UKPID MONOGRAPH SODIUM AND POTSSIUM ARSENITE SM Bradberry BSc MB MRCP WN Harrison PhD CChem MRSC ST Beer BSc JA Vale MD FRCP FRCPE FRCPG FFOM National Poisons Information Service (Birmingham Centre), West Midlands Poisons Unit, City Hospital NHS Trust, Dudley Road, Birmingham B18 7QH This monograph has been produced by staff of a National Poisons Information Service Centre in the United Kingdom. The work was commissioned and funded by the UK Departments of Health, and was designed as a source of detailed information for use by poisons information centres. Peer review group: Directors of the UK National Poisons Information Service. SODIUM AND POTASSIUM ARSENITE Toxbase summary Type of product Sodium arsenite is an active ingredient in insecticides and acaricides. Potassium arsenite is the active ingredient in Fowler's solution and is used in mirror manufacture. Toxicity Sodium and potassium arsenite are highly soluble (trivalent) arsenic salts. Substantial ingestions may be fatal (fatal dose not known). Features Systemic toxicity may follow ingestion, inhalation or topical exposure. Topical - May cause skin irritation and sensitization. Systemic arsenic poisoning may occur after substantial exposure. Ingestion Minor ingestions (small amounts of dilute solutions): - Usually no serious effects. Mild gastrointestinal upset may occur. Substantial ingestions: - Rapid onset (within 1-2 hours) of burning in the mouth and throat, hypersalivation, dysphagia, nausea, vomiting, abdominal pain and diarrhoea. - In severe cases gastrointestinal haemorrhage, cardiovascular collapse, renal failure, seizures, encephalopathy and rhabdomyolysis may occur. Other features: - Facial and peripheral oedema, ventricular arrhythmias (notably torsade de pointes), ECG abnormalities (QT interval prolongation, T-wave changes), muscle cramps. - Investigations may show anaemia, leucopenia, thrombocytopenia or evidence of intravascular haemolysis. - Death may occur from cardiorespiratory or hepatorenal failure. The adult respiratory distress syndrome (ARDS) has been reported. - Survivors of severe acute poisoning may develop a peripheral neuropathy and skin lesions typical of chronic arsenical poisoning. Inhalation - Rhinitis, pharyngitis, laryngitis and tracheobronchitis may occur. Tracheal and bronchial haemorrhage may complicate severe cases. Chronic arsenic exposure - May occur following ingestion, inhalation or topical exposure. - Features include weakness, lethargy, gastrointestinal upset, progressing to ulceration and gangrene), renal tubular or cortical damage and haematological abnormalities (notably pancytopenia). Management Topical 1. Irrigate with copious volumes of water. 2. Consider the possibility of systemic arsenic poisoning after significant exposure. Ingestion Minor ingestions: 1. Gastrointestinal decontamination is unnecessary. 2. Symptomatic and supportive care only. Substantial ingestions: 1. Most patients will vomit spontaneously but in those who do not, gastric lavage should be considered only if the patient presents within one hour. 2. Supportive measures are paramount. Intensive resuscitation may be required. Ensure adequate fluid replacement and close observation of vital signs including cardiac monitoring. 3. Diarrhoea can be controlled with loperamide. 4. Monitor blood urea, creatinine, electrolytes, liver function and full blood count. 5. Collect blood and urine for arsenic concentration measurements. 6. ECG evidence of QT prolongation may precede atypical ventricular arrhythmias (notably torsade de pointes). Avoid drugs which prolong the QT interval e.g. procainamide, quinidine or disopyramide. Isoprenaline is effective with phenytoin, lignocaine or propranolol as alternatives. 7. Antidotes - chelation therapy with either dimercaprol, DMSA or DMPS should be considered in symptomatic patients where there is analytical confirmation of the diagnosis, but only after specialist advice from the NPIS. References Donofrio PD, Wilbourn AJ, Albers JW, Rogers L, Salanga V, Greenberg HS. Acute arsenic intoxication presenting as Guillain-Barré-like syndrome. Muscle Nerve 1987; 10: 114-20. Engel RR, Hopenhayn-Rich C, Receveur O, Smith AH. Vascular effects of chronic arsenic exposure: a review. Epidemiol Rev 1994; 16: 184-209. Gerhardt RE, Crecelius EA, Hudson JB. Moonshine-related arsenic poisoning. Arch Intern Med 1980; 140: 211-3. Goldsmith S, From AHL. Arsenic-induced atypical ventricular tachycardia. N Engl J Med 1980; 303:1096-7. Greenberg C, Davies S, McGowan T, Schorer A, Drage C. Acute respiratory failure following severe arsenic poisoning. Chest 1979; 76: 596-8. Kosnett MJ, Becker CE. Dimercaptosuccinic acid as a treatment for arsenic poisoning. Vet Hum Toxicol 1987; 29: 462. Massey EW, Wold D, Heyman A. Arsenic: Homicidal intoxication. South Med J 1984; 77: 848-51. Roses OE, García Fernández JC, Villaamil EC, Camussa N, Minetti SA, Martínez de Marco M, Quiroga PN, Rattay P, Sassone A, Valle Garecca BS, López CM, Olmos V, Pazos P, Pińeiro A, Rodriguez Lenci J. Mass poisoning by sodium arsenite. Clin Toxicol 1991; 29: 209-13 Substance name Sodium arsenite Origin of substance Reaction of caustic soda with arsenious oxide (HSDB, 1995) Synonyms Arsenious acid, sodium salt Sodium arsenic oxide Sodium metaarsenite (DOSE, 1994a) Chemical group A compound of arsenic, a group VA element Reference number CAS 7784-46-5 (DOSE, 1994a) RTECS CG 3675000 (HSDB, 1995) UN 2027 (solid) 1686 (aqueous solution) (DOSE, 1994a) HAZCHEM 2X (DOSE, 1994a) Physicochemical properties Chemical structure NaAsO2 (DOSE, 1994a) Molecular weight 129.91 (DOSE, 1994a) Physical state at room temperature Solid (HSDB, 1995) Colour White or greyish-white (HSDB, 1995) Odour None (CHRIS, 1995) Viscosity NA pH Forms basic solution in water (OHM/TADS, 1995) Solubility Freely soluble in water, soluble in ethanol (DOSE, 1994a) Autoignition temperature NA Chemical interactions Arsine gas is evolved when sodium arsenite reacts with acids and metals. (OHM/TADS, 1995) Major products of combustion Arsenic fumes and sodium oxide may be generated during a fire. (OHM/TADS, 1995) Explosive limits NA Flammability Non-flammable (CHRIS, 1995) Boiling point Decomposes when heated (CHRIS, 1995) Density 1.87 at 25şC (DOSE, 1994a) Vapour pressure NA Relative vapour density NA Flash Point NA Reactivity Reacts with strong oxidizers (HSDB, 1995) Hygroscopic Uses Insecticide Acaricide Arsenical soap manufacture (DOSE, 1994a) Hazard/risk classification Index no. 033-002-00-5 Risk phrases 0.2% < conc T; R23/25 - Toxic by inhalation and if swallowed. 0.1% < conc < 0.2% Xn; R20/22 - Harmful by inhalation and in contact with the skin. Safety phrases S (1/2)-20/21-28-45 - Keep locked up and out of the reach of children. When using do not eat, drink or smoke. After contact with the skin, wash immediately with plenty of ....(to be specified by the manufacturer). In case of accident, or if you feel unwell, seek medical advice immediately (show label where possible). EEC No: NIF (CHIP2, 1994) Substance name Potassium arsenite Origin of substance Reaction of arsenic trioxide and potassium bicarbonate. (HSDB, 1995) Synonyms Arsenous acid, potassium salt Arsonic acid, potassium salt Fowler's solution Potassium metaarsenite (DOSE, 1994b) Chemical group A compound of arsenic, a group VA element Reference numbers CAS 10124-50-2 (DOSE, 1994b) RTECS CG 3800000 (RTECS, 1995) UN 1678 (DOSE, 1994b) HAZCHEM 2X (DOSE, 1994b) Physicochemical properties Chemical structure As2HKO4 (DOSE, 1994b) Molecular weight 253.95 (DOSE, 1994b) Physical state at room temperature Solid (HSDB, 1995) Colour White (HSDB, 1995) Odour Odourless (CHRIS, 1995) Viscosity NA pH Will form a basic solution (OHM/TADS, 1995) Solubility Soluble in water (DOSE, 1994b) Autoignition temperature NA Chemical interactions Arsine gas is released upon contact with acid. Slowly converted to arsenate by atmospheric oxygen when in aqueous solution. (HAZARDTEXT, 1995) Major products of combustion Toxic fumes of arsenic and potassium oxide may be generated during a fire. (HAZARDTEXT, 1995) Explosive limits NIF Flammability Non-flammable (OHM/TADS, 1995) Boiling point Decomposes at 300°C (HSDB, 1995) Density NIF Vapour pressure NA Relative vapour density NA Flash Point NA Reactivity Reacts with salts of iron and most heavy metals. (HAZARDTEXT, 1995) Uses In manufacture of mirrors, reducing silver salt to metallic silver. Used in herbal remedies, notably Fowler's solution. (DOSE, 1994b) Hazard/risk classification Index no. 033-002-00-5 Risk phrases 0.2% < conc T; R23/25 - Toxic by inhalation and if swallowed. 0.1% < conc < 0.2% Xn; R20/22 - Harmful by inhalation and in contact with the skin. Safety phrases S (1/2)-20/21-28-45 - Keep locked up and out of the reach of children. When using do not eat, drink or smoke. After contact with the skin, wash immediately with plenty of ....(to be specified by the manufacturer). In case of accident, or if you feel unwell, seek medical advice immediately (show label where possible). EEC No: NIF (CHIP2, 1994) INTRODUCTION Sodium arsenite is a trivalent arsenic salt formed from the reaction of arsenic trioxide with caustic soda (IPCS, 1981). Potassium arsenite is formed by the reaction of arsenic trioxide and potassium hydroxide. It has been used widely in the form of Fowler's solution. Arsenite salts interact with acids and reducing metals (e.g. iron and zinc) or aluminium to form arsine gas, the most acutely toxic form of arsenic. Sodium and potassium arsenite are highly soluble and represent a much more acute toxic hazard than less soluble trivalent arsenic compounds (e.g. arsenic trioxide) (Done and Peart, 1971). Interconversion of arsenites and arsenates may also occur readily. EPIDEMIOLOGY The main source of arsenic exposure in the world population is drinking water with an high inorganic arsenic concentration (Chiou et al, 1995; Das et al, 1995). Arsenic usually is found in water in the form of arsenite and arsenate, the proportions of each depending on conditions (IPCS, 1981). In 1987 an epidemic of arsenic poisoning occurred in Argentina when a solution of sodium arsenite was maliciously poured over meat in a butcher's shop. Over 700 people were involved but there were no fatalities (Roses et al, 1991). Potassium arsenite has been ingested with suicidal intent (Massey et al, 1984). Accidental exposure has occurred through its use in "traditional" ethnic remedies or other homeopathic medicines (Kerr and Saryan, 1986). Arsenic intoxication has followed the ingestion of pesticides containing sodium arsenite (Jenkins, 1966; Peoples et al, 1977; Vaziri et al, 1980), or fruit or vegetables that have been sprayed with such pesticides. Done and Peart (1971) found that the majority of deaths resulting from ingestion of arsenic-containing herbicides were attributable to products containing high sodium arsenite concentrations. Of 43 cases of human poisoning involving sodium arsenite or arsenate reported in the US between 1949-67, 65 per cent were fatal. Industrial arsenic exposure has occurred from accidents where arsine gas has been liberated from the reaction of arsenite solutions with hydrogen released by acids and metals such as aluminium (Levinsky et al, 1970; Elkins and Fahy, 1967) and zinc (Teitelbaum and Kier, 1969). MECHANISM OF TOXICITY The principle mechanism of arsenic intoxication is disruption of thiol proteins. For example, arsenic inactivates pyruvate dehydrogenase by complexing with the sulphydryl groups of a lipoic acid moiety (6,8-dithiooctanoic acid) of the enzyme (Jones, 1995). Enhanced cellular destruction of damaged thiol proteins may produce toxic oxygen radicals (Lee and Ho, 1994). Reduced lymphocyte proliferation (Gonsebatt et al, 1994) and impaired macrophage function also have been described (Lantz et al, 1994). Dong and Luo (1994) have suggested that while arsenic can directly damage DNA, a more important mechanism in arsenic-induced carcinogenicity is enhanced mutagenicity of other compounds via increased DNA-protein crosslinks. The affinity of arsenic for sulphydryl groups is utilized in chelation therapy. TOXICOKINETICS Absorption Soluble arsenic salts, such as sodium and potassium arsenite, are well absorbed after ingestion. Limited animal data suggest sodium arsenite is well absorbed through the lungs (Fielder et al, 1986). Sodium or potassium arsenite particles deposited in the upper respiratory tract after inhalation may be cleared via mucociliary transport, swallowed and then absorbed (Fielder et al, 1986). Direct evidence of transcutaneous arsenic absorption in man is scarce (Fielder et al, 1986). Robinson (1975) reported a case of systemic absorption in a patient whose cheek had been treated with a caustic arsenical paste but this involved significant arsenic uptake through damaged skin. Distribution Absorbed arsenic is distributed to all body tissues. High concentrations would be expected in keratin-rich tissues such as hair, skin and nails due to sulphydryl group binding (Fielder et al, 1986). Trivalent arsenic is methylated in the liver to methylarsonic acid and dimethylarsinic acid (IPCS, 1996). Short-term studies on humans indicate that daily intake in excess of 0.5 mg progressively, but not completely, saturates the capacity to methylate inorganic arsenic (IPCS, 1996). Excretion The half-life of arsenic in blood is about 60 hours with renal excretion predominantly as mono- and dimethyl- derivatives (Buchet et al, 1981; Waldron and Scott, 1994). The whole body half-life of arsenic in six human volunteers fitted a three compartment system, with 65.9 per cent of orally administered arsenic acid having a half-life of 2.1 days, 30.4 per cent a half-life of 9.5 days and 3.7 per cent a half-life of 38.4 days (mean values) (Pomroy et al, 1980). CLINICAL FEATURES: ACUTE EXPOSURE Dermal exposure Trivalent arsenic compounds are irritating to the skin and mucous membranes with dermatitis the most common feature following occupational exposure. Erythema, burning and itching, eczematous eruptions and folliculitis are typical (Fielder et al, 1986). Robinson (1975) reported the development of a peripheral polyneuropathy, "generalized skin lesions" and nail thickening in a patient who applied a caustic arsenical paste to his cheek. Ocular exposure Sodium and potassium arsenite are eye irritants. Most injuries result from exposure to dusts, causing conjunctivitis, lacrimation, photophobia and chemosis (Grant and Schuman, 1993). Ingestion The toxicity of ingested sodium or potassium arsenite is dependent on the amount and concentration of the preparation. Gastrointestinal toxicity Ingestion of a substantial quantity of sodium or potassium arsenite is followed, usually within two hours, by nausea and vomiting, abdominal pain and diarrhoea (Giberson et al, 1976; Vaziri et al, 1980; Roses et al, 1991). These features occurred following ingestion of 720 mg and 400 mg sodium arsenite respectively (Vaziri et al, 1980). Roses et al (1991) reported a mass poisoning when sodium arsenite was maliciously poured over meat in a butcher's shop. Thirty five per cent of 85 subjects said to have urine arsenic concentrations 36 µg/L or less reported symptoms while gastrointestinal symptoms occurred in all three subjects with urine arsenic concentrations reported to be greater than 10000 µg/L (there were some inconsistencies in the publication of these concentrations). Abdominal pain and gastritis were the most common symptoms in subjects with lower urine arsenic concentrations, whilst vomiting and nausea were more common at higher concentrations. No subjects were symptomatic at one month follow up. Other features of arsenic ingestion include burning of the mouth and throat, dysphagia (Heyman et al, 1956; Jenkins, 1966) and hypersalivation. In severe cases, gastrointestinal haemorrhage with cardiovascular collapse may ensue and is thought to reflect a direct toxic effect of arsenic on capillaries via sulphydryl-group binding (Morton and Dunnette, 1994). The mortality from substantial sodium (or potassium) arsenite ingestion may be high (Done and Peart, 1971). Hepatotoxicity Acute arsenic ingestions are associated frequently with increased liver enzyme activities and hyperbilirubinaemia although these abnormalities usually resolve. Nephrotoxicity Hypotension (Giberson et al, 1976; Vaziri et al, 1980) or rhabdomyolysis following substantial arsenic ingestion may precipitate renal failure; renal cortical necrosis has been described (Gerhardt et al, 1978). Jenkins (1966) described a 38 year-old woman who developed albuminuria and microscopic haematuria after ingesting an unknown amount of rat poison containing sodium arsenite. Cardiovascular toxicity Tachycardia is typical following arsenic ingestion (Peterson and Rumack, 1977; Levin-Scherz et al, 1987) and is contributed to by anxiety, hypovolaemia and possibly direct arsenic-induced cardiotoxicity. Ventricular arrhythmias, notably torsade de pointes (Beckman et al, 1991) have been observed. Other ECG abnormalities include prolongation of the QT interval (Goldsmith and From, 1980) and non-specific T wave changes. Sudden onset bradycardia, then asystole, despite vigorous resuscitation and no earlier arrhythmia, has also followed massive acute arsenic ingestion. Neurotoxicity Roses et al (1991) reported headache as a common feature in subjects who ingested sodium arsenite-contaminated meat. Ingestion of arsenic has resulted in muscle cramps, a sensorineural hearing deficit (Goldsmith and From, 1980), encephalopathy (Jenkins, 1966) and seizures. A peripheral sensory and/or motor neuropathy has been described in survivors of severe acute arsenic poisoning although this is more typical following chronic exposure. Jenkins (1966) described a 38 year-old woman who had ingested sodium arsenite rat poison (amount not stated) suicidally. She developed "pins and needles" in her hands and feet. Physical examination showed distal muscle weakness in the lower limbs. There was reduced vibration and position sense in the toes and ankle-jerks were absent. She received a "full course" of dimercaprol (not specified) and no disability was detectable 18 months later. Goebel et al (1990) demonstrated acute wallerian degeneration of myelinated nerve fibres in a patient who developed a symmetrical polyneuropathy after attempting suicide by arsenic ingestion. Clinical improvement was associated with microscopic evidence of neurological regeneration. Dermal toxicity Striate leukonychia (Mees' lines) may develop following severe arsenite poisoning (Jenkins, 1966; Massey, 1984), although associated typically with chronic exposure. Several weeks after attempted suicide by sodium arsenite ingestion, a 38 year-old woman developed transverse striate leukonychia and desquamated skin on her palms and soles; she recovered fully (Jenkins, 1966). Facial and peripheral oedema have been described (Heyman et al, 1956; Kyle and Pease, 1965). Haemotoxicity In moderate or severe arsenic poisoning investigations typically show anaemia, leucopenia or pancytopenia (Kyle and Pease, 1965). There may be evidence of intravascular haemolysis and basophilic stippling has been reported on the blood film (Kyle and Pease, 1965). Multi-organ toxicity Severe acute arsenic poisoning may result in death from cardiorespiratory or hepatorenal failure (Jenkins, 1966; Armstrong et al, 1984; Campbell and Alvarez, 1989; Morton and Dunnette, 1994). The adult respiratory distress syndrome has been described (Bolliger et al, 1992). Inhalation Inhalation of arsenic compounds causes rhinitis, pharyngitis, laryngitis and tracheobronchitis (Morton and Dunnette, 1994). Injection DiNapoli et al (1989) described a patient who injected sodium arsenite and potassium cyanide in a suicide attempt. He collapsed within minutes with probable cyanide-induced severe respiratory distress and coma. His condition improved following the intravenous administration of sodium nitrite and sodium thiosulphate although he subsequently experienced nausea and vomiting. The urine arsenic excretion in the first 12 hours following admission was 10 mg. Twenty two days later he complained of numbness and tingling in the upper extremities but there was no objective neurological abnormality. No cutaneous manifestations of arsenic poisoning developed. CLINICAL FEATURES: CHRONIC EXPOSURE Dermal exposure Occupational cutaneous exposure may lead to chronic poisoning. Arsenic salts have caused skin sensitization. Inhalation Occupational arsenical exposure may lead to chronic poisoning. Nasal septum perforation is also described. Ingestion Ingestion of arsenic-contaminated drinking water (Feinglass, 1973; Chiou et al, 1995), illicit whisky (Moonshine) (Gerhardt et al, 1980), "tonics" or traditional remedies containing arsenite notably Fowler's solution (Nevens et al, 1990), have caused chronic arsenic poisoning. Systemic arsenic toxicity The systemic features observed are similar for each source of exposure and for exposure to all inorganic forms of arsenic which are considered together. General toxic effects Patients may present with general debility, progressive weakness (Feinglass, 1973; Gerhardt et al, 1980), fever and sweats (Heyman et al, 1956). Dermal toxicity The characteristic dermal manifestations are hyperkeratosis and "raindrop" pigmentation of the skin (Heyman et al, 1956; Kyle and Pease, 1965; Shannon and Strayer, 1989; Sass et al, 1993). Hyperkeratoses appear as multiple small nodules which may coalesce to form plaques and are found most commonly on the palms and soles. By contrast, hyperpigmentation is more prominent in the axilla, groin, areola and around the waist, typically with mucosal sparing (Shannon and Strayer, 1989). These changes seem to be exacerbated by poor nutritional status (Das et al, 1995). Hyperkeratotic lesions may develop into squamous cell carcinomas which are notable for their occurrence on non light-exposed areas of the upper extremities and trunk (Shannon and Strayer, 1989). The fingernails may become brittle with transverse white striae (Mees' lines) (Mees, 1919; Heyman et al, 1956; Kyle and Pease, 1965; Gerhardt et al, 1980; Sass et al, 1993). Exfoliative dermatitis (Nicolis and Helwig, 1973) and perforation of the nasal septum have been reported. Sass et al (1993) described a 42 year-old man who had been prescribed Fowler's solution over one year. Arsenical keratoderma was diagnosed but the patient was lost to follow-up for 10 years. When seen again, an extension of the lesions and arsenical keratoses was apparent on the fingers with development of squamous cell carcinoma after a further 12 months. Neuropsychological toxicity A symmetrical peripheral neuropathy is typical. Sensory symptoms predominate with paraesthesiae, numbness and pain, particularly of the soles of the feet, extending in a "glove and stocking" distribution (Jenkins, 1966; Gerhardt et al, 1980). Motor involvement with symmetrical distal limb weakness, muscle atrophy and loss of deep tendon reflexes is recognized (Heyman et al, 1956; Gerhardt et al, 1980; Bansal et al, 1991). Complete respiratory muscle paralysis (Greenberg et al, 1979; Gerhardt et al, 1980), a phrenic neuropathy (Bansal et al, 1991) and cranial nerve involvement have been reported. The neuropathy may be confused with the Guillain-Barré syndrome (Kyle and Pease, 1965; Donofrio et al, 1987). Gastrointestinal symptoms and skin manifestations suggest arsenic poisoning, while a high CSF protein concentration and cranial nerve involvement are more typical of the Guillain-Barré syndrome. Electromyelography may show reduced peripheral nerve conduction velocities in the absence of symptoms. Psychological impairment is widely reported in chronic arsenical poisoning with defects of verbal learning ability and memory and personality changes. Gastrointestinal toxicity Nausea and vomiting, although more typical of acute arsenic poisoning, may occur also in chronic cases. Hepatotoxicity Nevens et al (1990) reported eight cases of non-cirrhotic portal hypertension in patients who had received potassium arsenite in a herbal remedy (as Fowler's solution) for several years. All showed signs of hypersplenism and massive bleeding from oesophageal varices was reported in seven cases. Cirrhosis has also been described but may involve concomitant excess ethanol consumption (Morton and Dunnette, 1994). Narang (1987) suggested increased arsenic consumption as a contributing factor in the aetiology of liver disease in the Indian population when he found significantly increased hepatic arsenic concentrations at autopsy in 178 patients dying from cirrhosis, non cirrhotic portal fibrosis, fulminant hepatitis, Wilson's disease or alcoholic liver disease. Nephrotoxicity Renal manifestations probably reflect capillary damage and include haematuria, proteinuria with casts and acute tubular or cortical necrosis (Morton and Dunnette, 1994). Peripheral vascular and cardiovascular toxicity "Black foot disease" refers to a severe form of peripheral vascular disease seen in Taiwan in those who drink artesian well water with an high arsenic concentration. Initial paraesthesiae and cold sensitivity progress to ulceration and gangrene (Chiou et al, 1995). It has been suggested that mortality due to all vascular diseases may be increased in these populations (Chen and Lin, 1994; Engel et al, 1994). Raynaud's syndrome has also been described in those chronically exposed to arsenic dust. Several authors refer to arsenic-induced myocardial toxicity (Schoolmeester and White, 1980; Hall and Harruff, 1989), which has been attributed to impaired oxidative metabolism of myocardial tissue plus a direct inflammatory effect. A 42 year-old agricultural worker presented with neuropathy and skin lesions and had a 24 hour urine arsenic excretion of 7000 µg (Hall and Harruff, 1989). He received a 15 day course of dimercaprol with some improvement in motor function. On the 26th day of hospital admission he suddenly collapsed and died following a cardiac arrest. At post-mortem he had a diffuse interstitial myocarditis which was assumed to have triggered a fatal arrhythmia. Haemotoxicity Anaemia, neutropenia (Heyman et al, 1956; Kyle and Pease, 1965), pancytopenia, haemolysis (Kyle and Pease, 1965), macrocytosis without anaemia (Heaven et al, 1994) and a myelodysplastic syndrome (Rezuke et al, 1991) have been reported. Chronic arsenic exposure complicated by aplastic anaemia may predispose to acute myeloid leukaemia (Kjeldsberg and Ward, 1972). Arsenic-induced disruption of haem metabolism with altered urinary porphyrin excretion is also described (Garcia-Vargas et al, 1994). Endocrine toxicity Epidemiological evidence from Taiwan (Lai et al, 1994) and occupational studies have associated chronic arsenic exposure with the development of diabetes mellitus. Pulmonary toxicity An irritating cough and haemoptysis are reported (Heyman et al, 1956). MANAGEMENT Dermal exposure Surface decontamination should be attempted where necessary. Treat burns conventionally. Consider the possibility of systemic arsenic poisoning and the need for chelation therapy (see below). Ocular exposure Irrigate the eye with copious lukewarm water. A topical anaesthetic may be necessary for pain relief. Seek an ophthalmic opinion if symptoms persist or examination is abnormal. Inhalation Immediate management involves removal from exposure and administration of supplemental oxygen if necessary. Evidence of systemic arsenic uptake should be sought and chelation therapy considered as discussed below. Ingestion Decontamination After acute ingestion of a substantial quantity of sodium or potassium arsenite most patients will vomit spontaneously but, in those who do not, gastric lavage should be considered only if it is possible to undertake the procedure within the first hour. Supportive measures Severe acute sodium or potassium arsenite poisoning requires prompt intensive resuscitation with adequate fluid replacement and close observation of vital signs including cardiac monitoring. Diarrhoea may be treated symptomatically with loperamide. Chelation therapy should be considered in symptomatic cases. Obtain blood and urine for arsenic concentration determination. Electrocardiographic evidence of QT prolongation in arsenic poisoning may precede atypical ventricular arrhythmias, notably torsade de pointes, and in these circumstances drugs which themselves prolong the QT interval, such as procainamide, quinidine or disopyramide, should be avoided. Isoprenaline is effective; phenytoin, lignocaine or propranolol are alternatives (Goldsmith and From, 1980). Antidotes Chelating agents used in the treatment of arsenic poisoning are dithiol compounds which can remove arsenic from endogenous sulphydryl groups, the targets of arsenic toxicity (Jones, 1995). Traditionally, dimercaprol (British anti-lewisite, BAL) has been the recommended chelator in arsenic intoxication (Jenkins, 1966; Greenberg et al, 1979; Roses et al, 1991). However, dimercaprol may produce unpleasant adverse effects and must be administered by deep intramuscular injection. There is increasing evidence that dimercaptosuccinic acid (DMSA, Succimer) (Aposhian et al, 1984; Graziano, 1986; Fournier et al, 1988; Inns et al, 1990) and dimercaptopropane sulphonate (DMPS, Unithiol) (Aposhian, 1983; Aposhian et al, 1984; Hruby and Donner, 1987; Inns et al, 1990) are less toxic and may be preferable. DMSA and DMPS are more effective in reducing the arsenic content of tissues, they increase biliary as well as urinary arsenic elimination and, unlike dimercaprol, do not appear to cause arsenic accumulation in the brain (Kreppel et al, 1990; Moore et al, 1994). On the other hand, arsenic mercaptide (the chelation complex of dimercaprol and arsenic) is dialysable and hence dimercaprol may be preferred in the presence of renal failure (Sheabar et al, 1989; Mathieu et al, 1992) The importance of an increased urine arsenic concentration in determining the need for chelation therapy is disputed. Kersjes et al (1987) suggested a spot urine concentration greater than 200 µg/L should be taken as an indication of "significant" arsenic exposure but Kingston et al (1993) emphasised that arsenic concentrations significantly higher than this (3500 µg/24 h and 5819 µg/24 h in two of their patients) may be observed in the acute phase following pentavalent arsenic ingestion without severe sequelae. Dimercaprol (British anti-lewisite; BAL) Dimercaprol was developed during the Second World War as an antidote for lewisite (dichloro(2-chlorovinyl) arsine) poisoning (Peters et al, 1945). It possesses two sulphydryl groups and forms a stable mercaptide ring with arsenic. The alcohol group on dimercaprol confers some degree of water solubility, thereby enhancing excretion from the body. As the chelation complex tends to dissociate it is necessary to maintain a constant excess of dimercaprol. Unlike DMSA and DMPS, dimercaprol is also lipid soluble and increases the brain arsenic concentration in arsenic-intoxicated animals (Jones, 1995). Though increasingly superseded by the less toxic thiol chelating agents, intramuscular dimercaprol remains useful in severe arsenic poisoning where vomiting prevents oral antidote administration, supplies of DMSA or DMPS are not rapidly available (Jolliffe et al, 1991) or renal failure requires haemodialysis; dimercaprol but not DMSA chelates can cross the dialysis membrane (Sheabar et al, 1989; Mathieu et al, 1992). Animal studies Stocken and Thompson (1946) demonstrated increased urine arsenic excretion (up to 33.5 per cent of the amount applied) in the 24 hours following cutaneous application of lewisite to rodents, when dimercaprol (dose not stated) was spread over the affected area up to one hour later. Dimercaprol also prevented arsenic-induced diarrhoea observed in control animals. Intravenous injection of dimercaprol glucoside 1.5 g/kg prevented death in two rabbits poisoned with cutaneous lewisite (12 mg/kg). Eleven control animals died, as did two treated with subcutaneous dimercaprol 0.07 g/kg (Danielli et al, 1947). A recent study has demonstrated that intramuscular dimercaprol protects rabbits against the lethal systemic effects of intravenously administered lewisite. No appreciable difference was found between the protective effect of dimercaprol and that of water soluble analogues DMPS and DMSA (Inns et al, 1990). Clinical studies In a case series, 12 men were exposed to smoke containing diphenylcyano-arsenic (1.6 mg/m3), "other forms of organic arsenic" (0.5 mg/m3) and "inorganic arsenic" (1.8 mg/m3) for six minutes. They were treated with 3.5 mg/kg intramuscular dimercaprol 6.5-78 hours post exposure. Urine arsenic excretion increased by an average of 40 per cent between two and four hours after the injection. The largest increase, both absolute and relative, was observed in those treated earliest (6.5 hours after exposure) (Wexler et al, 1946). Giberson et al (1976) described the treatment of a 44 year-old male who ingested 400 mg sodium arsenite. Intramuscular dimercaprol 250 mg was administered every four hours. Haemodialysis was initiated in response to renal failure with 3.3 mg arsenic removed over four hours. By the sixth day, when renal function had recovered, arsenic excretion had reached 75 mg/24h with at least 115 mg arsenic excreted between days two and six. A four year-old boy who had ingested an unknown amount of arsenic trioxide rat poison was treated with dimercaprol 5 mg/kg every four hours for 16 hours. The urine contained 2,120 µg arsenic over the first 12 hours. He developed an urticarial rash over the lower extremities which subsided with the discontinuation of dimercaprol. The urine arsenic concentration decreased gradually during d-penicillamine treatment (Peterson and Rumack, 1977). Schoolmeester and White (1980) reported a 16 year-old female who ingested 300 mg sodium arsenate in a suicide attempt. She received intramuscular dimercaprol 125 mg every four hours for the first 24 hours, then twice daily for 24 hours. A 24 hour urine arsenic concentration (starting time not specified) was 14,200 µg/L. The effect of chelation therapy on arsenic excretion is not known but the patient fully recovered. Mahieu et al (1981) described a 44 year-old male who ingested an unknown amount of arsenic trioxide which had been mistaken for sugar. The dose "certainly exceeded 1000 mg". Intramuscular dimercaprol 2.5-4 mg/kg tds was administered for 21 days. Initial arsenic excretion was low due to renal insufficiency but increased to 10 mg/24h from three to seven days post ingestion. The patient excreted a total of 129 mg arsenic during his 26 days in hospital. A 40 year-old woman poisoned at the same time and treated with the same regimen for 17 days excreted 16.7 mg arsenic on the first day, the amount decreasing on subsequent days. Seventy three milligrams arsenic were eliminated over three weeks. A 32 year-old man who ingested 900 mg sodium arsenate in a suicide attempt commenced treatment with intramuscular dimercaprol 5 mg/kg four hourly five hours later. Dimercaprol was stopped on day four. This patient also received oral d-penicillamine and intravenous then oral N-acetylcysteine between days two and 82 post ingestion. The urine arsenic concentration rose on the second hospital day then declined progressively during the next week although the data were incomplete and uninterpretable (Bansal et al, 1991). A 22 month-old female who developed diarrhoea, vomiting and lethargy after ingesting approximately 0.7 mg sodium arsenate was treated initially with one intramuscular dose of dimercaprol 3 mg/kg nine hours post ingestion. Three hours later the infant was asymptomatic and dimercaprol therapy discontinued although she subsequently received oral d-penicillamine then oral DMSA to treat persisting high urine arsenic concentrations (4880 µg/L in the first 24 hours after admission) (Cullen et al, 1995). On the third hospital day the urine arsenic concentration (from a 24 hour collection) was 1355 µg/L and fell progressively to 96 µg/L on day 12 . These data do not enable any conclusions to be drawn regarding enhanced arsenic elimination. No benefit from dimercaprol was reported by McCutchen and Utterback (1966) in the treatment of severe chronic arsenic poisoning. Other authors have reported disappointing results with dimercaprol in the management of arsenic neuropathy (Heyman et al, 1956) although Jenkins (1966) described "no detectable disability" 18 months after acute sodium arsenite ingestion in a patient who developed a peripheral neuropathy and received "a full course of dimercaprol" (details not given). Marcus (1987) described a 16 year-old male who survived ingestion of 56 mg arsenic trioxide following treatment with intramuscular dimercaprol 4 mg/kg every four hours (duration not stated). The maximum urine arsenic excretion was "over 50 mg/day" falling to 20 µg/day by day 31. At twelve month follow-up neurological effects persisted. Mahieu et al (1981) suggested that a high (greater than 90 per cent) proportion of methylated arsenic in the urine of poisoned patients could be used to indicate a late presentation with less likelihood of benefit from chelation therapy. Treatment protocol Dimercaprol must be given by deep intramuscular injection. After injection 90 per cent of an administered dose is absorbed and Cmax is attained within one hour (Peters et al, 1947). Dimercaprol is distributed throughout the intracellular space and metabolic degradation and excretion is complete in less than four hours. Depending on severity, 2.5-5 mg/kg should be administered four hourly for two days. This is to ensure that a constant excess of dimercaprol is always present as the chelation complex dissociates. Traditionally, this initial treatment is followed by 2.5 mg/kg bd intramuscularly for one to two weeks. However, this is an empirical recommendation and may be insufficient in severe cases. Dosage and duration should be adjusted therefore, depending on urine arsenic removal. Adverse effects The most common adverse effect of dimercaprol is dose-related hypertension (with an increase in systolic pressure of up to 50 mmHg) which usually resolves within three hours of administration (Dollery, 1991) but may be associated with nausea, headache, sweating and abdominal pain. Gastrointestinal disturbance may also occur without hypertension. Conjunctivitis, paraesthesiae and fever have been described. Dimercaprol is contraindicated in severe liver disease since it is metabolized by glucuronidation with subsequent biliary excretion. DMSA DMSA is commercially available in some countries (though not the UK) mainly as meso-DMSA, although a DL-form also exists. Animal studies Aposhian et al (1984) demonstrated that DMSA was moderately more effective than DMPS (and substantially more effective than dimercaprol) in protecting mice from the lethal effects of sodium arsenite. DMSA mobilizes arsenic from tissues, increasing urine arsenic excretion without a rise in brain arsenic concentrations (Aposhian et al, 1984). Mice administered subcutaneous arsenic trioxide (5 mg/kg) followed immediately by intraperitoneal DMSA 100 mg/kg, showed significantly increased urine arsenic excretion (p<0.01) in the first 12 hours post chelation although the 48 hour urine arsenic elimination was not significantly different between DMSA-treated mice and controls (Maehashi and Murata, 1986). In animal studies DMSA protected against the embryotoxic effects of sodium arsenite but only when given within one hour of exposure (Bosque et al, 1991). Recent experiments suggest that oral monoester DMSA analogues may offer renal protection in arsenic poisoning by increasing the enteral arsenic content to enhance faecal rather than renal elimination (Hannemann et al, 1995). In other animal studies lipophilic DMSA analogues were inferior to the parent compound as arsenic antidotes (Kreppel et al, 1993). Clinical studies Lenz et al (1981) described a 46 year-old man who ingested 200 mg arsenic and survived following treatment with oral DMSA 300 mg qds for three days. Kosnett and Becker (1987) reported an increase in the 24 hour urine arsenic excretion from 26 µg to a maximum of 340 µg on the second day of oral DMSA treatment 660 mg tds in a patient who presented more than 30 days after malicious acute arsenic ingestion. Nine days after ingesting approximately 0.7 mg of a soluble arsenic salt a 22 month-old female was treated with oral DMSA 30 mg/kg/day for at least four days (Cullen et al, 1995). The child had already received chelation therapy with dimercaprol and d-penicillamine, but further treatment was instituted because of a persistently raised urine arsenic concentration (650 µg/L on day five). Four days later the urine arsenic concentration had fallen to 96 µg/L. The authors reported an overall urine arsenic half-life of 2.6 days. Although the child initially experienced vomiting, diarrhoea and lethargy these features resolved within 12 hours and renal and hepatic function remained normal throughout (Cullen et al, 1995). There was no objective improvement in the neurological manifestations of chronic arsenic poisoning in a man poisoned by an ethnic remedy despite two weeks therapy with oral DMSA 400 mg tds (Kew et al, 1993). No urine arsenic excretion data were given. A 33 year-old woman with acute-on-chronic lead and arsenic poisoning from a herbal remedy clinically recovered following two one-week courses of oral DMSA 270 mg tds, though the effect of chelation therapy on urine arsenic excretion is difficult to interpret (Mitchell-Heggs et al, 1990). Treatment protocol DMSA is given orally in a dose of 30 mg/kg body weight per day; an intravenous preparation is available in some countries and may be preferable if the patient is vomiting (Hantson et al, 1995). Adverse effects Side-effects following treatment with DMSA are rare but include skin rashes, gastrointestinal disturbance, elevation of serum transaminase activities and flu-like symptoms (Reynolds, 1993). DMSA should be used with caution in patients with impaired renal function or a history of hepatic disease (Reynolds, 1993). DMPS Animal studies DMPS is commercially available as a racemic mixture of the dextro-rotatory and levo-rotatory forms which appear to be equally effective arsenic chelators (Aposhian, 1983), though animal studies suggest DMSA may be superior to either (Aposhian et al, 1984). Urine arsenic elimination of arsenic-poisoned rats in the 48 hours post treatment with DMPS 100 mg/kg intraperitoneally was significantly lower (p<0.05) than in either control (5 mg/kg subcutaneous arsenic trioxide only) or DMSA-treated mice (Maehashi and Murata, 1986). However DMPS significantly increased (p<0.01) faecal arsenic elimination in the 24 hours post chelation compared to control or DMSA treated mice, suggesting biliary excretion of the DMPS-arsenic chelate (Maehashi and Murata, 1986). Other authors have noted enhanced biliary but not faecal arsenic excretion following parenteral DMPS administration to arsenic-poisoned experimental animals. This suggests enterohepatic circulation of the chelate, which Reichl et al (1995) attempted to block using oral cholestyramine. They demonstrated enhanced faecal arsenic elimination (p<0.05) when intraperitoneal DMPS 0.1 mmol/kg and subcutaneous arsenic trioxide (0.02 mmol/kg) administration was followed by an oral combination of cholestyramine (0.2 g/kg) and DMPS 0.1 mmol/kg (Reichl et al, 1995). Domingo et al (1992) demonstrated a protective effect of DMPS 150-300 mg/kg, but not dimercaprol, against experimental arsenite-induced embryotoxicity and teratogenicity as judged by the incidence of foetal malformation or death in mice administered intraperitoneal sodium arsenite (12 mg/kg) on day nine of gestation. Clinical studies Two men inadvertently ingested 1 g and 4 g arsenic trioxide respectively (Moore et al, 1994). The more severely poisoned patient developed acute renal failure and 26 hours post ingestion had a blood arsenic concentration of 400 µg/L. He received intravenous DMPS 5 mg/kg every four hours for six days then oral DMPS 400 mg every four hours for one week. The other patient had a blood arsenic concentration of 98 µg/L, 36 hours post ingestion and received a shorter course of intravenous then oral DMPS. Both patients recovered fully but quantitative data showing the effect of chelation therapy on urine arsenic elimination were documented poorly. In another report there was no objective improvement in the neurological manifestations of chronic arsenic poisoning in a patient treated with oral DMPS 100 mg tds for three weeks (Kew et al, 1993). Treatment protocol DMPS is given orally or parenterally in a dose of 30 mg/kg body weight per day. Adverse effects Side effects following treatment with DMPS are infrequent but have included allergic skin reactions, nausea, vertigo and pruritis (Aposhian, 1983). d-Penicillamine Animal studies d-Penicillamine has been reported to be as effective as dimercaprol and NAC in prolonging the survival time of mice injected with a lethal dose of sodium arsenite (Shum et al, 1981). Other studies have disputed the validity of these results and have failed to demonstrate d-penicillamine as a useful chelator (Aposhian, 1982; Kreppel et al, 1989). Clinical studies Peterson and Rumack (1977) described three children who shared a bottle of rat poison containing arsenic trioxide 1.75 per cent. One died within hours following a rapidly deteriorating course of coma, convulsions and cardiac arrhythmias. The second, a four year-old male, presented with lethargy, a sinus tachycardia and tachypnoea. Oral d-penicillamine 25 mg/kg qds replaced dimercaprol treatment after 16 hours when the patient developed an urticarial rash over the lower extremities. The first twelve-hour urine collection during dimercaprol treatment contained 2,120 µg arsenic with the urine arsenic concentration decreasing during the five days d-penicillamine therapy. The child made a full recovery. The third patient (Peterson and Rumack, 1977) had no severe features of toxicity at presentation. He received the same chelation therapy regimen as patient 2. On the second day post ingestion the 24 hour urine arsenic excretion was 300 µg, increasing in the next 24 hours (the second day of d-penicillamine therapy) to approximately 800 µg. This patient also recovered fully. A one year-old child ingested 15-20 mg sodium arsenate (as ant poison) and was treated within six hours with 5 mg/kg intramuscular dimercaprol (Peterson and Rumack, 1977). The chelating agent was then changed to oral d-penicillamine 100 mg/kg/day and continued for five days. An initial 12 hour urine collection (commenced approximately six hours post ingestion) contained 192 µg arsenic, increasing to 2000 µg arsenic in the next 24 hours before falling to approximately 200 µg/24 h on day two. These authors advocated d-penicillamine 100 mg/kg/day as the treatment of choice in arsenic poisoning (where oral therapy is possible). They recommended d-penicillamine should be continued until the 24 hour urine arsenic excretion is less than 50 µg (Peterson and Rumack, 1977). A 16 month-old child was given a five day course of oral d-penicillamine 250 mg qds 14 hours after ingesting 9-14 mg arsenic trioxide. Clinical features of toxicity (diarrhoea, vomiting and lethargy) resolved within 24 hours and the child was discharged on day three. The arsenic concentration in urine collected during the first day of treatment was 560 µg/L. However, no earlier urine arsenic concentrations were measured and prior to d-penicillamine therapy the patient had received 185 mg dimercaprol over 18 hours (Watson et al, 1981). DiNapoli et al (1989) instituted d-penicillamine therapy in a patient unable to tolerate intramuscular dimercaprol following intravenous sodium arsenite injection. d-Penicillamine 500 mg tds was administered and after ten days a 24 hour urine arsenic excretion of 2 mg was reported. There were no symptoms of bone marrow depression, haemolysis or peripheral neuropathy. After a further ten days treatment the urine arsenic concentration was 20 µg/L. Bansal et al (1991) described a 35 year-old man with severe arsenic polyneuropathy involving the phrenic nerves bilaterally, who recovered following d-penicillamine therapy 250 mg tds for two weeks (route of administration not stated). However, the 24 hour urine arsenic excretion only rose to 82.4 µg/g creatinine in the first 72 hours of chelation compared to a pretreatment value of 73.5 µg/g creatinine. Cullen et al (1995) reported a 22 month-old child who ingested some 0.7 mg sodium arsenate. Following a single dose of dimercaprol 3 mg/kg, oral d-penicillamine therapy was commenced, 250 mg qds for nine doses. By day four the 24 hour urine arsenic concentration had dropped from 4880 to 682 µg/L. The child was discharged on day six on oral d-penicillamine therapy (dose not stated) but readmitted three days later due to a persistently high urine arsenic excretion (650 µg/L on day five). At this stage d-penicillamine was replaced by DMSA since the child had developed an erythematous rash. Oral d-penicillamine 250 mg qds for seven days failed to increase urinary arsenic elimination in a patient with chronic arsenic poisoning whose initial 24 hour urine arsenic excretion was 342 µg (normal <5 µg/24 h) (Heaven et al, 1994). In another report the urine arsenic concentration in a 67 year-old man with arsenic-associated aplastic anaemia had risen to 20,246 µg/L after four days penicillamine therapy 500 mg qds compared to a pretreatment concentration of 7840 µg/L (Kjeldsberg and Ward, 1972). The patient died from acute myeloid leukaemia some six months later. N-acetylcysteine Animal studies The survival time of mice injected subcutaneously with a lethal dose of sodium arsenite (25 mg/kg) was increased significantly (p<0.05) if intraperitoneal N-acetylcysteine (NAC) 100 mg/kg was administered 30 minutes later. There was no significant difference between this dose of NAC, dimercaprol 5 mg/kg and d-penicillamine 50 mg/kg as an antidote under these conditions (Shum et al, 1981). Clinical studies Martin et al (1990) reported "remarkable clinical improvement" in a 32 year-old man with severe arsenic poisoning following ingestion of a soluble salt when he was administered intravenous NAC 70 mg/kg four hourly after dimercaprol had "failed to improve his condition". However urinary arsenic excretion data were poorly documented and dimercaprol was continued during treatment with NAC. Antidotes: Conclusions and recommendations There are no controlled clinical trials of chelation therapy in arsenic poisoning and no conclusive evidence that dithiol antidotes reverse arsenic-induced neurological damage. On the present evidence it is difficult to recommend a single preferred antidote, though in the absence of renal failure DMSA may offer some advantages over other agents; if renal failure supervenes dimercaprol and haemodialysis should be employed. Chelation therapy should be considered in symptomatic patients where there is analytical confirmation of the diagnosis. Although urine arsenic concentrations are useful to confirm the diagnosis of arsenic poisoning chelation therapy should not be instituted on the basis of an increased urine arsenic concentration alone. Haemodialysis Haemodialysis removes arsenic from the blood but achieves less effective arsenic clearance than chelation therapy when normal renal function is present. It is indicated therefore only in the presence of renal failure. Giberson et al (1976) reported an arsenic dialysis clearance of 87 mL/min. During four hours of dialysis 3360 µg arsenic was removed in a patient with acute arsenic poisoning complicated by renal failure who was also receiving 250 mg intramuscular dimercaprol six times daily. The 24 hour urine arsenic excretion on the same day was 2030 µg though this increased to 75,000 µg/24 h on the sixth hospital day when renal function had recovered. A similar haemodialysis arsenic clearance of 76-87 mL/min was demonstrated in another patient with acute sodium arsenite intoxication complicated by acute renal failure (Vaziri et al, 1980). Levin-Scherz et al (1987) instituted haemodialysis promptly in a patient who presented 26 hours after ingesting 2 g arsenic trioxide. The patient also received intramuscular dimercaprol, 300 mg initially then 180 mg every four hours, but died within 72 hours of ingestion. The maximum amount of arsenic removed in the dialysate was 2.9 mg. Mathieu et al (1992) demonstrated a haemodialysis clearance comparable to some 40-77 per cent of the daily arsenic renal elimination on the day following diuresis recovery. In this case the total blood haemodialysis clearance (210 mL/min) exceeded the instantaneous plasma haemodialysis clearance (mean 85 mL/min), suggesting that some arsenic removed by haemodialysis originated in erythrocytes. These authors showed similar haemodialysis arsenic clearance with or without prior administration of intramuscular dimercaprol 250 mg, and advocated dimercaprol as the chelating agent of choice in arsenic poisoning complicated by renal failure, since it does not impair arsenic dialysis clearance. Experimental evidence in dogs (Sheabar et al, 1989) suggests DMSA-arsenic chelates do not pass through the dialyser membrane. Haemoperfusion A 37 year-old man presented within four hours of ingesting 90 mL of a 1.5 per cent arsenic trioxide solution (Smith et al, 1981). Although initially only tachycardic he subsequently became hypotensive and oliguric. For the first 48 hours he received 200 mg intramuscular dimercaprol four hourly then d-penicillamine 500 mg qds. Charcoal haemoperfusion was instituted 11 hours after admission followed by two hours haemodialysis. These therapies were repeated over the next four days but "discontinued because of continued good renal function and lack of clinical response". Serum arsenic concentrations immediately post haemoperfusion were slightly higher than pre-haemoperfusion values, suggesting no benefit. MEDICAL SURVEILLANCE Blood arsenic concentrations correlate poorly with exposure but may be useful in chronic poisoning (Morton and Dunnette, 1994). Arsenic concentrations in hair and nails have been used to indicate chronic systemic absorption, although their use as biological monitors of occupational exposure to airborne arsenic is limited by difficulty in excluding external contamination (Yamamura and Yamauchi, 1980). Urine arsenic concentrations are the most useful biomonitoring tool, ideally as a total 24 hour collection, although spot urine arsenic concentrations have been proposed in screening asymptomatic patients with a history of possible acute arsenic ingestion. Since certain marine organisms (especially mussels) may contain large amounts of organoarsenicals, it is advisable that workers refrain from eating seafood for at least 48 hours before urine collection (Buchet et al, 1994). Analytical speciation methods capable of separating inorganic arsenic and its methylated derivatives from dietary organoarsenicals partially overcome this problem (Smith et al, 1977; Farmer and Johnson, 1990; Buchet et al, 1994). However, Vahter (1994) has suggested that under certain circumstances arsenic compounds released from seafood can still invalidate assessment of inorganic arsenic exposure. Smith et al (1977) demonstrated a close correlation between airborne arsenic and urinary excretion of all arsenic species in arsenic-exposed workers and Farmer and Johnson (1990) found that high urine concentrations of inorganic arsenic plus its mono- and dimethyl derivatives corresponded to the possible workplace atmospheric arsenic concentrations for those involved in arsenic production or glass manufacture. Increased urine arsenic concentrations have also been noted in timber treatment workers using an arsenic-based wood preservative. Telolahy et al (1993) suggested a potential role for increased urine coproporphyrins as an indicator of chronic occupational arsenic exposure since arsenic is known to disrupt haem metabolism. Regular examination of the skin should be included in an occupational health surveillance programme. Workers with evidence of excessive arsenic exposure should be offered long-term monitoring for the development of skin, bladder or lung cancer, though in practice this may be difficult to execute. OCCUPATIONAL DATA Maximum exposure limit Long-term exposure limit (8 hour TWA reference period) 0.1 mg/m3 (Health and Safety Executive, 1995). OTHER TOXICOLOGICAL DATA Carcinogenicity Individuals who chronically ingest arsenic have an increased risk of developing skin cancer, usually squamous cell carcinoma but also basal cell carcinomas (Chen et al, 1988; Shannon and Strayer, 1989; Chiou et al, 1995). Squamous cell carcinomas may arise in areas of arsenic-induced Bowen's disease (Novey, 1969; Shannon and Strayer, 1989). Hsueh et al (1995) demonstrated a significant dose-response relation between skin cancer prevalence and arsenic exposure from artesian well water. These authors identified chronic hepatitis B carriage and malnutrition as risk factors for arsenic-induced dermatological malignancy. Skin cancer has also been documented among vineyard workers and farmers exposed to inhaled inorganic arsenic in pesticides (Thiers et al 1967; Chen and Lin, 1994) although skin and gastrointestinal absorption probably contributed to arsenic toxicity in these cases. There is an association between chronic arsenic exposure and cancer of the urinary tract (Chen et al, 1988; Chen and Lin, 1994), lung (Chen and Lin, 1994; Simonato et al, 1994; Tsuda et al 1995) and liver, both hepatic angiosarcoma (Lander et al, 1975) and hepatocellular carcinoma (Chen and Lin, 1994). Smoking exerts a synergistic effect with ingested and inhaled arsenic in the development of pulmonary malignancy (Tsuda et al, 1995). There is limited evidence that other internal cancers, particularly of the gastrointestinal tract and haematological malignancies, are linked aetiologically to arsenic exposure (Chen and Lin, 1994). Reprotoxicity Animal studies suggest arsenic is embryotoxic and teratogenic but reliable human data are scarce (Council on Scientific Affairs, 1985). A woman in the third trimester of pregnancy developed acute renal failure after ingesting a large quantity of an arsenical rat poison. Her baby was delivered on the fourth day post ingestion but died within a few hours from hyaline membrane disease. At autopsy the infant showed significant arsenic accumulation in the liver, brain and kidneys (liver arsenic concentration 0.74 mg/100 g tissue) (Lugo et al, 1969). Genotoxicity Sodium arsenite In vitro Chinese and Syrian hamster ovary cells: Induced sister chromatid exchanges. Cultured human leucocytes: Increased incidence of sister chromatid exchanges (DOSE, 1994a). Potassium arsenite In vitro human lymphocytes: Mitotic arrest and chromosomal aberrations (DOSE, 1994b). The lymphocytes of six patients treated with Fowler's solution showed an increased incidence of sister chromatid exchanges but not chromosomal aberrations (Burgdorf et al, 1977). Fish toxicity (potassium arsenite) Not toxic to brown trout, bluegill sunfish, yellow perch or goldfish at 5 ppm for 24 hours (DOSE, 1994b). EC Directive on Drinking Water Quality 80/778/EEC Maximum admissible concentration 50 µg/L, as arsenic (DOSE, 1994a). WHO Guidelines for Drinking Water Quality Guideline value 10 µg/L, as arsenic (WHO, 1993). 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