SM Bradberry BSc MB MRCP
    WN Harrison PhD CChem MRSC
    ST Beer BSc

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


    Toxbase summary

    Type of product

    A trivalent arsenic salt used in the production of herbicides and


    Generally less acutely toxic than soluble arsenic salts. A patient has
    died after ingesting 2 g.


    Systemic toxicity may follow arsenic trioxide ingestion, inhalation or
    topical exposure.


         -    Irritant to skin and mucous membranes. Systemic arsenic
              poisoning may occur after substantial exposure.


         -    Very small ingestions are likely to cause only mild gastro-
              intestinal upset.

    Substantial ingestions:
         -    Rapid onset (within 1-2 hours) of burning of the mouth and
              throat, hypersalivation, dysphagia, nausea, vomiting,
              abdominal pain and diarrhoea.
         -    In severe cases gastrointestinal haemorrhage, cardiovascular
              collapse, renal failure, seizures, encephalopathy and
              rhabdomyolysis may occur.
         -    Other features: facial and peripheral oedema, ventricular
              arrhythmias (notably torsade de pointes), ECG abnormalities
              (QT interval prolongation, T-wave changes), muscle cramps.
         -    Investigations may show anaemia, leucopenia,
              thrombocytopenia or evidence of intravascular haemolysis.
         -    Death may occur from cardiorespiratory or hepatorenal
              failure. The adult respiratory distress syndrome (ARDS) has
              been reported.
         -    Survivors of severe poisoning may develop a peripheral
              neuropathy and skin lesions typical of chronic arsenic


         -    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
         -    Also reported: peripheral vascular disease (cold sensitivity
              progressing to ulceration and gangrene), renal tubular or
              cortical damage and haematological abnormalities (notably



    1.   Irrigate with copious volumes of water.
    2.   Consider the possibility of systemic arsenic poisoning after
         significant exposure.


    Very small ingestions:
    1.   Gastrointestinal decontamination is unnecessary.
    2.   Symptomatic and supportive care only.

    Substantial ingestions:
    1.   Most patients will vomit spontaneously but in those who do not,
         gastric lavage should be considered only if the patient presents
         within one hour.
    2.   Supportive measures are paramount. Intensive resuscitation may be
         required. Ensure adequate fluid replacement and close observation
         of vital signs including cardiac monitoring.
    3.   Diarrhoea can be controlled with loperamide.
    4.   Monitor blood urea, creatinine, electrolytes, liver function and
         full blood count.
    5.   Collect blood and urine for arsenic concentration measurements.
    6.   ECG evidence of QT prolongation may precede atypical ventricular
         arrhythmias (notably torsade de pointes). Avoid drugs which
         prolong the QT interval e.g. procainamide, quinidine or
         disopyramide. Isoprenaline is effective with phenytoin,
         lignocaine or propranolol as alternatives.
    7.   Antidotes - chelation therapy with either dimercaprol, DMSA or
         DMPS should be considered in symptomatic patients where there is
         analytical confirmation of the diagnosis, but only after
         specialist advice from the NPIS.


    Bolliger CT, van Zijl P, Louw JA.
    Multiple organ failure with the adult respiratory distress syndrome in
    homicidal arsenic poisoning.
    Respiration 1992; 59: 57-61.

    Donofrio PD, Wilbourn AJ, Albers JW, Rogers L, Salanga V, Greenberg
    Acute arsenic intoxication presenting as Guillain-Barr-like syndrome.
    Muscle Nerve 1987; 10: 114-20.

    Engel RR, Hopenhayn-Rich C, Receveur O, Smith AH.
    Vascular effects of chronic arsenic exposure: a review.
    Epidemiol Rev 1994; 16: 184-209.

    Gerhardsson L, Dahlgren E, Eriksson A, Lagerkvist BEA, Lundstrm J,
    Nordberg GF.
    Fatal arsenic poisoning - a case report.
    Scand J Work Environ Health 1988; 14: 130-3.

    Gerhardt RE, Crecelius EA, Hudson JB.
    Moonshine-related arsenic poisoning.
    Arch Intern Med 1980; 140: 211-3.

    Goldsmith S, From AHL.
    Arsenic-induced atypical ventricular tachycardia.
    N Engl J Med 1980; 303: 1096-7.

    Greenberg C, Davies S, McGowan T, Schorer A, Drage C.
    Acute respiratory failure following severe arsenic poisoning.
    Chest 1979; 76: 596-8.

    Kew J, Morris C, Aihie A, Fysh R, Jones S, Brooks D.
    Arsenic and mercury intoxication due to Indian ethnic remedies.
    Br Med J 1993; 306: 506-7.

    Kosnett MJ, Becker CE.
    Dimercaptosuccinic acid as a treatment for arsenic poisoning.
    Vet Hum Toxicol 1987; 29: 462.

    Mathieu D, Mathieu-Nolf M, Germain-Alonso M, Neviere R, Furon D,
    Wattel F.
    Massive arsenic poisoning - effect of hemodialysis and dimercaprol on
    arsenic kinetics.
    Intensive Care Med 1992; 18: 47-50.

    Moore DF, O'Callaghan CA, Berlyne G, Ogg CS, Alban Davies H, House IM,
    Henry JA.
    Acute arsenic poisoning: absence of polyneuropathy after treatment
    with 2,3-dimercaptopropanesulphonate (DMPS).
    J Neurol Neurosurg Psychiatry 1994; 57: 1133-5.

    Peterson RG, Rumack BH.
    D-penicillamine therapy of acute arsenic poisoning.
    J Pediatr 1977; 91: 661-6.

    Substance name

         Arsenic trioxide

    Origin of substance

         Occurs in nature as the mineral claudetite.
                                                 (DOSE, 1992)


         Arsenic oxide
         Arsenic sesquioxide
         Arsenious oxide
         Arsenious acid
         Diarsenic trioxide
         Arsenous oxide
         Arsenous acid
         White arsenic                           (DOSE, 1992)

    Chemical group

         A compound of arsenic, a group VA element

    Reference numbers

         CAS            1327-53-3                (DOSE, 1992)
         RTECS          CG 3325000               (CSDS, 1991)
         UN             1561                     (DOSE, 1992)
         HAZCHEM        2Z                       (DOSE, 1992)

    Physicochemical properties

    Chemical structure
         As2O3                                   (DOSE, 1992)

    Molecular weight
         197.84                                  (DOSE, 1992)

    Physical state at room temperature
         Chrystalline solid                      (CSDS, 1991)

         Colourless                              (CSDS, 1991)

         None                                    (CHRIS, 1995)



         20 g/L at 25C                          (OHM/TADS, 1995)

    Autoignition temperature

    Chemical interactions
         Forms arsine gas when in contact with metals and acid.
         Dissolves in alkali to form arsenites.
         Forms toxic volatile halides when in contact with halide acids.
                                                 (HSDB, 1995)

    Major products of combustion
         Fumes of arsenic trioxide and arsine may be formed in fires.
                                                 (HSDB, 1995)

    Explosive limits

         Not flammable                           (HSDB, 1995)

    Boiling point
         465C                                   (DOSE, 1992)

         Claudetite 3.865 at 25C                (DOSE, 1992)
         Arsenolite 4.15 at 25C                 (DOSE, 1992)

    Vapour pressure
         8813 Pa at 312C                        (HSDB, 1995)

    Relative vapour density

    Flash Point

         Explodes on heating with zinc filings.
         Violent interaction with chlorine trifluoride.
         Incandesces in contact with hydrogen fluoride.
         Reacts vigorously with mercury, rubidium acetylide, oxygen
         difluoride or sodium chlorate.          (CSDS, 1991)


         A constituent of weedkillers, rodenticides and insecticides.
         In the manufacture of glass, Paris green and enamels.
                                                 (DOSE, 1992)

    Hazard/risk classification

    Index No. 033-003-00-0
         Risk phrases
         Carc. Cat. 1; R45 - May cause cancer
         T+; R28 - Also very toxic if swallowed
         C; R34 - Corrosive, causes burns
    Safety phrases
         S53-45- Avoid exposure-obtain special instructions before use. In
         case of accident, or if you feel unwell, seek medical advice
         immediately (show label where possible).
    EEC No:  215-481-4                           (CHIP2, 1994)


    Arsenic trioxide is the most important commercial form of arsenic and
    is produced as a by-product of copper and lead smelting. It is used in
    agriculture, forestry and to a lesser extent in the glass and ceramic
    industry, as a food additive and in some herbal remedies (IPCS, 1981).
    Chen et al (1996) recently demonstrated a potential clinical role for
    arsenic trioxide in the treatment of acute promyelocytic leukaemia.

    It has been suggested that arsenic trioxide poses less of an acute
    toxic hazard than water soluble arsenic salts (Done and Peart, 1971).

    Crude arsenic trioxide is relatively insoluble but may be converted to
    more soluble derivatives such as arsenious acid or sodium arsenite in
    some preparations.


    Arsenic trioxide is the major source of occupational exposure to
    arsenic compounds, especially from the processing of copper, gold and
    lead ores. Occupational exposure may also occur in the manufacture of
    glass, ceramics and pesticides (IPCS, 1981).

    Arsenic trioxide has been ingested accidentally (Mahieu, 1981; Moore
    et al, 1994) or with suicidal or homicidal intent (Marcus, 1987;
    Bolliger et al, 1992). Over two hundred students were poisoned after
    eating sausages containing 1.36 g/kg arsenic trioxide served at a hall
    of residence. Many students were ill but none died. Two people and one
    dog died after consuming sausages from an earlier batch containing
    14.3 g/kg arsenic trioxide (Renwick et al, 1981).

    The source of arsenic trioxide may be pesticides (Done and Peart,
    1971; Kuruvilla et al, 1975; Park and Currier, 1991), homeopathic or
    ethnic remedies (Kerr and Saryan, 1986) or Fowler's solution, the most
    notable source of medicinal arsenic intoxication. Fowler's solution is
    formed by dissolving arsenic trioxide in potassium hydroxide solution
    to form potassium arsenite.


    The principle mechanism of arsenic intoxication is disruption of thiol
    proteins. For example, arsenic inactivates pyruvate dehydrogenase by
    complexing with the sulphydryl groups of a lipoic acid moiety
    (6,8-dithiooctanoic acid) of the enzyme (Jones, 1995).

    Enhanced cellular destruction of damaged thiol proteins may produce
    toxic oxygen radicals. Arsenic-induced reduced lymphocyte
    proliferation and impaired macrophage function also have been

    Dong and Luo (1994) suggested that while arsenic can directly damage
    DNA, a more important mechanism in arsenic-induced carcinogenicity is
    enhanced mutagenicity of other compounds via increased DNA-protein

    The affinity of arsenic for sulphydryl groups is utilized in chelation



    Insoluble arsenic trioxide is less well absorbed than more soluble
    salts (Fielder et al, 1986). The efficiency of absorption following
    ingestion is dependent on the particle size; fine powders are better
    absorbed than larger particles (Done and Peart, 1971).

    A large proportion of irrespirable arsenic trioxide particles are
    trapped in the upper airways and deposited in the gastrointestinal
    tract by mucociliary clearance. This is likely to be an important
    source of arsenic trioxide exposure since the extent of absorption
    following ingestion and inhalation are similar (Smith et al, 1977;
    IPCS, 1981).

    Although direct evidence of transcutaneous arsenic absorption in man
    is scarce (Fielder et al, 1986) systemic arsenic toxicity following
    presumed dermal exposure has been reported (Heyman et al, 1956).


    Absorbed arsenic is distributed to all body tissues (Fielder et al,
    1986). Trivalent arsenic is methylated in the liver to methylarsonic
    acid and dimethylarsinic acid (IPCS, 1996). Short-term studies on
    humans indicate that daily intake in excess of 0.5 mg progressively,
    but not completely, saturates the capacity to methylate inorganic
    arsenic (IPCS, 1996).

    Very high arsenic concentrations have been found in the hair of
    workers exposed to arsenic trioxide dust but this may reflect external
    contamination rather than systemic absorption (Yamamura and Yamauchi,


    The half-life of arsenic in blood is about 60 hours with renal
    excretion predominantly as mono- and dimethyl- derivatives (Waldron
    and Scott, 1994). The whole body half-life of arsenic in six human
    volunteers fitted a three compartment system, with 65.9 per cent of
    orally administered arsenic having a half-life of 2.1 days, 30.4 per
    cent a half-life of 9.5 days and 3.7 per cent a half-life of 38.4 days
    (mean values) (Pomroy et al, 1980).

    In animal studies small amounts of parenterally administered arsenic
    trioxide appear in the faeces, suggesting minor biliary clearance
    (Reichl et al, 1994).


    Dermal exposure

    Trivalent arsenic compounds are irritating to the skin and mucous
    membranes with dermatitis the most common feature following
    occupational exposure. Erythema, burning and itching, eczematous
    eruptions and folliculitis are typical (Fielder et al, 1986).

    Ocular exposure

    Arsenic trioxide is an eye irritant. Most injuries result form
    exposure to dusts, causing conjunctivitis, lacrimation, photophobia
    and chemosis (Grant and Schuman, 1993).


    Inhalation of arsenic compounds causes rhinitis, pharyngitis,
    laryngitis and tracheobronchitis (Morton and Dunnette, 1994).
    Gerhardsson et al (1988) reported an occupational accident in which a
    worker was buried by arsenic trioxide powder and despite intensive
    resuscitation died six hours later. At autopsy there were submucosal
    tracheal and bronchial haemorrhages, widespread mucosal sloughing,
    alveolar haemorrhages and oedema.


    Insoluble, poorly absorbed arsenic trioxide presents a much less acute
    toxic hazard than soluble compounds such as sodium arsenite which are
    well absorbed after ingestion (Done and Peart, 1971). However,
    substantial arsenic trioxide ingestions may produce serious systemic
    toxicity. A patient has died after ingesting 2 g (Levin-Scherz et al,

    Gastrointestinal toxicity

    Nausea, vomiting, abdominal pain and diarrhoea are common after
    substantial arsenic trioxide ingestion (Watson et al, 1981; Marcus,
    1987; Moore et al, 1994).

    Gastrointestinal haemorrhage may lead to cardiovascular collapse. A
    direct toxic effect of arsenic on capillaries via sulphydryl-group
    binding is thought to contribute to this (Jolliffe et al, 1991; Morton
    and Dunnette, 1994).

    A 21 year-old man who ingested 2 g arsenic trioxide presented 26 hours
    later with diarrhoea, vomiting and cardiovascular shock (Levin-Scherz
    et al, 1987). Despite vigorous resuscitation with inotropic support
    and dimercaprol therapy he died 36 hours after admission from
    resistant ventricular fibrillation and asystole. The admission plasma
    arsenic concentration was shown subsequently to be 1.9 mg/L.

    Bolliger et al (1992) reported two patients maliciously poisoned with
    arsenic trioxide-contaminated chocolate (amount not stated). Both
    immediately experienced a burning sensation in the mouth and within
    minutes developed severe abdominal cramps, nausea and vomiting then
    diarrhoea. Three days later abdominal pain recurred with
    hypersalivation and haematemesis. Gastroscopy revealed a large gastric
    ulcer in the fundus with severe oesophagitis and gastritis in one of
    the subjects. Arsenic poisoning was not suspected initially and
    chelation therapy not started until eight days post ingestion.
    Analysis of urine samples taken on the day of admission showed arsenic
    concentrations of 5.3 mg/L and 5.8 mg/L respectively. Severe pulmonary
    and neurological features were also present but both patients


    Bolliger et al (1992) reported a 30 year-old male maliciously poisoned
    with arsenic trioxide (amount not stated) who developed transiently
    increased alkaline phosphatase and liver transaminase activities plus
    an increased bilirubin concentration. He eventually recovered.

    Another patient (Levin-Scherz et al, 1987) died 62 hours after
    ingesting 2 g arsenic trioxide following a clinical course complicated
    by cardiovascular collapse, renal failure and eventually an asystolic
    cardiac arrest. Hepatic transaminase activities were moderately
    increased on admission (aspartate aminotransferase 206 IU/L).


    Hypotension (Levin-Scherz et al, 1987; Jolliffe et al, 1991; Moore et
    al, 1994) or rhabdomyolysis following substantial ingestion (Sanz et
    al, 1989; Fernadez-Sola et al, 1991) may precipitate renal failure
    (Bolliger et al, 1992). A case of arsenic-induced renal cortical
    necrosis has been described (Gerhardt et al, 1978).

    Cardiovascular toxicity

    Tachycardia is typical following arsenic ingestion (Peterson and
    Rumack, 1977; Levin-Scherz et al, 1987) and is contributed to by
    anxiety, hypovolaemia and possibly direct arsenic-induced

    Ventricular arrhythmias (St. Petery et al, 1970), notably torsade de
    pointes (Beckman et al, 1991) have been observed. Other ECG
    abnormalities include prolongation of the QT interval (Bolliger et al,
    1992) and non-specific T wave changes.

    Jolliffe et al (1991) reported massive acute arsenic trioxide
    ingestion in a patient who developed sudden onset bradycardia then
    asystole despite vigorous resuscitation and no earlier arrhythmia.

    In another report (Levin-Scherz et al, 1987) a 21 year-old male
    developed cardiovascular collapse 26 hours after ingesting 2 g arsenic
    trioxide. The ECG initially showed a sinus tachycardia (140 bpm) and
    "non-specific ST-T wave abnormalities" with a normal QT interval.
    Thirty six hours after admission the patient became bradycardic (35
    bpm) then developed ventricular fibrillation unresponsive to
    cardioversion before an asystolic cardiac arrest from which he could
    not be resuscitated.


    Acute substantial arsenical ingestion has caused muscle cramps, a
    sensorineural hearing deficit (Goldsmith and From, 1980),
    encephalopathy (Jenkins, 1966; Levin-Scherz et al, 1987) and seizures
    (St. Petery et al, 1970; Peterson and Rumack, 1977).

    A peripheral sensory and/or motor neuropathy, although typical of
    chronic arsenic poisoning has been described also in survivors of
    severe acute poisoning, often in association with dermal
    manifestations of arsenic toxicity (Heyman et al, 1956; Kyle and
    Pease, 1965; Jenkins, 1966; Le Quesne and McLeod, 1977).

    Goebel et al (1990) demonstrated acute wallerian degeneration of
    myelinated nerve fibres in a patient who developed a symmetrical
    polyneuropathy after attempting suicide by ingesting arsenic. Clinical
    improvement was associated with microscopic evidence of neurological

    A 30 year-old male maliciously poisoned by arsenic trioxide (amount
    not stated) developed a peripheral neuropathy and mild generalized
    muscle weakness five days after ingestion (Bolliger et al, 1992). The
    arsenic concentration in an admission urine sample was 5.3 mg/L, but
    arsenic intoxication was not diagnosed until eight days after
    ingestion. Muscle weakness increased, he became confused and
    hallucinated. A decreased level of consciousness and respiratory
    distress necessitated intubation and mechanical ventilation. The
    neuropathy progressed following extubation and three weeks after
    admission an electromyogram showed a severe polyneuropathy with axonal
    degeneration. Muscle power in all limbs was 1/5. Severe paraesthesiae
    in the hands and feet continued and the patient was confined to a
    wheelchair. Twenty six months after intoxication he was able to walk
    with aid and had regained 70 per cent hand function (Bolliger et al,

    Dermal toxicity

    Striate leukonychia (Mees' lines) and hyperkeratotic, hyperpigmented
    skin lesions may be seen following severe acute arsenic poisoning
    although are associated typically with chronic exposure. Facial and
    peripheral oedema have also been described (Heyman et al, 1956; Kyle
    and Pease, 1965).

    Bolliger et al (1992), reported two subjects maliciously poisoned with
    arsenic trioxide. Both developed maculopapular, partly vesicular, skin
    rashes seven days after ingestion as well as severe gastrointestinal,
    pulmonary and neurological symptoms.


    In moderate or severe arsenic poisoning investigations typically show
    anaemia, leucopenia or pancytopenia (Kyle and Pease, 1965; Bolliger et
    al, 1992). There may be evidence of intravascular haemolysis and the
    blood film often shows basophilic stippling (Kyle and Pease, 1965; St.
    Petery et al, 1970).

    Oral toxicity

    Yakata et al (1985) reported a case of mandibular osteolysis with an
    occluded alveolar artery and alveolar nerve damage in which the
    suspected cause was arsenic trioxide applied to a tooth for

    Multi-organ toxicity

    Severe acute arsenic poisoning may result in death from
    cardiorespiratory or hepatorenal failure (Jenkins, 1966; Fernadez-Sola
    et al, 1991; Morton and Dunnette, 1994). Two adults maliciously
    poisoned by arsenic trioxide-contaminated chocolate developed
    multi-organ failure complicated by adult respiratory distress syndrome
    (Bolliger et al, 1992). They survived with persisting evidence of a
    sensory peripheral neuropathy two years later.


    Dermal exposure

    The major source of dermal exposure is occupational. Metal ore
    smelting is an important cause since arsenic trioxide is a by-product
    of many processes (Hine et al, 1977).

    Dermatitis is the most common manifestation of occupational arsenic
    trioxide exposure due to either a direct irritant action or to
    sensitization. Prolonged exposure has resulted in ulcerative lesions
    of the extremities (Fielder et al, 1986). Systemic arsenic toxicity
    may ensue (see below).


    Exposure to arsenic trioxide dust has been reported in the metal ore
    smelting industry and during the manufacture of inorganic arsenic
    compounds (Fielder et al, 1986). Local effects include conjunctivitis,
    hoarseness, pharyngitis, nasal irritation and haemoptysis (Heyman et
    al, 1956; Hine et al, 1977). Nasal septum perforation is also
    described (Fielder et al, 1986). Systemic features of arsenic
    poisoning may ensue.


    Arsenic trioxide has found widespread use in ethnic herbal remedies
    (Kerr and Saryan, 1986; Kew et al, 1993). Contamination of well water
    by arsenic trioxide and arsenic trisulphide has been reported as the
    cause of systemic arsenic intoxication (Tsuda et al, 1995).

    Systemic arsenic trioxide toxicity

    The systemic features observed are similar for each source of exposure
    which are considered together.

    General toxic effects

    Patients may present with general debility, progressive weakness,
    fever and sweats (Heyman et al, 1956).

    Dermal toxicity

    The characteristic dermal manifestations are hyperkeratosis and
    "raindrop" pigmentation of the skin (Heyman et al, 1956; Kyle and
    Pease, 1965; Shannon and Strayer, 1989; Sass et al, 1993).

    Hyperkeratoses appear as multiple small nodules which may coalesce to
    form plaques and are found most commonly on the palms and soles.
    Hyperkeratotic lesions may develop into squamous cell carcinomas which
    are notable for their occurrence on non light-exposed areas of the
    upper extremities and trunk (Shannon and Strayer, 1989).

    Hyperpigmentation is more prominent in the axilla, groin, areola and
    around the waist, typically with mucosal sparing (Shannon and Strayer,

    Skin changes in chronic arsenic poisoning seem to be exacerbated by
    poor nutritional status.

    The fingernails may become brittle with transverse white striae (Mees'
    lines) (Mees, 1919; Heyman et al, 1956; Kyle and Pease, 1965; Sass et
    al, 1993).

    Exfoliative dermatitis has been reported following arsenical drug
    administration (Nicolis and Helwig, 1973).

    Sass et al (1993) described a 37 year-old woman with chronic arsenic
    intoxication. Her sister had added an unstated quantity of arsenic
    trioxide to her coffee every morning for two years. She initially
    developed a generalized "melanoderma" followed by a punctate
    palmoplantar keratoderma. Histological examination showed dermal
    thickening, hyperkeratoses, hyperpigmentation and nuclear atypia
    analogous to Bowen's disease. Later examination revealed Mees' lines.
    Her cutaneous lesions remained unchanged four years later.

    A 35 year-old man developed Mees' lines on the fingernails and
    hyperkeratoses of the soles of the feet six weeks after starting to
    use an ethnic remedy for atopic eczema. The remedy contained arsenic
    trioxide, 210 mg per daily dose (Kew et al, 1993)

    Neuropsychological toxicity

    A symmetrical peripheral neuropathy is typical (Feldman et al, 1979).
    Sensory symptoms predominate with paraesthesiae, numbness and pain,
    particularly of the soles of the feet, extending in a "glove and
    stocking" distribution (Jenkins, 1966; Kew et al, 1993).

    Motor involvement with symmetrical distal limb weakness, muscle
    atrophy and loss of deep tendon reflexes is recognized (Heyman et al,
    1956; Bansal et al, 1991).

    Complete respiratory muscle paralysis (Greenberg et al, 1979; Gerhardt
    et al, 1980), a phrenic neuropathy (Bansal et al, 1991) and cranial
    nerve involvement have been reported.

    The neuropathy may be confused with the Guillain-Barr 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-Barr syndrome.

    Electromyelography may show reduced peripheral nerve conduction
    velocities in the absence of symptoms (Lagerkvist and Zetterlund,

    Psychological impairment is widely reported in chronic arsenic
    poisoning with defects of verbal learning ability and memory and
    personality changes (Heyman et al, 1956; Bolla-Wilson and Bleecker,
    1987). Beckett et al (1986) described a 50 year-old chemical plant
    engineer who developed delirium, agitation and emotional lability
    after some 20 years occupational arsenic exposure in an antimony
    smelting plant.

    Gastrointestinal toxicity

    Nausea and vomiting, although more typical of acute arsenic poisoning,
    may occur also in chronic cases.


    Although animal studies suggest arsenic trioxide inhalation or
    ingestion causes liver damage (Hine et al, 1977) there is little
    evidence for this following occupational exposure (Fielder et al,

    Narang (1987) suggested increased arsenic consumption as a
    contributing factor in the aetiology of liver disease in the Indian
    population when he found significantly increased hepatic arsenic
    concentrations at autopsy in 178 patients dying from cirrhosis, non
    cirrhotic portal fibrosis, fulminant hepatitis, Wilson's disease or
    alcoholic liver disease.

    Jhaveri (1959) reported the death of 46 year-old man from cirrhosis
    and primary carcinoma of the liver. Over 20 years occupational
    exposure (in chemical manufacture) to arsenic trioxide and sodium
    arsenite was thought to be aetiologically significant. The patient had
    increased urine, hair and nail arsenic concentrations.


    Renal manifestations of chronic arsenic poisoning probably reflect
    capillary damage and include haematuria, proteinuria with casts and
    acute tubular or cortical necrosis (Morton and Dunnette, 1994).

    In a study of 84 smelter workers chronically exposed to arsenic
    trioxide Telolahy et al (1993) found increased concentrations of
    urinary coproporphyrins compared to non-exposed controls. This
    reflects arsenic-induced impaired haem metabolism (see below).

    Peripheral vascular and cardiovascular toxicity

    "Black foot disease" refers to a severe form of peripheral vascular
    disease seen in Taiwan in those who drink artesian well water with an
    high arsenic concentration. Initial paraesthesiae and cold sensitivity
    progress to ulceration and gangrene (Chiou et al, 1995). It has been
    suggested that mortality due to all vascular diseases may be increased
    in these populations (Chen and Lin, 1994; Engel et al, 1994).

    Raynaud's syndrome has also been described in those chronically
    exposed to arsenical dust (Lagerkvist et al, 1988).

    Several authors refer to the myocardial toxicity of arsenic
    (Schoolmeester and White, 1980; Hall and Harruff, 1989) which has been
    attributed to impaired oxidative metabolism of myocardial tissue plus
    a direct arsenic-induced inflammatory process. A 42 year-old
    agricultural worker presented with systemic features of chronic
    arsenic poisoning (neuropathy and skin lesions) and had a 24 hour
    urine arsenic excretion of 7000 g (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


    Investigations in chronic arsenic poisoning often show anaemia,
    neutropenia (Heyman et al, 1956; Kyle and Pease, 1965), pancytopenia
    or evidence of haemolysis (Kyle and Pease, 1965) but macrocytosis
    without anaemia (Heaven et al, 1994) and a myelodysplastic syndrome
    (Rezuke et al, 1991) are also described.

    Haematological analyses of 130 smelter workers occupationally exposed
    to arsenic trioxide (concentrations not stated) revealed a relative
    neutropenia in 23 per cent of cases (Hine et al, 1977). Sass et al
    (1993) noted moderate anaemia and leucopenia (values not stated) in a
    37 year-old woman maliciously poisoned with an unstated amount of
    arsenic trioxide daily for over two years.

    Chronic arsenic exposure complicated by aplastic anaemia may
    predispose to acute myeloid leukaemia (Kjeldsberg and Ward, 1972).

    Disrupted haem metabolism with altered urinary porphyrin excretion
    (Telolahy et al, 1993) has been reported.

    Endocrine toxicity

    An occupational study among smelter workers in Sweden (Lagerkvist and
    Zetterlund, 1994) has associated chronic arsenic exposure with the
    development of diabetes mellitus.


    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.


    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



    After acute ingestion of a substantial quantity of arsenic trioxide
    most patients will vomit spontaneously but, in those who do not,
    gastric lavage should be considered only if it is possible to
    undertake the procedure within the first hour.

    Supportive measures

    Severe acute arsenic trioxide poisoning requires prompt intensive
    resuscitation with adequate fluid replacement and close observation of
    vital signs including cardiac monitoring. Diarrhoea may be treated
    symptomatically with loperamide. Chelation therapy should be
    considered in symptomatic cases. Obtain blood and urine for arsenic
    concentration determination.

    Electrocardiographic evidence of QT prolongation in arsenic poisoning
    may precede atypical ventricular arrhythmias, notably torsade de
    pointes, and in these circumstances drugs which themselves prolong the
    QT interval, such as procainamide, quinidine or disopyramide, should
    be avoided. Isoprenaline is effective; phenytoin, lignocaine or
    propranolol are alternatives (Goldsmith and From, 1980).


    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 g/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 g/24 h and 5819 g/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 g 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 g/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 g/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 g/L and
    fell progressively to 96 g/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

    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
    g/day by day 31. At twelve month follow-up neurological effects

    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

    Dimercaprol is contraindicated in severe liver disease since it is
    metabolized by glucuronidation with subsequent biliary excretion.


    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 g to a maximum of 340 g 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 g/L on day five). Four days later
    the urine arsenic concentration had fallen to 96 g/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).


    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 g/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 g/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).


    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,

    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 g 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 g, increasing in the next 24 hours
    (the second day of d-penicillamine therapy) to approximately 800 g.
    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 g arsenic, increasing to 2000 g
    arsenic in the next 24 hours before falling to approximately 200 g/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 g (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 g/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,

    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 g/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 g/g creatinine in the first 72 hours of
    chelation compared to a pretreatment value of 73.5 g/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 g/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 g/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 g
    (normal <5 g/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 g/L
    after four days penicillamine therapy 500 mg qds compared to a
    pretreatment concentration of 7840 g/L (Kjeldsberg and Ward, 1972).
    The patient died from acute myeloid leukaemia some six months later.


    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 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 g 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 g though
    this increased to 75,000 g/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.


    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.


    Blood arsenic concentrations correlate poorly with exposure but may be
    useful in chronic poisoning (Morton and Dunnette, 1994).

    Arsenic concentrations in hair and nails have been used to indicate
    chronic systemic absorption, although their use as biological monitors
    of occupational exposure to airborne arsenic is limited by difficulty
    in excluding external contamination (Yamamura and Yamauchi, 1980).

    Urine arsenic concentrations are the most useful biomonitoring tool,
    ideally as total excretion from a 24 hour collection although spot
    urine arsenic concentrations have been proposed in screening
    asymptomatic patients with a history of possible acute arsenic
    ingestion (Grande et al, 1987).

    Since certain marine organisms (especially mussels) may contain large
    amounts of organoarsenicals, it is advisable that workers refrain from
    eating seafood for at least 48 hours before urine collection (Buchet
    et al, 1994). Analytical speciation methods capable of separating
    inorganic arsenic and its methylated derivatives from dietary
    organoarsenicals partially overcome this problem (Smith et al, 1977;
    Farmer and Johnson, 1990; Buchet et al, 1994). However, Vahter (1994)
    has suggested that under certain circumstances these compounds are
    released from seafood which can invalidate assessment of inorganic
    arsenic exposure.

    Smith et al (1977) demonstrated a close correlation between airborne
    arsenic and urinary excretion of all arsenic species in arsenic-
    exposed workers and Farmer and Johnson (1990) found that high urine
    concentrations of inorganic arsenic plus its mono- and dimethyl
    derivatives corresponded to the possible workplace atmospheric arsenic
    concentrations for those involved in arsenic production or glass
    manufacture. Increased urine arsenic concentrations have also been
    noted in timber treatment workers using an arsenic-based wood
    preservative (Gollop and Glass, 1979).

    Telolahy et al (1993) suggested a potential role for increased urine
    coproporphyrins as an indicator of chronic occupational arsenic
    exposure since arsenic is known to disrupt haem metabolism.

    Regular examination of the skin should be included in an occupational
    health surveillance programme. Workers with evidence of excessive
    arsenic exposure should be offered long-term monitoring for the
    development of skin, bladder or lung cancer, though in practice this
    may be difficult to execute.


    Maximum exposure limit

    Long-term exposure limit (8 hour TWA reference period) 0.1 mg/m3
    (Health and Safety Executive, 1995).



    Individuals who chronically ingest arsenic have an increased risk of
    developing skin cancer, usually squamous cell carcinoma but also basal
    cell carcinomas (Chen et al, 1988; Shannon and Strayer, 1989; Chiou et
    al, 1995). Squamous cell carcinomas may arise in areas of arsenic-
    induced Bowen's disease (Shannon and Strayer, 1989).

    Hsueh et al (1995) demonstrated a significant dose-response
    relationship between skin cancer prevalence and arsenic exposure from
    artesian well water. These authors identified chronic hepatitis B
    carriage and malnutrition as risk factors for arsenic-induced
    dermatological malignancy.

    Skin cancer has also been documented among vineyard workers and
    farmers exposed to inhaled inorganic arsenic in pesticides (Thiers et
    al 1967; Chen and Lin, 1994) although skin and gastrointestinal
    absorption probably contributed to arsenic toxicity in these cases.

    Renwick et al (1981) investigated the long term effects of acute
    arsenic trioxide poisoning. Sixty two of over 200 students who had
    eaten sausages containing 1.36 g/kg arsenic trioxide were contacted 35
    years after the incident. Three had developed rodent ulcers but this
    incidence may have been related solely to tropical sunlight exposure.

    There is an association between chronic arsenic exposure and cancer of
    the urinary tract (Chen et al, 1988; Chen and Lin, 1994; Tsuda et al,
    1995), lung (Chen and Lin, 1994; Simonato et al, 1994; Tsuda et al,
    1995) and liver, both hepatic angiosarcoma (Lander et al, 1975) and
    hepatocellular carcinoma (Chen and Lin, 1994). Jhaveri (1959) reported
    a case of cirrhosis and primary liver cancer in a man occupationally
    exposed to arsenic trioxide and sodium arsenite for over 20 years.

    Arsenic may be responsible also for lung cancer occurring in workers
    employed in the lead, tin and copper-smelting industries (Axelson et
    al, 1978).

    Smoking exerts a synergistic effect with ingested and inhaled arsenic
    in the development of pulmonary malignancy (Tsuda et al, 1995).

    There is limited evidence that other internal cancers, particularly of
    the gastrointestinal tract and haematological malignancies, are linked
    aetiologically to arsenic exposure (Chen and Lin, 1994).


    Animal studies suggest arsenic is embryotoxic and teratogenic but
    reliable human data are scarce (Council on Scientific Affairs, 1985).

    Bolliger et al (1992) described a 39 year-old woman maliciously
    poisoned with arsenic trioxide when 28 weeks pregnant. Her initial
    urine arsenic concentration was 5.8 mg/L. She developed multiple organ
    failure with adult respiratory distress syndrome and the fetus died
     in utero. Fetal organs, notably the liver (26 mg/kg), kidneys (12
    mg/kg), spleen (8 mg/kg) and stomach (8 mg/kg) contained increased
    arsenic concentrations.

    A woman in the third trimester of pregnancy developed acute renal
    failure after ingesting a large quantity of an arsenical rat poison.
    Her baby was delivered on the fourth day post ingestion but died
    within a few hours from hyaline membrane disease. At autopsy the
    infant showed significant arsenic accumulation in the liver, brain and
    kidneys (liver arsenic concentration 0.74 mg/100 g tissue) (Lugo et
    al, 1969).


    The frequency of sister chromatid exchanges in human peripheral
    lymphocytes exposed to 2 g/mL was above that of controls.

    Neither chromatid nor chromosome aberrations were observed in
    spermatogonia or bone marrow cells following intraperitoneal
    administration of 0-12 mg arsenic per kilogram to mice (DOSE, 1992).

    Fish toxicity

    Rainbow trout (8 wk) : 1-137 g arsenic per gram in diet, no observed
                         : 137-1477 g arsenic per gram in diet reduced
    growth. Reduced feed behaviour has also been reported.

    LC50 (48 hr)  Channa punctatus 14.7 mg (DOSE, 1992).

    EC Directive on Drinking Water Quality 80/778/EEC

    Maximum admissible concentration 50 g/L, as arsenic (DOSE, 1992).

    WHO Guidelines for Drinking Water Quality

    Guideline value 10 g/L, as arsenic (WHO, 1993).


    SM Bradberry BSc MB MRCP
    WN Harrison PhD CChem MRSC
    ST Beer BSc

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

    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


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    Arsenic metabolites in hair, blood and urine in workers exposed to
    arsenic trioxide.
    Ind Health 1980; 18: 203-10.

    See Also:
       Toxicological Abbreviations
       Arsenic trioxide (ICSC)