ACUTE EXPOSURE GUIDELINE LEVELS (AEGLs)

FOR

CADMIUM

(CAS Reg. No. 7440-43-9)

Cd

PROPOSED
1

2

3 ACUTE EXPOSURE GUIDELINE LEVELS (AEGLs)

4 FOR

5 CADMIUM

6 (CAS Reg. No. 7440-43-9)

7

8

9

10

11 PROPOSED

12

13

14

15

16

17

18

19
CADMIUM PROPOSED: November 2009

3

1

2 PREFACE

3

4 Under the authority of the Federal Advisory Committee Act (FACA) P. L. 92-463 of 

5 1972, the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous 

6 Substances (NAC/AEGL Committee) has been established to identify, review and interpret 

7 relevant toxicologic and other scientific data and develop AEGLs for high priority, acutely toxic 

8 chemicals. 

9

10 AEGLs represent threshold exposure limits for the general public and are applicable to 

11 emergency exposure periods ranging from 10 minutes to 8 hours. Three levels C AEGL-1, 

12 AEGL-2 and AEGL-3 C are developed for each of five exposure periods (10 and 30 minutes, 1 

13 hour, 4 hours, and 8 hours) and are distinguished by varying degrees of severity of toxic effects. 

14 The three AEGLs are defined as follows:

15

16 AEGL-1 is the airborne concentration (expressed as parts per million or milligrams per 

17 cubic meter [ppm or mg/m3]) of a substance above which it is predicted that the general 

18 population, including susceptible individuals, could experience notable discomfort, 

19 irritation, or certain asymptomatic, non-sensory effects. However, the effects are not 

20 disabling and are transient and reversible upon cessation of exposure.

21

22 AEGL-2 is the airborne concentration (expressed as ppm or mg/m3) of a substance 

23 above which it is predicted that the general population, including susceptible individuals, 

24 could experience irreversible or other serious, long-lasting adverse health effects or an 

25 impaired ability to escape.

26

27 AEGL-3 is the airborne concentration (expressed as ppm or mg/m3) of a substance 

28 above which it is predicted that the general population, including susceptible individuals, 

29 could experience life-threatening health effects or death.

30

31 Airborne concentrations below the AEGL-1 represent exposure levels that could produce 

32 mild and progressively increasing but transient and nondisabling odor, taste, and sensory 

33 irritation or certain asymptomatic, non-sensory effects. With increasing airborne concentrations 

34 above each AEGL, there is a progressive increase in the likelihood of occurrence and the severity 

35 of effects described for each corresponding AEGL. Although the AEGL values represent 

36 threshold levels for the general public, including susceptible subpopulations, such as infants, 

37 children, the elderly, persons with asthma, and those with other illnesses, it is recognized that 

38 individuals, subject to unique or idiosyncratic responses, could experience the effects described

39 at concentrations below the corresponding AEGL

40

41

42
CADMIUM PROPOSED: November 2009

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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. Case Reports........................................................................................................................................11

9 2.2. Nonlethal 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. Nonlethal 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
CADMIUM PROPOSED: November 2009

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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

21

22
CADMIUM PROPOSED: November 2009

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1 LIST OF TABLES

2

3 TABLE 1. Summary of AEGL Values Cadmium ........................................................................................9

4 TABLE 2. Chemical and Physical Properties.............................................................................................10

5 TABLE 3. Chemical and Physical Properties of Cadmium Compounds....................................................11

6 TABLE 4. Blood Cd Concentrations of Workers and Air Cd Concentrations...........................................13

7 TABLE 5. Summary of Acute Inhalation Data in Laboratory Animals....................................................20

8 TABLE 6. Histopathological Findings in rats Exposed for 2 wks to Cadmium Oxide .............................23

9 TABLE 7. Histopathological Findings in Rats Exposed for 13 wks to Cadmium Oxide...........................24

10 TABLE 8. Histopathological Findings in Mice Exposed for 2 wks to Cadmium Oxide...........................26

11 TABLE 9. Histopathological Findings in Mice Exposed for 13 wks to Cadmium Oxide.........................27

12 TABLE 10. Summary of Repeat Dose Inhalation Data in Laboratory Animals........................................28

13 TABLE 11. Observations after Inhalation Exposures of Rats to Various Cd Compounds........................30

14 TABLE 12. AEGL-1 Values for Cadmium ...............................................................................................36

15 TABLE 13. AEGL-2 Values for Cadmium ...............................................................................................37

16 TABLE 14. AEGL-3 Values for Cadmium ...............................................................................................38

17 TABLE 15. Summary of AEGL Values....................................................................................................38

18 TABLE 16. Extant Standards and Guidelines for Cadmium....................................................................39

19

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CADMIUM PROPOSED: November 2009

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1 EXECUTIVE SUMMARY

2

3 Cadmium (Cd) is a metal used in a variety of consumer and industrial materials with a 

4 high percentage used in the production of nickel-cadmium batteries and in electroplating. It is 

5 also in pigments used in plastics, ceramics and glasses and is used as a stabilizer for polyvinyl 

6 chloride (PVC). World production between 1990 and 2000 was ~19,000 tons/year (Morrow, 

7 2001). Estimated U.S. production of cadmium was about 1450 metric tons in 2003 and 700 

8 metric tons in 2006 (ATSDR 2008).

9

10 Human exposure to cadmium can be from inhalation of cadmium containing particles, 

11 inhalation of cigarette smoke or inhalation from fumes/dust in an occupational setting. In case 

12 reports of accidental acute exposure, cadmium caused respiratory irritation, dyspnea, alveolar

13 damage, pneumonitis, and death. Chronic occupational exposure caused decreased lung 

14 function. Cadmium and cadmium compounds are characterized as “probable human 

15 carcinogens” based on evidence of carcinogenicity in humans (U.S. EPA 1994). Respiratory 

16 cancers were increased in workers at a Cd-nickel battery factory, however, chronic Cd exposure 

17 was not found to lead to lung carcinogenicity. In animal inhalation studies, cadmium oxide is 

18 used as it is the most common airborne form of cadmium. The size of the cadmium particle often 

19 determines the extent of absorption and distribution. Cadmium, in various forms, caused 

20 respiratory irritation, pulmonary edema, rales, pneumonitis, lacrimation, increased alveolar 

21 macrophages, and death in rabbits and rats exposed for 1-6 hours. Rats and mice exposed for 90 

22 days or less exhibited pulmonary inflammation and edema, pulmonary hyperplasia, nasal and 

23 respiratory epithelium degeneration, and renal lesions. In carcinogenicity studies, rats exposed 

24 to Cd had an increased incidence of primary lung carcinomas.

25

The AEGL-1 values are based on the experimental concentration, 0.55 mg Cd/m3 26 , that 

27 caused slight respiratory irritation in rats (Takenaka et al. 2004). After a 6 hour exposure, 

28 increased neutrophils and multifocal alveolar inflammation were observed. At the next higher 

29 experimental exposure, pneumonitis was observed (Grose et al. 1987). Although the exposure 

30 was a whole-body exposure, the size of the ultrafine particles (51 nM MMAD, 1.7 GSD) would 

31 mimic a gaseous state and the majority of the aerosol would be inhaled and not deposited on the 

32 fur. An interspecies uncertainty factor of 3 was applied because at acute exposures, cadmium is 

33 a direct-acting respiratory irritant as indicated by the signs of irritation in rabbits and rats. This 

34 mode of action is not expected to differ among species. Rabbits and rats exposed for 2 hours to 

0.25-4.5 mg/m3 35 displayed similar histological and biochemical pulmonary effects including 

36 pneumonitis, increased lung weight, pulmonary inflammatory cell influx, and decreased 

37 glutathione peroxidase activity (Grose et al. 1987). Rats exposed to cadmium (0.00169-5.3 

mg/m3 38 ) from 1-6 hours (Buckley and Bassett 1987; Oberdörster et al. 1987; Takenaka et al. 

39 2004) exhibited the same effects as those observed in the Grose et al. (1987) study. An 

40 intraspecies uncertainty factor of 3 was applied because at acute exposures, cadmium is a direct41 acting respiratory irritant in humans, and this mode of action is not expected to differ among 

42 individuals. After a five hour exposure to cadmium, workers experienced cough, throat 

43 irritation, dyspnea, and pulmonary edema (Beton et al. 1966) which are signs of respiratory 

44 irritation. The concentration-exposure time relationship for many irritant and systemicallyacting vapors and gases may be described by Cn 45 x t = k, where the exponent, n, ranges from 0.8 

46 to 3.5 (ten Berge et al. 1986). To obtain conservative and protective AEGL values in the absence 

47 of an empirically derived chemical-specific scaling exponent, temporal scaling was performed 

48 using n=3 when extrapolating to shorter time points and n = 1 when extrapolating to longer time 

points using the Cn 49 x t = k equation. The 30-minute AEGL-1 value was adopted as the 10-
CADMIUM PROPOSED: November 2009

8

1 minute value due to the added uncertainty of extrapolating from a 6-hour time point to 10 

2 minutes (NRC 2001).

3

The AEGL-2 values are based on the experimental concentration, 5.3 mg Cd/m3 4 , that 

5 caused overt respiratory irritation and pathology in rats (Buckley and Bassett 1987). The 3 hour 

6 exposure resulted in reduced weight gain and increased lung weight, protein content, DNA 

7 content, number of cuboidal alveolar cells, number of inflammatory cells, and focal areas of 

8 interstitial thickening. An interspecies uncertainty factor of 3 was applied because at acute 

9 exposures, cadmium is a direct-acting respiratory irritant as indicated by the signs of irritation in 

10 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 11 displayed similar histological and biochemical pulmonary 

12 effects including pneumonitis, increased lung weight, pulmonary inflammatory cell influx, and 

13 decreased glutathione peroxidase activity (Grose et al. 1987). Rats exposed to cadmium

(0.00169-5.3 mg/m3 14 ) from 1-6 hours (Buckley and Bassett 1987; Oberdörster et al. 1987; 

15 Takenaka et al. 2004) exhibited the same effects as those observed in the Grose et al. (1987) 

16 study. An intraspecies uncertainty factor of 3 was applied because at acute exposures, cadmium 

17 is a direct-acting respiratory irritant in humans, and this mode of action is not expected to differ 

18 among individuals. After a five hour exposure to cadmium, workers experienced cough, throat 

19 irritation, dyspnea, and pulmonary edema (Beton et al. 1966) which are signs of respiratory 

20 irritation. The concentration-exposure time relationship for many irritant and systemicallyacting vapors and gases may be described by Cn 21 x t = k, where the exponent, n, ranges from 0.8 

22 to 3.5 (ten Berge et al. 1986). To obtain conservative and protective AEGL values in the absence 

23 of an empirically derived chemical-specific scaling exponent, temporal scaling was performed 

24 using n=3 when extrapolating to shorter time points and n = 1 when extrapolating to longer time 

points using the Cn 25 x t = k equation. 

26

The AEGL-3 values are based on the 2 hour LC50 for cadmium fume in rats, 112 mg/m3 27

28 (Rusch et al. 1986). The LC50 was divided by 3 to estimate a threshold of lethality. An 

29 interspecies uncertainty factor of 3 was applied because at acute exposures, cadmium is a direct30 acting respiratory irritant as indicated by the signs of irritation in rabbits and rats. This mode of 

31 action is not expected to differ among species. Rabbits and rats exposed for 2 hours to 0.25-4.5 

mg/m3 32 displayed similar histological and biochemical pulmonary effects including pneumonitis, 

33 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 34 ) from 1-6 

35 hours (Buckley and Bassett 1987; Oberdörster et al. 1987; Takenaka et al. 2004) exhibited the 

36 same effects as those observed in the Grose et al. (1987) study. An intraspecies uncertainty 

37 factor of 3 was applied because at acute exposures, cadmium is a direct-acting respiratory irritant 

38 in humans, and this mode of action is not expected to differ among individuals. After a five hour 

39 exposure to cadmium, workers experienced cough, throat irritation, dyspnea, and pulmonary 

40 edema (Beton et al. 1966) which are signs of respiratory irritation. The concentration-exposure 

41 time relationship for many irritant and systemically-acting vapors and gases may be described by 

Cn 42 x t = k, where the exponent, n, ranges from 0.8 to 3.5 (ten Berge et al. 1986). To obtain 

43 conservative and protective AEGL values in the absence of an empirically derived chemical44 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 45 x t = k 

46 equation. 

47

48 The calculated values are listed in the table below.

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CADMIUM PROPOSED: November 2009

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TABLE 1. Summary of AEGL Values Cadmium

Classification 10-min 30-min 1-hr 4-hr 8-hr Endpoint 

(Reference)

AEGLB1

(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) 

AEGLB2

(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)

AEGLB3

(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)

1

2 References

3

4 ATSDR (Agency for Toxic Substances and Disease Registry). 2008. Draft toxicological profile for cadmium. U.S. 

5 Department of Health and Human Services, Atlanta, GA.

6

7 Beton, D.C., G. S. Andrews, H.J. Davies, L. Howells and G.F. Smith. 1966. Acute cadmium fume poisoning. Five 

8 cases with one death from renal necrosis. Brit. J. Industr. Med 23: 292-301.

9

10 Buckley, B.J. and D.J.P. Bassett. 1987 Pulmonary cadmium oxide toxicity in the rat. J. Toxicol. Environ. Health. 21: 

11 233-250.

12

13 Grose, E.C., J.H. Richards, R.H. Jaskot, M.G. Ménache, J.A. Graham and W.C. Dauterman. 1987. A comparative 

14 study of the effects of inhaled cadmium chloride and cadmium oxide: pulmonary response. J. Toxicol. Environ. 

15 Health, 21:219-232.

16

Morrow, H. 2001. Cadmium and Cadmium Alloys. Kirk-Othmer Encyclopedia of Chemical Technology, 4th 17 Ed., M. 

18 Howe-Grant, ed. Available. Online. http://mrw.interscience.wiley.com/emrw/978047123896.

19

20 NRC (National Research Council). 2001. Standing Operating Procedures for Developing Acute Exposure 

21 Guideline Levels for Hazardous Chemicals. The National Academies Press, Washington, DC.

22

23 Rusch, G.M., J.S. O’Grodnick and W.E. Rinehart. 1986. Acute inhalation study in the rat of comparative 

24 uptake, distribution and excretion for different cadmium containing materials. Am. Ind. Hyg. Assoc. J. 47(12): 

25 754-763.

26

27 Takenaka, S., E. Karg, W.G. Kreyling, B. Lentner, H. Schultz, A. Ziesenis, P. Schramel and J. Heyder. 

28 2004. Fate and toxic effects of inhaled ultrafine cadmium oxide particles in the rat lung. Inhal. Toxicol. 16 

29 (suppl.1): 83-92.

30

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CADMIUM PROPOSED: November 2009

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1

2 1. INTRODUCTION

3

4 Cadmium is used in a variety of consumer and industrial materials with a high percentage 

5 used in the production of nickel-cadmium batteries and in electroplating. It is also in pigments 

6 used in plastics, ceramics and glasses and as a stabilizer for polyvinyl chloride (PVC). The 

7 demand for cadmium has decreased since the 1990s as lithium-ion and nickel metal hydride 

8 batteries become more popular (ATSDR 2008). World production between 1990 and 2000 was 

9 ~19,000 tons/year (Morrow 2001). Estimated U.S. production of cadmium was about 1450

10 metric tons in 2003 and 700 metric tons in 2006 (ATSDR 2008). Human exposure to cadmium 

11 can be from consumption of food, drinking water, incidental ingestion of soil or dust, inhalation 

12 of cadmium containing particles, inhalation of cigarette smoke, or inhalation from fumes/dust in 

13 an occupational setting. Cadmium is usually not present in the environment as pure metal but as 

14 a mineral combined with other elements such as oxygen (cadmium oxide), chlorine (cadmium 

15 chloride) or sulfur (cadmium sulfate/sulfide) (ATSDR 2008). These forms are also solids but 

16 some are water soluble.

17

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 mm Hg @ 394°C ATSDR 2008

Vapor density (air =1) - -

Liquid density (water =1) - -

Melting point 321oC HSDB 2005

Boiling point 765oC HSDB 2005

Flammability limits Powder flammable in air; Auto-ignites 

at 250 oC 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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CADMIUM PROPOSED: November 2009

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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 CdCO3 CdCl2 CdCO CdSO4 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 mm Hg @ 656 

°C

1 mm Hg @ 

1000 °C

– –

Vapor density (air 

=1)

4.26 g/cm3 @ 

4°C

3.3 g/cm3 @ 20°C Crystals8.15 g/cm2

; 

amorphous 

powder6.95 g/cm3

4.69 g/cm3 Hexagonal 

structure4.82 g/cm3

; 

Cubic structure4.5 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

1 Data from ATSDR, 2008

2 - No data available

3

4

5 2. HUMAN TOXICITY DATA

6 2.1. Acute Lethality

7 2.1.1. Case Reports

8

9 Numerous case reports are available on acute inhalation exposure to Cd; while some 

10 report the Cd levels in tissues, very few have the actual Cd exposure concentrations. Panchal 

11 and Vaideeswar (2006) reported on a man exposed to an unknown concentration of Cd oxide 

12 fumes who developed a cough, dyspnea and finally died. Fernández et al. (1996) reported on a 

13 man exposed to Cd fumes for approximately 60-75 minutes while flame-cutting an alloy 

14 containing about 10% Cd. The man developed dyspnea 4 hours after finishing work, was 

15 hospitalized, and on day 15 after exposure, the blood and urine concentration of cadmium was 

16 0.34 μg/100 mL (control = 0.11 μg/100 mL) and creatinine was 17.6 μg/g (control = 0.2 μg/g). 

17 He had multi-organ failure and died after 19 days. Autopsy showed diffuse alveolar damage to

18 the lungs with beginning intra-alveolar fibrosis. Concentrations of cadmium in tissues were 823 

19 ng/g liver, 3571 ng/g kidney and 1143 ng/g lung. The author stated that exposures to 200-500 

μg/m3 20 usually result in “metal fume fever” that lasts for one to two days, so this patient was 

21 almost certainly exposed to a much higher concentration.

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CADMIUM PROPOSED: November 2009

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1 A man was exposed for ~5 hours to a brownish-yellowish smoke during a copper 

2 smelting process after which he complained of fatigue and nausea (Yamamoto et al. 1983). The

3 clinical signs continued to worsen with hypoxemia developing. On day 2, Cd was 6 μg/mL in the 

4 blood and on day 5 was 332 μg/mL in the urine. Twelve days after the accident, the man died, 

5 and the cadmium content of the right upper lung lobe was found to be 1.06 μg/g.

6

7 Five workers were accidentally exposed to Cd fumes for 5 hours in a tank while using an 

8 oxyacetylene burner to melt off bolts made of cadmium (Beton et al., 1966). Cadmium oxide 

9 was released due to the heat of the burner. None of the men except for the burner wore any type 

10 of respiratory protection. All men experienced coughing and slight irritation of the throat during 

11 exposure with dyspnea developing 4-10 hours later. One man died on post-exposure day 5; all 

12 others had degrees of pulmonary edema that resolved over time. The man that died was found to 

13 have severe pulmonary edema, alveolar metaplasia of the lungs and bilateral cortical necrosis of 

14 the kidneys. The lungs contained 0.25 g CdO per 100 g wet specimen. The author speculated that 

15 if 11% of the inhaled CdO was retained in the lungs (% retention was estimated based on earlier 

16 work in five animal species), approximately 51.7 mg CdO fume must have been inhaled. 

17 Working for 5 hours with a ventilatory rate of 20 L/min, the concentration of CdO in the air 

would have been about 8.6 mg/m3 or 2,580 minute-mg/m3 18 .

19

20 2.2. Nonlethal Toxicity

21 2.2.1. Odor Threshold/Odor Awareness

22

23 Cadmium is odorless (HSDB 2005).

24

25 2.2.2. Epidemiologic Studies

26

27 Jakubowski et al. (2004) looked at long-term occupational exposure and lung function of 

28 79 workers (median age: 50.4 ± 8.9 years; 35 men and 44 women) to Cd in a cadmium battery 

29 factory (mean period of 17.4 ± 9.1 years). For comparison, 159 non-exposed workers (48.4 ± 4.2 

30 years; 91 men and 68 women) were used as controls. Subjects were divided into four groups 

31 depending on their cumulative cadmium exposure calculated either by cadmium levels in the 

32 blood x time or cadmium levels in the air x time. The range of Cd-Blood (μg/L) x time (years) 

was < 25, 25-500, > 500-1000 or > 1000 and for Cd-Air (mg Cd/m3 33 ) x time (years) was <0.01, 

34 0.10-1.5, > 1.5-4.0 or > 4. Lung function was evaluated using a LUNGTEST 500 spirometer and 

35 measuring the following: forced expiratory volume in one second (FEV1), forced vital capacity 

36 (FVC), peak expiratory flow (PEF), mid expiratory flow (MEF) at 25, 50 and 75%, vital capacity 

37 (VC), inspiratory capacity (IC) and the percentage of the FEV1/FVC ratio. Statistically 

38 significant decreases in FEV1 (85% of predicted values, p=0.0208), PEF (76% of predicted 

39 values, p=0.0488), MEF 25% (103 % of predicted values, p=0.0404), MEF 50% (86% of 

40 predicted values, p=0.0169) and MEF 75% (78% of predicted values, p= 0.0248) were observed 

41 in the workers exposed to >1000 μg/L x years as measured by Cd-blood concentration compared 

42 to controls. Workers in the group exposed to > 4 mg Cd-air x time also had a significant decrease 

43 in MEF 50% and slight decrease in the FEV1. The results indicated that long-term exposure 

44 could cause some decrease in lung function suggestive of mild airway obstruction. Table 4 

45 provides the Cd concentrations in the blood of workers and Cd concentrations found at the plant.

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CADMIUM PROPOSED: November 2009

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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 (μg/L) 43 31.8 ± 2.14 9.11 - 166

Cd x A (mg/m3) 0.08 – 0.51

1986-1988

Cd x B (μg/L) 91 29.1 ± 2.01 4.1 – 120.3

Cd x A (mg/m3) 0.03 – 0.38

1998-1999

Cd x B (μg/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

1

2

3 Lauwerys et al. (1979) followed eleven male workers in a small factory producing 

4 cadmium salts and monitored the cadmium levels in their blood and urine as well as the air 

5 exposure levels for 13 months. Nine of eleven men wore personal air monitors and the exposure 

levels (excluding outliers) ranged from 88 to 6276 μg/m3

, equivalent to 0.088 to 6.276 mg/ m3 6 . 

7 Most of the exposures were to cadmium oxide. Health effects were not evaluated.

8

9 2.3. Neurotoxicity

10

11 No data were located.

12

13 2.4. Developmental/Reproductive Toxicity

14

15 Fifty seven Japanese women, 58.1% of whom had delivered infants of gestational age of 

16 more than 30 weeks, and their infants were tested to determine if maternal urinary levels of Cd 

17 had any effect on the infant growth, gestational age at birth and/or the Cd level in the breast milk 

18 (Nishijo et al., 2002). All subjects lived in areas close to a Cd polluted region where itai-itai

19 disease, the most severe manifestation of chronic cadmium poisoning, is still being eliminated. 

20 No differences were found in the women’s socioeconomic status, nutrition status or prenatal 

21 care. Maternal urine and breast milk samples were taken on the fifth or eighth day post-partum 

22 and information about occupational or environmental exposure to Cd, including smoking, was 

23 obtained. Eight women were smokers (6 in the low Cd group and 2 in the high Cd group);

24 however, 6/8 had stopped smoking early in pregnancy making smoking less relevant to current

25 Cd levels. Women were divided into two groups based on the samples, those with urinary Cd of 

26 < 2 μg/g Creatinine (Cr) (n= 45) and those with ≥ 2 μg/g Cr (n= 12). This value of 2 μg/g Cr 

27 was derived from previous studies stating that those exposed to 2 μg/g Cr were found to have 

28 10% proteinuria. In the infants from mothers with higher Cd levels, the mean gestational age at 

29 birth (37 weeks vs. 39.1 weeks), height at birth (47.2 cm vs. 49.2 cm) and weight at birth (2663 g 

30 vs. 3099g) were significantly lower (p< 0.01 and 0.05) than the infants of mothers with Cd levels 

31 < 2 μg/g Cr. The number of infants delivered by Cesarean section (7 % vs. 4%) was also higher 

32 in the high Cd mothers compared to the mothers having lower Cd levels. Multiple regression 

33 analysis indicated that an increase of maternal urinary Cd was related to a decrease in gestational 

34 age after adjustment for maternal age. Samples of breast milk also had a higher mean 

35 concentration of Cd in mothers in the high Cd group. Overall, the study suggested that Cd 

36 exposure may increase the possibility of pre-term births thus indirectly causing decreased birth 

37 weight.
CADMIUM PROPOSED: November 2009

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1

2 2.5. Genotoxicity

3

4 Data are summarized from IARC 2003.

5

6 Human female itai-itai patients (n=12) exposed to cadmium through the diet had higher 

7 incidences of chromosomal aberrations of all types in peripheral blood lymphocytes than age8 matched control subjects (n=9). However, there were no differences in the frequencies of cells 

9 with structural aberrations in cultures from blood of four female itai-itai patients compared to 

10 four control subjects. 

11

12 No differences in chromosomal aberrations of lymphocytes were observed between five 

13 alkaline battery factory workers and three office workers. The battery workers had been 

14 employed for 5-24 years and the average cadmium concentration in personal air samples was 

estimated to be 0.70 mg/m3 15 . Blood cadmium concentration in the battery workers was 37.7 ng/g 

16 and 2.3 ng/g in the office workers.

17

18 No differences were found in chromosomal or chromatid aberration frequency in workers 

19 exposed from six weeks to 34 years in a cadmium pigment plant when compared to controls, 

20 administrative and laboratory personnel at the same plant. 

21

22 No difference was observed in the incidence of chromosomal aberrations in workers 

23 exposed to cadmium dusts for 6-25 years when compared to the office worker controls. 

24

25 A small increase in the incidence of chromosomal aberrations was observed in smelter 

26 workers when compared to non-smelter control subjects. It was not determined if smoking 

27 habits were included as a source of cadmium exposure.

28

29 Abnormal metaphase rates were significantly higher in peripheral blood lymphocytes in 

30 male workers exposed to cadmium fumes and dusts compared to the age-matched controls. 

31

32 Cadmium chloride induced sister chromatid exchange in human lymphocytes in vitro.

33

34 2.6. Carcinogenicity

35

36 Sorahan and Esmen (2004) reported on a cohort study occurring from 1947-2000 

37 involving 926 males that worked at a Cd-nickel battery factory. The aim was to investigate 

38 mortality of the workers in relation to cumulative cadmium hydroxide exposure. All those 

39 included in the study were required to have worked at the factory for a minimum of 12 months. 

40 Work histories were available from 1947-1986 and the factory closed in 1992. Two approaches 

41 were used to analyze the data: indirect standardization and Poisson regression. Based on the 

42 serial mortality rates for England and Wales, significantly increased mortality was observed for 

43 cancers of the pharynx (observed 4, expected 0.7; standardized mortality ratio (SMR) 559, 

44 p<0.05), non-malignant diseases of the respiratory tract (observed 61, expected 43; SMR 142, p< 

45 0.05), and non-malignant diseases of the genitourinary system (observed 10, expected 4.1; SMR 

46 243, p< 0.05). Non-significantly increased SMRs were observed for lung cancer (observed 45, 

47 expected 40.7; SMR 111) and prostate cancer (observed 9, expected 7.5; SMR 116). The results 

48 do not indicate that chronic cadmium hydroxide exposure leads to carcinogenicity in the lung, 
CADMIUM PROPOSED: November 2009

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1 but that it does lead to increase in non-malignant diseases of the respiratory and genitourinary 

2 systems and pharyngeal cancers. 

3

4 A mortality study of 602 white males with at least 6 months of production work in the 

5 same factory between 1940 and 1969 was performed to determine the effects of Cd exposure 

6 (Thun et al., 1985). Workers were followed until 1978. Cause-specific mortality rates for seven 

7 causes of death were compared between the workers and average US white males. Cadmium 

inhalation exposure concentrations measured in the plant ranged from 0.007 to 1.5 mg/m3 8 from 

9 pre-1950 to 1976, depending on the area of work. Most of the Cd exposure was to Cd oxide. The 

10 study population was obtained from employment histories from the personnel files. Mortality 

11 was analyzed with the use of the modified life-table system developed by NIOSH. Of all the 

12 workers, 83% had over 20 years of follow-up. For respiratory cancer, the expected rate was 

13 12.15 and the actual rate was 20. All 20 had over 2 years of employment and all mortalities were 

14 due to cancers of the lung, trachea and bronchus. Six deaths (expected 4.45) from genitourinary 

15 cancer were observed with one due to renal cancer (expected 0.9), two due to cancers of the 

16 bladder or other urinary organs (expected 1.10) and three due to prostate cancer (expected 2.20). 

17 Nine deaths were from non-malignant gastrointestinal disease (NMGID) and the expected 

18 number was 2.35. Even with adjustments to account for the lack of knowledge of the worker’s 

19 smoking habits and the fact that arsenic was used in the same factory prior to 1926, there is still 

20 an increase in the respiratory cancers. 

21

22 Kjellström et al. (1979) reported on the mortality and cancer incidence of Swedish 

23 workers exposed to Cd for more than 5 years. Data were collected from 269 Cd-Ni battery 

24 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 μg Cd/m3 25 ; between 1962-1974: 50 

μg Cd/m3

; and 1979: < 5 μg Cd/m3 26 . In this same factory, similar levels of nickel hydroxide were 

27 found in the air. In the Cd-Cu factory, cadmium concentrations were not obtained until the 

1960s, when the levels were 100-400 μg Cd/m3 28 ; since the 1970s, the value has been about 50 μg

Cd/m3 29 . An internal reference group from the Cd-Cu factory was used; workers that were 

30 involved in processes not exposing them to any Cd. A life-table method with the national 

31 average cancer incidence rates for men in different age groups was used to help determine any 

32 correlation between Cd exposure and the cancer incidence. Among the cadmium nickel workers, 

33 the risk ratio for nasopharyngeal cancer was 10 (2 cases) which was statistically significantly 

34 higher than 1, the expected value. However, part of this increase could be attributed to the nickel 

35 hydroxide dust they were exposed to as well as the cadmium oxide dust. There was an increased 

36 tendency for mortality from prostate cancer (4 cases) in the Cd-Cu alloy workers; however, the 

37 risk ratio when calculated was not statistically significantly increased (2.4).

38

39 The U.S. EPA (1994) listed cadmium and cadmium compounds as probably human

40 carcinogens based on limited evidence in occupational epidemiologic studies and sufficient 

41 evidence of carcinogenicity in rats and mice by inhalation, injection, and subcutaneous injection. 

42 An inhalation unit risk factor was calculated based on lung, trachea, and bronchus cancer death

43 data in human males (Thun et al. 1985). 

44

45 The International Agency for Research on Cancer (IARC 2003) concluded that there is 

46 sufficient evidence in humans for carcinogenicity of cadmium and cadmium compounds and 

47 categorized cadmium and cadmium compounds as being carcinogenic to humans.

48
CADMIUM PROPOSED: November 2009

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1 2.7. Summary

2

3 Case reports, occupational studies, and epidemiological studies showed how inhalation of 

4 cadmium affected humans. Although the case reports did not include Cd exposure 

5 concentrations, they did show that acute accidental exposure to Cd caused respiratory irritation, 

6 dyspnea, alveolar damage, pneumonitis, and death. Chronic exposure to Cd in occupational 

7 settings caused decreased lung function and nephrotoxicity. The results of carcinogenicity 

8 studies in Cd workers were equivocal, which may be due to concurrent exposures to other metals 

9 in the workplace. Respiratory cancers were increased in workers at a Cd-nickel battery factory;

10 although, chronic Cd exposure was not statistically correlated with lung cancer. The U.S. EPA 

11 (1994) and IARC (2003) list cadmium and cadmium compounds as being carcinogenic to 

12 humans. Maternal urine Cd concentration was associated with decreased gestational age and 

13 lower weight at birth. 

14

15 3. ANIMAL TOXICITY DATA

16 3.1. Acute Lethality

17 3.1.1. Rat

18

19 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 20 of both CdCl2 and CdO for 2 hours (Grose et al. 1987). The exposure 

concentrations were given as mg Cd/m3 21 . Animals were killed immediately or 72 hours post22 exposure. The following parameters were determined: Cd content in the lungs, lung weight, body 

23 weight, biochemical responses and histopathological lesions in the lungs. Concentrations were 

24 measured using 47 mm cellulose acetate filters and analyzed by atomic absorption and found to 

25 be consistent in the chambers. Three exposed rats died during the study. Two rats in the 0.45 

mg/m3 26 CdO group died; one rat had cardiovascular failure associated with pulmonary congestion 

27 and the other had an undetermined cause of death. The exposure group of the third rat was not 

28 reported and cause of death was undetermined. It is believed that the rats died from causes 

29 related to complications with the exposure apparatus and not from exposure to cadmium. No 

30 deaths were reported in rats of the high-dose group. 

31

32 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 33 cadmium 

carbonate, or 112 mg/m3 34 cadmium fume (Rusch et al. 1986). The exposure concentrations are 

35 based on cadmium content. An air control group was also included. Animals were exposed in a 

36 glass and stainless steel exposure chamber that had a total volume of one cubic meter and an 

37 effective volume of 760 L. The Cd carbonate and pigments were sieved through a 60-mesh sieve 

38 and hand-packed into a Wright dust feed mechanism. Dry air was passed through the dust feed 

39 and diluted with room air before being delivered to the chamber. Samples from the chamber 

40 were taken with a dust monitor. The Cd fume was derived from a 10% aqueous solution of 

41 cadmium acetate dehydrate. An aerosol was created by putting the metered solution and dry air 

42 through a nebulizer. No mortality occurred in groups exposed to air (control), Cd red or Cd 

43 yellow pigment. In the cadmium carbonate group, one female rat died on Day 4 and one male 

44 and one female rat died on day 13. All animals were moribund prior to death. Blood and food 

45 matter were found in the gastrointestinal tract, and the lung and liver of the animals were 

46 enlarged and discolored. In the cadmium fume group, 25/52 rats died. Six males and one female

47 died on day 2, seven males and five females died on day 3, three females died on day 4, two 

48 females died on day 5, and one male rat died on day 6. Lung and liver discoloration and 
CADMIUM PROPOSED: November 2009

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1 congestion were observed in the animals that died from the Cd fume group. Based on the study, 

the LC50 for cadmium fume was 112 mg/m3 2 .

3

4 3.2. Nonlethal Toxicity

5 3.2.1. Rabbit

6

7 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/m3 8 of both CdCl2 and CdO for 2 

hours (Grose et al. 1987). The exposure concentrations were given as mg Cd/m3 9 . Animals were 

10 killed immediately or 72 hours post-exposure. The following parameters were determined: Cd 

11 content in the lungs, lung weight, body weight, biochemical responses and histopathological 

12 lesions in the lungs. Concentrations were measured and found to be consistent in the chambers. 

Rabbits exposed to 0.45 mg/m3 13 CdO had a greater number of alveolar macrophages present 

when compared to controls and those exposed to CdCl2. At 4.5 mg/m3 14 , the lungs of rabbits had 

15 moderate to severe multifocal interstitial pneumonitis that was more severe in the CdO group 

with the presence of fibrocytic-type cells as well as pneumocytes. Rabbits exposed 4.5 mg/m3 16 of 

17 either chemical had increased lung weight and lung-to-body weight ratios. In the rabbit, CdCl2

18 had an inhibitory effect on pulmonary GSH peroxidase activity at the lowest and highest 

19 concentrations. The two highest concentrations of CdO inhibited GSH peroxidase activity. The 

activity of GSH transferase was increased after treatment with 0.45 mg/m3 20 CdCl2. The authors 

21 hypothesized that the changes in GSH peroxidase and transferase activity could be a response to 

22 protect cells against lipid peroxidation.

23

24 3.2.2. Rat

25

26 Twenty-four female Fischer 344 rats were exposed for 6 hours to ultrafine particles of 

CdO at a concentration of 70 μg Cd/m3 27 in whole-body chambers (330 L volume; ventilation 

28 exchange of 20 times/hour) (Takenaka et al. 2004). The MMAD was 40 nm and the GSD 1.6. 

29 Four rats were sacrificed immediately after exposure and on days 1, 4, and 7 for morphology and 

30 elemental analysis. Eight rats were sacrificed on day 0 for lung lavage. An additional 16 rats 

were exposed to 550 μg Cd/m3 31 in a similar manner. The MMAD was 51 nm and the GSD was

1.7. When converted, 70 μg Cd/m3 is equivalent to 0.07 mg/m3 and 550 μg Cd/m3 32 is equivalent 

to 0.550 mg/m3 33 . Eight rats were sacrificed on day 0 for lung lavage and four rats were sacrificed 

34 on days 0 and 1 for morphology and elemental analysis. Twelve animals for each exposure were 

35 used as controls, and exposed to clean air only. Just after exposure, Cd in the lungs of rats 

exposed to 0.07 mg/m3 36 was 19% of the total inhaled dose and this remained the same at the other 

37 time points. A slight but significant increase of Cd in the liver was observed only in the rats 

38 sacrificed 7 days after exposure. The lung lavage indicated no exposure-related morphological 

39 changes in the lungs or inflammatory responses in the low-dose rats. In rats exposed to the 

higher concentration, 0.550 mg/m3 40 , Cd content was similar in the lungs on day 0 and 1 but was 

41 significantly elevated in the liver and kidneys on both days, and 2/4 of the rats had increased 

42 blood Cd. Lung lavage of the rats in the high-dose group showed increased neutrophils, and 

43 multifocal alveolar inflammation was observed histologically.

44

Four groups of ten male Long Evans rats were exposed to CdO dust (0.00195 mg/m3 45 ), 

CdO fume (0.00169 mg/m3), CdS (0.00180 mg/m3 46 ) or sham-exposed in a nose-only inhalation

47 chamber for 1 hour (Oberdörster et al. 1987). The exposure concentration was not reported as

mg Cd/m3 48 , therefore, the concentration of Cd in this study is unknown. The CdO dust was ball49 milled for 24 hours and had a mass median aerodynamic diameter (MMAD) of 0.51 μm. The 
CADMIUM PROPOSED: November 2009

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1 CdO fume was generated by an electric arc burning off metallic Cd electrodes, producing 

2 particles of 0.4 μm. Pure CdS with a MMAD of 0.45 μm was used. Twenty-four hours post3 exposure, the animals were sacrificed, and the lungs were lavaged, and the cellular components 

4 of the lavage fluid were analyzed. Lung epithelial permeability was also determined by 

measuring the activity of 99m 5 Tc-DTPA in the lung lavage fluid; this substance was injected 

6 intravenously 10 minutes prior to sacrifice. An increase in activity in the lung lavage fluid

7 indicates a loss of epithelial integrity. Administration of both CdO dust and CdO fume resulted 

8 in a significant decrease in the number of alveolar macrophages and a significant increase in 

9 numbers of polymorphonuclear neutrophils, with a more pronounced effect observed with the 

10 CdO dust. Epithelial permeability was increased with exposure to CdO dust, but not CdO fume. 

11 Inhalation exposure to CdS resulted in no differences in rats compared to those in the sham12 exposed group. The study report provided very little detail but did help to show that water 

13 solubility does not always correlate with increased toxicity.

14

Male Wistar rats (16/group) were exposed to 0, 0.5, or 5.3 mg/m3 15 CdO aerosols for 3 

16 hours in a laminar flow exposure chamber (Buckley and Bassett 1987). The animals were 

17 observed for up to 15 days post exposure. Interim sacrifices took place 2, 4, 7, and 15 day post 

18 exposure and 4 rats/group were sacrificed at each necropsy. The CdO aerosols were generated 

19 by oxidizing cadmium acetate aerosols as they passed through a heated quartz tube. The 

20 chamber atmosphere was sampled using 0.22 μm pore diameter polycarbonate filters and 

21 determined by gravimetric analysis of aerosol samples. The geometric standard deviations were 

22 2.31 and 3.18 with mass median aerodynamic diameters of 0.26 and 0.33 μm, respectively, for 

the low and high dose concentrations. Body weight of rats exposed to 0 or 0.5 mg/m3 23 increased 

from exposure through the end of the observation period, however, rats exposed to 5.3 mg/m3 24 did 

25 not gain weight until day 7 post exposure. Body weight was similar among all groups on day 15 

post exposure. At 0.5 mg/m3 26 , foci of petechial hemorrhage were occasionally observed 2 and 4 

days post exposure and were consistently observed at 5.3 mg/m3 27 . Mild hypercellularity at 

28 bronchoalveolar junctions and adjacent alveoli and inflammatory cell influx of mononuclear 

cells were observed at 0.5 mg/m3 29 prior to day 7 post exposure. Morphology of the lungs was 

normal in rats exposed to 0.5 mg/m3 30 7 days post exposure. Focal areas of interstitial thickening, 

31 increases in cuboidal alveolar cells, and numerous inflammatory cells (interstitial mononuclear 

cells, alveolar macrophages, eosinophils, and basophils) were observed at 5.3 mg/m3 32 in the 

33 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 34 compared to those of control on 

35 study days 2-15 post exposure, and DNA content was increased days 4-15. Glutathione 

36 peroxidase, glutathione reductase, glucose-6-phosphate dehydrogenase, and 6-phosphogluconate 

dehydrogenase activity were significantly increased in rats exposed to 5.3 mg/m3 37 compared to 

38 the activity levels in control rats. 

39

40 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 41 of both CdCl2 and CdO for 2 hours (Grose et al. 1987). The exposure 

concentrations were given as mg Cd/m3 42 . Animals were killed immediately or 72 hours post43 exposure. The following parameters were determined: Cd content in the lungs, lung weight, body 

44 weight, biochemical responses and histopathological lesions in the lungs. Concentrations were 

45 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 46 CdO group) had cardiovascular failure associated 

47 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 48 group. Groups of rats exposed 

to wither 4.5 mg/m3 49 CdCl2 or CdO had no lesions observed immediately after exposure, but at 72 
CADMIUM PROPOSED: November 2009

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1 hours there was moderate to severe multifocal interstitial pneumonitis that was more severe in 

2 the CdO group. It was characterized by the presence of fibrocytic-type cells, alveoli edema, 

3 goblet cell hyperplasia, as well as hyperplastic pneumocytes. The pneumonitis observed in rats 

4 exposed to CdCl2 presented as thickening of the alveolar walls, edema, hemorrhage, and 

5 increases in neutrophils and alveolar macrophages. There was no difference in Cd deposition in 

the lungs in animals exposed to 0.25 or 0.45 mg/m3 6 CdCl2 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 7 , at 72 hours 

there was significantly less Cd in the lungs of rats exposed to 4.5 mg/m3 8 CdCl2 than in those

exposed to 1 ppm CdO. Rats exposed to 0.25 mg/m3 9 CdCl2 had a 13% decrease in lung-to-body 

weight ratio. Rats exposed to 0.45 mg/m3 10 group CdCl2 had a decrease in body weight and at 4.5 

mg/m3 11 a 20% decrease in body weight and increased lung and lung-to-body weight ratio 72 

hours after exposure. In the 0.45 or 4.5 mg/m3 12 CdO exposed rats, there was an increase in lung 

13 weight but no effect on body weight. Cadmium (CdCl2) had an inhibitory effect (27%) on 

pulmonary GSH peroxidase activity at the lowest concentration and at 0.45 mg/m3 14 . Cadmium 

15 inhibited GSH peroxidase activity at the two highest dose levels.

16

17 Twenty six adult Sprague-Dawley CD rats/sex/group were exposed in a single 2-hour 

exposure to 97 mg/m3 of cadmium red pigment, 99 mg/m3 cadmium yellow pigment, 132 mg/m3 18

cadmium carbonate, or 112 mg/m3 19 cadmium fume (Rusch et al. 1986). The exposure 

20 concentrations are based on cadmium content. An air control group was also included. Animals 

21 were exposed in a glass and stainless steel exposure chamber that had a total volume of one 

22 cubic meter and an effective volume of 760L. The Cd carbonate and pigments were sieved 

23 through a 60-mesh sieve and hand-packed into a Wright dust feed mechanism. Dry air was 

24 passed through the dust feed and diluted with room air before being delivered to the chamber. 

25 Samples from the chamber were taken with a dust monitor. The Cd fume was derived from a 

26 10% aqueous solution of cadmium acetate dehydrate. An aerosol was created by putting the 

27 metered solution and dry air through a nebulizer. 

28

29 The rats exposed to Cd fume exhibited clinical signs (hypoactivity and closed eyes) 

30 during the exposure. Following exposure, excessive lacrimation was observed in rats exposed to 

31 Cd red and yellow, and dry rales and body tremors were observed in the animals exposed to Cd 

32 carbonate. Those exposed to Cd fume had dry rales, labored breathing, and excessive 

33 lacrimation. Animals exposed to Cd fume also had decreased body weight compared to the 

34 controls, with all others maintaining weight similar to that of controls. No gross abnormalities 

35 were observed in those sacrificed immediately following exposure. Renal discoloration was 

36 observed in the rats in the Cd red pigment group. Pulmonary edema, observed as increased lung 

37 weight was seen in the Cd carbonate exposed group starting at 24 hours post-exposure. 

38 Exposure to Cd carbonate or Cd fume resulted in an increased incidence of lung discoloration 

39 and erosions in the stomach. Blood levels indicated that Cd was absorbed to a greater degree in 

40 the carbonate and fume groups when compared to the pigment groups. Urine and feces samples 

41 were collected at 0-24 hrs, 24-48 hrs, 48-72 hrs, 6-7 days and 29-30 days post-treatment. 

42 Samples indicated that the highest levels of cadmium were excreted in the first 24 hour period 

43 and urinary excretion was similar in all three groups while 80% of the red and yellow pigments 

44 were excreted in the feces within the first 24 hours. Tissues were collected for cadmium analysis 

45 in all but the Cd fume-exposed animals and these were not collected due to the moribund 

46 condition of the animals. The Cd carbonate-exposed animals had the greatest amount of 

47 cadmium measured in both the kidneys and liver; Cd levels increased initially in the liver and 

48 then dropped off but continued to increase in the kidney. 

49
CADMIUM PROPOSED: November 2009

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TABLE 5. Summary of Acute Inhalation Data in Laboratory Animals

Species Concentration 

(mg Cd/m3)

Exposure 

Time Effect Reference

Rabbit

CdCl2

0.25

0.45

4.5

2 hr

↓ Pulmonary GSH peroxidase activity 25%

↑ GSH transferase activity 

Moderate-severe multifocal interstitial 

pneumonitis; ↑lung weight

Grose et al. 

1987

Rabbit

CdO

0.25

0.45

4.5

2 hr

No effects

↑ Alveolar macrophages; ↓ pulmonary GSH 

peroxidase activity

Moderate-severe multifocal interstitial 

pneumonitis; ↑lung weight; ↓ pulmonary GSH 

peroxidase activity

Grose et al. 

1987

Rat

CdO

0.07

0.550

6 hr

No morphological changes or inflammatory 

response

↑ Neutrophils and multifocal alveolar 

inflammation

Takenaka et 

al. 2004

Rat

0.00195 Cd dust

0.00169 Cd fume

0.00180 CdS

1 hr ↓ Alveolar macrophages; ↑PMNs; ↑epithelial 

permeability

↓ Alveolar macrophages; ↑PMNs

No effect

Oberdörster 

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, ↑ cuboidal alveolar cells, 

↑inflammatory cells, ↑dry lung weight, ↑protein 

content, ↑DNA content, ↑ GP, GR, G6PD, 

6PGD activity

Buckley and 

Bassett 1987

Rat

CdCl2

0.25

0.45

4.5

2 hr

↓ Pulmonary GSH peroxidase activity 27%

↓ bw; ↓pulmonary GSH peroxidase activity

↓ bw 20%; ↑lung weight; ↓ pulmonary GSH 

peroxidase activity; pneumonitis

Grose et al. 

1987

Rat

CdO

0.25

0.45

4.5

2 hr

No effects

↑ Lung weight; ↓ pulmonary GSH peroxidase 

activity; 2 deaths-cardiovascular failure (1)

↑ Lung weight; ↓ pulmonary GSH peroxidase 

activity; pneumonitis

Grose et al. 

1987

Rat

97 Cd red

99 Cd yellow

132 Cd carbonate

112 Cd fume 2 hr

Lacrimation; renal discoloration

Lacrimation

Dry rales, body tremors; 5.8% mortality

Hypoactivity; closed eyes; lacrimation; dry rales; ↓ 

bw; ↑ 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 

or 0.05 mg/m3 6 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 
CADMIUM PROPOSED: November 2009

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1 of Cd made from CdCl dissolved in distilled water. Total airflow to the chamber was 22 L 

2 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 μg/m3 3 and the 

4 MMAD was 0.3μm. Twenty-four hours after the last exposure, females were euthanized and the 

5 tissues processed. Tissue Cd content was determined by graphite furnace atomic absorption 

6 spectrophotometry and placental metallothionein and cadmium content were also determined. 

7

8 Inhalation exposure did not affect the maternal body weight, fetal body weight, maternal 

9 or fetal organ weight, or placental weight when compared to controls. Maternal rats had a 

10 significant increase (p<0.01) in lung Cd compared to controls after only a single day and a 

11 significant increase in both lung and liver after 5 days. In the fetus, brain, liver and heart Cd 

12 levels were significantly increased compared to controls after 1 day of exposure, and levels in 

13 brain and liver remained elevated after 5 days. Maternal blood Cd increased from 25.6 to 57.3 

14 pg/mg of protein after 5 days of treatment but the fetal blood had no change. The levels of Cd 

15 and MT in the placenta did not change upon exposure, but the placental cadmium decreased after 

16 the 5-day exposure.

17

18 Thirty two pregnant Sprague-Dawley female rats and thirty-three pregnant Swiss (CD-1) 

mice were exposed to 0, 0.05, 0.5 or 2 mg/m3 19 cadmium oxide by whole-body inhalation for 6 

20 hours/day, 7 days/week on gestation days (GD) 4-19 in the rats and GD 4-17 in mice (NTP

21 1995). Generation of the aerosol was by the same methods described in Section 3.5.1. One rat 

exposed to 2 mg/m3 22 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 23 had 

24 significant decreases (p≤ 0.01) in body weight (14% less than controls) and body weight gain 

25 (41% less than controls). The high dose female rats also had decreases in absolute and relative 

26 liver weight and absolute kidney weight, compared to controls. Developmental toxicity was 

observed at 2 mg/m3 27 in rats, and included a decrease in the weight of live fetuses. This 

28 concentration also caused significant increases in the mean percent of fetuses per litter with 

29 reduced ossification of the pelvis (12 vs. 2.4 in controls) and sternebrae (25 vs. 4.4 in controls). 

Dyspnea and hypoactivity were observed in mice exposed to concentrations ≥ 0.5 mg/m3 30

cadmium oxide. At ≥ 0.5 mg/m3 31 , the number of pregnant mice was significantly decreased. Fetal 

body weight following exposure to 0.5 mg/m3 32 was significantly less than control fetal body 

weight. Five mice in the 2 mg/m3 33 group were euthanized moribund before the end of the study. 

34 Maternal body weight gain, absolute and relative gravid uterine weights, and absolute liver 

35 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 36 . 

37 The total number of resorptions per litter was significantly increased in this group, and the fetal 

38 body weight and percentage of live male fetuses per litter were significantly decreased in the 2 

mg/m3 39 group. 

40

41 Male and female Fischer 344 rats (10 weeks old) were exposed whole body to 0, 0.3, 1.0 

or 2.0 mg CdCl2/m3 42 for 6 hours/day, 5 days/week for 62 exposures (Kutzman et al. 1986). 

43 Twenty male rats were used for multiple pulmonary endpoint assessments, eight males for 

44 pathology only, eight male and eight females for reproductive studies and ten males for 

cytogenetic endpoints. Rats were exposed in a 1.4 m3 45 stainless steel and Lucite chamber. 

46 Airflow was equivalent to 15 chamber volumes/hr. Laskin-type nebulizers were used to generate 

47 the aerosol. An optical particle size analyzer was used to characterize the size distribution of the 

48 aerosolized particles. RAM-1 aerosol mass monitors were used to continuously monitor the 
CADMIUM PROPOSED: November 2009

22

1 chamber atmosphere. Chamber atmospheres were 0.33 (± 0.02), 1.06 (± 0.04) and 2.13 (± 0.11) 

mg Cd Cl2/m3 in the 0.3, 1.0 and 2.0 mg/m3 2 chambers, respectively. 

3

All rats exposed to 2.0 mg/m3 4 lost weight rapidly and died within the first 45 days and 

5 were observed to have rapid and shallow breathing and appeared unkempt prior to death. The 

6 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 7 survived. Some exposed males and 

8 females were allowed to breed with unexposed mates and there were no decreases in 

9 reproductive potential. No findings were associated with treatment in the number of viable 

10 embryos, late deaths, early deaths (resorptions), number of corpea lutea, or pre-implantation 

11 losses. At necropsy, there was a dose-dependent increase in organ-to-body weight ratio for the 

12 lungs, heart, spleen, kidneys, and testis. Also, the liver and brain weight-to-body ratio was 

13 increased in the high-dose, compared to the controls. Lesions of type II hyperplasia, alveolar 

14 macrophages, and polymorphonuclear leukocytes were observed at the terminal bronchioles of 

15 both the low- and mid-dose rats. Areas of fibrosis were also observed in the mid-dose rats. 

16 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 17 CdCl2 and the NOAEL could not be 

18 determined.

19

20 3.4. Genotoxicity

21

22 Cadmium oxide was not mutagenic in Salmonella typhimurium strains TA98, TA100, 

23 TA1535 or TA1537 with or without metabolic activation and did not produce micronuclei in 

24 erythrocytes of mice exposed by inhalation for 13 weeks (NTP, 1995).

25

26 Cadmium chloride induced DNA strand breaks in Escherichia coli and induced 

27 differential toxicity in Bacillus subtilis and E. coli strains. It also induced gene conversion in 

28 Saccharomyces cerevisiae, but did not induce reverse mutation in S. cerevisiae. Unscheduled 

29 DNA synthesis and DNA strand breaks were observed in primary cultures of rat hepatocytes, but 

30 not in primary cultures of rat Leydig cells. Calcium chloride was mutagenic to Chinese hamster 

31 V79 cells and mouse lymphoma L5178Y cells (IPCS 1992).

32

33 3.5. Repeated Dose

34 3.5.1. Rat 

35

36 Male and female F344/N rats (6 wks old) were exposed to cadmium oxide aerosol 

37 (99.4% purity; mass median aerodynamic diameter (MMAD) = 1.1-1.6 μgm) for 6 hours/day, 5 

38 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 39 for the 2 week studies and 0, 0.025, 0.05, 0.1, 0.25 

or 1 mg/m3 40 for 13 weeks. Animals were exposed in whole-body chambers that had a total 

volume of 2.3 m3 41 . Chemical concentration, airflow, temperature and relative humidity were 

42 controlled and monitored with an automated system. Overall, concentration within the chamber 

43 was adequate. Cadmium oxide dust was mixed with compressed air to create an aerosol. The 

44 MMAD of the aerosol particles was measured in each exposure chamber before the studies 

45 began, once in the 2 week study and monthly in the 13 week study. Blood was obtained to 

46 measure hematology and clinical chemistry parameters, urine collected and histopathology 

47 performed. 

48
CADMIUM PROPOSED: November 2009

23

In the rats exposed for 2 weeks, all those exposed to 10 mg/m3 1 died by day 6; no other 

2 deaths occurred. Clinical signs of hypoactivity, dehydration, ruffled fur, dyspnea and nasal 

discharge were observed in rats at concentrations ≥ 1 mg/m3 3 . Lesions in the lungs including 

4 alveolar histiocytic infiltrate, focal inflammation and fibrosis were observed in all of the treated 

5 rats with a dose-dependent increase in severity. Effects on the nasal and respiratory epithelium 

were observed in those exposed to 1 mg/m3 6 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 7 Cd oxide in rats was 

8 established based on histopathological findings; a NOAEL could not be determined. 

9

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

Focal inflamm/fibrosis

0/5

0/5

5/5 (2.0)a

5/5 (1.0)

5/5 (2.0)

5/5 (2.0)

5/5 (3.0)

5/5 (3.0)

5/5 (3.8)

5.5 (2.8)

5/5 (4.0)

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

Focal inflamm/fibrosis

0/5

0/5

5/5 (2.0)

3/5 (1.0)

5/5 (2.2)

5/5 (2.0)

5/5 (3.0)

5/5 (3.0)

5/5 (4.0)

5.5 (3.0)

5/5 (4.0)

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) a Number in parenthesis is severity code: 1= minimal, 2= mild, 3= moderate and 4= marked

10

11

12 All rats survived the 13 week study and all treated rats had a nasal discharge that 

increased in frequency as the concentration increased. Rats at 1 mg/m3 13 consistently had lower 

14 body weight throughout the study compared to controls, but it was within 10%. No significant 

15 findings were observed in the hematology, clinical chemistry or urine parameters. Males and 

16 females had statistically significant increases (p ≤ 0.01 or 0.05) in organ weight at concentrations 

≥ 0.05 mg/m3 17 , compared to controls including relative kidney weight, and relative and absolute 

18 lung weight; however, there were no treatment-related microscopic findings in the kidney or 

19 liver. Blood pressure was measured in the animals and there were no findings observed with 

20 treatment. Grossly, the only treatment-related finding was enlargement and paleness of the 

21 tracheobronchial and mediastinal lymph nodes. Microscopic lesions were identified in the lungs 

in all treated animals except those in the 0.025 mg/m3 22 group. The lesions were similar to those 

23 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 24 .

25
CADMIUM PROPOSED: November 2009

24

1

TABLE 7. Histopathological 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

2

3

4 Sixty male Wistar (CHbb:THOM) rats, approximately 8 weeks old, with a mean body 

5 weight of 250 g were exposed nose-only 6 hours/day for up to 10 days to 0 (air control), 

0.3 mg/m3 CdCl2 or 0.2, 1.0 or 8.0 mg/ m3 6 CdS (Klimisch 1993). Four animals from each group 

7 were sacrificed on days 2, 10, 11, 12, 13, 17, 38, 66 and 94. The study was designed to expose 

8 rats to soluble (CdCl2) and insoluble (CdS) forms of Cd. Measurements of lung, renal and fecal 

9 Cd were obtained. Cadmium chloride was generated as an aerosol by taking an aqueous solution 

10 and putting it through an injection pump to a binary nozzle atomizer before diluting with air. 

11 Cadmium sulfide was generated as a dust using a rotating brush-type generator and passing the 

12 dust directly into the inhalation chamber. All concentrations were sampled and found to be 

13 within an acceptable range. Upon sacrifice, the lungs and kidneys were removed and weighed 

14 before being processed for Cd content. Feces were collected daily and pooled together. 

15

16 No adverse clinical signs or mortalities occurred during the study or post-exposure 

17 period. Pooled data from days 0-10 showed a statistically significant increase in mean lung 

weight and lung to body weight ratio in the CdCl2-exposed rats. Rats exposed to 8.0 mg/m3 18 CdS 

19 also had increased mean lung weight. No effects were observed on kidney weight. Cadmium 

20 accumulated in the kidney of all treated animals but at a much greater proportion in those 

21 exposed to CdCl2. Cadmium in feces was observed mostly during the exposure and for a few 

22 days post-exposure, with the highest amount observed in rats exposed to the highest dose of CdS. 

23 The analyzed Cd content of test atmospheres for both compounds was 0.17 μg/L; however, the 

24 Cd lung content in the CdCl2-exposed rats was about two times higher than the CdS exposed 

25 rats. This could have been caused by either the greater availability of the CdCl2 aerosol 
CADMIUM PROPOSED: November 2009

25

1 compared to the CdS dust or the fact that CdCl2 is held in the lung longer. Overall the study 

2 showed a much higher bioavailability of CdCl2 compared to the soluble CdS upon inhalation 

3 exposure. 

4

5 Three month old female Wistar rats (n= 13-14) were exposed by inhalation to CdO for 5 

hours/day, 5 days/week for 20 weeks at concentrations of 0.02, 0.16 or 1 mg/m3 6 (Barański and 

7 Sitarek 1987). A control group was exposed to clean air only. The aerosol concentration was 

8 determined by drawing air in an inhalation chamber through Sartorious membrane filters 

9 SM11306. Fractions of aerosols with particle sizes below 4.7 μm were determined with the 

Anderson Impactor 2000. Mortality occurred at 1 mg/m3 10 , although histopathology and gross 

findings were not described in the report. At 1 mg/m3 11 , mortality was 15% at the end of 7-8 

12 weeks, 38% at the end of 13-14 weeks and 100% at the end of the study. This was compared to 

13 0, 7 and 14% of the controls at the same time points, respectively. A significant decrease (p< 

0.05) in body weight gain was observed in the rats exposed to 1 mg/m3 14 throughout the study; at 

0.16 mg/m3 15 , exposed rats had a decrease in body weight gain compared to controls, but it was 

16 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 17 , rats showed this change only at the end 

of the study (weeks 19-20). At 1.0 mg/m3 18 , 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 19 CdO and the 

20 NOAEL could not be determined.

21

Twelve adult female Wistar rats/group were exposed continuously to 0, 25 or 50 μg Cd/m3 22

for 90 days and to 100 μg Cd/m3 23 for 63 days (Prigge 1978), equivalent to 0, 0.025, 0.052 and 

0.105 mg/m3 24 administered as CdO. The rats were removed from the chamber for only 10-20 

25 minutes daily to allow for cleaning and food was changed daily to prevent oral contamination. 

26 Inhalation chambers were 50 x 50 x 90 cm with a total volume of 225L. Cadmium was nebulized 

27 from a 0.2% solution of cadmium acetate. The volume flow into the chambers was about 80 

28 L/min equating to about 21 changes/hour. Aerosol concentrations were checked and found to be 

29 within range of the expected values. Size distribution of the particles had a mean aerodynamic 

30 diameter of 0.19 μm, and the geometric standard deviation was 1.5. Both are in the range of 

31 respirable fine dust in humans. Urine and blood samples were obtained after exposure. A 

32 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 33 between days 45 and 60. A significant 

34 increase in lung weight was observed in all of the treated animals. A slight increase was 

35 observed in hematocrit or hemoglobin with treatment, but there was no effect on serum iron or 

36 alkaline phosphatase activity. A significant (p<0.05) decrease in the partial pressure of O2 and an 

increase in the partial pressure of CO2 were observed in the rats exposed to 0.105 mg/m3 37 . 

38 Proteinuria was not observed in any of the treated females. Inhalation uptake of cadmium 

39 resulted in increased liver cadmium levels but they were not as high as those observed after oral 

40 administration; uptake of cadmium in the kidney was similar with both methods of 

41 administration. Histopathology showed a few areas of swellings in the kidney tubuli, no lesions 

42 in the liver, emphysematic areas and cell proliferation in the bronchi, bronchiole, alveoli, and 

43 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 μg/m3 44 Cd (0.025 

mg/m3 45 ) and the NOAEL was not established.

46
CADMIUM PROPOSED: November 2009

26

1 3.5.2. Mouse

2

3 Male and female B6C3F1 mice (6 wks old) were exposed to cadmium oxide aerosol (99.4% 

4 purity; MMAD = 1.1-1.6 μgm) 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 5 for 

the 2 week studies and 0, 0.025, 0.05, 0.1, 0.25 or 1 mg/m3 6 for 13 weeks. Animals were exposed 

in whole-body chambers that had a total volume of 2.3 m3 7 . Chemical concentration, airflow, 

8 temperature and relative humidity were controlled and monitored with an automated system. 

9 Overall, concentration within the chamber was adequate. Cadmium oxide dust was mixed with 

10 compressed air to create an aerosol. The mass median aerodynamic diameter (MMAD) of the 

11 aerosol particles was measured in each exposure chamber before the studies began, once in the 2 

12 week study and monthly in the 13 week study. Blood was obtained to measure hematology and 

13 clinical chemistry parameters, urine collected and histopathology performed.

14

15 Findings similar to those reported in rats (NTP, 1995) were observed in the mice. In the 2 

week study, all mice in the 10 mg/m3 16 group died and death was due to severe respiratory 

17 toxicity. Hypoactivity, abnormal posture, rapid breathing, ataxia, nasal discharge, and ruffled fur 

were observed at 1, 3, and 10 mg/m3 18 . Absolute and relative lung weights were significantly 

increased at concentrations ≥ 0.3 mg/m3 19 . Alveolar macrophage infiltration, fibrosis, focal 

20 inflammation, and necrosis of alveolar duct epithelium were observed. As in the rats, severity of 

21 effects increased with increasing concentration. Histopathologic lesions are listed in Table 8. In 

the 2 week study, a NOAEL could not be established and the LOAEL for mice was 0.1 mg/m3 22

23 cadmium based on microscopic lung lesions.

24

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

Focal inflamm/fibrosis

Necrosis

Acute inflammation

0/5

0/5

0/5

0/5

5/5 (1.2)a

0/5

0/5

0/5 

5/5 (2.0)

5/5 

1/5 (1.0)

0/5

5/5 (3.0)

5/5 

5/5 (2.0)

0/5

5/5 (3.0)

5/5

5/5 (2.2)

5/5

0/5 

0/5 

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

Focal inflamm/fibrosis

Necrosis

Acute inflammation

0/5

0/5

0/5

0/5

5/5 (1.0)

0/5 

0/5

0/5

5/5 (1.8)

5/5 

1/5 (1.0)

0/5

5/5 (3.0)

5/5 

5/5 (2.0)

0/5

5/5 (3.0)

5.5 

5/5 (2.0)

0/5

0/5 

0/5

5/5 (3.0)

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
CADMIUM PROPOSED: November 2009

27

1

2 In the 13 week study, one mouse from the control group died with no deaths in the treated 

3 animals. No clinical signs of toxicity were observed. Lung lesions were similar to those of the 

4 rat and consisted of macrophage infiltrates, hyperplasia, inflammation and fibrosis, although 

5 fibrosis was more prevalent in the rat as shown in Table 9. The absolute and relative lung weight 

6 of both sexes, absolute and relative kidney and thymus weights in male rats, and absolute and 

7 relative kidney, liver, and spleen weights in female rats in all treatment groups were increased 

8 compared to control weights. No microscopic changes were found in the liver, kidney, spleen, or 

9 thymus. In the 13 week study, a NOAEL could not be established and the LOAEL for mice was 

0.025 mg/m3 10 cadmium based on microscopic lung lesions.

11

TABLE 9. Histopathological 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 (1.1)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
CADMIUM PROPOSED: November 2009

28

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 CdCl2

CdS

0.2

1.0

8.0

6 hr/d

10 d 

0.3 CdCl2: ↑ absolute and relative lung weight

8.0 CdS: ↑ 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, ↓ body weight 

Barański 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: ↓ body weight, ↑ lung weight,

0.105: 42% mortality between days 45 and 60, ↓ 

body weight, ↓ pO2, ↑pCO2, ↑ 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
CADMIUM PROPOSED: November 2009

29

1 3.6. Chronic Toxicity/Carcinogenicity

2

3 As a follow-up to the Takenaka et al. (1983) study described below Oldiges et al. (1989) 

4 exposed thirty four groups of twenty male and female SPF Wistar rats/sex/group (8 wks old) to a 

5 variety of Cd compounds in aerosol, dust or fume form (Table 11). The animals were exposed 

6 22 hours a day, 7 days a week for 18 months. A few groups had discontinuous exposure for 40 

7 hours a week for 6 months. Inhalation and observation periods were terminated at mortality rates 

8 of more than 25% during the inhalation period and 75% during the observation period to assure a 

9 carcinogenic result. In addition, an aerosol combination with the antagonistic zinc oxide aerosol 

10 was used in some of the exposures. Results were similar to those from the Takenaka et al. (1983) 

11 study in that no primary lung tumors were identified in the control rats, but were identified in the 

12 Cd exposed animals. Lung tumors rats were increased for all Cd compounds. The inhalation 

13 period was shorter for the water insoluble Cd compounds CdS and CdO because of mortality, but 

14 primary lung tumors were still observed in the rats of these groups. 

15
CADMIUM PROPOSED: November 2009

30

1

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 tumorsa

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 CdSO4 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 7b 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
CADMIUM PROPOSED: November 2009

31

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 tumorsa

Exposure Study Nodules 

(n/n)

A B C D

n/n

6 CdCl2 0.09 6 29b 6/18 0 1 2 0

3/18

8 CdSO4 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 11b 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 

dust

18 31 11/20 1 3 1 2

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.

1

2

3 Forty male inbred Wistar rats/group (6 weeks old) were exposed to CdCl2 aerosol at 

concentrations of 0 (n=41), 12.5, 25 or 50 μg/m3 4 for 23 hrs/day, 7 days/week for 18 months 

5 (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 6 , 

7 respectively. Exposures took place in a 225 L inhalation chamber and the aerosol was generated 

8 by atomizing a solution of CdCl2 with an ultrasonic atomizer. Air flow through the atomizer was 

9 700 L/min and the aerosol flow through the inhalation chamber was 80 L/min. The aerosol was 

10 diluted at the lower concentrations with filtered air. Air samples were drawn through membrane 

11 filters twice weekly from the intake and exhaust of the chamber to check chamber concentration. 

12 The mass of Cd on the filters was determined by atomic absorption spectrometry. The mass 

13 median diameter was 0.55 μm and the geometric standard deviation was 1.8. Animals were 

14 weighed every 3 months and any animals dying were examined as soon as possible. 
CADMIUM PROPOSED: November 2009

32

1 Histopathology was performed as well as measurement of the Cd content in the lungs, livers and 

2 kidneys. 

3

4 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 5 was slightly below that of the others 

6 but the difference was not significant. Compared to the controls (0.03 μg/g), the Cd 

7 concentration in the lungs was higher in treated rats, 5.6 μg/g in the low-dose group, 4.7 μg/g in 

8 the mid-dose group and 10.4 μg/g in the high-dose group. Similar values were found in the liver, 

9 and the kidney values were 0.3, 13.5, 16.4 and 33.6 μg/g Cd in the control, low-, mid- and high10 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 11 , and 25/35 (71.4%) 

at 0.050 mg/m3 12 had primary lung carcinomas. These tumors were identified as adenocarcinomas, 

13 epidermoid carcinomas and combined epidermoid and adenocarcinomas. Some of the rats also 

14 had metastases in the regional lymph nodes and the kidneys. Other tumors were noted but either 

15 lacked a dose response or did not appear to be treatment-related. Limited data were provided on 

16 all other histopathological findings.

17

18 3.7. Summary

19

20 Cadmium, in various forms, caused respiratory irritation, pulmonary edema, rales, 

21 pneumonitis, lacrimation, increased alveolar macrophages, and death in rabbits and rats exposed 

22 for 1-6 hours. Rats and mice exposed for 90 days or less exhibited pulmonary inflammation and 

23 edema, pulmonary hyperplasia, and nasal and respiratory epithelium degeneration. Kidney 

24 weight was also increased with limited microscopic changes observed. In carcinogenicity 

25 studies, rats exposed to Cd had an increased incidence of primary lung carcinomas. 

26 Reproductive studies in rats resulted in decreased weight of live fetuses and reduced ossification 

27 of the pelvis and sternebrae. In mice, the number of pregnant mice decreased with exposure to 

28 Cd and fetal body weight was decreased. 

29

30 4. SPECIAL CONSIDERATIONS

31 4.1. Metabolism and Disposition

32

33 Cadmium can be absorbed by inhalation, oral and dermal routes of exposure; however, 

34 dermal absorption is relatively insignificant (ATSDR 2008). In humans, acute oral exposure to 

35 cadmium causes severe nausea, vomiting, diarrhea and salivation. Cadmium fumes may produce 

36 a metal fume fever, or at higher doses, pulmonary edema, inflammation and emphysema (U.S. 

37 EPA, 1986). In humans, cadmium adsorption in the gastrointestinal tract has been reported to be 

38 low, only about 3-8%, and dependent upon several blood and dietary factors. In contrast, 30-64% 

39 of inhaled cadmium can be absorbed (Morrow, 2001). For the non-smoker, 95% of the total 

40 cadmium intake comes from ingestion of terrestrial foods or meat from animals that ate plants 

41 grown in cadmium-containing soil. For a smoker, 50% of cadmium intake is through cigarettes. 

42 Based on a 50% absorption rate, a person smoking one pack a day will absorb about 1-3 μg 

43 cadmium (Wittman and Hu 2002). 

44

45 Järup et al. (1983) determined the half-life of cadmium in the blood of workers after 

46 exposure had ended. Five men were exposed to cadmium for 4-7 years and then followed up to 

47 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 48 . Two of the five men had developed renal 

49 tubular damage. The best fit with the data was a two compartment model with the biological 
CADMIUM PROPOSED: November 2009

33

1 half-life of cadmium in the blood being 75-128 days in the first compartment and 7.4 to 16.0 

2 years in the second. 

3

4 Once absorbed, cadmium is distributed to most tissues in the body but concentrates in the 

5 liver and kidneys of all animals (ATSDR 2008). Once in the blood, cadmium is not known to 

6 undergo any direct metabolic conversion, but the sulfhydryl groups in albumin and 

7 metallothionein have a high affinity for cadmium so it can adhere to plasma proteins (mostly 

8 albumin), plasma metallothionein or directly to the erythrocyte. Since cadmium is not easily 

9 absorbed in the GI tract, most is excreted in the feces. In the lungs, some clearance occurs but 

10 absorption can take place. In chronic exposure, approximately 1/3 of the cadmium in the body is 

11 stored in the kidney and biological half-lives are on the order of 10-30 years (Wittman and 

12 Hu 2002). 

13

14 Absorbed cadmium is excreted from the body primarily in urine. The excretion rate is 

15 low and as stated above, the half-life in humans can be 10-30 years (U.S. EPA 1986; Wittman 

16 and Hu 2002).

17

18 Hadley et al. (1980) dosed male Wistar rats by intratracheal instillation with 15 μg 

109 19 CdO having a particle size of approximately 1.0 μm. Rats were sacrificed 1, 2, 4, 6, 12, 24, 

20 48, 168, and 336 hours after instillation. At approximately 6 hours post instillation, 50% 

instilled 109 21 CdO 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 109 22 CdO had left the lung. At the end of the 2 week 

period, 20% instilled 109CdO remained in the lungs. Approximately 8% of the instilled 109 23 CdO 

24 was distributed to the kidney over 2 weeks, and the cumulative total eliminated in the urine and 

25 feces was less than 10% of total body burden. 

26

27 4.2. Mechanism of Toxicity

28

29 Acute exposure to cadmium by the inhalation route has produced inflammatory cell 

30 influx, pneumonitis, respiratory irritation, and pulmonary edema in humans, rabbits, and rats 

31 (Beton et al. 1966; Rusch et al. 1986; Grose et al. 1987). Chronic exposure to cadmium by the 

32 oral or inhalation route has produced renal proximal tubule damage, proteinuria, polyuria and 

33 glycosuria. Cadmium-induced renal injury initially presents as tubular proteinuria which can be 

34 quantified by measurement of low molecular weight proteins such as β2-microglobulin, retinol 

35 binding protein and protein HC. With continued exposure, the progression continues and 

36 glomerular damage occurs with a characteristic decrease in the glomerular filtration rate. For the 

37 most part, this damage is irreversible (Wittman and Hu 2002). Pneumonitis, inflammation, and 

38 fibrosis have been observed following chronic inhalation exposure (Prigge 1978; IPCS 1992; 

39 Klimisch 1993). Very little is known, however, regarding the biochemical mechanisms by which 

40 cadmium causes toxicity at the cellular level (U.S. EPA 1986).

41

42 4.3. Structure Activity Relationships

43

44 No data were located.

45
CADMIUM PROPOSED: November 2009

34

1 4.4. Other Relevant Information

2 4.4.1. Species Variability

3

4 Acute exposure to cadmium caused pneumonitis, increased lung weight, and pulmonary 

5 inflammatory cell influx in rabbits and rats (Rusch et al. 1986; Buckley and Bassett 1987; Grose 

6 et al. 1987; Takenaka et al. 2004).

7

8 In a 4-week study, male Fisher 344 rats and Balb-c mice (number of animals not 

specified) were exposed to CdCl2 aerosols at a concentration of 0 or 100 μg Cd/m3 9 for 6 

10 hours/day, 5 days/week to determine if the amount of metallothionein (MT) produced was 

11 substantially different between the species (Oberdörster et al. 1994). The study found a 

12 significant species difference in the pulmonary response which may explain the pulmonary 

13 carcinogenicity observed in long-term Cd exposure in rats, whereas there is none in mice. 

14 Cadmium exposure significantly increased MT in both species in the total lung, persisting for a 

15 28 day post-exposure period, however, the baseline MT level was higher in mice. Mice showed 

16 a 3 fold increase in MT in the lavaged lung compared to rats, the increase in mice persisted for 

17 28-days. Histochemical staining showed that the epithelial cells of mice in the conducting 

18 airways and alveolar region had a greater induction of MT compared to those of rats, and that 

19 mice had more effects on proliferative cells compared to rats. Overall, the study suggested 

20 species difference in carcinogenicity susceptibility to Cd exposure and recommended further 

21 human research to help determine the extent of MT induction in humans. 

22

23 To help further distinguish species differences observed in pulmonary inflammation, 

24 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 25 (0.22 ppm) of CdO fumes for 3 hours by 

26 nose-only inhalation. Control animals were exposed to a mixture of air and argon. Animals were 

27 sacrificed at 0, 1, 3 or 5 days post-exposure and control animals at one time point only. Overall, 

28 there were interspecies and interstrain differences observed, further indicating the wide range of 

29 effects that could be possible with human exposures. The main findings were that C57 mice had 

30 higher cell proliferation in lung tissue and neutrophil influx in the bronchoalveolar lavage fluid 

31 (BALF) compared to DBA mice and Wistar rats, DBA mice had a higher percentage of Cd dose 

32 in lung and higher levels of biochemical indices of injury in BALF, and rats responded to Cd 

33 inhalation with a more transient response in BALF and a higher degree of acute inflammatory 

34 lesions in the lung than mice. 

35

36 4.4.2. Susceptible Populations

37

38 In acute inhalation studies, cadmium caused respiratory irritation and adverse pulmonary 

39 effects, therefore, those with lung-associated diseases or conditions (such as asthma and COPD) 

40 could be affected more. Children may be slightly more sensitive to cadmium by inhalation 

41 exposure as the rate of respiration is usually higher than that of adults. Exposure to cadmium as 

42 a child may also increase susceptibility to renal toxicity later in life (ATSDR 2008). Women 

43 with low iron stores or iron deficiency typically show increased cadmium intake; however, very 

44 little is transferred through the placenta or breast milk (Schoeters et al., 2006). Those with pre45 existing renal and/or hepatic conditions would be more at risk in chronic exposures. Smokers 

46 would also be at more risk of toxicity as they are already receiving doses of cadmium from 

47 cigarettes. Other factors found to affect susceptibility to cadmium include: diet, age, sex and 

48 genetic background (U.S. EPA 1986). The factors may result in increased absorption, decreased 

49 detoxification or excretion, or compromised organ function. People living close to sources of 
CADMIUM PROPOSED: November 2009

35

1 cadmium pollution, especially in industrialized areas, are subjected to higher exposures than 

2 those in non-industrialized areas (ATSDR 2008). 

3

4 4.4.3. Concentration-Exposure Duration Relationship

5

6 The concentration-exposure time relationship for many irritant and systemically-acting 

vapors and gases may be described by Cn 7 x t = k, where the exponent, n, ranges from 0.8 to 3.5 

8 (ten Berge et al., 1986). To obtain conservative and protective AEGL values in the absence of an 

9 empirically derived chemical-specific scaling exponent, temporal scaling was performed using 

10 n=3 when extrapolating to shorter time points and n = 1 when extrapolating to longer time points 

using the Cn 11 x t = k equation.

12

13 4.4.4. Concurrent Exposure Issues

14

15 In occupational settings, workers are exposed to other metals in addition to cadmium. 

16 Smokers inhale cadmium along with other chemicals and compounds. 

17

18 5. DATA ANALYSIS FOR AEGL-1

19 5.1. Summary of Human Data Relevant to AEGL-1

20

21 No data were located.

22

23 5.2. Summary of Animal Data Relevant to AEGL-1

24

Female Fischer 344 rats exposed (whole body) to 0.07 mg/m3 25 Cd for 6 hours showed no 

26 morphological changes in the lungs or inflammatory response (Takenaka et al. 2004). Rabbits

and rats exposed (nose-only) to 0.25 mg/m3 27 CdCl2 or CdO for 2 hours had inhibited pulmonary 

28 GSH peroxidase activity (Grose et al. 1987). Rabbits and rats exposed (nose-only) to 0.45

mg/m3 29 CdCl2 or CdO for 2 hours had increased inflammatory response (Grose et al. 1987). 

Deaths were observed in rats exposed to 0.45 mg/m3 30 but no deaths were observed in rats exposed 

to 4.5 mg/m3 31 , and those deaths may be associated with the exposure apparatus. The mortality 

32 observed was also inconsistent with the data for rats exposed to similar concentrations. After 

exposure to 0.5 mg/m3 33 CdO for 3 hours, rats had increased inflammatory cell influx and transient 

34 hypercellularity, but no mortality (Buckley and Bassett 1987). After whole-body exposure to 

0.55 mg/m3 35 CdO for 6 hours, rats had increased neutrophils and multifocal alveolar 

36 inflammation and no mortality (Takenaka et al. 2004). 

37

38 5.3. Derivation of AEGL-1

39

The AEGL-1 values are based on the experimental concentration, 0.55 mg Cd/m3 40 , that 

41 caused slight respiratory irritation in rats (Takenaka et al. 2004). After a 6 hour exposure, 

42 increased neutrophils and multifocal alveolar inflammation were observed. At the next higher 

43 experimental exposure, pneumonitis was observed (Grose et al. 1987). Although the exposure 

44 was a whole-body exposure, the size of the ultrafine particles (51 nM MMAD, 1.7 GSD) would 

45 mimic a gaseous state and the majority of the aerosol would be inhaled and not deposited on the 

46 fur. An interspecies uncertainty factor of 3 was applied because at acute exposures, cadmium is 

47 a direct-acting respiratory irritant as indicated by the signs of irritation in rabbits and rats. This 

48 mode of action is not expected to differ among species. Rabbits and rats exposed for 2 hours to 

0.25-4.5 mg/m3 49 displayed similar histological and biochemical pulmonary effects including 
CADMIUM PROPOSED: November 2009

36

1 pneumonitis, increased lung weight, pulmonary inflammatory cell influx, and decreased 

2 glutathione peroxidase activity (Grose et al. 1987). Rats exposed to cadmium (0.00169-5.3 

mg/m3 3 ) from 1-6 hours (Buckley and Bassett 1987; Oberdörster et al. 1987 ; Takenaka et al. 

4 2004) exhibited the same effects as those observed in the Grose et al. (1987) study. An 

5 intraspecies uncertainty factor of 3 was applied because at acute exposures, cadmium is a direct6 acting respiratory irritant in humans, and this mode of action is not expected to differ among 

7 individuals. After a five hour exposure to cadmium, workers experienced cough, throat 

8 irritation, dyspnea, and pulmonary edema (Beton et al. 1966) which are signs of respiratory 

9 irritation. The concentration-exposure time relationship for many irritant and systemicallyacting vapors and gases may be described by Cn 10 x t = k, where the exponent, n, ranges from 0.8 

11 to 3.5 (ten Berge et al., 1986). To obtain conservative and protective AEGL values in the 

12 absence of an empirically derived chemical-specific scaling exponent, temporal scaling was 

13 performed using n=3 when extrapolating to shorter time points and n = 1 when extrapolating to 

longer time points using the Cn 14 x t = k equation. The 30-minute AEGL-1 value was adopted as 

15 the 10-minute value due to the added uncertainty of extrapolating from a 6-hour time point to 10 

16 minutes (NRC 2001). The calculations for the AEGL-1 values are in Appendix A.

17

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

18

19

20 6. DATA ANALYSIS FOR AEGL-2

21 6.1. Summary of Human Data Relevant to AEGL-2

22

23 No human data relevant to AEGL-2 were located.

24

25 6.2. Summary of Animal Data Relevant to AEGL-2

26

Rabbits and rats exposed for 2 hours to 4.5 mg/m3 27 CdCl2 or CdO exhibited increased lung 

28 weight and moderate-severe pneumonitis characterized by alveolar wall thickening, hemorrhage, 

and edema (Grose et al. 1987). At 5.3 mg/m3 29 , focal areas of interstitial thickening, an increase in 

30 cuboidal alveolar cells, numerous inflammatory cells (interstitial mononuclear cells, alveolar 

31 macrophages, eosinophils, and basophils), and increase in lung weight and protein content were 

32 observed (Buckley and Bassett 1987). 

33

34 6.3. Derivation of AEGL-2

35

The AEGL-2 values are based on the experimental concentration, 5.3 mg Cd/m3 36 , that 

37 caused overt respiratory irritation and pathology in rats (Buckley and Bassett 1987). The 3 hour 

38 exposure resulted in reduced weight gain and increased lung weight, protein content, DNA 

39 content, number of cuboidal alveolar cells, number of inflammatory cells, and focal areas of 

40 interstitial thickening. An interspecies uncertainty factor of 3 was applied because at acute 

41 exposures, cadmium is a direct-acting respiratory irritant as indicated by the signs of irritation in 

42 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 43 displayed similar histological and biochemical pulmonary 

44 effects including pneumonitis, increased lung weight, pulmonary inflammatory cell influx, and 

45 decreased glutathione peroxidase activity (Grose et al. 1987). Rats exposed to cadmium 

(0.00169-5.3 mg/m3 46 ) from 1-6 hours (Buckley and Bassett 1987; Oberdörster et al. 1987 ; 
CADMIUM PROPOSED: November 2009

37

1 Takenaka et al. 2004) exhibited the same effects as those observed in the Grose et al. (1987) 

2 study. An intraspecies uncertainty factor of 3 was applied because at acute exposures, cadmium 

3 is a direct-acting respiratory irritant in humans, and this mode of action is not expected to differ 

4 among individuals. After a five hour exposure to cadmium, workers experienced cough, throat 

5 irritation, dyspnea, and pulmonary edema (Beton et al. 1966) which are signs of respiratory 

6 irritation. The concentration-exposure time relationship for many irritant and systemicallyacting vapors and gases may be described by Cn 7 x t = k, where the exponent, n, ranges from 0.8 

8 to 3.5 (ten Berge et al. 1986). To obtain conservative and protective AEGL values in the absence 

9 of an empirically derived chemical-specific scaling exponent, temporal scaling was performed 

10 using n=3 when extrapolating to shorter time points and n = 1 when extrapolating to longer time 

points using the Cn 11 x t = k equation. The calculations for the AEGL-2 values are in Appendix 

12 A. 

13

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

14

15

16 7. DATA ANALYSIS FOR AEGL-3

17 7.1. Summary of Human Data Relevant to AEGL-3

18

Workers (n=5) exposed for 5 hours to Cd oxide fumes inhaled an estimated 8.6 mg/m3 19 . 

20 One worker died 5 days after the exposure with severe pulmonary edema, alveolar metaplasia of 

21 the lungs, and bilateral cortical necrosis of the kidneys (Beton et al. 1966). The other four 

22 workers had pulmonary edema that resolved over time.

23

24 7.2. Summary of Animal Data Relevant to AEGL-3

25

26 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/m3 27 (Rusch et al. 1986). One rat exposed 

to 0.45 mg/m3 28 Cd died of cardiovascular failure associated with pulmonary congestion (Grose et 

29 al. 1987). Two other rats died of unknown causes in the same study. Although death occurred at 

0.45 mg/m3 30 , this value was not used to derive AEGL-3. The deaths may be associated with the

31 exposure apparatus and may not be the result of exposure to cadmium. Lack of mortality in rats 

exposed to similar concentrations (0.5 mg/m3

, Buckley and Bassett 1987; 0.55 mg/m3 32 , Takenaka 

et al. 2004) and at a higher experimental dose within the same study, 4.5 mg/m3 33 , further support 

34 the dismissal of the mortality data from Grose et al. (1987) from being considered for derivation 

35 of AEGL-3 values.

36

37 7.3. Derivation of AEGL-3

38

The AEGL-3 values are based on the 2 hour LC50 for cadmium fume in rats, 112 mg/m3 39

40 (Rusch et al. 1986). The LC50 was divided by 3 to estimate a threshold of lethality. An 

41 intraspecies uncertainty factor of 3 was applied because in acute exposures, cadmium is a direct42 acting respiratory irritant. An interspecies uncertainty factor of 3 was applied because at acute 

43 exposures, cadmium is a direct-acting respiratory irritant as indicated by the signs of irritation in 

44 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 45 displayed similar histological and biochemical pulmonary 

46 effects including pneumonitis, increased lung weight, pulmonary inflammatory cell influx, and 
CADMIUM PROPOSED: November 2009

38

1 decreased glutathione peroxidase activity (Grose et al. 1987). Rats exposed to cadmium 

(0.00169-5.3 mg/m3 2 ) from 1-6 hours (Buckley and Bassett 1987; Oberdörster et al. 1987 ; 

3 Takenaka et al. 2004) exhibited the same effects as those observed in the Grose et al. (1987) 

4 study. An intraspecies uncertainty factor of 3 was applied because at acute exposures, cadmium 

5 is a direct-acting respiratory irritant in humans, and this mode of action is not expected to differ 

6 among individuals. After a five hour exposure to cadmium, workers experienced cough, throat 

7 irritation, dyspnea, and pulmonary edema (Beton et al. 1966) which are signs of respiratory 

8 irritation. The concentration-exposure time relationship for many irritant and systemicallyacting vapors and gases may be described by Cn 9 x t = k, where the exponent, n, ranges from 0.8 

10 to 3.5 (ten Berge et al. 1986). To obtain conservative and protective AEGL values in the absence 

11 of an empirically derived chemical-specific scaling exponent, temporal scaling was performed 

12 using n=3 when extrapolating to shorter time points and n = 1 when extrapolating to longer time 

points using the Cn 13 x t = k equation. The calculations for the AEGL-3 values are in Appendix A.

14

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

15

16

17 8. SUMMARY OF AEGLS

18 8.1. AEGL Values and Toxicity Endpoints

19

20 Cadmium was shown to be an irritating metal that caused developmental, respiratory, and 

21 renal effects following multiple exposures. The derived AEGL values would prevent these 

22 effects. The AEGL-1 values were based upon the experimental concentration that caused slight 

respiratory irritation in rats, 0.55 mg Cd/m3 23 , following a 6 hour exposure. The AEGL-2 values 

24 were based upon the experimental concentration that caused overt respiratory tract irritation and 

pathology in rats, 5.3 mg/m3 25 , 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 26 , 

27 in rats. AEGL values are summarized in Table 15. 

28

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

29

30

31 8.2. Comparison with Other Standards and Guidelines 

32

33 AEGL values for cadmium are compared to other guidelines and standards in Table 16. The 

34 OSHA values were established to protect against lung cancer and kidney dysfunction (OSHA 

35 2005). The IDLH was based upon acute inhalation toxicity in workers (NIOSH 1996). The 

36 ACGIH TWA inhalable particulate value was established to minimize kidney dysfunction and 
CADMIUM PROPOSED: November 2009

39

1 the respirable fraction value was set to minimize pulmonary accumulation of cadmium that could 

2 act as a carcinogen (ACGIH 1996).

3

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)a (fume)

0.1 mg/m3

0.3 mg/m3C

PEL-TWA

(OSHA)b (dust)

0.2 mg/m3

0.6 mg/m3C

IDLH (NIOSH)c 9 mg/m3

TLV-TWA

(ACGIH)d

0.01 mg/m3I

0.002 mg/m3R

MAC-Peak 

Category (The 

Netherlands)e

0.005 mg/m3

4 a 5 OSHA PEL-TWA (Occupational Health and Safety Administration, Permissible Exposure Limits - Time Weighted 

6 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 7 -Acceptable ceiling concentration.

8 b 9 OSHA PEL-STEL (Permissible Exposure Limits - Short Term Exposure Limit) (OSHA, 2005) is defined 

analogous to the ACGIH-TLV-STEL. C 10 -Acceptable ceiling concentration.

11 c 12 IDLH (Immediately Dangerous to Life and Health, National Institute of Occupational Safety and Health) (NIOSH, 

13 1996) represents the maximum concentration from which one could escape within 30 minutes without any 

14 escape-impairing symptoms, or any irreversible health effects.

15 d 16 ACGIH TLV-TWA (American Conference of Governmental Industrial Hygienists, Threshold Limit Value - Time 

17 Weighted Average) (ACGIH, 2008) is the time-weighted average concentration for a normal 8-hour 

18 workday and a 40-hour work week, to which nearly all workers may be repeatedly exposed, day after day, 

without adverse effect. I- Inhalable particulate; R 19 - Respirable fraction

20 e 21 MAC (Maximaal Aanvaaarde Concentratie [Maximal Accepted Concentration - Peak Category]) (SDU Uitgevers 

22 [under the auspices of the Ministry of Social Affairs and Employment], The Hague, The Netherlands 2000) 

23 is defined analogous to the ACGIH-Ceiling.

24

25

26 8.3. Data Adequacy and Research 

27

28 Toxicity data for cadmium are available for humans and animals. Most of the acute 

29 inhalation data for humans do not provide cadmium exposure concentrations, but report signs 

30 and symptoms of toxicity which are useful for noting effects of exposure. Short-term and 

31 chronic epidemiological studies in workers were available; however, the workers may have had 

32 concurrent exposures to other chemicals. Animal studies were conducted in at least three species 

33 and range from acute to chronic. The acute studies in rabbits and rats provide data suitable for 

34 deriving AEGL values and highlight the differences between the effects that occur following 

35 acute and chronic cadmium exposure. 

36

37

38
CADMIUM PROPOSED: November 2009

40

1

2 9. REFERENCES

3

4 ACGIH (American Conference of Governmental Industrial Hygienists). 1996. 1996 

Supplement to the 6th 5 Edition. Documentation of the Threshold Limit Values and Biological 

6 Exposure Indices: Cadmium and Compounds. Seventh ed., ACGIH, Cincinnati, OH.

7

8 ACGIH (American Conference of Governmental Industrial Hygienists). 2008. 

9 Threshold limit values (TLVs) for chemical and physical agents and biological exposure indices 

10 (BEIs). ACGIH, Cincinnati, OH.

11

12 ATSDR (Agency for Toxic Substances and Disease Registry). 2008. Draft toxicological 

13 profile for cadmium. U.S. Department of Health and Human Services, Atlanta, GA.

14

15 Barański, B. and K. Sitarek . 1987. Effect of oral and inhalation exposure to cadmium on the oestrous 

16 cycle in rats. Toxicol. Lett. 36: 267-273.

17

18 Beton, D.C., G. S. Andrews, H.J. Davies, L. Howells and G.F. Smith. 1966. Acute cadmium fume 

19 poisoning. Five cases with one death from renal necrosis. Brit. J. Industr. Med 23: 292-301.

20

21 Buckley, B.J. and D.J.P. Bassett. 1987 Pulmonary cadmium oxide toxicity in the rat. J. Toxicol. Environ. 

22 Health. 21: 233-250.

23

24 Crump, K.S. and R.B. Howe. 1984. The multistage model with a time-dependent dose pattern: 

25 Applications to carcinogenic risk assessment. Risk. Anal. 4: 163-176.

26

27 Fernández, M.A., P. Sanz, M. Palomar, J. Serra and E. Gadea. 1996. Fatal chemical pneumonitis due to 

28 cadmium fumes. Occup. Med. 46: 372-374. 

29

30 Grose, E.C., J.H. Richards, R.H. Jaskot, M.G. Ménache, J.A. Graham and W.C. Dauterman. 1987. A 

31 comparative study of the effects of inhaled cadmium chloride and cadmium oxide: pulmonary 

32 response. J. Toxicol. Environ. Health, 21:219-232. 

33

34 Haber, F.R. 1924. Zur geschichte des gaskrieges [On the history of the gas war]. In: Fuenf Vortraege aus 

35 den Jahren 1920-23 [Five lectures from the years 1920-1923]. Berlin, Germany: Verlag von 

36 Julius Springer; pp. 76-92.

37

Hadley, J.G., A.W. Conklin, and C.L. Sanders. 1980. Rapid solubilization and translocation of 109 38 CdO 

39 following pulmonary deposition. Toxicol. Appl. Pharmacol. 54: 156-160.

40

41 HSDB (Hazardous Substances Data Bank). 2005. Cadmium. TOXNET, Toxicology Data Network. US. 

42 Natl. Library of Medicine. Available Online. http://toxnet.nlm.nih.gov/.

43

44 IARC (International Agency for Research on Cancer). 2003. IARC Monographs on the evaluation of the 

45 carcinogenic risk of chemicals to humans. Cadmium and Cadmium Compounds. Vol: 58: 119-

46 237.

47

48 IPCS (International Programme on Chemical Safety). 1992. Environmental Health Criteria 134 

49 Cadmium. Available online. 

50 http://www.intox.org/databank/documents/chemical/cadmium/ehc134.htm.

51
CADMIUM PROPOSED: November 2009

41

1 Jakubowski, M., A. Abramowska-Guzik, W. Szymczak and M. Trzcinka-Ochocka. 2004. Influence of 

2 long-term occupational exposure to cadmium on lung function tests results. Int. J. Occup. Med. 

3 Environ. Health 17: 361-368

4

5 Järup. L., A. Rogenfelt, C-G Elinder, K. Nogawa and T. Kjellström. 1983. Biological half-time of 

6 cadmium in the blood of workers after cessation of exposure. Scand. J. Work Environ. Health 

7 9:327-331. 

8

9 Kjellström, T., L. Friberg and B. Rahnster. 1979. Mortality and cancer morbidity among cadmium10 exposed workers. Environ. Health Perspect. 28:199-204.

11

12 Klimisch, H.J. 1993. Lung deposition, lung clearance and renal accumulation of inhaled cadmium 

13 chloride and cadmium sulphide in rats. Toxicology 84:103-124. 

14

15 Kutzman, R.S., R.T. Drew and R.N. Shiotsuka. 1986. Pulmonary changes resulting from subchronic 

16 exposure to cadmium chloride aerosol. J. of Toxicol. Environ. Health 17: 175-189. 

17

18 Lauwerys, R., H. Roels, M. Refniers, J.P. Buchett, A. Bernard and A. Goret. 1979. Significance of 

19 cadmium concentration in blood and in urine in workers exposed to cadmium. Environ. Res. 20: 

20 375-391.

21

22 McKenna, I.M., M.P. Waalkes, L.C. Chen and T. Gordon. 1997. Comparison of inflammatory lung 

23 responses in Wistar rats and C57 and DBA mice following acute exposure to cadmium oxide 

24 fumes. Toxicol. Appl. Pharmacol. 146:196-207. 

25

26 Morrow, H. 2001. Cadmium and Cadmium Alloys. Kirk-Othmer Encyclopedia of Chemical 

Technology, 4th 27 Ed., M. Howe-Grant, ed. Available. Online. 

28 http://mrw.interscience.wiley.com/emrw/9780471238966/kirk/article/cadmcarr.a01/current/abstra

29 ct?hd=All,cadmium&hd=All,cadmium&hd=All,alloys.

30

31 NIOSH (National Institute for Occupational Safety and Health). 1996. Documentation 

32 for Immediately Dangerous to Life and Health Concentrations (IDLH). Available Online. 

33 http://www.cdc.gov/niosh/idlh/7440439.html.

34

35 NIOSH (National Institute for Occupational Safety and Health). 2005. NIOSH Pocket 

36 Guide to Chemical Hazards. NIOSH, Cincinnati, OH. Available Online. 

37 http://www.cdc.gov/niosh/npgd0088.html.

38

39 Nishijo, M., H. Nakagawa, R. Honda, K. Tanebe, S. Saito, H. Teranishi and K. Tawara. 2002. Effects of 

40 maternal exposure to cadmium on pregnancy outcome and breast milk. Occup. Environ. Med.

41 59:394-397. 

42

43 NRC (National Research Council). 2001. Standing Operating Procedures for Developing Acute 

44 Exposure Guideline Levels for Hazardous Chemicals. The National Academies Press, 

45 Washington, DC.

46

47 NRC (National Research Council). 1985. Emergency and Continuous Exposure Guidance Levels for 

48 Selected Airborne Contaminants, Vol 5. The National Academies Press, Washington, DC.

49

50 NTP (National Toxicology Program). 1995. NTP technical report on toxicity studies of cadmium oxide 

51 administered by inhalation to F344/N rats and B6C3F1 mice. NIH Publication 95-3388. U.S. 

52 Department of Health and Human Services, Public Health Service, National Institutes of Health.

53
CADMIUM PROPOSED: November 2009

42

1 Oberdörster, G., M.G. Cherian and R.B. Baggs. 1994. Importance of species difference in experimental 

2 pulmonary carcinogenicity of inhaled cadmium for extrapolation to humans. Toxicol. Lett.

3 72:339-343.

4

5 Oberdörster,G., D. Hochrainer and C. Cox. 1987. Acute pulmonary toxicity of cadmium compounds: 

6 dependence on physico-chemical form. Toxicology of Metals: Clinical and Experimental 

7 Research. S.S. Brown and Y. Kodama., eds. West Sussex, England: Ellis Horwood Limited. pp. 

8 319-320.

9

10 Oldiges, H., D. Hochrainer and U. Glaser. 1989. Long-term inhalation study with Wistar rats and four 

11 cadmium compounds. Toxicol. Environ. Chem. 19:217-222.

12

13 OSHA (Occupational Safety and Health Administration). 2005. Code of Federal Regulations, CFR 29, 

14 Part 1910, Table Z-2.

15

16 Panchal, L. and P. Vaideeswar. 2006. Acute lung injury due to cadmium inhalation- a case report. Indian 

17 J. Pathol. Microbiol. 49: 265-266.

18

19 Prigge, E. 1978. Early signs of oral and inhalative cadmium uptake in rats. Arch. Toxicol. 40: 231-247. 

20

21 Rinehart, W. E., Hatch, T. 1964. Concentration-time product (CT) as an expression of dose in 

22 sublethal exposures to phosgene. Ind. Hyg. J. 25: 545-553.

23

24 Rusch, G.M., J.S. O’Grodnick and W.E. Rinehart. 1986. Acute inhalation study in the rat of comparative 

25 uptake, distribution and excretion for different cadmium containing materials. Am. Ind. Hyg. 

26 Assoc. J. 47(12): 754-763. 

27

28 Schoeters, G., E. Den Hond, M. Zuurbier, R. Naginiene, P. Van Den Hazel, N. Stilianakis, R. Ronchetti 

29 and J.G. Koppe. 2006. Cadmium and children: exposure and health effects. Acta. Pædiatrica.

30 95:50-54. 

31

32 SDU Uitgevers 2000. MAC Ministry of Social Affairs and Employment. Nationale 

33 MAC (Maximum Allowable Concentration) List, 2000. The Hague, The Netherlands.

34

35 Sorahan, T. and N.A. Esmen. 2004. Lung cancer mortality in UK nickel-cadmium battery workers, 1947-

36 2000. Occup. Environ. Med. 61:108-116.

37

38 Takenaka, S., E. Karg, W.G. Kreyling, B. Lentner, H. Schultz, A. Ziesenis, P. Schramel and J. Heyder. 

39 2004. Fate and toxic effects of inhaled ultrafine cadmium oxide particles in the rat lung. Inhal.

40 Toxicol. 16 (suppl.1): 83-92. 

41

42 Takenaka, S., H. Oldiges, H. König, D. Hochrainer and G. Oberdöster. 1983. Carcinogenicity of cadmium 

43 chloride aerosols in W rats. J. Natl. Cancer Inst. 70: 367-373.

44

45 ten Berge, W.F., A. Zwart, and L.M. Appelman. 1986. Concentration-time mortality response 

46 relationship of irritant and systemically acting vapours and gases. J. Hazard. Materials: 13: 

47 301-309.

48

49 Thun, M.J., T.M. Schnorr, A.B. Smith, W.E. Halperin and R.A. Lemen. 1985. Mortality among a cohort 

50 of US cadmium production workers- an update. J. Natl. Cancer Inst. 74: 325-333.

51

52 Trottier, B., J. Athot, A.C. Ricard and J. Lafond. 2002. Maternal-fetal distribution of cadmium in the 

53 guinea pig following a low dose inhalation exposure. Toxicol. Lett. 129:189-197.
CADMIUM PROPOSED: November 2009

43

1

2 U.S. EPA (United States Environmental Protection Agency). 1994. Integrated Risk Information System 

3 Summary of Cadmium (CASRN 7440-43-9). United States Environmental Protection Agency, 

4 Washington, D.C. Available online. http://www.epa.gov/ncea/iris/subst/0141.htm.

5

6 U.S. EPA (United States Environmental Protection Agency). 1986. Final draft for the drinking water 

7 criteria document on cadmium. EPA PB89-192140. Office of Drinking Water, Washington, D.C.

8

9 Wittman, R. and H. Hu. 2002. Cadmium exposure and nephropathy in a 28-year old female metals 

10 worker. Environ. Health Perspecti. 110: 1261-1266. 

11

12 Yamamoto, K., M. Ueda, H. Kikuchi, H. Hattori and Y. Hiraoka. 1983. An acute fatal occupational 

13 cadmium poisoning by inhalation. Z. Rechtsmed. 91: 139-143.

14
CADMIUM PROPOSED: November 2009

44

1 APPENDIX A: Derivation of AEGL Values

2

3 Derivation of AEGL-1

4

5 Key Study: Takenaka, S., E. Karg, W.G. Kreyling, B. Lentner, H. Schultz, A. 

6 Ziesenis, P. Schramel and J. Heyder. 2004. Fate and toxic effects of 

7 inhaled ultrafine cadmium oxide particles in the rat lung. Inhal. Toxicol. 

8 16 (suppl.1): 83-92.

9

Toxicity endpoint: The experimental concentration, 0.55 mg Cd/m3 10 caused slight respiratory 

11 irritation in female rats exposed for 6 hours.

12

Time scaling: Cn 13 x t = k; n=3 when extrapolating to shorter time points and n = 1 when 

14 extrapolating to longer time points.

15

16 Uncertainty factors:

17 Interspecies: 3, Cadmium is a direct-acting respiratory irritant and it is not expected that 

18 toxicity would differ among species. Rabbits and rats exposed for 2 hours 

to 0.25-4.5 mg/m3 19 displayed similar histological and biochemical 

20 pulmonary effects including pneumonitis, increased lung weight, 

21 pulmonary inflammatory cell influx, and decreased glutathione peroxidase 

22 activity (Grose et al. 1987). Rats exposed to cadmium (0.00169-5.3 

mg/m3 23 ) from 1-6 hours (Buckley and Bassett 1987; Oberdörster et al. 

24 1987; Takenaka et al. 2004) exhibited the same effects as those observed 

25 in the Grose et al. (1987) study.

26 Intraspecies: 3, Cadmium is a direct-acting respiratory irritant, and respiratory effects 

27 due to irritation are not expected to differ greatly among individuals. 

28 After a five hour exposure to cadmium, workers experienced cough, throat 

29 irritation, dyspnea, and pulmonary edema (Beton et al. 1966) which are 

30 signs of respiratory irritation. 

31

32 Modifying factor: None applied.

33

Calculations: 0.55 mg/m3 / 10 = 0.055 mg/m3 34

C3 35 x t = k 

(0.055 mg/m3)

3 x 360 min = 0.059895 mg/m3 36 -min

37

C1 38 x t = k 

0.0055 mg/m3 x 360 min = 19.8 mg/m3 39 -min

40

10-min AEGL-1 30-min value adopted as 10-min value = 0.13 mg/m3 41

42

30-min AEGL-1 C3 x 30 min= 0.059895 mg/m3 43 -min

C = 0.13 mg/m3 44

45

1-hr AEGL-1 C3 x 60 min= 0.059895 mg/m3 46 -min

C = 0.10 mg/m3 47

48

4-hr AEGL-1 C3 x 240 min= 0.059895 mg/m3 49 -min
CADMIUM PROPOSED: November 2009

45

C = 0.063 mg/m3 1

2

8-hr AEGL-1 C1 x 480 min = 19.8 mg/m3 3 -min

C = 0.041 mg/m3 4

5
CADMIUM PROPOSED: November 2009

46

1 Derivation of AEGL-2

2

3 Key Studies: Buckley, B.J. and D.J.P. Bassett. 1987. Pulmonary cadmium oxide 

4 toxicity in the rat. J. Toxicol. Environ. Health. 21: 233-250.

5

Toxicity endpoints: The experimental concentration, 5.3 mg Cd/m3 6 caused overt respiratory 

7 irritation and pathology in exposed for 3 hours.

8

Time scaling: Cn 9 x t = k; n=3 when extrapolating to shorter time points and n = 1 when 

10 extrapolating to longer time points. 

11

12 Uncertainty factors:

13 Interspecies: 3, Cadmium is a direct-acting respiratory irritant and it is not expected that 

14 toxicity would differ among species. Rabbits and rats exposed for 2 hours 

to 0.25-4.5 mg/m3 15 displayed similar histological and biochemical 

16 pulmonary effects including pneumonitis, increased lung weight, 

17 pulmonary inflammatory cell influx, and decreased glutathione peroxidase 

18 activity (Grose et al. 1987). Rats exposed to cadmium (0.00169-5.3 

mg/m3 19 ) from 1-6 hours (Buckley and Bassett 1987; Oberdörster et al. 

20 1987; Takenaka et al. 2004) exhibited the same effects as those observed 

21 in the Grose et al. (1987) study.

22 Intraspecies: 3, Cadmium is a direct-acting respiratory irritant, and respiratory effects 

23 due to irritation are not expected to differ greatly among individuals. 

24 After a five hour exposure to cadmium, workers experienced cough, throat 

25 irritation, dyspnea, and pulmonary edema (Beton et al. 1966) which are 

26 signs of respiratory irritation.

27

28 Modifying factor: None applied.

29

Calculations: 5.3 mg/m3 / 10 = 0.53 mg/m3 30

C3 31 x t = k 

(0.53 mg/m3)

3 x 180 min = 26.79786 mg/m3 32 -min

33

C1 34 x t = k 

0.53 mg/m3 x 180 min = 95.4 mg/m3 35 -min

36

10-min AEGL-2 C3

x 10 min= 26.79786 mg/m3 37 -min

C = 1.4 mg/m3 38

39

30-min AEGL-2 C3 x 30 min= 26.79786 mg/m3 40 -min

C = 0.96 mg/m3 41

42

1-hr AEGL-2 C3 x 60 min= 26.79786 mg/m3 43 -min

C = 0.76 mg/m3 44

45

4-hr AEGL-2 C1 x 240 min = 95.4 mg/m3 46 -min

C = 0.40 mg/m3 47

48

8-hr AEGL-2 C1 x 480 min = 95.4 mg/m3 49 -min
CADMIUM PROPOSED: November 2009

47

C = 0.20 mg/m3 1

2

3

4
CADMIUM PROPOSED: November 2009

48

1 Derivation of AEGL-3

2

3 Key Studies: Rusch, G.M., J.S. O’Grodnick and W.E. Rinehart. 1986. Acute inhalation 

4 study in the rat of comparative uptake, distribution and excretion for 

5 different cadmium containing materials. Am. Ind. Hyg. Assoc. J. 47: 754-

6 763. 

7

8 Toxicity endpoint: The threshold of lethality was calculated from the 2-hr LC50 for cadmium 

fume in rats, 112 mg/m3 9 .

10

Time scaling: Cn 11 x t = k; n=3 when extrapolating to shorter time points, and n = 1 when 

12 extrapolating to longer time points. 

13

14 Uncertainty factors:

15 Interspecies: 3, Cadmium is a direct-acting respiratory irritant and it is not expected that 

16 toxicity would differ among species. Rabbits and rats exposed for 2 hours 

to 0.25-4.5 mg/m3 17 displayed similar histological and biochemical 

18 pulmonary effects including pneumonitis, increased lung weight, 

19 pulmonary inflammatory cell influx, and decreased glutathione peroxidase

20 activity (Grose et al. 1987). Rats exposed to cadmium (0.00169-5.3 

mg/m3 21 ) from 1-6 hours (Buckley and Bassett 1987; Oberdörster et al. 

22 1987; Takenaka et al. 2004) exhibited the same effects as those observed 

23 in the Grose et al. (1987) study.

24 Intraspecies: 3, Cadmium is a direct-acting respiratory irritant, and respiratory effects 

25 due to irritation are not expected to differ greatly among individuals. 

26 After a five hour exposure to cadmium, workers experienced cough, throat 

27 irritation, dyspnea, and pulmonary edema (Beton et al. 1966) which are 

28 signs of respiratory irritation.

29

30 Modifying factor: None applied.

31

Calculations 112 mg/m3 /3/10= 3.733 mg/m3 32

C3 33 x t = k 

(3.733 mg/m3)

3 x 120 min = 6242.45206 mg/m3 34 -min

35

C1 36 x t = k 

3.733 mg/m3 x 120 min = 447.96 mg/m3 37 -min

38

10-minute AEGL-3 C3x 10 min= 6242.45206 mg/m3 39 -min

C = 8.5 mg/m3 40

41

30-minute AEGL-3 C3 x 30 min= 6242.45206 mg/m3 42 -min

C = 5.9 mg/m3 43

44

1-hr AEGL-3 C3 x 60 min= 6242.45206 mg/m3 45 -min

C = 4.7 mg/m3 46

47

4-hr AEGL-3 C1 x 240 min = 44.796 mg/m3 48 -min

C = 1.9 mg/m3 49
CADMIUM PROPOSED: November 2009

49

1

8-hr AEGL-3 C1 x 480 min = 44.796 mg/m3 2 -min

C = 0.93 mg/m3 3

4

5
CADMIUM PROPOSED: November 2009

50

1 APPENDIX B: Time-Scaling Calculations

2

3 The relationship between dose and time for any given chemical is a function of the 

4 physical and chemical properties of the substance and the unique toxicological and 

5 pharmacological properties of the individual substance. Historically, the relationship according 

6 to Haber (1924), commonly called Haber=s Law or Haber=s Rule (i.e., C x t = k, where C = 

7 exposure concentration, t = exposure duration, and k = a constant) has been used to relate 

8 exposure concentration and duration to effect (Rinehart and Hatch 1964). This concept states 

9 that exposure concentration and exposure duration may be reciprocally adjusted to maintain a 

10 cumulative exposure constant (k) and that this cumulative exposure constant will always reflect a 

11 specific quantitative and qualitative response. This inverse relationship of concentration and 

12 time may be valid when the toxic response to a chemical is equally dependent upon the 

13 concentration and the exposure duration. However, an assessment by ten Berge et al. (1986) of 

14 LC50 data for certain chemicals revealed chemical-specific relationships between exposure 

15 concentration and exposure duration that were often exponential. This relationship can be 

expressed by the equation C n 16 x t = k, where n represents a chemical specific, and even a toxic 

17 endpoint specific, exponent. The relationship described by this equation is basically in the form 

18 of a linear regression analysis of the log-log transformation of a plot of C vs. ten Berge et al. 

19 (1986) examined the airborne concentration (C) and short-term exposure duration (t) relationship 

20 relative to death for approximately 20 chemicals and found that the empirically derived value of 

21 n ranged from 0.8 to 3.5 among this group of chemicals. Hence, the value of the exponent (n) in 

the equation Cn 22 x t = k quantitatively defines the relationship between exposure concentration 

23 and exposure duration for a given chemical and for a specific health effect endpoint. Haber's 

24 Rule is the special case where n = 1. As the value of n increases, the plot of concentration vs. 

25 time yields a progressive decrease in the slope of the curve.

26

27 The available data do not allow for empirical derivation of a temporal scaling factor (n) for 

28 cadmium. The exposure concentration-exposure duration relationship for many irritant and 

systemically acting vapors and gases may be described by Cn 29 x t = k, where the exponent, n, 

30 ranges from 0.8 to 3.5 (ten Berge et al., 1986). In the absence of an empirically derived 

31 exponent (n), temporal scaling from the experimental durations of the respective PODs to 

32 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 Cn 33 x t = k equation.

34
CADMIUM PROPOSED: November 2009

51

1 APPENDIX C: Carcinogenicity Assessment

2

3 The carcinogenicity data are summarized in Section 3.6 and Table 9. The U.S. EPA (1994) 

4 concluded that cadmium is a “probable human carcinogen” based on evidence of carcinogenicity 

5 in animals and limited evidence of carcinogenicity in an exposed human population. The 

inhalation unit risk calculated is 1.8 x 10-3 μg/m3 6 , and the concentration associated with a risk 

level of 1 in 10,000 is 6 x 10-2 μg/m3 7 . 

8

9 To convert a 70-year (25,600 days) exposure to a 24-hr exposure:

10

24-hr exposure = d x 25,600; where d = 6 x 10-2 μg/m3 11

= (6 x 10-2 μg/m3 12 ) x 25,600 days

= 1536 μg/m3 = 1.54 mg/m3 13

14

15 To account for uncertainty regarding the variability in the stage of the cancer process at which 

16 cadmium may act, a multi-stage factor of 6 is applied (Crump and Howe, 1984):

17

1.54 mg/m3

/ 6 = 0.26 mg/m3 18

19

Therefore, a single exposure to cadmium at 0.26 mg/m3 20 for 24 hrs would represent a cancer risk 

of 10-4 21 . If the exposure is limited to a fraction (f) of a 24-hr period, the fractional exposure 

22 becomes 1/f x 24 hr (NRC 1985).

23

24 hr exposure = 0.26 mg/m3 24

8 hr exposure = 0.78 mg/m3 25

4 hr exposure = 1.56 mg/m3 26

1 hr exposure = 6.24 mg/m3 27

30 min exposure = 12.48 mg/m3 28

10 min exposure = 36.66 mg/m3 29

30

31

32 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 33

34

Time (h) 10-4 10-5 10-6

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

35

36 These values based on carcinogenicity are not proposed for AEGL values.

37

38
CADMIUM PROPOSED: November 2009

52

1 APPENDIX D: Derivation Summary for Cadmium AEGLs

2

3 ACUTE EXPOSURE GUIDELINE LEVELS FOR

4 CADMIUM (CAS Reg. No. 7440-43-9)

5 DERIVATION SUMMARY

6

AEGL-1 VALUES

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

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; Oberdörster 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.

7

8
CADMIUM PROPOSED: November 2009

53

1

2

AEGL-2 VALUES

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

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, ↑ cuboidal alveolar cells, ↑inflammatory cells, ↑dry lung weight, 

 ↑protein content, ↑DNA content, ↑ 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; 

Oberdörster 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.

3
CADMIUM PROPOSED: November 2009

54

1

2

3

AEGL-3 VALUES

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

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 

Exposure Route/Concentrations/Duration: Inhalation/97 mg/m3 Cd red, 99 mg/m3 Cd yellow, 132 mg/m3 Cd 

carbonate, 112 mg/m3 Cd fume/2 hr 

Effects: 

97 mg/m3 Cd red Lacrimation, renal discoloration

99 mg/m3 Cd yellow Lacrimation

132 mg/m3 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 LC50 112 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; 

Oberdörster 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-, 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-3 values. 

4

5
CADMIUM PROPOSED: November 2009

55

1 APPENDIX E: Category Plot for Cadmium

2

3

0.0 

0.0 

0.1 

1.0 

10.0 

100.0 

1000.0 mg/m3

0 60 120 180 240 300 360 420 480 

Minutes

Human - No Effect

Human - Discomfort

Human - Disabling

Animal - No Effect

Animal - Discomfort

Animal - Disabling

Animal - Some Letha

Animal - Lethal

AEGL

Chemical Toxicity - TSD Data Cadmium

AEGL-1

AEGL-2

AEGL-3

4

The values for AEGL-2 and AEGL-3 are above a concentration, 0.45 mg Cd/m3 5 , at which 2 animals died. Based on 

6 the information provided in the study (Grose et al. 1987), it is possible that the animal deaths were not the result of 

7 exposure to cadmium but were the result of exposure apparatus difficulties (reversal of animal body and resulting 

8 asphyxiation). The mortality at this concentration was inconsistent with the other animal data resulting from 

9 exposures at similar concentrations. There was also a lack of dose response as no mortality occurred following 

10 exposure to a higher dose of cadmium. 
CADMIUM PROPOSED: November 2009

56

1

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

Beton et al. 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

Rusch et al. 1986 Rat b 1 97 120 1 Lacrimation; renal discoloration

Rusch et al. 1986 Rat b 1 99 120 1 Lacrimation

Rusch et al. 1986 Rat b 1 132 120 SL 5.8% mortality, dry rales; pulmonary 

edema

Rusch et al. 1986 Rat b 1 112 120 SL 48% mortality; hypoactivity, LC50

2