ACUTE EXPOSURE GUIDELINE LEVELS (AEGLs)
FOR
CADMIUM
(CAS Reg. No. 7440-43-9)
Cd
PROPOSED
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ACUTE EXPOSURE GUIDELINE LEVELS (AEGLs)
FOR
CADMIUM
(CAS Reg. No. 7440-43-9)
PROPOSED
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PROPOSED: November 2009
PREFACE
Under the authority of the Federal Advisory Committee Act (FACA) P. L. 92-463 of
1972, the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous
Substances (NAC/AEGL Committee) has been established to identify, review and interpret
relevant toxicologic and other scientific data and develop AEGLs for high priority, acutely toxic
chemicals.
AEGLs represent threshold exposure limits for the general public and are applicable to
emergency exposure periods ranging from 10 minutes to 8 hours. Three levels — AEGL-1,
AEGL-2 and AEGL-3 — are developed for each of five exposure periods (10 and 30 minutes, 1
hour, 4 hours, and 8 hours) and are distinguished by varying degrees of severity of toxic effects.
The three AEGLs are defined as follows:
AEGL-1 is the airborne concentration (expressed as parts per million or milligrams per
cubic meter [ppm or mg/m3]) of a substance above which it is predicted that the general
population, including susceptible individuals, could experience notable discomfort,
irritation, or certain asymptomatic, non-sensory effects. However, the effects are not
disabling and are transient and reversible upon cessation of exposure.
AEGL-2 is the airborne concentration (expressed as ppm or mg/m3) of a substance
above which it is predicted that the general population, including susceptible individuals,
could experience irreversible or other serious, long-lasting adverse health effects or an
impaired ability to escape.
AEGL-3 is the airborne concentration (expressed as ppm or mg/m3) of a substance
above which it is predicted that the general population, including susceptible individuals,
could experience life-threatening health effects or death.
Airborne concentrations below the AEGL-1 represent exposure levels that could produce
mild and progressively increasing but transient and nondisabling odor, taste, and sensory
irritation or certain asymptomatic, non-sensory effects. With increasing airborne concentrations
above each AEGL, there is a progressive increase in the likelihood of occurrence and the severity
of effects described for each corresponding AEGL. Although the AEGL values represent
threshold levels for the general public, including susceptible subpopulations, such as infants,
children, the elderly, persons with asthma, and those with other illnesses, it is recognized that
individuals, subject to unique or idiosyncratic responses, could experience the effects described
at concentrations below the corresponding AEGL
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1 TABLE OF CONTENTS
2 PREFACE 3
3 LIST OF TABLES 6
4 EXECUTIVE SUMMARY 7
5 1. INTRODUCTION 10
6 2. HUMAN TOXICITY DATA 11
7 2.1. Acute Lethality 11
8 2.1.1. CaseReports 11
9 2.2. Nonlethai Toxicity 12
10 2.2.1. Odor Threshold/Odor Awareness 12
11 2.2.2. Epidemiologic Studies 12
12 2.3. Neurotoxicity 13
13 2.4. Developmental/Reproductive Toxicity 13
14 2.5. Genotoxicity 14
15 2.6. Carcinogenicity 14
16 2.7. Summary 16
17 3. ANIMAL TOXICITY DATA 16
18 3.1. Acute Lethality 16
19 3.1.1. Rat 16
20 3.2. Nonle thai Toxicity 17
21 3.2.1. Rabbit 17
22 3.2.2. Rat 17
23 3.3. Developmental/Reproductive Toxicity 20
24 3.4. Genotoxicity 22
25 3.5. Repeated Dose 22
26 3.5.1. Rat 22
27 3.5.2. Mouse 26
28 3.6. Chronic Toxicity/Carcinogenicity 29
29 3.7. Summary 32
30 4. SPECIAL CONSIDERATIONS 32
31 4.1. Metabolism and Disposition 32
32 4.2. Mechanism of Toxicity 33
33 4.3. Structure Activity Relationships 33
34 4.4. Other Relevant Information 34
35 4.4.1. Species Variability 34
36 4.4.2. Susceptible Populations 34
37 4.4.3. Concentration-Exposure Duration Relationship 35
38 4.4.4. Concurrent Exposure Issues 35
39 5. DATA ANALYSIS FOR AEGL-1 35
40 5.1. Summary of Human Data Relevant to AEGL-1 35
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1 5.2. Summary of Animal Data Relevant to AEGL-1 35
2 5.3. Derivation of AEGL-1 35
3 6. DATA ANALYSIS FOR AEGL-2 36
4 6.1. Summary of Human Data Relevant to AEGL-2 36
5 6.2. Summary of Animal Data Relevant to AEGL-2 36
6 6.3. Derivation of AEGL-2 36
7 7. DATA ANALYSIS FOR AEGL-3 37
8 7.1. Summary of Human Data Relevant to AEGL-3 37
9 7.2. Summary of Animal Data Relevant to AEGL-3 37
10 7.3. Derivation of AEGL-3 37
11 8. SUMMARY OF AEGLS 38
12 8.1. AEGL Values and Toxicity Endpoints 38
13 8.2. Comparison with Other Standards and Guidelines 38
14 8.3. Data Adequacy and Research 39
15 9. REFERENCES 40
16 APPENDIX A: Derivation of AEGL Values 44
17 APPENDIX B: Time-Scaling Calculations 50
18 APPENDIX C: Carcinogenicity Assessment 51
19 APPENDIX D: Derivation Summary for Cadmium AEGLs 52
20 APPENDIX E: Category Plot for Cadmium 55
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LIST OF TABLES
TABLE 1. Summary of AEGL Values Cadmium 9
TABLE 2. Chemical and Physical Properties 10
TABLE 3. Chemical and Physical Properties of Cadmium Compounds 11
TABLE 4. Blood Cd Concentrations of Workers and Air Cd Concentrations 13
TABLE 5. Summary of Acute Inhalation Data in Laboratory Animals 20
TABLE 6. Histopathological Findings in rats Exposed for 2 wks to Cadmium Oxide 23
TABLE 7. Histopathological Findings in Rats Exposed for 13 wks to Cadmium Oxide 24
TABLE 8. Histopathological Findings in Mice Exposed for 2 wks to Cadmium Oxide 26
TABLE 9. Histopathological Findings in Mice Exposed for 13 wks to Cadmium Oxide 27
TABLE 10. Summary of Repeat Dose Inhalation Data in Laboratory Animals 28
TABLE 11. Observations after Inhalation Exposures of Rats to Various Cd Compounds 30
TABLE 12. AEGL-1 Values for Cadmium 36
TABLE 13. AEGL-2 Values for Cadmium 37
TABLE 14. AEGL-3 Values for Cadmium 38
TABLE 15. Summary of AEGL Values 38
TABLE 16. Extant Standards and Guidelines for Cadmium 39
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EXECUTIVE SUMMARY
Cadmium (Cd) is a metal used in a variety of consumer and industrial materials with a
high percentage used in the production of nickel-cadmium batteries and in electroplating. It is
also in pigments used in plastics, ceramics and glasses and is used as a stabilizer for polyvinyl
chloride (PVC). World production between 1990 and 2000 was -19,000 tons/year (Morrow,
2001). Estimated U.S. production of cadmium was about 1450 metric tons in 2003 and 700
metric tons in 2006 (ATSDR 2008).
Human exposure to cadmium can be from inhalation of cadmium containing particles,
inhalation of cigarette smoke or inhalation from fumes/dust in an occupational setting. In case
reports of accidental acute exposure, cadmium caused respiratory irritation, dyspnea, alveolar
damage, pneumonitis, and death. Chronic occupational exposure caused decreased lung
function. Cadmium and cadmium compounds are characterized as "probable human
carcinogens" based on evidence of carcinogenicity in humans (U.S. EPA 1994). Respiratory
cancers were increased in workers at a Cd-nickel battery factory, however, chronic Cd exposure
was not found to lead to lung carcinogenicity. In animal inhalation studies, cadmium oxide is
used as it is the most common airborne form of cadmium. The size of the cadmium particle often
determines the extent of absorption and distribution. Cadmium, in various forms, caused
respiratory irritation, pulmonary edema, rales, pneumonitis, lacrimation, increased alveolar
macrophages, and death in rabbits and rats exposed for 1-6 hours. Rats and mice exposed for 90
days or less exhibited pulmonary inflammation and edema, pulmonary hyperplasia, nasal and
respiratory epithelium degeneration, and renal lesions. In carcinogenicity studies, rats exposed
to Cd had an increased incidence of primary lung carcinomas.
"3
The AEGL-1 values are based on the experimental concentration, 0.55 mg Cd/m , that
caused slight respiratory irritation in rats (Takenaka et al. 2004). After a 6 hour exposure,
increased neutrophils and multifocal alveolar inflammation were observed. At the next higher
experimental exposure, pneumonitis was observed (Grose et al. 1987). Although the exposure
was a whole-body exposure, the size of the ultrafine particles (51 nM MMAD, 1.7 GSD) would
mimic a gaseous state and the majority of the aerosol would be inhaled and not deposited on the
fur. An interspecies uncertainty factor of 3 was applied because at acute exposures, cadmium is
a direct-acting respiratory irritant as indicated by the signs of irritation in rabbits and rats. This
mode of action is not expected to differ among species. Rabbits and rats exposed for 2 hours to
"3
0.25-4.5 mg/m displayed similar histological and biochemical pulmonary effects including
pneumonitis, increased lung weight, pulmonary inflammatory cell influx, and decreased
glutathione peroxidase activity (Grose et al. 1987). Rats exposed to cadmium (0.00169-5.3
mg/m3) from 1-6 hours (Buckley and Bassett 1987; Oberdorster et al. 1987; Takenaka et al.
2004) exhibited the same effects as those observed in the Grose et al. (1987) study. An
intraspecies uncertainty factor of 3 was applied because at acute exposures, cadmium is a direct-
acting respiratory irritant in humans, and this mode of action is not expected to differ among
individuals. After a five hour exposure to cadmium, workers experienced cough, throat
irritation, dyspnea, and pulmonary edema (Beton et al. 1966) which are signs of respiratory
irritation. The concentration-exposure time relationship for many irritant and systemically-
acting vapors and gases may be described by Cn x t = k, where the exponent, n, ranges from 0.8
to 3.5 (ten Berge et al. 1986). To obtain conservative and protective AEGL values in the absence
of an empirically derived chemical-specific scaling exponent, temporal scaling was performed
using n=3 when extrapolating to shorter time points and n = 1 when extrapolating to longer time
points using the Cn x t = k equation. The 30-minute AEGL-1 value was adopted as the 10-
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minute value due to the added uncertainty of extrapolating from a 6-hour time point to 10
minutes (NRC 2001).
"3
The AEGL-2 values are based on the experimental concentration, 5.3 mg Cd/m , that
caused overt respiratory irritation and pathology in rats (Buckley and Bassett 1987). The 3 hour
exposure resulted in reduced weight gain and increased lung weight, protein content, DNA
content, number of cuboidal alveolar cells, number of inflammatory cells, and focal areas of
interstitial thickening. An interspecies uncertainty factor of 3 was applied because at acute
exposures, cadmium is a direct-acting respiratory irritant as indicated by the signs of irritation in
rabbits and rats. This mode of action is not expected to differ among species. Rabbits and rats
exposed for 2 hours to 0.25-4.5 mg/m3 displayed similar histological and biochemical pulmonary
effects including pneumonitis, increased lung weight, pulmonary inflammatory cell influx, and
decreased glutathione peroxidase activity (Grose et al. 1987). Rats exposed to cadmium
(0.00169-5.3 mg/m3) from 1-6 hours (Buckley and Bassett 1987; Oberdorster et al. 1987;
Takenaka et al. 2004) exhibited the same effects as those observed in the Grose et al. (1987)
study. An intraspecies uncertainty factor of 3 was applied because at acute exposures, cadmium
is a direct-acting respiratory irritant in humans, and this mode of action is not expected to differ
among individuals. After a five hour exposure to cadmium, workers experienced cough, throat
irritation, dyspnea, and pulmonary edema (Beton et al. 1966) which are signs of respiratory
irritation. The concentration-exposure time relationship for many irritant and systemically-
acting vapors and gases may be described by Cn x t = k, where the exponent, n, ranges from 0.8
to 3.5 (ten Berge et al. 1986). To obtain conservative and protective AEGL values in the absence
of an empirically derived chemical-specific scaling exponent, temporal scaling was performed
using n=3 when extrapolating to shorter time points and n = 1 when extrapolating to longer time
points using the Cn x t = k equation.
"3
The AEGL-3 values are based on the 2 hour LC50 for cadmium fume in rats, 112 mg/m
(Rusch et al. 1986). The LC50 was divided by 3 to estimate a threshold of lethality. An
interspecies uncertainty factor of 3 was applied because at acute exposures, cadmium is a direct-
acting respiratory irritant as indicated by the signs of irritation in rabbits and rats. This mode of
action is not expected to differ among species. Rabbits and rats exposed for 2 hours to 0.25-4.5
"3
mg/m displayed similar histological and biochemical pulmonary effects including pneumonitis,
increased lung weight, pulmonary inflammatory cell influx, and decreased glutathione
peroxidase activity (Grose et al. 1987). Rats exposed to cadmium (0.00169-5.3 mg/m3) from 1-6
hours (Buckley and Bassett 1987; Oberdorster et al. 1987; Takenaka et al. 2004) exhibited the
same effects as those observed in the Grose et al. (1987) study. An intraspecies uncertainty
factor of 3 was applied because at acute exposures, cadmium is a direct-acting respiratory irritant
in humans, and this mode of action is not expected to differ among individuals. After a five hour
exposure to cadmium, workers experienced cough, throat irritation, dyspnea, and pulmonary
edema (Beton et al. 1966) which are signs of respiratory irritation. The concentration-exposure
time relationship for many irritant and systemically-acting vapors and gases may be described by
Cn x t = k, where the exponent, n, ranges from 0.8 to 3.5 (ten Berge et al. 1986). To obtain
conservative and protective AEGL values in the absence of an empirically derived chemical-
specific scaling exponent, temporal scaling was performed using n=3 when extrapolating to
shorter time points and n = 1 when extrapolating to longer time points using the Cn x t = k
equation.
The calculated values are listed in the table below.
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ABLE 1. Summary of AEGL Values Cadmium
Classification
10-min
30-min
1-hr
4-hr
8-hr
Endpoint
(Reference)
AEGL-1
(Nondisabling)
0.13 mg/m3
0.13 mg/m3
0.10 mg/m3
0.063 mg/m3
0.041 mg/m3
Respiratory irritation,
0.55 mg Cd/m3 for 6
hr (Takenaka et al.
2004)
AEGL-2
(Disabling)
1.4 mg/m3
0.96 mg/m3
0.76 mg/m3
0.40 mg/m3
0.20 mg/m3
Overt respiratory tract
irritation and
pathology, 5.3 mg/m3
CdO for 3 hr Buckley
and Bassett. 1987)
AEGL-3
(Lethal)
8.5 mg/m3
5.9 mg/m3
4.7 mg/m3
1.9 mg/m3
0.93 mg/m3
Threshold of lethality
based on the 2-hr rat
LC50 for Cd fumes,
112 mg/m3 (Rusch et
al. 1986)
References
ATSDR (Agency for Toxic Substances and Disease Registry). 2008. Draft toxicological profile for cadmium. U.S.
Department of Health and Human Services, Atlanta, GA.
Beton, D.C., G. S. Andrews, H.J. Davies, L. Howells and G.F. Smith. 1966. Acute cadmium fume poisoning. Five
cases with one death from renal necrosis. Brit. J. Industr. Med 23: 292-301.
Buckley, B.J. andD.J.P. Bassett. 1987 Pulmonary cadmium oxide toxicity in the rat. J. Toxicol. Environ. Health. 21:
233-250.
Grose, E.C., J.H. Richards, R.H. Jaskot, M.G. Menache, J. A. Graham and W.C. Dauterman. 1987. A comparative
study of the effects of inhaled cadmium chloride and cadmium oxide: pulmonary response. J. Toxicol. Environ.
Health, 21:219-232.
Morrow, H. 2001. Cadmium and Cadmium Alloys. Kirk-Othmer Encyclopedia of Chemical Technology, 4th Ed., M.
Howe-Grant, ed. Available. Online, http://mrw.interscience.wiley.com/emrw/978047123896.
NRC (National Research Council). 2001. Standing Operating Procedures for Developing Acute Exposure
Guideline Levels for Hazardous Chemicals. The National Academies Press, Washington, DC.
Rusch, G.M., J.S. O'Grodnick and W.E. Rinehart. 1986. Acute inhalation study in the rat of comparative
uptake, distribution and excretion for different cadmium containing materials. Am. Ind. Hyg. Assoc. J. 47(12):
754-763.
Takenaka, S., E. Karg, W.G. Kreyling, B. Lentner, H. Schultz, A. Ziesenis, P. Schramel and J. Heyder.
2004. Fate and toxic effects of inhaled ultrafine cadmium oxide particles in the rat lung. Inhal. Toxicol. 16
(suppl.l): 83-92.
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1. INTRODUCTION
Cadmium is used in a variety of consumer and industrial materials with a high percentage
used in the production of nickel-cadmium batteries and in electroplating. It is also in pigments
used in plastics, ceramics and glasses and as a stabilizer for polyvinyl chloride (PVC). The
demand for cadmium has decreased since the 1990s as lithium-ion and nickel metal hydride
batteries become more popular (ATSDR 2008). World production between 1990 and 2000 was
-19,000 tons/year (Morrow 2001). Estimated U.S. production of cadmium was about 1450
metric tons in 2003 and 700 metric tons in 2006 (ATSDR 2008). Human exposure to cadmium
can be from consumption of food, drinking water, incidental ingestion of soil or dust, inhalation
of cadmium containing particles, inhalation of cigarette smoke, or inhalation from fumes/dust in
an occupational setting. Cadmium is usually not present in the environment as pure metal but as
a mineral combined with other elements such as oxygen (cadmium oxide), chlorine (cadmium
chloride) or sulfur (cadmium sulfate/sulfide) (ATSDR 2008). These forms are also solids but
some are water soluble.
TABLE 2. Chemical and Physical Properties
Parameter
Value
References
Synonyms
Colloidal cadmium
Chemical formula
Cd
HSDB 2005
Molecular weight
112.41 g
HSDB 2005
CAS Reg. No.
7440-43-9
HSDB 2005
Physical state
Silver-white, blue-tinged, lustrous
metal; solid
HSDB 2005
Solubility in water
Insoluble in water
HSDB 2005
Vapor pressure
1 mmHg @ 394°C
ATSDR 2008
Vapor density (air =1)
-
-
Liquid density (water =1)
-
-
Melting point
321°C
HSDB 2005
Boiling point
765°C
HSDB 2005
Flammability limits
Powder flammable in air; Auto-ignites
at 250 °C
ACGIH 1996; NIOSH 2005
Conversion factors
1 ppm = 4.6 mg/m3
1 mg/m3 = 0.22 ppm
Calculated by reviewer using
1 ppm = mg/m3 x 24.45/112.4
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TABLE 3. Chemical and Physical Properties of Cadmium Compounds
Cd carbonate
Cd chloride
Cd oxide
Cd sulfate
Cd sulfide
Synonyms
Carbonic acid,
cadmium salt
Dichlorocadmium
Cadmium fume;
cadmium
monoxide
Sulfuric acid,
cadmium salt
Cadmium
yellow;
Cadmium orange
Chemical formula
CdC03
CdCl2
CdCO
CdS04
CdS
Molecular wt.
172.42
183.32
128.41
208.47
144.47
CAS No.
513-78-0
10108-64-2
1306-19-0
10124-36-4
1306-23-6
Physical state
White powder or
rhombohedral
leaflets
Colorless,
rhombohedral
crystals
Dark brown
infusible powder
or cubic crystals
Colorless
monoclinic
crystals
Light yellow or
orange cubic or
hexagonal
structure
Solubility in water
Insoluble
Soluble
Insoluble
Soluble
Soluble at 1.3
mg/L @ 18 °C
Vapor pressure
-
10 mmHg @ 656
°C
1 mmHg @
1000 °C
-
-
Vapor density (air
=1)
4.26 g/cm3 @
4°C
3.3 g/cm3 @ 20°C
Crystals-
8.15 g/cm2;
amorphous
powder-
6.95 g/cm3
4.69 g/cm3
Hexagonal
structure-
4.82 g/cm3;
Cubic structure-
4.5 g/cm3
Liquid density
(water=1)
-
-
-
-
-
Melting point
Decomposes
(< 500 °C)
568 °C
-
1000 °c
1750 °C
Boiling point
-
960 °C
Sublimes at 1559
°C
-
Sublimes in N2
@ 980 °C
Flammability limits
-
-
-
-
-
Conversion factors
1 mg/m3 =
0.14 ppm
1 mg/m3 =
0.13 ppm
1 mg/m3 =
0.19 ppm
1 mg/m3 =
0.12 ppm
1 mg/m3 =
0.17 ppm
Data from ATSDR, 2008
- No data available
2. HUMAN TOXICITY DATA
2.1. Acute Lethality
2.1.1. Case Reports
Numerous case reports are available on acute inhalation exposure to Cd; while some
report the Cd levels in tissues, very few have the actual Cd exposure concentrations. Panchal
and Vaideeswar (2006) reported on a man exposed to an unknown concentration of Cd oxide
fumes who developed a cough, dyspnea and finally died. Fernandez et al. (1996) reported on a
man exposed to Cd fumes for approximately 60-75 minutes while flame-cutting an alloy
containing about 10% Cd. The man developed dyspnea 4 hours after finishing work, was
hospitalized, and on day 15 after exposure, the blood and urine concentration of cadmium was
0.34 |ig/100 mL (control = 0.11 |ig/100 mL) and creatinine was 17.6 |ig/g (control = 0.2 jug/g).
He had multi-organ failure and died after 19 days. Autopsy showed diffuse alveolar damage to
the lungs with beginning intra-alveolar fibrosis. Concentrations of cadmium in tissues were 823
ng/g liver, 3571 ng/g kidney and 1143 ng/g lung. The author stated that exposures to 200-500
|ig/m usually result in "metal fume fever" that lasts for one to two days, so this patient was
almost certainly exposed to a much higher concentration.
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A man was exposed for ~5 hours to a brownish-yellowish smoke during a copper
smelting process after which he complained of fatigue and nausea (Yamamoto et al. 1983). The
clinical signs continued to worsen with hypoxemia developing. On day 2, Cd was 6 |ag/m L in the
blood and on day 5 was 332 jag/mL in the urine. Twelve days after the accident, the man died,
and the cadmium content of the right upper lung lobe was found to be 1.06 jug/g.
Five workers were accidentally exposed to Cd fumes for 5 hours in a tank while using an
oxyacetylene burner to melt off bolts made of cadmium (Beton et al., 1966). Cadmium oxide
was released due to the heat of the burner. None of the men except for the burner wore any type
of respiratory protection. All men experienced coughing and slight irritation of the throat during
exposure with dyspnea developing 4-10 hours later. One man died on post-exposure day 5; all
others had degrees of pulmonary edema that resolved over time. The man that died was found to
have severe pulmonary edema, alveolar metaplasia of the lungs and bilateral cortical necrosis of
the kidneys. The lungs contained 0.25 g CdO per 100 g wet specimen. The author speculated that
if 11% of the inhaled CdO was retained in the lungs (% retention was estimated based on earlier
work in five animal species), approximately 51.7 mg CdO fume must have been inhaled.
Working for 5 hours with a ventilatory rate of 20 L/min, the concentration of CdO in the air
3 3
would have been about 8.6 mg/m or 2,580 minute-mg/m .
2.2. Nonlethal Toxicity
2.2.1. Odor Threshold/Odor Awareness
Cadmium is odorless (HSDB 2005).
2.2.2. Epidemiologic Studies
Jakubowski et al. (2004) looked at long-term occupational exposure and lung function of
79 workers (median age: 50.4 ± 8.9 years; 35 men and 44 women) to Cd in a cadmium battery
factory (mean period of 17.4 ±9.1 years). For comparison, 159 non-exposed workers (48.4 ± 4.2
years; 91 men and 68 women) were used as controls. Subjects were divided into four groups
depending on their cumulative cadmium exposure calculated either by cadmium levels in the
blood x time or cadmium levels in the air x time. The range of Cd-Blood (|ig/L) x time (years)
was < 25, 25-500, > 500-1000 or > 1000 and for Cd-Air (mg Cd/m3) x time (years) was <0.01,
0.10-1.5, > 1.5-4.0 or > 4. Lung function was evaluated using a LUNGTEST 500 spirometer and
measuring the following: forced expiratory volume in one second (FEVi), forced vital capacity
(FVC), peak expiratory flow (PEF), mid expiratory flow (MEF) at 25, 50 and 75%, vital capacity
(VC), inspiratory capacity (IC) and the percentage of the FEVi/FVC ratio. Statistically
significant decreases in FEVi (85% of predicted values, p=0.0208), PEF (76% of predicted
values, p=0.0488), MEF 25% (103 % of predicted values, p=0.0404), MEF 50% (86% of
predicted values, p=0.0169) and MEF 75% (78% of predicted values, p= 0.0248) were observed
in the workers exposed to >1000 |ig/L x years as measured by Cd-blood concentration compared
to controls. Workers in the group exposed to > 4 mg Cd-air x time also had a significant decrease
in MEF 50% and slight decrease in the FEVi. The results indicated that long-term exposure
could cause some decrease in lung function suggestive of mild airway obstruction. Table 4
provides the Cd concentrations in the blood of workers and Cd concentrations found at the plant.
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TABLE 4. Blood Cd Concentrations of Workers and Air Cd Concentrations
Parameter
N
Geometric mean ± GSD
Range
1983
Cd x B (|ig/L)
43
31.8 ± 2.14
9.11 - 166
Cd x A (mg/m3)
0.08-0.51
1986-1988
Cd x B (|ig/L)
91
29.1 ±2.01
4.1-120.3
Cd x A (mg/m3)
0.03-0.38
1998-1999
Cd x B (|ig/L)
116
9.2 ±2.14
0.5-42.1
Cd x A (mg/m3)
0.03 -0.032
Data from Jakubowski et al. (2004)
B= Blood; A= Air
Lauwerys et al. (1979) followed eleven male workers in a small factory producing
cadmium salts and monitored the cadmium levels in their blood and urine as well as the air
exposure levels for 13 months. Nine of eleven men wore personal air monitors and the exposure
levels (excluding outliers) ranged from 88 to 6276 |ig/m3, equivalent to 0.088 to 6.276 mg/ m3.
Most of the exposures were to cadmium oxide. Health effects were not evaluated.
2.3. Neurotoxicity
No data were located.
2.4. Developmental/Reproductive Toxicity
Fifty seven Japanese women, 58.1% of whom had delivered infants of gestational age of
more than 30 weeks, and their infants were tested to determine if maternal urinary levels of Cd
had any effect on the infant growth, gestational age at birth and/or the Cd level in the breast milk
(Nishijo et al., 2002). All subjects lived in areas close to a Cd polluted region where itai-itai
disease, the most severe manifestation of chronic cadmium poisoning, is still being eliminated.
No differences were found in the women's socioeconomic status, nutrition status or prenatal
care. Maternal urine and breast milk samples were taken on the fifth or eighth day post-partum
and information about occupational or environmental exposure to Cd, including smoking, was
obtained. Eight women were smokers (6 in the low Cd group and 2 in the high Cd group);
however, 6/8 had stopped smoking early in pregnancy making smoking less relevant to current
Cd levels. Women were divided into two groups based on the samples, those with urinary Cd of
< 2 |ig/g Creatinine (Cr) (n= 45) and those with > 2 |ig/g Cr (n= 12). This value of 2 |ig/g Cr
was derived from previous studies stating that those exposed to 2 |ig/g Cr were found to have
10% proteinuria. In the infants from mothers with higher Cd levels, the mean gestational age at
birth (37 weeks vs. 39.1 weeks), height at birth (47.2 cm vs. 49.2 cm) and weight at birth (2663 g
vs. 3099g) were significantly lower (p< 0.01 and 0.05) than the infants of mothers with Cd levels
< 2 |ig/g Cr. The number of infants delivered by Cesarean section (7 % vs. 4%) was also higher
in the high Cd mothers compared to the mothers having lower Cd levels. Multiple regression
analysis indicated that an increase of maternal urinary Cd was related to a decrease in gestational
age after adjustment for maternal age. Samples of breast milk also had a higher mean
concentration of Cd in mothers in the high Cd group. Overall, the study suggested that Cd
exposure may increase the possibility of pre-term births thus indirectly causing decreased birth
weight.
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2.5. Genotoxicity
Data are summarized from IARC 2003.
Human female itai-itai patients (n=12) exposed to cadmium through the diet had higher
incidences of chromosomal aberrations of all types in peripheral blood lymphocytes than age-
matched control subjects (n=9). However, there were no differences in the frequencies of cells
with structural aberrations in cultures from blood of four female itai-itai patients compared to
four control subjects.
No differences in chromosomal aberrations of lymphocytes were observed between five
alkaline battery factory workers and three office workers. The battery workers had been
employed for 5-24 years and the average cadmium concentration in personal air samples was
estimated to be 0.70 mg/m3. Blood cadmium concentration in the battery workers was 37.7 ng/g
and 2.3 ng/g in the office workers.
No differences were found in chromosomal or chromatid aberration frequency in workers
exposed from six weeks to 34 years in a cadmium pigment plant when compared to controls,
administrative and laboratory personnel at the same plant.
No difference was observed in the incidence of chromosomal aberrations in workers
exposed to cadmium dusts for 6-25 years when compared to the office worker controls.
A small increase in the incidence of chromosomal aberrations was observed in smelter
workers when compared to non-smelter control subjects. It was not determined if smoking
habits were included as a source of cadmium exposure.
Abnormal metaphase rates were significantly higher in peripheral blood lymphocytes in
male workers exposed to cadmium fumes and dusts compared to the age-matched controls.
Cadmium chloride induced sister chromatid exchange in human lymphocytes in vitro.
2.6. Carcinogenicity
Sorahan and Esmen (2004) reported on a cohort study occurring from 1947-2000
involving 926 males that worked at a Cd-nickel battery factory. The aim was to investigate
mortality of the workers in relation to cumulative cadmium hydroxide exposure. All those
included in the study were required to have worked at the factory for a minimum of 12 months.
Work histories were available from 1947-1986 and the factory closed in 1992. Two approaches
were used to analyze the data: indirect standardization and Poisson regression. Based on the
serial mortality rates for England and Wales, significantly increased mortality was observed for
cancers of the pharynx (observed 4, expected 0.7; standardized mortality ratio (SMR) 559,
p<0.05), non-malignant diseases of the respiratory tract (observed 61, expected 43; SMR 142, p<
0.05), and non-malignant diseases of the genitourinary system (observed 10, expected 4.1; SMR
243, p< 0.05). Non-significantly increased SMRs were observed for lung cancer (observed 45,
expected 40.7; SMR 111) and prostate cancer (observed 9, expected 7.5; SMR 116). The results
do not indicate that chronic cadmium hydroxide exposure leads to carcinogenicity in the lung,
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but that it does lead to increase in non-malignant diseases of the respiratory and genitourinary
systems and pharyngeal cancers.
A mortality study of 602 white males with at least 6 months of production work in the
same factory between 1940 and 1969 was performed to determine the effects of Cd exposure
(Thun et al., 1985). Workers were followed until 1978. Cause-specific mortality rates for seven
causes of death were compared between the workers and average US white males. Cadmium
-3
inhalation exposure concentrations measured in the plant ranged from 0.007 to 1.5 mg/m from
pre-1950 to 1976, depending on the area of work. Most of the Cd exposure was to Cd oxide. The
study population was obtained from employment histories from the personnel files. Mortality
was analyzed with the use of the modified life-table system developed by NIOSH. Of all the
workers, 83% had over 20 years of follow-up. For respiratory cancer, the expected rate was
12.15 and the actual rate was 20. All 20 had over 2 years of employment and all mortalities were
due to cancers of the lung, trachea and bronchus. Six deaths (expected 4.45) from genitourinary
cancer were observed with one due to renal cancer (expected 0.9), two due to cancers of the
bladder or other urinary organs (expected 1.10) and three due to prostate cancer (expected 2.20).
Nine deaths were from non-malignant gastrointestinal disease (NMGID) and the expected
number was 2.35. Even with adjustments to account for the lack of knowledge of the worker's
smoking habits and the fact that arsenic was used in the same factory prior to 1926, there is still
an increase in the respiratory cancers.
Kjellstrom et al. (1979) reported on the mortality and cancer incidence of Swedish
workers exposed to Cd for more than 5 years. Data were collected from 269 Cd-Ni battery
factory workers and 94 Cd-Cu alloy factory workers. At the Cd-Ni factory, the levels of Cd in
the air were: before 1947: >1 mg Cd/m3; in the 1950's: 200 jug Cd/m3; between 1962-1974: 50
3 3
|ig Cd/m ; and 1979: < 5 |ig Cd/m . In this same factory, similar levels of nickel hydroxide were
found in the air. In the Cd-Cu factory, cadmium concentrations were not obtained until the
"3
1960s, when the levels were 100-400 |ig Cd/m ; since the 1970s, the value has been about 50 |ig
Cd/m3. An internal reference group from the Cd-Cu factory was used; workers that were
involved in processes not exposing them to any Cd. A life-table method with the national
average cancer incidence rates for men in different age groups was used to help determine any
correlation between Cd exposure and the cancer incidence. Among the cadmium nickel workers,
the risk ratio for nasopharyngeal cancer was 10 (2 cases) which was statistically significantly
higher than 1, the expected value. However, part of this increase could be attributed to the nickel
hydroxide dust they were exposed to as well as the cadmium oxide dust. There was an increased
tendency for mortality from prostate cancer (4 cases) in the Cd-Cu alloy workers; however, the
risk ratio when calculated was not statistically significantly increased (2.4).
The U.S. EPA (1994) listed cadmium and cadmium compounds as probably human
carcinogens based on limited evidence in occupational epidemiologic studies and sufficient
evidence of carcinogenicity in rats and mice by inhalation, injection, and subcutaneous injection.
An inhalation unit risk factor was calculated based on lung, trachea, and bronchus cancer death
data in human males (Thun et al. 1985).
The International Agency for Research on Cancer (IARC 2003) concluded that there is
sufficient evidence in humans for carcinogenicity of cadmium and cadmium compounds and
categorized cadmium and cadmium compounds as being carcinogenic to humans.
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2.7. Summary
Case reports, occupational studies, and epidemiological studies showed how inhalation of
cadmium affected humans. Although the case reports did not include Cd exposure
concentrations, they did show that acute accidental exposure to Cd caused respiratory irritation,
dyspnea, alveolar damage, pneumonitis, and death. Chronic exposure to Cd in occupational
settings caused decreased lung function and nephrotoxicity. The results of carcinogenicity
studies in Cd workers were equivocal, which may be due to concurrent exposures to other metals
in the workplace. Respiratory cancers were increased in workers at a Cd-nickel battery factory;
although, chronic Cd exposure was not statistically correlated with lung cancer. The U.S. EPA
(1994) and IARC (2003) list cadmium and cadmium compounds as being carcinogenic to
humans. Maternal urine Cd concentration was associated with decreased gestational age and
lower weight at birth.
3. ANIMAL TOXICITY DATA
3.1. Acute Lethality
3.1.1. Rat
Male Crl:CD(SD)Br rats, 24/group, were exposed by nose-only inhalation to 0, 0.25, 0.45
or 4.5 mg/m3 of both CdCh and CdO for 2 hours (Grose et al. 1987). The exposure
concentrations were given as mg Cd/m3. Animals were killed immediately or 72 hours post-
exposure. The following parameters were determined: Cd content in the lungs, lung weight, body
weight, biochemical responses and histopathological lesions in the lungs. Concentrations were
measured using 47 mm cellulose acetate filters and analyzed by atomic absorption and found to
be consistent in the chambers. Three exposed rats died during the study. Two rats in the 0.45
"3
mg/m CdO group died; one rat had cardiovascular failure associated with pulmonary congestion
and the other had an undetermined cause of death. The exposure group of the third rat was not
reported and cause of death was undetermined. It is believed that the rats died from causes
related to complications with the exposure apparatus and not from exposure to cadmium. No
deaths were reported in rats of the high-dose group.
Twenty six adult Sprague-Dawley CD rats/sex/group were exposed for 2 hours to 97
mg/m3 of cadmium red pigment, 99 mg/m3 cadmium yellow pigment, 132 mg/m3 cadmium
carbonate, or 112 mg/m cadmium fume (Rusch et al. 1986). The exposure concentrations are
based on cadmium content. An air control group was also included. Animals were exposed in a
glass and stainless steel exposure chamber that had a total volume of one cubic meter and an
effective volume of 760 L. The Cd carbonate and pigments were sieved through a 60-mesh sieve
and hand-packed into a Wright dust feed mechanism. Dry air was passed through the dust feed
and diluted with room air before being delivered to the chamber. Samples from the chamber
were taken with a dust monitor. The Cd fume was derived from a 10% aqueous solution of
cadmium acetate dehydrate. An aerosol was created by putting the metered solution and dry air
through a nebulizer. No mortality occurred in groups exposed to air (control), Cd red or Cd
yellow pigment. In the cadmium carbonate group, one female rat died on Day 4 and one male
and one female rat died on day 13. All animals were moribund prior to death. Blood and food
matter were found in the gastrointestinal tract, and the lung and liver of the animals were
enlarged and discolored. In the cadmium fume group, 25/52 rats died. Six males and one female
died on day 2, seven males and five females died on day 3, three females died on day 4, two
females died on day 5, and one male rat died on day 6. Lung and liver discoloration and
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congestion were observed in the animals that died from the Cd fume group. Based on the study,
"3
the LC50 for cadmium fume was 112 mg/m .
3.2. Nonlethal Toxicity
3.2.1. Rabbit
A maximum of eight male DLA:New Zealand White rabbits (-30 days old) were exposed
by nose-only inhalation to 0 (controls), 0.25, 0.45 or 4.5 mg/m of both CdCh and CdO for 2
hours (Grose et al. 1987). The exposure concentrations were given as mg Cd/m3. Animals were
killed immediately or 72 hours post-exposure. The following parameters were determined: Cd
content in the lungs, lung weight, body weight, biochemical responses and histopathological
lesions in the lungs. Concentrations were measured and found to be consistent in the chambers.
Rabbits exposed to 0.45 mg/m3 CdO had a greater number of alveolar macrophages present
when compared to controls and those exposed to CdCh. At 4.5 mg/m , the lungs of rabbits had
moderate to severe multifocal interstitial pneumonitis that was more severe in the CdO group
"3
with the presence of fibrocytic-type cells as well as pneumocytes. Rabbits exposed 4.5 mg/m of
either chemical had increased lung weight and lung-to-body weight ratios. In the rabbit, CdCh
had an inhibitory effect on pulmonary GSH peroxidase activity at the lowest and highest
concentrations. The two highest concentrations of CdO inhibited GSH peroxidase activity. The
activity of GSH transferase was increased after treatment with 0.45 mg/m CdCh. The authors
hypothesized that the changes in GSH peroxidase and transferase activity could be a response to
protect cells against lipid peroxidation.
3.2.2. Rat
Twenty-four female Fischer 344 rats were exposed for 6 hours to ultrafine particles of
CdO at a concentration of 70 |ig Cd/m3 in whole-body chambers (330 L volume; ventilation
exchange of 20 times/hour) (Takenaka et al. 2004). The MMAD was 40 nm and the GSD 1.6.
Four rats were sacrificed immediately after exposure and on days 1, 4, and 7 for morphology and
elemental analysis. Eight rats were sacrificed on day 0 for lung lavage. An additional 16 rats
were exposed to 550 |ig Cd/m3 in a similar manner. The MMAD was 51 nm and the GSD was
3 3 3
1.7. When converted, 70 |ig Cd/m is equivalent to 0.07 mg/m and 550 |ig Cd/m is equivalent
to 0.550 mg/m3. Eight rats were sacrificed on day 0 for lung lavage and four rats were sacrificed
on days 0 and 1 for morphology and elemental analysis. Twelve animals for each exposure were
used as controls, and exposed to clean air only. Just after exposure, Cd in the lungs of rats
exposed to 0.07 mg/m3 was 19% of the total inhaled dose and this remained the same at the other
time points. A slight but significant increase of Cd in the liver was observed only in the rats
sacrificed 7 days after exposure. The lung lavage indicated no exposure-related morphological
changes in the lungs or inflammatory responses in the low-dose rats. In rats exposed to the
higher concentration, 0.550 mg/m3, Cd content was similar in the lungs on day 0 and 1 but was
significantly elevated in the liver and kidneys on both days, and 2/4 of the rats had increased
blood Cd. Lung lavage of the rats in the high-dose group showed increased neutrophils, and
multifocal alveolar inflammation was observed histologically.
"3
Four groups of ten male Long Evans rats were exposed to CdO dust (0.00195 mg/m ),
CdO fume (0.00169 mg/m3), CdS (0.00180 mg/m3) or sham-exposed in a nose-only inhalation
chamber for 1 hour (Oberdorster et al. 1987). The exposure concentration was not reported as
mg Cd/m3, therefore, the concentration of Cd in this study is unknown. The CdO dust was ball-
milled for 24 hours and had a mass median aerodynamic diameter (MMAD) of 0.51 |im. The
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CdO fume was generated by an electric arc burning off metallic Cd electrodes, producing
particles of 0.4 |im. Pure CdS with a MMAD of 0.45 |im was used. Twenty-four hours post-
exposure, the animals were sacrificed, and the lungs were lavaged, and the cellular components
of the lavage fluid were analyzed. Lung epithelial permeability was also determined by
measuring the activity of "mTc-DTPA in the lung lavage fluid; this substance was injected
intravenously 10 minutes prior to sacrifice. An increase in activity in the lung lavage fluid
indicates a loss of epithelial integrity. Administration of both CdO dust and CdO fume resulted
in a significant decrease in the number of alveolar macrophages and a significant increase in
numbers of polymorphonuclear neutrophils, with a more pronounced effect observed with the
CdO dust. Epithelial permeability was increased with exposure to CdO dust, but not CdO fume.
Inhalation exposure to CdS resulted in no differences in rats compared to those in the sham-
exposed group. The study report provided very little detail but did help to show that water
solubility does not always correlate with increased toxicity.
"3
Male Wistar rats (16/group) were exposed to 0, 0.5, or 5.3 mg/m CdO aerosols for 3
hours in a laminar flow exposure chamber (Buckley and Bassett 1987). The animals were
observed for up to 15 days post exposure. Interim sacrifices took place 2, 4, 7, and 15 day post
exposure and 4 rats/group were sacrificed at each necropsy. The CdO aerosols were generated
by oxidizing cadmium acetate aerosols as they passed through a heated quartz tube. The
chamber atmosphere was sampled using 0.22 |im pore diameter polycarbonate filters and
determined by gravimetric analysis of aerosol samples. The geometric standard deviations were
2.31 and 3.18 with mass median aerodynamic diameters of 0.26 and 0.33 |im, respectively, for
the low and high dose concentrations. Body weight of rats exposed to 0 or 0.5 mg/m3 increased
"3
from exposure through the end of the observation period, however, rats exposed to 5.3 mg/m did
not gain weight until day 7 post exposure. Body weight was similar among all groups on day 15
"3
post exposure. At 0.5 mg/m , foci of petechial hemorrhage were occasionally observed 2 and 4
days post exposure and were consistently observed at 5.3 mg/m3. Mild hypercellularity at
bronchoalveolar junctions and adjacent alveoli and inflammatory cell influx of mononuclear
cells were observed at 0.5 mg/m3 prior to day 7 post exposure. Morphology of the lungs was
"3
normal in rats exposed to 0.5 mg/m 7 days post exposure. Focal areas of interstitial thickening,
increases in cuboidal alveolar cells, and numerous inflammatory cells (interstitial mononuclear
-3
cells, alveolar macrophages, eosinophils, and basophils) were observed at 5.3 mg/m in the
bronchoalveolar junctions and peripheral alveoli. Lung weight (dry) and protein content of the
lungs were significantly increased in rats exposed to 5.3 mg/m3 compared to those of control on
study days 2-15 post exposure, and DNA content was increased days 4-15. Glutathione
peroxidase, glutathione reductase, glucose-6-phosphate dehydrogenase, and 6-phosphogluconate
"3
dehydrogenase activity were significantly increased in rats exposed to 5.3 mg/m compared to
the activity levels in control rats.
Male Crl:CD(SD)Br rats, 24/group, were exposed by nose-only inhalation to 0, 0.25, 0.45
or 4.5 mg/m3 of both CdCh and CdO for 2 hours (Grose et al. 1987). The exposure
concentrations were given as mg Cd/m3. Animals were killed immediately or 72 hours post-
exposure. The following parameters were determined: Cd content in the lungs, lung weight, body
weight, biochemical responses and histopathological lesions in the lungs. Concentrations were
measured and found to be consistent in the chambers. Three rats exposed to cadmium died
during the study; only one rat (0.45 mg/m3 CdO group) had cardiovascular failure associated
with pulmonary congestion and both others had unknown causes of death. No effects were
observed in the lungs at 0 and 72 hours in rats in the 0.45 mg/m3 group. Groups of rats exposed
"3
to wither 4.5 mg/m CdCh or CdO had no lesions observed immediately after exposure, but at 72
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hours there was moderate to severe multifocal interstitial pneumonitis that was more severe in
the CdO group. It was characterized by the presence of fibrocytic-type cells, alveoli edema,
goblet cell hyperplasia, as well as hyperplastic pneumocytes. The pneumonitis observed in rats
exposed to CdCh presented as thickening of the alveolar walls, edema, hemorrhage, and
increases in neutrophils and alveolar macrophages. There was no difference in Cd deposition in
"3
the lungs in animals exposed to 0.25 or 0.45 mg/m CdCh or CdO at either 0 or 72 hours. While
there was an increase in Cd deposition in the lungs of the rats exposed to 4.5 mg/m3, at 72 hours
"3
there was significantly less Cd in the lungs of rats exposed to 4.5 mg/m CdCh than in those
exposed to 1 ppm CdO. Rats exposed to 0.25 mg/m3 CdCh had a 13% decrease in lung-to-body
"3
weight ratio. Rats exposed to 0.45 mg/m group CdCh had a decrease in body weight and at 4.5
mg/m3 a 20% decrease in body weight and increased lung and lung-to-body weight ratio 72
"3
hours after exposure. In the 0.45 or 4.5 mg/m CdO exposed rats, there was an increase in lung
weight but no effect on body weight. Cadmium (CdCh) had an inhibitory effect {21%) on
"3
pulmonary GSH peroxidase activity at the lowest concentration and at 0.45 mg/m . Cadmium
inhibited GSH peroxidase activity at the two highest dose levels.
Twenty six adult Sprague-Dawley CD rats/sex/group were exposed in a single 2-hour
3 3 3
exposure to 97 mg/m of cadmium red pigment, 99 mg/m cadmium yellow pigment, 132 mg/m
cadmium carbonate, or 112 mg/m3 cadmium fume (Rusch et al. 1986). The exposure
concentrations are based on cadmium content. An air control group was also included. Animals
were exposed in a glass and stainless steel exposure chamber that had a total volume of one
cubic meter and an effective volume of 760L. The Cd carbonate and pigments were sieved
through a 60-mesh sieve and hand-packed into a Wright dust feed mechanism. Dry air was
passed through the dust feed and diluted with room air before being delivered to the chamber.
Samples from the chamber were taken with a dust monitor. The Cd fume was derived from a
10%) aqueous solution of cadmium acetate dehydrate. An aerosol was created by putting the
metered solution and dry air through a nebulizer.
The rats exposed to Cd fume exhibited clinical signs (hypoactivity and closed eyes)
during the exposure. Following exposure, excessive lacrimation was observed in rats exposed to
Cd red and yellow, and dry rales and body tremors were observed in the animals exposed to Cd
carbonate. Those exposed to Cd fume had dry rales, labored breathing, and excessive
lacrimation. Animals exposed to Cd fume also had decreased body weight compared to the
controls, with all others maintaining weight similar to that of controls. No gross abnormalities
were observed in those sacrificed immediately following exposure. Renal discoloration was
observed in the rats in the Cd red pigment group. Pulmonary edema, observed as increased lung
weight was seen in the Cd carbonate exposed group starting at 24 hours post-exposure.
Exposure to Cd carbonate or Cd fume resulted in an increased incidence of lung discoloration
and erosions in the stomach. Blood levels indicated that Cd was absorbed to a greater degree in
the carbonate and fume groups when compared to the pigment groups. Urine and feces samples
were collected at 0-24 hrs, 24-48 hrs, 48-72 hrs, 6-7 days and 29-30 days post-treatment.
Samples indicated that the highest levels of cadmium were excreted in the first 24 hour period
and urinary excretion was similar in all three groups while 80%> of the red and yellow pigments
were excreted in the feces within the first 24 hours. Tissues were collected for cadmium analysis
in all but the Cd fume-exposed animals and these were not collected due to the moribund
condition of the animals. The Cd carbonate-exposed animals had the greatest amount of
cadmium measured in both the kidneys and liver; Cd levels increased initially in the liver and
then dropped off but continued to increase in the kidney.
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PROPOSED: November 2009
TABLE 5. Summary of Acute Inhalation Data in Laboratory Animals
Species
Concentration
(mg Cd/m3)
Exposure
Time
Effect
Reference
Rabbit
CdCL
0.25
0.45
4.5
2 hr
I Pulmonary GSH peroxidase activity 25%
t GSH transferase activity
Moderate-severe multifocal interstitial
pneumonitis; flung weight
Grose et al.
1987
Rabbit
CdO
0.25
0.45
4.5
2 hr
No effects
t Alveolar macrophages; j pulmonary GSH
peroxidase activity
Moderate-severe multifocal interstitial
pneumonitis; flung weight; j pulmonary GSH
peroxidase activity
Grose et al.
1987
Rat
CdO
0.07
0.550
6 hr
No morphological changes or inflammatory
response
t Neutrophils and multifocal alveolar
inflammation
Takenaka et
al. 2004
Rat
0.00195 Cd dust
0.00169 Cdfume
0.00180 CdS
1 hr
i Alveolar macrophages; fPMNs; tepithelial
permeability
i Alveolar macrophages; fPMNs
No effect
Oberdorster
et al. 1987
Rat
CdO
0.5
5.3
3 hr
Transient mild hypercellularity at bronchoalveolar
junctions and adjacent alveoli, inflammatory cell
influx
Interstitial thickening, f cuboidal alveolar cells,
"[inflammatory cells, tdry lung weight, tprotein
content, fDNA content, t GP, GR, G6PD,
6PGD activity
Buckley and
Bassett 1987
Rat
CdCL
0.25
0.45
4.5
2 hr
I Pulmonary GSH peroxidase activity 27%
i bw; Ipulmonary GSH peroxidase activity
i bw 20%; flung weight; j pulmonary GSH
peroxidase activity; pneumonitis
Grose et al.
1987
Rat
CdO
0.25
0.45
4.5
2 hr
No effects
t Lung weight; j pulmonary GSH peroxidase
activity; 2 deaths-cardiovascular failure (1)
t Lung weight; j pulmonary GSH peroxidase
activity; pneumonitis
Grose et al.
1987
Rat
97 Cd red
99 Cd yellow
132 Cd carbonate
112 Cdfume
2 hr
Lacrimation; renal discoloration
Lacrimation
Dry rales, body tremors; 5.8% mortality
Hypoactivity; closed eyes; lacrimation; dry rales; j
bw; t lung discoloration and stomach erosion;
48% mortality; LC50
Rusch et al.
1986
1
2
3 3.3. Developmental/Reproductive Toxicity
4
5 Four female Hartley guinea pigs/group were exposed in late gestation (days 50-55) to 0
6 or 0.05 mg/m3 cadmium chloride for 4 hours/day for 1 or 5 consecutive days by nose-only
7 inhalation (Trottier et al. 2002). Cadmium aerosol was generated in a nebulizer using a solution
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of Cd made from CdCl dissolved in distilled water. Total airflow to the chamber was 22 L
air/min and the concentration of Cd in the chamber was monitored by obtaining air samples
through filters during the exposure. The mean Cd concentration was 53.2 ± 4.6 |ig/m3 and the
MMAD was 0.3 |im. Twenty-four hours after the last exposure, females were euthanized and the
tissues processed. Tissue Cd content was determined by graphite furnace atomic absorption
spectrophotometry and placental metallothionein and cadmium content were also determined.
Inhalation exposure did not affect the maternal body weight, fetal body weight, maternal
or fetal organ weight, or placental weight when compared to controls. Maternal rats had a
significant increase (p<0.01) in lung Cd compared to controls after only a single day and a
significant increase in both lung and liver after 5 days. In the fetus, brain, liver and heart Cd
levels were significantly increased compared to controls after 1 day of exposure, and levels in
brain and liver remained elevated after 5 days. Maternal blood Cd increased from 25.6 to 57.3
pg/mg of protein after 5 days of treatment but the fetal blood had no change. The levels of Cd
and MT in the placenta did not change upon exposure, but the placental cadmium decreased after
the 5-day exposure.
Thirty two pregnant Sprague-Dawley female rats and thirty-three pregnant Swiss (CD-I)
mice were exposed to 0, 0.05, 0.5 or 2 mg/m3 cadmium oxide by whole-body inhalation for 6
hours/day, 7 days/week on gestation days (GD) 4-19 in the rats and GD 4-17 in mice (NTP
1995). Generation of the aerosol was by the same methods described in Section 3.5.1. One rat
"3
exposed to 2 mg/m died on GD 17. Clinical signs observed in rats were dyspnea in all those
exposed and hypoactivity at 2 mg/m3, in females. The female rats exposed to 2 mg/m3 had
significant decreases (p< 0.01) in body weight (14% less than controls) and body weight gain
(41% less than controls). The high dose female rats also had decreases in absolute and relative
liver weight and absolute kidney weight, compared to controls. Developmental toxicity was
observed at 2 mg/m3 in rats, and included a decrease in the weight of live fetuses. This
concentration also caused significant increases in the mean percent of fetuses per litter with
reduced ossification of the pelvis (12 vs. 2.4 in controls) and sternebrae (25 vs. 4.4 in controls).
"3
Dyspnea and hypoactivity were observed in mice exposed to concentrations^ 0.5 mg/m
cadmium oxide. At > 0.5 mg/m3, the number of pregnant mice was significantly decreased. Fetal
"3
body weight following exposure to 0.5 mg/m was significantly less than control fetal body
weight. Five mice in the 2 mg/m3 group were euthanized moribund before the end of the study.
Maternal body weight gain, absolute and relative gravid uterine weights, and absolute liver
weight were significantly lower compared to control values, and relative kidney weight was
significantly increased compared to control kidney weight in female mice exposed to 2 mg/m3.
The total number of resorptions per litter was significantly increased in this group, and the fetal
body weight and percentage of live male fetuses per litter were significantly decreased in the 2
mg/m3 group.
Male and female Fischer 344 rats (10 weeks old) were exposed whole body to 0, 0.3, 1.0
or 2.0 mg CdC^/m3 for 6 hours/day, 5 days/week for 62 exposures (Kutzman et al. 1986).
Twenty male rats were used for multiple pulmonary endpoint assessments, eight males for
pathology only, eight male and eight females for reproductive studies and ten males for
"3
cytogenetic endpoints. Rats were exposed in a 1.4 m stainless steel and Lucite chamber.
Airflow was equivalent to 15 chamber volumes/hr. Laskin-type nebulizers were used to generate
the aerosol. An optical particle size analyzer was used to characterize the size distribution of the
aerosolized particles. RAM-1 aerosol mass monitors were used to continuously monitor the
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CADMIUM
PROPOSED: November 2009
chamber atmosphere. Chamber atmospheres were 0.33 (± 0.02), 1.06 (± 0.04) and 2.13 (± 0.11)
3 3
mg Cd Ch/m in the 0.3, 1.0 and 2.0 mg/m chambers, respectively.
"3
All rats exposed to 2.0 mg/m lost weight rapidly and died within the first 45 days and
were observed to have rapid and shallow breathing and appeared unkempt prior to death. The
females averaged a higher survival (40 days; n= 10) compared to the males (32 days; n= 57). At
1.0 mg/m3, five males died and all animals at 0.3 mg/m3 survived. Some exposed males and
females were allowed to breed with unexposed mates and there were no decreases in
reproductive potential. No findings were associated with treatment in the number of viable
embryos, late deaths, early deaths (resorptions), number of corpea lutea, or pre-implantation
losses. At necropsy, there was a dose-dependent increase in organ-to-body weight ratio for the
lungs, heart, spleen, kidneys, and testis. Also, the liver and brain weight-to-body ratio was
increased in the high-dose, compared to the controls. Lesions of type II hyperplasia, alveolar
macrophages, and polymorphonuclear leukocytes were observed at the terminal bronchioles of
both the low- and mid-dose rats. Areas of fibrosis were also observed in the mid-dose rats.
Similar lesions were identified in those that died in the high-dose group. Based on the
histopathological findings, the LOAEL was 0.3 mg/m3 CdCh and the NOAEL could not be
determined.
3.4. Genotoxicity
Cadmium oxide was not mutagenic in Salmonella typhimurium strains TA98, TA100,
TA1535 or TA1537 with or without metabolic activation and did not produce micronuclei in
erythrocytes of mice exposed by inhalation for 13 weeks (NTP, 1995).
Cadmium chloride induced DNA strand breaks in Escherichia coli and induced
differential toxicity in Bacillus subtilis and E. coli strains. It also induced gene conversion in
Saccharomyces cerevisiae, but did not induce reverse mutation in S. cerevisiae. Unscheduled
DNA synthesis and DNA strand breaks were observed in primary cultures of rat hepatocytes, but
not in primary cultures of rat Leydig cells. Calcium chloride was mutagenic to Chinese hamster
V79 cells and mouse lymphoma L5178Y cells (IPCS 1992).
3.5. Repeated Dose
3.5.1. Rat
Male and female F344/N rats (6 wks old) were exposed to cadmium oxide aerosol
(99.4% purity; mass median aerodynamic diameter (MMAD) = 1.1-1.6 |igm) for 6 hours/day, 5
days/week for 2 weeks (n = 5/sex/group) or 13 weeks (n= 10/sex/group) (NTP 1995). Animals
were exposed to 0, 0.1, 0.3, 1, 3 or 10 mg/m3 for the 2 week studies and 0, 0.025, 0.05, 0.1, 0.25
or 1 mg/m3 for 13 weeks. Animals were exposed in whole-body chambers that had a total
"3
volume of 2.3 m . Chemical concentration, airflow, temperature and relative humidity were
controlled and monitored with an automated system. Overall, concentration within the chamber
was adequate. Cadmium oxide dust was mixed with compressed air to create an aerosol. The
MMAD of the aerosol particles was measured in each exposure chamber before the studies
began, once in the 2 week study and monthly in the 13 week study. Blood was obtained to
measure hematology and clinical chemistry parameters, urine collected and histopathology
performed.
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CADMIUM PROPOSED: November 2009
"3
In the rats exposed for 2 weeks, all those exposed to 10 mg/m died by day 6; no other
deaths occurred. Clinical signs of hypoactivity, dehydration, ruffled fur, dyspnea and nasal
discharge were observed in rats at concentrations > 1 mg/m3. Lesions in the lungs including
alveolar histiocytic infiltrate, focal inflammation and fibrosis were observed in all of the treated
rats with a dose-dependent increase in severity. Effects on the nasal and respiratory epithelium
"3
were observed in those exposed to 1 mg/m and greater. Based on the findings, the doses were
set for the 13 week study. For the two-week study, a LOAEL of 0.1 mg/m3 Cd oxide in rats was
established based on histopathological findings; a NOAEL could not be determined.
TABLE 6. Histopathological Findings in rats Exposed for 2 wks to Cadmium Oxide
(# Affected/Total # examined)
0 mg/m3
0.1 mg/m3
0.3 mg/m3
1 mg/m3
3 mg/m3
10 mg/m3
MALES
Lung
Alveolar infiltrate
0/5
5/5 (2.0)a
5/5 (2.0)
5/5 (3.0)
5/5 (3.8)
5/5 (4.0)
Focal inflamm/fibrosis
0/5
5/5 (1.0)
5/5 (2.0)
5/5 (3.0)
5.5 (2.8)
5/5 (4.0)
Nose
Olfactory epithelium
Degeneration
0/5
0/5
0/5
2/5 (1.0)
5/5 (2.0)
5/5 (2.2)
Respiratory epithelium
Squamous metaplasia
Inflammation
0/5
0/5
0/5
0/5
0/5
0/5
1/5 (1.0)
1/5 (1.0)
0/5
5/5 (1.4)
5/5 (1.0)
3/5 (1.7)
FEMALES
Lung
Alveolar infiltrate
0/5
5/5 (2.0)
5/5 (2.2)
5/5 (3.0)
5/5 (4.0)
5/5 (4.0)
Focal inflamm/fibrosis
0/5
3/5 (1.0)
5/5 (2.0)
5/5 (3.0)
5.5 (3.0)
5/5 (4.0)
Nose
Olfactory epithelium
Degeneration
0/5
0/5
0/5
4/5 (1.3)
4/5 (2.3)
4/4 (3.0)
Respiratory epithelium
Squamous metaplasia
Inflammation
0/5
0/5
0/5
0/5
0/5
0/5
0/5
0/5
4/5 (1.5)
4/5 (2.3)
4/4 (1.5)
3/4 (1.0)
Data from NTP (1995)
" Number in parenthesis is severity code: 1= minimal, 2= mild, 3= moderate and 4= marked
All rats survived the 13 week study and all treated rats had a nasal discharge that
"3
increased in frequency as the concentration increased. Rats at 1 mg/m consistently had lower
body weight throughout the study compared to controls, but it was within 10%. No significant
findings were observed in the hematology, clinical chemistry or urine parameters. Males and
females had statistically significant increases (p < 0.01 or 0.05) in organ weight at concentrations
> 0.05 mg/m , compared to controls including relative kidney weight, and relative and absolute
lung weight; however, there were no treatment-related microscopic findings in the kidney or
liver. Blood pressure was measured in the animals and there were no findings observed with
treatment. Grossly, the only treatment-related finding was enlargement and paleness of the
tracheobronchial and mediastinal lymph nodes. Microscopic lesions were identified in the lungs
in all treated animals except those in the 0.025 mg/m3 group. The lesions were similar to those
identified in the 2 week study. Based on the histopathological findings, the LOAEL for rats
treated for 13 weeks 0.05 mg/m3 cadmium and the NOAEL was 0.025 mg/m3.
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CADMIUM
PROPOSED: November 2009
TABLE 7. Histopathologic;!! Findings in Rats Exposed for 13 wks to Cadmium Oxide
(# Affected/Total # examined)
0
mg/m3
0.025
mg/m3
0.05 mg/m3
0.1 mg/m3
0.25
mg/m3
1 mg/m3
Males
Lung
Alveolar infiltrate
Inflammation
Fibrosis
0/10
0/10
0/10
0/10
0/10
5/5(1.0)
10/10 (1.0)a
0/10
5/5 (2.0)
10/10 (2.0)
0/10
5/5 (3.0)
10/10 (3.0)
10/10 (2.6)
5.5(2.8)
10/10(3.0)
10/10(2.1)
5/5 (4.0)
Tracheobronchial lymph node
Inflammation
0/9
0/7
0/5
3/7(1.0)
9/9 (3.0)
10/10(3.1)
Nose
Olfactory epithelium
Degeneration
0/10
0/10
0/10
0/10
1/10(1.0)
10/10(3.0)
Respiratory epithelium
Inflammation
0/10
0/10
0/10
0/10
7/10(1.0)
9/10 (2.6)
Females
Lung
Alveolar infiltrate
Inflammation
Fibrosis
0/10
0/10
0/10
0/10
0/10
0/10
10/10(1.0)
0/10
0/10
10/10(2.1)
0/10
10/10(1.0)
10/10 (3.0)
10/10(1.6)
10/10 (2.0)
10/10(3.0)
10/10(3.5)
10/10(2.1)
Tracheobronchial lymph node
Inflammation
0/7
0/4
0/8
6/8(1.2)
6/9 (2.8)
10/10(3.5)
Nose
Olfactory epithelium
Degeneration
0/10
0/10
0/10
0/10
2/10(1.0)
10/10 (2.8)
Respiratory epithelium
Inflammation
0/10
0/10
0/10
3/10(1.0)
10/10(1.6)
10/10(1.8)
Data from NTP (1995)
a Number in parenthesis is severity code: 1= minimal, 2= mild, 3= moderate and 4= marked
Sixty male Wistar (CHbb:THOM) rats, approximately 8 weeks old, with a mean body
weight of 250 g were exposed nose-only 6 hours/day for up to 10 days to 0 (air control),
0.3 mg/m3 CdCb or 0.2, 1.0 or 8.0 mg/ m3 CdS (Klimisch 1993). Four animals from each group
were sacrificed on days 2, 10, 11, 12, 13, 17, 38, 66 and 94. The study was designed to expose
rats to soluble (CdCh) and insoluble (CdS) forms of Cd. Measurements of lung, renal and fecal
Cd were obtained. Cadmium chloride was generated as an aerosol by taking an aqueous solution
and putting it through an injection pump to a binary nozzle atomizer before diluting with air.
Cadmium sulfide was generated as a dust using a rotating brush-type generator and passing the
dust directly into the inhalation chamber. All concentrations were sampled and found to be
within an acceptable range. Upon sacrifice, the lungs and kidneys were removed and weighed
before being processed for Cd content. Feces were collected daily and pooled together.
No adverse clinical signs or mortalities occurred during the study or post-exposure
period. Pooled data from days 0-10 showed a statistically significant increase in mean lung
weight and lung to body weight ratio in the CdCh-exposed rats. Rats exposed to 8.0 mg/m3 CdS
also had increased mean lung weight. No effects were observed on kidney weight. Cadmium
accumulated in the kidney of all treated animals but at a much greater proportion in those
exposed to CdCh. Cadmium in feces was observed mostly during the exposure and for a few
days post-exposure, with the highest amount observed in rats exposed to the highest dose of CdS.
The analyzed Cd content of test atmospheres for both compounds was 0.17 |ig/L; however, the
Cd lung content in the CdC^-exposed rats was about two times higher than the CdS exposed
rats. This could have been caused by either the greater availability of the CdCh aerosol
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PROPOSED: November 2009
compared to the CdS dust or the fact that CdCh is held in the lung longer. Overall the study
showed a much higher bioavailability of CdCh compared to the soluble CdS upon inhalation
exposure.
Three month old female Wistar rats (n= 13-14) were exposed by inhalation to CdO for 5
"3
hours/day, 5 days/week for 20 weeks at concentrations of 0.02, 0.16 or 1 mg/m (Baranski and
Sitarek 1987). A control group was exposed to clean air only. The aerosol concentration was
determined by drawing air in an inhalation chamber through Sartorious membrane filters
SMI 1306. Fractions of aerosols with particle sizes below 4.7 |im were determined with the
"3
Anderson Impactor 2000. Mortality occurred at 1 mg/m , although histopathology and gross
findings were not described in the report. At 1 mg/m3, mortality was 15% at the end of 7-8
weeks, 38% at the end of 13-14 weeks and 100% at the end of the study. This was compared to
0, 7 and 14% of the controls at the same time points, respectively. A significant decrease (p<
"3
0.05) in body weight gain was observed in the rats exposed to 1 mg/m throughout the study; at
0.16 mg/m3, exposed rats had a decrease in body weight gain compared to controls, but it was
not significant. All treated rats showed an increase in the length of estrous during treatment when
compared to pre-treatment, but at 0.02 and 0.16 mg/m3, rats showed this change only at the end
"3
of the study (weeks 19-20). At 1.0 mg/m , exposed rats had an increase in estrous length during
the entire study. Based on the increased estrous length, the LOAEL was 0.02 mg/m3 CdO and the
NOAEL could not be determined.
"3
Twelve adult female Wistar rats/group were exposed continuously to 0, 25 or 50 |ig Cd/m
for 90 days and to 100 |ig Cd/m3 for 63 days (Prigge 1978), equivalent to 0, 0.025, 0.052 and
-3
0.105 mg/m administered as CdO. The rats were removed from the chamber for only 10-20
minutes daily to allow for cleaning and food was changed daily to prevent oral contamination.
Inhalation chambers were 50 x 50 x 90 cm with a total volume of 225L. Cadmium was nebulized
from a 0.2% solution of cadmium acetate. The volume flow into the chambers was about 80
L/min equating to about 21 changes/hour. Aerosol concentrations were checked and found to be
within range of the expected values. Size distribution of the particles had a mean aerodynamic
diameter of 0.19 |im, and the geometric standard deviation was 1.5. Both are in the range of
respirable fine dust in humans. Urine and blood samples were obtained after exposure. A
significant dose-dependent decrease (p<0.05) in body weight was observed in the rats exposed
to 0.052 and 0.105 mg/m3, and 5/12 died at 0.105 mg/m3 between days 45 and 60. A significant
increase in lung weight was observed in all of the treated animals. A slight increase was
observed in hematocrit or hemoglobin with treatment, but there was no effect on serum iron or
alkaline phosphatase activity. A significant (p<0.05) decrease in the partial pressure of O2 and an
"3
increase in the partial pressure of CO2 were observed in the rats exposed to 0.105 mg/m .
Proteinuria was not observed in any of the treated females. Inhalation uptake of cadmium
resulted in increased liver cadmium levels but they were not as high as those observed after oral
administration; uptake of cadmium in the kidney was similar with both methods of
administration. Histopathology showed a few areas of swellings in the kidney tubuli, no lesions
in the liver, emphysematic areas and cell proliferation in the bronchi, bronchiole, alveoli, and
histiocytic cell granulomas in the lungs in the treated animals. Based on the histopathological
findings, the inhalation LOAEL for cadmium by inhalation in rats was 25 |ig/m3 Cd (0.025
"3
mg/m ) and the NOAEL was not established.
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3.5.2. Mouse
Male and female B6C3Fi mice (6 wks old) were exposed to cadmium oxide aerosol (99.4%
purity; MMAD = 1.1-1.6 |igm) for 6 hours/day, 5 days/week for 2 weeks (n = 5/sex/group) or 13
weeks (n= 10/sex/group) (NTP 1995). Animals were exposed to 0, 0.1, 0.3, 1, 3 or 10 mg/m3 for
"3
the 2 week studies and 0, 0.025, 0.05, 0.1, 0.25 or 1 mg/m for 13 weeks. Animals were exposed
in whole-body chambers that had a total volume of 2.3 m3. Chemical concentration, airflow,
temperature and relative humidity were controlled and monitored with an automated system.
Overall, concentration within the chamber was adequate. Cadmium oxide dust was mixed with
compressed air to create an aerosol. The mass median aerodynamic diameter (MMAD) of the
aerosol particles was measured in each exposure chamber before the studies began, once in the 2
week study and monthly in the 13 week study. Blood was obtained to measure hematology and
clinical chemistry parameters, urine collected and histopathology performed.
Findings similar to those reported in rats (NTP, 1995) were observed in the mice. In the 2
"3
week study, all mice in the 10 mg/m group died and death was due to severe respiratory
toxicity. Hypoactivity, abnormal posture, rapid breathing, ataxia, nasal discharge, and ruffled fur
"3
were observed at 1, 3, and 10 mg/m . Absolute and relative lung weights were significantly
increased at concentrations > 0.3 mg/m3. Alveolar macrophage infiltration, fibrosis, focal
inflammation, and necrosis of alveolar duct epithelium were observed. As in the rats, severity of
effects increased with increasing concentration. Histopathologic lesions are listed in Table 8. In
"3
the 2 week study, a NOAEL could not be established and the LOAEL for mice was 0.1 mg/m
cadmium based on microscopic lung lesions.
TABLE 8. Histopathological Findings in Mice Exposed for 2 wks to Cadmium Oxide
# Affected/Total # examined
0 mg/m3
0.1 mg/m3
0.3 mg/m3
1 mg/m3
3 mg/m3
10 mg/m3
MALES
Lung
Alveolar infiltrate
0/5
5/5 (1.2)a
5/5 (2.0)
5/5 (3.0)
5/5 (3.0)
0/5
Focal inflamm/fibrosis
0/5
0/5
5/5
5/5
5/5
0/5
Necrosis
Acute inflammation
0/5
0/5
0/5
0/5
1/5 (1.0)
0/5
5/5 (2.0)
0/5
5/5 (2.2)
5/5
5/5 (3.0)
5/5 (4.0)
Nose
Olfactory epithelium
Degeneration
0/5
0/5
0/5
5/5 (1.4)
5/5 (3.0)
3/5 (3.0)
Tracheobronchial lymph node
hyperplasia
0/5
3/5 (1.0)
5/5 (1.0)
5/5 (2.0)
5/5 (2.0)
1/5 (3.0)
FEMALES
Lung
Alveolar infiltrate
0/5
5/5 (1.0)
5/5 (1.8)
5/5 (3.0)
5/5 (3.0)
0/5
Focal inflamm/fibrosis
0/5
0/5
5/5
5/5
5.5
0/5
Necrosis
0/5
0/5
1/5 (1.0)
5/5 (2.0)
5/5 (2.0)
5/5 (3.0)
Acute inflammation
0/5
0/5
0/5
0/5
0/5
5/5 (4.0)
Nose
Olfactory epithelium
Degeneration
0/5
0/5
0/5
5/5 (2.0)
5/5 (3.0)
5/5 (3.0)
Tracheobronchial lymph node
hyperplasia
0/5
4/5 (1.0)
4/5 (1.0)
4/4 (1.5)
5/5 (1.8)
0/4
Data from Table 16, p. 69 in NTP 1995.
a Number in parenthesis is severity code: 1= minimal, 2= mild, 3= moderate and 4= marked
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In the 13 week study, one mouse from the control group died with no deaths in the treated
animals. No clinical signs of toxicity were observed. Lung lesions were similar to those of the
rat and consisted of macrophage infiltrates, hyperplasia, inflammation and fibrosis, although
fibrosis was more prevalent in the rat as shown in Table 9. The absolute and relative lung weight
of both sexes, absolute and relative kidney and thymus weights in male rats, and absolute and
relative kidney, liver, and spleen weights in female rats in all treatment groups were increased
compared to control weights. No microscopic changes were found in the liver, kidney, spleen, or
thymus. In the 13 week study, a NOAEL could not be established and the LOAEL for mice was
0.025 mg/m cadmium based on microscopic lung lesions.
TABLE 9. Histopathologic;!! Findings in Mice Exposed for 13 wks to Cadmium Oxide
(# Affected/Total # examined)
0
mg/m3
0.025 mg/m3
0.05 mg/m3
0.1 mg/m3
0.25 mg/m3
1 mg/m3
MALES
Lung
Alveolar infiltrate
Alveolar hyperplasia
Inflammation
Fibrosis
0/10
0/10
0/10
0/10
9/10 (l.l)a
1/10(1.0)
0/10
0/10
10/10 (1.0)
10/10 (1.0)
0/10
2/10 (1.0)
10/10 (2.0)
10/10 (1.8)
8/10 (3.0)
10/10/1.0)
10/10 (2.0)
10/10 (1.8)
10/10 (2.2)
10/10 (1.0)
10/10 (3.0)
10/10 (2.0)
10/10 (2.7)
10/10 (1.0)
Tracheobronchial lymph node
hyperplasia
0/6
0/8
4/9 (1.0)
9/9 (2.3)
8/10 (2.4)
9/10 (2.7)
Larynx squamous metaplasia
0/9
10/10 (1.0)
10/10 (1.0)
10/10 (1.0)
10/10 (1.0)
9/10 (1.0)
Nose
Olfactory epithelium
Degeneration
0/10
0/10
0/10
4/10 (1.0)
10/10 (1.7)
10/10 (2.0)
Respiratory epithelium
hyaline droplets
0/10
0/10
0/10
0/10
2/10 (1.0)
10/10 (1.0)
FEMALES
Lung
Alveolar infiltrate
Alveolar hyperplasia
Inflammation
Fibrosis
0/10
0/10
0/10
0/10
9/10 (1.0)
0/10
0/10
0/10
10/10 (1.0)
0/10
0/10
1/10 (1.0)
10/10 (2.0)
10/10 (1.4)
6/10 (2.3)
10/10 (1.0)
10/10 (2.0)
10/10 (2.0)
8/10(2.1)
10/10 (1.0)
10/10 (3.0)
10/10 (2.0)
8/10 (2.9)
10/10 (1.0)
Tracheobronchial lymph node
hyperplasia
0/6
0/6
2/9 (1.0)
8/9 (1.5)
9/10 (2.0)
10/10 (2.4)
Larynx squamous metaplasia
0/10
10/10 (1.0)
10/10 (1.0)
10/10 (1.0)
10/10 (1.0)
10/10 (1.0)
Nose
Olfactory epithelium
Degeneration
0/10
0/10
0/10
1/10 (1.0)
10/10 (1.0)
10/10 (1.0)
Respiratory epithelium
hyaline droplets
0/10
0/10
0/10
0/10
2/10 (1.0)
10/10 (1.0)
Data from Table 19, p. 76 in NTP 1995.
a Number in parenthesis is severity code: 1= minimal, 2= mild, 3= moderate and 4= marked
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CADMIUM
PROPOSED: November 2009
1 The repeat dose studies are summarized in Table 10.
2
TABLE 10. Summary of Repeat Dose Inhalation Data in Laboratory Animals
Species
Concentration
(mg/m3)
Exposure
Time
Effect
Reference
Rat
CdO aerosol
0.1
0.3
1
3
10
6 hr/d
5 d/wk
2 wk
All: Alveolar histiocytic infiltrate, pulmonary
focal inflammation, pulmonary fibrosis
0.1: LOAEL
> 1: Hypoactivity, dehydration, dyspnea, nasal
discharge, olfactory epithelium degeneration,
inflammation
10: 100% mortality
NTP 1995
Rat
CdO aerosol
0.025
0.05
0.1
0.25
1
6 hr/d
5 d/wk
13 wk
0.025: NOAEL
0.05: LOAEL
> 0.05: | organ weight, pulmonary fibrosis,
alveolar infiltrate
>0.1: Tracheobronchial lymph node inflammation,
respiratory epithelium inflammation, pulmonary
fibrosis, alveolar infiltrate
> 0.25: Tracheobronchial lymph node
inflammation, pulmonary fibrosis, alveolar
infiltrate , respiratory epithelium inflammation,
olfactory epithelium degeneration
NTP 1995
Rat
0.3 CdC12
CdS
0.2
1.0
8.0
6 hr/d
10 d
0.3 CdCl2: t absolute and relative lung weight
8.0 CdS: t absolute lung weight
Klimisch
1993
Rat
CdO aerosol
0.02
0.16
1
5 hr/d
5 d/wk
20 wk
0.02: LOAEL
All: | increased length of estrous (0.02, 0.16 at end
of the study)
1: 15% mortality at 7-8 wk, 38% mortality at 13-14
wk, i body weight
Barariski and
Sitarek 1987
Rat
mg Cd/m3
0.025
0.052
0.105
Continuous
63 d
All: Focal kidney tubuli swelling, emphysematic
areas and cell proliferation in bronchi
0.025: LOAEL, | lung weight,
0.052: I body weight, t lung weight,
0.105: 42% mortality between days 45 and 60, J,
body weight, j p02, ! pC02. f lung weight
Prigge 1978
Mouse
CdO aerosol
0.1
0.3
1
3
10
6 hr/d
5 d/wk
2 wk
0.1: LOAEL
>0.1: Alveolar infiltrate, tracheobronchial lymph
node hyperplasia
>0.3: | absolute and relative lung weight, alveolar
duct epithelium necrosis
> 1: Hypoactivity, abnormal posture, ataxia, rapid
breathing, olfactory epithelium degeneration
10: 100% mortality, severe respiratory toxicity
NTP 1995
Mouse
CdO aerosol
0.025
0.05
0.1
0.25
1
6 hr/d
5 d/wk
13 wk
0.025: LOAEL, alveolar infiltrate, larynx
squamous metaplasia
>0.05: alveolar infiltrate, larynx squamous
metaplasia, tracheobronchial lymph node
hyperplasia
>0.1: Olfactory epithelium degeneration
> 0.25: Respiratory epithelium hyaline droplets
NTP 1995
3
4
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7
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10
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CADMIUM
PROPOSED: November 2009
3.6. Chronic Toxicity/Carcinogenicity
As a follow-up to the Takenaka et al. (1983) study described below Oldiges et al. (1989)
exposed thirty four groups of twenty male and female SPF Wistar rats/sex/group (8 wks old) to a
variety of Cd compounds in aerosol, dust or fume form (Table 11). The animals were exposed
22 hours a day, 7 days a week for 18 months. A few groups had discontinuous exposure for 40
hours a week for 6 months. Inhalation and observation periods were terminated at mortality rates
of more than 25% during the inhalation period and 75% during the observation period to assure a
carcinogenic result. In addition, an aerosol combination with the antagonistic zinc oxide aerosol
was used in some of the exposures. Results were similar to those from the Takenaka et al. (1983)
study in that no primary lung tumors were identified in the control rats, but were identified in the
Cd exposed animals. Lung tumors rats were increased for all Cd compounds. The inhalation
period was shorter for the water insoluble Cd compounds CdS and CdO because of mortality, but
primary lung tumors were still observed in the rats of these groups.
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PROPOSED: November 2009
TABLE 11. Observations after Inhalation Exposures of Rats to Various Cd Compounds
# Affected/Total # examined
Group
No.
Compound
Concentration
(mg/m3)
Duration (month)
Lung
Primary lung tumors3
Exposure
Study
Nodules
(n/n)
A
B
C
D
n/n
Males
1
Control
—
—
31
0/20
0
0
0
0
0/20
3
CdCl2
0.03
18
30b
18/20
2
12
0
1
15/20
5
CdCL2
0.09
6
30b
12/20
3
5
3
0
11/20
7
CdS04
0.09
14b
31
10/20
2
7
0
2
11/20
9
CdS
0.09
18
30b
16/20
4
9
2
2
17/20
11
CdS
0.27
16b
30b
11/19
1
8
2
3
14/19
13
CdS
0.81
i°
30b
7/20
2
5
2
2
11/20
15
CdS
2.43
4b
30b
6/16
1
2
1
3
7/16
17
CdS
0.27
6
27b
2/20
3
0
0
0
3/20
19
CdO dust
0.03
18
31
15/20
4
6
1
4
15/20
21
CdO dust
0.09
7b
31b
11/15
2
5
0
2
9/17
23
CdO dust
0.09
6
31
8/20
1
2
1
0
4/20
25
CdO dust
0.03
18
29b
13/18
5
7
0
1
13/18
26
CdO dust
0.01
18
29b
13/20
6
5
0
1
12/20
27
CdO dust
0.03
18
31
1/19
0
0
0
0
0/19
28
CdO dust
0.03
18
31
1/19
0
0
0
0
0/19
29
CdO dust
0.03
18
31
8/19
2
1
0
0
3/20
30
CdO dust
0.09
18
31
5/17
3
1
0
0
4/17
31
CdO/ZnO
dust
18
31
1/20
0
0
0
0
0/20
33
CdO/ZnO
dust
18
31
11/20
1
3
2
2
8/20
Females
2
Control
—
-
31
0/20
0
0
0
0
0/20
4
CdCl2
0.03
18
31
15/20
4
7
0
2
13/18
30
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3
4
5
6
7
8
9
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CADMIUM
PROPOSED: November 2009
TABLE 11. Observations after Inhalation Exposures of Rats to Various Cd Compounds
# Affected/Total # examined
Group
No.
Concentration
(mg/m3)
Duration (month)
Lung
Primary lung tumors3
Compound
Exposure
Study
Nodules
A
B
C
D
(n/n)
n/n
6
CdCl2
0.09
6
29b
6/18
0
1
2
0
3/18
8
CdS04
0.09
18
29b
17/20
4
6
2
6
18/20
10
CdS
0.09
NR
NR
17/20
0
9
1
5
15/20
12
CdS
0.27
16b
30b
17/19
1
8
2
5
16/19
14
CdS
0.81
10b
29b
11/20
3
5
1
4
13/20
16
CdS
2.43
3b
31
9/19
3
3
0
0
6/19
18
CdS
0.27
6
29b
6/20
1
1
0
1
3/20
20
CdO dust
0.03
18
31
15/20
3
7
1
4
15/20
22
CdO dust
0.09
llb
3b
14/15
2
8
1
0
11/16
24
CdO dust
0.09
6
31
6/20
0
2
1
0
3/20
32
CdO/ZnO
dust
18
31
4/20
0
0
0
0
0/20
34
CdO/ZnO
18
31
11/20
1
3
1
2
dust
7/20
NR = not reported
Data from Oldiges et al. 1989
a Type of tumors: A- bronchioalveolar adenomas; B- adenocarcinomas; C- squamous cell tumors; D- combined
forms
b The exposure and the study were stopped after 25% and 75% morality, respectively.
Forty male inbred Wistar rats/group (6 weeks old) were exposed to CdCh aerosol at
concentrations of 0 (n=41), 12.5, 25 or 50 |ig/m3 for 23 hrs/day, 7 days/week for 18 months
(Takenaka et al. 1983). After exposure, animals were kept for another 13 months under normal
laboratory conditions. Equivalent concentrations were 0.0125, 0.025 or 0.050 mg/m3,
respectively. Exposures took place in a 225 L inhalation chamber and the aerosol was generated
by atomizing a solution of CdCh with an ultrasonic atomizer. Air flow through the atomizer was
700 L/min and the aerosol flow through the inhalation chamber was 80 L/min. The aerosol was
diluted at the lower concentrations with filtered air. Air samples were drawn through membrane
filters twice weekly from the intake and exhaust of the chamber to check chamber concentration.
The mass of Cd on the filters was determined by atomic absorption spectrometry. The mass
median diameter was 0.55 |im and the geometric standard deviation was 1.8. Animals were
weighed every 3 months and any animals dying were examined as soon as possible.
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24
25
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Histopathology was performed as well as measurement of the Cd content in the lungs, livers and
kidneys.
During and after the exposure, there was no difference in body weight between the
control and treated rats. Mean survival time at 0.050 mg/m3 was slightly below that of the others
but the difference was not significant. Compared to the controls (0.03 jug/g), the Cd
concentration in the lungs was higher in treated rats, 5.6 |ig/g in the low-dose group, 4.7 |ig/g in
the mid-dose group and 10.4 |ig/g in the high-dose group. Similar values were found in the liver,
and the kidney values were 0.3, 13.5, 16.4 and 33.6 |ig/g Cd in the control, low-, mid- and high-
dose groups, respectively. After the 13 month waiting period, the study reported that 0/38 in the
control group; 6/39 (15.4%) at 0.0125 mg/m3, 20/38 (52.6%) at 0.025 mg/m3, and 25/35 (71.4%)
"3
at 0.050 mg/m had primary lung carcinomas. These tumors were identified as adenocarcinomas,
epidermoid carcinomas and combined epidermoid and adenocarcinomas. Some of the rats also
had metastases in the regional lymph nodes and the kidneys. Other tumors were noted but either
lacked a dose response or did not appear to be treatment-related. Limited data were provided on
all other histopathological findings.
3.7. Summary
Cadmium, in various forms, caused respiratory irritation, pulmonary edema, rales,
pneumonitis, lacrimation, increased alveolar macrophages, and death in rabbits and rats exposed
for 1-6 hours. Rats and mice exposed for 90 days or less exhibited pulmonary inflammation and
edema, pulmonary hyperplasia, and nasal and respiratory epithelium degeneration. Kidney
weight was also increased with limited microscopic changes observed. In carcinogenicity
studies, rats exposed to Cd had an increased incidence of primary lung carcinomas.
Reproductive studies in rats resulted in decreased weight of live fetuses and reduced ossification
of the pelvis and sternebrae. In mice, the number of pregnant mice decreased with exposure to
Cd and fetal body weight was decreased.
4. SPECIAL CONSIDERATIONS
4.1. Metabolism and Disposition
Cadmium can be absorbed by inhalation, oral and dermal routes of exposure; however,
dermal absorption is relatively insignificant (ATSDR 2008). In humans, acute oral exposure to
cadmium causes severe nausea, vomiting, diarrhea and salivation. Cadmium fumes may produce
a metal fume fever, or at higher doses, pulmonary edema, inflammation and emphysema (U.S.
EPA, 1986). In humans, cadmium adsorption in the gastrointestinal tract has been reported to be
low, only about 3-8%, and dependent upon several blood and dietary factors. In contrast, 30-64%)
of inhaled cadmium can be absorbed (Morrow, 2001). For the non-smoker, 95% of the total
cadmium intake comes from ingestion of terrestrial foods or meat from animals that ate plants
grown in cadmium-containing soil. For a smoker, 50% of cadmium intake is through cigarettes.
Based on a 50% absorption rate, a person smoking one pack a day will absorb about 1-3 |ig
cadmium (Wittman and Hu 2002).
Jarup et al. (1983) determined the half-life of cadmium in the blood of workers after
exposure had ended. Five men were exposed to cadmium for 4-7 years and then followed up to
13 years after cessation of exposure. The estimated total inhaled amounts of cadmium during
their exposures ranged from 399 to 865 mg x hr/m3. Two of the five men had developed renal
tubular damage. The best fit with the data was a two compartment model with the biological
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7
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15
16
17
18
19
20
21
22
23
24
25
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27
28
29
30
31
32
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37
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CADMIUM
PROPOSED: November 2009
half-life of cadmium in the blood being 75-128 days in the first compartment and 7.4 to 16.0
years in the second.
Once absorbed, cadmium is distributed to most tissues in the body but concentrates in the
liver and kidneys of all animals (ATSDR 2008). Once in the blood, cadmium is not known to
undergo any direct metabolic conversion, but the sulfhydryl groups in albumin and
metallothionein have a high affinity for cadmium so it can adhere to plasma proteins (mostly
albumin), plasma metallothionein or directly to the erythrocyte. Since cadmium is not easily
absorbed in the GI tract, most is excreted in the feces. In the lungs, some clearance occurs but
absorption can take place. In chronic exposure, approximately 1/3 of the cadmium in the body is
stored in the kidney and biological half-lives are on the order of 10-30 years (Wittman and
Hu 2002).
Absorbed cadmium is excreted from the body primarily in urine. The excretion rate is
low and as stated above, the half-life in humans can be 10-30 years (U.S. EPA 1986; Wittman
and Hu 2002).
Hadley et al. (1980) dosed male Wistar rats by intratracheal instillation with 15 |ig
109CdO having a particle size of approximately 1.0 |im. Rats were sacrificed 1, 2, 4, 6, 12, 24,
48, 168, and 336 hours after instillation. At approximately 6 hours post instillation, 50%
instilled 109CdO was no longer present in the lungs and 70% of that which had left the lungs was
found in the liver. At 24 hours, 80% instilled 109CdO had left the lung. At the end of the 2 week
period, 20% instilled 109CdO remained in the lungs. Approximately 8% of the instilled 109CdO
was distributed to the kidney over 2 weeks, and the cumulative total eliminated in the urine and
feces was less than 10% of total body burden.
4.2. Mechanism of Toxicity
Acute exposure to cadmium by the inhalation route has produced inflammatory cell
influx, pneumonitis, respiratory irritation, and pulmonary edema in humans, rabbits, and rats
(Beton et al. 1966; Rusch et al. 1986; Grose et al. 1987). Chronic exposure to cadmium by the
oral or inhalation route has produced renal proximal tubule damage, proteinuria, polyuria and
glycosuria. Cadmium-induced renal injury initially presents as tubular proteinuria which can be
quantified by measurement of low molecular weight proteins such as P2-microglobulin, retinol
binding protein and protein HC. With continued exposure, the progression continues and
glomerular damage occurs with a characteristic decrease in the glomerular filtration rate. For the
most part, this damage is irreversible (Wittman and Hu 2002). Pneumonitis, inflammation, and
fibrosis have been observed following chronic inhalation exposure (Prigge 1978; IPCS 1992;
Klimisch 1993). Very little is known, however, regarding the biochemical mechanisms by which
cadmium causes toxicity at the cellular level (U.S. EPA 1986).
4.3. Structure Activity Relationships
No data were located.
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3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
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CADMIUM
PROPOSED: November 2009
4.4. Other Relevant Information
4.4.1. Species Variability
Acute exposure to cadmium caused pneumonitis, increased lung weight, and pulmonary
inflammatory cell influx in rabbits and rats (Rusch et al. 1986; Buckley and Bassett 1987; Grose
et al. 1987; Takenaka et al. 2004).
In a 4-week study, male Fisher 344 rats and Balb-c mice (number of animals not
specified) were exposed to CdCh aerosols at a concentration of 0 or 100 |ig Cd/m3 for 6
hours/day, 5 days/week to determine if the amount of metallothionein (MT) produced was
substantially different between the species (Oberdorster et al. 1994). The study found a
significant species difference in the pulmonary response which may explain the pulmonary
carcinogenicity observed in long-term Cd exposure in rats, whereas there is none in mice.
Cadmium exposure significantly increased MT in both species in the total lung, persisting for a
28 day post-exposure period, however, the baseline MT level was higher in mice. Mice showed
a 3 fold increase in MT in the lavaged lung compared to rats, the increase in mice persisted for
28-days. Histochemical staining showed that the epithelial cells of mice in the conducting
airways and alveolar region had a greater induction of MT compared to those of rats, and that
mice had more effects on proliferative cells compared to rats. Overall, the study suggested
species difference in carcinogenicity susceptibility to Cd exposure and recommended further
human research to help determine the extent of MT induction in humans.
To help further distinguish species differences observed in pulmonary inflammation,
McKenna et al. (1997) exposed forty-three 15-week old male Wistar Furth rats, and sixty 17-
week old mice/strain (C57 and DBA) to 1.0 mg/m3 (0.22 ppm) of CdO fumes for 3 hours by
nose-only inhalation. Control animals were exposed to a mixture of air and argon. Animals were
sacrificed at 0, 1, 3 or 5 days post-exposure and control animals at one time point only. Overall,
there were interspecies and interstrain differences observed, further indicating the wide range of
effects that could be possible with human exposures. The main findings were that C57 mice had
higher cell proliferation in lung tissue and neutrophil influx in the bronchoalveolar lavage fluid
(BALF) compared to DBA mice and Wistar rats, DBA mice had a higher percentage of Cd dose
in lung and higher levels of biochemical indices of injury in BALF, and rats responded to Cd
inhalation with a more transient response in BALF and a higher degree of acute inflammatory
lesions in the lung than mice.
4.4.2. Susceptible Populations
In acute inhalation studies, cadmium caused respiratory irritation and adverse pulmonary
effects, therefore, those with lung-associated diseases or conditions (such as asthma and COPD)
could be affected more. Children may be slightly more sensitive to cadmium by inhalation
exposure as the rate of respiration is usually higher than that of adults. Exposure to cadmium as
a child may also increase susceptibility to renal toxicity later in life (ATSDR 2008). Women
with low iron stores or iron deficiency typically show increased cadmium intake; however, very
little is transferred through the placenta or breast milk (Schoeters et al., 2006). Those with pre-
existing renal and/or hepatic conditions would be more at risk in chronic exposures. Smokers
would also be at more risk of toxicity as they are already receiving doses of cadmium from
cigarettes. Other factors found to affect susceptibility to cadmium include: diet, age, sex and
genetic background (U.S. EPA 1986). The factors may result in increased absorption, decreased
detoxification or excretion, or compromised organ function. People living close to sources of
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22
23
24
25
26
27
28
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31
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CADMIUM
PROPOSED: November 2009
cadmium pollution, especially in industrialized areas, are subjected to higher exposures than
those in non-industrialized areas (ATSDR 2008).
4.4.3. Concentration-Exposure Duration Relationship
The concentration-exposure time relationship for many irritant and systemically-acting
vapors and gases may be described by Cn x t = k, where the exponent, n, ranges from 0.8 to 3.5
(ten Berge et al., 1986). To obtain conservative and protective AEGL values in the absence of an
empirically derived chemical-specific scaling exponent, temporal scaling was performed using
n=3 when extrapolating to shorter time points and n = 1 when extrapolating to longer time points
using the Cn x t = k equation.
4.4.4. Concurrent Exposure Issues
In occupational settings, workers are exposed to other metals in addition to cadmium.
Smokers inhale cadmium along with other chemicals and compounds.
5. DATA ANALYSIS FOR AEGL-1
5.1. Summary of Human Data Relevant to AEGL-1
No data were located.
5.2. Summary of Animal Data Relevant to AEGL-1
"3
Female Fischer 344 rats exposed (whole body) to 0.07 mg/m Cd for 6 hours showed no
morphological changes in the lungs or inflammatory response (Takenaka et al. 2004). Rabbits
and rats exposed (nose-only) to 0.25 mg/m3 CdCh or CdO for 2 hours had inhibited pulmonary
GSH peroxidase activity (Grose et al. 1987). Rabbits and rats exposed (nose-only) to 0.45
mg/m CdCb or CdO for 2 hours had increased inflammatory response (Grose et al. 1987).
"3
Deaths were observed in rats exposed to 0.45 mg/m but no deaths were observed in rats exposed
to 4.5 mg/m3, and those deaths may be associated with the exposure apparatus. The mortality
observed was also inconsistent with the data for rats exposed to similar concentrations. After
exposure to 0.5 mg/m3 CdO for 3 hours, rats had increased inflammatory cell influx and transient
hypercellularity, but no mortality (Buckley and Bassett 1987). After whole-body exposure to
"3
0.55 mg/m CdO for 6 hours, rats had increased neutrophils and multifocal alveolar
inflammation and no mortality (Takenaka et al. 2004).
5.3. Derivation of AEGL-1
"3
The AEGL-1 values are based on the experimental concentration, 0.55 mg Cd/m , that
caused slight respiratory irritation in rats (Takenaka et al. 2004). After a 6 hour exposure,
increased neutrophils and multifocal alveolar inflammation were observed. At the next higher
experimental exposure, pneumonitis was observed (Grose et al. 1987). Although the exposure
was a whole-body exposure, the size of the ultrafine particles (51 nM MMAD, 1.7 GSD) would
mimic a gaseous state and the majority of the aerosol would be inhaled and not deposited on the
fur. An interspecies uncertainty factor of 3 was applied because at acute exposures, cadmium is
a direct-acting respiratory irritant as indicated by the signs of irritation in rabbits and rats. This
mode of action is not expected to differ among species. Rabbits and rats exposed for 2 hours to
0.25-4.5 mg/m displayed similar histological and biochemical pulmonary effects including
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pneumonitis, increased lung weight, pulmonary inflammatory cell influx, and decreased
glutathione peroxidase activity (Grose et al. 1987). Rats exposed to cadmium (0.00169-5.3
mg/m3) from 1-6 hours (Buckley and Bassett 1987; Oberdorster et al. 1987 ; Takenaka et al.
2004) exhibited the same effects as those observed in the Grose et al. (1987) study. An
intraspecies uncertainty factor of 3 was applied because at acute exposures, cadmium is a direct-
acting respiratory irritant in humans, and this mode of action is not expected to differ among
individuals. After a five hour exposure to cadmium, workers experienced cough, throat
irritation, dyspnea, and pulmonary edema (Beton et al. 1966) which are signs of respiratory
irritation. The concentration-exposure time relationship for many irritant and systemically-
acting vapors and gases may be described by Cn x t = k, where the exponent, n, ranges from 0.8
to 3.5 (ten Berge et al., 1986). To obtain conservative and protective AEGL values in the
absence of an empirically derived chemical-specific scaling exponent, temporal scaling was
performed using n=3 when extrapolating to shorter time points and n = 1 when extrapolating to
longer time points using the Cn x t = k equation. The 30-minute AEGL-1 value was adopted as
the 10-minute value due to the added uncertainty of extrapolating from a 6-hour time point to 10
minutes (NRC 2001). The calculations for the AEGL-1 values are in Appendix A.
TABLE 12. AEGL-1 Values for Cadmium
10-min
30-min
1-hr
4-hr
8-hr
0.13 mg/m3
0.13 mg/m3
0.10 mg/m3
0.063 mg/m3
0.041 mg/m3
6. DATA ANALYSIS FOR AEGL-2
6.1. Summary of Human Data Relevant to AEGL-2
No human data relevant to AEGL-2 were located.
6.2. Summary of Animal Data Relevant to AEGL-2
"3
Rabbits and rats exposed for 2 hours to 4.5 mg/m CdCh or CdO exhibited increased lung
weight and moderate-severe pneumonitis characterized by alveolar wall thickening, hemorrhage,
"3
and edema (Grose et al. 1987). At 5.3 mg/m , focal areas of interstitial thickening, an increase in
cuboidal alveolar cells, numerous inflammatory cells (interstitial mononuclear cells, alveolar
macrophages, eosinophils, and basophils), and increase in lung weight and protein content were
observed (Buckley and Bassett 1987).
6.3. Derivation of AEGL-2
-3
The AEGL-2 values are based on the experimental concentration, 5.3 mg Cd/m , that
caused overt respiratory irritation and pathology in rats (Buckley and Bassett 1987). The 3 hour
exposure resulted in reduced weight gain and increased lung weight, protein content, DNA
content, number of cuboidal alveolar cells, number of inflammatory cells, and focal areas of
interstitial thickening. An interspecies uncertainty factor of 3 was applied because at acute
exposures, cadmium is a direct-acting respiratory irritant as indicated by the signs of irritation in
rabbits and rats. This mode of action is not expected to differ among species. Rabbits and rats
exposed for 2 hours to 0.25-4.5 mg/m3 displayed similar histological and biochemical pulmonary
effects including pneumonitis, increased lung weight, pulmonary inflammatory cell influx, and
decreased glutathione peroxidase activity (Grose et al. 1987). Rats exposed to cadmium
(0.00169-5.3 mg/m3) from 1-6 hours (Buckley and Bassett 1987; Oberdorster et al. 1987 ;
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Takenaka et al. 2004) exhibited the same effects as those observed in the Grose et al. (1987)
study. An intraspecies uncertainty factor of 3 was applied because at acute exposures, cadmium
is a direct-acting respiratory irritant in humans, and this mode of action is not expected to differ
among individuals. After a five hour exposure to cadmium, workers experienced cough, throat
irritation, dyspnea, and pulmonary edema (Beton et al. 1966) which are signs of respiratory
irritation. The concentration-exposure time relationship for many irritant and systemically-
acting vapors and gases may be described by Cn x t = k, where the exponent, n, ranges from 0.8
to 3.5 (ten Berge et al. 1986). To obtain conservative and protective AEGL values in the absence
of an empirically derived chemical-specific scaling exponent, temporal scaling was performed
using n=3 when extrapolating to shorter time points and n = 1 when extrapolating to longer time
points using the Cn x t = k equation. The calculations for the AEGL-2 values are in Appendix
A.
TABLE 13. AEGL-2 Values for Cadmium
10-min
30-min
1-hr
4-hr
8-hr
1.4 mg/m3
0.96 mg/m3
0.76 mg/m3
0.40 mg/m3
0.20 mg/m3
7. DATA ANALYSIS FOR AEGL-3
7.1. Summary of Human Data Relevant to AEGL-3
"3
Workers (n=5) exposed for 5 hours to Cd oxide fumes inhaled an estimated 8.6 mg/m .
One worker died 5 days after the exposure with severe pulmonary edema, alveolar metaplasia of
the lungs, and bilateral cortical necrosis of the kidneys (Beton et al. 1966). The other four
workers had pulmonary edema that resolved over time.
7.2. Summary of Animal Data Relevant to AEGL-3
Mortality occurred in rats exposed to cadmium carbonate (5.8%) or cadmium fume
(48%) for 2 hours. The LC50 for the study was 112 mg/m (Rusch et al. 1986). One rat exposed
to 0.45 mg/m3 Cd died of cardiovascular failure associated with pulmonary congestion (Grose et
al. 1987). Two other rats died of unknown causes in the same study. Although death occurred at
0.45 mg/m3, this value was not used to derive AEGL-3. The deaths may be associated with the
exposure apparatus and may not be the result of exposure to cadmium. Lack of mortality in rats
3 3
exposed to similar concentrations (0.5 mg/m , Buckley and Bassett 1987; 0.55 mg/m , Takenaka
et al. 2004) and at a higher experimental dose within the same study, 4.5 mg/m3, further support
the dismissal of the mortality data from Grose et al. (1987) from being considered for derivation
of AEGL-3 values.
7.3. Derivation of AEGL-3
The AEGL-3 values are based on the 2 hour LC50 for cadmium fume in rats, 112 mg/m
(Rusch et al. 1986). The LC50 was divided by 3 to estimate a threshold of lethality. An
intraspecies uncertainty factor of 3 was applied because in acute exposures, cadmium is a direct-
acting respiratory irritant. An interspecies uncertainty factor of 3 was applied because at acute
exposures, cadmium is a direct-acting respiratory irritant as indicated by the signs of irritation in
rabbits and rats. This mode of action is not expected to differ among species. Rabbits and rats
exposed for 2 hours to 0.25-4.5 mg/m3 displayed similar histological and biochemical pulmonary
effects including pneumonitis, increased lung weight, pulmonary inflammatory cell influx, and
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decreased glutathione peroxidase activity (Grose et al. 1987). Rats exposed to cadmium
(0.00169-5.3 mg/m3) from 1-6 hours (Buckley and Bassett 1987; Oberdorster et al. 1987 ;
Takenaka et al. 2004) exhibited the same effects as those observed in the Grose et al. (1987)
study. An intraspecies uncertainty factor of 3 was applied because at acute exposures, cadmium
is a direct-acting respiratory irritant in humans, and this mode of action is not expected to differ
among individuals. After a five hour exposure to cadmium, workers experienced cough, throat
irritation, dyspnea, and pulmonary edema (Beton et al. 1966) which are signs of respiratory
irritation. The concentration-exposure time relationship for many irritant and systemically-
acting vapors and gases may be described by Cn x t = k, where the exponent, n, ranges from 0.8
to 3.5 (ten Berge et al. 1986). To obtain conservative and protective AEGL values in the absence
of an empirically derived chemical-specific scaling exponent, temporal scaling was performed
using n=3 when extrapolating to shorter time points and n = 1 when extrapolating to longer time
points using the Cn x t = k equation. The calculations for the AEGL-3 values are in Appendix A.
TABLE 14. AEGL-3 Values for Cadmium
10-min
30-min
1-hr
4-hr
8-hr
8.5 mg/m3
5.9 mg/m3
4.7 mg/m3
1.9 mg/m3
0.93 mg/m3
8. SUMMARY OF AEGLS
8.1. AEGL Values and Toxicity Endpoints
Cadmium was shown to be an irritating metal that caused developmental, respiratory, and
renal effects following multiple exposures. The derived AEGL values would prevent these
effects. The AEGL-1 values were based upon the experimental concentration that caused slight
"3
respiratory irritation in rats, 0.55 mg Cd/m , following a 6 hour exposure. The AEGL-2 values
were based upon the experimental concentration that caused overt respiratory tract irritation and
"3
pathology in rats, 5.3 mg/m , following a 3 hour exposure. The AEGL-3 values were a based
upon the estimated threshold of lethality from cadmium fumes from the 2-hour LC50, 112 mg/m3,
in rats. AEGL values are summarized in Table 15.
TABLE 15. Summary of AEGL Values
Classification
Exposure Duration
10-min
30-min
1-hr
4-hr
8-hr
AEGL-1
(Notable
Discomfort)
0.13 mg/m3
0.13 mg/m3
0.10 mg/m3
0.063 mg/m3
0.041 mg/m3
AEGL-2
(Disabling)
1.4 mg/m3
0.96 mg/m3
0.76 mg/m3
0.40 mg/m3
0.20 mg/m3
AEGL-3
(Lethal)
8.5 mg/m3
5.9 mg/m3
4.7 mg/m3
1.9 mg/m3
0.93 mg/m3
8.2. Comparison with Other Standards and Guidelines
AEGL values for cadmium are compared to other guidelines and standards in Table 16. The
OSHA values were established to protect against lung cancer and kidney dysfunction (OSHA
2005). The IDLH was based upon acute inhalation toxicity in workers (NIOSH 1996). The
ACGIH TWA inhalable particulate value was established to minimize kidney dysfunction and
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the respirable fraction value was set to minimize pulmonary accumulation of cadmium that could
act as a carcinogen (ACGIH 1996).
TABLE 16. Extant Standards and Guidelines for Cadmium
Guideline
Exposure Duration
10 min
30 min
1 hr
4 hr
8 hr
AEGL-1
0.13 mg/m3
0.13 mg/m3
0.10 mg/m3
0.063 mg/m3
0.041 mg/m3
AEGL-2
1.4 mg/m3
0.96 mg/m3
0.76 mg/m3
0.40 mg/m3
0.20 mg/m3
AEGL-3
8.5 mg/m3
5.9 mg/m3
4.7 mg/m3
1.9 mg/m3
0.93 mg/m3
PEL-TWA
(OSHA)3 (fume)
0.1 mg/m3
0.3 mg/m3C
PEL-TWA
(OSHA)b (dust)
0.2 mg/m3
0.6 mg/m3C
IDLH (NIOSH)0
9 mg/m3
TLV-TWA
(ACGM)d
0.01 mg/m31
0.002 mg/m3R
MAC-Peak
Category (The
Netherlands)6
0.005 mg/m3
a OSHA PEL-TWA (Occupational Health and Safety Administration, Permissible Exposure Limits - Time Weighted
Average) (OSHA, 2005) is defined analogous to the ACGIH-TLV-TWA, but is for exposures of no more
than 10 hours/day, 40 hours/week. C-Acceptable ceiling concentration.
b OSHA PEL-STEL (Permissible Exposure Limits - Short Term Exposure Limit) (OSHA, 2005) is defined
analogous to the ACGIH-TLV-STEL. C-Acceptable ceiling concentration.
0IDLH (Immediately Dangerous to Life and Health, National Institute of Occupational Safety and Health) (NIOSH,
1996) represents the maximum concentration from which one could escape within 30 minutes without any
escape-impairing symptoms, or any irreversible health effects.
d ACGIH TLV-TWA (American Conference of Governmental Industrial Hygienists, Threshold Limit Value - Time
Weighted Average) (ACGIH, 2008) is the time-weighted average concentration for a normal 8-hour
workday and a 40-hour work week, to which nearly all workers may be repeatedly exposed, day after day,
without adverse effect. :- Inhalable particulate; R- Respirable fraction
eMAC (Maximaal Aanvaaarde Concentratie [Maximal Accepted Concentration - Peak Category]) (SDU Uitgevers
[under the auspices of the Ministry of Social Affairs and Employment], The Hague, The Netherlands 2000)
is defined analogous to the ACGIH-Ceiling.
8.3. Data Adequacy and Research
Toxicity data for cadmium are available for humans and animals. Most of the acute
inhalation data for humans do not provide cadmium exposure concentrations, but report signs
and symptoms of toxicity which are useful for noting effects of exposure. Short-term and
chronic epidemiological studies in workers were available; however, the workers may have had
concurrent exposures to other chemicals. Animal studies were conducted in at least three species
and range from acute to chronic. The acute studies in rabbits and rats provide data suitable for
deriving AEGL values and highlight the differences between the effects that occur following
acute and chronic cadmium exposure.
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APPENDIX A: Derivation of AEGL Values
Derivation of AEGL-1
Key Study:
Toxicity endpoint:
Time scaling:
Takenaka, S., E. Karg, W.G. Kreyling, B. Lentner, H. Schultz, A.
Ziesenis, P. Schramel and J. Heyder. 2004. Fate and toxic effects of
inhaled ultrafine cadmium oxide particles in the rat lung. Inhal. Toxicol.
16 (suppl.l): 83-92.
"3
The experimental concentration, 0.55 mg Cd/m caused slight respiratory
irritation in female rats exposed for 6 hours.
Cn x t = k; n=3 when extrapolating to shorter time points and n = 1 when
extrapolating to longer time points.
Uncertainty factors:
Interspecies:
Intraspecies:
Modifying factor:
Calculations:
10-min AEGL-1
30-min AEGL-1
1-hr AEGL-1
4-hr AEGL-1
3, Cadmium is a direct-acting respiratory irritant and it is not expected that
toxicity would differ among species. Rabbits and rats exposed for 2 hours
to 0.25-4.5 mg/m3 displayed similar histological and biochemical
pulmonary effects including pneumonitis, increased lung weight,
pulmonary inflammatory cell influx, and decreased glutathione peroxidase
activity (Grose et al. 1987). Rats exposed to cadmium (0.00169-5.3
mg/m3) from 1-6 hours (Buckley and Bassett 1987; Oberdorster et al.
1987; Takenaka et al. 2004) exhibited the same effects as those observed
in the Grose et al. (1987) study.
3, Cadmium is a direct-acting respiratory irritant, and respiratory effects
due to irritation are not expected to differ greatly among individuals.
After a five hour exposure to cadmium, workers experienced cough, throat
irritation, dyspnea, and pulmonary edema (Beton et al. 1966) which are
signs of respiratory irritation.
None applied.
0.55 mg/m3 / 10 = 0.055 mg/m3
C3 x t = k
(0.055 mg/m3)3 x 360 min = 0.059895 mg/m3-min
C1 x t = k
0.0055 mg/m3 x 360 min = 19.8 mg/m3-min
30-min value adopted as 10-min value = 0.13 mg/m
C3 x 30 min= 0.059895 mg/m3-min
C = 0.13 mg/m3
C3 x 60 min= 0.059895 mg/m3-min
C = 0.10 mg/m3
C3 x 240 min= 0.059895 mg/m3-min
44
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CADMIUM
PROPOSED: November 2009
1
2
3 8-hr AEGL-1
4
5
C = 0.063 mg/m3
C1 x 480 min = 19.8 mg/m3-min
C = 0.041 mg/m3
45
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2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
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22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
CADMIUM
PROPOSED: November 2009
Derivation of AEGL-2
Key Studies:
Toxicity endpoints:
Time scaling:
Buckley, B.J. and D.J.P. Bassett. 1987. Pulmonary cadmium oxide
toxicity in the rat. J. Toxicol. Environ. Health. 21: 233-250.
"3
The experimental concentration, 5.3 mg Cd/m caused overt respiratory
irritation and pathology in exposed for 3 hours.
Cn x t = k; n=3 when extrapolating to shorter time points and n = 1 when
extrapolating to longer time points.
Uncertainty factors:
Interspecies: 3, Cadmium is a direct-acting respiratory irritant and it is not expected that
toxicity would differ among species. Rabbits and rats exposed for 2 hours
to 0.25-4.5 mg/m3 displayed similar histological and biochemical
pulmonary effects including pneumonitis, increased lung weight,
pulmonary inflammatory cell influx, and decreased glutathione peroxidase
activity (Grose et al. 1987). Rats exposed to cadmium (0.00169-5.3
mg/m3) from 1-6 hours (Buckley and Bassett 1987; Oberdorster et al.
1987; Takenaka et al. 2004) exhibited the same effects as those observed
in the Grose et al. (1987) study.
Intraspecies: 3, Cadmium is a direct-acting respiratory irritant, and respiratory effects
due to irritation are not expected to differ greatly among individuals.
After a five hour exposure to cadmium, workers experienced cough, throat
irritation, dyspnea, and pulmonary edema (Beton et al. 1966) which are
signs of respiratory irritation.
Modifying factor:
Calculations:
10-min AEGL-2
30-min AEGL-2
1-hr AEGL-2
4-hr AEGL-2
8-hr AEGL-2
None applied.
5.3 mg/m3 / 10 = 0.53 mg/m3
C3 x t = k
(0.53 mg/m3)3 x 180 min = 26.79786 mg/m3-min
C1 x t = k
0.53 mg/m3 x 180 min = 95.4 mg/m3-min
C3xl0min= 26.79786 mg/m3-min
C = 1.4 mg/m3
C3 x 30 min= 26.79786 mg/m3-min
C = 0.96 mg/m3
C3 x 60 min= 26.79786 mg/m3-min
C = 0.76 mg/m3
C1 x 240 min = 95.4 mg/m3-min
C = 0.40 mg/m3
C1 x 480 min = 95.4 mg/m3-min
46
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CADMIUM PROPOSED: November 2009
1 C = 0.20 mg/m3
2
3
4
47
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3
4
5
6
7
8
9
10
11
12
13
14
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17
18
19
20
21
22
23
24
25
26
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28
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30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
CADMIUM
PROPOSED: November 2009
Derivation of AEGL-3
Key Studies: Rusch, G.M., J.S. O'Grodnick and W.E. Rinehart. 1986. Acute inhalation
study in the rat of comparative uptake, distribution and excretion for
different cadmium containing materials. Am. Ind. Hyg. Assoc. J. 47: 754-
763.
Toxicity endpoint: The threshold of lethality was calculated from the 2-hr LC50 for cadmium
fume in rats, 112 mg/m3.
Time scaling: Cn x t = k; n=3 when extrapolating to shorter time points, and n = 1 when
extrapolating to longer time points.
Uncertainty factors:
Interspecies: 3, Cadmium is a direct-acting respiratory irritant and it is not expected that
toxicity would differ among species. Rabbits and rats exposed for 2 hours
to 0.25-4.5 mg/m3 displayed similar histological and biochemical
pulmonary effects including pneumonitis, increased lung weight,
pulmonary inflammatory cell influx, and decreased glutathione peroxidase
activity (Grose et al. 1987). Rats exposed to cadmium (0.00169-5.3
mg/m3) from 1-6 hours (Buckley and Bassett 1987; Oberdorster et al.
1987; Takenaka et al. 2004) exhibited the same effects as those observed
in the Grose et al. (1987) study.
Intraspecies: 3, Cadmium is a direct-acting respiratory irritant, and respiratory effects
due to irritation are not expected to differ greatly among individuals.
After a five hour exposure to cadmium, workers experienced cough, throat
irritation, dyspnea, and pulmonary edema (Beton et al. 1966) which are
signs of respiratory irritation.
Modifying factor: None applied.
Calculations 112 mg/m313110= 3.733 mg/m3
C3 x t = k
(3.733 mg/m3)3 x 120 min = 6242.45206 mg/m3-min
C1 x t = k
3.733 mg/m3 x 120 min = 447.96 mg/m3-min
10-minute AEGL-3 C3 x 10 min= 6242.45206 mg/m3-min
C = 8.5 mg/m3
30-minute AEGL-3 C3 x 30 min= 6242.45206 mg/m3-min
C = 5.9 mg/m3
1-hr AEGL-3 C3 x 60 min= 6242.45206 mg/m3-min
C = 4.7 mg/m3
4-hr AEGL-3 C1 x 240 min = 44.796 mg/m3-min
C = 1.9 mg/m3
48
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CADMIUM
PROPOSED: November 2009
1
2 8-hr AEGL-3 C1 x 480 min = 44.796 mg/m3-min
3 C = 0.93 mg/m3
4
5
49
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5
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7
8
9
10
11
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13
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23
24
25
26
27
28
29
30
31
32
33
34
CADMIUM
PROPOSED: November 2009
APPENDIX B: Time-Scaling Calculations
The relationship between dose and time for any given chemical is a function of the
physical and chemical properties of the substance and the unique toxicological and
pharmacological properties of the individual substance. Historically, the relationship according
to Haber (1924), commonly called Haber's Law or Haber's Rule (i.e., Cxt = k, where C =
exposure concentration, t = exposure duration, and k= a constant) has been used to relate
exposure concentration and duration to effect (Rinehart and Hatch 1964). This concept states
that exposure concentration and exposure duration may be reciprocally adjusted to maintain a
cumulative exposure constant (k) and that this cumulative exposure constant will always reflect a
specific quantitative and qualitative response. This inverse relationship of concentration and
time may be valid when the toxic response to a chemical is equally dependent upon the
concentration and the exposure duration. However, an assessment by ten Berge et al. (1986) of
LC50 data for certain chemicals revealed chemical-specific relationships between exposure
concentration and exposure duration that were often exponential. This relationship can be
expressed by the equation Cn x t = k, where n represents a chemical specific, and even a toxic
endpoint specific, exponent. The relationship described by this equation is basically in the form
of a linear regression analysis of the log-log transformation of a plot of C vs. ten Berge et al.
(1986) examined the airborne concentration (C) and short-term exposure duration (t) relationship
relative to death for approximately 20 chemicals and found that the empirically derived value of
n ranged from 0.8 to 3.5 among this group of chemicals. Hence, the value of the exponent (//) in
the equation C" x t = k quantitatively defines the relationship between exposure concentration
and exposure duration for a given chemical and for a specific health effect endpoint. Haber's
Rule is the special case where n = 1. As the value of n increases, the plot of concentration vs.
time yields a progressive decrease in the slope of the curve.
The available data do not allow for empirical derivation of a temporal scaling factor (n) for
cadmium. The exposure concentration-exposure duration relationship for many irritant and
systemically acting vapors and gases may be described by C" x t = k, where the exponent, n,
ranges from 0.8 to 3.5 (ten Berge et al., 1986). In the absence of an empirically derived
exponent (//), temporal scaling from the experimental durations of the respective PODs to
AEGL-specific durations was performed using n = 3 when extrapolating to shorter time points
and n= 1 when extrapolating to longer time points using the C" x l k equation.
50
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34
35
36
37
38
CADMIUM PROPOSED: November 2009
APPENDIX C: Carcinogenicity Assessment
The carcinogenicity data are summarized in Section 3.6 and Table 9. The U.S. EPA (1994)
concluded that cadmium is a "probable human carcinogen" based on evidence of carcinogenicity
in animals and limited evidence of carcinogenicity in an exposed human population. The
3 3
inhalation unit risk calculated is 1.8 x 10" |ig/m , and the concentration associated with a risk
level of 1 in 10,000 is 6 x 10"2 |ig/m3.
To convert a 70-year (25,600 days) exposure to a 24-hr exposure:
2 3
24-hr exposure = d x 25,600; where d = 6 x 10" |ig/m
= (6 x 10"2 |ig/m3) x 25,600 days
= 1536 |ig/m =1.54mg/m3
To account for uncertainty regarding the variability in the stage of the cancer process at which
cadmium may act, a multi-stage factor of 6 is applied (Crump and Howe, 1984):
1.54 mg/m3/ 6 = 0.26 mg/m3
Therefore, a single exposure to cadmium at 0.26 mg/m for 24 hrs would represent a cancer risk
of 10"4. If the exposure is limited to a fraction (f) of a 24-hr period, the fractional exposure
becomes 1/f x 24 hr (NRC 1985).
3
24 hr exposure = 0.26 mg/m
8 hr exposure = 0.78 mg/m3
"3
4 hr exposure = 1.56 mg/m
1 hr exposure = 6.24 mg/m3
30 min exposure = 12.48 mg/m
10 min exposure = 36.66 mg/m3
The AEGL values for 10 minutes, 30 minutes, 1, 4, and 8 hours are presented below for
risks of 10"4, 10"5, and 10"6
Time (h)
104
10 s
106
0.17
36.7
3.67
0.367
0.5
12.5
1.25
0.125
1
6.24
0.624
0.0624
4
1.56
0.156
0.0156
8
0.78
0.078
0.0078
These values based on carcinogenicity are not proposed for AEGL values.
51
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CADMIUM
PROPOSED: November 2009
1
2
3
4
5
6
APPENDIX D: Derivation Summary for Cadmium AEGLs
ACUTE EXPOSURE GUIDELINE LEVELS FOR
CADMIUM (CAS Reg. No. 7440-43-9)
DERIVATION SUMMARY
AEGL-1 VALUES
10-min
30-min
1-hr
4-hr
8-hr
0.13 mg/m
0.13 mg/m
0.10 mg/m
0.063 mg/m
0.041 mg/m
Key Reference:
Takenaka, S., E. Karg, W.G. Kreyling, B. Lentner, H. Schultz, A. Ziesenis, P. Schramel and J. Heyder. 2004. Fate
and toxic effects of inhaled ultrafine cadmium oxide particles in the rat lung. Inhal. Toxicol, (suppl. 1): 83-92.
Test Species/Strain/Number: Rat/Fischer 344/24/group
Exposure Route/Concentrations/Duration: Inhalation/0.07, 0.550 mg/m3/ 6 hr
Effects:
0.07 mg/m3 No morphological changes or inflammatory response
0.550 mg/m3 Increased neutrophils and multifocal alveolar inflammation
Endpoint/Concentration/Rationale: Slight respiratory irritation/0.55 mg Cd/m3 administered as CdO
Uncertainty Factors/Rationale:
Total uncertainty factors: 10
Interspecies: 3, Cadmium is a direct-acting respiratory irritant and it is not expected that toxicity would
differ among species. Rabbits and rats exposed for 2 hours to 0.25-4.5 mg/m3 displayed
similar histological and biochemical pulmonary effects including pneumonitis, increased
lung weight, pulmonary inflammatory cell influx, and decreased glutathione peroxidase
activity (Grose et al. 1987). Rats exposed to cadmium (0.00169-5.3 mg/m3) from 1-6
hours (Buckley and Bassett 1987; Oberdorster et al. 1987; Takenaka et al. 2004)
exhibited the same effects as those observed in the Grose et al. (1987) study.
Intraspecies: 3, Cadmium is a direct-acting respiratory irritant, and respiratory effects due to irritation
are not expected to differ greatly among individuals. After a five hour exposure to
cadmium, workers experienced cough, throat irritation, dyspnea, and pulmonary edema
(Beton et al. 1966) which are signs of respiratory irritation.
Modifying Factor: None
Animal to Human Dosimetric Adjustment: None
Time Scaling: Cn x t = k; n=3 when extrapolating to shorter time points (10-, 30-, and 60- min, and 4-hr), and n = 1
when extrapolating to longer time points (8 hr). The 30-minute AEGL-1 value was adopted as the 10-minute
value due to the added uncertainty of extrapolating from a 6-hr time point to 10 min.
Data Adequacy: Data were available and adequate for deriving AEGL-1 values.
52
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CADMIUM
PROPOSED: November 2009
AEGL-2 VALUES
10-min
30-min
1-hr
4-hr
8-hr
1.4 mg/m
0.96 mg/m
0.76 mg/m
0.40 mg/m
0.20 mg/m
Key Reference:
Buckley, B.J. and D.J.P. Bassett. 1987. Pulmonary cadmium oxide toxicity in the rat. J. Toxicol. Environ.
Health. 21: 233-250.
Test Species/Strain/Number: Rats/Wistar/16/group
Exposure Route/Concentrations/Duration: Inhalation/0.0.5, 5.3 mg/m3 CdO/ 3 hr
Effects:
0. 5 mg/m3 Transient mild hypercellularity at bronchoalveolar junctions and adjacent alveoli,
inflammatory cell influx
5.3 mg/m3 Interstitial thickening, f cuboidal alveolar cells, f inflammatory cells, tdry lung weight,
fprotein content, fDNA content, t GP, GR, G6PD, 6PGD activity
Endpoint/Concentration/Rationale: Overt respiratory tract irritation and pathology /5.3 mg/m3 administered as
CdO
Uncertainty Factors/Rationale:
Total uncertainty factors: 10
Interspecies: 3, Cadmium is a direct-acting respiratory irritant and it is not expected that toxicity
would differ among species. Rabbits and rats exposed for 2 hours to 0.25-4.5 mg/m3
displayed similar histological and biochemical pulmonary effects including
pneumonitis, increased lung weight, pulmonary inflammatory cell influx, and
decreased glutathione peroxidase activity (Grose et al. 1987). Rats exposed to
cadmium (0.00169-5.3 mg/m3) from 1-6 hours (Buckley and Bassett 1987;
Oberdorster et al. 1987; Takenaka et al. 2004) exhibited the same effects as those
observed in the Grose et al. (1987) study.
Intraspecies: 3, Cadmium is a direct-acting respiratory irritant, and respiratory effects due to
irritation are not expected to differ greatly among individuals. After a five hour
exposure to cadmium, workers experienced cough, throat irritation, dyspnea, and
pulmonary edema (Beton et al. 1966) which are signs of respiratory irritation.
Modifying Factor: None
Animal to Human Dosimetric Adjustment: None
Time Scaling: Cn x t = k; n=3 when extrapolating to shorter time points (10, 30, and 60 min), and n = 1 when
extrapolating to longer time points (4 hr, 8 hr).
Data Adequacy: Data were available and adequate for deriving AEGL-2 values.
53
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CADMIUM
PROPOSED: November 2009
AEGL-3 VALUES
10-min
30-min
1-hr
4-hr
8-hr
8.5 mg/m
5.9 mg/m
4.7 mg/m
1.9 mg/m
0.93 mg/m
Key Reference:
Rusch, G.M., J.S. O'Grodnick, and W.E. Rinehart. 1986. Acute inhalation study in the rat of comparative
uptake, distribution and excretion for different cadmium containing materials. Am. Ind. Hyg. Assoc. J 47: 754-
763.
Test Species/Strain/Number: Rat/Sprague-Dawley/26/group
«, -4 4
Exposure Route/Concentrations/Duration: Inhalation/97 mg/m Cd red, 99 mg/m Cd yellow, 132 mg/m Cd
carbonate, 112 mg/m3 Cd fume/2 hr
Effects:
97 mg/m3 Cd red
99 mg/m Cd yellow
Lacrimation, renal discoloration
Lacrimation
132 mg/m' Cd carbonate 5.8% mortality, dry rales, pulmonary edema
112 mg/m3 Cd fume 48% mortality, hypoactivity, closed eyes, dry and moist rales, LC50
Endpoint/Concentration/Rationale: Threshold of lethality based on 2-hr LC50112 mg/m3 for cadmium fumes"
Uncertainty Factors/Rationale:
Total uncertainty factors: 10
Interspecies: 3, Cadmium is a direct-acting respiratory irritant and it is not expected that toxicity
would differ among species. Rabbits and rats exposed for 2 hours to 0.25-4.5 mg/m3
displayed similar histological and biochemical pulmonary effects including
pneumonitis, increased lung weight, pulmonary inflammatory cell influx, and
decreased glutathione peroxidase activity (Grose et al. 1987). Rats exposed to
cadmium (0.00169-5.3 mg/m3) from 1-6 hours (Buckley and Bassett 1987;
Oberdorster et al. 1987; Takenaka et al. 2004) exhibited the same effects as those
observed in the Grose et al. (1987) study.
Intraspecies: 3, Cadmium is a direct-acting respiratory irritant, and respiratory effects due to
irritation are not expected to differ greatly among individuals. After a five hour
exposure to cadmium, workers experienced cough, throat irritation, dyspnea, and
pulmonary edema (Beton et al. 1966) which are signs of respiratory irritation.
Modifying Factor: None
Animal to Human Dosimetric Adjustment:
Time Scaling: Cn x t = k; n=3 when extrapolating to shorter time points (10-
when extrapolating to longer time points (4-hr, 8 hr).
Data Adequacy: Data were available and adequate for deriving AEGL-3 values.
30-, and 60- min), and n = 1
54
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3
4
5
6
7
8
9
10
CADMIUM
PROPOSED: November 2009
APPENDIX E: Category Plot for Cadmium
Chemical Toxicity - TSD Data Cadmium
1000.0
100.0
10.0
,1.0
0.1
o.o
o.o
A
1
r.
f /
¦
AEGL-3
'¦1
J
AEGL-2
*
»
€
2'
o
60
120
180
240 300
IVlnutes
360
420
~
Human - No Effect
¦
Hurran - Discomfort
Hurran - Disabling
Animal - No Effect
Animal - Discorrfort
/Viirral - Disabling
/Viirral - Some L^hs
/Viirral - L^hal
480
The values for AEGL-2 and AEGL-3 are above a concentration. 0.45 mg Cd/m , at wliich 2 animals died. Based on
the information provided in the study (Grose et al. 1987), it is possible that the animal deaths were not the result of
exposure to cadmium but were the result of exposure apparatus difficulties (reversal of animal body and resulting
asphyxiation). The mortality at this concentration was inconsistent with the other animal data resulting from
exposures at similar concentrations. There was also a lack of dose response as no mortality occurred following
exposure to a higher dose of cadmium.
55
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CADMIUM
PROPOSED: November 2009
Category Plot Data
For Category 0 = No effect, 1 = Discomfort, 2 = Disabling, SL = Some Lethality, 3 = Lethal
Source
Species
Sex
# Exposures
mg/m3
Min
Category
Comments
NAC/AEGL-1
0.13
10
AEGL
NAC/AEGL-1
0.13
30
AEGL
NAC/AEGL-1
0.10
60
AEGL
NAC/AEGL-1
0.063
240
AEGL
NAC/AEGL-1
0.041
480
AEGL
NAC/AEGL-2
1.4
10
AEGL
NAC/AEGL-2
0.96
30
AEGL
NAC/AEGL-2
0.76
60
AEGL
NAC/AEGL-2
0.40
240
AEGL
NAC/AEGL-2
0.20
480
AEGL
NAC/AEGL-3
8.5
10
AEGL
NAC/AEGL-3
5.9
30
AEGL
NAC/AEGL-3
4.7
60
AEGL
NAC/AEGL-3
1.9
240
AEGL
NAC/AEGL-3
0.93
480
AEGL
Betonetal. 1966
Human
m
1
8.6
300
SL
20% mortality, pulmonary edema,
dyspnea in others
Grose et al. 1987
Rabbit
m
1
0.25
120
1
Decreased GSH peroxidase activity
Grose et al. 1987
Rabbit
m
1
0.45
120
1
Increased GSH transferase activity
Grose et al. 1987
Rabbit
m
1
4.5
120
2
Pneumonitis
Grose et al. 1987
Rabbit
m
1
0.25
120
0
No effects
Grose et al. 1987
Rabbit
m
1
0.45
120
1
Increase alveolar macrophages
Grose et al. 1987
Rabbit
m
1
4.5
120
2
Pneumonitis
Grose et al. 1987
Rat
m
1
0.25
120
1
Decreased GSH peroxidase activity
Grose et al. 1987
Rat
m
1
0.45
120
1
Decreased GSH peroxidase activity;
body weight
Grose et al. 1987
Rat
m
1
4.5
120
2
Pneumonitis
Grose et al. 1987
Rat
m
1
0.25
120
0
No effects
Grose et al. 1987
Rat
m
1
0.45
120
SL
Pulmonary congestion
Grose et al. 1987
Rat
m
1
4.5
120
2
Pneumonitis
Takenaka et al 2004
Rat
f
1
0.07
360
0
No effects
Takenaka et al 2004
Rat
f
1
0.55
360
1
Alveolar inflammation, neutrophils
Oberdorster et al. 1987
Rat
m
1
0.00195
60
1
Decreased alveolar macrophages,
Oberdorster et al. 1987
Rat
m
1
0.00169
60
1
Decreased alveolar macrophages,
Oberdorster et al. 1987
Rat
m
1
0.00182
60
0
No effects
Ruschetal. 1986
Rat
b
1
97
120
1
Lacrimation; renal discoloration
Ruschetal. 1986
Rat
b
1
99
120
1
Lacrimation
Ruschetal. 1986
Rat
b
1
132
120
SL
5.8% mortality, dry rales; pulmonary
edema
Ruschetal. 1986
Rat
b
1
112
120
SL
48% mortality; hypoactivity, LC50
56
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