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

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                           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.

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                                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

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                             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

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                               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.

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                  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

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                 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

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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

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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.

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y

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                           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)

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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)

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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)

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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)

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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)

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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

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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

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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

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 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

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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

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 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

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    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

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     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

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            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

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 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

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           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

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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

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                              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

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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

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             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

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        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

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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

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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

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                       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

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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

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  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

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(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

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  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

-------




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creased plasma thyroxine levels, decreased se-
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thyroxine at 1 1 months, no definitive lesion to
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matter with moderate primary myelin degenera-
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changes were more pronounced in KCN-treated
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B12 and iodine deficient diets.


















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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

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                                    46

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