TOXICOLOGICAL PROFILE FOR 

COPPER 

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES 

Public Health Service 

Agency for Toxic Substances and Disease Registry
 

September 2004 
COPPER 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. 
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UPDATE STATEMENT 

A Toxicological Profile for Copper, Draft for Public Comment was released in September 2002. This 

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/Toxicology Information Branch 

1600 Clifton Road NE, 

Mailstop F-32 

Atlanta, Georgia 30333 



 

 

 

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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: 1-888-42-ATSDR or (404) 498-0110 Fax: (770) 488-4178 

E-mail: atsdric@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 chemicalspecific case studies. 
COPPER 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, 55 West Seegers Road, Arlington Heights, IL 60005 • Phone: 847-818-

1800 • FAX: 847-818-9266. 
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CONTRIBUTORS 

CHEMICAL MANAGER(S)/AUTHOR(S): 

Alfred Dorsey, DVM 

ATSDR, Division of Toxicology, Atlanta, GA 

Lisa Ingerman, Ph.D. 

Steven Swarts, Ph.D. 

Syracuse Research Corporation, 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 Research Implementation Branch reviews data needs sections to assure 

consistency across profiles and adherence to instructions in the Guidance. 

 

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PEER REVIEW 

A peer review panel was assembled for copper (September 2002 profile). The panel consisted of the 

following members: 

1.	 Dr. Jonathan H. Freedman, Center for Environmental Genomes, Duke University, Durham, North 

Carolina; 

2. Dr. Paul Mushak, PB Associates, Durham, North Carolina; and 

3.	 Dr. Robert B. Ruckner, School of Medicine, Department of Nutrition, University of California at 

Davis, Davis, California. 

4. Dr. Edward Massaro, U.S. Environmental Protection Agency, Reproductive Toxicology Facility, 

Durham, North Carolina 

These experts collectively have knowledge of copper'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. A list of databases reviewed and 

a list of unpublished documents cited are also included in the administrative record. 

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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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 COPPER?...................................................................................................................1 

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

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

1.4 HOW CAN COPPER ENTER AND LEAVE MY BODY? .......................................................6 

1.5 HOW CAN COPPER AFFECT MY HEALTH? ........................................................................6 

1.6 HOW CAN COPPER AFFECT CHILDREN? ...........................................................................7 

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

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

EXPOSED TO COPPER? ...........................................................................................................8
 

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 COPPER IN THE 

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

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

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

3. HEALTH EFFECTS..............................................................................................................................21 

3.1 INTRODUCTION.....................................................................................................................21 

3.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE ..................................21 

3.2.1 Inhalation Exposure ..............................................................................................................22 

3.2.1.1 Death ............................................................................................................................22 

3.2.1.2 Systemic Effects...........................................................................................................22 

3.2.1.3 Immunological and Lymphoreticular Effects...............................................................25 

3.2.1.4 Neurological Effects.....................................................................................................25 

3.2.1.5 Reproductive Effects....................................................................................................25 

3.2.1.6 Developmental Effects .................................................................................................31 

3.2.1.7 Cancer...........................................................................................................................31 

3.2.2 Oral Exposure........................................................................................................................32 

3.2.2.1 Death ............................................................................................................................32 

3.2.2.2 Systemic Effects...........................................................................................................32 

3.2.2.3 Immunological and Lymphoreticular Effects...............................................................62 

3.2.2.4 Neurological Effects.....................................................................................................63 

3.2.2.5 Reproductive Effects....................................................................................................63 
 

 

 

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3.2.2.6 Developmental Effects .................................................................................................63 

3.2.2.7 Cancer...........................................................................................................................64 

3.2.3 Dermal Exposure...................................................................................................................64 

3.2.3.1 Death ............................................................................................................................64 

3.2.3.2 Systemic Effects...........................................................................................................65 

3.2.3.3 Immunological and Lymphoreticular Effects...............................................................65 

3.2.3.4 Neurological Effects.....................................................................................................65 

3.2.3.5 Reproductive Effects....................................................................................................65 

3.2.3.6 Developmental Effects .................................................................................................65 

3.2.3.7 Cancer...........................................................................................................................65 

3.2.4 Other Routes of Exposure .....................................................................................................66 

3.3 GENOTOXICITY .....................................................................................................................66 

3.4 TOXICOKINETICS..................................................................................................................68 

3.4.1 Absorption.............................................................................................................................68 

3.4.1.1 Inhalation Exposure......................................................................................................68 

3.4.1.2 Oral Exposure...............................................................................................................70 

3.4.1.3 Dermal Exposure ..........................................................................................................72 

3.4.2 Distribution ...........................................................................................................................72 

3.4.2.1 Inhalation Exposure......................................................................................................72 

3.4.2.2 Oral Exposure...............................................................................................................72 

3.4.2.3 Dermal Exposure ..........................................................................................................73 

3.4.3 Metabolism............................................................................................................................73 

3.4.4 Elimination and Excretion.....................................................................................................74 

3.4.4.1 Inhalation Exposure......................................................................................................74 

3.4.4.2 Oral Exposure...............................................................................................................74 

3.4.4.3 Dermal Exposure ..........................................................................................................74 

3.4.4.4 Other Routes of Exposure ............................................................................................74 

3.4.5 Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models .............74 

3.5 MECHANISMS OF ACTION ..................................................................................................76 

3.5.1 Pharmacokinetic Mechanisms...............................................................................................76 

3.5.2 Mechanisms of Toxicity........................................................................................................78 

3.5.3 Animal-to-Human Extrapolations.........................................................................................79 

3.6 TOXICITIES MEDIATED THROUGH THE NEUROENDOCRINE AXIS ..........................80 

3.7 CHILDREN’S SUSCEPTIBILITY...........................................................................................81 

3.8 BIOMARKERS OF EXPOSURE AND EFFECT ....................................................................85 

3.8.1 Biomarkers Used to Identify or Quantify Exposure to Copper.............................................86 

3.8.2 Biomarkers Used to Characterize Effects Caused by Copper...............................................87 

3.9 INTERACTIONS WITH OTHER CHEMICALS ....................................................................88 

3.10 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE...........................................89 

3.11 METHODS FOR REDUCING TOXIC EFFECTS ..............................................................91 

3.11.1 Reducing Peak Absorption Following Exposure ..............................................................91 

3.11.2 Reducing Body Burden.....................................................................................................92 

3.11.3 Interfering with the Mechanism of Action for Toxic Effects ...........................................93 

3.12 ADEQUACY OF THE DATABASE ...................................................................................93 

3.12.1 Existing Information on Health Effects of Copper...........................................................93 

3.12.2 Identification of Data Needs .............................................................................................95 

3.12.3 Ongoing Studies..............................................................................................................102 

4. CHEMICAL AND PHYSICAL INFORMATION..............................................................................105 

4.1 CHEMICAL IDENTITY.........................................................................................................105 

4.2 PHYSICAL AND CHEMICAL PROPERTIES......................................................................105 
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5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL..........................................................111 

5.1 PRODUCTION .......................................................................................................................111 

5.2 IMPORT/EXPORT .................................................................................................................117 

5.3 USE..........................................................................................................................................117 

5.4 DISPOSAL..............................................................................................................................118 

6. POTENTIAL FOR HUMAN EXPOSURE .........................................................................................121 

6.1 OVERVIEW............................................................................................................................121 

6.2 RELEASES TO THE ENVIRONMENT................................................................................124 

6.2.1 Air .......................................................................................................................................129 

6.2.2 Water...................................................................................................................................135 

6.2.3 Soil ......................................................................................................................................141 

6.3 ENVIRONMENTAL FATE....................................................................................................142
 

6.3.1 Transport and Partitioning...................................................................................................143 

6.3.1.1 Ambient Air................................................................................................................143 

6.3.1.2 Ambient Waters..........................................................................................................144 

6.3.1.3 Ambient Soils.............................................................................................................146 

6.3.1.4 Bioconcentration and Biomagnification.....................................................................149 

6.3.2 Transformation and Degradation ........................................................................................151 

6.3.2.1 Air...............................................................................................................................151 

6.3.2.2 Water ..........................................................................................................................151 

6.3.2.3 Sediment and Soil.......................................................................................................155 

6.3.2.4 Other Media................................................................................................................158 

6.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT...............................158 

6.4.1 Air .......................................................................................................................................158 

6.4.2 Water...................................................................................................................................163 

6.4.3 Sediment and Soil ...............................................................................................................167 

6.4.4 Other Environmental Media................................................................................................171 

6.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE .....................................182 

6.6 EXPOSURES OF CHILDREN...............................................................................................183 

6.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES ...........................................184 

6.8 ADEQUACY OF THE DATABASE......................................................................................185 

6.8.1 Identification of Data Needs ...............................................................................................185 

6.8.2 Ongoing Studies ..................................................................................................................189 

7. ANALYTICAL METHODS ...............................................................................................................193 

7.1 BIOLOGICAL MATERIALS.................................................................................................193 

7.2 ENVIRONMENTAL SAMPLES............................................................................................193 

7.3 ADEQUACY OF THE DATABASE......................................................................................197 

7.3.1 Identification of Data Needs ...............................................................................................198 

7.3.2 Ongoing Studies ..................................................................................................................198 

8. REGULATIONS AND ADVISORIES ...............................................................................................201 

9. REFERENCES ....................................................................................................................................207 

10. GLOSSARY ......................................................................................................................................267 
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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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LIST OF FIGURES 

3-1. Levels of Significant Exposure to Copper – Inhalation...................................................................... 28 

3-2. Levels of Significant Exposure to Copper – Oral............................................................................... 50 

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

Hypothetical Chemical Substance .......................................................................................................77 

3-4. Existing Information on Health Effects of Copper.............................................................................94 

6-1. Frequency of NPL Sites with Copper Contamination ......................................................................122
 

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LIST OF TABLES 

3-1. Levels of Significant Exposure to Copper – Inhalation...................................................................... 26 

3-2. Levels of Significant Exposure to Copper – Oral............................................................................... 28 

3-3. Genotoxicity of Copper In Vivo..........................................................................................................67 

3-4. Genotoxicity of Copper In Vitro.........................................................................................................69 

3-5. Ongoing Studies on Copper..............................................................................................................103 

4-1. Chemical Identity of Copper ............................................................................................................106 

4-2. Chemical Identity of Copper Sulfate ................................................................................................107 

4-3. Physical and Chemical Properties of Copper and Copper Sulfate....................................................109 

5-1. Facilities that Produce, Process, or Use Copper...............................................................................112 

5-2. Facilities that Produce, Process, or Use Copper Compounds...........................................................114 

6-1. Releases to the Environment from Facilities that Produce, Process, or Use Copper........................125 

6-2. Releases to the Environment from Facilities that Produce, Process, or Use Copper Compounds ...127 

6-3. Summary of Copper Concentrations in Environmental Media ........................................................130 

6-4. Global Emissions of Copper from Natural Sources (x106

 kg/year)..................................................131 

6-5. Global Emissions of Copper from Anthropogenic Sources (x106

 kg/year)......................................132 

6-6. Concentrations of Copper in Particulate Matter (<10 μm) Generated from Various Sources..........134 

6-7. Concentrations of Copper in Water..................................................................................................139 

6-8. Concentrations of Copper in Air.......................................................................................................160 

6-9. Particle Size Distributions and Total Copper Concentrations in Dust Collected at Four Mine 

Waste Pump Sites in Butte, Montana ...............................................................................................162 

6-10. Concentration of Copper in Surface Soils of the United States (in ppm-Dry Weight [dw], 

Equivalent to mg/kg-dw).................................................................................................................168 

6-11. Geometric Means of Selected Soil Elements and Associated Soil Parameters in U.S. Surface 

Soils by Land Resource Regions.....................................................................................................169 

6-12. Copper Content of Selected Foods (mg/kg) ...................................................................................173 

6-13. Copper Content of Human Tissues and Body Fluids .....................................................................178 
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6-14. Agricultural Sources of Copper Contamination in Soils................................................................181
 

6-15. Ongoing Studies on Environmental Fate and the Potential for Human Exposure to Copper.........190 

7-1. Analytical Methods for Determining Copper in Biological Materials .............................................194 

7-2. Analytical Methods for Determining Copper in Environmental Samples........................................195 

8-1. Regulations and Guidelines Applicable to Copper...........................................................................202 
COPPER 1 

1. PUBLIC HEALTH STATEMENT 

This public health statement tells you about copper 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. Copper has been found in at least 906 of the 1,647 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 copper 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 and 

your body is able to absorb it. You may be exposed by breathing, eating, or drinking the 

substance, or by skin contact. 

If you are exposed to copper, 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 and other 

genetic traits, diet, family traits, lifestyle, and state of health, including pregnancy and 

developmental stage of embryo/fetus. 

1.1 WHAT IS COPPER? 

Copper is a reddish metal that occurs naturally in rock, soil, water, sediment, and, at low levels, 

air. Its average concentration in the earth's crust is about 50 parts copper per million parts soil 

(ppm) or, stated another way, 50 grams of copper per 1,000,000 grams of soil (1.8 ounces or 

0.11 pounds of copper per 2,200 pounds of soil). Copper also occurs naturally in all plants and 

animals. It is an essential element for all known living organisms including humans and other 
COPPER 2 

1. PUBLIC HEALTH STATEMENT 

animals at low levels of intake. At much higher levels, toxic effects can occur. The term copper 

in this profile not only refers to copper metal, but also to compounds of copper that may be in the 

environment. 

Metallic copper can be easily molded or shaped. The reddish color of this element is most 

commonly seen in the U.S. penny, electrical wiring, and some water pipes. It is also found in 

many mixtures of metals, called alloys, such as brass and bronze. Many compounds (substances 

formed by joining two or more chemicals) of copper exist. These include naturally occurring 

minerals as well as manufactured chemicals. The most commonly used compound of copper is 

copper sulfate. Many copper compounds can be recognized by their blue-green color. 

Copper is extensively mined and processed in the United States and is primarily used as the 

metal or alloy in the manufacture of wire, sheet metal, pipe, and other metal products. Copper 

compounds are most commonly used in agriculture to treat plant diseases, like mildew, or for 

water treatment and as preservatives for wood, leather, and fabrics. For more information on the 

properties and uses of copper, please see Chapters 4 and 5. 

1.2 WHAT HAPPENS TO COPPER WHEN IT ENTERS THE ENVIRONMENT? 

Copper can enter the environment through releases from the mining of copper and other metals, 

and from factories that make or use copper metal or copper compounds. Copper can also enter 

the environment through waste dumps, domestic waste water, combustion of fossil fuels and 

wastes, wood production, phosphate fertilizer production, and natural sources (for example, 

windblown dust, from native soils, volcanoes, decaying vegetation, forest fires, and sea spray). 

Therefore, copper is widespread in the environment. About 1,400,000,000 pounds 

(640,000,000,000 grams) of copper were released into the environment by industries in 2000. 

Copper is often found near mines, smelters, industrial settings, landfills, and waste disposal sites. 

When copper is released into soil, it can become strongly attached to the organic material and 

other components (e.g., clay, sand, etc.) in the top layers of soil and may not move very far when 

it is released. When copper and copper compounds are released into water, the copper that 
COPPER 3 

1. PUBLIC HEALTH STATEMENT 

dissolves can be carried in surface waters either in the form of copper compounds or as free 

copper or, more likely, copper bound to particles suspended in the water. Even though copper 

binds strongly to suspended particles and sediments, there is evidence to suggest that some 

water-soluble copper compounds do enter groundwater. Copper that enters water eventually 

collects in the sediments of rivers, lakes, and estuaries. Copper is carried on particles emitted 

from smelters and ore processing plants, and is then carried back to earth through gravity or in 

rain or snow. Copper is also carried into the air on windblown metallurgical dust. Indoor release 

of copper comes mainly from combustion processes (for example, kerosene heaters). 

Elemental copper does not break down in the environment. Copper can be found in plants and 

animals, and at high concentrations in filter feeders such as mussels and oysters. Copper is also 

found in a range of concentrations in many foods and beverages that we eat and drink, including 

drinking water. You will find additional information on the fate of copper in the environment in 

Chapters 5 and 6. 

1.3 HOW MIGHT I BE EXPOSED TO COPPER? 

Copper is common in the environment. You may be exposed to copper by breathing air, 

drinking water, eating food, and by skin contact with soil, water and other copper-containing 

substances. Most copper compounds found in air, water, sediment, soil and rock are strongly 

attached to dust and dirt or imbedded in minerals. You can take copper into your body upon 

ingestion of water or soil that contains copper or by inhalation of copper-containing dust. Some 

copper in the environment is less tightly bound to soil or particles in water and may be soluble 

enough in water to be taken up by plants and animals. In the general population, soluble copper 

compounds (those that dissolve in water), which are most commonly used in agriculture, are 

more likely to threaten your health. When soluble copper compounds are released into lakes and 

rivers, they generally become attached to particles in the water within approximately 1 day. This 

could lessen your exposure to copper in water, depending on how strongly the copper is bound to 

the particles and how much of the particles settle into lake and river sediments. However, fine 

particles have an enormous surface area and can remain suspended for prolonged periods of 
COPPER 4 

1. PUBLIC HEALTH STATEMENT 

time. Therefore, at high fine particle concentrations, both exposure and uptake can be 

considerable even under conditions of tight copper binding to the suspended particulates. 

The concentration of copper in air ranges from a few nanograms (1 nanogram equals 

1/1,000,000,000 of a gram or 4/100,000,000,000 of an ounce) in a cubic meter of air (ng/m3) to 

about 200 ng/m3

. A cubic meter (m3) is approximately 25% larger than a cubic yard. Near 

smelters, which process copper ore into metal, concentrations may reach 5,000 ng/m3. You may 

breathe high levels of copper-containing dust if you live or work near copper mines or 

processing facilities. 

You may be exposed to levels of soluble copper in your drinking water that are above the 

acceptable drinking water standard of 1,300 parts copper per billion parts of water (ppb), 

especially if your water is corrosive and you have copper plumbing and brass water fixtures. 

The average concentration of copper in tap water ranges from 20 to 75 ppb. However, many 

households have copper concentrations of over 1,000 ppb. That is more than 1 milligram per 

liter of water. This is because copper is dissolved from copper pipes and brass faucets when the 

water sits in the pipes overnight. After the water is allowed to run for 15–30 seconds, the 

concentration of copper in the water decreases below the acceptable drinking water standard. 

The concentration of copper in lakes and rivers ranges from 0.5 to 1,000 ppb with an average 

concentration of 10 ppb. The average copper concentration in groundwater (5 ppb) is similar to 

that in lakes and rivers; however, monitoring data indicate that some groundwater contains levels 

of copper (up to 2,783 ppb) that are well above the standard of 1,300 ppb for drinking water. 

This copper is generally bound to particles in the water. Lakes and reservoirs recently treated 

with copper compounds to control algae or receive cooling water from a power plant can have 

high concentrations of dissolved copper. Once in natural water, much of this copper soon 

attaches to particles or convert to other forms that can settle into sediments. This can limit 

exposure to copper unless the sediments are stirred; for example, by the resuspension and 

swallowing of sediments by swimmers in recreational waters. 
COPPER 5 

1. PUBLIC HEALTH STATEMENT 

Garden products containing copper that are used to control certain plant diseases are also a 

potential source of exposure through contact with skin or if they are accidentally swallowed. For 

example, you can find copper compounds in some fungicides. 

Soil generally contains between 2 and 250 ppm copper, although concentrations close to 

17,000 ppm have been found near copper and brass production facilities. High concentrations of 

copper may be found in soil because dust from these industries settles out of the air, or wastes 

from mining and other copper industries are disposed of on the soil. Another common source of 

copper in soil results from spreading sludge from sewage treatment plants. This copper 

generally stays strongly attached to the surface layer of soil. You may be exposed to this copper 

by skin contact. Children may also be exposed to this copper by hand to mouth contact and 

eating the contaminated dirt and dust. 

Food naturally contains copper. You eat and drink about 1 milligram (1/1,000 of a gram or 

4/100,000 ounces) of copper every day. 

While some hazardous waste sites on the NPL contain high levels of copper, we do not always 

know how high it is above natural levels. We also do not know what form it is in at most of 

these sites. However, evidence suggests that most copper at these sites is strongly attached to 

soil. 

You may be exposed to copper in the workplace. If you work in the industry of mining copper 

or processing the ore, you are exposed to copper by breathing copper-containing dust or by skin 

contact. If you grind or weld copper metal, you may breathe high levels of copper dust and 

fumes. Occupational exposure to forms of copper that are soluble or not strongly attached to 

dust or dirt would most commonly occur in agriculture, water treatment, and industries such as 

electroplating, where soluble copper compounds are used. Exposure to copper in air in the 

workplace is regulated and is set to be below concentrations that can be harmful to you. 

For more information on the potential for exposure to copper, please refer to Chapter 6. 
COPPER 6 

1. PUBLIC HEALTH STATEMENT 

1.4 HOW CAN COPPER ENTER AND LEAVE MY BODY? 

Copper can enter your body when you drink water or eat food, soil, or other substances that 

contain copper. Copper can also enter your body if you breathe air or dust containing copper. 

Copper may enter the lungs of workers exposed to copper dust or fumes. 

Copper rapidly enters the bloodstream and is distributed throughout the body after you eat or 

drink it. Certain substances in foods eaten with copper can affect the amount of copper that 

enters the bloodstream from the gastrointestinal tract. Your body is very good at blocking high 

levels of copper from entering the bloodstream. We do not know how much copper enters the 

body through the lungs or skin. Copper then leaves your body in feces and urine, mostly in 

feces. It takes several days for copper to leave your body. Generally, the amount of copper in 

your body remains constant (the amount that enters your body equals the amount that leaves). 

More information on how copper enters and leaves the body is presented in Chapter 3. 

1.5 HOW CAN COPPER AFFECT MY HEALTH? 

Scientists use many tests to protect the public from harmful effects of toxic chemicals and to find 

ways for treating persons who have been harmed. 

One way to learn whether a chemical will harm people is to determine how the body absorbs, 

uses, and releases the chemical. For some chemicals, animal testing may be necessary. Animal 

testing may also help identify health effects such as cancer or birth defects. Without laboratory 

animals, scientists would lose a basic method for getting information needed to make wise 

decisions that protect public health. Scientists have the responsibility to treat research animals 

with care and compassion. Scientists must comply with strict animal care guidelines because 

laws today protect the welfare of research animals. 

Copper is essential for good health. However, exposure to higher doses can be harmful. Longterm exposure to copper dust can irritate your nose, mouth, and eyes, and cause headaches, 

dizziness, nausea, and diarrhea. If you drink water that contains higher than normal levels of 
COPPER 7 

1. PUBLIC HEALTH STATEMENT 

copper, you may experience nausea, vomiting, stomach cramps, or diarrhea. Intentionally high 

intakes of copper can cause liver and kidney damage and even death. We do not know if copper 

can cause cancer in humans. EPA does not classify copper as a human carcinogen because there 

are no adequate human or animal cancer studies. 

More detailed information on the health effects of copper in animals and humans can be found in 

Chapter 3. 

1.6 HOW CAN COPPER AFFECT CHILDREN? 

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

conception to maturity at 18 years of age. 

Exposure to high levels of copper will result in the same types of effects in children and adults. 

We do not know if these effects would occur at the same dose level in children and adults. 

Studies in animals suggest that children may have more severe effects than adults; we do not 

know if this would also be true in humans. There is a very small percentage of infants and 

children who are unusually sensitive to copper. We do not know if copper can cause birth 

defects or other developmental effects in humans. Studies in animals suggest that ingestion of 

high levels of copper may cause a decrease in fetal growth. 

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

The greatest potential source of copper exposure is through drinking water, especially in water 

that is first drawn in the morning after sitting in copper piping and brass faucets overnight. To 

reduce copper in drinking water, run the water for at least 15–30 seconds before using it. 

Additionally, if there is concern about the concentration of copper in drinking water exceeding 

the minimum value of 1,300 ppb, families should have their water tested. 
COPPER 8 

1. PUBLIC HEALTH STATEMENT 

If your doctor finds that you have been exposed to substantial amounts of copper, ask whether 

your children might also have been exposed. Your doctor might need to ask your state health 

department to investigate. 

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

 EXPOSED TO COPPER? 

Copper is normally found in all tissues of the body, blood, urine, feces, hair, and nails. High 

levels of copper in the blood, urine, hair, and nails can show that you have been exposed to 

higher than normal levels of copper. Tests to measure copper levels in the body are not usually 

available at a doctor’s office because they require special equipment, but the doctor can send 

samples to a specialty laboratory. Although these tests can show that you have been exposed to 

higher than normal copper levels, they can not be used to predict the extent of exposure or 

potential health effects. More detailed information on the measurement of copper is provided 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. 
COPPER 9 

1. PUBLIC HEALTH STATEMENT 

Sometimes these not-to-exceed 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 copper include the following: 

The EPA has determined that drinking water should not contain more than 1.3 mg copper per 

liter of water (1.3 mg/L). The EPA has also developed regulations on the amount of copper that 

industry is allowed to release. 

The OSHA has set a limit of 0.1 milligrams/cubic meter (mg/m3

) for copper fumes (vapor 

generated from heating copper) and 1.0 mg/m3 for copper dusts (fine metallic copper particles) 

and mists (aerosols of soluble copper) in workroom air to protect workers during an 8-hour work 

shift (40-hour workweek). 

The Food and Nutrition Board of the Institute of Medicine has developed recommended dietary 

allowances (RDAs) of 340 micrograms (μg) of copper per day for children aged 1–3 years, 

440 μg/day for children aged 4–8 years, 700 μg/day for children aged 9–13 years, 890 μg/day for 

children aged 14–18 years, and 900 μg/day for adults. This provides enough copper to maintain 

health. Further information on regulations and guidelines pertaining to copper is provided in 

Chapter 8. 

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. 
 

 

 

 

COPPER 10 

1. PUBLIC HEALTH STATEMENT 

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 1-888-42ATSDR (1-888-422-8737), by e-mail at 

atsdric@cdc.gov, or by writing to: 

Agency for Toxic Substances and Disease Registry 

 Division of Toxicology 

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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2. RELEVANCE TO PUBLIC HEALTH 

2.1 BACKGROUND AND ENVIRONMENTAL EXPOSURES TO COPPER IN THE UNITED 

STATES 

Copper is a metallic element that occurs naturally as the free metal, or associated with other elements in 

compounds that comprise various minerals. Most copper compounds occur in +1 Cu(I) and +2 Cu(II) 

valence states. Copper is primarily used as a metal or an alloy (e.g., brass, bronze, gun metal). Copper 

sulfate is used as a fungicide, algicide, and nutritional supplement. Copper particulates are released into 

the atmosphere by windblown dust; volcanic eruptions; and anthropogenic sources, primarily copper 

smelters and ore processing facilities. Copper particles in the atmosphere will settle out or be removed by 

precipitation, but can be resuspended into the atmosphere in the form of dust. The mean concentration of 

copper in ambient air in the United States ranges from 5 to 200 ng/m3

. Copper is released into waterways 

by natural weathering of soil and rocks, disturbances of soil, or anthropogenic sources (e.g., effluent from 

sewage treatment plants). Copper concentrations in drinking water vary widely as a result of variations in 

pH and hardness of the water supply; the levels range from a few ppbs to 10 ppm. The mean 

concentration of copper in soil in the United States ranges from 5 to 70 mg/kg. The estimated daily intake 

of copper from food is 1.0–1.3 mg/day for adults (0.014–0.019 mg/kg/day). 

The general population is exposed to copper through inhalation, consumption of food and water, and 

dermal contact with air, water, and soil that contains copper. The primary source of copper intake is the 

diet; however, the amount of copper in the diet usually does not exceed the average dietary requirements 

(RDAs) for copper. Drinking water is the primary source of excess copper. Populations living near 

sources of copper emissions, such as copper smelters and refineries and workers in these and other 

industries may also be exposed to high levels of copper in dust by inhalation. Copper concentrations in 

soils near copper emission sources could be sufficiently high to result in significantly high intakes of 

copper in young children who ingest soil. For example, copper concentrations of 2,480–6,912 ppm have 

been measured near copper smelters. These levels of copper in soils would result in the intake of 0.74– 

2.1 mg copper per day in a child ingesting 300 mg of soil. Copper has been identified in at least 906 of 

the 1,647 hazardous waste sites that have been proposed for inclusion on the EPA NPL. 
COPPER 12 

2. RELEVANCE TO PUBLIC HEALTH 

2.2 SUMMARY OF HEALTH EFFECTS 

Copper is an essential nutrient that is incorporated into a number of metalloenzymes involved in 

hemoglobin formation, drug/xenobiotic metabolism, carbohydrate metabolism, catecholamine 

biosynthesis, the cross-linking of collagen, elastin, and hair keratin, and the antioxidant defense 

mechanism. Copper-dependent enzymes, such as cytochrome c oxidase, superoxide dismutase, 

ferroxidases, monoamine oxidase, and dopamine β-monooxygenase, function to reduce activated oxygen 

species or molecular oxygen. Symptoms associated with copper deficiency in humans include 

normocytic, hypochromic anemia, leukopenia, and osteoporosis; copper deficiency is rarely observed in 

the U.S. general population. In the United States, the median intake of copper from food is 0.93– 

1.3 mg/day for adults (0.013–0.019 mg Cu/kg body weight/day using a 70-kg reference body weight). A 

recommended dietary allowance (RDA) of 0.9 mg/day (0.013 mg/kg/day) has recently been established. 

Copper is readily absorbed from the stomach and small intestine. After nutritional requirements are met, 

there are several mechanisms that prevent copper overload. Excess copper absorbed into gastrointestinal 

mucosal cells induces the synthesis of and binds to the metal binding protein metallothionein. This bound 

copper is excreted when the cell is sloughed off. Copper that eludes binding to intestinal metallothionen 

is transported to the liver. It is stored in the liver bound to liver metallothionen, from which it is 

ultimately released into bile and excreted in the feces. Although copper homeostasis plays an important 

role in the prevention of copper toxicity, exposure to excessive levels of copper can result in a number of 

adverse health effects including liver and kidney damage, anemia, immunotoxicity, and developmental 

toxicity. Many of these effects are consistent with oxidative damage to membranes or macromolecules. 

Copper can bind to the sulfhydryl groups of several enzymes, such as glucose-6-phosphatase and 

glutathione reductase, thus interfering with their protection of cells from free radical damage. 

One of the most commonly reported adverse health effect of copper is gastrointestinal distress. Nausea, 

vomiting, and/or abdominal pain have been reported, usually occurring shortly after drinking a copper 

sulfate solution, beverages that were stored in a copper or untinned brass container, or first draw water 

(water that sat in the pipe overnight). The observed effects are not usually persistent and gastrointestinal 

effects have not been linked with other health effects. Animal studies have also reported gastrointestinal 

effects (hyperplasia of forestomach mucosa) following ingestion of copper sulfate in the diet. Copper is 

also irritating to the respiratory tract. Coughing, sneezing, runny nose, pulmonary fibrosis, and increased 

vascularity of the nasal mucosa have been reported in workers exposed to copper dust. 
COPPER 13 

2. RELEVANCE TO PUBLIC HEALTH 

The liver is also a sensitive target of toxicity. Liver damage (necrosis, fibrosis, abnormal biomarkers of 

liver damage) have been reported in individuals ingesting lethal doses of copper sulfate. Liver effects 

have also been observed in individuals diagnosed with Wilson’s disease, Indian childhood cirrhosis, or 

idiopathic copper toxicosis (which includes Tyrollean infantile cirrhosis). These syndromes are genetic 

disorders that result in an accumulation of copper in the liver; the latter two syndromes are associated 

with excessive copper exposure. Inflammation, necrosis, and altered serum markers of liver damage have 

been observed in rats fed diets with copper sulfate levels that are at least 100 times higher than the 

nutritional requirement. Damage to the proximal convoluted tubules of the kidney has also been observed 

in rats. The liver and kidney effects usually occur at similar dose levels; however, the latency period for 

the kidney effects is longer than for the liver effects. 

There is some evidence from animal studies to suggest that exposure to airborne copper or high levels of 

copper in drinking water can damage the immune system. Impaired cell-mediated and humoral-mediated 

immune function have been observed in mice. Studies in rats, mice, and mink suggest that exposure to 

high levels of copper in the diet can result in decreased embryo and fetal growth. 

The carcinogenicity of copper has not been adequately studied. An increase in cancer risk has been found 

among copper smelters; however, the increased risk has been attributed to concomitant exposure to 

arsenic. Increased lung and stomach cancer risks have also been found in copper miners. However, a 

high occurrence of smoking and exposure to radioactivity, silica, iron, and arsenic obscure the association 

of copper exposure with carcinogenesis. Animal studies have not found increased cancer risks in orally 

exposed rats or mice. The IARC has classified the pesticide, copper 8-hydroxyquinoline, in Group 3, 

unclassifiable as to carcinogenicity in humans and EPA has classified copper in Group D, not classifiable 

as to human carcinogenicity 

A more detailed discussion of the critical targets of copper toxicity, the gastrointestinal tract and the liver, 

follows. 

Gastrointestinal Effects. The available human and animal data suggest that the gastrointestinal tract 

is a sensitive target of toxicity. There are numerous reports of nausea, vomiting, and/or abdominal pain in 

humans ingesting beverages contaminated with copper or water containing copper sulfate. These 

symptoms typically occur shortly after ingestion and are not persistent. The results of three single 

exposure studies suggest that the threshold for gastrointestinal symptoms is between 4 and 6 ppm, which 

is equivalent to doses of 0.11 mg/kg and 0.017–0.018 mg Cu/kg. Nausea, vomiting, and/or abdominal 
COPPER 14 

2. RELEVANCE TO PUBLIC HEALTH 

pain also appear to be the most sensitive end point following repeated exposure to copper in drinking 

water. These symptoms were reported by adults drinking water containing ≥3 ppm copper as copper 

sulfate (0.0731 mg Cu/kg/day) for 1–2 weeks or 4 ppm copper as copper sulfate (0.091 mg Cu/kg/day) for 

2 months. Similar gastrointestinal effects were observed in adults ingesting copper oxide in drinking 

water. Although gastrointestinal irritation may play a role in the observed gastrointestinal effects, data 

from ferrets and monkeys suggest that vagal afferent fibers and 5-HT3 and 5-HT4 receptors are involved 

in copper-induced emesis. 

Hepatic Effects. In humans, copper-induced hepatic damage is dependent on several factors including 

genetics, age, and copper intake. Liver damage is rarely reported in adults; the few reported cases of liver 

damage (centrilobular necrosis, jaundice, and increased aspartate aminotransferase activity) have been 

associated with intentional ingestion of a lethal dose of copper sulfate. In infants and children, reported 

liver effects are usually manifested in one of three syndromes: Wilson’s disease, Indian childhood 

cirrhosis, and idiopathic copper toxicosis. Wilson’s disease is an autosomal recessive genetic disorder 

associated with impaired copper metabolism. Dietary exposure to higher than normal levels of copper 

does not appear to be necessary for the manifestation of liver damage. Some heterozygous carriers of 

Wilson’s disease also have elevated hepatic levels of copper and increased urinary excretion, although 

adverse health effects have not been reported in these individuals. There is evidence that Indian 

childhood cirrhosis and idiopathic copper toxicosis are also caused by a genetic defect that is transmitted 

in an autosomal recessive mode. However, unlike Wilson’s disease, manifestation of the disease is 

associated with exposure to unusually high levels of dietary copper from milk stored in copper or brass 

containers or from drinking water. The clinical age of onset is usually between 6 months and 5 years, and 

the observed liver effects include pericellular fibrosis, abnormal biochemical markers of liver damage 

(e.g., increased serum aspartate aminotransferase and alkaline phosphatase activities and serum bilirubin 

levels), and very high levels of copper in the liver. In general, the potential hepatotoxicity of copper has 

not been extensively investigated in healthy humans. No effect levels of 0.14–0.17 and 0.315 mg 

Cu/kg/day for liver effects in adults and infants (3–12 months of age), respectively, had been reported in 

intermediate-duration studies (2–9 months); these studies used serum chemistry biomarkers (e.g., alanine 

aminotransferase, aspartate aminotransferase) to assess liver damage. Two community survey studies 

also found no evidence of liver damage in infants living in households with 0.8 ppm copper in drinking 

water. The results of the three studies involving infants should be interpreted cautiously due to the high 

drop out rate, small number of subjects examined for possible liver damage, and the dismissal of 

anomalous findings as secondary to infection rather than possibly indicative of copper toxicity. 
COPPER 15 

2. RELEVANCE TO PUBLIC HEALTH 

Adverse liver effects have been observed in rats exposed to dietary copper levels that were more than 

100 times higher than the nutritional requirement. The liver effects included inflammation, necrosis, and 

abnormal serum chemistry markers of liver damage. Rats appear to develop a tolerance to copper doses 

of 180–<550 mg Cu/kg/day. Tolerance is defined as “the ability to endure the continued or increasing 

administration of a toxicant and the capacity to exhibit less response to a test dose than previous.” As the 

levels of hepatic copper increase, so does the severity of the damage until peak copper levels are reached. 

After about 3–5 weeks of exposure, the copper levels begin to decline and are maintained at a steady level 

for the remainder of the exposure period. When the hepatic levels decline, regeneration of hepatic tissue 

is observed, and continued exposure or exposure to higher doses does not result in more tissue damage. 

The decline in hepatic copper levels and regeneration of damaged tissue occurs early at higher doses. At 

doses >550 mg Cu/kg/day, the liver becomes permanently overloaded and chronic hepatitis develops. 

2.3 MINIMAL RISK LEVELS (MRLs) 

Estimates of exposure levels posing minimal risk to humans (Minimal Risk Levels or MRLs) have been 

made for copper. 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 1990), 

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. 

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. 
 

COPPER 16 

2. RELEVANCE TO PUBLIC HEALTH 

Inhalation MRLs 

The available data on the toxicity of inhaled copper were considered inadequate for derivation of acute-, 

intermediate-, or chronic-duration inhalation MRLs. Data on the inhaled toxicity of copper in humans 

following acute-duration exposure are limited to a report of workers developing metal fume fever while 

cutting brass pipe with an electric cutting tool in a poorly ventilated area (Armstrong et al. 1983); 

exposure levels were not reported. Respiratory effects and impaired immune function have been 

observed in mice following a single 3-hour exposure to 3.3 mg Cu/m3

 as copper sulfate or repeated 

exposure (3 hours/day, 5 days/week for 1–2 weeks) to 0.12–0.13 mg Cu/m3

 as copper sulfate (Drummond 

et al. 1986). The Drummond et al. (1986) study was not selected as the basis of an acute-duration 

inhalation MRL because a small number of animals was tested (four per group) and a limited number of 

end points (respiratory tract and immune function) were examined. Intermediate-duration data are limited 

to studies by Johansson et al. (1983, 1984), which did not find any histological alterations in the lungs or 

functional or morphological alterations in alveolar macrophages of rabbits exposed to copper chloride. 

As with the acute-duration data, the limited number of end points examined precludes deriving an 

intermediate-duration inhalation MRL. The chronic-duration database for copper consists of two 

occupational exposure studies reporting respiratory (Askergren and Mellgren 1975; Suciu et al. 1981) and 

gastrointestinal (Suciu et al. 1981) irritation, hepatic effects (Suciu et al. 1981), and possible neurological 

and reproductive effects (Suciu et al. 1981). Chronic-duration inhalation MRLs cannot be derived from 

these studies due to poor exposure characterization and/or lack of controls. 

Oral MRLs 

•	 An MRL of 0.01 mg/kg/day has been derived for acute-duration oral exposure (1–14 days) to 

copper. 

The available human and animal acute-duration studies strongly suggest that the gastrointestinal tract is 

the most sensitive target of copper toxicity. Numerous studies and case reports have reported nausea, 

vomiting, and/or abdominal pain in humans immediately following ingestion of copper-contaminated 

water or other beverages (Araya et al. 2001, 2003a, 2003b, 2003c; Chuttani et al. 1965; Gotteland et al. 

2001; Knobeloch et al. 1994; Nicholas and Brist 1968; Olivares et al. 2001; Pizarro et al. 1999, 2001; 

Spitalny et al. 1984). In human studies involving a single exposure to copper following an overnight fast, 

adverse gastrointestinal effects (nausea, vomiting, abdominal pain, and/or diarrhea) have been observed at 

doses of 0.011–0.03 mg Cu/kg (Araya et al. 2001, 2003a, 2003c; Gotteland et al. 2001; Olivares et al. 

2001). Under these experimental conditions, the apparent threshold appears to fall between 0.011 and 
 

COPPER 17 

2. RELEVANCE TO PUBLIC HEALTH 

0.017 mg Cu/kg (Araya et al. 2001, 2003a; Olivares et al. 2001). Slightly higher thresholds for 

gastrointestinal symptoms were observed in two acute-duration repeated exposure studies in which 

subjects used a copper-containing water as their primary source of drinking water for 1 or 2 weeks 

(Pizarro et al. 1999, 2001). In the 2-week study, 60 women were given copper sulfate containing water to 

be used for drinking and cooking purposes. No significant alterations in serum biomarkers of liver 

damage (alanine aminotransferase, aspartate aminotransferase, γ-glutamyl transferase) were observed in 

the subjects at the end of the study. An increased occurrence of nausea, vomiting, and/or abdominal pain 

was observed when the women were exposed to 3 ppm copper as copper sulfate (0.0731 mg Cu/kg/day) 

(Pizarro et al. 1999); no significant increases in the incidence of gastrointestinal symptoms were noted at 

1 ppm (0.0272 mg Cu/kg/day). Nausea, vomiting, and/or abdominal pain were also reported by women 

ingesting water containing 5 ppm (0.096 mg Cu/kg/day) as copper sulfate or copper oxide for 1 week 

(Pizarro et al. 2001). Animal studies support the identification of the gastrointestinal tract as a sensitive 

target of toxicity. Hyperplasia of the forestomach mucosa was observed in rats exposed to 44 mg 

Cu/kg/day as copper sulfate in the diet (NTP 1993) and in mice exposed to 197 mg Cu/kg/day as copper 

sulfate in the diet (NTP 1993). At higher doses, liver and kidney damage have been observed (Haywood 

1980; Haywood and Comerford 1980; Haywood et al. 1985b; NTP 1993). 

The Pizarro et al. (1999) 2-week study was selected as the basis of the acute-duration oral MRL for 

copper. This study identified no-observed-adverse-effect level (NOAEL) and lowest-observed-adverseeffect level (LOAEL) values of 0.0272 and 0.0731 mg Cu/kg/day for increases in the incidence of nausea, 

vomiting, and/or abdominal pain. Although the LOAEL values identified in the single exposure studies 

(Araya et al. 2001, 2003; Olivares et al. 2001) are slightly lower than the than the NOAEL identified in 

the Pizarro et al. (1999) study, the Pizarro et al. (1999) study was selected as the critical study because it 

is a longer-duration study and it more closely mimics an exposure scenario of a population drinking 

copper-contaminated drinking water. The NOAEL was divided by an uncertainty factor of 3 (to account 

for human variability) to yield an acute-duration oral MRL of 0.01 mg Cu/kg/day. The observed 

gastrointestinal effects were probably due to direct contact; thus, only a partial uncertainty factor of 3 was 

used to account for human variability because toxicokinetic differences among individuals should not 

affect sensitivity. The acute-duration MRL is intended to protect against the health effects associated 

with exposure to copper-contaminated drinking water; it assumes that the affected population will have a 

normal intake of copper from the diet. 
COPPER 18 

2. RELEVANCE TO PUBLIC HEALTH 

•	 An MRL of 0.01 mg/kg/day has been derived for intermediate-duration oral exposure (15– 

365 days) to copper. 

There are limited data on the intermediate-duration toxicity of copper in humans. Araya et al. (2003b) 

exposed groups of 327–355 adults to <0.01 (control group), 2, 4, or 6 ppm copper sulfate in water for 

2 months. The subjects prepared the copper sulfate solution to be used at home by mixing a stock copper 

sulfate solution with tap water; this solution was used for drinking water and preparing beverages and 

soups. Exposure to copper sulfate resulted in increases in the occurrence of gastrointestinal symptoms; 

the incidence was significantly higher than controls at 6 ppm when the data were analyzed using the chisquare test with Bonferroni correction and at 4 ppm when the Bonferroni correction was not used. Only 

one test was used to assess whether exposure to copper results in adverse gastrointestinal effects (reported 

symptoms); thus, the Bonferroni correction is not needed for this end point. Therefore, the 4 ppm 

concentration is identified as the LOAEL and the 2 ppm concentration as the NOAEL. The study authors 

reported copper intakes for 48–49 subjects per group who provided blood samples; no information on 

selection criteria were provided. The copper intakes were 0, 0.042, 0.091, and 0.17 mg Cu/kg/day for the 

control, 2, 4, and 6 ppm groups, respectively. The dietary intake of copper was not measured in this 

study; however, Araya et al. (2003b) noted that copper intake found in a survey of other community 

residents was 0.9 mg Cu/day. No significant alterations in copper status or liver function (as assessed by 

serum alanine aminotransferase, asparatate aminotransferase, and γ-glutamyl transferase activities) were 

observed in a subset of subjects from each group. In a study by Pratt et al. (1985), a group of seven adults 

were administered 10 mg Cu/day (0.14 mg Cu/kg/day) as copper gluconate in a capsule for 12 weeks. No 

significant alterations in serum markers of liver damage (cholesterol and triglyceride levels and serum 

aspartate aminotransferase, alkaline phosphatase, γ-glutamyl transferase, and lactate dehydrogenase 

activities) were found. Similarly, no alterations in total bilirubin or serum alanine aminotransferase, 

aspartate aminotransferase, or γ-glutamyl transferase activities were observed in infants exposed to 

0.315 mg Cu/kg/day for 9 months (Olivares et al. 1998). Zietz et al. (2003a, 2003b) also did not find 

evidence of liver damage in infants living in households with water concentrations of 0.8 ppm and higher. 

The Pratt et al. (1985), Olivares et al. (1998), and Zietz et al. (2003a, 2003b) studies did not report 

significant alterations in the occurrence of gastrointestinal disturbances and the study design did not 

include symptoms questionnaires, although the high dropout rate observed in the Olivares et al. (1998) 

study may have been related to gastrointestinal effects. Severe liver damage (pericellular fibrosis and 

increased serum aminotransferase and alkaline phosphatase activities) has been observed in children with 

a genetic susceptibility to high levels of copper in the liver. The liver was a critical target of toxicity in 

rats exposed to very high levels of copper in diet (greater than 100 times the nutritional requirement), 

Inflammation, necrosis, and increased alanine and aspartate aminotransferases activities have been 
 

COPPER 19 

2. RELEVANCE TO PUBLIC HEALTH 

reported in rats at exposure levels of 16 mg Cu/kg/day as copper sulfate in the diet (Haywood 1980, 1985; 

Haywood and Comerford 1980; Haywood and Loughran 1985; Haywood et al. 1985a; NTP 1993). No 

liver effects where observed at 8 mg Cu/kg/day (NTP 1993). Histological alterations in stomach, 

indicative of irritation (hyperplasia of the squamous mucosa on the limiting ridge separating the 

forestomach from the glandular stomach), have also been observed in rats and mice exposed to 33 or 

267 mg Cu/kg/day, respectively, as copper sulfate in the diet for 13 weeks (NTP 1993). 

An intermediate-duration oral MRL of 0.01 mg Cu/kg/day was derived for copper based on 

gastrointestinal effects using the data from the Araya et al. (2003b) study. This study identified NOAEL 

and LOAEL values of 0.042 and 0.091 mg Cu/kg/day, respectively; these copper doses were in excess of 

normal dietary intake. The NOAEL was divided by an uncertainty factor of 3 (to account for human 

variability) to yield an intermediate-duration oral MRL of 0.01 mg Cu/kg/day. As with the acute-duration 

MRL, the intermediate-duration MRL is intended to protect against exposure to excess copper in drinking 

water and assumes a normal copper dietary intake. 

The database on the chronic oral toxicity of copper is inadequate for derivation of a MRL. Massie and 

Aiello (1984) reported a 15% decrease in the lifespan in mice exposed to 4.2 mg Cu/kg/day as copper 

gluconate in drinking water. 

COPPER 21 

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 copper. 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. 

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, 

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 
COPPER 22 

3. HEALTH EFFECTS 

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. 

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 

3.2.1.1 Death 

No studies were located regarding death of humans or animals following inhalation exposure to copper. 

3.2.1.2 Systemic Effects 

No studies were located regarding cardiovascular, musculoskeletal, renal, dermal, or body weight effects 

in humans or animals following inhalation exposure to copper. 

Respiratory, gastrointestinal, hematological, hepatic, endocrine, and ocular effects were observed in 

humans. Respiratory effects have also been observed in animals exposed to copper sulfate aerosols. 

Respiratory Effects. In humans, copper is a respiratory irritant. Workers exposed to copper dust 

report a number of symptoms that are suggestive of respiratory irritation, including coughing, sneezing, 

thoracic pain, and runny nose (Askergren and Mellgren 1975; Suciu et al. 1981). In the Suciu et al. 

(1981) study of 75–100 workers involved in sieving copper, lung radiographs revealed linear pulmonary 

fibrosis, and in some cases, nodulation. During the first year of operation, the workers were exposed to 

434 mg Cu/m3

; the exposure levels declined each year, and by year 3, the levels were 111 mg Cu/m3. In 
 

COPPER 23 

3. HEALTH EFFECTS 

sheet metal workers exposed to patina dust (copper-hydroxide-nitrate, copper-hydroxide-sulfate, copper 

silicate, copper oxide), 6 of the 11 examined workers had increased vascularity and superficial epistatic 

vessels in the nasal mucosa (Askergren and Mellgren 1975); no exposure levels were reported. 

Copper is considered the etiologic agent in the occupational disease referred to as “vineyard sprayer’s 

lung”. This disease, which is observed in vineyard workers spraying an antimildew agent containing 1– 

2.5% copper sulfate neutralized with hydrated lime, was first described in humans by Cortez Pimentel and 

Marques (1969). In most cases, published information on this disease comes from case reports (Cortez 

Pimentel and Marques 1969; Cortez Pimentel and Menezes 1975; Stark 1981; Villar 1974; Villar and 

Nogueira 1980) with no concentration-response information. Common findings (obtained by alveolar 

lavage and biopsy) include intraalveolar desquamation of macrophages, formation of histiocytic and 

noncaseating granulomas containing inclusions of copper, and healing of lesions in the form of 

fibrohyaline nodules, very similar to those found in silicosis (Cortez Pimentel and Marques 1969; 

Plamenac et al. 1985). Higher incidences of abnormal columnar cells, squamous metaplasia without 

atypia, copper containing macrophages, eosinophilia, and respiratory spirals were found in the sputa of 

smoking and nonsmoking vineyard sprayers, as compared to rural workers from the same geographic 

region who did not work in the vineyards (Plamenac et al. 1985). 

The potential of copper to induce respiratory effects has been tested in mice, hamsters, and rabbits. 

Decreased cilia beating was observed in Syrian-Golden hamsters exposed to 3.3 mg Cu/m3

 as copper 

sulfate for 3 hours (Drummond et al. 1986); this effect was not observed in similarly exposed CD-1 mice. 

Repeated exposure resulted in alveolar thickening in CD-1 mice exposed to 0.12 mg Cu/m3

 as copper 

sulfate for 3 hours/day, 5 days/week for 1–2 weeks (Drummond et al. 1986); the severity of the effect 

increased with the duration of exposure. In rabbits (strain not reported) exposed to 0.6 mg Cu/m3

 as 

copper chloride for 6 hours/day, 5 days/week for 4–6 weeks, the only histological alteration in the lungs 

was a slight increase in alveolar type II cell volume density (Johansson et al. 1984); this effect was not 

considered adverse. No functional or morphological alterations were observed in the alveolar 

macrophages of similarly exposed rabbits (Johansson et al. 1983). 

Gastrointestinal Effects. In workers involved in grinding and sieving copper dust, anorexia, nausea, 

and occasional diarrhea were reported (Suciu et al. 1981); exposure levels ranged from 111 to 434 mg 

Cu/m3

 over a 3-year period. It is likely that the observed gastrointestinal effects were due to oral 

exposure to copper. Ingestion probably resulted from mucocilliary clearance of copper particles 

deposited in the nasopharyngeal and tracheobronchial regions of the respiratory tract. 
COPPER 24 

3. HEALTH EFFECTS 

No studies were located regarding gastrointestinal effects in animals following inhalation exposure to 

copper. 

Hematological Effects. Decreased hemoglobin and erythrocyte levels have been observed in 

workers exposed to airborne copper levels of 0.64–1.05 mg/m3

. Results of hair analysis reveal that the 

workers were also exposed to iron, lead, and cadmium (Finelli et al. 1981). 

No studies were located regarding hematological effects in animals following inhalation exposure to 

copper. 

Hepatic Effects. Hepatomegaly was observed in workers involved in grinding and sieving copper 

dust (Suciu et al. 1981); the exposure levels ranged from 111 to 434 mg Cu/m3

. 

No studies were located regarding hepatic effects in animals following inhalation exposure to copper. 

Endocrine Effects. Seven cases of enlargement of the sella turcica, nonsecretive hypophyseal 

adenoma, accompanied by obesity, arterial hypertension, and "red facies" were observed in a group of 

100 workers exposed to 111–434 mg Cu/m3

 as copper dust (Suciu et al. 1981). The study authors noted 

that there was a possibility that the clinical manifestations of hypophyseal adenoma or of Cushing's 

syndrome may have been the result of a disturbance of copper metabolism. The significance of this effect 

and its relationship to copper exposure cannot be determined. 

Ocular Effects. Eye irritation has been reported by workers exposed to copper dust (Askergren and 

Mellgren 1975). The irritation is likely due to direct contact with the copper rather than a systemic effect 

resulting from inhalation exposure. 

Other Systemic Effects. A few studies have reported metal fume fever, a 24–48-hour illness 

characterized by chills, fever, aching muscles, dryness in the mouth and throat, and headache, in workers 

exposed to copper dust or fumes (Armstrong et al. 1983; Gleason 1968). Gleason (1968) reported 

airborne copper dust concentrations of 0.075–0.12 mg/m3

. It has been suggested that other metals present 

in the workplace may have been the causative agent for the metal fume fever, rather than copper. This is 

supported by the small number of reports of metal fume fever despite the extensive use of copper in many 

industries (Borak et al. 2000). 
COPPER 25 

3. HEALTH EFFECTS 

3.2.1.3 Immunological and Lymphoreticular Effects 

No studies were located regarding immunological effects in humans following inhalation exposure to 

copper. 

An acute exposure study in mice reported an impaired immune response following exposure to copper 

sulfate and a bacterial challenge (Drummond et al. 1986). Increased mortality and decreased survival 

time were observed in CD-1 mice challenged by an aerosol of Streptococcus zooepidemicus following 

0.56 mg Cu/m3

 for 3 hours or 0.13 mg Cu/m3 for 3 hours/day, 5 days/week for 2 weeks. Decreased 

bactericidal activity of alveolar macrophages was also observed in mice exposed to 3.3 mg Cu/m3

 for 

3 hours or 0.12 mg Cu/m3

 for 3 hours/day, 5 days/week for 2 weeks following exposure to an aerosol of 

Klebsiella pneumonia. 

These LOAEL values for immunological effects are recorded in Table 3-1 and plotted in Figure 3-1. 

3.2.1.4 Neurological Effects 

Only one study examining neurological effects was located. Headache, vertigo, and drowsiness were 

reported in factory workers exposed to 111–434 mg/m3

 copper dust (Suciu et al. 1981). 

3.2.1.5 Reproductive Effects 

Sexual impotence was reported in 16% of workers (75–100 workers examined) exposed to 111– 

434 mg/m3

 copper dust during grinding and sieving operations (Suciu et al. 1981). The significance of 

this finding is difficult to assess because a control group was not used. 

No studies were located regarding reproductive effects in animals following inhalation exposure to 

copper. 
3.3

1517

0.12

1.21

16

3.3

0.13

18118

0.12 0.13

14

3.3 0.56

Table 3-1 Levels of Significant Exposure to Copper - Inhalation 

a

Key to 

figure 

Exposure/ 

Duration/ 

Frequency 

(Specific Route) Species (Strain) 

ACUTE EXPOSURE Systemic 

1 Mouse 3 hr

System 

Resp 

NOAEL 

(mg/m3) 

3.3 

Less Serious 

(mg/m3) 

LOAEL 

Serious 

(mg/m3) 

2 Mouse 1-2 wk 5d/wk 3hr/d 

Resp 0.12 (alveoli thickening) 

3 Hamster 3 hr 

Resp 1.21 3.3 (decr cilia beating frequency) 

4 Hamster 1-2 wk 5d/wk 3hr/d 

Resp 0.13 

5 

Immuno/ Lymphoret 

Mouse 1-2 wk 5d/wk 3hr/d

0.12 (decr bactericidal activity) 0.13 (decr mean survival time) 

6 Mouse 3 hr 

3.3 (decr bactericidal activity) 0.56 (decr mean survival time) 
0.6

12

0.6

19

198

0.64

Table 3-1 Levels of Significant Exposure to Copper - Inhalation (continued) 

a 

System 

Key to 

figure 

Exposure/ 

Duration/ 

Frequency 

(Specific Route) Species (Strain) 

INTERMEDIATE EXPOSURE Systemic 

7 

Resp

1 mo 5d/wk 6hr/d 

(NS) Rabbit 

NOAEL 

(mg/m3) 

0.6 M 

Less Serious 

(mg/m3) 

LOAEL 

Serious 

(mg/m3) 

8 

(NS) Rabbit 4-6 wk 5d/wk 6hr/d 

Resp 0.6 M 

9 

CHRONIC EXPOSURE Systemic 

Human 8 hr/d, 5 d/wk Hemato 0.64 (decr hemoglobin and 

erythrocyte levels) 

aThe number corresponds to entries in Figure 3-1. d = day(s); decr = decreased; hemato = hematological; hr = hour(s); LOAEL = lowest-observed-adverse-effect level; NOAEL = no-observed-adverse-effect levResp = respiratory;wk = week(s); yr = year(s) 
10 

Respiratory Immuno/Lymphor 

Figure 3-1. Levels of Significant Exposure to Copper- Inhalation 

Acute (≤14 days) 

Systemic 

mg/m3 

3s 1m 6m 3s 

1 

6m 

4s 5m

2m 5m 

0.1 

c-Cat -Humans f-Ferret n-Mink Cancer Effect Level-Animals Cancer Effect Level-Humans 

d-Dog k-Monkey j-Pigeon o-Other LOAEL, More Serious-Animals LOAEL, More Serious-Humans 

r-Rat m-Mouse e-Gerbil LOAEL, Less Serious-Animals LOAEL, Less Serious-Humans 

p-Pig h-Rabbit s-Hamster NOAEL - Animals NOAEL - Humans 

q-Cow a-Sheep g-Guinea Pig 
Respiratory 

Figure 3-1. Levels of Significant Exposure to Copper- Inhalation (Continued) 

Intermediate (15-364 days) 

Systemic 

mg/m3 

1 

7h 8h 

0.1 

c-Cat -Humans f-Ferret n-Mink Cancer Effect Level-Animals Cancer Effect Level-Humans 

d-Dog k-Monkey j-Pigeon o-Other LOAEL, More Serious-Animals LOAEL, More Serious-Humans 

r-Rat m-Mouse e-Gerbil LOAEL, Less Serious-Animals LOAEL, Less Serious-Humans 

p-Pig h-Rabbit s-Hamster NOAEL - Animals NOAEL - Humans 

q-Cow a-Sheep g-Guinea Pig 
Hematological 

Figure 3-1. Levels of Significant Exposure to Copper- Inhalation (Continued) 

Chronic (≥365 days) 

Systemic 

mg/m3 

1 

9 

0.1 

c-Cat -Humans f-Ferret n-Mink Cancer Effect Level-Animals Cancer Effect Level-Humans 

d-Dog k-Monkey j-Pigeon o-Other LOAEL, More Serious-Animals LOAEL, More Serious-Humans 

r-Rat m-Mouse e-Gerbil LOAEL, Less Serious-Animals LOAEL, Less Serious-Humans 

p-Pig h-Rabbit s-Hamster NOAEL - Animals NOAEL - Humans 

q-Cow a-Sheep g-Guinea Pig 
COPPER 31 

3. HEALTH EFFECTS 

3.2.1.6 Developmental Effects 

No studies were located regarding developmental effects in humans and animals following inhalation 

exposure to copper. 

3.2.1.7 Cancer 

There are limited data for humans and no data for animals on the carcinogenicity of inhaled copper. 

Although a number of studies have examined cancer risk among copper smelters, these papers are not 

discussed because the cancer risk has been attributed to exposure to arsenic rather than to copper. In a 

study of over 6,700 male workers at a Chinese copper mine, significant increases in the risk of cancer (all 

sites combined) (standardized mortality ratio [SMR] =123; 95% confidence interval [CI] =109–139), 

stomach cancer (SMR=131; 95% CI=105–161), and lung cancer (SMR=147; 95% CI=112–189) were 

observed (Chen et al. 1993). The cancer risk increased with increasing duration of employment and time 

since first exposure and was also higher in workers employed in the 1950s when there was a dramatic 

increase in production, dry drilling methods were used, and there was poor underground ventilation. 

Radon and radon daughters were detected in the underground mines; between 1960 and 1990, radioactivity levels of 1.29x10-11 Ci/L were measured. To assess the relative contribution of radon and radon 

daughters to the lung cancer risk, the workers were divided into two groups: underground miners and 

workers involved in drilling (presumably above ground). Increases in lung cancer risk were observed in 

both groups, thus suggesting that exposure to radioactivity was not the primary source of increased cancer 

risk. The copper ore also contained silica, iron, manganese, arsenic, titanium, and sulfur. The study 

authors noted that the arsenic level in the copper was relatively low (0.061%) and did not likely contribute 

to the lung cancer risk; however, the lung cancer risk from exposure to silica and iron could not be ruled 

out. A significant increase in the risk of silicosis was observed in the miners. In a 7-year follow-up of 

this cohort (Chen et al. 1995), the risk of all sites of cancer (SMR=129; 95% CI=117–142), stomach 

cancer (SMR=141; 95% CI=116–169), and lung cancer (SMR=152; 95% CI=123–187) were still 

significantly elevated. This study also conducted a smoking survey and found that a higher percentage of 

the miners were smokers (71.7%) than in the control population of local residents (64.3%); this increased 

smoking rate, along with exposure to radioactivity, silica, iron, and arsenic may have contributed to the 

increased cancer risk. 
 

 

 

 

COPPER 32 

3. HEALTH EFFECTS 

3.2.2 Oral Exposure 

3.2.2.1 Death 

A number of deaths have been reported in individuals intentionally ingesting large doses of copper sulfate 

(Chuttani et al. 1965). Thirteen of 53 individuals died after ingesting 6–637 mg/kg copper; because the 

amount of copper sulfate was self-reported, the estimated doses may be inaccurate. The deaths were 

attributed to shock and hepatic and/or renal complications. Deaths, probably due to central nervous 

system depression and hepatic and renal failure, have also been reported in individuals ingesting “spiritual 

green water”, which contains ≥100 mg copper sulfate/L (Akintonwa et al. 1989). 

Increased mortality was observed in rats fed a diet containing 4,000 ppm of copper (133 mg Cu/kg/day) 

for 1 week. Anorexia, possibly the result of taste aversion, contributed to the deaths (Boyden et al. 1938). 

Weanling rats exposed to 300 mg Cu/kg/day as Cu(II) in the diet (6,000 ppm) died after 2 weeks 

(Haywood 1985). The deaths were attributed to extensive centrilobular necrosis. 

Lifetime exposure to 42.5 mg Cu/kg/day as copper gluconate in drinking water resulted in a 12.8% 

reduction of the maximal lifespan (from 986 to 874 days) in mice (Massie and Aiello 1984). 

The doses associated with deaths in the Haywood (1985) and Massie and Aiello (1984) studies are 

recorded in Table 3-2 and plotted in Figure 3-2. 

3.2.2.2 Systemic Effects 

No studies were located regarding endocrine, dermal, ocular, or metabolic effects in humans or animals 

following oral exposure to copper. 

The highest NOAEL values and all reliable LOAEL values from each reliable study for systemic effects 

in each species and duration category are recorded in Table 3-2 and plotted in Figure 3-2. 

Respiratory Effects. Data on the potential of copper to induce respiratory effects are limited to the 

NTP (1993) study that found no histological alterations in the lungs of rats exposed to 285 or 134 mg 

Cu/kg/day as copper sulfate in the diet for 14 or 90 days, respectively, or in mice exposed to 717 or 

814 mg Cu/kg/day for 14 or 90 days. 
191

550

163

31

166

62

0.011

200

0.017

0.012

201

0.018

203

0.046

173

0.03

Table 3-2 Levels of Significant Exposure to Copper - Oral 

a

Key to 

figure 

Exposure/ 

Duration/ 

Frequency 

(Specific Route) Species (Strain) 

ACUTE EXPOSURE Death 

1 2-15 wk 

(Wistar) (F)Rat 

System 

NOAEL 

(mg/kg/day) 

Less Serious 

(mg/kg/day) 

LOAEL 

Serious 

(mg/kg/day) 

550 M (increased mortality) 

2 14 d 

(Fischer- 344) (W) Rat 31 F (100% mortality) 

3 4 

(B6C3F1) Mouse 

Systemic 

Human 

14 d (W) once (W) 

Gastro 0.011 0.017 (nausea, vomiting, diarrhea, or 

abdominal pain) 

62 M (increased mortality) 

5 Human once 

(W) 

Gastro 0.012 F 0.018 F (nausea) 

6 Human once 

(W) 

Gastro 0.046 (nausea, delayed gastric 

emptying) 

7 Human once 

(W) 

Gastro 0.03 (nausea and vomiting) 
Table 3-2 Levels of Significant Exposure to Copper - Oral (continued) 

Exposure/ LOAEL 

Duration/ 

a Frequency 

Key to Species NOAEL Less Serious Serious (Specific Route) figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) 

8 Human once 

Gastro 6 (vomiting) (W) 

6

77

9 Human once 

Gastro 0.08 M (vomiting, diarrhea) (W) 

0.08

37

10 Human once 

Gastro 0.0057 0.011 (nausea) (W) 

0.0057 0.011

174

11 Human 2 wks b 

Gastro 0.0272 F 0.0731 F (abdominal pain, nausea, and/or (W) 

0.0272 vomiting) 

0.0731

175

12 Human 1 wk 

Gastro 0.096 F (nausea, vomiting, and/or (W) 

abdominal pain)

0.096

176

13 Rat 1-2 wk 

Hepatic 300 M (parenchymal cell hypertrophy) (NS) (F) 

300

8

Renal 300 M 

300
83

300

117

450450

190

200

Table 3-2 Levels of Significant Exposure to Copper - Oral (continued) 

a

Key to 

figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Specific Route) System 

NOAEL 

(mg/kg/day) 

Less Serious 

(mg/kg/day) 

LOAEL 

Serious 

(mg/kg/day) 

14 

(NS) Rat 1-2 wk 

(F) Hepatic 300 M (increased alanine aminotransferase activity) 

15 

(Wistar) Rat 1-2 wk 

(F) Hepatic 450 M (hepatocellular necrosis) 

Renal 450 M (copper-containing droplets and 

granules in proximal tubule cells) 

16 

(Wistar) Rat 2 wk 

(F) 

Renal 200 M (droplets in proximal tubule 

lumen) 
Table 3-2 Levels of Significant Exposure to Copper - Oral (continued) 

a

Key to 

figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Specific Route) System 

NOAEL 

(mg/kg/day) 

LOAEL 

Less Serious 

(mg/kg/day) 

Serious 

(mg/kg/day) 

17 Rat 14 d 

(Fischer- 344) (W) 

164

Resp Cardio Gastro Hepatic Renal Bd Wt 

29 M 29 M 29 M 29 M 26 F 

2929292926

10 M (protein droplets in epithelial 

cells of proximal tubule) 

10
Table 3-2 Levels of Significant Exposure to Copper - Oral (continued) 

a 

Key to Species 

figure (Strain) 

Exposure/ 

Duration/

Frequency

(Specific Route) System 

NOAEL 

(mg/kg/day) 

LOAEL 

Less Serious 

(mg/kg/day) 

Serious 

(mg/kg/day) 

18 Rat 14 d 

(Fischer- 344) (F) 

165

RespCardio Gastro Hemato Hepatic Renal Bd Wt 

285 F 285 F 

23 F 93 F 92 M 46 M 93 F 

2852852393924693

44 F (hyperplasia of forestomach

mucosa)

44

196 F (depletion of hematopoietic cells

in bone marrow)

196

198 M (inflammation) 

198

92 M (increased protein droplets in

cortical tubules)

92

196 F (18% decrease in body weight

gain)

196
24

167

2424242424

Table 3-2 Levels of Significant Exposure to Copper - Oral (continued) 

a

Key to 

figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Specific Route) System 

NOAEL 

(mg/kg/day) 

Less Serious 

(mg/kg/day) 

LOAEL 

Serious 

(mg/kg/day) 

19 

(B6C3F1) Mouse 14 d 

(W) Resp 24 M 

Cardio Gastro Hepatic Renal Bd Wt 

24 M 24 M 24 M 24 M 24 M 
717

168

71792

197

7177177170.042

202

0.091

0.17

Table 3-2 Levels of Significant Exposure to Copper - Oral (continued) 

Exposure/ 

Duration/

a

Key to Species Frequency 

figure (Strain) (Specific Route) 

20 Mouse 14 d 

(B6C3F1) (F) 

INTERMEDIATE EXPOSURE Systemic 

21 Human daily 

2 months (W) 

NOAEL 

System (mg/kg/day) 

Resp 717 M Cardio 717 M Gastro 92 M Hepatic 717 M Renal 717 M Bd Wt 717 M 

c

Gastro 0.042 Hepatic 0.17 

Less Serious 

(mg/kg/day) 

Serious 

(mg/kg/day) 

197 M (hyperplasia of forestomach 

mucosa) 

0.091 (gastrointestinal symptoms) 

LOAEL 
0.319

199

0.3190.3190.14

196

0.140.1466

204

89

114

140

Table 3-2 Levels of Significant Exposure to Copper - Oral (continued) 

Exposure/ 

Duration/

a

Key to Species Frequency 

figure (Strain) (Specific Route) 

22 Human 9 months 

(W) 

23 Human 12 wks 

(C) 

24 3 mo 

(Fischer- 344) (F) Rat 

System 

Gastro HepaticBd WtGastroHematoHepaticHepaticBd Wt

NOAEL 

(mg/kg/day) 

0.319 0.319 0.319 

0.14 0.14 0.14 

66 M 

114 M 

LOAEL 

Less Serious 

(mg/kg/day) 

89 M (increased number of 

necroinflammatory foci in the liver) 

140 M (15% decreased in terminal 

body weight) 

Serious 

(mg/kg/day) 
20

177

20

72

8

8

194

150120

7

180180

Table 3-2 Levels of Significant Exposure to Copper - Oral (continued) 

a

Key to 

figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Specific Route) System 

NOAEL 

(mg/kg/day) 

Less Serious 

(mg/kg/day) 

LOAEL 

Serious 

(mg/kg/day) 

25 

(SpragueDawley) Rat 30-58 d 

(F) Hepatic 20 F 

Renal 20 F 

26 

(SpragueDawley) Rat 90 d 

(W) Hepatic 8 M (increased aspartate aminotransferase activity) 

Bd Wt 8M 

27 18 wks 

(Fischer- 344) (F) Rat 

Hepatic 150 M (inflammation and increased 

serum enzyme activity in adult rats) 

120 M (inflammation, necrosis, and 

increases serum enzyme levels in young rats) 

28 

(NS) Rat 3-15 wk 

(F) Hepatic 180 M (necrosis) 

Renal 180 M (cytoplasmic droplets and 

desquamation of epithelial cells in proximal tubules) 
90

280 550280

550280

84

180

108

320 640

640320

Table 3-2 Levels of Significant Exposure to Copper - Oral (continued) 

a

Key to Species 

figure (Strain) 

29 

(Wistar) Rat 

30 

(NS) Rat 

31 

(Wistar) Rat 

Exposure/ 

Duration/ 

Frequency 

(Specific Route) 

2-15 wk (F) 3-15 wk (F) 15 wk (F) 

System 

Hepatic Renal Bd Wt Hepatic Hepatic Bd Wt 

NOAEL 

(mg/kg/day) 

LOAEL 

Less Serious 

(mg/kg/day) 

280 M (inflammation, necrosis) 280 M (degeneration of proximal tubule 

cells) 

180 M (increased alanine

aminotransferase activity)

320 M (necrosis) 

Serious 

(mg/kg/day) 

550 M (chronic hepatitis) 550 M (weight loss) 280 M (50% decrease in body weight 

gain) 

640 M (chronic hepatitis) 640 M (weight loss) 320 M (50% decrease in body weight 

gain) 
192

280280

21

200

106

100100100

161

14

Table 3-2 Levels of Significant Exposure to Copper - Oral (continued) 

a

Key to Species 

figure (Strain) 

32 

(Wistar) Rat 

33 

(Wistar) Rat 

34 

(NS) Rat 

35 

(Wistar) Rat 

Exposure/ 

Duration/ 

Frequency 

(Specific Route) System 

NOAEL 

(mg/kg/day) 

Less Serious 

(mg/kg/day) 

LOAEL 

Serious 

(mg/kg/day) 

4-14 wks (F) Hepatic 280 M (hepatocellular necrosis) 

Renal 280 M (tubular cell necrosis) 

4-15 wk (F) 

Renal 200 M (reversible degeneration and 

necrosis of tubule cells) 

30 d (G) 

Hemato 100 M (decreased erythrocyte and 

hemoglobin levels) 

Hepatic 100 M (increased glucose, cholesterol, 

bilirubin, serum enzymes, and decreased total protein levels) 

Renal 100 M (increased BUN levels) 

15 wks (F) 

Cardio 14 M (increased blood pressure) 
120

20

120

Table 3-2 Levels of Significant Exposure to Copper - Oral (continued) 

a

Key to 

figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Specific Route) System 

NOAEL 

(mg/kg/day) 

Less Serious 

(mg/kg/day) 

LOAEL 

Serious 

(mg/kg/day) 

36 

(Holtzman) Rat 21 wks 

(F) 

Musc/skel 120 M 

Bd Wt 120 (23% decrease in body weight 

gain) 
134

170

13416

33

33

66

8

6616

9 17 13466

140

Table 3-2 Levels of Significant Exposure to Copper - Oral (continued) 

Exposure/ LOAEL 

a

Key to 

figure 

Duration/ 

Frequency 

(Specific Route) Species (Strain) 

37 13 wk 

(Fischer- 344) (F) Rat 

System 

Resp Cardio Gastro Hemato 

NOAEL 

(mg/kg/day) 

134 F 134 F 

16 M 33 M 

Hepatic 8M Renal Bd Wt 

9F 

66 M 

Less Serious Serious 

(mg/kg/day) (mg/kg/day) 

33 M (squamous mucosa hyperplasia

of forestomach)

66 M (decreases in hematocrit,

hemoglobin, reticulocytes, meancell volume, and mean cellhemoglobin levels andincreases in platelet levels)

66 M (chronic active inflammation

with focal necrosis)

16 M (increases serum alanine

aminotransferase)

17 F (increased BUN) 134 F (tubular degeneration) 

140 M (24% decrease in body weight

gain)
1

100100100

814

172

814126

267

814814187

398

Table 3-2 Levels of Significant Exposure to Copper - Oral (continued) 

a 

System 

Key to 

figure 

Exposure/ 

Duration/ 

Frequency 

(Specific Route) Species (Strain) 

38 

Hemato 

20 d 

(NS) (G)Rat 

Hepatic Renal 

39 

Resp 

13 wk 

(B6C3F1) (F)Mouse 

Cardio Gastro Hepatic Renal Bd Wt 

NOAEL 

(mg/kg/day) 

814 M 814 M 126 F 814 M 814 M 187 M 

LOAEL 

Less Serious 

(mg/kg/day) 

Serious 

(mg/kg/day) 

100 M (decreases in erythrocyte, 

hemoglobin, and hematocrit levels) 

100 M (hepatocellular necrosis) 100 M (tubular cell necrosis) 

267 F (hyperplasia of forestomach 

mucosa) 

398 M (12% decrease in body weight 

gain) 
11

26

24

11 24

115

3636

193

3535

189

24

178

13

Table 3-2 Levels of Significant Exposure to Copper - Oral (continued) 

a

Key to 

figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Specific Route) System 

NOAEL 

(mg/kg/day) 

Less Serious 

(mg/kg/day) 

LOAEL 

Serious 

(mg/kg/day) 

40 

(Hampshire) Pig 54 d 

(F) 

Hemato 11 24 (decreased hemoglobin levels) 

Bd Wt 11 24 (decreased body weight gain) 

41 

(NS) Pig 49 d 

(F) 

Hemato 36 F (decreased hemoglobin levels) 

Hepatic 36 F (increased asparate 

aminotransferase activity) 

42 

(NS) Pig 6 wks 

(F) 

Hemato 35 F (decreased hemoglobin level) 

43 

Immuno/ Lymphoret 

8 wks 

(C57BL/6N) (W)Mouse 

Hepatic 35 F (increased aspartate 

aminotransferase activity) 

24 (impaired immune function) 

44 

(C57BL/6N) Mouse 3-5 or 8-10 wks 

(W) 

13 (altered cell-mediated and 

humoral immunity) 
99

36

23

152

6668

184

398536

185

12

119

Table 3-2 Levels of Significant Exposure to Copper - Oral (continued) 

a

Key to 

figure 

Exposure/ 

Duration/ 

Frequency 

(Specific Route) Species (Strain) 

Neurological 

45 11 mo 

(Sprague- (W)Dawley) Rat 

System 

NOAEL 

(mg/kg/day) 

LOAEL 

Less Serious 

(mg/kg/day) 

36 F (decreased 

3,4-dihydroxyphenylacetic acid levels in corpus striatum) 

Serious 

(mg/kg/day) 

46 

(NS) Rat 30 d 

(F) 

23 

47 

Reproductive 

13 wk 

(Fischer- 344) (F) Rat 

66 M 68 F 

48 

(B6C3F1) Mouse 13 wk 

(F) 

398 M 536 F 

49 

(dark mink) Mink 153 or 367 d 

(F) 

12 
197

130

138

121

208

13

12030

4.2

42

31

Table 3-2 Levels of Significant Exposure to Copper - Oral (continued) 

a

Key to 

figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Specific Route) System 

NOAEL 

(mg/kg/day) 

Less Serious 

(mg/kg/day) 

LOAEL 

Serious 

(mg/kg/day) 

50 

Developmental 

60-73 d 

(Wistar) (W)Rat 

130 (delayed growth and 

development) 

51 

(C57BL/6N) Mouse 1 mo + gd 0-19 

(F) 

138 F 208 (decreased mean litter size and 

fetal body weights) 

52 

(dark mink) Other 153 or 367 d 

(F) 

13 

53 

CHRONIC EXPOSURE Death 

850 d 

(C57BL/6N) (W)Mouse 4.2 (14.7% decrease in lifespan) 

54 

Systemic 

(C57BL/6N) Mouse 850 d 

(W) 

Bd Wt 42 M 

a The number corresponds to entries in Figure 3-2.b Used to derive an acute-duration oral minimal risk level (MRL) of 0.01 mg Cu/kg/day; the NOAEL was divided by an uncertainty factor of 3 to account for humc Used to derive an intermediate-duration minimal risk level (MRL) of 0.01 mg Cu/kg/day; the NOAEL divided by an uncertainty factor of 3 to account for humaBd Wt = body weight; Cardio = cardiovascular; CEL = cancer effect level; d = day(s); Endocr = endocrine; (F) = feed; F = Female; G = gavage; Gastro = gastrogestational day; Gn pig = guinea pig; hemato = hematological; hr = hour(s); LOAEL = lowest-observed-adverse-effect level; M = male; min = minute(s); mo = mmusculoskeletal; NOAEL = no-observed-adverse-effect level; occup = occupational; NS = not specified; Resp = respiratory; (W) = drinking water; wk = week(s
Death Respiratory Cardiovascular Gastrointestinal Hematological Hepatic Renal 

Figure 3-2. Levels of Significant Exposure to Copper - Oral 

Acute (≤14 days) 

Systemic 

mg/kg/day 

1000 

20m 20m 20m 20m 

1r 15r 15r 

18r 13r 14r 13r 

20m 

18r 

18r 18r 16r 

100 18r 

3m 

20m 18r 18r 

18r 

2r 

18r 

17r 17r 17r 17r 19m 19m 19m 19m 19m 

10 

18r 

17r 

8 

1 

0.1 12 9 11 

6 7 11 

4 5 4 5 10 0.01 

10 

0.001 

c-Cat -Humans f-Ferret n-Mink Cancer Effect Level-Animals Cancer Effect Level-Humans 

d-Dog k-Monkey j-Pigeon o-Other LOAEL, More Serious-Animals LOAEL, More Serious-Humans 

r-Rat m-Mouse e-Gerbil LOAEL, Less Serious-Animals LOAEL, Less Serious-Humans 

p-Pig h-Rabbit s-Hamster NOAEL - Animals NOAEL - Humans 

q-Cow a-Sheep g-Guinea Pig 
Respiratory Cardiovascular Gastrointestinal Hematological Musculoskeletal Hepatic 

Figure 3-2. Levels of Significant Exposure to Copper - Oral (Continued) 

Intermediate (15-364 days) 

Systemic 

mg/kg/day 

1000 

39m 39m 39m 

31r 29r 31r 39m 29r 32r

28r 30r 27r 37r 37r 39m 36r 27r 100 34r 38r 34r 38r 24r 

37r 24r 37r 

37r 37r 41p 42p 41p 42p

40p 25r 

37r 37r 35r 

40p 10 

26r 37r 

1 

22 22 

21

23 23 23 

0.1 21 

21 

0.01 

c-Cat -Humans f-Ferret n-Mink Cancer Effect Level-Animals Cancer Effect Level-Humans 

d-Dog k-Monkey j-Pigeon o-Other LOAEL, More Serious-Animals LOAEL, More Serious-Humans 

r-Rat m-Mouse e-Gerbil LOAEL, Less Serious-Animals LOAEL, Less Serious-Humans 

p-Pig h-Rabbit s-Hamster NOAEL - Animals NOAEL - Humans 

q-Cow a-Sheep g-Guinea Pig 
Renal Body Weight Immuno/Lymphor Neurological Reproductive Develo

Figure 3-2. Levels of Significant Exposure to Copper - Oral (Continued) 

Intermediate (15-364 days) 

Systemic 

mg/kg/day 

1000 

39m 

31r 29r 48m 

39m 48m 

31r 29r 32r 29r 

33r 39m 51m 28r 

37r 24r 36r 37r 51m 

24r 100 34r 38r

37r 47r 47r

45r 

40p 43m 46r 25r 37r 

44m 52

40p 49n 10 37r 26r 

1 

22 

0.1 

0.01 

c-Cat -Humans f-Ferret n-Mink Cancer Effect Level-Animals Cancer Effect Level-Humans 

d-Dog k-Monkey j-Pigeon o-Other LOAEL, More Serious-Animals LOAEL, More Serious-Humans 

r-Rat m-Mouse e-Gerbil LOAEL, Less Serious-Animals LOAEL, Less Serious-Humans 

p-Pig h-Rabbit s-Hamster NOAEL - Animals NOAEL - Humans 

q-Cow a-Sheep g-Guinea Pig 
Death Body Weight 

Figure 3-2. Levels of Significant Exposure to Copper - Oral (Continued) 

Chronic (≥365 days) 

Systemic 

mg/kg/day 

100 

54m 

10 

53m 

1 

c-Cat -Humans f-Ferret n-Mink Cancer Effect Level-Animals Cancer Effect Level-Humans 

d-Dog k-Monkey j-Pigeon o-Other LOAEL, More Serious-Animals LOAEL, More Serious-Humans 

r-Rat m-Mouse e-Gerbil LOAEL, Less Serious-Animals LOAEL, Less Serious-Humans 

p-Pig h-Rabbit s-Hamster NOAEL - Animals NOAEL - Humans 

q-Cow a-Sheep g-Guinea Pig 
 

COPPER 54 

3. HEALTH EFFECTS 

Cardiovascular Effects. Several human studies have examined the possible relationship between 

increased serum copper levels and an increased risk of coronary heart disease. Although a number of 

studies have found increased risk of coronary heart disease deaths with increasing serum copper levels 

(Ford 2000), a number of studies have not found a relationship. However, whether copper directly affects 

atherosclerosis or is a marker of inflammation associated with atherosclerosis remains to be established. 

There are limited data on the toxicity of copper to the cardiovascular system. A significant increase in 

systolic blood pressure was observed in rats exposed to 14 mg Cu/kg/day as copper carbonate in the diet 

for 15 weeks (Liu and Mederios 1986). No histological alterations were observed in the hearts of rats or 

mice exposed to 285 or 717 mg Cu/kg/day, respectively, for 14 days or 134 or 814 mg Cu/kg/day for 

90 days (NTP 1993). 

Gastrointestinal Effects. There are numerous reports of acute gastrointestinal effects in humans 

after ingestion of large amounts of copper in drinking water or beverages. The most prevalent effects are 

nausea and vomiting, which typically occur shortly after ingestion and are not persistent (Araya et al. 

2001, 2003a, 2003b, 2003c; Chuttani et al. 1965; Eife et al. 1999; Gill and Bhagat 1999; Gotteland et al. 

2001; Holleran 1981; Jantsch et al. 1984, 1985; Karlsson and Noren 1965; Knobeloch et al. 1994, 1998; 

Nicholas and Brist 1968; Olivares et al. 2001; Pizarro et al. 1999, 2001; Semple et al. 1960; Spitalny et al. 

1984; Walsh et al. 1977). Abdominal pain and diarrhea have also been reported, but their incidence is 

typically much lower than nausea and vomiting. Although most of the data on gastrointestinal effects in 

humans come from case reports of accidental exposure from contaminated beverages with limited 

information on exposure levels, several recently conducted studies were designed to identify the threshold 

for gastrointestinal effects. These experiments typically involve adults ingesting a single dose of copper 

sulfate following an overnight fast (Araya et al. 2001, 2003a, 2003b; Gotteland et al. 2001; Olivares et al. 

2001). Olivares et al. (2001) identified the lowest LOAEL for gastrointestinal effects; a significant 

increase in the incidence of nausea was observed at 4 ppm copper (0.01 mg Cu/kg) and higher. At 6 ppm, 

a significant increase in the incidence of vomiting was also observed. Administering the copper sulfate in 

an orange-flavored drink increased the threshold for nausea to 8 ppm (0.022 mg Cu/kg) (Olivares et al. 

2001). In two multinational studies conducted by Araya and associates (Araya et al. 2001, 2003a), 

NOAEL and LOAEL values of 4 and 6 ppm (0.042 and 0.091 mg Cu/kg), respectively, were identified 

for nausea. Araya et al. (2003a) determined that both the copper concentration and the total copper dose 

are important variables in predicting a response; as the concentration and dose increase, the probability of 

eliciting nausea increases. 
 

COPPER 55 

3. HEALTH EFFECTS 

Similar thresholds for effects were observed in repeated exposure studies (Araya et al. 2003c; Pizarro et 

al. 1999, 2001). Abdominal pain, nausea, and/or vomiting were observed in women drinking water 

containing 5 ppm (0.096 mg Cu/kg) copper sulfate or copper oxide for 1 week (Pizarro et al. 2001). The 

occurrence of gastrointestinal effects (excluding diarrhea) was not significantly different in subjects 

ingesting copper sulfate and those ingesting copper oxide. In a 2-week exposure study by Pizarro et al. 

(1999), significant increases in the incidence of gastrointestinal symptoms were observed in subjects 

exposed to 3 or 5 ppm (0.0731 and 0.124 mg Cu/kg/day), but not to 1 ppm (0.0272 mg Cu/kg/day). The 

incidences of nausea, vomiting, and/or abdominal pain were 5, 2, 17, and 15% in the control, 1, 3, and 

5 ppm groups, respectively. In a similarly designed study, Araya et al. (2003b) examined the occurrence 

of gastrointestinal symptoms in adults exposed to copper sulfate for 2 months. The incidences of 

gastrointestinal symptoms were 11.7, 15.3, 18.3, and 19.7% in the control, 2, 4, and 6 ppm groups, 

respectively. As analyzed using the chi-square test with Bonferroni correction, the incidence was 

significantly elevated in the 6 ppm (0.17 mg Cu/kg/day) group; if the Bonferroni correction was not used, 

the incidence was significantly elevated in the 4 ppm (0.091 mg Cu/kg/day) group. A case report by 

Spitalny et al. (1984) also examined the effects of repeated exposure to copper. Recurrent, acute 

symptoms, including nausea, vomiting, and abdominal pain, were reported by three of four family 

members shortly after drinking juice, coffee, or water in the morning. The effects disappeared when the 

family switched to bottled water. An early morning water sample contained 7.8 ppm copper. A study by 

Buchanan et al. (1991) also examined individuals with elevated levels of copper in household water. The 

occurrence of vomiting and nausea with abdominal pain was not significantly different among residents 

with a first-draw water sample of 3 ppm or higher, as compared to controls with less than 1.3 ppm copper 

in first-draw sample. The investigators noted that in a case-control study of this population, all of the 

cases reported that none of the subjects obtained their water immediately from the tap, but most (70%) 

only let it run for less than 1 minute. The study found that copper content in the tap water used for 

drinking averaged 14% of first draw samples. 

Most of the available human studies examined the relationship between copper exposure and the 

manifestation of symptoms of gastrointestinal irritation; Gotteland et al. (2001) and Araya et al. (2003c) 

also looked at physiological alterations. Gotteland et al. (2001) found significant increases in gastric 

permeability to sucrose following the bolus ingestion of 10 ppm copper as copper sulfate (0.03 mg 

Cu/kg); no alterations in intestinal permeability to lactulose/mannitol were found. The increased gastric 

permeability was independent of gastrointestinal symptoms. A significant delay in decreasing the 

stomach’s antral area was found during the first hour after bolus ingestion of 10 ppm copper as copper 
COPPER 56 

3. HEALTH EFFECTS 

sulfate (0.046 mg Cu/kg) (Arayaet et al. 2003c). This change in antral area is suggestive of a delay in 

gastric emptying. As with gastric permeability, this effect was independent of gastrointestinal symptoms. 

Gastrointestinal effects have also been reported in animal studies. Hyperplasia with hyperkeratosis of the 

squamous mucosa on the limiting ridge separating the forestomach from the glandular stomach was 

observed in rats and mice exposed to 44 and 197 mg Cu/kg/day, respectively, as copper sulfate in the diet 

for 14 days or 33 and 267 mg Cu/kg/day, respectively, as copper sulfate in the diet for 13 weeks (NTP 

1990a). No gastrointestinal effects were observed in rats and mice exposed to 23 or 92 mg Cu/kg/day for 

14 days or in rats and mice exposed to 16 or 126 mg Cu/kg/day 13 weeks. Additionally, no 

gastrointestinal effects were observed in rats and mice exposed to 29 or 24 mg Cu/kg/day as copper 

sulfate in drinking water (NTP 1990a). 

Hematological Effects. There are limited data on the effect of copper on the human hematological 

system. Acute hemolytic anemia was observed in an 18-month-old child 2 days after he drank a solution 

containing approximately 3 g of copper sulfate (Walsh et al. 1977). Acute intravascular hemolysis was 

also reported in 5 of 125 individuals intentionally ingesting a large dose of copper sulfate (Ahasan et al. 

1994). No alterations in hematocrit level or mean corpuscular volume were observed in individuals 

ingesting 0.14 mg Cu/kg/day as copper gluconate in a capsule for 12 weeks (Pratt et al. 1985). 

Information on the hematological effects in animals associated with exposure to high levels of copper is 

also limited to several studies that measured hemoglobin and hematocrit values. Decreased hemoglobin 

and hematocrit values were observed in rats exposed to ≥66 mg Cu/kg/day (Kumar and Sharma 1987; 

NTP 1993; Rana and Kumar 1980) for 20–90 days and in pigs exposed to ≥24 mg Cu/kg/day for 48– 

54 days (Kline et al. 1971; Suttle and Mills 1966a, 1966b). Depletion of hematopoietic cells in the bone 

marrow was observed in rats exposed to 196 mg Cu/kg/day as copper sulfate in the diet for 14 days (NTP 

1993). Contrary to these findings, Liu and Medeiros (1986) observed an increase in hemoglobin levels 

and no change in hematocrit levels in rats fed a diet containing 14 mg Cu/kg/day as copper carbonate for 

20 weeks. 

Musculoskeletal Effects. No studies were located regarding musculoskeletal effects in humans 

following oral exposure to copper. 

Equivocal results on the effects of copper on the musculoskeletal system have been found. Depressed 

skeletal growth has been observed in rats administered 100 mg Cu/kg/day via gavage; tail length was used 
 

COPPER 57 

3. HEALTH EFFECTS 

to assess skeletal growth (Rana and Kumar 1980). Using radiographic data, no qualitative or quantitative 

differences were observed in bones of rats exposed to 120 mg Cu/kg/day as copper acetate in the diet for 

21 weeks (Llewellyn et al. 1985). The different outcomes may reflect the different methods used to 

assess skeletal growth. 

Hepatic Effects. With the exception of several defined syndromes—Wilson’s disease, Indian 

childhood cirrhosis, and idiopathic copper toxicosis—liver effects are rarely reported in humans, although 

this has not been extensively investigated. In a compilation of case reports of individuals intentionally 

ingesting copper sulfate, jaundice was reported in 11 of 53 individuals (Chuttani et al. 1965). 

Centrilobular necrosis, biliary stasis, elevated serum bilirubin level and aspartate aminotransferase 

activity, and elevated bile salts in the urine were found in five of the individuals with jaundice. Jaundice 

(Akintonwa et al. 1989), centrilobular congestion (Lamont and Duflou 1988), and acute hepatotoxicity 

(Ahasan et al. 1994) have also been reported in case reports of lethal ingestion of copper sulfate. 

O’Donohue et al. (1993) reported a case of an adult with jaundice and hepatomegaly following a 3-year 

exposure to copper supplements. For 2 years, the individual ingested 30 mg/day followed by 1 year of 

60 mg/day. In a study of seven adults receiving capsules containing 0.14 mg Cu/kg/day as copper 

gluconate, no significant alterations in serum aspartate aminotransferase, alkaline phosphatase, serum 

gamma glutamyl transferase, or lactate dehydrogenase activities were found (Pratt et al. 1985). No 

alterations in biomarkers of liver damage (serum aspartate aminotransferase, alanine aminotransferase, 

gamma glutamyl transferase) were observed in adults exposed to 0.17 mg Cu/kg/day as copper sulfate in 

drinking water for 2 months (Araya et al. 2003b). 

Several studies have examined liver function in infants exposed to elevated levels of copper in drinking 

water. A no adverse effect level for liver effects was identified in a study of infants (3 months of age at 

study initiation) exposed to 0.315 mg Cu/kg/day as copper sulfate in drinking water for 9 months 

(Olivares et al. 1998). No alterations in total bilirubin levels or serum alanine aminotranferase, aspartate 

aminotransferase, or gamma-glutamyl transferase activities were found. A higher percentage of copperexposed infants (30.4%) were withdrawn from the study, as compared to the control group (11.1%). The 

reasons for being withdrawn from the study were blood sampling refusal (eight infants in the copper 

group and two infants in the control group), protocol transgression (four infants in the copper group and 

no infants in the control group), and change of address (five infants in the copper group and one infant in 

the control group). Two recent surveys of infants exposed to 0.8 mg Cu/L in household water did not find 

significant alterations in serum parameters of liver function or alterations in liver ultrasound imaging tests 

(Zietz et al. 2003a, 2003b). 
COPPER 58 

3. HEALTH EFFECTS 

There is strong evidence to suggest that Wilson’s disease, Indian childhood cirrhosis, and possible 

idiopathic copper toxicosis are caused by an increased genetic susceptibility to copper toxicity. 

Wilson’s Disease. Wilson’s disease is an autosomal recessive genetic disorder with a worldwide 

occurrence of 1 in 30,000 to 1 in 100,000 depending on the population (Llanos and Mercer 2002; 

Scheinberg and Sternlieb 1996). It is characterized by high levels of copper in the liver and low levels of 

serum ceruloplasmin. The accumulation of copper in the liver is due to a genetic defect in one of the 

Cu-ATPases (ATP7B), resulting in impaired biliary excretion of copper. One of the early manifestations 

of the disease, typically at 8–12 years of age, is liver damage. Three types of liver damage are seen— 

cirrhosis, chronic active hepatitis, and fulminant hepatic failure. It is unlikely that the manifestation of 

Wilson’s disease is related to exposure to high levels of copper; high levels of hepatic copper have been 

observed in affected individuals consuming average copper intakes (Scheinberg and Sternlieb 1996). 

Indian Childhood Cirrhosis (ICC). ICC is a type of cirrhosis typically seen in infants and young 

children (6 months to 5 years of age with a mean of 18 months) living in rural areas of the Indian 

subcontinent. Other features include high rates of parental consanguinity and up to 22% of siblings 

affected (Pandit and Bhave 1996; Tanner 1998). Two of the most discriminatory features of ICC are 

coarse, dark brown orcein staining (representing copper) and intralobular pericellular fibrosis (Pandit and 

Bhave 1996). Liver copper levels ranging from 790 to 6,654 μg/g dry weight (mean of 939 μg/g) were 

found in 53 children diagnosed with ICC, as compared to levels of 8–118 μg/g (mean 42–45 μg/g) in 

12 controls aged 6 months to >1 year (Bhave et al. 1982); interpretation of these study results is limited 

by the small number of controls and the lack of detail on the control group. 

In a study of 100 children with ICC and 100 age-, sex-, and caste-matched controls, it was determined 

that ICC was attributable to the early introduction of cow or buffalo milk feeds contaminated with copper 

from brass vessels, which were used to store and heat the milk (Bhave et al. 1987). Although a cause and 

effect relationship between high copper intake and ICC has not been firmly established, there is strong 

evidence to support an association. In another study in which the parents of 100 children with ICC were 

advised to use aluminum or stainless steel vessels for preparing infant milk feeds, only 1 of 86 younger 

siblings of the children with ICC developed ICC (this child was known to have received coppercontaminated milk) as compared to 30 of 125 older siblings (Tanner 1998). 

Idiopathic Copper Toxicosis (ICT). Although there are limited data on ICT, it is also believed to be 

caused by an autosomal-recessive inherited defect in copper metabolism and excess dietary copper 
COPPER 59 

3. HEALTH EFFECTS 

(Müller et al. 1998; Wijmenga 2002). In the literature, ICT is also referred to as Indian childhood 

cirrhosis-like liver disease, copper-associated liver disease in childhood, and Tyrollean infantile cirrhosis. 

In the last 25 years, there have been <200 cases of ICT reported in a number of countries including 

Australia, Austria, Germany, Ireland, Italy, Kuwait, Mexico, United Kingdom, and United States. With 

the exception of a study of ICT in 138 children living in Tyrol Austria (Müller et al. 1996), most papers 

describe the clinical course of 1–4 children. Compiling the data from these studies, Müller et al. (1998) 

found a number of patterns: (1) the age of onset of clinical symptoms occurs before the age of 2 years 

(infantile onset) or before the age of 5 years (late onset), although onset as late as 10 years has also been 

observed; (2) rapid progression and death within 2 weeks to 11 months; (3) very high copper levels in the 

liver, 190–3,360 μg/g dry weight (normal is <50 μg/g); (4) abnormal biochemical markers of liver 

damage such as aminotransferases, alkaline phosphatase, bilirubin, albumin, and prothrombin time; and 

(5) marked panlobular and pericellular fibrosis associated with an usually mild inflammatory infiltrate, 

ballooning degeneration of hepatocytes, and an abundance of Mallory bodies. The high levels of copper 

in the liver, the identification of environmental copper exposure, and the similarity of the clinical 

presentation and histopathology with ICC suggest that copper is the causative agent. As with ICC, an 

increased genetic susceptibility to copper toxicity has been suggested. A genealogic investigation 

conducted by Müller et al. (1996) provided suggestive evidence that the disease is transmitted in an 

autosomal recessive mode. 

The hepatotoxicity of copper in animals has been described and investigated in a number of acute- and 

intermediate-duration oral exposure studies. The majority of these studies used rats; a small number of 

studies used pigs and mice. In addition to these studies, there are a number of studies in animals with 

similar genetic defects as Wilson’s disease, including Long Evans Cinnamon (LEC) rats and Bennington 

terrier dogs. The results of these studies were not considered relevant to healthy humans and will not be 

discussed. The earliest symptoms of hepatotoxicity in rats orally exposed to copper are increases in 

serum chemistry enzymes, particularly alanine aminotransferase and asparate aminotransferase (Epstein 

et al. 1982; Fuentealba et al. 2000; Haywood 1980; Haywood and Comerford 1980; Kumar and Sharma 

1987; NTP 1993; Sugawara et al. 1995). Continued exposure or exposure to higher concentrations can 

result in inflammation, parenchymal cell hypertrophy, and hepatocellular necrosis (Aburto et al. 2001b; 

Fuentealba et al. 2000; Haywood 1980, 1985; Haywood and Loughran 1985; Haywood et al. 1985a; NTP 

1993). At very high doses, chronic hepatitis (Haywood 1985; Haywood and Loughran 1985) has also 

been observed. 
COPPER 60 

3. HEALTH EFFECTS 

Studies in rats provide information on the dose-response relationships as a function of exposure duration. 

The highest NOAEL and lowest LOAEL for liver effects in acutely exposed rats are 92 and 198 mg 

Cu/kg/day, respectively, administered as copper sulfate in the diet for 14 days (NTP 1993). Chronic 

inflammation was observed at the LOAEL; a LOAEL for serum chemistry changes was not identified in 

the available acute exposure studies because the only study testing low doses (NTP 1993) did not assess 

this parameter. The threshold for hepatoxicity in rats following intermediate-duration exposure appears to 

be between 8 - 16 mg Cu/kg/day. NTP (1993) found a significant increase in serum alanine aminotransferase activity in Fischer 344 rats exposed to 16 mg Cu/kg/day as copper sulfate in the diet for 13 weeks; 

no effects were observed at 8 mg Cu/kg/day. However, Epstein et al. (1982) found a significant increase 

in asparate aminotransferase in Sprague-Dawley rats exposed to 8 mg Cu/kg/day as copper sulfate in 

drinking water for 90 days; differences in the exposure route and rat strain may have contributed to these 

differences. Histological damage (chronic active inflammation and focal hepatocellular necrosis) has 

been observed at 66 mg Cu/kg/day (administered as copper sulfate in the diet for 90 days) and higher 

(NTP 1993). Severe hepatic damage (chronic hepatitis) has been observed in rats exposed to >550 mg 

Cu/kg/day as copper sulfate in the diet for 15 weeks (Haywood 1985; Haywood and Loughran 1985). 

The available rat hepatoxocity data, along with toxicokinetic data, suggest that there are three phases of 

copper toxicity in the rat. In the first phase, copper levels increase in the liver, with minimal to no 

damage to hepatic tissues. As the hepatic copper levels increase, inflammation and necrosis occur. 

Thereafter, the copper levels in the liver begin to decrease and the parenchymal tissue begins to 

regenerate. At this point, the animal develops a tolerance to copper. Haywood et al. (1985a) speculated 

that the tolerance resulted from a shift in the liver from copper storage and biliary excretion to copper 

transport and renal clearance. Tolerance appears to protect the animals from subsequent liver toxicity. 

For example, no adverse liver effects were observed in rats exposed to 640 mg Cu/kg/day as copper 

sulfate in the diet when this exposure was preceded by a 15-week exposure to 320 mg Cu/kg/day as 

copper sulfate in the diet. This is in contrast to the severe hepatocellular necrosis that was observed in 

animals exposed to a control diet for 15 weeks followed by a 3-week exposure to 640 mg Cu/kg/day 

(Haywood and Loughran 1985). The time course of each phase of liver toxicity appears to be doserelated. At higher doses, the onset of the necrosis and regeneration occurred earlier as compared to lower 

doses. Additionally, there appears to be an upper limit of copper intake, which would induce copper 

tolerance; doses that exceed this level would result in permanent damage to the liver. Dietary exposure of 

rats to ≥550 mg Cu/kg/day as copper sulfate for 15 weeks resulted in chronic hepatitis with no evidence 

of regeneration of parenchymal tissue (Haywood and Loughran 1985). 
 

COPPER 61 

3. HEALTH EFFECTS 

There are limited experimental data on the hepatoxocity of copper in other animal species. Pigs fed a diet 

providing 35–36 mg Cu/kg/day for 7 weeks had a significant increase in aspartate aminotransferase 

activities (Suttle and Mills 1966a, 1966b). It appears that rats and pigs are equally sensitive to high levels 

of copper in the diet or drinking water. In contrast, mice do not appear to be as sensitive to the hepatic 

toxicity of copper as rats. No hepatic effects were observed in mice exposed to 814 mg Cu/kg/day for 

13 weeks as compared to rats, which exhibited an increase in alanine aminotransferase activity at 16 mg 

Cu/kg/day and chronic active inflammation at 66 mg Cu/kg/day (NTP 1993). 

Renal Effects. There is limited information on the renal toxicity of copper in humans. Congestion of 

the glomeruli and denudation of tubular cells were observed in four individuals consuming a single lethal 

dose of copper sulfate (Chuttani et al. 1965). Acute renal failure was reported in 5 of 125 individuals 

intentionally ingesting large doses of copper sulfate (Ahasan et al. 1994). Hematuria, glycosuria, 

cylindruria, and proteinuria, indicative of renal tubular damage, were observed in a child who drank a 

solution containing approximately 3 g of copper sulfate (Walsh et al. 1977). 

A number of animal studies confirm that the kidney is a target of copper toxicity. Renal toxicity as a 

result of copper loading follows a specific time course (Haywood 1980, 1985; Haywood et al. 1985a, 

1985b). No treatment-related effects were observed in rats exposed to 300 mg Cu/kg/day as copper 

sulfate in the diet for 1–2 weeks (Haywood 1980). However, eosinophilic droplets were observed in the 

epithelial cell cytoplasm of the proximal convoluted tubules in rats exposed to 450 mg Cu/kg/day for 

2 weeks (Haywood et al. 1985a). The number of eosinophilic droplets increased with increasing duration 

(Haywood 1980, 1985). Exposure to 100–280 mg Cu/kg/day for 3–5 weeks resulted in necrosis and 

degeneration of proximal tubule cells (Haywood 1985; Haywood et al. 1985a, 1985b; Rana and Kumar 

1980). After 9 weeks, extensive desquamation of the epithelial cells of the proximal convoluted tubules 

was evident in rats exposed to 180 mg Cu/kg/day (Haywood 1980). Complete regeneration of the 

proximal tubules was observed after 15 weeks of copper treatment in rats exposed to 180–280 mg 

Cu/kg/day (Haywood 1980, 1985; Haywood et al. 1985a, 1985b). In contrast to the Haywood and 

associates studies, a 13-week study by NTP (1993) did not find evidence of regeneration of renal tissue. 

An increase in protein droplets in epithelial cell cytoplasm and the lumen of the proximal convoluted 

tubules was observed in rats exposed to 10 or 92 mg Cu/kg/day as copper sulfate in drinking water or 

diet, respectively, for 2 weeks or to 33 mg Cu/kg/day as copper sulfate in the diet for 13 weeks. At 

134 mg Cu/kg/day, karyomegaly and tubule cell degeneration were also observed. Additional renal 

effects observed in the intermediate-duration study included an increase in serum urea nitrogen levels in 

females exposed to ≥17 mg Cu/kg/day, increased urinary glucose output in males exposed to ≥66 mg 
 

 

COPPER 62 

3. HEALTH EFFECTS 

Cu/kg/day, and increased urinary aspartate aminotransferase and N-acetyl-β-glucosaminidase activities in 

male and female rats exposed to 140 or 134 mg Cu/kg/day, respectively. The NTP (1993) study 

identified a NOAEL of 9 mg Cu/kg/day. No effects were observed in mice fed a diet for 13 weeks which 

provided 814 mg Cu kg/day as copper sulfate (NTP 1993). 

Body Weight Effects. No studies were located regarding body weight effects in humans following 

oral exposure to copper. 

Dietary exposure studies have reported 12–24% decreases in body weight gain in rats following exposure 

to 120–140 mg Cu/kg/day for 2–15 weeks (Llewellyn 1985; NTP 1993), in mice following exposure to 

398 mg Cu/kg/day for 13 weeks (NTP 1993), or in pigs (magnitude of decreased weight gain not 

reported) following exposure to 24 mg Cu/kg/day for 54 days (Kline et al. 1971). No effect levels of 

66 (NTP 1993), 187 (NTP 1993), and 11 mg Cu/kg/day (Kline et al. 1971) have been reported in rats, 

mice, and pigs, respectively; Epstein et al. (1982) also reported no adverse effects on body weight gain in 

rats exposed to 8 mg Cu/kg/day in drinking water. More severe decreases in body weight gain and weight 

loss have also been reported (Haywood 1985; Haywood and Loughran 1985); the weight loss was 

reported at lethal concentrations. Only one study examined the effect of copper on body weight gain 

following chronic-duration exposure (lifetime exposure beginning at 58 days of age); this study found no 

biologically significant effect in mice exposed to 42 mg Cu/kg/day as copper gluconate in drinking water 

(Massie and Aiello 1984). 

3.2.2.3 Immunological and Lymphoreticular Effects 

Information on the immunotoxicity of copper following oral exposure is limited to two drinking water 

studies in which mice were exposed to several concentrations of copper sulfate for 8 weeks (Pocino et al. 

1990) or copper chloride for 3–5 or 8–10 weeks (Pocino et al. 1991). In these studies, groups of mice 

underwent several tests to assess immune function: in vitro lymphoproliferative responses to Escherichia 

coli lipopolysaccharide (LPS), and concanavalin A (Con A), induction and evaluation of antibody 

response to sheep red blood cells, evaluation of autoantibody production, and induction and elicitation of 

delayed-type hypersensitivity response (only tested in the Pocino et al. 1991 study). At the lowest dose 

tested (13 mg Cu/kg/day as copper chloride), impaired cellular (proliferative response to LPS) and 

humoral (autoantibody production) immunity were observed. Impaired performance on the remaining 

immune function tests were observed at ≥26 mg Cu/kg/day as copper chloride (Pocino et al. 1991) or 
 

COPPER 63 

3. HEALTH EFFECTS 

≥24 mg Cu/kg/day as copper sulfate (Pocino et al. 1990). The LOAEL values from these studies are 

presented in Table 3-2 and Figure 3-2. 

3.2.2.4 Neurological Effects 

No studies were located regarding neurological effects in humans following oral exposure to copper. 

No effects on spontaneous motor activity (assessed using an actophometer), learning ability (assessed 

using a pole climbing chamber), or relearning capacity and memory (assessed using a Y-maze) were 

observed in rats fed a diet containing 23 mg Cu/kg/day as copper sulfate (Murthy et al. 1981). This study 

found no alterations in brain dopamine or norepinephrine levels. De Vries et al. (1986) also did not find 

significant alterations in corpus striatial dopamine levels in rats exposed to 36 mg Cu/kg/day as copper 

sulfate in drinking water for 11 months. However, a 25% decrease in a dopamine metabolite, 3,4-dihydroxyphenylacetic acid, was found in the corpus striatum. 

3.2.2.5 Reproductive Effects 

No studies were located regarding reproductive effects in humans following oral exposure to copper. 

Reproductive performance, as assessed by the length of gestation, number of kits whelped, and average 

kit weight, was not adversely affected in minks fed a diet containing 12 mg Cu/kg/day as copper sulfate 

(Aulerich et al. 1982). No other oral exposure studies examined reproductive function. The intermediateduration study by NTP (1993) did not find any histological alterations or alterations in sperm morphology 

or vaginal cytology in male and female rats exposed to 66 and 68 mg Cu/kg/day, respectively, or in male 

and female mice exposed to 398 and 536 mg Cu/kg/day, respectively. The NOAEL values for 

reproductive effects are reported in Table 3-2 and plotted in Figure 3-2. 

3.2.2.6 Developmental Effects 

No studies were located regarding developmental effects of humans following oral exposure to copper. 

There are limited data on the developmental toxicity of copper in experimental animals. Delayed growth 

and development were observed in the offspring of rats exposed to 130 mg Cu/kg/day as copper sulfate in 
 

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3. HEALTH EFFECTS 

the diet for 7 weeks prior to mating and during gestation (Haddad et al. 1991). In 11.5-day-old embryos, 

significant decreases in mean somite number, crown-rump length, and yolk sac diameter were observed. 

In 21.5-day-old fetuses and newborns, delayed ossification was observed in the cervical and cauda 

vertebrae, sternum, metacarpals, forelimb phalanges, metatarsals, and hindlimb phalanges. Exposure of 

mouse dams to a higher dose, 208 mg Cu/kg/day as copper sulfate in the diet, resulted in decreased mean 

litter size and decreased fetal body weights; the statistical significance of these effects is not known 

(Lecyk 1980). No statistically significant alterations in newborn mortality or body weight were observed 

in the offspring of mink exposed to 13 mg Cu/kg/day as copper sulfate in the diet (Aulerich et al. 1982). 

There was a trend toward increased kit mortality between birth and 4 weeks of age in the offspring of 

mink exposed to 6 or 13 mg Cu/kg/day. The incidences were 12, 9, 19, 38, and 32% in the 1, 6, 3, 6, and 

13 mg Cu/kg/day groups, respectively; the statistical significance of this effect was not reported. The 

NOAEL values and all reliable LOAEL values for developmental effects in each species are recorded in 

Table 3-2 and plotted in Figure 3-2. 

3.2.2.7 Cancer 

No studies were located regarding carcinogenic effects in humans following oral exposure to copper. 

Several oral studies have examined the carcinogenicity of copper compounds in animals. These studies 

did not find increases in the occurrence of tumors in mice exposed to 86 mg Cu/kg/day as the pesticide, 

copper 8-hydroxyquinoline (BRL 1968), liver tumors in rats exposed to 130 mg Cu/kg/day as copper 

acetate (Kamamoto et al. 1973), or large intestine tumors in rats exposed to 9 mg Cu/kg/day as an 

unspecified copper compound (Greene et al. 1987). These studies are limited in scope and it can not be 

determined whether the maximum threshold dose (MTD) was achieved. An increased occurrence of 

hepatocellular carcinomas has been reported in Long-Evans Cinnamon rats (Sawaki et al. 1994), an 

animal model for Wilson’s disease. However, liver cancer has not been reported in individuals with 

Wilson’s disease; thus the significance of this finding in not known. 

3.2.3 Dermal Exposure 

3.2.3.1 Death 

No studies were located regarding death in humans and animals following dermal exposure to copper. 
COPPER 65 

3. HEALTH EFFECTS 

3.2.3.2 Systemic Effects 

No studies were located regarding respiratory, cardiovascular, gastrointestinal, musculoskeletal, hepatic, 

renal, endocrine, dermal, or body weight effects in humans or animals following dermal exposure to 

copper. 

Hematological Effects. Hemolytic anemia was observed in a severely burned and debilitated child in 

whom copper sulfate crystals were being applied to granulation tissue. Increased serum and urine copper 

levels were observed (Holtzman et al. 1966). Because the skin was severely damaged, this study cannot 

be used to predict the dermal toxicity of copper following exposure to intact skin. No studies were 

located regarding hematological effects in animals following dermal exposure to copper. 

Ocular Effects. Eye irritation has been reported by factory workers exposed to copper dust 

(Askergren and Mellgren 1975). No studies were located regarding ocular effects in animals following 

exposure to copper. 

3.2.3.3 Immunological and Lymphoreticular Effects 

In some individuals, exposure to copper metal produces pruritic dermatitis. Saltzer and Wilson (1968) 

reported a case of a woman who had recurrent pruritus on her ring finger and wrist caused by copper 

metal in her ring and wristwatch. Allergic contact dermatitis has been observed in individuals following a 

patch test using a copper penny and/or a copper sulfate solution (Barranco 1972; Saltzer and Wilson 

1968). 

No studies were located regarding the following health effects in humans and/or animals after dermal 

exposure to copper: 

3.2.3.4 Neurological Effects 

3.2.3.5 Reproductive Effects 

3.2.3.6 Developmental Effects 

3.2.3.7 Cancer 
 

COPPER 66 

3. HEALTH EFFECTS 

3.2.4 Other Routes of Exposure 

Cardiovascular Effects. A dramatic decrease in pulse pressure and heart rate was observed in New 

Zealand white rabbits infused with 2.5 mg Cu/kg as copper sulfate with an infusion pump in the femoral 

vein for 10–15 minutes (Rhee and Dunlap 1990). Systolic and diastolic pressure initially increased, then 

rapidly decreased. 

Reproductive Effects. Intraperitoneal exposure to 0.95 or 1.4 mg Cu/kg/day for 26 days resulted in 

significant decreases in testes, seminal vesicle, and ventral prostate weights and in plasma testosterone 

levels in Wistar rats (Chattopadhyay et al. 1999); decreases in testicular ∆5-3β-hydroxysteroid dehydrogenases and 17β-hydroxysteroid dehydrogenase activities were also observed at 1.4 mg Cu/kg/day. 

An in vitro study (Holland and White 1988) demonstrated that cupric ions and cuprous ions decrease 

human spermatozoa motility. 

Cancer. Several studies have examined the carcinogenicity of copper compounds following parenteral 

administration. No significant alterations in tumor incidence were observed in male Wistar rats receiving 

subcutaneous injections of 2 mg Cu/kg/day as copper acetate (Yamane et al. 1984), in male and female 

F344 rats receiving intramuscular injections of 0.25 or 0.41 mg Cu/kg/day as finely ground copper (Furst 

1971), or in Wistar rats receiving 150 mg Cu/kg as copper oxide, 150 mg Cu/kg as copper sulfide, or 

70 mg Cu/kg as copper sulfate (Gilman 1962). An increase in the occurrence of renal cell carcinoma was 

observed in male Wistar rats receiving 3–5 mg Cu/kg as cupric nitrilotriacetate 5 days/week for 12 weeks 

(Toyokuni et al. 1996); cupric nitrilotriacetate is a chelated compound of copper that is water soluble. A 

study by BRL (1968) found a slight, but statistically significant, increase in the incidence of reticulum cell 

sarcomas in mice 18 months after receiving a single subcutaneous injection of copper 8-hydroxyquinoline; the significance of this finding is not known. 

3.3 GENOTOXICITY 

No studies were located regarding genotoxicity in humans after inhalation, oral, or dermal exposure to 

copper or its compounds. Several studies have assessed the genotoxicity of copper sulfate following oral 

or parenteral exposure; the results of these in vivo genotoxicity studies are summarized in Table 3-3. 

Significant increases in the occurrence of micronuclei and chromosomal aberrations have been observed 

in chick bone marrow cells and erythrocytes (Bhunya and Jena 1996) and mouse bone marrow cells 

(Agarwal et al. 1990; Bhunya and Pati 1987). A study by Tinswell and Ashby (1990) did not find 
COPPER 67 

3. HEALTH EFFECTS 

Table 3-3. Genotoxicity of Copper In Vivo 

Species (test system) End point Results Reference Compound 

Drosophila melanogaster Recessive lethals + Law 1938 Copper sulfate 

(injection into larvae) 

White Leghorn chick bone Chromosomal + Bhunya and Jena Copper sulfate 

marrow cells (intraperitoneal aberrations 1996 

injection and oral exposure) 

White Leghorn chick bone Micronuclei + Bhunya and Jena Copper sulfate 

marrow cells (intraperitoneal 1996 

injection and oral exposure) 

White Leghorn chick Micronuclei + Bhunya and Jena Copper sulfate 

erythrocytes (intraperitoneal 1996 

injection and oral exposure) 

Inbred Swiss mice bone Chromosomal + Bhunya and Pati Copper sulfate 

marrow cells (intraperitoneal aberrations 1987 

and/or subcutaneous 

injection) 

Inbred Swiss mice bone Micronuclei + Bhunya and Pati Copper sulfate 

marrow cells (intraperitoneal 1987 

and/or subcutaneous 

injection) 

Inbred Swiss mice Sperm + Bhunya and Pati Copper sulfate 

(intraperitoneal injection) abnormalities 1987 

CBA mice bone marrow cells Micronuclei – Tinwell and Ashby Copper sulfate 

(intraperitoneal injection) 1990 

Swiss mice (intraperitoneal Chromosomal + Agarwal et al. 1990 Copper sulfate 

injection) aberrations 

+ = positive results; – = negative results 
 

COPPER 68 

3. HEALTH EFFECTS 

increases in the number of micronuclei in mouse bone marrow cells. Increases in the occurrence of 

recessive lethals (Law 1938) and sperm abnormalities (Bhunya and Pati 1987) have also been observed in 

Drosophila and mice, respectively. 

Several studies copper sulfate and copper chloride genotoxicity did not find significant increases in the 

occurrence of reverse mutations in Salmonella typhimurium (Marzin and Phi 1985; Tso and Fung 1981; 

Wong 1988) or Saccharomyces cerevisiae (Singh 1983). In contrast, Demerec et al. (1951) found an 

increased occurrence of reverse mutations in Escherichia coli. Positive results have been found in studies 

testing for DNA damage. Errors in DNA synthesis by viral DNA polymerase (Sirover and Loeb 1976), a 

reduction in DNA synthesis (Garrett and Lewtas 1983; Sirover and Loeb 1976), and an increase in the 

occurrence of DNA strand breaks (Sideris et al. 1988; Sina et al. 1983) have been observed. The increase 

in sister chromatid exchange in Chinese hamster cells (Sideris et al. 1988) is consistent with the 

clastogenic effects observed in in vivo assays. The results of these studies are summarized and are 

presented in Table 3-4. 

3.4 TOXICOKINETICS 

Physiologically normal levels of copper in the body are held constant by alterations in the rate and 

amount of copper absorption, compartmental distribution, and excretion. 

3.4.1 Absorption 

3.4.1.1 Inhalation Exposure 

No studies were located regarding the rate and extent of absorption following inhalation exposure of 

humans to copper. There are limited data on copper absorption in animals. Copper oxide was observed 

in alveolar capillaries 3 hours after albino rats were exposed to a welding dust aerosol generated from 

pure copper wires (no additional exposure information was provided) (Batsura 1969). The half-time of 

copper sulfate in the lungs was estimated to be 7.5 hours after intratracheal instillation of 20 μg copper 

per Wistar rat (Hirano et al. 1990). 
 

 

 

 

 

 

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3. HEALTH EFFECTS 

Table 3-4. Genotoxicity of Copper In Vitro 

Results 

Species (test 

system) End point 

With 

activation 

Without 

activation Reference Compound 

Prokaryotic organisms: 

Salmonella 

typhimurium TA102 

Reverse mutation NT – Marzin and Phi 

1985 

Copper sulfate 

S. typhimurium 

TA98, TA102, 

TA1535, TA1537 

Reverse mutation – – Wong 1988 Copper chloride 

S. typhimurium 

TA100 

Reverse mutation NT – Tso and Fung 

1981 

Copper chloride 

Escherichia coli Reverse mutation NT + Demerec et al. 

1951 

Copper sulfate 

Avian 

myeloblastosis 

virus, DNA 

polymerase 

Errors in DNA 

synthesis 

NT + Sirover and Loeb 

1976 

Copper chloride 

Bacillus subtilis rec assay NT – Nishioka 1975 Copper chloride 

Eukaryotic organisms: 

Fungi: 

Saccharomyces 

cerevisiae 

Reverse mutation NT – Singh 1983 Copper sulfate 

S. cerevisiae Recombination NT – Sora et al. 1986 Copper sulfate 

Mammalian cells: 

 Chinese hamster 

ovary cells 

DNA synthesis NT + Garrett and 

Lewtas 1983 

Copper chloride 

Rat hepatocytes DNA strand 

breaks 

NT + Sina et al. 1983 Copper sulfate 

 Chinese hamster 

V79 cells 

DNA strand 

breaks 

NT + Sideris et al. 

1988 

Copper nitrate 

 Chinese hamster 

V79 cells 

Sister chromatid 

exchange 

NT + Sideris et al. 

1988 

Copper nitrate 

+ = positive results; – = negative results; DNA = deoxyribonucleic acid; NT = not tested 
COPPER 70 

3. HEALTH EFFECTS 

3.4.1.2 Oral Exposure 

Copper is absorbed from the stomach and small intestine; there appear to be species differences in the site 

of maximal absorption. The site of maximal copper absorption is not known for humans, but it is 

assumed to be the stomach and duodenum because of the rapid appearance of 64Cu in the plasma after oral 

administration (Bearn and Kunkel 1955). In rats, copper is primarily absorbed from the duodenum, and 

to a lesser extent from the stomach (Van Campen and Mitchell 1965); in Golden hamsters, copper is 

primarily absorbed from the lower small intestine (25–35 cm from the pylorus) (Crampton et al. 1965). 

Copper is absorbed from the gastrointestinal tract as ionic copper or bound to amino acids. Absorption of 

the latter apparently involves at least two kinetically distinguishable processes. The first mechanism 

transports copper from the mucosal side of the intestine to the serosal side. Only a small fraction of the 

ingested copper is transported via this mechanism (Crampton et al. 1965; Gitlan et al. 1960). The second 

mechanism of copper absorption involves the delivery of copper to the absorptive surface, mucosal 

uptake and binding to metallothionein or another intestinal binding protein (Evans and LeBlanc 1976). 

The copper bound to metallothionein can be slowly released to the blood (Marceau et al. 1970) or is 

excreted when the mucosal cell is sloughed off. 

A number of human studies have examined the oral absorption of 64Cu; the average absorption 

efficiencies ranged from 24 to 60% in presumably healthy adults (Jacob et al. 1987; Johnson et al. 1988b; 

Strickland et al. 1972; Turnlund et al. 1982, 1983, 1985, 1988a; 1988b; 1989; Weber et al. 1969). 

Numerous factors may affect copper absorption. These factors include: the amount of copper in the diet 

(Farrer and Mistilis 1967; Strickland et al. 1972; Turnland et al. 1989), competition with other metals, 

including zinc, iron, and cadmium (Davies and Campbell 1977; Hall et al. 1979; Haschke et al. 1986; 

Hoogenraad et al. 1979; Prasad et al. 1978; Turnland et al. 1988a) and age (Varada et al. 1993). The 

absorption of copper appears to be inversely related to the amount of copper in the gastrointestinal tract 

(Strickland et al. 1972; Turnland et al. 1989). In a study of 11 young men administered various copper 

doses in food over a period of 42–98 days, absorption efficiencies of 55–56, 36, and 12% were found at 

doses of 0.785, 1.68, and 7.53 mg/day, respectively (Turnland et al. 1989). In humans, the amount of 

stored copper does not appear to influence copper absorption (Strickland et al. 1972). In rats, the 

absorption of copper appears to be inversely related to the amount of cadmium in the diet (Davies and 

Campbell 1977). A significant decrease in copper absorption was observed when the copper:cadmium 
COPPER 71 

3. HEALTH EFFECTS 

ratio was 1:4. The amount of copper retained in the intestinal mucosal cells was also inversely related to 

cadmium dietary concentration. In addition, increased levels of zinc in the diet result in decreased in 

copper absorption in humans and rats (Hall et al. 1979; Hoogenraad et al. 1979; Prasad et al. 1978). 

Turnland et al. (1988a) found that diets low in zinc (below the dietary requirement) decreased copper 

absorption in humans; 48.1% of radiolabeled copper was absorbed when the diet contained 1.3 mg copper 

and 16.5 mg zinc (dietary requirement is 15 mg zinc), and 37.2–38.5% of radiolabelled copper was 

absorbed when the diet contained 1.3 mg copper and 5.5 mg zinc. A decrease in copper absorption has 

been observed in infants with high intakes of iron (Haschke et al. 1986). Apparently conflicting results 

have been reported on the effect of ascorbic acid on copper absorption in humans. Based on a decrease in 

serum ceruloplasmin levels, Finley and Cerklewski (1983) concluded that a diet high in ascorbic acid 

resulted in a decrease in copper status. In a study by Jacob et al. (1987), copper absorption was not 

affected by a high ascorbic acid intake. A decrease in serum ceruloplasmin activity was also found; 

however, the amount of ceruloplasmin protein was not affected. 

Studies in humans and animals provide suggestive evidence of age-related changes in copper absorption. 

Varada et al. (1993) found that copper absorption was linear and nonsaturable in suckling (16 days of age) 

and weanling (21–22 days of age) rats. In contrast, copper absorption was saturable in adolescent rats 

(6 weeks of age). The levels of copper retained in the intestine were greater in the suckling rats than in 

the weanling or adolescent rats. However, the increased retention was not related to increased 

metallothionen levels; the levels of metallothionen (after zinc induction) were higher in the adolescent 

rats compared to the younger rats. A linear relationship between copper intake and retention was also 

found in a balance study of infants (aged 2–16 weeks) (Dörner et al. 1989). Olivares et al. (2002) did not 

find significant differences in copper absorption between 1-month-old and 3-month-old infants. The 

relatively small range of doses used in this study does not allow for a determination of whether copper 

absorption is saturable in infants. Several studies of adults did not find differences in copper absorption 

between male and female adults aged 20–83 years (Johnson et al. 1992) or between elderly men (65– 

74 years) and young men (22–30 years) (Turnland et al. 1982, 1988b). 

Human studies did not find that increased levels of fiber (α-cellulose or phytate) (Turnland et al. 1985) or 

ascorbic acid (Turnland et al. 1987) significantly altered copper absorption. However, a study in rats 

found an increase in fecal excretion of copper (and a decrease in apparent absorption) in rats fed a high 

fiber (potato fiber or sugar beet pulp) diet (Gralak et al. 1996). The administration of copper in infant 

formula or in a solution high in fulvic acid did not appear to influence copper uptake from the intestinal 

lumen into the intestinal mucosa of suckling rats, as compared to copper in drinking water (Lind and 
COPPER 72 

3. HEALTH EFFECTS 

Glynn 1999). However, the absorption rate of copper into the circulatory system was decreased when 

administered in the infant formula or fulvic acid solutions. Gender does not appear to influence copper 

absorption. Johnson et al. (1992) found that women aged 20–59 years absorbed more copper (66.1– 

74.1%) than similarly aged men (62.0–69.2%); however, when net copper absorption was normalized by 

body weight, no sex-related differences in absorption were found. No sex-related differences in net 

copper absorption were found in older (60–83 years) men and women. 

3.4.1.3 Dermal Exposure 

The available in vivo data do not provide information on the rate and extent of absorption through intact 

skin following dermal exposure of humans or animals to copper. Following a copper azide explosion that 

yielded metallic copper and nitrogen fumes, a small increase in serum copper levels was found in the 

affected worker (Bentur et al. 1988). Similarly, animal studies demonstrate that copper can pass through 

dermal barriers when applied with an appropriate vehicle, (e.g., salicylic acid or phenylbutazone) 

(Beveridge et al. 1984; Walker et al. 1977). In vitro studies suggest that copper is poorly absorbed 

through intact skin. Less than 6% of copper deposited on ex vivo human skin samples was absorbed 

(Pirot et al. 1996a, 1996b); copper chloride was absorbed to a higher extent than copper sulfate (Pirot et 

al. 1996a). 

3.4.2 Distribution 

3.4.2.1 Inhalation Exposure 

No studies were located regarding the rate and extent of distribution of copper following inhalation 

exposure of humans or animals. 

3.4.2.2 Oral Exposure 

Following ingestion of copper, copper levels in the blood rapidly rise. The copper is predominantly 

bound to albumin. There is some evidence that albumin plays a passive role in copper transport, carrying 

a large portion of the exchangeable copper in the circulation and releasing this to other carriers for actual 

cell-specific uptake. There is also evidence that transcuprein is another plasma protein carrier (Weiss and 

Linder 1985). Thus, dietary copper is transported to, and enters, the liver and kidney. Copper then 

reemerges into the plasma bound to the ceruloplasmin. Ceruloplasmin, which tightly binds six or seven 
 

 

COPPER 73 

3. HEALTH EFFECTS 

copper atoms (Musci et al. 1993; Saenko et al. 1994), is the most abundant copper protein in the plasma; 

60–95% of the plasma copper is bound to ceruloplasmin (Harris 1993). Copper is transported from the 

liver to other tissues via ceruloplasmin. Ceruloplasmin does not enter the cell (Percival and Harris 1990). 

Copper, probably as Cu(I) rather than Cu(II) (Dameron and Harris 1989; Percival and Harris 1989), enters 

the cell via a carrier-mediated process. The membrane-bound copper transporting adenosine 

triphosphatase (Cu-ATPase), which selectively binds copper ions, transports copper ions into and out of 

cells (Harris et al. 1998). In most organs and tissues, copper turnover is biphasic (Levenson and 

Janghorbani 1994). In the plasma, the half-lives of the first and second components were 2.5 and 69 days, 

respectively. It is likely that the first order component is ceruloplasmin associated copper. The respective 

calculated copper half-lives for other tissues are 3.9 and 21 days for the liver, 5.4 and 35 days for the 

kidney, and 23 and 662 days for the heart; copper turnover in the brain appears to be monophasic with a 

half-life of 457 days. 

3.4.2.3 Dermal Exposure 

No studies were located regarding the rate and extent of distribution of copper following dermal exposure 

of humans or animals to copper. 

3.4.3 Metabolism 

The metabolism of copper consists mainly of its transfer to and from various organic ligands, most 

notably sulfhydryl and imidazole groups on amino acids and proteins. Several specific binding proteins 

for copper have been identified that are important in the uptake, storage, and release of copper from 

tissues. 

In the liver and other tissues, copper is stored bound to metallothionein and amino acids and in 

association with copper-dependent enzymes. Several studies have shown that copper exposure induces 

metallothionein synthesis (Mercer et al. 1981; Wake and Mercer 1985). Increased levels of metallothionein may be associated with resistance to copper toxicity in pigs (Mehra and Bremner 1984). 

Ceruloplasmin is synthesized in the liver. Copper is incorporated into the molecule, and it is released 

from the liver. Copper exposure has also been shown to induce ceruloplasmin biosynthesis (Evans et al. 

1970b; Haywood and Comerford 1980). 
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3.4.4 Elimination and Excretion 

3.4.4.1 Inhalation Exposure 

No studies were located regarding the rate and extent of excretion of copper following inhalation 

exposure of humans or animals. 

3.4.4.2 Oral Exposure 

Bile is the major pathway for the excretion of copper. After the oral administration of radioactive copper 

as copper acetate in healthy humans, 72% was excreted in the feces (Bush et al. 1955). A considerable 

fraction of fecal copper is of endogenous biliary origin. The remainder of the fecal copper is derived 

from unabsorbed copper and copper from desquamated mucosal cells. Copper in bile is associated with 

low molecular weight copper binding components as well as macromolecular binding species (Gollan and 

Dellar 1973). Reabsorption of biliary copper is negligible (Farrer and Mistilis 1967). 

Normally, 0.5–3.0% of daily copper intake is excreted into the urine (Cartwright and Wintrobe 1964). 

3.4.4.3 Dermal Exposure 

No studies were located regarding the rate and extent of excretion of copper following dermal exposure of 

humans or animals to copper. 

3.4.4.4 Other Routes of Exposure 

Biliary excretion of copper following intravenous administration does not increase proportionally with 

dosage, suggesting that the hepatobiliary transport of copper is saturable (Gregus and Klaassen 1986). 

Thus, at high copper intakes, urinary copper excretion increases (Gitlan et al. 1960). 

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 et al. 

1987; Andersen and Krishnan 1994). 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 parametrization, (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. 

A PBPK model for copper has not been identified. 

3.5 MECHANISMS OF ACTION 

3.5.1 Pharmacokinetic Mechanisms 

Copper is an essential element required for the normal functioning of more than 30 enzymes. The ability 

of copper to cycle between an oxidized state, Cu(II), and reduced state, Cu(I), is used by cuproenzymes 

involved in redox reactions. However, it is this property of copper that is also potentially toxic because 

the transitions between Cu(II) and Cu(I) can result in the generation of superoxide radicals and hydroxyl 

radicals (Camakaris et al. 1999). Under most circumstances, a number of homeostatic mechanisms 

maintain a physiologically essential concentration of copper. Copper homeostasis involves regulation of 

absorption, cellular uptake, intracellular transport, sequestration/storage, cellular efflux, and excretion 

from the body. Turnland et al. (1989) demonstrated that copper absorption from the gastrointestinal tract 

is inversely proportional to dietary intake; as dietary copper increases, absorption efficiency decreases. 

At dietary concentrations of 0.785, 1.68, and 7.53 mg/day (the recommended dietary allowance [RDA] 

for copper is 0.900 mg/day), 56, 36, and 12%, respectively, of the radiolabelled copper was absorbed. 

How the absorption of copper is regulated is not fully understood. In vitro studies provide evidence that 

copper uptake into intestinal cells appears to be saturable (Arredondo et al. 2000). This study also 

provides suggestive evidence that copper uptake into the intestinal cell and efflux are influenced by 

intracellular copper concentrations. There is evidence that copper diffuses across the intestinal cell 

membrane; however, it is unlikely that this is the only absorption mechanism. It is possible that recently 

identified copper transporters (hCtr1 and hCtr2) play a role in the regulation of copper uptake. The 

Menkes protein (MNK), a copper-translocating P-type ATPase, may be involved in the transport of 

copper across the basolateral membrane of intestinal cells (Pena et al. 1999). MNK protein is involved 

the delivery of copper to copper-dependent enzymes and the efflux of copper from the cell. The export of 
Inhaled chem ical E xhaled chem ical 

Lungs 

Liver 

Fat 

S low ly 

perfused 

tissues 

Richly 

perfused 

tissues 

K idney 

Skin 

V 

E 

N 

O 

U 

S 

B 

L 

O 

O 

D 

A 

R 

T 

E 

R 

I 

A 

L 

B 

L 

O 

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V ma x K m 

Ingestion 

GI 

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Feces 

Urine

 C hem icals in air 

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Figure 3-3. Conceptual Representation of a Physiologically Based Pharmacokinetic (PBPK) Model for a Hypothetical Chemical Substance 

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 et al. 1994 
 

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copper via the MNK protein appears to be regulated by intracellular copper concentration. Exposure to 

copper produces a conformational change in the MNK protein resulting in the formation of a copper 

cluster, which allows access to the phosphorylation site that upon phosphorylation, initiates copper 

translocation (Dameron and Harrison 1998). Once copper is released from the intestinal cells, it is 

transported bound to albumin and histidine to the liver via the portal circulation. Once in the hepatic 

cells, copper complexes with small cytoplasmic proteins known as copper chaperones. These copper 

chaperones are involved in intracellular distribution of copper ions. In the liver, another P-type ATPase, 

Wilson protein (WND), delivers copper to ceruloplasmin, which is then released to the blood for 

distribution to other tissues and organs. Under conditions of elevated copper, WND is involved in the 

release of copper at the canalicular membrane with ensuing biliary excretion of copper. The liver plays a 

critical role in copper homeostasis as both the storage site for this metal and as part of the physiologic 

route for excretion through the biliary system. The molecular mechanisms determining biliary copper 

excretion are becoming clearer due to the better understanding of genetic defects, such as Wilson’s 

disease. Specifically, the Wilson protein localized to the trans-Golgi network of hepatocytes not only 

delivers copper to ceruloplasmin, but also is essential for biliary copper excretion. Recently, other 

proteins have also been identified that interact with Wilson protein and appear to be equally important in 

the process of biliary copper excretion (Tao et al. 2003). 

3.5.2 Mechanisms of Toxicity 

Although a number of studies have investigated the mechanisms of copper hepatotoxicity in rats, it is not 

known whether rats would be a good model for human liver toxicity unrelated to a genetic defect in 

copper metabolism. Lysosomes serve an important role in hepatic copper metabolism. Excess copper is 

sequestered within hepatocyte lysosomes where it is complexed with metallothionein. However, this 

protective mechanism is saturable and liver lesions can develop above the saturation limit. In copper 

loaded rats, lysosomes become enlarged and more fragile with decreased membrane fluidity (Myers et al. 

1993). The results of the Haywood et al. (1985a) study do not suggest that liver damage is due to 

rupturing of lysosomes because lysosomal instability precedes and is not synchronous with liver damage. 

It is speculated that saturation of the lysosomes results in an accumulation of copper in the nucleus and 

subsequent nuclear damage (Fuentealba and Haywood 1988; Fuentealba et al. 1989; Haywood et al. 

1985a). The mechanism by which copper accumulates in the nucleus and the mechanisms by which it 

provokes injury are not clear. It has been suggested that excess copper results in oxidative damage, 

including lipid peroxidation. Increases in the level of thiobarbituric acid reactive substance (TBARS), a 

measure of lipid peroxidation, have been found in copper-loaded rats (Myers et al. 1993; Sokol et al. 
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1993). However, a study by Aburto et al. (2001b) did not find significant alterations in the levels of 

malaondialdehyde, a lipid peroxidation by product, prompting the study authors to postulate that lipid 

peroxidation does not play a major role in copper toxicity although it may occur as a terminal event as a 

consequence of cell injury. Sokol et al. (1990, 1993) suggested that oxidant injury to hepatocyte 

mitochondria may be one of the initiating factors in hepatocellular damage. Numerous studies have 

shown that rats can develop tolerance to high levels of copper. After 3–5 weeks of copper loading 

resulting in tissue damage, the copper levels in the liver begin to decline and the tissue begins to 

regenerate (Haywood and Loughran 1985). It is believed that the mechanism involved in tolerance 

development is the increased synthesis of metallothionein (Evering et al. 1991a, 1991b; Freedman and 

Peisach 1989). 

Studies in monkeys, dogs, and ferrets provide strong evidence that copper-induced emesis results from 

stimulation of the vagus nerve. Abdominal vagotomy resulted in a dramatic decrease in the occurrence of 

emesis in dogs (Fukui et al. 1994) and ferrets (Makale and King 1992) orally exposed to copper sulfate 

and in monkeys receiving oral or intravenous injections of copper sulfate (Fukui et al. 1993). In 

monkeys, administration of compounds that block 5-HT3 receptors also resulted in a decrease in emesis 

following oral or intravenous administration of copper sulfate (Fukui et al. 1993). In contrast, 5-HT3 

blockers did not affect the occurrence of emesis in dogs (Fukui et al. 1994) or ferrets (Bhandari and 

Andrew 1991) receiving an oral dose of copper sulfate, but compounds that block 5-HT4 receptors did 

inhibit copper-induced vomiting. Fukui et al. (1994) suggested that copper sulfate caused gastrointestinal 

irritation that resulted in the release of 5-HT and evoked emesis by activation of abdominal visceral 

afferents through 5-HT4 receptors. 

3.5.3 Animal-to-Human Extrapolations 

The toxicity of copper has been assessed in a number of experimental animal species, and sensitivity to 

copper toxicity is highly species dependent. Ruminants are more susceptible than nonruminant species. 

NTP (1993) demonstrated that rats are much more sensitive than mice to the hepatotoxicity of copper. In 

rats, dietary exposure to 16 mg Cu/kg/day for 13 weeks resulted in an increase in alanine aminotransferase activity; chronic active liver inflammation was observed at 66 mg Cu/kg/day. In contrast, no 

evidence of liver damage was observed in mice exposed to 814 mg Cu/kg/day for 13 weeks. 

Most of the experimental data on the toxicity of copper come from studies in which rats were used; 

however, the relevance of this species to human toxicity has not been fully evaluated. The dietary 
 

 

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requirement for copper in rats is 5 mg Cu/kg diet (NRC 1995); a commonly used diet for rats (AIN76, 

AIN 93G, AIN93M) has a cupric carbonate concentration of 300 mg/kg diet (160 mg Cu/kg diet). An 

intermediate-duration exposure to approximately 250 mg Cu/kg diet resulted in mild liver effects 

(increased serum alanine aminotransferase) (NTP 1993). It is unlikely that humans would tolerate 

prolonged exposure to a copper dose that is 50 times higher than the dietary requirement (0.65 mg 

Cu/kg/day); gastrointestinal disturbances were observed in women ingesting 0.0731 mg Cu/kg/day in 

drinking water (Pizarro et al. 1999). Thus, the applicability of these animal data to humans is not known. 

The Long-Evans Cinnamon rat is often used as a model for Wilson’s disease. This rat strain shares many 

characteristics with Wilson’s disease: accumulation of liver copper, decreased serum copper and ceruloplasmin levels, and impaired biliary excretion of copper (Sugawara et al. 1991, 1992, 1994; Suzuki et al. 

1995). 

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 Colborn and Clement (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 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 believe 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 include 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, 
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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 1997). 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). However, in the case of ambient human exposures, the validity 

of these possibilities has yet to be established conclusively. 

There is no evidence that copper interferes with the normal function of the neuroendocrine axis. 

3.7 CHILDREN’S SUSCEPTIBILITY 

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

conception to maturity at 18 years of age, 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 direct or indirect effects on the fetus and neonate resulting from maternal exposure during gestation 

and lactation. Potentially relevant animal and in vitro models are also discussed. 

Children should not be considered small adults. They may differ from adults in their exposures and 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 may 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 at which 

particular structures and/or functions will be most sensitive to perturbation. 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). Also, the distribution of xenobiotics may be different; for example, infants 
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have a larger proportion of their bodies as extracellular water, their brains and livers are proportionately 

larger, and the composition and quality of their lipid depots differ from those of adults (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 child more or less susceptible also 

depends on whether the relevant enzymes are involved in activation of the parent compound to its toxic 

form and/or in detoxification. There may also be differences in excretion, particularly in newborns who 

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). In addition, children and adults may 

differ in their capacity to repair damage from chemical insults. In general, children also have a longer 

remaining lifetime in which to express damage from chemicals; this potential is particularly relevant to 

the development of cancer. 

Certain characteristics of the developing human may increase exposure or susceptibility to certain 

toxicants, whereas others may decrease susceptibility to the same toxicant. For example, although infants 

breathe more air per kilogram of body weight than adults, 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). 

Copper is an essential element required for normal growth and development and for a variety of metabolic 

functions including iron metabolism, cross-linking of connective tissue, and lipid metabolism. Signs of 

copper deficiency in infants and children include anemia that is unresponsive to iron supplementation, 

neutropenia, bone abnormalities, and hypopigmentation of the hair (Cordano 1998; Danks 1988). 

Exposure to excess levels of copper has been associated with adverse health effects in infants and 

children. There is an extensive body of literature on two syndromes that have been associated with 

exposure to high levels of copper, Indian childhood cirrhosis and idiopathic copper toxicosis. Both are 

characterized by severe liver damage in infants and children (<5 years of age). In the case of Indian 

childhood cirrhosis, excessive copper exposure has been traced to the use of brass or copper containers 

for storage and heating of milk. Doses as high as 0.930 mg/kg/day have been estimated; this dose is 
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approximately 30 times higher than the dietary requirement for copper (Tanner 1998). Idiopathic copper 

toxicosis (also referred to as non-Indian childhood cirrhosis) has also been linked to exposure to high 

levels of copper in drinking water and/or the use of copper utensils (Wijemenga 2002). A common 

finding in both syndromes is the early dietary introduction of non-mother’s milk and/or formula. 

Genealogical investigations provide suggestive evidence that both syndromes are transmitted in an 

autosomal recessive mode. However, the mechanism of action has not been identified. It is possible that 

the genetic defect results in reduced copper efflux from the liver. Very high levels of copper have been 

detected in the livers of affected infants; copper levels ranging from 790 to 6,654 μg/g dry weight (mean 

of 939 μg/g) have been reported in infants diagnosed with Indian childhood cirrhosis (levels in control 

infants ranged from 8 to 118 μg/g (Bhave et al. 1982). Support for the genetic component comes from the 

finding that decreasing copper exposure levels dramatically decreases the occurrence of Indian childhood 

cirrhosis (Tanner 1998). Additionally, no alterations in serum biomarkers of liver damage (alanine 

aminotransferase activity, aspartate aminotransferase activity, gamma glutamyl transferase activity, and 

total bilirubin levels) were observed in infants ingesting water containing 2 mg/L copper 

(0.319 mg/kg/day) (Olivares et al. 1998) or infants living in households with tap water copper levels of 

0.8 mg/L (Zietz et al. 2003a, 2003b). Together, these data suggest that exposure to copper levels 

exceeding the copper metabolic capacity of certain individuals with a genetic defect is the causative agent 

for severe liver damage. 

Another adverse health effect that has been reported in infants and children is gastrointestinal upset. This 

effect, which is one of the most commonly reported adverse health effect in adults, is manifested in 

nausea, vomiting, abdominal pain, and/or diarrhea. Symptoms usually occur shortly after ingesting a 

copper-contaminated beverage or drinking water containing a high level of copper. In most of the reports 

of gastrointestinal upset in children (Gill and Bhagat 1999; Karlsson and Noren 1965; Knobeloch et al. 

1994; Spitalny et al. 1984; Walsh et al. 1977), no reliable information on copper concentration or dose 

was reported. In one report where school-age children ingested a beverage stored in an old urn, the 

concentration of copper in the beverage was estimated to be 300 mg/L (Gill and Bhagat 1999). Another 

study reported vomiting in infants ingesting a single dose of 7.5 mg/L copper sulfate (Karlsson and Noren 

1965). Knobeloch et al. (1994) noted that children appear to be more sensitive to the gastrointestinal 

effects of copper than adults. This statement was based on two surveys of residents with elevated copper 

levels in the drinking water. In the first survey, it appears that children who were described as “unusually 

irritable” or had recurrent headaches were categorized as having gastrointestinal upset. In the second 

survey, mothers were asked to recall the frequency of gastrointestinal effects for all family members. A 

significantly higher percentage of children, as compared to adults, were reported to have gastrointestinal 
 

 

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effects. It is difficult to determine what role recall bias had in the results and how well the mothers knew 

of symptoms of gastrointestinal upset in the adult members of the household. The available data are 

inconclusive to assess accurately whether there is an age-related difference in the gastrointestinal toxicity 

of copper. 

The potential age-related differences in the toxicity of copper has been assessed in rats exposed to 120 mg 

Cu/kg/day as copper sulfate in the diet for 12 weeks (Fuentealba et al. 2000). The observed liver effects 

were more severe in young rats (exposed in utero, during lactation, and for 12 weeks post weaning) as 

compared to the effects observed in adult rats. The copper levels in the liver were also higher in the 

young rats (1,553–1,635 versus 472–534 μg/g). The doses used in this study are very high, 1,000 times 

higher than the rat dietary requirement of 0.15–0.30 mg/kg/day (AIN 1977). It is not known if increased 

liver sensitivity would also occur at lower copper doses. Although these data are suggestive that children 

may be more sensitive to the hepatotoxicity of high doses of copper, uncertainty in the use of rats as a 

model for human toxicity limits the extrapolation of these study results to humans. 

Several studies have investigated the potential developmental toxicity of dietary copper sulfate; the results 

suggest that in utero exposure to copper can result in delays in growth and development in the offspring 

of rats exposed to 130 mg Cu/kg/day (Haddad et al. 1991) and mice exposed to 208 mg Cu/kg/day (Lecyk 

1980). No developmental effects were observed in the offspring of mink exposed to 13 mg Cu/kg/day 

(Aulerich et al. 1982). 

There is concern that toxicokinetic differences between infants and adults may result in increased 

sensitivity in infants. During the second half of pregnancy, particularly in the third trimester, the fetus 

accumulates copper at a rate of 50 g/kg/day (Widdowson et al. 1974). Approximately half of the copper 

in the fetus is stored in the liver, mostly bound to metallothionen. Additionally, the rate of transfer of 

copper from the liver to the bile or blood is decreased due to the immaturity of the liver. The magnitude 

of the amount of copper in the fetal liver is similar to levels observed in Wilson’s disease; however, the 

fetal/neonatal liver tolerates these high concentrations (Olivares et al. 2000). After birth, the copper 

levels in the liver steadily decrease from about 51 μg/g at birth to 5.7 μg/g at 6–14 months of age (Klein 

et al. 1991; Olivares et al. 2000). 
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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). 

Due to a nascent understanding of the use and interpretation of biomarkers, implementation of biomarkers 

as tools of exposure in the general population is very limited. 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 or 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 found in body tissues and fluids (e.g., essential mineral nutrients such as 

copper, zinc, and selenium). Biomarkers of exposure to copper 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 copper 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 may result in an increase in absorbed dose, a decrease in 

the dose-level required for biological effectiveness, or a target tissue response. Biomarkers of 

susceptibility are discussed in Section 3.10 “Populations that are Unusually Susceptible.” 
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3.8.1 Biomarkers Used to Identify or Quantify Exposure to Copper 

Copper levels can readily be measured in tissues, body fluids, and excreta. Depending on the dose and 

exposure duration, inhalation and/or oral exposure to copper can result in increased levels of copper in 

serum, urine, hair, and liver. Increased whole blood and serum copper levels have been reported in 

humans following intentional ingestion of a single dose of 1–30 g of copper as copper sulfate (Chuttani et 

al. 1965). The serum and whole blood levels of copper ranged from 239 to 346 and from 383 to 

684 μg/100 mL, respectively; the serum and whole blood levels in non-exposed individuals were 

151.6 and 217 μg/100 mL, respectively. Following chronic inhalation exposure to 111–464 mg Cu/m3 

copper dust, plasma serum levels of >200 μg/100 mL were observed in 16% of factory workers exposed 

to copper dust (Suciu et al. 1981). However, increased serum copper levels may only be reflective of 

recent exposure. Chuttani et al. (1965) observed that serum ionic copper rapidly diminished to normal 

levels following an acute bolus dose. 

A relationship between blood copper levels and the severity of symptoms has not been established. 

Among individuals intentionally ingesting a single dose of copper sulfate (1–30 g), Chuttani et al. (1965) 

noted that there did not appear to be any difference between serum copper levels in individuals only 

exhibiting gastrointestinal effects and those with more severe symptoms (jaundice, renal manifestations, 

or shock). In contrast, whole blood copper levels were much higher in the individuals with severe 

symptoms (798 μg/100 mL) compared to those with mild symptoms (287 μg/100 mL). 

Copper levels in hair and nails can also be used to assess copper exposure. In a study of preschool 

children, the levels of copper in hair and toenail samples were log-normally distributed (Wilhelm et al. 

1991). The geometric mean concentrations of copper in hair and toenails were 10.6 μg/g (range of 5.4– 

20.7 μg/g) and 7.5 μg/g (range of 3.0–18.6 μg/g), respectively. Based on a hair growth rate of 10 mm per 

month, the copper levels in the first 2 cm proximal to the scalp would represent copper intake over 

2 months (Hopps 1977). In contrast, toenail samples would represent copper intake over 12–18 months, 

based on a toenail growth rate of 1 mm/month (Fleckman 1985). Increased hair copper levels have been 

reported in workers exposed to 0.64–1.05 mg/m3

 of an unspecified copper compound; the concentration 

of copper in the hair was 705.7 μg/g, as compared to a 8.9 μg/g concentration in non-exposed workers 

(Finelli et al. 1981), and increased hair and fingernail copper levels were observed in children with Indian 

childhood cirrhosis (Sharda and Bhandari 1984). 
 

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3.8.2 Biomarkers Used to Characterize Effects Caused by Copper 

The harmful health effects of copper occur over a wide range of copper intakes from too little copper in 

the diet to excessive copper exposure. 

Low Intakes of Copper. The nutritional requirements of copper and the health effects associated with 

copper deficiency have been reviewed by numerous authors (Gallagher 1979; Mason 1979; O'Dell 1984). 

Copper deficiency is rarely observed in humans; the existence of covert copper deficiency among 

segments of the population is unknown. The limited data available on human health effects of inadequate 

copper intakes are derived mostly from case reports of severely malnourished children, patients 

maintained by total parenteral nutrition without copper, and children with Menkes' disease (a genetic 

disorder resulting in impaired copper absorption). Copper deficiency is characterized by hypochromic 

anemia, abnormalities of connective tissues, and central nervous system disorders. Sudden death 

associated with spontaneous rupture of a major blood vessel or the heart itself has been observed in some 

animal species. 

The manifestations of copper deficiency are related to a decrease in several of the copper-containing 

metalloenzymes. The most severe biochemical alteration is decreased cytochrome oxidase activity; this is 

manifested as poor growth, anemia, and central nervous system effects. The decreased oxidative 

metabolism associated with decreased cytochrome oxidase results in poor growth in infants, weight loss, 

and emaciation. The hypochromatic anemia observed during copper deficiency is not distinguishable 

from iron deficiency anemia; however, it is not responsive to iron administration. A decrease in 

protoheme synthesis, a result of decreased cytochrome oxidase, has also been observed. As with anemia, 

the central nervous system effects, primarily the result of hypomyelination, are associated with low 

activity levels of cytochrome oxidase; the decreased synthesis of phospholipids observed in copper 

deficiency may also contribute to the development of central nervous system effects. In addition to the 

decrease in cytochrome oxidase, a decrease in lysyl oxidase is also observed. Lysyl oxidase is involved 

in the formation of cross-links in collagen and elastin. Depending on the species, this impairment results 

in bone disorders, a defective cardiovascular system, or abnormal lung structure. 

Exposure to Excess Levels of Copper. No copper-specific biomarkers of effects have yet been identified. 

The most notable sign of toxicity in humans ingesting a beverage or water containing copper is 

gastrointestinal distress. Symptoms (typically nausea, vomiting, and abdominal pain) usually occur 

shortly after ingesting the contaminated beverage. The liver is another sensitive target of copper toxicity. 

Alterations in a number of serum enzymes have been observed in humans and animals with copper-
 

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induced liver damage (Chuttani et al. 1965; Epstein et al. 1982; Haywood 1980; Haywood and Comerford 

1980; Müller et al. 1998; NTP 1993; Sugawara et al. 1995). The affected serum enzymes include serum 

aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase. Increases in serum 

bilirubin levels have also been observed in humans. Animal studies demonstrate that the rise in serum 

enzyme activities are the first evidence of liver damage. However, alterations in serum enzyme levels are 

not unique to copper-induced liver damage. 

3.9 INTERACTIONS WITH OTHER CHEMICALS 

Numerous studies have demonstrated the interaction between copper and several other metals. Dietary 

zinc strongly affects copper absorption. A diet high in zinc can result in copper deficiency. Reductions in 

erythrocyte superoxide dismutase, indicative of marginal copper deficiency, have been found in studies of 

women ingesting zinc supplements (50 mg zinc/day) for 10 weeks (Yadrick et al. 1989) and men 

ingesting 50 mg zinc/day for 6 weeks (Fisher et al. 1984). The exact mechanism of the zinc-copper 

interaction is not known. However, increased dietary zinc results in induction of metallothionein 

synthesis in the intestine and metallothionein has a greater binding capacity for copper than for zinc. 

Thus, the dietary copper is sequestered in the intestinal mucosal cell and eventually is excreted in the 

feces when the mucosal cell is sloughed off (Hall et al. 1979; Whanger and Weswig 1971). Because 

exposure to excess dietary zinc results in decreased copper absorption, it is often used as a treatment for 

Wilson’s disease (Brewer et al. 1993). An oral/intraperitoneal study in mice provides some evidence that 

zinc and copper may interact at sites other than the intestine. In this study on the influence of zinc on 

mitigating the immunotoxicity of copper, mice were exposed to copper sulfate in the drinking water for 

8 weeks and received an intraperitoneal injection of zinc sulfate once a week (Pocino et al. 1990). 

Decreases in the magnitude of the proliferative response to con A or LPS and the antibody response to 

sheep red blood cells were observed in the copper-exposed mice, but not the mice receiving copper and 

zinc. However, zinc did not modify the increased production of auto-antibodies reactive with bromelaintreated mouse red blood cells. 

Several other divalent cations compete with copper for intestinal absorption. Exposure to dietary 

cadmium (Evans et al. 1970a), ferrous iron (Wapnir et al. 1993; Yu et al. 1994), and stannous tin 

(Pekelharing et al. 1994; Wapnir et al. 1993) can result in decreased copper absorption. In the case of 

cadmium, the decrease is related cadmium induction of metallothionein and the binding of copper to it. 

Tetrathiomolybdate is used for the treatment of Wilson’s disease (Brewer 1995) and excessive dietary 

molybdenum can also result in decreased uptakes and, therefore, copper utilization and toxicity. Two 
 

 

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3. HEALTH EFFECTS 

mechanisms of action of tetrathiomolybdate have been proposed: it reacts with copper-metallothionein to 

form a soluble complex which is excreted (Ogra et al. 1996) and it can complex with nonceruloplasmin 

plasma copper, preventing its cellular absorption (Brewer 1995). 

Because selenide is a strong reducing agent (Frost 1972), it has been postulated that selenium may play a 

role in detoxifying copper. Aburto et al. (2001a, 2001b) examined the possible interaction between 

copper and selenium. Selenium did not influence the hepatotoxicity of copper in rats fed diets with 

excess levels of copper and inadequate, adequate, or excess levels of dietary selenium. Hepatic copper 

levels and histological alterations were not significantly different in rats receiving a high copper/high 

selenium diet as compared to rats receiving a high copper/adequate selenium diet. 

3.10 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE 

A susceptible population will exhibit a different or enhanced response to copper than will most persons 

exposed to the same level of copper in the environment. Reasons may include genetic makeup, age, 

health and nutritional status, and exposure to other toxic substances (e.g., cigarette smoke). Whatever the 

basis of the increased susceptibility may be, the result is reduced detoxification or excretion of copper or 

compromised functioning of organs affected by copper. Populations at greater risk due to unusually high 

exposure to copper are discussed in Section 6.7, Populations with Potentially High Exposures. 

A number of populations of individuals unusually susceptible to copper toxicity have been identified. 

The increased susceptibility to copper toxicity is associated with genetic defects that impair copper 

homeostatic mechanisms. Wilson’s disease, also referred to as hepatolenticular degeneration, is an 

autosomal recessive disorder with a worldwide incidence of 1 in 30,000 (Scheinberg and Sternlieb 1996). 

The primary genetic defect in Wilson’s disease is in ATP7B, which encodes a P-type ATPase (Wilson 

protein), which delivers copper to ceruloplasmin. The genetic defect results in impaired biliary excretion 

of copper and an accumulation of copper in the liver. As described by Brewer and Yuzbasiyan-Gurkan 

(1992), the progression of the disease begins with an accumulation of copper in the liver, damage to the 

liver, and subclinical liver cirrhosis. Over time, the individual will develop hepatic, neurological, and 

psychiatric symptoms. The hepatic effects are characterized by jaundice, hypoalbuminemia, ascites, 

coagulation defects, hyperammonemia, hepatic encephalopathy, and/or liver failure; in the cases of 

massive liver failure, large amounts of copper are released from the liver resulting in hemolytic anemia. 

Neurological symptoms include tremors and other movement disorders and speech abnormalities. 

Psychiatric and behavioral symptoms are often found in individuals also manifesting neurological other 
COPPER 90 

3. HEALTH EFFECTS 

symptoms. The psychiatric symptoms include reduced performance in school or work, inability to cope, 

depression, very labile moods ranging from mania to depression, sexual exhibitionism, and frank 

psychosis. Individuals with Wilson’s disease have low serum ceruloplasmin levels, elevated urinary 

copper levels, and elevated liver copper levels; Kayser-Fleischer rings, which result from corneal copper 

deposits, are also detected in individuals with Wilson’s disease. Individuals who are heterozygotes for 

Wilson’s disease may also be unusually susceptible to the toxicity of copper. Increases in urinary copper 

and hepatic concentrations and decreased copper incorporation into ceruloplasmin have been observed in 

heterozygotes. These findings may suggest that long-term exposure to elevated levels of copper may 

result in copper overload. Although the incidence of heterozygotes is not known, NAS (2000) estimates 

that 1 in 40,000 individuals (approximately 1% of the U.S. population) may be heterozygotes for 

Wilson’s disease. 

Indian childhood cirrhosis (ICC) and idiopathic copper toxicosis (ICT) are two syndromes that result in 

severe, often fatal, liver cirrhosis in infants and young children. Although the basis of the defect has not 

been firmly established, it is believed to be due to an inherited autosomal recessive defect in copper 

metabolism aggravated by high copper intake (Bhave et al. 1982, 1987; Müller et al. 1996, 1998). ICC 

occurs in infants and children living in rural areas of the Indian subcontinent who are introduced early to 

cow or buffalo milk that is stored or heated in brass or copper vessels. Copper is believed to be the 

causative agent because the milk has very high copper levels, very high copper levels are found in the 

liver, and replacing the brass or copper vessels with aluminum or stainless steel vessels eliminates the 

occurrence of ICC in siblings of ICC affected children (Bhave et al. 1982; Tanner 1998). A high degree 

of parental consanguinity, the occurrence of ICC in children, but not the parents, and the fact that 22% of 

siblings affected suggest an autosomal recessive component to the disease (Pandit and Bhave 1996; 

Tanner 1998). For ICT, which includes Tyrolean infantile cirrhosis, sources of high copper exposure 

have been identified. For the 138 cases of ICT in children living in the Tyrolean region of Austria, the 

source of the copper was the use of a water/unpasteurized cow’s milk mixture that was heated in a copper 

pot (Müller et al. 1996). For the other cases of ICT that have been identified in a number of countries, the 

source of the excess copper intake was drinking water (Müller et al. 1998). The similarity of ICT to ICC 

has prompted investigators to suggest that ICT may also be due to an autosomal recessive genetic defect 

in copper metabolism and excessive copper intake at a very young age. A genealogical investigation by 

Müller et al. (1996) provides supportive evidence for a genetic basis of the disease. 

It has been postulated that individuals with a deficiency of the enzyme glucose-6-phosphate 

dehydrogenase would be susceptible to the toxic effects of oxidative stressors such as copper (Calabrese 
 

COPPER 91 

3. HEALTH EFFECTS 

and Moore 1979; Chugh and Sakhuja 1979). This has not been supported by epidemiological or 

experimental data. In the blood, most of the copper is bound to ceruloplasmin. With the exception of 

ingestion of a very large dose of copper salts, the levels of nonceruloplasmin bound copper remain low 

following copper exposure. Thus, it is unlikely that this relatively small change in free copper would alter 

the survival of glucose-6-phosphate dehydrogenase deficient red cells. 

3.11 METHODS FOR REDUCING TOXIC EFFECTS 

This section will describe clinical practice and research concerning methods for reducing toxic effects of 

exposure to copper. 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 copper. When 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 

copper: 

Ellenhorn MJ, Schonwald S, Ordog G, et al., eds. 1997. Medical toxicology: Diagnosis and treatment of 

human poisoning. Second edition. Baltimore, MD: Williams & Wilkins, 1554-1556. 

Goldfrank LR, Flomenbaum FE, Lewin NA, et al., eds. 1998. Goldfrank’s toxicologic emergencies. 

Sixth edition. Stamford, CT: Appleton & Lange, 1339-1340. 

Haddad LM, Shannon MW, Winchester JF, eds. 1998. Clinical management of poisoning and drug 

overdose. Third edition. Philadelphia, PA: WB Saunders, 165. 

3.11.1 Reducing Peak Absorption Following Exposure 

Following ingestion of copper or copper compounds, milk or water should be given immediately after 

ingestion and/or prior to vomiting. Because of the strong emetic properties of copper and copper 

compounds, vomiting usually occurs shortly after ingestion. Induction of vomiting and gastric lavage are 

contraindicated following ingestion of caustic copper salts, such as copper sulfate. Gastric lavage may be 

indicated after ingestion of noncorrosive copper compounds (HSDB 2002). 

For individuals with Wilson’s disease, the administration of a diet high in zinc is used as a maintenance 

treatment (Brewer et al. 1989). The zinc interferes with copper absorption by inducing intestinal 

metallothionein resulting in increased copper sequestration (Brewer et al. 1992). 
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3.11.2 Reducing Body Burden 

A number of methods have been employed to reduce copper body burden. These methods range from the 

use of chelating agents to increases in dietary levels of zinc and molybdenum. Gao et al. (1989) tested the 

in vitro effectiveness of five chelating agents using human serum albumin. The agents (in order of 

decreasing effectiveness) were ethylenediaminotetraacetate (EDTA), diethylene triaminopentaacetate, 

ethylene glycol-bis-(aminoethylether)-tetraacetate, nitrilotriacetate, and iminodiacetate. The in vivo 

effectiveness of these agents has not been established. D-penicillamine is often used to decrease the 

elevated levels of hepatic copper in individuals with Wilson’s disease (Walshe 1996; Walshe and 

Yealland 1993) and idiopathic childhood cirrhosis (Rodeck et al. 1999). However, a number of potential 

side effects have been associated with penicillamine treatment (Brewer and Yuzbasiyan-Gurkan 1992). A 

variety of other chelating agents have been tested in copper loaded rats. Tetraethylenepentamine 

pentahydrochloride (TETREN) was more effective in increasing urinary excretion of copper than 

1,4,7,11-tetraazaundecane tetrahydrochloride (TAUD) or penicillamine, which were equally effective 

(Domingo et al. 2000). TETREN did not result in a decrease in copper levels in the liver, although a 

significant decrease in kidney copper levels was observed. In contrast, TAUD and penicillamine reduced 

the levels of copper in the liver. None of the three chelating agents affected the amount of copper 

excreted into the feces. 

The known interaction between copper and molybdenum have been used to treat individuals with 

Wilson’s disease. The administration of tetrathiomolybdate to individuals with neurological or 

psychiatric symptoms associated with Wilson’s disease has resulted in an improvement or reversal of 

symptoms (Brewer 1995). In blood plasma, tetrathiomolybdate complexes with nonceruloplasmin plasma 

copper, preventing its cellular absorption. Studies in Long-Evans Cinnamon rats, a model for Wilson’s 

disease, and sheep have found that administration of tetrathiomolybdate results in a dramatic decrease in 

the levels of copper in the liver (Humphries et al. 1988; Kumaratilake and Howell 1989; Ogra et al. 1996) 

and decreased liver damage (Humphries et al. 1988). Tetrathiomolybdate also reacts with copper bound 

to metallothionein resulting in a soluble copper-tetrathiomolybdate complex (Ogra et al. 1996). The 

addition of molybdenum to a high sulfur, low copper diet can result in a decrease in liver and plasma 

copper levels in copper loaded sheep (van Ryssen 1994). 

Although zinc is used in the treatment of Wilson’s disease to decrease the absorption of copper, zinc does 

not appear to be effective in reducing the copper body burden. No alterations in hepatic copper levels 

were observed in sheep administered a low copper, high zinc diet (van Ryssen 1994). A reduction in 

hepatic copper levels has been observed in dogs administered a high zinc diet (Brewer et al. 1992); 
 

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however, it is believed that the reduction was secondary to the induction of copper deficiency and the 

mobilization of copper from the liver (van Ryssen 1994). 

3.11.3 Interfering with the Mechanism of Action for Toxic Effects 

There are limited data on methods for interfering with the mechanisms of action of copper. An in vitro 

study suggested that lazaroids (21-aminosteroids) may have a protective effect against copper-induced 

erythrocyte lipid peroxidation (Fernandes et al. 1992). Oxidative damage to the erythrocyte membrane 

may be the cause of the hemolysis observed following exposure to very high doses of copper. 

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 copper 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 copper. 

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. 

3.12.1 Existing Information on Health Effects of Copper 

The existing data on health effects of inhalation, oral, and dermal exposure of humans and animals to 

copper are summarized in Figure 3-4. The purpose of this figure is to illustrate the existing information 

concerning the health effects of copper. 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 
Death

Acute 

Intermediate 

Chronic 

Immunologic/Lymphoretic 

Neurologic 

Reproductive 

Developmental 

Genotoxic 

Cancer 

Systemic 

Human 

Inhalation 

Oral 

Dermal 

Death

Acute 

Intermediate 

Chronic 

Immunologic/Lymphoretic 

Neurologic 

Reproductive 

Developmental 

Genotoxic 

Cancer 

Systemic 

Animal 

Inhalation 

Oral 

Dermal 

Existing Studies 

COPPER 94 

3. HEALTH EFFECTS 

Figure 3-4. Existing Information on Health Effects of Copper 
COPPER 95 

3. HEALTH EFFECTS 

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. 

The toxicity of inhaled copper has been investigated in a couple of occupational exposure studies. These 

studies examined a limited number of systemic end points, and exposure is poorly characterized. There 

are numerous reports and studies on the toxicity of ingested copper in humans. Most of the reports and 

studies focused on the gastrointestinal effects following acute exposure to copper in drinking water or 

other beverages. Data on other health effects in humans comes from individuals with Wilson’s disease, 

Indian childhood cirrhosis, and idiopathic copper toxicosis. These diseases/syndromes are the result of 

genetic defect(s) resulting in impaired copper kinetics; the latter two syndromes are also associated with 

exposure to high levels of copper in drinking water or milk (due to storage of milk in brass vessels). 

These studies provide information on potential targets of toxicity, primarily the liver. 

Information on the dermal toxicity of copper is limited to reports of contact dermatitis in individuals and 

eye irritation in workers exposed to copper dust. 

As with the human database, there are limited data on the toxicity of inhaled copper in animals. The 

available studies have primarily focused on potential respiratory effects. There is a more extensive 

database on the toxicity of ingested copper in animals. These studies have found a number of systemic 

effects, including gastrointestinal, hepatic, and renal effects following acute, intermediate, and chronic 

exposure. Immunological and developmental effects have also been reported in animal studies. Several 

studies have also examined potential neurological and reproductive targets, but have not found effects. 

Carcinogenic effects were not found in several animal studies; however, the studies are limited in scope 

and tested low doses. No animal studies examining the dermal toxicity of copper were identified. 

3.12.2 Identification of Data Needs 

Acute-Duration Exposure. No data were located regarding health effects after acute inhalation 

exposure to copper in humans. Animal data are limited to information from studies in mice and hamsters 

conducted by Drummond et al. (1986). Respiratory tract irritation and impaired immune function were 
COPPER 96 

3. HEALTH EFFECTS 

observed. This study was not selected as the basis for an acute-duration inhalation MRL because it only 

examined a limited number of end points, and the liver and kidney, which are targets following oral 

exposure, were not examined; in addition, the animals were only exposed for 3 hours/day. Additional 

inhalation studies are needed to identify the critical targets of toxicity and to establish concentrationresponse relationships for copper. The most commonly reported effect in humans acutely exposed to 

copper is gastrointestinal upset. The reported symptoms include nausea, vomiting, abdominal pain, and 

diarrhea (Chutanni et al. 1965; Gill and Bhagat 1999; Gotteland et al. 2001; Nicholas and Brist 1968; 

Olivares et al. 2001; Pizarro et al. 1999, 2001; Semple et al. 1960; Walsh et al. 1977). Hepatic and renal 

effects have also been seen in individuals ingesting lethal doses of copper sulfate (Chuttani et al. 1965). 

Animal studies support the identification of the gastrointestinal tract, liver, and kidneys as sensitive 

targets of copper toxicity. Hyperplasia of the forestomach has been observed in rats and mice exposed to 

copper sulfate in the diet for 14 days (NTP 1993). Hepatic effects ranging from increases in alanine 

aminotransferase activity to hepatocellular necrosis and renal effects (protein droplets in proximal 

tubules) have been observed in rats exposed to fairly high doses of copper sulfate in the diet (Haywood 

1980; Haywood and Comerford 1980; Haywood et al. 1985b; NTP 1993). Decreases in body weight gain 

have also been observed in rats (NTP 1993). The acute-duration oral database was considered adequate 

for derivation of an MRL. The MRL was based on gastrointestinal upset in women ingesting drinking 

water containing copper sulfate for 2 weeks (Pizarro et al. 1999). There are limited data on the dermal 

toxicity of copper. Pruritic dermatitis and allergic contact dermatitis have been reported in humans 

exposed to copper. No animal studies were identified. These data provide suggestive evidence that 

copper may be irritative to the skin; additional dermal studies are needed to determine whether copper 

exposure will also result in systemic effects. 

Intermediate-Duration Exposure. No studies were located regarding health effects in humans after 

intermediate-duration inhalation. Only one animal inhalation exposure study was located. This study did 

not find any adverse histological alterations in the lungs or functional alterations in alveolar macrophages 

of rabbits exposed to copper chloride (Johansson et al. 1983, 1984). Because the lungs were the only 

tissues examined, these studies were not considered suitable for derivation of an intermediate-duration 

inhalation MRL for copper. Additional studies are needed to identify the critical targets of toxicity and 

establish concentration-response relationships for inhaled copper. Three experimental human studies and 

two community-based studies have examined the oral toxicity of copper in healthy humans. The primary 

focus of these studies was examination of the potential of low doses of copper to induce hepatic effects in 

adults (Araya et al. 2003b; Pratt et al. 1985) or infants (Olivares et al. 1998; Zietz et al. 2003a, 2003b); no 

adverse effects were found. The Araya et al. (2003b) study also assessed the potential for gastrointestinal 
COPPER 97 

3. HEALTH EFFECTS 

effects in adults and found significant increases in the incidence of effects as a function of dose/duration. 

A number of animal studies have reported adverse liver and kidney effects following intermediateduration oral exposure to copper compounds (Epstein et al. 1982; Fuentealba et al. 2000; Haywood 1980, 

1985; Haywood and Comerford 1980; Haywood and Loughran 1985; Haywood et al. 1985a, 1985b; 

Kumar and Sharma 1987; NTP 1993). The observed liver and kidney effects demonstrated dose- and 

duration-response relationships. The studies by Haywood and associates demonstrate that rats can 

develop a tolerance to copper following repeated oral exposure. Studies in other animal species are 

needed to determine if this phenomenon is unique to rats or is observed in other species as well. Other 

systemic effects that have been reported in animals include hyperplasia of the forestomach mucosa (NTP 

1993), decreased erythrocyte and hemoglobin levels (Kumar and Sharma 1987; Rana and Kumar 1980; 

Suttle and Mills 1966a), and decreased body weight gain or weight loss (Haywood 1985; Haywood and 

Loughran 1985; Kline et al. 1971; Llewellyn 1985; NTP 1993). For the most part, these studies involved 

dietary exposure of rats to copper sulfate; additional studies in other species would be useful for 

identifying a model for human toxicity. The Araya et al. (2003b) human study was used as the basis of an 

intermediate-duration oral MRL for copper. No data on the dermal toxicity of copper following 

intermediate-duration exposure were identified. Studies are needed to identify the critical targets of 

copper toxicity following dermal exposure. 

Chronic-Duration Exposure and Cancer. Systemic effects such as nausea (Suciu et al. 1981), 

hepatomegaly (Suciu et al. 1981), decreased hemoglobin and erythrocyte levels (Finelli et al. 1981), and 

respiratory irritation (Askergren and Mellgren 1975; Suciu et al. 1981) have been observed in workers 

exposed to copper dust. The mild gastrointestinal effects observed in some workers were attributed to 

swallowing airborne copper dust (Suciu et al. 1981). The poor characterization and/or the lack of controls 

preclude deriving a chronic-duration inhalation MRL based on the occupational exposure studies. 

Additional studies are needed to identify the critical targets of toxicity of inhaled copper. There are 

numerous reports of severe health effects in infants and children ingesting copper-contaminated milk or 

water containing high levels of copper (Müller et al. 1996, 1998; Pandit and Bhave 1996; Tanner 1998). 

Indian childhood cirrhosis and idiopathic copper toxicosis are characterized by severe liver cirrhosis 

occurring before the age of 5 years. There is suggestive evidence that both of these syndromes are related 

to increased dietary intake of copper in conjunction with increased genetic susceptibility. Nausea, 

vomiting, and abdominal pain were reported by members of a family with very high levels of copper in 

the drinking water (Spitalny et al. 1984). The animal database on the oral toxicity of copper following 

chronic-duration exposure is limited to one study (Massie and Aiello 1984) that found a decrease in 

lifespan and no effect on body weight gain in mice exposed to copper gluconate for 850 days. No other 
COPPER 98 

3. HEALTH EFFECTS 

end points of toxicity were examined in this study. The database was considered inadequate for 

derivation of a chronic-duration oral MRL. Additionally, studies that examine a variety of end points are 

needed to identify the critical targets of toxicity and establish dose-response relationships. Information on 

the dermal toxicity of copper is limited to a report of ocular irritation in workers exposed to copper dust 

(Askergren and Mellgren 1975). Additional dermal toxicity studies are needed to identify the critical 

targets of toxicity following dermal exposure. 

Data on the carcinogenicity of copper in humans are limited to a study of copper miners (Chen et al. 

1993) and a follow-up to this study (Chen et al. 1995). Increased risk of cancer, stomach cancer, and lung 

cancer were observed. Because the workers were also exposed to radon and radon daughters, silica, iron, 

titanium, sulfur, and arsenic, a causal relationship between copper and increased cancer risk can not be 

established. No studies examining the association between copper ingestion and cancer risk in humans 

were identified. Several animal studies have examined the carcinogenic potential of ingested copper 

(BRL 1968; Greene et al. 1987; Kamamoto et al. 1973). These studies are limited in scope, the studies by 

Green et al. (1987) and Kamamoto et al. (1973) only examined one potential target, and tested fairly low 

doses of copper. No dermal carcinogenicity studies in humans or animals were identified. Additional 

studies by the inhalation, oral, and dermal routes are needed to assess the carcinogenic potential of copper 

in humans. 

Genotoxicity. No data on the genotoxicity of copper in humans were located; studies of workers or 

individuals accidentally exposed to high levels of copper would provide value information on its 

genotoxic potential in humans. The available genotoxicity data suggest that copper is a clastogenic agent 

(Agarwal et al. 1990; Bhunya and Jena 1996; Bhunya and Pati 1987; Sideris et al. 1988). However, 

mixed results have been found in point mutation assays (Demerec et al. 1951; Marzin and Phi 1985; 

Singh 1983; Tso and Fung 1981; Wong 1988). Additional studies are needed to assess copper’s potential 

to induce point mutations. Several studies have also shown that exposure to copper can result in DNA 

damage (Garrett and Lewtas 1983; Sideris et al. 1988; Sina et al. 1983). 

Reproductive Toxicity. There are no human studies and two animal studies that examined the 

potential of copper to induce reproductive effects. These studies did not find any adverse alterations in 

reproductive performance in mink (Aulerich et al. 1982), sperm morphology in rats and mice (NTP 1993), 

or vaginal cytology in rats or mice (NTP 1993). The NTP (1993) study also did not find histological 

alterations in reproductive tissues. Multigeneration or continuous breeding studies would provide 

information on the reproductive effects of copper in animals, which may be used to assess possible 

reproductive effects in humans exposed to high levels of copper. 
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Developmental Toxicity. Developmental studies by the oral route in rats (Haddad et al. 1991) and 

mice (Lecyk 1980) have shown that high copper intakes can result in impaired growth. The 

developmental toxicity of copper in humans has not been adequately investigated. No data were located 

regarding developmental effects of copper after inhalation or dermal exposures in humans or animals. 

Further studies in other animal species would provide valuable information on the potential of copper to 

adversely affect development. Such information might be relevant to humans. 

Immunotoxicity. There are limited data on the immunotoxic potential of copper and its compounds. 

Reports on humans developing dermatitis after dermal exposure to copper (Barranco 1972; Saltzer and 

Wilson 1968) suggest that copper is an allergen. This is supported by a report of a woman developing 

dermatitis after insertion of a copper IUD (Barranco 1972). Immunological effects also have been 

observed in mice (Drummond et al. 1986) following acute inhalation exposure to copper sulfate. In 

addition, impaired immune function has been observed in mice exposed to copper chloride (Pocino et al. 

1991) or copper sulfate (Pocino et al. 1990) in drinking water. Intermediate-duration studies 

concentrating on immunologic effects in different species would be useful for establishing dose-response 

relationships and assessing whether there are species differences. More studies in humans and animals 

that examine the immune response to copper exposure and the mechanisms involved therein would be 

useful. 

Neurotoxicity. Neurological impairment has been observed in factory workers exposed to copper 

dust. No effects on neurobehavioral performance were observed in rats exposed to copper in the diet 

(Murthy et al. 1981). However, this study did find alterations in the levels of a dopamine metabolite, 

suggesting that copper may adversely affect the nervous system. Additional studies are needed to further 

investigate the neurotoxic potential of copper; these studies should assess the potential of copper to 

perturb dopaminergic pathways and related functions. 

Epidemiological and Human Dosimetry Studies. Several studies have examined the toxicity of 

inhaled copper in workers (Askergren and Mellgren 1975; Finelli et al. 1981; Suciu et al. 1981). These 

studies have primarily focused on the respiratory tract, although health examinations revealed other 

adverse effects (e.g., hepatomegaly). Chen et al. (1993, 1995) examined the carcinogenic potential of 

inhaled copper. In general, these studies are limited by poor exposure characterization, co-exposure to 

several toxic and/or carcinogenic compounds (e.g., arsenic, cadmium, radon, lead), and limited number of 

end points examined. Occupational exposure studies examining populations of workers exposed to 
COPPER 100 

3. HEALTH EFFECTS 

copper and with minimal exposure to other metals would be useful in assessing the toxicity of inhaled 

copper. These studies should examine a wide variety of end points, particularly the gastrointestinal tract, 

liver, and kidneys, which are targets of toxicity following oral exposure. 

There are numerous reports of accidental or intentional ingestion of copper. The most commonly 

reported effect in these studies is gastrointestinal upset. There have also been several experimental 

studies designed to identify a no effect level for gastrointestinal upset following short-term (2 weeks or 

less) exposure to copper in drinking water (Olivares et al. 2001; Pizarro et al. 1999, 2001). There are 

several subpopulations of individuals exposed to higher than normal levels of copper; these groups 

include communities with higher than normal levels of copper in drinking water and individuals ingesting 

higher than normal levels of copper in the form of supplements. Studies of these groups that involved 

examination for a variety of potential effects (including gastrointestinal, hepatic, and renal effects, which 

have been shown to be sensitive end points in animal studies) could provide useful information on the 

toxicity of copper in otherwise healthy humans. In addition, if the study group included both children and 

adults, these data could address the issue of age-related differences in toxicity. 

Biomarkers of Exposure and Effect. 

Exposure. Copper levels can be measured in tissues, body fluids, and excreta. Whole blood, serum, and 

urine copper levels have been established in healthy individuals. It has been demonstrated that copper 

levels in the body increase with increased exposure after acute poisoning. Similarly, increased copper 

levels were observed in workers after occupational exposure. Serum and urine copper levels, plasma 

ceruloplasmin levels, and clinical manifestations are specific indicators of copper status. It is doubtful 

that a single “specific” biomarker of intoxication resulting from exposure to a specific metal will be 

found. In any case, elevated tissue copper levels should be a sufficient indicator of exposure and the 

possibility of intoxication. 

Effect. There are no specific biomarkers for copper toxicity. Individuals with Wilson's disease are 

usually diagnosed by examining serum and urine copper levels, plasma ceruloplasmin levels, and clinical 

manifestations. However, the relationship between serum and urine levels of copper and health effects 

are not known. Studies examining the possible correlation between blood levels or excreta levels of 

copper with effects would facilitate medical surveillance leading to early detection and possible treatment. 

Absorption, Distribution, Metabolism, and Excretion. The absorption, distribution, 

metabolism, and excretion of copper administered orally have been studied in animals and, to some 
 

 

COPPER 101 

3. HEALTH EFFECTS 

extent, in humans. Furthermore, alterations in copper absorption, distribution, and excretion have been 

studied in deficiency and toxicity states. Despite the information on copper absorption, there is very little 

information on differences between absorption rates of the various Cu(II) compounds and differences 

between the bioavailability of copper from food and water. 

Several studies have shown that ingested or implanted metallic copper results in increased serum copper 

levels and liver toxicity (Keller and Kaminski 1984; Yelin et al. 1987). Studies on the release of copper 

ions from both ingested and implanted metallic copper would be useful. 

There is very limited information on copper absorption following inhalation exposure, and data on the 

absorption of copper through the skin are limited. Further studies in animals on the rate and extent of 

copper absorption following exposure from both the inhalation route and the dermal route would more 

fully characterize copper toxicokinetics in animals and by extrapolation in humans. 

There is evidence that animals develop a tolerance to continued high doses of copper; more information 

on the mechanism(s) involved might be useful to establish if humans also could develop tolerance, as well 

as to provide insight for the development of more effective and efficient treatment of copper toxicity. 

Comparative Toxicokinetics. The metabolism of copper has been studied in rats, pigs, hamsters, 

and humans. However, there are no comparative studies on the effects of high copper intakes on the 

distribution of copper in the body or the development of tolerance to continued high intakes of copper. 

Furthermore, the animal species that might serve as the best model for extrapolating results to humans is 

not known. 

Methods for Reducing Toxic Effects. Methods for reducing the toxic effects of copper have 

primarily focused on reducing body burdens. Many of these methods have been designed for individuals 

with Wilson’s disease; however, it is likely that these would also be effective in other instances of copper 

intoxication. D-penicillamine (Rodeck et al. 1999; Walshe 1996; Walshe and Yealland 1993) is the most 

commonly used palliative agent for Wilson’s disease; however, it has a number of potentially deleterious 

side effects. Studies in animals suggest that TETREN and TAUD may also be effective chelating agents 

(Domingo et al. 2000). Other treatment methods include administration of tetrathiomolybdate 

(Humphries et al. 1988; Kumaratilake and Howell 1989; Ogra et al. 1996), diets high in molybdenum and 

sulfur (van Ryssen 1994), and diets high in zinc (Brewer et al. 1992; van Ryssen 1994). Further studies 
COPPER 102 

3. HEALTH EFFECTS 

are needed to identify treatments that would interfere with copper’s mechanism of toxicity and reduce 

body burden with minimal side effects. 

Children’s Susceptibility. There are some data on the toxicity of copper in infants and children. 

Severe liver damage has been reported in infants and children. These effects are typically clustered in 

geographically regions and have been grouped into two syndromes: Indian childhood cirrhosis and 

idiopathic copper toxicosis. Both of these syndromes are associated with elevated copper intakes and 

early dietary introduction of milk and/or formula, and are believed to have a genetic component. Very 

high levels of copper are found in the livers of affected children, suggesting that the mechanism of action 

is related to impaired copper efflux. Additional studies are needed to determine the mechanism of 

toxicity and to ascertain copper’s role in the observed effects. Information that would provide a better 

understanding of copper absorption and excretion in early infancy and homeostatic mechanisms in infants 

would also provide valuable documentation on these syndromes and their relationship to copper. 

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 

Ongoing studies pertaining to copper have been identified and are shown in Table 3-5 (FEDRIP 2003). 
COPPER 

3. HEALTH

Table 3-5. Ongoing

 EFFECTS 

Studies on Copper 

103 

Investigator Affiliation Research description Sponsor 

Turnland JR Agricultural Research 

Service, Davis, California 

Influence of high copper 

intake on copper 

homeostasis and mineral 

USDA 

metabolism 

Kelvay LM Agricultural Research 

Service, Grand Forks, 

North Dakota 

Determination of a no 

effect level for copper 

USDA 

Reeves PG Agricultural Research 

Service, Grand Forks, 

North Dakota 

Correlation between 

sperm motility and 

copper status in humans 

and animals 

USDA 

Harris ED Texas A & M University Copper metabolism and 

homeostasis in humans 

CSREES TEX 

and animals 

Thiele DJ University of Michigan at 

Ann Arbor 

Copper homeostasis NIGMS 

Culotta VC John Hopkins University Intracellular pathways of 

copper trafficking 

NIEHS 

Gitlin JD Washington University Copper chaperones NIDDKD 

CSREES TEX = Cooperative State Research Education and Extension Service, Texas; NIDDKD = National Institute 

of Diabetes and Digestive and Kidney Disease; NIEHS = National Institute of Environmental Health and Science; 

NIGMS = National Institute of General Medical Sciences; USDA = U.S. Department of Agriculture 

COPPER 105 

4. CHEMICAL AND PHYSICAL INFORMATION 

4.1 CHEMICAL IDENTITY 

Copper is the first element of Group IB of the periodic table and displays four oxidation states: Cu(O), 

Cu(I), Cu(II), and Cu(III). Along with silver and gold, it is classified as a noble metal and, like them, can 

be found in nature in the elemental form. Copper's unique chemical and physical properties have made it 

one of the most important metals. These properties include high thermal conductivity, high electrical 

conductivity, malleability, low corrosion, alloying ability, and pleasing appearance. Properties of metallic 

copper such as electrical conductivity and fabricability vary markedly with purity. Standard 

classifications have been defined according to processing method. For example, ASTM B5-74 is 

>99.90% pure and is the accepted basic standard for electrolyte copper wire bars, etc. (Tuddenham and 

Dougall 1978). Data on the chemical identity of copper are shown in Table 4-1. Data on the chemical 

identity of copper sulfate, the most important commercial compound of copper, are shown in Table 4-2. 

4.2 PHYSICAL AND CHEMICAL PROPERTIES 

Copper is positioned below hydrogen in the electromotive-force series, so it will not displace hydrogen 

ions from dilute acid. Accordingly, copper will not dissolve in acid unless an oxidizing agent is present. 

Therefore, while it readily dissolves in nitric and hot concentrated sulfuric acid, it only dissolves slowly in 

hydrochloric and dilute sulfuric acid, and then only when exposed to the atmosphere (Hawley 1981). It is 

also attacked by acetic acid and other organic acids. When exposed to moist air, a characteristic green 

layer of the basic copper carbonate slowly forms (Windholz 1983). This tightly adherent coating protects 

the underlying metal from further attack and is also prized for its appearance. Copper dissolves in 

ammonia in the presence of air, forming the cupric ammonium complex ion Cu(NH3)4

2+ (Cotton and 

Wilkinson 1980). 

Cu(I) or the cuprous ion disproportionates rapidly (<1 second) in aqueous solution to form Cu(II) and 

Cu(0) (Cotton and Wilkinson 1980). The only Cu(I) compounds that are stable in water are extremely 

insoluble ones such as CuCl. It has been shown that Cu(I) complexes may be formed in seawater by 

photochemical processes and may persist for several hours (Moffett and Zika 1987). Cuprous compounds 

are generally colorless. 
 

 

COPPER 106 

4. CHEMICAL AND PHYSICAL INFORMATION 

Table 4-1. Chemical Identity of Copper 

Characteristic Information Reference 

Chemical name Copper 

Synonym(s) Not reported 

Registered trade names(s) Not reported 

Chemical formula Cu HSDB 2004 

Chemical structure Face-centered cubic Budavari 2001 

Identification numbers: 

CAS registry 7440-50-8 HSDB 2004 

 NIOSH RTECS GL5324000 HSDB 2004 

EPA hazardous waste Not reported 

 OHM/TADS Not reported

 DOT/UN/NA/IMCO shipping Not reported

 HSDB 1622 HSDB 2004 

NCI Not reported 

CAS = Chemical Abstracts Services; DOT/UN/NA/IMCO = 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 
 

COPPER 107 

4. CHEMICAL AND PHYSICAL INFORMATION 

Table 4-2. Chemical Identity of Copper Sulfate 

Characteristic Information Reference 

Chemical name Copper sulfate 

Synonym(s) Cupric sulfate; blue stone; blue Budavari 2001; Hawley 1997; 

vitriol; cupric sulphate; Roman HSDB 2004 

vitriol; Salzburg vitriol; blue 

copperas; copper(II) sulfate 

Registered trade names(s) Not reported 

Chemical formula CuO4S Budavari 2001 

Chemical structure CuSO4 Budavari 2001 

Identification numbers: 

CAS registry 7758-98-7 HSDB 2004 

 NIOSH RTECS GL8800000 HSDB 2004 

EPA hazardous waste Not reported 

 OHM/TADS Not reported

 DOT/UN/NA/IMCO shipping Not reported

 HSDB 916 HSDB 2004 

NCI Not reported
 

CAS = Chemical Abstracts Services; DOT/UN/NA/IMCO = 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 
COPPER 108 

4. CHEMICAL AND PHYSICAL INFORMATION 

Cu(II) or the cupric ion is the most important oxidation state of copper. Cu(II) is the oxidation state of 

copper generally encountered in water (Cotton and Wilkinson 1980). Cupric ions are coordinated with 

six water molecules in solution; the arrangement of the water molecules is distorted in that there are four 

molecules bound closely to the copper in a planar array while the other two are more loosely bound in 

polar position (Cotton and Wilkinson 1980). Addition of ligands such as NH3 to the solution will 

successively displace only the four planar water molecules. Most cupric compounds and complexes are 

blue or green in color. They are frequently soluble in water. 

When Cu(II) is introduced into the environment, the cupric ion typically binds to inorganic and organic 

materials contained within water, soil, and sediments. In water, Cu(II) binds to dissolved organics (e.g., 

humic or fulvic acids). The Cu(II) ion forms stable complexes with -NH2, -SH and, to a lesser extent, 

-OH groups of these organic acids. Cu(II) will also bind to inorganic and organic components in 

sediments and soils with varying affinities. For example, Cu(II) binds strongly to hydrous manganese and 

iron oxides in clay and to humic acids in organic matter, but much less strongly to aluminosilicates in 

sand. As in water, the binding affinities of Cu(II) with inorganic and organic matter in sediments and 

soils is dependent on pH, the oxidation-reduction potential in the local environment, and the presence of 

competing metal ions and inorganic anions. 

Cu(III) is strongly oxidizing and only occurs in a few compounds (Kust 1978). At this time, none of 

these compounds are industrially important or environmentally significant. 

Data on the physical and chemical properties of copper and copper sulfate are shown in Table 4-3. 
 

COPPER 109 

4. CHEMICAL AND PHYSICAL INFORMATION 

Table 4-3. Physical and Chemical Properties of Copper and Copper Sulfate 

Property Copper Copper sulfate 

Molecular weight 63.546a 159.61a 

Color Reddishb Blue crystals, white dehydratedb 

Physical state Solidb

 Solidb 

Melting point 1,083c

 Decomposes at 560a 

Boiling point 2,595c

 No data 

Specific gravity (20/4 °C) 8.94c

 3.60a 

2.286 (pentahydrate)a 

Odor No data Noned 

Odor threshold 

Air No data No data 

Water No data No data 

Taste No data No data 

Taste threshold No data No data 

pKa 

Solubility: 

 Water Insolublee 32.0g/100g (20 °C)f 

Organic solvent(s) Soluble in methanol, slightly 

soluble in ethanolb 

Partition coefficients: 

 Log Kow No data No data 

 Log Koc No data No data 

Vapor pressure: 1 (1,628 °C)g

 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 at 25 °C ppm 

to mg/m3 

Since these substances exist in the atmosphere in the particulate state, the 

concentration is expressed as mg/m3 

. 

Explosive limits No data No data 

a

Lide 2000 

b

Lewis 1997 

c

Budavari et al. 2001 

d

Meister et al. 2001 

e

Stewart and Lassiter 2001 

f

Dean 1985 

g

Lewis 2000 

pKa = The dissociation constant of the conjugate acid 

 

 

COPPER 111 

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

5.1 PRODUCTION 

Copper occurs naturally in many minerals, such as cuprite (Cu2O), malachite (CuCO3·Cu(OH)2), azurite 

(2CuCO3·Cu(OH)2), chalcopyrite (CuFeS2), chalcocite (Cu2S), and bornite (Cu5FeS4). It also occurs 

uncombined as the metal (Tuddenham and Dougall 1979; Weast 1980). The copper content of ore 

deposits ranges from 0.5 to 5% by weight, whereas in igneous rock copper content ranges from 0.0005 to 

0.011% (Duby 1980; Weant 1985). The three most important sources of copper are chalcocite, 

chalcopyrite, and malachite (Weant 1985). The major U.S. deposits are porphyry, indicating that they are 

of hydrothermal origin and are uniformly distributed in fractures or veins. 

The United States is the world's second leading copper producer. The country produced 148 million 

metric tons of mined ore in 2001, with an average copper content of 0.48% (USGS 2001). Mine 

production of recoverable copper in the United States totaled 1,340,000 metric tons in 2001, an estimated 

10% of world production behind Chile, which accounted for 35%. Copper was mined in six states in 

2001, with Arizona accounting for 67% of U.S. copper production, followed by Utah (13%), New Mexico 

(13%) and Nevada (1%). There were 23 copper-producing mines in 2001, down from 27 in 2000. 

Thirteen of these are copper mines accounting for 99% of production in the United States. The remaining 

mines yielded copper as a by-product of gold, lead, silver, or zinc mining. Of the 13 largest mines, 

10 were in Arizona, 2 were in New Mexico, and 1 was in Utah. Production, processing and use of copper 

and copper compounds in the United States, listed by state, are given in Tables 5-1 and 5-2, respectively. 

After mining, most of the ore is crushed and concentrated to a material containing 15–35% copper using 

flotation. The remaining copper is obtained by first leaching the ore or tailings and then concentrating the 

leachate by applying solvent extraction or ion exchange (Butterman 1982). 

Most primary copper is produced from its sulfide ore by matte smelting, an operation yielding a molten 

sulfide of copper and iron, called matte, which is further oxidized in a conversion step to yield metallic 

copper. The conversion operation takes place in two stages. In the first, slag-forming stage, FeS is 

oxidized to iron oxides, which combine with a silica flux to form a slag. In the second, copper-producing 

stage, CuS2 is oxidized to form sulfur dioxide and metallic copper. The product of the conversion 
 

Table 5-1. Facilities that Produce, Process, or Use Copper 

Number of Minimum amount Maximum amount 

Statea facilities on site in poundsb on site in poundsb Activities and usesc 

AK 

AL 

AR 

AZ 

CA 

CO 

CT 

FL 

GA 

HI 

IA 

ID 

IL 

IN 

KS 

KY 

LA 

MA 

MD 

ME 

MI 

MN 

MO 

MS 

MT 

NC 

ND 

NE 

NH 

NJ 

NM 

NV 

NY 

OH 

OK 

OR 

PA 

PR 

RI 

2 

47 

45 

26 

153 

14 

54 

28 

58 

2 

31 

3 

150 

148 

23 

69 

10 

59 

7 

10 

133 

49 

73 

33 

1 

72 

2 

18 

19 

36 

7 

6 

100 

204 

51 

23 

207 

22 

28 

10,000 

100 

1,000 

0 

0 

1,000 

100 

1,000 

0 

1,000 

1,000 

10,000 

0 

0 

100 

100 

100 

1,000 

1,000 

10,000 

0 

100 

100 

100 

1,000 

0 

10,000 

1,000 

100 

1,000 

1,000 

1,000 

0 

100 

100 

0 

0 

1,000 

1,000 

99,999 

49,999,999 

49,999,999 

999,999,999 

99,999,999 

499,999,999 

49,999,999 

9,999,999 

9,999,999 

9,999 

99,999,999 

999,999 

99,999,999 

499,999,999 

9,999,999 

9,999,999 

9,999,999 

9,999,999 

999,999 

9,999,999 

49,999,999 

9,999,999 

499,999,999 

9,999,999 

9,999 

99,999,999 

99,999 

9,999,999 

49,999,999 

49,999,999 

9,999,999 

99,999 

49,999,999 

49,999,999 

99,999,999 

999,999 

49,999,999 

9,999,999 

9,999,999 

12 

1, 2, 3, 5, 7, 8, 9, 11, 12, 13 

1, 2, 3, 4, 7, 8, 9, 12, 13, 14 

1, 3, 4, 5, 7, 8, 9, 11, 12, 13, 14 

1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14 

2, 3, 4, 7, 8, 11, 12, 14 

1, 2, 3, 4, 5, 6, 7, 8, 9, 11 

2, 3, 4, 6, 7, 8, 9, 10, 11, 12 

1, 2, 3, 4, 5, 6, 7, 8, 9, 12, 13, 14 

12 

1, 2, 3, 4, 5, 7, 8, 9, 12 

1, 3, 8, 9, 12 

1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 14 

1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

2, 3, 4, 6, 7, 8, 9, 11, 12, 14 

1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 

2, 6, 8, 10, 12, 13, 14 

1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12 

1, 2, 4, 5, 7, 8, 9 

2, 3, 8 

1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12 

1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

1, 2, 3, 4, 5, 7, 8, 9, 11, 12 

4, 7, 8, 9, 12 

6, 11 

1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12 

7, 8 

1, 3, 5, 7, 8, 9, 11, 12, 13 

2, 3, 4, 7, 8, 9 

1, 2, 3, 4, 6, 7, 8, 9, 11, 12 

2, 3, 8, 12 

7, 8, 11, 12 

1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14 

1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

1, 2, 3, 4, 7, 8, 9, 11, 12, 13 

1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12 

1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13, 14 

1, 2, 3, 8, 11 

2, 3, 4, 6, 7, 8, 9, 12 

COPPER 112 

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 
COPPER 113 

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

Table 5-1. Facilities that Produce, Process, or Use Copper 

Number of Minimum amount Maximum amount 

Statea facilities on site in poundsb on site in poundsb Activities and usesc 

SC 53 100 9,999,999 1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 12, 14 

SD 11 1,000 49,999,999 1, 5, 7, 8, 12, 14 

TN 75 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13, 14 

TX 102 100 99,999,999 1, 2, 3, 4, 5, 7, 8, 9, 10, 11, 12, 14 

UT 10 1,000 9,999,999 1, 3, 4, 5, 6, 7, 8, 11, 12 

VA 42 1,000 9,999,999 1, 2, 3, 5, 6, 7, 8, 10, 11, 12, 13, 14 

VT 4 1,000 99,999 2, 3, 4, 6, 8, 9 

WA 24 1,000 999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

WI 148 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 14 

WV 12 1,000 9,999,999 2, 3, 6, 7, 8, 12 

WY 4 0 99,999 1, 4, 9, 10, 12 

Source: TRI01 2003 

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 
COPPER 114 

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

Table 5-2. Facilities that Produce, Process, or Use Copper Compounds 

Number of Minimum amount Maximum amount 

Statea facilities on site in poundsb on site in poundsb Activities and usesc 

AK 5 10,000 9,999,999 1, 2, 3, 4, 5, 7, 10, 12, 13, 14 

AL 37 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 

AR 26 100 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13, 14 

AZ 27 1,000 10,000,000,000 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13, 14 

CA 74 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

CO 7 100 99,999 1, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13, 14 

CT 24 1,000 999,999,999 1, 3, 5, 6, 7, 8, 9, 10, 11, 12 

DC 1 1,000 9,999 12 

DE 5 1,000 99,999 1, 2, 3, 5, 7, 9, 12, 13 

FL 36 100 999,999 1, 2, 3, 4, 5, 7, 8, 9, 10, 11, 12, 13, 14 

GA 36 0 99,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 

IA 26 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

ID 8 1,000 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 

IL 92 0 99,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

IN 72 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

KS 11 0 999,999 1, 3, 5, 7, 8, 9, 10, 11, 12, 13 

KY 39 100 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13, 14 

LA 26 0 99,999,999 1, 2, 3, 4, 5, 7, 8, 10, 11, 12, 13 

MA 25 100 9,999,999 1, 3, 4, 5, 6, 7, 8, 10, 11, 12 

MD 10 100 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 12, 13 

ME 5 100 999,999 1, 3, 5, 7, 8, 11, 13 

MI 52 100 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13, 14 

MN 29 100 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

MO 34 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

MS 14 100 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 13 

MT 9 1,000 99,999,999 1, 2, 3, 4, 5, 6, 8, 9, 10, 11, 12, 13, 14 

NC 48 100 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

ND 8 100 99,999 1, 5, 7, 9, 12, 13, 14 

NE 10 10,000 99,999,999 1, 3, 4, 5, 7, 8, 9, 10, 11, 12, 13, 14 

NH 12 100 9,999,999 1, 3, 5, 6, 7, 8, 9, 11, 12, 13 

NJ 24 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13, 14 

NM 8 1,000 99,999,999 1, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13 

NV 17 100 10,000,000,000 1, 4, 5, 6, 7, 9, 10, 11, 12, 13, 14 

NY 30 100 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

OH 83 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

OK 14 100 999,999 1, 3, 4, 5, 6, 8, 9, 10, 11, 12, 13, 14 

OR 16 100 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 

PA 92 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

PR 3 1,000 99,999 7, 10 
COPPER 115 

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

Table 5-2. Facilities that Produce, Process, or Use Copper Compounds 

Number of Minimum amount Maximum amount 

Statea facilities on site in poundsb on site in poundsb Activities and usesc 

RI 12 100 999,999 1, 2, 3, 4, 7, 8, 10, 12 

SC 31 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13, 14 

SD 2 1,000 999,999 1, 3, 5, 6, 10, 13 

TN 47 100 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 

TX 89 0 99,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

UT 14 1,000 10,000,000,000 1, 3, 4, 5, 6, 7, 8, 9, 12, 13 

VA 36 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

WA 13 1,000 999,999 1, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 

WI 35 0 999,999 1, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

WV 17 1,000 999,999 1, 3, 4, 5, 7, 8, 9, 12, 13, 14 

WY 4 100 999,999 1, 5, 9, 12, 13 

Source: TRI01 2003 

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 
COPPER 116 

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

operation is blister copper, which is 98.5–99.5% copper. Concentrated leachate from low-grade ore is 

subject to electrowinning, which electrolyzes aqueous sulfate solutions, or to cementation, which 

displaces copper from solution by a more active metal such as iron (Duby 1980). Further purification is 

obtained by electrolytic refining. For more details on copper mining, ore processing, smelting, and 

refining, see Duby (1980) and EPA (1980b). 

Production of copper in the United States includes not only the processing of both domestic and foreign 

ores, but also the recovery of scrap. Scrap is a significant part of the U.S. copper supply. Scrap refers to 

both 'old scrap' (metal that has been used) and 'new scrap' (generated during fabrication). In 1999, 

smelting was performed in the United States by four primary smelters and two secondary smelters with a 

combined capacity of 1,750,000 metric tons per year (USGS 2000). Together, they produced 

1,290,000 metric tons of copper from both domestic and foreign ores and scrap in 1999 (USGS 2001). In 

2000, smelting was performed in the United States by four primary smelters and one secondary smelter 

with a combined capacity of 1,180,000 metric tons per year. Production of copper from U.S. smelters in 

2000 was reported to be 1,000,000 metric tons, down from 1,290,000 metric tons in 1999 (USGS 2001). 

During 2000, 23 refineries operating with a combined capacity of 2,400,000 tons, produced 

1,587,000 metric tons of copper from domestic and foreign ores. An additional 208,000 metric tons of 

copper was produced from new and old scrap for a combined total refinery production in the United 

States of 1,790,000 tons (USGS 2001). This level of refinery production was down from a level of 

2,120,000 metric tons in 1999 (USGS 2001). Production of secondary copper and copper-alloys 

amounted to 1,490,000 metric tons in both 1999 and 2000 (USGS 2000). Apparent consumption for 

2000 was 3,130,000 metric tons (USGS 2001). This includes domestic refined copper production, net 

imports of refined copper, copper recovered from old scrap, and stock adjustments. These alloys, 

primarily brass and bronze, contain approximately 60–>90% copper. 

Most industrially important copper compounds are made starting with copper metal. Copper sulfate, the 

most commercially important copper compound, was produced by at least six companies in plants in Casa 

Grande, Arizona; Sewaren and Oak Bridge, New Jersey; El Paso and Garland, Texas; Sante Fe Springs, 

California; Union, Illinois; Copperhill, Tennessee; and Sumter, South Carolina (Jolly and Edelstein 

1987). 

Copper sulfate also is produced as a by-product of copper production by ore-leaching with sulfuric acid. 

Production of copper sulfate increased by 29% from 1996 to 2000, standing at 55,500 metric tons in 2000 
 

 

COPPER 117 

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

(USGS 2000). However, in 2001, production of copper sulfate decreased slightly to 55,200 metric tons 

(USGS 2001). Recent production figures for other copper compounds were not located. 

5.2 IMPORT/EXPORT 

In 2000, 1,340,000 million tons of unmanufactured copper and 1,060,000 metric tons of refined copper 

were imported (USGS 2001). Peru, Canada, and Chile were the principal sources of imported refined 

copper. The quantity of imported unmanufactured copper increased by 93% since 1994; the increase was 

almost entirely in the importation of refined powder, as opposed to ore concentrate, blister copper, or 

scrap (USGS 1994, 2001). Imports of copper sulfate amounted to 4,650 metric tons and were primarily 

obtained from Australia and Mexico (USGS 2001). 

In 2000, 483,000 metric tons of copper were exported, of which 19% was refined copper (USGS 2000). 

In 2001, exports dropped to 379,000 metric tons with a large decrease in exports of refined copper (from 

93,600 metric tins in 2000 to 22,500 metric tons in 2001); exports of unalloyed copper scrap increased 

from 228,000 metric tons in 2000 to 262,000 metric tons in 2001 (USGS 2001). 

5.3 USE 

Copper is one of the most important metals because of its durability, ductility, malleability, and electrical 

and thermal conductivity. It is used primarily as the metal or in alloys. Its alloys, including brass, 

bronze, gun metal, and Monel metal, are important commodities. All current American coins are copper 

alloys. A small percentage of copper production goes into the manufacture of copper compounds, 

primarily copper sulfate. 

The Copper Development Association's 2000 estimates of the end-use distribution of copper and copperalloy products by the industrial sector were: construction, 39%; electrical and electrical products, 28%; 

transportation equipment, 11%; industrial machinery and equipment, 11%; and consumer and general 

products, 11% (USGS 2002). The top 10 markets for copper and copper-alloy during 1986 were, in order 

of importance: plumbing, building wire, telecommunications, power utilities, in-plant equipment, air 

conditioning, automotive electrical, automotive nonelectrical, business electronics, and industrial valves 

and fittings (Jolly and Edelstein 1987). 
COPPER 118 

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

Copper sulfate was the only copper compound for which end-use distribution data were available; these 

data addressed only domestic producers. Sixty-five percent of production went into agricultural use, 28% 

for industrial uses such as metal finishing, mineral froth flotation and wood preservatives, and 7% for 

water treatment. 

In agriculture, copper compounds are used as fungicides and to prepare copper fungicidal products, 

algicides for reservoirs and streams and nutritional supplements in animal feed and fertilizers. Industrial 

applications of copper sulfate include use as an activator in froth flotation of sulfide ores, production of 

chromated copper arsenate wood preservatives, electroplating, azo dye manufacture, mordant for textile 

dyes, petroleum refining and in the manufacture of other copper compounds such as copper hydroxide 

and copper carbonate (Mannsville Chemical Products 1984). 

Copper compounds are applied as fungicides to foliage, seed, wood, fabric, and leather to protect against 

blight, downy mildew and rust. The 1982 consumption of copper-containing fungicides was 2.8 million 

pounds (Mannsville Chemical Products 1984). The major copper compound used for this purpose was 

the basic copper sulfate (1.8 million pounds). Other important fungicidal compounds were copper 

hydroxide, copper ammonium carbonate, copper oxychloride and copper oxychloride sulfate. The major 

target crops of copper-containing fungicides are citrus fruits, peanuts, deciduous fruits (other than apples), 

potatoes, vegetables and other field crops. Copper compounds are also used as algicides, insecticides and 

repellents. Products containing copper compounds frequently contain other chemicals and may be sold 

under various trade names. Formulation may be in wettable powders or aqueous solutions. 

5.4 DISPOSAL 

It is estimated that 60% of copper in scrap is recycled (Tuddenham and Dougall 1978). In 1986, ~40% of 

the copper produced came from this source (Jolly and Edelstein 1987). Copper-containing wastes can be 

concentrated using ion exchange, reverse osmosis, or evaporation, and then reclaimed by electrolysis 

(HSDB 2002). Copper and copper compounds not recycled are disposed of in landfills or released into 

waste water. Methods of copper containing sludge disposal from waste water treatment facilities include 

landfilling, landspreading, incineration or ocean disposal. 

In case of a solid copper sulfate spill on land, the solids should be protected from rain and fire-fighting 

water by covering the material with plastic sheeting (HSDB 2002). In the event of a water spill, the 
COPPER 119 

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

copper sulfate should be neutralized with crushed limestone, slaked lime, or sodium bicarbonate, and the 

solidified masses should be removed. 

 

 

COPPER 121 

6. POTENTIAL FOR HUMAN EXPOSURE 

6.1 OVERVIEW 

Copper has been identified in at least 906 of the 1,647 hazardous waste sites that have been proposed for 

inclusion on the EPA National Priorities List (NPL) (HazDat 2004). However, the number of sites 

evaluated for copper is not known. The frequency of these sites can be seen in Figure 6-1. Of these sites, 

895 are located within the United States, 2 are located in the Territory of Guam, 8 are located in the 

Commonwealth of Puerto Rico, and 1 is located in the U.S. Virgin Islands (the sites in the Territory of 

Guam, the Commonwealth of Puerto Rico, and the U.S. Virgin Islands are not shown). 

Copper and its compounds are naturally present in the earth's crust. Natural discharges to air and water, 

such as windblown dust, volcanic eruptions, etc., may be significant. Therefore, it is important to 

consider the copper concentrations within a specific environment, geographical region, or human 

population study site that has been minimally affected by anthropogenic sources of copper in order to 

accurately assess the contribution of an anthropogenic activity to human exposures to copper. In air, the 

mean copper concentrations in the atmosphere range between 5 and 200 ng/m3

 in rural and urban 

locations. Airborne copper is associated with particulates that are obtained from suspended soils, 

combustion sources, the manufacture or processing of copper-containing materials, or mine tailings. The 

median concentration of copper in natural water (e.g., rivers, lakes, and oceans) is 4–10 ppb. It is 

predominantly in the Cu(II) state. Most of it is complexed or tightly bound to organic matter. Little is 

present in the free (hydrated) or readily exchangeable form. The combined processes of complexation, 

adsorption, and precipitation control the level of free Cu(II). The chemical conditions in most natural 

water are such that, even at relatively high copper concentrations, these processes will reduce the free 

Cu(II) concentration to extremely low values. The mean concentration of copper in soil ranges from 5 to 

70 mg/kg and is higher in soils near smelters, mining operations, and combustion sources. Sediment is an 

important sink and reservoir for copper. In relatively clean sediment such as those found in some of the 

bays and estuaries along the New England Coast, the copper concentration is <50 ppm; polluted sediment 

may contain several thousand ppm of copper. The form of copper in the sediment also will be sitespecific. In aerobic sediments, copper is bound mainly to organics (humic substances) and iron oxides. 

However, in some cases, copper is predominantly associated with carbonates. In anaerobic sediments, 

Cu(II) will be reduced to Cu(I) and insoluble cuprous salts will be formed. 
COPPER 122 

6. POTENTIAL FOR HUMAN EXPOSURE 

Figure 6-1. Frequency of NPL Sites with Copper Contamination 

Frequency of 

NPL Sites 

1-2
 

4-10
 

11-20
 

21-33
 

Derived from HazDat 2004
 41-60
 

73
 
COPPER 123 

6. POTENTIAL FOR HUMAN EXPOSURE 

The largest release of copper to the environment by anthropogenic activities is by far to land. The major 

sources of release are mining operations, agriculture, sludge from publicly-owned treatment works 

(POTWs) and municipal and industrial solid waste. Mining and milling contribute the most waste. 

Copper is released to water as a result of natural weathering of soil and discharges from industries and 

sewage treatment plants. Copper compounds may also be intentionally applied to water to kill algae. 

Copper associated with particulate matter is emitted into the air naturally from windblown dust, 

volcanoes, and anthropogenic sources, the largest of which are being primary copper smelters and ore 

processing facilities. The concentration of copper in emissions from copper smelters has been found to 

range between 7 and 137.8 ng/m3

 (Hutchinson 1979; Romo-Kröger et al. 1994). 

In the general population, the highest exposures to copper come from drinking water and food. Of special 

concern is copper that gets into drinking water from water distribution systems (both from the water 

treatment plant and in the home). When a system has not been flushed after a period of disuse, the 

concentration of copper in tap water may exceed 1.3 ppm, the EPA drinking water limit. The estimated 

intakes of copper in the general population are 0.15 mg/day from drinking water, and approximately 

2 mg/day from food. The dietary intake of copper can be increased from the regular consumption of 

certain foods, such as shellfish, organ meats (e.g., liver and kidney), legumes, and nuts. However, except 

for shellfish, where an additional intake of 2–150 mg/day is possible for those individuals who regularly 

consume shellfish, these other sources of higher copper intake are not expected to increase the total daily 

intake of copper beyond the recommended limit of 10–12 mg/day for adults (WHO 1996). In comparison 

to intake of copper through ingestion of water and food, the intake of copper through inhalation of copper 

in dust is much less significant at an estimated rate of 0.1–4.0 μg copper/day. Contact with available 

copper also may result from the use of copper fungicides and algicides. 

Many workers are exposed to copper in agriculture, industries connected with copper production, metal 

plating, and other industries. Little information is available concerning the forms of copper to which 

workers are exposed. 

At this time, copper has been identified in 906 out of 1,647 NPL hazardous waste sites in the United 

States (HazDat 2004). The frequency of these sites within the United States is noted in Figure 6-1. Based 

on the available data, people living close to NPL sites may be at greater risk for exposure to copper than 

the general population with respect to inhalation of airborne particulates from the NPL sites, ingestion of 
 

 

 

COPPER 124 

6. POTENTIAL FOR HUMAN EXPOSURE 

contaminated water or soil, and/or uptake of copper into fruits and vegetables raised in gardens of 

residents living near NPL sites. People living near copper smelters and refineries and workers in these 

and other industries may be exposed to high levels of dust-borne copper by both inhalation and ingestion 

routes. For example, ingestion of 300 mg of soils near copper smelters by children could result in the 

intake as high as 0.74–2.1 mg copper per day, based on measurements of copper concentrations in these 

soils of 2,480–6,912 mg/kg. 

6.2 RELEASES TO THE ENVIRONMENT 

Industrial manufacturers, processors, and users of copper and copper compounds are required to report the 

quantities of this substance released to environmental media annually (EPA 1988d). The data compiled in 

the Toxics Release Inventory (TRI01 2003) are for releases in 2001 to air, water, soil, and transfer of 

copper and copper compounds for offsite disposal. These data are summarized in Tables 6-1 (copper) and 

6-2 (copper compounds). Total releases (rounded to three significant digits) of copper into the 

environment in 2001 were approximately 11,100,000 pounds (approximately 5,050 metric tons) (TRI01 

2003), of which approximately 821,000 pounds (373 metric tons), or 7.4% of the total, were released to 

air. Another 46,600 pounds (21 metric tons) or approximately 0.4% of the total, were released into water, 

0.5% (53,800 pounds, 24 metric tons) was injected underground, and 91.9% (10,200,000 pounds, 

4,360 metric tons) was released to land. Total releases (rounded to three significant digits) of copper 

compounds to the environment in 2001 were approximately 1,000,000,000 pounds (approximately 

455,000 metric tons) (TRI01 2003) of which approximately 1,420,000 pounds (645 metric tons), or 0.1% 

of the total, were released to air. Another 418,000 pounds (190 metric tons), or approximately 0.04% of 

the total, were released into water, 0.09% (894,000 pounds or 406 metric tons) was injected underground, 

and 99.8% (998,000,000 pounds or 454,000 metric tons) was released to land. The TRI data should be 

used with caution because only certain types of facilities are required to report them (i.e., this is not an 

exhaustive list). 

Industrial releases are only a fraction of the total environmental releases of copper and copper 

compounds. Other sources of copper release into the environment originate from domestic waste water, 

combustion processes, wood production, phosphate fertilizer production, and natural sources (e.g., wind 

blown dust, volcanoes, decaying vegetation, forest fires, sea spray, etc.) (Georgopoulos et al. 2001; 
COPPER 125 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-1. Releases to the Environment from Facilities that Produce, Process, or 

Use Coppera
 

Reported amounts released in pounds per yearb 

Number Under- Total on and 

Statec of 

facilities Aird

 Water 

ground 

injection Land 

Total on-site 

releasee 

Total off-site 

releasef 

off-site 

release 

AK 2 0 No data 0 27,324 27,324 0 27,324 

AL 51 11,825 1,321 0 14,906 28,052 47,708 75,760 

AR 48 5,951 573 0 143,970 150,494 231,861 382,355 

AZ 30 978 48 0 227,993 229,019 9,094 238,113 

CA 168 9,745 908 0 2,608,971 2,619,624 171,791 2,791,415 

CO 18 472 16 0 125,387 125,875 15,991 141,866 

CT 63 10,662 904 0 5 11,571 47,415 58,985 

FL 35 832 303 51,262 158,561 210,958 40,092 251,050 

GA 72 4,473 575 0 135,127 140,175 30,052 170,227 

HI 2 0 No data 0 117,010 117,010 0 117,010 

IA 39 3,050 566 0 250 3,866 35,144 39,010 

ID 5 120 5 0 450,820 450,945 4,000 454,945 

IL 160 46,380 4,623 0 1,601,420 1,652,423 658,745 2,311,168 

IN 161 42,775 1,239 0 369,664 413,678 2,223,563 2,637,241 

KS 24 2,535 251 0 297,190 299,976 24,566 324,542 

KY 73 18,633 390 0 269,927 288,950 179,301 468,251 

LA 15 126,947 710 2,200 2,426 132,283 690 132,973 

MA 69 2,530 77 0 0 2,607 64,821 67,427 

MD 12 250 10 0 250 510 89,168 89,678 

ME 11 106 321 0 500 927 9,034 9,961 

MI 142 35,480 685 0 849 37,014 161,721 198,735 

MN 50 16,129 10 0 5 16,144 825,881 842,025 

MO 79 9,204 671 0 52,581 62,456 409,753 472,209 

MS 35 2,350 657 0 520 3,527 56,712 60,239 

MT 1 161 No data 0 1,030,000 1,030,161 No data 1,030,161 

NC 83 7,965 1,076 0 193,576 202,617 107,899 310,516 

ND 3 23 5 0 0 28 339 367 

NE 19 3,638 5 0 47,005 50,648 7,628 58,276 

NH 22 1,005 25 0 0 1,030 37,543 38,573 

NJ 46 15,584 165 5 22,973 38,727 12,291 51,018 

NM 7 500 No data 0 118,680 119,180 23,453 142,633 

NV 6 905 No data 0 500 1,405 5,201 6,606 

NY 104 11,484 14,198 0 114,462 140,144 894,995 1,035,138 

OH 251 55,122 5,424 0 606,137 666,683 481,776 1,148,459 

OK 64 8,712 303 0 80,952 89,967 29,726 119,693 

OR 23 771 9 0 81,984 82,764 1,495 84,259 

PA 222 85,511 2,913 0 43,546 131,970 343,353 475,324 
COPPER 126 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-1. Releases to the Environment from Facilities that Produce, Process, or 

Use Coppera
 

Reported amounts released in pounds per yearb 

Number Under- Total on and 

Statec of 

facilities Aird

 Water 

ground 

injection Land 

Total on-site 

releasee 

Total off-site 

releasef 

off-site 

release 

PR 21 15,944 5 0 0 15,949 9,247 25,196 

RI 33 5,093 5 0 0 5,098 22,759 27,857 

SC 55 10,018 875 0 76,761 87,654 59,678 147,332 

SD 10 4,885 No data 0 750 5,635 280 5,915 

TN 89 165,328 567 0 206 166,101 87,117 253,218 

TX 117 26,388 4,006 369 574,322 605,085 178,081 783,166 

UT 12 1,179 56 0 46,085 47,320 298 47,618 

VA 46 21,649 694 5 239,776 262,124 210,846 472,970 

VT 5 0 No data 0 250 250 1,025 1,275 

WA 28 474 633 0 166,530 167,637 150,773 318,410 

WI 159 25,741 617 0 26,845 53,203 257,886 311,089 

WV 12 1,951 116 5 30,759 32,831 8,102 40,933 

WY 5 381 0 0 60,882 61,263 75 61,338 

Total 2,807 821,838 46,559 53,846 10,168,637 11,090,881 8,268,966 19,359,847 

Source: TRI01 2003 

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

The sum of fugitive and stack releases are included in releases to air by a given facility.
 e

The sum of all releases of the chemical to air, land, water, and underground injection wells. 

f

Total amount of chemical transferred off-site, including to publicly owned treatment works (POTW). 
COPPER 127 

6. POTENTIAL FOR HUMAN EXPOSURE 

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

Use Copper Compoundsa
 

Reported amounts released in pounds per yearb 

Number UnderStatec of 

facilities Aird

 Water 

ground 

injection Land 

Total on-site 

releasee 

Total off-site 

releasef 

Total on and 

off-site release 

AK 6 475 57 670,000 5,193,578 5,864,110 750 5,864,860 

AL 66 27,363 28,896 0 2,315,767 2,372,026 66,409 2,438,435 

AR 60 17,082 3,277 0 86,510 106,869 173,666 280,535 

AZ 27 135,813 584 0 451,467,272 451,603,669 76,083 451,679,752 

CA 92 5,374 878 0 111,029 117,281 166,771 284,053 

CO 15 720 15,810 0 115,190 131,720 61,086 192,806 

CT 24 2,072 635 0 0 2,707 354,565 357,272 

DC 1 0 0 0 4,600 4,600 0 4,600 

DE 9 3,203 9,196 0 25,029 37,428 30,509 67,937 

FL 54 85,273 22,720 0 648,038 756,031 169,746 925,777 

GA 69 14,994 48,943 0 776,472 840,409 369,367 1,209,776 

IA 52 15,425 3,386 0 156,575 175,386 152,607 327,993 

ID 11 1,305 800 0 424,736 426,841 272 427,113 

IL 114 46,746 5,233 0 503,051 555,030 1,021,024 1,576,054 

IN 88 52,013 20,411 250 1,098,611 1,171,285 1,044,431 2,215,716 

KS 20 3,774 0 0 247,277 251,051 112,520 363,571 

KY 49 37,298 40,320 0 889,385 967,003 529,758 1,496,761 

LA 33 5,626 17,074 7 274,009 296,716 156,664 453,380 

MA 27 720 39 0 3 762 104,579 105,341 

MD 19 7,471 8,993 0 20,391 36,855 163,428 200,283 

ME 5 2,200 485 0 0 2,685 37,187 39,872 

MI 68 60,059 14,850 0 643,734 718,643 511,519 1,230,162 

MN 46 9,598 882 0 281,020 291,500 2,115,492 2,406,992 

MO 55 20,270 2,900 0 4,658,137 4,681,307 248,752 4,930,059 

MS 35 45,892 279 12,000 22,708 80,879 54,015 134,894 

MT 10 12,595 10 47,757 3,385,422 3,445,784 32,403 3,478,187 

NC 88 21,656 15,299 0 758,429 795,384 124,485 919,869 

ND 8 632 11,877 0 138,516 151,025 124,852 275,877 

NE 21 1,999 155 0 207,272 209,426 21,672 231,098 

NH 13 561 12 0 0 573 28,554 29,127 

NJ 30 1,187 5,754 0 18,117 25,058 1,869,339 1,894,397 

NM 10 11,839 4,005 0 55,651,587 55,667,431 43,010 55,710,441 

NV 18 2,034 160 1 27,004,822 27,007,017 3,067 27,010,084 

NY 35 9,816 9,830 1 52,320 71,967 161,344 233,311 

OH 105 14,459 17,520 8,100 1,158,856 1,198,935 1,555,185 2,754,120 

OK 23 2,466 5,082 662 212,835 221,045 48,189 269,234 

OR 25 2,160 1,021 0 216,646 219,827 19,130 238,957 
 

309 

COPPER 128 

6. POTENTIAL FOR HUMAN EXPOSURE 

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

Use Copper Compoundsa
 

Reported amounts released in pounds per yearb 

Number Underof ground Total on-site Total off-site Total on and 

Statec facilities Aird

 Water injection Land releasee releasef off-site release 

PA 115 484,099 14,493 0 371,008 869,600 3,121,602 3,991,202 

PR 7 44 265 0 0 309 0 

RI 13 253 608 0 108 969 2,927 3,896 

SC 53 32,578 2,664 0 203,101 238,343 309,623 547,966 

SD 5 6,150 1,340 0 88,000 95,490 18 95,508 

TN 60 17,676 20,876 0 11,178,079 11,216,631 336,292 11,552,923 

TX 124 99,287 12,731 155,405 1,302,462 1,569,885 849,639 2,419,524 

UT 18 63,960 2,860 0 424,682,491 424,749,311 36,408 424,785,719 

VA 50 10,518 19,707 0 390,234 420,459 184,428 604,887 

WA 23 6,200 756 0 212,242 219,198 35,097 254,295 

WI 56 7,319 13,315 0 59,775 80,409 221,765 302,174 

WV 18 4,390 11,557 0 769,830 785,777 199,314 985,091 

WY 5 1,470 118 0 235,587 237,175 46,668 283,843 

Total 1,978 1,416,114 418,663 894,183 998,260,861 1,000,989,82117,096,211 1,018,086,032 

Source: TRI01 2003 

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

The sum of fugitive and stack releases are included in releases to air by a given facility.
 e

The sum of all releases of the chemical to air, land, water, and underground injection wells. 

f

Total amount of chemical transferred off-site, including to publicly owned treatment works (POTW). 
 

 

 

 

COPPER 129 

6. POTENTIAL FOR HUMAN EXPOSURE 

Harrison 1998). Quantitative information on release of copper to specific environmental media is 

discussed below. A summary of copper concentrations in environmental media is provided in Table 6-3. 

6.2.1 Air 

Copper is emitted into the air from both natural and anthropogenic sources. Since copper is a component 

of the earth's crust, the earth’s crust is the primary natural source of copper. Windblown dust has an 

estimated mean worldwide emission of 0.9–15x106

 kg/year of copper into the atmosphere (WHO 1998). 

Other natural sources of copper emitted into air (in terms of estimated ranges of worldwide emissions) are 

forest fires (0.1–7.5x106

 kg/year), volcanoes (0.9–18x106 kg/year), biogenic processes (0.1– 

6.4x106

 kg/year), and sea spray (0.2–6.9x106 kg/year) (WHO 1998). Based on these data, the mean total 

non-crustal sources of copper emitted into the atmosphere is 1.3–38.8x106

 kg/year. Anthropogenic 

emission sources include nonferrous metal production, wood production, iron and steel production, waste 

incineration, industrial applications, coal combustion, nonferrous metal mining, oil and gasoline 

combustion, and phosphate fertilizer manufacture. It is estimated that only 0.04% of copper released to 

the environment is released into the air (Perwak et al. 1980). Global atmospheric anthropogenic and 

natural emissions of copper have been estimated to be 35x106

 and 28x106 kg/year, respectively (Giusti et 

al. 1993; Nriagu 1989; Nriagu and Pacyna 1988). The estimates for the anthropogenic and natural 

emissions are based on the sum of copper emissions from various sources as shown in Tables 6-4 and 6-5, 

respectively. 

The EPA conducted a detailed study of the total amount of copper emitted into the atmosphere (Weant 

1985). The sources of emissions and the estimated quantities of copper emitted in 106

 kg/year are: 

primary copper smelters, 0.043–6; copper and iron ore processing, 0.480–0.660; iron and steel 

production, 0.112–0.240; combustion sources, 0.045–0.360; municipal incinerators, 0.0033–0.270; 

secondary copper smelters, 0.160; copper sulfate production, 0.045; gray iron foundries, 0.079; primary 

lead smelting, 0.0055–0.065; primary zinc smelting, 0.024–0.340; ferroalloy production, 0.0019–0.0032; 

brass and bronze production, 0.0018–0.036; and carbon black production, 0.013. Using the ranges of 

copper emitted from these sources, it is estimated that U.S. copper emissions into air are 0.9424– 

7.974(x106

) kg per annum. Daily stack emission rates have been reported for three coal-burning power 

plants on a kg/day/1,000 megawatt basis (Quee Hee et al. 1982); they are 0.3–0.7 and 

2.00 kg/day/1,000 megawatt for those using low-sulfur western coal and high-sulfur eastern coal, 

respectively. This amounts to annual emission rates of 110–260 and 730 kg/1,000 megawatt, 

respectively. In another report, emission of copper into air from a 650 megawatt electrical power plant, 
 

 

 

 

 

COPPER 130 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-3. Summary of Copper Concentrations in Environmental Mediaa 

Environmental media Concentration Units 

Atmosphere 

 Aerosol 0.1–382 ppt 

Hydrosphere—water

 Coastal Dissolved 0.06–4.3 ppb 

Total 0.5–13.8 ppb 

Suspended solids 0.6–370,000 ppm 

 Estuarine Dissolved 0.02–4.7 ppb 

Total 1.2–71.6 ppb 

Suspended solids 0.38–72 ppm 

 Ocean Dissolved Not detected–10 ppb 

Total 0.04–10 ppb 

Suspended solids 0.01–2.8 ppm 

Lake Dissolved 0.1–15.6 ppb 

Total 0.1–15.6 ppb 

 River Dissolved 0.18–3,000 ppb 

Total 0.5–5,800 ppb 

 Groundwater Dissolved 0.003–70 ppb 

Total 1–1,160 ppb 

 Drinking water Total 0.3–1,352 ppb 

Hydrosphere—sediments

 Coastal Particulate 0.03–3,789 ppm 

Interstitial water 25.5–32.7 ppb 

 Estuarine Particulate 0.3–2,985 ppm 

Interstitial water 0.3–100 ppb 

 Ocean Particulate 3.1–648 ppb 

Interstitial water 22–45 ppm 

Lake Particulate 0.4–796 ppm 

Interstitial water 45.6–52 ppb 

River Particulate 5.3–4,570 ppm 

Pedosphere 

Soil Total 0.01–3,138 ppm 

Organic 293–7,634 ppm 

 Dust Total 2.9–76 ppm 

a

As reported in the Copper Sourcebook 1998 (Harrison 1998), covering the years 1993–1996. 

Source: Georgopoulos et al. 2001 
COPPER 131 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-4. Global Emissions of Copper from Natural Sources (x106 kg/year) 

Median Range 

Wind-borne particulates 8.0 0.9–15 

Marine spray—seasalt and surface organic 4.0 0.25–7.7 

microlayers 

Volcanoes 9.4 0.9–18 

Forest fires 3.8 0.1–7.5 

Biogenic—continental particulates and volatiles 2.9 0.11–5.6 

Total emissions 28 2.3–54 

Source: Nriagu 1989 
COPPER 132 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-5. Global Emissions of Copper from Anthropogenic Sources 

(x106

 kg/year) 

Median Range 

Coal combustion 5.15 2.3–8.0 

Oil combustion 1.86 0.42–3.3 

Pyrometallurgical 23.5 15–32 

Secondary nonferrous metal production 0.115 0.06–0.17 

Steel and iron manufacturing 1.47 0.14–2.8 

Refuse incineration 1.5 1.0–2.0 

Phosphate fertilizers 0.415 0.14–0.69 

Wood combustion 0.9 0.60–1.2 

Total emissions 35 20–51 

Source: Nriagu and Pacyna 1988 
COPPER 133 

6. POTENTIAL FOR HUMAN EXPOSURE 

burning bituminous coal, was estimated at 213 kg/year, based on a summary of reportable TRI releases 

(Rubin 1999). 

Emission factors in grams of copper released to the atmosphere per ton of product have been estimated 

for various industries (Nriagu and Pacyna 1988). These factors would enable estimation of an industry's 

copper emissions from its production volume. Missing from these emission estimates is fugitive dust 

arising from drilling, blasting, loading, and transporting operations associated with copper mining. The 

only control for reducing fugitive dust is the manual use of water sprays (EPA 1980b). The highest 

concentrations of copper in atmospheric particulate matter were obtained from mining activities, primary 

and secondary production, and industrial manufacturing (Table 6-6). 

Romo-Kröger et al. (1994) were able to show, through the use of radioactive tracers and cluster analysis 

of interelemental correlations, that Cu, S, Zn, and As measured near a copper smelter in Chile were 

derived from the plant and not from the surrounding soil. The concentration of copper in air near the 

plant decreased from 66 ng/m3

 (fine particles) and 131 ng/m3 (coarse particles) to 22 ng/m3 (fine 

particles) and 50 ng/m3

 (coarse particles) during a period of inactivity at the plant, clearly demonstrating 

the contribution of plant emissions to copper levels in the surrounding area. 

The amount of copper and other pollutants in fugitive dust originating from copper production sites, such 

as from smelter bag houses, or waste sites, is of some concern. In one study, the amount of airborne 

copper and other heavy metals deposited near a large refuse dump that received municipal and industrial 

waste and sewage sludge was determined by first measuring the amount of the metal accumulated in moss 

bags suspended 1–3 meters above the ground. The deposition rate was then determined from the amount 

of copper in the moss bags accumulated over the summer of 1985 and compared with that for an 

agricultural control area. The mean copper deposition rates in the two areas were about the same, 

0.55 mg/kg-month (range of 0.04–1.6 mg/kg-month) over the refuse dump and 0.51 mg/kg-month (range 

of 0.26–0.76 mg/kg-month) in the control area (Lodenius and Braunschweiler 1986). 

In a study of automobile exhaust emitted from light duty vehicles conducted in Denver, Colorado, it has 

been shown that this source of copper emission makes a small local contribution to copper in air. The 

amount of copper emitted in the exhaust from automobiles powered by regular gasoline has been 

measured to be 0.001–0.003 mg/mile driven using the Urban Dynamometer Driving Schedule (UDDS) of 

the Federal Test Schedule (FTS) during the summer of 1996 and the winter of 1997 (Cadle et al. 1999). 
COPPER 134 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-6. Concentrations of Copper in Particulate Matter (<10 μm) Generated 

from Various Sourcesa 

Source Copper concentration (percent, w/w) 

Metal mining 6.17b 

Secondary metal production 4.6b 

Primary metal production 3.50b 

Industrial manufacturing 2.16b 

Steel production 0.55b 

Gray iron foundries 0.19b 

Steel foundry, general 0.17b 

Solid waste 0.09b 

Food and agriculture 0.05b 

Chemical manufacturing 0.03b 

Petroleum industry 0.03b 

Gasoline vehicle exhaust 0.05c 

Paved road dust 0.0162c 

Construction dust 0.0102c 

Landfill dust 0.0102c 

Unpaved road dust 0.0087c 

Agricultural lands, dust 0.0067c 

Diesel vehicle exhaust 0.003c 

a

Values obtained from CEIDARS 2000 

b

Data obtained from USEPA Speciate 3.0; Shareef, G.S; Radian, September, 1987 c

Data obtained from KVB Literature Search 
COPPER 135 

6. POTENTIAL FOR HUMAN EXPOSURE 

Diesel powered vehicles were also studied and found to emit 0.005–0.039 mg of copper per mile driven 

for vehicles using #2 diesel fuel. 

Only in a few cases has the form of copper released into the air been determined. Copper released into 

the atmosphere will be in particulate matter in the elemental form or in the form of an oxide, sulfate, or 

carbonate. Because copper smelters co-emit SOX gases, copper is expected to be released largely as the 

sulfate in particulate matter from these facilities. Combustion processes are reported to release copper 

into the atmosphere as the oxide, elemental copper, and adsorbed copper. Cupric oxide has been 

identified in emissions from steel manufacturing and in fly ash from oil-fired power plants and openhearth steel mills (Graedel 1978; Perwak et al. 1980). Copper associated with fine particles (<1 μm) 

tends to result from combustion, while that associated with large particles (>10 μm) is likely to originate 

from wind blown soil and dust (Schroeder et al. 1987). 

Copper was detected in air at 39 of the 906 NPL hazardous waste sites where copper has been detected in 

environmental media (HazDat 2004). Copper was detected in offsite air samples at concentrations 

ranging from 0.02 to 10 μg/m3

 (median concentration of 0.38 μg/m3) (HazDat 2002). These copper 

concentrations in air are generally above the annual atmospheric concentrations of 0.005–0.2 μg/m3

 (EPA 

1987a). 

6.2.2 Water 

Much of the copper that enters environmental waters will be associated with particulate matter. Copper is 

a natural constituent of soil and will be transported into streams and waterways in runoff either due to 

natural weathering or anthropogenic soil disturbances. Sixty-eight percent of releases of copper to water 

is estimated to derive from these processes. Copper sulfate use represents 13% of releases to water and 

urban runoff contributes 2% (Perwak et al. 1980). In the absence of specific industrial sources, runoff is 

the major factor contributing to elevated copper levels in river water (Nolte 1988). In the EPA-sponsored 

National Urban Runoff Program, in which 86 samples of runoff from 19 cities throughout the United 

States were analyzed, copper was found in 96% of samples, at concentrations of 1–100 μg/L (ppb) with a 

geometric mean of 18.7 μg/L (Cole et al. 1984). This mean concentration of copper in runoff water is 

higher than the geometric mean concentration of 4.2 ppb for copper in surface water based on 

measurements in EPA’s STORET database (Eckel and Jacob 1988). Of the 71 priority pollutants 

analyzed, copper, along with lead and zinc, was the most frequently detected. 
COPPER 136 

6. POTENTIAL FOR HUMAN EXPOSURE 

Giusti et al. (1993) provided estimates of global anthropogenic and natural copper inputs into oceans that 

are derived from two sources, atmospheric deposition and riverine input. Atmospheric input has been 

estimated at 14–45x106 kg/year for copper in a dissolved form (e.g., rainwater) and 2–7x106

 kg/year for 

copper in a particulate form (e.g., aerosols). Riverine input is estimated to be 10x106 kg/year as dissolved 

copper and 1,500x106

 kg/year as copper bound to particulates. 

Domestic waste water is the major anthropogenic source of copper in waterways (Isaac et al. 1997; 

Nriagu and Pacyna 1988). Studies in Cincinnati and St. Louis showed discharges of copper into sewer 

systems from residential areas to be significant, with an average loading of 42 mg/person/day (Perwak et 

al. 1980). In a more comprehensive review, Jenkins and Russell (1994) reported a range of average 

copper loadings derived from residential and some small industrial contributions of 2.8– 

83 mg/person/day. Concentrations of copper in influents to 239 waste water treatment plants 

(12,351 observations) were 0.0001–36.5 ppm, and the median value was ~0.4 ppm (Minear et al. 1981). 

Copper is not entirely removed in POTWs, and releases from these facilities contribute ~8% of all copper 

released to water (Perwak et al. 1980). Inputs into the Narraganset Bay, Rhode Island, in decreasing 

order of importance, are sewage effluent, rivers, urban runoff, and atmospheric fallout (Mills and Quinn 

1984; Santschi et al. 1984). Ninety percent of both dissolved and particulate copper was from the effluent 

of sewage treatment plants that discharged into the Providence River. 

While some copper is removed from the waste stream by sewage treatment facilities, considerable copper 

remains in the effluent and is released into receiving waters (EPA 1981; Perwak et al. 1980). Because 

removal efficiencies for copper from waste streams tend to remain constant rather than proportional to 

influent copper concentrations, increases in copper concentrations in POTW influent streams will also 

result in increased copper concentrations in the effluent streams (Isaac et al. 1997). The copper in 

domestic waste water has been found to make up a substantial fraction of the copper found in POTW 

influent in the waste water systems of four Massachusetts municipalities. The range of removal 

efficiencies reported for pilot and full scale plants suggests that removal depends strongly on plant 

operation or influent characteristics. 

A source of copper released into waterways is from urban storm water runoff. Copper in storm water 

runoff originates from the sidings and roofs of buildings, various emissions from automobiles, and wet 

and dry depositional processes (Davis et al. 2001). Concentrations of between 1 and 100 μg/L of copper 

in storm water runoff have been measured (Georgopoulos et al. 2001). Storm water runoff normally 

contributes approximately 2% to the total copper released to waterways. In contrast, copper in runoff that 
COPPER 137 

6. POTENTIAL FOR HUMAN EXPOSURE 

is obtained from the natural weathering of soil or is release from disturbed soils contributes 68% of the 

copper released to waterways (Georgopoulos et al. 2001). 

The best data on typical POTWs using secondary treatment show that 55–90% of copper is removed in 

these plants with a median and mean removal efficiency of 82% (Perwak et al. 1980). By contrast, those 

plants using only primary treatment had a 37% median removal efficiency. A more recent study focused 

on heavy metal removal in three POTWs that received primarily municipal sewage and used activated 

sludge as a secondary treatment. The study looked at removals in both the primary and secondary 

treatment stage. The mean removals of soluble copper and total copper after secondary treatment were 

49–82 and 83–90%, respectively. The average copper concentration in the final effluent was 17–102 ppb, 

which would amount to an output of between 0.58 and 3.47 kg of copper into receiving waters per day, 

based on an effluent volume of 34,000 cubic meters (9 million gallons) per day (Aulenbach et al. 1987; 

Stephenson and Lester 1987). 

Overflow outfalls within combined sewer systems (e.g., combination of domestic and industrial waste 

water plus storm water) are the primary sources of copper pollutants entering estuaries and other coastal 

areas of the United States (Crawford et al. 1995; Georgopoulos et al. 2001; Huh 1996; Iannuzzi et al. 

1997). For example, Crawford et al. (1995) compiled a summary of the sources of various metals and 

other contaminants into the Newark Bay estuary. The mass loadings of copper into the estuary as a 

function of source are (in kg/day): municipal treatment systems, 103.4; industry direct discharge, 8.82; 

combined sewer overflows, 48.0; storm-water runoff, 62.2; tributary flow, 39.1 and discharges from the 

Passaic Valley Commission and Middlesex County Sewerage Authority, 126.5. 

Discharges to water from active mining and milling are small and most of the western operations do not 

release any water because water is a scarce resource and is recycled (Perwak et al. 1980). Discharges 

from electroplating operations are either made directly to the water environment or indirectly via POTWs. 

Runoff from abandoned mines is estimated to contribute 314 metric tons annually to surface water 

(Perwak et al. 1980). These discharges are primarily insoluble silicates and sulfides and readily settle out 

into stream, river, or lake beds. Releases from manufactured products containing copper may be 

substantial, but are difficult to predict. Corrosion of copper in plumbing or construction may result in 

direct discharges or runoff into waterways. Copper and brass production releases relatively little copper 

to water. 
 

 

 

COPPER 138 

6. POTENTIAL FOR HUMAN EXPOSURE 

Waste water generated from copper mining operations comes from seepage, runoff from tailing piles, or 

utility water used for mine operation. The amount of waste water generated ranges from 0–300 L 

water/metric ton of ore mined for open pit copper mines and 8–4,000 L water/metric ton of ore mined 

underground (EPA 1980b). Copper concentrations in waste water from a selected open pit and 

underground copper mine were 1.05 and 0.87 ppm, respectively. Data regarding copper concentrations in 

waste water associated with selected concentrating, smelting, and refining operations can be found in 

EPA (1980b). Drainage from mining operations and abandoned mines has been shown to have an effect 

on copper content in local surface waters (see Table 6-7) with concentrations as high as 69,000 ppb being 

measured (Rösner 1998). 

Results of an EPA industrial effluent survey show that mean and maximum levels of copper in treated 

waste water from six industries exceeded 1 and 10 ppm, respectively (EPA 1981). These industries and 

their mean and maximum discharges in ppm are: inorganic chemicals manufacturing (<1.6, 18); 

aluminum forming (<160, 2,200); porcelain enameling (1.3, 8.8); gum and wood chemicals (1.4, 3.0); 

nonferrous metals manufacturing (1.4, 27.0) and paint and ink formulation (<l.0, 60.0). Emission factors 

in nanograms of copper released per L of water outflow have been estimated for various industries. These 

factors would enable estimation of an industry's copper releases if the discharge volumes were known 

(Nriagu and Pacyna 1988). 

Effluents from power plants that use copper alloys in the heat exchangers of their cooling systems 

discharge copper into receiving waters (Harrison and Bishop 1984). The largest discharges occur after 

start-up and decrease rapidly thereafter. At the Diablo Canyon Nuclear Power Station, a very high startup discharge containing 7,700 ppb of copper fell to 67 ppb after 24 hours (Harrison et al. 1980). During 

normal operation at two nuclear power stations 6.5x106

 cubic meters (1,700 million gallons) of seawater 

per day is used as cooling water for these facilities and discharged into the ocean with copper levels in the 

effluent ranging between 0.6 and 3.3 ppb (Harrison et al. 1980). This amounts to a total output of copper 

in the discharged seawater of 3.9–42 kg per day or 1,400–15,000 kg/annum from these two power plants. 

Except for after start-up of the cooling system, most of the soluble copper (that which passes through a 

0.45 μm filter) discharged was in bound forms (Harrison et al. 1980). During normal operation, <20% of 

the copper released was in the <1,000 molecular weight fraction, which contains the more available 

copper species. 

Copper sulfate is added directly to lakes, reservoirs, and ponds for controlling algae. However, the 

copper concentration in the water column generally returns to pretreatment levels within a few days 
COPPER 139 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-7. Concentrations of Copper in Water 

Sample type/ Concentration (ppb) 

source Location Range (mean) [median] Comments Reference 

Drinking water 

Private wells 

Private wells 

 Not specified 

River water 

Lake water 

Well water 

 School drinking 

water 

 Municipal water 

supply 

 Municipal water 

supply 

Groundwater 

 Representative 

sample 

Shallow 

monitoring well 

Surface water 

U.S. Geological 

Survey stations 

Nova Scotia, four 

communities 

New Bedford, 

Massachusetts 

Seattle, 

Washington 

Canada (National 

Survey) 

Canada (National 

Survey) 

Canada (National 

Survey) 

New Jersey 

Berlin, Germany 

Lower Saxony, 

Germany 

New Jersey 

Denver, Colorado 

United States 

40–200 

130–2,450, 53% of 

samples >1,000 ppm 

(330) 

(160) 

(450), 24% of samples 

>1,000 ppm 

≤5–530 [≤5] 

≤5–100 [≤5] 

≤5–220 [20] 

≤5–80 [≤5] 

≤5–100 [≤5] 

≤5–560 [40] 

≤5–110 [≤5] 

≤5–70 [≤5] 

10–260 [75] 

BD–10,200a

BD–7,800 

BD–8,500 

0.009–4.2 (0.561) 

<0.1–6.40 (0.183) 

<0.1–3.00 (0.106) 

[5.0] 

<1–14 [2] 

(4.2) [4.0] 

at tap, running water 

at tap, standing water 

at tap, running water 

running water 

standing water 

raw water 

treated water 

distributed water 

raw water 

treated water 

distributed water 

raw water 

treated water 

distributed water 

 first draw 

10-minute flush 

mid-day, first draw 

at tap, running water 

at tap, standing water 

at tap, running water 

1,063 samples, 90th 

percentile 64.0 ppb, 

maximum 2,783 ppb, 

groundwater may or 

may not be used for 

drinking water 

30 monitoring wells, 

22 with PVC casings 

and 8 with metal 

casings; samples 

obtained after purging 

well 20 minutes 

53,862 occurrences 

Maessen et al. 

1985 

Yannoni and 

Piorkowski 1995 

Maessen et al. 

1985 

Meranger et al. 

1979 

Meranger et al. 

1979 

Meranger et al. 

1979 

Murphy 1993

Zietz et al. 

2003a 

Zietz et al. 

2003b 

Page 1981 

Bruce and 

McMahon 1996 

Eckel and Jacob 

1988 
 

 

 

COPPER 

6. POTENTIAL FOR HUMAN EXPOSURE 

140 

Table 6-7. Concentrations of Copper in Water 

Sample type/ 

source Location 

Concentration (ppb) 

Range (mean) [median] Comments Reference 

 Representative New Jersey [3.0] 

sample 

Surface, marine East Arctic Ocean (0.126) 

Surface, marine Atlantic Ocean 0.0572–0.0210 

Pond Massachusetts <10–105 

Lakes Canada 1–8 (2) 

Lakes Great Lakes 629–834 (756) 

703–1,061 (870) 

540–1,098 (830) 

Representative 32-1,200 (736) 

samples, nearby 

to acidic mine 

drainage 

Representative 100–69,000 [1,200] 

samples from 

copper mining 

areas in Arizona 

a

BD = below detection limit 

PVC = Polyvinyl chloride 

590 samples, 90th 

percentile 9.0 ppb, 

maximum 261 ppb 

26 locations 0.5–1 m 

depth 

20 sites, 2 cruises, 0– 

1 m depth 

Low in summer, high 

in winter 

Acid sensitive lakes 

Lake Superior 

Lake Erie 

Lake Ontario 

12 samples taken 

from streams and 

ponds near 

abandoned coal 

mines in Indiana 

Samples obtained 

from the Cerbat 

Mountains mining 

area; 15 surface 

water sites with 

14 sites downstream 

from old tailings and 

adits 

Page 1981 

Mart and 

Nurnberg 1984 

Yeats 1988 

Kimball 1973 

Reed and 

Henningson 

1984 

Nriagu et al. 

1996 

Allen et al. 1996 

Rösner 1998 
COPPER 141 

6. POTENTIAL FOR HUMAN EXPOSURE 

(Effler et al. 1980; Perwak et al. 1980). The reduction in dissolved copper during this period was 

accompanied by an increase in particulate copper (e.g., sorption to algae or other organic matter, which 

settles into the sediments of these bodies of water). The copper in the settled particulates is in equilibrium 

with the water column, which greatly favors copper in a bound state. 

A potential source of copper release into waterways is leachate from municipal landfills. Copper 

concentrations in leachate obtained from waste sites have been found to vary widely. For example, 

copper concentrations in leachate from municipal landfills have been found to range from 0.005 to 

1,110 ppm (Christensen et al. 1994; Perwak et al. 1980; Roy 1994). Although copper was measured in 

these leachates, its origin may not be from copper contained within the waste site, but from the 

surrounding soils. Cyr et al. (1987) reported that leachate from three municipal landfills in New 

Brunswick, Canada, did not contain copper concentrations significantly above those in control samples 

representing the surrounding soil types. Therefore, the emissions of copper from landfills into leachates 

should be made relative to the contribution of copper from surrounding soils, as determined from 

appropriately selected control samples. 

Copper can enter surface waters as a result of agricultural runoff. For example, estimated loading rates of 

copper into surface water from irrigation water runoff near the Stillwater National Wildlife Refuge ranged 

from 0.307 to 8.34 mg/hour, depending on what period of the irrigation season samples were taken 

(Kilbride et al. 1998). The highest loading rates were obtained during the middle period (August through 

mid-September) of the irrigation season. The copper in the runoff water was found to be predominantly 

bound to drift material in the water (e.g., algae, vascular plants, invertebrates, vertebrates, and detritial 

material). 

Copper was detected in groundwater and surface water at 558 and 308 of the 906 NPL hazardous waste 

sites, respectively, where copper has been detected in environmental media (HazDat 2004). Copper was 

detected at concentrations ranging from 0.006 to 5.6 ppm (median concentration of 0.103 ppm) in offsite 

groundwater and 0.00025–590 ppm (median concentration of 0.0282 ppm) in offsite surface water 

(HazDat 2002). 

6.2.3 Soil 

An estimated 97% of copper released from all sources into the environment is primarily released to land 

(Perwak et al. 1980). These include primarily tailings and overburdens from copper mines and tailings 
 

 

COPPER 142 

6. POTENTIAL FOR HUMAN EXPOSURE 

from mills. The copper in tailings represents the portion of copper that could not be recovered from the 

ore and is generally in the form of insoluble sulfides or silicates (Perwak et al. 1980). These wastes 

accumulate in mining states. Other releases to land include sludge from POTWs, municipal refuse, waste 

from electroplating, iron and steel producers, and discarded copper products (e.g., plumbing, wiring) that 

are not recycled. The copper content of municipal solid waste is ~0.16%. Much of this waste is 

landfilled directly or is in the form of residues following incineration. Emission factors in milligrams of 

copper released per gram of solid waste have been estimated for various industries. These factors would 

enable estimation of an industry's copper releases in terms of total quantity of solid waste discharged. 

Sludge from sewage treatment plants is a major source of copper released to land (Nriagu and Pacyna 

1988). Agricultural products are believed to constitute 2% of the copper released to soil (Perwak et al. 

1980). However, even though the largest releases of copper are to land, uptake of copper in human 

populations through ingestion of copper in soil are expected to be minimal in comparison to the primary 

route of exposure through the ingestion of drinking water (see Section 6.5). 

Copper was detected in soil and sediment (e.g., lakes, streams, ponds, etc.) at 528 and 338 of the 906 NPL 

hazardous waste sites, respectively, where copper has been detected in environmental media (HazDat 

2004). Copper was detected at concentrations ranging from 0.01 to 182,000 ppm (median concentration 

of 0.103 ppm) in offsite soils and 0.022–14,000 ppm (median concentration of 43 ppm) in offsite 

sediments (HazDat 2002). 

6.3 ENVIRONMENTAL FATE 

When considering the environmental fate of a metal, it is not always possible to clearly separate the 

processes related to the transport and partitioning of a metal, its compounds, and complexes from those 

related to transformation and degradation of these metal species. Because of analytical limitations, 

investigators do not often identify the form of a metal present in the environment. A change in the 

transport or partitioning of a metal may result from the transformation of the metal from one form to 

another. For example, complexation of a metal with small organic compounds may result in enhanced 

mobility, while formation of a less-soluble sulfide would decrease its mobility in water or soil. 

Adsorption may be the result of strong bonds being formed (transformation) as well as weak ones. 

Characterizing weak and strong adsorption is dependent on the analytical method that is used and care 

should be exercised when comparing results from different studies. Deposition and general adsorption of 

copper are discussed in Section 6.3.1. Speciation, compound formation, and oxidation-reduction are 

examined in Section 6.3.2. 
 

 

COPPER 143 

6. POTENTIAL FOR HUMAN EXPOSURE 

6.3.1 Transport and Partitioning 

6.3.1.1 Ambient Air 

Copper is released to the atmosphere in the form of particulate matter or adsorbed to particulate matter. It 

is removed by gravitational settling (bulk deposition), dry deposition (inertial impaction characterized by 

a deposition velocity), in-cloud scavenging (attachment of particles by droplets within clouds), and 

washout (collision and capture of particles by falling raindrops below clouds) (Schroeder et al. 1987). 

The removal rate and distance traveled from the source will depend on a number of factors, including 

source characteristics, particle size, turbulence, and wind velocity. 

Gravitational settling governs the removal of large particles with mass median aerodynamic (MMA) 

diameters of >5 μm, whereas smaller particles are removed by the other forms of dry and wet deposition. 

The importance of wet to dry deposition generally increases with decreasing particle size. The 

scavenging ratio (ratio of the copper concentration in precipitation [ppm] to its air concentration [μg/m3

]) 

for large particles displays a seasonal dependence that reflects more effective scavenging by snow than by 

rain (Chan et al. 1986). Copper from combustion sources is associated with sub-micron particles. These 

particles remain in the troposphere for an estimated 7–30 days. In that time, some copper may be carried 

far from its source (Perwak et al. 1980). 

Rates of metal deposition (e.g., depositional fluxes) vary between dry and wet depositional processes and 

show spatial variability. Dry depositional fluxes of copper tend to decrease between highly urbanized 

area such as Chicago, Illinois with an average depositional rate of 0.06 mg/m2

/day, to less urbanized areas 

such as South Haven, Michigan with rate of 0.007 mg/m2

/day or areas with minimal anthropogenic 

activity such as Lake Michigan (between 6 and 10 km off shore) with a rate of 0.01 mg/m2

/day (Paode et 

al. 1998). Estimated copper deposition rates in urban areas are 0.119 and 0.164 kg per hectare per year 

(kg/ha/year) or 0.0326 and 0.0449 mg/m2

/day for dry and wet deposition, respectively (Schroeder et al. 

1987). Bulk deposition reportedly ranges from 0.002–3.01 kg/ha/year or 0.0005–0.825 mg/m2

/day 

(Golomb et al. 1997; Landing et al. 1995; Schroeder et al. 1987). For rural areas, the range of bulk 

deposition reportedly is 0.018–0.5 kg/ha/year or 0.0049–0.14 mg/m2

/day, and wet deposition is 

0.033 kg/ha/year or 0.009 mg/m2

/day. The washout ratio is 114,000–612,000 (μg/m3 rain)/(μg/m3 air) or, 

expressed on a mass basis, 140–751 (μg/kg rain)/(μg/kg air). In southern Ontario, Canada, where the 

average concentration of copper in rain was 1.57 ppb during 1982, 1.36 mg of copper was deposited 

annually per square meter, or 13.6 kg/ha, as a result of wet deposition (Chan et al. 1986). For central and 
COPPER 144 

6. POTENTIAL FOR HUMAN EXPOSURE 

northern Ontario, the mean concentrations of copper in rain were 1.36 and 1.58 ppb, respectively, and the 

annual wet depositions averaged in both instances 1.13 mg/m2

 or 11.3 kg/ha. 

For the majority of time, the concentration in air of toxic trace elements, like copper, in a study conducted 

by Sweet et al. (1993) approached levels measured at a rural site (Bondville, Illinois). These rural levels 

of airborne copper represented regional background levels in urban study sites with only episodic 

increases, depending on wind speed and direction and location relative to local point sources. In one 

urban study site (East St. Louis), smelters are the primary source of copper. Copper depositional fluxes 

follow an exponential decay as one transitions from urban to rural settings (Sweet et al. 1993). Soil is not 

the major source of copper in cities or nearby rural soils, but is the predominant source for copper in the 

atmosphere over more remote areas (Fergusson and Stewart 1992). Sources of copper in urban areas 

include coal combustion, soil, tire wear, and automobile emissions (Kim and Fergusson 1994). Copper 

emission from combustion processes is typically associated with fine particles; however, there can be 

instances where the highest concentrations of copper are measured in coarse particles obtained from 

paved and unpaved roads and industries (Paode et al. 1998). 

Estimated depositional velocities for fine particles (<2.5 μm) and coarse particles (2.5–10 μm) in urban 

(Chicago) and rural (Kankalee, Illinois) areas have been made (Pirrone and Keeler 1993). These are: 

urban, 0.25–0.46 cm/second and rural, 0.18–0.25 in (rural) Kankalee, Illinois for fine particles; and urban, 

1.47–2.93 cm/second and rural, 0.87–1.71 cm/second for coarse particles. The differences in velocities 

are due to higher surface roughness and wind velocities in Chicago. 

Copper concentrations in particulates formed in a controlled study of waste oil combustion are (in μg/g): 

687±11 (10 μm), 575±8 (50 μm), 552±12 (100 μm), 568±9 (300 μm), and 489±8 (500 μm). 

Approximately 25% of copper is in the 10 μm fraction and ~18% is in each of the larger fractions (e.g., 

50, 100, 300, and 500 μm) (Nerín et al. 1999). 

6.3.1.2 Ambient Waters 

The average concentrations of copper in Lakes Superior, Erie, and Ontario are 760, 870, and 830 ng/L, 

respectively (Georgopoulos et al. 2001; Nriagu et al. 1996). These values were derived from 

measurements taken from 11, 11, and 9 nearshore and offshore sampling sites at different points in the 

water column up to depths of 251, 55, and 145 meters for Lakes Superior, Erie, and Ontario, respectively 

(Nriagu et al. 1996). In Lake Ontario, the highest copper concentrations were found at nearshore 
 

 

 

 

COPPER 145 

6. POTENTIAL FOR HUMAN EXPOSURE 

sampling sites neighboring Buffalo, New York (887–1,051 ng/L), Rochester, New York (1,041– 

1,098 ng/L), and Kingston, Ontario (921–1,026 ng/L). The lowest concentrations of copper in Lake 

Ontario were measured in an offshore sampling site (540–710 ng/L) that was approximately 40 km from 

the Buffalo sampling site. 

The atmospheric input of copper into the Great Lakes is substantial, 330–1,470 ng/m2

/year, which 

amounts to a total deposition of 8.00–35.6x1013 ng/year. This input of copper accounts for 60–80% of the 

anthropogenic input into Lake Superior and 20–70% into Lakes Erie and Ontario (Georgopoulos et al. 

2001; Nriagu et al. 1996). The mean residency times of copper in sediments are estimated to be 15 years 

in Lake Erie and 101 years in Lake Superior. 

Much of the copper discharged into waterways is in particulate matter and settles out. In the water 

column and in sediments, copper adsorbs to organic matter, hydrous iron and manganese oxides, and clay. 

In the water column, a significant fraction of the copper is adsorbed within the first hour of introduction, 

and in most cases, equilibrium is obtained within 24 hours (Harrison and Bishop 1984). In fact, most of 

the copper in POTW effluent and surface runoff is already in the form of complexes (Sedlak et al. 1997). 

Copper in waste water discharged into Back River leading into Chesapeake Bay, Maryland, contained 

53 ppb of copper, of which 36 ppb (based on weight) were in the form of settleable solids (Helz et al. 

1975). The concentration of copper rapidly decreased downstream of the outfall so that 2–3 km from the 

outfall, the copper concentration had fallen to 7 ppb. The concentration of copper in sediment 2–3 km 

downstream from the outfall was about a factor of 10 higher than in uncontaminated areas (e.g., 

Rappahannock River). Based on their data and the results from other studies, Helz et al. (1975) estimated 

a total of 200 metric tons of copper entered the Cheasapeake Bay from the effluent discharged from waste 

treatment plants. 

Copper binds primarily to organic matter in estuarine sediment, unless the sediment is low in organic 

matter content. A study evaluated the importance of the absorption properties of different nonlithogenic 

components of aerobic estuarine sediment to copper binding by determining copper's adsorptivity to 

model components (phases) in artificial seawater (Davies-Colley et al. 1984). The phases included 

hydrous iron and manganese oxides, clay, aluminosilicates, and organic matter. The binding affinities 

varied by over a factor of 10,000 and were in the following order: hydrous manganese oxide > organic 

matter > hydrous iron oxide > aluminosilicates > clay (montmorillonite). The partition coefficients at pH 

7 for the more strongly bound phases (manganese oxide, iron oxide, and estuarine humic material), were 

6,300, 1,300, and 2,500, respectively. The affinity increased somewhat with pH; but did not vary 
COPPER 146 

6. POTENTIAL FOR HUMAN EXPOSURE 

appreciably when the salinity was reduced from 35 to 5%. Considering the compositional characteristics 

of estuarine sediment in terms of binding capacity, the results indicate that copper binds predominantly to 

organic matter (humic material) and iron oxides. Manganese oxide contributes only 1% to the binding 

because of its generally low concentration in sediment; the other phases are usually unimportant. These 

findings concur with results of selective extraction experiments (Badri and Aston 1983) and studies of the 

association of copper with humic material (Raspor et al. 1984). 

6.3.1.3 Ambient Soils 

Most copper deposited on soil from the atmosphere, agricultural use, and solid waste and sludge disposal 

will be adsorbed with greater concentrations of copper measured in the upper 5–10 centimeters of soil in 

comparison to lower soil depths, except in sandy soils where the lability of bound copper is greater 

(Breslin 1999; Giusquiani et al. 1992; Hutchinson 1979; Luncan-Bouché et al. 1997; Keller and Védy 

1994; Levy et al. 1992; Perwak et al. 1980). Copper's movement in soil is determined by a host of 

physical and chemical interactions of copper with the soil components. In general, copper will adsorb to 

organic matter, carbonate minerals, clay minerals, or hydrous iron and manganese oxides (EPA 1979; 

Fuhrer 1986; Janssen et al. 1997; Petruzzelli 1997; Tyler and McBride 1982). Sandy soils with low pH 

have the greatest potential for leaching. In a laboratory study, Luncan-Bouché et al. (1997) have shown 

that between 55 and 85% of copper bound to sand (with no other soil components added) is remobilized 

upon reduction of the pH from 9 to 4. In most temperate soils, the pH, organic matter, concentrations of 

metal oxyhydroxides and ionic strength of the soil solutions are the key factors affecting adsorption 

(Elliot et al 1986; Fuhrer 1986; Gerritse and Van Driel 1984; Janssen et al. 1997; Rieuwerts et al. 1998; 

Tyler and McBride 1982). The ionic strength and pH of the soil solution affect the surface charge of soils 

and thereby influence ionic interaction (Rieuwerts et al. 1998). Soil microorganisms also affect the 

absorption of copper in soils due to the uptake and assimilation of the metal by these microorganisms 

(Rieuwerts et al. 1998). However, it is not known how the rate of uptake and absorption capacity of the 

microorganisms for copper compares with the binding capacity and affinities of copper by organic matter 

in soils, such as humic and fulvic acids. When the amount of organic matter is low, the mineral content 

or Fe, Mn, and Al oxides become important in determining the adsorption of copper. Fuhrer (1986) 

reported that, in oxidized estuarine sediment, adsorption of copper is dominated both by amorphous iron 

oxide and humic material. 

Copper binds strongly to soils with high organic content (14–34% organic matter, dry weight) and the 

distribution of copper in the soil solution is less affected by changes in pH (within the range of pHs 
 

 

COPPER 147 

6. POTENTIAL FOR HUMAN EXPOSURE 

normally encountered in the environment) than other metals are (Gerritse and Van Driel 1984). In a 

laboratory study of competitive adsorption and leaching of metals in soil columns of widely different 

characteristics, copper eluted in a 0.01 M CaCl2 leaching solution much more slowly and in much lower 

quantities than Zn, Cd, and Ni from a low-pH and a high-pH mineral soils and not at all from peat soil, 

which contained the greatest amount of organic matter (Tyler and McBride 1982). Elliot et al. (1986) 

investigated at pH-dependent adsorption of the divalent transition metal cations Cd, Cu, Pb, and Zn in two 

mineral soils (silty clay loam, 0.5 g/kg organic dry weight, and sandy clay, 1.6 g/kg organic) and two soils 

containing considerable organic matter (loamy sand, 20.5 g/kg organic, and silt loam, 42.5 g/kg organic). 

Adsorption increased with pH, and Cu and Pb were much more strongly retained than Cd and Zn. 

Reduction in absorptivity after removal of the organic matter demonstrated the importance of organic 

matter in binding copper. In a study of clay soils, Wu et al. (1999) observed preferential copper binding 

to organic matter, but found higher binding affinities to fine (<0.2 μm) clay fractions once the organic 

matter had been removed. 

To determine the factors affecting copper solubility in soil, Hermann and Neumann-Mahlkau (1985) 

performed a study in the industrial Ruhr district of West Germany, which has a high groundwater table 

(10–80 cm from the surface) and a history of heavy metal pollution. Groundwater samples were taken 

from six locations and two soil horizons, an upper oxidizing loam, and a lower reducing loam. Total 

copper concentrations were high in the upper soil horizons and low in the lower horizons. Copper 

showed a pronounced solubility only in the oxidizing environment. In the reducing environment, 

solubility was low, possibly due to the formation of sulfides. 

The form of copper at polluted and unpolluted sites may affect its leachability, particularly by acid rain. 

The leaching of heavy metals by simulated acid rain (pH 2.8–4.2) was measured by applying this 

rainwater to columns containing humus layers obtained from sites in a Swedish spruce forest both near to 

and far from a brass mill (Strain et al. 1984). Leaching of copper increased considerably when water with 

a pH <3.4 was applied to soil from polluted sites. Acid rain produced from SOX emitted from smelters 

may increase the leachability of copper in areas affected by smelter stack emissions. The mobility of 

copper from soils was also found to increase following the introduction of 10–100 mM sodium chloride 

or calcium magnesium acetate deicing salts into soil (Amrhein et al. 1992). The concentration of sodium 

chloride or calcium magnesium acetate used in the study approximate those in runoff water produced 

from the melting of snow along salted roadways. 
 

 

 

 

COPPER 148 

6. POTENTIAL FOR HUMAN EXPOSURE 

Since, in the range of 0.01–1.97 mg of copper per liter of water, 25–75% of copper entering POTWs is 

removed in sludge, much of which is disposed of by spreading on land, it is important to ascertain 

whether copper in sludge is apt to leach into soil. Where it stands, this does not appear to be the case and 

leachate collected from the sludge-amended soil contained <12 ppb of copper (Perwak et al. 1980). In 

laboratory experiments, three sludges containing 51, 66, and 951 ppm (dry weight) of copper were 

applied to the top of soil columns containing four coastal plain soils. These soils, Sassafras loamy sand, 

Woodstown sandy loam, Evesboro loamy sand, and Matapeake silt loam, had similar pHs, 5.1–5.8, and 

contained 0.9, 1.4, 1.6, and 3.5% organic matter (dry weight), respectively. The sludge containing 

51 ppm copper was loaded on the soil columns at amounts that approximated field loadings of between 

0 and 90 metric tons per hectare; the sludges containing 66 and 951 ppm copper were loaded in amounts 

that approximated field loadings of between 0 and 180 metric tons per hectare. The columns were 

subsequently leached with distilled water at a flow rate of 2.5 cm/day for a total column application of 

25.4 cm of water. Only small amounts (<0.01–0.87 ppm) of copper were found in the leachate (Ritter and 

Eastburn 1978). This suggests that hazardous amounts of copper leach only slowly into groundwater 

from sludge, even from sandy soils. In another study, soil cores taken after sewage sludge were applied 

to grassland for 4 years showed that 74 and 80% of copper remained in the top 5 cm of a sandy loam and 

calcareous loam soil (Davis et al. 1988). Similar studies have also shown that copper is typically 

confined to the upper 5–10 cm of sludge-amended agricultural soils (Breslin 1999; Giusquiani et al. 

1992). In soils receiving long-term, heavy applications of sludge, high copper concentrations (471 mg/kg 

in comparison to 19.1 mg/kg in unamended control soils) were reported to depths of up to 25 cm 

(Richards et al. 1998). The mobility of copper into soil from sludge was found to be determined mainly 

by the amount of soil organic carbon and soil surface area (Domergue and Védy 1992; Gao et al. 1997). 

In addition, soils amended by sludge with low metal content were found to have increased sorption for 

copper due to the increased binding capacity provided by the “low metal” organics in the sludge 

(Petruzzelli et al. 1994). 

Similarly, copper remains in the surface layer when it is applied to soil as a liquid. Secondary sewage 

effluent spiked with 0.83 ppm of copper was applied weekly to four different soils. After 1 year of 

treatment, the concentration of copper in the surface horizons increased greatly: 50–76% of the applied 

copper was found in the upper 2.5 cm and 91–138% was found in the upper 12.7 cm (Brown et al. 1983). 

In a study of accumulation and movement of metal in sludge-amended soils, field plots received massive 

amounts of sewage over a period of 6 years. Two sludges (one containing industrial waste), with average 

copper contents of 0.29 and 23 ppm were incorporated into the top 20 cm of soil in the spring. Barley 

was grown and, after harvest, core samples of soil were taken down to 1 m. Some movement of copper 
COPPER 149 

6. POTENTIAL FOR HUMAN EXPOSURE 

into the 22.5–25 cm layer of soil was observed, but little, if any, below this zone. However, at this depth, 

the copper is still within the root zone of many important food crops and, therefore, is available for uptake 

into these plants. Also, the availability of the copper in soil, as determined by its extractability with 

diethylenetriamine pentaacetic acid (DTPA) and nitrate, remained constant over a 4-year period at all 

depths. From the results of other work, the major portion of the copper (40–74%) is expected to be 

associated with the organic, Fe-Mn-oxide and carbonate fractions of most soils (Ma and Rao 1997). 

6.3.1.4 Bioconcentration and Biomagnification 

The bioconcentration factor (BCF) of copper in fish obtained in field studies is 10–667, indicating a low 

potential for bioconcentration (Perwak et al. 1980). The BCF is higher in mollusks, such as oysters, and 

squid where it may reach 30,000 and 2.1x107

, respectively, (Perwak et al. 1980) and may present a major 

dietary source of copper that could be of concern for those individuals who regularly consume oysters, 

clams, or squid. Due to the fact that molluscs are filter feeders and copper concentrations are higher in 

particulates than in water, this is to be expected. On the other hand, there are limited data suggesting that 

there is little biomagnification of copper in the aquatic food chain (Perwak et al. 1980). For example, a 

study was conducted with white suckers and bullheads, both bottom-feeding fish, in two acidic 

Adirondack, New York, lakes (Heit and Klusek 1985). These lakes were known to have received 

elevated loadings of copper; but the suckers and bullhead had average copper levels of only 0.85 and 

1.2 ppm (dry weight) in their muscle tissue. The biomagnification ratio (the concentration of copper in 

fish compared to that in their potential food sources on a wet weight/wet weight basis) was <l, indicating 

no biomagnification in the food chain. Similarly, the copper content of muscle tissue of fish from coppercontaminated lakes near Sudbury, Ontario, did not differ significantly from that of the same fish species 

in lakes far from this source (Bradley and Morris 1986). 

No evidence of bioaccumulation was obtained from a study of pollutant concentrations in the muscle and 

livers of 10 mammal species in Donana National Park in Spain (Hernandez et al. 1985). The park is 

impacted by organochlorine compounds and heavy metals emitted from anthropogenic activities that 

surround the park. For example, the Guadalquivir River that flows through the park first flows through a 

major mining region in addition to a large urban area and industrial areas, carrying with it contaminants 

acquired from these sites. The animal species in the study were classified into three categories 

(herbivorous, omnivorous, and carnivorous) to ascertain if the pollutants were showing biomagnification 

in higher trophic levels of animals. No evidence of copper biomagnification in the food chain was 

observed. Likewise, in a study of a food web in a beech tree forest in Northern Germany, there was no 
COPPER 150 

6. POTENTIAL FOR HUMAN EXPOSURE 

evidence of biomagnification in tertiary consumers (e.g., vole, shrew, and mouse) compared to secondary 

consumers (e.g., earthworm, snail, beetle, and isopod) (Scharenberg and Ebeling 1996). A study of heavy 

metals in cottontail rabbits on mined land treated with sewage sludge showed that, while the 

concentration of copper in surface soil was 130% higher than in a control area, the elevation was 

relatively little in foliar samples and no significant increase in copper was observed in rabbit muscle, 

femur, kidney, or liver. Apparently, copper was not bioaccumulating in the food chain of the rabbit 

(Dressler et al. 1986). 

At the lowest levels of the food chain, there is little evidence of copper bioaccumulation. In a study of 

copper uptake in earthworms as a function of copper concentration (6–320 mg/kg dry weight) in sludge 

amended soils, a bioconcentration factor of <1 (0.67) was obtained (Neuhauser et al. 1995). In another 

example, a study of earthworms and soil from 20 diverse sites in Maryland, Pennsylvania, and Virginia, 

copper concentrations in earthworms showed a poor correlation with that in soil (Beyer and Cromartie 

1987). These results are consistent with the results of another study that also showed no clear correlation 

between copper concentrations in earthworm tissues and two soils that were heavily contaminated with 

heavy metals (copper concentrations of 242 and 815 mg/kg dry weight) (Marinussen et al. 1997). 

However, there is some evidence in one study for bioconcentration of copper at low copper 

concentrations in soil. Even though Scharenberg and Ebeling (1996) showed that there was no evidence 

for biomagnification of copper in a forest food web, their results did show that the total concentrations of 

copper in the secondary (18.3–192.0 mg/kg dry weight) and tertiary consumers (9.9–17.4 mg/kg dry 

weight) were higher than the concentrations of the metal in the dominant vegetation (5.3–10.9 mg/kg dry 

weight) and soil (1.8–5.8 mg/kg dry weight) in the ecosystem. 

Diks and Allen (1983) added copper to four sediment/water systems and studied the distribution of copper 

among five geochemical phases, namely, absorbed/exchangeable, carbonate, easily reducible (Mn-oxides 

and amorphous Fe-oxides), organic, and moderately reducible (hydrous Fe-oxides). The investigators 

then attempted to correlate the concentration in each phase with the copper uptake by tubificid worms. 

Only copper extracted from the manganese oxide/easily-reducible phase correlated with the copper 

content of worms at the 95% confidence level. This result suggests that the redox potential and pH in the 

gut of the worm is such that manganese oxide coatings are dissolved. The copper in the dissolved 

manganese oxide phase is now soluble and available for uptake by other organisms. 
COPPER 151 

6. POTENTIAL FOR HUMAN EXPOSURE 

6.3.2 Transformation and Degradation 

6.3.2.1 Air 

Few data are available regarding the chemical forms of copper in the atmosphere and their 

transformations. In the absence of specific information, it is generally assumed that metals of 

anthropogenic origin, especially those from combustion sources, exist in the atmosphere as oxides 

because metallic species are readily attacked by atmospheric oxidants. As these oxides age, sulfatization 

may occur, but only when SOX gases are present in the atmosphere in sufficient amount. For example, in 

Arizona, atmospheric copper oxide levels derived from copper smelters was strongly correlated with coemitted sulfur (Schroeder et al. 1987). 

In fog water, Cu(II) is reduced to Cu(I) by sulfite, which becomes enhanced by the fact that sulfite is also 

a ligand of and binds to Cu(I) (Xue et al. 1991). Concentrations of Cu(I) in fog water ranged between 

0.1 and 1 μM or, respectively, 4 and >90% of copper in the Cu(I) state. The reduction of Cu(II) to Cu(I) 

is pH dependent and occurs rapidly at pHs>6 (Xue et al. 1991). 

6.3.2.2 Water 

The Cu(I) ion is unstable in aqueous solution, tending to disproportionate to Cu(II) and copper metal 

unless a stabilizing ligand is present (EPA 1979; Kust 1978). The only cuprous compounds stable in 

water are insoluble ones such as Cu2S, CuCN, and CuF. Therefore, human exposures to copper will 

predominately be in the form of Cu(II). Copper in its Cu(II) state forms coordination compounds or 

complexes with both inorganic and organic ligands. Ammonia and chloride ions are examples of species 

that form stable ligands with copper. Copper also forms stable complexes with organic ligands such as 

humic acids, binding to -NH2 and -SH groups and, to a lesser extent, with -OH groups. Natural waters 

contain varying amounts of inorganic and organic species. This affects the complexing and binding 

capacity of the water and the types of complexes formed. In seawater, organic matter is generally the 

most important complexing agent (Coale and Bruland 1988). In water, the formation of ligands may 

affect other physicochemical processes such as adsorption, precipitation, and oxidation-reduction (EPA 

1979). More specific information on the transformation and degradation of copper in its cupric [Cu(II)] 

and cuprous [Cu(I)] states is given below. 

At the pH values and carbonate concentrations characteristic of fresh surface waters, most dissolved 

Cu(II) exists as carbonate complexes rather than as free (hydrated) cupric ions (Stiff 1971). 
 

 

COPPER 152 

6. POTENTIAL FOR HUMAN EXPOSURE 

Based on the results of a theoretical model, the major species of soluble copper found in freshwater, 

seawater, and a 50:50 combination of the freashwater and seawater over a pH range of 6.5–7.5 is Cu2+, 

Cu(HCO3)

+

, and Cu(OH)2 (Long and Angino 1977). 

The concentration of dissolved copper depends on factors such as pH, the oxidation-reduction potential of 

the water and the presence of competing cations (Ca2+, Fe2+, Mg2+, etc.), salts (OH-

, S2-, PO4

3-, CO32-), and 

anions of insoluble cupric-organic and -inorganic complexing agents. If the combination of a particular 

anion with copper forms an insoluble salt, precipitation of that salt will occur. The most significant 

precipitate formed in fresh surface waters is malachite (Cu2[OH]2CO3) (Sylva 1976). Other important 

precipitates are Cu(OH)2 (and ultimately CuO) and azurite (Cu3[OH]2[CO3]2). In anaerobic waters, Cu2S, 

Cu2O, and metallic copper forms and settles out (EPA 1979). The combined processes of complexation, 

adsorption, and precipitation control the level of free Cu(II) in water. The chemical conditions in most 

natural water are such that, even at relatively high copper concentrations, these processes will reduce the 

free Cu(II) concentration to extremely low values. 

As a result of the aforementioned physico-chemical processes, copper in water may be dissolved or 

associated with colloidal or particulate matter. Copper in particulate form includes precipitates, insoluble 

organic complexes, and copper adsorbed to clay and other mineral solids. In a survey of nine rivers in the 

United Kingdom, 43–88% of the copper was in the particulate fraction (Stiff 1971). A study using 

suspended solids from the Flint River in Michigan found that the fraction of adsorbed copper increased 

sharply with pH, reaching a maximum at a pH of 5.5–7.5 (McIlroy et al. 1986). 

The soluble fraction of copper in water is usually defined as that which will pass through a 0.45 μm filter. 

It includes free copper and soluble complexes as well as fine particulates and colloids. The soluble 

fraction may be divided according to the lability (e.g., the relative ability of the copper to dissociate from 

the bound form to the free ion) of the copper forms in the water. Categories range from the very labile 

(e.g., free metal ion, ion pairs, inorganic or organic complexes) to slowly or nonlabile (e.g., colloidally 

bound to inorganic colloidal phases of other metals such as Fe(OH)3 or FeOOH, or bound to high 

molecular weight organic material) metal (Tan et al. 1988). For example, in a typical study, 18–70% of 

dissolved copper in river water was labile and 13–30% was slowly labile (Tan et al. 1988). Various 

techniques may be used to classify the lability of different fractions of soluble copper; these techniques 

include solvent extraction, ion-specific electrodes, ion exchange, ultrafiltration, electrochemical methods 

such as anodic stripping voltammetry, and gel filtration chromatography (Harrison and Bishop 1984). 
 

 

COPPER 153 

6. POTENTIAL FOR HUMAN EXPOSURE 

The resulting classification depends on the specific procedure employed. Therefore, a comparison of the 

results of different researchers should be done in general terms 

The nature of copper's association with inorganic and organic ligands will vary depending on the pH, 

copper concentration, concentration of competing ligands, binding capacity of the ligands, and hardness 

or salinity of the water (Breault et al. 1996; Cao et al. 1995; Gardner and Ravenscroft 1991; Giusti et al. 

1993; Lores and Pennock 1998; Town and Filella 2000). In river water from the northwestern United 

States that had a relatively high pH (7.0–8.5) and alkalinity (24–219 ppm as CaCO3), inorganic species 

like CO3

2- and OH-

 were the most important ligands at high copper concentrations (McCrady and 

Chapman 1979). However, other species such as organic compounds were important at low copper 

concentrations. On the other hand, copper in samples from surface water of lakes and rivers in southern 

Maine with a relatively low pH (4.6–6.3) and alkalinity (1–30 ppm as CaCO3) was largely associated with 

organic matter (Giesy et al. 1978). The binding of copper to dissolved organics was found to be 

dependent on the specific organic chemical species (e.g., fulvic acid) and their concentrations in the 

surface water, the number of available binding sites per fulvic acid carbon, and the hardness of the water 

(Breault et al. 1996). Increasing water hardness results in deceased fulvic acid binding sites. This effect 

is due more to the depression of the solubility of high molecular weight fulvic acid in the presence of Ca 

and Mg ions than to competition of these ions with copper for fulvic acid binding sites. Increasing pH 

from 8 to 6 resulted in a 7-fold increase in the binding constant for Cu(II) with humic acid (Cao et al. 

1995). 

The extent to which copper binds to inorganic and organic ligands can be altered by materials carried in 

runoff. For example, after a period of rain in southeastern New Hampshire, inorganic constituents 

contributed more to copper binding in lakes and rivers than did dissolved organic matter (Truitt and 

Weber 1981). A green precipitate, confirmed to be malachite (Cu2[OH]2CO3) was formed in river water 

in Exeter. This water had the highest pH (7.4) and alkalinity (43.5 mg/L as CaCO3) than six other surface 

waters (e.g., three rivers, two reservoirs, a pond, and a swamp) with pH and alkalinity values of 5.7– 

7.4 and 1.7–41 mg/L, respectively. A computer simulation of the copper species in water of a pond and 

water obtained from an artesian well that fed the pond predicted that 98% of the copper in the artesian 

well water would exist as the free copper ion (Cu+2), whereas 88 and 63% of the copper in pond water 

would be bound to organics in the spring and fall, respectively (Giesy et al. 1983). These estimates were 

based on experimentally determined binding capacities of the organic matter in the two water sources and 

stability constants for the copper-organic matter complexes. 
 

 

COPPER 154 

6. POTENTIAL FOR HUMAN EXPOSURE 

Seawater samples obtained in a transect of the uppermost Narragansett Bay in August 1980 were 

analyzed for dissolved, particulate and organically bound copper to investigate the geochemistry of 

copper-organic complexes (Mills and Quinn 1984). Narragansett Bay is a partly mixed estuary in 

Massachusetts and Rhode Island that receives organic matter and metals from rivers, municipal and 

industrial effluents and from runoff. The Fields Point waste treatment facility accounts for 90% of the 

copper input into the bay through the Providence River with dissolved copper representing 60% of the 

total copper input. The concentrations of dissolved and organic copper ranged from 16.4 and 2.3 μg/kg, 

respectively, in the Providence River to 0.23 and 0.12 μg/kg, respectively, in Rhode Island Sound. 

Particulate copper concentrations in Narragansett bay ranged from 2.42 to 0.06 μg/kg and generally 

comprised 40% of the total copper in the bay. Analysis of the data indicated that ~75% of the dissolved 

copper that enters the bay from the Providence River is removed within the bay. 

Organic ligands may contain a variety of binding sites, and the strength of the resulting copper complexes 

will vary accordingly. Over 99.7% of the total dissolved copper in ocean surface water from the northeast 

Pacific was associated with organic ligands (Coale and Bruland 1988). The dominant organic complex, 

limited to surface water, was a strong ligand of biological origin. A second, weaker class of organic 

ligand was of geologic origin. An independent study showed the copper binds to humic material at a 

number of sites. The binding strength of the sites varied by two orders of magnitude (Giesy et al. 1986). 

The humic material in this study was derived from nine surface waters in the southeastern United States. 

Soluble copper in water discharged from a nuclear power station was primarily complexed with organic 

matter in the 1,000–100,000 molecular weight range (Harrison et al. 1980). Ten to 75% of the discharged 

copper was in particulate form. 

The bioavailability of Cu(I) has been difficult to access due to its thermodynamic instability in the 

environment (Xue et al. 1991). Cu(I) is a reactive reducing agent, and its concentrations in the 

environment will be determined both by its reaction with oxygen and other oxidants in the aqueous 

environment to form Cu(II) and its rate of production through the reaction of Cu(II) with reducing agents 

(Sharma and Millero 1988). Investigators have shown the presence of Cu(I) in seawater, which is thought 

to occur through the reduction of Cu(II) to Cu(I) by photochemical processes (Moffett and Zika 1987; 

Xue et al. 1991). The detection of Cu(I) in seawater is likely the result of the stabilization of Cu(I) 

through complex formation with chloride ions. Cu(II)-organic complexes absorb radiation at wavelengths 

>290 nm and can undergo charge transfer reactions where the Cu(II) is reduced and a ligand is oxidized. 

Photochemically-generated reducing agents such as O2

- and H2O2 in the surface water of oceans and 
 

 

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6. POTENTIAL FOR HUMAN EXPOSURE 

possibly other natural waters (e.g., lakes) may contribute to the reduction of Cu(II) to Cu(I) in these 

waters (Moffett and Zika 1987; Sharma and Millero 1988). 

Experiments performed in synthetic seawater and water from Biscayne Bay, Florida, showed that in the 

reduction of Cu(II) to Cu(I), the rate was first-order in Cl-

 and second-order in H2O2 (Sharma and Zika 

1987). The chloride ion is thought to be required for stabilizing Cu(I) by forming the copper complex 

CuClOH-

, although experimental evidence suggests that the reduction of Cu(II) may also occur through 

the formation of a complex between Cu(II) and HO2

-

. Experiments have shown that as much as 15% of 

copper in surface seawater exists as Cu(I). Photochemical reduction by sunlight increases the percentage 

of free Cu(I). The photochemical reduction mechanism is supported by the observation that the Cu(I) 

concentration is highest in the surface layer of seawater and that the hydrogen peroxide concentration 

increases in parallel to that of Cu(I) (Moffett and Zika 1987). In addition, the percentage of free Cu(I) is 

highest on the surface. 

Once Cu(I) is formed, its lifetime is determined by its rate of oxidation to Cu(II). After Biscayne Bay 

water was exposed to sunlight for 5 hours, the Cu(I) formed was oxidized to Cu(II). The half-life of Cu(I) 

was 12 hours. Primarily, dissolved oxygen is responsible for this oxidative reaction. Since the oxidation 

of Cu(I) by O2 in distilled water occurs in <6 minutes, Cu(I) in seawater apparently is stabilized by the 

formation of complexes. In the presence of humic acids, the oxidation of Cu(I) occurs very rapidly. In 

coastal water off the Everglades in Florida, no Cu(I) was detected. This is due to the binding of Cu(II) in 

organic complexes and the high concentration of radical oxidants in the water. Sharma and Millero 

(1988) measured the rate of Cu(I) oxidation in seawater as a function of pH, temperature and salinity. 

The rate of reaction increased with pH and temperature, and decreased with increasing ionic strength (or 

- salinity). The results suggested that the rates are controlled by Mg2+, Ca2+, Cl- and HCO3 through their 

involvement in complex formation and ligand exchange. 

6.3.2.3 Sediment and Soil 

The adsorption of copper to soil and sediment was discussed in Section 6.3.1 under transport and 

partitioning, even though adsorption may really be complexation and transformation. Understanding the 

transport and fate of copper and its compounds in soils and sediments is important because these 

compartments tend to be large reservoirs of copper and could have an impact on human exposures to 

copper. Copper concentrations in drinking water obtained from groundwater can be affected by the 

leaching of copper from soil. Reservoir sediments have been shown to be sources of copper in drinking 
 

 

 

 

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6. POTENTIAL FOR HUMAN EXPOSURE 

water (Georgopoulos et al. 2001). Although much of the copper is bound to inorganic or organic matrices 

in soils and sediments, there is the potential for release of copper into pore water within soils and 

sediments depending on the extractability of the copper and soil conditions. There is evidence to suggest 

that copper binding in soil is correlated with pH, cation exchange capacity, the organic content of the soil, 

the presence of manganese and iron oxides and even the presence of inorganic carbon such as carbonates 

(Petruzzelli 1997; Rieuwerts et al. 1998). At pHs above 5, absorption of copper from pore water on to 

soil components becomes a significant process, whereas at pHs below 5, copper largely remains in pore 

water and is therefore mobile in soil (Perwak et al. 1980). However, broad generalizations about the 

lability of copper in soils are not possible since the situation will differ among different soil types and 

environmental conditions. More specific information on the lability (e.g., extractability) of copper from 

differing soils and conditions is given below. 

The form of copper in soil is determined by measuring the extractability of the copper with different 

solvents. Extractability is a function of the nature of the soil and the form of copper deposited in the soil. 

If a relatively labile form of copper is applied, binding to inorganic and organic ligands may occur, as 

well as other transformations. On the other hand, if a mineral form is deposited, it would be unavailable 

for binding. The capacity of soil to remove copper and the nature of the bound copper were evaluated by 

incubating 70 ppm of copper with 5 g samples of soil for 6 days (King 1988). Twenty-one samples of 

soils (10 mineral and 3 organic) from the southeastern United States were included in the study. Some 

soil samples were taken from the subsoil as well as the surface. The amount of adsorbed copper ranged 

from 36 to 100%, of which 13–100% was nonexchangeable when extracted with KCl. Removal of 

copper from solution was much higher with surface soils than with subsurface sandy soils; 95–100% of 

the copper was removed by five of the mineral surface soils and all three organic soils. The percentage of 

copper that was nonexchangeable was relatively high in all but some of the acid subsoils. While the 

fraction of exchangeable copper was not dependent on pH in surface soils, 96% of the variation in 

exchangeability was correlated with pH in subsoils. The soil/water partition coefficient for copper was 

>64 for mineral soils and >273 for organic soils. Of the eight heavy metals in the study, only Pb and Sb 

had higher partition coefficients than copper. Most of the copper in Columbia River estuary sediment and 

soil was correlated with inorganic carbon (e.g., carbonate), but not with the amount of extractable Fe or 

the organic carbon content of the sediment (Fuhrer 1986). 

The amount of ammonium acetate- and DTPA-extractable copper in wetland soil/sediment resulting from 

atmospheric deposition from smelters in Sudbury, Ontario, showed the same pattern as total copper, 

despite random variations in soil pH, redox potential and organic carbon (Taylor and Crowder 1983). 
COPPER 157 

6. POTENTIAL FOR HUMAN EXPOSURE 

Therefore, in this case, soil characteristics were not the dominant factors determining extractability and 

availability, but rather the form of copper that was deposited. The median concentrations of total copper, 

ammonium acetate-extractable copper, and DTPA-extractable copper at 25 sample sites were 371, 49, and 

98 ppm, respectively. 

In another study of copper partitioning in nine different contaminated soils, sequential extractions were 

used to operationally define six soil fractions in decreasing order of copper availability: water soluble > 

exchangeable > carbonate > Fe-Mn oxide > organic > residual (Ma and Rao 1997). The results of this 

study showed that the distribution of copper in these six soil fractions differed depending on the total 

copper concentration in the soil. As the copper concentration increased above 240 mg/kg, between 

69 and 74.4% of the total copper was found in the water soluble, carbonate, Fe-Mn oxide, and organic 

fractions. In relatively uncontaminated soils (<240 mg/kg copper), between 97.6 and 99.6% of the copper 

was found to be associated with the residual fraction. 

Within the estuarine environment, anaerobic sediments are known to be the main reservoir of trace 

metals. Under anaerobic conditions, cupric salts will reduce to cuprous salts. The precipitation of cupric 

sulfide and the formation of copper bisulfide and/or polysulfide complexes determine copper's behavior in 

these sediments (Davies-Colley et al. 1985). In the more common case where the free sulfide 

concentration is low due to the controlling coexistence of iron oxide and sulfide, anaerobic sediment acts 

as a sink for copper, that is, the copper is removed from water and held in the sediment as an insoluble 

cuprous sulfide. However, in the unusual situation where the free sulfide concentration is high, soluble 

cuprous sulfide complexes may form, and the copper concentration in sediment pore water may then be 

high. 

In sediment, copper is generally associated with mineral matter or tightly bound to organic material 

(Kennish 1998). As is common when a metal is associated with organic matter, copper generally is 

associated with fine, as opposed to coarse, sediment. Badri and Aston (1984) studied the association of 

heavy metals in three estuarine sediments with different geochemical phases. The phases were identified 

by their extractability with different chemicals and termed easily or freely leachable and exchangeable; 

oxidizable-organic (bound to organic matter); acid-reducible (Mn and Fe oxides and possibly carbonates); 

and resistant (lithogenic). In the three sediments, the nonlithogenic fraction accounted for ~14–18% of 

the total copper and the easily exchangeable component was 5% of the total copper. In addition, the 

compositional associations of copper in sediment samples taken from western Lake Ontario were 

analyzed employing a series of sequential extractions (Poulton et al. 1988). The mean and standard 
 

 

COPPER 158 

6. POTENTIAL FOR HUMAN EXPOSURE 

deviation percentages of copper in the various fractions were: exchangeable, 0 (0); carbonate, 0.1 (0.3); 

iron or manganese oxide-bound, 0.2 (0.3); organic-bound, 40 (11); and residual, 60 (8). Another study 

found that 10–20% of the copper in Lake Ontario sediment samples was bound to humic acids, with 

virtually all of the copper bound to organic matter (Nriagu and Coker 1980). The concentration of copper 

associated with humic acids was 21–40 times greater than in the sediment as a whole. 

6.3.2.4 Other Media 

Copper is an essential nutrient in plant metabolism. Therefore, uptake of copper from soil in plants 

through the roots is a natural and necessary process, a process that is actively regulated by the plant 

(Clemens 2001). The uptake of copper into plants is dependent on the concentration and bioavailability 

of copper in soils. The bioavailability of copper is determined largely by the equilibrium between copper 

bound to soil components and copper in soil solution. As noted in the discussion of copper binding in 

soils (Section 6.3.1.3), this is determined by copper concentrations in soil, soil type, soil components, pH, 

oxidation-reduction potential in the soil, and concentrations of other cations and anions in the soil, etc. 

(Rieuwerts et al. 1998). Other factors include root surface area, plant genotype, stage of plant growth, 

weather conditions, interaction with other nutrients in the soil and the water table (Gupta 1979). Liming 

is another factor that affects copper uptake. For example, liming acidic soils has been shown to increase 

copper uptake in hay, but to decrease copper uptake in wheat (Gupta 1979). However, the effect that 

liming has on increasing soil pH does not appear to be the overriding mechanism behind the changes in 

copper uptake in plants, even though there is evidence that the addition of lime to soil to increase the pH 

to 7 or 8 reduces copper availability to some plants (Perwak 1980). This is evidenced by the fact that 

changes in pH (5.4–8.0) have been found to have little effect on copper concentrations in plant tissues 

(Gupta 1979). 

6.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT 

6.4.1 Air 

Human exposure to copper in air comes from both natural and anthropogenic sources. For the general 

population, exposures to copper concentrations in air average between 5 and 200 ng/m3

. The 

concentrations of copper in air can be higher in the proximity of major sources such as smelters, mining 

operations, and combustion sources (e.g., power plants, incinerators, automobiles, etc.). The results of 
 

 

COPPER 159 

6. POTENTIAL FOR HUMAN EXPOSURE 

several studies in which concentrations of copper in air were reported and described below and are 

summarized in Table 6-8. 

According to the EPA's National Air Surveillance Network report for the years 1977, 1978, and 1979, 

median copper concentrations were 133, 138, and 96 ng/m3

, respectively, for urban samples and 120, 179, 

and 76 ng/m3

 for nonurban samples, respectively (Evans et al. 1984). In this study, 10,769 urban and 

1,402 nonurban air samples collected for 24 hours were analyzed. For 1977, 1978, and 1979, 1% of 

urban samples exceeded 1,156, 975, and 843 ng/m3

, respectively, and 1% of nonurban samples exceeded 

1,065, 1,396, and 645 ng/m3

, respectively. The maximum urban and nonurban copper concentrations 

reported were 4,625 and 4,003 ng/m3

, respectively. Davies and Bennett (1985) reported average 

atmospheric copper concentrations of 5–50 ng/m3

 in rural areas and 20–200 ng/m3 in urban locations. 

The concentrations in rural areas are considerably lower than those reported in the EPA survey. Data 

from many urban locations in the United States show concentrations of copper associated with particulate 

matter ranging from 3 to 5,140 ng/m3

 (Schroeder et al. 1987). Remote and rural areas have 

concentrations of 0.029–12 and 3–280 ng/m3

, respectively. The levels reported by Schroeder et al. (1987) 

are consistent with those obtained in a study of airborne trace elements in national parks (Davidson et al. 

1985). In the Smokey Mountain National Park, the copper concentration in air was 1.6 ng/m3

, while in 

the Olympic National Park, where several locations were monitored, 3.3–6.7 ng/m3

 of copper was 

measured in the atmosphere. The lower copper concentrations found in Smokey Mountain Park 

compared with those in the Olympic National Park have been attributed to greater vegetative cover and 

higher moisture in the former and larger amounts of exposed rock and soil in the latter. Average copper 

crustal enrichment factors (the concentration of copper in air compared with the average concentration in 

the earth's crust) were 31 and 76, respectively. 

As part of the Airborne Toxic Element and Organic Substances (ATEOS) project for determining patterns 

of toxic elements in different settings, three urban areas (Camden, Elizabeth, and Newark) and one rural 

site (Ringwood) in New Jersey were studied during two summers and winters between 1981 and 1983 

(Lioy et al. 1987). Each site was sampled every 24 hours for 39 consecutive days. As an example, the 

geometric mean copper concentrations in the summer of 1983 were 16.0, 21.0, 21.0, and 6.0 ng/m3

 for 

Camden, Elizabeth, Newark, and Ringwood, respectively. In the winter of 1983, the mean copper 

concentrations were slightly higher with values of 21.0, 36.0, 33.0, and 63.0 ng/m3

, respectively. The 

levels of copper measured in these industrial urban areas are considerably higher than the mean values 

reported in the National Air Surveillance survey where arithmetic means of 0.201 and 0.259 ng/m3

 for 

copper in air were obtained in1978 and 1979, respectively (Evans et al. 1984). Summer and winter 
 

 

COPPER 160 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-8. Concentrations of Copper in Air 

Concentrationa

 (ng/m3) 

Date/sample Location (mean) [median] Comments Reference 

1977, urban United States [133], 43390, 1,15699 4,648 samples, EPA 1984 

(207.5), 3,296max National Survey 

1978, urban United States [138], 43090, 97599 3,615 samples, EPA 1984 

(200.8), 4,625max National Survey 

1979, urban United States [96], 36390, 51999 2,507 samples, EPA 1984 

(259.3), 1,627max National Survey 

1977, United States [120], 45090, 1,06599 709 samples, National EPA 1984 

nonurban (193.2), 16,706max Survey 

1978, United States [179], 60790, 1,39699 458 samples, National EPA 1984 

nonurban (265.7), 1,396max Survey 

1977, United States [76], 32290, 64599 235 samples, National EPA 1984 

nonurban (141.7), 4,003max Survey 

Urban 20–200, [50] Representative values Davies and 

Rural 5–50, [20] Bennett 1985 

Remote 0.29–12 Values from literature Schroeder et 

Rural 3–280 survey al. 1987 

 Urban Canada 17–500 

 Urban United States 3–5,140 

 Urban Europe 13–2,760 

 Urban Other 2.0–6,810 

1979, remote Smokey Mountain (1.6) Above canopy, crustal Davidson et al. 

National Park enrichment factor 31 1985 

1980, remote Olympic National 3.3–6.7, (5.6) Crustal enrichment Davidson et al. 

Park factor 76 1985 

1981, 1982, Camden, New 16.0–18.0b

, 100.0max Seasonal variations Lioy et al. 1987 

summer Jersey noted; three urban 

 Elizabeth, New 21.0–29.0, 120.0max areas and one rural 

Jersey area. 

Newark, New Jersey 25.0–33.0, 131.0max

 Ringwood, New 13.0–63.0, 77.0max 

Jersey 

1982, 1983, Camden, New 17.0–21.0, 231.0max

winter Jersey 

 Elizabeth, New 28.0–36.0, 493.0max 

Jersey 

Newark, New Jersey 21.0–27.0, 380.0max

 Ringwood, New 6.0–18.0, 29.0max 

Jersey 

a

Percentile level and maximum indicated as subscripts. 

b

Concentrations in Lioy et al. (1987) are geometric means, unless otherwise noted. 
 

 

COPPER 161 

6. POTENTIAL FOR HUMAN EXPOSURE 

maxima in the four ATEOS study areas were: 100.0 and 131.0 ng/m3 in Camden, 231.0 and 493.0 ng/m3 

in Elizabeth, 131.0 and 380.0 ng/m3

 in Newark, and 77.0 and 29.0 ng/m3 in Ringwood, respectively. 

Copper follows the same pattern as other heavy metals, in that increased copper levels are present in 

winter in urban areas and in summer in rural areas. No explanation for this pattern has been offered. 

Anderson et al. (1988) performed a study of the atmospheric aerosols collected at a site in Chandler, 

Arizona, over a 12-day period in February and March 1982. Several major copper smelters are located 

~120 km to the southeast, which were upwind of the sampling site during approximately 50% of the study 

period. Particles containing >0.5% Cu were termed 'Cu-bearing' particles; 5.6% of the fine (0.4 to ~2 μm) 

particles collected were in this category. The most abundant type of Cu-bearing particle, representing 

74% of the total, was associated with sulfur. However, the analysis was not able to specify the form of 

sulfur present. These particles were often associated with Zn, Fe, Pb, As, and Ca. Sixteen percent of the 

Cu-bearing particles were associated with silicon and 4% were associated with chloride. The 

concentration of Cu-S particles was highest when the surface and upper level winds were from the 

southeast to the east, and reached a maximum 1–2 days after the winds began to blow. Therefore, the 

smelters to the southeast appear to be the probable source. The particles associated with silicon and 

chlorine did not show any apparent correlation with wind and were either from a diffuse regional source 

or a local source. 

Mine waste dump sites are a source of airborne copper carried in dust (Table 6-9). Particle size 

distribution and the concentration of copper in particle size ranges differ depending on the mine waste site 

(Mullins and Norman 1994). For example, the mean concentrations (ppm, w/w) of copper in dust 

(<10 μm particle size range) collected at four mine waste dump sites in Butte, Montana, were 3,370 (Gray 

Rock), 1,950 (Corra), 1,960 (Late Acquisition), and 2,570 (Railroad Bed). 

Mean concentration ranges of copper in remote (any area of lowest copper concentration such as the 

Antarctic or Arctic) and rural (any site that represents a regional background that is not directly 

influenced by local anthropogenic emissions) precipitation ranges were 0.013–1.83 and 0.68–1.5 ppb, 

respectively, based on a weight per unit volume basis (Barrie et al. 1987). Although an earlier survey 

referred to by these investigators (Galloway et al. 1982) yielded much higher values, 0.060 and 5.4 ppb, 

these were ascribed to sample contamination. The mean concentration of copper in rain reported in an 

extensive study in southern Ontario, Canada, was 1.57 (0.36 standard deviation) ppb during 1982 (Chan 

et al. 1986). These concentrations showed little spatial variability. Concentration of copper 
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6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-9. Particle Size Distributions and Total Copper Concentrations in Dust 

Collected at Four Mine Waste Pump Sites in Butte, Montana 

Percent in total Concentration of 

Site Particle size (μm) dust collected copper (ppm, w/w) 

Corra 4.7–10 76.6±4.8 1,550 

1.1–4.7 20.9±0.63 3,110 

<1.1 1.9±0.14 4,900 

Gray rock 4.7–1.0 

1.1–4.7 

84.5±0.93 

13.6±0.82 

3,240 

4,120 

<1.1 1.9±0.14 4,370 

Railroad bed 4.7–10 61.5±1.06 2,580 

1.1–4.7 31.3±0.96 2,850 

<1.1 7.2±0.26 1,400 

Late acquisition 4.7–10 

1.1–4.7 

70.3±1.36 

25.0±1.18 

1,560 

2,730 

<1.1 4.7±0.44 3,330 

Source: Mullins and Norman 1994 
COPPER 163 

6. POTENTIAL FOR HUMAN EXPOSURE 

in cloud water over Olympic Peninsula in Washington State has been measured at 1.7±1.6 μg/L (airequivalent mean concentration of 0.5 ng/m3

) (Vong et al. 1997). 

The concentration of copper in rain samples taken within 2–15 km downwind of the Claremont, New 

Hampshire, municipal waste incinerator was found to range from 0.11 to 2.12 μg/L with a mean 

concentration of 0.87 μg/L. The total mean deposition rate of airborne copper from rain was measured to 

be 4.0 μg/m2

/day for the eight sampling sites used in the study (Feng et al. 2000). However, copper 

deposition from automobile emissions, as measured by the concentration of copper in snow, did not vary 

significantly as a function of distance (15–150 meters) from an expressway in Montreal, Canada. Mean 

concentrations of copper in the snow (expressed as mg/L [and standard deviations]) were measured as 

0.051 (0.073), 0.065 (0.127), 0.034 (0.027), and 0.044 (0.051) at 15, 20, 15, and 150 meters, respectively 

(Loranger et al. 1996). 

Airborne concentrations of copper in the indoor atmosphere within homes located in Suffolk and 

Onondaga counties in New York average between 8 and 12 ng/m3

 (Koutrakis et al. 1992). The 

concentration was significantly affected by the use of kerosene heaters, which were found to emit copper 

into the indoor air at a rate of 15,630 ng/hour (Koutrakis et al. 1992). 

Elevated levels of copper in fog water have been observed 3 km downwind from a refuse incinerator in 

Switzerland (Johnson et al. 1987). High concentrations of copper were associated with low pH. The 

maximum concentration, 673 ppb, occurred at pH 1.94; levels >127 ppb were associated with pH values 

<3.6. Copper(II) concentrations in fog water from the central valley of California ranged from 1.7 to 

388 ppb (Miller et al. 1987). The source of the copper was not investigated. The highest values were 

recorded just as the fog was dissipating. 

6.4.2 Water 

Copper is widely distributed in water since it is a naturally occurring element. Copper levels in surface 

water range from 0.5–1,000 ppb, with a median of 10 ppb; seawater contains <1–5 ppb (Davies and 

Bennett 1985; Mart and Nurnberg 1984; Page 1981; Perwak et al. 1980; Yeats 1988). The results of 

several studies in which copper was detected in drinking water, groundwater, and surface water are 

described in this section and summarized in Table 6-7. The information in Table 6-7 demonstrates that 

copper concentrations in drinking water can vary widely (≤5–10,200 ppb) and can exceed the action 

limits of 1,300 ppb that have been set for copper in drinking water (EPA 1991). The table also 
COPPER 164 

6. POTENTIAL FOR HUMAN EXPOSURE 

emphasizes the importance of running tap water before using it and the need to control corrosion of 

piping in water distribution systems. 

Copper concentrations in drinking water vary widely as a result of variations in pH, hardness of the water 

supply and copper released from the water distribution system (Davies and Bennett 1985; Yannoni and 

Piorkowski 1995). Copper concentrations in drinking water range from a few ppb to 10 ppm. A 

Canadian national survey of copper and other metals in drinking water was conducted from November 

1976 to January 1977 (Meranger et al. 1979). Supplies from 70 municipalities representing 38% of the 

Canadian population were included in the survey, including 50 derived from river or lake water and 

20 derived from groundwater. Unfiltered raw, treated and distributed drinking waters were analyzed. 

Whether the water was derived from river, lake, or well water did not significantly affect the copper 

concentration in the raw water. Only in a few supplies did copper levels in raw water exceed 20 ppb and 

only one of these was derived from groundwater. The results in groundwater contrast with those of Page 

(1981) in New Jersey, in which over 100 wells contained copper levels in excess of 64 ppb. However, 

that study included groundwater that was a source of drinking water, in addition to groundwater that was 

not. The copper concentration in Canadian treated water was generally ~10 ppb (Meranger et al. 1979). 

In 20% of the samples, the copper level in distributed water was significantly higher than the treated 

water. The increase was greater in areas where the water was soft and corrosive, thus enhancing leaching 

of copper from the distribution system. 

Elevated concentrations of copper in drinking water can result as a consequence of leaching processes 

that occur in water distribution systems. A study of 1,000 water samples from random households in 

Ohio found that ~30% contained copper levels >1 ppm (Strain et al. 1984). The highest copper level in 

the study was 18 ppm. In a study of private water wells in four communities in Nova Scotia, Maessen et 

al. (1985) found that the concentrations of copper increased in water that remained in the distribution 

system overnight, indicating that copper was mobilized from the distribution system. Whereas the level 

of copper in running water was generally very low, that in the standing water was variable and exceeded 

1.0 ppm in 53% of the homes. Similar results were reported for U.S. cities (Maessen et al. 1985; Schock 

and Neff 1988; Strain et al. 1984). In a study in Seattle, Washington, the mean copper concentrations in 

running and standing water were 0.16 and 0.45 ppm, respectively, and 24% of the standing water samples 

exceeded 1.0 ppm (Maessen et al. 1985). The difference in copper level between standing and flushed 

systems became evident at pH 7 and increased with decreasing pH (Strain et al. 1984). Copper levels in 

school drinking water were found to differ by 3-fold between first draw and 10-minute flush water 

samples, irrespective of the corrosiveness of the water (Murphy 1993). However, the concentration of 
COPPER 165 

6. POTENTIAL FOR HUMAN EXPOSURE 

copper in both first draw and 10-minute flush samples decreased by approximately 10-fold as the 

corrosiveness of the water decreased. Increasing pH in water distribution lines has been found to result in 

an overall decrease in metal concentrations. For example, increasing the pH of water from 7.5 to 8.5 in 

distribution lines decreased copper concentration by 50% (Yannoni and Piorkowski 1995). 

In homes with copper piping, the mean concentration of copper in tap water has been shown to decline 

with the age of the home. In a sampling of tap water of 2,619 households in Berlin, Germany, that are 

supplied with municipal drinking water, the mean concentration of copper decreased from 0.77 ppm in 

homes with stated ages of 0–<5 years to 0.23 ppm in homes with stated ages of 35–<40 years (Zietz et al. 

2003a). In another study of 1,619 homes in Lower Saxony, Germany, the mean concentration of copper 

in first draw tap water decreased from 0.37 ppm in homes with stated ages of 0–<5 years to 0.05 ppm in 

homes with stated ages of 35–<40 years (Zietz et al. 2003b). These decreases of copper concentration 

with age were attributed to a buildup of a surface layer on the piping that reduced corrosion. However, in 

these same two studies, it was found that the concentration of copper in tap water began to increase with 

increasing age in homes with stated ages of >45 years. This increase in copper concentration was 

attributed to the increased probability of repair or partial placement (or unknown total replacement) of 

piping in these homes. 

In a study of groundwaters and surface waters throughout New Jersey in which >1,000 wells and 

600 surface sites were sampled, the median copper levels in groundwater and surface water were 5.0 and 

3.0 ppb, respectively (Page 1981). The respective 90th percentile and maximum levels were 64.0 and 

2,783.0 ppb for groundwater and 9.0 and 261.0 ppb for surface water. The pattern of contamination in 

surface water correlates with light hydrocarbons, while that in groundwater correlates with heavy metals. 

This suggests that the sources of contamination of surface water and groundwater are different. The 

nature of the sites with elevated levels of copper was not indicated. 

The geometric mean (standard deviation) and median concentration of dissolved copper in surface water 

based on 53,862 occurrences in EPA's STORET database are 4.2 (2.71) and 4.0 ppb, respectively (Eckel 

and Jacob 1988). Higher concentrations tend to be found in New England, the western Gulf and the lower 

Colorado River (Perwak et al. 1980). The finding of high concentrations of copper species in minor river 

basins reported in EPA's STORET database in 1978 revealed that sources of copper in the Gila, Coeur 

D'Alene, and Sacramento River Basins appear to be primarily mining activities, especially abandoned 

sites (Perwak et al. 1980). Generally, the high concentrations (>120 μg/L) were generally observed at 

localized stations and correlated with low pH of the surface water. However, in another study concerning 
COPPER 166 

6. POTENTIAL FOR HUMAN EXPOSURE 

75 Canadian headwater lakes sensitive to acid rain, copper values were relatively low (1–8 ppb range, 

2 ppb mean) regardless of pH or alkalinity (Reed and Henningson 1984). 

Copper concentrations were measured in surface water obtained from sampling sites in the Spearfish 

Creek, Whitewood Creek, and Bear Butte Creek watersheds. These watersheds are affected by water 

leaching from tailings and acid-mine drainage from gold mining operations in the Black Hills of South 

Dakota. Copper concentrations of <0.24–28 μg/L were measured in surface water, whereas 

concentrations in sediments were much higher, ranging from 7.8 to 159 mg/kg (May et al. 2001). 

In a survey of sources of copper in storm water, measurements of copper concentrations in storm water 

samples were taken from various urban locations in Birmingham, Alabama. Copper concentrations were 

generally low in filtered samples (dissolved copper), ranging between 1.4 and 20 μg/L; but were much 

higher in unfiltered samples (copper bound to particulate matter) with mean values (in μg/L) of 110 (roof 

areas), 116 (parking areas), 280 (street runoff), 135 (vehicle service areas), 81 (landscaped areas), 

50 (urban creeks), and 43 (retention ponds) (Pitt et al. 1995). 

As a result of improvements in controlling the quality of discharges from municipal and industrial waste 

water treatment plants mandated in the Clean Water Act, copper concentrations have been declining in 

surface waters. For example, median copper concentrations in the Hudson River estuary have fallen 36– 

56% between the mid-1970s and the mid-1990s (Sañudo-Wilhelmy and Gill 1999). 

The copper concentration in some bodies of water evidently varies with season. In a study of a small 

pond in Massachusetts from April of 1971 to March 1972, the concentration of copper was found to vary, 

decreasing during the spring and early summer to lows of <10–30 ppm in early August and then 

increasing when the pond was under the cover of ice to a maximum values of 80–105 ppb in late January 

and early February (Kimball 1973). Similar seasonal variations were noted in the epilimnion of the 

offshore waters of the Great Lakes (Nriagu et al. 1996). In both examples, the cycling in copper 

concentrations is thought to be a response to biological need and copper uptake during the growing season 

and its subsequent release from seasonal die-off and decay of biota. 

Copper concentrations in seawater usually are in the 1–5 ppb range (Perwak et al. 1980). Copper levels 

are overall lower in the Pacific Ocean than in the Atlantic Ocean and higher near the continental shelf 

than in the open ocean. Copper concentrations in surface water at a depth of 1 meter transected on a 

cruise from Nova Scotia to the Sargasso sea ranged from 57.2 to 210 parts per trillion (ppt) (Yeats 1988). 
 

 

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6. POTENTIAL FOR HUMAN EXPOSURE 

The mean value in surface water sampled at a depth of 1 meter of the eastern Arctic Ocean was 93 ppt 

(Mart and Nurnberg 1984). As noted in a review by Kennish (1998), concentrations of copper in 

estuarine and coastal waters in the United States were 0.3–3.8 and 0.1–2.5 ppb, respectively. 

6.4.3 Sediment and Soil 

Copper occurs naturally at levels of ~50 ppm in the earth's crust, which includes soil and parent rock 

(Perwak et al. 1980). In the United States, copper concentrations in differing soil types can vary over a 

large range (1–300 mg/kg, dry weight); but the mean values are relatively similar (14–41 mg/kg, dry 

weight) as a function of soil type (Table 6-10) and land resource region (Table 6-11) (Chen et al. 1999; 

Fuhrer 1986). These copper levels are similar to those given in a review of soil copper concentrations 

that reported a median concentration of 30 ppm (dry weight) and a range of 2–250 ppm (Davies and 

Bennett 1985). In other studies of copper concentrations in U.S. soils, the mean copper concentrations are 

within the range of 14–41 mg/kg. In the work of Ma et al. (1997), the mean concentration of copper in 

soils of the United States was determined to be 30 mg/kg, whereas the copper concentration in 

agricultural surface soils in the United States that had not received an application of sludges from 

municipal waste treatment plants was found to be 18 mg/kg. In Florida surface soils, the geometric mean 

of copper concentration in 40 different soil types was 4.10 mg/kg, with a range of 1.89–10.7 mg/kg (Ma 

et al. 1997). Chen et al. (1999) reported copper concentrations in Florida soils ranging from 0.1 to 

318 mg/kg with a geometric mean of 2.21±3.15 mg/kg (arithmetic mean of 6.10±22.1 mg/kg). These 

investigators also reported geometric means of 24.0 mg/kg in California soils and 17 mg/kg in U.S. soils. 

In agriculturally productive soils, copper ranges from 1 to 50 ppm, while in soil derived from mineralized 

parent material the copper levels may be much higher (NRC 1977; Perwak et al. 1980). 

Copper concentrations in soil may be much higher in the vicinity of a source of copper emissions, such as 

a mining operation or smelter. Concentrations in the top 5 cm of soil near the boundary of a secondary 

copper smelter were 2,480±585 ppm (Davies and Bennett 1985). Maximum wetland soil/sediment 

copper concentrations were 6,912 ppm in the immediate vicinity of a Sudbury, Ontario, smelter but the 

concentration decreased logarithmically with increasing distance from the smelter (Taylor and Crowder 

1983). The observation that the copper concentrations were highest in soils within 1–2 km from the 

smelter and decreased exponentially with increasing distance from the plant suggests that copper in the 

soil from the study area was primarily derived from particulate emissions from the smelter. 
 

 

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6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-10. Concentration of Copper in Surface Soils of the United States 

(in ppm-Dry Weight [dw], Equivalent to mg/kg-dw) 

Soil Range Mean 

Sandy soils and lithosols on sandstones 1–70 14 

Light loamy soils 3–70 25 

Loess and soils on silt deposits 7–100 25 

Clay and clay loamy soils 7–70 29 

Alluvial soils 5–50 27 

Soils over granites and gneisses 7–70 24 

Soils over volcanic rocks 10–150 41 

Soils over limestones and calcareous rocks 7–70 21 

Soils on glacial till and drift 15–50 21 

Light desert soils 5–100 24 

Silty prairie soils 10–50 20 

Chernozems and dark prairie soils 10–70 27 

Organic light soils 1–100 15 

Forest soils 7–150 17 

Various soils 3–300 26 

Source: EPA 1995 
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6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-11. Geometric Means of Selected Soil Elements and Associated Soil 

Parameters in U.S. Surface Soils by Land Resource Regions 

Land resource region mg/kg dry soil 

Mineral soils 

 Northwestern specialty 34.3

 Northwestern wheat 23.2 

 California subtropical 43.4 

Western range and irrigated 26.8 

 Rocky Mountain 19.1 

Northern Great Plains 20.2 

Western Great Plains 16.3 

Central Great Plains 12.6 

 Southwest Plateau 10.0 

 Southwest Prairie 4.9 

Northern lake states 15.4 

 Lake states 18.2 

 Central feed grains 19.7 

East and central farming 8.0 

 Mississippi Delta 21.1 

South Atlantic and Gulf slope 6.3 

 Northeastern forage 34.0 

Northern Atlantic slope 13.5 

Atlantic and Gulf coast 7.6 

 Florida subtropical 31.9 

All mineral soils 15.6 

Histosols 

Northern lake states 59.6 

 Lake states 84.7 

 Northeastern forage 149.0 

 Florida subtropical 94.3 

 All histosols 86.9 

Source: Holmgren et al. 1993 
 

 

 

 

COPPER 170 

6. POTENTIAL FOR HUMAN EXPOSURE 

Copper and its compounds were found at 906 of 1,647 hazardous waste sites on the NPL of highest 

priority sites for possible remedial action (HazDat 2002). Since copper is commonly found in soil, it 

should occur at all sites. In past work, data analysis of metal concentrations measured in soil from 

hazardous waste sites taken from the 1980–1983 Contract Laboratory Program (CLP) Analytical Results 

Data Base (CARD) was conducted to ascertain whether elemental concentrations at hazardous waste sites 

were elevated above that which normally would be expected in soil of similar composition and derivation. 

Of the 1,307 samples in CARD, 10.5 and 7.3% had copper concentrations exceeding the number normally 

expected in soil at the 95 and 99% confidence intervals, respectively (Eckel and Langley 1988). 

In a study in which the copper concentrations of 340 soil samples collected from diverse land-use 

situations, the average copper concentrations reported were 25 ppm in agricultural land, 50 ppm in 

suburban/residential land, 100 ppm in mixed industrial/residential land, and 175 ppm in industrial/inner 

urban areas (Haines 1984). From an analysis of the spatial distribution of the copper concentrations in 

soils where lowest copper soil concentrations are observed for rural (agricultural) soils and highest in 

soils obtained from industrialized urban areas, it was concluded that most of the contamination was a 

result of airborne deposition from industrial sources. 

The concentration of copper in soils and sediments was assessed as part of the National Water-Quality 

Assessment Program (Rice 1999). The median concentrations of copper at 541 sites throughout the 

conterminous United States ranged from 5 to 70 μg/g (dry weight). At nonurban indicator sites, the 

median concentrations ranged from 13 to 47 μg/g. The same study derived an average crustal abundance 

of copper of 60 μg/g. 

Sediment is an important sink and reservoir for copper. In areas where there is no known input of copper 

obtained from anthropogenic sources, sediment generally contains <50 ppm copper. The level can reach 

several thousand ppm in polluted areas (Harrison and Bishop 1984). The mean copper level in surficial 

sediment of Penobscot Bay, Maine, was 14.1 ppm (dry weight), while that in estuaries or bays in other 

New England locations ranged from 4.4 to 57.7 ppm (Larsen et al. 1983b). Levels reflect anthropogenic 

input as well as the mineral content of the regional bedrock. Copper levels in sediment from 24 sites 

along the New Jersey coast ranged from <1.0 to 202 ppm, with a mean value of 66 ppm (Renwick and 

Edenborn 1983). The texture of the sediment varied from 94% clay to 100% sand, and the copper level 

was correlated negatively with the percentage of sand in the sediment. 
 

 

 

COPPER 171 

6. POTENTIAL FOR HUMAN EXPOSURE 

Surficial sediment in lakes in the Sudbury region of northeastern Ontario, where several smelters operate, 

decreased rapidly with increasing distance from the smelters (Bradley and Morris 1986). Three lakes, 

10 km from the Sudbury smelters, contained copper concentrations in sediment approaching 2,000 ppm 

dry weight, over 100 times the concentration in a lake selected as a baseline lake 180 km away. 

An analysis of the Coastal Sediment Database (COSED) showed that 73% of coastal waterways had 

copper concentrations below 42 μg/g; 25% had copper concentrations between 42 and 210 μg/g; and 2% 

were above 210 μg/g. These higher concentrations are associated with locations of high ship traffic, 

industrial activity, and relatively poor water flushing (Daskalakis and O’Connor 1995). In coastal areas 

receiving persistently high influxes of contaminants, high concentrations of copper (151 ppm) have been 

measured to sediments to depths of 54 cm (Bopp et al. 1993). Combined sewer outflows can also 

contribute significantly to the copper content in sediments. For example, mean (arithmetic) copper 

concentrations of 180, 208, 280, and 284 mg/kg were measured in sediment samples obtained near four 

sewer outflows in the lower Passaic River, New Jersey (Iannuzzi et al. 1997). In Jamaica Bay, New 

York, copper concentrations in sediments were 151–406 ppm, with a concentration of 151 ppm in 

sediment core samples obtained at a depth of 52–54 cm (Bopp et al. 1993). The highest concentrations 

were found in the middle depths (16–44 cm) ranging from 280 to 406 ppm during a period where 

untreated industrial effluents and sewage outflows were allowed to enter the bay. However, copper 

concentrations in surface sediments (0–2 cm) where measured at 208 ppm. The decrease in copper 

concentration in the surface sediments suggests that efforts to reduce metal contaminants from sewage 

outflows have been making an impact on the copper concentrations in receiving waters and their 

sediments. 

6.4.4 Other Environmental Media 

In addition to the ingestion of drinking water, the consumption of food is the other primary route for 

copper intake in the general population. Several studies of copper content in a variety of foods have been 

conducted as part of the FDA’s Total Diet Survey and are described in this section. These data have been 

used to estimate the average intakes of copper in the human diet within various age groups. For example, 

in the 25–30-year-old age group, copper intake has been estimated to be 0.93 mg/day for women and 

1.24 mg/day for men (Pennington 1983). The levels of copper in other food sources such as mollusks, 

fish, and agricultural plants have been measured and the results summarized in this section. One highlight 

in the data is the potential for high dietary intakes of copper for those individuals who regularly consume 

of mollusks where the daily intake of copper could increase by 5.7–136 mg/day in comparison to the 
 

 

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6. POTENTIAL FOR HUMAN EXPOSURE 

general population (see Section 6.5). Other media covered in this section are human tissues, cigarette 

smoke, industrial and municipal waste streams, and agricultural products. 

The FDA Total Diet Survey has provided copper concentration in various foods, examples of which are 

given in Table 6-12 (FDA 2001). The highest concentrations of copper were found in liver, in some oat 

and bran cereals, in some legumes and nuts, and in raw avocadoes and mushrooms. Coleman et al. (1992) 

reported copper concentrations in the edible tissues of livestock and poultry with the highest mean 

concentrations (ppm) found in liver (cow 43.7; lamb 89.8; chicken 4.60; turkey 7.14), followed by kidney 

(cow 8.15; lamb 5.39; chicken 3.07; turkey 3.68), and muscle (cow 1.41; lamb 1.47; chicken 0.67; turkey 

0.83) (Coleman et al. 1992). 

More recent measurements of copper concentrations in 265 foods analyzed from 1991 to 1996 and from 

1991 to 1999 have been obtained from the FDA Total Diet Study (Capar and Cummingham 2000; FDA 

2000). The copper contents of selected foods provided in the most recent FDA Total Diet Study (FDA 

2000) are similar to those obtained from the 1982–1984 FDA study. The contribution of food groups to 

copper intake varies depending on the age group (Pennington and Schoen 1996). For example, animal 

flesh only contributes to 18% of the copper intake for a 2-year-old child, but contributes to 38% of the 

copper intake for a 60–65-year-old male. The results of a 1994–1996 Continuing Survey of Food Intakes 

(CSFII) found that the daily intakes of copper for men and women ages ≥60 years old are 1.3 and 

1.0 mg/day, respectively (Ma and Betts 2000). In a separate study by Ellis et al. (1997), copper intake for 

male and female African-Americans ages 21–65 years old was determined to be 1.0 mg/day for both 

sexes. 

Daily intakes of copper and other essential minerals were estimated for eight age-sex groups of the United 

States population as part of the FDA's Total Diet Study (Pennington et al. 1986). By analyzing the mean 

mineral content of samples of 234 foods obtained in 24 cities from mid-1982 to mid-1984 and by using 

previously determined daily intakes of each food as determined from data obtained from the National 

Food Consumption Survey (1977–1978) and the Second National Health and Nutrition Examination 

Survey (1976–1980) (Pennington 1983), the daily mineral intake for the age-sex groups was determined. 

The copper intakes in mg/day of the eight age-sex groups were: 6–11-month-old infant, 0.47; 2-year-old 

child, 0.58; 14–16-year-old girl, 0.77; 14–16- year-old boy, 1.18; 25–30-year-old woman, 0.93; 25–30-

year-old man, 1.24; 60–65-year-old woman, 0.86; and 60–65-year-old man, 1.17. All values were low in 

terms of the estimated safe and adequate daily dietary intake of this nutrient. The food item with the 

highest copper level was beef/calf liver (61 ppm). 
 

 

 

 

 

 

 

 

 

COPPER 173 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-12. Copper Content of Selected Foods (mg/kg)a 

Food description Mean SDb Food description Mean SDb 

Breads green pepper, raw 0.7 0.3 

bagel, plain 1.3 0.2 iceberg lettuce, raw 0.2 0.2 

cracked wheat bread 1.8 0.2 lima beans, immature, frozen, boiled 1.5 0.2 

English muffin, plain, toasted 1.3 0.1 mixed vegetables, frozen, boiled 0.6 0.2 

graham crackers 1.5 0.3 mushrooms, raw 2.4 0.6 

rye bread 1.5 0.2 okra, fresh/frozen, boiled 0.8 0.3 

saltine crackers 1.4 0.1 onion, mature, raw 0.4 0.1 

white bread 1.1 0.2 peas, mature, dry, boiled 2.3 0.3 

white roll 1.3 0.2 spinach, fresh/frozen, boiled 0.8 0.3 

whole wheat bread 2.3 0.3 summer squash, fresh/frozen, boiled 0.5 0.1 

sweet potato, fresh, baked 1.4 0.4 

Cereal, rice, and pasta tomato, red, raw 0.5 0.2 

corn flakes 0.5 0.1 tomato sauce, plain, bottled 1.2 0.4 

crisped rice cereal 2.0 0.2 tomato, stewed, canned 0.7 0.2 

egg noodles, boiled 1.0 0.2 turnip, fresh/frozen, boiled 0 0.1 

granola cereal 3.0 0.4 white potato, baked with skin 1.0 0.4 

macaroni, boiled 0.9 0.1 white potato, boiled without skin 0.6 0.2 

oatmeal, quick (1–3 minutes), 0.7 0.1 winter squash, fresh/frozen, baked, 0.6 0.2 

cooked mashed 

oatring cereal 3.3 0.4 

raisin bran cereal 4.4 0.4 Fruits 

shredded wheat cereal 3.7 0.5 apple, red, raw 0.2 0.2 

wheat cereal, farina, quick (1– 0.3 0.3 applesauce, bottled 0.2 0.1 

3 minutes), cooked 

white rice, cooked 0.7 0.1 apricot, raw 0.8 0.3 

avocado, raw 2.2 0.6 

Vegetables banana, raw 1.1 0.2 

asparagus, fresh/frozen, boiled 1.0 0.2 cantaloupe, raw 0.3 0.1 

beets, fresh/frozen, boiled 0.7 0.2 fruit cocktail, canned in heavy syrup 0.5 0.1 

black olives 1.4 0.4 grapefruit, raw 0.3 0.1 

broccoli, fresh/frozen, boiled 0.2 0.1 grapes, red/green, seedless, raw 1.1 0.6 

Brussels sprouts, fresh/frozen, 0.4 0.1 orange, raw 0.4 0.1 

boiled 

cabbage, fresh, boiled 0 0 peach, canned in light/medium syrup 0.3 0.2 

carrot, fresh, boiled 0.3 0.2 peach, raw 0.7 0.2 

cauliflower, fresh/frozen, boiled 0 0 pear, canned in light syrup 0.4 0.1 

celery 0 0.1 pear, raw 0.8 0.1 

collards, fresh/frozen, boiled 0.5 0.4 pineapple, canned in juice 0.5 0.1 

corn, fresh/frozen, boiled 0.3 0.2 plums, raw 0.6 0.1 

cream style corn, canned 0.1 0.2 prunes, dried 2.9 0.3 

cucumber, raw 0.2 0.2 raisins, dried 3.3 0.4 

eggplant, fresh, boiled 0.5 0.2 strawberries, raw 0.5 0.3 

green beans, fresh/frozen, boiled 0.5 0.3 watermelon, raw 00.4 0.1 

green peas, fresh/frozen, boiled 1.0 0.2 
 

 

 

 

 

 

 

 

COPPER 174 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-12. Copper Content of Selected Foods (mg/kg)a 

Food description Mean SDb Food description Mean SDb 

Fruit juices pork roast, baked 0.8 0.1 

apple juice, bottled 0 0.1 pork sausage, pan-cooked 0.8 0.1 

grape juice, bottled 0 0.1 quarter-pound hamburger on bun, 0.9 0.1 

fast-food 

grapefruit juice, from frozen 0.3 0.1 salami, sliced 1.0 0.2 

concentrate 

orange juice, from frozen 0.3 0.1 salmon, steaks or filets, fresh or 0.5 0.1 

concentrate frozen, baked 

pineapple juice from frozen 0.4 0.1 shrimp, boiled 2.3 0.6 

concentrate 

prune juice 0.1 0.1 tuna, canned in oil 0.5 0.1 

tomato juice, bottle 0.6 0.1 turkey breast, roasted 0.4 0.1 

veal cutlet, pan-cooked 1.0 0.3 

Dairy products 

American, processed cheese 0.1 0.2 Legumes, nuts, and nut products 

cheddar cheese 0.3 0.2 kidney beans, dry, boiled 2.7 0.5 

chocolate milk, fluid 0.3 0.2 mixed nuts, no peanuts, dry roasted 15.5 2.6 

cottage cheese, 4% milkfat 0 0 peanut butter, smooth 5.2 0.6 

cream cheese 0 0 peanuts, dry roasted 5.8 0.6 

eggs, boiled/fried 0.6 0.1 pinto beans, dry, boiled 2.4 0.2 

eggs, scrambled 0.5 0.1 pork and beans, canned 1.8 0.2 

half & half 0 0 

lowfat (2%) milk, fluid 0 0 Fats, oils, condiments, snacks, and sweets 

skim milk 0 0 butter, regular (salted) 0 0 

sour cream 0 0 corn chips 1.0 0.2 

Swiss cheese 0.4 0.4 fruit flavor sherbet 0 0.1 

whole milk 0 0 gelatin dessert, any flavor 0 0 

honey 0 0 

Meat, poultry, and seafood jelly, any flavor 0 0.1 

beef chuck roast, baked 1.0 0.1 margarine, stick, regular (salted) 0 0 

beef steak, loin, pan-cooked 1.0 0.2 mayonnaise, regular, bottled 0 0 

bologna, sliced 0.4 0.2 olive/safflower oil 0 0 

chicken breast, roasted 0.3 0.1 popcorn, popped in oil 1.7 0.4 

chicken, fried (breast, leg, and thigh) 0.7 0.1 potato chips 2.8 0.8 

frankfurters, beef, boiled 0.4 0.1 pretzels, hard, salted, any shape 1.6 0.2 

ground beef, pan-cooked 0.8 0.1 vanilla ice cream 0.06 0.24 

haddock, pan-cooked 0.06 0.13 white sugar, granulated 0 0 

ham, baked 0.6 0.2 

ham luncheon meat, sliced 0.5 0.1 Beverages 

lamb chop, pan-cooked 1.4 0.2 coffee, from ground 0 0 

liver, beef, fried 123 57 cola carbonated beverage 0 0 

pork bacon, pan-cooked 1.2 0.4 tea, from tea bag 0 0 

pork chop, pan-cooked 0.8 0.2 

a

Source: FDA 2000 

b

SD = Standard Deviation 
COPPER 175 

6. POTENTIAL FOR HUMAN EXPOSURE 

A baseline value for the copper content of mother's milk was determined by a survey of literature values. 

Based on the data obtained from 28 study sets, a baseline copper concentration of 331 ppb was 

determined from a range of values of 197–751 ppb and a median of 290 ppb (Iyengar and Woittiez 1988). 

In a separate study of 11 lactating women, it was found that the variability in the copper content of 

mother’s milk was primarily subject-related. The copper concentration in milk declined moderately, from 

0.43 μg/mL between 1 and 3 months postpartum to 0.24 μg/mL between 10 and 12 months postpartum 

(Vaughan et al. 1979). In a study of 82 lactating women, the copper concentration in breast milk ranged 

between 0.8 and 1.1 ppm and remained relatively constant in individual women over the first 7 days 

postpartum (Arnaud and Favier 1995). 

The concentrations of copper in the soft tissue in mussels and oysters collected as part of the U.S. Mussel 

Watch Program in 1976–1978 were 4–10 ppm (dry weight) for mussels and 25–600 ppm for oysters 

(Goldberg 1986). Copper concentrations in mussels collected from 11 sites near Monterey Bay, 

California, were 4.63–8.93 ppm (dry weight) (Martin and Castle 1984). Perwak et al. (1980) reported 

similar results for mussels (3.9–8.5 ppm) and for clams (8.4–171 ppm). Recent measurements of copper 

concentrations in zebra and quagga mussels taken from Lakes Erie and Ontario in 1997 ranged from 21 to 

41 ppm (dry weight) (Rutzke et al. 2000). In the National Oceanic and Atmospheric Administration 

(NOAA) Mussel Watch Project, copper concentrations were quantified in mollusks (M. edulis, 

M. californianus, C. virginica, and Ostrea equestris) from 113 sites around the United States in 1993 and 

compared to copper concentrations measured in mollusks taken from the same site in the EPA2 Mussel 

Watch Program, 1976–1978 (Lauenstein and Daskalakis 1998). The results of the comparison indicate 

that the decreasing and increasing trends in copper concentrations in mollusks were approximately equal 

among the sites, except in California, where increasing trends were noted at five sites. 

As a part of the National Contaminant Biomonitoring Program of the U.S. Fish and Wildlife Service, 

eight species of freshwater fish were collected at 112 stations in the United States in 1978–1979 and 

1980–1981 (Lowe et al. 1985). The geometric mean concentrations of copper in ppm (wet weight, whole 

fish) for these two periods were 0.86 and 0.68, respectively; the 85th percentiles were 1.14 and 0.90, 

respectively, and the ranges were 0.29–38.75 and 0.25–24.10, respectively. The highest concentration, 

38.75 and 24.10 ppm, during both collecting periods was in white perch from the Susquehanna River and 

the second highest concentration, 19.3 ppm, was found in white perch from the Delaware River near 

Trenton, New Jersey. However, copper concentrations in common carp and white catfish collected from 

the same station at the same time were 0.76 and 1.35 ppm, respectively. 
 

 

COPPER 176 

6. POTENTIAL FOR HUMAN EXPOSURE 

In bluefin tuna caught in the northwest Atlantic off Newfoundland, the mean copper concentration in 

muscle tissue has been measured at 1.0 ppm (dry weight) (Hellou et al. 1992a). In cod caught off the 

coast of Newfoundland, mean copper concentrations of <1.2–1.5 μg/g (dry weight) in muscle and 5– 

10 ppm (dry weight) in liver have been determined (Hellou et al. 1992b). 

Copper residues in muscle of 268 fish specimens from 17 species were analyzed over a 5-year period in 

several surface water systems in eastern Tennessee (Blevins and Pancorbo 1986). The mean residue 

levels in the muscle of different species of fish from nine stations ranged from 0.12–0.86 ppm (wet 

weight). Maximum levels ranged from 0.14 to 2.2 ppm. 

Concentrations of copper in three species of fish living in storm treatment ponds have been compared to 

copper concentrations in controls collected from surrounding surface waters near Orlando, Florida 

(Campbell 1994). In bluegill sunfish collected from storm water ponds, the mean whole body copper 

concentrations were 6.37 and 2.08 mg/kg wet weight, respectively, and were significantly higher than the 

mean concentrations of copper, 0.879 and 1.07 mg/kg wet weight, respectively, measured in controls 

collected in natural lakes or ponds. However, in largemouth bass, the mean copper concentrations in fish 

collected from storm water ponds and controls did not significantly differ, with values of 3.81 and 

4.71 mg/kg wet weight, respectively. 

Respective mean and median copper concentrations of 127 samples of finfish from Chesapeake Bay and 

its tributaries were 1.66 and 0.36 ppm in 1978, and 1.85 and 0.61 ppm in 1979 (Eisenberg and Topping 

1986). In striped bass taken from Turkey Point in the bay, copper levels were below the detection limit of 

the study (<0.1 μg/g) in muscle, but were higher in liver tissue ranging from 0.86 to 23.5 μg/g. In gonad 

tissue obtained from tissue from a different site on the bay, there was also an increase in the mean copper 

concentration in this tissue (4.25 μg/g) as compared to muscle (0.76 μg/g). The copper content of muscle 

tissue of several species of fish collected from metal-contaminated lakes near Sudbury, Ontario, ranged 

from 0.5 to 1.4 ppm (dry weight). No major pattern in variation was evident among species or among the 

study lakes (Bradley and Morris 1986). The copper concentration in the livers, however, ranged from 5 to 

185 ppm (dry weight) and differed significantly among species and among lakes. Unlike muscle tissue, 

liver tissue is a good indicator of copper availability, although the data indicate that there are other 

factor(s) that influence the availability and bioaccumulation of copper in these fish. 
 

 

 

COPPER 177 

6. POTENTIAL FOR HUMAN EXPOSURE 

The copper concentrations in the liver of lake trout and grayling taken from four fresh water lakes in 

Alaska did not correlate well with the concentrations of copper in the sediments of these lakes (Allen-Gil 

et al. 1997). Lake trout were found to have statistically significant higher burdens of copper in their livers 

than grayling, and the concentrations of copper in the livers of trout varied considerably depending on the 

lake from which they were collected. The species and site differences in copper concentrations in fish 

livers have been attributed to differences in diet, (grayling consume mainly insects, whereas trout 

consume a mix of snails, insects and small fish) and time spent at various depths of the water column. 

Although the concentrations of copper in plants vary widely, they usually range from 1 to 50 ppm (dry 

weight) (Davies and Bennett 1985) and from 1 to 143 ppm (dry weight) in edible plants (Perwak et al. 

1980). Concentration ratios of copper in plants relative to soil (concentration factors or CF) demonstrate 

that copper uptake differs significantly between plants. For example, CF values have been found to vary 

from 0.02 (onion), 0.13 (celery), 0.21 (lettuce), and 0.30 (potato) to 2 (grapes), 4.5 (alfalfa), and 

6.8 (grass) (Pinochet et al. 1999). Concentration factors in rice were found to vary among soil types 

(0.59–3.58) with copper concentrations in rice ranging from 1.7 to 5.1 μg/g (Herawati et al. 2000). 

Copper concentrations in rice grain have been found to increase significantly from 1.4 to 15.5 μg/g when 

copper concentrations in waste water irrigated soils increased from 17.0 mg/kg (wet weight) to 

101.2 mg/kg (wet weight) (Cao and Hu 2000). 

Studies of copper in human tissues suggest that copper content in a 70 kg adult ranges from 50–70 mg 

(Davies and Bennett 1985). Wise and Zeisler (1984) reported an average copper concentration of 10 ppm 

in the human liver in 36 samples. Despite the wide variation in copper concentrations in the environment, 

the copper concentration in the liver only varied by a factor of 2–3.5. Copper concentrations in human 

tissues are given in Table 6-13 (Georgopoulos et al. 2001). The concentration of copper in blood is not 

expected to be predictive of the total body burden of copper: Saltzman et al. (1990) found that the 

correlation between copper concentrations measured in blood and total body burden was poor (r=0.54). 

The mean copper content of tobacco in Finnish cigarettes was 24.7 ppm, with a standard deviation of 

10.8 ppm (Mussalo-Rauhamaa et al. 1986). However, only 0.2% of this copper passes into mainstream 

smoke. This translates to a daily exposure of approximately 1 μg of copper in a pack of 20 cigarettes. 

In an EPA-sponsored study conducted to determine the metal concentration in sewage sludge (Feiler et al. 

1980), copper concentrations in primary sludge at seven POTWs were reported to be 3.0–77.4 ppm, with 
COPPER 178 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-13. Copper Content of Human Tissues and Body Fluids 

Mean content (μg/g dry weight) 

Tissue Normal Wilson’s disease 

Adrenal 7.4 17.6 

Aorta 6.7 — 

Bone 4.2 — 

Brain — — 

Caudate nucleus — 212 

Cerebellum — 261 

Frontal lobe cortex — 118 

Globus pallidus — 255 

Putamen — 314 

Cornea — 92.9 

Erythrocytes (per 100 mL packed red blood cells) 23.1 — 

Hair 89.1 — 

Heart 16.5 12.7 

Kidney 14.9 96.2 

Leukocytes (per 109 cells) 0.9 — 

Liver 25.5 584 

Lung 9.5 15.5 

Muscle 5.4 25.9 

Nail 18.1 — 

Ovary 8.1 5.2 

Pancreas 7.4 4.2 

Placenta 13.5 — 

Prostate 6.5 — 

Skin 2 5.2 

Spleen 6.8 5.6 

Stomach and intestines 12.6 22.9 

Thymus 6.7 — 

Thyroid 6.1 — 

Uterus 8.4 — 

Aqueous humor 12.4 — 

Bile (common duct) 1,050 173 

Cerebrospinal fluid 27.8 — 

Gastric juice 28.1 — 

Pancreatic juice 28.4 — 

Plasma, Wilson’s disease — 

Saliva 50 — 
COPPER 

6. POTENTIAL FOR HUMAN EXPOSURE 

179 

Table 6-13. Copper Content of Human Tissues and Body Fluids 

Tissue 

Mean content (μg/g dry weight) 

Normal Wilson’s disease 

Serum 

Female 120 — 

Male 109 — 

 Newborn 36 — 

Sweat 

Female 148 — 

Male 55 — 

Tissue 

 Synovial fluid 21 — 

 Urine (24-hour) 18 — 

Source: Georgopoulos et al. 2001; Scheinberg 1979; Sternlieb and Scheinberg 1977 
COPPER 180 

6. POTENTIAL FOR HUMAN EXPOSURE 

a median concentration of 20.5 ppm. The plant with the highest copper concentrations received wastes 

from plating industries, foundries, and coking plants. In a comprehensive survey of heavy metals in 

sewage sludge, 30 sludges from 23 American cities were analyzed (Mumma et al. 1984). The copper 

concentration in the sludges ranged from 126 to 7,729 ppm (dry weight), with a median value of 

991 ppm. Gutenmann et al. (1994) report similar concentrations (217–793 ppm, dry weight) in sewage 

sludge obtained from 16 major cities in the United States. The proposed limit for copper in sludge spread 

on agricultural land is 1,000 ppm (Mumma et al. 1984). For comparison, the concentration of copper in 

cow's manure is ~5 ppm (Mumma et al. 1984). 

In municipal solid waste compost obtained from nine sites in the United States, a mean copper 

concentration of 281 mg/kg (dry weight) was obtained with range of 36.4–424 mg/kg (He et al. 1995). 

Lisk et al. (1992) reported copper concentrations in composts formed from yard waste ranging from 

22.7 to 327 ppm, from sewage sludge ranging from 432 to 1,019 ppm and from municipal solid waste 

ranging from 191 to 1,143 ppm. 

Copper concentrations in waste from the combustion of municipal solid waste and other combustion 

processes have been reported. Copper in incinerator bottom ash and fly ash has been measured at mean 

concentrations of 1,700 and 1,000 mg/kg, respectively (Goldin et al. 1992). Buchholz and Landberger 

(1995) report concentrations of copper of 390–530 μg/g in fly ash, 1,560–2,110 μg/g in bottom ash, and 

1,140–1,540 μg/g in combined ash. In sewage sludge incineration process steams, copper concentrations 

were 4,561 mg/kg in sludge cake, 3,465 mg/kg in bottom ash, 3,707 mg/kg in cyclone ash, 3,684 mg/kg 

in scrubber particulate matter, and 6,666 mg/kg in stack particulate matter (Balogh 1996). In fossil fuel 

wastes, copper concentrations of 33–2,200 mg/kg in fly ash, 4–930 mg/kg in bottom ash, 6–340 mg/kg in 

flue gas desulfurization sludge, 10–130,000 mg/kg oil ash, and 2–190 mg/kg in coal have been obtained 

(Eary et al. 1990). 

Agricultural sources of copper contamination in soils has been summarized by EPA (1995) and are shown 

in Table 6-14. Concentrations of copper in fertilizers, soil amendments and other agricultural materials 

have been measured by Raven and Loeppert (1997). The materials and mean concentrations: urea 

(<0.6 μg/g), ammonium nitrate (<0.6 μg/g), ammonium sulfate (<0.6 μg/g), ammonium phosphate (<2– 

41.8 μg/g), potassium chloride (<2–3.5 μg/g), potassium-magnesium-sulfate (1.4–5 μg/g), North Carolina 

rock phosphate (9.6 μg/g), calcite (2.3 μg/g), corn leaves (9.4 μg/g), manure (17.5 μg/g), and austinite 

(300 μg/g). 
COPPER 181 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-14. Agricultural Sources of Copper Contamination in Soils 

Source Concentration (ppm dry weight)a 

Sewage sludges 50–3,300 

Phosphate fertilizers 1–300 

Limestones 2–125 

Nitrogen fertilizers <1–15 

Manure 2–60 

Pesticides (percent) 12–50 

Source: EPA 1995 

a

Equivalent to mg/kg-dry weight 
COPPER 182 

6. POTENTIAL FOR HUMAN EXPOSURE 

6.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE 

Due to the ubiquitousness of copper in the environment and the general occurrence of copper in airborne 

particulates, exposure to copper through inhalation is commonplace. Estimates of atmospheric copper 

concentrations from different source categories (e.g., smelters, ore processing, steel production, and 

combustion) yielded a maximum annual concentration of 30 μg/m3

 (EPA 1987a). If a person is assumed 

to inhale 20 m3

 of air/day, this would amount to an average daily intake of 600 μg of copper. For the 

reported range of annual atmospheric copper concentrations, 5–200 ng/m3

 (EPA 1987a), the average daily 

intake by inhalation, would range from 0.1 to 4.0 μg. At the maximum reported ambient air 

concentration, 100 μg/m3

 for a 24-hour period at a location within one-half mile of a major source (EPA 

1987a), the average daily intake would rise to 2,000 μg. These estimates assume that all of the copper is 

attached to particles of inhalable size, which is usually not the case. The average daily dietary intake of 

copper from food is ~2 mg/day. The dietary intake of copper is expected to be above this average for 

those individuals who regularly consume organ meats (e.g., liver and kidney), nuts, seeds (including 

cocoa powder), legumes, and bran and germ portions of grains; these intakes are not expected to exceed 

the maximum recommended limits of 10–12 mg/day (WHO 1996). Those individuals who regularly 

consume oysters or clams may increase their dietary intake of copper by 2–150 mg/day when consuming 

250 g of edible tissue per day, based on copper concentrations of 25–600 and 8.4–171 ppm in oysters and 

clams, respectively (Goldberg 1986; Perwak et al. 1980). Assuming a median copper concentration in 

drinking water of 75 μg/L, the average daily copper exposure from consumption of 2 L of water per day is 

0.15 mg. However, many people may have high levels of copper in their tap water that have been 

acquired during transport through the water distribution system. If the system is not permitted to flush 

out, average intakes from water may be >2 mg/day. It is less likely that high dermal exposures will result 

from bathing in this tap water because the distribution system will flush itself out as the water is drawn. 

The total exposure of copper for the average person from all sources (e.g., air, drinking water, and food) 

is estimated to be 2.75 mg/day. 

A National Occupational Exposure Survey (NOES) conducted by NIOSH from 1981 to 1983 estimated 

that potentially 505,982 workers, including 42,557 women, were occupationally exposed to copper in the 

United States (NIOSH 1988). The NOES estimate is provisional because all of the data for trade name 

products that may contain copper have not been analyzed. Of the potential exposures, 1,073 are to pure 

copper, while in the other cases, the molecular form of copper was unspecified. Additionally, according 

to the NOES, 125,045 workers, including 38,075 women, were potentially exposed to copper sulfate 
COPPER 183 

6. POTENTIAL FOR HUMAN EXPOSURE 

(NIOSH 1988). The NOES was based on field surveys of 4,490 facilities and was designed as a 

nationwide survey based on a statistically valid sample of virtually all workplace environments in the 

United States where eight or more persons are employed in all standard industrial codes (SIC) except 

mining and agriculture. The exclusion of mining and agriculture is significant for estimating exposure to 

copper since there is a high potential for exposure in these industries. Current occupational exposure 

limits for copper fume are 0.2 and 1 mg/m3

 for dust and mists (Frazier and Hage 1998). 

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). 

With respect to inhalation, exposures of children to copper are not expected to be very different from 

those of the rest of the general population. However, exposure of copper through oral routes may differ, 

due to differences in the consumption of various food groups between children and adults and ingestion of 

dust and soils. The dietary copper intake for infants who receive the major portion of their nutritional 

requirements from breast milk is likely to be different from infants whose nutritional needs are either 

supplemented or entirely received through the consumption of formula. Estimates of copper intake from 

inhalation and ingestion in children in the United States are limited. From the work of Pennington et al. 

(1986), the copper intakes for a 6–11-month-old infant and a 2-year-old child were estimated to be 

0.47 and 0.58 mg/day, values which are lower than the adult intake of ~1 mg/day. However, one study 

has provided estimated inhalation and ingestion exposures of copper for children in India (Raghunath et 

al. 1997). In this work, concentrations of copper in particulates in air were measured at 0.01–0.26 μg/m3

. 

Based on these measurements, estimated inhalation exposures of children to copper were calculated to be 
COPPER 184 

6. POTENTIAL FOR HUMAN EXPOSURE 

0.1–3.2 μg/day. In this same work, exposures to copper through ingestion were estimated to be between 

684–1,732 μg/day. 

Exposures of children to copper are likely to increase in areas where copper concentrations in air are 

expected to be high, such as mining sites, waste dump sites, smelters, and foundries. For example, copper 

burdens in children living near a lead smelter, as measured by copper concentration in teeth, increased 

with decreasing distance from the smelter (Blanuša et al. 1990). Children are also at risk for increased 

copper intake through consumption of drinking water where leaching of copper from the distribution 

system has occurred (Murphy 1993; Yannoni and Piorkowski 1995). This route of copper exposure can 

be minimized through the flushing of drinking water supply lines or increasing the pH of the water in the 

distribution system. 

6.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES 

In discussing exposure to copper, the important question is whether individuals are exposed to readily 

available copper, which in general, means free (hydrated) Cu(II) and perhaps some weakly complexed or 

adsorbed forms of copper. The data indicate that copper in natural water, sediment, and soil mainly exists 

in bound form. Even so, the free form of copper can be released readily from ingested materials, for 

example a child’s sampling of soil, following exposure to the low pHs encountered in the stomach 

(Pizarro et al. 2001). Potential for high uptake copper in the general population may exist where people 

consume large amounts of tap water that has picked up copper from the distribution system, or already 

has a high copper background due to natural or anthropogenic activities (e.g., close proximity to mining 

activities or mine drainage). Leaching of copper from water distribution systems is likely to occur where 

the water is soft and not allowed to run to flush out the system. In such cases, the concentration of copper 

frequently exceeds 1 ppm, a large fraction of the copper may be in the form of free cupric ion, and uptake 

will result by ingestion and, perhaps, dermal contact. Soluble cupric salts are used extensively in 

agriculture and in water treatment. Workers engaged in the formulation and application of these 

chemicals and industrial workers, such as those in the plating industry, may come into dermal contact 

with these chemicals. Exposure to high levels of free Cu(II) may occur, for example, from swimming in 

water that has been recently treated with a copper-containing algicide. 

Based on the available data, people living close to NPL sites may be at greater risk for exposure to copper 

than the general population. In this case, exposure can occur through inhalation of airborne particulates 

from the NPL sites, ingestion of water from private wells which are in close proximity to the sites, 
 

 

COPPER 185 

6. POTENTIAL FOR HUMAN EXPOSURE 

ingestion of contaminated soil, and/or uptake of copper into fruits and vegetables raised in gardens of 

residents living near NPL sites. 

People living near copper smelters and refineries and workers in these and other industries may be 

exposed to high levels of dust-borne copper by both inhalation and ingestion. In some industries, workers 

may be exposed to fumes or very fine dust that may be more hazardous than coarse-grained dust, because 

it can be inhaled more deeply into the lung, thereby evading the mucocilliary escalator. 

6.8 ADEQUACY OF THE DATABASE 

Section 104(i)(5) of CERCLA, as amended, directs the Administrator of the ATSDR (in consultation with 

the Administrator of EPA and agencies and programs of the Public Health Service) to pursue assessment 

of the adequacy of the available information on the health effects of copper. Where adequate information 

is not available, the 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 copper. 

The following categories of possible data needs have been identified by a joint team of scientists from the 

ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that, if met, would 

reduce uncertainties of regarding 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 refined substance-specific research agenda will be proposed. 

6.8.1 Identification of Data Needs 

Physical and Chemical Properties. In general, the available data on the physical and chemical 

properties of elemental copper and copper sulfate are sufficient for estimating their environmental fate. 

That no numerical value is listed for the water solubility of copper in Table 4-3 is of no special 

significance. For inorganic salts, the solubility product coupled with stability constants for the ionic 

species in solution are the factors determining how much of a compound goes into solution (i.e., the 

concentration). The solubility products and stability constants for copper that are required for 

determining the copper species in natural water and their concentrations are known (Schnoor et al. 1987; 

Town and Filella 2000). Although no Koc values are listed, copper binds very strongly to organic matter, 

and values for the binding constants and solubility products to humic acids are available (Schnoor et al. 
COPPER 186 

6. POTENTIAL FOR HUMAN EXPOSURE 

1987). Similarly, there are binding constants and solubility products for other species that bind or 

coprecipitate with copper, such as clay minerals and iron and manganese oxides (Schnoor et al. 1987). 

Binding constants for copper in specific natural waters are also available (Town and Filella 2000). Other 

physical and chemical properties in Table 4-3 for which there is no data are not well defined for these 

copper compounds. 

In general, experimental confirmation is required for predicting copper's fate in the environment. The 

factors which determine the copper species present or the material to which copper may be bound and the 

strength of the binding can be site specific. If the level of detail requires knowledge of, for example, the 

percentage of copper associated with iron oxides or that which is easily exchangeable, experimental 

confirmation is necessary. 

Production, Import/Export, Use, Release, and Disposal. Information on the production, use, 

release, and disposal of copper is used for evaluating the potential for exposure of people to copper who 

live or work near waste sites and other sources. Copper exposure is widespread; but much of this 

exposure is to generally benign forms, such as metallic copper. The information available often does not 

distinguish between these forms and those of greater toxicological significance. 

Information on the production, use, release, and disposal of metallic copper and copper sulfate is 

generally available. These two forms of copper account for most of the copper used. This information is 

tabulated by the U.S. Geological Survey every year in the Minerals Yearbook and predictions of future 

trends in production and use are available. Such information is not available for other copper compounds. 

We also know the major uses of copper and where these uses occur (e.g., the home, workplace, etc.). 

According to the Emergency Planning and Community Right-to-Know Act of 1986 (EPCRTKA), (§313), 

(Pub. L. 99-499, Title III, §313), industries are required to submit release information to the EPA. The 

TRI contains release information for copper and copper compounds and is updated yearly. 

For disposal, industrial waste copper is generally either recycled or landfilled. Data on secondary copper 

production (i.e., copper produced from scrap) is compiled by the U.S. Geological Survey. Effluent and 

disposal regulations for copper and its compounds are listed in the Clean Water Act and the Resource 

Conservation and Recovery Act (RCRA). 
 

 

COPPER 187 

6. POTENTIAL FOR HUMAN EXPOSURE 

Environmental Fate. Reliable information on how copper and its compounds partition in the 

environment (i.e., to soil and sediment), and the type of transformations that occur in different media, is 

available from over 35 published studies included in this chapter. We also have data concerning its 

transport in the environment from over 50 reliable studies. Although information on the fate of copper in 

air, water, and soil is available, the fate of copper is both species- and site- specific. Information 

concerning the forms of copper (i.e., specific compound, to what it is bound or complexed, or, in the case 

of air, the particle size) or the lability of the copper in particular media is available from only a few, -yet 

reliable, studies. These are sufficient to identify numerous contributors to the fate of copper and its 

compounds; but are insufficiently comprehensive for developing accurate fate maps. In addition, studies 

of how fate data relate to human exposures, especially in regard to projecting copper toxicity in children, 

is inadequate. 

Bioavailability from Environmental Media. Copper is found in food, water, ambient air, and soil. 

The bioavailability of copper from food and water has been investigated in animals and humans. No 

information on the availability of copper from air was located. Copper in air originating from smelter 

sites is predominantly associated with sulfur, and presumably exists as the sulfate. Copper dust from soil 

in general as well as around mining and smelter sites may occur in ore dust or a silicate. No information 

was located on the bioavailability of copper in air. Copper in soil often is bound to organic molecules. 

Therefore, the bioavailability of the copper from soil cannot be assessed based on bioavailability 

information from drinking water or food studies. Studies on the bioavailability of copper from soil and 

ambient air would be useful in assessing potential toxicity to people living near a hazardous waste site. 

The form and lability of copper in the environment is known in only a few site-specific cases. None of 

these cases include hazardous waste sites. More information on the forms of copper found at industrial 

sites and hazardous waste sites would be useful, especially since data from the Hazardous Substances 

Data Bank (HSDB) indicate that concentrations of copper as high as 182,000 ppm in soil and 14,000 ppm 

in sediments have been measured offsite of listed NPL sites (HazDat 2002). Monitoring groundwater 

near industries that use highly acid, copper-containing solutions, such as electroplating, electrowinning, 

and ore leaching industries, is important for the protection of human populations at risk of exposure to 

their highly mobile and highly bioavailable copper to human risk populations. 

Food Chain Bioaccumulation. Because copper occurs in different forms in the environment, its 

bioaccumulation is expected to vary according to site and species. Data are available on the 

bioconcentration of copper in aquatic organisms, plants, and animals, as well as biomagnification in food 
 

 

COPPER 188 

6. POTENTIAL FOR HUMAN EXPOSURE 

chains. This information is useful in assessing the potential for exposure from ingesting food originating 

from contaminated areas. However, little information is available on the potential for intoxication from 

foodstuffs from apparently nonpolluted areas or where they may have accumulated toxic levels of copper 

through biomagnification resulting from foraging in polluted areas. 

Exposure Levels in Environmental Media. Data are available regarding the concentrations of 

copper in environmental media, including the concentration of copper in soil at some hazardous waste 

sites. Since copper is naturally present in soil, trace quantitative analytical and statistical techniques can 

be used to determine whether the copper found at these sites is elevated above normal levels. Monitoring 

data are reasonably current and human intake of copper from food, water, and air can be estimated. 

Exposure Levels in Humans. There are reasonably current data on levels of copper in human tissue 

and human milk. Although information on copper concentrations in individuals exposed within specific 

work settings is increasing (for example, Gerhardsson et al. 1993; Saltzman et al. 1990), none of the 

studies address specific U.S. populations living around hazardous waste sites. There are some 

quantitative data relating occupation, level and route of exposure to the form of copper to which people 

are exposed. There is some limited information correlating copper concentration and form to body 

burden in the general population. However, more information is needed for occupational and other at-risk 

populations. 

Exposures of Children. Reasonably current data report levels of copper intake in infants and 

children. Information on copper intake by infants from human milk also is available. Exposure of 

children to copper in drinking water has been assessed and methods to decrease this exposure have been 

identified and implemented. However, only limited information on inhalation and ingestion is available. 

Some information on exposure of children to copper near mining, smelting, refining, manufacture 

facilities, waste sites and other hazardous sites is available; but not for U.S. populations. This 

information is needed to better estimate exposures of children in U.S. populations living near these 

facilities and sites. The use of copper concentrations in toenails and hair has been investigated as a 

surrogate measure of copper exposure in children and adults and more research into establishing the 

validity of these surrogates is underway. 

Child health data needs relating to susceptibility are discussed in Section 3.12.2 Identification of Data 

Needs: Children’s Susceptibility. 
 

 

COPPER 189 

6. POTENTIAL FOR HUMAN EXPOSURE 

Exposure Registries. No exposure registries for copper and its compounds were located. No 

subregistry has currently been established for these chemicals. They 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 epidemiological research needed to assess adverse health 

outcomes that may be related to the exposure to these chemicals. 

6.8.2 Ongoing Studies 

Ongoing studies of copper in soils, sediments and aquifers have been identified and are listed in 

Table 6-15. Also included in Table 6-15 are ongoing investigations of human exposures to copper. 
COPPER 190 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-15. Ongoing Studies on Environmental Fate and the Potential for Human 

Exposure to Copper 

Investigator Affiliation Research description Sponsora 

Gardea-Torresdey J Stanford University Uptake of copper and 

lead into creosote bushes 

National Center for 

Research Services 

in regions with heavy 

metal contamination 

Naqvi SM Southern University A&M Bioaccumulation and 

biomagnification of 

copper in crayfish 

National Institute of 

General Medical 

Sciences 

Conklin MH University of Arizona 

College of Pharmacy 

Characterization of 

abandoned mine sites 

and mine wastes in 

National Institute of 

Environmental Health 

Sciences 

Arizona; assess stability 

of these sites to emission 

of copper and other 

metals to surface waters 

Sparks DL University of Delaware Influence of aging and 

competitive sorption on 

stabilization of metals 

CSREES Delaware 

through surface 

precipitates in soils 

Reeve AS University of Maine Use of stable isotope 

tracing techniques to 

determine the source of 

CSREES Maine 

salts in Maine 

groundwater, including 

copper 

Welch RM Agricultural Research 

Service, Ithaca, New 

Study the soil chemistry, 

distribution, and 

ARS 

York bioavailability to crops of 

health-related elements 

(e.g., Fe, Zn, Ca, Se, Cd, 

B) and their movement 

into edible plant parts. 

Ahner BA Cornell University Determine the nature and 

source of organic ligands 

in marine waters to better 

SAES New York 

understand the cycling 

and bioavailability of Cu 

and Fe. 

Hesterberg DL North Carolina State 

University 

Determine the 

significance of heavymetal sulfides (and other 

stable chemical species) 

for reducing the mobility 

and bioavailability of 

potentially-toxic metals in 

complex clay-organic 

CSREES North Carolina 

systems. 
 

 

COPPER	 191 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-15. Ongoing Studies on Environmental Fate and the Potential for Human 

Exposure to Copper 

Hunt JR Agricultural Research 

Center, Grand Forks, 

North Dakota 

Zelazny LW Virginia Polytechnic 

Institute 

Determine how changes ARS 

in the U.S. diet may 

affect nutritional status, 

with emphasis on intakes 

and bioavailabilities of 

iron, zinc, copper, and 

selenium 

Determine and compare CSREES Virginia 

the quantity, chemical 

forms, and plant available 

levels of P, Cu, and Zn 

from manures treated 

with phytase after 

reacting with selected 

soils for various time 

periods 

Source: CRIS 2003; FEDRIP 2003 

a

ARS = Agricultural Research Service; CSREES = Cooperative State Research, Education, and Extension Service; 

SAES = State Agricultural Research Station–Multistate Research Projects 

COPPER 193 

7. ANALYTICAL METHODS 

The purpose of this chapter is to describe the analytical methods that are available for detecting, 

measuring, and/or monitoring copper, its metabolites, and other biomarkers of exposure to and affects of 

copper. 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 

Analytical methods and detection limits for copper in biological materials are given in Table 7-l. Copper 

in other biological materials such as hair and nails can be determined by using suitable procedures for 

dissolving the sample matrix and employing the same analytical techniques as with blood and tissue. 

These methods determine the total amount of copper in the sample. The methodology for analyzing 

biological material is similar to that used for environmental samples. The most commonly employed 

methods use atomic adsorption spectroscopy (AAS) or inductively coupled plasma-atomic emission 

spectroscopy (ICP-AES) (Araki et al. 1990; Lo and Araki 1989; Lopez-Artiguez et al. 1993). 

Differential-pulse anodic stripping voltammetry techniques have also been used to quantify copper in 

urine, yielding detection limits of 0.041 μg/L and an accuracy of 97% (Horng 1996). 

7.2 ENVIRONMENTAL SAMPLES 

Analytical methods and detection limits for copper in environmental media are given in Table 7-2. 

Analytical methods determine the total copper content of the samples. Determining specific copper 

compounds and complexes in samples is difficult. The most common methods used for environmental 

samples are AAS, either flame or graphite furnace, ICP-AES, and inductively coupled plasma-mass 

spectrometry (ICP-MS). Water and waste water samples can be analyzed for copper by EPA Test 

Method 200.1 (flame atomic absorption), 200.7 ICP-AES, or EPA Test Method 200.9 (temperature 
COPPER 194 

7. ANALYTICAL METHODS 

Table 7-1. Analytical Methods for Determining Copper in Biological Materials 

Sample Analytical Sample detection Percent 

matrix Preparation method method limit recovery Reference 

Blood or Acid digestion Method 8005a

; 1 μg/100 mL Not available NIOSH 1987 

tissue ICP-AES blood; 0.2 μg/g 

tissue 

Urine Filter and polydithio- Method 8310a

; 0.1 μg Not available NIOSH 1987 

carbamate resin ICP-AES 

collection followed by 

low temperature plasma 

ashing or acid digestion 

Tissue HNO3 digestion AAS/graphite 0.25 μg/g wet 103.1±7.7% Lowe et al. 

furnace weight mean recovery; 1985 

8.2±6.9% mean 

difference in 

duplicatesb

; 

0.01% accuracy 

Toenails HNO3 digestion AAS/graphite 0.6 μg/g <5% within run Wilhelm et al. 

furnace precision; 3.5% 1991 

day-to-day 

precision 

a

Simultaneous, multielemental analysis, not compound specific. 

b

Mean±1 standard deviation 

AAS = atomic absorption spectrometry; ICP-AES = inductively coupled plasma-atomic emission spectroscopy 
COPPER 195 

7. ANALYTICAL METHODS 

Table 7-2. Analytical Methods for Determining Copper in Environmental Samples 

Analytical Sample Percent 

Sample matrix Preparation method method detection limit recovery Reference 

Air Filter collection on Method 730, 1 μg No bias NIOSH 1987 

0.8 mμ membrane filter ICP-AES identified 

and acid digestion 

Air Filter collection on Method 7029, 0.05 μg No NIOSH 1987 

0.8 mμ membrane filter AAS significant 

and acid digestion bias 

Water, waste Acidify with 1:1 HNO3 to Method 220.1, 20 μg/L 0.9–29.7% EPA 1983 

water a pH<2 AAS/direct bias 

aspiration between 

7.5 and 

332 μg/L 

Water, waste Sample solutions should Method 220.2, 1 μg/L Not EPA 1983 

water contain 0.5% HNO3 AAS/furnace available 

technique 

Water, waste Filter and acidify sample Method 200.7 6 μg/L Not EMMI 1997 

water CLP-M ICP- available 

AES 

Water, waste Digestion with H2SO4 Neocuproine, 120 μg/L in Not Greenberg et 

water and HNO3 spectrometric 1 cm cell available al. 1985 

Waste water Adjust pH to 1.65–1.85, Method 200.1, 4 mg/L Not EMMI 1997 

mix, filter flame atomic available 

absorption 

Water, waste Filter and acidify Method 25 μg/L Not EMMI 1997 

water 200.7_M, ICP- available 

AES 

Groundwater, Filter and acidify Method 200.8, 20 μg/L Not EMMI 1997 

surface water, ICP-MS available 

and drinking 

water 

Marine waters Digest in HNO3, Method 7 μg/L Not EMMI 1997 

concentrate on iminodi­ 200.10, ICP- available 

acetate chelating resin, MS 

elute with 1.25 M HNO3 

Marine waters, Digest in HNO3, Method 5 μg/L Not EMMI 1997 

estuarine waters, concentrate on iminodi­ 200.13, GFAA available 

seawaters, and acetate chelating resin, 

brines elute with 1.25 M HNO3 

Soil, sediment, Digestion with HNO3 Method 7210, 20 μg/L As in EPA 1986 

sludge, and solid and H2O2, reflux with AAS Method 

waste dilute HCl 220.1 
COPPER 196 

7. ANALYTICAL METHODS 

Table 7-2. Analytical Methods for Determining Copper in Environmental Samples 

Sample matrix Preparation method 

Analytical 

method 

Sample 

detection limit 

Percent 

recovery Reference 

Food Closed-system digestion AAS or ASV 0.32 μg/g 

(ASV), not 

reported (AAS) 

94–100 Holak 1983 

Biological tissues HNO3 digestion, 

reaction with H2O2 

Method 200.3, 

ICP-MS 

18 μg/L Not 

available 

EMMI 1997 

Fish tissue (fresh 

edible tissue) 

Dissociate tissue in 

tetraammonium 

hydroxide, acidify with 

HNO3 

Method 

200.11, ICPAES 

18 μg/L Not 

available 

EMMI 1997 

AAS = atomic absorption spectrometry; ASV = anodic stripping voltammetry; GFAA = graphite furnace atomic 

absorption; ICP-AES = inductively coupled plasma-atomic emission spectroscopy; ICP-MS = inductively coupled 

plasma-mass spectrometry 
 

 

COPPER 197 

7. ANALYTICAL METHODS 

stabilized graphite furnace atomic absorption spectroscopy) (EMMI 1997). These methods are suitable 

for groundwater and surface water as well as domestic and industrial effluents. EPA Test Method 

200.8 ICP-MS or EPA Test Method 200.15 ICP-AES are suitable for analysis of groundwater, surface 

water, and drinking water. EPA Test Method 200.8, EPA Test Method 200.10 (on-line chelation and 

ICP-MS), or EPA Test Method 200.13 (chelation and graphite furnace atomic absorption spectroscopy) 

are suitable for marine, estuary, and brine waters. If determination of dissolved and suspended copper is 

required, samples should be filtered using a 0.45 μm membrane filter. Suspended solids, as well as 

sludge and sediment, may be analyzed by EPA Methods 200.1 and 200.13 after an initial acid digestion 

with HNO3. Interference by other elements is not a problem in the analysis. However, background 

correction may be required when using atomic absorption spectroscopy to correct for nonspecific 

absorption and scattering, which may be significant at the analytical wavelength, 324.7 nm (EPA 1986). 

In the determination of trace metals, major concerns are contamination and loss. Contamination can be 

introduced from impurities in reagents and containers as well as from laboratory dust. Losses may also 

occur due to adsorption onto containers. 

Other analytical methods used for copper analysis include x-ray fluorescence, anodic stripping 

voltammetry, neutron activation analysis, photon-induced x-ray emission, as well as chemical 

derivatization, followed by gas chromatographic or liquid chromatographic analysis. Discussion of these 

methods is beyond the scope of this profile. However, methodology for the determination of copper has 

been reviewed by Gross et al. (1987) for food, by Fox (1987) for air, by MacCarthy and Klusman (1987) 

for water, and Lichte et al. (1987) for geological materials. 

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 copper 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 copper. 

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 certain uncertainties of human health assessment. This definition should not be interpreted to 
COPPER 198 

7. ANALYTICAL METHODS 

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. 

7.3.1 Identification of Data Needs 

Methods for Determining Biomarkers of Exposure and Effect. 

Exposure. Methods for determining background and elevated levels of copper in biological materials are 

well developed, sensitive, specific, and reliable. Standardized methods are available from NIOSH and 

other sources. The use of copper concentrations in toenails and hair has been investigated as surrogate 

markers of copper exposure, with validation studies currently underway. 

Effect. No specific biomarkers of copper toxicity have been determined. Until such biomarkers are 

determined, the methodology needed to identify them cannot be established. 

Methods for Determining Parent Compounds and Degradation Products in Environmental 

Media. Methods for determining background and elevated levels of copper in environmental media are 

well-developed, sensitive, and selective. Water is the medium of most concern, since the form of copper 

generally associated with health effects is soluble copper(II). Standardized methods of analysis for 

copper in air, water, soil, and food are available from EPA, NIOSH, and other sources. Analytical 

methods measure total copper. Therefore, the methods can not specifically analyze for a parent 

compound and a degradation product. 

7.3.2 Ongoing Studies 

Ongoing studies regarding new analytical methods for measuring copper in biological materials or 

environmental media were located in the literature. Dr. M. Longnecker at the National Institute of 

Environmental Health Sciences is working to validate toenail copper concentrations as a surrogate 

measure of exposure to copper. Development of high-performance liquid chromatography (HPLC) and 

derivatization techniques for identifying natural copper chelators in marine water is being conducted at 

Cornell University under the guidance of Drs. B.A. Ahner and J.W. Moffett. Dr. D.L. Sparks, at the 

University of Delaware, is developing x-ray absorption fine structure (XAFS) and atomic force 

microscopy (AFS) techniques for the study of metal/metalloid reactions in soil. Dr. J.F. Tyson and 
COPPER 199 

7. ANALYTICAL METHODS 

colleagues at the University of Massachusetts at Amherst are developing liquid-liquid extraction 

pretreatment techniques that can be interfaced with HPLC-ICP-MS instrumentation. 

 

 

COPPER 201 

8. REGULATIONS AND ADVISORIES 

ATSDR has derived acute- and intermediate-duration oral MRLs for copper. These MRLs are intended to 

protect against the health effects associated with exposure to copper-contaminated drinking water; it 

assumes that the affected population will have a normal intake of copper from the diet. The acuteduration oral MRL is 0.01 mg copper/kg/day. It is based on the occurrence of gastrointestinal 

disturbances in women ingesting 0.0731 mg Cu/kg/day in drinking water for 2 weeks; no adverse effects 

were observed at a drinking water dose of 0.0272 mg Cu/kg/day (Pizarro et al. 1999). To calculate an 

MRL, the NOAEL of 0.0272 mg Cu/kg/day was divided by an uncertainty factor of 3 to account for 

human variability. 

An intermediate-duration oral MRL of 0.01 mg copper/kg/day was derived for copper. This MRL is 

based on the occurrence of gastrointestinal disturbances in men and women ingesting 0.091 mg 

Cu/kg/day in drinking water for 2 months; no adverse effects were observed at a drinking water dose of 

0.042 mg Cu/kg/day (Araya et al. 2003b). To calculate an MRL, the NOAEL of 0.042 mg Cu/kg/day was 

divided by an uncertainty factor of 3 to account for human variability. 

International, national, and state regulations and guidelines regarding human exposure to copper are 

summarized in Table 8-1. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

COPPER 202 

8. REGULATIONS AND ADVISORIES 

Table 8-1. Regulations and Guidelines Applicable to Copper 

Agency Description Information Reference 

INTERNATIONAL 

Guidelines: 

IARC Carcinogenicity classification 

Copper 8-hydroxyquinoline Group 3a 

IARC 2002 

NATIONAL 

Regulations and 

Guidelines: 

a. Air 

ACGIH TLV (8-hour TWA) 

 Fume (Cu) 

Dusts and mists (as Cu) 

0.2 mg/m3 

1.0 mg/m3 

ACGIH 2001 

EPA Serious health effects form ambient air EPA 2002b 

exposure (Cu) 40CFR1910.1000 

NIOSH REL (10-hour TWA) 

 Fume (as Cu) 

Dusts and mists (as Cu) 

0.1 mg/m3 

1.0 mg/m3 

NIOSH 2002

IDLH 

Fume, dusts, and mists (as Cu) 100 mg/m3 

OSHA PEL (8-hour TWA) for general industry OSHA 2002c 

29CFR1910.1000 

 Fume (as Cu) 

Dusts and mists (as Cu) 

0.1 mg/m3 

1.0 mg/m3 

PEL (8-hour TWA) for construction 

industry 

 Fume (as Cu) 

Dusts and mists (as Cu) 

0.1 mg/m3 

1.0 mg/m3 

 OSHA 2002b 

29CFR1926.55 

PEL (8-hour TWA) for shipyard industry OSHA 2002a 

29CFR1915.1000 

 Fume (as Cu) 

Dusts and mists (as Cu) 

0.1 mg/m3 

1.0 mg/m3 

b. Water 

DOT Marine pollutant (Cu metal powder and 

cupric sulfate) 

DOT 2002 49 

CFR172.101, Appendix B 

EPA Drinking water standard EPA 2002c 

Action level (Cu) 1.3 mg/L 

 MCLG (Cu) 1.3 mg/L EPA 2002d 

40CFR141.51(b) 

Groundwater monitoring (Cu) EPA 2002g 

40CFR264, Appendix IX 

 Suggested method PQL

 6010 60 μg/L 

7210 200 μg/L 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

COPPER 

8. REGULATIONS AND ADVISORIES 

203 

Agency 

Table 8-1. Regulations and Guidelines Applicable to Copper 

Description Information Reference 

NATIONAL (cont.)

 EPA Hazardous substance in accordance with EPA 2002j 

Section 311(b)(2)(A) of the Clean Water 40CFR116.4 

Act (cupric sulfate and cupric sulfate 

ammoniated) 

Reportable quantity of hazardous EPA 2002k 

substance designated pursuant to 40CFR117.3

Section 311 of the Clean Water Act 

 Cupric sulfate 10 pounds 

 Cupric sulfate, ammoniated 100 pounds 

Secondary MCL for public water systems 1.0 mg/L EPA 2002e 

(Cu) 40CFR143.3 

Toxic pollutant designated pursuant to EPA 2002a 

Section 307(a)(1) of the Federal Water 40CFR401.15 

Pollution Control Act and is subject to 

effluent limitations (Cu and compounds) 

Water quality criteria (Cu) EPA 1999 

 Fresh water

 CMC 13.0 μg/L 

 CCC 9.0 μg/L 

 Salt water 

CMC 4.8 μg/L 

 CCC 3.1 μg/L 

Human health for consumption of 1,300 μg/L 

water and organism 

 Organoleptic effect criteria 1,000 μg/L 

c. Food and Drugs 

EPA Exemption from requirement of a EPA 2002f 

tolerance in meat, milk, poultry, eggs, 40CFR180.1021 

fish, shellfish, and irrigated crops when it 

results from the use as an algaecide, 

herbicide, and fungicide when used in 

accordance with good agricultural 

practices (Cu)

FDA Bottled water; allowable level (Cu) 1.0 mg/L FDA 2001a 

21CFR165.110 

Clinical chemistry test system; copper Exempt from FDA 2001b 

test system measures copper levels in premarket 21CFR862.1190 

plasma, serum, and urine notification 

procedures in 

Subpart E of 

Part 807 

Color additives exempt from Cu not less FDA 2001e 

certification—copper powder for use in than 95% 21CFR73.1647 

externally applied drugs 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

COPPER 204 

8. REGULATIONS AND ADVISORIES 

Table 8-1. Regulations and Guidelines Applicable to Copper 

Agency Description Information Reference 

NATIONAL (cont.) 

FDA Color additives exempt from FDA 2001f 

certification—copper powder for use in 21CFR73.2647 

cosmetics 

Direct food substance affirmed as FDA 2001c 

generally recognized as safe when used 21CFR184.1261 

as a nutrient supplement or as a 

processing aid (cupric sulfate) 

Drug products containing certain active Weight control FDA 2001g 

ingredients offered over-the-counter; drug product 21CFR310.545(a)(20) 

inadequate data to establish general 

recognition of the safety and 

effectiveness of these ingredients for the 

specified uses (Cu) 

Trace minerals added to animal feeds as FDA 2001i 

nutritional dietary supplements are 21CFR582.80 

generally recognized as safe when 

added at levels consistent with good 

feeding practices (Cu compounds) 

IOM Recommended dietary allowance (RDA) 0.9 mg/day IOM 2001 

Tolerable upper intake level 10 mg/day 

d. Other 

EPA Carcinogenicity classification (Cu) Group Db

 IRIS 2004 

RfC No data 

RfD No data 

Reportable quantity designated as a 5,000 pounds EPA 2002h 

CERCLA hazardous substance under 40CFR302.4 

Section 307(a) of the Clean Water Act 

(Cu) 

Reportable quantity designated as a 10 pounds EPA 2002h 

CERCLA hazardous substance under 40CFR302.4 

Section 311(b) (4) of the Clean Water 

Act (cupric sulfate) 

Toxic chemical release reporting; 01/01/87 EPA 2002i 

community right-to-know; effective date 40CFR372.65(a) 

of reporting (Cu) 

STATE 

Regulations and 

Guidelines 

a. Air 

Illinois Toxic air contaminant (Cu) BNA 2001 

Louisiana Toxic air pollutantc BNA 2001 

Minimum emission rate (Cu and 25 pounds/year 

compounds) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

COPPER 205 

8. REGULATIONS AND ADVISORIES 

Table 8-1. Regulations and Guidelines Applicable to Copper 

Agency Description Information Reference 

STATE (cont.) 

New Mexico Toxic air pollutant BNA 2001 

 Fume (Cu)

 OEL 0.2 mg/m3

 Emissions 0.0133 pounds/ 

hour 

Dusts and mists (as Cu) 

OEL 1.0 mg/m3

 Emissions 0.0667 pounds/ 

hour 

Vermont Cu compounds BNA 2001 

Hazardous ambient air standard 100 μg/m3

 Averaging time 8 hours 

 Action level 4 pounds/hour 

b. Water 

Arizona Drinking water guideline (Cu) 1,300 μg/L HSDB 2004 

North Carolina Groundwater quality standard (Cu) 1.0 mg/L BNA 2001 

c. Food No data 

d. Other 

Arizona Soil remediation levels (Cu and BNA 2001 

compounds) 

 Residential 2,800 mg/kg 

 Non-residential 63,000 mg/kg 

Florida Toxic substance in the workplace (Cu BNA 2001 

fume, dust, and mist) 

a

Group 3: unclassifiable as to carcinogenicity to humans 

b

Group D: not classifiable as to human carcinogenicity 

c

Class II: suspected human carcinogen and known or suspected human reproductive toxin 

ACGIH = American Conference of Governmental Industrial Hygienists; BNA = Bureau of National Affairs; 

CERCLA = Comprehensive Environmental Response Compensation and Liability Act; CFR = Code of Federal 

Regulations; CCC = criterion continuous concentration; CMC = criteria maximum concentration; Cu = copper; 

DOT = Department of Transportation; EPA = Environmental Protection Agency; FDA = Food and Drug 

Administration; HSDB = Hazardous Substances Data Bank; IARC = International Agency for Research on Cancer; 

IDLH = immediately dangerous to life and health; IOM = Institute of Occupational Medicine; IRIS = Integrated Risk 

Information System; MCL = maximum contaminant level; MCLG = maximum contaminant level goal; 

NIOSH = National Institute for Occupational Safety and Health; OEL = occupational exposure limit; 

OSHA = Occupational Safety and Health Administration; PEL = permissible exposure limits; PQL = practical 

quantitation limits; RDA = recommended dietary allowance; REL = recommended exposure limit; RfC = inhalation 

reference concentration; RfD = oral reference dose; TLV = threshold limit value; TWA = time-weighted average 

 

 

_______________________ 

COPPER 207 

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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. 
COPPER 268 

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. 

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. 
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10. GLOSSARY 

Intermediate Exposure—Exposure to a chemical for a duration of 15–364 days, as specified in the 

Toxicological Profiles. 

Immunologic Toxicity—The occurrence of adverse effects on the immune system that may result from 

exposure to environmental agents such as chemicals. 

Immunological Effects—Functional changes in the immune response. 

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. 
COPPER 270 

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) which 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 odds ratio 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 
COPPER 271 

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) concentrations 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. 
 

 

COPPER 272 

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. 

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. 
COPPER 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 
COPPER 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, 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, Agency for Toxic Substances and Disease 

Registry, 1600 Clifton Road NE, Mailstop F-32, Atlanta, Georgia 30333. 
 

 

 

 

 

 

 

 

COPPER A-3 

APPENDIX A 

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: Copper and Compounds 

CAS Number: 

Date: Septem ber 8, 2004 

Profile Status: Final Post-Public Comment 

Route: [ ] Inhalation [X] Oral 

Duration: [X] Acute [ ] Intermediate [ ] Chronic 

Key to Figure: 11 

Species: Humans 

Minimal Risk Level: 0.01 [X] mg copper/kg/day [ ] ppm 

Reference: Pizarro F, Olivares M, Uauy R, et al. 1999. Acute gastrointestinal effects of graded levels of 

copper in drinking water. Environ Health Perspect 107:117-121. 

Experimental design: (human study details or strain, number of animals per exposure/control groups, sex, 

dose administration details): A group of 60 healthy women (mean ages of 32.9–36.3 years) were divided 

into four groups. Each group consumed water containing 0, 1, 3, or 5 mg/L ionic copper as copper sulfate 

(0.006, 0.0272, 0.0731, and 0.124 mg Cu/kg/day) for a 2-week period with a 1-week rest between copper 

exposures. Each week, the subjects received a bottle containing copper sulfate solution and were asked to 

mix the contents of the bottle with 3 L water; this water was then used for drinking and cooking. The 

subjects recorded daily water consumption and any symptoms. Blood samples were collected 1 week 

before the study, at the end of the first 2-week exposure period, and at the end of the study; the blood was 

analyzed for serum copper, aspartate aminotransferase, alanine aminotransferase, and gamma glutamyl 

transferase activities, and hemoglobin levels. The average copper dietary intake, based on a 24-hour 

dietary recall, was 1.7 mg Cu/day (0.0266 mg Cu/kg/day using an average body weight of 64 kg). 

Effects noted in study and corresponding doses: No significant alterations in serum copper, 

ceruloplasmin, hemoglobin, or liver enzymes were observed. Twenty-one subjects reported 

gastrointestinal symptoms, predominantly nausea. Nine subjects reported diarrhea with or without 

abdominal pain, no association between copper level and diarrhea was found. Six of these episodes of 

diarrhea occurred during the first week of the study independent of copper concentration. Twelve 

subjects reported abdominal pain, nausea, and/or vomiting; the incidences were 3/60, 1/60, 10/60, and 

9/60 in the control, 0.0272, 0.0731, and 0.124 mg Cu/kg/day groups, respectively. There was a 

significant difference between in the incidences at concentrations of ≤1 mg/L (0.0272 mg/kg/day) versus 

≥3 mg/L (0.0731 mg/kg/day). No other differences between groups were found. 

Dose and end point used for MRL derivation: The MRL is based on the NOAEL of 0.0272 mg 

Cu/kg/day for gastrointestinal effects in women ingesting copper sulfate in drinking water for 2 weeks 

(Pizarro et al. 1999). 

[X] NOAEL [ ] LOAEL 

Uncertainty Factors used in MRL derivation: 

[ ] 10 for use of a extrapolation from animals to humans 

[X] 3 for human variability; a partial uncertainty factor was used because toxicokinetic 

differences among individuals should not affect the sensitivity of this direct contact effect. 
 

COPPER A-4 

APPENDIX A 

Was a conversion factor used from ppm in food or water to a mg/body weight dose? Yes. Daily doses of 

copper from drinking water were calculated using reported daily copper intakes (0.04, 1.74, 4.68, and 

7.94 mg) and the average of the mean reported body weights (64 kg). 

If an inhalation study in animals, list conversion factors used in determining human equivalent dose: NA 

Was a conversion used from intermittent to continuous exposure? No 

Other additional studies or pertinent information that lend support to this MRL: Numerous experimental 

studies and case reports support the identification of the gastrointestinal tract as the most sensitive end 

point of toxicity in humans acutely exposed to copper in drinking water or in contaminated beverages 

(Araya et al. 2001, 2003a, 2003b, 2003c; Chuttani et al. 1965; Gotteland et al. 2001; Knobeloch et al. 

1994; Nicholas and Brist 1968; Olivares et al. 2001; Pizarro et al. 1999, 2001; Spitalny et al. 1984). In 

single exposure experiments in which subjects ingested copper sulfate in drinking water following an 

overnight fast, nausea, vomiting, and/or abdominal pain were reported at doses ranging from 0.011 to 

0.03 mg Cu/kg/day as copper sulfate (Araya et al. 2001, 2003a, 2003c; Gotteland et al. 2001; Olivares et 

al. 2001). NOAEL values identified in these studies ranged from 0.0057 to 0.011 mg Cu/kg. Daily 

exposure to 0.096 mg Cu/kg/day as copper sulfate or copper oxide for 1 week also resulted in an 

increased occurrence of nausea, vomiting, and/or abdominal pain (Pizarro et al. 2001). Animal studies 

support the identification of the gastrointestinal tract as the most sensitive target of toxicity following 

acute-duration oral exposure. Hyperplasia of the forestomach mucosa was observed in rats exposed to 

44 mg Cu/kg/day as copper sulfate in the diet (NTP 1993) and in mice exposed to 197 mg Cu/kg/day as 

copper sulfate in the diet (NTP 1993). At higher doses, liver and kidney damage have been observed 

(Haywood 1980; Haywood and Comerford 1980; Haywood et al. 1985b; NTP 1993). 

Although the LOAEL values identified in the single exposure studies are lower than the NOAEL 

identified in the Pizarro et al. (1999) study, the Pizarro et al. (1999) study was selected as the critical 

study because it is a longer-duration study and it more closely mimics an exposure scenario of a 

population drinking copper-contaminated drinking water. 

Agency Contact (Chemical Manager): Alfred Dorsey, DVM 
 

 

 

 

 

 

 

 

COPPER A-5 

APPENDIX A 

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: Copper and Compounds 

CAS Number: 

Date: Septem ber 8, 2004 

Profile Status: Final Post-Public Comment 

Route: [ ] Inhalation [X] Oral 

Duration: [ ] Acute [X] Intermediate [ ] Chronic 

Key to Figure: 21 

Species: Humans 

Minimal Risk Level: 0.01 [X] mg copper/kg/day [ ] ppm 

Reference: Araya M, Olivares M, Pizarro F, et al. 2003b. Gastrointestinal symptoms and blood 

indicators of copper load in apparently healthy adults undergoing controlled copper exposure. Am J Clin 

Nutr 77:646-650. 

Experimental design (human study details or strain, number of animals per exposure/control groups, sex, 

dose administration details): Groups of 327–340 men and women (mean age 32.9 years) were exposed to 

0, 2, 4, or 6 mg Cu/L in drinking water for 2 months. The subjects prepared the copper sulfate solution 

daily using tap water and a stock copper sulfate solution. The copper solution was used for drinking and 

preparation of beverages and soups. The subjects completed a daily survey on gastrointestinal and other 

symptoms. Blood samples were analyzed for a subset of 48–49 subjects for red blood cell copper, 

monocyte copper, serum copper, serum ceruloplasmin, superoxide dismutase, aspartate aminotransferase, 

alanine amino transferases, γ-glutamyltransferase, and hemoglobin levels. Reported copper intakes from 

water in the subset of subjects were 0, 42.5, 92.9, and 177.9 μmol/day (0, 2.7, 5.9, and 11.3 mg/day). 

Doses were calculated using reported copper intakes for the subset of subjects and a reference body 

weight of 65 kg. 2 ppm: 2.7 mg Cu/day x 1/65 kg = 0.042 mg Cu/kg/day; 4 ppm: 

5.9 mg/day = 0.091 mg Cu/kg/day; 6 ppm: 11.3 mg/day = 0.17 mg Cu/kg/day 

Effects noted in study and corresponding doses: The incidences of gastrointestinal symptoms were 11.7, 

15.3, 18.3, and 19.7% in the 0, 0.042, 0.091, and 0.17 mg Cu/kg/day groups, respectively. Using a chisquare test with Bonferroni correction, the incidence of gastrointestinal symptoms was significantly 

increased in the 0.17 mg Cu/kg/day group. However, if the Bonferroni correction was not used, the 

incidence was also significantly increased in the 0.091 mg Cu/kg/day group. Only one test is used to 

assess whether exposure to copper results in adverse gastrointestinal effects (reported symptoms); thus, 

the Bonferroni correction is not needed for this end point. No significant alterations in copper status 

parameters or biomarkers of liver disease were observed. 

Dose and end point used for MRL derivation: The MRL is based on the NOAEL of 0.042 mg Cu/kg/day 

for gastrointestinal effects in men and women ingesting copper sulfate in drinking water for 2 months. 

[X] NOAEL [ ] LOAEL 
COPPER A-6 

APPENDIX A 

Uncertainty Factors used in MRL derivation: 

[ ] 10 for use of a extrapolation from animals to humans 

[X] 3 for human variability; a partial uncertainty factor was used because toxicokinetic 

differences among individuals should not affect the sensitivity of this direct contact effect 

Was a conversion factor used from ppm in food or water to a mg/body weight dose? Yes. Daily doses 

were calculated using reported daily copper intakes (2.7, 5.9, and 11.3 mg) and a reference body weight 

of 65 kg. 

If an inhalation study in animals, list conversion factors used in determining human equivalent dose: NA 

Was a conversion used from intermittent to continuous exposure? No 

Other additional studies or pertinent information that lend support to this MRL: There are limited data on 

the intermediate-duration toxicity of copper in humans. The Araya et al. (2003b) is the only human study 

located that examined the gastrointestinal tract following intermediate-duration exposure to copper. A 

number of acute-duration studies (Araya et al. 2001, 2003a, 2003c; Gotteland et al. 2001; Nicholas and 

Brist 1968; Olivares et al. 2001) support the identification of the gastrointestinal tract as the sensitive 

target of toxicity in humans. An intermediate-duration study by Pratt et al. (1985) did not find alterations 

in serum biomarkers of liver damage (cholesterol and triglyceride levels and aspartate aminotransferase, 

alkaline phosphatase, γ-glutamyl transferase, and lactate dehydrogenase activities) in seven adults 

administered 10 mg Cu/day (0.14 mg Cu/kg/day) as copper gluconate in a capsule for 12 weeks. Three 

intermediate-duration studies in infants also found no significant evidence of liver damage (Olivares et al. 

1998; Zietz et al. 2003a, 2003b). 

Numerous animal studies have examined the toxicity of copper following intermediate-duration oral 

exposure (Epstein et al. 1982; Fuentealba et al. 2000; Haywood 1980, 1985; Haywood and Comerford 

1980; Haywood and Loughran 1985; Haywood et al. 1985a, 1985b; Kumar and Sharma 1987; NTP 1993; 

Rana and Kumar 1980). Most of these studies have focused on the liver and kidneys, with adverse effect 

levels of at least 100 times higher than the adverse effect level for gastrointestinal effects in humans. 

Gastrointestinal tract alterations were observed in rats and mice. Hyperplasia of the squamous mucosa on 

the limiting ridge separating the forestomach from the glandular stomach was observed in rats and mice 

exposed to 33 or 267 mg Cu/kg/day, respectively, as copper sulfate in the diet for 13 weeks (NTP 1993). 

Agency Contact (Chemical Manager): Alfred Dorsey, DVM 
 

COPPER 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 
 

 

COPPER B-2 

APPENDIX B 

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. 

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). 
COPPER B-3 

APPENDIX B 

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. 

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 
COPPER B-4 

APPENDIX B 

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"). 

(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 
COPPER B-5 

APPENDIX B 

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. 

(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. 
1 

3 4 

SAMPLE 

→ Table 3-1. Levels of Significant Exposure to [Chemical x] – Inhalat

LOAEL (effect) Exposure Less serious Serious (ppm) frequency/ NOAEL (ppm) Key to figurea Species duration System (ppm) 

2 → INTERMEDIATE EXPOSURE 

5 

→ Systemic ↓

18 Rat 

→

CHRONIC EXPOSURE Cancer 38 Rat 

39 Rat 40 Mouse 

6 ↓13 wk 5 d/wk 6 hr/d 18 mo 5 d/wk 7 hr/d 89–104 wk 5 d/wk 6 hr/d 79–103 wk 5 d/wk 6 hr/d 

7 ↓Resp 

8 ↓3b 

9 

↓

10 (hyperplasia) 

11 ↓20 (CEL, multiple 

organs) 

10 (CEL, lung tumors, 

nasal tumors) 

10 (CEL, lung tumors, 

hemangiosarcomas) 

12 → 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 

by an uncertainty factor of 100 (10 for extrapolation from animal to humans, 10 for human variability). 

COPPER 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 benchmark dose 

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 

DOT Department of Transportation 
 

COPPER C-2 

APPENDIX C 

DOT/UN/ Department of Transportation/United Nations/ 

NA/IMCO North America/International Maritime Dangerous Goods Code 

DWEL drinking water exposure level 

ECD electron capture detection 

ECG/EKG electrocardiogram 

EEG electroencephalogram 

EEGL Emergency Exposure Guidance Level 

EPA Environmental Protection Agency 

F Fahrenheit 

F1 first-filial generation 

FAO Food and Agricultural Organization of the United Nations 

FDA Food and Drug Administration 

FEMA Federal Emergency Management Agency 

FIFRA Federal Insecticide, Fungicide, and Rodenticide Act 

FPD flame photometric detection 

fpm feet per minute 

FR Federal Register 

FSH follicle stimulating hormone 

g gram 

GC gas chromatography 

gd gestational day 

GLC gas liquid chromatography 

GPC gel permeation chromatography 

HPLC high-performance liquid chromatography 

HRGC high resolution gas chromatography 

HSDB Hazardous Substance Data Bank 

IARC International Agency for Research on Cancer 

IDLH immediately dangerous to life and health 

ILO International Labor Organization 

IRIS Integrated Risk Information System 

Kd adsorption ratio 

kg kilogram 

kkg metric ton 

Koc organic carbon partition coefficient 

Kow octanol-water partition coefficient 

L liter 

LC liquid chromatography 

LC50 lethal concentration, 50% kill 

LCLo lethal concentration, low 

LD50 lethal dose, 50% kill 

LDLo lethal dose, low 

LDH lactic dehydrogenase 

LH luteinizing hormone 

LOAEL lowest-observed-adverse-effect level 

LSE Levels of Significant Exposure 

LT50 lethal time, 50% kill 

m meter 

MA trans,trans-muconic acid 

MAL maximum allowable level 

mCi millicurie 

MCL maximum contaminant level 
COPPER C-3 

APPENDIX C 

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 

OW Office of Water 
COPPER C-4 

APPENDIX C 

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 
COPPER C-5 

APPENDIX C 

> 

≥

= 

< 

≤

% 

α

β

γ

δ

μm

μg 

q1

* 

– 

+ 

(+) 

(–) 

greater than 

greater than or equal to 

equal to 

less than 

less than or equal to 

percent 

alpha 

beta 

gamma 

delta 

 micrometer 

microgram 

cancer slope factor 

negative 

positive 

weakly positive result 

weakly negative result 

COPPER D-1 

APPENDIX D. INDEX 

absorbed dose..............................................................................................................................................85 

adsorbed .................................................................................................... 135, 143, 145, 146, 152, 156, 184 

adsorption.................................................................................. 121, 142, 146, 147, 151, 152, 155, 193, 197 

aerobic............................................................................................................................................... 121, 145 

alanine aminotransferase........................................................... 14, 17, 18, 57, 59, 60, 61, 79, 80, 83, 88, 96 

ambient air .................................................................................................................. 11, 182, 187, 202, 205 

anaerobic................................................................................................................................... 121, 152, 157 

anemia........................................................................................................................... 12, 56, 65, 82, 87, 89 

aspartate aminotransferase ................................................................................ 14, 17, 18, 57, 61, 62, 83, 88
 

bioaccumulation................................................................................................................ 149, 150, 176, 187 

bioavailability ........................................................................................................... 101, 154, 158, 187, 190 

bioconcentration factor ..................................................................................................................... 149, 150 

biomarker ............................................................................................................................................ 85, 100 

biomarkers ...................................................................................... 13, 14, 17, 57, 83, 85, 87, 100, 193, 198 

body weight effects ......................................................................................................................... 22, 62, 65 

breast milk......................................................................................................................................... 175, 183 

cancer .......................................................................................................................... 6, 7, 13, 31, 64, 82, 98 

carcinogen............................................................................................................................................. 7, 205 

carcinogenic ........................................................................................................................ 15, 21, 64, 98, 99 

carcinogenicity............................................................................................................ 13, 31, 64, 66, 98, 205 

carcinoma....................................................................................................................................................66 

carcinomas ..................................................................................................................................................64 

cardiovascular ........................................................................................................................... 22, 54, 65, 87 

cardiovascular effects............................................................................................................................ 54, 66 

ceruloplasmin............................................................................................ 58, 71, 72, 73, 78, 80, 89, 91, 100 

chromosomal aberrations ............................................................................................................................66 

clearance ............................................................................................................................................... 23, 60 

death................................................................................................................................ 7, 21, 22, 59, 64, 87 

deoxyribonucleic acid .................................................................................................................................69 

DNA.......................................................................................................................................... 68, 69, 85, 98 

dopamine......................................................................................................................................... 12, 63, 99 

endocrine................................................................................................................................... 22, 32, 65, 80 

endocrine effects .........................................................................................................................................24 

fetus................................................................................................................................................... 1, 81, 84 

gastrointestinal distress ......................................................................................................................... 12, 87 

gastrointestinal effects ...................................... 12, 13, 14, 16, 17, 18, 19, 23, 24, 54, 55, 56, 83, 86, 95, 97 

general population....................................................................... 3, 11, 12, 85, 123, 158, 171, 183, 184, 188
 

genotoxic............................................................................................................................................... 21, 98 

genotoxicity..................................................................................................................................... 66, 68, 98 

groundwater ...................................................... 3, 4, 139, 141, 147, 148, 155, 163, 164, 165, 187, 190, 197 

half-life.......................................................................................................................................... 73, 85, 155 

hematological effects ...................................................................................................................... 24, 56, 65 

hematopoietic..............................................................................................................................................56 

hepatic effects ......................................................................................................... 14, 16, 24, 57, 61, 89, 96 

hydroxyl radical ..........................................................................................................................................76 

immune system ...........................................................................................................................................13 

immunological ...................................................................................................................................... 21, 25 

immunological effects.................................................................................................................................25 
COPPER D-2 

APPENDIX D 

Kow ............................................................................................................................................................109 

leukopenia...................................................................................................................................................12 

metabolic effects .........................................................................................................................................32 

metallothionen................................................................................................................................. 12, 71, 84

micronuclei ........................................................................................................................................... 66, 68

milk ................................................................................. 14, 58, 82, 90, 91, 95, 97, 102, 174, 175, 188, 203

musculoskeletal effects...............................................................................................................................56 

neonatal.......................................................................................................................................................84 

neurobehavioral..................................................................................................................................... 81, 99

neutropenia..................................................................................................................................................82 

norepinephrine ............................................................................................................................................63 

nuclear......................................................................................................................................... 78, 138, 154

ocular effects......................................................................................................................................... 22, 65

partition coefficients ......................................................................................................................... 145, 156 

pharmacodynamic .......................................................................................................................................75 

pharmacokinetic........................................................................................................................ 74, 75, 76, 77 

pharmacokinetics ........................................................................................................................................81 

pulmonary fibrosis ................................................................................................................................ 12, 22 

renal effects............................................................................................................................. 61, 95, 96, 100

retention .............................................................................................................................................. 71, 166

sequestered............................................................................................................................................ 78, 88 

solubility ................................................................................................................................... 147, 153, 185 

spermatozoa ................................................................................................................................................66 

toxicokinetic.............................................................................................................................. 17, 21, 60, 84

toxicokinetics ............................................................................................................................................101 

tremors ........................................................................................................................................................89 

tumors .........................................................................................................................................................64 

weanling......................................................................................................................................................71