
    d) Acute toxic symptoms have occurred with as little as 5.2 milligrams intramuscularly over 26 hours in a 21-month-old to 30 grams over 8 days in a 7.5-year-old. A summary of the onset of symptoms in a number of subacute cases ranged from 4 hours to 7 weeks (Gryboski & Gotoff, 1961).
    3) TRIPOTASSIUM DICITRATO BISMUTHATE
    a) CASE REPORT: A 16-year-old girl presented to the hospital with a 4- to 5-day history of nausea, vomiting, dizziness, and a 2-day history of oliguria. The patient had ingested 10 to 15 tablets of tripotassium dicitrato bismuthate (3 to 4.5 g) 1 week prior to presentation. Laboratory data, obtained at admission, revealed a BUN of 146 mg/dL and a serum creatinine of 17.9 mg/dL. A renal biopsy showed necrosis and prominent regeneration primarily in the proximal tubule epithelium and moderate cell infiltration in the interstitium, minimal edema, congestion, and narrowing of the Bowman's capsular space in the glomeruli, leading to a diagnosis of acute tubular necrosis. With supportive care, including hemodialysis, the patient gradually recovered (Akpolat et al, 1996).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) GENERAL/SUMMARY
    a) "Normal" background levels are generally less than 20 micrograms/deciliter. The manufacturer states that the average bismuth level after taking 480 mg of Bi(2)0(3) per day for 4 weeks in 500 patients, was 7 micrograms (34 nanomoles)/Liter (Eskens, 1988).
    b) Blood levels less than 5 micrograms/deciliter are rarely associated with toxicity (Serfontein & Mekel, 1979).
    2) SPECIFIC SUBSTANCE
    a) BISMUTH IODOFORM
    1) CASE REPORT: A 67-year-old man with a sacral chondroma developed neurological features of bismuth toxicity (blood and urine bismuth concentrations, 340 mcg/L and 2800 mcg/L, respectively) 5 days after bismuth iodoform paraffin paste (BIPP) packing was used postoperatively for his surgical wound breakdown. Following the removal of BIPP packing and 51 days of DMPS chelation therapy, his blood bismuth concentration declined to 5 mcg/L and his condition gradually improved (Ovaska et al, 2008).
    b) BISMUTH SUBCITRATE
    1) CASE REPORT: A 27-year-old man developed renal and neurotoxicity 10 days after ingesting 12 grams of bismuth subcitrate. Blood bismuth concentrations were 260 micrograms/liter 11 days after ingestion and 8 micrograms/liter 96 days after ingestion (Hudson & Mowat, 1989).
    2) CASE REPORT: A 22-year-old woman developed acute renal failure and proximal tubular dysfunction after intentionally ingesting 5.4 grams of colloidal bismuth subcitrate. Serum bismuth concentration, obtained approximately 3 days post-ingestion, was 640 mcg/L (Hruz et al, 2002).
    c) BISMUTH SUBGALLATE
    1) CASE REPORT: A 74-year-old man developed bismuth encephalopathy after ingesting bismuth subgallate tablets (120 mg/day) for over one year. On presentation to the hospital he had a reported 24-hour urine bismuth level of 889 mcg/liter and a whole blood bismuth concentration of 67 mcg/liter (Friedland et al, 1993).
    d) BISMUTH SUBNITRATE
    1) Patients who had been ingesting 5 to 20 grams of bismuth subnitrate over time periods ranging from 4 months to 3 years developed blood levels of 15 to 220 micrograms/deciliter, urinary levels of 20 to 96 micrograms/deciliter, and CSF levels of 1 to 10 micrograms/deciliter (Buge et al, 1981).
    2) In France, bismuth intoxications in the form of encephalopathies reached epidemic proportions between 1973 and 1980. The salt involved was mostly bismuth subnitrate.
    a) An epidemiological study found that these intoxications were uniformly associated with prolonged treatment and high doses, sometimes exceeding 20 grams daily.
    b) Bismuth levels ranged from 10 to 200 micrograms/deciliter, and it was clear that the risk of toxicity is greater as the duration of treatment increases (Bader, 1987).
    3) BISMUTH SUBSALICYLATE
    a) CASE REPORT: A 45-year-old patient with AIDS and cytomegalovirus colitis ingesting 5.2 to 9.4 grams bismuth subsalicylate orally per day for 7 days developed blood bismuth concentration of 957 nanomoles/liter and urine bismuth concentration of 14,164 nanomoles/liter and clinical effects consistent with bismuth encephalopathy (Mendelowitz et al, 1990).
    3) POTENTIALLY NEUROTOXIC SALTS
    a) Bismuth subnitrate
    b) Bismuth subgallate
    4) POTENTIALLY NEPHROTOXIC COMPOUNDS
    a) Triglycollamate
    b) Bisodium Thioglycollamate
    c) Thioglycollamate

Workplace Standards

    A) ACGIH TLV Values for CAS7440-69-9 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) NIOSH REL and IDLH Values for CAS7440-69-9 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    C) Carcinogenicity Ratings for CAS7440-69-9 :
    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 CAS7440-69-9 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Colloidal bismuth subcitrate (CBS) preferentially coats the crater of gastric ulcers in mice, compared with normal adjacent mucosa. It has been shown to increase the ability of rat gastric mucosa to produce prostaglandin E2 in a dose-dependent manner. It has also been shown to protect against aspirin-induced lesions in man.
    B) Bismuth inhibits the growth of Campylobacter pylori in vitro; this organism has been implicated in several types of gastric disease (Hall, 1989).

Toxicologic Mechanism

    A) The mechanism of action of bismuth encephalopathy is still unclear. One idea is that bismuth binds with the thiol containing enzymes reducing cerebral oxidation and metabolism (Kruger et al, 1976).
    B) After bismuth subsalicylate is ingested, it mixes with gastric hydrochloric acid resulting in bismuth oxychloride and salicylic acid. Bismuth oxychloride passes to the gut and through the action of bicarbonate ions, is transformed into bismuth subcarbonate. Anaerobic bacteria in the colon transform all bismuth derived into black bismuth sulfite (Ruiz-Maldonado et al, 1997).

Physicochemical

Physical Characteristics

    A) Bismuth is grayish-white with reddish tinge and bright metallic luster; soft, brittle, frequently iridescent.

Molecular Weight

    A) 208.98 (Slikkerveer & de Wolff, 1989)

References

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