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    UKPID MONOGRAPH




    BISMUTH




    SM Bradberry BSc MB MRCP
    ST Beer BSc
    JA Vale MD FRCP FRCPE FRCPG FFOM

    National Poisons Information Service
    (Birmingham Centre),
    West Midlands Poisons Unit,
    City Hospital NHS Trust,
    Dudley Road,
    Birmingham
    B18 7QH


    This monograph has been produced by staff of a National Poisons
    Information Service Centre in the United Kingdom.  The work was
    commissioned and funded by the UK Departments of Health, and was
    designed as a source of detailed information for use by poisons
    information centres.

    Peer review group: Directors of the UK National Poisons Information
    Service.


    BISMUTH

    Toxbase summary

    Type of product

    Used in alloys as components of thermoelectric safety appliances.
    Bismuth subnitrate and carbonate are used in surgical dressings and
    bismuth chelate (tripotassium dicitratobismuthate) is used in the
    treatment of gastric and duodenal ulcers.

    Toxicity

    Bismuth toxicity is associated primarily with exposure to bismuth
    salts, notably the ingestion of bismuth chelate. Occupational bismuth
    exposure is rare.

    Features

    Topical

         -    Bismuth salts may cause contact sensitivity.
         -    The use of bismuth iodoform paraffin packs in surgical
              dressings and the use of bismuth-containing skin creams have
              led to bismuth encephalopathy (see below).

    Ingestion

    Minor ingestions:

         -    Nausea, epigastric discomfort only.

    Moderate/substantial ingestions:
         -    Nausea, vomiting and abdominal pain usually occur within
              hours and precede features of nephrotoxicity and
              neurotoxicity. These may be delayed for several days and
              include renal glomerular and tubular failure, muscle cramps
              and weakness, blurred vision and hyperreflexia. Liver
              transaminase activities may be increased transiently.
              Bismuth encephalopathy is more typical of chronic bismuth
              poisoning (see below).
         -    Chronic excess ingestion of bismuth chelate (either the
              daily ingestion of more than the recommended dose or
              exceeding the advised duration of therapy) may lead to
              bismuth encephalopathy with insidious onset of
              incoordination, behavioural changes, memory deterioration
              and psychiatric symptoms progressing to fulminant
              encephalopathy with myoclonic jerks, confusion, dysarthria
              and in severe cases coma and convulsions. Those who survive
              the acute phase can make a full recovery.

         -    Other features of chronic bismuth poisoning are erythematous
              rashes, renal failure, thrombocytopenia, bone
              demineralisation, spontaneous fractures of the thoracic
              vertebrae and a paralytic ileus-like syndrome.

    Inhalation

         -    There are no reports of bismuth or bismuth salt inhalation.

    Injection

         -    Historically, the parenteral administration of bismuth salts
              has led to cardiovascular collapse (probably a Herxheimer
              reaction), renal failure, a blue gumline, stomatitis,
              generalised skin eruptions, osteoporosis, spontaneous
              fractures and jaundice.

    Management

    Topical

         -    Symptomatic and supportive measures.
              Consider the possibility of systemic bismuth toxicity (see
              below).

    Ingestion

    Minor ingestions:
    1.   Gastrointestinal decontamination is not necessary.
    2.   If any symptoms other than nausea develop manage as for
         moderate/substantial ingestions.

    Management is essentially supportive.
    1.   Gastric lavage should be considered only if the patient presents
         within one hour.
    2.   Bismuth is radiopaque and can be seen on a plain abdominal x-ray
         for several hours following ingestion.
    3.   Replace fluids and electrolytes.
    4.   Monitor renal and liver function for several days and treat
         failure conventionally.
    5.   Measurement of blood bismuth concentrations will confirm the
         diagnosis.
    6.   The onset of neurological features may be delayed for several
         days but are most unlikely to occur in a patient who has no
         initial gastrointestinal features.
    7.   Mechanical ventilation and sedation may be required for severe
         agitation and myoclonus.
    8.   Chelation therapy with DMPS, DMSA, dimercaprol or d-penicillamine
         may be indicated in severe cases, but only after discussion with
         NPIS.

    Injection

         -    Bismuth injection is now rare and management is as for
              bismuth ingestion (decontamination has no role).

    References

    Beckingham IJ, Baird G, Kesteven PJL.
    Acute thrombocytopenia after De-Nol.
    Gut 1989; 30: 1016-7.

    Bridgeman AM, Smith AC.
    Iatrogenic bismuth poisoning. Case report.
    Aust Dent J 1994; 39: 279-81.

    Goh CL, Ng SK.
    Contact allergy to iodoform and bismuth subnitrate.
    Contact Dermatitis 1987; 16: 109-10.

    Gordon MF, Abrams RI, Rubin DB, Barr WB, Correa DD.
    Bismuth subsalicylate toxicity as a cause of prolonged encephalopathy
    with myoclonus.
    Mov Disord 1995; 10: 220-2. 

    Hudson M, Ashley N, Mowat G.
    Reversible toxicity in poisoning with colloidal bismuth subcitrate.
    Br Med J 1989; 299: 159.

    Huwez F, Pall A, Lyons D, Stewart MJ.
    Acute renal failure after overdose of colloidal bismuth subcitrate.
    Lancet 1992; 340: 1298.

    Jungreis AC, Schaumburg HH.
    Encephalopathy from abuse of bismuth subsalicylate (Pepto-Bismol).
    Neurology 1993; 43: 1265.

    McLean AJ, Islam S, Lambert JR.
    Anomalous short plasma elimination half life in a patient intoxicated
    with bismuth subcitrate.
    Gut 1990; 31: 1086.

    Mendelowitz PC, Hoffman RS, Weber S.
    Bismuth absorption and myoclonic encephalopathy during bismuth
    subsalicylate therapy.
    Ann Intern Med 1990; 112: 140-1.

    Playford RJ, Matthews CH, Campbell MJ, Delves HT, Hla KK, Hodgson HJF,
    Calam J.
    Bismuth induced encephalopathy caused by tri potassium dicitrato
    bismuthate in a patient with chronic renal failure.
    Gut 1990; 31: 359-60.

    Taylor EG, Klenerman P.
    Acute renal failure after colloidal bismuth subcitrate overdose.
    Lancet 1990; 335: 670-1.

    Substance name

         Bismuth

    Origin of substance

         Occurs naturally in the metallic state and in minerals such as
         bismite.                                 (CSDS, 1989)

    Synonyms

         Bismuth-209                              (CSDS, 1989)

    Chemical group

         A group VA element                       (PATTY, 1994)

    Reference Numbers

         CAS            7440-69-9                 (CSDS, 1989)
         RTECS          EB2600000                 (RTECS, 1996)
         UN             NIF
         HAZCHEM CODE   NIF

    Physico-chemical properties

    Chemical structure
         Bismuth, Bi                              (RTECS, 1996)

    Molecular weight
         208.98                                   (RTECS, 1996)

    Physical state at room temperature
         Solid

    Colour
         Crystalline, with pink tinge.            (CSDS, 1989)

    Odour
         NIF

    Viscosity
         NA

    pH
         NA

    Solubility
         Insoluble in hot or cold water.          (HSDB, 1996)
         Forms precipitates in sodium hydroxide, hydrochloric acid and
         nitric acid.                             (CSDS, 1989)

    Autoignition temperature
         NIF

    Chemical interactions
         Bismuth explodes if mixed with chloric or perchloric acid.
         Molten bismuth explodes and bismuth powder glows red-hot on
         contact with concentrated nitric acid.
         Bismuth reacts incandescently with nitrosyl fluoride or iodine
         pentafluoride, and violently with bromine pentafluoride which may
         ignite.
         Bismuth ignites with liquid chlorine at 80°C.
         Bismuth mixed with aluminium ignites spontaneously in air.
                                                  (CSDS, 1989)

    Major products of combustion
         When heated in air burns with a blue flame, forming yellow fumes
         of the oxide.                            (HSDB, 1996)

    Explosive limits
         NA

    Flammability
         Flammable in powder form.                (HSDB, 1996)

    Boiling point
         1420 - 1560°C                            (CSDS, 1989)

    Density
         9.8 at 20°C                              (CSDS, 1989)

    Vapour pressure
         133.3 Pa at 1021°C                       (CSDS, 1989)

    Relative vapour density
         NA

    Flash Point
         NA

    Reactivity
         NIF

    USES

         Bismuth is used in the manufacture of alloys which by virtue of
         their low melting point are key components of thermoelectric
         safety appliances, such as automatic shutoffs for gas and
         electric water heating systems and safety plugs in compressed gas
         cylinders.

         Historically, several bismuth salts including bismuth tartrate
         were used to treat syphilis, while bismuth sodium triglycollamate
         has been used to treat warts, stomatitis and upper respiratory
         tract infections.

         Inorganic bismuth compounds, including the nitrate, subcarbonate,
         subgallate, sodium tartrate and subsalicylate have been utilised
         in the management of diarrhoea, constipation, flatulence and
         abdominal pain. The use of bismuth subgallate, as a powder,
         ointment or paste in the topical treatment of eczema and other
         skin complaints has long been abandoned but bismuth iodoform
         paraffin paste (containing bismuth subnitrate or carbonate) is
         still used in surgical dressings. Colloidal bismuth subcitrate
         (the active ingredient in "De-Nol") eradicates Helicobacter
         pylori, especially when given in combination with antibiotics,
         and is therefore effective in the treatment of gastric and
         duodenal ulcers.
                                   (Jones, 1990; Slikkerveer and de Wolff,
                                   1992; PATTY, 1994)

    HAZARD/RISK CLASSIFICATION

         NIF

    INTRODUCTION

    Bismuth exists in trivalent and pentavalent oxidation states (the
    trivalent being more abundant and stable) and forms soluble and
    insoluble, organic and inorganic salts (Table 1).

    Table 1. Solubility of bismuth salts1

                                                                  

    Soluble bismuth salts              Insoluble bismuth salts
                                                                  
    Tripotassium dicitratobismuthate 
      (De-Nol)                         Bismuth oxide
    Bismuth sodium tri(thio) 
      glycollamate                     Bismuth (sub) carbonate
    Bismuth sodium tartrate            Bismuth (sub) gallate
                                       Bismuth hydroxide
                                       Bismuth (sub) salicylate
                                       Bismuth oxychloride2
                                       Bismuth iodide
                                       Bismuth subnitrate3
                                                                  
                                             (after Budavari, 1989)
    1 In cold water
    2 Formed from bismuth chloride in water
    3 Formed from bismuth nitrate in water

    Although occupational exposure to bismuth may occur in the manufacture
    of cosmetics, industrial chemicals and pharmaceuticals, most cases of
    poisoning occur following accidental or deliberate overdosage with
    bismuth-containing drugs. In general, insoluble salts, such as bismuth
    subcarbonate, are of low toxicity while lipid soluble organic salts
    (e.g. bismuth subgallate) are associated predominantly with
    neurotoxicity, and water soluble organic compounds (e.g. bismuth
    sodium triglycollamate) more usually cause renal damage (Winship,
    1983).

    MECHANISM OF TOXICITY

    There is evidence from animal studies that the absorption of orally
    administered bismuth is enhanced by the co-administration of thiol
    compounds via formation of a bismuth-sulphydryl group complex which
    readily crosses the gastrointestinal mucosa (Chaleil et al, 1981). An
    interaction between bismuth and thiol compounds has been proposed as
    the likely mechanism of bismuth neurotoxicity (Chaleil et al, 1981).

    TOXICOKINETICS

    Absorption

    The gastrointestinal absorption of bismuth salts depends on their
    water solubility. Most pharmaceutical preparations contain insoluble
    bismuth compounds which are absorbed poorly whatever the route of
    administration. However, appreciable blood bismuth concentrations have
    been documented in patients taking oral colloidal bismuth subcitrate
    (CBS). Hespe et al (1988) observed a peak bismuth concentration within
    one hour of ingestion of 120 mg CBS in five volunteers, with no
    detectable bismuth in the blood by four hours. However, with repeated
    doses bismuth accumulates. In nine patients taking 480 mg CBS daily
    Gavey et al (1989) demonstrated that plasma bismuth concentrations
    rose to a steady-state median value of 12 µg/L after three weeks with
    a slower rise to a median concentration of 17 µg/L after six weeks.

    Distribution

    Absorbed bismuth concentrates predominantly in the kidney, with
    significant amounts also in the lung, spleen, liver, brain and muscle
    (Slikkerveer and de Wolff, 1992). In the kidney, bismuth is bound to a
    protein which is distinct from metallothionein. The brain
    concentration of bismuth is likely to be higher following the
    ingestion of more lipid soluble compounds (Winship, 1983). The tissue
    distribution of the metal also is affected by its physical form. After
    an intravenous injection of ionized or chelated bismuth, most is found
    in the kidney but when injected as a colloid or adsorbed to charcoal,
    it deposits in the lung and reticuloendothelial system (Slikkerveer
    and de Wolff, 1992). In rats, co-administration of selenium with
    bismuth produced a 50 per cent reduction in the kidney bismuth
    concentration possibly because synthesis of the bismuth-binding
    protein was inhibited by selenium (Szymanska et al, 1978; Slikkerveer
    and de Wolff, 1992).

    Excretion

    Bismuth is eliminated in urine and faeces (via bile and intestinal
    secretions) to an extent that varies according to the salt and dose
    administered (Slikkerveer and de Wolff, 1992). Following a six week
    course of colloidal bismuth subcitrate 480 mg daily, significantly
    increased urine bismuth excretion continued for at least three months
    after cessation of therapy even though plasma bismuth concentrations
    fell to pretreatment levels within three weeks, suggesting gradual
    loss of bismuth from body stores (Gavey et al, 1989). McLean et al
    (1990) emphasised the importance of extrarenal bismuth elimination in
    patients with renal failure and provided evidence for biliary bismuth
    clearance in three patients with T-tubes in place following
    cholecystectomy.

    CLINICAL FEATURES: ACUTE EXPOSURE

    Ocular exposure

    Bismuth pentafluoride is highly toxic, and irritating to the skin,
    eyes and respiratory tract (Budavari, 1989).

    Ingestion

    Gastrointestinal toxicity

    Acute overdose of bismuth-containing pharmaceuticals is followed
    within hours by anorexia, nausea, vomiting, abdominal pain and
    possibly a dry mouth and thirst (Czerwinski and Ginn, 1964; James,
    1968; Hudson et al, 1989; Huwez et al, 1992). Other features of
    bismuth toxicity may follow (see below).

    Nephrotoxicity

    Acute renal failure has complicated bismuth salt ingestion. A 14
    year-old girl developed transient acute renal failure some 12 days
    after ingesting seven to eight sodium triglycollamate tablets (each
    containing 75 mg elemental bismuth) as a sore throat remedy (James,
    1968).

    Czerwinski and Ginn (1964) demonstrated temporary reduced glomerular
    filtration and proximal tubular reabsorption with glycosuria,
    phosphaturia and aminoaciduria in a 19 year-old patient who ingested
    21 tablets of sodium bismuth trithioglycollamate (1.5 g elemental
    bismuth).

    More recently, several cases of CBS overdose have been associated with
    renal impairment. Hudson et al (1989) described a 27 year-old man
    admitted with acute renal failure ten days after ingesting 100
    "De-Nol" tablets (12 g CBS). On admission the serum bismuth
    concentration was 260 µg/L with a plasma creatinine concentration of
    2804 µmol/L but renal function returned to normal following five days
    haemodialysis.

    In another report a 76 year-old man died nine days after taking 80
    "De-Nol" tablets (9.6 g CBS) (Taylor and Klenerman, 1990). The
    admission blood bismuth concentration was 1600 µg/L. Within hours this
    patient developed malaena and became oliguric with rapidly
    deteriorating renal function requiring dialysis. He developed an acute
    abdomen on day five but was deemed unfit for surgery and died. A
    perforated duodenal ulcer was found at autopsy and the kidneys
    contained bismuth in concentrations of 11 mg/g and 16 mg/g
    respectively. The authors concluded that bismuth nephropathy had
    contributed to renal failure precipitated by acute gastrointestinal
    haemorrhage.

    Huwez et al (1992) described a further patient who developed acute
    renal failure after ingesting 39 bismuth subcitrate tablets (4.7 g).
    Renal biopsy four days later showed acute tubular necrosis but he was
    discharged well on day 120.

    Neurotoxicity

    A 19 year-old female complained of hand paraesthesiae and leg cramps
    eight hours after ingesting 1.5 g elemental bismuth as sodium bismuth
    trithioglycollamate (21 tablets) but neurological examination was
    unremarkable and she made a full recovery (Czerwinski and Ginn, 1964).

    Hudson et al (1989) reported a 27 year-old man who presented with leg
    muscle weakness and blurred vision (in addition to features of
    gastrointestinal and renal toxicity) ten days after an overdose of 100
    De-Nol tablets (12 g CBS). Clinical examination confirmed increased
    tone with ankle clonus, proximal muscle weakness and hyperreflexia of
    the lower limbs. The patient did not become encephalopathic and the
    neurological signs resolved within five days of admission.

    Ocular toxicity

    Blurred vision has been reported following ingestion of 8 g of bismuth
    subnitrate (Grant and Schuman, 1993).

    Injection

    Gastrointestinal toxicity

    Stomatitis, a blue 'bismuth gumline' and constipation occurred with
    other features of severe bismuth poisoning some two to four weeks
    after the subcutaneous injection of sodium bismuth tartrate (maximum
    two doses) (Dowds, 1936).

    A six year-old child developed epigastric and right upper quadrant
    pain 18 hours after an intramuscular injection of sodium bismuth
    thioglycolate (Karelitz and Freedman, 1951). He subsequently developed
    hepatitis and renal failure but made a full recovery.

    Hepatotoxicity

    A six year-old child developed jaundice following a single
    intramuscular injection of 100 mg bismuth thioglycollate (Karelitz and
    Freedman, 1951) and a 21 year-old man developed transiently increased
    liver enzyme activities (aspartate aminotransferase 56 IU/L, alanine
    aminotransferase 95 IU/L) three days after ingesting 4.68 g bismuth
    subcitrate (Huwez et al, 1992). Both patients recovered fully.

    Two further patients who died following one or two subcutaneous
    injections of sodium bismuth tartrate had pathological fatty liver at
    autopsy (Dowds, 1936).

    Nephrotoxicity

    In a review of 30 cases of bismuth nephropathy, Urizar and Vernier
    (1966) described 12 cases of acute renal failure following
    intramuscular therapy with bismuth salts (usually bismuth
    thioglycollate). The interval between medication and the onset of
    symptoms varied between eight hours and eight days which is similar to
    case histories reported by other authors (Gryboski and Gotoff, 1961).

    Cardiovascular toxicity

    Acute bismuth poisoning is rare. Historically, the intramuscular or
    intravenous injection of bismuth compounds in the treatment of
    syphilis or yaws resulted in several fatalities, often from
    cardiovascular collapse within minutes to hours of injection (Beerman,
    1932). These cases probably reflect a Herxheimer reaction.

    Goodman (1948) described two women who collapsed and died within
    minutes of accidentally receiving 650 mg intravenous sodium bismuth
    tartrate (some three times the recommended dose) in the treatment of
    yaws. At post-mortem there was "flaccidity of the heart" and pulmonary
    congestion. A third woman who received the same treatment collapsed
    within minutes but survived for ten days before succumbing to acute
    renal failure. At post mortem she was noted to have blue gingivae,
    enlarged liver and kidneys and haemorrhagic colitis.

    Dowds (1936) reported three deaths two to four weeks after the
    subcutaneous administration of sodium bismuth tartrate (maximum two
    doses). These patients had features suggesting cardiovascular
    compromise ('feeble' or 'weak and irregular' pulse) though in each
    case there was evidence of systemic bismuth poisoning (stomatitis, a
    blue gumline and renal failure).

    Rectal administration

    Several paediatric deaths were reported by Weinstein (1947) some two
    to five days after the administration of bismuth-containing
    suppositories. Death was preceded by vomiting, abdominal pain,
    drowsiness, coma or convulsions and hepatic necrosis was the
    predominant finding at autopsy.

    CLINICAL FEATURES: CHRONIC EXPOSURE

    Dermal exposure

    Dermal toxicity

    Bismuth contact sensitivity has followed the topical application of
    bismuth salts (Goh and Ng, 1987).

    Bismuth bucal pigmentation occurring as part of systemic bismuth
    poisoning is often associated with gingivitis and ulcerative lesions
    (Dummett, 1971).

    Neurotoxicity

    Neuropsychiatric symptoms have occurred following the use of bismuth
    iodoform paraffin paste packs (Lee et al, 1990; Bridgeman and Smith,
    1994; Sharma et al, 1994) and in patients using skin creams containing
    bismuth. The features are identical to those seen following ingestion
    (see below) (Krüger et al, 1976).

    Ingestion

    Gastrointestinal toxicity

    Umeki (1988) reported a paralytic ileus-like syndrome due to a bismuth
    subnitrate "stercolith stercoroma" in a 72 year-old woman given this
    bismuth salt for three weeks (2 g daily) as an antidiarrhoeal agent. A
    patient who died from systemic bismuth toxicity following a six month
    course of weekly bismuth subsalicylate injections as treatment for
    syphilis was found at post-mortem to have "gangrenous enteritis ....
    stomatitis, gastritis and deposition of bismuth in gingiva and colon"
    (Wachstein, 1944).

    Nephrotoxicity

    Bismuth sodium triglycollamate and bismuth sodium thioglycollate have
    been associated with renal toxicity after long-term therapy. Urizar
    and Vernier (1966) reported an eight year-old girl who developed acute
    renal failure requiring haemodialysis after five months treatment with
    oral bismuth sodium triglycollamate for dermal warts. She made a full
    recovery.

    Neurotoxicity

    Neuropsychiatric symptoms have occurred in patients chronically taking
    oral bismuth pharmaceuticals (Burns et al, 1974; Supino-Viterbo et al,
    1977; Hasking and Duggan, 1982; Weller, 1988; Mendelowitz et al, 1990;
    Playford et al, 1990; Jungreis and Schaumburg, 1993; Gordon et al,
    1995), although bismuth-based indigestion remedies and ulcer-healing
    drugs appear safe when used strictly according to the manufacturers'
    recommendations (Dekker and Reisma, 1979; Eskens, 1988; Wagstaff et
    al, 1988; Bierer, 1990; Dunk et al, 1990; Noach et al, 1995).

    Slikkerveer and de Wolff (1992) proposed three phases of bismuth
    encephalopathy. A prodromal phase lasting two to six weeks with
    incoordination, behavioural changes, memory deterioration and various
    psychiatric symptoms is followed in the second phase by fulminant
    encephalopathy in which myoclonic jerks, confusion, dysarthria and
    sometimes hysteria predominate. The third phase is one of recovery and
    is usually complete within two to six weeks. Buge et al (1981)
    observed seizures in 22 of 70 patients with bismuth encephalopathy
    (all exhibited myoclonic jerks). Rarely reported features of bismuth
    encephalopathy include transient gustatory and olfactory malfunction
    (Friedland et al, 1993), pyramidal signs and diplopia (Slikkerveer and
    de Wolff, 1992).

    Weller (1988) described a 41 year-old man who developed paraesthesiae,
    irritability, insomnia, fatigue, reduced concentration and poor short-
    term memory after taking bismuth subcitrate (240 mg daily) for two
    years. All symptoms resolved when treatment was discontinued. A 58
    year-old woman who had self-medicated bismuth subgallate powder (up to
    1.5 g daily) as an antacid for several years presented with
    progressive dementia, apraxia, incoordination, tremor and dysarthria.
    Six days after drug withdrawal the blood bismuth concentration was 70
    µg/L and she made a full physical and intellectual recovery within
    five months (Kendel et al, 1993).

    A 68 year-old man with chronic renal failure developed hallucinations,
    ataxia and an abnormal EEG when he took twice the recommended daily
    dose of De-Nol (864 mg/day) for two months (Playford et al, 1990). The
    peak whole blood bismuth concentration was 880 µg/L and he recovered
    completely when the drug was withdrawn.

    Hasking and Duggan (1982) reported a 60 year-old man who presented
    with confusion, muscle twitching and urinary incontinence after taking
    bismuth subsalicylate for several years to control chronic diarrhoea.
    An EEG showed abnormal beta rhythm and the blood bismuth concentration
    was 72 µg/L but he made a complete recovery within one month of drug
    withdrawal. In a similar report a 68 year-old lady developed
    myoclonus, tremor, confusion, ataxia and dysarthria after taking
    bismuth subsalicylate (11.4 g weekly) for two years but she was
    asymptomatic within six months of discontinuing medication (Jungreis
    and Schaumburg, 1993).

    Bismuth encephalopathy complicating bismuth-salt ingestion solely as
    prescribed is rare. After seven days oral bismuth subsalicylate
    therapy (5.2-9.4 g total bismuth daily) for intractable diarrhoea, a
    45 year-old man with acquired immunodeficiency syndrome developed
    myoclonic jerks, dysarthria and lethargy (Mendelowitz et al, 1990). He
    became comatosed over the next two days, all medications were
    withdrawn and a blood bismuth concentration of 200 µg/L was recorded.
    Despite d-penicillamine chelation therapy (dose not stated) he died
    within 24 hours. There was no evidence of bacterial, viral or fungal
    infection and a CT brain scan was normal.

    In another case a 69 year-old man developed myoclonus, delirium,
    impaired cognitive function, dysarthria and ataxia after some 15
    months oral bismuth nitrate therapy at the prescribed dose (8 g daily
    for three weeks then 4 g daily). The patient recovered fully within
    four months of bismuth withdrawal although a blood bismuth
    concentration was not measured and bismuth was not detected in urine
    collected five days after the medication was discontinued (Von Bose
    and Zaudig, 1991).

    Slikkerveer and de Wolff (1992) emphasised that a high bismuth
    concentration in blood, plasma, serum or CSF is necessary to diagnose
    bismuth encephalopathy; urine bismuth concentrations are less useful.
    Whole blood bismuth concentrations are preferable to serum or plasma
    since animal studies suggest considerable bismuth accumulation in red
    blood cells (Dresow et al, 1991). Patients with encephalopathy show
    great individual variation in blood bismuth concentrations with a
    range of 10 µg/L to 4600 µg/L in one series of 618 cases
    (Martin-Bouyer et al, 1978).

    Supino-Viterbo et al (1977) reported a "characteristic" EEG pattern in
    31 of 45 patients with bismuth encephalopathy (monomorphic waves in
    the temperofronto-rolandic and frontal regions, absent occipital alpha
    rhythm and a diffuse beta rhythm) but the specificity of these
    findings is doubtful. Hyperdensities in cortical grey matter, basal
    ganglia and the cerebellum have been described on CT in patients with
    bismuth encephalopathy with resolution during recovery (Buge et al,
    1981). Although high bismuth concentrations have been found in the
    brain of patients dying from bismuth encephalopathy, there are no
    specific post-mortem pathological findings in these patients
    (Slikkerveer and de Wolff, 1992).

    Haemotoxicity

    A 72 year-old man who had taken De-Nol (240 mg tds) for two weeks for
    recurrent dyspepsia presented with widespread petechiae, buccal
    haemorrhagic lesions, epistaxis, haematuria and rectal bleeding
    secondary to severe thrombocytopenia (platelet count less than
    10x109/L) with a hypoplastic bone marrow (Beckingham et al, 1989).
    De-Nol therapy was discontinued, oral prednisolone (15 mg daily) and
    daily platelet transfusions were administered with full recovery of
    the platelet count and bone marrow histology by day 12 (Beckingham et
    al, 1989). Methaemoglobinaemia has been reported in association with
    bismuth subnitrate ingestion (Mayer and Baehr, 1912; Bradley et al,
    1989) but these are cases of nitrate or nitrite not bismuth-induced
    methaemoglobin formation.

    Bone toxicity

    A 49 year-old man with chronic peptic ulceration who had been treated
    intermittently with oral bismuth subnitrate or bismuth citrate for
    some 25 years developed an osteolytic glenohumeral arthropathy
    associated with increased blood and bone bismuth concentrations (10
    µg/L and 2000 µg/kg respectively) some six months after bismuth

    therapy had been discontinued (Gaucher et al, 1979). Demineralisation
    of the humeral head and fractures of the thoracic vertebrae have been
    noted in patients with bismuth encephalopathy (Slikkerveer and de
    Wolff, 1992).

    Dermal toxicity

    Maculopapular erythema and angioedema have occurred in patients taking
    oral bismuth subcitrate (Ottervanger and Stricker, 1994).

    Injection

    Dermal toxicity

    Pityriasis rosea-like eruptions, stomatitis, a blue 'bismuth gum line'
    and diffuse pigmentation have been reported following parenteral
    bismuth therapy (Peters, 1942; Silverman, 1944; Dobes and Alden, 1949;
    Zala et al, 1993). Historically the injection of bismuth salts to
    tuberculoid abscess cavities has produced similar effects, often in
    association with systemic features of bismuth poisoning (Mayer and
    Baehr, 1912). Vaginal melanosis has also been described (Bradley et
    al, 1989).

    Goldman and Clarke (1939) described two cases of "erythema of the
    ninth day syndrome", (normally associated with parenteral arsphenamine
    therapy) in patients who had received several injections of bismuth
    subsalicylate. The syndrome was characterized by a general skin
    eruption associated with joint pains, malaise and fever which resolved
    spontaneously over a few days and did not recur with further
    parenteral bismuth administration.

    Hepatotoxicity

    Kulchar and Reynolds (1942) reported 120 cases of jaundice in patients
    receiving 20 week courses of parenteral iodobismitol in the treatment
    of syphilis although previous arsphenamine therapy and alcoholism were
    likely to have contributed to some cases. Jaundice was associated to a
    varying extent with nausea and vomiting, abdominal pain, a palpable
    liver and rarely fever or ascites with resolution in all but eight
    cases within two months of discontinuation of therapy.

    Nephrotoxicity

    A 58 year-old man died one week after completing a six month course of
    weekly bismuth subsalicylate injections. The diagnosis at post-mortem
    was bismuth intoxication complicated by "gangrenous enteritis .....
    toxic nephropathy, stomatitis, gastritis and deposition of bismuth in
    gingiva and colon" (Wachstein, 1944).

    Bone toxicity

    Historically, syphilitics receiving parenteral bismuth developed
    osteoporosis and spontaneous fractures of the pelvis, necrosis of the
    femoral head or isolated osteoporosis of the femur and vertebrae
    (Slikkerveer and de Wolff, 1992) sometimes in association with
    confirmed increases in bone bismuth concentrations (Gaucher et al,
    1979).

    Children with syphilis who received parenteral bismuth compounds
    developed bone inclusions thought to be due to calcification of the
    cartilaginous matrix (Bradley et al, 1989).

    MANAGEMENT

    Fortunately severe bismuth poisoning is now rare and in most cases
    features resolve when exposure ceases. The diagnosis may be confirmed
    by measuring the whole blood bismuth concentration. Bismuth is
    radiopaque and can be seen in a plain abdominal x-ray for several
    hours after ingestion (Taylor and Klenerman, 1990). Management is
    essentially supportive. Benzodiazepines and possibly mechanical
    ventilation may be required for severe agitation and myoclonus.

    Antidotes

    DMPS

    All mice (n=10) administered intraperitoneal bismuth 54 mg/kg (as
    bismuth citrate) and treated at 20 minutes with intraperitoneal DMPS
    (at a 10:1 molar ratio of antidote:bismuth) survived two weeks whereas
    no animals survived in the control group (Basinger et al, 1983). More
    recently, Slikkerveer et al (1992) demonstrated a significant
    reduction in the blood and kidney bismuth concentrations in
    association with a four-fold increase in urine bismuth elimination in
    rats given a three day course of intraperitoneal DMPS
    (250 µmol/kg/day) following 14 days intraperitoneal loading with
    colloidal bismuth subcitrate (50 µmol/kg/day).

    Playford et al (1990) observed a 10-fold increase in renal bismuth
    clearance when oral DMPS (100 mg tds) was given to a patient with
    renal failure and bismuth intoxication.

    DMSA

    Basinger et al (1983) observed a zero mortality in ten mice
    administered intraperitoneal DMSA 20 minutes after bismuth loading
    (54 mg/kg intraperitoneal bismuth citrate), whereas there was a 100
    per cent mortality in the control group. However, Slikkerveer et al
    (1992) found DMSA less effective than DMPS in reducing blood bismuth
    concentrations in rats given a 14 day course of intraperitoneal
    colloidal bismuth subcitrate, then a three day intraperitoneal course
    of chelating agent (250 µmol/kg/day). Furthermore, in these
    experiments DMSA did not significantly enhance urine bismuth
    elimination (Slikkerveer et al, 1992).

    d-Penicillamine

    Nine of ten mice administered intraperitoneal bismuth 54 mg/kg (as
    bismuth citrate) and treated at 20 minutes with intraperitoneal
    d-penicillamine (at a 10:1 molar ratio of antidote:bismuth) survived
    two weeks whereas there was a 100 per cent mortality in the control
    group (Basinger et al, 1983). However, d-penicillamine was not an
    effective chelator in rats administered a three day intraperitoneal
    course of 250 µmol/kg/day following 14 days loading with
    intraperitoneal colloidal bismuth subcitrate (50 µmol/kg/day)
    (Slikkerveer et al, 1992). D-penicillamine 1 gram orally did not
    increase elimination in five patients who had received a course of
    bismuth subcitrate 480 mg daily for a median of eight weeks in the
    preceding four to eight weeks (Nwokolo and Pounder, 1990).

    Dimercaprol

    Animals administered intraperitoneal dimercaprol 250 µmol/kg/day for
    three days after a two week course of intraperitoneal colloidal
    bismuth subcitrate (50 µmol/kg/day), showed a significant increase in
    urine bismuth elimination and reduced blood and tissue bismuth
    concentrations (Slikkerveer et al, 1992).

    Molina et al (1989) reported significant improvement in two patients
    with bismuth encephalopathy after two days therapy with intramuscular
    dimercaprol 1200-1800 mg daily, although Karelitz and Freedman (1951)
    observed no clinical benefit in a patient with acute renal failure and
    hepatitis treated with intramuscular dimercaprol 6 mg/kg body weight
    daily. Liessens et al (1978) described a fatal case of bismuth
    encephalopathy in a 20 year-old female who was treated for ten days
    with intramuscular dimercaprol 200-800 mg daily. Dimercaprol therapy
    produced a seven fold increase initially in the 24-hour urine bismuth
    elimination (from 1000 to 7000 µg) (Liessens et al, 1978).

    Conclusions and recommendations

    Animal studies and limited clinical experience suggest that DMPS and
    DMSA are the chelating agents of choice in bismuth poisoning. Either
    may be administered orally in a daily dose of 30 mg/kg body weight.

    Side-effects following treatment with DMPS or DMSA are rare but
    include skin rashes, gastrointestinal disturbances, transient
    elevation of hepatic transaminase activities and flu-like symptoms
    (Aposhian, 1983).

    Dimercaprol is an effective bismuth chelator and may have a role in
    circumstances where the newer chelating agents are unavailable or
    parenteral administration is preferred. Dimercaprol is give by deep
    intramuscular injection 2.5-5 mg/kg four hourly for two days followed
    by 2.5 mg/kg bd for up to 14 days. Its use is associated but with a
    significantly higher incidence of adverse effects, notably transient
    hypertension and gastrointestinal disturbance (Dollery, 1991).

    MEDICAL SURVEILLANCE

    Occupational bismuth exposure is rare. The possibility of bismuth
    toxicity should be considered in patients on appropriate therapy who
    develop unexplained neuropsychological features. As stated above
    bismuth is radiopaque and therefore will show on a plain abdominal
    film following ingestion or injection. Measurement of blood
    concentrations will confirm the diagnosis. Hillemand et al (1977)
    recommended the determination of blood bismuth concentrations in
    patients receiving bismuth-containing antacids and suggested drug
    withdrawal for values greater than 100 µg/L although Benet (1991)
    believes this is an "overcautious" recommendation.
    Nwokolo et al (1994) found no evidence of subclinical neurotoxicity
    (assessed via brain MRI, nerve conduction studies, visual evoked
    responses and neuropsychological screening) in eight patients treated
    with tripotassium dicitrato bismuthate (De-nol) 480 mg daily for eight
    weeks, even though urine bismuth concentrations increased to a mean of
    560 µg/L (range 140-1300 µg/L) immediately after treatment. There was
    similarly no evidence of neurotoxicity in 37 patients receiving CBS
    (480 mg daily) or bismuth subnitrate (1800 mg daily) for eight weeks
    in the treatment of Helicobacter pylori gastritis. Mean blood bismuth
    concentrations at the end of the course of treatment were 17.2 ± (SD)
    9.7 µg/L and 5.4 ± (SD) 2.8 µg/L respectively (Noach et al, 1995).

    OCCUPATIONAL DATA

    NIF

    OTHER TOXICOLOGICAL DATA

    Carcinogenicity

    There are no data available regarding the possible carcinogenicity of
    bismuth (Reprotext, 1996).

    Reprotoxicity

    Bismuth can cross the placenta and is present in foetal blood
    following the oral administration of bismuth salts to the mother
    (Thompson et al, 1941). Quéreux et al (1976) reported a pregnant woman
    who presented with bismuth encephalopathy at 34 weeks gestation but
    delivered a normal child at 38 weeks.

    Genotoxicity

    NIF

    Fish toxicity

    NIF

    EC Directive on Drinking Water Quality 80/778/EEC

    NIF

    AUTHORS

    SM Bradberry BSc MB MRCP
    ST Beer BSc
    JA Vale MD FRCP FRCPE FRCPG FFOM

    National Poisons Information Service (Birmingham Centre),
    West Midlands Poisons Unit,
    City Hospital NHS Trust,
    Dudley Road,
    Birmingham
    B18 7QH
    UK

    This monograph was produced by the staff of the Birmingham Centre of
    the National Poisons Information Service in the United Kingdom. The
    work was commissioned and funded by the UK Departments of Health, and
    was designed as a source of detailed information for use by poisons
    information centres.

    Date of last revision
    16/7/96

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    See Also:
       Toxicological Abbreviations