UKPID MONOGRAPH NICKEL CARBONYL SM Bradberry BSc MB MRCP 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. NICKEL CARBONYL Toxbase summary Type of product An intermediate in nickel refining and used as a catalyst in the petroleum, plastic and rubber industries. Toxicity Vapourised nickel carbonyl is highly toxic; inhalation may be fatal. Features Topical - Nickel carbonyl is a potential skin irritant but transcutaneous absorption is poor. Inhalation Minor inhalation: - Dry sore throat, cough, dizziness and headache. Substantial inhalation: - Sore throat, cough, chest tightness and dyspnoea occur within minutes, often associated with dizziness, nausea, headache and muscle cramps. - A chemical pneumonitis may develop in severe cases, sometimes after a latent period of a few days. Anorexia, abdominal pain, jaundice and diarrhoea are also reported and rarely myocarditis, delirium, convulsions or coma. Death may occur due to pulmonary haemorrhage, pulmonary or cerebral oedema or toxic myocarditis. - Investigations may show increased hepatic transaminase activities and a neutrophil leukocytosis. There may be diffuse opacifications and/or a pleural effusion on chest x- ray in those with symptoms or signs of pneumonitis. ECG changes include ventricular ectopic beats in mild poisoning or ST and T wave changes and QT interval prolongation (suggesting a toxic myocarditis) in more severe cases. - Chronic low-level occupational nickel carbonyl inhalation may cause an obstructive airways defect. EEG abnormalities and reduced monoamine oxidase activities are also reported. Management Topical 1. Remove from exposure and treat symptomatically. Inhalation 1. Remove from exposure. 2. Patients who are asymptomatic following minimal exposure are not at risk of developing a delayed pneumonitis and can be released if clinical assessment is normal. 3. Administer supplemental oxygen by face mask. 4. Intravenous hydrocortisone may be beneficial for severe pulmonary complications but this is not confirmed. 5. Collect urine for nickel concentration estimation. 6. Perform a chest X-ray, ECG, biochemical profile and blood count. 7. Chelation therapy with oral (or intravenous in severely ill patients) diethyldithiocarbamate (DDC), if available, or oral disulfiram should be considered in symptomatic cases. 8. Although the urine nickel concentration in the first eight hours after exposure correlates with poisoning severity, these results are unlikely to be available acutely and treatment must be guided by symptoms. Discuss with NPIS. 9. Alcohol should be avoided for at least 48 hours following treatment with DDC or disulfiram. References Jones CC. Nickel carbonyl poisoning. Report of a fatal case. Arch Environ Health 1973; 26: 245-8. Kurta DL, Dean BS, Krenzelok EP. Acute nickel carbonyl poisoning. Am J Emerg Med 1993; 11: 64-6. Shi Z. Acute nickel carbonyl poisoning: a report of 179 cases. Br J Ind Med 1986; 43: 422-4. Shi Z. Long-term effects of exposure to low concentrations of nickel carbonyl on workers' health. In: Nieboer E, Nriagu JO, eds. Nickel and human health - current perspectives. Vol 25. New York: John Wiley & Sons, Inc, 1992; 273-9. Shi Z, Lata A, Yuhua H. A study of serum monoamine oxidase (MAO) activity and the EEG in nickel carbonyl workers. Br J Ind Med 1986; 43: 425-6. Sunderman Sr FW. Use of sodium diethyldithiocarbamate in the treatment of nickel carbonyl poisoning. Ann Clin Lab Sci 1990; 20: 12-21. Substance name Nickel carbonyl Origin of substance Nickel carbonyl is produced by passing carbon monoxide over finely divided nickel. (CSDS, 1991) Synonyms Tetracarbonyl nickel (CSDS, 1991) Nickel tetracarbonyl (DOSE, 1994) Chemical group A compound of nickel, a transition metal (d block) element. Reference numbers CAS 13463-39-3 (DOSE, 1994) RTECS QR6300000 (RTECS, 1996) UN 1259 (DOSE, 1994) HAZCHEM CODE NIF Physico-chemical properties Chemical structure Nickel carbonyl, Ni(CO)4 (DOSE, 1994) Molecular weight 170.75 (DOSE, 1994) Physical state at room temperature Liquid (CSDS, 1991) Colour The liquid is colourless, the solid is white. (CSDS, 1991) Odour Musty, sooty odour. (HSDB, 1996) Viscosity 0.212 cP at 25°C (HSDB, 1996) pH NIF Solubility Sparingly soluble in water: 0.18 g/L at 9.8°C. (MERCK, 1989; HSDB,1996) Soluble in alcohol, benzene, chloroform, acetone and carbon tetrachloride. (DOSE, 1994) Autoignition temperature <93°C (vapour) (HSDB, 1996) Chemical interactions Nickel carbonyl reacts violently with dinitrogen tetroxide, and may explode when mixed with bromine, or a butane-oxygen mixture. A shock-sensitive explosive is formed following reaction with tetrachloropropadiene. (CSDS, 1991) Major products of combustion NIF Explosive limits Vapour explodes in air or oxygen at 20°C, partial pressure 15°mm, liquid explodes at 60°C. (HSDB, 1996) Flammability Flammable - burns with yellow flame. In direct sunlight, both the liquid and gas will flash. (HSDB, 1996) Boiling point 43°C (CSDS, 1991) Density 1.32 at 17°C (liquid) (CSDS, 1991) Vapour pressure 53329 Pa at 25.8°C (CSDS, 1991) Relative vapour density 5.95 at 50°C (gas) (HSDB, 1996) Flash Point <-20°C (closed cup) (CSDS, 1991) Reactivity On exposure to atmospheric oxygen, a deposit is produced on nickel carbonyl which may ignite. Mixtures with air or oxygen at low partial and total pressures explode after an induction period. The vapour forms an explosive mixture with air. It is highly flammable and may explode if heated to 60°C or above. (CSDS, 1991) Uses Nickel carbonyl is an intermediate in the Mond process of nickel refining. It is used in organic synthesis, the manufacture of catalysts and nickel vapour plating. (CSDS, 1991; DOSE, 1994) Hazard/risk classification Index no. 028-001-00-1 Risk phrases F; R11, Carc. Cat. 3; R40, Repr. Cat. 2; R61, T+; R26 - Highly flammable. Possible risk of irreversible effects. May cause harm to the unborn child. Very toxic by inhalation. Safety phrases S53-45 - Avoid exposure - obtain special instruction before use. In case of accident or if you feel unwell, seek medical advice immediately (show label where possible). EEC no. 236-669-2 (CHIP2, 1994) INTRODUCTION Gaseous nickel carbonyl is formed in the Mond process of nickel purification by the reaction of elemental nickel with carbon monoxide. Most exposures are occupational via inhalation. The gas can be condensed into a liquid which boils at 43°C. MECHANISM OF TOXICITY In vitro studies demonstrate that nickel causes crosslinking of amino acids to DNA, alters gene expression, induces gene mutations and the formation of reactive oxygen species (Costa et al, 1994a and b; Haugen et al, 1994; Huang et al, 1994; Shi et al, 1994). Nickel also suppresses NK cell activity and interferon production (Shen and Zhang, 1994). TOXICOKINETICS Absorption Nickel carbonyl can be absorbed by inhalation and ingestion, the former being more important occupationally. Significant percutaneous absorption does not occur. Vapourised nickel carbonyl is the most readily absorbed form of inhaled nickel. Distribution and excretion Following nickel carbonyl inhalation, nickel is transported in the blood bound principally to albumin. High concentrations are found in the kidneys, liver, lungs and brain. Nickel is excreted primarily in the urine with a half-life following acute inhalation of up to 50 hours although some absorbed nickel is retained in body stores and excreted over several months (IPCS, 1991; Sunderman, 1992b). Nickel crosses the placenta and is passed to the child in maternal milk (Fairhurst and Illing, 1987; IPCS, 1991). CLINICAL FEATURES: ACUTE EXPOSURE Inhalation Pulmonary toxicity The clinical features observed following acute nickel carbonyl exposure have been classified as immediate and delayed although such a distinction may not be clear (Sunderman and Kincaid, 1954). Individuals who are moderately poisoned typically will develop a dry sore throat, cough, chest tightness and dyspnoea within minutes often associated with dizziness, nausea, headache, and muscle cramps (Vuopala et al, 1970; Shi, 1986). In more severe cases a chemical pneumonitis may develop sometimes after a latent period of a few days (Brandes, 1934). These patients may exhibit features of generalised systemic upset (muscle pains, fatigue) in addition to gastrointestinal and neurological symptoms (see below) (Sunderman and Kincaid, 1954; Jones, 1973; Sunderman, 1989). Haemoptysis has also been described (Shi, 1986). Clinical signs include hyperaemia of the conjunctivae and throat, cyanosis, tachycardia and tachypnoea with wheeze and crackles on auscultation of the lung fields (Shi, 1986). There may be diffuse opacifications and/or a pleural effusion on chest x-ray (Shi, 1986). Death may occur in cases with severe pulmonary manifestations (Anonymous, 1903; Brandes, 1934; Sunderman and Kincaid, 1954; Jones, 1973) with post-mortem evidence of pulmonary nickel deposition, pulmonary consolidation or haemorrhage, pleural thickening, a fibrinoid alveolar infiltrate and/or pulmonary or cerebral oedema (Brandes, 1934; Sunderman and Kincaid, 1954; Jones, 1973). Gastrointestinal toxicity The respiratory effects of mild nickel carbonyl exposure are associated frequently with nausea (Vuopala et al, 1970; Shi, 1986). More substantial exposures cause anorexia, vomiting, abdominal pain and diarrhoea which usually accompany development of a chemical pneumonitis (Vuopala et al, 1970; Shi, 1986). Neurotoxicity Dizziness and headache are very common following mild or moderate nickel carbonyl exposure (Anonymous, 1903; Shi, 1986). In more severe cases there may be dysphoria, somnolence, blurred vision (Shi, 1986) and rarely delirium, convulsions (Sunderman and Kincaid, 1954; Sunderman, 1989) or coma (Brandes, 1934). Exaggerated limb reflexes have also been reported (Brandes, 1934). Nickel particles have been identified in the brain of fatal cases (Brandes, 1934). Hepatotoxicity Patients with nickel carbonyl poisoning may have transiently raised hepatic transaminase activities (Shi, 1986), hepatic tenderness (Vuopala et al, 1970) and/or hepatomegaly (Brandes, 1934). Jaundice has been reported in more severely poisoned patients (Sunderman and Kincaid, 1954). Haemotoxicity A leukocytosis is common in moderate to severe acute nickel carbonyl poisoning (Sunderman and Kincaid, 1954; Shi, 1986). Cardiotoxicity Electrocardiographic changes have been reported following acute nickel carbonyl exposure and vary from a sinus tachycardia or ventricular ectopic beats in mild cases (Shi, 1986) to ST and T wave changes and QT interval prolongation (suggesting a toxic myocarditis), in those more significantly exposed (Shi, 1986). Post mortem findings from early nickel carbonyl fatalities described "fatty" (Anonymous, 1903) and dilated (Anonymous, 1903; Brandes, 1934) heart chambers. CLINICAL FEATURES: CHRONIC EXPOSURE Inhalation Chronic exposure to low concentrations of nickel carbonyl may result in an obstructive airways defect (low FEV1 and PEFR) (Shi, 1992; Shi, 1994). Pulmonary eosinophilia (Loeffler's syndrome) due to a type III hypersensitivity reaction to nickel has been described (Sunderman and Sunderman, 1961). EEG abnormalities and reduced monoamine oxidase activity are also reported in those subject to repeated occupational exposure (Shi et al, 1986). MANAGEMENT Inhalation Patients who are completely asymptomatic following suspected nickel carbonyl inhalation are not at risk of developing delayed sequelae and can be discharged if clinical assessment is normal. Symptomatic patients require a full assessment including collecting urine for nickel concentration estimation, checking a biochemical profile and blood count and performing a chest x-ray and ECG. Acute severe nickel carbonyl inhalation requires prompt supportive treatment. Intravenous hydrocortisone may be beneficial in the management of severe pulmonary complications but its value has not been confirmed in controlled clinical trials. The role of chelation therapy is discussed below. Antidotes Calcium EDTA Parenteral calcium disodium EDTA did not protect mice or rabbits against the lethal effects of nickel carbonyl (West and Sunderman, 1958b). There are no human data. Diethyldithiocarbamate and disulfiram Diethyldithiocarbamate (DDC) has been advocated in the treatment of acute nickel carbonyl poisoning (Sunderman, 1992a; Kurta et al, 1993). DDC forms a chelate with Ni2+ such that 2(DDC) + Ni2+ ---- nickel bis(DDC) which is renally excreted. DDC is not available as a pharmaceutical preparation in many countries although disulfiram (Antabuse), which is metabolised to DDC (two molecules of DDC from each of disulfiram) has been employed. All rats exposed to lethal concentrations of nickel carbonyl vapour survived if treated immediately with 50 or 100 mg/kg parenteral DDC (West and Sunderman, 1958a). A similar degree of protection was observed when DDC was administered at eight hours, but this benefit was at least partially lost at 24 hours. In the same study immediate oral administration of the antidote offered some protection against nickel carbonyl poisoning but was less effective than parenteral DDC, especially at higher nickel carbonyl concentrations (West and Sunderman, 1958a). Baselt and Hanson (1982) compared the effect of oral disulfiram, DDC and d-penicillamine in the treatment of rats acutely exposed to nickel carbonyl vapour (1.4 mg/L) for 15 minutes. Disulfiram was not an effective antidote in these circumstances and although d-penicillamine protected against death at a nickel carbonyl concentration of 1.4 mg/L, only DDC was effective following exposure to a nickel carbonyl concentration of 1.7 mg/L (Baselt and Hanson, 1982). Well documented clinical studies involving DDC in nickel carbonyl poisoning are scarce. Sunderman and Sunderman (1958) reported the first clinical case of acute nickel carbonyl poisoning treated effectively with oral DDC. A 25 year-old male was accidentally sprayed with nickel carbonyl and immediately developed dizziness, nausea, tachypnoea, cyanosis and chest pain (Sunderman and Sunderman, 1958). He was administered 95 per cent oxygen, 2 g oral DDC and 2 g oral sodium bicarbonate within minutes, then 1 g oral DDC twice daily for ten days. The urine nickel concentration on the day of exposure was 2000 µg/L (normal <30 µg/L). He made a full recovery. This and other individual case reports involving the use of DDC and disulfiram in nickel carbonyl poisoning are summarised in Table 1. Table 1. Case reports of DDC and disulfiram in nickel carbonyl poisoning Max urine Treatment Outcome Study [Ni] µg/L 2000 2g oral DDC daily from Survived Sunderman day 1 - 11 & Sunderman, 1958 535 4 g oral DDC on day 2 Died (day 4) Jones, 1973 1720 0.75 - 2.25 g oral Survived Kurta et al, disulfiram daily days 1993 1, 2, 9-11 1.2 - 2.8 g oral DDC daily days 2 - 8 The patient described by Jones (1973) presented the day following exposure to nickel carbonyl, had a maximum urine nickel concentration of 535 µg/L 24 hours post exposure, received 4 g oral DDC on day two and died from respiratory complications on day four. Another patient with severe nickel carbonyl poisoning survived despite the development of a chemical pneumonitis requiring 60 per cent oxygen and continuous positive airways pressure (CPAP) ventilation for four days (Kurta et al, 1993). The maximum urine nickel concentration was 1720 µg/L and the patient received 0.75 - 2.25 g oral disulfiram daily on days one, two and 9-11 with 1.2 - 2.8 g oral DDC daily on days two to eight. Sunderman (1990) reported that more than 375 persons exposed to nickel carbonyl vapour over 30 years had been treated successfully with DDC. No deaths occurred in those who received "adequate" doses of DDC within four days of exposure. However data for only 23 of these cases have been published (Sunderman and Sunderman, 1958; Sunderman, 1979; Sunderman, 1990; Table 2). Although the details of these cases are scarce and the data are uncontrolled, it is noteworthy that 75-100 per cent recovered. Only three of the four nickel carbonyl poisoned patients described by Sunderman (1979) received treatment; the fourth (untreated) patient died. There is experimental evidence that disulfiram and DDC promote the accumulation of bivalent nickel ions in the brain (Jasim and Tjälve, 1984; Belliveau et al, 1985; Tjälve and Borg-Neczak, 1994; Nielsen and Andersen, 1994) and this may limit the use of these agents as nickel antidotes (Tjälve and Borg-Neczak, 1994). Antidotes: Conclusions and recommendations 1. Well documented clinical studies using DDC (or disulfiram) in nickel carbonyl poisoning are scarce. 2. Sunderman (1992a) has recommended a treatment protocol for DDC in acute nickel carbonyl poisoning (Table 3), variations of which are advocated widely (Poisindex, 1996). This is based on urine nickel concentrations in the first eight hours following exposure and makes no allowance for urine volume. These treatment doses have no firm scientific rationale and, moreover, the analytical results are unlikely to be available in the necessary time course. However, it is reasonable to consider treatment with DDC (where available) in life-threatening nickel carbonyl poisoning. 3. Disulfiram is a therapeutic alternative but clinical experience with this antidote is very limited. Although theoretically the dose of disulfiram required should be approximately half that of DDC (Poisindex, 1996) this is not borne out in animal studies in which disulfiram is less effective than DDC and higher doses are required. MEDICAL SURVEILLANCE Prior to employment involving nickel carbonyl exposure special consideration should be given to those with a history of respiratory disease. Monitoring of nickel concentrations in 'spot' samples of blood and urine is not indicated routinely as these concentrations do not reflect the total body nickel burden in those exposed to nickel carbonyl. Furthermore, urine nickel concentrations vary considerably and should be interpreted as groups of 24 hour samples rather than individual urine specimens (Sunderman et al, 1986; Nickel Producers Environmental Research Association and the Nickel Development Institute, 1994). Table 2. Case series of DDC in nickel carbonyl poisoning Mean ± SD DDC treatment max urine Day started Daily Duration % n= [Ni] µg/L mean ± SD dose g days Recovery Study 6 935 ± 610 5.7 ± 3.9 1 - 2 ? 100 Sunderman & Sunderman, 1958 4 450 - 580 2.0 ± 0 ? ? 75 Sunderman, 1979 ("Range") (n = 3) 13 638 ± 656 ? 2 "2 - 14" 100 Sunderman, 1990 "average" Table 3. DDC in nickel carbonyl poisoning: Sunderman's treatment protocol (Sunderman, 1992a) -> Mild exposure (initial 8 h urine nickel concentration < 100µg/L) Oral DDC 1.0 g (0.2 g every 2 min for 5 doses) -> Moderate or severe exposure (initial 8 h urine nickel concentration > 100µg/L)* First day: Oral DDC 1.0 g 0 h 0.8 g 4 h 0.6 g 8 h 0.4 g 16 h Thereafter: Oral DDC 0.4 g tds (until urine nickel concentration normal) -> Consider parenteral DDC (25 mg/kg) if urine nickel concentration >500 µg/L * In very severe poisoning (initial 8 h urine nickel concentration >500 µg/L) an initial intravenous DDC dose of 25 mg/kg (dissolved in phosphate buffer) is suggested. Following acute nickel carbonyl exposure the urine nickel concentration in an initial eight hour urine collection is a useful guide to the severity of poisoning although this analysis is not widely available; a concentration greater than 500 µg/L indicates substantial intoxication (Sunderman, 1992a). OCCUPATIONAL DATA Occupational exposure standard Short-term exposure limit (15-minute reference period) 0.24 mg/m3 (Health and Safety Executive, 1995). OTHER TOXICOLOGICAL DATA Carcinogenicity Epidemiological studies have shown a significant increase in deaths from carcinoma of the lung and nasal sinuses among nickel refinery workers (Morgan, 1958; Roberts et al, 1992; Anderson, 1992; Morgan and Usher, 1994). The excess risk of death continues for several years after leaving employment (Muir et al, 1994). The exact aetiological agent is unknown. Although animal data suggest nickel carbonyl may be carcinogenic there is insufficient human evidence to confirm this (IARC, 1990). In a study of respiratory tract cancer among nickel refinery workers, Morgan (1958) proposed that nickel-containing dusts, copper sulphate or arsenic-contaminated sulphuric acid were more likely causative agents than nickel carbonyl. Fortunately, measures to improve industrial hygiene have greatly reduced the occupational hazard of nickel carbonyl exposure (Doll et al, 1977) but respiratory tract malignancies among employees in the nickel industry remain notifiable diseases in the UK (Seaton et al, 1994). Reprotoxicity Occupational exposure of fertile women to nickel carbonyl is avoided in some industries although there are no conclusive human data regarding its reprotoxicity (Reprotox, 1996). Genotoxicity NIF Fish toxicity NIF EC Directive on Drinking Water Quality 80/778/EEC Nickel: Maximum admissible concentration 50 µg/L (DOSE, 1994). AUTHORS SM Bradberry BSc MB MRCP ST Beer BSc JA Vale MD FRCP FRCPE FRCPG FFOM National Poisons Information Service (Birmingham Centre), West Midlands Poisons Unit, City Hospital NHS Trust, Dudley Road, Birmingham B18 7QH UK This monograph was produced by the staff of the Birmingham Centre of the National Poisons Information Service in the United Kingdom. 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