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TOXICOLOGICAL PROFILE FOR
 

CADMIUM
 

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
 

Public Health Service
 

Agency for Toxic Substances and Disease Registry
 

September 2008 
 

 


 

CADMIUM ii 

DISCLAIMER

The use of company or product name(s) is for identification only and does not imply endorsement by the 

Agency for Toxic Substances and Disease Registry. 

This information is distributed solely for the purpose of pre dissemination public comment under 

applicable information quality guidelines. It has not been formally disseminated by the Agency for Toxic 

Substances and Disease Registry. It does not represent and should not be construed to represent any 

agency determination or policy. 

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CADMIUM iii 

UPDATE STATEMENT
 

A Toxicological Profile for Cadmium was released in 1999. This present edition supersedes any 

previously released draft or final profile. 

Toxicological profiles are revised and republished as necessary. For information regarding the update 

status of previously released profiles, contact ATSDR at: 

Agency for Toxic Substances and Disease Registry
 

Division of Toxicology and Environmental Medicine/Applied Toxicology Branch
 

1600 Clifton Road NE
 

Mailstop F-32
 

Atlanta, Georgia 30333
 

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CADMIUM iv 

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CADMIUM v 

FOREWORD 

This toxicological profile is prepared in accordance with guidelines developed by the Agency for Toxic 

Substances and Disease Registry (ATSDR) and the Environmental Protection Agency (EPA). The 

original guidelines were published in the Federal Register on April 17, 1987. Each profile will be revised 

and republished as necessary. 

The ATSDR toxicological profile succinctly characterizes the toxicologic and adverse health effects 

information for the hazardous substance described therein. Each peer-reviewed profile identifies and 

reviews the key literature that describes a hazardous substance’s toxicologic properties. Other pertinent 

literature is also presented, but is described in less detail than the key studies. The profile is not intended 

to be an exhaustive document; however, more comprehensive sources of specialty information are 

referenced. 

The focus of the profiles is on health and toxicologic information; therefore, each toxicological profile 

begins with a public health statement that describes, in nontechnical language, a substance’s relevant 

toxicological properties. Following the public health statement is information concerning levels of 

significant human exposure and, where known, significant health effects. The adequacy of information to 

determine a substance’s health effects is described in a health effects summary. Data needs that are of 

significance to protection of public health are identified by ATSDR and EPA. 

Each profile includes the following: 

(A) The examination, summary, and interpretation of available toxicologic information and 

epidemiologic evaluations on a hazardous substance to ascertain the levels of significant human 

exposure for the substance and the associated acute, subacute, and chronic health effects; 

(B) A determination of whether adequate information on the health effects of each substance 

is available or in the process of development to determine levels of exposure that present a 

significant risk to human health of acute, subacute, and chronic health effects; and 

(C) Where appropriate, identification of toxicologic testing needed to identify the types or 

levels of exposure that may present significant risk of adverse health effects in humans. 

The principal audiences for the toxicological profiles are health professionals at the Federal, State, and 

local levels; interested private sector organizations and groups; and members of the public. We plan to 

revise these documents in response to public comments and as additional data become available. 

Therefore, we encourage comments that will make the toxicological profile series of the greatest use. 

Comments should be sent to: 

Agency for Toxic Substances and Disease Registry
 

Division of Toxicology and Environmental Medicine
 

1600 Clifton Road NE
 

Mail Stop F-32
 

Atlanta, Georgia 30333
 

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CADMIUM vi 

Background Information 

The toxicological profiles are developed in response to the Superfund Amendments and Reauthorization 

Act (SARA) of 1986 (Public Law 99 499) which amended the Comprehensive Environmental Response, 

Compensation, and Liability Act of 1980 (CERCLA or Superfund). This public law directed ATSDR to 

prepare toxicological profiles for hazardous substances most commonly found at facilities on the 

CERCLA National Priorities List and that pose the most significant potential threat to human health, as 

determined by ATSDR and the EPA. The availability of the revised priority list of 275 hazardous 

substances was announced in the Federal Register on December 7, 2005 (70 FR 72840). For prior 

versions of the list of substances, see Federal Register notices dated April 17, 1987 (52 FR 12866); 

October 20, 1988 (53 FR 41280); October 26, 1989 (54 FR 43619); October 17,1990 (55 FR 42067); 

October 17, 1991 (56 FR 52166); October 28, 1992 (57 FR 48801); February 28, 1994 (59 FR 9486); 

April 29, 1996 (61 FR 18744); November 17, 1997 (62 FR 61332); October 21, 1999(64 FR 56792); 

October 25, 2001 (66 FR 54014) and November 7, 2003 (68 FR 63098). Section 104(i)(3) of CERCLA, 

as amended, directs the Administrator of ATSDR to prepare a toxicological profile for each substance on 

the list. 

This profile reflects ATSDR’s assessment of all relevant toxicologic testing and information that has been 

peer-reviewed. Staff of the Centers for Disease Control and Prevention and other Federal scientists have 

also reviewed the profile. In addition, this profile has been peer-reviewed by a nongovernmental panel 

and was made available for public review. Final responsibility for the contents and views expressed in 

this toxicological profile resides with ATSDR. 

Howard Frumkin M.D., Dr.P.H. Julie Louise Gerberding, M.D., M.P.H. 

Director Administrator 

National Center for Environmental Health/ Agency for Toxic Substances and 

Agency for Toxic Substances and Disease Registry 

Disease Registry 

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CADMIUM vii 

QUICK REFERENCE FOR HEALTH CARE PROVIDERS 

Toxicological Profiles are a unique compilation of toxicological information on a given hazardous 

substance. Each profile reflects a comprehensive and extensive evaluation, summary, and interpretation 

of available toxicologic and epidemiologic information on a substance. Health care providers treating 

patients potentially exposed to hazardous substances will find the following information helpful for fast 

answers to often-asked questions. 

Primary Chapters/Sections of Interest 

Chapter 1: Public Health Statement: The Public Health Statement can be a useful tool for educating 

patients about possible exposure to a hazardous substance. It explains a substance’s relevant 

toxicologic properties in a nontechnical, question-and-answer format, and it includes a review of 

the general health effects observed following exposure. 

Chapter 2: Relevance to Public Health: The Relevance to Public Health Section evaluates, interprets, 

and assesses the significance of toxicity data to human health. 

Chapter 3: Health Effects: Specific health effects of a given hazardous compound are reported by type 

of health effect (death, systemic, immunologic, reproductive), by route of exposure, and by length 

of exposure (acute, intermediate, and chronic). In addition, both human and animal studies are 

reported in this section. 

NOTE: Not all health effects reported in this section are necessarily observed in the clinical 

setting. Please refer to the Public Health Statement to identify general health effects observed 

following exposure. 

Pediatrics: Four new sections have been added to each Toxicological Profile to address child health 

issues: 

Section 1.6 How Can (Chemical X) Affect Children?
 

Section 1.7 How Can Families Reduce the Risk of Exposure to (Chemical X)?
 

Section 3.7 Children’s Susceptibility
 

Section 6.6 Exposures of Children
 

Other Sections of Interest: 

Section 3.8 Biomarkers of Exposure and Effect 

Section 3.11 Methods for Reducing Toxic Effects 

ATSDR Information Center 

Phone: 1-800-CDC-INFO (800-232-4636) or 1-888-232-6348 (TTY) Fax: (770) 488-4178 

E-mail: cdcinfo@cdc.gov Internet: http://www.atsdr.cdc.gov 

The following additional material can be ordered through the ATSDR Information Center: 

Case Studies in Environmental Medicine: Taking an Exposure History—The importance of taking an 

exposure history and how to conduct one are described, and an example of a thorough exposure 

history is provided. Other case studies of interest include Reproductive and Developmental 

Hazards; Skin Lesions and Environmental Exposures; Cholinesterase-Inhibiting Pesticide 

Toxicity; and numerous chemical-specific case studies. 

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CADMIUM viii 

Managing Hazardous Materials Incidents is a three-volume set of recommendations for on-scene 

(prehospital) and hospital medical management of patients exposed during a hazardous materials 

incident. Volumes I and II are planning guides to assist first responders and hospital emergency 

department personnel in planning for incidents that involve hazardous materials. Volume III— 

Medical Management Guidelines for Acute Chemical Exposures—is a guide for health care 

professionals treating patients exposed to hazardous materials. 

Fact Sheets (ToxFAQs) provide answers to frequently asked questions about toxic substances. 

Other Agencies and Organizations 

The National Center for Environmental Health (NCEH) focuses on preventing or controlling disease, 

injury, and disability related to the interactions between people and their environment outside the 

workplace. Contact: NCEH, Mailstop F-29, 4770 Buford Highway, NE, Atlanta, 

GA 30341-3724 • Phone: 770-488-7000 • FAX: 770-488-7015. 

The National Institute for Occupational Safety and Health (NIOSH) conducts research on occupational 

diseases and injuries, responds to requests for assistance by investigating problems of health and 

safety in the workplace, recommends standards to the Occupational Safety and Health 

Administration (OSHA) and the Mine Safety and Health Administration (MSHA), and trains 

professionals in occupational safety and health. Contact: NIOSH, 200 Independence Avenue, 

SW, Washington, DC 20201 • Phone: 800-356-4674 or NIOSH Technical Information Branch, 

Robert A. Taft Laboratory, Mailstop C-19, 4676 Columbia Parkway, Cincinnati, OH 45226-1998 

• Phone: 800-35-NIOSH. 

The National Institute of Environmental Health Sciences (NIEHS) is the principal federal agency for 

biomedical research on the effects of chemical, physical, and biologic environmental agents on 

human health and well-being. Contact: NIEHS, PO Box 12233, 104 T.W. Alexander Drive, 

Research Triangle Park, NC 27709 • Phone: 919-541-3212. 

Referrals 

The Association of Occupational and Environmental Clinics (AOEC) has developed a network of clinics 

in the United States to provide expertise in occupational and environmental issues. Contact: 

AOEC, 1010 Vermont Avenue, NW, #513, Washington, DC 20005 • Phone: 202-347-4976 

• FAX: 202-347-4950 • e-mail: AOEC@AOEC.ORG • Web Page: http://www.aoec.org/. 

The American College of Occupational and Environmental Medicine (ACOEM) is an association of 

physicians and other health care providers specializing in the field of occupational and 

environmental medicine. Contact: ACOEM, 25 Northwest Point Boulevard, Suite 700, Elk 

Grove Village, IL 60007-1030 • Phone: 847-818-1800 • FAX: 847-818-9266. 

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CADMIUM ix 

CONTRIBUTORS 

CHEMICAL MANAGER(S)/AUTHOR(S): 

Obaid Faroon, Ph.D. DVM
 

Annette Ashizawa, Ph.D.
 

Scott Wright, M.S.
 

Pam Tucker, M.D.
 

Kim Jenkins, B.A.
 

ATSDR, Division of Toxicology and Environmental Medicine, Atlanta, GA
 

Lisa Ingerman, Ph.D., DABT
 

Catherine Rudisill, B.S.
 

Syracuse Research Corporation, North Syracuse, NY
 

THE PROFILE HAS UNDERGONE THE FOLLOWING ATSDR INTERNAL REVIEWS: 

1.	 Health Effects Review. The Health Effects Review Committee examines the health effects 

chapter of each profile for consistency and accuracy in interpreting health effects and classifying 

end points. 

2.	 Minimal Risk Level Review. The Minimal Risk Level Workgroup considers issues relevant to 

substance-specific Minimal Risk Levels (MRLs), reviews the health effects database of each 

profile, and makes recommendations for derivation of MRLs. 

3.	 Data Needs Review. The Applied Toxicology Branch reviews data needs sections to assure 

consistency across profiles and adherence to instructions in the Guidance. 

4.	 Green Border Review. Green Border review assures the consistency with ATSDR policy. 

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CADMIUM x 

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CADMIUM xi 

PEER REVIEW
 

A peer review panel was assembled for cadmium. The panel consisted of the following members: 

1.	 Maryka H. Bhattacharyya, Ph.D., Senior Biochemist, Biosciences Division (BIO), Argonne 

National Laboratory, Lemont, Illinois 60439, 

2.	 Masayuki Ikeda, Ph.D., M.D., Professor, Kyoto Industrial Health Association, Kyoto, Japan 

604-8472, and 

3.	 Zahir A Shaikh, Ph.D., Professor of Pharmacology and Toxicology, Director of the Center for 

Molecular Toxicology, University of Rhode Island, Kingston, Rhode Island 02881. 

These experts collectively have knowledge of cadmium’s physical and chemical properties, 

toxicokinetics, key health end points, mechanisms of action, human and animal exposure, and 

quantification of risk to humans. All reviewers were selected in conformity with the conditions for peer 

review specified in Section 104(I)(13) of the Comprehensive Environmental Response, Compensation, 

and Liability Act, as amended. 

Scientists from the Agency for Toxic Substances and Disease Registry (ATSDR) have reviewed the peer 

reviewers' comments and determined which comments will be included in the profile. A listing of the 

peer reviewers' comments not incorporated in the profile, with a brief explanation of the rationale for their 

exclusion, exists as part of the administrative record for this compound. 

The citation of the peer review panel should not be understood to imply its approval of the profile's final 

content. The responsibility for the content of this profile lies with the ATSDR. 

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CADMIUM xii 

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CADMIUM xiii 

CONTENTS
 

DISCLAIMER ..............................................................................................................................................ii
 

UPDATE STATEMENT .............................................................................................................................iii
 

FOREWORD ................................................................................................................................................v
 

QUICK REFERENCE FOR HEALTH CARE PROVIDERS....................................................................vii
 

CONTRIBUTORS.......................................................................................................................................ix
 

PEER REVIEW ...........................................................................................................................................xi
 

CONTENTS...............................................................................................................................................xiii
 

LIST OF FIGURES ..................................................................................................................................xvii
 

LIST OF TABLES.....................................................................................................................................xix
 

1. PUBLIC HEALTH STATEMENT..........................................................................................................1
 

1.1 WHAT IS CADMIUM? ..............................................................................................................2
 

1.2 WHAT HAPPENS TO CADMIUM WHEN IT ENTERS THE ENVIRONMENT?.................2
 

1.3 HOW MIGHT I BE EXPOSED TO CADMIUM? .....................................................................3
 

1.4 HOW CAN CADMIUM ENTER AND LEAVE MY BODY? ..................................................4
 

1.5 HOW CAN CADMIUM AFFECT MY HEALTH? ...................................................................5
 

1.6 HOW CAN CADMIUM AFFECT CHILDREN?.......................................................................6
 

1.7 HOW CAN FAMILIES REDUCE THE RISK OF EXPOSURE TO CADMIUM? ..................7
 

1.8 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN EXPOSED
 

TO CADMIUM? .........................................................................................................................7
 

1.9 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO 

PROTECT HUMAN HEALTH?.................................................................................................8
 

1.10 WHERE CAN I GET MORE INFORMATION? .......................................................................9
 

2. RELEVANCE TO PUBLIC HEALTH .................................................................................................11
 

2.1 BACKGROUND AND ENVIRONMENTAL EXPOSURES TO CADMIUM IN THE
 

UNITED STATES.....................................................................................................................11
 

2.2 SUMMARY OF HEALTH EFFECTS......................................................................................12
 

2.3 MINIMAL RISK LEVELS (MRLs) .........................................................................................15
 

3. HEALTH EFFECTS..............................................................................................................................43
 

3.1 INTRODUCTION.....................................................................................................................43
 

3.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE ..................................43
 

3.2.1 Inhalation Exposure ..............................................................................................................45
 

3.2.1.1 Death ............................................................................................................................45
 

3.2.1.2 Systemic Effects...........................................................................................................48
 

3.2.1.3 Immunological and Lymphoreticular Effects...............................................................92
 

3.2.1.4 Neurological Effects.....................................................................................................93
 

3.2.1.5 Reproductive Effects....................................................................................................94
 

3.2.1.6 Developmental Effects .................................................................................................97
 

3.2.1.7 Cancer...........................................................................................................................98
 

3.2.2 Oral Exposure......................................................................................................................102
 

3.2.2.1 Death ..........................................................................................................................102
 

3.2.2.2 Systemic Effects.........................................................................................................103
 

3.2.2.3 Immunological and Lymphoreticular Effects.............................................................159
 

3.2.2.4 Neurological Effects...................................................................................................160
 

3.2.2.5 Reproductive Effects..................................................................................................161
 

3.2.2.6 Developmental Effects ...............................................................................................164
 

3.2.2.7 Cancer.........................................................................................................................167
 

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CADMIUM xiv 

3.2.3 Dermal Exposure.................................................................................................................170
 

3.2.3.1 Death ..........................................................................................................................170
 

3.2.3.2 Systemic Effects.........................................................................................................170
 

3.2.3.3 Immunological and Lymphoreticular Effects.............................................................171
 

3.2.3.4 Neurological Effects.......................................................................................................173
 

3.2.3.5 Reproductive Effects.......................................................................................................173
 

3.2.3.6 Developmental Effects....................................................................................................173
 

3.2.3.7 Cancer.........................................................................................................................173
 

3.3 GENOTOXICITY ...................................................................................................................173
 

3.4 TOXICOKINETICS................................................................................................................180
 

3.4.1 Absorption...........................................................................................................................181
 

3.4.1.1 Inhalation Exposure....................................................................................................181
 

3.4.1.2 Oral Exposure.............................................................................................................182
 

3.4.1.3 Dermal Exposure........................................................................................................185
 

3.4.2 Distribution .........................................................................................................................187
 

3.4.2.1 Inhalation Exposure....................................................................................................187
 

3.4.2.2 Oral Exposure.............................................................................................................187
 

3.4.2.3 Dermal Exposure........................................................................................................189
 

3.4.3 Metabolism..........................................................................................................................189
 

3.4.4 Elimination and Excretion...................................................................................................189
 

3.4.4.1 Inhalation Exposure....................................................................................................190
 

3.4.4.2 Oral Exposure.............................................................................................................190
 

3.4.4.3 Dermal Exposure........................................................................................................191
 

3.4.5 Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models...........191
 

3.4.5.1 Summary of Cadmium PBPK Models............................................................................193
 

3.4.5.2 Cadmium PBPK Model Comparison .........................................................................193
 

3.4.5.3 Discussion of Cadmium Models ................................................................................193
 

3.5 MECHANISMS OF ACTION ................................................................................................205
 

3.5.1 Pharmacokinetic Mechanisms.............................................................................................205
 

3.5.2 Mechanisms of Toxicity......................................................................................................208
 

3.5.3 Animal-to-Human Extrapolations.......................................................................................212
 

3.6 TOXICITIES MEDIATED THROUGH THE NEUROENDOCRINE AXIS ........................213
 

3.7 CHILDREN’S SUSCEPTIBILITY.........................................................................................214
 

3.8 BIOMARKERS OF EXPOSURE AND EFFECT ..................................................................219
 

3.8.1 Biomarkers Used to Identify or Quantify Exposure to Cadmium.......................................220
 

3.8.2 Biomarkers Used to Characterize Effects Caused by Cadmium.........................................223
 

3.9 INTERACTIONS WITH OTHER CHEMICALS ..................................................................226
 

3.10 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE.............................................229
 

3.11 METHODS FOR REDUCING TOXIC EFFECTS.................................................................229
 

3.11.1 Reducing Peak Absorption Following Exposure............................................................230
 

3.11.2 Reducing Body Burden...................................................................................................231
 

3.11.3 Interfering with the Mechanism of Action for Toxic Effects .........................................233
 

3.12 ADEQUACY OF THE DATABASE......................................................................................234
 

3.12.1 Existing Information on Health Effects of Cadmium.....................................................235
 

3.12.2 Identification of Data Needs ...........................................................................................235
 

3.12.3 Ongoing Studies..............................................................................................................247
 

4. CHEMICAL AND PHYSICAL INFORMATION..............................................................................249
 

4.1 CHEMICAL IDENTITY.........................................................................................................249
 

4.2 PHYSICAL AND CHEMICAL PROPERTIES......................................................................249
 

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CADMIUM xv 

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL..........................................................255
 

5.1 PRODUCTION .......................................................................................................................255
 

5.2 IMPORT/EXPORT .................................................................................................................261
 

5.3 USE..........................................................................................................................................261
 

5.4 DISPOSAL..............................................................................................................................262
 

6. POTENTIAL FOR HUMAN EXPOSURE .........................................................................................265
 

6.1 OVERVIEW............................................................................................................................265
 

6.2 RELEASES TO THE ENVIRONMENT................................................................................269
 

6.2.1 Air .......................................................................................................................................270
 

6.2.2 Water...................................................................................................................................275
 

6.2.3 Soil ......................................................................................................................................276
 

6.3 ENVIRONMENTAL FATE....................................................................................................278
 

6.3.1 Transport and Partitioning...................................................................................................278
 

6.3.2 Transformation and Degradation ........................................................................................283
 

6.3.2.1 Air...............................................................................................................................283
 

6.3.2.2 Water ..........................................................................................................................283
 

6.3.2.3 Sediment and Soil.......................................................................................................283
 

6.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT...............................284
 

6.4.1 Air .......................................................................................................................................284
 

6.4.2 Water...................................................................................................................................286
 

6.4.3 Sediment and Soil ...............................................................................................................287
 

6.4.4 Other Environmental Media................................................................................................288
 

6.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE .....................................293
 

6.6 EXPOSURES OF CHILDREN...............................................................................................303
 

6.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES ...........................................305
 

6.8 ADEQUACY OF THE DATABASE......................................................................................307
 

6.8.1 Identification of Data Needs ...............................................................................................307
 

6.8.2 Ongoing Studies..................................................................................................................311
 

7. ANALYTICAL METHODS................................................................................................................315
 

7.1 BIOLOGICAL MATERIALS.................................................................................................315
 

7.2 ENVIRONMENTAL SAMPLES............................................................................................317
 

7.3 ADEQUACY OF THE DATABASE......................................................................................320
 

7.3.1 Identification of Data Needs ...............................................................................................324
 

7.3.2 Ongoing Studies..................................................................................................................324
 

8. REGULATIONS, ADVISORIES, AND GUIDELINES.....................................................................327
 

9. REFERENCES ....................................................................................................................................333
 

10. GLOSSARY ......................................................................................................................................449
 

APPENDICES 

A. ATSDR MINIMAL RISK LEVELS AND WORKSHEETS .............................................................A-1
 

B. USER’S GUIDE.................................................................................................................................. B-1
 

C. ACRONYMS, ABBREVIATIONS, AND SYMBOLS...................................................................... C-1
 

D. INDEX ................................................................................................................................................D-1
 

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CADMIUM xvii 

LIST OF FIGURES
 

2-1. Combined Chronic Oral Cadmium Intakes (μg/kg/day) and Inhalation Cadmium Exposures (μg/m3

) 

that Achieve a Urinary Cadmium Excretion of 0.5 μg/g Creatinine at Age 55 Years Predicted by 

the Cadmium Pharmacokinetic Model and the International Commission on Radiological 

Protection (ICRP) Human Respiratory Tract Model..........................................................................24
 

2-2. Estimates of the UCD10 from Environmental Exposure Dose-Response Studies...............................39
 

2-3. Urinary Cadmium (μg/g creatinine) and Renal Cortex Cadmium Concentration (μg/g wet tissue)
 

Predicted by the Cadmium Pharmacokinetic Model..........................................................................40
 

3-1. Levels of Significant Exposure to Cadmium - Inhalation .................................................................. 67
 

3-2. Levels of Significant Exposure to Cadmium - Oral ......................................................................... 128
 

3-3. Conceptual Representation of a Physiologically Based Pharmacokinetic (PBPK) Model for a
 

Hypothetical Chemical Substance....................................................................................................194
 

3-4. A Schematic Representation of the Nordberg-Kjellström Model.....................................................196
 

3-5. A Schematic Representation of the Shank Model ............................................................................201
 

3-6. Existing Information on Health Effects of Cadmium.......................................................................236
 

6-1. Frequency of NPL Sites with Cadmium Contamination ..................................................................266
 

6-2. Frequency of NPL Sites with Cadmium Compounds Contamination..............................................267
 

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CADMIUM xix 

LIST OF TABLES 

2-1. Summary of Human Studies Finding Dose-Response Relationships Between Biomarkers of
 

Renal Dysfunction and Cadmium Exposure ......................................................................................32
 

2-2. Selected Benchmark Dose Estimations of Urinary Cadmium Levels Associated with Increases 

in the Prevalence of Low Molecular Weight Proteinuria...................................................................35
 

2-3. Selected Studies of Dose-Response Relationship for Cadmium-Induced Low Molecular Weight
 

Proteinuria ..........................................................................................................................................37
 

3-1. Levels of Significant Exposure to Cadmium - Inhalation .................................................................. 49
 

3-2. Comparison of Lung Effects Across Intermediate-Duration Inhalation Studies................................76
 

3-3. Severity of Respiratory Effects in Rats and Mice Exposed to Cadmium Oxide for 13 Weeks..........77
 

3-4. Summary of Occupational Exposure Studies Examining Renal Effects............................................85
 

3-5. Guidelines for Interpreting β2-microglobulin Levels.........................................................................89
 

3-6. Levels of Significant Exposure to Cadmium - Oral ......................................................................... 104
 

3-7. Summary of Human Studies Examining Renal Effects....................................................................143
 

3-8. Benchmark Dose Estimations of Urinary Cadmium Levels.............................................................153
 

3-9. Levels of Significant Exposure to Cadmium - Dermal..................................................................... 172
 

3-10. Genotoxicity of Cadmium In Vivo..................................................................................................174
 

3-11. Genotoxicity of Cadmium In Vitro.................................................................................................177
 

3-12. Assumed Model Parameters and Some Physiologic Parameters for the Nordberg-Kjellström
 

Model .............................................................................................................................................197
 

3-13. Estimated Parameters, Rate of Uptake, Rate Constants, and Biological Half-Lives in Selected 

Mouse Organs After Subcutaneous and Oral Administrations of 109CdCI2 ...................................204
 

3-14. Ongoing Studies on Cadmium........................................................................................................248
 

4-1. Chemical Identity of Cadmium and Compounds .............................................................................250
 

4-2. Physical and Chemical Properties of Cadmium and Compounds ....................................................252
 

5-1. Facilities that Produce, Process, or Use Cadmium...........................................................................256
 

5-2. Facilities that Produce, Process, or Use Cadmium Compounds.......................................................258
 

6-1. Releases to the Environment from Facilities that Produce, Process, or Use Cadmium....................271
 

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CADMIUM xx 

6-2. Releases to the Environment from Facilities that Produce, Process, or Use Cadmium
 

Compounds ......................................................................................................................................273
 

6-3. Mean Concentrations of Cadmium for FDA’s Total Diet Study Market Baskets 91-3 

through 97-1 .....................................................................................................................................290
 

6-4. Geometric Mean and Selected Percentile Blood Concentrations (μg/L) of Cadmium in the 

U.S. Population From 1999 to 2002.................................................................................................295
 

6-5. Geometric Mean and Selected Percentile Urine Concentrations (Creatine Corrected) (μg/L) of
	

Cadmium in the U.S. Population From 1999 to 2002......................................................................296
 

6-6. Geometric Mean and Selected Percentile Urine Concentrations (μg/L) of Cadmium in the
	

U.S. Population From 1999 to 2002.................................................................................................297
 

6-7. Blood Cadmium Concentrations, Geometric Means, Adjusted Proportional Change in Means,
 

and 95th Percentiles in New York City Adults in Population Subgroups........................................298
 

6-8. Occupations with Potential Exposure to Cadmium and Cadmium Compounds ..............................301
 

6-9. Estimated Number of Workers Potentially Exposed to Various Chemicals in the Workplace
 

in 1981–1983....................................................................................................................................302
 

6-10. Ongoing Studies on Cadmium........................................................................................................312
 

7-1. Analytical Methods for Determining Cadmium in Biological Materials.........................................318
 

7-2. Analytical Methods for Determining Cadmium in Environmental Samples....................................321
 

7-3. Ongoing Analytical Methods Studies on Cadmium .........................................................................326
 

8-1. Regulations, Advisories, and Guidelines Applicable to Cadmium ..................................................329
 

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CADMIUM 1 

1. PUBLIC HEALTH STATEMENT 

This public health statement tells you about cadmium and the effects of exposure to it. 

The Environmental Protection Agency (EPA) identifies the most serious hazardous waste sites in the 

nation. These sites are then placed on the National Priorities List (NPL) and are targeted for long-term 

federal clean-up activities. Cadmium has been found in at least 1,014 of the 1,669 current or former NPL 

sites. Although the total number of NPL sites evaluated for this substance is not known, the possibility 

exists that the number of sites at which cadmium is found may increase in the future as more sites are 

evaluated. This information is important because these sites may be sources of exposure and exposure to 

this substance may harm you. 

When a substance is released either from a large area, such as an industrial plant, or from a container, 

such as a drum or bottle, it enters the environment. Such a release does not always lead to exposure. You 

can be exposed to a substance only when you come in contact with it. You may be exposed by breathing, 

eating, or drinking the substance, or by skin contact. 

If you are exposed to cadmium or cadmium compounds, many factors will determine whether you will be 

harmed. These factors include the dose (how much), the duration (how long), and how you come in 

contact with it. You must also consider any other chemicals you are exposed to and your age, sex, diet, 

family traits, lifestyle, and state of health. 

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CADMIUM 2 

1. PUBLIC HEALTH STATEMENT 

1.1 WHAT IS CADMIUM? 

Description Metal found in the earth’s crust, associated with zinc, lead, and 

copper ores. 

Pure cadmium is a soft, silver-white metal. Cadmium chloride 

and cadmium sulfate are soluble in water. 

Uses 

 • Manufacturing 

 • Consumer products 

Most cadmium used in the United States is extracted as a 

byproduct during the production of other metals such as zinc, 

lead, or copper. Cadmium is also recovered from used batteries. 

Cadmium is used for the following: 

• batteries (83%) 

• pigments (8%) 

• coatings and platings (7%) 

• stabilizers for plastics (1.2%) 

• nonferrous alloys, photovoltaic devices, and other uses 

(0.8%) 

For more information on the properties and uses of cadmium, see Chapters 4 and 5. 

1.2 WHAT HAPPENS TO CADMIUM WHEN IT ENTERS THE ENVIRONMENT? 

Sources Cadmium is emitted to soil, water, and air by non-ferrous metal mining 

and refining, manufacture and application of phosphate fertilizers, fossil 

fuel combustion, and waste incineration and disposal. 

Cadmium can accumulate in aquatic organisms and agricultural crops. 

Fate

 • Air Cadmium (as oxide, chloride, and sulfate) will exist in air as particles or 

vapors (from high temperature processes). It can be transported long 

distances in the atmosphere, where it will deposit (wet or dry) onto soils 

and water surfaces. 

 • Soil Cadmium and its compounds may travel through soil, but its mobility 

depends on several factors such as pH and amount of organic matter, 

which will vary depending on the local environment. Generally, 

cadmium binds strongly to organic matter where it will be immobile in 

soil and be taken up by plant life, eventually, entering the food supply. 

 • Water Cadmium exists as the hydrated ion or as ionic complexes with other 

inorganic or organic substances. Soluble forms migrate in water. 

Insoluble forms of cadmium are immobile and will deposit and absorb to 

sediments. 

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CADMIUM 3 

1. PUBLIC HEALTH STATEMENT 

1.3 HOW MIGHT I BE EXPOSED TO CADMIUM? 

Food and In the United States, for nonsmokers the primary source of cadmium 

smoking— exposure is from the food supply. People who regularly consume shellfish 

primary sources and organ meats will have higher exposures. In general, leafy vegetables 

of exposure such as lettuce and spinach, potatoes and grains, peanuts, soybeans, and 

sunflower seeds contain high levels of cadmium. 

Tobacco leaves accumulate high levels of cadmium from the soil. 

The national geometric mean blood cadmium level for adults is 0.47 μg/L. 

A geometric mean blood cadmium level of 1.58 μg/L for New York City 

smokers has been reported. The amount of cadmium absorbed from 

smoking one pack of cigarettes per day is about 1–3 μg/day. Direct 

measurement of cadmium levels in body tissues confirms that smoking 

roughly doubles cadmium body burden in comparison to not smoking. 

Air Except for people living near cadmium-emitting industries, inhalation of 

cadmium is not expected to be a major concern. 

Water EPA has mandated that water suppliers control cadmium concentrations in 

drinking water to <5 μg/L. Therefore, exposure to cadmium through public 

drinking water sources is not a major concern. 

Elevated cadmium levels in water sources in the vicinity of cadmiumemitting industries (historical and current) have been reported. Aquatic 

organisms will accumulate cadmium, possibly entering the food supply. 

People who fish in local waters as a means of food should be cautious and 

abide by any advisories. 

Occupational Highest risk of exposure from processes involving heating cadmiumexposure containing materials such as smelting and electroplating. Risk will vary 

depending on the workplace. 

Major route of exposure is through inhalation of dust and fumes or 

incidental ingestion from contaminated hands, food, or cigarettes. 

Exposure can be controlled through personal protective equipment, good 

industrial hygiene practices, and control and reduction of cadmium 

emissions. 

In Chapter 6, you can find more information on how you might be exposed to cadmium. 

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CADMIUM 4 

1. PUBLIC HEALTH STATEMENT 

1.4 HOW CAN CADMIUM ENTER AND LEAVE MY BODY? 

Enter your body 

• Inhalation 

• Ingestion 

• Dermal 

contact 

About 25–60% of the cadmium you breathe will enter your body through 

your lungs. 

A small amount of the cadmium in food and water (about 5–10%) will enter 

your body through the digestive tract. If you do not have enough iron or 

other nutrients in your diet, you are likely to take up more cadmium from 

your food than usual. 

Virtually no cadmium enters your body through your skin. 

Leave your body Most of the cadmium that enters your body goes to your kidney and liver 

and can remain there for many years. A small portion of the cadmium that 

enters your body leaves slowly in urine and feces. 

Your body can change most cadmium to a form that is not harmful, but too 

much cadmium can overload the ability of your liver and kidney to change 

the cadmium to a harmless form. 

More information on how cadmium enters and leaves the body is found in Chapter 3. 

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CADMIUM 5 

1. PUBLIC HEALTH STATEMENT 

1.5 HOW CAN CADMIUM AFFECT MY HEALTH? 

Workers Breathing air with very high levels of cadmium can severely damage the 

• Inhalation lungs and may cause death. 

In the United States, where proper industrial hygiene is generally practiced, 

inhaling very high levels of cadmium at work is expected to be rare and 

accidental. 

Breathing air with lower levels of cadmium over long periods of time (for 

years) results in a build-up of cadmium in the kidney, and if sufficiently high, 

may result in kidney disease. 

Laboratory 

animals 

• Inhalation Damage to the lungs and nasal cavity have been observed in animals 

exposed to cadmium. 

Humans 

• Oral Eating food or drinking water with very high cadmium levels severely 

irritates the stomach, leading to vomiting and diarrhea, and sometimes 

death. 

Eating lower levels of cadmium over a long period of time can lead to a 

build-up of cadmium in the kidneys. If the levels reach a high enough level, 

the cadmium in the kidney will cause kidney damage. 

Exposure to lower levels of cadmium for a long time can also cause bones 

to become fragile and break easily. 

Laboratory 

animals 

• Oral Kidney and bone effects have also been observed in laboratory animals 

ingesting cadmium. 

Anemia, liver disease, and nerve or brain damage have been observed in 

animals eating or drinking cadmium. We have no good information on 

people to indicate what levels people would need to eat or drink cadmium to 

result in these diseases, or if they would occur at all. 

Cancer Lung cancer has been found in some studies of workers exposed to 

cadmium in the air and studies of rats that breathed in cadmium. 

The U.S. Department of Health and Human Services (DHHS) has 

determined that cadmium and cadmium compounds are known human 

carcinogens. The International Agency for Research on Cancer (IARC) has 

determined that cadmium is carcinogenic to humans. The EPA has 

determined that cadmium is a probable human carcinogen. 

More information on how cadmium can affect your health is found in Chapters 2 and 3. 

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CADMIUM 6 

1. PUBLIC HEALTH STATEMENT 

1.6 HOW CAN CADMIUM AFFECT CHILDREN? 

This section discusses potential health effects in humans from exposures during the period from 

conception to maturity at 18 years of age. 

Effects in children The health effects seen in children from exposure to toxic levels of cadmium 

are expected to be similar to the effects seen in adults (kidney, lung, and 

intestinal damage depending on the route of exposure). 

Harmful effects on child development or behavior have not generally been 

seen in populations exposed to cadmium, but more research is needed. 

A few studies in animals indicate that younger animals absorb more 

cadmium than adults. Animal studies also indicate that the young are more 

susceptible than adults to a loss of bone and decreased bone strength from 

exposure to cadmium. 

Cadmium is found in breast milk and a small amount will enter the infant’s 

body through breastfeeding. The amount of cadmium that can pass to the 

infant depends on how much exposure the mother may have had. 

Birth defects We do not know whether cadmium can cause birth defects in people. 

Studies in animals exposed to high enough levels of cadmium during 

pregnancy have resulted in harmful effects in the young. The nervous 

system appears to be the most sensitive target. Young animals exposed to 

cadmium before birth have shown effects on behavior and learning. There 

is also some information from animal studies that high enough exposures to 

cadmium before birth can reduce body weights and affect the skeleton in 

the developing young. 

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CADMIUM 7 

1. PUBLIC HEALTH STATEMENT 

1.7 HOW CAN FAMILIES REDUCE THE RISK OF EXPOSURE TO CADMIUM? 

Do not smoke 

tobacco products 

Cadmium accumulates in tobacco leaves. The national geometric mean 

blood cadmium level for adults is 0.47 μg/L. Mean blood cadmium levels for 

smokers have been reported as high as 1.58 μg/L. 

Good Occupational exposure can be controlled through personal protective 

occupational equipment, good industrial hygiene practices, and control and reduction of 

hygiene cadmium emissions. 

Children can be exposed to cadmium through parents who work in 

cadmium-emitting industries. Therefore, good hygiene practices such as 

bathing and changing clothes before returning home may help reduce the 

cadmium transported from the job to the home. 

Avoid cadmium Check and obey local fishing advisories before consuming fish or shellfish 

contaminated from local waterways. 

areas and food 

Avoid hazardous waste sites. 

Proper disposal of Dispose of nickel-cadmium batteries properly. Many states have laws in 

cadmium- effect that ban the disposal of batteries as municipal waste. Recycle old 

containing batteries whenever possible. 

products 

Contact your local waste and recycling authority on how to properly dispose 

of paints and coatings. 

Handle properly Do not allow children to play with batteries. If mishandled, batteries could 

rupture. 

Children may also swallow small nickel-cadmium batteries. 

1.8 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN EXPOSED TO 

CADMIUM? 

Detecting 

exposure 

Cadmium can be measured in blood, urine, hair, or nails. Urinary cadmium 

has been shown to accurately reflect the amount of cadmium in the body. 

Measuring 

exposure 

The amount of cadmium in your blood shows your recent exposure to 

cadmium. The amount of cadmium in your urine shows both your recent 

and your past exposure. 

Cadmium levels in hair or nails are not as useful as an indication of when or 

how much cadmium you may have taken in, partly because cadmium from 

outside of your body may attach to the hair or nails. 

Tests are also available to measure the amount of cadmium inside your liver 

and kidneys. 

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CADMIUM 8 

1. PUBLIC HEALTH STATEMENT 

More information on how cadmium can be measured in exposed humans is presented in Chapters 3 and 7. 

1.9 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO 

PROTECT HUMAN HEALTH? 

The federal government develops regulations and recommendations to protect public health. Regulations 

can be enforced by law. The EPA, the Occupational Safety and Health Administration (OSHA), and the 

Food and Drug Administration (FDA) are some federal agencies that develop regulations for toxic 

substances. Recommendations provide valuable guidelines to protect public health, but cannot be 

enforced by law. The Agency for Toxic Substances and Disease Registry (ATSDR) and the National 

Institute for Occupational Safety and Health (NIOSH) are two federal organizations that develop 

recommendations for toxic substances. 

Regulations and recommendations can be expressed as “not-to-exceed” levels, that is, levels of a toxic 

substance in air, water, soil, or food that do not exceed a critical value that is usually based on levels that 

affect animals; they are then adjusted to levels that will help protect humans. Sometimes these not-toexceed levels differ among federal organizations because they used different exposure times (an 8-hour 

workday or a 24-hour day), different animal studies, or other factors. 

Recommendations and regulations are also updated periodically as more information becomes available. 

For the most current information, check with the federal agency or organization that provides it. Some 

regulations and recommendations for cadmium include the following: 

Drinking water The EPA has determined that exposure to cadmium in drinking water at a 

concentration of 0.04 mg/L for up to 10 days is not expected to cause any 

adverse effects in a child. 

The EPA has determined that lifetime exposure to 0.005 mg/L cadmium in 

drinking water is not expected to cause any adverse effects. 

Consumer 

products 

The FDA has determined that cadmium levels in bottled water should not 

exceed 0.005 mg/L. 

Workplace air OSHA set a legal limit of 5 μg/m3 cadmium averaged over an 8-hour work 

day. 

More information on governmental rules regarding cadmium can be found in Chapter 8. 

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CADMIUM 9 

1. PUBLIC HEALTH STATEMENT 

1.10 WHERE CAN I GET MORE INFORMATION? 

If you have any more questions or concerns, please contact your community or state health or 

environmental quality department, or contact ATSDR at the address and phone number below. 

ATSDR can also tell you the location of occupational and environmental health clinics. These clinics 

specialize in recognizing, evaluating, and treating illnesses that result from exposure to hazardous 

substances. 

Toxicological profiles are also available on-line at www.atsdr.cdc.gov and on CD-ROM. You may 

request a copy of the ATSDR ToxProfilesTM CD-ROM by calling the toll-free information and technical 

assistance number at 1-800-CDCINFO (1-800-232-4636), by e-mail at cdcinfo@cdc.gov, or by writing 

to: 

Agency for Toxic Substances and Disease Registry
 

Division of Toxicology and Environmental Medicine
 

1600 Clifton Road NE
 

Mailstop F-32
 

Atlanta, GA 30333
 

Fax: 1-770-488-4178
 

Organizations for-profit may request copies of final Toxicological Profiles from the following: 

National Technical Information Service (NTIS)
 

5285 Port Royal Road
 

Springfield, VA 22161
 

Phone: 1-800-553-6847 or 1-703-605-6000
 

Web site: http://www.ntis.gov/
 

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CADMIUM 10 

1. PUBLIC HEALTH STATEMENT 

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CADMIUM 11 

2. RELEVANCE TO PUBLIC HEALTH 

2.1 BACKGROUND AND ENVIRONMENTAL EXPOSURES TO CADMIUM IN THE UNITED 

STATES 

Cadmium occurs in the earth’s crust at a concentration of 0.1–0.5 ppm and is commonly associated with 

zinc, lead, and copper ores. It is also a natural constituent of ocean water with average levels between 

<5 and 110 ng/L, with higher levels reported near coastal areas and in marine phosphates and 

phosphorites. The cadmium concentration of natural surface water and groundwater is usually <1 μg/L. 

Surface soil concentrations will depend on several factors such as its mobility, natural geochemistry, and 

magnitude of contamination from sources such as fertilizers and atmospheric deposition. Natural 

emissions of cadmium to the environment can result from volcanic eruptions, forest fires, generation of 

sea salt aerosols, or other natural phenomena. 

In the environment, cadmium exists in only one oxidation state (+2) and does not undergo oxidationreduction reactions. In surface water and groundwater, cadmium can exist as the hydrated ion or as ionic 

complexes with other inorganic or organic substances. Soluble forms of cadmium can migrate in water. 

Insoluble forms of cadmium will settle and adsorb to sediments. Cadmium’s fate in soil depends on 

several factors such as pH of the soil and the availability of organic matter. Generally, cadmium will bind 

strongly to organic matter and this will, for the most part, immobilize it. However, cadmium’s behavior 

in soil will vary depending on the environmental conditions. It is not likely that cadmium will undergo 

significant transformation in the atmosphere. It will exist in particulate form and sometimes vapor form 

(emitted from high temperature processes) where it will undergo atmospheric transport and eventually 

deposit onto soils and surface waters. 

Non-ferrous metal mining and refining, manufacture and application of phosphate fertilizers, fossil fuel 

combustion, and waste incineration and disposal are the main anthropogenic sources of cadmium in the 

environment. Except for those who live near cadmium-emitting industries, inhalation of cadmium in the 

ambient air may occur, but is not a major source of exposure. Water sources near cadmium-emitting 

industries, both with historic and current operations, have shown a marked elevation of cadmium in water 

sediments and aquatic organisms. Concentrations of cadmium in these polluted waters have ranged from 

<1.0 to 77 μg/L. For the U.S. population, cadmium exposure through the drinking water supply is of 

minor concern. Cadmium from polluted soil and water can accumulate in plants and organisms, thus 

entering the food supply. 

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CADMIUM 12 

2. RELEVANCE TO PUBLIC HEALTH 

In the United States, the largest source of cadmium exposure for nonsmoking adults and children is 

through dietary intake. The estimated daily intakes of cadmium in nonsmoking adult males and females 

living in the United States are 0.35 and 0.30 μg Cd/kg/day, respectively. Females generally absorb 

greater amounts of cadmium in the gastrointestinal tract. In general, leafy vegetables such as lettuce and 

spinach and staples such as potatoes and grains contain relatively high values of cadmium. Peanuts, 

soybeans, and sunflower seeds have naturally high levels of cadmium. People who regularly consume 

shellfish and organ meats (liver and kidney) have increased cadmium exposure. 

Mean values of cadmium in the blood and urine of the U.S. population were reported in the National 

Health and Nutrition Examination Survey (NHANES) 1999–2002. Blood cadmium reflects both recent 

and cumulative exposures and urinary cadmium reflects cadmium exposure and the concentration of 

cadmium in the kidneys. The 20 years or older age group had geometric mean levels of blood and urine 

cadmium that were slightly higher than the younger age groups (0.468 and 0.273–0.281 μg/L in blood and 

urine, respectively). Females (0.421 μg/L, blood; 0.187–0.219 μg/L urine) had slightly higher blood and 

urine cadmium levels than males (0.403 μg/L, blood; 0.199–0.201 μg/L, urine). 

Smoking greatly increases exposure to cadmium, as tobacco leaves naturally accumulate high amounts of 

cadmium. It has been estimated that tobacco smokers are exposed to 1.7 μg cadmium per cigarette, and 

about 10% is inhaled when smoked. A geometric mean blood cadmium level for a heavy smoker has 

been reported as high as 1.58 μg/L, compared to the estimated national mean of 0.47 μg/L for all adults. 

Nonsmokers may also be exposed to cadmium in cigarettes via second-hand smoke. 

2.2 SUMMARY OF HEALTH EFFECTS 

Since the early 1950s, when the hazards of occupational cadmium exposure were recognized, a large 

amount of information has been generated concerning the toxic effects of cadmium exposure in humans 

and laboratory animals. Toxicological properties of cadmium are similar for the several different salts 

and oxides of cadmium that have been investigated, although differences in absorption and distribution 

lead to different effect levels. For inhalation exposure, particle size and solubility in biological fluids (in 

contrast to solubility in water) appear to be the more important determinants of the toxicokinetics. For 

oral exposure, most experimental studies have used soluble cadmium, which exists as the Cd+2 ion 

regardless of the initial salt. Absorption appears to be similar for cadmium ion and cadmium complexed 

with proteins in food, except for a few specific types of foods such as Bluff oysters and seal meat. Also, 

poorly soluble cadmium pigments may be absorbed to a lesser extent than soluble cadmium ion. For the 

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CADMIUM 13 

2. RELEVANCE TO PUBLIC HEALTH 

general population, dietary exposure to cadmium is the most likely route of exposure. There is an 

extensive database on the toxicity of cadmium in environmentally exposed populations and in cadmium 

workers; however, most of these studies were focused on the presumed sensitive targets. These sensitive 

targets of cadmium toxicity are the kidney and bone following oral exposure and kidney and lung 

following inhalation exposure. Studies in animals support the identification of these sensitive targets and 

provide some suggestive evidence that the developing organisms may also be a sensitive target. There is 

also evidence to suggest that cadmium is a human carcinogen. Other effects that have been observed in 

humans and/or animals include reproductive toxicity, hepatic effects, hematological effects, and 

immunological effects. 

The earliest indication of kidney damage in humans is an increased excretion of low molecular weight 

proteins, particularly β2-microglobulin, human complex forming glycoprotein (pHC) (also referred to as 

α1-microglobulin), and retinol binding protein; increased urinary levels of intracellular enzymes such as 

N-acetyl-β-glucosaminidase (NAG); and increased excretion of calcium and metallothione. Numerous 

studies of cadmium workers and populations living in areas with low, moderate, or high cadmium 

pollution have found significant associations between urinary cadmium levels and biomarker levels or 

significant increases in the prevalence of abnormal biomarker levels. At higher exposure levels, 

decreases in glomerular filtration rate, increased risk of renal replacement therapy (dialysis or kidney 

transplantation), and significant increases in the risk of deaths from renal disease have been observed. 

The sensitivity of the kidney to cadmium is related to its distribution in the body and de novo synthesis of 

metallothionein in the kidney. In the blood, cadmium is bound to metallothionein and is readily filtered at 

the glomerulus and reabsorbed in the proximal tubule. Within the tubular cells, the metallothionein is 

degraded in lysosomes and free cadmium is released; the synthesis of endogenous metallothionein by the 

tubular cells is then stimulated. However, when the total cadmium content in the renal cortex reaches 

between 50 and 300 μg/g wet weight, the amount of cadmium not bound to metallothionein becomes 

sufficiently high to cause tubular damage. Free cadmium ions may inactivate metal-dependent enzymes, 

activate calmodulin, and/or damage cell membranes through activation of oxygen species. Because the 

toxicity of cadmium is dependent on its concentration in the kidney, adverse effects in humans are 

typically not observed after shorter durations. 

Acute inhalation exposure to cadmium at concentrations above about 5 mg/m3 may cause destruction of 

lung epithelial cells, resulting in pulmonary edema, tracheobronchitis, and pneumonitis in both humans 

and animals. A single, high-level cadmium exposure can result in long-term impairment of lung function. 

At the cellular level, catalase, superoxide dismutase, non-protein sulfhydryl, glucose-6-phosphate 

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CADMIUM 14 

2. RELEVANCE TO PUBLIC HEALTH 

dehydrogenase, and glutathione peroxidase are decreased in response to cadmium lung insults. The 

respiratory response to cadmium is similar to the response seen with other agents that produce oxidative 

damage. There typically is an alveolar pneumocyte type 2 cell hyperplasia in response to type 1 cell 

damage and necrosis. Longer-term inhalation exposure at lower levels also leads to decreased lung 

function and emphysema in cadmium workers. Some tolerance to cadmium-induced lung irritation 

develops in exposed humans and animals, and respiratory function may recover after cessation of 

cadmium exposure. Another effect of long-term inhalation cadmium exposure is damage to the olfactory 

function and nasal epithelium. Lung damage has also been seen in a few studies of oral cadmium 

exposure in rats, but the lung effects are likely to be related to liver or kidney damage and subsequent 

changes in cellular metabolism. 

Prolonged inhalation or ingestion exposure of humans to cadmium at levels causing renal dysfunction can 

lead to painful and debilitating bone disease in individuals with risk factors such as poor nutrition; the 

occurrence of these bone effects in elderly Japanese women exposed to high levels of cadmium in rice 

and water was referred to as Itai-Itai disease. Decreases in bone mineral density, increases in the risk of 

fractures, and increases in the risk of osteoporosis have also been observed in populations living in 

cadmium polluted areas or in cadmium nonpolluted areas. Similar effects have also been observed in 

young rats orally exposed to cadmium. Animal data strongly suggest that cadmium exposure results in 

increases in bone turnover and decreases in mineralization during the period of rapid bone growth. 

Although animal studies suggest that these effects are due to direct damage to the bone, it is likely that 

renal damage resulting in the loss of calcium and phosphate and alteration in renal metabolism of 

vitamin D would compound these effects. 

There are few human data on developmental effects from exposure to cadmium. Some studies indicate 

that maternal cadmium exposure may cause decreased birth weight in humans, but most of these studies 

are of limited use because of weaknesses in the study design and lack of control for confounding factors. 

A number of other studies did not find a significant relationship between maternal cadmium levels and 

newborn body weight. In animals, cadmium has been shown to be a developmental toxin by the 

inhalation, oral, and parenteral routes. Decreased fetal weight, skeletal malformations, and delayed 

ossification are produced by relatively high maternal doses (1–20 mg/kg/day) due to placental toxicity, 

interference with fetal metabolism, and damage to the maternal liver. Neurodevelopmental effects have 

been observed at lower doses. Impaired performance on neurobehavioral tests were observed in the 

offspring of rats exposed to 0.02 mg/m3 or ≥0.04 mg/kg/day. 

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CADMIUM 15 

2. RELEVANCE TO PUBLIC HEALTH 

The results of occupational exposure studies examining the possible association between cadmium 

exposure and an increased risk of lung cancer are inconsistent, with some studies finding significant 

increases in lung cancer deaths and other studies not finding increases. Interpretation of the results of 

many of the studies is complicated by inadequate controls for confounding factors such as co-exposure 

with other metal carcinogens and smoking, small number of lung cancer deaths, and the lack of 

significant relationships between cadmium exposure and duration. For prostate cancer, initial studies in 

European workers indicated an elevation in prostate cancer, but subsequent investigations found either no 

increases in prostate cancer or increases that were not statistically significant. Strong evidence from 

animal studies exists that cadmium inhalation can cause lung cancer, but only in rats. Most oral studies in 

laboratory animals have not found significant increases in cancer incidence. The Department of Health 

and Human Services concluded that there were sufficient human and animal data to conclude that 

cadmium is a known human carcinogen; likewise, IARC classified cadmium as carcinogenic to humans 

(Group 1). The EPA has classified cadmium as a probable human carcinogen by inhalation (Group B1), 

based on its assessment of limited evidence of an increase in lung cancer in humans and sufficient 

evidence of lung cancer in rats. 

2.3 MINIMAL RISK LEVELS (MRLs) 

Estimates of exposure levels posing minimal risk to humans (MRLs) have been made for cadmium. An 

MRL is defined as an estimate of daily human exposure to a substance that is likely to be without an 

appreciable risk of adverse effects (noncarcinogenic) over a specified duration of exposure. MRLs are 

derived when reliable and sufficient data exist to identify the target organ(s) of effect or the most sensitive 

health effect(s) for a specific duration within a given route of exposure. MRLs are based on 

noncancerous health effects only and do not consider carcinogenic effects. MRLs can be derived for 

acute, intermediate, and chronic duration exposures for inhalation and oral routes. Appropriate 

methodology does not exist to develop MRLs for dermal exposure. 

Although methods have been established to derive these levels (Barnes and Dourson 1988; EPA 1990d), 

uncertainties are associated with these techniques. Furthermore, ATSDR acknowledges additional 

uncertainties inherent in the application of the procedures to derive less than lifetime MRLs. As an 

example, acute inhalation MRLs may not be protective for health effects that are delayed in development 

or are acquired following repeated acute insults, such as hypersensitivity reactions, asthma, or chronic 

bronchitis. As these kinds of health effects data become available and methods to assess levels of 

significant human exposure improve, these MRLs will be revised. 

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CADMIUM 16 

2. RELEVANCE TO PUBLIC HEALTH 

The database on the toxicity of cadmium in humans and animals following inhalation or oral exposure is 

extensive. Target organs are similar among species and, in general, toxicokinetic properties after oral and 

inhalation exposures are similar. Most of the human data involve chronic inhalation exposure of workers 

or chronic dietary exposure of the general population or populations living in cadmium-polluted areas. 

Several approaches for characterizing cadmium exposure have been used in these studies. Occupational 

exposure studies have used current air concentrations or have estimated cumulative exposure based on 

historical and current monitoring data. Some epidemiology studies have estimated cumulative intake 

based on the levels of cadmium in rice, in populations where rice has been the dominant source of oral 

exposure to cadmium. However, most studies (particularly oral studies) have used urinary cadmium 

levels as a biomarker of exposure. As discussed in greater detail in Section 3.8.1, urinary cadmium levels 

correlate with cadmium body burden and cadmium concentration in kidney (a critical target organ for 

chronic exposure). The relationship between renal and urinary cadmium appears to be nearly linear at 

chronic intakes and kidney burdens that do not produce nephrotoxicity (i.e., elimination half-time is 

independent of dose). However, at high kidney cadmium burdens, associated with renal damage (>50 μg 

Cd/g cortex), the elimination half-time increases with increasing severity of renal damage. Linearity in 

the dose-urinary excretion relationship also does not appear to apply following an acute high exposure to 

cadmium. The Nordberg-Kjellström model (described in detail in Section 3.4.5.3) is a multicompartment 

pharmacokinetic model that can be used to estimate cadmium intakes (inhalation and oral exposure) 

associated with a given urinary cadmium level and/or kidney cadmium burden. The model has been 

extensively evaluated for predicting dose-kidney-urinary cadmium relationships within the linear range of 

the dose-urinary cadmium relationship. 

Inhalation MRLs 

Acute-duration Inhalation MRL 

•	 An MRL of 3x10-5 mg Cd/m3 (0.03 μg Cd/m3

) has been derived for acute-duration inhalation 

exposure (<14 days) to cadmium.
 

The acute toxicity of airborne cadmium, particularly cadmium oxide fumes, was first recognized in the 

early 1920s and there have been numerous case reports of cadmium workers dying after brief exposures 

to presumably high concentrations of cadmium fumes (European Chemicals Bureau 2007). The initial 

symptoms, similar to those observed in metal fume fever, are usually mild but rapidly progress to severe 

pulmonary edema and chemical pneumonitis. Persistent respiratory effects (often lasting years after the 

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CADMIUM 17 

2. RELEVANCE TO PUBLIC HEALTH 

exposure) have been reported in workers surviving these initial effects. There are limited monitoring data 

for these human reports; however, Elinder (1986b) estimated that an 8-hour exposure to 1–5 mg/m3 would 

be immediately dangerous. 

Animal studies support the findings in humans that acute exposure to cadmium results in lung damage. 

Single exposures to approximately 1–10 mg Cd/m3 as cadmium chloride or cadmium oxide resulted in 

interstitial pneumonitis, diffuse alveolitis with hemorrhage, focal interstitial thickening, and edema 

(Boudreau et al. 1989; Buckley and Bassett 1987b; Bus et al. 1978; Grose et al. 1987; Hart 1986; 

Henderson et al. 1979; Palmer et al. 1986). Repeated exposure to 6.1 mg Cd/m3 1 hour/day for 5, 10, or 

15 days resulted in emphysema in rats (Snider et al. 1973). Lower concentrations of 0.4–0.5 mg Cd/m3 as 

cadmium oxide for 2–3 hours (Buckley and Bassett 1987b; Grose et al. 1987) or 0.17 mg Cd/m3 as 

cadmium chloride 6 hours/day for 10 days (Klimisch 1993) resulted in mild hypercellularity and increases 

in lung weight. Alveolar histiocytic infiltration and focal inflammation and minimal fibrosis in alveolar 

septa were observed in rats exposed to 0.088 mg Cd/m3 as cadmium oxide 6.2 hours/day, 5 days/week for 

2 weeks (NTP 1995); in similarly exposed mice, histiocytic infiltration was observed at 0.088 mg Cd/m3 

(NTP 1995). At similar concentrations (0.19 or 0.88 mg Cd/m3

as cadmium chloride), decreases in 

humoral immune response were observed in mice exposed for 1–2 hours (Graham et al. 1978; 

Krzystyniak et al. 1987). Other effects that have been reported in animals acutely exposed to cadmium 

include erosion of the stomach, decreased body weight gain, and tremors in rats exposed to 132 mg Cd/m3 

as cadmium carbonate for 2 hours (Rusch et al. 1986) and weight loss and reduced activity in rats exposed 

to 112 mg Cd/m3 as cadmium oxide for 2 hours (Rusch et al. 1986). 

The NTP (1995) study was selected as the basis of an acute duration inhalation MRL. In this study, 

groups of five male and five female F344 rats were exposed to 0, 0.1, 0.3, 1, 3, or 10 mg cadmium 

oxide/m3 (0, 0.088, 0.26, 0.88, 2.6, or 8.8 mg Cd/m3

) 6.2 hours/day, 5 days/week for 2 weeks. The mean 

median aerodynamic diameter (MMAD) of the cadmium oxide particles was 1.5 μm with a geometric 

standard deviation of 1.6–1.8. The animals were observed twice daily and weighed on days 1, 8, and at 

termination. Other parameters used to assess toxicity included organ weights (heart, kidney, liver, lungs, 

spleen, testis, and thymus) and histopathological examination (gross lesions, heart, kidney, liver, lungs, 

tracheobronchial lymph nodes, and nasal cavity and turbinates). All rats in the 8.8 mg Cd/m3 group died 

by day 6; no other deaths occurred. A slight decrease in terminal body weights was observed at 2.6 mg 

Cd/m3

; however, the body weights were within 10% of control weights. Significant increases in relative 

and absolute lung weights were observed at 0.26 (males only), 0.88, and 2.6 mg Cd/m3

. Histological 

alterations were limited to the respiratory tract and consisted of alveolar histiocytic infiltrate and focal 

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CADMIUM 18 

2. RELEVANCE TO PUBLIC HEALTH 

inflammation and minimal fibrosis in alveolar septa at ≥0.088 mg Cd/m3, necrosis of the epithelium lining 

alveolar ducts at ≥0.26 mg Cd/m3

, tracheobronchiolar lymph node inflammation at ≥0.88 mg Cd/m3, 

degeneration of the nasal olfactory epithelium at 0.88 mg Cd/m3

, and inflammation and metaplasia of the 

nasal respiratory epithelium at 2.6 mg Cd/m3

. 

The lowest-observed-adverse-effect level (LOAEL) of 0.088 mg Cd/m3 was selected as the point of 

departure for derivation of the MRL; benchmark dose analysis was considered; however, the data were 

not suitable for benchmark dose analysis because the data do not provide sufficient information about the 

shape of the dose-response relationship below the 100% response level. The LOAELHEC was calculated 

using the equations below. 

LOAELHEC = LOAELADJ x RDDR 

The duration-adjusted LOAEL (LOAELADJ) was calculated as follows: 

LOAELADJ = 0.088 mg Cd/m3 x 6.2 hours/24 hours x 5 days/7 days 

LOAELADJ = 0.016 mg Cd/m3 

The regional deposited dose ratio (RDDR) for the pulmonary region of 0.617 was calculated with EPA’s 

RDDR calculator (EPA 1994a) using the final body weight of 0.194 kg for the male rats exposed to 

0.088 mg Cd/m3

, the reported MMAD of 1.5 μm and the midpoint of the reported range of geometric 

standard deviations (1.7). 

LOAELHEC = 0.016 mg Cd/m3 x 0.617 

LOAELHEC = 0.01 mg Cd/m3 

The LOAELHEC was divided by an uncertainty factor of 300 (10 for the use of a LOAEL, 3 for 

extrapolation from animals to humans with dosimetric adjustments, and 10 for human variability) 

resulting in an acute-duration inhalation MRL of 3x10-5 mg Cd/m3 (0.03 μg Cd/m3

). 

Intermediate-duration Inhalation MRL 

There are no studies examining the intermediate-duration toxicity of inhaled cadmium in humans; 

however, numerous animal studies have identified several targets of cadmium toxicity. Increases in the 

number of bronchioalveolar macrophages, alveolar histiocytic infiltration, degeneration or metaplasia in 

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CADMIUM 19 

2. RELEVANCE TO PUBLIC HEALTH 

the larynx, and proliferations have been observed in rats and mice exposed to 0.022 mg Cd/m3 as 

cadmium oxide or cadmium chloride (Glaser et al. 1986; NTP 1995; Prigge 1978a). At higher 

concentrations (>0.88 mg Cd/m3

), marked inflammation and fibrosis was observed in lungs of rats 

(Kutzman et al. 1986; NTP 1995). In general, these studies did not identify no-observed-adverse-effect 

levels (NOAELs) for lung effects. The NTP (1995) study also found significant increases in the 

incidence of inflammation of the nasal respiratory epithelium in rats exposed to 0.22 mg Cd/m3 and 

degeneration of the nasal olfactory epithelium in mice exposed to 0.088 mg Cd/m3

. The NTP (1995) 

study did not find any histological alterations in non-respiratory tract tissues, alterations in urinalysis 

parameters, or changes in blood pressure (rats only) in rats or mice. Prigge (1978a, 1978b) reported 

increases in hemoglobin and hematocrit levels in rats continuously exposed to ≥0.052 mg Cd/m3

; 

however, this effect was not observed in the NTP (1995) studies. Reproductive effects (increased 

duration of estrous cycle and decreased spermatid counts) have also been observed at higher 

concentrations (0.88–1 mg Cd/m3

) (Baranski and Sitarek 1987; NTP 1995). 

The studies by Baranski (1984, 1985) provide suggestive evidence that the developing organism is also a 

sensitive target of cadmium toxicity. Significant alterations in performance on neurobehavioral tests were 

observed in the offspring of rats exposed to 0.02 mg Cd/m3 as cadmium oxide 5 hours/day, 5 days/week 

for 5 months prior to mating, during a 3-week mating period, and during gestation days 1–20. No other 

studies examined neurodevelopmental end points following inhalation exposure. However, the 

identification of neurodevelopmental effects as a sensitive target of cadmium toxicity is supported by 

several intermediate-duration animal studies finding neurodevelopmental effects including alterations in 

motor activity and delays in the development of sensory motor coordination reflexes (Ali et al. 1986; 

Baranski 1985; Desi et al. 1998; Nagymajtenyi et al. 1997). Other developmental effects observed in the 

inhalation studies included decreases in fetal body weight in the fetuses of rats exposed to 1.7 or 0.581 mg 

Cd/m3 (NTP 1995; Prigge 1978b) and mice exposed to 0.4 mg Cd/m3 (NTP 1995). 

Based on the available animal data, the LOAEL of 0.022 mg Cd/m3 for lung and larynx effects in mice 

(NTP 1995) and the LOAEL of 0.02 mg Cd/m3 for neurodevelopmental effects (Baranski 1984, 1985) 

were evaluated as possible points of departure for the intermediate-duration inhalation MRL for cadmium. 

The LOAEL of 0.022 mg Cd/m3 identified in the NTP (1995) mouse study was considered as the point of 

departure for the MRL because the NTP study provided more study details and information on particle 

size distribution. Because an MRL based on this LOAEL (LOAELHEC of 1 μg Cd/m3

) would be lower 

than the chronic-duration inhalation MRL based on human data, an intermediate-duration inhalation MRL 

was not derived. 

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CADMIUM 20 

2. RELEVANCE TO PUBLIC HEALTH 

Chronic-duration Inhalation MRL 

•	 An MRL of 0.01 μg Cd/m3 has been derived for chronic-duration inhalation exposure (≥1 year) to 

cadmium. 

Numerous studies examining the toxicity of cadmium in workers have identified the respiratory tract and 

the kidney as sensitive targets of toxicity. A variety of respiratory tract effects have been observed in 

cadmium workers including respiratory symptoms (e.g., dyspnea, coughing, wheezing), emphysema, and 

impaired lung function. However, many of these studies did not control for smoking, and thus, the role of 

cadmium in the induction of these effects is difficult to determine. Impaired lung function was reported 

in several studies that controlled for smoking (Chan et al. 1988; Cortona et al. 1992; Davison et al. 1988; 

Smith et al. 1976); other studies have not found significant alterations (Edling et al. 1986). The observed 

alterations included an increase in residual volume in workers exposed to air concentrations of cadmium 

fumes ranging from 0.008 (in 1990) to 1.53 mg/m3 (in 1975) (mean urinary cadmium level in the workers 

was 4.3 μg/L) (Cortona et al. 1992); alterations in several lung function parameters (e.g., forced 

expiratory volume, transfer factor, transfer coefficient) in workers exposed to 0.034–0.156 mg/m3 

(Davison et al. 1988); and decreased force vital capacity in workers exposed to >0.2 mg/m3 (Smith et al. 

1976). Additionally, Chan et al. (1988) found significant improvements in several parameters of lung 

function of workers following reduction or cessation of cadmium exposure. 

The renal toxicity of cadmium in workers chronically exposed to high levels of cadmium is well 

established. Observed effects include tubular proteinuria (increased excretion of low molecular weight 

proteins), decreased resorption of other solutes (increased excretion of enzymes such as NAG, amino 

acids, glucose, calcium, inorganic phosphate), evidence of increased glomerular permeability (increased 

excretion of albumin), increased kidney stone formation, and decreased glomerular filtration rate (GFR). 

The earliest sign of cadmium-induced kidney damage is an increase in urinary levels of low molecular 

weight proteins (particularly, β2-microglobulin, retinol binding protein, and pHC) in cadmium workers, 

as compared to levels found in a reference group of workers or the general population (Bernard et al. 

1990; Chen et al. 2006a, 2006b; Chia et al. 1992; Elinder et al. 1985a; Falck et al. 1983; Jakubowski et al. 

1987, 1992; Järup and Elinder 1994; Järup et al. 1988; Shaikh et al. 1987; Toffoletto et al. 1992; 

Verschoor et al. 1987). Although increases in the excretion of low molecular weight proteins are not 

diagnostic of renal damage (Bernard et al. 1997; Järup et al. 1998b), tubular proteinuria is considered an 

adverse effect because it is an early change in a sequence of events which ultimately may result in 

compromised renal function (Bernard et al. 1997). Most investigators consider a 10% cadmium­

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CADMIUM 21 

2. RELEVANCE TO PUBLIC HEALTH 

associated increase in the prevalence of abnormal levels of renal biomarkers (urinary β2-microglobulin, 

retinol binding protein, pHC) to be indicative of cadmium-induced renal disease in the population. 

However, there is less consensus on the low molecular protein level regarded as elevated or abnormal 

(cut-off point). 

Several biomarkers of tubular damage have been used in occupational exposure studies; these include 

β2-microglobulin, retinol binding protein, NAG, and pHC. Of these biomarkers, which differ in their 

sensitivities to detect tubular damage, β2-microglobulin is the most widely used in occupational exposure 

studies. In healthy humans, urinary β2-microglobulin levels are <300 μg/24 hours (approximately 

300 μg/g creatinine). Four studies have estimated the prevalence of abnormal urinary β2-microglobulin 

levels among cadmium workers using cut-off levels of 187–380 μg/g creatinine (Chen et al. 2006a; 

Elinder et al. 1985a; Jakubowski et al. 1987; Järup and Elinder 1994). The prevalence of abnormal 

urinary β2-microglobin levels was 10% among workers with urinary cadmium levels of 1.5 (≥60 years of 

age) or 5 (<60 years of age) μg/g creatinine (β2-microglobulin cut-off level of 220 μg/g creatinine) (Järup 

and Elinder 1994), 25% among workers with urinary cadmium levels of 2–5 μg/g creatinine (cut-off level 

of 300 μg/g creatinine) (Elinder et al. 1985a), 40% among workers with urinary cadmium levels of 5– 

10 μg/g creatinine (cut-off level of 187 μg/g creatinine) (Chen et al. 2006a), and 10% among workers 

with urinary cadmium levels of 10–15 μg/g creatinine (cut-off level of 380 μg/g creatinine (Jakubowski et 

al. 1987). A 10% prevalence of abnormal β2-microglobulin levels (cut-off level of 300 μg/g creatinine) 

was also observed in workers with a cumulative blood cadmium level of 300 μg-years/L (30 years of 

10 μg/L) (Jakubowski et al. 1992) or blood cadmium level of 5.6 μg/L (cumulative exposure of 

691 μg-years/m3

) (Järup et al. 1988). 

Most of the studies reporting respiratory effects expressed cadmium exposure as air concentrations; 

however, these air concentrations may not be indicative of cadmium exposure over time. For example, in 

the Cortona et al. (1992) study, cadmium levels of 0.030 mg/m3 were measured in 1990 in one foundry; in 

1976, the cadmium levels in this foundry were 1.53 mg/m3

. Cortona et al. (1992) also reported cadmium 

body burden data; the mean urinary cadmium level in the workers was 4.3 μg/L (roughly equivalent to 

4 μg/g creatinine). Renal effects have been observed at similar cadmium burdens. Most studies have 

reported renal effects in workers with urinary cadmium levels of ≥5 μg/g creatinine; Järup and Elinder 

(1994) found an increased prevalence of low molecular weight proteinuria in workers ≥60 years of age 

with mean urinary cadmium of 1.5 μg/g creatinine. The air concentration that would result in this urinary 

cadmium level would be considered a LOAEL. However, cadmium in the workplace air was not the only 

source of cadmium. The workers were also exposed to other sources of cadmium (e.g., cadmium in the 

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CADMIUM 22 

2. RELEVANCE TO PUBLIC HEALTH 

diet); both sources contributed to the renal cadmium burden. Thus, in order to calculate a chronicduration inhalation MRL from the LOAEL identified in the Järup and Elinder (1994) study, the workers’ 

other sources of cadmium need to be taken into consideration; this information was not reported in the 

study. 

An alternative approach would be to use environmental exposure studies to establish a point of departure 

for the urinary cadmium-renal response relationship and pharmacokinetic models (ICRP 1994; Kjellström 

and Nordberg 1978) to predict cadmium air concentrations. As described in greater detail in the chronic 

oral MRL section, a meta-analysis of available environmental exposure studies was conducted to estimate 

an internal dose (urinary cadmium expressed as μg/g creatinine) corresponding to a 10% excess risk of 

low molecular weight proteinuria (urinary cadmium dose, UCD10). For the inhalation MRL, the metaanalysis also included dose-response data from three occupational exposure studies (Chen et al. 2006a, 

2006b; Järup and Elinder 1994; Roels et al. 1993). Analysis of the environmental exposure studies 

resulted in an estimation of a urinary cadmium level that would result in a 10% increase in the prevalence 

of β2-microglobulin proteinuria (1.34 μg/g creatinine); the 95% lower confidence limit on this value was 

0.5 μg/g creatinine. The UCD10 values from the occupational exposure studies were 7.50 μg/g creatinine 

for the European cohorts (Järup and Elinder 1994; Roels et al. 1993) and 4.58 μg/g creatinine for the 

Chinese cohort (Chen et al. 2006a, 2006b). Because the dose-response analysis using the European 

environmental exposure studies provided the lowest UCD10, it was selected for derivation of the chronicduration inhalation MRL; the 95% lower confidence limit on this value (UCDL10) of 0.5 μg/g creatinine 

was used as the point of departure for the MRL. 

Deposition and clearance of inhaled cadmium oxide and cadmium sulfide particles were modeled using 

the ICRP Human Respiratory Tract Model (ICRP 1994). The ICRP model simulates deposition, 

retention, and absorption of inhaled cadmium particles of specific aerodynamic diameters, when specific 

parameters for cadmium clearance are used in the model (ICRP 1980). Cadmium-specific parameters 

represent categories of solubility and dissolution kinetics in the respiratory tract (e.g., slow, S; moderate, 

M; or fast, F). Cadmium compounds are classified as follows: oxides and hydroxides, S; sulfides, halides 

and nitrates, M; all other, including chloride salts, F. 

Inhalation exposures (μg/m3

) to cadmium oxide or cadmium sulfide aerosols having particle diameters of 

1, 5, or 10 μg (AMAD) were simulated using the ICRP model. Predicted mass transfers of cadmium from 

the respiratory tract to the gastrointestinal tract (i.e., mucocilliary transport) and to blood (i.e., absorption) 

were used as inputs to the gastrointestinal and blood compartments of the Nordberg-Kjellström 

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CADMIUM 23 

2. RELEVANCE TO PUBLIC HEALTH 

pharmacokinetic model (Kjellström and Nordberg 1978) to simulate the kidney and urinary cadmium 

levels that correspond to a given inhalation exposure. 

As illustrated in Figure 2-1, an airborne cadmium concentration of 1.8–2.4 μg/m3 as cadmium oxide or 

1.2–1.4 μg/m3 as cadmium sulfide would result in a urinary cadmium level of 0.5 μg/g creatinine, 

assuming that there was no dietary source of cadmium. This assumption is not accurate because the diet 

is a significant contributor to the cadmium body burden. Thus, inhalation exposures were combined with 

ingestion intakes to estimate an internal dose in terms of urinary cadmium. The age-weighted average 

intakes of cadmium in non smoking males and females in the United States are 0.35 and 0.30 μg 

Cd/kg/day, respectively (0.32 μg/kg/day for males and females combined) (estimated from data in 

Choudhury et al. 2001). Based on the relationship predicted between chronic inhalation exposures to 

cadmium sulfide (activity median aerodynamic diameter [AMAD]=1 μm) and oral intakes that yield the 

same urinary cadmium level (Figure 2-1), exposure to an airborne cadmium concentration of 0.1 μg/m3 

and a dietary intake of 0.3 μg/kg/day would result in a urinary cadmium level of 0.5 μg/g creatinine. 

Dividing this cadmium air concentration (0.1 μg Cd/m3

) by an uncertainty factor of 3 for human 

variability and a modifying factor of 3 results in chronic-duration inhalation MRL of 0.01 μg Cd/m3

. The 

uncertainty factor of 3 for human variability was used to account for the possible increased sensitivity of 

diabetics (Åkesson et al. 2005; Buchet et al. 1990) and the modifying factor of 3 was used to account for 

the lack of adequate human data, which could be used to compare the relative sensitivities of the 

respiratory tract and kidneys. Although based on exposure to cadmium sulfide, the MRL would be 

protective of exposure to cadmium oxide; the pharmacokinetic models predict that exposure to 0.1 μg/m3 

as cadmium oxide (AMAD=1 μm) in combination with a dietary intake of 0.3 μg/kg/day would result in a 

urinary cadmium level of 0.4 μg/g creatinine. 

Oral MRLs 

Acute-duration Oral MRL 

There are no reliable studies on the acute toxicity of cadmium in humans; animal studies have identified 

several targets of toxicity. High exposures (>10 mg Cd/kg/day) to cadmium chloride administered via 

gavage or drinking water resulted in increases in hematological (increased hemoglobin, hematocrit, and 

erythrocytes, anemia), liver (focal necrosis and degeneration), kidney (focal necrosis of tubular 

epithelium), intestine (necrosis, hemorrhage, ulcers), stomach (gastritis, necrosis), neurological 

(decreased motor activity), and testicular (atrophy and necrosis, loss of spermatogenic elements) effects 

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CADMIUM 24 

2. RELEVANCE TO PUBLIC HEALTH 

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Figure 2-1. Combined Chronic Oral Cadmium Intakes (μg/kg/day) and Inhalation 

Cadmium Exposures (μg/m3

) that Achieve a Urinary Cadmium Excretion of 

0.5 μg/g Creatinine at Age 55 Years Predicted by the Cadmium 

Pharmacokinetic Model and the International Commission on 

Radiological Protection (ICRP) Human Respiratory 

Tract Model* 

*The upper panel shows simulations of inhalation exposures to cadmium oxide (AMAD=1, 5, or 10 μm); the lower 

panel shows simulations of inhalation cadmium sulfide aerosols. 

0.0 

0.5 

1.0 

1.5 

2.0 

2.5 

0.0 0.1 0.2 0.3 0.4 

Oral (μg Cd/kg/day) 

Air (μg/m3 ) 

CdS (1 μm) 

CdS (5 μm) 

CdS (10 μm) 

0.0 

0.5 

1.0 

1.5 

2.0 

2.5 

0.0 0.1 0.2 0.3 0.4 

Oral (μg Cd/kg/day) 

Air (μg/m3 ) 

CdO (1 μm) 

CdO (5 μm) 

CdO (10 μm) 
 

 

 

 

	 
 


 

CADMIUM 25 

2. RELEVANCE TO PUBLIC HEALTH 

and decreases in body weight in rats and mice (Andersen et al. 1988; Basinger et al. 1988; Bomhard et al. 

1987; Borzelleca et al. 1989; Dixon et al. 1976; Kotsonis and Klaassen 1977; Machemer and Lorke 1981; 

Sakata et al. 1988; Shimizu and Morita 1990). The NOAELs for these effects ranged from 1.12 to 

65.6 mg Cd/kg/day. 

Developmental effects have been observed at lower cadmium doses. Delayed ossification of the sternum 

and ribs was observed in the offspring of rats administered 2 mg Cd/kg/day via gavage on gestation 

days 7–16; at 40 mg Cd/kg/day, fused lower limbs, decreased number of live fetuses, and increased 

resorptions were observed (Baranski 1985). A significant increase in malformations was observed in the 

offspring of rats administered 18.39 mg Cd/kg/day on gestation days 6–15 (Machemer and Lorke 1981); 

no developmental effects were observed in the offspring of rats administered 12.5 mg Cd/kg/day via 

drinking water on gestation days 6–15 (Machemer and Lorke 1981). 

Although the Baranski (1985) study identified the lowest LOAEL (2 mg Cd/kg/day) following acuteduration exposure, this study was not considered suitable for derivation of an MRL. The investigators 

noted that “a retarded process of ossification of the sternum and ribs was observed after exposure to 

cadmium at any of the doses used.” However, the data were not shown and the statistical significance of 

the finding was not reported. Additionally, an intermediate-duration study conducted earlier by this 

investigator (Baranski et al. 1983) did not find delays in ossification in the offspring of rats administered 

up to 4 mg Cd/kg/day for 5 weeks prior to mating, during the 3-week mating period, and throughout 

gestation. 

Intermediate-duration Oral MRL 

•	 An MRL of 0.5 μg Cd/kg/day has been derived for intermediate-duration oral exposure (15–
 

364 days) to cadmium.
 

There are limited data on the toxicity of cadmium in humans following intermediate-duration exposure. 

Numerous animal studies have examined the systemic, immunological, neurological, reproductive, and 

developmental toxicity of cadmium. The most sensitive systemic effect following intermediate-duration 

oral exposure to cadmium appears to be damage to growing bone. Exposure to 0.2 mg Cd/kg/day as 

cadmium chloride in drinking water for 3–12 months resulted in decreases in bone mineral density, 

impaired mechanical strength of the lumbar spine, tibia, and femur bones, increased bone turnover, and 

increased incidence of deformed or fractured lumbar spine bone in young female rats (3 weeks of age at 

study initiation) (Brzóska and Moniuszko-Jakoniuk 2005d; Brzóska et al. 2004b, 2005a, 2005b, 2005c); 

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CADMIUM 26 

2. RELEVANCE TO PUBLIC HEALTH 

similar findings were observed in young male rats exposed to 0.5 mg Cd/kg/day for up to 12 months 

(Brzóska and Moniuszko-Jakoniuk 2005a, 2005b). Decreases in bone strength were also observed in 

young rats exposed to 0.8 mg Cd/kg/day as cadmium chloride in drinking water for 4 weeks (Ogoshi et al. 

1989); however, no skeletal effects were observed in adult or elderly female rats exposed to doses >20 mg 

Cd/kg/day for 4 weeks (Ogoshi et al. 1989). Decreases in bone calcium were observed in mice 

undergoing repeated pregnancy/lactation periods (Bhattacharyya et al. 1988b) or ovariectomized mice 

(Bhaattacharyya et al. 1988c); these changes were not observed in groups not under physiological stress. 

Renal effects have been observed at higher doses than the skeletal effects. Vesiculation of the proximal 

tubules was observed in rats exposed to 1.18 mg Cd/kg/day as cadmium chloride in drinking water for 

40 weeks (Gatta et al. 1989). At approximately 3–8 mg Cd/kg/day, proteinuria, tubular necrosis, and 

decreased renal clearance were observed in rats (Cha 1987; Itokawa et al. 1974; Kawamura et al. 1978; 

Kotsonis and Klaassen 1978; Prigge 1978a). Liver necrosis and anemia (Cha 1987; Groten et al. 1990; 

Kawamura et al. 1978) were observed at similar cadmium doses. 

Immunological effects have been observed in studies of monkeys, rats, and mice. The observed effects 

include increases in cell-mediated immune response in monkeys exposed to 5 mg Cd/kg/day as cadmium 

chloride in the diet for 10 weeks (Chopra et al. 1984), decreased humoral immune response in mice 

exposed to 2.8 mg Cd/kg/day as cadmium chloride in drinking water for 3 weeks (Blakley 1985), and 

greater susceptibility to lymphocytic leukemia virus in mice exposed to 1.9 mg Cd/kg/day as cadmium 

chloride in drinking water for 280 days (Blakley 1986). 

Neurological effects observed in rats include decreases in motor activity at 3.1 or 9 mg Cd/kg/day 

(Kotsonis and Klaassen 1978; Nation et al. 1990) and increased passive avoidance at 5 mg Cd/kg/day 

(Nation et al. 1984). Reproductive effects (necrosis and atrophy of seminiferous tubules, decreased sperm 

count and motility) were observed in rats exposed to 8–12 mg Cd/kg/day (Cha 1987; Saxena et al. 1989). 

A number of developmental effects have been observed in the offspring of rats exposed to cadmium 

during gestation and lactation. Decreases in glomerular filtration rates and increases in urinary fractional 

excretion of phosphate, magnesium, potassium, sodium, and calcium were observed in 60-day-old 

offspring of rats administered via gavage 0.5 mg Cd/kg/day on gestation days 1–21 (Jacquillet et al. 

2007). Neurodevelopmental alterations have also been observed at the low maternal doses. Delays in the 

development of sensory motor coordination reflexes and increased motor activity were observed at 

0.706 mg Cd/kg/day (gestation days 1–21) (Ali et al. 1986), decreased motor activity at 0.04 mg 

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CADMIUM 27 

2. RELEVANCE TO PUBLIC HEALTH 

Cd/kg/day (5–8 weeks of pre-gestation exposure, gestation days 1–21) (Baranski et al. 1983), decreased 

ambulation and rearing activity and altered ECG at 14 mg Cd/kg/day (gestation days 5–15, lactation days 

2–28, postnatal days 1–56) (Desi et al. 1998) or 7 mg Cd/kg/day (F2 and F3 generations) (Nagymajtenyi et 

al. 1997) have been observed. Decreases in pup body weight were observed at ≥5 mg Cd/kg/day 

(Baranski 1987; Gupta et al. 1993; Kostial et al. 1993; Pond and Walker 1975) and decreases in fetal body 

weight or birth weight were observed at ≥2.4 mg Cd/kg/day (Petering et al. 1979; Sorell and Graziano 

1990; Webster 1978; Sutou et al. 1980). Another commonly reported developmental effect was 

alterations in hematocrit levels or anemia in the offspring of animals exposed to ≥1.5 mg Cd/kg/day 

(Baranski 1987; Kelman et al. 1978; Webster 1978). Increases in the occurrence of malformations or 

anomalies is limited to a study by Sutou et al. (1980), which reported a significant delay in ossification in 

rats exposed to 10 mg Cd/kg/day. 

The animal studies identify several sensitive targets of toxicity following intermediate-duration exposure 

to cadmium; these include skeletal mineralization in young female rats exposed for at least 3 months to 

0.2 mg Cd/kg/day (Brzóska and Moniuszko-Jakoniuk 2005d; Brzóska et al. 2004b, 2005a, 2005b, 2005c), 

decreased glomerular filtration in young rats exposed during gestation to maternal doses of 0.5 mg 

Cd/kg/day (Jacquillet et al. 2007), and neurodevelopmental effects following gestational exposure to 

0.04 mg Cd/kg/day (Baranski et al. 1983). Although the Baranski et al. (1983) study reported the lowest 

LOAEL, it was not selected as the principal study for derivation of an intermediate-duration MRL. For 

locomotor activity, a significant decrease in activity was observed in female offspring exposed to 0.04, 

0.4, and 4 mg Cd/kg/day, as compared to controls; however, no significant differences were found 

between the cadmium groups despite the 100-fold difference in doses. Locomotor activity was also 

decreased in males exposed to 0.4 or 4 mg Cd/kg/day. For the rotorod test, a significant decrease in the 

length of time the rat stayed on the rotorod was observed in males exposed to 0.04 and 0.4 mg Cd/kg/day, 

but not to 4 mg Cd/kg/day and in females exposed to 0.4 and 4 mg Cd/kg/day; no differences between the 

cadmium groups were observed in the males and females. The results were not well described and the 

investigators did not explain the lack of dose-response of the effects or the discrepancy between genders. 

The skeletal effects observed in young rats exposed to cadmium during the period of rapid skeletal growth 

and mineralization was selected as the critical effect. The Brzóska and associate study (Brzóska and 

Moniuszko-Jakoniuk 2005d; Brzóska et al. 2005a, 2005c) was selected as the principal study. In this 

study, groups of 40 3-week-old female Wistar rats were exposed to 0, 1, 5, or 50 mg Cd/L as cadmium 

chloride in drinking water for 12 months. The investigators noted that cadmium intakes were 0.059– 

0.219, 0.236–1.005, and 2.247–9.649 mg Cd/kg/day in the 1, 5, and 50 mg/L groups, respectively. Using 

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CADMIUM 28 

2. RELEVANCE TO PUBLIC HEALTH 

cadmium intake data presented in a figure, cadmium intakes of 0.2, 0.5, and 4 mg Cd/kg/day were 

estimated. Bone mineral density, bone mineral concentration, and mineralization area of the lumbar 

spine, femur, and total skeleton (bone mineral density only) were assessed after 3, 6, 9, or 12 months of 

exposure. The mechanical properties of the femur and tibia were evaluated after 12 months of exposure. 

Markers for bone resorption (urinary and serum levels of C-terminal cross-linking telopeptide of type I 

collagen [CTX]) and bone formation (serum osteocalcin, total alkaline phosphatase, and cortical bone and 

trabecular bone alkaline phosphatase), and serum and urinary levels of calcium were also measured at 3, 

6, 9, and 12 months. 

No significant alterations in body weight gain or food and water consumption were observed. Significant 

decreases in total skeletal bone mineral density was observed at ≥0.2 mg Cd/kg/day; the decrease was 

significant after 3 months in the 4 mg Cd/kg/day group, after 6 months in the 0.5 mg Cd/kg/day group, 

and after 9 months in the 0.2 mg Cd/kg/day group. Significant decreases in whole tibia and diaphysis 

bone mineral density were observed at ≥0.2 mg Cd/kg/day after 12 months of exposure. At 0.2 mg 

Cd/kg/day, bone mineral density was decreased at the proximal and distal ends of the femur after 

6 months of exposure; diaphysis bone mineral density was not affected. At 0.5 mg Cd/kg/day, bone 

mineral density was decreased at the femur proximal and distal ends after 3 months of exposure and 

diaphysis bone mineral density after 6 months of exposure. At 4 mg Cd/kg/day decreases in femoral 

proximal, distal, and diaphysis bone mineral density were decreased after 3 months of exposure. 

Similarly, bone mineral density was significantly decreased in the lumbar spine in the 0.2 and 0.5 mg 

Cd/kg/day groups beginning at 6 months and at 3 months in the 4 mg Cd/kg/day group. Significant 

decreases in the mineralization area were observed in the femur and lumbar spine of rats exposed to 4 mg 

Cd/kg/day; lumbar spine bone mineral area was also affected at 0.5 mg Cd/kg/day. Significant decreases 

in tibia weight and length were observed at 4 mg Cd/kg/day. In tests of the mechanical properties of the 

tibia diaphysis, significant alterations in ultimate load, yield load, and displacement at load were observed 

at ≥0.2 mg Cd/kg/day; work to fracture was also significantly altered at 4 mg Cd/kg/day. In the 

mechanical properties compression tests of the tibia, significant alterations were observed in ultimate 

load, ultimate load, and stiffness at 0.2 mg Cd/kg/day; displacement at yield and work to fracture at 

≥0.5 mg Cd/kg/day; and displacement at ultimate at 4 mg Cd/kg/day. Multiple regression analysis 

showed that the the cadmium-induced weakness in bone mechanical properties of the tibia was primarily 

due to its effects on bone composition, particularly the non-organic components, organic components, and 

the ratio of ash weight to organic weight. The mechanical properties of the femur were strongly 

influenced by the bone mineral density (at the whole bone and diaphysis). A significant decrease in 

femur length was observed at 6 months of exposure to ≥0.2 mg Cd/kg/day; however, decreases in length 

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CADMIUM 29 

2. RELEVANCE TO PUBLIC HEALTH 

were not observed at other time points in the 0.2 or 0.5 mg Cd/kg/day groups. Femur weight was 

significantly decreased at 4 mg Cd/kg/day. In tests of mechanical properties of the femur (neck and distal 

portions), decreases in yield load, ultimate load, displacement at ultimate, work to fracture (neck only), 

and stiffness (distal only) were observed at ≥0.2 mg Cd/kg/day. For the femoral diaphysis, significant 

alterations were observed for yield load, displacement at yield, and stiffness at ≥0.2 mg Cd/kg/day. 

Significant decreases in osteocalcin concentrations were observed in all cadmium groups during the first 

6 months of exposure, but not during the last 6 months. Decreases in total alkaline phosphatase levels at 

4 mg Cd/kg/day, trabecular bone alkaline phosphatase at 0.2 mg Cd/kg/day, and cortical bone alkaline 

phosphatase at 4 mg Cd/kg/day were observed. CTX was decreased at ≥0.2 mg Cd/kg/day. Total urinary 

calcium and fractional excretion of calcium were increased at ≥0.2 mg Cd/kg/day. 

At the lowest dose tested, 0.2 mg Cd/kg/day, a number of skeletal alterations were observed including 

decreases in bone mineral density in the lumbar spine, femur, and tibia, alterations in the mechanical 

properties of the femur and tibia, decreases in osteocalcin levels, decreases in trabecular bone alkaline 

phosphatase, and decreases in CTX. Of these skeletal end points, the decrease in bone mineral density 

was selected as the critical effect because Brzóska et al. (2005a, 2005c) demonstrated that the bone 

mineral density was a stronger predictor of femur and tibia strength and the risk of fractures. As 

discussed in greater detail in Appendix A, available continuous models in the EPA Benchmark Dose 

Software (version 1.4.1c) were fit to data for changes in bone mineral density of the femur and lumbar 

spine in female rats resulting from exposure to cadmium in the drinking water for 6, 9, or 12 months 

(Brzóska and Moniuszko-Jakoniuk 2005d). The benchmark dose (BMD) and the 95% lower confidence 

limit (BMDL) is an estimate of the doses associated with a change of 1 standard deviation from the 

control. The BMDLsd1 derived from the best fitting models for each dataset ranged from 0.05 to 0.17 mg 

Cd/kg/day. The BMDLsd1 of 0.05 mg Cd/kg/day estimated from the 9-month lumbar spine data set was 

selected as the point of departure for the MRL. In young female rats, the process of intense bone 

formation occurs during the first 7 months of life (the first 6 months of exposure in this study); thereafter, 

the increase in bone mineral density slows. In the lumbar spine of the control group, the changes in bone 

mineral density at 3–6 months, 6–9 months, and 9–12 months were 15, 4, and 1%, respectively. Thus, the 

9-month data may best reflect the effect of cadmium on bone mineral density during the period of rapid 

skeletal growth. The lumbar spine data was selected over the femur data set because trabecular bone, 

which is abundant in the spine, appears to be more susceptible to cadmium toxicity than cortical bone. 

The BMDLsd1 was divided by an uncertainty factor of 100 (10 for extrapolation from animals to humans 

and 10 for human variability) resulting in an intermediate-duration oral MRL of 0.5 μg Cd/kg/day. 

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CADMIUM 30 

2. RELEVANCE TO PUBLIC HEALTH 

Chronic-duration Oral MRL 

•	 An MRL of 0.1 μg/kg/day has been derived for chronic-duration oral exposure (≥1 year) to 

cadmium.
 

The database examining the chronic toxicity of cadmium following oral exposure is extensive. Although 

there are some chronic studies in animals, the majority of the studies in the chronic database examine the 

relationship between urinary cadmium levels (or cumulative cadmium intake) and adverse health effects 

in the general population or in populations living in cadmium polluted areas. A variety of health effects 

have been observed including increased blood pressure, skeletal defects (osteoporosis, increased bone 

fractures, decreased bone mineral density), kidney dysfunction, and alterations in reproductive hormone 

levels. These environmental exposure studies strongly support the identification of bone and kidney as 

the most sensitive targets of chronic cadmium toxicity. 

Bone effects, particularly osteomalacia and/or osteoporosis and increased bone fractures, were first 

reported in Japanese women living in areas with heavy cadmium contamination. Chronic cadmium 

exposure has been shown to play a role in this disorder, referred to as Itai-Itai disease; however, other 

factors such as multiple pregnancies, poor nutrition (low calories, calcium, protein, vitamin D, and iron 

intakes), and low zinc levels in food also play important roles in the etiology. Although a conclusive role 

of cadmium in Itai-Itai has not been established, several other studies have found bone defects. Observed 

bone effects include increased risk of bone fractures in post-menopausal women with urinary cadmium 

levels of >1 μg/day (approximately >0.7 μg Cd/g creatinine; Staessen et al. 1999), individuals (>50 years 

of age) with urinary cadmium levels of >2 μg/g creatinine (Alfvén et al. 2004), and men and women 

(>40 years of age) with urinary cadmium levels of 9.20 and 12.86 μg/g creatinine, respectively (Wang et 

al. 2003); increased risk of osteoporosis in men (>60 years of age) with urinary cadmium levels of 

≥1.5 μg/g creatinine (Alfvén et al. 2000), in males and females with urinary cadmium levels of ≥10 μg/g 

creatinine (Jin et al. 2004b), and in males and females (>40 years of age) with urinary cadmium levels of 

9.20 and 12.86 μg/g creatinine, respectively (Wang et al. 2003); and decreased bone mineral density in 

women with urinary cadmium levels of >0.6 μg/g creatinine (Schutte et al. 2008) and post-menopausal 

women with urinary cadmium levels of >20 μg/g creatinine (Nordberg et al. 2002). 

Evidence of renal dysfunction in environmentally exposed populations include increases in deaths from 

renal dysfunction in residents living in cadmium polluted areas of Japan (Arisawa et al. 2001, 2007b; 

Iwata et al. 1991a, 1991b; Matsuda et al. 2002; Nakagawa et al. 1993; Nishijo et al. 1995, 2004a, 2006), 

increases in renal replacement therapy which is indicative of severe renal dysfunction (Hellström et al. 

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CADMIUM 31 

2. RELEVANCE TO PUBLIC HEALTH 

2001), and increases in the excretion of biomarkers of renal dysfunction in association with increased 

cadmium intake, increased renal cadmium concentrations, increased blood cadmium levels, and/or 

increased urinary cadmium concentrations (Buchet et al. 1990; Cai et al. 1990, 1992, 1998, 2001; Hayano 

et al. 1996; Horiguchi et al. 2004; Ishizaki et al. 1989; Izuno et al. 2000; Järup et al. 2000; Jin et al. 2002, 

2004a, 2004c; Kawada et al. 1992; Kido and Nogawa 1993; Kobayashi et al. 2002a; Monzawa et al. 

1998; Nakadaira and Nishi 2003; Nakashima et al. 1997; Nogawa et al. 1989; Noonan et al. 2002; 

Nordberg et al. 1997; Olsson et al. 2002; Oo et al. 2000; Osawa et al. 2001; Roels et al. 1981b; Suwazono 

et al. 2006; Teeyakasem et al. 2007; Trzcinka-Ochocka et al. 2004; Uno et al. 2005; Yamanaka et al. 

1998; Wu et al. 2001). The urinary excretion of several biomarkers have been shown to increase due to 

cadmium-related alterations in kidney function; these biomarkers include low molecular weight proteins 

(e.g., β2-microglobulin, pHC, retinol binding protein), intracellular tubular enzymes (e.g., NAG), amino 

acids, high molecular weight proteins (e.g., albumin), metallothionein, and electrolytes (e.g., potassium, 

sodium, calcium). Although the more severe renal effects have been observed in populations living in 

highly contaminated areas (e.g., decreased glomerular filtration rate), alterations in the above biomarkers 

have been observed in areas not considered to be cadmium polluted. Alterations in these biomarker levels 

appear to be the most sensitive indicator of cadmium toxicity. Many of the studies examining biomarkers 

have reported significant correlations between urinary cadmium levels and biomarker levels. However, 

these correlations do not provide insight into exposure levels associated with renal dysfunction. In this 

MRL analysis, attention was given to dose-response studies examining the derived quantitative 

relationships between cadmium exposure and the prevalence of abnormal biomarker levels. As discussed 

in the inhalation MRL section, a 10% increase in the prevalence of abnormal biomarker levels 

(particularly β2-microglobulin, pHC, or retinol binding protein) in association with increasing cadmium 

exposure is generally considered to be indicative of cadmium-associated renal dysfunction in populations. 

However, when examining the prevalence of abnormal levels, careful consideration should be given to the 

response criterion (cut-off level) used in the study. A wide range of cut-off levels have been used in the 

environmental exposure studies. For β2-microglobulin, the most commonly used biomarker, the cut-off 

values ranged from 283 to 1,129 μg/g creatinine. A summary of environmental studies finding significant 

dose-response associations between urinary cadmium (or cumulative cadmium intake) and the prevalence 

of abnormal levels of urinary biomarkers of renal dysfunction is presented in Table 2-1. The adverse 

effect levels range from urinary cadmium levels of 1 μg/g creatinine (Järup et al. 2000) to 9.51 μg/g 

creatinine (Jin et al. 2004a). 

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CADMIUM 32 

2. RELEVANCE TO PUBLIC HEALTH 

Table 2-1. Summary of Human Studies Finding Dose-Response Relationships 

Between Biomarkers of Renal Dysfunction and Cadmium Exposure
 

Adverse 

effect level 

Effect (urinary 

Population biomarker Response criterion cadmium) Reference 

General population (Japan) Total prt 157.4 μg/g creat. (M) 2.4 μg/g creat.a Suwazono et 

158.5 μg/g creat. (F) al. 2006 

β2M 507 μg/g creat. (M) 

400 μg/g creat. (F) 

NAG 8.2 μg/g creat. (M) 

8.5 μg/g creat. (F) 

General population 

(Belgium) 

β2M 

RBP 

283 μg/24 hours 

338 μg/24 hours 

1.92 μg/g 

creat.b 

Buchet et al. 

1990 

NAG 3-6 IU/24 hours 

amino acid 357 mg α-N/24 hours 

calcium 4-9 mmol/24 hours 

Residents in cadmiumpolluted area (China) β2M 355 μg/g creat. (M <45 years) 

>2,500 μg/g creat. (M ≥45 years) 

4–7.99 μg/g 

creat.c 

Cai et al. 

1998 

500 μg/g creat. (F) 

Residents in cadmium­ β2M 300 μg/g creat. ≥5 μg/g creat. Jin et al. 

polluted area (China) RBP 300 μg/g creat. 2002 

albumin 15 mg/g creat. 

Residents in cadmium­ β2M 800 μg/g creat. 9.51 μg/g Jin et al. 

polluted area (China) NAG 15 U/g creat. creat. 2004a 

albumin 20 mg/g creat. 

Residents in cadmiumpolluted area (China) β2M 800 μg/g creat. 2–4 μg/g 

creat.c 

Nordberg et 

al. 1997 

Residents in cadmium­ β2M 1,000 μg/g creat. 6.9 μg/g creat. Cai et al. 

polluted area (Japan) 2001 

Residents in cadmium­ β2M 1,000 μg/g creat. (M,F) Cadmium Nogawa et 

polluted area (Japan) intake: al. 1989; 

150 μg/day Kido and 

Nogawa 

1993 

Residents in cadmiumpolluted area (Japan) β2M 1,129 μg/g creat. (M) 

1,059 μg/g creat. (F) 

4–4.9 μg/g 

creat.c 

Ishizaki et al. 

1989; 

Hayano et al. 

1996 

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CADMIUM 33 

2. RELEVANCE TO PUBLIC HEALTH 

Table 2-1. Summary of Human Studies Finding Dose-Response Relationships 

Between Biomarkers of Renal Dysfunction and Cadmium Exposure
 

Adverse 

effect level 

Effect (urinary 

Population biomarker Response criterion cadmium) Reference 

Residents in cadmium­ β2M 400 μg/g creat. 6–10 μg/g Teeyakasem 

polluted area (Thailand) creat. et al. 2007 

Residents in cadmium­ pHC 7.1 mg/g creat. (M) 1 μg/g creat.d Järup et al. 

polluted area (includes 5.3 mg/g creat. (F) 2000 

occupationally exposed 

subjects (Sweden) 

a

Mean urinary cadmium level

b

>10% prevalence of abnormal β2-microglobulin, retinal binding protein, amino acid, and calcium values at 3.05, 

2.87, 2.74, 4.29, or 1.92 μg/24 hours, respectively.

c

Urinary cadmium level associated with an approximate doubling of prevalence of abnormal β2-microglobulin levels d

The European Chemicals Bureau (2007) recalculated this value (using raw data from Järup et al. 2000) to account 

for differences in age of the reference population and study population; based on these recalculations, a doubling of 

the probability of abnormal pHC values would occur at 2.62 μg/g creatinine for the total population and a 0.5 μg/g 

creatinine for the environmentally exposed population. 

AAP = alanine aminopeptidase; β2M = β2-microglobulin; creat. = creatinine; F = female; M = male; NAG = N-acetylβ-glucosaminidase; pHC = human complex-forming glycoprotein, also referred to as α1M; RBP = retinol binding 

protein 

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CADMIUM 34 

2. RELEVANCE TO PUBLIC HEALTH 

The adverse effect levels for renal effects were similar to those observed for skeletal effects. Because the 

renal effects database is stronger, it was used for derivation of a chronic-duration oral MRL for cadmium. 

Several approaches were considered for derivation of the MRL: (1) NOAEL/LOAEL approach using a 

single environmental exposure study finding an increased prevalence of abnormal renal effect biomarker 

levels, (2) selection of a point of departure from a published benchmark dose analysis, or (3) selection of 

a point of departure based on an analysis of the dose-response functions from a number of environmental 

exposure studies. 

In the first approach, all studies in which individual internal doses for subjects were estimated based on 

urinary cadmium were considered. The Järup et al. (2000) study is selected as the principal study because 

it identified the lowest adverse effect level (Table 2-1). In this study, 1,021 individuals living near a 

nickel-cadmium battery factory (n=799) or employed at the factory (n=222) were examined. The mean 

urinary cadmium concentrations were 0.81 μg/g creatinine in men and 0.65 μg/g creatinine in women. A 

significant association was found between urinary cadmium concentrations and urinary pHC levels, after 

adjustment for age; the association remained statistically significant after removal of the cadmium 

workers from the analysis. The investigators estimated that a urinary cadmium level of 1 μg/g creatinine 

would be associated with a 10% increase in the prevalence of abnormal pHC levels above background 

prevalence (approximately a 10% added risk). However, the European Chemicals Bureau (2007) 

recalculated the probability of HC proteinuria because the reference population and the study population 

were not matched for age (40 versus 53 years, respectively). They estimated that the probability of HC 

proteinuria (13%) would be twice as high as the reference population at a urinary cadmium concentration 

of 0.5 μg/g creatinine. 

The second approach involves the evaluation of five published benchmark dose analyses. The benchmark 

doses and the lower 95% confidence interval of the benchmark dose (BMDL) for low molecular weight 

proteinuria are presented in Table 2-2 (benchmark doses and BMDLs for all effect parameters are 

presented in Table 3-8 in the toxicological profile). The BMDL values corresponding to a 10% increase 

in the prevalence of low molecular weight proteinuria above background (excess risk) ranged from 

0.7 μg/g creatinine (Uno et al. 2005) to 9.9 μg/g creatinine (Kobayashi et al. 2006). Both studies 

examined populations living in non-cadmium polluted areas of Japan and used β2-microglobulin as the 

effect biomarker. The large difference in cut-off values (233 versus 784 μg/g creatinine) likely 

contributed to the order of magnitude difference in BMDLs. The BMDL10 of 0.7 μg/g creatinine is 

supported by the Suwazono et al. (2006) benchmark dose analysis, which found a similar BMDL10 

(0.81 μg/g creatinine) using pHC as the effect biomarker. The Uno et al. (2005) study examined 410 men 

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CADMIUM 35 

2. RELEVANCE TO PUBLIC HEALTH 

Table 2-2. Selected Benchmark Dose Estimations of Urinary Cadmium
 

Levels Associated with Increases in the Prevalence of
 

Low Molecular Weight Proteinuria
 

Study 

population 

Effect 

biomarker 

Response 

criterion 

BMD 

model 

5% BMR 

BMD BMDL 

10% BMR 

BMD BMDL Reference 

General 

population 

(Sweden) 

pHC 6.8 mg/g creat. 

(95% cut-off)a 

0.63 (F) 0.49 (F) 1.05 (F) 0.81 (F) Suwazono 

et al. 2006 

Residents in 

cadmiumpolluted and 

non-polluted 

areas (Japan) 

β2M 507 μg/g creat. (M) 

400 μg/g creat. (F) 

(84% cut-off)b 

Quantal 

linear 

model 

994 μg/g creat. (M) 

784 μg/g creat. (F) 

(95% cut-off)c 

1.5 (M) 

1.4 (F) 

2.3 (M) 

1.7 (F) 

1.2 (M) 

1.1 (F) 

1.8 (M) 

1.4 (F) 

3.1 (M) 

2.9 (F) 

4.7 (M) 

3.5 (F) 

2.5 (M) 

2.3 (F) 

3.7 (M) 

2.9 (F) 

Shimizu et 

al. 2006 

General 

population 

(Japan) 

β2M 507 μg/g creat. (M) 

400 μg/g creat. (F) 

(84% cut-off)d 

Loglogistic 

model 

2.9 (M) 

3.8 (F) 

2.4 (M) 

3.3 (F) 

5.0 (M) 

6.6 (F) 

4.0 (M) 

5.5 (F) 

Kobayashi 

et al. 2006 

994 μg/g creat. (M) 

784 μg/g creat. (F) 

(95% cut-off)e 

6.4 (M) 

8.7 (F) 

4.5 (M) 

7.3 (F) 

10.2 (M) 

12.0 (F) 

7.1 (M) 

9.9 (F) 

General 

population 

(Japan) 

β2M 233 μg/g creat. (M) 

274 μg/g creat. (F) 

(84% cut-off)f 

Quantal 

linear 

model 

0.5 (M) 

0.9 (F) 

0.4 (M) 

0.8 (F) 

1.0 (M) 

1.8 (F) 

0.7 (M) 

1.3 (F) 

Uno et al. 

2005 

Residents in 

cadmium 

highly, or 

moderately 

polluted area 

(China) 

β2M 

RBP 

800 μg/g creat. 

(95% cut-off)g 

0.300 mg/g creat. 

(95% cut-off)g 

Quantal 

linear 

logistic 

regression 

model 

5.86 (M) 

9.98 (F) 

4.74 (M) 

8.47 (F) 

5.99 (M) 

9.03 (F) 

4.87 (M) 

7.63 (F) 

Jin et al. 

2004b 

a

95th percentile of effect biomarkers on the “hypothetical” control distribution at a urinary cadmium level of zero.
 b

84% upper limit values from a group of 424 males and 1,611 females who did not smoke and lived in three different
 

cadmium nonpolluted areas.

c

95% upper limit values from a group of 424 males and 1,611 females who did not smoke and lived in three different
 

cadmium nonpolluted areas.

d

84% upper limit value of the target population of people who have not smoked.

e

95% upper limit value of the target population of people who have not smoked.
 f

84% upper limit value of the target population.

g

95% upper limit value from a control group 98 males and 155 females living in a cadmium nonpolluted area.
 

BMD = benchmark dose; BMDL = benchmark dose low; BMR = benchmark response; β2M = β2-microglobulin;
 

creat. = creatinine; F = female; M = male; NAG = N-acetyl-β-D-glucosaminidase;
 

NAG-B = N-acetyl-β-D-glucosaminidase’s isoform B; RBP = retinol binding protein
 

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CADMIUM 36 

2. RELEVANCE TO PUBLIC HEALTH 

and 418 women (aged 40–59 years) living in three areas of Japan without any known environmental 

cadmium pollution. Mean urinary cadmium concentrations were 1.3 and 1.6 μg/g creatinine in men and 

women, respectively. Cut-off levels for β2-microglobulin were 233 and 274 μg/g creatinine in males and 

females; these values represent the 84% upper limit values calculated from the target population assuming 

a log normal distribution. 

The third approach involved a meta-analysis of selected environmental exposure dose-response studies. 

Studies were selected for inclusion in this analysis based on the following qualitative criteria: (1) the 

study measured urinary cadmium as indicator of internal dose; (2) the study measured reliable indicators 

of low molecular weight (LMW) proteinuria; (3) a dose-response relationship was reported in sufficient 

detail so that the dose-response function could be reproduced independently; (4) the study was of 

reasonable size to have provided statistical strength to the estimates of dose-response model parameters 

(i.e., most studies selected included several hundred to several thousand subjects); and (5) major covariables that might affect the dose-response relationship (e.g., age, gender) were measured or constrained 

by design and included in the dose-response analysis. No attempt was made to weight selected studies for 

quality, statistical power, or statistical uncertainty in dose-response parameters. Studies using a cut-off 

value for β2-microglobulin of ≥1,000 μg/g creatinine were eliminated from the analysis based on the 

conclusions of Bernard et al. (1997) that urinary β2-microglobulin levels of 1,000–10,000 μg/g creatinine 

were indicative of irreversible tubular proteinuria, which may lead to an age-related decline in GFR. 

Additionally, an attempt was made to avoid using multiple analyses of the same study population. 

The individual dose-response functions from each study were implemented to arrive at estimates of the 

internal dose (urinary cadmium expressed as μg/g creatinine) corresponding to probabilities of 10% 

excess risk of low molecular weight proteinuria (urinary cadmium dose, UCD10). Estimates were derived 

from the seven environmental exposure studies listed in Table 2-3. When available, male and female data 

were treated separately; thus, 11 dose-response relationships were analyzed. For studies that did not 

report the UCD10, the value was estimated by iteration of the reported dose response relationship for 

varying values of urinary cadmium, until an excess risk of 10% was achieved: 

P(d) − P(0) ER = 1− P(0) 

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CADMIUM 37 

2. RELEVANCE TO PUBLIC HEALTH 

Table 2-3. Selected Studies of Dose-Response Relationship for CadmiumInduced Low Molecular Weight Proteinuria
 

Dose­ UCD10 

Effect Response response (μg/g 

Reference Population Number biomarker criterion model creat.) 

Buchet et al.	 General population 

1990	 (Belgium) 

Suwazono et al.	 General population 

2006	 (Sweden) 

Järup et al. 2000 Residents in 

cadmium polluted 

area (Sweden) 

Kobayashi et al.	 General population 

2006	 (Japan) 

Shimizu et al.	 Residents in 

2006	 cadmium polluted 

and non-polluted 

areas (Japan) 

Jin et al. 2004c	 Residents in 

cadmium polluted 

or non-polluted 

area (China) 

Wu et al. 2001	 Residents in 

cadmium polluted 

area (China) 

1,699 M 

2,080 F 

790 F 

1,465 

M,F 

1,114 M 

1,664 F 

1,865 M 

1,527 F 

790 M,F 

247 M,F 

β2M 

pHC 

pHC 

β2M 

β2M 

β2M 

β2M 

283 μg/24 hours 

3.6 U/g creat. 

7.1 mg/g creat. M 

5.3 mg/g creat. F 

507 μg/g creat. M 

400 μg/g creat. F 

507 μg/g creat. M 

400 μg/g creat. F 

800 μg/g creat. 

800 μg/g creat. M 

900 μg/g creat. F 

Logistica 2.51 M 

1.44 F 

Logistic 0.81 

Logistic 0.6 

Log-logistic 5.0 M 

6.6 F 

Log-logistic 5.1 M 

4.2 F 

Logistic 9.5 M 

15.4 F 

Linearb 3.75 

a

Digitized from Figure 2 in Lauwerys et al. 1991

b

Digitized from Figure 2 in Wu et al. 2001 

β2M = β2-microglobulin; creat. = creatinine; F = female; M = male; pHC = human complex-forming glycoprotein (also 

referred to as α1-microglobulin); UCD10 = urinary cadmium level corresponding to a probability of 10% excess risk of 

low molecular weight proteinuria 

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CADMIUM 38 

2. RELEVANCE TO PUBLIC HEALTH 

where ER is the excess risk, P(d) is the probability of low molecular weight proteinuria associated with a 

given internal (i.e., urinary cadmium) dose, and P(0) is the background probability (i.e., the probability 

predicted by the dose-response model when urinary cadmium was zero). For studies that reported the 

dose-response relationship graphically, but did not report the actual dose-response function, a function 

was derived by least squares fitting based on data from a digitization of the graphic. 

Aggregate UCD10 estimates and the estimates stratified by location (i.e., Europe, Japan, China) are 

presented in Figure 2-2. The lowest UCD10 (1.34 μg/g creatinine) was estimated from the European 

database and the 95% lower confidence limit on this UCD10 (UCDL10) of 0.5 μg/g creatinine was 

considered as a potential point of departure for the MRL. 

Points of departure selected using the three different approaches are similar: 0.5 μg/g creatinine from the 

Järup et al. (2000) study (using the European Chemicals Bureau 2007 recalculation), 0.7 μg/g creatinine 

from the Uno et al. (2005) benchmark dose analysis, and 0.5 μg/g creatinine from the dose-response 

analysis. The third approach (meta-analysis of environmental exposure studies) was selected for the 

derivation of the MRL because it uses the whole dose-response curves from several studies rather than 

data from a single study. 

The UCDL10 of 0.5 μg/g creatinine was transformed into estimates of chronic cadmium intake (expressed 

as μg Cd/kg/day) that would result in the UCDL10 at age 55 (approximate age of peak cadmium 

concentration in the renal cortex associated with a constant chronic intake; Figure 2-3). The dose 

transformations were achieved by simulation using a modification of the Nordberg-Kjellström model 

(Kjellström and Nordberg 1978). The following modifications (Choudhury et al. 2001; Diamond et al. 

2003) were made to the model: (1) the equations describing intercompartmental transfers of cadmium 

were implemented as differential equations in Advanced Computer Simulation Language (acslXtreme, 

version 2.4.0.9); (2) growth algorithms for males and females and corresponding organ weights 

(O’Flaherty 1993) were used to calculate age-specific cadmium concentrations from tissue cadmium 

masses; (3) the cadmium concentration in renal cortex (RC, μg/g) was calculated as follows: 

K RC =1.5⋅

KW 

where K is the age-specific renal cadmium burden (μg) and KW is the age-specific kidney wet weight (g) 

(Friberg et al. 1974). 

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0 6

CADMIUM 39 

2. RELEVANCE TO PUBLIC HEALTH 

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Figure 2-2. Estimates of the UCD10 from Environmental Exposure Dose-Response 

Studies* 

*Estimates of urinary cadmium concentrations (μg/g creatinine) associated with a 10% excess risk of urinary 

β2-microglobulin (UCD10) using data from European, Japanese, and Chinese studies. For the aggregate of studies 

(plot #4), the mean (-), median (▪), and 95% confidence intervals (CI) on the median are shown. All other plots show 

the mean and 95% CI on the mean. Numbers in parenthesis are the number of estimates of the UCD10. 

0 

2 

4 

6 

8 

10 

12 

14 

16 

18 

1 2 3 4 5 

UCD10 (μg/g creatinine)

Gen, Europe 

Gen, Japan 

Gen, China 

Gen, Europe, Japan 

Gen, All 

(4) 

(4) 

(3) 

(11) 

(9) 
 

 


 


 


 

CADMIUM 40 

2. RELEVANCE TO PUBLIC HEALTH 

Figure 2-3. Urinary Cadmium (μg/g creatinine) and Renal Cortex Cadmium
 

Concentration (μg/g wet tissue) Predicted by the Cadmium
 

Pharmacokinetic Model*
 

*Shown is a simulation of peak renal cadmium concentration (at age 55) in females based on a chronic intake of 

0.33 μg Cd/kg/day. 

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CADMIUM 41 

2. RELEVANCE TO PUBLIC HEALTH 

(4) the rate of creatinine excretion (e.g., Crur, g creatinine/day) was calculated from the relationship 

between lean body mass (LBM) and Crur; and (5) absorption of ingested cadmium was assumed to be 

5% in males and 10% in females. The rate of creatinine excretion (e.g., Crur, g creatinine/day) was 

estimated from the relationship between LBM (kg) and Crur: 

LBM = 27.2 ⋅Crur + 8.58 

where the constants 27.2 and 8.58 are the sample size-weighted arithmetic mean of estimates of these 

variables from eight studies reported in (Forbes and Bruining 1976). Lean body mass was estimated as 

follows (ICRP 1981): 

LBM = BW ⋅0.85,adult females 

LBM = BW ⋅0.88,adultmales 

where the central tendency for adult body weight for males and females were assumed to be 70 and 58 kg 

for adult European/American males and females, respectively. 

Dose units expressed as cadmium intake (μg/kg/day), urinary cadmium excretion (μg/g creatinine), or 

kidney tissue cadmium (μg/g cortex) were interconverted by iterative pharmacokinetic model simulations 

of constant intakes for the life-time to age 55 years, the age at which renal cortex cadmium concentrations 

are predicted to reach their peak when the rate of intake (μg/kg/day) is constant. 

The dietary cadmium intakes which would result in urinary cadmium levels of 1.34 and 0.5 μg/g 

creatinine (UCD10 and UCDL10) are 0.97 and 0.33 μg/kg/day in females and 2.24 and 0.70 μg/kg/day in 

males. The dietary concentration associated with the UCDL10 in females (0.33 μg/kg/day) was divided by 

an uncertainty factor of 3 for human variability resulting in a chronic-duration oral MRL of 0.1 μg/kg/day 

(1x10-4 mg Cd/kg/day). The UCD is based on several large-scale environmental exposure studies that 

likely included sensitive subpopulations; however, there is concern that individuals with diabetes may be 

especially sensitive to the renal toxicity of cadmium (Åkesson et al. 2005; Buchet et al. 1990) and 

diabetics were excluded from a number of the human studies, and thus, an uncertainty factor of 3 was 

used. 

The urinary cadmium point of departure used as the basis of the MRL (0.5 μg/g creatinine) is 

approximately 2-fold higher than the geometric mean urinary cadmium concentrations in the United 

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CADMIUM 42 

2. RELEVANCE TO PUBLIC HEALTH 

States, which is 0.261 μg/g creatinine for adults 20 years and older (CDC 2005). The MRL of 

0.1 μg/kg/day is lower than the estimated age-weighted cadmium intake of 0.3 μg/kg/day (estimated from 

data in Choudhury et al. 2001). Because this intake is derived from the cadmium dietary exposure model 

which estimates food cadmium concentrations from national survey data and food consumption patterns, 

it should not be considered a precise value. A better comparison would be between the mean urinary 

cadmium concentration in adults living in the United States (0.261 μg/g creatinine) and the MRL 

expressed as a urinary cadmium concentration (0.2 μg/g creatinine). 

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CADMIUM 43 

3. HEALTH EFFECTS 

3.1 INTRODUCTION 

The primary purpose of this chapter is to provide public health officials, physicians, toxicologists, and 

other interested individuals and groups with an overall perspective on the toxicology of cadmium. It 

contains descriptions and evaluations of toxicological studies and epidemiological investigations and 

provides conclusions, where possible, on the relevance of toxicity and toxicokinetic data to public health. 

A glossary and list of acronyms, abbreviations, and symbols can be found at the end of this profile. 

The form of cadmium and the route of exposure can greatly affect the absorption and distribution of 

cadmium to various target sites, and therefore, the concentration at the target site and the severity of the 

observed effect. The mechanism of action, however, involves the cadmium cation’s effect on the target 

site, and the cation is the same regardless of the anionic species. For inhaled cadmium compounds, the 

size of the cadmium particle (i.e., fume or aerosol) can also affect the absorption and distribution. The 

form of cadmium that is of most interest for health effects from inhalation exposure is cadmium oxide 

because that is the main form of airborne cadmium. For oral exposures, cadmium chloride is most often 

tested in animal studies because of its high water solubility and the resulting high concentrations of 

cadmium delivered to target sites. Studies on cadmium bound to metallothionein are also of interest 

because cadmium-metallothionein complexes may have different toxic profiles and are found in relatively 

high levels in organ meats (e.g., liver and kidney). Cadmium oxide and cadmium carbonate, which are 

relatively insoluble in water (but may dissolve at gastric pH), appear to be similar in absorption and 

toxicity to soluble cadmium. There are fewer studies available on other forms of cadmium including 

insoluble forms in water such as cadmium sulfide (a yellow pigment) and cadmium selenium sulfide (a 

red pigment), and a soluble form, cadmium sulfate, which is less soluble in a closed air system where 

there is a limited amount of dissolved carbon dioxide. Chapter 4 lists the chemical and physical 

properties of several cadmium compounds. 

3.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE 

To help public health professionals and others address the needs of persons living or working near 

hazardous waste sites, the information in this section is organized first by route of exposure (inhalation, 

oral, and dermal) and then by health effect (death, systemic, immunological, neurological, reproductive, 

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CADMIUM 44 

3. HEALTH EFFECTS 

developmental, genotoxic, and carcinogenic effects). These data are discussed in terms of three exposure 

periods: acute (14 days or less), intermediate (15–364 days), and chronic (365 days or more). 

Levels of significant exposure for each route and duration are presented in tables and illustrated in 

figures. The points in the figures showing no-observed-adverse-effect levels (NOAELs) or lowestobserved-adverse-effect levels (LOAELs) reflect the actual doses (levels of exposure) used in the studies. 

LOAELs have been classified into "less serious" or "serious" effects. "Serious" effects are those that 

evoke failure in a biological system and can lead to morbidity or mortality (e.g., acute respiratory distress 

or death). "Less serious" effects are those that are not expected to cause significant dysfunction or death, 

or those whose significance to the organism is not entirely clear. ATSDR acknowledges that a 

considerable amount of judgment may be required in establishing whether an end point should be 

classified as a NOAEL, "less serious" LOAEL, or "serious" LOAEL, and that in some cases, there will be 

insufficient data to decide whether the effect is indicative of significant dysfunction. However, the 

Agency has established guidelines and policies that are used to classify these end points. ATSDR 

believes that there is sufficient merit in this approach to warrant an attempt at distinguishing between 

"less serious" and "serious" effects. The distinction between "less serious" effects and "serious" effects is 

considered to be important because it helps the users of the profiles to identify levels of exposure at which 

major health effects start to appear. LOAELs or NOAELs should also help in determining whether or not 

the effects vary with dose and/or duration, and place into perspective the possible significance of these 

effects to human health. 

The significance of the exposure levels shown in the Levels of Significant Exposure (LSE) tables and 

figures may differ depending on the user's perspective. Public health officials and others concerned with 

appropriate actions to take at hazardous waste sites may want information on levels of exposure 

associated with more subtle effects in humans or animals (LOAELs) or exposure levels below which no 

adverse effects (NOAELs) have been observed. Estimates of levels posing minimal risk to humans 

(Minimal Risk Levels or MRLs) may be of interest to health professionals and citizens alike. 

Levels of exposure associated with carcinogenic effects (Cancer Effect Levels, CELs) of cadmium are 

indicated in Tables 3-1 and 3-6 and Figures 3-1 and 3-2. Because cancer effects could occur at lower 

exposure levels, Figure 3-1 also shows a range for the upper bound of estimated excess risks, ranging 

from a risk of 1 in 10,000 to 1 in 10,000,000 (10-4 to 10-7), as developed by EPA. 

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CADMIUM 45 

3. HEALTH EFFECTS 

A User's Guide has been provided at the end of this profile (see Appendix B). This guide should aid in 

the interpretation of the tables and figures for Levels of Significant Exposure and the MRLs. 

3.2.1 Inhalation Exposure 

The information in this section on health effects of inhalation exposure to cadmium in humans is derived 

from studies of workers exposed to cadmium fume or dusts in industries such as smelting, battery 

manufacturing, soldering, and pigment production. Adverse effects of human exposure to cadmium were 

first established among workers in a cadmium battery factory (Friberg 1950). Workers are exposed 

occupationally to cadmium primarily by inhalation of fumes or dust. Some gastrointestinal tract exposure 

may also occur when dust is removed from the lungs by mucociliary clearance and subsequently 

swallowed, or by ingestion of dust on hands, cigarettes, or food (Adamsson et al. 1979). In experiments 

with animals, some ingestion may also occur from inhalation exposures by mucociliary clearance or from 

animal grooming. The primary form of cadmium in occupational exposures is cadmium oxide. 

Experimental studies in laboratory animals have used cadmium oxide, cadmium chloride, and 

occasionally other forms of cadmium such as cadmium sulfide and cadmium sulfate. In general, the 

different forms of cadmium have similar toxicological effects by the inhalation route, although 

quantitative differences may exist from different absorption and distribution characteristics, particularly 

for the less soluble cadmium pigments such as cadmium sulfide and cadmium selenium sulfide (Buckley 

and Bassett 1987b; Klimisch 1993; Oldiges and Glaser 1986; Oldiges et al. 1989; Rusch et al. 1986). 

Smokers inhale cadmium, but studies of cadmium exposure in the general population are considered in 

Section 3.2.2 because the primary route of exposure for the general population is through the diet. Also, 

the many other toxic compounds in cigarette smoke make it difficult to attribute specific adverse effects 

of smoking to the inhalation of cadmium. 

3.2.1.1 Death 

Numerous studies have shown that acute inhalation exposure to cadmium can cause death in humans and 

animals. In humans, several fatal inhalation exposures have occurred in occupational accidents. During 

the acute exposure, the general symptoms are relatively mild but, within a few days following exposure, 

severe pulmonary edema and chemical pneumonitis develop, leading to death due to respiratory failure 

(Beton et al. 1966; Lucas et al. 1980; Patwardhan and Finckh 1976; Seidal et al. 1993). The cadmium 

concentration in air was not measured in these cases of accidental death in humans. However, the lung 

concentrations of cadmium in the men who died from these accidental acute exposures were measured. 

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CADMIUM 46 

3. HEALTH EFFECTS 

In micrograms of cadmium per gram wet weight (w/w) of lung tissue (μg/g), Patwardhan and Finckh 

(1976) reported 1.5 μg/g, Beton et al. (1966) reported 2.5 μg/g, Barrett et al. (1947) reported 3.5 μg/g, and 

Lucas et al. (1980) reported 4.7 μg/g. Based upon estimates of the percentage of inhaled cadmium fume 

that would be retained in the lungs, Barrett et al. (1947) calculated an exposure of 2,500 minutes x mg/m3 

in air would be fatal to humans. Beton et al. (1966) used a similar technique to estimate that an exposure 

to cadmium oxide in air of 8.63 mg/m3 for 5 hours led to the fatal deaths of the five workers with 

cadmium lung burdens of 2.5 μg/g. The lower lung concentrations reported by Patwardhan and Finckh 

(1976) prompted Elinder (1986b) to estimate that an exposure of 1–5 mg/m3 for 8 hours could be 

immediately dangerous. These estimates of air concentrations, however, are based on a number of 

uncertain assumptions concerning the duration of exposure and the retention of cadmium in the human 

lung being similar to that found in animal studies (Barrett et al. 1947; Elinder 1986b). No studies on 

deaths in humans from intermediate inhalation exposures were found. In a study on chronic exposures, 

Friberg (1950) attributes the deaths of 2 workers to exposure to cadmium dust in the air averaging 6.8 mg 

Cd/m3 (range 3–15 mg/m3

). One worker was 57 years old at death (after 14 years of exposure to the dust) 

and the other was 60 years old at death (after 25 years of exposure to the dust). A detailed post-mortem 

evaluation for the 60-year-old worker showed the presence of emphysema and the occurrence of hyaline 

casts in renal tubules, as well as slight nephrotic changes. Pneumonia was the direct cause of death as an 

acute complication of chronic bronchitis and pulmonary emphysema. The exposure estimate of 6.8 mg 

Cd/m3 is from only six samples taken in 1946. The conditions in earlier years were thought to be similar, 

but this exposure value is, at best, a very rough approximation of the actual exposures spanning 34 years. 

Acute inhalation of cadmium oxide fumes has also led to death in rats, mice, rabbits, guinea pigs, dogs, 

and monkeys, with the mortality rate apparently being directly proportional to the product of the duration 

of exposure and the concentration of inhaled cadmium (Barrett et al. 1947). The most reliable LC50 

(lethal concentration, 50% kill) (at 7 days) established by this study was 500 minute-mg cadmium 

oxide/m3 for rats, equivalent to a 15-minute exposure to 30 mg Cd/m3 (Barrett et al. 1947). Rusch et al. 

(1986) demonstrated high mortality rates in the Sprague-Dawley rat from a 2-hour exposure to cadmium 

fumes at 112 mg Cd/m3 (25 of 32 died within 1 week). A 2-hour exposure to a different form of 

cadmium, cadmium carbonate, at 132 mg Cd/m3 resulted in considerably lower mortality (3 of 22 died by 

day 30). No deaths resulted from a 2-hour exposure to cadmium sulfide at 99 mg Cd/m3 or cadmium 

selenium sulfide (cadmium red pigment) at 97 mg Cd/m3

. Grose et al. (1987) reported 2 out of 36 rats 

died from a 2-hour, nose-only inhalation exposure to only 0.45 mg Cd/m3 of cadmium oxide dusts, but the 

statistical significance of this low rate of mortality was not reported. A 3-day, 1-hour/day exposure to 

cadmium chloride aerosol at 61 mg Cd/m3 resulted in the death of 17 of 18 rats exposed (Snider et al. 

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CADMIUM 47 

3. HEALTH EFFECTS 

1973). In another study, no deaths were observed in rats from a cadmium yellow (cadmium sulfide) 

pigment exposure 6 hours/day for 10 days at 6.29 mg Cd/m3 (Klimisch 1993). Thus, it appears that in 

acute exposures, the relatively more soluble cadmium chloride, cadmium oxide fume, and cadmium 

carbonate compounds are more toxic than the relatively less soluble cadmium sulfide compounds 

(Klimisch 1993; Rusch et al. 1986). Rusch et al. (1986) attribute this difference to higher lung absorption 

and retention times for the more soluble compounds, and greater mucociliary clearance for the lesssoluble pigments. Glaser et al. (1986), however, demonstrated that toxicity does not strictly correlate 

with solubility, and that solubility of cadmium oxide in biological fluids may be greater than its solubility 

in water. In hamsters, Henderson et al. (1979) reported that a 30-minute exposure to 10.1 mg Cd/m3 from 

cadmium chloride resulted in the death of 3 of 30 animals by day 6 postexposure. In rabbits, Friberg 

(1950) reported an LC50 (by day 14) from a 4-hour exposure to cadmium metal dusts at 28.4 mg Cd/m3

. 

Barrett et al. (1947) also reported LC50 values for cadmium oxide fume of 940 mg Cd/m3 for a 14-minute 

exposure in the monkey, 46.7 mg/m3 for a 15-minute exposure in the mouse, 204 mg Cd/m3 for a 

15-minute exposure in the guinea pig, and 230 mg Cd/m3 for a 15-minute exposure in the dog. However, 

the authors report that these LC50 values are only approximations because of insufficiencies in the data or 

the small numbers of animals used. 

At longer durations of exposure, lower concentrations cause lethality in rats. Cadmium oxide dust 

resulted in the deaths of 100% of the females at 1 mg Cd/m3 for 5 hours/day, 5 days/week for 20 weeks, 

(Baranski and Sitarek 1987), and of 5 of 12 female rats at only 0.105 mg Cd/m3 22 hours/day, 

7 days/week for 63 days (Oldiges and Glaser 1986). Continuous inhalation exposure to cadmium oxide 

dust at 0.105 mg Cd/m3 (i.e., 24 hours/day) for 63 days resulted in 5 of 12 deaths in female rats (Prigge 

1978a). Five of 54 males died from a cadmium chloride exposure to 1.06 mg Cd/m3 for 62 days, 

5 days/week, 6 hours/day (Kutzman et al. 1986). Kutzman et al. (1986) determined that the concentration 

times hours of exposure to produce 50% mortality in rats was 390 mg-hour/m3 (males) and 489 mghour/m3 (females). Takenaka et al. (1983) reported that cadmium chloride at 0.0508 mg Cd/m3 

23 hours/day, 7 days/week for 18 months resulted in the death of 5 of 40 male rats. 

Oldiges et al. (1989) evaluated the long-term effects in rats of inhaling cadmium as either cadmium 

chloride, cadmium sulfate, cadmium sulfide, or cadmium oxide. Rats were exposed to aerosols in nearly 

continuous exposures of 22 hours/day, 7 days/week for 18 months. An observation period of 12 months 

followed the exposure period. Oldiges et al. (1989) recorded mortality as exceeding 25% of the test 

animals during the exposure period or 75% of the test animals during the observation period. If either 

25 or 75% mortality occurred, the exposure period or the observation period, respectively, was 

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CADMIUM 48 

3. HEALTH EFFECTS 

terminated. The results showed that cadmium chloride at 0.030 mg Cd/m3 was lethal to >75% of the male 

and female rats by 12 months of exposure; cadmium oxide dusts at 0.090 mg Cd/m3 were lethal for >25% 

of the males by 7 months and 25% of the females by 11 months of exposure; cadmium oxide fume at the 

highest dose of 0.03 mg Cd/m3 did not result in >25% mortality during exposure or 75% during the 

postexposure period; cadmium sulfate at 0.090 mg Cd/m3 was lethal for >25% of the males during the 

exposure and for >75% of the females by 14 months following exposure; and cadmium sulfide at 

0.090 mg Cd/m3 was not lethal during the exposure period but was lethal to >75% of the males and 

females by 12 months postexposure. In these chronic studies, cadmium's lethal effects differed among the 

chemical forms in the following order from most to least toxic: cadmium chloride>cadmium sulfate ≈ 

cadmium oxide dust>cadmium sulfide, but lethality still occurred from all forms of cadmium. Oldiges 

and Glaser (1986) report that in their chronic studies and at the doses tested, cadmium toxicity appeared 

to be more related to the long-term lung retention of the bioavailable amounts of cadmium than to a 

simple function of solubility in water. Representative LOAEL and LC50 values for lethality in each 

species and duration category are recorded in Table 3-1 and are plotted in Figure 3-1. 

3.2.1.2 Systemic Effects 

The highest NOAEL values and all LOAEL values from each reliable study for systemic effects in each 

species and duration category are recorded in Table 3-1 and plotted in Figure 3-1. 

Respiratory Effects. In humans, inhalation exposure to high levels of cadmium oxide fumes or dust 

is intensely irritating to respiratory tissue, but symptoms can be delayed. During and immediately after 

(up to 2 hours) an acute exposure for 5 hours of 8.63 mg/m3

, Beton et al. (1966) reported that there were 

few symptoms of toxicity limited to coughing and slight irritation of the throat and mucosa. From 4 to 

10 hours postexposure, influenza-like symptoms began to appear, including cough, tight chest, pain in 

chest on coughing, dyspnea, malaise, ache, chilling, sweating, shivering, and aching pain in back and 

limbs. From 8 hours to 7 days postexposure, more advanced stages of pulmonary response included 

severe dyspnea and wheezing, chest pain and precordial constriction, persistent cough, weakness and 

malaise, anorexia, nausea, diarrhea, nocturia, abdominal pain, hemoptysis, and prostration. Acute, 

high-level exposures can be fatal (see Section 3.2.1.1), and those who survive may have impaired lung 

function for years after a single acute exposure. A 34-year-old worker exposed to cadmium fume from 

soldering for 1 hour (dose not determined) had persistent impaired lung function when examined 4 years 

following the exposure (Barnhart and Rosenstock 1984). Initial symptoms were dyspnea, cough, 

myalgia, and fever. An initial chest X-ray revealed infiltrates. Townshend (1982) reports the case of a 

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Table 3-1 Levels of Significant Exposure to Cadmium - Inhalation 

Exposure/ 

Duration/ 

a Frequency Key to Species (Route) Figure (Strain) NOAEL Less Serious System (mg/m3) (mg/m3) 

LOAEL 

Reference Chemical Form 

Serious 

(mg/m3) 

ACUTE EXPOSURE

Death 

1 Human 5 hr 

(occup) 8.63 M (5 male workers died after a 5 hour exposure) Beton et al. 1966 CdO fume 

8.63

2

2 Rat 10-15 min 

(NS) 

7

30 (LC50 at 7 days) 

30

Barrett et al. 1947 CdO fume 

3 Rat 6.2 hr/d 

(Fischer- 344) 5 d/wk 2 wk 8.8 (100% mortality by day 6) 8.8 NTP 1995 CdO 

1020

4 Rat 2 hr 

(SpragueDawley) 112 (25/32 died within 1 week) Rusch et al. 1986 CdO fume 

112

13

5 Rat 3 d 

1 hr/d (SpragueDawley) 61 M (17/18 died within 3 days) Snider et al. 1973 CdCl2 

61

17

6 Mouse 6.2 hr/d 

5 d/wk (B6C3F1) 2 wk 8.8 (100% mortality by day 7) 8.8 NTP 1995 CdO 

1023

7 Rabbit 4 hr 

(NS) 

24

28.4 (LC50 at 14 days) 

28.4

Friberg 1950 Cd metal dust 
Table 3-1 Levels of Significant Exposure to Cadmium - Inhalation (continued) 

Exposure/ 

Duration/ 

a Frequency Key to Species (Route) Figure (Strain) 

LOAEL 

Reference Chemical Form 

NOAEL Less Serious Serious 

System (mg/m3) (mg/m3) (mg/m3) 

Systemic 

8 Rat 1 hr 

(Long- Evans) Resp 5 M (pulmonary edema, enzyme changes 

associated with type 2 cell hyperplasia) 

Boudreau et al. 1989 CdCl2 

28

5

9 Rat 3 hr 

(Wistar) Resp 0.4 M (mild hypercellularity at 4.6 M (persistent focal the bronchoalveolar interstitial thickening, 

junction and in adjacent increased collagen, 

alveoli) general hypercellularity) 

Buckley and Bassett 19CdO dust 

29

0.4 4.6

Bd Wt 0.4 M 4.6 M (15% decreased body 

0.4 weight) 

4.6

10 Rat 1 hr 

(SpragueDawley) 

30

Resp 6.5 M (severe pneumonitis) 

6.5

Bd Wt 6.5 M (10.8% decreased body 

weight) 

Bus et al. 1978 CdCl2 

6.5

11 Rat 2 hr 

(SpragueDawley) Resp 0.45 M 4.5 M (moderate to severe 0.45 pneumonitis, hemorrhage, edema) Grose et al. 1987 CdCl2 

34

4.5

Bd Wt 4.5 M (20% decreased body 

weight) 

4.5
a 

Key to 

Figure 

12 

Table 3-1 Levels of Significant Exposure to Cadmium - Inhalation (continued) 

Exposure/ 

Duration/ 

Frequency Species (Route) (Strain) 

LOAEL 

Reference Chemical Form 

NOAEL Less Serious Serious 

System (mg/m3) (mg/m3) (mg/m3) 

Rat 2 hr (SpragueDawley) Resp 0.45 M (significant increased 4.5 M (severe pneumonitis, absolute and relative hyperplasia of type 2 lung weight) cells and fibroblasts) Grose et al. 1987 CdO dust 

35

0.45 4.5

Bd Wt 0.45 M 

0.45

13 Rat 1-6 wk 

5 d/wk (Lewis) 3 hr/d 

36

Resp 1.6 M (interstitial pneumonitis) 

1.6

Hart 1986 CdO dust 

14 Rat 10 d 

6 hr/d (Wistar) 

38

Bd Wt 0.17 M 

0.17

Klimisch 1993 CdCl2 

15 Rat 10 d 

6 hr/d (Wistar) 

39

Bd Wt 6.29 M 

6.29

Klimisch 1993 CdS 

16 Rat 6.2 hr/d 

(Fischer- 344) 5 d/wk 2 wk Resp 0.88 F (degeneration of nasal 8.8 (marked necrosis of olfactory epithelium) alveolar ducts) NTP 1995 CdO 

0.88 8.8

b

0.088 (alveolar histiocytic 

infiltrate and focal inflammation in alveolar septa) 

1017

0.088

Hepatic 2.6 

2.6

Renal 2.6 

2.6
Table 3-1 Levels of Significant Exposure to Cadmium - Inhalation (continued) 

a 

Key to Species 

Figure (Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) 

LOAEL 

ReferenceChemical Form 

NOAEL Less Serious Serious 

System (mg/m3) (mg/m3) (mg/m3) 

17 Rat 

(SpragueDawley) 

2 hr Resp 6 M (alveolar type 1 cell 

damage and necrosis) 

Palmer et al. 1986 CdCl2 

40

6

Endocr 6 M 

6

Bd Wt 6 M 

6

18 Rat 

(SpragueDawley) 

41

2 hr Gastro 132 (erosions of the stomach) 

132

Rusch et al. 1986 CdCO3 

19 Rat 

(SpragueDawley) 

45

5, 10, or 15 d 1 hr/d 

Resp 6.1 M (emphysema) 

6.1

Snider et al. 1973 CdCl2 

20 Rat 

(SpragueDawley) 

46

3 d 1 hr/d Resp 61 M (pulmonary hemorrhage) 61 Snider et al. 1973 

CdCl2 

21 Mouse 

(B6C3F1) 

6.2 hr/d 5 d/wk 2 wk 

Resp 0.88 (fibrosis and 

inflammation around the alveolar ducts, necrosis 

NTP 1995 CdO 

of the alveolar duct epithelium) 

0.88

0.088 (histiocytic infiltrates) 

1022

0.088

Hepatic 2.6 

2.62.6

Renal 2.6 
Table 3-1 Levels of Significant Exposure to Cadmium - Inhalation 

Exposure/ LOAEL 

Duration/ 

a Frequency Key to Species NOAEL Less Serious Serious (Route) Figure (Strain) System (mg/m3) (mg/m3) (mg/m3) 

22 Hamster 30 min Resp 1.1 (moderate increase in 10.1 (severe pneumonitis) (Golden 10.1 PMN, 2-fold increase in Syrian) acid phosphatase) 

(continued) 

Reference Chemical Form 

Henderson et al. 1979 CdCl2 

1.1

47

23 Rabbit 2 hr Resp 4.5 M (mild, multifocal (New interstitial pneumonitis) Zealand) Grose et al. 1987 CdCl2 

4.5

48

24 Rabbit 2 hr Resp 0.45 M (increase in alveolar 4.5 M (multifocal interstitial (New macrophages) pneumonitis) Zealand) Grose et al. 1987 CdO dust 

0.45 4.5

49

Bd Wt 0.45 M (unspecified decrease in 

body weight) 

0.45

Immuno/ Lymphoret 

25 Mouse 2 hr 0.11 F 0.19 F (decreased humoral (Swiss) 0.11 immune response) Graham et al. 1978 CdCl2 

0.19

53

26 Mouse 60 min 0.88 F (reduction in spleen (C57BI/6) lymphocyte viability Krzystyniak et al. 1987 CdCl2 

[35%], numbers, and humoral response (75%)] 

0.88

54

INTERMEDIATE EXPOSURE Death 

27 Rat 20 wk 1 F (13/13 died by week 20) 5 d/wk (Wistar) 1 5 hr/d Baranski and Sitarek 19

CdO dusts 

58
Table 3-1 Levels of Significant Exposure to Cadmium - Inhalation (continued) 

Exposure/ 

Duration/ 

a Frequency Key to Species (Route) Figure (Strain) 

LOAEL 

Reference Chemical Form 

NOAEL Less Serious Serious

System (mg/m3) (mg/m3) (mg/m3) 

28 Rat 62 d 

5 d/wk (Fischer 344) 6 hr/d 

62

2.13 M (100% mortality by day 

45) 

2.13

Kutzman et al. 1986 CdCl2 

29 Rat 6 mo 

40 hr/wk (Wistar) 0.09 (> 75% mortality by 11-12 months 

postexposure) 

Oldiges et al. 1989 CdCl2 

65

0.09

30 Rat 6 mo 

40 hr/wk (Wistar) 0.27 (> 75% mortality by 21-23 months 

postexposure) 

Oldiges et al. 1989 CdS 

67

0.27

31 Rat 63d 

24 hr/d (Wistar) 

68

Systemic 

32 Rat 20 wk 

5 d/wk (Wistar) 5 hr/d 

71

0.105 F (5/12 died) 

0.105

Bd Wt 0.16 F 1 F (30-50% decreased body 

0.16 weight gain) 

1

Prigge 1978a CdO dust Baranski and Sitarek 19CdO dusts 

33 Rat 30 d 

7 d/wk (Wistar) 22 hr/d Resp 0.105 M (increased total bronchoalvelolar macrophage numbers, 

leukocytes, and macrophage cytotoxicity) 

Glaser et al. 1986 CdCl2 

72

0.105

Hemato 0.105 M (45% increase in WBC) 

0.105
Table 3-1 Levels of Significant Exposure to Cadmium - Inhalation (continued) 

Exposure/ 

Duration/ 

a Frequency Key to Species (Route) Figure (Strain) 

LOAEL 

Reference Chemical Form 

NOAEL Less Serious Serious 

System (mg/m3) (mg/m3) (mg/m3) 

34 Rat 30 d 

7 d/wk (Wistar) 22 hr/d Resp 0.098 M (increased total bronchoalvelolar macrophage numbers, Glaser et al. 1986 CdO dust 

leukocytes, and macrophage cytotoxicity) 

0.098

73

Hemato 0.098 M (45% increase in WBC) 

35 Rat 30 d 

7 d/wk (Wistar) 22 hr/d 

0.098

Resp 1.034 M (increased total 

bronchoalvelolar macrophage numbers, 

Glaser et al. 1986 CdS 

leukocytes, and macrophage cytotoxicity) 

1.034

74

Hemato 1.034 M 

1.034

Bd Wt 1.034 M 

1.034

36 Rat 62 d 

5 d/wk (Fischer 344) 6 hr/d Resp 1.06 M (marked fibrosis with significant increase in collagen) Kutzman et al. 1986 CdCl2 

1.06

78

Bd Wt 0.33 1.06 (14% decreased body 2.13 (42-51% decreased body 

0.33 weight) weight) 

1.06 2.13
a

Key to 

Figure 

37 

Table 3-1 Levels of Significant Exposure to Cadmium - Inhalation (continued) 

Exposure/ 

Duration/ 

Frequency Species (Route) (Strain) 

LOAEL 

Reference Chemical Form 

NOAEL Less Serious Serious 

System (mg/m3) (mg/m3) (mg/m3) 

Rat 6.33 hr/d 

5 d/wk (Fischer- 344) 13 wk Resp 0.022 F (epithelial degeneration 0.88 (marked inflammation in the larynx) and moderate fibrosis in interstitium around NTP 1995 CdO 

0.022 alveolar ducts and 

0.22 (Inflammation of nasal terminal bronchioles) 

respiratory epithelium) 

0.88

0.22

1018

Cardio 0.88 

0.88

Gastro 0.88 

0.88

Hemato 0.88 

0.88

Hepatic 0.88 

0.88

Renal 0.88 

0.88

Bd Wt 0.88 

0.88

38 Rat 4 wks 

5 d/wk (Fischer 344) 6 hr/d Resp 0.1 M 0.1 Oberdorster et al. 1994 CdCl2 

79
Table 3-1 Levels of Significant Exposure to Cadmium - Inhalation (continued) 

a 

Key to Species 

Figure (Strain) 

Exposure/ 

Duration/ 

Frequency

(Route)

LOAEL 

Reference Chemical Form 

NOAEL Less Serious Serious 

System (mg/m3) (mg/m3) (mg/m3) 

39 Rat 

(Wistar) 

63 or 90 d 24 hr/d Resp 0.025 F (proliferations, histiocytic cell granulomas) Prigge 1978a CdO dust 

82

0.025

Hemato 0.052 F (increased hemoglobin 

and hematocrit) 

0.052

Hepatic 0.105 F 

0.105

Renal 0.105 F 

0.105

Bd Wt 0.105 F (11% decrease in body 

weight) 

0.105

Metab 0.105 F (decreased blood pH and 

pO2, increased pCO2) 

0.105

40 Rat 

(Wistar) 

83

21 d Gd 1-2124 hr/d 

Resp 0.204 F (77% increased lung 

relative weight) 

0.204

Hemato 0.204 F (8% increased 

hemoglobin, 5% increased hematocrit ) 

Prigge 1978b CdCl2 

0.204

Hepatic 0.581 F 

0.581

Renal 0.581 F 

0.581

Bd Wt 0.394 F 

0.394
Table 3-1 Levels of Significant Exposure to Cadmium - Inhalation (continued) 

a 

Key to Species 

Figure (Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route)

LOAEL 

Reference Chemical Form 

NOAEL Less Serious Serious 

System (mg/m3) (mg/m3) (mg/m3) 

41 Rat 

(Wistar) 

21 d Gd 1-21 24 hr/d 

Resp 0.204 F (70% increased lung 

relative weight) 

Prigge 1978b CdCl2 

0.204

84

Hemato 0.581 F (increased hemoglobin 

[12%], hematocrit [12%], total biliurin [2-fold]) 

0.581

Hepatic 0.581 F 

0.581

Renal 0.581 F 

0.581

Bd Wt 0.394 F (12% decreased 

maternal weight gain) 

0.394

42 Mouse 

(B6C3F1) 

6.33 hr/d 5 d/wk 13 wk 

Resp 0.088 M (Degeneration of nasal 

olfactory epithelium) 

NTP 1995 CdO 

0.088

0.022 (alveolar histiocytic 

infiltrates and squamous metaplasia of the larynx) 

0.022

1024

Cardio 0.88 

0.88

Gastro 0.88 

0.88

Hepatic 0.88 

0.88

Renal 0.88 

0.880.88

Bd Wt 0.88 
Table 3-1 Levels of Significant Exposure to Cadmium - Inhalation (continued) 

a 

Key to Species 

Figure (Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route)

LOAEL 

Reference Chemical Form 

NOAEL Less Serious Serious 

System (mg/m3) (mg/m3) (mg/m3) 

43 Mouse 

(BALB/c) 

4 wks 5 d/wk 6 hr/d 

Resp 0.1 M (increased neutrophils, 

LDH and beta-glucuronidase; 

Oberdorster et al. 1994 CdCl2 

pulmonary inflammation) 

0.1

86

44 Rabbit 

(NS) 

9 mo 21 d/mo 3 hr/d 

Resp 4 (chronic pneumonia, 

emphysema) 

Friberg 1950 Cd metal dust 

4

87

Hemato 4 (eosinophilia, lower 

hemoglobin) 

4

Renal 4 (proteinuria) 

45 Rabbit 

(NS) 

7 mo 23 d/mo 3 hr/d 

4

Resp 5.6 (emphysema) 

5.6

Friberg 1950 Cd metal dust 

88

Renal 5.6 (proteinuria in 6/10 

surviving to the end of exposure) 

5.6

46 Rabbit 

(NS) 

4-6 wk 5 d/wk 6 hr/d 

Resp 0.4 M (lung interstitial 

inflammation, type 2 cell hyperplasia) 

Johansson et al. 1984 CdCl2 

0.4

89
Table 3-1 Levels of Significant Exposure to Cadmium - Inhalation (continued) 

Exposure/ 

Duration/ 

a Frequency Key to Species (Route) Figure (Strain) 

LOAEL 

Reference Chemical Form 

NOAEL Less Serious Serious 

System (mg/m3) (mg/m3) (mg/m3) 

Reproductive 

47 Rat 5 hr/d 

5 d/wk (Wistar) 5 mo 0.16 F 0.16 Baranski 1984 CdO 

premating, mating, Gd 1-20 

1026

48 Rat 20 wk 

5 d/wk (Wistar) 5 hr/d 1 F (increased duration of estrous cycle) Baranski and Sitarek 19

CdO dusts 

1

97

49 Rat 62 d 

(Fischer 344) 5 d/wk 6 hr/d 1.06 M ( t Kutzman et al. 1986 CdCl2 

1.06

98

50 Rat 6.33 hr/d 

5 d/wk (Fischer- 344) 13 wk 0.22 M 0.88 M (decreased spermatid 0.22 counts 0.22 F NTP 1995 CdO 

0.22

0.88

0.88 F (increased estrous cycle 

length) 

0.88

1019

Developmental 

51 Rat 5 hr/d 

5 d/wk (Wistar) 5 mo 0.02 F (altered performance on neurobehavioral tests) Baranski 1984 CdO 

premating, 0.02

mating, Gd 1-20 

1027
Table 3-1 Levels of Significant Exposure to Cadmium - Inhalation (continued) 

Exposure/ 

Duration/ 

a Frequency Key to Species (Route) Figure (Strain) 

LOAEL 

Reference Chemical Form 

NOAEL Less Serious Serious 

System (mg/m3) (mg/m3) (mg/m3) 

52 Rat 4-5 mo 

5 d/wk (Wistar) 5 hr/d 0.02 (altered performance on 0.16 (decreased pup viability) 0.16 neurobehavioral tests) Baranski 1985 CdO dusts 

0.02

100

53 Rat 6.27 hr/d 

7 d/wk (SpragueDawley) Gd 4-19 0.4 F 1.7 F (decreased fetal body 0.4 weight and reduced ossification) NTP 1995 CdO 

1.7

1021

54 Rat 21 d 

Gd 1-21 (Wistar) 24 hr/d 0.581 (9% decreased fetal body weight, 12% increase in fetal alkaline Prigge 1978b CdCl2 

phosphatase) 

0.581

101

55 Mouse 6.27 hr/d 

7 d/wk (Swiss) Gd 4-17 0.04 F 0.4 F (decreased fetal body 0.04 weight) NTP 1995 CdO 

0.4

1025

Cancer 

56 Rat 6 mo 

40 hr/wk (Wistar) 0.09 (CEL: lung bronchioalveolar Oldiges et al. 1989 CdCl2 

adenomas, adenocarcinomas, and squamous cell carcinomas) 

0.09

103

CHRONIC EXPOSURE Death 

57 Human 1-34 yr 

5 d/wk 8 hr/d (occup) 

6.8 M (2 fatalities from 14 years 

or 25 years of exposure to Cd dust) 

Friberg 1950 Cd dust 

6.8

106
Table 3-1 Levels of Significant Exposure to Cadmium - Inhalation (continued) 

a 

Key to Species 

Figure (Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) NOAEL Less Serious System (mg/m3) (mg/m3) 

LOAEL 

Reference Chemical Form 

Serious 

(mg/m3) 

58 Rat 

(Wistar) 

413-455 d 7 d/wk 22 hr/d 

0.095 M (6/20 died) 

0.095

Oldiges and Glaser 198CdSO4 

108

59 Rat 

(Wistar) 

18 mo 7 d/wk 22 hr/d 

0.03 M (>75% mortality by 12 

months postexposure) 

Oldiges et al. 1989 CdCl2 

0.03

109

60 Rat 

(Wistar) 

18 mo 7 d/wk 22 hr/d 

0.09 (more than 25% died 

after 7 months [M] and 11 months [F] of 

Oldiges et al. 1989 CdO dust 

exposure) 

0.09

110

61 Rat 

(Wistar) 

18 mo 7 d/wk 22 hr/d 

0.09 (>75% mortality after 12 

months postexposure) 

Oldiges et al. 1989 CdS 

0.09

112

62 Rat 

(Wistar) 

18 mo 7 d/wk 22 hr/d 

0.09 M (>25% mortality by 14 

months of exposure) 

Oldiges et al. 1989 CdSO4 

0.09

0.09 F (>75% by 11 months 

postexposure) 

0.09

113

Systemic 

63 Human c Renal 0.0001 F Buchet et al. 1990; Jaru

0.0001 2000; Suwazono et al. 2

1035 form not specified 
Table 3-1 Levels of Significant Exposure to Cadmium - Inhalation (continued) 

a 

Key to Species 

Figure (Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) NOAEL Less Serious System (mg/m3) (mg/m3) 

LOAEL 

Reference Chemical Form 

Serious 

(mg/m3) 

64 Human 4-24 yr 

5 d/wk 8 hr/d (occup) 

Resp 0.025 

0.025

Edling et al. 1986 CdO fume 

129

65 Human 30 yr 

5 d/wk 8 hr/d (occup) 

Renal 0.033 

0.033

0.067 (pronounced proteinuria) 

0.067

Elinder et al. 1985b CdO fume 

131

66 Human 30 yr 

5 d/wk 8 hr/d (occup) 

Renal 0.0153 M 

0.0153

0.0379 M (100% incidence of 

proteinuria in the cohort exposed to this level for 21 years) 

Falck et al. 1983 CdO fume 

0.0379

132

67 Human 30 yr 

5 d/wk 8 hr/d 

Renal 0.017 

0.017

0.023 (9.2% incidence of 

proteinuria) 

Jarup et al. 1988 CdO dust 

(occup) 0.023

138

68 Human 30 yr 

5 d/wk 8 hr/d (occup) 

Renal 0.0367 M 

0.0367

Mason et al. 1988 form not specified 

150

69 Human 30 yr 

5 d/wk 8 hr/d (occup) 

Renal 0.027 

0.027

Thun et al. 1989 CdO dust or fume 

169
a 

Key to 

Figure 

70 

Table 3-1 Levels of Significant Exposure to Cadmium - Inhalation (continued) 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) NOAEL Less Serious System (mg/m3) (mg/m3) 

LOAEL 

Reference Chemical Form 

Serious 

(mg/m3) 

Rat (Wistar) 

18 mo 7 d/wk 23 hr/d 

Resp 0.0134 M (adenomatous 

hyperplasia in the bronchoalveolar area) 

Takenaka et al. 1983 CdCl2 

0.0134

174

Bd Wt 0.0508 M 

0.0508

Cancer 

71 Human 6 mo - 43 yr 

7 d/wk 8 hr/d (occup) 

0.1 M (CEL: 50-111 lung 

cancer deaths per 1000 workers; 45 year 

exposure) 

Stayner et al. 1992 CdO dust or fumes 

0.1

209

72 Rat 

(Wistar) 

18 mo 7 d/wk 22 hr/d 

0.03 (CEL: lung 

bronchioalveolar adenomas, adenocarcinomas, and squamous cell carcinomas) 

Oldiges et al. 1989 CdCl2 

0.03

210

73 Rat 

(Wistar) 

18 mo 7 d/wk 22 hr/d 

0.03 (CEL: lung 

bronchioalveolar adenomas, adenocarcinomas, and squamous cell carcinomas) 

Oldiges et al. 1989 CdO dust 

0.03

211
Table 3-1 Levels of Significant Exposure to Cadmium - Inhalation (continued) 

a 

Key to Species 

Figure (Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) NOAEL Less Serious System (mg/m3) (mg/m3) 

LOAEL 

Reference Chemical Form 

Serious 

(mg/m3) 

74 Rat 

(Wistar) 

18 mo 7 d/wk 22 hr/d 

0.03 (CEL: lung 

bronchioalveolar adenomas, adenocarcinomas) 

Oldiges et al. 1989 CdO fume 

0.03

212

75 Rat 

(Wistar) 

18 mo 7 d/wk 22 hr/d 

0.09 (CEL: lung 

bronchioalveolar adenomas, adenocarcinomas, and squamous cell carcinomas) 

Oldiges et al. 1989 CdS 

0.09

213

76 Rat 

(Wistar) 

18 mo 7 d/wk 22 hr/d 

0.09 (CEL: lung 

bronchio-alveolar adenomas, adenocarcinomas, squamous cell carcinomas) 

Oldiges et al. 1989 CdSO4 

0.09

214
Table 3-1 Levels of Significant Exposure to Cadmium - Inhalation (continued) 

Exposure/ LOAEL 

Duration/ 

a Frequency Reference Key to Species NOAEL Less Serious Serious (Route) Figure (Strain) System (mg/m3) (mg/m3) (mg/m3) Chemical Form 

77 Rat 18 mo 0.0134 M (CEL: lung epidermoid Takenaka et al. 1983 7 d/wk (Wistar) carcinomas, 23 hr/d CdCl2 adenocarcinomas, and 

mucoepidermoid carcinomas) 

0.0134

215

a The number corresponds to entries in Figure 3-1. b Used to derive an acute-duration inhalation minimal risk level (MRL) of 0.00003 mg Cd/m3 (0.03 ug Cd/m3); concentration was adjusted for intermittent exposure days/week) and divided by an uncertainty factor of 300 (10 for use of a LOAEL, 3 for extrapolation from animals to humans with dosimetric adjustment, and 10 for hc The chronic-duration inhalation MRL of 0.00001 mg Cd/m3 (0.01 ug Cd/m3) was calculated from the 95% lower confidence limit of the urinary cadmium level assoincreased risk of low molecular weight proteinuria (0.5 ug/g creatinine) estimated from a meta-analysis of select environmental exposure studies. An air concentratan assumed dietary intake of 0.3 ug Cd/kg/day) which would result in this urinary cadmium concentration was estimated using the ICRP human respiratory tract momodification of the Nordberg-Kjellström pharmacokinetic model (see Appendix A for details on the meta-analysis and extrapolation to air concentration). This air coug Cd/m3 was divided by an uncertainty factor of 3 for human variability and a modifying factor of 3. Bd Wt = body weight; Cardio = cardiovascular; CEL = cancer effect level; d = day(s); Endocr = endocrine; F = Female; Gastro = gastrointestinal; Gd = gestational dhematological; hr = hour(s); Immuno/Lymphoret = immunological/lymphoreticular; LC50 = lethal concentration, 50% kill; LDH = lactate dehydrogenase; LOAEL = lowest-observed-adverse-effect level; M = male; min = minute(s); Metab = metabolic; mo = month(s); NOAEL = no-observed-adverse-effect level; NS = not specifieoccupational; PMN = polymorphonuclear leukocyte; Resp = respiratory; WBC = white blood cells; wk = week(s); yr = year(s) 
Death 

Respiratory Gastrointestinal Hepatic Renal Endocrine Body Weight Immuno/Lymphor 


	


	

Figure 3-1 Levels of Significant Exposure to Cadmium - Inhalation
	

Acute (≤14 days)

Systemic 

mg/m3 

1000 

18r 4r 

5r 

100 

20r 

2r 7h 

10 22s 1 6m 3r 16r 10r 17r 19r 17r 10r 15r 17r 8r 9r 11r 12r 23h 24h 9r 11r 

21m 16r 21m 16r 

13r 

1 22s 21m 16r 26m 

9r 11r 12r 24h 9r 12r 24h

14r 25m

0.1 25m 21m 16r 

0.01 

0.001 

0.0001 

1E-5 

c-Cat -Humans f-Ferret n-Mink Cancer Effect Level-Animals Cancer Effect Level-Humans LD50/LC50

d-Dog k-Monkey j-Pigeon o-Other LOAEL, More Serious-Animals LOAEL, More Serious-Humans Minimal Risk Level 

r-Rat m-Mouse e-Gerbil LOAEL, Less Serious-Animals LOAEL, Less Serious-Humans for effects 

p-Pig h-Rabbit s-Hamster NOAEL - Animals NOAEL - Humans other than 

q-Cow a-Sheep g-Guinea Pig Cancer 
Death 

Respiratory Cardiovascular Gastrointestinal Hematological Hepatic Renal Body Weight 


 


	

Figure 3-1 Levels of Significant Exposure to Cadmium - Inhalation (Continued)

Intermediate (15-364 days)
	

Systemic 

mg/m3 

10 

45h 45h 

44h 44h 44h 

28r 

1 27r 35r 36r 35r 32r 

37r 42m 37r 42m 37r 37r 42m 37r 42m 37r 42m 

41r 40r 41r 40r 41r 

46h 

30r 

37r 40r 41r 40r 

32r 

31r 33r 33r 39r 39r 0.1 43m 34r 38r 34r 29r 42m 

39r 

39r 

42m 37r 

0.01 

c-Cat -Humans f-Ferret n-Mink Cancer Effect Level-Animals Cancer Effect Level-Humans LD50/LC50

d-Dog k-Monkey j-Pigeon o-Other LOAEL, More Serious-Animals LOAEL, More Serious-Humans Minimal Risk Level 

r-Rat m-Mouse e-Gerbil LOAEL, Less Serious-Animals LOAEL, Less Serious-Humans for effects 

p-Pig h-Rabbit s-Hamster NOAEL - Animals NOAEL - Humans other than 

q-Cow a-Sheep g-Guinea Pig Cancer 
Body Weight 

Metabolic Reproductive Developmental Cancer * 

 

 


 


	

Figure 3-1 Levels of Significant Exposure to Cadmium - Inhalation (Continued)

Intermediate (15-364 days)
	

Systemic 

mg/m3 

10 

36r 

53r 

35r 36r 49r 1 48r 

37r 50r 50r 

54r 

40r 55m 53r 

36r 

41r 

50r 50r 

47r 52r 

39r 39r 0.1 56r 

55m 

51r 52r 

*Doses represent the lowest dose tested per study that produced a tumorigenic 

response and do not imply the existence of a threshold for the cancer endpoint. 0.01 

c-Cat -Humans f-Ferret n-Mink Cancer Effect Level-Animals Cancer Effect Level-Humans LD50/LC50

d-Dog k-Monkey j-Pigeon o-Other LOAEL, More Serious-Animals LOAEL, More Serious-Humans Minimal Risk Level 

r-Rat m-Mouse e-Gerbil LOAEL, Less Serious-Animals LOAEL, Less Serious-Humans for effects 

p-Pig h-Rabbit s-Hamster NOAEL - Animals NOAEL - Humans other than 

q-Cow a-Sheep g-Guinea Pig Cancer 
Death 

Respiratory Renal Body Weight Cancer * 

 

 


	 
	


	


	


	 
	 
	


	


	


	


	


	


	


	

Figure 3-1 Levels of Significant Exposure to Cadmium - Inhalation (Continued)

Chronic (≥365 days) 

Systemic 

mg/m3 

10
	 57
	

1
	

0.1 58r 60r 61r 62r 62r 71 75r 76r 65
	 70r

65 66
	 68 59r 69 72r 73r 74r 64
	 67
	

70r 66
	 67 77r 0.01 

0.001 

0.0001 63
	

10-4
	

Estimated
	

Upper-Bound 1E-5 

10-5 Human Cancer 
	

Risk Levels
	

1E-6 

10-6
	

1E-7 

10-7
	

*Doses represent the lowest dose tested per study that produced a tumorigenic 

response and do not imply the existence of a threshold for the cancer endpoint. 1E-8 

c-Cat -Humans f-Ferret n-Mink Cancer Effect Level-Animals Cancer Effect Level-Humans LD50/LC50

d-Dog k-Monkey j-Pigeon o-Other LOAEL, More Serious-Animals LOAEL, More Serious-Humans Minimal Risk Level 

r-Rat m-Mouse e-Gerbil LOAEL, Less Serious-Animals LOAEL, Less Serious-Humans for effects 

p-Pig h-Rabbit s-Hamster NOAEL - Animals NOAEL - Humans other than 

q-Cow a-Sheep g-Guinea Pig Cancer 
 

 

 

CADMIUM 71 

3. HEALTH EFFECTS 

male welder who developed acute cadmium pneumonitis from a single exposure (dose not determined). 

Nine years after the exposure, this worker continued to show signs of progressive pulmonary fibrosis and 

had no improvement in respiratory function. Precise estimates of cadmium concentrations leading to 

acute respiratory effects in humans are not currently available. 

The initial symptoms of respiratory distress observed in the higher acute exposures do not occur 

following lower-level, longer-term inhalation exposures (Friberg 1950). Longer-term occupational 

exposure to levels of cadmium below those causing lung inflammation, however, have been reported to 

cause emphysema and dyspnea in humans (Bonnell 1955; Friberg 1950; Lane and Campbell 1954; Smith 

et al. 1960). Kjellström et al. (1979) reported a significant increase in deaths due to respiratory diseases 

in cadmium-exposed battery factory workers exposed for >5 years. 

A significant, dose-dependent excess in the ratio of observed to expected deaths from bronchitis (i.e., 

standardized mortality ratio [SMR]=434) but not emphysema was found among 6,995 men occupationally 

exposed to cadmium for an average of 11 years (Armstrong and Kazantzis 1983). The dose level was not 

determined. 

The earlier occupational studies did not control for the health effects of cigarette smoking. There is some 

evidence that cadmium may accelerate the development of emphysema in smokers. Leduc et al. (1993) 

report a case history of a 59-year-old male worker who smoked a pack of cigarettes per day since age 16, 

but had no prior history of respiratory disease in 1975 until developing emphysema in 1979 after inhaling 

various concentrations of cadmium (range of 0.0164–1.192 mg/m3

, mean of 0.446 mg/m3, about nine 

times the threshold value of 0.050 mg/m3

) for 4 years as a furnace operator. Very high levels of cadmium 

in air samples at the workplace and in the patient’s blood, urine, and lung tissue confirmed massive 

exposures. Lung-function tests declined rapidly, with a faster than usual onset of emphysema compared 

to other smokers. The mean concentration of cadmium in a removed section of lung was 580 μg/g dry 

tissue, compared to 14 μg/g in three unexposed controls matched for age, sex, and smoking habit who had 

also undergone resection of a bronchial carcinoma. The authors state that this case supports the 

hypothesis for an etiological role of cadmium fume inhalation in the development of emphysema. 

More recent studies that controlled for smoking report lung impairment in cadmium-exposed workers 

(Chan et al. 1988; Cortona et al. 1992; Davison et al. 1988; Smith et al. 1976). Cortona et al. (1992) 

measured respiratory function parameters in 69 smoking and nonsmoking male subjects (average age 45) 

who were exposed to concentrations of 0.008–1.53 mg/m3 of cadmium fumes over a period of 

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CADMIUM 72 

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several years in a factory that produced cadmium alloys (silver-cadmium-copper). Forced Expiratory 

Volume (FEV), Forced Vital Capacity (FVC), Residual Volume (RV), Transfer Factor by the carbon 

monoxide method (TLCO), and Transfer Coefficient (KCO) were measured in these exposed individuals. 

The study found that there were no significant differences in the FVC, FEV, TLCO, and KCO between 

the workers exposed to cadmium fumes and control (non-exposed) individuals. There was a significant 

increase in RV of >8% in exposed workers; this effect was notably greater in those with higher 

cumulative exposures to cadmium (>10%). It is uncertain how much of a factor on the increased RV was 

due to the tendency of smokers to develop an initial emphysematous alteration in lung tissue due to 

smoking. 

Davison et al. (1988) evaluated lung function in 101 men who had manufactured copper-cadmium alloy 

in a plant in England for ≥1 years since 1926. The exposed men were compared to controls from the 

factory’s other seven divisions matched for age and employment status. Smoking in exposed and control 

men was similar. Between 1951 and 1983, 933 measurements of airborne cadmium had been made, 

697 with static samplers and 236 with personal samplers. The various sampling methods used before 

1964 are no longer considered to be reliable, so estimates of air concentrations were made based on 

changes in production techniques, ventilation, levels of production, and discussions with occupational 

health physicians, industrial hygienist, the management, and the workers. Cadmium concentrations in air 

from 1926 to 1972 were determined to have declined from 0.6 to 0.156 mg/m3

. In 1973, concentrations 

were 0.085 mg/m3

; from 1974 to 1983, concentrations ranged from 0.034 to 0.058 mg/m3. The lung 

function of 77 of the men occupationally exposed to cadmium was significantly impaired compared to the 

unexposed controls, with the greatest abnormalities in the highest-dose group. Forced expiratory volume 

in one second, ratio of forced expiratory volume to forced vital capacity, transfer factor, or transfer 

coefficient were significantly lower than expected and radiographic total lung capacity, residual volume, 

and the ratio of these two were significantly higher than expected. The greatest abnormalities were 

observed in workers with the highest cumulative exposure and the highest liver cadmium levels. 

Regression of the lung transfer coefficient versus cadmium exposure indicated a linear relationship with 

no apparent threshold. 

Smith et al. (1976) studied the pulmonary function of 17 high-exposure workers, 12 low-exposure 

workers, and 17 controls. Cadmium air concentrations where high-exposure subjects worked were 

>0.2 mg/m3

. High-exposure subjects had worked at the plant a median of 26.4 years, with a maximum of 

40.2 years, and low-exposure subjects had worked a median of 27.1 years, with a maximum of 34.8 years. 

Workers with high exposure to cadmium had significantly decreased the FVC compared to low-exposure 

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CADMIUM 73 

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workers and controls. Chest X-rays indicated mild or moderate interstitial fibrosis in 29% of high 

exposure workers. A dose-response relationship was found between FVC and urinary cadmium, and 

with months of exposure to cadmium fume, but not cadmium sulfate aerosol. In an analysis of the 

smoking habits, there was no significant difference between the two cadmium-exposed groups with 

respect to the proportion of present or past cigarette smokers, the intensity or duration of cigarette 

smoking, or cigar or pipe smoking habits. The control subjects, however, had a significantly (p<0.05) 

“higher” exposure to cigarette smoke than the cadmium exposed workers with substantially greater 

numbers of pack-years, cigarettes smoked per day, and years smoked. A step-down and multiple 

regression analyses with a dependent variable of FVC (as percent of predicted), and the independent 

variables, age-height, cigarette pack-years, and urinary cadmium, resulted in no indication that an 

interaction between the independent variables led to the observed relationship between FVC and 

cadmium excretion. 

Other studies, however, have not shown a cadmium-related increase in impaired respiratory function. 

Edling et al. (1986) studied Swedish workers occupationally exposed to cadmium oxide fume from 

cadmium-containing solders. Cadmium-containing solder had been used at the plant from 1955 to 1978. 

The results from the lung-function analysis showed no significant difference in symptoms or lung 

function between the cadmium-exposed and the reference group. The exposed and the reference groups 

were similar with respect to sex, age, and height. There was a higher percentage of smokers in the 

reference group (52%) than in the exposed group (42%), but the difference was not statistically 

significant. The authors could not explain why significant differences in effects were not seen in these 

workers since other studies have shown significant effects at comparable cadmium exposure levels. The 

authors suggest that a possible bias could have been introduced if people who had worked for >5 years in 

the plant had changed their occupation because of lung disease, so that only “healthy” workers remained. 

Significant effects may also have been found if the reference group included workers other than those 

who worked with solder, but the purpose of the study was to resolve the effects of cadmium exposure 

among workers with similar occupations. Evaluating the data from smokers and nonsmokers separately 

also showed no significant impairment in lung function between smoking exposed and smoking 

unexposed or nonsmoking exposed and nonsmoking unexposed. The lung impairment due to smoking 

was observed in that smokers in both the exposed and unexposed groups had a somewhat deteriorated 

closing volume and other lung function indicators in accordance with previous studies on the effects of 

smoking. These results support the hypothesis that the response to occupational dust exposure differs 

from the response to tobacco smoking. 

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CADMIUM 74 

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Another possible reason for differing results is that lung injury caused by high-level cadmium exposure 

may be partially reversible (Bonnell 1955; Chan et al. 1988), with a return towards normal several years 

after exposures have been significantly reduced. Chan et al. (1988) studied a cohort of 36 female and 

8 male workers at a Singapore cadmium battery factory exposed to cadmium oxide dust. Cadmium 

concentrations in air were 0.03–0.09 mg/m3 (geometric means). Lung function was measured using 

spirometry, helium dilution, tidal sampling, X-ray, and respiratory symptoms. The recovery of lung 

function after reduction or cessation of occupational exposure to cadmium dusts was assessed. Total lung 

capacity increased following reduction of exposure and, following cessation of exposure, vital capacity, 

FEV, and prevalence of respiratory symptoms all improved. Blood and urine cadmium concentrations 

were considerably lower with the reduction or cessation of exposure and were consistent with a decrease 

in the cadmium air levels. 

Additional respiratory symptoms less frequently reported in workers occupationally exposed to cadmium 

are chronic rhinitis and impairment or loss of the sense of smell (Adams et al. 1969; Bonnell 1955; 

Friberg 1950; Liu et al. 1985; Rose et al. 1992). The cause of these effects may be chronic irritation or 

necrosis of the nasal membranes, as they are generally found only in individuals with high-level exposure. 

An increased prevalence of abnormal parasinus radiographic findings in cadmium-exposed workers 

compared to other published reports on non-exposed populations was reported by Shaham et al. (1993). 

Studies in animals confirm that inhalation exposure to cadmium can lead to respiratory injury. Single 

acute exposures in rats to 5–10 mg Cd/m3 as cadmium oxide dust, cadmium oxide fume, or cadmium 

chloride for 1–5 hours resulted in moderate to severe, multifocal interstitial pneumonitis, diffuse alveolitis 

with hemorrhage, increased lung weight, inhibition of macrophages, focal interstitial thickening, edema, 

and necrosis of alveolar type 1 cells leading to type 2 cell hyperplasia and fibroblasts (Boudreau et al. 

1989; Buckley and Bassett 1987b; Bus et al. 1978; Grose et al. 1987; Hart et al. 1989a; NTP 1995; 

Palmer et al. 1986). Similar results (i.e., severe pneumonitis) were seen in hamsters exposed to cadmium 

chloride at 10 mg/m3 for 30 minutes (Henderson et al. 1979) and in rabbits exposed to cadmium oxide 

dusts at 4.5 mg/m3 for 2 hours (Grose et al. 1987). Exposures in rats to cadmium chloride at 6.1 mg 

Cd/m3 1 hour/day for 5, 10, or 15 days resulted in emphysema; a 3-day exposure to 61 mg Cd/m3 for 

1 hour/day resulted in pulmonary hemorrhage (Snider et al. 1973). Repeated exposure to 0.088 mg Cd/m3 

as cadmium oxide for 2 weeks resulted in minimal to mild alveolar histiocytic (macrophage) infiltration 

in rats and mice, focal inflammation surrounding alveolar ducts and extending into the adjacent alveolar 

septa in rats, and hyperplasia in tracheobronchial lymph nodes in mice (NTP 1995). At higher 

concentrations, the severity of these lesions increased (the severity of the lung lesions was scored as 

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CADMIUM 75 

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moderate at ≥0.88 mg Cd/m3) and necrosis of the epithelial lining of the alveolar ducts was observed at 

≥0.26 mg Cd/m3 in rats and 0.88 mg Cd/m3 in mice. The NTP (1995) study also found significant 

increases in the incidence of lesions in the nasal cavity; minimal-to-mild degeneration of the olfactory 

epithelium was observed in rats and mice exposed to 0.88 mg Cd/m3 and hyperplasia and inflammation of 

respiratory epithelium were observed in rats at 2.6 mg Cd/m3

. 

Persistent damage has been reported in an animal model following a single intratracheal exposure to 25, 

100, or 400 μg cadmium chloride/kg body weight (Driscoll et al. 1992). Although most BALF 

biochemical (lactate dehydrogenase, total protein, and N-acetylglucosaminidase) and cellular (neutrophils 

and lymphocyte numbers) parameters returned to control levels 28 days after exposure, histopathological 

alterations including inflammation and fibrosis were still present 90 days post-exposure and the incidence 

and severity of the lesions were greater at 90 days compared to 28 days. 

Intermediate-duration exposure to cadmium results in similar respiratory effects as seen in the acute 

exposures. Concentration-related increases in the severity and types of respiratory lesions have been 

observed. Because the intermediate-duration studies used different exposure protocols, intermittent 

exposure studies were duration-adjusted to continuous exposure (Table 3-2) to facilitate comparisons 

across these studies. The lowest adverse effect level for lung effects was 0.004 mg Cd/m3 for alveolar 

epithelial hyperplasia in mice (NTP 1995). At 0.008–0.07 mg Cd/m3

, inflammation and minimal fibrosis 

were observed in rats, mice, and rabbits (Johansson et al. 1984; NTP 1995; Oberdörster et al. 1994) and 

marked inflammation and moderate fibrosis were observed in rats at 0.17 mg Cd/m3 (NTP 1995). At 

≥0.34 mg Cd/m3

, emphysema and chronic pneumonia were observed in rats and rabbits (Friberg 1950; 

Prigge 1978b). In addition to the widely reported effects in the lungs, NTP (1995) reported minimal 

lesions in the larynx of rats (epithelial degeneration) and mice (squamous metaplasia) exposed to 

0.022 mg Cd/m3 and minimal lesions in the nasal cavity in rats (inflammation of respiratory epithelium) 

and mice (degeneration of olfactory epithelium) exposed to 0.088 mg Cd/m3

. The toxicity of cadmium to 

the respiratory tract following intermediate-duration exposure is highlighted by the NTP (1995) rat and 

mouse studies. As summarized in Table 3-3, rats and mice were exposed to five concentrations (0.022, 

0.044, 0.088, 0.22, and 0.88 mg Cd/m3 as cadmium oxide) 6.33 hours/day, 5 days/week for 13 weeks. 

The earliest effects observed were alveolar histiocytic infiltrates, alveolar epithelial hyperplasia, and 

tracheal epithelial hyperplasia or squamous metaplasia; these lesions were all graded as minimal. With 

increasing concentrations, the severity of most lesions increased as did the type of lesion. 

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Table 3-2. Comparison of Lung Effects Across Intermediate-Duration Inhalation 

Studies
 

Durationadjusted 

Adverse adverse 

Species 

Exposure 

frequency/duration 

effect level 

(mg Cd/m3) 

effect level 

(mg Cd/m3) Effect Reference 

Mouse 6.33 hours/day, 0.022 0.004 Alveolar NTP 1995 

5 days/week, 13 weeks hyperplasia 

Rat 6.33 hours/day, 0.044 0.008 Alveolar NTP 1995 

5 days/week, 13 weeks histiocytic 

infiltrates and 

hyperplasia 

Mouse 6.33 hours/day, 0.044 0.008 Minimal NTP 1995 

5 days/week, 13 weeks fibrosis 

Mouse 6.33 hours/day, 0.088 0.017 Moderate NTP 1995 

5 days/week, 13 weeks inflammation 

Rat 6.33 hours/day, 0.22 0.017 Minimal NTP 1995 

5 days/week, 13 weeks fibrosis 

Mouse 6 hours/day, 0.1 0.02 Inflammation Oberdörster 

5 days/week, 4 weeks et al. 1994 

Rat 24 hours/day, 0.025 0.025 Proliferations Prigge 1978a 

7 days/week, 90 days 

Rat 6.33 hours/day, 0.22 0.04 Inflammation NTP 1995 

5 days/week, 13 weeks 

Rat 6.33 hours/day, 0.88 0.17 Marked NTP 1995 

5 days/week, 13 weeks inflammation 

and 

moderate 

fibrosis 

Mouse 6.33 hours/day, 0.88 0.17 Moderate NTP 1995 

5 days/week, 13 weeks fibrosis 

Rat 6 hours/day, 0.33 0.06 Fibrosis Kutzman et 

5 days/week, 62 days al. 1986 

Rabbit 6 hours/day, 0.4 0.07 Inflammation Johansson et 

5 days/week 4–6 weeks al. 1984 

Rabbit 3 hours/day, 4 0.34 Pneumonia/ Friberg 1950 

21 days/month, 9 months emphysema 

Rabbit 3 hours/day, 5.6 0.53 Emphysema Friberg 1950 

23 days/month, 7 months 

Rat 24 hours/day, Prigge 1978b 

7 days/week 

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Table 3-3. Severity of Respiratory Effects in Rats and Mice Exposed to
 

Cadmium Oxide for 13 Weeksa
 

Concentration (mg Cd/m3) 

0 0.022 0.044 0.088 0.22 0.88 

Male rats 

Lung 

Alveolar histiocytic infiltrate — —b 1.0c 2.0 3.0 3.0 

Alveolar epithelial hyperplasia — — 1.0 1.0 2.0 2.1 

Inflammation — — — — 2.6 4.0 

Fibrosis — — — 1.0 2.0 2.7 

Mediastinal lymph node 

inflammation — — — 1.3 3.2 3.3 

Larynx 

Epithelial degeneration 1.0 1.0 1.0 1.0 1.0 

Nose 

Olfactory epithelium — — — 1.0 3.0 

degeneration 

Olfactory epithelium — — — — — 1.3 

respiratory metaplasia 

Olfactory epithelium — — — — — 1.9 

squamous metaplasia 

Respiratory epithelium — — — — 1.0 2.6 

inflammation 

Respiratory epithelium — — — — — 1.5 

degeneration 

Female rats 

Lung 

Alveolar histiocytic infiltrate — — 1.0 2.1 3.0 3.0 

Alveolar epithelial hyperplasia — — 1.0 1.0 2.0 2.1 

Inflammation — — — 1.6 3.5 

Fibrosis — — — 1.0 2.0 2.1 

Mediastinal lymph node 

inflammation — — 1.0 1.5 3.6 4.0 

Larynx 

Epithelial degeneration — 1.0 1.0 1.0 1.0 1.0 

Nose 

Olfactory epithelium — — — — 1.0 2.8 

degeneration 

Olfactory epithelium — — — — 1.0 1.0 

respiratory metaplasia 

Olfactory epithelium — — — — — 1.4 

squamous metaplasia 

Respiratory epithelium — — — 1.0 1.8 1.8 

inflammation 

Male mice 

Lung 

Alveolar epithelial hyperplasia — 1.0 1.0 1.8 1.7 2.0 

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Table 3-3. Severity of Respiratory Effects in Rats and Mice Exposed to
 

Cadmium Oxide for 13 Weeksa
 

Concentration (mg Cd/m3) 

0 0.022 0.044 0.088 0.22 0.88
 

Inflammation — — — 3.0 2.2 2.7 

Fibrosis — — 1.0 1.0 1.0 1.0 

Tracheobronchial lymph node 

hyperplasia — — 1.0 2.3 2.4 2.7 

Larynx 

Squamous metaplasia — 1.0 1.0 1.0 1.0 1.1 

Nose 

Olfactory epithelium — — — 1.0 1.7 2.0 

degeneration 

Olfactory epithelium — — — — 1.0 1.5 

respiratory metaplasia 

Olfactory epithelium — — — — 1.0 

squamous metaplasia 

Respiratory epithelium — — — — 1.0 1.0 

hyaline droplets 

Female mice 

Lung 

Alveolar histiocytic infiltrate — 1.0 1.0 2.0 2.0 3.0 

Alveolar epithelial hyperplasia — — — 1.4 2.0 2.0 

Inflammation — — — 2.3 2.1 2.9 

Fibrosis — — 1.0 1.0 1.0 1.0 

Tracheobronchial lymph node 

hyperplasia — — 1.0 1.5 2.0 2.4 

Larynx 

Squamous metaplasia — 1.0 1.0 1.0 1.0 1.0 

Nose 

Olfactory epithelium — — — 1.0 1.0 2.0 

degeneration 

Olfactory epithelium — — — — — 1.0 

respiratory metaplasia 

Respiratory epithelium — — — — 1.0 1.0 

hyaline droplets 

a

Animals were exposed for 6.33 hours/day, 5 days/week.

b

No lesions present or not significantly different from control group. c

Severity score: 1 = minimal, 2 = mild, 3 = moderate, 4 = marked 

Source: NTP 1995 

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There are fewer chronic-inhalation exposure studies that specifically reported systemic respiratory effects. 

Oldiges and Glaser (1986) report increased lung weights (amount unspecified) in rats from exposure to 

either cadmium sulfate at 0.092 mg Cd/m3 or cadmium sulfide at 0.254 mg Cd/m3 for 22 hours/day, 

7 days/week for 413–455 days. Takenaka et al. (1983) observed adenomatous hyperplasia in the 

bronchoalveolar region in rats from exposure to cadmium chloride at 0.0134 mg Cd/m3 for 23 hours/day, 

7 days/week for 18 months. 

The available data suggest that there may be species differences in the respiratory toxicity of cadmium. 

In a comparison of the pulmonary response to exposure to 0.1 mg Cd/m3 as cadmium chloride 

6 hours/day, 5 days/week for 4 weeks, Oberdörster et al. (1994) found that the inflammatory response in 

the lungs of mice was greater than that of rats exposed to the same cadmium concentration. However, the 

cadmium lung burden in mice was twice as high as the rat’s lung burden. In the NTP (1995) study, 

adverse lung effects were observed at lower concentrations in mice compared to rats, but at the higher 

concentrations, the severity of the lung effects were greater in the rats. Although these data suggest 

species differences in the pulmonary toxicity of cadmium, more information is needed to evaluate if there 

are differences at given lung burdens. 

Based on differences in the pharmacokinetic properties of various cadmium compounds, it is expected 

that differences in toxicity would be observed. As discussed in Oberdörster (1992), cadmium chloride 

and cadmium oxide elicited similar responses following a single intratracheal dose, whereas no response 

was observed for cadmium sulfide. However, Glaser et al. (1990) found similar responses following 

repeated exposures to various cadmium compounds. 

Hart and colleagues (Hart 1986; Hart et al. 1989a, 2001) demonstrated that repeated low-concentration 

exposure to cadmium results in the development of adaptive survival response. In rats exposed to 1.6 mg 

Cd/m3 as cadmium acetate 3 hours/day, 5 days/week, thickening of the alveolar septa and mononuclear 

cell and polymorphonuclear leukocyte aggregates were observed after 2 weeks of exposure (Hart 1986). 

However, the inflammatory response was decreased after 3 weeks of exposure and no significant 

histopathological alteration were observed in rats exposed for 4, 5, or 6 weeks. After 5 weeks of 

cadmium exposure, a single high concentration (8.4 mg Cd/m3

) resulted in less pulmonary damage 

compared to non-pretreated animals (Hart et al. 1989a). Multiple pulmonary resistance factors appear to 

contribute to this resistance/tolerance. These factors include increased levels of metallothionein, 

glutathione, and γ-glutamylcysteinesynthetase (Hart et al. 2001). However, as suggested by Hart et al. 

(2001), cadmium-adapted alveolar epithelial cells have a reduced ability to repair DNA damage and 

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CADMIUM 80 

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apoptotic cell death is attenuated in these cells; thus, cadmium adapted animals may be more susceptible 

to tumor formation. 

Cardiovascular Effects. Inhalation exposure to cadmium does not appear to have significant effects 

on the cardiovascular system. Most studies of workers occupationally exposed to cadmium have not 

found cadmium-related cardiovascular toxicity. In some studies, the mortality from cardiovascular 

disease was lower in the cadmium-exposed population. Armstrong and Kazantzis (1983) reported that a 

cohort of 6,995 British men occupationally exposed to cadmium for an average duration of 11 years had a 

significantly lower mortality from vascular disease. 

Fifty-three male workers exposed to cadmium and lead and 52 male controls were examined for 

correlations in urine levels and blood pressure. The average duration of exposure was 12.5 years. 

Correlations between blood pressure and urinary cadmium in exposed workers were not significant after 

controlling for age or age and heart rate. Exposure to lead was a significant confounding factor (de Kort 

et al. 1987). 

Friberg (1950) investigated the health of workers in a manufacturing plant that made cadmium-containing 

electrodes used in the production of batteries. Fifty-eight workers (30–50 years of age) were divided into 

two groups based on number of years at the plant. Workers were clinically examined for subjective 

symptoms and corresponding morphological or functional changes of the respiratory, cardiovascular, and 

excretory systems. The cardiovascular exam was largely unremarkable. Only a slight rise in blood 

pressure in a few cases was observed in Group 1. Electrocardiograms (EKG) were not significantly 

different from a matched control group in Group 1. Group 2 had neither increased blood pressure nor 

altered EKGs. 

Kazantzis et al. (1988) studied mortality in a cohort of 6,958 cadmium-exposed male workers with 

average occupational exposures of 12 years. This was a follow-up study to the work of Armstrong and 

Kazantzis (1983). There was a significant deficit in deaths from cerebrovascular disease among men 

occupationally exposed to cadmium. There was no significant excess risk from hypertensive or renal 

disease. 

Smith et al. (1980) studied 16 male high-exposure production workers and 11 male low-exposure office 

and supervisory workers for renal function. Average duration of exposure was 25 years. High-exposure 

workers were exposed to cadmium oxide concentrations of 0.23–45.2 mg/m3 and cadmium sulfide 

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CADMIUM 81 

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concentrations of 0.04–1.27 mg/m3. No difference was found in hypertension between high- and lowexposure workers, adjusted for age and weight or cigarette smoking. 

Sorahan and Waterhouse (1983) examined mortality rates in a cohort of 3,025 nickel-cadmium battery 

workers (2,559 males and 466 females). Cadmium levels in air ranged from 0.05 to 2.8 mg/m3

, primarily 

as cadmium oxide. Duration of exposure ranged from 1 to >6 years. No increase in mortality from 

diseases of the circulatory system (e.g., hypertension) was seen in cadmium-exposed workers. 

Staessen and Lauwerys (1993), in a study known as the Cadmibel Study (a cross-sectional population 

study), evaluated 2,327 people from a random sample of the population of four Belgian districts chosen to 

provide a wide range of environmental exposure to cadmium. Participants completed a questionnaire 

regarding their medical history, current and past occupations, smoking habits, alcohol consumption, and 

intake of medications. Urine and blood samples were taken, and pulse rate, blood pressure, height, and 

weight were recorded. Exposure to cadmium was considered to be by both the oral and inhalation routes. 

Cadmium levels in blood and urine were significantly increased in the high-exposure areas compared to 

the low-exposure areas (p<0.001). Blood pressure was not correlated with the urine or blood cadmium 

levels. The prevalence of hypertension or other cardiovascular diseases was similar in all four districts, 

and was not correlated with urine or blood cadmium levels. A follow-up investigation of 692 participants 

of this study also showed no correlation with urine or blood calcium levels and the prevalence of 

hypertension after 5 years (Staessen et al. 2000). These results do not support a hypothesis that cadmium 

increases blood pressure, prevalence of hypertension, or other cardiovascular diseases. 

One study found a statistically significant increase in blood pressure in exposed workers compared to 

controls (Thun et al. 1989), but mortality in this cohort was lower than expected (Thun et al. 1985). 

There are limited data on the cardiotoxicity of cadmium in animals. No significant alterations in systolic 

blood pressure or histological alterations in the heart were observed in rats exposed to cadmium oxide 

concentrations as high as 0.88 mg Cd/m3 for 13 weeks (NTP 1995). 

Gastrointestinal Effects. In the cohort he studied, Friberg (1950) found no association between 

inhalation cadmium exposure in workers and symptoms of gastrointestinal toxicity. Symptoms that had 

been reported in case histories from the 1920s included pain or tenderness at the epigastrium associated 

with nausea and some constipation. No other human studies report any cadmium associated gastrointestinal toxicity from inhalation exposure. 

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In the only animal study located, Rusch et al. (1986) observed erosion of the stomach in rats from 

exposure to cadmium carbonate at 132 mg Cd/m3 for 2 hours. Postmortem evaluation was performed at 

1, 3, 7, and 30 days postexposure. After the inhalation exposure in a whole-body chamber, rats were 

vacuumed to remove any cadmium carbonate dust adhering to the ventral and dorsal fur. The 132 mg 

Cd/m3 dose is relatively high. Three of the 10 test animals died during the 2-hour exposure so the 

significance of the gastrointestinal effect in this study is unclear. 

Hematological Effects. The evidence concerning hematological effects following inhalation 

exposure to cadmium is conflicting. Lowered hemoglobin concentrations and decreased packed cell 

volumes have been observed in some studies of workers occupationally exposed to cadmium (Bernard et 

al. 1979; Friberg 1950; Kagamimori et al. 1986), but not in others (Bonnell 1955; Chan et al. 1988; 

Davison et al. 1988). The changes that were found often were not statistically significant (Bernard et al. 

1979; Friberg 1950), and examination of bone marrow of some workers with lowered hemoglobin 

revealed no detectable abnormalities (Friberg 1950). 

Conflicting results on the hematologic effect of cadmium after inhalation exposure have also been 

obtained with animal studies. Rabbits exposed to cadmium oxide dust at 4 mg/m3 for 3 hours/day, 

21 days/month for 9 months developed eosinophilia and a slightly lower hemoglobin (Friberg 1950). In 

contrast, rats exposed to cadmium oxide dust at 0.052 mg Cd/m3 for 24 hours/day for 90 days had 

increased hemoglobin and hematocrit that were attributed to decreased lung function (Prigge 1978a). 

Prigge (1978b) also reported increased hemoglobin and hematocrit in rats continuously exposed to 

cadmium chloride at 0.204 mg Cd/m3 and higher for 21 days. Other studies report no Cd-related 

hematological effects. A nearly continuous 30-day exposure in rats to cadmium sulfide at 1.034 mg 

Cd/m3 had no effect on red blood cell counts (Glaser et al. 1986). A nearly continuous 218-day exposure 

in rats to cadmium oxide dust or fume at 0.090 mg Cd/m3 had no effect on a routine hematological 

evaluation (specific tests not reported) (Oldiges and Glaser 1986). A partial explanation for these 

conflicting results may be that Cd-induced anemia primarily results from impaired absorption of iron 

from the diet following gastrointestinal exposure to cadmium (see Section 3.2.2.2), and the amount of 

gastrointestinal exposure following cadmium inhalation is variable depending on the form and dose. 

Musculoskeletal Effects. Case studies indicate that calcium deficiency, osteoporosis, or 

osteomalacia can develop in some workers after long-term occupational exposure to high levels of 

cadmium (Adams et al. 1969; Blainey et al. 1980; Bonnell 1955; Kazantzis 1979; Scott et al. 1980). 

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Effects on bone generally arise only after kidney damage has occurred and are likely to be secondary to 

resulting changes in calcium, phosphorus, and vitamin D metabolism (Blainey et al. 1980). 

No studies were located regarding musculoskeletal effects in animals after inhalation exposure to 

cadmium. 

Hepatic Effects. Liver effects are not usually associated with inhalation exposure to cadmium. 

Friberg (1950) reported some nonspecific signs of liver disease in some workers from a group exposed to 

cadmium in the air for 20 years. Test results included increased serum gamma-globulin, and other 

indicators of abnormal serum globulins, including the flocculation test results of a positive Takata 

reaction and/or an elevated thymol values. These tests (the latter of which are not used today) were 

nonspecific indicators of cirrhosis or hepatitis. The significance of these test results with respect to 

cadmium exposure is questionable. Subsequent studies on workers exposed to cadmium in the air have 

not reported adverse liver effects (Adams et al. 1969; Bonnell 1955). 

Liver effects have occasionally been found in animal studies. Cats examined within one day of inhalation 

exposure to an unspecified concentration of cadmium oxide fume had a variety of hepatic lesions, and 

liver changes from cell granulation at low doses to fatty infiltration at high doses (Prodan 1932). 

Increased serum alanine aminotransferase activity, indicative of liver damage, was seen in rats exposed 

for 30 days to 0.1 mg/m3 cadmium, but activity had returned to normal 2 months after exposure (Glaser et 

al. 1986). Kutzman et al. (1986) reported an increased liver relative weight in rats from a cadmium 

chloride exposure at 1.06 mg Cd/m3 for 6 hours/day, 5 days/week, for 62 days. Increased liver weight 

was not observed from a continuous cadmium chloride exposure at 0.029 mg Cd/m3 for 255 days, from a 

continuous cadmium oxide exposure at 0.090 mg Cd/m3 for 218 days, or from a continuous cadmium 

sulfate exposure at 0.095 mg Cd/m3 for 413 days (Oldiges and Glaser 1986). Similar negative results 

were reported by Prigge (1978a, 1978b) for a 21-day exposure to cadmium chloride at 0.581 mg Cd/m3

, 

and for a 63-day exposure to cadmium oxide at 0.105 mg Cd/m3 (a dose that was very toxic to the lungs). 

A continuous high-dose exposure to cadmium sulfide at 2.247 mg Cd/m3 for 105 days did result in an 

unspecified increase in liver weight in surviving rats (Oldiges and Glaser 1986). Cadmium accumulates 

in the liver as well as the kidney, the main target organ for cadmium toxicity. The resistance of the liver 

to toxic effects from cadmium may be related to a higher capacity of the liver to produce metallothionein 

that would bind to cadmium and would lower the concentrations of free cadmium ions (see Section 3.4.3). 

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CADMIUM 84 

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Renal Effects. There is very strong evidence that the kidney is the main target organ of cadmium 

toxicity following extended inhalation exposure. The sensitivity of the kidney to cadmium was 

recognized in an early investigation of workers exposed to cadmium oxide dust and cadmium fumes in a 

factory producing nickel-cadmium batteries (Friberg 1950). These workers suffered from a high 

incidence of abnormal renal function, indicated by proteinuria and a decrease in glomerular filtration rate. 

Many studies examining cadmium workers have reported various effects on the kidneys. Similar signs of 

renal damage have been observed in many other studies of workers occupationally exposed to cadmium 

(Adams et al. 1969; Bernard et al. 1979; Beton et al. 1966; Bonnell 1955; Bustueva et al. 1994; Chia et al. 

1989; Elinder et al. 1985a, 1985b; Falck et al. 1983; Gompertz et al. 1983; Iwata et al. 1993; Jakubowski 

et al. 1987; Järup and Elinder 1993; Järup et al. 1988; Kjellström et al. 1977a; Liu et al. 1985; Mason et 

al. 1988; Piscator 1966; Roels et al. 1981b; Rose et al. 1992; Smith et al. 1980; Thun et al. 1989). Most 

of these studies did not report cadmium exposure levels; rather, urinary cadmium, blood cadmium, or 

cumulative exposures were used as biomarkers of exposure. Thus, these studies are not presented in the 

LSE table (Table 3-1). Selected occupational exposure studies are summarized in Table 3-4. 

One of the first signs of kidney effects is tubular dysfunction characterized by an increased urinary 

excretion of low-molecular-weight proteins such as β2-microglobulin, human complex-forming 

glycoprotein (pHC) (also referred to as α1-microglobulin), and retinol binding protein or increased 

urinary levels of intracellular enzymes such as N-acetyl-β-glucosaminidase (NAG) (European Chemicals 

Bureau 2007; Järup et al. 1998b). Numerous occupational exposure studies have reported increases in 

urinary levels of these biomarkers (Bernard et al. 1990; Chen et al. 2006a, 2006b; Chia et al. 1992; 

Elinder et al. 1985b; Falck et al. 1983; Jakubowski et al. 1987, 1992; Järup and Elinder 1994; Järup et al. 

1988; Kawada et al. 1989; Roels et al. 1993; Shaikh et al. 1987; Thun et al. 1989; Toffoletto et al. 1992; 

Verschoor et al. 1987). At higher exposure levels, increased urinary levels of high-molecular-weight 

proteins such as albumin have been reported (Bernard et al. 1979, 1990; Chen et al. 2006a, 2006b; Elinder 

et al. 1985b; Mason et al. 1988; Roels et al. 1989, 1993; Thun et al. 1989), but there is some debate as to 

whether this represents glomerular damage (Bernard et al. 1979; Roels et al. 1989) or severe tubular 

damage (Elinder et al. 1985a; Mason et al. 1988; Piscator 1984). 

Chronic exposure to very high cadmium levels can result in glomerular damage resulting in decreases in 

glomerular filtration rate (GFR) (Friberg 1950; Järup et al. 1995b; Roels et al. 1991). Järup et al. (1995b) 

found a dose-response relationship between blood cadmium levels and GFR in cadmium workers. At 

blood cadmium levels of 5.6 to <8.4 μg/L, 33.3% of the workers had decreased GFR (defined as <80% of 

referents); whereas all subjects with blood cadmium levels of ≥8.4 μg/L exhibited a decreased GFR. 

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CADMIUM 85 

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Table 3-4. Summary of Occupational Exposure Studies Examining Renal Effects 

Population Effect Adverse effect level Reference 

Zinc-cadmium smelter 

workers (n=87) 

Workers using 

cadmium pigments in 

plastic production or 

using cadmium in 

welding (n=27) 

Cadmium alloy workers 

(n=164) 

Cadmium smelter 

workers (n=53) 

Non-ferrous smelter 

workers (n=58) 

Workers exposed to 

cadmium pigment dust 

(n=58) 

Zinc-cadmium smelter 

workers (n=50) 

Battery workers 

(n=561) 

Alkaline battery factory 

workers (n=102) 

Workers at a factory 

using cadmiumcontaining solders 

(n=60) 

Age-related decline in maximal 

GFR was exacerbated in workers 

with cadmium-induced 

microproteinuria. 

Significant increase in urinary β2M 

and NAG levels. 

Higher incidence of increased 

urinary β2M levels (>250 μg/L cutoff) when urinary cadmium levels 

exceeded 10 μg/g creatinine on 

one or more occasions, as 

compared to workers who never 

exceeded the 10 μg/g creatinine 

level.
 

Significant increase in urinary
 

protein and β2M levels. 

Significant increase in urinary 

β2M, RBP protein, pHC, albumin, 

and transferrin levels.
 

Significant correlation between 

urinary cadmium and NAG levels;
 

significant correlation with β2M at 

one of the two time points. 

Significant association between 

urinary cadmium levels and 

urinary levels of NAG, albumin, 

and transferrin. At higher urinary 

cadmium levels (10 μg/g 

creatinine), there were significant 

associations with RBP and β2M. 

10% prevalence of abnormal β2M 

levels (220 μg/g creatinine cut-off). 

10% prevalence of renal 

dysfunction (β2M >380 μg/g 

creatinine; RBP >130 μg/g 

creatinine). 

25% prevalence of abnormal β2M 

levels (300 μg/g creatinine cut-off). 

U-Cd: 11.1 μg/g 

creatinine 

U-Cd: 5 μg/g 

creatinine 

U-Cd: 10 μg/g 

creatinine 

U-Cd: 13.3 μg/g 

creatinine 

U-Cd: >10 μg/g 

creatinine 

U-Cd: 1.1–1.4 μg/g 

creatinine 

U-Cd: 4 μg/g 

creatinine 

U-Cd: 1.5 μg/g 

creatinine for 

≥60 years of age 

U-Cd: 5 μg/g 

creatinine for 

<60 years of age 

U-Cd: 10–15 μg/g 

creatinine 

U-Cd: 2–5 μg/g 

creatinine 

Roels et al. 1991 

Verschoor et al. 

1987 

Toffoletto et al. 1992 

Shaikh et al. 1987 

Bernard et al. 1990 

Kawada et al. 1989 

Roels et al. 1993 

Järup and Elinder 

1994 

Jakubowski et al. 

1987 

Elinder et al. 1985a 

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CADMIUM 86 

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Table 3-4. Summary of Occupational Exposure Studies Examining Renal Effects 

Population Effect	 Adverse effect level Reference 

Workers at nickel- Significant increase in pHC and U-Cd: 5–10 μg/g Chia et al. 1992 

cadmium battery factory NAG levels (after adjustment for creatinine 

(n=92) age, gender, and race). 

Cadmium smelter Significant increases in levels β2M U-Cd: 5–10 μg/g Chen et al. 2006a, 

workers (n=85) and NAG levels and increased creatinine 2006b 

prevalence of abnormal levels of 

these biomarkers. 

Alkaline battery factory 10% prevalence of renal B-Cd: 300 μg-years/L Jakubowski et al. 

workers (n=141) dysfunction (β2M >300 μg/L; RBP (30 years of 10 μg/L) 1992 

>300 μg/L). 

Battery workers Approximately 10% prevalence of B-Cd: 5.6 μg/L Järup et al. 1988 

(n=440) abnormal β2M levels (35 μg/mmol Cumulative exposure: 

creatinine cut-off). 691 μg-years/m3 

Cadmium recovery Significant association between Cumulative exposure: Thun et al. 1989 

plant workers (n=45) cumulative exposure and urinary 300 mg/m3 

β2M, RBP, phosphate, and 

calcium and serum creatinine 

levels. 

Workers exposed to Increased urinary β2M and protein Cumulative exposure: Falck et al. 1983 

cadmium fumes (n=33)	 levels (mean 6,375 μg/g creatinine 1,137 μg/m3/years 

and 246 mg/g creatinine, 

respectively) in 7 workers (mean 

in remaining 23 workers 53 μg/g 

creatinine and 34 mg/g creatinine). 

U-Cd = urinary cadmium, B-Cd = blood cadmium; GFR = glomerular filtration rate; pHC = human complex-forming 

glycoprotein (also referred to as α1-microglobulin); NAG = N-acetyl-β-glucosaminidase; β2M = β2-microglobulin; 

prt = protein; RBP = retinol binding protein 

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CADMIUM 87 

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Another study did not find alterations in GFR in workers with urinary cadmium levels of approximately 

11 μg/g creatinine; however, an exacerbation of the age-related decline in maximal GFR was observed 

(Roels et al. 1991). Other studies reported increases in serum creatinine levels, which are suggestive of 

impaired GFR (Roels et al. 1989; Thun et al. 1989). 

Depressed tubular resorption of other solutes such as enzymes, amino acids, glucose, calcium, copper, 

and inorganic phosphate have been reported in workers with signs of tubular proteinuria (Elinder et al. 

1985a, 1985b; Falck et al. 1983; Gompertz et al. 1983; Mason et al. 1988). An increased frequency of 

kidney stone formation has also been reported in cadmium workers (Elinder et al. 1985a; Falck et al. 

1983; Järup and Elinder 1993; Kazantzis 1979; Scott et al. 1978; Thun et al. 1989; Trevisan and Gardin 

2005). This effect is likely to be secondary to disruption of calcium metabolism due to kidney damage. 

Järup and Elinder (1993) calculated an incidence rate ratio (IRR) (after adjustment for age and calendar 

time) of 3.0 (95% CI 1.3–6.8) for the occurrence of kidney stones among workers with a cumulative 

exposure of ≥5000 μg/m3 years; the IRR was not significantly elevated at lower cumulative exposure 

levels. Significant increases in kidney stone formation were observed in workers with increased urinary 

cadmium (median of 3.7 μg/g creatinine), blood cadmium (median of 7 μg/L), and urinary 

β2-microglobulin (median of 155 μg/g creatinine). The increased kidney stone formation may be 

secondary to the cadmium-induced kidney damage disruption of calcium metabolism. 

Hellström et al. (2001) evaluated the association between occupational cadmium exposure and end stage 

renal disease among cadmium workers and residents living near a cadmium facility; renal replacement 

therapy was used as a surrogate for renal disease. The standardized rate ratios (SRRs) (95% CI) were 

2.1 (0.6–5.3) and 2.5 (0.7–6.5) in male workers aged 20–79 or 40–79 years, respectively. Although the 

SRRs were not statistically significant, the ratios were significantly elevated in residents presumably 

exposed to lower cadmium levels (see Section 3.2.2.2 for more information on these results). Studies 

examining the cause of death among cadmium workers have not found significant increases in the 

standardized mortality ratios (SMRs) for nephritis or nephrosis (Armstrong and Kazantzis 1983; Järup et 

al. 1998a) or nonmalignant renal disease (Thun et al. 1985). 

The data from studies of cadmium workers provide strong, clear evidence that the kidney is a sensitive 

target following chronic exposure, but the data do not clearly identify a threshold of toxicity. The earliest 

indication of an effect on the kidney is an increase in urinary levels of low molecular weight proteins 

particularly β2-microglobulin, retinol binding protein, and pHC. However, there is some question as to 

the adversity of these early indicators because increased excretion of low molecular weight proteins 

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CADMIUM 88 

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precede the clinical manifestations (Bernard et al. 1997; Järup et al. 1998b). As noted by Bernard et al. 

(1997), the assessment of the health significance of changes affecting a biomarker involves localizing the 

changes in the sequence of events that ultimately results in compromised renal function and appreciating 

the probability that these changes may lead to a deterioration of renal function. Their guidelines for 

interpreting β2-microglobulin levels in cadmium workers are presented in Table 3-5. 

Another aspect of interpreting alterations in renal biomarkers and assessing risk is the issue of the 

reversibility of cadmium-induced tubular dysfunction and impaired glomerular filtration rate. In workers 

exposed to high levels of cadmium, cessation of exposure does not generally result in a reversibility of 

kidney damage. Increases in urinary levels of β2-microglobulin, retinol binding protein, or total protein 

(Elinder et al. 1985b; Järup et al. 1993; Mason et al. 1999; Piscator 1984; Roels et al. 1989; Thun et al. 

1989) or a decrease in glomerular filtration rate (Järup et al. 1993; Piscator 1984; Roels et al. 1989) have 

been observed in workers years after cadmium exposure cessation. However, in workers exposed to low 

levels of cadmium, cessation of exposure resulted in decreased or no change in urinary β2-microglobulin 

levels (McDiarmid et al. 1997; van Sittert et al. 1993). In studies by Roels et al. (1997) and TrzcinkaOchocka et al. (2002), former cadmium workers were divided into groups based on historical cadmium 

levels and urinary β2-microglobulin or retinol binding protein levels. Both studies found that the 

reversibility of tubular dysfunction was dependent on the cadmium body burden and the severity of 

microproteinuria at the time cadmium exposure was reduced or ceased. In the Roels study, significant 

decreases in retinol binding protein levels and no change in β2-microglobulin levels were observed in 

workers whose urinary cadmium levels never exceeded 10 μg/g creatinine. Decreases in 

β2-microglobulin and retinol binding protein levels were also observed in workers whose 

β2-microglobulin levels were <300 μg/g creatinine or between 300 and 1,500 μg/g creatinine and urinary 

cadmium levels were >10 μg/g creatinine, but were never >20 μg/g creatinine. However, a progression of 

microproteinuria (increased urinary levels of β2-microglobulin and retinol binding protein levels) was 

observed in workers who had initial β2-microglobulin levels >1,500 μg/g creatinine and urinary cadmium 

levels >20 μg/g creatinine. In contrast, Trzcinka-Ochocka et al. (2002) found decreases in 

β2-microglobulin and retinol binding protein levels in groups of workers with initial β2-microglobulin 

and retinol binding protein levels of ≤300, >300, ≤1,500, or ≥1,500 μg/g creatinine; in all groups, the 

initial mean urinary cadmium levels were >20 μg/g creatinine. However, the risk of increased excretion 

of retinol binding protein was higher in the groups of workers with initial retinol binding protein levels of 

>300 μg/g creatinine. Logistic regression analysis demonstrated that the initial level of retinol binding 

protein was the most important determinant in reversibility of tubular proteinuria and that the influence of 

urinary cadmium level or length of time since exposure cessation was not statistically significant. 

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CADMIUM 89 

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Table 3-5. Guidelines for Interpreting β2-microglobulin Levels 

β2-Microglobulin level	 Significance 

<300 μg/g creatinine		 Normal value. 

300–1,000 μg/g creatinine		 Incipient cadmium tubulopathy (possibility of 

reversibility after removal from exposure). No 

change in GFR. 

1,000–10,000 μg/g creatinine		 Irreversible tubular proteinuria which may lead to 

accelerated decline in the GFR with age. GFR 

normal or slightly altered. 

>10,000 μg/g creatinine		 Overt cadmium nephropathy usually associated 

with decreased GFR. 

GFR = glomerular filtration rate 

Source: Bernard et al. 1997 

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The available occupational exposure data suggest that tubular dysfunction generally develops only after 

cadmium reaches a threshold concentration in the renal cortex. However, a number of factors can 

influence urinary levels of β2-microglobulin or retinol binding protein and direct relationship between 

urinary levels of these proteins and a kidney cadmium concentration has not been established. Based on 

the findings of early occupational exposure studies, a number of investigators estimated that the “critical 

concentration” of cadmium in the renal cortex associated with increased incidence of renal dysfunction in 

an occupational setting was about 200 μg/g wet weight (Friberg et al. 1974; Kjellstr öm et al. 1977a; Roels 

et al. 1983); this corresponds to a urinary cadmium levels of 5–10 μg/g creatinine (European Chemicals 

Bureau 2007). Although 10 μg/g creatinine was initially established as a threshold urinary cadmium 

concentration, there is sufficient evidence to suggest that adverse effects occur at lower urinary cadmium 

levels (Chen et al. 2006a, 2006b; Chia et al. 1992; Elinder et al. 1985b; Järup and Elinder 1994; Kawada 

et al. 1989; Roels et al. 1993; Verschoor et al. 1987). 

Early animal studies confirmed that renal damage occurs following inhalation exposure to cadmium. 

Rabbits developed proteinuria after a 4-month inhalation exposure to cadmium metal dust at 4 mg/m3 for 

3 hours/day, 21 days/month; histologic lesions were found after an additional 3–4 months of exposure 

(Friberg 1950). Friberg (1950) noted that the degree of proteinuria was not especially pronounced. Most 

subsequent studies using inhalation exposure have not found proteinuria (Glaser et al. 1986; Kutzman et 

al. 1986; Prigge 1978a, 1978b), primarily because the levels of exposure and durations of follow-up (e.g., 

1–5 mg/m3 for intermediate exposures; 0.2–2 mg/m3 for chronic exposures) that produce serious 

respiratory effects have not been sufficient to produce a critical concentration of cadmium in the kidney. 

Dermal Effects. Dermal toxicity does not appear to be a significant effect of inhalation exposure to 

cadmium. Studies of workers occupationally exposed to cadmium have not reported dermal effects 

following acute or chronic exposure (Barnhart and Rosenstock 1984; Bonnell 1955; Friberg 1950). No 

study was located that specifically examined dermal toxicity in humans or animals following inhalation 

exposure to cadmium. 

Ocular Effects. Ocular toxicity does not appear to be a significant effect of inhalation exposure to 

cadmium. Studies of workers occupationally exposed to cadmium have not reported ocular effects 

following acute or chronic exposure (Barnhart and Rosenstock 1984; Bonnell 1955; Friberg 1950). No 

study was located that specifically examined ocular toxicity in humans following inhalation exposure to 

cadmium. 

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CADMIUM 91 

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Rats exposed to a single 2-hour inhalation exposure to about 100 mg Cd/m3 as cadmium pigments had 

excessive lacrimation 4 hours after exposure (Rusch et al. 1986), but this was likely due to a direct 

irritation of the eyes rather than a systemic effect. 

Body Weight Effects. No data were found regarding the effects of inhaled cadmium on human body 

weights. 

In animals, cadmium has been shown to significantly reduce body weights. An acute exposure to 

cadmium oxide fumes at 112 mg Cd/m3 for 2 hours (Rusch et al. 1986) and cadmium oxide dust at 4.6 mg 

Cd/m3 for 3 hours (Buckley and Bassett 1987b) resulted in a significant reduction of body weight in male 

rats. Cadmium chloride at 6.5 mg Cd/m3 for 1 hour or 4.5 mg Cd/m3 for 2 hours produced significant 

reductions in male rat body weights (Bus et al. 1978; Grose et al. 1987). Cadmium carbonate at 132 mg 

Cd/m3 for 2 hours slowed rat body weight gains (Rusch et al. 1986). NOAELs for acute cadmium 

chloride exposure have been reported at 0.45 mg Cd/m3 for 2 hours (Grose et al. 1987); 0.17 mg Cd/m3 

for 6 hours/day for 10 days (Klimisch 1993); and 6 mg Cd/m3 for 2 hours (Palmer et al. 1986). NOAELs 

for cadmium sulfide and cadmium selenium sulfide were much higher at 99 mg Cd/m3 for 2 hours and 

97 mg Cd/m3 for 2 hours, respectively (Rusch et al. 1986). The effect of cadmium on body weight gain 

appears to compound-related, with cadmium chloride the most toxic and cadmium sulfide the least toxic. 

These compound-related differences are probably related to difference in absorption. 

The body weight response also appears to be duration-related; lower NOAELs and LOAELs have been 

identified for intermediate-duration exposure. Levels of cadmium that significantly reduce rat body 

weights when administered for an intermediate exposure duration have been reported for cadmium 

chloride at around 1 mg Cd/m3 for female and male rats (Baranski and Sitarek 1987; Kutzman et al. 

1986), for cadmium chloride at around 0.394 mg Cd/m3 for pregnant female rats (Prigge 1978a), and for 

cadmium dusts at 0.1 mg Cd/m3 for female rats (Prigge 1978a). NOAELs have been reported for 

intermediate exposures to cadmium chloride at 0.394 mg Cd/m3 for female nonpregnant rats (Prigge 

1978a), 0.33 mg Cd/m3 for rats (Kutzman et al. 1986), and 0.0508 mg Cd/m3 for male rats (Takenaka et 

al. 1983). NOAELs have been reported for intermediate exposures to cadmium oxide dust at 0.16 mg 

Cd/m3 for female rats (Baranski and Sitarek 1987) and 0.45 mg Cd/m3 for male rabbits (Grose et al. 

1987); and for cadmium sulfide at 1.034 mg Cd/m3 for male rats (Glaser et al. 1986). A NOAEL for 

chronic exposure in rats to cadmium sulfate has been reported as 0.95 mg Cd/m3 (Oldiges and Glaser 

1986). 

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CADMIUM 92 

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Other Systemic Effects. Yellow discoloration of the teeth has occasionally been reported in 

workers occupationally exposed to high levels of cadmium (Friberg 1950; Liu et al. 1985). No data were 

located to indicate that this was related to any functional impairment. 

3.2.1.3 Immunological and Lymphoreticular Effects 

There is limited evidence for immunological effects following inhalation exposure to cadmium. The 

blood of workers exposed to cadmium for 1–14 years had a slight but statistically significant decrease in 

the generation of reactive oxygen species by leukocytes compared to unexposed controls (Guillard and 

Lauwerys 1989). The toxicological significance of this effect is unclear. 

Karakaya et al. (1994) measured blood and urine concentrations of cadmium, and serum IgG, IgM, and 

IgA in a group of 37 males employed in zinc/cadmium smelters and a small Cd-electroplating plant. 

Blood cadmium concentrations were significantly higher in exposed workers compared to controls in both 

the urine (2.39 versus 0.69 μg/100 mL, p<0.001) and the blood (5.55 versus 2.01 μg/g creatinine, p<0.05). 

No differences between the exposed and control serum concentrations of IgG, IgM, and IgA populations 

were observed. No changes in blood counts of white blood cells (lymphocyte, neutrophil, and eosinophil) 

were found between exposed and control populations, except for significantly increased monocyte counts. 

No other studies were located regarding immunological effects in humans following inhalation exposure 

to cadmium. 

Acute inhalation exposure to cadmium chloride in mice at 0.190 mg Cd/m3 for 2 hours can affect immune 

function, causing suppression of the primary humoral immune response (Graham et al. 1978). The 

NOAEL for immunological effects from the study by Graham et al. (1978) was 0.11 mg Cd/m3

. 

Krzystyniak et al. (1987) reported spleen lymphocyte cytotoxicity at 0.88 mg Cd/m3 for 1 hour. 

At intermediate-duration exposures, Kutzman et al. (1986) observed increased spleen relative weights and 

lymphoid hyperplasia from inhalation of cadmium chloride aerosols at 1.06 mg Cd/m3 6 hours/day, 

5 days/week for 62 days. Prigge (1978b) also observed increased relative spleen weights in pregnant 

females at 0.394 mg Cd/m3 for an exposure of 24 hours/day for 21 days during gestation. Oldiges and 

Glaser (1986) observed enlarged thoracic lymph nodes in dead animals in a chronic-exposure study with 

cadmium sulfate at 0.092 mg Cd/m3 for 22 hours/day, 7 days/week for 413–455 days; and in an 

intermediate study with cadmium oxide dust at 0.090 mg Cd/m3 for 22 hours/day, 7 days/week for 

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CADMIUM 93 

3. HEALTH EFFECTS 

218 days. However, other studies have found no effect on natural killer cell activity or viral induction of 

interferon in mice (Daniels et al. 1987). Evidence concerning the effect of inhalation exposure to 

cadmium on resistance to infection is conflicting, because the same exposure decreases resistance to 

bacterial infection while increasing resistance to viral infection (Bouley et al. 1982). The highest NOAEL 

values and all LOAEL values from each reliable study for immunological effects in each species and 

duration category are recorded in Table 3-1 and plotted in Figure 3-1. 

3.2.1.4 Neurological Effects 

Neurotoxicity is not generally associated with inhalation exposure to cadmium, although a few studies 

have specifically looked for neurological effects. Hart et al. (1989b) reported that in a group of 31 men 

occupationally exposed to cadmium in a refrigerator coil manufacturing plant (average 

exposure=14.5 years) there was a modest correlation between cadmium exposure and decreased 

performance on neuropsychologic tests for attention, psychomotor speed, and memory. The limited 

number of men studied makes it difficult to evaluate the significance of this effect. 

Rose et al. (1992) studied the presence and severity of olfactory impairment in workers chronically 

exposed to cadmium fumes generated during a brazing operation. Detailed occupational history, medical 

history, and smoking history, and symptoms were collected for 55 workers. Body burden was estimated 

using urinary cadmium levels, and renal damage was assessed by urinary β2-microglobulin levels. 

Olfactory test scores from these workers were compared to a reference group of 16 male subjects that 

were selected according to the following criteria: (1) no history of taste or smell complaints, (2) no 

history of surgery to the upper respiratory tract, (3) no upper respiratory tract infection within 2 days of 

testing, and (4) no history of having been tested. The dose of the cadmium oxide fume received by the 

workers being evaluated in this study was not reported or estimated. For both the exposed workers and 

the reference group, 38% were smokers. A significant olfactory impairment was observed in the workers 

compared to the reference group (p<0.003). Thirteen percent of the workers were either moderately or 

severely hyposmic compared to none in the reference group, 44% of the workers were mildly hyposmic 

compared to 31% of the reference group, and only 44% of workers were normosmic. Although the 

odor-identification test findings for workers were similar to those of the reference group, butanol 

detection threshold scores were significantly lower in the worker population (p<0.005). The workers with 

both higher urinary cadmium levels and tubular proteinuria had the most significant olfactory 

dysfunction, with a selective defect in odor threshold. The results suggest that chronic occupational 

cadmium exposure sufficient to cause renal damage is also associated with impairment in olfactory 

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CADMIUM 94 

3. HEALTH EFFECTS 

function. Some limitations of the study are that historical exposure to other confounders cannot be ruled 

out, the classification for nephrotoxicity is based on a single 24-hour urine β2-microglobulin level, and 

the smoking history of the reference group was unknown. No other human neurological studies from 

inhaled cadmium were found. 

In rats, cadmium carbonate produced tremors from exposure to 132 mg Cd/m3 for 2 hours, and cadmium 

fumes produced reduced activity at 112 mg Cd/m3 for 2 hours (Rusch et al. 1986). Studies on continuous 

exposure to cadmium for 30 days have shown no neurological effects at 0.105 mg Cd/m3 for cadmium 

chloride, 0.098 mg Cd/m3 for cadmium dusts, or 1.034 mg Cd/m3 for cadmium sulfide (Glaser et al. 

1986). Cadmium chloride had no neurological effects at 0.33 mg Cd/m3 for 5 days/week, 6 hours/day for 

a total of 62 daily exposures, but did significantly increase relative brain weight at 1.034 mg Cd/m3 

(Kutzman et al. 1986). No other studies were located regarding neurological effects in adult animals after 

inhalation exposure to cadmium. Neurological effects in offspring of rats exposed to cadmium by 

inhalation during gestation are discussed in Section 3.2.1.5. The highest NOAEL values and all LOAEL 

values from each reliable study for neurological effects in each species and duration category are recorded 

in Table 3-1 and plotted in Figure 3-1. 

3.2.1.5 Reproductive Effects 

Evidence is insufficient to determine an association between inhalation exposure to cadmium and 

reproductive effects. 

Gennart et al. (1992) studied male reproductive effects of cadmium in 83 occupationally exposed bluecollar Belgian workers in two smelting operations. The workers were exposed to cadmium in dust and 

fumes. Information was recorded on age, residence, education, occupational and health history, actual 

and previous occupations, smoking habits, and coffee and alcohol consumption. Fertility parameters 

included dates of birth of wife and husband, date of marriage, and number of children born alive and their 

dates of birth. Blood and urine samples were also collected from each worker. Some cadmium workers 

had been excessively exposed; 25% of them already had signs of kidney dysfunction as evidenced by 

microproteinuria and/or a serum creatinine level >13 mg/L. No effects were observed on male fertility as 

evidenced by no significant influence of cadmium on the probability of a live birth. The limitation of this 

study, as described by the authors, included the fact that the wives were not interviewed and, therefore, 

factors that could have influenced their reproductive ability were not considered. 

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CADMIUM 95 

3. HEALTH EFFECTS 

Men occupationally exposed to cadmium at levels causing renal damage had no change in testicular 

endocrine function, as measured by serum levels of testosterone, luteinizing hormone, and folliclestimulating hormone (Mason 1990). 

Noack-Fuller et al. (1993) measured concentrations of cadmium, lead, selenium, and zinc in whole semen 

and seminal fluid of 22 unexposed men (13 were smokers) to evaluate intra-individual variability and to 

examine the statistical association between element concentrations and semen characteristics and sperm 

motion parameters. None of the men had any known occupational exposure to cadmium. 

Concentrations of cadmium were similar in semen and seminal plasma (0.40±0.23 and 0.34±0.19 μg/L, 

respectively). Sperm motility (p<0.02), linear velocity (p<0.001), and curvilinear velocity (CV) 

(p<0.002) were significantly correlated with semen cadmium levels. Intra-individual coefficients of 

variation for sperm count (CV=46±4%) and sperm concentration (CV=37±6%) showed the highest 

variability. No positive correlation was found between cadmium concentration in semen and sperm 

density. The smokers had slightly elevated levels of cadmium. The concentrations of cadmium in semen 

of these volunteers were very low. Additional studies are needed (preferably with larger sample sizes) to 

evaluate the robustness of this association between cadmium (at the low levels detected) and sperm 

motion parameters. Saaranen et al. (1989) measured cadmium, selenium, and zinc in seminal fluid and 

serum in 64 men, half of whom were smokers. Smokers had significantly higher serum cadmium 

concentration than nonsmokers. Seminal fluid cadmium was also elevated in smokers, and was higher 

than serum cadmium in smokers consuming >20 cigarettes daily. Semen quality was measured for 

volume, sperm density, morphology, motility, and number of immature germ cells. No differences were 

found in semen quality or fertility between smokers and nonsmokers. There was no significant 

correlation between seminal fluid cadmium levels and semen quality or fertility. 

Xu et al. (1993a) measured trace elements in blood and seminal plasma and their relationship to sperm 

quality in 221 Singapore men (age range 24–54; mean 34.8) who were undergoing initial screening for 

infertility. Men with significant past medical history and those who had been occupationally exposed 

were excluded. Parameters monitored included semen volume and sperm density, motility, morphology, 

and viability. Graphite furnace atomic absorption was used to determine cadmium concentration in blood 

and semen. No differences were observed in sperm quality (density, motility, morphology, volume, and 

viability) of the 221 men compared to a cohort of 38 fertility proven men (wives had recently conceived). 

Cadmium levels in blood did have a significant inverse relationship with sperm density (r=-0.15, p<0.05) 

in oligospermic men (sperm density <20 million/mL), but not in normospermic men. There was a 

significant reduction in sperm count in men with blood cadmium of >1.5 μg/L. Also, there was a weak 

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CADMIUM 96 

3. HEALTH EFFECTS 

negative correlation between defective sperm and concentration of cadmium in semen (r=-0.21, p<0.05). 

The volume of semen was inversely proportional to the cadmium concentration in semen (r=-0.29, 

p<0.05). These findings suggest that cadmium may have an effect on the male reproductive system. 

Limitations of the study include lack of control for potential confounding factors such as the lower levels 

of zinc in seminal plasma, and the validity of using infertile men as the study group (i.e., again because of 

confounding factors that may be affecting both cadmium levels and sperm levels). 

A postmortem study of men occupationally exposed to cadmium who died from emphysema found high 

levels of cadmium in their testes, but no histologic lesions other than those attributable to terminal illness 

(Smith et al. 1960) 

Russian women occupationally exposed to cadmium concentrations up to 35 mg/m3 had no irregularities 

in their menstrual cycles (Tsvetkova 1970). Fertility and other indices of reproductive function were not 

measured. No studies were located that showed reproductive effects in women following inhalation 

exposure to cadmium. 

In rats, exposure to cadmium oxide dusts at 1 mg Cd/m3 for 5 hours/day, 5 days/week for 20 weeks, 

increased the duration of the estrous cycle (Baranski and Sitarek 1987). Male and female rats exposed to 

cadmium concentrations of 1.06 mg/m3 as cadmium chloride for 6 hours/day, 5 days/week for 62 days 

and subsequently mated with unexposed controls showed no loss in reproductive success measured by 

viable embryos and preimplantation losses, but males did have an increased relative testes weight 

(Kutzman et al. 1986). Similarly, no alterations in fertility in female rats exposed to 0.16 mg Cd/m3 as 

cadmium oxide for 5 months prior to mating with unexposed males and during the mating and gestation 

periods (Baranski 1984). Tsvetkova (1970) studied rats exposed to cadmium sulfate aerosols at 2.8 mg 

Cd/m3 before and during pregnancy. A lengthening of the estrous cycle was observed 2 months after the 

start of exposure in one-half of the exposed animals. By the fourth month, diestrus was 6.2 days in the 

exposed group compared to 1.2 days in controls. An increased in estrous cycle length was also observed 

in rats exposed to 0.88 mg Cd/m3 as cadmium oxide for 13 weeks (NTP 1995); this study also reported a 

significant decrease in spermatid counts in males exposed to the same cadmium concentration. No other 

studies were found on reproductive effects in animals. The highest NOAEL values and all LOAEL 

values from each reliable study for reproductive effects in each species and duration category are 

recorded in Table 3-1 and plotted in Figure 3-1. 

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CADMIUM 97 

3. HEALTH EFFECTS 

3.2.1.6 Developmental Effects 

Russian women occupationally exposed to cadmium at concentrations ranging from 0.02 to 35 mg/m3 had 

offspring with decreased birth weights compared to unexposed controls, but without congenital 

malformations (Tsvetkova 1970). No association was found between birth weights of offspring and 

length of maternal cadmium exposure. Moreover, no control was made for parity, maternal weight, 

gestational age, or other factors known to influence birth weight (Tsvetkova 1970). A nonsignificant 

decrease in birth weight was found in offspring of women with some occupational exposure to cadmium 

in France; however, no adverse effects were documented in these newborns (Huel et al. 1984). Huel et al. 

(1984) used hair samples to estimate exposure, and this method is limited without controls to distinguish 

between exogenous and endogenous sources. No other studies were located regarding developmental 

effects in humans after inhalation exposure to cadmium. 

In utero exposure to cadmium results in significant decreases in pup viability, fetal body weight, pup 

body weight gain, delays in ossification, and impaired performance on neurobehavioral tests. Decreases 

in pup viability (percentage of pups born alive that survived until postnatal day 4) were observed in the 

offspring of rats exposed to 0.16 mg Cd/m3 as cadmium oxide for 5 months prior to mating and during 

mating and gestation day 1–20 (Baranski 1984). Decreases in fetal body weight were observed in the 

offspring of rats exposed to ≥0.581 mg Cd/m3 as cadmium chloride (Prigge 1978b) or cadmium oxide 

(NTP 1995) and mice exposed ≥0.4 mg Cd/m3 as cadmium oxide (NTP 1995); maternal toxicity 

(decreased body weight gain and/or hypoactivity and dyspnea) were also observed at these exposure 

levels. Although Baranski (1984) did not find significant alterations in birth weight, a decrease in pup 

body weight gain was observed in the offspring of rats exposed to 0.16 mg Cd/m3 as cadmium oxide. 

Delays in skeletal ossification have also been observed in the offspring of rats and mice exposed to 

1.7 mg Cd/m3 as cadmium oxide (NTP 1995); although Baranski (1985) also reported a delay in 

ossification in the offspring of rats, it is unclear whether the effect was observed at 0.02 mg Cd/m3

, 

0.16 mg Cd/m3

, or both. 

Baranski (1984, 1985) evaluated the potential of cadmium to induce neurobehavioral effects in the 

offspring of rats exposed to 0.02 or 0.16 mg Cd/m3 as cadmium oxide for 5 months prior to mating, 

during mating and gestation day 1–20; the studies reported similar effects and it is unclear whether the 

papers are reporting the results from separate experiments. The neurobehavioral alterations included 

decreased exploratory motor activity and avoidance acquisition in 3 month old male and female offspring, 

respectively, exposed to 0.02 mg Cd/m3

. At 0.16 mg Cd/m3, decreased avoidance acquisition in 3 month 

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CADMIUM 98 

3. HEALTH EFFECTS 

old female offspring, exploratory motor activity in 3 month old male and female offspring, ambulations in 

open field test in 5 month old male offspring, and spontaneous mobility in male offspring and 

prolongation of latency in negative geotaxis test. 

3.2.1.7 Cancer 

The relationship between occupational exposure to cadmium and increased risk of cancer (particularly 

lung and prostate cancer) has been explored in a number of occupational exposure studies. The results of 

these studies are conflicting and the carcinogenicity of cadmium has not been unequivocally established. 

Overall, the results provide suggestive evidence of an increased risk of lung cancer in humans following 

prolonged inhalation exposure to cadmium. Initial studies indicated an elevation in prostate cancer 

among men occupationally exposed to cadmium (Kipling and Waterhouse 1967; Kjellström et al. 1979; 

Lemen et al. 1976), but subsequent investigations found either no increases in prostate cancer or increases 

that were not statistically significant (Elinder et al. 1985c; Kazantzis et al. 1988; Sorahan 1987; Sorahan 

and Esmen 2004; Thun et al. 1985). Based on an analysis of the mortality data from a 5-year update of 

the cohort from 17 plants in England and a review of the other epidemiological evidence, Kazantzis et al. 

(1992) concluded that cadmium does not appear to act as a prostatic carcinogen. 

Significant increases in mortality from lung cancer have been reported in workers employed at a U.S. 

cadmium recovery facility (Stayner et al. 1992a; Thun et al. 1985), nickel-cadmium battery facilities in 

England (Sorahan 1987) and Sweden (Järup et al. 1998a), and in a cohort of workers at cadmium 

processing facilities and/or smelters (Ades and Kazantzis 1988; Kazantzis et al. 1988). However, no clear 

relationships between level and duration of cadmium exposure and lung cancer risk have been established 

and many of these studies did not account for confounding exposure to other carcinogenic metals 

(particularly arsenic and nickel) and cigarette smoking. 

The possible association between occupational exposure to cadmium and lung cancer was investigated in 

several studies of a cohort of workers employed at a U.S. cadmium recovery facility. The cohort was 

initially examined by Lemen et al. (1976) who found a significant increase in deaths from malignant 

neoplasms of the respiratory tract among hourly workers employed for at least 2 years between 1940 and 

1969. A re-examination of the cohort (deaths through 1978) also found statistically significant 

standardized mortality rates (SMRs) for malignant neoplasms in the respiratory tract (Thun et al. 1985). 

To adjust for possible arsenic exposure (between 1918 and 1925, the facility functioned as an arsenic 

smelter), workers were divided based on year of hire. Mortality from lung cancer was significantly 

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CADMIUM 99 

3. HEALTH EFFECTS 

elevated in workers hired prior to 1926 and among workers hired after 1926 with 2 or more years of 

employment. Dividing the workers into three exposure groups based on estimated cumulative exposure 

resulted in a significant dose-related trend for lung cancer deaths; in the highest exposure group 

(cumulative exposures >8 years-mg/m3

), a 2- to 8-fold increase in the risk of lung cancer deaths was 

observed (Thun et al. 1985). A subsequent analysis of these data (workers followed through 1985) used 

comparisons of rates with the cohort rather than the U.S. population (Stayner et al. 1992a). Lung cancer 

mortality was significantly increased among non-Hispanic whites, among workers with the highest 

cumulative exposure (>2,291 days-mg/m3

), and among workers with the longest time since first exposure 

(>20 years). Lamm et al. (1992, 1994) used nearly the same data set for the U.S. cohort as Stayner et al. 

(1992a) in a nested case-control analysis that used the period of hire as a surrogate for arsenic exposure. 

Based on this analysis as a means to control for the confounding factor of arsenic exposure, Lamm et al. 

(1992, 1994) reported no residual association of lung cancer with cadmium. They also reported that cases 

were eight times more likely to have been cigarette smokers than were controls. Lamm et al. (1992, 

1994) conclude that arsenic exposure and cigarette smoking were the major determinants of lung cancer 

risk, not cadmium exposure. 

The reasons for these conflicting conclusions based on the same cohort data are unclear. Doll (1992) 

suggested some possible reasons including: (1) that the total number of cases was small (n=25) and that 

only 21 of these cases were included in both studies (i.e., each study included some cases that were not 

included in the other study); (2) that Stayner et al. (1992a) used national rather than regional mortality 

rates; (3) that the Lamm et al. (1992, 1994) control series was overmatched, although the matching by 

date of hire was necessary to control for arsenic exposure; and (4) that there are some concerns about the 

validity (i.e., biological relevance) of the dose-response-models used by Stayner et al. (1992a). In a 

response to Doll (1992), Stayner et al. (1993) reported that use of regional mortality rates would increase 

rather than decrease support for their conclusion, and that the nested case-control analysis of Lamm et al. 

(1992) used overmatched controls. Stayner et al. (1993) provided additional analyses including the use of 

the Armitage-Doll multistage model to support the conclusion of an increased risk of cancer from 

cadmium exposure. Sorahan and Lancashire (1994) subsequently raised concerns about inconsistencies 

and inaccuracies in the NIOSH job history data used in these studies on the U.S. cohort. Sorahan and 

Lancashire (1997) then conducted further analyses, based on detailed job histories extracted from time 

sheet records, to better resolve the potential confounding affects of arsenic. Poisson regression was used 

to investigate risks of mortality from lung cancer in relation to four concentrations of accumulative 

exposure to cadmium (<400, 400–999, 1,000–1,999, and >2,000 mg-days/m3

). After adjustment for age 

attained, year of hire, and Hispanic ethnicity; Sorahan and Lancashire (1997) report a significant positive 

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CADMIUM 100 

3. HEALTH EFFECTS 

trend (p<0.05) between cumulative exposure to cadmium and risks of mortality from lung cancer. 

However, when the exposure to cadmium was evaluated with or without concurrent exposure to arsenic, a 

significant trend for lung cancer was only found for exposure to cadmium received in the presence of 

arsenic trioxide. Since there were only 21 deaths from lung cancer, Sorahan and Lancashire (1997) state 

that it is impossible to determine which of the following three hypotheses is the correct one: (1) cadmium 

oxide in the presence of arsenic trioxide is a human lung carcinogen, (2) cadmium oxide and arsenic 

trioxide are human lung carcinogens and cadmium sulphate and cadmium sulphide are not (i.e., cadmium 

sulphate and cadmium sulphide were the main cadmium compounds of exposure when arsenic was not 

present), or (3) arsenic trioxide is a human carcinogen and the three cadmium compounds are not 

carcinogenic. 

The carcinogenicity of cadmium has also been examined in European alloy, battery, smelter, and process 

workers. A study of workers at two copper-cadmium alloy facilities in the United Kingdom found no 

significant increase in lung cancer mortality (Sorahan et al. 1995). Dividing the workers into groups 

based on cumulative cadmium exposure or time since first exposure did not result in significant increases 

in lung cancer deaths in the alloy workers. An initial study of workers at nickel-cadmium battery 

manufacturing facilities in the United Kingdom found a significant increase in cancer of the respiratory 

tract (Sorahan and Waterhouse 1983). A subsequent study (Sorahan 1987) found an increase in lung 

cancer deaths among workers with the highest exposure first employed between 1926 and 1946; no 

association was found in workers employed after 1946. Another study of nickel-cadmium battery 

workers in the United Kingdom did not find significant increases in lung cancer deaths (Sorahan and 

Esmen 2004), although a significant increase in pharyngeal cancer deaths was observed. A study of 

nickel cadmium battery workers in Sweden found an increase in lung cancer mortality, but the increase 

was not statistically significant (Elinder et al. 1985c). An update of this study, which includes additional 

workers, found a significant increase in lung cancer deaths (Järup et al. 1998a). However, there was no 

exposure-response relationship between cumulative exposure to cadmium (or nickel) and the risk of lung 

cancer. A significant increase in lung cancer mortality was observed in workers employed at a zinc-leadcadmium smelter (Ades and Kazantzis 1988). However, no relationship between cumulative cadmium 

exposure and lung cancer deaths was found, suggesting that cadmium was not the causative agent. 

Another study of workers in 19 facilities in the United Kingdom that process cadmium did not find a 

statistically significant increase in lung cancer deaths (Armstrong and Kazantzis 1983). An update of this 

study found a significant increase in lung cancer deaths (Kazantzis et al. 1988). However, >60% of the 

lung cancer deaths were workers at the zinc-lead-cadmium smelter examined by Ades and Kazantzis 

(1988). 

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CADMIUM 101 

3. HEALTH EFFECTS 

Studies in rats provide strong evidence of the lung carcinogenic potential of chronically inhaled cadmium. 

Oldiges et al. (1989) reported a clear dose response increase in lung tumors in male and female rats from 

an 18-month continuous exposure to either cadmium chloride, cadmium oxide dusts, cadmium oxide 

fume, cadmium sulfate, or cadmium sulfide. In the cadmium chloride study at 30 μg/m3

, the observation 

period in the males had to be shortened to 30 months (rather than 31) because of mortality in excess of 

75%. No lung tumors were observed in control rats after 31 months of observation. A high incidence of 

nodules and tumors was seen in 30 μg/m3 exposures to cadmium chloride in both males and females. 

Results showed lung nodules in 18 of 20 males and 15 of 18 females and primary lung tumors in 15 of 

20 males and 13 of 18 females. Tumor incidence as bronchioalveolar adenomas, adenocarcinomas, 

squamous cell carcinomas, or combined epidermoid carcinoma and adenocarcinoma were 2, 12, 0, and 

1 for males; and 4, 7, 0, and 2 for females, respectively. Increased lung tumors in males and females were 

also observed with chronic exposures to cadmium oxide dust or fume at 30 μg/m3

, to cadmium sulfate at 

90 μg/m3

, and to cadmium sulfide at 90 μg/m3 (Oldiges et al. 1989). Cadmium sulfate produced by 

photolysis of cadmium sulfide under the experimental conditions may have contributed to some of the 

response observed with cadmium sulfide (Konig et al. 1992). 

Takenaka et al. (1983) also demonstrated cadmium carcinogenicity in male rats exposed to cadmium 

chloride aerosols at 0.0134, 0.0257, and 0.0508 mg Cd/m3 for 18 months. The exposure produced a doserelated increase in lung epidermoid carcinomas, adenocarcinomas, and mucoepidermoid carcinomas 

starting at 20 months. No other type of tumor was observed to increase with increasing dose. 

In a protocol similar to the studies by Oldiges et al. (1989), Heinrich et al. (1989) did not observe an 

increase in lung tumors in male or female Syrian golden hamsters from chronic inhalation exposure to 

either cadmium oxide dust or fumes, cadmium chloride, cadmium sulfate, or cadmium sulfide. In female 

mice, lung tumor incidence increased at all dose levels, but incidence in the controls was also high, and 

the cadmium-induced increases were not statistically significant. Lung tumors in the cadmium-treated 

mice also did not increase in a dose-responsive manner except for a weak increase from exposure to the 

cadmium oxide fumes (Heinrich et al. 1989). 

The available data provide inconclusive evidence on the potential of cadmium to induce lung cancer in 

humans. The strongest evidence comes from early studies of workers at a U.S. cadmium recovery facility 

(Stayner et al. 1992a; Thun et al. 1985), but later examinations of this cohort did not find conclusive 

evidence (Lamm et al. 1992, 1994; Sorahan and Lancashire 1997). The inconsistent results may be due to 

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CADMIUM 102 

3. HEALTH EFFECTS 

the small number of lung cancer cases and adjustments for possible early exposure to arsenic. Some 

studies of European cadmium workers have found significant increases in lung cancer (Ades and 

Kazantzis 1988; Järup et al. 1998a; Kazantzis et al. 1988; Sorahan 1987; Sorahan and Waterhouse 1983), 

but lung cancer deaths were not significantly associated with cumulative cadmium levels or duration of 

exposure and the investigators concluded that the effects may not have been related to cadmium exposure. 

Based on an early 1990s analysis of the available human and animal data, IARC (1993) classified 

cadmium as carcinogenic to humans (Group 1), based on sufficient evidence for carcinogenicity in both 

human and animal studies. Similarly, the DHHS (NTP 2005) classified cadmium and certain cadmium 

compounds as substances known to be human carcinogens. EPA classified cadmium as a probable human 

carcinogen by inhalation (Group B1), based on limited evidence of an increase in lung cancer in humans 

and sufficient evidence of lung cancer in rats (IRIS 2008). EPA estimated an inhalation unit risk (the risk 

corresponding to lifetime exposure to 1 μg/m3

) of 1.8x10-3 based on the Thun et al. (1985) study (IRIS 

2008). A range of concentrations that correspond to upper bound lifetime excess risks of 10-4–10-7 is 

shown in Figure 3-1. 

3.2.2 Oral Exposure 

Information on health effects of oral exposure to cadmium in humans is derived mainly from studies of 

residents living in cadmium-polluted areas. Cadmium exposure in these populations is often estimated by 

blood or urinary cadmium levels (see Section 3.8.1). Exposure in these cases occurs primarily through 

the diet, but smokers in these cohorts are also exposed to cadmium by inhalation. When evaluating oral 

exposure studies, smoking was treated as a confounding variable rather than an exposure route because of 

the large number of toxic compounds (in addition to cadmium) present in cigarette smoke, and because 

the primary concern is effects attributable to cadmium. Cadmium is more readily found in the free ionic 

form in water, while in food, the cadmium ion generally exists in a complex with a variety of ligands, 

including proteins such as metallothionein (Crews et al. 1989; Groten et al. 1990; Nordberg et al. 1986). 

Experimental studies in animals have generally used soluble salts of cadmium (such as cadmium chloride) 

for food, drinking water, and gavage exposures. The toxicological properties of the cadmium ion do not 

appear to depend on the counter ion, although absorption may be significantly affected by protein 

complexes (see Section 3.3.1.2). 

3.2.2.1 Death 

Intentional ingestion of cadmium has been used as a means of suicide, causing death due to massive fluid 

loss, edema, and widespread organ destruction (Buckler et al. 1986; Wisniewska-Knypl et al. 1971). The 

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CADMIUM 103 

3. HEALTH EFFECTS 

doses ingested in two known fatal cases were estimated to be 25 mg Cd/kg from cadmium iodide 

(Wisniewska-Knypl et al. 1971) and 1,840 mg Cd/kg from cadmium chloride (Buckler et al. 1986). Time 

to death after cadmium iodide ingestion was 7 days (Wisniewska-Knypl et al. 1971) and 33 hours after 

ingestion of the cadmium chloride (Buckler et al. 1986). 

In rats and mice, acute oral LD50 (lethal dose, 50% kill) values for cadmium range from about 100 to 

300 mg/kg (Baer and Benson 1987; Basinger et al. 1988; Kostial et al. 1978; Kotsonis and Klaassen 1978; 

Shimizu and Morita 1990). The lowest dose causing death (2 of 20 animals) was 15.3 mg/kg in SpragueDawley rats (Borzelleca et al. 1989). Very young animals have lower LD50 values than adult animals 

(Kostial et al. 1978, 1989); this effect may be related to the greater fractional absorption of ingested 

cadmium in the immature organism (see Section 3.4.1.2). For example, the LD50 values in rats aged 2, 3, 

6, 18, and 54 week are 47, 240, 216, 170, and 109 mg/kg, respectively (Kostial et al. 1978). 

Deaths related to cadmium exposure have been reported in only two of the intermediate exposure studies 

found. In a study in Wistar rats exposed to cadmium chloride by gavage at 40 mg Cd/kg/day, 

5 days/week for up to 14 weeks; 4 of 13 female Wistar rats died by 8 weeks (Baranski and Sitarek 1987). 

In mice, Blakley (1986) studied the effect of cadmium on chemical- and viral-induced tumor production. 

Female albino Swiss mice (8 weeks old, n=41) were administered cadmium chloride in the drinking water 

for 280 days at doses of 0, 5, 10, or 50 ppm. These mice have a high incidence of spontaneous 

lymphocytic leukemia of thymic origin. A significant 33% increase (p=0.0228, chi-square analysis) in 

deaths from virally induced leukemia was observed from exposure to 1.9 or 9.5 mg Cd/kg/day. The 

deaths were attributed to cadmium-impaired immunosurveillance mechanisms that control expression of 

the murine lymphocytic leukemia virus. 

The LOAEL values from each reliable study for lethality in each species and duration category are 

recorded in Table 3-6 and plotted in Figure 3-2. 

3.2.2.2 Systemic Effects 

The highest NOAEL values and all LOAEL values from each reliable study for systemic effects in each 

species and duration category are recorded in Table 3-6 and plotted in Figure 3-2. 

Respiratory Effects. No studies were located regarding respiratory effects in humans after oral 

exposure to cadmium. 

***DRAFT FOR PUBLIC COMMENT*** 
Table 3-6 Levels of Significant Exposure to Cadmium - Oral 

Exposure/ 

Duration/ 

a Frequency Key to Species (Route) Figure (Strain) NOAEL Less Serious System (mg/kg/day) (mg/kg/day) 

LOAEL 

Reference Chemical Form 

Serious

(mg/kg/day) 

ACUTE EXPOSURE Death 

1 Rat once 

(NS) (G) 29 (LD50 at 8 days; 2 weeks old) Kostial et al. 1978 CdCl2 

29

129 F (LD50 at 8 days; 6 weeks 

old) 

129

104 F (LD50 at 8 days; 18 

weeks old) 

104

230

2 Rat once 

(Sprague- (GW)

Dawley)

225 M (LD50 at 14 days) 

225

Kotsonis and Klaassen CdCl2 

232

3 Rat 2 wk 

(Sprague- (W)

Dawley)

42 M (7/9 died within 2 weeks) 

42

Kotsonis and Klaassen CdCl2 

233

4 Rat once 

(Sprague- (GW)

Dawley)

327 M (LD50 at 24 hours; fed 

rats) 

Shimizu and Morita 199CdCl2 

327

107 M (LD50 at 24 hours; fasted 

rats) 

107

236

5 Mouse once 

(Swiss- (GW)Webster)

95.5 M (LD50 at 96 hours) 

95.5

Baer and Benson 1987 CdCl2 

238

6 Mouse once 

(ICR) (GW) 

239

112 M (5/10 died within 8 days) 

112

Basinger et al. 1988 CdCl2 
Table 3-6 Levels of Significant Exposure to Cadmium - Oral (continued) 

a 

Key to Species 

Figure (Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) 

LOAEL 

Reference Chemical Form 

NOAEL Less Serious Serious 

System (mg/kg/day) (mg/kg/day) (mg/kg/day) 

Systemic 

7 Rat 

(Wistar) 

245

10 d Gd 7-16 once (GW) 

Bd Wt 2 F 12 F (14% decreased 

2 maternal body weight) 

12

Baranski 1985 CdCl2 

8 Rat 

(SpragueDawley) 

246

10 d 1 x/d (GW) 

Hemato 31.3 M 65.6 M (increased hemoglobin, 

31.3 hematocrit, erythrocytes) 

138 F 

138

65.6

Hepatic 65.6 M 138 M (focal necrosis of 

65.6 hepatocytes) 

Borzelleca et al. 1989 CdCl2 

138

Renal 15.3 (focal necrosis of tubular 

epithelium) 

15.3

Bd Wt 15.3 M (18% decreased body 31.3 M (23% decreased body 

weight) weight) 

15.3 31.3

31.3 F 65.6 F (18% decreased body 

31.3 weight) 

65.6

9 Rat 

(SpragueDawley) 

247

10 d (W) Hepatic 13.9 13.9

Renal 13.9 

13.9

Bd Wt 13.9 

13.9

1.1 M 7.8 M (14% decreased body 11.2 M (25% decreased body 

1.1 weight) weight) 

Borzelleca et al. 1989 CdCl2 

7.8 11.2
Table 3-6 Levels of Significant Exposure to Cadmium - Oral (continued) 

Exposure/ 

Duration/ 

a Frequency Key to Species (Route) Figure (Strain) 

LOAEL 

Reference Chemical Form 

NOAEL Less Serious Serious 

System (mg/kg/day) (mg/kg/day) (mg/kg/day) 

10 Rat once 

(Sprague- (GW) Dawley) 

248

Cardio 150 M 

150

Hemato 150 M 

150

Hepatic 150 M 

150

Renal 25 M (50% decrease in urine 

flow for first 2 days) 

Kotsonis and Klaassen CdCl2 

25

Bd Wt 100 150 M (initial 12% decreased 

100 body weight) 

150

11 Rat Gd 6-15 

(Long- Evans) (GW) Gastro 6.13 F 61.32 F (intestinal necrosis, 6.13 hemorrhage, ulcers) Machemer and Lorke 19

CdCl2 

249

61.32

Bd Wt 1.84 F 6.13 F (27% decrease in body 18.39 F (persistent 50% decrease 

1.84 weight gain during in maternal body weight 

treatment) gain) 

6.13 18.39

12 Rat Gd 6-15 

(Long- Evans) (F) 

250

Gastro 12.5 F 

12.5

Bd Wt 3.5 F 12.5 F (transient 19% decrease 

3.5 in maternal body weight 

gain during treatment) 

Machemer and Lorke 19CdCl2 

12.5

13 Rat 12 d 

(Wistar) (W) 

251

Hemato 12 M (anemia) 

12

Sakata et al. 1988 CdCl2 
Table 3-6 Levels of Significant Exposure to Cadmium - Oral (continued) 

Exposure/ 

Duration/ 

a Frequency Key to Species (Route) Figure (Strain) 

LOAEL 

Reference Chemical Form 

NOAEL Less Serious Serious 

System (mg/kg/day) (mg/kg/day) (mg/kg/day) 

14 Rat once 

(Sprague- (GW) Dawley) 

Hepatic 75 M (focal degeneration and 

necrosis of parenchymal cells) 

Shimizu and Morita 199CdCl2

75

252

15 Mouse once 

(CBA/Bom) (GW) 

253

Gastro 15.7 M 30.4 M (gastritis and enteritis) 88.8 M (severe gastric necrosis) 

15.7 30.4 88.8

Andersen et al. 1988 CdCl2 

Hepatic 15.7 M 30.4 M (fatty infiltration of liver 

15.7 cells, occasional 

hepatocellular necrosis) 

30.4

Renal 59.6 88.8 M (tubular necrosis and 

59.6 casts) 

88.8

16 Mouse once 

(ICR) (GW) Gastro 112 M (glandular stomach epithelial necrosis) Basinger et al. 1988 CdCl2 

112

254

Hepatic 112 M (extensive hepatocellular 

coagulative necrosis) 

112

Renal 112 M 

112

Immuno/ Lymphoret 

17 Rat 10 d 

1 x/d (SpragueDawley) (GW) 65.6 M 65.6 F (increased leukocyte 65.6 counts) 31.3 F Borzelleca et al. 1989 CdCl2 

255

31.3

65.6

Neurological 

18 Rat once 

(Sprague- (GW) Dawley) 

25 M 50 M (decreased motor 

25 activity) 

Kotsonis and Klaassen CdCl2 

50

256
Table 3-6 Levels of Significant Exposure to Cadmium - Oral (continued) 

Exposure/ 

Duration/ 

a Frequency Key to Species (Route) Figure (Strain) NOAEL Less Serious System (mg/kg/day) (mg/kg/day) 

LOAEL 

Reference Chemical Form 

Serious 

(mg/kg/day) 

Reproductive 

19 Rat once 

(Wistar) (GW) 

257

50 M 

50

100 M (testicular necrosis) 

100

Bomhard et al. 1987 CdCl2 

20 Rat 10 d 

1 x/d (SpragueDawley) (GW) 138 F 138 65.6 M (testicular atrophy and loss of spermatogenic elements) Borzelleca et al. 1989 CdCl2 

65.6

258

21 Rat once 

(Sprague- (GW) Dawley) 

25 M 

25

Dixon et al. 1976 CdCl2 

259

22 Rat once 

(Sprague- (GW) Dawley) 

50 M 

50

100 M (testicular necrosis; 

decreased spermatogenesis; 

Kotsonis and Klaassen CdCl2 

decreased number females producing pups) 

100

260

23 Mouse once 

(CBM/ Bom) (GW) 

263

30.3 M 

30.3

59.6 M (testicular necrosis) 

59.6

Andersen et al. 1988 CdCl2 

Developmental 

24 Rat 10 d 

Gd 7-16 (Wistar) once (GW) 

2 F (delayed ossification of 

the sternum and ribs) 

2

40 (fused lower limbs, 

absent limbs, decreased number of live fetuses, increased number of 

Baranski 1985 CdCl2 

resorptions) 

40

264
Table 3-6 Levels of Significant Exposure to Cadmium - Oral (continued) 

Exposure/ 

Duration/ 

a Frequency Key to Species (Route) Figure (Strain) NOAEL Less Serious System (mg/kg/day) (mg/kg/day) 

LOAEL 

Reference Chemical Form 

Serious 

(mg/kg/day) 

25 Rat 1 x/d 

Gd 6-15 (Long- Evans) (GW) 

6.13 

6.13

18.39 (increased number of 

fetuses with malformations) 

Machemer and Lorke 19CdCl2 

18.39

265

26 Rat 10 d 

Gd 6-15 (Long- Evans) (F) 

12.5 

12.5

Machemer and Lorke 19CdCl2 

266

INTERMEDIATE EXPOSURE Death 

27 Rat 14 wk 

5 d/wk (Wistar) (GW) 

40 F (4/13 died by week 8; 

7/13 by week 14) 

Baranski and Sitarek 19CdCl2 

40

269

28 Mouse 280 d 

(Swiss) (W) 

273

1.9 F (24/41 died by 280 days) 

1.9

Blakley 1986 CdCl2 

Systemic 

29 Monkey 10 wk 

(Rhesus) (F) 

276

Bd Wt 5 M 

5

Chopra et al. 1984 CdCl2 

30 Rat 14 wk 

5 d/wk (Wistar) (GW) 

Bd Wt 4 F 

4

40 F (29% decreased 

maternal body weight) 

Baranski and Sitarek 19CdCl2 

40

280

31 Rat 2-10 mo 

(Sprague- (W) Dawley) 

Renal 30 F (B2-microglobulinuria) 

30

Bernard et al. 1988a CdCl2 

282
Table 3-6 Levels of Significant Exposure to Cadmium - Oral (continued) 

a 

Key to Species 

Figure (Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) 

LOAEL 

Reference Chemical Form 

NOAEL Less Serious Serious 

System (mg/kg/day) (mg/kg/day) (mg/kg/day) 

32 Rat 

(Wistar) 

daily 12 mo (W) 

Musc/skel 0.2 M 0.5 M (increased lumbar spine 

0.2 deformities, decreased in 

lumbar spine 

Brzoska and Moniuszko-Jakoniuk 202005b 

mineralization, altered CdCl2 bone turnover parameters) 

0.5

1031

33 Rat 

(Wistar) 

daily 12 mo (W) 

b

Musc/skel 0.2 F (decreased bone 

mineralization, mechanical properties of 

Brzoska and Moniuszko-Jakoniuk 20Brzoska et al. 2005a, 20

tibia and femur, and CdCl2 altered bone turnover parameters) 

0.2

1030

34 Rat 

(Wistar) 

daily 12 mo (W) 

Musc/skel 0.3 F (alterations in bone 

mineral content and density and mechanical 

Brzoska et al. 2004b, 20CdCl2 

properties of lumbar vertebral and femoral bones) 

0.3

1029

35 Rat 

(SpragueDawley) 

4 or 7 mo (W) Renal 15.2 F (albuminuria, transferrinuria, 

B2-microglobulinuria) 

Cardenas et al. 1992a CdCl2 

15.2

283

36 Rat 

(SpragueDawley) 

190 d (W) Cardio 1.4 M (20% increase in diastolic blood pressure) Carmignanti and Bosco

Cd acetate 

1.4

284

2.8

Bd Wt 2.8 M 
Table 3-6 Levels of Significant Exposure to Cadmium - Oral (continued) 

a 

Key to Species 

Figure (Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) 

LOAEL 

Reference Chemical Form 

NOAEL Less Serious Serious 

System (mg/kg/day) (mg/kg/day) (mg/kg/day) 

37 Rat 

(SpragueDawley) 

12 wk (W) Hepatic 8.58 M (necrosis of central lobules) Cha 1987 CdCl2 

8.58

285

Renal 8.58 M (necrosis of proximal 

tubular epithelial cells and cloudy swelling) 

8.58

Bd Wt 8.58 M (23% decreased in body 

weight gain; 9% total body weight decrease) 

8.58

38 Rat 

(Wistar) 

286

170 d (W) Bd Wt 56 F 56 Cifone et al. 1989a CdCl2 

39 Rat 

(SpragueDawley) 

3 mo (W) Hemato 2 (anemia) 2 Decker et al. 1958 CdCl2 

287

Bd Wt 2 F (15% decreased body 2 M (25% decreased body 

weight) weight) 

2 2

40 Rat 

(Wistar) 

4-60 wk (W) Renal 1.18 (vesiculation of proximal tubules) Gatta et al. 1989 CdCl2 

1.18

288

41 Rat 

290

4 wk (F) Hemato 2.5 M (anemia) 2.5 Groten et al. 1990 CdCl2 

2.5

Renal 2.5 M 
Table 3-6 Levels of Significant Exposure to Cadmium - Oral (continued) 

a 

Key to Species 

Figure (Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) NOAEL Less Serious System (mg/kg/day) (mg/kg/day) 

LOAEL 

Reference Chemical Form 

Serious 

(mg/kg/day) 

42 Rat 

(Wistar) 

292

120 d (W) Hemato 3.6 M (anemia) 3.6 Itokawa et al. 1974 CdCl2 

Renal 3.6 M (tubular necrosis and 

casts, glomerular adhesions) 

3.6

43 Rat 

(SpragueDawley) 

7 wk (F) Cardio 2.5 M (congested myocardium, separation of muscle 

fibers) 

Jamall et al. 1989 CdCl2 

2.5

293

Renal 2.5 M 

2.5

Bd Wt 2.5 M 

2.5

44 Rat 

(Wistar) 

294

90 d (W) Hemato 8 F (anemia) 8 Kawamura et al. 1978 CdCl2 

Musc/skel 8 F (osteomalacia changes) 

8

Renal 8 F (decreased renal 

clearance) 

8

Endocr 8 F 

8

Bd Wt 8 F (12% decreased body 

weight) 

8

45 Rat 

(SpragueDawley) 

22 d Gd 0-21 (W) 

Hemato 1.5 F (slight anemia) 

1.5

Kelman et al. 1978 form not specified 

295

Musc/skel 3.8 F 

3.8
Table 3-6 Levels of Significant Exposure to Cadmium - Oral (continued) 

a 

Key to Species 

Figure (Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) NOAEL Less Serious System (mg/kg/day) (mg/kg/day) 

LOAEL 

Reference Chemical Form 

Serious 

(mg/kg/day) 

46 Rat 

(SpragueDawley) 

297

24 wk (W) Resp 8 M 8

Cardio 8 M 

8

Gastro 8 M 

8

Hemato 8 M 

8

Musc/skel 8 M 

8

Hepatic 8 M 

8

Renal 1.2 M 

1.2

3.1 M (proteinuria, slight focal 

tubular necrosis) 

Kotsonis and Klaassen CdCl2 

Endocr 8 M 

8

Bd Wt 8 M 

8

3.1

47 Rat 

(Wistar) 

302

3 mo (F) Cardio 3 3

Hemato 3 

3

Hepatic 3 

3

Renal 3 

3

Endocr 3 

3

Bd Wt 3 

3

Loeser and Lorke 1977a CdCl2 

48 Rat 

(SpragueDawley) 

304

6-16 wk (W) Resp 2.4 (lung fibrosis) 2.4 Miller et al. 1974b CdCl2 
Table 3-6 Levels of Significant Exposure to Cadmium - Oral (continued) 

a 

Key to Species 

Figure (Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) 

LOAEL 

Reference Chemical Form 

NOAEL Less Serious Serious 

System (mg/kg/day) (mg/kg/day) (mg/kg/day) 

49 Rat 

(SpragueDawley) 

306

6 wk 5 d/wk 1 x/d (GW) 

Hepatic 0.25 M 

0.25

Muller et al. 1988 Cd acetate 

Bd Wt 0.25 M 

0.25

50 Rat 

(NS) 

4 wk (W) Hemato 0.8 F (decreased hematocrit and hemoglobin) Ogoshi et al. 1989 CdCl2 

307

0.8

Musc/skel 0.8 F (decreased bone 

strength in young animals) 

0.8

Bd Wt 0.8 1.6 F (10% decreased body 

0.8 weight gain) 

1.6

51 Rat 

(NS) 

200 d (W) Resp 0.6 M 1.2 M (reduced static 0.6 compliance, lung lesions) Petering et al. 1979 CdCl2 

309

1.2

52 Rat 

(SpragueDawley) 

310

120 d (W) Resp 3.62 M (emphysema) 3.62 Petering et al. 1979 CdCl2 

53 Rat 

(SpragueDawley) 

111 d (90 d prior to Gd 1-21) 

Hemato 5.23 F 

5.23

Petering et al. 1979 CdCl2 

311

(W) 
Table 3-6 Levels of Significant Exposure to Cadmium - Oral (continued) 

a

Key to Species 

Figure (Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) NOAEL Less Serious System (mg/kg/day) (mg/kg/day) 

LOAEL 

Reference Chemical Form 

Serious 

(mg/kg/day) 

54 Rat 

(SpragueDawley) 

Gd 1- Ld 1 (F) Bd Wt 19.7 F (77-80% decreased maternal weight gain) Pond and Walker 1975 CdCl2 

315

19.7

55 Rat 

(Wistar) 

316

90 d (W) Resp 16 F 16 Prigge 1978a CdCl2 

Hemato 4 F (23% decreased serum 

iron) 

4

Renal 4 F 8 F (35% increase in urine 

4 protein) 

8

Bd Wt 8 F 

8

56 Rat 

(Wistar) 

317

12, 26, 50, or 100 d (W) 

Hemato 12 M (iron deficient anemia) 

12

Sakata et al. 1988 CdCl2 

57 Rat 

(SpragueDawley) 

324

7-12 mo (W) Renal 13 F 13 Viau et al. 1984 CdCl2 

Bd Wt 13 F 

13

58 Mouse 

(CF1) 

252 d (F) Musc/skel 0.65 F (decrease in femur calcium content in mice Bhattacharyya et al. 198

1988b 

undergoing repeated pregnancy/lactation periods) 

327

0.65
Table 3-6 Levels of Significant Exposure to Cadmium - Oral (continued) 

a

Key to Species 

Figure (Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) 

NOAEL Less Serious 

System (mg/kg/day) (mg/kg/day) 

LOAEL 

Reference Chemical Form 

Serious 

(mg/kg/day) 

59 Mouse 

(C57BL/6) 

3-11 wk (W) Bd Wt 12.5 M (63% decreased body weight gain) Malave and de Ruffino 

CdCl2 

356

12.5

60 Mouse 

(B6C3F1) 

16-46 wk (W) Bd Wt 232 M (45% decreased body weight) Waalkes et al. 1993 CdCl2 

331

232

61 Mouse 

(QS/CH) 

332

Gd 1-19 (W) Hemato 4.8 F 9.6 F (anemia) 4.8 9.6

Bd Wt 4.8 F 9.6 F (14% decrease in 

4.8 maternal weight gain) 

Webster 1978 CdCl2 

9.6

62 Dog 

(Beagle) 

335

3 mo (F) Cardio 0.75 0.75

Hemato 0.75 

0.75

Hepatic 0.75 

0.75

Renal 0.75 

0.75

Bd Wt 0.75 

0.75

Loeser and Lorke 1977CdCl2 

63 Rabbit 

(New Zealand) 

9 mo (W) Cardio 1.6 M (increased aortic resistance, reduced 

contractility) 

Boscolo and CarmignanCdCl2 

336

1.6

Renal 1.6 M 

1.6

Bd Wt 1.6 M 

1.6
Table 3-6 Levels of Significant Exposure to Cadmium - Oral (continued) 

Exposure/ 

Duration/ 

a Frequency Key to Species (Route) Figure (Strain) 

LOAEL 

Reference Chemical Form 

NOAEL Less Serious Serious 

System (mg/kg/day) (mg/kg/day) (mg/kg/day) 

64 Rabbit 200 d 

(New Zealand (W) and Belgian 

Hemato 14.9 M (anemia) 

14.9

Stowe et al. 1972 CdCl2 

Giant) 

338

Hepatic 14.9 M (focal hepatic fibrosis and 

biliary hyperplasia) 

14.9

Renal 14.9 M (tubular necrosis, 

glomerular and interstitial fibrosis) 

14.9

Endocr 14.9 

14.9

Bd Wt 14.9 M (11% decrease in body 

weight) 

14.9

Immuno/ Lymphoret 

65 Monkey 10 wk 

(Rhesus) (F) 5 M (increased cell-mediated immune response) Chopra et al. 1984 CdCl2 

5

341

66 Rat 170 d 

(Wistar) (W) 28 F (biphasic decrease then increase in natural killer Cifone et al. 1989a CdCl2 

cell activity) 

28

343

67 Rat 3 mo 

(Wistar) (F) 

344

3 

3

Loeser and Lorke 1977a CdCl2 
a 

Key to 

Figure 

68 

Table 3-6 Levels of Significant Exposure to Cadmium - Oral (continued) 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) NOAEL Less Serious System (mg/kg/day) (mg/kg/day) 

LOAEL 

Reference Chemical Form 

Serious 

(mg/kg/day) 

Mouse (BDF1) 

3 wk (W) 1.4 F 2.8 F (decreased humoral 1.4 immune response) Blakley 1985 CdCl2 

349

2.8

69 Mouse 

(Swiss) 

280 d (W) 1.9 F (greater susceptibility to murine lymphocytic Blakley 1986 CdCl2 

leukemia virus) 

350

1.9

70 Mouse 

(BDF1) 

351

26 d (W) 12.5 F 12.5 Blakley 1988 CdCl2 

71 Mouse 

(SwissWebster) 

353

30 d (W) 22 M 22 Bouley et al. 1984 Cd acetate 

72 Mouse 

(SwissWebster) 

354

10 wk (W) 57 M 57 Exon et al. 1986 CdCl2, Cd acetate, or C

sulfate 

73 Mouse 

(C57BL/6N) 

12-16 wk (W) 19 F 57 F (reduced number of 19 SRBC-activated, Krzystyniak et al. 1987 CdCl2 

plaque-forming cells) 

355

57

74 Mouse 

(C57BL/6) 

3-11 wk (W) 12.5 M (decreased suppressor cell activity) Malave and de Ruffino 

CdCl2 

356

12.5
Table 3-6 Levels of Significant Exposure to Cadmium - Oral (continued) 

a 

Key to Species 

Figure (Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) 

LOAEL 

Reference Chemical Form 

NOAEL Less Serious Serious 

System (mg/kg/day) (mg/kg/day) (mg/kg/day) 

75 Mouse 

(ICR) 

10 wk (W) 0.75 M (induction of anti-nuclear autoantibodies) Ohsawa et al. 1988 CdCl2 

0.75

357

Neurological 

76 Rat 

(Wistar) 

14 wk 5 d/wk (GW) 

4 F 40 F (aggressive behavior) 

4 40

Baranski and Sitarek 19CdCl2

358

77 Rat 

(SpragueDawley) 

3-24 wk (W) 

1.2 M 3.1 M (decreased motor 

1.2 activity) 

Kotsonis and Klaassen CdCl2 

3.1

359

78 Rat 

(SpragueDawley) 

55 d (F) 1 M 5 M (increased passive 1 avoidance) Nation et al. 1984 CdCl2 

5

361

79 Rat 

(SpragueDawley) 

60 d (F) 9 M (decreased motor activity) Nation et al. 1990 CdCl2 

9

363

Reproductive 

80 Rat 

(Wistar) 

14 wk 5 d/wk (GW) 

4 F 40 F (increased duration of 

4 estrus cycle) 

Baranski and Sitarek 19CdCl2

40

367

81 Rat 

(Wistar) 

11 wk 5 d/wk (GW) 

4 F 

4

Baranski et al. 1983CdCl2

368
Table 3-6 Levels of Significant Exposure to Cadmium - Oral (continued) 

Exposure/ 

Duration/ 

a Frequency Key to Species (Route) Figure (Strain) 

LOAEL 

Reference Chemical Form 

NOAEL Less Serious Serious 

System (mg/kg/day) (mg/kg/day) (mg/kg/day) 

82 Rat 10 wk 

1 x/wk (Wistar) (GW) 

370

5 M 

5

Bomhard et al. 1987 CdCl2 

83 Rat 12 wk 

(Sprague- (W) Dawley) 

8.58 M (necrosis and atrophy of 

seminiferous tubule epithelium) 

Cha 1987 CdCl2 

372

8.58

84 Rat 4 wk 

(F) 

374

2.5 M 

2.5

Groten et al. 1990 CdCl2 

85 Rat 4 wk 

(albino) (W) 

376

4.8 F 

4.8

Kostial et al. 1993 CdCl2 

86 Rat 24 wk 

(Sprague- (W) Dawley) 

377

8 M 

8

Kotsonis and Klaassen CdCl2 

87 Rat 3 mo 

(Wistar) (F) 

379

3 

3

Loeser and Lorke 1977a CdCl2 

88 Rat 120 d 

(NS) (W) 12.6 M (decreased sperm count and motility, seminiferous 

tubular damage) 

Saxena et al. 1989 Cd acetate 

384

12.6

89 Rat 70-80 d 

(Long- Evans) (W) 

387

4.64 M 

4.64

Zenick et al. 1982 CdCl2 
Table 3-6 Levels of Significant Exposure to Cadmium - Oral (continued) 

a 

Key to Species 

Figure (Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) 

LOAEL 

Reference Chemical Form 

NOAEL Less Serious Serious 

System (mg/kg/day) (mg/kg/day) (mg/kg/day) 

90 Dog 

(Beagle) 

390

Developmental 

91 Rat 

(Wistar) 

3 mo (F) 

21 d Gd 1-21 (W) 

0.75 

0.75

0.706 (delayed development of 

sensory motor coordination reflexes; increased motor activity) 

Loeser and Lorke 1977CdCl2 

Ali et al. 1986 Cd acetate 

391

0.706

92 Rat 

(Wistar) 

20 d Gd 1-20 (W) 

9.6 (decreased fetal body 

weight [12%], body 

length [7%], and hematocrit [13%]) 

Baranski 1987 CdCl2 

392

9.6

93 Rat 

(Wistar) 

393

11 wk 5 d/wk 1 x/d (GW) 

0.04 (pup behavioral 

alterations) 

0.04

Baranski et al. 1983 CdCl2 

94 Rat 

(Wistar) 

11-94 d Gd 5-15 Ld 2-28 1 x/d ppd 1-56 5 d/wk 1 x/d (GW) 

14 M (decreased horizontal 

ambulation and rearing activity; increased frequency of somatosensory, visual, and auditory electrocorticogram; prolonged latency and duration of evoked potentials) 

Desi et al. 1998 CdCl2 

1002

14
Table 3-6 Levels of Significant Exposure to Cadmium - Oral (continued) 

a 

Key to Species 

Figure (Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) 

LOAEL 

Reference Chemical Form 

NOAEL Less Serious Serious 

System (mg/kg/day) (mg/kg/day) (mg/kg/day) 

95 Rat 

(Druckery) 

Gd 0- Ld 21 (W) 5 (decreased pup brain and body weight at 7, 14, 

and 21 days) 

Gupta et al 1993Cd acetate 

394

5

96 Rat 

(SpragueDawley) 

Gd 0-20 (W) 1.5 (12% decreased hematocrit) Kelman et al. 1978 form not specified 

395

1.5

97 Rat 

(albino) 

10 wk (W) 4.8 (12% decrease in pup body weight at weaning) Kostial et al. 1993 CdCl2 

396

4.8

98 Rat 

(Wistar) 

approx. 49 d 4 wk old through 

mating 7 d/wk 1 x/d (GO) 

7 M (alterations in ambulation 

behavior; prolonged latency and duration ofsomatosensory evokedpotentials)

Nagymajtenyi et al. 199CdCl2 

1016

7

99 Rat 

(SpragueDawley) 

60 d prior to Gd 1 or Gd 1-21 

2.61 (decreased live birth 

weight) 

Petering et al. 1979 CdCl2 

397

(W) 

2.61

100 Rat 

(SpragueDawley) 

Gd 1- Ld 1 (F) 19.7 (13-19% decreased pup birth weight) Pond and Walker 1975 CdCl2 

399

19.7
Table 3-6 Levels of Significant Exposure to Cadmium - Oral (continued) 

Exposure/ 

Duration/ 

a Frequency Key to Species (Route) Figure (Strain) 

LOAEL 

Reference Chemical Form 

NOAEL Less Serious Serious 

System (mg/kg/day) (mg/kg/day) (mg/kg/day) 

101 Rat 21 d 

Gd 0-20 (ITRC) (W) 

21 

21

Saxena et al. 1986 Cd acetate 

400

102 Rat 15 d 

Gd 6-20 (SpragueDawley) (W) 0.63 4.7 (8% decreased fetal body 0.63 weight) Sorell and Graziano 199

CdCl2 

4.7

401

103 Rat 9 wk 

1 x/d (SpragueDawley) (GW) 1 10 (delayed ossification, 1 decreased body weight) Sutou et al. 1980 form not specified 

10

402

104 Mouse 19 d 

Gd 1-19 (QS/CH) (W) 

2.4 (decreased fetal body 

weight; severe anemia) 

Webster 1978 CdCl2 

2.4

404

CHRONIC EXPOSURE Systemic 

105 Human c Renal 0.0003 F Buchet et al. 1990; Jaru

0.0003 2000; Suwazono et al. 2

1036 form not specified 

106 Human NS 

lifetime Renal 0.0021 0.0021 Nogawa et al. 1989 

(F) form not specified 

437
Table 3-6 Levels of Significant Exposure to Cadmium - Oral (continued) 

a 

Key to Species 

Figure (Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) 

LOAEL 

Reference Chemical Form 

NOAEL Less Serious Serious 

System (mg/kg/day) (mg/kg/day) (mg/kg/day) 

107 Human 

441

>25 yr lifetime (environ) 

Hemato 0.0078 

0.0078

Musc/skel 0.0078 

0.0078

Renal 0.0078 (increased excretion of 

low molecular weight proteins) 

Shiwen et al. 1990 Cd metal 

0.0078

108 Monkey 

(Rhesus) 

9 yr (F) Cardio 0.53 M 1.71 M (increased blood 0.53 pressure during the first 

1.5 years) 

Akahori et al. 1994 CdCl2 

448

1.71

109 Rat 

(SpragueDawley) 

18 mo (W) Renal 13 F (loss of glomerular polyanion charge barrier, 

proteinuria) 

Bernard et al. 1992 CdCl2 

451

13

110 Rat 

(Wistar) 

72 wk (F) Renal 3.5 17.5 (8 to 9-fold increase in 3.5 LDH and GST starting at 

13 weeks) 

Bomhard et al. 1984 CdCl2 

452

17.5

111 Rat 

(Wistar) 

daily 24 mo (W) 

Musc/skel 0.08 F (decreases in bone 

mineral content and density of lumbar spine, altered bone turnover paramters, increases in deformed and fractured vertebral bodies) 

Brzoska and Moniuszko-Jakoniuk 202004b CdCl2 

1032

0.08
Table 3-6 Levels of Significant Exposure to Cadmium - Oral (continued) 

a 

Key to Species 

Figure (Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) 

LOAEL 

Reference Chemical Form 

NOAEL Less Serious Serious 

System (mg/kg/day) (mg/kg/day) (mg/kg/day) 

112 Rat 

(SpragueDawley) 

453

12 mo (W) Hemato 0.79 0.79 Decker et al. 1958 CdCl2 

Bd Wt 0.79 

0.79

113 Rat 

(SpragueDawley) 

454

M: 92 wk F: 84 wk (W) 

Cardio 4.01 

4.01

Fingerle et al. 1982 CdCl2 

Renal 0.8 1.51 (proximal tubule lesions) 

0.8 1.51

Bd Wt 4.01 

4.01

114 Rat 

(SpragueDawley) 

456

6, 12, or 18 mo (W) Cardio 2.281 F 2.281 Mangler et al 1988 CdCl2 

Hepatic 2.281 F 

2.281

Renal 2.337 F (cloudy swelling of 

tubular cells) 

2.337

Bd Wt 2.281 F 

2.281

115 Rat 

(Wistar) 

458

31 mo (W) Musc/skel 3.6 (muscle atrophy) 3.6 Sato et al. 1978 CdCl2 

Bd Wt 3.6 

3.6

116 Rat 

(Wistar) 

460

2 yr (W) Renal 2.6 M 2.6 Shaikh et al. 1989 CdCl2 
Table 3-6 Levels of Significant Exposure to Cadmium - Oral (continued) 

a 

Key to Species 

Figure (Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) NOAEL Less Serious System (mg/kg/day) (mg/kg/day) 

LOAEL 

Reference Chemical Form 

Serious 

(mg/kg/day) 

117 Rat 

(Wistar) 

77 wk (F) Bd Wt 3.5 M 7 M (10% decreased body 3.5 weight) Waalkes and Rehm 199

CdCl2 

461

7

118 Mouse 

(CF1) 

18 months (F) Musc/skel 0.65 F 6.5 F (loss of bone calcium in 0.65 ovariectomized mice) Bhattacharyya et al. 198

1038

6.5

119 Mouse 

(CBA/H) 

464

12 mo (W) Hemato 

Renal 57 

57

Bd Wt 

57 (anemia and bone 

marrow hypoplasia) 

57

57 (21% decreased terminal 

body weight) 

Hays and Margaretten 1form not specified 

Neurological 

120 Rat 

(Wistar) 

469

31 mo (W) 

57

3.6 (peripheral neuropathy) 

3.6

Sato et al. 1978 CdCl2 
Table 3-6 Levels of Significant Exposure to Cadmium - Oral (continued) 

Exposure/ LOAEL 

Duration/ 

a Frequency Reference Key to Species NOAEL Less Serious Serious (Route) Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

Cancer 

121 Rat 77 wk 3.5 M (CEL: increased rates of Waalkes and Rehm 199

(Wistar) (F) prostatic adenomas) CdCl2 

3.5

488

a The number corresponds to entries in Figure 3-2. b The intermediate-duration oral MRL of 0.0005 mg Cd/kg/day (0.5 ug Cd/kg/day) was calculated using a benchmark dose analysis. The BMDL1std of 0.05 mg Cd/divided by an uncertainty factor of 100 (10 to account for extrapolation from animals to humans and 10 for human variability). c The chronic-duration oral MRL of 0.0001 mg Cd/kg/day (0.1 ug Cd/kg/day) was calculated from the 95% lower confidence limit of the urinary cadmium level associncreased risk of low molecular weight proteinuria (0.5 ug/g creatinine) estimated from a meta-analysis of select environmental exposure studies. An intake which wurinary cadmium concentration was estimated using a modification of the Nordberg-Kjellström pharmacokinetic model (see Appendix A for details on the meta-analextrapolation to dietary intake). This dose of 0.3 ug/kg/day was divided by an uncertainty factor of 3 for human variability. Bd Wt = body weight; Cardio = cardiovascular; CEL = cancer effect level; d = day(s); Endocr = endocrine; (F) = feed; F = Female; (G) = gavage; Gastro = gastrointegestational day; (GO) = gavage in oil; GST = glutathione-S-transferase; (GW) = gavage in water; Hemato = hematological; Immuno/Lymphoret = immunological/lym= lethal dose, 50% kill; LDH = Lactate dehydrogenase; LOAEL = lowest-observed-adverse-effect level; M = male; mo = month(s); Musc/skel = musculoskeletal; NOno-observed-adverse-effect level; NS = not specified; ppd = post-parturition day; Resp = respiratory; SRBC = sheep red blood cells; (W) = drinking water; wk = wee= year(s) 
Death 

Systemic Cardiovascular Gastrointestinal Hematological Hepatic Renal Body Weight Immuno/Lymphor Neurological Reproductive Developmental 


	


	

Figure 3-2 Levels of Significant Exposure to Cadmium - Oral

Acute (≤14 days)
	

Systemic
	

mg/kg/day 

1000 

4r 

2r 

10r 10r 10r 10r 8r 8r 20r 1r 

6m 4r 16m 16m 16m 100 1r 10r 19r 22r 5m 15m 15m 

14r 

8r 8r 8r 17r 17r 20r 11r 15m 23m 

18r 19r 22r 

3r 24r 

1r 8r 15m 8r 15m 8r 17r 23m

10r 18r 21r 

11r 25r 

15m 15m 8r 8r 9r 9r 9r 12r 13r 7r 12r 26r 9r 10 

9r 

11r 11r 25r 

12r 

7r 24r 11r 

9r 1 

c-Cat -Humans f-Ferret n-Mink Cancer Effect Level-Animals Cancer Effect Level-Humans LD50/LC50

d-Dog k-Monkey j-Pigeon o-Other LOAEL, More Serious-Animals LOAEL, More Serious-Humans Minimal Risk Level 

r-Rat m-Mouse e-Gerbil LOAEL, Less Serious-Animals LOAEL, Less Serious-Humans for effects 

p-Pig h-Rabbit s-Hamster NOAEL - Animals NOAEL - Humans other than 

q-Cow a-Sheep g-Guinea Pig Cancer 
Death 

Respiratory Cardiovascular Gastrointestinal Hematological Musculoskeletal Hepatic Renal Endocrine 

Figure 3-2 Levels of Significant Exposure to Cadmium - Oral (Continued)

Intermediate (15-364 days) 

Systemic 

mg/kg/day 

1000 

100 

27r 

31r 

55r 64h 64h 35r 64h 56r 57r 10 61m 46r 46r 46r 44r 46r 44r 46r 37r 46r 37r 44r 55r 44r 

61m 53r

52r 55r 45r 55r 42r 42r 47r 47r 47r 46r 47r 48r 43r 41r 41r 43r 28m 39r 63h 45r 63h 36r 51r 40r 46r 1 

62d 62d 50r 50r 62d 62d 51r 58m 32r 

34r 49r 32r 33r 

0.1 

0.01 

0.001 

0.0001 

c-Cat -Humans f-Ferret n-Mink Cancer Effect Level-Animals Cancer Effect Level-Humans LD50/LC50

d-Dog k-Monkey j-Pigeon o-Other LOAEL, More Serious-Animals LOAEL, More Serious-Humans Minimal Risk Level 

r-Rat m-Mouse e-Gerbil LOAEL, Less Serious-Animals LOAEL, Less Serious-Humans for effects 

p-Pig h-Rabbit s-Hamster NOAEL - Animals NOAEL - Humans other than 

q-Cow a-Sheep g-Guinea Pig Cancer 
Endocrine 

Immuno/Lymphor Neurological Reproductive Developmental 


 


	

Body Weight 

Figure 3-2 Levels of Significant Exposure to Cadmium - Oral (Continued)
 

Intermediate (15-364 days)
	

Systemic
	

mg/kg/day 

1000 

60m 

100 

38r 72m 73m

30r 76r 80r 

66r

54r 71m 73m 100r

64h 57r 64h 88r 94r 59m 70m 74m 10 61m 79r 92r 46r 37r 44r 46r 55r 83r 86r 98r 

29k 61m 65k 78r 82r 85r 89r 95r 97r 30r 76r 80r 81r

47r 36r 47r 68m 67r 77r 87r 43r 84r 104m 99r 39r 39r 69m 50r 63h 68m 96r 77r 1 78r

62d 50r 75m 90d 91r 

49r 

0.1 

93r 

0.01 

0.001 

0.0001 

c-Cat -Humans f-Ferret n-Mink Cancer Effect Level-Animals Cancer Effect Level-Humans LD50/LC50

d-Dog k-Monkey j-Pigeon o-Other LOAEL, More Serious-Animals LOAEL, More Serious-Humans Minimal Risk Level 

r-Rat m-Mouse e-Gerbil LOAEL, Less Serious-Animals LOAEL, Less Serious-Humans for effects 

p-Pig h-Rabbit s-Hamster NOAEL - Animals NOAEL - Humans other than 

q-Cow a-Sheep g-Guinea Pig Cancer 
Developmental 

Figure 3-2 Levels of Significant Exposure to Cadmium - Oral (Continued)
 

Intermediate (15-364 days)
	

mg/kg/day 

1000 

100 

101r 

10 103r 

102r 

1 103r 

102r 

0.1 

0.01 

0.001 

0.0001 

c-Cat -Humans f-Ferret n-Mink Cancer Effect Level-Animals Cancer Effect Level-Humans LD50/LC50

d-Dog k-Monkey j-Pigeon o-Other LOAEL, More Serious-Animals LOAEL, More Serious-Humans Minimal Risk Level 

r-Rat m-Mouse e-Gerbil LOAEL, Less Serious-Animals LOAEL, Less Serious-Humans for effects 

p-Pig h-Rabbit s-Hamster NOAEL - Animals NOAEL - Humans other than 

q-Cow a-Sheep g-Guinea Pig Cancer 
Cardiovascular 

Hematological Musculoskeletal Hepatic Renal Body Weight Neurological Cancer * 

 

 


	


	


	 
	 
	


	

Figure 3-2 Levels of Significant Exposure to Cadmium - Oral (Continued)

Chronic (≥365 days) 

Systemic 

mg/kg/day 

100 

119m 119m 119m 

110r
	 109r
	 10 

118m 117r 

113r 113r 115r 110r 115r 117r 120r 121r 

116r 114r 114r 114r 114r
	 108k
	 113r
	

1
	 112r 113r 112r 118m 108k 

0.1 111r 

0.01 

107 107 107 

106 

0.001 

105 

*Doses represent the lowest dose tested per study that produced a tumorigenic 

response and do not imply the existence of a threshold for the cancer endpoint. 0.0001 

c-Cat -Humans f-Ferret n-Mink Cancer Effect Level-Animals Cancer Effect Level-Humans LD50/LC50

d-Dog k-Monkey j-Pigeon o-Other LOAEL, More Serious-Animals LOAEL, More Serious-Humans Minimal Risk Level 

r-Rat m-Mouse e-Gerbil LOAEL, Less Serious-Animals LOAEL, Less Serious-Humans for effects 

p-Pig h-Rabbit s-Hamster NOAEL - Animals NOAEL - Humans other than 

q-Cow a-Sheep g-Guinea Pig Cancer 
 

 

 

 

 

 

 

 

 

 

 

 

 

CADMIUM 133 

3. HEALTH EFFECTS 

No respiratory effects were observed in Rhesus monkeys from 4 mg/kg/day of cadmium chloride in the 

food for 9 years (Masaoka et al. 1994). Intermediate-duration oral exposure caused fibrosis in lungs of 

rats exposed to 2.4 mg Cd/kg/day of cadmium chloride after 6 and 16 weeks (Miller et al. 1974b). 

Petering et al. (1979) observed a reduced static compliance and lung lesions (not specified) in male 

Sprague-Dawley rats exposed to 1.2 mg Cd/kg/day in water for 200 days. Zinc-deficient rats were more 

susceptible to lung lesions from exposure to cadmium chloride (Petering et al. 1979). Rats exposed to 

cadmium chloride at 3.62 mg Cd/kg/day in the drinking water for 120 days developed emphysema 

(Petering et al. 1979). No histopathologic lesions of the lung were found in male Sprague-Dawley rats 

after 24 weeks of exposure to cadmium in drinking water at a maximum dose of 8 mg/kg/day (Kotsonis 

and Klaassen 1978). Lung weight was unchanged in Wistar rats after 90 days of exposure in drinking 

water at 16 mg/kg/day (Prigge 1978a). Effects on the lung following oral exposure to cadmium may be 

secondary to systemic changes (Petering et al. 1979); however, the studies that found lung effects did not 

examine other systemic effects in the exposed rats (Miller et al. 1974b; Petering et al. 1979). 

Cardiovascular Effects. Studies regarding cardiovascular effects in humans after oral exposure to 

cadmium have primarily investigated relationships between blood pressure and biomarkers of cadmium 

exposure such as cadmium levels in blood, urine, or other tissues. Smoking is an important confounding 

factor, because of the higher blood, urine, and tissue cadmium levels of smokers (see Section 3.4) and the 

known cardiovascular toxicity of cigarette smoking. Case-control and cohort epidemiologic studies that 

adequately control for smoking have typically found no association between body cadmium levels 

(primarily reflecting dietary exposure) and hypertension (Beevers et al. 1980; Cummins et al. 1980; 

Ewers et al. 1985; Lazebnik et al. 1989; Shiwen et al. 1990); however, some studies have found positive 

correlations (Geiger et al. 1989; Tulley and Lehmann 1982) or negative correlations (Kagamimori et al. 

1986; Staessen et al. 1984). Similar conflicting findings have been reported in studies analyzing death 

rates from cardiovascular disease among populations with dietary cadmium exposure (Inskip et al. 1982; 

Shigematsu 1984). Disorders of the cardiac conduction system, lower blood pressure, and decreased 

frequency of cardiac ischemic changes were found among elderly women with past high dietary exposure 

to cadmium (Kagamimori et al. 1986). Rhythmic disturbances, including ventricular fibrillation, were 

seen in an individual who had ingested 25 mg/kg cadmium as cadmium iodide (Wisniewska-Knypl et al. 

1971). 

Several studies conducting cross-sectional analysis on data from the National Health and Nutrition 

Examination Surveys (NHANES), investigated associations between blood and urine cadmium levels and 

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CADMIUM 134 

3. HEALTH EFFECTS 

cardiovascular effects (Everett and Frithsen 2008; Navas-Acien et al. 2005; Tellez-Plaza et al. 2008). 

Urinary cadmium levels were found to be strongly associated with peripheral arterial disease (PAD, 

defined as blood pressure ankle brachial index <0.0 in at least one leg) in analysis conducted on 

728 participants (at least 40 years of age) in the NHANES 1999–2000 study (Navas-Acien et al. 2005). 

Individuals with PAD had a 36% higher mean urine cadmium level than individuals without PAD. This 

study also found that individuals with PAD had 49% higher urinary tungsten levels and urinary antimony 

levels exceeding 0.1 μg/L. Another study found a modest increase in systolic or diastolic blood pressure 

associated with increasing blood cadmium levels (geometric mean blood cadmium levels among all 

participants was 0.4 μg/L); no associations with blood pressure and urinary cadmium levels were found 

(Tellez-Plaza et al. 2008). The association between blood cadmium levels and blood pressure was 

stronger in participants who never smoked than in former smokers or current smokers. There were no 

associations between hypertension and cadmium levels in blood or urine. In the third study, analysis on 

4,912 participants (45–79 years old) in the NHANES 1988–1994 survey found a significant association 

between urinary cadmium levels and myocardial infarction in women, but not men (Everett and Frithsen 

2008). After adjusting for numerous risk factors including smoking, race, and family history, a 

significant increase in the risk of myocardial infarction was observed in women with urinary cadmium 

levels of ≥0.88 μg/g creatinine. 

A single gavage dose of 150 mg/kg cadmium in male Sprague-Dawley rats had no effect on blood 

pressure (Kotsonis and Klaassen 1977). Oral exposure of rats, rabbits, and monkeys to cadmium over 

intermediate and chronic durations has been found to increase blood pressure in some studies (Akahori et 

al. 1994; Boscolo and Carmignani 1986; Carmignani and Boscolo 1984; Kopp et al. 1982; Perry et al. 

1989; Tomera and Harakal 1988), but not in others (Fingerle et al. 1982; Kotsonis and Klaassen 1978; 

Loeser and Lorke 1977a, 1977b; Mangler et al. 1988; Wills et al. 1981). In general, studies showing an 

effect on blood pressure have had control groups with lower blood pressure than studies showing no 

effect, and observed increases in blood pressure are generally small. At least in rats, the effect on blood 

pressure appears to be biphasic, reaching a maximum effect (an increase of 12–14 mm Hg in average 

systolic pressure) at intakes of 0.07 mg/kg/day, but decreasing to normal or even below normal at intakes 

10–100 times higher (Kopp et al. 1982). Enlarged and arteriosclerotic hearts have been found in rats 

orally exposed to 0.35 mg Cd/kg/day for 3 years (Schroeder et al. 1965) or to 2.79 mg Cd/kg/day for 

100 days (Wilson et al. 1941), but this effect is likely to be secondary to cadmium-induced anemia 

(Wilson et al. 1941). Histopathologic lesions of heart tissues (congestion, separation of muscle fibers) 

and decreased activity of antioxidant enzymes, but no increase in peroxidation, were found among rats 

given 2.5 mg/kg/day of cadmium in the diet for 7 weeks (Jamall et al. 1989). 

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CADMIUM 135 

3. HEALTH EFFECTS 

Gastrointestinal Effects. Numerous human and animal studies indicate that oral exposure to 

cadmium in high concentrations causes severe irritation to the gastrointestinal epithelium (Andersen et al. 

1988; Frant and Kleeman 1941). Common symptoms in humans following ingestion of food or 

beverages containing high concentrations of cadmium include nausea, vomiting, salivation, abdominal 

pain, cramps, and diarrhea (Baker and Hafner 1961; Buckler et al. 1986; Frant and Kleeman 1941; 

Nordberg et al. 1973; Shipman 1986; Wisniewska-Knypl et al. 1971). Although exact doses have not 

been measured, gastrointestinal symptoms have been caused in children by 16 mg/L cadmium in soft 

drinks (Nordberg et al. 1973) and 13 mg/L cadmium in popsicles (Frant and Kleeman 1941). Assuming 

an intake of 0.15 L (Nordberg et al. 1973) and a body weight of 35 kg, the emetic dose is 0.07 mg/kg. 

Although few studies have specifically examined gastrointestinal effects of longer-term cadmium 

exposure, no surveys of environmentally exposed populations have reported gastrointestinal symptoms 

(Morgan and Simms 1988; Roels et al. 1981a; Shigematsu 1984). 

In rats and mice, histopathologic lesions (e.g., severe necrosis, hemorrhage, ulcers) in the gastrointestinal 

epithelium have been observed after high (>30 mg/kg/day) acute-duration oral cadmium exposure by 

gavage (Andersen et al. 1988; Basinger et al. 1988; Machemer and Lorke 1981), but not after lower levels 

(8 mg/kg/day in drinking water) for 24 weeks (Kotsonis and Klaassen 1978). 

Hematological Effects. Oral cadmium exposure reduces gastrointestinal uptake of iron, which can 

result in anemia if dietary intake of iron is low. Anemia has been found in some instances among humans 

with chronic dietary exposure to cadmium (Kagamimori et al. 1986), but other studies have found no 

significant relationship between dietary cadmium exposure and anemia in humans (Roels et al. 1981a; 

Shiwen et al. 1990). Hypoproteinemia and hypoalbuminemia were reported in a male who ingested 

25 mg/kg cadmium as cadmium iodide (Wisniewska-Knypl et al. 1971). 

A number of studies have demonstrated that oral exposure to cadmium frequently produces anemia in 

laboratory animals, and that additional iron prevents anemia (Decker et al. 1958; Groten et al. 1990; Hays 

and Margaretten 1985; Itokawa et al. 1974; Kawamura et al. 1978; Kelman et al. 1978; Kozlowska et al. 

1993; Ogoshi et al. 1989; Pleasants et al. 1992, 1993; Pond and Walker 1972; Sakata et al. 1988; Sorell 

and Graziano 1990; Stowe et al. 1972; Watanabe et al. 1986; Webster 1978; Wilson et al. 1941). 

Decreases in serum iron have also been reported (Prigge 1978a). Borzelleca et al. (1989) reported slight 

but statistically significant increases in hemoglobin, hematocrit, and erythrocytes in male rats at 

65.6 mg/kg/day once a day for 10 days, but no change in females. Male Sprague-Dawley rats receiving a 

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CADMIUM 136 

3. HEALTH EFFECTS 

single gavage dose of 150 mg/kg cadmium showed no signs of anemia 14 days later (Kotsonis and 

Klaassen 1977), but anemia was produced in male Wistar rats after 12 days of drinking-water exposure to 

12 mg/kg/day (Sakata et al. 1988). Most intermediate-duration exposure studies in rats have shown 

evidence of anemia at doses of 2–14 mg/kg day (Decker et al. 1958; Groten et al. 1990; Itokawa et al. 

1974; Kawamura et al. 1978; Pleasants et al. 1993; Pond and Walker 1972; Sakata et al. 1988; Wilson et 

al. 1941). However, some intermediate-duration studies have found no change in hemoglobin (Kotsonis 

and Klaassen 1978; Loeser and Lorke 1977a; Petering et al. 1979; Prigge 1978a) in rats treated at similar 

doses. Anemia has also been seen in intermediate-duration studies in mice (Webster 1978) and rabbits 

(Stowe et al. 1972), but not in dogs (Loeser and Lorke 1977b). The result in dogs may be due to the 

relatively low dose of cadmium (0.75 mg/kg/day) used in this study. Hematological effects following 

chronic-duration oral exposure to cadmium are less well characterized. In monkeys maintained on 

4 mg/kg/day cadmium in food, pale feces, and clinical signs of anemia occurred after 90 weeks, but the 

anemia was associated with a decreased food intake rather than an increase in reticulocytes (Masaoka et 

al. 1994). Anemia was not present in rats exposed via drinking water for 12 months to the relatively low 

dose of 0.79 mg/kg/day (Decker et al. 1958). The number of erythroid progenitor cells in bone marrow is 

decreased in mice exposed to 57 mg/kg/day of cadmium in drinking water for 12 months (Hays and 

Margaretten 1985), but is increased in rats exposed to 12 mg/kg/day of cadmium in drinking water for up 

to 100 days (Sakata et al. 1988). Thus, the question remains open whether factors, in addition to reduced 

gastrointestinal absorption of iron, such as direct cytotoxicity to marrow or inhibition of heme synthesis 

may contribute to anemia. 

Musculoskeletal Effects. Osteomalacia, osteoporosis, bone fractures, and decreased bone mineral 

density have been observed in several populations exposed to elevated levels of cadmium in the diet. 

Bone effects were first reported in residents in the Jinzu River Basin, a cadmium-contaminated area in 

Japan. The disease termed Itai-Itai or "ouch-ouch" disease most often affected women with several risk 

factors such as poor nutrition, multiparity, and post-menopausal status (Shigematsu 1984). The disease 

was characterized by multiple fractures of the long bones, osteomalacia, and osteoporosis in combination 

with proteinuria (Järup et al. 1998b; Nordberg et al. 1997). Other Japanese populations with dietary 

cadmium exposure have also been found to have elevated osteoporosis and osteomalacia in both men and 

women (Kido et al. 1989b). Kagamimori et al. (1986) evaluated elderly Japanese women with heavy 

cadmium exposure from ingesting polluted drinking water, rice, and fish during World Wars I and II; and 

continued low-grade cadmium exposure from agricultural produce. Of 56 cases of Itai-Itai disease, 

26 were accompanied by osteomalacia and 26 were without osteomalacia. Another study found that the 

degree of loss of bone density is correlated with urinary excretion of β2-microglobulin, an index of renal 

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CADMIUM 137 

3. HEALTH EFFECTS 

injury (see Section 3.5.2) (Kido et al. 1990a). The bone effects observed in Itai-Itai disease and in other 

studies of Japanese populations exposed to high levels of cadmium in rice are primarily due to kidney 

damage, which results from a progressive disturbance in renal metabolism of vitamin D to its biologically 

active form (Nogawa et al. 1987, 1990) and an increased urinary excretion of calcium (Buchet et al. 

1990). These results suggest that bone changes may be secondary to disruption in kidney of vitamin D 

metabolism and resulting imbalances in calcium absorption and excretion. A recent study of women 

living in the Jinzu River basin found that bone turnover, particularly bone formation, was influenced by 

renal tubular function (Aoshima et al. 2003). However, it is possible that some bone effects are not 

mediated via the kidney. 

Bone effects have also been observed in communities outside of Japan and in populations exposed to low 

levels of cadmium. In a study of Swedish women environmentally exposed to cadmium, a significant 

negative relationship between urinary cadmium levels and bone mineral density was observed (Åkesson 

et al. 2005); the mean urinary cadmium level of the population was 0.52 μg/L. In Swedish residents 

living in an area with known cadmium pollution from battery manufacturing facilities, significant 

associations were noted between blood cadmium levels and bone mineral density and between urinary 

cadmium levels and risk of fractures and osteoporosis. There were significant decreases in bone mineral 

density in environmentally exposed subjects older than 60 years of age with blood cadmium levels of 

≥0.56 μg/L (Alfvén et al. 2002a). Increases in the risk of bone fractures were observed in subjects 

(approximately 10% of all subjects examined had environmental and occupational exposure to cadmium) 

older than 50 years of age with urinary cadmium levels >2 μg/g creatinine; no significant associations 

were found in subjects under 50 years of age (Alfvén et al. 2004). Another study of this population found 

significant increases in the risk of osteoporosis among men >60 years of age with urinary cadmium levels 

≥5 μg/g creatinine; however, an increased risk of osteoporosis was not observed in women (Alfvén et al. 

2000). A Belgian study in which residents living near zinc smelters found a 2-fold increase in cadmium 

exposure (as assessed via urinary cadmium levels) was associated with a decrease in proximal and distal 

forearm bone density of approximately 0.1 g/cm2 among post-menopausal women (Staessen et al. 1999). 

For women with urinary cadmium levels >1 μg/day, the incidence of bone fracture was 13.5 per 

1,000 person-years. Another study of a subset of the women living near a zinc smelters (Schutte et al. 

2008) provides suggestive evidence that cadmium has a direct osteotoxic effect. Significant associations 

between urinary cadmium levels and the levels of two pyridinium crosslinks of collagen (urinary levels of 

hydroxylysylpyridinoline and lysylpyridinoline), proximal forearm bone mineral density, and serum 

parathyroid hormone levels were found. In almost all of the examined women, urinary levels of retinol 

binding protein were below the cut-off level of 338 μg/day, suggesting no cadmium-induced effect on 

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CADMIUM 138 

3. HEALTH EFFECTS 

renal tubular function. Similar results have been observed in several studies of residents living in areas of 

China with moderate or high cadmium pollution levels (Jin et al. 2004b; Nordberg et al. 2002; Wang et al. 

2003; Zhu et al. 2004). There were significant increases in the prevalence of low forearm bone mineral 

density in post-menopausal women with urinary cadmium levels >20 μg/g creatinine and in men, premenopausal women, and post-menopausal women with blood cadmium levels >20 μg/L (Nordberg et al. 

2002). An increase in bone fractures was observed in males and females over the age of 40 years living 

in the area of high cadmium exposure (mean urinary cadmium levels in the area were 9.20 and 12.86 μg/g 

creatinine in the males and females, respectively) (Wang et al. 2003). A significant dose-response 

relationship between urinary cadmium levels and the prevalence of osteoporosis was observed (Jin et al. 

2004b; Wang et al. 2003; Zhu et al. 2004); the Jin et al. (2004b) study found that 23 of the 31 subjects 

with osteoporosis also exhibited signs of renal dysfunction. 

A number of animal studies confirm the findings of the epidemiology data suggesting that the bone is a 

sensitive target of cadmium toxicity. Decreases in bone mineralization and bone mineral density have 

been observed in female rats exposed to ≥0.2 mg Cd/kg/day in the lumbar spine, femur, and tibia 

(Brzóska et al. 2004b, 2005a, 2005b, 2005c) and in male rats exposed to 0.5 mg Cd/kg/day (Brzóska and 

Moniuszko-Jakoniuk 2005a, 2005b) for an intermediate duration and in female rats chronically exposed 

to 0.08 mg Cd/kg/day (Brzóska and Moniuszko-Jakoniuk 2004a, 2004b). In the series of studies 

conducted by Brzóska and associates, the occurrence of osteopenia and osteoporosis was evaluated using 

data for bone mineral density of the cadmium-exposed rats, control rats, and healthy adult rats. 

Osteopenia was observed in male rats exposed to 0.5 mg Cd/kg/day for 12 months (Brzóska and 

Moniuszko-Jakoniuk 2005a, 2005b) and in female rats exposed to 0.08 mg Cd/kg/day for 12 or 

18 months (Brzóska and Moniuszko-Jakoniuk 2004a, 2004b); osteoporosis was observed in male rats 

exposed to 4 mg Cd/kg/day for 12 months (Brzóska and Moniuszko-Jakoniuk 2005a, 2005b) and in 

female rats exposed to 0.08 mg Cd/kg/day for 24 months (Brzóska and Moniuszko-Jakoniuk 2004a, 

2004b). 

The decreases in bone mineralization resulted in altered mechanical properties (e.g., stiffness, load, 

displacement at load) of the vertebral body, femur, and tibia and increases in the number of animals with 

deformed or fractured lumbar spinal bone in female rats exposed to ≥0.2 mg Cd/kg/day for an 

intermediate duration (Brzóska and Moniuszko-Jakoniuk 2005d; Brzóska et al. 2004b, 2005b, 2005a, 

2005c; Ogoshi et al. 1989); increases in lumbar spine deformities were also observed in male rats exposed 

to 0.5 mg Cd/kg/day for 12 months (Brzóska and Moniuszko-Jakoniuk 2005a, 2005b) and in female rats 

exposed to 0.08 mg Cd/kg/day for 24 months (Brzóska and Moniuszko-Jakoniuk 2004a, 2004b). 

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CADMIUM 139 

3. HEALTH EFFECTS 

The studies by Brzóska and associates reported significant alterations in biochemical markers of bone 

turnover. During the first 6 months of a 1-year study, significant decreases in osteocalcin concentrations 

were observed in female rats exposed to ≥0.2 mg Cd/kg/day; no alterations were observed during the last 

6 months of the study (Brzóska and Moniuszko-Jakoniuk 2005d). Observed changes in alkaline 

phosphatase levels included decreases in total serum levels in the 4 mg Cd/kg/day group after 6, 9, or 

12 months of exposure, decreases in trabecular bone levels at ≥0.2 mg Cd/kg/day after 3, 6, or 9 months 

of exposure and at 0.5 mg Cd/kg/day at 12 months, decreases in cortical bone levels at 4 mg Cd/kg/day 

after 3 months of exposure, and increases in trabecular bone and cortical bone alkaline phosphatase at 

4 mg Cd/kg/day after 12 months (Brzóska and Moniuszko-Jakoniuk 2005d). Serum C-terminal 

telopeptides of type I collagen concentration (CTX) was significantly decreased after 3 or 6 months of 

exposure or increased after 9 or 12 months in rats exposed to ≥0.2 mg Cd/kg/day (Brzóska and 

Moniuszko-Jakoniuk 2005d). As noted by Brzóska and Moniuszko-Jakoniuk (2005d), these alterations in 

bone turnover markers indicate that cadmium exposure at the stage of intensive skeletal development 

leads to low bone turnover and induces high bone turnover due to enhanced resorption at the stage of 

consolidation of bone mass and at skeletal maturity. 

Decreased calcium content of bone and increased urinary calcium excretion are common findings in 

intermediate- and chronic-duration studies in the 0.2–8 mg Cd/kg/day range (Brzóska and MoniuszkoJakoniuk 2005d; Kawamura et al. 1978; Nogawa et al. 1981b; Pleasants et al. 1992; Watanabe et al. 

1986). In contrast, Kotsonis and Klaassen (1978) reported no change in bone calcification after a 

24-week exposure via drinking water at 8 mg/kg/day, and Kelman et al. (1978) reported no significant 

change in stable or radiolabeled calcium in any maternal rat tissues from a 3.8 mg/kg/day in drinking 

water for 22 days during gestation. 

Gender, age, and nutritional state appear to influence cadmium toxicity on bone. In the series of 

experiments conducted by Brzóska and associates, alterations in bone mineral density and the mechanical 

strength of the lumbar spine and femur were observed in female rats exposed to ≥0.2 mg Cd/kg/day and 

in male rats at 0.5 mg Cd/kg/day (Brzóska and Moniuszko-Jakoniuk 2005a, 2005b, 2005d; Brzoska et al. 

2005a, 2005c); no adverse bone effects were observed in males exposed to 0.2 mg Cd/kg/day. In the 

Ogoshi et al. (1989) study, decreases in the mechanical strength of the femur bone were observed in 

young rats (21 days of age) exposed to 0.8 mg Cd/kg/day for 4 weeks; however, no alterations in bone 

strength were observed in adult (24 weeks of age) or elderly (1.5 years of age) rats exposed to cadmium 

doses as high as 25.6 mg Cd/kg/day for 4 weeks. Adverse effects on bone are exacerbated by a calcium­

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CADMIUM 140 

3. HEALTH EFFECTS 

deficient diet (Itokawa et al. 1974; Kimura et al. 1974; Larsson and Piscator 1971; Wang and 

Bhattacharyya 1993; Wang et al. 1994), by ovariectomy (Bhattacharyya et al. 1988c), or by multiple 

rounds of gestation and lactation (Bhattacharyya et al. 1988b). 

Hepatic Effects. Liver damage is not usually associated with oral cadmium exposure, except at very 

high levels of exposure. In humans, a fatal dose of cadmium can cause pronounced liver damage 

(Buckler et al. 1986; Wisniewska-Knypl et al. 1971). Nishino et al. (1988) reported increased serum 

concentrations of the urea-cycle amino acids among individuals exposed to cadmium in the diet, and that 

these levels reflected liver as well as kidney damage. No cadmium-related alterations in liver biomarkers 

including serum levels of alkaline phosphatase, alanine aminotransferase, asparate aminotransferase, 

lactate dehydrogenase, and γ-glutamyl transpeptidase were observed in women living in cadmium nonpolluted areas in Japan (Ikeda et al. 1997, 2000). No other studies were located regarding hepatic effects 

in humans after oral exposure to cadmium. 

Hepatic effects have been found in rats, mice, and rabbits after oral cadmium exposure. Acute exposure 

via gavage at doses of 30–138 mg/kg/day causes liver necrosis in most studies (Andersen et al. 1988; 

Basinger et al. 1988; Borzelleca et al. 1989; Shimizu and Morita 1990), although histopathologic 

evidence of liver damage was not seen in one study at a gavage dose of 150 mg/kg (Kotsonis and 

Klaassen 1977). Exposure of rats for 10 days to drinking water containing 13.9 mg Cd/kg/day was 

without effect on the liver (Borzelleca et al. 1989). Depletion of liver glutathione by fasting increases the 

liver necrosis following acute oral exposure to cadmium in rats (Shimizu and Morita 1990). 

In a 10-week study, male Rhesus monkeys exposed to 4 mg/kg/day cadmium chloride via gavage, had a 

significant decrease in glutathione peroxidase in liver, kidney, heart, and lung in the following order: 

liver>kidney>heart>lung; a significant decrease in glutathione S-transferase (GST) activity towards 

1-chloro-2,4-dinitrobenzene in all four organs in the following order: liver>lung>kidney>heart; and a 

significant increase in GST activity towards ethacrynic acid in all four organs in the following order: 

heart>lung>kidney>liver (Sidhu et al. 1993). Intermediate-duration exposure causes histopathologic 

changes in the liver (e.g., necrosis of central lobules, focal hepatic fibrosis, biliary hyperplasia) at doses of 

1.6–15 mg/kg/day (Cha 1987; Gill et al. 1989b; Miller et al. 1974a; Schroeder et al. 1965; Stowe et al. 

1972; Wilson et al. 1941), and metabolic alterations (e.g., decreased cytochrome c oxidase activity in 

mitochondria, increased ALT and AST activities) at doses of 0.05–10 mg/kg/day (Groten et al. 1990; 

Muller and Stacey 1988; Muller et al. 1988; Sporn et al. 1970; Steibert et al. 1984; Tewari et al. 1986b). 

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CADMIUM 141 

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Decreased relative liver weight to body weight has also been reported in male rats fed 5.95 mg/kg/day for 

6 weeks (Kozlowska et al. 1993). 

Other intermediate and chronic duration studies have not found liver effects in animals following oral 

exposure. These studies include a daily gavage exposure of 14 mg/kg/day for 6 weeks in rats (Hopf et al. 

1990), a 3-month exposure to cadmium in food at 3 mg/kg/day in rats (Loeser and Lorke 1977a), a 

24-week exposure to cadmium in water at 8 mg/kg/day in rats (Kotsonis and Klaassen 1978), and a 

3-month exposure in food at 0.75 mg/kg/day in dogs (Loeser and Lorke 1977b). Kopp et al. (1982) report 

no hepatic effects from a chronic exposure of 18 months to cadmium in water at 0.65 mg/kg/day in rats. 

Renal Effects. Numerous studies indicate that the kidney is the primary target organ of cadmium 

toxicity following extended oral exposure, with effects similar to those seen following inhalation 

exposure (see Section 3.2.1.2). Most of the data involves chronic exposure to cadmium; two case reports 

involving acute exposure to large doses of cadmium also found kidney effects. In two fatal cases of oral 

cadmium poisoning, anuria was present in one individual who ingested 25 mg/kg cadmium as cadmium 

iodide. Damage to the kidneys was reported at autopsy, but was not further specified (Wisniewska-Knypl 

et al. 1971). The kidneys were reported as normal at autopsy in an individual who died 2 days after 

ingesting 1,840 mg/kg cadmium (Buckler et al. 1986). 

Several studies have found associations between increased mortality and renal dysfunction in residents 

living in cadmium polluted areas. Significant increases in SMRs were found in residents living in 

cadmium polluted areas of Japan with elevated levels of biomarkers of renal dysfunction (Arisawa et al. 

2001, 2007b; Iwata et al. 1991a, 1991b; Matsuda et al. 2002; Nakagawa et al. 1993; Nishijo et al. 1995, 

2004a, 2006). Among the studies that examined cause of death, significant increases in deaths from renal 

diseases were found in the residents that were categorized as biomarker-positive (urinary levels of the 

renal biomarker was higher than the cut-off value); the cut-off values used were β2-microglobulin 

≥1,000 μg/g creatinine (Arisawa et al. 2001, 2007b; Iwata et al. 1991a, 1991b; Nakagawa et al. 1993; 

Nishijo et al. 2004a, 2006) or retinol binding protein ≥4 mg/L (Nishijo et al. 1995). Other studies have 

found that mortality increased in proportion to the renal biomarker level (β2-microglobulin, protein, or 

glucose) (Iwata et al. 1991a, 1991b; Matsuda et al. 2002; Nakagawa et al. 1993; Nishijo et al. 2004a, 

2006). Increases in mortality from renal diseases have also been observed among populations living in 

cadmium polluted areas of Belgium (Lauwerys and De Wals 1981) and England (Inskip et al. 1982); 

however, statistical analysis was not reported in the Belgium study and the increase in renal disease was 

not statistically significant in the other study. 

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CADMIUM 142 

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Elevated levels of several biomarkers of renal dysfunction and/or associations between cadmium burden 

and these biomarkers have been found in studies of populations living in cadmium non-polluted areas of 

Japan (Ezaki et al. 2003; Ikeda et al. 1999; Suwazono et al. 2000; Oo et al. 2000; Uno et al. 2005; 

Yamanaka et al. 1998), Belgium (Buchet et al. 1990; Roels et al. 1981a), and the United States (Noonan 

et al. 2002) and in populations living in cadmium polluted areas of China (Cai et al. 1990, 1992, 1998; Jin 

et al. 2002, 2004a, 2004c; Nordberg et al. 1997; Wu et al. 2001), Japan (Cai et al. 2001; Hayano et al. 

1996; Ishizaki et al. 1989; Izuno et al. 2000; Kawada et al. 1992; Kido and Nogawa 1993; Kobayashi et 

al. 2002b; Monzawa et al. 1998; Nakadaira and Nishi 2003; Nakashima et al. 1997; Nogawa et al. 1989; 

Osawa et al. 2001; Watanabe et al. 2002), Thailand (Teeyakasem et al. 2007), Sweden (Järup et al. 2000; 

Olsson et al. 2002), and Poland (Trzcinka-Ochocka et al. 2004). Most of these studies did not estimate 

cadmium intake; rather, exposure was characterized based on the levels of cadmium in rice, blood, or 

urine. The oral route is assumed to be the primary route of exposure, although the inhalation route, 

particularly in smokers, may have contributed to the overall cadmium body burden. The epidemiology 

data are summarized in Table 3-7 and brief discussions of the better designed studies providing valuable 

dose-response data follows. 

Buchet et al. (1990) examined 1,699 non-occupationally exposed males and females (aged 20–80 years) 

living in Belgium. Urinary cadmium levels significantly correlated with urinary β2-microglobulin, retinol 

binding protein, NAG, amino acid, and calcium levels; the partial r2 values were 0.0036, 0.0210, 0.0684, 

0.0160, and 0.0168, respectively. The probability that individuals would have abnormal values for the 

renal biomarkers (defined as >95th percentile for subjects without diabetes or urinary tract diseases and 

who did not regularly take analgesics) was estimated using logistic regression models with adjustments 

for age, gender, smoking, disease, and use of analgesics. It was estimated that >10% of 

β2-microglobulin, retinol binding protein, amino acid, and calcium values would be abnormal when 

24-hour urinary cadmium levels were >3.05, 2.87, 2.74, 4.29, or 1.92 μg/24 hour, respectively. 

Järup et al. (2000) examined 1,021 individuals living near a nickel-cadmium battery plant in Sweden for 

at least 5 years (n=799) or employed as battery workers (n=222). The mean urinary cadmium levels were 

0.81 and 0.65 μg/g creatinine in males and females, respectively. Urinary cadmium levels were 

significantly associated with urinary human complex-forming glycoprotein (pHC; also referred to as 

α1-microglobulin) levels, after adjustment for age. The relationship remained statistically significant 

after removal of the cadmium workers from the analysis. The prevalence of abnormal pHC values 

(defined as exceeding the 95th percentile in a Swedish reference population; >7.1 and 5.3 mg/g creatinine 

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CADMIUM 143 

3. HEALTH EFFECTS 

Table 3-7. Summary of Human Studies Examining Renal Effects 

Mean urinary Effect 

Population studied cadmium level biomarker Results Reference 

General population 

(Japan) 

10,753 females; 35– 

60 years old 

General population 

(Japan) 

470 nonsmoking 

females 

General population 

(Japan) 

1,105 males, 

1,648 females; 

>50 years old 

General population 

(Japan) 

568 males, 

742 females; 

≥50 years old 

General population 

(Japan) 

558 males, 

743 females; 

≥50 years old 

General population 

(Japan) 

410 males, 

418 females; 40– 

59 years old 

General population 

(Belgium) 

175 females; mean 

age 81.1–82.3 years 

old 

1.26 μg/g creat. 

2.1 μg/g creat. 

1.8 μg/g creat. (M) 

2.4 μg/g creat. (F) 

2.2–3.4 μg/L (M) 

2.8–3.9 μg/L (F) 

1.3 μg/g creat. (M) 

1.3 μg/g creat. (F) 

0.8 μg/g creat. (M) 

1.8 μg/g creat. (F) 

(median levels) 

0.040–0.093 μg/hour 

β2M 

pHC 

β2M 

pHC 

β2M 

Total protein 

NAG 

total protein 

NAG 

β2M 

β2M 

total protein 

NAG 

β2M 

protein 

NAG 

β2M 

protein 

amino acids 

albumin 

Significant correlation between 

urinary cadmium and effect 

biomarkers; however, no 

significant relationship was 

established when age was 

factored into analysis. 

Significant correlation between 

urinary cadmium (not corrected 

for creat.) and pHC and β2M. 

Significant correlation between 

urinary cadmium and protein 

and β2M. Dose-response 

relationship between urinary 

cadmium and prevalence of 

abnormal effect biomarker 

levels. 

Significant correlation (with age 

adjustment) between urinary 

cadmium and effect 

biomarkers. 

Significant correlation between 

urinary cadmium and effect 

biomarkers (NAG was only 

significant in females). 

Dose-response relationship 

between urinary cadmium and 

prevalence of abnormal effect 

biomarker levels. 

Significant associations 

between urinary cadmium and 

effect biomarkers (protein only 

significant in males). 

Dose-response relationship 

between urinary cadmium and 

prevalence of abnormal effect 

biomarker levels. 

Dose-response relationship 

between urinary cadmium and 

urinary protein and amino 

acids; significant relationship 

with β2M and albumin only in 

the two areas with highest 

urinary cadmium levels. 

Ezaki et al. 

2003 

Ikeda et al. 

1999 

Suwazono et 

al. 2000 

Oo et al. 

2000 

Yamanaka et 

al. 1998 

Uno et al. 

2005 

Roels et al. 

1981a 

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CADMIUM 144 

3. HEALTH EFFECTS 

Table 3-7. Summary of Human Studies Examining Renal Effects 

Mean urinary Effect 

Population studied cadmium level biomarker Results Reference 

General population β2M Significant correlation between Buchet et al. 

(Belgium) protein urinary cadmium and effect 1990 

1,699 males, NAG biomarkers. 

females; 20–80 years amino acids Dose-response relationship 

old calcium between urinary cadmium and 

prevalence of abnormal effect 

biomarker levels. 

General population 0.07 μg/g creat. β2M No significant associations Noonan et al. 

(United States) (M, child) NAG (after correction for age, sex) 2002 

88 males, 0.08 μg/g creat. AAP between urinary cadmium and 

71 females; 6– (F, child) albumin effect biomarkers in children. 

17 years old; 0.24 μg/g creat. Significant association (after 

71 males, (M, adult) age and gender adjustment) 

80 females; 0.23 μg/g creat. between urinary cadmium and 

≥18 years old (F, adult) NAG and AAP in adults. Doseresponse relationship between 

urinary cadmium and NAG and 

AAP. 

Residents in 11.27 μg/g creat. β2M Significantly higher effect Cai et al. 

cadmium-polluted NAG biomarkers levels. 1990, 1992 

area (China) 

433 males and 

females 

Residents in β2M Significant dose-response Cai et al. 

cadmium-polluted relationship between urinary 1998 

area (China) cadmium, blood cadmium, and 

219 males and cumulative Cd intake and β2M; 

females prevalence of abnormal values. 

Residents in High: 11.18 μg/g β2M Significant correlation between Jin et al. 

cadmium-polluted creat. RBP urinary cadmium and effect 2002 

area (China) Mod.: 3.55 μg/g albumin biomarkers. 

118 males, creat. 

170 females in high Dose-response relationship 

exposure group between urinary cadmium and 

80 males, prevalence of abnormal effect 

158 females in biomarker levels. 

moderate exposure 

group 

Residents in β2M Dose-response relationship Jin et al. 

cadmium-polluted NAG between urinary cadmium and 2004c 

area (China) NAG-B prevalence of abnormal effect 

118 males, RBP biomarker levels. 

170 females in high albumin 

exposure group 

80 males, 

158 females in 

moderate exposure 

group 

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CADMIUM	 145 

3. HEALTH EFFECTS 

Table 3-7. Summary of Human Studies Examining Renal Effects 

Mean urinary Effect 

Population studied cadmium level biomarker Results Reference 

Residents in 

cadmium-polluted 

area (China) 

66 males, 22 females 

Residents in 

cadmium-polluted 

area (China) 

120 males, 

127 females in high 

exposure group 

125 males, 

122 females in 

moderate exposure 

group 

Residents in 

cadmium-polluted 

area (China) 

122 males, 

125 females 

Residents in 

cadmium-polluted 

area (Japan) 

127 males; mean 

age 72.1–73.6 years 

old 

Residents in 

cadmium-polluted 

area (Japan) 

1,178 females 

Residents in 

cadmium-polluted 

area (Japan) 

82 males, 56 females 

Residents in 

cadmium-polluted 

area (Japan) 

634 males, 

411 females 

Residents in 

cadmium-polluted 

area (Japan) 

1,419 males, 

1,745 females 

9.12 μg/g creat.		 β2M 

NAG 

albumin 

High: 9.40 μg/L (M)	 β2M 

12.13 μg/L (F) albumin 

Mod.: 1.28 μg/L (M) 

2.05 μg/L (F) 

6.1 μg/g creat. (M)	 β2M 

7.5 μg/g creat. (F) NAG 

calcium 

6.8–6.9 μg/g creat.	 β2M 

3.16–4.08 μg/g creat. β2M 

β2M 

Protein 

4.6 μg/g creat. (M)	 Potassium 

7.2 μg/g creat. (F)	 sodium 

Dose-response relationship 

between urinary cadmium and 

prevalence of abnormal effect 

biomarker levels. 

Dose-response relationship 

between urinary cadmium and 

prevalence of abnormal effect 

biomarker levels. 

Effect biomarkers significantly 

higher than controls. 

Dose-response relationship 

between urinary cadmium and 

effect biomarkers. 

Higher prevalence of abnormal 

effect biomarkers compared to 

controls. 

No significant association 

between urinary cadmium and 

effect biomarkers. 

Significant association between 

cadmium intake and effect 

biomarkers in males only. 

Significant association between 

cadmium intake and increased 

prevalence of abnormal levels 

of urinary protein in males. 

Significantly higher urinary 

potassium levels, compared to 

controls. Significant correlation 

between urinary potassium and 

urinary cadmium and β2M. 

Urinary sodium not significantly 

different than controls and not 

correlated with urinary 

cadmium. 

Jin et al. 

2004a 

Nordberg et 

al. 1997 

Wu et al. 

2001 

Cai et al. 

2001 

Horiguchi et 

al. 2004 

Izuno et al. 

2000 

Kobayashi et 

al. 2002a; 

Watanabe et 

al. 2002 

Monzawa et 

al. 1998 

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CADMIUM 146 

3. HEALTH EFFECTS 

Table 3-7. Summary of Human Studies Examining Renal Effects 

Mean urinary Effect 

Population studied cadmium level biomarker Results Reference 

Residents in 2.69 μg/g creat. (M) β2M Significant correlation between Nakadaira 

cadmium-polluted 4.68 μg/g creat. (F) pHC urinary cadmium and effect and Nishi 

area (Japan) NAG biomarkers (except β2M in 2003 

44 males, 54 females protein males). 

inorganic 

phosphorus 

Residents in β2M Significant correlation between Nakashima 

cadmium-polluted protein cadmium concentration in rice et al. 1997 

area (Japan) amino and effect biomarkers. 

832 males, nitrogen Dose-response relationship 

871 females between cadmium levels in rice 

and prevalence of abnormal 

β2M (males) and protein 

(females) levels. 

Residents in Protein Dose response relationship Osawa et al. 

cadmium-polluted between cadmium levels in rice 2001 

area (Japan) and prevalence of abnormal 

826 males, effect biomarker levels. 

641 females 

Residents in β2M Dose response relationship Nogawa et 

cadmium-polluted between cadmium in rice and al. 1989 

area (Japan) effect biomarkers. 

878 males, 

972 females 

Residents in 4.56 μg/g creat. (M) β2M β2M significantly higher than Ishizaki et al. 

cadmium-polluted 7.15 μg/g creat. (F) controls. 1989 

area (Japan) Dose-response relationship 

1,424 males, between urinary cadmium and 

1,754 females prevalence of abnormal β2M 

levels. 

Residents in β2M Dose response relationship Kido and 

cadmium-polluted between cadmium in rice and Nogawa 

area (Japan) prevalence of abnormal β2M 1993 

878 males, levels. 

972 females 

Residents in 4.56 μg/g creat. (M) β2M Dose response relationship Hayano et al. 

cadmium-polluted 7.15 μg/g creat. (F) between urinary cadmium and 1996 

area (Japan) prevalence of abnormal β2M 

1,403 males, levels. 

1,716 females; 

≥50 years old 

Residents in 1.78 μg/g creat. (M) NAG Significant correlation between Kawada et 

cadmium-polluted 2.27 μg/g creat. (F) urinary cadmium and NAG. al. 1992 

area (Japan) 

120 males, 

280 females 

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CADMIUM 147 

3. HEALTH EFFECTS 

Table 3-7. Summary of Human Studies Examining Renal Effects 

Mean urinary Effect 

Population studied cadmium level biomarker Results Reference 

Residents in 12 μg/g creat. β2M Significant correlation between Teeyakasem 

cadmium-polluted pHC urinary cadmium and effect et al. 2007 

area (Thailand) NAG biomarkers. 

58 males, 70 females protein Dose-response relationship 

albumin between urinary cadmium and 

prevalence of abnormal β2M 

levels. 

Residents in 0.81 μg/g creat. (M) pHC Linear relationship between Järup et al. 

cadmium-polluted 0.66 μg/g creat. (F) urinary cadmium and pHC 2000 

area (includes (relationship remained 

occupationally significant after removal of 

exposed subjects occupationally exposed 

(Sweden) subjects. 

Residents in 0.26 μg/g creat. β2M Significant correlation between Olsson et al. 

cadmium-polluted protein HC urinary and blood cadmium and 2002 

area (Sweden) NAG effect biomarkers. 

57 males, 48 females albumin β2M clearance was significantly 

explained by urinary cadmium 

levels. 

Residents in 0.97 μg/g creat. β2M In childhood exposure group, Trzcinkacadmium-polluted (childhood exposure) RBP significant correlations between Ochocka et 

area (Poland) 2.23 μg/g creat. NAG urinary cadmium and β2M, al. 2004 

44 males, (adult exposure) NAG-A RBP, and albumin. In adult 

128 females only NAG-B exposure group, significant 

exposed as adults albumin correlations between urinary 

72 males, 64 females cadmium and all effect 

exposed as children biomarkers. 

AAP = alanine aminopeptidase; β2M = β2-microglobulin; creat. = creatinine; F = female; M = male; Mod. = moderate;
 

NAG = N-acetyl-β-glucosaminidase; pHC = human complex-forming glycoprotein, also referred to as α1M;
	

RBP = retinol binding protein
 

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CADMIUM 148 

3. HEALTH EFFECTS 

for males and females, respectively) was estimated to increase by 10% at urinary cadmium levels of 

1 μg/g creatinine. The European Chemicals Bureau (2007) recalculated the probability of HC proteinuria 

(using the raw data from Järup and associates) to account for the differences in age of the reference 

population (mean of 40 years) and study population (mean of 53 years). Based on these recalculations, 

the urinary cadmium level associated with a 10% increased probability of abnormal pHC values (20% 

total probability) was 2.62 μg/g creatinine for the total population. In the environmental exposed 

subgroup, a urinary cadmium level of 0.5 μg/g creatinine was associated with a 13% probability 

(doubling of the probability in reference population) of abnormal pHC values. 

Noonan et al. (2002) examined residents in Pennsylvania living near a defunct zinc smelting facility 

(geometric mean urinary cadmium level of 0.14 μg/g creatinine) and a reference community located 

10 miles from the facility (geometric mean urinary cadmium levels of 0.12 μg/g creatinine). The data 

from the two communities were pooled because there were no differences in urinary cadmium levels 

between them. β2-microglobulin, NAG, alanine aminopeptidase (AAP), and albumin levels were 

measured as biomarkers of renal dysfunction. The geometric mean urinary cadmium levels were 0.07 and 

0.08 μg/g creatinine in 88 males and 71 females aged 6–17 years and 0.24 and 0.23 μg/g creatinine in 

71 males and 80 females aged ≥18 years. No significant correlations between urinary cadmium levels 

and renal biomarkers were observed in the children, after adjustment for creatinine, age, and gender. In 

adults, significant correlations (after adjustment for creatinine, age, gender, smoking, and self-reported 

diabetes or thyroid disease) between urinary cadmium and NAG (partial correlation coefficient of 0.20, 

95% CI of 0.05–0.36) and AAP (partial correlation coefficient of 0.21 and 95% CI of 0.05–0.36) were 

observed. Significant dose-effect relationships were also found for these two biomarkers. Urinary 

cadmium levels were not significantly associated with elevated levels of β2-microglobulin or albumin. 

Nogawa et al. (1980) examined 878 males and 972 females aged ≥50 years living in the Kakehashi River 

basin in Japan; the Kakehashi River, cadmium polluted from an upstream mine, was used to irrigate rice 

fields. β2-Microglobulin measured in morning urine samples was used as a biomarker of renal 

dysfunction and cadmium intake was estimated from rice samples collected in 1974. Cadmium levels in 

rice were considered to be representative of cadmium intake because over 70% of the total cadmium 

intake has been shown to come from rice. Cadmium in the rice ranged from 0.10 to 0.69 μg/g. 

β2-Microglobulin levels were significantly higher in the study population compared to a reference 

population of 113 males and 161 females living in a nearby area. A significant dose-related association 

between total cadmium intake and prevalence of abnormal β2-microglobulin values (defined as 

β2-microglobulin levels of ≥1,000 μg/g creatinine) was found. The total cadmium intake, which resulted 

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CADMIUM 149 

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in a prevalence of abnormal β2-microglobulin levels equal to the control group, was 1,678 mg in males 

(prevalence in controls was 6.0%) and 1,763 mg in females (prevalence in controls was 5.0%). A further 

analysis of the exposed subjects (Hochi et al. 1995) found that the prevalence of abnormal 

β2-microglobulin levels (using a cut-off level of 1,000 μg/g creatinine) exceeded the prevalence in the 

reference population when cadmium intake was ≥2 g and the subjects were divided into subgroups by 

age. The prevalence of abnormal β2-microglobulin levels at a given cadmium intake increased with age. 

Yamanaka et al. (1998) examined 558 males and 743 females aged ≥50 years living in a cadmium nonpolluted area in Japan. Urinary cadmium level was used as a biomarker of exposure and urinary 

β2-microglobulin, total protein, and NAG as biomarkers of renal dysfunction. The geometric mean 

urinary cadmium levels were 1.3 and 1.3 μg/g creatinine in males and females, respectively. Significant 

correlations (after adjustment for age) between urinary cadmium levels and total protein, 

β2-microglobulin, and NAG were found. Abnormal levels of renal biomarkers were defined as exceeding 

the 84% upper limit value calculated from a referent group of 2,778 non-exposed individuals; the cut-off 

values were 124.8 and 120.8 mg/g creatinine for total protein in males and females, 492 and 403 μg/g 

creatinine for β2-microglobulin, and 8.0 and 8.5 U/g creatinine for NAG. Dose-response relationships 

between urinary cadmium levels and prevalence of abnormal levels of β2-microglobulin, total protein, 

and NAG were found. The odds ratios (95% CI) were 6.589 (3.383–12.833), 3.065 (1.700–5.526), and 

1.887 (1.090–3.268) for protein, β2-microglobulin, and NAG in males and 17.486 (7.520–40.660), 

5.625 (3.032–10.435), and 2.313 (1.399–3.824) for protein, β2-microglobulin, and NAG in females. 

Another study of residents living in a cadmium non-polluted area of Japan examined 346 males and 

529 females from one area (area A) and 222 males and 413 females in another area (area B); all subjects 

were ≥50 years of age and were not occupationally exposed to heavy metals (Oo et al. 2000). The 

geometric mean urinary cadmium levels were 2.2 and 2.8 μg/L in males and females in area A and 

3.4 and 3.9 μg/L in area B. Significant correlations (with adjustment for age) were found between urinary 

cadmium and urinary levels of protein, β2-microglobulin (not significant in males in area B) and NAG 

levels. A significant association between urinary cadmium levels and the prevalence (cut-off levels from 

same referent population as Yamanaka et al. 1998) of abnormal levels of urinary protein (cut-off level of 

113.8 and 96.8 μg/L in males and females), β2-microglobulin (378 and 275 μg/L) (only significant in 

females in area A), and NAG (8.0 and 7.2 μg/L). The odds ratios (95% CI) for an increase in prevalence 

of abnormal renal biomarkers were 8.810 (3.401–22.819) and 11.282 (3.301–38.362) for protein in males 

in areas A and B, respectively, 8.234 (3.696–18.343) and 23.901 (8.897–64.210) for protein in females in 

areas A and B; 2.558 (1.246–5.248) for β2-microglobulin in females in area A; 47.944 (14.193–161.954) 

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CADMIUM 150 

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and 9.940 (3.153–31.340) for NAG in males in areas A and B; and 72.945 (21.873–243.263) and 

25.374 (9.452–68.117) for NAG in females in areas A and B. 

In a re-examination of the populations studied by Yamanaka et al. (1998) and Oo et al. (2000), Suwazono 

et al. (2000) measured cadmium levels in blood and urine and urinary levels of total protein, 

β2-microglobulin, and NAG in 1,105 males and 1,648 females over the age of 50 years. The geometric 

mean concentrations of cadmium in urine were 1.8 and 2.4 μg/g creatinine in males and females, 

respectively, and blood cadmium levels were 2.0 and 1.8 ng/g in males and females. After adjustment for 

age, significant associations between urinary cadmium levels and urinary protein and β2-microglobulin in 

males and females were found. Additionally, blood cadmium levels were significantly associated with 

urinary protein and NAG levels in males and urinary protein, β2-microglobulin, and NAG levels in 

females. Cut-off levels (defined as the 84% upper limit values from 424 male and 1,611 female 

nonsmoking subjects) of 157.4 and 158.5 mg/g creatinine for protein in males and females, respectively, 

507 and 400 μg/g creatinine for β2-microglobulin in males and females, respectively, and 8.2 and 

8.5 μg/g creatinine for NAG in males and females, respectively, were used to evaluate the prevalence of 

abnormal levels of renal biomarkers. Logistic regression analysis demonstrated significant associations 

between urinary cadmium levels and increased prevalence of abnormal levels of total protein (odds ratio 

of 3.923, 95% CI of 2.2028–7.590) and β2-microglobulin (odds ratio of 2.259, 95% CI of 1.372–3.717) in 

males; in females, significant associations were found for total protein (odds ratio of 7.763; 95% CI of 

4.231–14.243), β2-microglobulin (odds ratio of 2.259, 95% CI of 1.879–4.281), and NAG (odds ratio of 

1.882, 95% CI of 1.311–2.702). For blood cadmium levels, the only significant association found was for 

an increased prevalence of abnormal total protein levels in females (odds ratio of 3.490, 95% CI of 1.661– 

7.331). 

Jin et al. (2002) examined three populations living various distances from a nonferrous metal smelter. 

The geometric mean levels of urinary cadmium were 11.18 and 12.86 μg/g creatinine in males (n=294) 

and females (n=171) in the highly polluted area, 3.55 and 4.45 μg/g creatinine in males (n=243) and 

females (n=162) in the moderately polluted area, and 1.83 and 1.79 μg/g creatinine in males (n=253) and 

females (n=155) in the control area. Significant correlations were found between urinary (and blood) 

cadmium levels and renal biomarkers (β2-microglobulin, retinol binding protein, and albumin). Cut-off 

values for β2-microglobulin, retinol binding protein, and albumin of 300 μg/g creatinine, 300 μg/g 

creatinine, and 15 mg/g creatinine, respectively, were used to assess possible dose-response relationships 

(no additional information was provided); although 300 μg/g creatinine was reported as the cut-off values 

for β2-microglobulin, subsequent analysis of this data set (Jin et al. 2004c) reported a cut-off value of 

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CADMIUM 151 

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800 μg/g creatinine. Significant dose-response relationships between urinary (and blood) cadmium and 

the prevalence of abnormal levels of renal markers of kidney dysfunction were found. 

Unlike the studies discussed above, Hellström et al. (2001) used the incidence of renal replacement 

therapy (dialysis or kidney transplantation) as an indicator of renal dysfunction, in particular, end-stage 

renal disease. Residents of Kalmar County, Sweden were divided into four exposure groups: high 

exposure (workers at cadmium battery production facility), moderate (residents living within 2 km of the 

cadmium battery facility), low (residents living between 2 and 10 km of the facility), and no exposure 

(residents living at least 10 km from the facility); all subjects were 20–79 years of age. The MentelHaenszel rate ratio (MH-RR) for renal replacement therapy in the cadmium exposed group was 

1.8 (95% CI 1.3–2.3); among the environmentally exposed group, the MH-RR was 1.7 (95% CI 1.3–2.3). 

The age SRRs were 1.9 (95% CI 1.3–2.5) and 1.9 (95% CI 1.2–2.6) for subjects in the moderate exposure 

group aged 20–79 years or 40–79 years, respectively. The trend for increasing MH-RR with increasing 

exposure was statistically significant. The age SRRs were not significantly elevated in the low exposure 

group. The investigators noted that the causes of end stage renal disease were similar in the cadmium 

exposed and unexposed groups. When only primary renal diseases (excludes renal failure secondary to 

diabetes or vascular or systemic diseases) were considered, the MH-RR was 1.7 (95% CI 1.1–2.6) for all 

cadmium exposed individuals and 2.1 (95% CI 1.4–3.2) for cadmium exposed individuals aged 40– 

79 years. Although urinary cadmium levels were not assessed in this study, other studies in this area 

found mean urinary cadmium levels of 1.0 and 0.46 μg/g creatinine in residents living within 0.5 and 0.5– 

1 km, respectively, of the battery facility (Järup et al. 1995a) and 0.38 and 0.55 μg/g creatinine in men 

and women, respectively, living in the contaminated area (Alfvén et al. 2000). 

Although there is strong evidence to suggest a relationship between urinary cadmium excretion and 

excretion of renal biomarkers (particularly low molecular weight proteins such as β2-microglobulin, pHC, 

and retinol binding protein), there is less agreement about the significance of the early renal changes and 

the threshold urinary cadmium levels associated with renal damage. Several studies monitoring 

populations following a decrease in cadmium exposure have attempted to address the question of the 

reversibility of early renal changes. In Japan, cadmium-contaminated soil used in rice paddies was 

replaced resulting in decreasing urinary cadmium levels in residents consuming rice grown in these fields 

(Cai et al. 2001; Iwata et al. 1993; Kobayashi et al. 2008). Although, cadmium exposure decreased over 

the same time period, the levels of renal biomarkers increased (Cai et al. 2001; Iwata et al. 1993; Kido et 

al. 1988; Kobayashi et al. 2008) and the prevalence of abnormal values remained higher compared to the 

reference population (Cai et al. 2001). Although significant decreases in urinary cadmium levels were 

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CADMIUM 152 

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observed over time, cadmium burdens still remained high; urinary cadmium levels at the later time 

periods were 6.03–9.6 μg/g creatinine (Cai et al. 2001; Iwata et al. 1993; Kido et al. 1988). Kobayashi et 

al. (2008) found significant correlations (after adjustment for age) between the amount of time since soil 

replacement and increases in urinary levels of retinol binding protein, total protein, and glucose (males 

only). In contrast, a follow-up study of a portion of the population examined by Buchet et al. (1990) 

found small, but statistically significant, decreases in urinary cadmium levels and urinary levels of 

β2-microglobulin, NAG, and retinol binding protein (Hotz et al. 1999). Urinary cadmium levels in this 

study (0.6–0.9 μg/g creatinine at baseline and 0.5–0.8 μg/g creatinine at follow-up) were much lower than 

levels in the Japanese studies. Although the data are inconclusive, there is some indication of reversibility 

of renal damage associated with exposure to low levels of cadmium following a substantial decrease in 

cadmium intake. 

A number of investigators have examined different approaches to establishing a safe cadmium body 

burden (as assessed by urinary cadmium levels). Several benchmark dose analyses of data from 

populations living in cadmium non-polluted areas in Sweden (Suwazono et al. 2006) or Japan (Kobayashi 

et al. 2006; Uno et al. 2005) or cadmium polluted areas in Japan (Shimizu et al. 2006) or China (Jin et al. 

2004c) have been conducted. The analyses used urinary cadmium levels as a biomarker of cadmium 

exposure and the prevalence of abnormal levels of β2-microglobulin, pHC, protein, NAG, retinol binding 

protein, albumin, or glomerular filtration rate as biomarkers of renal effects. As summarized in Table 3-8, 

the BMDs for urinary cadmium levels vary widely between the studies depending on the renal biomarker 

and the cut-off level used. For example, when NAG is used as the effect biomarker, the BMD0.05 (dose 

associated with a 5% extra risk) values of 0.64, 12.0–10.8, and 6.36–7.74 μg/g creatinine were calculated 

by Suwazono et al. (2006), Kobayashi et al. (2006), and Jin et al. (2004c) when the 95% upper limit cutoff value of 3.6, 16.0–16.6, and 15.0 U/g creatinine, respectively, was used. The BMDL (95% confidence 

bound of the BMD) is typically considered a no adverse effect levels; the results of these benchmark 

doses analyses suggest that chronic exposure to cadmium resulting in urinary cadmium levels of 0.3– 

11.31 or 0.6–11.4 μg/g creatinine would be associated with a 5 or 10% additional risk of renal 

dysfunction. 

Ikeda and associates used regression analysis to predict a threshold urinary cadmium level. Plotting 

urinary cadmium levels against β2-microglobulin levels taken from published data from populations 

living in cadmium polluted and non polluted areas of Japan resulted in a distribution shaped like the letter 

“J”. The threshold level was defined as the point of flexion in the “J” shaped curve. In the first 

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Table 3-8. Benchmark Dose Estimations of Urinary Cadmium Levels 

Study 

population 

Effect 

biomarker 

Response 

criterion 

BMD 

model 

5% BMR 

BMD BMDL 

10% BMR 

BMD BMDL Reference 

General 

population 

(Sweden) 

790 females; 

53–64 years old 

NAG 

pHC 

Estimated 

3.6 U/g creat. 

(95% cut-off)a 

6.8 mg/g creat. 

(95% cut-off)a 

78.5 

0.64 

0.63 

1.08 

0.50 

0.49 

0.70 

1.08 

1.05 

1.80 

0.83 

0.81 

1.18 

Suwazono et 

al. 2006 

GFR mL/minute 

(95% cut-off)a 

Residents in 

cadmiumpolluted 

(1,397 males, 

1,706 females) 

and cadmium 

nonpolluted 

areas (Japan) 

(130 males, 

159 females); 

≥50 years old 

β2M 507 μg/g creat. 

(M) 

400 μg/g creat. 

(F) 

(84% cut-off)b 

Quantal 

linear 

model 

507 μg/g creat. 

(M) 

400 μg/g creat. 

(F) 

(84% cut-off)b 

Loglogistic 

model 

994 μg/g creat. 

(M) 

784 μg/g creat. 

(F) 

(95% cut-off)c 

Quantal 

linear 

model 

1.5 (M) 

1.4 (F) 

3.7 (M) 

2.6 (F) 

2.3 (M) 

1.7 (F) 

1.2 (M) 

1.1 (F) 

2.9 (M) 

1.5 (F) 

1.8 (M) 

1.4 (F) 

3.1 (M) 

2.9 (F) 

5.1 (M) 

6.3 (F) 

4.7 (M) 

3.5 (F) 

2.5 (M) 

2.3 (F) 

4.2 (M) 

2.7 (F) 

3.7 (M) 

2.9 (F) 

Shimizu et 

al. 2006 

994 μg/g creat. 

(M) 

784 μg/g creat. 

(F) 

(95% cut-off)c 

Loglogistic 

model 

4.8 (M) 

4.4 (F) 

3.9 (M) 

3.2 (F) 

6.3 (M) 

6.4 (F) 

5.5 (M) 

5.1 (F) 

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CADMIUM 154 

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Table 3-8. Benchmark Dose Estimations of Urinary Cadmium Levels 

Study Effect Response BMD 5% BMR 10% BMR 

population biomarker criterion model BMD BMDL BMD BMDL Reference 

General Protein 157 mg/g Log- 3.6 (M) 3.1 (M) 5.6 (M) 4.9 (M) Kobayashi et 

population creat. (M) logistic 4.8 (F) 4.2 (F) 7.5 (F) 6.6 (F) al. 2006 

(Japan) 159 mg/g model 

1,114 males, creat. (F) 

1,664 females (84% cut-off)d 

309 mg/g 10.6 (M) 6.8 (M) 15.3 (M) 9.6 (M)
 

creat. (M) 8.7 (F) 7.3 (F) 12.0 (F) 9.9 (F)
 

311 mg/g 

creat. (F)
 

(95% cut-off)e
 

β2M 507 μg/g creat. 2.9 (M) 2.4 (M) 5.0 (M) 4.0 (M) 

(M) 3.8 (F) 3.3 (F) 6.6 (F) 5.5 (F) 

400 μg/g creat. 

(F) 

(84% cut-off)d
 

994 μg/g creat. 6.4 (M) 4.5 (M) 10.2 (M) 7.1 (M)
 

(M) 8.7 (F) 7.3 (F) 12.0 (F) 9.9 (F) 

784 μg/g creat. 

(F)
 

(95% cut-off)e
 

NAG 8.2 U/g creat. 4.8 (M) 3.3 (M) 8.3 (M) 5.7 (M) 

(M) 4.7 (F) 3.7 (F) 8.3 (F) 6.4 (F) 

8.5 U/g creat. 

(F)
 

(84% cut-off)d
 

16.0 U/g creat. 12.0 (M) 7.7 (M) 16.4 (M) 10.3 (M) 

(M) 10.8 (F) 8.5 (F) 14.8 (F) 11.4 (F) 

16.6 U/g creat. 

(F) 

(95% cut-off)e 

General Protein 70 mg/g creat. Quantal 0.9 (M) 0.6 (M) 1.9 (M) 1.2 (M) Uno et al. 

population (M) linear 3.2 (F) 1.8 (F) 6.6 (F) 3.6 (F) 2005 

(Japan) 70 mg/g creat. model 

410 males, (F) 

418 females; (84% cut-off)f 

40–59 years old β2M 233 μg/g creat. 0.5 (M) 0.4 (M) 1.0 (M) 0.7 (M) 

(M) 0.9 (F) 0.8 (F) 1.8 (F) 1.3 (F) 

274 μg/g creat. 

(F) 

(84% cut-off)f 

NAG 2.4 U/g creat. 0.3 (M) 0.3 (M) 0.7 (M) 0.6 (M) 

(M) 0.8 (F) 0.6 (F) 1.6 (F) 1.2 (F) 

2.5 U/g creat. 

(F)
 

(84% cut-off)f
 

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Table 3-8. Benchmark Dose Estimations of Urinary Cadmium Levels 

Study Effect Response BMD 5% BMR 10% BMR 

population biomarker criterion model BMD BMDL BMD BMDL Reference 

Residents in NAG 15.0 U/g creat. Quantal 6.36 (M) 5.83 (M) Jin et al. 

cadmium highly (95% cut-off)g linear 7.74 (F) 5.46 (F) 2004c 

polluted area NAG logistic -B 4.0 U/g creat. 4.88 (M) 3.98 (M) (China) regression (95% cut-off)g 4.24 (F) 3.70 (F) 123 males, model β2M 800 μg/g creat. 5.86 (M) 4.74 (M) 171 females (95% cut-off)g 9.98 (F) 8.47 (F) Residents in 

cadmium RBP 0.300 mg/g 5.99 (M) 4.87 (M) 

moderately creat. 9.03 (F) 7.63 (F) 

polluted area (95% cut-off)g 

(China) albumin 25.0 mg/g 16.72 11.18 

81 males, creat. (M) (M) 

162 females (95% cut-off)g 14.42 (F) 11.31 (F) 

a

95th percentile of effect biomarkers on the “hypothetical” control distribution at a urinary cadmium level of zero.
 b

84% upper limit values from a group of 424 males and 1,611 females who did not smoke and lived in three different
 

cadmium nonpolluted areas.
 c

95% upper limit values from a group of 424 males and 1,611 females who did not smoke and lived in three different
 

cadmium nonpolluted areas.

d

84% upper limit value of the target population of people who have not smoked.

e

95% upper limit value of the target population of people who have not smoked.
 f

84% upper limit value of the target population.

g

95% upper limit value from a control group 98 males and 155 females living in a cadmium nonpolluted area.
 

BMD = benchmark dose; BMDL = lower 95% confidence limit on the benchmark dose; BMR = benchmark response;
 

β2M = β2-microglobulin; creat. = creatinine; F = female; M = male; NAG = N-acetyl-β-D-glucosaminidase;
 

NAG-B = N-acetyl-β-D-glucosaminidase’s isoform B; RBP = retinol binding protein
 

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investigation (Ikeda et al. 2003b), the point of flexion was estimated as the point of intersection between 

two regression lines: one with no elevation in β2-microgloublin from non-exposed populations and the 

other when β2-microglobulin was >400 or >1,000 μg/g creatinine using data from exposed populations. 

Although no specific data were given for the two populations, the investigators noted that the highest 

urinary cadmium levels in the non-exposed populations were 5.6 and 3.6 μg/g creatinine in females and 

males, respectively. The points of intersection of the regression lines were 11.0 and 11.7 μg/g creatinine 

in females using the >400 and 1,000 μg/g creatinine criteria, respectively, and 10.0 and 11.0 μg/g 

creatinine in males. The second investigation also used published data on Japanese populations living in 

polluted and non-polluted areas (Ikeda et al. 2005b). The urinary cadmium levels ranged from 0.2 to 

7.8 μg/g creatinine and from 0.8 to 31.6 μg/g creatinine in the non-polluted and polluted areas, 

respectively, and the data for the two populations were combined. Plotting urinary cadmium levels 

against β2-microglobulin levels showed that there was a marked increase in β2-microglobulin levels 

(levels exceeded 1,000 μg/g creatinine) when urinary cadmium levels exceeded 4 μg/g creatinine. The 

urinary cadmium levels at the point of intersection of the regression line for urinary cadmium levels of 

≤2 or ≤5 μg/g creatinine was 6.7 and 6.7 μg/g creatinine using ordinary scales and 3.7 and 3.7 μg/g 

creatinine using double logarithmic scales. These urinary cadmium levels corresponded to β2-microglobluin levels of 139 and 267 μg/g creatinine with the ordinary scales and 118 and 118 μg/g creatinine 

using the double logarithmic scales. Using these regression equations and a critical β2-microglobulin 

level of 1,000 μg/g creatinine resulted in urinary cadmium levels of 7.6 (ordinary scales) or 8.1 (double 

logarithmic scales) μg/g creatinine. Based on this analysis, the investigators concluded that at urinary 

cadmium levels of >4 μg/g creatinine, there is a substantial increase in β2-microglobulin levels (Ikeda et 

al. 2005b). 

A third approach used to identify a threshold level was a meta-analysis conducted by Gamo et al. (2006) 

using published data on environmentally exposed populations. Urinary cadmium was used as a 

biomarker of exposure and the prevalence of abnormal levels of β2-microglobulin as an indicator of renal 

dysfunction. The investigators estimated maximum permissible geometric mean urinary cadmium levels 

in age- and gender-specific populations that would not result in a significant increase in the prevalence of 

abnormal β2-microglobulin levels. They concluded that the geometric mean urinary cadmium level for a 

population in a small geographical area should not exceed 3 μg/g creatinine; in a nationwide population, 

the geometric mean should not exceed 2 μg/g creatinine. 

Numerous studies in rats, mice, and rabbits confirm that oral exposure to cadmium causes kidney damage 

including proteinuria and tubular damage (Andersen et al. 1988; Bernard et al. 1980, 1988a, 1992; 

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Bomhard et al. 1984; Borzelleca et al. 1989; Cardenas et al. 1992a, 1992b; Cha 1987; Fingerle et al. 1982; 

Gatta et al. 1989; Gill et al. 1989b; Itokawa et al. 1974; Kawamura et al. 1978; Kotsonis and Klaassen 

1978; Kozlowska et al. 1993; Mangler et al. 1988; Masaoka et al. 1994; Pleasants et al. 1992, 1993; 

Prigge 1978a; Steibert et al. 1984; Stowe et al. 1972; Wilson et al. 1941). Histopathological findings 

include focal necrosis of proximal tubular epithelial cells and cloudy swelling in renal tubules (Cha 1987). 

Some studies have also shown no effect on renal function (Basinger et al. 1988; Borzelleca et al. 1989; 

Boscolo and Carmignani 1986; Groten et al. 1990; Jamall et al. 1989; Loeser and Lorke 1977a, 1977b). 

In acute-duration gavage studies in rats, decreased urine flow (Kotsonis and Klaassen 1977) and 

histopathologic evidence of kidney damage have been reported (Borzelleca et al. 1989) at the very high 

doses of 150 and 138 mg/kg/day, respectively. No effect on renal function was reported in rats receiving 

13.9 mg/kg/day for 10 days in drinking water (Borzelleca et al. 1989). Mice treated with a single gavage 

dose showed tubular necrosis at 88.8 mg/kg in one study (Andersen et al. 1988), but no effects on the 

kidney in another study at a dose of 112 mg/kg (Basinger et al. 1988). Proteinuria is a common finding in 

intermediate-duration oral exposure studies in rats (Bernard et al. 1988a; Cardenas et al. 1992a, 1992b; 

Kotsonis and Klaassen 1978; Prigge 1978a), as are histopathologic changes in the kidney (Gatta et al. 

1989; Itokawa et al. 1974; Kotsonis and Klaassen 1978; Wilson et al. 1941). Renal clearance was 

decreased in one study (Kawamura et al. 1978). Both increases (Pleasants et al. 1992, 1993) and 

decreases (Kozlowska et al. 1993) in relative kidney weight have been reported. These effects occurred 

in rats at doses ranging from 2 to 30 mg/kg/day. No renal effects were seen in dogs receiving 

0.75 mg/kg/day cadmium for 3 months (Loeser and Lorke 1977b), but interstitial renal fibrosis was 

observed in rabbits exposed to 14.9 mg/kg/day for 200 days (Stowe et al. 1972). Renal dysfunction has 

been reported in Rhesus monkeys exposed to 1.2 mg/kg/day for 9 years, but not at 0.4 mg/kg/day 

(Masaoka et al. 1994). Adverse renal effects are common in rats following chronic-duration oral 

exposure to cadmium. Proteinuria (Bernard et al. 1992; Bomhard et al. 1984) and histopathologic damage 

(Fingerle et al. 1982; Mangler et al. 1988) have been reported at doses ranging from 1.8 to 

12.5 mg/kg/day cadmium. 

The hypothesis that a critical concentration of approximately 200 μg/g in the renal cortex must be reached 

before proteinuria develops is generally supported by the animal data (Bhattacharyya et al. 1988c; 

Kotsonis and Klaassen 1978; Mangler et al. 1988; Shaikh et al. 1989; Viau et al. 1984). 

Endocrine Effects. Using data from the NHANES 1988–1994, Schwartz et al. (2003) investigated 

possible associations between cadmium exposure (as measured by urinary cadmium levels) and the 

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prevalence of impaired fasting glucose and diabetes. Analysis on 8,722 participants of the survey 

(≥40 years old) showed a dose-related increase in both impaired fasting glucose and diabetes after 

adjusting for age, ethnicity, sex, and BMI. No other studies were located regarding endocrine effects in 

humans after oral exposure to cadmium. 

Evidence for endocrine effects in animals after oral exposure to cadmium is limited to histopathologic 

examination of endocrine tissues. No adverse effects were seen in parathyroid glands from female Wistar 

rats exposed to 8 mg Cd/kg/day via drinking water for 90 days (Kawamura et al. 1978) or in adrenal gland 

from male Sprague-Dawley rats exposed to 8 mg/kg/day via drinking water for 24 weeks (Kotsonis and 

Klaassen 1978). Pituitary, adrenals, thyroid, and thymus were unaffected in Wistar rats exposed to 

3 mg/kg/day cadmium via feed for 3 months (Loeser and Lorke 1977a). Wilson et al. (1941) reported 

pancreatic atrophy and pancreatitis in rats from cadmium at 2.79 mg/kg/day via feed for 100 days. In 

rabbits exposed to 14.9 mg Cd/kg body weight/day via drinking water for 200 days, the pancreas had 

moderate concentrations of cadmium, but no interstitial fibrosis or other pathologic alterations (Stowe et 

al. 1972). 

Dermal Effects. No studies were located regarding dermal effects in humans after oral exposure to 

cadmium. 

Coarse fur was reported in Long-Evans rats receiving 6.13 mg/kg/day cadmium during Gd 6–15 

(Machemer and Lorke 1981). A ruffled hair coat was reported in Wistar rats receiving 40 mg/kg/day 

cadmium by gavage 5 days/week for 14 weeks (Baranski and Sitarek 1987). No other reports of dermal 

effects after oral exposure to cadmium were located. 

Ocular Effects. No studies were located regarding ocular effects in humans or animals after oral 

exposure to cadmium. 

Body Weight Effects. No studies were located regarding body weight effects in humans after oral 

exposure to cadmium. 

Decreased body weight and decreased rates of growth are common findings in studies where experimental 

animals are orally exposed to cadmium. Sprague-Dawley rats receiving a single gavage dose of 

150 mg/kg cadmium exhibited a 12% decrease in body weight, but 100 mg/kg had no effect (Kotsonis 

and Klaassen 1977). Daily gavage doses of 15.3 mg/kg over a 10-day period caused a 79% decrease in 

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CADMIUM 159 

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body weight gain in male Sprague-Dawley rats (Borzelleca et al. 1989). Significant reductions in 

maternal weight gain have also been reported (Baranski 1985; Machemer and Lorke 1981). 

Body weight reductions are also seen in intermediate-duration studies. For example, in a 14-week 

exposure via drinking water in male Long-Evans rats, 2.9 mg/kg/day had no effect on body weight gain; 

however, 5.8 mg/kg/day caused a 6–23% decrease and 11.6 mg/kg/day caused a 47–58% decrease 

(Pleasants et al. 1992, 1993). In general, intermediate-duration doses in feed or drinking water of 

≤3 mg/kg/day have either no effect or only a small effect (10–20% decrease) on body weight in rats 

(Carmignani and Boscolo 1984; Jamall et al. 1989; Loeser and Lorke 1977a; Muller et al. 1988; Ogoshi et 

al. 1989; Perry et al. 1989; Wilson et al. 1941). Higher doses (4–14 mg/kg/day) had no effect in some 

studies (Kostial et al. 1993; Kotsonis and Klaassen 1978; Prigge 1978a; Viau et al. 1984) and small 

effects in others (Cha 1987; Kawamura et al. 1978; Kozlowska et al. 1993). A 29% decrease in maternal 

weight gain was observed in rats exposed to a high dose of 40 mg/kg/day (Baranski and Sitarek 1987). In 

mice, a dose of 4.8 mg/kg/day had no effect on maternal weight gain, but a dose of 9.6 mg/kg/day caused 

a 14% decrease (Webster 1978). A high dose of 232 mg/kg/day in mice caused a 29% decrease in body 

weight (Waalkes et al. 1993). Beagle dogs were unaffected at 0.75 mg/kg/day (Loeser and Lorke 1977b), 

as were rabbits at up to 2.2 mg/kg/day (Boscolo and Carmignani 1986; Tomera and Harakal 1988). A 

small decrease (11%) was seen in rabbits exposed to 14.9 mg/kg/day for 200 days (Stowe et al. 1972). 

A chronic-duration study in Rhesus monkeys reported decreased growth rates at 0.4 mg/kg/day, but no 

effect at 0.12 mg/kg/day (Masaoka et al. 1994). No effect on body weight was seen in rats at up to 

4.4 mg/kg/day (Decker et al. 1958; Fingerle et al. 1982; Mangler et al. 1988), but a small effect was seen 

at 7 mg/kg/day (Waalkes and Rehm 1992). Decreased terminal body weight was observed in mice after 

12 months of drinking-water exposure to a high dose of 57 mg/kg/day (Hays and Margaretten 1985). 

Metabolic Effects. Hyperthermia and metabolic acidosis were reported in a human male who had 

ingested 25 mg/kg cadmium as cadmium iodide (Wisniewska-Knypl et al. 1971). 

No studies were located regarding metabolic effects in animals after oral exposure to cadmium. 

3.2.2.3 Immunological and Lymphoreticular Effects 

No studies were located regarding immunological effects in humans after oral exposure to cadmium. 

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Numerous studies in rats, mice, and monkeys have established the capability of cadmium to affect the 

immune system, but the clinical significance of the effects is not clear. In mice, intermediate-duration 

oral exposure to cadmium has been shown to increase resistance to viral infection (Exon et al. 1986), to 

be without effect on natural or acquired resistance to infection (Bouley et al. 1984), and to increase 

mortality from virally-induced leukemia (Blakley 1986; Malave and de Ruffino 1984). Oral cadmium 

exposure has also been found to suppress the humoral immune response of mouse splenic cells to sheep 

red blood cell antigen in 6-week-old mice (Blakley 1985), but not in 12-month-old mice (Blakley 1988). 

The author suggests that “natural” age-related immune system dysfunction masked any cadmium 

suppressive effect in the 12-month-old mice, and that immunotoxicological investigations in aged models 

appear to be a poor indicator of immune response in the general population. Oral cadmium exposure has 

also been found to increase the cell-mediated immune response of monkeys (Chopra et al. 1984), to 

induce anti-nuclear antibodies in mice (Ohsawa et al. 1988), to increase circulating leukocytes in female 

rats (Borzelleca et al. 1989), and to exhibit time-dependent inhibitory and stimulative effects (Cifone et al. 

1989b) or no effect (Stacey et al. 1988a) on natural killer cell activity in rats. The highest NOAEL values 

and all LOAEL values from each reliable study for immunological effects in each species and duration 

category are recorded in Table 3-6 and plotted in Figure 3-2. 

3.2.2.4 Neurological Effects 

A few studies have reported an association between environmental cadmium exposure and neuropsychological functioning. These studies used hair cadmium as an index of exposure (see Section 3.8.1 for a 

discussion of the limitations of using hair as an indicator of exposure). End points that were affected 

included verbal IQ in rural Maryland children (Thatcher et al. 1982), acting-out and distractibility in rural 

Wyoming children (Marlowe et al. 1985), and disruptive behavior in Navy recruits (Struempler et al. 

1985). The usefulness of the data from these studies is limited because of the potential confounding 

effects of lead exposure; lack of control for other possible confounders including home environment, 

caregiving, and parental IQ levels; and an inadequate quantification of cadmium exposure. 

Although cadmium-induced neurotoxicity has not been clearly demonstrated in human studies, it has been 

observed in animal studies. Both a single oral exposure (Kotsonis and Klaassen 1977) and intermediateduration exposure of adult rats to cadmium resulted in significantly decreased motor activity (Kotsonis 

and Klaassen 1978; Nation et al. 1990). Intermediate-duration oral exposure to cadmium has also been 

reported to cause weakness and muscle atrophy (Sato et al. 1978), induce aggressive behavior (Baranski 

and Sitarek 1987), induce anxiety as manifested by increased passive avoidance behavior (Nation et al. 

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1984) and by increased ethanol consumption (Nation et al. 1989), and alter brain biogenic amine content 

and enzyme activities (Murthy et al. 1989). Doses associated with these effects range from 5 to 

40 mg/kg/day cadmium. Degenerative changes in the choroid plexus have been reported in mice exposed 

to 1.4 mg/kg/day cadmium in drinking water for 22 weeks (Valois and Webster 1989). Peripheral 

neuropathy has been reported in rats after a 31-month exposure to cadmium in drinking water (Sato et al. 

1978). Neurological effects in offspring of animals orally exposed to cadmium during gestation are 

discussed in Section 3.2.2.5. The highest NOAEL values and all LOAEL values from each reliable study 

for neurological effects in each species and duration category are recorded in Table 3-6 and plotted in 

Figure 3-2. 

3.2.2.5 Reproductive Effects 

Several studies have examined the possible association between increased cadmium exposure and male 

reproductive toxicity; however, most studies focused on sex steroid hormone levels and the results appear 

to be inconsistent. Akinloye et al. (2006) found significant associations between increasing blood 

cadmium levels and increasing levels of serum luteinizing hormone, follicle stimulating hormone, 

prolactin, and testosterone among infertile men (sperm counts <20 million/cm3 or no spermatozoa in 

semen). A significant association between increased blood cadmium levels and increased serum 

testosterone was also found in a group of workers with slight to moderate lead exposure (Telišman et al. 

2000); however, neither study controlled for smoking. A study by Jurasović et al. (2004) found 

significant associations between blood cadmium levels and increased serum estradiol, follicle stimulating 

hormone, and testosterone levels in infertile men after adjusting for age, smoking, alcohol consumption, 

and biomarkers of lead, copper, zinc, and selenium. In contrast, a study of Chinese men living in areas 

with high levels of cadmium in rice did not find significant correlations between urinary or blood 

cadmium levels and serum testosterone, follicle stimulating hormone, or luteininzing hormone levels after 

adjusting for BMI, age, smoking, and alcohol consumption (Zeng et al. 2004a). However, they did find 

that the prevalence of abnormally elevated serum testosterone levels (>95th percentile for controls) 

increased with exposure to cadmium. Using NHANES III data, Menke et al. (2008) found significant 

associations between urinary cadmium levels and serum testosterone and estradiol levels, but the 

associations were no longer significant after adjusting from smoking status and serum cotinine levels. 

Differences in study populations (e.g., infertile men, background cadmium exposure, high cadmium 

dietary exposure) and confounding factors (e.g., smoking, lead exposure) limit the interpretation of these 

results. 

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Three studies examined the possible association between cadmium exposure and sperm quality. In 

infertile men, increasing serum cadmium levels were significantly associated with abnormal sperm 

morphology and decreased sperm counts, sperm motility, and sperm viability (Akinloye et al. 2006). 

Another study found significant associations between blood cadmium levels and abnormal sperm 

morphology and decreased sperm motility in workers with slight to moderate lead exposure (Telišman et 

al. 2000). As noted previously, neither study adjusted for smoking. No significant correlations between 

blood cadmium levels and sperm quality were observed in infertile men with or without adjustment for 

smoking (Jurasović et al. 2004). Among men exposed to high levels of environmental cadmium, blood 

cadmium levels were significantly higher in men with abnormal digital rectal examinations of the prostate 

and trend analysis showed a dose-response relationship between cadmium exposure and the prevalence of 

abnormal prostate specific antigen (Zeng et al. 2004b). 

No studies were located regarding reproductive effects in women after oral exposure to cadmium, 

A number of animal studies have shown adverse reproductive effects to male and female reproductive 

capacity from cadmium exposure. In male rats and mice, acute oral exposure to near-lethal (60– 

100 mg/kg) doses can cause testicular atrophy and necrosis (Andersen et al. 1988; Bomhard et al. 1987; 

Borzelleca et al. 1989), and concomitant decreased fertility (Kotsonis and Klaassen 1978). Lower-dose 

acute exposures of 25–50 mg/kg did not result in reproductive toxicity in male animals (Andersen et al. 

1988; Bomhard et al. 1987; Dixon et al. 1976). 

The following intermediate-duration dosing regimens resulted in neither testicular histopathologic lesions 

nor a decrease in male reproductive success: 0.25 mg Cd/kg/day via gavage for 10 weeks (Bomhard et al. 

1987); 5 mg/kg/day via water for 30–90 days (Dixon et al. 1976); 2.5 mg/kg/day via food for 4 weeks 

(Groten et al. 1990); 8 mg/kg/day via water for 24 weeks (Kotsonis and Klaassen 1978); 3 mg/kg/day via 

food for 12 weeks (Loeser and Lorke 1977a, 1977b); 2.9 mg/kg/day via water for 14 weeks (Pleasants et 

al. 1992); and 4.64 mg/kg/day via water for 70–80 days (Zenick et al. 1982). Some dosing regimens have 

resulted in adverse reproductive effects. Male rats exposed to 8.58 mg Cd/kg/day in water for 10 weeks 

developed necrosis and atrophy of seminiferous tubule epithelium (Cha 1987). Rats exposed to 

5.8 mg/kg/day via water for 14 weeks (Pleasants et al. 1992) or 11.6 mg/kg/day via water for 14 weeks 

(Pleasants et al. 1993) developed increased testes weight. Rats exposed to 12.9 mg/kg/day in water for 

120 days developed significantly increased relative testis weight, decreased sperm count and motility, 

decreased seminiferous tubular diameter, and seminiferous tubular damage (pyknotic nuclei, 

multinucleated giant cells, interstitial edema, and dilated blood vessels) (Saxena et al. 1989). In a 

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protocol designed to assess the effects of vitamins on cadmium toxicity, Pleasants et al. (1992, 1993) 

reported that vitamins A and D3 reduced the amount of cadmium-related increase in testis weight. 

Bomhard et al. (1987) reported no histopathologic lesions (other than those found in control animals as 

part of aging) in testes of rats receiving 10 weekly doses of 5 mg Cd/kg and followed for up to 30 months. 

Higher doses of cadmium were generally needed to elicit a reproductive toxic response in females 

compared to the males. Although a dose of 65.6 mg Cd/kg/day via gavage for 10 days was sufficient to 

produce testicular atrophy and loss of spermatogenic element in male rats, no effects were seen in female 

rats up to 138 mg/kg/day (Borzelleca et al. 1989). Decreased percentage of fertilized females and 

percentage of pregnancies were reported at 61.32 mg Cd/kg/day via gavage for 10 days during gestation 

(Gd 6–15) (Machemer and Lorke 1981). No effect was seen at doses up to 18.39 mg/kg/day (Machemer 

and Lorke 1981). Baranski (1987) also reported no treatment related effects on number or percentage of 

females pregnant with 28.8 mg Cd/kg/day via gavage for gestation days (Gds) 1–20. Baranski and 

Sitarek (1987), however, administered 40 mg/kg by gavage 5 days/week for 14 weeks to female rats and 

observed a significant increased duration (twice as long) of the estrus cycle starting at 7–8 weeks and 

persisting to 14 weeks of exposure and the termination of the experiment. This adverse effect was not 

seen at 4 mg/kg (Baranski et al. 1983; Baranski and Sitarek 1987). 

Petering et al. (1979) exposed female rats to either 2.61 mg/kg/day via drinking water for 60 days prior to 

gestation or during gestation, or 5.23 mg/kg/day via drinking water for 111 days including 90 days prior 

gestation plus 21 days during gestation. These doses had no significant effects compared with controls 

for the number of pups stillborn. Pond and Walker (1975) also observed no effects in females from a 

cadmium exposure of 19.7 mg/kg/day via food for 21–25 days, including Gd 1 through lactation day (Ld) 

1, on number of pups born. No effects from a cadmium exposure on number of pups born to females 

were observed for an exposure of 8.2 mg/kg/day via food for 15 days, including Gd 6–20 (Sorell and 

Graziano 1990). 

A dose of 10 mg Cd/kg/day once a day via gavage for 9 weeks (6 weeks prior to gestation and 3 weeks of 

gestation) significantly decreased the number of copulating and pregnant females, and the number of 

implants and live fetuses (Sutou et al. 1980). No effect was seen at 1 mg/kg/day (Sutou et al. 1980). 

Reproductive effects on both male and female rats orally exposed to 2.5 mg/kg/day via drinking water for 

180 days may have resulted in the observed decrease in litter size and increased interval between litters. 

Both males and females were treated over two generations. Three of five pairs failed to breed in the 

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second generations (Schroeder and Mitchener 1971). No histopathologic lesions were found in testes or 

uteri of dogs given cadmium chloride at 0.75 mg/kg/day via food for 3 months (Loeser and Lorke 1977b). 

Male rats were exposed to 0–14 mg Cd/kg/day via food for 77 weeks. The incidence of prostatic 

hyperplasias was increased above controls (1.8%) from the 3.5 mg Cd/kg/day dose. The overall incidence 

for prostatic lesions for all cadmium-treated groups was much lower in zinc-deficient rats, possibly 

because of a marked increase in prostatic atrophy that was associated with reduced zinc intake. 

Moreover, there was not a clear dose-response increase in prostatic proliferative lesions. Testicular 

tumors (exclusively benign interstitial tumors) increased significantly only at the highest-dose cadmium 

with diets adequate in zinc. Male Wistar rats exposed to cadmium in the drinking water at 0, 25, 50, 100, 

or 200 ppm developed tumors of the prostate (50 ppm), testes (200 ppm), and hematopoietic system 

(50 ppm), while dietary zinc deficiency has complex, apparently inhibitory effects on cadmium 

carcinogenesis by this route (Waalkes and Rehm 1992). 

The highest NOAEL values and all LOAEL values from each reliable study for reproductive effects in 

each species and duration category are recorded in Table 3-6 and plotted in Figure 3-2. 

3.2.2.6 Developmental Effects 

There are very limited data on the developmental effects of cadmium in humans. Several studies have 

examined the possible relationship between maternal cadmium levels and newborn size. No significant 

association between maternal blood cadmium levels and newborn body weight were observed in women 

with mean blood cadmium levels of 0.7 μg/L (Mokhtar et al. 2002), 1.04 μg/L (Nishijo et al. 2004b), 

1.4 μg/L (Galicia-García et al. 1997), or 1.72 μg/L (Zhang et al. 2004) or urinary cadmium levels of 

>2 nmol/mmol creatinine (Nishijo et al. 2002); the Nishijo et al. (2002, 2004b), and Zhang et al. (2004) 

studies used statistical adjustments for maternal age, maternal size, and/or gestation age. Two studies 

found an association between cord blood cadmium levels and decreasing birthweight (Galicia-García et 

al. 1997; Salpietro et al. 2002); however, the association was only statistically significant in the Salpietro 

et al. (2002) study. A significant association between newborn height and maternal blood cadmium levels 

was observed in women with a mean blood cadmium level of 9.29 nmol/L (Nishijo et al. 2004b); other 

studies have not found this association (Mokhtar et al. 2002; Nishijo et al. 2002; Zhang et al. 2004). 

Nishijo et al. (2002) found a significant negative correlation between maternal urinary cadmium levels 

and gestation length; Mokhtar et al. (2002) did not find a significant association between maternal blood 

cadmium levels and gestation length. 

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Urinary cadmium content was measured in women 3 days after giving birth and compared to smoking 

habits and birth weight of offspring. Among nonsmoking women, when cadmium content was expressed 

as μg/L, cadmium levels were higher in women with infants of below-normal birth weight. However, 

when cadmium content was expressed as μg/g creatinine, cadmium levels were lower in women with 

infants with below-normal birth weight. Cadmium levels in smoking women were lower in both μg/L 

and μg/g in women with infants with below-normal birth weight (Cresta et al. 1989). 

A number of studies in rats and mice indicate that cadmium can be fetotoxic from oral exposures prior to 

and during gestation. This fetotoxicity is most often manifested as reduced fetal or pup weights (Ali et al. 

1986; Baranski 1987; Gupta et al. 1993; Kelman et al. 1978; Kostial et al. 1993; Petering et al. 1979; 

Pond and Walker 1975; Sorell and Graziano 1990; Sutou et al. 1980; Webster 1978; Whelton et al. 1988), 

but malformations, primarily of the skeleton, have been found in some studies (Baranski 1985; Machemer 

and Lorke 1981; Schroeder and Mitchener 1971). Malformations or skeletal effects reported include 

sirenomelia (fused lower limbs), amelia (absence of one or more limbs), and delayed ossification of the 

sternum and ribs (Baranski 1985); dysplasia of facial bones and rear limbs, edema, exenteration, 

cryptorchism, and palatoschisis (Machemer and Lorke 1981); and sharp angulation of the distal third of 

the tail (Schroeder and Mitchener 1971). Dosing levels were in the 1–20 mg/kg/day range. 

The most sensitive indicator of developmental toxicity of cadmium in animals appears to be neurobehavioral development. Offspring of female rats orally exposed to cadmium at a dose of 0.04 mg/kg/day 

prior to and during gestation had reduced exploratory locomotor activity and rotorod performance at age 

2 months (Baranski et al. 1983). Pups from dams exposed to 0.7 mg/kg/day during gestation had 

significant delays in cliff aversion and swimming behavior. Locomotor activity was significantly 

increased. In post-weaning measurements, locomotor activity was significantly decreased in treated 

groups at 60 days of age; conditioned avoidance behavior was also significantly decreased when tested at 

60 and 90 days of age (Ali et al. 1986). 

Nagymajtenyi et al. (1997) also reported behavioral and functional neurotoxicological changes caused by 

cadmium in a three-generational study in rats. Three consecutive generations of Wistar rats were orally 

treated by gavage with 3.5, 7.0, or 14.0 mg Cd/kg bw (as cadmium chloride diluted in distilled water) 

over the period of pregnancy, lactation, and 8 weeks after weaning. Behavioral (open field behavior) and 

electrophysiological (spontaneous and evoked cortical activity, etc.) parameters of male rats from each 

generation were investigated at the age of 12 weeks. The main behavioral outcomes were increased 

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vertical exploration activity (rearing) and increased exploration of an open-field center. The spontaneous 

and evoked electrophysiological variables showed dose- and generation-dependent changes (increased 

frequencies in the electrocorticogram, lengthened latency and duration of evoked potentials, etc.) 

signaling a change in neural functions. The results indicate that low-level, multigeneration exposure of 

rats to inorganic cadmium can affect nervous system function. 

Desi et al. (1998) continued the above studies to further evaluate cadmium associated changes in behavior 

and neurological function in rats following different dosage regimens during pregnancy. Female Wistar 

rats were given 3.5, 7.0, or 14.0 mg Cd/kg body weight (cadmium chloride dissolved in distilled water) in 

three different treatment regimes: days 5–15 of pregnancy; days 5–15 of pregnancy + 4 weeks of 

lactation; and days 5–15 of pregnancy + 4 weeks of lactation followed by the same oral treatment of male 

rats of the F1 generation for 8 weeks. The behavioral (open-field exploration) and electrophysiological 

(electrocorticogram, cortical-evoked potentials, conduction velocity and refractory periods of a peripheral 

nerve) parameters of F1 male rats exposed by various treatments were investigated at the age of 12 weeks. 

The results indicate that cadmium altered the spontaneous and evoked electrophysiological functions 

(e.g., increased the frequency of the electrocorticogram, lengthened the latency and duration of evoked 

potentials, etc.) in a dose- and duration-dependent manner. Only combining treatment during the prenatal 

development and the 4-week suckling period resulted in a significant dose-dependent decrease of 

horizontal and vertical exploratory activity and a significantly lower exploration frequency of the openfield center. The results suggest that low-level pre- and postnatal inorganic cadmium exposure affects the 

electrophysiological and higher order functions of the nervous system. 

A study by Gupta et al. (1993) examined the developmental profiles of DNA, RNA, proteins, DNA 

synthesis, thymidine kinase activity, and concentrations of zinc and cadmium in the brain of neonates 

from dams exposed to cadmium acetate at 5–6.3 mg/kg/day in drinking water during gestation, and 7– 

8 mg/kg/day during a 21-day lactation period. Pup brain and body weights were significantly decreased 

in the cadmium exposed pups on Ld 7–21. Cadmium brain accumulation was significantly increased in 

exposed pups on Ld 7 and remained at similar levels on Ld 14 and 21. DNA and thymidine kinase brain 

levels were significantly decreased in treated pups compared with controls on Ld 7, 14, and 21. The 

toxicological significance of changes in DNA incorporation and thymidine kinase activity are uncertain. 

Xu et al. (1993b) determined lipid peroxide (LPO) concentrations in rat pups in various organs as an 

index of cadmium toxicity. Male and female Wistar mice were exposed to cadmium in drinking water at 

0, 5.7, or 14.25 mg/kg/day for 2 months prior to mating. The pregnant females continued to be exposed 

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during gestation and lactation. Litter size and pup survival rates were unaffected by cadmium. Body 

weights were not statistically different between the exposed and control groups. In pups, brain weights 

(at 5.7 and 14.25 mg/kg/day) and liver, kidney, and heart weights (at 14.25 mg/kg/day) were significantly 

decreased. Although the relative organ weights were lower in the high-dose group, the difference from 

controls was not statistically significant. LPO concentrations in all organs were significantly increased in 

pups on Ld 7 at 14.25 mg/kg/day except in the kidney; concentrations in the liver, heart, and brain were 

131.5, 156, and 237.4%, respectively, of the concentrations in controls. 

In contrast to most of the study results, Saxena et al. (1986) reported no developmental effects from an 

exposure to 21 mg Cd/kg/day via drinking water during gestation (Gd 0–20). This study evaluated 

simultaneous exposure to lindane (20 mg lindane/kg via gavage on Gd 6–14) and cadmium acetate in 

drinking water at doses that individually did not cause maternal or developmental effects. Maternal 

toxicity (significantly decreased weight gain) and developmental toxicity were only observed in the 

cadmium plus lindane group. Fetal body weight was significantly decreased; intrauterine death and the 

rate of skeletal anomalies were significantly increased. Anomalies consisted of decreased ossification, 

wavy ribs, and scrambled sternebrae. 

The highest NOAEL values and all LOAEL values from each reliable study for developmental effects in 

each species and duration category are recorded in Table 3-6 and plotted in Figure 3-2. 

3.2.2.7 Cancer 

A few studies of cancer rates among humans orally exposed to cadmium have been performed. No 

significant increase in cancer rates was found among residents of a cadmium-polluted village in England 

(Inskip et al. 1982) or in prostate, kidney, or urinary tract cancer among residents of a cadmium-polluted 

area of Belgium (Lauwerys and De Wals 1981). The geographic distribution of elevated rates of prostate 

cancer incidence was shown to parallel the distribution of elevated cadmium concentrations in water, soil, 

or grain crops in Alberta, Canada (Bako et al. 1982). In none of these three studies were estimates made 

of cadmium exposures of populations as a whole or of individuals with cancer. A retrospective mortality 

study was done for three areas of Japan classified on the basis of rice cadmium content as highly polluted, 

slightly polluted, or non-polluted. No significant differences were found in mortality from cancer of all 

sites including prostate cancer (Shigematsu 1984). 

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One study examined cadmium, zinc, and copper in human kidney tumors and normal kidneys. Kidneys 

with renal cell carcinoma in cortex from 31 cases (20 men and 11 women) were compared to kidneys of 

patients who had died from causes other than a malignant disease from 17 controls (9 men and 8 women). 

No one in this study had been occupationally exposed. Smoking habits for patients were recorded. The 

level of cadmium in tumor tissue did not correlate with cadmium in cortex or medulla in the same kidney. 

No significant difference was found between cases and controls, although smoking cases had higher 

levels of cadmium. It was concluded that cadmium was not a risk factor for renal cell carcinoma (Hardell 

et al. 1994). 

Inhabitants of cadmium-polluted areas of Japan with elevated urinary retinol binding protein excretion 

had a mortality rate from malignant neoplasms no different from expected (Nakagawa et al. 1987). 

Overall, there is little evidence of an association between oral exposure to cadmium and increased cancer 

rates in humans, but the statistical power of the available studies to detect an effect was not high. 

In rats and mice, earlier studies on chronic oral exposure to cadmium have not reported an increased 

overall cancer incidence or the incidence of specific tumor types (Kanisawa and Schroeder 1969; Levy 

and Clack 1975; Levy et al. 1975; Löser 1980; Mangler et al. 1988; Schroeder et al. 1964, 1965). 

However, maximum daily doses tested were only 1 mg/kg/day in mice (Schroeder et al. 1964) and 

3.5 mg/kg/day in rats (Löser 1980) and, in most of these studies, histopathologic examination was limited 

compared to contemporary standards. Löser (1980) did perform a relatively thorough histological 

examination. A few additional animal studies of noncancer effects of chronic-duration oral cadmium 

exposure have indicated that no dose-related increases in tumors were found at maximum doses of 

4.01 mg/kg/day in rats (Fingerle et al. 1982) or 8 mg/kg/day in mice (Watanabe et al. 1986). 

Waalkes and Rehm (1992) evaluated the effects of chronic dietary zinc deficiency on oral cadmium 

carcinogenesis in male Wistar rats. Rats were exposed to cadmium at 0, 25, 50, 100, or 200 ppm with 

adequate (60 ppm) zinc or deficient zinc (7 ppm) in the diet for 77 weeks. A complete necropsy was 

performed on all animals. Survival rate and food consumption were not affected in this study. The 

incidence of prostatic proliferative lesions, both hyperplasias and adenomas, was significantly increased 

above controls (1.9%) in both zinc adequate (22.7%) and zinc deficient (15.4%) only in rats fed 50 ppm 

cadmium; the incidence in the higher exposure groups (13 and 0% in the 100 ppm group and 11.5 and 4% 

in the 200 ppm group). The overall incidence for prostatic lesions for all cadmium-treated groups was 

much lower in zinc-deficient rats, possibly because of a marked increase in prostatic atrophy that was 

associated with reduced zinc intake. Moreover, there was not a clear dose-response increase in prostatic 

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proliferative lesions. Cadmium treatment resulted in an elevated leukemia incidence (large granular 

lymphocytes; maximum 4.8-fold over control) in both zinc-adequate and zinc-deficient groups. A 

significant increase in the incidence of leukemia in the zinc-adequate diet was seen at 50 and 100 ppm 

cadmium, but not at 200 ppm. Zinc deficiency reduced the potency of cadmium (i.e., higher doses needed 

for comparable incidence). There was a consistent increase in the incidence of leukemia with an 

increasing cadmium dose in the zinc-deficient group, but the increase was statistically significant only at 

200 ppm. The highest incidence of leukemia observed from cadmium (28%), however, was seen in the 

200 ppm zinc-deficient rats. Testicular tumors (exclusively benign interstitial tumors) increased 

significantly only at 200 ppm cadmium with diets adequate in zinc. A significant positive trend was 

noted for development of testicular neoplasia with increased cadmium dose. Thus, oral cadmium 

exposure, in this study, was associated with tumors of the prostate, testes, and hematopoietic system in 

rats, while dietary zinc deficiency has complex, apparently inhibitory, effects on cadmium carcinogenesis 

by this route. 

A subsequent study by Waalkes et al. (1993) using male B6C3F1 mice evaluated the effects of cadmium 

exposure on tumor incidence at various times after the initiation of the carcinogenic process. The 

possible role of metallothionein in the susceptibility of transformed cells to cadmium cytotoxicity was 

also evaluated. At 5 weeks of age, mice received an intraperitoneal injection of N-nitrosodiethylamine 

(NDEA) at 90 mg/kg. At 2, 4, 8, 16, or 32 weeks post-NDEA injection, mice received water containing 

1,000 ppm cadmium ad libitum for up to 48 weeks of post-NDEA exposure. Cadmium exposure caused a 

marked "reduction" in liver tumor incidence in NDEA treated mice even when given as late as 32 weeks 

after the initial NDEA treatment. Cadmium alone eliminated the spontaneously occurring incidence of 

liver tumors (i.e., none out of 25 compared with 5 of 25 in the controls). Liver tumors produced by 

NDEA were typically basophilic adenomas. Cadmium resulted in a modest reduction in lung tumor 

incidence, statistically significant (28% reduction) only for the 16–48-week cadmium treated group 

pretreated with NDEA. Lung tumors were typically adenomas of alveolar cell origin. Cadmium alone 

eliminated spontaneously occurring lung tumors compared with the controls. Cadmium did significantly 

reduce the multiplicity of tumors induced by NDEA. NDEA alone typically induced seven tumors per 

lung, while NDEA plus cadmium treatment reduced the number of tumors to 2.5–3.5 (data taken from a 

graph) with some cases showing an 80% reduction in tumor numbers. Lung tumors found in the 

cadmium plus NDEA-treatment groups were also of a smaller overall size than those found in the NDEAonly treatment groups. Relatively little metallothionein was present in liver carcinomas, liver adenomas, 

and lung adenomas as indicated by immunohistochemistry. This finding was confirmed biochemically 

for the liver tumors. The authors concluded that cadmium can effectively “impair” tumor formation in 

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the lungs and liver of male B6C3F1 mice, and appears to be able to selectively destroy existing 

preneoplastic and/or tumor cells (adenomas). The mechanism may involve a reduced activity and 

responsiveness of the metallothionein system in transformed liver cells. 

A two-stage initiation/promotion experiment evaluated the promoting effects of cadmium chloride in the 

drinking water in rats. Cadmium exposure resulted in the following alterations in tumorigenic outcome: 

in the liver, hepatocellular carcinomas (initiated with diethyl nitrosamine) were decreased; in the stomach, 

tumors (initiated with N-methyl-N’-nitro-nitrosoguanidine plus NaCl at 10% in the diet) were not 

affected; in the kidney, tumors (initiated with N-ethyl-N-hydroxyethyl nitrosamine) showed increased 

dysplastic foci but no increase in renal cell tumors; in the pancreas, tumors (initiated with N-nitrosobis 

[2-oxopropyl] amine), had a nonsignificant increase in adenocarcinomas (female hamster study); and in 

the skin (initiated with 7,12-dimethyl benz(a)anthracene), there was no effect (female SENCAR mouse 

study) (Kurokawa et al. 1989). 

Neither the human nor the animal studies provide sufficient evidence to determine whether or not 

cadmium is a carcinogen by the oral route. 

3.2.3 Dermal Exposure 

3.2.3.1 Death 

No studies were located regarding death in humans after dermal exposure to cadmium. 

Some guinea pigs died 2 or 6 weeks after being exposed in a skin depot (3.1 cm2

) to 2 mL of 0.239 molar 

aqueous of cadmium chloride (0.14 mg/kg body weight) (Wahlberg 1965). However, it is difficult to 

attribute these deaths to cadmium exposure, due to the low dose compared to oral LD50 values and to the 

fact that no necropsy was done to determine whether the exposed guinea pigs might have died from 

pneumonia (which killed some control guinea pigs) (Wahlberg 1965). 

3.2.3.2 Systemic Effects 

No studies were located regarding respiratory, cardiovascular, gastrointestinal, hematological, 

musculoskeletal, hepatic, or renal effects in humans or animals after dermal exposure to cadmium. 

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CADMIUM 171 

3. HEALTH EFFECTS 

Dermal Effects. Among eczema patients routinely patch-tested with 2% cadmium chloride, 25 out of 

1,502 showed some reaction (Wahlberg 1977). Since no reaction was found at lower dilutions in reactive 

patients (Wahlberg 1977), the effect was likely direct irritation of the skin and is indicated as a LOAEL 

value in Table 3-9. 

No studies were located regarding dermal effects in animals after dermal exposure to cadmium. 

Ocular Effects. No studies were located regarding ocular effects in humans after dermal exposure to 

cadmium. 

Rats exposed to high concentrations of cadmium pigments or cadmium oxide in air had excessive 

lacrimation four hours after exposure (Rusch et al. 1986), possibly due to a direct irritation effect on the 

eyes. 

3.2.3.3 Immunological and Lymphoreticular Effects 

Dermal exposure to cadmium does not appear to affect the immune system significantly. One report of 

workers with extensive exposure to cadmium dust reported an increase in complaints of eczema (Friberg 

1950); however, no subsequent studies have confirmed any association. Routine patch tests among 

dermatitis and eczema patients using up to 2% cadmium chloride solutions have found skin irritation at 

2%, but no evidence of allergic reactions at a dose of 1% among people without known prior cadmium 

exposure (Rudzki et al. 1988; Wahlberg 1977) or among workers occupationally exposed to cadmium 

(Rudzki et al. 1988). Individuals with yellow tattoos containing cadmium sulfide often experience 

swelling of the surrounding skin on exposure to ultra violet (UV) irradiation (Bjornberg 1963); however, 

this may be the result of dermal damage from the photoconductivity of cadmium sulfide rather than a 

direct immunological reaction. 

Guinea pigs showed no contact sensitization following intradermal or topical exposure to cadmium 

chloride at concentrations up to 0.5% (Wahlberg and Boman 1979). The NOAEL values from each 

reliable study for immunological effects in each species and duration category are recorded in Table 3-9. 

***DRAFT FOR PUBLIC COMMENT*** 
Table 3-9 Levels of Significant Exposure to Cadmium - Dermal 

Exposure/ LOAEL 

Duration/ 

Species Frequency Reference (Route) (Strain) System NOAEL Less Serious Serious Chemical Form 

ACUTE EXPOSURE 

Systemic 

Human once Dermal Wahlberg 1977 1 2 (skin irritation) 

Percent (%) CdCl2 Percent (%) 492

Percent (%) Percent (%)

Rat 2 hr Ocular Rusch et al. 1986 99 (excessive lacrimation) 112 (eyes closed from (Sprague- exposure) CdSeS Dawley) mg/m3 mg/m3 

1002 mg/m3 mg/m3

97 (excessive lacrimation) 

mg/m3 

mg/m3

Immuno/ Lymphoret 

Human once Rudzki et al. 1988 1 493

Percent (%) CdCl2 

Percent (%)

hr = hour(s); Immuno/Lymphoret = immunological/lymphoreticular; LOAEL = lowest-observed-adverse-effect level; NOAEL = no-observed-adverse-effect level 
 

 

 

 

 

CADMIUM 173 

3. HEALTH EFFECTS 

No studies were located regarding the following health effects in humans or animals after dermal 

exposure to cadmium: 

3.2.3.4 Neurological Effects 

3.2.3.5 Reproductive Effects 

3.2.3.6 Developmental Effects 

3.2.3.7 Cancer 

3.3 GENOTOXICITY 

The genotoxic potential of cadmium has been studied in in vivo studies of cadmium workers, members of 

the general population, and rodents as summarized in Table 3-10. Although not always consistent, these 

results suggest that cadmium is a clastogenic agent, as judged by the induction of DNA damage, 

micronuclei, sister chromatid exchange (SCE), and chromosomal aberrations. 

Palus et al. (2003) examined peripheral lymphocytes from workers occupationally exposed to cadmium 

and found statistically significant increases compared to the control population in micronuclei rates and 

sister chromatid exchanges as well as evidence of an increased incidence of leukocytes with DNA 

fragmentation. Examination of lymphocytes and leukocytes from workers occupationally exposed to 

cadmium and lead or to cadmium, lead, and zinc showed increased frequency of chromosomal aberrations 

compared to control groups (Bauchinger et al. 1976; Deknudt and Leonard 1975; Deknudt et al. 1973), 

but this effect was not observed in men exposed primarily to cadmium (Bui et al. 1975; O'Riordan et al. 

1978). Human lymphocytes from individuals inhabiting cadmium-polluted areas of China have been 

found to have increased micronuclei rates and a higher frequency of chromosomal aberrations and severe 

aberration types, in comparison to control populations with either no known exposure to cadmium or lowlevel exposure (Fu et al. 1999; Tang et al. 1990). Bui et al. (1975) examined blood samples from four 

female Japanese patients with Itai-Itai disease and found no evidence to indicate that cadmium is capable 

of inducing chromosomal damage. 

For the most part, cadmium exposure via inhalation (Valverde et al. 2000), oral (Devi et al. 2001; Kasuba 

et al. 2002), and parenteral (Fahmy and Aly 2000; Kasuba et al. 2002; Mukherjee et al. 1988a; Saplakoglu 

et al. 1997; Wronska-Nofer et al. 1999; Zhou et al. 2004b) routes has been shown to be associated with 

DNA damage and induction of micronuclei in rodent cells. 

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CADMIUM 174 

3. HEALTH EFFECTS 

Table 3-10. Genotoxicity of Cadmium In Vivo 

Species (test system) End point Results Reference 

Mammalian cells: 

Inhalation exposure: 

Human lymphocytes Chromosomal aberrations + Deknudt et al. 1973 

Human lymphocytes Chromosomal aberrations – Bui et al. 1975 

Human lymphocytes Chromosomal aberrations + Deknudt and Leonard 1975 

Human lymphocytes Chromosomal aberrations + Bauchinger et al. 1976 

Human lymphocytes Chromosomal aberrations – O’Riordan et al. 1978 

Human lymphocytes Chromosomal aberrations + Alessio et al. 1993 

Mouse bone marrow DNA damage + Valverde et al. 2000 

Mouse brain cells DNA damage + Valverde et al. 2000 

Mouse testicular cells DNA damage + Valverde et al. 2000 

Mouse liver cells DNA damage + Valverde et al. 2000 

Mouse kidney cells DNA damage + Valverde et al. 2000 

Mouse lung cells DNA damage + Valverde et al. 2000 

Mouse nasal epithelial cells DNA damage + Valverde et al. 2000 

Human lymphocytes DNA damage + Palus et al. 2003 

Human lymphocytes Micronuclei + Palus et al. 2003 

Human lymphocytes Sister chromatid exchanges + Palus et al. 2003 

Oral exposure: 

Rat bone cells Altered gene expression + Ohba et al. 2007 

Mouse bone marrow Chromosomal aberrations – Deknudt and Gerber 1979 

Mouse bone marrow Chromosomal aberrations + Mukherjee et al. 1988b 

Rat bone marrow Chromosomal aberrations – Desi et al. 2000 

Human leukocytes Chromosomal aberrations + Shiraishi and Yoshida 1972 

Human lymphocytes Chromosomal aberrations – Bui et al. 1975 

Human lymphocytes Chromosomal aberrations + Tang et al. 1990 

Human lymphocytes Chromosomal aberrations + Fu et al. 1999 

Mouse leukocytes DNA damage + Devi et al. 2001 

Rat lymphocytes DNA damage + Kasuba et al. 2002 

Rat spermatogenesis Dominant lethal mutations – Sutou et al. 1980 

Rat spermatogenesis Dominant lethal mutations – Zenick et al. 1982 

Rat lymphocytes Micronuclei + Kasuba et al. 2002 

Human lymphocytes Micronuclei + Fu et al. 1999 

Intraperitoneal exposure:
 

Mouse oocytes Aneuploidy – Mailhes et al. 1988
 

Mouse spermatocytes Chromosomal aberrations + Selypes et al. 1992
 

Mouse bone marrow Chromosomal aberrations + Fahmy and Aly 2000
 

Mouse spermatocytes Chromosomal aberrations + Fahmy and Aly 2000
 

Mouse bone marrow Chromosomal aberrations – Bruce and Heddle 1979
 

Mouse bone marrow Chromosomal aberrations + Mukherjee et al. 1988a
 

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CADMIUM 175 

3. HEALTH EFFECTS 

Table 3-10. Genotoxicity of Cadmium In Vivo 

Species (test system) End point Results Reference 

Mouse spermatocytes Chromosomal translocations – Gilliavod and Leonard 1975 

Rat lung cells DNA strand breaks + Saplakoglu et al. 1997 

Rat kidney cells DNA strand breaks + Saplakoglu et al. 1997 

Rat liver cells DNA strand breaks – Saplakoglu et al. 1997 

Mouse spermatogenesis Dominant lethal mutations – Epstein et al. 1972 

Mouse spermatogenesis Dominant lethal mutations – Gilliavod and Leonard 1975 

Mouse oocytes Dominant lethal mutations – Suter 1975 

Rat lymphocytes hprt locus Gene mutation ± Jianhua et al. 2006 

Mouse bone marrow Micronuclei ± Mukherjee et al. 1988a 

Mouse bone marrow Micronuclei + Wronska-Nofer et al. 1999 

Mouse bone marrow Micronuclei + Fahmy and Aly 2000 

Mouse bone marrow Sister chromatid exchanges + Mukherjee et al. 1988a 

Mouse bone marrow Sister chromatid exchanges + Fahmy and Aly 2000 

Mouse spermatozoa Sperm morphology – Bruce and Heddle 1979 

Mouse spermatozoa Sperm morphology + Mukherjee et al. 1988a 

Syrian hamster embryo cells Transformation + DiPaulo and Castro 1979 

Subcutaneous exposure: 

Mouse testicular cells Altered gene expression + Zhou et al. 2004b 

Mouse blastocysts Aneuploidy + Watanabe and Endo 1982 

Syrian hamster oocytes Aneuploidy + Watanabe et al. 1979 

Mouse bone marrow Chromosomal aberrations + Karmakar et al. 1998 

Mouse testicular cells DNA damage – Zhou et al. 2004b 

Rat lymphocytes DNA damage + Kasuba et al. 2002 

Rat lymphocytes Micronuclei + Kasuba et al. 2002 

Mouse bone marrow Sister chromatid exchanges – Nayak et al. 1989 

Mouse fetal liver and lung Sister chromatid exchanges – Nayak et al. 1989 

cells 

– = negative result; + = positive result; ± = weakly positive result; DNA = deoxyribonucleic acid 

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CADMIUM 176 

3. HEALTH EFFECTS 

Evidence of the potential for cadmium to induce SCE (Fahmy and Aly 2000; Mukherjee et al. 1988a; 

Nayak et al. 1989) and chromosomal aberrations (Bruce and Heddle 1979; Desi et al. 2000; DiPaulo and 

Castro 1979; Fahmy and Aly 2000; Karmakar et al. 1998; Mukherjee et al. 1988a; Tang et al. 1990; 

Watanabe et al. 1979) is mixed. Data regarding the aneugenic potential of cadmium are limited and also 

conflicting. Watanabe and Endo (1982) observed an increased incidence of mouse blastocysts with 

trisomies and triploidies from female mice treated subcutaneously with cadmium compared to control 

mice. Watanabe et al. (1979) reported that subcutaneous exposure to cadmium induced mutagenicity in 

hamster oocytes, and in particular, induced the production of diploid oocytes. However, Mailhes et al. 

(1988) did not observe an increased incidence of hyperploid oocytes in female mice treated with cadmium 

via intraperitoneal injection. 

No evidence for germ cell mutations (the dominant lethal test) has been observed in male rats orally 

exposed to cadmium (Sutou et al. 1980; Zenick et al. 1982) or in mice exposed to cadmium via inhalation 

(Gilliavod and Leonard 1975; Suter 1975) or intraperitoneal exposure (Epstein et al. 1972). However, 

chromosomal aberrations in mouse spermatocytes and Syrian hamster oocytes (Fahmy and Aly 2000; 

Selypes et al. 1992; Watanabe et al. 1979) and altered gene expression in mouse testicular cells (Zhou et 

al. 2004b) have been observed following cadmium exposure. 

Data based on in vitro examination of the genotoxic effects of cadmium in microorganisms, yeast, insects, 

and mammalian cells are summarized in Table 3-11. For the most part, in vitro data support the in vivo 

data suggesting that cadmium has the potential to induce DNA damage, micronuclei, chromosomal 

aberrations, and genetic mutations. 

In vitro studies have shown that cadmium induces genetic mutations in hamster and mouse cells 

(Amacher and Paillet 1980; Filipic and Hei 2004; Honma et al. 1999; Jianhua et al. 2006; Oberly et al. 

1982), transformation in rodent cells (Casto et al. 1979; Terracio and Nachtigal 1988), unscheduled DNA 

synthesis in rat cells (Denizeau and Marion 1989), DNA breaks in human cells (Depault et al. 2006; 

Lopez-Ortal et al. 1999; Mikhailova et al. 1997), DNA lesions in hamster cells (Jianhua et al. 2006), and 

inhibits DNA repair in human and hamster cells (Lutzen et al. 2004; Lynn et al. 1997). Misra et al. 

(1998) did not observe DNA damage in rat cells following treatment with cadmium, but DNA damage 

has been noted in human cells (Fatur et al. 2002; Rozgaj et al. 2002). 

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CADMIUM	 177 

3. HEALTH EFFECTS 

Table 3-11. Genotoxicity of Cadmium In Vitro 

Results 

With Without 

Species (test system) End point activation activation Reference 

Prokaryotic organisms: 

Bacillus subtilis 

B. subtilis 

Salmonella typhimurium 

(plate incorporation) 

S. typhimurium 

(liquid suspension) 

S. typhimurium 

(liquid suspension) 

S. typhimurium 

(plate incorporation) 

Eukaryotic organisms: 

Yeast: 

Saccharomyces cerevisiae 

S. cerevisiae 

Insects: 

Drosophila melanogaster 

D. melanogaster 

D. melanogaster 

Mammalian cells: 

Mouse spleen cells 

Chinese hamster ovary Hy 

cells 

Chinese hamster ovary CHO 

cells 

Chinese hamster ovary CHO 

cells 

Human leukocytes 

Human blood lymphocytes 

Human blood lymphocytes 

Human blood lymphocytes 

DNA repair 

DNA repair 

Gene mutation 

Gene mutation 

Gene mutation 

Gene mutation 

Gene mutation 

lntrachromosomal 

recombination 

Dominant lethal 

mutations 

Nondisjunction 

Sex-linked 

recessive lethal 

mutations 

Chromosomal 

aberration 

Chromosomal 

aberration 

Chromosomal 

aberration 

Chromosomal 

aberration 

Chromosomal 

aberrations 

Chromosomal 

aberration 

Chromosomal 

aberration 

Chromosomal 

aberration 

No data
 

No data
 

–
 

–
 

No data
 

–
 

No data
 

No data
 

No data 

No data 

No data 

No data 

No data 

No data 

No data 

No data 

No data 

No data 

No data 

± Nishioka 1975 

± Kanematsu et al. 1980 

–	 Bruce and Heddle 1979 

– Milvy and Kay 1978 

± Mandel and Ryser 1984 

+	 Wong 1988 

+	 Putrament et al. 1977 

+	 Schiestl et al. 1989 

+	 Vasudev and Krishnamurthy 

1979 

–	 Ramel and Magnusson 

1979 

–	 Inoue and Watanabe 1978 

+	 Fahmy and Aly 2000 

+	 Rohr and Bauchinger 1976 

+	 Deaven and Campbell 1980 

+	 Cai and Arenaz 1998 

+	 Shiraishi et al. 1972 

–	 Paton and Allison 1972 

+	 Shiraishi et al. 1972 

–	 Deknudt and Deminatti 1978 

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CADMIUM	 178 

3. HEALTH EFFECTS 

Table 3-11. Genotoxicity of Cadmium In Vitro 

Results 

With Without 

Species (test system) End point activation activation Reference 

Human blood lymphocytes 

Human blood lymphocytes
 

Human lymphoblastoid cells
 

Human fetal hepatic WRL-68 

cells 

Chinese hamster ovary 

CHO-K1 cells 

Rat L6 myoblast cells 

Rat Clone 9 liver cells 

Rat TRI 1215 liver cells 

Human blood lymphocytes 

Human hepatoma cells 

(HepG2) 

V79 Chinese hamster lung 

cells 

Chinese hamster ovary 

CHO-K1 cells 

Human 293T-Tet-Off-hMLH1 

cells 

V79 Chinese hamster lung 

cells hprt locus 

AL human-hamster hybrid 

CD59 gene 

Mouse lymphoma L5178Y 

thymidine kinase locus 

Mouse lymphoma L5178Y 

thymidine kinase locus 

Mouse lymphoma L5178Y 

thymidine kinase locus 

Human blood lymphocytes 

Human blood lymphocytes 

(G0 phase) 

Human blood lymphocytes
 

(S phase)
 

Human diploid fibroblasts
 

(MRC-5)
 

Mouse spleen cells
 

Human blood lymphocytes
 

Human blood lymphocytes
 

(G0 phase)
 

Chromosomal 

aberration 

DNA breaks 

DNA breaks 

DNA breaks 

DNA damage 

DNA damage 

DNA damage 

DNA damage 

DNA damage 

DNA damage 

DNA lesions 

DNA repair 

DNA repair 

Gene mutation 

Gene mutation 

Gene mutation 

Gene mutation 

Gene mutation 

Micronuclei 

Micronuclei 

Micronuclei 

Micronuclei 

Sister chromatid 

exchanges 

Sister chromatid 

exchanges 

Sister chromatid 

exchanges 

No data 

No data 

No data 

No data 

No data 

No data 

No data 

No data 

No data 

No data 

No data 

No data 

No data 

No data 

No data 

No data 

No data 

+ 

No data 

No data 

No data 

No data 

No data 

No data 

No data 

±	 Gasiorek and Bauchinger
 

1981
 

+	 Depault et al. 2006
 

+	 Mikhailova et al. 1997
 

+	 Lopez-Ortal et al. 1999
 

–	 Misra et al. 1998
 

–	 Misra et al. 1998
 

–	 Misra et al. 1998
 

–	 Misra et al. 1998
 

+	 Rozgaj et al. 2002
 

+	 Fatur et al. 2002
 

+	 Jianhua et al. 2006
 

+	 Lynn et al. 1997
 

+	 Lutzen et al. 2004
 

+	 Jianhua et al. 2006
 

+ Filipic and Hei 2004
 

± Amacher and Paillet 1980
 

+	 Oberly et al. 1982
 

+	 Honma et al. 1999
 

+	 Migliore et al. 1999
 

–	 Kasuba and Rozgaj 2002
 

+	 Kasuba and Rozgaj 2002
 

+	 Seoane and Dulout 2001
 

+	 Fahmy and Aly 2000
 

–	 Bassendowska-Karska and
 

Zawadzka-Kos 1987
 

–	 Saplakoglu and Iscan 1998
 

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CADMIUM 179 

3. HEALTH EFFECTS 

Table 3-11. Genotoxicity of Cadmium In Vitro 

Results 

With Without 

Species (test system) End point activation activation Reference 

Human blood lymphocytes Sister chromatid No data + Saplakoglu and Iscan 1998 

(S phase) exchanges 

Syrian hamster embryo cells Transformation No data + Casto et al. 1979 

Rat ventral prostate cells Transformation No data + Terracio and Nachtigal 1988 

Rat hepatocytes Unscheduled DNA No data + Denizeau and Marion 1989 

synthesis 

C = negative result; + = positive result; ± = weakly positive; CHO = Chinese hamster ovary; DNA = deoxyribonucleic 

acid; NA = not applicable; RNA = ribonucleic acid 

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CADMIUM 180 

3. HEALTH EFFECTS 

Chromosomal aberrations following cadmium exposure have been observed in Chinese hamster ovary 

cells (Cai and Arenaz 1998; Deaven and Campbell 1980; Rohr and Bauchinger 1976), but studies on 

human cells have shown mixed results (Deknudt and Deminatti 1978; Gasiorek and Bauchinger 1981; 

Paton and Allison 1972; Shiraishi et al. 1972). For the most part, in vitro studies have not shown 

cadmium to induce SCE in human cells (Bassendowska-Karska and Zawadzka-Kos 1987; Saplakoglu and 

Iscan 1998). However, a study by Fahmy and Aly (2000) did observe SCE in mouse spleen cells 

following cadmium treatment. Kasuba and Rozgaj (2002) and Saplakoglu and Iscan (1998) evaluated the 

ability of cadmium to induce micronuclei and SCE in human lymphocytes in vitro respectively, at two 

different stages of the cell cycle, G0 and S phase. These studies observed that the genotoxicity of 

cadmium may vary depending on the stage of the cell cycle as both micronuclei and SCE were induced in 

cells in S phase, but not in cells in G0 phase. These observations may in part explain some of the 

contradictory findings regarding cadmium genotoxicity in the literature. 

Positive mutagenicity results have been found in some studies using bacterial cells (Kanematsu et al. 

1980; Mandel and Ryser 1984; Nishioka 1975; Wong 1988), in studies using yeast (Putrament et al. 1977; 

Schiestl et al. 1989), and in a single study using Drosophila melanogaster (Vasudev and Krishnamurthy 

1979). Other studies report negative mutagenicity results in bacterial cells (Bruce and Heddle 1979; 

Milvy and Kay 1978) and in D. melanogaster (Inoue and Watanabe 1978; Ramel and Mangusson 1979). 

3.4 TOXICOKINETICS 

Cadmium metal and cadmium salts are not well absorbed; approximately 25, 1–10, or <1% of the dose is 

absorbed following inhalation, oral, or dermal exposure. Several factors can influence inhalation and oral 

absorption efficiency; for example, cadmium in cigarette smoke has a higher absorption efficiency due to 

its small particle size and because cadmium is more efficiently absorbed from the gastrointestinal tract in 

individuals with poor iron status. Following absorption from any route of exposure, cadmium widely 

distributes throughout the body, with the highest concentrations found in the liver and kidney. 

Cadmium is not known to undergo any direct metabolic conversion such as oxidation, reduction, or 

alkylation. Absorbed cadmium is excreted very slowly, with urinary and fecal excretion being 

approximately equal. Approximately 0.007 and 0.009% of the body burden is excreted in the urine and 

feces, respectively, per day. 

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CADMIUM 181 

3. HEALTH EFFECTS 

3.4.1 Absorption 

3.4.1.1 Inhalation Exposure 

Cadmium metal and cadmium salts have low volatility and exist in air primarily as fine suspended 

particulate matter. When inhaled, some fraction of this particulate matter is deposited in the airways or 

the lungs, and the rest is exhaled. Large particles (greater than about 10 μm in diameter) tend to be 

deposited in the upper airway, while small particles (approximately 0.1 μm) tend to penetrate into the 

alveoli. While some soluble cadmium compounds (cadmium chloride and cadmium sulfate) may undergo 

limited absorption from particles deposited in the respiratory tree, the major site of absorption is the 

alveoli. Thus, particle size, which controls alveolar deposition, is a key determinant of cadmium 

absorption in the lung (Nordberg et al. 1985). 

No direct data are available on cadmium deposition, retention, or absorption in the human lung. Data 

from animal studies indicate that lung retention is greatest after short-term exposure (5–20% after 

15 minutes to 2 hours) (Barrett et al. 1947; Henderson et al. 1979; Moore et al. 1973; Rusch et al. 1986). 

The initial lung burden declines slowly after exposure ceases (Henderson et al. 1979; Moore et al. 1973; 

Rusch et al. 1986) due to absorption of cadmium and lung clearance of deposited particles. After longer 

periods of inhalation exposure to cadmium, somewhat lower lung retentions are found (Glaser et al. 

1986). The absorption of cadmium in lung differs somewhat among chemical forms, but the pattern does 

not correlate with solubility (Glaser et al. 1986; Rusch et al. 1986). 

Based on comparison of cadmium body burdens in human smokers and nonsmokers, cadmium absorption 

from cigarettes appears to be higher than absorption of cadmium aerosols measured in animals (Nordberg 

et al. 1985). The chemical form of cadmium in cigarette smoke is likely to be similar to that produced by 

other combustion processes, primarily cadmium oxide aerosols. The greater absorption of cadmium from 

cigarette smoke is likely due to the very small size of particles in cigarette smoke and the consequent very 

high alveolar deposition (Nordberg et al. 1985; Takenaka et al. 2004). 

Based on the physiology of the human respiratory tree, a comprehensive model has been developed to 

predict the kinetics of inhaled cadmium in humans (Nordberg et al. 1985). Results of this model suggest 

that only about 5% of particles >10 μm in diameter will be deposited, up to 50% of particles <0.1 μm will 

be deposited, and between 50 and 100% of cadmium deposited in the alveoli will ultimately be absorbed 

(Nordberg et al. 1985). 

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CADMIUM 182 

3. HEALTH EFFECTS 

3.4.1.2 Oral Exposure 

Most ingested cadmium passes through the gastrointestinal tract without being absorbed (Kjellström et al. 

1978). Measurement of gastrointestinal absorption is complicated by the fact that not all of a dose 

initially retained in the gastrointestinal system can be considered to be absorbed, because some portion 

may be trapped in the intestinal mucosa without crossing into the blood or lymph (Foulkes 1984). Thus, 

measures of whole-body cadmium retention may overestimate cadmium absorption (at least in the shortterm). On the other hand, some absorbed cadmium may be excreted in urine or feces, so that retention 

may underestimate exposure. However, this underestimate is probably minor because excretion of 

absorbed cadmium is very slow (see Section 3.4.4.2). 

Cadmium absorption has been estimated based on the retention of cadmium in the bodies of humans 

following ingestion of radioactive cadmium. Estimated cadmium absorption ranged from 1.1 to 10.6% 

(Flanagan et al. 1978; McLellan et al. 1978; Newton et al. 1984; Rahola et al. 1973; Shaikh and Smith 

1980; Vanderpool and Reeves 2001). Although some studies have reported higher absorption levels (25– 

42%), this was based on cadmium retention measurements for 3–5 days after exposure that was probably 

too short to accurately measure cadmium transfer from the intestinal mucosa to circulation (Crews et al. 

2000; Rahola et al. 1973). Using estimated cadmium intakes from national data and measured renal and 

urinary cadmium levels in healthy nonsmokers, cadmium absorption rates of 3–5% have been estimated 

(Ellis et al. 1979; Morgan and Sherlock 1984). In a balance study of women with high background 

cadmium intakes (mean urinary cadmium levels of 2.7–5.16 μg/g creatinine); the mean absorption rate in 

subjects examined for 7 days was 6.5% (Horiguchi et al. 2004). 

The body store of iron influences cadmium absorption; subjects with low iron stores (assessed by serum 

ferritin levels) had an average absorption of 6 and 8.9%, while those with adequate iron stores had an 

average absorption of 2.3 and 2.4% (Flanagan et al. 1978; Shaikh and Smith 1980). A third study of 

anemic females with high background cadmium levels did not find a significant alteration in cadmium 

absorption, as compared to healthy females; however, cadmium absorption was lower in the anemic group 

(13.6%) than in healthy group (27.4%) (Horiguchi et al. 2004). It is not known if the differences in the 

methods used to estimate cadmium absorption (kinetic study using radiolabelled cadmium versus a 

balance study) or the high background cadmium intake in the Horiguchi study resulted in the discrepancy 

between the two studies. There is some indication that not all forms of cadmium are equally absorbed. 

Some populations with high dietary-cadmium exposure from Bluff oysters (McKenzie-Parnell et al. 1988) 

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CADMIUM 183 

3. HEALTH EFFECTS 

or seal meat (Hansen et al. 1985) have been found not to have elevated blood-cadmium levels, perhaps 

due to the particular form of cadmium in these foods. 

Crews et al. (2000) estimated that 42% of a cadmium dose incorporated into porridge was retained in the 

body 5 days after exposure (as measured by fecal excretion of radiolabelled cadmium); however, the fecal 

collection period was probably too short to accurately measure cadmium absorption. The investigators 

also attempted to measure cadmium absorption in 12-month-old infants; 18% of the labeled cadmium in 

the porridge was retained in the body after 4 days. As with the adult data, the collection period may have 

been too short to accurately measure cadmium absorption in the infants. 

Most estimates of cadmium absorption in animals are somewhat lower than the values found from human 

studies, particularly after prolonged exposure. In mice, 0.27–3.2% of an oral dose of cadmium chloride 

was retained after 3–5 days (Bhattacharyya et al. 1981; Engstrom and Nordberg 1979), and in rats, 2–3% 

of a single oral dose of cadmium chloride was retained (Moore et al. 1973; Schafer et al. 1990). 

Following 30 days of oral exposure, 0.2–0.3% of an administered dose was retained in rats (Muller et al. 

1986). After 4 weeks of dietary exposure to cadmium, absorption of cadmium was reduced to one-third 

the absorption of rats without pre-exposure to cadmium (Schafer et al. 1990). Cadmium pigments 

(cadmium sulfide and cadmium sulfoselenide) appear to be absorbed much less than cadmium chloride in 

rats (ILZRO 1977). Increases in absorption have been observed during gestation and lactation, 0.37 and 

0.35% of cadmium administered via gavage was absorbed in mice on gestation days 8 and 15 and 0.56, 

0.60, and 0.30% on lactation days 10, 17, and 24, as compared to 0.27% in nonpregnant controls; 

absorption was only significantly different from nonpregnant controls on lactation days 10 and 17 

(Bhattacharyya et al. 1981). Similar findings were observed in mice continuously exposed to cadmium 

during pregnancy and/or lactation (Bhattacharyya et al. 1982, 1986). 

The absorption of cadmium from the gastrointestinal tract has been extensively studied in rats and mice, 

and a number of factors are recognized that influence absorption. Absorption appears to take place in two 

phases: uptake from lumen into mucosa, and transfer into the circulation (Foulkes 1985). Phase 1 may 

involve sequestering of cadmium by metallothionein (Foulkes 1980), but any protective effect is 

overloaded at moderate doses (Kotsonis and Klaassen 1978). Uptake behaves like a saturable process 

with fractional absorption decreasing at high concentrations (Foulkes 1980). There is evidence, however, 

to suggest that this saturation results from charge neutralization at the membrane (Foulkes 1985), so that 

it need not be assumed that there is a specific system for carrying cadmium into the body. At doses high 

enough to damage gastrointestinal mucosa, fractional absorption is increased (Andersen et al. 1988; Goon 

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CADMIUM 184 

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and Klaassen 1989; Lehman and Klaassen 1986). Cadmium bound to metallothionein was absorbed by 

rats to a lesser extent than cadmium added to the diet as cadmium chloride, but kidney cadmium content 

was only slightly less (Groten et al. 1990). 

Maitani et al. (1984) compared the distribution of cadmium after oral administration of either cadmium 

ions or Cd-thionein in male CF-1 mice given 0.5 mg Cd/kg, per os (po), as cadmium chloride in saline, 

cadmium chloride in control rat liver homogenate, cadmium thionein in saline, Cd-TH in liver 

homogenate, or liver homogenate from Cd-treated rats. In all cases, 85–90% of the cadmium dose was 

present in feces within 24 hours. However, in groups receiving cadmium chloride, more cadmium was 

found in feces on days 2 and 3, compared to those receiving cadmium-thionein. In a companion study, 

tissue levels indicated that less cadmium was absorbed when rats received cadmium-thionein in saline 

than cadmium chloride in saline. Cadmium-thionein added to liver homogenate or liver homogenate 

containing cadmium-thionein increased the absorption of cadmium, resulting in renal cadmium levels 

similar to those in mice receiving cadmium chloride in saline. The kidney/liver cadmium concentration 

ratio (9) was the same for cadmium-thionein in all three media. Although Cd-TH gave much higher 

kidney/liver cadmium ratios than cadmium chloride (9 versus 2), renal cadmium concentrations were the 

same or lower than after cadmium chloride treatments. The authors concluded that the high kidney/liver 

cadmium ratio after cadmium-thionein treatment versus cadmium chloride was due to lower 

concentrations of cadmium in liver rather than marked increases in renal cadmium levels. While the 

chemical form of cadmium administered affects the absorption and distribution, the amount of cadmium 

reaching the kidney after cadmium-thionein administration is similar to that after cadmium chloride 

administration. 

At moderate doses of cadmium, the presence of divalent and trivalent cations, such as calcium, 

chromium, magnesium, and zinc, may decrease cadmium uptake, probably by a nonspecific effect on the 

charge distribution of the intestinal brush border membrane (Foulkes 1985). However, the influence of 

cations on cadmium absorption is complex, because zinc can increase the amount of cadmium absorbed 

from the intestine (Jaeger 1990). A refined diet high in fat and protein increases cadmium absorption in 

mice, partially due to increased gastrointestinal passage time (Schafer et al. 1986). Studies in newborn 

rats and pigs also provide evidence that diet consituents influence cadmium absorption; absorption of 

cadmium chloride was higher when administered in water compared to cereal-based infant formula 

(Eklund et al. 2001, 2004). Diets low in iron increase cadmium absorption (Flanagan et al. 1978; Reeves 

and Chaney 2001, 2002; Schafer et al. 1990); a diet low in calcium will also increase cadmium absorption 

(Reeves and Chaney 2001, 2002). In contrast, low levels of dietary iron did not increase cadmium 

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CADMIUM 185 

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absorption in suckling piglets; however, iron supplementation did increase cadmium absorption (Öhrvik 

et al. 2007); this difference may be due to the high cadmium dose used in the study. Zinc deficiency may 

result in an increased accumulation of cadmium in the intestinal wall, but does not affect transport into the 

blood (Foulkes and Voner 1981; Hoadley and Cousins 1985). The absorption of cadmium in rats depends 

on age, with measured absorption decreasing from 12 to 5 to 0.5% at 2 hours, 24 hours, and 6 weeks after 

birth, respectively (Sasser and Jarboe 1977). Sasser and Jarboe (1980) also reported that absorption of 

cadmium in the gastrointestinal tract of young guinea pigs was 20-fold higher than in adult guinea pigs. 

Thus, for a given individual, the absorption following oral exposure to cadmium is likely to depend on 

physiologic status (age; body stores of iron, calcium, and zinc; pregnancy history; etc.) and, also, on the 

presence and levels of ions and other dietary components ingested with the cadmium. 

3.4.1.3 Dermal Exposure 

A few measurements of dermal absorption of cadmium in animals have been made, with only one in vitro 

study using human skin to determine the percutaneous absorption of cadmium. 

A study by Wester et al. (1992) evaluated the percutaneous absorption of cadmium from water and soil 

into and through human skin using in vitro skin cells. Radioactive cadmium (109cadmium chloride) was 

made to a concentration of 116 ppb in water or 13 ppb in filtered soil (26% sand, 26% clay, 48% silt, 

0.9% organic content). Cadmium chloride was administered either at 5 μL/cm2 or 2 volumes of 

2.5 μL/cm2 (the same amount of cadmium apparently applied). Human cadaver skin dermatomed at 

500 μm was placed in flow-through skin cells and perfused with human plasma. Approximately 0.1– 

0.6% of the cadmium chloride in water entered the plasma perfusate over the 16-hour perfusion period, 

while 2.4–12.7% of applied dose remained in the skin. Most of the cadmium (74–93%) remained 

unabsorbed and was recovered from the skin surface. Total recoveries ranged from 88±20 to 103±3. 

When cadmium-contaminated soil (13 ppb cadmium chloride) was applied to the skin surface, plasma 

levels ranged from 0.02 to 0.07% of the applied dose, while the skin contained 0.06–0.13% of applied 

dose. Surface wash ranged from 82 to 102% of applied dose. Total recoveries were from 83±33 to 

106±2. The large differences between water and soil absorption into the plasma and retention in the skin 

were attributed to differences in cadmium partition coefficients, measured to be 3.61x101 for stratum 

corneum (powdered):water and 1.03x105 for soil:water. These measurements indicate that soil has a 

relatively higher affinity for cadmium than does the stratum corneum. The transfer of cadmium from soil 

to skin depends on the soil’s binding capacity and water retention and variables describing the physical 

contact with the skin. When cadmium levels in the soil were increased from 6.5 to 65 ppb, skin levels 

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correspondingly increased, but plasma receptor fluid levels remained constant. This suggests that, with in 

vitro perfusion, the surface concentration of cadmium will influence skin cadmium concentration, but that 

absorption into plasma receptor fluid is relatively independent of the skin surface concentration. The 

authors offer the caveat that in vitro methods can influence results and therefore, the receptor fluid 

accumulation must be interpreted with caution. The authors calculate that a whole-body exposure to 

cadmium at 116 ppb in water with a 0.5% absorption will result in a daily systemic intake of about 10 μg 

cadmium. 

A few animal studies are available that describe the percutaneous absorption of cadmium as estimated 

from the accumulation of cadmium in the liver and kidneys of mice and rabbits. Male rabbits (strain not 

specified) was dosed with cadmium chloride percutaneously with a 1% aqueous solution (6.1 mg 

cadmium) or 2% ointment (12.2 mg cadmium) over a 10-cm2 shaved area (Kimura and Otaki 1972). 

Animals were treated 5 times over 3 weeks (duration of exposure not reported) and were killed 2 weeks 

after the last application. Only cadmium contents of liver and kidney were measured, so total absorption 

through the skin may have been greater. Accumulated amounts of cadmium in the liver and kidneys were 

found to be 0.4–0.61% 2 weeks after the end of cadmium exposure. This percentage was similar for 

aqueous solution or hydrocarbon ointment. Similarly, male hairless mice (strain not specified) were 

dosed with cadmium chloride percutaneously with a 2% ointment (containing 0.61 mg cadmium) 1 or 

5 times in a week (duration of exposure not reported) and killed 1 week later (Kimura and Otaki 1972). 

Accumulated amounts of cadmium in the liver and kidneys were found to be 0.2–0.87%. 

Cadmium was detected in liver, kidneys, and urine following dermal exposure in guinea pigs (Skog and 

Wahlberg 1964). The disappearance of cadmium from cadmium chloride in water applied to guinea pig 

skin was dependent on concentration, with a peak mean absorption of 1.8% over 5 hours at 0.239 molar 

cadmium (about a 2.7% solution). Less absorption occurred both at higher and lower concentrations of a 

cadmium chloride solution applied to the skin (Skog and Wahlberg 1964). 

The results from all of these studies suggest that dermal absorption is slow, and would be of concern only 

in situations where concentrated solutions would be in contact with the skin for several hours or longer. 

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3.4.2 Distribution 

Cadmium is widely distributed in the body, with the major portion of the body burden located in the liver 

and kidney. Animals and humans appear to have a similar pattern of distribution that is relatively 

independent of route of exposure, but somewhat dependent on duration of exposure. 

3.4.2.1 Inhalation Exposure 

Cadmium was found in autopsy samples from nearly all organs of a worker extensively exposed to 

cadmium dust, with greatest concentrations in the liver, kidney, pancreas, and vertebrae (Friberg 1950). 

In workers dying from inhalation of cadmium, lung-cadmium concentration was somewhat lower than 

liver or kidney cadmium concentration (Beton et al. 1966; Lucas et al. 1980; Patwardhan and Finckh 

1976). The concentration of cadmium in the liver of occupationally exposed workers generally increases 

in proportion to intensity and duration of exposure to values up to 100 μg/g (Gompertz et al. 1983; Roels 

et al. 1981b). The concentration of cadmium in the kidney rises more slowly than in the liver after 

exposure (Gompertz et al. 1983) and begins to decline after the onset of renal damage at a critical 

concentration of 160–285 μg/g (Roels et al. 1981b). 

In animals acutely exposed to cadmium carbonate aerosols, about 60% of the inhaled dose is found in the 

gastrointestinal tract, transported by mucociliary clearance (Moore et al. 1973). Following a 2-hour 

inhalation of approximately 100 mg/m3 of cadmium, cadmium concentration in rat liver increased from 

an initial concentration of 0.8 μg/g in males and 1.9 μg/g in females immediately after exposure up to a 

peak of about 2 μg/g in males and 3.8 μg/g in females 1 week postexposure, then declined to 1.7 and 

2.5 μg/g, respectively, by 30 days postexposure. The kidney concentrations were initially <0.5 μg/g in 

males and females, rising to approximately 8 μg/g in both sexes by 1 week postexposure and to 18 μg/g in 

males and 15 μg/g in females by 30 days postexposure (Rusch et al. 1986). 

3.4.2.2 Oral Exposure 

As discussed in Chapter 6, most nonoccupationally exposed people are exposed to cadmium primarily 

through the diet. Cadmium can be detected in virtually all tissues in adults from industrialized countries, 

with greatest concentrations in the liver and kidney (Chung et al. 1986; Sumino et al. 1975). Average 

cadmium concentrations in the kidney are near zero at birth, and rise roughly linearly with age to a peak 

(typically around 40–50 μg/g wet weight) between ages 50 and 60, after which kidney concentrations 

plateau or decline (Chung et al. 1986; Hammer et al. 1973; Lauwerys et al. 1984). Liver cadmium 

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concentrations also begin near zero at birth, increase to typical values of 1–2 μg/g wet weight by age 20– 

25, then increase only slightly thereafter (Chung et al. 1986; Hammer et al. 1973; Lauwerys et al. 1984; 

Sumino et al. 1975). 

Distribution of cadmium in animals after oral exposure is similar to that found in humans, with highest 

accumulation in the liver and kidneys, and lower levels spread throughout the rest of the body (Kotsonis 

and Klaassen 1978; Weigel et al. 1984). Liver and kidney cadmium concentrations are comparable after 

short-term exposure (Andersen et al. 1988; Jonah and Bhattacharyya 1989), but the kidney concentration 

exceeds the liver concentration following prolonged exposure (Kotsonis and Klaassen 1978), except at 

very high exposures (Ando et al. 1998; Bernard et al. 1980; Hiratsuka et al. 1999). In mice orally 

exposed to cadmium during lactation, 53% of the whole-body cadmium was found in the kidneys as 

compared to 27% in nonpregnant controls (Bhattacharyya et al. 1982). 

Maitani et al. (1984) compared the distribution of cadmium in rats after an acute oral administration of 

either cadmium ions or cadmium bound to metallothionein. In all cases, 85–90% of the dose was present 

in the feces within 24 hours postexposure. More of the cadmium-thionein was retained after 2–3 days, 

and less of the cadmium-thionein was distributed to the liver than was the case for the ionic cadmium. 

Kidney levels were comparable. 

The placenta may act as a partial barrier to fetal exposure to cadmium. Cadmium concentration has been 

found to be approximately half as high in cord blood as in maternal blood in several studies including 

both smoking and nonsmoking women (Kuhnert et al. 1982; Lauwerys et al. 1978; Truska et al. 1989). 

Accumulation of cadmium in the placenta at levels about 10 times higher than maternal blood cadmium 

concentration has been found in studies of women in Belgium (Roels et al. 1978) and the United States 

(Kuhnert et al. 1982); however, in a study in Czechoslovakia, the concentration of cadmium in the 

placenta was found to be less than in either maternal or cord blood (Truska et al. 1989). In mice orally 

exposed to cadmium during pregnancy, maternal blood, placental, and fetal cadmium concentrations were 

essentially equal among control animals (with environmental cadmium exposure), but placental 

concentration increased with cadmium dose much more rapidly than either maternal blood or fetal 

cadmium concentration (Sorell and Graziano 1990). Thus, timing and level of cadmium exposure may 

influence the uptake of cadmium by the placenta, perhaps explaining the conflicting human studies. 

Goyer and Cherian (1992) localized metallothionein in full-term human placenta and in fetal cells in 

human placenta. Metallothionein was present in trophoblasts (which facilitate transport of substances 

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entering the placenta from the maternal blood), Hofbauer cells (motile macrophages capable of 

phagocytosis and protein ingestion), amniotic epithelial cells (fetal derivatives), and decidual cells 

(endometrial stromal cells that have been transformed under hormonal influence into large pale cells, rich 

in glycogen). The mechanism by which the placenta transports the essential metals, copper and zinc, 

while limiting the transport of cadmium is unknown, but may involve the approximately 1,000-fold 

higher concentration of zinc in the placenta and the higher affinity of cadmium than zinc for 

metallothionein. 

Cadmium levels in human milk are 5–10% of levels in blood, possibly due to inhibited transfer from 

blood because of metallothionein binding of cadmium in blood cells (Radisch et al. 1987). Bhattacharyya 

et al. (1982) examined the maternal transfer of cadmium to pups during gestation and lactation in mice. 

Approximately 3, 11, and 25% of maternal cadmium was transferred to the pups following gestation-only 

exposure, lactation-only exposure, and gestation and lactation exposure, respectively. 

3.4.2.3 Dermal Exposure 

No studies were located regarding distribution in humans after dermal exposure to cadmium. Elevated 

levels of cadmium were found in the liver and kidneys of rabbits and mice dermally exposed to cadmium 

(Kimura and Otaki 1972). 

3.4.3 Metabolism 

Cadmium is not known to undergo any direct metabolic conversion such as oxidation, reduction, or 

alkylation. The cadmium (+2) ion does bind to anionic groups (especially sulfhydryl groups) in proteins 

(especially albumin and metallothionein) and other molecules (Nordberg et al. 1985). Plasma cadmium 

circulates primarily bound to metallothionein, and albumin (Foulkes and Blanck 1990; Roberts and Clark 

1988). 

3.4.4 Elimination and Excretion 

Most cadmium that is ingested or inhaled and transported to the gut via mucociliary clearance is excreted 

in the feces. However, almost all excreted cadmium represents material that was not absorbed from the 

gastrointestinal tract. Most absorbed cadmium is excreted very slowly, with urinary and fecal excretion 

being approximately equal (Kjellström and Nordberg 1978). The half-time for cadmium in the whole 

body in humans was >26 years (Shaikh and Smith 1980) and half-times of several months up to 

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several years have been calculated in mice, rats, rabbits, and monkeys (Kjellström and Nordberg 1985). 

Half-times in the slowest phase were from 20 to 50% of the maximum life span of the animal (Kjellström 

and Nordberg 1985). In the human body, the main portion of the cadmium body burden is found in the 

liver and kidney and in other tissues (particularly muscle, skin, and bone). After reviewing the literature, 

Kjellström and Nordberg (1985) developed a range of half-times from their kinetic model of 6–38 years 

for the human kidney and 4–19 years for the human liver. 

3.4.4.1 Inhalation Exposure 

Cadmium excretion in urine of occupationally exposed workers increases proportionally with body 

burden of cadmium, but the amount of cadmium excreted represents only a small fraction of the total 

body burden unless renal damage is present; in this case, urinary cadmium excretion markedly increases 

(Roels et al. 1981b). Fecal excretion in workers occupationally exposed to cadmium reflects mainly 

cadmium dust swallowed from industrial air and/or incidentally ingested from contaminated hands 

(Adamsson et al. 1979). 

In rats, following a 2-hour inhalation exposure to cadmium carbonate, cadmium was primarily eliminated 

in the feces, with a minor component (approximately 1% of fecal excretion) in the urine (Rusch et al. 

1986). Cadmium excretion by both routes declined with time after exposure, with significantly elevated 

excretion found at 7 days, but not 30 days, after exposure (Rusch et al. 1986). Most of the cadmium 

initially excreted in the feces was probably not absorbed, but rather represented particles transported from 

the lung to the gastrointestinal tract (Moore et al. 1973). 

3.4.4.2 Oral Exposure 

Following oral exposure, the major proportion of administered cadmium is found in the feces, because 

absorption is so low (see Section 3.4.1.2) (Kjellström et al. 1978). Among five healthy adult volunteers, 

fecal excretion of a single dose of radiolabeled cadmium declined with time up to 45 days after ingestion, 

while urinary excretion remained at a low, near-constant level (Rahola et al. 1973). After about 20 days, 

fecal and urinary excretion appeared to be comparable (Rahola et al. 1973). In contrast, among 

four healthy adults ingesting cadmium in intrinsically labeled crabmeat, fecal excretion was 30 times 

higher than urinary excretion up to 10 weeks after ingestion of the test meal (Newton et al. 1984). In rats 

orally exposed to up to 0.35 mg/kg/day of cadmium in the diet for 60 days, no significant increase in 

urinary cadmium content was found (Weigel et al. 1984). The overall excretion of absorbed cadmium is 

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CADMIUM 191 

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slow, with biological half-times of 70–270 days in rats or mice orally exposed to cadmium (Engstrom and 

Nordberg 1979; Moore et al. 1973). 

In a comprehensive model developed for human cadmium toxicokinetics, parameters for urinary and fecal 

excretion were derived by adjustments to empirical data derived from human and animal studies 

(Kjellström and Nordberg 1978, 1985). Fecal excretion constitutes unabsorbed cadmium plus "true" 

excretion originating from blood via the intestinal wall (a function of cadmium body burden) and from 

bile via the liver (a function of cadmium liver burden) (Kjellström and Nordberg 1985). Urinary 

excretion depends on blood concentration and kidney concentration, and total excretion is assumed to 

equal daily intake at steady state. Using these methods and assumptions, daily fecal and urinary excretion 

is estimated to be 0.007 and 0.009% of body burden, respectively (Kjellström and Nordberg 1978, 1985). 

A whole-body retention half-time estimate of >26 years was obtained by Shaikh and Smith (1980) in a 

study using orally ingested radiolabelled cadmium and monitoring a subject for over 2 years. 

Groups of 10 female outbred albino rats were exposed to cadmium in drinking water (as cadmium 

chloride) at 0 or 4.8 mg/kg/day for 10 weeks (at 4 weeks prior to mating, at 3 weeks of gestation, or 

3 weeks into lactation). After weaning, exposure to cadmium was terminated. In dams, kidney 

concentrations exceeded liver concentrations, while in pups, the renal and liver concentrations were 

similar at all times during exposure. In pups, both hepatic and renal cadmium concentrations 

considerably increased only during the second half of the lactation period (Ld 11–21). The concentrations 

in the dams were several orders higher than in the offspring. After discontinuation of exposure, organ 

concentration slightly decreased in dams (2% in liver and 12% in kidneys), while in pups, the decrease 

was 84% in the liver and 62% in the kidneys. These values do not indicate cadmium elimination but 

rather dilution caused by growth (Kostial et al. 1993). 

3.4.4.3 Dermal Exposure 

No studies were located regarding excretion in humans after dermal exposure to cadmium. Cadmium was 

reportedly detected in urine in guinea pigs dermally exposed to aqueous cadmium chloride, but no details 

are available (Skog and Wahlberg 1964). 

3.4.5 Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models 

Physiologically based pharmacokinetic (PBPK) models use mathematical descriptions of the uptake and 

disposition of chemical substances to quantitatively describe the relationships among critical biological 

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processes (Krishnan et al. 1994). PBPK models are also called biologically based tissue dosimetry 

models. PBPK models are increasingly used in risk assessments, primarily to predict the concentration of 

potentially toxic moieties of a chemical that will be delivered to any given target tissue following various 

combinations of route, dose level, and test species (Clewell and Andersen 1985). Physiologically based 

pharmacodynamic (PBPD) models use mathematical descriptions of the dose-response function to 

quantitatively describe the relationship between target tissue dose and toxic end points. 

PBPK/PD models refine our understanding of complex quantitative dose behaviors by helping to 

delineate and characterize the relationships between: (1) the external/exposure concentration and target 

tissue dose of the toxic moiety, and (2) the target tissue dose and observed responses (Andersen and 

Krishnan 1994; Andersen et al. 1987a). These models are biologically and mechanistically based and can 

be used to extrapolate the pharmacokinetic behavior of chemical substances from high to low dose, from 

route to route, between species, and between subpopulations within a species. The biological basis of 

PBPK models results in more meaningful extrapolations than those generated with the more conventional 

use of uncertainty factors. 

The PBPK model for a chemical substance is developed in four interconnected steps: (1) model 

representation, (2) model parameterization, (3) model simulation, and (4) model validation (Krishnan and 

Andersen 1994). In the early 1990s, validated PBPK models were developed for a number of 

toxicologically important chemical substances, both volatile and nonvolatile (Krishnan and Andersen 

1994; Leung 1993). PBPK models for a particular substance require estimates of the chemical substancespecific physicochemical parameters, and species-specific physiological and biological parameters. The 

numerical estimates of these model parameters are incorporated within a set of differential and algebraic 

equations that describe the pharmacokinetic processes. Solving these differential and algebraic equations 

provides the predictions of tissue dose. Computers then provide process simulations based on these 

solutions. 

The structure and mathematical expressions used in PBPK models significantly simplify the true 

complexities of biological systems. If the uptake and disposition of the chemical substance(s) are 

adequately described, however, this simplification is desirable because data are often unavailable for 

many biological processes. A simplified scheme reduces the magnitude of cumulative uncertainty. The 

adequacy of the model is, therefore, of great importance, and model validation is essential to the use of 

PBPK models in risk assessment. 

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PBPK models improve the pharmacokinetic extrapolations used in risk assessments that identify the 

maximal (i.e., the safe) levels for human exposure to chemical substances (Andersen and Krishnan 1994). 

PBPK models provide a scientifically sound means to predict the target tissue dose of chemicals in 

humans who are exposed to environmental levels (for example, levels that might occur at hazardous waste 

sites) based on the results of studies where doses were higher or were administered in different species. 

Figure 3-3 shows a conceptualized representation of a PBPK model. 

If PBPK models for cadmium exist, the overall results and individual models are discussed in this section 

in terms of their use in risk assessment, tissue dosimetry, and dose, route, and species extrapolations. 

3.4.5.1 Summary of Cadmium PBPK Models 

Several models have been reported to describe the kinetics of cadmium in mammalian systems. Of these 

models, the Nordberg-Kjellström model (Kjellström and Nordberg 1978; Nordberg and Kjellström 1979) 

has been the most widely used for cadmium risk assessment. Three of the most relevant cadmium models 

will be discussed here. 

3.4.5.2 Cadmium PBPK Model Comparison 

Although the Nordberg-Kjellström model (Kjellström and Nordberg 1978; Nordberg and Kjellström 

1979) has its limitations, it provides the best overall description of cadmium toxicokinetics and is largely 

based on human data. The Shank (Shank et al. 1977) and Matsubara-Khan (Matsubara-Khan 1974) 

models are not as useful for human risk assessment applications, but they do provide useful insights into 

the absorption, distribution, and compartmentalization of cadmium in laboratory animals. These insights 

may have some future use in human risk assessment as PBPK models for cadmium continue to be refined. 

3.4.5.3 Discussion of Cadmium Models 

The Nordberg-Kjellström Model 

The Nordberg-Kjellström model (Kjellström and Nordberg 1978; Nordberg and Kjellström 1979) is a 

linear multicompartment model that is the most commonly used model for cadmium risk assessment work 

today. The Nordberg-Kjellström schematic model diagram is shown in Figure 3-4. 

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Lungs 

Liver 

Fat 

Slowly 

perfused 

tissues 

Richly 

perfused 

tissues 

Kidney 

Skin 

V 

E 

N 

O 

U 

S 

B 

L 

O 

O 

D 

A 

R 

T 

E 

R 

I 

A 

L 

B 

L 

O 

O 

D 

Vmax 

Km 

Ingestion 

Inhaled chemical Exhaled chemical 

GI 

Tract 

Feces 

Urine

 Chemicals 

contacting skin 

Note: This is a conceptual representation of a physiologically based pharmacokinetic (PBPK) model for a 

hypothetical chemical substance. The chemical substance is shown to be absorbed via the skin, by inhalation, or by 

ingestion, metabolized in the liver, and excreted in the urine or by exhalation. 

Source: adapted from Krishnan and Andersen 1994 


 


 

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Figure 3-3. Conceptual Representation of a Physiologically Based
 

Pharmacokinetic (PBPK) Model for a 

Hypothetical Chemical Substance
 

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Risk assessment. The Nordberg-Kjellström model has been demonstrated to be a useful model in 

human risk assessment work. Frazier (1994), however, noted that the model has two major limitations: 

(1) the linear nature of the model may not adequately allow a good description of known nonlinearities in 

biological responses to cadmium dosing, and (2) the phenomenological approach taken with this model 

does not provide a foundation for incorporating biological variability into the model parameters. 

Description of the Model. The Nordberg-Kjellström model (see Figure 3-4) is a linear multicompartment model that describes the disposition of cadmium via the oral and inhalation routes of 

exposure only. Dermal exposure and subsequent absorption through the skin were assumed to be 

negligible in this model. For inhalation exposures, the model accounts for different deposition patterns 

for different size particles in nasopharyngeal, tracheobronchial, and alveolar regions of the respiratory 

tract. Particles with mass median aerodynamic diameter (MMAD) of 5 μm (i.e., cadmium-laden dust) 

were assumed to distribute mainly to the nasopharyngeal region (75%), with lesser amounts depositing in 

the alveolar (20%) and tracheobronchial (5%) regions. Particles of 0.05 μm MMAD (i.e., cigarette 

smoke) were assumed to deposit 50% in the alveolar compartment, 10% in the tracheobronchial 

compartment, and none in the nasopharyngeal compartment. The remaining amounts are exhaled. For all 

particle sizes initially deposited in the nasopharyngeal and tracheobronchial compartments, mucociliary 

clearance clears some particles from the respiratory tract to enter the oral compartment for absorption or 

out of the body and back to the environment. Assumed model coefficient values and the available 

physiological parameters are shown in Table 3-12. 

For the oral route of exposure, cadmium may enter the gastrointestinal tract via food or water 

contaminated with cadmium, or as cadmium particles embedded in mucus from the respiratory tract via 

the mucociliary/tracheobronchial escalator. By either route of exposure, the model assumes that cadmium 

enters into any of three blood compartments (B) (see Figure 3-4). B1 is the plasma compartment where 

cadmium may bind to plasma components (i.e., albumin and other organic constituents). B2 is the redblood cell compartment, which represents the accumulation of cadmium in erythrocytes, while 

B3 represents the binding of cadmium to metallothionein. The model does not take into account 

induction of metallothionein after cadmium exposure. From the blood, cadmium is calculated to 

distribute to either the liver, kidney, or "other tissues," the major accumulation sites. Elimination is either 

via the feces or in the urine. The transport of cadmium between the compartments is assumed to follow 

first-order exponential functions and is driven on concentration-dependent gradients. 

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A G 

Lung E1 

Intestines E2 

Daily uptake 1 

Blood 2. B2 Blood 3. B3 

Liver 

L 

Kidney 

K 

Feces 

F 

Urine 

U 

C1 = A 

C2 = A 

C6 = E2

C3 = E1 

I2 = C7 = I (mo = C8)

I1 = I – I2 

CX = B1 C16 = B2 

C11 = B1 C15 = L 

12 = B1 

C13 = L C14 = L 

C17 = B3 

C19 = K 

(1 – C17) = B3 

C18 = K 

Gastrointestinal 

tract intake 

Blood 1. B1 C9 = E1 C10 = T 

C

Other tissues 

T 

Source: Kjellström and Nordberg 1978 

CADMIUM 196 

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Figure 3-4. A Schematic Representation of the Nordberg-Kjellström Model 

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Table 3-12. Assumed Model Parameters and Some Physiologic Parameters for 

the Nordberg-Kjellström Model 

Values fitting to 

Coefficient or parameter Assumed range Unita empirical data 

Model parameters 

C1 0.1–0.2 (cigarette smoke) 0.1 

0.4–0.9 (factory smoke) 0.7 

C2 0.4–0.6 (cigarette smoke) 0.4 

0.1–0.3 (factory smoke) 0.13 

C3 0.01–1.0 day-1 0.05 

C4 0.1xC3 = 0.001–0.1 day-1 0.005 

C5 0.03–0.1 0.048 

C6 0.05 day-1 0.05 

C7 0.2–0.4 0.25 

C8 0.5–5.0 μg 1 

C9 0.4–0.8 0.44 

C10 0.00004–0.0002 day-1 0.00014 

C11 0.05–0.5 0.27 

C12 0.1–0.4 0.25 

C13 0–0.0001 day-1 0.00003 

C14 0.0001–0.0003 day-1 0.00016 

C15 0–0.0001 day-1 0.00005 

C16 0.004–0.015 day-1 0.012 

C17 0.8–0.98 0.95 

C18 0–0.0001 day-1 0.00001 

C19 0.00002–0.0002 day-1 0.00014 

CX 0 01–0.05 0.04 

C20 0.05–0.5 0.1 

C21 0–0.000002 day-1 0.0000011 

Physiologic parameters 

Average liver weight 1,500 gram 

Average blood volume 70 mL/kg 

Average blood specific gravity 1.06 

Average daily urine excretion (adult) 1.0 L 

Average daily urine excretion (aged) 0.9 L 

Average daily urine excretion (child) 0.5 L 

a

Blanks indicate a unitless value 

Source: Kjellström and Nordberg 1978; Nordberg and Kjellström 1979 

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Validation of the model. The Nordberg-Kjellström model was validated using several independent 

sets of human data from both Sweden and Japan. The data set by Friberg et al. (1974) estimated that 

smoking 20 cigarettes a day would result in an inhalation of 2–4 μg/day of cadmium, assuming smoking 

started at 20 years of age and daily cadmium intake from food was 16 μg/day. Based on the Friberg et al. 

(1974) data, the model predictions of cadmium concentrations in the kidney agreed well with the 

observed data from a study by Elinder et al. (1978); however, the model predicted higher than expected 

values for liver cadmium compared to the observed data from the Elinder study. The model's urinary 

excretion of cadmium (0.84 μg/24 hours for a 50-year-old person) agreed well with the observed data 

(0.56–0.8 μg/24 hours). The model predicted blood cadmium levels for Swedish smokers to be about 

2 ng/g which compared well to the actual concentration of 1.6 ng/g. 

The model was also validated against a data set for an average 45-year-old Japanese person living in 

Tokyo whose daily intake of cadmium is 40 μg via food and 2.7 μg via the inhalation route. Subjects 

were assumed to be smokers averaging 24 cigarettes a day starting at age 20. Based on these exposure 

conditions, the measured values for cadmium in the kidney, liver, and "other tissues" (in this case, muscle 

only) were reported to be 65, 3.4, and 0.2 μg/g, respectively, with the model predicting 48, 3.2, and 

0.18 μg/g. For blood and urine, the measured values were 4.5 μg/g for blood and 1.1 μg/L for urine; the 

model predicted 3.4 μg/g and 1.3 μg/24 hours (assuming 1 L of urine output/day, the value would be 

1.3 μg/L). 

Another study of Japanese people reported cadmium concentrations in urine in relation to high cadmium 

concentrations in rice in their daily diet. For people who consumed rice containing 0.04 μg/g of rice 

(240 μg/day), the observed urinary level of cadmium was 7 μg/L; consumption of rice containing 1.1 μg 

cadmium/g of rice (660 μg/day), resulted in an observed value of 14 μg/L of urine. After making certain 

assumptions about the average daily consumption of rice containing an assumed amount of cadmium, and 

assuming an average urine production of 1 L/day, the model calculated urinary levels of 4.8 and 

15.5 μg/L of urine, agreeing well with the observed values. 

The model was also validated against a data set with high concentrations of cadmium in air (50 μg/m3

) 

(Piscator 1972) and blood cadmium concentrations ranging from 10 to 50 ng/g whole blood. Calculated 

blood, urine, liver, and kidney levels of cadmium agreed only roughly with the observed values; however, 

the authors concluded that the model predictions may not be accurate based on the observations that 

workers with long exposure histories had most likely experienced higher exposure levels in the past, 

skewing the data set, resulting in poor model predictions. Another data set by Piscator (1984) involved a 

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CADMIUM 199 

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group of Swedish workers involved in polishing cadmium-plated objects, who were exposed to high 

concentrations of cadmium for ≤2 years. Cadmium levels were measured in the urine and blood. When 

this exposure data set was input into the model, the model could not adequately predict blood and urine 

levels for these workers. 

Target tissues. The Nordberg-Kjellström model assumes that the kidney and liver are the two 

specific target tissues in which cadmium accumulates. The model also accounts for all other tissue 

accumulation in the "other tissues" compartment (i.e., muscle). The model assumes a human liver tissue 

half-life (t1/2) of 4–19 years and a kidney t1/2 of 6–38 years. For the "other tissue" compartments, t1/2 was 

assumed to be 9–47 years. The Nordberg-Kjellström model does account for the loss of renal tubular 

epithelial cells leading to a loss of tubular reabsorptive capacity. This loss of cells could conceivably 

result in an increase in the excretion of cadmium from the tubules and an increase in the transport of 

cadmium from the tubules to the blood. This loss of cells is theorized to account for the large t1/2 range 

for cadmium in the kidney. The model assumed that no changes in the movement of cadmium from the 

kidney to blood occurred with age and that the loss of cadmium from the kidney to the urine increased 

linearly after the age of 30. 

The Nordberg-Kjellström model also accounted for differences in kidney and liver weights among 

different age groups and between peoples of different ethnic origins. The model corrected for differences 

in liver, kidney, blood, and "other tissue" weights with relation to age (1 and 79 years of age) and 

ethnicity (Japan and Sweden). 

Species extrapolation. The Nordberg-Kjellström model was based solely on data collected from 

humans and was intended for human risk assessment applications. The model did not address any 

potential application for this model of cadmium in laboratory animals. 

High-low dose extrapolation. The Nordberg-Kjellström model has been shown to adequately 

predict fluid and tissue concentrations via the oral and inhalation routes of exposure for humans exposed 

to low doses of cadmium. However, the model has difficulty in adequately predicting fluid and tissue 

concentrations in humans exposed to high concentrations of cadmium, especially for those individuals 

exposed to high concentrations via the inhalation route. 

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Interroute extrapolation. The Nordberg-Kjellström model adequately predicted the fate of cadmium 

in target tissues after exposure via the inhalation and oral routes. The dermal route of exposure was not 

incorporated into the model parameters and was considered an insignificant route of exposure in humans. 

The Shank Model 

Risk assessment. The Shank model (Shank et al. 1977) may have the potential to serve as an 

alternative mathematical model for predicting the retention of cadmium in biological systems. 

Unfortunately, no human data were used to validate the Shank model for use as a risk assessment tool in 

cases of human exposure. In addition, the Shank model was validated only for the intravenous and 

subcutaneous routes of exposure; no data were presented for the oral, inhalation, or dermal routes of 

exposure. 

Description of the model. A schematic representation of the Shank model is illustrated in 

Figure 3-5. The model mathematically represents the dynamic transport of cadmium between 

compartments in a mammalian biological system based on the male adult SW/NIH mouse as the test 

animal species. The intent was to predict the retention of cadmium in other species of animals (including 

humans) without requiring an adjustment of species-specific rate constants from within the model. 

Male adult mice of the SW/NIH strain were dosed intravenously with 109Cd as 109Cd acetate. Mice 

received 1–3 intravenous injections spaced 48 hours apart. Animals in each group were sacrificed at 

2 and 10 minutes and 1, 10, and 48 hours after the last dose. Tissues (liver, kidney, pancreas, spleen, 

gastrointestinal tract, testes, carcass, and feces) were harvested and the radioactivity recorded. A ninecompartment model was derived. Cadmium kinetics between compartments are described by first-order 

kinetics. The individual compartment retention values, obtained from the distribution study, were 

incorporated into the model equations and the rate constants derived. 

Validation of the model. The Shank model was validated using three independent data sets. Mann 

(1973) dosed dogs, goats, and sheep with one intravenous injection of 109Cd acetate (30 μCi), and the liver 

and kidneys were examined for cadmium content 8 weeks after administration. The Shank model's 

predicted values of cadmium retention in liver and kidneys at 8 weeks after a single administration were 

in good agreement with the observed values of the Mann (1973) study in all three species. Only data 

from the liver and kidneys were available for evaluation. A data set from a study by Gunn et al. (1968b) 

was used to evaluate the ability of the Shank model to predict the retention of cadmium in liver and 

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Figure 3-5. A Schematic Representation of the Shank Model 

Kidney 

Blood 

Liver 

Spleen 

Residual 

carcass 

Testes 

G.I. 

Pancreas 

RKB*K RBK*B 

RSB*S 

RBS*B 

RBL*B 

RGB*G 

RGB*B 

RGF*G 

RLB*L 

RBP*B 

RPB*P 

Feces 

RTB*T 

RBT*B 

RTB*T 

RBC*B 

Source: Forrester 1968
 

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3. HEALTH EFFECTS 

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CADMIUM 202 

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kidney after a single subcutaneous administration of cadmium chloride. Animals in that study were 

sacrificed 2 weeks after administration, and the liver and kidneys were examined for cadmium content. 

The model values for the same time period were in very close agreement with observed values. Again, 

only data from the liver and kidneys were available for evaluation. Finally, a data set by Shanbaky (1973) 

was used to test the model's validity with multiple injections of cadmium acetate in rats. Five injections 

of cadmium acetate were administered over a 48-hour period; liver, kidneys, pancreas, spleen, and 

gastrointestinal tract were examined for cadmium content. The Shank model was found to be in close 

agreement with the arithmetic means of observed values found in the Shanbaky (1973) study. 

No human data were presented to validate the model's effectiveness in predicting the cadmium retention 

in human target tissues after either a single or multiple dosing regime. 

Target tissues. The target tissues for this model included the liver, kidney, pancreas, spleen, 

gastrointestinal tract, testes, and carcass of laboratory animals. No human tissue was used to derive 

cadmium retention in any of these tissues. 

Species extrapolation. The model used goats, dogs, rats, mice, and sheep with various doses and 

dosing schemes of cadmium acetate and cadmium chloride and was found to serve as a good predictor of 

cadmium retention in the target tissues listed above. No human data were presented to determine if the 

model could satisfactorily predict the cadmium retention in human target tissues. 

High-low dose extrapolation. High- and low-dose extrapolation was not specifically addressed by 

the Shank model. 

Interroute extrapolation. Interroute extrapolations were addressed in a limited fashion by the Shank 

model. The model appeared to adequately predict the amount of cadmium retention in the target organs 

of laboratory animals, in particular the liver and kidney, when dosed by either the intravenous or 

subcutaneous routes. The inhalation and dermal routes of exposure, and other parenteral routes of 

exposure (intramuscular, intraperitoneal, intradermal, etc.) were not addressed by the Shank model. No 

human data were presented to determine if interroute extrapolations were valid. 

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CADMIUM 203 

3. HEALTH EFFECTS 

The Matsubara-Khan Model 

Risk assessment. The Matsubara-Khan model (Matsubara-Khan 1974) has not been used as a tool 

in risk assessment for humans. This model does demonstrate that cadmium kinetics and biological halflives vary by tissue. 

Description of the model. The Matsubara-Khan model is a simple model that attempted to fit 

cadmium elimination kinetic parameters into either a one- or two-compartment model. To obtain the data 

for the model, male and female ICR mice (8 weeks of age) were administered a single subcutaneous 

injection of a known amount of 109cadmium chloride. Specific groups of mice were sacrificed at 1, 2, 4, 

8, 16, 32, 64, or 128 days after injection. At the time of sacrifice, blood, liver, kidney, salivary gland, 

stomach wall and stomach contents, small intestine and small intestine contents, and colon wall and colon 

contents were removed and the amount of 109Cd remaining in these tissues was determined. 

An oral study was conducted in conjunction with the subcutaneous study described above. In the oral 

study, 8-week-old male mice (ddd x BALB/c; F1) were orally administered 115mcadmium chloride by 

gavage. Groups of mice were sacrificed at 1, 2, 4, 8, 16, 32, 64, or 128 days after injection. At the time 

of sacrifice, liver, kidney, salivary gland, stomach wall, gonad, and spleen were removed and the amount 

of 115mCd remaining in these tissues was determined. 

The rate of uptake, rate constants, and biological half-lives determined for the subcutaneous and orally 

dosed mice are summarized in Table 3-13. Matsubara-Khan found that tissue kinetics in mice dosed 

subcutaneously with 109cadmium chloride fit into either a one- or two-compartment model, depending on 

the tissue. The data from the digestive tract organs (stomach wall, small intestine, and colon) were best 

fitted into a 1-compartment model, with a strained fit of the data from the digestive tract contents 

(stomach, small intestine, and colon contents) to the one-compartment model. Data from the blood, liver, 

kidneys, and salivary glands were best fitted to the two-compartment model. Extremely small second-rate 

constants in the kidneys and salivary glands indicate that the elimination of cadmium from these tissues is 

very slow. For the oral study, similar findings were observed, with data from the gonads and spleen 

fitting the one-compartment model best. Biological half-lives were invariably longer for the 

subcutaneously dosed animals, while the rate constants were slightly smaller for the subcutaneously dosed 

animals. Sex-related differences in rate of uptake, rate constants, and biological half-lives were not 

found, except in the kidney data in which females had slightly smaller rate constants. 

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3. HEALTH EFFECTS 

Table 3-13. Estimated Parameters, Rate of Uptake, Rate Constants, and 

Biological Half-Lives in Selected Mouse Organs After Subcutaneous 

and Oral Administrations of 109CdCI2 

Rate of uptake Rate constants b and c Biological half-life 

(95% CL) (95% CL) (days) 

Organ SC PO SC PO SC PO 

Liver 21 8.7 0.011 0.016 631.2 430.76 

0.57 0.91 

Kidney 22 1.4 0.0007 0.016 9902.3 4332.3 

0.30 0.30 

Salivary gland 21 0.33 0.0016 0.0047 4330.95 1500.89 

0.73 0.78 

Blood 0.15 NM 0.024 NM 291.1 NM 

0.65 

Stomach wall 1.7 0.36 0.0073 0.017 95 41 

Stomach contents 0.68 NM 0.062 NM 11 NM 

Small intestine 0.95 NM 0.01 NM 69 NM 

Small intestine contents 2.5 NM 0.067 NM 10 NM 

Colon 1.4 NM 0.013 NM 53 NM 

Colon contents 4.1 NM 0.15 NM 4.6 NM 

Gonad NM 0.37 NM 0.012 NM 58 

Spleen NM 0.44 NM 0.0011 NM 630 

CL = confidence limits; PO = oral; SC = subcutaneous; NM = not measured 

Source: Matsubara-Khan 1974 

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Validation of the model. No independent data sets were used to validate the Matsubara-Khan 

model. 

Target tissues. For the subcutaneous injection study, the Matsubara-Khan model used blood, liver, 

kidney, salivary gland, stomach wall and stomach contents, small intestine and small intestine contents, 

and colon wall and colon contents. For the oral study, the model used liver, kidney, salivary glands, 

stomach wall, gonads, and spleen. 

Species extrapolation. No species extrapolations were performed in the Matsubara-Khan model. 

High-low dose extrapolation. No high-low dose extrapolations were performed in the MatsubaraKhan model. 

Interroute extrapolation. The Matsubara-Khan model compared the oral and subcutaneous routes 

and reported similar rate constants for many of the tissues examined. Biological half-lives varied 

considerably for the kidney and salivary gland, but were not much different for liver between the two 

routes of exposure. 

3.5 MECHANISMS OF ACTION 

3.5.1 Pharmacokinetic Mechanisms 

Absorption. Cadmium can be absorbed by the inhalation, oral, and dermal routes of exposure 

regardless of its chemical form (chloride, carbonate, oxide, sulfide, sulfate, or other forms). Absorption 

by the dermal route of exposure, however, is relatively insignificant for cadmium, although small 

amounts are absorbed percutaneously over a long period of time (Wester et al. 1992). Absorption is 

mainly of concern from inhalation and oral exposures. 

Gastrointestinal tract absorption of cadmium (in any chemical form) is relatively low when compared to 

the total amount of cadmium absorbed via the inhalation route. In humans, cadmium absorption has been 

reported to be approximately 1–10% ((Flanagan et al. 1978; McLellan et al. 1978; Newton et al. 1984; 

Rahola et al. 1973; Shaikh and Smith 1980; Vanderpool and Reeves 2001). In other species, 

gastrointestinal tract absorption of cadmium has been determined to be 1–2% in mice and rats (Decker et 

al. 1958; Ragan 1977), 0.5–3.0% in monkeys (Friberg et al. 1974), 2% in goats (Miller et al. 1969), 5% in 

pigs and lambs (Cousins et al. 1973; Doyle et al. 1974), and nearly 16% in cattle (Miller et al. 1967). 

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Lehman and Klaassen (1986) investigated the dose-dependence of cadmium absorption and disposition in 

male Sprague-Dawley rats. Cadmium absorption was estimated to be 0.35 and 1% following oral 

exposure to 1 or 10,000 μg/kg, respectively. Goon and Klaassen (1989) measured absorption of cadmium 

in rat intestine in situ and reported that the intestinal absorption of cadmium is dosage independent at low 

dosages of cadmium (<10 μg/kg) and dosage dependent at high dosages (>10 μg/kg). They also 

evaluated the role of metallothionein and concluded that saturation of intestinal metallothionein is not a 

major determinant of the observed dosage-dependent absorption of cadmium. 

Although the mechanism involved in the intestinal absorption of cadmium has not been fully elucidated, 

there is evidence that one or more transporter proteins are involved. Several studies have found evidence 

that divalent metal transporter I protein plays an important role in the gastrointestinal absorption of 

cadmium (Kim et al. 2007; Park et al. 2002; Ryu et al. 2004). However, studies in knockout mice suggest 

that other transporter proteins are involved with cadmium absorption (Min et al. 2008; Ryu et al. 2004; 

Suzuki et al. 2007). 

In some cases, cadmium bound to metallothionein (as in food) is not absorbed or distributed from the 

gastrointestinal tract as readily as ionic cadmium. Mice had lower blood and liver cadmium levels from 

oral exposure to cadmium-metallothionein, compared to levels from cadmium chloride exposure for 

comparable doses, but the cadmium-metallothionein resulted in higher kidney cadmium levels. Sharma et 

al. (1983) reported that human exposure to very high intakes of cadmium during the consumption of 

oysters resulted in increases in whole blood and urine cadmium levels; however, the increase was not 

proportional to the level of intake. 

A higher fraction of inhaled cadmium than ingested cadmium is absorbed. The total amount of cadmium 

absorbed by the body via the lungs depends on the particle size. Larger particles are deposited in the 

nasopharyngeal and tracheobronchial airways via impaction, and are largely cleared by mucociliary 

processes, leading to absorption by the gastrointestinal tract. Smaller particles reach the smaller airways 

and alveoli, and depending on the particle's solubility, are absorbed and distributed to the rest of the body. 

Solubility in lung fluids plays a role in absorption from the lung into the body of cadmium salts. 

Theoretically, the highly soluble salts, chloride, nitrate, acetate, and sulfate would be expected to give the 

highest blood levels following inhalation exposure to a given air concentration. The insoluble cadmium 

salts, the various sulfides, should yield the lowest blood level. The lung, however, is rich in carbon 

dioxide that is continuously transferred from the blood. Particles of the various cadmium sulfides within 

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CADMIUM 207 

3. HEALTH EFFECTS 

the lung can react with this carbon dioxide. Lung tissue may then absorb and transfer solubilized or 

released cadmium ions to the blood. 

No direct data, however, are available on cadmium deposition, retention, or absorption in the human lung. 

Data from animal studies indicate that lung retention is greatest after short-term exposure, 5–20% after 

15 minutes to 2 hours (Barrett et al. 1947; Henderson et al. 1979; Moore et al. 1973; Rusch et al. 1986). 

The initial lung burden declines slowly after exposure ceases (Henderson et al. 1979; Moore et al. 1973; 

Rusch et al. 1986), due to the absorption of cadmium and the lung clearance of deposited particles. After 

longer periods of inhalation exposure to cadmium, somewhat lower lung retentions are found (Glaser et 

al. 1986). The absorption of cadmium in the lung differs somewhat among chemical forms, but the 

pattern apparently does not correlate well with solubility in water (Glaser et al. 1986; Rusch et al. 1986). 

Retention of cadmium has been reported to be >40% in rats (Moore et al. 1973), 40% in canines (Friberg 

et al. 1974), and 10–20% in mice (Potts et al. 1950). 

The cadmium levels in cigarettes range from 0.28 to 3.38 μg (Elinder et al. 1985b; Watanabe et al. 1987); 

the mean in 38 U.S. brands was 1.07 μg (Watanabe et al. 1987). Approximately 10% of the cadmium in 

cigarettes is inhaled (Elinder et al. 1985b). Based on comparison of cadmium body burdens in human 

smokers and nonsmokers, cadmium absorption from cigarettes appears to be higher than absorptions of 

cadmium aerosols measured in animals (Nordberg et al. 1985). The chemical form of cadmium in 

cigarette smoke is likely to be similar to that produced by other combustion processes, primarily cadmium 

oxide aerosols. The greater absorption of cadmium from cigarette smoke is likely due to the very small 

size of particles in cigarette smoke and the consequent very high alveolar deposition (Nordberg et al. 

1985). 

Distribution and Metabolism. Absorbed cadmium is distributed throughout the body, with the 

highest concentrations found in the liver and kidneys. Cadmium is not known to undergo direct 

metabolic conversions. It has a high affinity for the sulfydryl groups of albumin and metallothionein 

(Nordberg et al. 1985). The interaction between cadmium and metallothionein plays a critical role in the 

toxicokinetices and toxicity, as discussed in Section 3.5.2, of cadmium. Metallothionein sequesters a 

large fraction of tissue cadmium (Shaikh 1982) and studies in metallothionein transgenic and 

metallothionein-null mice suggest that metallothionein influences tissue retention, but may not affect 

cadmium distribution to the liver, kidney, pancreas, or spleen (Liu and Klaassen 1996; Liu et al. 1996; 

Wong and Klaassen 1980a). Metallothionein turns over with half-lives of 2.8 days in the rat liver and 

5 days in the kidney (Shaikh and Smith 1976); however, cadmium is retained in both organs bound 

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CADMIUM 208 

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mainly to methallothionein. It has a retention half-time of 73 days in the liver and a life-time in the 

kidneys (Shaikh 1982). 

Shaikh et al. (1993) report that disposition of cadmium in mouse liver, kidney, and testes is different for 

different strains, sex, or age. Different dose levels (i.e., subcutaneous doses in the 5–30 μmol/kg body 

weight range) also altered the disposition. Liver cadmium levels and metallothionein levels did not 

always correlate with hepatotoxicity. The difference in the tissue accumulation of cadmium may relate to 

variations in the hormonal or other intrinsic factors that affect cellular uptake of cadmium, subcellular 

distribution of cadmium, or metallothionein metabolism. 

Excretion. Since a small fraction of the cadmium presented to the gastrointestinal tract is absorbed, 

most of the oral dose is excreted via the feces. After inhalation exposure to cadmium, the initial lung 

burden of cadmium-laden particles depositing in the nasopharyngeal or central airways will be cleared via 

the mucociliary mechanisms, possibly undergoing a small amount of absorption by the oral route. The 

remaining cadmium particles will be absorbed in the lung. Once absorbed cadmium has distributed 

throughout the body (primarily to the liver and kidney), the amounts of fecal and urinary excretion of 

cadmium are approximately equal. The amount of cadmium in the urine of occupationally exposed 

workers increases proportionally with body burden of cadmium, but the amount of cadmium excreted 

represents only a small fraction of the total body burden unless renal damage is present; in this case, 

urinary cadmium excretion increases markedly (Roels et al. 1981b). 

Klaassen and Kotsonis (1977) evaluated biliary excretion of an intravenous bolus of cadmium chloride in 

the rat, rabbit, and dog. Marked species variation in biliary excretion was observed with rabbits at about 

1/6th the rate of the rats, and dogs about 1/300th the rate of the rats. In the rat, the bile/plasma 

concentration ratio of cadmium was highly dose dependent, increasing with higher dose; at 0.1 mg/kg, the 

bile/plasma ratio was 2.6 and at 3.0 mg/kg, the bile/plasma ratio was 133. The bile/liver concentration 

ratio of cadmium was equal to or much lower than 1 decreasing to <1% for the low dose regimen. 

3.5.2 Mechanisms of Toxicity 

Cadmium is toxic to a wide range of organs and tissues; however, the primary target organs of cadmium 

toxicity are the kidneys; bone and lung (following inhalation exposure) are also sensitive targets of 

toxicity. Changes in the kidney due to cadmium toxicosis have been well established. Chronic exposure 

to cadmium by the oral or inhalation routes has produced proximal tubule cell damage, proteinuria 

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(mainly low-molecular weight proteins, such as β2-microglobulin), glycosuria, amino aciduria, polyuria, 

decreased absorption of phosphate, and enzymuria in humans and in a number of laboratory animal 

species. The clinical symptoms result from the degeneration and atrophy of the proximal tubules, or (in 

worse cases) interstitial fibrosis of the kidney (Stowe et al. 1972). Cadmium has been shown to perturb 

lipid composition and enhance lipid peroxidation (Gill et al. 1989b). Depletion of antioxidant enzymes, 

specifically glutathione peroxidase and superoxide dismutase, has been proposed as the mechanism of 

cadmium’s cardiotoxic effects (Jamall and Smith 1985a), but subsequent studies showed that cardiotoxic 

mechanisms other than peroxidation are also present (Jamall et al. 1989). Cadmium has been shown to 

alter zinc, iron and copper metabolism (Petering et al. 1979) as well as selenium (Jamall and Smith 

1985b). Xu et al. (1995) propose that an initiating step in cadmium-induced toxicity to the testes is 

cadmium interference with zinc-protein complexes that control DNA transcription which subsequently 

leads to apoptosis. Cadmium sequestration by metallothionein (or a chelator in the case of the Xu et al. 

[1995] study) prevents cadmium from disrupting zinc-dependent transcriptional controls. 

Cardenas et al. (1992a) investigated a cadmium-induced depletion of glomerular membrane polyanions 

and the resulting increased excretion of high-molecular-weight proteins. Interference with glomerular 

membrane polyanionic charge may precede the tubular damage as a more sensitive and early response to 

cadmium (Roels et al. 1993). Acute or chronic doses of cadmium have also been reported to reduce 

hepatic glycogen stores and to increase blood glucose levels. Intralobular fibrosis, cirrhosis, focal 

mononuclear infiltrates, and proliferation of the smooth endoplasmic reticulum are among the nonspecific 

histopathological indicators of cadmium toxicity. 

Cadmium complexed with metallothionein from the liver can redistribute to the kidney (Dudley et al. 

1985). When metallothionein-bound cadmium is transported to the kidney, it readily diffuses and is 

filtered at the glomerulus, and may be effectively reabsorbed from the glomerular filtrate by the proximal 

tubule cells (Foulkes 1978). In the kidneys, exogenous metallothionein is degraded in lysosomes and 

released cadmium is sequested by the endogenous metallothionein as well as other proteins (Cherian and 

Shaikh 1975; Squibb et al. 1984; Vestergaard and Shaikh 1994). This non-metallothionein-bound 

cadmium can then induce new metallothionein synthesis in the proximal tubule (Squibb et al. 1984). 

Early work indicated that metallothionein binding decreased the toxicity of cadmium, and the ability of 

the liver to synthesize metallothionein appeared to be adequate to bind all the accumulated cadmium 

(Goyer et al. 1989; Kotsonis and Klaassen 1978). The rate of metallothionein synthesis in the kidney is 

lower than in the liver (Sendelbach and Klaassen 1988), and is thought to be insufficient, at some point, to 

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bind the intrarenal cadmium (Kotsonis and Klaassen 1978). Renal damage is believed to occur when the 

localization of cadmium, or an excessive concentration of cadmium, is unbound to metallothionein. 

Acute exposure to low levels of cadmium bound to metallothionein produced an intracellular renal 

damage as described above (Squibb et al. 1984), but damage to brush-border membranes of the renal 

tubule has also been reported from metallothionein-bound cadmium (Suzuki and Cherian 1987) 

suggesting other toxic mechanisms may be present. 

Dorian et al. (1992a) evaluated the intra-renal distribution of 109cadmium-metallothionein injected 

(intravenously) into male Swiss mice at a nonnephrotoxic dose (0.1 mg Cd/kg) and concluded that 

cadmium-metallothionein-induced nephrotoxicity might be due, at least in part, to its preferential uptake 

of cadmium-metallothionein into the S1 and S2 segments of the proximal tubules, the site of cadmiuminduced nephrotoxicity. In a companion study, Dorian et al. (1992b) reported that this preferential renal 

uptake was also observed after administration of various doses of [35S]cadmium-metallothionein. In 

contrast to the earlier observed persistency of 109cadmium in the kidney after 109cadmium-metallothionein 

administration, however, 35S disappeared rapidly (with a half-life of approximately 2 hours); 24 hours 

after injection of [35S]cadmium-metallothionein, there was very little 35S left in the kidneys. These 

observations indicate that the protein portion of cadmium-metallothionein is rapidly degraded after renal 

uptake of cadmium metallothionein and that the released cadmium is retained in the kidney. 

The toxic effects and distribution of cadmium were compared after intravenous injection of 109cadmiummetallothionein at 0.05–1 mg Cd/kg body w eight and 109cadmium chloride at 0.1–3 mg/kg in male Swiss 

mice (Dorian et al. 1995). Cadmium-metallothionein increased urinary excretion of glucose, and protein 

indicated renal injury, with dosages as low as 0.2 mg Cd/kg. In contrast, renal function was unaltered by 

cadmium chloride administration, even at dosages as high as 3 mg Cd/kg. Cadmium-metallothionein 

distributed almost exclusively to the kidney, whereas cadmium chloride preferentially distributed to the 

liver. However, a high concentration of cadmium was also found in the kidneys after cadmium chloride 

administration (i.e., the renal cadmium concentration after administration of a high but nonnephrotoxic 

dose of cadmium chloride was equal to or higher than that obtained after injection of nephrotoxic doses of 

cadmium-metallothionein). Light microscopic autoradiography studies indicated that cadmium from 

cadmium-metallothionein preferentially distributed to the convoluted segments (S1 and S2) of the 

proximal tubules, whereas cadmium from cadmium chloride distributed equally to the various segments 

(convoluted and straight) of the proximal tubules. However, the concentration of cadmium at the site of 

nephrotoxicity, the proximal convoluted tubules, was higher after cadmium chloride than after cadmiummetallothionein administration. A higher cadmium concentration in both apical and basal parts of the 

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proximal cells was found after cadmium chloride than after cadmium-metallothionein administration. 

The authors suggest that cadmium-metallothionein is nephrotoxic, and cadmium chloride is not 

nephrotoxic because of a higher concentration of cadmium in the target cells after cadmiummetallothionein. Dorian and Klaassen (1995) evaluated the effects of zinc-metallothionein on 

109cadmium-metallothionein renal uptake and nephrotoxicity and concluded that zinc-metallothionein is 

not only nontoxic to the kidney at a dose as high as 5 μmole metallothionein/kg, but it can also protect 

against the nephrotoxic effect of cadmium-metallothionein without decreasing renal cadmium 

concentration. 

To further test the hypothesis that nephrotoxicity produced from chronic cadmium exposure results from a 

cadmium-metallothionein complex, Liu et al. (1998) exposed metallothionein-null mice to a wide range 

of cadmium chloride doses, 6 times/week for up to 10 weeks. Renal cadmium burden increased with dose 

and duration up to 140 μg Cd/g kidney in control mice (i.e., metallothionein normal) with a 150-fold 

increase in renal metallothionein levels (800 μg metallothionein/g kidney). Renal cadmium was much 

lower in metallothionein-null mice (10 μg Cd/g), and metallothionein levels were not detectable. The 

maximum tolerated dose of cadmium (as indicated by routine urinalysis and histopathology measures) 

was approximately 8 times higher in control mice than in metallothionein-null mice. Lesions were more 

severe in metallothionein-null mice than in controls. 

The critical concentration of cadmium in the renal cortex that is likely to produce renal dysfunction also 

remains a topic of intense investigation. Whether the critical concentration of urinary cadmium is closer 

to 5 or 10 μg Cd/g creatinine, corresponding to about 100 and 200 μg cadmium/g kidney, respectively, is 

the current focus of the debate. In one analysis, the critical concentration producing dysfunction in 10% 

of a susceptible population has been estimated to be approximately 200 μg cadmium/g kidney; 50% of the 

susceptible population would experience dysfunction with a kidney concentration of 300 μg/g (Ellis et al. 

1984, 1985; Roels et al. 1983). 

Studies in humans and animals have demonstrated that the bone is a sensitive target of cadmium toxicity. 

It is likely that cadmium acts by direct and indirect mechanisms, which can lead to decreased bone 

mineral density and increased fractures (Brzóska and Moniuszko-Jakoniuk 2005c, 2005d). Studies in 

young animals suggest that cadmium inhibits osteoblastic activity, resulting in a decrease in the synthesis 

of bone organic matrix and mineralization (Brzóska and Moniuszko-Jakoniuk 2005d). The decreased 

osteoblastic activity may also influence osteoclastic activity leading to increased bone resorption. During 

intense bone growth, effects on osteoblasts result in decreased bone formation; after skeletal maturity, 

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cadmium exposure results in increased bone resorption. Cadmium-induced renal damage can also result 

in secondary effects on bone (Brzóska and Moniuszko-Jakoniuk 2005c). Cadmium-induced renal damage 

interferes with the hydroxylation of 25-hydroxy-vitamin D to form 1,25-dihydroxy-vitamin D. Decreased 

serum concentration of 1,25-dihydroxy-vitamin D, along with impaired kidney resorptive function, result 

in calcium and phosphate deficiency (via decreased gastrointestinal absorption and increased calcium and 

phosphate urinary loss). To maintain calcium and phosphate homeostasis, parathyroid hormone is 

released, which enhances bone resorption. 

3.5.3 Animal-to-Human Extrapolations 

The effects of cadmium exposure have been studied in humans and in many laboratory animal species. 

The target organs are similar among species, with the kidneys, bone, and lungs (inhalation only) being the 

primary organs for cadmium induced toxicity. Absorption, distribution, and excretion of cadmium after 

oral and inhalation exposures are roughly similar among species; however, there are some notable 

differences and caveats. Most estimates of cadmium absorption in animals are somewhat lower than the 

values found from human studies, particularly after prolonged exposure. Differences in the breathing 

patterns between rats (obligatory nose breathers) and humans (mouth and nose breathers) may also result 

in radically different lung burden patterns (and hence, different absorption profiles) of cadmium particles 

in the lungs. Many of the common laboratory animals (in particular the mouse and rat) provide useful 

information on the toxic effects of cadmium; due to their relatively short lifespan, however, they may not 

be as useful from a risk assessment point of view in determining the human lifetime effects from inhaling 

cadmium in air, or ingesting it in food and water. Rates of synthesis and inducibility of metallothionein 

also differ among species, sex, and target organ. 

Even within species there can be significant differences in metallothionein synthesis, and these 

differences correlate to the degree of cadmium toxicity observed (e.g., the mouse) (Shaikh et al. 1993). 

The Shaikh et al. (1993) study employed acute exposures. Strain differences in carcinogenic effects have 

also been reported for chronic exposures of subcutaneously administered cadmium chloride in male DBA 

and NFS mice. DBA mice developed lymphomas, while NFS mice developed hepatocellular adenomas 

and carcinomas, and sarcomas at the injection site. Both strains developed nonneoplastic testicular 

lesions (fibrosis and mineralization) (Waalkes and Rhem 1992). 

Metal-metal interactions are also an important factor in cadmium kinetics and toxicity, and organ specific 

metal concentrations and metabolism can differ among species. It is thought that further development of 

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PBPK/PD models will assist in addressing these differences and in extrapolating the animal data to 

support risk assessments in humans. 

3.6 TOXICITIES MEDIATED THROUGH THE NEUROENDOCRINE AXIS 

Recently, attention has focused on the potential hazardous effects of certain chemicals on the endocrine 

system because of the ability of these chemicals to mimic or block endogenous hormones. Chemicals 

with this type of activity are most commonly referred to as endocrine disruptors. However, appropriate 

terminology to describe such effects remains controversial. The terminology endocrine disruptors, 

initially used by Thomas and Colborn (1992), was also used in 1996 when Congress mandated the EPA to 

develop a screening program for “...certain substances [which] may have an effect produced by a 

naturally occurring estrogen, or other such endocrine effect[s]...”. To meet this mandate, EPA convened a 

panel called the Endocrine Disruptors Screening and Testing Advisory Committee (EDSTAC), and in 

1998, the EDSTAC completed its deliberations and made recommendations to EPA concerning endocrine 

disruptors. In 1999, the National Academy of Sciences released a report that referred to these same types 

of chemicals as hormonally active agents. The terminology endocrine modulators has also been used to 

convey the fact that effects caused by such chemicals may not necessarily be adverse. Many scientists 

agree that chemicals with the ability to disrupt or modulate the endocrine system are a potential threat to 

the health of humans, aquatic animals, and wildlife. However, others think that endocrine-active 

chemicals do not pose a significant health risk, particularly in view of the fact that hormone mimics exist 

in the natural environment. Examples of natural hormone mimics are the isoflavinoid phytoestrogens 

(Adlercreutz 1995; Livingston 1978; Mayr et al. 1992). These chemicals are derived from plants and are 

similar in structure and action to endogenous estrogen. Although the public health significance and 

descriptive terminology of substances capable of affecting the endocrine system remains controversial, 

scientists agree that these chemicals may affect the synthesis, secretion, transport, binding, action, or 

elimination of natural hormones in the body responsible for maintaining homeostasis, reproduction, 

development, and/or behavior (EPA 1997a). Stated differently, such compounds may cause toxicities that 

are mediated through the neuroendocrine axis. As a result, these chemicals may play a role in altering, 

for example, metabolic, sexual, immune, and neurobehavioral function. Such chemicals are also thought 

to be involved in inducing breast, testicular, and prostate cancers, as well as endometriosis (Berger 1994; 

Giwercman et al. 1993; Hoel et al. 1992). 

No studies were located regarding endocrine disruption in humans and/or animals after exposure to 

cadmium. 

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No in vitro studies were located regarding endocrine disruption of cadmium. 

3.7 CHILDREN’S SUSCEPTIBILITY 

This section discusses potential health effects from exposures during the period from conception to 

maturity at 18 years of age in humans, when all biological systems will have fully developed. Potential 

effects on offspring resulting from exposures of parental germ cells are considered, as well as any indirect 

effects on the fetus and neonate resulting from maternal exposure during gestation and lactation. 

Relevant animal and in vitro models are also discussed. 

Children are not small adults. They differ from adults in their exposures and may differ in their 

susceptibility to hazardous chemicals. Children’s unique physiology and behavior can influence the 

extent of their exposure. Exposures of children are discussed in Section 6.6, Exposures of Children. 

Children sometimes differ from adults in their susceptibility to hazardous chemicals, but whether there is 

a difference depends on the chemical (Guzelian et al. 1992; NRC 1993). Children may be more or less 

susceptible than adults to health effects, and the relationship may change with developmental age 

(Guzelian et al. 1992; NRC 1993). Vulnerability often depends on developmental stage. There are 

critical periods of structural and functional development during both prenatal and postnatal life, and a 

particular structure or function will be most sensitive to disruption during its critical period(s). Damage 

may not be evident until a later stage of development. There are often differences in pharmacokinetics 

and metabolism between children and adults. For example, absorption may be different in neonates 

because of the immaturity of their gastrointestinal tract and their larger skin surface area in proportion to 

body weight (Morselli et al. 1980; NRC 1993); the gastrointestinal absorption of lead is greatest in infants 

and young children (Ziegler et al. 1978). Distribution of xenobiotics may be different; for example, 

infants have a larger proportion of their bodies as extracellular water, and their brains and livers are 

proportionately larger (Altman and Dittmer 1974; Fomon 1966; Fomon et al. 1982; Owen and Brozek 

1966; Widdowson and Dickerson 1964). The infant also has an immature blood-brain barrier (Adinolfi 

1985; Johanson 1980) and probably an immature blood-testis barrier (Setchell and Waites 1975). Many 

xenobiotic metabolizing enzymes have distinctive developmental patterns. At various stages of growth 

and development, levels of particular enzymes may be higher or lower than those of adults, and 

sometimes unique enzymes may exist at particular developmental stages (Komori et al. 1990; Leeder and 

Kearns 1997; NRC 1993; Vieira et al. 1996). Whether differences in xenobiotic metabolism make the 

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child more or less susceptible also depends on whether the relevant enzymes are involved in activation of 

the parent compound to its toxic form or in detoxification. There may also be differences in excretion, 

particularly in newborns who all have a low glomerular filtration rate and have not developed efficient 

tubular secretion and resorption capacities (Altman and Dittmer 1974; NRC 1993; West et al. 1948). 

Children and adults may differ in their capacity to repair damage from chemical insults. Children also 

have a longer remaining lifetime in which to express damage from chemicals; this potential is particularly 

relevant to cancer. 

Certain characteristics of the developing human may increase exposure or susceptibility, whereas others 

may decrease susceptibility to the same chemical. For example, although infants breathe more air per 

kilogram of body weight than adults breathe, this difference might be somewhat counterbalanced by their 

alveoli being less developed, which results in a disproportionately smaller surface area for alveolar 

absorption (NRC 1993). 

Occupational and environmental exposure studies in adults provide strong evidence that the lung 

(inhalation exposure only) and kidneys are sensitive targets of toxicity; it is likely that these effects would 

also be seen in children. Because cadmium is a cumulative toxin and has a very long half-time in the 

body, exposures to children in even low amounts may have long-term adverse consequences. Average 

cadmium concentrations in the kidney are near zero at birth, and rise roughly linearly with age to a peak 

(typically around 40–50 μg/g wet weight) between the ages of 50 and 60 years, after which kidney 

concentrations plateau or decline (Chung et al. 1986; Hammer et al. 1973; Lauwerys et al. 1984). There 

are limited data on the renal toxicity of cadmium in children. One study found significant associations 

between urinary and blood cadmium levels with urinary levels of NAG and retinol binding protein (de 

Burbure et al. 2006); however, the investigators cautioned that the early response observed in this group 

of children exposed to elevated levels of cadmium (and other metals) may reflect an early renal response 

that may be adaptive and/or reversible. Another study (Trzcinka-Ochocka et al. 2004) found higher 

urinary concentrations of β2-microglobulin and retinol binding protein in a population exposed to high 

levels of cadmium starting in childhood as compared to a group only exposed as adults even though 

urinary cadmium levels were lower (statistical comparisons of urinary cadmium levels were not made 

between the groups). These data suggest that adults exposed to cadmium as children may be more 

susceptible to the renal toxicity of cadmium than persons only exposed as adults. This is supported by the 

findings of Jacquillet et al. (2007) of renal damage in mature rats exposed to cadmium via gestation and 

lactation. 

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There are epidemiological data suggesting that the bone is also a sensitive target of cadmium toxicity 

(Åkesson et al. 2005; Alfvén et al. 2000, 2002a, 2004; Aoshima et al. 2003; Jin et al. 2004b; Nordberg et 

al. 2002; Staessen et al. 1999; Wang et al. 2003; Zhu et al. 2004). Epidemiology studies suggest that the 

elderly may be more susceptible than younger adults; however, no studies examined childhood exposure. 

Animal studies suggest that young animals are more susceptible than adult or elderly animals (Ogoshi et 

al. 1989). 

A potential for cadmium to have adverse neurological effects is an important consideration. However, 

only a few studies have reported an association between environmental cadmium exposure and 

neuropsychological functioning. End points that were affected included verbal IQ in rural Maryland 

children (Thatcher et al. 1982), and acting-out and distractibility in rural Wyoming children (Marlowe et 

al. 1985). The usefulness of the data from these studies is limited, however, because of the potential 

confounding effects of lead exposure; lack of control for other possible confounders including home 

environment, caregiving, and parental IQ levels; and inadequate quantification of cadmium exposure (i.e., 

the studies used hair cadmium as an index of exposure, which has some limitations because of potential 

confounding from exogenous sources). Several animal studies have reported alterations in performance 

on neurobehavioral tests in rats exposed to cadmium via gestation and lactation (Ali et al. 1986; Baranski 

et al. 1983; Desi et al. 1998; Nagymajtenyi et al. 1997). Several studies have examined the possible 

association between cadmium exposure and newborn birth weight, and most reliable studies have not 

found a significant association (Galicia-García et al. 1997; Mokhtar et al. 2002; Nishijo et al. 2002, 

2004b; Zhang et al. 2004). Animal studies have found significant decreases in body weight or skeletal 

anomalies or malformations in the offspring of rats exposed to high doses of cadmium (Ali et al. 1986; 

Baranski 1985, 1987; Gupta et al. 1993; Kelman et al. 1978; Kostial et al. 1993; Machemer and Lorke 

1981; Petering et al. 1979; Pond and Walker 1975; Schroeder and Mitchener 1971; Sorell and Graziano 

1990; Sutou et al. 1980; Webster 1978; Whelton et al. 1988). 

Oral cadmium exposure has also been reported to suppress the T-lymphocyte and macrophage-dependent 

humoral immune response of 6-week-old mice against sheep red blood cells (Blakley 1985), but not of 

12-month-old mice (Blakley 1988). The investigators cautioned that “natural” age-related immune 

system dysfunction may have masked any cadmium suppressive effect. 

Children are most likely to be exposed to cadmium in food or water. Most ingested cadmium passes 

through the gastrointestinal tract without being absorbed. In adults, only about 1/20 of the total ingested 

cadmium (in food or water) is absorbed (McLellan et al. 1978, Rahola et al. 1973; Shaikh and Smith 

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1980). The retention of cadmium in the gut slowly decreases over a period of 1–3 weeks after ingestion 

in adults (Rahola et al. 1973). The absorption of cadmium in rats depends on age, with measured 

absorption decreasing from 12 to 5 to 0.5% at 2 hours, 24 hours, and 6 weeks after birth, respectively 

(Sasser and Jarboe 1977). Sasser and Jarboe (1980) also reported that absorption of cadmium in the 

gastrointestinal tract of young guinea pigs was 20-fold higher than in adult guinea pigs. 

Tissue distribution and retention of cadmium differed between 4- and 70-day-old rats. Cadmium was 3– 

6 times more concentrated in the newborn spleen, bone, brain, testes, and muscle than in the adult rat 

2 hours after an intravenous administration of 1 mg Cd/kg body weight. Liver concentration of 

metallothionein was 20 times greater in the newborn than in the adult; kidney metallothionein concentrations were comparable, but liver cadmium was only 30% higher and kidney cadmium was 50% higher 

in the newborn. Nineteen days post-cadmium exposure, the retention of cadmium in the liver, kidney, 

and lung was similar in both the newborn and the adult rat (Wong and Klaassen 1980a). Goering and 

Klaassen (1984b) report that high levels of metallothionein in 10-day-old rats play an important role in 

their resistance to liver damage, presumably by binding and retaining cadmium. However, the tissue 

distribution data led Wong and Klaassen (1980a) to propose that metallothionein does not play a major 

role in the tissue distribution and retention of cadmium in the young. 

Cadmium can be transferred to offspring in breast milk. Cadmium levels in human milk are 5–10% of 

levels in blood, possibly due to inhibited transfer from blood because of metallothionein binding of 

cadmium in blood cells (Radisch et al. 1987). A significant association between urinary cadmium levels 

and cadmium levels in breast milk was found in women environmentally exposed to cadmium (Nishijo et 

al. 2002). In female outbred albino rats exposed to cadmium in drinking water (as cadmium chloride) at 

0 or 4.8 mg/kg/day for 10 weeks (at 4 weeks prior to mating, 3 weeks of gestation, or 3 weeks into 

lactation), kidney concentrations exceeded liver concentrations, while in their pups, the renal and liver 

concentrations were similar at all times during exposure. In pups, both hepatic and renal cadmium 

concentrations considerably increased only during the second half of the lactation period (Ld 11–21). The 

cadmium tissue concentrations in dams were several orders higher than in offspring. Another study found 

a positive correlation between cadmium levels in breast milk and cadmium levels in the pups’ kidneys in 

rats receiving an intravenous injection of cadmium on lactation days 3–16 (Petersson Grawé and 

Oskarsson 2000). 

Although studies on elimination of cadmium from the tissues of children are not available, the results of 

studies in animals provide some insight. Most cadmium that is ingested or inhaled and transported to the 

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gut via mucociliary clearance is excreted in the feces. Of the cadmium that is absorbed into the body, 

most is excreted very slowly, with urinary and fecal excretion being approximately equal (Kjellström and 

Nordberg 1978). Half-times for cadmium in the whole body of mice, rats, rabbits, and monkeys have 

been calculated to be from several months up to several years (Kjellström and Nordberg 1985). Halftimes in the slowest phase were 20–50% of the maximum life span of the animal (Kjellström and 

Nordberg 1985). In the human body, the main portion of the cadmium body burden is found in the liver 

and kidney and in other tissues (particularly muscle, skin, and bone). After reviewing the literature, 

Kjellström and Nordberg (1985) developed a range of half-times from their kinetic model of between 

6 and 38 years for the human kidney and between 4 and 19 years for the human liver. These high values 

indicate the persistence of cadmium in the body and the importance of minimizing exposures in children 

to prevent long-term accumulation and toxicity. 

The placenta may act as a partial barrier to fetal exposure to cadmium. Cadmium concentration has been 

found to be approximately half as high in cord blood as in maternal blood in several studies including 

both smoking and nonsmoking women (Kuhnert et al. 1982; Lauwerys et al. 1978; Truska et al. 1989). 

Accumulation of cadmium in the placenta at levels about 10 times higher than maternal blood cadmium 

concentration has been found in studies of women in Belgium (Roels et al. 1978) and the United States 

(Kuhnert et al. 1982); however, in another study in Czechoslovakia, the concentration of cadmium in the 

placenta was found to be less than in either maternal or cord blood (Truska et al. 1989). In mice orally 

exposed to cadmium during pregnancy, maternal blood, placental, and fetal cadmium concentrations were 

essentially equal among control animals (with environmental cadmium exposure), but placental 

concentration increased with cadmium dose much more rapidly than either maternal blood or fetal 

cadmium concentration (Sorell and Graziano 1990). Thus, timing and level of cadmium exposure may 

influence the uptake of cadmium by the placenta, perhaps explaining the conflicting human studies. 

Of particular importance to the toxicokinetics and toxicity of cadmium is its interaction with the protein 

metallothionein. Metallothionein is a low-molecular-weight protein, very rich in cysteine, which is 

capable of binding as many as seven cadmium atoms per molecule and is inducible in most tissues by 

exposure to cadmium, zinc, and other metals (Waalkes and Goering 1990). Metallothionein binding 

decreases the toxicity of cadmium (Goyer et al. 1989; Kotsonis and Klaassen 1978). Goyer and Cherian 

(1992) localized metallothionein in full-term human placenta and in fetal cells in human placenta. 

Metallothionein was present in trophoblasts (which facilitate transport of substances entering the placenta 

from the maternal blood), Hofbauer cells (motile macrophages capable of phagocytosis and protein 

ingestion), amniotic epithelial cells (fetal derivatives), and decidual cells (endometrial stromal cells that 

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have been transformed under hormonal influence into large pale cells, rich in glycogen). The mechanism 

by which the placenta transports the essential metals, copper and zinc, while limiting the transport of 

cadmium is unknown, but may involve the approximately 1,000-fold higher concentration of zinc in the 

placenta and the higher affinity of cadmium than zinc for metallothionein. 

Chan and Cherian (1993) report that pregnancy in Sprague-Dawley rats previously administered cadmium 

chloride (1.0 mg Cd/kg body weight subcutaneously, daily for 8 days) leads to a mobilization of cadmium 

from the liver (40% decrease compared to nonpregnant cadmium treated controls) and an increase in the 

kidneys (60% increase). A similar pattern is seen for metallothionein. Plasma cadmium and 

metallothionein also increased in the pregnant group. Placental cadmium increased in the cadmiumtreated rats compared to the untreated controls. In this rat model, then, pregnancy resulted in a transfer of 

hepatic cadmium and metallothionein via the blood to the kidney and placenta. 

3.8 BIOMARKERS OF EXPOSURE AND EFFECT 

Biomarkers are broadly defined as indicators signaling events in biologic systems or samples. They have 

been classified as markers of exposure, markers of effect, and markers of susceptibility (NAS/NRC 

1989). 

The National Report on Human Exposure to Environmental Chemicals provides an ongoing assessment 

of the exposure of the U.S. population to environmental chemicals using biomonitoring. This report is 

available at http://www.cdc.gov/exposurereport/. The biomonitoring data for cadmium from this report is 

discussed in Section 6.5. A biomarker of exposure is a xenobiotic substance or its metabolite(s) or the 

product of an interaction between a xenobiotic agent and some target molecule(s) or cell(s) that is 

measured within a compartment of an organism (NAS/NRC 1989). The preferred biomarkers of exposure 

are generally the substance itself, substance-specific metabolites in readily obtainable body fluid(s), or 

excreta. However, several factors can confound the use and interpretation of biomarkers of exposure. 

The body burden of a substance may be the result of exposures from more than one source. The 

substance being measured may be a metabolite of another xenobiotic substance (e.g., high urinary levels 

of phenol can result from exposure to several different aromatic compounds). Depending on the 

properties of the substance (e.g., biologic half-life) and environmental conditions (e.g., duration and route 

of exposure), the substance and all of its metabolites may have left the body by the time samples can be 

taken. It may be difficult to identify individuals exposed to hazardous substances that are commonly 

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found in body tissues and fluids (e.g., essential mineral nutrients such as copper, zinc, and selenium). 

Biomarkers of exposure to cadmium are discussed in Section 3.8.1. 

Biomarkers of effect are defined as any measurable biochemical, physiologic, or other alteration within an 

organism that, depending on magnitude, can be recognized as an established or potential health 

impairment or disease (NAS/NRC 1989). This definition encompasses biochemical or cellular signals of 

tissue dysfunction (e.g., increased liver enzyme activity or pathologic changes in female genital epithelial 

cells), as well as physiologic signs of dysfunction such as increased blood pressure or decreased lung 

capacity. Note that these markers are not often substance specific. They also may not be directly 

adverse, but can indicate potential health impairment (e.g., DNA adducts). Biomarkers of effects caused 

by cadmium are discussed in Section 3.8.2. 

A biomarker of susceptibility is an indicator of an inherent or acquired limitation of an organism's ability 

to respond to the challenge of exposure to a specific xenobiotic substance. It can be an intrinsic genetic or 

other characteristic or a preexisting disease that results in an increase in absorbed dose, a decrease in the 

biologically effective dose, or a target tissue response. If biomarkers of susceptibility exist, they are 

discussed in Section 3.10, Populations That Are Unusually Susceptible. 

3.8.1 Biomarkers Used to Identify or Quantify Exposure to Cadmium 

Cadmium levels in blood, urine, feces, liver, kidney, hair, and other tissues have been used as biological 

indicators of exposure to cadmium. A discussion of the utility and limitations of each for human 

biomonitoring is provided below. 

Blood cadmium levels are principally indicative of recent exposure(s) to cadmium rather than whole-body 

burdens (Ghezzi et al. 1985; Järup et al. 1988; Lauwerys et al. 1994; Roels et al. 1989). The 50th 

percentile of blood cadmium concentrations in adults living in the United States was 0.300 μg/L (CDC 

2005). Environmental exposure can elevate blood cadmium concentration to above 10 μg/L (Kido et al. 

1990a, 1990b; Shiwen et al. 1990). Workers occupationally exposed to cadmium by inhalation may have 

blood cadmium levels ranging up to 50 μg/L (Roels et al. 1981b). 

Urine cadmium levels primarily reflect total body burden of cadmium, although urine levels do respond 

somewhat to recent exposure (Bernard and Lauwerys 1986). Use of a biokinetic model, such as the 

Nordberg-Kjellström model, allows estimation of cadmium dietary consumption or airborne cadmium 

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levels from urinary cadmium levels; these models are described in greater detail in Section 3.4.5.3. When 

the critical level for renal damage has been reached, urinary cadmium levels rise sharply because of the 

release of intrarenal cadmium along with decreased renal reabsorption of cadmium (Lauwerys et al. 1994; 

Roels et al. 1981b). In the U.S. general population, the geometric mean urinary cadmium level in adults 

is 0.273 μg/L (or 0.261 μg/g creatinine) (CDC 2005). In populations with substantial environmental or 

occupational exposure, values can range up to 50 μg/g creatinine, (Falck et al. 1983; Roels et al. 1981b; 

Tohyama et al. 1988). In environmentally exposed individuals, Buchet et al. (1990) report that abnormal 

values of various biomarkers are found in 5% of the population with urinary excretion of cadmium above 

the 2–4 μg Cd/24 hour level (approximately 1–3 μg/g creatinine). Significant correlations between total 

cadmium exposure and urinary cadmium levels have been found in environmentally exposed populations 

(Kido et al. 2004; Kobayashi et al. 2005; Shimbo et al. 2000). Among environmentally exposed subjects, 

there was good agreement between urinary cadmium levels measured at different times, suggesting that a 

single determination would be an accruement measure (Ikeda et al. 2005a). 

Fecal cadmium may be used as a direct indicator of daily dietary intake of cadmium because dietary 

cadmium is poorly absorbed in the gastrointestinal tract (Kjellström et al. 1978). In workers exposed by 

inhalation, fecal cadmium has been used to estimate the amount of inhaled cadmium transported to the 

gastrointestinal tract and the amount of dust ingested incidentally at work (Adamsson et al. 1979). Fecal 

cadmium primarily reflects recently ingested cadmium and, therefore, is not a good indicator of past 

cadmium exposure (Shaikh and Smith 1984). 

Liver and kidney tissues preferentially accumulate cadmium, and concentrations of cadmium in liver and 

kidney may be measured in vivo by neutron activation analysis or in the kidney by X-ray fluorescence 

analysis (Christoffersson et al. 1987; Scott and Chettle 1986). Levels in both tissues increase with age 

and level of cadmium exposure, but kidney cadmium concentration tends to peak around age 50–60, 

while liver cadmium concentration continues to rise. Typical values for a 60-year-old North American 

with average environmental cadmium exposure are 25–40 μg/g wet weight in kidney cortex and 1–3 μg/g 

wet weight in liver (Elinder 1985b). In workers exposed to cadmium by inhalation, values up to 300 μg/g 

wet weight in kidney and 100 μg/g wet weight in liver can be found (Christoffersson et al. 1987; Roels et 

al. 1981b). Because kidney cadmium content begins to decline after the onset of cadmium-induced renal 

dysfunction, liver cadmium may be a better indicator of cadmium exposure than kidney cadmium, and it 

has been suggested that kidney dysfunction is likely to appear at liver cadmium concentrations between 

30 and 60 μg/g wet weight (Roels et al. 1981b). In vivo liver and kidney cadmium measurements 

involving neutron activation analysis or X-ray fluorescence require complex and costly equipment and 

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may pose a radiation hazard (Shaikh and Smith 1984), and those involving biopsy specimens (Lindqvist 

et al. 1989) require a painful and invasive procedure. Therefore, these methods for in vivo analysis are 

better suited for monitoring of occupationally exposed workers than environmentally exposed populations 

(Scott and Chettle 1986). Among cadmium workers, significant correlations of kidney cadmium levels 

with urinary and blood cadmium levels and liver cadmium with urinary cadmium levels were found 

(Börjesson et al. 1997, 2001). Similar correlations (urinary cadmium with renal cadmium) in an autopsy 

study of subjects without occupational exposure to cadmium; a urinary cadmium level of 1.7 μg/g 

creatinine was equivalent to a renal cadmium level of 50 μg/g (Orlowski et al. 1998). 

Hair levels of cadmium have been used as a measure of cadmium exposure, although the possibility of 

exogenous contamination has led to substantial controversy concerning the reliability of hair levels as a 

measure of absorbed dose (Frery et al. 1993; Huel et al. 1984; Lauwerys et al. 1994, Shaikh and Smith 

1984; Wilhelm et al. 1990). Recent evidence has shown a correlation between cadmium levels in the hair 

of newborn infants and their mothers (Huel et al. 1984) and between cadmium levels in scalp and pubic 

hair (Wilhelm et al. 1990), indicating that among environmentally exposed populations, external 

contamination may not be significant for hair samples taken close to the scalp. Under occupational 

conditions, external contamination may be a more substantial problem (Shaikh and Smith 1984). 

On the other hand, Frery et al. (1993) evaluated hair levels in a male population with a high expected 

exposure to tobacco smoke and in a population of pregnant woman and their newborns; they concluded 

that cadmium hair analysis was a reliable indicator for the subjects with the highest exposure, but was not 

sensitive enough to resolve differences for low level exposures. Newborn cadmium hair levels were a 

more sensitive indicator than mother’s hair, but the research was not able to determine if this was 

attributable to physiological changes or the lower reliability of the mother’s head hair. Exogenous 

contamination is not considered a problem for newborn hair. The authors state that the variability 

introduced by exogenous contamination can be minimized by using the first 8 cm of hair from the scalp 

and by using careful washing techniques. There was also no significant difference between hair levels for 

passive or nonsmokers indicating that either the above mentioned precautions worked or that the passive 

smoke source of exposure was not significant. 

Cadmium measurements have been made on a variety of other biological materials, including milk 

(Schulte-Lobbert and Bohn 1977; Sikorski et al. 1989), placenta (Kuhnert et al. 1982; Roels et al. 1978; 

Saaranen et al. 1989), nails (Takagi et al. 1988), teeth (Sharon 1988), and cataractous lenses (Racz and 

Erdohelyi 1988). Although in some cases it could be established that levels in these tissues were higher 

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among smokers than nonsmokers, the significance of cadmium levels as a marker of recent or total 

cadmium exposure has not been established for any of these tissues. 

Studies in cadmium workers suggest that metallothionein levels may also be a biomarker of cadmium 

exposure. Elevated levels of metallothionein gene expression were observed in peripheral blood 

lymphocytes in highly exposed workers. The level of metallothionein gene expression was significantly 

correlated with blood and urinary cadmium levels (Lu et al. 2001). Urinary metallothionein correlates 

with cadmium concentrations in liver, kidney, and urine (Shaikh and Smith 1984; Tohyama et al. 1981). 

Relatively strong correlations have been found between urinary metallothionein and urinary cadmium 

levels in exposed humans (Kawada et al. 1990), and a dose-related increase in urinary metallothionein 

was found in rats exposed to cadmium in drinking water for up to 2 years (Shaikh et al. 1989). Hochi et 

al. (1995) also found a significant relationship between cadmium intake and urinary metallothionein 

levels among residents consuming cadmium-contaminated rice. However, the specificity of 

metallothionein for cadmium exposure may be questioned, because many other exposures are known to 

induce metallothionein (Waalkes and Goering 1990). 

3.8.2 Biomarkers Used to Characterize Effects Caused by Cadmium 

Acute inhalation exposure to high levels of cadmium causes respiratory damage and may lead to death. 

No information was located on biomarkers of respiratory effects in humans, but based on animal 

experiments, activity of alkaline phosphatase in the surfactant fraction of BALF has been suggested as a 

sensitive marker of pulmonary damage following acute cadmium inhalation (Boudreau et al. 1989). Such 

a biomarker of effect is not specific to cadmium exposure and would be most relevant to occupational 

exposures. 

Renal dysfunction, usually first manifested as impaired tubular reabsorption of filtered solutes, is 

generally considered the primary toxic effect of chronic cadmium exposure (see Section 3.2). Impaired 

kidney function has been measured by increased levels of solutes (proteins, amino acids, uric acid, 

calcium, copper, phosphorous, etc.) in urine and/or serum. Excess urinary excretion of low-molecularweight proteins and solutes is associated with decreased tubular reabsorption. Increased excretion of 

high-molecular-weight proteins or decreased serum clearance of creatinine reflect glomerular 

dysfunction, which is generally associated with progressive renal damage (Roels et al. 1989). A brief 

discussion of the utility and limitations of several measures of tubular damage as biomarkers of effects of 

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cadmium exposure is provided below. These biomarkers are normally found in the urine and elevated 

levels are not specific for cadmium. 

Urinary β2-microglobulin, a low molecular weight protein, has been widely used as an indicator of 

tubular renal dysfunction (Arisawa et al. 1997; Piscator 1984; Roels et al. 1981a; Smith et al. 1980). 

However, tubular renal dysfunction can be caused by exposures and diseases other than cadmium, so 

β2-microglobulin is not a specific marker of cadmium-induced effects (Shaikh and Smith 1984). 

Practical considerations in using urinary β2-microglobulin as a marker of tubular renal dysfunction 

include the need to control the pH of samples to prevent the rapid degradation that occurs at pH values 

below 5.5 (Shaikh and Smith 1984), and the fact that urinary β2-microglobulin excretion normally rises 

with age (Roels et al. 1989). 

Urinary retinol-binding protein is also considered to be a sensitive indicator of decreased tubular 

reabsorption, but it also is not specific for cadmium-induced damage in the kidney (Shaikh and Smith 

1984; Topping et al. 1986). Retinol-binding protein is more stable in urine than β2-microglobulin 

(Bernard and Lauwerys 1981) and appears to be of approximately equal sensitivity and specificity for 

detecting tubular proteinuria in cadmium-exposed populations (Topping et al. 1986). Levels of both 

proteins fluctuate over time, so regular, repeated sampling may be necessary to establish abnormal levels 

(Ormos et al. 1985). 

Human complex-forming glycoprotein (pHC, also referred to as α1-microglobulin) is another sensitive 

marker of tubular renal dysfunction (Moriguchi et al. 2004, 2005a; Pless-Mulloli et al. 1998; Tohyama et 

al. 1986). As with retinol binding protein, pHC is more stable in urine than β2-microglobulin at room 

temperature and low urinary pH levels. 

Urinary N-acetyl-β-D-glucosaminidase (NAG), a lysosomal enzyme present in high concentrations in the 

proximal tubule, has been shown to correlate with urinary cadmium levels in occupationally and 

environmentally exposed subjects (Jin et al. 1999; Kalahasthi et al. 2007) and has a better correlation with 

urinary cadmium levels than does β2-microglobulin at low cadmium exposure levels (urinary cadmium 

<10 μg/g creatinine) (Chia et al. 1989; Kawada et al. 1990; Mueller et al. 1989). However, increased 

urinary NAG activity can result from effects other than nephrotoxicity (Bernard and Lauwerys 1989). Jin 

et al. (1999) suggest that measurement of the B isozyme (NAG-B), which is released into the urine 

following tubular cell breakdown, may be a sensitive measure of renal damage. 

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Other enzymes, proteins, and amino acids in urine have been suggested as biological markers of incipient 

renal or liver damage resulting from cadmium exposure. Markers found to be sensitive indicators in 

exposed humans include trehalase (Iwata et al. 1988), alanine aminopeptidase (Mueller et al. 1989), and 

calcium (Buchet et al. 1990). Changes in urinary alkaline phosphatase, γ-glutamyl transferase, urate, and 

phosphate tend to be significant only after other markers of renal damage are clearly elevated (Mason et 

al. 1988). Several other enzymatic markers of cadmium-induced renal damage have been suggested 

based on animal studies (Bomhard et al. 1984; Gatta et al. 1989; Girolami et al. 1989). Aminoaciduria 

has been found to be more sensitive than proteinuria for renal damage in animal studies (Nomiyama et al. 

1975), but less sensitive in humans (Axelsson and Piscator 1966). Recent work by Prozialeck et al. 

(2007) suggest that kidney injury molecule 1 may be a sensitive marker for renal dysfunction. At present, 

not enough information is available to determine which, if any, of these parameters provide sensitive and 

specific indicators of cadmium-induced renal damage. 

At the present time, there is no single biological indicator for cadmium toxicity that is entirely adequate 

when considered alone. Measurement of cadmium levels in various biological materials can provide an 

indication of recent or total cadmium exposure, but the probability of adverse effects cannot be reliably 

predicted except at high exposure levels. Measurement of a variety of markers of renal dysfunction can 

provide a sensitive measure of early kidney toxicity, but cannot establish whether cadmium exposure was 

the cause. 

There is also considerable controversy as to whether the critical concentration of urinary cadmium is 

closer to 5 or 10 μg Cd/g creatinine, corresponding to about 100 and 200 ppm in the kidney, respectively. 

Roels et al. (1993) correlated a number of markers with cadmium in blood and urine in a study population 

of workers occupationally exposed to cadmium from cadmium smelting operations. Three main 

groupings of thresholds were identified corresponding with different markers of effects: one around 2 μg 

Cd/g creatinine mainly associated with biochemical alterations (increased urinary 6-keto-prostaglandin 

F1x and urinary sialic acid), a second around 4 μg Cd/g creatinine associated with increased excretion of 

high molecular weight proteins (possibly due to disruption of the glomerular membrane polyanionic 

charge) and tubular antigens or enzymes (BBA, NAG), and a third around 10 μg Cd/g creatinine 

associated with increased excretion of low molecular weight proteins and other indicators. The 10 μg 

Cd/g creatinine level had previously been proposed as the biological threshold for cadmium-induced 

nephropathy. Whether the earlier changes are indicative of irreversible adverse renal effects remains an 

area of continued investigation. 

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To further evaluate the reversibility of proteinuria, Roels et al. (1997) studied the progression of 

cadmium-induced renal tubular dysfunction in cadmium workers according to the severity of the 

microproteinuria at the time the exposure was substantially decreased. A total of 32 cadmium male 

workers were divided into two groups on the basis of historical records of urinary cadmium concentration 

(CdU) covering the period until 1984. The workers with CdU values of >10 μg Cd/g creatinine were 

subdivided further on the basis of the urinary concentration of β2-microglobulin (β2-MG-U) measured 

during the first observation period (1980–1984). In each group, the tubular microproteinuria as reflected 

by β2-MG-U and the concentration of retinol-binding protein in urine as well as the internal cadmium 

dose as reflected by the concentration of cadmium in blood and urine were compared between the first 

and second (1990–1992) observation periods. Increased microproteinuria was often diagnosed in cases 

with CdU values of >10 μg Cd/g creatinine. The progression of tubular renal function was found to 

depend on the extent of the body burden of cadmium (as reflected by CdU) and the severity of the initial 

microproteinuria at the time high cadmium exposure was reduced or ceased. When cadmium exposure 

was reduced and β2-MG-U did not exceed the upper reference limit of 300 μg/g creatinine, the risk of 

developing tubular dysfunction at a later stage was likely to be low, even in cases with historical CdU 

values occasionally >10 but always <20 μg Cd/g creatinine. When the microproteinuria was mild 

(β2-MG-U >300 and ≤1,500 μg/g creatinine) at the time exposure was reduced, and the historical CdU 

values had never exceeded 20 μg Cd/g creatinine, there was indication of a reversible tubulotoxic effect 

of cadmium. When severe microproteinuria (β2-MG-U >1,500 μg/g creatinine) was diagnosed in 

combination with historical CdU values exceeding 20 μg Cd/g creatinine, Cd-induced tubular dysfunction 

was progressive in spite of reduction or cessation of cadmium exposure. 

For more information on biomarkers for renal and hepatic effects of chemicals see Agency for Toxic 

Substances and Disease Registry Subcommittee Report on Biological Indicators of Organ Damage 

(Agency for Toxic Substances and Disease Registry 1990a). For information on biomarkers for 

neurological effects see OTA (1990). 

3.9 INTERACTIONS WITH OTHER CHEMICALS 

Cadmium toxicity can be influenced by a wide variety of other chemicals. In humans, dietary 

deficiencies of calcium, protein, and vitamin D are likely to account for increased susceptibility to bone 

effects following cadmium exposure (Kjellström 1986c). Iron deficiency has been shown to increase 

gastrointestinal absorption of cadmium in humans (Flanagan et al. 1978), while oral zinc supplementation 

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has been demonstrated to decrease the oral absorption of cadmium. No other information was located 

concerning interaction of cadmium with other chemicals in humans. 

In animals, a few interactions following inhalation exposure have been evaluated. In rats exposed to 

cadmium chloride by inhalation, simultaneous exposure to zinc oxide prevents fatalities (Oldiges and 

Glaser 1986) and lung cancer (Oldiges et al. 1989). Exposure to an atmosphere containing 80% oxygen 

aggravated pulmonary damage from cadmium chloride inhalation in mice (Martin and Witschi 1985). 

The toxicity of oral exposure to cadmium in animals has been shown to be influenced by several factors. 

In Japanese quail, cadmium toxicity was intensified by single or combined deficiencies of zinc, copper, 

iron, calcium, and protein (Fox et al. 1979). A calcium-deficient diet in animals has been shown to 

aggravate cadmium immunotoxicity (Chopra et al. 1984) and fetotoxicity (Pond and Walker 1975). 

Simultaneous exposure to lindane increased the developmental toxicity of cadmium in rats (Saxena et al. 

1986). Female rats have an increased susceptibility to cadmium-induced bone loss due to multiple rounds 

of gestation and lactation (Bhattacharyya et al. 1988b) or ovariectomy (Bhattacharyya et al. 1988c), 

possibly related to associated effects on trace element status. Hopf et al. (1990) report that exposure to 

ethanol and cadmium in a liquid diet produced liver damage in rats at doses that were not separately 

hepatotoxic. In contrast, Kershaw et al. (1990) reported that ethanol pretreatment in male SpragueDawley rats substantially reduced the lethal and hepatotoxic properties of cadmium, possibly due to a 

reduced interaction between cadmium and target sites in liver organelles and cytosolic high-molecularweight (HMW) proteins. Ethanol pretreatment in this study decreased (approximately 60%) the content 

of cadmium in nuclei, mitochondria, and endoplasmic reticulum, and nearly eliminated the association of 

cadmium with cytosolic HMW proteins. Reduction in the concentration of cadmium in potential target 

sites of intoxication was caused by a metallothionein-promoted sequestration of cadmium to the cytosol. 

When cadmium is co-administered with ethanol in rats, there is a pronounced increase in cadmium 

accumulation in various regions of the brain (e.g., the corpus striatum and cerebral cortex). The cadmium 

is not bound to metallothionein, and there is a marked increase in lipid peroxidation and inhibition of 

membrane bound enzymes (Pal et al. 1993a, 1993b). Rats pretreated with acetaminophen are more 

sensitive to the renal toxicity of cadmium in water (Bernard et al. 1988a). Co-administration of lead and 

cadmium in the diet of rats had additive effects in reducing body weights, but neurologic toxicity was 

antagonized (Nation et al. 1990). 

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Numerous interactions have been demonstrated in animals using parenteral exposure, generally indicating 

that induction of metallothionein by pretreatment with zinc, selenium, or other metals, reduces toxicity of 

parenteral cadmium exposure (Gunn et al. 1968a, 1968b; Naruse and Hayashi 1989; Yamane et al. 1990). 

Zinc, calcium, or magnesium can prevent injection site, testicular, and prostatic cancers induced by 

subcutaneous or intramuscular injection of cadmium, but these interactions have been shown to be a 

complex phenomenon, dependent on dose, route, and target organ (Poirier et al. 1983; Waalkes et al. 

1989). Mn(II) pretreatment reduces Cd(II)-induced lethality (Goering and Klaassen 1985). Cadmium has 

been noted to have an inhibitory effect on manganese uptake (Gruden and Matausic 1989). In addition, 

manganese appears to be capable of increasing the synthesis of the metal-binding protein metallothionein 

(Waalkes and Klaassen 1985). Data from a study by Goering and Klaasen (1985) suggest that manganese 

pretreatment increases the amount of Cd+2 bound to metallothionein, thereby decreasing hepatotoxicity 

due to unbound Cd+2. The significance of these observations to humans exposed to cadmium and 

manganese by the oral or inhalation routes is not clear. 

Induction of hepatic metallothionein by cold stress reduced the acute toxicity of cadmium given by 

gavage to mice (Baer and Benson 1987). In addition to effects on metallothionein induction, substances 

may interact with cadmium by altering the competition among metal ions for enzyme or regulatory 

protein binding sites. For example, simultaneous administration of garlic (which is high in reduced 

sulfhydryl groups) decreases oral cadmium renal toxicity in rats (Cha 1987). 

Coexposure to selenium reduced the clastogenic effect of cadmium on mouse bone marrow (Mukherjee et 

al. 1988b). Selenium deficiency enhances cadmium-induced cardiotoxicity possibly mediated via lipid 

peroxidation indicated by a significant reduction in the activities of the selenoenzyme, glutathione 

peroxidase. Selenium supplements in the diet prevented cadmium’s cardiotoxic effect (Jamall and Smith 

1985a). Selenium has also been shown to prevent testicular damage in rats (Kar et al. 1960; Omaye and 

Tappel 1975). In testes, selenium as selenite given before or during cadmium administration was shown 

to divert the binding of cadmium from low molecular proteins to higher molecular weight proteins (Chen 

et al. 1975; Whanger 1992). In contrast, Jamall and Smith (1985c) report a shift in cadmium binding 

from metallothionein to lower weight proteins in kidney and liver from a diet supplemented with 

selenium compared to a selenium deficient diet. The selenium-cadmium interaction thus appears to be 

dependent on the duration and sequence of coexposure and possibly the organ-specific levels of 

selenoenzymes or other essential metals. 

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3.10 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE 

A susceptible population will exhibit a different or enhanced response to cadmium than will most persons 

exposed to the same level of cadmium in the environment. Reasons may include genetic makeup, age, 

health and nutritional status, and exposure to other toxic substances (e.g., cigarette smoke). These 

parameters result in increased absorption, reduced detoxification or excretion of cadmium, or 

compromised function of organs affected by cadmium. Populations who are at greater risk due to their 

unusually high exposure to cadmium are discussed in Section 6.7, Populations with Potentially High 

Exposures. 

Differences in individual sensitivity to cadmium have not been systematically studied, but based on what 

is known about cadmium toxicity, some inferences can be made. Populations with depleted stores of 

calcium, iron, or other dietary components due to multiple pregnancies and/or dietary deficiencies could 

be expected to have increased cadmium absorption from the gastrointestinal tract. Urinary cadmium 

levels have been shown to be correlated with iron status among pregnant women (Åkesson et al. 2002). 

However, a general population study of women living in Japan (Tsukahara et al. 2003) did not find 

significantly elevated levels of urinary cadmium, β2-microglobulin, or pHC among women with anemia 

or iron deficiency, as compared to healthy women. Populations with kidney damage from causes 

unrelated to cadmium exposure, including diabetes, some drugs and chemicals, and the natural age-related 

decline in kidney function, could be expected to exhibit nephrotoxicity at lower cadmium exposures than 

those of normal healthy adults (Buchet et al. 1990). There is also some evidence to suggest that diabetics 

may be more susceptible to the toxicity of cadmium (Åkesson et al. 2005; Buchet et al. 1990). Elevated 

levels of metallothionein-antibody have been significantly associated with excretion of biomarkers of 

tubular dysfunction among cadmium workers (Chen et al. 2006a), but not with urinary or blood cadmium 

levels. In a study of diabetics, metallothionein-antibodies were significantly associated with urinary 

levels of β2-microglobulin levels, which were indicative of cadmium toxicity but not with urinary 

albumin levels, which would be indicative of glomerular damage (Chen et al. 2006c). 

A discussion of the susceptibility of children is found in Section 3.7, Children’s Susceptibility. 

3.11 METHODS FOR REDUCING TOXIC EFFECTS 

This section will describe clinical practice and research concerning methods for reducing toxic effects of 

exposure to cadmium. However, because some of the treatments discussed may be experimental and 

unproven, this section should not be used as a guide for treatment of exposures to cadmium. When 

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specific exposures have occurred, poison control centers and medical toxicologists should be consulted 

for medical advice. The following texts provide specific information about treatment following exposures 

to cadmium: 

Caravati EM, McGuigan MA, MacGregor Whyte I, et al. Cadmium fume pneumonitis. In: Medical 

toxicology, 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins, 1411-1414. 

Leikin JB, Paloucek FP. 2002. Cadmium. In: Poisoning and toxicology handbook. Hudson, OH: LexiComp, Inc., 309-310. 

Viccellio P. 1998. Cadmium, mercury, and arsenic. In: Emergency toxicology. 2nd ed. Philadelphia, 

PA: Lippincott-Raven Publishers, 379-380. 

3.11.1 Reducing Peak Absorption Following Exposure 

Inhalation exposure to high concentrations of cadmium can be particularly dangerous because initial 

symptoms are often as mild as those associated with low-level exposure, and exposed individuals who are 

unaware either of the presence of cadmium or of the dangers of inhaling cadmium may allow exposure to 

continue until a harmful or even fatal dose is received (Beton et al. 1966; Lucas et al. 1980). Severe 

respiratory symptoms that may develop within a few hours of high-dose inhalation exposure include 

tracheobronchitis, pneumonitis, and pulmonary edema, accompanied by additional nonspecific flu-like 

symptoms (sweating, shivering, malaise) (Beton et al. 1966). Aside from removing a victim to fresh air 

and providing supportive medical care, no effective means have been reported for reducing absorption 

following inhalation exposure to cadmium (Bronstein and Currance 1988; EPA 1989d). Supportive 

medical care of individuals with inhalation exposure to high levels of cadmium includes monitoring for 

respiratory distress, assisting ventilation as needed, and administering humidified oxygen (Bronstein and 

Currance 1988; EPA 1989d). If pulmonary edema develops, individuals may be treated with 

supplemental oxygen, positive-pressure mechanical ventilation, and administration of diuretics, 

intravenous fluids, and steroid medications. Antibiotic therapy and monitoring fluid balance (due to 

kidney function impairment) may also be required (Beton et al. 1966; Bronstein and Currance 1988; EPA 

1989d; Haddad and Winchester 1990). 

Oral exposure to cadmium is not an immediate threat because high doses are irritating enough to induce 

vomiting. In fact, the only known acute fatalities from oral exposure to cadmium followed intentional 

ingestion of high doses (Baker and Hafner 1961; Buckler et al. 1986; Frant and Kleeman 1941; Nordberg 

et al. 1973; Shipman 1986; Wisniewska-Knypl et al. 1971). Although inducing vomiting is sometimes 

recommended following ingestion of cadmium (Ellenhorn and Barceloux 1988; Stutz and Janusz 1988), 

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concentrated cadmium solutions may be caustic, and esophageal damage could result from spontaneous or 

induced vomiting. Administration of water or milk may be indicated for patients able to swallow 

(Bronstein and Currance 1988; EPA 1989d). Administration of cathartics such as sorbitol or magnesium 

sulfate to enhance elimination from the gastrointestinal tract has been recommended (EPA 1989d; Stutz 

and Janusz 1988); however, the administration of activated charcoal to bind unabsorbed cadmium does 

not appear to be effective (Agency for Toxic Substances and Disease Registry 1990b; Ellenhorn and 

Barceloux 1988). 

The intestinal absorption of cadmium at levels below those leading to gastrointestinal damage is relatively 

low (5–10% of the administered dose) (Flanagan et al. 1978; McLellan et al. 1978; Newton et al. 1984; 

Rahola et al. 1973). Other polyvalent cations including calcium, magnesium, and zinc can interfere with 

cadmium uptake (Foulkes 1985), but administration of competing cations can in some cases increase 

rather than decrease cadmium absorption (Jaeger 1990), and is therefore not recommended for the 

treatment of cadmium ingestion. Oral administration of some compounds that chelate cadmium such as 

meso-2,3-dimercaptosuccinic acid has been found in rodent studies to reduce absorption following acute 

oral exposure to cadmium, but other chelators such as dithiocarbamates can increase toxicity (see 

Section 3.4.1.2). At present, no recommendations for chelation treatment to reduce absorption can be 

made (Jones and Cherian 1990). Administration of garlic (which is high in reduced sulfhydryl groups) 

has been shown to decrease oral cadmium toxicity in rats (Cha 1987). Thus, use of garlic could be an 

area of future research. 

Dermal or ocular exposure to high levels of cadmium may cause irritation (Wahlberg 1977) and should be 

treated by removing contaminated clothing, washing the skin, and thoroughly flushing the eyes (EPA 

1989d; Stutz and Janusz 1988). These measures will also reduce the relatively small potential for dermal 

absorption of cadmium (see Section 3.4.1.3). 

3.11.2 Reducing Body Burden 

A variety of chelating agents have been evaluated (Cantilena and Klaassen 1981; Jones et al. 1992, 1994; 

Kostial et al. 1996; Singh et al. 1996). Some of the more familiar chelators that are beneficial for other 

toxic metals actually increase cadmium toxicity by mobilizing the cadmium and substantially increasing 

the renal concentrations and toxicity (Agency for Toxic Substances and Disease Registry 1990b; 

Goldfrank et al. 1990; Jones and Cherian 1990). One such agent is the chelating agent dimercaprol (also 

known as BAL, British Anti-Lewisite), commonly used for treating cases of lewisite toxicosis. BAL is 

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widely recognized as harmful in treating cadmium exposures. Some sources recommend using ethylenediamine tetraacetic acid (EDTA) salts (Cantilena and Klaassen 1980, 1981; Ellenhorn and Barceloux 

1988; Stutz and Janusz 1988) or use of EDTA with caution about potential nephrotoxicity (EPA 1989d; 

Haddad and Winchester 1990). Other chelators that have reduced the cadmium burden in animal studies 

include diethylenetriaminepentaacetic acid (DTPA), 2,3-dimercaptosuccinic acid (DMSA), and various 

dithiocarbamates (Cantilena and Klaassen 1981, 1982b; Kamenosono et al. 2002a; Wang et al. 1999). 

Cantilena and Klaassen (1982a) demonstrated the importance of rapid administration of DTPA, EDTA, or 

DMSA following acute cadmium exposure if they are to be effective. Waalkes et al. (1983) evaluated the 

role of metallothionein in the acute drop in chelator efficacy following cadmium poisoning in male 

Sprague-Dawley rats. Although the chelator, DTPA, reduced cadmium content in the various organs 

when given immediately after cadmium, it was ineffective at all later times. Increases in hepatic and 

renal metallothionein did not occur until 2 hours after cadmium, and did not coincide with the earlier drop 

in chelator efficacy. Blockade of metallothionein synthesis by actinomycin D treatment (1.25 mg/kg, 

1 hour before Cd) failed to prolong the chelators effectiveness. Furthermore, newborn rats have high 

levels of hepatic metallothionein, which had no effect on the time course of chelator effectiveness since 

DTPA still decreased cadmium organ contents, if given immediately following cadmium, but had no 

effect if given 2 hours after cadmium. The authors concluded that metallothionein does not have an 

important role in the acute decrease in efficacy of chelation therapy for cadmium poisoning. The quick 

onset of chelator ineffectiveness may be due to the rapid uptake of cadmium into tissues, which makes it 

relatively unavailable of chelation. 

Jones et al. (1992, 1994) investigated a series of monoalkyl and monoarakyl esters of meso-2,3-dimercaptosuccinic acid. Monoisoamyl meso-2,3-dimercaptosuccinate (Mi-ADMS) was an effective 

chelating agent for reduction of kidney and liver cadmium when administered either parenterally or orally 

(Jones et al. 1992). This finding was supported by a study by Eybl et al. (1994), which showed that 

Mi-ADMS, administered orally every 48 hours for 12 days after acute cadmium exposure, was effective 

at reducing cadmium in the kidney and liver, but not in the testes and brain. Monophenylethyl-, 

mono(3-phenylpropyl)-, and mono(2-phenoxyethyl) meso-2,3-dimercaptosuccinic acid compounds 

successfully remove “aged” cadmium deposits and can be administered via a variety of routes (Jones et 

al. 1994). 

Another area of chelation therapy research is in the use of multiple chelators. Blaha et al. (1995) 

evaluated the ability of two carbodithioate chelators, sodium N-(4-methylbenzyl)-4-O-(β-D-galacto­

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pyranosyl)-D-glucamine-N-carbodithioate (MeBLDTC) and sodium 4-carboxyamidopiperidineN-carbothioate (INADTC), singly or in combination to reduce cadmium burden from chronically exposed 

rats. The combination therapy resulted in a synergistic effect on increased biliary excretion and reduced 

renal cadmium that, in the case of biliary excretion, was more than doubled that expected for a simple 

additive interaction. 

3.11.3 Interfering with the Mechanism of Action for Toxic Effects 

The toxic effects of cadmium are generally thought to be caused by "free" cadmium ions; that is, 

cadmium not bound to metallothionein or other proteins (Goyer et al. 1989). However, cadmium bound 

to metallothionein may have the capacity to directly damage renal tubular membranes during uptake 

(Suzuki and Cherian 1987). Free cadmium ions may have a number of adverse effects, including 

inactivation of metal-dependent enzymes, activation of calmodulin, and initiation of the production of 

active oxygen species (Palmer et al. 1986; Waalkes and Goering 1990). 

Respiratory damage caused by acute, high-level inhalation exposure to cadmium can cause impaired lung 

function that can last many years after exposure (Barnhart and Rosenstock 1984; Townshend 1982). No 

treatments other than supportive care and avoidance of additional risk factors for lung injury are presently 

known. 

The kidneys appear to be highly vulnerable to chronic cadmium exposure by either the oral or inhalation 

routes. The basis for the preferential sensitivity of the kidney is related to the filtering and reabsorption of 

circulating cadmium-metallothionein complex, which is then thought to be degraded in the tubular cell 

lysosomes and released as free intracellular cadmium. The toxic effect results from the limited ability of 

the kidney to synthesize new cytosolic metallothionein in response to an increasing cadmium load (Goyer 

et al. 1989). Cadmium bound to metallothionein, however, may also have nephrotoxic activity (Suzuki 

and Cherian 1987). 

No treatments are currently available that specifically target free cadmium ions in the renal cortex, but 

zinc and calcium can stimulate metallothionein synthesis and may also compete with cadmium for 

enzyme binding sites. Thus, zinc, and/or calcium supplementation might help reduce renal cadmium 

toxicity, at least in zinc- or calcium-deficient individuals. It is not known whether administration of these 

compounds would be beneficial in individuals with adequate zinc and calcium intakes, and their clinical 

use is not currently recommended. Since one of the postulated mechanisms of cadmium toxicity is the 

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stimulation and production of active oxygen species, it is possible that increasing the cellular levels of 

antioxidants such as superoxide dismutase, reduced sulfur compounds (particularly glutathione), 

vitamin C, vitamin E, or β-carotene could reduce renal cadmium toxicity by scavenging active oxygen 

species prior to reaction with cellular components. Several animal studies have examined coadministration of several antioxidants on cadmium-induced kidney damage. Beneficial effects were 

found for vitamin E (Shaikh and Tang 1999; Shaikh et al. 1999a), N-acetyl cysteine (Kaplan et al. 2008; 

Shaikh et al. 1999a, 1999b), glycine (Shaikh and Tang 1999), glyceryrrhizin (Nomiyama and Nomiyama 

1998), and a drug containing glyceryrrhizin, glycine, and cystein (Shaikh and Tang 1999; Shaikh et al. 

1999a). However, antioxidants are not currently recommended for the treatment of cadmium-exposed 

humans. 

Treatments for the cadmium-related effects on bone have not been evaluated. Although the mechanism of 

bone damage has not been fully elucidated, it is likely that calcium loss and altered vitamin D 

metabolism, which result from cadmium-induced kidney damage, play an important role. Thus, 

treatments that interfere with the renal damage will likely have a beneficial effect on bone. 

Research in chelation therapy is promising for agents that can interfere or possibly reverse the toxic 

effects of cadmium. Xu et al. (1995, 1996) demonstrated that monoisoamyl meso-2,3-dimercaptosuccinate, when administered within 1 hour after acute exposure, prevents the formation of cadmiuminduced apoptotic DNA fragmentation and associated histopathological injury in the testes of rats. Perry 

et al. (1989) report a reversal of the cadmium induced hypertension in rats with the chelator d-myoinositol-1,2,6-triphosphate. 

3.12 ADEQUACY OF THE DATABASE 

Section 104(I)(5) of CERCLA, as amended, directs the Administrator of ATSDR (in consultation with the 

Administrator of EPA and agencies and programs of the Public Health Service) to assess whether 

adequate information on the health effects of cadmium is available. Where adequate information is not 

available, ATSDR, in conjunction with the National Toxicology Program (NTP), is required to assure the 

initiation of a program of research designed to determine the health effects (and techniques for developing 

methods to determine such health effects) of cadmium. 

The following categories of possible data needs have been identified by a joint team of scientists from 

ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that if met would 

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reduce the uncertainties of human health assessment. This definition should not be interpreted to mean 

that all data needs discussed in this section must be filled. In the future, the identified data needs will be 

evaluated and prioritized, and a substance-specific research agenda will be proposed. 

3.12.1 Existing Information on Health Effects of Cadmium 

The existing data on health effects of inhalation, oral, and dermal exposure of humans and animals to 

cadmium are summarized in Figure 3-6. The purpose of this figure is to illustrate the existing information 

concerning the health effects of cadmium. Each dot in the figure indicates that one or more studies 

provide information associated with that particular effect. The dot does not necessarily imply anything 

about the quality of the study or studies, nor should missing information in this figure be interpreted as a 

“data need”. A data need, as defined in ATSDR’s Decision Guide for Identifying Substance-Specific 

Data Needs Related to Toxicological Profiles (Agency for Toxic Substances and Disease Registry 1989), 

is substance-specific information necessary to conduct comprehensive public health assessments. 

Generally, ATSDR defines a data gap more broadly as any substance-specific information missing from 

the scientific literature. 

There is a massive database regarding the health effects of cadmium. In humans, the majority of studies 

have involved workers exposed by inhalation or residents of cadmium-polluted areas exposed primarily in 

the diet. Quantitative estimates of exposure levels are not available for many of these studies; however, 

many studies provided information on urinary cadmium levels that would be reflective of the cadmium 

body burden. Lethality, systemic toxicity, genotoxicity, and cancer have been studied in humans more 

extensively than immunotoxicity or neurotoxicity, with less being known about reproductive or 

developmental toxicity of cadmium in humans following inhalation or oral exposure. In animals, effects 

following oral exposures have generally been more thoroughly investigated than those following 

inhalation exposure, and few studies of cadmium toxicity following dermal exposure in humans were 

located. 

3.12.2 Identification of Data Needs 

Acute-Duration Exposure. There are limited data on the acute toxicity of cadmium in humans. 

Although there are numerous reports of respiratory effects in workers exposed to high concentrations of 

cadmium, there are no reliable estimates of levels associated with these effects. Animal studies provide 

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Figure 3-6. Existing Information on Health Effects of Cadmium 

Death 

Acute 

Intermediate

Chronic 

Immunologic/Lymphoretic

Neurologic

Reproductive

Developmental

Genotoxic

Cancer 

Systemic 

Human 

Inhalation 

Oral 

Dermal 

CADMIUM 236 

3. HEALTH EFFECTS 

Death 

Acute 

Intermediate

Chronic 

Immunologic/Lymphoretic

Neurologic

Reproductive

Developmental

Genotoxic

Cancer 

Systemic 

Animal 

Inhalation 

Oral 

Dermal 

Existing Studies 

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support for identification of the respiratory tract as the most sensitive target of toxicity following 

inhalation exposure. Acute exposures to high levels of airborne cadmium has resulted in pneumonia, 

emphysema, and edema in laboratory animals (Boudreau et al. 1989; Buckley and Bassett 1987b; Bus et 

al. 1978; Grose et al. 1987; Hart 1986; Henderson et al. 1979; NTP 1995; Palmer et al. 1986) and lower 

concentrations were associated with focal inflammation and minimal fibrosis (NTP 1995). A decreased 

immune response in mice was observed at similar cadmium concentrations (Graham et al. 1978; 

Krzystyniak et al. 1987). Other adverse effects observed at higher concentrations include erosions of the 

stomach, decreases in body weight, and reduced activity (Rusch et al. 1986). The available acuteduration animal data were considered adequate for derivation of an acute-duration inhalation MRL for 

cadmium. 

There are no reliable human studies on the toxicity of cadmium following acute-duration oral exposure. 

In laboratory animals, acute exposure to high doses of cadmium resulted in a variety of effects, including 

altered hematological parameters, focal necrosis and degeneration of the liver, focal necrosis in renal 

tubular epithelium, necrosis and ulceration in the stomach and intestines, decreased motor activity, and 

testicular atrophy and necrosis (Andersen et al. 1988; Basinger et al. 1988; Bomhard et al. 1987; 

Borzelleca et al. 1989; Dixon et al. 1976; Kotsonis and Klaassen 1977; Machemer and Lorke 1981; 

Sakata et al. 1988; Shimizu and Morita 1990). There is some indication that developmental effects 

(delays in ossification and increased malformations) may occur at lower cadmium doses (Baranski 1985; 

Machemer and Lorke 1981). The acute-duration oral database was not considered adequate for derivation 

of an MRL because the results of the study that identified the lowest LOAEL (Baranski 1985) were 

inadequately reported and were inconsistent with a longer-duration study conducted by the same 

investigator. Although the data suggest that the developing organism is the most sensitive target, 

additional studies are needed to support this assumption. Studies characterizing the dose-response 

relationships for the most sensitive effects are needed for derivation of an acute-duration oral MRL. 

No reliable information was located regarding toxicity following dermal exposure to cadmium, but based 

on the lack of reported effects in the workers handling cadmium compounds, it seems unlikely that 

dermal exposure could deliver a significant dose of cadmium. 

Intermediate-Duration Exposure. There are limited data on the toxicity of cadmium in humans 

following intermediate-duration exposure. 

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Intermediate-duration inhalation studies in laboratory animals have identified several targets of toxicity 

including the respiratory tract (Glaser et al. 1986; Kutzman et al. 1986; NTP 1995; Prigge 1978a), 

reproductive effects (Baranski and Sitarek 1987; NTP 1995), and developing nervous system (Baranski 

1984, 1985). At the lowest cadmium concentration tested, alveolar histiocytic infiltration and 

degeneration or metaplasia in the larynx were observed in mice (NTP 1995) and neurodevelopmental 

effects were observed in rats (Baranski 1984, 1985). These LOAELs were considered for derivation of an 

intermediate-duration inhalation MRL; however, an MRL based on the human equivalent concentration 

of the LOAELs would be lower than the chronic-duration inhalation MRL based on human data. 

Additional studies are needed to identify no-adverse-effect levels in animals for these sensitive targets of 

toxicity. 

A number of studies have been conducted involving intermediate-duration oral exposure to laboratory 

animals. The results of these studies suggest that the growing bone is the most sensitive target. The 

skeletal effects observed in young rats include decreases in bone mineral density, impaired mechanical 

strength, increased fractures, and increased bone turnover (Brzóska and Moniuszko-Jakoniuk 2005a, 

2005b, 2005d; Brzóska et al. 2004b, 2005a, 2005b, 2005c; Ogoshi et al. 1989). Developmental effects, 

including impaired renal function and neurodevelopmental alterations, have been observed at similar dose 

levels (Ali et al. 1986; Baranski et al. 1983; Jacquillet et al. 2007). At higher doses, observed effects 

included renal damage (proteinuria, tubular necrosis, and decreased renal clearance), liver necrosis, and 

anemia (Cha 1987; Gatta et al. 1989; Groten et al. 1990; Itokawa et al. 1974; Kawamura et al. 1978; 

Kawamura et al. 1978; Kotsonis and Klaassen 1978; Prigge 1978a), altered immune response (Blakley 

1985, 1986; Chopra et al. 1984), decreased motor activity (Kotsonis and Klaassen 1978; Nation et al. 

1990), and necrosis and atrophy of seminiferous tubules and decreased sperm count and motility (Cha 

1987; Saxena et al. 1989). The database of intermediate-duration animal studies was considered adequate 

for derivation an intermediate-duration oral MRL based on skeletal effects in growing rats. 

No intermediate-duration dermal data were identified in humans or animals. Studies of possible toxicity 

in animals following intermediate-duration dermal exposure to cadmium are needed to evaluate potential 

health effects in humans exposed to cadmium primarily by the dermal route. 

Chronic-Duration Exposure and Cancer. Data on the chronic toxicity of inhaled cadmium in 

humans come from numerous occupational exposure studies; no reliable animal studies examining 

noncancerous end points were identified. These studies have identified the respiratory tract (emphysema, 

impaired lung function) (Chan et al. 1988; Cortona et al. 1992; Davison et al. 1988; Smith et al. 1976) and 

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the kidney (tubular proteinuria, decreased glomerular filtration rate, increased excretion of low molecular 

weight proteins) (Bernard et al. 1990; Chen et al. 2006a, 2006b; Chia et al. 1992; Elinder et al. 1985a; 

Falck et al. 1983; Jakubowski et al. 1987, 1992; Järup and Elinder 1994; Järup et al. 1988; Shaikh et al. 

1987; Toffoletto et al. 1992; Verschoor et al. 1987) as the most sensitive targets of toxicity. Comparisons 

of the adverse effect levels for these two end points are difficult because the studies on respiratory effects 

typically reported air concentrations (current levels or estimated cumulative exposure) as the exposure 

biomarker and those examining renal effects typically used urinary cadmium levels as the exposure 

biomarker; based on limited data, the kidney appears to be the more sensitive target. Studies examining 

both end points in occupationally exposed populations would provide valuable information on sensitivity. 

None of the available human studies were considered adequate for derivation of an inhalation MRL 

because cadmium air concentrations were poorly characterized or no data were provided on the 

contribution of dietary cadmium to the cadmium body burden. However, the similarities on the toxicity 

and toxicokinetics of cadmium following inhalation and oral exposure allow for the use of the oral 

database to derive an inhalation MRL. 

There is an extensive database of studies examining the chronic oral toxicity of cadmium in humans. 

These environmental exposure studies have identified two sensitive targets of cadmium toxicity—the 

skeletal system and the kidney. The skeletal effects included increased risk of osteoporosis and bone 

fractures and decreases in bone mineral density (Alfvén et al. 2000, 2004; Nordberg et al. 2002; Schutte et 

al. 2008; Staessen et al. 1999; Wang et al. 2003). Renal effects range from death due to renal failure 

(Arisawa et al. 2001, 2007b; Iwata et al. 1991a, 1991b; Matsuda et al. 2002; Nakagawa et al. 1993; 

Nishijo et al. 1995, 2004a, 2006) to increases in the prevalence of low molecular weight proteinuria 

(Buchet et al. 1990; Cai et al. 1990, 1992, 1998, 2001; Hayano et al. 1996; Ishizaki et al. 1989; Izuno et 

al. 2000; Järup et al. 2000; Jin et al. 2002, 2004a, 2004c; Kawada et al. 1992; Kido and Nogawa 1993; 

Kobayashi et al. 2002a; Monzawa et al. 1998; Nakashima et al. 1997; Nogawa et al. 1989; Noonan et al. 

2002; Nordberg et al. 1997; Olsson et al. 2002; Oo et al. 2000; Osawa et al. 2001; Roels et al. 1981b; 

Suwazono et al. 2006; Teeyakasem et al. 2007; Trzcinka-Ochocka et al. 2004; Uno et al. 2005; Yamanaka 

et al. 1998; Wu et al. 2001). Animal studies confirm the identification of the kidney and bone as the most 

sensitive targets of cadmium toxicity (Akahori et al. 1994; Bernard et al. 1992; Bomhard et al. 1984; 

Brzóska and Moniuszko-Jakoniuk 2004a, 2004b; Fingerle et al. 1982; Mangler et al. 1988). Sufficient 

information from human studies is available to derive a chronic oral MRL. No information was located 

regarding dermal toxicity of chronic cadmium exposure in humans or animals, and studies of dermal 

toxicity are needed to evaluate risks to populations exposed to cadmium primarily by dermal contact. 

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The evidence of carcinogenicity from human studies is limited, due to uncertainties in cadmium exposure 

estimates and confounding factors including exposure to arsenic, a known human lung carcinogen, and 

smoking. Occupational exposure studies have found significant increases in lung cancer mortalities 

(Ades and Kazantzis 1988; Järup et al. 1998a; Kazantzis et al. 1988; Stayner et al. 1992a; Sorahan 1987; 

Sorahan and Waterhouse 1983; Thun et al. 1985). However, lung cancer deaths were often not 

significantly associated with cadmium exposure or duration. Other studies have not found increases in 

lung cancer deaths (Armstrong and Kazantzis 1983; Elinder et al. 1985c; Lamm et al. 1992, 1994; 

Sorahan and Esmen 2004; Sorahan and Lancashire 1997). Additional occupational exposure studies 

controlling for these exposures and providing more precise cadmium dose estimates are needed to provide 

more definitive evidence of the carcinogenic potential in humans of inhaled cadmium. Evidence for the 

carcinogenicity of cadmium by the inhalation route is available from studies in rats (Takenaka et al. 

1983). Additional studies in animals are needed to evaluate the lack of an observed increase in lung 

cancer in mice and hamsters exposed to cadmium by inhalation (Heinrich et al. 1989). Cadmium has not 

been shown to be carcinogenic following oral exposure in humans (Bako et al. 1982; Hardell et al. 1994; 

Inskip et al. 1982; Lauwerys and De Wals 1981; Nakagawa et al. 1987; Shigematsu 1984). In rats, 

however, cadmium increased tumors of the prostate, testes, and hematopoietic system (Waalkes et al. 

1992). Additional lifetime-exposure studies in rats, mice, and hamsters orally exposed to cadmium at 

sufficiently high doses are needed to further define the carcinogenic potential of cadmium. 

Genotoxicity. The evidence for the genotoxicity of cadmium is mixed (see Tables 3-10 and 3-11). In 

vitro studies have provided both positive and negative results (Amacher and Paillet 1980; Bruce and 

Heddle 1979; Casto et al. 1979; Denizeau and Marion 1989; Depault et al. 2006; Fatur et al. 2002; Filipic 

and Hei 2004; Honma et al. 1999; Jianhua et al. 2006; Lopez-Ortal et al. 1999; Lutzen et al. 2004; Lynn et 

al. 1997; Mikhailova et al. 1997; Oberly et al. 1982; Rozgaj et al. 2002; Shiraishi et al. 1972; Terracio and 

Nachtigal 1988). Studies of chromosomal aberrations in humans (Bui et al. 1975; Deknudt and Leonard 

1975; Fu et al. 1999; O'Riordan et al. 1978; Tang et al. 1990) and animals (Bruce and Heddle 1979; Desi 

et al. 2000; DiPaulo and Castro 1979; Fahmy and Aly 2000; Karmakar et al. 1998; Mukherjee et al. 

1988a; Tan et al. 1990; Watanabe et al. 1979) exposed to cadmium have also found both positive and 

negative results. DNA damage has been consistently observed in in vitro studies (Devi et al. 2001; 

Fahmy and Aly 2000; Kasuba et al. 2002; Mukherjee et al. 1988a; Saplakoglu et al. 1997; Valverde et al. 

2000; Wronska-Nofer et al. 1999; Zhou et al. 2004b). In animals, parenteral, but not inhalation or oral, 

cadmium exposure has been found to cause germ cell mutations (Gilliavod and Leonard 1975; Suter 

1975; Sutou et al. 1980; Watanabe and Endo 1982; Zenick et al. 1982). Additional studies investigating 

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effects in exposed humans using larger populations with quantitative estimates of exposure would be 

useful to evaluate the human genotoxicity of cadmium. 

Reproductive Toxicity. Only limited or conflicting evidence is available to evaluate the potential for 

cadmium exposure to cause reproductive toxicity in humans. Some studies report no effect on male 

fertility (Gennart et al. 1992), sex hormone levels (Mason 1990; Menke et al. 2008; Zeng et al. 2004a), 

sperm density (Noack-Fuller et al. 1993), or semen quality (Jurasović et al. 2004; Saaranen et al. 1989), 

while others report a reduction in sperm number or viability (Akinloye et al. 2006; Telišman et al. 2000; 

Xu et al. 1993a) or alterations in sex steroid hormone levels (Akinloye et al. 2006; Jurasović et al. 2004; 

Telišman et al. 2000). In one study, men occupationally exposed to cadmium at levels resulting in renal 

damage had no change in testicular function (Mason 1990). Adverse effects in animals from inhalation 

exposure have been reported including increased duration of the estrous cycle (Baranski and Sitarek 1987; 

NTP 1995; Tsvetkova 1970), and increased relative testes weight but no loss in reproductive success 

(Kutzman et al. 1986). Adverse reproductive effects in animals from high-dose, acute, oral cadmium 

exposure have been reported including testicular atrophy and necrosis (Andersen et al. 1988; Bomhard et 

al. 1987; Borzelleca et al. 1989), and decreased fertility (Kotsonis and Klaassen 1978; Machemer and 

Lorke 1981). At lower doses and intermediate exposures, adverse effects have included necrosis and 

atrophy of seminiferous tubule epithelium (Cha 1987), increased testes weight (Pleasants et al. 1992, 

1993), increased prostatic hyperplasias (Waalkes and Rehm 1992), significantly increased relative testes 

weight, decreased sperm count and motility, decreased seminiferous tubular diameter, seminiferous 

tubular damage (Saxena et al. 1989), and decreased fertility (Sutou et al. 1980). Other animal studies for 

lower dose intermediate exposures, however, report no adverse effects (Baranski et al. 1983; Bomhard et 

al. 1987; Groten et al. 1990; Kostial et al. 1993; Kotsonis and Klaassen 1978; Loeser and Lorke 1977a; 

Pleasants et al. 1992; Pond and Walker 1975; Zenick et al. 1982). Additional studies in animals, as well 

as retrospective, case-matched studies of reproductive success of populations for which occupational or 

environmental exposure to cadmium has been estimated, are needed to further evaluate the potential 

reproductive toxicity of cadmium in humans. Additional studies would be useful (preferably with larger 

sample sizes) to evaluate the robustness of the association between cadmium and adverse effects on 

sperm. 

Developmental Toxicity. The potential for cadmium exposure to cause developmental toxicity from 

pre- or postnatal exposures in humans is not known. One study in occupationally exposed women 

reported children with lowered birth weights, but with no increase in malformations (Tsvetkova 1970). 

However, no control was made for parity, maternal weight, gestational age, or other factors known to 

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influence birth weight. Many animal studies demonstrate that developmental toxicity may occur 

following cadmium exposure by oral routes with a relatively few studies reporting developmental effects 

following inhalation or oral exposure (Ali et al. 1986; Baranski 1985, 1987; Baranski et al. 1983; Gupta et 

al. 1993; Kelman et al. 1978; Kostial et al. 1993; Machemer and Lorke 1981; Petering et al. 1979; Pond 

and Walker 1975; Schroeder and Mitchener 1971; Sorell and Graziano 1990; Sutou et al. 1980; Webster 

1978; Whelton et al. 1988). At lower inhalation and oral doses, impaired performance on 

neurobehavioral tests have been observed (Ali et al. 1986; Baranski et al. 1983; Desi et al. 1998; 

Nagymajtenyi et al. 1997). Retrospective, case-matched studies of developmental toxicity among 

children of women with known occupational or environmental exposure to cadmium are needed to 

evaluate the potential for cadmium exposure to cause human developmental toxicity such as skeletal 

malformations and neurobehavioral effects (as suggested in animal studies). Studies are also needed to 

follow-up on the results of increased susceptibility of young to bone damage (Ogoshi et al. 1989) or 

suppression of the immune response (Blakley 1985) reported in animals. The difference in the immune 

response (using the same protocol) between young mice (Blakley 1985) and older mice (Blakley 1988) 

should also be further evaluated. Studies of postnatal cadmium exposure to children, especially for 

children with diets deficient in calcium, protein, or iron, would be useful to evaluate whether increased 

cadmium absorption from the diet leads to developmental effects. 

Immunotoxicity. A variety of immunologic effects have been found in animals exposed to cadmium 

by the oral or inhalation routes (Blakley 1988; Bouley et al. 1984; Cifone et al. 1989a). However, the 

biological significance of these effects is not clear, and there is little information available on 

immunotoxicity in humans. Investigations of immunologic function of populations occupationally or 

environmentally exposed to cadmium, and follow-up mechanistic studies in animals are needed to 

evaluate the potential immunotoxicity of cadmium exposure in humans. 

Neurotoxicity. A few studies have suggested an association between cadmium exposure in humans 

and impaired neuropsychologic functioning at levels below those causing nephrotoxicity (Hart et al. 

1989b; Marlowe et al. 1985; Thatcher et al. 1982). Neurotoxicity has also been found in animal studies 

(Nation et al. 1984; Wong and Klaassen 1982). Additional studies to investigate neurologic effects in 

populations with known cadmium exposure and studies of possible mechanisms of neurotoxicity in 

animals are needed to evaluate the potential neurotoxicity of cadmium exposure to humans. In addition, 

studies examining neurobehavioral end points in children would be useful. 

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Epidemiological and Human Dosimetry Studies. Cause/effect relationships for renal toxicity of 

cadmium have been derived from studies of workers occupationally exposed to cadmium by inhalation 

(Bernard et al. 1990; Chen et al. 2006a, 2006b; Chia et al. 1992; Elinder et al. 1985b; Falck et al. 1983; 

Jakubowski et al. 1987, 1992; Järup and Elinder 1994; Järup et al. 1988; Kawada et al. 1989; Roels et al. 

1993; Shaikh et al. 1987; Thun et al. 1989; Toffoletto et al. 1992; Verschoor et al. 1987) and of 

populations environmentally exposed to cadmium in the diet (Buchet et al. 1990; Cai et al. 1990, 1992, 

1998, 2001; Hayano et al. 1996; Ishizaki et al. 1989; Izuno et al. 2000; Järup et al. 2000; Jin et al. 2002, 

2004a, 2004c; Kawada et al. 1992; Kido and Nogawa 1993; Kobayashi et al. 2002b; Monzawa et al. 

1998; Nakadaira and Nishi 2003; Nakashima et al. 1997; Nogawa et al. 1989; Noonan et al. 2002; 

Nordberg et al. 1997; Roels et al. 1981a; Olsson et al. 2002; Oo et al. 2000; Osawa et al. 2001; Suwazono 

et al. 2000; Teeyakasem et al. 2007; Trzcinka-Ochocka et al. 2004; Uno et al. 2005; Watanabe et al. 

2002Wu et al. 2001; Yamanaka et al. 1998). There is also epidemiological evidence that chronic 

environmental exposure to cadmium can result in decreases in bone mineral density and increases in the 

risk of bone fractures and osteoporosis (Åkesson et al. 2005; Alfvén et al. 2000, 2004; Schutte et al. 2008; 

Staessen et al. 1999). Additional studies are needed to elucidate the mechanisms of these bone effects in 

humans and to determine if the skeletal system is a more sensitive target of cadmium toxicity than the 

kidney effects. Measurement of additional toxicity end points (reproductive, developmental, 

immunological, and neurological) in these well characterized populations are needed to evaluate whether 

any of these effects may occur at exposure levels below those leading to kidney damage. Additional 

development of PBPK/PD models is needed to evaluate human exposure scenarios. In its assessment of 

the U.S. population’s exposure to environmental chemicals, the CDC measured urinary cadmium levels. 

If urinary cadmium levels are monitored in future assessments, it would be useful to also measure 

biomarkers of tubular dysfunction; these data would be useful in examining possible relationships 

between cadmium exposure and renal function in the general population. 

Biomarkers of Exposure and Effect. 

Exposure. Cadmium levels can be measured in a variety of tissues and fluids, including blood, urine, 

milk, liver, kidney, hair, and nails (Elinder and Lind 1985; Roels et al. 1981b; Sharma et al. 1982). Blood 

cadmium is a useful indicator of recent cadmium exposure, and urinary cadmium is a useful indicator of 

total body burden (Shaikh and Smith 1984). The most important indicator of the potential for 

toxicological injury is generally considered to be the cadmium concentration in the renal cortex, but 

individuals vary in the concentration causing renal effects (the "critical concentration") (Roels et al. 

1981b). Methods for in vivo measurement of cadmium content in the kidney exist, but they are complex 

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CADMIUM 244 

3. HEALTH EFFECTS 

and expensive, and involve some exposure to ionizing radiation (Scott and Chettle 1986). Efforts to 

develop easier, safer, and less costly methods for in vivo analysis are needed, as well as studies to 

determine factors influencing individual variation in critical concentrations. Although many studies 

correct urinary cadmium levels for creatinine concentration, several investigators (Alessio et al. 1985; 

Ikeda et al. 2003a; Moriguichi et al. 2005b) have questioned the validity of this approach due to wide 

intra- and interindividual variability and age-related decline in levels. Additional studies are needed to 

further investigate methods to account for dilution in urine spot samples. 

Effect. A number of sensitive tests are available to detect early stages of renal dysfunction that are 

known to be caused by cadmium exposure. These include analysis of urinary excretion of 

β2-microglobulin, retinol-binding protein, metallothionein, or enzymes (Shaikh and Smith 1984). 

However, renal damage detected by these tests is not necessarily associated with cadmium exposure. 

Additional studies are needed to evaluate current or potentially new urinary or serum biomarkers in 

cadmium-exposed populations and their association with incipient injury to the kidney caused by 

cadmium. The bone is a sensitive target of cadmium toxicity, particularly during growth and in the 

elderly; studies are needed to develop sensitive biomarkers to detect early signs of bone damage. 

Absorption, Distribution, Metabolism, and Excretion. Good information exists on cadmium 

toxicokinetics in humans and animals. PBPK/PD models have been developed to predict the critical 

organ dose as a function of route, duration, and level of exposure by the inhalation and oral routes 

(Kjellström and Nordberg 1978, 1985). Although general factors influencing absorption, distribution, 

metabolism, and excretion are known, additional studies are needed to provide information on metal 

metabolism and interactions that support quantitative evaluation of individual variations and resulting 

differences in renal cadmium accumulation. Very limited information exists on the dermal absorption of 

cadmium (Skog and Wahlberg 1964; Wester et al. 1992). Additional studies on the dermal absorption of 

cadmium are needed. 

Comparative Toxicokinetics. Animal and human studies have generally reported comparable 

toxicokinetics of cadmium (Kjellström and Nordberg 1985; Nordberg et al. 1985), suggesting that rats, 

mice, and rabbits are suitable models for cadmium toxicity in humans. However, some concerns have 

been raised about the appropriateness of the rat model for cadmium-induced lung tumors in humans 

because of differences in the morphology of the rat respiratory tract and resulting differences in cadmium 

particle deposition patterns and target cell populations. This is especially of concern because cadmium 

appears to be a contact carcinogen for lung cancer. Additional studies on the differences between the rat 

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CADMIUM 245 

3. HEALTH EFFECTS 

and human clearance rates, speciation at the level of the target cell, and protein transporters (as they relate 

to solubility and susceptibility) are needed to evaluate the appropriateness of the rat model for predicting 

cadmium-induced human lung cancers. Additional studies on differences in species, strain, sex, age, and 

other factors on cadmium kinetics and carcinogenic or other systemic effects are also needed to 

extrapolate the animal data to potential human toxicity. Additional studies establishing the toxicokinetics 

of cadmium in pregnant animals are needed to assess the relevance of the developmental effects observed 

in animals. 

Methods for Reducing Toxic Effects. The mechanisms of cadmium absorption across epithelial 

layers are likely to be via nonspecific mechanisms (Foulkes 1989). No methods are known for 

influencing absorption across the lung, but absorption across the gastrointestinal tract may be influenced 

by dietary status (Flanagan et al. 1978). Studies to determine whether dietary adjustments might help 

decrease cadmium uptake from food or water are needed. Studies to determine the effects of dietary 

deficiencies in calcium are needed to further evaluate the risk of cadmium exposure to susceptible 

populations. Uptake across the skin is probably sufficiently slow that simple washing of exposed areas is 

adequate to prevent excessive absorption (Skog and Wahlberg 1964). 

Once cadmium is absorbed, it tends to accumulate in the kidney, which is the main target tissue for 

chronic low-dose exposure. The cellular and molecular basis for the preferential accumulation in the 

kidney is only partially understood (Waalkes and Goering 1990), and additional studies to define the ratelimiting steps in renal uptake and renal clearance of cadmium are needed to design strategies for reducing 

the rate of cadmium accumulation in this tissue. Additional studies on existing and new chelating agents 

and different treatment regimens are needed to improve the clinical therapies for acute and chronic 

exposures to cadmium. 

The mechanism of cadmium toxicity in renal cells and other tissues probably involves binding of free 

cadmium ions to key cellular enzymes and proteins (Waalkes and Goering 1990). Thus, any agent that 

prevents cadmium from binding might help prevent toxicity. The endogenous cadmium-binding protein 

can serve this function; however, metallothionein-cadmium complexes may have renal toxicity (Suzuki 

and Cherian 1987). Additional studies on the role of metallothionein in cadmium toxicity would be 

useful. Additional studies are needed on alternative substrate molecules or drugs that could interact with 

free cadmium and prevent binding to key cellular enzymes, as well as the ability of antioxidants to reduce 

damage from active-oxygen species produced by cadmium in tissues. 

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CADMIUM 246 

3. HEALTH EFFECTS 

The impaired renal function that is the typical adverse effect of excessive cadmium exposure is neither 

clinically treatable nor reversible (Agency for Toxic Substances and Disease Registry 1990b; Roels et al. 

1989). Studies on potential supportive treatment or remedies for cadmium-induced mild renal impairment 

would be valuable. 

The bone is also a sensitive target of cadmium toxicity; however, methods for the treatment of the 

observed effects, decreased bone mineral density and increased fractures, have not been developed and 

are needed. 

Children’s Susceptibility. Data needs relating to both prenatal and childhood exposures, and 

developmental effects expressed either prenatally or during childhood, are discussed in detail in the 

Developmental Toxicity subsection above. 

There is limited information on the toxicity of cadmium in children. Although it is likely that children 

will have similar effects as adults, there is some suggestive evidence that childhood exposure may result 

in increased renal toxicity, as compared to persons only exposed as adults (Trzcinka-Ochocka et al. 2004). 

Additionally, studies in animals suggest that young animals are more susceptible to cadmium-induced 

bone damage than adults (Ogoshi et al. 1989); this has not been investigated in humans. Studies are 

needed to evaluate whether there are age-specific differences in the toxicity of cadmium in humans. As 

discussed in the Developmental Toxicity section above, there are limited data on the developmental 

toxicity of cadmium in humans, particularly potential neurodevelopmental effects and additional studies 

are needed. 

Additional research is needed on the toxicokinetics of cadmium during long-term, low-level exposures to 

determine the potential long-term tissue burdens that are likely to result especially for the susceptible 

tissues of liver, kidney, and bone. Data in animals suggest that children may absorb more cadmium than 

adults, but there are no human data examining these potential differences in the toxicokinetic properties of 

cadmium. Additional information is needed on cadmium transport across the blood-brain barrier in the 

developing fetus, and the role of metallothionein in the placenta. 

Neurological and behavioral studies are needed that use the more sophisticated measures available today 

to evaluate children for in utero, acute, and longer term exposures. These studies should have the 

appropriate controls for confounding factors such as lead, parental use of ethanol, and living conditions. 

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CADMIUM 247 

3. HEALTH EFFECTS 

Additional studies are needed to evaluate whether or not biomarkers of cadmium exposure and effects 

that have been developed for adults are also applicable to children. If not, new biomarkers of exposure 

and effect need to be developed. 

The effects of nutritional status (iron, zinc, and calcium levels) on cadmium absorption and accumulation 

in children need further evaluation. Improved regimens and choices for chelation therapy are also 

needed. 

Child health data needs relating to exposure are discussed in Section 6.8.1, Identification of Data Needs: 

Exposures of Children. 

3.12.3 Ongoing Studies 

A number of research projects are in progress investigating the health effects of cadmium. These projects 

are summarized in Table 3-14. 

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CADMIUM 248 

3. HEALTH EFFECTS 

Table 3-14. Ongoing Studies on Cadmium 

Investigator Study topic Institution Sponsor 

Fadrowski, J Determination if environmental 

cadmium exposure is 

associated with chronic kidney 

disease in children 

John Hopkins University National Institute of 

Environmental Health 

Sciences 

Wande, LI Examination of cadmium 

modulation of lysyl oxidase in 

the lung which may provide 

insight into the molecular 

mechanism of cadmiumBoston University National Institute of 

Environmental Health 

Sciences 

induced emphysema. 

Nebert, DW Characterization of the ZIPS 

transporter protein and the 

role of ZIPS in cadmiumUniversity of Cincinnati National Institute of 

Environmental Health 

Sciences 

induced renal damage 

Prozialeck, WC Mechanisms of cadmium 

toxicity in epithelial cells 

Midwestern University National Institute of 

Environmental Health 

Sciences 

Zahler, NH Mechanisms involved in the 

cadmium-induced DNA 

University of Michigan, 

Ann Arbor 

National Institute of 

Environmental Health 

damage and oxidative stress Sciences 

Thomas, DG 

and Kennedy 

TS 

Examination of the possible 

association between cadmium 

levels in maternal blood and 

Oklahoma State 

University 

National Research Initiative 

breast milk and cognitive 

development in infants 

Source: FEDRIP 2008 

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CADMIUM 249 

4. CHEMICAL AND PHYSICAL INFORMATION 

4.1 CHEMICAL IDENTITY 

Table 4-1 lists the common synonyms, trade names, and other pertinent identification information for 

cadmium and its most important compounds. 

4.2 PHYSICAL AND CHEMICAL PROPERTIES 

Table 4-2 lists important physical and chemical properties of cadmium and its most important 

compounds. 

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CADMIUM 250 

4. CHEMICAL AND PHYSICAL INFORMATION 

Table 4-1. Chemical Identity of Cadmium and Compoundsa 

Characteristic Information 

Chemical name Cadmium Cadmium carbonate Cadmium chloride 

Synonym(s) Colloidal cadmium Otaviteb

; cadmium 

monocarbonate; 

Caddyb; Vi-Cadb; cadmium 

dichloride; dichlorocadmium 

carbonic acid; cadmium 

salt 

Registered trade name(s) No data No data No data 

Chemical formula Cdb CdCO3 

b CdCl2 b 

Chemical structure Cdb CdCO3 

b CdCl2 b 

Identification numbers: 

CAS registry 7440-43-9b 513-78-0b 10108-64-2 

NIOSH RTECS No data No data No data 

EPA hazardous waste D006 D006 D006 

OHM/TADS No data No data No data 

DOT/UN/NA/IMDG shipping No data No data NA2570/IMCO 6.1 

HSDB 282 1612 278 

NCI No data No data No data 

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CADMIUM	 251 

4. CHEMICAL AND PHYSICAL INFORMATION 

Table 4-1. Chemical Identity of Cadmium and Compoundsa 

Characteristic	 Information 

Chemical name Cadmium oxide Cadmium sulfate Cadmium sulfide 

Synonym(s)	 Aska-Ridb

; cadmium Cadmium sulphate; Cadmium monosulfide; 

fume; cadmium sulfuric acid; cadmium cadmium yellow; cadmium 

monoxide (2+) salt orange; cadmopur yellow; 

greenockiteb; capsebonb 

Registered trade name(s) No data No data No data 

Chemical formula CdOb CdSO4

b CdSb 

Chemical structure CdOb CdSO4

b CdSb 

Identification numbers: 

CAS registry 1306-19-0b 10124-36-4b 1306-23-6b
 

NIOSH RTECS No data No data No data 

EPA hazardous waste D006 D006 D006 

OHM/TADS No data No data No data 

DOT/UN/NA/IMDG shipping UN2570/IMCO 6.1 No data No data 

HSDB 1613 274 1614 

NCI No data No data No data 

a

All information obtained from HSDB 2008 except where noted 

b

O’Neil et al. 2006 

CAS = Chemical Abstracts Service; DOT/UN/NA/IMDG = Department of Transportation/United Nations/North 

America/International Maritime Dangerous Goods Code; EPA = Environmental Protection Agency; 

HSDB = Hazardous Substances Data Bank; NCI = National Cancer Institute; NIOSH = National Institute for 

Occupational Safety and Health; OHM/TADS = Oil and Hazardous Materials/Technical Assistance Data System; 

RTECS = Registry of Toxic Effects of Chemical Substances 

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CADMIUM 252 

4. CHEMICAL AND PHYSICAL INFORMATION 

Table 4-2. Physical and Chemical Properties of Cadmium and Compoundsa 

Property Cadmium Cadmium carbonate 

Molecular weight 112.41b 172.42b 

Color Silver-whiteb Whitec 

Physical state Lustrous metalb Powder or rhombohedral leafletsb 

Melting point 321 °Cb Decomposes at 357 °C 

Boiling point 765 °Cb No data 

Density at 20 °C 8.65 g/cm3 at 25 °Cb 4.58 g/cm3f 

Odor Odorless No data 

Odor threshold: 

Water No data No data 

Air No data No data 

Solubility: 

Water at 20 °C Insolubleb Insolublef 

Organic solvents Acids, NH4NO3 

f Acids, especially HNO3, 

concentrated NH4 solutionc 

Partition coefficients: 

Log Kow No data No data 

Log Koc No data No data 

Vapor pressure 7.5x10-3 mmHg at 257 °C No data 

Henry's law constant at 25 °C No data No data 

Autoignition temperature 250 °C No data 

Flashpoint No data No data 

Flammability limits No data No data 

Conversion factors No data No data 

Explosive limits No data No data 

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CADMIUM 253 

4. CHEMICAL AND PHYSICAL INFORMATION 

Table 4-2. Physical and Chemical Properties of Cadmium and Compoundsa 

Property Cadmium chloride Cadmium oxide 

Molecular weight 183.32 128.41b 

Color Whitec Dark brownb 

Physical state Rhombohedral crystalsb Infusible powder or cubic crystalsb 

Melting point 568 °Cb Decomposes at 950 oC 

Boiling point 960 °Cb Decomposes at 950 oC 

Density at 20 °C 4.047g/cm3 at 25 °Ce Crystals 8.15 g/cm3; amorphous 

powder 6.95 g/cm3c 

Odor Odorlessc Odorless 

Odor threshold: 

Water No data No data 

Air No data No data 

Solubility: 

Water at 20 °C Solubleb Insolubleb 

Organic solvents Acetone, slightly soluble in MEOH 

and ETOHb 

Dilute acid, slowly soluble in NH4 

saltsb 

Partition coefficients: 

Log Kow No data No data 

Log Koc No data No data 

Vapor pressure 10 mmHg at 656 °Ce, 40 mmHg at 

736 °Cd, 760 mmHg at 967 °Cd 

1 mmHg at 1,000 °Ce; 10 mm Hg at 

1149 oC; 40 mm Hg at 1257 oC 

Henry's law constant at 25 °C No data No data 

Autoignition temperature No data No data 

Flashpoint No data No data 

Flammability limits No data No data 

Conversion factors No data No data 

Explosive limits No data No data 

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CADMIUM 254 

4. CHEMICAL AND PHYSICAL INFORMATION 

Table 4-2. Physical and Chemical Properties of Cadmium and Compoundsa 

Property Cadmium sulfate Cadmium sulfide 

Molecular weight 208.47b 144.48b 

Color Colorlessc Light yellow or orangeb; brownc 

Physical state Monoclinic crystalsb Cubic or hexagonal structureb 

Melting point 1,000 °Cc 1,750 °Cc 

Boiling point No data Sublimes in N2 at 980 °Cc 

Density at 20 °C 4.69 g/cm3b 4.82 g/cm3, hexagonal structureb , 

4.5 g/cm3, cubic structureb 

Odor Odorless No data 

Odor threshold: 

Water No data No data 

Air No data No data 

Solubility: 

Water at 20 °C Solublec Soluble at 1.3 mg/L at 18 °Cb 

Organic solvents Insoluble in alcoholc, acetone, 

ammoniaf 

Concentrated or warm dilute 

mineral acidsb 

Partition coefficients: 

Log Kow No data No data 

Log Koc No data No data 

Vapor pressure at 20 °C No data No data 

Henry's law constant at 25 °C No data No data 

Autoignition temperature No data No data 

Flashpoint No data No data 

Flammability limits No data No data 

Conversion factors No data No data 

Explosive limits No data No data 

a

All information from HSDB 2008, except where noted.

b

O’Neil et al. 2006 

c

Sax and Lewis 2001 

d

Farnsworth 1980 

e

Sax and Lewis 2000 

f

Lide 2005 

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CADMIUM 255 

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

5.1 PRODUCTION 

Cadmium is a widely but sparsely distributed element found in the earth's crust at concentrations ranging 

from 0.1 to 5 ppm, primarily as sulfide minerals in association with zinc ores, zinc-bearing lead ores, and 

or complex copper-lead-zinc ores (Morrow 2001). Approximately 3 kg of cadmium for each ton of zinc 

are produced (OECD 1995). About 80% of cadmium production is associated with zinc production, 

while the other 20% is associated with lead and copper byproduct production and the recapture of 

cadmium from finished products (Morrow 2001). Between 2003 and 2006, the annual cadmium refinery 

production in the United States declined from 1,450 to 700 metric tons, dropping 52% between 2005 and 

2006 (USGS 2007, 2008). Demand for cadmium in the nickel-cadmium (Ni-Cd) battery industry is 

strengthening as demand in other areas, like coatings and pigments, has been decreasing due to 

environmental concerns and regulations. Despite this demand, primary production of cadmium may 

decrease as zinc prices increase, since producers may choose to discard the cadmium byproduct instead of 

refining it (USGS 2008). 

One company produced primary cadmium in the United States during 2007: Clarksville (Zinifex Ltd.), 

Clarksville, Tennessee. The Big River Zinc Corporation (Korea Zinc Co, Ltd), Sauget, Illinois operation 

was closed in 2006, citing mine closures and the increasing price of zinc concentrate (USGS 2008). In 

June 2006, it was purchased by ZincOx Resources plc, Surrey, United Kingdom (USGS 2007). A third 

company in Ellwood, Pennsylvania, International Metals Reclamation Co. Inc. (INMETCO), recovers 

cadmium from spent nickel-cadmium batteries, which began reclaiming cadmium in 1995 (USGS 2007). 

In 2005, it was estimated that the total cadmium recovery rate was only 12%, with an estimated 

40,000 tons of cadmium being disposed of in municipal waste or held in household storage or industry 

stockpiles between 1996 and 2005 (USGS 2007). 

The following companies are currently cited as major producers of cadmium compounds: GFS 

Chemicals Inc., Columbus, Ohio (cadmium chloride, cadmium sulfate); CERAC Inc., Milwaukee, 

Wisconsin (cadmium sulfide); and EP Scientific Products, LLC (cadmium sulfide) (SRI 2007). BASF 

Catalysts LLC, Louisville, Kentucky was specifically cited as a major producer of cadmium sulfide/ 

sulfoselenide pigments (SRI 2007). 

Tables 5-1 and 5-2 list the facilities in each state that manufacture or process cadmium and cadmium 

compounds, respectively, the intended use, and the range of maximum amounts stored on site. The data 

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CADMIUM 256 

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

Table 5-1. Facilities that Produce, Process, or Use Cadmium 

Minimum Maximum 

Number of amount on site amount on site 

Statea facilities in poundsb in poundsb Activities and usesc 

AL 19 0 999,999 1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

AR 10 0 999,999 1, 2, 3, 5, 6, 8, 10, 12, 13 

AZ 10 0 999,999 1, 2, 3, 4, 5, 7, 8, 10, 13 

CA 40 0 99,999 1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

CO 7 1,000 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 12 

CT 5 0 99,999 7, 8, 10, 11 

FL 4 100 99,999 1, 2, 3, 4, 6, 7, 8, 10, 12 

GA 6 0 999,999 1, 3, 6, 8, 13, 14 

IA 8 0 99,999 1, 5, 7, 8, 12, 13 

ID 5 10,000 999,999 1, 3, 5, 12, 13 

IL 25 0 999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 13, 14 

IN 10 0 999,999 1, 2, 5, 7, 8, 9, 10, 12 

KS 5 100 99,999 1, 3, 7, 8, 12 

KY 12 0 999,999 1, 2, 3, 5, 6, 7, 8, 11, 14 

LA 7 0 999,999 1, 3, 5, 6, 8, 10, 12, 13 

MA 12 0 99,999 1, 2, 3, 4, 7, 8, 10 

MD 5 100 49,999,999 1, 2, 4, 5, 6, 13 

MI 19 0 99,999 1, 2, 3, 5, 6, 7, 8, 10, 12, 13, 14 

MN 10 0 999,999 1, 3, 4, 7, 8, 9, 10, 11, 12, 13 

MO 7 0 999,999 1, 2, 3, 4, 5, 6, 8, 14 

MS 7 0 9,999 5, 7, 8, 12 

NC 12 0 9,999,999 1, 5, 7, 8, 9, 10, 12, 14 

NE 8 100 99,999 1, 2, 5, 7, 8, 12 

NH 4 0 999 1, 3, 8, 12 

NJ 18 0 999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 

NM 1 10,000 99,999 12 

NV 1 10,000 99,999 1, 5, 13 

NY 19 0 9,999,999 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14 

OH 28 0 999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

OK 16 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 12, 13 

OR 6 0 9,999,999 1, 5, 8, 12 

PA 34 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 

PR 1 0 99 8 

RI 4 0 9,999 2, 3, 7, 8 

SC 20 0 9,999,999 1, 3, 5, 6, 7, 8, 9, 10, 11, 12 

TN 13 0 9,999,999 1, 2, 3, 4, 7, 8, 9, 11, 12, 13 

TX 23 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 13, 14 

UT 6 100 99,999 1, 5, 6, 7, 8, 12, 13 

VA 11 0 99,999 1, 5, 7, 8, 10, 11, 13 

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CADMIUM 257 

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

Table 5-1. Facilities that Produce, Process, or Use Cadmium 

Minimum Maximum 

Number of amount on site amount on site 

Statea facilities in poundsb in poundsb Activities and usesc 

WA 4 0 9,999 1, 2, 3, 5, 10, 13 

WI 12 100 49,999,999 3, 7, 8, 10, 11, 12 

WV 3 100 99,999 7, 8, 12 

WY 1 0 99 1, 13 

a

Post office state abbreviations used b

Amounts on site reported by facilities in each state 

c

Activities/Uses: 

1. Produce 6. Impurity 11. Chemical Processing Aid 

2. Import 7. Reactant 12. Manufacturing Aid 

3. Onsite use/processing 8. Formulation Component 13. Ancillary/Other Uses 

4. Sale/Distribution 9. Article Component 14. Process Impurity 

5. Byproduct 10. Repackaging 

Source: TRI06 2008 (Data are from 2006) 

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CADMIUM 258 

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

Table 5-2. Facilities that Produce, Process, or Use Cadmium Compounds 

Minimum Maximum 

Number of amount on site amount on site 

Statea facilities in poundsb in poundsb Activities and usesc 

AK 11 100 499,999,999 1, 5, 7, 9, 11, 12, 14 

AL 28 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13 

AR 17 100 999,999 1, 2, 3, 5, 7, 8, 12, 13, 14 

AZ 24 0 99,999,999 1, 2, 3, 4, 5, 6, 7, 8, 12, 13, 14 

CA 27 0 49,999,999 1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 12, 13 

CO 7 100 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 13 

CT 27 0 999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 

DE 2 100 9,999 1, 5 

FL 9 0 999,999 1, 2, 3, 5, 6, 8, 12, 13, 14 

GA 12 0 999,999 1, 3, 5, 6, 7, 8, 13 

IA 4 0 99,999 1, 5, 7, 8, 9, 12 

ID 9 100 9,999,999 1, 5, 6, 7, 11, 14 

IL 41 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 13, 14 

IN 17 0 999,999 1, 5, 7, 8, 13, 14 

KS 7 0 99,999 1, 7, 8, 11, 13 

KY 19 100 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 12, 13 

LA 11 0 999,999 1, 2, 3, 5, 7, 8, 12, 13 

MA 12 0 999,999 1, 3, 4, 5, 6, 7, 8, 12, 13 

MD 9 1,000 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 13 

MI 24 0 99,999,999 1, 3, 5, 6, 7, 8, 10, 11, 12, 13 

MN 10 100 999,999 1, 5, 7, 8, 9, 13 

MO 14 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 13 

MS 9 0 999,999 1, 5, 7, 8, 12 

MT 3 1,000 9,999,999 1, 2, 3, 4, 5, 6, 13 

NC 12 0 49,999,999 1, 7, 8, 13 

NE 6 1,000 999,999 1, 2, 5, 8, 13, 14 

NH 1 1,000 9,999 7, 10 

NJ 34 0 9,999,999 1, 2, 3, 4, 6, 7, 8, 9, 10, 12 

NM 6 1,000 9,999,999 1, 5, 13 

NV 21 100 49,999,999 1, 2, 3, 5, 6, 7, 9, 10, 12, 13, 14 

NY 25 100 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13, 14 

OH 76 0 999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

OK 17 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 11, 12, 13 

OR 4 100 99,999 1, 5, 8 

PA 58 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 12, 13 

PR 1 100 999 8 

RI 8 100 99,999 2, 3, 7, 8, 11 

SC 15 0 999,999 1, 4, 5, 6, 7, 8, 11, 12, 14 

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CADMIUM 259 

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

Table 5-2. Facilities that Produce, Process, or Use Cadmium Compounds 

Minimum Maximum 

Number of amount on site amount on site 

Statea facilities in poundsb in poundsb Activities and usesc 

TN 30 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 11, 12, 13, 14 

TX 32 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13, 14 

UT 15 1,000 49,999,999 1, 5, 6, 7, 8, 12, 13 

VA 11 0 99,999 1, 5, 7, 8, 12, 14 

WA 13 0 999,999 1, 2, 3, 5, 6, 7, 8, 11, 12, 13 

WI 11 100 49,999,999 1, 3, 5, 7, 8, 10, 11, 12 

WV 7 1,000 999,999 1, 2, 3, 7, 8, 11, 13 

a

Post office state abbreviations used 

b

Amounts on site reported by facilities in each state 

c

Activities/Uses: 

1. Produce 6. Impurity 11. Chemical Processing Aid 

2. Import 7. Reactant 12. Manufacturing Aid 

3. Onsite use/processing 8. Formulation Component 13. Ancillary/Other Uses 

4. Sale/Distribution 9. Article Component 14. Process Impurity 

5. Byproduct 10. Repackaging 

Source: TRI06 2008 (Data are from 2006) 

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CADMIUM 260 

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

listed in Tables 5-1 and 5-2 are derived from the Toxics Release Inventory (TRI) (TRI06 2008). Because 

only certain types of facilities were required to report, this is not an exhaustive list. 

Cadmium metal is available in purities ranging from 99.5 to 99.999% in the following grades: technical, 

powder, pure sticks, ingots, slabs, and high-purity crystals (<10 ppm impurities) (HSDB 2008). 

Cadmium (as cadmium oxide) is obtained mainly as a byproduct during the processing of zinc-bearing 

ores (e.g., sphalerites), and also from the refining of lead and copper from sulfide ores (e.g., galena) 

(Morrow 2001). Cadmium oxide produced during roasting of ores is reduced with coke, and cadmium 

metal is separated by distillation or electrodeposition (Elinder 1985a). Commercial-grade cadmium oxide 

is available in purities ranging from 99 to 99.9999%; common impurities are lead and thallium (NTP 

2005). Cadmium chloride is produced by reacting molten cadmium with chlorine gas at 600 °C or by 

dissolving cadmium metal or the oxide, carbonate, sulfide, or hydroxide in hydrochloric acid and 

subsequently vaporizing the solution to produce a hydrated crystal (HSDB 2008; IARC 1993). In 

preparing the anhydrous cadmium chloride salt, the hydrate is refluxed with thionyl chloride or calcined 

in a hydrogen chloride atmosphere (HSDB 2008). Commercial cadmium chloride is available as a 

hydrate mixture with a purity range of 95.0–99.999% (NTP 2005). 

The commercial preparation of cadmium sulfate usually involves dissolution of the metal oxide, 

carbonate, or sulfide in sulfuric acid with subsequent cooling or evaporation (HSDB 2008). Anhydrous 

cadmium sulfate is prepared by oxidation of the sulfide or sulfite at elevated temperatures (Herron 2003); 

or by melting cadmium with ammonium or sodium peroxodisulfate (Schulte-Schrepping and Piscator 

2002). Cadmium sulfate monohydrate, which is the cadmium compound most often marketed, is 

produced by evaporating a cadmium sulfate solution above 41.5 °C (Schulte-Schrepping and Piscator 

2002). Cadmium sulfate is available in technical and C.P. (chemically pure) grades (Lewis 2001). 

Cadmium sulfide can be prepared by a direct reaction with hydrogen sulfide and cadmium vapor or 

between sulfur and cadmium metal or cadmium oxide (Herron 2003). Cadmium sulfide is available in 

technical, N.F. (national formulary grade), and high-purity (single crystals) (Lewis 2001). Cadmium 

carbonate is produced by heating an acidified solution of cadmium chloride and urea in a sealed tube at 

200 °C, the slow absorption of carbon dioxide to cadmium oxide, or the precipitation of the hemihydrate 

from reaction of ammonium carbonate in cadmium ion solution (Herron 2003). 

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5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

5.2 IMPORT/EXPORT 

Imports of cadmium into the United States declined steadily from 1994 through 1998, dropping from 

1,110 metric tons per year to an estimated 650 metric tons in 1998 (USGS 1999). In 1986, imports of 

cadmium metal for consumption increased significantly to 3,000 metric tons, but continually decreased 

into the 1990s. From 2003 to 2005, cadmium imports of metal, alloys, and scrap increased from 112 to 

288 tons, 74–207 tons of which were metal-only imports (USGS 2008). Cadmium imports peaked in 

2005 and then declined through 2007, with 172 tons of cadmium metal only and 174 tons of metal, alloys, 

and scrap imported (USGS 2008). The principal supplying countries were Australia (41%), Canada 

(20%), China (10%), and Peru (9%) (USGS 2008). 

In the mid-1990s, exports varied widely from 38 metric tons in 1993, to 1,450 metric tons in 1994, to 

550 metric tons in 1997. In 2003, cadmium exports (reported as metal, alloys, and scraps) were 615 tons, 

with exports decreasing to only 154 tons the following year (USGS 2008). Exports surged again in 2005 

to 686 tons, but have since been steadily decreasing from 483 tons in 2006 to 304 tons in 2007 (USGS 

2008). 

5.3 USE 

Cadmium, its alloys, and its compounds are used in a variety of consumer and industrial materials. The 

dominant use of cadmium is in active electrode materials in Ni-Cd batteries (83% of total cadmium use) 

(USGS 2008). Cadmium demand for other uses such as pigments for plastics, ceramics, and glasses; 

stabilizers for polyvinyl chloride (PVC) against heat and light; engineering coatings on steel and some 

nonferrous metals; and components of various specialized alloys have been decreasing. (Elinder 1992; 

IARC 1993; Thornton 1992; USGS 2008). Cadmium salts have been used in a limited capacity as a 

fungicide for golf courses and home lawns (EPA 2006d). Cadmium chloride is used in photography, 

photocopying, dyeing, calico printing, vacuum tube manufacture, pigment manufacture, galvanoplasty, 

lubricants, ice-nucleation agents, and in the manufacture of special mirrors (Herron 2003). However, the 

significance of cadmium chloride as a commercial product is declining (IARC 1993). 

Cadmium-based colorants are used mainly in engineering plastics, ceramics, glasses, and enamels (IARC 

1993; OECD 1995). Cadmium sulfide is especially important in this industry, especially in glasses and 

plastics; however, environmental and health concerns have contributed to a decrease in its production 

(Herron 2003). Cadmium sulfide (yellow) and cadmium selenide (red) are combined to create solid 

C.P. toners ranging in color from yellows and oranges to reds and maroons (Herron 2003). Cadmium 

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5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

sulfide and cadmium telluride are used in solar cells and a variety of electronic devices which depend on 

cadmium’s semiconducting properties (Herron 2003; IARC 1993; OECD 1995). The photoconductive 

and electroluminescent properties of cadmium sulfide have been applied in manufacturing a variety of 

consumer goods (IARC 1993). Cadmium sulfate solution is used in standard Weston cells (Herron 2003). 

Though cadmium metal consumption for batteries has grown steadily since the 1980s and currently 

consumes 83% of the cadmium produced, other uses of cadmium began declining in the mid 1990s. 

Pigment, stabilizer, coating, and alloy markets for cadmium are decreasing due to environmental concerns 

(USGS 1997, 2008). Proposed legislation, particularly in the European Union, restricting cadmium in 

consumer products may have a negative effect on cadmium demand (USGS 2008). Excessive exports 

from Bulgaria and Russia in 1997 caused a drop in the average price of cadmium from $1.84 per pound in 

1995 to $0.51 per pound in 1997. Also, Ni-Cd batteries have been replaced in some markets by lithiumion and nickel metal hydride batteries (USGS 2008). As of 2006, Ni-Cd batteries made up 18% of the 

rechargeable battery market, down from 56% in 1996 with global sales decreasing 16% between 2005 and 

2006 (USGS 2008). Despite this trend, demand for cadmium may increase due to new market 

opportunities for Ni-Cd batteries (USGS 2008). Regulations by local authorities have forced the 

recycling of cadmium in Ni-Cd batteries, further depressing the demand for primary cadmium metal 

(USGS 1999). 

5.4 DISPOSAL 

Cadmium-containing wastes are subject to regulations concerning their treatment, storage, and disposal 

(see Chapter 8) (EPA 1982a; HSDB 2008; U.S. Bureau of Mines 1990). In many states, the disposal of 

Ni-Cd batteries as municipal waste is prohibited (USGS 2007). Incineration of municipal wastes, 

particularly from older, poorly controlled facilities, is a potential environmental source of cadmium. In 

modern incineration plants, about 99.9% of cadmium was captured in boilers and control equipment 

(OECD 1995). 

A range of physicochemical processes is available for treatment of cadmium in liquid waste process 

streams, including ion exchange, electrolysis, cementation, and adsorption. Both ion exchange and 

sulfide precipitation are used as alternate processes aimed at achieving low cadmium residuals in liquid 

wastes (UN 1985). Combining processes, for example, conducting the primary precipitation of cadmium 

as hydroxide followed by secondary precipitation of residual cadmium as sulfide, has also been adopted. 

The more general application of the sulfide precipitation technique, however, is constrained due to a 

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CADMIUM 263 

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

tendency for formation of colloidal precipitate, the toxicity and odor of hydrogen sulfide, and the 

necessity to oxidize residual sulfide occurring in emissions prior to discharge (UN 1985). 

The most widely used treatment process involves the alkaline precipitation of cadmium as hydroxide or 

basic salts (UN 1985). Removal of specific metal species during hydroxide precipitation is pHdependent, and some components of the waste stream can influence the solubility of cadmium hydroxide. 

After filtration, the sludge formed from the conversion of soluble cadmium compounds to insoluble 

compounds can be deposited in a suitable landfill (UN 1985). 

Various cadmium-bearing wastes are subject to aggressive leaching in refuse media, particularly under 

aerobic conditions (UN 1985). While liquid wastes are banned from land disposal, the leaching tendency 

is accentuated in the presence of brine solutions. Also, the mobility of cadmium in landfill conditions 

could be enhanced in the presence of mineral acids, which tend to solubilize cadmium compounds, or 

amine-containing materials, which tend to complex cadmium ions. Waste containing mineral acids, 

cyanides, organic solvents, and amine-type substances should not be landfilled near cadmium-bearing 

wastes (UN 1985). 

In the laboratory, a recommended method for recovering cadmium from small quantities of cadmium 

oxide wastes uses a minimum amount of concentrated nitric acid to form nitrates. The solution is 

evaporated in a hood to form a thin paste, and then diluted with water and saturated with hydrogen 

sulfide. After the filtration, the precipitate is washed, dried, and returned to the supplier (UN 1985). 

Cadmium recovery from scrap metals and batteries is becoming increasingly popular, with the main 

emphasis being on recycling Ni-Cd batteries (Morrow 2001). Battery recycling is relatively easy and can 

be achieved using pyrometalllurigical (high temperature) or hydrometallurgical (wet chemical) processes 

(Morrow 2001). In these processes, the metallic waste that contains iron, nickel, cadmium, and their 

oxides and hydroxides are separated from the other battery components and then converted back to a 

metal that has a technical purity required for the production of new batteries (Morrow 2001). Cadmiumbased coatings can be recycled using electric-arc furnace (EAF) dust, which is obtained through the remelting of scrap steel that contains cadmium coatings and cadmium impurities (Morrow 2001). 

INMETCO in Ellwood, Pennsylvania recovers cadmium from spent Ni-Cd batteries, and has developed 

several collection programs to help facilitate battery recycling (USGS 2007). Although participation in 

battery recycling has increased in businesses, communities, and retailers, the total recovery of cadmium in 

2005 was only 12% (USGS 2007). 

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CADMIUM 264 

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

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6. POTENTIAL FOR HUMAN EXPOSURE 

6.1 OVERVIEW 

Cadmium has been identified in at least 1,014 of the 1,669 hazardous waste sites that have been proposed 

for inclusion on the EPA National Priorities List (NPL) (HazDat 2008). Cadmium compounds have been 

identified in at least 3 of the 1,669 hazardous waste sites. However, the number of sites evaluated for 

cadmium is not known. The frequency of these sites can be seen in Figures 6-1 and 6-2. Of the 

1,014 sites where cadmium has been identified, 1,005 are located within the United States, 6 are located 

in the Commonwealth of Puerto Rico (not shown), 2 are located in Guam, and 1 is located in the Virgin 

Islands. All sites where cadmium compounds were detected are located in the United States. 

Cadmium occurs in the earth’s crust at an abundance of 0.1–0.5 ppm and is commonly associated with 

zinc, lead, and copper ores. It is also a natural constituent of ocean water, with average levels between 

<5 and 110 ng/L; with higher levels have been reported near coastal areas and in marine phosphates and 

phosphorites (Morrow 2001). Natural emissions of cadmium to the environment can result from volcanic 

eruptions, forest fires, generation of sea salt aerosols, or other natural phenomena (EPA 1985a; Morrow 

2001; Shevchenko et al. 2003). Cadmium is refined and consumed for uses in batteries (83%), pigments 

(8%), coatings and platings (7%), stabilizers for plastics (1.2%), and nonferrous alloys, photovoltaic 

devices, and other uses (0.8%) (USGS 2008). Nonferrous metal mining and refining, manufacture and 

application of phosphate fertilizers, fossil fuel combustion, and waste incineration and disposal are the 

main anthropogenic sources of cadmium in the environment. 

Cadmium can be released to the atmosphere through metal production activities, fossil fuel combustion, 

and waste incineration. The main cadmium compounds found in air are cadmium oxide, chloride, and 

sulfate, and these compounds are expected to undergo minimal transformation in the atmosphere (EPA 

1980d). The major fate of cadmium in air is through transport and deposition. Cadmium can travel long 

distances in the atmosphere and then deposit (wet or dry) onto surface soils and water, which can result in 

elevated cadmium levels even in remote locations (Shevchenko et al. 2003). Results from the 2006 final 

report of EPA’s Urban Air Toxic Monitoring program reported average daily cadmium levels of 

<0.01 μg/m3 at several monitoring sites throughout the United States. These sites include: Bountiful, 

Utah; Northbrook, Illinois; Austin, Texas; St. Louis, Missouri; Indianapolis, Indiana; and Birmingham, 

Alabama (EPA 2007). Atmospheric concentrations of cadmium are generally highest in the vicinity of 

cadmium-emitting industries (Elinder 1985a; Pirrone et al. 1996). Due to advances in pollution control 

technology, cadmium emissions to air are not expected to increase, even though cadmium-emitting 

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Figure 6-1. Frequency of NPL Sites with Cadmium Contamination

Frequency of 

NPL Sites 

1-6 

7-12 

14-22 

25-32 

40-59 Derived from HazDat 2008 

67-85 

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CADMIUM 266

6. POTENTIAL FOR HUMAN EXPOSURE
Figure 6-2. Frequency of NPL Sites with Cadmium Compounds Contamination

Frequency of 

NPL Sites 

1 

Derived from HazDat 2008 

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CADMIUM 267

6. POTENTIAL FOR HUMAN EXPOSURE
 

 

 

 

 

 

 

 

 

 

 

CADMIUM 268 

6. POTENTIAL FOR HUMAN EXPOSURE 

industries are expected to grow (Herron 2003; Morrow 2001; Schulte-Schrepping and Piscator 2002). 

Except for those who live near cadmium-emitting industries, inhalation of cadmium in the ambient air is 

not a major source of exposure. 

The main sources of cadmium to soil include atmospheric deposition and direct application methods such 

as phosphate fertilizer use and sewage sludge disposal. Some phosphate fertilizers can contain up to 

300 mg Cd/kg (Alloway and Steinnes 1999). Wet and dry deposition of cadmium from the atmosphere 

may also contribute sizable amounts of cadmium to soil in the areas surrounding sources of atmospheric 

emissions (EPA 1985a; Mielke et al. 1991). Cadmium’s mobility in soil depends on several factors 

including the pH of the soil and the availability of organic matter. Generally, cadmium will bind strongly 

to organic matter and this will, for the most part, immobilize cadmium (Autier and White 2004). 

However, immobilized cadmium is available to plant life and can easily enter the food supply. Cadmium 

in soil tends to be more available when the soil pH is low (acidic) (Elinder 1992). 

Water sources near cadmium-emitting industries, both with historic and current operations, have shown a 

marked elevation of cadmium in water sediments and aquatic organisms (Angelo et al. 2007; Arnason and 

Fletcher 2003; Brumbaugh et al. 2005; Mason et al. 2000; Paulson 1997). In surface water and 

groundwater, cadmium can exist as the hydrated ion or as ionic complexes with other inorganic or organic 

substances. While soluble forms may migrate in water, cadmium is relatively nonmobile in insoluble 

complexes or adsorbed to sediments. Cadmium is taken up and retained by aquatic and terrestrial plants 

and is concentrated in the liver and kidney of animals that eat the plants (Elinder 1985a). 

For the U.S. population, cadmium exposure through the drinking water supply is of minor concern. EPA 

requires water suppliers to limit the cadmium concentration in water to <5 μg/L (EPA 2006a). 

In the United States, the largest source of cadmium exposure for nonsmoking adults and children is 

through dietary intake (NTP 2005). Based on the mean cadmium daily intakes of males and females aged 

6–60 years reported by Choudhury et al. (2001), age-weighted mean cadmium intakes of 0.35 μg/kg/day 

for males and 0.30 μg/kg/day for females were calculated for U.S. nonsmokers. Females generally absorb 

greater amounts of cadmium in the gastrointestinal tract (CDC 2005). In general, leafy vegetables, such 

as lettuce and spinach, and staples, such as potatoes and grains, contain relatively high values of 

cadmium. Peanuts, soybeans, and sunflower seeds have naturally high levels of cadmium (Morrow 

2001). People who regularly consume shellfish and organ meats (liver and kidney) have an increased risk 

of cadmium exposure, as these organisms tend to accumulate cadmium (Elinder 1985a). 

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CADMIUM 269 

6. POTENTIAL FOR HUMAN EXPOSURE 

Tobacco leaves naturally accumulate large amounts of cadmium (Morrow 2001). Cadmium levels in 

cigarettes vary greatly depending on the source of production. Cigarettes produced in Mexico were found 

to have the highest level of cadmium per cigarette (arithmetic mean [AM] ± arithmetic standard deviation 

[ASD] = 2.03 μg/cigarette ±0.33), while cigarettes from India were found to have the lowest (arithmetic 

mean ± arithmetic standard deviation = 0.35 μg/cigarette ±0.09). The arithmetic mean for the United 

States was 1.07 μg/cigarette ±0.11 (Watanabe et al. 1987). It has been estimated that tobacco smokers are 

exposed to 1.7 μg cadmium per cigarette, and about 10% is inhaled when smoked (Morrow 2001; NTP 

2005). The geometric mean blood cadmium level for the heavy smoker subgroup in New York City was 

reported as 1.58 μg/L, compared to the geometric mean of 0.77 μg/L for all New York City adults 

(McKelvey et al. 2007). 

6.2 RELEASES TO THE ENVIRONMENT 

The Toxics Release Inventory (TRI) data should be used with caution because only certain types of 

facilities are required to report (EPA 2005). This is not an exhaustive list. Manufacturing and processing 

facilities are required to report information to the TRI only if they employ 10 or more full-time 

employees; if their facility is included in Standard Industrial Classification (SIC) Codes 10 (except 1011, 

1081, and 1094), 12 (except 1241), 20–39, 4911 (limited to facilities that combust coal and/or oil for the 

purpose of generating electricity for distribution in commerce), 4931 (limited to facilities that combust 

coal and/or oil for the purpose of generating electricity for distribution in commerce), 4939 (limited to 

facilities that combust coal and/or oil for the purpose of generating electricity for distribution in 

commerce), 4953 (limited to facilities regulated under RCRA Subtitle C, 42 U.S.C. section 6921 et seq.), 

5169, 5171, and 7389 (limited S.C. section 6921 et seq.), 5169, 5171, and 7389 (limited to facilities 

primarily engaged in solvents recovery services on a contract or fee basis); and if their facility produces, 

imports, or processes ≥25,000 pounds of any TRI chemical or otherwise uses >10,000 pounds of a TRI 

chemical in a calendar year (EPA 2005). 

Additional releases of cadmium to the environment occur from natural sources and from processes such 

as combustion of fossil fuel, incineration of municipal or industrial wastes, or land application of sewage 

sludge or fertilizer (EPA 1985a). Quantitative information on releases of cadmium to specific 

environmental media is discussed below. 

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6. POTENTIAL FOR HUMAN EXPOSURE 

6.2.1 Air 

Estimated releases of 5,308 pounds (~2.4 metric tons) of cadmium to the atmosphere from 74 domestic 

manufacturing and processing facilities in 2006, accounted for about 0.45% of the estimated total 

environmental releases from facilities required to report to the TRI (TRI06 2008). These releases are 

summarized in Table 6-1. Estimated releases of 8,908 pounds (~4.0 metric tons) of cadmium compounds 

to the atmosphere from 98 domestic manufacturing and processing facilities in 2006, accounted for about 

0.31% of the estimated total environmental releases from facilities required to report to the TRI (TRI06 

2008). These releases are summarized in Table 6-2. 

Cadmium is released to the atmosphere from both natural and anthropogenic sources. Cadmium is widely 

distributed in the earth's crust (EPA 1985a) with concentrations reported between 0.1 and 0.5 ppm and 

higher levels in sedimentary rocks (Morrow 2001). Consequently, cadmium may be released to the air 

from entrainment of dust particles, volcanic eruptions, forest fires, or other natural phenomena (EPA 

1985a; Morrow 2001). Cadmium exists in ocean waters at average levels ranging from <5 to 110 ng/L 

and may transport to the atmosphere through natural processes like generation of sea-salt aerosols 

(Morrow 2001; Shevchenko et al. 2003). Increased cadmium levels in the air over the Russian Arctic 

have been detected during the summer and autumn seasons and are believed to be attributed to natural 

processes, while the levels detected during the winter and spring seasons were due to anthropogenic 

sources (Shevchenko et al. 2003). 

However, industrial activities are the main sources of cadmium release to air (EPA 1985a), and emissions 

from anthropogenic sources have been found to exceed those of natural origin by an order of magnitude 

(IARC 1993). Major industrial sources of cadmium emissions include zinc, lead, copper, and cadmium 

smelting operations; coal and oil-fired boiler; other urban and industrial emissions; phosphate fertilizer 

manufacture; road dust; and municipal and sewage sludge incinerators (Alloway and Steinnes 1999; 

Morrow 2001). Emission of cadmium through nonferrous metal production in 1995 was highest in Asia 

with 1,176 tonnes and North America emitting 191 tonnes. Estimated emissions of cadmium from 

municipal waste and sewage sludge incineration in North America were 8 and 7 tonnes/year, respectively, 

in the mid-1990s (Pacyna and Pacyna 2001). Additional sources that contribute negligible amounts of 

cadmium are rubber tire wear, motor oil combustion, cement manufacturing, and fertilizer and fungicide 

application (Wilber et al. 1992). Average cadmium emission factors for combustion of coal and oil are 

about 0.1 and 0.05 g/ton, respectively. Cement production releases an estimated 0.01 g/ton cement and 

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CADMIUM 271 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-1. Releases to the Environment from Facilities that Produce, Process, or
 

Use Cadmiuma
 

Reported amounts released in pounds per yearb 

Total release 

On- and offStatec RFd Aire Waterf UIg Landh Otheri On-sitej Off-sitek site 

AL 2 87 4 0 39,510 750 39,663 754 40,417 

AR 1 1 0 0 0 0 1 0 1 

AZ 2 0 0 0 0 0 0 0 0 

CA 9 575 1,002 0 29,248 4,593 17,193 18,475 35,668 

FL 1 0 0 0 0 0 0 0 0 

GA 2 5 0 0 5 250 5 255 260 

IA 2 0 1 0 1 0 0 2 2 

ID 1 50 0 0 282,046 0 282,096 0 282,096 

KS 3 0 0 0 18 0 0 18 18 

KY 2 28 0 0 250 0 28 250 278 

LA 2 99 0 0 13,000 192 13,099 192 13,291 

MI 5 0 0 0 14 0 0 14 14 

MO 1 0 0 0 0 0 0 0 0 

NC 2 67 0 0 0 0 67 0 68 

NE 1 5 0 0 26,499 0 25,982 522 26,504 

NY 4 1 0 0 85 27 17 112 129 

OH 6 48 0 65,582 169,171 0 148,630 86,171 234,802 

OK 2 6 0 0 18,652 0 18,305 353 18,658 

OR 1 3 0 0 123,833 0 123,836 0 123,836 

PA 3 0 0 0 986 1 0 987 987 

PR 1 0 0 0 5 0 0 5 5 

SC 2 19 0 0 0 3 19 3 22 

TN 1 4,000 0 0 0 0 4,001 0 4,001 

TX 13 297 0 50,347 11,514 26 62,180 26 62,206 

UT 2 16 0 0 343,190 0 328,620 14,586 343,206 

WI 2 0 0 0 0 0 0 0 0 

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CADMIUM 272 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-1. Releases to the Environment from Facilities that Produce, Process, or
 

Use Cadmiuma
 

Reported amounts released in pounds per yearb 

Total release 

On- and offStatec RFd Aire Waterf UIg Landh Otheri On-sitej Off-sitek site 

WV 1 0 0 0 250 0 250 0 250 

Total 74 5,308 1,008 115,929 1,058,277 5,842 1,063,993 122,725 1,186,719 

a

The TRI data should be used with caution since only certain types of facilities are required to report. This is not an 

exhaustive list. Data are rounded to nearest whole number.
 b

Data in TRI are maximum amounts released by each facility.
 c

Post office state abbreviations are used.
 d

Number of reporting facilities. e

The sum of fugitive and point source releases are included in releases to air by a given facility.
 f

Surface water discharges, waste water treatment-(metals only), and publicly owned treatment works (POTWs) (metal
 

and metal compounds).
 g

Class I wells, Class II-V wells, and underground injection. h

Resource Conservation and Recovery Act (RCRA) subtitle C landfills; other on-site landfills, land treatment, surface 

impoundments, other land disposal, other landfills.

i

Storage only, solidification/stabilization (metals only), other off-site management, transfers to waste broker for
 

disposal, unknown

j

The sum of all releases of the chemical to air, land, water, and underground injection wells.

k

Total amount of chemical transferred off-site, including to POTWs.
 

RF = reporting facilities; UI = underground injection 

Source: TRI06 2008 (Data are from 2006) 

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CADMIUM 273 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-2. Releases to the Environment from Facilities that Produce, Process, or
 

Use Cadmium Compoundsa
 

Reported amounts released in pounds per yearb 

Total release 

On- and offStatec RFd Aire Waterf UIg Landh Otheri On-sitej Off-sitek site 

AK 3 128 5 0 62,879 1 63,012 1 63,014 

AL 3 466 48 0 854,657 515 852,514 3,172 855,686 

AR 3 44 3 0 23 20,935 47 20,958 21,005 

AZ 2 634 755 0 457,303 5 450,837 7,860 458,697 

CA 2 0 0 0 250 0 0 250 250 

CT 1 0 0 0 0 0 0 0 0 

FL 2 30 0 0 0 26 30 26 56 

GA 1 7 5 0 0 0 9 3 12 

IA 1 0 0 0 0 0 0 0 0 

ID 2 2,971 10 0 319,827 0 322,808 0 322,808 

IL 7 73 485 1,097 36,120 4,449 26,123 16,101 42,224 

IN 4 263 17 0 32,229 12,000 270 44,239 44,509 

KY 1 0 0 0 0 0 0 0 0 

LA 2 5 0 0 36 0 41 0 41 

MA 1 1 0 0 0 3,600 1 3,600 3,601 

MD 1 0 0 0 0 0 0 0 0 

MI 3 43 1 0 13,830 0 10,007 3,867 13,874 

MO 2 1,024 123 0 9,088 0 10,186 49 10,235 

MT 1 6 0 0 2,841 0 2,847 0 2,847 

NC 3 0 0 0 12,205 35,789 0 47,994 47,994 

NE 1 255 5 0 0 30,000 260 30,000 30,260 

NH 1 0 0 0 0 0 0 0 0 

NJ 2 5 1 0 11,293 185 5 11,479 11,484 

NV 3 50 0 0 255,122 130 255,172 130 255,302 

NY 2 27 53 0 2,505 3,931 2,559 3,957 6,516 

OH 11 70 683 0 32,915 10,441 179 43,930 44,109 

OK 2 501 0 32 0 293,634 533 293,634 294,167 

PA 7 1,046 23 0 19,474 1,803 1,059 21,287 22,346 

SC 1 19 1 0 0 0 20 0 20 

TN 5 909 431 0 177,051 0 178,385 5 178,390 

TX 9 57 80 0 146 5,374 57 5,600 5,657 

UT 5 258 500 0 80,338 29,340 76,142 34,294 110,436 

WA 2 4 0 0 102 3 106 3 109 

WI 1 10 18 0 0 9 10 27 37 

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CADMIUM 274 

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Table 6-2. Releases to the Environment from Facilities that Produce, Process, or
 

Use Cadmium Compoundsa
 

Reported amounts released in pounds per yearb 

Total release 

On- and offStatec RFd Aire Waterf UIg Landh Otheri On-sitej Off-sitek site 

WV 1 2 7 0 213 0 118 105 222 

Total 98 8,908 3,255 1,129 2,380,447 452,170 2,253,338 592,572 2,845,910 

a

The TRI data should be used with caution since only certain types of facilities are required to report. This is not an 

exhaustive list. Data are rounded to nearest whole number.
 b

Data in TRI are maximum amounts released by each facility.
 c

Post office state abbreviations are used.
 d

Number of reporting facilities.

e

The sum of fugitive and point source releases are included in releases to air by a given facility.
 f

Surface water discharges, waste water treatment-(metals only), and publicly owned treatment works (POTWs) (metal
 

and metal compounds).
 g

Class I wells, Class II-V wells, and underground injection. h

Resource Conservation and Recovery Act (RCRA) subtitle C landfills; other on-site landfills, land treatment, surface 

impoundments, other land disposal, other landfills.

i

Storage only, solidification/stabilization (metals only), other off-site management, transfers to waste broker for
 

disposal, unknown

j

The sum of all releases of the chemical to air, land, water, and underground injection wells.

k

Total amount of chemical transferred off-site, including to POTWs.
 

RF = reporting facilities; UI = underground injection 

Source: TRI06 2008 (Data are from 2006) 

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6. POTENTIAL FOR HUMAN EXPOSURE 

pig iron and steel production releases an estimated 0.1 g/ton (Pacyna and Pacyna 2001). Atmospheric 

cadmium exists mainly in the forms of cadmium oxide and cadmium chloride (Morrow 2001). 

Cadmium emissions have decreased dramatically since the 1960s as primary cadmium producers now use 

the electrolytic process and pollution control technologies such as agglomerization, electrostatic 

purification of gas exhaust, and exhaust filtration have been implemented (Herron 2003; Morrow 2001; 

Schulte-Schrepping and Piscator 2002). In addition, EPA has proposed risk-based regulations for 

cadmium emissions from hazardous waste incinerators (EPA 1990a). Therefore, although there may be 

an increase in fossil fuel combustion and waste incineration, it does not appear likely that overall 

cadmium emissions to air will increase substantially. 

There is a potential for release of cadmium to air from hazardous waste sites. Cadmium has been 

detected in air samples collected at 50 of the 1,014 NPL hazardous waste sites where cadmium has been 

detected in some environmental medium (HazDat 2008). Cadmium compounds have been detected in air 

samples collected at one of three NPL hazardous waste sites where cadmium compounds have been 

detected. The HazDat information used includes data from NPL sites only. 

6.2.2 Water 

Estimated releases of 1,008 pounds (~0.46 metric tons) of cadmium to surface water from 74 domestic 

manufacturing and processing facilities in 2006, accounted for about 0.085% of the estimated total 

environmental releases from facilities required to report to the TRI. This is estimate includes releases to 

wastewater treatment and publicly owned treatment works (TRI06 2008). These releases are summarized 

in Table 6-1. Estimated releases of 3,255 pounds (~1.5 metric tons) of cadmium compounds to surface 

water from 98 domestic manufacturing and processing facilities in 2006, accounted for about 0.11% of 

the estimated total environmental releases from facilities required to report to the TRI. This is estimate 

includes releases to wastewater treatment and publicly owned treatment works (TRI06 2008). These 

releases are summarized in Table 6-2. 

Cadmium may be released to water by natural weathering processes, by discharge from industrial 

facilities or sewage treatment plants, atmospheric deposition, by leaching from landfills or soil, or 

phosphate fertilizers (EPA 1981a, 1985a; IJC 1989; Morrow 2001). Cadmium may also leach into 

drinking water supplies from pipes in the distribution system (Elinder 1985a). The average level of 

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cadmium in ocean water has been reported between <5 and 110 ng/L, with higher levels reported near 

coastal areas and in marine phosphates and phosphorites (Morrow 2001). 

Smelting of nonferrous metal ores has been estimated to be the largest anthropogenic source of cadmium 

released into the aquatic environment. Cadmium contamination can result from entry into aquifers of 

mine drainage water, waste water, tailing pond overflow, and rainwater runoff from mine areas (IARC 

1993). The upper Clark Fork River in Montana is contaminated with large amounts of cadmium from 

past mining activities between 1880 and 1972. While mining wastes are no longer released into the river, 

an estimated 14.5 million cubic meters of tailings have been incorporated into the river bed, floodplain, 

and reservoir sediments (Canfield et al. 1994). Other human sources include spent solutions from plating 

operations and phosphate fertilizers. Cadmium constitutes up to 35 mg/kg of phosphorous pentoxide in 

the United States (IARC 1993). Atmospheric fallout of cadmium to aquatic systems is another major 

source of cadmium to the environment (IARC 1993; Muntau and Baudo 1992). 

A large proportion of the cadmium load in the aquatic environment is due to diffuse pollution originating 

from many different sources rather than from point sources. In the estuarine portion of the Hudson River, 

it has been found that more cadmium was released from agricultural and urban run-off than from 

industrial and municipal sewage treatment plants (Muntau and Baudo 1992). In an urban environment, 

there are also multiple sources of cadmium to waste water, based on an urban waste water study 

conducted in the United Kingdom. Cadmium was detected in the foul water originating from industrial, 

commercial, and private sectors, with the highest average cadmium concentration detected in the foul 

water of new (<5 years old) private housing (0.375 μg/L) (Rule et al. 2006). 

There is also a potential for release of cadmium to water from hazardous waste sites. Cadmium has been 

detected in surface water samples collected at 354 of the 1,014 NPL hazardous waste sites, and in 

groundwater samples collected at 675 of the 1,014 NPL hazardous waste sites where cadmium has been 

detected in some environmental medium (HazDat 2008). The HazDat information used includes data 

from NPL sites only. 

6.2.3 Soil 

Estimated releases of 1,058,277 pounds (~480 metric tons) of cadmium to soils from (74) domestic 

manufacturing and processing facilities in 2006, accounted for about 89% of the estimated total 

environmental releases from facilities required to report to the TRI (TRI06 2008). An additional 

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115,929 pounds (~53 metric tons), constituting about 9.8% of the total environmental emissions, were 

released via underground injection and to Class I wells, Class II-V wells (TRI06 2008). These releases 

are summarized in Table 6-1. Estimated releases of 2,380,447 pounds (~1,080 metric tons) of cadmium 

compounds to soils from (98) domestic manufacturing and processing facilities in 2006, accounted for 

about 84% of the estimated total environmental releases from facilities required to report to the TRI. An 

additional 1,129 pounds (~53 metric tons), constituting about 0.040% of the total environmental 

emissions, were released via underground injection and to Class I wells, Class II-V wells (TRI06 2008). 

These releases are summarized in Table 6-2. 

Major sources of cadmium to soil include atmospheric emissions, direct application, and accidental or 

fugitive contamination. Direct application emissions refer to phosphate fertilizers, phosphogypsum and 

other byproduct gypsums (from the manufacture of phosphoric acid and phosphorite), sewage sludges, 

composted municipal solid waste, and residual ashes from wood, coal, or other types of combustion. 

Contamination sources include industrial site contamination, mine waste dumps, and corrosion of metal 

structures (Alloway and Steinnes 1999). 

EPA estimated that about 31% of the 11 billion pounds of sewage sludge produced annually in the United 

States is landspread (EPA 1985a). Estimated cadmium concentrations in sewage sludge range from 

<1 μg/g to >1,000 μg/g (EPA 1985a). Although EPA has set limits (EPA 1993c) on the cadmium content 

of sludge applied to land (maximum permitted cadmium concentration of 85 mg/kg in sewage sludge; 

maximum cadmium concentration of 39 mg/kg in “clean” sewage sludge; maximum annual cadmium 

loading of 1.9 kg-ha-1·year-1; and maximum cumulative cadmium loading of 39 kg/ha), significant 

amounts of cadmium are still likely to be transferred to soil by this practice. Sludges from treatment 

plants that serve cadmium industries (i.e., battery manufacturing) tend to have higher levels of cadmium 

(Alloway and Steinnes 1999). 

Phosphate fertilizers are a major source of cadmium input to agricultural soils (EPA 1985a). The natural 

cadmium concentration in phosphates ranges from 3 to 100 μg/g (EPA 1985a; Singh 1994). Some can 

contain up to 300 mg Cd/kg (Alloway and Steinnes 1999). It is estimated that 880,000 pounds of 

phosphate fertilizer were used in the United States in 1980 (EPA 1985a). Any soil treated with these 

fertilizers will have a cadmium input, but exactly how much will vary (Alloway and Steinnes 1999). 

Continuous fertilization with a high rate of triple super-phosphate (1,175 kg P-ha-1·year-1) for a period of 

36 years resulted in a 14-fold increase in cadmium content of surface soils (Singh 1994). 

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Wet and dry deposition of cadmium from the atmosphere may also contribute sizable amounts of 

cadmium to soil in the areas surrounding sources of atmospheric emissions, such as incinerators and 

vehicular traffic, which may release cadmium from burned fuel and tire wear (EPA 1985a; Mielke et al. 

1991). High-temperature sources, such as smelters and incinerators, release small particles that are ideal 

for long-range atmospheric transport. Also, vapors emitted from high temperature processes will 

preferentially condense onto smaller particles, thus making vapor emissions available for transport 

(Steinnes and Friedland 2006). Aerosols containing cadmium can be carried very long distances in the 

atmosphere before being deposited to soils. In the soils in southern Norway, most of the cadmium and 

other heavy metals that are deposited from the atmosphere originate from other parts of Europe (Alloway 

and Steinnes 1999). Long-range atmospheric deposition is more evident in organic-rich soils as they have 

a tendency to concentrate heavy metals (Steinnes and Friedland 2006). 

There is also a potential for release of cadmium to soil from hazardous waste sites. Cadmium has been 

detected in soil samples collected at 606 of the 1,014 NPL hazardous waste sites and in sediment samples 

collected at 392 of the 1,014 NPL hazardous waste sites where cadmium has been detected in some 

environmental medium (HazDat 2008). The HazDat information used includes data from NPL sites only. 

6.3 ENVIRONMENTAL FATE 

6.3.1 Transport and Partitioning 

Cadmium is expected to partition mostly to soil (80–90%) when released to the environment. Although 

particulate and vapor cadmium may be released to the air, the net flux to soil will be positive as cadmium 

will eventually deposit onto soils (Morrow 2001; Wilber et al. 1992). 

Cadmium and cadmium compounds have negligible vapor pressures (see Table 4-2) but can be released 

to the environment by emissions from municipal waste incinerators, nonferrous metal production, and 

other high-temperature processes (Morrow 2001). Cadmium emitted to the atmosphere from combustion 

processes condense onto very small particulates that are in the respirable range (<10 μm) and are subject 

to long-range transport (Steinnes and Friedland 2006; Wilber et al. 1992). These cadmium pollutants may 

be transported from a hundred to a few thousand kilometers and have a typical atmospheric residence 

time of about 1–10 days before deposition occurs (EPA 1980d). Larger cadmium-containing particles 

from smelters and other pollutant sources are also removed from the atmosphere by gravitational settling, 

with substantial deposition in areas downwind of the pollutant source. Cadmium-containing particulates 

may dissolve in atmospheric water droplets and be removed from air by wet deposition. 

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Cadmium is more mobile in aquatic environments than most other heavy metals (e.g., lead). In most 

natural surface waters, the affinities of complexing ligands for cadmium generally follow the order of 

humic acids > CO3

2– > OH– ≥ Cl– ≥ SO42– (EPA 1979). In unpolluted natural waters, most cadmium 

transported in the water column will exist in the dissolved state as the hydrated ion Cd(H2O)6

2+. Minor 

amounts of cadmium are transported with the coarse particulates, and only a small fraction is transported 

with the colloids. In unpolluted waters, cadmium can be removed from solution by exchange of cadmium 

for calcium in the lattice structure of carbonate minerals (EPA 1979). In polluted or organic-rich waters, 

adsorption of cadmium by humic substances and other organic complexing agents plays a dominant role 

in transport, partitioning, and remobilization of cadmium (EPA 1979). Cadmium concentration in water 

is inversely related to the pH and the concentration of organic material in the water (EPA 1979). Because 

cadmium exists only in the +2 oxidation state in water, aqueous cadmium is not strongly influenced by 

the oxidizing or reducing potential of the water. However, under reducing conditions, cadmium may 

form cadmium sulfide, which is poorly soluble and tends to precipitate (EPA 1983c; McComish and Ong 

1988). Free (ionic) cadmium seems to be the toxic form and becomes much more prevalent at low 

salinity (Sprague 1986). Cadmium has a relatively long residence time in aquatic systems. In Lake 

Michigan, a mean residence time of 4–10 years was calculated for cadmium compared to 22 years 

calculated for mercury (Wester et al. 1992). 

Precipitation and sorption to mineral surfaces, hydrous metal oxides, and organic materials are the most 

important processes for removal of cadmium to bed sediments. Humic acid is the major component of 

sediment responsible for adsorption. Sorption increases as the pH increases (EPA 1979). Sediment 

bacteria may also assist in the partitioning of cadmium from water to sediments (Burke and Pfister 1988). 

Both cadmium-sensitive and cadmium-resistant bacteria reduced the cadmium concentration in the water 

column from 1 ppm to between 0.2 and 0.6 ppm, with a corresponding increase in cadmium concentration 

in the sediments in the simulated environment (Burke and Pfister 1988). Studies indicate that 

concentrations of cadmium in sediments are at least one order of magnitude higher than in the overlying 

water (EPA 1979). The mode of sorption of cadmium to sediments is important in determining its 

disposition to remobilize. Cadmium associated with carbonate minerals, precipitated as stable solid 

compounds or co-precipitated with hydrous iron oxides, is less likely to be mobilized by resuspension of 

sediments or biological activity. Cadmium that is adsorbed to mineral surfaces such as clay, or to organic 

materials, is more easily bioaccumulated or released in the dissolved state when the sediment is disturbed 

(EPA 1979). Cadmium may redissolve from sediments under varying ambient conditions of pH, salinity, 

and redox potential (DOI 1985; EPA 1979; Feijtel et al. 1988; Muntau and Baudo 1992). Cadmium is not 

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known to form volatile compounds in the aquatic environment, so partitioning from water to the 

atmosphere does not occur (EPA 1979). 

Debusk et al. (1996) studied the retention and compartmentalization of lead and cadmium in wetland 

microcosms. Differences between measured concentrations in inflow and outflow samples indicated that 

approximately half of the added cadmium was retained in the wetland microcosms. Experiments showed 

that nearly all trace metals were present in the sediments as sulfides, limiting their bioavailability and 

toxicity. The results of their analyses and a lack of noticeable biological effects suggested that in 

wetlands containing organic sediments, the sediment chemistry dominates cycling of the trace metals. 

In soils, pH, oxidation-reduction reactions, and formation of complexes are important factors affecting the 

mobility of cadmium (Bermond and Bourgeois 1992; Herrero and Martin 1993). Cadmium can 

participate in exchange reactions on the negatively charged surface of clay minerals. In acid soils, the 

reaction is reversible. However, adsorption increases with pH and may become irreversible (Herrero and 

Martin 1993). Cadmium also may precipitate as insoluble cadmium compounds, or form complexes or 

chelates by interaction with organic matter. Available data suggest that organic matter is more effective 

than inorganic constituents in keeping cadmium unavailable (McBride 1995). Examples of cadmium 

compounds found in soil are Cd3(PO4)2, CdCO3, and Cd(OH)2 (Herrero and Martin 1993). These 

compounds are formed as the pH rises. It has been found that about 90% of cadmium in soils remains in 

the top 15 cm (Anonymous 1994). 

The mobility and plant availability of cadmium in wetland soils are substantially different from upland 

soils. Cadmium tends to be retained more strongly in wetland soils and is more available to plants under 

upland conditions (Gambrell 1994). Debusk et al. (1996) compared heavy metal uptake by cattails and 

duckweed wetland microcosms and found that duckweed, on a whole-plant basis, accumulates cadmium 

more effectively than cattail does. The potential cadmium removal rate for duckweed is 2–4 mg 

Cd/m2

/day. 

Cadmium in soils may leach into water, especially under acidic conditions (Elinder 1985a; EPA 1979). 

Roy et al. (1993) demonstrated that Cl complexation in the leachate of ash from a municipal solid waste 

incinerator can result in a decrease in cadmium sorption by two common clays, kaolinite and illite. They 

also found that cationic competitive sorption enhances mobility in soils. Cadmium-containing soil 

particles may also be entrained into the air or eroded into water, resulting in dispersion of cadmium into 

these media (EPA 1985a). Contamination of soil by cadmium is of concern because the cadmium is taken 

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up efficiently by plants and, therefore, enters the food chain for humans and other animals. A low soil 

pH, which is becoming prevalent in many areas of the world due to acid rain, increases the uptake of 

cadmium by plants (Elinder 1992). 

Aquatic and terrestrial organisms bioaccumulate cadmium (Handy 1992a, 1992b; Kuroshima 1992; Naqvi 

and Howell 1993; Roseman et al. 1994; Suresh et al. 1993). Cadmium concentrates in freshwater and 

marine animals to concentrations hundreds to thousands of times higher than in the water (EPA 1979). 

Reported bioconcentration factors (BCFs) range from <200 to 18,000 for invertebrates (van Hattum et al. 

1989), from 3 to 4,190 for fresh water aquatic organisms (ASTER 1995), and from 5 to 3,160 for 

saltwater aquatic organisms (ASTER 1994). Bioconcentration in fish depends on the pH and the humus 

content of the water (John et al. 1987). Because of their high ability to accumulate metals, some aquatic 

plants have been suggested for use in pollution control. For example, it has been suggested that the 

rapidly-growing water hyacinth (Eichhornia crassipes) could be used to remove cadmium from domestic 

and industrial effluents (Ding et al. 1994; Muntau and Baudo 1992). 

The data indicate that cadmium bioaccumulates in all levels of the food chain. Cadmium accumulation 

has been reported in grasses and food crops, and in earthworms, poultry, cattle, horses, and wildlife 

(Alloway et al. 1990; Beyer et al. 1987; Gochfeld and Burger 1982; Kalac et al. 1996; Munshower 1977; 

Ornes and Sajwan 1993; Rutzke et al. 1993; Sileo and Beyer 1985; Vos et al. 1990). The metal burden of 

a crop depends on uptake by the root system, direct foliar uptake and translocation within the plant, and 

surface deposition of particulate matter (Nwosu et al. 1995). In general, cadmium accumulates in the 

leaves of plants and, therefore, is more of a risk in leafy vegetables grown in contaminated soil than in 

seed or root crops (Alloway et al. 1990). He and Singh (1994) report that, for plants grown in the same 

soil, accumulation of cadmium decreased in the order: leafy vegetables > root vegetables > grain crops. 

Alloway et al. (1990) also demonstrated that uptake of cadmium decreased in the order: lettuces, 

cabbages, radishes, and carrots. Nwosu et al. (1995) investigated the uptake of cadmium and lead in 

lettuce and radish grown in loam soil spiked with known mixtures of CdCl2 and Pb(NO3)2. They found 

that the mean uptake of cadmium by lettuce and radish increased as the concentrations of cadmium and 

lead in the soil increased. Their results supported previous findings that cadmium is absorbed by passive 

diffusion and translocated freely in the soil. The observed decline in cadmium uptake by lettuce at 

400 mg/kg could be attributed to saturation of the active binding sites on the plant root system or by early 

toxicological responses of the plant root. The study also supported earlier findings that radish did not 

accumulate as much cadmium as lettuce. 

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Some studies have concluded that soil pH is the major factor influencing plant uptake of cadmium from 

soils (Smith 1994). Liming of soil raises the pH, increasing cadmium adsorption to the soil and reducing 

bioavailability (He and Singh 1994; Thornton 1992). One study found that in peeled potato tubers, potato 

peelings, oat straw, and ryegrass, cadmium concentrations generally decreased as simple linear functions 

of increasing soil pH over the range of pH values measured (pH 3.9–7.6) (Smith 1994). Soil type also 

affects uptake of cadmium by plants. For soils with the same total cadmium content, cadmium has been 

found to be more soluble and more plant-available in sandy soil than in clay soil (He and Singh 1994). 

Similarly, cadmium mobility and bioavailability are higher in noncalcareous than in calcareous soils 

(Thornton 1992). Oxidation-reduction potential may also have a large effect on soil-to-plant cadmium 

transport. The absorption of cadmium paddy rice is significantly affected by the oxidation-reduction 

potential of the soil. The oxidation-reduction potential of rice paddy soils shifts drastically compared to 

upland soils due to submerging and draining techniques. Cadmium to rice ratios (cadmium concentration 

in brown rice/cadmium concentration in soil) were the smallest when the rice was grown under 

submerged conditions during the whole growth period. The ratios were the largest when the soil (coarse 

Toyama soil) was drained after the tillering stage. This is due to changes in cadmium solubility. Under 

flooded conditions, cadmium sulfide formation increases, and thus, cadmium solubility decreases (Iimura 

1981). 

Since cadmium accumulates largely in the liver and kidneys of vertebrates and not in the muscle tissue 

(Harrison and Klaverkamp 1990; Sileo and Beyer 1985; Vos et al. 1990), and intestinal absorption of 

cadmium is low, biomagnification through the food chain may not be significant (Sprague 1986). In a 

study of marine organisms from the Tyrrhenian Sea, no evidence of cadmium biomagnification was found 

along pelagic or benthic food webs (Bargagli 1993). Although some data indicate increased cadmium 

concentrations in animals at the top of the food chain, comparisons among animals at different trophic 

levels are difficult, and the data available on biomagnification are not conclusive (Beyer 1986; Gochfeld 

and Burger 1982). Nevertheless, uptake of cadmium from soil by feed crops may result in high levels of 

cadmium in beef and poultry (especially in the liver and kidneys). This accumulation of cadmium in the 

food chain has important implications for human exposure to cadmium, whether or not significant 

biomagnification occurs. 

Boularbah et al. (1992) isolated sic cadmium-resistant bacterial strains from a soil receiving dredged 

sediments and containing 50 mg Cd/kg. The isolates tolerated higher cadmium concentrations than the 

control strain and accumulated cadmium at concentrations ranging from 0 to 100 mg/L. One of the 

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isolates, Bacillus brevis, was found to be the most resistant to cadmium, with the ability to accumulate up 

to 70 mg Cd/g of cells dry weight, and may have some use in reclamation of metal-contaminated soils. 

6.3.2 Transformation and Degradation 

6.3.2.1 Air 

Little information is available on the atmospheric reaction of cadmium (EPA 1980d). The common 

cadmium compounds found in air (oxide, sulfate, chloride) are stable and not subject to photochemical 

reactions (EPA 1980d). Cadmium sulfide may photolyze to cadmium sulfate in aqueous aerosols (Konig 

et al. 1992). Transformation of cadmium among types of compounds in the atmosphere is mainly by 

dissolution in water or dilute acids (EPA 1980d). 

6.3.2.2 Water 

In fresh water, cadmium is present primarily as the cadmium(+2) ion and Cd(OH)2 and CdCO3 

complexes, although at high concentrations of organic material, more than half may occur in organic 

complexes (McComish and Ong 1988). Some cadmium compounds, such as cadmium sulfide, cadmium 

carbonate, and cadmium oxide, are practically insoluble in water. However, water-insoluble compounds 

can be changed to water-soluble salts by interaction with acids or light and oxygen. For example, 

aqueous suspensions of cadmium sulfide can gradually photoxidize to soluble cadmium (IARC 1993). 

Cadmium complexation with chloride ion increases with salinity until, in normal seawater, cadmium 

exists almost entirely as chloride species (CdCl+

, CdCl2, CdCl3

–

) with a minor portion as Cd2+. In 

reducing environments, cadmium precipitates as cadmium sulfide in the presence of sulfide ions 

(McComish and Ong 1988). Photolysis is not an important mechanism in the aquatic fate of cadmium 

compounds (EPA 1983c), nor is biological methylation likely to occur (EPA 1979). 

6.3.2.3 Sediment and Soil 

Transformation processes for cadmium in soil are mediated by sorption from and desorption to water, and 

include precipitation, dissolution, complexation, and ion exchange (McComish and Ong 1988). 

Important factors affecting transformation in soil include the cation exchange capacity, pH, and content of
 

clay minerals, carbonate minerals, oxides, organic matter, and oxygen (McComish and Ong 1988).
 

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6.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT 

Reliable evaluation of the potential for human exposure to cadmium depends in part on the reliability of 

supporting analytical data from environmental samples and biological specimens. Concentrations of 

cadmium in unpolluted atmospheres and in pristine surface waters are often so low as to be near the limits 

of current analytical methods. In reviewing data on cadmium levels monitored or estimated in the 

environment, it should also be noted that the amount of chemical identified analytically is not necessarily 

equivalent to the amount that is bioavailable. The analytical methods available for monitoring cadmium 

in a variety of environmental media are detailed in Chapter 7. 

6.4.1 Air 

Cadmium levels in ambient air generally range from 0.1 to 5 ng/m3 in rural areas, 2–15 ng/m3 in urban 

areas, and 15–150 ng/m3 in industrialized areas. Remote areas can contain lower levels of cadmium 

(Morrow 2001). Cadmium can undergo long-range atmospheric transport and deposition causing 

cadmium contamination in areas with no local cadmium inputs. Smoking can greatly affect indoor air 

concentrations of cadmium. In nonsmoking environments, there is little difference between indoor and 

outdoor air quality (Morrow 2001). Monitoring studies conducted for EPA’s 2006 Final Report for the 

Urban Air Toxics Monitoring Program detected cadmium in ambient air at several monitoring sites 

throughout the United States. At all detection sites in Bountiful, Utah; Northbrook, Illinois; Austin, 

Texas; St. Louis, Missouri; Indianapolis, Indiana; and Birmingham, Alabama average daily cadmium 

levels in ambient air were <0.01 μg/m3

. In Bountiful, Utah average daily cadmium levels were reported 

as 0.0008 μg/m3 (EPA 2007). 

Emission rates of cadmium from solid waste incinerators have been found to range from 20 to 

2,000 μg/m3 from the stacks of traditional incinerators and from 10 to 40 μg/m3 from advanced 

incinerators. Advances in pollution control and increased government regulations have resulted in 

decreased cadmium emissions to the environment (EPA 1990a; Herron 2003; Morrow 2001; SchulteSchrepping and Piscator 2002). Although there may be an increase in fossil fuel combustion and waste 

incineration, it does not appear likely that overall cadmium emissions to air will increase substantially in 

the United States. 

Cadmium levels in aerosols over Russian Arctic seas were measured in order to understand the magnitude 

of long-range atmospheric deposition. Ten-year average monthly mean concentrations ranged from 

0.002 to 0.080 ng/m3 in Franz Josef Land and from 0.0026 to 0.048 ng/m3 in Sevemaya Zemlya. The 

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highest concentrations were reported in the spring season and the lowest concentrations reported in the 

autumn for both sampling sites. During the winter and spring months, it was estimated that >50% of the 

average air pollutant concentrations in the Russian Arctic are due to atmospheric pollution. The 

anthropogenic sources of cadmium to the Russian Arctic are the industrial areas of Northern Europe, Kola 

Peninsula, and the Urals and Norilsk regions (Shevchenko et al. 2003). 

Atmospheric concentrations of cadmium are generally highest in the vicinity of cadmium-emitting 

industries such as smelters, municipal incinerators, or fossil fuel combustion facilities (Elinder 1985a; 

Pirrone et al. 1996). The mean annual concentration of airborne cadmium in an area about 1 km from a 

zinc smelter in Colorado was 0.023 μg/m3 (2.3x10-5 mg/m3

) (IARC 1993). Sweet et al. (1993) conducted 

a study of airborne inhalable particulate matter (PM-10) over a 2-year period in two urban/industrial areas 

(southeast Chicago and East St. Louis) and one rural area in Illinois. There was a significant difference 

between the cadmium levels in the urban areas and the cadmium levels in the rural area. Cadmium 

concentrations in the East St. Louis area were 5–10 times higher, with a range of <4 to 115 ng/m3 

(average 15[24] ng/m3

) for fine particles and a range of <4–97 ng/m3 (average 10[18] ng/m3) for course 

particles. In the Kikinda region of Serbia and Montenegro, where metal processing and construction 

industries are located, a mean annual atmospheric deposit of 36.0 μg/m2 per day was reported in 1995. A 

period of decreased industrial production, which decreased atmospheric cadmium deposits by 93%, 

resulted in 17% cadmium reduction in cattle feed and 13% in milk (Vidovic et al. 2005). Moss studies 

conducted by Hasselbach et al. (2005) in the area of the Red Dog Mine in Alaska reported cadmium 

levels >24 mg/kg dry weight in moss adjacent to the ore haul road. Ore dust containing heavy metals 

escapes from the ore trucks on the haul road and can be deposited in the nearby area (Hasselbach et al. 

2005). 

Annual average concentrations of atmospheric cadmium over three Great Lakes reflect the influence of 

industrialization and urbanization; Lake Erie’s levels of 0.6 ng/m3 were higher than fine particle 

concentrations of 0.2 ng/m3 over Lake Michigan and <0.2 ng/m3 over Lake Superior (Sweet et al. 1998). 

In the Lake Michigan Urban Air Toxics Study of dry deposition of metals, the flux of cadmium on the 

south side of Chicago was reported at about 0.01 mg/m2

/day and levels in rural Michigan and over Lake 

Michigan were far lower (Holsen et al. 1993). 

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6.4.2 Water 

The average level of cadmium in ocean water has been reported between <5 and 110 ng/L, with higher 

levels reported near coastal areas and in marine phosphates and phosphorites (Morrow 2001). 

Thornton (1992) reports that waters from the vicinity of cadmium-bearing mineral deposits may have 

cadmium concentrations of ≥1,000 μg/L. The cadmium concentration of natural surface water and 

groundwater is usually <1 μg/L (Elinder 1985a, 1992). EPA requires water suppliers to limit the 

cadmium concentration in drinking water to <5 μg/L (EPA 2006a). 

Groundwater in New Jersey has an estimated median level of 1 μg Cd/L with a high level of 405 μg/L. In 

a survey of groundwater surrounding waste sites, a concentration of 6,000 μg Cd/L was found (NTP 

1994). The National Urban Runoff Program measured cadmium concentrations in urban storm water 

runoff; concentrations ranged from 0.1 to 14 μg/L in 55% of samples that were positive for cadmium 

(Cole et al. 1984). Cadmium in highway run-off has been detected at levels of 0.0–0.06 mg/L (0.0– 

60 μg/L). 

In the estuarine portion of the Hudson River, more cadmium was released from agricultural and urban 

run-off than from industrial and municipal sewage treatment plants (Muntau and Baudo 1992). In an 

urban environment, there are also multiple sources of cadmium to waste water, based on an urban waste 

water study conducted in the United Kingdom. Cadmium was detected in the waste water originating 

from industrial, commercial, and private sectors, with the highest average cadmium concentration 

detected in the foul water of new (<5 years old) private housing (0.375 μg/L) (Rule et al. 2006). 

Cadmium was detected in the contaminated groundwater plume near in the Moon Creek watershed in the 

Couer D’Alene Mining District of Idaho at concentrations of ≤0.077 mg/L. The cadmium was 

transported to the creek with the plume where it was subsequently diluted (Paulson 1997). In the Spring 

River Basin of Kansas, Missouri, and Oklahoma, part of the Tri-State Mining District, cadmium was 

detected in surfaces waters at concentrations ranging from <1.0 to 24 μg/L (peak flow) and from <1.0 to 

75.0 μg/L (base flow). It was detected in the sediment of the sampling sites at concentrations ranging 

from 0.62 to 300 μg/g dry weight in the <250 μm sediment fraction and from 0.89 to 180 μg/g dry weight 

in the <63 μm fraction (Angelo et al. 2007). 

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6. POTENTIAL FOR HUMAN EXPOSURE 

6.4.3 Sediment and Soil 

Cadmium concentrations in soils not contaminated by anthropogenic sources range from 0.06 to 

1.1 mg/kg, with a minimum of 0.01 mg/kg and a maximum of 2.7 mg/kg (Alloway and Steinnes 1999). 

Cadmium content in marine sediments ranges from 0.1 to 1.0 μg/g (ppm) in the Atlantic and Pacific 

oceans (Thornton 1992). Average cadmium concentration in agricultural soils of remote locations was 

reported as 0.27 mg/kg (Holmgren et al. 1993). Soils with parent materials such as black shale (cadmium 

content up to 24 mg/kg) may have higher concentrations of natural cadmium. Since the U.S. mandatory 

limit of cadmium in sewage sludge is <20 mg/kg, soils receiving sewage sludge should not have 

heightened cadmium levels (Alloway and Steinnes 1999). Topsoil concentrations are often more than 

twice as high as subsoil levels as the result of atmospheric fallout and contamination (Pierce et al. 1982). 

Cadmium will partition mostly to soil and sediment when released to the environment. Atmospheric 

deposition is a major source of surface soil contamination, which allows cadmium to be introduced into 

the food supply (Alloway and Steinnes 1999; Morrow 2001). 

Markedly elevated levels may occur in topsoils near sources of contamination. Moss studies conducted 

by Hasselbach et al. (2005) in the area of the Red Dog Mine in Alaska reported cadmium levels 

>24 mg/kg dry weight in moss (n=151), as a measure atmospheric deposition onto soil surfaces, within 

10 m of the ore haul road. Ore dust containing heavy metals escapes from the ore trucks during loading 

and unloading at the mine and port site settles on the surfaces of the trucks, which blow off the trucks 

during transport on the haul road and deposited in the nearby area. The mean cadmium concentrations in 

moss and subsurface soil throughout the entire study were 1.86 and 0.27 mg/kg dry weight, respectively. 

Cadmium concentrations in moss and subsurface soil were 0.08–24.30 and 0.07–0.75 mg/kg dry weight. 

There did not appear to be a connection between the elevated subsurface cadmium levels and the local 

geochemistry. Geospatial analysis showed that areas as far as 12 km north of the haul road may be 

affected by mining emission depositions (Hasselbach et al. 2005). In the vicinity of a smelter in Helena, 

Montana, average soil values were 72 ppm within 1 km and 1.4 ppm between 18 and 60 km (EPA 1981a). 

Total cadmium concentrations in soil samples taken from a Superfund site in southeast Kansas ranged 

from 15 to 86 mg/kg (ppm). In the same study, soil samples were extracted with diethylenetriaminepentaacetic acid (DPTA) to approximate the plant-available metal concentrations. Extractable cadmium 

concentrations ranged from 0.6 to 10 mg/kg (ppm) (Abdel-Saheb et al. 1994). Soil cadmium levels in 

five Minnesota cities were highest in areas with the most vehicular traffic (>2 ppm in about 10% of innercity samples) and also showed a pattern consistent with past deposition from a sewage-sludge incinerator 

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6. POTENTIAL FOR HUMAN EXPOSURE 

(Mielke et al. 1991). Cadmium levels >750 mg/kg have been found in sites polluted by nonferrous metal 

mining and smelting have been reported (Alloway and Steinnes 1999). 

In the Spring River Basin of Kansas, Missouri, and Oklahoma, part of the Tri-State Mining District, 

cadmium was detected in surfaces waters at concentrations of <1.0–24 μg/L (peak flow) and <1.0– 

75.0 μg/L (base flow). Cadmium was detected in the sediment of the sampling sites at concentrations 

ranging from 0.62 to 300 μg/g dry weight in the <250 μm sediment fraction and from 0.89 to 180 μg/g 

dry weight in the <63 μm fraction (Angelo et al. 2007). A study conducted in 1999 at the Patroon Creek 

Reservoir in Albany County, New York sampled sediment cores for heavy metals, including cadmium. 

The watershed includes two industrial sites: one in operation from 1955 to present and the other 

operating from 1958 to 1984. Sediment samples in the interval of 0–1.68 m showed an average cadmium 

concentration of 1.69 mg/kg. This concentration is comparable to other stream and reservoir sediments 

impacted by industrial pollution (Arnason and Fletcher 2003). Sediments of the Sawmill River in 

Yonkers, New York contained the highest cadmium levels (6.9 mg/kg) in the Hudson River Basin during 

a sampling study conducted between 1992 and 1995 (USGS 1998b). 

Surficial sediments collected from 18 locations in three major tributaries to Newark Bay, New Jersey, had 

a mean cadmium concentration of 10±6 mg/kg (ppm) dry weight (Bonnevie et al. 1994). The highest 

cadmium concentrations were found in the Ironbound section of the Passaic River, a heavily 

industrialized area (29 mg/kg and 14 mg/kg), and in the Arthur Kill on the northwest side of Prall’s Island 

(15 mg/kg). An investigation of metals distribution in sediments along the Hudson River estuary revealed 

that cadmium concentrations in suspension were higher than in the bottom sediments by a factor of 30 

(Gibbs 1994). 

Soils derived from dredged material in confined disposal facilities in the Great Lakes Region had 

cadmium concentrations (dry weight) of <1.9–32 ppm (Beyer and Stafford 1993). In an analytical survey 

of sewage sludges from 16 large cities in the United States, cadmium concentrations ranged from 2.72 to 

242 ppm (dry weight). Besides the sample with a cadmium concentration of 242 ppm, all other sludges 

had cadmium contents ≤14.7 ppm (Gutenmann et al. 1994). 

6.4.4 Other Environmental Media 

Cadmium levels in food can vary greatly depending on the type of food, agricultural and cultivating 

practices, and amount atmospheric deposition and other anthropogenic contamination. In general, leafy 

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vegetables, such as lettuce and spinach, and staples, such as potatoes and grains, contain relatively high 

values of cadmium. Peanuts, soybeans, and sunflower seeds have naturally high levels of cadmium. 

Meat and fish container lower amounts of cadmium, with the exception of animal organ meats, such as 

kidney and liver, as these organs concentrate cadmium (Morrow 2001). 

As part of the U.S. Food and Drug Administration (FDA) Total Diet Study, average concentrations of 

cadmium in 14 food groups were analyzed from samples collected in 56 American cities. Cadmium was 

found in nearly all samples at varying concentrations. In general, the milk and cheese (no detection to 

<0.010 mg/kg) and fruits (no detection to 0.027 mg/kg) groups contained low concentrations of cadmium. 

Food items that contained high levels of cadmium were dry roasted peanuts (0.051 mg/kg); smooth 

peanut butter (0.056 mg/kg); shredded wheat cereal (0.057 mg/kg); boiled spinach (0.125 mg/kg); potato 

chips (0.062 mg/kg); and creamed spinach for infant and junior foods (0.090 mg/kg) (Capar and 

Cunningham 2000). Table 6-3 summarizes the data from this study. 

Watanabe et al. (1996) measured the cadmium content in rice samples from various areas in the world 

during the period from 1990 to 1995. Twenty-nine samples collected in the United States had a geometric 

mean of 7.43 ng Cd/g, with a standard deviation of 2.11. Shellfish, liver, and kidney meats have higher 

concentrations than other fish or meat (up to 1 ppm) (Elinder 1985a; IARC 1993; Schmitt and 

Brumbaugh 1990). Particularly high concentrations of cadmium of 2–30 mg/kg (ppm) fresh weight have 

been found in the edible brown meat of marine shellfish (Elinder 1992). Cadmium concentrations up to 

8 μg/g in oysters and 3 μg/g in salmon flesh have been reported (IARC 1993). Sprague (1986) has 

reviewed tissue concentrations of cadmium for marine molluscs and crustaceans. They found that drills 

were higher in cadmium (average, 26 μg/g dry weight) than almost all other mollusks, although scallops 

and whelks also tended to be high. Clams were relatively low in cadmium (average, 0.5–1.0 μg/g dry 

weight). Oysters from polluted areas averaged 18 μg/g dry weight. The average concentration of 

cadmium in clams from polluted areas was only 2.7 μg/g dry weight, but this was significantly higher 

than levels in clams from clean areas. In Fiscal Year (FY) 1985/1986, the FDA conducted a survey of 

cadmium, lead, and other elements in fresh clams and oysters collected from U.S. coastal areas used for 

shellfish production. Average cadmium levels (wet weight) were 0.09±0.06 mg/kg (ppm) (n=75) in 

hardshell clams, 0.05±0.04 mg/kg (n=59) in softshell clams, 0.51±0.31 mg/kg (n=104) in Eastern oysters, 

and 1.1±0.6 mg/kg (n=40) in Pacific oysters (Capar and Yess 1996). In FY91, FDA analyzed 5 samples 

of domestic clams and 24 samples of domestic oysters (collected from both coasts) for cadmium and 

found average concentrations of 0.06 and 0.62 mg/kg, respectively. Although no conclusions can be 

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Table 6-3. Mean Concentrations of Cadmium for FDA’s Total Diet Study Market
 

Baskets 91-3 through 97-1
 

Food product Mean concentration range (mg/kg)a 

Milk and cheese Not detected–<0.010 

Eggs Not detected–<0.005 

Meat, poultry, and fish Not detected–0.077 

Legumes and nuts <0.005–0.056 

Grain products <0.005–0.030 

Fruit Not detected–0.027 

Vegetables <0.004–0.125 

Mixed dishes and meals <0.005–0.020 

Desserts Not detected–0.031 

Snacks <0.010–0.062 

Condiments and sweeteners Not detected–0.029 

Fats and dressings Not detected–<0.024 

Beverages Not detected–<0.003 

Infant and junior foods Not detected–0.090 

a

A < symbol indicates that manganese was detected, but at a level lower than the limit of quantification. 

Source: Capar and Cunningham 2000 

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drawn in light of the small numbers of FY91 samples, these results to not appear to be appreciably 

different from those of the FY85/86 survey (Capar and Yess 1996). 

Cadmium is accumulated mainly in the hepatopancreas (digestive gland) of the crab, and cadmium levels 

as high as 30–50 ppm have been detected in this edible part of the animal. Cadmium levels as high as 

10 ppm also have been measured in some species of wild-growing edible mushrooms (Lind et al. 1995). 

Lind et al. (1995) conducted a feeding study in mice to determine the bioavailability of cadmium from 

crab hepatopancreas and mushroom in relation to organic cadmium. The cadmium accumulation in the 

liver and kidney of the mice was used as an estimate of the intestinal absorption. The group that was fed 

crab accumulated less cadmium in the liver and kidney than the groups fed mushrooms or inorganic 

cadmium salt. They concluded from the results of the study that cadmium from boiled crab has a lower 

bioavailability for absorption in the gastrointestinal tract of mice than inorganic cadmium and cadmium 

from dried mushrooms. Almost all (99%) of the cadmium in the boiled crab hepatopancreas was 

associated with insoluble ligands, probably denatured protein. In fresh crab hepatopancreas, most of the 

cadmium is in a soluble form bound to metallothionein (Lind et al. 1995). 

Significant concentrations of cadmium have been observed in fish living in stormwater ponds in Florida, 

especially in the redear sunfish, a bottom feeder (Campbell 1994). The mean cadmium concentration in 

redear sunfish living in stormwater ponds was 1.64 mg/kg wet weight compared to 0.198 mg/kg for 

redear sunfish living in control ponds. Similarly, the mean cadmium concentration in largemouth bass 

living in stormwater ponds was 3.16 mg/kg wet weight compared to 0.241 mg/kg for largemouth bass 

living in control ponds. Red drum, flounder, and seatrout collected from South Carolina estuaries during 

the period 1990–1993 had consistently low cadmium levels throughout the sampling area and with 

respect to species (Mathews 1994). The mean concentration for all fillets and whole fish was 86.2 ppb 

wet weight, with 70.7% (n=164) of the samples having <25 ppb. 

Cadmium and other heavy metals were detected in several of the freshwater invertebrates and fish of two 

Maryland streams. Due to their remote location and lack of source inputs, it is believed that the cadmium 

contamination was a result of long-range atmospheric deposition. Samples were taken from the 

Herrington Creek tributary (HCRT) and Blacklick Run (BLK) during October 1997, April 1998, and July 

1998. Cadmium concentrations in the trout of BLK ranged from about 37 to 90 ng/g wet, with the older 

specimens having the higher cadmium concentrations. Cadmium concentrations in crayfish ranged from 

about 40 to 160 ng/g wet in BLK, with the younger specimens containing the highest levels of cadmium. 

Crayfish in HRCT ranged from 45 to 155 ng/g, with the highest levels in the middle age group. In 

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6. POTENTIAL FOR HUMAN EXPOSURE 

crayfish, cadmium strongly accumulates in the gills, while the kidney accumulates cadmium in trout 

(Mason et al. 2000). 

Cadmium concentrations in the fish of the mining-contaminated waters of Oklahoma were reported by 

Brumbaugh et al. (2005). This area was part of the Tri-State Mining District that was extensively mined 

for lead and zinc from the mid-1800s to the 1950s, and contains nonremediated sites. Blood and carcass 

cadmium concentrations differed between species and sites, but were generally greatest in carp. Carcass 

cadmium in catfish were relatively low, with <0.1 μg/g dry weight in 34 of 36 samples. 

Cadmium concentrations of ≥0.5 ppm have been found in rice grown in cadmium-polluted areas of Japan 

(Nogawa et al. 1989) and China (Shiwen et al. 1990). Tobacco also concentrates cadmium from the soil, 

and cadmium content of cigarettes typically ranges from 1 to 2 μg/cigarette (Elinder 1985a, 1992). 

Some food crops, including confectionery sunflowers, have a propensity to take up cadmium from the soil 

in which they are grown and deposit it in the kernels. In a study to determine the cadmium burden of 

persons who report regular consumption of sunflower kernels, Reeves and Vanderpool (1997) analyzed 

19 different lots of sunflower kernels from the 1995 crop grown in the northern Great Plains region of 

North Dakota and Minnesota. They found a range of 0.33–0.67 μg Cd/g, with a mean±standard deviation 

of 0.48±0.11 μg/g fresh weight. The study showed that high intakes of sunflower kernels increased the 

intake of cadmium. However, the amount of cadmium in whole blood or in red blood cells was not 

affected by cadmium intake. The authors pointed out that an increased intake of sunflowers will increase 

not only the cadmium intake, but also the intake of copper and phytate. In turn, this could reduce the 

availability of cadmium from this food source. 

DOI (1985) examined the concentrations of cadmium in a variety of aquatic and terrestrial flora and fauna 

and identified six trends: (1) in general, marine biota contained significantly higher cadmium residues 

than their freshwater or terrestrial counterparts; (2) cadmium tends to concentrate in the viscera of 

vertebrates, especially in the liver and kidneys; (3) cadmium concentrations are higher in older organisms 

than in younger ones, especially in carnivores and marine vertebrates; (4) higher concentrations for 

individuals of a single species collected at various locations are almost always associated with proximity 

to industrial/urban areas or point-source discharges of cadmium-containing wastes; (5) background levels 

of cadmium in crops and other plants are generally <1.0 mg/kg (ppm); and (6) cadmium concentrations in 

biota are dependent upon the species analyzed, the season of collection, ambient cadmium levels, and the 

sex of the organism. 

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6. POTENTIAL FOR HUMAN EXPOSURE 

During a study monitoring cadmium levels in 331 cigarette packs from over 20 areas around the world it 

was found that the mean cadmium level per cigarette was 1.15 μg/cigarette ±0.43 (AM±ASD) or 

1.06 μg/cigarette ±1.539 (geometric mean [GM]±geometric standard deviation[GSD]). Cigarettes from 

Mexico had the highest mean level of cadmium with an AM±ASD of 2.03 μg/cigarette ±0.33 or a 

GM±GSD of 2.00 μg/cigarette ±1.190. Cigarettes from India had the lowest mean levels of cadmium 

with an AM±ASD of 0.35 μg/cigarette ±0.09 or a GM±GSD of 0.34 μg/cigarette ±1.284. The arithmetic 

mean for the United States was 1.07 μg/cigarette ±0.11 and the GM±GSD was 1.06 μg/cigarette ±1.115 

(Watanabe et al. 1987). 

The cadmium content of coals varies widely; concentrations of 0.01–180 μg/g (ppm) have been reported 

for the United States (Thornton 1992; Wilber et al. 1992). 

6.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE 

The general population may be exposed to cadmium through ingestion of food and drinking water, 

inhalation of particulates from ambient air or tobacco smoke, or ingestion of contaminated soil or dust. 

For nonsmokers, food is the major source of cadmium exposure (NTP 2005). Inhalation of cigarette 

smoke is the major source of cadmium exposure for smokers (CDC 2005). Cadmium is introduced to the 

food chain through agricultural soils, which may naturally contain cadmium, or from anthropogenic 

sources such as atmospheric deposition or direct application methods such as phosphate fertilizer 

application and municipal waste composting (Alloway and Steinnes 1999; Morrow 2001). Cadmiumplated utensils and galvanized equipment used in food processing and preparation; enamel and pottery 

glazes with cadmium-based pigments; and stabilizers used in food-contact plastics are also sources of 

food contamination (Galal-Gorchev 1993). Cadmium levels in soils are not a direct indicator of the level 

of cadmium in the food supply, with the exception of extreme contamination, as other factors such as the 

type of crop and farming methods are important (Morrow 2001). 

Based on food intake rates and food-cadmium concentrations, the estimated geometric mean daily intake 

of cadmium for the U.S. population is 18.9 μg/day, down from an estimated 30 μg/day in the 1980s 

(Choudhury et al. 2001; Gartrell et al. 1986). Based on the mean cadmium daily intakes for males and 

females aged 6–60 years reported by Choudhury et al. (2001), age-weighted mean cadmium intakes of 

0.35 μg/kg/day for males and 0.30 μg/kg/day for females were calculated for U.S. nonsmokers. The 

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average gastrointestinal absorption of dietary cadmium is about 5%, but it may be 5–10 times greater in 

young women (CDC 2005). 

In the Third National Report on Human Exposures to Environmental Chemicals reported by the CDC 

(2005) results from the National Health and Nutrition Examination Survey (NHANES) 1999–2002 were 

reported. Cadmium levels in blood (see Table 6-4), urine (creatine corrected [see Table 6-5]), and urine 

(see Table 6-6) was evaluated for a variety age groups and ethnicities. Blood cadmium reflects both 

recent and cumulative exposures and urinary cadmium reflects cadmium exposure and the concentration 

of cadmium in the kidneys. Cadmium targets the kidneys in the body and high-dose chronic cadmium 

exposure can cause renal tubular damage and glomerular damage. Even relatively low levels of cadmium 

exposure have resulted in biomarkers of renal dysfunction or diminished bone mineral density (CDC 

2005). 

As a part of the New York City Health and Nutrition Examination Survey (NYC HANES), 2004 blood 

cadmium levels were evaluated in 1,811 New York City adults (age 20 years and older). The variables 

used in this study were sex, age, race/ethnicity, place of birth, family income, education, and smoking 

status (see Table 6-7 for detailed results of this study). The geometric mean blood cadmium 

concentration in New York City adults was 0.77 μg/L, slightly higher than the 1999–2000 estimated 

national mean of 0.47 μg/L with heavy smokers having the highest geometric mean blood cadmium level 

of 1.58 μg/L, higher than any other subgroup. The reason for the elevated blood cadmium levels in 

nonsmoking, New York City adults is not known, although it was speculated that higher shellfish 

consumption may be the cause of elevated blood cadmium levels in Asian subgroup (McKelvey et al. 

2007). 

Vahter et al. (1996) studied the dietary intake and uptake of cadmium in nonsmoking women consuming 

a mixed diet low in shellfish (n=34) or with shellfish once a week or more (n=17). The shellfish diets, 

with a median of 22 μg Cd/day, contained twice as much cadmium as the mixed diets, which had a 

median of 10.5 μg Cd/day. In spite of the differences in the daily intake of cadmium, there were no 

statistically significant differences in the blood cadmium concentrations of the shellfish group (0.25 μg/L) 

and the mixed diet group (0.23 μg/L) or in the urinary cadmium concentrations of the shellfish and mixed 

diet groups (0.10 μg/L in both groups). These results indicate a lower absorption of cadmium in the 

shellfish group than in the mixed diet group or a difference in kinetics. The authors suggested that a 

higher gastrointestinal absorption of cadmium in the mixed diet group could be explained in part by their 

lower body iron stores as measured by the concentrations of serum ferritin (S-fer). A median S-fer 

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6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-4. Geometric Mean and Selected Percentile Blood Concentrations (μg/L) 

of Cadmium in the U.S. Population From 1999 to 2002 

Geometric Selected percentiles (95 percent confidence interval) 

meana 

(95 percent 

Group 

Survey 

years 

confidence 

interval) 50th 75th 90th 95th 

Sample 

size 

Total, age 1 and 1999–2000 0.412 (0.378– 0.300 (0.300– 0.600 (0.500– 1.00 (0.900– 1.30 (1.20– 7,970 

older 0.449) 0.400) 0.600) 1.00) 1.40) 

2001–2002 Not calculated 0.300 (<LOD– 0.400 (0.400– 0.900 (0.900– 1.30 (1.20– 8,945, 

0.300) 0.500) 1.10) 1.60) 

Age group 

1–5 Years 1999–2000 Not calculated <LOD 0.300 (<LOD– 0.400 (0.300– 0.400 (0.300– 723 

0.300) 0.400) 0.400) 

2001–2002 Not calculated <LOD <LOD <LOD 0.300 (<LOD– 898 

0.300) 

6–11 Years 1999–2000 Not calculated <LOD 0.300 (<LOD– 0.400 (0.300– 0.400 (0.400– 905 

0.300) 0.400) 0.500) 

2001–2002 Not calculated <LOD <LOD <LOD 0.400 (0.300– 1,044 

0.400) 

12–19 Years 1999–2000 0.333 (0.304– 0.300 (<LOD– 0.300 (0.300– 0.800 (0.600– 1.10 (0.900– 2,135 

0.366 0.300) 0.400) 0.900) 1.10) 

2001–2002 Not calculated <LOD 0.300 (<LOD– 0.400 (0.400– 0.800 (0.600– 2,231 

0.300) 0.500) 1.10) 

20 Years and 1999–2000 0.468 (0.426– 0.400 (0.300– 0.600 (0.600– 1.00 (1.00– 1.50 (1.40– 4,207 

older 0.513) 0.400) 0.700) 1.10) 1.60) 

2001–2002 Not calculated 0.300 (0.300– 0.600 (0.500– 1.10 (0.900– 1.60 (1.30– 4,772 

0.400) 0.600) 1.20) 1.80) 

Gender 

Males 1999–2000 0.403 (0.368– 0.400 (0.300– 0.600 (0.500– 1.00 (0.900– 1.30 (1.20– 3,913 

0.441) 0.400) 0.600) 1.10) 1.50) 

2001–2002 Not calculated 0.300 (<LOD– 0.400 (0.400– 0.900 (0.900– 1.40 (1.20– 4,339 

0.300) 0.500) 1.10) 1.80) 

Females 1999–2000 0.421 (0.386– 0.300 (0.300– 0.600 (0.500– 1.00 (0.800– 1.30 (1.10– 4,057 

0.460) 0.400) 0.600) 1.00) 1.40) 

2001–2002 Not calculated 0.300 (0.300– 0.500 (0.500– 1.00 (0.900– 1.40 (1.20– 4,606 

0.400) 0.600) 1.10) 1.60) 

Race/ethnicity 

Mexican 1999–2000 0.395 (0.367– 0.400 (0.300– 0.400 (0.400– 0.700 (0.700– 1.10 (0.900– 2,742 

Americans 0.424) 0.400) 0.500) 0.900) 1.30) 

2001–2002 Not calculated <LOD 0.300 (0.300– 0.600 (0.500– 1.00 (0.700– 2,268 

0.400) 0.700) 1.30) 

Non-Hispanic 1999–2000 0.393 (0.361– 0.300 (0.300– 0.600 (0.500– 1.00 (0.800– 1.40 (1.10– 1,842 

blacks 0.427) 0.400) 0.600) 1.10) 1.50) 

2001–2002 Not calculated <LOD 0.400 (0.400– 1.00 (0.900– 1.40 (1.20– 2,219 

0.500) 1.00) 1.50) 

Non-Hispanic 1999–2000 0.376 (0.470– 0.400 (0.300– 0.500 (0.500– 1.00 (0.900– 1.30 (1.20– 2,716 

whites 0.209) 0.400) 0.600) 1.10) 1.40) 

2001–2002 Not calculated <LOD 0.500 (0.500– 0.900 (0.900– 1.40 (1.20– 3,806 

0.600) 1.10) 1.80) 

a

The proportion of results below limit of detection was too high to provide a valid result. 

Source: CDC 2003, 2005b 

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Table 6-5. Geometric Mean and Selected Percentile Urine 

Concentrations (Creatine Corrected) (μg/L) of Cadmium 

in the U.S. Population From 1999 to 2002 

Geometric Selected percentiles (95 percent confidence interval) 

meana 

(95 percent 

Group 

Survey 

years 

confidence 

interval) 50th 75th 90th 95th 

Sample 

size 

Total, age 6 and 1999–2000 0.181 (0.157– 0.219 (0.199– 0.423 (0.391– 0.712 (0.645– 0.933 (0.826– 2,257 

older 0.209) 0.238) 0.446) 0.757) 1.07) 

2001–2002 0.199 (0.181– 0.212 (0.194– 0.404 (0.377– 0.690 (0.630– 0.917 (0.813– 2,689 

0.218) 0.232) 0.440) 0.754) 0.998) 

Age group 

6–11 Years 1999–2000 Not calculated 0.085 (0.063– 0.147 (0.123– 0.210 (0.171– 0.300 (0.184– 310 

0.107) 0.182) 0.316) 0.607) 

2001–2002 0.075 (0.059– 0.100 (0.083– 0.166 (0.136– 0.233 (0.206– 0.291 (0.221– 368 

0.094) 0.112) 0.192) 0.281) 0.440) 

12–19 Years 1999–2000 0.071 (0.051– 0.093 (0.084– 0.147 (0.130– 0.215 (0.204– 0.283 (0.222– 648 

0.098) 0.106) 0.163) 0.240) 0.404) 

2001–2002 0.078 (0.067– 0.091 (0.085– 0.136 (0.123– 0.191 (0.175– 0.280 (0.234– 762 

0.091) 0.101) 0.143) 0.234) 0.321) 

20 Years and 1999–2000 0.267 (0.247– 0.288 (0.261– 0.484 (0.433– 0.769 (0.727– 1.07 (0.927– 1,299 

older 0.289) 0.304) 0.545) 0.818) 1.17) 

2001–2002 0.261 (0.236– 0.273 (0.247– 0.481 (0.426– 0.776 (0.691– 0.979 (0.874– 1,559 

0.289) 0.303) 0.518) 0.850) 1.12) 

Gender 

Males 1999–2000 0.154 (0.131– 0.174 (0.158– 0.329 (0.293– 0.617 (0.537– 0.788 (0.696– 1,121 

0.182) 0.191) 0.382) 0.700) 0.929) 

2001–2002 0.159 (0.143– 0.168 (0.157– 0.334 (0.304– 0.532 (0.491– 0.757 (0.690– 1,334 

0.177) 0.182) 0.364) 0.653) 0.856) 

Females 1999–2000 0.211 (0.170– 0.267 (0.239– 0.473 (0.423– 0.783 (0.690– 1.09 (0.813– 1,136 

0.261) 0.308) 0.551) 0.917) 1.38) 

2001–2002 0.245 (0.216– 0.263 (0.228– 0.479 (0.414– 0.792 (0.687– 0.985 (0.876– 1,355 

0.278) 0.297) 0.541) 0.884) 1.16) 

Race/ethnicity 

Mexican 1999–2000 0.175 (0.137– 0.181 (0.144– 0.331 (0.266– 0.612 (0.441– 0.843 (0.674– 780 

Americans 0.223) 0.225) 0.418) 0.828) 1.13) 

2001–2002 0.156 (0.136– 0.170 (0.150– 0.282 (0.263– 0.501 (0.388– 0.693 (0.507– 682 

0.177) 0.184) 0.340) 0.614) 0.839) 

Non-Hispanic 1999–2000 0.183 (0.140– 0.201 (0.168– 0.414 (0.343– 0.658 (0.516– 0.873 (0.722– 546 

blacks 0.240) 0.241) 0.472) 0.827) 0.962) 

2001–2002 0.190 (0.156– 0.195 (0.174– 0.385 (0.336– 0.676 (0.559– 0.917 (0.725– 667 

0.232) 0.225) 0.449) 0.850) 1.08) 

Non-Hispanic 1999–2000 0.175 (0.146– 0.219 (0.191– 0.432 (0.387– 0.729 (0.666– 1.00 (0.826– 760 

whites 0.209) 0.250) 0.470) 0.783) 1.16) 

2001–2002 0.205 (0.184– 0.224 (0.208– 0.421 (0.382– 0.719 (0.668– 0.931 (0.806– 1,132 

0.229) 0.242) 0.470) 0.784) 1.05) 

a

The proportion of results below limit of detection was too high to provide a valid result. 

Source: CDC 2003, 2005b 

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Table 6-6. Geometric Mean and Selected Percentile Urine Concentrations (μg/L) 

of Cadmium in the U.S. Population From 1999 to 2002 

Geometric Selected percentiles (95 percent confidence interval) 

meana 

(95 percent 

Group 

Survey 

years 

confidence 

interval) 50th 75th 90th 95th 

Sample 

size 

Total, age 6 and 1999–2000 0.193 (0.169– 0.232 (0.214– 0.475 (0.436– 0.858 (0.763– 1.20 (1.06– 2,257 

older 0.220) 0.249) 0.519) 0.980) 1.33) 

2001–2002 0.210 (0.189– 0.229 (0.207– 0.458 (0.423– 0.839 (0.753– 1.20 (1.07– 2,690 

0.235) 0.255) 0.482) 0.919) 1.28) 

Age group 

6–11 Years 1999–2000 Not calculated 0.078 (0.061– 0.141 (0.115– 0.219 (0.178– 0.279 (0.211– 310 

0.101) 0.173) 0.233) 0.507) 

2001–2002 0.061 (<LOD– 0.077 (0.067– 0.140 (0.112– 0.219 (0.184– 0.282 (0.260– 368 

0.081) 0.092) 0.160) 0.262) 0.326) 

12–19 Years 1999–2000 0.092 (0.067– 0.128 (0.107– 0.202 (0.183– 0.329 (0.272– 0.424 (0.366– 648 

0.126) 0.148) 0.232) 0.372) 0.596) 

2001–2002 0.109 (0.087– 0.135 (0.114– 0.210 (0.189– 0.327 (0.289– 0.442 (0.366– 762 

0.136) 0.157) 0.247) 0.366) 0.480) 

20 Years and 1999–2000 0.281 (0.253– 0.306 (0.261– 0.551 (0.510– 0.979 (0.836– 1.31 (1.13– 1,299 

older 0.313) 0.339) 0.621) 1.13) 1.57) 

2001–2002 0.273 (0.249– 0.280 (0.261– 0.545 (0.493– 0.955 (0.855– 1.28 (1.20– 1,560 

0.299) 0.308) 0.607) 1.06) 1.43) 

Gender 

Males 1999–2000 0.199 (0.165– 0.227 (0.193– 0.462 (0.381– 0.892 (0.748– 1.41 (0.980– 1,121 

0.241) 0.263) 0.539) 1.15) 1.83) 

2001–2002 0.201 (0.177– 0.223 (0.191– 0.445 (0.393– 0.870 (0.741– 1.22 (1.12– 1,335 

0.229) 0.257) 0.481) 1.03) 1.38) 

Females 1999–2000 0.187 (0.153– 0.239 (0.220– 0.492 (0.456– 0.806 (0.705– 1.10 (1.01– 1,136 

0.229) 0.255) 0.540) 0.980) 1.19) 

2001–2002 0.219 (0.192– 0.234 (0.202– 0.466 (0.433– 0.817 (0.733– 1.17 (0.918– 1,355 

0.251) 0.265) 0.519) 0.886) 1.36) 

Race/ethnicity 

Mexican 1999–2000 0.191 (0.157– 0.202 (0.167– 0.438 (0.351– 0.813 (0.686– 1.12 (0.886– 780 

Americans 0.233) 0.221) 0.551) 0.977) 1.38) 

2001–2002 0.160 (0.135– 0.181 (0.171– 0.321 (0.285– 0.559 (0.430– 0.766 (0.633– 683 

0.189) 0.198) 0.362) 0.733) 1.15) 

Non-Hispanic 1999–2000 0.283 (0.208– 0.312 (0.243– 0.633 (0.498– 1.22 (0.892– 1.48 (1.30– 546 

blacks 0.387) 0.412) 0.806) 1.38) 1.72) 

2001–2002 0.277 (0.229– 0.302 (0.257– 0.580 (0.476– 1.04 (0.843– 1.51 (1.28– 667 

0.336) 0.354) 0.713) 1.38) 1.74) 

Non-Hispanic 1999–2000 0.175 (0.148– 0.220 (0.194– 0.455 (0.388– 0.797 (0.714– 1.17 (0.963– 760 

whites 0.206) 0.246) 0.510) 1.01) 1.47) 

2001–2002 0.204 (0.179– 0.221 (0.191– 0.445 (0.394– 0.813 (0.717– 1.17 (0.989– 1,132 

0.231) 0.255) 0.479) 0.875) 1.24) 

a

The proportion of results below limit of detection was too high to provide a valid result. 

Source: CDC 2003, 2005b 

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Table 6-7. Blood Cadmium Concentrations, Geometric Means, Adjusted 

Proportional Change in Means, and 95th Percentiles in
 

New York City Adults in Population Subgroups
 

Results 

Crude weighted 

geometric mean 

Adjusted proportional 

change in mean 

Crude weighted 

95th percentile 

blood cadmium blood cadmium blood cadmium 

Variable Numbera (μg/L) (μg/L)b (μg/L) 

Total: 1,811 0.77 — 1.88 

Male 762 0.76 1.00 1.95 

Female 1,049 0.79 1.07 1.83 

20–39 years old 903 0.76 1.00 1.82 

40–59 years old 673 0.84 1.16 2.19 

≥60 years old 235 0.77 1.15 1.52 

White, non-Hispanicc 529 0.73 1.04 1.71 

Black, non-Hispanicc 390 0.80 1.11 1.97 

Asian, non-Hispanicc 231 0.99 1.41 2.36 

Hispanicc 630 0.73 1.00 1.73 

Place of birth: 

United States 882 0.76 1.00 1.95 

Outside the United 

States 923 0.79 1.02 1.73 

Family income ($US): 

<20,000 610 0.86 1.00 2.33 

20,000–49,999 566 0.77 0.94 1.76 

50,000–74,999 256 0.74 0.92 1.76 

≥75,000 304 0.69 0.91 1.43 

Education: 

<Bachelor’s 1,252 0.82 1.09 2.02 

Bachelors or greater 551 0.69 1.00 1.43 

Smoking status: 

Never smoked 1,036 0.66 1.00 1.28 

Former smoker 310 0.71 1.07 1.32 

Current smoker 449 1.22 1.88 3.00 

a

Totals do not all equal 1,811 because of missing data.

b

The exponential β coefficient from a log-linear multiple regression that includes all covariates in the table. Sample 

size for adjust analysis is 1,707, after excluding study participants for whom covariate data are missing.

c

Excludes 27 participants who self-classified as “other”.
 

Source: McKelvey et al. 2007 

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concentration of 18 μg/L was measured for the mixed diet group compared to a median of 31 μg/L for the 

shellfish group. 

Except in the vicinity of cadmium-emitting industries or incinerators, the intake of cadmium from 

drinking water or ambient air is of minor significance (Elinder 1985a). Cadmium is removed from waste 

water and sewage through precipitation to hydroxide or carbonate compounds and ultimate separation 

(Schulte-Schrepping and Piscator 2002). EPA requires water suppliers to limit the cadmium 

concentration in water to <5 μg/L (EPA 2006a). 

IARC (1993) reports that the total body burden of non-occupationally exposed adult subjects has been 

estimated to range from 9.5 to 50 mg in the United States and Europe. People living near sources of 

cadmium pollution may be exposed to higher levels of cadmium. Ambient air cadmium concentrations in 

industrialized areas was been estimated between 15 and 150 ng/m3 (Morrow 2001). During a study 

conducted in Germany between March and May 2000, cadmium levels in child-mother pairs, as a 

function of ambient air quality, were compared between populations in the urban, industrialized area of 

Duisberg and the rural area of North Rhine Westphalia. Cadmium levels in the ambient air of DuisburgSouth ranged from 1.5 to 31 ng/m3

, compared to 0.5 ng/m3 in the rural are of Westphalia. Cadmium 

levels in the blood and urine of mothers in the industrialized area were higher than in the rural areas. 

Cadmium levels in the blood and urine of the children did not differ between the two areas. In the 

industrialized area, regression analysis indicated a significant influence of cadmium in ambient air on 

cadmium in blood (Wilhelm et al. 2005). 

It has been estimated that tobacco smokers are exposed to 1.7 μg cadmium per cigarette, and about 10% 

is inhaled when smoked (Morrow 2001; NTP 2005). Tobacco leaves naturally accumulate large 

amounts of cadmium (Morrow 2001). During a study monitoring cadmium levels in 331 cigarette packs 

from over 20 areas around the world, it was found that the mean cadmium level per cigarette was 

1.15 μg/cigarette ±0.43 (AM±ASD) or 1.06 μg/cigarette ±1.539 GM±GSD. Cigarettes from Mexico had 

the highest mean level of cadmium with an AM±ASD of 2.03 μg/cigarette ±0.33 or a GM±GSD of 

2.00 μg/cigarette ±1.190. Cigarettes from India had the lowest mean levels of cadmium with an 

AM±ASD of 0.35 μg/cigarette ±0.09 or a GM±GSD of 0.34 μg/cigarette ±1.284 (Watanabe et al. 1987). 

The amount of cadmium absorbed from smoking one pack of cigarettes per day is about 1–3 μg/day 

(Lewis et al. 1972a; Nordberg et al. 1985), roughly the same as from the diet. This large contribution is 

due to the greater absorption of cadmium from the lungs than from the gastrointestinal tract (Elinder 

1985a). Direct measurement of cadmium levels in body tissues confirms that smoking roughly doubles 

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cadmium body burden in comparison to not smoking, with kidney concentrations averaging 15–20 μg/g 

wet weight for nonsmokers and 30–40 μg/g wet weight for heavy smokers at the age of 50–60 (Ellis et al. 

1979; Hammer et al. 1973; Lewis et al. 1972a, 1972b). Ellis et al. (1979) found an increase in kidney 

cadmium of 0.11±0.05 mg per pack-year (AM±ASD) of smoking and an increase in liver cadmium 

concentration of 0.077±0.065 μg/g per pack-year (AM±ASD). Because excretion of cadmium is very 

slow, half-lives of cadmium in the body are correspondingly long (17–38 years) (Wester et al. 1992). 

Workers in a variety of occupations may be exposed to cadmium and cadmium compounds. Occupations 

with potential exposure to cadmium are listed in Table 6-8 (IARC 1993). 

Highest levels of occupational exposure would be expected to occur in operations involving heating 

cadmium-containing products by smelting, welding, soldering, or electroplating, and also in operations 

associated with producing cadmium powders (OSHA 1990). The primary route of occupational exposure 

is through inhalation of dust and fumes, and also incidental ingestion of dust from contaminated hands, 

cigarettes, or food (Adamsson et al. 1979). 

Concentrations of airborne cadmium found in the workplace vary considerably with the type of industry 

and the specific working conditions. Processes that involve high temperatures can generate cadmium 

oxide fumes that are absorbed very efficiently through the lungs (IARC 1993). Deposition and absorption 

of dust containing different compounds depend upon particle size (IARC 1993). These exposures can be 

controlled through use of personal protective equipment and good industrial hygiene practices, and 

through operating procedures designed to reduce workplace emissions of cadmium (OSHA 1990). 

Data from the National Occupational Exposure Survey (NOES), conducted by NIOSH from 1981 to 

1983, estimated the number of workers potentially exposed to various chemicals in the workplace during 

the same period (NIOSH 1990); these data are summarized in Table 6-9. 

The NOES database does not contain information on the frequency, level, or duration of exposure of 

workers to any of the chemicals listed. It provides only estimates of workers potentially exposed to the 

chemicals. 

The OSHA final rule has established a permissible exposure limit (PEL) of 5 μg/m3 for occupational 

exposure to airborne cadmium (OSHA 2007a). The American Conference of Governmental and 

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Table 6-8. Occupations with Potential Exposure to Cadmium and Cadmium
 

Compounds
 

Occupation 

Alloy productiona Phosphorous production 

Battery productiona Pigment production and usea 

Brazing Plastics productiona 

Coating Plating 

Diamond cutting Printing 

Dry color formulation Semiconductor and superconductor production 

Electroplating Sensors production 

Electrical contacts production Smelting and refininga 

Enameling Solar cells production 

Engraving Soldering 

Glasswork Stabilizer production 

Laser cutting Textile printing 

Metallizing Thin film production 

Paint production and use Transistors production 

Pesticide production and use Welding 

a

Activity with high risk because atmospheric concentrations of cadmium are high and the number of workers 

employed is significant. 

Source: IARC 1993 

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6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-9. Estimated Number of Workers Potentially Exposed to Various
 

Chemicals in the Workplace in 1981–1983
 

Chemical Number of workers potentially exposed 

Cadmium sulfide 45,562 

Cadmium oxide 15,727 

Cadmium (pure) 335 

Cadmium dust (form unknown) 3,893 

Cadmium powder (form unknown) 486 

Cadmium sulfate 1,313 

1:1 Cadmium salt of carbonic acid 164 

Cadmium (form unknown) 88,968 

Total 153,486 

Source: NIOSH 1990 

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6. POTENTIAL FOR HUMAN EXPOSURE 

Industrial Hygienists (ACGIH) has set their biological exposure index (BEI) at 10 μg/L (Aurelio et al. 

1993). 

6.6 EXPOSURES OF CHILDREN 

This section focuses on exposures from conception to maturity at 18 years in humans. Differences from 

adults in susceptibility to hazardous substances are discussed in Section 3.7, Children’s Susceptibility. 

Children are not small adults. A child’s exposure may differ from an adult’s exposure in many ways. 

Children drink more fluids, eat more food, breathe more air per kilogram of body weight, and have a 

larger skin surface in proportion to their body volume. A child’s diet often differs from that of adults. 

The developing human’s source of nutrition changes with age: from placental nourishment to breast milk 

or formula to the diet of older children who eat more of certain types of foods than adults. A child’s 

behavior and lifestyle also influence exposure. Children crawl on the floor, put things in their mouths, 

sometimes eat inappropriate things (such as dirt or paint chips), and spend more time outdoors. Children 

also are closer to the ground, and they do not use the judgment of adults to avoid hazards (NRC 1993). 

Children are most likely to be exposed to cadmium in from ingestion of food (NTP 2005). There are no 

data on gastrointestinal absorption of cadmium in children, although very limited evidence exists that 

cadmium absorption from the gut may be greater in young animals. Oral absorption is discussed in more 

detail in Section 3.4.1.2. A study performed in Cincinnati, Ohio, investigated cadmium in human milk 

and found a mean concentration of 19 ppb (0.019 ppm) (Jensen 1983). The NHANES 1999–2002 

reported cadmium levels in blood (see Table 6-4) and urine (see Table 6-5) for children in different age 

groups (CDC 2005). The NYC HANES did not test for blood cadmium levels in children, although the 

blood cadmium levels in adults were slightly higher than the national average (McKelvey et al. 2007). 

Results of the U.S. FDA Total Diet Study (Capar and Cunningham 2000) reported cadmium levels in 

infant and junior foods ranged from no detection to 0.090 mg/kg. According to the National Human 

Exposure Assessment Survey (NHEXAS), children in EPA Region V (Great Lakes Region) have a mean 

dietary cadmium exposure of 17 (±1.8) μg/kg for minority children and 21 (±2.2) μg/kg for non-minority 

children (Pellizzari et al. 1999). 

Except in the vicinity of cadmium-emitting industries or incinerators, the intake of cadmium from 

drinking water or ambient air is of minor significance (Elinder 1985a). Ambient air cadmium 

concentrations in industrialized areas has been estimated between 15 and 150 ng/m3 (Morrow 2001). 

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Cadmium levels in the ambient air of Duisburg-South, Germany ranged from 1.5 to 31 ng/m3, compared 

to 0.5 ng/m3 in the rural are of Westphalia. Cadmium levels in the blood and urine of mothers in the 

industrialized area were higher than in the rural areas. Cadmium levels in the blood and urine of the 

children did not differ between the two areas. In the industrialized area, regression analysis indicated a 

significant influence of cadmium in ambient air on cadmium in blood (Wilhelm et al. 2005). Children in 

the homes of parents who smoke also can be exposed to cadmium through the inhalation of environmental 

tobacco smoke. There is potential for cadmium originating from second-hand smoke to settle onto 

surfaces; thus, there is a possibility that children may ingest cadmium from contaminated surfaces by the 

hand-to-mouth pathway. Although no data were found, children playing near hazardous waste sites could 

be exposed to cadmium in soil by hand-to-mouth activity and/or soil pica. No case studies were found on 

accidental poisoning of children by swallowing cadmium-containing batteries or by ingesting cadmiumcontaining household pesticides, which also are potential routes of exposure. No information was found 

concerning differences in the weight-adjusted intakes of cadmium by children. 

In the Workers’ Home Contamination Study conducted under the Workers’ Family Protection Act 

(DHHS 1995), several studies were identified that reported home contamination with cadmium 

originating from parental occupation in a lead smelter. In a study of 396 children of ages 1–9 years living 

<900 m from a primary lead smelter, 380 children (96%) had blood cadmium (CdB) levels >0.0089 μg/L 

(Carvalho et al. 1986). The geometric mean and standard deviation were 0.087 μmol/L and 2.5, 

respectively. No significant relationship was found between parental occupation in the smelter and CdB 

in children, but a significant relationship was found between presence of smelter dross in the house and 

elevated CdB in children. Higher CdB was significantly associated with shorter distance from the home 

to the smelter. In a similar study of 263 children (ages 1–9 years), living <900 m from a primary lead 

smelter, the mean cadmium in hair was significantly higher at 6.0 ppm for children whose fathers worked 

in lead smelters than the concentration of 3.7 ppm for children whose fathers had other jobs (Carvalho et 

al. 1989). In a study of 9 children from families of lead workers and 195 children (ages 4–17 years) from 

other families, the children from the families of lead workers had significantly higher geometric mean 

urinary cadmium (CdU) (0.34 μg/L ±2.6) than children from other families (0.13 μg/L ±2.2). The CdB 

levels of children from families of lead workers were higher than those of the children from other 

families, but the difference was not statistically significant (Brockhaus et al. 1988). Maravelias et al. 

(1989) measured the CdBs of 514 children (ages 5–12) from four schools located within various distances 

(500–1500 m) from a lead smelter. The geometric mean and geometric standard deviation CdB was 

0.36 μg/L ±1.4, respectively, with a range of 0.1–3.1 μg/L. Children from the school closest to the 

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6. POTENTIAL FOR HUMAN EXPOSURE 

smelter had higher CdB levels than children from other schools, but no relationship was found between 

childrens’ CdB and parental employment in the smelter. 

The placenta may act as a partial barrier to fetal exposure to cadmium. Cadmium concentration has been 

found to be approximately half as high in cord blood as in maternal blood in several studies including 

both smoking and nonsmoking women (Kuhnert et al. 1982; Lauwerys et al. 1978; Truska et al. 1989). 

Accumulation of cadmium in the placenta at levels about 10 times higher than maternal blood cadmium 

concentration has been found in studies of women in Belgium (Roels et al. 1978) and the United States 

(Kuhnert et al. 1982); however, in a study in Czechoslovakia, the concentration of cadmium in the 

placenta was found to be less than in either maternal or cord blood (Truska et al. 1989). Baranowska 

(1995) also measured the concentrations of cadmium and lead in human placenta and in maternal and 

neonatal (cord) blood to assess the influence of a strongly polluted environment on the content of metals 

in tissues and on the permeability of the placenta to cadmium and lead. Samples for the study were 

collected from women living in the industrial district of Upper Silesia, one of the most polluted regions in 

Poland. The mean (range) concentration of cadmium in the air was 11.3 (2.1–25.4) ng/m3 

(0.0113 [0.0021–0.0254] μg/m3

). The mean concentrations of cadmium were 4.90 ng/mL 

(0.00490 μg/mL) in venous blood, 0.11 μg/g in placenta, and 1.13 ng/mL (0.00113 μg/mL) in cord blood. 

The researcher concluded that the placenta is a better barrier for cadmium than for lead, based upon the 

relative decrease in metal concentrations from placenta to cord blood. The mechanism by which the 

placenta transports the essential metals, copper and zinc, while limiting the transport of cadmium is 

unknown, but may involve the approximately 1,000-fold higher concentration of zinc in the placenta and 

the higher affinity of cadmium than zinc for metallothionein (Goyer and Cherian 1992). Timing and level 

of cadmium exposure may influence the uptake of cadmium by the placenta, perhaps explaining the 

conflicting human studies. Galicia-García et al. (1995) performed analyses of cadmium in maternal, cord, 

and newborn blood for 50 births in a Mexico City hospital. Multiple regression analyses applied to the 

data indicated a significant association between cord and newborn blood and between cord and maternal 

blood, but not among maternal and newborn blood. Birth weight of the newborns was found to be 

inversely associated with cord blood cadmium levels and smoking habits. 

6.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES 

The greatest potential for above-average exposure of the general population to cadmium is from smoking, 

which may double the exposure of a typical individual. Smokers who are exposed to cadmium in the 

workplace are at highest risk (CDC 2005). Individuals living near zinc or lead smelting operations, 

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municipal incinerators, or other industrial processes emitting cadmium to the air will also have aboveaverage exposure (Elinder 1985a). Exposures through inhalation are diminishing due to pollution 

controls at such facilities, but exposure resulting from soil contamination may continue to be significant. 

Persons who have corrosive drinking water and cadmium-containing plumbing, who habitually consume 

cadmium-concentrating foods (kidney, liver, and shellfish), or who ingest grains or vegetables grown in 

soils treated with municipal sludge or phosphate fertilizer all may have increased exposure (Elinder 

1985a). The 2004 NYC HANES indicated that the New York City Asian population, especially those 

born in China, had higher concentrations of cadmium in blood. The authors speculate that this might be 

due to higher consumption of fish and shellfish (McKelvey et al. 2007). 

Multiple pathways of exposure may exist for populations at hazardous waste sites contaminated with 

cadmium (ingestion of contaminated drinking water or garden vegetables, inhalation of airborne dust, 

incidental ingestion of contaminated soil). 

Persons who consume large quantities of sunflower kernels can be exposed to higher levels of cadmium. 

Reeves and Vanderpool (1997) identified specific groups of men who were likely to consume sunflower 

kernels. The groups included baseball and softball players, delivery and long-distance drivers, and line 

workers in sunflower kernel processing plants. 

Recreational and subsistence fishers that consume appreciably higher amounts of locally caught fish from 

contaminated waterbodies may be exposed to higher levels of cadmium associated with dietary intake 

(EPA 1993a). Cadmium contamination has triggered the issuance of several human health advisories. As 

of December 1997, cadmium was identified as the causative pollutant in five fish and shellfish 

consumption advisories in New York and another in New Jersey. EPA is considering including cadmium 

as a target analyte and has recommended that this metal be monitored in fish and shellfish tissue samples 

collected as part of state toxics monitoring programs. EPA recommends that residue data obtained from 

these monitoring programs be used by states to conduct risk assessments to determine the need for issuing 

fish and shellfish consumption advisories for the protection of the general public as well as recreational 

and subsistence fishers. Under the same program, EPA has issued a statewide advisory in Maine for 

cadmium in moose (EPA 1998). 

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6.8 ADEQUACY OF THE DATABASE 

Section 104(i)(5) of CERCLA, as amended, directs the Administrator of ATSDR (in consultation with the 

Administrator of EPA and agencies and programs of the Public Health Service) to assess whether 

adequate information on the health effects of cadmium is available. Where adequate information is not 

available, ATSDR, in conjunction with NTP, is required to assure the initiation of a program of research 

designed to determine the health effects (and techniques for developing methods to determine such health 

effects) of cadmium. 

The following categories of possible data needs have been identified by a joint team of scientists from 

ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that if met would 

reduce the uncertainties of human health assessment. This definition should not be interpreted to mean 

that all data needs discussed in this section must be filled. In the future, the identified data needs will be 

evaluated and prioritized, and a substance-specific research agenda will be proposed. 

6.8.1 Identification of Data Needs 

Physical and Chemical Properties. The chemical and physical properties of cadmium and its salts 

are known well enough to permit estimation of the environmental fate of the compounds (Elinder 1985a, 

1992). Additional information on properties does not appear to be crucial for evaluating potential fate. 

Production, Import/Export, Use, Release, and Disposal. According to the Emergency 

Planning and Community Right-to-Know Act of 1986, 42 U.S.C. Section 11023, industries are required 

to submit substance release and off-site transfer information to the EPA. The TRI, which contains this 

information for 2006, became available in February of 2008. This database is updated yearly and should 

provide a list of industrial production facilities and emissions. 

The production volume, producers, import/export quantities, and uses of cadmium in the United States are 

well documented (SRI 2007; USGS 2007, 2008). Recycling of cadmium from spent batteries is 

increasing, and there are some data to suggest that there is still a large portion of cadmium being disposed 

of as municipal waste (USGS 2007). More data concerning the amount of municipal disposal would be 

helpful. Disposal of cadmium-containing wastes is regulated by the federal government, and data are 

available for industrial disposal practices (EPA 1982a; HSDB 2008; U.S. Bureau of Mines 1990). Most 

releases of cadmium are not from production of the metal or its compounds, but from combustion or 

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CADMIUM 308 

6. POTENTIAL FOR HUMAN EXPOSURE 

smelter emissions, land application of sewage sludge and fertilizers, and other sources; estimates of these 

releases have been made (TRI06 2008). 

Environmental Fate. Cadmium partitioning among media occurs, and this partitioning depends on 

local environmental conditions (Elinder 1985a, 1992). Cadmium may be subject to long-range transport 

in air and water (EPA 1980d). Cadmium is persistent in all media, although it may form organic 

complexes in soil and water under certain environmental conditions (EPA 1979). These processes, which 

are important for determining the environmental fate of cadmium, seem to be relatively well understood. 

Therefore, additional information on environmental fate does not appear to be essential to evaluate 

potential human exposure to cadmium. 

Bioavailability from Environmental Media. Factors that control the bioavailability of cadmium 

from air, water, soil, and food have been investigated. Intestinal absorption of cadmium from food is low, 

about 5–10% (McLellan et al. 1978; Newton et al. 1984; Rahola et al. 1973), but the absorption of 

cadmium from soil is not known. Absorption from the lungs is somewhat greater, averaging about 25% 

(Nordberg et al. 1985). Estimates of dermal absorption of cadmium from soil and water on human skin 

have been made (Wester et al. 1992). There is some evidence that bioavailability of cadmium to plants 

and worms from contaminated soil is greater following remediation (Van Gestel et al. 1988). Additional 

information on the factors influencing bioavailability, particularly from remediated soil, are needed to 

assess residual risk to populations in the vicinity of reclaimed hazardous waste sites. 

Food Chain Bioaccumulation. Sufficient data are available to indicate that cadmium is 

concentrated in plants, aquatic organisms, and animals (Alloway et al. 1990; Beyer 1986; Handy 1992a, 

1992b; Kuroshima 1992; Naqvi and Howell 1993; Roseman et al. 1994; Suresh et al. 1993; Vos et al. 

1990). In vertebrates, cadmium accumulates in the liver and kidneys (Harrison and Klaverkamp 1990; 

Sileo and Beyer 1985; Vos et al. 1990). There is strong evidence for food chain bioaccumulation, but the 

potential for biomagnification is uncertain. Additional studies on biomagnification are needed to provide 

data for more accurate evaluation of the environmental impact of cadmium contamination. 

Exposure Levels in Environmental Media. Reliable monitoring data for the levels of cadmium in 

contaminated media at hazardous waste sites are needed so that the information obtained on levels of 

cadmium in the environment can be used in combination with the known body burden of cadmium to 

assess the potential risk of adverse health effects in populations living in the vicinity of hazardous waste 

sites. 

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CADMIUM 309 

6. POTENTIAL FOR HUMAN EXPOSURE 

Current ambient air quality surveys testing for cadmium concentrations in rural and urban locations in the 

United States is lacking. Since the major source of exposure to cadmium is through dietary intake and 

since cadmium emissions to air are not expected to increase, there may be less interest in these data. 

There are several long-range atmospheric transport studies, but since these were conducted Europe and 

Russia, they only illustrate the potential for cadmium contamination via atmospheric deposition in the 

United States (Reimann et al. 1997; Shevchenko et al. 2003; Vidovic et al. 2005). There is also minimal 

data on current levels of cadmium in agricultural soils of the United States and the identification of the 

sources of cadmium levels, whether they are native geochemistry, phosphate fertilizers, atmospheric 

deposition, etc. (Xue et al. 2000). Continuing monitoring efforts in all media would allow more precise 

estimation of current sources and levels of human exposure and would assist in identifying major sources 

contributing to current exposure. 

Exposure Levels in Humans. Cadmium has been detected in human blood, urine, breast milk, 

liver, kidney, and other tissues, both in occupationally exposed individuals and in the general population 

(CDC 2005; McKelvey et al. 2007; NTP 2005; OSHA 1990). The NHANES and NYC HANES provide 

current data on the levels of cadmium in humans (CDC 2005; McKelvey et al. 2007). Other large-scale 

surveys concentrating on urban, agricultural, and suburban communities would be beneficial in 

understanding cadmium exposure to the U.S. population. Also, more information is needed on the 

specific exposure levels for different cadmium salts to determine if cadmium sulfides, for example, are 

associated with less harmful effects than cadmium oxides (Chettle and Ellis 1992). 

This information is necessary for assessing the need to conduct health studies on these populations. 

Exposures of Children. Cadmium has been measured in maternal and neonatal (cord) blood and in 

placenta (Baranowska 1995; Galicia-García et al. 1995; Kuhnert et al. 1982; Lauwerys et al. 1978; Roels 

et al. 1978; Truska et al. 1989), but the resulting data are sometimes conflicting with respect to the uptake 

of cadmium by the placenta. Research on the effects of timing and level of exposure on cadmium uptake 

by the placenta might help to explain these conflicting human studies. More recent data would be useful, 

both from women and children living in unpolluted areas (for background levels) and in polluted areas 

such as those near existing or former lead smelters. 

There are some current data concerning cadmium exposure in children (Capar and Cunningham 2000; 

CDC 2005; Pellizzari et al. 1999). The NHANES 1999–2002 reported cadmium levels in blood (see 

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CADMIUM 310 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-4) and urine (see Table 6-5) for children in different age groups (CDC 2005). The NYC HANES 

did not test for blood cadmium levels in children, although the blood cadmium levels in adults were 

slightly higher than the national average (McKelvey et al. 2007). Results of the U.S. FDA Total Diet 

Study (Capar and Cunningham 2000) reported cadmium levels in infant and junior foods ranged from no 

detection to 0.090 mg/kg. According to the NHEXAS, children in EPA Region V (Great Lakes Region) 

have a mean dietary cadmium exposure of 17 (±1.8) μg/kg for minority children and 21 (±2.2) μg/kg for 

non-minority children (Pellizzari et al. 1999). 

Some body burden data are available for children living near lead smelters (Lagerkvist and Lundstrom 

2004; Leroyer et al. 2001; Jin et al. 2002). However, none of the studies took place in the United States. 

Body burden data from children living in polluted and unpolluted regions (for background levels) of the 

United States are needed. 

Current information on whether children are different in their weight-adjusted intake of cadmium via oral, 

inhalation, and dermal exposures was not located. A study to determine this information would be useful. 

Also, no information was found on childhood specific means to reduce cadmium exposure. 

Child health data needs relating to susceptibility are discussed in Section 3.12.2, Identification of Data 

Needs: Children’s Susceptibility. 

Exposure Registries. The State of New York has established the Heavy Metals Registry for 

surveillance of occupational heavy metals absorption. Cadmium levels >10 μg/L in blood and 5 μg/L in 

urine are reported to the registry. The number of adults with reportable levels has varies per year, but 

there have always been <50 adults reported per year. Between 1995 and 2003, the number of reportable 

adults was <5, and these exposures are do mostly to exposure for people working as jewelers and casting 

machine operators (NYS Dept of Health 2006). 

No other exposure registries for cadmium were located. This substance is not currently one of the 

compounds for which a subregistry has been established in the National Exposure Registry. The 

substance will be considered in the future when chemical selection is made for subregistries to be 

established. The information that is amassed in the National Exposure Registry facilitates the 

epidemiological research needed to assess adverse health outcomes that may be related to exposure to this 

substance. 

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CADMIUM 311 

6. POTENTIAL FOR HUMAN EXPOSURE 

6.8.2 Ongoing Studies 

The Federal Research in Progress (FEDRIP 2008) database provides additional information obtainable 

from a few ongoing studies that may fill in some of the data needs identified in Section 6.8.1. These 

studies are summarized in Table 6-10. 

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CADMIUM 312 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-10. Ongoing Studies on Cadmium 

Investigator Affiliation Research description Sponsor 

Birnbaum ER 

Chen Z 

Dweik BM 

Fallin MD 

Fox MA 

Larkin PM 

Mo J 

Polette-Niewold 

LA 

Santra S 

Basta N; Raun 

WR 

Basta NT 

Basta NT; Lower 

SK; Lanno R 

Bleam WF; 

Helmke PA 

Chaney RL 

Chaney RL 

Caldera 

Pharmaceuticals, 

Inc., Los Alamos, 

New Mexico 

X-Ray Optical 

Systems, Inc. 

East Greenbush, 

New York 

Giner, Inc., 

Newton, 

Massachusetts 

Johns Hopkins 

University, 

Baltimore, 

Maryland 

Johns Hopkins 

University, 

Baltimore, 

Maryland 

Ecoarray, Inc. 

Alachua, Florida 

Kumetrix, Inc, 

Union City, 

California 

Mayan Pigments, 

Inc. 

University of 

Central Florida 

Oklahoma State 

University 

Oklahoma State 

University 

Ohio State 

University 

University of 

Wisconsin 

Beltsville 

Agricultural 

Research Center 

Beltsville 

Agricultural 

Research Center 

Biomarkers of response to environmental 

stressors 

Direct measurement of trace elements in 

body fluids 

Field-deployable monitor to assess personal 

exposure to multiple heavy metals 

AGE-related epigenetic changes ­

environmental causes and disease 

consequences 

Environmental exposure to metal mixtures 

and kidney disease 

Developing and using sheepshead minnow 

microarrays for ecotoxicology 

Automatic multi-analyte in-situ bioassay for 

monitoring exposure to toxic metals 

SBIR phase II: One-step environmentallyfriendly synthesis of novel organic/inorganic 

hybrid pigments 

Selective detection of toxic heavy metal ions 

using highly sensitive quantum dot probes 

Chemistry and bioavailability of waste 

constituents in soils 

Heavy metal and trace element chemistry in 

soils: Chemical speciation and bioavailability 

Heavy metal and trace element 

biogeochemistry in soils: Chemical 

speciation, bioavailability, and toxicity 

Verifying and quantifying the specific 

complexation of metals to humic substances 

Characterization and remediation of potential 

trace element and phosphate risks from 

contaminated soils 

Risk assessment and remediation of soil and 

amendment trace elements 

National Institute of 

Environmental 

Health Sciences 

National Center for 

Research 

Resources 

National Institute of 

Environmental 

Health Sciences 

National Institute of 

Environmental 

Health Sciences 

National Institute of 

Environmental 

Health Sciences 

National Institute of 

Environmental 

Health Sciences 

National Institute of 

Environmental 

Health Sciences 

National Science 

Foundation 

National Science 

Foundation 

U.S. Department of 

Agriculture 

U.S. Department of 

Agriculture 

U.S. Department of 

Agriculture 

U.S. Department of 

Agriculture 

U.S. Department of 

Agriculture 

U.S. Department of 

Agriculture 

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CADMIUM 

6. POTENTIAL FOR HUMAN EXPOSURE 

313 

Investigator 

Table 6-10. Ongoing Studies on Cadmium 

Affiliation Research description Sponsor 

Chaney RL; Virginia Effects of long-term biosolids applications on U.S. Department of 

Daniels WL Polytechnic phytoavailability of soil cadmium and zinc Agriculture 

Institute 

Chang AC; Page University of Chemistry and bioavailability of waste U.S. Department of 

AL California, constituents in soils Agriculture 

Riverside 

Eick MJ Virginia Trace element and ligand adsorption/ U.S. Department of 

Polytechnic desorption from soil constituent surfaces Agriculture 

Institute 

Hopkins DG North Dakota Influence of geologic materials and pedogenic U.S. Department of 

State University processes on trace elements in soil Agriculture 

landscapes 

Hunt JR; Lykken University of Whole body counting and radiotracer U.S. Department of 

GI North Dakota methods in research on mineral requirements Agriculture 

in human nutrition 

Kpomblekou- Tuskegee Trace elements in broiler littered soils: Fate U.S. Department of 

Ademawou K; University and effects on nitrogen transformation Agriculture 

Ankumah RO 

Martinez CE Pennsylvania Chemical and biogeochemical processes U.S. Department of 

State University involved in trace and toxic element cycling in Agriculture 

soils 

Morrissey MT Oregon State Characterization of the cadmium health risk, U.S. Department of 

University concentrations and ways to minimize Agriculture 

cadmium residues in shellfish 

Schwab AP; Purdue University Chemistry and bioavailability of waste U.S. Department of 

Joern B; Johnston constituents in soils Agriculture 

C 

Sparks DL University of Rates and mechanisms of metal and U.S. Department of 

Delaware metalloid sorption/surfaces Agriculture 

Thomas, DG; Oklahoma State Maternal dietary nutrients and neurotoxins in U.S. Department of 

Kennedy TS University infant cognitive development Agriculture 

Williams PL	 University of Environmental health impacts of soil U.S. Department of 

Georgia contamination Agriculture 

National Risk Biomonitoring of source water quality U.S. Environmental 

Management Protection Agency 

Research 

Laboratory 

Petterson L	 National Efficient monitoring of heterogeneous media U.S. Environmental 

Exposure and electronic wastes Protection Agency 

Research Lab 

Environmental 

Sciences Division 

Characterization 

and Monitoring 

Branch 

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CADMIUM 314 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-10. Ongoing Studies on Cadmium 

Investigator Affiliation Research description Sponsor 

Petterson L National Geochemical and interfacial applications for U.S. Environmental 

Exposure assessing ecological toxicant exposures Protection Agency 

Research Lab 

Ecosystems 

Research Division 

Ecosystems 

Assessment 

Branch 

Nolan P Office of Regional Lower Merrimack River fish tissue study U.S. Environmental 

Administrator Protection Agency 

Office of 

Environmental 

Measurement and 

Evaluation 

Janes D Office of Risks of heavy metals to aquatic organisms U.S. Environmental 

Research and from multiple exposure routes Protection Agency 

Development 

National Health 

and 

Environmental 

Effects Research 

Lab MidContinent 

Ecology Division 

Sources: FEDRIP 2008; SI/EPA 2007 

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CADMIUM 315 

7. ANALYTICAL METHODS 

The purpose of this chapter is to describe the analytical methods that are available for detecting, 

measuring, and/or monitoring cadmium, its metabolites, and other biomarkers of exposure and effect to 

cadmium. The intent is not to provide an exhaustive list of analytical methods. Rather, the intention is to 

identify well-established methods that are used as the standard methods of analysis. Many of the 

analytical methods used for environmental samples are the methods approved by federal agencies and 

organizations such as EPA and the National Institute for Occupational Safety and Health (NIOSH). Other 

methods presented in this chapter are those that are approved by groups such as the Association of 

Official Analytical Chemists (AOAC) and the American Public Health Association (APHA). 

Additionally, analytical methods are included that modify previously used methods to obtain lower 

detection limits and/or to improve accuracy and precision. 

7.1 BIOLOGICAL MATERIALS 

The most common analytical procedures for measuring cadmium concentrations in biological samples use 

the methods of atomic absorption spectroscopy (AAS) and atomic emission spectroscopy (AES). In AAS 

analysis, the sample is heated by a flame or in a furnace until the element atomizes. In AES analysis, the 

emitted radiation resulting from the thermal energy from a flame or inductively coupled plasma discharge 

(ICP) is measured. These basic methods of analysis are well defined and generally accepted for the 

analysis of cadmium. 

Samples are prepared for AAS and AES methods in a variety of ways. Digestion with nitric acid is most 

common (Roberts and Clark 1986; Sharma et al. 1982). Cadmium in blood and plasma measured by 

graphite furnace atomic absorption spectroscopy (GFAAS) facilitated by a wet ashing pretreatment of 

samples resulted in good accuracy and reproducibility. The sample detection limit using this method was 

0.4 μg/L (Roberts and Clark 1986). This method was also precise and highly reproducible in determining 

cadmium in whole blood, urine, and hair with 99–99.4% recoveries reported (Sharma et al. 1982). The 

matrix may also be modified with diammonium hydrogen phosphate or other agents such as palladium 

(Pd)-based modifiers (Moreira et al. 1995). Detection limits as low as 0.1 μg/L with recoveries ranging 

from 93 to 111% are reported using this technique (Subramanian and Meranger 1981; Subramanian et al. 

1983). If the concentration of cadmium in the dissolved sample is below the detection limit, 

preconcentration techniques, such as chelation and extraction, may be employed (Gross et al. 1976; 

Sharma et al. 1982). Since cadmium is a ubiquitous element, the risk of contamination during sampling, 

processing, and analysis must be minimized by strict laboratory procedures (Elinder and Lind 1985). In 

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CADMIUM 316 

7. ANALYTICAL METHODS 

procedures for micro-determination, all glass and plastic-ware should be acid-washed and subsequently 

rinsed with double-distilled water. 

Current analytical improvements deal primarily with the methods of sample preparation and sample 

introduction to the analytical systems in order to lower the detection limits or decrease sample analysis 

time. Various improvements in the methods of extraction, preconcentration, chelation, complexation, and 

sample introduction have been developed for use with biological media. Detection limits as low as 

0.003 μg/L were reported (Espinosa Almendro et al. 1992; Cordero et al. 1994; Jeng et al. 1994; Katskov 

et al. 1994; Komárek et al. 1991; Ma et al. 1994b; Welz et al. 1991). 

The cadmium concentration in biological samples may also be measured by a number of other methods 

such as radiochemical neutron activation analysis (RNAA). One RNAA procedure involving a rapid 

two-step solvent extraction was used for determining cadmium in tissue samples (Tandon et al. 1994). 

Another method to determine cadmium in biological materials is based on the ion-exchange scheme 

developed by SAMSAHL where cadmium is trapped on an anion exchange resin. With this method, 

recovery of 98% and a detection limit of 4 μg/kg were reported. The accuracy of the method was 

estimated by three different approaches: analysis using radiotracers in inactive sample solutions; by 

analyzing standards, pipetted on filter paper, and processed as samples; and determination by RNAA 

(Woittiez and Tangonan 1992). 

Cadmium concentration in tissue may be measured both in vivo (Ellis 1985; Scott and Chettle 1986) and 

in vitro (Lieberman and Kramer 1970) by neutron activation analysis (NAA). Direct in vivo assessment 

of body burden in humans focused on the measurements of cadmium in the kidney and liver by NAA. 

The detection limits reported are approximately 2 mg cadmium for the total kidney and 1.5 μg/g for the 

liver (Ellis 1985); 1.9 mg cadmium for the kidney; and 1.3 μg/g for the liver (Scott and Chettle 1986). 

X-ray fluorescence is also used for in vivo measurement of cadmium in the kidney (Christoffersson et al. 

1987; Nilsson and Skerfving 1993; Scott and Chettle 1986; Skerfving and Nilsson 1992). The in vivo 

techniques are used for clinical measurements of individuals occupationally exposed to cadmium. 

Additional methods applicable to the analysis of cadmium in biological media include inductively 

coupled plasma/mass spectrometry (ICP/MS) (Stroh 1993; Vanhoe et al. 1994) and high performance 

liquid chromatography (HPLC) (Chang and Robinson 1993; Steenkamp and Coetzee 1994). 

Electrothemal vaporization ICP/MS has been utilized for the analysis of dentin and enamel from teeth 

(Grünke et al. 1996). Electrochemical methods such as adsorptive cathodic stripping voltametry (ACSV) 

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CADMIUM 317 

7. ANALYTICAL METHODS 

and potentiometric stripping analysis (PSA) have been applied to hair analysis (Zhang et al. 1993), animal 

tissues (LaBar and Lamberts 1994), and body fluids (Ostapczuk 1993). 

Table 7-1 summarizes some of the methods used for sample preparation and analysis of cadmium in 

biological samples. 

7.2 ENVIRONMENTAL SAMPLES 

Analysis for cadmium in environmental samples is usually accomplished by AAS or AES techniques, 

with samples prepared by digestion with acid, preconcentrated with a chelating resin, or direct aspiration 

with no preparation (APHA 1977a, 1977b; EPA 1983a, 1983b, 1997b; OSHA 2002a, 2004; USGS 1985). 

Since cadmium in air is usually associated with particulate matter, standard methods involve collection of 

air samples on glass fiber or membrane filters, acid extraction of the filters, and subsequent (APHA 

1977a, 1977b; OSHA 2002a, 2002b). Inductively-coupled plasma spectrometry (ICP) analysis in 

standard methods is also popular. ICP analysis for water and air samples can be run in tandem with mass 

spectrometry (MS) or AES (EPA 1996b, 1997b, 2003b; NIOSH 2003; OSHA 2002b). ACSV (Nimmo 

and Fones 1994), differential pulse anodic stripping voltametry (DP-ASV) (Nam et al. 1994), and 

epithermal NAA (Landsberger and Wu 1993) have also been used for air analysis. The accuracy of the 

analysis of cadmium in acid digested atmospheric samples, measured by ACSV, was evaluated and 

compared with GFAAS and ICP/MS. The ASCV limit of detection for cadmium was 0.6 ng/mL, higher 

than that of GFAAS at 0.3 ng/mL, but lower than that of ICP-MS for a 1-minute collection period. 

ACSV has advantages for analysis of low concentrations of cadmium in aerosol acid digest samples 

(Nimmo and Fones 1994). 

Several methods standardized by EPA (1983a, 1983b, 1994b, 1996a, 1996b, 1997b, 2000, 2003b) are 

used for measuring concentrations of cadmium in water. Techniques to compensate for chemical and 

matrix interferences in all three methods are described by EPA (1983a, 1983b, 1994b, 1996a, 1996b, 

1997b, 2000, 2003b). After soils and solid wastes are extracted or solubilized by acid digestion, they may 

be analyzed for cadmium by the same AAS methods that are used for water (EPA 1986d, 1986e). Water 

can also be analyzed for cadmium by NAA methods (Saleh et al. 1993), PSA methods (Ostapczuk 1993), 

and anodic stripping voltametry (ASV) (Daih and Huang 1992). 

Sediment and soil samples have been analyzed for cadmium using the methods of GFAAS (Klemm and 

Bombach 1995). Preparation of the samples is generally accomplished by treatment with HCl and HNO3. 

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CADMIUM 318 

7. ANALYTICAL METHODS 

Table 7-1. Analytical Methods for Determining Cadmium in Biological Materials 

Sample matrix Preparation method 

Analytical 

method 

Sample 

detection 

limit 

Percent 

recovery Reference 

Blood Digestion with nitric acid; 

chelation with APDC and 

AAS <1 ng/mLa 99 Sharma et al. 

1982 

extraction with MIBK 

Blood Modification of matrix with 

diammonium hydrogen 

phosphate/Triton X-100 

GFAAS 0.1 μg/L 100.8±4.3 Subramanian 

and Meranger 

1981 

Blood/plasma Digestion with nitric acid; wet 

ashed 

GFAAS 0.4 μg/L No data Roberts and 

Clark 1986 

Serum Dilution with ammonia/Triton 

X-100 

ICP/MS 0.01 ng/mL No data Stroh 1993 

Tissue and blood Microwave digestion FAAS/flow 

injection 

system 

0.15 μg/L No data Welz et al. 

1991 

Human milk Dilution with deionized and 

double distilled water 

AAS <0.01 ppba No data SchulteLobbert and 

Bohn 1977 

Hair Digestion with nitric acid AAS 0.07 μg/ga 99 Sharma et al. 

1982 

Kidney None (in vivo) XRF 170.1 μg/g No data Christoffersson 

et al. 1987 

Kidney/liver Chelation and extraction with 

solvent 

AAS/direct 

aspiration 

0.01 ppma 

(liver) 

1.9 mg 

(kidney) 

No data Gross et al. 

1976 

Kidney/liver None (in vivo) NAA 1.3 μg/g 

(liver) 

1.9 mg 

(kidney) 

No data Scott and 

Chettle 1986 

Muscle Wet ashed with concentrated 

sulfuric acid 

NAA 50 ppb 50–65 Lieberman and 

Kramer 1970 

Urine Dilution with nitric acid ETAAS 0.045 μg/L 97–101 Komárek et al. 

1991 

Urine Modification of matrix with 

diammonium hydrogen 

phosphate/nitric acid 

GFAAS 0.09 ng/mL 92.7–111.1 Subramanian 

et al. 1983 

Urine Digestion with nitric acid AAS 5.67 ng/mLa 99.4 Sharma et al. 

1982 

Biological 

materials 

Microwave digestion followed 

by extraction with APTH in 

MlBK 

ICP/AES 0.15 ng/mL No data Cordero et al. 

1994 

Biological 

materials 

Digestion with acid GFAAS/flow 

injection 

system 

0.003 μg/L No data Ma et al. 1994a 

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CADMIUM 319 

7. ANALYTICAL METHODS 

Table 7-1. Analytical Methods for Determining Cadmium in Biological Materials 

Sample matrix Preparation method 

Analytical 

method 

Sample 

detection 

limit 

Percent 

recovery Reference 

Biological fluids 

(blood, urine) 

Acidification PSA 0.001 μg/kg No data Ostapczuk 

1993 

Biological 

materials 

Dry tissues; irradiation 

followed by acid digestion 

RNAA 4 μg/kg 98 Woittiez et al. 

1992 

Teeth, dentin, 

and enalmel 

Digested in nitric acid, diluted ETV-ICP-MS 

with water PN-ICP-MS 

No data No data Grünke et al. 

1996 

Whole blood, 

urine 

Modified with palladium 

based modifier 

ETAAS 0.22 μg/L No data Moreira et al. 

1995 

Biological 

materials 

Digested with nitric acid and 

hydrogen peroxide 

B-9001-95; 

ICP-AES 

No data 93 USGS 1996 

a

Lowest concentration found 

AAS = atomic absorption spectroscopy; APDC = ammonium pyrrolidenedithiocarbamate; APTH = 13-bis[-(2­

pyridyl)ethylidene]thiocarbonhydride; ETAAS = electrothermal atomic absorption spectroscopy; FAAS = flame atomic 

absorption; GFAAS = graphite furnace atomic absorption; ICPIAES = inductively coupled plasma atomic emission 

spectroscopy; ICPIMS = inductively coupled plasma mass spectrometry; MlBK = methyl isobutyl ketone; 

NAA = neutron activation analysis; PSA = potentiometric stripping analysis; RNAA = radio chemical neutron 

activation analysis; XRF = x-ray fluorescence 

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CADMIUM 320 

7. ANALYTICAL METHODS 

The most common method for analysis of cadmium in foods is AAS (Bruhn and Franke 1976; Dabeka 

1979; Muys 1984), with GFAAS being one of the most common AAS methods used (Cabrera et al. 

1995). The FDA’s Total Diet Study 1991–1996 analyzed cadmium and other element concentrations in 

food by dry ash mineralization and GFAAS (Capar and Cunningham 2000). RNAA (Greenberg et al. 

1979), differential pulse ASV (Satzger et al. 1982, 1984), and the calorimetric dithizone method (AOAC 

1984) may also be employed. The AAS techniques appear to be most sensitive, with recoveries ranging 

from 94 to 109% (Bruhn and Franke 1976; Muys 1984). A method used to isolate cadmium by first 

extracting with bismuth diethyldithiocarbamate (Bi[DDC]3) and then with zinc diethyldithiocarbamate 

(Zn[DDC]2) in chloroform and then measuring by RNAA showed 94–106% recovery (Greenberg et al. 

1979). 

Table 7-2 summarizes some of the methods used for sample preparation and analysis of cadmium in 

environmental samples. 

7.3 ADEQUACY OF THE DATABASE 

Section 104(i)(5) of CERCLA, as amended, directs the Administrator of ATSDR (in consultation with the 

Administrator of EPA and agencies and programs of the Public Health Service) to assess whether 

adequate information on the health effects of cadmium is available. Where adequate information is not 

available, ATSDR, in conjunction with NTP, is required to assure the initiation of a program of research 

designed to determine the health effects (and techniques for developing methods to determine such health 

effects) of cadmium. 

The following categories of possible data needs have been identified by a joint team of scientists from 

ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that if met would 

reduce the uncertainties of human health assessment. This definition should not be interpreted to mean 

that all data needs discussed in this section must be filled. In the future, the identified data needs will be 

evaluated and prioritized, and a substance-specific research agenda will be proposed. 

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CADMIUM	 321 

7. ANALYTICAL METHODS 

Table 7-2. Analytical Methods for Determining Cadmium in Environmental
 

Samples
 

Sample Analytical Sample Percent 

matrix Preparation method method detection limit recovery Reference 

Air	 Collection on glass fiber Method 0.005 μg/m3 90 APHA 1977b 

filter; ashed with 311; AAS 

hydrochloric and nitric 

acids 

Air	 Collection on membrane Method 0.05 μg per No data NlOSH 1994 

filter; ashed with 7048; AAS sample 

hydrochloric and nitric 

acids 

Air	 Collection on membrane Method 0.3 ng/mL 99.8– NIOSH 2003 

filter; digestion with nitric 7300; ICP 105.2 

acid and perchloric acid 

Air	 Collection using filters, Method 0.004 μg/mL 99.5 OSHA 2002a 

wipes, or bulk materials; 121; 

desorbed with water AAS/AES 

extractions and mineral 

acid digestions 

Air	 Collection on membrane Method 0.14 μga No data OSHA 2002b 

filter; digested in nitric 125G; 0.47 μgb 

acid, sulfuric acid, and ICP-AES 

hydrogen peroxide 

Air	 Collection on membrane Method 0.2 μg/m3 (AAS)a No data OSHA 2004 

filter; digested with nitric 189; AAS/ 0.70 μg/m3 (AAS)b 

acid and small amounts of AAS-HGA 0.007μg/m3 (AAShydrochloric acid HGA)a 

0.025 μg/m3 

(AAS-HGA)b 

Air	 Collection on membrane Method 0.0062 μg/mLa No data OSHA 1991 

filter, wipe, or bulk 206; ICP- 0.0205 μg/mLb 

material; digest with nitric AES 

and hydrochloric acids 

Air	 Irradiation UF filters Epithermal 8 ng No data Landsberger et al. 

NAA 1993 

Air Acid digestion with filters ACSV 0.6 ng/mL 100 Nimmo and Fones 

(aerosols) 1994 

Atmospheric Direct analysis ETV-ICP- pg/m3 range No data Lüdke et al. 1997 

particles MS 

Water Digestion with nitric acid	 Method 5 μg/L 94±24 EPA 1983a 

213.1; 

AAS/direct 

aspiration 

Water Digestion with nitric acid	 Method 0.1 μg/L 96–99 EPA 1983b 

213.2; 

AAS/ 

GFAAS 

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CADMIUM	 322 

7. ANALYTICAL METHODS 

Table 7-2. Analytical Methods for Determining Cadmium in Environmental
 

Samples
 

Sample Analytical Sample Percent 

matrix Preparation method method detection limit recovery Reference 

Water	 On-line preconcentration GFAAS/ 0.8 ng/L No data Welz et al. 1992 

with ion exchange or flow 

sorbent extraction injection 

columns system 

Water Digestion with nitric acid	 Method 0.0075 μg/L No data EPA 1996a 

1637; 

chelation 

and 

GFAAS 

Water Digestion with nitric acid	 Method 0.025 μg/L No data EPA 1996b 

1638; ICPMS 

Water	 Preconcentrated with Method 0.0024 μg/L No data EPA 1997b 

chelating resin	 1640;
 

Online 

Chelation/
 

ICP-MS
 

Water	 Digested with hydrochloric Method 0.1 μg/L 98±1.1 EPA 2003 

and nitric acids	 200.5;
 

AVICPAES
 

Water and Digestion with acids Method 1 μg/L (aqueous); 82–98 EPA 1994a 

Wastes 200.7; 0.2 mg/kg (solids) 

ICP-AES 

Various Digestion with nitric and Method No data 97 EPA 2000 

hydrochloric acids 6010C; 

ICP-AES 

Water and No preconcentration or I-1135; 10 μg/L No data USGS 1985 

sediments pretreatment AAS 

Water Digested with whole water I-4471-97; 5 μg/L No data USGS 1998a 

ICP-OES 

Various	 Direct aspiration with no I-5135; 10 μg/L No data USGS 1985 

preconcentration or AAS 

pretreatment 

Soil Digestion with nitric acid	 Method 0.005 mg/L No data EPA 1986e 

7130; 

AAS/direct 

aspiration 

Soil Digestion with nitric acid	 Method 0.1 μg/L No data EPA 1986d 

7131; 

GFAAS 

Soil and Ultrasonic slurry in dilute GFAAS No data 100±10 Klemm and Bombach 

sediment nitric acid 1995 

Sediment	 Digestion with LEAFS 500 fg No data Zhou et al. 1998 

hydrochloric and nitric 

acid 

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CADMIUM 323 

7. ANALYTICAL METHODS 

Table 7-2. Analytical Methods for Determining Cadmium in Environmental
 

Samples
 

Sample Analytical Sample Percent 

matrix Preparation method method detection limit recovery Reference 

Soil and Digestion with hydrofluoric GFAAS/ 0.8 μg/L No data Ma et al. 1994b 

sediment acid and nitric acid; flow 

complexation with DDPA injection 

using on-line sorbent system 

extraction system 

Food Dry ashed; oxidization ASV/ 1 ng/g 99–108 Satzger et al. 1984 

with nitric acid differential 

pulse 

Food Dry ashed; complexation AAS 0.1 ng/g 97.5±2.5 Bruhn and Franke 

with APCD; extraction 1976 

with isoamyl acetate 

Food Extraction with Bi(DDC)3 RNAA 0.029 μg/gc 94–106 Greenberg et al. 1979 

then with Zn(DDC)2 in 

chloroform 

Food Microwave digestion with GFAAS 0.004 μg/g 94–101 Yang et al. 1995 

(24 hour nitric acid and hydrogen 

diet) peroxide 

Food Dry ashed; complexation GFAAS 0.1 ppbc 94–109 Muys 1984 

with NaDDTC; extraction 

with IBMK 

Food Homogenization followed GFAAS 0.01 ppb 94–108 Zhang et al. 1997 

by wet ashing 

Fruit Homogenized fruit slurried ETAAS 0.3 ng/g 97.7±0.3 Cabrera et al. 1995 

with zirconia 

a

Qualitative detection limit

b

Quantitative detection limit 

c

Lowest concentration found 

AAS = atomic absorption spectroscopy; ACSV = adsorptive cathodic stripping voltametry; APCD = ammonium 

pyrrolidino carbodithioate; ASV = anodic stripping voltametry; AVICP-AES = axially viewed inductively coupled 

plasma-atomic emission spectrometry; Bi(DDC)3 = bismuth diethyldithiocarbamate; DDPA = ammonium 

diethyldithiophosphate; ETV-ICP-MS = electrothermal vaporization inductively coupled plasma mass spectrometry; 

GFAAS = graphite furnace atomic absorption; HGA = heated graphite atomizer; IBMK = isobutyl methyl ketone; 

ICP = inductively coupled plasma; LEAFS = laser-excited atomic fluorescence spectrometry; MS = mass 

spectrometry; NAA = neutron activation analysis; NaDDTC = sodiumdiethyl-dithiocarbomate; OES = optical emission 

spectroscopy; RNAA = radiochemical neutron activation analysis; Zn(DDC)2 = zinc diethyldithiocarbamate 

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CADMIUM 324 

7. ANALYTICAL METHODS 

7.3.1 Identification of Data Needs 

Methods for Determining Biomarkers of Exposure and Effect. 

Exposure. Measurements of cadmium in liver and kidney are all useful biological indices for human 

exposure to cadmium (Roels et al. 1981b). Human milk, human placentas, and maternal and neonatal 

blood have been investigated as means to determine exposures of women and infants to cadmium 

(Baranowska 1995; Abadin et al. 1997). Sensitive and selective methods are available for the detection 

and quantitation of cadmium in these biological materials (Elinder and Lind 1985; Sharma et al. 1982). 

Improved methods for sample preparation and in vivo analysis of liver and kidney content are needed to 

assist in monitoring environmentally exposed populations. 

Effect. Sensitive methods are also available for measuring biological markers of cadmium effect, 

particularly urine or serum concentration of β2-microglobulin, retinol-binding protein, metallothionein, 

and creatinine (Kawada et al. 1990; Roels et al. 1989; Topping et al. 1986). Additional studies to 

establish background levels of these indicators in unexposed populations are needed to evaluate the 

sensitivity of these biomarkers of effect. 

Methods for Determining Parent Compounds and Degradation Products in Environmental 

Media. Cadmium is ubiquitous in the environment and does not degrade. It is found in air, water, soil, 

sediments, and food. Analytical methods exist for the analysis of cadmium in all of these environmental 

media, and these methods have the sensitivity to measure background levels and detect elevated 

concentrations due to anthropogenic sources such as hazardous waste sites (EPA 1983a, 1983b, 1994b, 

1996a, 1996b, 1997b, 2000, 2003b). Additional research to reduce chemical and matrix interferences are 

needed to improve the speed and accuracy of the analyses. 

7.3.2 Ongoing Studies 

The EPA is conducting a pilot program for comprehensive monitoring of human exposure. 

The National Human Exposure Assessment Study (NHEXAS) is being conducted in three regions of the 

United States in order to establish relationships between environmental concentrations, exposure, dose, 

and health response and to determine the incidence and causes of high exposures, especially for 

biologically susceptible persons. One of the aims of the pilot study is to test measurement methodology 

for a variety of pollutants, including cadmium, in food, air, and water. As an adjunct to this pilot study, 

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CADMIUM 325 

7. ANALYTICAL METHODS 

the EPA and the State of Minnesota are conducting a study of children’s exposure to toxic chemicals, 

including cadmium. 

The information in Table 7-3 was found as a result of a search of the Federal Research in Progress 

database (FEDRIP 2008). 

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CADMIUM 326 

7. ANALYTICAL METHODS 

Table 7-3. Ongoing Analytical Methods Studies on Cadmium 

Investigator Affiliation Research description Sponsor 

Parker D 

Pierzynski G 

Schwab AP; Joern B; 

Johnston C 

Santra S 

Swain G 

Source: FEDRIP 2008 

University of 

California 

Kansas State 

University 

Purdue 

University 

University of 

Central Florida 

Michigan 

State 

University 

Isotopic dilution methods for probing the 

bioavailability of trace elements in soils and 

sediments 

Chemistry, bioavailability, and toxicity of 

constituents in residuals and residual treated 

soils 

Chemistry and bioavailability of waste 

constituents in soils 

Selective detection of toxic heavy metal ions 

using highly sensitive quantum dot probes 

Diamond microelectrode arrays: New 

materials for the electrochemical detection of 

aqueous analytes 

U.S. Department of 

Agriculture 

U.S. Department of 

Agriculture 

U.S. Department of 

Agriculture 

National Science 

Foundation 

U.S. Department of 

Agriculture 

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CADMIUM 327 

8. REGULATIONS, ADVISORIES, AND GUIDELINES
 

MRLs are substance-specific estimates, which are intended to serve as screening levels, are used by 

ATSDR health assessors and other responders to identify contaminants and potential health effects that 

may be of concern at hazardous waste sites. 

ATSDR has derived an acute-duration inhalation MRL of 0.03 μg Cd/m3 for cadmium. This MRL is 

based on a LOAEL of 0.088 mg Cd/m3 (LOAELHEC of 0.01 mg Cd/m3

) for respiratory effects in rats 

exposed to cadmium oxide 6.2 hours/day, 5 days/week for 2 weeks (NTP 1995) and an uncertainty factor 

of 300 (10 for the use of a LOAEL, 3 for extrapolation from animals to humans with dosimetric 

adjustments, and 10 for human variability). 

ATSDR has derived a chronic-duration inhalation MRL of 0.01 μg Cd/m3 for cadmium. This MRL is 

based on the 95% lower confidence limit of the urinary cadmium level associated with a 10% extra risk of 

low molecular weight proteinuria (UCDL10) estimated from a meta-analysis of environmental exposure 

data. An air concentration that would result in this urinary cadmium level (0.5 μg/g creatinine), assuming 

a dietary cadmium intake of 0.3 μg/kg/day, was estimated using biokinetic models. The estimated air 

concentration of 0.1 μg Cd/m3 was divided by an uncertainty factor of 3 for human variability and a 

modifying factor of 3. 

The EPA has not established a reference concentration (RfC) for cadmium. 

ATSDR has derived an intermediate-duration oral MRL of 0.5 μg Cd/kg/day for cadmium. This MRL is 

based on a BMDLstd1 of 0.05 mg Cd/kg/day for skeletal effects in young female rats exposed to cadmium 

chloride in drinking water for 6, 9, or 12 months (Brzóska and Moniuszko-Jakoniuk 2005d) and an 

uncertainty factor of 100 (10 for extrapolation from animals to humans and 10 for human variability). 

ATSDR has derived a chronic-duration oral MRL of 0.1 μg Cd/kg/day for cadmium. This MRL is based 

on the UCDL10 for low molecular weight proteinuria estimated from a meta-analysis of environmental 

exposure data. A cadmium intake that would result in the UCDL10 (0.5 μg/g creatinine) at age 55 was 

estimated using pharmacokinetic models. The cadmium intake of 0.33 μg/kg/day was divided by an 

uncertainty factor of 3 for human variability. 

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CADMIUM 328 

8. REGULATIONS AND ADVISORIES 

The EPA has established a reference dose (RfD) of 5x10-4 mg/kg/day in water and 1x10-3 mg/kg/day in 

food (IRIS 2008). The RfD is based on a chronic intake that would result in a kidney concentration of 

200 μg/g ww. 

The international and national regulations, advisories, and guidelines regarding cadmium in air, water, 

and other media are summarized in Table 8-1. 

Cadmium compounds are included on the list of 189 chemicals listed as hazardous air pollutants under 

Section 112 of the Clean Air Act as amended (EPA 2007). Cadmium also is on the list of chemicals 

appearing in the Emergency Planning and Community Right-To-Know Act of 1986 (EPA 2008g). Under 

Title III of this statute, owners and operators of facilities that manufacture, import, process, or otherwise 

use the chemicals on this list of report annually their release of those chemicals to any environmental 

media. 

Cadmium and cadmium chloride are designed as hazardous substances under Section 311 of the Clean 

Water Act; any discharge of these chemicals over a specified threshold level into navigable waters is 

subject to reporting requirements (EPA 2008c). 

Cadmium is a hazardous waste under the Resource Conservation and Recovery Act (RCRA) under 

several circumstances. Groundwater monitoring is required at municipal solid waste landfills (EPA 

2008d) and cadmium is considered a priority persistent, bioaccumulative, and toxic (PBT) chemical under 

RCRA waste minimization chemical listing (EPA 1998). 

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CADMIUM 329 

8. REGULATIONS AND ADVISORIES 

Table 8-1. Regulations, Advisories, and Guidelines Applicable to Cadmium 

Agency Description Information Reference 

INTERNATIONAL 

Guidelines: 

IARC Carcinogenicity classification 

Cadmium and cadmium compounds Group 1a 

IARC 2008 

WHO Air quality guidelines 

Cadmiumb,c 5 ng/m3 

WHO 2000 

Drinking water quality guidelines WHO 2004 

Cadmium 0.003 mg/L 

NATIONAL 

Regulations and 

Guidelines: 

a. Air 

ACGIH Biological exposure indices ACGIH 2007 

Cadmium and inorganic compounds 

Cadmium in urine 5 μg/g creatinine 

Cadmium in blood 5 μg/L 

TLV (8-hour TWA) 

Cadmium 

Cadmium compounds (as Cd)d 

0.01 mg/m3 

0.002 mg/m3 

TLV basis (critical effects) 

Cadmium Kidney damage 

Cadmium compounds (as Cd) Kidney damage 

EPA Second list of AEGL priority chemicals 

for guideline development 

Cadmium and compoundse Yes 

EPA 2008a 

Hazardous air pollutant 

Cadmium compounds Yes 

EPA 2007 

42 USC 7412 

NIOSH REL (10-hour TWA) 

Cadmiumf Potential occupational 

carcinogens 

NIOSH 2005 

Cadmium oxide Potential occupational 

carcinogens 

IDLH 

Cadmium (as Cd) 

Cadmium oxide (as Cd) 

9 mg/m3 

9 mg/m3 

Target organs 

Cadmium Respiratory system, 

kidneys, prostate, and 

blood 

Cadmium oxide Respiratory system, 

kidneys, and blood 

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CADMIUM 330 

8. REGULATIONS AND ADVISORIES 

Table 8-1. Regulations, Advisories, and Guidelines Applicable to Cadmium 

Agency Description Information Reference 

NATIONAL (cont.) 

NIOSH Category of pesticides 

Cadmium carbonate 

Cadmium chloride 

Cadmium sulfate 

OSHA PEL (8-hour TWA) for general industry 

Cadmium (as Cd) 

PEL (8-hour TWA) for shipyard industry 

Cadmium (as Cd) 

PEL (8-hour TWA) for construction 

industry 

Cadmium (as Cd) 

b. Water 

EPA Designated as hazardous substances in 

accordance with Section 311(b)(2)(A) of 

the Clean Water Act 

Cadmium chloride 

Drinking water standards and health 

advisories 

Cadmium 

1-day health advisory for a 

10-kg child 

10-day health advisory for a 

10-kg child 

DWEL 

Lifetime 

National primary drinking water 

standards 

Cadmium 

MCL 

Public health goal 

National recommended water quality 

criteria 

Cadmiumi 

Freshwater CMC 

Freshwater CCC 

Saltwater CMC 

Saltwater CCC 

Reportable quantities of hazardous 

substances designated pursuant to 

Section 311 of the Clean Water Act 

Cadmium chloride 

Group II pesticideg 

Group I pesticideh 

Group II pesticideg 

5 μg/m3 

5 μg/m3 

5 μg/m3 

Yes 

0.04 mg/L 

0.04 mg/L 

0.02 mg/L 

0.005 mg/L 

0.005 mg/L 

0.005 mg/L 

2.0 μg/L 

0.25 μg/L 

40 μg/L 

8.8 μg/L 

10 pounds 

NIOSH 1992b 

OSHA 2007a 

29 CFR 1910.1027 

OSHA 2007b 

29 CFR 1915.1027 

OSHA 2007c 

29 CFR 1926.1127 

EPA 2008b 

40 CFR 116.4 

EPA 2006b 

EPA 2003a 

EPA 2006c 

EPA 2008c 

40 CFR 117.3 

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CADMIUM	 331 

8. REGULATIONS AND ADVISORIES 

Table 8-1. Regulations, Advisories, and Guidelines Applicable to Cadmium 

Agency Description	 Information Reference 

NATIONAL (cont.) 

EPA Toxic pollutants designated pursuant to EPA 2008h 

Section 307(a)(1) of the Clean Water 40 CFR 401.15 

Act 

Cadmium and compounds Yes 

c. Food 

FDA	 Bottled drinking water FDA 2007 

Cadmium 21 CFR 165.110 0.005 mg/L 

EAFUS No data FDA 2008 

d. Other 

ACGIH	 Carcinogenicity classification ACGIH 2007 

A2j Cadmium 

Cadmium compounds (as Cd) A2j
 

EPA Carcinogenicity classification IRIS 2008
 

Cadmium Group B1k
 

Inhalation unit risk
 

Cadmium 1.8x10-3 per μg/m3
 

RfC
 

Cadmium No data
 

RfD
 

Cadmium
 

Food 1x10-3 mg/kg-day
 

Water 5x10-4 mg/kg-day 

RCRA waste minimization PBT priority EPA 1998 

chemical list 63 FR 60332 

Cadmium Yes 

Standards for owners and operators of EPA 2008d 

hazardous waste TSD facilities; 40 CFR 264, 

groundwater monitoring list Appendix IX 

Cadmium Yes 

Superfund, emergency planning, and 

community right-to-know 

Designated CERCLA hazardous EPA 2008e 

substance 40 CFR 302.4 

Yesl,m Cadmium 

Cadmium and compounds Yesn 

Cadmium chloride Yeso 

Reportable quantity 

Cadmium 10 pounds 

Cadmium and compounds Nonep 

Cadmium chloride 10 pounds 

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CADMIUM	 332 

8. REGULATIONS AND ADVISORIES 

Table 8-1. Regulations, Advisories, and Guidelines Applicable to Cadmium 

Agency Description	 Information Reference 

NATIONAL (cont.) 

EPA Superfund, emergency planning, and 

community right-to-know 

Effective date of toxic chemical EPA 2008g 

release reporting 40 CFR 372.65 

Cadmium 01/01/1987 

Cadmium compoundsq 01/01/1987 

Extremely Hazardous Substances	 EPA 2008f 

Cadmium oxide 40 CFR 355, 

Appendix A Reportable quantity 100 pounds 

Threshold planning quantity 100/10,000 pounds 

NTP Carcinogenicity classification No data NTP 2005 

Cadmium and cadmium compounds Known to be human 

carcinogens 

a

Group 1: The agent is carcinogenic to humans. b

The guideline value is based on the prevention of a further increase of cadmium in agricultural soils, which is
 

likely to increase the dietary intake.

c

TWA based on effects other than cancer or odor/annoyance using an averaging time of 1 year. d

Respriable fraction.

e

Higher current priority chemical for guideline development.
 f

REL applies to all cadmium compounds (as Cd).

g

Group II pesticide: Contains the pesticides that pose as significant risk of carcinogenic, teratogenic, neurotoxic, or
 

reproductive effects h

Group I pesticide: Contains the pesticides that pose as significant risk of adverse acute health effects at low
 

concentrations
 i

The CMC is an estimate of the highest concentration of a material in surface water to which an aquatic community can 

be exposed briefly without resulting in an unacceptable effect. The CCC is an estimate of the highest concentration of a 

material in surface water to which an aquatic community can be exposed indefinitely without resulting in an unacceptable
 

effect.
 j

A2: Suspected human carciongen.

k

Group B1: Probable human carcinogen based on limited evidence of carcinogenicity in humans.
 l

Designated CERCLA hazardous substance pursuant to Section 307(a) of the Clean Water Act.
 mNo reporting of releases of this hazardous substance is required if the diameter of the pieces of the solid metal
 

released is larger than 100 micrometers (0.004 inches).

n

Designated CERCLA hazardous substance pursuant to Section 307(a) of the Clean Water Act and Section 112 of the 

Clean Air Act.
 o

Designated CERCLA hazardous substance pursuant to Section 311(b)(2) of the Clean Water Act.

p

Indicates that no reportable quantity is being assigned to the generic or broad class.

q

Cadmium compounds: Includes any unique chemical substance that contains cadmium as part of that chemical's
 

infrastructure.
 

ACGIH = American Conference of Governmental Industrial Hygienists; AEGL = acute exposure guideline levels;
 

CCC = Criterion Continuous Concentration; CERCLA = Comprehensive Environmental Response, Compensation, and
 

Liability Act; CFR = Code of Federal Regulations; CMC = Criteria Maximum Concentration; DWEL = drinking water
 

equivalent level; EAFUS = Everything Added to Food in the United States; EPA = Environmental Protection Agency;
 

FDA = Food and Drug Administration; IARC = International Agency for Research on Cancer; IDLH = immediately
 

dangerous to life or health; IRIS = Integrated Risk Information System; MCL = maximum contaminant level;
 

NIOSH = National Institute for Occupational Safety and Health; NTP = National Toxicology Program;
 

OSHA = Occupational Safety and Health Administration; PBT = persistant, bioaccumulative, and toxic;
 

PEL = permissible exposure limit; RCRA = Resource Conservation and Recovery Act; REL = recommended exposure 

limit; RfC = inhalation reference concentration; RfD = oral reference dose; TLV = threshold limit values; TSD = treatment,
 

storage, and disposal; TWA = time-weighted average; USC = United States Code; WHO = World Health Organization
 

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CADMIUM 333 

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Toxicology 239:204-212. 

Zhang G, Lindars E, Chao Z, et al. 2002. Biological monitoring of cadmium exposed workers in a 

nickel-cadmium battery factory in China. J Occup Health 44:15-21. 

Zhang X, Sun H, Zhang Z, et al. 2007a. Enhanced bioaccumulation of cadmium in carp in the presence 

of titanium dioxide nanoparticles. Chemosphere 67:160-166. 

Zhang Y, Li Q, Meng A, et al. 2007b. Effects of sulfur compounds on Cd partitioning in a simulated 

municipal solid waste incinerator. Chinese J Chem Eng 15(6):889-894. 

*Zhang YL, Zhao YC, Wang JX, et al. 2004. Effect of environmental exposure to cadmium on 

pregnancy outcome and fetal growth: A study on healthy pregnant women in China. J Environ Sci 

Health A 39(9):2507-2515. 

*Zhang ZQ, Chen SZ, Lin HM, et al. 1993. Simultaneous determination of copper, nickel, lead, cobalt 

and cadmium by adsorptive voltammetry. Anal Chim Acta 272:227-232. 

Zhao F, Peng S, Zheng B, et al. 2006a. The leaching behavior of cadmium, arsenic, zinc, and chlorine in 

coal and its ash from coal-fired power plant. Environ Eng Sci 23(1):68-76. 

Zhao Z, Hyun JS, Satsu H, et al. 2006b. Oral exposure to cadmium chloride triggers an acute 

inflammatory response in the intestines of mice, initiated by the over-expression of tissue macrophage 

inflammatory protein-2 mRNA. Toxicol Lett 164:144-154. 

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CADMIUM 448 

9. REFERENCES 

Zhou D, Zhang L, Zhou J, et al. 2004a. Cellulose/chitin beads for adsorption of heavy metals in aqueous 

solution. Water Res 38:2643-2650. 

*Zhou T, Jia X, Chapin RE, et al. 2004b. Cadmium at a non-toxic dose alters gene expression in mouse 

testes. Toxicol Lett 154(3):191-200. 

*Zhu G, Wang H, Shi Y, et al. 2004. Environmental cadmium exposure and forearm bone density. 

Biometals 17:499-503. 

*Ziegler EE, Edwards BB, Jensen RL, et al. 1978. Absorption and retention of lead by infants. Pediatr 

Res 12(1):29-34. 

Zyadah MA, Abdel-Baky TE. 2000. Toxicity and bioaccumulation of copper, zinc, and cadmium in 

some aquatic organisms. Bull Environ Contam Toxicol 64(5):740-747. 

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CADMIUM 449 

10. GLOSSARY 

Absorption—The taking up of liquids by solids, or of gases by solids or liquids. 

Acute Exposure—Exposure to a chemical for a duration of 14 days or less, as specified in the 

Toxicological Profiles. 

Adsorption—The adhesion in an extremely thin layer of molecules (as of gases, solutes, or liquids) to the 

surfaces of solid bodies or liquids with which they are in contact. 

Adsorption Coefficient (Koc)—The ratio of the amount of a chemical adsorbed per unit weight of 

organic carbon in the soil or sediment to the concentration of the chemical in solution at equilibrium. 

Adsorption Ratio (Kd)—The amount of a chemical adsorbed by sediment or soil (i.e., the solid phase) 

divided by the amount of chemical in the solution phase, which is in equilibrium with the solid phase, at a 

fixed solid/solution ratio. It is generally expressed in micrograms of chemical sorbed per gram of soil or 

sediment. 

Benchmark Dose (BMD)—Usually defined as the lower confidence limit on the dose that produces a 

specified magnitude of changes in a specified adverse response. For example, a BMD10 would be the 

dose at the 95% lower confidence limit on a 10% response, and the benchmark response (BMR) would be 

10%. The BMD is determined by modeling the dose response curve in the region of the dose response 

relationship where biologically observable data are feasible. 

Benchmark Dose Model—A statistical dose-response model applied to either experimental toxicological 

or epidemiological data to calculate a BMD. 

Bioconcentration Factor (BCF)—The quotient of the concentration of a chemical in aquatic organisms 

at a specific time or during a discrete time period of exposure divided by the concentration in the 

surrounding water at the same time or during the same period. 

Biomarkers—Broadly defined as indicators signaling events in biologic systems or samples. They have 

been classified as markers of exposure, markers of effect, and markers of susceptibility. 

Cancer Effect Level (CEL)—The lowest dose of chemical in a study, or group of studies, that produces 

significant increases in the incidence of cancer (or tumors) between the exposed population and its 

appropriate control. 

Carcinogen—A chemical capable of inducing cancer. 

Case-Control Study—A type of epidemiological study that examines the relationship between a 

particular outcome (disease or condition) and a variety of potential causative agents (such as toxic 

chemicals). In a case-controlled study, a group of people with a specified and well-defined outcome is 

identified and compared to a similar group of people without outcome. 

Case Report—Describes a single individual with a particular disease or exposure. These may suggest 

some potential topics for scientific research, but are not actual research studies. 

Case Series—Describes the experience of a small number of individuals with the same disease or 

exposure. These may suggest potential topics for scientific research, but are not actual research studies. 

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CADMIUM 450 

10. GLOSSARY 

Ceiling Value—A concentration of a substance that should not be exceeded, even instantaneously. 

Chronic Exposure—Exposure to a chemical for 365 days or more, as specified in the Toxicological 

Profiles. 

Cohort Study—A type of epidemiological study of a specific group or groups of people who have had a 

common insult (e.g., exposure to an agent suspected of causing disease or a common disease) and are 

followed forward from exposure to outcome. At least one exposed group is compared to one unexposed 

group. 

Cross-sectional Study—A type of epidemiological study of a group or groups of people that examines 

the relationship between exposure and outcome to a chemical or to chemicals at one point in time. 

Data Needs—Substance-specific informational needs that if met would reduce the uncertainties of human 

health assessment. 

Developmental Toxicity—The occurrence of adverse effects on the developing organism that may result 

from exposure to a chemical prior to conception (either parent), during prenatal development, or 

postnatally to the time of sexual maturation. Adverse developmental effects may be detected at any point 

in the life span of the organism. 

Dose-Response Relationship—The quantitative relationship between the amount of exposure to a 

toxicant and the incidence of the adverse effects. 

Embryotoxicity and Fetotoxicity—Any toxic effect on the conceptus as a result of prenatal exposure to 

a chemical; the distinguishing feature between the two terms is the stage of development during which the 

insult occurs. The terms, as used here, include malformations and variations, altered growth, and in utero 

death. 

Environmental Protection Agency (EPA) Health Advisory—An estimate of acceptable drinking water 

levels for a chemical substance based on health effects information. A health advisory is not a legally 

enforceable federal standard, but serves as technical guidance to assist federal, state, and local officials. 

Epidemiology—Refers to the investigation of factors that determine the frequency and distribution of 

disease or other health-related conditions within a defined human population during a specified period. 

Genotoxicity—A specific adverse effect on the genome of living cells that, upon the duplication of 

affected cells, can be expressed as a mutagenic, clastogenic, or carcinogenic event because of specific 

alteration of the molecular structure of the genome. 

Half-life—A measure of rate for the time required to eliminate one half of a quantity of a chemical from 

the body or environmental media. 

Immediately Dangerous to Life or Health (IDLH)—The maximum environmental concentration of a 

contaminant from which one could escape within 30 minutes without any escape-impairing symptoms or 

irreversible health effects. 

Immunologic Toxicity—The occurrence of adverse effects on the immune system that may result from 

exposure to environmental agents such as chemicals. 

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CADMIUM 451 

10. GLOSSARY 

Immunological Effects—Functional changes in the immune response. 

Incidence—The ratio of individuals in a population who develop a specified condition to the total 

number of individuals in that population who could have developed that condition in a specified time 

period. 

Intermediate Exposure—Exposure to a chemical for a duration of 15–364 days, as specified in the 

Toxicological Profiles. 

In Vitro—Isolated from the living organism and artificially maintained, as in a test tube. 

In Vivo—Occurring within the living organism. 

Lethal Concentration(LO) (LCLO)—The lowest concentration of a chemical in air that has been reported 

to have caused death in humans or animals. 

Lethal Concentration(50) (LC50)—A calculated concentration of a chemical in air to which exposure for 

a specific length of time is expected to cause death in 50% of a defined experimental animal population. 

Lethal Dose(LO) (LDLo)—The lowest dose of a chemical introduced by a route other than inhalation that 

has been reported to have caused death in humans or animals. 

Lethal Dose(50) (LD50)—The dose of a chemical that has been calculated to cause death in 50% of a 

defined experimental animal population. 

Lethal Time(50) (LT50)—A calculated period of time within which a specific concentration of a chemical 

is expected to cause death in 50% of a defined experimental animal population. 

Lowest-Observed-Adverse-Effect Level (LOAEL)—The lowest exposure level of chemical in a study, 

or group of studies, that produces statistically or biologically significant increases in frequency or severity 

of adverse effects between the exposed population and its appropriate control. 

Lymphoreticular Effects—Represent morphological effects involving lymphatic tissues such as the 

lymph nodes, spleen, and thymus. 

Malformations—Permanent structural changes that may adversely affect survival, development, or 

function. 

Minimal Risk Level (MRL)—An estimate of daily human exposure to a hazardous substance that is 

likely to be without an appreciable risk of adverse noncancer health effects over a specified route and 

duration of exposure. 

Modifying Factor (MF)—A value (greater than zero) that is applied to the derivation of a Minimal Risk 

Level (MRL) to reflect additional concerns about the database that are not covered by the uncertainty 

factors. The default value for a MF is 1. 

Morbidity—State of being diseased; morbidity rate is the incidence or prevalence of disease in a specific 

population. 

Mortality—Death; mortality rate is a measure of the number of deaths in a population during a specified 

interval of time. 

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CADMIUM 452 

10. GLOSSARY 

Mutagen—A substance that causes mutations. A mutation is a change in the DNA sequence of a cell’s 

DNA. Mutations can lead to birth defects, miscarriages, or cancer. 

Necropsy—The gross examination of the organs and tissues of a dead body to determine the cause of 

death or pathological conditions. 

Neurotoxicity—The occurrence of adverse effects on the nervous system following exposure to a 

chemical. 

No-Observed-Adverse-Effect Level (NOAEL)—The dose of a chemical at which there were no 

statistically or biologically significant increases in frequency or severity of adverse effects seen between 

the exposed population and its appropriate control. Effects may be produced at this dose, but they are not 

considered to be adverse. 

Octanol-Water Partition Coefficient (Kow)—The equilibrium ratio of the concentrations of a chemical 

in n-octanol and water, in dilute solution. 

Odds Ratio (OR)—A means of measuring the association between an exposure (such as toxic substances 

and a disease or condition) that represents the best estimate of relative risk (risk as a ratio of the incidence 

among subjects exposed to a particular risk factor divided by the incidence among subjects who were not 

exposed to the risk factor). An OR of greater than 1 is considered to indicate greater risk of disease in the 

exposed group compared to the unexposed group. 

Organophosphate or Organophosphorus Compound—A phosphorus-containing organic compound 

and especially a pesticide that acts by inhibiting cholinesterase. 

Permissible Exposure Limit (PEL)—An Occupational Safety and Health Administration (OSHA) 

allowable exposure level in workplace air averaged over an 8-hour shift of a 40-hour workweek. 

Pesticide—General classification of chemicals specifically developed and produced for use in the control 

of agricultural and public health pests. 

Pharmacokinetics—The dynamic behavior of a material in the body, used to predict the fate 

(disposition) of an exogenous substance in an organism. Utilizing computational techniques, it provides 

the means of studying the absorption, distribution, metabolism, and excretion of chemicals by the body. 

Pharmacokinetic Model—A set of equations that can be used to describe the time course of a parent 

chemical or metabolite in an animal system. There are two types of pharmacokinetic models: data-based 

and physiologically-based. A data-based model divides the animal system into a series of compartments, 

which, in general, do not represent real, identifiable anatomic regions of the body, whereas the 

physiologically-based model compartments represent real anatomic regions of the body. 

Physiologically Based Pharmacodynamic (PBPD) Model—A type of physiologically based doseresponse model that quantitatively describes the relationship between target tissue dose and toxic end 

points. These models advance the importance of physiologically based models in that they clearly 

describe the biological effect (response) produced by the system following exposure to an exogenous 

substance. 

Physiologically Based Pharmacokinetic (PBPK) Model—Comprised of a series of compartments 

representing organs or tissue groups with realistic weights and blood flows. These models require a 

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CADMIUM 453 

10. GLOSSARY 

variety of physiological information: tissue volumes, blood flow rates to tissues, cardiac output, alveolar 

ventilation rates, and possibly membrane permeabilities. The models also utilize biochemical 

information, such as air/blood partition coefficients, and metabolic parameters. PBPK models are also 

called biologically based tissue dosimetry models. 

Prevalence—The number of cases of a disease or condition in a population at one point in time. 

Prospective Study—A type of cohort study in which the pertinent observations are made on events 

occurring after the start of the study. A group is followed over time. 

q1*—The upper-bound estimate of the low-dose slope of the dose-response curve as determined by the 

multistage procedure. The q1* can be used to calculate an estimate of carcinogenic potency, the 

incremental excess cancer risk per unit of exposure (usually μg/L for water, mg/kg/day for food, and 

μg/m3 for air). 

Recommended Exposure Limit (REL)—A National Institute for Occupational Safety and Health 

(NIOSH) time-weighted average (TWA) concentration for up to a 10-hour workday during a 40-hour 

workweek. 

Reference Concentration (RfC)—An estimate (with uncertainty spanning perhaps an order of 

magnitude) of a continuous inhalation exposure to the human population (including sensitive subgroups) 

that is likely to be without an appreciable risk of deleterious noncancer health effects during a lifetime. 

The inhalation reference concentration is for continuous inhalation exposures and is appropriately 

expressed in units of mg/m3 or ppm. 

Reference Dose (RfD)—An estimate (with uncertainty spanning perhaps an order of magnitude) of the 

daily exposure of the human population to a potential hazard that is likely to be without risk of deleterious 

effects during a lifetime. The RfD is operationally derived from the no-observed-adverse-effect level 

(NOAEL, from animal and human studies) by a consistent application of uncertainty factors that reflect 

various types of data used to estimate RfDs and an additional modifying factor, which is based on a 

professional judgment of the entire database on the chemical. The RfDs are not applicable to 

nonthreshold effects such as cancer. 

Reportable Quantity (RQ)—The quantity of a hazardous substance that is considered reportable under 

the Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA). Reportable 

quantities are (1) 1 pound or greater or (2) for selected substances, an amount established by regulation 

either under CERCLA or under Section 311 of the Clean Water Act. Quantities are measured over a 

24-hour period. 

Reproductive Toxicity—The occurrence of adverse effects on the reproductive system that may result 

from exposure to a chemical. The toxicity may be directed to the reproductive organs and/or the related 

endocrine system. The manifestation of such toxicity may be noted as alterations in sexual behavior, 

fertility, pregnancy outcomes, or modifications in other functions that are dependent on the integrity of 

this system. 

Retrospective Study—A type of cohort study based on a group of persons known to have been exposed 

at some time in the past. Data are collected from routinely recorded events, up to the time the study is 

undertaken. Retrospective studies are limited to causal factors that can be ascertained from existing 

records and/or examining survivors of the cohort. 

Risk—The possibility or chance that some adverse effect will result from a given exposure to a chemical. 

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CADMIUM 454 

10. GLOSSARY 

Risk Factor—An aspect of personal behavior or lifestyle, an environmental exposure, or an inborn or 

inherited characteristic that is associated with an increased occurrence of disease or other health-related 

event or condition. 

Risk Ratio—The ratio of the risk among persons with specific risk factors compared to the risk among 

persons without risk factors. A risk ratio greater than 1 indicates greater risk of disease in the exposed 

group compared to the unexposed group. 

Short-Term Exposure Limit (STEL)—The American Conference of Governmental Industrial 

Hygienists (ACGIH) maximum concentration to which workers can be exposed for up to 15 minutes 

continually. No more than four excursions are allowed per day, and there must be at least 60 minutes 

between exposure periods. The daily Threshold Limit Value-Time Weighted Average (TLV-TWA) may 

not be exceeded. 

Standardized Mortality Ratio (SMR)—A ratio of the observed number of deaths and the expected 

number of deaths in a specific standard population. 

Target Organ Toxicity—This term covers a broad range of adverse effects on target organs or 

physiological systems (e.g., renal, cardiovascular) extending from those arising through a single limited 

exposure to those assumed over a lifetime of exposure to a chemical. 

Teratogen—A chemical that causes structural defects that affect the development of an organism. 

Threshold Limit Value (TLV)—An American Conference of Governmental Industrial Hygienists 

(ACGIH) concentration of a substance to which most workers can be exposed without adverse effect. 

The TLV may be expressed as a Time Weighted Average (TWA), as a Short-Term Exposure Limit 

(STEL), or as a ceiling limit (CL). 

Time-Weighted Average (TWA)—An allowable exposure concentration averaged over a normal 8-hour 

workday or 40-hour workweek. 

Toxic Dose(50) (TD50)—A calculated dose of a chemical, introduced by a route other than inhalation, 

which is expected to cause a specific toxic effect in 50% of a defined experimental animal population. 

Toxicokinetic—The absorption, distribution, and elimination of toxic compounds in the living organism. 

Uncertainty Factor (UF)—A factor used in operationally deriving the Minimal Risk Level (MRL) or 

Reference Dose (RfD) or Reference Concentration (RfC) from experimental data. UFs are intended to 

account for (1) the variation in sensitivity among the members of the human population, (2) the 

uncertainty in extrapolating animal data to the case of human, (3) the uncertainty in extrapolating from 

data obtained in a study that is of less than lifetime exposure, and (4) the uncertainty in using lowestobserved-adverse-effect level (LOAEL) data rather than no-observed-adverse-effect level (NOAEL) data. 

A default for each individual UF is 10; if complete certainty in data exists, a value of 1 can be used; 

however, a reduced UF of 3 may be used on a case-by-case basis, 3 being the approximate logarithmic 

average of 10 and 1. 

Xenobiotic—Any chemical that is foreign to the biological system. 

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CADMIUM A-1 

APPENDIX A. ATSDR MINIMAL RISK LEVELS AND WORKSHEETS 

The Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA) [42 U.S.C. 

9601 et seq.], as amended by the Superfund Amendments and Reauthorization Act (SARA) [Pub. L. 99– 

499], requires that the Agency for Toxic Substances and Disease Registry (ATSDR) develop jointly with 

the U.S. Environmental Protection Agency (EPA), in order of priority, a list of hazardous substances most 

commonly found at facilities on the CERCLA National Priorities List (NPL); prepare toxicological 

profiles for each substance included on the priority list of hazardous substances; and assure the initiation 

of a research program to fill identified data needs associated with the substances. 

The toxicological profiles include an examination, summary, and interpretation of available toxicological 

information and epidemiologic evaluations of a hazardous substance. During the development of 

toxicological profiles, Minimal Risk Levels (MRLs) are derived when reliable and sufficient data exist to 

identify the target organ(s) of effect or the most sensitive health effect(s) for a specific duration for a 

given route of exposure. An MRL is an estimate of the daily human exposure to a hazardous substance 

that is likely to be without appreciable risk of adverse noncancer health effects over a specified duration 

of exposure. MRLs are based on noncancer health effects only and are not based on a consideration of 

cancer effects. These substance-specific estimates, which are intended to serve as screening levels, are 

used by ATSDR health assessors to identify contaminants and potential health effects that may be of 

concern at hazardous waste sites. It is important to note that MRLs are not intended to define clean-up or 

action levels. 

MRLs are derived for hazardous substances using the no-observed-adverse-effect level/uncertainty factor 

approach. They are below levels that might cause adverse health effects in the people most sensitive to 

such chemical-induced effects. MRLs are derived for acute (1–14 days), intermediate (15–364 days), and 

chronic (365 days and longer) durations and for the oral and inhalation routes of exposure. Currently, 

MRLs for the dermal route of exposure are not derived because ATSDR has not yet identified a method 

suitable for this route of exposure. MRLs are generally based on the most sensitive chemical-induced end 

point considered to be of relevance to humans. Serious health effects (such as irreparable damage to the 

liver or kidneys, or birth defects) are not used as a basis for establishing MRLs. Exposure to a level 

above the MRL does not mean that adverse health effects will occur. 

MRLs are intended only to serve as a screening tool to help public health professionals decide where to 

look more closely. They may also be viewed as a mechanism to identify those hazardous waste sites that 

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CADMIUM A-2 

APPENDIX A 

are not expected to cause adverse health effects. Most MRLs contain a degree of uncertainty because of 

the lack of precise toxicological information on the people who might be most sensitive (e.g., infants, 

elderly, nutritionally or immunologically compromised) to the effects of hazardous substances. ATSDR 

uses a conservative (i.e., protective) approach to address this uncertainty consistent with the public health 

principle of prevention. Although human data are preferred, MRLs often must be based on animal studies 

because relevant human studies are lacking. In the absence of evidence to the contrary, ATSDR assumes 

that humans are more sensitive to the effects of hazardous substance than animals and that certain persons 

may be particularly sensitive. Thus, the resulting MRL may be as much as 100-fold below levels that 

have been shown to be nontoxic in laboratory animals. 

Proposed MRLs undergo a rigorous review process: Health Effects/MRL Workgroup reviews within the 

Division of Toxicology and Environmental Medicine, expert panel peer reviews, and agency-wide MRL 

Workgroup reviews, with participation from other federal agencies and comments from the public. They 

are subject to change as new information becomes available concomitant with updating the toxicological 

profiles. Thus, MRLs in the most recent toxicological profiles supersede previously published levels. 

For additional information regarding MRLs, please contact the Division of Toxicology and 

Environmental Medicine, Agency for Toxic Substances and Disease Registry, 1600 Clifton Road NE, 

Mailstop F-32, Atlanta, Georgia 30333. 

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CADMIUM A-3 

APPENDIX A 

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: Cadmium 

CAS Numbers: 7440-43-9 

Date: July, 2008 

Profile Status: Second Pre-Public Comment Draft 

Route: [X] Inhalation [ ] Oral 

Duration: [X] Acute [ ] Intermediate [ ] Chronic 

Graph Key: 16 

Species: Rat 

Minimal Risk Level: 0.03 [ ] mg/kg/day [X] μg Cd/m3 

Reference: NTP. 1995. Cadmium oxide administered by inhalation to F344/N rats and B6C3F1 mice. 

National Toxicology Program, U.S. Department of Health and Human Services, Research Triangle Park, 

NC. 

Experimental design: Groups of five male and five female F344 rats were exposed to 0, 0.1, 0.3, 1, 3, or 

10 mg cadmium oxide/m3 (0, 0.088, 0.26, 0.88, 2.6, or 8.8 mg Cd/m3

) 6.2 hours/day, 5 days/week for 

2 weeks. The mean MMAD of the cadmium oxide particles was 1.5 μm with a geometric standard 

deviation of 1.6–1.8. The animals were observed twice daily and weighed on days 1 and 8, and at 

termination. Other parameters used to assess toxicity included organ weights (heart, kidney, liver, lungs, 

spleen, testis, and thymus) and histopathological examination (gross lesions, heart, kidney, liver, lungs, 

tracheobronchial lymph nodes, and nasal cavity and turbinates). 

Effect noted in study and corresponding doses: All rats in the 8.8 mg Cd/m3 group died by day 6; no 

other deaths occurred. A slight decrease in terminal body weights was observed at 2.6 mg Cd/m3

; 

however, the body weights were within 10% of control weights. Significant increases in relative and 

absolute lung weights were observed at 0.26 (males only), 0.88, and 2.6 mg Cd/m3

. Histological 

alterations were limited to the respiratory tract and consisted of alveolar histiocytic infiltrate and focal 

inflammation in alveolar septa in all rats exposed to ≥0.088 mg Cd/m3

, necrosis of the epithelium lining 

alveolar ducts in all rats exposed to ≥0.26 mg Cd/m3

, tracheobronchiolar lymph node inflammation at 

≥0.88 mg Cd/m3 (incidences in the 0, 0.088, 0.26, 0.88, 2.6, and 8.8 mg Cd/m3 groups were 0/3, 0/5, 5/5, 

5/5, and 3/4 in males and 0/4, 1/5, 1/5, 3/5, 5/5, and 3/5 in females), degeneration of the nasal olfactory 

epithelium at 0.88 mg Cd/m3 (0/5, 0/5, 0/5, 2/5, 5/5, and 5/5 in males and 0/5, 0/5, 0/5, 4/5, 4/5, and 4/4 in 

females) and inflammation (0/5. 0/5. 0/5, 1/5, 5/5, and 3/5 in males and 0/5, 0/5, 0/5, 0/5, 4/5, and 3/4 in 

females) and metaplasia (0/5. 0/5. 0/5, 1/5, 0/5, and 5/5 in males and 0/5, 0/5, 0/5, 0/5, 4/5, and 4/4 in 

females)of the nasal respiratory epithelium at 2.6 mg Cd/m3

. 

Dose and end point used for MRL derivation: The LOAEL of 0.088 mg Cd/m3 was selected as the point 

of departure for derivation of the MRL; benchmark dose analysis was considered; however, the data were 

not suitable for benchmark dose analysis because the incidence data for alveolar histiocytic infiltration do 

not provide sufficient information about the shape of the dose-response relationship below the 100% 

response level. 

[ ] NOAEL [X] LOAEL 

Uncertainty Factors used in MRL derivation: 

[X] 10 for use of a LOAEL 

[X] 3 for extrapolation from animals to humans with dosimetric adjustment 

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CADMIUM A-4 

APPENDIX A 

[X] 10 for human variability 

Was a conversion factor used from ppm in food or water to a mg/body weight dose? No. 

If an inhalation study in animals, list conversion factors used in determining human equivalent dose: 

The LOAELHEC was calculated using the equations below. 

LOAELHEC = LOAELADJ x RDDR 

The duration-adjusted LOAEL (LOAELADJ) was calculated as follows: 

LOAELADJ = 0.088 mg Cd/m3 x 6.2 hours/24 hours x 5 days/7 days 

LOAELADJ = 0.016 mg Cd/m3 

The regional deposited dose ratio (RDDR) for the pulmonary region of 0.617 was calculated with EPA’s 

RDDR calculator (EPA 1994a) using the final body weight of 0.194 kg for the male rats exposed 

0.088 mg Cd/m3

, the reported MMAD of 1.5 μm and the midpoint of the reported range of geometric 

standard deviations (1.7) 

LOAELHEC = 0.016 mg Cd/m3 x 0.617 

LOAELHEC = 0.01 mg Cd/m3 

Was a conversion used from intermittent to continuous exposure? Yes (see above) 

Other additional studies or pertinent information that lend support to this MRL: The acute toxicity of 

airborne cadmium, particularly cadmium oxide fumes, was first recognized in the early 1920s and there 

have been numerous case reports of cadmium workers dying after brief exposures to presumably high 

concentrations of cadmium fumes (European Chemicals Bureau 2007). The initial symptoms, similar to 

those observed in metal fume fever, are usually mild but rapidly progress to severe pulmonary edema and 

chemical pneumonitis. Persistent respiratory effects (often lasting years after the exposure) have been 

reported in workers surviving these initial effects. There are limited monitoring data for these human 

reports; however, Elinder (1986b) estimated that an 8-hour exposure to 1–5 mg/m3 would be immediately 

dangerous. 

Animal studies support the findings in humans that acute exposure to cadmium results in lung damage. 

Single exposures to approximately 1–10 mg Cd/m3 as cadmium chloride or cadmium oxide resulted in 

interstitial pneumonitis, diffuse alveolitis with hemorrhage, focal interstitial thickening, and edema 

(Boudreau et al. 1989; Buckley and Bassett 1987b; Bus et al. 1978; Grose et al. 1987; Hart 1986; 

Henderson et al. 1979; Palmer et al. 1986). Repeated exposure to 6.1 mg Cd/m3 1 hour/day for 5, 10, or 

15 days resulted in emphysema in rats (Snider et al. 1973). At lower concentrations of 0.4–0.5 mg Cd/m3 

as cadmium oxide for 2–3 hours (Buckley and Bassett 1987b; Grose et al. 1987) or 0.17 mg Cd/m3 as 

cadmium chloride 6 hours/day for 10 days (Klimisch 1993) resulted in mild hypercellularity and increases 

in lung weight. Alveolar histiocytic infiltration and focal inflammation and minimal fibrosis in alveolar 

septa were observed in rats exposed to 0.088 mg Cd/m3 as cadmium oxide 6.2 hours/day, 5 days/week for 

2 weeks (NTP 1995); in similarly exposed mice, histiocytic infiltration was observed at 0.088 mg Cd/m3 

(NTP 1995). At similar concentrations (0.19 or 0.88 mg Cd/m3

as cadmium chloride), decreases in 

humoral immune response were observed in mice exposed for 1–2 hours (Graham et al. 1978; 

Krzystyniak et al. 1987). Other effects that have been reported in animals acutely exposed to cadmium 

include erosion of the stomach, decreased body weight gain, and tremors in rats exposed to 132 mg Cd/m3 

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CADMIUM A-5 

APPENDIX A 

as cadmium carbonate for 2 hours (Rusch et al. 1986) and weight loss and reduced activity in rats exposed 

to 112 mg Cd/m3 as cadmium oxide for 2 hours (Rusch et al. 1986). 

Agency Contact (Chemical Manager): Obaid Faroon, DVM, Ph.D. 

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CADMIUM A-6 

APPENDIX A 

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: Cadmium 

CAS Numbers: 7440-43-9 

Date: July, 2008 

Profile Status: Second Pre-Public Comment Draft 

Route: [X] Inhalation [ ] Oral 

Duration: [ ] Acute [ ] Intermediate [X] Chronic 

Graph Key: 63 

Species: Human 

Minimal Risk Level: 0.01 [ ] mg/kg/day [X] μg Cd/m3 

Reference: Buchet JP, Lauwerys R, Roels H, et al. 1990. Renal effects of cadmium body burden of the 

general population. Lancet 336:699-702. 

Järup L, Hellstrom L, Alfven T, et al. 2000. Low level exposure to cadmium and early kidney damage: 

The OSCAR study. Occup Environ Med 57(10):668-672. 

Suwazono Y, Sand S, Vahter M, et al. 2006. Benchmark dose for cadmium-induced renal effects in 

humans. Environ Health Perspect 114:1072-1076. 

Experimental design: As detailed in the chronic oral MRL worksheet, a meta-analysis of select 

environmental exposure dose-response studies examining the relationship between urinary cadmium and 

the prevalence of elevated levels of biomarkers of renal function in environmentally exposed populations 

was conducted; for the inhalation MRL, the meta-analysis also included dose-response data from 

three occupational exposure studies (Chen et al. 2006a, 2006b; Järup and Elinder 1994; Roels et al. 1993). 

The meta-analysis was used to establish a point of departure for the urinary cadmium-response 

relationship and pharmacokinetic models (ICRP 1994; Kjellström and Nordberg 1978) were used to 

predict cadmium air concentrations. 

Dose and end point used for MRL derivation: Analysis of the available environmental exposure studies 

and occupational exposure studies resulted in an estimation of a urinary cadmium level that would result 

in a 10% increase in the prevalence of β2-microglobulin proteinuria (UCD10). The lowest UCD10 

(1.34 μg/g creatinine) was estimated from the European environmental exposure studies (Buchet et al. 

1990; Järup et al. 2000; Suwazono et al. 2006); the UCD10 values from the occupational exposure studies 

were 7.50 μg/g creatinine for the European cohorts (J ärup and Elinder 1994; Roels et al. 1993) and 

4.58 μg/g creatinine for the Chinese cohort (Chen et al. 2006a, 2006b). The UCD10 from the 

environmental exposure studies was selected as the basis of the MRL. The 95% lower confidence limit 

on this value (UCDL10) of 0.5 μg/g creatinine was used as the point of departure for the MRL. 

[ ] NOAEL [ ] LOAEL [X] UCDL10 

Deposition and clearance of inhaled cadmium oxide and cadmium sulfide particles were modeled using 

the ICRP Human Respiratory Tract Model (ICRP 1994). The ICRP model simulates deposition, 

retention, and absorption of inhaled cadmium particles of specific aerodynamic diameters, when specific 

parameters for cadmium clearance are used in the model (ICRP 1980). Cadmium-specific parameters 

represent categories of solubility and dissolution kinetics in the respiratory tract (e.g., slow, S; moderate, 

M; or fast, F). Cadmium compounds are classified as follows: oxides and hydroxides, S; sulfides, halides 

and nitrates, M; all other, including chloride salts, F. 

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CADMIUM A-7 

APPENDIX A 

Inhalation exposures (μg/m3) to cadmium oxide or cadmium sulfide aerosols having particle diameters of 

1, 5, or 10 g (AMAD) were simulated using the ICRP model. Predicted mass transfers of cadmium 

from the respiratory tract to the gastrointestinal tract (i.e., mucocilliary transport) and to blood (i.e., 

absorption) were used as inputs to the gastrointestinal and blood compartments of the KjellströmNordberg pharmacokinetic model (1978) to simulate the kidney and urinary cadmium levels that 

correspond to a given inhalation exposure. 

An airborne cadmium concentration of 1.8–2.4 μg/m3 as cadmium oxide or 1.2–1.4 μg/m3 as cadmium 

sulfide would result in a urinary cadmium level of 0.5 μg/g creatinine, assuming that the air was the only 

source of cadmium. This assumption is not accurate because the diet is a significant contributor to the 

cadmium body burden. Thus, inhalation exposures were combined with ingestion intakes to estimate an 

internal dose in terms of urinary cadmium. The age-weighted average intakes of cadmium in nonsmoking 

males and females in the United States are 0.35 and 0.30 μg Cd/kg/day, respectively (0.32 μg/kg/day for 

males and females combined) (Choudhury et al. 2001). 

Based on the relationship predicted between chronic inhalation exposures to cadmium sulfide 

(AMAD=1 μm) and oral intakes that yield the same urinary cadmium level, exposure to an airborne 

cadmium concentration of 0.1 μg/m3 and a dietary intake of 0.3 μg/kg/day would result in a urinary 

cadmium level of 0.5 μg/g creatinine. 

Uncertainty Factors and Modifying Factors used in MRL derivation: 

[ ] 10 for use of a LOAEL
 

[ ] 10 for extrapolation from animals to humans with dosimetric adjustment
 

[X] 3 for human variability 

The uncertainty factor of 3 for human variability was used to account for the possible increased sensitivity 

of diabetics (Åkesson et al. 2005; Buchet et al. 1990). 

[X] modifying factor of 3 

The modifying factor of 3 was used to account for the lack of adequate human data that could be used to 

compare the relative sensitivities of the respiratory tract and kidneys. 

Was a conversion factor used from ppm in food or water to a mg/body weight dose? No. 

If an inhalation study in animals, list conversion factors used in determining human equivalent dose: Not 

applicable. 

Was a conversion used from intermittent to continuous exposure? The pharmacokinetic model assumes 

continuous exposure. 

Other additional studies or pertinent information that lend support to this MRL: Numerous studies 

examining the toxicity of cadmium in workers have identified the respiratory tract and the kidney as 

sensitive targets of toxicity. A variety of respiratory tract effects have been observed in cadmium workers 

including respiratory symptoms (e.g., dyspnea, coughing, wheezing), emphysema, and impaired lung 

function. However, many of these studies did not control for smoking, and thus, the role of cadmium in 

the induction of these effects is difficult to determine. Impaired lung function was reported in several 

studies that controlled for smoking (Chan et al. 1988; Cortona et al. 1992; Davison et al. 1988; Smith et 

al. 1976); other studies have not found significant alterations (Edling et al. 1986). The observed 

alterations include an increase in residual volume in workers exposed to air concentrations of cadmium 

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CADMIUM A-8 

APPENDIX A 

fumes ranging from 0.008 (in 1990) to 1.53 mg/m3 (in 1975) (mean urinary cadmium level in the workers 

was 4.3 μg/L) (Cortona et al. 1992); alterations in several lung function parameters (e.g., forced 

expiratory volume, transfer factor, transfer coefficient) in workers exposed to 0.034–0.156 mg/m3 

(Davison et al. 1988); and decreased force vital capacity in workers exposed to >0.2 mg/m3 (Smith et al. 

1976). Additionally, Chan et al. (1988) found significant improvements in several parameters of lung 

function of workers following reduction or cessation of cadmium exposure. 

The renal toxicity of cadmium in workers chronically exposed to high levels of cadmium is well 

established. Observed effects include tubular proteinuria (increased excretion of low molecular weight 

proteins), decreased resorption of other solutes (increased excretion of enzymes such as N-acetylβ-glucosaminidase (NAG), amino acids, glucose, calcium, inorganic phosphate), evidence of increased 

glomerular permeability (increased excretion of albumin), increased kidney stone formation, and 

decreased glomerular filtration rate. The earliest sign of cadmium-induced kidney damage is an increase 

in urinary levels of low molecular weight proteins (particularly, β2-microglobulin, retinol binding protein, 

and human complex-forming glycoprotein [pHC]) in cadmium workers, as compared to levels found in a 

reference group of workers or the general population (Bernard et al. 1990; Chen et al. 2006a, 2006b; Chia 

et al. 1992; Elinder et al. 1985a; Falck et al. 1983; Jakubowski et al. 1987, 1992; Järup and Elinder 1994; 

Järup et al. 1988; Shaikh et al. 1987; Toffoletto et al. 1992; Verschoor et al. 1987). Significant alterations 

in the prevalence of low molecular weight proteinuria among cadmium workers has been observed at 

urinary cadmium levels of 1.5 μg/g creatinine and higher (Chen et al. 2006a; Elinder et al. 1985a; 

Jakubowski et al. 1987; Järup and Elinder 1994). 

Agency Contact (Chemical Manager): Obaid Faroon, DVM, Ph.D. 

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CADMIUM A-9 

APPENDIX A 

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: Cadmium 

CAS Numbers: 7440-43-9 

Date: May, 2008 

Profile Status: First Draft Pre-Public Comment 

Route: [ ] Inhalation [X] Oral 

Duration: [ ] Acute [X] Intermediate [ ] Chronic 

Graph Key: 33 

Species: Rat 

Minimal Risk Level: 0.5 [X] μg Cd/kg/day [ ] ppm 

Reference: Brzóska MM, Moniuszko-Jakoniuk J. 2005d. Disorders in bone metabolism of female rats 

chronically exposed to cadmium. Toxicol Appl Pharmacol 202(1):68-83. 

Brzóska MM, Majewska K, Moniuszko-Jakoniuk J. 2005a. Bone mineral density, chemical composition 

and biomechanical properties of the tibia of female rats exposed to cadmium since weaning up to skeletal 

maturity. Food Chem Toxicol 43(10):1507-1519. 

Brzóska MM, Majewska K, Moniuszko-Jakoniuk J. 2005c. Weakness in the mechanical properties of 

the femur of growing female rats exposed to cadmium. Arch Toxicol 79(5):277-288. 

Experimental design: Groups of 40 3-week-old female Wistar rats were exposed to 0, 1, 5, or 50 mg 

Cd/L as cadmium chloride in drinking water for 12 months. The investigators noted that cadmium 

intakes were 0.059–0.219, 0.236–1.005, and 2.247–9.649 mg Cd/kg/day in the 1, 5, and 50 mg/L groups, 

respectively. Using cadmium intake data presented in a figure, cadmium intakes of 0.2, 0.5, and 4 mg 

Cd/kg/day were estimated. Bone mineral density, bone mineral concentration, and mineralization area of 

the lumbar spine, femur and total skeleton (bone mineral density only) were assessed after 3, 6, 9, or 

12 months of exposure. The mechanical properties of the femur and tibia were evaluated after 12 months 

of exposure. Markers for bone resorption (urinary and serum levels of C-terminal cross-linking 

telopeptide of type I collagen [CTX]) and bone formation (serum osteocalcin, total alkaline phosphatase, 

and cortical bone and trabecular bone alkaline phosphatase), and serum and urinary levels of calcium 

were also measured at 3, 6, 9, and 12 months. 

Effect noted in study and corresponding doses: No significant alterations in body weight gain or food and 

water consumption were observed. Significant decreases in total skeletal bone mineral density was 

observed at ≥0.2 mg Cd/kg/day; the decrease was significant after 3 months in the 4 mg Cd/kg/day group, 

after 6 months in the 0.5 mg Cd/kg/day group, and after 9 months in the 0.2 mg Cd/kg/day group. 

Significant decreases in whole tibia and diaphysis bone mineral density were observed at ≥0.2 mg 

Cd/kg/day after 12 months of exposure. At 0.2 mg Cd/kg/day, bone mineral density was decreased at the 

proximal and distal ends of the femur after 6 months of exposure; diaphysis bone mineral density was not 

affected. At 0.5 mg Cd/kg/day, bone mineral density was decreased at the femur proximal and distal ends 

after 3 months of exposure and diaphysis bone mineral density after 6 months of exposure. At 4 mg 

Cd/kg/day decreases in femoral proximal, distal, and diaphysis bone mineral density were decreased after 

3 months of exposure. Similarly, bone mineral density was significantly decreased in the lumbar spine in 

the 0.2 and 0.5 mg Cd/kg/day groups beginning at 6 months and at 3 months in the 4 mg Cd/kg/day 

group. Significant decreases in the mineralization area were observed in the femur and lumbar spine of 

rats exposed to 4 mg Cd/kg/day; lumbar spine bone mineral area was also affected at 0.5 mg Cd/kg/day. 

Significant decreases in tibia weight and length were observed at 4 mg Cd/kg/day. In tests of the 

mechanical properties of the tibia diaphysis, significant alterations in ultimate load, yield load, and 

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CADMIUM A-10 

APPENDIX A 

displacement at load were observed at ≥0.2 mg Cd/kg/day; work to fracture was also significantly altered 

at 4 mg Cd/kg/day. In the mechanical properties compression tests of the tibia, significant alterations 

were observed in ultimate load, ultimate load, and stiffness at 0.2 mg Cd/kg/day; displacement at yield 

and work to fracture at ≥0.5 mg Cd/kg/day; and displacement at ultimate at 4 mg Cd/kg/day. Multiple 

regression analysis showed that the cadmium-induced weakness in bone mechanical properties of the tibia 

was primarily due to its effects on bone composition, particularly the non-organic components, organic 

components, and the ratio of the ash weight to organic weight. The mechanical properties of the femur 

were strongly influenced by the bone mineral density (at the whole bone and diaphysis). A significant 

decrease in femur length was observed at 6 months of exposure to ≥0.2 mg Cd/kg/day; however, 

decreases in length were not observed at other time points in the 0.2 or 0.5 mg Cd/kg/day groups. Femur 

weight was significantly decreased at 4 mg Cd/kg/day. In tests of mechanical properties of the femoral 

neck and distal, decreases in yield load, ultimate load, displacement at ultimate, work to fracture (neck 

only), and stiffness (distal only) were observed at ≥0.2 mg Cd/kg/day. For the femoral diaphysis, 

significant alterations were observed for yield load, displacement at yield, and stiffness at ≥0.2 mg 

Cd/kg/day. Significant decreases in osteocalcin concentrations were observed in all cadmium groups 

during the first 6 months of exposure, but not during the last 6 months. Decreases in total alkaline 

phosphatase levels at 4 mg Cd/kg/day, trabecular bone alkaline phosphatase at 0.2 mg Cd/kg/day, and 

cortical bone alkaline phosphatase at 4 mg Cd/kg/day were observed. CTX was decreased at ≥0.2 mg 

Cd/kg/day. Total urinary calcium and fractional excretion of calcium were increased at ≥0.2 mg 

Cd/kg/day. 

Dose and end point used for MRL derivation: 

[ ] NOAEL [ ] LOAEL [X] BMDLsd1 

At the lowest dose tested, 0.2 mg Cd/kg/day, a number of skeletal alterations were observed including 

decreases in bone mineral density in the lumbar spine, femur, and tibia, alterations in the mechanical 

properties of the femur and tibia, decreases in osteocalcin levels, decreases in trabecular bone alkaline 

phosphatase, and decreases in CTX. Of these skeletal end points, the decrease in bone mineral density 

was selected as the critical effect because Brzóska et al. (2005a, 2005c) demonstrated that the bone 

mineral density was a stronger predictor of femur and tibia strength and the risk of fractures. 

Available continuous models in the EPA Benchmark Dose Software (version 1.4.1c) were fit to data 

(Table A-1) for changes in bone mineral density of the femur and lumbar spine in female rats resulting 

from exposure to cadmium in the drinking water for 6, 9, or 12 months (Brzóska and MoniuszkoJakoniuk 2005d). The BMD and the 95% lower confidence limit (BMDL) is an estimate of the doses 

associated with a change of 1 standard deviation from the control. The model-fitting procedure for 

continuous data is as follows. The simplest model (linear) is applied to the data while assuming constant 

variance. If the data are consistent with the assumption of constant variance (p ≥0.1), then the other 

continuous models (polynomial, power, and Hill models) are applied to the data. Among the models 

providing adequate fits to the means (p≥0.1), the one with the lowest Akaike information criterion (AIC) 

for the fitted model is selected for BMD derivation. If the test for constant variance is negative, the linear 

model is run again while applying the power model integrated into the benchmark dose software (BMDS) 

to account for nonhomogenous variance. If the nonhomogenous variance model provides an adequate fit 

(p≥0.1) to the variance data, then the other continuous models are applied to the data. Among the models 

providing adequate fits to the means (p≥0.1), the one with the lowest AIC for the fitted model is selected 

for BMD derivation. If the tests for both constant and non-constant variance are negative, then the data 

set is considered not to be suitable for BMD modeling. 

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CADMIUM A-11 

APPENDIX A 

Table A-1. Data Sets for Changes in Mineral Bone Density of the Femur and
 

Lumbar Spine in Female Rats Exposed to Cadmium in 

Drinking Water for 6, 9, or 12 Months
 

Dose (mg Cd/kg/day) 

Dataseta 0 0.2 0.5 4 

Femurb 

6 month 329.7±3.6 317.6±2.7c 308.5±3.4d 303.4±3.4e 

9 month 343.8±3.1 328.2±2.9d 322.8±3.0e 310.4±3.4e 

12 month 354.3±3.7 338.0±1.9d 330.9±3.1d 318.7±3.4e 

Lumbar spineb 

6 month 272.0±2.4 263.4±2.6c 258.3±2.7d 249.5±2.9e 

9 month 282.4±2.3 271.8±1.6d 267.8±1.8e 259.5±2.7e 

12 month 286.1±2.3 275.5±1.9d 269.1±1.9e 257.1±3.0e 

a

n=10 

b

mean±SE; standard errors were transformed to standard deviations for benchmark dose modeling via a function in 

the BMD software. 

c

Significantly different (p≤0.05) from the control group d

Significantly different (p≤0.01) from the control group e

Significantly different (p≤0.001) from the control group 

Source: Brzóska and Moniuszko-Jakoniuk 2005d 

The potential points of departures derived from the best fitting models for each dataset are summarized in 

Table A-2. 

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CADMIUM A-12 

APPENDIX A 

Table A-2. Summary of BMDs and BMDLs From the Best Fitting Models
 

Predicting Changes in Bone Mineral Density in Female Rats After
 

Cadmium Exposure From Drinking Water
 

Exposure 

Period Number of BMDsd1 a BMDLsd1 a 

(months) Best-fitting model doses (mg Cd/kg/day) (mg Cd/kg/day) 

Femur 

6 Linear 3 0.24 0.17 

9 Hill 4 0.11 0.05 

12 Hill 4 0.09 0.05 

Lumbar spine 

6 Hill 4 0.19 0.08 

9 Hill 4 0.11 0.05 

12 Hill 4 0.12 0.07 

a

BMDs and BMDLs from continuous data are associated with a 1 standard deviation change from the control. 

The BMDLsd1 of 0.05 mg Cd/kg/day estimated from the 9-month lumbar spine data set was selected as the 

point of departure for the MRL. In young female rats, the process of intense bone formation occurs 

during the first 7 months of life (the first 6 months of exposure in this study); thereafter, the increase in 

bone mineral density slows. In the lumbar spine of the control group, the changes in bone mineral density 

at 3–6 months, 6–9 months, and 9–12 months were 15, 4, and 1%, respectively. Thus, the 9-month data 

may best reflect the effect of cadmium on bone mineral density during the period of rapid skeletal growth. 

The lumbar spine data was selected over the femur data set because trabecular bone, which is abundant in 

the spine, appears to be more susceptible to cadmium toxicity than cortical bone. 

For the 9-month lumbar spine data set, the simplest model (linear) was applied to the data first to test for a 

fit for constant variance. The constant variance model did provide an adequate fit (as assessed by the 

p-value for variance) to the data. The polynomial, power, and Hill models were then fit to the data with 

constant variance assumed. The Hill model was the only model that provided an adequate fit to the data 

(as assessed by the p-value for the means) (Table A-3). Using the constant-variance Hill model, the 

BMDsd1 and BMDLsd1 are 0.11 mg/kg and 0.05 mg Cd/kg/day, respectively (Figure A-1). 

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Hill Model with 0.95 Confidence Level
 

290
 

285
 

280
 

275
 

270
 

265
 

260
 

255
 

250
 

dose 

15:24 05/27 2008 

*BMDs and BMDLs indicated are associated with a 1 standard deviation change from the control, and are in units of 

mg Cd/kg/day. Mean Response 

BMDL BMD 

Hill 

0 0.5 1 1.5 2 2.5 3 3.5 4 


 


 


 

Figure A-1. Predicted and Observed Incidence of Changes in Lumbar Spine Bone
 

Mineral Density in Female Rats Exposed to Cadmium in Drinking Water for
 

9 Months (Brzóska and Moniuszko-Jakoniuk 2005d)*
 

Table A-3. Model Predictions for Changes in Bone Mineral Density of the Lumbar
 

Spine in Female Rats Exposed to Cd in Drinking Water for 9 Months
 

Variance p-Value for BMDsd1 BMDLsd1 

Modela p-valueb the meansb AIC (mg Cd/kg/day) (mg Cd/kg/day) 

Linearc 0.36 0.00 211.92 1.93 1.42 

Polynomial (1-degree)c 0.36 0.00 211.92 1.93 1.42 

Polynomial (2-degree)c 0.36 0.00 211.92 1.93 1.42 

Polynomial (3-degree)c 0.36 0.00 211.92 1.93 1.42 

Power 0.36 0.00 211.92 1.93 1.42 

Hill 0.36 0.60 197.21 0.11 0.05 

a

Constant variance assumed for all models b

Values <0.1 fail to meet conventional goodness-of-fit criteria. c

Restriction = non-positive 

AIC = Akaike’s Information Criteria; BMD = benchmark dose; BMDL = lower confidence limit (95%) on the 

benchmark dose; p = p value from the Chi-squared test; Std1 = a 1 standard deviation change from the control. 

Source: Brzóska and Moniuszko-Jakoniuk 2005d 


 


 

CADMIUM A-13
 

APPENDIX A
 

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CADMIUM A-14 

APPENDIX A 

Uncertainty Factors used in MRL derivation: 

[ ] 10 for use of a LOAEL 

[X] 10 for extrapolation from animals to humans 

[X] 10 for human variability 

Was a conversion factor used from ppm in food or water to a mg/body weight dose? Investigators 

estimated doses based on body weight and water consumption. 

If an inhalation study in animals, list conversion factors used in determining human equivalent dose: Not 

applicable. 

Was a conversion used from intermittent to continuous exposure? Not applicable. 

Other additional studies or pertinent information that lend support to this MRL: There are limited data on 

the toxicity of cadmium in humans following intermediate-duration exposure. Numerous animal studies 

have examined the systemic, immunological, neurological, reproductive, and developmental toxicity of 

cadmium. The most sensitive systemic effect following intermediate-duration oral exposure to cadmium 

appears to be damage to growing bone. Exposure to 0.2 mg Cd/kg/day as cadmium chloride in drinking 

water for 3–12 months resulted decreases in bone mineral density, impaired mechanical strength of the 

lumbar spine, tibia, and femur bones, increased bone turnover, and increased incidence of deformed or 

fractured lumbar spine bone in young female rats (3 weeks of age at study initiation) (Brzóska and 

Moniuszko-Jakoniuk 2005d; Brzóska et al. 2004b, 2005a, 2005b, 2005c); similar findings were observed 

in young male rats exposed to 0.5 mg Cd/kg/day for up to 12 months (Brzóska and Moniuszko-Jakoniuk 

2005a, 2005b). Decreases in bone strength were also observed in young rats exposed to 0.8 mg 

Cd/kg/day as cadmium chloride in drinking water for 4 weeks (Ogoshi et al. 1989); however, no skeletal 

effects were observed in adult or elderly female rats exposed to doses >20 mg Cd/kg/day for 4 weeks 

(Ogoshi et al. 1989). 

Renal effects have been observed at higher doses than the skeletal effects. Vesiculation of the proximal 

tubules was observed in rats exposed to 1.18 mg Cd/kg/day as cadmium chloride in drinking water for 

40 weeks (Gatta et al. 1989). At approximately 3–8 mg Cd/kg/day, proteinuria, tubular necrosis, and 

decreased renal clearance were observed in rats (Cha 1987; Itokawa et al. 1974; Kawamura et al. 1978; 

Kotsonis and Klaassen 1978; Prigge 1978a). Liver necrosis and anemia (Cha 1987; Groten et al. 1990; 

Kawamura et al. 1978) were observed at similar cadmium doses. 

A number of developmental effects have been observed in the offspring of rats exposed to cadmium 

during gestation and lactation. Decreases in glomerular filtration rates and increases in urinary fractional 

excretion of phosphate, magnesium, potassium, sodium, and calcium were observed in 60-day-old 

offspring of rats administered via gavage 0.5 mg Cd/kg/day on gestation days 1–21 (Jacquillet et al. 

2007). Neurodevelopmental alterations have also been observed at the low maternal doses. Delays in the 

development of sensory motor coordination reflexes and increased motor activity were observed at 

0.706 mg Cd/kg/day (gestation days 1–21) (Ali et al. 1986), decreased motor activity at 0.04 mg 

Cd/kg/day (5–8 weeks of pre-gestation exposure, gestation days 1–21) (Baranski et al. 1983), decreased 

ambulation and rearing activity and altered ECG at 14 mg Cd/kg/day (gestation days 5–15, lactation 

days 2–28, postnatal days 1–56) (Desi et al. 1998) or 7 mg Cd/kg/day (F2 and F3 generations) 

(Nagymajtenyi et al. 1997) have been observed. Decreases in pup body weight were observed at ≥5 mg 

Cd/kg/day (Baranski 1987; Gupta et al. 1993; Kostial et al. 1993; Pond and Walker 1975) and decreases 

in fetal body weight or birth weight were observed at ≥2.4 mg Cd/kg/day (Petering et al. 1979; Sorell and 

Graziano 1990; Webster 1978; Sutou et al. 1980). Another commonly reported developmental effect was 

alterations in hematocrit levels or anemia in the offspring of animals exposed to ≥1.5 mg Cd/kg/day 

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CADMIUM A-15 

APPENDIX A 

(Kelman et al. 1978; Baranski 1987; Webster 1978). Increases in the occurrence of malformations or 

anomalies is limited to a study by Sutou et al. (1980), which reported a significant delay in ossification in 

rats exposed to 10 mg Cd/kg/day. 

The animal studies identify several sensitive targets of toxicity following intermediate-duration exposure 

to cadmium; these include skeletal mineralization in young female rats exposed for at least 3 months to 

0.2 mg Cd/kg/day (Brzóska and Moniuszko-Jakoniuk 2005d; Brzóska et al. 2004b, 2005a, 2005b, 2005c), 

decreased glomerular filtration in young rats exposed during gestation to maternal doses of 0.5 mg 

Cd/kg/day (Jacquillet et al. 2007), and neurodevelopmental effects following gestational exposure to 

0.04 mg Cd/kg/day (Baranski et al. 1983). Although the Baranski et al. (1983) study reported the lowest 

LOAEL, it was not selected as the principal study for derivation of an intermediate-duration MRL. For 

locomotor activity, a significant decrease in activity was observed in female offspring exposed to 0.04, 

0.4, and 4 mg Cd/kg/day, as compared to controls; however, no significant differences were found 

between the cadmium groups despite the 100-fold difference in doses. Locomotor activity was also 

decreased in males exposed to 0.4 or 4 mg Cd/kg/day. For the rotorod test, a significant decrease in the 

length of time the rat stayed on the rotorod was observed in males exposed to 0.04 and 0.4 mg Cd/kg/day, 

but not to 4 mg Cd/kg/day and in females exposed to 0.4 and 4 mg Cd/kg/day; no differences between the 

cadmium groups were observed in the males and females. The results were poorly reported and the 

investigators did not explain the lack of dose-response of the effects or the discrepancy between genders. 

Agency Contact (Chemical Manager): Obaid Faroon, DVM, Ph.D. 

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CADMIUM A-16 

APPENDIX A 

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: Cadmium 

CAS Numbers: 7440-43-9 

Date: July, 2008 

Profile Status: Second Pre-Public Comment Draft 

Route: [ ] Inhalation [X] Oral 

Duration: [ ] Acute [ ] Intermediate [X] Chronic 

Graph Key: 105 

Species: Human 

Minimal Risk Level: 0.1 [X] μg Cd/kg/day [ ] μg Cd/m3 

Reference: Buchet JP, Lauwerys R, Roels H, et al. 1990. Renal effects of cadmium body burden of the 

general population. Lancet 336:699-702. 

Järup L, Hellstrom L, Alfven T, et al. 2000. Low level exposure to cadmium and early kidney damage: 

The OSCAR study. Occup Environ Med 57(10):668-672. 

Suwazono Y, Sand S, Vahter M, et al. 2006. Benchmark dose for cadmium-induced renal effects in 

humans. Environ Health Perspect 114:1072-1076. 

Experimental design: ATSDR conducted a meta-analysis of select environmental exposure dose-response 

studies examining the relationship between urinary cadmium and the prevalence of elevated levels of 

biomarkers of renal function (Buchet et al. 1990; Järup et al. 2000; Jin et al. 2004c; Kobayashi et al. 2006; 

Shimizu et al. 2006; Suwazono et al. 2006; Wu et al. 2001). The studies were selected based on the 

following qualitative criteria: (1) the study measured an urinary cadmium as indicator of internal dose; 

(2) the study measured reliable indicators of low molecular weight (LMW) proteinuria; (3) a doseresponse relationship was reported in sufficient detail so that the dose-response function could be 

reproduced independently; (4) the study was of reasonable size to have provided statistical strength to the 

estimates of dose-response model parameters (i.e., most studies selected included several hundred to 

several thousand subjects); and (5) major co-variables that might affect the dose-response relationship 

(e.g., age, gender) were measured or constrained by design and included in the dose-response analysis. 

No attempt was made to weight selected studies for quality, statistical power, or statistical uncertainty in 

dose-response parameters. Studies using a cut-off value for β2-microglobulin of ≥1,000 μg/g creatinine 

were eliminated from the analysis based on the conclusions of Bernard et al. (1997) that urinary 

β2-microglobulin levels of 1,000–10,000 μg/g creatinine were indicative of irreversible tubular 

proteinuria, which may lead to an age-related decline in glomerular filtration rate. Additionally, an 

attempt was made to avoid using multiple analyses of the same study population. 

The individual dose-response functions from each study were implemented to arrive at estimates of the 

internal dose (urinary cadmium expressed as μg/g creatinine) corresponding to probabilities of 10% 

excess risk of low molecular weight proteinuria (urinary cadmium dose, UCD10). Estimates were derived 

from the seven environmental exposure studies listed above. When available, male and female data were 

treated separately; thus, 11 dose-response relationships were analyzed. For studies that did not report the 

UCD10, the value was estimated by iteration of the reported dose response relationship for varying values 

of urinary cadmium, until an excess risk of 10% was achieved. For studies that reported the doseresponse relationship graphically, but did not report the actual dose-response function, a function was 

derived by least squares fitting based on data from a digitization of the graphic 

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CADMIUM A-17 

APPENDIX A 

Dose and end point used for MRL derivation: Aggregate UCD10 estimates and the estimates stratified by 

location (i.e., Europe, Japan, China) are presented in Table A-4. The lowest UCD10 (1.34 μg/g creatinine) 

was estimated from the European database; and the 95% lower confidence limit on this UCD10 (UCDL10) 

of 0.5 μg/g creatinine was considered as the point of departure for the MRL. 

Table A-4. Estimates of the UCD10 and Cadmium Intake from Environmental
 

Exposure Dose-Response Studies 

Cadmium intakeb 

UCD10 a (μg/kg/day) 

(μg Cd/g creatinine) Females Males 

Europe (n=4)c 

Mean 1.34 0.97 2.24 

Median — — — 

95% CI 0.50, 2.18 0.33, 1.75 0.70, 3.94 

Japan (n=4)d 

Mean 5.23 4.59 10.1 

Median — — — 

95% CI 4.24, 6.21 3.67, 5.49 8.07, 12.0 

China (n=3)e 

Mean 9.55 8.60 18.8 

Median — — — 

95% CI 2.96, 16.1 2.48, 14.7 5.51, 31.9 

All (n=11) 

Mean 4.99 4.37 9.58 

Median 4.20 3.63 7.99 

95% CI 1.44, 6.60 1.06, 5.86 2.45, 12.8 

a

Estimates of urinary cadmium level corresponding to probabilities of 10% excess risk of low molecular weight
 

proteinuria (UCD10) b

UCD was transformed into estimates of chronic cadmium intake that would result in the UCD at age 55 using a
 

modification (Choudhury et al. 2001; Diamond et al. 2003) of the Kjellström and Nordberg (1978) model.

c

Dose-response function data from Buchet et al. (1990), Suwazono et al. (2006), and Järup et al. (2000); dose
 

response data from males and females in the Buchet et al. (1990) study were treated separately. d

Dose-response function data from Kobayashi et al. (2006) and Shimizu et al. (2006); dose response data from
 

males and females were treated separately.

e

Dose-response function data from Jin et al. (2004c) and Wu et al. (2001); dose response data from males and 

females in the Jin et al. (2004c) study were treated separately.
 

UCD = urinary cadmium dose 

[ ] NOAEL [ ] LOAEL [X] UCDL10 

The UCDL10 of 0.5 μg/g creatinine was transformed into estimates of chronic cadmium intake (expressed 

as μg/kg/day) that would result in the UCDL10 at age 55 (approximate age of peak cadmium concentration 

in the renal cortex associated with a constant chronic intake). The dose transformations were achieved by 

simulation using a modification of the Kjellström and Nordberg (1978) model. The following 

modifications (Choudhury et al. 2001; Diamond et al. 2003) were made to the model: (1) the equations 

describing intercompartmental transfers of cadmium were implemented as differential equations in 

Advanced Computer Simulation Language (acslXtreme, version 2.4.0.9); (2) growth algorithms for males 

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CADMIUM A-18 

APPENDIX A 

and females and corresponding organ weights (O’Flaherty 1993) were used to calculate age-specific 

cadmium concentrations from tissue cadmium masses; (3) the cadmium concentration in renal cortex 

(RC, μg/g) was calculated as follows: 

K RC =1.5⋅

KW 

where K is the age-specific renal cadmium burden (μg) and KW is the age-specific kidney wet 

weight (g) (Friberg et al. 1974) 

(4) the rate of creatinine excretion (e.g., Crur, g creatinine/day) was calculated from the relationship 

between lean body mass (LBM) and Crur); and (5) absorption of ingested cadmium was assumed to be 5% 

in males and 10% in females. The rate of creatinine excretion (e.g., Crur, g creatinine/day) was estimated 

from the relationship between LBM (kg) and Crur: 

LBM = 27.2 ⋅Crur + 8.58 

where the constants 27.2 and 8.58 are the sample size-weighted arithmetic mean of estimates of 

these variables from eight studies reported in (Forbes and Bruining 1976). Lean body mass was 

estimated as follows (ICRP 1981): 

LBM = BW ⋅0.85,adult females 

LBM = BW ⋅0.88,adultmales 

where the central tendency for adult body weight for males and females were assumed to be 

70 and 58 kg for adult European/American males and females, respectively. 

Dose units expressed as cadmium intake (μg/kg/day), urinary cadmium excretion (μg/g creatinine), or 

kidney tissue cadmium (μg/g cortex) were interconverted by iterative pharmacokinetic model simulations 

of constant intakes for the life-time to age 55 years, the age at which renal cortex cadmium concentrations 

are predicted to reach their peak when the rate of intake (μg/kg/day) is constant. 

The dietary cadmium intakes which would result in urinary cadmium levels of 1.34 and 0.5 μg/g 

creatinine (UCD10 and UCDL10) are 0.97 and 0.33 μg/kg/day in females and 2.24 and 0.70 μg/kg/day in 

males. 

Uncertainty Factors used in MRL derivation: 

[ ] 10 for use of a LOAEL
 

[ ] 10 for extrapolation from animals to humans
 

[X] 3 for human variability 

The UCD is based on several large-scale environmental exposure studies that likely included sensitive 

subpopulations; however, there is concern that individuals with diabetes may be especially sensitive to the

renal toxicity of cadmium (Åkesson et al. 2005; Buchet et al. 1990) and diabetics were excluded from a 

number of human studies, and thus, an uncertainty factor of 3 was used. 

Was a conversion factor used from ppm in food or water to a mg/body weight dose? No. 

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CADMIUM A-19 

APPENDIX A 

If an inhalation study in animals, list conversion factors used in determining human equivalent dose: Not 

applicable. 

Was a conversion used from intermittent to continuous exposure? No. 

Other additional studies or pertinent information that lend support to this MRL: The results of numerous 

studies of environmentally exposed populations provide strong evidence that the kidney, and possibly 

bone, is the most sensitive target of toxicity following chronic exposure to cadmium. Most of the studies 

have focused on subclinical alterations of kidney function, as measured by the urinary excretion of several 

biomarkers including low molecular weight proteins (β2-microglobulin, pHC, retinol binding protein), 

intracellular tubular enzymes (NAG), amino acids, high molecular weight proteins (albumin), and 

electrolytes (potassium, sodium, calcium). Significant associations between urinary cadmium levels and 

an increased prevalence of abnormal levels of these biomarkers have been found in populations living in 

areas with moderate or high cadmium pollution or low cadmium pollution (Buchet et al. 1990; Cai et al. 

1990, 1992, 1998, 2001; Hayano et al. 1996; Horiguchi et al. 2004; Ishizaki et al. 1989; Izuno et al. 2000; 

Järup et al. 2000; Jin et al. 2002, 2004a, 2004c; Kawada et al. 1992; Kido and Nogawa 1993; Kobayashi 

et al. 2002a; Monzawa et al. 1998; Nakashima et al. 1997; Nogawa et al. 1989; Noonan et al. 2002; 

Nordberg et al. 1997; Olsson et al. 2002; Oo et al. 2000; Osawa et al. 2001; Roels et al. 1981b; Suwazono 

et al. 2006; Teeyakasem et al. 2007; Trzcinka-Ochocka et al. 2004; Uno et al. 2005; Yamanaka et al. 

1998; Wu et al. 2001). Increases in the prevalence of abnormal biomarker levels appear to be the most 

sensitive indicator of cadmium toxicity and alterations have been observed at urinary cadmium levels 

ranging from 1 μg/g creatinine (Järup et al. 2000) to 9.51 μg/g creatinine (Jin et al. 2004a). 

Several studies have examined the possible association between exposure to cadmium and bone effects. 

Significant associations between urinary cadmium levels and an increased risk of bone fractures at urinary 

cadmium levels of ≥0.7 μg/g creatinine (Alfvén et al. 2004; Staessen et al. 1999; Wang et al. 2003), 

increased risk of osteoporosis at urinary cadmium levels of ≥1.5 μg/g creatinine (Alfvén et al. 2000; Jin et 

al. 2004b; Wang et al. 2003), and decreased bone mineral density at urinary cadmium levels of ≥0.6 μg/g 

creatinine (Nordberg et al. 2002; Schutte et al. 2008). 

The adverse effect levels for renal effects were similar to those observed for skeletal effects. Because the 

renal effects database is stronger, it was used for derivation of a chronic-duration oral MRL for cadmium. 

Three approaches were considered for derivation of the MRL: (1) NOAEL/LOAEL approach using a 

single environmental exposure study finding an increased prevalence of abnormal renal effect biomarker 

levels, (2) selection of a point of departure from a published benchmark dose analysis, or (3) selection of 

a point of departure on an analysis of the dose-response functions from a number of environmental 

exposure studies. 

In the first approach, all studies in which individual internal doses for subjects were estimated based on 

urinary cadmium were considered. The Järup et al. (2000) study identified the lowest adverse effect 

level; the investigators estimated that a urinary cadmium level of 1 μg/g creatinine would be associated 

with a 10% increase in the prevalence of abnormal pHC levels above background prevalence 

(approximately a 10% added risk). The European Chemicals Bureau (2007) recalculated the probability 

of HC proteinuria because the reference population and the study population were not matched for age 

(40 versus 53 years, respectively). They estimated that the probability of HC proteinuria (13%) would be 

twice as high as the reference population at a urinary cadmium concentration of 0.5 μg/g creatinine. For 

the second approach, five published benchmark dose analyses were evaluated (Jin et al. 2004b; Kobayashi 

et al. 2006; Shimizu et al. 2006; Suwazono et al. 2006; Uno et al. 2005). The lower 95% confidence 

interval of the benchmark dose (BMDL) for low molecular weight proteinuria ranged from 0.7 μg/g 

creatinine (Uno et al. 2005) to 9.9 μg/g creatinine (Kobayashi et al. 2006). The third approach involved a 

meta-analysis of selected environmental exposure dose-response studies. Using individual dose-response 

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CADMIUM A-20 

APPENDIX A 

functions from each study, estimates of the internal cadmium dose corresponding to probabilities of 10% 

excess risk of low molecular weight proteinuria were calculated. The lowest UCD10 (1.34 μg/g 

creatinine) was estimated from the European database; and the 95% lower confidence limit on this UCD10 

(UCDL10) of 0.5 μg/g creatinine was considered as a potential point of departure for the MRL. 

The points of departure selected using the three different approaches are similar: 0.5 μg/g creatinine from 

the Järup et al. (2000) study (using the European Chemicals Bureau 2007 recalculation), 0.7 μg/g 

creatinine from the Uno et al. (2005) benchmark dose analysis, and 0.5 μg/g creatinine from the doseresponse analysis. The third approach was selected for the derivation of the MRL because it uses the 

whole dose-response curves from several studies rather than data from a single study. 

Agency Contact (Chemical Manager): Obaid Faroon, DVM, Ph.D. 

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CADMIUM	 B-1 

APPENDIX B. USER'S GUIDE 

Chapter 1 

Public Health Statement 

This chapter of the profile is a health effects summary written in non-technical language. Its intended 

audience is the general public, especially people living in the vicinity of a hazardous waste site or 

chemical release. If the Public Health Statement were removed from the rest of the document, it would 

still communicate to the lay public essential information about the chemical. 

The major headings in the Public Health Statement are useful to find specific topics of concern. The 

topics are written in a question and answer format. The answer to each question includes a sentence that 

will direct the reader to chapters in the profile that will provide more information on the given topic. 

Chapter 2 

Relevance to Public Health 

This chapter provides a health effects summary based on evaluations of existing toxicologic, 

epidemiologic, and toxicokinetic information. This summary is designed to present interpretive, weightof-evidence discussions for human health end points by addressing the following questions: 

1.	 What effects are known to occur in humans? 

2.	 What effects observed in animals are likely to be of concern to humans? 

3.	 What exposure conditions are likely to be of concern to humans, especially around hazardous 

waste sites? 

The chapter covers end points in the same order that they appear within the Discussion of Health Effects 

by Route of Exposure section, by route (inhalation, oral, and dermal) and within route by effect. Human 

data are presented first, then animal data. Both are organized by duration (acute, intermediate, chronic). 

In vitro data and data from parenteral routes (intramuscular, intravenous, subcutaneous, etc.) are also 

considered in this chapter. 

The carcinogenic potential of the profiled substance is qualitatively evaluated, when appropriate, using 

existing toxicokinetic, genotoxic, and carcinogenic data. ATSDR does not currently assess cancer 

potency or perform cancer risk assessments. Minimal Risk Levels (MRLs) for noncancer end points (if 

derived) and the end points from which they were derived are indicated and discussed. 

Limitations to existing scientific literature that prevent a satisfactory evaluation of the relevance to public 

health are identified in the Chapter 3 Data Needs section. 

Interpretation of Minimal Risk Levels 

Where sufficient toxicologic information is available, ATSDR has derived MRLs for inhalation and oral 

routes of entry at each duration of exposure (acute, intermediate, and chronic). These MRLs are not 

meant to support regulatory action, but to acquaint health professionals with exposure levels at which 

adverse health effects are not expected to occur in humans. 

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CADMIUM B-2 

APPENDIX B 

MRLs should help physicians and public health officials determine the safety of a community living near 

a chemical emission, given the concentration of a contaminant in air or the estimated daily dose in water. 

MRLs are based largely on toxicological studies in animals and on reports of human occupational 

exposure. 

MRL users should be familiar with the toxicologic information on which the number is based. Chapter 2, 

"Relevance to Public Health," contains basic information known about the substance. Other sections such 

as Chapter 3 Section 3.9, "Interactions with Other Substances,” and Section 3.10, "Populations that are 

Unusually Susceptible" provide important supplemental information. 

MRL users should also understand the MRL derivation methodology. MRLs are derived using a 

modified version of the risk assessment methodology that the Environmental Protection Agency (EPA) 

provides (Barnes and Dourson 1988) to determine reference doses (RfDs) for lifetime exposure. 

To derive an MRL, ATSDR generally selects the most sensitive end point which, in its best judgement, 

represents the most sensitive human health effect for a given exposure route and duration. ATSDR 

cannot make this judgement or derive an MRL unless information (quantitative or qualitative) is available 

for all potential systemic, neurological, and developmental effects. If this information and reliable 

quantitative data on the chosen end point are available, ATSDR derives an MRL using the most sensitive 

species (when information from multiple species is available) with the highest no-observed-adverse-effect 

level (NOAEL) that does not exceed any adverse effect levels. When a NOAEL is not available, a 

lowest-observed-adverse-effect level (LOAEL) can be used to derive an MRL, and an uncertainty factor 

(UF) of 10 must be employed. Additional uncertainty factors of 10 must be used both for human 

variability to protect sensitive subpopulations (people who are most susceptible to the health effects 

caused by the substance) and for interspecies variability (extrapolation from animals to humans). In 

deriving an MRL, these individual uncertainty factors are multiplied together. The product is then 

divided into the inhalation concentration or oral dosage selected from the study. Uncertainty factors used 

in developing a substance-specific MRL are provided in the footnotes of the levels of significant exposure 

(LSE) tables. 

Chapter 3 

Health Effects 

Tables and Figures for Levels of Significant Exposure (LSE) 

Tables and figures are used to summarize health effects and illustrate graphically levels of exposure 

associated with those effects. These levels cover health effects observed at increasing dose 

concentrations and durations, differences in response by species, MRLs to humans for noncancer end 

points, and EPA's estimated range associated with an upper- bound individual lifetime cancer risk of 1 in 

10,000 to 1 in 10,000,000. Use the LSE tables and figures for a quick review of the health effects and to 

locate data for a specific exposure scenario. The LSE tables and figures should always be used in 

conjunction with the text. All entries in these tables and figures represent studies that provide reliable, 

quantitative estimates of NOAELs, LOAELs, or Cancer Effect Levels (CELs). 

The legends presented below demonstrate the application of these tables and figures. Representative 

examples of LSE Table 3-1 and Figure 3-1 are shown. The numbers in the left column of the legends 

correspond to the numbers in the example table and figure. 

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CADMIUM	 B-3 

APPENDIX B 

LEGEND 

See Sample LSE Table 3-1 (page B-6) 

(1)	 Route of Exposure. One of the first considerations when reviewing the toxicity of a substance 

using these tables and figures should be the relevant and appropriate route of exposure. Typically 

when sufficient data exist, three LSE tables and two LSE figures are presented in the document. 

The three LSE tables present data on the three principal routes of exposure, i.e., inhalation, oral, 

and dermal (LSE Tables 3-1, 3-2, and 3-3, respectively). LSE figures are limited to the inhalation 

(LSE Figure 3-1) and oral (LSE Figure 3-2) routes. Not all substances will have data on each 

route of exposure and will not, therefore, have all five of the tables and figures. 

(2)	 Exposure Period. Three exposure periods—acute (less than 15 days), intermediate (15– 

364 days), and chronic (365 days or more)—are presented within each relevant route of exposure. 

In this example, an inhalation study of intermediate exposure duration is reported. For quick 

reference to health effects occurring from a known length of exposure, locate the applicable 

exposure period within the LSE table and figure. 

(3)	 Health Effect. The major categories of health effects included in LSE tables and figures are 

death, systemic, immunological, neurological, developmental, reproductive, and cancer. 

NOAELs and LOAELs can be reported in the tables and figures for all effects but cancer. 

Systemic effects are further defined in the "System" column of the LSE table (see key number 

18). 

(4)	 Key to Figure. Each key number in the LSE table links study information to one or more data 

points using the same key number in the corresponding LSE figure. In this example, the study 

represented by key number 18 has been used to derive a NOAEL and a Less Serious LOAEL 

(also see the two "18r" data points in sample Figure 3-1). 

(5)	 Species. The test species, whether animal or human, are identified in this column. Chapter 2, 

"Relevance to Public Health," covers the relevance of animal data to human toxicity and 

Section 3.4, "Toxicokinetics," contains any available information on comparative toxicokinetics. 

Although NOAELs and LOAELs are species specific, the levels are extrapolated to equivalent 

human doses to derive an MRL. 

(6)	 Exposure Frequency/Duration. The duration of the study and the weekly and daily exposure 

regimens are provided in this column. This permits comparison of NOAELs and LOAELs from 

different studies. In this case (key number 18), rats were exposed to “Chemical x” via inhalation 

for 6 hours/day, 5 days/week, for 13 weeks. For a more complete review of the dosing regimen, 

refer to the appropriate sections of the text or the original reference paper (i.e., Nitschke et al. 

1981). 

(7)	 System. This column further defines the systemic effects. These systems include respiratory, 

cardiovascular, gastrointestinal, hematological, musculoskeletal, hepatic, renal, and 

dermal/ocular. "Other" refers to any systemic effect (e.g., a decrease in body weight) not covered 

in these systems. In the example of key number 18, one systemic effect (respiratory) was 

investigated. 

(8)	 NOAEL. A NOAEL is the highest exposure level at which no harmful effects were seen in the 

organ system studied. Key number 18 reports a NOAEL of 3 ppm for the respiratory system, 

which was used to derive an intermediate exposure, inhalation MRL of 0.005 ppm (see 

footnote "b"). 

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CADMIUM	 B-4 

APPENDIX B 

(9)	 LOAEL. A LOAEL is the lowest dose used in the study that caused a harmful health effect. 

LOAELs have been classified into "Less Serious" and "Serious" effects. These distinctions help 

readers identify the levels of exposure at which adverse health effects first appear and the 

gradation of effects with increasing dose. A brief description of the specific end point used to 

quantify the adverse effect accompanies the LOAEL. The respiratory effect reported in key 

number 18 (hyperplasia) is a Less Serious LOAEL of 10 ppm. MRLs are not derived from 

Serious LOAELs. 

(10)	 Reference. The complete reference citation is given in Chapter 9 of the profile. 

(11)	 CEL. A CEL is the lowest exposure level associated with the onset of carcinogenesis in 

experimental or epidemiologic studies. CELs are always considered serious effects. The LSE 

tables and figures do not contain NOAELs for cancer, but the text may report doses not causing 

measurable cancer increases. 

(12)	 Footnotes. Explanations of abbreviations or reference notes for data in the LSE tables are found 

in the footnotes. Footnote "b" indicates that the NOAEL of 3 ppm in key number 18 was used to 

derive an MRL of 0.005 ppm. 

LEGEND 

See Sample Figure 3-1 (page B-7) 

LSE figures graphically illustrate the data presented in the corresponding LSE tables. Figures help the 

reader quickly compare health effects according to exposure concentrations for particular exposure 

periods. 

(13)	 Exposure Period. The same exposure periods appear as in the LSE table. In this example, health 

effects observed within the acute and intermediate exposure periods are illustrated. 

(14)	 Health Effect. These are the categories of health effects for which reliable quantitative data 

exists. The same health effects appear in the LSE table. 

(15)	 Levels of Exposure. Concentrations or doses for each health effect in the LSE tables are 

graphically displayed in the LSE figures. Exposure concentration or dose is measured on the log 

scale "y" axis. Inhalation exposure is reported in mg/m3 or ppm and oral exposure is reported in 

mg/kg/day. 

(16)	 NOAEL. In this example, the open circle designated 18r identifies a NOAEL critical end point in 

the rat upon which an intermediate inhalation exposure MRL is based. The key number 18 

corresponds to the entry in the LSE table. The dashed descending arrow indicates the 

extrapolation from the exposure level of 3 ppm (see entry 18 in the table) to the MRL of 

0.005 ppm (see footnote "b" in the LSE table). 

(17)	 CEL. Key number 38m is one of three studies for which CELs were derived. The diamond 

symbol refers to a CEL for the test species-mouse. The number 38 corresponds to the entry in the 

LSE table. 

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CADMIUM	 B-5 

APPENDIX B 

(18)	 Estimated Upper-Bound Human Cancer Risk Levels. This is the range associated with the upperbound for lifetime cancer risk of 1 in 10,000 to 1 in 10,000,000. These risk levels are derived 

from the EPA's Human Health Assessment Group's upper-bound estimates of the slope of the 

cancer dose response curve at low dose levels (q1*). 

(19)	 Key to LSE Figure. The Key explains the abbreviations and symbols used in the figure. 

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1 2 3 4 

→

SAMPLE 

Table 3-1. Levels of Significant Exposure to [Chemical x] – Inhalation 

→→

Exposure 

Key to frequency/ 

figurea Species duration 

INTERMEDIATE EXPOSURE 

5 6 

Systemic ↓ ↓

NOAEL 

System (ppm) 

7 8 ↓ ↓

LOAEL (effect) Less serious (ppm) 

9 

↓

Serious (ppm) 

Re

10 

↓

→→

18 Rat 13 wk Resp 3b 10 (hyperplasia) 

5 d/wk Nit

6 hr/d 

CHRONIC EXPOSURE 

Cancer 11 

↓

38 Rat 18 mo 20 (CEL, multiple Wo

5 d/wk organs) 

7 hr/d 

39 Rat 89–104 wk 10 (CEL, lung tumors, NT

5 d/wk nasal tumors) 

6 hr/d 

40 Mouse 79–103 wk 10 (CEL, lung tumors, NT

5 d/wk hemangiosarcomas) 

6 hr/d 

a The number corresponds to entries in Figure 3-1. b Used to derive an intermediate inhalation Minimal Risk Level (MRL) of 5x10-3 ppm; dose adjusted for intermittent ex

by an uncertainty factor of 100 (10 for extrapolation from animal to humans, 10 for human variability). 

12 
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CADMIUM B-8 

APPENDIX B 

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CADMIUM C-1 

APPENDIX C. ACRONYMS, ABBREVIATIONS, AND SYMBOLS 

ACGIH American Conference of Governmental Industrial Hygienists 

ACOEM American College of Occupational and Environmental Medicine 

ADI acceptable daily intake 

ADME absorption, distribution, metabolism, and excretion 

AED atomic emission detection 

AFID alkali flame ionization detector 

AFOSH Air Force Office of Safety and Health 

ALT alanine aminotransferase 

AML acute myeloid leukemia 

AOAC Association of Official Analytical Chemists 

AOEC Association of Occupational and Environmental Clinics 

AP alkaline phosphatase 

APHA American Public Health Association 

AST aspartate aminotransferase 

atm atmosphere 

ATSDR Agency for Toxic Substances and Disease Registry 

AWQC Ambient Water Quality Criteria 

BAT best available technology 

BCF bioconcentration factor 

BEI Biological Exposure Index 

BMD/C benchmark dose or benchmark concentration 

BMDX dose that produces a X% change in response rate of an adverse effect 

BMDLX 95% lower confidence limit on the BMDX 

BMDS Benchmark Dose Software 

BMR benchmark response 

BSC Board of Scientific Counselors 

C centigrade 

CAA Clean Air Act 

CAG Cancer Assessment Group of the U.S. Environmental Protection Agency 

CAS Chemical Abstract Services 

CDC Centers for Disease Control and Prevention 

CEL cancer effect level 

CELDS Computer-Environmental Legislative Data System 

CERCLA Comprehensive Environmental Response, Compensation, and Liability Act 

CFR Code of Federal Regulations 

Ci curie 

CI confidence interval 

CL ceiling limit value 

CLP Contract Laboratory Program 

cm centimeter 

CML chronic myeloid leukemia 

CPSC Consumer Products Safety Commission 

CWA Clean Water Act 

DHEW Department of Health, Education, and Welfare 

DHHS Department of Health and Human Services 

DNA deoxyribonucleic acid 

DOD Department of Defense 

DOE Department of Energy 

DOL Department of Labor 

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CADMIUM C-2 

APPENDIX C 

DOT 

DOT/UN/ 

NA/IMDG 

DWEL 

ECD 

ECG/EKG 

EEG 

EEGL 

EPA 

F 

F1 

FAO 

FDA 

FEMA 

FIFRA 

FPD 

fpm 

FR 

FSH 

g 

GC 

gd 

GLC 

GPC 

HPLC 

HRGC 

HSDB 

IARC 

IDLH 

ILO 

IRIS 

Kd 

kg 

kkg 

Koc 

Kow 

L 

LC 

LC50 

LCLo 

LD50 

LDLo 

LDH 

LH 

LOAEL 

LSE 

LT50 

m 

MA 

MAL 

mCi 

Department of Transportation 

Department of Transportation/United Nations/ 

North America/Intergovernmental Maritime Dangerous Goods Code 

drinking water exposure level 

electron capture detection 

electrocardiogram 

electroencephalogram 

Emergency Exposure Guidance Level 

Environmental Protection Agency 

Fahrenheit 

first-filial generation 

Food and Agricultural Organization of the United Nations 

Food and Drug Administration 

Federal Emergency Management Agency 

Federal Insecticide, Fungicide, and Rodenticide Act 

flame photometric detection 

feet per minute 

Federal Register 

follicle stimulating hormone 

gram 

gas chromatography 

gestational day 

gas liquid chromatography 

gel permeation chromatography 

high-performance liquid chromatography 

high resolution gas chromatography 

Hazardous Substance Data Bank 

International Agency for Research on Cancer 

immediately dangerous to life and health 

International Labor Organization 

Integrated Risk Information System 

adsorption ratio 

kilogram 

metric ton 

organic carbon partition coefficient 

octanol-water partition coefficient 

liter 

liquid chromatography 

lethal concentration, 50% kill 

lethal concentration, low 

lethal dose, 50% kill 

lethal dose, low 

lactic dehydrogenase 

luteinizing hormone 

lowest-observed-adverse-effect level 

Levels of Significant Exposure 

lethal time, 50% kill 

meter 

trans,trans-muconic acid 

maximum allowable level 

millicurie 

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CADMIUM C-3 

APPENDIX C 

MCL maximum contaminant level 

MCLG maximum contaminant level goal 

MF modifying factor 

MFO mixed function oxidase 

mg milligram 

mL milliliter 

mm millimeter 

mmHg millimeters of mercury 

mmol millimole 

mppcf millions of particles per cubic foot 

MRL Minimal Risk Level 

MS mass spectrometry 

NAAQS National Ambient Air Quality Standard 

NAS National Academy of Science 

NATICH National Air Toxics Information Clearinghouse 

NATO North Atlantic Treaty Organization 

NCE normochromatic erythrocytes 

NCEH National Center for Environmental Health 

NCI National Cancer Institute 

ND not detected 

NFPA National Fire Protection Association 

ng nanogram 

NHANES National Health and Nutrition Examination Survey 

NIEHS National Institute of Environmental Health Sciences 

NIOSH National Institute for Occupational Safety and Health 

NIOSHTIC NIOSH's Computerized Information Retrieval System 

NLM National Library of Medicine 

nm nanometer 

nmol nanomole 

NOAEL no-observed-adverse-effect level 

NOES National Occupational Exposure Survey 

NOHS National Occupational Hazard Survey 

NPD nitrogen phosphorus detection 

NPDES National Pollutant Discharge Elimination System 

NPL National Priorities List 

NR not reported 

NRC National Research Council 

NS not specified 

NSPS New Source Performance Standards 

NTIS National Technical Information Service 

NTP National Toxicology Program 

ODW Office of Drinking Water, EPA 

OERR Office of Emergency and Remedial Response, EPA 

OHM/TADS Oil and Hazardous Materials/Technical Assistance Data System 

OPP Office of Pesticide Programs, EPA 

OPPT Office of Pollution Prevention and Toxics, EPA 

OPPTS Office of Prevention, Pesticides and Toxic Substances, EPA 

OR odds ratio 

OSHA Occupational Safety and Health Administration 

OSW Office of Solid Waste, EPA 

OTS Office of Toxic Substances 

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CADMIUM C-4 

APPENDIX C 

OW Office of Water 

OWRS Office of Water Regulations and Standards, EPA 

PAH polycyclic aromatic hydrocarbon 

PBPD physiologically based pharmacodynamic 

PBPK physiologically based pharmacokinetic 

PCE polychromatic erythrocytes 

PEL permissible exposure limit 

pg picogram 

PHS Public Health Service 

PID photo ionization detector 

pmol picomole 

PMR proportionate mortality ratio 

ppb parts per billion 

ppm parts per million 

ppt parts per trillion 

PSNS pretreatment standards for new sources 

RBC red blood cell 

REL recommended exposure level/limit 

RfC reference concentration 

RfD reference dose 

RNA ribonucleic acid 

RQ reportable quantity 

RTECS Registry of Toxic Effects of Chemical Substances 

SARA Superfund Amendments and Reauthorization Act 

SCE sister chromatid exchange 

SGOT serum glutamic oxaloacetic transaminase 

SGPT serum glutamic pyruvic transaminase 

SIC standard industrial classification 

SIM selected ion monitoring 

SMCL secondary maximum contaminant level 

SMR standardized mortality ratio 

SNARL suggested no adverse response level 

SPEGL Short-Term Public Emergency Guidance Level 

STEL short term exposure limit 

STORET Storage and Retrieval 

TD50 toxic dose, 50% specific toxic effect 

TLV threshold limit value 

TOC total organic carbon 

TPQ threshold planning quantity 

TRI Toxics Release Inventory 

TSCA Toxic Substances Control Act 

TWA time-weighted average 

UF uncertainty factor 

U.S. United States 

USDA United States Department of Agriculture 

USGS United States Geological Survey 

VOC volatile organic compound 

WBC white blood cell 

WHO World Health Organization 

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CADMIUM C-5 

APPENDIX C 

> greater than 

≥ greater than or equal to 

= equal to 

< less than 

≤ less than or equal to 

% percent 

α alpha 

β beta 

γ gamma 

δ delta 

μm micrometer 

μg microgram 

q1

* cancer slope factor 

– negative 

+ positive 

(+) weakly positive result 

(–) weakly negative result 

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CADMIUM C-6 

APPENDIX C 

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CADMIUM D-1 

APPENDIX D. INDEX
 

absorbed dose.................................................................................................................................... 220, 222
 

adenocarcinoma ................................................................................................................................ 101, 170
 

adrenal gland.............................................................................................................................................158
 

adrenals .....................................................................................................................................................158
 

adsorbed............................................................................................................................................ 268, 279
 

adsorption.................................................................................................................. 262, 279, 280, 282, 313
 

aerobic.......................................................................................................................................................263
 

alanine aminotransferase (see ALT) ................................................................................................... 83, 140
 

ALT (see alanine aminotransferase).........................................................................................................140
 

ambient air .................................................................................................. 11, 268, 284, 293, 299, 303, 309
 

anemia....................................................................................................... 23, 26, 27, 82, 134, 135, 229, 238
 

anthropogenic.............................................................................. 11, 265, 270, 276, 285, 287, 288, 293, 324
 

atmospheric deposition ....................................................... 11, 268, 275, 278, 284, 287, 288, 291, 293, 309
 

batteries................................................................................. 2, 7, 80, 84, 255, 261, 262, 263, 265, 304, 307
 

bioaccumulation........................................................................................................................................308
 

bioavailability ........................................................................................... 280, 282, 291, 308, 312, 313, 326
 

bioconcentration factor .............................................................................................................................281
 

biokinetic .......................................................................................................................................... 220, 327
 

biological half-time...................................................................................................................................191
 

biomarker ............................................... 13, 16, 21, 31, 32, 34, 35, 37, 84, 86, 88, 133, 140, 141, 142, 143, 

144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 155, 156, 161, 

219, 220, 221, 223, 226, 229, 239, 243, 244, 247, 294, 315, 324
 

blood cadmium......................... 3, 7, 12, 21, 31, 81, 84, 86, 87, 95, 134, 137, 144, 147, 150, 161, 162, 164, 

188, 198, 215, 218, 220, 222, 229, 269, 294, 298, 303, 304, 305, 310
 

blood cell count...........................................................................................................................................82
 

body weight effects............................................................................................................................. 91, 158
 

bone mineral density........................... 14, 25, 28, 29, 30, 136, 137, 138, 139, 211, 238, 239, 243, 246, 294
 

breast milk..................................................................................................................... 6, 217, 248, 303, 309
 

cadmium carbonate ..................................................................................... 17, 43, 46, 82, 94, 187, 190, 283
 

cadmium chloride............. 17, 19, 23, 25, 26, 27, 43, 45, 46, 47, 74, 75, 79, 82, 83, 91, 92, 94, 96, 97, 101, 

102, 103, 133, 140, 164, 165, 166, 170, 171, 181, 183, 184, 185, 186, 191, 

202, 206, 208, 210, 211, 212, 217, 219, 227, 255, 260, 261, 275, 327, 328
 

cadmium oxide................... 16, 17, 19, 22, 23, 24, 43, 45, 46, 47, 48, 73, 74, 75, 79, 80, 81, 82, 83, 84, 91, 

92, 93, 96, 97, 100, 101, 171, 181, 207, 260, 263, 265, 275, 283, 300, 309, 327
 

cadmium sulfate.............................................. 2, 43, 45, 47, 73, 79, 83, 91, 92, 96, 101, 181, 255, 260, 283
 

cadmium sulfide................................................................. 22, 23, 24, 43, 45, 46, 47, 79, 80, 82, 83, 91, 94, 

101, 171, 183, 206, 255, 262, 279, 282, 283, 309
 

cancer............................................ 5, 15, 44, 98, 99, 100, 101, 167, 168, 173, 215, 227, 235, 240, 244, 332
 

carcinogen................................................................................... 5, 13, 15, 98, 100, 102, 170, 240, 244, 332
 

carcinogenic ................................................................ 5, 15, 44, 98, 100, 101, 102, 169, 212, 240, 245, 332
 

carcinogenicity.................................................................................................... 98, 100, 101, 102, 240, 332
 

carcinoma............................................................................................................ 71, 101, 168, 169, 170, 212
 

cardiovascular ............................................................................................................... 80, 81, 133, 134, 170
 

cardiovascular effects.................................................................................................................. 80, 133, 134
 

chromosomal aberrations.......................................................................................................... 173, 176, 240
 

clearance ........................................... 22, 26, 45, 47, 147, 157, 181, 187, 189, 195, 207, 218, 223, 238, 245
 

coatings ..................................................................................................................... 2, 7, 255, 261, 263, 265
 

crustaceans ................................................................................................................................................289
 

death.................................................... 5, 43, 44, 45, 46, 47, 80, 87, 102, 103, 133, 141, 167, 170, 223, 239
 

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CADMIUM D-2 

APPENDIX D 

deoxyribonucleic acid (see DNA)..................................................................................................... 175, 179
 

dermal effects.............................................................................................................................. 90, 158, 171
 

developmental effects ................................................. 14, 19, 25, 26, 97, 164, 167, 173, 237, 242, 245, 246
 

dietary intake................................................................................. 12, 23, 135, 221, 268, 294, 306, 309, 332
 

DNA (see deoxyribonucleic acid)....... 79, 166, 173, 174, 175, 176, 177, 178, 179, 209, 220, 234, 240, 248
 

elimination half-time...................................................................................................................................16
 

endocrine............................................................................................................................. 95, 158, 213, 214
 

endocrine effects ............................................................................................................................... 157, 158
 

fetus................................................................................................................................................... 214, 246
 

fish ............................................................................................ 3, 7, 136, 281, 289, 290, 291, 292, 306, 314
 

follicle stimulating hormone .....................................................................................................................161
 

food ...............2, 3, 4, 5, 7, 8, 11, 12, 28, 30, 42, 45, 102, 133, 135, 136, 141, 162, 163, 164, 168, 195, 198, 

206, 212, 216, 245, 268, 281, 282, 287, 288, 289, 292, 293, 300, 303, 308, 320, 324, 328
 

fractional absorption ......................................................................................................................... 103, 183
 

gastrointestinal effects ........................................................................................................................ 81, 135
 

general population....................................... 13, 16, 20, 30, 45, 160, 173, 219, 221, 229, 243, 293, 305, 309
 

genotoxic..................................................................................................................................... 44, 173, 176
 

genotoxicity............................................................................................................................... 180, 235, 240
 

groundwater ................................................................................................................ 11, 268, 276, 286, 331
 

half-life.............................................................................................................................. 199, 204, 210, 219
 

hematological effects .................................................................................................................... 13, 82, 135
 

hematopoietic............................................................................................................................ 164, 169, 240
 

hepatic effects ............................................................................................................... 13, 83, 140, 141, 226
 

immune system ......................................................................................................................... 160, 171, 216
 

immunological .................................................................................... 13, 25, 43, 92, 93, 159, 160, 171, 243
 

immunological effects............................................................................................. 13, 92, 93, 159, 160, 171
 

incinerators........................................................................................ 270, 275, 278, 284, 285, 299, 303, 306
 

Kow ............................................................................................................................................ 252, 253, 254
 

LD50................................................................................................................................................... 103, 170
 

leukemia.............................................................................................................................. 26, 103, 160, 169
 

menstrual.....................................................................................................................................................96
 

metabolic effects .......................................................................................................................................159
 

metallothionein .................. 13, 31, 43, 79, 83, 102, 169, 183, 188, 189, 195, 206, 207, 208, 209, 210, 211, 

212, 217, 218, 219, 223, 227, 228, 229, 232, 233, 244, 245, 246, 291, 305, 324
 

micronuclei ............................................................................................................................... 173, 176, 180
 

milk ................................................................................... 189, 217, 222, 231, 243, 285, 289, 303, 318, 324
 

mucociliary ........................................................................................... 45, 47, 187, 189, 195, 206, 208, 218
 

musculoskeletal effects ................................................................................................................. 82, 83, 136
 

neonatal..................................................................................................................................... 305, 309, 324
 

neurobehavioral............................................................................................... 14, 19, 97, 165, 213, 216, 242
 

neurodevelopmental.............................................................................................................. 19, 27, 238, 246
 

neurological effects....................................................................................... 93, 94, 160, 161, 173, 216, 226
 

nuclear.......................................................................................................................................................160
 

ocular effects............................................................................................................................... 90, 158, 171
 

odds ratio........................................................................................................................................... 149, 150
 

partition coefficients .................................................................................................................................185
 

pharmacodynamic.....................................................................................................................................192
 

pharmacokinetic.................................................................. 16, 22, 23, 41, 79, 191, 192, 193, 194, 214, 327
 

photolysis..................................................................................................................................................101
 

pigments.................................................................. 2, 12, 45, 47, 85, 91, 171, 183, 255, 261, 265, 293, 312
 

placenta ..................................................................................................... 188, 218, 219, 222, 246, 305, 309
 

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CADMIUM D-3 

APPENDIX D 

properties .................................................. 2, 12, 16, 28, 29, 43, 79, 102, 138, 219, 227, 246, 249, 262, 307
 

proteinuria............................................................ 20, 21, 22, 26, 34, 36, 37, 38, 84, 87, 88, 89, 90, 93, 136, 

148, 156, 157, 208, 224, 225, 226, 238, 239, 327
 

pulmonary fibrosis ......................................................................................................................................71
 

rate constant .............................................................................................................................. 200, 203, 205
 

renal effects......................................................... 21, 31, 34, 84, 85, 141, 143, 152, 157, 170, 225, 239, 243
 

reproductive effects....................................................................... 94, 96, 161, 162, 164, 173, 238, 241, 332
 

respiratory effects.............................................. 16, 21, 48, 71, 75, 77, 79, 90, 103, 133, 223, 235, 239, 327
 

retention ............................................................ 22, 46, 47, 48, 181, 182, 185, 191, 200, 202, 207, 217, 280
 

salivation...................................................................................................................................................135
 

shellfish............................................................................................... 3, 7, 12, 268, 289, 294, 299, 306, 313
 

smelter............................................................................................. 85, 86, 98, 100, 150, 285, 287, 304, 308
 

smoking...................................................... 3, 15, 20, 23, 45, 71, 73, 81, 93, 94, 98, 99, 102, 133, 134, 142, 

148, 161, 162, 165, 168, 188, 198, 218, 240, 294, 299, 305
 

solubility ............................................................................. 12, 22, 43, 47, 48, 181, 206, 207, 245, 263, 282
 

spectroscopy.............................................................................................................................. 315, 319, 323
 

spermatozoa ...................................................................................................................................... 161, 175
 

systemic effects..................................................................................................... 48, 92, 103, 133, 170, 245
 

T3................................................................................................................................................ 49, 104, 172
 

thyroid............................................................................................................................................... 148, 158
 

tobacco...................................................................................................... 7, 12, 73, 222, 269, 293, 299, 304
 

toxicokinetic.................................................................................... 12, 16, 43, 191, 193, 218, 239, 244, 246
 

tremors .................................................................................................................................................. 17, 94
 

tumors ....................................................................................................... 101, 164, 168, 169, 170, 240, 244
 

vapor pressure ....................................................................................................................................... 2, 278
 

volatility....................................................................................................................................................181
 

zinc..........................2, 11, 30, 92, 95, 96, 100, 137, 148, 161, 164, 166, 168, 173, 184, 189, 209, 211, 218, 

220, 226, 227, 228, 231, 233, 247, 255, 260, 265, 270, 285, 292, 305, 313, 320, 323
 

β2-microglobulin.......... 13, 20, 21, 22, 31, 33, 34, 35, 36, 37, 39, 84, 86, 87, 88, 89, 90, 93, 136, 141, 142, 

147, 148, 149, 150, 151, 152, 155, 156, 209, 215, 224, 226, 229, 244, 324
 

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