B15

Hydrogen Cyanide

Chiu-Wing Lam, Ph.D., and King Lit Wong, Ph.D.

Johnson Space Center Toxicology Group

Medical Operations Branch

Houston, Texas

PHYSICAL AND CHEMICAL PROPERTIES

Hydrogen cyanide (HCN) is a colorless liquid with a boiling point close to room temperature. Thus, at ambient temperature, HCN exists essentially as a gas. HCN has a faint odor of bitter almonds (Sax 1984; ACGIH 1991).

Synonyms:

Hydrocyanic acid, prussic acid, formonitrile

Formula:

HCN

CAS no:

74-90-8

Molecular weight:

27.0

Boiling point:

25.7°C

Melting point:

–13.2°C

Vapor pressure:

400 torr at 9.8°C

Solubility:

Miscible with water

Odor threshold:

2 to 5 ppm (Hartung 1982)

Conversion factors at 25°C, 1 atm:

1 ppm = 1.10 mg/m3 1 mg/m3 = 0.91 ppm

OCCURRENCE AND USE

HCN is used mainly in the production of acrylonitrile, methyl methacrylate, sodium cyanide, and cyanuric chloride (Hartung 1982). HCN can be generated when acid is added to cyanide salts (Gosselin et al. 1984) or, to a lesser extent, when alkaline cyanide, especially calcium cyanide, is exposed to water or moisture (NIOSH 1976). HCN is volatile; its volatilization increases as pH



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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 B15 Hydrogen Cyanide Chiu-Wing Lam, Ph.D., and King Lit Wong, Ph.D. Johnson Space Center Toxicology Group Medical Operations Branch Houston, Texas PHYSICAL AND CHEMICAL PROPERTIES Hydrogen cyanide (HCN) is a colorless liquid with a boiling point close to room temperature. Thus, at ambient temperature, HCN exists essentially as a gas. HCN has a faint odor of bitter almonds (Sax 1984; ACGIH 1991). Synonyms: Hydrocyanic acid, prussic acid, formonitrile Formula: HCN CAS no: 74-90-8 Molecular weight: 27.0 Boiling point: 25.7°C Melting point: –13.2°C Vapor pressure: 400 torr at 9.8°C Solubility: Miscible with water Odor threshold: 2 to 5 ppm (Hartung 1982) Conversion factors at 25°C, 1 atm: 1 ppm = 1.10 mg/m3 1 mg/m3 = 0.91 ppm OCCURRENCE AND USE HCN is used mainly in the production of acrylonitrile, methyl methacrylate, sodium cyanide, and cyanuric chloride (Hartung 1982). HCN can be generated when acid is added to cyanide salts (Gosselin et al. 1984) or, to a lesser extent, when alkaline cyanide, especially calcium cyanide, is exposed to water or moisture (NIOSH 1976). HCN is volatile; its volatilization increases as pH

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 decreases or as temperature increases. Potassium cyanide (KCN) and sodium cyanide (NaCN) are basic; the pH of a 0.1N KCN solution is 11. When these alkaline salts are neutralized, the majority of cyanide ions (CN-) are converted to HCN. At pH 8,93% of cyanide exits as HCN; at pH 7,99% is HCN (Towill et al. 1978, as cited in ATSDR 1997). Alkaline cyanide salts are used extensively in industrial processes, including the manufacture of dyes, pigments, or nylon; cleaning; and electroplating (NTP 1993). Neither HCN nor cyanide salts have ever been used in any payload experiment aboard the space shuttle. Pyrolysis of polyurethane foam or polyacrylonitrile can produce HCN (Wooley et al. 1979). Polyurethane foam that was pyrolyzed at 700°C released HCN at 0.2% of the polymer weight; the amount of HCN increased 10-fold at 900°C. When polyacrylonitrile was pyrolyzed at 400°C, 700°C, or 900°C, HCN yields were 1%, 6%, or 36% of the polymer weight, respectively. Burning wool, silk, paper, or nylon also can generate HCN (Terrill et al. 1978). HCN was detected in thermodegradation of electrical cables containing polyimide and polyfluorocarbon (Bourdin 1991); these cables were similar to those used aboard U.S. spacecraft. However, HCN has not been generated in the few thermodegradation events that occurred aboard spacecraft; the pyrolysis did not involve urethane foam or other polymers containing nitrogen atoms. Lowry et al. (1985) detected HCN in 12% of the fires examined in Dallas. HCN concentrations reached 15 ppm in 10% of those fires; the maximum HCN concentration detected was 40 ppm. Increased serum concentrations of thiocyanate (a metabolite of HCN) was found in 12% of the fire fighters, after accounting for the contributions from cigarette smoking. TOXICOKINETICS, METABOLISM, AND MECHANISM OF TOXICITY Toxicokinetics HCN is a very weak acid with a dissociation constant of 4.93 × 10-10 and pKa of 9.31 (CRC 1985). At pH 2, the ratio of CN- to HCN is 4.89 × 10-8; that value indicates that essentially all of any ingested KCN or NaCN is converted to HCN in the stomach. The nonionized form is rapidly absorbed, and thus cyanide salts are rapidly fatal by the oral route (ATSDR 1997). At pH 7.4, the ratio of CN- to HCN is 0.012, which indicates that about 1% of the HCN absorbed from the stomach or lung is ionized in the blood or intracellular fluid, and about 99 mole-percent of KCN or NaCN given parenterally exists as HCN in the body fluid. Thus, data on KCN or NaCN given enterally or parenterally are useful for

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 toxicological assessment of HCN exposures. However, given the rapid conversion of cyanide ions to HCN and the rapid absorption of HCN in the stomach, a bolus dose will generate a sudden high blood concentration, whereas continuous uptake from inhalation exposures will produce a different blood profile. Moreover, cyanide given orally (such as in drinking water) is subject to the first-pass effect through the liver uptake and detoxification. The first-pass processes can greatly affect the distribution of HCN to target organs. For example, Gettler and Baine (1938) reported that the proportionate tissue concentrations of HCN were lung > brain> heart>liver in two dogs and one human who died after exposure to HCN vapor at unknown concentrations. HCN concentration in the brain was half that in the lung in both dogs and the human. Liver HCN concentrations in both dogs were half those in the brain; for the human, the liver HCN was two-thirds that in the brain. In contrast to those results from inhalation exposures, six rats given KCN or NaCN at 4 mg CN-/kg orally and an unspecified number of rabbits gavaged with 11.9-20.3 mg CN-/kg had five times the HCN in the liver as in the brain (Ahmed and Farooqui 1982; Ballantyne 1983). These data demonstrate that the first-pass effect must be considered in assessing the effects of cyanide in the brain, the primary target organ. However, the first-pass effect will have little influence on the toxicity outcome resulting from the metabolic products of cyanide (such as thiocyanate) on extrahepatic organs. Wolfsie and Shaffer (1959) predicted that HCN can readily diffuse across cellular membranes and be absorbed in the lung. Landahl and Herrmann (1950) compared HCN concentrations in inhaled versus exhaled gases from two volunteers who inhaled (by mouth) 450 mL of HCN at 0.46-4.6 ppm in 1.5 s and held their breath for 2 s. Under those conditions, the lung retained 58.5% of the inhaled HCN. When the holding time was doubled, the absorption increased to 73%. Nasal inhalation and mouth exhalation yielded nasal absorption estimated at 10-20%. Thus, about 75% of HCN inhaled through the nose in normal breathing would be retained in the body. In monkeys exposed to HCN via face mask, HCN uptake was rapid, and the blood cyanide concentration reached steady state in only 10-20 min (Purser et al. 1984). Trace amounts of cyanide are present normally in healthy subjects; it probably comes from the breakdown of cyanogenic food, bacterial actions in the gastrointestinal tract, and cigarette smoking (Ansell and Lewis 1970). Yamanaka et al. (1991) reported that mainstream cigarette smoke contains HCN at 40-70 ppm, and side-stream cigarette smoke contains less than 5 ppm. Urinary cyanide concentrations average about 0.07 µg/mL in nonsmokers and 0.17 µg/mL in smokers (Ansell and Lewis 1970). In adult humans, the half-lives of cyanide and thiocyanate in blood have been estimated at 20-60 min and 4-8 d, respectively (Ansell and Lewis 1970; Levine

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 and Radford 1978). The large difference between the two supports the notion that the metabolism of cyanide to thiocyanate is favored over the reverse reaction. By monitoring the blood cyanide concentration in rats for 2 to 60 min after gavage with KCN (1 mg/kg), Leuschner et al. (1991) calculated a half-life of 14 min. Cyanide concentrations in blood samples collected from dogs 5 to 245 min after a KCN intravenous (iv) injection (0.82 mg/kg) showed a biphasic elimination (T1/2α = 23 min; T1/2β = 5.5 h). Although these findings suggest that blood cyanide concentrations should decline significantly in the first 60 min after the exposure ends, Purser et al. (1984) found that exposing monkeys to HCN gas at 100-147 ppm for 30 min via face mask produced no appreciable decline in blood cyanide concentrations 1 h after the exposure. These authors concluded that cyanide has a fairly long half-life in monkeys. At exposure concentrations that high and for that length of time, the amounts of thiosulfate and 3-mercaptopyruvate, the two endogenous compounds that normally react with cyanide in the body (see below), might have been depleted to the extent that blood cyanide concentrations showed no appreciable decline 1 h after the exposure. In any event, all the exposed monkeys were incapacitated within 15 min. Metabolism and Disposition Cyanide is metabolized through several pathways. Thiocyanate, the major metabolite, is formed from the reaction of cyanide either with thiosulfate, catalyzed by rhodanase (a mitochondrial enzyme found in many tissues, particularly liver), or with 3-mercaptopyruvate catalyzed by cyanide-sulfur transferase (Baumann et al. 1934; Himwich and Saunders 1948; Wood and Cooley 1956; Singh et al. 1989). A minor metabolic pathway is the reaction of HCN with cystine to form 2-aminothiazoline-4-carboxylic acid and 2-iminothizolidine-4-carboxylic acid (Wood and Cooley 1956). Other minor pathways include oxidation of HCN or thiocyanate to CO 2, reaction with hydroxocobalamine to form cyanocobalamin, and conversion of HCN to formic acid, which enters one-carbon metabolism in the body (Boxer and Richards 1952; Ansell and Lewis 1970; Baumeister et al. 1975). After a cyanide exposure, some of the body burden of HCN is exhaled unchanged, producing the characteristic odor of bitter almonds on the breath (Ansell and Lewis 1970). Boxer and Richards (1952) showed that rats exhaled cyanide gas following a subcutaneous injection of KCN at 0.65 mg/kg. However, most of the body burden is excreted in the urine as thiocyanate, and a small amount is metabolized to CO2 (Ansell and Lewis 1970). Wood and Cooley (1956) reported that 80% of cyanide injected intraperitoneally in rats

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 was recovered as thiocyanate and 15% was recovered as 2-aminothiazoline-4-carboxylic acid. Thiocyanate formation from cyanide is quite rapid. Pettersen and Cohen (1985) showed that the thiocyanate concentration in plasma of mice doubled in 5 min and peaked at 30 min after a subcutaneous injection of KCN at 4 mg/kg (a sublethal dose). Some thiocyanate can be converted back to cyanide by thiocyanate oxidase in red blood cells (Goldstein and Reiders 1953). When rats were given potassium cyanide in drinking water at a daily dose of 40, 80, or 150 mg/kg for 13 w, both blood cyanide and urinary thiocyanate concentrations increased proportionally with the doses (Leuschner et al. 1991). The authors concluded that exposing rats to the maximum tolerated dose did not saturate cyanide detoxification pathways. Blood cyanide concentrations remained fairly constant in each dosing group during the test. Okoh (1983) showed that rats fed 2 mg KCN daily for 6 months showed no statistically significant changes in the fractions of the dose excreted in urine, feces, and expired air. These results suggest that neither the metabolism nor the pattern of excretion of cyanide is affected by long-term cyanide intake. Mechanism of Toxicity HCN, the nonionized form of cyanide, can permeate tissues much more readily than cyanide ions and is distributed widely throughout the body (Wolfsie and Shaffer 1959). The toxicity, especially the acute one, of cyanide is due mainly to its inhibition of cytochrome oxidase. HCN, a small molecule, can diffuse very rapidly into the mitochrondria, where it binds to cytochrome C oxidase and forms a stable but reversible coordination complex with the heme (F+++) sites. The inhibition of cytochrome oxidase by cyanide in the tissue prevents oxygen utilization in situ (Albaum et al. 1946). Organs that are very sensitive to tissue hypoxia, such as the brain and heart, are the primary targets of cyanide toxicity. Blockage of oxygen utilization in tissues resulted in an accumulation of oxyhemoglobin. Venous blood becomes bright red or cherryred, a characteristic sign of cyanide intoxication (Gosselin et al. 1984). Ballantyne and Bright (1979) showed that cytochrome C oxidase activities were reduced by 76% in the myocardium and 54% in the cerebral cortex of rabbits immediately after they were killed by an intramuscular injection of KCN at 8 mg of CN- per kilogram. In another study, rats injected subcutaneously with NaCN at 3, 6, 9 or 12 mg/kg (LD50 9 mg/kg) showed inhibition of brain cytochrome C oxidase by about 2%, 22%, 35%, or 42%, respectively, 20 min after the injection (Tadic 1992). It took only 3.5 to 8 min to inhibit 50% of the cytochrome oxidase in the brains of rats injected intraperitoneally with a lethal

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 dose of NaCN (5 mg/kg) (Albaum et al. 1946). In mice administered KCN intraperitoneally at 10 mg/kg, 83% of the brain cytochrome oxidase was inhibited 3 min after the injection (Isom and Way 1976). Rapid inhibition of cytochrome oxidase in other organs also has been reported; hepatic cytochrome oxidase was inhibited maximally (about 80%) in mice 5 min after an intraperitoneal injection of KCN at 5 mg/kg (Isom et al. 1982). In the study by Pettersen and Cohen (1985), 30 min after mice were given a subcutaneous injection of KCN at 4 mg/kg (i.e., 10 min following the peak inhibition), cytochrome oxidase activity in the heart recovered fully, and that in the brain recovered to 85% of the pre-injection level. From this trend of recovery, the brain cytochrome oxidase could be expected to have recovered fully 40 min after the injection (i.e., 20 min after the peak inhibition). The hepatic cytochrome oxidase activity in mice recovered fully by 10, 20 or 25 min after a KCN injection intraperitoneally at 1, 3, or 5 mg/kg, respectively. In rats exposed to KCN, the enzyme recovered fully 1 h after a 3 or 5 mg/kg injection; recovery time was doubled when the dose was increased to 8 mg/kg. TOXICITY SUMMARY Cyanide is an extremely potent and fast-acting poison regardless of the route of exposure. Typical symptoms of acute poisoning from a lethal dose include headache, vertigo, lack of motor coordination, nausea, vomiting, tachypnea, weak pulse, cardiac arrhythmia, convulsion, coma, and death. Pathological findings might include petechiae of the brain, meninges, and pericardium; cerebral and pulmonary edema; and tracheal congestion with hemorrhage (NTP 1993). These effects result mostly from direct inhibition of cellular respiration by binding cytochrome oxidase in the brain and heart, the two primary targets of cyanide poisoning. The toxic effects of this direct-acting poison are similar in humans and in animals (NTP 1993). Acute or Short-Term Exposures Neurological Effects Humans Being the most sensitive to tissue hypoxia, the brain is a primary target of cyanide toxicity. Signs and symptoms of acute cyanide poisoning reflect cellular hypoxia and anoxia and often are nonspecific. Exposures to high

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 concentrations of HCN vapor can produce flushing, headache, tachypnea, and dizziness within 30 s. Toxic effects progress to stridor, irregular breathing, coma, seizures, and death within 10 min (Ellenhorn and Barceloux 1988). The onset of toxic sequelae is less rapid in oral exposures than in other routes of exposure because of slower entry of cyanide into the circulation and passage through the portal system, where the liver detoxifies some cyanide through the first-pass effect. However, the rapid uptake of HCN from the stomach and the ease with which HCN passes through the blood-brain barrier make this toxin rapidly dangerous even by the oral route. Because of the dangerous nature of cyanide and the small margin of safety, very few controlled human studies have been conducted on the cyanides. Flury and Zernik (1931) and Henderson and Haggard (1943) stated that exposing humans to HCN at 20-40 ppm for several hours produced only slight symptoms. The authors also noted that a 1-h exposure to HCN at 50-60 ppm could be tolerated without serious consequences but that an exposure at 100-240 ppm for 30 min or more is dangerous. However, it is not clear whether this information, which referred to work originally done by Lehman (1919) and cited by McNamara (1976), had been obtained from human experiments or from extrapolations from rabbit data. Peden et al. (1986) reported that 12 men who were exposed to unknown concentrations of HCN in separate industrial accidents experienced dizziness (n = 8), dyspnea (n = 8), a shaky feeling (n = 6), headaches (n = 4), nausea (n = 4), and unconsciousness (n = 5). All the unconscious victims rapidly regained consciousness ''probably less than 10 min" after having been removed from the accident sites. However, the headaches persisted for up to 8 h after hospital admission. Similar symptoms and toxic signs also were reported by Nagler et al. (1978) in three cases of HCN poisoning at unknown concentrations from the accidental addition of 0.5 kg of a cyanide salt to a sulfuric acid bath in the electroplating department of a factory in Belgium. Those victims experienced semiconsciousness, headaches, nausea, sinus bradycardia, and atrial fibrillation. Grubbs (1917) generated HCN gas in a practically airtight room by dropping 0.5 NaCN per 1000 ft3 space into acid, which generated HCN at about 240 ppm. Several human volunteers (the exact number was not specified) breathed the HCN atmosphere for 2 min without showing any symptoms, but a similar HCN atmosphere had "at other times caused dizziness." Also, no toxic effects were noted for human volunteers breathing HCN gas generated by dropping 0.75 oz of NaCN into acid per 1000 ft3 of space (estimated HCN concentration of 360 ppm) for 1.5 min. Barcroft (1931) quoted a 1923 report by Katz and Longfellow: "Men employed in fumigation with HCN have been tested while at rest in 250 ppm of air for 2 min and in 350 ppm for 1.5 min, but felt no dizziness, although possibly on exertion they might have done so." According to

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 McNamara (1976), Katz and Longfellow were describing the data that Grubbs had gathered with human subjects. Bonsail (1984) reported the case of a worker poisoned in a tank that contained residual hydrazodiisobutyronitrile, which decomposes to HCN upon exposure to water. This man was in the tank for about 6 min, during which time he was exposed to HCN at about 500 mg/m3 (460 ppm) and probably also to hydrazodiisobutyronitrile vapor. He collapsed in the tank and was rescued; he was comatose, with marked conjunctivitis, vomiting, and paralysis upon arrival at a hospital. After being placed on a ventilator and treated with sodium thiosulfate and phenytoin, the victim regained full consciousness within 72 h. He was discharged from the hospital 2 w later with only minor loss of peripheral vision. Barcroft (1931), of the U.S. War Department, exposed a man and a dog to HCN at a nominal concentration of 625 ppm (the actual concentration was between 500 and 625 ppm) in an airtight chamber. The man was more tolerant than the dog. The dog became unsteady at 50 s and unconscious at 1 min 15 s. It made "crying sounds" and went into tetanic convulsions at 1 min 30 s, at which time the man left the chamber. He put on a respirator and went back into the chamber at 1 min 30 s to retrieve the dog and remained outside the chamber thereafter. At 5 min after the start of the experiment, the man developed a "momentary feeling of nausea." At 10 min, he had difficulty in concentrating in close conversation. Animals Exposing monkeys to HCN at 100, 125 or 150 ppm produced semiconsciousness or unconsciousness in 17, 14, or 8 min, respectively (Purser et al. 1984). When the exposure was terminated, the animals recovered within 10 min to a fairly active state. The effects of HCN in monkeys and other laboratory animals were compared in an earlier study conducted by Dudley et al. (1942). The symptoms in monkeys exposed at 125 ppm for 12 min were described as "distinctly toxic." Clinical signs in cats, according to the authors, were "markedly toxic" after exposure to the same concentration for 7 min, but no symptoms were observed in rabbits. Exposing dogs at 35-60 ppm (for an unspecified duration) led to vomiting, convulsions, or death, but the dogs could tolerate HCN at 30 ppm. Guinea pigs could tolerate HCN at 200 ppm for 1.5 h without toxic signs. Dudley et al. (1942) concluded that sensitivity to HCN toxicity increases progressively in guinea pigs, rabbits, monkeys, cats, and dogs. One of two rats exposed to HCN at 50 ppm showed violent agitation, paralysis, unconsciousness, and gasping after 3 min of exposure (Moss et al. 1951).

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 The other rat survived the exposure for an unspecified duration without paralysis. Rats and mice injected intraperitoneally with KCN at 3-5 mg/kg became unconscious in 1-1.5 min and recovered at about the same time as the hepatic cytochrome oxidase activity had returned to normal (Schubert and Brill 1968). Histopathological Lesions in the Brain HCN produces central-nervous-system (CNS) effects through blocking cytochrome C oxidase. Prolonged hypoxia or anoxia, which can occur when HCN concentrations are high enough or the exposure duration is long enough, can result in permanent brain damage. Humans Long-term cerebellar spasmodic symptoms were documented in one man after he recovered from a coma after acute HCN intoxication (Fiessinger et al., 1938). Another man was comatose for 7 h after ingesting about 1 g of KCN in an attempted suicide; he acquired parkinsonism after the incident (Uitti et al. 1985). This man had hallucinations and delusions over the first few days after regaining consciousness; in the weeks that followed, he had difficulty expressing himself, personality changes, and depression. Four months after the cyanide ingestion, he experienced marked and generalized rigidity, bradykinesia, and tremors of the tongue, eyelids, and arms. He died 2 years later from an overdose of imipramine and alcohol. Autopsy revealed a shrunken striatum of spongy consistency with widespread lacunar formation, focal atrophy of cerebellar folia, and resolved laminar necrosis in the occipital lobes. Animals When 11 rats and 11 monkeys were infused with NaCN solution (0.07-0.15 mg/min-kg for rats and 0.05-0.10 mg/min-kg for monkeys) for approximately 35-120 min, 4 rats and 4 monkeys developed brain damage (Brierley et al. 1976, 1977). The animals were killed within 4 d after the exposure. All eight animals showed white-matter brain damage, but only one rat and one monkey suffered gray-matter damage. The time course of brain damage induced by acute HCN intoxication was investigated by Levine and colleagues (Levine and Stypulskowski 1959;). Rats exposed for 20-45 min to an unspecified HCN concentration (sufficient to

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 incapacitate the rats within 10 min) showed initial neuronal damage followed by incomplete myelination loss of the damaged neurons. Extensive brain-tissue injury was observed 1 to 2 d after the exposure. At 4 mo after the exposure, the lost neural cells in corpus callosum, striatum, and hippocampus had been replaced by glial cells and vessels (Levine and Stypulskowski 1959; Hirano et al. 1968). However, the remyelination process in the CNS was slow and incomplete (Hirano et al. 1968). Cardiac Effects Blockage of oxygen utilization resulting from binding of HCN on cytochrome C has a devastating effect on the heart. The initial effect is tachycardia, followed by bradycardia. Dysrhythmias and hypotension often precede peripheral vascular collapse (Ellenhorn and Barceloux 1988). Humans Electrocardiographic (EKG) changes in four men executed by HCN inhalation at unspecified concentrations were monitored and documented by Wexler et al. (1947). During the first 7 min of the inhalation, the heartbeat occasionally slowed to varying degrees with periods of either absence of P waves or irregular P waves. All four men also experienced A-V dissociation. After the first 7 min, the heartbeat slowed even further, followed by either heart block or ventricular fibrillation. Three workers were poisoned by HCN vapor when one accidentally added 0.5 kg of cyanide salt into a sulfuric acid bath, generating 280 g HCN (Nagler et al. 1978). One worker, who was about 1 m away from the bath, immediately became semiconscious and developed atrial fibrillation. Another worker rushed to rescue the man and soon complained of headache, nausea, and throat irritation; when admitted to a hospital, the rescuer had crushing chest pain, profuse diaphoresis, vomiting, and tachycardia. Another worker who had been standing 3 m from the bath experienced throat irritation, nausea, vomiting, profuse diaphoresis, sinus bradycardia (36 beats per min), and crushing chest pain. Animals Purser et al. (1984) observed that cardiac changes after HCN exposures were accompanied by incapacitation and were always preceded by a hyperventilatory

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 episode. Hyperventilation was inevitable upon incapacitation. During a 30-min exposure of monkeys to HCN at 147 ppm, the heart rate slowed and the amplitude of T waves either increased or decreased. EKG data from the monkeys showed that HCN could produce EKG changes only in severe intoxication. Effects on the Respiratory System Humans HCN poisoning in humans produces biphasic changes in respiration (i.e., initial rapid and deep respiration), followed by slow and irregular respiration (Parmenter 1926; Wood and Cooley 1956). Animals In monkeys and mice, HCN's respiratory effects are monophasic. Respiration rate was not affected in monkeys exposed to HCN for 30 min at 80 ppm or less. At 90 ppm, hyperventilation was noted 20 min into the exposure. At 180 ppm, however, hyperventilation was almost immediate. In monkeys exposed to HCN at 147 ppm for 30 min, hyperventilation (about 130% increase in minute volume most of the time) developed within 0.5 min and lasted until 13 min into the exposure (Purser et al. 1984). Purser and co-workers attributed the hyperventilatory response to HCN's stimulatory effect on respiration. In contrast, Matijak-Schaper and Alarie (1982) found that HCN in mice slowed respiration, which they hypothesized as being due to depression of the respiratory centers. In mice exposed for 30 min to HCN at 23 or 120 ppm, the respiratory rate was reduced by 20% or 80%, respectively. Lethality Humans HCN is rapidly lethal if inhaled at sufficient concentrations. NcNamara (1976) estimated the average fatal concentration for humans to be 546 ppm for a 10-min exposure. According to Henderson and Haggard (1943), an exposure at 200 to 480 ppm for 30 min is fatal to humans. However, according to Dudley et al. (1942), HCN at 270 ppm can cause death immediately.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 RATIONALE FOR ACCEPTABLE CONCENTRATIONS Table 15-7 presents exposure limits for HCN set by other organizations and Table 15-8 presents the SMACs established by NASA. SMACs are derived in accordance with guidelines developed by the SMAC subcommittee of the Committee on Toxicology (NRC 1992). The SMACs are set by choosing the lowest values among the acceptable concentrations (ACs) (see Table 15-9). The major difficulty in setting exposure limits for HCN is the lack of good dose-response inhalation data from human and animal studies. Even with the data from a few epidemiological studies on HCN-exposed workers, the correlation between exposure concentrations and cyanide toxicity cannot be established with certainty. Most of the human studies were conducted to investigate the consequences of brief exposures to high concentrations. Most of the animal inhalation data also were obtained from brief exposures to high concentrations; these results on lethality or serious toxicity are of little value in setting exposure limits. TABLE 15-7 Exposure Limits Set by Other Organizations   Exposure Limit Organization ppm mg/m3 Reference ACGIH's TLV 10 (TWA) (ceiling) 11 ACGIH 1991 OSHA's PEL 4.7 5 NIOSH 1990 NIOSH's IDLH 50 55 NIOSH 1990 TLV, Theshold Limit Value; TWA, time-weighted average; PEL, permissible exposure limit; IDLH, immediately dangerous to life and health. TABLE 15-8 Spacecraft Maximum Allowable Concentrations Duration Concentration, ppm Concentration, mg/m3 Target Toxicity 1 h 8 9 CNS effects 24 h 4 4.5 CNS effects 7 d 1 1.1 CNS effects 30 d 1 1.1 CNS effects 180 d 1 1.1 CNS effects, testicular toxicity, thyroid effects

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 The brain is known to be the organ most sensitive to HCN toxicity. However, a recent NTP rodent study showed that the reproductive system also is sensitive to HCN. Chronic cyanide exposures have resulted in goiters in humans. Data on these toxicity end points will be considered in setting the SMAC values. ACs Set Based on CNS Effects in Humans The most relevant data for setting exposure limits come from the reports of 36 workers in three electroplating factories where cyanide salts were used (El Ghawabi et al. 1975). Unfortunately, the subjects in those factories were exposed to other chemicals besides HCN. Symptoms reported from past and "present" medical histories and from interviews of these workers, who had worked for periods of a few years to more than 15 y in those facilities. HCN concentrations in the three factories during the 2-mo survey were measured at 6.4 ± 6.9, 8.1 ± 8.2, and 10.4 ± 10.9 ppm; the highest concentration was found in factory A, which had no ventilation. The most prevalent and least-severe symptoms were headache and weakness, which were reported by 80% of the workers (20-30% in controls). Vomiting and more-serious CNS effects were reported by 44% of the subjects during their tenures. The authors did not mention whether any symptoms were present during the survey period. The symptoms were reported by the workers who had worked for many years in these factories. The concentrations reported were obtained by analyzing air samples taken several times from each factory during the 3-mo survey. It is likely that the more serious symptoms, such as vomiting, were the result of brief exposures to high HCN concentrations at work. Therefore, it is reasonable to conclude that 8 ppm would likely produce no more than mild CNS effects (e.g., mild headache), which would be acceptable for 1-h exposures in a spacecraft. Therefore, 8 ppm is set as the 1-h AC for HCN. The concentration is reduced by half to 4 ppm to ensure that exposure would produce no more than slight CNS effects. This AC is further reduced to 1 ppm as the AC for 7-d, 30-d and 180-d exposures. HCN at 1 ppm is not expected to produce any CNS effects. Testicular Effects in Rats When rats and mice were fed drinking water containing NaCN at 300 ppm, which is equivalent to HCN at 15.6 ppm in the air (see Table 15-4), they had

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 mild but statistically significant decreases in the weights of the left epididymis and left cauda epididymis. Statistically significant changes in testicular weight, sperm counts and sperm motility were also observed in rats but not in mice (NTP 1993). NTP concluded that those changes are probably not biologically significant and are insufficient to decrease fertility in rats; however, NTP cautioned that "humans are considered to be relatively more sensitive than rats to such changes." Thus, 300 ppm in drinking water or the equivalent of 16 ppm continuous (24-h) inhalation exposure was treated as the no-observed-adverse-effect level (NOAEL) for rats. A species factor of 10 is used to account for the possibility that humans are more sensitive to the reproductive toxicity of HCN. Therefore, the AC for 7 d and 30 d is set at 1.6 ppm (NOAEL ÷ 10). The 180-d AC is calculated below: 180-d AC = 16 ppm ÷ 10 × (90 d/180 d) = 0.8 ppm   = 1 ppm (rounded up from 0.8 ppm). Thyroid Effects El Ghawabi et al. (1976) reported that mild goiter was detected in 44% of the 36 Egyptian workers working for up to 15 y in poorly ventilated electroplating factories where the HCN concentration varied greatly. The great variations in exposure length and concentrations make these data unsuitable for setting SMACs. A recent 13-w study on HCN toxicity to all major organs and tissues, including thyroid, has more direct relevance to the assessment of HCN exposures (≤ 180 d) in spacecraft. In the latter study, rats and mice were fed water containing as much cyanide as 300 ppm; histopathological examination revealed no thyroid lesions. As discussed above, the exposure concentration is roughly equivalent to a 24-h continuous airborne HCN concentration of 15.6 ppm for the rats or 34.7 ppm for the mice. Rats are known to be more sensitive than mice to the effects of chemicals on the thyroid; therefore, the equivalent exposure of 15.6 ppm to rats are used to establish ACs. A species factor of 10 is applied to obtain an AC of 1.6 ppm for a 30-d exposure. A factor of 2 is applied to obtain an AC of 0.8 ppm (which was rounded up to 1 ppm) for 180-d exposure, which is twice the duration of that in the NTP study. It is very unlikely that exposures to low concentrations of HCN for 7 d or less could alter thyroid function. Therefore, ACs for exposures of 7 d or less will not be set on the basis of thyroid toxicity.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 RECOMMENDATIONS The major difficulty in setting exposure limits for HCN is the lack of controlled human inhalation exposure data, or good dose-response inhalation data from animals. It is recommended that experiments be carried out to better elucidate the concentration response of HCN at exposure concentrations at 20 ppm and below. These results will be useful for reevaluating SMACs, TLVs, and the OSHA PEL. The current TLV and PEL for HCN are 10 and 4.7 ppm, respectively.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 TABLE 15-9 Acceptable Concentrations End Point, Exposure Data Reference   Uncertainty factors Acceptable Concentrations, ppm Species Species Time 1 h 24 h 7 d 30 d 180 d Headache and weakness Human 1 1 8 4 1 1 1 6.4 ± 6.9, 8.1 ± 8.2, and 10.4 ± 10.9 ppm for 5-15 y (El Ghawabi et al. 1975)                 Testicular toxicity Rat 10 2b — — 1.6 1.6 1c NOEAL, 15.6 ppm × 13 wa (NTP 1993)                 Thyroid Effect Rat 10 2b — — — 1.6 1c NOEAL, 15.6 ppm × 13 wa (NTP 1993)                 SMACs       8 4 1 1 1 a See text for detail. b For 180 d. c Rounded up from 0.8 ppm.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 REFERENCES ACGIH. 1991. Hydrogen cyanide. Pp. 775-779 in Documentation of the Threshold Limit Values and Biological Exposures Indices, Vol 2, 6th Ed. American Conference of Governmental Industrial Hygienists, Cincinnati, OH. Ahmed, A.E., and M.Y. Farooqui. 1982. Comparative toxicities of aliphatic nitriles. Toxicol. Lett. 12:157-163. Albaum, H.G., J. Tepperman and O. Bodansky. 1946. The in vivo inactivation by cyanide of brain cytochrome oxidase and its effect on glycolysis and on the high energy phosphorus compounds in brain. J. Biol. Chem. 164:45-51. Ansell, M. and F.A.S. Lewis. 1970. A review of cyanide concentrations found in human organs. A survey of literature concerning cyanide metabolism, 'normal', non-fatal, and fatal body cyanide levels. J. Forensic Med. 17:148-155. ATSDR. 1997. Draft Toxicological Profile for Cyanide. Agency for Toxic Substances and Disease Registry. U. S. Dept. of Health and Human Service, Public Health Service. Atlanta, GA. Ballantyne, B. and J.E. Bright. 1979. Comparison of kinetic and end-point microdensitometry for the direct quantitative histochemical assessment of cytochrome oxidase activity. Histochem. J. 11:173-186. Ballantyne, B. 1983. The influence of exposure route and species on the acute lethal toxicity and tissue concentrations of cyanide. Pp. 583-586. In: Developments in the Science and Practice of Toxicology. A. W. Hayes, R.C. Schnell, and T.S. Miya, eds. New York, NY: Elsevier Science. (cite ATSDR 1997). Barcroft, J. 1931. The toxicity of atmospheres containing hydrocyanic acid gas. J. Hyg. 31: 1-34. Baumann, E.J., D.B. Sprinson and N. Metzger 1934. The estimation of thiocyanate in urine. J. Biol. Chem. 105:269-277. Baumeister, R.G.H., H. Schievelbein and G. Zickgraf-Rudel. 1975. Toxicological and clinical aspects of cyanide metabolism. Arzneim.-Forsch. 25:1056-1064. Blanc, P., M. Hogan, K. Mallin, D. Hryhorczuk, S. Hessl and B. Bernard. 1985. Cyanide intoxication among silver-reclaiming workers. J. Am. Med. Assoc. 253:367-371. Bonsail, J.L. 1984. Survival without sequelae following exposure to 500 mg/m3 of hydrogen cyanide. Hum. Toxicol. 3:57-60. Bourdin, M. 1991. Materials Destined to an Aerospatial Use - Determination of Toxicological Risk Due to the Products of Thermal Degradation Test at 800, 550, and 300°C. Report No. /CERTSM/91. Pp. 36. CERTSM/DCN Toulon/Etudes Sous-Marins, Ministere de la Defense, Delegation Generale Pour L'Armement, Direction des Constructions Navales. Toulon, France. Boxer, G.E. and J.C. Richards. 1952. Studies on the metabolism of the carbon of cyanide and thiocyanate. Arch. Biochem. 39:7-26. Brierley, J.B., A.W. Brown and J. Calverley. 1976. Cyanide intoxication in the rat: Physiological and neuropathological aspects. J. Neurol. Neurosurg. Psychiatry. 39:129-140.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 Brierley, J.B., P.M. Prior, J. Calverley and A. W. Brown. 1977. Cyanide intoxication in Macaca mulatta. Physiological and neuropathological aspects. J. Neurol. Sci. 31:133-157. Chandra, H., B.N. Gupta, S.K. Bhargava, S.H. Clerk and P.N. Mahendra. 1980. Chronic cyanide exposure - A biochemical and industrial hygiene study. J. Anal. Toxicol. 4:161-165. Chandra, H., B.N. Gupta, N. Mathur. 1988. Threshold limit value of cyanide: A reappraisal in Indian context. Indian J. Environ. Protection. 8:170-174. Crampton, R.F., I.F. Gaunt, R. Harris, J.F. Knowles, M.J. Langman, J.C. Linnell, D.M. Matthews, D.L. Mollin, A.R. Pettigrew, W.T. Smith, A.H. Waters, J. Wilson and I.J. Wise. 1979. Effects of low cobalamin diet and chronic cyanide toxicity in baboons . Toxicology. 12 :221-234. CRC. 1985. Pp. D-165 in CRC Handbook of Chemistry and Physics. 65th Ed., R.C. Weast, M.J. Astle, and W.H. Beyer, eds. Boca Raton, Fl: CRC Press. Doherty, P.A., V.H. Ferm and R.P. Smith. 1982. Congenital malformation induced by infusion of sodium cyanide in the golden hamster. Toxicol. Appl. Pharmacol. 64:456-464. Dudley, H.C., T.R. Sweeney and J.W. Miller. 1942. Toxicology of acrylonitrile (vinyl chloride) II. Studies of effects of daily inhalation. J. Ind. Hyg. Toxicol. 24:255-258. El Ghawabi, S.H., M.A. Gaafar, A.A. El-Saharti, S.H. Ahmed, K.K. Malash and R. Fares. 1975. Chronic cyanide exposure: A clinical, radioisotope, and laboratory study. Br. J. Ind. Med. 32 : 215-219. Ellenhorn, M.J., and D.G. Barceloux. 1988. Cyanide. Pp. 829-835. In: Medical Toxicology: Diagnosis and Treatment of Human Poisoning. New York, NY: Elsevier. Etteldorf, J.N. 1939. The treatment of gaseous hydrocyanic acid poisoning by sodium thiosulfate and sodium nitrite combination. J. Pharmacol. Exp. Ther. 66:125-131. Fiessinger, N., M. Duvoir and G. Bondin. 1938. Prolonged cerebellar-spasmodic symptoms after a coma caused by hydrocyanide acid. Med. Travail. 10:23-32. Flury, F. and F. Zernik. 1931. Schädliche Gase: Dämpfe, Nebel, Rauch-und Staubarten. Berlin: Julius Springer. Gettler, A.O. and J.O. Baine. 1938. The toxicology of cyanide. Am. J. Med. Sci. 195 : 182-198. Goldstein, F. and R. Reiders. 1953. Conversion of thiocyanate to cyanide by an erythrocytic enzyme. Am. J. Physiol. 173:287-290. Gosselin, R.E., R.P. Smith and H.C. Hodge. 1984. Toxicology information about selected ingredients. Pp. 125-130. in: Clinical Toxicology of Commercial Products, Fifth Ed. Baltimore, Maryland: Williams & Wilkins. Grabois, B. 1954. Exposure to hydrogen cyanide in the processing of apricot kernels. N.Y. State Dept. Labor Month. Rev., Div. Ind. Hyg. 33:33-36. Grubbs, S.B. 1917. Detection of hydrocyanic acid gas. Use of small animals for this purpose. Pub. Health Rep. 32:565-570. Hardy, H.L., W.M. Jeffries, M.M. Wasserman and W.R. Waddell. 1950. Thiocyanate

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 effect following industrial cyanide exposure. N. Engl. J. Med. 242:968-972. Hartung, R. 1982. Cyanides and Nitriles. Pp. 4845-4900. In: Patty's Industrial Hygiene and Toxicology, 3rd Ed., G.D. Clayton and F.E. Clayton, eds. New York, NY: John Wiley & Sons. Henderson, Y. and H.W. Haggard (1943). Group II B. Chemical asphyxiants. In Noxious Gases and the Principles of Respiration Influencing Their Action, pp. 172-175. Reinhold Pub. Corp., New York, New York. Himwich, W.A. and J.P. Saunders. 1948. Enzymatic conversion of cyanide to thiocyanate. Am. J. Physiol. 153:348-354. Hirano, A., S. Levine and H.M. Zimmerman 1968. Remyelination in the central vervous system after cyanide intoxication. J. Neuropathol. Exp. Neurol. 27:234-245. Howard, J.W. and R.F. Hanzal. 1955. Chronic toxicity for rats of food treated with hydrogen cyanide. J. Agr. Food Chem. 3:325-329. Hugod, C. 1981. Myocardial morphology in rabbits exposed to various gas-phase constituents of tobacco smoke--an ultrastructural study. Atherosclerosis. 40:181-190. Isom, G.E. and J.L. Way. 1976. Lethality of cyanide in the absence of inhibition of liver cytochrome oxidase. Biochem. Pharmacol. 25:605-608. Isom, G.E., G.E. Burrows and J.L. Way. 1982. Effect of oxygen on the antagonism of cyanide intoxication-cytochrome oxidase, in vivo. Toxicol. Appl. Pharmacol. 65:250-256. Jandorf, B.J. and O. Bodansky. 1946. Therapeutic and prophylactic effect of methemoglobinemia in inhalation poisoning by hydrogen cyanide and cyanogen chloride. J. Ind. Hyg. Toxicol. 28:125-132. Katz and Longfellow. 1923. Serial Report No. 240507. American Bureau of Mines. Kushi, A., T. Matsumoto and D. Yoshida. 1983. Mutagen from the gaseous phase of protein pyrolyzate. Agri. Biol. Chem. 47:1979-1982. Lai, Y.-L. 1991. Comparative Ventilation of the normal lung. Pp.217-240 in Treatise on Pulmonary Toxicology Volume I: Comparative Biology of the Normal Lung. R.A. Parent ed.. Boca Raton, Fl.: CRC Press. Landahl, H.D. and R.G. Herrmann. 1950. Retention of vapors and gases in the human nose and lung. Arch. Ind. Hyg. Occup. Med. 1:36-45. Lehmann, K.B. 1919. Short Textbook on Mechanical and Industrial Hygiene. Leipzig: S. Hirzel. [As cited by McNamara, Edgewood Arsenal Technical Report EB-TR-76023, August 1976]. Lessell, S. 1971. Experimental cyanide optic neuropathy. Arch. Ophthal. 86:194-204. Leuschner, J., A. Winkler and F. Leuschner 1991. Toxicokinetic aspects of chronic cyanide exposure in the rat. Toxicol. Letters. 57:195-201. Levine, M.S. and E.P. Radford. 1978. Occupational exposures to cyanide in Baltimore fire fighters . J. Occup. Med. 20:53-56. Levine, S. and W. Stypulskowski. 1959. Experimental cyanide encephalopathy. Arch. Pathol. 67:306-323.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 Liappis, N. 1973. Sex-specific differences in the free amino acids in adult urine.[ in German] Z. Klin. Chem. Klin Biochem. 11(7):279-285. Lowry, W.T., L. Juarez, C.S. Petty and B. Roberts. 1985. Studies of toxic gas production during actual structural fires in the Dallas area. J. Forensic Sci. 30:59-72. Matijak-Schaper, M. and Y. Alarie. 1982. Toxicity of carbon monoxide, hydrogen cyanide and low oxygen. J. Combus. Toxicol. 9:21-61. Mauderly, J.L. 1986. Respiration of F344 rats in nose-only inhalation exposure tubes. J. Appl. Toxicol. 6:25-30. McNamara, B.P. 1976. Pp. 1-22. In: Estimates of the Toxicity of Hydrocyanic Acid Vapors in Man. Report No. Edgewood Arsenal Technical Report EB-TR-76023. Department of the Army. Edgewood Arsenal Aberdeen Proving Ground, Maryland. Moore, S.J., I.K. Ho and A.S. Hume. 1991. Severe hypoxia produced by concomitant intoxication with sublethal doses of carbon monoxide and cyanide. Toxicol. Appl. Pharmacol. 109:412-420. Moss, R.H., C.F. Jackson and J. Seiberlich. 1951. Toxicity of carbon monoxide and hydrogen cyanide gas mixtures. Arch. Ind. Hyg. Occup. Med. 4:53-64. Nagler, J., R.A. Provoost and G. Parizel. 1978. Hydrogen cyanide poisoning: Treatment with cobalt EDTA. J. Occup. Med. 20:414-416. NIOSH. 1976. Pp. 37-114. In: Criteria for a Recommended Standard . . . . Occupational Exposure to Hydrogen Cyanide and Cyanide Salts (NaCN, KCN, and Ca(CN)2). Report No. DHEW (NIOSH) Pub. No. 77-108. U.S. Department of Health, Education, and Welfare, National Institute for Occupational Safety and Health. Washington, D.C. NIOSH. 1990. Pp. 126 in NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 90-117. U.S. Department of Health and Human Services, National Institute for Occupational Safety and Health. Washington, D.C. NRC. 1992. Guidelines for Developing Spacecraft Maximum Allowable Concentrations for Space Station Contaminants. Washington, DC.: National Academy Press. NTP. 1993. NTP Technical Report on Toxicity Studies of Sodium Cyanide. Toxicity Report Number 37 (NIH Publication 94-3386). National Toxicology Program. Okoh, P.N. 1983. Excretion of 14C-labeled cyanide in rats exposed to chronic intake of potassium cyanide. Toxicol. Appl. Pharmacol. 70:335-339. Parmenter, D.C. 1926. Observations on mild cyanide poisoning: Report of a case. J. Ind. Hyg. 8:280-282. Peden, N.R., A. Taha, P.D. McSorley, G.T. Bryden, I.B. Murdoch, and J.M. Anderson. 1986. Industrial exposure to hydrogen cyanide: implications for treatment. Br. Med. J. 293:538. Pettersen, J.C., and S.D. Cohen. 1985. Antagonism of cyanide poisoning by chlorpromazine and sodium thiosulfate. Toxicol. Appl. Pharmacol. 81:265-273. Philbrick, D.J., J.B. Hopkins, D.C. Hill, J.C. Alexander, and R.G. Thomson. 1979. Effects of prolonged cyanide and thiocyanate feeding in rats. J. Toxicol. Environ. Health. 5:579-592.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 Potter, E.B. 1944. Acute goiter due to cyanate therapy: report of two cases with thyroidectomy . JAMA 124:568-570. Purser, D.A., P. Grimshaw, and K.R. Berrill. 1984. Intoxication by cyanide in fires: A study in monkeys using polyacrylonitrile. Arch. Environ. Health 39:394-400. Radojicic, B. 1973. Determining rhodanine in urine of workers occupationally exposed to cyanide [in Serbo-Croatian]. Arh. Hig. Rada Toksikol. 24:227-232. Rawson, R.W., S. Hertz and J.H. Means. 1943. Thiocyanate goiter in man. Ann. Int. Med. 19:829-842. Sax, N.I. 1984. Pp. 1547-1548 in Dangerous Properties of Industrial Materials, 6th Ed. New York: Van Nostrand Reinhold. Schubert, J., and W.A. Brill. 1968. Antagonism of experimental cyanide toxicity in relation to the in vivo activity of cytochrome oxidase. J. Pharmacol. Exp. Ther. 162:352-359. Singh, B.M., N. Coles, P. Lewis, R.A. Braithwaite, M. Nattrass, and M.G. FitzGerald. 1989. The metabolic effects of fatal cyanide poisoning. Postgraduate Med. J. 65:923-925. Spratt, N.T. 1950. Nutritional requirements of the early chick embryo. III. The metabolic basis of morphogenesis and differentiation as revealed by the use of inhibitors. Biol. Bull. 99:120-135. Sweet, D.V. 1987. Registry of Toxic Effects of Chemical Substances, 1985-86 Edition. User Guide. Report No. DHHS (NIOSH) Pub. No. 87-114. Pp.XLVI. U.S. Department of Health and Human Services, National Institute for Occupational Safety and Health, Washington, DC. Tadic, V. 1992. The in vivo effects of cyanide and its antidotes on rat brain cytochrome oxidase activity. Toxicology 76:59-67. Terrill, J.B., R.R. Montgomery, and C.F. Reinhardt. 1978. Toxic gases from fires. Science 200:1343-1347. Thautman, J.A. 1933. Methylene blue in the treatment of HCN gas poisoning. Public Health Rep. 48:1443-1447. Towill L.E., J.S. Drury, B.L. Whitfield, and others. 1978. Review of the environmental effects of pollutants V. Cuamode. EPA Health Effect Research Laboratory, Office of Research and Development, Cincinnati, OH. NTIS PB 28-9920. Uitti, R.J., A.H. Rajput, E.M. Ashenhurst, and B. Rozdilsky. 1985. Cyanide-induced parkinsonism: A clinicopathologic report. Neurology 35:921-925. Vernot, E.H., J.D. MacEwen, C.C. Haun, and E.R. Kinkead. 1977. Acute toxicity and skin corrosion data for organic and inorganic compounds and aqueous solutions. Toxicol. Appl. Pharmacol. 42:417-423. Wexler, J., J.L. Wittenberger and P.R. Dumke. 1947. The effect of cyanide on the electrocardiogram of man. Am. Heart J. 34:163-173. Wolfsie, J.H. and C.B. Shaffer. 1959. Hydrogen cyanide. Hazards, toxicology, prevention and management of poisoning. J. Occup. Med. 1:281-288. Wood, J.L. and S.L. Cooley. 1956. Detoxication of cyanide by cystine. J. Biol. Chem. 218:449-457.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 Wooley, W.D., S.A. Ames and P.J. Fardell 1979. Chemical aspects of combustion toxicology of fires. Fire and Materials 3:110-120. Yamanaka, S., S. Takaku, Y. Takaesu, et al. 1991. Validity of salivary thiocynate as an indicator of cyanide exposure from smoking. Bull Tokyo Dental Coll. 32(4):157-163.