EPA-540/1-86-038
Office of Emergency and
Remedial Response
Washington DC 20460
Off'ce of Research and Development
Office of Health and Environmental
Assessment
Environmental Criteria and
Assessment Office
Cincinnati OH 45268
Superfund
&EPA
HEALTH EFFECTS ASSESSMENT
FOR CADMIUM
-------
EPA/540/1-86-038
September 1984
HEALTH EFFECTS ASSESSMENT
FOR CADMIUM
U.S. Environmental Protection Agency
Office of Research and Development
Office of Health and Environmental Assessment
Environmental Criteria and Assessment Office
Cincinnati, OH 45268
U.S. Environmental Protection Agency
Office of Emergency and Remedial Response
Office of Solid Waste and Emergency Response
Washington, DC 20460
-------
DISCLAIMER
This report has been funded wholly or 1n part by the United States
Environmental Protection Agency under Contract No. 68-03-3112 to Syracuse
Research Corporation. It has been subject to the Agency's peer and adminis-
trative review, and It has been approved for publication as an EPA document.
Mention of trade names or commercial products does not constitute endorse-
ment or recommendation for use.
11
-------
PREFACE
This report summarizes and evaluates Information relevant to a prelimi-
nary Interim assessment of adverse health effects associated with cadmium.
All estimates of acceptable Intakes and carcinogenic potency presented 1n
this document should be considered as preliminary and reflect limited re-
sources allocated to this project. Pertinent toxlcologlc and environmental
data were located through on-Hne literature searches of the Chemical
Abstracts, TOXLINE, CANCERLINE and the CHEMFATE/DATALOG data bases. The
basic literature searched supporting this document Is current up to
September, 1984. Secondary sources of Information have also been relied
upon 1n the preparation of this report and represent large-scale health
assessment efforts that entail extensive peer and Agency review. The
following Office of Health and Environmental Assessment (OHEA) sources have
been extensively utilized:
U.S. EPA. 1980b. Ambient Water Quality Criteria for Cadmium.
Environmental Criteria and Assessment Office, Cincinnati, OH. EPA
440/5-80-025. NTIS PB 81-117368.
U.S. EPA. 1982. Review of Toxlcologlc Data 1n Support of Evalua-
tion for Carcinogenic Potential of Cadmium and Compounds. Prepared
by Carcinogen Assessment Group, OHEA, Washington, DC for the Office
of Solid Waste and Emergency Response, Washington, DC.
U.-S. EPA. 1983a. Reportable Quantity for Cadmium {and compounds).
Prepared by the Environmental Criteria and Assessment Office,
Cincinnati, OH, OHEA for the Office of Solid Waste and Emergency
Response, Washington, DC.
U.S. EPA. 1984. Updated mutagenldty and cardnogenldty assess-
ment of cadmium. Carcinogen Assessment Group, OHEA. EPA 600/8-83-
025B. NTIS PB 85-116150.
The Intent 1n these assessments 1s to suggest acceptable exposure levels
whenever sufficient data were available. Values were not derived or larger
uncertainty factors were employed when the variable data were limited In
scope tending to generate conservative (I.e., protective) estimates. Never-
theless, the Interim values presented reflect the relative degree of hazard
associated with exposure or risk to the chemlcal(s) addressed.
Whenever possible, two categories of values have been estimated for sys-
temic toxicants (toxicants for which cancer 1s not the endpolnt of concern).
The first, the AIS or acceptable Intake subchronlc, Is an estimate of an
exposure level that would not be expected to cause adverse effects when
exposure occurs during a limited time Interval (I.e., for an Interval that
does not constitute a significant portion of the Hfespan). This type of
exposure estimate has not been extensively used or rigorously defined, as
previous risk assessment efforts have, been primarily directed towards
exposures from toxicants 1n ambient air or water where lifetime exposure 1s
111
-------
assumed. Animal data used for AIS estimates generally Include exposures
with durations of 30-90 days. Subchronlc human data are rarely available.
Reported exposures are usually from chronic occupational exposure situations
or from reports of acute accidental exposure.
The AIC, acceptable Intake chronic, 1s similar 1n concept to the ADI
(acceptable dally Intake). It 1s an estimate of an exposure level that
would not be expected to cause adverse effects when exposure occurs for a
significant portion of the Hfespan [see U.S. EPA (1980a) for a discussion
of this concept]. The AIC Is route specific and estimates acceptable
exposure for a given route with the Implicit assumption that exposure by
other routes 1s Insignificant.
Composite scores (CSs) for noncardnogens have also been calculated
where data permitted. These values are used for ranking reportable quanti-
ties; the methodology for their development 1s explained 1n U.S. EPA (1983b).
For compounds for which there Is sufficient evidence of carclnogenlcHy,
AIS and AIC values are not derived. For a discussion of risk assessment
methodology for carcinogens refer to U.S. EPA (1980a). Since cancer Is a
process that 1s not characterized by a threshold, any exposure contributes
an Increment of risk. Consequently, derivation of AIS and AIC values would
be Inappropriate. For carcinogens, q-j*s have been computed based on oral
and Inhalation data If available.
-------
ABSTRACT
In order to place the risk assessment evaluation 1n proper context, the
reader 1s referred to the preface of this document. The preface outlines
limitations applicable to all documents of this series as well as the appro-
priate Interpretation and use of quantitative estimates presented.
A dose-related Increase In lung carcinoma has been reported In rats
exposed to cadmium chloride aerosols. Cadmium exposure has been linked to
excess respiratory cancers 1n cadmium smelter workers. The CAG (U.S. EPA,
1984) has estimated an upper bound unit risk for continuous Inhalation expo-
sure of 2.228xlO~3 yg/m3 cadmium based on human data for respiratory
cancers. From this data a unit risk of 7.8 (mg/kg/day)"1 was calculated.
The CAG document was 1n draft form at the time of this review.
Evidence 1s currently Inadequate to consider cadmium a carcinogen
through the oral route. As a result of the ubiquitous nature of the com-
pound and chronic baseline exposure neither an AIS nor an AIC are suggested.
It 1s proposed that the additional exposure Increment through drinking water
should not exceed the drinking water standard of 10 yg/S,. This value
may require revision when the cadmium RMCL is finalized.
-------
ACKNOWLEDGEMENTS
The Initial draft of this report was prepared by Syracuse Research
Corporation under Contract No. 68-03-3112 for EPA's Environmental Criteria
and Assessment Office, Cincinnati, OH. Dr. Christopher DeRosa and Karen
Blackburn were the Technical Project Monitors and Helen Ball wasithe Project
Officer. The final documents In this series were prepared for the Office of
Emergency and Remedial Response, Washington, DC.
Scientists from the following U.S. EPA offices provided review comments
for this document series:
Environmental Criteria and Assessment Office, Cincinnati, OH
Carcinogen Assessment Group
Office of A1r Quality Planning and Standards
Office of Solid Waste
Office of Toxic Substances
Office of Drinking Water
Editorial review for the document series was provided by:
Judith Olsen and Erma Durden
Environmental Criteria and Assessment Office
Cincinnati, OH
Technical support services for the document series was provided by:
Bette Zwayer, Pat Daunt, Karen Mann and Jacky Bohanon
Environmental Criteria and Assessment Office
Cincinnati, OH
v1
-------
TABLE OF CONTENTS
1.
2.
3.
4.
5.
ENVIRONMENTAL CHEMISTRY AND FATE
ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS . . .
2.1.
2.2.
ORAL
INHALATION
TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1.
3.2.
3.3.
3.4.
SUBCHRONIC
3.1.1. Oral
3.1.2. Inhalation
CHRONIC
3.2.1. Oral
3.2.2. Inhalation
TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS. . . . .
3.3.1. Oral
3.3.2. Inhalation ,
TOXICANT INTERACTIONS
CARCINOGENICITY ,
4.1.
4.2.
4.3.
4.4.
HUMAN DATA
4.1.1. Oral
4.1.2. Inhalation
BIOASSAYS
4.2.1. Oral
4.2.2. Inhalation
OTHER RELEVANT DATA
WEIGHT OF EVIDENCE
REGULATORY STANDARDS AND CRITERIA
Page
. . . 1
3
. . . 3
. . . 3
4
4
. . . 4
. . . 6
. . . 6
. . . 6
8
. . . 10
. . . 10
. . . 10
. . . 11
, . . 12
. . . 12
. . . 12
. . . 12
. . . 13
. . . 13
14
, . . 14
. . . 20
, . . 21
-------
TABLE OF CONTENTS (cont.)
Page
6. RISK ASSESSMENT 24
6.1. ACCEPTABLE INTAKE SUBCHRONIC (AIS) 24
6.1.1. Oral 24
6.1.2. Inhalation 24
6.2. ACCEPTABLE INTAKE CHRONIC (AIC) 24
6.2.1. Oral 24
6.2.2. Inhalation 24
6.3. CARCINOGENIC POTENCY (q-j*) 24
6.3.1. Oral 24
6.3.2. Inhalation 25
7. REFERENCES 26
APPENDIX: Summary Table for Cadmium 39
-------
LIST OF TABLES
No. Title Page
3-1 Subchronlc Oral Tox1c1ty of Cadmium 5
3-2 Chronic Oral Toxldty of Cadmium 7
3-3 Chronic Inhalation Toxldty of Cadmium 9
4-1 Mutagenldty of Cadmium: Evaluations Using Prokaryotes. ... 15
4-2 Mutagenldty of Cadmium: Evaluations Using Eukaryotlc
Cells 16
4-3 Mutagenldty of Cadmium: Evaluations Using Insects 17
4-4 Mutagenldty of Cadmium: In_ vitro Chromosome Aberrations. . . 18
4-5 Mutagenldty of Cadmium: Jji vivo Mammalian Systems 19
5-1 Regulatory Standards, Limits or Criteria for Human Health
Protection 22
1x
-------
LIST OF ABBREVIATIONS
ADI Acceptable dally Intake
AIC Acceptable Intake chronic
AIS Acceptable Intake subchronlc
BCF B1oconcentrat1on factor
bw Body weight
CS Composite score
DNA Oeoxyrlbonuclelc add
LOEL Lowest-observed-effect level
STEL Short-term exposure limit
TLV Threshold limit value
TWA Time-weighted average
-------
1. ENVIRONMENTAL CHEMISTRY AND FATE
Cadmium Is a metal belonging to Group IIB of the Periodic Table. Ele-
mental cadmium has a CAS Registry number of 7440-43-9. It occurs 1n nature
In the zero valence (metal and alloys) and 1n the +2 valence (compound)
states. Besides forming 1on1c and covalent compounds with anlons and
groups, cadmium also complexes with ammonia, cyanide, halldes and thlocya-
nate (Hollander and Carapella, 1978).
In the atmosphere cadmium Is expected to be present as dust and fumes
from smelting of ores, manufacturing of metallic alloys, reprocessing of
cadmium-containing alloys, recycling of steel scrap, coal-fired power plants
and Incineration of solid wastes (Flshbein, 1981). The atmospheric fate of
cadmium has not been studied comprehensively. Any chemical Interaction of
cadmium compounds 1n the atmosphere 1s likey to result 1n spedatlon (I.e.,
conversion Into a more stable species such as CdO), and not 1n Its direct
removal through decomposition, as frequently occurs with organic compounds.
The principal removal mechanisms for atmospheric cadmium may occur through
wet and dry deposition (Flshbein, 1981). The atmospheric half-life for the
physical removal mechanism 1s expected to depend on the particle size and
particle density of atmospheric cadmium. There 1s considerable evidence
that cadmium 1s concentrated 1n smaller (<3 ym) particles 1n the atmo-
sphere (Flshbein, 1981). Therefore, 1t may have a long half-life In the
atmosphere, although no estimate for this half-life 1s available.
The dominant fate of cadmium 1n the aquatic media Is sedimentation
through sorptlon onto clays or organic matter, copredpltatlon and Iso-
morphous substitution In carbonate minerals. Smaller amounts of cadmium may
persist 1n the aquatic phase In solution, either as hydrated cations or as
organic or Inorganic complexes.
-1-
-------
In m'ost unpolluted water, the majority of soluble cadmium may exist as
the hydrated cation, whereas 1n polluted waters, complexatlon with organic
material may be most Important (Callahan et al., 1979).
The fate of cadmium In soil has not been studied adequately. However,
by analogy with Us fate 1n aquatic media, cadmium 1s expected to be
strongly sorbed 1n soil, and sorptlon will Increase as the organic matter
content of soil Increases (Callahan et al., 1979). Conditions that may
weaken the sorptlon process, such as a decrease of pH (<7) and an Increase
In salinity, may enhance desorptlon of cadmium from soil. Cadmium 1s mobile
1n soil, as evidenced by the detection of this element in 100% of the
groundwater samples collected from New Jersey (Page, 1981).
The BCFs for cadmium In aquatic organisms have been determined by
several Investigators. In freshwater and marine fish the BCF have been
found to vary between 1000 and 3000 (Callahan et al., 1979.)
-2-
-------
2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL MAMMALS
2.1. ORAL
Several studies Indicate that cadmium 1s' poorly absorbed following oral
administration. Frlberg et al. (1974) reported that -2% of orally adminis-
tered cadmium was absorbed by experimental animals (species and compound not
specified 1n the review). Absorption appears to be slightly more extensive
1n humans, with reported absorption values of 6 and 4.6% (Rahola et al.,
1973; McLellan et al., 1978).
The absorption of orally administered cadmium may be altered by a
variety of dietary parameters (Bremner, 1974). Washko and Cousins (1976)
found that diets low In calcium result 1n a significant Increase In cadmium
absorption. Diets deficient 1n vitamin D, protein, zinc, Iron and copper
also Increase the extent of cadmium absorption (Worker and M1g1covsky, 1961;
Suzuki et al., 1969; Banls et al., 1969; Bunn and Matrone, 1966; H111 et
al., 1963). Ascorbic add deficiency has been observed to Increase cadmium
toxlcity (Fox and Fry, 1970).
2.2. INHALATION
Absorption of cadmium from the respiratory tract appears to be much more
extensive than absorption from the gastrointestinal tract. Up to 25% of
Inhaled cadmium dust and aerosols may be absorbed when a large proportion of
the particles are 1n the resplrable range and the compound 1s relatively
soluble (U.S. EPA, 1980b). Up to 50% of the cadmium 1n cadmium fumes or
cigarette smoke may be absorbed (WHO Task Group, 1977; EUnder et al., 1976).
-3-
-------
3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
The major effects of long-term exposure to cadmium are similar following
both oral and Inhalation exposure. Renal dysfunction, resulting 1n disturb-
ances 1n mineral metabolism and, eventually, formation of kidney stones or
osteomalada, Is the major effect In humans. Pulmonary dysfunction 1s
observed following higher inhalation exposures. Cadmium exposure has been
correlated with hypertension in humans.
3.1. SUBCHRONIC
3.1.1. Oral. The subchronic oral toxicity of cadmium Is summarized 1n
Table 3-1.
No data were located on the subchronic oral exposure of humans to
cadmium. Three subchronic oral toxlcity studies and one 3-generation repro-
duction study Investigated the toxic response of rats and mice to cadmium.
Schroeder and MHchener (1971) Investigated the effect of 10 mg cadmium
(unspecified soluble salt)/a, drinking water on reproductive performance In
mice. The treated mice failed to reproduce past the second generation.
Nearly a third of the offspring died before weaning, and 13.3% of the
survivors were classified as runts. Assuming that mice drink 17% of their
body weight per day as water, the dose was 1.7 mg Cd/kg bw/day. Fitzhugh
and Melller (1941) observed anemia in rats exposed to similar doses of
cadmium (2.25 mg/kg bw/day).
Yuhas et al. (1979) administered cadmium acetate (0, 1, 10 or 100
mg/J.) in the drinking water to male Sprague-Dawley rats for 13 weeks. The
doses reported 1n the paper are not consistent with the reported water con-
centration, water consumption and body weights. Based on the data reported,
the correct doses appear to be 0, 0.118, 0.947 and 8.041 mg/kg bw/day. At
-4-
-------
TABLE 3-1
Subchronlc Oral Toxlclty of Cadmium
Compound
Cadmium
acetate
Species/Strain/
Sex
rat/Sprague-
Dawley/N
Dose
0, 1. 10 or 100
tig/Cd/t drinking
water (116, 947 or
8041 mg/kg bw/day)
Length of
Exposure
13 weeks .
Effects Reference
Decreased weight gain at 100 ug/i; no Yuhas et al.,
effect on cellular structure of liver, kid- 1979
ney or duodenum at any dose'1, decreased serum
alkaline phosphatase In all dose groups;
Increased cadmium content In bone at 10 and
100 pg/Cd/mt t^O; decreased zinc content
of bone at 100 pg/ml.
I
(Jl
I
Cadmium
chloride
Cadmium
mice/Swiss
Webster/NR
rats/NR/NR
Unspecified mlce/NR/N.F
soluble salt
3 or 300 vq Cd/l
H20 (0.51 or 51
mg/kg bw/day)
0, 15. 45. 75 or
135 mg/kg diet
(0. 0.75, 2.25,
3.75 or 6.75
mg/kg bw/day)
10 mg/l H20
(1.7 mg/kg bw/day)
70 days Decrease In the number of lymphocytes
secreting antibodies to sheep red blood cells
at both dose levels; necrosis of renal epi-
thelial cells In the proximal convoluted
tubules and collecting tubules at both doses
6 months Narked anemia, decreased weight gain and
Increased mortality at 135 mg/kg diet; anemia
at doses of 45 and 75 mg/kg diet
3 generations Decreased reproductive performance (no 3rd
generation); Increased postnatal mortality;
Increased congenital malformations
Koller et al.,
1975
Fltzhugh and
Helller. 1941
Schroeder and
MHchener. 1971
NR * Not reported
-------
the high-dose level, weight gain was depressed, the cadmium content of bone
was increased, the zinc content of bone was decreased and serum phosphorus
concentrations were elevated. At a dose of 0.947 mg/kg bw/day, bone cadmium
content was Increased. Serum alkaline phosphatase activity was decreased in
all dose groups. No histological effects were observed in any dose group.
Koller et al. (1975) administered drinking water containing 3 or 300 mg
Cd/J, to Swiss Webster mice (390 mice/group) for 70 days. The controls
consisted of 80 mice that received deionized water. Mice were immunized
with sheep red blood cells during treatment or 1, 7, 14 or 42 days after the
end of treatment. The number of lymphocytes secreting antibodies to sheep
red blood cells was markedly decreased in both dose groups. There was a
dose-related incidence of necrosis of the renal epithelial cells in the
proximal convoluted tubules and collecting tubules. Assuming that mice
drink water equivalent to 17% of their body weight each day, this corre-
sponds to a dose of 0.51 mg/kg bw/day.
3.1.2. Inhalation. Pertinent data regarding the subchronlc Inhalation
toxicity of cadmium were not located in the available literature.
3.2. CHRONIC
3.2.1. Oral. The chronic oral toxicity of cadmium 1s summarized in
Table 3-2.
Schroeder et al. (1963, 1964, 1965} administered cadmium acetate in the
drinking water (5 mg/Cd/i) to Long-Evans rats and Charles River mice for
their lifetimes. Survival was decreased in both sexes of rats and in male
mice. In rats, treatment was associated with renal and cardiac arterio-
sclerosis, cardiac hypertrophy and neurological effects. The major effect
reported in mice was an altered renal morphology. Renal degeneration and
necrosis have also been reported in Wlstar rats receiving 123 mg Cd (as
cadmium chloride)/8,drink1ng water (Kajikawa et al., 1981).
-6-
-------
TABLE 3-2
Chronic Oral Toxlclty of Cadmium
Compound
Cadmium
acetate
Cadmium
acetate
Cadmium
NR
NR
Species/Strain/
Sex
rats/Long-
Evans/N.F
mice/Charles
River /H.F
rats/Wlstar/
NR
human/NA/
H.F
human/NA/
H.F
Dose
0 or 5 mg Cd/i
H20 (0 or 0.39
mg Cd/kg bw/day)
0 or 5 mg Cd/i
H20 (0 or 0.85
mg Cd/kg bw/day
0 or 123 mg Cd/i
H20 (0 or 9.57
mg Cd/kg bw/day)
228 ng/day (esti-
mated LOEL; 30 t>g/
day for a 70 kg
man)
250-350 ng Cd/day
(estimated LOEL)
Length of
Exposure
lifetime
(-2.5 years)
lifetime
(-2 years)
4-91 weeks
lifetime
50 years
Effects
Decreased survival; systolic hypertension;
renal and cardiac arteriosclerosis and cardiac
hypertrophy; severe vestlbular disturbances
Decreased survival In males; Tiyaltnlzed
glomerull, thickened basement membranes, and
a reduction In the lumen/wall ratio In the
arterloles of the kidneys
Vacuolar degeneration of the kidneys;
cellular necrosis In the proximal convoluted
tubules; Increased urinary protein excretion
Ital-ltal disease; tubular protelnurla
Renal dysfunction
Reference
Schroeder
et al.. 1963.
1964. 1965;
Kanlsawa and
Schroeder, 1969
Schroeder
et al., 1964;
Kanlsawa and
Schroeder, 1969
Kajlkawa et al..
1981
Frlberg et al..
1974; Muraraatsu,
1974; Nogawa
et al.. 1978;
U.S. EPA, 1980b
Frlberg et al.,
1974
NA . Not applicable
NR = Not reported
-------
The U.S. EPA (1980b) has estimated the threshold dose for Induction -of
protelnurla, based upon dietary Intake data from areas of Japan 1n which
1ta1-Ha1 disease 1s prevalent. In these areas, -85% of the dally cadmium
Intake Is derived from rice (Muramatsu, 1974). Nogawa et al. (1978) found
that the prevalence of tubular protelnurla 1n persons under 70 did not
exceed the prevalence In control populations until the cadmium levels 1n
Mce were >0.40-0.49 yg/g rice. The U.S. EPA (1980b) estimated a LOEL of
228 yg Cd/day, using an average value of 0.45 yg Cd/g rice. For a
corresponding Western European or American population, the dally dose that
would result 1n an equivalent mg/kg bw/day was estimated to be 301 yg
Cd/day.
This LOEL 1s 1n good agreement with the estimate of 250-350 yg Cd/day
determined by Frlberg et al. (1974), based on the "generally accepted"
critical cadmium level at which renal dysfunction occurs, 200 yg Cd/g wet
weight of renal cortex.
3.2.2. Inhalation. The chronic Inhalation tox1c1ty of cadml-um 1s summa-
rized 1n Table 3-3.
Frlberg (1948 a,b, 1950), 1n a study of workers exposed to cadmium Iron
oxide dust 1n a Swedish alkaline battery factory, was the first to observe a
correlation between cadmium exposure and the development of emphysema.
These findings have since been confirmed by a number of Investigators
(Paterson, 1947; Baader, 1952; Lane and Campbell, 1954; Buxton, 1956; Smith
et al., 1960, 1976; Kazantzls et al., 1963; Potts, 1965; Holden, 1965; Lewis
et al., 1969; Snider et al., 1973; Lauwerys et al., 1974). Cadmium-Induced
emphysema 1s only observed following Inhalation exposure.
-8-
-------
TABLE 3-3
Chronic Inhalation Toxlclty of Cadmium
Species/Strain/
Compound Sex
Cadmium dust human/NA/M
(<5. diameter)
Cadmium fumes human/NA/NR
^ Cadmium Iron human/NA/NR
i oxide dust
Length of
Dose Exposure
21 tg total
Cd/m»)
125 ng Cd/m* 9 months to
12 years
NR NR
Effects
Decreased pulmonary ventllatory function;
Increased Incidence of kidney dysfunction;
Increased protelnurla
Anemia; elevated urinary protein levels
Emphysema; protelnurla
Reference
Lauwerys
et al., 1974
Tsuchlya, 1967
Frlberg,
194Ba,b, 1950
NA » Not applicable
NR = Not reported
-------
Tsuchiya (1967) studied 13 workers who had been exposed to cadmium fumes
(TWA = 125 yg Cd/m3) for 9 months to 12 years. The control group
consisted of 13 age-matched nonexposed workers. The only effects noted were
decreased blood hemoglobin levels and elevated urinary protein levels.
Lauwerys et al. (1974) studied 22 male workers who were exposed to an
average resplrable cadmium dust (<5 y, aerodynamic diameter) concentration
of 21 yg Cd/m3 for 21-40 years. The total airborne cadmium concentra-
tion averaged 66 yg Cd/m3. The control group was matched to the exposed
group by age, sex, weight, height, smoking habits and sodoeconomlc status.
Kidney dysfunction, as Indicated by protelnurla, was observed 1n 68% of the
cadmium-exposed group as compared with 15% 1n the control group. Measures
of pulmonary ventHatory function (forced vital capacity, forced expiratory
volume/second, and peak expiratory flow rate) were reduced 1n the cadmium-
exposed group.
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS
3.3.1. Oral. Dixon et al. (1976) reported that a concentration of 0.1 mg
cadmium/8, administered to rats In their drinking water for 90 days
produced no detectable effects on reproduction. At a higher concentration
(10 mg cadmium/a,), Schroeder and MHchener (1971) reported the Induction
of decreased fertility, runtlng, young deaths and sharp angulatlon of the
distal third of the tall 1n a three-generation reproduction study In
rodents. Cadmium has also been demonstrated to be teratogenlc and to reduce
fertility following Intravenous, 1ntraper1toneal and subcutaneous adminis-
tration (U.S. EPA, 1980b).
3.3.2. Inhalation. No data pertinent to the teratogenlclty or other
reproductive effects of Inhaled cadmium were located 1n the available
literature.
-10-
-------
3.4. TOXICANT INTERACTIONS
The absorption and toxldty of cadmium may be altered by a number of
dietary factors. These are discussed In Section 2.1. In experimental
animals, zinc has been reported to prevent or reduce cadmium-Induced testlc-
ular damage, teratogenlc effects, growth Inhibition and tumor Induction
(PaMzek, 1957; PaMzek et al., 1969; Perm and Carpenter, 1967; Gunn et a!.,
1963a,b, 1964). Increased dietary copper has been demonstrated to prevent
or reduce mortality, anemia and degeneration of aortic elastln (Hill et al.,
1963; Bunn and Matrone, 1966). Dietary cadmium Inhibits Intestinal absorp-
tion of copper and calcium, possibly leading to deficiencies of these
elements (Starcher, 1969; Ando et al., 1977; Kobayashi, 1970).
-11-
-------
4. CARCINOGENICITY
4.1. HUMAN DATA
4.1.1. Oral. Pertinent data regarding the oral carcinogenicity of
cadmium in humans were not located in the available literature.
4.1.2. Inhalation. It is beyond the scope and resources of the present
document to present all of the available epidemiologic data concerning
cadmium and cancer. The Carcinogen Assessment Group (CAG) has prepared an
excellent in-depth review of the evidence available concerning the carcino-
genicity of cadmium (U.S. EPA, 1984). The reader is referred to this docu-
ment for a summary and critical review of the literature. The conclusions
drawn from their review were that the weight of the evidence suggests a
significant risk of lung cancer from exposure to cadmium; however, the
evidence that cadmium is a potent lung carcinogen is not compelling.
The considered opinion presented in this document is that the data
presented by Thun et al. (1984) provide the strongest evidence for cadmium
as a causative agent in human cancer. Briefly, this study examines a cohort
of cadmium smelter workers who were employed for at least 2 years in a pro-
duction capacity within one plant between January 1, 1940 and December 31,
1969. This cohort had a total of 16 deaths from respiratory cancer through
December 31, 1978; 6.99 deaths from this cause would have been expected
based on calendar time age-specific death rates for white males in the
United States.
The CAG points out several problems associated with using this study for
risk assessment purposes:
1. Smoking rate may have been higher for this cohort as compared
to the general population.
2. Exposure is confounded by exposure to arsenic, a known respira-
tory carcinogen.
-12-
-------
3. Very limited characterization of exposure levels and duration.
4. No exposure estimates for Individuals.
5. Available data do not allow evaluation of goodness of fit for
the mathematical model(s) used 1n risk assessment.
Despite these reservations, the CAG feels that a risk assessment based on
these data could be useful. The cancer response did correspond 1n terms of
site to animal response. In addition, the confounding factors should
Increase the apparent cancer risk thus producing an upper-bound estimate.
4.2. BIOASSAYS
4.2.1. Oral. Schroeder et al. (1964) administered drinking water con-
taining cadmium acetate (5 yg Cd/mj, H_0) to a group of 48 male and 39
female mice for the lifetime of the animals. Significant decreases In the
Incidence of pulmonary tumors and total tumor Incidence were observed 1n the
cadmium-treated animals; however, mean survival time was also reduced.
Levy et al. (1975) administered weekly doses of cadmium sulfate by
gavage to groups of 50 male Swiss mice (0.44, 0.88 or 1.75 mg Cd/kg bw) for
18 months. No tumors of the prostate gland were detected.
Schroeder et al. (1965) and Kanlsawa and Schroeder (1969) administered
cadmium acetate (5 yg Cd/ms, drinking water) to Long-Evans rats for the
lifetime of the animals. No significant differences were observed 1n total
tumor Incidence or the Incidence of any specific tumor type between treated
and control groups.
Levy and Clark (1975) administered weekly doses of 0.09, 0.18 or 0.35 mg
Cd/kg bw as cadmium sulfate to groups of 30 male CB hooded rats by gavage
for 2 years. There was no treatment-related Increase In either the total
tumor Incidence or the Incidence of prostate tumors.
-13-
-------
Decker et al. (1958) administered cadmium chloride (0.1, 0.5, 2.5, 5.0
or 10.0 mg Cd/s, drinking water) to groups of eight male and eight female
Sprague-Dawley rats for 1 year. No tumors were found that could be attrib-
uted to cadmium treatment. Loser (1980) and Sato (1977) also failed to find
an association between oral administration of cadmium and the development of
tumors.
4.2.2. Inhalation. Paterson (1947) reported a study In which rats were
exposed to cadmium oxide and cadmium chloride fumes; however, IARC (1976)
concluded that the duration of exposure was too short to draw any conclu-
sions from the reported absence of tumors.
Takenaka et al. (1983) exposed male Wlstar rats to three concentrations
of cadmium chloride aerosols. Measured cadmium chloride concentrations
averaged 50.8, 25.7 and 13.4 yg/m3 for the three groups, respectively.
Forty rats were Included 1n each cadmium group plus 41 rats exposed to
filtered air. Animals were exposed continuously for 18 months. Following
the treatment period animals were kept an additional 13 months and then
sacrificed.
There were no significant differences between groups 1n terms of body
weights or survival times (p<0.05). A dose-related Increase 1n primary lung
carcinomas was seen. Lung carcinoma Incidences were 0/38, 6/39, 20/38 and
25/35 for the 0, 13.4, 25.7 and 50.8 yg/m3 cadmium chloride groups,
respectively.
4.3. OTHER RELEVANT DATA
The results of mutagenldty studies with cadmium are summarized 1n
Tables 4-1 through 4-5. It 1s obvious that the results obtained 1n a
variety of tests have been conflicting. It appears that cadmium Is muta-
genlc 1n some test systems under some conditions; however, the relationship
-14-
-------
TABLE 4-1
MutagenlcHy of Cadmium: Evaluations Using Prokaryotes*
Test Organism
Salmonella
typhlmuMum
Salmonella
typhlmurlum
Salmonella
typhlmurlum
Salmonella
typhlmurlum
Bacillus .
subtlUs
Bacillus
subtlUs
Bacillus
subtlUs
Cadmium Compound
aqueous cadmium
chloride
cadmium red 1n
DMSO
cadmium chloride
cadmium dlethyl-
thlocarbamate 1n
DMSO
aqueous cadmium
chloride
aqueous cadmium
nitrate
cadmium chloride,
nitrate and
sulfHe
Activation
phenobarbltol-
Induced rat liver
Aroclor-lnduced
mouse liver
unlnduced mouse
liver
Aroclor-lnduced
rat liver
none
none
none
Results
negative
negative
negative
one dose positive,
no dose response
weakly positive
negative
weakly positive
*Source: U.S. EPA, 1984
-15-
-------
TABLE 4-2
MutagenlcHy of Cadmium: Evaluations Using Eukaryotlc Cells*
Test System
Cadmium Compound
Results
Saccharomyces
cerevlslae
Saccharomyces
cerevlslae
Mouse lymphoma
Mouse lymphoma
Chinese hamster,
lung
Chinese hamster,
ovary
Chinese hamster,
V79
cadmium chloride
cadmium chloride
cadmium chloride
cadmium sulfate
cadmium acetate,
cadmium chloride
cadmium chloride
cadmium chloride
positive
negative
weakly positive
positive
positive
weakly positive
positive
'Source: U.S. EPA, 1984
-16-
-------
TABLE 4-3
Mutagenldty of Cadmium: Evaluations Using Insects*
Organism
DrosophUa
melanoqaster
Drosophlla
melanoqaster
Drosophlla
melanoqaster
Drosophlla
melanoqaster
Drosophlla
melanoqaster
Drosophlla
melanoqaster
Poekllocerus
plctus
Test System
sex-linked reces-
sive lethal
larval development
sex-linked reces-
sive lethal, sex
chromosome loss
dominant lethal
sex-linked reces-
sive lethal
sex chromosome
loss
sex-linked reces-
sive lethal
testlcular melotlc
chromosomes
Compound
cadmium
chloride
cadmium
chloride
cadmium
chloride
cadmium
stearate
cadmium
chloride
cadmium
chloride
cadmium
chloride
Results
negative
negative
positive
negative
negative
negative
positive
'Source: U.S. EPA, 1984
-17-
-------
TABLE 4-4
Mutagenldty of Cadmium: Jji vitro Chromosome Aberrations*
Test Cells
Cadmium Compound
Results
Human lymphocytes
Human lymphocytes
Human lymphocytes
WI38 and MCR5
Human lymphocytes
(G0 stage)
Chinese hamster
HY cells
Chinese hamster
CHO cells
Mouse mammary
carcinoma, FM3A
cadmium sulflde
cadmium chloride
cadmium chloride
cadmium chloride
cadmium acetate
cadmium sulfate
cadmium chloride
cadmium chloride
positive
negative
negative
negative
weakly positive
positive '
positive with
newborn calf or
human serum,
negative with
fetal calf
serum
negative
*Source: U.S. EPA, 1984
-18-
-------
TABLE 4-5
Mutagenldty of Cadmium: in vivo Mammalian Systems*
Organism
Mouse
Mouse
Mouse
Mouse
Mouse
Mouse
Mouse
Mouse
Mouse
Syrian
hamster
Endpolnt
bone marrow cells
bone marrow
m1cronucle1
dominant lethals
dominant lethal
post-Implantation
loss
heritable trans-
location
spermatocytes
oocytes
blastocysts
oocytes
Test Compound
cadmium chloride
cadmium chloride
cadmium chloride
cadmium chloride
cadmium chloride
cadmium chloride
cadmium chloride
cadmium chloride
cadmium chloride
cadmium chloride
Results
negative
negative
negative
negative
negative
negative
negative
positive
positive for
aneuploldy
positive
*Source: U.S. EPA, 1984
-19-
-------
between mutagenlcHy and cardnogenldty 1s not as well established for
metals as for some other classes of carcinogens. McCann et al. (1975)
reported that 75% of the metal carcinogens tested In the standard Ames test
produced negative results.
For a thorough review of the available literature concerning cadmium
mutagenlcHy, the reader Is referred to U.S. EPA (1984). The preceding
tables, adapted from the CAG document, are meant only to Illustrate the
scope of the testing effort and a general Idea of the results. As can be
readily seen, cadmium compounds have been extensively evaluated and most
types of mutagenlcHy screening systems have produced mixed results. In
addition to the material In the tables, evaluation of lymphocytes from
occupatlonally exposed workers has produced equivocal results and tests for
chromosomal aberrations 1n plants have 1n general been positive (U.S. EPA,
1984).
4.4. WEIGHT OF EVIDENCE
IARC (1982) has classified cadmium and certain cadmium compounds as
group 28 chemicals. They considered the evidence for cardnogenldty to
humans to be "limited," since H 1s "still far from clear which were the
target organs for the putative carcinogenic action of cadmium 1n humans."
Evidence for cardnogenldty 1n animals was considered "sufficient" based
upon subcutaneous and Intramuscular Injection studies, which were not
reviewed for this document (U.S. EPA, 1980b). Evidence for activity In
short-term tests was considered "Inadequate" because of the conflicting
results reported by various authors (see Section 4.3.). Applying the
classification criteria proposed by the Carcinogen Assessment Group of the
U.S. EPA (Federal Register, 1984) for evaluating the overall weight of
evidence of cardnogenldty to humans, cadmium and compounds are most appro-
priately classified a Group 81, a probable human carcinogen.
-20-
-------
5. REGULATORY STANDARDS AND CRITERIA .
The current regulatory standards and criteria are presented In Table
5-1. Values for water concentrations range from 0.7-10 yg/l; recom-
mended occupational air concentrations range from 0.12-100 yg/m3.
-21-
-------
TABLE 5-1
Regulatory Standards, Limits or Criteria for Human Health Protection3
A1r
(inhalation)
100 yg/m3b
40 yg/m3
NR
NR
NR
50 yg/m3
0.12 yg/m3
NR
NR
NR
NR
NR
TLV =0.05 mg/m3
Media
Water
(Ingestlon)
NR
NR
10 yg/9.
NR
10 yg/8.
NR
WH1-1.9 yg/id
WH2-0.7 yg/&d
10 yg/8.
1 yg/le
10 yg/8.
5 yg/a, (streams)
10 yg/a.
NR
Food
(Ingestlon)
NR
NR
NR
0.5 yg/ma.c
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
Reference
NIOSH, 1974
NIOSH, 1976
U.S. EPA, 1975
FDA, 1974
WHO, 1971
AC6IH, 1977
MEG/EPC, 1977
NAS, 1972
Krasovsk11
et al., 1976
Canada, 1969
Lyklns and
Smith, 1976f
U.S. EPA, 1980b
ACGIH, 1980
-22-
-------
TABLE 5-1 (cent.)
Media
Air
'Inhalation!
Mater
(1ngest1on)
Food
(1ngest1on)
Reference
STEL = 0.2 mg/m3
NR
Celling L1mit9 = NR
0.05 mg/m3
40 yg/m3
NR
NR
NR
NR
ACGIH, 1980
ACGIH, 1983
NIOSH, 1976
aAdapted from U.S. EPA, 1980b
cadmium fume. Limit for cadmium dust Is 200 yg/m3.
cBased on ceramic pottery and enamelware leaching solution test.
<*EPC (estimated permissible concentration) WH1 1s derived from the assump-
tion that the maximum dally safe dosage results from 24-hour exposure to
air containing the estimated permissible concentration In air, assuming
100% absorption, and that the same dose Is therefore permissible 1n the
volume of water consumed per day; WH2 1s the estimated permissible concen-
tration of the substance 1n water based on considerations of the safe
maximum body concentration and the biological half-life of the substance.
eUSSR (suggested)
fOh1o
9Cadm1um oxide fumes
NR = Not reported
-23-
-------
6. RISK ASSESSMENT
6.1. ACCEPTABLE INTAKE SUBCHRONIC (AIS)
6.1.1. Oral. Since at present there 1s chronic baseline exposure of the
human population (primarily through food) and since the critical effects of
cadmium are dependent upon reaching a critical body burden, development of a
separate subchronlc estimate Is not recommended.
6.1.2. Inhalation. Cadmium 1s a metal that Is a known carcinogen through
the Inhalation route and for which data are sufficient for computing a
q *. It 1s, therefore, inappropriate to calculate an oral or Inhalation
AIS for cadmium.
6.2. ACCEPTABLE INTAKE CHRONIC (AIC)
6.2.1. Oral. U.S. EPA (1980b) has proposed a drinking water criterion
level of 10 yg/8, cadmium. Assuming an adult water consumption of 2
a/day this would contribute 20 vg/day to the daily exposure in addition
to food (major source) and ambient air. Therefore, 1t Is suggested that 20
vg/8. be applied as the maximum additional increment from drinking water
sources. U.S. EPA 1s in the process of developing a Recommended Maximum
Contaminant Level (RMCL) for cadmium. When this value to published it
should supercede the value proposed here.
6.2.2. Inhalation. Cadmium 1s a metal that is a known carcinogen through
the Inhalation route and for which data are sufficient for computing a
q,*. It is, therefore, Inappropriate to calculate an oral or Inhalation
AIC for cadmium.
6.3. CARCINOGENIC POTENCY (q.,*)
6.3.1. Oral. Cadmium has not been shown to be carcinogenic in laboratory
animals by oral administration. There are no human data (U.S. EPA, 1984).
-24-
-------
Using the dose data for rats from Schroeder et al. (1965) and assuming a 10%
upper limit of detection of tumors, CAG (U.S. EPA, 1984) has estimated an
upper limit for the carcinogenic potency of Ingested cadmium which 1s 2
orders of magnitude less than for Inhalation. It 1s possible that as a
result of extremely poor absorption from the GI tract, cadmium 1s not
carcinogenic when Ingested; however, the negative data available at this
time can only be used to set an upper limit on potency. For these reasons,
quantitative risk assessment for oral exposure to cadmium 1s Impractical at
the present time as a result of Inadequate data.
6.3.2. Inhalation. The data of Takenaka et al. (1983) for induction of
lung carcinoma in rats could be used for quantitative risk assessment.
However, the CAG (U.S. EPA, 1984) felt that an extrapolation based on the
human data for respiratory cancer (Thun et al., 1984) provided a more
realistic assessment. Since this opinion was based on an 1n-depth, critical
review of the literature which far exceeded the scope of the current
document, this approach will be adopted here.
Using these data, CAG (U.S. EPA, 1984) has estimated that the most
plausible estimate for the upper-bound unit risk for continuous Inhalation
exposure to 1 yg/m3 cadmium to be 2.228xlO~3. This corresponds to a
unit risk 1n units of (mg/kg/day)'1 of 7.8.
-25-
-------
7. REFERENCES
ACGIH (American Conference of Governmental Industrial Hyglenists). 1977.
TLVs. Threshold Limit Values for Chemical Substances and Physical Agents 1n
the Workroom Environment with Intended Changes for 1977. Cincinnati, OH.
(Cited In U.S. EPA, 1980b)
ACGIH (American Conference of Governmental Industrial Hyglenists). 1980.
Documentation of the Threshold Limit Values for Substances 1n Workroom A1r,
4th ed. with supplements through 1981. Cincinnati, OH. p. 59-61. (Cited
In U.S. EPA, 1983a)
ACGIH (American Conference of Governmental Industrial Hyglenists). 1983.
Threshold Limit Values for Chemical Substances 1n the Work Environment
Adopted by ACGIH for 1984. 19.85.
Ando, M., et al. 1977. Studies on excretion and uptake of calcium by rats
after continuous oral administration of cadmium. Toxlcol. Appl. Pharmacol.
39: 321. (Cited 1n U.S. EPA, 1980b)
Baader, E.W. 1952. Chronic cadmium poisoning. Ind. Med. Surg. 21: 427.
(Cited 1n U.S. EPA, 1980b)
Banls, R.J., et al. 1969. Dietary cadmium, Iron, and zinc Interactions 1n
the growing rat. Proc. Soc. Exp. Biol. Med. 130: 802. (Cited In U.S. EPA,
1980b)
-26-
-------
Bremner, I. 1974. Heavy metal tox1cH1es. Q. Rev. Blophys. 7: 75-124.
(Cited In U.S. EPA, 1980b)
Bunn, C.R. and G. Matrone. 1966. In. vivo Interactions of cadmium, copper,
zinc, and Iron In the mouse and rat. J. Nutr. 90: 395. (Cited 1n U.S.
EPA, 1980b)
Buxton, R.St.J. 1956. Respiratory function 1n cadmium alloy casters. Br.
J. Ind. Med. 13: 36. (Cited 1n U.S. EPA, 1980b)
Callahan, M.A., M.W. Sllmak, N.W. Gabel, et al. 1979. Water-Related
Environmental Fate of 129 Priority Pollutants, Vol. I. Office of Water
Planning and Standards, Office of Water and Waste Management, U.S. EPA,
Washington, DC. EPA 440/4.790229a.
Canada. 1969. Canadian Drinking Water Standards and Objectives for 1968.
Published by authority of Minister of National Health and Welfare. (Cited
In U.S. EPA, 1980b)
Decker, I.E., R.U. Byerrum, C.F. Decker, C.A. Hoppert and R.F. Langham.
1958. Chronic toxldty studies. I. Cadmium administered 1n drinking water
to rats. Arch. Ind. Health. 18: 228-231. (Cited 1n U.S. EPA, 1982)
Dlxon, R.L., et al. 1976. Methods to assess reproductive effects of
environmental chemicals: Studies of cadmium and boron administered orally.
Environ. Health Perspect. 13: 59. (Cited 1n U.S. EPA, 1980b)
-27-
-------
EUnder, C.G., et al. 1976. -Cadmium 1n kidney cortex, liver, and pancreas
from Swedish autopsies. Arch. Environ. Health. 30: 292. (Cited 1n U.S.
EPA, 19805)
FDA (Food and Drug Administration). 1974. Total diet studies (7320.08).
Compliance Program Evaluation, Bur. Foods. (Cited 1n U.S. EPA, 19805)
Federal Register. 1984. Environmental Protection Agency. Proposed guide-
lines for carcinogenic risk assessment. Federal Register 49: 46294-46299.
Ferm, V.H. and S.J. Carpenter. 1967. Teratogenlc effect of cadmium and Us
Inhibition 5y zinc. Nature. 216: 1123. (Cited 1n U.S. EPA, 19805)
F1sh5e1n, L. 1981. Sources, transport and alterations of metal compounds:
An overview. I. Arsenic, beryllium, cadmium, chromium and nickel. Environ.
Health Perspect. 40-: 43-64.
Fltzhugh, O.G. and F.H. Melller. 1941. The chronic toxldty of cadmium.
J. Pharm. Exp. Ther. 72: 15. (Cited 1n U.S. EPA, 1983a)
Fox, M.R.S. and B.E. Fry. 1970. Cadmium toxldty decreased by dietary
ascor51c add supplements. Science. 169: 989.
Fr15erg, L. 1948a. Protelnurla and kidney Injury among workers exposed to
cadmium and nickel dust. 0. Ind. Hyg. 30: 32-36. (Cited 1n U.S. EPA,
19805)
-28-
-------
FMberg, L. 1948b. Prote1nur1a and kidney Injury among workers exposed to
cadmium and nickel dust 1n a storage battery plant. Proc. Int. Congr. Ind.
Med. 9: 641. (Cited In U.S. EPA, 1980b)
FMberg, L. 1950. Health hazards 1n the manufacture of alkaline accumu-
lators with special reference to chronic cadmium poisoning -- A clinical and
experimental study. Acta Med. Scand. 138 Supplement CCXL. (Cited In U.S.
EPA, 1980b)
Frlberg, L., M. Plscator, G.F. Nordberg and T. Kjellstrom. 1974. Cadmium
In the Environment, 2nd ed. CRC Press, Cleveland, OH. (Cited In U.S. EPA,
1980b)
Gunn, S.A., T.C. Gould and W.A.D. Anderson. 1963a. Cadmium-Induced
Interstitial .cell tumors 1n rats and mice and their prevention by zinc. J.
Natl. Cancer Inst. 31: 745-759. (Cited 1n U.S. EPA, 1980b)
Gunn, S.A., T.C. Gould and W.A.D. Anderson. 1963b. The selective Injurious
response of testlcular and epldldymal blood vessels to cadmium and Its
prevention by zinc. Am. J. Path. 42: 685-693. (Cited 1n U.S. EPA, 1980b)
Gunn, S.A., et al. 1964. Effect of zinc on cancerogenesis by cadmium.
Proc. Soc. Exp. B1ol. Med. 115: 653. (Cited 1n U.S. EPA, 1980b)
H111, C.H., G. Matrone, W.L. Payne and C.W. Barber. 1963. in vivo Inter-
actions of cadmium with copper, zinc, and Iron. J. Nutr. 80: 227-235.
(Cited 1n U.S. EPA, 1980b)
-29-
-------
Holden, H. 1965. Cadmium fume. Ann. Occup. Hyg. 8: 51-54. (Cited In
U.S. EPA, 1980b)
Hollander, M.L. and S.C. Carapella, Jr. 1978. Cadmium and cadmium alloys.
In,: Kirk-Othmer Encyclopedia of Chemical Technology, 3rd ed., Vol. 4, M.
Grayson and D. Eckroth, Ed. John WHey and Sons, Inc., NY. p. 387-396.
IARC (International Agency for Research on Cancer). 1976. Cadmium and
compounds, in: Cadmium, Nickel, Some Epoxldes, Miscellaneous Industrial
Chemicals, and General Considerations on Volatile Anaesthetics. IARC
Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man.
WHO, IARC, Lyon, France. Vol. 11, p. 39-76. (Cited In U.S. EPA, 1983a)
IARC (International Agency for Research on Cancer). 1982. IARC Monographs
on the Evaluation of the Carcinogenic Risk of Chemicals to Humans.
Chemicals, Industrial Processes and Industries Associated with Cancer In
Humans. WHO, IARC, Lyon, France. IARC Monographs Supplement 4.
Kajikawa, K., I. Nakanlshi and K. Kuroda. 1981. Morphological changes of
the kidney and bone of rats In chronic cadmium poisoning. Exp. Molec.
Pathol. 34: 9-24. (Cited 1n U.S. EPA, 1983a)
Kanlsawa, M. and H.A. Schroeder. 1969. Life term studies on the effect of
trace elements on spontaneous tumors 1n mice and rats. Cancer Res. 29:
892-895. (Cited 1n U.S. EPA, 1982)
-30-
-------
Kazantzls, G., et al. 1963. Renal tubular malfunction and pulmonary
emphysema 1n cadmium pigment workers. 0- J. Med. New Series. 32: 165.
(CHed in U.S. EPA, 1980b)
Kobayashi, J. 1970. Relation between the "Hai-1ta1" disease and the
pollution of river water by cadmium from a mine. Proc. Int. Water Pollut.
Res. Conf. 1-25/1-7. (CHed in U.S. EPA, 1980b)
Keller, L.D., J.H. Exon and J.6. Roan. 1975. Antibody suppression by
cadmium. Arch. Environ. Health. 30: 598-601.
Krasovskii, 6.N., et al. 1976. Toxic and gonadotropic effects of cadmium
and boron relative to standards for these substances in drinking water.
Environ. Health Perspect. 13: 69. (Cited in U-.S. EPA, 1980b)
Lane, R.E. and A.C.P. Campbell. 1954. Fatal emphysema in two men making'a
copper cadmium alloy. Br. J. Ind. Med. 11: 118. (Cited 1n U.S. EPA, 1980b)
Lauwerys, R., J.P. Buchet, H.A. Roels, J. Brouwers and 0. Stanescu. 1974.
Epidemiological survey of workers exposed to cadmium — Effect on lung,
kidney, and several biologic indices. Arch. Environ. Health. 28: 145-148.
(Cited in U.S. EPA, 1980b, 1983a)
Levy, L.S. and J. Clark. 1975. Further studies on the effect of cadmium on
the prostate gland. I. Absence of prostatlc changes in rats given oral
cadmium sulphate for two years. Ann. Occup. Hyg. 17: 205-211. (Cited in
IARC, 1976; U.S. EPA, 1982}
-31-
-------
Levy, L.S., J. Clark and F.J.C. Roe. 1975. Further studies on the effect
of cadmium on the prostate gland. II. Absence of prostatlc changes 1n mice
given oral cadmium sulphate for eighteen months. Ann. Occup. Hyg. 17:
213-220. (Cited 1n IARC, 1976; U.S. EPA, 1982)
Lewis, G.P., H. Lyle and S. Miller. 1969. Association between elevated
hepatic water-soluble protein-bound cadmium levels and chronic bronchitis
and/or emphysema. Lancet. 2: 1330-1333. (Cited 1n U.S. EPA, 1980b)
Loser, E. 1980. A 2-year oral carclnogenldty study with cadmium In rats.
Cancer Lett. 9(3): 191-198. (Cited 1n U.S. EPA, 1982)
Lyklns, B.W., Jr. and J.M. Smith. 1976. Interim Report on the Impact of
Public Law 92-500 on Municipal Pollution Control Technology. EPA 600/2-76-
018. (Cited In U.S. EPA, 1980b)
McCann, J., E. Choi, E. Yamasakl and B.N. Ames. 1975. Detection of carcin-
ogens as mutagens In the Salmonella/mlcrosome test: Assay of 300 chemicals.
Proc. Natl. Acad. Sd. 72: 5135-5139. (Cited 1n U.S. EPA, 1980b)
McLellan, J.S., et al. 1978. Measurement of dietary cadmium 1n humans. J.
Toxlcol. Environ. Health. 4: 131. (Cited 1n U.S. EPA, 1980b)
MEG/EPC (Multimedia Environmental Goals for Environmental Assessment).
1977. IERL, U.S. EPA, Research Triangle Park, NC. EPA 600/7-77-136.
(Cited 1n U.S. EPA, 1980b)
-32-
-------
Muramatsu, S. 1974. Research about cadmium-pollution in the Kakehashi
River basin. Jap. J. Pub. Health. 21: 299. (Cited in U.S. EPA, 1980b)
NAS (National Academy of Sciences). 1972. Water quality criteria. A
Report of the Committee on Water Quality Criteria. Cadmium. (Cited In U.S.
EPA, 1980b)
NIOSH (National Institute for Occupational Safety and Health). 1974.
Registry of Toxic Effects of Chemical Substances. U.S. DHEW, PHS, CDC.
Rockville, MD.
NIOSH (National Institute for Occupational Safety and Health). 1976.
Criteria for a Recommended Standard...Occupational Exposure to Cadmium.
U.S. DHEW, PHS, CDC, Rockville, MD. Publ. No. 76-192. (Cited in U.S. EPA,
1980b, 1983a)
Nogawa, K., et al. 1978. Statistical observations of the dose-response
relationships of cadmium based on epidemiologlcal studies in the Kakehashi
River basin. Environ. Res. 15: 185. (Cited in U.S. EPA, 1980b)
Page, G.W. 1981. Comparison of groundwater and surface water for patterns
and levels of contamination by toxic substances. Environ. Sc1. Technol.
15: 1475-1481.
Parlzek, J. 1957. The destructive effect of cadmium ion on testlcular
tissue and its prevention by zinc. J. Endocrin. 15: 56. (Cited in U.S.
EPA, 1980b)
-33-
-------
PaMzek, J., et al. 1969. Metabolic Interrelationships of trace elements.
Effects of zinc salts on the survival of rats Intoxicated with cadmium.
Phys1olog1a Bohemoslov. 18: 89. (Cited 1n U.S. EPA, 1980b)
Paterson, J.C. 1947. Studies on the toxldty of Inhaled cadmium. III. The
pathology of cadmium smoke poisoning 1n man and 1n experimental animals. J.
Ind. Hyg. Toxlcol. 29: 294. (CHed In U.S. EPA, 1980b, 1982)
Potts, C.L. 1965. Cadmium protelnurla -- The health of battery workers
exposed to cadmium oxide dust. Ann. Occup. Hyg. 8: 55-61. (Cited 1n U.S.
EPA, 1980b)
Rahola, T., et al. 1973. Retention and elimination of 155mCd 1n man.
In; Health Physics Problems of Internal Contamination. Akademlal K1ado,
Budapest. (CHed In U.S. EPA, 1980b)
Sato, K. 1977. Peripheral nerve lesions and cardnogenesls after long-term
administration of cadmium 1n the rat. Kumamoto Med. J. 51(4): 242-264.
(CHed In U.S. EPA, 1982)
Schroeder, H.A. and M. MHchener. 1971. Toxic effects of trace elements on
the reproduction of mice and rats. Arch. Environ. Health. 23: 102-106.
(CHed In U.S. EPA, 1980b, 1983a)
Schroeder, H.A., W.H. Vlnton and J.J. Balassa. 1963. Effects of chromium,
cadmium, and lead on the growth and survival of rats. J. Nutr. 80: 48-54.
(CHed 1n U.S. EPA, 1983a)
-34-
-------
Schroeder, H.A., J.J. Balassa and W.H. Vlnton, Jr. 1964. Chromium, lead,
cadmium, nickel and titanium 1n mice: Effect on mortality, tumors and tissue
levels. J. Nutr. 83: 239-250. (Cited 1n U.S. EPA, 1982, 1983a)
Schroeder, H.A., J.J. Balassa and W.H. Vlnton, Jr. 1965. Chromium, cadmium
and lead 1n rats: Effects on life span, tumors and tissue levels. J. Nutr.
86: 51-66. (Cited 1n U.S. EPA, 1982, 1983a)
Smith, J.P., J.C. Smith and A.J. McCall. 1960. Chronic poisoning from
cadmium fume. J. Path. Bact. 80: 287-296. (Cited 1n U.S. EPA, 1980b)
Smith, T.J., et al. 1976. Pulmonary effects of chronic exposure to air-
borne cadmium. Am. Rev. Resp. D1s. 114: 161. (Cited In U.S. EPA, 1980b)
Snider, G.G., et al. 1973. CentMlobular emphysema experimentally Induced
by cadmium chloride aerosol. Am. Rev. Resp. D1s. 108: 40. (Cited 1n U.S.
EPA, 1980b)
Starcher, B.C. 1969. Studies on the mechanism of copper absorption 1n the
chick. J. Nutr. 97: 321-326. (Cited 1n U.S. EPA, 1980b)
Suzuki, S., et al. 1969. Dietary factors Influencing upon retention rate
of orally administered CdCl~ 1n mice with special reference to
calcium and protein concentrations 1n diet. Ind. Health. 7: 155. (Cited
1n U.S. EPA, 1980b)
-35-
-------
Takenaka, S., H. Oldlges, H. Konlg, 0. Hochralner and G. Oberdoerster.
1983. Carclnogenldty of cadmium aerosols in Wlstar rats. J. Natl. Cancer
Inst. 70: 367-373.
Thun, M.J., T.M. Schnorr, A.B. Smith and W.E. Halperln. 1984. Mortality
among a cohort of U.S. cadmium production workers: An update. NIOSH,
Washington, DC. (Unpublished) (Cited 1n U.S. EPA, 1984)
Tshuchlya, K. 1967. Prote1nur1a of workers exposed to cadmium fume — The
relationship to concentration 1n the working environment. Arch. Environ.
Health. 14: 875-880. (Cited 1n NIOSH, 1976; U.S. EPA, 1983a)
U.S. EPA. 1975. Scientific and technical assessment report on cadmium.
National Environmental Research Center, Research Triangle Park, NC. EPA
600/6-75-003. (Cited 1n U.S. EPA, 1980b)
U.S. EPA. 1980a. Guidelines and Methodology Used 1n the Preparation of
Health Effects Assessment Chapters of the Consent Decree Water Quality
Criteria. Federal Register. 45:79347-79357.
U.S. EPA. 1980b. Ambient Water Quality Criteria for Cadmium. Environ-
mental Criteria and Assessment Office, Cincinnati, OH. EPA 440/5-80-025.
NTIS PB 81-117368.
U.S. EPA. 1982. Review of Tox1colog1c Data In Support of Evaluation for
Carcinogenic Potential of Cadmium and Compounds. Prepared by Carcinogen
Assessment Group, OHEA, Washington, DC for the Office of Solid Waste and
Emergency Response, Washington, DC.
-36-
-------
U.S. EPA. 1983a. Reportable Quantity for Cadmium (and compounds). Pre-
pared by the Environmental Criteria and Assessment Office, Cincinnati, OH,
OHEA for the Office of Solid Waste and Emergency Response, Washington, DC.
U.S. EPA. 1983b. Methodology and Guidelines for Reportable Quantity Deter-
minations Based on Chronic Toxlcity Data. Prepared by the Environmental
Criteria and Assessment Office, Cincinnati, OH, OHEA for the Office of Solid
Waste and Emergency Response, Washington, DC.
U.S. EPA. 1984. Updated mutagenlcity and cardnogenicity assessment of
cadmium. Carcinogen Assessment Group, OHEA. EPA 600/8-83-025B. NTIS PB
85-116150.
Washko, P.W. and R.J. Cousins. 1976. Metabolism of 109Cd In rats fed
normal and low-calcium diets. J. Toxlcol. Environ. Health. 1: 1055.
(Cited in U.S. EPA, 1980b)
Worker, N.A. and B.B. Mlgicovsky. 1961. Effect of vitamin D on the utili-
zation of zinc, cadmium and mercury 1n the chick. J. Nutr. 75: 222.
(Cited in U.S. EPA, 1980b)
WHO (World Health Organization.) 1971. International Standards for
Drinking Water, 3rd ed. WHO, Geneva. (Cited in U.S. EPA, 1980b)
WHO (World Health Organization) Task Group. 1977. Environmental health
aspects of cadmium. WHO, Geneva. (Cited in U.S. EPA, 1980b)
-37-
-------
Yuhas, E.M., T.S. M1ya and R.C. Schnell. 1979. Dose-related alterations 1n
growth and mineral disposition by chronic oral cadmium administration 1n the
male rat. Toxicology. 12: 19-29. (CHed 1n U.S. EPA, 1983a)
-38-
-------
APPENDIX
Summary Table for Cadmium
Carcinogenic Effects
Carcinogenic Species Experimental Effect Unit Risk Reference
Potency Dose/Exposure or q-|*
Inhalation 7.8 Thun et a!.,
(mg/kg/day)'1 1984;
U.S. EPA,
1984
Oral NO*
*Ev1dence 1s Inadequate to consider cadmium a carcinogen through the oral
route. The additional exposure Increment through drinking water should be
restricted to correspond to 10 yg/S. (U.S. EPA, 1980b).
ND = Not derived
-39-
------- |