CYNIDE TOXICITY

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Cyanogenic Glycosides and Cyanide Toxicity

This is a copy of a scientific paper covering the subject of cyanide toxicity in depth. It does not discuss toxic effects occurring in people consuming foodstuffs, other than one example, again with cassava. And again there are no case studies reporting death from consuming cyanogenic glycosides.

Given the extensive list of references to this study, this is presumably because they were unable to find any.
It shows that the real dangers of cyanide come from industrial chemicals, smoking, car fumes, etc. But if cyanogenic glycosides were really a health danger, this is the kind of research paper I would find compelling. Quite possibly the University of Iowa is working on one right now.


Cyanide Toxicity Profile

Cyanide most commonly occurs as hydrogen cyanide and its salts–sodium and potassium cyanide. Cyanides are both man-made and naturally occurring substances. They are found in several plant species as cyanogenic glycosides and are produced by certain bacteria, fungi, and algae. In very small amounts, cyanide is a necessary requirement in the human diet. Cyanides are released to the environment from industrial sources and car emissions (ATSDR, 1989).

Cyanides are readily absorbed by the inhalation, oral, and dermal routes of exposure. The central nervous system (CNS) is the primary target organ for cyanide toxicity. Neurotoxicity has been observed in humans and animals following ingestion and inhalation of cyanides. Cardiac and respiratory effects, possibly CNS-mediated, have also been reported. Short-term exposure to high concentrations produces almost immediate collapse, respiratory arrest, and death (Hartung, 1982; EPA, 1985). Symptoms resulting from occupational exposure to lower concentrations include breathing difficulties, nervousness, vertigo, headache, nausea, vomiting, precordial pain, and electrocardiogram (EKG) abnormalities (Carmelo, 1955; El Ghawabi et al., 1975; Sandberg, 1967; Wuthrich, 1954). Thyroid toxicity has been observed in humans and animals following oral and inhalation exposure to cyanides (Philbrick et al., 1979; EPA, 1984). In animal studies, cyanides have produced fetotoxicity and teratogenic effects, including exencephaly, encephalocele, and rib abnormalities (Doherty et al., 1982; Frakes et al., 1986; Tewe and Maner, 1981b; Willhite, 1982).

Reference doses (RfDs) have been calculated for subchronic and chronic oral exposure to cyanide and several cyanide compounds (EPA, 1990a-e; 1991a-e). The values, derived from a single study, are based on a no-observed-adverse-effect level (NOAEL) of 10.8 mg/kg/day for cyanide in a 2-year dietary study with rats (Howard and Hanzal, 1955). The subchronic and chronic oral RfDs are 0.02 mg/kg/day for cyanide; 0.04 mg/kg/day for sodium cyanide, calcium cyanide, and cyanogen; 0.05 mg/kg/day for potassium cyanide, chlorine cyanide, and zinc cyanide; 0.1 mg/kg/day for silver cyanide; and 0.2 mg/kg/day for potassium silver cyanide. Data were insufficient to derive a reference concentration (RfC) for cyanide.


No suitable cancer bioassays or epidemiological studies are available to assess the carcinogenicity of cyanide. Therefore, EPA (1991b) has placed cyanide in weight-of-evidence group D, not classifiable as to human carcinogenicity.

1. INTRODUCTION

Cyanide (CN-, CAS No. 57-12-5) most commonly occurs as hydrogen cyanide (HCN, CAS No. 74-90-8) and its salts–sodium cyanide (NaCN, CAS No. 143-33-9) and potassium cyanide (KCN, CAS No. 151-50-8). Cyanides are ubiquitous in nature, arising from both natural and anthropogenic sources. Cyanogenic glycosides, producing hydrogen cyanide upon hydrolysis, are found in a number of plant species. Cyanides are also produced by certain bacteria, fungi, and algae. Minute amounts of cyanide in the form of vitamin B12 (cyanocobalamine) are a necessary requirement in the human diet (ATSDR, 1989). Hydrogen cyanide, a colorless liquid with a characteristic odor of bitter almonds (Verschueren, 1983), has a molecular weight of 27.03 and a boiling point of 25.6C. It is miscible with water and alcohol and slightly soluble in ether (Budavari et al., 1989).
Cyanide is released to the environment from numerous sources. Metal finishing and organic chemical industries as well as iron and steel production are major sources of cyanide releases to the aquatic environment. More than 90% of emissions to the air are attributed to releases in automobile exhaust. Workers in a wide variety of occupations may be exposed to cyanides. The general population may be exposed to cyanides by inhalation of contaminated air, ingestion of contaminated drinking water, and/or consumption of a variety of foods (ATSDR, 1989).

2. METABOLISM AND DISPOSITION

2.1 ABSORPTION

Hydrogen cyanide is rapidly absorbed by the gastrointestinal and respiratory tract; the liquid and possibly the concentrated vapor are absorbed directly through the intact skin (Hartung, 1982; EPA, 1984). Hydrogen cyanide, a weak acid with a pKa of 9.2, is more rapidly absorbed from the gastrointestinal tract than cyanide salts (EPA, 1984). Gettler and Baine (1938) calculated that dogs treated with 20, 50, or 100 mg/kg potassium cyanide by gavage absorbed 72, 24, or 17% of the administered dose. Absorption of cyanide from smoke inhaled by cigarette smokers is inferred by higher plasma levels of thiocyanate (a metabolite) in smokers compared to nonsmokers (EPA, 1984). Landahl and Herrmann (1950) reported that humans retained 57-77% of inhaled hydrogen cyanide in the lungs. Cyanides are moderately lipid-soluble and penetrate the epidermis readily. In addition, some cyanides, such as potassium cyanide, have a corrosive effect on the skin that increases the rate of dermal absorption (NIOSH, 1976).

2.2 DISTRIBUTION

Following absorption, cyanide is rapidly distributed throughout the body by the blood. Cyanide enters erythrocytes and is found at low concentrations in normal human blood and other organs. Transplacental transfer of cyanide can occur. Higher plasma concentrations of thiocyanate were found in the umbilical cord blood of infants born to smokers compared with those born to nonsmokers (EPA, 1985). After nonlethal exposure, plasma cyanide levels tend to return to normal levels within 4-8 hours. The estimated plasma half-life is 20 minutes to 1 hour (Hartung, 1982). In cases of fatal oral poisoning, cyanide was detected in the brain, blood, kidney, stomach wall, liver, and urine (Ansell and Lewis, 1970). Gettler and Baine (1938) reported brain and liver cyanide levels of 0.06-1.37 mg/100 g and 0.22-0.91 mg/100 g tissue, respectively, in four humans who ingested fatal doses of cyanide. Tissue levels in a human after inhalation of hydrogen cyanide were 0.75, 0.42, 0.41, 0.33, and 0.32 mg hydrogen cyanide/100 g in the lung, heart, blood, kidney, and brain, respectively. Elevated levels of cyanide were seen in erythrocytes and elevated levels of thiocyanate in the blood, liver, and kidneys of rats receiving food fumigated with hydrogen cyanide (Howard and Hanzal, 1955). Results of a drinking water study with rats indicate that subchronic cyanide administration (up to 160 mg/kg/day potassium cyanide for 13 weeks) does not lead to saturation of cyanide detoxification pathways (Leuschner et al., 1991).

2.3 METABOLISM

The principal pathway of cyanide metabolism is conversion to thiocyanate catalyzed by either rhodanese (thiosulfate sulfurtransferase) or by 3-mercaptopyruvate sulfurtransferase. Both enzymes are widely distributed in the body. Conversion of cyanide to the less toxic thiocyanate by rhodanese is enhanced when cyanide poisoning is treated with the intravenous administration of a sulfur donor such as sodium thiosulfate (ATSDR, 1989; Westley, 1980). The toxicity of thiocyanate is significantly less than that of cyanide, but chronically elevated levels of blood thiocyanate can inhibit the uptake of iodine by the thyroid gland, thereby reducing the formation of thyroxine (Hartung, 1982). Other metabolic pathways include the conversion to 2-aminothiazoline-4-carboxylic acid; incorporation into a 1-carbon (formate) metabolic pool; combination with hydroxycobalamine to form cyanocobalamine (B12); and combination with cystine to form 2-aminothiazoline-4-carboxylic acid (ATSDR, 1989).

2.4 EXCRETION

In humans and animals, the major route of cyanide elimination from the body is via urinary excretion of thiocyanate. Small amounts of thiocyanate are also eliminated via lung and feces (EPA, 1985). Some free hydrogen cyanide is excreted unchanged in breath, saliva, sweat, and urine (Hartung, 1982). An increased urinary excretion of thiocyanate was observed in case hardeners exposed to 4-6 ppm cyanide vapor and cyanide salts over a period of several years (NIOSH, 1976).


3. NONCARCINOGENIC HEALTH EFFECTS

3.1 ORAL EXPOSURES

3.1.1 Acute Toxicity

3.1.1.1 Human

Hydrogen cyanide and its simple soluble salts such as sodium and potassium cyanide are among the most rapidly acting poisons with the central nervous system (CNS) as the target organ. Ingestion of 50-100 mg sodium or potassium cyanide is followed by almost instantaneous collapse and cessation of respiration. At much lower doses, the earliest symptoms are weakness, headache, confusion, and occasionally nausea and vomiting. The respiratory rate and depth usually increase at the beginning and at later stages become slow and gasping. If cyanosis is present, it usually indicates that respiration has ceased or has been inadequate for some minutes. The most specific symptom in acute cyanide poisoning is the bright red color of venous blood which is evidence of the inability of the tissues to use oxygen (Hartung, 1982).


Cyanide exerts its toxic effect by forming a complex with ferric ion (Fe+3) of mitochondrial cytochrome oxidase, the enzyme that catalyzes the terminal step in the electron transport chain, thereby preventing use of oxygen by cells. Since cytochrome oxidase occupies a central role in the use of oxygen in all cells, its inhibition leads to the disruption of cellular respiration producing cytotoxic hypoxia. In addition to binding to cytochrome oxidase, cyanide combines with approximately 2% of methemoglobin normally present (ATSDR, 1989; U.S. EPA, 1985; Hardy and Boylen, 1983).


Numerous reports describe suicides or suicide attempts through ingestion of cyanide compounds (NIOSH, 1976). However, these studies generally do not report dose levels. Wolnik et al. (1984) reported an incident in which seven persons died after ingestion of capsules of a pain medication contaminated with 500-800 mg potassium cyanide. Recoveries from ingestion of 3-5 g potassium cyanide without therapy and up to 6 g potassium cyanide with therapy have been documented. However, results of oral intoxication with cyanide must be interpreted with caution because the presence of food in the digestive tract may retard absorption (U.S. Air Force, 1989). A recent case report described cyanide poisoning in a 2-year-old child who had ingested acetonitrile in a cosmetic nail glue remover. When ingested, acetonitrile is slowly metabolized to cyanide, and symptoms of cyanide toxicity develop over a latency period of several hours (Losek et al., 1991).


3.1.1.2 Animal

Oral LD50s in rats are 8.5 mg/kg for hydrogen cyanide (U.S. Air Force, 1989), 6.4 mg/kg for sodium cyanide, 10 mg/kg for potassium cyanide, 39 mg/kg for calcium cyanide, 21 mg/kg for potassium silver cyanide, and 123 mg/kg for silver cyanide (ATSDR, 1989). Gettler and Baine (1938) reported that dogs treated orally with 20, 50, or 100 mg/kg potassium cyanide died 155, 21, or 8 minutes, respectively, after dosing.


3.1.2 Subchronic Toxicity

3.1.2.1 Human

Information on the subchronic oral toxicity of cyanide to humans was unavailable.


3.1.2.2 Animal

Adult rats exposed to 200 mg potassium cyanide/L drinking water for 21 days had significantly higher liver weights compared with controls, but no effect on liver weight occurred when potassium cyanide was administered in the diet at a dose of 200 mg/kg diet (Palmer and Olson, 1979).

No adverse effects were seen in dogs exposed to sodium cyanide at dietary doses of 3 mg cyanide/kg body weight/day for 30-32 days (EPA, 1985). However, Hertting et al. (1960) observed degenerative changes (necrosis, reduced RNA content, and inflammation) in ganglion cells of the CNS of dogs administered sodium cyanide in capsules containing 3 mg cyanide/kg/day for 15 months.


3.1.3 Chronic Toxicity

3.1.3.1 Human

In tropical regions of Africa, a high incidence of ataxic neuropathy, goiter, amblyopia, and other disorders has been associated with chronic ingestion of cassava, one of the dietary staples containing cyanogenic glycosides that release hydrogen cyanide when metabolized in vivo (EPA, 1984; Westley, 1980). Nutritional deficiencies such as diets low in vitamin B12, riboflavin, and protein exacerbate the neurotoxic effects of cyanides (Westley, 1980).


3.1.3.2 Animal

Howard and Hanzal (1955) exposed male and female rats to a diet fumigated with hydrogen cyanide at levels of 0, 76, or 190 mg HCN/kg food for 104 weeks. No treatment-related effects on growth rate, no gross signs of toxicity, and no histologic lesions in tissues examined were observed.

Philbrick et al. (1979) treated male rats with 0 or 1500 mg potassium cyanide/kg diet for 11.5 months. Decreased weight gain and primary myelin degeneration of the spinal cord were seen at the end of the treatment period. Decreased plasma thyroxin levels occurred at 4 months with recovery by 11 months. Rats maintained on a methionine- or vitamin B12-deficient diet appeared to be affected more severely.


3.1.4 Developmental and Reproductive Toxicity

3.1.4.1 Human

Congenital hypothyroidism is present in 15% of newborns in certain areas of Zayre where cassava is a staple food. This incidence is approximately 500 times that observed in industrial countries (Ermans, 1980).


3.1.4.2 Animal

No adverse effects were observed on reproductive performance or lactation of rats fed 500 mg cyanide/kg diet throughout gestation and lactation. Litter size, weight of pups at birth, and food consumption and growth rate of pups were not significantly different from controls (Tewe and Maner, 1981a). However, fetuses of sows fed 277 or 521 mg cyanide/kg diet throughout gestation and lactation exhibited decreased organ to body weight ratios for thyroid, heart, and spleen when compared with those born to sows fed 31 mg cyanide/kg diet for the same time period. Hyperplasia of the kidney glomeruli and morphological changes in thyroid cells were seen in sows at all three exposure levels (Tewe and Maner, 1981b).

Frakes et al. (1986) exposed female golden hamsters to cyanogenic glycosides in diets containing cassava meal on days 3-14 of gestation. The low cyanide cassava contained approximately 0.6 mmol/kg (46 ppm), and the high cyanide cassava 7.9 mmol/kg (600 ppm) cyanide. Cassava-fed dams gained less weight than the controls, and the offspring showed reduced fetal weight and reduced ossification. In another study, hamsters treated orally with 200-275 mg/kg D,L-amygdalin (a cyanogenic glycoside and most common constituent of laetrile) on gestation day 8 exhibited maternal toxicity at doses of 250 mg/kg and greater (Willhite, 1982). Dams treated simultaneously with thiosulfate were protected from toxicity. Fetuses of amygdalin-treated dams revealed a dose-related increase in abnormalities such as exencephaly (brain outside skull), encephalocele (hernia of brain), and rib anomalies, whereas simultaneous treatment with thiosulfate induced a low incidence of such abnormalities. The teratogenic effects after oral amygdalin exposure were attributed to cyanide released by bacterial action in the gastrointestinal tract.


3.1.5 Reference Dose

3.1.5.1 Subchronic

ORAL RfDs:

0.02 mg/kg/day (cyanide, free)
0.04 mg/kg/day (sodium cyanide)
0.04 mg/kg/day (calcium cyanide)
0.04 mg/kg/day (cyanogen)
0.05 mg/kg/day (potassium cyanide)
0.05 mg/kg/day (chlorine cyanide)
0.05 mg/kg/day (zinc cyanide)
0.1 mg/kg/day (silver cyanide)
0.2 mg/kg/day (potassium silver cyanide)
(EPA, 1991a)
UNCERTAINTY FACTOR: 100
MODIFYING FACTOR: 5

PRINCIPAL STUDY: Howard and Hanzal, 1955; derivation reported in EPA, 1990a-e; 1991b-e).
COMMENT: The same study and comments apply to the subchronic and chronic RfD. The study is described in Subsect. 3.1.3.2.
3.1.5.2 Chronic

ORAL RfDs:

0.02 mg/kg/day (cyanide, free)
0.04 mg/kg/day (sodium cyanide)
0.04 mg/kg/day (calcium cyanide)
0.04 mg/kg/day (cyanogen)
0.05 mg/kg/day (potassium cyanide)
0.05 mg/kg/day (chlorine cyanide)
0.05 mg/kg/day (zinc cyanide)
0.1 mg/kg/day (silver cyanide)
0.2 mg/kg/day (potassium silver cyanide)
(EPA, 1990a-e; 1991b-e)
NOAELs:
10.8 mg/kg/day (cyanide, free)
20.4 mg/kg/day (sodium cyanide)
19.1 mg/kg/day (calcium cyanide)
21.6 mg/kg/day (cyanogen)
27.0 mg/kg/day (potassium cyanide)
25.3 mg/kg/day (chlorine cyanide)
24.3 mg/kg/day (zinc cyanide)
55.7 mg/kg/day (silver cyanide)
82.7 mg/kg/day (potassium silver cyanide)
UNCERTAINTY FACTOR: 100
MODIFYING FACTOR: 5
CONFIDENCE:
Study Medium
Data Base Medium
RfD Medium
VERIFICATION DATES: 08/05/85 (all compounds)

PRINCIPAL STUDY: Howard and Hanzal, 1955; derivation reported in EPA, 1990a-e; 1991b-e)

COMMENTS: All RfD calculations are based on data from one study in which no effects were observed in rats fed hydrogen cyanide in the diet for 2 years at a level that provided females a dose of 10.8 mg/kg/day cyanide (NOAEL). The corresponding NOAEL for each cyanide compound was based on molecular weights. An uncertainty factor (UF) of 100 was used to account for species extrapolation (10) and sensitive populations (10). A modifying factor (MF) of 5 was used to account for the apparent tolerance to cyanide when it is ingested with food rather than when it is administered by gavage or in drinking water.

3.2 INHALATION EXPOSURES

3.2.1 Acute Toxicity

3.2.1.1 Human

Numerous cases of acute cyanide intoxication via inhalation have been cited in the literature. Of the different routes of exposure and different cyanide compounds, inhalation of hydrogen cyanide results in the most rapid onset of poisoning, producing almost immediate collapse, respiratory arrest, and death within minutes (EPA, 1985). Inhalation of 270 ppm is immediately fatal; exposure to 110-135 ppm is fatal after 1/2-1 hour or longer. The estimated LC50 after 10 minutes is 546 ppm (Hartung, 1982).

3.2.1.2 Animal

Inhalation of cyanide by animals also leads to rapid acute toxicity and death. Higgins et al. (1972) reported LC50s of 323 ppm for mice and 503 ppm for rats exposed to hydrogen cyanide for 5 minutes. The estimated LC50s for 30-min exposures to hydrogen cyanide are 142 ppm for rats (U.S. Air Force, 1989), 182 ppm for cats, and 410 ppm for goats (ten Berge et al., 1986). Dogs exposed to 1.1 or 1.6 mg/kg hydrogen cyanide died following a 10- to 15-min exposure (Gettler and Baine, 1938). Loss of consciousness, hyperventilation, bradycardia, arrhythmias, and T-wave abnormalities were observed in monkeys exposed to 87-196 ppm hydrogen cyanide for 30 minutes (Purser et al., 1984).

3.2.2 Subchronic Toxicity

3.2.2.1 Human

An individual who had been exposed sporadically to cyanide vapor for 6 years exhibited loss of appetite, nervousness, vertigo, headache, nausea, and vomiting (Wuthrich, 1954). Sandberg (1967) described symptoms of cyanide toxicity in a goldsmith apprentice who polished gold 5-10 times/day for 4 years and was exposed to cyanide by both inhalation and dermal contact. The polishing solution used was prepared by adding potassium cyanide to water, heating to boiling, and then adding hydrogen peroxide; this process liberated hydrogen cyanide gas and splattered the skin. Symptoms included headache, listlessness, numbness, and partial paralysis of the left arm and leg, partial loss of vision in the left eye, and an altered EKG. All symptoms disappeared within 4 months.


3.2.2.2 Animal

No effects on the myocardial ultrastructure were seen in rabbits exposed continuously to 0.55 mg/m3 hydrogen cyanide for 28 days (Hugod, 1981).

3.2.3 Chronic Toxicity

3.2.3.1 Human

El Ghawabi et al. (1975) reported mild to moderate thyroid enlargement and increased uptake of iodine by the thyroid in 20/36 male electroplating workers exposed to an average of 6.4-10.4 ppm cyanide for 5-15 years. Other symptoms included breathing difficulties, headache, weakness, changes in smell and taste, giddiness, throat irritation, vomiting, and precordial pain. Also reported were significantly increased hemoglobin levels and lymphocyte counts. Nonexposed workers had much lower incidences of these symptoms. Hardy and Boylen (1983) reported dermatitis, itching, scarlet rash, papules, and severe irritation of the nose leading to obstruction, bleeding, and in some cases perforation of the septum in electroplaters chronically exposed to cyanide.

Carmelo (1955) examined a group of 17 cyanide fumigators, 13 of which had experienced acute symptoms of cyanide poisoning with loss of consciousness. The men had worked with cyanide for 1-27 years. A high incidence of nervous disorders, including vertigo, equilibrium disturbances, and nystagmus, was reported. Also noted were precordial pain, EKG abnormalities, and hypertrophic gastritis.

Exposure to cyanide in tobacco smoke has been associated with amblyopia, Leber’s hereditary optic atrophy, retrolobular neuritis, and optic nerve atrophy, disorders involving defective cyanide metabolism and vitamin B12 deficiency (EPA, 1984).
According to NIOSH (1976), chronic cyanide toxicity bears a striking similarity to thiocyanate intoxication, and it has been suggested that the symptoms ascribed to chronic cyanide poisoning may, in fact, be due to the toxicity of its metabolic product, thiocyanate. Heavy smoking and eating of cabbage-type vegetables can exacerbate the symptoms of cyanide exposure due to additional formation of thiocyanate.


3.2.3.2 Animal

Information on the chronic inhalation toxicity of cyanide in animals was unavailable.
3.2.4 Developmental and Reproductive Toxicity

3.2.4.1 Human

Pregnant women who smoke may increase the susceptibility of their infants to the toxic effects of cyanide. Smoking during pregnancy has been associated with a higher risk of giving birth to low body weight infants and of perinatal death (EPA, 1985).

3.2.4.2 Animals

Information on the developmental and reproductive inhalation toxicity of cyanide in animals was unavailable.

3.2.5 Reference Concentration/Dose

Data are presently insufficient to calculate an RfC.

3.3 OTHER ROUTES OF EXPOSURE

3.3.1 Acute Toxicity

3.3.1.1 Human

Rieders (1971) reported that fatalities occurred following dermal exposure to 5% aqueous hydrogen cyanide and 10% aqueous potassium cyanide.

3.3.1.2 Animals

Neurotoxic effects including convulsions and coma preceded death in guinea pigs dermally exposed to hydrogen cyanide (Walton and Witherspoon, 1926). LD50 values reported for rabbits, administered aqueous solutions of cyanides by instillation into the conjunctival sac of the eye, are 1.09 mg/kg, 7.87 mg/kg, and 5.05 mg/kg for hydrogen cyanide, potassium cyanide, and sodium cyanide, respectively. For all compounds, signs of toxicity and death occurred 3-12 minutes after the eyes were treated (Ballantyne, 1983).


3.3.2 Subchronic Toxicity

3.3.2.1 Human

In an early study, Collins and Martland (1908) reported permanent disability resulting from dermal exposure to cyanide in a hotel worker who polished silver for 2 years by dropping silver into a potassium cyanide solution and wiping it off without gloves. Symptoms included itching, diarrhea, headache, pain and stiffness in the back, weakness of arms and legs, urine retention, and dark discoloration of arms, legs, and nails. Eventually, clinical manifestations resembling acute anterior poliomyelitis developed.

3.3.2.2 Animal

Rats treated by subcutaneous injection with sodium cyanide at doses of 0.61, 1.31, or 1.72 mg/kg/day (as cyanide), 3 days/week for 3 months developed necrotic lesions of the corpus callosum and optic nerve. High mortality was observed at all dose levels (Lessell, 1971).


3.3.3 Chronic Toxicity

Information on the chronic toxicity of cyanide in humans and animals by other routes of exposure was unavailable.
3.3.4 Developmental and Reproductive Toxicity

3.3.4.1 Human

Information on the developmental and reproductive toxicity of cyanide in humans by other routes of exposure was unavailable.

3.3.4.2 Animal

Cyanide was administered to golden hamsters by continuous infusion at a rate of 0, 0.126, 0.1275, or 0.1295 mmol/kg/hr on gestational days 6 through 9 (Doherty et al., 1982). The total dose administered was equivalent to 30-40 times the subcutaneous LD50. A high incidence of malformations and resorptions was observed in all offspring of all treatment groups. Neural tube defects, the most common malformation, consisted of exencephaly and encephalocele. Also observed were hydropericardium, crooked tail, and decreased fetal crown to rump length. Administration of both cyanide and thiocyanate simultaneously protected against the toxic and teratogenic effects of sodium cyanide.


3.4 TARGET ORGANS/CRITICAL EFFECTS

3.4.1 Oral Exposures

3.4.1.1 Primary Target Organs

1. Central nervous system: In humans, chronic ingestion of cassava, a food rich in cyanogenic glycosides, caused various neuropathies and amblyopia. Chronic exposure of rats and subchronic exposure of dogs to cyanide produced degenerative changes of spinal cord and ganglion cells of the CNS, respectively. Although the CNS is a primary target organ, the toxic effects of cyanide are due to blockage of electron transport by cytochrome oxidase, thereby causing cytotoxic hypoxia in all tissues.


2. Thyroid: Thyroid abnormalities have been reported in humans chronically exposed to cyanogens in cassava. In rats, increased thyroid weights and decreased levels of plasma thyroxin, indicative of depressed thyroid function, were reported. Histopathologic thyroid changes have been observed in sows exposed to cyanide during gestation and lactation.

3. Reproduction and Development: Congenital hypothyroidism was reported in human newborns in areas were cassava is staple food. Offspring of hamsters fed diets containing cassava showed decreased fetal weight and ossification. Teratogenic effects (exencephaly, encephalocele, and rib abnormalities) occurred in hamsters fed diets containing amygdalin.


3.4.1.2 Other Target Organs

Kidney: Hyperplasia of kidney glomeruli was seen in sows exposed to cyanide during gestation and lactation.


3.4.2 Inhalation Exposures

3.4.2.1 Primary Target Organs

1. Central nervous system: Subchronic and chronic effects of cyanide in humans include vertigo, equilibrium disturbances, nystagmus, nervousness, headache, weakness, loss of appetite, and changes in smell and taste. Exposure to cyanide in tobacco smoke has been associated with effects on the optic nerve.

2. Cardiovascular and/or respiratory system: Precordial pain, EKG abnormalities, and breathing difficulties were recorded in humans occupationally exposed to cyanides. These effects may be related to CNS toxicity rather than direct effects.

3. Gastrointestinal tract: After exposure to cyanide, workers developed nausea, vomiting, and gastritis. However, these effects may also be related to CNS effects.

4. Thyroid: Enlarged thyroids were reported in electroplaters exposed to cyanides.


5. Reproduction and Development: Smoking during pregnancy has been associated with a higher risk of giving birth to low body weight infants and of perinatal death. However, other agents than cyanide present in tobacco smoke could be responsible for this effect.

3.4.2.2 Other Target Organs

Skin: Dermatitis, itching, scarlet rash, papules, and severe irritation of the nose have been reported in workers chronically exposed to cyanide


4. CARCINOGENICITY

4.1 ORAL EXPOSURES

Information on the carcinogenicity of cyanide in humans or animals for oral exposure was unavailable.


4.2 INHALATION EXPOSURES

Information on the carcinogenicity of cyanide in humans or animals for inhalation was unavailable.

4.3 OTHER ROUTES OF EXPOSURE

Information on the carcinogenicity of cyanide in humans or animals for other routes of exposure was unavailable.

4.4 EPA WEIGHT-OF-EVIDENCE

Classification D–Not classifiable as to human carcinogenicity (EPA, 1991b)

Basis–Pertinent data regarding the carcinogenicity of cyanide have not been located in the available literature.

4.5 CARCINOGENICITY SLOPE FACTORS

No carcinogenicity slope factors were calculated.


5. REFERENCES

Ansell, M. and F.A.S. Lewis. 1970. “A review of cyanide concentrations found in human organs–A survey of literature concerning metabolism, “normal,” nonfatal, and fatal body cyanide levels.” J. Forensic Med. 17: 148-155. (Cited in ATSDR, 1989).
ATSDR (Agency for Toxic Substances and Disease Registry). 1989. Toxicological Profile for Cyanide. ATSDR/TP-88/12; PB90-162058. Prepared by Syracuse Research Corporation for ATSDR, U.S. Public Health Service, under Contract No. 68-C8-0004.
Ballantyne, B. 1983. “Acute systemic toxicity of cyanides by topical application to the eye.” J. Toxicol. Cut. Ocular Toxicol. 2: 119-129. (Cited in ATSDR, 1989).
Budavari, S., M.J. O’Neil, and A. Smith (eds). 1989. The Merck Index. Merck & Co., Inc., Rahway, NJ, p. 4722.
Carmelo, S. 1955. “New contributions to the study of subacute-chronic hydrocyanic acid intoxication in men.” Rass. Med. Ind. 24: 254-271. (Cited in U.S. EPA, 1984)
Collins, J. and H.S. Martland. 1908. “Disease of the primary motor neurons causing the clinical picture of acute poliomyelitis: The result of poisoning by KCN–a clinical and experimental contribution to the toxic effects of KCN upon the peripheral motor neurons.” J. Nerv. Dis. 35: 417-426. (Cited in U.S. Air Force, 1989).
Doherty, P.A., V.H. Ferm, and R.P. Smith. 1982. “Congenital malformations induced by infusion of sodium cyanide in the golden hamster.” Toxicol. Appl. Pharmacol. 64: 456-464.
El Ghawabi, S.H., M.A. Goofar, A.A. El-Saharti, et al. 1975. “Chronic cyanide exposure: a clinical, radioisotope and laboratory study.” Br. J. Ind. Med. 32: 215-219. (Cited in EPA, 1985).
Ermans, A.M. 1980. “General Conclusions.” In: Role of Cassava in the Etiology of Endemic Goitre and Cretinism. A.M. Ermans, N.M. Mbulamoko, F. Delange and R. Ahlvertartia, eds. Report on International Development Research Centre, Ottawa, Canada; pp. 147-152. (Cited in ATSDR, 1989).
Frakes, R.A., R.P. Sharma, C.C. Willhite, et al. 1986. “Effect of cyanogenic glycosides and protein content in cassava diets on hamster prenatal development.” Fundam. Appl. Toxicol. 7: 191-198.
Gettler, A.O. and J.O. Baine. 1938. “The toxicology of cyanide.” Am. J. Med. Sci. 195: 182-198.
Hardy, H.L. and G.W. Boylen, Jr. 1983. “Cyanogen, hydrocyanic acid and cyanides.” In: Encyclopaedia of Occupational Health and Safety, 3rd ed, Vol. 1, L. Parmeggiani, ed. International Labour Office, Geneva, pp. 574-577.
Hartung, R. 1982. “Cyanides and nitriles.” In: Patty’s Industrial Hygiene and Toxicology, vol. 2C, G.D. Clayton and E. Clayton, eds. John Wiley & Sons, New York, NY, pp. 4845-4900.
Hertting, G.O., Kraupp, E. Schnetz, et al. 1960. “Untersuchungen ├╝ber die Folgen einer chronischen Verabreichung akut toxischer Dosen von Natrium Cyanid an Hunden.” Acta Pharmacol. Toxicol. 17: 27-43. (In German; cited in EPA, 1985).
Higgins, E.A., V. Fiorca, A.A. Thomas, et al. 1972. “Acute toxicity of brief exposures to HF, HCI, NO2, and HCN with and without CO.” Fire Technol. 8: 120-130. (Cited in ATSDR, 1989; NIOSH, 1976).
Howard, J.W. and R.F. Hanzal. 1955. “Chronic toxicity to rats of food treated with hydrogen cyanide.” J. Agric. Food Chem. 3: 325-329.
Hugod, C. 1981. “Myocardial morphology in rabbits exposed to various constituents of tobacco smoke–an ultrastructural study.” Atherosclerosis 4: 181-190. (Cited in EPA, 1984).
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.
Lessell, S. 1971. “Experimental cyanide optic neuropathy.” Arch. Ophthalmol. 86: 194-204. (Cited in ATSDR, 1989).
Leuschner, J., A. Winkler, and F. Leuschner. 1991. “Toxicokinetic aspects of chronic cyanide exposure in the rat.” Toxicology Lett. 57: 195-201.
Losek, J.D., A.L. Rock, and R.R. Boldt. 1991. “Cyanide poisoning from a cosmetic nail remover.” Pediatrics 88: 337-340.
NIOSH (National Institute for Occupational Safety and Health). 1976. Occupational Exposure to Hydrogen Cyanide and Cyanide Salts. U.S. Department of Education and Welfare, Public Health Service, Rockville, MD. Publ. No. 1-191.
Palmer, I.S. and O.E. Olson. 1979. “Partial prevention by cyanide of selenium poisoning in rats.” Biochem. Biophys. Res. Commun. 90: 1379-1386.
Philbrick, D.J., J.B. Hopkins, D.C. Hill, et al. 1979. “Effects of prolonged cyanide and thiocyanate feeding in rats.” J. Toxicol. Environ. Health 5: 579-592.
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. (Cited in ATSDR, 1989).
Rieders, F. 1971. “Noxious gases and vapors I. Carbon monoxide, cyanides, methemoglobin, and sulfhemoglobin.” In: Drills Pharmacology in Medicine, J.R. DiPalma, ed. McGraw Hill Book Co., New York, pp. 1198-1205
Sandberg, C.G. 1967. “A case of chronic poisoning with potassium cyanide.” Acta Med. Scand. 181: 233-236.
ten Berge, W.F., A. Zwart, and L.M. Appelman. 1986. “Concentration-time mortality response relationship of irritant and systemically acting vapour and gases.” J. Hazard. Mat. 13: 301-309.
Tewe, O.O. and J.H. Maner. 1981a. “Long-term and carry-over effect of dietary inorganic cyanide (KCN) in the life cycle performance and metabolism of rats.” Toxicol. Appl. Pharmacol. 58: 1-7.
Tewe, O.O. and J.H. Maner. 1981b. “Performance and pathophysiological changes in pregnant pigs fed cassava diets containing different levels of cyanide.” Res. Vet. Sci. 30: 147-151.
U.S. Air Force. 1989. “Cyanide.” In: The Installation Restoration Program Toxicology Guide, Vol. 4. Wright-Patterson Air Force Base, Ohio, pp. 56-1 to 56-38.
U.S. EPA. 1984. Health Effects Assessment for Cyanides. Prepared by the Environmental Criteria and Assessment Office, Cincinnati, OH for the Emergency and Remedial Response Office, Washington, DC. EPA/540/1-86-011.
U.S. EPA. 1985. Drinking Water Criteria Document for Cyanide (Final Draft). Prepared by the Environmental Criteria and Assessment Office for the Office of Drinking Water, Cincinnati, OH. ECAO-CIN-442, PB86-117793.
U.S. EPA. 1990a. Calcium cyanide. Integrated Risk Information System (IRIS). Environmental Criteria and Assessment Office, Office of Health and Environmental Assessment, Cincinnati, OH.
U.S. EPA. 1990b. Cyanogen. Integrated Risk Information System (IRIS). Environmental Criteria and Assessment Office, Office of Health and Environmental Assessment, Cincinnati, OH.
U.S. EPA. 1990c. Potassium cyanide. Integrated Risk Information System (IRIS). Environmental Criteria and Assessment Office, Office of Health and Environmental Assessment, Cincinnati, OH.
U.S. EPA. 1990d. Potassium silver cyanide. Integrated Risk Information System (IRIS). Environmental Criteria and Assessment Office, Office of Health and Environmental Assessment, Cincinnati, OH.
U.S. EPA. 1990e. Silver cyanide. Integrated Risk Information System (IRIS). Environmental Criteria and Assessment Office, Office of Health and Environmental Assessment, Cincinnati, OH.
U.S. EPA. 1991a. Health Effects Assessment Summary Tables. Annual FY-1991. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH, for the Office of Emergency and Remedial Response, Washington, DC. NTIS PB91-921199.
U.S. EPA. 1991b. Cyanide, free. Integrated Risk Information System (IRIS). Environmental Criteria and Assessment Office, Office of Health and Environmental Assessment, Cincinnati, OH.
U.S. EPA. 1991c. Chlorine cyanide. Integrated Risk Information System (IRIS). Environmental Criteria and Assessment Office, Office of Health and Environmental Assessment, Cincinnati, OH.
U.S. EPA. 1991d. Sodium cyanide. Integrated Risk Information System (IRIS). Environmental Criteria and Assessment Office, Office of Health and Environmental Assessment, Cincinnati, OH.
U.S. EPA. 1991e. Zinc cyanide. Integrated Risk Information System (IRIS). Environmental Criteria and Assessment Office, Office of Health and Environmental Assessment, Cincinnati, OH.
Verschueren, K. 1983. Handbook of Environmental Data on Organic Chemicals. Van Nostrand, New York, pp. 741-743.
Walton, D.C. and M.G. Witherspoon. 1926. “Skin absorption of certain gases.” J. Pharmacol. Exptl. The. 26: 315-324.
Westley, J. 1980. “Rhodanese and the sulfane pool.” In: Enzymatic Basis of Detoxication, Vol. II. Academic Press, New York, pp. 245-262.
Willhite, C.C. 1982. “Congenital malformations induced by laetrile.” Science 215: 1513.
Wolnik, K.A., F.L. Fricke, E. Bonnin, et al. 1984. “The Tylenol tampering incident–tracing the source.” Anal. Chem. 56: 466A-474A. (Cited in ATSDR, 1989).
Wuthrich, F. 1954. “Chronic cyanide poisoning as industrial intoxicant.” Schweiz. Med. Wochenschr. 84: 105-107. (In German; cited in U.S. Air Force, 1989).

Originally from the Risk Assessment Information System website (no longer online) – http://risk.lsd.ornl.gov/tox/profiles/cyanide_f_V1.shtml

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