CADMIUM
Ambient Water Quality Criteria
Criteria and Standards Division
Office of Water Planning and Standards
U.S. Environmental Protection Agency
Washington, D.C.
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CRITERIA DOCUMENT
CADMIUM
CRITERIA
Aquatic Life
<^or cadmium the criterion to protect freshwater aquatic
,j^ • j • ,. — * j t• • (0.87 In (hardness)
life as derived using the Guidelines is e
as a 24-hour average (see the figure "24-hour average
cadmium concentration vs. hardness should not exceed
In (hardness)-3.92) ^geg thg figure "maximum cadmium con-
centration vs. hardness") at any time.
£For cadmium the criterion to protect saltwater aquatic
lifejas derived using the Guidelines[is 1.0 pq/l as a 24-
hour average and]the concentrationfshould not exceed 16
/ig/lj at any time.
Human Health
[jot the protection of human health from the toxic pro-
perties of cadmium ingested through water and through con-
taminated aquatic organisms, the ambient water criterion
is determined to be 10 yug/lTj
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Introduction
Cadmium is a soft white metal which dissolves readily
in mineral acids. It is used in electroplating, paint and
pigment manufacture and as a stabilizer in plastics manu-
facture (Fulkerson and Goeller, 1973). The solubility of
cadmium compounds in water depends on the nature of the
compounds and on water quality. However, in most situations
sufficient cadmium can be dissolved to cause toxic effects
to aquatic organisms (Baes, 1973). Cadmium ion is precipitated
from solution by carbonate, a hydroxide and sulfide ions
(Baes, 1973) and forms soluble complexes with other anions
(Samuelson, 1963). Most freshwaters in the United States
contain less than 1 jug/1 of cadmium, although levels as
high as 120 yug/1 have been reported (Kopp and Kroner, 1967).
Cadmium reaches waterways as fallout from air and in
effluents from pigments, plastics, alloys and other manu-
facturing 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 column by preci-
pitation.
In the aquatic environment, cadmium is acutely toxic
to fish at concentratitons as low as about 1 ug/1 (Eaton,
In Press; Carroll, et al. 1979). Chronic toxicity to fish
has been reported at approximately the same levels (Sauter,
et al. 1976). Water quality also affects cadmium toxicity
independent of its effect on solubility. Tabata (1969)
and Carroll, et al. (1979) have shown that in acute tests
A-l
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calcium ion protects fishes against cadmium toxicity. Cadmium
has been reported to bioconcentrate in fish tissues to levels
2,000 times as great as those of ambient waters (Spehar,
1976). Since cadmium is an element, it will not be destroyed
and may be expected to persist indefinitely in the environ-
ment in some form.
Cadmium tends to accumulate in liver and kidney of
exposed organisms. In humans the threshold for kidney dysfunction
is about 200 mg/kg in the renal cortex (Friberg, et al.
1974). Cadmium has been identified as a cause of Itai-itai
disease in Japan and has been implicated as a mutagen and
carcinogen (42 FR 56575, October 26, 1977).
A-2
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REFERENCES
Baes, C.F., Jr. 1973. The properties of cadmium. Pages
29 to 54 in W. Fulkerson, and H.E. Goeller, eds. Cadmium,
the dissipated element. Oak Ridge Natl. Lab., Oak Ridge,
Tenn.
Carroll, J.J. et al. 1979. Influences of hardness constituents
on the acute toxicity of cadmium to brook trout (Salvelinus
fontinalis). Bull. Environ. Contam. Toxicol. In Press.
Eaton, J. et al. In Press. Metal toxicity to embryos and
larvae of seven freshwater fish species. Bull. Environ.
Contam. Toxicol.
Friberg, L., et al. 1974. Cadmium in the environment.
2nd ed. CRC Press, Cleveland, Ohio.
Fulkerson, W. and H.E. Goeller, eds. 1973. Cadmium the
dissipated element. Oak Ridge Natl. Lab., Oak Ridge, Tenn.
Kopp, J.F. and R.C. Kroner, 1967. Trace metals in waters
of the United States. Fed. Water Pollut. Control Admin.,
Dep. Interior, Cincinnati, Ohio.
Samuelson, 0. 1963. Ion exchange separations in analytical
chemistry. John Wiley and Sons, New York.
A-3
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Sauter, et al. 1976. Effects of exposure to heavy metals
on selected freshwater fish: Toxicity of copper, cadmium,
chromium and lead to eggs and fry of seven fish species.
Ecol. Res. Ser. 600/3-76-105. U.S. Environ. Prot. Agency,
Washington, D.C.
Tabata, K. 1969. Studies on the toxicity of heavy metals
to aquatic animals and factors that decrease such toxicity
- II; The antagonistic action of water hardness on the toxicity
of heavy metal ions. Bull. Tokai Reg. Fish. Res. Lab. 58:
215.
Watson, M.R. 1973. Pollution control in metal finishing.
Noyes Data Corp., Park Ridge, N.J.
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AQUATIC LIFE TOXICOLOGY*
FRESHWATER ORGANISMS
Introduction
Cadmium is a common component of natural freshwaters
and can occur at extremely low concentrations (less than
0.01 pg/1). In environments impacted by man, total cadmium
concentrations can be several micrograms per liter or greater.
The determination of the significance of total cadmium concen-
trations with respect to possible adverse effects on aquatic
life can be complicated. For example, there are a variety
of possible chemical forms of cadmium in natural waters
which may display different toxicity or bioaccumulation
in addition to substances causing synergistic and antagonistic
effects.
In regard to the latter case, hardness components,
common to all natural waters, are known to act antagonistically
with cadmium to reduce toxicity. Therefore, by expressing
toxicity as a function of both cadmium concentration and
hardness (see Figures labeled "24-hour average cadmium concen-
tration vs. hardness" and "maximum cadmium concentration
vs. hardness"), the ability to derive criteria for freshwater
organisms is significantly improved.
*The reader is referred to the Guidelines for Deriving Water
Quality Criteria for the Protection of Aquatic Life £43
FR 21506 (May 18, 1978) and 43 FR 29028 (July 5, 1978)3
and the Methodology Document in order to better understand
the following discussion and recommendation. The following
tables contain the appropriate data that were found in the
literature, and at the bottom of each table are the calcu-
lations for deriving various measures of toxicity as described
in the Guidelines.
B-l
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Attempts to measure one or more of the forms of cadmium
in freshwater toxicity tests have rarely been made. However,
first-approximations of cadmium's water chemistry can be
obtained by knowing the total cadmium concentration, pH,
total calcium, total magnesium, and total alkalinity (total
carbonate species) of the test water. This may then be
used to estimate possible cadmium carbonate precipitation.
In the case of cadmium, complex formation by common anions
(e.g., chloride, sulfate) in well-oxygenated fresh water
is relatively weak. It is only when concentrations of these
- 2
components become high (e.g., 10 M) that a large portion
(approximately 1/2) of cadmium is complexed. Since these
conditions should not be common in toxicity testing, free
2+
cadmium (Cd ) is the predominant dissolved species. This
applies to waters with low total organic carbon and the
absence of other less prevalent but relatively strong complex-
ing agents, such as aminopolycarboxylic acids.
If it is assumed that complex formation and precipitation
reactions involving carbonate and hydroxide are probable
equi-libria governing free cadmium concentrations for toxicity
test waters, application of such a model provides a useful
first estimate of whether cadmium carbonate or cadmium hydrox-
ide species are possible in a particular system. As a result,
the relationship for total dissolved cadmium and total precip-
itated cadmium may be written:
(1) total dissolved cadmium = (Cd2+) + (CdOH+) + (CdCO^)
(2) total precipitated cadmium = (CdC03^x
B-2
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Based on reasonable assumptions and the use of known equilib-
rium constants, several other reactions have been eliminated.
For example, it can be readily calculated that cadmium hydrox-
ide precipitation should only begin in the vicinity of pH
10 to 11 with relatively high total cadmium concentrations.
Therefore, it follows that cadmium hydroxide precipitation
should usually not occur under natural toxicity testing
circumstances—thus making the reaction relatively umimportant.
Furthermore, cadmium concentrations of approximately 1 ug/1
and below probably will not precipitate as cadmium carbonate,
provided that the approximate limits of pH 8.5 and total
- 2
carbonate of 10 M—usually near the maximum for natural
waters—are not exceeded.
For saltwater test systems with typical salinity, the
number of probable cadmium species is reduced to a few.
Cadmium chloride complexes are predicted to predominate.
The rate at which a precipitate is formed can be somewhat
unpredictable. Application of the model is particularly
useful for the case of determining when precipitation by
carbonate will likely not occur. Under defined cases of
high cadmium concentration, high alkalinity, and high pH,
equilibrium calculations can be expected to be useful in
predicting whether precipitation will occur, while
keeping in mind such limitations, these considerations can
be of aid in determining possible forms of cadmium in test
systems.
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The following data on the effects of cadmium (Tables
1-7) represent appropriate information from the past and
current literature. However, there is a limited knowledge
of the importance of the various processes involving cadmium
in natural waters such as adsorption, precipitation, complexa-
tion, and bioaccumulation in addition to effects these processes
vJ'
may have on changing the toxicity of cadmium.
Acute Toxicity
Examination of LC50 values for fish (Table 1) shows
concentrations, adjusted only for differences in toxicity
test methods, ranging from a low of 0.55 pg/1 to a high
of 40,182 pg/1, with several intermediate values showing
intraspecific variability, possibly due to water quality
effects (Pickering and Gast, 1972). Although some of the
adjusted LC50 values appear relatively low, there is credence
in the fact that four independent studies (Chapman, In press;
Hale, 1977; Davies, 1976; Kumada, et al. 1973) present values
below 10 jug/1, which is the maximum allowable cadmium concen-
tration for potable water in the United States. It should
be noted that there is a relatively large difference between
data from Rehwoldt, et al. (1972) and Hughes (1973) for
striped bass tested at about the same hardness. There are
few LC50 data for salmonids in harder waters, although Davies
(1976) (Table 7) found rainbow trout considerably less sensitive
in hardwater than in softwater with a 96-hour LC20 of 20
pg/1 at a hardness of 326 mg/1. In accord with these low
acute values are the somewhat longer term acute mortality
data of Chapman (In press) and Chapman and Stevens (In press)
in Table 7. Almost all of their LC50 and LC10 values, approx-
imately 200- to 400-hour tests, were relatively low.
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The toxicity data in Table 1 indicate that water hardness
significantly influences the acute toxicity of cadmium to
fish.
Following the Guidelines, an exponential equation de-
scribing the relationship of toxicity to hardness for each
species was fit by least squares regression of the natural
logarithms of the toxicity values and hardness.
For cadmium, sufficient acute toxicity data and hardness
ranges were available for four (4) fish species to fit re-
gression equations. The slope of these equations ranged
from 1.01 for green sunfish to 1.63 for goldfish, with a
mean of 1.30.
As a measure of relative species sensitivity to cadmium,
logarithmic intercepts were calculated for each species
by fitting the mean slope (1.30) through the geometric mean
toxicity value and hardness for each species. These intercepts
varied from -3.92 for rainbow trout to 4.30 for mosquitofish,
with a mean intercept of 1.20 for all 16 fish species.
This variation in logarithmic intercepts indicates a range
of species sensitivity to cadmium of 3,700 fold, even when
adjusted for hardness effects. Even after the mean intercept
(1.20) is adjusted by the species sensitivity factor of
3.9, rainbow trout and three other species have lower inter-
cepts, i.e., are more sensitive. Since rainbow trout had
the lowest intercept based on the results of flowthrough
tests with measured concentrations, the Final Fish Acute
Value is derived using the geometric mean slope (1.30) and
the intercept for rainbow trout (-3.92).
B-5
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Variation observed for invertebrate acute values is
seen to be nearly as great as the acute data on fish; the
adjusted invertebrate LC50 range is 3.8 to 28,000 >ug/l.
However, there also was a relatively more narrow range of
hardness in the toxicity test waters (10 to 81 mg/1) as
compared to the fish acute tests (10 to 360 mg/1). Few
flow-through tests have been conducted with invertebrate
species. Cladocerans, such as Daphnia magna, were the most
sensitive species and mayflies and stoneflies were the most
resistant. However, insects and many other invertebrate
species are more sensitive when they molt, an event not
usually occurring among most individuals (daphnids and copepods
excepted) in 2- to 4-day toxicity tests. Only in the work
of Giesy, et al. (1977) with cladocerans are LC50 values
below 10 jug/1. Particularly noteworthy is their work suggest-
ing changing toxicity as a function of introducing different
sources of natural organic material capable of complexing
cadmium. Although relatively little is reported on this
subject at the present time, it is reasonaable to assume
that various forms of cadmium in polluted waters, besides
the free form, may be factors in causing toxicity. No data
were available to indicate hardness effects on acute toxicity
to invertebrate species since no species has been tested
over a range of water hardness. Assuming that a similar
relationship to hardness probably exists for toxicity of
cadmium to invertebrate species as with fish, the slope
from the fish acute equation was used to determine the loga-
rithmic intercepts (relative species sensitivity) for inverte-
brate species. The intercepts ranged from -1.02 for the
B-6
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scud (Ganunarus sp. ) to 3.74 for damselfly, with a mean
of 1.47. After adjustment using the species sensitivity
factor of 21, the intercept is -1.57. This would indicate
that the invertebrate species tested are acutely less sensitive
to cadmium than fish. Therefore, the Final Fish Acute Value
becomes the Final Acute Value.
Chronic Toxicity
The fish chronic values ranged from 0.9 to 50 pg/1
(Table 3). Except for the fathead minnow and bluegill which
were tested in hard water, all chronic values were in the
range of 0.9 to 7.5 }ig/l. Consistent with the acute tests,
salmonids tended to be the most sensitive group. The three
sets of brook trout data by three different investigators
may be in closer agreement than indicated (Table 3). Without
the use of the embryo-larval adjustment factor of 2 they
are practically identical. However, LC10 values (Chapman,
In press) as low as 0.7 jug/1 (Table 7) were also obtained
for rainbow trout. Because of the extent to which Chapman
(In press) investigated the sensitivity of various life
stages, these results are probably more nearly comparable
to embryo-larval test results. The only chronic test data
relating fish chronic toxicity to hardness (Sauter, 1976)
is unexplainably contradictory. Brook trout were found
to be several times more sensitive in soft water than hard
water, while channel catfish were equally sensitive in both.
Toxicity and hardness data for brook trout were used
to determine the slope for the hardness relationship, since
the data available for channel catfish seemed to be inconsis-
B-7
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tent with the rest of the data on acute and chronic toxicity.
Using the book trout slope (0.867), calculated intercepts
for the 12 species tested ranged from -2.98 for brook trout
to -0.71 for bluegill, with a mean of -1.80. The adjusted
mean intercept (-3.70) is below that for all species and
is therefore used,in the Final Fish Chronic Value.
A chronic value of 0.34 pg/1 (Table 4) was obtained
for Daphnia magna from the data of Biesinger and Christensen
(1972) for reproductive impairment in Daphnia magna. Marshall
(1978) found the long-term (22 week) average numbers of
Daphnia galeata mendotae in laboratory populations in harder
Lake Michigan water (the hardness was estimated to be 120
mg/1) were reduced by 50 percent at 7.7 ^ig/1 (Table 7).
A concentration of 4 pg/1 and higher significantly reduced
biomass.
The three application factors for fish are surprisingly
similar considering the different species and water hardness
involved. In the case of the one set of comparable inverte-
brate data, a similar wide difference between acute (65
pg/1) and chronic (0.34 pg/1) test results was observed
for Daphnia magna (Biesinger and Christensen, 1972). An
invertebrate application factor derived from values (0.00523)
would be very similar to those for the fish.
Only a single chronic toxicity test with Daphnia magna
is available for cadmium. The chronic value obtained, however,
is significantly below that for any fish species at equivalent
hardness.
B-8
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Daphnia magna and other cladocerans are the most sensitive
invertebrate species tested (Table 2). Therefore, it would
appear to be inappropriate to use the Guidelines species
sensitivity factor of 5.1 with the chronic data for Daphnia
magna. Consequently, that sensitivity factor will not be
used in the calculations to derive the Final Invertebrate
Chronic Value. Since appropriate invertebrate data were
not available to establish a relationship between chronic
toxicity values and hardness, a relationship was estimated
by using the slope (0.867) from the Final Fish Chronic Value
and the cadmium value and water hardness from the Daphnia
magna test. The calculated intercept for invertebrate species
is -4.38. The derived equation for invertebrate species
(0. 867 ln(hardness) -4.38) . TT ,
e ' becomes the Final Chronic Value
since it is lower than the comparable value for fish.
Plant Effects
Growth reduction was the major effect employed for
detecting toxicity to aquatic plants (Table 5). Species
ranged from diatoms to duckweed. Correspondingly, the effect
concentrations ranged from 2 ^jg/1 for the diatom (Conway,
1978) to 7,400 /jg/1 for Eurasian watermilfoil (Stanley,
1974). Some values were lower than several LC50 values
for fish. Although some plant studies demonstrated toxicity
at low cadmium concentrations, it must be considered that
growth media, used to sustain the plants, appeared to be
less similar with respect to components added to natural
lake and stream waters than dilution waters used in fish
toxicity test. Since toxicity values for fish and invertebrate
species were lower than plant data, these data do not enter
into formulation of the criterion.
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Residues
Bioconcentration factors (Table 6) ranged from 151
for brook trout (Benoit, et al. 1976) to 1,988 for flagfish
(Spehar, 1976). By comparison, brook trout was observed
to approach steady-state bioconcentration much more slowly
(Benoit, et al. 1976) than Daphnia magna (Poldoski, manuscript).
In the work with Daphnia magna, the species displaying the
lowest chronic value, significant bioconcentration occurred
within 1 day. The work of Hutchinson and Czyska (1972)
provided the only available values for plants, 603 and 960.
One noteworthy characteristic of cadmium bioconcentration
is the possible long half-life of residues. Benoit, et
al. (1976) found that certain organs did not lose significant
amounts of cadmium when exposed trout were placed in clean
water for several weeks.
When the mallard was fed a diet containing 20 mg cadmium/kg
for 90 days, there was testicular damage (White, et al.
In press). Division of 29 mg/kg by the geometric mean biocon-
centration factor of 515 gives a Residue Limited Toxicant
Concentration (RLTC) of 39 /ig/1.
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CRITERION FORMULATION
Freshwater - Aquatic Life
Summary of Available Data
Final Fish Acute Value = e(1.30 ln(hardness)-3.92)
Final Invertebrate Acute Value =^(1.30 ln(hardness)-l.57
Final Acute Value = e(1.30 (hardness)-3.92
Final Fish Chronic Value = e(0.867 In(hardness)-3.70)
Final Invertebrate Chronic Value = e(0.867 In(hardness)-4.38)
Final Chronic Value = (0.867 ln(hardness)-4.38)
Final Plant Value = 2 jug/1
Residue Limited Toxicant Concentration = 39 pq/l
The maximum concentration of cadmium is the Final Acute
value o£ e'1-30 1"(hardness)-3.92) an
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4.0r
24-HOUR AVERAGE
CADMIUM CONCENTRATION
VS.
HARDNESS
2.0
Q
5? 8
0.40
UJ C
<2 ~
0.20
CM
0.10
0.04
400
200
100
40
20
TOTAL HARDNESS (mg/l)
In scale
B-12
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40j0
20.0
o>
3
z
0
1
I-
2
iLi
O 93
10.0
8
3
2
o
<
o
s
3
o
CO 4.0
2.0
1.0
0.4
MAXIMUM CADMIUM CONCENTRATION
VS.
HARDNESS
/
/
6?
Is?
10
20
40
100
200
400
TOTAL HARDNESS (mg/l)
In scale
B-13
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Table 1. Freshwater fish
Bioassay Test
Organisw Method* Cone.**
American eel, S M
Angullla rostrata
Chinook salmon (swim-up), FT M
Oncorhynchus tshawytscha
Chinook salmon (piarr), FT M
Oncorhynchus tshawytscha
Rainbow trout (swim-up), FT M
Salmo gairdneri
Rainbow trout (parr), FT M
Salmo gairdneri
Rainbow trout (2-mos), FT M
Salmo gairdneri
Rainbow trout, FT M
Salmo gairdneri
Rainbow trout, S U
Salmo gairdneri
Rainbow trout, S U
Salmo gairdneri
Goldfish, S U
Carassius auratus
Goldfish. S M
Carassius auratus
Goldfish, S M
Carassius auratus
Fathead minnow, S U
Pimephales promelas
Fathead minnow, . S U
Pimephales promelas
Fathead minnow, S U
Pimephales promelas
te values for cadmium
Hardness
(mq/i as Time
CaCQj) Jhrs)
55
23
23
23
23
96
96
96
96
96
96
Adjusted
LC50 LCSO
luq/i> (uq/i> freterence
820 582 Rehwoldt, et al.
1972
1.8 1.8 Chapman, In
press
3.5 3.5 Chapman, In
press
1.3 1.3 Chapman, In'
press
1.0 1.0 Chapman, In
press
6.6 6.6 Hale, 1977
31
20
20
140
20
20
360
96
96
96
96
96
96
96
96
1.75
6
7
2,340
2,130
46,800
1,050
630
96 72,600
1.75 Davies, 1976
3.28 Kumada, et al.
1973
3.83 Kumada, et al.
1973
1,279 Pickering &
Henderson, 1966
1,512 McCarty, et al.
1978
33,228 McCarty, et al.
1978
574 Pickering &
Henderson, 1966
344 Pickering &
Henderson, 1966
39,690 Pickering &
Henderson, 1966
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Organism
Fathead minnow,
Pimephales promelas
Fathead minnow,
Pimephales promelas
Fathead minnow,
Pimephales promelas
Fathead minnow,
Pimephales promelas
Fathead minnow,
Pimephales promelas
Fathead minnow,
Pimephales promelas
Carp,
Cyprinus carplo
Banded killifish,
Fundulus diaphanus
Flagfish,
Jordanella floridae
Mosquitofish,
Gambusia affinis
Mosquitofish,
Gambusia affinis
Mosquitofish,
Gambusia affinis
Mosquitofish,
Gambusia affinis
Mosquitofish,
Gambusia affinis
Guppy,
Lebistes reticulatus
Table 1. (Continued)
Hardness
Bxoassay Test (inq/1 as
Method* Cone .** CaCO-j)
S U 360
FT M 201
FT M 201
FT M 201
FT M 201
FT M 201
S M 55
S M 55
FT M 44
FT M 10.0
FT M 10.0
FT M 10.0
FT M 11.1
FT M 11.1
S U 20
LC50
Jya^Ai
Adjusted
(uq/i.1 fretetfence
73,500 40,182
11,000 11,000
12,000 12,000
6,400 6,400
2,000 2,000
4,500 4,500
240 170
110 78
2,500 2,500
1,300 1,300
1,400 1,400
2,600 2,600
900 900
2,200 2,200
1,270 694
Pickering &
Henderson, 1966
Pickering &
Gast, 1972
Pickering &
Gast, 1972
Pickering &
Gast. 1972
Pickering &
Gast, 1972
Pickering &
Gast, 1972
Rehwoldt, et al
1972
Rehwoldt, et al
1972
Spehar, 1976
Giesy, et al.
1977
Giesy, et al.
1977
Giesy, et al.
1977
Giesy, et al.
1977
Giesy, et al.
1977
Pickering &
Henderson, 1966
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Table 1, (Continued)
CD
I-*
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Table 1. (Continued)
Organism
Hardness
Bioassay Test (mq/1 as Time
Method Cone. CaCO^) i!i£S
i!i£a) >.
Adjusted
LC50 LCt.0
(uq/I) (gq/i> Eeterfence
Adlusted LC50 vs. hardness;
Goldfish) slope = 1.63, intercept = 2.35, r - 0,99, Not significant, N = 3
Fathead minnow: slope •* 1,37, intercept ¦» 1,82, r ¦ 0,91, p = 0.01, N = 9
Green sunfish: slope = 1.01, intercept ¦ 4.33, r = 0.99, Not significant, M » 3
Bluegill: slope » 1.28, intercept = 3.13, r = 1.0, Not significant, N = 2
Geometric mean slope = 1.30
Mean intercept for 16 fish species - 1,20
Adjusted mean intercept - 1.20 - ln(3.9) = -0,16
Intercept for rainbow trout = -3.92
Final Fish Acute Value
e
(1.30•In(hardness)-3,92)
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Table 2. Freshwater invertebrate acute values for cadmium
Organism
Bioassay Test
Method* Cone.**
Hardness
(iikj/1 as Time
CaCO^) tfirs)
Adjusted
LCf>0 LC5U
(ug/it (ug/i> Keterence
td
I
h-*
00
Rotifer, R
Philodina acuticornis
Rotifer, R
Philodina acuticornis
Rotifer, R
Philodina acuticornis
Bristle worm, S
Nais sp.
Snail (egg), S
Amnicola sp.
Snail (adult), S
Amnicola sp.
Cladoceran, S
Paphnia hyalina
Cladoceran, S
Paphnia magna
Cladoceran, S
Simoephalus serrulatus
Cladoceran, S
Simoephalus serrulatus
Cladoceran, S
Simoephalus serrulatus
Cladoceran, S
Simoephalus serrulatus
Cladoceran, S
Simoephalus serrulatus
Cladoceran, S
Simoephalus serrulatus
Copepod, S
Cyclops ahyssorum
U
U
U
U
U
U
U
U
M
M
M
H
M
M
25 96 500 424 Buikema, et
al. 1974
25 96 200 169 Buikema, et
al. 1974
81 96 300 254 Buikema, et
al. 1974
50 96 1,700 1,440 Rehwoldt, et
al. 1973 -
50 96 3,800 3,219 Rehwoldt, et
al. 1973
50 96 8,400 7,115 Rehwoldt, et
al. 1973
48 55 47 Baudouin &
Scoppa, 1974
45 48 65 55 Biesinger &
Christensen, 1972
10.0 48 35.0 38.5 Giesy, et al.
1977
11.1 48 7.0 7.7 Giesy, et al.
1977
11.1 48 3.5 3.8 Giesy, et al.
1977
11.1 48 12.0 13.2 Giesy, et al.
1977
11.1 48 16.5 18.1 Giesy, et al.
1977
11.1 48 8.6 9.5 Giesy, et al.
1977
48 • 3,300 1,384 Baudouin &
Scoppa, 1974
-------
Table 2. (Continued)
Organisa
Copepod,
Eudlaptomus padanus
Scud,
fiammarus sp.
Mayfly,
Ephemerella grandis
grandis"
Mayfly.
Ephemerella grandis
grandis
Stonefly,
Pteronarcella bodia
Damselfly,
Unidentified
Midge,
Chironomous
Caddisfly,
Unidentified
Bioassay Test
MeUiQQ* Cone ,** CaCO?) Hits)
A 8
Hardness
(mq/1 as Tine
l3>
FT
FT
S
S
S
U
U
M
M
M
U
U
U
50
54
50
50
50
96
96
96
96
96
96
96
LCSU
550
70
28,000
2.000
Adjusted
LCbO
im/x) frfciei.fence
200
59
28,000
2,200
18,000 18,000
8,100 6,861
1.200 1.016
3,400 2,880
Baudouin &
Scoppa, 1974
Rehwoldt, et
al. 1973
Clubb, et al.
1975
Warnick &
Bell, 1969
Clubb, et al.
1975
Rehwoldt, et
al. 1973
Rehwoldt, et
al, 1973
Rehwoldt, et
al. 1973
* S = static, FT « flow-through, R = renewal
** U = unmeasured, M » measured
Adlusted LC50 vs. hardnessi
No hardness relationship could be derived for any invertebrate species.
Using the geometric mean slope from the fish acute values, the mean intercept for 10
invertebrate species ¦ 1*47
Adjusted mean intercept = 1.47 - ln(2|) = ~1,57
Final Invertebrate Acute Value = e(l.30'In(hardness)- 1.57)
-------
Tattle 3. Freshwater fish chronic values
Chronic
Limits Value
Organism Test* |uq/ll (ug/ll
Coho salmon (Lake Superior), E-L 1,3-3,4 1,0
Oncorhynchus kisutch
Coho salmon (West Coast), E-L 4.1-12.5 3,6
Oncorhynchus kisutch
Brook trout, E-L 1.1-3.8 1,0
Salvellnus fontinalis
Brook trout, LC 1,7-3,4 2,4
Salvellnus fontinalis
Brook trout, E-L 1-3 0,9
Salvellnus fontinalis
Brook trout, E-L 7-12 4,6
_ Salvellnus fontinalis
tU "— —
Lake trout, E-L 4,4-12,3 3,7
O Salvelinus namaycush
Brown trout, E-L 3.8-11,7 3,3
Salmo trutta
Northern pike, E-L 4,2-12.9 3,7
Esox lucius
Fathead minnow, LC 37-57 46
Pimephales promelas
White sucker, E-L 4.2-12.0 3,5
Catostomus conwersoni
Channel catfish, E-L 11-17 6.8
Ictalurus punctatus •
Channel catfish, E-L 12-17 7,1
Ictalurus punctatus
Flagfish, LC 4.1-8,1 5,8
Jordanella floridae
Smallinouth bass, E-L 4,3-12.7 3,7
Micropterus dolomieui
cadmium
UaioneES
(mq/l as
CaCOj)
44
44
44
44
36
187
44
44
44
201
44
37
185
44
44
Reference
Eaton, et al. 1978
Eaton, et al. 1978
Eaton, et al. 1978
Benoit, et al> 1976
Sauter, et al. 1976
Sauter, et al. 1976
Eaton, et al. 1978
Eaton, et al. 1978
Eaton, et al. 1978
Pickering & Gast, 1972
Eaton, et al. 1978
Sauter, et al. 1976
Sauter, et al. 1976
Spehar, 1976
Eaton, et al. 1978
-------
Table 3. (Continued)
organism
Bluegill,
Lepomis macrochirus
Walleye,
Stizostedion vltreum
Test*
LC
E-L
Limits
31-8Q
9-25
Chronic
Value
isaOl
50
7.5
Haianess
(inq/l as
CaCQj)
207
35
Reference
Eaton, 1974
Sauter, et al. 1976
* E-L - embryo-larval, LC» life cycle or partial life cycle
Fish chronic value vs. hardness:
Brook trout: slope = 0.867, intercept ~ -2.98, r » 0,86, Not significant, N =¦ 4
Geometric mean slope ¦ 0,867 (only value available)
Mean intercept for 12 fish species ¦» -1,80
Adjusted mean intercept - -l,80-ln(6,7) =» -3,70
Final Fish Chronic Value = (0.867'ln(hardness)-3,70)
Application Factor Values**
Species
Fathead minnow,
Pimephales promelas
Flagfish,
Jordanella floridae
Bluegill.
Lepomis macrochirus
96-hr LC50
.
-------
Tattle 3. (Continued)
Organiaw
Bluegill,
Lepomis macrochlrus
Walleye,
Stizoscedlon vicreura
Test*
LC
E-L
Limits
31-80
9-25
Chronic
Value
JLna^ii
50
7.5
Haraness
(iiHj/i as
CaCO-j)
207
35
Reference
Eaton, 1974
Saucer, et al. 1976
* E-L = embryo-larva1, LC= life cycle or partial life cycle
Fish chronic value vs. hardness:
Brook trout: slope » 0.867, intercept = -2.98, r ¦ 0,86( Not significant, N - 4
Geometric mean slope ¦ 0,867 (only value available)
Mean intercept for 12 fish species «• -1,80
Adjusted mean intercept - -l,80-ln(6.7) = -3,70
Final Fish Chronic Value = e(Q.867'ln(hardness)-3t70)
Species
Fathead minnow,
Pimephales promelas
Flagfish,
Jordanella florldae
Bluegill,
Lepomis macrochirus
Application Factor Values**
96-hr LC50 MATC
(iir/1) (m?/1I
AF
Reference
5,973
2,500
21,100
37-57 0,00770 Pickering & Gast, 1972
4,1-8.1 0.00232 Spehar, 1976
31-80 0.00237 Andrew, et al. Manuscript
Geometric mean AF *» 0.00348 .
** The Final Fish Chronic Value is below the chronic value derived using the application factor.
-------
Table A. Freshwater invertebrate chronic values for cadmium (Biesinger & Chrlstensen, 1972)
Organise
Chronic
UMts Value
Teat* luq/lt
-------
Table 5. Freshwater plane effects for cadmium
Organism
Diatom,
Asterionella formosa
Diatom,
Scenedeamus
quadracauda
Green alga,
Chlorella pyrenoidoaa
Green alga,
Chlorella vulgaris
Green alga,
Chlorella vulgaris
Green alga,
Selanastrum
capricornutum
Fern,
Salvina naCans
Eurasian watermilfoil,
Hyriophyllmn
spicatum
Duckweed,
Lerana valdiviana
Effect.
Concentration
Factor of 10 2
growth rate
decrease
Reduction in 6.1
cell count
Reduction in 250
growth
Reduction in 50
growth
50X reduction in 60
growth
Reduction in 50
growth
Reduction in 10
number of fronds
50Z root weight 7,400
inhibition
Reduction in 10
number of fronds
Reference
Conway, 1978
Klass, et al. 1974
Hart & Scaife. 1977
Hutchinson & Stokes, 1975
Rosko & Rachlin, 1977
Bartlett, et al. 1974
Hutchinson & Czyrska, 1972
Stanley, 1974
Hutchinson & Czyrska, 1972
Lowest plant value - 2 ng/1
-------
Organism
Table 6. Freshwater residues for cadmium
Bioconcentration Factoi
Time
(days)
rtfcteience
Duckweed,
Lemna valdiviana
Fern,
Salvlnia natans
Cladoceran.
Daphnia magna
Crayfish,
Orconectes propinquus
Rainbow trout,
Salmo gairdneri
Brook trout,
Salvelinus fontlnalis
Brook trout,
SalveLinus fontinalis
Flagfish,
Jordanella floridae
Threespined stickleback,
Gastrosteus aculeatus L.
603
960
320
184
540
3*
151
1,988
900
21
21
2-4
8
140
490
84
30
33
Hutchinson & Czyrska,
1972
Hutchinson & Czyrska,
1972
Poldoski, Manuscript
Gillespie, et al. 1977
Kumada, et al. 1973
Benoit, et al. 1976
Benoit, et al. 1976
Spehar, 1976
Pascoe & Mattey, 1977
Organism
Mallard,
Anas platyrhynchoB
Maximum Permissible Tissue Concentration
Action Level or Effect
Testicular damage,
90 days
Concentration
20
Reference
White, et al. In press
* Indicates muscle tissue only, data not used in calculating geometric mean bioconcentration factors.
Geometric mean bioconcentration factor for all species = 515
Lowest residue concentration = 20 mg/kg
20
515
- = 0.039 mg/kg or 39 ug/1
-------
Table 7. Other freshwater data for cadmium
03
I
NJ
a\
Organ!a»
Cladoceran.
Daphnia galeata
mendotae
Cladoceran,
Daphnia galeata
mendotae
Test
Oaration Effect
Hardness,
ng/1
(CaCO-j)
22 wks 50 percent
reduction in
relative mean
numbers
22 wks Reduced
biomass
Coho salmon (Juvenile), 217 hrs LC50
Oncorhynchus kisutch
Coho salmon (adult),
Oncorhynchus kisutch
215 hrs LC50
Chinook salmon (alevin), 200 hrs LC10
Oncorhynchus tshawytscha
Chinook salmon
(swim-up),
Oncorhynchus tshawytscha
200 hrs LC10
Chinook salmon (parr), 200 hrs LC10
Oncorhynchus tshawytscha
Chinook salmon (smolt), 200 hrs LC10
Oncorhynchus tshawytscha
Brook trout,
Salvelinus fontinalis
Rainbow trout,
Salmo gairdnerl
Rainbow trout,
Salmo gairdneri
Rainbow trout
(juvenile),
Salmo gairdneri
Rainbow trout (adult) ,
Salmo p.airdnerl
21 days Testicular
damage (blood
vessel col-
lapse,
reduced 11-
ketotestoster-
one synthesis
240 hrs LC50
240 hrs LC50
390 hrs LC50
22
22
23
23
23
23
20
408 hrs LC50
Result
ing/j)
7.7
4.0
2.0
3.2
1.2
1.3
1.5
10
5
0.9
4.8
Reference
Marshall, 1978
Marshall, 1978
Chapman & Stevens, In
press
Chapman & Stevens, In
press
18-26 Chapman, In press
Chapman, In press
Chapman, In press
Chapman, In press
Sangalang & O'Halloran,
1972, 1973
Kumada, et al. 1973
Kumada, et al. 1973
Chapman & Stevens, In
press
Chapman & Stevens, In
press
-------
Table 7. (Continued)
Organjaw
Rainbow trout (alevin),
Salmo galrdneri
Rainbow trout
(swim-up).
Salmo gairdneri
Rainbow trout (parr),
Salmo gairdnerl
Rainbow trout (smolt),
Salmo galrdneri
Rainbow trout,
Salmo gairdneri
Goldfish,
Carassius auratus
Threespine stickleback,
Gasterosteus aculeatus
Test
Duration
186 hrs
Effect
LC10
200 hrs LC10
200 hrs LC10
200 hra LC10
96 hrs L£20
SO days
Hardness,
mg/1
(CaCOi)
23
23
23
23
326
Reduced
plasma sodium
level (osmo-
rigulatory
changes)
33 days LC50
* Tests were conducted in water from Lake Michigan.
Result
(uq/11 Reterence
>6 Chapman, In press
1.0 Chapman. In press
0.7 Chapman, In press
0.8 Chapman, In press
20 Davies, 1976
44.5 McCarty & Houston, 1976
0.8 Pascoe & Mattey, 1977
-------
SALTWATER ORGANISMS
Acute Toxicity
Data on acute cadmium toxicity to saltwater fishes
covers four species, different life stages and exposure
conditions (Table 8). Unadjusted LC50 values ranged from
1,600 yug/1 for larval Atlantic silversides (Middaugh and
Dean, .1977) to 114,000 pg/1 for juvenile mummichog (Voyer,
1975). Intraspecific differences in sensitivity relating
to life stage are also evident. Middaugh and Dean (1977)
have shown that larvae of the mummichog and Atlantic silverside
were an average of four times more sensitive than adults
tested under the same conditions. Studies of the effect
of salinity on cadmium toxicity to adult mummichog and Atlantic
silverside indicate cadmium is more toxic at 30 °/oo than
at 20 °/oo (Voyer, 1975; Middaugh and Dean, 1977).
When the geometric mean LC50 (11,010 /jg/1 is divided
by the sensitivity factor of 3.7, the result is 3,000 ;jg/l
(Table 8). This concentration becomes the Pinal Fish Acute
Value for saltwater fish and cadmium.
This result is higher than adjusted LC50 values for
larvae of the Atlantic silverside. The geometric mean of
six tests (Middaugh and Dean, 1977) is 1,800 jug/1. However,
the geometric mean LC50 value for combined data for adults
and larvae is 3,600 ,yg/l. In addition, the acute toxicity
data base for saltwater fish is limited to four species
of which three are in the same family (Cyprinodontidae).
The data base is too limited to evaluate the applicability
to cadmium of the sensitivity factor.
B-28
-------
A variety of saltwater invertebrate species are more
sensitive to acute cadmium poisoning than saltwater fishes
(Table 9). The invertebrate data include results of studies
on four phyla: Annelida, Mollusca, Anthropoda (Crustaceans)
and Echinoderms. The adjusted LC50 values ranged from 15.5
jug/1 for Mysidopsis bahia (Nimmo, et al. 1977a) to 39,470
jug/1 for the fiddler crab (O'Hara, 1973). Adult and juvenile
polychaete worms were relatively insensitive to cadmium
with adjusted LC50 values ranging from 6, 353 to 10,588 jjg/1
(Reish, et al. 1976). Larvae of the polychaete (Capitella
capitata), however, were more sensitive than the adult (Reish,
et al. 1976). The gastropod molluscs were also relatively
insensitive to cadmium as evidenced by the values for the
mud snail, 35,000 jug/1 (Eisler and Hennekey, 1977) and the
oyster drill, 6,600 jjg/1 (Eisler, 1972). The unadjusted
LC50 values for the bivalve molluscs ranged from 1,480 >ug/l
for the bay scallop (Nelson, et al. 1976) to 4,300 Ajg/1
for the mussel (Ahsanullah, 1976). The data from Eisler
(1971) on the mussel is atypical with a 96-hour LC50 of
25,000 p<3/1. The arthropods (Crustaceans) manifested the
widest range of sensitivity to acute cadmium exposure.
The most sensitive species and their unadjusted LC50 values
were: Mysidopsis bahia (15.5 pg/1); Homarus americanus
(78 jjg/1); and Acartia tonsa (90 pg/1). The least sensitive
species was the crab, Oca pugilator with 96-hour LC50 values
as high as 46,600 pg/1.
Acute cadmium toxicity to Uca pugilator was not altered
by salinities of 10, 20, and 30 °/oo. Temperature, however,
B-29
-------
increased cadmium toxicity by a factor of five between 20°C
and 30°C at 10 °/oo and by a factor of 1.6 at 30 °/oo.
When the geometric mean of 1,550 pg/1 is divided by
the species sensitivity factor of 49 the result is 32 /ug/1
(Table 9). The data base, however, contains a flow-through,
measured LC50 value of 15.5 pg/1 for Mysidopsis bahia.
Using the recommended Guideline's procedures of selecting
the lower of these two values, the Final Invertebrate Acute
Value is 16 pg/1. All the values reported in Table 9 are
equal to or greater than 16 pg/1.
Since the Final Invertebrate Acute Value of 16 jug/1
is lower than the Final Fish Acute Value of 3,000 wg/1,
the Final Acute Value for saltwater aquatic life is 16 jug/1.
Chronic Toxicity
No life cycle or embryo-larval data are available with
cadmium for saltwater fishes.
The chronic toxicity of cadmium to the mysid shrimp,
Mysidopsis bahia was studied (Table 10). Four parameters
were addressed; survival, appearance of first brood, time
of release of young from the brood pouch, and the average
number of young per female released after a 23-day exposure.
Decreased survival (90 percent) was evident at 10.6 g/1;
a 48-hour delay in brood formation and 24-hour delay in
brood release at 6.4 jag/l was observed and a 57 percent
decrease in the number of young per female occurred at 6.4
^ig/1. There were no measurable effects on the above parameters
at 4.8 pg/1. For Msidopsis bahia, with its short-life cycle,
the difference between the 96-hour LC50 and chronic toxicity
of cadmium is small (i.e., 15.5 ug/1 to 4.8 pg/1). Comparison
B-30
-------
of acute and chronic mortality data for other invertebrate
species indicates a wider range of response. The acute
toxicity values for Penaeus duorum (3,500 pg/1), Paleomentes
vulgar is (760 jug/1). Capitella capitata (7,500 ug/1), and
Neanthes arenaceodentata (12,000 pq/1) are compared to the
corresponding 28-day LC50 values (Table 13) of 720 yug/1,
120 pq/1, 700 ^g/1, and 3,000 pq/1, respectively. For species
with long life cycles, the differences between acute and
chronic toxicity are greater than that of the mysid shrimp.
Since chronic toxicity data are limited to one species,
no indication of the range of species sensitivity can be
determined. Mysidopsis bahia is, however, the most sensitive
invertebrate species acutely tested (Table 9). Without
additional chronic data, it is difficult to judge the appro-
priateness of the species sensitivity factor of-5.1 which,
when applied to the geometric mean of the chronic value
of 5.5 pg/1, results in a Final Invertebrate Chronic Value
of 1.0 jug/1. Based upon data on bioconcentration (Table
12) and sublethal effects reported in Table 13, this value
is protective of saltwater aquatic life.
Plant Effects
The sensitivity of saltwater plants to cadmium has
only been tested with microalgae (Table 11). Cadmium inhibited
the growth rate of Skeletonema costatum and Cyclotella nana
at 175 /ig/1 and 160 /ig/1* respectively. The Final Plant
Value is 160 yug/1.
B-31
-------
Bioconcentration
Cadmium is bioconcentrated by a wide variety of marine
species (Table 12). The highest bioconcentration factors
for cadmium are those with bivalve molluscs. Zaroogian
and Cheer (1976) demonstrated that the American oyster could
bioconcentrate cadmium 2,600 times after a 280-day exposure.
Tissue residues reached 10.75 mg/kg which closely approximate
the emetic threshold (13-15 mg/kg) established for man (Anon.,
1950). This indicates that a commercially important shellfish
can bioconcentrate cadmium to potentially harmful concentrations
when the seawater cadmium concentration is only 5 ug/1.
Kerfoot and Jacobs (1976) have also shown oyster tissue
residues of 16 mg/kg after a 40-day exposure to 30 ug/1.
George and Coombs (1977) reported on the effects of metal
speciation on accumulation of cadmium in- the soft tissues
Mytilus edulis. Cadmium complexed as Cd-alginate, Cd-
EDTA, Cd-humate, and Cd-pectate was bioconcentrated at twice
the rate as CdCl2. Pish bioconcentration factors were 48
for the mummichog (Eisler, 1972). Crustaceans were
intermediate between the fish and molluscs in their ability
to bioconcentrate cadmium. Vernberg, et al. (1977) reported
700 for grass shrimp while the pink shrimp had a bioconcen-
tration factor of only 57 (Nimmo, et al. 1977b).
A Residue Limited Toxicant Concentration (RLTC) can
be derived using the available data base (Table 12). Biocon-
centration factors are known for a variety of forms and
species from algae to fish. The geometric mean of these
factors is 144. When the lowest maximum permissible tissue
concentration, 20 mg/kg for the mallard, is divided by 144,
the derived RLTC is 140 jjg/1.
-------
Miscellaneous
Several studies have reported on the chronic sublethal
effects of cadmium on saltwater fish (Table 13). Significant
reduction in gill-tissue respiratory rates and alteration
of liver enzyme activity have been reported in the cunner
after a 30-day exposure to 50 pg/1 (Maclnnes, et al. 1977).
Dawson, et al. (1977) also.reported a significant decrease
in gill-tissue respiration for striped bass at 0.5 ^Lig/1
above ambient after a 30-day but not a 90-day exposure.
A similar study on the winter flounder has been reported
(Calabrese, et al. 1975). This study demonstrated significant
alterations in gill-tissue respiration rates measured in
vitro after a 60-day exposure to 5 jug/1.
The significance of these sublethal effects on survival,
growth, and reproduction have yet to be evaluated. While
the above data are not sufficient for development of a crite-
rion, we must be cognizant that there are demonstratable
sublethal effects due to chronic exposure at very low cadmium
concentrations.
Most of the remaining data in Table 13 are for effects
on survival at higher concentrations or for short exposures.
B-33
-------
CRITERION FORMULATION
Saltwater - Aquatic Life
Summary of Available Data
The concentrations below have been rounded to two signif-
icant figures. All concentrations herein are expressed
in terms of.cadmium.
Final Fish Acute Value = 3,000 /jg/1
Final Invertebrate Acute Value = 16 jug/1
Final Acute Value = 16 jug/1
Final Fish Chronic Value = not available
Final Invertebrate Chronic Value = 1.0 /jg/1
Final Plant Value - 160 ^ug/1
Residue Limited Toxicant Concentration = 140 fiq/1
Final Chronic Value = 1.0 /jg/1
0.44 x Final Acute Value = 7.0 jug/1
The maximum concentration of cadmium is the Final Acute
Value of 16 jug/1 and the 24-hour average concentration is
the Final Chronic Value of 1.0 jug/l. No important adverse
effects on saltwater organisms have been reported to be
caused by concentrations lower than the 24-hour average
concentration.
CRITERION: For cadmium the criterion to protect saltwater
aquatic life as derived using the Guidelines is 1.0 /ag/1
as a 24-hour average and the concentration should not exceed
16 /jg/1 at any time.
B-34
-------
Table 8. Marine fish acute values for cadmium
W
I
u>
cn
Organise
Sheepshead minnow,
Cyprinodon variegatus
Mummichog (adult) ,
Fundulus heteroclitus
Mummichog (adulc),
Fundulus heteroclltus
Mumnichog (adult),
Fundulus heteroclitus
Mummichog (adult),
Fundulus heteroclitus
Mumnichog (juvenile),
Fundulus heteroclitus
Muuimichog (juvenile),
Fundulus heteroclitus
Mummichog (juvenile),
Fundulus heteroclitus
Mummichog (juvenile),
Fundulus heteroclitus
Mummichog (juvenile),
Fundulus heteroclitus
Mummichog (juvenile),
Fundulus heteroclitus
Mumnichog (juvenile),
Fundulus heteroclitus
Mummichog (juvenile),
Fundulus heteroclitus
Mummichog (larva),
Fundulus heteroclitus
Mummichog (larva),
Fundulus heteroclitus
Bioaasay Test Time LC50
Method* Cone.** Ihra) luq/l>
S U 96 50,000
S M 48 60,000
S M 48 43,000
S U 96 49,000
S U 96 22,000
S U 96 63,000
S U 96 73,000
S U 96 114,000
S U 96 92,000
S U 96 78,000
S U 96 29,000
S U 96 31,000
S U 96 30,000
S M 48 16,200
S M 48 9,000
Adjusted
LCS0
(uq/l> reference
27.335 Eisler, 1971
34,506 Middaugh & Dean, 1977
24,729 Middaugh 6. Dean, 1977
26,788 Eisler, 1971
12 027 Eisler & Henneky,
1977
34.442 Voyer, 1975
39,909 Voyer, 1975
62,323 Voyer. 1975
50,296 Voyer, 1975
42,642 Voyer, 1975
15,854 Voyer, 1975
16,948 Voyer, 1975
16,401 Voyer. 1975
9,317 Middaugh & Dean, 1977
5,176 Middaugh & Dean, 1977
-------
Table 8. (Continued)
Bioassay Test
Organism Method* Cone.
Muawiichog (larva), S M
Fundulus heteroclitua
Muamichog (larva), S M
Fundulua heteroclitua
Mumnichog (larva), S M
Fundulus heteroclitua
Muinnichog (larva), S M
Fundulus heteroclitua
Striped klllifish S U
(adult),
Fundulus ma jails
Atlantic silverside S M
(adult),
Menidia menidia
Atlantic silverside S M
(adult),
Menidia menidia
Atlantic silverside S M
(larva),
Menidia menidia
Atlantic silverside S M
(larva),
Miinidia menidia
Atlantic silverside S M
(larva),
Meni dia menidia
Atlantic silverside S M
(larva),
Menidia menidia
Atlantic silverside S M
(larva),
Menidia menidia
Adjusted
Tine LC50 LCSO
fhrs) lug/11 fug/ii
48 32,000 18,403
48 23,000 13,227
48 12,000 6,901
.48 7,800 4,486
96 21,000 11,480
48 12,000 6,901
48 13,000 7,476
48 3,800 2,185
48 3,200 1,840
48 3,400 1,955
48 2,200 1,265
48 1 ,.600 920
Keterei.ee
Middaugh & Dean, 1977
Middaugh & Dean, 1977
Middaugh & Dean, 1977
Middaugh & Dean, 1977
Eisler, 1971
Middaugh & Dean, 1977
Middaugh & Dean, 1977
Middaugh & Dean, 1977
Middaugh & Dean, 1977
Middaugh & Dean, 1977
Middaugh £> Dean, 1977
Middaugh & Dean, 1977
-------
Table 8. (Oontinued)
Bioassay Test
Organisa Method* Cone.**
Atlantic silverside S M
(larva),
Menldla menldla
* S = static
** U = unmeasured, M — measured
Geometric mean of adjusted values - 11,610 Mg/l
Tine
Ittfg)
48
Adjusted
LC50 LCdO
(uq/l| fug/it Keteret.cfe
5.600 3,221 Middaugh & Dean, 1977
11,010
3.7
3,000 Mg/1
-------
Table 9. Marine invertebrate acute values for cadmium
Organism
fiioassay Test Time
Metnou* Cor.c. ** tins)
Polychaete worm (adult), S
Capltella capitata
Polychaete worm (larva), S
Capltella capitata
Polychaete worn (adult), S
Neanthes arenaceodentata
Polychaete worn (juvenile),S
Neanthes arenaceodentata
Polychaete worn, S
Nereis virens
Polychaete worm, S
Nereis virena
Bay scallop (juvenile), S
ArRopecten irradians
American oyster (larva), S
Crassostrea virRinica
Soft shelled clam, S
Mya arenaria
Soft shelled clam, S
Mya arenaria
Mussel, S
Mytilus edulis
Mussel, S
Mycilus edulis planulatus
Mussel, FT
Stilus edulis planulatus
Mussel, FT
Mytilus edulis planulatus
Mud snail, S
Nassarius obsoletus
U
U
U
U
U
U
U
U
U
M
M
M
96
96
96
96
96
96
96
48
96
96
96
96
96
96
96
LC50
7,500
220
12,000
12,500
9,300
11,000
1,480
3,800
2,500
2,200
25,000
1,620
3,600
4,300
35,000
Adjusted
LCbO
Kctftence
6,353 Reish, et al. 1976
186 Reish, et al. 1976
10,164 Reish, et al. 1976
10,588 Reish, et al. 1976
7,877 Eisler & Henneky,
1977
9,317 Eisler. 1971
1,254 Nelson, et al. 1976
3,219 Calabrese, et al. 1973
2,118 Eisler & Henneky,
1977
1,863 Eisler, 1971
21,175 Eisler. 1971
1,782 Ahsanullah, 1976
3,600 Ahsunullah, 1976
4.300 Ahsanullah, 1976
29,645 Eisler & Henneky, 1977
-------
Table 9. (Continued)
Organism
Bioasaay Test Tine LC50
Method* cone.** (tira) lug/11
CO
I
OJ
vf>
Mud snail, S U
Nassarius obaoletua
Oyster drill, S U
Urosalpinx cinerea
Calanoid copepod, S U
Acartla tonsa
Calanoid copepod, S U
Acartia tonsa
Calanoid copepod, S U
Acartla tonsa
Calanoid copepod, S U
Acartia tonsa
Copepod, S U
Tigriopus laponlcua
Mysid shrimp, FT M
Mysidopsis bahla
Green crab, S U
Carcinus maenaa
Sand ahrimp, S U
Crangon septemspinoaa
Mud crab, S U
Eurvpanopus depreasua
American lobster (larva), S U
Homarus americanus
Hermit crab, S U
Pagurus longicarpus
Hermit crab, S U
Pagurus 1oneicarpus
Crass shrimp. S U
Palaemonetes vulgaris
96
96
96
96
96
96
72
96
96
96
72
96
96
96
96
10,500
6,600
90
337
220
122
4.400
15.5
4,100
320
4,900
78
320
1,300
420
Adjusted
LC50
tuq/ll Beterence
8,894 Eisler, 1971
5.590 Eisler. 1971
76 Sosnowski & Gentile,
1978
285 Sosnowski & Gentile,
1978
186 Sosnowski £> Gentile,
1978
103 Sosnowski & Gentile,
1978
2,273 D'Agostino 6t Finney,
1974
15.5 Nimmo, et al. 1977a
3,473 Eisler. 1971
271 Eisler, 1971
2,532 Collier, et al. 1973
66 Johnson & Gentile,
1978
271 Eisler. 1971
1,101 Eisler & Henneky,
1977
356 Eisler. 1971
-------
Table 9. (Continued)
Organism
Bioassay Test Time LCSO
Method* Cone.** Ifrrsl (ug/i|
Adjusted
1.C50
fuq/ll Reference
CO
I
O
Grass shrimp, FT M
Palaeroonetes vulgaris
Pink shrimp, FT M
Penaeus duoraruw
Fiddler crab, S U
Uca puRilator
Fiddler crab, S U
Uca puRilator
Fiddler crab, S U
Uca pugilator
Fiddler crab, S U
Uca puRilator
Fiddler crab, S U
Uca puRilator
Fiddler crab, S U
Uca puRilator
Starfish, S U
Asterias forbesi
Starfish, S U
Asterias forbesi
96
760
760
96 3,500 3,500
96 32,200 27,273
96 46,600 39,470
96 37,000 31,339
96 6,800 5,760
96 10,400
96
96
820
8,809
96 23,300 19,735
695
7,100 6.01A
Nimruo, et al. 1977b
Nimmo, et al. 1977b
O1 tiara, 1973
O'Hara, 1973
O'Hara, 1973
O'Hara. 1973
O'Hara, 1973
O'Hara. 1973
Eisler, 1971
Eisler & Henneky, 1977
* S = static. FT = flow-through
** U = unmeasured, M — measured
Geometric mean of adjusted values » 1,550 |ig/l = ^ vg/l
Lowest value from a flow-through test with measured concentrations = 15.5 i
-------
Table 10.Marine Invertebrate chronic values for cadmium (Nimmo, et al. 1977a)
Chronic
Limits Value
Organism Teat* (uq/1)
Mysld shrimp, LC 4.8-6.4 5.5
Mysldopsls bahla
* LC = life cycle or partial life cycle
Geometric mean of chronic values <= 5.5 Mg/l - 1.0 ug/1
Lowest chronic value - 5.5 Mg/1
-------
Table 11. Marine plant effects for cadmium (Gentile & Johnson, 1974)
Organiaa
Effect
Concentration
Alga.
Cyclotella nana
Alga.
Skeletonema costatum
96-hr EC-50
growth rate
96-hr EC-50
growth rate
160
175
Lowest plant value = 160 )ig/l
-------
Table 12, Marine residues for cadmium
ta
i
Organjaw
American oyster,
Crassostrea virginica
American oyster,
Crassostrea virginica
American oyster,
Crassostrea virginica
American oyster,
Crassostrea virginica
Soft shell clam,
Mya arenaria
Mussel,
Mytilus edulis
Quahaug,
Mercenaria mercenaria
Bay scallop,
Aquipecten irradiana
Mummichog,
Fundulus heteroclitua
Alga,
Prasinocladus tricornutum
Grass shrimp,
Palaemonetes pugio
Shrimp,
Crangon crangon
Pink shrimp,
Penaeus durorarum
Shore crab,
Carcinus maenas
Bioconcentration Factor
2,600
677
149
1,230
160
45*
109
168
48
670*
700
37*
57
120
Time
(days) neterence
280 Zaroogian & Cheer, 1976
40 Kerfoot & Jacobs, 1976
21 Eisler, et al. 1972
140 Shuster & Pringle, 1969
70 Pringle, et al. 1968
20 George & Coombs, 1977
40 Kerfoot & Jacobs, 1976
21 Eisler, et al. 1972
21 Eisler, et al. 1972
5 Kerfoot & Jacobs, 1976
21 Vernberg, et al. 1977
40 Dethlefsen, 1977
30 Nimmo, et al. 1977b
14 Wright, 1977
-------
Table 12. (Continued)
Maximum Permissible Tissue Concentration
Concentration
Organism Effect (mg/kg) Reference
Mallard, Testicular damage, 20 White, et al. In press
Anas 90 days
platyrhynchos
* Dry weight to wet weight conversion
Geometric mean bloconcentration factor for all species •> 144
20
Lowest residue concentration - 20 mg/kg " 0.14 mg/kg or 140 yg/1
-------
Table 13. Other marine data for cadmium
Organist
Grass shrimp,
Palaemonetes pugio
Test
Duration
(days)
14
Pink shrimp, 30
Penaeus duorarum
Fiddler crab (adult), 10
Uca pugilator
Fiddler crab (larva),
Uca puRilator
Hermit crab, 7
PaRurus longicarpus
Rock crab, 4
Cancer irroratus
Starfish, 7
Asterias forbeai
Sea urchin (embryo),
Acanthocidaris crassispina
Winter flounder, 8
Pseudopleuronectes
americanus
Winter flounder, 60
Pseudopleuronectes
amerlcanus
Spot (larva), 9
Leiostomus xanthurus
Striped bass (juvenile), 90
Morone saxatills
Striped bass (juvenile), 30
Morone saxatills
Juvenile mullet, 5
Aldrichetta forsteri
Result
Eifect (uq/1)
25% mortality 50
50% mortality 720
50% mortality 2,900
Respiratory and 1.0
activity
25% mortality 270
Enzyme activity 1,000
257. mortality 270
Effect on 1,600
fertilization
Viable hatch-50% 300
Increased gill tissue
respiration
Incipient LC50 200
Significant decrease 5
in enzyme activity
Significant decrease . 0.5-5.0
in oxygen consumption
50% mortality
14,300
Reference
Vemberg, et al. 1977
Nimroo, et al. 1977b
0'Hara, 1973
Vernberg, et al. 1974
Eisler & Henneky, 1977
Gould, et al. 1976
Eisler & Henneky, 1977
Kobayashi, 1971
Voyer, et al. 1977
Calabrese, et al. 1975
Middaugh, et al. 1975
Dawson, et al. 1977
Dawson, et al. 1977
Negilski, 1976
-------
Table 13 (cont. ) ')
Organism
CO
I
«T»
Test
Duration
(days)
Small mouth hardy head, 7
Atherinasoma microstoma
Cunner (adult), 60
Tautogolabrus adspersua
Cunner (adult), 30
Tautogolabrus adsperaus
Cunner (adult), 4
TautoRolabrus adspersua
Colonial hydroid,
Campanularia flexuosa
Colonial hydroid, 11
Campanularia flexuosa
Polychaete worm, 28
Capitella capitata
Polychaete worm,
Eudistylia vancouverl
Polychaete worm, 28
Neanthes arenaceodentata
Polychaete worm, 7
Neanthes vaall
Polychaete worm, 17
Ophryotrocha labronica
Cockle, 4
Cardium edule
Soft shell qlau. 7
Mya arenaria
Copepod , 3
Tifiriopus japonicus
Opossum shrimp, 17
Mysidopsis bghia
Ettect
50% mortality
37.5% mortality
Depressed gill tissue
oxygen consumption
Result
12,700
100
50
Decreased enzyme activity 3,000
Enzyme inhibition 40-75
Growth rate inhibition 110-280
50% mortality
Enzyme inhibition
50% mortality
50% mortality
50% mortality
50% mortality
50% mortality
700
300
3,000
6,400
1,000
2,000
700
Inhibition-egg development 40
50% mortality
11.3
Rfetorei.cfc
Negilski, 1976
Maclnnes, et al. 1976
Maclnnes, et al, 1976
Gould fii Karolus, 1974
Moore & Stebbing, 1976
Stebbing. 1976
Reish, et al. 1976
May & Brown, 1973
Reish, et al. 1976
Ahsanullah, 1976
Brown & Ahsanullah, 1971
Portmann & Wilson, 1971
Eisler & Henneky, 1977
D'Agostino & Finney, 1974
Nimmo, et al. 1977a
-------
Table 13 (cont.)
Organism
Amphipod,
Allorchestea compresaa
Isopod,
Idotaa baltica
Grass shrimp,
Palaeinonetes vulgaris
Test
Duration Et tect
5 50% mortality
5 50% mortality
29 50% mortality
Result
lug/1> ReteteiiCfc
200-400 Ahsanullah, 1976
10.000 Jones. 1975
120 Nioimo, et al. 1977b
-------
CADMIUM
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effects on physiology and behavior of the fiddler crab,
Uca pugilator. In Pollution and physiology of marine orga-
nisms. Academic Press, New York.
Vernberg, W.B., et al. 1977. Effects of sublethal concen-
trations of cadmium on adult Paleomonetes pugio under static
and flow-through conditions. Bull. Environ. Contam. Toxicol.
17: 16.
Voyer, R.A. 1975. Effect of dissolved oxygen concentration
on the acute toxicity of cadmium to the mummichog, Fundulus
heteroclitus. Trans. Am. Fish. Soc. 104: 129.
Voyer, R.A., et al. 1977. Viability of embryos of the
winter flounder Pseudopleuronectes americanus exposed to
combinations of cadmium and salinity at selected tempera-
tures. Mar. Biol. 44: 117.
Warnick, S.L., and H.L. Bell. 1969. The acute toxicity
of some heavy metals to different species of aquatic insects.
Jour. Water Pollut. Control Fed. 41: 280.
B-59
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White, D.M., et al. Histopathological effects of dietary
cadmium on kidneys and testis of mallard ducks. (In press).
Wright, D.A. 1977. The effect of salinity of cadmium uptake
by the tissues of the shore crab Carcinus maenas. Exp.
Biol. 67: 137.
Zaroogian, G.E., and S. Cheer. 1976. Cadmium accumulation
by the American oyster, Crassostrea virginica. Nature 261:
408.
B-60
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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 attention was primarily paid to further
cases of acute cadmium poisoning 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 definitive reports of chronic effects were those of
Friberg (Friberg, 1948a and 1948b) who clearly identified
emphysema and renal damage among male workers 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. Nonetheless, a significant
number of excellent general reviews have appeared in recent
years and serve as guides to the more significant papers
in the scientific literature (Friberg, et al. 1974; Flick,
et al. 1971; Kendrey and Roe, 1969; Nordberg, 1974; Fleischer,
C-l
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et al. 1974; Buell, 1975; Perry, et al. 1976; Fassett,
1975; Webb, 1975; U.S. EPA, 1975b, 1975a.)
EXPOSURE
The major non-occupational routes of human cadmium
exposure are through food and tobacco smoke. Data published
by the Food and Drug Administration (Compliance Program
» Vv'
Evaluation, 1974) based on market basket surveys over 7
years, show that the average cadmium intake of 15 to 20-
year-old males is 39 yug/day, which includes that found in
water. If this figure is adjusted by the recommended daily
calorie intake for various age groups, the average daily
cadmium intake from birth to age 50 is 33 jig/d for men and
26 /jg/d for women. More recent domestic data based on fecal
excretion give intake figures of 18 /ig/d and 21 /ig/d for
teen-age males residing in Dallas, Texas, (Kjellstrom, 1978c)
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.
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TABLE 1
Daily Cadmium Intake Via Food
Country
ug/day
Reference
United States
39
Compliance Program Evaluation 1974
Canada
52
Kirkpatrick and Coffin, 1977
West Germany
48
U.S. EPA, 1975b
Rumania
38-64
U.S. EPA, 1975b
Czechoslovakia
60
U.S. EPA, 1975b
Japan (unpolluted area)
59
U.S. EPA, 1975b
Sweden
17
Kjellstrom, 1978a
Australia
30-50
Miller, et al. 1976
New Zealand
21-27
Guthrie and Robinson, 1977
C-3
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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 cadmium content depends to a high
degree on the soil solution concentration of the element
(Pahren, et. al. 19*78). Municipal sewage sludges, containing
high levels of cadmium of industrial origin, applied to
agricultural lands as fertilizer are potentially important
sources of cadmium entry into the human food chain (Counc.
Agric. Sci. Tech. 1976). To date there have been no occur-
rences of cadmium toxicity in animals or man attributed
solely to direct consumption of vegetation grown on land
amended with municipal sludge (Garrigan, 1977). The wide-
spread usage of phosphate fertilizers, most of which contain
significant amounts of cadmium (U.S. EPA, 1975a), is potenti-
ally a more important source of cadmium entry into human
foodstuffs and will ultimately increase the amount of cadmium
in the diet.
Balanced diets generally contain approximately 0.05
mg/Kg of cadmium (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 water to the concentration in aquatic organisms.
Since BCF's are not available for the edible portions of
all four major groups of aquatic organisms consumed in the
United States, some have to be estimated. A recent survey
on fish and shellfish consumption in the United States (Cordle,
et al. 1978) found that the per capita consumption is 18,7
g/day. From the data on the 19 major species identified
in the survey, the relative consumption of the four major
groups can be calculated.
Benoit, et al. (1976) found a BCF of three for cadmium
in muscle of brook trout. All other tests with freshwater
and saltwater fish reported data for the whole body or for
non-edible tissues that accumulated more cadmium than muscle.
Since no data are available for saltwater fish, they will
be assumed to be comparable to freshwater fish. Many studies
have been conducted with saltwater molluscs (Zaroogian and
Cheer, 1976; Kerfoot and Jacobs, 1976? Eisler, et al. 1972;
Schuster and Pringle, 1969; Pringle, et al. 1968; and George
and Combs, 1977) with values ranging from 45 to 2,600.
A geometric mean was calculated to be 158. Eisler, et al.
(1972) found a BCF of 5 for lobster muscle after correcting
for lead in the muscle of the control organisms.
Group
Freshwater fishes
Consumption
(Percent)
Bioconcentration
factor
12
3
Saltwater fishes
61
3
Saltwater molluscs
9
158
Saltwater decapods
18
5
C-5
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Tobacco in all its forms contains appreciable amounts
of cadmium. Since the absorption of cadmium from the lung
is substantially greater than that from the gastrointestinal
tract, smoking contributes significantly to total body burdens.
American cigarettes (Menden, et al. 1972) have been found
to contain 1.5 to 2". 0 ^g per cigarette and about 70 percent
of this passes into the smoke (Nandi, et al. 1969). All
data agree that 0.1 to 0.2 pg cadmium are inhaled for each
cigarette smoked. Thus, smoking 20 cigarettes per day will
result in the inhalation of about 3 pg. It has been pointed
out that workers handling cadmium compounds may contaminate
their cigarette or pipe tobacco and further augment the
high metal load contributed by smoking (Piscator, 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 sum-
marized 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 2 - 370 and 0.4 - 26
ng per cubic meter, respectively. The data emphasize that
nearly all airborne cadmium is due to man's activities.
Highest concentrations are consistently found in industri-
alized cities and in the vicinity of smelting operations
(Fleischer, 1974). In areas where there are no such sources
of airborne cadmium pollution the levels observed have generally
been around 0.001 /ig/m^, which leads to an average inhaled
C-6
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amount of approximately 0.02 - 0.03 jug per day for adults.
In those cities with the highest levels of cadmium air pollu-
3
tion, i.e. up to approximately 400 ng/m , the maximum amount
inhaled could rise on extreme occasion to 8.0 ^jg 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 average daily intake. A survey of 969 U.S. community
water supply systems, representing 5 percent of the national
total, revealed an average cadmium concentration of 1.3
jug/1. Only three systems exceeded concentrations of 10
/ug/1. Of 2,595 distribution samples taken during this same
survey (McCabe, 1970) only four samples exceeded the 10
pg/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 pg/1 (Fleischer, 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 effectively removed by co-precipitation with
or adsorption on clays, hydrous manganese oxide, or phos-
phorites (Posselt, 1971). Based on the above community
water supply study and an average adult consumption rate
of 2 liters/d, drinking water sources probably contribute
not more than 3-4 jug/d to the total average cadmium intake.
C-7
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Very little is known concerning the absorption of cadmium
compounds 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 percent absorption occurred.
V«:'
Since these levels are higher by a factor of approximately
20 million than household waters used for washing or bathing
there seems to be virtually no risk of significant absorption
through the skin. However, it should be pointed out that
human studies have apparently not been done. Wastewater,
indirectly, may 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 propotion, i.e., approximately 5 percent, is
absorbed, the rest passing directly into the feces. Gastro-
intestinal 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. 1978). Cadmium inhibits
the jjn vitro uptake of calcium from the rat duodendum, but
calcium was not shown to have an inhibitory effect on the
in vitro uptake of cadmium (Hamilton and Smith, 1978).
-------
While confirming the jjn vitro inhibitory effect of cadmium
on intestinal calcium absorption it has been recently demons-
trated that the ^n 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 tp increased cadmium absorption (Worker
and Migicovsky, 1961). Low protein diets also lead to consi-
derably 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 adverse effects
(Banis, et al. 1969; Bunn and Matrone, 1966; and 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
absorption 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 cadmium absorption in 14
healthy subjects aged 21-61 years. A trivalent chromium
(CrCl3) marker, which is poorly absorbed from the gastro-
intestinal tract, was given along with 115mCd, assuming
that unabsorbed cadmium would have the same transit time
as chromium. The average body retention of radiocadmium
determined between 7 and 14 days after the disappearance
C-9
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of the chromium marker from the body was 4.6 percent with
a standard deviation of + 4 percent. Various animal experi-
ments 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 occupa-
tionally exposed persons. The fate of inhaled cadmium,
in common with other respirable pollutants, depends upon
particle size, solubility, and lung status. When a large
proportion of particles are in the respirable range and
the compound is relatively soluble, 25 percent of the inhaled
amount may be absorbed. Cadmium fume 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 (WHO Task
Group, 1977; Elinder, 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
following 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 administration the red cell
content becomes many times greater than the plasma. Further
distribution within the body is dependent on the elapsed
time since absorption (U.S. EPA, 1975b).
C-10
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Irrespective of the route of entry, cadmium is princi-
pally 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 pathologic 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-binding protein, metallo-
thionein (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 speculation 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 reproducible. In addition,
glucose -6- phosphatase dehydrogenase may be activated by
cadmium (Cadmium Research Digest, 1977). Confirmation of
these findings, while of great scientific interest, would
not lessen 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 bio-
C-ll
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accumulate. Elinder and Kjellstrom (1977) have compared
renal cadmium levels in specimens taken in recent autopsies
(57 yug/gm dry weight) with specimens collected in the last
century (15 pg/gtn 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 minimal levels at birth
( < 1 ug), (Henke, et al. 1970) to an average of up to 30-
40 mg by the age of 50 in non-occupationally exposed indi-
viduals (Friberg, et al. 1974). About 75 percent of this
accumulation 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 continues 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 concentrations of cadmium
while the brain and bone acquire only very small quantities
(Nordberg, 1974). Age appears to have significant effects
on how cadmium distributes after absorption. Using ~ CdClj
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 accumu-
lation in the liver. Smokers have an appreciably greater
C-12
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body burden of cadmium than non-smokers. The average con-
centration in the renal cortex is approximately doubled
in smokers (Elinder, et al. 1976; Hammer, et al. 1973).
It is of interest that in Japan where the average diet 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, 1978). In environmentally exposed children,
urinary cadmium levels were a more sensitive indicator of
exposure than blood cadmium (Roels, et al. 1978).
In non-occupationally exposed persons the mean level
of cadmium in the blood is usually less than 1 ^pg/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 jug/100 ml (Smith, et al. 1976). Smokers
are reported as having blood cadmium levels 50 percent greater
than non-smokers (Einbrodt, et al. 1976).
Several reports indicate that urinary excretion of
cadmium is approximately 1-2 /jg/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
C-13
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occur due to cadmium accumulation, the rate of urinary cadmium
excretion will further increase, which in turn results in
a considerable decrease in renal cadmium levels, even though
irreversible tubular damage has already occurred (Kjellstrom,
1976). It should be mentioned that renal levels fall after
age 50 even in "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 anticipated from the previously discussed absorp-
tion data. Smokers have a slightly increased fecal excretion
rate averaging 3.2 jag/d (Kjellstrom, et al. 1978a). It
is unknown as to how much fecal cadmium may be derived from
intestinal epithelium or biliary excretion. Saliva contains
up to 0.1 /jg/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 gastrointestinal
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 cadmium 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 pg/g (Friberg, 1974). In rats, continued exposure
to cadmium in drinking water leads to initially high hair
levels, which decline dramatically with continued adminis-
tration; and it has been concluded that hair cadmium would
not be useful in estimating either concentrations in vital
C-14
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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 correlations
have been reported between environmental levels (Hammer,
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 cadmium.
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 number 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 exposure (Lauwerys, et
al. 1976). Direct comparison of urinary excretion levels
and estimated body burden have also been performed using
C-15
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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 burdens cannot be ascertained
for the living subject and are assumed to be the same as
averages derived from autopsy studies.
Only two human studies using radioisotopes are available.
Rahola (Rahola, et al. 1973) stated it was not possible
to accurately determine a biologic half-time, but provided
a shortest estimate of 130 d and a longest of infinity.
In a single human subject for whom the figure could be calculated
the biologic half-time was 100 d (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 vs. decades). Since this
is a critical issue in terms of maximum daily limits for
standard-setting purposes, 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.
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In summary, from the exposure, intake, absorption,
and excretion 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 decline are unknown.
It is unrelated to the presence or absence of renal disease,
but may be due to the lessened intake of food as caloric
needs also decline in later life. It has also been suggested
that the observed decrease may be an artifact related to
the possibility that older persons may have been exposed
to far lower cadmium levels during their youth (Hammer,
et al. 1973).
C-17
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EFFECTS
Acute Effects
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 hydrochloric acid into cadmium
chloride which has an inflammatory action on the mucus mem-
branes of the stomach and intestine (Browning, 1969). Oral
administration of cadmium produces emesis at a concentration
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 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. 250 mg/Kg has
been given as the lowest oral dose producing death in rats
using cadmium fluroborate. The LE>5o for guinea pigs given
cadmium fluoride is reported to be 150 mg/Kg (Toxic Substances
List, 1974). More complete acute toxicity data is given
in EPA-560/3-75-005 (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 responsible for numerous outbreaks of acute poisoning
in the past. Some 689 cases of cadmium poisoning were reported
C-18
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within the 5-year period 1941-1946 (Fairhall, 1957) and
doubtless numerous other undiagnosed and unreported cases
also occurred. Largely as a result of these outbreaks various
sanitary codes and national standards have been amended
to prohibit the use of cadmium in any article used for food
or drink preparation or storage. The most significant clinical
feature of acute cadrtium poisoning is the rapidity 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 salivation, 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, et al. 1974).
Because numerous cases of acute industrial poisoning
from cadmium 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, 1963a).
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
C-19
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(Health, et al. 1968), permanently impaired lung function
(Townshend, 1968) and disturbed liver function (Blejer,
et al. 1971). Barrett and Card (1947) estimated that the
lethal dose for a man doing light work would not exceed
2,900 min. mg/m . From these figures it may be estimated
that a lethal exposure to cadmium fume may result from breathing
a concentration of approximately 5 mg/m^ over an 8-hour
period. In Blejer's fatal case it was thought that the
3
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). Phil and Parkes (1977) noted elevated
cadmium and lead levels in the hair of children with learning
disability.
Chronic Effects
A host of chronic effects attributed to cadmium exposure
have been reported by numerous investigators over the past
three decades. 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 (1948, 1950) was the first to note emphysema
in his now classic studies of workmen exposed to cadmium
iron oxide dust in a Swedish alkaline battery factory.
Since then numerous investigators have confirmed and expanded
upon these initial findings (Paterson, 1947; Baader, 1952;
Lane and Campbell, 1954; Buxton, 1956; Smith, et al. 1960;
C-20
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Kazantzis, et al. 1963a; Potts, 1965; Holden, 1965; Lewis,
et al. 1969; Snider, et al. 1973; Lauwerys, et al. 1974;
and Smith, et al. 1976).
A possible mechanism for cadmium emphysema has been
suggested by Chowdhury and Lauria (1976) who noted that
the addition of cadmium to human plasma caused an inhibition
of alpha-l-antitrypsin with a decrease in trypsin inhibitory
capacity. Other metals had little or no effect at equimolar
concentrations. Persons with congenital alpha-l-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 contradicting animal data it seems apparent that cadmium
induced emphysema is related only to the inhalation route
of exposure. Apparently no studies have been done relating
the incidence of emphysema in the general population to
varying ambient levels of airborne 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 molecular weight (20,000-25,000) protein
in the urine (Bj-microglobulin). 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
C- 21
-------
(Browning, 1969). First reported in 1948 by Friberg in
workers exposed to cadmium oxide dust, Bj-microglobulin
has subsequently been reported in the urine of workers exposed
to other forms of cadmium and in the urine of animals experi-
mentally exposed. As cadmium accumulates in the kidney
it inhibits tubular. reabsorption resulting in proteinuria
(Berggard and Beam, 1968). Other signs of renal tubular
dysfunction resulting from cadmium exposure are glycosuria,
aminoaciduria, and changes in the metabolism of calcium
and phosphorus (Kazantzis, 1963a). The dysfunction rarely
progresses 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 disease patients where increased excretion is strongly
correlated to residence time in exposed areas and the use
of cadmium contaminated river water (Kjellstrom, et al.
1977a). Tsuchiya, et al. (1978) has found that B2~micro-
globulin excretion is highly correlated with aging in both
high and low cadmium exposure population groups. Kjellstrom,
et al. (1977a,b,c) has attempted to determine a dose response
between Bj-microglobulin excretion and cadmium in air (estimated
concentration 50 jug/m3). He determined the geometric average
Bj-microglobulin concentration to be 84 pq/1 in normal unexposed
persons with 95 percent confidence limits of 24-290 jjg/1.
Using the upper 95 percent limit he found an elevated excretion
prevalence of 19 percent for workers with 6-12 years exposure.
C-22
-------
Smokers were also noted to have about 2 to 3 times the prevalence
of elevated excretion found for non-smokers. 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 (1977a) is careful to point out that elevated
chronic excretion of Bj-microglobulin does not equate with
clinically significant proteinuria and that its definition
was 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 pro-
teinuria for many years without serious impairment of glo-
merular filtration. 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. It would seem reasonable to conclude that
in the vast majority of cases mild or moderate excretion
of B2"microglobulin is a relatively benign condition. On
occasion the renal lesion may be severe enough to produce
osteomalacia and multiple fractures as in Itai-itai disease.
However, in all such cases (Friberg, 1974; Nicaud, et al.
1942; Adams, et al. 1969) there appear to have been multiple
dietary deficiencies (calcium, protein, Vitamin C, vitamin
D) in addition to an excessive cadmium exposure. For example,
Itai-itai disease occurs almost exclusively in grand multiparous
C-23
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women over the age of 50 who live predominantly on a rice
diet with a high (600 jug/d) cadmium content. The Japanese
government has monitored for new cases of Itai-itai disease
since 1969. Since then no new patients with the disease
have been found, although the frequency 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
secondary to the renal defect it has been shown in animals
that cadmium may directly cause osteoporotic bone changes
(Yoshiki, et al. 1975). Such evidence implies that certain
segments of the population 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, 1977; Friberg, et
al. 1974; Nordberg, 1976). The 28 human cases used to support
this figure show an extremely large variation in concentration.
Nomiyama (1977a) points out that this figure should be determined
from data in cases where proteinuria was the only finding,
i.e. exclude 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
C-24
-------
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. 1977b).
Kjellstrom (1977b,c) 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
Bj-microglobulin excretion for a given daily cadmium intake,
is expected to approximate the following sequence: 0.1
percent-32 jug Cd/d; 1.0 percent-60 jug Cd/d; 2.5 percent-
80 jug Cd/d; 5.0 percent-100 jug Cd/d; 10 percent-148 pg
Cd/d; and 50 percent-440 /jg Cd/d. These estimates are
for non-smokers. Smoking will reduce the above allowable
intake from food by approximately 25 fig/d for each package
of cigarettes smoked. Water consumption will reduce the
allowance for food on a ug for ug basis assuming equilivent
gastrointestinal 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.
C- 25
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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 essential hypertension. Three major lines
of evidence have been set forth to support this thesis:
(1) in some animal experiments cadmium has induced hyper-
tension; (2) hypertension is positively correlated with
the ingestion of soft drinking waters, which often contain
higher concentrations of heavy metals than hard waters;
and (3) that 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 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 resistant 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 appreciated,
or have tended to ignore this factor. Much careful work
now tends to indicate that the association between hyper-
C-26
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tension 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 between 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 minimize 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, epidemiologic studies
of industrially exposed persons have failed to support the
concept that cadmium is a significant factor in human hyper-
tension (Friberg, et al. 1974; Holden, 1969). In addition,
Japanese patients with Itai-itai disease do not have hyper-
tension (Perry, 1972; Nogawa and Kawana, 1969).
Besides the effects previously discussed, chronic ex-
posure 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 individually are
C-27
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of lesser importance to human health, but collectively re-
present possibly an important gap in the knowledge of con-
cerning cadmium toxicity. A brief discussion of several
of the more significant of these adverse effects follows.
Friberg (1950) noted abnormal liver function tests
in his classic study first documenting emphysema and kidney
>v'
damage. Blejer (1971) also found such changes in cases
of acute overwhelming exposure. Other authors have commented
upon the rarity of such findings (Bonnell, 1965; Kazantzis,
et al. 1963a).
Renal stones have been reported for both Swedish and
British workers (Ahlmark, et al. 1961; Adams, et al. 1969).
These have occurred in both proteinuric and non-proteinuric
workmen. Since renal stones are a common problem more definitive
industry wide studies are needed to determine the true pre-
valence 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 (Cotter and Cotter, 1951), dental caries (Hardy
and Skinner, 1947), and non-specific 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
C-28
-------
pseudorabies virus, 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.
Compounds Antagonistic to Cadmium
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 biologic systems
and appears to be in many instances due to competition with
other metallic elements 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. 1969a; and Ferm and Carpenter, 1967).
It reportedly reduces cadmium's ability to induce tumors
(Gunn, et al. 1963, 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 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; Pox 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.
C-29
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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 component 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 consequence
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
effect of cadmium on the renal synthesis of 1,25-dihydroxy
cholecalciferol, which is the active form of Vitamin D^.
This inhibition has been demonstrated i_n vitro (Feldman
and Cousins, 1973).
Rats which have been pre-treated with cadmium show
decreased intestinal absorption of calcium and markedly
increased fecal calcium excretion. These animals also demonstrate
a 30 percent decrease in calcium incorporation in bone and
the investigators suggest these effects are important in
the etiology of Itai-itai disease (Ando, et al. 1977; Kobayashi,
1970).
The effects of protein in reducing cadmium toxicity
have previously been mentioned. It has been suggested that
the protective effects are actually due to increased avail-
ability of zinc and/or iron (Fox, et al. 1973).
C-30
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Cadmium itself will induce tolerance if given by small
repetitive injections (Nordberg, 1971). This effect is
postulated to be due to the stimulation or induction of
a protective protein, metallothionein. Probst, et al.
(1977) have demonstrated that hepatic metallothionein con-
centrations increase in proportion to the cadmium pretreatment
dose and found a positive correlation between dose related
increases in hepatic metallothionein and cadmium LD^q 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 cations, 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 cadmium
as metallothionein. The inactivity of cadmium-metallothionein
complexes in reducing SH enzyme activity and 1,25-dihydro-
xycholecalciferol 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 necrosis (Gunn, et al. 1968).
The synthesis of metallothionein-like proteins can be induced
by at least two essential elements, i.e. zinc and copper,
and the protein may have a fundamental role in the metabolism
of these elements. The induction by cadmium and mercury
C-31
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may therefore simply be a fortunate circumstance occasioned
by chemical similarities (Webb, 1972a). Beryllium, manganese,
barium, strontium, tin, arsenic, selenium, chromium, and
nickel administration 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, 1976).
Selenium is yet another protective element which is
able to prevent lethal cadmium effects or the induction
of testicular damage in rodents (Gunn, et al. 1968b; Parizek,
et al. 1969a). Conversely, cadmium is able to reverse both
the lethal and the growth retardation 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-
phosphatase), 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 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
C- 32
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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
v*"' *
and nutrients suggests strongly that certain sectors of
the public will in all likelihood be at greater risk from
cadmium than the community 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. Studies
of these and other sensitive groups is only now beginning.
Reproductive Effects and 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 sub-
cutaneously results in testicular hemorrhage and complete
testicular necrosis. Subsequently, a similar effect was
noted in rabbits, hamsters, guinea pigs and mice. (Parizek,
1957? Meek, 1959). This effect is mediated by selective
damage to the internal spermatic artery and pampiniform
venous plexus rather than by a direct effect on testicular
tissue (Gunn, et al. 1963b). This renders the animal permanently
C-33
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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 regenerates 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 controls, but the
seminal vesicles and other accessory sex organs decrease
in size implying a decreased secretory capacity of testosterone
from the damaged Leydig cells (Nordberg, 1975b). This effect
is prevented by the simultaneous administration of zinc
with cadmium (Gunn, et al. 1963). 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 variety 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 observed 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 exposure and death (Beton,
C-34
-------
et al. 1966; Blejer, 1971; Smith, et al. 1960).
Somewhat analogous effects have been observed in female
rodents. Cadmium damages the ovaries of non-ovulating rats
in persistent estrus and in prepubertal females (Parizek,
et al. 1968b; 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 non-gravid 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 pulmonary thrombosis are prominent
findings. No similar changes were seen in non-pregnant
or immediately post-partum animals (Parizek, 1965).
In the pregnant rat cadmium results in a complete des-
truction of the fetal portions of the placenta and death
of the fetuses (Parizek, 1964). In mice, of differing strains,
embryos and fetuses show a wide range of sensitivity to
cadmium induced embryotoxicity 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 placenta and it is unknown
whether higher species would be affected in a similar manner.
C-35
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Schroeder and Mitchener (1971) have carried out three
generation rodent studies with a number of trace elements.
Cadmium in drinking water (10 ppm) resulted in "loss of
the strain." In the generation 39 young deaths occurred
and 25 runts were noted compared with none in the controls.
In the F2 there were two dead litters, 48 young deaths,
v«-'
three failures to breed and nine runts. Again, both runting
and young deaths were statistically significantly increased.
A congenital abnormality, sharp angulation of the distal
third of the tail was seen in 16.1 percent of live offspring.
Because of breeding failures the experiment was terminated
after the Fj generation. In contrast, Suter (1975) found
no detectable 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 reproductive effects in rats
supplied with drinking water containing 0.1 mg/1 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-36
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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 meso-
dermal deficiency rather than to delays in shelf transportation.
Selenium has been shown to have a markedly protective effect
against cadmium teratogensis 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 indicating a specific retardation
and not merely a reflection of differential organ growth
rates and overall growth retardation. A single intravenous
dose of 1.25 mg cadmium/Kg body weight given between the
8th and 15th days of gestation produces more than 90 percent
fetal deformities in rats (Samarawickrama and Webb, 1978).
The commonest 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
C-37
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TABLE 2
Experiments in Tissue Culture Systems Using Cadmium
Authors
Cell Culture
Observations
Zasukhina, et al.
(1975)
Rohr and Bauchinger
(1976)
Casto, et al.
(1976)
Shiraishi, et al.
(1972)
Paton and Allison
(1972)
Rat embryo
Chinese hamster
fibroblasts
Hamster embryo
Human leukocytes
Human leukocytes
and fibroblasts
+ 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-38
-------
it has been postulated that this may modify normal cell
development and serve as a possible basis for teratogenic
effects (Enger, 1976). The possibility of human teratogeni-
city 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 credence can be placed on this report.
Mutagenicity
In the past decade cadmium has been studied in a variety
of ^_n vitro and i_n vivo test systems with somewhat conflicting
results. Sunderman (1978) has recently reviewed in vitro
experiments that may be relevant to metal carcinogenesis.
The Environmental Protection 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 summarized in Table 2. The majority of these studies
suggest a cadmium effect. In addition, several vitro
studies in biochemical systems have now been reported.
Sirover and Loeb (1976) have studied 31 metal compounds
in vitro using a system designed to detect infidelity of
DNA synthesis. Both cadmium acetate and cadmium chloride
demonstrated decreased fidelity, i.e. increased error fre-
quency. Decreased fidelity of DNA synthesis in vitro has
C-39
-------
also been reported by Hoffman and Niyogi (1977) for cadmium,
lead, cobalt, copper, and manganese. These investigators
also found that these metals stimulated chain initiation
of RNA synthesis at concentrations that inhibited overall
RNA synthesis. Murray and Flessel (1976) have reported
that in vitro addition of cadmium and manganese ions to
solutions of synthetic polynucleotides caused pairing of
noncomplementary nucleotides and have emphasized that direct
metal-nucleic acid interactions 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 DNA replicative activity. In their assay the uptake
3
into mouse testicular 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
3
.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 in-
hibitory 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 three-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 3). McCann, et al. (1975) have reported that three
of four metal carcinogens tested in the standard Ames test
C-40
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TABLE 3
Mutagenesis Studies of Microbial Systems Using Cadmium
Author
Organism
Result
Nishioka
(1975)
Takahoshi
(1972)
Sunderman
(1978)
B. subtilis
S. cerevisiae
S. typhimurium
Weak response (CdCl-)
Cd(N03)2
Reported in CAG
Assessment
Two independent
investigators reported
to Sunderman
C-41
-------
have been negative. They do not name these metals, but
suggest that the system is not favorable for bacterial absorption
of metals because of the large amount of Mg salts, citrate,
and phosphate in the minimal medium.
A fairly large number of studies now exist which have
examined a variety of mammalian cells for cytogenetic abnormal-
ities following exposure of the intact animal or man to
cadmium (Table 4). "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 commonly process relatively
crude materials exposure to other metals such as chromium,
arsenic, nickel, etc. cannot be eliminated as possible contri-
butors to the observed effects. Synergistic effects between
metals may also confuse the results from such studies.
Table 5 lists several studies dealing with point mutation.
Drosophilia studies have been negative to date (Table 5)
as have dominant lethal tests in mice (Table 4).
Although some of the above cited studies demonstrate
mutagenic activity, at this point in time the relationship
between a substance's mutagenic activity in lower forms
and its potential as a human carcinogen is still not clear.
Correlations between mutagenicity 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.
C-42
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Carcinogenesis
This particular aspect of cadmium toxicology has received
a number of recent reviews (IARC Monographs, 1973, 1976?
U.S. EPA, 1977; NIOSH, 1976; Sunderman, 1977, 1978; and
Hernberg, 1977).
Injection Studies
Animal studies have amply shown that the injection
of cadmium metal or salts causes malignancies (sarcoma)
at the site of injection and testicular tumors (Leydig cell
interstitial cell). These studies are summarized in Table
6.
Injection site sarcomas arise from either subcutaneous
or intramuscular administration. In comparison with other
similar sarcomas in rodents they appear to be well differentia
(Heath, 1962), but give rise to distant metastases and may
be permanently transplanted (Heath and Webb, 1967). There
is now general agreement that studies demonstrating the
production of sarcomas in rodents at thte 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 perhaps
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
C-43
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TABLE k
Chromosome Mutation Studies on Mammalian Cells Exposed In Vivo
Author
Cells
Result and Comment
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)
Epstein,
et al. (1972)
Leonard,
et al. (1975)
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 Fj translocation test
Mouse dominant lethal
Bovine leucocytes
+ 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. Chromatid breaks
exchanges.
+ Mixed metal exposure.
(including Cd)
Swedish battery workers
- Itai-Itai patients
No translocations.
Heavy mixed metal exposure
(Cadmium 50 control levels)
Exposure fatai to 6 of 15
animals.
Deknudt,
et al. (1973)
Suter
(1975)
Human leucocytes
Dominant lethal
test in female mice
+ Mixed metal exposure
(including Cd)
Actual increase in living
implants. No increase in
dead implants.
C-44
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TABLE 5
Point Mutation Studies with Cadmium
Author Organism Result
Shabalina Drosophilia
(1968)
Friberg, et al. Drosophilia
(1974)
Takahashi Saccharomyces + Reported in
(1975) CAG Assessment
C-45
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TABLE 6
Animal Tumorogenesis Induced by Cadmium Injection
Authors
Species
Compound
Route
Tumor and Incidence
Haddow,
et al. 1961
Heath,
1962
Heath and
Daniel, 1964
Kazantzis,
1963b
Kazantzis and
Hanbury, 1966
Haddow,
et al. 1964
Roe, et al.
1964
Gunn, et al.
1963
Gunn, et al.
1964
Gunn, et al.
1967
Knorre, 1970
Knorre, 1971
Rats
Rats
Rats
Rats
Rats
Rats
Rats
Rats
Mice
Rats
Rats
Rats
Rats
Rats
Rats
Cd containing
ferritin
Cd powder
Cd powder
CdS
CdS
CdO
CdSO.
CdSO,
CdCL
CdCl.
CdCL
CdCL
CdCL
CdCL
CdCL
S.C.
I.M.
I.M.
S.C.
S.C.
S.C.
S.C.
S.C.
S.C.
S.C.
S.C.
S.C.
S.C.
S.C.
S.C.
Sarcomas (35%)
Interstitial cell tumors
Sarcomas (75%)
Sarcomas (90% and 75%)
Sarcomas (60%)
Sarcomas (60%)
Sarcomas (80%)
Sarcomas (70%)
Interstitial cell
tumors (55%)
Interstitial cell
tumors (77%)
Interstitial cell
tumors (68%)
Sarcfcmas (41%)
Interstitial cell
tumors (86%)
Sarcomas (10%)
Sacromas (13%)
Interstitial cell
tumors (40%)
C-46
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Lucis, et al. Rats
1972
Reddy, et al. Rats
1973
Furst and Rats
Cassetta, 1972
Favino, et al. Rats
1968
Malcolm, 1972 Rats
CdCl2 S.C.
CdCl2 S.C.
Cd powder I.M.
CdCl2 S.C.
CdCl2 S.C.
Interstitial cell
tumors (87%)
Sarcomas (13%)
Interstitial cell
tumors (80%)
Sarcomas (54%)
Interstitial cell
tumors (100%)
Sarcomas (?)
Interstitial cell
tumors (?)
C-47
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producing this effect in rodents, supra vide. Interstitial
tumors do not differ morphologically 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 steroidogenic characteristics. These tumors
are androgenically functional (Gunn, et al. 1965; Favino,
et al. 1968), although producing less testosterone than
normal. The malignant potential of interstitial cell tumors
is problematical: "The dividing line between hyperplasia
and neoplasia is as indefinite as the rats studied and an
even greater problem and one of vital concern in prognosis,
is the distinction between benign and malignant tumors.
At present, problably the only reliable criterion of malignancy
is the presence of metastases" (Roe, et al. 1964). Cadmium
induced interstitial tumors have never been reported to
metastasize. The spontaneous development of interstitial
cell tumors in rats varies considerably 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
C-48
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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 protective against the formation of either sarcoma and/or
interstitial cell tumor development (Gunn, et al. 1963b,
1964). However, zinc powder given intramuscularly fails
to prevent formation when the inducing agent is cadmium
powder (Furst and Cassetta, 1972).
Other Animal Studies
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
studies in Swiss mice. The animals were supplied with drinking
water containing 5 ppm of cadmium acetate. Both males and
females experienced some shortening of life span in comparison
with the controls. The exposed animals had fewer tumors
than the controls. Using rats at the same dosage they sub-
sequently 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
C-49
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at 18 months. Similar experiments 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 termin-
ated at 8 months because of appreciable stunting. Two animals
from each of the other groups were sacrificed quarterly
up to 1 year. There were no differences in body weight
between control animals and those 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 cadmium (as cadmium chloride) for 4 years. Aside from
a splenic nodule 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 treated in the following ways 136 rats surviving
the acute (800-1,000 min. mg/m^); 100 rats surviving
one-half the LD^q; and 200 rats exposed to approximately
one-quarter the LD5Q 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.
C-50
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Malcolm (1972) gave rats up to 0.2 mg of cadmium sulphate
subcutaneously 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 described oral
intake and inhalation studies have been termed inadequate
(IARC, 1976), apparently on the basis of the relatively
small doses employed. Schroeder's work was speci-
fically designed to simulate human exposure and for the
most part the doses given seem realistic. Obviously, the
doses were well below the maximum tolerable doses usually
used today in attempting to establish the carcinogenic potential
of various substances. Nonetheless, there seems to be a
rather large volume of negative animal data.
Other Pertinent Studies
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 inhibition of tumor growth was seen
in those mice receiving cadmium. At 3 and 30 ppm dose levels,
no inhibition of body weight accompanied tumor growth reduction,
whereas at 300 ppm, there was a small inhibition of body
weight gain. Cadmium exposed animals demonstrated signifi-
cantly higher levels of cell mediated tumor cytotoxicity
than controls. No data on the effects of cadmium upon the
growth of non-viral-induced tumors has yet appeared.
C-51
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Carcinogenesis in Man
Potts (1965) was the first to draw attention to the
possibility 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. While 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 tumor sites follow (Table 7):
TABLE 7
Adopted from Potts (1965)
Age Years of Exposure Cause of Death
75 14 Carcinoma of prostate
65 37 Carcinoma of prostate
53 35 Carcinoma of bronchus
65 38 Carcinoma of prostate
59 24 Carcinomatosis
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- 52
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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 ascertained. The twelve include the eight
reported by Potts. They computed the expected number of
cases by site which would have occured by chance and compared
it against the obsSived. Their table follows (Table 8):
TABLE 8
From Kipling and Waterhouse (1967)
Site of Cancer Expected Observed Probability of Occurrence
All sites 13.13 12 0.660
Bronchus bAO 5 0.^9
Bladder 0.51 1 0.398
Prostate 0.58 k 0.003
Testis 0.11 0 0.898
From the above it is obvious that for cancers at sites
other than the four listed a total of 7.53 were expected
(13.13-5.60), but that 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. 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 percentage of cancer deaths due to
prostate cancer for these two age groups is 7.6 and 19.3
C-53
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percent respectively. Slightly over 2 percent 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 (Natl. Cancer Inst. 1977). Thus, the expected
figure of Kipling and Waterhouse seems about half of that
anticipated based on England's national prostate cancer
statistics. It is of considerable interest that the rates
for cancer of the 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 lowest yet repor-
ted (Kjellstrom, et al. 1978a).
Holden (1969) in a letter to the editor mentions two
cancer deaths in cadmium workers (prostate, bronchus).
He gives no denominator 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
mortality 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 between the observed number of deaths
C-54
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and that expected based on age and calender-time, cause-
specific mortality rates for the total U.S. white male population.
There was a slight deficit of total deaths, i.e. 92 observed
vs. 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 significant at the p
-------
cancer. Certainly the idea that prostatic cancer in man
is somehow related to cadmium cannot be entirely discounted
without careful industry wide studies. However, the prostate
is an unusual site for an occupational cancer and other
chemicals have not been suspected of causing cancer in this
organ.
While of questionable relevance to the human prostate
cancer question, Levy's (1973, 1975) specifically designed
long term rodent studies failed to detect evidence of prostate
neoplasi a.
Humperdinck (1968) followed up eight cases of chronic
poisoning 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 relation between
cadmium exposure and cancer.
McMichael, et al. (1976) studied the mortality of workers
from four rubber producing plants. The SMR was 94 for the
full cohort. The standard mortality rates for all cancer
sites was not elevated, but at some specific sites an increase
was noted: stomach, 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, and the relationship of these tumors to
cadmium is highly problematical.
C-56
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Kolonel (1972, 1976) has suggested that there may be
an association between cadmium and renal cancer. He examined
the incidence of cancer at several sites for persons with
an inferred occupational history of cadmium exposure and
in a control population. Cadmium exposure was based solely
on job classification information provided 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
four-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, non-smoking, 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 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 suggest that cadmium can be definitely implicated as
a human carcinogen.
C-57
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CRITERION FORMULATION
Existing Guidelines 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 presented in Table 9.
TABLE 9
CADMIUM
Regulatory Standards, Limits, or Criteria for
Human Health Protection
Media
Establishing
Air(Inhalation)
Water(Ingestion)
Food (Ingestion)
Enti ty
OSHA (1974)
NIOSH (1977)
EPA (1975)
FDA (1978)
WHO (1971)
ACGHI (1977)
MEG/EPC (1977
NAS/NAE (1972)
USSR
(suggested)XJ'
CANADA (1968)
OHIO
100 pg/m (1)
40 jug/m
50 pg/m -
0.12 pg/m
10 /jg/ml
10 jug/ml
WH1-1.9 /ig/l(3)
WH2-0.7 jig/l(4)
10 pq/1
1/jg/l
10 /ig/1
5 jug/1 (streams)
0.5
g/ml
(2)
1. For cadmium fume. Limit for cadmium dust is 200 ug/m3
2. Based on ceramic pottery and enamelware leaching solution test
3,4. EPC (estimated permissible concentration) WHl 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 there-
fore permissible in the volume of water comsumed per day; WH2 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
5. Krasovskii, G.N., et al. 1976
6. Lykins, B.W.,Jr., and J.M. Smith, 1976
-------
Current Levels of Exposure
Section 1 of this document deals with general environmental
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 concerning these effects are presently scant. Such
a risk is obviously 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.
C- 59
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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 Criterion
There is no doubt that cadmium is a teratogen in several
rodent 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 report, 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 Leonard, 1975). Studies of mutagenic
activity in non-mammalian life forms have given inconsistent
results.
C-60
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There is no question that the injection of cadmium
into rodents results in injection-site sarcomas and interstitial
cell tumors of the testis. Sarcoma production in rats is
a common sequela to the injection of irritants and could
be regarded as a non-specific 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 evidence 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 conjectural, 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 1/100's-2/200•s
of cadmium exposure level. Kolonel's (1972, 1976) work
confirmed neither of these sites, but suggested an association
with renal cancer. This work is inadequate in that it assumes
an exposure to cadmium based upon an occupational 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 cadium. 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 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
C-61
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is not persuasive when the existing 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 human carcinogen for purposes of calculating a water
quality criterion. 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 Carcinogen Assessment Group has
reviewed cadmium and their summary is included 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 conclude 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 ug/g wet weight of renal cortex. Autopsy studies indicate
that at present the average kidney concentration in non-smokers
is approximately one-twelfth this level. In smokers the
concentration is about twice as high, i.e. 30-39 ug/g.
C-fi7
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Friberg (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, non-occupationally exposed
American probably does not have an intake from all sources
exceeding 25-50 ug 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
C-62a
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recommended by toxicologists it should provide a margin
of "safety" to the general public for the foreseeable future.
NIOSH (1976) recommends that workers should not be
exposed to airborne cadmium at a concentration greater than
3
40 pg/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 adverse
3
effects at levels of 31 and 16-29 jjg/m (Lauwerys, et al. 1974;
Tsuchya, 1976). Effects of renal function (proteinuria)
and a reduction in mean pulmonary function have been noted
at levels of 66 pg/m although some of these workers probably
had experienced exposure, at least intermittently to cadmium
fume at higher, but unknown concentrations. The limit of
3
40 jug/m offers a greater, and "probably sufficient margin
3
of safety" in comparison with the 50 jug/m recommended by
ACGIH (1977) and Lauwerys, et al. (1974).
From the figure 40 jUg/m^ it can be calculated that
a worker might absorb about a 1000 jug during a work week,
3 3
i.e. 40 pg/m x 10m inhaled/day 5 days 0.5 (lung absorption
rate). This is approximately 286 jug/day intake and 143
jig/day absorbed. To this the average daily intake from
food and general environmental sources can be added, i.e.
10-50 ^g. This suggests that an exposed worker may have
an approximate intake of 300 jag/d and still be safe. However,
a healthy worker may not be representative of the American
population as a whole.
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From Japanese dietary intake data where Itai-Itai disease
is prevalent, and studies on the age-specific incidence of
proteinuria, it is possible to estimate a no-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 control populations until the cadmium
levels in rice exceed 0.40-0.49 pg/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,
1974). Approximately 2100 calories are consumed daily,
with carbohydrate accounting for about 1725 calories
daily, which is equivalent to the ingestion of 430 gm/d.
The no-effect level for Japanese can be calculated as follows:
430 gm/d X 0.45 juq/qm (rice) ¦ 228 ^ig/day
0.85
This Japanese figure is slightly below the estimate of 250
^ig/day given by Friberg (1974) as an effect level. The
no-effect level for a western European or American population
with correspondingly larger body size would be expected
to be somewhat greater (i.e., 301 jjg/day) .
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
at around 200 ug daily corresponding to an actual absorption
of 12 ^ig/day. For smokers this estimate is reduced by about
C-64
-------
1.9 /ig to 10.1 pg which corresponds to an oral intake of
169 pg. Using a second approach based on metabolic modeling
of the above type, this same group derived a threshold effect
level of 248 pg 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 encompassing possible best-to-worse case exposure
situations that might be domestically encountered:
C-65
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Worst Case - Maximally Exposed Persons
Exposure Sources Exposure Cd Intake/d Absorption Factor + Cd Retention/
Air-Occupational *0.1 mg/m3 714.0 pg 0.5 357.0 pg
Air-Ambient 400 pg/m3 8.0 pg 0.5 4.0
Air-Smoking 3.0 pg/pack 9.0 pg 0.5 4.5 ug
(three packs)
Foods . 75.0 pg** 0.1 7.5 pg
Drinking Water 10 pg/1*** 20.0 pg 0.1 2.0 pg
826.0 jug 375.0 jug
* OSHA Standard for Cadmium fume
** Pahren and Kowal, 1978. Less than 1 percent of diets are expected to
exceed this value
*** Section One. Less than one water supply in 300 exceeds this value
+ These absorption factors may be considered maximal for man
Average Case
Exposure Sources Exposure Cd Intake/d Absorption Factor'1' Cd Retention/
3
Air-Ambient 0.03 pg/m 0.60 ^g 0.25 0.150 pg
Air Smoking 3.0 jug/pack 3.00 pg 0.25 0.750 ug
(one pack)
Pood 30.00 pg 0.05 1.500 pg
Drinking Water 1.3 pg/1 2.6 pg 0.05 0.130 pg
36.2 pg 2.530 pg
* Average for both sexes excluding drinking water (Section One)
+ These absorption factors are considered to be the most realistic
available
C-66
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Best Case - Minimally Exposed Persons
Exposure Sources Exposure Cd Intake/d Absorption Factor Cd Reten
Air-Ambient 0.001 fig/m3 0.02 pg 0.25 0.005 jug
Food 12.00 jag 0.05 0.600 jug
Water 0.5 ^g/1* 1.00 pg 0.05 0.050 ua
McCabe, 1974.
C-67
-------
From these scenarios it can be calculated that ingested
water contributes relatively little to the daily retained
cadmium entering 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 all over 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 /ig/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 jug/d intake and 2.605 jug/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 analysis it is obvious (average case scenario)
that drinking water contributes substantially less to human
cadmium intake and/or retention than smoking a package of
cigarettes daily. From this analysis it appears that a
water criterion needs to be no more stringent than the existing
Primary Drinking Water Standard (10 jug/1) to provide ample
protection of human health.
C-68
-------
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APPENDIX I
Summary and Conclusions Regarding The
Carcinogenicity of Cadmium
Environmental exposure to cadmium occurs by several
routes. The estimated cadmium retention of an individual
from food is about 3.0 yug/day; water, 0.09 ^g/day; and air,
0.15 ^g/day. People smoking five cigarettes per day have
an additional retention of about 0.35 ^ag cadmium. The pro-
duction 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 ;ug/l, but
may be as high as 10 pq/1.
Cadmium has been reported to cause chromosomal or mitotic
aberrations in mammalian cell culture lines. In vitro,
it induces cellular transformation and also enhances trans-
formation of virus-infected mammalian cells. These tests
are known to be highly correlated with oncogenicity. Further
it has been shown to produce adverse effects in both man
and experimental animals, eg. 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,
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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.
-5
A water quality criterion 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 17.0, 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)
Prom the CAG document 1, 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/m3 of Cd
in the air is:
1 ug/m3 x 24 ug/day = 24 ug/day assuming 100 percent
absorption
Studies show that 50 percent absorption may be more
realisticf therefore the Cd intake is:
24 ug/day x 0.5 3 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 0.0187 kg/day of fish products) with
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a fish bioconcentration factor of 17, the resulting level
of Cd in ambient water, C, would be:
12 jug/day = Cx (2 + (0.0187) (17))
5.117 jug/1 =
In order to absorb this much from water and fish (assume
10 percent absorption from the GI tract), the water concen-
tration corresponding to 1 jug/m3 of air would have to be
51.77 jug/1. Therefore, 1 jug/m in air produces a risk equivalent
to a water and fish consumption resulting from 51.77 ;ig/l
_ 5
in the water. The air level giving a lifetime risk of 10 is:
X1 = 10~5/(1.879 x 10"3) = 0.532 x 10~2 ;ag/m3
This corresponds to a water level of
C = 51.77 x 0. 532 x 10~2 = 0.2754 ;ug/l
~0.28 jag/1
1. Assessment
Exposure to Cadmium
Group report May 19,
of Carcinogenic Risk
in the Ambient Air.
1978.
from Population
Carcinogen Assessment
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