UKPID MONOGRAPH
SODIUM AND POTSSIUM ARSENITE
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.
SODIUM AND POTASSIUM ARSENITE
Toxbase summary
Type of product
Sodium arsenite is an active ingredient in insecticides and
acaricides. Potassium arsenite is the active ingredient in Fowler's
solution and is used in mirror manufacture.
Toxicity
Sodium and potassium arsenite are highly soluble (trivalent) arsenic
salts. Substantial ingestions may be fatal (fatal dose not known).
Features
Systemic toxicity may follow ingestion, inhalation or topical
exposure.
Topical
- May cause skin irritation and sensitization. Systemic
arsenic poisoning may occur after substantial exposure.
Ingestion
Minor ingestions (small amounts of dilute solutions):
- Usually no serious effects. Mild gastrointestinal upset may
occur.
Substantial ingestions:
- Rapid onset (within 1-2 hours) of burning in 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 acute poisoning may develop a peripheral
neuropathy and skin lesions typical of chronic arsenical
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,
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
Minor 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
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.
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.
Kosnett MJ, Becker CE.
Dimercaptosuccinic acid as a treatment for arsenic poisoning.
Vet Hum Toxicol 1987; 29: 462.
Massey EW, Wold D, Heyman A.
Arsenic: Homicidal intoxication.
South Med J 1984; 77: 848-51.
Roses OE, García Fernández JC, Villaamil EC, Camussa N, Minetti SA,
Martínez de Marco M, Quiroga PN, Rattay P, Sassone A, Valle Garecca
BS, López CM, Olmos V, Pazos P, Pińeiro A, Rodriguez Lenci J.
Mass poisoning by sodium arsenite.
Clin Toxicol 1991; 29: 209-13
Substance name
Sodium arsenite
Origin of substance
Reaction of caustic soda with arsenious oxide
(HSDB, 1995)
Synonyms
Arsenious acid, sodium salt
Sodium arsenic oxide
Sodium metaarsenite (DOSE, 1994a)
Chemical group
A compound of arsenic, a group VA element
Reference number
CAS 7784-46-5 (DOSE, 1994a)
RTECS CG 3675000 (HSDB, 1995)
UN 2027 (solid)
1686 (aqueous solution) (DOSE, 1994a)
HAZCHEM 2X (DOSE, 1994a)
Physicochemical properties
Chemical structure
NaAsO2 (DOSE, 1994a)
Molecular weight
129.91 (DOSE, 1994a)
Physical state at room temperature
Solid (HSDB, 1995)
Colour
White or greyish-white (HSDB, 1995)
Odour
None (CHRIS, 1995)
Viscosity
NA
pH
Forms basic solution in water (OHM/TADS, 1995)
Solubility
Freely soluble in water, soluble in ethanol
(DOSE, 1994a)
Autoignition temperature
NA
Chemical interactions
Arsine gas is evolved when sodium arsenite reacts with acids and
metals. (OHM/TADS, 1995)
Major products of combustion
Arsenic fumes and sodium oxide may be generated during a fire.
(OHM/TADS, 1995)
Explosive limits
NA
Flammability
Non-flammable (CHRIS, 1995)
Boiling point
Decomposes when heated (CHRIS, 1995)
Density
1.87 at 25şC (DOSE, 1994a)
Vapour pressure
NA
Relative vapour density
NA
Flash Point
NA
Reactivity
Reacts with strong oxidizers (HSDB, 1995)
Hygroscopic
Uses
Insecticide
Acaricide
Arsenical soap manufacture (DOSE, 1994a)
Hazard/risk classification
Index no. 033-002-00-5
Risk phrases
0.2% < conc T; R23/25 - Toxic by inhalation and if swallowed.
0.1% < conc < 0.2% Xn; R20/22 - Harmful by inhalation and
in contact with the skin.
Safety phrases
S (1/2)-20/21-28-45 - Keep locked up and out of the reach of
children. When using do not eat, drink or smoke. After contact
with the skin, wash immediately with plenty of ....(to be
specified by the manufacturer). In case of accident, or if you
feel unwell, seek medical advice immediately (show label where
possible).
EEC No: NIF (CHIP2, 1994)
Substance name
Potassium arsenite
Origin of substance
Reaction of arsenic trioxide and potassium bicarbonate.
(HSDB, 1995)
Synonyms
Arsenous acid, potassium salt
Arsonic acid, potassium salt
Fowler's solution
Potassium metaarsenite (DOSE, 1994b)
Chemical group
A compound of arsenic, a group VA element
Reference numbers
CAS 10124-50-2 (DOSE, 1994b)
RTECS CG 3800000 (RTECS, 1995)
UN 1678 (DOSE, 1994b)
HAZCHEM 2X (DOSE, 1994b)
Physicochemical properties
Chemical structure
As2HKO4 (DOSE, 1994b)
Molecular weight
253.95 (DOSE, 1994b)
Physical state at room temperature
Solid (HSDB, 1995)
Colour
White (HSDB, 1995)
Odour
Odourless (CHRIS, 1995)
Viscosity
NA
pH
Will form a basic solution (OHM/TADS, 1995)
Solubility
Soluble in water (DOSE, 1994b)
Autoignition temperature
NA
Chemical interactions
Arsine gas is released upon contact with acid.
Slowly converted to arsenate by atmospheric oxygen when in
aqueous solution. (HAZARDTEXT, 1995)
Major products of combustion
Toxic fumes of arsenic and potassium oxide may be generated
during a fire. (HAZARDTEXT, 1995)
Explosive limits
NIF
Flammability
Non-flammable (OHM/TADS, 1995)
Boiling point
Decomposes at 300°C (HSDB, 1995)
Density
NIF
Vapour pressure
NA
Relative vapour density
NA
Flash Point
NA
Reactivity
Reacts with salts of iron and most heavy metals.
(HAZARDTEXT, 1995)
Uses
In manufacture of mirrors, reducing silver salt to metallic
silver.
Used in herbal remedies, notably Fowler's solution.
(DOSE, 1994b)
Hazard/risk classification
Index no. 033-002-00-5
Risk phrases
0.2% < conc T; R23/25 - Toxic by inhalation and if swallowed.
0.1% < conc < 0.2% Xn; R20/22 - Harmful by inhalation and
in contact with the skin.
Safety phrases
S (1/2)-20/21-28-45 - Keep locked up and out of the reach of
children. When using do not eat, drink or smoke. After contact
with the skin, wash immediately with plenty of ....(to be
specified by the manufacturer). In case of accident, or if you
feel unwell, seek medical advice immediately (show label where
possible).
EEC No: NIF (CHIP2, 1994)
INTRODUCTION
Sodium arsenite is a trivalent arsenic salt formed from the reaction
of arsenic trioxide with caustic soda (IPCS, 1981).
Potassium arsenite is formed by the reaction of arsenic trioxide and
potassium hydroxide. It has been used widely in the form of Fowler's
solution.
Arsenite salts interact with acids and reducing metals (e.g. iron and
zinc) or aluminium to form arsine gas, the most acutely toxic form of
arsenic.
Sodium and potassium arsenite are highly soluble and represent a much
more acute toxic hazard than less soluble trivalent arsenic compounds
(e.g. arsenic trioxide) (Done and Peart, 1971). Interconversion of
arsenites and arsenates may also occur readily.
EPIDEMIOLOGY
The main source of arsenic exposure in the world population is
drinking water with an high inorganic arsenic concentration (Chiou et
al, 1995; Das et al, 1995). Arsenic usually is found in water in the
form of arsenite and arsenate, the proportions of each depending on
conditions (IPCS, 1981). In 1987 an epidemic of arsenic poisoning
occurred in Argentina when a solution of sodium arsenite was
maliciously poured over meat in a butcher's shop. Over 700 people were
involved but there were no fatalities (Roses et al, 1991).
Potassium arsenite has been ingested with suicidal intent (Massey et
al, 1984). Accidental exposure has occurred through its use in
"traditional" ethnic remedies or other homeopathic medicines (Kerr and
Saryan, 1986).
Arsenic intoxication has followed the ingestion of pesticides
containing sodium arsenite (Jenkins, 1966; Peoples et al, 1977; Vaziri
et al, 1980), or fruit or vegetables that have been sprayed with such
pesticides. Done and Peart (1971) found that the majority of deaths
resulting from ingestion of arsenic-containing herbicides were
attributable to products containing high sodium arsenite
concentrations. Of 43 cases of human poisoning involving sodium
arsenite or arsenate reported in the US between 1949-67, 65 per cent
were fatal.
Industrial arsenic exposure has occurred from accidents where arsine
gas has been liberated from the reaction of arsenite solutions with
hydrogen released by acids and metals such as aluminium (Levinsky et
al, 1970; Elkins and Fahy, 1967) and zinc (Teitelbaum and Kier, 1969).
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 (Lee and Ho, 1994). Reduced lymphocyte
proliferation (Gonsebatt et al, 1994) and impaired macrophage function
also have been described (Lantz et al, 1994).
Dong and Luo (1994) have 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
Soluble arsenic salts, such as sodium and potassium arsenite, are well
absorbed after ingestion.
Limited animal data suggest sodium arsenite is well absorbed through
the lungs (Fielder et al, 1986).
Sodium or potassium arsenite particles deposited in the upper
respiratory tract after inhalation may be cleared via mucociliary
transport, swallowed and then absorbed (Fielder et al, 1986).
Direct evidence of transcutaneous arsenic absorption in man is scarce
(Fielder et al, 1986). Robinson (1975) reported a case of systemic
absorption in a patient whose cheek had been treated with a caustic
arsenical paste but this involved significant arsenic uptake through
damaged skin.
Distribution
Absorbed arsenic is distributed to all body tissues. High
concentrations would be expected in keratin-rich tissues such as hair,
skin and nails due to sulphydryl group binding (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).
Excretion
The half-life of arsenic in blood is about 60 hours with renal
excretion predominantly as mono- and dimethyl- derivatives (Buchet et
al, 1981; 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 acid 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).
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).
Robinson (1975) reported the development of a peripheral
polyneuropathy, "generalized skin lesions" and nail thickening in a
patient who applied a caustic arsenical paste to his cheek.
Ocular exposure
Sodium and potassium arsenite are eye irritants. Most injuries result
from exposure to dusts, causing conjunctivitis, lacrimation,
photophobia and chemosis (Grant and Schuman, 1993).
Ingestion
The toxicity of ingested sodium or potassium arsenite is dependent on
the amount and concentration of the preparation.
Gastrointestinal toxicity
Ingestion of a substantial quantity of sodium or potassium arsenite is
followed, usually within two hours, by nausea and vomiting, abdominal
pain and diarrhoea (Giberson et al, 1976; Vaziri et al, 1980; Roses et
al, 1991). These features occurred following ingestion of 720 mg and
400 mg sodium arsenite respectively (Vaziri et al, 1980).
Roses et al (1991) reported a mass poisoning when sodium arsenite was
maliciously poured over meat in a butcher's shop. Thirty five per cent
of 85 subjects said to have urine arsenic concentrations 36 µg/L or
less reported symptoms while gastrointestinal symptoms occurred in all
three subjects with urine arsenic concentrations reported to be
greater than 10000 µg/L (there were some inconsistencies in the
publication of these concentrations). Abdominal pain and gastritis
were the most common symptoms in subjects with lower urine arsenic
concentrations, whilst vomiting and nausea were more common at higher
concentrations. No subjects were symptomatic at one month follow up.
Other features of arsenic ingestion include burning of the mouth and
throat, dysphagia (Heyman et al, 1956; Jenkins, 1966) and
hypersalivation.
In severe cases, gastrointestinal haemorrhage with cardiovascular
collapse may ensue and is thought to reflect a direct toxic effect of
arsenic on capillaries via sulphydryl-group binding (Morton and
Dunnette, 1994).
The mortality from substantial sodium (or potassium) arsenite
ingestion may be high (Done and Peart, 1971).
Hepatotoxicity
Acute arsenic ingestions are associated frequently with increased
liver enzyme activities and hyperbilirubinaemia although these
abnormalities usually resolve.
Nephrotoxicity
Hypotension (Giberson et al, 1976; Vaziri et al, 1980) or
rhabdomyolysis following substantial arsenic ingestion may precipitate
renal failure; renal cortical necrosis has been described (Gerhardt et
al, 1978).
Jenkins (1966) described a 38 year-old woman who developed albuminuria
and microscopic haematuria after ingesting an unknown amount of rat
poison containing sodium arsenite.
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, notably torsade de pointes (Beckman et al,
1991) have been observed. Other ECG abnormalities include prolongation
of the QT interval (Goldsmith and From, 1980) and non-specific T wave
changes. Sudden onset bradycardia, then asystole, despite vigorous
resuscitation and no earlier arrhythmia, has also followed massive
acute arsenic ingestion.
Neurotoxicity
Roses et al (1991) reported headache as a common feature in subjects
who ingested sodium arsenite-contaminated meat.
Ingestion of arsenic has resulted in muscle cramps, a sensorineural
hearing deficit (Goldsmith and From, 1980), encephalopathy (Jenkins,
1966) and seizures.
A peripheral sensory and/or motor neuropathy has been described in
survivors of severe acute arsenic poisoning although this is more
typical following chronic exposure.
Jenkins (1966) described a 38 year-old woman who had ingested sodium
arsenite rat poison (amount not stated) suicidally. She developed
"pins and needles" in her hands and feet. Physical examination showed
distal muscle weakness in the lower limbs. There was reduced vibration
and position sense in the toes and ankle-jerks were absent. She
received a "full course" of dimercaprol (not specified) and no
disability was detectable 18 months later.
Goebel et al (1990) demonstrated acute wallerian degeneration of
myelinated nerve fibres in a patient who developed a symmetrical
polyneuropathy after attempting suicide by arsenic ingestion. Clinical
improvement was associated with microscopic evidence of neurological
regeneration.
Dermal toxicity
Striate leukonychia (Mees' lines) may develop following severe
arsenite poisoning (Jenkins, 1966; Massey, 1984), although associated
typically with chronic exposure.
Several weeks after attempted suicide by sodium arsenite ingestion, a
38 year-old woman developed transverse striate leukonychia and
desquamated skin on her palms and soles; she recovered fully (Jenkins,
1966).
Facial and peripheral oedema have been described (Heyman et al, 1956;
Kyle and Pease, 1965).
Haemotoxicity
In moderate or severe arsenic poisoning investigations typically show
anaemia, leucopenia or pancytopenia (Kyle and Pease, 1965). There may
be evidence of intravascular haemolysis and basophilic stippling has
been reported on the blood film (Kyle and Pease, 1965).
Multi-organ toxicity
Severe acute arsenic poisoning may result in death from
cardiorespiratory or hepatorenal failure (Jenkins, 1966; Armstrong et
al, 1984; Campbell and Alvarez, 1989; Morton and Dunnette, 1994). The
adult respiratory distress syndrome has been described (Bolliger et
al, 1992).
Inhalation
Inhalation of arsenic compounds causes rhinitis, pharyngitis,
laryngitis and tracheobronchitis (Morton and Dunnette, 1994).
Injection
DiNapoli et al (1989) described a patient who injected sodium arsenite
and potassium cyanide in a suicide attempt. He collapsed within
minutes with probable cyanide-induced severe respiratory distress and
coma. His condition improved following the intravenous administration
of sodium nitrite and sodium thiosulphate although he subsequently
experienced nausea and vomiting. The urine arsenic excretion in the
first 12 hours following admission was 10 mg. Twenty two days later he
complained of numbness and tingling in the upper extremities but there
was no objective neurological abnormality. No cutaneous manifestations
of arsenic poisoning developed.
CLINICAL FEATURES: CHRONIC EXPOSURE
Dermal exposure
Occupational cutaneous exposure may lead to chronic poisoning. Arsenic
salts have caused skin sensitization.
Inhalation
Occupational arsenical exposure may lead to chronic poisoning. Nasal
septum perforation is also described.
Ingestion
Ingestion of arsenic-contaminated drinking water (Feinglass, 1973;
Chiou et al, 1995), illicit whisky (Moonshine) (Gerhardt et al, 1980),
"tonics" or traditional remedies containing arsenite notably Fowler's
solution (Nevens et al, 1990), have caused chronic arsenic poisoning.
Systemic arsenic toxicity
The systemic features observed are similar for each source of exposure
and for exposure to all inorganic forms of arsenic which are
considered together.
General toxic effects
Patients may present with general debility, progressive weakness
(Feinglass, 1973; Gerhardt et al, 1980), 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. By
contrast, hyperpigmentation is more prominent in the axilla, groin,
areola and around the waist, typically with mucosal sparing (Shannon
and Strayer, 1989). These changes seem to be exacerbated by poor
nutritional status (Das et al, 1995).
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).
The fingernails may become brittle with transverse white striae (Mees'
lines) (Mees, 1919; Heyman et al, 1956; Kyle and Pease, 1965; Gerhardt
et al, 1980; Sass et al, 1993).
Exfoliative dermatitis (Nicolis and Helwig, 1973) and perforation of
the nasal septum have been reported.
Sass et al (1993) described a 42 year-old man who had been prescribed
Fowler's solution over one year. Arsenical keratoderma was diagnosed
but the patient was lost to follow-up for 10 years. When seen again,
an extension of the lesions and arsenical keratoses was apparent on
the fingers with development of squamous cell carcinoma after a
further 12 months.
Neuropsychological toxicity
A symmetrical peripheral neuropathy is typical. Sensory symptoms
predominate with paraesthesiae, numbness and pain, particularly of the
soles of the feet, extending in a "glove and stocking" distribution
(Jenkins, 1966; Gerhardt et al, 1980).
Motor involvement with symmetrical distal limb weakness, muscle
atrophy and loss of deep tendon reflexes is recognized (Heyman et al,
1956; Gerhardt et al, 1980; 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.
Psychological impairment is widely reported in chronic arsenical
poisoning with defects of verbal learning ability and memory and
personality changes.
Gastrointestinal toxicity
Nausea and vomiting, although more typical of acute arsenic poisoning,
may occur also in chronic cases.
Hepatotoxicity
Nevens et al (1990) reported eight cases of non-cirrhotic portal
hypertension in patients who had received potassium arsenite in a
herbal remedy (as Fowler's solution) for several years. All showed
signs of hypersplenism and massive bleeding from oesophageal varices
was reported in seven cases. Cirrhosis has also been described but may
involve concomitant excess ethanol consumption (Morton and Dunnette,
1994).
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.
Nephrotoxicity
Renal manifestations probably reflect capillary damage and include
haematuria, proteinuria with casts and acute tubular or cortical
necrosis (Morton and Dunnette, 1994).
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 arsenic dust.
Several authors refer to arsenic-induced myocardial toxicity
(Schoolmeester and White, 1980; Hall and Harruff, 1989), which has
been attributed to impaired oxidative metabolism of myocardial tissue
plus a direct inflammatory effect. A 42 year-old agricultural worker
presented with 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
Anaemia, neutropenia (Heyman et al, 1956; Kyle and Pease, 1965),
pancytopenia, haemolysis (Kyle and Pease, 1965), macrocytosis without
anaemia (Heaven et al, 1994) and a myelodysplastic syndrome (Rezuke et
al, 1991) have been reported.
Chronic arsenic exposure complicated by aplastic anaemia may
predispose to acute myeloid leukaemia (Kjeldsberg and Ward, 1972).
Arsenic-induced disruption of haem metabolism with altered urinary
porphyrin excretion is also described (Garcia-Vargas et al, 1994).
Endocrine toxicity
Epidemiological evidence from Taiwan (Lai et al, 1994) and
occupational studies have associated chronic arsenic exposure with the
development of diabetes mellitus.
Pulmonary toxicity
An irritating cough and haemoptysis are reported (Heyman et al, 1956).
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 sodium or potassium
arsenite 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 sodium or potassium arsenite 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 treatment 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 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
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.
Chelation therapy should be considered in symptomatic patients where
there is analytical confirmation of the diagnosis.
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 a total 24 hour collection, although spot urine arsenic
concentrations have been proposed in screening asymptomatic patients
with a history of possible acute arsenic ingestion.
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 arsenic compounds
released from seafood can still 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.
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 (Novey, 1969; Shannon and Strayer,
1989).
Hsueh et al (1995) demonstrated a significant dose-response relation
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.
There is an association between chronic arsenic exposure and cancer of
the urinary tract (Chen et al, 1988; Chen and Lin, 1994), 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).
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).
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
Sodium arsenite
In vitro Chinese and Syrian hamster ovary cells: Induced sister
chromatid exchanges.
Cultured human leucocytes: Increased incidence of sister chromatid
exchanges (DOSE, 1994a).
Potassium arsenite
In vitro human lymphocytes: Mitotic arrest and chromosomal
aberrations (DOSE, 1994b).
The lymphocytes of six patients treated with Fowler's solution showed
an increased incidence of sister chromatid exchanges but not
chromosomal aberrations (Burgdorf et al, 1977).
Fish toxicity (potassium arsenite)
Not toxic to brown trout, bluegill sunfish, yellow perch or goldfish
at 5 ppm for 24 hours (DOSE, 1994b).
EC Directive on Drinking Water Quality 80/778/EEC
Maximum admissible concentration 50 µg/L, as arsenic (DOSE, 1994a).
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
REFERENCES
Aposhian HV.
Biological chelation: 2,3-Dimercapto-propanesulfonic acid and
meso-dimercaptosuccinic acid.
Adv Enzyme Regul 1982; 20: 301-19.
Aposhian HV.
DMSA and DMPS - water soluble antidotes for heavy metal poisoning.
Ann Rev Pharmacol Toxicol 1983; 23: 193-215.
Aposhian HV, Carter DE, Hoover TD, Hsu C-A, Maiorino RM, Stine E.
DMSA, DMPS, and DMPA - as arsenic antidotes.
Fundam Appl Toxicol 1984; 4: S58-70.
Armstrong CW, Stroube RB, Rubio T, Siudyla EA, Miller GB.
Outbreak of fatal arsenic poisoning caused by contaminated drinking
water.
Arch Environ Health 1984; 39: 276-9.
Bansal SK, Haldar N, Dhand UK, Chopra JS.
Phrenic neuropathy in arsenic poisoning.
Chest 1991; 100: 878-80.
Beckman KJ, Bauman JL, Pimental PA, Garrard C, Hariman RJ.
Arsenic-induced torsade de pointes.
Crit Care Med 1991; 19: 290-2.
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.
Bosque MA, Piera V, Domingo JL, Corbella J.
Meso-2,3-Dimercaptosuccinic acid (DMSA) alleviation of
arsenite-induced embryofetotoxicity in mice: effectiveness with time.
Toxicologist 1991; 11: 295.
Buchet JP, Lauwerys R, Roels H.
Comparison of the urinary excretion of arsenic metabolites after a
single oral dose of sodium arsenite, monomethylarsonate, or
dimethylarsinate in man.
Int Arch Occup Environ Health 1981; 48: 71-9.
Buchet JP, Pauwels J, Lauwerys R.
Assessment of exposure to inorganic arsenic following ingestion of
marine organisms by volunteers.
Environ Res 1994; 66: 44-51.
Burgdorf W, Kurvink K, Cervenka J.
Elevated sister chromatid exchange rate in lymphocytes of subjects
treated with arsenic.
Hum Genet 1977; 36: 69-72.
Campbell JP, Alvarez JA.
Acute arsenic intoxication.
Am Fam Physician 1989; 40: 93-7.
Chen C-J, Kuo T-L, Wu M-M.
Arsenic and cancers.
Lancet 1988; 1: 414-5.
Chen C-J, Lin L-J.
Human carcinogenicity and atherogenicity induced by chronic exposure
to inorganic arsenic.
In: Nriagu JO, ed. Arsenic in the environment. Part II: Human health
and ecosystem effects. Vol 27.
New York: John Wiley & Sons, Inc., 1994; 109-31.
Chiou H-Y, Hsueh Y-M, Liaw, K-F, Horng S-F, Chiang M-H, Pu Y-S et al.
Incidence of internal cancers and ingested inorganic arsenic: a
seven-year follow-up study in Taiwan.
Cancer Res 1995; 55: 1296-300.
CHIP2/Chemicals (Hazard Information and Packaging for Supply)
Regulations 1994.
Health and Safety Commission.
Sudbury: Heath and Safety Executive, 1994.
CHRIS/Chemical Hazard Response Information System.
In: Tomes plus. Environmental Health and Safety Series I. Vol 26.
United States Coast Guard, 1995.
Council on Scientific Affairs.
Effects of toxic chemicals on the reproductive system.
JAMA 1985; 253: 3431-7.
Cullen NM, Wolf LR, St Clair D.
Pediatric arsenic ingestion.
Am J Emerg Med 1995; 13: 432-5.
Danielli JF, Danielli M, Fraser JB, Mitchell PD, Owen LN, Shaw G.
BAL-intrav: a new non-toxic thiol for intravenous injection in
arsenical poisoning.
Biochem J 1947; 41: 325-33.
Das D, Chatterjee A, Mandal BK, Samanta G, Chakraborti D.
Arsenic in ground water in six districts of West Bengal, India: the
biggest arsenic calamity in the world. Part 2. Arsenic concentration
in drinking water, hair, nails, urine, skin-scale and liver tissue
(biopsy) of the affected people.
Analyst 1995; 120: 917-24.
DiNapoli J, Hall AH, Drake R, Rumack BH.
Cyanide and arsenic poisoning by intravenous injection.
Ann Emerg Med; 1989: 308-11.
Dollery C, ed.
Therapeutic drugs.
London: Churchill Livingstone, 1991; D148-51.
Domingo JL, Bosque MA, Llobet JM, Corbella J.
Amelioration by BAL (2,3-dimercapto-1-propanol) and DMPS (sodium
2,3-dimercapto1-propanesulfonic acid) of arsenite developmental
toxicity in mice.
Ecotoxicol Environ Safety 1992; 23: 274-81.
Done AK, Peart AJ.
Acute toxicities of arsenical herbicides.
Clin Toxicol 1971; 4: 343-55.
Dong J-T, Luo X-M.
Effects of arsenic on DNA damage and repair in human fetal lung
fibroblasts.
Mutat Res 1994; 315: 11-5.
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.
DOSE/Dictionary of substances and their effects. Vol 7.
Cambridge: Royal Society of Chemistry, 1994a.
DOSE/Dictionary of substances and their effects. Vol 6.
Cambridge: Royal Society of Chemistry, 1994b.
Elkins HB, Fahy JP.
Arsine poisoning from aluminium tank cleaning.
Ind Med Surg 1967; 36: 747-9.
Engel RR, Hopenhayn-Rich C, Receveur O, Smith AH.
Vascular effects of chronic arsenic exposure: a review.
Epidemiol Rev 1994; 16: 184-209.
Farmer JG, Johnson LR.
Assessment of occupational exposure to inorganic arsenic based on
urinary concentrations and speciation of arsenic.
Br J Ind Med 1990; 47: 342-8.
Feinglass EJ.
Arsenic intoxication from well water in the United States.
N Engl J Med 1973; 288: 828-30.
Fielder RJ, Dale EA, Williams SD.
Toxicity review 16. Inorganic arsenic compounds.
London: HMSO, 1986.
Fournier L, Thomas G, Garnier R, Buisine A, Houze P, Pradier F, Dally
S.
2,3-dimercaptosuccinic acid treatment of heavy metal poisoning in
humans.
Med Toxicol 1988; 3: 499-504.
Garcia-Vargas GG, Del Razo LM, Cebrián ME, Albores A, Ostrosky-Wegman
P, Montero R, Gonsebatt ME, Lim CK, De Matteis F.
Altered urinary porphyrin excretion in a human population chronically
exposed to arsenic in Mexico.
Hum Exp Toxicol 1994; 13: 839-47.
Gerhardt RE, Hudson JB, Rao RN, Sobel RF.
Chronic renal insufficiency from cortical necrosis induced by arsenic
poisoning.
Arch Intern Med 1978; 138: 1267-9.
Gerhardt RE, Crecelius EA, Hudson JB.
Moonshine-related arsenic poisoning.
Arch Intern Med 1980; 140: 211-3.
Giberson A, Vaziri ND, Mirahamadi K, Rosen SM.
Hemodialysis of acute arsenic intoxication with transient renal
failure.
Arch Intern Med 1976; 136: 1303-4.
Goebel HH, Schmidt PF, Bohl J, Tettenborn B, Krämer G, Gutmann L.
Polyneuropathy due to acute arsenic intoxication: biopsy studies.
J Neuropathol Exp Neurol 1990; 49: 137-49.
Goldsmith S, From AHL.
Arsenic-induced atypical ventricular tachycardia.
N Engl J Med 1980; 303: 1096-7.
Gonsebatt ME, Vega L, Montero R, Garcia-Vargas G, Del Razo LM, Albores
A, Cebrian ME, Ostrosky-Wegman P.
Lymphocyte replicating ability in individuals exposed to arsenic via
drinking water.
Mutat Res 1994; 313: 293-9.
Grant WM, Schuman JS.
Toxicology of the eye. 4th ed.
Illinois: Charles C Thomas, 1993.
Graziano JH.
Role of 2,3-dimercaptosuccinic acid in the treatment of heavy metal
poisoning.
Med Toxicol 1986; 1: 155-62.
Greenberg C, Davies S, McGowan T, Schorer A, Drage C.
Acute respiratory failure following severe arsenic poisoning.
Chest 1979; 76: 596-8.
Hall JC, Harruff R.
Fatal cardiac arrhythmia in a patient with interstitial myocarditis
related to chronic arsenic poisoning.
South Med J 1989; 82: 1557-60.
Hannemann M, Kreppel H, Kraus M, Szinicz L, Kauth I, Reichl FX, Singh
PK, Jones MM.
BAL, DMPS, DMSA and new DMSA analogues as arsenic antidotes.
Przeglad Lekarski 1995; 52: 175.
Hantson Ph, Mahieu P, Lauwerys R.
Tolerance of intravenous dimercaptosuccinic acid (DMSA) therapy for
acute arsenic poisoning.
Przeglad Lekarski 1995; 52: 175.
Hazardtext.
In: Tomes plus. Environmental Health and Safety Series I. Vol 26.
Colorado: Micromedex, Inc., 1995.
Health and Safety Executive.
EH40/95. Occupational exposure limits 1995.
Sudbury: Heath and Safety Executive, 1995.
Heaven R, Duncan M, Vukelja SJ.
Arsenic intoxication presenting with macrocytosis and peripheral
neuropathy, without anemia.
Acta Haematol 1994; 92: 142-3.
Heyman A, Pfeiffer JB, Willett RW, Taylor HM.
Peripheral neuropathy caused by arsenical intoxication. A study of 41
cases with observations on the effects of BAL
(2,3-dimercapto-propanol).
N Engl J Med 1956; 254: 401-9.
Hruby K, Donner A.
2,3-dimercapto-1-propanesulphonate in heavy metal poisoning.
Med Toxicol 1987; 2: 317-23.
HSDB/Hazardous Substances Data Bank.
In: Tomes plus. Environmental Health and Safety Series I. Vol 26.
National Library of Medicine, 1995.
Hsueh Y-M, Cheng G-S, Wu M-M, Yu H-S, Kuo T-L, Chen C-J.
Multiple risk factors associated with arsenic-induced skin cancer:
effects of chronic liver disease and malnutritional status.
Br J Cancer 1995; 71: 109-14.
Inns RH, Rice P, Bright JE, Marrs TC.
Evaluation of the efficacy of dimercaprol chelating agents for the
treatment of systemic organic arsenic poisoning in rabbits.
Hum Exp Toxicol 1990; 9: 215-20.
IPCS.
Environmental Health Criteria 18. Arsenic.
Geneva: WHO, 1981.
IPCS.
Guidelines for drinking-water quality. 2nd ed. Vol 2. Health criteria
and other supporting information.
Geneva: WHO, 1996.
Jenkins RB.
Inorganic arsenic and the nervous system.
Brain 1966; 89: 479-98.
Jolliffe DM, Budd AJ, Gwilt DJ.
Massive acute arsenic poisoning.
Anaesthesia 1991; 46: 288-90.
Jones MM.
Chemistry of chelation: Chelating agent antagonists for toxic metals.
Chapter 13.
In: Goyer RA, Cherian MG, eds. Toxicology of metals: biochemical
aspects. Handbook of Experimental Pharmacology Vol 115.
Heidelberg: Springer Verlag 1995; 279-304.
Kerr HD, Saryan LA.
Arsenic content of homeopathic medicines.
Clin Toxicol 1986; 24: 451-9.
Kersjes MP, Maurer JR, Trestrail JH, McCoy DJ.
An analysis of arsenic exposures referred to the Blodgett Regional
Poison Center.
Vet Hum Toxicol 1987; 29: 75-8.
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.
Kingston RL, Hall S, Sioris L.
Clinical observations and medical outcome in 149 cases of arsenate ant
killer ingestion.
Clin Toxicol 1993; 31: 581-91.
Kjeldsberg CR, Ward HP.
Leukemia in arsenic poisoning.
Ann Intern Med 1972; 77: 935-7.
Kosnett MJ, Becker CE.
Dimercaptosuccinic acid as a treatment for arsenic poisoning.
Vet Hum Toxicol 1987; 29: 462.
Kreppel H, Reichl FX, Forth W, Fichtl B.
Lack of effectiveness of d-penicillamine in experimental arsenic
poisoning.
Vet Hum Toxicol 1989; 31: 1-5.
Kreppel H, Reichl F-X, Szinicz L, Fichtl B, Forth W.
Efficacy of various dithiol compounds in acute As2O3 poisoning in
mice.
Arch Toxicol 1990; 64: 387-92.
Kreppel H, Paepcke U, Thiermann H, Szinicz L, Reichl FX, Singh PK,
Jones MM.
Therapeutic efficacy of new dimercaptosuccinic acid (DMSA) analogues
in acute arsenic trioxide poisoning in mice.
Arch Toxicol 1993; 67: 580-5.
Kyle RA, Pease GL.
Hematologic aspects of arsenic intoxication.
N Engl J Med 1965; 273: 18-23.
Lai M-S, Hsueh Y-M, Chen C-J, Shyu M-P, Chen S-Y, Kuo T-L, Wu M-M,
Tai T-Y.
Ingested inorganic arsenic and prevalence of diabetes mellitus.
Am J Epidemiol 1994; 139: 484-92.
Lander JJ, Stanley RJ, Sumner HW, Boswell DC, Aach RD.
Angiosarcoma of the liver associated with Fowler's solution (potassium
arsenite).
Gastroenterology 1975; 68: 1582-6.
Lantz RC, Parliman G, Chen GJ, Carter DE.
Effect of arsenic exposure on alveolar macrophage function. I. Effect
of soluble As(III) and As(V).
Environ Res 1994; 67: 183-95.
Lee T-C, Ho I-C.
Differential cytotoxic effects of arsenic on human and animal cells.
Environ Health Perspect 1994; 102: 101-5.
Lenz K, Hruby K, Druml W, Eder A, Gaszner A, Kleinberger G, Pichler M,
Weiser M.
2,3-dimercaptosuccinic acid in human arsenic poisoning.
Arch Toxicol 1981; 47: 241-3.
Levin-Scherz JK, Patrick JD, Weber FH, Garabedian C Jr.
Acute arsenic ingestion.
Ann Emerg Med 1987; 16: 702-4.
Levinsky WJ, Smalley RV, Hillyer PN, Shindler RL.
Arsine hemolysis.
Arch Environ Health 1970; 20: 436-40.
Lugo G, Cassady G, Palmisano P.
Acute maternal arsenic intoxication with neonatal death.
Am J Dis Child 1969; 117: 328-30.
Maehashi H, Murata Y.
Arsenic excretion after treatment of arsenic poisoning with DMSA or
DMPS in mice.
Jpn J Pharmacol 1986; 40: 188-190.
Mahieu P, Buchet JP, Roels HA, Lauwerys R.
The metabolism of arsenic in humans acutely intoxicated by As2O3.
Its significance for the duration of BAL therapy.
Clin Toxicol 1981; 18: 1067-75.
Marcus SM.
Survival after massive arsenic trioxide ingestion.
Vet Hum Toxicol 1987; 29: 481.
Martin DS, Willis SE, Cline DM.
N-acetylcysteine in the treatment of human arsenic poisoning.
J Am Board Fam Pract 1990; 2: 293-6.
Massey EW, Wold D, Heyman A.
Arsenic: Homicidal intoxication.
South Med J 1984; 77: 848-51.
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.
McCutchen JJ, Utterback RA.
Chronic arsenic poisoning resembling muscular dystrophy.
South Med J 1966; 59: 1139-45.
Mees RA.
The nails with arsenical polyneuritis.
JAMA 1919; 72: 1337.
Mitchell-Heggs CAW, Conway M, Cassar J.
Herbal medicine as a cause of combined lead and arsenic poisoning.
Hum Exp Toxicol 1990; 9: 195-6.
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.
Morton WE, Dunnette DA.
Health effects of environmental arsenic.
In: Nriagu JO, ed. Arsenic in the environment. Part II: Human health
and ecosystem effects. Vol 27.
New York: John Wiley & Sons, Inc., 1994; 17-34.
Narang APS.
Arsenicosis in India.
Clin Toxicol 1987; 25: 287-95.
Nevens F, Fevery J, Van Steenbergen W, Sciot R, Desmet V, De Groote J.
Arsenic and non-cirrhotic portal hypertension. A report of eight
cases.
J Hepatol 1990; 11: 80-5.
Nicolis GD, Helwig EB.
Exfoliative dermatitis. A clinicopathologic study of 135 cases.
Arch Dermatol 1973; 108: 788-97.
Novey HS, Martel SH.
Asthma, arsenic, and cancer
J Allergy 1969; 44: 315-9.
OHM/TADS-Oil and Hazardous Materials/Technical Assistance Data System.
In: Tomes plus. Environmental Health and Safety Series I. Vol 26.
United States Environmental Protection Agency, 1995.
Peoples SA, Maddy KT, Johnston L, Ray C, Weindler F.
Poison exposures of children in California due to ingestion of
liquid-formulation pesticides containing sodium arsenite.
Clin Toxicol 1977; 10: 477.
Peters RA, Stocken LA, Thompson RHS.
British anti-lewisite (BAL).
Nature 1945; 156: 616-9.
Peters RA, Spray GH, Stocken LA, Collie CH, Grace MA, Wheatley GA.
The use of British anti-lewisite containing radioactive sulphur for
metabolism investigations.
Biochem J 1947; 41: 370-3.
Peterson RG, Rumack BH.
D-penicillamine therapy of acute arsenic poisoning.
J Pediatr 1977; 91: 661-6.
Pomroy C, Charbonneau SM, McCullough RS, Tam GKH.
Human retention studies with 74As.
Toxicol Appl Pharmacol 1980; 53: 550-7.
Reichl F-X, Hunder G, Liebl B, Fichtl B, Forth W.
Effect of DMPS and various adsorbents on the arsenic excretion in
guinea-pigs after injection with As2O3.
Arch Toxicol 1995; 69: 712-7.
Reynolds JEF, ed.
Martindale: The Extra Pharmacopoeia.
London: The Pharmaceutical Press, 1993.
Rezuke WN, Anderson C, Pastuszak WT, Conway SR, Firshein SI.
Arsenic intoxication presenting as a myelodysplastic syndrome: a case
report.
Am J Hematol 1991; 36: 291-3.
Robinson TJ.
Arsenical polyneuropaphy due to caustic arsenical paste.
Br Med J 1975; 3: 139.
Roses OE, García Fernández JC, Villaamil EC, Camussa N, Minetti SA,
Martínez de Marco M et al.
Mass poisoning by sodium arsenite.
Clin Toxicol 1991; 29: 209-13.
RTECS/Registry of Toxic Effects of Chemical Substances.
In: Tomes plus. Environmental Health and Safety Series I. Vol 26.
National Institute for Occupational Safety and Health (NIOSH), 1995.
Sass U, Grosshans E, Simonart JM.
Chronic arsenicism: criminal poisoning or drug-intoxication? Report of
two cases.
Dermatology 1993; 186: 303-5.
Schoolmeester WL, White DR.
Arsenic poisoning.
South Med J 1980; 73: 198-208.
Shannon RL, Strayer DS.
Arsenic-induced skin toxicity.
Hum Toxicol 1989; 8: 99-104.
Sheabar FZ, Yannai S, Taitelman V.
Efficiency of arsenic clearance from human blood in vitro and from
dogs in vivo by extracorporeal complexing hemodialysis.
Pharmacol Toxicol 1989; 64: 329-33.
Shum S, Skarbovig J, Habersang R.
Acute lethal arsenite poisoning in mice: effect of treatment with
N-acetylcysteine, d-penicillamine and dimercaprol on survival time.
Vet Hum Toxicol 1981; 23: 39-42.
Simonato L, Moulin JJ, Javelaud B, Ferro G, Wild P, Winkelmann R,
Saracci R.
A retrospective mortality study of workers exposed to arsenic in a
gold mine and refinery in France.
Am J Ind Med 1994; 25: 625-33.
Smith TJ, Crecelius EA, Reading JC.
Airborne arsenic exposure and excretion of methylated arsenic
compounds.
Environ Health Perspect 1977; 19: 89-93.
Smith SB, Wombolt DG, Venkatesan R.
Results of hemodialysis and hemoperfusion in the treatment of acute
arsenic ingestion.
Clin Exp Dial Apheresis 1981; 5: 399-404.
Stocken LA, Thompson RHS.
British anti-lewisite. Arsenic and thiol excretion in animals after
treatment of lewisite burns.
Biochem J 1946; 40: 548-54.
Teitelbaum DT, Kier LC.
Arsine Poisoning.
Arch Environ Health 1969; 19: 133-43.
Telolahy P, Javelaud B, Cluet J, de Ceaurriz J, Boudene C.
Urinary excretion of porphyrins by smelter workers chronically exposed
to arsenic dust.
Toxicol Lett 1993; 66: 89-95.
Thiers H, Colomb D, Moulin G, Colin L.
Le cancer cutané arsenical des viticulteurs du Beaujolais.
[Arsenical skin cancer in Beaujolais wine growers].
Ann Dermatol Venereol 1967; 94: 133-158.
Tsuda T, Babazono A, Yamamoto E, Kurumatani N, Mino Y, Ogawa T, et
al..
Ingested arsenic and internal cancer: a historical cohort study
followed for 33 years.
Am J Epidemiol 1995; 141: 198-209.
Vahter M.
What are the chemical forms of arsenic in urine, and what can they
tell us about exposure?
Clin Chem 1994; 40: 679-80.
Vaziri ND, Upham T, Barton CH.
Hemodialysis clearance of arsenic.
Clin Toxicol 1980; 17: 451-6.
Waldron HA, Scott A.
Metals - Arsenic.
In: Raffle PAB, Adams PH, Baxter PJ, Lee WR, eds. Hunter's disease of
occupations. 8th ed.
London: Edward Arnold, 1994; 109-12.
Watson WA, Veltri JC, Metcalf TJ.
Acute arsenic exposure treated with oral d-penicillamine.
Vet Hum Toxicol 1981; 23: 164-6.
Wexler J, Eagle H, Tatum HJ, Magnuson HJ, Watson EB.
Clinical uses of 2,3-dimercaptopropanol (BAL). II. The effect of BAL
on the excretion of arsenic in normal subjects and after minimal
exposure to arsenical smoke.
J Clin Invest 1946; 25: 467-73.
WHO.
Guidelines for drinking-water quality. 2nd ed. Vol 1. Recommendations.
Geneva: World Health Organization, 1993.
Yamamura Y, Yamauchi H.
Arsenic metabolites in hair, blood and urine in workers exposed to
arsenic trioxide.
Ind Health 1980; 18: 203-10.