v>EPA
Ur.itecl States
Environmental Protection
Agency
Office of Water
Regulations and Standards
Criteria and Standards Division
Washington DC 20460
EPA 440/5-80-037
October 1980
Ambient
Water Quality
Criteria for
Cyanides
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AMBIENT WATER QUALITY CRITERIA FOR
CYANIDE
Prepared By
U.S. ENVIRONMENTAL PROTECTION AGENCY
Office of Water Regulations and Standards
Criteria and Standards Division
Washington, D.C.
Office of Research and Development
Environmental Criteria and Assessment Office
Cincinnati, Ohio
Carcinogen Assessment Group
Washington, D.C.
Environmental Research Laboratories
Corvalis, Oregon
Duluth, Minnesota
Gulf Breeze, Florida
Narragansett, Rhode Island
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DISCLAIMER
This report has been reviewed by the Environmental Criteria and
Assessment Office, U.S. Environmental Protection Agency, and approved
for publication. Mention of trade names or commercial products does not
constitute endorsement or recommendation for use.
AVAILABILITY NOTICE
This document is available to the public through the National
Technical Information Service, (NTIS), Springfield, Virginia 22161.
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FOREWORD
Section 304 (a)(l) of the Clean Water Act of 1977 (P.L. 95-217),
requires the Administrator of the Environmental Protection Agency to
publish criteria for water quality accurately reflecting the latest
scientific knowledge on the kind and extent of all identifiable effects
on health and welfare which may be expected from the presence of
pollutants in any body of water, including ground water. Proposed water
quality criteria for the 65 toxic pollutants listed under section 307
(a)(l) of the Clean Water Act were developed and a notice of their
availability was published for public comment on March 15, 1979 (44 FR
15926), July 25, 1979 (44 FR 43660), and October 1, 1979 (44 FR 56628).
This document is a revision of those proposed criteria based upon a
consideration of comments received from other Federal Agencies, State
agencies, special interest groups, and individual scientists. The
criteria contained in this document replace any previously published EPA
criteria for the 65 pollutants. This criterion document is also
published in satisifaction of paragraph 11 of the Settlement Agreement
in Natural Resources Defense Counci 1, et. a!.. vs. Train, 8 ERC 2120
(D.D.C. 1976), modified, 12 ERC 1833 (D.D.C. 1979).
The term "water quality criteria" is used in two sections of the
Clean Water Act, section 304 (a)(l) and section 303 (c)(2). The term has
a different program impact in each section. In section 304, the term
represents a non-regulatory, scientific assessment of ecological ef-
fects. The criteria presented in this publication are such scientific
assessments. Such water quality criteria associated with specific
stream uses when adopted as State water quality standards under section
303 become enforceable maximum acceptable levels of a pollutant in
ambient waters. The water quality criteria adopted in the State water
quality standards could have the same numerical limits as the criteria
developed under section 304. However, in many situations States may want
to adjust water quality criteria developed under section 304 to reflect
local environmental conditions and human exposure patterns before
incorporation into water quality standards. It is not until their
adoption as part of the State water quality standards that the criteria
become regulatory.
Guidelines to assist the States in the modification of criteria
presented in this document, in the development of water quality
standards, and in other water-related programs of this Agency, are being
developed by EPA.
STEVEN SCHATZOW
Deputy Assistant Administrator
Office of Water Regulations and Standards
111
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ACKNOWLEDGEMENT
Aquatic Life Toxicology:
Charles E. Stephan , ERL-Duluth John H. Gentile, ERL-Narragansett
U.S. Environmental Protection Agency U.S. Environmental Protection Agency
Mammalian Toxicology and Human Health Effects:
Roger Smith (author) Robert M. Bruce, ECAO-RTP
Dartmouth Medical College U.S. Environmental Protection Agency
Steven D. Lutkenhoff (doc. mgr.) Edward Calabrese
ECAO-Cin University of Massachusetts
U.S. Environmental Protection Agency
J.F. Stara, ECAO-Cin, (doc. mgr.) Patrick Durkin
U.S. Environmental Protection Agency Syracuse Research Corporation
David Fankhauser Vincent Finelli
University of Cincinnati University of Cincinnati
Ernest Foulkes A.N. Milbert
University of Cincinnati National Institute for Occupational
Safety and Health
Havish Sikka
Syracuse Research Corporation
Technical Support Services Staff: D.J. Reisman, M.A. Garlough, B.L. Zwayer,
P.A. Daunt, K.S. Edwards, T.A. Scandura, A.T. Pressley, C.A. Cooper,
M.M. Denessen.
Clerical Staff: C.A. Haynes, S.J. Faehr, L.A. Wade, D. Jones, B.J. Bordicks,
B.J. Quesnell, T. Highland, B. Gardiner.
IV
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TABLE OF CONTENTS
Criteria Summary
Introduction A-l
Aquatic Life Toxicology B-l
Introduction B-l
Effects B-3
Acute Toxicity B-3
Chronic Toxicity B-4
Plant Effects B-5
Residues B-5
Miscellaneous B-5
Summary B-6
Criteria B-7
References B-28
Mammalian Toxicology and Human Health Effects C-l
Introduction C-l
Exposure C-2
Ingestion from Water C-4
Ingestion from Food C-5
Inhalation C-7
Dermal C-8
Pharmacokinetics C-8
Absorption C-8
Distribution C-9
Metabolism C-10
Excretion C-14
Effects C-14
Acute, Subacute, and Chronic Toxicity C-14
Synergism and/or Antagonism C-20
Teratogenicity, Mutagenicity, and Carcinogenicity C-22
Criterion Formulation C-24
Existing Guidelines and Standards C-24
Special Groups at Risk C-25
Basis and Derivation of Criteria C-25
References C-29
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CRITERIA DOCUMENT
CYANIDE
CRITERIA
Aquatic Life
For free cyanide (sum of cyanide present as HCN and CN~, expressed as
CN) the criterion to protect freshwater aquatic life as derived using the
Guidelines is 3.5 ug/1 as a 24-hour average, and the concentration should
not exceed 52 wg/1 at any time.
The available data for free cyanide (sum of cyanide present as HCN and
CN~, expressed as CN) indicate that acute toxicity to saltwater aquatic
life occurs at concentrations as low as 30 ug/1 and would occur at lower
concentrations among species that are more sensitive than those tested. If
the acute-chronic ratio for saltwater organisms is similar to that for
freshwater organisms, chronic toxicity would occur at concentrations as low
as 2.0 yg/1 for the tested species and at lower concentrations among species
that are more sensitive than those tested.
Human Health
The ambient water quality criterion for cyanide is recommended to be
identical to the existing water standard which is 200 ug/1. Analysis of the
toxic effects data resulted in a calculated level which is protective of
human health against the ingestion of contaminated water and contaminated
aquatic organisms. The calculated value is comparable to the present stan-
dard. For this reason a selective criterion based on exposure solely from
consumption of 6.5 grams of aquatic organisms was not derived.
VI
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INTRODUCTION
Cyanides are defined as organic or inorganic compounds which contain the
-CN group. Hydrogen cyanide (HCN) is lighter than air and diffuses rapid-
ly. Free HCN is very reactive and occurs only rarely in nature; it is us-
ually prepared commercially from ammonia and methane at elevated tempera-
tures with a platinum catalyst. Hydrogen cyanide is soluble in all propor-
tions in water. It is quite volatile, having a vapor pressure of 100 torr
at -178'C; 360 torr at 7*C; 658.7 torr at 21.9'C; and 760 torr at 26.7*C
(boiling point) (Towill, et al. 1978). Cyanide ions form complexes with a
variety of metals, especially those of the transition series. Ferricyanides
and ferrocyanides have a variety of industrial uses but do not release cya-
nide unless exposed to ultraviolet light. Thus, sunlight can lead to the
mobilization of cyanide in waters containing iron cyanides. Cyanogen
[(CNL] is a flammable gas of high toxicity which has a vapor pressure of
about 5 atm. at 20°C (Towill, et al. 1978). It reacts slowly with water to
produce HCN, cyanic acid, and other compounds. Cyanates contain the -OCN
radical. Inorganic cyanates, which are formed industrially by the oxidation
of cyanide salts, hydrolyze in water to form ammonia and bicarbonate ion.
Alkyl cyanates trimerize readily (when sufficiently concentrated) to form
cyanurates. Alkyl isocyanates contain the -NCO radical and are formed from
cyanates; they, too, are readily hydrolyzed. Thiocyanates (-SCN radical)
are formed from cyanides and sulfur-containing materials and are more stable
than cyanates. Solutions of thiocyanates form free hydrogen cyanide in a-
cidic media. Nitriles are organic compounds that have a cyanide group as a
substituent. The nitriles are generally much less toxic than the free hy-
drogen cyanide or the metal cyanides. Cyanohydrins [R,,C(QH)CN] are toxic
compounds which can decompose with the release of HCN or CN~ under en-
vironmental conditions (U.S. EPA, 1979).
A-l
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REFERENCES
Towill, I.E., et al. 1978. Reviews of the environmental effects of pollu-
tants. V. Cyanide. U.S. EPA. NTIS-PB 289-920. p. 11.
U.S. EPA. 1979. Water-related environmental fate of 129 priority pollu-
tants. Vol. I. EPA 440/4-79-029a.
A-2
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Aquatic Life Toxicology*
INTRODUCTION
Compounds containing the cyanide group (CN) are used and readily formed
in many industrial processes and can be found in a variety of effluents,
such as those from the steel, petroleum, plastics, synthetic fibers, metal
plating, mining, and chemical industries. Cyanide commonly occurs in water
as hydrocyanic acid (HCN), the cyanide ion (CN~), simple cyanides, roetal-
locyanide complexes, or as simple chain and complex ring organic compounds.
"Free cyanide" is defined as the sum of the cyanide present as HCN and as
CN~. The alkali metal salts such as potassium cyanide (KCN) and sodium
cyanide (NaCN) are very soluble in aqueous solutions and the resulting cya-
nide ions readily hydrolyze with water to form HCN. The extent of HCN for-
mation is mainly dependent upon water temperature and pH. At 20°C and a
pH of 8 or below the fraction of free cyanide existing as HCN is at least
0.96.
The cyanide ion (CN~) can combine with various heavy metal ions to
form metallocyanide complex anions, whose stability is highly variable.
Zinc and cadmium cyanide complexes, when diluted with water, are known to
dissociate rapidly and nearly completely to form HCN. Some of the other
metallocyanide anions, such as those formed with copper, nickel, and iron,
demonstrate varying degrees of stability. The hexacyanoferrate(II) and
-(III) complexes are subject to direct photolysis by natural light. The
*The reader is referred to the Guidelines for Deriving Water Quality Criter-
ia for the Protection of Aquatic Life and Its Uses in order to better under-
stand the following discussion and recommendation. The following tables
contain the appropriate data that were found in the literature, and at the
bottom of each table are calculations for deriving various measures of tox-
icity as described in the Guidelines.
B-l
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release of cyanide ion by this phenomenon may be important in relatively
clear receiving waters.
The toxicity to aquatic organisms of most simple cyanides and metallo-
cyanide complexes is due mostly to the presence of HCN as derived from ioni-
zation, dissociation, and photodecomposition of cyanide-containing compounds
(Doudoroff, et al. 1966; Smith, et al. 1979), although the cyanide ion
(CN~) is also toxic (Broderius, et al. 1977). In most cases the complex
ions themselves have relatively low toxicity. The available literature on
the toxicity to fish of cyanides and related compounds was critically re-
viewed by Doudoroff (1976).
Since both HCN and CN~ are toxic to aquatic life and since the vast
majority of free cyanide usually exists as the more toxic HCN, and since al-
most all existing CN~ can be readily converted to HCN at pH values that
commonly exist in surface waters, the cyanide criterion will be stated in
terms of free cyanide expressed as CN. Free cyanide is a much more reliable
index of toxicity than total cyanide since total cyanide could include ni-
triles (organic cyanides) and stable metallocyanide complexes. In highly
alkaline waters a free cyanide criterion based on the relative toxicity of
HCN and the CN~ ion may be appropriate due to the dependence of the form
of free cyanide on pH.
All of the cyanide concentrations given herein are free cyanide ex-
pressed as CN. Data reported in the original literature as ug of HCN/1 were
adjusted to free cyanide as CN as follows:
(ug of Free Cyanide as CN/1) = (yg of HCN/1) (1 + IQPH-pKHCN) x mol. wt. CN
mol. wt. HCN
B-2
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3 i-3440 * 2347.2 (izatt, et al. 1962)
T + 273.16
where T » degrees Celsius.
EFFECTS
Acute Toxicity
The results of 7 acute tests with 6 freshwater invertebrate species are
given in Table 1. With three exceptions (Oseid and Smith, 1979; U.S. EPA,
1980a), results are based on static tests with unmeasured concentrations.
Most of the species tested were considerably more tolerant than fishes.
Daphnia pulex and Gammarus pseudolimnaeus, however, were comparable to
fishes in sensitivity. There was greater variability in sensitivity of
invertebrate species to free cyanide than was observed for fish species.
The 96-hour LC5Q values based on acute toxicity tests with 10 fish
species are summarized in Table 1. The greatest number of tests were con-
ducted with brook trout, bluegill, and fathead minnows. About 80 percent of
the data resulted from studies conducted by Smith, et al. (1978) and Bro-
derius, et al. (1977). All of their tests were conducted using flow-through
techniques with the reported HCN levels calculated from analytically
measured free cyanide concentrations.
Certain life stages and species of fishes appear to be more sensitive to
cyanide than others. Embryos, sac fry, and warmwater species tended to be
the most resistant. A review of pertinent data for juvenile fishes indi-
cates that free cyanide concentrations in the range from about 50 to 200
ug/1 have eventually proven fatal to most of the more sensitive fish spe-
cies, with concentrations much above 200 yg/1 being rapidly fatal to most
fish species. Thus there is a relatively narrow range of species sensitivi-
ty for fish. A comparison of acute toxicity results for fishes supports the
B-3
-------
hypothesis that the toxicity of simple cyanide solutions is underestimated
by static tests, especially when the cyanide concentrations in the test sol-
utions are not measured.
A number of authors have reported an increase in toxicity of cyanide
with reduction in dissolved oxygen below the saturation level (Doudoroff,
1976; Smith, et al. 1978). The tolerance of fishes to cyanide solutions
that are rapidly lethal has been observed to decrease with a rise of temper-
ature. Long-term lethality tests, however, have demonstrated that juvenile
fishes are more susceptible to cyanide with a reduction in temperature
(Smith, et al. 1978). No pronounced relationship has been observed between
the acute toxicity of cyanide to fishes and alkalinity, hardness, or pH
below about 8.3.
Based on Species Mean Acute Values summarized in Table 3, the Freshwater
Final Acute Value, derived using the calculation procedures described in the
Guidelines, is 52 pg/1.
For saltwater species, acute toxicity data are available for three in-
vertebrate and one fish species and range from 30 to 372 ug/1- These few
values suggest that free cyanide is very toxic to saltwater species, which
have about the same sensitivity as freshwater organisms.
Chronic Toxicity
The long-term survival and growth of various freshwater fish species was
observed to be seriously reduced at free cyanide concentrations of about 20
to 50 vg/1 (Kimball, et al. 1978; Koenst, et al. 1977) (Table 5). Results
from only a few full and partial life cycle chronic tests with fishes have
been reported (Table 2). Based on reduced long-term survival in an early
life stage test with bluegills and reduced reproduction by brook trout and
fathead minnows in a partial life cycle and life cycle test, the chronic
values were 14, 7.9, and 16 pg/1, respectively.
8-4
-------
Two freshwater invertebrate life cycle tests (Table 2) were conducted;
one with the isopod, Asellus communis, and the other with the scud, Gammarus
pseudolimnaeus. The chronic values were 34 and 18 yg/1, respectively.
The Final Acute-Chronic Ratio of 14.8 is the geometric mean of the five
acute-chronic ratios (Table 3). The Freshwater Final Acute Value of 52 yg/1
divided by the Final Acute-Chronic Ratio of 14.8 results in the Freshwater
Final Chronic Value for free cyanide (expressed as CN) of 3.5 ug/1 (Table 3).
No chronic data are available for cyanide and any saltwater species.
Plant Effects
Data on the toxicity of free cyanide to one freshwater and two salt-
water species of algae are presented in Table 4. Apparently algae are not
very sensitive to cyanide when compared with other aquatic organisms, and
adverse effects of cyanide on plants are unlikely at concentrations protec-
tive of acute effects on most freshwater and saltwater invertebrate and fish
species.
Residues
No residue data were found for cyanide.
Miscellaneous
Table 5 contains no data that would alter the selection of 3.5 yg/1 as
the Final Chronic Value. In fact, there are some pertinent additional
studies, on physiological and behavioral responses of fishes to low levels
of free cyanide, that are supportive of the calculated chronic value.
Several authors (Neil, 1957; Broderius, 1970; Dixon, 1975; Lesniak,
1977; Leduc, 1978; Oseid and Smith, 1979; Rudy, et al. 1979) reported ad-
verse effects due to cyanide at concentrations as low as 10 yg/1. In
another study, Kimball, et al. (1978) reported that no reproduction occurred
among adult bluegills when exposed for 289 days to the lowest concentration
tested (5.2 yg of HCN/1 = 5.4 yg of free cyanide as CN/1). During this
B-5
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period, however, only a total of 13 spawnings occurred in two controls and
no dose-response relationship was observed. Because of reservations regard-
ing the spawning data, the chronic value for bluegills was based on long
term fry survival. On the other hand, the most sensitive adverse effect
caused by cyanide on both fathead minnows and brook trout was reduced repro-
duction. The freshwater Final Chronic Value of 3.5 ug/1, based on fish and
invertebrate chronic data, appears to be supported by these miscellaneous
studies.
Summary
All concentrations herein for free cyanide (sum of cyanide present as
HCN and CN~) are expressed as CN. The data used in deriving the criterion
are predominantly from flow-through tests in which toxicant concentrations
were measured.
Data on the acute toxicity of free cyanide are available for a wide
variety of freshwater organisms that are involved in diverse community func-
tions. Except for the more sensitive invertebrate species, such as Daphnia
pulex and Gammartis pseudolimnaeus, invertebrate species are usually more
tolerant of cyanide than are freshwater fish species, which have most acute
values clustered between 50 to 200 ug/1. A long-term survival and two life
cycle tests with fish gave chronic values of 7.9, 14, and 16 ug/1,
respectively. Chronic data for the freshwater invertebrate species were
more variable, with Gammarus pseudolimnaeus being comparable to fishes in
sensitivity and isopods being considerably more tolerant.
The acute toxicity of free cyanide to saltwater organisms is comparable
to that observed for freshwater organisms, but no data are available con-
cerning chronic toxicity. For saltwater aauatic life no criterion for free
cyanide can be derived using the Guidelines.
B-6
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Plants are much more resistant to cyanide than animals and thus their
well-being is assured if more sensitive aquatic animals are protected.
CRITERIA
For free cyanide (sum of cyanide present as HCN and CN~, expressed as
CN) the criterion to protect freshwater aquatic life as derived using the
Guidelines is 3.5 pg/1 as a 24-hour average, and the concentration should
not exceed 52 wg/l at any time.
The available data for free cyanide (sum of cyanide present as HCN and
CN~ expressed as CN) indicate that acute toxicity to saltwater aquatic
life occurs at concentrations as low as 30 ^g/1 and would occur at lower
concentrations among species more sensitive than those tested. If the
acute-chronic ratio for saltwater organisms is similar to that for fresh-
water organisms, chronic toxicity would occur at concentrations as low as
2.0 yg/1 for the tested species and at lower concentrations among species
that are more sensitive than those tested.
B-7
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Table 1. Acute values for cyanide
Species
Method*
LC50/EC50
(UQ/D
Species Mean
Acute Value
(Uq/l)
FRESHWATER SPECIES
Snail,
Physa heterostropha
Snal 1,
Physa heterostropha
Cladoceran,
Daphnla pulex
Isopod,
Ase 1 1 us conmun 1 s
Scud,
Gamnarus pseudo 1 1 mnaeus
Midge,
Tanytarsus dlssimllls
Brook trout (sac fry),
Salvellnus fontlnalls
Brook trout (sac fry),
Salvellnus fontlnalls
Brook trout (sac fry),
Salvellnus fontlnalls
Brook trout (sac fry),
Salvellnus fontlnalls
Brook trout (swim-up fry),
Salvetlnus fontlnalls
Brook trout (swim-up fry),
Salvellnus fontlnalls
Brook trout (swim-up fry),
Salvellnus fontlnalls
Brook trout (swim-up fry).
s.
s,
s,
FT,
FT,
s,
FT.
FT,
FT,
FT,
FT,
FT,
FT,
FT,
U
U
U
M
M
M
H
M
M
M
M
H
M
H
432
431
83
2,326
167
2,240
105
342
507
252
84
54.4
86.5
104
431
83
2,326
167
2,240
Salvellnus fontlnalls
Reference
Patrick, et a I. 1968
Cairns & Scheler,
1958
Lee, 1976
Oseld & Smith, 1979
Oseld 4 Smith, 1979
U.S. EPA, 1980a
Smith, et al. 1978
Smith, et al. 1978
Smith, et al. 1978
Smith, et al. 1978
Smith, et al. 1978
Smith, et al. 1978
Smith, et al. 1978
Smith, et al. 1978
B-8
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Table 1. (Continued)
LC50/EC50
Species Method* (ug/l)
Brook trout (swim-up fry), FT, M 90.3
Salvellnus fontlnalls
Brook trout (Juvenile), FT, M 73.5
Salvellnus tontlnalls
Brook trout (Juvenile), FT, M 83
Salvellnus fontlnalls
Brook trout (juvenile), FT, M 75
Salvellnus fontlnalls
Brook trout (Juvenile), FT, M 86.4
SaIve11nus font Ina11s
Brook trout (juvenile), FT, M 91.9
Salvellnus fontlnalls
Brook trout (juvenile), FT, M 99
SaIveI Inus font InaI Is
Brook trout (juvenile), FT, M 96.7
Salvellnus tontlnalls
Brook trout (juvenile), FT, M 112
SaIvelInus fontlnalIs
Brook trout (juvenile), FT, M 52
SalvelInus fontlnalIs
Brook trout (juvenile), FT, M 60.2
Salvellnus fontlnalls
Brook trout (juvenile), FT, M 66.8
SalvelInus fontlnalIs
Brook trout (juvenile), FT, M 71.4
Salvellnus fontlnalls
Brook trout (juvenile), FT, M 97
Salvellnus fontlnalls
Species Mean
Acute Value
Reference
Smith, et al. 1978
Smith, et al. 1978
Smith, et al. 1978
Smith, et al. 1978
Smith, et al. 1978
Smith, et al. 1978
Smith, et al. 1978
Smith, et al. 1978
Smith, et al. 1978
Smith, et al. 1978
Smith, et al. 1978
Smith, et al. 1978
Smith, et al. 1978
Smith, et al. 1978
B-9
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Table 1. (Continued)
Species
Brook trout • (Juvenl le) ,
Salvel Inus fontlnal Is
Brook trout (adult),
Salvel Inus font! nails
Rainbow trout (Juvenile),
Sal mo galrdnerl
Goldfish (juvenile),
Carasslus auratus
Fathead minnow (fry),
Plmephales promelas
Fathead minnow (fry),
Plmephales promelas
Fathead minnow (fry),
Plmephales prome las
Fathead minnow (fry),
Plmephales promelas
Fathead minnow (fry),
Plmephales promelas
Fathead minnow (juvenile),
Plmephales promelas
Fathead minnow (juvenile),
Plmephales promelas
Fathead minnow (juvenile),
Plmephales promelas
Fathead minnow (Juvenile),
Plmephales promelas
Fathead minnow (juvenile),
Plmephales promelas
Method*
FT,
FT.
FT,
FT,
FT,
FT,
FT,
FT,
FT,
FT,
FT,
FT,
FT,
FT,
M
M
M
M
M
M
M
M
M
M
M
M
M
M
Species Mean
LC50/EC50 Acute Value
Cug/l) (wo/1)
143
156 103
57 57
318 318
120
98.7
81.8
110
116
119
126
81.5
124
137
Reference
Smith, et
Cardwel 1,
1976
Smith, et
Cardwel 1,
1976
Smith, et
Smith,
Smith,
Smith,
Smith,
Smith,
Smith,
Smith,
Smith,
Smith,
et
et
et
et
et
et
et
et
et
al
et
al
et
al
al
al
al
al
al
al
al
al
al
. 1978
al.
. 1978
al.
. 1978
. 1978
. 1978
. 1978
. 1978
. 1978
. 1978
. 1978
. 1978
. 1978
B-10
-------
Table t. (Continued)
Species
Fathead minnow (juveni
Ptmephales promelas
Fathead minnow (Juveni
Plmephales promelas
Fathead minnow (juveni
Plmephales promelas
Fathead minnow (juveni
Plmephales promelas
Fathead minnow (juveni
Plmephales promelas
Fathead minnow (juveni
Plmephales promelas
Fathead minnow (juveni
Plmephales promelas
Fathead minnow (juveni
Plmephales promelas
Fathead minnow (juveni
P 1 mepha 1 es promelas
Fathead minnow (juveni
Plmephales promelas
Fathead minnow (juveni
Plmephales promelas
Fathead minnow (juveni
Plmephales promelas
Fathead minnow (juveni
PI mepha tes promelas
Fathead minnow (juveni
Plmephales promelas
Method*
le),
le),
le),
le).
le).
le),
le).
le),
le).
le).
le),
le).
le).
le).
FT,
FT,
FT,
FT,
FT,
FT,
FT,
FT.
FT,
FT,
s.
FT,
FT.
FT,
M
M
M
M
M
M
M
M
M
M
U
M
M
M
LC50/EC50
(ug/n
131
105
119
131
122
161
188
175
163
169
230
120
113
128
Species Mean
Acute Value
(ug/l) Reference
Smith.
Smith,
Smith,
Smith,
Smith,
Smith,
Smith,
Smith,
Smith,
Smith,
et
et
et
et
et
et
et
et
et
et
Doudorof f
Broderlus
1977
Broderlus
1977
Broderlus
1977
al.
al.
al.
al.
al.
al.
al.
al.
al.
al.
1978
1978
1978
1978
1978
1978
1978
1978
1978
1978
, 1956
. et
, et
, et
al.
al.
al.
B-ll
-------
Table 1. (Continued)
Species Method*
Fathead minnow (Juvenile), FT, M
Plmephales promelas
Fathead minnow, S, M
Plmephales promelas
Fathead minnow, S, M
Plmephales promelas
Mosqultoflsh, S, U
Gambusla afflnls
Guppy (adult), FT, M
Poec Ilia ret 1 cu 1 ata
Blueglll (fry), FT, M
Lepomls macrochlrus
Blueglll (fry), FT, M
Lepomls macrochlrus
Blueglll (fry), FT, M
Lepomls macrochlrus
Bluegll 1 (fry), FT, M
Lepomls macrochlrus
Blueglll (juvenile), FT, M
Lepomls macrochlrus
Blueglll (juvenile), FT, M
Lepomls macrochlrus
Blueglll (Juvenile), FT, M
Lepomls macrochlrus
Blueglll (juvenile), FT, M
Lepomls macrochlrus
Blueglll (Juvenile), FT, M
Lepomls macrochlrus
Species Mean
LC50/EC50 Acute Value
(u^/l ) (ug/l) Reference
128 - Broderlus, et al.
1977
350 - Henderson, et al.
1961
230 125 Henderson, et al.
1961
639 639 Wat ten, et al.
1957
147 147 Anderson & Weber,
1975
364 - Smith, et al. 1978
232 - Smith, et al. 1978
279 - Smith, et al. 1978
273 - Smith, et al. 1978
81 - Smith, et al. 1978
85.7 - Smith, et al. 1978
74 - Smith, et al. 1978
100 - Smith, et al. 1978
107 - Smith, et al. 1978
B-12
-------
Table I. (Continued)
LC50/EC50
Species Method* (ug/1)
Blueglll (juvenile), FT, M 99
Lepomls macrochlrus
Blueglll (juvenile), FT, M 113
Lepomls macrochlrus
Blueglll (Juvenile), FT, M 121
Lepomls macrochlrus
Blueglll (juvenile), FT, M 126
Lepomls macrochlrus
Blueglll (juvenile), S, U 180
Lepomls macrochlrus
Blueglll, S, U ISO
Lepomls macrochlrus
Bluegill (juvenile), S, M 150
Lepomls macrochlrus
Blueglll (juvenile), S, M 160
Lepomls macrochlrus
Largemouth boss FT, M 102
(juvenlle),
Mlcropterus salmoIdes
Black crapple, FT, M 102
Pomoxls nlgromaculntus
Yellow perch (fry), FT, M 288
Perca flavescens
Yellow perch (fry), FT, M 330
Perca flavescens
Yellow perch (Juvenile), FT, M 88.9
Perca flavescens
Yellow perch (Juvenile), FT, M 93
Perca flavescens
Species Mean
Acute Value
(ug/l)
137
102
102
Reference
Smith, et al. 1978
Smith, et al. 1978
Smith, et al. 1978
Smith, et al. 1978
Cairns & Scheler,
1958
Patrick, et al,
1968
Henderson, et al.
1961
Cairns & Scheler,
1963
Smith, et al. 1979
Smith, et al. 1979
Smith, et al. 1978
Smith, et al. 1978
Smith, et al. 1978
Smith, et al. 1978
B-13
-------
Table 1. (Continued)
Species
Yellow parch (Juvenile),
Perca flavescens
Yellow perch (juvenile),
Perca flavescens
Yellow perch (Juvenile),
Perca flavescens
Yellow perch (juvenile),
Perca flavescens
Copepod,
Acartla clausl
Mysld shrimp,
Hysldopsls bah la
Mysld shrimp,
Mysldopsls btgelowt
Winter flounder,
Pseudop leuronectes
amer 1 cana
Method*
FT, M
FT, M
FT, M
FT, M
S, U
S, U
S, U
S, U
Species Mean
LC50/EC50 Acute Valve
(itfl/l) (ug/1)
74.7
94.7
101
107 125
SALTWATER SPECIES
30 30
93 93
124 124
372 372
Reference
Smith, et
Smith, et
Smith, et
Smith, et
U.S. EPA,
U.S. EPA,
U.S. EPA,
U.S. EPA,
al. 1978
al. 1978
al. 1978
al. 1978
1980b
19605
19806
1980b
* S = static, FT » flow-through, U » unmeasured, M * measured
B-14
-------
Table 2. Chronic values for cyanide
Species
Isopod,
Asellus communls
Scud,
Gammarus pseudol Imnaeus
Brook trout,
Salvellnus font! nails
Fathead minnow,
PI map hales promelas
B 1 ueg 1 1 1 ,
Lepomls macrochlrus
Test*
LC
LC
LC
LC
as
LlMltS
(tifl/l)
FRESHWATER SPE
29-40
16-21
5.6-11.0
13.3-20.2
9.3-19.8
Chronic
Value
CIES
34
18
7.6
16
14
Reference
Oseld & Smith, 1979
Oseid & Smith, 1979
Koenst, et al. 1977
Llnd, et al. 1977
Klmbal 1, et al. 1978
* LC - Ufa cycle or partial life cycle; ELS = early life stage
Acute-Chronic Ratios
Species
Isopod,
Ase 1 1 us coomun 1 s
Scud,
Ganmarus pseudol Imnaeus
Brook trout,
Sa 1 ve 1 1 nus font 1 na 1 i s
Fathead minnow,
Plroephales promelas
Acute
Value
(uq/l)
2,326
167
103
141
Chronic
Value
tug/D
34
18
7.8
16
Ratio
68
9.3
13
8.8
B-15
-------
TabU 2. (Continued)
Acute-Chronic Ratios
Species
Bluegll I,
Lepomls macrochlrus
Chronic
Value
(ua/D
14
B-16
-------
Table 3. Species neon acute values and acute-chronic ratios for cyanide
ink*
15
14
13
12
11
10
9
8
7
6
5
4
3
Species
FRESHWATER
1 sopod,
Asel lus communls
Midge,
Tany tarsus dlssimllls
Mosqultoflsh,
Gambusla afflnls
Snail,
Physa heterostropha
Goldfish,
Carasslus auratus
Scud,
Gammarus pseudol Imnaeus
Guppy,
Poecl lla retlculata
Blueglll,
Lepomls macrochlrus
Fathead minnow,
Plmephales promelas
Yel low perch.
Per ca flavescens
Brook trout,
Salvellnus fontlnalls
Largemouth bass,
Mlcropterus sal mo Ides
Black cr apple,
Pomoxls nigromaculatus
Species Mean Species Mean
Acute Value Acute-Chronic
(ua/D Ratio
SPECIES
2,326 68
2,240
639
431
318
167 9.3
147
137 9.8
125 8.8
125
103 13
102
102
B-17
-------
Table 3. (Continued)
Rank* Species
2 Cladoceran,
Daphnla putex
I Rainbow trout,
SaImo galrdnerI
Species Mean
Acute Value
(ug/l)
83
57
Species Mean
Acute-Chronic
Ratio
SALTWATER SPECIES
Winter flounder,
Pseudopleuronectes
amerlcana
Mysld shrimp,
Mysldopsls blgelowl
Mysld shrimp,
Mysldopsls bah I a
Copepod,
Acartla clausl
372
124
30
* Ranked from least sensitive to most sensitive based on species mean
acute value.
Freshwater Final Acute Value » 52 pg/l
Final Acute-Chronic Ratio = 14.8
Freshwater Final Chronic Value = (52 iig/O/M.8 - 3.5 ug/l
B-18
-------
Table 4. Plant values for cyanide
Species
Blue-green alga,
Mlcrocystls aeruglnosa
Green alga,
Prototheca zopfI
Green alga,
Chiorel la sp
Effect
FRESHWATER SPECIES
90* kill
SALTWATER SPECIES
Result
(yg/l)
7,990
Respiration
Inhibition
3,000
Enzyme Inhibition 30,000
Reference
Fitzgerald, et al.
1952
Webster & Hackett,
1965
Nelson 4 Tolbert,
1970
B-19
-------
TnbU 5. Other data for cyanide
Species
Snai 1,
Gonlobasls 1 1 vescens
Snail,
Lymnaea emarglnata
Snal 1 (embryo),
Lymnaea spp.
Sna 1 1 ,
Physa Integra
Scud,
Gammarus pseudol Imnaeus
Cladoceran,
Daphnla magna
Mayfly,
Stenonema rubrum
Caddlsf ly,
Hydropsyche sp
Coho salmon,
Oncorhynchus klsutch
Chinook salmon (juvenile),
Oncorhynchus tshawytscha
Rainbow trout (juvenile),
Salmo galrdnerl
Rainbow trout (adult),
Sa Imo galrdner 1
Rainbow trout (adult),
Salmo galrdnerl
Duration
48 hrs
48 hrs
96 hrs
48 hrs
98 days
96 hrs
48 hrs
48 hrs
2 hrs
64 days
250 min
2 min
8 min
Effect
FRESHWATER SPECIES
LC50
LC50
LC50
LC50
Competition with
Asel lus affects
HCN toxlclty
LC50
LC50
LC50
Swimming speed
reduced
21% reduction In
blomass
Approximate median
survival time
Mean survival time
Mean survival time
Result
(U9/I)
760,000
3,300
51,900
1,350
9
160
500
2,000
10
20
200
2,000
300
Reference
Cairns, et al. 1976
Cairns, et al. 1976
Dowden & Bennett,
1965
Cairns, et al. 1976
Oseld 4 Smith, 1979
Dowden & Bennett,
1965
Roback, 1965
Roback, 1965
broderlus, 1970
Negllskl, 1973
Dep. Scl. Ind. Res.,
1956
Herbert i Merkens,
1952
Herbert i Merkens,
1952
B-20
-------
Table 5. (Continued)
Species
Duration
Rainbow trout (adult),
Sal mo galrdner 1
Rainbow trout (adult),
Sal mo galrdnerl
Rainbow trout (adult),
Sal mo galrdner!
Rainbow trout (adult),
Sal mo galrdnerl
Rainbow trout (adult),
Sal mo galrdnerl
Rainbow trout (adult),
Sal mo galrdnerl
Rainbow trout (adult),
Salmo galrdnerl
Rainbow trout (adult),
Salmo galrdnerl
Rainbow trout (adult),
Salmo galrdnerl
Rainbow trout,
Salmo galrdnerl
Rainbow trout (Juvenile),
Salmo galrdner I
Rainbow trout (juvenile),
Salmo galrdnerl
Rainbow trout (juvenile),
Salmo galrdnerl
Rainbow trout (yearling),
Salmo galrdnerl
12 min
12 mln
24 min
72 mln
90 mln
2,525 mln
1,617 mln
3,600 mln
4,441 min
48 hrs
9 days
4 days
9 days
21 days
Mean survival time
Mean survival time
Mean survival time
Mean survival time
Mean survival time
Mean survival time
Mean survival time
Mean survival time
Mean survival time
LC50
Weight gain reduced
Increased respira-
tion rate
L I ver damage
(necroblosls)
65$ reduction in
weight gain
Result
Effect (uq/|)
250
200
180
160
140
100
90
80
70
Reference
Herbert 4 Merkens,
1952
Herbert 1 Merkens,
1952
Herbert & Merkens,
1952
Herbert 4 Merkens,
1952
Herbert 4 Merkens,
1952
Herbert 4 Merkens,
1952
Herbert 4 Merkens,
1952
Herbert 4 Merkens,
1952
Herbert & Merkens,
1952
68 Brown, 1968
10 Dixon, 1975
10 Dixon, 1975
10 Dixon, 1975
20 Speyer, 1975
B-21
-------
Tabla 5. (Continued)
Species
Rainbow trout (yearling),
Sal mo galrdnerl
Rainbow trout (Juvenile),
Sa lino gairdner 1
Rainbow trout,
Sal mo galrdnerl
Rainbow trout.
Sal mo gairdnerl
Atlantic salmon,
Sal mo salar
Brook trout (fry),
Salvellnus fontlnalls
Brook trout (fry),
Salvellnus font) nails
Brook trout (fry),
Salvellnus fontlnalls
Brook trout (fry),
Sa 1 ve 1 1 nus font 1 na 1 Is
Brook trout (fry),
Sa 1 ve 1 1 nus f ont 1 na 1 1 s
Brook trout (fry),
Salvellnus fontlnalls
Brook trout (fry),
Sa 1 ve 1 1 nus font 1 na 1 Is
Brook trout (fry),
Salvellnus fontlnalls
Duration
21 days
20 days
IS days
18 days
58 days
15.2 mln
10.8 mln
11.7 mln
26 mln
58 mln
210 mln
130 hrs
27 days
Effect
75< reduction In
swimming abl 1 Ity
Abnormal oocyte
development
Production of
s per ma togon 1 a
reduced by 13J
Production of
sperma togon 1 a
reduced by 50$
Teratogenlc
effects to embryos
Death
Death
Death
Death
Death
Death
Death
lOOJt survival
Rasult
(ug/l)
20
10
10
30
10
8,640
4,290
2,130
853
392
217
50
20
Reference
Speyer, 1975
Lesnlak, 1977
Ruby, et al. 1979
Ruby, et al. 1979
Leduc, 1978
Karsten, 1934
Karsten, 1934
Karsten, 1934
Karsten, 1934
Karsten, 1934
Karsten, 1934
Karsten, 1934
Karsten, 1934
3-22
-------
Table 5. (Continued)
Species
Brook trout (Juvenile),
Salvellnus font Ina Its
Brook trout (juvenile),
Salvellnus fontlnalls
Brook trout (juvenile),
Salvellnus fontlnalls
Brook trout (juvenile),
Salvellnus fontlnalls
Brown trout (fry).
So lino trutta
Brown trout (fry).
Sal mo trutta
Brown trout (fry).
Sal mo trutta
Brown trout (fry),
Sal mo trutta
Brown trout (juvenile),
Salmo trutta
Brown trout (juvenile),
Salmo trutta
Brown trout (juvenile),
Salmo trutta
Brown trout (juvenile),
Salmo trutta
Fathead minnow,
Plmephales promelas
Fathead minnow (juvenile),
Plmephales promelas
Duration
3.6 days
40 days
25.5 mln
90 days
8.2 mln
8.9 mln
8.2 mln
140 mln
6.58 mln
15 mln
30.1 mln
5 hrs
48 hrs
5 days
Effect
Let ha I
Not lethal
75} reduction In
swimming endurance
Reduced growth
Death
Death
Death
Death
Geometric mean
time to death
Geometric mean
time to death
Geometric mean
time to death
Oxygen uptake
Inhibited
LC50
LC50
Result
(up/I)
80
50
10
33
8,030
4,140
2,070
217
1,006
510
320
25
240
120
Reference
Nell, 1957
Nell, 1957
Nell, 1957
Koenst, et al. 1977
Karsten, 1934
Karsten, 1934
Karsten, 1934
Karsten, 1934
Burdlck, et al. 1958
Burdlck, et al. 1958
Burdlck, et al. 1958
Carter, 1962
Black, et al. 1957
Cardwel 1, et al.
1976
B-23
-------
TabU 5. (ContlMi«l)
Specie*
Fathead minnow (juvenile),
Plmephales prcunelas
Fathead minnow (juvenile),
Plmephales promelas
Fathead minnow (embryo),
Plroephales promelas
Fathead minnow (embryo),
Plmephales promelas
Fathead minnow (embryo),
Plmephales promelas
Fathead minnow (embryo),
Plmaphalas promelas
Fathead minnow (embryo),
Plmephales promelas
Fathead minnow (embryo),
Plmephales promelas
Fathead minnow (embryo),
Plmephales promelas
Black-nosed dace,
Rhlnlchthyfi atratulus
Channel catfish (juvenile),
Ictalurus punctatus
Guppy (juvenile),
Poecllla ratlculata
Stickleback,
Gasterosteus aculeatus
Threesplne stickleback
(adult),
Gasterosteus aculeatus
Duration
28 days
56 days
96 hrs
96 hrs
96 hrs
96 hrs
95 hrs
96 hrs
96 hrs
24 hrs
26 hrs
120 hrs
90 mln
824 mln
Effect
Reduced growth In
length
Reduced growth In
length and weight
LC50
LC50
LC50
LC50
LC50
LC50
LC50
LC50
LC50
Threshold
concentration
Depressed respira-
tion rate to 32 %
of norrna 1
Median survival
time
Result
(HO/I)
35
62
347
272
201
123
186
200
206
220
161
236
1,040
134
Reference
Llnd, et al. 1977
Llnd, et al. 1977
Smith, et al. 1978
Smith, et al. 1978
Smith, et al. 1978
Smith, et al. 1978
Smith, et al. 1978
Smith, et al. 1978
Smith, et al. 1978
Llpschuetz & Cooper,
1955
Card we 1 1, et al.
1976
Chen, 1968
Jones, 1947
Broderlus, 1973
B-24
-------
Table 5. (Continued)
Species
Threesplne stickleback
(adult),
Gasterosteus aculeatus
Threesplne stickleback
(adult),
Gasterosteus aculeatus
Blueglll (juvenile),
Lepomls macrochlrus
Blueglll (juvenile),
Lepomls macrochlrus
Blueglll (Juvenile),
Lepomls macrochlrus
Blueglll (juvenile),
Lepomls macrochlrus
Blueglll (juvenile),
Lepomls macrochlrus
Bluegll I (juvenile),
Lepomls macrochlrus
BluegllI (juvenile),
Lepomls macrochlrus
Blueglll (juvenile),
Lepomls macrochlrus
BluegllI (juvenlle),
Lepomls macrochlrus
Blueglll (adult),
Lepomls macrochlrus
Blueglll (adult),
Lepomls macrochlrus
Blueglll (adult),
Lepomls macrochlrus
Duration
642 mln
412 mln
202 mln
260 mln
351 mln
258 mln
352 mln
655 mln
48 hrs
48 hrs
72 hrs
48 hrs
Effect
Median survival
time
Median survival
time
Median survival
time
Median survival
time
Median survival
time
Median survival
time
Median survival
time
Median survival
time
LC50
LC50
LC50
LC50
289 days Survival reduced
289 days No reproduction
Result
(pg/1) Reference
170 BrOder I us, 1973
237 Broderlus, 1973
198 Broderlus, 1973
194 Broderlus, 1973
165 Broderlus, 1973
165 Broderlus, 1973
144 Broderlus, 1973
127 Broderlus, 1973
134 Cardwell, et al.
1976
280 TurnbulI, et al.
1954
154 Doudoroff, et al.
1966
160 Cairns, et al. 1965
67.8 Klmball. et al. 1978
5.4 Klmball, et al. 1978
B-25
-------
Tabie 5. (Continued)
Species Duration
Effect
Sinai imouth bass
(Juvenlle),
Micropterus uoloniieui
Sinai iffiouth bass
(juvenile),
Mi croptorus ciolofiiieii!
Sinsi I mouth bass
(Juvenlle),
Micropterus doiosiieu!
SmalImouth bass
(Juvenlle),
Mlcropterus do Iomleu I
7.8 mm Geometric mean
time to death
12.4 mIn Geometric mean
time to death
15.4 win Geoinetric mean
time to death
Smal Imouth bass 30.6 mln
(Juvenlle),
Mlcropterus dolornleu I
Smal Imouth bass 42.8 mln
(juvenile),
Mlcropterus do IomIeuI
Smal Imouth bass 133 mln
(Juvenlle),
Mlcropterus dolorn leu I
Smal Imouth bass 290 mln
(Juvenlle),
Mlcropterus do lorn leu I
Largemouth bass 2 days
(Juvenlle),
Mlcropterus sal mo Ides
Yellow perch (embryo), 96 hrs
Perca flavescens
Geometric mean
time to death
Geometric mean
time to death
80.5 mln Geometric mean
time to death
Geometric mean
time to death
Geometric mean
time to death
Significant
Increases In
opercular rate
LC50
Result
(ltg/'i) Reference
i,980 Burdick, et ai. 1958
1,430 Burdick, at ai. 1958
978 Burdick, at ai. !958
755 Burdick, et al. 1958
478 Burdick, et al. 1958
338 Burdick, et al. 1958
243 Burdick, et al. 1958
175 Burdick, et al. 1958
40 Morgan & Kuhn, 1974
281 Smith, et al. 1978
B-26
-------
Table 5. (Continued)
Species
Oyster,
Crassostrea sp.
Oyster,
Crassostrea sp.
Duration Effect
SALTWATER SPECIES
10 mln Activity
suppression
3 hrs Activity
Inhibition
Result
(ug/l) Reference
150 Usukl, 1965
30,000 Usukl, 1965
B-27
-------
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B-28
-------
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B-29
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B-30
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acid dissociation in aqueous solution. Inorg. Chem. 1: 828.
Jones, J.R.E. 1947. The oxygen consumption of Gasterosteus aculeatus L. in
toxic colutions. Jour. Exp. Biol. 23: 298.
Karsten, A. 1934. Investigations of the effect of cyanide on Black Hills
trout. Black Hills Eng. 22: 145.
Kimball, G., et al. 1978. Chronic toxicity of hydrogen cyanide to blue-
gills. Trans. Am. Fish. Soc. 107: 341.
Koenst, W., et al. 1977. Effect of chronic exposure of brook trout to sub-
lethal concentrations of hydrogen cyanide. Environ. Sci. Technol. 11: 883.
Leduc, G. 1978. Deleterious effects of cyanide on early life stages of
Atlantic salmon (Salmo salar). Jour. Fish. Res. Board Can. 35: 166.
Lee, D. 1976. Development of an invertebrate bioassay to screen petroleum
refinery effluents discharged into freshwater. Ph.D. thesis. Virginia
Polytechnic Inst. State University, Blacksburg.
8-31
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Lesniak, J.A. 1977. A histological approach to tne study of sublethal
cyanide effects on rainbow trout ovaries. M.S. thesis. Concordia Universi-
ty, Montreal.
Lind, D., et al. 1977. Chronic effects of hydrogen cyanide on the fathead
minnow. Jour. Water Pollut. Control Fed. 49: 262.
Lipschuetz, M. and A.L. Cooper. 1955. Comparative toxicities of potassium
cyanide and potassium cuprocyanide to the western blacknosed dace (Rhinich-
tys atratulus meleagris). N.Y. Fish Game Jour. 2: 194.
Morgan, W.S.G. and P.C. Kuhn. 1974. A method to monitor the effects of
toxicants upon breathing rates of largemouth bass (Micropterus salmoides
Lacepede). Water Res. 8: 67.
Negilski, D.S. 1973. Individual and combined effects of cyanide penta-
chlorphenol and zinc on juvenile Chinook salmon and invertebrates in model
stream communities. M.S. thesis. Oregon State University, Corvallis.
Neil, J.H. 1957. Some effects of potassium cyanide on speckled trout (Sal-
velinus fontinalisj. In: Papers presented at 4th Ontario Ind. Waste Conf.
Water Pollut. Adv. Comm., Ontario Water Resour. Comm., Toronto, p. 74-96.
Nelson, E.B. and N.E. Tolbert. 1970. Glycolate dihydrogenase in green al-
gae. Arch. Biochem. Biophys. 141: 102.
B-32
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Oseid, D. and L. Smith. 1979. The effects of hydrogen cyanide on Asellus
communis and Ganvnarus pseudolimnaeus and changes in their competitive re-
sponse when exposed simultaneously. Bull. Environ. Comtam. Toxicol.
21: 439.
Patrick, R., et al. 1968. The relative sensitivity of diatoms, snails, and
fish to twenty common constituents of industrial wastes. Prog. Fish-Cult.
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Roback, S.S. 1965. Environmental requirments of Trichoptera. In: Bio-
logical problems in water pollution. 3rd Seminar (1962), R.A. Taft Sanit.
t-.ig. Center, Cincinnati, Ohio. p. 118-126.
Ruby, S.M., et al. 1979. Inhibition of spermatogensis in rainbow trout
during chronic cyanide poisoning. Arch. Environ. Contam. Toxicol. 8: 533.
Smith, L.L., Jr., et al. 1978. Acute toxicity of hydrogen cyanide to
freshwater fishes. Arch. Environ. Contam. Toxicol. 7: 325.
Smith, L.L., Jr., et al. 1979. Acute and chronic toxicity of HCN to fish
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U.S. Environ. Prot. Agency, Duluth, MM. 115 p.
Speyer, M.R. 1975. Some effects of cnronic combined arsenic and cyanide
poisning on the physiology of rainbow trout. M.S. tnesis. Concordia
University, Montreal.
3-33
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Turnbull, H., et al. 1954. Toxicity of various refinery materials to
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Usuki, I. 1965. A comparison of the effects of cyanide and azide on the
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B-34
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Mammalian Toxicology and Human Health Effects
INTRODUCTION
Cyanides are defined as hydrogen cyanide (HCN) and its salts.
The toxicological effects of cyanides are based upon their poten-
tial for rapid conversion by mammals to HCN. Various organic com-
pounds containing the cyanide (CN) moiety which may have a poten-
tial for conversion to HCN in vivo will not be considered in this
document. Cyanides have long been feared for their high lethality
and their fulminating action. At the present time, however, cya-
nides do not constitute an important or widespread environmental
health problem. Almost all examples of human cyanide poisoning or
adverse environmental effects in the past have involved occupation-
al exposures or relatively localized sources of pollution. Cya-
nides are uncommon in U.S. water supplies and in the atmosphere.
Although some food plants clearly can cause acute cyanide poisoning
if ingested in sufficient amount, the evidence associating cyanide
compounds in other plants with chronic neuropathies is not convinc-
ing.
Some evidence suggests that the uses of cyanide in the U.S.
are increasing, and, therefore, continued vigilance in the form of
monitoring is indicated. However, a number of properties and char-
acteristics of cyanide indicate that it will probably remain only a
potential pollutant or one of secondary concern. For example, cya-
nide has a low degree of persistence in the environment, and it is
not accumulated or stored in any mammalian species that has
been studied. In keeping with the latter, a sizeable body of
C-l
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experimental evidence suggests that cyanide has an unusually low
degree of chronic toxicity. It does not appear to be mutagenic,
teratogenic, or carcinogenic.
No new evidence was encountered to suggest that the Public
Health Service (PHS) drinking water standard for cyanide set in
1962 should be lowered (National Institute Occupational Safety
Health (NIOSH), 1976).
EXPOSURE
The toxicological effects of cyanides are based upon their
potential for rapid conversion by mammals to HCN.
Cyanide production in the U.S. is now over 700 million pounds
per year and appears to be increasing steadily (Towill, et al.
1978). The sources and industrial uses of cyanide compounds in the
United States have recently been reviewed exhaustively (NIOSH,
1976; Towill, et al. 1978). Briefly, the major industrial users of
cyanide in the U.S. are the producers of steel, plastics, synthetic
fibers and chemicals, and the electroplating and metallurgical in-
dustries. In addition to these industries (see Table 1) , cyanide
wastes are discharged into the environment from the pyrolysis of a
number of synthetic and natural materials and from chemical, bio-
logical, and clinical laboratories. Although wool, silk, poly-
acrylonitrile, nylon, polyurethane, and paper are all said to lib-
erate HCN on combustion, the amounts vary widely with the condi-
tions. As yet there is no standardized fire toxicity test protocol
in the U.S. (Terrill, et al. 1978).
Despite numerous potential sources of pollution, cyanide is
relatively uncommon in most U.S. water supplies. A survey of 969
C-2
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TABLE 1
*
Inorganib Cyanide Wastes
Source and
I II
Bureau of
III IV
the Census regions
V VI
Total
VII VIII IX
Annual waste production (Ib/year)
Cyanides from fi e t f. t. r. t. e. c, i,
electroplating 2.78 x 10 6.07 x 10 6.86 x 10 0.96 x 10° 1.04 x 10 0.49 x 10° 0.77 x 10 0.15 x 10 2.20 x 10 21.32 x 10
E'aint sludge
cyanides 1,000 9,900 13,800 2,900 3,850 2,150 3,350 550 7,300 44,900
sludge 0.92 x 106 8.12 x 106 11.32 x 106 2.40 x 106 3.16 x 106 1.76 x 106 2.74 x 106 0.44 x 106 5.97 x 106 36.83 x 106
I'aint residue ccc cccccct
cyanides 0.18 x 10 0.57 x 10 0.62 x 10 0.23 x 103 0.47 x 10 0.20 x 10D 0.30 x 10 0.13 x 10 0.41 x 10 3.11 x 10
old paint 13 x 106 41 x 106 44 x 106 16 x 106 34 x 106 14 x 106 21 x 106 9 x 106 29 x 106 221 x 106
Stored wastes (lb)
Sodium (;yanide 1,400 16 1,416
Calcium cyanide 180 25 205
('oppet cyanide 100 32 132
L'otassium cyanide 2 2
liilvt-r cyanide 16 10 26
Potass iuin
ferr icyanide 4 4
pot ,jiia iuin
fecrocyanide 12 12
Souice: Ottinger, et al. 1973.
C-3
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U-,S. public water supply systems in 1970 revealed no cyanide con-
centrations above the mandatory limit (McCabe, et al. 1970). In
2,595 water samples, the highest cyanide concentration found was 8
ppb and the average concentration was 0.09 ppb (Towill, et al.
1978). In part, this must be ascribed to the volatility of undis-
sociated hydrogen cyanide which would be the predominant form in
all but highly alkaline waters. Also, in part, cyanide ion would
have a decided tendency to be "fixed" in the form of insoluble or
undissociable complexes by trace metals. Cyanide may complex irre-
versibly with heavy metals in water supplies and thereby be biolo-
gically inactivated in terms of toxicity attributable to cyanide.
Conversely, some cyanide complexes, such as nitroprusside, are
readily dissociable and elicit toxic responses directly attribut-
able to the release of cyanide in vivo. In view of the increased
production and uses of cyanide in the U.S., however, continued
vigilance in the form of monitoring is certainly indicated, parti-
cularly in the proximity of known potential sources of pollution.
Techniques for monitoring have been reviewed elsewhere (NIOSH,
1976; Towill, et al. 1978).
Ingestion from Water
As noted above, cyanide is an uncommon pollutant in most U.S.
water supplies, and documented examples of levels in excess of the
1962, U.S. Public Health Service limits (U.S. PHS, 1962) are ex-
tremely rare. No human cases of illness or death due to cyanide in
water supplies are known. The lack of such documentation, of
course, cannot be accepted complacently. It is entirely possible
that pulse discharges of industrial wastes result in high localized
C-4
-------
concentrations which have escaped detection, but general recogni-
tion of the high toxicity of cyanide has made its removal standard
practice in most industries (Reed, et al. 1971). Fortunately,
known methods for cyanide removal including alkaline chlorination,
hypochlorite treatment, reaction with aldehydes, electrolytic
decomposition, exposure to ionizing radiation, and heating are
effective and relatively economical (Lawes, 1972; Watson, 1973).
A few accidents have resulted in massive fish kills, some
livestock deaths, and environmental damage. Cyanide, unknowingly
released from a sewage plant in Oak Ridge, Tenn., was responsible
for the death of 4r800 fish in Melton Hill Lake near the sewage out-
fall (The Oak Ridger, 1975). About 1,500 drums (30 and 55 gallon)
containing cyanides disposed of near Byron, Illinois resulted in
long-range environmental damage and livestock death. Surface water
runoff from the area contained up to 365 ppm cyanide (Towill, et
al. 1978).
Ingestion from Food
Except for certain naturally occurring organonitriles in
plants, it is uncommon to find cyanide in foods in the U.S. Addi-
tionally, there is no data available indicating bioconcentration of
cyanide. The U.S. EPA Duluth laboratory states that the bioconcen-
tration factor will be very close to zero (Stephan, 1980). For
criterion calculation purposes, however, a tissue content approach-
ing that of the surrounding medium is assumed. In higher plants
the major group of organonitriles are the cyanogenic glycosides,
and at least 20 distinct compounds are known. Perhaps the best
known of this group is the compound amygdalin, which is found in
C-5
-------
many parts of the cherry laurel and the seeds of cherries, plums,
peaches, apricots, apples, and pears. Amygdalin is the chief in-
gredient in Laetrile. Both Laetrile and amygdalin-containing fruit
pits have been implicated as causes of acute cyanide poisoning in
humans (Braico, et al. 1979; Gosselin, et al. 1976). The release
of free cyanide from cyanogenic glycosides can be effected by acid
hydrolysis or most rapidly by /^-glucosidases, enzymes present in
plants and in the intestinal microflora of mammals but found in
only trace amounts in animal tissues (Conchie, et al. 1959).
Another naturally occurring group of organonitriles are called
the pseudocyanogenic glycosides of which the best known example is
cycasin from the Cycadaceae. As implied by the name, cyanide re-
lease from these compounds is unlikely to occur in vivo since alka-
line hydrolysis is required (Miller, 1973). Cycasin and related
glycosides are highly toxic and their ingestion along with food-
stuffs has been implicated in a variety of so-called "tropical
neuropathies" and amblyopias (Osuntokun, 1968). Although these
neurological disturbances have frequently been cited in the litera-
ture (Towill, et al. 1978) as examples of "chronic cyanide poison-
ing," the evidence for that extrapolation is indirect and inconclu-
sive. The failure of repeated attempts to produce similar syn-
dromes with pure hydrogen cyanide or its salts (see following dis-
cussion), strongly suggests that the neuropathies produced by
cycasin-containing foods are due to other unrecognized toxins, to
the cycasin per se, or to uncharacterized toxic metabolites, rather
than to cyanide.
C-6
-------
Other organonitrlies found in plants include the lathyrogenic
compounds, such as ^-glutamyl-^-cyanoalanine, the glucosinolates
such as glucobrassicin, and the cyanopyridine alkaloids such as
ricinine and indoleacetonitrile (Towill, et al. 1978). Although
many of these are toxic to mammals, no evidence links their toxi-
city to cyanide poisoning.
Inhalation
Hydrogen cyanide vapor is absorbed rapidly through the lungs
{Gettler and St. George, 1934). Because HCN has a pKa of 9.2 and
exists primarily as the acid under biological conditions, absorp-
tion across the alveolar membrane should be rapid (Wolfsie and
Shaffer, 1959). Human inhalation of 270 ppm HCN vapor brings death
immediately, while 135 ppm is fatal after 30 minutes (Dudley, et
al. 1942).
Cyanide absorption following inhalation of very low concentra-
tions is indicated by the observation that smokers have higher
thiocyanate levels in plasma and other biological fluids than do
nonsmokers (Wilson and Matthews, 1966). Cyanide levels usually are
not significantly different in smokers as compared with nonsmokers
(Pettigrew and Fell, 1973; Wilson and Matthews, 1966), since cya-
nide absorbed from inhaled tobacco smoke is rapidly converted to
thiocyanate (Johnstone and Plimmer, 1959; Pettigrew and Fell,
1973). Inhalation of cyanide salt dusts is also dangerous because
the cyanide will dissolve on contact with moist mucous membranes
and be absorbed into the bloodstream (Davison, 1969; Knowles and
Bain, 1968).
-------
The so-called distinctive odor of bitter almonds ascribed to
HCN does not necessarily serve as a warning of exposure. The abil-
ity to smell hydrogen cyanide appears to be a genetically deter-
mined trait. Individuals vary widely from being unable to detect
the odor to being extremely sensitive to it (Kirk and Stenhouse,
1953).
Dermal
Hydrogen cyanide, in either liquid or vapor form, is absorbed
through the skin (Drinker, 1932; Potter, 1950; Tovo, 1955; Walton
and Witherspoon, 1926). Absorption is probably increased if the
skin is cut, abraded, or moist. Many accidents involving skin con-
tamination also involve inhalation exposure; the contribution due
to skin absorption in these cases is difficult to assess. Potter
(1950) described a case in which liquid HCN ran over the bare hand
of a worker wearing a fresh air respirator. Cyanide inhalation was
prevented, but the worker collapsed into deep unconsciousness with-
in five minutes, suggesting significant percutaneous absorption.
PHARMACOKINETICS
Absorption
Probably the common commercial inorganic cyanides are rapidly
absorbed from the stomach and duodenum. Certainly, the human ex-
perience in regard to the rapidly lethal effects (Gosselin, et al.
1976) of ingested cyanides is in accord with the above, but experi-
mental studies which actually define quantitatively the rates of
penetration are not available.
Hydrogen cyanide is a weak acid with a pKa of 9.2. Thus, the
acid milieu of the stomach would greatly favor the undissociated
C-8
-------
species, HCN, which should further hasten absorption. Even at the
physiological pH of 7.4, however, cyanide would exist predominantly
as the unionized moiety which would serve to facilitate its trans-
fer among various body compartments (see previous discussion). In
accord with the theory of nonionic diffusion cyanide would be pre-
dicted to accumulate in body compartments which are at a higher pH
{more alkaline) than blood. At present, no evidence can be cited
to substantiate directly that prediction.
It has long been common knowledge that hydrogen cyanide gas or
vapors are rapidly absorbed via the lungs, producing reactions
within a few seconds and death within minutes (Gosselin, et al.
1976). Hydrogen cyanide has been used as the instrument of execu-
tion for convicted criminals in some states of the U.S. primarily
because of its rapid lethal effects on inhalation of high concen-
trations.
Hydrogen cyanide gas or solutions are absorbed through the in-
tact skin much more readily than are the ionized salts which are
less lipid soluble (Wolfsie and Shaffer, 1959). Absorption is
probably increased in both cases if the skin has been cut or abrad-
ed. Alleged cases of human skin absorptions, however, are often
complicated by the possibility of concomitant inhalation of cyanide
gas. Again, quantitative estimates of the rate of penetration of
skin by various forms of cyanide are not available.
Distribution
Cyanide is distributed to all organs and tissues via the
blood, where its concentration in red cells is greater than that in
plasma by a factor of two to three. Presumably, the accumulation
C-9
-------
Qf cyanide in erythrocytes is a reflection of its binding to met-
hemoglobin. Methemoglobin is found normally in the blood of non-
smokers at concentrations as high as 2 percent of the total cir-
culating pigment (Smith and Olson, 1973). However, there may be
other factors as yet unrecognized which favor the accumulation of
cyanide in red cells. Cyanide may also accumulate locally in body
cells because of binding to metalloproteins or enzymes such as
catalase or cytochrome c oxidase (Smith, et al. 1977). The possi-
bility of concentration differences due to pH gradients between
body compartments was mentioned above. Certainly, one would pre-
dict that cyanide would readily cross the placenta, but again quan-
titative data are lacking.
Metabolism
By far, the major pathway for the metabolic detoxication of
cyanide involves its conversion to thiocyanate via the enzyme rho-
danese (de Duve, et al. 1955). Rhodanese is widely distributed in
the body, but the highest activity is found in mammalian liver
(Table 2). The rate of the rhodanese reaction in vivo is limited by
the availability of the endogenous sulfur-containing substrate, the
identity of which is still unknown. Thiosulfate can serve as a
substrate for rhodanese with a high degree of efficiency both in
vivo and in vitro (Chen and Rose, 1952; Himwich and Saunders,
1948).
Alternative minor metabolic pathways for cyanide metabolism
include conjugation with cysteine to form 2-iminothiazolidene-4-
carboxylic acid, a reaction that is said to proceed nonenzymati-
cally (Figure 1). In rats given a total dose of 30 mg over an
C-LO
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TABLE 2
Rhodanese Activity In Tissues Of The Dog, Rhesus Monkey, Rabbit, And Rat
(mg CN converted to SCN~ per gram of tissue)
Dog
Tissue
Suprarenals
whole
cor tex
medulla
Liver
iii ain
cor tex
caudate nucleus
midbrain
cere be 11 ura
medulla
Spinal cord
cervical
lumbar
sacral
Heart
Kidney
Tcstes
Epidydymis
Ovar Ics
Lung
Spleen
Muscle
Intest i ne
duodenum
jejunum
Eye
Optic nerve
Rhesus Monkey
Number Number
Range3 of Range3 of
observations observations
2.14-
(5.46,
2.86-
0.27-
0.78-
(4.91,
0.34-
0.27-
0.52-
0.21-
0. 38-
0.15-
0.12-
0.16-
0.11-
0.42-
0.32-
0.29
0.42
0.16-
0. 10-
0.03-
O.OS-
0.04
0.02
0. 35
3.60
4.50)
5.62
1.12
1.46
6.28)
0.92
1.06
1.35
1.22
1.52
1.08
0.84
1.41
0. 14
0.74
0.41
0.17
0. 14
0.19
0. 11
6
2
2
7
7
7
6
7
7
7
4
4
6
6
5
1
1
3
2
6
3
1
1
1
0.14-1
.35
10.98-15.16
(5.
0.27
0.34-0
0. 22-0
0.33
0.49-D
0.56-0
0.20-0
0.23-0
0.48-0
2.46-3
0.38-0
0. 11-0
0.12-0
0.23-0
98)
.50
.80
.85
.57
.42
.28
.82
.58
.46
.21
.34
.57
3
4
1
2
2
1
2
2
2
2
3
4
3
2
2
3
1.
7.
1.
0.
1.
0.
0.
0.
0.
0.
6.
0.
0.
0.
0.
0.
Rabbit
Rat
Number Number
Range of Range o£
observations observations
24-3.
98-18
41-1.
13-0.
17-1.
63-1.
91
89-0.
35-1.
59-1.
20-7.
32-0.
30
40
20
18
94
.92
44
18
39
24
90
74
10
69
36
2
9
2
2
2
2
1
2
2
3
3
2
1
1
1
1
0.27-0.41 2
14.24-28.38 9
0.70-0.72 2
0.73-1.13 2
0.16-0.18 2
0.23-0.27 2
0.56-0.74 2
10.44-11.08 2
1.24-1.61 2
Oil
-------
TABLE 2 (Cont.)
Dog
Rhesus Monkey
Rabbit
Rat
Tissue
Salivary gland, parotid
Lymph node
Pancreas
Thy 10 id
Anterior pituitary
Whole blood
Ery throcy tes
ljlasma
Range3
0
0
0
0
0
0
0
0
.05-0.
.08-0.
.14-0.
.05-0.
.26
.01-0.
.01-0.
.01
36
13
28
94
02
02
Number Number Number Number
of Range3 of Range of Range ol
observations observations observations observations
3 0.99
2
4 0.12-0.44
3
I
2
2
1
1
2
Figures in parentheses are single observations falling outside the normal range.
SOULCC-: Adapted from tiimwich and Saunders, 1948.
C-12
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NITRILES
CN-
minor path
2-imino-thiazolidine-
4-carboxylic acid
HCN
in expired air
Major path
* CNS- -
,CN- pool
Excretion
CO,
^. cyanocobalarmn
HCNO HCOOH
metabolism of
one-carbon
compounds
some excreted
in urine
FIGURE 1
Fate of Cyanide Ion in the Body
Source: Williams, 1959
C-13
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eight-day period, this pathway accounts for no more than 15 percent
of the total cyanide (Wood and Cooley, 1956). A very small frac-
tion of the total cyanide is bound by hydroxocobalamin, probably
less than 1 percent (Brink, et al. 1950). A small amount (about 1
to 2 percent) is excreted unchanged as HCN via the \lungs (Friedberg
and Schwarzkopf, 1969). By reactions that are not well understood,
cyanide gains access to metabolic pathways for one-carbon compounds
and is converted to formate and to carbon dioxide.
Excretion
As estimated in rats given 30 mg sodium cyanide intraperi-
toneally over a period of eight days, 80 percent of the total cya-
nide is excreted in the urine in the form of thiocyanate (Wood and
Cooley, 1956). Because the fate of cyanide is largely determined
by a single metabolic pathway, one would predict that it would fit
a relatively simple pharmacokinetic model, e.g., first order kinet-
ics in plasma, but such detailed analyses have not been made. Cya-
nide does not appear to accumulate significantly in any body com-
partment with repeated doses or chronic exposures.
Because the liver contains the highest activity of rhodanese,
it is possible that pre-existing liver disease might slow the rate
of cyanide metabolism, but no studies appear to address this ques-
tion. No inhibitors of rhodanese are known which are active in
vivo.
EFFECTS
Acute, Subacute, and Chronic Toxicity
Hydrogen cyanide and its alkali metal salts are chemicals of
high inherent lethality to man and other mammals. The mean lethal
C-14
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dose of these substances by mouth in human adults is in the range of
50 to 200 mg (1 to 3 mg/kg), and death is rarely delayed more than
an hour (Gosselin, et al. 1976). In respiratory exposures to hy-
drogen cyanide gas, death occurs in 10 to 60 minutes at approximate
ambient concentrations of 0.1 to 0.3 mg/1 (or 100 to 300 ppm)
(Table 3). In nonfatal poisonings recovery is generally rapid and
complete.
The acute effects of cyanide poisoning in all obligate aerobic
species can be ascribed directly or indirectly to a single specific
biochemical lesion, namely the inhibition of cytochrome c oxidase
(Gosselin, et al. 1976). Inhibition of this terminal enzyme com-
plex in the respiratory electron transport chain of mitochondria
impairs both oxidative metabolism and the associated process of ox-
idative phosphorylation (Lehninger, 1975). The ensuing syndrome
has been well characterized in man and in laboratory animals
{Gosselin, et al. 1976). In its major features cyanide poisoning
resembles the effects of acute hypoxia whether the latter is due to
airway obstruction or to the absence of oxygen (anoxic hypoxia),
carbon monoxide poisoning (anemic hypoxia), or shock (stagnant or
hypokinetic hypoxia), all of which result in a decreased supply of
oxygen to peripheral tissues.
Cyanide poisoning differs from other types of hypoxia in that
the oxygen tension in peripheral tissues usually remains normal or
may even be elevated (Brobeck, 1973). This paradoxical difference
arises because the effect of cyanide is to block the utilization of
oxygen by aerobic cells, a novel condition referred to as histo-
toxic hypoxia. The organ systems most profoundly affected,
C-15
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TABLE 3
Human Response To Inhaled Cyanide And Cyanide-Containing Compounds
Compound
Cyanogen
Cyanide concentration
Response
16
Nasal and eye irritation after
6 to 8 rain
Reference
Hydrogen cyanide
(mg/liter )
0.3
0.2
0.15
0.12-0.15
(ppm)
270
181
135
110-135
Immediately fatal
Fatal after 10-mln exposure
Fatal after 30-min exposure
Fatal after % to 1 hr or
later, or dangerous to life
Prentiss, 1937
Prentiss, 1937
Prentiss, 1937
Fassett, 1963
McNerney and
Schrenk,1960
Cyanogen chloride
Cyanogen bromide
0.40
0.120
0.005
0.0025
0.40
0.035
0.006
159
48
2
I
92
8
1.4
Fatal after 10-win exposure
Fatal after 30-min exposure
Intolerable concentration,
10-min exposure
Lowest irritant concentration,
10-min exposure
Fatal after 10-min exposure
Intolerable concentration
Greatly irritating to
conjunctiva and the mucous
membranes of the respiratory
system
Prentiss, 1937
Fassett, 1963
Fassett, 1963
Fassett, 1963
Prentiss, 1937
Prentiss, 1937
Prentiss, 1937
C-16
-------
however, are the same as those impaired in any hypoxia irrespective
of etiology, namely the brain and the heart because of their high
dependence on oxidative metabolism. Two signs associated with cya-
nide poisoning in man (Gosselin, et al. 1976) follow from the pre-
ceding: (1) the failure to utilize molecular oxygen in peripheral
tissues results in abnormally high concentrations of oxyhemoglobin
in the venous return which accounts for a flush or brick-red color
of the skin; and (2) attempts to compensate for the inhibition of
oxidative metabolism leads to increased demands on glycolysis which
accounts for a metabolic (lactic) acidosis.
A special but less unique effect of cyanide is stimulation of
the chemoreceptors of the carotid body which elicits a character-
istic pattern of reflex activity (Heymans and Neil, 1958). Since
the nature of these chemoreceptors is unknown, it is possible that
the effect of cyanide on them is due also in some way to the inhibi-
tion of cytochrome c oxidase. Stimulation of the carotid body
chemoreceptors by cyanide results in an immediate, well-sustained,
and marked augmentation of the respiration. Circulatory effects
which often accompany the increase in ventilation include a tran-
sient rise in blood pressure which is probably secondary to a re-
flex sympathetic discharge. The rise in blood pressure is often
accompanied by a bradycardia which some authorities insist is not
due to the common baroreceptor reflex via the vagus nerves. The
pressor response is followed by a fall in blood pressure to hypo-
tensive levels from which the victim may not recover (Heymans and
Neil, 1958).
C-17
-------
The other prominent effect of cyanide on the respiration is a
direct depression or fatal arrest which is the result of an action
of cyanide at the level of the brain stem nuclei responsible for
the control of breathing. In poisoned victims, the heart beat in-
variably outlasts breathing movements. The cardiac irregularities
often noted may be secondary to respiratory embarrassment, but di-
rect histotoxic effects of cyanide on myocardial cells are an even
more likely mechanism.
Massive oral doses or concentrated respiratory exposures may
result in a sudden unconsciousness which may simply represent
fainting secondary to the delayed drop in blood pressure noted
previously. Presumably, the histotoxic hypoxia triggers a massive
peripheral vasodilation resulting in orthostatic hypotension and
collapse. The sequence of events is slower on exposure to lower
concentrations (Table 3) and victims may experience anxiety, confu-
sion, vertigo, and giddiness before loss of consciousness. Uncon-
sciousness is followed by asphyxial convulsions which may be vio-
lent and generalized. Opisthotonus, trismus, and incontinence are
common. The seizures may be followed by a brief period of paraly-
sis or rigidity and by death from apnea (Gosselin, et al. 1976).
Despite the high lethality of large single doses or acute re-
spiratory exposures to high vapor concentrations of cyanide, re-
peated sublethal doses do not result in cumulative adverse effects.
Thus, cyanide is an example of a chemical which has a high acute
toxicity, but an unusually low degree of subacute or chronic toxic-
ity. Hertting, et al. (1960) administered doses (0.5 to 2 mg/kg)
of sodium cyanide once or twice each day to dogs. This usually
C-18
-------
resulted in acute toxic signs from which the animals recovered com-
pletely within half an hour. This regimen was continued over a
period of 15 months with no evident pathophysiologic changes in
organ function or permanent alteration in intermediary metabolism.
Similarly, rats tolerated the equivalent of an acute oral LD of
potassium cyanide each day for 25 days when it was mixed with their
regular diet (Hayes, 1967).
Workers at American Cyanamid (1959) fed to beagle dogs a diet
containing 150 ppm sodium cyanide for 30 days without observing a
significant effect on their food consumption, hematologic para-
meters, behavioral characteristics, or microscopic changes in their
organs or tissues. Howard and Hanzal (1955) fed a diet that had
been fumigated with cyanide gas and contained the equivalent of 100
to 300 ppm hydrogen cyanide to rats for two years, also with essen-
tially negative findings. The conclusion seems inescapable that
cyanide, in substantial but sublethal intermittent doses, can be
tolerated for long periods of time and perhaps indefinitely.
It seems reasonable to assume that continuous exposure to some
as yet undefined, but low concentration of hydrogen cyanide gas,
could lead inevitably to an exhaustion of the reserve capacity of
mammals to inactivate and detoxify cyanide. The rate at which cya-
nide can be inactivated during acute exposure has been measured in
guinea pigs. By continuously infusing cyanide solutions intraven-
ously at different rates, Lendle (1964) showed that at a rate of
0.076 mg/kg~ /min" about 90 percent of the single lethal dose as
determined by "bolus" injection could be detoxified over the course
of an hour. When the rate of administration was slowed, multiple
C-19
-------
lethal doses could be tolerated. Extrapolation to a dose rate that
could be tolerated indefinitely, however, does not seem justified
with such a highly artificial model system.
Synergism and/or Antagonism
Since cyanide acts by inhibiting cytochrome c oxidase, it is
reasonable to presume that any other established inhibitor of the
same enzyme would have toxic effects synergistic with (or additive
to) those of cyanide. An established example of such a substance
is sulfide which is encountered as hydrogen sulfide gas or as the
alkali metal salts (Smith and Gosselin, 1979). Sulfide is even
more potent than is cyanide as an inhibitor of cytochrome c oxi-
dase, and similarities between sulfide and cyanide inhibition sug-
gest that they act by similar mechanisms (Nicholls, 1975; Smith, et
al. 1977). No specific experimental studies can be cited, however,
on the combined effects of cyanide and sulfide in either in vitro
or in vivo systems.
The only other established inhibitor of cytochrome c oxidase
is azide (given either as hydrazoic acid or its alkali metal
salts). Azide is a much weaker inhibitor of cytochrome c oxidase
than is cyanide or sulfide, and it appears to act by a different
inhibitory mechanism (Smith, et al. L977). Again, no specific
studies can be cited to establish whether azide has synergistic or
additive effects in combination with cyanide.
Although cyanide produces the cellular equivalent of hypoxia,
there is no reason to suppose that other causes of hypoxia would
have effects additive to or synergistic with those o£ cyanide. By
coincidence one cause of anemic hypoxia (Brobeck, 1973), namely,
C-20
-------
methemoglobinemia, is a specific antagonist to cyanide (see follow-
ing). Oxygen has no effect on cyanide inhibition of cytochrome c
oxidase in vitro, and it does not reverse the course of cyanide
poisoning in vivo. Since cyanide blocks the utilization of molecu-
lar oxygen in peripheral tissues, its effects on oxygen tension are
opposite in direction to those of "true" hypoxia. Since cytochrome
c oxidase has a very high affinity for molecular oxygen, it seems
unlikely that the oxygen tension in peripheral tissues in cyanide
poisoning is ever a limiting parameter.
Cyanide poisoning is specifically antagonized by any chemical
agent capable of rapidly generating methemoglobin in vivo such as
sodium nitrite, hydroxylamine, amyl nitrite, and a large number of
aromatic amino- and nitro-compounds such as aniline, p-aminopropio-
phenone, and nitrobenzene (Smith and Olson, 1973). Methemoglobin
binds cyanide tightly in the form of the biologically inactive com-
plex, cyanmethemoglobin. From a therapeutic standpoint there are
several disadvantages to the induction of methemoglobinemia despite
its established efficacy. Cyanmethemoglobin is a dissociable com-
plex, and eventually the dissociation of free cyanide from it may
result in a recurrence of symptoms. The procedure is limited by
the concentration of methemoglobin that can be tolerated by the
victim, and the chemicals used to generate methemoglobin have toxic
side effects of their own (Gosselin, et al. 1976).
A second therapeutically useful approach to the antagonism of
cyanide poisoning is to provide an exogenous substrate for the
enzyme rhodanese, which converts cyanide to the considerably less
toxic form of thiocyanate. The endogeneous substrate for rhodanese
C-21
-------
is not known, but p-toluene thiosulf onate (CH-,CgH4-S02-S~) is 4.5
times more active than thiosulfate as a substrate in vitro
(Sorbo, 1953). Ethyl thiosulfate (C,H[--S-SO.,-0~) , ethyl xanthate
£ J J
(C2H5OCS2~), diethyl dithiocarbamate ((C-Hc)2NCS2~)/ hydrosulfite
(S204~) and colloidal sulfur are all inactive as substrates for
rhodanese (Sorbo, 1953). It is probable that other sulfur com-
pounds as yet untested can also serve as substrates for rhodanese.
A variety of cobalt compounds effectively antagonize cyanide
poisoning, presumably by reacting chemically with free cyanide,
e.g., cobaltous chloride, hydroxocobolamine, and cobalt EDTA. The
latter two compounds have been used in humans (Gosselin, et al.
1976). Although oxygen alone has no effect on cyanide poisoning,
it is said to potentiate the anti-cyanide actions of thiosulfate
and particularly the thiosulfate-nitrite combination (Way, et al.
1966).
Teratogenicity, Mutagenicity, and Carcinogenicity
Data are not available on teratogenic, mutagenic, or carcino-
genic effects of cyanide, nor do there appear to be any published
studies with analagous compounds from which one might postulate the
possible adverse effects of long-term, low-level exposure. As pre-
viously indicated, a number of studies designed to show chronic or
cumulative adverse effects yielded only negative findings. It is
possible that cyanide has anti-neoplastic activity; at least one
study (Perry, 1935) reported a low therapeutic index for cyanide
against rat sarcomas.
In contrast, thiocyanate, the major product of cyanide detoxi-
fication in vivo, has produced developmental abnormalities in the
C-22
-------
chick (Nowinski and Pandra, 1946) and ascidian embryo (Ortolan!,
1969) at high concentrations. Unfortunately, these studies with
thiocyanate cannot be extrapolated to man, nor can those of Hrizu,
et al. (1973), who reported a cytostatic effect of thiocyanate on
human KB cells in culture as well as an increased survival rate in
mice inoculated with Ehrlich ascites tumor cells. Again, the
amounts used preclude any meaningful extrapolation to human pa-
tients. Thus, there is no evidence that chronic exposure to cya-
nide results in teratogenic, mutagenic, or carcinogenic effects.
C-23
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CRITERION FORMULATION
Existing Guidelines and Standards
The U.S. Public Health Service Drinking Water Standards of
1962 established 0.2 rag CN~/1 as the acceptable criterion for water
supplies. In addition to defining the 0.2 mg/1 criterion for cya-
nide, the PHS set forth an "objective" to achieve concentrations
below 0.01 mg CN~/1 in water "because proper treatment will reduce
cyanide levels to 0.01 mg/1 or less" (U.S. PHS, 1962). The Canadi-
an government has adopted criterion and objective concentrations of
0.2 mg CN~/1 and 0.02 mg CN~/1, respectively. The latter figure
represents the lower limit of detection by colorimetric methods
(Health and Welfare, Canada, 1977).
The U.S. PHS criterion was based on cyanide toxicity to fish
and not to man. Obviously, a disparity exists between the exposure
condition for man and for fish. The cited human experience in-
volved discrete single doses by mouth whereas the fish data are de-
rived from continuous total body exposure. The latter conditions
are not a very realistic model from which to assess the human haz-
ard. Even chronic occupational exposures of men to hydrogen cya-
nide gas allows for respite at the end of each working day.
Current Levels of Exposure
Since cyanide is encountered only infrequently in water sup-
plies or in the atmosphere and since long-term and large-scale mon-
itoring has not been conducted, insufficient data exist to estimate
current levels of exposure of the general population. A number of
factors contribute to the rapid disappearance of cyanide from wa-
ter. Bacteria and protozoa may degrade cyanide by converting it to
C-24
-------
carbon dioxide and ammonia (Leduc, et al. 1973). Cyanide is con-
verted to cyanate during chlorination of water supplies (Rosehart
and Chu, 1974). An alkaline pH favors the oxidation by chlorine,
whereas an acid pH favors volatilization of HCN into the atmos-
phere. As cited, cyanide concentrations above 8 ppb were not found
in a survey of 2,595 water samples collected throughout the United
States (Towill, et al. 1978). Thus, these concentrations were well
below the objective levels established by the PHS.
Special Groups at Risk
Although it was speculated that the elderly and the debili-
tated individuals in our population may be at special risk with re-
spect to cyanide, no experimental or epidemiological studies can be
cited to prove the point.
Basis and Derivation of Criteria
As shown in Table 4, the criterion of 0.2 mg CN~/1 (200 pg/1)
allows for safety factors ranging from 41 to 2,100. El Ghawabi, et
al. (1975) studied the effects of chronic cyanide exposure in the
electroplating sections of three Egyptian factories. A total of 36
male employees with exposures up to 15 years were studied and com-
pared with a control group of 20 normal, nonsmoking males. Only
minimal differences with respect to thyroid gland size and function
were found. The El Ghawabi study was given considerable weight in
formulating the NIOSH recommendations for occupational exposure
which gives a safety factor of 41 when applied to drinking water by
the usual extrapolations (Table 4). Finally, a safety factor of
2,100 is obtained using the results of a two-year chronic feeding
study in rats. When fed at the rate of 12 mg/kg per day over the
C-25
-------
TABLE 4
Basis and Derivation of Cyanide Criterion
Exposure Route Species Calculated Margin.of
Levels Daily Exposure Safety
9.2 mg/m3 Inhalation Han 60.6 «gb 152
2.5 mg/m3 Inhalation Man 16.5 mgb 41
12 rag/kg Oral Rat 840 mgc 2100
Investigator
t
El Ghawabi, et al. 1975
NIOSII, 1976
Howard and
Hanzal, 1955
aNOAEL
Based on 100% retention and on alveolar exchange of 6.6m for 8 hours.
cRat data converted to human equivalent assuming food consumption of 60 g/kg for rats and 70
kg human.
Daily exposure compared with 0.4 rag/day exposure from the consumption of 2 1 water containing
0.2 mg/1.
C-26
-------
equivalent of a lifetime, these rats showed no overt signs of cya-
nide poisoning, and hematological values were normal. Gross and
microscopic examinations of tissues revealed no abnormalities. The
only abnormality found was an elevation of thiocyanate levels in
the liver and kidneys. Consequently, the ADI for man is derived by
taking the no-observable-adverse-effeet level in mammals (12
nig/kg/day) multiplied by the weight of the average man (70 kg) and
dividing by a safety factor of 100. This safety factor was derived
by methods discussed in the Federal Register (44 FR 15980). Thus,
ADI = 12 mg/kg/day x 70 kg -f 100 = 8.4 mg/day.
The equation for calculating the criterion for the cyanide
content of water given an Acceptable Daily Intake is
2X + [Jo.0065) (X0 = ADI
Where
2 = amount of drinking water, I/day
X = cyanide concentration in water, mg/1
0.0065 = amount of fish consumed, kg/day
F = bioconcentration factor, mg cyanide/kg fish per
mg cyanide/1 water
ADI = limit on daily exposure for a 70 kg person =8.4 mg/day
2X + (0.0065) (1)X = 8.4
X = 4.19 mg/1 (or £2 4.2 mg/1)
Thus, the current and recommended criterion (0.2 mg/1) has a
margin of safety of 21.0 (4. 2 -f- 0.2).
No new additional evidence was encountered to suggest that the
1962 PHS Drinking Water Standard for cyanide should be lowered.
The concentration of 0.2 mg/1 or less is easily achieved by proper
treatment and concentrations in excess of that amount have been
C-27
-------
encountered only on rare occasions in U.S. water supplies. The ex-
perience since 1962 suggests that 0.2 mg CN~/1 is a safe criterion
for man.
Although a case could be made for using the epidemiologic data
(El Ghawari, et al. 1975) or the rat feeding study (Howard and
Hanzal, 1955) to derive alternative higher criteria, such an ap-
proach is not recommended at this time. The epidemiologic data was
obtained on a very limited number of individuals exposed by inhala-
tion rather than oral administration, on which there was a statis-
tically significant biological effect. In the rat feeding study,
cyanide was added to the chow by fumigation. Consequently, some
uncertainty exists concerning the actual dose levels. The current
PHS drinking water standard represents a body of human experience
which has proven both protective and achievable. At this time, the
epidemiologic data and animal toxicity studies are not of suffi-
ciently high quality to justify a water quality criterion above the
PHS standard.
C-28
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