Sodium cyanide is extensively employed in a large number of industrial processes, including electroplating and case-hardening of metals; the extraction (cyanidation) of gold and silver from ores; base metal flotation; coal gasification; and the fumigation of ships, railroad cars, buildings, grain silos, flour mills, seeds in vacuum chambers, and soil. Large quantities of sodium cyanide are used to introduce cyano groups into organic compounds, in particular through a reaction with organic halogen compounds to yield nitriles. The nitriles can then be converted to a variety of carboxylic acids, amides, esters, and amines. Potassium cyanide is used for electrolytic refining of platinum, for metal colouring, and as an electrolyte for the separation of gold, silver, and copper from platinum (Eisler et al., 1999; Patnaik, 1999; ACGIH, 2001; ECETOC, 2004). Cyanide salts are used as chelating agents, and the complex cyanides of copper, zinc, and cadmium are used in electroplating processes, principally the plating of iron, steel, and zinc (ECETOC, 2004).
Calcium cyanide is used chiefly as a fumigant, because it readily releases hydrogen cyanide when exposed to air; as a fertilizer, defoliant, herbicide, and rodenticide; as a stabilizer for cement; and in stainless steel manufacture (ACGIH, 2001).
Cyanides, reported as cyanide, hydrogen cyanide, sodium cyanide, potassium cyanide, calcium cyanide, or copper(I) cyanide, have been detected in surface water samples at 70 of the 154 hazardous waste sites where they were studied in the USA; they have also been detected in groundwater samples at 191 of the 419 waste sites studied and in leachate samples of 16 of the 52 sites studied. The median concentrations in the positive samples were 160 µg/litre for groundwater, 70 µg/litre for surface water, and 479 µg/litre for the leachates (HazDat, 2003).
Many edible plants contain cyanogenic glycosides, whose concentrations can vary widely as a result of genetic and environmental factors, location, season, and soil types (Ermans et al., 1980; JECFA, 1993). Some of the foodstuffs and their cyanide contents are shown in Table 3. Cassava tubers vary widely in their cyanogenic glycoside content, although most varieties contain 15–400 mg cyanide/kg fresh weight. Occasionally varieties of cassava tubers contain 1300–2000 mg cyanide/kg fresh weight, and cassava leaves contain 1000–2000 mg cyanogenic glucosides/kg on a dry matter basis (Padmaja, 1995). Fermentation of cassava pulp for 96 h during gari production reduced the hydrogen cyanide content by 50%; soaking of sliced cassava for 24 h, 40%; and sun-drying, some 15% (Kendirim et al., 1995). It should be noted that the ranges of cyanide concentrations shown in Table 3 are very broad in several cases (i.e., cereals and their products, soy protein products, and apricot pits), which may be due to their different sources and differences in analytical procedures; as well, the values may reflect the older literature.
Hydrogen cyanide can be produced by hydrolytic reaction catalysed by one or more enzymes from the plants containing cyanogenic glycosides. In kernels, for example, this reaction is catalysed by the enzyme emulsin (Lasch & El Shawa, 1981) when the seeds are crushed and moistened. Amygdalin (which is also present in cassava, bitter almonds, and peach stones) is converted to glucose, benzaldehyde, and hydrogen cyanide (Figure 2) (IPCS, 1992). Hydrogen cyanide release can occur during maceration, which activates intracellular -glucosidases. This reaction can also result from chewing, which causes the enzyme and the cyanogenic glycosides stored in different compartments to combine (Ermans et al., 1980; Nahrstedt, 1993). The reaction occurs rapidly in an alkaline environment, and the hydrolysis is complete in 10 min. Hydrolysis is possible in an acid solution and takes place slowly.
While absorbed cyanide is principally excreted as thiocyanate in the urine, traces of free hydrogen cyanide may also be excreted unchanged in the lungs, saliva, sweat, or urine (Hartung, 1982), as carbon dioxide in expired air, or as -thiocyanoalanine in saliva and sweat (Friedberg & Schwartzkopf, 1969; Hartung, 1982; JECFA, 1993).
A number of other sulfur transferases can also metabolize cyanide, and albumin, which carries elemental sulfur in the body in the sulfane form, can assist in the catalysis of cyanide to thiocyanate as well (Sylvester et al., 1982; Westley et al., 1983). Cyanide and thiocyanate can also be metabolized by several minor routes, including the combination of cyanide with hydroxycobalamin (vitamin B12a) to yield cyanocobalamin (vitamin B12) (Boxer & Rickards, 1952) and the non-enzymatic combination of cyanide with cystine, forming 2-iminothiazoline-4-carboxylic acid, which appears to be excreted without further change (Rieders, 1971) (Figure 3).
Although cyanide can interact with substances such as methaemoglobin in the bloodstream, the majority of cyanide metabolism occurs within the tissues. Cyanide is metabolized in mammalian systems by one major route and several minor routes. The major route of metabolism for hydrogen cyanide and cyanides is detoxification in the liver by the mitochondrial enzyme rhodanese, which catalyses the transfer of the sulfane sulfur of thiosulfate to the cyanide ion to form thiocyanate (Figure 3) (Williams, 1959; Ansell & Lewis, 1970). About 80% of cyanide is detoxified by this route. The rate-limiting step is the amount of thiosulfate. While rhodanese is present in the mitochondria of all tissues, the species and tissue distributions of rhodanese are highly variable. In general, the highest concentrations of rhodanese are found in the liver, kidney, brain, and muscle, but the supply of thiosulfate is limited (Aminlari et al., 1994). Rhodanese is present in rat nasal mucosal tissues, particularly in the olfactory region, at a 7-fold higher concentration (on a per milligram of mitochondrial protein basis) than in the liver (Dahl, 1989). Dogs have a lower overall activity of rhodanese than monkeys, rats, and rabbits (ATSDR, 1997).
Symptoms of cyanide toxicity can occur within seconds of inhalation of hydrogen cyanide or within minutes of ingestion of cyanide salts. Onset may be delayed up to 12 h after ingestion of cyanogenic glycosides, nitriles, or thiocyanates.
Hydrogen cyanide has a pa of 9.22; thus, at physiological pH (about pH 7), hydrocyanic acid is distributed in the body as hydrogen cyanide and is not present as the free cyanide ion. Hence, the form of cyanide to which exposure occurs, the salt or the free acid, does not influence distribution, metabolism, or excretion from the body (ECETOC, 2004). Inhaled or percutaneously absorbed hydrogen cyanide passes immediately into the systemic circulation. The distribution of cyanide to the various tissues is rapid and fairly uniform. Somewhat higher levels are generally found in the liver, lungs, blood, and brain. The tissue levels of hydrogen cyanide were 0.75, 0.42, 0.41, 0.33, and 0.32 mg/100 g of tissue in lung, heart, blood, kidney, and brain, respectively, in a man who died following inhalation exposure to hydrogen cyanide gas (Gettler & Baine, 1938; Ballantyne, 1983a; ATSDR, 1997; ECETOC, 2004). In contrast, high proportions of ingested sodium and potassium cyanide will pass through the liver and are detoxified by the first-pass effect.
Inhalation LC50 values of hydrogen cyanide in rats ranged from 158 mg/m3 for 60 min to 3778 mg/m3 for 10 s (Ballantyne, 1983a). Exposure of mice to cyanide resulted in similar LC50 values (Higgins et al., 1972; Matijak-Schaper & Alarie, 1982), and LC50 values of hydrogen cyanide in rabbits ranged from 2432 mg/m3 for 45 s to 208 mg/m3 for 35 min (Ballantyne, 1983a). The concentration of hydrogen cyanide in inhaled air markedly affects the acute toxicity: the total amount of hydrogen cyanide inhaled leading to death is disproportionately larger at low exposure levels than at high exposure levels (and thus the time leading to death is disproportionately longer) (Table 4). A similar dose rate dependence of acute toxicity was observed in hamsters: (pregnant) hamsters did not show signs of toxicity until they had received a total dose of 30–40 times the single subcutaneous LD50 when given sodium cyanide subcutaneously by an osmotic minipump (Doherty et al., 1982).