EPA/600/8-90/002F
May 1990
Summary Review of Health Effects
Associated with Hydrogen Cyanide
Health Issue Assessment
Environmental Criteria and Assessment Office
Office of Health and Environmental Assessment
Office of Research and Development
U. S. Environmental Protection Agency
Research Triangle Park, NC 27711
-------
Disclaimer
This document has been reviewed in accordance with U.S. Environmental
Protection Agency policy and approved for publication. Mention of trade
names or commercial products does not constitute endorsement or
recommendation for use.
-------
Contents
Tables
Figures ' iv
Preface '.'.'.'.'.'.'. iv
Authors and Contributors v
vi
1- Summary and Conclusions
2. Introduction
2.1 Historical Background J?
2.2 Physical and Chemical Properties ]V
2.3 Analysis '
2.4 Manufacture and Use }^
2.5 Disposal of Cyanide Waste ]~
2.6 Recommended Exposure Limits .'.'.'.'.' '.'.'.'. '. .'.'.".'.'.' " ]Q
3. Air Quality and Environmental Fate 1Q
3.1 Sources ' ia
3.2 Environmental Fate . . 1?
3.3 Ambient Levels ,?
4. Pharmacokinetics and Toxicokinetics 23
5. Mutagenicity and Carcinogenicity
5.1 Mutagenicity ll
5.2 Carcinogenicity 07
6. Developmental and Reproductive Toxicity 29
7. Other Toxic Effects
7.1 Acute and Subacute Toxicity ^
7.1.1 Humans ... ^
7.1.2 Animals *?
7.2 Subchronic and Chronic f oxicity ™
7.2.1 Humans ... ff
7.2.2 Animals '. i?°
7.3 Toxicant Interactions ... ,o
oo
8. References ..
41
HI
-------
Tables
1
2
3
4
5
6
7
Physical and Chemical Properties of Hydrogen Cyanide 5
Methods of Determining Cyanide 14
Fetotoxic and Teratogenic Effects of NaCN in Hamsters 30
Reported (Estimated) Human Responses to Various
Concentrations of HCN Vapors • 34
Sensitivity of Various Species to Inhalation Exposures of HCN 36
Acute Experimental Exposure to HCN 37
Effects of Chronic Exposure of Laboratory Animals to Cyanide 39
Figures
1 Fate of cyanide in the body 24
IV
-------
Preface
The Office of Health and Environmental Assessment has prepared this
health assessment to serve as. a source document for EPA use. The health
assessment was developed for use by the Office of Air Quality Planning and
Standards to support decision making regarding possible regulation of
Hydrocyanic Acid as a hazardous air pollutant.
In the development of the assessment document, the scientific literature
has been inventoried, key studies have been evaluated, and
summary/conclusions have been prepared so that the chemical's toxicity and
related characteristics are qualitatively identified. Observed effect levels and
other measures of dose-response relationships are discussed, where
appropriate, so that the nature of the adverse health responses is placed in
perspective with observed environmental levels.
The relevant literature for this document has been reviewed through
December 1989.
Any information regarding sources, emissions, ambient air concentrations,
and public exposure has been included only to give the reader a preliminary
indication of the potential presence of this substance in the ambient air. While
the available information is presented as accurately as possible, it is
acknowledged to be limited and dependent in many instances on assumption
rather than specific data. This information is not intended, nor should it be
used, to support any conclusions regarding risks to public health.
If a review of the health information indicates that the Agency should
consider regulatory action for this substance, a considerable effort will be
undertaken to obtain appropriate information regarding sources, emissions,
and ambient air concentrations. Such data will provide additional information
for drawing regulatory conclusions regarding the extent and significance of
public exposure to this substance.
-------
Authors and Contributors
The author of this Health Effects Summary is Bimal C. Pal, Ph.D., from the
Office of Information .Research and Analysis, Oak Ridge National Laboratory.
The U.S. EPA project officer on this document was Harriet M. Ammann,
Ph.D., MD-52, ECAO, U.S. EPA, Research Triangle Park, N.C. 27711 (919)
541-4930, (FTS) 629-4930.
VI
-------
1. Summary and Conclusions
Hydrogen cyanide (HCN, CAS No. 74-90-8) is ubiquitous in the
environment, arising from both natural and anthropogenic sources. It has been
found to be present in the stratosphere and the northern hemisphere's
nonurban troposphere at the 150 to 170 ppt (parts per trillion) (0.165 to 0.187
ng/m3) level. The relative contribution of natural and anthropogenic sources to
the atmospheric burden of HCN is not known.
Cyanide is a normal constituent of human blood, usually present at
concentrations below 12 nM. Apart from the ambient level of HCN in the
atmosphere (166 ppt; 0.183 }ig/m3), additional human exposure by inhalation
may take place as follows: (1) from cigarette smoke, reported to contain 160 to
550 wg of HCN/cigarette; (2) from the combustion of N-containing natural and
synthetic polymers such as silk, wool, nylon, polyurethane, urea-
formaldehyde; (3) from auto emissions; and (4) from industrial sources such as
plants producing HCN, industrial processes using cyanide, and production of
coke-oven gas which contains a large amount of HCN, if the emission control
systems are inadequate. The annual U.S. consumption of HCN in 1983 was
947 mp (million pounds), indicating an emissions potential at manufacturing
and use sites. The major end use of HCN in the United States in 1983 was in
the production of adiponitrile (461 mp) and acetone cyanhydrin (282 mp).
The principal sinks of HCN in the atmosphere are attack by UV photons in
the stratosphere and complicated and unresolved reactions with atmospheric
OH and O(1D). Precipitation in rain appears to be a negligible sink for atmos-
pheric HCN since the equilibrium concentration of HCN in water is very low at
low partial pressures. Its atmospheric residence time has been calculated to
be 2.5 years. Volatility plays an important role in determining the environ-
mental fate of HCN present in water. Hydrogen cyanide (pKa 9.2) exists
mostly in undissociated form in natural waters (pH <7) and escapes easily
into air due to its high vapor pressure (>800 mm Hg at 27°C). Hydrogen
cyanide may be hydrolyzed under both acidic and alkaline conditions to
ammonia and formic acid. It can also be biodegraded by both plants and
bacteria. Both aerobic and anaerobic microbial degradation of cyanide during
sewage treatment have been demonstrated. The disposal of wastes
containing cyanide is still a problem with the chemical industries.
Both nonoccupational and occupational exposure to hydrogen cyanide
mainly takes place by inhalation or through dermal absorption. Ingestion is of
secondary importance in industrial accidental poisonings. With inhalation
exposure, the liver, which is the major detoxification site of HCN, is bypassed
causing severe symptoms of HCN-poisoning. All animals including humans
have a limited capacity to detoxify cyanide. The major detoxification route is
the enzyme rhodanese-mediated conversion of cyanide to thiocyanate in the
presence of sulfur donors such as thiosulfate. Rhodanese is widely present in
different body tissues and the availability of thiosulfate or any other suitable
-------
sulfur donor is the limiting factor in the detoxification process. Thiocyanate is
excreted in urine.
Cyanide exerts its acute effects through the inhibition of cellular
respiration by inactivation of tissue cytochrome oxidase, producing a state of
histotoxic anoxia. Cyanide combines with Fe3 + /Fe2+ contained in the
cytochrome oxidase. It can also inhibit several other metallo-enzymes
containing, for the most part, iron, copper, or molybdenum (e.g., alkaline
phosphatase, carbonic anhydrase) as well as enzymes containing Schiff base
intermediates. Hydroxycobalamine (vitamin B12) has the ability to restore the
activity of cytochrome oxidase by removing cyanide through the formation of
cyanocobalamine.
Two negative and one marginally positive bacterial mutagenicity studies
are reported in the literature; there are no cancer bioassay data available.
Hydrogen cyanide is considered to be a Group D compound (not classifiable
as to human carcinogenicity) by the U.S. EPA.
The developmental and reproductive toxicity of HCN per se has not been
reported in the literature. A study using substantially high doses of NaCN did,
however, demonstrate fetotoxic and teratogenic effects in hamsters.
Physiological responses of various animals and humans exposed to
varying concentration of HCN vapor have been reported. Relative sensitivity of
various animals to HCN vapor has been found to be: dog > mouse, cat, rabbit
> rat, monkeys. Goats and monkeys can indefinitely tolerate 240 mg/m3 (218
ppm) and 180 mg/m3 (164 ppm) of HCN in air, respectively. The warning
symptoms of cyanide poisoning in humans are: dizziness, numbness,
headache, rapid pulse, nausea, reddened skin, and blood-shot eyes. These
may be followed by vomiting, dyspnea, loss of consciousness, cessation of
breathing, rapid weak heart beat, and death. Cyanide lethality is known to
occur without any apparent inhibition of liver cytochrome oxidase activity. The
inhibition of cytochrome oxidase in the brain has been implicated as the cause
of death.
The intravenous LD50s for HCN in mg/kg are 1.34, 0.81, 1.30, 0.66, 1.43,
0.81, 0.99, and 1.1 (estimated) for dog, cat, monkey, rabbit, guinea pig, rat,
mouse, and man, respectively. The LCt50s (mg/m3min) for humans have been
estimated at various exposure times: 2,032 (0.5 min), 3,404 (1 min), 4,400 (3
min), 6,072 (10 min), 20,632 (30 min). The IDLH (immediately dangerous to
life and health) level has been recommended at 60 mg/m3 by the National
Institute for Occupational Safety and Health (NIOSH). The inhalation exposure
limit to HCN has been set at 11 mg/m3 by the Occupational Safety and Health
Administration (OSHA) and carries a skin notation.
No information is available on chronic nonoccupational exposure of HCN
to humans. However, epidemiological studies, conducted in Nigeria where a
significant number of people ingest cyanide by eating cassava roots (contains
cyanogenic glycoside linamarin), have implicated the chronic effects of
cyanide in specific diseases, mostly neuropathological in nature - Nigerian
nutritional neuropathy, Leber's optical atrophy, retrobulbar neuritis, pernicious
anemia, tobacco amblyopia, cretinism, and ataxic neuropathy. Some of the
diseases such as tobacco amblyopia can be effectively treated with
-------
hydroxycobalamine (vitamin B12) which can react with cyanide to form
cyanocobalamine. This reinforces the correlation between cyanide ingestion
and the disease state. Poor nutritional status, particularly lack of vitamin B12
and sulfur-containing amino acids in the diet, potentiate the chronic effects of
cyanide by slowing down the rate of natural detoxification in the body.
Thiocyanate, the major detoxification product of cyanide, prevents the uptake
of iodine and leads to the development of goiter and cretinism. The effect is
pronounced in the case of individuals unable to excrete thiocyanate in urine at
a sufficient rate due to kidney dysfunction.
Several cases of chronic occupational exposure to HCN have been
documented. Chronic HCN poisoning resulting in serious injury is rather rare.
Symptoms usually include headache, dizziness, confusion, muscular
weakness, poor vision, slurred speech, gastrointestinal disturbance, tremor,
body rash, and enlarged thyroid. The reversibility of the chronic effects of
cyanide is still an open question.
Only one animal study on the chronic exposure of HCN has been
published (104-week dietary exposure to rats). No effect was observable at the
administered dose level, 3.2 - 10.4 mg CN7kg/day.
Daily intake of HCN by inhalation for an adult male has been calculated to
be about 3.7 yg, assuming an ambient level of 166 ppt (0.183 ng/m3) of HCN
in air (Daily Inhalation Intake = 20 [m3 of air inhaled in 24 h] x (166 x 10-3) x
1.1 (Factor for converting ppm to mg/mS) [pg HCN/m3]). This intake level
appears to be of little environmental concern considering that an RfD for oral
exposure has been calculated as 1.5 mg/kg and the cyanide detoxifying
capacity of a normal adult male has been estimated to be 17 ng/kg/min.
However, monitoring data near point sources are needed to determine if
segments of the population may be exposed to potentially hazardous levels.
-------
y
-------
2. Introduction
The purpose of this review is to briefly summarize the available informa-
tion concerning the potential health effects associated with exposure to hydro-
gen cyanide (CAS No. 74-90-8). Available data on pharmacokinetics, acute
and chronic toxicity, teratogenicity, mutagenicity, and carcinogenicity are
covered in this report. Physical and chemical properties and air quality data
including sources, distribution, fate, and ambient concentrations in the United
States, are also included to allow a preliminary evaluation of the effects of
hydrogen cyanide (HCN) on human health under conditions commonly
encountered by the general public.
In recent years, several related documents have been published by the
U.S. Environmental Protection Agency: Drinking Water Criteria Document for
Cyanides (U.S. Environmental Protection Agency, 1985a), Health Effects
Assessment for Cyanide (U.S. Environmental Protection Agency, 1984) The
Determination of a Range of Concern for Mobile Source Emissions of Hydro-
gen Cyanide (DeMeyer, 1981), Hydrogen Cyanide Health Effects (Carson et
al., 1981), Ambient Water Quality Criteria for Cyanides (U.S. Environmental
Protection Agency, 1980, 1985b), Water-related Environmental Fate of 129
Priority Pollutants (Callahan et al., 1979), Review of the Environmental Effects
of Pollutants: V. Cyanide (Towill et al., 1978), and Toxicity to Fish of Cyanides
and Related Compounds - A Review, (Doudoroff, 1976). Since the earlier
literature on hydrogen cyanide has been reviewed in these documents, this
report concentrates on the more recent literature. We have also extensively
utilized the earlier literature identified in these EPA documents.
Multimedia data have been included, although this report is primarily
concerned with atmospheric HCN. This is particularly relevant since HCN is
capable of existing in air, water, and soil in a bound form. Due to its high pK
it exists in natural waters mostly in undissociated form and can easily escape
from water into air due to its high volatility (see Table 1).
Table 1. Physical and Chemical Properties of Hydrogen Cyanide
Parameter Data Reference
CAS Registry Number
RTECS Number
Hazardous Substances
Data Bank Number
Chemical Name
74-90-8
NIOSH/MW 6825000
165
Hydrogen Cyanide
TOXNET, 1986
TOXNET, 1986
TOXNET, 1986
(continued)
-------
Table 1. (Continued)
Parameter
Data
Reference
Synonyms
Molecular Formula
Structural Formula
Carbon Hydride
Nitride
Cyclon
Cyclon B
Evercyn
Formic Anammonide
Formonitrile
HCN
Hydrocyanic Acid
Prussic Acid
Zaclondiscoids
CHN
H-C = N (All efforts to
isolate isometric HCN
have failed)
Polymeric forms of
HCN have been
reported: the dimer,
trimer and tetramer
are depicted below.
HN
CN
Dimer
TOXNET, 1986
TOXNET, 1986
Hollidayetal.,1973
ORNL-DWG 87-13402
CN
HC CH
x/
Trimef
(Bellstein, 1960)
NH
NC
NH,
CN
Molecular Weight 27.03
Melting Point -13.24°C
Boiling Point 25.70 °C
Triple Point (Three Phase -13.32°C
Equilibrium)
Tetramer
(Ballar et al., 1973)
Jenks, 1979
Jenks, 1979
Jenks, 1979
Jenks, 1979
(continued)
-------
Table 1. (Continued)
Parameter
Data
Reference
Density, d4l, Liquid, g/mL
0°C
10°C
20°C
Physical State
Solubility
Odor
0.7150
0.7017
0.6884
Colorless gas or liquid.
Miscible in water,
ethanol, and ether.
Slightly soluble in ether.
In contrast with the data
above, equilibrium
concentration of HCN in
water is very low at low
partial pressures.
KH = P/X, where KH is
Henry's constant, P is
the partial pressure (torr)
of HCN and X is the
mole fraction of HCN in
water. When KH=4000
at 18°C and 7.6 mm
Hg, X is only 0.0019
mole fraction in water.
Odor of bitter almonds.
Most people can detect
HCN by odor or
sensation at 5 ppm
concentration in air, but
a very few people
cannot smell it even at
toxic levels.
Detection by odor can
be made more sensitive
if the person smokes
since a trace of HCN
imparts a highly
characteristic flavor to
tobacco smoke.
Jenks, 1979
Windholz, 1983
Sax, 1984
Windholz, 1983
Cicerone and
Zellner, 1983
Sax, 1984
Jenks, 1979
Fieser and
Fieser, 1967
Specific gravity, aqueous
solution, d1818
10.04% HCN
20.29% HCN
60.23% HCN
Vapor Pessure, mm Hg
-29.5 °C
0°C
9.8°C
27.2°C
0.9838
0.9578
0.829
50.23
264.3
400
807
Jenks, 1979
Jenks, 1979
Jenks, 1979
Jenks, 1979
Jenks, 1979
Sax, 1984
Jenks, 1979
(continued)
-------
Table 1. (Continued)
Parameter
Data
Reference
Vapor density, at 31 °C
(air=l)
Surface Tension at 20°C,
mN/m ( = dyn/cm)
Viscosity at 20.2°C, mPa.s
Specific heat, J/mol
-33.1 °C, Liquid
16.9°C, Liquid
27°C, Gas
Heat of Fusion at -14°C,
kJ/mol
Heat of Formation, kJ/mol
Gas
Liquid at 18°C, 100
kPa
Heat of Combustion, kJ/mol
Critical Temperature, °C
Critical Density, g/mL
Critical Pressure MPa
Dielectric Constant
0°C
20°C
Dipole moment, gas, C-
m,at3-l5°C
Conductivity, S/cm
Heat of Vaporization kJ/mol
Heat of Polymerization,
kJ/mol
Entropy, gas at 27°C, 100
kPa, J/(mol.°C)
Flash Point, Closed Cup,
°C
Explosive limits at 1 00 kPa
and 20°C
Autoignition Temperature,
°C
Light Sensitivity
Refractive Index, n10D
Enthalpy, kJ/mol
0.947
19.68
0.2014
58.36
70.88
36.03
7.1 x 103
-128.6
-10.1
667
183.5
0.195
5.4
158.1
114.9
7.0 x 10-3
3.3X10-6
25.2
42.7
202.0
-17.8
6-41 vol% in air
538
Not sensitive to light
1.2675
140
Jenks, 1979
Jenks, 1979
Jenks, 1979
Jenks, 1979
Jenks, 1979
Jenks, 1979
Jenks, 1979
Jenks, 1979
Jenks, 1979
Jenks, 1979
Jenks, 1979
Jenks, 1979
Jenks, 1979
Jenks, 1979
Jenks, 1979
Jenks, 1979
Jenks, 1979
Jenks, 1979
Jenks, 1979
Jenks, 1979
Jenks, 1979
Jenks, 1979
Jenks, 1979
Jenks, 1979
Jenks, 1979
Jenks, 1979
(continued)
-------
Table 1. (Continued)
Parameter
Dissociation Constant (pKa)
Data
9.63 ± 0.01 at 10°C
9.49 ± 0.01 at20°C
.21 ± 0.01 at25°C
9.11 ± 0.01 at30°C
8.99 ± 0.01 at 35 °C
8.88 ± 0.02 at 40 °C
8.78 ± 0.02 at 45 °C
Reference
Izatteta!., 1962
Izattetal., 1962
Izattetal., 1962
Izattetal., 1962
Izattetal., 1962
Izattetal., 1962
Izattetal., 1962
The percentages of
undissociated HCN in
aqueous solution at
different pHs
Log Po/w (Partition
Coefficient, octanol/water)
Bioconcentration Factor
(BCF) (Using the equation
of Veithetal. 1979 incase
of whole fish: log BCF =
0.76 log P)
The data above are in error
in U.S. EPA, 1985a; the
corrected data in U.S. EPA
I985bread:
Bioconcentration Factor
(BCF) (Using the equation
of Veith et al., 1979 in case
of whole fish: log BCF =
0.85 log P-0.70)
When data are reported in
the original literature in
terms of HCN, rather than
in terms of free cyanide,
the data are converted from
molecular HCN to free
cyanide as CN as follows
Ed
<7
8
9
10
0.66
% undissociated HCN
>99
93.3
58
13
(Average of values)
1.9
Callahanetal.,1979
Leoetal., 1971
U.S. EPA, 1985a
0.72
U.S. EPA, 1985b
(yg of free cyanide as CN7L. = (jig of HCN/L) (1 + TOpH-pK)
x mol wt. CN'
mol wt. HCN
This equation appears to be
in error. It should be
corrected to read
(continued)
-------
Table 1. (Continued)
of free cyanide as CNVL = (ng of HCN/L) lOpH-pK/(l + lOpH-pK)
mol wt. CN'
Jenks, 1 979
Jenks, 1979
mol wt. HCN
Specifications for HCN ( > 99.5%), H2O ( < 0.5%),
commercial grade of HCN cyanogen, acrylonitrile, acetonitnle,
propionitrile traces, acidity (0.06
0.10%)
Color not darker than APHA 20.
Stabilizer A combination of H2SO4 (H3PO4)
and SO2 acts as a stabilizer to
prevent polymerization: H2SO4
stabilizes the liquid phase and SO2
stabilizes the vapor phase.
2.1 Historical Background
The following tabulation of landmarks in the history of the chemistry and
toxicology of HCN is intended to provide a proper perspective on this
compound (Sykes, 1981). It is important to note that most of the major
advances in our knowledge of HCN took place in the last century.
Cyanogenic glycoside extract from bitter almonds was used as a
poison by Wepfer.
Maddern established the poisonous characteristic of cherry laurel
water (contains cyanogenic glycosides) used as a flavoring agent in
cooking and to dilute brandy.
1679
«
1731
1786
1787
1802
1815
1817
1830
1837
HCN was first prepared by Scheele, the Swedish chemist.
Berthellot established the proximate composition of HCN.
Schrader first showed that HCN can be obtained from a natural
source namely bitter almonds; demonstrated that HCN was the toxic
ingredient in bitter almonds.
Gay-Lussac achieve^ the preparation of HCN in a semi-pure form and
called it hydrocyanic acid.
Megendie introduced the therapeutic use of HCN for treatment of dry
cough.
Robiquet and Charland isolated amygdalin from bitter almonds and
hydrolyzed it to form HCN. Riccordo-Mandiana isolated the cyano-
genic glycoside from cassava.
Wohler and Liebig demonstrated in plants, the presence of enzymatic
activity which liberates HCN from cyanogenic glycosides.
10
-------
1876
1891
1894
1909
Hoppe-Seyler established the mechanism of the action of HCN -
inhibition of tissue respiration.
Kobert showed that the oxidized form of hemoglobin, methemoglobin,
has a great affinity for HCN. Sodium or amyl nitrite induce
methemoglobin formation and can be used as a possible antidote.
S. Lang demonstrated the formation of greater amounts of
thiocyanate in the body in presence of HCN, a conversion which is
promoted by thiosulfate. This is the basis of the body's natural ability
to detoxify HCN.
Antal discovered that cobalt has marked cyanide binding properties.
Hydroxycobalamine (vitamin B12) and cobalt edetate are still in use as
antidotes today.
Cyanide is no longer looked upon as an unusual poison but a
somewhat commonplace plant metabolite. Greshoff discovered so
many cyanogenic plants at Kew that he remarked "Indeed, in the
ordinary plane tree of the London streets there is so much
hydrocyanic acid present that the amount from every plane leaf would
kill a London sparrow."
Keilin showed that HCN combines with Fe3+ present in the tissue
enzyme, cytochrome oxidase.
K. Lang discovered the enzyme rhodanese which converts cyanide to
thiocyanate in the presence of a sulfur donor.
1948 Cyanide is removed from the British Pharmacopeia.
1981 Coffey et al. (1981) detected the presence of HCN in the atmosphere.
2.2 Physical and Chemical Properties
The physical and chemical properties of hydrogen cyanide are shown in
Table 1. Hydrogen cyanide is a very weak acid, with a pKa value of 9.22 at
25°C in aqueous solution. Callahan et al. (1979) have calculated the
percentage of undissociated HCN at different pHs (see Table 1). Since the pH
of most natural waters ranges from 6 to 9, HCN is expected to be present
mostly in undissociated form. The acid is also highly miscible in water. These
properties are partly responsible for the ready absorption of HCN through the
mucous membrane, cuts and abrasions, and the skin'(Jenks, 1979). Cases are
known when workers wearing gas masks developed toxic symptoms of HCN
poisoning apparently due to dermal exposure (U.S. Environmental Protection
Agency, 1985a).
Explosively violent hydrolysis may occur when an excess of a strong acid
(>2 percent H2SO4 in HCN) is added to confined HCN.
Hydrogen cyanide is a fire hazard and it can undergo oxidation to CO2
and N2 by oxidizing agents like CI2-NaOH (shown below), Ca or Na
1929
1933
11
-------
hypochlorite bleaching powder, etc. This reaction is the basis for treatment of
cyanide wastes (Towill et al., 1978).
2 NaCN + 5 CI2 + 12 NaOH -» N2 + 2 Na2CO3 + 10 NaCI + 6 H2O
Ozonation to cyanate is another reaction used in the disposal of cyanide
wastes (Jenks, 1979). Hydrogen cyanide can undergo electrolysis to form
CO2, NH3, and cyanate (Jenks, 1979). This process has also been used for
treatment of cyanide wastes.
Gas masks have been developed for use by workers at risk from exposure
to HCN in military installations and industry. Since physical absorption of HCN
onto activated carbon is rather weak, a granular form of activated carbon
impregnated with divalent copper, hexavalent chromium, and silver (ASC
whetlerite) is used. The mechanism of removal of HCN by whetlerite has been
elucidated by Alves and Clark (1986). Hydrogen cyanide is converted into
oxamide via cyanogen.
Although HCN is not normally corrosive, it is known to exert a corrosive
effect under two special conditions: (1) aqueous solution of HCN causes trans-
crystalline stress-cracking of carbon steels under stress even at room
temperature and in dilute solution; (2) aqueous solution of HCN containing
sulfuric acid as a stabilizer severely corrodes steel above 40°C and stainless
steel above 80 °C (Jenks, 1979).
Hydrogen cyanide can add across reactive carbon-carbon double bonds.
The most important industrial use of HCN is the reaction with butadiene to
form adiponitrile:
HCN + CH2 = CH-CH = CH2 -»NC(CH2)4CN
butadiene adiponitrile
Hydrogen cyanide can react with aldehydes and ketones forming
cyanohydrins; for example, it reacts with acetone forming acetone cyanohydrin
which on treatment with concentrated sulfuric acid is converted into
methacrylamide sulfate (Gerry et al., 1985).
Hydrogen cyanide can react with chlorine to form CNCI which can be con-
verted into cyanuric chloride, a starting material in the manufacture of triazine
herbicides such as atrazine, simazine, etc., dyestuffs, Pharmaceuticals, explo-
sives, and surfactants (Gerry et al., 1985).
Hydrogen cyanide is also used in the manufacture of NaCN which has a
number of industrial applications such as heat treatment of steel, extraction of
gold and silver from their ores, electroplating of copper, zinc, brass and other
metals, ore flotation, and production of a broad range of organic intermediates
for the dyestuff, pharmaceutical, and plastic industries (Gerry et al., 1985).
Metallurgical applications of cyanides depend on the ease of formation of
metal complexes as exemplified below (Towill et al., 1978).
8 NaCN + 4 Au + O2 + 2 H2O ^ 4 NaAu(CN)2 + 4 NaOH
12
-------
2.3 Analysis
Analysis of cyanides in environmental samples has been reviewed in
depth by Towill et al. (1978). Absorption spectrophotometry and volumetric
titrimetry are widely used because of their simplicity, reliability, and low cost.
In the former procedure, HCN solution is treated with chloramine-T followed
by an aqueous pyridine solution of bispyrazolone and 3-methylene-1-phenyl-
5-pyrazolone, leading to the formation of a blue dye which is measured
spectrophotometrically. In the titrimetric procedure, silver nitrate in conjunction
with p-dimethylaminobenzalrhodanine as the indicator, is used. Ion-selective
electrodes have been used for direct and sensitive measurements of cyanide
in selected samples. Two electrochemical methods of detecting HCN vapor in
the battlefield have been developed by the Chemical Defense Establishment
in the UK (Powell, 1988). Indirect atomic absorption spectrophotometry has
been used for analysis of samples containing cyanide in the parts per million
range. A less commonly used fluorometric measurement of cyanide at the ppb
level is based on the UV-induced fluorescence of fluorescein formed from its
nonfluorescent leucobase precursor on oxidation in the presence of Cu2+ and
CN'. Cyanide in biological samples such as blood, urine, etc. has been
separated by microdiffusion and treated with chloramine-T. The resulting CNCI
has been extracted with hexane and measured by gas chromatography using
an electron capture detector. Various aspects of these different methods of
analysis for cyanides such as applications, sensitivity, precision, interfering
substances, and selectivity are shown in Table 2. Nonomura (1988) reported a
detailed study on the endogenous formation of hydrogen cyanide during
distillation, a widely used sample pretreatment for the assay of cyanide in
industrial waste water. For example, using the testing method for industrial
waste water of the Japanese Industrial Standard, Nonomura reported the
endogenous formation of 16.2, 11.1, 88.6, 141.0, 100.0, 55.2, 17.5, 12.2, 141.0
and 130 nmol/mmol of malic acid, L-aspartic acid, nitrioltriacetic acid, ethylene
diaminetetracetic acid, cyclohexane-diaminetetra acetic acid, sodium gluco-
nate, acrolein, benzene, hydroxyl ammonium hydrochloride, and hyroxylamine
sulfate, respectively. A number of interfering agents such as oxidizing agents
sulfide, fatty acids, carbonate, aldehydes, glucose and other sugars, and
others, which act during the sample pretreatment, have been discussed in
APHA (1985) and U.S. EPA (1982).
The latest entry in this field is the method based on high-resolution (0.06
cm-1 full width at half-maximum, apodized) Fourier-transform infrared
spectroscopy (FTIR). It was first used for detection and measurement of stra-
tospheric HCN by Coffey et al. (1981). The method has also been used by
Rmsland et al. (1982) for detection and measurement of atmospheric cyanide
at a higher resolution (-0.01 cm-1). A preliminary investigation on the appli-
cability of FTIR to routine qualitative and quantitative analysis of Table 2
semiconductor process gas emissions including HCN, has been published
(Herget and Levine, 1986). The minimum detectable concentration was found
to be 20 ppb in the range of 3200-3400 cnV for HCN in the presence of
common mterferents such as H2O, CO2, CO, etc., when the instrument was
operated at a resolution of 0.5 to 1.0 cm-1.
2.4 Manufacture and Use
Hydrogen cyanide is manufactured primarily by the Andrussow process
(shown below) which is based on the reaction of ammonia, air, and methane in
13
-------
Table 2. Methods of Determining Cyanide
Precision
(Relative
Limit of Standard
Accuracy
(Relative Interfering
r\t laiy u\scii IMIJ^WI «*• n. •— >••••» — •
Method Application Detection
Absorption Natural and 0.5 ug in
spectra- treated al5-ml
photom- waters, trade solution3
etry and 1 to 5
industrial ug/Lb
effluents, 0.02 mg/L
biologic
materials
Volumetric Natural and 0.1 mg/Ld
titrimetry treated
waters and
trade and
industrial
effluents
where
concen-
trations
exceed 1
mg/L
cyanide
Ion- Natural and 25 iig/Ld
selective treated
electrodes waters,
industrial
wastewaters
Indirect Industrial 60 ppbe
atomic effluents (iron
absorption polluted complex)
spectra- wastewaters 30 ppbe
photom- (silver
etry cyanide)
Fluorom- Natural and 1 ppb'
etry treated
waters,
processed
industrial
effluents,
biologic
materials
Deviation) Error)
8.3% 2% to 7%
(0.06 (1.5
mg/L)<= ug/L)b
15.1% 2% to
(0.62 15%
mg/L)c (0.28 to
1 .2% (40 0.62
yg/L»> mg/L)<=
2% (>1
mg/L
cyanide)
0% to 5% 0% to 5%
(0.2 ppm (0.2 ppm
cyanide)d cyanide)d
2.2%
(3ppm)e
1.5%
(2ppm)e
11% (2.6
ppb)'
a American Public Health Association et al., 1971.
b Gouldenetal., 1972.
Substances Selectivity
Sulfides, Substances
thiocyanates, yielding
and fatty cyanide
acids inter- when di-
fere but are gested with
removed by sulfuric
the sample acid will be
preparation determined.
procedure
These are All
believed to cyanide-
be removed yielding
in the substances
sample will be
preparation determined.
• step.
Strongly All sub-
complexing stances
cations, which yield
sulfide cyanide
ions will be
determined.
None Both
reported techniques
have good
specificity
for cyanide.
Sulfide, Only
persulfate cyanide ion
ferricyanide, is de-
mercury (II), termined.
and iron (II)
interfere.
(continued)
= U.S. Environmental Protection Agency, 1 974.
d Frantetal., 1971.
e Danchik and Boltz, 1970.
1 Ryan and Holzbecher, 1971.
a Sass et al., 1 971 .
h Valentouretal., 1974.
14
-------
Table 2. (Continued)
Precision
(Relative
Analytical Important Limit of Standard
Method Application Detection Deviation)
Gas Natural and 0.2 • 2.5% (10
Chroma- treated ng/mL9 ng/mL)h
tography waters, 25 ng/mLh
industrial
effluents,
biologic
fluids and
solids
a American Public Health Association et al., 1971
b Goulden etal., 1972.
c U.S. Environmental Protection Agency, 1974.
d Frant etal., 1971.
e Danchik and Boltz, 1970.
' Ryan and Holzbecher, 1 971 .
3 Sassetal., 1971.
h Valentour et al., 1 974.
Accuracy
(Relative Interfering
Error) Substances
2% (7 When
ng/mL)9 treated with
chioramine-
T, thio-
cyanate
yields a
peak coin-
cidental with
cyanogen
chloride
which is
about 2% or
of that from
an equal
concentra-
tion of
cyanide.
Selectivity
Cyanide is
determined.
Source: Adapted from Towill et al. (1978).
the presence of a catalyst at high temperature (Jenks, 1979; Gerry et al.
1985).
2 NH3 + 2 CH4 + 3 O2
Pt-Rh (9:1)
1200°C *
2 HCN -*• 6 H2O + 115.2 Kcal/mole
The annual capacity of the U.S. Producers of HCN is 1,056 mp (million
pounds) (Direct production) as of January 1, 1985 (Gerry et al., 1985). The
annual U.S. consumption of HCN in 1983 was 947 mp. The major end use of
HCN in the U.S. in 1983 was in the production of adiponitrile (461 mp) and
acetone cyanhydrin (282 mp), followed by cyanuric chloride (63 mp), sodium
cyanide (44 mp), chelating agents (35 mp), nitrilotriacetic acid and salts (20
mp), and other uses (44 mp).
The major industrial uses of cyanides are in electroplating, photography,
extraction of precious metals, case hardening of steels, and fumigation
(Howard and Hanzal 1955). The potential exists for worker exposure to
cyanide in all these industries. A chronic cyanide exposure in the
electroplating industry in India has been investigated (Chandra et al., 1980).
15
-------
Hydrogen cyanide has probably accounted for more human fatalities than
any other known chemical because of its application in legal executions and
as a genocidal agent during World War II (Way, 1981). Although neither side
engaged in chemical warfare during World War II, both sides stockpiled HCN
in quantities from 500,000 to over 1,000,000 pounds. .Cyanide was recently
used for more than 900 religious "suicide-murders" in Guyana (Klaassen,
1980).
Hydrogen cyanide has been used as a fumigant on ships and for food
(Way, 1981). Residues of HCN from fumigation may persist for a long time in
food. The tolerances prescribed for HCN residues in food in the U.S. vary from
25 ppm in beans to 250 ppm in spices.
2.5 Disposal of Cyanide Waste
Alkaline chlorination is widely used for the treatment of wastes containing
cyanides This process converts cyanide to relatively innocuous cyanate. (see
Section 2.2, U.S. EPA 1988c). However the disposal of cyanide is still a
problem in industries. Cyanides including hydrogen cyanide, are designated
as hazardous substances under CERCLA. They have a importable quantity
limit of 4.54 kg. Reportable quantities have also been issued for RCRA
hazardous waste of chemicals in the waste stream (U.S. EPA, 1988b).
2.6 Recommended Exposure Limits
Exposure limits to HCN have been set at 11 mg/m3 (10 ppm) (Code of
Federal Regulations, 1985), and an IDLH (immediately dangerous to life and
health) level has been recommended to be 60 mg/m3 (54.5 ppm) (National
Institute of Occupational Safety and Health, 1985). Recently, the permissible
exposure limit (PEL) has been lowered to 4.7 ppm STEL (short-term exposure
limit) skin (OSHA, 1989). A change in exposure limit to 5 mg/m3 (4.5 ppm)
(with a 10-minute ceiling) has been recommended by the NIOSH based on the
following considerations: (1) absence of any literature demonstrating major
lesions resulting from occupational exposure to HCN at 10 ppm; (2) the
epidemiological study by El Ghawabi et al. (1975) showing an increase in the
subjective symptoms of headache, weakness, changes in taste and smell,
irritation of the throat, vomiting, dyspnea, lachrymation, abdominal colic,
precordial pain, and nervous instability among cyanide workers exposed for an
average of 7.5 years at concentrations ranging from 4.2 to 12.4 ppm (4.6 to
13.6 mg/m3) (National Institute of Occupational Safety and Health, 1976).
Federal and state exposure limits to hydrogen qyanide in ambient air are as
follows (Brown, 1987):
Federal - no standards
Connecticut - 0.22 mg/m3 (8-hr)
Nevada - 0.238 mg/m3 (8-hr)
New Hampshire (proposed guideline) - 33 mg/m3
New York - 0.033 mg/mS (1-yr)
Virginia - 0.080 mg/m3 (24-yr)
North Carolina (proposed) - 0.120 mg/m3 (24-hr)
- 1.000mg/m3(1-hr)
South Carolina (policy) - 0.250 mg/m3 (24-hr)
(Category I, Low Toxicity")
16
-------
Although ingestion is considered of less importance than inhalation for
HCN exposure, an oral RfD (Reference Dose) of 1.5 mg/day for a 70 kg man
has been derived on the basis of a NOAEL (no observable adverse effect
level) of 10.8 mg/kg/day based on the data of Howard and Hanzal (1955) (U.S.
Environmental Protection Agency, 1985a; U.S. EPA, 1986). An uncertainty
factor of 100 based upon the National Academy of Sciences/Office of Drinking
Water guidelines and an additional 5-fold uncertainty factor (to allow for the
possible problems associated with a dietary study to estimate a drinking water
criterion) were used in the computation. In this extrapolation from rat to
humans, body weight rather than body surface area has been used. The RfD
of cyanide from food has been set at 3.5 mg/day for a 70-kg adult male by the
Food and Agriculture Association/World Health Organization (Vettorazzi, 1977).
The cyanide in soybean meal or soybean products (0.1 to 1.5 mg/kg) in the
diet is the major source of dietary exposure to the general population in the
U.S. The daily intake of cyanide has been calculated to be 0.3 to 4.5
ng/person/day assuming a consumption of <3 g/person/day in the U.S. (U.S.
Environmental Protection Agency, 1985a).
The permitted cyanide level in drinking water under the U.S. Public Health
Service Standards of 1982 is <0.2 mg/L (U.S. Environmental Protection
Agency, 1980). The U.S. EPA is planning to regulate cyanide concentration in
drinking water. The health advisories are: for 10 kg child for one day: 200 ng/L;
10 day: 200 ng/L; longer-term: 200 ng/L. For 70-kg adult: longer-term: 800
pg/L; RfD: 22 ng/kg/day (RfD = Reference Dose); DWEL: 800 ng/L; lifetime:
200 pg/L. DWEL (Drinking Water Equivalent Level) represents a medium
specific (i.e., drinking water) lifetime exposure at which adverse,
noncarcinogenic health effects are not anticipated to occur. The DWEL
assumes 100% exposure for drinking water. The DWEL provides the
noncarcinogenic health effects basis for establishing a drinking water standard.
(U.S. EPA, 1988a). Over 2500 samples of potable water were analyzed for
cyanide and found to contain cyanide below this limit. The maximum cyanide
concentration found was 0.008 mg/L (U.S. Environmental Protection Agency
1985a).
Recently, the Health and Safety Commission of Great Britain has
introduced a new control limit for HCN effective January 31, 1987: 10 mg/m3,
10-minute time-weighted average (TWA). No recommendation has been made
for a long-term exposure limit (Anonymous, 1986).
"Those pollutants which cause readily reversible changes which disappear
after the exposure ends.
17
-------
-------
3. Air Quality and Environmental Fate
3.1 Sources
Hydrogen cyanide is ubiquitous in nature, arising from both natural and
anthropogenic sources. Its presence in the atmosphere was first detected by
Coffey et al. (1981) and confirmed by others (Rinsland et al.,1982; Carli et al.,
1982). Apart from this atmospherjc HCN, human exposure may take place as
discussed below.
An important source of human exposure is tobacco smoke which is
reported to contain 1,600 ppm of HCN (Surgeon General of the United States,
1964). The MS (mainstream smoke) of commercial cigarettes has been
reported to contain 160 to 550ng/cigarette of HCN; the MS emission of HCN
is lower (less than 100 ng/cigarette) for cigarettes with filter tips containing
charcoal, with perforated filter tips, or with filter tips containing longitudinal air
channels (International Agency for Research on Cancer, 1985). Hydrogen
cyanide in smoke may arise from nitrate and also tobacco proteins such as
glycine, proline, and aminodicarboxylic acids.
Hydrogen cyanide has been identified as a product of combustion of a
number of natural and synthetic polymers such as wood, silk, nylon, polyure-
thane, and melamine resins (Summer and Haponik, 1981). One of the
polymers releasing the most HCN upon combustion was reported to be urea-
formaldehyde used for home insulation (Griffin, 1981). Levin et al. (1985)
studied the generation of HCN from flexible polyurethane foam decomposed
under different combustion conditions. The maximum yield of HCN/g foam
was found to range from 0.37 mg to 0.93 mg under nonflaming conditions and
0.50 mg to 1.02 mg under flaming combustion, respectively. However, a two-
phase decomposition process in which the foam was first decomposed in the
nonflaming mode and then heated to flaming temperatures resulted in
maximum HCN yields of 7 to 12 mg/g of foam. The role of HCN in fire fatalities
is discussed in Section 7.
Some industrial chemicals may form hydrogen cyanide. Methyl isocyanate
(MIC) can liberate HCN on heating (Union Carbide Corporation, 1976). Organic
thiocyanate insecticides are another potential source of cyanides
(Solomonson, 1981).
The presence of HCN in auto exhausts was first reported in 1974
(Voorhoeve et al., 1975). The use of a catalytic converter under oxidizing
conditions reduces the formation of HCN in auto exhaust; however, laboratory
experiments on catalytic reduction of NO with CO and H2 indicate formation of
as much as 80 ppm of HCN under these conditions (Voorhoeve et al 1975)
The EPA has evaluated the health effects of HCN in auto emissions'. It has
been determined that mobile source emission of HCN does not result in
19
-------
ambient levels of concern for the air quality in microenvironments such as
tunnels, parking garages, etc. (Harvey et al., 1983).
Emission of HCN in air may also take place from industrial sources such
as plants producing HCN, industrial processes using HCN, and production of
coke-oven gas (containing a large amount of HCN) (Grosick and Kovacic,
1981), if the emission control systems are not adequate.
3.2 Environmental Fate
The principal sinks of HCN in the atmosphere are attack by UV photons in
the stratosphere and complicated and unresolved reactions with atmospheric
OH and 0(1D) (Cicerone and Zellner, 1983). Precipitation appears to be a
negligible sink since the equilibrium concentration of HCN is very low at low
partial pressures (see Table 1). Its atmospheric residence time has been
calculated by the authors to be 2.5 years (range 1 to 5 years). This is in
contrast with the surmise "Physical transfer mechanisms, such as wet and dry
deposition, may dominate the fate of cyanide in the atmosphere" (U.S.
Environmental Protection Agency, 1984).
The importance of volatility in determining the environmental fate of HCN
present in water has been emphasized (Callahan et al., 1979). This is the
major route for loss of HCN from aqueous medium rather than hydrolysis,
oxidation, photolysis, or biodegradation. The vapor pressure of HCN at 27.2°C
is >800 mm Hg. The rate of volatilization is affected by other factors such as
temperature, pH, mixing characteristics of the water, wind speed, and ice
cover. Laboratory experiments at the University of Minnesota-St. Paul indicate
that volatilization is a rapid process and the relationship of HCN loss and
concentration of HCN is first order. Half-lives were calculated to be 22 to 111
hours in the case of HCN evaporation from solutions at concentrations of 25 to
200 ug/L. When the same experiment was conducted outdoors, the rate of
HCN loss was increased by a factor of 2 to 2.5 due to moderate wind (U.S.
Environmental Protection Agency, 1985a).
Although hydrolysis is a minor route for loss of HCN in the environment, it
occurs under both acid and alkaline conditions to form ammonium formate or
ammonia and formate, respectively, as shown below (Callahan et al., 1979).
HCN
H2O
HCONH2
H?O
NH4* + HCOO - (acidic conditions)
HCN
H2O
HCONH,
OH"
NH3 + HCOO - (alkaline conditions)
Hydrogen cyanide can be biodegraded by plants and bacteria. For
instance, if one gram of young sorghum seedlings is exposed to HCN at 20
ppm 15 to 50 percent of HCN is metabolized by the seedlings (Conn and
Butler, 1969). Harris and Knowles (1983) reported isolation of Gram-negative
bacteria (tentatively identified as strains of Pseudomonas fluorescence) pro-
20
-------
ducing a fluorescent green pigment and capable of utilizing cyanide as a
source of nitrogen for growth. Both aerobic and anaerobic microbial degrada-
tion of cyanide during sewage treatment plant operations have been demon-
strated (Callahan et al., 1979). Raef et al. (1977) has reported metabolism of
cyanide to the extent of 50 percent using starved, acclimated heterogenous
culture (sewage organisms containing a small inoculum of Bacillus
megaterium), K14CN, and a medium containing glucose. A combination of hot
alkali digestion and chemical coagulation followed by a two-stage biological
extended aeration system can reduce the cyanide level in waste from
acrylonitrile plants to the extent of 85 to 90 percent (Dave et al., 1985).Bacillus
megaterium), K14CN, and a medium containing glucose. A combination of hot
alkali digestion and chemical coagulation followed by a two-stage biological
extended aeration system can reduce the cyanide level in waste • from
acrylonitrile plants to the extent of 85 to 90 percent (Dave et al., 1985).
3.3 Ambient Levels
Towill et al. (1978) stated that HCN is not a normal atmospheric contami-
nant; however, there has been recent spectroscopic detection and
measurement of HCN in the atmosphere (Coffey et al., 1981; Carli et al 1982-
Rinsland et al., 1982). According to Cicerone and Zellner (1983), HCN is
present in the stratosphere and the northern hemisphere's nonurban
troposphere at the 150 to 170 ppt level. To maintain the atmospheric burden of
HCN at this level, it has been calculated that about 2 x 10" g of nitrogen as
HCN is required. The issue of whether atmospheric HCN is mostly natural or
anthropogenic is still unresolved. Contribution from jet aircraft, volcanoes,
lightning, and automotive emissions to the atmospheric burden of HCN is
probably negligible.
21
-------
-------
4. Pharmacokinetics and Toxicokinetics
Hydrogen cyanide is most readily absorbed by inhalation and also
through skin (Towill et al., 1978). It is also rapidly absorbed through the eyes
of rabbits producing systemic toxicity with an LD50 of 0.039 mmol/kg
(Ballantyne, 1983). After absorption, cyanide is rapidly distributed in the body
through blood. The concentration of cyanide is higher in erythrocytes than in
•plasma. It is known to combine with iron in both methemoglobin and
hemoglobin present in erythrocytes (U.S. Environmental Protection Agency
1985a). The cyanide level in different human tissues in a fatal case of HCN
poisoning has been reported (Finck, 1969): (cyanide content in mg/100 g or
mg/100 ml is indicated in parentheses) gastric contents (0.03), blood (050)
hver (0.03), kidney (0.11), brain (0.07), urine (0.20). The effect of routes of
exposure on the cyanide distribution in various organs has been investigated
using rats (Yamamoto et al., 1982). The relative concentration (concentration in
the organ w/w: concentration in blood w/v) in liver was found to be 1 81 after
per os administration and 0.71 after inhalation. The relative concentration of
cyanide in the lung was 1.47 after inhalation and 1.19 after per os administra-
tion.
The effect of cyanide on cellular respiration was demonstrated about 50
years ago (Way, 1981). It is acknowledged that the toxicity of cyanide is
mainly due to the decrease in the utilization of the oxygen in the tissues
producing a state of histotoxic anoxia. This is achieved through the inactivation
of tissue cytochrome oxidase by cyanide which combines with Fe3+/Fe2+
contained in the enzyme. The reaction of cyanide with cytochrome oxidase
has been extensively studied (Solomonson, 1981). The enzyme-cyanide
complex dissociation constant has been found to be 1x10-6 and 1x10-4
(moles/L) for the oxidized and reduced form of the enzyme, respectively
Thus, the affinity of cyanide for the oxidized form of the enzyme is two orders
of magnitude higher than that for the reduced form. However, the rate of
reaction of cyanide with the reduced enzyme is twice that with the oxidized
form. Apparently, during active turnover, cyanide reacts with the reduced
cytochrome oxidase which is then oxidized to the more stable complex In the
presence of reducing equivalents, however, cyanide readily dissociates from
the complex to. form active cytochrome oxidase. It has been pointed out that
cyanide can inhibit several other metallo-enzymes containing for the most part
iron, copper or molybdenum (e.g., alkaline phosphatase, carbonic anhydrase)
as well as enzymes containing Schiff base intermediates (eg 2-keto-4-
hydroxyglutarate aldolase) (Solomonson, 1981).
The major defense of the body to counter the toxic effects of cyanide is
its conversion to thiocyanate mediated by the enzyme rhodanese (Way, 1981)
(see Figure 1). The trivial name rhodanese is more widely used than that
assigned by the Enzyme Commission (thiosulfate-cyanide sulfur-transferase
EC 2.8.1.1) since the enzyme catalyzes reactions other than the transfer of
sulfur to cyanide (Volini and Alexander, 1981). It has been inappropriately
23
-------
Hemoglobin
NaNO2 Amyl Nitrite
Methemoglobin -<-
2-lmino-Thiazolidine-
4-Carboxylic Acid
(Excreted in Saliva,
Urine)
Cysteine
Minor
Cytochrome Oxiddase (Mitochondria)
Major Effect: Stops Cellular Respiration
Minor
HCN in Expired Air,
Saliva, Sweat, Urine
HCNO
CNS" —
Thiocyanate Oxidase?
(In Red Blood Cells)
Slow Excretion
in Urine
HCOOH
Cyanocobalamine
(Excreted in Urine, Bile)
Metabolism of One-Carbon
Compound
CO2
Some Excreted in Urine
Figure 1. Fate of cyanide in the body. nnQ*\
Adapted from Williams (1959), Hartung (1982), Solomonson (1981)
called rhodanase in two reports from the U.S. Environmental Protection
Aqency (Carson et al., 1981) and U.S. Environmental Protection Agency
(1984), since this implies an enzyme which splits rhodanid (the German for
thiocyanate) (Sykes, 1981). '
Rhodanese is present in plants, fungi, bacteria, and in animals. In
mammals, the liver is the richest source of rhodanese followed by the kidney
and other organs. In liver, it exists exclusively in the mitochondria! matrix
(Westley, 1981). The species and tissue distribution of rhodanese has been
reported (Himwich and Saunders, 1948).
The conversion of cyanide to the less toxic thiocyanate by rhodanese was
discovered by Lang (1933). Thiosulfate and 3-mercaptopyruvate can act as
sulfur donors, but free cystine or cysteine cannot. The enzyme contains an
active disulfide group which reacts with the thiosulfate and cyanide as shown
below (Williams, 1959):
24
-------
ssso.
S - SO3
+ CN
+ SON + SO,
The rhodanese-catalyz'ed irreversible conversion of cyanide to
thiocyanate, in the presence of thiosulfate, provides a means for the treatment
of cyanide poisoning (Way, 1981). Since the enzyme is relatively abundant,
thiosulfate becomes the limiting factor for the treatment of the cyanide victim.
One problem is that the thiosulfate distribution after an intravenous
administration does not parallel the cyanide distribution in the body. Moreover,
the enzyme is usually localized in the mitochondria in different tissues, and
these sites are not readily accessible to thiosulfate.
Rhodanese is a very well investigated enzyme. Its amino acid sequence
and active sites are known (Westley, 1981). The structure of one form of the
enzyme has been established by X-ray crystallography. The endogenous
source of sulfur for this enzyme has not been identified (U.S. Environmental
Protection Agency, 1985a). However, Westley (1981) has suggested that the
sulfane pool (thiosulfate, disulfide anion, colloidal sulfur, protein persulfides,
etc.) is the endogenous source of sulfur. Some members of the sulfane pool
may be formed from 3-mercaptopyruvate by 3-mercaptopyruvate
sulfurtransferase. The dilution of the sulfane pool should be considered among
the potential effects of cyanide in vivo.
The pharmacokinetics of 14CN' and S14CN" in rats exposed to the agent in
diet for 3 weeks has been investigated by Okoh and Pitt (1981). All tissues
contained radioactivity 9 hours after injection of 14CN', highest radioactivity
being found in the stomach (18 percent). Eighty percent of this activity was in
the form of thiocyanate. When S14CN" was given per os to rats with elevated
plasma thiocyanate levels due to chronic oral exposure to cyanide, most of the
activity was eliminated in the urine and only small amounts were found in the
feces. This indicated the existence of a gastrointestinal circulation of
thiocyanate. In another experiment, Okoh (1983) studied the excretion of 14CN"
in rats chronically exposed to daily intake of unlabelled KCN in diet for 6
weeks. Eighty-nine percent of the total radioactivity was eliminated in 24 hours
in urine and 79 percent of this activity was due to the metabolite SCN-. Only 4
percent of the radioactivity was excreted in the expired air in 24 hours; 90
percent of this radioactivity was due to carbon dioxide and the rest due to
cyanide. A comparison of these results with those from control rats indicated
that the mode of elimination of cyanide in both urine and breath was not
altered by the chronic ingestion of cyanide.
The overall rate of in vivo detoxification of cyanide may be influenced by
several minor reactions (see Figure 1). Ermans et al. (1972) stated that
thiocyanate may be oxidized to cyanide by thiocyanate oxidase present in
erythrocytes (Ermans et al., 1972). However, this view has been contradicted
by McMillan and Svoboda (1982) who reported that oxidation of thiocyanate to
cyanide was not observed in human erythrocytes or in vivo in rats. Cystine
may directly react with cyanide to form 2-imino-thiazolidine-4-carboxylic acid
which is excreted in saliva and urine. Traces of hydrogen cyanide may be
25
-------
found in expired air, saliva, sweat, and urine. A minor amount of cyanide may
be oxidized via cyanate to CO2. Small amounts may be converted into formic
acid which may be excreted in urine or participate in the metabolism of one-
carbon compounds. One other detoxification route is the combination of
cyanide with hydroxycobalamine (vitamin B12) to form cyanocobalamine which
is excreted in urine or bile (see Figure 1) (Muskett et al., 1952). It may be
reabsorbed by the intrinsic factor mechanism at the level of the ileum allowing
effective recirculation of vitamin B12- Methemoglobin effectively competes with
cytochrome oxidase for cyanide and its formation from hemoglobin, effected
by sodium nitrite or amyl nitrite, is exploited in the treatment of cyanide
poisoning (U.S. Environmental Protection Agency, 1985a) (Figure 1). A
detoxification rate of 0.017 mg/kg/minute has been estimated for humans
injected iv with HCN (McNamara, 1976). It has been pointed out that the route
of exposure is very important in cyanide toxicity. Hydrogen cyanide is rapidly
absorbed by inhalation and bypasses the "First Pass" detoxification in liver in
contrast to orally ingested chemicals (U.S. Environmental Protection Agency,
1984). Cyanide lethality is known to occur without any apparent inhibition of
liver cytochrome oxidase activity. Inhibition of cytochrome oxidase activity in
the brain may be the cause of death (Solomonson, 1981).
The effect of sublethal doses of cyanide on the metabolism of glucose in
mice has been studied using radiorespirometric techniques (Solomonson,
1981). Cyanide was found to cause an increase in blood glucose and lactic
acid levels and a decrease in the ATP/ADP ratio indicating a shift from the
aerobic to anaerobic metabolism. Cyanide apparently activated glycogenolysis
and shunted glucose to the pentose phosphate pathway decreasing the rate of
glycolysis and inhibiting the TCA (tricarboxylic acid) cycle.
Rhodanese-mediated detoxification of cyanide operates in most higher
plants and microorganisms (Solomonson, 1981). In these organisms, cyanide
can also react with cysteine or serine to form 0-cyanoalanine which may be
converted into asparagine or other derivatives such as yglutamyl-p-
cyanoalanine. This is a major pathway for cyanide detoxification in many
nonmammalian species.
26
-------
5. Mutagenicity and carcinogenicity
5.1 Mutagenicity
ne!at'V,et an? °ne mar9'naHy Positive genotoxicity studies have been
mutanPnirl IT""6' i?6/'^ (1981) found that P^assium cyanide was
not mutagenic in Salmonella typhimurium strains TA 1535, TA 1537, TA 1538
ini.frifS TAJ°°tWith or rithout S'9 mix (PrePared from 'ivers of Arochlor-
mduced rats). Negative results from a rec-assay of cyanide in Bacillus subtilis
was reported by Karube et al. (1981). More recently Kushietaf
in
without S-9
5.2 Carcinogenicity
mutagenic to strain TA 98 with or
Kteru nata °n J1^6" cVanide nave not been located in the
literature searched. Previous EPA reports (U.S Environmental PrntPrtirm
Agency, 1984, 1985a) also pointed out the lack of dSS^SS^aSSSS
ant.carcinogenic effects of cyanide have been reported. Perry (1935) reported
the mhibition of the growth of implanted Jensen rat sarcomas when the
animals were exposed to HCN by inhalation; however, the range of hi
effective dose was limited and too close to the lethal dose to be practicaf
Longev,ty of m,ce w.th transplanted Ehrlich ascites tumors and Sarcoma 180
was increased 20 to 70 percent on intraperitoneal injection of sodium Tan de
in the dose range, 0.75 to 2.0 mg/kg (Brown et al., 1960). «-y*niae
? ^vanide is classified as a group D (not classifiable as to human
to EPA's -«*—«— «** -
27
-------
-------
6. Developmental and Reproductive Toxicity
The developmental and reproductive toxicity of hydrogen cyanide per se
has not been reported in the literature. However, some information is available
for such effects for NaCN and KCN.
Teratogenicity of NaCN has been studied by Doherty et al. (1982) using
pregnant Golden Syrian hamsters. The animals (5 to 7 animals/group) were
continuously exposed to NaCN from days 6 to 9 of gestation at 0 1482
149.9, or 152.3 mg/kg/day (equivalent to 0, 78.7 or 80.8 mg CN7kg/day) by
using osmotic minipumps implanted subcutaneously at the back of the necks.
The hamsters were sacrificed on day 11 of gestation and data on litter size
maternal body weight changes, absorption, resorption, and malformation were
collected. Severe teratogenic effects were observed at all three dose levels
(Table 3). Toxicity .in the dams increased with the dose level and toxic
symptoms included shortness of breath, incoordination, reduced body
temperature, and loss of body weight. Maternal toxicity was not related to the
incidence of fetal malformations as found by analysis of variance of the
transformed data (p >0.05). Coadministration of thiosulfate eliminated the
teratogenic effect, confirming the cyanide as the causative agent (see Section
The long-term and carry-over reproductive effects of dietary inorganic
cyanide (KCN) in the life cycle performance and metabolism of female Wistar
rats and their female weanlings have been studied by Tewe and Maner
(1981 a). Four groups (10 animals/group) of adult female rats were subjected to
four different dietary regimens - ACE, ACF, BDE, and BDF, where A is a
basal diet containing 11.6 mg CNVkg fed 16.3 q 1.1 days before pregnancy B
is a test diet containing 511.6 mg CNVkg fed 19.7 q 1.8 days before
pregnancy; C, is the basal diet fed during gestation; D is the test diet fed
during gestation; E is the basal diet fed during lactation; and F is the test diet
fed during lactation. Ten female weanlings from the ten litters (one from each
litter) in each of the four groups were fed the basal diet during the post-
weaning phase and another set of female weanlings similarly selected was
continued on the test diet during postweaning period. Male rats did not receive
these diets. There was no significant difference among the various treated and
control groups with respect to weight gain during gestation, litter size, birth
weight of pups, feed consumption and body weight change during lactation-
weights of maternal liver and kidney, weaning weights, or mortality-of off-
spring. However, the offspring that were continued on the test diets during the
postweaning period consumed significantly less food and grew at a signif-
icantly slower rate than the basal diet offspring, regardless of previous cyanide
exposure during gestation, lactation, or postweaning phase. Protein efficiency
ratio was not only reduced by the high cyanide diet during the postweaning
growth phase but also there was a carry-over effect from gestation. Serum
thiocyanate was significantly increased in lactating rats and their offspring
during lactation and the postweaning growth phase of the pups. No apparent
29
-------
Table 3. Fetotoxic and Teratogenic Effects of NaCN in Hamsters
Treatment3
Distilled Water NaCN (mg/kg bw/day)b
Litters
Maternal bw change
(1.7. pi/hour) -
6
-4 + 5
148.2
5
-16 ± 9
149.9
6
-13 ± 10
152.3
6
-16 + 12
g ± SD
Litters completely 0
absorbed
Total resorptions/total 8/83(10)
implantations (%)
Number littersd 3 (50
affected (%)
Total malformed/total 4/75 (5)
number live fetuses
44/70 (63)c 60/83 (72)= 72/87 (83)c
2 (67) 3 (100) 1 (100)
16/26(62)= 10/23(43)= 1/15 (7)<*
Abnormalities in live
fetuses
Neural tube'
Heart
Limb or Tail
Others
Crown-rump length,
mm + SD
0
0
3
1
8.19 + 0.54
16
0
0
0
3.33 ± 0.29e
6
4
4
1
6.61 ± 1.64=
1
0
NR
a The NaCN was delivered by osmotic minipumps implanted subcutaneously.
b The doses correspond to rates of 0.126, 0.1275, and 0.1295 mmole/kg/hour.
c Significantly different from control (P < 0.05).
d Litters affected of those litters with one or more live fetuses.
e Not included in statistical analysis, too few fetuses.
' Included exencephaly, encephalocele and nonclosure.
a Includes microphthalmia and one fetus with a small caudal half.
NR = Not reported
Source: Doherty et al. (1982).
carry-over effect was noticed on this parameter. Rhodanese activity in liver
and kidney was unaffected by feeding the high cyanide diet during gestation,
lactation, and/or during postweaning growth.
A similar study on the reproductive effects of potassium cyanide was
carried out by Tewe and Maner (I981b) with pregnant Yorkshire pigs. Three
qroups of animals (6 animals/group) were kept on a low-cyanide basal diet
(30.3 mg CNVkg diet) (group 1), basal diet supplemented with cyanide
providing total CN/ levels of 276.6 (group 2) and 520.7 (group 3) mg CM /kg
diet The animals were kept on the prescribed diets from the day after
breeding to parturition. Two pregnant pigs/group were sacrificed on day 110 of
qestation- the rest of the animals were continued on their respective diets until
parturition and then fed standard diets (no cyanide) during the 56 days of
lactation The piglets were not fed any cyanide. No significant differences
were found among the groups of piglets sacrificed on day 110 of gestation for
30
-------
body weight, body weight gain during gestation, organ-to-body weight ratios of
thyroid, spleen, liver, kidney and heart, number of fetuses/litter, weight of
fetuses, or weight of fetal liver or kidney. Hyperplasia of kidney glomerular
cells was observed in one sow from each of the low- and medium-cyanide
groups and in both sows of the high-cyanide group. An accumulation of colloid
and follicular cells of low height was observed in the thyroid of both high-
cyanide sows. No change was observed in the hypophysis, adrenal, pancreas,
tongue, esophagus, stomach, liver, cardiovascular tissues, lymphoreticular
system of the spleen, tonsils, thymus, intestinal mesenteries, eye, brain or
spinal cord of the treated sows when compared with the controls. Fetal spleen-
to-body weight and heart-to-body weight ratios in the high-cyanide group were
significantly reduced (p >0.05) compared with the low-cyanide group.
31
-------
-------
7. Other Toxic Effects
7.1 Acute and Subacute Toxicity
7.1.1 Humans
Exposure of humans to hydrogen cyanide may be by inhalation, oral or
skin absorption. It is a true noncumulative protoplasmic poison, i.e. it can 'be
detoxified readily (Jenks, 1979). It combines with cytochrome oxidase at the
blood tissue interface and reduces cellular respiration (see Section 4 for more
details); however, unless the cyanide is removed promptly, death results
through asphyxia. Severe inhalation exposure can cause immediate
unconsciousness. The warning symptoms of cyanide poisoning include-
dizziness, numbness, headache, rapid pulse, nausea, reddened skin and
bloodshot eyes. These symptoms may be followed by vomiting, labored
breathing, loss of consciousness, cessation of breathing, rapid weak heart
beat, and death.
Table 4 summarizes types of effects observed to occur in case histories
or with experimental human exposures (at low levels) at various HCN
concentrations and exposure durations. As seen in Table 4 an HCN
concentration of 297 mg/mS can be immediately fatal to humans within only 6
to 8 minutes exposure. Even lower concentrations may be fatal with somewhat
longer exposure durations, as in the case of concentrations as low as 100 to
150 mg/m3 after 30 to 60 minutes exposure. Other serious effects noted in
In !6 in3" °?Cf at Sti" lower HCN exposures, ranging from 5.0 to more than
50 to 60 mg/m3 with exposure periods that vary from several minutes to
several hours.
As is evident from the above discussion, response to HCN is a function of
air concentration and time. An .expression often used for exposure calculations
that include both concentration of poison (actually calculated as dose- see
explanation below) and time of exposure is LCt50 expressed in mg/mSmin
• u5,0!3,3 statlstlcallv derived number which indicates the concentration of an
inhaled lethal agent that will kill 50 percent of exposed animals of a given
species at a given exposure duration. A number of animals are exposed to a
yanetyof mnalable concentrations and varying exposure times and the result-
ing number of deaths are then used to calculate LCt50.
Accurate estimates of the exposure-effect or dose-response relationships
for• toxicity of HCN in humans are not available and it is generally necessary to
extrapolate from animal experiments (Bright and Marrs, 1984) Humans are
relatively resistant to cyanide when compared with animals such as the doq
mouse, or rat, but seem to fall within a range of susceptibility close to that of
the goat or monkey. Precise dose-response data for lethality in humans does
not exist and must be extrapolated from animal data. Despite the greater
sensitivity of mice to cyanide (about 4 times that of goat, monkey or human)
33
-------
Table 4. Reported (Estimated) Human Responses to Various Concentrations
of HCN Vapors
Concentration
Responses (mg/m3)a
Nausea and difficulty concentrating after 91 second exposure
No serious consequences in 1 minute
No injury in 1 minute
No injury in 1.5 minutes
Immediately fatal
Rapidly fatal
Fatal in 6-8 minutes
No injury in 2 minutes
Fatal after 30 minutes
Fatal after 10 minutes
Fatal after 30 minutes
Fatal after 30-60 minutes
Fatal after 30-60 minutes
Fatal after 60 minutes
Fatal or immediately dangerous to life
Numbness, vertigo, weakness, nausea, rapid pulse, flushed face
and headache
Tolerated for 30-60 minutes without immediate or after effects
Complaints of headache, nausea, vomiting, cardiac symptoms
Minimal symptoms after several hours of exposure
Effects after several hours of exposure
No symptoms after 6 hours
Some headache, vertigo
No observed effect
Fatigue, headache, body weakness, tremor, pain, nausea
Headache, weakness, changes in taste and smell, throat irritation,
nausea, effort dyspnea,enlarged thyroids, changes in blood
chemistry
Increased thiocyanate excretion in urine, but to a lesser extent than
in cigarette smokers: no other effects noted
No effects
Slight decrease in leukocytic activity of cytochrome oxidase,
peroxldase and succinate dehydrogenase after an average of 5.4
years of exposure.
550-688
550
550
413
297
330
297
275
243-528
199
149
121-149
110-264
99
99
>55
50-59
50
22-44
20-40
20-40
5.5-20
0-19;
mean 5.4
5.5-14.3
4.6-13.6;
mean, 9.1
2.2-8.8;
mean 5.5
0.11-0.99
0.25
a The concentrations in mg/m3 were calculated from concentrations expressed in
ppm by multiplying by 1.1.
Source: Adapted from NIOSH (1976).
34
-------
human data was calculated from that of mice because exposure time 'data
were most complete for this animal (encompassing 0.5-, 1.0- and 2.0-minute
GXpOSUrGS ).
h* ™050/ fo,r 1 minute exP°sure of HCN to humans has been estimated to
be 4,400 mg/m3 assuming a minute volume of 25 L, and a human LD.n for
intravenous HCN of 1.1 mg/kg (Bright and Mars, 1984). The first figure is
higher han the LC50 of 3,404 mg/m3 reported by McNamara (1976): Moore
as follows3 Can bS US8d t0 der'Ve thS LCso fr°m the intravenous LD50
VaC - Dt = K, where V = volume of air inhaled (L/kg), a = fraction of
^nSOrbedt(70fPe;Cent meaSUred in d°9s>' C ^concentration of
H« nm^ 7, ? °f detoxificat'on (experimentally determined at low
dose; 0.017 mg/kg/mm), t = time of exposure (min), K = LD,n for
mtravenously injected cyanide (mg/kg). 50
(9\ ~, °fjhis.formu'a are: (1) uncertainty of the human LD50 and
(2) the lack of quantif.cat.ion of the effect of respiratory stimulation on Vie
the volume of inhaled air (Bright and Mars, 1984).
LCt50!f (m9/m3m'n) for man have been estimated by McNamara
usmg the relationship, Man LCt50 = 4 X Mouse LCt50 at various
(3 min): 6,072 (10
LCt, (lethal concentration for 1 percent of animals exposed, multiplied by
time of exposure) was also calculated for the various animals soecies
exposed. For the mouse, the LCt! for one minute was 612 mg/m3mjn which
compares with the median LCt50 of 851 mg/m3min for one minute
Extrapolated to humans (at 4 times LC, of the mouse), the median LCti for
eXp°SUre time is 2'448 m9/m3min, compared to the LCt50 of 3,404
Several fatal cases of human exposure to cyanide have been cited in the
National Institute of Occupational Safety and Health (1976) (see Table 4)
Recently Bonsall (1984) reported a case of human survival wi hout sequelae
followmg exposure to 500 mg/m3 of HCN for 6 minutes. This is not surprising
since McNamara '(1976) suggested that an exposure to 607 mg/m" for 10
minutes could I be survived by 50 percent of humans (Bright and Marrs, 1984)
The fatal oral dose of HCN ranges from 0.5 to 3.5 mg CN/kg body weight (The
U.S. Environmental Protection Agency, 1985a).
7.1.2 Animals
Physiological responses of a variety of laboratory animals (mouse rat cat
'Ume? ,?,&, ^^"i, SP3rrOW' ^ mOnkey> SXPOSed tO V™™S COn-
«nnQ f t V?u m,a'r have bee" reported (Nationa' Institute of Occupa-
tional Safety and Health, 1976). The relative sensitivity of various species to
inhalation exposure of HCN is shown in Table 5. Since man is considered to
be similar to .goats and monkeys in susceptibility to HCN, acute lethality for
these an.mals are shown in Table 6 (Carson et al., 1981). Goats can indefi-
S^S8,^0 m3/m\H™ j" air' althO"9h 360 mg/m3\or 24 mfnutes was
found to be 100 percent lethal for four goats. According to Dudley et al
35
-------
(1942), a 12-minute exposure to HCN at 140 mg/m3 was distinctly .toxic: to
monkeys; yet Barcroft (1931) reports an indefinitely tolerable dose level of 180
mq/m3 HCN in air for monkeys (see Table 6). Similar data on other animals
(mice, rats, guinea pigs, rabbits, cats, dogs, and donkeys) have also been
reported (Carson et a!., 1981).
Table 5. Sensitivity of Various Species to Inhalation Exposures of HCN
„ Lethal Time of Exposure to a Concentration
Species (Number/Species Not Given) Of 1,000 mg HCN/m3 (Minutes)
Dog
Mouse
Cat
Rabbit
Rat
Guinea pig
Goat
Monkey
o.a
1.0
1.0
1.0
2.0
2.0
3.0
3.5
Source: Barcroft (1931).
The intravenous LD50's for HCN in mg/kg are 1.34, 0.81, 1.30, 0.66, 1.43,
0.81, and 0.99 for dog, cat, monkey, rabbit, guinea pig, rat, and mouse,
respectively (McNamara, 1976).
7.2 Subchronic and Chronic Toxicity
7.2.1 Humans
Most of the earlier literature on cyanide focussed on the acute effects and
the chronic effects were ignored (Way, 1981). In epidemiological studies it is
difficult to ascribe any particular effect to cyanide because usually a number
of chemicals is involved. No information is available on chronic oral exposure
of humans to HCN, NaCN or KCN (U.S. Environmental Protection Agency,
1985a) However, in the past two decades, various correlations have
implicated the chronic effects of cyanide in specific diseases, mostly
neuropathological in nature - Nigerian nutritional neuropathy, Leber s optical
atrophy retrobulbar neuritis, pernicious anemia, tobacco amblyopia, cretinism,
and ataxic tropical neuropathy. Some of the diseases such as tobacco
amblyopia and retrobulbar neuritis can be effectively treated with
hydroxycobalamine (vitamin B12) which can react with cyanide to form
cyanocobalamine (Wilson et al., 1971), lending credence to the belief that
such neuropathies are probably the effects of chronic exposure to cyanide. A
recent outbreak of spastic paraparesis mostly affecting women and children in
a northern province of Mozambique in 1981 has been related to chronic
cyanide intoxication associated with a diet consisting almost exclusively of
cassava (Casadei et al., 1984). The nutritional status of the population was not
36
-------
Table 6. Acute Experimental Exposure to HCN
Concen- Number Duration and
tration Mode of of Test Frequency of
mg/m3 Exposure Species
1 ,000 Exposure Goat
Chamber
360 Exposure Goats
Chamber
240 Exposure Goat
Chamber
1,000 NRa Monkeys
180 NRa Monkeys
Animals Exposure
NRa 3 min., once
4 15 min., once
4 20 min., once
4 24 min., once
NRa Indefinite
NRa 3.5 min.
NRa Indefinite
Effects
Lethal
1 died, 3
recovered
3 died, 1
lived
All died
Highest
approximate
concentration
that could be
breathed
indefinitely
Lethal
Highest
"tolerable
concen-
References
Barcroft, 1931
Barcroft, 1931
Barcroft, 1931
Barcroft, 1931
Barcroft, 1931
140 NRa Monkeys NRa 12 min.
Distinctly Dudley et al.,
toxic • 1942
aNR = not reported.
very poor although metabolic detoxification of cyanide was probably reduced
due to the deficiency of sulfur-containing amino acids in the diet.
Chronic cyanide neurotoxicity and neuropathy in Nigeria have been
reported by Osuntokun (1972). Nutritional deficiencies, particularly vitamin B19
deficiency and deficiency of sulfur-containing amino acids, potentiate the
chronic effects of cyanide ingested daily through the consumption of
cyanogenic cassava roots. Thiocyanate is the major end product of
detoxification of cyanide (see Section 4). However, thiocyanate is not
completely innocuous. It prevents the uptake of iodine and leads to the
development of goiter and cretinism. This effect is more pronounced in the
case of individuals unable to excrete thiocyanate at a sufficient rate due to
kidney dysfunction (National Institute of Occupational Safety and Health
1976). The possible role of cyanide and thiocyanate in the etiology of endemic
cretinism has been discussed at length by Ermans et al. (1972).
There is very little evidence of chronic toxic effects of cyanide in normal
well- nourished subjects; however, adverse chronic effects of cyanide may be
seen in circumstances where cyanide detoxification is abnormal A defective
metabolic conversion of cyanide to thiocyanate due to rhodanese deficiency
37
-------
has been implicated in Leber's hereditary optic atrophy (Wilson, 1983).
Smokinq carries the risk of blindness in the affected population. Other
hereditary optic atrophies may be due to the inborn errors of cyanide
metabolism. A defective or abnormal cyanide metabolism in smokers is
implicated in retrobulbar neuritis and optic atrophy and subacute combined
degeneration of the cord in vitamin B12 deficiency. The serum vitamin B12
levels in pregnant women were significantly lower for smokers than for
nonsmokers, probably due to a disorder of cyanide detoxification (Surgeon
General of the United States, 1979). Andrews (1973) has suggested that
increased levels of cyanide and thiocyanate in smoking pregnant women are
of importance in the etiology of the increased incidence of low-birth-weight
babies and the increase in hypertension during pregnancy.
Several cases of chronic occupational exposure to cyanide have been
described (Carson et al., 1981; U.S. Environmental Protection Agency, 1985a;
National Institute of Occupational Safety and Health, 1976). Chronic HCN poi-
soning resulting in serious or incapacitating injury is rather rare. Symptoms
usually include headaches, dizziness, confusion, muscular weakness, poor
vision slurred speech, gastrointestinal disturbances, tremor, body rash, and in
extreme cases, an enlarged thyroid. The question whether chronic effects of
cyanide exposure are reversible or not has not been resolved (National Insti-
tute of Occupational Safety and Health, 1976).
7.2.2 Animals
Fourteen studies on the subchronic exposure of laboratory animals to
cyanide have been reported (U.S. Environmental Protection Agency, 1985a).
All the studies except one used either NaCN or KCN as the test material. In
general the animals tolerated higher doses of cyanide when the compounds
were administered in the diet than otherwise (e.g., subcutaneously,
intramuscularly, inhalation), allowing sufficient detoxification in the liver to
account for sublethal effects. In most cases where cyanide was administered
in the diet at 0.4 to 100 mg as CN-/kg bw/day, there was no mortality, no
effect on food consumption or weight gain, no change in organ to body weight
ratios of thyroid, liver, kidney, spleen or heart, and no histopathological
changes In the one study with HCN where male Danish rabbits in groups of
22 weighing 2 to 2.5 kg, were exposed to HCN in air (0.55 mg/mS as HCN) for
28 days no significant ultrastructural changes in the myocardium were
observed in the exposed animals compared with the controls (Hugod, 1981).
Only two studies on the chronic exposure of laboratory animals to cyanide
were found. The results are shown in Table 7. In Howard and Hanzal (1955),
studies on male and female rats exposed to HCN in the diet for 104 weeks
showed that no effect was observable at the dose level (3.2 to 10.4 mg CN-/kg
bw/day) used. However, at an increased dose level (30 mg CNVkg bw/day),
rats exposed to KCN in the diet showed some noticeable effects (Philbrick et
al., 1979) (see Table 7).
7.3 Toxicant Interactions
In recent years, attention has been focused on the role of HCN in fire
fatalities Hydrogen cyanide is one of the products of combustion of natural
and synthetic N-containing polymers present in every household - wool, silk
nylon, polyurethane, melamine resins, polyacrylonitrile, etc. (Summer and
38
-------
0)
2
'c
5.
(
o? S
c
2
a
t:
UJ
i.§
Q *-
°-S§
O o5 "c ^
** Co CD CO
S
ECO
z "°
7i5 gi
$i
•= fc
"W
O TJ
0 §
m-o^f
Ilia
X x *~
No effect on growth rate, no noticeable signs of
toxicity, no histopathological changes in heart,
lungs, liver, spleen, stomach, small and large in-
testines, kidney adrenals, thyroid, testes, uterus,
ovary and the cerebrum and cerebellum of the
brain. Hematological values within normal limits.
a 2
o ffl
CO ^ Si£
S||l
o o ,_ (a
|i|i
CQ ^ co =^
f"N. O)frt O)
CD E 6
S
TO
o §•
^ 2
S o
!>o)
P
j|f 1
.
§? "i
No deaths or clinical signs. Significantly (no p
values) reduced bw gain, increased excretion of
thiocyanate at 4 months and at 1 1 months, de-
s.l
«1
C- E
in E TO
* cq 3
-^t-
s§-
C 8
U- 0)
creased plasma thyroxine levels, decreased se-
cretion rates at 4 months. No effect on plasma
S
thyroxine at 1 1 months, no definitive lesion to
sciatic, thyroid, optic or CNS tissue. Vacuoles
and accumulation of fluid in spinal cord white
matter with moderate primary myelin degenera-
tion were observed in treated rats. These
changes were more pronounced in KCN-treated
rats that were maintained on methionine, vitamin
B12 and iodine deficient diets.
•s
S nj £?
£ " *"
CO
in £
T §
E
.|5 o>
§r* O) CO
_|)£5
t
"55 en
ipf
O D> |s» _Q
E —
*
;—
a °-
§Q
O)
IH
DC
1
o
bw supplied in the report.
unt of food equal to 5% of its body weighVday.
TD O
c c
S c
.2 S
id consump
[ consumes
o 2
C ^5
If
§ w
fs
E
||
~c6
S? o
03 (O
fi
?s
O) *-^. •
— c
o o
(U CD
-------
Haponik, 1981). The importance of cyanide in fire deaths in the United
Kingdom during the period 1976 to 1979 has been assessed by Anderson and
Harland (1982). Seventy-eight percent of the fatalities had elevated cyanide
levels; thirty-one percent had toxic levels of cyanide and twelve percent would
have shown symptoms of severe cyanide poisoning. No additive or synergistic
effect was observed in the fatalities between cyanide and other factors such as
CO alcohol the age of the victim, and the presence of heart disease.
Additivity of the toxic effects of HCN and CO has been reported by other
investigators (Yamamoto and Kuwahara, 1981; Pitt et al., 1979; Levin et al.,
1987a), and the possibility of synergistic effect of CO and'HCN on cerebral
metabolism has been pointed out by Pitt et al. (1979) and Levin et al (1985b).
Recently Levin et al. (1987b) have addressed the issue in detail. These
studies have potential application in the toxicological evaluation of automobile
exhausts containing both CO and HCN.
High intake of ascorbic acid (Vitamin C) has been found to decrease the
availability of cysteine for cyanide detoxification (Basu, 1983).
The medical treatment of fire victims has recently become a controversial
issue Jones (1988) suggested that unconscious fire victims may be given
sodium thiosulfate solution as an antidote to cyanide poisoning using spring-
loaded syringes. Bryson (1988) has pointed out that amyl nitrite treatment of
mice, dosed with potassium cyanide and subsequently exposed to carbon
monoxide, showed 43-59 percent greater mortality than that of the non-treated
controls. Clark and Campbell (1988) stated that smoke inhalation victims are
not routinely treated with cyanide antidotes for reasons of safety and efficacy.
The most effective antidote, cobalt edetate, has major side-effects. A
combination treatment with slow-acting thiosulfate and nitrite is also not
acceptable since the latter is toxic in therapeutic dosage. The role of cyanide
influencing mortality in fire survivors could not be demonstrated, van Heijst et
al (1987) have also emphasized the risk associated with the use of sodium
nitrite and 4-dimethylaminophenol in the treatment of acute cyanide poisoning
because of the difficulty in controlling the induced methemoglobin level.
40
-------
8. References
Alves, B. R.; Clark, A. J. (1986) An examination of the products formed on
reaction of hydrogen cyanide and cyanogen with copper, chromium (6 +) and
copper-chromium (6 + ) impregnated activated carbons. Carbon 24: 287-294.
American Public Health Association; American Water Works Association;
Water Pollution Control Federation. (1971) Standard methods for the
examination of water and wastewater. 13th ed. Washington, DC: American
Public Health Association.
Anderson, R. A.; Harland, W. A. (1982) Fire deaths in the Glasgow area: III the
role of hydrogen cyanide. Med. Sci. Law 22: 35-40.
Andrews, J. (1973) Thiocyanate and smoking in pregnancy. J. Obstet.
Gynecol. Br. Comm. 80: 810-814.
Anonymous. (1986) Control limit for cyanide. Chem. Br. 22: 787.
Ballantyne, B. (1983) Acute systemic toxicity of cyanides by topical application
to the eye. J. Toxicol. Cutaneous Ocul. Toxicol. 2: 119-129
Barcroft,, J. (1931) The toxicity of atmospheres containing hydrocyanic acid
gas. J. Hyg. 31: 1-34.
Basu, T. K. (1983) High-dose ascorbic acid decreases detoxification of
cyanide derived from amygdalin (laetrile): studies in guinea pigs. Can. J
Physiol. Pharmacol. 61: 1426-1430.
Bonsall, J. L. (1984) Survival without sequelae following exposure to 500
mg/m3 of hydrogen cyanide. Hum. Toxicol. 3: 57-60.
Bright, J.; Marrs, T. C. (1984) Toxicity of inhaled HCN. Hum. Toxicol 3- 521-
522.
Brown, J.F. (1987) Toxicological review of cyanide process/gold mining
operation permit application for Ridgeway (S.C.) area. Div. of Health Hazard
Evaluation, South Carolina Department of Health and Environmental Control.
Brown, W. E.; Wood, C. D.; Smith, A. N. (1960) Sodium cyanide as a cancer
chemotherapeutic agent: laboratory and clinical studies. Am. J Obstet
Gynecol. 80:907-918.
Bryson, D. D. (1988) Cyanide and fire victims. Lancet 11:796.
Callahan, M. A.; Slimak, M. W.; Gabel, N. W.; May, I. P.; Fowler, C. F.; Freed,
J. R.; Jennings, P.; Durfee, R. L.; Whitmore, F. C.; Maestri, B.; Mabey, W. R.;
41
-------
Holt B R- Gould C (1979) Water-related environmental fate of 129 priority
pollutants,'volume 1: introduction and technical background metals and
inorganics, pesticides and PCBs. Washington, DC: U.S. Environmental
Protection Agency, Office of Water and Waste Management, EPA report no.
EPA-440/4-79-029a. Available from: NTIS, Springfield, VA; PB80-24373.
Carli, B.; Mencaraglia, F.; Bonetti, A. (1982) New assignments in the
submillimeter emission spectrum of the stratosphere. Int. J. Infrared Millimeter
Waves 3: 385-394.
Carson, B. L; Horn, E. M.; Ellis, H. V., Ill; Herndon, B. L; Baker, L H. (1981)
Hydrogen cyanide health effects. Ann Arbor, Ml: U^>. Environmental
Protection Agency, Office of Mobile Source Air Pollution Control; EPA report
no EPA-460/3- 81-026. Available from: NTIS, Springfield, VA; PB82-116039.
Casadei, E.; Jansen, P.; Rodrigues, A.; Molin. A.; Rosling, H. (1984)
Mantakassa: an epidemic of spastic paraparesis associated with chronic
cyanide intoxication in a cassava staple area of Mozambique 2 Nutntional
factors and hydrocyanic acid content of cassava products. Bull. W. H. O. 62.
485-492.
Chandra, H.; Gupta, B. N.; Bhargava, S. K.; Clerk, S. H.; Mahendra, P N.
(1980) Chronic cyanide exposure - a biochemical and industrial hygiene study.
J. Anal. Toxicol. 4:161-165.
Cicerone. R. J.; Zellner, R. (1983) The atmospheric chemistry of hydrogen
cyanide (HCN). JGR J. Geophys. Res, Sect. C. 88: 10,689-10,696.
Clark, C. J.; Campbell, D. (1988) Cyanide and fire victims. Lancet ll:796.
Code of Federal Regulations. (1985) Subpart 2 - toxic and hazardous
substances. C. F. R. 29: §1910.1000, table Z-1.
Coffey, M. T.; Mankin, W. G.; Cicerone, R. J. (1981) Spectroscopicdetection
of stratospheric hydrogen cyanide. Science (Washington, DC) 214: 3JJ-JJb.
Conn E E.; Butler, G. W. (1969) The biosynthesis of cyanogenic glycosides
and other simple nitrogen compounds. In: Harborne, J. B.; Swain, T., eds.
Perspectives in phytochemistry: proceedings of the phytochemical society
symposium; April 1968; Cambridge, United Kingdom. New York, NY:
Academic Press; pp. 47-74.
Danchik R. S.; Boltz, D. F. (1970) Indirect atomic absorption spectrometric
methods for the determination of cyanide. Anal. Chim. Acta 49: 567-569.
Dave, Y. I.; Oza, K. T.; Puranik, S. A. (1985) Hazard prevention: biodegradation
of toxic cyanide waste. Chem. Age India 36: 775-777.
De Flora, S. (1981) Study of 106 organic and inorganic compounds in the
Sa/mone//a/microsome test. Carcinogenesis 2: 283-298.
DeMeyer, C. L.; Garbe, R. J. (1981) The determination of a range of concern
for mobile source emissions of hydrogen cyanide. Ann Arbor, Ml: U.b.
Environmental Protection Agency, Office of Mobile Source Air Pollution
42
-------
Control; EPA report no. EPA/AA/CTAB/PA/81-13. Available from- NTIS
Springfield, VA; PB82-1 20098.
Doherty P. A.; Perm, V. H.; Smith, R. P. (1982) Congenital malformations
induced by infusion of sodium cyanide in the golden hamster. Toxicol Appl
Pharmacol. 64: 456-464. '
Doudoroff, P. (1976) Toxicity to fish of cyanides and related compounds- a
review. Duluth, MN: U.S. Environmental Protection Agency, Environmental
Research Laboratory; EPA report no. EPA-600/3-76-038. Available from- NTIS
Springfield, VA; PB-253528/4.
Dudley, H. C.; Sweeney, T. R.; Miller, J. W. (1942) Toxicology of acrylonitrile
(vinyl cyanide): II. studies of effects of daily inhalation. J. Ind. Hyg. Toxicol. 24:
~
El Ghawabi, S. H.; Gaafar, M. A.; El-Saharti, A. A.; Ahmed, S. H.; Malash, K. K •
Fares, R. (1975) Chronic cyanide exposure: a clinical, radioisotope and
laboratory study. Br. J. Ind. Med. 32: 215-219.
Ermans, A. M.; Delange, F.; Van Der Velden, M.; Kinthaert, J. (1972) Possible
role of cyanide and thiocyanate in the etiology of endemic cretinism In-
Stanbury, J. B.; Kroc, R. L., eds. Human development and the thyroid gland-
relation to endemic cretinism, proceedings of a symposium; January Santa
Ynez Valley, CA. New York, NY: Plenum Press; pp. 455-486. (Advances in
experimental biology and medicine: v. 30).
Federal Register. (1986) Guidelines for carcinogen risk assessment F R
(September 24) 51: 33992-34003.
Fieser, L. F.; Fieser, M. (1967) Reagents for organic synthesis. New York NY-
John Wiley and Sons, Inc.; pp. 454-455.
Finck, P. A. (1969) Postmortem distribution studies of cyanide. Med. Ann. D.
C. 38i357~358.
Frant, M. S.; Ross, J. W., Jr.; Riseman, J. H. (1972) Electrode indicator
technique for measuring low levels of cyanide. Anal. Chem. 44: 2227-2230.
Gerry R. T.; Garnett, A.; Tsuchiya, K. (1985) CEH product review: hydrogen
cyanide. In: Chemical economics handbook. Menlo Park, CA: SRI International-
pp. 664.5020C-664.5020V. ouurwi,
Goulden, P. D.; Afghan, B. K.; Brooksbank, P. (1972) Determination of
nanogram quantities of simple and complex cyanides in water. Anal Chem
44: 1845-1849.
Griffin, H. E. (1981) Discussion: session 2, detection of health effects of
exposure to low doses of agents - epidemiological problems. EHP Environ
Health Perspect. 42: 57-60.
43
-------
Grosick H A- Kovacic, J. E. (1981) Coke-oven gas and effluent treatment. In:
Elliott, M. A., ed. Chemistry of coal utilization. New York, NY: Wiley and Sons;
pp. 1085-1152.
Harris, R.; Knowles, C. J. (1983) Isolation and growth of a Pseuoto/nonas
species that utilizes cyanide as a source of nitrogen. J. Gen. Microbiol. 129:
1005-1011.
Hartung R. (1982) Cyanides and nitriles. In: Clayton, G. D.; Clayton, F. E. eds.
Patty's industrial hygiene and toxicology: v. 2C, toxicology. 3rd ed. New York,
NY: John Wiley & Sons; pp. 4845-4900.
Harvey C A; Garbe, R. J.; Baines, T. M.; Somers, J. H.; Hellman, K. H.;
Carey P M (1983) A study of the potential impact of some unregulated motor
vehicle emissions. Presented at: Passenger car meeting; June; Dearborn, Ml.
Warrendale, PA: Society of Automotive Engineers, Inc.; SAE technical paper
no. 830987.
Herget, W. F.; Levine, S. P. (1986) Fourier transform infrared (FTIR)
spectro'scopy for monitoring semiconductor process gas emissions. Appl. Ind.
Hyg. 1: 110-112.
Himwich, W. A.; Saunders, J. P. (1948) Enzymatic conversion of cyanide to
thiocyanate. Am. J. Physiol. 153: 348-354.
Holliday, A. K.; Hughes, G.; Walker, S. M. (1973) Carbon. In: Bailar, J. C., Jr.;
Emeleus, H. J.; Nyholm, R.; Trotman-Dickenson, A. F., eds. Comprehensive
inorganic chemistry. New York, NY: Pergamon Press; p. 1243-1250.
Howard, J. W.; Hanzal, R. F. (1955) Chronic toxicity for rats of food treated
with hydrogen cyanide. Agric. 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.
International Agency for Research on Cancer. (1985) IARC monographs on the
evaluation of carcinogenic risk of chemicals to humans: v. 38, tobacco
smoking. Geneva, Switzerland: World Health Organization; pp. 96, 165-168.
Izatt R. M.; Christensen, J. J.; Pack, R. T.; Bench, R. (1962) Thermodynamics
of metal-cyanide coordination. I. pK, AH°, and AS" values as a function of
temperature for hydrocyanic acid dissociation in aqueous solution. Inorg.
Chem. 1:828-831.
Jenks W R (1979) Cyanides. In: Grayson, M., ed. Kirk-Othmer encyclopedia
of chemical technology: v. 7. 3rd ed. New York, NY: John Wiley & Sons, Inc.;
pp. 307- 331.
Jones, G. R.N. (1988) Cyanide and fire victims. Lancet II: 457.
44
-------
Karube, I.; Matsunaga, T.; Nakahara, T.; Suzuki, S.; Kada, T (1981)
1024 I'ol^ SCreenm9 °f mutaaens w'th a microbial sensor. Anal. Chem. 53:
Klaassen, C. D. (1980) Nonmetallic environmental toxicants: air pollutants
solvents and vapors, and pesticides - cyanide. In: Gilman, A. G.; Goodman L'
S.; Gilman, A., eds. The pharmacological basis of therapeutics. 6th ed. New
York, NY: Macmillan Publishing Co.; pp. 1651-1652.
Kushi, A.; Matsumoto, T.; Yoshida, D. (1983) Mutagen from the gaseous phase
of protein pyrolyzate. Agric. Biol. Chem. 47: 1979-1982.
Lang, K. (1933) Die Rhodanbildung im Tierkoerper [Thiocyanoqen in the
bodies of animals]. Biochem. Z. 259: 243-256.
Leo, A.; Hansch, C.; Elkins, D. (1971) Partition coefficients and their uses
Chem. Rev. 71 : 525, 555.
Levin, B. C.; Paabo, M.; Fultz, M. L.; Bailey, C. S. (1985) Generation of
hydrogen cyanide from flexible polyurethane foam decomposed under
different combustion conditions. Fire Mater. 9: 125-134.
Levin, B. C ; Paabo, M.; Gurman, J. L; Harris, S. E.; Braun, E. (1985b)
Evidence of toxicological synergism between carbon monoxide and carbon
diox.de. Presented in part at the Annual Meeting of the Society of Toxicoloqy
BeacfrFL°A Hi 1985*' ''985 ^ ^ American Chemical Society, Miami
Levin, B. C.; Paabo, M.; Gurman, J. L.; Harris, S. E. (1987a) Effects of
exposure to single or multiple combinations of the predominant toxic qases
and low oxygen atmospheres produced in fires. Fundam. Appl Toxicol •
submitted.
Levin BO; Gurman, J. L.; Paabo, M.; Baier, L.; Holt, T. (1987b) Toxicological
effects of different time exposures to the fire gases: carbon monoxide or
hydrogen cyanide or to carbon monoxide combined with hydrogen cyanide or
carbon dioxide. Presented at: U.S.-Japan Panel on Fire Research and Safety-
May; Norwood, MA. y>
McMillan D. E ; Svoboda, A. C., IV. (1982) The role of erythrocytes in cyanide
detoxification. J. Pharmacol. Exp.Ther. 221:37-42. ^y«"«ue
McNamara, B. P. (1976) Estimates of the toxicity of hydrocyanic acid vapors
in man. Aberdeen Proving Ground, MD: U.S. Department of the Army
l: rep°rt no' EB-TR-/6023- Available from: NTIS, Alexandria!
Mushett, C W.; Kelley, K. L.; Boxer, G. E.; Rickards, J. C. (1952) Antidotal
efficacy of Vitamin B12. (hydroxo-cobalamin) in experimental cyanide
poisoning. Proc. Soc. Exp. Biol. Med. 81 : 234-237. *-y«"iiue
National Institute for Occupational Safety and Health. (1976) Criteria for a
recommended standard ... occupational exposure to hydrogen cyanide and
cyan.de salts (NaCN, KCN, and Ca(CN)2). Washington, DC: U.S. Department
45
-------
of Health, Education, and Welfare; DREW (NIOSH) publication no. 77-108.
Available from: NTIS, Springfield, VA: PB-266230/2.
National Institute for Occupational Safety and Health. (1985) Hydrogen
cyanide. In: NIOSH pocket guide to chemical hazards. Washington, DC: U.S.
Department of Health and Human Services; pp. 138-139. Available from: GPO,
Washington, DC; S/N 017-033-00418-8.
Nonomura, M. (1988) Endogenous formation of hydrogen cyanide during
distillation for the determination of total cyanide. Toxicol. Environ. Chem. 17:
47-57.
Occupational Safety and Healty Administration. (1989) Part III. 29 CFR Part
1910. Air Contaminants; Final Rule. Federal Register, Vol. 54, No. 12, p. 2543,
Jan. 19, 1989.
Okoh, P. N. (1983) Excretion of 14C-labeled cyanide in rats exposed to chronic
intake of potassium cyanide. Toxicol. Appl. Pharmacol. 70: 335-339.
Okoh, P. N.; Pitt, G. A. J. (1982) The metabolism of cyanide and the gastro-
intestinal circulation of the resulting thiocyanate under conditions of chronic
cyanide intake in the rat. Can. J. Physiol. Pharmacol. 60: 381-386.
Osuntokun, B. 0. (1972) Chronic cyanide neurotoxicity and neuropathy in
Nigerians. Plant Foods Hum. Nutr. (Great Britain) 2: 215-266.
Perry, I. H. (1935) The effect of prolonged cyanide treatment on body and
tumor growth in rats. Am. J. Cancer 25: 592-598.
Philbrick, D. J.; Hopkins, J. B.; Hill, D. C.; Alexander, J. C.; Thomson, R. G.
(1979) Effects of prolonged cyanide and thiocyanate feeding in rats. J. Toxicol.
Environ. Health 5: 579-592.
Pitt, B. R.; Radford, E. P.; Gurtner, G. H.; Traystman, R. J. (1979) Interaction of
carbon monoxide and cyanide on cerebral circulation and metabolism. Arch.
Environ. Health 34: 354-359.
Powell, R. J. (1988) Detectors in battle. Chemistry in Britain 24: 665-669.
Raef, S. F.; Characklis, W. G.; Kessick, M. A.; Ward, C. H. (1977) Fate of
cyanide and related compounds in aerobic microbial systems-ll. Microbial
degradation. Water Res. 11: 485-492.
Richter, F., ed. (1960) Beilsteins Handbuch der organischen Chemie
[Beilstein's handbook of organic chemistry]. 4th ed. Berlin, Federal Republic of
Germany: Springer-Verlag; p. 61.
Rinsland, C. P.; Smith, M. A. H.; Rinsland, P. L; Goldman, A.; Brault, J. W.;
Stokes. G. M. (1982) Ground-based infrared spectroscopic measurements of
atmospheric hydrogen cyanide. JGR J. Geophys. Res. Sect. C 87: 11,119-
11,125.
46
-------
Ryan, D. E.; Holzbecher, J. (1971) Fluorescence and anions determination Int
J. Environ. Anal. Chem. 1: 159-168.
Sass, S.; Fisher, T. L; Jascot, M. J.; Herban, J. (1971) Gas-liquid
^o0^3, grap y of some irritants at various concentrations. Anal. Chem 43-
- ---
v M' Dan9erous properties of industrial materials. 6th ed. New
Yprk, NY: Van Nostrand Reinhold Company; pp. 1547-1549.
Solomonson, L P (1981) Cyanide as a metabolic inhibitor. In: Vennesland B •
n"v V ^r'f1 C' JD; WeSt'ey' J': Wissin9' F" eds' Cyanide in biology-
York, NY: Academic Press; pp. 11-28.
'; HaP°nik' E- <1981) Inhalation of irritant gases. Clin. Chest Med.
Surgeon General of the United States. (1964) Smoking and health: report of
he Advisory Committee to the Surgeon General of the Public Health Service
Washington, DC: U.S. Department of Health, Education, and Welfare; Public
neaitn service; p. 60.
Surgeon General of the United States. (1979) Smoking and health: a report of
the Surgeon. General/ Washington, DC: U.S. Department of Health, Education
*nn«Wel iare'^[C Health Service; P- 8-73; DHEW publication no. (PHS)79-
50066. Available from: GPO, Washington, DC; S/N-1 7-000-0021 8-0.
Rr™ P C Ear!V StU^ieS °n the toxic°logy of cyanide. In: Vennesland,
B Conn E, E.; Knowles, C. J.; Westley, J.; Wissing, F., eds. Cyanide in
biology. New York, NY: Academic Press; pp. 1-9. . "ydniae m
Tewe, O. O.; Maner, J. H. (1981 a) Long-term and carry-over effect of dietary
inorganic cyanide (KCN) in the life cycle performance and metabolism o f rats
Toxicol. Appl. Pharmacol. 58: 1-7.
Tewe, O. 0.; Maner, J. H. (1981b) Performance and pathophysiological
°f
Massachusetts
Towill, L E.; Drury, J. S.; Whitfield, B. L; Lewis, E. B.; Galyan' E L-
Mammons, A. S. (1978) Reviews of the environmental effects of pollutants- v'
cyanide. Cincinnati, OH: U.S. Environmental Protection Agency, Health Effects
from: NT,S,
TOXNET Toxicology Data Network. (1986) [Printout of data on hydrogen
Rlah±, ro»7n M tHaZa,rd°"S Substances Data Bank (HSDB) as of March 3].
D EBSDK? : 3ry °f Medicine' Toxic°logy Information Program
47
-------
U S Environmental Protection Agency. (1974) Manual of Methods for chemical
analysis of water and wastes. Washington, DC: Office of Technology Transfer,
EPA report no. EPA-625/6-74-003. Available from: NTIS, Springfield, VA, PB-
211968/3BA.
US. Environmental Protection Agency. (1980) Ambient water qua'"* criteria
for cyanides. Washington, DC: Prepared by the Office of Health and
Environmental Assessment, Environmental Criteria and Assessment Office
Cincinnati, OH for Office of Water Regulations and Standards, Criteria and
Standards Division; EPA report no. EPA-440/5-80-037. Available from: NTIS,
Springfield, VA; PB81-117483.
US Environmental Protection Agency. (1984) Health effects assessment for
cyanide. Office of Health and Environmental Assessment, Environmental
Criteria and Assessment Office, Cincinnati, OH; EPA report no. EPA-540/1 -86-
011. Available from: NTIS, Springfield, VA; PB86-134228/AS.
U.S. Environmental Protection Agency. (1985a) Drinking water criteria
document for cyanide [draft]. Cincinnati, OH: Office of Heath and
Environmental Assessment, Environmental Criteria ^Assessment Office
EPA report no. EPA-600/X-84-192-1. Available from: NTIS, Springfield, VA,
PB86-117793.
US Environmental Protection Agency, (1986) IRIS (Integrated Risk
Information System) [Reference doses (RfDs) for oral exposure from hydrogen
cyanide as of March 17]. Cincinnati, OH: Office of Health and Environmental
Assessment, Environmental Criteria and Assessment Office.
US Environmental Protection Agency. (1985b) Ambient water quality criteria
for cyanide - 1984. Washington, DC: Prepared by the Office of Health and
Environmental Assessment, Environmental Criteria and Assessment Office,
Cincinnati, OH for Office of Water Regulations andI Standards; EPA.report no.
EPA-440/5-84-028. Available from: NTIS, Springfield, VA; PB85-227460.
U.S. Environmental Protection Agency. (1988a) Drinking water regulations and
health advisories. Washington, DC : Office of Drinking Water, U.S.
Environmental Protection Agency.
U S Environmental Protection Agency. (1988b) List of hazardous substances
and' reportable quantities. 40 CFR Ch. 1 (7-1-88 Edition), Section 302.4, p.
131.
U.S. Environmental Protection Agency. (1988c) ATSDR Toxicological Profile
for Cyanide.
Union Carbide Corporation. (1976) Methyl isocyanate CH3N = C = O. New York,
NY: Union Carbide Corporation; report no. F-41443A,
Valentour, J. C.; Aggarwal, V.; Sunshine I. (^Sensitive gas
chromatographic determination of cyanide. Anal. Chem. 46: 924-925.
48
-------
Van Heijst, A. N. P.; Douze, J. M. C.; van Kesteren, R. G.; van Bergen, J. E. A.
M.; van Dijk, A. (1987) Therapeutic problems in cyanide poisoning Clin
Toxicol. 25:383-398.
Veith, G. D.; DeFoe, D. L; Bergstedt, B. V. (1979) Measuring and estimating
the bioconcentration factor of chemicals in fish. J. Fish. Res. Board Can 36-
1040-1048.
Vettorazzi, G. (1977) State of the art of the toxicological evaluation carried out
by the Joint FAO/WHO Expert Committee on Pesticide Residues III
Miscellaneous pesticides used in agriculture and public health. Residue Rev
66: 137-184.
Volini, M.; Alexander, K. (1981) Multiple forms and multiple functions of the
rhodaneses. In: Vennesland, B.; Conn, E. E.; Knowles, C. J.; Westley J •
Wissmg, F., eds. Cyanide in biology. New York, NY: Academic Press; pp.' 77-
y i.
Voorhoeve, R. J. H.; Patel, C. K. N.; Trimble, L. E.; Kerl, R. J. (1975) Hydrogen
cyanide production during reduction of nitric oxide over platinum catalvsts
Science (Washington, DC) 190: 149-151.
Way, J. L. (1981) Pharmacologic aspects of cyanide and its antagonism In-
Vennesland, B.; Conn, E. E.; Knowles, C. J.; Westley, J.; Wissing F eds
Cyanide in biology. New York, NY: Academic Press; pp. 29-49.
Westley, J. (1981) Cyanide and sulfane sulfur. In: Vennesland, B.; Conn E E •
Knowles, C. J.; Westley, J.; Wissing, F., eds. Cyanide in biology. New York
NY: Academic Press; pp. 61-76.
Wilkerson, I. (1986) 17 Michigan concerns to pay big pollution fines. New York
Times November 20: 17 (cols. 3-5)
Williams, R. T. (1959) Detoxication mechanisms: the metabolism and
detoxication of drugs, toxic substances and other organic compounds 2nd ed
New York, NY: John Wiley & Sons Inc.; pp. 390-409
Wilson, J. (1983) Cyanide in human disease: a review of clinical and laboratory
evidence. Fundam. Appl. Toxicol. 3: 397-399.
Wilson, J.; Linnell, J. C.; Matthews, D. M. (1971) Plasma-cobalamins in neuro-
ophthalmological diseases. Lancet 1: 259-261.
Windholz, M., ed. (1983) The Merck index: an encyclopedia of chemicals
drugs, and biologicals. 10th ed. Rahway, NJ: Merck & Co., Inc.; p. 696.
Yamamoto, K.; Kuwahara, C. (1981) A study on the combined action of CO
and HCN in terms of concentration-time products. Z. Rechtsmed 86- 287-294
[DIALOG abstract]
Yamamoto, K.; Yamamoto, Y.; Hattori, H.; Samori, T. (1982) Effects of routes of
administration on the cyanide concentration distribution in the various oraans
of cyanide-intoxicated rats. Tohoku J. Exp. Med. 137: 73-78.
49
-------
------- |