EPA/600/8-89/087
August, 1988
HEALTH EFFECTS ASSESSMENT
FOR CADMIUM
ENVIRONMENTAL CRITERIA AND ASSESSMENT OFFICE
OFFICE OF HEALTH AND ENVIRONMENTAL ASSESSMENT
OFFICE OF RESEARCH AND DEVELOPMENT
U.S. ENVIRONMENTAL PROTECTION AGENCY
CINCINNATI, OH 45268
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DISCLAIMER
This document has been reviewed 1n accordance with the U.S. Environ-
mental Protection Agency's peer and administrative review policies and
approved for publication. Mention of trade names or commercial products
does not constitute endorsement or recommendation for use.
11
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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 In
this document should be considered as preliminary and reflect limited
resources allocated to this project. Pertinent toxicologic and environ-
mental data were located through on-line literature searches of the TOXLINE,
CANCERL1NE and the CHEMFATE/DATALOG data bases. The basic literature
searched supporting this document Is current up to May, 1987. Secondary
sources of Information have also been relied upon In 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. 1980a. Ambient Water Quality Criteria for Cadmium.
Prepared by the Office of Health and Environmental Assessment,
Environmental Criteria and Assessment Office, Cincinnati, OH for
the Office of Water Regulations and Standards, Washington, 0C. EPA
440/5-80-025. NTIS PB 81-117368.
U.S. EPA. 1982. Review of Toxicologic Data 1n Support of Evalua-
tion for Carcinogenic Potential of Cadmium and Compounds. Prepared
by the Office of Health and Environmental Assessment, Carcinogen
Assessment Group, Washington, DC for the Office of Solid Waste and
Emergency Response, Washington, DC.
U.S. EPA. 1983. Reportable Quantity for Cadmium (and Compounds).
Prepared by the Office of Health and Environmental Assessment,
Environmental Criteria and Assessment Office, Cincinnati, OH for
the Office of Solid Waste and Emergency Response, Washington, DC.
U.S. EPA. 1985a. Updated mutagenicity and carcinogenicity assess-
ment of cadmium. Prepared by the Office of Health and Environ-
mental Assessment, Carcinogen Assessment Group, Washington, DC.
NTIS PB 85-243533.
The Intent 1n these assessments 1s to suggest acceptable exposure levels
for noncarclnogens and risk cancer potency estimates for carcinogens
whenever sufficient data were available. Values were not derived nor were
larger uncertainty factors employed when the variable data were limited In
scope tending to generate conservative (i.e., protective) estimates.
Nevertheless, the Interim values presented reflect the relative degree of
hazard or risk associated with exposure to the chemlcal(s) addressed.
Whenever possible, two categories of values have been estimated for
systemic toxicants (toxicants for which cancer 1s not the endpolnt of
concern). The first, RfD$ (formerly AIS) or subchronlc reference dose, 1s
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 lifespan).
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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 In ambient air or water where lifetime
exposure 1s assumed. Animal data used for RFD$ 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. These
values are developed for both Inhalation (RfDjl) an^ ora^ (RfDgQ)
exposures.
The RfD (formerly AIC) 1s similar 1n concept and addresses chronic
exposure. It Is an estimate of an exposure level that would not be expected
to cause adverse effects when exposure occurs for a significant portion of
the lifespan [see U.S. EPA (1980b) for a discussion of this concept]. The
RfD 1s route-specific and estimates acceptable exposure for either oral
(RfDg) or Inhalation (RfDj) with the Implicit assumption that exposure
by other routes 1s Insignificant.
Composite scores
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ABSTRACT
In order to place the risk assessment evaluation 1n proper context,
refer to the preface of this document. The preface outlines limitations
applicable to all documents of tMs series as well as the appropriate
Interpretation and use of the quantitative estimates presented.
A dose-related Increase 1n lung cancer has been reported 1n rats exposed
to cadmium chloride aerosols. U.S. EPA (1985a) based cancer risk assessment
on the maximum likelihood estimate of unit risk of 1.8xl0~3 for 1
tig/ma In a 1r, based on an epidemiologic study associating occupational
exposure with lung cancer. This unit risk corresponds to a unit risk slope
of 6.1 (mg/kg/day)-1. This value was verified by the CRAVE Workgroup
(U.S. EPA, 1988a).
Cancer Induction has not been shown 1n animal studies by the oral route
(possibly due to poor absorption). U.S. EPA (1988b) calculated an RfO for
oral exposure to cadmium based on the generally accepted critical level of
cadmium In the renal cortex, 200 yg/g, which Is associated with abnormal
kidney function In humans. A pharmacokinetic model was used to calculate a
dally oral dose that would produce this level In a chronic exposure situa-
tion. The resulting RfD was 0.04 mg/day or 0.0005 mg/kg/day for a 70 kg
adult for waterborne exposures. In addition, U.S. EPA (1988b) calculated an
RfO of 0.001 mg/kg/day for dietary exposures by reducing the assumed absorp-
tion factor.
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ACKNOWLEDGEMENTS
The Initial draft of this report was prepared by Syracuse Research
Corporation for EPA1s Environmental Criteria and Assessment Office,
Cincinnati, OH. Dr. Christopher DeRosa and Karen Blackburn were the
Technical Project Monitors and Helen Ball was the Project Officer. The
final documents 1n this series were prepared for the Office of Emergency and
Remedial Response, Washington, DC.
Scientists from the following U.S. EPA offices provided review coitments
for this document series:
Environmental Criteria and Assessment Office, Cincinnati, OH
Carcinogen Assessment Group
Office of Air Quality Planning and Standards
Office of Solid Waste
Office of Toxic Substances
Office of Drinking Water
Office of Pesticide Programs
Editorial review for the document series was provided by the following:
Judith Olsen and Erma Durden
Environmental Criteria and Assessment Office
Cincinnati, OH
Technical support services for the document series was provided bv the
following:
Bette Zwayer, Pat Daunt, Karen Mann and Jacky Bohanon
Environmental Criteria and Assessment Office
Cincinnati, \>H
v1
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TABLE OF CONTENTS
Page
1. ENVIRONMENTAL CHEMISTRY AND FATE 1
2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS 3
2.1. ORAL 3
2.2. INHALATION 4
3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS 5
3.1. SUBCHRONIC 5
3.1.1. Oral 5
3.1.2. Inhalation 7
3.2. CHRONIC. 7
3.2.1. Oral 7
3.2.2. Inhalation 9
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS 12
3.3.1. Oral 12
3.3.2. Inhalation 12
3.4. TOXICANT INTERACTIONS 12
4. CARCINOGENICITY 14
4.1. HUMAN DATA ' 14
4.1.1. Oral 14
4.1.2. Inhalation 14
4.2. BIOASSAYS 16
4.2.1. Oral 16
4.2.2. Inhalation 17
4.3. OTHER RELEVANT DATA 18
4.4. WEIGHT OF EVIDENCE 18
5. REGULATORY STANDARDS AND CRITERIA 25
6. RISK ASSESSMENT 27
6.1. REFERENCE DOSE SUBCHRONIC (RfDs) 27
6.1.1. Oral (RfOso) 27
6.1.2. Inhalation (RfDSj) 27
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TABLE OF CONTENTS
Page
6.2. REFERENCE DOSE (RFC) 27
6.2.1. Oral (RfDg) 27
6.2.2. Inhalation (RfDj) 28
6.3. CARCINOGENIC POTENCY (q-|*) 28
6.3.1. Oral 28
6.3.2. Inhalation 29
7. REFERENCES 31
APPENDIX: Summary Table for Cadmium 48
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LIST OF TABLES
No. Title Page
3-1 Subchronlc Oral Toxicity of Cadmium 6
3-2 Chronic Oral Toxicity of Cadmium 8
3-3 Chronic Inhalation Toxicity of Cadmium from Occupational
Exposure 10
4-1 Epidemiology of Cadmium-associated Respiratory Cancer .... 15
4-2 Mutagenicity of Cadmium: Evaluations Using Prokaryotes. ... 19
4-3 Mutagenicity of Cadmium: Evaluations Using Eukaryotlc
Cells 20
4-4 Mutagenicity of Cadmium: Evaluations Using Insects 21
4-5 Mutagenicity of Cadmium: In vitro Chromosome Aberrations. . . 22
4-6 Mutagenicity of Cadmium: In vivo Mammalian Systems 23
1x
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LIST OF ABBREVIATIONS
BCF
Bloconcentratlon factor
bw
Body weight
CAS
Chemical Abstract Service
CS
Composite score
DMSO
Dimethyl sulfoxide
DNA
Deoxyribonucleic acid
HA
Health advisory
LOEL
Lowest-observed-effect level
NOAEL
No-observed-adverse-effect level
PEL
Permissible exposure limit
RfD
Reference dose
RfDi
Inhalation reference dose
RfD0
Oral reference dose
RfDS
Subchronlc reference dose
RfDsi
Subchronlc Inhalation reference dose
RfD§o
Subchronlc oral reference dose
SNARL
Suggested no adverse response level
STEL
Short-term exposure limit
TLV
Threshold limit value
TWA
Time-weighted average
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1. ENVIRONMENTAL CHEMISTRY AND FATE
Cadmium 1s a metal belonging to Group IIB of the Periodic Table.
Elemental cadmium has a CAS Registry number of 7440-43-9. It occurs 1n the
environment In the zero valence (metal and alloys) and In the +2 valence
(compound) states. Besides forming simple Ionic and covalent compounds with
anions and groups, cadmium also forms complexes with ammonia, cyanide,
halldes and thlocyanate (Hollander and Carapella, 1978). Several of the
Inorganic cadmium compounds are quite soluble 1n water (for example,
chloride and sulfate). Cadmium oxide and sulfide are almost Insoluble In
water (Weast, 1985).
In the atmosphere cadmium Is expected to be present as dust and fumes
from smelting of ores, manufacturing and reprocessing of alloys, recycling
of steel scrap, emissions of coal-fired power plants and Incineration of
solid wastes (Flshbeln, 1981). The atmospheric fate of cadmium has not been
studied comprehensively. Any chemical Interaction of cadmium compounds In
the atmosphere Is likely to result 1n speclatlon (for example, 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 mechanism for atmospheric cadmium may be wet and dry
deposition (Flshbeln, 1981). The atmospheric half-Hfe for the physical
removal mechanism Is expected to depend on the particle size and particle
density of atmospheric cadmium. There 1s considerable evidence that cadmium
Is concentrated In smaller (<3 ym) particles 1n the atmosphere (Flshbeln,
1981). Therefore, It may have a long half-life 1n the atmosphere, although
no estimate for this half-life Is available.
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The dominant fate of cadmium 1n aquatic media 1s sedimentation through
sorption onto Iron oxides, magnesium oxides or organic matter; copredplta-
tlon with hydrous Iron, aluminum and manganese oxides; and Isomorphous
substitution 1n carbonate minerals. Smaller amounts of cadmium may persist
In the aquatic phase 1n solution, either as hydrated cations or as organic
or Inorganic complexes (Davles-Colley et al., 198*; Callahan et al., 1979).
In most unpolluted water, the majority of soluble cadmium may be present
as the hydrated cation; whereas, 1n polluted water, complexatlon with
organic material may be most Important (Callahan et al., 1979). Under
anaerobic conditions, sediments may commonly act as a sink for cadmium In
the form of Us bisulfide or polysulflde (Davles-Colley et al., 1985).
BCFs for cadmium In aquatic organisms have been determined by a number
of Investigators. In freshwater and marine fish, BCFs vary between 1000 and
3000 (Callahan et al., 1979). These BCF values suggest that bloaccumulatlon
1n aquatic organisms would be significant.
The fate of cadmium In soil 1s complicated, depending upon soil charac-
teristics and the concentrations of a large number of organic and Inorganic
species. The two major mobile forms of cadmium 1n soils are soluble 1on1c
forms and complexed (with organic and Inorganic Ugands) forms. Both the
free 1ons and the complexed species are subject to 1on exchange, nonspecific
adsorption, precipitation and surface complexatlon (GerrHse and Van Drlel,
1984). In general, cadmium Is expected to adsorb strongly to soil with
sorption Increasing as the organic content of the soil Increases (Elliot et
al., 1986). Conditions that may weaken the adsorption process 1n soil
(i.e., acidic conditions or Increased salinity) may enhance desorptlon from
soil and lead to Increased mobility. For near neutral and alkaline soils,
precipitation and complexatlon reactions will be more Important than adsorp-
tion (Elliot et al., 1986).
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2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS
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 In the review). Stoklnger (1981) reported that 88% of an oral
dose of cadmium administered to rats was excreted 1n the feces. About 1% of
the dose was located 1n the liver and the kidneys. These data suggest a
maximum for gastrointestinal absorption of ~12%. More recently, Andersen et
al. (1906) administered 10*Cd 1n water to male CBA mice by stomach tube
and determined elimination and body retention In a gamma counter. Doses
ranged from 140-790 ymol/kg (~16-89 mg/kg). Gastrointestinal absorption
was estimated as residual body burden after the rapid (elimination) phase
and ranged from 1.4-4.2%. Absorption Increased with Increasing dose because
of cadmium-Induced constipation, which Increased gut passage time. Absorp-
tion appears to be slightly more extensive In humans, with reported absorp-
tion 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 1n calcium result 1n a significant Increase In cadmium
absorption. Diets deficient In vitamin D, protein, zinc. Iron and copper
also Increase the extent of cadmium absorption (Worker and Mlglcovsky, 1961;
Suzuki et al., 1969; Banls et al., 1969; Bunn and Matrone, 1966; H111 et
al., 1963). Ascorbic acid deficiency has been observed to Increase cadmium
toxicity (Fox and Fry, 1970).
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2.2. INHALATION
Absorption of cadmium from the respiratory tract appears to be much more
extensive than absorption from the gastrointestinal tract. Up to 25X of
Inhaled cadmium dust and aerosols may be absorbed when a large proportion of
the particles are In the resplrable range and the compound 1s relatively
soluble (U.S. EPA, 1980a). Lewis et al. (1977) exposed rats, guinea pigs
and cynomolgus monkeys to cadmium fumes at a TWA of 1 mg/m" for 3-6 months
before sacrifice. Based on estimations of Inhaled doses, the Investigators
determined that rats and guinea pigs retained 11 and 36% of the dose after 3
months and monkeys retained 35% of the dose after 6 months. Up to 50% of
the cadmium 1n cadmium fumes or cigarette smoke may be absorbed (WHO Task
Group, 1977; Ellnder et al., 1976).
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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, which results In
disturbances In mineral metabolism and (eventually) formation of kidney
stones or osteomalacia, 1s the major effect 1n 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. Subchronlc oral toxicity data for cadmium are summarized 1n
Table 3-1.
No data were located on the subchronlc oral exposure of humans to
cadmium.
Yuhas et al. (1979) administered cadmium acetate (0, 1, 10 or 100 mg
Cd/t) 1n the drinking water to male Sprague-Dawley rats for 13 weeks. The
reported doses are not consistent with the reported water concentration,
o
water consumption and body weights. Based on the data reported, the correct
doses appear to be 0, 0.118, 0.947 and B.041 mg/kg bw/day. At 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, cadmium content of bone was
Increased. Serum alkaline phosphatase levels was Increased 1n all dose
groups and serum phosphorus was elevated 1n the 100 ppm cadmium group. No
histological effects were observed 1n any dose group. In a dietary study,
6.75 mg/kg bw/day was associated with mortality and 2.25 mg/kg bw/day was
associated with anemia (Fltzhugh and Melller, 1941).
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TABLE 3-1
Subchronlc Oral Toxicity of Cadmium
Compound
Species/
Strain/Sex
Dose
Length of
Exposure
Effects
Reference
Cadmium
acetate
rats/Sprague-
Dawley/M
i
CT>
I
Cadmium
rats/NR/NR
Cadmium
chloride
mice/Swiss
Uebster/NR
o
rsj
0, 1, 10 or 100 mg
Cd/t drinking water
(0.118. 0.947 or
8.041 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)*
3 or 300 mg Cd/t
H20 (0.57 or 57
mg/kg bw/day)
13 weeks Decreased weight gain at
100 mg/t; no effect on
cellular structure of
liver, kidney or duodenum
at any dose; Increased serum
alkaline phosphatase In all
dose groups; Increased cad-
mium content In bone at 10
and 100 mg Cd/l H?0; de-
creased zinc content of
bone at 100 mg/t.
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
70 days Decrease In the number of
lymphocytes secreting anti-
bodies to sheep red blood
cells at both dose levels;
necrosis of renal epithelial
cells In the proximal convo-
luted tubules and collecting
tubules at both doses
Yuhas et al.,
1979
Fltzhugh and
Melller, 1941
Koller
et al., 1975
IN)
CD
OO
*Est1mated using a food factor for rats of 0.05 (U.S. EPA, 1986a).
NR = Not reported
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Koller et al. (1975) administered drinking water containing 3 or 300 mg
Cd/s. to Swiss Webster mice (390 mice/group) for 70 days. The controls
consisted of 80 mice that received delonlzed 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 1n the
proximal convoluted tubules and collecting tubules. Assuming that mice
drink 0.0057 4 water /day and weigh 0.03 kg (U.S. EPA, 1986a), 3 mg/l
corresponds to a dose of 0.57 mg/kg bw/day.
3.1.2. Inhalation. The only subchronlc Inhalation study available was
that of Kolakowskl et al. (1983), who exposed rats to cadmium oxide fumes at
concentrations of 0.16 or 1 mg Cd/m3, 5 hours/day, 5 days/week for 3-6
months. Rats were examined for effects on cardiac muscle ultrastructure.
Treated rats experienced alterations of Intercalated disc structure that
were dependent on the level and length of exposure.
3.2. CHRONIC
3.2.1. Oral. Chronic oral toxicity data for cadmium are summarized 1n
Table 3-2.
Schroeder et al. (1963, 1964, 1965) administered cadmium acetate 1n the
drinking water (5 mg Cd/l) to Long-Evans rats and Charles River mice for
their lifetimes. Survival was decreased In both sexes of rats and 1n 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 altered renal morphology. Renal degeneration and
necrosis have also been reported In Ulstar rats given 123 mg Cd (from
cadmium chloride)/! drinking water (KaJIkawa et al., 1981).
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TABLE 3-2
Chronic Oral Toxicity of Cadmium
Compound Species/ Dose Length of Effects Reference
Strain/Sex Exposure
Cadmium
rats/Long-
0 or 5 mg
lifetime
Decreased survival; systolic
Schroeder
acetate
Evans/H,F
Cd/l H20
(-2.5 years)
hypertension; renal and
et al., 1963,
cardiac arteriosclerosis and
1964, 1965;
cardiac hypertrophy; severe
Kanlsawa and
vestibular disturbances
Schroeder, 1969
Cadmium
mice/Charles
0 or 5 mg
lifetime
Decreased survival In males;
Schroeder
acetate
River/N,F
Cd/l H20
(-2 years)
hyallnlzed glomeruli,
et al., 1964;
thickened basement membranes.
Kanlsawa and
and a reduction In the lumen/
Schroeder, 1969
wall ratio In the arterioles
of the kidneys
Cadmium
rats/Wlstar/
0 or 123 mg
4-91 weeks
Vacuolar degeneration of the
KaJIkawa
NR
Cd/l H20
kidneys; cellular necrosis
et al., 1981
In the proximal convoluted
tubules; Increased urinary
protein excretion
NR
human/NA/
228 pg/day
lifetime
1ta1-1tal disease; tubular
Frlberg et al.,
H.F
(estimated
proteinuria
1974; Nuramatsu,
LOEL; 30
1974; Nogawa
tig/day for
et al., 1978;
a 70 kg man)
U.S. EPA, 19B0a
NR
human/NA/
250-350 tig
50 years
Renal dysfunction
Frlberg et al..
H.F
Cd/day (esti-
1974
mated LOEL)
NA - Not applicable; NR = not reported
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The U.S. EPA (1980a) has estimated the threshold dose for Induction of
proteinuria, based upon dietary Intake data from areas of Japan 1n which
1ta1-1ta1 disease 1s prevalent. In these areas, -85% of the dally cadmium
Intake 1s derived from rice (Muramatsu, 1974). Nogawa et al. (1978) found
that the prevalence of tubular proteinuria 1n persons <70 years old did not
exceed the prevalence In control populations until the cadmium levels in
rice were >0.40-0.49 vg/g rice. The U.S. EPA (1980a) estimated a L0EL 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 tig
Cd/day.
This L0EL 1s In good agreement with the estimate of 164-616 tig Cd/day
determined by Frlberg et al. (1974), based on the "generally accepted"
critical cadmium level at which renal dysfunction occurs, 200 tig Cd/g wet
weight of renal cortex. The Frlberg assessment utilized a tox1cok1net1c
model for cadmium accumulation In the renal cortex. The model assumed a
body weight of 70 kg, an adult kidney weight of 300 g, an adult calorie
Intake of 2500 cal., gastrointestinal absorption of 4.5%, one-third of the
body burden 1n the kidney and that the concentration in the renal cortex Is
50% higher than the average kidney concentration. The range of dally
Intakes, from 196-616 vg/day to reach 200 yg/g wet weight 1n the cortex
by age 50, was estimated by varying the percent excretion per day from
0-0.02, which effectively changes the biological half-Hfe by an order of
magnitude. Frlberg (1984) felt that the three lowest excretion rates that
corresponded to Intakes of 164, 196 and 248 fig/day gave the most plausible
Intake figures.
3.2.2. Inhalation. Chronic Inhalation toxicity data for cadmium are
summarized 1n Table 3-3.
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TABLE 3-3
Chronic Inhalation Toxicity of Cadmium from Occupational Exposure
Compound
Dose
Length of
Exposure
Effects
Reference
Cadmium dust
(<5 iit diameter)
21 i«g Cd/m*
(66 v9 total Cd/ma)
21-40 years
Decreased pulmonary ventilatory
function; Increased Incidence
of kidney dysfunction; In-
creased proteinuria
Lauwerys
et al., 1974
Cadmium fumes
125 yg Cd/m"
9 months to
12 years
Anemia; elevated urinary
protein levels
Tsuchlya, 1967
Cadmium Iron
..oxide dust
NR
NR
Emphysema; proteinuria
Frlberg,
1948a.b. 1950
Cadmium fumes
<100 ng/m*
>21 years
Renal dysfunction
Falck et al.,
1983
Various compounds
of cadmium plus
nickel or copper
exposure classified
as "always low,"
"ever medium" or
"ever high"
NR
Significantly Increased Inci-
dence of deaths from bron-
chitis or emphysema In the
"ever high" group, directly
related to duration of exposure
Armstrong and
Kazantzls, 1985
NR - Not reported
fS)
\
ro
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In a study of workers exposed to cadmium Iron oxide dust 1n a Swedish
alkaline battery factory, Frlberg (1948a,b, 1950) observed 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 Is
only observed following Inhalation exposure.
Tsuchlya (1967) studied 13 workers who had been exposed to cadmium fumes
(TWA - 125 yg Cd/m8) 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 pg Cd/m8 for 21-40 years. The total airborne cadmium concentra-
tion averaged 66 yg Cd/m8. The control group was matched to the exposed
group by age, sex, weight, height, smoking habits and socioeconomic status.
Kidney dysfunction, as Indicated by proteinuria, was observed In 68% of the
cadmium-exposed group as compared with 15% 1n the control group. Measures
of pulmonary ventilatory function (forced vital capacity, forced expiratory
volume/second and peak expiratory flow rate) were reduced 1n the cadmium-
exposed group.
Falck et al. (1983) examined 33 male workers exposed to cadmium fumes at
or below the current OSHA (1985) PEL of 100 yg/m8 for at least 21 years.
These workers had an Increased Incidence of renal dysfunction compared with
a control group, and this effect did not appear to be related to smoking
habits or Ingestion of cadmium. In British workers exposed to various
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compounds of cadmium, some In addition to nickel or copper, Armstrong and
Kazantzls (1985) found a positive association with Increased risk of death
from bronchitis or emphysema. Risk appeared to Increase with duration of
exposure. There was also a marginal but not statistically significant
association with Increased risk of death from nephritis or nephrosis In the
"ever high" group.
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS
3.3.1. Oral. Dixon et al. (1976) reported that a concentration of 0.1 mg
cadm1um/i administered to rats 1n their drinking water for 90 days pro-
duced no detectable effects on reproduction. Schroeder and MUchener (1971)
Investigated the effect of 10 mg cadmium (unspecified soluble salt)/t
drinking water on reproductive performance 1n 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.
Cadmium has also been demonstrated to be teratogenic and to reduce fertility
following Intravenous, Intraperitoneal and subcutaneous administration (U.S.
EPA, 1980a).
3.3.2. Inhalation. Pertinent data regarding the teratogenicity or other
reproductive effects of Inhaled cadmium were not located 1n the available
literature.
3.4. TOXICANT INTERACTIONS
The absorption and toxicity of cadmium may be altered by a number of
dietary factors (see Section 2.1.). In experimental animals, zinc has been
reported to prevent or reduce cadmium-Induced testicular damage, teratogenic
effects, growth Inhibition and tumor Induction (Parlzek, 1957; Parlzek et
al., 1969; Ferm and Carpenter, 1967; Gunn et al., 1963a,b, 1964). Increased
dietary copper has been demonstrated to prevent or reduce cadmium-Induced
0038H
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mortality, anemia and degeneration of aortic elastln (Hill et al., 1963;
Bunn and Matrone, 1966). Dietary cadmium Inhibits Intestinal absorption of
copper and calcium, possibly leading to deficiencies of these elements
(Starcher, 1969; Ando et al., 1977; Kobayashl, 1970).
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4. CARCINOGENICITY
4.1. HUMAN DATA
4.1.1. Oral. Pertinent data regarding the oral carcinogenicity of
cadmium In humans were not located 1n the available literature.
4.1.2. Inhalation. It Is beyond the scope of this document to present
all of the available epidemiologic data concerning cadmium and cancer. A
summary of relevant studies was compiled by Oberdorster (1986) (Table 4-1).
The Carcinogen Assessment Group (CAG) has prepared an 1n-depth review of the
evidence available concerning the carcinogenicity of cadmium (U.S. EPA,
1985a). The conclusions drawn from this review were that the weight of the
evidence suggests a significant risk of lung cancer from exposure to
cadmium, that the evidence that cadmium 1s a potent lung carcinogen Is to be
considered limited, and that cadmium 1s classified as a B1 carcinogen.
U.S. EPA (1985a) considered that the data presented by Thun et al.
(1985) provided the strongest evidence for cadmium as a causative agent In
human cancer. The Thun et al. (1985) study examined a cohort of cadmium
smelter workers employed for >2 years 1n a production 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; 7.00
deaths from this cause would have been expected based on calendar time
age-specific death rates for white males In the United States. In this
study, there was a 2-fold excess risk of lung cancer 1n cadmium smelter
workers; this was attributed to cadmium exposure and not to the confounding
factors of cigarette smoking and arsenic exposure. Other studies provided
supporting evidence for Increased risk of lung cancer from cadmium exposure,
but these studies were less well-conducted than the Thun et al. (1985) study.
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TABLE 4-1
Epldealology of CiMia-issoclited Respiratory Cancer*
o
u
X
Exposure
Study Group
findings
Reference
CdO dust
14 workers In an alkaline
battery factory
One cancer of bronchus (no control group for
coaparlson)
Potts. 1965
CdO dust
24ft workers
No excess lung cancers
Kipling and Uaterhouse,
1967
Cd(0H)2, NI{0H)2
536 workers In an alkaline
battery factory
No excess cancer of any organ
Huaperdlnck, 1968
CdO (soae As)
292 cadalua saelter workers
Increased aortalIty froa lung cancer (no
correction for arsenic or saoklng)
Leaen et al.. 1976
Cd(0H)2. NI(0N)2
269 workers In a cadalua-nlckel
factory and 94 cadalua-copper
alloy workers
Excess cancer of nasopharynx (concurrent
exposure to nickel)
KJellstrte et al.. 1979
1
cn
i
CdO (fuw)
347 cadatua-copper alloy
workers and 624 vicinity
workers
Excess deaths froa pulaonary disease (not
cancer), elevated risk of lung cancer In
vicinity workers (arsenic?, saoklng?)
Molden, 1980
CdO md Cd(0H)2 dust.
N1(0H)2
3025 nlckel-cadalun battery
workers
Significant Increase In respiratory cancer In
'highly or aoderately' exposed workers but not
In "high exposure" group (nickel hydroxide and
welding funes confounding factors?)
Sorahan and Uaterhouse,
1983
CdO dust and fuse, CdS,
dust froa Cd stabilizers
6995 aale cadalua workers of
1? different plants
Significant excess of lung cancers In the
'always low" exposure group only, probably not
related to cadalua; high risk of dying froa
bronchitis In "ever high' exposure group
Arastrong and Kaiantzls,
1983
CdO dust, NI(0H)2
S22 workers of cadalua-nlckel
battery factory
Insignificant Increase In lung cancer (eight
observed, six expected); one cancer of naso-
pharaynx (nickel?)
Cllnder et al.. 1985
(update of study by
Kjellstrfia et al. (1979)]
CdO dust and fuae.
CdS04, CdS (sow As)
602 cadalua production workers
lung cancer Incidence Increased significantly
with cuaulatlve exposure; saoklng and arsenic
exposure did not account for Increase
Thun et al., 1985
(update of study by
Leaen et al. (1976)]
o
—j
N
CO
CdO dust and fuae. CdS.
CdS04 (sow As)
672 cadalua production workers
[saae plant as In Thun et al.
(1985) study]
No excess lung cancer froa cadalua when
corrected for personal saoklng history and
arsenic exposure
Mhlte et al., 1985
00
00
'Source: Oberdorster, 1986
-------
U.S. EPA (1985a) 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
with the general population.
2. Exposure 1s confounded by exposure to arsenic, a known respira-
tory carcinogen.
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, U.S. EPA (1985a) felt 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 or
more protective estimate.
In addition to an increased Incidence of lung cancer, exposure to
cadmium has been weakly associated with an Increased Incidence of prostatic
cancer 1n humans (Plscator, 1981; Lemen et al., 1976; Kipling and Water-
house, 1967). U.S. EPA (1985a) concluded that the evidence was Insufficient
to conclude that cadmium was a prostatic carcinogen.
4.2. BIOASSAYS
4.2.1. Oral. Schroeder et al. (1964) administered drinking water
containing cadmium acetate (5 yg Cd/mt H^O) to a group of 48 male and
39 female mice for their lifetime. Significant decreases 1n the Incidence
of pulmonary tumors and total tumor Incidence were observed In the cadmium-
treated animals; however, mean survival time was also reduced.
0038H
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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
drinking water containing cadmium acetate (5 yg Cd/ml) to Long-Evans
rats for their lifetime. 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.
Decker et al. (1958) administered cadmium chloride (0.1, 0.5, 2.5, 5.0
or 10.0 mg Cd/(L drinking water) to groups of eight male and eight female
Sprague-Dawley rats for 1 year. No tumors were found that could be
attributed 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/m* for the three groups, respectively.
Forty rats were Included In each cadmium group and 41 control rats were
exposed to filtered air. Rats were exposed continuously for 18 months.
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Following the treatment period rats 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 In 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 mutagenicity studies with cadmium are summarized 1n
Tables 4-2 through 4-6. U.S. EPA (1985a) contains a thorough review of the
available literature concerning cadmium mutagenicity. Results obtained 1n a
variety of tests have been mixed. It appears that cadmium Is mutagenic 1n
some test systems under some conditions; however, the relationship between
mutagenicity and carcinogenicity 1s not as well established for metals as
for some other classes of carcinogens. HcCann et al. (1975) reported that
75% of the metal carcinogens tested In the standard Ames test produced
negative results.
Evaluation of lymphocytes from occupatlonally exposed workers has
produced equivocal results and tests for chromosomal aberrations In plants
have generally been positive (U.S. EPA, 1985a).
In a short-term screening test, Sanders and Mahaffey (1984) observed an
Increase In mammary tumors and an Increase 1n tumors at multiple sites In
male rats that were given 1-3 Intratracheal Instillations of cadmium oxide.
4.4. WEIGHT OF EVIDENCE
IARC (1982) has classified cadmium and certain cadmium compounds as
Group 2B chemicals. They considered the evidence for carcinogenicity to
humans to be "limited,* since 1t is "still far from clear which were the
target organs for the putative carcinogenic action of cadmium in humans."
0038H -18- 07/18/88
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TABLE 4-2
Mutagenicity of Cadmium: Evaluations Using Prokaryotes*
Test
Organism
Cadmium Compound
Activation
Results
Salmonella
tvDhlmurlum
aqueous cadmium
chloride
phenobarbltol-
Induced rat liver
negative
S.
tvDhlmurlum
cadmium red 1n
DMSO
Aroclor-lnduced
mouse liver
negative
S.
tvDhlmurium
cadmium chloride
unlnduced mouse
Hver
negative
S.
tvohlmurlum
cadmium dlethyl-
thlocarbamate 1n
DMSO
Aroclor-lnduced
rat liver
one dose positive,
no dose response
Bacillus
subtlUs
aqueous cadmium
chloride
none
weakly positive
B.
subtlUs
aqueous cadmium
nitrate
none
negative
B.
subtlUs
cadmium chloride,
nitrate and
sulfite
none
weakly positive
~Source: U.S.
EPA. 1985a
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TABLE 4-3
Mutagenicity of Cadmium: Evaluations Using Eukaryotlc Cells*
Test System
Cadmium Compound
Results
Saccharomvces
cerevlslae
cadmium
chloride
posl tWe
S.
cerevlslae
cadmium
chloride
negative
Mouse lymphoma
cadmium
chloride
weakly positive
Mouse lymphoma
cadmium
sulfate
positive
Chinese hamster,
lung
cadmium
cadmium
acetate,
chloride
positive
Chinese hamster,
ovary
cadmium
chloride
weakly positive
Chinese hamster,
V79
cadmium
chloride
positive
~Source: U.S. EPA, 1985a
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TABLE 4-4
Hutagen1c1ty of Cadmium: Evaluations Using Insects*
Organism
Test System
Compound
Results
DrosoDhlla
melanoqaster
sex-linked recessive
lethal
cadmium
chloride
negative
DrosoDhlla
melanoaaster
larval development
sex-Hnked recessive
lethal, sex chromo-
some loss
cadmium
chloride
negative
DrosoDhlla
melanoaaster
dominant lethal
cadmium
chloride
positive
DrosoDhlla
melanoaaster
sex-Hnked recessive
lethal
cadmium
stearate
negative
DrosoDhlla
melanoaaster
sex chromosome loss
cadmium
chloride
negative
Drosoohlla
melanoaaster
sex-linked recessive
lethal
cadmium
chloride
negative
Poekllocerus
Dlctus
testicular melotlc
chromosomes
cadmium
chloride
positive
~Source: U.S. EPA,
1985a
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TABLE 4-5
Mutagenicity of Cadmium: In vitro Chromosome Aberrations*
Test Cells
Cadmium Compound
Results
Human lymphocytes
cadmium sulfide
positive
Human lymphocytes
cadmium chloride
negative
Human lymphocytes
cadmium chloride
negative
VII38 and MCR5
cadmium chloride
negative
Human lymphocytes
(G0 stage)
cadmium acetate
weakly positive
Chinese hamster
HY cells
cadmium sulfate
positive
Chinese hamster
CHO cells
cadmium chloride
positive with
newborn calf or
human serum,
negative with
fetal calf serum
House mammary
carcinoma, FM3A
cadmium chloride
negative
•Source: U.S. EPA, 1985a
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TABLE 4-6
Mutagenicity of Cadmium: In vivo Mammalian Systems*
Organism
Endpolnt
Test Compound
Results
Mouse
bone marrow cells
cadmium chloride
negative
Mouse
bone marrow mlcronuclel
cadmium chloride
negative
Mouse
dominant lethals
cadmium chloride
negative
Mouse
dominant lethal
cadmium chloride
negative
Mouse
postlmplantatlon loss
cadmium chloride
negative
Mouse
heritable translocation
cadmium chloride
negative
Mouse
spermatocytes
cadmium chloride
negative
Mouse
oocytes
cadmium chloride
positive
Mouse
blastocysts
cadmium chloride
positive for
aneuploldy
Syrian
oocytes
cadmium chloride
positive
hamster
~Source: U.S. EPA, 1985a
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Evidence for carcinogenicity 1n animals was considered "sufficient" based
upon subcutaneous and Intramuscular Injection studies, which were not
reviewed for this document (U.S. EPA, 1980a). Evidence for activity 1n
short-term tests was considered "Inadequate" because of the conflicting
results reported by various authors (see Section 4.3.).
In a more recent evaluation, U.S. EPA (1985a) classified cadmium as a
Group B1 substance, probable human carcinogen, using the Agency's guidelines
for carcinogen risk assessment (U.S. EPA, 1986b). This classification was
based on sufficient evidence of carcinogenicity 1n animals and limited
evidence 1n humans. The animal evidence Included the finding of lung
carcinomas In rats exposed to cadmium chloride by Inhalation, and Injection
site and testicular tumors 1n rats and mice given cadmium metal or salts.
The human evidence consisted of a dose-related increase 1n lung cancer among
humans exposed to airborne cadmium that could not be explained by confound-
ing, factors. U.S. EPA (1985a) also classified cadmium In IARC Group 2A,
which Indicated that 1t 1s a probable human carcinogen.
While there are positive dose-response data for the Inhalation and
Injection routes, the oral exposure experiments have not shown a response.
The lack of a response following oral exposure 1s felt to be an Issue of
dosimetry (I.e., low absorption efficiency). As a result, the Carcinogen
Assessment Group feels that the negative oral data are not a basis for
concluding that the human potential for carcinogenicity, as Implied from the
weight of the evidence classification of Bl, should be viewed differently
for oral exposure.
0038H
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5. REGULATORY STANDARDS AND CRITERIA
U.S. EPA (1987) calculated a 1-day HA based on a NOAEL for gastrointes-
tinal Irritation of 3 mg cadmium administered as a single oral dose to adult
humans (0.043 mg/kg for a 70 kg adult) (Lauwerys et al., 1979). The 1-day
HA was 0.043 mg/l for a 10 kg child.
U.S. EPA (1987) also calculated 10-day HAs based on a rat NOAEL for
proteinuria of 10 mg/l In drinking water (0.84 mg/kg/day) that was deter-
mined 1n a 24-week study by Kotsonls and Klaassen (1978). However, the
10-day HA calculated from this NOAEL for a 10 kg child would be 0.08 mg/l.
Since this value 1s greater than the 1-day HA, U.S. EPA (1987) suggests that
the 1-day number be used for the 10-day HA.
U.S. EPA (1987) calculated a DUEL of 0.018 mg/l based on an RfD of
0.0005 mg/kg/day for a 70 kg adult consuming 2 I of drinking water/day. A
DUEL of 0.005 mg/l was calculated using a relative source contribution
from water of 25%.
WHO (1983) recommended that cadmium concentrations 1n drinking water be
<5 yg/l. NAS (1982) calculated SNARLs of 5 yg/l for chronic expo-
sure, 21 yg/l for 7-day exposure and 150 yg/l for 24-hour exposure.
WHO (1972) proposed a provisional tolerable weekly intake of 400-500 yg
(57.1-71.4 yg/day). U.S. EPA (1985b) proposed an RMCL of 0.005 mg
cadm1um/l drinking water.
U.S. EPA (1980a) recommended an ambient water quality criterion of 10
vg/l to protect against human health effects that were due to exposure
to cadmium in drinking water and from eating contaminated fish and shellfish.
0038H
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The ACGIH (1986) TLV for cadmium dust and salts 1s 0.05 mg/m3 as
cadmium. The NIOSH (1976) criterion 1s 0.04 mg/m3. OSHA (1985) lists an
8-hour TWA-PEL and acceptable celling concentration for cadmium fume of 0.1
and 0.3 mg/m3, respectively. For cadmium dust, the TWA-PEL and acceptable
celling concentrations were 0.2 and 0.6 mg/m3.
0038H
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6. RISK ASSESSMENT
6.1. SUBCHRONIC REFERENCE DOSE (RfDg)
6.1.1. Oral (RfDgQ). 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 (RfDSI). Cadmium Is a metal that 1s a known carcino-
gen by the Inhalation route and for which data are sufficient for computing
a q^*. It Is, therefore, inappropriate to calculate an Inhalation RfD for
cadmium.
6.2. REFERENCE DOSE (Rf0)
6.2.1. Oral (Rf Oq) . U.S. EPA (1988b) calculated an RfD for oral
exposure to waterborne cadmium based on data provided by Frlberg et al.
(1974). This RfD was based on a critical level of cadmium 1n the renal
cortex of humans that Is associated with renal dysfunction of 200 yg/g wet
weight. Frlberg et al. (1974) used a model to estimate that a dally Intake
of 0.352 mg cadm1um/day for the first 50 years of life would result In a
renal cortex level of 200 yg/g 1n adult humans (70 kg). Assumptions used
1n the model were that 4.5% of a dally oral dose was absorbed, 33% of the
total body burden was In the kidneys, renal cortex concentration was 150%
that of whole kidney, and that excretion amounted to 0.01% of the total body
burden per day. The estimated Intake of 0.352 mg/day was divided by an
uncertainty factor of 10, resulting 1n an RfD of 0.04 mg/day for a 70 kg
human, or 0.0005 mg/kg/day.
U.S. EPA (1988b) also verified an RfD for dietary exposure of 0.001
mg/kg/day by assuming that cadmium absorption from food Is 2.5%. There
appears to be considerable variability 1n cadmium uptake as a result of
species differences, chemical form of the cadmium and dietary Influences.
0038H -27- 08/19/88
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01 et composition, at least 1n experimental animals, appears to affect the
absorption of cadmium administered either In the food or In water. Both 2.5
and 5% are within the range of reports for absorption following dietary
exposure (Frlberg, 1984). Data comparing uptake from food versus water In
subjects consuming similar diets do not appear to be available. Both of the
proposed absorption estimates appear to be reasonably conservative 1n the
context of western diets when evaluated both In terms of the effects of
dietary components on uptake, and In the context of retrospective evalua-
tions of dally Intake versus renal concentrations at autopsy. While a
number of human studies have suggested absorption percentages up to 10% In
humans (Frlberg, 1984), there 1s a potential for overestlmatlon of absorp-
tion In studies that estimate absorption based upon fecal elimination. The
reason for this concern Is that apparently absorption of cadmium takes place
In two phases, uptake Into the Intestinal mucosa followed by slower and
possibly Incomplete absorption from the mucosa (Foulkes, 1986). Fecal
elimination studies would only evaluate this first step, mucosal uptake.
6.2.2. Inhalation (RfDj). Cadmium 1s a metal that Is a known carcino-
gen by the inhalation route and for which data are sufficient for computing
a q.j*. It 1s, therefore. Inappropriate, 1n the context of the guidelines
for this series of documents, to calculate an Inhalation RfO for cadmium.
6.3. CARCINOGENIC POTENCY (q^)
6.3.1. Oral. Cadmium has not been shown to be carcinogenic 1n laboratory
animals by oral administration. There are no human data (U.S. EPA, 1985a).
Using the dose data for rats from Schroeder et al. (1965) and assuming a 10%
upper limit of detection of tumors, U.S. EPA (1985a) estimated an upper
limit for the carcinogenic potency of Ingested cadmium that 1s 2 orders of
magnitude less than for Inhalation. It Is possible that as a result of
0038H
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extremely poor absorption from the gastrointestinal tract, cadmium 1s not
carcinogenic when Ingested; however, the negative data available can only be
used to set an upper limit on potency. For these reasons, quantitative risk
assessment for oral exposure to cadmium Is not attempted here.
6.3.2. Inhalation. The data of Takenaka et al. (1983) for Induction of
lung carcinoma 1n rats could be used for quantitative risk assessment;
however, U.S. EPA (1985a) felt that an extrapolation based on the human data
for respiratory cancer (Thun et al., 1985) provided a more realistic assess-
ment. Since this was based on an 1n-depth and critical review of the
literature, which far exceeded the scope of the current document, this
approach will be adopted here.
U.S. EPA (1985a) used a number of different approaches to derive unit
risk estimates for Inhalation exposure to cadmium. They suggested that 1f a
single estimate 1s desired, 1t may be based on the maximum likelihood esti-
mate of the linear parameter obtained from fitting the linear nonthreshold
model to the Thun et al. (1985) data. This estimate for risk from a
constant lifetime exposure to 1 yg/ma Is 1.8x10"*. A higher unit risk
estimate of 3.5xl0~3 would be obtained 1f the 95% upper bound of the
parameter estimate were used, but U.S. EPA (1985a) felt that this would
Introduce an unnecessary added level of conservatism because the model
already overestimates the risk If nonlinear components exist or 1f confound-
ing factors are present.
For purposes of comparison, U.S. EPA (1985a) also used the animal data
of Takenaka et al. (1983) to derive a unit risk estimate for Inhalation
exposure to cadmium. They used the linearized multistage model to calculate
human q-j* values of 2.1x10""1 (yg/kg/day)"1 for Inhalation of cadmium
chloride and 3.4x10"* (yg/kg/day)"1 for elemental cadmium. These
0038H
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values correspond to 6.0xl0~2 and 9.7xl0~a (vg/m3)-1. respec-
tively. The Incremental unit risk from the Inhalation of 1 jig of
elemental cadmlum/m3 of air was calculated to be 9.2xl0~2. Following
careful consideration of all of the data, U.S. EPA (1985a) decided that the
human data provided the best current basis for risk assessment. The unit
risk of exposure to 1 yg/m3 based on human data, 1.8xl0~9, was there-
fore recommended by U.S. EPA (1985a). The unit risk slope 1s equivalent to
6.1 (mg/kg/day)_1. This analysis has been verified by the CRAVE Workgroup
and 1s available on IRIS (U.S. EPA, 1988a).
0038H
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7. REFERENCES
AC6IH (American Conference of Governmental Industrial Hyg1en1sts). 1986.
Threshold 11mlt values and biological exposure Indices for 1986-1987
Cincinnati, OH.
Anderson, 0., J.B. Nielsen and P. Svendsen. 1986. Oral cadmium toxicology.
Acta. Pharmacol. Toxicol. (Copenhagen). 59(Suppl. 7): 44-47.
Ando, M., et al. 1977. Studies on excretion and uptake of calcium by rats
after continuous oral administration of cadmium. Toxicol. Appl. Pharmacol.
39: 321. (Cited 1n U.S. EPA, 1980a)
Armstrong, 6.B. and G. Kazantzls. 1983. The mortality of cadmium workers.
Lancet. 1: 1425-1427. (Cited 1n Oberdorster, 1986)
Armstrong, B.G. and G. Kazantzls. 1985. Prostatic cancer and chronic
respiratory and renal disease 1n British cadmium workers: A case control
study. Br. J. Ind. Med. 42: 540-545.
Baader, E.W. 1952. Chronic cadmium poisoning. Ind. Med. Surg. 21: 427.
(Cited 1n U.S. EPA, 1980a)
Banls, R.J., et al. 1969. Dietary cadmium, Iron, and zinc Interactions 1n
the growing rat. Proc. Soc. Exp. B1ol. Med. 130: 802. (Cited 1n U.S. EPA,
1980a)
0038H
-31-
08/19/88
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Bremner, I. 1974. Heavy metal toxicities. Q. Rev. Blophys. 7: 75-124.
(Cited 1n U.S. EPA, 1980a)
Bunn, C.R. and G. Matrone. 1966. in vivo Interactions of cadmium, copper,
zinc, and Iron 1n the mouse and rat. J. Nutr. 90: 395. (Cited 1n U.S.
EPA, 1980a)
Buxton, R.St.J. 1956. Respiratory function In cadmium alloy casters. Br.
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APPENDIX
Summary Table for Cadmium
Species Dose/Exposure
Effect
Reference Dose
(RfO or RfOs)
Reference
Oral
RfOso
RfD0
NA NA
human 0.352 mg/day
NONCARCINOGENIC EFFECTS
NA
renal dysfunction
ND
5E-4 mg/kg/day
(waterborne)
IE —3 mg/kg/day
(dtetary)
NA
Frlberg et al..
1974; U.S. EPA,
1988b
CARCINOGENIC EFFECTS
Inhalation human occupational lung cancer Unit Risk Slope: Thun et al., 1985;
6.1 (mg/kg/day)-1 U.S. EPA. 1985a
NA = Not applicable; ND = not derived
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