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