## ACUTE EXPOSURE GUIDELINE LEVELS (AEGLs)

FOR

CADMIUM

(CAS Reg. No. 7440

- 43

- 9)

Cd

PROPOSED1

2 

## ACUTE EXPOSURE GUIDELINE LEVELS (AEGLs) 3



## FOR 4



## CADMIUM 5



## (CAS Reg. No. 7440

- 43

- 9) 6

7

8

9

10



## PROPOSED 11

12

13

14

15

16

17

18

19CADMIUM PROPOSED : November 2009

3 1

PREFACE 2

3

Under the authority of the Fede ral Advisory Committee Act (FACA) P. L. 92

- 463 of 4

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

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

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

chemicals. 8

9

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

emergency exposure periods ranging from 10 minutes to 8 hours. Three levels

C AEGL

- 1, 11

AE GL

- 2 and AEGL

- 3

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

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

The three AEGLs are defined as follows: 14

15

AEGL

- 1 is the airborne conc entration (expressed as parts per million or milligrams per 16

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

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

irritation, or certain a symptomatic, non

- sensory effects. However, the effects are not 19

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

21

AEGL

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

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

could experience irreversible or other serious, long

- lasting adverse health effects or an 24

impaired ability to escape. 25

26

AEGL

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

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

could experience life

- threatening health effects or death. 29

30

Airborne concentrations below the AEGL

- 1 represent exposure levels that could produce 31

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

irritation or certain asymptomatic, non

- sensory effects. With increasing airborne concentrations 33

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

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

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

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

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

at concentrations below the corresponding AEGL 39

40

41

42CADMIUM PROPOSED : November 2009

4 TABLE OF CONTENTS 1

P REFACE

................................ ................................ ................................ ................................ ................................ ...... 3 2

LIST OF TABLES

................................ ................................ ................................ ................................ ......................... 6 3

EXECUTIVE SUMMARY

................................ ................................ ................................ ................................ ........... 7 4

1. INTRODUCTION

................................ ................................ ................................ ................................ ............. 10 5

2. HUMAN TOXICITY DATA

................................ ................................ ................................ ............................. 11 6

2.1. Acute Lethality

................................ ................................ ................................ ................................ .......... 11 7

2.1.1. Case R eports

................................ ................................ ................................ ................................ ........ 11 8

2.2. Nonlethal Toxicity

................................ ................................ ................................ ................................ .... 12 9

2.2.1. Odor Threshold/Odor Awareness

................................ ................................ ................................ ........ 12 10

2.2.2. Epidemiologic Studies

................................ ................................ ................................ ......................... 12 11

2.3. Neurotoxicity

................................ ................................ ................................ ................................ ............ 13 12

2.4. Developmental/Reproductive Toxicity

................................ ................................ ................................ ...... 13 13

2.5. Genotoxicity

................................ ................................ ................................ ................................ .............. 14 14

2.6. Carcinogenicity

................................ ................................ ................................ ................................ ........ 14 15

2.7. Summary

................................ ................................ ................................ ................................ ................... 16 16

3. ANIMAL TOXICITY DATA

................................ ................................ ................................ ............................ 16 17

3.1. Acute Lethality

................................ ................................ ................................ ................................ .......... 16 18

3.1.1. Rat

................................ ................................ ................................ ................................ ........................ 16 19

3.2. Nonlethal Toxicity

................................ ................................ ................................ ................................ .... 17 20

3.2.1. Rabbit

................................ ................................ ................................ ................................ ................... 17 21

3.2.2. Rat

................................ ................................ ................................ ................................ ........................ 17 22

3.3. Developmental/Reproductive Toxicity

................................ ................................ ................................ ...... 20 23

3.4. Genotoxicity

................................ ................................ ................................ ................................ .............. 22 24

3.5. Repeated Dose

................................ ................................ ................................ ................................ .......... 22 25

3.5.1. Rat

................................ ................................ ................................ ................................ ........................ 22 26

3.5.2. Mouse

................................ ................................ ................................ ................................ .................. 26 27

3.6. Chronic Toxicity/Carcinogenicit y

................................ ................................ ................................ ............ 29 28

3.7. Summary

................................ ................................ ................................ ................................ ................... 32 29

4. SPECIAL CONSIDERATIONS

................................ ................................ ................................ ........................ 32 30

4.1. Metabolis m and Disposition

................................ ................................ ................................ ..................... 32 31

4.2. Mechanism of Toxicity

................................ ................................ ................................ .............................. 33 32

4.3. Structure Activity Relationships

................................ ................................ ................................ ............... 33 33

4.4. Other Relevant Information

................................ ................................ ................................ ...................... 34 34

4.4.1. Species Variability

................................ ................................ ................................ ............................... 34 35

4.4.2. Susceptible Populations

................................ ................................ ................................ ....................... 34 36

4.4.3. Concentration

- Exposure Duration Relationship

................................ ................................ .................. 35 37

4.4.4. Concurrent Exposure Issues

................................ ................................ ................................ ................. 35 38

5. DATA ANALYSIS FOR AEGL

- 1

................................ ................................ ................................ .................... 35 39

5.1. Summary of Human Data Relevant to AEGL

- 1

................................ ................................ ........................ 35 40CADMIUM PROPOSED : November 2009

5 5.2. Summary of Anima l Data Relevant to AEGL

- 1

................................ ................................ ........................ 35 1

5.3. Derivation of AEGL

- 1

................................ ................................ ................................ .............................. 35 2

6. DATA ANALYSIS FOR AEGL

- 2

................................ ................................ ................................ .................... 36 3

6.1. Summary of Human Data Relevant to AEGL

- 2

................................ ................................ ........................ 36 4

6.2. Summary of Animal Data Relevant to AEGL

- 2

................................ ................................ ........................ 36 5

6.3. Derivation of AEGL

- 2

................................ ................................ ................................ .............................. 36 6

7. DATA ANALYSIS FOR AEGL

- 3

................................ ................................ ................................ .................... 37 7

7.1. Summary of Human Data Relevant to AEGL

- 3

................................ ................................ ........................ 37 8

7.2. Summary of Animal Data Relevant to AEGL

- 3

................................ ................................ ........................ 37 9

7.3. Derivation of AEGL

- 3

................................ ................................ ................................ .............................. 37 10

8. SUMMA RY OF AEGLS

................................ ................................ ................................ ................................ ... 38 11

8.1. AEGL Values and Toxicity Endpoints

................................ ................................ ................................ ...... 38 12

8.2. Comparison with Other Standards and Guidelines

................................ ................................ .................. 38 13

8.3. Data Adequacy and Research

................................ ................................ ................................ ................... 39 14

9. REFERENCES

................................ ................................ ................................ ................................ ................... 4 0 15

APPENDIX A: Derivation of AEGL Values

................................ ................................ ................................ .............. 44 16

APPENDIX B: Time

- Scaling Calculations

................................ ................................ ................................ ................ 50 17

APPENDIX C: Carcinogenicity Assessment

................................ ................................ ................................ .............. 51 18

APPENDIX D: Derivation Summary for Cadmium AEGLs

................................ ................................ ...................... 52 19

APPENDIX E: Category Plot for Cadmium

................................ ................................ ................................ ............... 55 20

21

22CADMIUM PROPOSED : November 2009

6 LIST OF TABLES 1

2

TABLE 1. Summary of AEGL Values Cadmium

................................ ................................ ........................ 9 3

TABLE 2. Chemical and Physical Properties

................................ ................................ ............................. 10 4

TABLE 3. Chemical and Physical Properties of Cadmium Compounds

................................ .................... 11 5

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

................................ ........... 13 6

TABLE 5. Summary of Acute Inhalation Data in Laboratory Animals

................................ .................... 20 7

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

............................. 23 8

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

........................... 24 9

TABLE 8. Histopathological Findings in Mice Exposed for 2 wks to Cadm ium Oxide

........................... 26 10

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

......................... 27 11

TABLE 10. Summary of Repeat Do se Inhalation Data in Laboratory Animals

................................ ........ 28 12

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

........................ 30 13

TABLE 12. AEGL

- 1 Values for Cadmium

................................ ................................ ............................... 36 14

TABLE 13. AEGL

- 2 Values for Cadmium

................................ ................................ ............................... 37 15

TABLE 14. AEGL

- 3 Values for Cadmium

................................ ................................ ............................... 38 16

TABLE 15. Summary of AEGL Values

................................ ................................ ................................ .... 38 17

TABLE 16. Extant Standards and Guidelines for Cadmium

................................ ................................ .... 39 18

19

20CADMIUM PROPOSED : November 2009

7 EXEC UTIVE SUMMARY 1

2

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

high percentage used in the production of nickel

- cadmium batteries and in electroplating. It is 4

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

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

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

metric tons in 2006 (ATSDR 2008). 8

9

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

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

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

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

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

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

cancers were increased in workers at a Cd

- nickel battery factory, however, chronic Cd exposure 16

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

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

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

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

macrophages, and death in rab bits and rats exposed for 1

- 6 hours. Rats and mice exposed for 90 21

days or less exhibited pulmonary inflammation and ed ema, pulmonary hyperplasia, nasal and 22

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

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

25

The AEGL

- 1 values are based on the experimental concentration, 0.55 mg Cd /m 3

, that 26

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

increased neutrophils an d multifocal alveolar inflammation were observed

. At the next higher 28

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

. Although the exposure 29

was a whole

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

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

fur. An inter species uncertainty fa ctor of 3 was applied because at acute exposures, cadmium is 32

a direct

- acting respiratory irritant as indicated by the signs of irritation in rabbits and rats

. This 33

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

0.25

- 4.5 mg/m 3 displayed similar histological and biochemical pulmonary effects including 35

pneumonitis, increased lung wei ght, pulmonary inflammatory cell influx, and decreased 36

glutathione peroxidase activity (Grose et al. 1987). R ats exposed to cadmium (0.00169

- 5.3 37

mg/m 3 ) from 1

- 6 hours (Buckley and Bassett 1987; Oberdörster et al. 1987 ; Takenaka et al. 38

2004) exhibited the same effects as those observed in the G rose et al. (1987) study

. An 39

intraspecies uncertainty factor of 3 was applied because at acute exposures, cadmium is a direct

40

acting respiratory irritant in humans, and this mode of action is not expected to differ a mong 41

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

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

irritation . The concentration

- exposure time relationship for many irrit ant and systemically

44

acting vapors and gases may be described by C n x t = k, where the exponent, n, ranges fr om 0.8 45

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

of an empirically derived chemical

- specifi c scaling exponent, temporal scaling was performed 47

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

points using the C n x t = k equation. The 30

- minute AEGL

- 1 value was adopted as the 10

- 49CADMIUM PROPOSED : November 2009

8 minute value due to the added uncertainty of extrapolating from a 6

- hour time point to 10 1

minutes (NRC 2001). 2

3

The AEGL

- 2 values are based on the experimental concentration, 5.3 mg Cd/m 3 , that 4

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

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

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

interstitial thickening

. An interspecies uncertainty facto r of 3 was applied because at acute 8

exposures, cadmium is a direct

- acting respiratory irritant as indicated by the signs of irritation in 9

rabbits and rats. This mode of action is not expected to differ among species. Rabbits and rats 10

exposed for 2 hours to 0.25

- 4.5 mg/m 3 displayed similar histological and biochemical pulmonary 11

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

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

(0.00169

- 5.3 mg/m 3 ) from 1

- 6 hours (Buckley and Bassett 1987; Oberdörster et al. 1987 ; 14

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

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

is a direct

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

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

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

irritation. The concentration

- exposure time relationship for many irritant and systemically

20

acting vapors and gases may be described by C n x t = k, where the exponent, n, ranges fr om 0.8 21

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

of an empirically derived chemical

- specific scaling exponent, temporal scaling was performed 23

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

points using the C n x t = k equation. 25

26

The AEGL

- 3 values are based on the 2 hour LC 50 for cadmium fume in rats, 112 mg/m 3 27

(Rusch et al. 1986). The LC 50 was divided by 3 to estimate a threshold of lethality. An 28

interspecies uncertainty f actor of 3 was applied because at acute exposures, cadmium is a direct

29

acting respiratory irritant as indicated by the signs of irritation in rabbits and rats. This mode of 30

action is not expected to differ among species. Rabbits and rats exposed for 2 ho urs to 0.25

- 4.5 31

mg/m 3 displayed similar histological and biochemical pulmonary effects including pneumonitis, 32

increased lung weight, pulmonary inflammatory cell influx, and decreased glutathione 33

peroxidase activity (Grose et al. 1987). Rats exposed to cad mium (0.00169

- 5.3 mg/m 3 ) from 1

- 6 34

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

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

factor of 3 was applied because at acute exposures, cadmium is a direct

- acting respiratory irritant 37

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

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

e dema (Beton et al. 1966) which are signs of respiratory irritation. The concentration

- exposure 40

time relationship for many irritant and systemically

- acting vapors and gases may be described by 41

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

conservative and protective AEGL values in the absence of an empirically derived chemical

43

specific scaling exponent, temporal scaling was performed using n=3 when extrapolating to 44

shorter time points and n = 1 when extrapola ting to longer time points using the C n x t = k 45

equation. 46

47

The calculated values are listed in the table below. 48

49CADMIUM PROPOSED : November 2009

9 TABLE 1

. Summary of AEGL Values Cadmium

Classification 10

- min 30

- min 1

- hr 4

- hr 8

- hr Endpoint

(Reference)

AEGL

B 1

(N ondisabling) 0.13 mg/m 3 0.13 mg/m 3 0.10 mg/m 3 0.063 mg/m 3 0.041 mg/m 3 Respiratory irritation

, 0. 55 mg Cd/m 3 for 6

hr (Takenaka et al.

2004)

AEGL

B 2

(Disabling) 1.4 mg/m 3 0.96 mg/m 3 0.76 mg/m 3 0.40 mg/m 3 0.20 mg/m 3 Overt respiratory tract

irritation and

p athology, 5 .3 mg/m 3

CdO for 3 hr Buckley

and Bassett. 1987 )

AEGL

B 3

(Lethal) 8.5 mg/m 3 5.9 mg/m 3 4.7 mg/m 3 1.9 mg/m 3 0.93 mg/m 3 Threshold of lethality

based on the 2

- hr rat

LC 50 for Cd fumes

, 112 mg/m 3 (Rusch et

al. 1986)

1

References 2

3

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

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

6

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

ca ses with one death from renal necrosis. Brit. J. Industr. Med 23: 292

- 301. 8

9

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

233

- 250. 11

12

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

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

Health, 21:219

- 232. 15

16

Morrow, H. 2001. Cadmium and Cadmium Alloys. Kirk

- Othmer Encyclopedia of Chemical Technology, 4 th Ed., M. 17

Howe

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

19

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

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

22

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

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

754

- 763. 25

26

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

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

(suppl.1): 83

- 92. 29

30

31CADMIUM PROPOSED : November 2009

10 1

1. INTRODUCTION 2

3

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

used in the production of nickel

- cadmium batteries and in electroplating. It is also in pigments 5

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

demand for cadmium has decreased since the 1990s as lithium

- ion and nickel metal hydride 7

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

~19,000 tons /y ea r (Morrow 2001) . Es timated U.S. production of cadmium was about 1450 9

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

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

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

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

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

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

some are water soluble. 16

17

TABLE 2 . Chemical and Physical Properties

Parameter Value References

Synonyms Colloidal cadmium

Chemic al 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 ATS DR 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/ m 3

1 mg/m 3 = 0.22 ppm Calculated by reviewer using

1 ppm = mg/m 3 x 24.45/112.4

18

19CADMIUM PROPOSED : November 2009

11 TABLE 3 . Chemical and Physical Properties of Cadmium Compounds

Cd carbonate Cd chloride Cd oxide Cd sulfate Cd sulfide

Synonyms Carbonic acid,

ca dmium salt Dichlorocadmium Cadmium fume;

cadmium

monoxide Sulfuric acid,

cadmium salt Cadmium

yellow;

Cadmium orange

Chemical formula CdCO 3 CdCl 2 CdCO CdSO 4 CdS

Molecular wt. 172.42 183.32 128.41 208.47 144.47

CAS No. 513

- 78

- 0 10108

- 64

- 2 1306

- 19

- 0 101 24

- 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 In soluble 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/cm 3 @

4°C 3.3 g/cm 3 @ 20°C C rystals

8.15 g /cm 2 ;

amorphous

powder

6.95 g/cm 3 4.69 g/cm 3 Hexagonal

struc ture

4.82 g/cm 3 ;

C ubic structure

4.5 g/cm 3

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 N 2

@ 980 °C

Flammability limits

– – – – –

Conversi on factors 1 mg/m 3

=

0.14 ppm 1 mg/m 3

=

0.13 ppm 1 mg/m 3

=

0.19 ppm 1 mg/m 3

= 0.12 ppm 1 mg/m 3

=

0.17 ppm

Data from ATSDR, 2008 1

- N o data available 2

3

4

2. HUMAN TOXICITY DATA 5

2.1. Acute Lethality 6

2.1.1. Case Reports 7

8

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

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

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

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

man exposed to Cd fumes for approximately 60

- 75 minutes while flame

- cutting an alloy 13

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

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

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

He had multi

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

the lungs with beginning intra

- alveolar fibrosis. Concentrations of cadmium in tissues were 823 18

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

- 500 19

μg/m 3 usually result in “metal fume fever” that lasts for one to t wo days, so this patient was 20

almost certainly exposed to a much higher concentration. 21

22CADMIUM PROPOSED : November 2009

12 A man was exposed for ~5 hours to a brownish

- yellowish smoke during a copper 1

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

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

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

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

6

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

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

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

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

exposure with dyspnea developing 4

- 10 hours later. One man died on post

- exposure day 5; all 11

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

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

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

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

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

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

would have been about 8.6 mg/m 3 or 2,580 minute

- mg/m 3

. 18

19

2.2. Nonlethal Toxicity 20

2.2.1. Odor Threshold/Odor Awareness 21

22

Cadmium is odorless (HSDB 2005). 23

24

2.2. 2

. Epidemiologic Studies 25

26

Jakubowski et al. (2004) looked at long

- term occupationa l exposure and lung function of 27

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

factory (mean period of 17.4 ± 9.1 years). For comparison, 159 non

- exposed workers (48.4 ± 4.2 29

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

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

blood x time or cadmium levels in the air x time. The range of Cd

- B lood (μg/L) x time (years) 32

was < 25, 25

- 500, > 500

- 1000 or > 1000 and for Cd

- A ir (mg Cd/m 3 ) x time (years) was <0.01, 33

0.10

- 1.5, > 1.5

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

measuring the following: forced expiratory volume in one second (FEV 1 ), forced vital capacit y 35

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

(VC), inspiratory capacity (IC) and the percentage of the FEV 1 /FVC ratio. Statistically 37

significant decreases in FEV 1 (85% of predicted values, p=0.0208), PEF (76% of predicted 38

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

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

in the workers ex p osed to >1000 μg/L x years as measured by Cd

- b lood concentration compared 41

to controls. Workers in the group exposed to > 4 mg Cd

- air x time also had a significant decrease 42

in MEF 50% and slight decrease in the FEV 1 . The results indicate d that long

- term exposure 43

could cause some decrease i n lung funct ion suggestive of mild airway obstruction . Table 4 44

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

46CADMIUM PROPOSED : November 2009

13 TABLE 4 . Blood Cd Concentrations of Wo rkers and Air Cd Con cen trations

Parameter N Geometric mean ± GSD Range

1983

Cd x B (μg/L) 43 31.8 ± 2.14 9.11

- 166

Cd x A (mg/m 3 ) 0.08

– 0.51

1986

- 1988

Cd x B (μg/L) 91 29.1 ± 2.01 4.1

– 120.3

Cd x A (mg/m 3 ) 0.03

– 0.38

1998

- 1999

Cd x B (μg/L) 116 9.2 ± 2.14 0.5

– 42.1

Cd x A (mg/m 3 ) 0.03

– 0.032

Data from Jakubowski et al. (2004)

B= Blood; A= Air

1

2

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

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

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

levels (excluding outliers) ranged from 88 to 6276 μg/m 3 , equivalent to 0.088 to 6.276 mg/ m 3

. 6

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

8

2.3. Neurotoxicity 9

10

No data were located. 11

12

2.4. Developmental/Reproductive Toxicity 13

14

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

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

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

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

- itai 18

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

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

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

- partum 21

and informa ti on about occupational or environmental exposure to Cd, including smoking, was 22

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

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

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

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

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

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

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

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

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

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

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

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

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

exposure may increase the possibility of pre

- term births thus indirectly causing decreased birth 36

weight. 37CADMIUM PROPOSED : November 2009

14 1

2.5. Genotoxicity 2

3

Data are summarized from IARC 2003

. 4

5

Human female itai

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

incidences of chromosomal aberrations of all types in peripheral blood lymphocytes than age

7

matched control subjects (n=9). Howeve r, there were no difference s in the frequencies of cells 8

with structural aberrations in cultures from blood of four female itai

- itai patients compared to 9

four control subjects. 10

11

No differences in chromosomal aberrations of lymphocytes were observed betwe en five 12

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

employed for 5

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

estimated to be 0.70 mg/m 3 . Blood cadmium concentration in the batte ry workers was 37.7 ng/g 15

and 2.3 ng/g in the office workers. 16

17

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

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

administrative and laboratory personnel at the same plant. 20

21

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

exposed to cadmium dusts for 6

- 25 years when compared to the office worker controls. 23

24

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

workers when compared to non

- smelter control subjects. It was not determined if smoking 26

habits were included as a source of cadmium exposure. 27

28

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

male workers exposed to cadmium fumes and dusts compared to the age

- matched controls. 30

31

Cadmium chloride induced sister chromatid exchange in human lymphocytes in vitro

. 32

33

2.6. Carcinogenicity 34

35

Sorahan and Esmen (200 4 ) reported on a c ohort study occurring from 1947

- 2000 36

involving 926 males that worked at a Cd

- nickel battery factory. The aim was to investigate 37

mortality of the workers in r el ation to cumulative cadmium hydroxide exposure. All those 38

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

Work histories were available from 1947

- 1986 and the factory closed in 1992. Two approaches 40

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

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

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

p<0.05), non

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

0.05), and non

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

243, p< 0.05). Non

- significantly increased SMRs were observed for lung cancer (observed 45, 46

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

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

15 but that it does lead to increase in non

- malignant diseases of the respiratory and genitourinary 1

systems and pharyngeal cance rs. 2

3

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

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

(Thun et al., 1985). Workers were followed until 1978. Cause

- specific mort ality rates for seven 6

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

inhalation exposure concentrations measured in the plant ranged from 0.007 to 1.5 mg/m 3 from 8

pre

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

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

was analyzed with the use of the modified life

- table system developed by NIOSH. Of all the 11

workers, 83% had over 20 years of follow

- up. For respiratory cancer, the expected rate was 12

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

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

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

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

Nine deaths were from non

- malignant gastrointestinal disease (NMGID) a nd the expected 17

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

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

an increase in the respiratory cancers. 20

21

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

workers exposed to Cd for more than 5 years. Data were collected from 269 Cd

- Ni battery 23

factory workers and 94 Cd

- Cu alloy factory workers. At the Cd

- Ni factory, the levels of Cd in 24

the air were: before 1947: >1 mg Cd/ m 3 ; in the 1950’s: 200 μg Cd/ m 3 ; between 1962

- 1974: 50 25

μg Cd/ m 3 ; and 1979: < 5 μg Cd/ m 3 . In this same factory, similar levels of nickel hydroxide were 26

found in the air. In the Cd

- Cu factory, cadmium concentrations w ere not obtained until the 27

1960s, when the levels were 100

- 400 μg Cd/ m 3 ; since the 1970s, the value has been about 50 μg 28

Cd/ m 3 . An internal reference group from the Cd

- Cu factory was used; workers that were 29

involved in processes not exposing them to any C d. A life

- table method with the national 30

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

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

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

higher than 1 , the expected value

. However, part of this increase could be attributed to the nickel 34

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

tendency for mortality from prostate cancer (4 cases) in the Cd

- Cu alloy workers; however, the 36

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

38

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

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

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

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

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

44

The International Agency for Research on Cancer (IARC 200 3) concluded that there is 45

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

categorize d cadmium and cadmium compounds as being carcinogenic to humans. 47

48CADMIUM PROPOSED : November 2009

1 6 2.7. Summary 1

2

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

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

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

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

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

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

in the workplace. Respiratory cancers were increased in workers at a Cd

- nickel battery factory; 9

although , chronic Cd exposure was not statistic ally correla ted with lung cancer. The U.S. EPA 10

(1994) and IARC ( 200 3) list cadmium and cadmium compounds as being carcinogenic to 11

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

lower weight at birth. 13

14

3. ANIMA L TOXICITY DATA 15

3.1. Acute Lethality 16

3.1. 1

. Rat 17

18

Male Crl: CD(SD)Br rats, 24 /group

, were exposed by nose

- only inhalation to 0, 0.25, 0.45 19

or 4.5 mg/m 3 of both CdCl 2 an d CdO for 2 hours (Grose et al. 1987). The exposure 20

concentrations were given as mg Cd/m 3

. Animals were killed immediately or 72 hours post

21

exposure. The following parameters were determined: Cd content in the lungs, lung weight, body 22

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

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

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

mg/m 3 CdO group died; one rat had cardiovascular failure associated with pul monary congestion 26

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

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

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

deaths were reported in rats of the high

- dose group. 30

31

Twenty six adult Sprague

- Dawley CD rats/sex/group were exposed for 2 hour s to 97 32

mg/m 3 of cadmium red pigment, 99 mg/m 3 cadmium yellow pigment

, 132 mg/m 3 cadmium 33

c arbonate

, or 112 mg/m 3 cadmium f ume (Rusch et al. 1986). The exposure concentrations are 34

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

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

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

- mesh sieve 37

and hand

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

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

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

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

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

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

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

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

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

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

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

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

the LC 50 for cadmium fume was 112 mg/m 3

. 2

3

3.2. Nonlethal To xicity 4

3.2.1. Rabbit 5

6

A maximum of eight male DLA:New Zealand White rabbits (~30 days old) were exposed 7

by nose

- only inhalation to 0 (controls), 0.25, 0.45 or 4.5 mg/m 3 of both CdCl 2 an d CdO for 2 8

hours (Grose et al. 1987). The exposure concentrations wer e given as mg Cd/m 3

. Animals were 9

killed immediately or 72 hours post

- exposure. The following parameters were determined: Cd 10

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

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

Rabbits exposed to 0. 45 mg/m 3 CdO had a greater number of alveolar macrophages pres ent 13

when compared to controls and those exposed to CdCl 2 . At 4.5 mg/m 3

, the lungs of rabbits had 14

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

with the presence of fibrocytic

- type cells as well as pneumocytes. Rabbits exposed 4.5 mg/m 3 of 16

either chemical had increased lung weight and lung

- to

- body weight ratios

. In the r abbit, Cd Cl 2 17

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

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

activity of GSH transferase was increased after treatment wi th 0.45 mg/m 3 CdCl 2 . The authors 20

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

protect cells against lipid peroxidation. 22

23

3.2.2. Rat 24

25

Twenty

- four female Fischer 344 rats were exposed for 6 hours to ultrafi ne particles of 26

CdO at a concentration of 70 μg Cd/m 3 in whole

- body chambers (330 L volume; ventilation 27

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

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

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

were exposed to 550 μg Cd/m 3 in a similar manner . The MMAD was 51 nm and the GSD was 31

1.7. When converted, 70 μg Cd/m 3 is equiv alent to 0.07 mg/m 3 and 550 μg Cd/m 3 is equivalent 32

to 0.550 mg/m 3

. Eight rats were sacrificed on day 0 for lung lavage and four rats were sacrificed 33

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

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

exposed to 0.07 mg/m 3 was 19% of the total inhaled dose and this remained the same at the other 36

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

sacrificed 7 days after exposure. The lung lavage indicated no exposure

- related morphological 38

changes in the lungs or inflammatory responses in the low

- dose rats. In rats exposed to the 39

higher concentration, 0.550 mg/m 3 , Cd content was s imilar in the lungs on day 0 and 1 but was 40

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

blood Cd. L ung l avage of the rats in the high

- dose group showed increased neutrophils, and 42

multifocal alveolar infla mmation was observed histologically. 43

44

Four groups of ten male Long Evans rats were exposed to CdO dust (0.00195 mg/m 3 ), 45

CdO fume (0.00169 mg/m 3 ), CdS (0.00180 mg/m 3 ) or sham

- exposed in a nose

- only inhalation 46

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

mg Cd/m 3 , therefore, the concentration of Cd in this study is unknown. The CdO dust was ball

48

milled for 24 hours and had a mass median aerodynamic diameter (MMAD) of 0.51 μm. The 49CADMIUM PROPOSED : November 2009

18 CdO fume was generated by a n electric arc burning off metallic Cd electrodes, producing 1

particles of 0.4 μm. P ure CdS with a MMAD of 0.45 μm was used. Twenty

- four hours post

2

exposure, the animals were sacrificed

, and the lungs were lavaged

, and the cellular components 3

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

measuring the activity of 99m Tc

- DTPA in the lung lavage fluid; this substance was injected 5

intravenously 10 minute s prior to sacrifice. A n increase in activity in the lung lavage f luid 6

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

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

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

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

Inhalation exposure to CdS resulted in no differences in rats compared to tho s e in the sham

11

exposed group. The study report provided very little detail but did help t o show that water 12

solubility does not always correlate with increased toxicity. 13

14

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

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

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

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

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

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

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

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

the low and high dose concentrations. Body weight of rats exposed to 0 or 0.5 mg/m 3 increased 23

from exposure through the end of the observation period, however, rats exposed to 5.3 mg/m 3 d id 24

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

post exposure. At 0.5 mg/m 3 , foci of petechial hemorrhage were occasionally observed 2 and 4 26

days post exposure and were consistently observ ed at 5.3 mg/m 3

. Mild hypercellularity at 27

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

cells were observed at 0.5 mg/m 3 prior to day 7 post exposure. Morphology of the lungs was 29

normal in rats exposed to 0.5 mg/m 3 7 days post exposure. Focal areas of in terstitial thickening, 30

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

cells, alveolar macrophages, eosinophils, and basophils) were observed at 5.3 mg/m 3 in the 32

bronchoalveolar j unctions and peripheral alveoli. Lung weight (dry) and protein content of the 33

lungs were significantly increased in rats exposed to 5.3 mg/m 3 compared to those of control on 34

study days 2

- 15 post exposure , and DNA content was increased days 4

- 15

. Glutathi one 35

peroxidase, glutathione reductase, glucose

- 6

- phosphate dehydrogenase, and 6

- phosphogluconate 36

dehydrogenase activity were significantly increased in rats exposed to 5.3 mg/m 3 compared to 37

the activity levels in control rats. 38

39

M ale Crl: CD(SD)Br rats, 24 /group

, were exposed by nose

- only inhalation to 0 , 0.25, 0.45 40

or 4.5 mg/m 3 of both CdCl 2 an d CdO for 2 hours (Grose et al. 1987). The exposure 41

concentrations were given as mg Cd/m 3

. Animals were killed immediately or 72 hours post

42

exposure. The f ollowing parameters were determined: Cd content in the lungs, lung weight, body 43

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

measured and found to be consistent in the chambers. Three rats exposed to cadmium died 45

during the study; only one rat ( 0.45 mg/m 3 CdO group) had cardiovascular failure associated 46

w ith pulmonary congestion and both others had unknown cause s of death. No effects were 47

observed in the lungs at 0 and 72 hours in rats in the 0.45 mg/m 3 grou p. G roups of rats exposed 48

to wither 4.5 mg/m 3 CdCl 2 or CdO had no lesions observed immediately after exposure

, but at 72 49CADMIUM PROPOSED : November 2009

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

the CdO group . It was characterized by the presence of fibrocytic

- type cells , alveoli edema, 2

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

exposed to CdCl 2 presented as thickening of the alveolar walls, edema, hemorrhage, and 4

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

the lungs in animals exposed to 0. 25 or 0. 45 mg/m 3 CdCl 2 or CdO at either 0 or 72 hours . While 6

there was an increase in Cd deposition in the lungs of the rats exposed to 4.5 mg/ m 3 , at 72 hours 7

there was significantly less Cd in the lungs of rats exposed to 4.5 mg/m 3 CdCl 2 than in those 8

exposed to 1 ppm CdO. Rats exposed to 0.25 mg/m 3 CdCl 2 had a 13% decrease in lung

- to

- body 9

weight ratio. Rats exposed to 0.45 mg/m 3 group CdCl 2 ha d a decrease in body weight and at 4.5 10

mg/m 3 a 20% decrease in body weight and increased lung and lung

- to

- body weight ratio 72 11

hours after exposure. In the 0.45 or 4.5 mg/m 3 CdO exposed rats, there was an increase in lung 12

weight but no effect on body weigh t. Cadmium (CdCl 2 ) had an inhibitory effect (27%) on 13

pulmonary GSH peroxidase activity at the lowest concentration and at 0.45 mg/m 3 . Cadmium 14

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

16

Twenty six adult Sprague

- Dawley CD rats/sex/g roup were exposed in a single 2

- hour 17

exposure to 97 mg/m 3 of cadmium red pigment, 99 mg/m 3 cadmium yellow pigment

, 132 mg/m 3 18

cadmium carbonate

, or 112 mg/m 3 cadmium f ume (Rusch et al. 1986). The exposure 19

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

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

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

through a 60

- mesh sieve and hand

- packed into a Wright dust feed mechanism. Dry air was 23

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

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

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

metered solution and dry air through a nebulizer. 27

28

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

during the exposure. Following exposure, excessi ve lacrimation w as obse rved in rats exposed to 30

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

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

lacrimation

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

controls

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

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

observed in the rats in the Cd red pigment group. P ulmonary edema

, observed as increased lung 36

weight was seen in the Cd carbonate exposed group starting at 24 hours post

- exposure. 37

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

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

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

were collected at 0

- 24 hrs, 24

- 48 hrs, 48

- 72 hrs, 6

- 7 days and 29

- 30 days post

- treatment. 41

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

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

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

in all but the Cd fume

- exposed animals and these were not collected due to the moribund 45

condition of the animals. The Cd carbonate

- exposed animals had the greatest amount of 46

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

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

49CADMIUM PROPOSED : November 2009

20 TABLE 5

. Summary of Acute Inhalation Data in Laboratory Animals

Species Concentration

( mg Cd / m 3 ) Exposure

Time Effect Reference

Rabbit CdCl 2

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 Taken aka et

al. 2004

Rat 0.00195 Cd dust

0.00169 Cd fume

0.00180 CdS 1 hr ↓ Alveolar macrophages; ↑PMNs; ↑epithelial

permeability

↓ Alveolar macrophages; ↑PM Ns

No effect Oberdörster

et al. 1987

Rat CdO

0.5

5.3 3 hr

Transient m ild hypercellularity at bron choalveolar

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 Cd Cl 2

0.25

0.45

4.5 2 hr

↓ Pulmonary GSH peroxidase activity 27%

↓ bw; ↓pulmonary GSH peroxidase activity

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

p eroxidase activity; pneumonitis Grose et al.

1987

Rat CdO

0.25

0.45

4.5 2 hr

No effects

↑ Lung weight; ↓ pu lmonary 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

Lacrimatio n

Dry rales, body tremors ; 5.8% mortality

Hypoactivity; closed eyes; lacrimation; dry rales; ↓

bw; ↑ lung discoloration and stomach erosion ;

48% mortality; LC 50 Rusch et al.

1986

1

2

3.3

. Developmental/Reproductive Toxicity 3

4

Four female Hartley guinea pigs/ group were exposed in late gestation ( days 50

- 55) to 0 5

or 0.05 mg/m 3 cadmium chloride for 4 hours/day for 1 or 5 consecutive days by nose

- only 6

inhalation (Trottier et al. 2002). Cadmium aerosol was generated in a nebulizer using a solution 7CADMIUM PROPOSED : November 2009

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

air/min and the concentration of Cd in the chamber was monitored by obtaining air samples 2

through filters during the exposure. The mean Cd concentration was 53.2 ± 4.6 μg/m 3 and the 3

MMAD was 0.3μm. Twenty

- four hours after the last exposure, females were euthanized and the 4

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

spectrophotometry and placental metallothionein and cadmium content were a lso determined. 6

7

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

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

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

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

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

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

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

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

the 5

- day exposure. 16

17

Thirty two p regnant Sprague

- Dawley female rats and thirty

- three pregnant Swiss (CD

- 1) 18

mice were exposed to 0, 0.05, 0.5 or 2 mg/m 3 cadmium oxide by whole

- body inhalation for 6 19

hours/day, 7 days/week on gestation days (GD) 4

- 19 in th e ra ts and GD 4

- 17 in mice (NTP 20

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

exposed to 2 mg/m 3 died on GD 17. Clinical signs observed in rats were dyspnea in all those 22

exposed and hypoactivity at 2 mg/m 3 , i n females. The female rats exposed to 2 mg/m 3 had 23

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

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

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

observed at 2 mg/m 3 in rats, and included a decrease in the weight of live fetuses. This 27

concentration also caused significant increase s in the mean percent of fetuses per litter wit h 28

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

Dyspnea and hypoactivity were observed in mice exposed to concentrations ≥ 0.5 mg/m 3 30

cadmium oxide. At ≥ 0.5 mg/m 3 , t he number of pregnant mice was signi ficantly decreased

. Fetal 31

body weigh t following exposure to 0.5 mg/m 3 was significantly less than control fetal body 32

weight. Five mice in the 2 mg/m 3 group were euthanized moribund before the end of the study. 33

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

weight were significantly lower compared to control values, and relative kidney weight was 35

significantly increased compared to control kidney weight in female mice exposed to 2 mg/m 3

. 36

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

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

mg/m 3 group. 39

40

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

or 2.0 mg CdCl 2 /m 3 for 6 hours/day, 5 days/week for 62 exposures (Kutzman et al. 1986). 42

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

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

cytogenetic endpoints. Rats were exposed in a 1.4 m 3 stainless steel and Lucite chamber. 45

Airflow was equivalent to 15 chamber volumes/hr. Laskin

- type nebulizers were used to generate 46

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

aerosolized particles. RAM

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

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

mg Cd Cl 2 /m 3 in the 0.3, 1.0 and 2.0 mg/m 3 chambers, respectively. 2

3

All rats exposed to 2.0 mg/m 3 lost weight rapidly and died within the first 45 days and 4

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

females averaged a higher survival (40 days; n= 10) compared to the males (32 days; n= 57). At 6

1.0 mg/m 3 , five males died and all animals at 0.3 mg/m 3 survived. Some exposed males and 7

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

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

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

- implantation 10

losses. At necropsy, there was a dose

- dependent increas e in organ

- to

- body w eight ratio for the 11

lungs, heart, spleen, kidneys, and testis. Also, the liver and brain weight

- to

- body ratio was 12

increased in the high

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

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

both the low

- and mid

- dose rats. Areas of fibrosis were also observed in the mid

- dose rats. 15

Similar lesions were identified in those that died in the high

- dose group. Based on the 16

histopathological findings, the LOAEL was 0.3 mg/m 3 CdCl 2 and the NOAEL could not be 17

determined. 18

19

3.4

. Genotoxicity 20

21

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

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

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

25

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

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

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

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

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

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

32

3.5

. Repeated Dose 33

3.5.1. Rat 34

35

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

(99.4% purity; mass median aerodynamic diameter ( MMAD ) = 1.1

- 1.6 μgm) for 6 hours/day, 5 37

days/w ee k for 2 weeks (n = 5/sex/group) or 13 weeks (n= 10/sex/group) (NTP 1995). Animals 38

were exposed to 0, 0.1, 0.3, 1, 3 or 10 mg/m 3 for the 2 week studies and 0, 0.025, 0.05, 0.1, 0.25 39

or 1 mg/m 3 for 13 weeks. Animals were exposed in whole

- body chambers that had a total 40

volume of 2.3 m 3 . Chemical concentration, airflow, temperature and relative humidity were 41

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

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

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

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

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

performed. 47

48CADMIUM PROPOSED : November 2009

23 In the rats exposed for 2 weeks, all those exposed to 10 mg/m 3 died by day 6; no other 1

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

discha rge were observed in ra ts at concentrations ≥ 1 mg/m 3 . Lesions in the lungs including 3

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

rats with a dose

- dependent increase in severity. Effects on the nasal and respiratory epith elium 5

were observed in those exposed to 1 mg/m 3 and greater. Based on the findings, the doses were 6

set for the 13 week study. For the two

- week study, a LOAEL of 0.1 mg/m 3 Cd oxide in rats was 7

established based on histopathological findings; a NOAEL could n ot be determined. 8

9

TABLE 6

. H istopathological Findings in rats Exposed for 2 wks to Cadmium Oxide

(# Affected/Total # examined)

0 mg/m 3 0. 1 mg/m 3 0. 3 mg/m 3 1 mg/m 3 3 mg/m 3 10 mg/m 3

MALES

Lung

A lveolar infiltrate

Focal inflam m/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 me taplasia

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

Infl ammation 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)

Dat a from NTP ( 1995 )

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

10

11

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

increased in frequency as the concentration increased. Rats a t 1 mg/m 3 consistently had lower 13

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

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

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

≥ 0.05 mg/m 3 , compared to controls including relative kidney weight, and relative and absolute 17

lung weight; however, there were no treatment

- related microscopic findings in the kidney or 18

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

treatment. Grossly, the only treatment

- related finding was enlargement and paleness of the 20

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

in all treated animals except those in the 0.025 mg/m 3 group. The lesions were similar to those 22

identified in the 2 week study. Based on the histopathological findings, the LOAEL for rats 23

treated for 13 weeks 0.05 mg/m 3 cadmium and the NOAEL was 0. 025 mg/m 3

. 24

25CADMIUM PROPOSED : November 2009

24 1

TABLE 7

. Histopathological F indings in R ats E xposed for 13 wks to C admium O xide

(# Affected/Total # examined)

0

mg/m 3 0.025

mg/m 3 0.05 mg/m 3 0.1 mg/m 3 0.25

mg/m 3 1 mg/m 3

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

D egeneration 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

I nflammation 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= mil d, 3= moderate and 4= marked

2

3

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

weight of 250 g were exposed nose

- only 6 hours/day for up to 10 days to 0 (air control), 5

0.3 mg/m 3 CdCl 2 or 0.2, 1.0 or 8.0 mg/ m 3 CdS (Klimisch 1993). Four animals from each group 6

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

rats to soluble ( CdCl 2 ) and insoluble (CdS) forms of Cd. Measurements of lung, renal and fecal 8

Cd were obtained. Cadm ium c hloride was generated as an aerosol by taking an aqueous solution 9

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

Cadmium sulfide was generated as a dust using a rotating brush

- type generator and passing the 11

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

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

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

15

No adverse clinical signs or mortalities occurred during the study or post

- exposure 16

period. Pooled data from days 0

- 10 showed a statistically significant increase in mean lung 17

weight and lung to body weight ratio in the CdCl 2

- exposed rats. Rats exposed to 8.0 mg/m 3 CdS 18

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

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

exposed to CdCl 2

. Cadmium in feces was observe d mostly during the exposure and for a few 21

days post

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

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

Cd lung content in the Cd Cl 2

- exposed rats was about two times higher than the CdS exposed 24

rats. This could have been caused by either the greater availability of the CdCl 2 aerosol 25CADMIUM PROPOSED : November 2009

25 compared to the CdS dust or the fact that CdCl 2 is held in the lung longer. Overall the study 1

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

exposure. 3

4

Three month old female Wistar rats (n= 13

- 14) were exposed by inhalation to CdO for 5 5

hours/day, 5 days/week for 20 weeks at concentrations of 0.02, 0.16 or 1 mg /m 3 (Barański and 6

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

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

SM11306. Fractions of aerosols with particle sizes below 4 .7 μm were determined with the 9

Anderson Impactor 2000. Mortality occurred at 1 mg/ m 3 , although histopathology and gross 10

findings were not described in the report. At 1 mg/ m 3

, mortality was 15% at the end of 7

- 8 11

weeks, 38% at the end of 13

- 14 weeks and 10 0% at the end of the study. This was compared to 12

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

0.05) in body weight gain was observed in the rats exposed to 1 mg/ m 3 throughout the study; at 14

0.16 mg/ m 3 , expos ed rats had a decrease in body weight gain compared to controls, but it was 15

not significant. All treated rats showed an increase in the length of estrous during treatment when 16

compared to pre

- treatment, but at 0.02 and 0.16 mg/ m 3

, rats showed this change o nly at the end 17

of the study (weeks 19

- 20). At 1.0 mg/ m 3 , exposed rats had an increase in estrous length during 18

the entire study. Based on the increased estrous length, the LOAEL was 0.02 mg/m 3 CdO and the 19

NOAEL could not be determined. 20

21

Twelve adult femal e Wistar rats/group were exposed continuously to 0, 25 or 50 μg Cd/m 3 22

for 90 days and to 100 μg Cd/m 3 for 63 days (Prigge 1978), equivalent to 0, 0.025, 0.052 and 23

0.105 mg/ m 3 administered as CdO. The rats were removed from the chamber for only 10

- 20 24

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

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

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

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

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

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

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

significant dose

- dependent decrease (p<0.05) in body weight was observed in the rats exposed 32

to 0.052 and 0.105 mg/m 3 , and 5/12 died at 0.105 mg/m 3 between days 45 and 60. A significant 33

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

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

alkaline ph osphatase activity. A significant (p<0.05) decrease in the p artial pressure of O 2 and an 36

increase in the p artial pressure of C O 2 were observed in the rats exposed to 0.105 mg/m 3

. 37

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

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

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

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

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

histiocytic cell granulomas in the lungs in the treated animals. Based on the histopathological 43

findings, the inhalation LOAEL for cadmium by inhalation in rats was 25 μg/m 3 Cd (0.025 44

mg/ m 3 ) and the NOAEL was not established. 45

46CADMIUM PROPOSED : November 2009

26 3.5.2. Mouse 1

2

Male and female B6C3F 1 mice (6 wks old) were exposed to cadmium oxide aerosol (99.4% 3

purity; MMAD = 1.1

- 1.6 μgm) for 6 hours/day, 5 days/w ee k for 2 weeks (n = 5/sex/group) or 13 4

weeks (n= 10/sex/group) (NTP 1995). Animals were exposed to 0, 0.1, 0.3, 1, 3 or 10 mg/m 3 for 5

the 2 week studies and 0, 0.025, 0.05, 0.1, 0.25 or 1 mg/m 3 for 13 weeks. Animals were exposed 6

in whole

- body chambers that had a total volume of 2.3 m 3 . Chemical concentration, airflow, 7

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

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

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

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

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

clinical chemistry parameters, urine collected and histopathology performed. 13

14

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

week study, all mice in the 10 mg/m 3 group died and death was due to severe respirat ory 16

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

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

increased at concentrations ≥ 0.3 mg/m 3 . Alveolar macrophage infiltration, fibrosis, focal 19

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

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

the 2 week study, a NOAEL could not be established and the LOAEL for mice was 0.1 mg/m 3 22

cadmium based on microscopic lung lesions. 23

24

TABLE 8

. Histopat hological Findings in Mice Exposed for 2 wks to Cadmium Oxide

# Affected/Total # examined

0 mg/m 3 0.1 mg/m 3 0.3 mg/m 3 1 mg/m 3 3 mg/m 3 10 mg/m 3

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= markedCADMIUM PROPOSED : November 2009

27 1

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

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

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

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

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

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

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

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

0.025 mg/m 3 cadmium based on microscopic lung lesions. 10

11

TABLE 9

. Histopathological Findings in Mice Exposed for 13 wks to Cadmium Oxide

(# Affected/ Total # examined)

0

mg/m 3 0.025 mg/m 3 0.05 mg/m 3 0.1 mg/m 3 0.25 mg/m 3 1 mg/m 3

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) 1 0/10 (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)

Nos e

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= markedCADMIUM PROPOSED : November 2009

28 The repeat dose studies are summarized in Table 10. 1

2

TABLE 10

. Summary of Repeat Dose Inhalation Data in Laboratory Animals

Species Concentration

(mg/m 3 ) 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 : H ypoactivity, dehydration, dyspnea, nasal

discharge , olfactory epithelium degenerati on,

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 ep ithelium 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 CdCl 2 : ↑ 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% mort ality at 7

- 8 wk, 38% mortality at 13

- 14

wk, ↓ body weight Barański and

Sitarek 1987

Rat mg Cd/m 3

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, ↓ pO 2 , ↑pCO 2 , ↑ 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 hype rplasia

≥ 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 aeroso l

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: Re spiratory epithelium hyaline droplets NTP 1995

3

4CADMIUM PROPOSED : November 2009

29 3. 6

. Chronic Toxicity/Carcinogenicity 1

2

As a follow

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

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

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

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

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

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

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

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

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

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

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

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

15CADMIUM PROPOSED : November 2009

30 1

TABLE 11

. Observations after Inhalation Expos ures of Rats to Various Cd Compounds

# Affected/Total # examined

Group

No. Compound Concentration

(mg/m 3 ) Duration (mon th ) Lung Primary lung tumors a

Exposure Study Nodules

(n/n) A B C D

n/n

Males

1 Control

– – 31 0/20 0 0 0 0

0/20

3 CdCl 2 0.03 18 30 b 18/20 2 12 0 1

15/20

5 CdCL 2 0.09 6 30 b 12/20 3 5 3 0

11/20

7 CdSO 4 0.09 14 b 31 10/20 2 7 0 2

11/20

9 CdS 0.09 18 30 b 16/20 4 9 2 2

17/20

11 CdS 0.27 16 b 30 b 11/19 1 8 2 3

14/19

13 CdS 0.81 7 b 30 b 7/20 2 5 2 2

11/20

15 CdS 2.43 4 b 30 b 6/16 1 2 1 3

7/16

17 CdS 0.27 6 27 b 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 7 b 31 b 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 29 b 13/18 5 7 0 1

13/18

26 CdO dust 0.01 18 29 b 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 CdCl 2 0.03 18 31 15/20 4 7 0 2

13/18CADMIUM PROPOSED : November 2009

31 TABLE 11

. Observations after Inhalation Expos ures of Rats to Various Cd Compounds

# Affected/Total # examined

Group

No. Compound Concentration

(mg/m 3 ) Duration (mon th ) Lung Primary lung tumors a

Exposure Study Nodules

(n/n) A B C D

n/n

6 Cd Cl 2 0.09 6 29 b 6/18 0 1 2 0

3/18

8 CdSO 4 0.09 18 29 b 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 16 b 30 b 17/19 1 8 2 5

16/19

14 CdS 0.81 10 b 29 b 11/20 3 5 1 4

13/20

16 CdS 2.43 3 b 31 9/19 3 3 0 0

6/19

18 CdS 0.27 6 29 b 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 11 b 3 b 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 stopp ed after 25% and 75% morality, respectively

. 1

2

Forty male inbred Wistar rats/group (6 weeks old) were exposed to CdCl 2 aerosol at 3

concentrations of 0 (n=41), 12.5, 25 or 50 μg/m 3 for 23 hrs/day, 7 days/week for 18 months 4

(Takenaka et al. 1983). After expo sure, animals were kept for another 13 months under normal 5

laboratory conditions. Equivalent concentrations were 0.0125, 0.025 or 0.050 mg/m 3

, 6

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

by atomizing a sol ution of CdCl 2 with an ultrasonic atomizer. Air flow through the atomizer was 8

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

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

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

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

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

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

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

kidneys. 2

3

During and after the exposure, there was n o difference in body weight between the 4

control and treated rats. Mean survival time at 0.050 mg/m 3 was slightly below that of the others 5

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

concentration in the lungs was hi gher in treated rats, 5.6 μg/g in the low

- dose group, 4.7 μg/g in 7

the mid

- dose group and 10.4 μg/g in the high

- dose group. Similar values were found in the liver, 8

and the kidney values were 0.3, 13.5, 16.4 and 33.6 μg/g Cd in the control, low

- , mid

- and hi gh

9

dose group s , respectively. After the 13 month waiting period, the study reported that 0/38 in the 10

control group; 6/39 (15.4%) at 0.0125 mg/m 3 , 20/38 (52.6%) at 0.025 mg/m 3 , and 25/35 (71.4%) 11

at 0.050 mg/m 3 had primary lung carcinomas. These tumors were identified as adenocarcinomas, 12

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

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

lacked a dose response or did not appear to be treatment

- related. Limited data were provided on 15

all other histopathological findings. 16

17

3. 7

. Summary 18

19

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

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

f or 1

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

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

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

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

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

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

Cd and fetal body weight was decreased. 28

29

4. SPECIAL CONSIDERATION S 30

4.1. Metabolism and Disposition 31

32

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

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

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

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

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

low, only about 3

- 8%, and dependent upon several blood and dietary factors. In contrast, 30

- 64% 38

of inhaled cadmium can be absorbed (Morro w, 200 1). For the non

- smoker , 95% of the total 39

cadmium intake comes from ingesti on of terrestrial foods or meat from animal s that ate plants 40

grown in cadmium

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

Based on a 50% absorp tion rate, a person smoking one pack a day will absorb about 1

- 3 μg 42

cadmium (Wittman and Hu 2002). 43

44

Järup et al. (1983) determined the half

- life of cadmium in the blood of workers after 45

exposure had ended. Five men were exposed to cadmium for 4

- 7 years an d then followed up to 46

13 years after cessation of exposure. The estimated total inhaled amounts of cadmium during 47

their exposures ranged from 399 to 865 mg x hr/m 3 . Two of the five men had developed renal 48

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

33 half

- life of cadmium in the blood being 75

- 128 days in the first compartment and 7.4 to 16.0 1

years in the second. 2

3

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

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

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

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

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

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

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

stored in the kidney and biological half

- lives are on the order of 10

- 30 years (Wittman and 11

Hu 2002). 12

13

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

low and as stated above, the half

- life in humans can be 10

- 30 years (U.S. EPA 1986; Wittman 15

and Hu 2002 ). 16

17

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

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

48, 1 68, and 336 hours after instillation. At approximately 6 hours post instillation, 50% 20

instilled 109 CdO was no longer present in the lungs and 70% of that which had left the lungs was 21

found in the liver. At 24 hours, 80% instilled 109 CdO had left the lung . At the end of the 2 week 22

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

was distributed to the kidney over 2 weeks

, and the cumulative total eliminated in the urine and 24

feces w as less than 10% of total body burden. 25

26

4.2. Mechanism of Toxicity 27

28

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

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

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

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

glycosuria. Cadmium

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

quantifie d by measurement of low molecular weight proteins such as β 2

- microglobulin, retinol 34

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

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

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

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

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

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

41

4.3. Structure Activity Relationships 42

43

No data were located. 44

45CADMIUM PROPOSED : November 2009

34 4.4. Other Relevant Information 1

4.4.1. Species Variability 2

3

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

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

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

7

In a 4

- week study, male Fisher 344 rats and Balb

- c mice (number of anima ls not 8

specified) were exposed to CdCl 2 aerosols at a concentration of 0 or 100 μg Cd/m 3 for 6 9

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

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

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

carcinogenicity observed in long

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

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

28 day post

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

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

28

- days. Histochemical staini ng showed that the epithelial cells of mice in the conducting 17

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

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

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

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

22

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

McKenna et al. (1997) exposed forty

- three 15

- week old male Wistar Furth rats, and sixty 17

- 24

week old mice/strain (C57 and DBA) to 1.0 mg/m 3 (0.22 ppm) of CdO fumes for 3 hours by 25

nose

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

sacrificed at 0, 1, 3 or 5 days post

- exposure and control animals at one time point only. Overall, 27

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

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

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

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

in lung and higher levels of biochemical indices of injury in BAL F

, and r ats responded to Cd 32

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

lesions in the lung than mice

. 34

35

4.4.2. Susceptible Populations 36

37

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

effects, therefore, those with lung

- associated diseases or conditions (such as asthma and COPD) 39

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

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

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

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

little is transferred through the placenta or breast milk (Schoeters et al., 2006). Those with pre

44

existing renal and/or hepatic conditions would be more at risk in chronic exposures. Smokers 45

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

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

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

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

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

those in non

- industrialized areas (ATSDR 2008). 2

3

4.4.3. Concentration

- Exposure Durat ion Relationship 4

5

The concentration

- exposure time relationship for many irritant and systemically

- acting 6

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

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

empirically derived chemical

- specific scaling exponent, temporal scaling was performed using 9

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

using the C n x t = k equ ation. 11

12

4.4.4. Concurrent Exposure Issues 13

14

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

Smokers inhale cadmium along with other chemicals and compounds. 16

17

5. DATA ANALYSIS FOR AEGL

- 1 18

5.1. Summary of Human Data R elevant to AEGL

- 1 19

20

No data were located. 21

22

5.2. Summary of Animal Data Relevant to AEGL

- 1 23

24

Female Fischer 344 rats exposed (whole body) to 0.07 mg/m 3 Cd for 6 hours showed no 25

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

and rats exposed (nose

- only) to 0.25 mg/m 3 CdCl 2 or CdO for 2 hours had inhibited pulmonary 27

GSH peroxidase activity (Grose et al. 1987). Ra bbi ts and rats exposed (nose

- only) to 0.45 28

mg/m 3 CdCl 2 or CdO for 2 hours had in creased inflammatory res ponse (Grose et al. 1987). 29

Deaths were observed in rats exposed to 0.45 mg/m 3 but no deaths were observed in rats exposed 30

to 4.5 mg/m 3 , and those deaths may be associated with the exposure apparatus. The mortality 31

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

exposure to 0.5 mg/m 3 CdO for 3 h ou r s , rats had increa sed inflammatory cell influx and transient 33

hypercellularity , but no mortality (Buckley and Bassett 1987). After whole

- body exposure to 34

0.55 mg/m 3 CdO for 6 hours, rats had increased neutrophils and multifocal alveolar 35

inflammation and no mortality (Takenak a et al. 2004). 36

37

5.3. Derivation of AEGL

- 1 38

39

The AEGL

- 1 values are based on the experimental concentration, 0.55 mg Cd/m 3 , that 40

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

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

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

was a whole

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

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

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

a direct

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

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

0.25

- 4.5 mg/m 3 displayed similar histological and biochemical pulmonary effects including 49CADMIUM PROPOSED : November 2009

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

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

- 5.3 2

mg/ m 3 ) from 1

- 6 hours (Buckley and Bassett 1987; Oberdörster et al. 1987 ; Takenaka et al. 3

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

intraspecies uncertainty factor of 3 was applied because at acute exposures, ca dmium is a direct

5

acting respiratory irritant in humans, and this mode of action is not expected to differ among 6

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

irritation, dyspnea, and pulmonary edema (Beton et al. 1 966) which are signs of respiratory 8

irritation. The concentration

- exposure time relationship for many irritant and systemically

9

acting vapors and gases may be described by C n 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 11

absence of an empirically derived chemical

- specific scaling exponent, temporal scaling was 12

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

longer time points using the C n x t = k equation. The 30

- minute AEGL

- 1 value was adopted as 14

the 10

- minute value due to the added uncertainty of extrapolating from a 6

- hour time point to 10 15

minutes (NRC 2001). The calculations for the AEGL

- 1 values are in Appendix A

. 16

17

TABLE 12 . AEGL

- 1 Values for Cadmium

10

- min 30

- min 1

- hr 4

- hr 8

- hr

0.13 mg/m 3 0.13 mg/m 3 0.10 mg/m 3 0.063 mg/m 3 0.041 mg/m 3

18

19

6. DATA ANALYSIS FOR AEGL

- 2 20

6.1. Summary of Human Data Relevant to AEGL

- 2 21

22

No human data relevant to AEGL

- 2 were located. 23

24

6.2. Summary of Animal Data Relevant to AEGL

- 2 25

26

Rabbits and rats exposed for 2 hours to 4.5 mg/m 3 CdCl 2 or CdO exhibited increased lung 27

weight and moderate

- severe pneumonitis characterized by alveolar wall thickening, hemorrhage, 28

and edema (Grose et al. 1987). At 5.3 mg/m 3

, focal areas of interstitial thickening, an increase in 29

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

macrophages, eosinophils, and basophils), an d increase in lung w eight and protein content were 31

observed (Buckley and Bassett 1987)

. 32

33

6.3. Derivation of AEGL

- 2 34

35

The AEGL

- 2 values are based on the experimental concentration, 5.3 mg Cd/m 3 , that 36

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

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

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

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

exposures, cadmium is a direct

- acting respiratory irritant as indicated by the signs of irritation in 41

rabbits and rats. This mode of action is not expected to differ among species. Rabbits and rats 42

exposed fo r 2 hours to 0.25

- 4.5 mg/m 3 displayed similar histological and biochemical pulmonary 43

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

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

(0.00169

- 5.3 mg/m 3 ) from 1

- 6 hours (Buckley and Bassett 1987; Oberdörster et al. 1987 ; 46CADMIUM PROPOSED : November 2009

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

study. An intraspecies uncertainty factor of 3 was applied bec ause at acute exposures, cadmium 2

is a direct

- acting respiratory irritant in humans, and this mode of action is not expected to differ 3

among individuals. After a five hour exposure to cadmium, workers experienced cough, throat 4

irritation, dyspnea, and pulm onary edema (Beton et al. 1966) which are signs of respiratory 5

irritation. The concentration

- exposure time relationship for many irritant and systemically

6

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

to 3. 5 (ten Berge et al. 1986). To obtain conservative and protective AEGL values in the absence 8

of an empirically derived chemical

- specific scaling exponent, temporal scaling was performed 9

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

points using the C n x t = k equation. The calculations for the AEGL

- 2 values are in Appendix 11

A. 12

13

TABLE 13 . AEGL

- 2 Values for Cadmium

10

- min 30

- min 1

- hr 4

- hr 8

- hr

1.4 mg/m 3 0.96 mg/m 3 0.76 mg/m 3 0.40 mg/m 3 0.20 mg/m 3

14

15

7. DATA ANALYSIS FOR AEGL

- 3 16

7.1. Summary of Human Data Relevant to AEGL

- 3 17

18

Workers (n=5) exposed for 5 hours to Cd oxide fumes inhaled an estimated 8.6 mg/m 3

. 19

One worker died 5 days after the exposure with severe pulmonary edema, alveolar metaplasia of 20

the lungs, and bilateral cortical necrosis of the kidneys (Beton et al. 1966). The other four 21

workers had pulmonary edema that resolved over time. 22

23

7.2. Summary of Animal Data Relevant to AEGL

- 3 24

25

Mortality occurred in rats exposed to cadmium carbonate (5.8%) or cadmium fume 26

(48%) for 2 hours. The LC 50 for the study was 112 mg/m 3 (Rusch et al. 1986). One rat exposed 27

to 0.45 mg/m 3 Cd died of cardiovascular failure associated with pulmonary congestion (Grose et 28

al. 1987). Two other rats died of unknown causes in the same study. Although death occurred at 29

0.45 mg/m 3 , this value was not used to derive AEGL

- 3 . The deaths may be associated with the 30

exposure apparatus and may not be the result of exposure to cadmium. L ack of mortality in rats 31

exposed to similar concentrations (0.5 mg/m 3 , Buckley and Bassett 1987; 0.55 mg/m 3

, Takenaka 32

et al. 2004 ) and at a higher experimental dose within the same study , 4.5 mg/m 3 , further support 33

the dismissal of the mortality data from Grose et al. (19 87) from being considered for derivation 34

of AEGL

- 3 values

. 35

36

7.3. Derivation of AEGL

- 3 37

38

The AEGL

- 3 values are based on the 2 hour LC 50 for cadmium fume in rats, 112 mg/m 3 39

(Rusch et al. 1986). The LC 50 was divided by 3 to estimate a threshold of lethality

. An 40

intraspecies uncertainty factor of 3 was applied because in acute exposures, cadmium is a direct

41

acting respiratory irritant

. An interspecies uncertainty factor of 3 was applied because at acute 42

exposures, cadmium is a direct

- acting respiratory irri tant as indicated by the signs of irritation in 43

rabbits and rats. This mode of action is not expected to differ among species. Rabbits and rats 44

exposed for 2 hours to 0.25

- 4.5 mg/m 3 displayed similar histological and biochemical pulmonary 45

effects includi ng pneumonitis, increased lung weight, pulmonary inflammatory cell influx, and 46CADMIUM PROPOSED : November 2009

38 decreased glutathione peroxidase activity (Grose et al. 1987). Rats exposed to cadmium 1

(0.00169

- 5.3 mg/m 3 ) from 1

- 6 hours (Buckley and Bassett 1987; Oberdörster et al. 1987 ; 2

T akenaka et al. 2004) exhibited the same effects as those observed in the Grose et al. (1987) 3

study. An intraspecies uncertainty factor of 3 was applied because at acute exposures, cadmium 4

is a direct

- acting respiratory irritant in humans, and this mode of action is not expected to differ 5

among individuals. After a five hour exposure to cadmium, workers experienced cough, throat 6

irritation, dyspnea, and pulmonary edema (Beton et al. 1966) which are signs of respiratory 7

irritation. The concentration

- exposu re time relationship for many irritant and systemically

8

acting vapors and gases may be described by C n x t = k, where the exponent, n, ranges from 0.8 9

to 3.5 (ten Berge et al. 1986). To obtain conservative and protective AEGL values in the absence 10

of an e mpirically derived chemical

- specific scaling exponent, temporal scaling was performed 11

using n=3 when extrapolating to shorter time points and n = 1 when extrapolating to longer time 12

points using the C n x t = k equation. The calculations for the AEGL

- 3 va lues are in Appendix A. 13

14

TABLE 14 . AEGL

- 3 Values for Cadmium

10

- min 30

- min 1

- hr 4

- hr 8

- hr

8.5 mg/m 3 5.9 mg/m 3 4.7 mg/m 3 1.9 mg/m 3 0.93 mg/m 3

15

16

8. SUMMARY OF AEGLS 17

8.1. AEGL Values and Toxicity Endpoints 18

19

Cadmium was shown to be an irritating metal that caused developmental, respiratory, and 20

renal effects following multiple exposures. The derived AEGL values would prevent these 21

effects. The AEGL

- 1 values were based upon the experimental concentration that caused slight 22

respirat ory irritation in rats, 0.55 mg Cd/m 3

, following a 6 hour exposure. The AEGL

- 2 values 23

were based upon the experimental concentration that caused overt respiratory tract irritation and 24

pathology in rats, 5.3 mg/m 3 , f ollowing a 3 hour exposure. The AEGL

- 3 values were a based 25

upon the estimated threshold of lethality from cadmium fumes from the 2

- hour LC 50 , 112 mg/m 3

, 26

in rats. AEGL values are summarized in Table 15

. 27

28

TABLE 15 . Summary of AEGL Values

Classification Exposure Du ration

10

- min 30

- min 1

- hr 4

- hr 8

- hr

AEGL

- 1

(Notable

Discomfort) 0.13 mg/m 3 0.13 mg/m 3 0.10 mg/m 3 0.063 mg/m 3 0.041 mg/m 3

AEGL

- 2

(Disabling) 1.4 mg/m 3 0.96 mg/m 3 0.76 mg/m 3 0.40 mg/m 3 0.20 mg/m 3

AEGL

- 3

(Lethal) 8.5 mg/m 3 5.9 mg/m 3 4.7 mg/m 3 1.9 mg/m 3 0.93 mg/m 3

29

30

8.2. Comparison with Other Standards and Guidelines 31

32

AEGL values for cadmium are compared to other guidelines and standards in Table 16

. The 33

OSHA values were established to protect against lung cancer and kidney dysfunction (OSHA 34

2005)

. Th e IDLH was based upon acute inhalation toxicity in workers (NIOSH 1996). The 35

ACGIH TWA inhalable particulate value was established to minimize kidney dysfunction and 36CADMIUM PROPOSED : November 2009

39 the respirable fraction value was set to minimize pulmonary accumulation of cadmium that could 1

act as a carcinogen (ACGIH 1996). 2

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/m 3 0.13 mg/m 3 0.10 mg/m 3 0.063 mg/m 3 0.041 mg/m 3

AEGL

- 2 1 .4 mg/m 3 0.96 mg/m 3 0.76 mg/m 3 0.40 mg/m 3 0.20 mg/m 3

AEGL

- 3 8.5 mg/m 3 5.9 mg/m 3 4.7 mg/m 3 1.9 mg/m 3 0.93 mg/m 3

PEL

- TWA

(OSHA) a (fume) 0.1 mg/m 3

0.3 mg/m 3 C

PEL

- TWA

(OSHA) b (dust) 0.2 mg/m 3

0.6 mg/m 3 C

IDLH (NIOSH) c 9 mg/m 3

TLV

- TWA

(ACGIH) d 0.01 mg/m 3 I

0.002 mg/m 3 R

MAC

- Peak

Category (The

Netherlands) e 0.005 mg/m 3

4

a OSHA PEL

- TWA (Occupational Health and Safety Administration, Permissible Exposure Limits

- Time Weighted 5

Average) (OSHA, 2005) is defined analogous to the ACGIH

- TLV

- TWA, but is for exposures of no more 6

than 10 hours/day, 40 hours/week. C

- Acceptable ceiling concentration. 7

8

b OSHA PEL

- STEL (Permissible Exposure Limits

- Short Term Exposure Limit) (OSHA, 2005 ) is defined 9

analogous to the ACGIH

- TLV

- STEL. C

- Acceptable ceiling con centration. 10

11

c IDLH (Immediately Dangerous to Life and Health, National Institute of Occupational Safety and Health) (NIOSH, 12

1996) represents the maximum concentration from which one could escape within 30 minutes without any 13

escape

- impairing symptoms, or any irreversible health effects. 14

15

d ACGIH TLV

- TWA (American Conference of Governmental Industrial Hygienists, Threshold Limit Value

- Time 16

Weighted Average) (ACGIH, 200 8 ) is the time

- weighted average concentration for a normal 8

- hour 17

workday and a 40

- hour work week, to which nearly all workers may be repeatedly exposed, day after day, 18

without adverse effect

. I

- Inhalable particulate; R

- Respirable fraction 19

20

e MAC (Maximaal Aanvaaarde Concentratie [Maximal Accepted Concentration

- Peak Category]) (SDU Uitge vers 21

[under the auspices of the Ministry of Social Affairs and Employment], The Hague, The Netherlands 2000) 22

is defined analogous to the ACGIH

- Ceiling. 23

24

25

8.3. Data Adequacy and Research 26

27

Toxicity data for cadmium are available for humans and animals. Mo st of the acute 28

inhalation data for humans do not provide cadmium exposure co ncentrations, but report signs 29

and symptoms of toxicity which are useful for noting effects of exposure . Short

- term and 30

chronic epidemiological st udies in workers were available; however, the workers may have had 31

concurrent exposures to other chemicals. Animal studies were conducted in at least three species 32

and range from acute to chronic. The acute studies in rabbits and rats provide data suitable for 33

deriving AEGL values and highlight the differences between the effects that occur following 34

acute and chronic cadmium exposure. 35

36

37

38CADMIUM PROPOSED : November 2009

40 1

9. REFERENCES 2

3

ACGIH (American Conference of Governmental Industrial Hygienists). 1996. 1996 4

Supplement to the 6 th Edition. Documentation of the Threshold Limit Values and Biological 5

Exposure Indices: Cadmium and Compounds. Seventh ed., ACGIH, Cincinnati, OH. 6

7

ACGIH (American Conference of Governmental Industrial Hygienists). 2008. 8

Threshold limit values (TLVs) for chemical and physical ag ents and biological exposure indices 9

(BEIs). ACGIH, Cincinnati, OH. 10

11

ATSDR (Agency for Toxic Substances and Disease Registry). 2008. Draft toxicological 12

profile for cadmium. U.S. Department of Health and Human Services, Atlanta, GA. 13

14

Barański, B. and K. Sitarek . 198 7 . Effect of oral and inhalation exposure to cadmium on the oestrous 15

cycle in rats. Toxicol . Lett. 36 : 2 6 7

- 273. 16

17

Beton, D.C., G. S. Andrews, H.J. Davies, L. Howells and G.F. Smith. 1966. Acute cadmium fume 18

poisoning. Five cases with one death from renal necrosis. Brit. J. Industr. Med 23: 292

- 301. 19

20

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

Health. 21: 233

- 250. 22

23

Crump, K.S. and R.B. Howe. 1984. The multistage model with a time

- depen dent dose pattern: 24

Applications to carcinogenic risk assessment. Risk. Anal. 4: 163

- 176. 25

26

Fernández, M.A., P. Sanz, M. Palomar, J. Serra and E. Gadea. 1996. Fatal chemical pneumonitis due to 27

cadmi um fumes. Occup. Med. 46 : 372

- 374. 28

29

Grose, E.C., J.H. Ric hards, R.H. Jaskot, M.G. Ménache, J.A. Graham and W.C. Dauterman. 1987. A 30

comparative study of the effects of inhaled cadmium chloride and cadmium oxide: pulmonary 31

response. J

. Toxicol

. Environ

. Health, 21:219

- 232. 32

33

Haber, F.R. 1924. Zur geschichte des g askrieges [On the history of the gas war]. In: Fuenf Vortraege aus 34

den Jahren 1920

- 23 [Five lectures from the years 1920

- 1923]. Berlin, Germany: Verlag von 35

Julius Springer; pp. 76

- 92. 36

37

Hadley, J.G., A.W. Conklin, and C.L. Sanders. 1980. Rapid solubilizat ion and translocation of 109 CdO 38

following pulmonary deposition. Toxicol. Appl. Pharmacol. 54: 156

- 160. 39

40

HSDB (Hazardous Substances Data Bank). 2005. Cadmium. TOXNET, Toxicology Data Network. US. 41

Natl. Library of Medicine. Available Online. http://toxnet.n lm.nih.gov/

. 42

43

I ARC (International Agency for Research on Cancer). 2003. IARC Monographs on the evaluation of the 44

carcinogenic risk of chemicals to humans. Cadmium and Cadmium Compounds. Vol: 58: 119

- 45

237

. 46

47

IPCS (International Programme on Chemical Safety) . 1992. Environmental Health Criteria 134 48

Cadmium. Available online. 49

h ttp://www.intox.org/databank/documents/chemical/cadmium/ehc134.htm

. 50

51CADMIUM PROPOSED : November 2009

41 Jakubowski, M., A. Abramowska

- Guzik, W. Szymczak and M. Trzcinka

- Ochocka. 2004. Influence of 1

long

- term occupational exposure to cadmium on lung function tests results. Int. J. Occup. Med. 2

Environ. Health 17: 361

- 368 3

4

Järup. L., A. Rogenfelt, C

- G Elinder, K. Nogawa and T. Kjellström. 1983. Biological half

- time of 5

cadmium in the blood of workers after cessation of exposu re. Scand

. J

. Work Environ

. Health 6

9:327

- 331. 7

8

Kjellström, T., L. Friberg and B. Rahnster. 1979. Mortality and cancer morbidity among cadmium

9

exposed workers. Environ

. Health Perspect

. 28:199

- 204. 10

11

Klimisch, H.J. 1993. Lung deposition, lung clearance and renal accumulation of inhaled cadmium 12

chloride and cadmium sulphide in rats. Toxicology 84:103

- 124. 13

14

Kutzman, R.S., R.T. Drew and R.N. Shiotsuka. 1986. Pulmonary changes resulting from subchronic 15

exposure to cadmium chloride aerosol. J

. of Toxicol

. Enviro n

. Health 17: 175

- 189. 16

17

Lauwerys, R., H. Roels, M. Refniers, J.P. Buchett, A. Bernard and A. Goret. 1979. Significance of 18

cadmium concentration in blood and in urine in workers exposed to cadmium. Environ. Res. 20: 19

375

- 391. 20

21

McKenna, I.M., M.P. Waalkes, L .C. Chen and T. Gordon. 1997. Comparison of inflammatory lung 22

responses in Wistar rats and C57 and DBA mice following acute exposure to cadmium oxide 23

fumes. Toxicol

. App l. Pharmacol

. 146:196

- 207. 24

25

Morrow, H. 2001. Cadmium and Cadmium Alloys. Kirk

- Othmer Encyclopedia of Chemical 26

Technology, 4 th Ed., M. Howe

- Grant, ed. Available. Online. 27

http://mrw.interscience.wiley.com/emrw/9780471238966/kirk/article/cadmcarr.a01/current/abstra 28

ct?hd=All,cadmium&hd=All,cadmium&hd=All,alloys. 29

30

NIOSH (National Institute for Occupational Safety and Health). 1996. Documentation 31

for Immediately Dangerous to Life and Health Concentrations (IDLH). Available Online. 32

http://www.cdc.gov/niosh/idlh/7440439.html. 33

34

NIOSH (National Institute for Occupational Safety and Health). 2005 . NIOSH Pocket 35

Guide to Chemical Hazards. NIOSH, Cincinnati, OH. Available Online. 36

http://www.cdc.gov/niosh/npgd0088.html. 37

38

Nishijo, M., H. Nakagawa, R. Honda, K. Tanebe, S. Saito, H. Teranishi and K. Tawara. 2002. Effects of 39

maternal exposure to ca dmium on pregnancy outcome and breast milk. Occup

. Environ

. Med

. 40

59:394

- 397. 41

42

NRC (National Research Council). 2001. Standing Operating Procedures for Developing Acute 43

Exposure Guideline Levels for Hazardous Chemicals. The National Academies Press, 44

Was hington, DC. 45

46

NRC (National Research Council). 1985. Emergency and Continuous Exposure Guidance Levels for 47

Selected Airborne Contaminants, Vol 5. The National Academies Press, Washington, DC. 48

49

NTP (National Toxicology Program). 1995. NTP technical report on toxicity studies of cadmium oxide 50

administered by inhalation to F344/N rats and B6C3F 1 mice. NIH Publication 95

- 3388. U.S. 51

Department of Health and Human Services, Public Health Service, National Institutes of Health

. 52

53CADMIUM PROPOSED : November 2009

42 Oberdörster, G., M.G. Cherian and R.B. Baggs. 1994. Importance of species difference in experimental 1

pulmonary carcinogenicity of inhaled cadmium for extrapolation to humans. Toxicol

. Lett

. 2

72:339

- 343. 3

4

Oberdörster,G., D. Hochrainer and C. Cox. 1987. Acute pulmonary toxicity of cadmium co mpounds: 5

dependence on physico

- chemical form. Toxicology of Metals: Clinical and Experimental 6

Research. S.S. Brown and Y. Kodama., eds. West Sussex, England : Ellis Horwood Limited. pp. 7

319

- 320. 8

9

Oldiges, H., D. Hochrainer and U. Glaser. 1989. Long

- term i nhalation study with Wistar rats and four 10

cadmium compounds. Toxicol

. Environ

. Chem

. 19:217

- 222. 11

12

OSHA (Occupational Safety and Health Administration). 2005. Code of Federal Regulations, CFR 29, 13

Part 1910, Table Z

- 2. 14

15

Panchal, L. and P. Vaideeswar. 2006. Acute lung injury due to cadmium inhalation

- a case report. Indian 16

J. Pathol

. Microbiol

. 49: 265

- 266. 17

18

Prigge, E. 1978. Early signs of oral and inhalative cadmium uptake in rats. Arch. Toxicol

. 40: 231

- 247. 19

20

Rinehart, W. E., Hatch, T. 1964. Concentration

- time product (CT) as an expression of dose in 21

sublethal exposures to phosgene. Ind. Hyg. J. 25: 545

- 553. 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 differ ent cadmium containing materials. Am. Ind. Hyg. 25

Assoc. J

. 47(12): 754

- 763. 26

27

Schoeters, G., E. Den Hond, M. Zuurbier, R. Naginiene, P. Van Den Hazel, N. Stilianakis, R. Ronchetti 28

and J.G. Koppe. 2006. Cadmium and children: exposure and health effects. Acta

. Pædiatrica

. 29

95:50

- 54. 30

31

SDU Uitgevers 2000. MAC Ministry of Social Affairs and Employment. Nationale 32

MAC (Maximum Allowable Concentration) List, 2000. The Hague, The Netherlands. 33

34

Sorahan, T. and N.A. Esmen. 2004. Lung cancer mortality in UK nickel

- ca dmium battery workers, 1947

- 35

2000. Occup

. Environ

. Med

. 61:108

- 116. 36

37

Takenaka, S., E. Karg, W.G. Kreyling, B. Lentner, H. Schultz, A. Ziesenis, P. Schramel and J. Heyder. 38

2004. Fate and toxic effects of inhaled ultrafine cadmium oxide particles in the rat l ung. Inhal

. 39

Toxicol

. 16 (suppl.1): 83

- 92. 40

41

Takenaka, S., H. Oldiges, H. König, D. Hochrainer and G. Oberdöster. 1983. Carcinogenicity of cadmium 42

chloride aerosols in W rats. J

. Natl

. Cancer Inst

. 70: 367

- 373. 43

44

ten Berge, W.F., A. Zwart, and L.M. Appelman. 1986. Concentration

- time mortality response 45

relationship of irritant and systemically acting vapours and gases. J. Hazard. Materials: 13: 46

301

- 309. 47

48

Thun, M.J., T.M. Schnorr, A.B. Smith, W.E. Halperin and R.A. Lemen. 1985. Mortality among a cohort 49

of US cadmium production workers

- an update. J

. Natl

. Cancer Inst

. 74: 325

- 333. 50

51

Trottier, B., J. Athot, A.C. Ricard and J. Lafond. 2002. Maternal

- fetal distribution of cadmium in the 52

guinea pig following a low dose inhalation exposure. Toxicol

. Lett

. 129:189

- 19 7. 53CADMIUM PROPOSED : November 2009

43 1

U.S. EPA (United States Environmental Protection Agency). 1994. Integrated Risk Information System 2

Summary of Cadmium (CASRN 7440

- 43

- 9). United States Environmental Protection Agency, 3

Washington, D.C. Available online. http://www.epa.gov/ncea/iris/subs t/0141.htm. 4

5

U.S. EPA (United States Environmental Protection Agency). 1986. Final draft for the drinking water 6

criteria document on cadmium. EPA PB89

- 192140. Office of Drinking Water, Washington, D.C. 7

8

Wittman, R. and H. Hu. 2002. Cadmium exposure and nep hropathy in a 28

- year old female metals 9

worker. Environ

. Health Perspecti . 110 : 1261

- 1266. 10

11

Yamamoto, K., M. Ueda, H. Kikuchi, H. Hattori and Y. Hiraoka. 1983. An acute fatal occupational 12

cadmium poisoning by inhalation. Z. Rechtsmed

. 91: 139

- 143. 13

14CADMIUM PROPOSED : November 2009

44 APPEN DIX A: Derivation of AEGL Values 1

2

Derivation of AEGL

- 1 3

4

Key Study: Takenaka, S., E. Karg, W.G. Kreyling, B. Lentner, H. Schultz, A. 5

Ziesenis, P. Schramel and J. Heyder. 2004. Fate and toxic effects of 6

inhaled ultrafine cadmium oxide particles in the rat lung. Inhal

. Toxico l. 7

16 (suppl.1): 83

- 92. 8

9

Toxicity endpoint: The experimental concentration, 0.55 mg Cd/m 3 caused slight respiratory 10

irritation in female rats exposed for 6 hours. 11

12

Time scaling: C n x t = k; n=3 when extrapolating to shorter time points and n = 1 when 13

extrapolating to longer time points. 14

15

Uncertainty factors: 16

Interspecies: 3

, Cadmium is a direct

- acting respiratory irritant and it is not expected that 17

toxicity would differ among species. Rabbits and rats exposed for 2 hours 18

to 0.25

- 4.5 mg/m 3 displayed similar histological and biochemical 19

pulmonary effects including pneumonitis, increased lung weight, 20

pulmonary inflammatory cell influx, and decreased glutathione peroxidase 21

activity (Grose et al. 1987). Rats exposed to cadmium (0.00169

- 5 .3 22

mg/m 3 ) from 1

- 6 hours (Buckley and Bassett 1987; Oberdörster et al. 23

1987 ; Takenaka et al. 2004) exhibited the same effects as those observed 24

in the Grose et al. (1987) study. 25

Intraspecies: 3

, Cadmium is a direct

- acting respiratory irritant, and respira tory effects 26

due to irritation are not expected to differ greatly among individuals. 27

After a five hour exposure to cadmium, workers experienced cough, throat 28

irritation, dyspnea, and pulmonary edema (Beton et al. 1966) which are 29

signs of respiratory irrit ation. 30

31

Modifying factor: None applied. 32

33

Calculations: 0.55 mg/m 3 / 10 = 0.0 55 mg/m 3 34

C 3 x t = k 35

(0.0 55 mg/m 3 ) 3 x 360 min = 0.0 59895 mg/m 3

- min 36

37

C 1 x t = k 38

0.00 55 mg/m 3 x 360 min = 1 9

. 8 mg/m 3

- min 39

40

10

- min AEGL

- 1 30

- min value adopted as 10

- min value = 0.13 mg/m 3 41

42

30

- min AEGL

- 1 C 3 x 30 min= 0.059895 mg/m 3

- min 43

C = 0. 1 3 mg/m 3 44

45

1

- hr AEGL

- 1 C 3 x 60 min = 0.059895 mg/m 3

- min 46

C = 0. 1 0 mg/m 3 47

48

4

- hr AEGL

- 1 C 3 x 240 min = 0.059895 mg/m 3

- min 49CADMIUM PROPOSED : November 2009

45 C = 0.0 63 mg/m 3 1

2

8

- hr AEGL

- 1 C 1 x 480 min = 1 9

. 8 mg/m 3

- min 3

C = 0.0 41 mg/m 3 4

5CADMIUM PROPOSED : November 2009

46 Derivation of AEGL

- 2 1

2

Key Studies: Buckley, B.J. and D.J.P. Bassett. 1987

. Pulmonary cadmium oxide 3

toxicity in the rat. J. Toxicol. Environ. Health. 21: 233

- 250. 4

5

Toxicity endpoints: The experimental concentration, 5.3 mg Cd/m 3 caused overt respir atory 6

irritation and pathology in exposed for 3 hours. 7

8

Time scaling: C n x t = k; n=3 when extrapolating to shorter time points and n = 1 when 9

extrapolating to longer time points. 10

11

Uncertainty factors: 12

Interspecies: 3, Cadmium is a direct

- acting respira tory irritant and it is not expected that 13

toxicity would differ among species. Rabbits and rats exposed for 2 hours 14

to 0.25

- 4.5 mg/m 3 displayed similar histological and biochemical 15

pulmonary effects including pneumonitis, increased lung weight, 16

pulmonary inflammatory cell influx, and decreased glutathione peroxidase 17

activity (Grose et al. 1987). Rats exposed to cadmium (0.00169

- 5.3 18

mg/m 3 ) from 1

- 6 hours (Buckley and Bassett 1987; Oberdörster et al. 19

1987 ; Takenaka et al. 2004) exhibited the same effects as those observed 20

in the Grose et al. (1987) study. 21

Intraspecies: 3, Cadmium is a direct

- acting respiratory irritant, and respiratory effects 22

due to irritation are not expected to differ greatly among individuals. 23

After a five hour exposure to cadmium, wor kers experienced cough, throat 24

irritation, dyspnea, and pulmonary edema (Beton et al. 1966) which are 25

signs of respiratory irritation. 26

27

Modifying factor: None applied. 28

29

Calculations: 5.3 mg/m 3 / 10 = 0. 53 mg/m 3 30

C 3 x t = k 31

(0. 53 mg/m 3 ) 3 x 1 8 0 min = 26

. 79786 mg/m 3

- min 32

33

C 1 x t = k 34

0. 53 mg/m 3 x 1 8 0 min = 9 5

. 4 mg/m 3

- min 35

36

10

- min AEGL

- 2 C 3

x 1 0 min= 26.79786 mg/m 3

- min 37

C = 1

. 4 mg/m 3 38

39

30

- min AEGL

- 2 C 3 x 30 min= 26.79786 mg/m 3

- min 40

C = 0. 96 mg/m 3 41

42

1

- hr AEGL

- 2 C 3 x 60 min

= 26.79786 mg/m 3

- min 43

C = 0. 76 mg/m 3 44

45

4

- hr AEGL

- 2 C 1 x 240 min = 9 5

. 4 mg/m 3

- min 46

C = 0. 40 mg/m 3 47

48

8

- hr AEGL

- 2 C 1 x 480 min = 9 5

. 4 mg/m 3

- min 49CADMIUM PROPOSED : November 2009

47 C = 0. 20 mg/m 3 1

2

3

4CADMIUM PROPOSED : November 2009

48 Derivation of AEGL

- 3 1

2

Key Studies: Rusch, G.M., J.S. O’Grodnick and W.E. Rinehart. 1986. Acute inhalation 3

study in the rat of comparative uptake, distribution and excretion for 4

different cadmium containing materials. Am. Ind. Hyg. Assoc. J

. 47: 754

- 5

763. 6

7

Toxicity endpoint: T he t hreshold of lethality was calculated from the 2

- hr LC 50 for cadmium 8

fume in rats, 112 mg/m 3

. 9

10

Time sc aling: C n x t = k; n=3 when extrapolating to shorter time points , and n = 1 when 11

extrapolating to longer time points. 12

13

Uncertainty factors: 14

Interspecies: 3, Cadmium is a direct

- acting respiratory irritant and it is not expected that 15

toxicity would diffe r among species. Rabbits and rats exposed for 2 hours 16

to 0.25

- 4.5 mg/m 3 displayed similar histological and biochemical 17

pulmonary effects including pneumonitis, increased lung weight, 18

pulmonary inflammatory cell influx, and decreased glutathione peroxidase 19

activity (Grose et al. 1987). Rats exposed to cadmium (0.00169

- 5.3 20

mg/m 3 ) from 1

- 6 hours (Buckley and Bassett 1987; Oberdörster et al. 21

1987 ; Takenaka et al. 2004) exhibited the same effects as those observed 22

in the Grose et al. (1987) study. 23

Intraspecies : 3, Cadmium is a direct

- acting respiratory irritant, and respiratory effects 24

due to irritation are not expected to differ greatly among individuals. 25

After a five hour exposure to cadmium, workers experienced cough, throat 26

irritation, dyspnea, and pulmon ary edema (Beton et al. 1966) which are 27

signs of respiratory irritation. 28

29

Modifying factor: None applied. 30

31

Calculations 112 mg/m 3 /3/1 0= 3

. 733 mg/m 3 32

C 3 x t = k 33

( 3

. 733 mg/m 3 ) 3 x 120 min = 624 2.45206 mg/m 3

- min 34

35

C 1 x t = k 36

3

. 733 mg/m 3 x 120 min = 44 7

. 96 mg/m 3

- min 37

38

10

- minute AEGL

- 3 C 3

x 1 0 min= 6242.45206 mg/m 3

- min 39

C = 8

. 5 mg/m 3 40

41

30

- minute AEGL

- 3 C 3 x 30 min= 6242.45206 mg/m 3

- min 42

C = 5

. 9 mg/m 3 43

44

1

- hr AEGL

- 3 C 3 x 60 min = 6242.45206 mg/m 3

- min 45

C = 4

. 7 mg/m 3 46

47

4

- hr AEGL

- 3 C 1 x 240 min = 44.796 mg/m 3

- min 48

C = 1

. 9 mg/m 3 49CADMIUM PROPOSED : November 2009

49 1

8

- hr AEGL

- 3 C 1 x 480 min = 44.796 mg/m 3

- min 2

C = 0. 93 mg/m 3 3

4

5CADMIUM PROPOSED : November 2009

50 APPENDIX B: Time

- Scaling Calculations 1

2

The relationship between dose and time for any given chemical is a function of the 3

physical and chemical properties of the substan ce and the unique toxicological and 4

pharmacological properties of the individual substance. Historically, the relationship according 5

to Haber (1924), commonly called Haber = s Law or Haber = s Rule (i.e., C x t = k , where C = 6

exposure concentration, t = expos ure duration, and k = a constant) has been used to relate 7

exposure concentration and duration to effect (Rinehart and Hatch 1964). This concept states 8

that exposure concentration and exposure duration may be reciprocally adjusted to maintain a 9

cumulative exposure constant ( k ) and that this cumulative exposure constant will always reflect a 10

specific quantitative and qualitative response. This inverse relationship of concentration and 11

time may be valid when the toxic response to a chemical is equally depend ent upon the 12

concentration and the exposure duration. However, an assessment by ten Berge et al. (1986) of 13

LC 50 data for certain chemicals revealed chemical

- specific relationships between exposure 14

concentration and exposure duration that were often expone ntial. This relationship can be 15

expressed by the equation C n x t = k , where n represents a chemical specific, and even a toxic 16

endpoint specific, exponent. The relationship described by this equation is basically in the form 17

of a linear regression analys is of the log

- log transformation of a plot of C vs. ten Berge et al. 18

(1986) examined the airborne concentration (C) and short

- term exposure duration (t) relationship 19

relative to death for approximately 20 chemicals and found that the empirically derived va lue of 20

n ranged from 0.8 to 3.5 among this group of chemicals. Hence, the value of the exponent ( n ) in 21

the equation C n x t = k quantitatively defines the relationship between exposure concentration 22

and exposure duration for a given chemical and for a spec ific health effect endpoint. Haber's 23

Rule is the special case where n = 1. As the value of n increases, the plot of concentration vs. 24

time yields a progressive decrease in the slope of the curve. 25

26

The available data do not allow for empirical derivation of a temporal scaling factor ( n ) for 27

cadmium . The exposure concentration

- exposure duration relationship for many irritant and 28

systemically acting vapors and gases may be described by C n x t = k , where the exponent, n

, 29

ranges from 0.8 to 3.5 (ten Berge et al., 1986). In the absence of an empirically derived 30

exponent ( n ), temporal scaling from the experimental durations of the respective PODs to 31

AEGL

- specific durations was performed using n = 3 when extrapolating to shorter time points 32

and n = 1 when extrap olating to longer time points using the C n x t = k equation. 33

34CADMIUM PROPOSED : November 2009

51 APPENDIX C: Carcinogenicity Assessment 1

2

The carcinogenicity data are summarized in Section 3.6 and Table 9. The U.S. EPA (1994) 3

concluded that cadmium is a “probable human carcinogen” based on evidence o f carcinogenicity 4

in animals and limited evidence of carcinogenicity in an exposed human population. The 5

inhalation unit risk calculated is 1.8 x 10

- 3 μg/m 3 , and the concentration associated with a risk 6

level of 1 in 10,000 is 6 x 10

- 2 μg/m 3

. 7

8

To convert a 70

- year (25,600 days) exposure to a 24

- hr exposure: 9

10

24

- hr exposure = d x 25,600; where d = 6 x 10

- 2 μg/m 3 11

= (6 x 10

- 2 μg/m 3 ) x 25,600 days 12

= 1536 μg/m 3 = 1.54 mg/m 3 13

14

To account for uncertainty regarding the variability in the stage of the cancer process at which 15

cadmium may act, a multi

- stage factor of 6 is applied (Crump and Howe, 1984): 16

17

1.54 mg/m 3 / 6 = 0.26 mg/m 3 18

19

Therefore, a single exposure to cadmium at 0.26 mg/m 3 for 24 hrs would represent a cancer risk 20

of 10

- 4 . If the exposure is limited to a fraction (f) of a 24

- hr period, the fractional exposure 21

becomes 1/f x 24 hr (NRC 1985). 22

23

24 hr exposure

= 0.26 mg/m 3 24

8 hr exposure

= 0.78 mg/m 3 25

4 hr exposure

= 1.56 mg/m 3 26

1 hr exposure

= 6.24 mg/m 3 27

30 min exposure = 12.48 mg/m 3 28

10 min exp osure = 36.66 mg/m 3 29

30

31

The AEGL values for 10 minutes, 30 minutes, 1, 4, and 8 hours are presented below for 32

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

These values based on carcinogenicity are not proposed for AEGL values

. 36

37

38CADMIUM PROPOSED : November 2009

52 APPENDIX D: Derivation Summary for Cadmium AEGLs 1

2

ACUTE EXPOSURE GUIDELINE LEVELS FOR 3

CADMIUM (CAS Reg. No. 7440

- 43

- 9 ) 4

DERIVATION SUMMARY 5

6

AEGL

- 1 VALUES

10

- min 30

- min 1

- hr 4

- hr 8

- hr

0.13 mg/m 3 0.13 mg/m 3 0.10 mg/m 3 0.063 mg/m 3 0.041 mg/m 3

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 inh aled 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/m 3 / 6 hr

Effects:

0.07 mg/m 3 No morpholog ical changes or inflammatory response

0.550 mg/m 3 Increased neutrophils and multifocal alveolar inflammation

Endpoint/Concentration/Rationale : Slight respiratory irritation / 0. 55 mg Cd /m 3 administered as CdO

Uncertainty Factors/Rationale:

Total u ncertai nty 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/m 3 displayed

similar histological and biochemical pulmo nary 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/m 3 ) from 1

- 6

hours (Buckley and Bassett 1987; Oberdör ster 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 g reatly 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: C n 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 t he 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

8CADMIUM PROPOSED : November 2009

53 1

2

AEGL

- 2 VALUES

10

- min 30

- min 1

- hr 4

- hr 8

- hr

1.4 mg/m 3 0. 96 mg/m 3 0. 7 6 mg/m 3 0. 40 mg/m 3 0. 20 mg/m 3

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/m 3 CdO/ 3 hr

Effects :

0. 5 mg/m 3 Transient m ild hypercellularity at bronchoalveolar junctions and adjacent alveoli

, inflammatory cell influx

5.3 mg/m 3 Inter stitial 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 patholo gy /5.3 mg/m 3 administered as

CdO

Uncertainty Factors/Rationale:

Total u ncertainty 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 fo r 2 hours to 0.25

- 4.5 mg/m 3

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/m 3 ) 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: C n 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.

3CADMIUM PROPOSED : November 2009

54 1

2

3

AEGL

- 3 VALUES

10

- min 30

- min 1

- hr 4

- hr 8

- hr

8.5 mg/m 3 5

. 9 mg/m 3 4

. 7 mg/m 3 1

. 9 mg/m 3 0. 93 mg/m 3

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 Ro ute/Concentrations/Duration: Inhalation/97 mg/m 3 Cd red, 99 mg/m 3 Cd yellow , 132 mg/m 3 Cd

carbonate, 112 mg/m 3 Cd fume /2 hr

Effects :

97 mg/m 3 Cd red Lacrimation, renal discoloration

99 mg/m 3 Cd yellow Lacrimation

132 mg/m 3 Cd carbonate 5.8% mortality, dry rales, pulmonary edema

112 mg/m 3 Cd fume 48% mortality, hypoactivity, closed eyes, dry and moist rales, LC 50 Endpoint/Concentration/Rationale: Threshold of lethality based on 2

- hr LC 50 112 mg/m 3 for cadmium fumes

Uncertainty Factors/Rationale:

Total u ncertainty 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/m 3

displayed similar histological and biochemi cal 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/m 3 ) 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 Do simetric Adjustment:

Time Scaling: C n x t = k; n=3 when extrapolating to shorter time points (10

- , 30

- , and 60

- min)

, and n = 1

when extr apolating to longer time points (4

- hr, 8 hr )

. Data Adequacy: Data were available and adequate for deriving AEGL

- 3 va lues.

4

5CADMIUM PROPOSED : November 2009

55 APPENDIX E : Category Plot for C admium 1

2

3

0.0 0.0 0.1 1.0 10.0 100.0 1000.0mg/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/m 3 , at which 2 animals died. Based on 5

the information provided in the study (Grose et al. 1987) , it i s possible that the animal deaths were not the result of 6

exposure to cadmium but were the result of exposure apparatus difficulties (reversal of animal body and resulting 7

asphyxiation). The mortality at this concentration was inconsistent with the other a nimal data resulting from 8

exposures at similar concentrations. There was also a lack of dose response as no mortality occurred following 9

exposure to a higher dose of cadmium. 10CADMIUM PROPOSED : November 2009

56 1

Category Plot Data

For Category 0 = No effect, 1 = Discomfort, 2 = Disabli ng, SL = Some Lethality, 3 = Lethal

Source Species Sex # Exposures mg/m 3 Min Category Comments

NAC/AEGL

- 1 0.13 10 AEGL

NAC/AEGL

- 1 0.13 30 AEGL

NAC/AEGL

- 1 0.1 0 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 transfera s e 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;

b ody w eight

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 i nflammation, neutrophils

Oberdorster et al. 198 7 Rat m 1 0.00195 60 1 Decreased alveolar macrophages,

Oberdorster et al. 1987 Rat m 1 0.00169 60 1 Decreased alveolar macrophages,

Ober dorster 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% morta lity; hypoactivity, LC50

2