UKPID MONOGRAPH
ARSENIC ACID
SM Bradberry BSc MB MRCP
WN Harrison PhD CChem MRSC
ST Beer BSc
JA Vale MD FRCP FRCPE 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 ACID
Toxbase entry
Type of product
Used in wood preservatives and insecticides. In water arsenic acid
forms the arsenate ion.
Toxicity
Small ingestions of dilute (<3%) arsenate solutions usually are
without serious adverse effects. A patient has survived the deliberate
ingestion of 10 g arsenate (Mathieu et al, 1992).
Features
Systemic toxicity may follow arsenic acid ingestion, inhalation or
topical exposure.
Topical
- Causes skin burns. Systemic arsenic poisoning may occur
after substantial exposure.
Ingestion
Minor ingestions (small amounts of dilute (<3%) solutions):
- Usually no serious effects. Mild gastrointestinal upset may
occur.
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 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, 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. Treat burns conventionally.
3. 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
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.
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.
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.
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.
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.
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.
McWilliams ME.
Accidental acute poisoning by a concentrated solution of arsenic acid
from percutaneous absorption: a case report.
Vet Hum Toxicol 1989; 31: 354.
Peterson RG, Rumack BH.
D-penicillamine therapy of acute arsenic poisoning.
J Pediatr 1977; 91: 661-6.
Substance name
Arsenic acid
Origin of substance
Reaction of arsenic trioxide with nitric acid
(HSDB, 1995)
Synonyms
Orthoarsenic acid (DOSE, 1992)
Chemical group
A compound of arsenic, a group VA element
Reference numbers
CAS 7778-39-4 (DOSE, 1992)
RTECS CG0700000 (RTECS, 1995)
UN 1554 (solid) 1553 (liquid) (DOSE, 1992)
HAZCHEM 2X (DOSE, 1992)
Physicochemical properties
Chemical structure
H3AsO4 (DOSE, 1992)
Molecular weight
141.94 (DOSE, 1992)
Physical state at room temperature
Solid (HSDB, 1995)
Colour
White (HSDB, 1995)
Odour
NIF
Viscosity
NA
pH
Weakly acidic (HSDB, 1995)
Solubility
3020 g/L in water at 12.5°C (HSDB, 1995)
Autoignition temperature
NA
Chemical interactions
Aqueous solutions emit arsine gas when in contact with active
metals such as arsenic, iron, aluminium and zinc.
(HSDB, 1995)
Major products of combustion
Produces arsine gas (HSDB, 1995)
Explosive limits
NA
Flammability
Not flammable (HSDB, 1995)
Boiling point
NIF
Density
2.2 at 20°C (HSDB, 1995)
Vapour pressure
NIF
Relative vapour density
NIF
Flash Point
NA
Reactivity
Arsenic acid is a strong oxidizer. (HSDB, 1995)
Uses
Preparation of arsenate salts
Manufacture of pesticides (DOSE, 1992)
Hazard/risk classification
Index no. 033-005-00-1
Risk phrases
Carc. Cat. 1; R45 - May cause cancer
T: R23/25 - Also toxic by inhalation and if swallowed
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: NIF (CHIP2, 1994)
INTRODUCTION
Arsenic acid is one of the most commercially important pentavalent
compounds of arsenic. It is formed from the treatment of arsenic
trioxide with nitric acid and used in the manufacture of arsenate
salts and pesticides. It is also formed by the slow reaction of
arsenic pentoxide in water (Fielder et al, 1986).
Aqueous solutions of arsenic acid can liberate arsine gas, the most
acutely toxic form of arsenic, when in contact with active metals
(HSDB, 1995).
It has been suggested that soluble arsenic compounds such as arsenic
acid represent a much more acute toxic hazard than insoluble, poorly
absorbed forms (Done and Peart, 1971).
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). In water arsenic acid forms the arsenate
ion. Arsenate is the most thermodynamically stable oxide of arsenic in
water and as such is believed to be the predominant species,
especially under aerobic conditions (IPCS, 1981).
Arsenic acid and its salts have been used widely in industry (Fielder
et al, 1986; McWilliams 1989) and in pesticide formulations (Done and
Peart, 1971; Miller et al, 1980) where they have been the source of
acute and chronic, accidental and deliberate intoxication.
MECHANISM OF TOXICITY
Once absorbed pentavalent arsenic is reduced in vivo to trivalent
arsenic. The principle mechanism of arsenic intoxication is disruption
of thiol proteins. For example, trivalent 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 (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 arsenical compounds such as arsenic acid are well absorbed
after ingestion, when absorption is almost complete. Following
inhalation there is significant mucociliary clearance and
gastrointestinal absorption of respired particles (Fielder et al,
1986).
From very limited animal data arsenic acid appears to be well absorbed
through the lungs (Fielder et al, 1986).
Although direct evidence of transcutaneous arsenic absorption in man
is scarce (Fielder et al, 1986) there are reports of systemic arsenic
toxicity following presumed dermal exposure (Garb and Hine, 1977;
McWilliams, 1989).
Distribution
Absorbed arsenic is distributed to all body tissues (Fielder et al,
1986). Once absorbed pentavalent arsenic is reduced in vivo to
trivalent arsenic. 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 (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
Severe foot burns occurred in a patient exposed to concentrated
arsenic acid-saturated clothing for eight hours (McWilliams, 1989).
Soft tissue deposits believed to be metallic arsenic were noted on
X-ray. The patient was transiently encephalopathic and developed a
chronic painful foot motor neuropathy. Twenty four hour urine arsenic
elimination ranged from 2500 mg falling to 160 mg during an eight week
course of penicillamine.
Garb and Hine (1977) reported a worker splashed down the left side of
his body with arsenic acid in an industrial accident. He immediately
removed a contaminated glove and washed his hands but did not notice
arsenic acid in his left shoe for some ten minutes. After washing the
affected leg and removing a soiled sock he continued to work for a
further four hours by which time he had sustained second degree burns
in the acid-exposed areas. Eleven hours after the incident he
developed pain and swelling at the contact sites plus nausea,
vomiting, diarrhoea and abdominal pain necessitating hospital
admission. During the next three days his vision became "foggy" and he
complained of a sore tongue and "aching teeth". After seven days he
developed a burning sensation in the unexposed foot accompanied by
paraesthesiae in all extremities. He became progressively weaker and
was confined to a wheelchair. Two years after the accident diminished
touch sensation and tendon reflexes persisted and he could walk only
with a left leg brace and crutches. Chelation therapy was not employed
at any time.
Ocular exposure
Arsenic acid is an eye irritant and may cause burns. Most injuries
result from exposure to dusts, causing conjunctivitis, lacrimation,
photophobia and chemosis (Grant and Schuman, 1993).
Ingestion
The oral toxicity of arsenic acid is dependent on the amount ingested
and the concentration of the preparation. Tallis (1989) noted that
arsenate salts can react with hydrochloric acid in the stomach to
liberate arsenic acid and the corresponding metal chloride. In this
way poorly soluble salts such as lead arsenate can be a source of
arsenic acid which is soluble and well absorbed.
Although pentavalent arsenic is reduced in vivo to the generally
more toxic trivalent arsenic (Waldron and Scott, 1994) ingestion of
dilute arsenic acid salt solutions (less than three per cent) usually
are without serious adverse effects (Kingston et al, 1993). In 149
such cases involving sodium arsenate (2.28 per cent) ant killer, 97
per cent of patients were asymptomatic and only one required hospital
admission (Kingston et al , 1993).
Gastrointestinal toxicity
Of 57 cases of ant killer ingestion involving arsenic acid salts
(maximum arsenate concentration three per cent) only seven patients
were symptomatic. All these vomited, with abdominal pain, diarrhoea
and nausea also reported (Kersjes et al 1987).
Armstrong et al (1984) reported eight family members (two of whom
died) poisoned by well-water which contained arsenic 108 mg/L (form
unknown). All had gastrointestinal symptoms including dry mouth,
vomiting, dysphagia and/or diarrhoea. Urine arsenic concentrations
were directly related to the amount of water consumed. The estimated
daily dose of arsenic ingested by the surviving family members ranged
from 26-127 mg. An 11 year-old girl and a 27 year-old man died after
ingesting approximately 77 mg and 166 mg arsenic daily respectively
(duration unknown). Autopsy of the most severely poisoned patient
showed diffuse gastrointestinal tract inflammation.
A 32 year-old man ingested 900 mg of an arsenic acid salt, vomited
within one hour and developed diarrhoea three hours later. His
clinical course was complicated by hypotension and renal failure but
after 82 days chelation therapy with N-acetylcysteine he fully
recovered (Martin et al, 1990).
Another patient survived the deliberate ingestion of 10 g of an
arsenic acid salt (Mathieu et al, 1992). Severe nausea, vomiting and
abdominal tenderness developed within three hours with cardiovascular
collapse and subsequent acute renal failure requiring haemodialysis.
The patient made a full recovery over three months.
Other gastrointestinal features of arsenic poisoning include burning
of the mouth and throat with dysphagia (Heyman et al, 1956) and
hypersalivation (Schoolmeester and White, 1980).
Hepatotoxicity
Armstrong et al (1984) reported a 27 year-old man poisoned by well
water containing 108 mg/L arsenic. He presented after feeling unwell
for six days and on examination was jaundiced with a bilirubin
concentration of 120 µmol/L. He collapsed and died later that day and
autopsy showed a liver arsenic concentration of 86 mg/kg. He had
ingested an estimated 166 mg arsenic daily (duration unknown) and had
a urine arsenic concentration of 1.6 mg/L at post mortem. Seven other
members of his family with lower arsenic exposure showed transiently
elevated serum hepatic transaminase activities and total bilirubin
concentrations (values not given).
Schoolmeester and White (1980) reported a 16 year-old female who
ingested 300 mg sodium arsenate in a suicide attempt. She developed
severe abdominal pain and vomiting within 30 minutes. A 24 hour urine
collection had an arsenic concentration of 14.2 mg/L (time of
collection not stated). Forty-eight hours later serum liver
transaminase and alkaline phosphatase activities were elevated (values
not given) but these abnormalities resolved within six months.
Nephrotoxicity
Hypotension (Martin et al, 1990; Mathieu et al, 1992) or
rhabdomyolysis following substantial arsenic acid ingestion may
precipitate renal failure. Renal cortical necrosis has been described
(Gerhardt et al, 1978). Haematuria was reported in one patient in a
series of 57 cases of sodium arsenate ingestion (Kersjes et al, 1987).
Pyuria, proteinuria and elevated serum creatinine concentrations were
reported in members of a family poisoned with arsenic-contaminated
well-water (Armstrong et al, 1984). The most severely poisoned
patient, who died after a six day illness, developed gross haematuria,
a serum creatinine concentration of 390 µmol/L and heavy proteinuria.
He had consumed an estimated 166 mg arsenic daily (duration unknown)
and had a urine arsenic concentration at post mortem of 1.6 mg/L. No
chelation therapy was given. The other family members were treated
with dimercaprol and penicillamine. Six eventually recovered.
Cardiovascular toxicity
Tachycardia is reported frequently following ingestion of arsenic acid
salts and is contributed to by anxiety, intravascular fluid depletion
and possibly direct arsenic-induced cardiotoxicity (Le Quesne and
McCleod, 1977; Martin et al, 1990; Cullen et al, 1995).
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; Schoolmeester and White,
1980), idioventricular rhythm (Armstrong et al, 1984) and non-specific
T wave changes. Sudden onset bradycardia then asystole has been
reported following massive acute arsenic ingestion despite vigorous
resuscitation and no earlier arrhythmia.
Armstrong et al (1984) reported a 27 year-old man who had consumed an
unstated quantity of well-water containing 108 mg/L arsenic. After a
six day illness (diagnosed as an upper respiratory tract infection) he
collapsed and sustained a respiratory arrest and seizures. An
idioventricular rhythm was noted. He was resuscitated but remained
comatose and died a few hours later.
Pericardial effusion with tamponade was reported in another member of
the same family who had also drunk arsenic-contaminated water; the
outcome in this case was not stated (Armstrong et al, 1984).
Neurotoxicity
In 57 sodium arsenate ingestions involving solutions containing
1.5-3.0 per cent arsenate, headache, dizziness, lethargy and
somnolence were each reported in 2 per cent of cases; 88 per cent of
patients were asymptomatic (Kersjes et al 1987).
More substantial arsenic ingestions have caused 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.
Armstrong et al (1984) reported eight family members poisoned with
well-water containing 108 mg/L arsenic. All developed gastrointestinal
symptoms with "altered mental status" and seizures noted in four. Coma
developed in three patients and a peripheral neuropathy in two.
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 46 year-old man developed feet numbness ten days after drinking a
solution of sodium arsenate (concentration unknown) in attempted
suicide. Two months after ingestion neurological examination
demonstrated distal muscle weakness bilaterally, absent knee and ankle
reflexes and reduced position and vibration sense with a high-stepping
gait. Sixteen months later there was improvement in both sensory and
motor deficits although residual disability was evident at eight year
follow-up (Le Quesne and McCleod, 1977).
Dermal toxicity
Le Quesne and McCleod (1977) described a patient who developed a
papular erythematous rash and generalized epidermal desquamation one
week after drinking 10 mL of an arsenate solution (concentration
unknown).
Striate leukonychia (Mees' lines) and hyperkeratotic or hyperpigmented
skin lesions are characteristic of chronic arsenic intoxication but
have been described also following substantial acute ingestion (Heyman
et al, 1956; Kyle and Pease, 1965; Jenkins, 1966).
Facial and peripheral oedema have also been reported following arsenic
ingestion (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; Armstrong
et al, 1984). There may be evidence of intravascular haemolysis and
the blood film often shows basophilic stippling (Kyle and Pease,
1965).
Mathieu et al (1992) described a 30-year-old male who ingested 10 g
sodium arsenate with suicidal intent. He developed severe
gastrointestinal features of arsenic poisoning within hours and
required haemodialysis for management of acute renal failure. Five
days after ingestion he developed thrombocytopenia and anaemia. Bone
marrow examination showed maturation arrest but recovery ensued over
10 days.
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 (ARDS) has been described
(Bolliger et al, 1992).
Inhalation
Inhalation of arsenic compounds causes rhinitis, pharyngitis,
laryngitis and tracheobronchitis (Morton and Dunnette, 1994).
CLINICAL FEATURES: CHRONIC EXPOSURE
Dermal exposure
Occupational exposure may lead to chronic arsenical toxicity.
Contact dermatitis has been reported in workers exposed to arsenic
acid salts used in crystal manufacture (Barbaud et al, 1995).
Ingestion
Ingestion of arsenic-contaminated drinking water (Feinglass, 1973;
Chiou et al, 1995), illicit whisky (Moonshine) (Gerhardt et al, 1980)
"tonics" or traditional remedies have caused chronic arsenical
poisoning.
Inhalation
Occupational exposure may lead to chronic arsenical poisoning.
Perforation of the nasal septum has been reported.
Systemic arsenic acid toxicity
The systemic features observed are similar for each source of exposure
which are considered together.
General toxic effects
Patients with chronic arsenic acid poisoning 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). 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).
Exfoliative dermatitis (Nicolis and Helwig, 1973) has been reported.
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 (Schoolmeester and White, 1980) 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 (Heyman et al, 1956; Schoolmeester and White,
1980).
Hutton et al (1982) described a case of chronic self-intoxication with
sodium arsenate ant poison. The patient was initially admitted with
gastrointestinal symptoms and pancytopenia. He subsequently developed
severe peripheral neuropathy and myelopathy. Urinalysis revealed an
arsenic concentration of 3600 mg/L. The patient eventually admitted
self-administering arsenic in order to secure early retirement on
medical grounds.
Gastrointestinal toxicity
Nausea is common in chronic arsenical poisoning. In the German
literature Reinl (1970) reported a 53 year-old man who had been
exposed to arsenic acid used as an oxidizing agent in chemical
manufacture. During his ten year employment he developed symptoms
including diarrhoea and vomiting. He died of lung cancer believed to
be related to arsenic exposure.
Hepatotoxicity
Abnormal liver enzyme activities (Schoolmeester and White, 1980) have
been observed in chronic arsenic poisoning.
Arsenic-induced cirrhosis has been described but may be explained by
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.
In the German literature cirrhosis and splenomegaly were reported at
autopsy of a 53 year-old man occupationally exposed to arsenic acid
for ten years. Dermal and gastrointestinal symptoms occurred during
his employment and arsenic induced lung cancer was cited as the cause
of death (Reinl, 1970).
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 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
Pancytopenia has been reported in cases of chronic intoxication by
arsenic acid salts (Schoolmeester and White, 1980; Hutton et al,
1982). Anaemia, neutropenia (Heyman et al, 1956; Kyle and Pease,
1965), or evidence of haemolysis (Kyle and Pease, 1965) have also been
reported as have macrocytosis without anaemia (Heaven et al, 1994) and
a myelodysplastic syndrome (Rezuke et al, 1991).
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
(Garcia-Vargas et al, 1994) has been reported.
Pulmonary toxicity
An irritating cough and haemoptysis have been reported in chronic
arsenic intoxication (Heyman et al, 1956).
Endocrine toxicity
Epidemiological evidence from Taiwan (Lai et al, 1994) has recently
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.
Ingestion
Decontamination
After acute ingestion of a substantial quantity of arsenic acid 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 acid 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).
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.
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 (Bansal et al, 1991). 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.
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 (Cullen et al, 1995). 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). 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 (Watson et al, 1981). 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 24 hour urine arsenic excretion 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 (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.
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 practise 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 (Schoolmeester and White, 1980; 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 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 (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) and liver, both hepatic angiosarcoma and hepatocellular
carcinoma (Chen and Lin, 1994).
Reinl (1970) reported the death of a 53 year-old man who had been
exposed to arsenic acid for ten years. The compound had been used an
as oxidizing agent in a chemical manufacturing process. He suffered
gastrointestinal and dermal symptoms of arsenic toxicity during his
employment and at autopsy arsenic induced metastatic bronchial
carcinoma was diagnosed as the cause of death.
Smoking exerts a synergistic effect with ingested and inhaled arsenic
in the development of pulmonary malignancy. 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).
Daya et al (1989) reported a 22 year-old female who ingested 340 mg
sodium arsenate while 20 weeks pregnant. Treatment with dimercaprol
150 mg four hourly was commenced two hours post ingestion, the maximum
24 hour urine arsenic excretion was 3030 µg/L and a healthy infant was
delivered at 36 weeks.
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 arsenate)
Cultured human peripheral lymphocytes: Induced chromosomal aberrations
and sister chromatid exchanges.
Syrian hamster cells and human lymphocytes: Induced sister chromatid
exchanges and chromosomal aberrations.
Chinese hamster ovary cells: Induced chromosomal aberrations.
Drosophilia melanogaster: Wing spot test negative (sodium arsenate
is highly toxic to Drosophilia and hence could only be tested at
very low concentrations) (DOSE, 1994).
Fish toxicity (arsenic)
EC50 (96 hr) fathead minnow 141-144 mg/L.
LC50 96 hr) knifefish 31 mg/L.
Oral administration (0.52 mg/kg/day for 24 weeks) to rainbow trout
caused chronic inflammatory changes in subepithelial tissues of the
gall bladder wall in 71 per cent of the group.
LC50 (96 hr) striped base 30 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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