UKPID MONOGRAPH
ARSENIC TRIOXIDE
SM Bradberry BSc MB MRCP
WN Harrison PhD CChem MRSC
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.
ARSENIC TRIOXIDE
Toxbase summary
Type of product
A trivalent arsenic salt used in the production of herbicides and
pesticides.
Toxicity
Generally less acutely toxic than soluble arsenic salts. A patient has
died after ingesting 2 g.
Features
Systemic toxicity may follow arsenic trioxide ingestion, inhalation or
topical exposure.
Topical
- Irritant to skin and mucous membranes. Systemic arsenic
poisoning may occur after substantial exposure.
Ingestion
- Very small ingestions are likely to cause only mild gastro-
intestinal upset.
Substantial ingestions:
- Rapid onset (within 1-2 hours) of burning of the mouth and
throat, hypersalivation, dysphagia, nausea, vomiting,
abdominal pain and diarrhoea.
- In severe cases gastrointestinal haemorrhage, cardiovascular
collapse, renal failure, seizures, encephalopathy and
rhabdomyolysis may occur.
- Other features: facial and peripheral oedema, ventricular
arrhythmias (notably torsade de pointes), ECG abnormalities
(QT interval prolongation, T-wave changes), muscle cramps.
- Investigations may show anaemia, leucopenia,
thrombocytopenia or evidence of intravascular haemolysis.
- Death may occur from cardiorespiratory or hepatorenal
failure. The adult respiratory distress syndrome (ARDS) has
been reported.
- Survivors of severe poisoning may develop a peripheral
neuropathy and skin lesions typical of chronic arsenic
poisoning.
Inhalation
- Rhinitis, pharyngitis, laryngitis and tracheobronchitis may
occur. Tracheal and bronchial haemorrhage may complicate
severe cases.
Chronic arsenic exposure
- may occur following ingestion, inhalation or topical
exposure. Features include weakness, lethargy,
gastrointestinal upset, dermal manifestations
(hyperkeratosis and raindrop pigmentation of the skin), a
peripheral (motor and sensory) neuropathy and psychological
impairment.
- Also reported: peripheral vascular disease (cold sensitivity
progressing to ulceration and gangrene), renal tubular or
cortical damage and haematological abnormalities (notably
pancytopenia).
Management
Topical
1. Irrigate with copious volumes of water.
2. Consider the possibility of systemic arsenic poisoning after
significant exposure.
Ingestion
Very small ingestions:
1. Gastrointestinal decontamination is unnecessary.
2. Symptomatic and supportive care only.
Substantial ingestions:
1. Most patients will vomit spontaneously but in those who do not,
gastric lavage should be considered only if the patient presents
within one hour.
2. Supportive measures are paramount. Intensive resuscitation may be
required. Ensure adequate fluid replacement and close observation
of vital signs including cardiac monitoring.
3. Diarrhoea can be controlled with loperamide.
4. Monitor blood urea, creatinine, electrolytes, liver function and
full blood count.
5. Collect blood and urine for arsenic concentration measurements.
6. ECG evidence of QT prolongation may precede atypical ventricular
arrhythmias (notably torsade de pointes). Avoid drugs which
prolong the QT interval e.g. procainamide, quinidine or
disopyramide. Isoprenaline is effective with phenytoin,
lignocaine or propranolol as alternatives.
7. Antidotes - chelation therapy with either dimercaprol, DMSA or
DMPS should be considered in symptomatic patients where there is
analytical confirmation of the diagnosis, but only after
specialist advice from the NPIS.
References
Bolliger CT, van Zijl P, Louw JA.
Multiple organ failure with the adult respiratory distress syndrome in
homicidal arsenic poisoning.
Respiration 1992; 59: 57-61.
Donofrio PD, Wilbourn AJ, Albers JW, Rogers L, Salanga V, Greenberg
HS.
Acute arsenic intoxication presenting as Guillain-Barré-like syndrome.
Muscle Nerve 1987; 10: 114-20.
Engel RR, Hopenhayn-Rich C, Receveur O, Smith AH.
Vascular effects of chronic arsenic exposure: a review.
Epidemiol Rev 1994; 16: 184-209.
Gerhardsson L, Dahlgren E, Eriksson A, Lagerkvist BEA, Lundström J,
Nordberg GF.
Fatal arsenic poisoning - a case report.
Scand J Work Environ Health 1988; 14: 130-3.
Gerhardt RE, Crecelius EA, Hudson JB.
Moonshine-related arsenic poisoning.
Arch Intern Med 1980; 140: 211-3.
Goldsmith S, From AHL.
Arsenic-induced atypical ventricular tachycardia.
N Engl J Med 1980; 303: 1096-7.
Greenberg C, Davies S, McGowan T, Schorer A, Drage C.
Acute respiratory failure following severe arsenic poisoning.
Chest 1979; 76: 596-8.
Kew J, Morris C, Aihie A, Fysh R, Jones S, Brooks D.
Arsenic and mercury intoxication due to Indian ethnic remedies.
Br Med J 1993; 306: 506-7.
Kosnett MJ, Becker CE.
Dimercaptosuccinic acid as a treatment for arsenic poisoning.
Vet Hum Toxicol 1987; 29: 462.
Mathieu D, Mathieu-Nolf M, Germain-Alonso M, Neviere R, Furon D,
Wattel F.
Massive arsenic poisoning - effect of hemodialysis and dimercaprol on
arsenic kinetics.
Intensive Care Med 1992; 18: 47-50.
Moore DF, O'Callaghan CA, Berlyne G, Ogg CS, Alban Davies H, House IM,
Henry JA.
Acute arsenic poisoning: absence of polyneuropathy after treatment
with 2,3-dimercaptopropanesulphonate (DMPS).
J Neurol Neurosurg Psychiatry 1994; 57: 1133-5.
Peterson RG, Rumack BH.
D-penicillamine therapy of acute arsenic poisoning.
J Pediatr 1977; 91: 661-6.
Substance name
Arsenic trioxide
Origin of substance
Occurs in nature as the mineral claudetite.
(DOSE, 1992)
Synonyms
Arsenic oxide
Arsenic sesquioxide
Arsenious oxide
Arsenic(III)oxide
Arsenious acid
Diarsenic trioxide
Arsenous oxide
Arsenous acid
White arsenic (DOSE, 1992)
Chemical group
A compound of arsenic, a group VA element
Reference numbers
CAS 1327-53-3 (DOSE, 1992)
RTECS CG 3325000 (CSDS, 1991)
UN 1561 (DOSE, 1992)
HAZCHEM 2Z (DOSE, 1992)
Physicochemical properties
Chemical structure
As2O3 (DOSE, 1992)
Molecular weight
197.84 (DOSE, 1992)
Physical state at room temperature
Chrystalline solid (CSDS, 1991)
Colour
Colourless (CSDS, 1991)
Odour
None (CHRIS, 1995)
Viscosity
NA
pH
NIF
Solubility
20 g/L at 25°C (OHM/TADS, 1995)
Autoignition temperature
NA
Chemical interactions
Forms arsine gas when in contact with metals and acid.
Dissolves in alkali to form arsenites.
Forms toxic volatile halides when in contact with halide acids.
(HSDB, 1995)
Major products of combustion
Fumes of arsenic trioxide and arsine may be formed in fires.
(HSDB, 1995)
Explosive limits
NA
Flammability
Not flammable (HSDB, 1995)
Boiling point
465°C (DOSE, 1992)
Density
Claudetite 3.865 at 25°C (DOSE, 1992)
Arsenolite 4.15 at 25°C (DOSE, 1992)
Vapour pressure
8813 Pa at 312°C (HSDB, 1995)
Relative vapour density
NIF
Flash Point
NA
Reactivity
Explodes on heating with zinc filings.
Violent interaction with chlorine trifluoride.
Incandesces in contact with hydrogen fluoride.
Reacts vigorously with mercury, rubidium acetylide, oxygen
difluoride or sodium chlorate. (CSDS, 1991)
Uses
A constituent of weedkillers, rodenticides and insecticides.
In the manufacture of glass, Paris green and enamels.
(DOSE, 1992)
Hazard/risk classification
Index No. 033-003-00-0
Risk phrases
Carc. Cat. 1; R45 - May cause cancer
T+; R28 - Also very toxic if swallowed
C; R34 - Corrosive, causes burns
Safety phrases
S53-45- Avoid exposure-obtain special instructions before use. In
case of accident, or if you feel unwell, seek medical advice
immediately (show label where possible).
EEC No: 215-481-4 (CHIP2, 1994)
INTRODUCTION
Arsenic trioxide is the most important commercial form of arsenic and
is produced as a by-product of copper and lead smelting. It is used in
agriculture, forestry and to a lesser extent in the glass and ceramic
industry, as a food additive and in some herbal remedies (IPCS, 1981).
Chen et al (1996) recently demonstrated a potential clinical role for
arsenic trioxide in the treatment of acute promyelocytic leukaemia.
It has been suggested that arsenic trioxide poses less of an acute
toxic hazard than water soluble arsenic salts (Done and Peart, 1971).
Crude arsenic trioxide is relatively insoluble but may be converted to
more soluble derivatives such as arsenious acid or sodium arsenite in
some preparations.
EPIDEMIOLOGY
Arsenic trioxide is the major source of occupational exposure to
arsenic compounds, especially from the processing of copper, gold and
lead ores. Occupational exposure may also occur in the manufacture of
glass, ceramics and pesticides (IPCS, 1981).
Arsenic trioxide has been ingested accidentally (Mahieu, 1981; Moore
et al, 1994) or with suicidal or homicidal intent (Marcus, 1987;
Bolliger et al, 1992). Over two hundred students were poisoned after
eating sausages containing 1.36 g/kg arsenic trioxide served at a hall
of residence. Many students were ill but none died. Two people and one
dog died after consuming sausages from an earlier batch containing
14.3 g/kg arsenic trioxide (Renwick et al, 1981).
The source of arsenic trioxide may be pesticides (Done and Peart,
1971; Kuruvilla et al, 1975; Park and Currier, 1991), homeopathic or
ethnic remedies (Kerr and Saryan, 1986) or Fowler's solution, the most
notable source of medicinal arsenic intoxication. Fowler's solution is
formed by dissolving arsenic trioxide in potassium hydroxide solution
to form potassium arsenite.
MECHANISM OF TOXICITY
The principle mechanism of arsenic intoxication is disruption of thiol
proteins. For example, arsenic inactivates pyruvate dehydrogenase by
complexing with the sulphydryl groups of a lipoic acid moiety
(6,8-dithiooctanoic acid) of the enzyme (Jones, 1995).
Enhanced cellular destruction of damaged thiol proteins may produce
toxic oxygen radicals. Arsenic-induced reduced lymphocyte
proliferation and impaired macrophage function also have been
described.
Dong and Luo (1994) suggested that while arsenic can directly damage
DNA, a more important mechanism in arsenic-induced carcinogenicity is
enhanced mutagenicity of other compounds via increased DNA-protein
crosslinks.
The affinity of arsenic for sulphydryl groups is utilized in chelation
therapy.
TOXICOKINETICS
Absorption
Insoluble arsenic trioxide is less well absorbed than more soluble
salts (Fielder et al, 1986). The efficiency of absorption following
ingestion is dependent on the particle size; fine powders are better
absorbed than larger particles (Done and Peart, 1971).
A large proportion of irrespirable arsenic trioxide particles are
trapped in the upper airways and deposited in the gastrointestinal
tract by mucociliary clearance. This is likely to be an important
source of arsenic trioxide exposure since the extent of absorption
following ingestion and inhalation are similar (Smith et al, 1977;
IPCS, 1981).
Although direct evidence of transcutaneous arsenic absorption in man
is scarce (Fielder et al, 1986) systemic arsenic toxicity following
presumed dermal exposure has been reported (Heyman et al, 1956).
Distribution
Absorbed arsenic is distributed to all body tissues (Fielder et al,
1986). Trivalent arsenic is methylated in the liver to methylarsonic
acid and dimethylarsinic acid (IPCS, 1996). Short-term studies on
humans indicate that daily intake in excess of 0.5 mg progressively,
but not completely, saturates the capacity to methylate inorganic
arsenic (IPCS, 1996).
Very high arsenic concentrations have been found in the hair of
workers exposed to arsenic trioxide dust but this may reflect external
contamination rather than systemic absorption (Yamamura and Yamauchi,
1980).
Excretion
The half-life of arsenic in blood is about 60 hours with renal
excretion predominantly as mono- and dimethyl- derivatives (Waldron
and Scott, 1994). The whole body half-life of arsenic in six human
volunteers fitted a three compartment system, with 65.9 per cent of
orally administered arsenic having a half-life of 2.1 days, 30.4 per
cent a half-life of 9.5 days and 3.7 per cent a half-life of 38.4 days
(mean values) (Pomroy et al, 1980).
In animal studies small amounts of parenterally administered arsenic
trioxide appear in the faeces, suggesting minor biliary clearance
(Reichl et al, 1994).
CLINICAL FEATURES: ACUTE EXPOSURE
Dermal exposure
Trivalent arsenic compounds are irritating to the skin and mucous
membranes with dermatitis the most common feature following
occupational exposure. Erythema, burning and itching, eczematous
eruptions and folliculitis are typical (Fielder et al, 1986).
Ocular exposure
Arsenic trioxide is an eye irritant. Most injuries result form
exposure to dusts, causing conjunctivitis, lacrimation, photophobia
and chemosis (Grant and Schuman, 1993).
Inhalation
Inhalation of arsenic compounds causes rhinitis, pharyngitis,
laryngitis and tracheobronchitis (Morton and Dunnette, 1994).
Gerhardsson et al (1988) reported an occupational accident in which a
worker was buried by arsenic trioxide powder and despite intensive
resuscitation died six hours later. At autopsy there were submucosal
tracheal and bronchial haemorrhages, widespread mucosal sloughing,
alveolar haemorrhages and oedema.
Ingestion
Insoluble, poorly absorbed arsenic trioxide presents a much less acute
toxic hazard than soluble compounds such as sodium arsenite which are
well absorbed after ingestion (Done and Peart, 1971). However,
substantial arsenic trioxide ingestions may produce serious systemic
toxicity. A patient has died after ingesting 2 g (Levin-Scherz et al,
1987).
Gastrointestinal toxicity
Nausea, vomiting, abdominal pain and diarrhoea are common after
substantial arsenic trioxide ingestion (Watson et al, 1981; Marcus,
1987; Moore et al, 1994).
Gastrointestinal haemorrhage may lead to cardiovascular collapse. A
direct toxic effect of arsenic on capillaries via sulphydryl-group
binding is thought to contribute to this (Jolliffe et al, 1991; Morton
and Dunnette, 1994).
A 21 year-old man who ingested 2 g arsenic trioxide presented 26 hours
later with diarrhoea, vomiting and cardiovascular shock (Levin-Scherz
et al, 1987). Despite vigorous resuscitation with inotropic support
and dimercaprol therapy he died 36 hours after admission from
resistant ventricular fibrillation and asystole. The admission plasma
arsenic concentration was shown subsequently to be 1.9 mg/L.
Bolliger et al (1992) reported two patients maliciously poisoned with
arsenic trioxide-contaminated chocolate (amount not stated). Both
immediately experienced a burning sensation in the mouth and within
minutes developed severe abdominal cramps, nausea and vomiting then
diarrhoea. Three days later abdominal pain recurred with
hypersalivation and haematemesis. Gastroscopy revealed a large gastric
ulcer in the fundus with severe oesophagitis and gastritis in one of
the subjects. Arsenic poisoning was not suspected initially and
chelation therapy not started until eight days post ingestion.
Analysis of urine samples taken on the day of admission showed arsenic
concentrations of 5.3 mg/L and 5.8 mg/L respectively. Severe pulmonary
and neurological features were also present but both patients
survived.
Hepatotoxicity
Bolliger et al (1992) reported a 30 year-old male maliciously poisoned
with arsenic trioxide (amount not stated) who developed transiently
increased alkaline phosphatase and liver transaminase activities plus
an increased bilirubin concentration. He eventually recovered.
Another patient (Levin-Scherz et al, 1987) died 62 hours after
ingesting 2 g arsenic trioxide following a clinical course complicated
by cardiovascular collapse, renal failure and eventually an asystolic
cardiac arrest. Hepatic transaminase activities were moderately
increased on admission (aspartate aminotransferase 206 IU/L).
Nephrotoxicity
Hypotension (Levin-Scherz et al, 1987; Jolliffe et al, 1991; Moore et
al, 1994) or rhabdomyolysis following substantial ingestion (Sanz et
al, 1989; Fernadez-Sola et al, 1991) may precipitate renal failure
(Bolliger et al, 1992). A case of arsenic-induced renal cortical
necrosis has been described (Gerhardt et al, 1978).
Cardiovascular toxicity
Tachycardia is typical following arsenic ingestion (Peterson and
Rumack, 1977; Levin-Scherz et al, 1987) and is contributed to by
anxiety, hypovolaemia and possibly direct arsenic-induced
cardiotoxicity.
Ventricular arrhythmias (St. Petery et al, 1970), notably torsade de
pointes (Beckman et al, 1991) have been observed. Other ECG
abnormalities include prolongation of the QT interval (Bolliger et al,
1992) and non-specific T wave changes.
Jolliffe et al (1991) reported massive acute arsenic trioxide
ingestion in a patient who developed sudden onset bradycardia then
asystole despite vigorous resuscitation and no earlier arrhythmia.
In another report (Levin-Scherz et al, 1987) a 21 year-old male
developed cardiovascular collapse 26 hours after ingesting 2 g arsenic
trioxide. The ECG initially showed a sinus tachycardia (140 bpm) and
"non-specific ST-T wave abnormalities" with a normal QT interval.
Thirty six hours after admission the patient became bradycardic (35
bpm) then developed ventricular fibrillation unresponsive to
cardioversion before an asystolic cardiac arrest from which he could
not be resuscitated.
Neurotoxicity
Acute substantial arsenical ingestion has caused muscle cramps, a
sensorineural hearing deficit (Goldsmith and From, 1980),
encephalopathy (Jenkins, 1966; Levin-Scherz et al, 1987) and seizures
(St. Petery et al, 1970; Peterson and Rumack, 1977).
A peripheral sensory and/or motor neuropathy, although typical of
chronic arsenic poisoning has been described also in survivors of
severe acute poisoning, often in association with dermal
manifestations of arsenic toxicity (Heyman et al, 1956; Kyle and
Pease, 1965; Jenkins, 1966; Le Quesne and McLeod, 1977).
Goebel et al (1990) demonstrated acute wallerian degeneration of
myelinated nerve fibres in a patient who developed a symmetrical
polyneuropathy after attempting suicide by ingesting arsenic. Clinical
improvement was associated with microscopic evidence of neurological
regeneration.
A 30 year-old male maliciously poisoned by arsenic trioxide (amount
not stated) developed a peripheral neuropathy and mild generalized
muscle weakness five days after ingestion (Bolliger et al, 1992). The
arsenic concentration in an admission urine sample was 5.3 mg/L, but
arsenic intoxication was not diagnosed until eight days after
ingestion. Muscle weakness increased, he became confused and
hallucinated. A decreased level of consciousness and respiratory
distress necessitated intubation and mechanical ventilation. The
neuropathy progressed following extubation and three weeks after
admission an electromyogram showed a severe polyneuropathy with axonal
degeneration. Muscle power in all limbs was 1/5. Severe paraesthesiae
in the hands and feet continued and the patient was confined to a
wheelchair. Twenty six months after intoxication he was able to walk
with aid and had regained 70 per cent hand function (Bolliger et al,
1992).
Dermal toxicity
Striate leukonychia (Mees' lines) and hyperkeratotic, hyperpigmented
skin lesions may be seen following severe acute arsenic poisoning
although are associated typically with chronic exposure. Facial and
peripheral oedema have also been described (Heyman et al, 1956; Kyle
and Pease, 1965).
Bolliger et al (1992), reported two subjects maliciously poisoned with
arsenic trioxide. Both developed maculopapular, partly vesicular, skin
rashes seven days after ingestion as well as severe gastrointestinal,
pulmonary and neurological symptoms.
Haemotoxicity
In moderate or severe arsenic poisoning investigations typically show
anaemia, leucopenia or pancytopenia (Kyle and Pease, 1965; Bolliger et
al, 1992). There may be evidence of intravascular haemolysis and the
blood film often shows basophilic stippling (Kyle and Pease, 1965; St.
Petery et al, 1970).
Oral toxicity
Yakata et al (1985) reported a case of mandibular osteolysis with an
occluded alveolar artery and alveolar nerve damage in which the
suspected cause was arsenic trioxide applied to a tooth for
devitalization.
Multi-organ toxicity
Severe acute arsenic poisoning may result in death from
cardiorespiratory or hepatorenal failure (Jenkins, 1966; Fernadez-Sola
et al, 1991; Morton and Dunnette, 1994). Two adults maliciously
poisoned by arsenic trioxide-contaminated chocolate developed
multi-organ failure complicated by adult respiratory distress syndrome
(Bolliger et al, 1992). They survived with persisting evidence of a
sensory peripheral neuropathy two years later.
CLINICAL FEATURES: CHRONIC EXPOSURE
Dermal exposure
The major source of dermal exposure is occupational. Metal ore
smelting is an important cause since arsenic trioxide is a by-product
of many processes (Hine et al, 1977).
Dermatitis is the most common manifestation of occupational arsenic
trioxide exposure due to either a direct irritant action or to
sensitization. Prolonged exposure has resulted in ulcerative lesions
of the extremities (Fielder et al, 1986). Systemic arsenic toxicity
may ensue (see below).
Inhalation
Exposure to arsenic trioxide dust has been reported in the metal ore
smelting industry and during the manufacture of inorganic arsenic
compounds (Fielder et al, 1986). Local effects include conjunctivitis,
hoarseness, pharyngitis, nasal irritation and haemoptysis (Heyman et
al, 1956; Hine et al, 1977). Nasal septum perforation is also
described (Fielder et al, 1986). Systemic features of arsenic
poisoning may ensue.
Ingestion
Arsenic trioxide has found widespread use in ethnic herbal remedies
(Kerr and Saryan, 1986; Kew et al, 1993). Contamination of well water
by arsenic trioxide and arsenic trisulphide has been reported as the
cause of systemic arsenic intoxication (Tsuda et al, 1995).
Systemic arsenic trioxide toxicity
The systemic features observed are similar for each source of exposure
which are considered together.
General toxic effects
Patients may present with general debility, progressive weakness,
fever and sweats (Heyman et al, 1956).
Dermal toxicity
The characteristic dermal manifestations are hyperkeratosis and
"raindrop" pigmentation of the skin (Heyman et al, 1956; Kyle and
Pease, 1965; Shannon and Strayer, 1989; Sass et al, 1993).
Hyperkeratoses appear as multiple small nodules which may coalesce to
form plaques and are found most commonly on the palms and soles.
Hyperkeratotic lesions may develop into squamous cell carcinomas which
are notable for their occurrence on non light-exposed areas of the
upper extremities and trunk (Shannon and Strayer, 1989).
Hyperpigmentation is more prominent in the axilla, groin, areola and
around the waist, typically with mucosal sparing (Shannon and Strayer,
1989).
Skin changes in chronic arsenic poisoning seem to be exacerbated by
poor nutritional status.
The fingernails may become brittle with transverse white striae (Mees'
lines) (Mees, 1919; Heyman et al, 1956; Kyle and Pease, 1965; Sass et
al, 1993).
Exfoliative dermatitis has been reported following arsenical drug
administration (Nicolis and Helwig, 1973).
Sass et al (1993) described a 37 year-old woman with chronic arsenic
intoxication. Her sister had added an unstated quantity of arsenic
trioxide to her coffee every morning for two years. She initially
developed a generalized "melanoderma" followed by a punctate
palmoplantar keratoderma. Histological examination showed dermal
thickening, hyperkeratoses, hyperpigmentation and nuclear atypia
analogous to Bowen's disease. Later examination revealed Mees' lines.
Her cutaneous lesions remained unchanged four years later.
A 35 year-old man developed Mees' lines on the fingernails and
hyperkeratoses of the soles of the feet six weeks after starting to
use an ethnic remedy for atopic eczema. The remedy contained arsenic
trioxide, 210 mg per daily dose (Kew et al, 1993)
Neuropsychological toxicity
A symmetrical peripheral neuropathy is typical (Feldman et al, 1979).
Sensory symptoms predominate with paraesthesiae, numbness and pain,
particularly of the soles of the feet, extending in a "glove and
stocking" distribution (Jenkins, 1966; Kew et al, 1993).
Motor involvement with symmetrical distal limb weakness, muscle
atrophy and loss of deep tendon reflexes is recognized (Heyman et al,
1956; Bansal et al, 1991).
Complete respiratory muscle paralysis (Greenberg et al, 1979; Gerhardt
et al, 1980), a phrenic neuropathy (Bansal et al, 1991) and cranial
nerve involvement have been reported.
The neuropathy may be confused with the Guillain-Barré syndrome (Kyle
and Pease, 1965; Donofrio et al, 1987). Gastrointestinal symptoms and
skin manifestations suggest arsenic poisoning, while a high CSF
protein concentration and cranial nerve involvement are more typical
of the Guillain-Barré syndrome.
Electromyelography may show reduced peripheral nerve conduction
velocities in the absence of symptoms (Lagerkvist and Zetterlund,
1994).
Psychological impairment is widely reported in chronic arsenic
poisoning with defects of verbal learning ability and memory and
personality changes (Heyman et al, 1956; Bolla-Wilson and Bleecker,
1987). Beckett et al (1986) described a 50 year-old chemical plant
engineer who developed delirium, agitation and emotional lability
after some 20 years occupational arsenic exposure in an antimony
smelting plant.
Gastrointestinal toxicity
Nausea and vomiting, although more typical of acute arsenic poisoning,
may occur also in chronic cases.
Hepatotoxicity
Although animal studies suggest arsenic trioxide inhalation or
ingestion causes liver damage (Hine et al, 1977) there is little
evidence for this following occupational exposure (Fielder et al,
1986).
Narang (1987) suggested increased arsenic consumption as a
contributing factor in the aetiology of liver disease in the Indian
population when he found significantly increased hepatic arsenic
concentrations at autopsy in 178 patients dying from cirrhosis, non
cirrhotic portal fibrosis, fulminant hepatitis, Wilson's disease or
alcoholic liver disease.
Jhaveri (1959) reported the death of 46 year-old man from cirrhosis
and primary carcinoma of the liver. Over 20 years occupational
exposure (in chemical manufacture) to arsenic trioxide and sodium
arsenite was thought to be aetiologically significant. The patient had
increased urine, hair and nail arsenic concentrations.
Nephrotoxicity
Renal manifestations of chronic arsenic poisoning probably reflect
capillary damage and include haematuria, proteinuria with casts and
acute tubular or cortical necrosis (Morton and Dunnette, 1994).
In a study of 84 smelter workers chronically exposed to arsenic
trioxide Telolahy et al (1993) found increased concentrations of
urinary coproporphyrins compared to non-exposed controls. This
reflects arsenic-induced impaired haem metabolism (see below).
Peripheral vascular and cardiovascular toxicity
"Black foot disease" refers to a severe form of peripheral vascular
disease seen in Taiwan in those who drink artesian well water with an
high arsenic concentration. Initial paraesthesiae and cold sensitivity
progress to ulceration and gangrene (Chiou et al, 1995). It has been
suggested that mortality due to all vascular diseases may be increased
in these populations (Chen and Lin, 1994; Engel et al, 1994).
Raynaud's syndrome has also been described in those chronically
exposed to arsenical dust (Lagerkvist et al, 1988).
Several authors refer to the myocardial toxicity of arsenic
(Schoolmeester and White, 1980; Hall and Harruff, 1989) which has been
attributed to impaired oxidative metabolism of myocardial tissue plus
a direct arsenic-induced inflammatory process. A 42 year-old
agricultural worker presented with systemic features of chronic
arsenic poisoning (neuropathy and skin lesions) and had a 24 hour
urine arsenic excretion of 7000 µg (Hall and Harruff, 1989). He
received a 15 day course of dimercaprol with some improvement in motor
function. On the 26th day of hospital admission he suddenly collapsed
and died following a cardiac arrest. At post-mortem he had a diffuse
interstitial myocarditis which was assumed to have triggered a fatal
arrhythmia.
Haemotoxicity
Investigations in chronic arsenic poisoning often show anaemia,
neutropenia (Heyman et al, 1956; Kyle and Pease, 1965), pancytopenia
or evidence of haemolysis (Kyle and Pease, 1965) but macrocytosis
without anaemia (Heaven et al, 1994) and a myelodysplastic syndrome
(Rezuke et al, 1991) are also described.
Haematological analyses of 130 smelter workers occupationally exposed
to arsenic trioxide (concentrations not stated) revealed a relative
neutropenia in 23 per cent of cases (Hine et al, 1977). Sass et al
(1993) noted moderate anaemia and leucopenia (values not stated) in a
37 year-old woman maliciously poisoned with an unstated amount of
arsenic trioxide daily for over two years.
Chronic arsenic exposure complicated by aplastic anaemia may
predispose to acute myeloid leukaemia (Kjeldsberg and Ward, 1972).
Disrupted haem metabolism with altered urinary porphyrin excretion
(Telolahy et al, 1993) has been reported.
Endocrine toxicity
An occupational study among smelter workers in Sweden (Lagerkvist and
Zetterlund, 1994) has associated chronic arsenic exposure with the
development of diabetes mellitus.
MANAGEMENT
Dermal exposure
Surface decontamination should be attempted where necessary. Treat
burns conventionally. Consider the possibility of systemic arsenic
poisoning and the need for chelation therapy (see below).
Ocular exposure
Irrigate the eye with copious lukewarm water. A topical anaesthetic
may be necessary for pain relief. Seek an ophthalmic opinion if
symptoms persist or examination is abnormal.
Inhalation
Immediate management involves removal from exposure and administration
of supplemental oxygen if necessary. Evidence of systemic arsenic
uptake should be sought and chelation therapy considered as discussed
below.
Ingestion
Decontamination
After acute ingestion of a substantial quantity of arsenic trioxide
most patients will vomit spontaneously but, in those who do not,
gastric lavage should be considered only if it is possible to
undertake the procedure within the first hour.
Supportive measures
Severe acute arsenic trioxide poisoning requires prompt intensive
resuscitation with adequate fluid replacement and close observation of
vital signs including cardiac monitoring. Diarrhoea may be treated
symptomatically with loperamide. Chelation therapy should be
considered in symptomatic cases. Obtain blood and urine for arsenic
concentration determination.
Electrocardiographic evidence of QT prolongation in arsenic poisoning
may precede atypical ventricular arrhythmias, notably torsade de
pointes, and in these circumstances drugs which themselves prolong the
QT interval, such as procainamide, quinidine or disopyramide, should
be avoided. Isoprenaline is effective; phenytoin, lignocaine or
propranolol are alternatives (Goldsmith and From, 1980).
Antidotes
Chelating agents used in the treatment of arsenic poisoning are
dithiol compounds which can remove arsenic from endogenous sulphydryl
groups, the targets of arsenic toxicity (Jones, 1995).
Traditionally, dimercaprol (British anti-lewisite, BAL) has been the
recommended chelator in arsenic intoxication (Jenkins, 1966; Greenberg
et al, 1979; Roses et al, 1991). However, dimercaprol may produce
unpleasant adverse effects and must be administered by deep
intramuscular injection. There is increasing evidence that
dimercaptosuccinic acid (DMSA, Succimer) (Aposhian et al, 1984;
Graziano, 1986; Fournier et al, 1988; Inns et al, 1990) and
dimercaptopropane sulphonate (DMPS, Unithiol) (Aposhian, 1983;
Aposhian et al, 1984; Hruby and Donner, 1987; Inns et al, 1990) are
less toxic and may be preferable. DMSA and DMPS are more effective in
reducing the arsenic content of tissues, they increase biliary as well
as urinary arsenic elimination and, unlike dimercaprol, do not appear
to cause arsenic accumulation in the brain (Kreppel et al, 1990; Moore
et al, 1994). On the other hand, arsenic mercaptide (the chelation
complex of dimercaprol and arsenic) is dialysable and hence
dimercaprol may be preferred in the presence of renal failure (Sheabar
et al, 1989; Mathieu et al, 1992)
The importance of an increased urine arsenic concentration in
determining the need for chelation therapy is disputed. Kersjes et al
(1987) suggested a spot urine concentration greater than 200 µg/L
should be taken as an indication of "significant" arsenic exposure but
Kingston et al (1993) emphasised that arsenic concentrations
significantly higher than this (3500 µg/24 h and 5819 µg/24 h in two
of their patients) may be observed in the acute phase following
pentavalent arsenic ingestion without severe sequelae.
Dimercaprol (British anti-lewisite; BAL)
Dimercaprol was developed during the Second World War as an antidote
for lewisite (dichloro(2-chlorovinyl) arsine) poisoning (Peters et al,
1945). It possesses two sulphydryl groups and forms a stable
mercaptide ring with arsenic. The alcohol group on dimercaprol confers
some degree of water solubility, thereby enhancing excretion from the
body. As the chelation complex tends to dissociate it is necessary to
maintain a constant excess of dimercaprol. Unlike DMSA and DMPS,
dimercaprol is also lipid soluble and increases the brain arsenic
concentration in arsenic-intoxicated animals (Jones, 1995).
Though increasingly superseded by the less toxic thiol chelating
agents, intramuscular dimercaprol remains useful in severe arsenic
poisoning where vomiting prevents oral antidote administration,
supplies of DMSA or DMPS are not rapidly available (Jolliffe et al,
1991) or renal failure requires haemodialysis; dimercaprol but not
DMSA chelates can cross the dialysis membrane (Sheabar et al, 1989;
Mathieu et al, 1992).
Animal studies
Stocken and Thompson (1946) demonstrated increased urine arsenic
excretion (up to 33.5 per cent of the amount applied) in the 24 hours
following cutaneous application of lewisite to rodents, when
dimercaprol (dose not stated) was spread over the affected area up to
one hour later. Dimercaprol also prevented arsenic-induced diarrhoea
observed in control animals.
Intravenous injection of dimercaprol glucoside 1.5 g/kg prevented
death in two rabbits poisoned with cutaneous lewisite (12 mg/kg).
Eleven control animals died, as did two treated with subcutaneous
dimercaprol 0.07 g/kg (Danielli et al, 1947).
A recent study has demonstrated that intramuscular dimercaprol
protects rabbits against the lethal systemic effects of intravenously
administered lewisite. No appreciable difference was found between the
protective effect of dimercaprol and that of water soluble analogues
DMPS and DMSA (Inns et al, 1990).
Clinical studies
In a case series, 12 men were exposed to smoke containing
diphenylcyano-arsenic (1.6 mg/m3), "other forms of organic arsenic"
(0.5 mg/m3) and "inorganic arsenic" (1.8 mg/m3) for six minutes.
They were treated with 3.5 mg/kg intramuscular dimercaprol 6.5-78
hours post exposure. Urine arsenic excretion increased by an average
of 40 per cent between two and four hours after the injection. The
largest increase, both absolute and relative, was observed in those
treated earliest (6.5 hours after exposure) (Wexler et al, 1946).
Giberson et al (1976) described the treatment of a 44 year-old male
who ingested 400 mg sodium arsenite. Intramuscular dimercaprol 250 mg
was administered every four hours. Haemodialysis was initiated in
response to renal failure with 3.3 mg arsenic removed over four hours.
By the sixth day, when renal function had recovered, arsenic excretion
had reached 75 mg/24h with at least 115 mg arsenic excreted between
days two and six.
A four year-old boy who had ingested an unknown amount of arsenic
trioxide rat poison was treated with dimercaprol 5 mg/kg every four
hours for 16 hours. The urine contained 2,120 µg arsenic over the
first 12 hours. He developed an urticarial rash over the lower
extremities which subsided with the discontinuation of dimercaprol.
The urine arsenic concentration decreased gradually during
d-penicillamine treatment (Peterson and Rumack, 1977).
Schoolmeester and White (1980) reported a 16 year-old female who
ingested 300 mg sodium arsenate in a suicide attempt. She received
intramuscular dimercaprol 125 mg every four hours for the first 24
hours, then twice daily for 24 hours. A 24 hour urine arsenic
concentration (starting time not specified) was 14,200 µg/L. The
effect of chelation therapy on arsenic excretion is not known but the
patient fully recovered.
Mahieu et al (1981) described a 44 year-old male who ingested an
unknown amount of arsenic trioxide which had been mistaken for sugar.
The dose "certainly exceeded 1000 mg". Intramuscular dimercaprol 2.5-4
mg/kg tds was administered for 21 days. Initial arsenic excretion was
low due to renal insufficiency but increased to 10 mg/24h from three
to seven days post ingestion. The patient excreted a total of 129 mg
arsenic during his 26 days in hospital. A 40 year-old woman poisoned
at the same time and treated with the same regimen for 17 days
excreted 16.7 mg arsenic on the first day, the amount decreasing on
subsequent days. Seventy three milligrams arsenic were eliminated over
three weeks.
A 32 year-old man who ingested 900 mg sodium arsenate in a suicide
attempt commenced treatment with intramuscular dimercaprol 5 mg/kg
four hourly five hours later. Dimercaprol was stopped on day four.
This patient also received oral d-penicillamine and intravenous then
oral N-acetylcysteine between days two and 82 post ingestion. The
urine arsenic concentration rose on the second hospital day then
declined progressively during the next week although the data were
incomplete and uninterpretable (Bansal et al, 1991).
A 22 month-old female who developed diarrhoea, vomiting and lethargy
after ingesting approximately 0.7 mg sodium arsenate was treated
initially with one intramuscular dose of dimercaprol 3 mg/kg nine
hours post ingestion. Three hours later the infant was asymptomatic
and dimercaprol therapy discontinued although she subsequently
received oral d-penicillamine then oral DMSA to treat persisting high
urine arsenic concentrations (4880 µg/L in the first 24 hours after
admission) (Cullen et al, 1995). On the third hospital day the urine
arsenic concentration (from a 24 hour collection) was 1355 µg/L and
fell progressively to 96 µg/L on day 12. These data do not enable any
conclusions to be drawn regarding enhanced arsenic elimination.
No benefit from dimercaprol was reported by McCutchen and Utterback
(1966) in the treatment of severe chronic arsenic poisoning. Other
authors have reported disappointing results with dimercaprol in the
management of arsenic neuropathy (Heyman et al, 1956) although Jenkins
(1966) described "no detectable disability" 18 months after acute
sodium arsenite ingestion in a patient who developed a peripheral
neuropathy and received "a full course of dimercaprol" (details not
given).
Marcus (1987) described a 16 year-old male who survived ingestion of
56 mg arsenic trioxide following treatment with intramuscular
dimercaprol 4 mg/kg every four hours (duration not stated). The
maximum urine arsenic excretion was "over 50 mg/day" falling to 20
µg/day by day 31. At twelve month follow-up neurological effects
persisted.
Mahieu et al (1981) suggested that a high (greater than 90 per cent)
proportion of methylated arsenic in the urine of poisoned patients
could be used to indicate a late presentation with less likelihood of
benefit from chelation therapy.
Treatment protocol
Dimercaprol must be given by deep intramuscular injection. After
injection 90 per cent of an administered dose is absorbed and Cmax is
attained within one hour (Peters et al, 1947). Dimercaprol is
distributed throughout the intracellular space and metabolic
degradation and excretion is complete in less than four hours.
Depending on severity, 2.5-5 mg/kg should be administered four hourly
for two days. This is to ensure that a constant excess of dimercaprol
is always present as the chelation complex dissociates. Traditionally,
this initial treatment is followed by 2.5 mg/kg bd intramuscularly for
one to two weeks. However, this is an empirical recommendation and may
be insufficient in severe cases. Dosage and duration should be
adjusted therefore, depending on urine arsenic removal.
Adverse effects
The most common adverse effect of dimercaprol is dose-related
hypertension (with an increase in systolic pressure of up to 50 mmHg)
which usually resolves within three hours of administration (Dollery,
1991) but may be associated with nausea, headache, sweating and
abdominal pain. Gastrointestinal disturbance may also occur without
hypertension. Conjunctivitis, paraesthesiae and fever have been
described.
Dimercaprol is contraindicated in severe liver disease since it is
metabolized by glucuronidation with subsequent biliary excretion.
DMSA
DMSA is commercially available in some countries (though not the UK)
mainly as meso-DMSA, although a DL-form also exists.
Animal studies
Aposhian et al (1984) demonstrated that DMSA was moderately more
effective than DMPS (and substantially more effective than
dimercaprol) in protecting mice from the lethal effects of sodium
arsenite. DMSA mobilizes arsenic from tissues, increasing urine
arsenic excretion without a rise in brain arsenic concentrations
(Aposhian et al, 1984).
Mice administered subcutaneous arsenic trioxide (5 mg/kg) followed
immediately by intraperitoneal DMSA 100 mg/kg, showed significantly
increased urine arsenic excretion (p<0.01) in the first 12 hours post
chelation although the 48 hour urine arsenic elimination was not
significantly different between DMSA-treated mice and controls
(Maehashi and Murata, 1986).
In animal studies DMSA protected against the embryotoxic effects of
sodium arsenite but only when given within one hour of exposure
(Bosque et al, 1991).
Recent experiments suggest that oral monoester DMSA analogues may
offer renal protection in arsenic poisoning by increasing the enteral
arsenic content to enhance faecal rather than renal elimination
(Hannemann et al, 1995). In other animal studies lipophilic DMSA
analogues were inferior to the parent compound as arsenic antidotes
(Kreppel et al, 1993).
Clinical studies
Lenz et al (1981) described a 46 year-old man who ingested 200 mg
arsenic and survived following treatment with oral DMSA 300 mg qds for
three days.
Kosnett and Becker (1987) reported an increase in the 24 hour urine
arsenic excretion from 26 µg to a maximum of 340 µg on the second day
of oral DMSA 660 mg tds in a patient who presented more than 30 days
after malicious acute arsenic ingestion.
Nine days after ingesting approximately 0.7 mg of a soluble arsenic
salt a 22 month-old female was treated with oral DMSA 30 mg/kg/day for
at least four days (Cullen et al, 1995). The child had already
received chelation therapy with dimercaprol and d-penicillamine, but
further treatment was instituted because of a persistently raised
urine arsenic concentration (650 µg/L on day five). Four days later
the urine arsenic concentration had fallen to 96 µg/L. The authors
reported an overall urine arsenic half-life of 2.6 days. Although the
child initially experienced vomiting, diarrhoea and lethargy these
features resolved within 12 hours and renal and hepatic function
remained normal throughout (Cullen et al, 1995).
There was no objective improvement in the neurological manifestations
of chronic arsenic poisoning in a man poisoned by an ethnic remedy
despite two weeks therapy with oral DMSA 400 mg tds (Kew et al, 1993).
No urine arsenic excretion data were given.
A 33 year-old woman with acute-on-chronic lead and arsenic poisoning
from a herbal remedy clinically recovered following two one-week
courses of oral DMSA 270 mg tds, though the effect of chelation
therapy on urine arsenic excretion is difficult to interpret
(Mitchell-Heggs et al, 1990).
Treatment protocol
DMSA is given orally in a dose of 30 mg/kg body weight per day; an
intravenous preparation is available in some countries and may be
preferable if the patient is vomiting (Hantson et al, 1995).
Adverse effects
Side-effects following treatment with DMSA are rare but include skin
rashes, gastrointestinal disturbance, elevation of serum transaminase
activities and flu-like symptoms (Reynolds, 1993). DMSA should be used
with caution in patients with impaired renal function or a history of
hepatic disease (Reynolds, 1993).
DMPS
Animal studies
DMPS is commercially available as a racemic mixture of the
dextro-rotatory and levo-rotatory forms which appear to be equally
effective arsenic chelators (Aposhian, 1983), though animal studies
suggest DMSA may be superior to either (Aposhian et al, 1984).
Urine arsenic elimination of arsenic-poisoned rats in the 48 hours
post treatment with DMPS 100 mg/kg intraperitoneally was significantly
lower (p<0.05) than in either control (5 mg/kg subcutaneous arsenic
trioxide only) or DMSA-treated mice (Maehashi and Murata, 1986).
However DMPS significantly increased (p<0.01) faecal arsenic
elimination in the 24 hours post chelation compared to control or DMSA
treated mice, suggesting biliary excretion of the DMPS-arsenic chelate
(Maehashi and Murata, 1986).
Other authors have noted enhanced biliary but not faecal arsenic
excretion following parenteral DMPS administration to arsenic-poisoned
experimental animals. This suggests enterohepatic circulation of the
chelate, which Reichl et al (1995) attempted to block using oral
cholestyramine. They demonstrated enhanced faecal arsenic elimination
(p<0.05) when intraperitoneal DMPS 0.1 mmol/kg and subcutaneous
arsenic trioxide (0.02 mmol/kg) administration was followed by an oral
combination of cholestyramine (0.2 g/kg) and DMPS 0.1 mmol/kg (Reichl
et al, 1995).
Domingo et al (1992) demonstrated a protective effect of DMPS
150-300 mg/kg, but not dimercaprol, against experimental
arsenite-induced embryotoxicity and teratogenicity as judged by the
incidence of foetal malformation or death in mice administered
intraperitoneal sodium arsenite (12 mg/kg) on day nine of gestation.
Clinical studies
Two men inadvertently ingested 1 g and 4 g arsenic trioxide
respectively (Moore et al, 1994). The more severely poisoned patient
developed acute renal failure and 26 hours post ingestion had a blood
arsenic concentration of 400 µg/L. He received intravenous DMPS 5
mg/kg every four hours for six days then oral DMPS 400 mg every four
hours for one week. The other patient had a blood arsenic
concentration of 98 µg/L, 36 hours post ingestion and received a
shorter course of intravenous then oral DMPS. Both patients recovered
fully but quantitative data showing the effect of chelation therapy on
urine arsenic elimination were documented poorly.
In another report there was no objective improvement in the
neurological manifestations of chronic arsenic poisoning in a patient
treated with oral DMPS 100 mg tds for three weeks (Kew et al, 1993).
Treatment protocol
DMPS is given orally or parenterally in a dose of 30 mg/kg body weight
per day.
Adverse effects
Side effects following treatment with DMPS are infrequent but have
included allergic skin reactions, nausea, vertigo and pruritis
(Aposhian, 1983).
d-Penicillamine
Animal studies
d-Penicillamine has been reported to be as effective as dimercaprol
and NAC in prolonging the survival time of mice injected with a lethal
dose of sodium arsenite (Shum et al, 1981). Other studies have
disputed the validity of these results and have failed to demonstrate
d-penicillamine as a useful chelator (Aposhian, 1982; Kreppel et al,
1989).
Clinical studies
Peterson and Rumack (1977) described three children who shared a
bottle of rat poison containing arsenic trioxide 1.75 per cent. One
died within hours following a rapidly deteriorating course of coma,
convulsions and cardiac arrhythmias. The second, a four year-old male,
presented with lethargy, a sinus tachycardia and tachypnoea. Oral d-
penicillamine 25 mg/kg qds replaced dimercaprol treatment after 16
hours when the patient developed an urticarial rash over the lower
extremities. The first twelve-hour urine collection during dimercaprol
treatment contained 2,120 µg arsenic with the urine arsenic
concentration decreasing during the five days d-penicillamine therapy.
The child made a full recovery.
The third patient (Peterson and Rumack, 1977) had no severe features
of toxicity at presentation. He received the same chelation therapy
regimen as patient 2. On the second day post ingestion the 24 hour
urine arsenic excretion was 300 µg, increasing in the next 24 hours
(the second day of d-penicillamine therapy) to approximately 800 µg.
This patient also recovered fully.
A one year-old child ingested 15-20 mg sodium arsenate (as ant poison)
and was treated within six hours with 5 mg/kg intramuscular
dimercaprol (Peterson and Rumack, 1977). The chelating agent was then
changed to oral d-penicillamine 100 mg/kg/day and continued for five
days. An initial 12 hour urine collection (commenced approximately six
hours post ingestion) contained 192 µg arsenic, increasing to 2000 µg
arsenic in the next 24 hours before falling to approximately 200 µg/24
h on day two. These authors advocated d-penicillamine 100 mg/kg/day as
the treatment of choice in arsenic poisoning (where oral therapy is
possible). They recommended d-penicillamine should be continued until
the 24 hour urine arsenic excretion is less than 50 µg (Peterson and
Rumack, 1977).
A 16 month-old child was given a five day course of oral
d-penicillamine 250 mg qds 14 hours after ingesting 9-14 mg arsenic
trioxide. Clinical features of toxicity (diarrhoea, vomiting and
lethargy) resolved within 24 hours and the child was discharged on day
three. The arsenic concentration in urine collected during the first
day of treatment was 560 µg/L. However, no earlier urine arsenic
concentrations were measured and prior to d-penicillamine therapy the
patient had received 185 mg dimercaprol over 18 hours (Watson et al,
1981).
DiNapoli et al (1989) instituted d-penicillamine therapy in a patient
unable to tolerate intramuscular dimercaprol following intravenous
sodium arsenite injection. d-Penicillamine 500 mg tds was administered
and after ten days a 24 hour urine arsenic excretion of 2 mg was
reported. There were no symptoms of bone marrow depression, haemolysis
or peripheral neuropathy. After a further ten days treatment the urine
arsenic concentration was 20 µg/L.
Bansal et al (1991) described a 35 year-old man with severe arsenic
polyneuropathy involving the phrenic nerves bilaterally, who recovered
following d-penicillamine therapy 250 mg tds for two weeks (route of
administration was not stated). However, the 24 hour urine arsenic
excretion only rose to 82.4 µg/g creatinine in the first 72 hours of
chelation compared to a pretreatment value of 73.5 µg/g creatinine.
Cullen et al (1995) reported a 22 month-old child who ingested some
0.7 mg sodium arsenate. Following a single dose of dimercaprol 3
mg/kg, oral d-penicillamine therapy was commenced, 250 mg qds for nine
doses. By day four the 24 hour urine arsenic concentration had dropped
from 4880 to 682 µg/L. The child was discharged on day six on oral
d-penicillamine therapy (dose not stated) but readmitted three days
later due to a persistently high urine arsenic excretion (650 µg/L on
day five). At this stage d-penicillamine was replaced by DMSA since
the child had developed an erythematous rash.
Oral d-penicillamine 250 mg qds for seven days failed to increase
urinary arsenic elimination in a patient with chronic arsenic
poisoning whose initial 24 hour urine arsenic excretion was 342 µg
(normal <5 µg/24 h) (Heaven et al, 1994).
In another report the urine arsenic concentration in a 67 year-old man
with arsenic-associated aplastic anaemia had risen to 20,246 µg/L
after four days penicillamine therapy 500 mg qds compared to a
pretreatment concentration of 7840 µg/L (Kjeldsberg and Ward, 1972).
The patient died from acute myeloid leukaemia some six months later.
N-acetylcysteine
Animal studies
The survival time of mice injected subcutaneously with a lethal dose
of sodium arsenite (25 mg/kg) was increased significantly (p<0.05) if
intraperitoneal N-acetylcysteine (NAC) 100 mg/kg was administered 30
minutes later. There was no significant difference between this dose
of NAC, dimercaprol 5 mg/kg and d-penicillamine 50 mg/kg as an
antidote under these conditions (Shum et al, 1981).
Clinical studies
Martin et al (1990) reported "remarkable clinical improvement" in a 32
year-old man with severe arsenic poisoning following ingestion of a
soluble salt when he was administered intravenous NAC 70 mg/kg four
hourly after dimercaprol had "failed to improve his condition".
However urinary arsenic excretion data were poorly documented and
dimercaprol was continued during treatment with NAC.
Antidotes: Conclusions and recommendations
1. There are no controlled clinical trials of chelation therapy in
arsenic poisoning and no conclusive evidence that dithiol
antidotes reverse arsenic-induced neurological damage. On the
present evidence it is difficult to recommend a single preferred
antidote, though in the absence of renal failure DMSA may offer
some advantages over other agents; if renal failure supervenes
dimercaprol and haemodialysis should be employed.
2. Chelation therapy should be considered in symptomatic patients
where there is analytical confirmation of the diagnosis.
3. Although urine arsenic concentrations are useful to confirm the
diagnosis of arsenic poisoning chelation therapy should not be
instituted on the basis of an increased urine arsenic
concentration alone.
Haemodialysis
Haemodialysis removes arsenic from the blood but achieves less
effective arsenic clearance than chelation therapy when normal renal
function is present. It is indicated therefore only in the presence of
renal failure.
Giberson et al (1976) reported an arsenic dialysis clearance of 87
mL/min. During four hours of dialysis 3360 µg arsenic was removed in a
patient with acute arsenic poisoning complicated by renal failure who
was also receiving 250 mg intramuscular dimercaprol six times daily.
The 24 hour urine arsenic excretion on the same day was 2030 µg though
this increased to 75,000 µg/24 h on the sixth hospital day when renal
function had recovered.
A similar haemodialysis arsenic clearance of 76-87 mL/min was
demonstrated in another patient with acute sodium arsenite
intoxication complicated by acute renal failure (Vaziri et al, 1980).
Levin-Scherz et al (1987) instituted haemodialysis promptly in a
patient who presented 26 hours after ingesting 2 g arsenic trioxide.
The patient also received intramuscular dimercaprol, 300 mg initially
then 180 mg every four hours, but died within 72 hours of ingestion.
The maximum amount of arsenic removed in the dialysate was 2.9 mg.
Mathieu et al (1992) demonstrated a haemodialysis clearance comparable
to some 40-77 per cent of the daily arsenic renal elimination on the
day following diuresis recovery. In this case the total blood
haemodialysis clearance (210 mL/min) exceeded the instantaneous plasma
haemodialysis clearance (mean 85 mL/min), suggesting that some arsenic
removed by haemodialysis originated in erythrocytes. These authors
showed similar haemodialysis arsenic clearance with or without prior
administration of intramuscular dimercaprol 250 mg, and advocated
dimercaprol as the chelating agent of choice in arsenic poisoning
complicated by renal failure, since it does not impair arsenic
dialysis clearance.
Experimental evidence in dogs (Sheabar et al, 1989) suggests
DMSA-arsenic chelates do not pass through the dialyser membrane.
Haemoperfusion
A 37 year-old man presented within four hours of ingesting 90 mL of a
1.5 per cent arsenic trioxide solution (Smith et al, 1981). Although
initially only tachycardic he subsequently became hypotensive and
oliguric. For the first 48 hours he received 200 mg intramuscular
dimercaprol four hourly then d-penicillamine 500 mg qds. Charcoal
haemoperfusion was instituted 11 hours after admission followed by two
hours haemodialysis. These therapies were repeated over the next four
days but "discontinued because of continued good renal function and
lack of clinical response". Serum arsenic concentrations immediately
post haemoperfusion were slightly higher than pre-haemoperfusion
values, suggesting no benefit.
MEDICAL SURVEILLANCE
Blood arsenic concentrations correlate poorly with exposure but may be
useful in chronic poisoning (Morton and Dunnette, 1994).
Arsenic concentrations in hair and nails have been used to indicate
chronic systemic absorption, although their use as biological monitors
of occupational exposure to airborne arsenic is limited by difficulty
in excluding external contamination (Yamamura and Yamauchi, 1980).
Urine arsenic concentrations are the most useful biomonitoring tool,
ideally as total excretion from a 24 hour collection although spot
urine arsenic concentrations have been proposed in screening
asymptomatic patients with a history of possible acute arsenic
ingestion (Grande et al, 1987).
Since certain marine organisms (especially mussels) may contain large
amounts of organoarsenicals, it is advisable that workers refrain from
eating seafood for at least 48 hours before urine collection (Buchet
et al, 1994). Analytical speciation methods capable of separating
inorganic arsenic and its methylated derivatives from dietary
organoarsenicals partially overcome this problem (Smith et al, 1977;
Farmer and Johnson, 1990; Buchet et al, 1994). However, Vahter (1994)
has suggested that under certain circumstances these compounds are
released from seafood which can invalidate assessment of inorganic
arsenic exposure.
Smith et al (1977) demonstrated a close correlation between airborne
arsenic and urinary excretion of all arsenic species in arsenic-
exposed workers and Farmer and Johnson (1990) found that high urine
concentrations of inorganic arsenic plus its mono- and dimethyl
derivatives corresponded to the possible workplace atmospheric arsenic
concentrations for those involved in arsenic production or glass
manufacture. Increased urine arsenic concentrations have also been
noted in timber treatment workers using an arsenic-based wood
preservative (Gollop and Glass, 1979).
Telolahy et al (1993) suggested a potential role for increased urine
coproporphyrins as an indicator of chronic occupational arsenic
exposure since arsenic is known to disrupt haem metabolism.
Regular examination of the skin should be included in an occupational
health surveillance programme. Workers with evidence of excessive
arsenic exposure should be offered long-term monitoring for the
development of skin, bladder or lung cancer, though in practice this
may be difficult to execute.
OCCUPATIONAL DATA
Maximum exposure limit
Long-term exposure limit (8 hour TWA reference period) 0.1 mg/m3
(Health and Safety Executive, 1995).
OTHER TOXICOLOGICAL DATA
Carcinogenicity
Individuals who chronically ingest arsenic have an increased risk of
developing skin cancer, usually squamous cell carcinoma but also basal
cell carcinomas (Chen et al, 1988; Shannon and Strayer, 1989; Chiou et
al, 1995). Squamous cell carcinomas may arise in areas of arsenic-
induced Bowen's disease (Shannon and Strayer, 1989).
Hsueh et al (1995) demonstrated a significant dose-response
relationship between skin cancer prevalence and arsenic exposure from
artesian well water. These authors identified chronic hepatitis B
carriage and malnutrition as risk factors for arsenic-induced
dermatological malignancy.
Skin cancer has also been documented among vineyard workers and
farmers exposed to inhaled inorganic arsenic in pesticides (Thiers et
al 1967; Chen and Lin, 1994) although skin and gastrointestinal
absorption probably contributed to arsenic toxicity in these cases.
Renwick et al (1981) investigated the long term effects of acute
arsenic trioxide poisoning. Sixty two of over 200 students who had
eaten sausages containing 1.36 g/kg arsenic trioxide were contacted 35
years after the incident. Three had developed rodent ulcers but this
incidence may have been related solely to tropical sunlight exposure.
There is an association between chronic arsenic exposure and cancer of
the urinary tract (Chen et al, 1988; Chen and Lin, 1994; Tsuda et al,
1995), lung (Chen and Lin, 1994; Simonato et al, 1994; Tsuda et al,
1995) and liver, both hepatic angiosarcoma (Lander et al, 1975) and
hepatocellular carcinoma (Chen and Lin, 1994). Jhaveri (1959) reported
a case of cirrhosis and primary liver cancer in a man occupationally
exposed to arsenic trioxide and sodium arsenite for over 20 years.
Arsenic may be responsible also for lung cancer occurring in workers
employed in the lead, tin and copper-smelting industries (Axelson et
al, 1978).
Smoking exerts a synergistic effect with ingested and inhaled arsenic
in the development of pulmonary malignancy (Tsuda et al, 1995).
There is limited evidence that other internal cancers, particularly of
the gastrointestinal tract and haematological malignancies, are linked
aetiologically to arsenic exposure (Chen and Lin, 1994).
Reprotoxicity
Animal studies suggest arsenic is embryotoxic and teratogenic but
reliable human data are scarce (Council on Scientific Affairs, 1985).
Bolliger et al (1992) described a 39 year-old woman maliciously
poisoned with arsenic trioxide when 28 weeks pregnant. Her initial
urine arsenic concentration was 5.8 mg/L. She developed multiple organ
failure with adult respiratory distress syndrome and the fetus died
in utero. Fetal organs, notably the liver (26 mg/kg), kidneys (12
mg/kg), spleen (8 mg/kg) and stomach (8 mg/kg) contained increased
arsenic concentrations.
A woman in the third trimester of pregnancy developed acute renal
failure after ingesting a large quantity of an arsenical rat poison.
Her baby was delivered on the fourth day post ingestion but died
within a few hours from hyaline membrane disease. At autopsy the
infant showed significant arsenic accumulation in the liver, brain and
kidneys (liver arsenic concentration 0.74 mg/100 g tissue) (Lugo et
al, 1969).
Genotoxicity
The frequency of sister chromatid exchanges in human peripheral
lymphocytes exposed to 2 µg/mL was above that of controls.
Neither chromatid nor chromosome aberrations were observed in
spermatogonia or bone marrow cells following intraperitoneal
administration of 0-12 mg arsenic per kilogram to mice (DOSE, 1992).
Fish toxicity
Rainbow trout (8 wk) : 1-137 µg arsenic per gram in diet, no observed
effects.
: 137-1477 µg arsenic per gram in diet reduced
growth. Reduced feed behaviour has also been reported.
LC50 (48 hr) Channa punctatus 14.7 mg (DOSE, 1992).
EC Directive on Drinking Water Quality 80/778/EEC
Maximum admissible concentration 50 µg/L, as arsenic (DOSE, 1992).
WHO Guidelines for Drinking Water Quality
Guideline value 10 µg/L, as arsenic (WHO, 1993).
AUTHORS
SM Bradberry BSc MB MRCP
WN Harrison PhD CChem MRSC
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
17/1/97
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See Also:
Toxicological Abbreviations
Arsenic trioxide (ICSC)