United States
Environmental Protection
Agency
Office of Water
Regulations and Standards
Criteria and Standards Division
Washington DC 20460
EPA 440/5-80-025
October 1980
&EPA
Ambient
Water Quality
Criteria for
Cadmium
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AMBIENT WATER QUALITY CRITERIA FOR
CADMIUM
Prepared By
U.S. ENVIRONMENTAL PROTECTION AGENCY
Office of Water Regulations and Standards
Criteria and Standards Division
Washington, O.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.
11
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FOREWORD
Section 304 U)(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 Council, et. al. 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
develooed bv EPA.
developed by EPA.
STEVEN SCHATZOW
Deputy Assistant Administrator
Office of Water Regulations and Standards
111
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ACKNOWLEDGEMENTS
Aquatic Life Toxicology
Charles E. Stephan, ERL-Duluth
U.S. Environmental Protection Agency
John H. Gentile, ERL-Narragansett
U.S. Environmental Protection Agency
Mammalian Toxicity and Human Health Effects
James Lucas, HERL (author)
U.S. Environmental Protection Agency
Michael L. Dourson (doc. mgr.), ECAO-Cin
U.S. Environmental Protection Agency
Donna Siyulka (doc. mgr.), ECAO-Cin
U.S. Environmental Protection Agency
Patrick Durkin
Syracuse Research Corporation
Lester Grant, ECAO-RTP
U.S. Environmental Protection Agency
Steven D. Lutkenhoff, ECAO-Cin
U.S. Environmental Protection Agency
Harry Ska!sky
Reynolds Metal Company
Roy E. Albert*
Carcinogen Assessment Group
John Carroll
U.S. Environmental Protection Agency
Thomas Clarkson
University of Rochester
Jeff Gaba
U.S. Environmental Protection Agency
Paul Hammond
University of Cincinnati
William Marcus, ODW
U.S. Environmental Protection Agency
Terri Laird, ECAO-Cin
U.S. Environmental Protection Agency
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.
*CAG Participating Members:
Elizabeth L. Anderson, Larry Anderson, Dolph Arnicar, Steven Bayard, David
L. Bayliss, Chao W. Chen, John R. Fowle III, Bernard Haberman, Charalingayya
Hiremath, Chang S. Lao, Robert McGaughy, Jeffrey Rosenblatt, Dharm V. Singh,
and Todd W. Thorslund.
IV
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TABLE OF CONTENTS
Criteria Summary
Introduction A-l
Aquatic Life Toxicology 8-1
Introduction B-l
Effects B-2
Acute Toxicity B-2
Chronic Toxicity B-5
Plant Effects B-8
Residues B-9
Miscellaneous B-ll
Summary B-14
Criteria B-15
References B-56
Mammalian Toxicology and Human Health Effects C-l
Introduction C-l
Exposure C-l
Pharmacokinetics C-8
Effects C-17
Acute, Subacute, and Chronic Toxicity C-17
Synergism and/or Antagonism C-27
Teratogenicity C-31
Mutagenicity C-36
Carcinogenicity C-40
Criterion Formulation C-58
Existing Guidelines and Standards C-58
Current Levels of Exposure C-58
Special Groups at Risk C-58
Basis and Derivation of Criteria C-60
References C-69
Appendix C-108
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CRITERIA DOCUMENT
CADMIUM
CRITERIA
Aquatic Life
For total recoverable cadmium the criterion (in pg/1) to pro-
tect freshwater aquatic life as derived using the Guidelines is the
numerical value given by e(1'05
For example, at hardnesses of 50, 100, and 200 mg/1 as CaC03 the
criteria are 0.012, 0.025, and 0.051 pg/1, respectively, and the
concentration of total recoverable cadmium should not exceed 1.5,
3.0, and 6.3 pg/i, respectively, at any time.
For total recoverable cadmium the criterion to protect salt-
water aquatic life as derived using the Guidelines is 4.5 pg/1 as a
24-hour average and the concentration should not exceed 59 ug/1 at
any time.
Human Health
The ambient water quality criterion for cadmium is recommended
to be identical to the existing water standard which is 10 pg/l.
Analysis of the toxic effects data resulted in a calculated level
which is protective of human health against the ingestion of con-
taminated water and contaminated aquatic organisms. The calculated
value is comparable to the present standard. 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
Cadmium, atomic weight 112.40, is a soft silver white metal
with a melting point of 321°C and a boiling point of 765°C
(Windholz, 1976). It is used in electroplating, paint and pigment
manufacture and as a stabilizer in plastics manufacture (Fulkerson
and Goeller, 1973). The solubility of cadmium compounds in water
depends on the nature of the compounds and on water quality. Com-
pared to other heavy metals, cadmium is relatively mobile in the
aquatic environment and may be transported in solution as either
hydrated cations or as organic or inorganic complexes (U.S. EPA,
1979). Cadmium ion is precipitated from solution by carbonate, as
hydroxide and sulfide ions (Baes, 1973) and forms soluble complexes
with other anions (Samuelson, 1963).
Cadmium reaches waterways as fallout from air and in effluents
from pigments, plastics, alloys and other manufacturing operations
as well as from municipal effluents. Cadmium is strongly adsorbed
to clays, muds, humic and organic materials and some hydrous oxides
(Watson, 1973), all of which tend to remove it from the water col-
umn by precipitation. In polluted waters complexing with organic
materials is the most important factor in determining the aquatic
fate and transport of cadmium. Sorption processes account for re-
moval of dissolved cadmium to bed sediments and are increasingly
effective as pH increases (U.S. EPA, 1979).
A-l
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REFERENCES
Baes, C.F., Jr. 1973. The Properties of Cadmium. In: W. Fulkerson
and H.E. Goeller (eds.) Cadmium, the Dissipated Element. Oak
Ridge Natl. Lab., Oak Ridge, Tennessee, p. 29.
Fulkerson, W. and H.E. Goeller, (eds.) 1973. Cadmium, the dissi-
pated element. Oak Ridge Natl. Lab., Oak Ridge, Tennessee.
Samuelson, 0. 1963. Ion Exchange Separations in Analytical Chem-
istry. John Wiley and Sons, New York.
U.S. EPA. 1979. Water-related environmental fate of 129 priority
pollutants. EPA-440/4-79-029.
Watson, M.R. 1973. Pollution Control in Metal Finishing. Noyes
Data Corp., Park Ridge, New Jersey.
Windholz, M., (ed.) 1976. The Merck Index. 9th ed. Merck and
Co., Inc., Rahway, New Jersey.
A-2
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Aquatic Life Toxicology*
INTRODUCTION
In natural freshwaters cadmium sometimes occurs at extremely low concen-
trations (less than 0.01 ug/l)» but in environments impacted by man, cadmium
concentrations can be several micrograms per liter or greater. Predicting
the impact of cadmium on aquatic organisms may be complicated by the variety
of possible chemical forms of cadmium, which may display different levels of
toxicity and bioaccumulation. In addition synergism and antagonism may
occur.
However, a first-approximation of the aqueous chemistry of cadmium can
be obtained from the pH, carbonate alkalinity and concentrations of calcium,
magnesium, and cadmium. Complex formation by common anions, such as chlo-
ride and sulfate, in well-oxygenated fresh water is relatively weak. Only
_2
when concentrations of these components become high (e.g., 10~ M) is ap-
proximately half of the cadmium complexed. Thus in waters with low total
organic carbon and low concentrations of other less prevalent but relatively
strong complexing agents, such as aminopolycarboxylic acids, the free cad-
mium ion should be the predominant dissolved species.
Precipitation of cadmium hydroxide should occur only when the pH reaches
10 or 11 with relatively high cadmium concentrations. Furthermore, at con-
centrations of approximately 1 »g/l and below cadmium carbonate probably
will not precipitate, provided that the approximate limits of pH 8.5 and
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In saltwater systems with typical salinity, the number of probable cad-
mium species is reduced to a few because cadmium chloride complexes probably
predominate.
Of the analytical measurements currently available, a water quality cri-
terion for cadmium is probably best stated in terms of total recoverable
cadmium, because of the variety of forms that can exist in bodies of water
and the various chemical and toxicological properties of these forms. The
forms of cadmium that are commonly found in bodies of water and are not
measured by the total recoverable procedure, such as the cadmium that is a
part of minerals, clays and sand, probably are forms that are less toxic to
aquatic life and will not be converted to the more toxic forms very readily
under natural conditions. On the other hand, forms of cadmium that are com-
monly found in bodies of water and are measured by the total recoverable
procedure, such as the free ion, and the hydroxide, carbonate, and sulfate
salts, probably are forms that are more toxic to aquatic life or can be con-
verted to the more toxic forms under natural conditions.
Because the criterion is derived on the basis of tests conducted on sol-
uble inorganic salts of cadmium, the total and total recoverable concentra-
tions in the tests will probably be about the same, and a variety of analy-
tical procedures will produce about the same results. Except as noted, all
concentrations reported herein are expected to be essentially equivalent to
total recoverable cadmium concentrations. All concentrations are expressed
as cadmium, not as the compound tested.
EFFECTS
Acute Toxicity
Freshwater acute toxicity values for cadmium range from 1 to 73,500 ug/1
for fish species and from 3.5 to 28,000 pg/1 for invertebrate species (Table
B-2
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1). A reduction in toxicity associated with increased hardness is evident
for several fish and invertebrate species. Carrol, et al. (1979) verified
that the calcium reduces the acute toxicity of cadmium. In most natural
waters, calcium and magnesium are both present, with calcium being somewhat
more abundant. Giesy, et al. (1977) found that equilibrium associations of
cadmium with dissolved organics changed its toxicity to daphnids substan-
tially but little to fish. No consistent relationship of toxicity to
organic particle size was demonstrated.
Among invertebrates, cladocerans were the most sensitive species, and
mayflies and stoneflies were the most resistant, However, insects and other
^J/^<(jw &«& fa*
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several the hardnesses were not well distributed. In spite of these prob-
lems seven of the eight slopes were between 0.48 and 1.56 with an arithmetic
mean of 1.05. The other slope was slightly negative and was not used.
The arithmetic mean slope (1.05) was used with the geometric mean toxic-
ity value and hardness for each species to obtain a logarithmic intercept
for each of the 29 freshwater species for which acute values are available
for cadmium. The species mean acute intercept, calculated as the exponen-
tial of the logarithmic intercept, was used to compare the relative acute
sensitivities (Table 3). A freshwater Final Acute Intercept of 0.024 ug/l
was obtained for cadmium using the Species Mean Acute Intercepts listed in
Table 3 and the calculation procedures described in the Guidelines. Thus
the Final Acute Equation is e(1'05f> (hardness)]-3.73).
Acute toxicity data for cadmium are available for 31 species of salt-
water fish and invertebrate species (Table 1). The invertebrates are repre-
sented by 26 species with acute values ranging from 15.5 ug/1 for the mysid
shrimp (Nimmo, et al. 1977a) to 46,600 for the adult fiddler crab (O'Hara,
1973). The acute values for adult saltwater polychaetes range from 7,500
ug/1 for Capitella capitata to 12,000 ug/1 for Neanthes arenaceodentata
(Reish, et al. 1976), and the larvae of Capitella capitata are 35 times more
sensitive than the adults. Saltwater molluscs have acute values from 850
ug/1 for the soft-shelled clam (Eisler, 1977) to 35,000 ug/1 for the mud
snail (Eisler and Hennekey, 1977).
Frank and Robertson (1979) reported that the acute toxicity to juvenile
blue crabs was related to salinity. The 96-hour acute toxicities were 320,
4,700, and 11,600 wg/1 at salinities of 1, 15, and 35 g/kg, respectively.
O'Hara (1973) investigated the effect of temperature and salinity on cadmium
toxicity with the fiddler crab and did not find a significant effect of sa-
B-4
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Unity. Acute toxicities at 20°C were 32,300, 46,600, and 37,000 at 10, 20,
and 30 g/kg salinity. Increasing the temperature from 20* to 30°C increases
toxicity at all salinities tested.
The calanoid copepods Acartia tonsa and Acartia clausi were an order of
magnitude more sensitive than other copepods with species acute values of
169 wg/1 and 144 wg/1. respectively. Acute toxicity values for the mysid
shrimp, Mysidopsis bahia, were 15.5 wg/1 at 25*C to 28°C and 10 to 77 g/kg
salinity (Nimmo, et al. 1977a), and 110 wg/1 at 21°C and 30 g/kg salinity
(U.S. EPA, 1980). M. bigelow had a 96-hour LC5Q and 135 ug/l which was
similar to M. bahia (U.S. EPA, 1980). Lobster larvae were acutely sensitive
to cadmium with a 96-hour LC5Q of 78 wg/1.
The saltwater of fish species were generally more resistant to cadmium
with acute values ranging from 577 for the larvae of Atlantic silversides
(U.S. EPA, 1980) to 114,000 ug/1 for juvenile mummichog (Voyer, 1975). In a
study of the interaction of dissolved oxygen salinity on the acute toxicity
of cadmium to the mummichog, Voyer (1975) found similar toxicities at salin-
ities of 10 and 20 g/kg but a doubling of the sensitivity at 30 g/kg. Re-
sistance of mummichogs to acute cadmium poisoning was not influenced by
reductions in dissolved oxygen levels to 4 mg/1.
The saltwater Final Acute Value for cadmium, derived from the Species
Mean Acute Values listed in Table 3 using the calculation procedures
described in the Guidelines, 58.6 ug/1.
Chronic Toxicity
The range in freshwater chronic toxicity values (0.15 to 50 wg/1) is
much less than the range in acute toxicity values. Daphnia magna is the
most sensitive species tested, and Bertram and Hart (1979) found chronic
toxicity to Daphnia pulex at 1 wg/1 (Table 6). A 200-hour LC1Q vaiue Of
B-5
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0.7 ug/1 for rainbow trout was obtained by Chapman (1978) and probably would
be close to the result of an early life stage test because of the extent to
which various life stages were investigated (Table 6). Other salmonids and
many invertebrates are also quite sensitive, with effects having been
observed at 5 ug/1 or less (Table 6). These organisms include decomposers
(Giesy, 1978), crayfish (Thorp, et al. 1979), copepods and annelids (Giesy,
et al. 1979), midges (Anderson, et al. 1980) and mayflies (Spehar, et al.
1978).
The acute-chronic ratios for all freshwater species are surprisingly
similar considering the variety of organisms, hardnesses, and chronic toxic-
ities involved. The geometric mean acute-chronic ratio for Daphm'a magna is
122, and that for all four freshwater organisms is 231. The acute«chronic
ratio appears to be independent of hardness, but more sensitive species
appear to have a lower ratio than less sensitive ones. Thus 122 will be
used as the Final Acute-Chronic Ratio, and the Freshwater Final Chronic In-
tercept of 0.000197 yg/1 is obtained by dividing the Final Acute Intercept
of 0.024 ug/1 by 122. Also, if the acute-chronic ratio is independent of
hardness, the chronic slope must be equal to the mean acute slope of 1.05.
Thus the Freshwater Final Chronic Equation (Table 3) is
a(1.05[ln(hardness)]-8.53)
C •
Some data are available concerning the effect of hardness on chronic
toxicity of cadmium. If a chronic slope is calculated using the technique
described earlier for calculating the acute slope, the four chronic tests
with Daphnia magna produce a slope of 0.35. If only the three tests of
Chapman (Manuscript) are used, the slope is 0.79. The slope calculated from
all four chronic tests with brook trout is 1.01. Thus it appears that hard-
ness affects the acute and the chronic toxicity of cadmium similarly.
8-6
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Using the slope of 1.05, species mean chronic intercepts were calculated
for all 13 species with which chronic tests have been conducted on cadmium.
These chronic intercepts range from 0.359 ug/1 for the walleye to 0.00248
for Daphnia magna (Table 2). Even though four salmonids and only one inver-
tebrate are on the list, the range of sensitivities is rather large.
Two chronic toxicity studies have been conducted with the saltwater in-
vertebrate, Mysidopsis bahia (Table 2). Nimmo, et al. (1977a) conducted a
23-day life cycle test at 20* to 28°C and 15 to 23 g/kg salinity. Decreased
survival occurred at 10.6 ug/l» whereas a 48-hour delay in brood formation,
24-hour delay in brood release, and a 57 percent decrease in the number of
young per female resulted at 6.4 ug/1. No adverse effects were detected at
4.8 ug/1. The chronic toxicity limits, therefore, are 4.8 and 6.4 ug/1 with
a chronic value of 5.5 ug/1. The 96-hour LC5Q was 15.5 ug/1 resulting in
an acute-chronic ratio of 2.8.
A second life cycle study was conducted with cadmium and Mysidopsis
bahia under different environmental conditions (U.S. EPA, 1980). Experimen-
tal conditions included constant temperature (21°C) and salinity (30 g/kg).
Complete mortality occurred after 28 days exposure at 25 ug/1. At 11.5
ug/1 a series of morphological aberrations occurred at the onset of sexual
maturity. External genitalia in males were aberrant, females failed to
develop brood pouches, and both sexes developed a carapace malformation that
prohibited molting after the release of the initial brood. Although initial
reproduction at this concentration was successful, successive broods could
not be borne because molting resulted in death. No malformations or effects
on initial or successive reproductive processes were noted in the controls
or at 5.5 ug/1. The chronic limits for this study are 5.5 and 11.5 with a
chronic value of 8.0 ug/1. The LC50 at 21°C and 30 g/kg salinity was 110
ug/1 which results in an acute-chronic ratio of 14 from this study.
B-7
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These two studies showed excellent agreement between the chronic values
but considerable divergence between the acute values and acute-chronic
ratios. Several studies have demonstrated an increase in acute toxicity of
cadmium with decreasing salinity and increasing temperature (Table 6). The
observed differences in acute toxicity to the mysids might be explained on
this basis. Nimmo, et al. (1977a) conducted their acute test at 25° to 28*C
and 10 to 17 g/kg salinity, whereas the other test (U.S. EPA, 1980) was
performed at 21°C and 30 g/kg salinity.
Because only one chronic test has been conducted with a saltwater spe-
cies and the resulting acute-chronic ratio is so different from those found
with freshwater species, it would be inappropriate to use the geometric mean
of all available acute-chronic ratios to calculate the saltwater Final
Chronic Value. Therefore, no Final Acute-Chronic Ratio and no Final Chronic
Value can be calculated for saltwater species.
Plant Effects
Growth reduction was the major toxic effect observed with freshwater
aquatic plants (Table 4), and several values are in the range of concentra-
tions causing chronic effects in animals. The influence that plant growth
media may have had on the toxicity studies is unknown but is probably minor,
at least in the case of Conway (1978), who used a medium patterned after
natural Lake Michigan water. Because the lowest toxicity values for fish
and invertebrates species are lower than the values for plants, water quali-
ty criteria which protect aquatic animals should also protect aquatic plants.
Plant studies were reported with two species of saltwater phytoplankton
(Table 4). Thalassiosira pseudonana and Skeletonema costatum had 96-hour
EC^Q values of 160 and 175 ug/1, respectively, based on growth inhibi-
tion. These values are considerably above the chronic values for mysid
shrimp and are above the acute values for many saltwater animal species.
B-8
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Residues
Bioconcentration factors for cadmium in freshwater (Table 5) were highly
variable, ranging from 3 for brook trout muscle (Benoit, et al. 1976) to
12,400 in the whole body of mosquitofish (Giesy, et al. 1977). Usually,
fish accumulate only small amounts of cadmium in muscle as compared to most
other tissues and organs (Benoit, et al. 1976; Sangalang and Freeman,
1979). Also, cadmium residues in fish reach steady-state only after expo-
sure periods greatly exceeding 28 days (Benoit, et al. 1976; Sangalang and
Freeman, 1979; Giesy, et al. 1977). Daphm'a magna, and presumably other in-
vertebrates of about this size or smaller, often reach steady-state within a
few days (Poldoski, 1979). Cadmium accumulated by fish from water is elimi-
nated slowly (Benoit, et al. 1976; Kumada, et al. 1980), but Kumada, et al.
(1980) found that cadmium accumulated from food is eliminated much more
rapidly.
Mallard ducks are the only native wildlife species whose chronic sensi-
tivity to cadmium has been studied. These birds can be expected to ingest
many of the different freshwater plants and animals listed in Table 4.
White and Finley (1978a,b) found significant damage occurring at a cadmium
concentration of 200 mg/kg in food for 90 days. Division of 200 mg/kg by
the geometric mean bioconcentration factor of 766 gives a Final Residue
Value of 260 ug/1. This is a concentration which would cause damage to mal-
lard ducks, but no additional data are available.
Among saltwater species, bioconcentration factors for cadmium have been
determined for 1 species of alga, 13 species of invertebrates, and 1 species
of fish (Table 5). Values range from 22 to 3,160 for whole body and from 5
to 2,040 for muscle. Kerfoot and Jacobs (1976) reported a bioconcentration
factor of 670 for the alga Prasinocladus tricornutum. Theede, et al. (1979)
B-9
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found that the colonial hydroid Laomedea loveni bioconcentrated cadmium 153
times within a 10-day exposure period. The highest bioconcentration factor
was reported for the polychaete Ophryotrocha diadema (Klockner, 1979).
After 64 days' exposure using the renewal technique, a bioconcentration fac-
tor of 3,160 was attained. Tissue residues^ however, had not reached
steady-state.
Bioconcentration factors for five species of bivalve molluscs range from
83 for the hard shelled clam (Kerfoot and Jacobs, 1976) to 3,650 for the
American oyster (Zaroogian and Cheer, 1976). In addition, the range of
reported bioconcentration factors is rather large for some individual spe-
cies. Bioconcentration factors for the oyster include 149 (Eisler, et al.
1972), 677 (Kerfoot and Jacobs, 1976), 1,220 (Schuster and Pringle, 1969),
and 3,650 (Zaroogian, 1979). Similarly, two reported studies on bay scal-
lops report bioconcentration factors of 168 (Eisler, et al. 1972) and 2,040
(Pesch and Stewart, 1980), and three studies on the mussel report bioconcen-
tration factors of 113 (George and Coombs, 1977), 306 (Phillips, 1976), and
710 (Janssen and Scholz, 1979). Because bivalve molluscs do not, as a rule,
reach steady-state, comparisons between species may be difficult. The
length of exposure may be the major determinant in the size of the
bioconcentration factor.
Bioconcentration factors for six species of crustaceans range from 22 to
307 for whole body and from 5 to 25 for muscle (Table 5). Nimmo, et al.
(1977) reported bioconcentration factors for two species of grass shrimp,
Palaemonetes pugio and Palaemonetes vulgaris, of 203 and 307, respectively,
for whole body. Vernberg, et al. (1977) reported a factor of 140 for P_.
pugio at 25*C, while Pesch and Stewart (1980) reported a factor of only 22
for the same species exposed at 10*C, indicating that temperature is
probably an important variable.
B-10
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The commercially important crustaceans, the pink shrimp and lobster,
were not effective bioaccumulators of cadmium with factors of 57 for whole
body and 25 for muscle, respectively. A single bioconcentration factor of
48 is reported for saltwater fishes {Eisler, et al. 1972) which probably
indicates that fish also do not bioconcentrate cadmium effectively.
George and Coombs (1977) studied the importance of metal speciation on
cadmium accumulation in the soft tissues of Mytilus edulis. Cadmium com-
plexed as Cd-£DTA, Cd-alginate, Cd4iumate, and Cd-pectate (Table 6) was bio-
concentrated at twice the rate of inorganic cadmium (Table 5).
Although a high degree of variability exists between the bioconcentra-
tion factors reported for saltwater organisms, shellfish can accumulate cad-
mium in tissues to concentrations potentially harmful to man. Zaroogian and
Cheer (1976) and Zaroogian (1979) reported BCFs of 2,600 and 3,650, respec-
tively, with oysters after long-term exposures. The emetic threshold of
cadmium is 13 to 15 mg/kg for man (Anon., 1950), which results in a Salt-
water Final Residue Value of 4.5 yg/1 (Table 5).
Miscellaneous
The cumulative mortality resulting from exposure to cadmium for more
than 96 hours is clearly evident from the studies of Reish, et al. (1976) on
polychaetes; Eisler and Hennekey (1977) on bivalve molluscs, crabs, and
starfish; Pesch and Stewart (1980) on scallops, shrimp, crabs; and on mysid
shrimp (U.S. EPA, 1980; Nimmo, et al. 1977a). Nimrno, et al. (1977a) in
studies with mysid shrimp, Mysidopsis bahia, reported a 96-hour LC^Q of
15.5 ug/l (Table 1) and a 17-day LC5Q of 11 ug/l (Table 6) at 25° to 28°C
and 15 to 23 g/kg salinity. In another series of studies on this mysid
(U.S. EPA, 1980), the 96-hour LC5Q was 105 ug/l (Table 1), and the 28-day
LC50 was 16 ug/l (Table 6) at 20°C and 30 g/kg salinity. Comparison of
B-ll
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these data leads to the hypothesis that short-term acute toxicity may be
strongly influenced by environmental variables, whereas long-term effects,
including mortality, are not. This pattern was also reflected in the simi-
larity of reproductive responses of this species (Table 2) tested under dis-
similar environmental conditions.
Two studies of chronic exposure are illustrative of the effects of cad-
mium on growth and fecundity (Table 6). Pesch and Stewart (1980) in a
42-day study of cadmium toxicity to the bay scallop reported that 60 and 120
ug/1 reduced growth 42 and 69 percent, respectively, which results in an
EC50 of about 78 ug/1. D'Agostino and Finney (1974) studied the effects
of cadmium on the development and sexual maturation of the copepod Tigriopus
japonicus. Cadmium inhibited the development of ovigerious females and
hence the production of the young at concentrations greater than 44 wg/1.
The 964iour LCgg for T. japonicus is 5,290 (Table 1). Although the con-
centration of cadmium in the test solution was not measured, these results
do indicate that cadmium can produce long-term cumulative effects on
reproduction.
Considerable data exist concerning the effect of salinity and tempera-
ture on the acute toxicity of cadmium. Unfortunately the conditions and
durations of exposure are so different that adjustment of acute toxicity
data for salinity is not possible. Rosenberg and Costlow (1976) studied the
synergistic effects of cadmium and salinity combined with constant and
cycling temperatures on the larval development of two estuarine crab spe-
cies. They reported reduction in survival and significant delay in develop-
ment of the blue crab with decreasing salinity. Three times as much cadmium
was required to produce an LC50 at 30 than at 10 g/kg salinity. Studies
with the mud crab resulted in a similar cadmium-salinity response. In addi -
8-12
-------
tion, the authors report that cycling temperatures may have a stimulating
effect on survival of larvae compared to constant temperatures.
Theede, et al. (1979) investigated the effect of temperature and salini-
ty on the acute toxicity of cadmium to the colonial hydroid Laomedea
loveni. At 17.5°C cadmium concentrations inducing irreversible retraction
of half of the polyps ranged from 12.4 pg/1 at 25 g/kg salinity (Table 6).
At 25 g/kg salinity the toxicity of cadmium decreased as temperature
increased.
The effect of environmental factors on the acute toxicity of cadmium is
also evident for the early life stages of saltwater vertebrates. Alderdice,
et al. (1979a,b,c,) reported that salinity influenced the effects of cadmium
on the volume, capsule strength, and osmotic response of embryos of the
Pacific herring. Voyer, et al. (1979) reported a significant linear rela-
tionship between salinity and cadmium toxicity to Atlantic silverside
embryos. Previous studies on the embryos of the winter flounder indicated a
quadratic salinity-cadmium relationship (Voyer, et al. 1977).
Several studies have reported on the chronic sublethal effects of cadmi-
um on saltwater fishes (Table 6). Significant reduction in gill tissue res-
piratory rates and the alteration of liver enzyme activity have been
reported for the cunner after a 30-day exposure to 50 yg/1 (Maclnnes, et al.
1977). Oawson, et al. (1977) also reported a significant decrease in gill-
tissue respiration for striped bass at 0.5 yg/1 above ambient after a
30-day, but not a 90-day, exposure. A similar study on the winter flounder
(Calabrese, et al. 1975) demonstrated a significant alteration in gill tis-
sue respiration rates measured im vitro after a 60-day exposure to 5 ug/1.
The significance of these sublethal effects on growth and reproduction have
yet to be evaluated.
B-13
-------
Summary
The results of acute toxicity tests on cadmium with 29 freshwater spe-
cies range from 1 to 73,500 yg/1 with both fish and invertebrates distrib-
uted throughout the range. The antagonistic effect of hardness on acute
toxicity has been demonstrated with seven species. Chronic tests have been
conducted on cadmium with 12 freshwater fish species and one invertebrate
species. The seven available acute-chronic ratios are all between 66 and
431.
Freshwater aquatic plants are affected by cadmium at concentrations
ranging from 2 to 7,400 wg/1. These values are in the same range as the
acute toxicity values for fish and invertebrate species, and are consider-
ably above the chronic values. Bioconcentration factors for cadmium reach
3,000 for some invertebrates and may be as high as 12,000 for some fish
species.
The saltwater acute values for cadmium and five species of fishes ranged
from 577 gg/1 for larval Atlantic silversides to 114,000 ug/1 for juvenile
mummichog. Acute values for 26 species of invertebrates ranged from 15.5
ug/1 for the mysid shrimp to 46,600 wg/1 for the fiddler crab. The acute
toxicity of cadmium seems to increase as salinity decreases and as tempera-
ture increases, although the magnitudes of the effects seem to vary with
species. Two life cycle tests on Mysidopsis bahia under different test con-
ditions resulted in similar chronic values of 5.5 and 8.0 ug/1, but the
acute-chronic ratios were 2.8 and 14, respectively. These acute values
appear to reflect the effects of salinity and temperature, whereas the
chronic values apparently do not. Plant studies with microalgae report
growth inhibition at 160 ug/1.
Tissue residues were reported for 1 species of algae, 10 species of
B-14
-------
invertebrates, and 1 species of fish. Biconcentration factors for fish and
crustaceans were generally less than 400, whereas those for bivalve molluscs
were above 2,500 in long exposures, with no indication that steady-state was
reached, and resulted in a Final Residue Value of 4.5 ug/1. Cadmium mortal-
ity is cumulative for exposure periods beyond four days. Chronic cadmium
exposure resulted in significant effects on the growth of bay scallops at 78
ug/1 and on reproduction of a copepod at 44 ug/1.
CRITERIA
For total recoverable cadmium the criterion (in ug/1) to protect fresh-
water aquatic life as derived using the Guidelines is the numerical value
given by e(1-0^ln(hardness^-8-53^ as a 24-*our average, and the concen-
tration (in ug/1) should not exceed the numerical value given by
e(1.05[ln(hardness)-3.73) at any time> For example> at hardnesses of 50,
100, and 200 mg/1 as CaC03 the criteria are 0.012, 0.025, and 0.051 ug/l,
respectively, and the concentration of total recoverable cadmium should not
exceed 1.5, 3.0 and 6.3 ug/1» respectively, at any time.
For total recoverable cadmium the criterion to protect saltwater aquatic
life as derived using the Guidelines is 4.5 ug/1 as a 24-hour average, and
the concentration should not exceed 59 ug/1 at any time.
B-15
-------
Table I. Acute values for
Species
Method* Chemical
Hardness
(•9/1 as LC50/EC50"
CaCOx) (yg/l) Reference
FRESHWATER SPECIES
Rotifer,
Phllodlna acuticornls
Rotifer,
Phllodlna acuticornls
Rotifer,
Phllodlna acuticornls
Bristle worm.
Nals sp.
Snail (adult).
Amnlcola sp.
Snail (adult).
Physa gyrlna
Snail (Immature),
Physa gyrlna
Cladoceran,
Daphnla magna
Cladoceran,
Daphnla magna
Cladoceran,
Daphnla magna
C 1 adocoran.
Daphnla magna
Cladoceran,
Daphnla magna
Cladoceran,
Daphnla magna
R.
R.
R.
S.
s.
s.
s.
s.
s.
s.
s.
s.
s.
U Cadmium chloride
U Cadmium su 1 fate
U Cadmium su 1 f ate
U
U
M
M
U Cadmium chloride
H Cadmium chloride
M Cadmium chloride
M Cadmium chloride
M Cadmium chloride
M Cadmium chloride
25
25
Bl
50
50
200
200
45
51
104
105
197
209
500
200
300
1,700
6,400
1,370
410
65
9.9
33
34
63
49
Bulkema, et al. 1974
Bulkema, et al. 1974
Bulkema, et al. 1974
Rehwoldt, et al. 1973
Rehwoldt, et al. 1973
Wler & Walter, 1976
Wler & Walter, 1976
Bleslnger &
Chrlstensen, 1972
Chapman, Manuscript
Chapman, Manuscript
Chapman, Manuscript
Chapman, Manuscript
Chapman, Manuscript
B-16
-------
Table I. (Continued)
Species
Cladoceran,
Daphnla magna
Cladoceran,
Daphnla pulex
Cladoceran,
Slmocephalus serrulatus
Cladoceran,
Slmocephalus serrulatus
Cladoceran,
Slmocephalus serrulatus
Cladoceran,
Slmocephalus serrulatus
Cladoceran,
Slmocephalus serrulatus
Cladoceran,
Slmocephalus serrulatus
Scud,
Gammarus sp.
Mayfly,
Ephemeral la grandls
grand Is
Mayfly,
Ephemerella grandls
arandls
Stonefly,
Pteronarce11 a bad I a
Method* Chemical
S. U
Hardness
<*g/l as LC50/EC50««
CaCOQ (ug/l) Reference
Cadmium nitrate
S, U Cadmium nitrate
S, M Cadmium chloride
S, M Cadmium chloride
S, M Cadmium chloride
S, M Cadmium chloride
S, M Cadmium chloride
S, M Cadmium chloride
S, U
FT, H Cadmium chloride
S. U Cadmium sulfate
FT, M Cadmium chloride
47 Canton & Adema, 197B
140 Canton & Adema, 1978
10.0 35.0 Glesy, et al. 1977
11.1 7.0 Glesy, et al. 1977
11.1 3.5 Glesy, et al. 1977
11.1 12.0 Glesy, et al. 1977
11.1 16.5 Glesy, et al. 1977
II.I 6.6 Glesy, et al. 1977
50 70 Rehwoldt, et al. 1973
28,000 Clubb, et al. 1975
54 2,000 Warnlck & Bel I, 1969
18,000 Clubb, et al. 1975
B-17
-------
Table 1. (Continued)
Species
Damsel fly.
Unidentified
Midge,
Ch 1 ronomus
Caddlsf ly.
Unidentified
American eel,
Angul 1 la rostrata
Chinook salmon (swim-up),
Oncorhynchus tshawytscha
Chinook salmon (parr),
Oncorhynchus tshawytscha
Rainbow trout.
Sal mo gairdnerl
Rainbow trout (swim-up).
Sal mo gairdnerl
Rainbow trout (parr),
Salmo gairdnerl
Rainbow trout (2-mos),
Salmo gairdnerl
Rainbow trout,
Salmo gairdnerl
Rainbow trout,
Salmo galr drier 1
Rainbow trout,
Salmo gairdnerl
Brook trout,
Salvellnus fontlnalls
Method" Chemical
S, U
s, u
S, U
S, M
FT. M Cadmium chloride
FT, M Cadmium chloride
S, U Cadmium chloride
FT. M Cadmium chloride
FT, M Cadmium chloride
FT. M Cadmium nitrate
FT. M Cadmium sulfate
S. U
S. U
S, M Cadmium sulfate
Hardness
(•g/l as
CaC03)
50
50
50
55
23
23
23
23
31
340
(calcium
carbonate)
LC50/EC50"
(va/l)
8,100
1.200
3,400
820
1.8
3.5
6.0
1.3
1.0
6.6
1.75
6
7
26
Reference
Rehwoldt, et al
1973
Rehwoldt, et al
Rehwoldt, et al
Rehwoldt, et al
Chapman, 1978
Chapman, 1978
Kumada, et al.
Chapman, 1978
Chapman, 1978
Hale. 1977
Oavles, 1976
Kumada. et al.
Kumada, et al.
Carrol 1 , et al.
•
. 1973
. 1973
. 1972
1980
1973
1973
1979
B-18
-------
Table 1. (Continued)
Species
Method* Chemical
Hardness
(«g/l as LC50/EC50"
CaCOQ (tig/1) Reference
__!_
Brook trout.
Salve! Inus fontlnalls
Brook trout.
Salvellnus fontlnalls
Brook trout.
Salvellnus fontlnalls
Brook trout.
Salvellnus fontlnalls
Goldfish,
Carasslus auratus
Goldfish,
Carasslus auratus
Goldfish.
Carasslus auratus
Fat lead minnow,
Plmephales promelas
Fathead minnow,
Plmephales promelas
Fathead minnow.
Plmephales promelas
Fathead minnow,
Plmophales promelas
Fathead minnow,
H 1 mopha 1 es promelas
Fathead minnow,
Plmephales promelas
S, M
S, M
S, M
S, M
S, U
S, M
S, M
S, U
S, U
S, U
S, U
FT, M
FT, M
Cadmium sul fate
Cadmium sul fate
Cadmium sul fate
Cadmium sul fate
Cadmium chloride
Cadmium chloride
Cadm 1 um ch 1 or 1 de
Cadmium chloride
Cadmium chloride
Cadmium chloride
Cadmium chloride
Cadmium sul fate
Cadmium sul fate
340
(calcium
sul fate)
350
(magnesium
carbonate)
330
(magnesium
su 1 fate)
44
(sodium
sul fate)
20
20
140
20
20
360
360
201
201
29
3.8
4.4
2.4
2,340
2,130
46,800
1,050
630
72,600
73,500
11,000
12,000
Carrol 1, et al. 1979
Carrol 1, et al. 1979
Carrol 1, et al. 1979
Carroll, et al. 1979
Pickering 4
Henderson, 1966
McCarty, et al. 1978
McCarty, et al. 1978
Pickering &
Henderson, 1966
Pickering &
Henderson, 1966
Pickering &
Henderson, 1966
Pickering 4
Henderson, 1966
Pickering 4 Gast,
1972
Pickering 4 Gast,
1972
B-19
-------
Table 1. (Continued)
Species
Fathead minnow,
Plmephales promt) las
Fathead minnow,
Plmaphales promt) las
Fathead minnow,
Plmephales promelas
Northern squawflsh,
Ptychochel lus oreqonensls
Northern squawflsh,
Ptychochel lus oregonensls
Carp,
Cyprlnus carplo
Banded kllllflsh,
Fundulus dlaphanus
Flagflsh,
Jordanella florldae
Mosqultof Ish,
Gambusla af f inis
Mosqultof Ish,
Gambusla afflnls
Mosqultof Ish,
Gambusla afflnls
Mosqultof Ish,
Gambusla afflnls
Mosqultof Ish,
Gambusla af f Inls
Guppy ,
Leblstes retlculatus
Method*
FT, M
FT, M
FT, M
F, M
F, M
S, M
S, M
FT, M
FT, M
FT, M
FT, M
FT, M
FT, M
S, U
Chemical
Cadmium sul fate
Cadmium sul fate
Cadmium sul fate
Cadmium chloride
Cadmium chloride
-
Cadmium chloride
Cadmium chloride
Cadmium chloride
Cadmium chloride
Cadmium chloride
Cadmium chloride
Cadmium chloride
Hardness
(ng/l as
CaC03>
201
201
201
20-30
20-30
55
55
44
10.0
10.0
10.0
11.1
11. 1
20
LC50/EC50"
(ug/l) Reference
6,400
2,000
4,500
1,092
1,104
240
110
2,500
1,500
1,500
2,600
900
2,200
1,270
P Ickerlng & Gast,
1972
Pickering & Gast,
1972
Pickering & Gast,
1972
Andros & Garten, I960
Andros & Carton, I960
Rehwoldt, et al. 1972
Rehwoldt, et al, 1972
Spehar, 1976a
Glesy, et al. 1977
Glesy, et al. 1977
Glsey, et al. 1977
Glesy, et al. 1977
Glesy, et al. 1977
Pickering &
(fender son, 1966
B-20
-------
Table I. (Continued)
Species
Threes pine stickleback,
Gasterosteus aculeatus
Threesplne stickleback,
Gasterosteus aculeatus
White perch,
Morone amarlcanus
Striped bass,
Morone saxatllus
Striped bass (larvae),
Morone saxatllus
Striped bass (f Ingerl Ing),
Morone saxatllus
Green sunflsh,
Lepomls cyanellus
Green sunflsh,
Lepomls cyanellus
Green sunflsh,
Lepomls cyanel lus
Pumpklnseed,
Lepomls glbbosus
Blueglll,
Lepomls macrochlrus
Blueglll,
Method*
s. u
R, M
S. M
S, M
S, U
S, U
S. U
S, U
FT, M
S. M
S, U
FT, M
ClMMlcal
Cadmium i
Cadmium <
Cadmium <
Cadmium <
Cadmium <
Cadmium '
Cadmium i
Cadmium i
Cadmium <
Lepomls •acrochlrus
Hardness
(•9/1 as
CaCOx)
115
103-1 1 1
55
55
70
70
20
360
335
55
20
207
LC50/EC50"
(U9/I)
6.500
23.000
8.400
1,100
1
2
2,840
66,000
20,500
1,500
1,940
21,100
Reference
Pascoe & (
Pascoe & >
Rehwoldt,
Relwol dt.
Hughes, 1<
Hughes, 1<
Pickering
Henderson
Pickering
Henderson,
Jude, 197:
Rehwoldt,
Pickering
Henderson,
Eaton, 191
B-21
-------
Table 1. (Continued)
Species
Polychaete worm (adult),
Capital la capltata
Polychaete worn (larva),
Capital la cap!fata
Polychaete worm (adult),
Neanthes arenaceodentata
Method* Chan leaI
S, U
s, u
S, U
Polychaete worm (juvenile), S, U
Neanthes arenaceodentata
Polychaete worm, S, U
Nereis vlrens
Polychaete worm, S, U
Nereis vlrens
Bay scallop (juvenile), S, U
Aroppecten Irradians
American oyster (larva), S, U
Crassostrea virgin lea
Soft she I led clam. S, U
Mya arenarla
Soft she I led clam, S, U
Mya arenarla
Soft she I led clam. S, U
Mya arenarla
Mussel, S, U
Mytllus edulIs
Mussel, S, M
Mytllus edulIs
Species Mean
LC50/EC50" Acute Value**
(ug/l) (tig/1) Reference
SALTWATER SPECIES
Cadmium chloride 7,500
Cadmium chloride
Cadmium chloride
200
Cadmium chloride 12,000
Cadmium chloride 12,500
Cadmium chloride 9,300
Cadmium chloride 11,000
Cadmium chloride 1,480
Cadmium chloride 3,600
Cadmium chloride 2,500
Cadmium chloride 2,200
650
Cadmium chloride 25,000
Cadmium chloride 1,620
1,220
12,200
10.100
1,480
3,800
1,670
Relsh. et al. 1976
Relsh, et al. 1976
Relsh. et al. 1976
Relsh, et al. 1976
Elsler & Hennekey,
1977
Elsler, 1971
Nelson, et al. 1976
Calabrese, et al.
1973
Elsler & Hennekey,
1977
Elsler, 1971
Elsler, 1977
Elsler, 1971
Ahsanullah, 1976
B-22
-------
Table I. (Continued)
Species Method*
Mussel, FT, M
Mytllus edulls
Mussel, FT, M
MytlI us edulls
Mud snail, S, U
Nassarlus obsoletus
Mud snail, S, U
Nassarlus obsoletus
Oyster drill, S, U
Urosalplnx clnerea
Copepod, S, U
A cart I a cjausl
Copepod, S, U
Acartla tonsa
Copepod, S, U
Acartla tonsa
Copepod, S, U
Acartla tonsa
Copepod, S, U
Acartla tonsa
Copepod, S, U
Etiryteroora afflnls
Copepod, S, U
Nltocra splnlpes
Copepod, S, U
Pseudodlaptorous corpnatus
Copepod, S, U
Tlgrlopus Japonlcus
Chemical
Cadmium chloride
Cadmium chloride
Species Mean
LC50/EC50** Acute Value'*
(ug/l) (uo/l) Reference
3,600
4,300 3,940
Cadmium chloride 35,000
Cadmium chloride 10,500 19,200
Cadmium chloride 6,600 6,600
Cadmium chloride 144 144
Cadmium chloride 90
Cadmium chloride 122
Cadmium chloride 220
Cadmium chloride 337 169
Cadmium chloride 1,080 1,080
Cadmium chloride 1,800 1,800
Cadmium chloride 1,708 1,710
Cadmium chloride 5,290 5,290
Ahsanullah, 1976
Ahsanullah, 1976
Elsler & Hennekey,
1977
Elsler, 1971
Elsler, 1971
U.S. EPA, I960
Sosnowskl & Gentile,
1978
Sosnowskl & Gentile,
1978
Sosnowskl & Gentile,
1978
Sosnowskl & Gentile,
1978
U.S. EPA, 1980
Bengtsson, 1978
U.S. EPA, 1980
U.S. EPA, 1980
B-23
-------
Table 1. (Continued)
Species
Mysld shrimp,
Mysldopsls bah la
Mysld shrimp,
Mysldopsls bah la
Mysld shrimp,
Mysldopsls blgelowl
Blue crab (juveniles),
Callinectes sapldus
Blue crab (juveniles),
Ca 1 1 1 nectes sap 1 dus
Blue crab (juveniles),
Callinectes sapldus
Green crab,
Carclnus maenas
Sand shrimp,
Crangon septemsp 1 nosa
American lobster (larva),
Homarus amerlcanus
Hermit crab,
Pagurus jongl carpus
Hermit crab,
Pagurus longl carpus
Grass shrimp,
Palaemonetes vulgar Is
Grass shrimp,
Palaemonetes vulgar Is
Pink shrimp,
Penaeus duorarum
Method*
FT, M
FT, M
F. M
S. U
S, U
S, U
S, U
S, U
S, U
S, U
S, U
S, U
FT, M
FT, M
Chemical
Cadmium chloride
Cadmium chloride
Cadmium chloride
Cadmium chloride
Cadmium chloride
Cadmium chloride
Cadmium chloride
Cadmium chloride
Cadmium chloride
Cadmium chloride
Cadmium chloride
Cadmium chloride
Cadmium chloride
Cadmium chloride
Species Mean
LC50/EC50" Acute Value**
(ug/l) (ug/l) Reference
15.5
110 41.3
135 135
11,600
4,700
320 2,590
4,100 4,100
320 320
78 78
320
1,300 645
420
760 760
3,500 3,500
Nlmmo, et al. 1977
U.S. EPA, 1980
U.S. EPA, 1980
Frank & Robertson,
1979
Frank & Robertson,
1979
Frank & Robertson,
1979
Elsler, 1971
Elsler, 1971
Johnson & Gentile,
1979
Elsler, 1971
Elsler & Hennekey,
1977
Elsler, 1971
Nlmmo, et al. 19771
Nlmmo, et al. 1977
B-24
-------
Table I. (Continued)
Species
Fiddler crab,
Uca pug I lator
Fiddler crab,
Uca pug I lator
Fiddler crab,
Uca pugl lator
Fiddler crab,
Uca pugl lator
Fiddler crab,
Uca u I lator
Fiddler crab.
Uca pugl |ator
Starfish,
Aster las forbesl
Starfish,
Aster I as forbesl
Sheepshead minnow,
Cyprlnodon varlegatus
Mummlchog (adult),
Fundulus heteroclltus
Mumrnlchog (adult),
Fundulus heteroclltus
Mummlchog (juvenile),
Fundulus heteroclltus
Mummlchog (juvenile),
Fundulus heteroclltus
Method*
S, U
S, U
S, U
S, U
S, U
S, U
S, U
S, U
S, U
Striped kllllflsh (adult), S, U
Fundulus majal Is
S, U
S, U
S, U
S. U
Chemical
Cadmium chloride
Cadmium chloride
Cadmium chloride
Species Mean
LC50/EC50" Acute Value"
(ugyi) (UP./I) Reference
46,600
Cadmium chloride 37,000
Cadmium chloride 32,300
Cadmium chloride 23,300
Cadmium chloride 10,400
6,800
Cadmium chloride 7,100
820
Cadmium chloride 50,000
Cadmium chloride 21,000
Cadmium chloride 49,000
Cadmium chloride 22,000
Cadmium chloride 114,000
Cadmium chloride 92,000
21,200
2,410
50,000
21,000
O'Hara, 1973
O'Hara, 1973
O'Hara, 1973
O'Hara, 1973
O'Hara, 1973
O'Hara, 1973
Elsler & Hennekey,
1977
Elsler, 1971
Elsler, 1971
Elsler, 1971
Elsler, 1971
Elsler & Hennekey,
1977
Voyer, 1975
Voyer, 1975
B-25
-------
Table 1. (Continued)
Species Mean
LC50/EC50" Acute Value"
Species Method* Chen) cat (M9/O (ua/l)
Mummlchog (juvenile), S, U Cadmium chloride 78,000
Fundulus heterocl Itus
Mumnlchog (juvenlla), S, U Cadmium chloride 73,000
Fundulus heterocl Itus
Munmlchog (juvenile). S. U Cadmium chloride 63,000
Fundulus heterocl Itus
Mumnlchog (juvenile), S, U Cadmium chloride 31,000
Fundulus heterocl Itus
Mumnlchog (juvenile), S. U Cadmium chloride 30,000
Fundulus heterocl Itus
Mummlchog (juvenile), S, U Cadmium chloride 29,000 50,600
Fundulus heterocl Itus
Atlantic si Iverslde (adult), S, U Cadmium chloride 2,032
Men Id la menldla
Atlantic si Iverslde S, U Cadmium chloride 28,532
(juvenile).
Menldla menldla
Atlantic si Iverslde S. U Cadmium chloride 13,652
( juvenl le),
Menldla menldla
Atlantic silver side (larva), S, U Cadmium chloride 1.054
Menldla menldla
Atlantic si Iverslde ( larva), S, U Cadmium chloride 577 3.400
Menldla menldla
Winter flounder (larva), S. U Cadmium chloride 14,297
Pseudop 1 euronectes
amerlcanus
Winter flounder (larva), S, U Cadmium chloride 602 2,930
Pseudop 1 euronectes
amerlcanus
Reference
Voyer, 1975
Voyer, 1975
Voyer, 1975
Voyer, 1975
Voyer, 1975
Voyer, 1975
U.S. EPA, 1980
U.S. EPA, I960
U.S. EPA, 1980
U.S. EPA, 1980
U.S. EPA, 1980
U.S. EPA, 1980
U.S. EPA, 1980
B-26
-------
Table t. (Continued)
* S= static, FT = flow-through, R
•"Values are expressed as cadmium
Freshwater
Acute
= renewal, M
, not as the
Toxlclty vs.
Species Slope
Rotifer, -0.045
Ph 1 1 od 1 na acut 1 corn 1 s
Cladoceran,
Oaphnla maqna
Rainbow trout,
Sal mo galrdneri
Brook trout,
Salvellnus fontlnalls
Goldfish,
Carasslus auratus
Fathead minnow,
Plmephales promelas
Green sunflsh,
Lepomls cyanel lus
Bluegll 1,
Lepomls macrochlrus
0.48
1.44
0.72
1.56
1.25
0.90
1.02
= measured.
compound.
Hardness
Intercept
5.90
1.39
-4.37
-1.86
3.03
2.66
5.23
4.51
U = unmeasured
r
-0.07
0.44
0.86
0.57
1.0
0.83
0.94
1.0
N
3
6
3
5
3
9
3
2
Arithmetic mean acute slope = 1.05 (N=7; see text)
B-27
-------
Table 2. Chronic values for cadmium
Species
Test*
Chemical
Hardness
(mg/l as Limits" Chronic Value"
CaftM (uq/l) (U9/D
FRESHWATER SPECIES
Cladoceran,
Daphnla maqna
Cladoceran,
Daphnla magna
Cladoceran,
Daphnla magna
Cladoceran,
Daphnla maqna
Coho salmon (Lake Superior),
Oncorhynchus klsutch
Coho salmon (West Coast),
Oncorhynchus klsutch
Brook trout,
Salvellnus fontlnalls
Brook trout,
Salvellnus fontlnalls
Brook trout,
Salvellnus fontlnalls
Brook trout,
Salvellnus fontlnalls
Lake trout,
Salvellnus namaycush
Brown trout.
Sal mo trutta
Northern pike,
Esox luclus
LC
LC
LC
LC
ELS
ELS
ELS
LC
ELS
ELS
ELS
ELS
ELS
Cadmium chloride
Cadmium chloride
Cadmium chloride
Cadmium chloride
Cadmium chloride
Cadmium chloride
Cadmium chloride
Cadmium chloride
Cadmium chloride
Cadmium chloride
Cadmium chloride
Cadmium chloride
Cadmium chloride
45
53
103
209
44
44
44
44
36
187
44
44
44
0.17-0.7
0.08-O.29
0.16-0.28
0.21-0.91
1.3-3.4
4.1-12.5
1.1-3.8
1.7-3.4
1-3
7-12
4.4-12.3
3.8-11.7
4.2-12.9
0.34
0.15
0.21
0.44
2.1
7.2
2.0
2.4
1.7
9.2
7.4
6.7
7.4
Reference
bleslnger &
Chrlstensen, 1972
Chapman, Manuscript
Chapman, Manuscript
Chapman, Manuscript
Eaton, et al. 1978
Eaton, et al. 1978
Eaton, et al. 1978
Benolt, et al. 1976
Sauter, et al. 1976
Sauter, et al. 1976
Eaton, el al. 1978
Eaton, et al. 1978
Eaton, et al. 1978
B-28
-------
Table 2. (Continued)
Species
Fathead minnow.
Plmephales prone las
White sucker.
Catostomus commersonl
Channel catfish.
Ictalurus punctatus
Channel catfish.
Ictalurus punctatus
Flagfish,
Jordanella florldae
Smal 1 mouth bass.
Mlcropterus dolomleul
B 1 ueg 1 1 1 ,
Lepomls macrochlrus
Wai leye.
Stlzostedlon vitreum
Mysid shrimp.
Mysidopsis bah la
Mysid shrimp,
Mysldopsls bah la
Test*
LC
ELS
ELS
ELS
LC
ELS
LC
ELS
LC
LC
Hardness
(ng/l as LI alts** Chronic Value**
Chemical CaCO,) (ug/l) (uq/l)
Cadmium su If ate 201 37-57 46
Cadmium chloride 44 4.2-12.0 7.1
Cadmium chloride 37 11-17 13.7
Cadmium chloride 185 12-17 14.3
Cadmium chloride 44 4.1-8.1 5.8
Cadmium chloride 44 4.3-12.7 7.4
Cadmium sulfate 207 31-80 50
Cadmium chloride 35 9-25 15
SALTWATER SPECIES
Cadmium chloride - 4.8-6.4 5.5
Cadmium chloride - 5.5-11.5 8.0
Reference
Pickering & Cast,
1972
Eaton, et al. 1978
Sauter, et al. 1976
Sauter, et al. 1976
Spehar, 1976a
Eaton, et al. 1978
Eaton, 1974
Sauter, et al. 1976
Nlmmo et al. 1977a
U.S. EPA, 1980
* ELS = early life stage, LC = life cycle or partial life cycle
*"Values are expressed as cadmium, not as the compound.
B-29
-------
Table 2. (Continued)
Acute-chronic Ratios
Species
Cladoceran,
Daphnfa magna
Cladoceran,
Daphnla magna
Cladoceran/
Daphnla ma an a
Cladoceran,
Daphnla magna
Fathead minnow,
Plmephales promelas
Flagflsh,
Jordanella Morldae
Blueglll,
Lepojnls macrochlrus
Mysld shrimp,
Mysldopsls bah I a
Mysld shrimp,
Mysldopsls bah la
Hardness
(mg/l as
CaCOy
45
53
103
209
201
44
207
Acute
Value
(ufl/l)
65
9.9
33
49
5, 970
2,500
21,100
15.5
110
Chronic
Value
(ug/j)
0.34
0.15
0.21
0.44
46
5.8
50
5.5
8.0
Ratio
191
66
157
III
130
431
422
2.8
14
B-30
-------
Table 2. (Continued)
Freshwater Species Mean Chronic Intercepts
Rank*
13
12
11
10
9
8
7
6
5
4
3
2
1
Species
Wai leye,
Stlzostedlon vltreum
Blueglll.
Lepomls macrochlrus
Fathead minnow,
Plmephales promelas
Lake trout,
Salvellnus namaycush
Northern pike,
Esox luclus
Smal 1 mouth bass,
Mlcropterus do lorn leu I
Channel catfish,
Ictalurus punctatus
White sucker,
Catostomus commerson 1
Brook trout,
Salvellnus fontlnalls
Flagflsh,
jordanella florldae
Coho salmon,
Oncorhynchus klsutch
Brown trout.
Sal mo trutta
Cladoceran,
Daphnla magna
Species Mean
Chronic Intercept
UO./I)
0.359
0.185
0.176
0.139
0.139
0.139
0.136
0.134
0.126
0.109
0.0731
0.0399
0.00248
* Ranked from least sensitive to most sensitive based on Species Mean Chronic
Intercept.
B-31
-------
Table 3. Species moan acute Intercepts and values and acute-chronic
ratios for cadnlua
Species Mean Species Mean
Acute Intercept Acute-Chronic
Rank* Species (no/I) Ratto
FRESHWATER SPECIES
29
26
27
26
25
24
23
22
21
20
19
18
17
Sna 1 1 .
Amnlcola sp.
Mosquitof Ish,
Gambusla afflnls
Goldfish,
Carassius auratus
Damsel fly.
Unidentified
White perch,
Mor one anerlcanus
Green sunflsh,
Lepomls cyanel lus
Threesplne stickleback,
Gasterosteus aculeatus
Blueglll,
Lapomls macrochlrus
Caddlsf ly.
Unidentified
Guppy,
leblstes reticulatus
Klagflsh,
Jordanella florldae
Fathead minnow,
Plmephales protnelas
Northern squawflsh,
Ptychochel lus oregonensls
138
135
134
133
125
91.4
86.7
80.7
55.9
54.7
47.0
38.2
35.9
422
431
130
B-32
-------
Table 3. (Continued)
SpecIas Mean Species Mean
Acute Intercept Acute-Chronic
Rank"
16
15
14
13
12
II
10
9
8
7
6
5
4
3
Species
Mayfly,
Ephemeral la grand Is grand Is
Bristle worm.
Nals, sp.
Pumpklnseed,
Lepomls glbbosus
Midge,
Chlronomus
American eel.
Angul 1 la rostrata
Rotifer,
Philodlna acutlcornls
Carp,
Cyprlnos carpi o
Snail,
Physa gyrlna
Banded kll llflsh.
Fundulus dlaphanus
Scud,
Gammarus sp.
Cladoceran,
Slmocephalus serrulatus
Cladoceran,
Daphnla magnet
Chinook salmon.
Oncorhynchus tshawytscha
Rainbow trout,
Sal mo qalrdnerl
(ua/D
30.3
28.0
22.3
19.7
12.2
7.01
3.57
2.87
1.67
1.15
0.87
0.29
0.09
0.04
Ratio
_
_
-
-
—
_
_
-
_
_
_
122
-
_
B-33
-------
Table 3. (Continued)
Species Mean Species Mean
Acute Intercept Acute-Chronic
Rank* Species (ug/l) Ratio
2
1
Rank*
31
30
29
26
27
26
25
24
23
22
Brook trout,
Salvelinus fontlnalls
Striped bass,
Mor one saxltal Is
Species
SALTWATER
Mummichog,
Fundulus heteroclltus
Sheepshead minnow,
Cyprlnodon varlegatus
Fiddler crab,
Uca pugl lator
Striped kllllflsh.
Fundulus majal Is
Mud snail,
Nassarlus obsoletus
Polychaete worm,
Neanthes arenaceodentata
Polychaete worm.
Nereis vlrens
Oyster drill,
Urosalplnx clnerea
Copepod,
Tlqrlopus japonlcus
Green crab,
Carclnus maenus
0.03
0.02
Species Mean
Acute Value
SPECIES
50,600
50,000
21,200
21,000
19,200
12,200
10,100
6,600
5,290
4,100
Species Mean
Acute-Chronic
Ratio
-
B-34
-------
Table 3. (Continued)
Rank*
21
20
19
18
17
16
15
14
13
12
11
10
9
8
Species
Mussel,
Mytl lus edulls
American oyster,
Crassostrea vlrqinica
Pink shrimp,
Penaeus duorarum
Atlantic si Iverslde
Men Id la men Id la
Winter flounder,
Pseudop 1 euronectes
amerlcanus
Blue crab,
Calllnectes sapldus
Starfish,
Aster las forbesl
Copepod,
Nltocra splnlpes
Copepod,
Pseudodlaptomus cornatus
Soft shel led clam,
Mya arenarla
Bay seal lop,
Argopecten Irradlans
Polychaete worm,
Capital la capltata
Copepod ,
Eurytemora afflnls
Grass shrimp.
Pa 1 aemonetes vu 1 gar 1 s
Species Mean
Acute Value
(U9/D
3,940
3,800
3,500
3,440
2,930
2,590
2,410
1,800
1,710
1,670
1,480
1,220
1,080
760
Species Mean
Acute-Chronic
Ratio
-
B-35
-------
Table 3. (Continued)
Species Mean Species Mean
Acute Value Acute-Chronic
Rank* Species (tig/1) Ratio
7 Hermit crab 645
Pagurus longIcarpus
6 Sand shrimp, 320
Crangon septemspInosa
5 Copepod, 169
Acartla tonsa
4 Copepod, 144
Acartla clausl
3 Mysld Shrimp, 135
Hysldopsls blqelowl
2 American lobster, 78
Homarus amarlcanus
I Mysld shrimp, 41.3 6.3
Mysldopsls bahI a
* Ranked from least sensitive to most sensitive based on species mean acute
Intercept or value.
Freshwater
Final Acute Intercept = 0.024 ug/l
Natural logarithm of 0.024 = -3.73
Acute slope = 1.05 (see Table I)
Final Acute Equation = e< 1.051 In(hardness) 1-3.73)
Final Acute-Chronic Ratio = 122 (see text)
B-36
-------
Table 3. (Continued)
Final Chronic Intercept = (0.024 ug/l)/122 = 0.000197 ug/l
Natural logarithm of 0.000197 = -8.53
Chronic slope = I.05 (see text)
Final Chronic Equation - e('-051In(hardness)1-8.53)
SaItwater
Final Acute Value = 58.6 ug/l
B-37
-------
Table 4. Plant values for each* I urn
Species
Diatom,
Aster lonel la formosa
Diatom,
Scenedesmus quadracauda
Green alga,
Chlorolla pyrenoidosa
Green alga,
Chi orel la vulgar Is
Croon alga.
Chloral la vulgar Is
Greon alga,
Selanastrum caprlcornutum
Algae (mixed spp. )
Fern,
Salvlna riatans
Eurasian waterml 1 foil,
Myrlophyllum splcaturo
Duckweed,
Lomiid valdlvlana
Hardness
Chemical (ng/l as CaC03) Effect
FRESHWATER SPECIES
Factor of 10
growth rate
decrease
Cadmium chloride - Reduction In
ce 1 1 count
Reduction In
growth
Reduction In
growth
Cadmium chloride - 50? reduction
In growth
Cadmium chloride - Reduction In
growth
Cadmium chloride 11.1 Significant
reduction In
populat Ion
Cadmium nitrate - Reduction In
number of
fronds
50* root
weight
Inhibition
Cadmium nitrate - Reduction In
number of
fronds
Result*
(UQ/I)
2
6.1
250
50
60
50
5
10
7,400
10
Reference
Conway, 1978
Mass, et al. 1974
Hart & Scalfe, 1977
Hutch Inson & Stokes,
1975
Rosko 4 Rachl In, 1977
Bart left, et al. 1974
Glesy, et al. 1979
Hutchinson & Czyrska,
1972
Stanley, 1974
Hutchinson & Cyrska,
1972
Alga.
Thalassloslra pseudonana
Cadmium chloride
SALTWATER SPECIES
96-hr EC50 160
growth rate
U.S. EPA, 1980
B-38
-------
Table 4. (Continued)
Hardness Result*
Species Chemical («g/l as CaC03) Effect (ug/l) Reference
Alga, Cadmium chloride - 96 hr EC50 175 U.S. EPA, I960
Skeletonema costaturo growth rate
* Results are expressed as cadmium, not as the compound.
B-39
-------
Table 5. Residues for cadalirn
Species Tissue
Aufwuchs (attached
microscopic plants and
animals
Aufwuchs (attached
microscopic plants and
animals
Duckweed, Whole plant
Lemna valdlvlana
Fern, Whole plant
Salvlnla natans
Rush, Leaves
Juncus dlffuslsslams
Pond weed. Whole plant
Callltrlche heterophylla
Cladoceran, Whole body
Daphnla magna
Crayfish, Whole body
Orconectes proplnquus
Stonefly, Whole body
Pteronarcys dor sat a
Mayfly, Whole body
Ephemeral la sp.
Mayfly, Whole body
Ephemerella sp.
Dragonfly, Whole body
Pantala hymenea
Dragonfly, Whole body
Pantala hymenea
Chealcat
BloconcentratIon
Factor
Duration
(days) Reference
FRESHWATER SPECIES
m ch lorlde
im ch 1 or 1 de
im nitrate
im nl trate
im chloride
im chloride
im su 1 fate
-
im chloride
im chloride
im chlorl de
ira chloride
im chloride
7,100 at 5 ug/l
5,800 at 10 ug/l
603
960
1,300
1,200
320
164
373
1,630 at 5 ug/l
3,520 at 10 ug/l
736 at 5 ug/l
680 at 10 ug/l
52 wks
52 wks
21
21
52 «ks
52 wks
2-4
8
28
52 wks
52 wks
52 wks
52 wks
Glesy, et al.
Glesy, et al.
Hutchlnson & C
1972
Hutchlnson & C
1972
Gie&y, et al.
Glesy, et al.
Poldoskl, 1979
Gl 1 lesple, et
1977
Spehar, et al.
Glesy, et al.
Glesy, et al.
Glesy, et al.
Giesy, et al.
1979
1979
zyrsk.
zyrski
1979
1979
al.
1978
1979
1979
1979
1979
B-40
-------
Table 5. (Continued)
Bloconcentration Duration
Species
Dragonfly.,
1 schnura sp.
Dragonf ly,
1 schnura sp.
Caddisf ly,
Hydropsyche better) I
Beet le,
Dytlscldae
Beet le,
Dytlscldae
Midge,
Chlronomidae
Midge,
Chlrooomidae
Biting midge,
Cera top ogan Idae
Biting midge,
Ceratopogan 1 dae
Snail,
Physa Integra
Rainbow trout.
Sal mo gairdnerl
Rainbow trout.
Sal mo galrdneri
Brook trout,
Salvellnus font! nails
Brook trout ,
Salvellnus fontlnalls
Brook trout ,
Salvellnus fontlnalls
Tissue
•^••MMM^—
Whole body
Whole body
Whole body
Whole body
Whole body
Whole body
Whole body
Whole body
Whole body
Whole body
Whole body
Whole body
Muscle
Muscle
Muscle
Chemical
Cadmium chloride
Cadmium chloride
Cadmium chloride
Cadmium chloride
Cadmium chloride
Cadmium chloride
Cadmium chloride
Cadmium chlorde
Cadmium chlorl de
Cadmium chloride
Cadmium chloride
Cadmium chloride
Cadmium chloride
Cadmium chloride
Factor
1,300 at 5 ug/l
928 at 10 ug/l
4,190
164 at 5 M9/I
260 at 10 ug/l
2,220 at 5 ug/l
1,830 at 10 Mg/l
936 at 5 ug/l
662 at 10 ug/l
1,750
540
33 at 4 ug/l
3
151
10
(days)
52 wks
52 wks
28
.52 wks
52 wks
52 wks
52 wks
52 wks
52 wks
28
140
10 wks
490
84
93
Reference
Glesy, et al. 1979
Giesy, et al. 1979
Spehar, et al. 1978
Giesy, et al. 1979
Glesy, et al. 1979
Glesy, et al. 1979
Glesy, et al. 1979
Glesy, et al. 1979
Glesy, et al. 1979
Spehar, et al. 1978
Kumada, et al. 1973
Kumada et al. 1980
Benolt, et al. 1976
Benolt, et al. 1976
Sangalang & Freeman
1979
B-41
-------
Table 5. (Continued)
Bloconcwitratlon Duration
Species
Flagflsh.
Jordanella florldae
Mosqultoflsh.
Gambusla afflnls
Mosqultoflsh,
Combust a afflnls
Mosqultoflsh,
Gambusla afflnls
Mosqultof Ish,
Gambusla afflnls
Threesplned stickleback,
Gasterosteus aculeatus L.
Alga.
Praslnocladus trlcornutum
Hydro) d polyp,
Laomedea lovenl
Polychaete worm,
Ophryotrocha dladema
American oyster,
Crassostrea virgin lea
American oyster,
Crassostrea vlrglnlca
Tissue
Whole body
Whole body
Whole body
Whole body
(not steady
state)
Whole body
(not steady
state)
Whole body
Whole organism
Whole body
Soft parts
Soft parts
Chemical
Factor
Cadmium chloride 1,968
Cadmium chloride 4,100 at 0.02 ug/l
(0.115 ppm In food)
Cadmium chloride 938 at 10 ug/l
(0. > 15 ppm In food)
Cadmium chloride 7,440 at 5 ug/l
Cadmium chloride 12,400 at 10 uo/l
Cadmium chloride 900
SALTWATER SPECIES
Cadmium Iodide
Cadmium chloride
Cadmium chloride
Cadmium chloride
Cadmium chloride
670
153
3,160
2.600
3,650
(days)
30
8 wks
8 Mks
180
180
33
5
10
64
280
280
Reference
Spehar, 19766
Williams & Glesy,
1978
Williams & Glesy,
1978
Glesy, et al. 1977
Glesy, et al. 1977
Pascoe & Hattey,
1977
Kerfoot & Jacobs,
1976
Theede, et al. 197<
Klockner, 1979
Zarooglan & Cheer,
1976
Zarooglan, 1979
3-42
-------
Table 5. (Continued)
Species
American oyster.
Crassostrea vlrglnica
Soft she 1 I clam.
Mya arenaria
Quahaug,
Mercenarla mercenarla
Bay scallop,
Aqulpeclen Irradlans
Comnon mussel ,
Mytl lus edulls
Common mus se 1 ,
Mytl lus edul Is
Pink shrimp,
Penaeus durorarm
Grass shrimp.
Pa 1 eoinonetes puglo
Grass shrimp,
Palaenonetes vulgar Is
Grass shrimp,
Palaemonetes puglo
Tissue
Soft parts
Soft parts
Soft parts
Muscle
Soft parts
Soft parts
Whole body
Whole body
Whole body
Whole body
Chemical
Cadmium nitrate
Cadmium nitrate
Cadmium nitrate
Cadmium chloride
Cadmium chlori de
Cadmium chloride
Cadmium chloride
Cadmium chloride
Cadmium chloride
Cadmium chloride
B 1 oconcentrat i on
Factor
1,220
160
83
2.040
113
306
57
22
307
203
Ourat ion
(days)
98
70
40
42
28
35
30
42
28
28
Reference
Schuster & Prim
1969
Pr Ingle, et al .
1968
Kerfoot & Jacob:
1976
Pesch & Stewart
1980
George & Coombs
1977
Phi Hips, 1976
Nlmmo, et al . 1'
Pesch & Stewart
1980
Nimmo, et al. 1
Nlmmo, et al. 1'
B-43
-------
Table 5. iContinued)
Species
Crab,
Carclnus s-.aer.3s
Crab.
Carclnus maenas
Spec | as
8 ! GCGTiCSiTtrat ioii
Tissue Chemical Factor
Muscle Cadmium chloride 5
Muscle Cadmium chloride 7
Maximum Permissible Tissue Concentration
Concentration
Effect (mg/kq)
Duration
(days) Reference
68 Wright. 1977
40 Jennlnas & Rainbow.
1979
Reference
Mai lard,
Anas platyrhynchus
Man
Kidney tubule degeneration;
significant testls weight
reduction; evidence of
Inhibited spermatozoa
production
Emltlc threshold
200 mg/kg In food
for 90 days
13-5 mg/kg
White & Flnley, 1976 (a&b)
Anon., 1950
Freshwater;
Geometric mean of all whole body BCF values = 766
Final Residue Value = (200 mg/kg)/766 = 0.26 mg/kg •= 260 ug/l
SaItwater:
Geometric mean BCF for long-term exposure of oyster - 3,080
Final Residue Value = (14 mg/kg)/3,080 = 0.0045 mg/kg * 4.5 ug/l
B-44
-------
Table 6« Other data for cad-lms
Species
Mixed natural fungi
and bacterial colonies
on leaf fitter
Mixed macro in vertebrates
Cladoceran,
Daphnia pulex
Cladoceran,
Daphnia pulex
Cladoceran,
Daphnia pulex
Cladoceran,
Daphnia galeata
mendotae
Cladoceran,
Daphnia galeata
mendotae
Annel Id,
Prlstlna sp.
Copepod,
Eu eye lops agl 1 is
Crayf Ish,
Cambarus latimanus
Maytly,
Ephemeral la sp.
Chemical
Cadmium chloride
Cadmium ch ioriue
Cadmium chloride
Cadmium chloride
Cadmium chloride
Cadmium chloride
Cadmium chloride
Cadmium chloride
Cadmium chlorl de
Cadmium chlorl do
Cadmium ch lor Ide
Hardness
an/I
(CaCOO
FRESHWATER
10.7
11 .1
57
57
57
II. 1
11.1
11.1
44-48
Duration
SPECIES
28 wks
52 wks
140 days
96 hrs
72 hrs
22 wks
22 wks
52 wks
52 wks
5 ino
28 days
Effect
Inhibition of
leaf
decompos i ton
Reduction in
mean total
numbers arid in
numbers of taxa
Reduced
reproduction
LC50
LC50
50? reduction
in relative
mean numbers
Reduced blomass
Population
reduct Ion
Popu It ion
reduct Ion
Sign! f leant
mortality as
compared to
controls
LC50
Result*
(ug/l)
5
5
1
47
62
7.7
4.0
5
5
5
<3.0
Reference
Glesy, 1978
Giesy, et ai.
Bertram & Hart
Bertram & Hart
Bertram & Hart
Marshall, 1978
Marshall, 1978
Glesy, et al.
Giesy, et al.
Thorp, et al .
Spehar, et al.
1979
, 1979
, 1979
, 1979
1979
1979
1979
I97«
B-45
-------
Table 6. (Continued)
Spec 1 es
Midge,
Tanytarsus dlss (mills
Snail (embryo).
Antnlcola sp.
Snail,
Physa Integra
Coho salmon (juvenile).
Oncorhynchus klsutch
Coho salmon (adult).
Oncorhynchus Klsutch
Chinook salmon (a lev In),
Oncorhynchus tshawytscha
Chinook salmon (swim-up).
Oncorhynchus tshawytscha
Chinook salmon (parr).
Qncorhynchus tshawytscha
Chinook salmon (smolt).
Oncorhynchus tshawytscha
Brook trout ,
Salvellnus fontl nails
Chemical
Cadmium chloride
_
Cadmium chloride
Cadmium chloride
Cadmium chloride
Cadmium chloride
Cadmium chloride
Cadmium chloride
Cadmium chlorl de
Cadmium chloride
Hardness
•fl/l
(CaCOA)
47
50
44-48
22
22
23
23
23
23
10
Duration
10 days
96 hrs
28 days
217 hrs
215 hrs
200 hrs
200 hrs
200 hrs
200 hrs
21 days
Effect
LC50
LC50
LC50
LC50
LC50
LCIO
LC10
LCIO
LCIO
Test leu lar
damage (blood
Result*
(ug/l)
3.8
3,800
10.4
2.0
3.7
18-26
1.2
1.3
1.5
20
Reference
Anderson, et al. 1980
Rehwoldt, et al. 1973
Spehar, et al. 1978
Chapman & Stevens,
1978
Chapman & Stevens,
1978
Chapman, 1978
Chapman, 1978
Chapman, 1978
Chapman, 1978
Sangalang &
O'Hal loran, 1972,
Rainbow trout,
Salmo galrdnarl
Rainbow trout,
Salmo galrdnarl
Cadmium stearate
Cadmium acetate
96 hrs
96 hrs
vesseI
col lapse,
reduced 1I-
ketotestosterone
synthesis)
LC50
LC50
1973
6.0 Kumada, et al. 1980
6.2 Kumada, et al. 1980
B-46
-------
Table 6. (Continued)
Species
Rainbow trout,
Salmo qalrdnerl
Rainbow trout,
Salmo galrdnerl
Rainbow trout,
Salmo galrdnerl
Rainbow trout (adult),
Salmo galrdnerl
Rainbow trout (alevln),
Salmo galrdnerl
Rainbow trout (swim-up),
Salmo galrdnerl
Rainbow trout (parr),
Salmo galrdnerl
Rainbow trout (smolt),
Salmo galrdnerl
Rainbow trout,
Salmo galrdnerl
Rainbow trout,
Salmo galrdnerl
Rainbow trout,
Salmo galrdnerl
Rainbow trout,
Salmo galrdnerl
Rainbow trout,
Salmo galrdnorl
Rainbow trout,
Salno galrdnerl
Chemical
lum chloride
-
-
lum chloride
lum chloride
1 urn ch 1 or! de
lum chloride
lum chloride
lum sulfate
lum stearate
lum stearate
lum acetate
lum chloride
lum chloride
Hardness
•a/i
(CaCOO
104
-
-
54
23
23
23
23
326
-
-
-
125
125
Durat 1 on
2B days
240 hrs
240 hrs
408 hrs
186 hrs
200 hrs
200 hrs
200 hrs
96 hrs
10 wks
10 wks
10 wks
10 days
10 days
Effect
LC50
LC50
LC50
LC50
LC10
LC10
LCIO
LCIO
LC20
BCF
BCF
BCF
LC50 (18*C)
LC50 (12'C)
Result"
(ug/l)
130
7
5
5.2
>6
1.0
0.7
0.8
20
27
40
63
10-30
30
Reference
Blrge. 1978
Kumada, et al
Kuroada, et al
. 1973
. 1973
Chapman & Stevens,
1978
Chapman, 1978
Chapman, 1978
Chapman, 1978
Chapman, 1978
Da vies, 1976
Kumada, et al
Kumada, et al
Kumada, et al
Roch & Maly,
Roch & Maly.
. 1980
. 1980
. 1980
1979
1979
B-47
-------
Table 6. (Continued)
Hardness
•9/1
Species Chemical (CaCCK)
Rainbow trout. Cadmium chloride 125
Sal mo galrdnerl
Goldfish, Cadmium chloride 195
Carasslus auratus
Goldfish,
Caraslus auratus
Mosqultof Ish, Cadmium chloride
Gambusla af finis
Duration
10 days
7 days
50 days
8 wks
Effect
LC50 (6*C)
LC50
Reduced plasma
sodium level
(osmoregu latory
changes)
BCF
Result*
(ug/l)
30-100
170
44.5
6,100 at
0.02 ug/l
Reference
Roch & Maly, 1979
Blrge, 1978
McCarty & Houston,
1976
Wll Hams 4 Glesy,
Mosquftof Ish,
Gambusla affinis
Threesplne stickleback,
Gasterpsteus aculeatus
Largemouth bass,
Mlcropterus salmoIdes
Salamander,
Ambystoma opacuro
Toad,
Gastrophyryne
carolInensls
Colonial hydrold,
CampanuIarIa fIexuosa
Cadmium chloride
Cadmium chloride
Cadmium chloride
Cadmium chloride
Cadmium chloride
II
99
99
195
8 wks
33 days
8 days
8 days
7 days
SALTWATER SPECIES
BCF
LC50
LC50
LC50
LC50
4 1.13 ppm
cadm I urn
spiked
I nto food
1,430 at Williams & Glesy, 1978
10 ug/l &
1.13 ppm
cadmium
spiked
I nto food
0.8 Pascoe 4 Mattey, 1977
1,640 Blrge, et al. 1978
150 Blrge, et al. 1978
40 Blrge, 1978
Enzyme
Inhibition
40-75 Moore 4 Stebblng, 1976
B-48
-------
Table 6. (Continued)
Species
Colonial hydrold,
Campanularia flexuosa
Colonial hydrold,
Laomedea lovenl
Colonial hydrold,
Laomedea lovenl
Colonial hydrold,
Laomedea lovenl
Colonial hydrold,
Laomedea lovenl
Colonial hydrold,
Laomedea lovenl
Colonial hydrold,
Laomedea lovenl
Colonial hydrold,
Laontotlea lovenl
Colonial hydrold,
Laomedea lovenl
Polychaete worm,
Capltel la capltata
Polychaete worm,
Capltel la capltata
Polychaete worm,
Neanthes arenaceodentata
Polychaele worm,
Ophryolrocha labronica
American oyster,
Crassostrea vlrginlca
Hardness
«9/l
Chemical (CaOH>
Cadmium chloride
Cadmium chloride
Cadmium chloride
Cadmium chloride
Cadmium chloride
Cadmium chloride
Cadmium chloride
Cadmium chloride
Cadmium chloride
Cadmium chloride
Cadmium ch lorlde
Cadmium chloride
Cadm 1 urn lod 1 de
Duration
II days
7 days
7 days
7 days
7 days
7 days
7 days
7 days
7 days
28 days
26 days
28 days
17 days
40 days
Effect
Growth rate
EC 50 (10 g/kg
salinity)
EC50 (15 g/kg
salinity)
EC50 (20 g/kg
salinity)
BC50 (25 g/kg
sal Inlty)
EC50 (7.5 C)
BC50 (10 C)
BC50 (15 C)
EC50 (17.5 C)
LC50
50* morta 1 1 ty
50* mortal ity
50* mortality
BCF = 677
Result*
(yg/l) Reference
110-280 St ebbing, 1976
3 Theede, et al. 1979
5.6 Theede, et al. 1979
11 Theede, et al. 1979
12.4 Theede, et al. 1979
52 Theede, et al. 1979
34 Theede, et al. 1979
9 Theede, et al. 1979
5.6 Theede, et al. 1979
630 Kelsh, et al. 1978
700 Reish, et al. 1976
3,000 Relsh, et al. 1976
1,000 Brown & Ahsanullah,
1971
Kerfoot & Jacobs, 11
B-49
-------
Table 6. (Continued)
Species
American oyster,
Crassostrea vlrglnlca
Soft shell clam.
My a arenarla
Soft shol 1 clam,
Mya arenarla
Bay scallop,
Aquipecten Irradians
Bay scallop,
Aqulpecten irradlans
Common oussel,
Mytl lus edulis
Common mussel,
Mytl lus edulls
Common mussel,
Myti lus edul Is
Common mussel,
Mytl lus edulls
Common mussel,
Myti lus edulls
American lobster,
Homarus amer Icanus
Copepod,
ligrlopus Japonicus
My s I d shr 1 mp ,
Mysidopsis bahia
My bid shrimp,
Mysidopsis bad I a
Hardness
•9/1
Che* lea 1 (CaCO^i
Cadmium chloride
Cadmium chloride
Cadmium chloride
Cadmium chloride
Cadmium chloride
Cadmium EOT A
Cadmium alglnate
Cadmium humate
Cadmium pectate
Cadmium chloride
Cadmium chloride
Cadmium sulfate
Cadmium chloride
Duration
21 days
7 days
7 days
42 days
21 days
28 days
28 days
28 days
28 days
21 days
21 days
48 days
17 days
28 days
Effect (MO/1)
BCF=I49
LC50 150
LC50 700
EC 50 growth 76
reduction
BCF=168
BCF=252
BCF=252
ECF=252
ECF=252
BCF=710
BCF=25
Inhibited 44
reproduct Ion
LC50 1 1
LC50 16
Reference
Elsler, et al. 1972
tlsler, 1977
Eisler & Hennekey,
1977
Pesch & Stewart, I960
Elsler, et al. 1972
George & Coambs. 1977
George & Coambs, 1977
George & Coambs, 1977
George & Coambs, 1977
Janssen & Scholz, 1979
Eisler, et al. 1972
O'Agostino & Flnney
1974
Nimmo, et al. I977a
U.S. EPA, 1980
B-50
-------
Table 6. (Continued)
Species
Mysid shrimp,
Mysldopsls bahia
Mysid shrimp,
Mysldopsls blgelowl
Mysid shrimp,
Mysldopsls blgelowl
1 sopod ,
Idotea bait lea
1 sopod ,
Idotea bait lea
1 sopod,
1 doled baltlca
1 sopod,
Jaera alblfrons
1 sopod ,
Jaera alblfrons
Pink shrimp,
Punaeus duorarum
Grass shrimp, -
Palaemonetes vulgar is
Grass shrimp,
Palaemonetes pugio
Grass shrimp,
Palaemonetes puyio
Grass shrimp,
Palaemonetos pugio
Grass shrimp.
Pa 1 aenonetes pucjio
Hardness
•9/1
Chemical (CaCO,)
Cadmium chloride
Cadmium ch lorl de
Cadmium chloride
Cadmium su Ifate
Cadmium sulfate
Cadmium su 1 fate
Cadmium sul fate
Cadmium sulfate
Cadmium chloride
Cadmium chloride
Cadmium chloride
Cadmium chloride
Cadmium chloride
Cadmium chloride
Duration
8 days
8 days
28 days
5 days
3 days
1.5 days
5 days
5 days
30 days
29 days
42 days
21 days
21 days
21 days
Effect
LC50
LC50
LC50
LC50 (3 g/kg
salinity)
LC50 (21 g/kg
salinity)
LC50 (14 g/kg
sal Inlty)
LC50 (3.5 g/kg
sal inlty)
LC10 (35 g/kg
salinity)
LC50
LC50
LC50
LC25 (5 g/kg
sal inity)
LC10 (10 g/kg
sal inity)
LCb (20 g/kg
salinity)
Result*
(ug/l)
60
70
18
10,000
10,000
10,000
10.000
10,000
720
120
300
50
50
50
Reference
U.S. EPA, 1980
U.S. EPA, 1980
U.S. EPA, I960
Jones, 1975
Jones, 1975
Jones, 1975
Jones, 1975
Jones, 1975
Nlnroo, et al. 1977b
Nlrnno, et al. 1977b
Pesch 4 Stewart, 1980
Vernberg, et al. 1977
Vernberg, et al. 1977
Vernberg, et al. 1977
B-51
-------
Table 6. (Continued)
Species
Grass shrimp,
Palaemonetes pugio
Grass shrimp,
Palaemonetes pugio
Grass shrimp,
Palaemonetes pugio
Grass shrimp,
Palaemonetes pugio
Blue crab,
Callinectes sapldus
Blue crab,
Callinectes sapldus
Mud crab,
Rhlthropanopeus harrlsli
Mud crab,
Rhithropanopeus harrlsli
Mud crab,
Hh 1 thropanopeus harr 1 s 1 1
Fiddler crab,
Uca pugl lator
Fiddler crab
Uca pugl lator
Hermit crab,
Pagurus longlcarpus
Hermit crab,
Paqurus longlcarpus
Crab ( larva) ,
Eurypanopeus depresses
Hardness
•og/l
Chemical (CaCOA)
Cadmium chloride
Cadmium ch lorlde
Cadmium chloride
Cadmium chloride
Cadmium nitrate
Cadmium nitrate
Cadmum nitrate
Cadmium nitrate
Cadmium nitrate
Cadmium chloride
Cadmium chloride
Cadmium chloride
Cadmium chloride
Duration
6 days
6 days
6 days
21 days
7 days
7 days
11 days
11 days
11 days
10 days
7 days
60 days
8 days
Effect
LC75 (10 y/ky
salinity)
LC50 (15 g/kg
salinity)
LC25 (30 gAg
salinity)
BCF=140
LC50 (10 g/Kg
salinity)
LC50 (30 a/kg
salinity)
LC80 (10 g/kg
salinity)
LC75 (20 g/kg
sal Inlty)
LC40 (30 g/kg
sal Inlty)
50) mortality
Effect on
resplrat Ion
25* mortality
50) mortal 1 ty
50 j mortal Hy
Result*
(M9/I)
300
300
300
50
150
50
50
50
2,900
1.0
270
70
10
Reference
Middaugh & Floyd, 1978
Mlddaugh & Floyd, 1978
Middaugh & Floyd, 1978
Vernbarg, et al. 1977
Rosenberg & Cost low,
1976
Rosenberg A Costlow,
1976
Kosenberg & Cost low,
1976
Rosenberg & Cost low,
1976
Rosenberg A Costlow,
1976
O'Hara, 1973
Vernberg, et al. 1974
tlsler and Hennekey,
1977
Pesch & Stewart, 1980
Mlrkes, et al. 1978
B-52
-------
Table 6. (Continued)
Species
Rock crab,
Cancer Irroratus
Starfish.
Aster I as forbesl
Herring (larva),
Clupea harengus
Herring (larva),
Clupea harengus
Pacific herring (embryo),
CIupea pa 11 as I
Pacific herring (embryo),
Clupea pal Ias I
Pacific herring (embryo),
Clupea pal Ias I
Chemical
Cadmium chloride
Cadmium chloride
Cadmium chloride
Cadmium chloride
Cadmium chloride
Cadmium chloride
Cadmium chloride
Hardness
•9/1
(CaCO^j
Striped bass (juvenile), Cadmium chorlde
Morone saxatlMs
Striped bass (juvenile). Cadmium chloride
Morone saxatfI Is
Spot (larva),
Lelostomus xanthurus
Cunner (adult),
Tautogolabrus adspersus
Cunner (adult),
Tautogolabrus adspersus
Cunner (adult),
Tautogolabrus adspersus
Cadmium chloride
Cadmium chloride
Cadmium chloride
Cadmium ch lorlde
Duration
4 days
7 days
-------
Table 6. (Continued)
Species
Juvenl le mul let,
Aldrlchetta forsterl
Atlantic si Iverslde,
Men Id la men Id la
Atlantic si Iverslde,
Men Id la men Id) a
Al lant Ic si Iverslde,
Menldla men Id la
Mummichog (adult),
Fundulus heteroclltus
Mummlchog (adult),
Fundulus heteroclltus
Mummlchog,
Fundulus heteroclltus
Mummlchog (larva),
Fundulus heteroclltus
Mummichog (larva),
Fundulus heteroclltus
Atlantic sllvorslde
(adult),
Menidla menldla
Atlantic si Ivor side
(adult),
Man I d i a men I d I a
At lant Ic si Iverslde
( larva).
Men Id id menidia
Atlantic si Iverslde
( larva),
Mon 1 dia menldia
Hardness
•9/1
Che* leal (CaCOj)
Cadmium chloride
Cadmium chloride
Cadmium chloride
Cadmium chloride
Cadmium chloride
Cadmium chloride
Cadmium chloride
Cadmium chloride
Cadmium chloride
Cadmium chloride
Cadmium chloride
Cadm i urn ch 1 or 1 de
Cadmium chloride
Duration
5 days
19 days
19 days
19 days
2 days
2 days
21 days
2 days
2 days
2 days
2 days
2 days
2 days
Result*
Effect (ug/l) Reference
50* mortality 14,300 Negllski, 1976
LC50 (12 g/kg 970
sal Inity)
LC50 (20 g/kg 60,000
salInity)
LC50 (30 g/kg 43,000
sal Inity)
BCF=48
LC50 (20 g/kg 32,000
sal inlty)
LC50 (30 g/kg 7,800
salInlty)
LC50 (30 g/kg 12,000
salInlty)
Voyer, et al. 1979
Voyer, et al. 1979
Voyer, et al. 1979
Mlddaugh 4 Dean, 1977
Mlddaugh & Dean, 1977
Eisler, et al. 1972
Middaugh & Dean, 1977
Middaugh & Dean, 1977
Mlddaugh & Dean, 1977
LC50 (20 g/kg 13,000 Mlddaugh & Dean, 1977
salinity)
LC50 (20 g/kg 2,200 Mlddaugh & Dean, 1977
salinlty)
LC50 (30 g/kg 1,600 Mlddaugh & Dean, 1977
salinity)
B-54
-------
Table 6. (Continued)
Species
Winter f founder,
Pseodop leuronectes
amerlcanus
Winter flounder,
Pseudop 1 euronectes
amerlcanus
Hardness
•pg/l
Chen leal (CaCOO Duration
Cadmium chloride - 8 days
Cadmium chloride - 60 days
Effect
Viable hatch -
50*
Increased gi 1 1
tissue
respiration
Result*
(ug/l) Reference
300 Voyer, et al. 1977
5 Calabrese, et al. 1975
* Results are expressed as cadmium, not as the compound.
3-55
-------
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Mammalian Toxicology and Human Health Effects
INTRODUCTION
Over 50 years have now passed since the first fatal case of
acute industrial cadmium poisoning was reported (Legge, 1924) by
the British Factory Inspectorate. During the ensuing decades at-
tention was primarily paid to further cases of acute cadmium poi-
soning occuring via inhalation in industry or through ingestion
(Frant and Kleeman, 1941). Harriet Hardy (Hardy and Skinner, 1947)
was among the first to suggest significant chronic effects when she
reported five cases of ill health in cadmium exposed workmen who
had symptoms of anemia and respiratory complaints. The first de-
finitive reports of chronic effects were those of Friberg (1948a,b)
who clearly identified emphysema and renal damage among male work-
ers exposed to cadmium oxide dust in a Swedish alkaline battery
factory. That cadmium might be associated with health effects as a
result of general environmental pollution was gradually recognized
during the 1960's as various investigators examined facets of the
endemic disease complex called itai-itai in Toyama Prefecture,
Japan (Friberg, et al. 1974). These and other reports have spawned
a vast literature which now defies concise summarization. None-
theless, a significant number of excellent general reviews have
appeared in recent years and serve as guides to the more signifi-
cant papers in the scientific literature (Friberg, et al. 1974;
Flick, et al. 1971; Kendrey and Roe, 1969; Nordberg, 1974;
Fleischer, et al. 1974; Buell, 1975; Perry, et al. 1976; Fassett,
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1975; Webb, 1975; U.S. EPA, 1975a,b; National Academy of Science
(NAS), 1977).
EXPOSURE
The major non-occupational routes of human cadmium exposure are
through food and tobacco smoke. Data published by the Food and
Drug Administration (FDA, 1974) based on market basket surveys over
7 years, show that the average cadmium intake of 15- to 20-year-old
males is 39 ug/day, which includes that found in water. If this
figure is adjusted by the recommended daily calorie intake for var-
ious age groups, the average daily cadmium intake from birth to age
50 is 33 ^ig/d for men and 26 jag/d for women. More recent domestic
data based on fecal excretion give intake figures of 18 jjg/d and 21
jjg/d for teen-age males residing in Dallas, Texas, (Kjellstrom,
1978) and Chicago, Illinois (Pahren and Kowal, 1978), respectively.
The data in Table 1 indicate that the daily intake of cadmium via
food for individuals living in the United States is comparable to
that in other parts of the world.
Cadmium is concentrated by certain food crop classes to an
appreciable extent. In particular, potatoes, root crops, and leafy
vegetables show the greatest tendency in this regard and their cad-
mium content depends to a high degree on the soil solution concen-
tration of the element (Pahren, et al. 1978). Municipal sewage
sludges, containing high levels of cadmium of industrial origin and
applied to agricultural lands as fertilizer, are potentially impor-
tant sources of cadmium entry into the human food chain (Counc.
Agric. Sci. Tech., 1976). To date there have been no occurrences
of cadmium toxicity in animals or man attributed solely to direct
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TABLE 1
Daily Cadmium Intake Via Food
Country
ug/day
Reference
United States
Canada
West Germany
Rumania
Czechoslovakia
Japan (unpolluted area)
Sweden
Australia
New Zealand
39
52
48
38-64
60
59
17
30-50
21-27
Food and Drug Administration, 1974
Kirkpatrick and Coffin, 1977
U.'S. EPA, 1975b
U.S. EPA, 1975b
U.S. EPA, 1975b
U.S. EPA, 1975b
Kjellstrom, et al. 1978a
Miller, et al. 1976
Guthrie and Robinson, 1977
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consumption of vegetation grown on land amended with municipal
sludge (Garrigan, 1977). The widespread usage of phosphate ferti-
lizers, most of which contain significant amounts of cadmium (U.S.
EPA, 1975a), is potentially a more important source of cadmium en-
try into human foodstuffs and will ultimately increase the amount
of cadmium in the diet.
Balanced diets generally contain levels of cadmium approximat-
ing 0.05 mg/kg (Nordberg, 1974). Aquatic food species including
fish, crabs, oysters, and shrimps bioconcentrate cadmium, as do
visceral meats (liver, kidney, pancreas). Cadmium content depends
on the age of animals at slaughter, older animals having higher
concentrations (Kreuzer, et al. 1976; Nordberg, 1974).
A bioconcentration factor (BCF) relates the concentration of a
chemical in aquatic animals to the concentration in the water in
which they live. An appropriate BCF can be used with data concern-
ing food intake to calculate the amount of cadmium which might be
ingested from the consumption of fish and shellfish. Residue data
for a variety of inorganic compounds indicate that bioconcentration
factors for the edible portion of most aquatic animals is similar,
except that for some compounds bivalve molluscs (clams, oysters,
scallops, and mussels) should be considered a separate group. An
analysis (U.S. EPA, 1980) of data from a food survey was used to
estimate that the per capita consumption of freshwater and estuar-
ine fish and shellfish is 6.5 g/day (Stephan, 1980). The per cap-
ita consumption of bivalve molluscs is 0.8 g/day and that of all
other freshwater and estuarine fish and shellfish is 5.7 g/day.
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Bioconcentration factors are available for the edible portion
of many species of fish and shellfish (Table 2).
The geometric mean of the values available for bivalve mol-
luscs is 444 whereas that for all other species is 11. If the val-
ues of 444 and 11 are used with the consumption data, the weighted
average bioconcentration factor for cadmium and the edible portion
of all freshwater and estuarine aquatic organisms consumed by Amer-
icans is calculated to be 64.
Tobacco in all its forms contains appreciable amounts of cad-
mium. Since the absorption of cadmium from the lung is substan-
tially greater than that from the gastrointestinal tract, smoking
contributes significantly to total body burdens. American cigar-
ettes (Menden, et al. 1972) have been found to contain 1.5 to 2.0 ug
per cigarette and about 70 percent of this passes into the smoke
(Nandi, et al. 1969). Most data indicate that 0.1 to 0.2 ug cadmium
are inhaled for each cigarette smoked. Thus, smoking 20 cigarettes
per day will result in the inhalation of about 3 ug per day of cad-
mium or an absorption of 0.75 ug per day (assuming 25 percent ab-
sorption). It has been pointed out that workers handling cadmium
compounds may contaminate their cigarette or pipe tobacco and fur-
ther augment the high metal load contributed by smoking (Piscator,
et al. 1976).
Ambient air is not a significant source of cadmium exposure
for the vast majority of the United States population. Data from
the National Air Sampling Network have been summarized by Tabor and
Warren (1958) and Schroeder (1970). Data collected in 1966 in 58
urban and 29 nonurban areas showed a range of concentrations of
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TABLE 2
BCFs for Some Species of Fish and Shellfish
Species
BCF
Reference
Brook trout,
Salvelinus fontinalis
Brook trout,
Salvelinus fontinalis
Brook trout,
Salvelinus fontinalis
American oyster,
Crassostrea virginica
American oyster,
Crassostrea virginica
American oyster,
Crassostrea virginica
American oyster,
Crassostrea virginica
American oyster,
Crassostrea virginica
Soft shell clam,
Mya arenaria
Quahaug,
Mercenar ia mercenar ia
Bay scallop,
Aquipecter irradians
Bay scallop,
Aquipecter irradians
Common mussel,
Mytilus edulis
Crab,
Carcinus maenas
Crab,
Carcinus maenas
3
151
10
677
2,600
1,830
149
1,220
160
83
168
2,040
113
5
Benoit, et al. 1976
Benoit, et al. 1976
Sangalang & Freeman,
1979
Kerfoot & Jacobs,
1976
Zaroogian & Cheer,
1976
Zaroogian, 1979
Eisler, et al., 1972
Schuster & Pringle,
1969
Pringle, et al.
1968
Kerfoot & Jacobs,
1976
Eisler, et al., 1972
Pesch & Stewart,
1980
George & Coombs,
1979
Wright, 1977
Jennings & Rainbow,
1979
C-6
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2-370 and 0.4-26 ng per cubic meter, respectively. The data empha-
size that nearly all airborne cadmium is due to man's activities.
Highest concentrations are consistently found in industrialized
cities and in the vicinity of smelting operations (Fleischer,- et
al. 1974), In areas where there are no such sources of airborne
cadmium pollution the levels observed have generally been around
0.001 ug/m , which leads to an average inhaled amount of approx-
imately 0.02 - 0.03 ug per day for adults. In those cities with
the highest levels of cadmium air pollution (up to approximately
400 ng/m ) the maximum amount inhaled could rise on extreme occa-
sions to 8.0 ug per day. As controls on emissions continue to
tighten, intake via the respiratory route is expected to diminish.
Drinking water also contributes relatively little to the aver-
age daily intake. A survey of 969 U.S. community water supply sys-
tems, representing 5 percent of the national total, revealed an
average cadmium concentration of 1.3 ug/1. Only three systems ex-
ceeded concentrations of 10 ug/1. Of 2,595 distribution samples
taken during this same survey (McCabe et al., 1970) only four sam-
ples exceeded the 10 ug/1 standard with the maximum sample having a
concentration of 0.11 mg/1. Apparently an occasional water source
is aggressive enough to cause some dissolution of metal from
distribution piping, i.e., galvanized pipe. Most analyses of sea
waters have reported average concentrations of 0.1 -0.15 ug/1
(Fleischer, et al. 1974). Since this is less than fresh water
sources entering the sea and far below the levels expected from
solubility factors it has been suggested that cadmium is effective-
ly removed by co-precipitation with or adsorption on clays, hydrous
C-7
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manganese oxide, or phosphorites (Posselt, 1971). Based on the
above community water supply study and an average adult consumption
rate of 2 1/d, drinking water sources probably contribute not more
than 3-4 ug/d to the total average cadmium intake.
Very little is known concerning the absorption of cadmium com-
pounds through the skin and only the chloride salt has been studied
(Skog and Wahlberg, 1964; Wahlberg, 1965). Maximum absorption of
1.8 percent over 5 hours was observed when a cadmium concentration
of 26 gm/1 was applied. At lower concentrations, less than 1 per-
cent absorption occurred. Since these levels are higher by a fac-
tor of approximately 20 million than household waters used for
washing or bathing there seems to be virtually no risk of signifi-
cant absorption through the skin. However, it should be pointed
out that human studies have apparently not been done. Wastewater
may indirectly play a considerably greater role since cadmium may
enter the food chain from contaminated water used to irrigate
fields producing crops for human consumption.
PHARMACOKINETICS
While ingestion constitutes the major part of human intake
only a small proportion, i.e., approximately 5 percent, is ab-
sorbed, the rest passing directly into the feces. Gastrointestinal
absorption is influenced by a number of dietary factors. Diets low
in calcium lead to significantly higher levels of absorption and
deposition of cadmium into intestinal mucosa, liver, and kidneys
(Washko and Cousins, 1976) and corresponding decreases in fecal
excretion. Cadmium increases the urinary excretion of calcium
without affecting the excretion of phosphorus (Itokawa, et al.
C-8
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1978). Cadmium inhibits the in vitro uptake of calcium from the
rat duodendum/ but calcium was not shown to have an inhibitory ef-
fect on the in vitro uptake of cadmium (Hamilton and Smith, 1978).
While confirming the rn vitro inhibitory effect of cadmium on in-
testinal calcium absorption it has been recently demonstrated that
the in vivo treatment of rats with cadmium, either acutely or
chronically, does not decrease intestinal calcium absorption
(Yuhas, et al. 1978). Diets deficient in vitamin D lead to in-
creased cadmium absorption (Worker and Migicovsky, 1961). Low pro-
tein diets also lead to considerably higher levels of cadmium in
various organs irrespective of the calcium content of the diet
(Suzuki, et al. 1969). Similarly, deficiencies of zinc, iron, and
copper have been shown to enhance cadmium uptake and subsequent ad-
verse effects (Banis, et al. 1969; Bunn and Matrone, 1966; Hill, et
al. 1963). Ascorbic acid deficiency also promotes cadmium toxicity
(Fox and Fry, 1970). The complex relationships between cadmium and
various heavy metals and nutrients has been reviewed by Bremner
(1974).
Human studies using mCd given orally have yielded absorp-
tion values of 6 percent (range 4.7 - 7.0 percent) and 4.6 (range
0.7 - 15.6 percent) (Rahola, et al. 1973; McLellan, et al. 1978).
In the latter study, total body counting was used to determine cad-
mium absorption in 14 healthy subjects aged 21-61 years. A triva-
lent chromium (CrCl.,) marker, which is poorly absorbed from the
gastrointestinal tract, was given along with mCd, assuming that
unabsorbed cadmium would have the same transit time as chromium.
The average body retention of radiocadmium determined between 7 and
C-9
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14 days after the disappearance of the chromium marker from the
body was 4.6 percent with a standard deviation of + 4 percent. Var-
ious animal experiments have usually given lower oral absorption
figures, i.e., approximately 2 percent, for ingested cadmium
(Friberg, et al. 1974).
In contrast to ingestion, a relatively large proportion of
respired cadmium is absorbed and inhalation represents a major mode
of entry into the body for smokers and occupationally exposed per-
sons. The fate of inhaled cadmium, in common with other respirable
pollutants, depends upon particle size, solubility, and lung sta-
tus. When a large proportion of particles are in the respirable
range and the compound is relatively soluble, 25 percent of the in-
haled amount may be absorbed. Cadmium fumes may have an absorption
of up to 50 percent and it is estimated that up to 50 percent of
cadmium in cigarette smoke may be absorbed (World Health Organiza-
tion (WHO) Task Group, 1977; Blinder, et al. 1976). Retrograde
movement of particulate cadmium due to mucociliary transport may
lead to eventual swallowing and gastrointestinal tract absorption.
Most studies on the transport and tissue distribution follow-
ing absorption have been done in animals. Following intravenous or
intraperitoneal administration most of the cadmium is initially
found in the blood plasma. After 12-24 hours the plasma is cleared
and most of the cadmium has entered erythrocytes which contain the
metal-binding protein, metallothionein. With repeated administra-
tion the red cell content becomes many times greater than the plas-
ma. Further distribution within the body is dependent on the
elapsed time since absorption (U.S. EPA, 1975b).
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Irrespective of the route of entry, cadmium is principally
stored in the liver and kidneys with higher levels initially found
in the liver. Following single exposures, relocation occurs and
liver concentrations eventually are exceeded by the renal cortex.
Repeated exposures result in eventual high concentrations in both
organs. Continued exposure eventually leads to a level of about
200-300 mg/kg wet weight in the renal cortex, after which patho-
logic changes occur which result in increased excretion of cadmium
and protein in the urine, and no further accumulation occurs (WHO
Task Group, 1977). The accumulation in the liver and kidneys seems
to be mainly dependent on the storage of cadmium in association
with the cadmium-bind ing protein, metallothionein (Chen, et al.
1975; Nordberg, et al. 1975).
Cadmium, unlike many trace metals, has no known function in
normal metabolic processes. Recently there has been some specula-
tion that cadmium may be an essential trace element. It has been
reported that cadmium deficient animals respond with significant
growth effects when cadmium salts are added to a basal diet. These
effects are said to be dose-dependent, consistent, and reproduci-
ble. In addition, glucose-6-phosphatase dehydrogenase may be acti-
vated by cadmium (Cadmium Research Digest, 1977). Confirmation of
these findings, while of great scientific interest, would not less-
en the need to control potential toxic exposures to the element.
The factor which makes cadmium contamination of the environment a
particularly serious hazard from the human health standpoint, is
its pronounced tendency to bioaccumulate. Blinder and Kjellstrom
(1977) have compared renal cadmium levels in specimens taken in
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recent autopsies (57 jjg/gm dry weight) with specimens collected in
the last century (15 ug/gm dry weight). These data indicate that
cadmium body burdens are increasing, perhaps reflecting increased
general environmental exposure to the element. A review of a great
number of studies indicates that the total body burden of cadmium
in humans increases with age, (Friberg, et al. 1974) from very min-
imal levels at birth ( < 1 ug)/ (Henke, et al. 1970) to an average
of up to 30-40 mg by the age of 50 in nonoccupationally exposed in-
dividuals (Friberg, et al. 1974). About 75 percent of this accu-
mulation is found in the kidneys and liver, the kidneys containing
approximately one-third of the average body burden with the highest
levels localized in the renal cortex. In general, the liver con-
tinues to concentrate cadmium until the late decades of life while
kidney concentrations increase to the fourth decade, peak, and
steadily decline from the sixth decade (Gross, et al. 1976). The
pancreas and salivary glands also contain considerable concentra-
tions of cadmium while the brain and bone acquire only very small
quantities (Nordberg, 1974). Age appears to have significant ef-
fects on how cadmium distributes after absorption. Using mCdC!2
in rats, Kello and Kostial (1977) demonstrated that cadmium whole
body retention declined with increasing age. Young animals had
disproportionately more cadmium in their kidney and blood than
older animals and correspondingly less accumulation in the liver.
Smokers have an appreciably greater body burden of cadmium than
nonsmokers. The average concentration in the renal cortex is ap-
proximately doubled in smokers (Blinder, et al. 1976; Hammer, et
al. 1973). It is of interest that in Japan where the average diet
C-12
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contains appreciably more cadmium than in Western countries, the
metal could be detected in 57 percent of human embryos of 31 to 35
days gestation and this figure increased to 80 percent during the
second trimester (Chaube, et al. 1973). Blood levels in newborn
babies are correlated with maternal blood levels, but average only
50 percent of the maternal levels (Lauwerys, et al. 1978). In
environmentally exposed children, urinary cadmium levels were a
more sensitive indicator of exposure than blood cadmium (Roels, et
al. 1978).
In nonoccupationally exposed persons the mean level of cadmium
in the blood is usually less than 1 jjg/100 ml. Children without
known exposure, aged 2 months to 13 years (average 4.9 years), are
reported as having slightly lower levels, i.e., 0.66 jjg/100 ml
(Smith, et al. 1976). Smokers are reported as having blood cadmium
levels 50 percent greater than nonsmokers (Einbrodt, et al. 1976).
Several reports indicate that urinary excretion of cadmium is
approximately 1-2 jug/day in the general population (Imbus, et al.
1963; Szadkowski, et al. 1969). There is a modest increment in
urinary levels with age (Katagiri, et al. 1971). Urinary excretion
may be markedly elevated in exposed workers including those without
renal damage (Friberg, et al. 1974). If renal tubular dysfunction
should occur due to cadmium accumulation, the rate of urinary cad-
mium excretion will further increase, which in turn results in a
considerable decrease in renal cadmium levels, even though irrever-
sible tubular damage has already occurred (Kjellstrom, 1976). It
should be mentioned that renal levels fall after age 50 even in
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"normal" persons and decreased renal levels are not necessarily due
to cadmium-induced renal disease.
Fecal excretion appears to closely reflect the dietary intake
(Tipton and Stewart, 1970; Kojima, et al. 1977) as might be antici-
pated from the previously discussed absorption data. Smokers have
a slightly increased fecal excretion rate averaging 3.2 ug/d
(Kjellstrom, et al. 1978a). It is unknown how much fecal cadmium
may be derived from intestinal epithelium or biliary excretion.
Saliva contains up to 0.1 wg/g cadmium (Driezen, et al. 1970) and
may contribute significantly to fecal excretion since a normal
adult will secrete 1,000-1,500 ml/d. The amount of gastro-
intestinal reabsorption is unknown. Biliary excretion has been
studied by Stowe (1976) who observed normal rat bile to contain 22
+ 3 ppb cadmium. Rats fed 100 ppm cadmium excreted bile containing
58 ^ 6 ppb. Less than 0.1 percent of subcutaneously-injected cad-
mium was excreted in the bile within the first 5 hours following
administration.
Hair is a minor excretory pathway and may contain from 0.5 to
3.5 ug/g (Friberg, et al., 1974). In rats, continued exposure to
cadmium in drinking water leads to initially high hair levels,
which decline dramatically with continued administration. It
has been concluded that hair cadmium would not be useful in esti-
mating either concentrations in vital organs or degree of organ
damage (Brancato, et al. 1976). In infancy human hair has been
shown to have relatively high levels of cadmium which thereafter
decline throughout life (Gross, et al. 1976). While positive cor-
relations have been reported between environmental levels (Hammer,
C-14
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et al. 1971) and occupational exposure and visceral organ levels
(Oleru, 1975) these associations are generally too weak to permit
accurate quantitative assessments of human exposure to cadmium.
Estimates of the biologic half-time of absorbed cadmium have
been derived in a number of ways, i.e., by theoretical metabolic
balance studies, determining the half-time in blood or urine, and
by measuring the decrease in whole-body retention of isotopic cad-
mium.
Studies on the half-time in urine (Sudo and Nomiyama, 1972) or
blood (Tsuchiya, 1970) have given values of 200 days and 1 year,
respectively, for former occupationally-exposed workers. The num-
ber of workers studied was very small. Obviously, this approach
may not reflect the total body burden of cadmium, some of which may
be very tightly bound in various tissues. Also, these subjects are
not representative of normal environmental exposure in which urine
may reflect the total body burden (Tsuchiya, et al. 1976), but of
current exposure when such exposure has been or is high (Lauwerys,
et al. 1976). Blood also is thought to best represent current ex-
posure (Lauwerys, et al. 1976). Direct comparison of urinary ex-
cretion levels and estimated body burden have also been performed
using Japanese, American, and German data. These data suggest a
half-time of 13-47 years. Similar time frames have been found
using more complex metabolic models and Friberg (Friberg, et al.
1974) has concluded that the biologic half-time is probably 10-30
years. These methods suffer the disadvantage that actual body bur-
dens cannot be ascertained for the living subject and are assumed
to be the same as averages derived from autopsy studies.
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Only two human studies using radioisotopes are available.
Rahola, et al. (1973) stated it was not possible to accurately
determine a biologic half-time, but provided a shortest estimate of
130 days and a longest of infinity. In a single human subject for
whom the figure could be calculated the biologic half-time was 100
days (McLellan, et al. 1978).
From the foregoing, it is obvious that the data are not in
good agreement regarding cadmium half-time with estimates varying
at least 100-fold (months v. decades). Since this is a critical
issue in terms of maximum daily limits for standard-setting pur-
poses, it is essential that more new data be generated to resolve
this facet of cadmium metabolism. Nomiyama, et al. (1978) has
demonstrated in Rhesus monkeys that cadmium half-time is inversely
related to the oral intake of the element. This may explain some of
the wide variation seen in human studies.
In summary, from the exposure, intake, absorption, and excre-
tion data it appears that most persons exposed to cadmium in the
general environment are in an approximate cadmium balance. Autopsy
data suggest a slight positive balance until approximately age 50
after which a negative balance ensues. The reasons for this de-
cline are unknown. It is unrelated to the presence or absence of
renal disease, but may be due to the lessened intake of food as cal-
oric needs also decline in later life. It has also been suggested
that the observed decrease may be an artifact related to the possi-
bility that older persons have been exposed to far lower cadmium
levels during their youth (Hammer, et al. 1973).
C-16
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EFFECTS
Acute, Subacute, and Chronic Toxicity
When adminstered orally, cadmium acts as an emetic in both man
and subhuman species. Cadmium metal is quite soluble in weak acids
such as those commonly found in many foods and beverages. Organic
cadmium salts may be transformed upon contact with gastric hydro-
chloric acid into cadmium chloride which has an inflammatory action
on the mucus membranes of the stomach and intestine (Browning,
1969). Oral administration of cadmium produces emesis at a concen-
tration of about 400 ppm (23 mg/kg) in food (Schwarze and Alsberg,
1923). These authors cite the case of Burdach, who induced vomiting
with one-half grain of cadmium sulfate, which contains about 15 mg
of cadmium.
The oral LDjQ in rats varies only slightly with the cadmium
compound employed, i.e., oxide, 72 mg/kg; chloride, 88 mg/kg; and
fluorosilicate, 100 mg/kg. The lowest oral dose producing death in
rats using cadmium fluroborate has been given as 250 mg/kg. The
LD50 for guinea pigs given cadmium fluoride is reported to be 150
mg/kg (National Institute for Occupational Safety and Health
(NIOSH), 1974). More complete acute toxicity data are given in an
U.S. EPA report (U.S. EPA, 1975a). The lethal oral dose of cadmium
for man is not known (Thienes and Haley, 1972).
Because of its acid solubility and formerly widespread usage
in plating metal utensils and containers, cadmium has been responsi-
ble for numerous outbreaks of acute poisoning in the past. Some
689 cases of cadmium poisoning were reported within the 5-year
C-17
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period 1941-1946 (Fairhall, 1957) and doubtless numerous other
undiagnosed and unreported cases also occurred. Largely as a re-
sult of these outbreaks various sanitary codes and national stan-
dards have been amended to prohibit the use of cadmium in any arti-
cle used for food or drink preparation or storage. The most sig-
nificant clinical feature of acute cadmium poisoning is the rapid-
ity with which symptoms become apparent following ingestion. Most
persons become symptomatic within 15 to 30 minutes after ingesting
either food or drink containing toxic amounts of the metal. The
symptoms typically include persistent vomiting, increased saliva-
tion, choking sensations, abdominal pain, tenesmus, and diarrhea
(Browning, 1969; Frant and Kleeman, 1941). The dose causing such
symptoms has been estimated to be within the range of 15-30 mg
(Gleason, et al. 1969; Nordberg, 1974).
Because numerous cases of acute industrial poisoning from cad-
mium have occurred from dust or fume generated by the burning,
heating, welding, melting, or pouring of cadmium metal, cadmium
alloys, or cadmium plate, the respiratory tract effects have been
well documented (Kazantzis, 1963).
Symptoms from acute poisoning by cadmium oxide fumes appear 4-
6 hours after exposure and include cough, shortness of breath and
tightness of the chest. Pulmonary edema may ensue within 24 hours,
often to be followed by bronchopneumonia. Most cases are resolved
within a week. The fatality rate ranges between 15 and 20 percent
(Bonnell, 1965). Later effects from acute overexposure include
pulmonary fibrosis (Health, et al. 1968), permanently impaired lung
function (Townshend, 1968) and disturbed liver function (Blejer, et
C-18
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al. 1971). Barrett and Card (1947) estimated that the lethal dose
for a man doing light work would not exceed 2,900 minutes mg/m .
From these figures it may be estimated that a lethal exposure to
cadmium fume may result from breathing a concentration of approx-
imately 5 mg/m over an 8-hour period. In Blejer's fatal case it
was thought that the atmospheric concentration exceeded 1 mg/m .
Ansomia is a well described defect in those employed in the
cadmium industry and correlates with the appearance of proteinuria,
i.e., both depend upon length of service (Potts, 1965; Friberg,
1950; Adams and Crabtree, 1961; Tsuji, et al. 1972). Pihl and
Parkes (1977) noted elevated cadmium and lead levels in the hair of
children with learning disability.
A host of chronic effects attributed to cadmium exposure have
been reported by numerous investigators over the past three de-
cades. Without doubt, at least in terms of human effects, the two
cardinal pathologic lesions associated with cadmium are pulmonary
emphysema and renal tubular damage.
Friberg (1948a,b; 1950) was the first to note emphysema in his
now classic studies of workers exposed to cadmium iron oxide dust
in a Swedish alkaline battery factory. Since then numerous inves-
tigators have confirmed and expanded upon these initial findings
(Paterson, 1947; Baader, 1952; Lane and Campbell, 1954; Buxton,
1956; Smith, et al. 1960; Kazantzis, et al. 1963; Potts, 1965;
Holden, 1965; Lewis, et al. 1969; Snider, et al. 1973; Lauwerys, et
al. 1974; Smith, et al. 1976).
A possible mechanism for cadmium emphysema has been suggested
by Chowdbury and Lauria (1976) who noted that the addition of
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cadmium to human plasma caused an inhibition of alpha-1-antitrypsin
with a decrease in trypsin inhibitory capacity. Other metals had
little or no effect at equimolar concentrations. Persons with con-
genital alpha-1-antitrypsin deficiency have a marked increased risk
of emphysema and cadmium may stimulate or augment this defect.
Based on data from studies of the acute pulmonary effects, the
studies of long-term industrial exposure, and the absence of con-
tradicting animal data it seems apparent that cadmium induced em-
physema is related only to the inhalation route of exposure. Ap-
parently no studies have been done relating the incidence of emphy-
sema in the general population to varying ambient levels of air-
borne cadmium.
There is general agreement that renal tubular damage is the
most important chronic effect of cadmium exposure irrespective of
route. The hallmark of this injury is the appearance of a low mole-
cular weight (20,000-25,000) protein in the urine (B--microglobu-
lin). Industrial studies have shown that proteinuria is not only
much more common than emphysema, but also that it appears after
shorter periods of exposure. This protein is not the same as that
excreted after conventional kidney damage and doesn't react in the
usual laboratory tests designed to detect urinary protein (Brown-
ing, 1969). First reported in 1948 by Friberg in workers exposed
to cadmium oxide dust, B_-microglobulin has subsequently been re-
ported in the urine of workers exposed to other forms of cadmium
and in the urine of animals experimentally exposed. As cadmium
accumulates in the kidney it inhibits tubular reabsorption result-
ing in proteinuria (Derggard and Beam, 1968). Other signs of
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renal tubular dysfunction resulting from cadmium exposure are gly-
cosuria, aminoaciduria, and changes in the metabolism of calcium
and phosphorus (Kazantzis, 1963). The dysfunction rarely progress-
es to renal failure, but hypercalcinuria may occasionally lead to a
negative calcium balance and to osteomalacia (Nicaud, et al. 1942;
Adams, et al. 1969).
High levels of proteinuria have been found in itai-itai dis-
ease patients where increased excretion is strongly correlated to
residence time in exposed areas and the use of cadmium contaminated
river water (Kjellstrom, et al. 1977). Tsuchiya, et al. (1978) has
found that B2-microglobulin excretion is highly correlated with
aging in both high and low cadmium exposure population groups.
Kjellstrom has attempted to determine a dose response between B~-
microglobulin excretion and cadmium in air (Kjellstrom, 1977a,b;
Kjellstrom, et al. 1977). He determined the geometric average B_-
microglobulin concentration to be 84 ug/1 in normal unexposed per-
sons with 95 percent confidence limits of 24-290 jug/1. Using the
upper 95 percent limit he found an elevated excretion prevalence of
19 percent for workers with 6-12 years exposure. Smokers were also
noted to have about 2 to 3 times the prevalence of elevated excre-
tion found for nonsmokers. This applies to both the industrially-
exposed smokers as well as non-exposed workers. Women are noted to
have a lower prevalence than men and this is attributed to sex
differences in smoking habits.
Kjellstrom, et al. (1977) is careful to point out that ele-
vated chronic excretion of B2-nucroglobulin does not equate with
clinically significant proteinuria and that its definition was
C-21
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designed for comparative epidemiological purposes. While pointing
out that the relationship of cadmium proteinuria to life expectancy
is unknown, Kazantzis (1977) believes it is evidence of a critical
effect. Adams, et al. (1969) long-term observations indicate that
some men have had proteinuria for many years without serious im-
pairment of kidney function. He notes that retired men do not seem
to have more serious renal disease than those still at work and
that there is no good evidence of progression to terminal renal
failure. On occasion the renal lesion may be severe enough to pro-
duce osteomalacia and multiple fractures as in itai-itai disease.
However, in all such cases (Friberg, et al. 1974; Nicaud, et al.
1942; Adams, et al. 1969) there appears to have been multiple die-
tary deficiencies (calcium, protein, Vitamin C, Vitamin D) in addi-
tion to an excessive cadmium exposure. For example, itai-itai
disease occurs almost exclusively in grand multiparous women over
the age of 50 who live predominantly on a rice diet with a high (up
to 600 jjg/d) cadmium content. The Japanese government has moni-
tored for new cases of itai-itai disease since 1969. Since then no
new patients with the disease have been found, although the fre-
quency of tubular dysfunction and urinary cadmium are higher in
polluted than in control areas (Shigematsu and Yoshida, 1978).
Nicaud's cases occurred under wartime factory conditions in France.
It seems apparent that multiple nutritional deficiencies may be
more important than cadmium in producing this complex disorder.
While the bone changes (osteomalacia) have been assumed to be sec-
ondary to the renal defect, it has been shown in animals that cad-
mium may directly cause osteoporotic bone changes (Yoshiki, et al.
C-22
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1975). Such evidence implies that certain segments of the popula-
tion living on subsistence diets may well be at increased risk from
cadmium.
Based on animal and limited human data, the critical cadmium
concentration in the renal cortex has been estimated to be about
200 mg/kg wet weight (WHO Task Group, 1977; Friberg, et al. 1974;
Nordberg, 1976). The 28 human cases used to support this figure
show an extremely large variation in concentration. Nomiyama
(1977) points out that this figure should be determined from data
in cases where proteinuria was the only finding, i.e., excluding
those cases with obvious pathologic changes since in long standing
severe disease the net amount of cadmium may be decreased from that
at disease inception. In the eight cases with proteinuria only,
the concentration varied from 150 to 395 mg/kg wet weight with the
exception of a single specimen with a level of 21 mg/kg wet weight.
Four had levels in excess of 300. He suggests that 300 mg/kg wet
weight is a more appropriate critical level. This is supported by
his findings on monkeys (Nomiyama, et al. 1977).
Kjellstrom (1977a,b) has used the figure of 200 mg/kg wet
weight of cadmium in the renal cortex as an estimate of the level
where tubular damage occurs in constructing a metabolic model from
which to calculate a dose-response corresponding to daily intake.
His model gives lower values for Japanese than Europeans because of
the former's smaller average body and kidney weight. For Europeans
the expected response rate, i.e., the proportion of the population
with evidence of renal tubular damage, as manifested by excessive
B2-microglobulin excretion for a given daily cadmium intake, is
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expected to approximate the following sequence: 0.1 percent-32 ug
Cd/d; 1.0 percent-60 ug Cd/d; 2.5 percent-80 pg Cd/d; 5.0 percent-
100 pg Cd/d; 10 percent-148 yg Cd/d; and 50 percent-440 ug Cd/d.
These estimates are for nonsmokers. Smoking will reduce the above
allowable intake from food by approximately 25 ug/d for each pack-
age of cigarettes smoked. Water consumption will reduce the allow-
ance for food on a yg for ug basis assuming equilivent gastrointes-
tinal absorption for food and water. Other sources of cadmium
would normally have only very minor effects. If the value for
renal damage averages closer to 300 mg cadmium/kg wet weight of
cortex instead of 200 this would result in a proportional increase
in allowable daily intake.
In addition to the generally conceded major toxic effects of
cadmium in man it has been hypothesized that exposure to ambient
cadmium levels may be an important factor in the etiology of essen-
tial hypertension. Three major lines of evidence have been set
forth to support this thesis: (1) in some animal experiments cad-
mium has induced hypertension; (2) hypertension is positively cor-
related with the ingestion of soft drinking waters, which often
contain higher concentrations of heavy metals than hard waters; and
(3) hypertension patients have higher renal, bone, and body fluid
cadmium levels (Schroeder and Vinton, 1962; Schroeder, 1964a,b,
1965, 1966; Schroeder and Balassa, 1961; Crawford, et al. 1968;
Lener and Bibr, 1971; Thind and Fischer, 1976; Crawford, 1973;
Perry, 1972). Hypertension is not always found in animals exposed
to cadmium (Lener and Bibr, 1971); and this effect shows variability
among strains and is related to the amount of sodium chloride in
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the diet (Nordberg, 1974). In rats, genetic composition is a
critical determinant for the induction of hypertension by cadmium.
Selective inbreeding has led to animals which are completely resis-
tant to this effect (Ohanian and Iwai, 1978). Most of the studies
relating elevated tissue levels of cadmium to hypertension
(Schroeder, 1965; Perry and Schroeder, 1955; Thind and Fischer,
1976; Lener and Bibr, 1971; Glauser, et al. 1976) were carried out
before the impact of smoking on cadmium accumulation was appreciat-
ed, or have tended to ignore this factor. Much careful work now
tends to indicate that the association between hypertension and
cadmium may be a spurious one. Morgan (1972) in a large autopsy
series was unable to correlate hypertension and mean renal cadmium.
Similarly, Lewis, et al. (1972) failed to find a relationship be-
tween renal levels of cadmium and hypertension. Beevers, et al.
(1976) were unable to find any significant differences in blood
cadmium between 70 hypertensive patients and 70 controls who were
matched for age and sex. 0stergaard (1977) compared renal cadmium
tissue levels in 39 hypertensive and 43 normotensive subjects. In
this series only subjects 45-65 years of age were studied to mini-
mize the effects of age on cadmium accumulation. The data suggest
that hypertensive renal disease may enhance cadmium excretion.
Szadkowski's (1969) study measured the urinary excretion of cadmium
in a large series of persons and could find no relationship between
cadmium excretion and hypertension. Very significantly, epidemio-
logic studies of industrially exposed persons have failed to sup-
port the concept that cadmium .is a significant factor in human
hypertension (Friberg, et al. 1974; Holden, 1969). In addition,
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Japanese patients with itai-itai disease do not have hypertension
(Perry, 1972; Nogawa and Kawana, 1969).
Besides the effects previously discussed, chronic exposure to
cadmium has been suggested to play a causative role in a number of
other pathologic changes in man. These studies are usually in the
form of case reports and often have been reported by only a single
author or group. In general, these effects when considered indivi-
dually are of lesser importance to human health, but collectively
represent possibly an important gap in the knowledge concerning
cadmium toxicity. A brief discussion of several of the more sig-
nificant of these adverse effects follows.
Friberg (1950) noted abnormal liver function tests in his
classic study first documenting emphysema and kidney damage.
Blejer, et al. (1971) also found such changes in cases of acute
overwhelming exposure. Other authors have commented upon the rar-
ity of such findings (Bonnell, 1965? Kazantzis, et al. 1963).
Renal stones have been reported for both Swedish and British
workers exposed to cadmium (Ahlmark, et al. 1961; Adams, et al.
1969). These have occurred in both proteinuric and nonproteinuric
workmen. Since renal stones are a common problem more definitive
industry wide studies are needed to determine the true prevalence
of this problem.
Moderate anemia has been described in a number of studies
(Friberg, 1950; Hardy and Skinner, 1947). This effect is also seen
in animals with experimental cadmium poisoning (Prodan, 1932).
Other reported effects include changes in lipids (Schroeder
and Balassa, 1965), rhinorrhea (Baader, 1952), bone marrow changes
:-26
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(Cotter and Cotter, 1951), dental caries (Hardy and Skinner, 1947),
and nonspecific nervous system signs and symptoms (Vorobjeva,
1957).
Roller has published a series of papers describing various
forms of immunosuppression in experimental animals treated with
cadmium, i.e. , lower neutralizing titers against pseudorabies vi-
rus, decreased antibody synthesis, decreased levels of IgG, etc.
(Roller, 1973; Roller, et al. 1975, 1976). In animals, cadmium has
been shown to affect various enzymes which control blood glucose
levels. The significance of these findings in terms of human
health is conjectural.
Synergism and/or Antagonism
A wide range of chemical and natural substances have been
shown to modify the toxicologic properties of cadmium. This effect
has been seen in highly varying biological systems and appears to
be in many instances due to competition with other metallic ele-
ments for protein-binding sites.
Cadmium toxicity is decreased by other metal ions. In animals
zinc has been shown to prevent cadmium-induced testicular damage
and teratogenic effects (Parizek, 1957; Parizek, et al. 1969; Ferm
and Carpenter, 1967). It reportedly reduces cadmium's ability to
induce tumors (Gunn, et al. 1963a,b; 1964) and it reduces cadmium-
induced growth inhibition. Copper has also been shown to reduce
mortality and anemia induced by cadmium in various species and to
prevent the degenerative effects of cadmium on aortic elastin
(Hill, et al. 1963; Bunn and Matrone, 1966). Starcher (1969) has
C-27
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shown that cadmium decreases intestinal copper uptake, probably
through competition for binding sites.
The anemia produced experimentally in fowl fed high cadmium
diets is remedied by increases in iron or ascorbic acid intake
(Hill, et al. 1963; Fox and Fry, 1970; Fox, 1975). The protective
effect of these agents may be mediated by increased iron absorption
in the intestine (Freeland and Cousins, 1973). The situation seems
analogous to copper.
There is mounting evidence that elevated cadmium intake can
adversely affect calcium metabolism (Bremner, 1974). Bone disease
was first recognized as a toxic manifestion of cadmium during World
War II (Nicaud, et al. 1942) and osteomalcia is an important com-
ponent of itai-itai disease. Two explanations are attractive: (1)
that the bone disease is secondary to cadmium induced renal tubular
dysfunction or (2) that cadmium accumulation is in part a conse-
quence of diets deficient in calcium and Vitamin D. The latter
explanation seems the most appropriate (Larsson and Piscator,
1971). The osteoporotic changes may arise from an inhibitory ef-
fect of cadmium on the renal synthesis of 1,25-dihydroxy-chole-
calciferol, which is the active form of Vitamin D.,. This inhibi-
tion has been demonstrated in vitro (Feldman and Cousins, 1973).
Rats which have been pre-treated with cadmium show decreased
intestinal absorption of calcium and markedly increased fecal cal-
cium excretion. These animals also demonstrate a 30 percent de-
crease in calcium incorporation in bone and the investigators sug-
gest these effects are important in the etiology of itai-itai dis-
ease (Ando, et al. 1977; Kobayashi, 1970).
C-28
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The effects of protein in reducing cadmium toxicity have pre-
viously been mentioned. It has been suggested that the protective
effects are actually due to increased availability of zinc and/or
iron (Fox, et al. 1973).
Cadmium itself will induce tolerance if given by small repeti-
tive injections (Nordberg, 1971). This effect is postulated to be
due to the stimulation or induction of a protective protein, metal-
lothionein. Probst, et al. (1977) have demonstrated that hepatic
metallothionein concentrations increase in proportion to the cad-
mium pretreatment dose and found a positive correlation between
dose related increases in hepatic metallothionein and cadmium LD5Q
values. This cadmium binding protein apparently plays a key role
in cadmium detoxication. It contains a high (30) percentage of
cysteinyl residues and hence has an extreme affinity for metal
binding. About one metal ion is bound per three -SH groups and it
may contain up to 9 percent metal. Zinc usually occupies the vast
majority of binding sites, but may be replaced by various other ca-
tions, i.e., cadmium, cobalt, mercury, copper, etc. The protective
effect of prior administration of zinc against cadmium has been
attributed to the increased accumulation of hepatic and renal cad-
mium as metallothionein. The inactivity of cadmium-metallothionein
complexes in reducing SH enzyme activity and 1,25-dihydroxy-chole-
calciferol synthesis suggests that the bound form is inactive
(Webb, 1975; Feldman and Cousins, 1973). As might be anticipated
cysteine similarly protects against cadmium induced testicular ne-
crosis (Gunn, et al. 1968a). The synthesis of metallothionein-like
proteins can be induced by at least two essential elements, i.e.,
C-29
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zinc and copper, and the protein may have a fundamental role in the
metabolism of these elements. The induction by cadmium and mercury
may therefore simply be a fortunate circumstance occasioned by
chemical similarities (Webb, 1972). Beryllium, manganese, barium,
strontium, tin, arsenic, selenium, chromium, and nickel administra-
tion have been shown not to influence liver or kidney levels of
metallothionein-like protein whereas cobalt and iron increase
liver levels and bismuth increases renal tissue concentrations
(Pitrowski, et al. 1976).
Selenium is yet another protective element which is able to
prevent lethal cadmium effects or the induction of testicular dam-
age in rodents (Gunn, et al. 1968b; Parizek, et al. 1969). Con-
versely, cadmium is able to prevent both the lethal and the growth
retardation effects induced by toxic quantities of selenium (Hill,
1974).
Cadmium administration also causes the elevation of a number
of enzymes (hepatic pyruvate carboxylase, phosphoenol-pyruvate
carboxykinase, fructose 1,6-disphosphatase and glucose 6-phospha-
tase), increases the concentrations of hepatic cyclic adenosine
monophosphate and blood glucose while simultaneously reducing serum
insulin. The administration of selenium prevents the elevation of
the cadmium hepatic gluconeogenic enzymes and ameliorates the
hyperglycemia, hypoinsulinemia, and glucose intolerance. Selenium
does not, however, alter the cadmium induced elevation of hepatic
cyclic AMP levels (Merali and Singhal, 1975). Selenium causes an
increase in the biliary excretion of cadmium (Stowe, 1976). This
contrasts with zinc which causes a significant reduction of biliary
C-30
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cadmium excretion. The mechanisms involved in the protection by
selenium against cadmium toxicity have been investigated by Chen,
et al. (1975) and appear to be the result of cadmium diversion by
selenium from low-molecular weight proteins to less critical higher
molecular weight moieties. Both selenium and cadmium are equally
bound in a 1:1 ratio in plasma protein fractions ranging in size
from 130,000 to 420,000 daltons (Gasiewicz and Smith, 1976).
The number of complex interactions with various metals and
nutrients suggests strongly that certain sectors of the public will
in all likelihood be at greater risk from cadmium than the commu-
nity as a whole. For example, cadmium may pose an increased hazard
to those with anemia or for those in need of additional calcium,
such as pregnant women or growing children. Cadmium may be more
toxic for those living in areas where zinc deficiency is common,
i.e., Egypt, Iran, etc. and where protein deficiency states such as
Kwashiorkor are common, i.e., many "third-world" countries. Stud-
ies of these and other sensitive groups are only now beginning.
Teratogenicity
Relatively low doses of parenterally administered cadmium have
been shown to have profound effects upon the reproductive abilities
of various species of experimental rodents.
Parizek and Zahor (1956) first noted in rats that a single
small dose of cadmium chloride (2 mg/kg) given subcutaneously re-
sults in testicular hemorrhage and complete testicular necrosis.
Subsequently, a similar effect was noted in rabbits, hamsters, gui-
nea pigs and mice (Parizek, 1957; Meek, 1959). This effect is
mediated by selective damage to the internal spermatic artery and
C-31
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pampiniform venous plexus rather than by a direct effect on testi-
cular tissue (Gunn, et al. 1963b). This renders the animal per-
manently sterile (Parizek, 1960). Following necrosis the majority
of the seminiferous tubules remain atrophic and only a few contain
germinal epithelium. The Leydig cell component of the testis re-
generates sporadically throughout the tissue resulting in both
hyperplastic nodules and Leydig cell tumors of variable histologic
appearance. These tumors exhibit a moderate degree of pleomorphism
and occasional mitotic figures (Roe, et al. 1964). There is no
difference in testicle size between cadmium treated mice and con-
trols, but the seminal vesicles and other accessory sex organs de-
crease in size implying a decreased secretory capacity of testos-
terone from the damaged Leydig cells (Nordberg, 1975). This effect
is prevented by the simultaneous administration of zinc with cad-
mium (Gunn, et al. 1963a,b). It should be pointed out that this
effect is not seen in certain inbred strains of mice (Gunn, et al.
1965; Lucis and Lucis, 1969) and apparently identical Leydig cell
tumors (interstitial cell tumors) are caused in rodents by a vari-
ety of other agents besides cadmium, i.e., estrogenic substances
(Andarvont, et al. 1957), implanted testicular fragments (Biskind
and Biskind, 1945), minor testicular trauma (Malcolm, 1972), and
ligation of the internal spermatic artery and vas deferens (Pels
and Bur, 1958). Testicular necrosis and subsequent interstitial
cell tumor formation due to cadmium apparently have not been ob-
served in man. Necropsy and subsequent histologic examination of
the testis in fatal cases of cadmium poisoning have revealed no
abnormalities despite the passage of some days or years following
C-32
-------
exposure before death (Beton, et al. 1966; Blejer, et al. 1971;
Smith, et al. 1960).
Somewhat analogous effects have been observed in female ro-
dents. Cadmium damages the ovaries of nonovulating rats in per-
sistent estrus and in prepubertal females (Parizek, et al. 1968;
Kar, et al. 1959). The lactating mammary gland is also affected by
cadmium and important changes occur in the form of acinar necrosis,
intralobular hyperemia, and interestitial edema. The effects on
both ovary and mammary gland are prevented by the simultaneous
administration of selenium (Parizek, 1968; Parizek, et al. 1968).
Rats in late pregnancy are apparently more sensitive to cadmium
than nongravid animals or those immediately post-partum. A single
dose of 2-3 mg/kg of body weight given during the last 4 days of
pregnancy results in a high mortality (76 percent) within 1 to 4
days of injection. On autopsy generalized visceral congestion,
pleural effusion, enlarged kidneys, adrenal hemorrhage, and pulmo-
nary thrombosis are prominent findings. No similar changes were
seen in nonpregnant or immediately postpartum animals (Parizek,
1965).
In the pregnant rat, cadmium results in a complete destruction
of the fetal portions of the placenta and death of the fetuses
(Parizek, 1964). In mice, of differing strains, embryos and fetus-
es show a wide range of sensitivity to cadmium induced embryo-
toxicity and death. Crosses between resistant and sensitive
strains indicate an inherited pattern of sensitivity, with cadmium
crossing the placenta in both strains, but less well in the more
resistant animals (Wolkowski, 1976). Rodents have a hemochorial
C-33
-------
placenta and it is unknown whether higher species would be affected
in a similar manner.
Schroeder and Mitchener (1971) have carried out three genera-
tion rodent studies with a number of trace elements. Cadmium in
drinking water (10 ppm) resulted in "loss of the strain." In the F,
generation 39 young deaths occurred and 25 runts were noted com-
pared with none in the controls. In the F2 there were two dead
litters, 48 young deaths, three failures to breed and nine runts.
Again, both ranting and young deaths were statistically signifi-
cantly increased. A congenital abnormality, sharp angulation of
the distal third of the tail was seen in 16.1 percent of live off-
spring. Because of breeding failures the experiment was terminated
after the F2 generation. In contrast, Suter (1975) found no de-
tectable fertility effects, except superovulation and larger than
normal litters, in inbred mouse strains injected with 1 or 2 mg/kg
of cadmium chloride. Doses of 3 and 4 mg/kg resulted in a very high
immediate mortality rate. Dixon, et al. (1976) found no reproduc-
tive effects in rats supplied with drinking water containing 0.1
ppm for 90 days.
While cadmium crosses the placental barrier quite poorly some
passage definitely occurs. In rats this has been shown to be dose-
dependent and to increase with gestational age (Sonawane, et al.
1975). In the hamster, significant amounts of cadmium cross the
placenta and enter the embryo by the 8th day of gestation, the time
frame corresponding to the teratogenic effects seen in the species.
Zinc can prevent these effects, but does not prevent the placental
transfer of radioactive cadmium (Ferm, et al. 1969).
C-34
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When cadmium is administered to pregnant hamsters on days 12-
14, marked effects have been noted in the facial development of the
offspring. Effects include unilateral and bilateral clefts of the
palate, midline clefts through the nose, thyroglossal clefts, and
anophthalmia (Ferm and Carpenter, 1967; Ferm, 1967). Mulvihill, et
al. (1970) have suggested that this failure of fusion is due to a
mesodermal deficiency rather than to delays in shelf transporta-
tion. Selenium has been shown to have a markedly protective effect
against cadmium teratogenesis in the hamster (Holnberg and Ferm,
1969). Similarly, cadmium administered to rats on gestation days
13-16 produced a dose related increase in anomalies, including
micrognathia, cleft palate, clubfoot, and small lungs (Chernoff,
1973). In addition, the lung/body weight ratio was reduced indi-
cating a specific retardation and not merely a reflection of dif-
ferential organ growth rates and overall growth retardation. A
single intravenous dose of 1.25 mg cadmium/kg body weight given be-
tween the 8th and 15th days of gestation produces more than 90 per-
cent fetal deformities in rats (Samarawickrama and Webb, 1978).
The most common anomaly was hydrocephalus with an incidence of 80
percent when the cadmium was given on day 10 of gestation. The
mechanism of action of cadmium in producing teratologic effects,
i.e., directly upon differentiating embryonic tissue or indirectly
via effects on maternal tissues, remains unknown. However, it has
been shown that low levels of cadmium which do not affect cellular
growth can alter RNA metabolism in Chinese hamster ovary cells to a
significant extent and it has been postulated that this may modi-
fy normal cell development and serve as a possible basis for
C-35
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teratogenic effects (Enger, 1976). The possibility of human tera-
togenicity has not been systematically examined and only one report
(Tsvetkova, 1970) suggests such an effect. In this brief report
children of women occupationally exposed to cadmium were found to
have lower birth weights than 20 control infants. In view of the
many factors which may contribute to lowered birth weight, i.e.,
parity, maternal weight, chronic maternal illness, socioeconomic
conditions, maternal smoking, prenatal nutrition, etc., little cre-
dence can be placed on this report.
Mutagenicity
In the past decade cadmium has been studied in a variety of ^_n
vitro and ir\ vivo test systems with somewhat conflicting results.
Sunderman (1978) has recently reviewed in vitro experiments that
may be relevant to metal carcinogenesis. The Environmental Protec-
tion Agency's Carcinogen Assessment Group has performed a similar
review of these tests (U.S. EPA, 1977).
Cadmium has been reported to cause chromosomal or mitotic
aberrations in mammalian tissue culture cell lines. These are sum-
marized in Table 3. The majority of these studies suggest a cad-
mium effect. In addition, several in vi tro studies in biochemical
systems have now been reported.
Sirover and Loeb (1976) have studied 31 metal compounds in
vi tro using a system designed to detect infidelity of DNA synthe-
sis. Both cadmium acetate and cadmium chloride demonstrated de-
creased fidelity, i.e., increased error frequency. Decreased fi-
delity of DNA synthesis in vitro has also been reported by Hoffman
and Niyogi (1977) for cadmium, lead, cobalt, copper, and manganese.
C-36
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TABLE 3
Experiments in Tissue Culture Systems Using Cadmium
Authors
Zasukhina, et al.
(1975)
Rohr and Bauchinger
(1976)
Casto, et al.
(1976)
Shiraishi, et al.
(1972)
Paton and Allison
(1972)
Cell Culture
Rat embryo
Chinese hamster
fibroblasts
Hamster embryo
Human leukocytes
Human leukocytes
and fibroblasts
Observations
+ Chromosomal aberrations
+ Chromatid aberrations
Persistent morphologic
alternations; enhanced
transformation by simian
adenovirus 7; 8-azag-
uanine resistance
unscheduled DNA synthesis
Chromatid breaks,
dicentric chromosomes
C-37
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These investigators also found that these metals stimulated chain
initiation of RNA synthesis at concentrations that inhibited over-
all RNA synthesis. Murray and Flessel (1976) have reported that in
vi tro addition of cadmium and manganese ions to solutions of syn-
thetic polynucleotides caused pairing of noncomplementary nucleo-
tides and have emphasized that direct metal-nucleic acid interac-
tions may be responsible for neoplastic transformation by metals.
Zinc and magnesium did not show this effect.
Friedman and Staub (1976) have studied cadmium and numerous
other compounds to determine if mutagenic substances modify DMA
replicative activity. In their assay the uptake into mouse testi-
cular DNA of ( H) thymidine is measured 3.5 hours after injection
of the test compound. Cadmium treated (10 mg/kg) mice showed a
significant decrease (p<.05) in ( H) thymidine uptake in comparison
to control animals. The effect was, however, much less than the
inhibition caused by 3-methylcholanthrene and diethylnitrosamine.
This inhibitory effect may be due to cadmium's ability to impair
testicular blood supply and cause complete necrosis of the testis.
The dose given was at least 3-fold that required to induce this
acute effect.
The results with cadmium in various microbial systems designed
to detect mutations have shown quite mixed results (Table 4).
McCann, et al. (1975) have reported that three of four metal car-
cinogens tested in the standard Ames test have been negative. They
do not name these metals, but suggest that the system is not favor-
able for bacterial absorption of metals because of the large amount
of Mg salts, citrate, and phosphate in the minimal medium.
C-38
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TABLE 4
Mutagenesis Studies of Microbial Systems Using Cadmium
Author
Organism
Result
Nishioka
(1975)
Takahashi
(1972)
Sunderman
(1978)
B. subtilis
S. cerevisiae
S. typhimur ium
+ Weak response (CdCl-)
- Cd(N03)2
+ Reported in CAG
Assessment
Two independent
investigators reported
to Sunderman
C-39
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A fairly large number of studies now exist which have examined
a variety of mammalian cells for cytogenetic abnormalities follow-
ing exposure of the intact animal or man to cadmium (Table 6).
Again mixed results have been obtained. It should not be forgotten
that most of the studies on workers reflect a mixed exposure to
zinc and lead, in addition to cadmium. Since smelters also common-
ly process relatively cruds materials exposure to other metals such
as chromium, arsenic, nickel, etc. cannot be eliminated as possible
contributors to the observed effects, Synergistic effects between
metals may also confuse the results from such studies.
Table 6 lists several studies dealing with point mutation.
Drosophilia studies have been negative to date (Table 6) as have
dominant lethal tests in mice (Table 5).
Although some of the above cited studies demonstrate mutagenic
activity, at this point in time the relationship between a sub-
stance's mutagenic activity in lower forms and its potential as a
human carcinogen is still not clear. Correlations between muta-
genicity and carcinogenesis are quite good for certain classes of
compounds and relatively poor for others. A major problem is that
relatively few substances are recognized as unequivocal carcinogens
for man. Chromosomal aberrations have now been noted in human
leucocytes in response to a wide variety of diverse substances.
The ultimate significance in terms of human health remains to be
elucidated.
Carcinogenieity
This particular aspect of cadmium toxicology has received a
number of recent reviews (International Agency for Research on
C-40
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Author
Shiraishi and
Yosida (1972)
Doyle, et. al.
(1974)
Shimada,
et. al. (1976)
Deknudt and
Leonard (1976)
Bauchinger,
et al. (1976)
Bui, et al.
(1975)
Gilliavod
and Leonard
(1975)
TABLE 5
Chromosome Mutation Studies on Mammalian Cells Exposed In vivo
Cells
Epste in,
et al. (1972)
Human leucocytes
from Itai-Itai Patients
Sheep leukocytes
Mouse cocytes
Human leucocytes
from exposed workers
Human leucocytes
from exposed workers
Human leucocytes
Dominant lethal
test in mice
Mouse spermatocytes
Mouse F, translocation test
Mouse dominant lethal
Result and Comment
+ Increased chromatid breaks,
isochromated breaks, chromatid
translocations, dicentrics, and
acentric fragments
+ Reported in CAG Assessment
+ Reported in CAG Assessment
+ Chromatid aberrations and
chromosome anomalies. Similar
rate of effect in both high and
low exposure groups. Chroma-
tid breaks exchanges.
+ Mixed metal exposure.
(including Cd)
Swedish battery workers
Itai-Itai patients
No translocations.
C-41
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TABLE 5 (Continued)
Author
Leonard,
et al.(1975)
Deknudt,
et al. (1973)
Suter
(1975)
Cells
Bovine leucocytes
Human leucocytes
Dominant lethal
test in female mice
Result and Comment
Heavy mixed metal exposure
(Cadmium 50 x control levels)
Exposure fatal to 6 of 15
animals.
Mixed metal exposure
(including Cd)
Actual increase in living
implants. No increase in
dead implants.
C-42
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TABLE 6
Point Mutation Studies with Cadmium
Author Organism Result
Shabalina Drosophilia
(1968)
Friberg, et al. Drosophilia
(1974)
U.S. EPA Saccharomyces +
(1977)
C-43
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Cancer (IARC) Monographs, 1973, 1976; U.S. EPA, 1977; NIOSH, 1976?
Sunderman, 1977, 1978; Hernberg, 1977).
Animal studies have amply shown that the injection of cadmium
metal or salts causes malignancies (sarcoma) at the site of injec-
tion and testicular tumors (Leydig cell interstitial cell). These
studies are summarized in Table 7.
Injection site sarcomas arise from either subcutaneous or
intramuscular administration. In comparison with other similar
sarcomas in rodents they appear to be well differentiated (Heath,
1962), but give rise to distant metastases and may be permanently
transplanted (Heath and Webb, 1967). There is now general agree-
ment that studies demonstrating the production of sarcomas in ro-
dents at the site of injection are not germane to cancer in man. A
large number of chemical irritants and physical agents are known to
cause sarcomas in rodents and they should not be considered as
acceptable evidence of carcinogenicity for the human, except per-
haps by the injection route.
Leydig cell (interstitial cell) tumor formation was briefly
considered in a previous section of this evaluation. These tumors
develop in rodents many months following the complete necrosis of
the testis. Cadmium is only one agent producing this effect in
rodents, supra vide. Interstitial tumors do not differ morpholo-
gically irrespective of their mode of origin although those induced
by cadmium exhibit more androgenic activity than those resulting
from total vascular ligation (Gunn, et al. 1965). Histologically,
the tumors are well-differentiated and composed of Leydig cells of
relatively uniform appearance (Reddy, et al. 1973) and retain their
C-44
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TABLE 7
Animal Tumorogenesis Induced by Cadmium Injection
Authors Species Compound
Haddow , Rats Cd containing
et al. 1961 ferritin
Heath, Rats Cd powder
1962
Heath and Rats Cd powder
Daniel, 1964
Kazantzis, Rats CdS
1963
Kazantzis and Rats CdS
Hanbury, 1966 Rats CdO
Route Tumor and Incidence
s.c. Sarcomas (35%)
Interstitial cell
tumors
i.m. Sarcomas (75%)
i.m. Sarcomas (90%
and 75%
s.c. Sarcomas (60%)
s.c. Sarcomas (60%)
s.c. Sarcomas (80%)
Haddow,
et al. 1964
Roe, et al.
1964
Gunn, et al.
1963a
Gunn, et al.
1964
Rats
Rats
Mice
Rats
Rats
Rats
CdSO,
CdSO,
CdCl.
CdCl.
CdCl.
CdCl.
s.c.
s.c.
s.c.
s.c.
s.c.
s.c.
Sarcomas (70%)
Interstitial cell
tumors (55%)
Interstitial cell
tumors (77%)
Interstitial cell
t umo r s (68%)
Sarcomas (41%)
Interstitial cell
tumors (86%)
C-45
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TABLE 7 (continued)
Authors
Gunn, et al.
1967
Knorre, 1970
Knorre, 1971
Lucis, et al.
1972
Reddy, et al.
1973
Furst and
Cassetta, 1972
Favino, et al.
1968
Malcolm, 1972
Species
Rats
Rats
Rats
Rats
Rats
Rats
Rats
Rats
Compound
Route
Tumor and Incidence
CdCl2
CdCl2
CdCl2
CdCl2
CdCl2
Cd powder
CdCl2
CdCl0
s .c.
s .c.
s .c.
s .c.
s.c.
i .m.
s.c.
s.c.
Sarcomas (10%)
Sacromas (13%)
Interstitial cell
tumors (40%)
Interstitial cell
tumors (87%)
Sarcomas (13%)
Interstitial cell
tumors (80%)
Sarcomas (54%)
Interstitial cell
tumors (100%)
Sarcomas (?)
Interstitial cell
tumors (?)
C-46
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steroidogenic characteristics. These tumors are androgenically
functional {Gunn, et al. 1965; Favino, et al. 1968), although pro-
ducing less testosterone than normal. The malignant potential of
interstitial cell tumors is problematical: "The dividing line be-
tween hyperplasia and neoplasia is as indefinite as the rats stud-
ied and an even greater problem and one of vital concern in progno-
sis, is the distinction between benign and malignant tumors. At
present, probably the only reliable criterion of malignancy is the
presence of metastases" (Roe, et al. 1964). Cadmium induced inter-
stitial tumors have never been reported to metastasize. The spon-
taneous development of interstitial cell tumors in rats varies con-
siderably with the strain. Aged Fischer rats have been shown to
have a very high rate (68 percent) of spontaneous interstitial cell
tumor formation (Jacobs and Huseby, 1967). Malcolm (1972) has
noted the development of these tumors in control animals from the
weekly palpation during examination. Interstitial tumors of the
testis are rare in man and account for less than 2 percent of all
testicular tumors (Dixon and Moore, 1953). Out of a total of 49
cases reported in the literature only five were reported as being
malignant. None of the 12 cases in the Army series, followed from 4
to 16 years had evidence of metastases or recurrence (Dixon and
Moore, 1953). This tumor has yet to be reported in association
with human exposure to cadmium.
In general, the simultaneous administration of zinc is protec-
tive against the formation of either sarcoma and/or interstitial
cell tumor development (Gunn, et al. 1963b, 1964). However, zinc
C-47
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powder given intramuscularly fails to prevent formation when the
inducing agent is cadmium powder (Furst and Cassetta, 1972).
Several long term feeding and inhalation studies with cadmium
have been carried out, but the induction of tumors has not been
noted.
Schroeder, et al. (1964) has conducted lifetime exposure stud-
ies in Swiss mice. The animals were supplied with drinking water
containing 5 ppm of cadmium acetate. Both males and females exper-
ienced some shortening of life span in comparison with the con-
trols. The exposed animals had fewer tumors than the controls.
Using rats at the same dosage they subsequently reported similar
negative results and concluded that cadmium could not be considered
carcinogenic in the doses given (Schroeder, et al. 1965).
Levy, et al. (1973) gave three groups of mice weekly doses
(1.0, 2.0 and 4.0 mg/kg body weight) by gavage for 18 months. No
difference between exposed and control animals was noted in regard
to general health or tumor incidence at 18 months. Similar experi-
ments with hooded CB rats using doses of 0.2, 0.4 and 0.8 mg/kg of
cadmium sulphate weekly for 2 years were carried out by Levy and
Clark (1975) with again no difference in tumor incidence in exposed
and control groups. Decker, et al. (1958) reported on a rat study
in which rats were supplied cadmium chloride in drinking water in
the following concentrations: 0.1, 0.5, 2.5, 5.0, 10.0 and 50 ppm
as cadmium. The highest dose group was terminated at 8 months be-
cause of appreciable stunting. Two animals from each of the other
groups were sacrificed quarterly for up to 1 year. There were no
differences in body weight between control animals and those
C-48
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receiving up to and including 10 ppm; nor were there differences in
food or water intake or pathologic changes.
Anwar, et al. (1961) exposed eight dogs to 0.5 to 10 ppm cad-
mium (as cadmium chloride) for 4 years. Aside from a splenic nod-
ule in a dog treated with the lowest dose, no tumors were observed.
Paterson (1947) carried out inhalation studies with cadmium
oxide and cadmium chloride fume using rats. He used animals treat-
ed in the following way: 136 rats surviving the acute LD5Q (800-
1,000 min. mg/m ); 100 rats surviving one-half the LD5Q; and 200
rats exposed to approximately one-quarter the LD of cadmium
chloride every 2 weeks for 6 months (12 exposures). Sacrifices
were made periodically and the experiments were terminated 6 months
after beginning exposure. No tumors were noted in the lungs.
Apparently other organs were not examined.
Malcolm (1972) gave rats up to 0.2 mg of cadmium sulphate sub-
cutaneously and up to 0.8 mg weekly by stomach tube for 2 years. In
a third experiment, mice were given doses up to 0.02 mg/kg of body
weight subcutaneously at weekly intervals for 2 years. Except for
a few sarcomas seen in the rats given subcutaneous injections and
Leydig cell tumors (also seen in the controls) these studies were
negative at the time reported. Several of the above briefly de-
scribed oral intake and inhalation studies have been termed inade-
quate (IARC, 1976), apparently on the basis of the relatively small
doses employed. Schroeder's work was specifically designed to
simulate human exposure and for the most part the doses given seem
realistic. Obviously, the doses were well below the maximum toler-
able doses usually used today in attempting to establish the
C-49
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carcinogenic potential of various substances. Nonetheless, there
seems to be a rather large volume of negative animal data.
Roller (1978) has reported on the effect of cadmium exposure
on tumor growth and cell-mediated cytotoxicity in mice inoculated
with MSB-6, a MSV derived tumor cell line. A dose-dependent inhi-
bition of tumor growth was seen in those mice receiving cadmium.
At 3 and 30 ppm dose levels, no inhibition of body weight accom-
panied tumor growth reduction, whereas at 300 ppm, there was a
small inhibition of body weight gain. Cadmium exposed animals
demonstrated significantly higher levels of cell mediated tumor
cytotoxicity than controls. No data on the effects of cadmium upon
the growth of nonviral-induced tumors has yet appeared.
Potts (1965) was the first to draw attention to the possibi-
lity of cancer in man as a result of cadmium exposure. Previously,
Friberg (1950) had noted three cases of cancer among 17 deaths in
alkaline battery workers. The sites were bladder, lung, and colon.
tfhile there was no control group this would not seem an excessive
number of cancer deaths, i.e., 17.6 percent. Potts reported on the
causes of death of eight men with at least 10 years exposure. Five
of the eight died of cancer. Their ages, years of exposure, and tum-
or sites are shown in Table 8.
The remaining three men died from auricular fibrillation,
bronchitis, and atheroma. Potts, while recognizing that the number
of cases was very limited, felt that the association between cancer
in man and cadmium should be "fully explored." Normally, one would
not expect more than two cancer deaths out of the eight deaths
observed.
C-50
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TABLE 8
Data Related to Five Deaths from Cancer
Age
75
65
53
65
59
Years of Exposure Cause of
14
37
35
38
24
Carcinoma of
Carci
Carci
Carci
Carci
noma of
noma of
noma of
nomatos
Death
prostate
prostate
bronchus
prostate
is
Source: Potts, 1965
C-51
-------
Kipling and Waterhouse (1967) surveyed a group of 248 workers
who had been exposed for a minimum period of 1 year to cadmium
oxide. Twelve of these men had died and the causes of death ascer-
tained. The twelve include the eight reported by Potts. They com-
puted the expected number of cases by site which would have oc-
curred by chance and compared it against the observed. Their data
are shown in Table 9.
From Table 9, for cancers at sites other than the four listed,
a total of 7.53 cases were Expected (13.13-5.60), but only two at
other sites were observed. It is unclear as to why the number of
expected prostate cancers is so small, i.e., 0.58, even adjusting
for age. Cancer of the prostate is very common in elderly males and
at least three of the four cases (Potts' cases) were elderly, i.e.,
65, 65, and 75 years. Cancer of the prostate in the United States
is the third leading cause of cancer death in males aged 55-74 and
the second leading cancer cause of death in males over 75. The per-
centage of cancer deaths due to prostate cancer for these two age
groups is 7.6 and 19.3 percent, respectively. Slightly over 2 per-
cent of all U.S. male deaths and about 10 percent of cancer deaths
are from this cause. The long term incidence (death rate 13-
14/100,000) trends for cancer at this site have not changed over
the period 1940-1974. The death rates are similar for this site
between England and Wales, 11.51/100,000, and the U.S., 13.90/
100,000 (National Cancer Institute (NCI), 1977). Thus, the expect-
ed figure of Kipling and Waterhouse seems about half of that anti-
cipated based on England's national prostate cancer statistics. It
is of considerable interest that the rates for cancer of the
C-52
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TABLE 9
Survey of Workers Exposed to Cadmium Oxide
Site of Cancer
All sites
Bronchus
Bladder
Prostate
Test is
Expected
13
4
0
0
0
.13
.40
.51
.58
.11
Observed
12
5
1
4
0
Probabili ty
of Occurrence
0.
0.
0.
0.
0.
660
449
398
003
898
*
Source: Kipling and Waterhouse, 1967
C-53
-------
prostate in Japan, the country with by far the highest daily intake
of cadmium, are the lowest for any developed country in the world,
i.e., 1.93/100,000. This contrasts sharply with the rate for
Sweden (18.33/100,000) which is the highest in the world. The
Swedish daily intake and body burdens of cadmium are among the low-
est yet reported (Kjellstrom, et al. 1978a).
Holden (1969) in a letter to the editor mentions two cancer
deaths in cadmium workers (prostate, bronchus). He gives no denom-
inator data. It seems possible that these cases were included in
the previous survey by Kipling and Waterhouse.
Lemen, et al. (1976) conducted a retrospective cohort mortal-
ity study using reported causes of death among cadmium smelter
workers who had achieved at least 2 years of exposure in the years
1940-1969. Ninety-two deaths were known to have occurred out of
the employee cohort of 292 white males. Comparison was made be-
tween the observed number of deaths and that expected based on age,
time, and cause-specific mortality rates for the total U.S. white
male population. There was a slight deficit of total deaths, i.e.,
92 observed v. 99.32 expected. All this deficit is accountable by
the extremely low number of deaths due to heart disease; only 24
were observed and 43.52 were expected, a difference significant at
the p<0.01 level. Twenty-seven deaths were observed as a result
of malignant neoplasms and 17.57 were expected. This is signifi-
cant at the p<.05 level. Most of this excess was accounted for by
neoplasia of the respiratory system, where 12 were observed and
5.11 expected, a difference significant at p<0.05. The risk of
prostatic cancer was also elevated, i.e., 4 cases observed v. 1.15
C-54
-------
expected although this difference is not significant. When further
consideration was given to the time interval since onset of expo-
sure, a significant risk of prostate cancer was demonstrated (4
observed v. 0.88 expected, p<0.05) 20 years after onset of cadmium
exposure. It should be pointed out that Lemen's group was exposed
to arsenic, a well-documented human carcinogen, and Potts' group to
nickel, another generally accepted human carcinogen. These ele-
ments may account for the increased incidence of respiratory tract
tumors in the studies previously discussed. Kjellstrom, et al.
(1978b) has reported preliminary mortality data for 269 cadmium-
nickel battery workers and a control group of 328 alloy factory
workers. Cancer deaths were not statistically different in the two
groups, but the alloy factory workers were found to have an in-
creased mortality from prostate cancer. Certainly the idea that
prostatic cancer in man is somehow related to cadmium cannot be
entirely discounted without careful industry wide studies.
While of questionable relevance to the human prostate cancer
question, specifically designed long term rodent studies reported
by Levy (1973) and Levy and Clark (1975) failed to detect evidence
of prostate neoplasia.
Humperdinck (1968) followed up eight cases of chronic poison-
ing previously reported by Baader (1952). Four had died, one of
lung cancer. Out of 536 workers with some cadmium exposure he was
only able to find five cases of cancer (including the one of lung
cancer) and concluded that his data did not support a causal rela-
tion between cadmium exposure and cancer.
C-55
-------
McMichael, et al. (1976) studied the mortality of workers from
four rubber producing plants. The standard mortality rate (SMR)
was 94 for the full cohort. The SMRs for all cancer sites was not
elevated, but at some specific sites an increase was noted: stom-
ach, 148; rectum, 116; prostate, 119; all leukemia, 130; lymphatic
leukemia, 158; and lymphosarcoma-Hodgkin's disease, 129. Rubber
plant workers are exposed to a great number of compounds including
benzene, an accepted human carcinogen. The relationship of these
tumors to cadmium is highly problematical.
Kolonel (1972, 1976) has suggested that there may be an asso-
ciation between cadmium and renal cancer. He examined the inci-
dence of cancer at several sites for persons with an inferred occu-
pational history of cadmium exposure and in a control population.
Cadmium exposure was based solely on job classification information
provided by patients on admission to a cancer research hospital.
The only significant association was with renal cancer. He had
expected to find an increased incidence of prostatic cancer, but
none was detected. To help substantiate and refine the association
he noted a 4-fold increase in renal cancer among smokers with an
occupation suggesting cadmium exposure in comparison to controls.
Tobacco, as previously mentioned, contains appreciable amounts of
cadmium. However, nonsmoking, cadmium exposed workers actually
were found to have less renal cancer than controls. This suggests
that some other agent in tobacco smoke may be responsible, or that
at most, smoking operates in some synergistic manner with cadmium.
Obviously this is an extremely tenuous association. Among all the
C-56
-------
tumor sites specifically reported for cadmium workers, many of whom
probably were smokers, the kidney has yet to be mentioned.
In summary, the available epidemiologic evidence does not sug-
gest that cadmium can be definitely implicated as a human car-
cinogen.
C-57
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CRITERION FORMULATION
Exist ing_ sidelines and Standards
Numerous domestic official agencies, foreign governments, and
private parties have suggested standards or limits for cadmium in
various environmental media. The more germane of these are pre-
sented in Table 10.
Current Levels of Exposure
The exposure section of this document deals with general en-
vironmental exposure to cadmium. Food represents the major route
of human exposure, with air contributing only a negligible amount
to the total intake, except in tobacco smokers. Drinking water
normally would account for less than 10 percent of the daily total
absorption for the vast majority of the population. Percutaneous
absorption is inconsequential.
It is recognized that approximately 100,000 Americans have
potential occupational exposure to cadmium (NIOSH, 1976). The
spectrum of occupational exposure varies from negligible to those
situations producing acute and/or chronic toxicity and even death.
While efforts are being made by those in occupational health to
reduce exposure to a minimum and eliminate adverse health effects
it must be recognized that no general environmental standard can
prevent damage from overexposure in the occupational setting.
Special Groups at Risk
Persons with severe nutritional deficiency, i.e., calcium,
zinc, protein, Vitamin C and D, etc., which may be aggravated by
cadmium are conceivably at special risk, although human data
C-58
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TABLE 10
Regulatory Standards, Limits, or Criteria for
Human Health Protection
Source
Occupational Safety and Health
Administration (OSIIA) (1974)
(39 (125) FR 23543)
NIOSH (1976)
U.S. EPA (1975b)
FDA (1978)
(21 CPU 109.4, 509.4)
WHO (1971)
American Conference of Governmental
Hygenists (ACGII1) (1977)
Multimedia Environmental Goals for
Environmental Assessment (1977)
NAS (1972)
USSR
(suggested)
CANADA (1969)
OH10(6)
(5)
Media
Ai r
(Inhalat ion)
Water
(Ingestion)
Food (Ingestion)
Ent i ty
100 ug/ra
40 uy/ra
3(1)
50 ug/ni
0.12 ug/m
10 Mg/l
10 ug/1
Wlll-1.9 "
WH2-0.7 ug/11 '
10 ijg/l
1 ug/1
10 Mg/l
!> ug/1 ( streams )
0.5 ug/ml
(2)
1. For cadmium fume. Limit for cadmium dust is 200 ug/m
2. Based on ceramic pottery and enamelware leaching solution test
3,4. EPC (estimated permissible concentration) Will is derived from the assumption that the maximum daily
safe dosage results from 24-hour exposure to air containing the estimated permissible concentration in
air, assuming 100 percent absorption and that the same dose is therefore permissible in the volume of
water comsumed per day; WII2 is the estimated permissible concentration of the substance in water based
on considerations of the safe maximum body concentration and the biological half-life of the substance
b. Krasovskii, G.N., et al. 1976
6. Lykins, B.W.,Jr. and J.M. Smith, 1976
C-59
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concerning these effects are presently scant. Such a risk is ob-
viously additive since these deficiences can in and of themselves
be sufficient to cause disability and/or fatal disease. Obviously,
persons in such precarious physiologic balance are particularly
vulnerable to a wide variety of biologic and chemical hazards.
Some persons with diets that are adequate in terms of vital
nutrients, calories, etc., but who subsist on otherwise skewed
diets such as vegetarians or those eating unusual quantities of
visceral meats, fish, or seafoods, which can contain rather large
amounts of cadmium, may also be at increased risk. The additional
risk to such population groups posed by an additional exposure
increment from ambient cadmium remains to be assessed.
Basis and Derivation of Criteria
There is no doubt that cadmium is a teratogen in several ro-
dent species when given in large parenteral doses. Doses of this
magnitude (4-12 mg/kg) would surely produce severe, if not fatal
toxic symptoms in man. In the human only small amounts of cadmium
cross the placental barrier (Lauwerys, et al. 1978). Only one re-
port, from Russia (Tsvetkova, 1970), suggests any effect, i.e., low
birth weight and "several children with rickets or dental trouble."
Details are lacking in this report and it should not be construed
as implicating cadmium without further data.
The studies of whether cadmium is mutagenic are inconsistent.
The reports of chromosomal aberrations in both itai-itai patients
and cadmium workers are conflicting. Dominant lethal studies have
been negative as are tests for spermatocytic chromosome aberrations
in male mice and their first-generation offspring (Gilliavod and
C-60
-------
Leonard , 1975 ). Stud ies of mutagenic activity in nonmammalian life
forms have given inconsistent results.
There is no question that the injection of cadmium into ro-
dents results in injection-site sarcomas and interstitial cell tu-
mors of the testis. Sarcoma production in rats is a common sequela
to the injection of irritants and could be regarded as a nonspecif-
ic response to fibroblast injury. Interstitial tumors appear to
result from the hyperplasia and metaplasia of tissue regeneration
following vascular-mediated testicular damage. There is no evi-
dence that these tumors are malignant neoplasms; however, this does
not refute the tumorogenic potential of cadmium.
The human evidence for the carcinogenicity of cadmium is con-
jectural, based on very small numbers, and confounded by exposures
to other elements which are known to be human carcinogens. The
reports on British battery workers and the work of Lemen, et al.
(1976) suggest an increase in prostrate and lung cancer. These men
were also exposed to nickel and/or arsenic, but in amounts of one
hundred to two hundred times less of cadmium exposure level.
Kolonel's (1972, 1976) work confirmed neither of these sites, but
suggested an association with renal cancer. This work is inade-
quate in that it assumes an exposure to cadmium based upon an occu-
pational questionnaire. There have been no case reports of renal
cancer in known cadmium-exposed workers. Cigarette smoking would
appear to have a firmer association with renal neoplasia, rather
than cadmium. The geographic distribution of prostrate cancer
(Japan, Sweden, USA) suggests that an inverse relationship exists
to cadmium exposure. From the known mortality study data cited it
C-61
-------
might be argued that cadmium exposure reduces general mortality or
is a potent protective factor against cardiovascular disease. The
case for cadmium as a carcinogen is not persuasive when the exist-
ing data are critically reviewed, but it has been viewed by some as
suggestive from the public health perspective.
It is not recommended that cadmium be considered a suspect hu-
man carcinogen for purposes of calculating a water quality criter-
ion. However, the weight of evidence for oncogenic potential of
cadmium is sufficient to be "qualitatively suggestive" and is not
to be ignored from a public health point of view. The EPA Carcino-
gen Assessment Group has reviewed cadmium and their summary is in-
cluded in the Appendices of this document.
The criterion is based on established health effects. The
data implicating cadmium as a cause of emphysema and renal tubular
proteinuria is firmly established. Emphysema has been reported
only after airborne exposures and has been documented for both man
and animals. It would seem to result from a direct effect upon lung
tissue of which cadmium salts are known irritants.
There is evidence from occupational studies that the kidney is
more sensitive to the effects of cadmium than the lung. In exposed
workers proteinuria occurs in higher incidence and in a shorter
time period than emphysema. It seems entirely justified to con-
clude that the kidney is the critical target organ.
It is generally accepted that the critical cadmium level at
which renal dysfunction occurs is approximately 200 pg/g wet weight
of renal cortex. Autopsy studies indicate that at present the
average kidney concentration in nonsmokers is approximately one-
:-62
-------
twelfth this level. In smokers the concentration is about twice as
high, i.e. 30-39 yg/g.
Friberg, et al. (1974) has estimated that the critical level
is reached at daily ingestion levels of 250-350 ug per day over 50
years. Since the average, nonoccupationally exposed American prob-
ably does not have an intake from all sources exceeding 25-50 ug/d
there would again seem to be a reasonable "safety-factor" of 5 to
12 in existence. While this is not the comfortable margin or many
orders of magnitude usually recommended by toxicologists it should
provide a margin of "safety" to the general public for the foresee-
able future.
NIOSH (1976) recommends that workers should not be exposed to
airborne cadmium at a concentration greater than 40 ug/m as a time
weighted exposure for up to a 40 hour work week. This standard is
designed to protect the health and safety of workers over an entire
working life time. Compliance should prevent adverse effects on
the health of the worker. Several studies have indicated no ad-
verse effects at levels of 31 and 16-29 ug/m (Lauwerys, et al.
1974; Tsuchiya, et al. 1976). Effects of renal function (protein-
uria) and a reduction in mean pulmonary function have been noted at
levels of 66 ug/m cadmium dust (21 ug/m respirable dust; < 5 urn)
although some of these workers probably had experienced exposure,
at least intermittently, to cadmium dust at higher, but unknown,
concentrations. A limit of 20 ug/m respirable dust offers a
greater, and "probably sufficient margin of safety" in comparison
with the 50 ug/m recommended by ACGIH (1977) and Lauwerys, et al.
(1974).
>63
-------
From the figure 20 ug/m it can be calculated that a worker
might absorb about 500 ug during a work week, i.e., 20 ug/m respi-
rable particle (anything less than 5 microns mean average diameter)
x 10m inhaled/day x 5 days x 0.5 (lung absorption rate). This is
approximately 143 ug/day intake and 72 ug/day absorbed. To this
intake the average daily intake from food and general environmental
sources can be added, i.e., 10-50 ug (5 percent absorption). This
suggests that an exposed worker may have an approximate intake of
150 ug/d or 75 M9/d absorbed and still be safe. However, a healthy
worker may not be representative of the American population as a
whole.
From Japanese dietary intake data where itai-itai disease is
prevalent, and studies on the age-specific incidence of protein-
uria, it may be possible to estimate a lowest observed effect level
for ingested cadmium. In areas where itai-itai disease is most
common, about 85 percent of the daily cadmium intake is derived
from rice, the locally grown grain staple (Muramatsu, 1974).
Nogawa, et al. (1978) have shown that the prevalence of tubular
proteinuria, as measured by retinol binding protein excretion, in
persons under age 70 does not begin to rise above that seen in con-
trol populations until the cadmium levels in rice exceed 0.40-0.49
jug/gm. The Japanese diet in the area of endemic itai-itai disease
and even in the homes of patients with the disease are precisely
known (Friberg, et al. 1974). Approximately 2,100 calories are
consumed daily, with carbohydrate accounting for about 1,725 calo-
ries daily, which is equivalent to the ingestion of 430 gm/d. The
C-64
-------
lowest observed effect level for Japanese can be calculated as
follows:
430 gm/d X 0.45 ug/gm (rice) _ 22Q ug/day
0.85
This Japanese figure is slightly below the estimate of 250 ug/day
given by Friberg, et al. (1974) as an effect level. The lowest ob-
served effect level for a Western European or American population
with correspondingly larger body size would be expected to be some-
what greater (i.e., 301 pg/day).
Assuming 5 percent absorption, 301 ug/day ingested represents
15 ug/day absorbed. Approaching the problem of estimating minimal
effect input using inhalation data yields only somewhat higher
minimal effect input. From the data of Lauwreys, et al. (1974):
21 ug/m3 x 10 m3 x 0.25 x y = 37.5 ;jg/day
In the above, lung retention is assumed to be 25 percent and work-
ers are assumed to inhale 21 ug/m five days per week.
The Working Group of Experts for the Commission of European
Communities has estimated (Comm. Eur. Communities, 1978) that the
threshold effect level of cadmium by ingestion is around 200 ug
daily corresponding to an actual absorption of 12 yug/day. For
smokers this estimate is reduced by about 1.9 yg to 10.1 ug which
corresponds to an oral intake of 169 ug. Using a second approach
based on metabolic modeling of the above type, this same group
derived a threshold effect level of 248 ug daily when pulmonary
absorption is negligible.
Using the data presented in this and preceeding sections of
the document, it is possible to construct several exposure scenarios
C-65
-------
encompassing possible best-to-worse case exposure situations
that might be domestically encountered as seen in Table 11.
From these scenarios it can be calculated that ingested water
contributes relatively little to the daily retained cadmium enter-
ing the body i.e., 0.53, 5.1, and 7.6 percent respectively for the
worst, average, and best cases. Water could become a significant
contributor to overall cadmium intake and retention only if the
secenarios are reconstructed by substituting the worst case water
data for that in the average and best cases. However, even in the
very unlikely event that such situations occur the total cadmium
intake and retention remain comparatively modest, i.e., 53.6 ug/d
intake and 4.4 jug/d retained in the average case. The totals for
the best case substitution are substantially less, i.e., 32.02 ug/d
intake and 2.605 ^ig/d retention. Therefore, it may be concluded
that there are no circumstances in which ambient waters meeting
current drinking water standards pose a threat to human health.
Based on the foregoing data and discussion it seems entirely
justifiable to conclude that water constitutes only a relatively
minor portion of man's daily cadmium intake. From the above analy-
sis it is obvious (average case scenario) that drinking water con-
tributes substantially less to human cadmium intake and/or reten-
tion than smoking a package of cigarettes daily. From this analy-
sis it appears that a water criterion needs to be no more stringent
than the existing primary drinking water standard (10 ug/1) to pro-
vide ample protection of human health.
C-66
-------
TABLE 11
Worst Case - Maximally Exposed Persons
Exposure Sources
Air-Occupational
Ai r-Ambient
Ai r- Smoking
( three packs)
Foods
Drinking Water
Exposure
0.1 mg/m *
0.4 jug/m3
3.0 ug/pack
10 pg/1***
Cd Intake/d Absorption Factor
714 pg
8 jug
9 pg
75 pg**
20 pg
826 ug
0.
0.
0.
0.
0.
5
5
5
1
1
Cd Retention/d
357.
4.
4.
7.
2.
375.
0 pg
0 ug
5 ug
5 pg
0 /jg
0 ug
*
**
OSHA Standard for Cadmium fume (OSHA, 1974. 39 (125) FR 23543).
Pahren and Kowal, 1978. Less than 1 percent of diets are expected to exceed this value,
*** See Exposure Section. Less than one water supply in 300 exceeds this value.
+ These absorption factors may be considered maximal for man.
Average Case
Exposure Sources
Exposure1
Cd Intake/d
Absorption Factor
Cd Retention/d
Ai r-Ambient
Ai r-Smoking
(one pack)
Food
Dr inking Water
0.03
3.0 jjg/pack
1.3 pg/1**
0.6 jug
3.0 pg
30.0 ug
2.6 jug
36.2 pg
0.25
0.25
0.05
0.05
0. 15 pg
0.75 jug
1. 50 jug
0.13 jug
2.53 pg
Average for both sexes excluding drinking water (Exposure Section).
See Exposure section. Average cadmium concentration in a survey of 969 U.S. Community
Water Supply systems (McCabe, et al. 1970).
These absorption factors are considered to be the most realistic available.
C-67
-------
Exposure Sources
Ai r-Ambient
Food
Water
TABLE 11 (continued)
Best Case - Minimally Exposed Persons
0.
0.
Exposure
001 ug/m
5 ug/1*
Cd
0.
12.
1.
13.
Intake/d
02 pg
00 ug
00 jjg
02 ju2
Absorption
0.
0.
0.
Factor
25
05
05
Cd Retention/d
0.005 ug
0.600 ug
0.050 ug
0.655 ug
McCabe, 1974. This data indicates that 37 percent of community water supplies had less
than 1.0 xig Cd/1, which was the practical limit of analytic sensitivity at the time of
his survey.
C-68
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APPENDIX I
Summary and Conclusions Regarding The
Carcinogenicity of Cadmium
A water quality criterion for cadmium based on epidemiology
studies of workers exposed to cadmium dust is included here for
reference, even though the Agency recommends that the criterion
based on renal toxicity be used. The reason for this inclusion is
that the evidence is suggestive, but not conclusive, that inhaled
cadmium induces prostate cancer and that ingested cadmium that is
systemically absorbed is expected to induce the same response as
inhaled cadmium.
Environmental exposure to cadmium occurs by several routes.
The estimated cadmium retention of an individual from food is about
3.0 jag/day; water, 0.09 ug/day; and air, 0.15 ug/day. People smok-
ing five cigarettes per day have an additional retention of about
0.35 .ug cadmium. The production of refined cadmium metal is a
potential source of cadmium for local surface water. In drinking
water the average level of cadmium is on the order of 1 wg/1, but
may be as high as 10 ug/1.
Cadmium has been reported to cause chromosomal or mitotic
aberrations in mammalian cell culture lines. In vi tro, it induces
cellular transformation and also enhances transformation of virus-
infected mammalian cells. These tests are known to be highly cor-
related with oncogenicity. Further it has been shown to produce
adverse effects in both man and experimental animals, e.g.,
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pulmonary emphysema and renal tubular damage. In human tissues,
the concentration of cadmium increases up to the age of 50 years.
There is suggestive evidence from four occupational studies of
highly-exposed workers that inhalation of cadmium may be associated
with prostrate cancer in humans. Subcutaneous injection of soluble
cadmium salts in both rats and mice caused interstitial cell tumors
of the testis. However, orally-administered cadmium has failed to
induce carcinogenic responses in rats and mice, perhaps because it
is not absorbed readily from the gastro-intestinal tract.
It is, therefore, possible that cadmium in drinking water and
fish could induce prostate cancer in humans. A water quality cri-
terion based on lifetime risk of 10" is calculated using the data
of Potts, (1965) for proportional mortality in alkaline battery
factory workers with the assumption of a 50 percent absorption for
inhaled cadmium, 10 percent absorption for ingested cadmium, a fish
bioconcentration factor of 64.0, and other assumptions common to
the water quality risk assessments. The result is that the water
concentration should be less than 0.28 micrograms per liter in
order to keep the lifetime risk below 10~ .
Quantitative Risk Estimates for Carcinogenicity of Cadmium (Cd)
From the CAG document (U.S. EPA, 1978), the lifetime risk to
atmospheric Cd is R=(1.879) (10~3) (X), where X is the lifetime
average daily air concentration in ug/m .
The Cd intake from a concentration of 1 ug/m of Cd in the air
is:
1 ug/m x 24 pg/day = 24 ug/day assuming 100 percent absorp-
tion.
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Studies show that 50 percent absorption may be more realistic,
therefore the Cd intake is:
24 ug/day x 0.5 = 12 ug/day
If this amount of Cd were absorbed from the typical ambient
water exposure pathways (assumed to be 2 liters/day of drinking
water, and 0.0065 kg/day of fish products) with a fish bioconcen-
tration factor of 64, the resulting level of Cd in ambient water,
C, would be:
12 jag/day = Cl (2 + (0.0065) (64))
4.966 jug/1 = Cl
In order to absorb this much from water and fish (assume 10 percent
absorption from the GI tract), the water concentration correspond-
ing to 1 pg/m of air would have to be 49.66 ug/1. Therefore, 1
ug/m in air produces a risk equivalent to a water and fish con-
sumption resulting from 49.66 ug/1 in the water. The air level
giving a lifetime risk of 10~ is:
Xl = 10"5/(1.879 x 10"3) = 0.532 x 10"2 ug/m3
This corresponds to a water level of
•2
0.26 ug/1
C = 49.66 x 0.532 x 10"2 = 0.2642 jjg/1
•O.S. OOVEBKHQIT PRIHTINO OFFICE: 1980-0-730-016/4376
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