EPA-600/8-79-003
January 1979
HEALTH
ASSESSMENT
DOCUMENT
FOR CADMIUM
(PREPRINT)
VS. ENVIRONMENTAL PROTECTION AGENCY
Office of Research and Development
Environmental Criteria and Assessment Office
Research Triangle Park, North Carolina 27711
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EPA-600/8-79-003
January 1979
HEALTH ASSESSMENT
DOCUMENT
FOR CADMIUM
(PREPRINT)
U.S. ENVIRONMENTAL PROTECTION AGENCY
Office of Research and Development
Environmental Criteria and Assessment Office
Research Triangle Park, North Carolina 27711
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PREFACE
This document deals with the various aspects of cadmium as an Air
pollutant in accordance with Section 122(a) of the Clean Air Act as
amended in August 1977. Section 122(a) requires that
"Not later than one year after date of enactment of this
section and after notice and opportunity for public hearing, the
Administrator shall review all available relevant information and
determine whether or not emissions of ... cadmium ... into the ambient
air will cause, or contribute to, air pollution which may reasonably
be anticipated to endanger public health."
If the Administrator does affirmatively decide that emissions of
cadmium do endanger public health,
"he shall simultaneously with such determination include such
substance in the list published under section 108(a)(l) or 122(b)(l)(A)
..., or shall include each category of stationary sources limiting such
substance in significant amounts in the list published under section
lll(b)(l)(A), or take any combination of such actions."
This decision document is intended to serve as the basis for the
Administrator's evaluation of cadmium as an air pollutant. While the
preparation of this document has required a comprehensive review of current
scientific knowledge regarding airborne cadmium, the references cited do
not constitute a complete bibliography.
The Agency acknowledges the contributions of each individual who
participated in the development of this document. However, the Environ-
mental Protection Agency accepts full responsibility for the contents
herein.
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ABSTRACT
The purpose of the present document is to provide a critical assessment
of health effects and public health risks associated with environmental
exposure to cadmium. In keeping with this objective, major current sources
and routes of exposure are identified and discussed as are key health
effects associated with cadmium exposure. Furthermore, dose-effect and
dose-response relationships are characterized and populations at special
risk are delineated. Lastly, the potential impact of current and likely
future exposure patterns on the health of the American public is analyzed.
Cadmium is naturally present in trace amounts in most environmental
media including soil, water, air, and food. Substantial additional amounts
of the element are added to each of these media as a consequence of man's
activities. Included among major anthropogenic sources are: (1) smelting
and mining operations; (2) electroplating and certain other manufacturing
operations; and (3) waste disposal operations, e.g., municipal incineration
and land application of solid waste materials. Man is exposed to cadmium
dissipated by each of these sources either directly through emissions into
ambient air or water or indirectly via secondary deposition of the element
on soils and subsequent uptake into the human food chain.
Food is presently the single largest environmental source of cadmium
exposure for most humans. Current estimates of average daily dietary
cadmium intake for Americans vary from 10 to 50 ug/day. Cigarette smoking
(one to three packs per day) can significantly increase cadmium intake in
amounts equal to or exceeding that obtained from food. General ambient
IV
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air and drinking water contribute only small increments in cadmium uptake
beyond that of food or cigarette smoking. Exceptions to this may exist in
areas surrounding certain point sources that emit high levels of cadmium.
Two major types of adverse health effects of cadmium exposure can be
distinguished—acute and chronic. Acute cadmium toxicity usually results
from inhalation of cadmium at high-dose levels encountered in occupational
settings. In cases of nonlethal inhalation exposure, chronic respiratory
effects (pneumonitis) are of primary concern. In contrast, long-term,
lower-level exposures to cadmium via air or other media, e.g., food, are of
most concern because consequent accumulations of cadmium in the kidney
induce associated renal tubular dysfunction as the "critical effect" of
chronic cadmium exposure.
The most accurate index of the effective internal cadmium dose necessary
to induce renal dysfunction is the concentration of the metal in the renal
cortex. The most common currently accepted value for the "critical concen-
tration" of cadmium in the kidney is 200 ug/g wet weight of renal cortex.
Estimates of external exposure levels sufficient to cause the critical
renal cortex concentration to be reached vary considerably. For example,
estimates of requisite ingestion levels derived from various metabolic
modeling approaches range from 200 to 480 ug/day, and levels near the lower
end of the range (200 to 250 |jg/day) are presently being seen as the best
estimates of "threshold" dietary intake levels typically needed to result
in the critical renal cortex concentration being reached over a 50-year
exposure period. Other approaches utilizing actual measures of dietary
cadmium exposures and associated prevalence of renal dysfunction, however,
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suggest that wide variability may exist across human populations in regard
to ingestion levels necessary to induce the critical effect; such studies
suggest that 1 percent, 2.5 percent, and 5 percent of the American popu-
lation, for example, would be affected at 60, 80, and 100 ug cadmium intake
per day, respectively, assuming a 50-year period.
Due to the accumulative nature of cadmium retention in the kidney,
older members (i.e., over 40 to 50 years of age) of exposed populations
typically have both the highest renal cortex concentrations of the metal
and the highest prevalence of cadmium-induced renal dysfunction. Thus,
older members of the United States population would be expected to be most
immediately at risk for future increments in cadmium exposure. Also, due
to increased absorption of cadmium being associated with certain nutritional
deficiencies, e.g., insufficient levels of dietary iron, zinc, or cadmium,
older members of the population with such nutritional deficits are likely
to be at even greater risk. Since everyone ages and is therefore subject
to long-term renal cadmium accumulation, the entire United States population
should be considered at potential risk for cadmium-induced renal dysfunction.
Also, since smokers are exposed to and retain significantly higher levels
of cadmium than non-smokers, they are clearly at greater risk for cadmium-
induced adverse health effects.
VI
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SCIENCE ADVISORY BOARD
SUBCOMMITTEE ON CADMIUM AS A POSSIBLE HAZARDOUS AIR POLLUTANT
The substance of this document was reviewed by the Environmental
Protection Agency's Science Advisory Board Subcommittee on Cadmium as a
Possible Hazardous Air Pollutant, in public session. The subcommittee was
comprised of the following individuals:
Chairman:
Dr. Ruth R. Levine, Chairman, Graduate Division of Medicine and
Dentistry, Boston University Medical School, Boston, Massachusetts
02215
Members:
Dr. Ursula M. Cowgill, Professor of Biology, University of
Pittsburgh, Pittsburgh, Pennsylvania 15260
Dr. Robert A. Duce, Professor, Graduate School of Oceanography,
University of Rhode Island, West Kingston, Rhode Island 02892
Dr. Thomas J. Haley, Assistant to the Director, National Center ofr
Toxicological Research, Jefferson, Arkansas 72079
Dr. Harold M. Peck, Senior Director, Department of Safety Assessment,
Merck Institute of Therapeutic Research, Merck, Sharp, and Dohme, West
Point, Pennsylvania 19486
Ms. Anne Wolven, Consultant, Atlanta, Georgia 30328
Staff Officer:
Dr. Joel L. Fisher, Science Advisory Board, U.S. Environmental Protection
Agency, 401 M Street S.W., Washington, D.C. 20460
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CONTRIBUTORS AND REVIEWERS
Authors
Dr. Lester D. Grant, Associate Professor, Departments of Psychiatry and
Anatomy, University of North Carolina, School of Medicine, Chapel
Hill, North Carolina 27514
Dr. Paul Mushak, Associate Professor of Pathology, School of Medicine,
University of North Carolina, Chapel Hill, North Carolina 27514
Dr. Annemarie Crocetti, Adjunct Associate Professor of Preventive and
Community Medicine, New York Medical College, New York, New York
10029
Mr. Warren Galke, Environmental Criteria and Assessment Office, Environmental
Research Center, U.S. Environmental Protection Agency, Research Triangle
Park, North Carolina 27711
Consultants
Dr. George M. Cherian, Assistant Professor, Department of Pathology,
University of Western Ontario, London, Ontario, Canada
Dr. Gunnar Nordberg, Institute of Community Health and Environmental
Medicine, Odense University, Odense, Denmark.
Dr. H. M. Perry, Jr., Washington University School of Medicine, St.
Louis, Missouri
Dr. Magnus Piscator, Department of Environmental Hygiene, The
Karolinska Institute, Stockholm, Sweden
Dr. Samuel Shibko, Division of Toxicology, Food and Drug Administration,
Washington, D.C.
EPA Review Committee
Dr. J. H. B. Garner, Chairman, Environmental Criteria and Assessment
Office, Environmental Research Center, U.S. Environmental Protection
Agency, Research Triangle Park, North Carolina 27711
Dr. Donald E. Gardner, Health Effects Research Laboratory, U.S. Environ-
mental Protection Agency, Research Triangle Park, North Carolina
27711
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Dr. Vic Hasselblad, Health Effects Research Laboratory, Environmental
Research Center, U.S. Environmental Protection Agency, Research
Triangle Park, North Carolina 27711
Dr. Robert J. M. Morton, Health Effects Research Laboratory, Environ-
mental Research Center, U.S. Environmental Protection Agency,
Research Triangle Park, North Carolina 27711
Dr. Joel!en Huisingh, Health Effects Research Laboratory, Environmental
Research Center, U.S. Environmental Protection Agency, Research
Triangle Park, North Carolina 27711
Mr. Richard Johnson, Strategies and Air Standards Division, Office of
Air Quality Planning and Standards, U.S. Environmental Protection
Agency, Research Triangle Park, North Carolina 27711
Technical and Editorial Assistance
Ms. Gayla Benignus, Private Consultant, Chapel Hill, North Carolina
27514
Mr. Douglas B. Fennell, Environmental Criteria and Assessment Office,
U.S. Environmental Protection Agency, Research Triangle Park,
North Carolina 27711
Ms. Evelynne Rash, Environmental Criteria and Assessment Office,
U.S. Environmental Protection Agency, Research Triangle Park,
North Carolina 27711
Ms. Frances V. P. Duffield, Environmental Criteria and Assessment
Office, U.S. Environmental Protection Agency, Research Triangle
Park, North Carolina 27711
IX
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CONTENTS
Page
LIST OF FIGURES xiii
LIST OF TABLES xiv
ABSTRACT iv
1. SUMMARY AND CONCLUSIONS 1-1
1.1 INTRODUCTION 1-1
1.2 HEALTH ASPECTS OF CADMIUM IN MAN AND ANIMALS 1-4
1.2.1 Metabolism of Cadmium in Man and
Experimental Animals 1-4
1.2.2 Biological and Adverse Health Effects in
Man and Animals 1-7
1. 3 EFFECTS OF CADMIUM ON HUMAN POPULATIONS 1-13
1.4 HUMAN HEALTH RISK ASSESSMENT OF CADMIUM 1-18
1.4.1 Introduction 1-18
1.4.2 Sources and Routes of Exposure 1-18
1.4.3 Human Population Responses to Cadmium
in Human Risk Assessment 1-21
1.4.4 Overall Conclusions 1-33
2. BIOLOGICAL SIGNIFICANCE AND ADVERSE HEALTH EFFECTS OF
CADMIUM 2-1
2.1 INTRODUCTION 2-1
2.2 METABOLISM OF CADMIUM 2-2
2.2.1 Sources of Exposure 2-2
2.2.2 Inhalation 2-3
2.2.3 Gastrointestinal Absorption 2-4
2.2.4 Other Absorption Routes 2-4
2.2.5 Transport and Deposition 2-4
2.2.6 Excretion 2-6
2.3 SUB-CELLULAR AND CELLULAR ASPECTS OF
CADMIUM TOXICITY 2-7
2.3.1 General Sub-Cellular Effects 2-7
2.3.2 Metal lothionein 2-22
2.4 RESPIRATORY EFFECTS OF CADMIUM 2-27
2.4.1 Effects on Humans 2-27
2.4.2 Animal Studies 2-29
2.5 RENAL EFFECTS OF CADMIUM 2-32
2.5.1 Animal Studies 2-33
2.5.2 Human Studies 2-37
2.6 THE CARDIOVASCULAR SYSTEM 2-41
2.6.1 Animal Studies 2-41
2.6.2 Human Hypertension 2-44
2.7 EFFECTS OF CADMIUM ON REPRODUCTION AND
DEVELOPMENT 2-44
2.7.1 Testicular Effects 2-44
2.7.2 Ovarian Effects 2-54
2.7.3 Embryotoxic and Teratogenic Effects 2-55
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Page
2.8 ENDOCRINE EFFECTS OF CADMIUM 2-70
2.8.1 Gonadal Effects 2-71
2.8.2 Pancreatic Effects 2-71
2.8.3 Adrenal Effects 2-73
2.8.4 Thyroid Effects 2-75
2.8.5 Pituitary Effects 2-76
2.9 EFFECTS OF CADMIUM ON BONE AND MINERAL METABOLISM 2-76
2.9.1 Animal Studies 2-77
2.9.2 Human Aspects 2-78
2.10 HEPATIC EFFECTS OF CADMIUM 2-78
2.10.1 Animal Studies 2-79
2.10.2 Human Aspects 2-80
2.11 NEUROLOGICAL EFFECTS OF CADMIUM 2-81
2.12 GASTROINTESTINAL EFFECTS OF CADMIUM 2-85
2.13 HEMATOLOGICAL EFFECTS OF CADMIUM 2-86
2.14 IMMUNOSUPPRESSIVE EFFECTS OF CADMIUM 2-88
2.15 MUTAGENIC AND CARCINOGENIC EFFECTS OF CADMIUM 2-90
2.15.1 Mutagenic Effects of Cadmium 2-91
2.15.2 Tumorigenic Cadmium Effects in Animals 2-94
2.15.3 Human Carcinogenesis Studies 2-100
2.16 INTERACTIONS OF CADMIUM WITH OTHER METABOLIC
FACTORS 2-103
2.16.1 Zinc 2-103
2.16.2 Selenium 2-104
2.16.3 Calcium 2-107
2.16.4 Iron 2-107
2.16.5 Cooper 2-108
2.17 REFERENCES FOR CHAPTER 2 2-110
HUMAN EPIDEMIOLOGY 3-1
3.1 INTRODUCTION 3-1
3.2 CADMIUM IN HUMAN POPULATIONS 3-1
3.2.1 Sources of Variations in Human
Blood Cadmium Levels 3-2
3.2.2 Sources of Variation in Human
Uri ne Cadmi urn Level s 3-14
3.2.3 Sources of Cadmium Variation in Human Hair 3-20
3.3 RESULTS OF AUTOPSY STUDIES 3-22
3.4 EPIDEMIOLOGICAL STUDIES OF CADMIUM EXPOSURE
IN JAPAN 3-29
3.4.1 Itai-Itai Disease 3-30
3.4.2 Epidemic!ogical Studies of Other Cadmium-
Polluted Areas in Japan 3-33
3.5 EPIDEMIOLOGY OF CADMIUM, HYPERTENSION, AND CARDIO-
VASCULAR DISEASES 3-35
3.6 EPIDEMIOLOGICAL STUDIES OF THE RESPIRATORY TRACT 3-38
3.7 CADMIUM AND CANCER 3-39
3.8 EPIDEMIOLOGICAL STUDIES RELATING TO CHROMOSOMAL
ABNORMALITIES 3-43
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Page
3.9 EPIDEMIOLOGICAL STUDIES OF OCCUPATIONAL EXPOSURE
IN JAPAN 3-44
3.10 REFERENCES FOR CHAPTER 3 3-45
HUMAN HEALTH RISK ASSESSMENT OF CADMIUM 4-1
4.1 INTRODUCTION AND DEFINITION OF TERMS 4-1
4. 2 EXPOSURE ASPECTS 4-4
4.2.1 Ambient-Air Levels of Cadmium 4-5
4.2.2 Drinking Water 4-13
4.2.3 Soils 4-15
4.2.4 Food 4-30
4.2.5 Other Sources 4-46
4.3 HEALTH EFFECTS SUMMARY 4-48
4.4 DOSE-EFFECT AND DOSE-RESPONSE RELATIONSHIPS
OF CADMIUM IN HUMANS 4-52
4.4.1 Dose Aspects 4-52
4.4.2 Dose-Effect/Dose-Response Aspects 4-53
4.5 POPULATIONS AT RISK TO EFFECTS OF CADMIUM 4-66
4.6 UNITED STATES POPULATION GROUPS IN RELATION TO
PROBABLE CADMIUM EXPOSURES 4-79
4.7 REFERENCES FOR CHAPTER 4 4-89
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FIGURES
Number Page
3-1. Cadmium concentration in urine of Tokyo inhabitants
plotted by age shows age-dependent relationship 3-18
3-2. Geometric and arithmetic means of cadmium concentration
in kidney cortex are shown for each decade of life 3-26
3-3. Cadmium in whole kidney tissues and its relation-
ship to age 3-29
4-1. Diagrammatic representation of multi-media routes by which
cadmium exposure of man can occur after dissipation of
the element into the environment by anthropogenic
activities 4-6
4-2. Trends in 50th percentile of annual averages for
cadmium associated with metal industry sources
at urban sites 4-11
4-3. Contribution of food groups to cadmium intake 4-36
4-4. Effects of soil pH on cadmium uptake by vegetables 4-41
4-5. Calculated (lines) and observed (symbols) dose-response
relationships for cadmium-induced increase (>97.5) per-
cent! le of reference group) of urinary Pp-microglobulin
excretion. (From Kjellstrbm, 1977) 4-62
4-6. Regions used in cadmium analysis 4-85
xi n
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TABLES
Number Page
1-1. Cadmium exposure required for reaching a kidney cortex
concentration of 200 ug Cd/g using different alterna-
tives for biological half-time in kidney cortex and
exposure time 1-23
1-2. Media contributions to normal retention of cadmium 1-24
1-3. Food exposure: calculated intakes that may give a
certain response rate at age 50 1-26
1-4. Estimated relative contribution of dietary intake,
cigarette smoking, and ambient air cadmium levels to
total daily cadmium retention from all sources 1-31
2-1. Sub-cellular and cellular cadmium toxicity in experi-
mental animals 2-9
2-2. Species variations in susceptibility to cadmium-induced
testicular necrosis 2-47
2-3. Cadmium in placentas and fetuses 2-65
2-4. Placenta! to maternal blood concentration ratios 2-66
2-5. Placental to fetal cadmium concentration ratios 2-67
2-6. Effects of maternal dietary cadmium, given during
gestation, on body weights and body trace metals of
neonates 2-69
2-7. Summary of mutagenicity test results 2-92
2-8. Studies on cadmium tumorigenesis in experimental
animals 2-96
2-9. Summary of results of human epidemiologic studies of
cancer effects associated with occupational exposures
to cadmium 2-102
3-1. "Normal" blood cadmium levels 3-7
3-2. "Normal" urine cadmium levels 3-16
3-3. Urine cadmium levels for "normal" males in Dallas,
Texas, determined by atomic absorption 3-19
3-4. Cadmium in human liver 3-24
3-5. Cadmium concentration in human renal cortex by age:
means and 99% level of significance 3-25
3-6. Age group means and standard deviations for tissue
cadmi urn 3-25
3-7. Mean cadmium values related to place of residence 3-28
4-1. Annual average urban atmospheric cadmium concentrations
reported by National Air Surveillance Networks,
1970-1974 4-8
4-2. Cadmium in soils 4-16
4-3. Concentrations of cadmium in urban and suburban
soils - 1972 4-17
4-4. Amounts of municipal sewage sludge of varying cadmium
content annually produced by major U.S. cities and
applied to agricultural land by landspreading 4-20
xiv
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Number Page
4-5. Cadmium content in different food categories in the
U.S. A 4-32
4-6. Cadmium content of selected adult foods 4-34
4-7. Food groups by mean cadmium content and their contri-
bution to daily cadmium intake 4-35
4-8. Cadmium intake of teen-age males by food class 4-37
4-9. Cadmium content of several crops and tissues as a
function of cadmium loading of soil 4-40
4-10. Cadmium content of soils and crops grown on acid and
limed sludged sites 4-42
4-11. Media contributions to normal retention of cadmium 4-47
4-12. Cadmium exposure required for reaching a kidney cortex
concentration of 200 ug Cd/g using different alter-
natives for biological half-time in kidney cortex and
exposure time 4-57
4-13. Food exposure: calculated intakes that may give a
certai n response rate at age 50 4-64
4-14. Prevalence of tubular proteinuria and suspected
patients among adults more than 50 years of age in
relation to village average rice cadmium concentra-
tions 4-65
4-15. Prevalence of tubular proteinuria in relation
to age and village average rice cadmium concentation.. 4-67
4-16. Relative contribution of cigarette smoking to total
daily cadmium retention 4-47
4-17. Estimated relative contribution of dietary intake,
cigarette smoking, and ambient air cadmium levels
to total daily cadmium retention from all sources 4-73
4-18. Percentage of critical daily cadmium retention level
yielding renal dysfunction achieved by smokers at two
exposures times and two dietary levels 4-74
4-19. Percentage of critical daily cadmium retention level
yielding renal dysfunction achieved by smokers as
a function of ambient air cadmium levels 4-75
4-20. Average exposure and number of people exposed to annual
cadmium levels greater than 0.1 ng/m by specified
source types 4-81
4-21. Comparison of cadmium exposures among sources 4-82
4-22. Population exposed to cadmium concentrations 4-83
4-23. Regional breakdown on population exposed to cadmium
concentrations greater than 0.1 ng/m from selected
stationary sources 4-86
4-24. Number of births by race and size of population 4-87
xv
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1. SUMMARY AND CONCLUSIONS
1.1 INTRODUCTION
The purpose of the present document is to evaluate the toxic effects of
cadmium in man and animals and to assess the potential risk to human health
associated with environmental exposure to that element. This chapter
summarizes the main issues addressed in the document, the most important
evidence bearing on these issues, and major conclusions based on the evidence
discussed.
Among the issues addressed in the document are the following points of
primary concern:
(1) Can demonstrable adverse human health effects presently be associated
with exposure to cadmium; and are such health effects reversible or irreversible?
Of particular interest is whether cadmium induces sufficiently deleterious
effects on human health or welfare to warrant its classification as a "hazardous
air pollutant?"
(2) What are the major sources of cadmium exposure in human populations,
especially among Americans, and what are the most important routes of exposure
that currently exist? Can the relative contributions of different sources and
routes of exposure to uptake and retention of the element in the general
population be estimated? If so, with what degree of confidence? Related to
this is the issue of sensitivity and accuracy of existing measurement method-
ology for determining levels of cadmium in tissue matrices and nonbiological
materials.
(3) Based on known exposure information and taking into account other
interacting factors, can particular human populations be identified
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as being at special risk for adverse health effects due to cadmium exposure?
If so, under what circumstances and in what numbers are the members of those
populations expected to be at unacceptable risk?
No exhaustive compilation of the extensive currently available literature
on the toxicity of cadmium is provided. Rather, a much more selective review
and evaluation of the pertinent literature related to the above points of
concern is presented. The evaluation of toxic effects of cadmium in animals
and man is based upon (1) studies of cadmium intoxication in experimental
animal models and (2) human epidemiological and clinical research. In
addition, in assessing the potential risk to human health associated with
exposure to cadmium, major sources of cadmium exposure are identified, and
their present relative contributions to human intake and retention of the
metal are estimated, dose-effect and dose-response relationships for the
occurrence of certain crucial health effects are defined, and the levels of
cadmium retention at which such "critical effects" of acute and chronic
exposure occur are indicated. Estimations are also made of cadmium exposure
levels necessary to achieve sufficient retention of the metal for induction of
the critical effects of acute and chronic exposure. Lastly, populations at
special risk for exhibiting the critical adverse health effects are delineated
according to particular factors that place them at greater risk than others,
and projections are made regarding numbers of such people likely to be
adversely affected by excessive environmental exposure to cadmium.
Several points of considerable concern from a public health standpoint
emerge from the present analysis. One is that cadmium appears to be
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somewhat unique among the elements exerting toxic effects on man and other
living organisms in that: (1) its half-time in the body is unusually long,
sufficiently long that active accumulation of the element occurs over most of
the lifetime of man; (2) its accumulation does not include major deposition as
an "inert" fraction in bone, as is the case with lead, but rather it is lodged
in soft tissue, chiefly the kidney; and (3) its consequent adverse health
effects, especially where clinically manifest, appear to be essentially
irreversible.
Another matter of concern is that "large numbers of the general American
population appear to be regularly exposed to cadmium from many sources, but
mainly food, and that retention levels are such that only a relatively small
margin of safety exists for some individuals. Thus, any additional cadmium
accumulation over a long period of time may approach levels sufficient to
cause adverse health effects in significant segments of the United States
population. Of particular concern in that regard is the fact that cigarette
smoking contributes very significant amounts of cadmium to body levels, at
times equivalent to or more than that derived from food, thus placing millions
of existing and future smokers at special risk.
Also of much concern are projections that can reasonably be made re-
garding certain developments that could potentially increase hazards from
cadmium exposure in the future, if adequate safeguards or regulatory controls
are not implemented. More specifically, although present exposures to
existing levels of atmospheric cadmium generally do not now appear to pose
much risk to most Americans, two developments could substantially increase
ambient air levels of cadmium, i.e.: (1) expanded municipal incineration
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of high-cadmium content sewage sludge or other waste materials; and (2)
expanded fossil fuel use, especially anticipated large increases in coal
burning at coal-fired power plants. Increased ambient air cadmium levels from
the above sources, if not adequately controlled, would not only pose greater
health risks via increased cadmium exposure through direct inhalation, but
would also be expected to increase levels of cadmium ingested in food and
water via secondary deposition of airborne particles on agricultural land and
water. Other developments which could more directly impact on amounts of
cadmium introduced into the human food chain are: (1) expanded use of cadmium-
contaminated phosphate fertilizers on agricultural land; and (2) increased
landspreading of cadmium-containing sewage sludge or other waste materials on
agricultural land used for growing food crops.
1.2 HEALTH ASPECTS OF CADMIUM IN MAN AND ANIMALS
A variety of biological and adverse health effects have been documented
in experimental animals and man under conditions of acute and chronic cadmium
exposure. It should be noted that, as far as can best be determined, cadmium
plays no beneficial or essential role in the health of man or animals. In
view of this, demonstrated biological and adverse health effects of this
particular element must be considered in the absence of any health benefit--
health cost balance.
1.2.1 Metabolism of Cadmium in Man and Experimental Animals
Cadmium, like other multi-media environmental contaminants, may be introduced
into the target organism from a number of sources, including air, food, and
water. The relative amount of cadmium inhaled and absorbed via the pulmonary
tract depends on the physiochemical character of the form of airborne cadmium
as well as subsequent fate of the cadmium deposited in the respiratory tract.
1-4
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More specifically, the extent of deposition in the pulmonary tract is a
function of particle size and solubility. Deposition in lung is about 50
percent for particles of 0.1 micromet^e^ mass diameter (MMD) down to 10
percent for particles of 5.0 micrometers MMD. Systemic absorption of the
amount deposited in the respiratory tract of man is estimated to be from 20 to
25 percent of the deposited fraction. The amount of cadmium absorbed from
inhalation of cigarette smoke, however, may be significantly higher.
Since human populations generally acquire most of their cadmium from
dietary intake, gastrointestinal absorption is the major route of entry of
cadmium into man. About 6 percent of the cadmium entering the gastro-
intestinal tract is absorbed; based on clinical and epidemiological
observations, however, nutritional deficiencies such as low calcium and iron
can markedly increase this figure.
Blood is the vehicle for transport of cadmium absorbed via inhalation or
ingestion. Cadmium is then taken up from the blood into the liver, where
incorporation into metallothionein occurs, followed by release'into blood and
deposition of cadmium-thionein in the kidney. In populations with minimal
exposure to cadmium, about half of the organ distribution of cadmium is in the
liver and kidneys, with the kidneys accounting for about one-third of the
total body burden. Other organs accumulating cadmium include the testes,
lungs, pancreas, spleen, and various endocrine organs. In contrast, cadmium
concentration in bone, brain, and muscle tissue is very low.
The half-time of cadmium in the body, a measure of its retention or
accumulation, has been calculated to be 18 to 38 years. Whereas, little
cadmium is typically found in man at birth, a steady accumulation of the
element occurs up to about 50 years of age, with a very large portion of the
1-5
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accumulating cadmium being retained in soft tissue such as the kidney. Beyond
50 years of age, the levels of renal cadmium usually reach an asymptotic level
and remain essentially constant or dec1 fe
Cadmium is excreted mainly via the urinary and gastrointestinal tracts;
daily urinary excretion is less than 1 ug in the non-smoking population.
Cadmium exposure from whatever source tends to increase the daily urinary
output of the element. Biliary excretion occurs in animals but has not yet
been demonstrated to be significant in man.
The transport and toxicity of cadmium are intimately associated with an
inducible metal-binding protein, metallothionein, which binds cadmium, zinc,
and certain other divalent metal ions. On absorption, cadmium is transported
via blood to the liver where it is incorporated into metallothionein. The
protein-bound cadmium is then released back into the blood and undergoes
deposition in the kidney and other soft tissues. The binding of cadmium by
metallothionein and the deposition of the complex in kidney and other soft
tissue apparently accounts for its very long half-time in the body, and a
number of studies show that the relative toxicity of cadmium incorporated into
metallothionein is greater than would be the case if the formation of such a
chemical complex did not occur. Thus, for example, nephrotoxic effects of
cadmium are a consequence of its mode of transport to and deposition in the
kidney.
Acquisition of data on the uptake, deposition in body tissues, and
excretion of cadmium has been achieved through the use of sensitive measure-
ment techniques for the detection of the element in biological tissues. A
number of methods are presently available which, when employed in competent
laboratories and using good quality control, can reliably measure cadmium at
1-6
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o
ultra-trace levels (i.e., at ng/g or ng/m concentrations). At present,
atomic absorption spectrometry appears to be the most satisfactory analytical
approach for assessing cadmium levels in media of interest for human health
evaluations, e.g., urine, blood and tissue levels, as well as in air and
foodstuffs. Details of specific analyses used in particular studies involving
biological media are included in portions of the Human Epidemiology Chapter
(Chapter 3).
1.2.2 Biological and Adverse Health Effects in Man and Animals
Extensive information exists on the acute and chronic effects of cadmium
in man and experimental animals. Much of the data on animals, however, is
derived from studies utilizing relatively high exposures to cadmium adminis-
tered by direct systemic injections of the metal; such data, while often of
questionable environmental relevance, are valuable in delineating the upper
range of toxicological effects in a number of organ systems. Also, once high
exposure effects have been demonstrated, follow-up studies have been conducted
in some cases to define dose-effect relationships at much lower levels of
exposure and, at times, by means of inhalation or oral routes of exposure.
Adverse health effects observed in experimental animals exposed to high
cadmium levels include serious acute or chronic damage to several organ
systems. Among the more dramatic types of high exposure effects are morpho-
logical or functional signs of: renal damage, testicular necrosis, injury of
the pulmonary tract, embryotoxic and teratogenic responses, endocrine system
derangement, experimental hypertension and related cardiovascular responses,
anemia, hepatotoxicity, carcinogenesis and mutagenesis, and reduced immunological
responses. Such effects have been most consistently demonstrated to occur
after single intraperitoneal or subcutaneous injections of various cadmium
1-7
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salts in solution and at dose levels exceeding 0.5 to 1.0 mg Cd/kg body
weight.
Only a few of the above types of damage, usually of much reduced
severity, have been produced in experimental animals with lower, chronic
cadmium exposures. Probably the most typical and severe effect of chronic low
level cadmium exposure is renal damage. More specifically, cadmium affects
the reabsorption capacity of the proximal tubules in the kidney, initially
inducing increased urinary excretion of low molecular weight proteins. Thus,
tubular proteinuria is one of the earliest signs of chronic cadmium intoxi-
cation. Progressively more severe damage to the kidney results from continued
exposure, producing aminoaciduria, glucosuria and phosphaturia as later signs
of more advanced renal damage. Significant morphological changes accompany
these biochemical signs of renal dysfunction and include: diffuse scarring of
peritubular capillaries, interstitial edema, adhesions between Bowman's capsule
and glomerular capillaries, and tubular atrophy. One or more of these functional
and morphological signs of renal damage have been observed in rats and rabbits
with prolonged oral exposure to cadmium over periods of weeks or months,
starting at exposure levels of 2 ppm or 10 ppm in the drinking water. Kidney
cortex cadmium levels at which definite signs of severe kidney damage are
observed in animals have been reported to fall in the range of 150 to 450 ug
Cd/g wet weight.
Additional of health effects have been observed in animals with long-term
exposure to cadmium. For example, significant reductions in birth weights
have been reported for offspring born to female rats exposed via inhalation to
•3
cadmium sulfate (at 3 mg/m ) for seven months or to cadmium chloride in the
diet (at 200 ppm). The reductions in birth weights appear to result from
1-8
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cadmium effects on maternal and fetal nutritional status and likely occur
secondarily to reductions in fetal copper, iron and zinc levels.
Significant immune suppression effects have also been observed with oral
exposures of mice and rabbits to cadmium chloride in drinking water (at levels
as low as 10 ppm in that medium) for periods of 5 to 10 weeks. Such immune
suppression effects have been observed in the absence of other more classic
signs of cadmium toxicity, e.g., indications of renal damage, and may represent
heretofore unrecognized "subclinical" effects of chronic low level cadmium
exposure. Some experimental evidence suggests that immune suppresssion effects
may at times persist beyond the cessation of exposure to cadmium.
The literature relevant to man deals with both acute and chronic health
effects arising from cadmium exposure. Much of the data is derived from
occupational settings and responses of populations residing in geographic
areas of demonstrated high cadmium pollution.
In human beings, acute effects of cadmium generally result from occupa-
tional exposure via inhalation. The chief clinical feature of acute cadmium
inhalation exposure is pneumonitis, i.e., pulmonary congestion and edema.
Individuals who survive this acute episode regain partial lung function but
appear to have a higher probability of subsequently dying of chronic pulmonary
2
insufficiency. The inhalation of approximately 1 mg/m of cadmium over an 8
hour period gives rise to clinically evident symptoms in sensitive individuals,
o
whereas an air level of 5 mg/m inhaled over the same time period can be
o
lethal. At much lower exposure levels, in the range of 1 to 100 ng/m , no
acute exposure effects appear to occur. Rather, the main risk associated with
such air levels arises from secondary contamination of water or soils that may
increase cadmium levels entering the human food chain.
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Chronic adverse health effects of cadmium in man consist chiefly of
effects on the renal system and the respiratory tract. The renal effects have
been well documented as a systemic index of toxicity outside of occupational
settings; chronic respiratory effects, in contrast, are mainly seen in cadmium
workers who experience long, steady exposure to the element. The kidney is
therefore considered the main target organ affected by chronic cadmium exposure,
with renal dysfunction being the "critical effect" manifested by tubular
proteinuria at first, followed by aminoaciduria, glycosuria, and other signs
of more severe kidney damage if exposure is continued at the same level.
Cadmium-induced tubular proteinuria can be distinguished biochemically
from other types of renal dysfunction by the elevated excretion of the protein
P2~microglobulin, and a number of studies have shown that this protein is
elevated many-fold in cases where cadmium played a clear-cut role in renal
dysfunction. It has been demonstrated that the prevalence of proteinuria
increases with age and/or duration of cadmium exposure.
Disturbances in kidney function also exert their effects on bone and
mineral metabolism, via effects on calcium and phosphorus, extreme examples of
which are osteoporosis and osteomalacia. Itai-Itai or "Ouch-Ouch" disease,
observed in Japan is essentially renal tubular dysfunction with osteoporosis
and osteomalacia. Additional secondary effects of renal dysfunction are
kidney stones, observed in Swedish workers exposed to cadmium; and osteo-
malacia, in French workers.
It should be emphasized that, once renal tubular dysfunction has
proceeded to the point of pronounced proteinuria, it is essentially
irreversible. Also, there is considerable evidence, both from human and
animal studies, that such irreversible damage typically occurs when cadmium
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levels in the kidney cortex exceed approximately 200 pg/g wet weight,
especially under conditions of continued exposure (see Risk Assessment
Summary).
The chief chronic pulmonary effect of cadmium appears to be centrolobular
emphysema and bronchitis resulting from several years of occupational exposure
to cadmium oxide fumes, cadmium oxide dust, and cadmium pigment dust. Lung
impairment is possible at cadmium oxide fume levels below 100 ng/m of work
place air, depending upon exposure time.
As for other health effects, although hypertension has been demonstrated
in laboratory animals chronically exposed through the diet, there is presently
no conclusive evidence that cadmium is an etiological factor in human hyper-
tension. In addition, only a few effects on the hematopoietic system, chiefly
anemia of the iron-deficiency type, have been noted in man, usually under
conditions of occupational exposure to cadmium.
At present, few data are available concerning the direct effects of
cadmium on human reproduction and development; the few existing data, however,
are consistent with results from animal experiments that have yielded evidence
of significant reductions in birth weights as a consistent finding after oral
exposures of pregnant animals. Apparently, based on human and animal tissue
analysis, little cadmium crosses the transplacental barrier per se; however,
animal studies have shown that cadmium exposure during pregnancy has an effect
on zinc and copper levels in the newborn, probably indirectly due to nutritional
deficits, such as zinc deficiency, induced by cadmium. Lastly, although
teratogenic effects have been demonstrated in animals at high exposure levels,
no evidence has yet been advanced for cadmium being a human teratogen.
1-11
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In regard to possible mutagenic effects of cadmium, some mutagenic
effects in animals have been reported to occur with systemic injections of
high doses of cadmium or in i_n vitro test systems; but no data are available
that demonstrate mutagenic effects with either oral or inhalation exposure of
animals. As for the little available data on mutagenicity in man, particularly
with long-term exposure, the findings reported are contradictory and no firm
conclusions can be reached at this time. The case for cadmium being carcinogenic
in animals is supported only by data obtained at high exposure levels achieved
via systemic injections. As for carcinogenic effects in man, some evidence
suggests that heavily-exposed industrial workers are at higher risk for prostate
cancer; on the other hand, there are no data which currently show that cadmium
exposure in the general population is in any way associated with prostate
cancer.
As indicated above, several well established health effects of cadmium,
e.g., renal damage and its secondary consequences, have been shown to be
essentially irreversible and can exert a significant negative impact on the
health and well-being of humans. Furthermore, there is no medical treatment
presently available that can prevent the accumulation of cadmium in the kidney
or achieve elimination or reduction of cadmium stored in the kidney or other
soft tissues. Thus, minimization of exposure to cadmium is the only effective
approach currently available for averting its adverse health effects.
1.3 EFFECTS OF CADMIUM ON HUMAN POPULATIONS
Studies of various population groups that directly relate cadmium exposure
to human health effects are required to define the levels of exposure at which
the particular population groups demonstrate adverse health effects and to
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identify the specific population segments at high risk. At present, only
occupationally exposed workers and some population segments residing in areas
of high cadmium exposure in Japan have been extensively studied. Using data
from these and other studies, a chain of relationships can be defined from
exposure to absorption level to adverse health effects for human populations.
This can be done by (1) examining the distribution of cadmium sources to which
humans are exposed; (2) assessing the levels of cadmium in blood, urine or
soft tissues in various human population segments; and (3) correlating these
findings with other research demonstrating adverse health effects at various
cadmium levels in human tissue.
A number of studies have measured blood, urine, and hair cadmium levels
as a function of demographic variability. When considering the relative
validity of these studies, it is important to keep in mind the accuracy and
precision of the methodology used for measuring cadmium levels. Some methods
appear to be more subject to analytical error than others and, in the course
of evaluating data at variance with the literature at large, it becomes
apparent that at least part of the difficulty arises from deficient cadmium
analyses.
"Average" cadmium blood values for the general population in the United
States and elsewhere are in the neighborhood of 1.0 ug Cd/dl whole blood or
less, while occupational groups usually exhibit considerably higher values.
Unfortunately, little data presently exist that clearly relate age, sex, and
race to human blood cadmium levels. For example, no obvious age gradient is
discernible among children's blood cadmium values, unlike the case with blood
lead levels. In contrast, a clear relationship does exist between smoking
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status and blood cadmium levels. That is, it has been shown that adult blood
cadmium values are invariably higher in the case of smokers. This finding has
significance as one indication of smokers being at special risk for cadmium
exposure.
It should be noted that blood cadmium values are generally a relatively
poor index of chronic cadmium exposure and body accumulation, but rather are
best used as indicators of acute high exposures. Urinary cadmium levels, on
the other hand, appear to be reasonably good indicators of chronic low level
cadmium exposure and body accumulation. In relation to that, regardless of
the population groups studied, the urinary excretion of cadmium is seen to be
age-dependent, increasing up to about 50 years of age, and then declining.
The mean urine cadmium values from various studies generally indicate normal
daily urine cadmium excretion levels to be from 1 to 2 ug Cd/day.
A number of studies have evaluated levels of cadmium in hair as an
indication of exposure. Some question exists, however, as to the relevance of
hair cadmium values in the case of studying general populations with low
exposure to cadmium. Also, a number of analytical problems exist with hair
analysis, including the problem of external contamination. Since a number of
studies have shown no association between hair cadmium levels and the exposure
status of their population groups, the utility of hair cadmium levels remains
to be demonstrated.
Autopsy studies of cadmium levels in various human tissues have proven
valuable in assessing levels of the element in key organs and total body
burden. Such studies are of two types: case studies concerned with
specific diseases and general population studies. Such studies have shown
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that cadmium levels in human kidney and liver increase with age. The values
in liver decrease after 60 to 70 years of age, and kidney values level off
after 50 years of age. Smokers show higher cadmium levels in organs than
non-smokers. As a function of age, kidney values range from 5 ug/g wet weight
in the first decade of life up to 100 or more ug/g at 50 years of age; mean
values for adults are generally 20 to 40 ug/g. Smoking adds to the renal
cadmium burden up to 50 percent or more above the corresponding values of
non-smokers. Liver values increase from about 0.2 ug/g wet weight in the
first decade of life up to 1.0 ug/g or more at age 70. Smoking also appears
to increase liver cadmium values, particularly in the later decades of life.
A number of epidemiologic studies have dealt with areas of high cadmium
exposure in Japan, including the main "Itai-Itai" belt area. Such studies
identified Itai-Itai disease as a trio of symptoms--renal dysfunction with
osteomalacia and osteoporosis—resulting from high cadmium exposure of people
with a history of calcium and vitamin D deficiencies. Other areas of Japan
having increased cadmium exposures were also studied, with particular
reference to the prevalence of proteinuria. Collectively, these studies show
that in high-cadmium areas significant numbers of the inhabitants have tubular
proteinuria, with such renal derangement increasing with the age of the
individuals and the time of residence in areas of high cadmium exposure.
The Japanese experience with Itai-Itai disease is an informative
example of the potential widespread health problems that can ultimately
result from cadmium contamination of the human food chain via deposition in
water and soils used for agricultural purposes. The problem of detecting
and coping with continuous cadmium exposure is well demonstrated by the
1-15
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late appearance of osteomalacia seen in Itai-Itai disease only after
several decades of exposure. The Japanese experience also illustrates the
difficulty in ending exposures due to heavy contamination of agricultural
land, as noted in Chapter 4.
In regard to other cadmium health effects possibly being associated
with exposure of specific population groups, the epidemiologic evidence for
human hypertension and other cardiovascular diseases does not conclusively
implicate any etiological role for cadmium. In particular, investigators
who have controlled for smoking status have not shown an independent
association between cadmium levels and hypertension. Also, studies
focusing on the role of cadmium in producing chronic diseases of the lung
other than cancer have virtually all centered on occupational groups and
provide few data clearly demonstrating such effects in the general
population. More specifically, although autopsy data have shown cadmium
levels in tissue to be higher in persons with a diagnosis of emphysema,
smoking status has not been controlled for as a confounding factor.
Similarly, epidemiologic evidence often cited as implicating cadmium in the
induction of prostatic or other cancers in human populations, while
suggestive at this time, is not sufficiently strong so as to conclusively
establish that the metal exerts carcinogenic effects on humans. Of major
importance in evaluating data bearing on the issue is the fact that cadmium
exposure has usually been confounded with exposure to other toxic agents,
some being known carcinogens, in the pertinent epidemiologic studies.
1.4 HUMAN HEALTH RISK ASSESSMENT OF CADMIUM
1.4.1 Introduction
Summarized above is our current knowledge concerning the biological
and adverse health effects of cadmium in man and experimental animals,
1-16
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drawing on both clinical and epidemiological studies. This information,
along with consideration of exposure aspects, is integrated in the last
chapter of the present document in order to address the broader issue of
risk to public health in the United States posed by cadmium exposure.
Two aspects of such a risk assessment must be considered: exposure
aspects and population response. Key questions that must be addressed for
exposure considerations include: (1) what are the environmental sources of
cadmium in the United States; and, (2) what are the various routes by which
cadmium enters the body? In regard to population health aspects, several
additional questions must be considered: (1) What are the human biological
and pathophysiological responses to cadmium? (2) Do there exist within the
general population in the United States or elsewhere certain sub-groups at
special risk to the adverse health effects of cadmium? (3) Quantitatively,
what is the magnitude of the risk in terms of numbers of individuals
potentially exposed to cadmium levels sufficient to induce particular
adverse health effects?
1.4.2 Sources and Routes of Exposure
Trace amounts of cadmium are widely distributed naturally in the
environment. Much higher amounts of the metal enter the environment,
however, as a result of the manufacture, use, or disposal of cadmium-
containing products or in the form of contaminants of other substances.
Since virtually no recycling of the element occurs, its use is said to be
dissipative, i.e., the amount entering the environment equals the amount
produced or used. The current amount of cadmium entering the environment
yearly in the United States ranges from 2,000 to 5,000 tons. Dissipation of
cadmium in the general environment occurs via contamination of air, water and
soil.
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Ambient air levels of cadmium across the United States are usually in the
range of nanograms per cubic meter (ng/m ); however, much higher ambient air
values, around 0.1 ug/m , are at times found in regions of high cadmium pro-
duction and industrial use. This may be compared to work place levels of
3
about 100 ug/m of cadmium in air associated with the induction of chronic
health effects in cadmium workers. Airborne cadmium, in addition to being
inhaled, may contribute to human exposure via secondary contamination of water
and soil due to fallout and entry into the human foodchain. A matter of
concern in this regard is that future increased fossil fuel use could lead to
higher ambient air cadmium levels and, indirectly through soil contamination,
to increased cadmium in food crops.
Significant human exposure from cadmium-contaminated water supplies has
occurred in some areas of the world, e.g., Japan; and certain waterways in the
United States are contaminated with notable amounts of cadmium. Sources of
drinking water in the United States, however, generally are not contaminated;
in fact extensive surveys of the drinking water supplies of a large number of
areas within the United States indicate that the vast majority of these supplies
have cadmium levels below the recommended Public Health Service value of 10
parts per billion (ppb) (0.010 mg/1). It would be desirable, however, to
determine whether any contamination of drinking water by cadmium from supply
distribution systems, particularly household plumbing, occurs.
In soils, cadmium levels reflect geochemical and anthropogenic sources.
Man's activities add substantial cadmium to agricultural soils not only via
fallout from the air or contamination of irrigation water, but also through
intentional application of phosphate fertilizer and the increasing use of
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sewage sludge on agricultural land. Background soil levels in rural areas are
normally of the order of 0.1 parts per million (ppm), while contaminated
agricultural land and soils in urban areas have considerably higher concentra-
tions of 1.0 ppm or more. Furthermore, highly industrialized areas have much
higher proximate soil levels of cadmium than do areas where little industrial
activity occurs. Of considerable concern is the fact that soil cadmium
constitutes the single greatest source of cadmium affecting the general
population through introduction of the metal into man's food chain via uptake
into food crops consumed by humans or livestock.
Extensive data entailing both food cadmium determination and human tissue
analysis, indicate that most adults in the United States, on the average,
presently ingest 10 to 50 ug of cadmium in their daily diets. Based on a six
percent absorption value in the absence of nutritional deficiencies, this
represents an absorbed value of 0.6 to 3.0 ug per person per day from food
alone.
It should be pointed out that these values currently apply to existing
food levels of cadmium. It is possible that the cadmium content of foodstuffs
will increase in the future as a result of use of superphosphate fertilizers.
Also, it is possible that food levels may increase as a result of future
municipal incineration of high cadmium content sewage sludge or the use of
such sludge as agricultural land dressing. In regard to the latter, for
example, sludge used for landspreading on agricultural land has been reported
to be at times very high in cadmium, ranging up to 1,000 to 3,000 ppm (EPA
Multimedia Levels Cadmium, 1977). Thus, given the long residence time of
cadmium in soil, without implementation of proper regulatory controls on
sewage sludge disposal, dietary cadmium intake would likely rise significantly.
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However, guidance currently available from EPA, USDA and state agricultural
agencies as well as regulatory controls being developed by the EPA under the
Clean Water Act and the Resource Conservation and Recovery Act to directly
control land application of wastes such as sewage sludge, may help to minimize
any future increase in dietary cadmium levels as a result of applying these
wastes to agricultural land.
Increased future use of cadmium-containing fossil fuels should also be
considered as a potential source of increased future dietary cadmium levels.
In addition to ingestion of dietary cadmium as the main route of exposure
of most Americans, cigarette smoking has been conclusively shown to add greatly
to body burdens of cadmium; and heavy smokers may assimilate as much or more
cadmium from cigarettes as they do from the diet. Amounts of respiratory
intake from cigarettes range from 4 to 6 pg from two packs smoked per day.
This demonstrated added intake of cadmium from cigarettes accounts well for
higher levels of cadmium consistently found in urine and kidney tissue of
smokers by epidemiologic studies.
1.4.3 Human Population Responses to Cadmium in Human Risk Assessment
1.4.3.1 Summary of human health effects of cadmium--As indicated above, human
populations are exposed to cadmium via inhalation and ingestion, and the
health effects associated with these routes of exposure are generally chronic
in nature.
Of most relevance to human populations are chronic respiratory and renal
effects of cadmium. Of these two effects, it is more appropriate to consider
chronic renal effects, so the kidney (kidney cortex) is considered the critical
organ in chronic exposure to cadmium so far as a public risk assessment dis-
cussion is concerned.
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Tubular proteinuria is the earliest demonstrable marker for renal
dysfunction induced by cadmium, with other effects such as aminoaciduria,
glycosuria, and hypophosphaturia seen with continued exposure. Renal
dysfunction, once manifested clinically in terms of such effects, is often
irreversible, as demonstrated by studies on cadmium workers who continued to
show renal tubular dysfunction long after cadmium exposure had ceased. Also,
cadmium-induced tubular proteinuria is generally accepted as a significant
adverse health effect because by the time such an effect is manifested the
kidney is already well on the way to increasingly severe damage and has
essentially no reserve for protection against other pathological stresses.
This vulnerability is reflected in observations of increased health complica-
tions among certain cadmium workers subsequent to their first exhibiting renal
tubular proteinurea.
According to both clinical-epidemiological and model-calculation data, a
kidney cortex level of 200 ug Cd/g kidney can be taken as the critical concen-
tration, i.e., the level of cadmium in the kidney (critical organ) at which
the earliest discernible adverse effect (the critical effect of renal tubular
proteinuria) can be expected to occur.
1.4.3.2 Dose-effect/dose-response relationships of cadmium—As reviewed in
the health effects section of this document, the severity of any given marker
effect increases as the level of cadmium exposure increases, and the quantita-
tive aspects of response, i.e., the frequency of occurrence of a stated effect
in an organism population, comprises the dose-response relationship.
With cadmium, the usual indicators cannot be used to assess the status of
the critical organ, the kidney cortex, in terms of that organ's direct exposure
to the insulting agent, because measurements of blood or urine cadmium are not
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precise ways to assess the extent to which the kidney is on its way to
functional impairment. An alternative strategy has been to define an
approximate critical concentration in the kidney cortex above which renal
tubular dysfunction can be expected to occur. As was stated earlier, this
value is now generally accepted to be 200 \jg Cd/g wet weight renal cortex.
Using this approach, the probable level of total exposure necessary to produce
the critical concentration via ingestion and/or inhalation can then be
calculated.
As indicated in the risk assessment section of the document, one may use
this approach with two previously calculated half-times of cadmium in the
body: 18 and 38 years (see Table 1-1). Furthermore, in that section (4) is
determined the daily retention values of cadmium in the body for these half-
times and various exposure periods.
For populations at large, the main factor determining the level of daily
cadmium retention is daily dietary intake. This is certainly the case with
non-smokers; heavy smoking on the other hand, can lead to retention of amounts
of cadmium which approach or even exceed that retained from the dietary intake
(see Table 1-2).
Calculations, based on metabolic models, regarding levels of daily dietary
intake of cadmium necessary to achieve the critical renal cortex concentration
of 200 ug/g associated with renal dysfunction, have yielded widely varying
estimates for critical dietary intake levels. Thus, dietary intake levels
ranging from 200 to 480 ug/day have been projected as being sufficient to
eventually induce proteinuria in the 40- to 50-year-old age group. Various
epidemiologic studies have yielded data that fit well with various estimates
within the above range of theoretical estimates; a Working Group of Experts
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Table 1-1. CADMIUM EXPOSURE REQUIRED FOR REACHING A KIDNEY CORTEX
CONCENTRATION OF 200 |jg Cd/g USING DIFFERENT ALTERNATIVES
FOR BIOLOGICAL HALF-TIME IN KIDNEY CORTEX AND EXPOSURE TIME3
L
Basis of calculation
Constant daily retention during
whole exposure time
3
25% pulmonary absorption, 10 m
inhaled per work day, 225 work
days/year
Exposure
time
(yr)
10
25
50
10
25
Levels of cadmium intake
or retention yielding renal
dysfunction, assuming cadmium
half-times of:
38 yr
Daily
36
16
10
Indust
(ug/m
23
11
18 yr
retention (ug)
39
20
13
rial air concentration
)
25
13
Food exposure for 50-yr-old person
(2500 ca/day) (4.5% retention)
(changing caloric intake by age
accounted for)
50
Daily cadmium intake (ug)
250 360
Corresponding average con-
centration in foodstuffs (ug/g)
Total amount (net weight) 300 g
of food/day 600 g
1000 g
50 0.8
0.4
0.25
1.2
0.6
0.35
Adapted from Friberg, L. M. Piscator, G. G. Nordberg, and T. Kjellstrom.
Cadmium in the Environment. CRC Press, Cleveland, 1974.
Assumptions: one-third of whole body retention reached kidney and kidney
cortex concentration 50% higher than average kidney concentration. From
Nordberg, G. F. (ed.). Effects and Dose-Response Relationships of Heavy
Metals. Elsevier, Amsterdam, 1976.
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Table 1-2. MEDIA CONTRIBUTIONS TO NORMAL RETENTION
OF CADMIUM3
Medium
Ambient air
Water
Cigarettes
packs/day
1/2
1
2
3
Food
Exposure level
0.03 pg/m3
1 ppb
ug/day
1.1
2.2
4.4
6.6
50 (jg/day
Daily retention
(M9)
0.15
0.09
0.70C
lAlc
2.82
4.22C
3.0
Source: Deane, L. G., D. A. Lynn, and N. F. Surprenant.
Cadmium: Control Strategy Analysis. ECA Cong., Bedford,
Mass. U.S. Environmental Protection Agency. 1976.
Based on 0.11 pg per cigarette.
Assumes a 64% retention rate.
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for the Committee of European Communities (CEC), however, has tentatively
concluded that 200 to 248 ug/day is the best estimate of daily dietary intake
necessary to reach the renal critical concentration of 200 um/g in kidney
cortex over a 50 year exposure period for nonsmokers. For smokers, a level of
dietary intake of 169 ug/day was estimated as being sufficient for the critical
renal cortex concentration to be reached.
The above approaches are aimed at estimating "threshold" dietary intake
values necessary to produce a critical cadmium concentration in renal cortex
associated with the critical effect of renal tubular dysfunction. Such approaches,
however, may not adequately take into account individual biological variability
in terms of dietary levels yielding significant renal dysfunction; this is
suggested by certain recently published studies on dose-response relationships
that relate dietary cadmium intake levels to numbers of individuals in study
populations showing increased proteinuria over background levels.
In regard to such dose-response aspects of cadmium exposure, i.e., defining
that proportion of a target population that would be expected to show a given
health effect at a particular level of cadmium exposure, there exist both
modeling and empirical data (see Chapter 4) which have been recently compiled
into a dose-response framework. Using renal tubular damage as the adverse
health effect for which response rates were calculated and daily dietary
intake of cadmium as the exposure variable, the theoretical framework predicts
increasing response rates for renal damage as a function of dietary intake of
cadmium. As illustrated in Table 1-3, a daily dietary intake of 60 ug/day,
for example, would be predicted to produce, by age 50, a renal damage response
in 1.0 percent of this age-group population. Further, at daily cadmium intake
rates of 80 and 100 ug/day, approximately 2.5 percent and 5 percent of the
population, respectively, would be predicted to sustain renal tubular injury.
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Actual, observed prevalence rates in several epidemiologic studies match well
the predicted rates; due to the small number of observations at lower dietary
intake levels, however, little confidence can yet be placed in rates indicated
for dietary levels under 80 to 100 ug/day.
The data in Table 1-3 describe dose-response relationships for non-smokers
and individuals with "average" dietary habits. In the case of smokers the
total cadmium retention from both diet and smoking increases and, based on
data discussed in Chapter 4, heavy smokers could conceivably have a consequently
greatly increased response rate over non-smokers. Similarly, for individuals,
such as vegetarians, having certain idiosyncratic dietary habits that likely
Table 1-3. FOOD EXPOSURE; CALCULATED INTAKES (ug Cd/day)
THAT MAY GIVE A CERTAIN RESPONSE RATE AT AGE 50a
Response rate (proportion) with
renal tubular dysfunction
0.1% 1% 2.5% 5% 10% 50%
Europeans,
body 32 60 80 100 148 440
weight 70 kg.
Japanese,
body 24 44 60 76 100 325
weight 53 kg.
Gastrointestinal absorption rate 4.8%; Non-smokers, from Kjellstrom, T.
Comparative study of Itai-Itai disease. In: Cadmium 77: Edited Proceedings,
First International Cadmium Conference. Metal Bulletin Ltd., London, 1978.
pp. 224-231.
1-26
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lead to higher than "average" dietary intake of cadmium, there may exist a
greater risk for increased response.
1.4.3.3 Populations at Risk to the Adverse Health Effects of Cadmium—
Populations at risk are those segments of a defined population exhibiting
characteristics associated with a significantly higher probability of
developing an abnormal condition, illness, or status. This enhanced risk may
come about because of some greater inherent susceptibility or from exposure
situations peculiar to that group.
In the case of cadmium, based on the collective experience with widespread
exposure in Japan and other data cited in this document, certain large segments
of the United States population can be identified as likely being at risk for
experiencing adverse health effects associated with exposure to the metal.
Generally speaking, other than for certain occupationally exposed workers,
acute toxic effects of cadmium are not of much concern in assessing its
potential public health impact in the United States. Rather, chronic effects,
mainly renal dysfunction or damage, are of primary concern due to the propensity
of cadmium to accumulate in the body (especially in the kidney) over very long
time periods, e.g., for 40 to 50 years or more.
Given the fact cadmium is retained in the kidney over long time periods,
then it is not surprising that older segments of various populations studied
(i.e., those over 45 to 50 years of age) have generally been found to have the
highest levels of cadmium in the kidney and also to display the highest
incidence of renal dysfunction. Based on this, it would appear that those
individuals in the United States population over 40 to 50 years old are most
immediately at risk for exhibiting cadmium-induced renal dysfunction as a
1-27
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consequence of further cadmium exposure. Also, given the dependence of
cadmium absorption on nutritional factors, e.g., increased uptake in the
presence of iron, zinc, or calcium defiency, the risk would be greatest among
those older Americans who are poorly nourished.
It is obviously the case that aging affects all members of any population
and, in view of that, the entire population of the United States must therefore
be viewed as being at potential risk for adverse effects associated with
cadmium exposure. In fact, due to the accumulation of cadmium in the kidney
essentially over an entire lifetime, present cadmium exposure levels and any
future increments in exposure, in the long run, would be expected to impact
most heavily on present younger members of the population. Thus, any assessment
for the American public of potential risk associated with cadmium exposure
must attempt to project the likely eventual consequences of present and/or
increased cadmium exposure levels for the general United States population.
In attempting to make such projections, dietary cadmium intake, as the chief
source of cadmium for the general public, is of primary concern in the analysis.
In regard to current daily dietary cadmium intake levels for Americans,
different estimates have been generated depending upon the measurement approaches
employed. FDA "market basket" surveys, for example, have yielded estimates
ranging from approximately 30 to 50 ug/day, or even around 70 ug/day for
teenage males. On the other hand, estimates based on fecal cadmium excretion
measurements tend to be much lower, i.e., with mean dietary intake for
non-smokers being around 18 ug/day with a standard deviation of approximately
8 ug. Taking that degree of variability into account and comparing the fecal
excretion-derived estimates in relation to the above market basket survey-
derived estimates, it seems reasonable to state that current American daily
1-28
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dietary cadmium intake levels, on the average, fall within the range of 10 to
50 jjg/day.
It is next necessary to compare the above estimate(s) of current daily
dietary cadmium intake with ingestion levels that, over an extended period of
time (40 to 50 years), will lead to sufficient cadmium being accumulated in
the kidney so as to induce the critical effect associated with chronic cadmium
exposure, i.e., renal tubular dysfunction. As noted earlier in the present
summary and discussed in more detail in Chapter 4 of this document, various
modeling approaches have yielded estimates ranging from 200 to 480 M9/day as
the requisite ingestion level eventually resulting in the critical renal
cortex cadmium concentration of 200 ug/g wet weight being reached and, thus,
associated renal dysfunction occurring. Also as noted earlier, a concensus of
opinion among a group of experts working for the Committee of European
Communities (CEC) was that 200 to 248 ug/day is probably the best estimate of
the critical daily cadmium ingestion level necessary to induce renal dysfunction.
If the latter view is accepted, then average American dietary cadmium intake
levels of 10 to 50 ug/day would be from approximately 4 to 25 fold less than
ingestion levels estimated to yield renal dysfunction over a 50 year exposure
period. For some individuals with distinctly higher than average dietary
cadmium intake levels, however, that margin could be significantly less.
Certain empirically obtained data suggest that attempts at defining a
single daily ingestion level eventually yielding renal dysfunction as a
consequence of a critical renal cortex cadmium concentration being reached may
not adequately take into account individual variability in rates of uptake and
retention of cadmium. Projections based on dose-response data relating
measured dietary cadmium intake levels to observed prevalence of renal
proteinuria, in fact, suggest that 1, 2.5, and 5 percent of the American
1-29
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population would exhibit renal dysfunction at daily dietary cadmium ingestion
levels of 60, 80, and 100 |jg/day. Viewed from that perspective, current daily
dietary cadmium intake level(s) of 10 to 50 pg/day for Americans may not
provide even a two-fold margin of safety before a small (1 percent), but
significant, portion of the general United States population would be expected
to experience cadmium-induced renal dysfunction.
Furthermore, based on data discussed previously, cigarette smokers
constitute a large population at still greater risk than the general public.
In regard to increased risk for smokers, tabulations have been carried out in
an effort to demonstrate the relative contribution of cigarette smoking to the
total daily added burden of cadmium (daily retained cadmium) as a function of
the amount of cigarettes consumed (see Table 1-4). For example, assuming a 25
ug/day daily dietary intake level, smoking one, two, or three packs of cigarettes
daily can contribute as much or more than the average level of cadmium retained
due to dietary ingestion, as illustrated in the table. When the amounts of
cadmium retained daily in individuals who smoke heavily are compared to critical
daily retention values (10 pg/day) above which the critical concentration of
cadmium in kidney will eventually be exceeded, the relative margin of safety
for exposure to other sources of cadmium is significantly reduced. Thus, at
present, cigarette smokers who constitute a large portion of the United States
population are at greater risk for cadmium-induced renal dysfunction than
non-smokers.
A third group at possible risk for adverse health effects of cadmium are
those with unusual dietary habits, such as vegetarians and those consuming
large quantities of shellfish (e.g., oysters) over an extended period of time.
These groups would be at even greater future risk in the event that cadmium
1-30
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Table 1-4. ESTIMATED RELATIVE CONTRIBUTION OF DIETARY INTAKE, CIGARETTE SMOKING AND AMBENT AIR CADMIUM
LEVELS TO TOTAL DAILY CADMIUM RETENTION FROM ALL SOURCES9
i
GO
Dietary Intake
(Net Retention)
Food Level A = 25
nig/day
(1.50 my/day)
Food Level 8 = 50
•y/day
(3.00 My/day)
Food Level C - 75
my/day
(4.50 «y /day)
0.0 ng/a3
Smokiny Status (Net Retention) (0.0 mg/day) (.
Non-saoker
% pack/day
1 pack/day
2 pack/day
3 pack/day
Non-smoker
>» pack/day
1 pack/day
2 pack/day
3 pack/day
Non-smoker
>i pack/day
1 pack/day
2 pack/day
3 pack/day
(0.00
(0.70
(1.41
(2.82
(4.22
(0.00
(0.70
(1.41
(2.82
(4.22
(0.00
(0.70
(1.41
(2.82
(4.22
•g/day)
mg/day)
mg/day)
Bg/day)
mg/day)
•g/day)
•g/day)
mg/day)
mg/day)
mg/day)
•g/day)
•g/day)
•g/day)
•g/day)
•g/day)
1.590
2.290
3.000
4.410
5.810
3.090
3.790
4.500
5.910
7.310
4.590
5.290
6.000
7.410
8.810
(0;OX)*
(31;OX)
(47;OX)
(64;OX)
(73;OX)
(0;OX)
(18;OX)
(31;OX)
(48;OX)
(58;OX)
(0.0%)
(13;OX)
(24; OX)
(38;OX)
(48;OX)
1.
2.
3.
4.
5.
3.
3.
4.
5.
7.
4.
5.
6.
7.
8.
Air Cadniu
1.0 ng/a3
0005 ag/day)
591
291
001
411
an
091
791
501
911
311
591
291
001
411
811
(0,0%)
<31;OX)
(47;OX)
(64;OX)
(73;OX)
(0,0%)
(18;OX)
(31;OX)
(salox)
(O.OX)
(13;OX)
(24;OX)
(38;OX)
<48;OX)
• Levels (Net Retention) ,
10 ng/a3 100 ng/a3
(.005 ag/day) (.05 By/day)
1.595 (0;OX)
2.295 (3l;OX)
3.005 (47;OX)
4.415 (64;OX)
5.815 (73;OX)
3.095 (0;OX)
3.795 (18;OX)
4.505 (31;OX)
5.915 (48;OX)
7.315 (58;OX)
4.575 (0;OX)
5.295 (13;OX)
6.005 (24;OX)
7.415 (38; OX)
8.815 (48;OX)
1.630 (0;3X)
2.330 (30;2X)
3.050 (46; IX)
4.460 (63; IX)
5.860 (72; IX)
3.140 (0;2X)
3.840 (18; IX)
4.550 (31; IX)
5.960 (47;1X)
6.360 (57; IX)
4.640 (0;1X)
5.340 (12; IX)
6.050 (23; IX)
6.460 (38; IX)
8.860 (48; IX)
1000 ng/a3
(0.5 ay/day)
2.090 (0;24X)
2.790 (25;18X)
3.500 (40;14X)
4.910 (57;10X)
6.310 (67;8X)
3.590 (0;14X)
4.290 (16;12X)
5.000 (28;10X)
6.410 (44;8X)
7.810 (54;6X)
5.090 (0;10X)
5.790 (12; 9%)
6.500 (22;8X)
7.910 (36;6X)
9.310 (45;5X)
*Each first value equals total daily cadaiua retention levels (in By/day) from all sources, assuming constant daily retention fro* water of
0.09 My/day derived fro* consumption of water with cadaiuB concentration of 1 ppb. The two values in parentheses ( ) indicate percentage
of total daily cadaiu* retention attributed to cigarette smoking and ambient air cadaitw exposure, respectively, at a given ambient air
caduiuv level.
aNote that daily cadaiua retention of 10 mg/day would be projected to result in a critical cadmium concentration of 200 mg/g wet weight
of kidney coretx being reached over a 50-year exposure period, assuming a kidney half-time for cadmium of 38 years.
-------
levels in their preferred foodstuffs were to substantially increase in the
future.
One could also hypothesize that children may be another population
segment at potential risk due to increased exposure or absorption of cadmium.
Such increased risk, however, is questionable in terms of projected lifetime
tissue accumulations of cadmium except in cases where unique behavior patterns
of children, e.g., mouthing of non-food objects, bring them into contact with
cadmium-contaminated house dust or soils.
1.4.4 Overall Conclusions
Uptake of cadmium in man via a variety of routes of exposure can result
in serious adverse health effects. These include significant irreversible
pulmonary and renal damage that typically occur as a result of chronic
occupational and non-occupational exposure.
The levels of chronic cadmium exposure necessary to induce significant
renal dysfunction, the "critical effect" typically observed earliest with
ambient environmental exposures, may not exceed by much the levels presently
encountered through "average" dietary intake by many Americans. Thus,
increases in cadmium exposure from whatever source will reduce an already low
margin of safety before adverse effects are seen.
Possible sources of exposure that can be identified as presently contribut-
ing additional burdens of cadmium include cigarette smoking as well as high
air levels encountered in some industrial settings. As for ambient air as a
possible source of increased environmental cadmium exposure, calculations
summarized in Table 1-4 suggest that, in general, ambient air exposures below
10 ng/m do not result in any increased kidney cortex concentration of cadmium.
1-32
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However, as discussed in Chapter 4 under Exposure Sources, ambient air levels
of cadmium in the vicinity of certain industrial facilities have been observed
3 3
to exceed 10 ng/m and, at times, to approach 100 ng/m , a point at which
significant accumulation of cadmium occurs.
Several recent developments in waste management, energy production, and
food production appear to have the potential for markedly changing the present
United States population exposure profile for cadmium. Specifically, substan-
tially increased ambient air levels of cadmium could result from future un-
controlled expanded municipal incineration of solid waste materials and expanded
fossil fuel use, especially increased coal combustion. Also, future uncontrolled
expanded agricultural use of cadmium-contaminated phosphate fertilizers or
high-cadmium content sewage sludge could potentially introduce increased
amounts of cadmium into the human food chain and thereby raise levels of
dietary cadmium.
In view of the above, regulatory action addressing any single source of
exposure, but not taking into account all other possible sources of exposure
and expected changes in levels resulting from them, is likely to be inadequate
in terms of truly safeguarding the public health. Instead, a well-coordinated
comprehensive plan for controlling exposure of the general population would be
desirable; it would be prudent to have as an overall goal the objective of
reducing total cadmium exposure from current levels rather than allowing
exposure to rise. Realistically, this would probably require control at many
points along the dissipation pathway for the element: from mining and smelting
operations, through industrial manufacturing processing or other utilization
as in fossil fuel or phosphate fertilizer usage, to ultimate disposal of
1-33
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cadmium-contaminated wastes. In the absence of effective control procedures,
gradually increasing environmental contamination, especially of agricultural
soils, should be expected to occur. Also, as demonstrated by the Japanese
experience with cadmium contamination of agricultural soils, once significant
soil contamination with cadmium does occur, then it is virtually impossible to
reverse and may ultimately result in the loss or restricted use of large
tracts of farm land (see Exposure Aspects, Chapter 4).
The cost of uncontrolled environmental exposures to cadmium in terms of
populations at risk, it should be noted, could be immense. The populations
most at risk include: (1) older people, who number in the millions and whose
numbers are growing; (2) smokers, who also number in the millions and whose
ranks will probably continue to be filled by virtue of expanding numbers of
teenagers who smoke; (3) people with dietary habits that result in consumption
mainly of food groups (e.g., grains, leafy vegetables, and beef kidney and
liver) with comparatively high cadmium content; and (4) children, during both
pre- and postnatal development.
1-34
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2. BIOLOGICAL SIGNIFICANCE AND ADVERSE HEALTH EFFECTS OF CADMIUM
2.1 INTRODUCTION
A variety of biological and adverse health effects have been docu-
mented in both man and experimental animals under conditions of acute and
chronic exposure to cadmium. These responses are discussed in this section.
From the standpoint of relevance of these effects to the hazards posed
by cadmium on populations at large, the chronic effects are considerably
more important than those of an acute nature. In turn, those chronic
effects elicited by ingestion of the element are probably of more signifi-
cance than that by inhalation, although this should not be taken to mean
that the opposite might not be the case in certain situations. Studies
involving the parenteral administration of the metal to experimental animals
are also included because they are potentially valuable in defining the
metabolic and toxic parameters of cadmium.
Assessment of the effects of an element follows closely on an under-
standing of the element's metabolism in an organism. Therefore, the first
section of this report deals with the absorption, transport, distribution,
and excretion of cadmium in man and animals.
Systemic effects of cadmium are, in large measure, macroscopic mani-
festations of injury at the cellular, subcellular, and molecular level.
Thus, enzymological, subcellular and cellular studies, both jji vivo and
in vitro, are discussed first along with consideration of the role of
metal!othionein. Studies of the effects of cadmium on various specific
organ systems are reviewed and evaluated next. Special attention is
accorded the renal, pulmonary, cardiovascular, and reproductive systems.
2-1
-------
Also discussed are endocrine, skeletal, hepatic, gastrointestinal, neural,
and immunosuppressive effects of the metal.
No toxic element functions in a metabolically static milieu, and this
is especially true of cadmium. Therefore, discussion of the effects of
cadmium should take into account various interactions between cadmium and
other elements which either ameliorate or potentiate its effects. This
includes, for example, cadmium/zinc, cadmium/selenium, and cadmium/iron
relationships. The interactive effects of these metal/metal combinations
are discussed in a separate, final section in addition to being alluded to
in other sections where appropriate.
2.2 METABOLISM OF CADMIUM
No discussion of the health effects of a toxic substance is complete
without consideration of the metabolism of that element, i.e., the processes
of absorption, transport, deposition, remobilization in organs, and excretion.
While a sizable body of data exists on the quantitative and qualitative
aspects of cadmium metabolism in man and experimental animals, the present
report is concerned with those features of cadmium metabolism that impinge
directly on health effects and is not meant to be an exhaustive review of
the relevant literature.
2.2.1 Sources of Exposure
Cadmium, like other multimedia environmental contaminants such as
lead, is introduced into the host organism from several sources including
air, food, and water. Information on amounts of cadmium encountered in
various media is considered later in a separate section on exposure in the
risk-assessment portion of the present report.
2-2
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2.2.2 Inhalation
Factors that require consideration in dealing with pulmonary absorption
include the physiochemical features of the form of airborne cadmium at the
time of external exposure, as well as subsequent handling of the deposited
form of cadmium in the respiratory tract. The extent of deposition in the
various pulmonary tract compartments is a function of particle size and
solubility. The quantitative features of this relationship have been
reviewed by the Task Group on Lung Dynamics (1966), Fulkerson and Goeller
(1973), Friberg et aJL (1974), and Nordberg (1974). Cadmium-containing
matter (usually aerosols) in air is lodged in the lungs and the tracheo-
bronchial tract in quantities inversely related to particle size; lung
deposition is about 50 percent for particles of 0.1 micrometer mean mass
diameter (MMD) ranging down to 10 percent for particles with an MMD of 5
micrometers. Deposition in the nasopharyngeal tract, on the other hand, is
a direct function of particle size.
Part of the inhaled material deposited in the respiratory tract under-
goes retropassage via ciliary activity and is then swallowed. Factors
governing, this portion of the intake are therefore related to gastro-
intestinal absorption, which is discussed below. Many of the earlier
studies on retention time of inhaled cadmium in the form of aerosols or
fumes are not amenable to interpretation due to lack of knowledge about
particle size. The Task Group on Lung Dynamics (1966), however, has
arrived at a half-time range of several days to a year for retention of
cadmium in the lung. Systemic absorption from the lung of inhaled cadmium
is estimated for man to range from less than 20 to 50 percent, depending on
particle size, solubility of the cadmium compound, etc. Animal studies
2-3
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provide figures of 10 to 40 percent (Friberg et al_. , 1974; Elinder et al.,
1976; WHO, in press).
2.2.3 Gastrointestinal Absorption
Human populations generally acquire the major part of their cadmium
intake from the diet and some from water. The amount of such intake is
discussed elsewhere in this report. The extent of gastrointestinal
absorption of ingested cadmium in man is about six percent; it is somewhat
less in animals (Friberg et al_. , 1974; Nordberg, 1976). Dietary factors,
as well as the chemical form of the metal, play a role in modifying this
figure, with certain nutritional deficiencies leading to an enhancement of
cadmium absorption in man and animals (Friberg et a_[., 1974). As a specific
example, the group most affected with the symptomatology of Itai-Itai
disease in Japan were women who had a history of Vitamin 0 and calcium
deficiency (see Health Effects and Epidemiology sections).
2.2.4 Other Absorption Routes
Two other routes of absorption may potentially play a role in the
exposure of humans to cadmium: cutaneous absorption and transplacental
transfer. Cutaneous cadmium absorption has been shown in animals (Skog and
Wahlberg, 1964; Wahlberg, 1965; Kimura and Otaki, 1972); however, this
route is probably minor in man compared to inhalation and ingestion.
Transplacental transfer is discussed in the Reproduction and Development
section (2.7) of this chapter.
2.2.5 Transport and Deposition
Blood is the vehicle for transport of cadmium via inhalation or inges-
tion and the kinetics of its movement in the body rest heavily on the type
of exposure (Friberg et a_]_. , 1974). What constitutes "normal" blood levels
2-4
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of cadmium is a subject of controversy as is discussed later in the Risk
Assessment section (4.)- In the general population, more cadmium is found
in plasma than erythrocytes; with increasing exposure, however, the ratio
shifts toward higher amounts being found in the erythrocytes (Friberg et
a_L , 1974).
Animal studies (Friberg et a_L , 1974) show that, in the time immedi-
ately following parenteral administration of cadmium ion, most of blood
cadmium is found in plasma. Furthermore, there is initially a rather rapid
clearance of cadmium from blood. This is followed by a slower decline and
a subsequent rise in in the Cd content of both plasma and cells, with a
larger comparative amount accumulating in the erythrocyte. This increase
corresponds to the time required for enhanced metallothionein synthesis.
The half-time of blood cadmium following cessation of a chronic exposure
appears to be about six months (Friberg et a_L , 1974).
Much data exist on the relative distribution of cadmium among various
organs in man and experimental animals and these have been reviewed (Friberg
et a_L , 1974; Nordberg, 1972). In populations witn minimal exposure to
cadmium, about half of the organ distribution of cadmium is in liver and
kidney, with kidney accounting for 30 percent of the total body burden. A
higher proportion of cadmium is found in liver during chronic exposure
because of cadmium-induced synthesis of metal!othionein in the liver..
Other organs that accumulate cadmium include the testes, lungs, pancreas,
spleen, and various endocrine organs. In contrast, relatively low concen-
trations of cadmium are found in bone, brain, and muscle tissue. However,
due to the much greater mass of muscle versus liver and kidney tissue, the
2-5
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absolute amount of cadmium found in muscle within a given mammalian organ-
ism can be considerable.
Simple model projections for the half-time value for cadmium in various
organs predict, for example, a value between 17.6 yr (Tsuchiya and Sugita,
1971) and 38 yr (Kjellstrom, 1971) for kidney and kidney cortex in man.
Although these values were derived from data on representative samplings of
Japanese and American populations, Nordberg (1976) has cautioned that they
involved use of a simple model dependent on a fixed fraction of cadmium
directly transferred to kidney, whereas the true picture is rendered more
complex by hepatic-renal transfer of cadmium. Nevertheless, the simple
model is still useful for most practical purposes.
Metal!othionein, it should be noted, plays a major role in the move-
ment and excretion of cadmium j_n vivo in various species. Details concern-
ing this cadmium-binding protein are presented in a subsequent section
(section 2.3.2).
2.2.6 Excretion
Excretion of cadmium by man and experimental animals is mainly via the
j
urinary and gastrointestinal tracts. Since only about six percent of
cadmium is absorbed from the gastrointestinal tract, the bulk of ingested
cadium is lost in feces. Thus, it is difficult to assess the relative
differential excretion of absorbed cadmium by the renal and intestinal
routes. Renal excretion in the urine, nevertheless, is of a magnitude such
that it can be taken as a relatively good indicator of internal exposure.
Urinary output is seen to increase slowly with age as the cadmium body
burden increases. In the presence of renal dysfunction, however, urinary
levels of cadmium may rise markedly. That is, in both animals and man, it
2-6
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has been observed that only relatively small amounts of cadmium are
excreted in the urine early in exposure, but sudden increases then occur
concomitantly with the appearance of proteinuria or other signs of renal
damage (Friberg, 1952; Axelsson and Piscator, 1966; Nordberg and Piscator,
1972; Suzuki, 1974; Friberg et al_., 1974; Lauwerys et al_. , 1974; Singerman,
1976).
In man, under conditions of low-level, chronic cadmium exposure,
cadmium loss via the urine is typically < 1 ug/day (Johnson et aK, 1977;
Elinder et al_., 1978) for non-smokers. For smokers and other cadmium-
exposed individuals, urinary cadmium values are higher; and there appears
to be some overall relationship between urinary excretion of cadmium and
total body burden. While it has been demonstrated that biliary excretion
occurs in animals, it has yet to be demonstrated that it is a significant
factor in man (Stowe, 1976; Cherian, 1977; Cherian and Vostal, 1977).
2.3 SUB-CELLULAR AND CELLULAR ASPECTS OF CADMIUM TOXICITY
Various studies focusing on the toxic effects of cadmium at the cellu-
lar and sub-cellular level are discussed in this section. Types of effects
discussed include: (1) general subcellular effects, e.g., the interaction
of cadmium with enzymes and non-enzymic biomolecules crucial to the physio-
logical functioning of the organism and (2) the induction of metal!othionein
and its role in cadmium metabolism and toxicity.
2.3.1 General Sub-Cellular Effects
The literature on the interaction of cadmium with enzymes spans a
spectrum of effects, ranging from the observation of nonspecific activation
or inhibition of purified enzyme preparations HI vitro to enzymic effects
that constitute a significant part of the i_n vivo pathology of cadmium.
2-7
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Since much of the former tends to have little relevance to jji vivo conditions,
much of the data is not given detailed consideration here. Rather, one is
directed to a more general review, such as that of Vallee and Ulmer (1972).
In some cases, it is more appropriate to discuss enzyme effects as part of
the systemic toxicity of cadmium; this is done elsewhere in this report.
There are several mechanisms by which cadmium may influence enzyme
function. The metal ion may interact with the enzyme directly via the
marked affinity of cadmium for the sulfhydryl and imidazolyl nitrogen
groups at sites necessary for enzyme function and may even substitute for
native metal ions in various metal!oenzymes, as in the case of substituting
for zinc in zinc metal 1oenzymes. Similarly, cadmium may interact with the
substrate for an enzyme, sufficiently perturbing the conformation to markedly
alter enzyme-substrate binding kinetics. Circulating levels of enzymes may
also be altered due to organ derangement and cellular release, as in the
case of changes in marker enzymes for hepatic function. Another important
mechanism, particularly in cases of zinc deficiency, may be alterations in
the pattern of distribution of zinc.
Virtually all of the studies dealing with the cellular and sub-cellular
aspects of cadmium toxicity have involved experimental animals. In Table
2-1 are tabulated the various effects reported, divided as to whether the
studies were _ui vivo or j_n vitro in nature. In the text, i_n vivo and i_n
vitro studies are discussed together under the different types of subcell-
ular effects or sites studied. It should be noted that many of the dosages
employed are well above what might be encountered by man.
A number of reports indicate that cadmium has an effect on metabolizing
enzymes of organisms. For example, Furst and Mogannam (1975) have reported
2-8
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Table 2-1. SUBCELLULAR AND CELLULAR
CADMIUM TOXICITY IN EXPERIMENTAL ANIMALS
Species Cd Dose*
System(s) studied**
Effect(s) found**
Reference
Ir\ vivo Studies
Rat 2.5 or 3.8
mg/kg b.w.;
i.p.
Rat
Mouse
Rat
2.0 mg/kg
b.w. ; single;
i.p.
Hepatic drug-metabolizing
enzymes
Hepatic drug-metabolizing
enzymes
5 and 3 mg/kg
b.w.; i.p.; after
i.p. injection of
3 methyl
cholanthrene/
octanoin
solution
0.25 and 1.0
mg/kg b.w.;
i.p. daily for
21 or 45 days
Hepatic drug-metabolizine
enzymes
Cyclic AMP
associated
and
enzymes
25 to 60% inhibition of aniline
hydroxylase and nitro reductase
activity;
50% reduction of microsomal P-450
content
24% increase in hexobarbital
sleeping time;
27% reduction in cytochrome
P-450;
44% reduction in cytochrome
b5;
57% inhibition of ami no pyrine
demethylase (3rd day post-
injection);
32% aniline hydroxylase inhibition
of (3rd day post-injection)
Total inhibition of AHH activity
at higher dose;
little inhibition of AHH
activity at lower dose
Increase in cyclic AMP level;
increase in both basal and
fluoride-stimulated activity
Teare e_t al. ,
1977
Krasny and
Holbrook, 1977
Furst and
Mogannam,
1975
Singhal et al.,
1976
-------
Table 2-1. SUBCELLULAR AND CELLULAR CADMIUM
TOXICITY IN EXPERIMENTAL ANIMALS (CONTINUED)
Species Cd Dose*
System(s) studied
Effect(s) Found**
Reference
ro
i
Rat 100 ppm in
drinking water;
ad lib. for
30 days
Rat 3.2 mg/kg (0.03
m mole/kg);
single i.p.
Rat 300 ppm in
drinking water;
ad lib.
Rat 0.34 to 3.4
mg/kg b.w.;
i.p.
Rat 2 mg/kg b.w.;
once per wk.;
for 2 to 3 wk.
Enzymes of duodenal
mucosa
Dehydrogenase
enzyme activity
Osidatine phosphorylation
RNA synthesis in
hepatic fractions
Protein synthesis by
ribosomes
Decrease in brush-border ATP-ase
activity;
decrease in alkaline phosphatase
activity;
increase in isocitrate
dehydrogenase activity;
increase in G-6-PD activity
89% inhibition of succinic
dehydrogenase activity in
liver and testis;
increase in lactate
dehydrogenase activity
Reduction in respiration and
P/0 ratios;
increase in mitochondria!
cytochrome A and cytochrome C
Inhibition of RNA synthesis
in hepatic nuclei;
significant inhibition of
polyuridylic acid-directed
incorporation of L-(14C)-
phenylanine in microsomes
Inhibition of protein synthesis
in isolated ribosomes using an
ami no-acid incorporating system
Sugawara and
Sugawara, 1975
Singh and
Nath, 1975
Kamata et al.,
1976
Stoll et al_. ,
1976
Norton and
Kench, 1977
-------
Table 2-1. SUBCELLULAR AND CELLULAR CADMIUM
TOXICITY IN EXPERIMENTAL ANIMALS (CONTINUED)
Species Cd Dose"
System(s) studied**
Effect(s) found**
Reference
ro
i
Rat
Turkey Up to 0.7 mM
Turkey; 1 x 10~4 M
mouse;
rabbit;
guinea
pig; dog;
cat
Rat
Chick
Rat
Rabbit
20 ppm in the
preparations
2.5 x 10~5M
and greater
0.5-3.0 uM
Up to 3mM
in medium
for 20 hr.
Cyclic AMP and associated
enzymes of tissue
homogenates
Adenylate Cyclase
activity in
erythrocyte membrane
Renal ATP-ase activity
Kidney, intestine, and
salivary gland (homogenates)
phosphatases
25-hydroxy-Vitamin
metabolism
Liver mitochondria
respiration
Alveolar macrophages
tissue culture
Inhibition of both cyclic AMP
phosphodiesterase and
adenylate cyclase activity
Up to 100% inhibition (at
0.7 mM) of both forms of
adenylate cyclase
activity
Inhibition of renal
Na+-K+ ATPase 10 times
greater than Mg++ ATPase
for all species tested
13 to 20% inhibition of acid
phosphates in all preparations;
40% inhibition of alkaline
phosphatase in salivary gland
Complete inhibition of 1,25-
dihydroxy-Vitamine D- at lowest
level 6
Uncoupling of oxidative phos-
phoratin;
acceleration of State IV
respiration
Reduction of cell viability;
reduction of phophatase activity;
disturbance in morphology
(Cd 1 of 2 most toxic metals
studied)
Anthanson and
Bloom, 1976
Spiegel
et al. ,
1976
Nechay
and
Saunders,
1977
Iqbal et a!. ,
1976
Suda et al.,
1974
Kamata et al.,
1976
Waters and
Gardner, 1975
-------
Table 2-1. SUBCELLULAR AND CELLULAR CADMIUM
TOXICITY IN EXPERIMENTAL ANIMALS (CONTINUED)
Species Cd Dose*
System(s) studied**
Effect(s) found**
Reference
Mouse 4.3 mg/kg b.w.
) i.p.
I
1—»
IN3
Mouse 0.15 mg/kg b.w.;
intragastric dose
for 90 days
Mouse 50 ppm in
drinking
water for up
to 8 mo.
Rat 2.1 mg/kg b.w.;
single injection
with 115Cd
tracer
Rat 2 mg/kg/wk for
2 to 3 wk. by
injection
I_ri Vitro Studies
Rat Various concen-
trations of Cd
and other heavy
metals
Heterolysosome formation
and function in kidney
and liver
Catalase and carbonic
anhydrase activity
Subcellular localization
of Cd
Liver localization of
Cd
Subcellular localization
of Cd
AHH of 10%
liver homogenate
Inhibition (increasing over time)
of proteolysis in liver
particles 2 to 20 hr. after injection;
less effect on kidney particles
Decrease in
activity in
blood after
decrease in
carbonic anhydrase
liver, kidney, and
20 days;
catalase activity
after 60 days
Localization of Cd mainly in
apical vessicles, lysosomes,
lysosomes, and proximal
tubular cells
Appearance of label in
nucleus and cytoplasmic fractions;
concentration of nuclear Cd
higher in non-hostine protein
Appearance of significant
amounts in purified
ribosomes and enzyme
preparations
Marked inhibition of AHH
complex with Cd most
inhibitory of all ions
studied
Mego and
Cain, 1975
Ogawa
et al_.
1973
Popham and
Webster,
1976
Hidalgo and
Bryan, 1977
Norton and
Kench, 1977
Tsang and
Furst, 1976
-------
Table 2-1. SUBCELLULAR AND CELLULAR CADMIUM
TOXICITY IN EXPERIMENTAL ANIMALS (CONTINUED)
Species Cd Dose*
System(s) studied**
Effect(s) found**
Reference
(N5
I
Mouse
Hamster
C3H-
strai n
mouse
Mouse
About 4 mg/ml
medium and
higher
2.2 X 10~5 M
15.6 mg/ml
medium
Alveolar macrophages,
peritoneal macrophages,
and polymorphonuclear
neutrophils
Phagocytic activity of
alveolar macrophages
L-strain fibroblasts
2.8 to 88.0 mM Subcutaneous connective-
CD.3 to 9.4 mg/ml) tissue L-cells
Significant depression of res-
piratory burst when heat-
killed P. aeruginosa added
to medium
Significant reduction
phagocytic index (PI)
in
Disappearance of ribosomes;
changes in mitochondria
including total destruction;
swelling of endoplasmic reticulum
Reduction in cell viability;
cellular LD5Q 5.5 for
exponential phase, 30.5
for stationary phase
Loose e_t al. ,
1977
Graham et al.,
1975
Kawahara
et aJL ,
1975
Ozawa et a_[. ,
1976
*Abbreviations: b.w.: body weight; i.p.: intraperitoneal injection; ppm: parts per mil lion; —: information
not available
**Abbreviations: AHH: aryl hydrocarbon hydroxylase; G-6-PD: glucose-6-phosphate dehydrogenase
Cyclic AMP: adenosine 3':5'-cyclic phosphate
-------
that inhibition of the inducible enzyme complex aryl hydrocarbon hydroxylase
(AHH) occurs in mice given 3-methylcholanthrene intraperitoneally (i.p.) in
trioctanoin (0.01 ml/g) and cadmium ion in one of two injected doses: 5
mg/kg and 3 mg/kg. At the higher dose, enzymic activity was almost com-
pletely quenched, while little inhibition was noted at the lower exposure
level. In a related iji vitro study, using a 10 percent liver homogenate,
Tsang and Furst (1976) showed marked inhibition of this enzyme complex by
five different metal ions, of which cadmium was the most inhibitory.
An acute effect of cadmium on hepatic metabolizing enzymes in the rat
was noted by Teare and coworkers (1977). A single i.p. injection of cadmium
chloride at levels of either 2.5 or 3.8 mg/kg into male rats produced
significant (25 to 60 percent) inhibition of aniline hydroxylase and nitro-
reductase activity and reduced microsomal P-450 content to about 50 percent
of control values. These effects are not seen with o-demethylase activity.
Complicating these observations is an apparent "buffer effect", the last-
named enzyme showing some inhibition in phosphate buffer and more signifi-
cant inhibition in Tris buffer.
Krasny and Hoi brook (1977) assessed various parameters of drug meta-
bolism in rats following a single i.p. dose of cadmium acetate (2.0 mg/kg).
At 3 days post-exposure, hexobarbital-induced sleeping time was increased
24 percent while microsomal levels of cytochromes P-450 and be were
decreased by 44 percent and 27 percent, respectively. At day 7 these
values returned to normal. The microsomal enzymes aminopyrine dejnethylase
and aniline hydroxylase both showed inhibition: the former, 47 and 37
percent at days 3 and 7, and the latter, 32 and 23 percent at these same
2-14
-------
time points. Heme oxygenase showed the greatest increase (350 percent of
control) at 2 days post-injection, returning to normal at the end of 1 wk,
while biliverdin reductase activity was not altered at any time.
Several reports have appeared describing the J_n vivo and i_n vitro
effects of cadmium on adenylate cyclase and other components of cyclic AMP
(adenosine 3':5'-cyclic phosphate) metabolism in animals.
Singhal and coworkers (1976) observed that, while chronic cadmium
treatments in rats (daily i.p. injection of 0.25 or 1.0 mg/kg for 21 or 45
days) failed to alter AMP-phosphodiesterase activity, the amount of cyclic
AMP and the activity of basal and fluoride-stimulated forms of hepatic
adenylate cyclase were markedly increased. However, the amount of cyclic
AMP binding to hepatic protein kinase was decreased, as was the kinase
activity ratio.
In an i_n vitro study, Nathanson and Bloom (1976) have shown that both
basal and hormone-stimulated adenylate cyclase activity of various tissue
homogenates and their particulate fractions were inhibited by very low
levels of cadmium and other heavy metal ions. Cadmium also inhibited
cyclic AMP phosphodiesterase activity.
Using turkey erythrocyte membranes, Spiegal et al. (1976) showed
cadmium inhibition of all forms of adenylate cyclase activity, with 100-
percent inhibition at 0.7 millimolar (mM) concentration (78 ug/ml). Such
effect could be offset by the use of mercaptoethanol and British anti-
Lewisite (BAL), both metal chelants.
Nechay and Saunders (1977) studied the effects of cadmium on renal
adenosinetriphosphatase (ATPase) preparations from various regions of
kidney obtained from dog, cat, rat, rabbit, guinea pig, and mouse. At
2-15
-------
-4 + +
cadmium levels of 10 M, Na -K ATPase was inhibited, regardless of source
or type of enzyme preparation, with the effect being ten-fold greater than
I L
the corresponding inhibition of Mg -ATPase. The inhibitory effects were
not altered by sodium or potassium levels, but were decreased by ethylene-
diaminetetraacetic acid (EDTA) addition.
Sugawara and Sugawara (1975) studied the effects of cadmium admini-
stration (100 ppm cadmium solution ad libitum for 30 days) on selected
enzyme activity in duodenal mucosa in male Wistar rats. Inhibition of
brush border ATPase and alkaline phosphatase and increase in the activities
of isocitrate dehydrogenase and glucose-6-phosphate dehydrogenase (G-6-PD)
were noted. Such jjn vivo effects could not be duplicated, however, with in
vitro studies using comparable cadmium levels.
Iqbal et aJL (1976) studied the i_n vitro effect of cadmium on phospha-
tases using homogenates of kidney, intestine, and salivary gland. Cadmium
at 20 parts per million (ppm) inhibited acid phosphatases 13 to 20 percent
in all these preparations, while significant inhibition of alkaline phospha-
tases (40 percent) at this level was seen only in a salivary gland prepara-
tions. Prior addition of zinc ion abolished the inhibitory effect of
cadmium on alkaline phosphatase but had little effect on acid phosphatase.
Both i_n vitro and jin vivo inhibition of succinic dehydrogenase and
lactate dehydrogenase activity have been reported by Singh and Nath (1975).
Injection of cadmium chloride (3.2 mg/kg) into rats caused 89 percent
inhibition of succinic dehydrogenase activity using liver and testis prepar-
ations, but enhancement of lactate dehydrogenase activity. Both enzymes
were inhibited on cadmium addition in vitro. '
2-16
-------
A number of studies have been concerned with the influence of Cd on
biochemical activity in discrete subcellular components. Membranes, in
particular, are especially vulnerable to the effects of cadmium and other
heavy metals. They mediate the transer of materials in and out of cells
via active transport and exchange mechanisms that require initial complexing.
Such complexing may be easily interfered with by the surface binding of
metals.
An organelle that is also quite sensitive to the effects of cadmium is
the mitochondrion. Since all of the enzymatic machinery required for
cellular oxidation, including oxidative phosphorylation, sugars, amino
acids, and fatty acids are located in the mitochondria, there are poten-
tially a number of sites within the mitochondrion where cadmium may impart
an effect. According to Berry et a_K (1974), the ion is active at three
places.
(1) It binds to sulfhydryl groups of enzymes necessary for electron
transport from the citric acid cycle to the electron transport chain.
(2) It inactivates one or more enzymes necessary for the synthesis of
adenosinetriphosphate (ATP).
(3) It binds to ATPase, the enzyme required for the conversion of
ATP, or adenosine diphosphate (ADP), an important energy source in cellular
reactions.
In the study of Suda et al_. (1974), kidney mitochondria were isolated
from rachitic chicks, and their activity in tritiated 25-hydroxy-Vitamin D-
3
( H-25-OH-D3) metabolism was studied as a function of added cadmium ion.
As little as 2.5 x 10 M cadmium ion completely inhibited the biosynthesis
of the active form of Vitamin D3- This is in contrast to i_n vivo studies
in rats, where a Vitamin D-deficient diet also containing 300 ppm of
2-17
-------
cadmium chloride for 3 wk furnished significant amounts of 1,25-dihydroxy-
Vitamin D3 (1,25-(OH)2-D3). These and other data led the authors to conclude
that metallothionein (discussed below) serves as a protective factor against
this aspect of cadmium toxicity.
Diamond and Kench (1974) studied liver mitochondria from rats chroni-
cally poisoned with cadmium (i.p. injection, twice weekly, 1 mg/kg/wk).
Mitochondria exhibited diminished respiratory control with progressive
cadmium intoxication. Cadmium added i_n vitro to mitochondria from exposed
animals did not stimulate oxygen uptake, but control mitochondria respiring
on succinate did show stimulation of oxygen utilization. While no pattern
difference is seen between poisoned and control animals in reduced cyto-
chromes, cadmium added i_n vitro at levels greater than or equal to 10 M
prevented subsequent reduction of the cytochromes. This appears to be
indicative of a cadmium effect prior to electron transfer through the
cytochrome system.
Kamata et al_. (1976) showed, in an j_n vitro study, that State III
respiration with succinate in rat-liver mitochondria is strongly inhibited
by cadmium. This inhibition is greater than for other heavy metals such as
lead or mercury. At 0.5 to 3 micromolar cadmium, oxidative phosphorylation
was decoupled, and State IV respiration was accelerated. Jji vivo, oral
administration of cadmium (300 ppm in water) reduced the respiration control
ratio and the P/0 ratio but increased mitochondrial cytochrome a (+a.,) and
cytochrome c (+C,).
Stroll and coworkers (1976) have investigated the behavior of hepatic
nuclei and microsomes from rats given cadmium chloride (0.34 to 3.4 mg
Cd/kg, i.p.). When cadmium was added to isolated hepatic nuclei,
2-18
-------
ribonucleic acid (RNA) synthesis was inhibited. When hepatic microsomes were
preincubated to destroy messenger RNA (mRNA), the polyuridylic acid-directed
incorporation of L-[ C] phenylalanine was significantly inhibited by cadmium
pretreatment; and such activity was inhibited in the same way when cadmium
was added to preincubated microsomes from control animals.
In a related study by Norton and Kench (1977), cadmium administered to
rats (2 mg Cd/kg/wk for 2 to 3 wk) caused inhibition of protein synthesis
ut vitro by isolated ribosomes in an ami no acid-incorporating system.
Mego and Cain (1975) investigated the effect of cadmium on heterolyso-
some formation and function from the kidney and liver of mice. Pretreat-
ment with cadmium inhibited proteolysis in liver particles 2 hr after i.p.
injections of LDrQ doses (4.3 mg Cd/kg), such inhibition becoming more
pronounced up to 20 hr post-exposure. Kidney particles were less affected.
Injections of cadmium also inhibited proteolysis of albumin in isolated
liver heterolysosomes prepared 1 hr later.
Several studies have investigated the subcellular localization of
cadmium. In one case, Popham and Webster (1976) employed a technique for
the ultrastructural localization of cadmium in proximal tubule cells of
mice consisting of precipitation of cadmium as the sulfide using ammonium
sulfide after brief fixation in glutaraldehyde. In mice chronically exposed
to cadmium (50 ppm in drinking water for up to 8 mo), cadmium was localized
mainly in the apical vesicles, lysosomes, and cytoplasm of proximal tubular
cells.
Hidalgo and Bryan (1977) used radioisotopic cadmium ( Cd) to assess
distribution of cadmium in rat liver after a single exposure (20 u mol
Cd/kg). The label was associated with the nucleus and the cytoplasmic
2-19
-------
fractions. The nuclear cadmium was more concentrated in non-histone pro-
teins than in the hi stone proteins. Cytoplasmic cadmium was associated
with two metal-binding protein subfractions.
In the report of Norton and Kench (1977), significant quantities of
cadmium were found in purified ribosomes and enzyme preparations when
cadmium was given to rats (2 mg Cd/kg/wk for 2 to 3 wk).
The cytotoxicity of cadmium as seen in cell-culture studies has been
reported by several investigators. In this regard, Waters et al_. (1975)
have employed an i_n vitro system for assessing the cytotoxic effect of
cadmium and other heavy metals using rabbit alveolar macrophages exposed in
tissue culture for 20 hr. Of the various toxic substances assessed, cadmium
was one of the two most toxic at metal levels below 3 mM, with cadmium
reducing cell viability without lysis. Cadmium also caused a reduction in
the activity of acid phosphatase, a lysosomal indicator enzyme and an
active component of alveolar macrophages, in a manner that parallels decreases
in cellular viability. On the basis of parallel morphologic evidence, the
following sequence of damaging events is suggested by the authors: (1)
retraction of normally extended pseudopodia, (2) appearance of surface
structures, (3) smoothing of the plasma membrane, and (4) effacement of
cell architecture.
An in vitro technique has been developed to assess alveolar macrophage
function specific for phagocytosis (Graham et aj_. , 1975) and determine the
effect of various metal ions, including cadmium. This entails a double-
viability stain to eliminate non-functioning dead cells from phagocytic
measurement. Cadmium, at a concentration of 2.2 x 10 M, showed signifi-
cant lowering (p < 0.001) of the phagocytic index (PI)
2-20
-------
Using pulmonary alveolar macrophages, peritoneal macrophages, and
polymorphonuclear neutrophils from the mouse, Loose et aj. (1977) observed
no significant alteration in their resting oxygen consumption when incubated
in media containing cadmium salts. When heat-killed P. aeruginosa were
added to the cell suspension, however, a significant depression in respira-
tory burst following phagocytosis was apparent and dependent on cadmium
concentration, starting at 3.6 x 10 M. According to the authors, impair-
ment of phagocytosis by cadmium ion may be associated with the known inhibi-
tory action of this toxin on the ATPases of myosin and cell membranes.
Altered phagocytotic activity by these cells may explain the enhanced
bacterial susceptibility posed by cadmium, as reported by Cook et al.
(1975a,b).
An i_n vitro investigation by Kawahara et aj. (1975) involved cells
3
from L-strain fibroblasts derived from the C H-strain mouse, cultured with
YLH medium and supplemented with 10 percent bovine serum. A level of
cadmium ion of 15.6 pg/ml medium was used. Severe changes were noted under
an electron microscope: ribosomal disappearance, mitochondrial changes
from waning of membrane and irregular arrangement of cristae to total
disintegration, and a swollen and bead-like endoplasmic reticulum. The
organellar damage appeared to be much worse than that from mercuric chloride.
Ozawa et alL (1976) monitored the differential susceptibility of L
cells in the exponential and stationary phases to cadmium ion. L cells
derived from mouse subcutaneous connective tissue were grown in Ham's F12
medium supplemented with 15-percent calf serum, 50 U/ml Penicillin G, and
50 ug/ml streptomycin. Cadmium ion was added on the first, second, and
fourth days (exponential phase) and the ninth, eleventh, and twenty-second
2-21
-------
days (stationary phase) at a level to make a final concentration of 2.8 to
88.0 |jM. The 10™ of cadmium ion for these cells in the two phases was 5.5
and 30.5 uM, respectively. Enhanced susceptibility in the exponential
phase may be due to an increased cell membrane permeability. The corres-
ponding cadmium contents of the cells in the two phases were 0.12 and 0.065
ug/106 cells.
2.3.2 Metallothionein
No discussion dealing with the subcellular metabolism and toxicity of
cadmium would be complete without a consideration of the physiological role
played by metallothionein. Metallothionein (the protein moiety thionein
plus a complexed metal or metals) is a low-molecular-weight intracellular
protein with a propensity for binding cadmium, zinc, mercury, copper, and
to a lesser degree, certain other ions. It exists in at least two molec-
ular forms. Structurally, cadmium binds to thionein through three sulfhy-
dryl groups per metal atom, the sulfhydryl groups being available from the
rather high cysteine content of the protein. While much in the way of
metallothionein biochemistry has been reported, our interest is mainly
centered on its function in the regulation of cadmium toxicity. An early
review of metallothionein is presented in Friberg et aJL (1974).
Cadmium-thionein and other metal!othionein-like proteins have been
isolated and studied from a number of organ systems of varous species,
including man. Since metal!othionein is an inducible protein, with its
biosynthesis in liver and other organs being accelerated by challenging the
organism with cadmium and certain other ions, much interest has centered on
the role of metallothionein in mediating the movement and affecting the
toxicity of cadmium.
2-22
-------
While this protein may be involved in transport of cadmium in the
blood, in organ distribution, and in excretion (Nordberg, 1972), questions
have been raised as to whether metal!othionein provides a protective function,
as was first suggested by Piscator (1964), or whether this role is secondary
to its regulation of zinc and/or copper metabolism.
In various experimental animals, pretreatment with a low dose of
cadmium ion protects against a subsequent, usually fatal dose of the toxic
agent (Parizek, 1957; Gunn et aJL , 1968), since with repeated doses a
larger portion of the dose accumulates in liver and kidney as metallo-
thionein (Webb, 1972).
In the study of Leber and Miya (1976), mice exhibited tolerance to
cadmium toxicity after pretreatment with either cadmium or zinc acetate.
Cadmium doses of 1.0 and 3.2 mg/kg given 2 days before cadmium challenge
resulted in LD5Q values of 6.0 and 8.2 mg/kg respectively, versus a value
of 4.5 mg/kg without pretreatment. Similarly, the LD5Q value is roughly
doubled (6.5 mg/kg) when pretreatment with zinc is carried out 12, 30, and
48 hours before cadmium exposure. The amount of hepatic metal!othionein
was seen to be proportional to pretreatment dosing.
Webb and Verschoyle (1976) reported that pretreatment of female rats
with a low dose of cadmium ion provided defense against a subsequent,
usually lethal dose of the meta! and also induced the synthesis of hepatic
cadmium-thionein. While this protection was at optimum one to three days
after pretreatment, both the increased content and increased biosynthesis
of cadmium-thionein persisted beyond this time. Using radioisotopic cad-
1 flQ
mi urn ( Cd), these workers also noted that, although cadmium ion is bound
more strongly by the apoprotein, thionein, rats in which the levels of
2-23
-------
zinc-thionein were elevated by starvation showed the same susceptibility to
cadmium as animals on normal diet. This indicates that while synthesis of
cadmium-thionein probably accounts for tolerance by animals of a larger
quantity of cadmium given in multiple doses, Webb claims that neither
preinduction of the protein nor zinc-thionein serves a protective function.
This may be contrasted to the observation in the earlier study that zinc-
thionein induced by zinc pretreatment does ameliorate lethality. As might
be expected, accumulation of cadmium in the liver is greater under condi-
tions of pretreatment, while uptake of the ion in other tissues (heart,
spleen and pancreas) is unchanged.
In the related study of Probst et al_. (1977), a dose-dependent toler-
ance to acute cadmium toxicity was evidenced by elevated LD5Q values in
cadmium-pretreated mice. Also, hepatic metal!othionein levels increased
with the increase in pretreatment dosing. Since pretreatment at a level of
2.0 mg Cd/kg, but not at 0.6 mg/kg or 0.2 mg/kg, resulted in elevated LD5Q
and cadmium-binding capacity relative to controls, it appears that a mini-
mum dose of cadmium must be exceeded in order to occasion sufficient induc-
tion of metal!othionein to modify the acute toxicity of the metal (Probst,
1977).
The protective behavior of cadmium pretreatment was also studied by
Squibb and coworkers (1976), who observed that rats pretreated with 20 mg
Cd/kg followed by another oral dose of 100 mg Cd/kg showed greater uptake
of cadmium by liver, kidney, and testis. At all time points (1, 3 or 5
hr), liver cadmium was associated entirely with metal!othionein. In ani-
mals not given pretreatment, metal!othionein-bound cadmium was not observed
2-24
-------
35
until 15 hr later. Radio-labeled cystein studies ( S) showed that bio-
synthesis of the binding protein occurred following metal exposure. The
observation that all of the cadmium in intestine was bound to metal!o-
thionein may suggest that the protein has a role in affecting cadmium
absorption during low-level cadmium exposure.
Chen et a_L (1975a) studied the synthesis and metabolic degradation of
rat hepatic metallothionein stimulated by cadmium challenge. In regard to
degradation of the protein, the half-life of 4.2 days observed after a
single exposure to cadmium (subcutaneously, 26.7 u mol/kg body weight) was
not materially different from the value (4.9 days) observed after a second
dosing, although liver cadmium content was doubled. Here, there is no
stabilizing effect on the protein imparted by cadmium. Zinc, however, was
lost from the metal!othionein fraction at a rate similar to that of cystein
14
[ C]. Cadmium persisted in the liver-binding protein fraction up to 29
days post-injection and may do so in the face of observed protein breakdown
by being released and immediately stimulating more thionein biosynthesis.
Cherian and Shaikh (1975) induced metal!othionein in rats with cad-
mium, labeling the formed metal!oprotein ui vito with either Cd, C or
35
S. After isolation from liver and subsequent intravenous administration
to rats (at Cd levels of 10, 30 and 200 ug Cd), it was observed that tissue
distribution of the radiolabeled ion in the metal!oprotein was different
from that given as the chloride (200 ug Cd). When given as cadmium-thionein,
the deposition of cadmium in kidney was higher than in liver and a significant
urinary excretion of the ion was observed when given in that form.
Furthermore, the distribution and excretion of the thionein moiety was
similar to that of cadmium.
2-25
-------
Several reports have since appeared in the literature relating the
comparative toxicity of cadmium-thionein to ionic cadmium when administered
as such. Cherian et al. (1976), for instance, isolated cadmium metal 1othi-
109
onein from livers of metal-exposed rats, labelled the metalloprotein Cd,
and injected the material into a second group of rats. When compared with
exposure to cadmium chloride, the organellar distribution of label from
both forms in renal tubule cells was similar; but within 12 hours, degener-
ative changes were observed in the ultrastructure of renal tubule cells of
animals dosed with the cadmium-thionein but not the cadmium salt. In a
related study, Cherian et aj. (1978) fed cadmium to mice in the form of
109
either cadmium chloride or cadmiurn-metal!othionein labeled with Cd. The
inorganic salt was accumulated in the liver, while protein-bound cadmium
appeared in the kidney. The extent of absorption in both forms was similar.
These data are significant in terms of exposure of human populations to
cadmium in diet. In particular, food-animal organs such as liver and
kidney, which are high in heat-stable metal 1othionein-bound cadmium, may
provide an unacceptably high level of cadmium in terms of human renal
burdens of the element.
Further evidence that cadmium-thionein is involved in the pathogenesis
of renal tubular cell injury is the study of Nordberg and Nordberg (1975).
109
Cadmi urn-metal! othi onein, labeled with Cd jri vitro, was injected into
rats (1.6 ug Cd as either metalloprotein or CdCl2). After 4 hr, over 80
percent of the injected dose was in the kidney when pure metal 1othionein
was used.
Webb and Etienne (1977) observed that cadmium, when bound to thionein
from either rabbit or rat liver, was 7 to 8 times more lethal to the rat
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than was ionic cadmium. Zinc-thionein was not only nontoxic, however, but
protected the animals from a subsequent, usually fatal dose of the cadmium-
thionein. As also noted above, cadmium-thionein accumulated in the kidney;
its lethality was associated with severe tubular damage. Other data in
this study suggest that parenteral dosing with cadmium-thionein is followed
by renal tubular uptake, and ensuing breakdown of the protein moiety liber-
ates cadmium in the directly toxic ionic form.
In summary, the literature dealing with the cadmium-metallothionein
relationship rather conclusively demonstrates that (1) with relatively
acute exposure to cadmium, metallothionein serves a protective function for
the organism, while (2) in the long-term chronic exposure situation, cadmium
bound to metallothionein may be more systematically toxic than cadmium not
bound to metal!othionein.
2.4 RESPIRATORY EFFECTS OF CADMIUM
A number of acute and chronic respiratory effects of cadmium have been
documented in man and animals. Friberg et aT_. reviewed the earlier liter-
ature in 1974.
2.4.1 Effects on Humans
In man, acute effects of cadmium via inhalation may not appear until
some time after exposure, about 24 hours. Chief symptoms and signs are
shortness of breath, general weakness, fever, and in extreme exposure
cases, respiratory insufficiency with shock and death. These exposures are
associated with pulmonary congestion and edema. Individuals surviving the
exposure episode regain partial lung function but have a high probability
of subsequently dying of chronic pulmonary insufficiency (Friberg et al.,
1974). It has been estimated that the pulmonary retention of 4 mg in man
is fatal (Gleason et aj. , 1969).
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A recently reported case of fatal cadmium-fume pneumonitis (Patwardhan
and Finckh, 1976) typifies the characteristics of the lethal form of acute
cadmium intoxication. A welder spent the day welding handles to cadmium-
plated drums. He went home at the end of the day showing no ill effects.
Late that same evening, throat irritation developed and was followed by
coughing, difficulty in breathing, fever and rigors. By the middle of the
second day, he was severely dyspneic, cyanotic, febrile, and sweating.
Impaired gait and speech were noted. Examination by X-ray showed heart
enlargement, gross pulmonary edema, and elevated diaphragm. The patient
expired about 3 days after exposure to occupational cadmium fumes. The
lungs were voluminous, dark, congested and firm. Microscopic examination
revealed degeneration; epithelial loss in bronchioles was present, and
areas of regeneration were seen in which epithelial cells were spreading
across the mucosal surface. Also present was diffuse congestion of alve-
olar capillaries with intra-alveolar proteinaceous exudate and shed alve-
olar lining cells and macrophages. Liver and lung cadmium values were 2.3
and 1.5 ppm, wet weight, respectively.
The chief pulmonary effect of chronic cadmium inhalation in man appears
to be centrilobular emphysema and bronchitis arising after several years of
occupational exposure to cadmium-oxide fumes, cadmium-oxide dust and cadmium-
pigment dust (Friberg et al., 1974). Furthermore, lung impairment is
likely at cadmium oxide fume levels below 0.1 mg/m .
With respect to populations at large, it should be noted that while
the added body burden of cadmium contributed by cigarette smoking has been
established, the role of cigarette cadmium in a cause/effect relationship
to chronic pulmonary disorders, as distinct from smoking, per se, has yet
to be demonstrated.
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Several reports have appeared dealing with the effect of cadmium salts
j_n \m/o and jjn vitro on human alpha- 1-antitrypsin, the major proteinase
inhibitor in human plasma, a deficiency of which is associated with chronic
obstructive lung disease. Chowdhurdy and Louria (1976) reported a concen-
tration-dependent decrease in both antitrypsin level and inhibitory capa-
city in response to added cadmium. No other heavy metal was seen to have
this effect. Glaser et a_L (1977), however, claim that this effect is an
artifact due at least in part to the acid content of the cadmium-dosing
solution. Chowdhurdy and Louria (1977) in turn claim that a pH effect can
only be part of the answer, since their j_n vivo work with mice indicates
that a similar response occurs where pH is not a factor. A second report
which is even more significant regarding the effect of cadmium on a-^-anti-
trypsin is that of Bernard et aJL (1977). Their results, using workers
exposed to excessive amounts of cadmium and showing signs of cadmium intox-
ication, did not indicate any reduction of c^-antitrypsin in the blood of
these workers.
2.4.2 Animal Studies
The acute effects of cadmium on the lung have been studied in experi-
mental animals using generated cadmium fumes or cadmium aerosols. In one
3
relevant study, mice exposed to cadmium fumes (1.3 to 1.7 mg/m ) for 1 hr
were studied by Fukase and Isomura (1976), who observed that such treatment
caused increased content of glutathione as well as increased enzyme activi-
ties of the peroxidative metabolic pathway in the lung.
Yoshikawa and Homma (1974) assessed the 50-percent lethal concen-
tration (LC5Q) of cadmium fumes in rats using a particle size of 0.2 u and
found the value to be 25 mg/m for a period of 30 min. Retention of
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inhaled cadmium in the lung was 15 percent at a 30-min exposure level of 20
3
mg/m , and at 1 wk post-exposure 54 percent of the cadmium body burden was
still retained in the lung.
3
Cadmium dust (1.1 mg/m up to 4 wk) was seen by Watanabe et a/L (1974a)
to produce effects in rats that included septal interstitial pneumonitis
and cell nuclear changes.
Hayes and coworkers (Strauss et a_L , 1976; Hayes et a_L , 1976) have
carried out a series of inhalation studies in rats using a polydispersal
cadmium chloride/saline aerosol. Using an aerosol of 0.1 percent cadmium
chloride (4.5 u, 10 mg Cd/m ) for an exposure period of 2 hr, these workers
(Strauss et a_L , 1976) found morphological evidence for acute lung injury
by 24 hr post-inhalation. Examination by microscopy revealed multifocal
damage in respiratory bronchioles. Ultrastructural studies showed:
(1) There was Type 1 cell edema with loss of plasma membranes by 24
hr.
(2) By the second day, the number of Type 2 cells had increased.
(3) By day 3, the damaged alveoli were lined by cuboidal cells.
(4) By day 10, these cells had regained the appearance of Type 1
cells.
In a related study (Hayes et al., 1976) assessing biochemical aspects
of lung injury in rats using the above aerosol-exposure model, this same
group noted that by the fourth day after exposure the total lipid content
and lactate dehydrogenase and G-6-PD activities had all doubled, coinciding
with doubling of lung weight and total lung DNA content. Mai ate dehydro-
genase activity was very high 1 hr post-exposure, followed by subsequent
reduction to a level comparable to the other enzymes. With the exception
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of the effect on malate dehydrogenase, which is an index of mitochondria!
injury, the biochemical responses appear to be nonspecific.
Ada!is et a|. (1977) studied the effect of cadmium on ciliary activity
using isolated hamster tracheal rings and an organ-culture system. Statis-
tically significant reductions in ciliary activity were seen at cadmium
concentrations as low as 6 uM. Similarly, cilia from hamsters exposed to a
cadmium chloride aerosol (2 uM, 2 hr, 50 to 1420 ug/m ) were studied. In
this case, the mean cilia-beating frequencies in all treatment groups were
lower for recovery periods of 24 and 48 hr.
Gardner et al_. (1977) have reported that cadmium inhalation (aerosol)
also reduces the lung's ability to fend off microbial insults. Increase in
mortality (15 to 70 percent) was observed in mice exposed to levels of 80
to 1600 ug/m followed by streptococcal challenge. There was a marked
decrease in the total number of alveolar macrophages recovered from lungs
post-exposure, with a return to normal seen within 24 hr. Polymorpho-
nuclear leucocytes increased dramatically by 24 hr after exposure, while
lymphocyte numbers were unchanged. It is of interest to note the studies
cited in the cytotoxicity section regarding the cell-culture studies of
these same cells exposed to cadmium in a culture medium. Streptococci
clearance from the lung was correlated with the mortality pattern.
Cadmium appears to affect the pulmonary tract even when the exposure
is other than by inhalation. Miller et aJL (1974) studied the effect of
cadmium in rats exposed to dietary cadmium (17.2 ug/ml cadmium chloride; 6,
16 and 41 wk) in regard to the fine structure of connective tissue. After
6 wk of exposure, a general process of fibrosis was well established in
sub-pleura! tissue of the treated rats. Collagen fibrils were bundled.
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There was increased density of the interstitial space merging into the
basal lamina. An inflammatory response characterized by plasma cells and
the deposition of the primary elements of fibrosis seem to be an early
reaction to cadmium, progressing rapidly over a period of 16 wk, leaving
the interstitium thickened at the lung periphery. The sub-pleura! elastic
layer showed focal disruption. Few polymorphonuclear leucocytes were seen.
No abnormal fiber types were present after 16 wk of exposure. After 41 wk
of exposure, there was a slow progression of the fibrosis. It is possible
at least part of these effects are related to cadmium effects on copper
metabolism via interference with copper enzymes (O'Dell et a_L , 1966;
Murthy et aJL, 1972).
In the exposure study of Stelzner et a_K (1975), intratracheal injec-
tion of 10 mM cadmium chloride resulted in degeneration of bronchial
epithelium and widespread alterations in the lung. Regeneration of bron-
chial epithelium occurred by 8 wk, while the distal lung showed areas of
emphysema and extensive scarring. Histochemically, there was a return by 8
wk to the normal pattern of staining for lysosomal enzymes. Ultrastruc-
turally, rapid regeneration and ciliogenesis in bronchi and denuded base-
ment membrane were seen, proceeding to hyperplastic Type II cells and
layered membranous cells in the distal lung.
2.5 RENAL EFFECTS OF CADMIUM
The effects of both acute and chronic exposure to cadmium on the renal
system have been noted in the literature from experimental animals and from
clinical and epidemiological data. Both acute and chronic aspects of renal
toxicity of cadmium have been reviewed by Friberg et aL (1974), Nordberg
(1976), and Kawai (1976).
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The most typical feature of chronic cadmium intoxication is renal
damage, and thus, the kidney may be considered the critical organ in
chronic exposure (Nordberg, 1976).
In particular, cadmium affects the reabsorption function of the
proximal tubules, with an early sign of this effect being an increase in
the urinary excretion of low-molecular-weight proteins—tubular protein-
uria. The proteins, occurring in plasma, are normally almost totally
reabsorbed, but the cadmium-injured kidney is less able to achieve complete
resorption.
Later effects are aminoaciduria, glucosuria, and phosphaturia (Piscator,
1966a). Disturbances in kidney function are also manifested by effects on
bone and mineral metabolism, via increased excretion of calcium and phos-
phorus. Early reports have described kidney stones in Swedish workers
(Friberg, 1950) and osteomalacia in French workers (Nicand et al., 1942),
as well as certain populations in Japan exposed to dietary cadmium (Friberg,
et al_. 1974). According to Piscator (1966a), once tubular proteinuria is
seen, it is essentially irreversible.
2.5.1 Animal Studies
In experimental animals, the level of kidney damage due to chronic
cadmium exposure is dose-related, from early-detected degenerative changes
in the proximal tubules passing on to interstitial edema, glomerular capsule
thickening, and basement membrane fibrosis as exposure continues. It is
possible that renal vasculopathy accounts for the interstitial and fibrotic
sequelae, while cadmium acting on the renal tubule directly may account for
tubular changes (Kawai et al., 1976).
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According to Kawai et al_. (1976), there are morphologically distinct
features of acute cadmium insult to the kidney in experimental animals in
contrast to chronic exposure. In the acute case, hydropic swelling and
acidophilic necrosis are seen, while tubular atrophy characterizes the
chronic case. Pronounced edema in the surrounding interstitium is present,
eventually resulting in interstitial fibrosis and nephrosclerosis at a
later stage. Acute lesioning in tubular epithelium may be seen and is dose
dependent. These observations suggest that vascular injury probably plays
a major role in acute nephropathy.
In the studies of Kawai and coworkers (Kawai and Fukuda, 1974; Kawai
et al_. , 1974) involving chronic cadmium poisoning in rats (10 to 200 ppm
cadmium in tap water for 8.5 to 18 mo), tubular atrophy with interstitial
edema was found in the kidneys of rats receiving 100 ppm cadmium or greater;
and slight lesioning was observed in some animals at 50 ppm. The corres-
ponding kidney metal levels were 150 and 37 ug/g wet weight, respectively.
Cadmium excretion from kidney apparently increases as renal injury becomes
more severe.
Itokawa et aj. (1974) studied two groups of rats that received 50 (jg
Cd/g of diet with and without sufficient calcium for a period of 4 mo and
observed considerable renal injury. The tubular epithelium was desquamated
and vacuolized, and there was necrosis and partial hyalinization in glomer-
ular capillaries with adhesions between the Bowman capsule and glomerular
capillaries.
After 16 wk of feeding, Nomiyama (1975) observed that rabbits given
300 ug Cd/g in food began to show increased urinary ami no acid excretion,
concomitant with increases in certain enzymes. After 38 and 42 wk, total
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protein and sugar levels respectively were elevated, but ami no acid levels
after 30 wk were similar for both control and exposed animals. The corres-
ponding kidney cadmium levels for these time points were 200 and 300 ug
Cd/g wet weight.
Axelsson and Piscator (1966) showed that in the rabbit proteinuria
appeared before aminoaciduria. In man, proteinuria is certainly an earlier
sign than aminoaciduria.
Suzuki (1974) found that, in rats exposed to low levels of cadmium for
16 wk, a kidney cortex level of 225 ug Cd was associated with proteinuria
and a dramatic increase in urine cadmium.
Gonick et a1_. (1975), in their studies of cadmiurn-induced experimental
Fanconi syndrome in female rats, gave repeated injections of cadmium ion
(0.6 mg Cd/kg, i.p.) until the onset of glycosuria (24 days). By 2 days
after the occurrence of glycosuria, the Fanconi syndrome was essentially
complete in terms of: urinary volume increases; increased excretion of
protein, glucose, and a-amino nitrogen; and increased fractional excretion
of sodium, potassium, calcium, magnesium, and phosphate. Also, renal
cortical Na -K -ATPase activity was reduced to less than half that of
controls with reduction in ATP levels. The effect on this enzyme activity
was consistent with ultrastructural evidence, i.e., extensive loss of basal
membrane infoldings, the principal site of the enzyme's activity. Like-
wise, reduction in ATP levels paralleled evidence of alterations in the
mitochondria.
Fowler et al_. (1975) studied the effects of chronic cadmium admini-
stration on rat renal vasculature using low and normal calcium diets. Both
diet groups of rats were exposed to cadmium via drinking water (0.2 to 200
2-35
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ppm cadmium, 6 or 12 wk). Constriction of smaller renal arteries, mild
dilation of larger arteries, and a diffuse scarring of peritubular capill-
aries were observed at 6 wk at even low doses (2 and 20 ppm Cd), with
arterial constriction appearing to subside by week 12. These changes would
indicate a decrease in effective renal circulation with time. While vari-
ation in calcium intake did not appear to influence the vascular effects
studied, increased renal depositon of cadmium in the low-calcium rats was
observed.
Since chronic cadmium exposure occasions renal tubular dysfunction,
one might expect that this in turn would influence the metabolism of
Vitamin D. In the section dealing with subcellular aspects, it was noted
(Suda et a_L , 1974) that j_n vivo formation of 1,25-dihydroxy-vitamin D3 was
not markedly altered by a diet containing cadmium but that was Vitamin D
deficient.
In the study of Lorentzon and Larsson (1977), however, in which rats
were chronically exposed to cadmium in drinking water (0.22 and 0.69 m mole
Cd/1) for a period of 3 mo and were on either normal or low-calcium diets,
both levels of cadmium exposure led to reduced formation of 1,25-dihydroxy-
Vitamin D., in kidneys as well as serum and liver, with the higher level
yielding only minute amounts in the kidney. Even at the higher dose, there
was only a slight effect on reduction of the conversion product with low
calcium intake. Further, cadmium exposure showed a shift in Vitamin D
metabolism over to formation of the less active metabolite 24,25-dihydroxy-
cholecalciferol.
Pierce et al. (1977) investigated the use of urinary enzyme activities
as markers for the nephrotoxicity of cadmium in the marmoset and rat.
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Excretion of urinary enzymes in rats that had been dosed by subcutaneous
(s.c.) injection (1.5 mg/kg/day) remained at control-animal levels to day
15. An increase of 0-glucosidase activity occurred and continued to rise
until the experiment was terminated (p < 0.01). N-acetyl-p-glucosaminidase
activity increased by day 18. With marmosets, oral exposure to cadmium was
without effect on urinary enzyme levels, but s.c. injection (6 days, 5
mg/kg/day) gave rise to an increase in enzyme activity by day 2 in the case
of N-acetyl-p-glucosaminodase.
2.5.2 Human Studies
A number of studies have been directed to the chronic nephrotoxicity
of cadmium in man, particularly cadmium workers and Japanese populations
receiving environmental exposure via rice, fish, and water contamination.
The earlier clinical and epidemiological studies have been reviewed by
Friberg, et a_L (1974).
Current investigations have included assessment of the extent and
nature of the tabular derangement seen in man with chronic cadmium exposure,
including the occurrence of proteinuria. In chronic cadmium poisoning in
man, the urinary proteins vary in molecular weight from 10,000 to 200,000
with more than half of the total protein being smaller than albumin. The
globulin fraction includes ^2*^2" ant* a 9^°bulins, p^-microglobulin, retinol-
binding protein, and a-globulin L chains.
Several studies have been directed to characterizing the nature of
urinary proteins excreted in excess in response to chronic cadmium exposure.
Peterson and Berggard (1971), for example, reported that retinol-binding
protein (RBP) appears in human urine as a result of cadmium poisoning, and
later investigators have studied the nature of the protein as well as its
occurrence in other species in response to cadmium challenge.
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Clark and coworkers (1975) in their studies of tritium-labeled retinol
show that cadmium-treated rats excreted excess amounts of a protein bound
to retinol or a retinol metabolite and having a molecular weight of about
4600.
Muto and coworkers (1976) exposed rabbits to cadmium (0.8 and 1.5
mg/kg body weight, s.c. 5 times per wk) and found a large excretion of
retinol-bound protein of molecular weight 20,000. Though similar to human
RBP (Kawai et a\_. , 1971, 1972) they are immunologically distinct.
Perhaps a more significant urinary protein in terms of its being an
index of renal damage induced by cadmium is pp-microglobin. The bio-
chemical and diagnostic aspects of this protein have been reviewed by
Kjellstrb'm and Piscator (1977).
Piscator (1966b,c) found relatively high levels of the plasma protein
p2~microglobulin in the urine of cadmium workers, and Berggard and Beard
(1968) subsequently isolated and characterized this protein from cadmium-
worker urine.
In the normal kidney, reabsorption of P2-microglobulin is essentially
complete: 99.9 percent reabsorption (Johansson and Ravnkov, 1972; Evrin
and Wibell, 1972). According to Evrin and Wibell (1972), 100 pg is excreted
daily via the normal kidney.
Coupling of the known data regarding the renal biochemistry of
globulin with its increased excretion in cadmium exposure indicates that
levels of this protein are rather good indicators of tubular proteinuria
induced by cadmium, and efforts have been made to evolve both good quanti-
tative measurements of the protein and baseline levels for diagnostic
purposes. Furthermore, the much higher relative increase in P-
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bulin excretion than in total protein levels suggested that ^-micro-
globulin analysis may be the most sensitive method of detecting the early
stages of cadmium-induced renal tubular injury.
Of the various methods for quantitative assessment of this protein,
the radioimmunoassay technique of Evrin et al_. (1971) appears to be the
most sensitive (2 ug/1), having a sensitivity about 50 times above that
required for normal urine levels, about 100 ug. Details of the analysis
have been reviewed (Kjellstrom and Piscator, 1977).
A number of epidemiological studies have been carried out using $^-
microglobulin measurement to assess proteinuria (Kjellstrom et a^., 1977a,b;
Kojima et al_. , 1977). The frequency distribution of individuals in normal
groups was log-normal. Geometric average values of (^niicroglobulin in the
general population range from about 50 to 100 ug/urine, while excretion
levels in excess of 200 pg/1 may be considered to be abnormal.
The dose-response relationship between increases in urinary excretion
of this protein and cadmium exposure are evidenced by the data of Kojima et al_.
(1977) and Kjellstrom et al_. (1977a).
In a number of cadmium-exposed areas in Japan, proteinuria has also
been regarded as a manifestation of cadmium poisoning of the general popu-
lation. These studies have been extensively reviewed and evaluated by
Friberg et al_. (1974) and by Shigematsu (1975), and particular attention
has been given to Itai-Itai (Ouch-Ouch) disease, a condition embodying a
number of toxic effects of cadmium and representing a classic case of
environmental pollution in an industrialized society having severe conse-
quences for the individuals involved. Itai-Itai disease is essentially
cadmium-induced renal tubular dysfunction in a nutritionally-deficient
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population, leading to osteomalacia and osteoporosis. Most of the victims
were post-menopausal women who had given birth to several children and had
a history of calcium and vitamin D deficiency.
Itai-Itai disease was first found in Fuchu in Toyama Prefncture where
rice fields irrigated by the Jintsu River were contamininated by waste
products from a mine. As cited by Friberg et a_K (1974), proteinuria and
glucosuria were more prevalent in the Itai-Itai disease belt than in a
control area.
Presently, a large amount of data has been collected from parts of
Japan other than Fuchu where cadmium exposure has been suspected. Methods
of assessment of proteinuria vary in the study areas, however; and this may
play a role in the fact that findings of different proteinuria studies are
at variance with each other.
In many of the cadmium-polluted areas for which age-related prevalence
of proteinuria was amenable to calculation (such as the areas of Fuchu and
Tsushima), there is a substantial increase in prevalence with age; and in
Fuchu the causal role of cadmium in this relationship is apparent. Further-
more, the population in many of the polluted areas showed enhancement of
proteinuria with age which was significantly different with control popula-
tions.
In a recent report (Shiroishi et aJL , 1977) detailing the results of a
joint Japanese-Swedish study of the nature of cadmium-induced renal changes
in individuals with Itai-Itai disease, as assessed by P2-microglobulin
excretion, it was determined that proteinuria in Itai-Itai disease is
tubular. In particular, p^-microglobulin excretion, an index of tubular
injury, was found to be over 100 times higher than in a reference popula-
tion.
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Epidemiological aspects of cadmium-polluted areas of Japan are dis-
cussed in a later section dealing with epidemiological studies.
2.6 THE CARDIOVASCULAR SYSTEM
This section will consider mainly the major aspect of cadmium's effect
on the cardiovascular system: hypertension. A sizable body of data exists
regarding the induction of hypertension in experimental animals in response
to chronic cadmium exposure. While the cause/effect relationship of cadmium
to experimentally induced hypertension appears to be well established, the
issue of cadmium's role in the etiology of human hypertension still remains
to be resolved.
2.6.1 Animal Studies
Perry (1976) and Friberg et aJL (1974), have critically reviewed the
earlier literature with regard to cadmium-induced hypertension in experi-
mental animals such as the rat. The most relevant animal model for assess-
ment of cadmiurn-induced hypertension is that employing oral exposure of the
toxic element. Schroeder and Vinton (1962) first reported hypertension in
animals fed cadmium, and this was confirmed by Perry and Erlanger (1971,
1974) and Sorenson et ajL (1973).
Perry et al_. (1977b) have recently reported that cadmium concentra-
tions as low as 0.1 ppm in drinking water have induced the same degree of
hypertension as the standard 5 ppm dose of cadmium; moreover, occasional
subpopulations of "responders" have had a marked increase in pressure
(Perry et aJL , 1978). In addition, simultaneous feeding of lead and cad-
mium can markedly augment cadmiurn-induced hypertension (Perry et aJL ,
1977a).
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The level of hypertension noted with chronic oral exposure, while
statistically significant, is not great; and it is apparent from the liter-
ature that, in addition to a dosing regimen of a low cadmium level (5 ppm)
in drinking water, other experimental details are important in observing
the effect.
Frickenhaus et al_. (1976) exposed rats to cadmium sulfide in their
diets (26 mg Cd S/kg diet and 52 mg CdS/kg diet) for 3 mo, at which time no
significant changes in blood pressure were seen, although the levels of
cadmium ingested may have exceeded the lower exposure levels in the work
described above. In this connection, Perry et a\_. (1977a) point out that
hypertension in animals appears to be associated with a particular level of
renal cadmium or a particular zinc-cadmium ratio, and that deviation in
level up or down may cause the effect to disappear.
Parenteral adminstration of cadmium occasions acute hypertension in
rats (Perry and Erlanger, 1971; Schroeder, 1967), rabbits (Thind et al.,
1970), and dogs (Thind, 1973). While the hypertension caused by low-level
cadmium feeding is moderate and permanent, hypertension from cadmium injec-
tion is transitory.
Thind (1974) studied blood-vessel wall characteristics in experimental
hypertension induced by parenteral cadmium. Utilizing i_n vitro techniques,
the vascular reactivity and elasticity of blood vessels from rabbits and
dogs exposed to cadmium were measured. It was found that the vascular
reactivity of rabbit aorta to angiotensin was significantly reduced in
cadmium-treated animals, while hypertensive dog carotid artery was less
responsive to angiotensin, norepinephrine, and serotonin. Furthermore, the
hypertensive dog carotid artery developed significantly lower passive elasticity
modulus.
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In a related study, Thind and Fischer (1975) measured cadmium and zinc
distribution in cardiovascular tissue of cadmium-treated and normal dogs.
Cardiovascular tissue levels of cadmium in both groups were high in peri-
pheral and smaller arteries and myocardium. The distal mesenteric artery,
mesenteric artery branches, main renal artery, and coronary arteries,
however, tended to accumulate cadmium while zinc levels were highest in the
mesenteric artery branches. Kopp et al. (1978) using rats exposed to 5 ppm
cadmium for 24 months found (a) depressed myocardial excitability, (b)
decreased high energy phosphate in the heart, and (c) morphologic changes in
cardiac muscle.
Thind (1973) found an approximately seven-fold increase in renin
activity of generated angiotensin I following cadmium treatment in dogs.
Perry and Erlanger (1973) reported an increase in plasma renin activity in
cadmium-fed rats.
Porter et aj. (1975), in studies of rats given cadmium, failed to find
elevated blood pressure but noted that the treated animals evidenced
decreased blood-pressure responses to norepinephrine, acetylcholine, isopro-
terenol, and atropine. Aortic strips from the animals also showed reduced
reactivity to angiotensin, epinephrine, barium, and tyramine. These data
suggested to the authors that production of hypertension and desensitiza-
tion of vasculature to vasoconstrictors and vasodilators may be unrelated
biological events.
The effects of low dietary cadmium on blood pressure and on sodium,
potassium, and water retention in growing rats were investigated by Doyle
et al. (1975). Sodium retention was greater in both male and female rats
fed cadmium. There was a transitory greater retention or loss of potassium
2-43
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in males and females, respectively, which abated by 330 days, although
water retention was greater in treated animals at about the same time. No
effect on blood pressure was seen, however. The absence of induced hyper-
tension in this study was ascribed to differences in zinc in the diet, with
zinc content being only a fraction of that used in the Perry and Schroeder
models (vide supra) and other dietary differences as well.
2.6.2 Human Hypertension
As noted above, the case for cadmium as a factor in human hypertension
is not clear-cut, and studies relating to this issue are discussed in the
Human Epidemiology Section (4.).
2.7 EFFECTS OF CADMIUM ON REPRODUCTION AND DEVELOPMENT
An extensive literature documents cadmium effects on the gonads,
associated organs, and other aspects of reproduction and development, as
reviewed by Fleischer et al_. (1974), Friberg et al_. (1975), and NIOSH
(1976). Many of the more dramatic effects reported, however, have been
obtained with injections of the metal at relatively high dosage levels;
this has led to questions about the environmental relevance of such findings.
Other research has focused on: (1) mechanisms of action by which the toxic
effects are exerted, (2) whether such effects occur at lower, environmen-
tally encountered exposure levels and via relevant exposure routes, and (3)
whether comparable effects occur in occupationally or environmentally
exposed humans.
2.7.1 Testicular Effects
Induction of acute testicular necrosis by cadmium has attracted consi-
derable attention in the literature on experimental animal models, but is
of questionable relevance in assessing the impact of environmental cadmium
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exposure on humans. In early studies (Parizek and Zahor, 1956; Parizek,
1957), a single subcutaneous (s.c.) injection of cadmium chloride at high
doses (2.2 to 4.5 mg Cd/kg) was found to cause severe testicular damage in
rats and mice. Within a few hours after cadmium injection, histologically
detectable testicular changes such as interstitial edema occurred and
progressed to extensive necrosis of the testes by 48 hr. Resorption of
testicular tissue occurred by 10 days post-injection, and weights of access-
ory sex organs, seminal vesicles, and prostate glands were reduced. In a
later study, Mason et al. (1964) injected a wider range of cadmium chloride
doses (0.51 to 6.8 mg Cd/kg) s.c. into male rats and found the lowest
effective dose to be 0.85 mg/kg.
The role of the testicular vasculature in determining cadmium effects
on the testes has been one issue dealt with extensively in regard to charac-
terizing mechanism(s) by which the metal damages male gonads. Much atten-
tion, for example, has been directed to whether cadmium-induced testicular
necrosis results from a direct action of cadmium on the seminiferous tabule
epithelium or occurs secondarily as a consequence of a primary damaging
effect on the testicular vasculature. The case for the primacy of vascular
damage has been well-argued in numerous individual research reports and
several general review articles (e.g., Gunn and Gould, 1970; Friberg et
aJL , 1975) and that view is the currently most widely accepted one in the
field.
Arguments for the primacy of vascular effects underlying cadmium-
induced testicular necrosis gained credence, in part, by virtue of varia-
tions in susceptibility of different species. It was first well-established
that mammalian species possessing scrotal testicles were susceptible to the
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effect, since virtually all such species tested show marked acute testicu-
lar necrosis following a single systemic injection of cadmium. Such suscep-
tible species are listed in Table 2-2. In contrast, several non-scrotal
species with abdominal testes, as listed in Table 2-2, appear to be resis-
tant to the induction of testicular necrosis by cadmium. That factors
beyond vascularization patterns are important, however, is suggested by:
(1) demonstration of susceptibility among some non-scrotal species listed
in Table 2-2, and (2) demonstration of variations in susceptibility between
strains within the same scrotal species (Gunn et al. , 1965; Taylor et aj. ,
1973).
Other evidence supports the view that cadmium causes testicular necrosis
via a primary effect on testicular vasculature. This includes ultrastruc-
tural studies demonstrating: (1) signs of cadmium-induced increases in
vascular permeability in testes (Clegg and Carr, 1967), (2) evidence of
pinocytotic activity in testicular capillary endothelial and peri vascular
cells as well as loosened endothelial desmosome junctional complexes and
signs of microhemorrhaging (Berliner and Jones-Witters, 1975), and (3)
changes in intratesticular capillary endothelial cell junctions leading to
separation of endothelial cells (Fende and Niewenhuis, 1977). Also,
Koskimies (1973) showed that serum protein increased in rete testis fluid
within 10 min after cadmium injection, but not in seminiferous tubule fluid
until 2 hr.
Additional studies have focused on biochemical mechanisms possibly
underlying cadmium-induced testicular damage. For example, the activity of
carbonic anhydrase (CAR), a zinc-containing metalloenzyme, was decreased in
testes after cadmium administration; and inhibition of CAM was taken to be
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Table 2-2. SPECIES VARIATIONS IN SUSCEPTIBILITY TO CADMIUM-INDUCED
TESTICULAR NECROSIS
Species
tested
Testicular damage
susceptibility
Reference
Scrotal species
Rat
Rat
Mouse
Mouse
Guinea pig
Rabbit
Gerbil
Gerbil
Hamster
Dog
Dog
Goat
Monkey
Non-scrota! species
Suncus
Fowls
Frog
Toad
Toad
Doves
Parizek (1957)
Mason et aJL (1964)
Parizek (1957)
Gunn et aj.. (1965)
Parizek (1960)
Kar and Das (1962)
Ramaswami and Kaul (1966)
Berliner and Jones-Witters (1975)
Girod and Dubois (1976)
Chatterjee and Kar (1968)
Donnelly and Monty (1977)
Kar and Das (1962)
Kar (1961)
Dryden and McAllister (1970)
Johnson et al_. (1970)
Chiquoine (1964)
Biswas et al_. (1976)
Chiquoine and Sunzeft (1965)
Maekawa et al. (1964)
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Table 2-2. SPECIES VARIATIONS IN SUSCEPTIBILITY TO CADMIUM-INDUCED
TESTICULAR NECROSIS (CONTINUED)
Species Testicular damage
tested susceptibility Reference
Fish (+) Maekawa and Tsunenari (1967)
Fish (+) Sarkar and Mondal (1973)
Fish (+) Tafanelli (1972)
Brook trout (+) Sangalong and O'Hallran (1973)
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important in the etiology of cadmium-induced testicular necrosis (Johnson
and Walker, 1970). Subsequent work reported by Alsen et aj_. (1976),
however, provides strong evidence against this. As for other research
attempting to identify particular proteins as pathogenic targets for cad-
mium in the testes, that of Chen et aj. (1974) revealed two cadmium-binding
moieties corresponding to proteins of molecular weights (MW) of 10,000 and
30,000 in the soluble fraction of whole testes; and Chen and Ganther (1975)
later provided evidence for involvement of the 30,000 MW protein in the
pathogenesis of testicular necrosis. This, however, is not supported by
the more recent data of Prohaska et a_K (1977). Lastly, Omaye and Tappel
(1975) demonstrated reductions in plasma and testicular glutathione (GTH)
peroxidase activity that they hypothesized to be important in mediating
cadmiurn-induced testicular necrosis.
Certain data suggest that some cadmiurn-induced degenerative changes
might occur secondarily to damage androgen-producing (Leydig) cells of the
testes. Such data include the demonstration after cadmium treatment of:
(1) decreased plasma levels of androgens (Chandler et ah, 1976; Saksena et
a_L , 1977), and increased testicular cholesterol levels indicative of
decreased androgen production by the testes (Dixit et a^., 1975); (2)
alterations of cyclic AMP metabolism in the primary and secondary reproduc-
tive organs of the male rat consistent with reductions in testosterone
(Sutherland et ajL , 1974); (3) evidence of Leydig-cell necrosis or reduc-
tions in metabolic activities in those cells (Girod and Dubois, 1974, 1976;
Dixit et aL , 1975); (4) signs of hyperplasia of gonadotropic cells in the
anterior pituitary (Girod and Dubois, 1974, 1976), as well as increases in
plasma levels of leuteinizing hormone (LH) (Chandler et a_K , 1976) and (5)
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autoradiographic localization of cadmium in testicular interstitial tissue
(Nordberg and Nishiyama, 1972).
Chandler et a_L (1976) observed changes in the ultrastructural integ-
rity of the lateral prostate of the rat as early as one day after cadmium
injections, too soon for decreases in circulating testosterone to have
occurred. This suggests that cadmium may also exert a direct influence on
the prostate before any further effects of reduced androgen levels are
manifested. In addition Nordberg (1975) found that morphological changes
in the seminal vesicles indicative of reduced testosterone levels occurred
as a result of chronic exposures to doses of cadmium too low to produce
alterations in testicular weight or histology, suggesting that cadmium can
also exert effects on testosterone-producing testicular cells before necrosis
occurs after vascular damage. Further support for this possibility is
gained from another observation by Nordberg and Piscator (1972) on chronic
cadmium doses below those producing testicular necrosis causing a signifi-
cant decrease in the protein excretion of male mice before the onset of
renal tubular dysfunction. Since the usual cadmium-induced proteinuria in
mice was previously shown to be testosterone-dependent (Thung, 1956;
Finlayson et a_L , 1965), the decreased production of testosterone was
hypothesized as being an early effect of long-term cadmium exposure.
In view of the above results, much remains to be clarified concerning
mechanisms by which acute high doses of cadmium cause testicular necrosis.
Of greater importance here, however, is the issue of whether or not more
chronic, lower-level exposures to cadmium cause significant morphological
or functional changes in the testes.
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Piscator and Axelsson (1970) reported that 0.5 mg Cd/kg doses of
cadmium chloride, when administered subcutaneously to rabbits 5 times per
week for 24 wk, caused no macroscopically or microscopically evident testi-
cular changes but did cause marked kidney damage. In another study,
Nordberg (1971) demonstrated that single, subcutaneous (s.c.) injections of
cadmium chloride at 1 mg Cd/kg caused complete testicular necrosis in CBA
mice, while single doses of 0.25 to 0.50 mg Cd/kg caused little or no
damage to the testes. After administration of such doses 5 days/wk for 6
mo, no significant testicular changes were apparent at the 0.25 mg/kg dose
level and only slight changes were evident at the 0.50 mg/kg level. This
occurred despite the fact that testicular cadmium levels in these animals
were 6 to 7 ppm, i.e., approximately 20 times as high as the levels (0.3
ppm) found to exist in the mice experiencing severe testicular necrosis
after a single 1.0 mg Cd/kg injection. Repeated injections of 0.25 mg/kg
doses, to stimulate metaHothionein synthesis, prevented the induction of
testicular necrosis by a 1.0 mg Cd/kg dose administered later. Also, no
testicular necrosis occurred after injections of cadmium (1.1 mg Cd/kg)
partially bound to metallothionein. When the same chronic dosage regimen
as the first one used in the Nordberg (1971) study was employed in a subse-
quent experiment on renal effects, Nordberg and Piscator (1972) found that
CBA mice receiving s.c. injections of 0.25 to 0.5 mg Cd/kg, 5 days/wk for 6
wk, developed signs of kidney damage.
Considered together, the above results appear to indicate that testi-
cular damage does not occur after repeated administration of cadmium com-
pounds at doses causing only slight or no kidney malfunction. Other data
suggest, however, that more subtle testicular effects may occur in the
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absence of clear-cut kidney damage. Nordberg and Piscator (1972), for
example, found a significant decrease in protein excretion before the onset
of renal tubular dysfunction resulting in marked proteinuria, and Nordberg
(1975) demonstrated effects on the seminal vesicles in the absence of
changes in testicular weight or histology after chronic cadmium dosing that
produced little renal dysfunction. Thus, even in the absence of demon-
strable morphological damage to the testes, biological changes suggestive
of probable altered testicular function were detected at cadmium exposure
levels below or equal to those producing signs of relatively slight renal
damage.
In regard to dietary cadmium exposure, very low oral cadmium doses
were reported to have been used as part of a joint Soviet-American project,
as reported by Russian workers (Krasovskii et al., 1976). Chronic oral
administration of cadmium chloride to adult male rats at four dose levels
(control, 0.00005, 0.0005, and 0.005 mg Cd/kg) was achieved by cadmium
concentrations of 0, 0.001, 0.01 and 0.1 mg/1, respectively, in the drinking
water. At dose levels as low as 0.0005 mg/kg, numerous statistically
significant gonadotoxic effects were reported to have occurred in conjunc-
tion with other, more general toxic effects. The Russian findings, which
are difficult to evaluate adequately from their published description, must
be viewed with caution, however, in view of unusually high blood cadmium
levels reported for their control (70 ug Cd/1) and cadmium exposed animals
(> 85 ug Cd/1) and in view of the cadmium doses used being far less than
those likely to be present in food.
American phases of the same Soviet-American cooperative project have
not yielded much evidence of testicular damage. Dixon et aj_. (1976) reported
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that possible "subtle reproductive effects" of cadmium were assessed in
male rats exposed orally to cadmium chloride at concentrations of 0, 0.001,
0.01, or 0.1 mg/1 in the drinking water, yielding estimated maximum doses
of 14 ug/kg/day. Randomly selected animals were taken for study after 30,
60 and 90 days of exposure. Using a variety of evaluations, no significant
differences were observed between control and cadmium-exposed animals at
any dose level or exposure time. Nor were any significant general toxic
effects obtained with a variety of clinical serum chemistry tests.
In another study, Loeser and Lorde (1977a) reported that cadmium
chloride fed to groups of 20 male and 20 female rats over a period of 3 mo
in concentrations of 0, 1, 2, 3, 10, and 30 ppm caused no histopathological
signs of damage in the gonads or any other organs. Similarly, no signifi-
cant effects were observed after the administration of the same doses of
cadmium chloride for 3 mo to groups of 2 male and 2 female beagle dogs each
(Loeser and Lorke, 1977b).
The Loeser and Lorke (1977a,b) and Dixon et al. (1976) results raise
serious questions about cadmium having significant effects on male repro-
ductive organs or functions when administered chronically at low dose
levels. Still, since little or no data were reported on tissue levels of
cadmium achieved in those studies, it is difficult to place them in perspec-
tive in relation to cadmium exposures known to produce other types of
damage, e.g., renal dysfunction. Also, it remains to be assessed as to
whether longer periods of exposure at the dose levels used might not produce
significant testicular effects.
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2.7.2 Ovarian Effects
Stimulated in part by findings of testicular necrosis in rodents after
exposure to high doses of cadmium, several early studies have analogously
focused on the effects of high-dose cadmium exposures on the ovaries of
female rodents. Kar and coworkers (1959) exposed female rats, 6 to 8 wk
old, to cadmium chloride via subcutaneous injections of 10 mg Cd/kg and
found some acute ovarian effects. More specifically, although ovarian and
uterine weights were not significantly altered, the rate of follicular
atresia was clearly affected. Medium- and large-sized follicles were
initially damaged, as indicated by signs of atrophy among granulosa cells
and ova, followed by complete destruction of follicles of all sizes by 48
hr postinjection. In addition, the normal response of the ovaries to
exogenously administered gonadotropins was blocked, suggesting a possible
interference of cadmium with actions of endogenous pituitary factors on the
ovaries. In a later study, Kar et al. (1960) demonstrated that simul-
taneous injections of zinc or selenium along with cadmium prevented the
ovarian damage otherwise obtained with cadmium alone. This is analogous to
preventive effects of zinc and selenium against cadmium-induced testicular
necrosis.
Evidence for cadmium-induced ovarian damage of the type described by
Kar et al_. (1959) has not been universally obtained by other workers. In
that regard, Gunn et a\_. (1961) did not detect any pathological changes in
the female reproductive tract or any other major organs in rats of another
strain treated with 0.03 mM/kg of cadmium chloride; nor did Der et a/L
(1977b) observe any pathologic or abnormal histology of ovary or uterus
after daily intramuscular injections of 50 or 250 ug CdCl2 in adult Wistar
female rats for 54 days, although persistent diestrus was seen in the 250
2-54
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ng dose animals. On the other hand, very distinct gross and morphological
correlates of antigonadal effects were observed by Kaul and Ramaswami
(1970) in the female gerbil. After a single subcutaneous injection of
either 0.22 mg Cd/kg in immature animals or 0.45 mg/kg in mature animals,
considerable reductions in the weight of the oviduct in both the immature
and adult female gerbils were seen, and histological examinations revealed
widespread follicular atreasia and extensive ovarian hemorrhages. No
evidence exists, however, for the induction of such ovarian damage by
cadmium with lower-level exposure by inhalation or ingestion.
2.7.3 Embryotoxic and Teratogenic Effects
Considerably more information than that on effects of cadmium on the
ovaries has been generated by the investigation of more general effects of
cadmium on reproduction and early development. This includes studies on
the erabryotoxic and teratogenic effects of cadmium, as well as research on
the transplacental transfer of the metal as a prenatal exposure route.
Such studies indicate that both embryotoxic and teratogenic effects occur
in many mammalian species after administration of high doses via systemic
injection, but much less evidence has been advanced for such effects occur-
ring at lower-level exposures via more environmentally relevant inhalation
or oral exposure routes.
Early studies on the rat documented adverse effects of cadmium admini-
stration during pregnancy, including the demonstration of placenta! necrosis
after high dose s.c. cadmium injections (Parizek, 1964) and heightened
vulnerability of maternal animals themselves in terms of s.c. injections on
day 21 of pregnancy causing hemorrhagic kidney necrosis and a 40-percent
death rate among dams (Parizek et a_K , 1968).
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In another study, Chernoff (1973) injected rats with cadmium chloride
(2.5 to 7.5 mg Cd/kg) on each of 4 consecutive days, starting either on day
13, 14, 15, or 16 of pregnancy, and observed (1) a dose-dependent increase
in fetal deaths, (2) decreased fetal weights, and (3) an increased rate of
congenital anomalies (micrognathia, cleft palate, club foot, and small
lungs). In contrast, Barr (1973) reported that cadmium chloride was not
teratogenic when a dose of 16 umole Cd/kg was injected s.c. into two dif-
ferent rat strains on gestation day 9, 10 or 11; but teratogenicity was
observed for both strains after i.p. injections of the same doses of cad-
mium chloride, with marked differences between the stocks occurring in
fetal mortality and incidence and types of malformations.
Studies on mice have provided further evidence for cadmium-induced
embryotoxicity and teratogenicity in mammalian species. In one study,
Yamamura (1972) reported that i.p. injections of 5 mg/kg of cadmium sulfate
(CdSCL) into pregnant mice from day 6 to 14 of gestation resulted in embryo
deaths and congenital anomalies such as exencephaly, cleft palate, and bone
malformations. Results obtained depended on the day of injection; that is,
injections on gestation day 9 caused a low incidence of embryo!ethality (15
percent) and day 11 injections a high incidence of fetal death (87 percent)
while injections of the same dose on day 12 produced a high lethality
incidence (82 percent) but a low teratogenicity rate (5 percent). This
pattern of results suggests possible differential sensitivity of fetuses or
dams to various cadmium-induced effects depending upon gestation stage at
which exposure occurs.
Other studies on mice have yielded information on dose-response rela-
tionships, including data suggesting a "no effect" level, and additional
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evidence regarding genetic influences on the induction of fetal cadniura
effects. For example, Ishizu et al_. (1973) exposed pregnant mice on gesta-
tion day 7 to cadmium chloride via s.c. injections of doses of 0, 0.33,
0.63, 2.5, and 5 mg Cd/kg. Dose-dependent effects were observed at doses
above a no-effect level of 0.33 mg/kg. This included dose-related increases
in percentages of dead fetuses (9.7, 9.9, 11.9, 12.0 and 17.5 percent at
the above respective doses) and increases in percentages of malformed
fetuses found when sampled on day 18 of pregnancy (0, 0, 0.97, 19.5 and
59.0 percent, respectively). Consistent with findings discussed earlier,
placenta! but not fetal concentrations of cadmium were detected, which
reinforces the idea that the metal may not cross the placenta! barrier very
well.
Evidence for genetically inherited differential susceptibility to
cactariurn-induced embryotoxicity has been provided by Wolkowski et al_. (1974-).
Pregnant female mice of two different inbred strains were injected subcu-
taneously on different days of gestation. Mouse embryos and fetuses of one
strain (NAW) were relatively resistant to death caused by maternal injec-
tions of cadmium, whereas embryos and fetuses of the other strain (C57BL)
were relatively susceptible. Pierro and Haines (1976), have also reported
findings confirming the relatively high susceptibility of the C57BL strain
to embryotoxic effects of cadmium, and Eto et al_. (1976) have shown A/Jax
mice to be susceptible to increases in the incidence of cleft lip after
i.p. injections of 5.9 mg/kd of CdSO. on day 10 of gestation.
The hamster is another species that has been shown to be vulnerable to
cadmium-induced embryotoxicity and teratogenicity as indicated mainly by
studies carried out by Perm and coworkers. In one of their earliest studies
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(Perm and Carpenter, 1968), intravenous injections of cadmium in hamsters
on day 8 of pregnancy were found to produce teratogenic effects, especially
facial malformations such as cleft palate and lips. Further characteriza-
tions of teratogenic effects were carried out in subsequent studies
(Mulvihill et a_L , 1970; Perm, 1971; Gale and Perm, 1973), with similar
intravenous injections of CdSO^ at a dose of 0.88 mg Cd/kg being used in
each. Mulvihill et a_K (1970), for example, presented evidence suggesting
that the palatal clefts induced by cadmium in the golden hamster are likely
due to mesodermal deficiencies in the palate region typified by defects in
bone formation and delays in ossification. Other congenital malformations
were reported by Perm (1971) to occur in the hamster embryo, including limb
defects such as amelia and phocomelia; and Gale and Perm (1973) reported
similar effects plus others following intravenous injections of 0.88 mg
Cd/kg on gestation days 8 and 9, which correspond to the time of major
organ differentiation in the hamster. Effects observed included malfor-
mations of the brain, eye, jaw, and tail as well as the fore and hindlimbs.
Several investigations by Perm and coworkers have also provided infor-
mation on protective effects against cadmium-induced fetal malformations.
Perm and Carpenter (1968) showed that the simultaneous injection of zinc
with cadmium protects against the teratogenic effects of cadmium. In the
same study, however, Perm and Carpenter (1968) found that cobalt did not
protect against cadmium-induced teratogenic effects, in contrast to the
demonstration by Gabbiani et a_L (1976b) of cobalt protection against the
toxic effects of cadmium on sensory ganglia and testes. Subsequent research
indicated that the protective effect of zinc was not simply due to that
metal's influence on the transplacental transfer of cadmium (Perm et al_. ,
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1969). Overall, these results were interpreted by Perm (1971) as indi-
cating that cadmium may act directly on embryonic tissue by interfering
with zinc-metal!oenzymes such as carbonic anhydrase or alkaline phosphatase.
By anology, possible interactions of cadmium with selenium-dependent enzymes
may also be indicated in view of protection being offered against terato-
genic effects of cadmium by selenium administered within 30 minutes of an
injection of an otherwise teratogenic dose of cadmium. Also, Semba et a_K
(1974) demonstrated that pretreatment with low doses of cadmium before
injections of high doses of the metal protects against high-dose cadmium
teratogenic effects such as exencephaly. In view of these latter results,
a possible induction of a protective metal!othionein protein might be
hypothesized to explain the protective effects of zinc and other metals
against cadmium's teratogenic effects.
It should be noted that not all heavy metals exert beneficial effects
when administered with cadmium. Thus, although simultaneous injections of
cadmium and inorganic lead salts in the pregnant hamster yielded protective
effects against typical teratogenic effects of cadmium, such combined
injections apparently potentiated characteristic teratogenic effects of
lead. They also induced some effects, e.g., severe malformations of the
lower extremities and umbilical hernias, not usually seen after the injec-
tion of either metal alone (Perm and Carpenter, 1968). Similarly, additive
embryotoxic effects are seen if cadmium is injected along with mercury
(Gale, 1973).
The above studies utilized acute or subacute systemic injections of
relatively high doses of cadmium; questions can therefore be raised about
the relevance of the observed fetotoxic and teratogenic effects for the
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assessment of potential effects in humans typically exposed via different
routes (oral and inhalation) and to much lower levels of cadmium. Of more
importance for present purposes, then, are animal studies which have employed
inhalation or oral exposure routes for the administration of low levels of
cadmium on a more chronic basis. The papers to be considered are those by
Cvetkova (1970), Schroeder and Mitchener (1971), Pound and Walker (1975),
Wills et al_. (1976), Choudhury et aj.. (1977), and Campbell and Mills (1974).
In the Cvetkova (1970) study, female rats were exposed for up to 7 mo
to CdSO. (3 mg/m ) via inhalation. Alterations in the estrous cycle were
observed in 50 percent of the exposed rats by 2 mo and in 75 percent by 4
mo, before mating was carried out. Upon sacrifice of half of the pregnant
dams on gestation day 22, no significant effects on fetal mortality were
found, nor was evidence obtained for prenatal teratogenic effects of cadmium.
The remaining control and exposed mothers delivered litters of comparable
sizes, but the offspring of the exposed mothers were smaller, weighed less
than those in control litters, and experienced a higher perinatal mortality
rate.
Evidence for teratogenicity of orally administered cadmium was reported
by Schroeder and Mitchener (1971). They exposed mice to cadmium in the
drinking water at doses of 10 ug Cd/ml continuously throughout a sequence
of breeding of randomly selected pairs of males and females over a 6-mo
exposure period. Males and females randomly selected from among the F^
generation litters were similarly allowed to breed ad libitum, as were
pairs from the succeeding F2 generation. Control animals not exposed to
cadmium were bred in a similar manner. The results indicated that orally
administered cadmium was quite toxic to breeding mice, with some congenital
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anomalies such as sharp angulation of the tail being seen in exposed FI and
F? generation offspring as well as increased mortality before weaning and
reduced rates of growth. The experiment was discontinued when 3 of 5
exposed F« generation pairs failed to breed.
Pond and Walker (1975) assessed the effects on reproduction of 200 ppra
of Cd as CdCl2 added to diets varying in calcium content (0.07 percent and
0.96 percent calcium). Although numbers of live or stillborn pups per
litter were not significantly altered and no gross anomalies were seen,
high cadmium content in the diet did significantly reduce pup birth weight.
Concentrations of cadmium in the bodies of pups were doubled in the low-
calcium groups when compared to the high-calcium dosed animals.
Wills et a_L (1976) evaluated the effects of orally administered
cadmium on both rats and monkeys. Both male and female rats were exposed
via feed containing 33 or 73 ppb of cadmium chloride, and monogamous matings
were allowed until four litters per couple were produced. Exposure at 33
or 73 ppb of cadmium via the feed continued for the offspring, which were
also mated, as were successive generations until four generations had been
produced. There was a slight increase in fertility among the 73 ppb exposure
group animals but not in the 33 ppb group. Body-weight gain deficits were
observed at both exposure levels, but no significant macroscopic or micro-
scopic changes were found in the 286 rats assessed that could be attributed
to the cadmium exposures. Rather, relatively minor changes observed were
thought to be due to spontaneous disease, including tumors of similar types
found in control and both cadmium-exposure groups. The lack of striking
morphological changes might be expected, however, in view of the very low,
almost trace amounts of cadmium used (which were below levels normally seen
in most rat chows).
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The same authors (Wills et al_. , 1976) also fed four female monkeys
cadmium chloride in a sweetened beverage at 1.5 or 3.0 pg/kg/day, with a
fifth monkey serving as a nonexposed control. Unfortunately, the control
monkey and one exposed at 1.5 ug/kg died after 6 months from disease pro-
cesses apparently unrelated to the cadmium exposure. The other females,
which survived 18 months of cadmium exposure, were mated with nonexposed
males; one at each dose level became pregnant and each later delivered a
single infant, the lower-dose animal prematurely. No congenital anomalies
were seen, and both infants appeared to nurse and develop normally. These
results do not suggest that the cadmium exposure used had any major effects.
They are, however, of very limited value due to the very small numbers of
animals tested.
While the results of Wills et al. (1976) on monkeys are of very ques-
tionable import, the findings obtained in the other studies on rats and
mice do appear to have some value for the analysis of the effects of chronic
low-level cadmium exposures on reproduction and development. In at least
one study (Schroeder and Mitchener, 1971), for example, significant terato-
genic effects were found, but with the anomalies seen after long-term oral
exposure being different from those reported in earlier studies to be
induced by acute, high-level exposure via systemic injections. Another,
much more consistent effect reported in several of the studies, however, is
that of reduced birth weights and/or deficits in postnatal body weight gain
for the offspring of rats or mice chronically exposed to cadmium. One
crucial question, then, concerns the etiological bases underlying the
observed body weight deficits, i.e., are they due to direct effects of
cadmium on the fetus resulting from transplacental transfer of the metal or
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do such deficits occur secondarily as the result of other cadmium effects,
including possible actions on mothers of affected offspring? A number of
studies have generated results bearing on this issue and, in general,
appear to indicate that transplacental transfer of the metal probably plays
a far less important role than other factors.
Many studies Indicate that transplacental transfer of cadmium does not
occur to any great degree. Ishizu et a_L (1973), for example, reported on
pregnant mice which were given s.c. injections of 2.5 mg Cd/kg as cadmium
chloride on day 7 of pregnancy. Cadmium concentrations were about 10 times
higher in the placentas of the cadmium-exposed animals than in controls,
but the fetal concentrations were similar in each group (about 0.03 ug/g)
although the levels in the liver and placenta of exposed mothers were 17
ug/g and 0.19 ug/g, respectively.
The Ishizu et al_. (1973) results are consistent with findings of
little fetal uptake during late gestation as assessed by autoradiography
(Berlin and Ullberg, 1963). They also comport well with other results.
Specifically, Perm et al_. (1969) showed that only small amounts of radio-
active cadmium reached the fetus on the eight to ninth day of gestation in
109
the hamster, while Wolkowski (1974) found that trace amounts of Cd
corssed into the fetus on days 13 and 17 of gestation in mice and Lucis et
al_. (1971) reported that only low amounts of cadmium crossed the placenta
during the first third of gestation in the rat.
More specific characterization of parameters associated with transpla-
cental transfer of cadmium in animals has been attempted, both by auto-
radiography (Dencker, 1975) and biochemical evaluations (Sonawane et a_L ,
1975). In the Dencker study, pregnant hamsters and mice were injected
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•too i no
intravenously with 20 uCi iu:7CdCl2 (i.e., 0.21 ug Cd) at different times
during pregnancy. Then, the whole animal, the uterus, or the embryos were
processed for autoradiography. On the eighth day of gestation, low amounts
of cadmium accumulated in the gut of embryos of both species. None,
however, was found in the embryos with injection beyond the ninth day
(hamster) or the eleventh day (mouse).
In the Sonawane et aL (1975) study, placenta! transfer rates of
cadmium in rats were assessed in relation to dose (0.1, 0.4 and 1.6 mg
Cd/kg) and gestational age (12, 15 and 20 days) at which pregnant dams were
109
injected intravenously with a single dose of CdClp (approximately 20
uCi/animal). The animals were sacrificed 24 hr after injection of the
109
tracer, and Cd concentrations were measured in the fetus, placenta,
maternal liver, and blood. As shown in Table 2-3, very small amounts of
cadmium were found to cross the placenta at each dose and gestation age,
with increasing amounts accumulating in the fetus as a function of increas-
ing dose and gestational age. Also, placenta! to maternal blood cadmium
concentration ratios increased with gestational age but not with dose
(Table 2-4), and placental to fetal cadmium concentration ratios decreased
in reverse relationship to increasing dose and age, as shown in Table 2-5.
These results contrast with some of those described above, which suggested
that some early cadmium crossing of the placental barrier occurs, but not
late in pregnancy. In either case, it appears that only a very small
amount of transplacental transfer of the metal occurs in experimental
animals during pregnancy.
As for transplacental transfer of cadmium in humans, only barely
detectable levels have been reported to exist in human fetuses at various
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Table 2-3. CADMIUM IN PLACENTAS AND FETUSES'
Dose,
mg/kg
Placentas6 0.1
0.4
1.6
Fetusesf 0.1
0.4
1.6
Cd,
Gestation
day 12
0.063 ± 0.043
(1.6)
0.232 ± 0.032C
(1.6)
0.206 ± 0.057
(1.3)
0.00012 ± 0.00004
(1.1) d
0.0022 ± 0.0023°
(1.1) d
0.0217 ± 0.0111°
(0.9)
%/g of injected dose
Gestation
day 15
0.0115 ± 0.49
(5.8)
0.142 ± 0.124a
(4.7)
0.466 ± 0.147
(3.8)
0.0014 ± 0.0001
(6.8)
0.0027 ± 0.001a
(7.6)
0.0096 ± 0.0026
(4.9)
b
Gestation
day 20
1.403 ± 0.293
(5.6)
1.347 ± 0.127
(5.8)
0.587 ± 0.167
(6.9)
0.0019 ± 0.0003
(64.7)
0.0036 ± 0.0016°
(69.1)
0.0152 ± 0.0058
(50.8)
From Sonawane et al., 1975; rats sacrificed 24 hr after Cd treatment at various
dose levels.
Numbers in parentheses indicates average weight of placentas per litter or average
fetal weight per litter. At least three animals were used to obtain each value.
GSignificantly different from 0.1 mg/kg dose level, p < 0.05.
Significantly different from 0.1 mg/kg dose level, p < 0.01.
eThe dose-response test for placental data revealed significant dose-response
relationships for day 12 and day 15 groups significant gestational day relation-
ships at the 0.1 and 1.6 doses at least at p < 0.05.
The dose-response test for fetal data revealed significant dose-response
relationships for all gestational groups and gestational day differences at the
0.1 dose at least at p < 0.01.
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Table 2-4. PLACENTAL TO MATERNAL BLOOD CONCENTRATION RATIOS3
Ratio placental: maternal blood Cd
Dose,
mg/kg
0.1
0.4
1.6
Gestation
day 12
14.9 ±3.0
12.3 ± 6.4
11.8 ± 7.9
Gestation
day 15
37.9 ± 7.8
26.8 ± 4.5
25.9 ± 8.8
Gestation
day 20
118.8 ± 47.
58.7 ± 17.
52.5 ± 36.
7b,c
2b,c
3b,c
aFrom Sonawane et al_., 1975.
The dose-response test revealed significant gestational day
differences for all doses at least at p < 0.05.
cSignificantly different from the 12th day treatment,
p < 0.01.
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Table 2-5. PLACENTAL TO FETAL CADMIUM CONCENTRATION RATIOS3
Oose,
mg/kg per day
O.lc
0.4
1.6
Gestation
day 12
618.00 ± 409.11
266.11 ± 232. 92b
11.23 ± 4.16b
Ratio placenta!:
Gestation
day 15
103.94 ± 29.28
55.92 ± 17.41
56.64 ± 7.56
fetal Cd
Gestation
day 20
78.877 ± 32.248
41.852 ± 16.786b
42.690 ± 2.244b
aFrom Sonawane et al_., 1974; ratios are based on percentage of injected
dose/g found in placentas and fetuses.
Significantly different from 0.1 mg/kg dose level, p < 0.01.
GThe dose-response test revealed significant dose-response relationships
for the day 12 and day 15 groups at least at p < 0.01.
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gestation stages based on analysis of autopsy materials (Chaube, 1973).
Further confirmation of this applying to humans is provided by the work of
Baglan et al_. (1974) demonstrating only relatively small amounts of cadmium
in freshly obtained human placentas, umbilical cord blood, and fetuses.
Given that only very small amounts of cadmium cross the placenta and
accumulate in the fetus based on the above data, other factors are probably
crucial in mediating cadmium effects on fetal and neonatal growth and
development. Among such factors implicated as likely being important are
effects of cadmium on maternal and fetal levels of essential elements such
as zinc and copper. Maternal zinc deficiency has been shown to cause fetal
abnormalities in experimental animals (Hurley and Swenerton, 1966; Hurley
et al_., 1971), and it would not be surprising if well-known effects of
cadmium on zinc distribution were exacerbated in pregnant animals in a
manner so as to induce fetal abnormalities secondary to a maternal or fetal
zinc deficiency. Consistent with this, Pond and Walker (1975) and Choudhury
et a_L (1977) have reported lowered zinc concentrations and decreases in
birth weight in pups of rats orally exposed to cadmium during gestation
either at 200 mg/kg of cadmium in the diet or at 17.4 mg/1 of cadmium in
the drinking water, respectively. The results of the Choudhury et a_[.
(1977) study are summarized in Table 2-6. Interestingly, no increase in
fetal cadmium accompanied decreases in fetal zinc and other elements in the
Choudhury et a_L study, suggesting that such effects were likely secondary
to cadmium influences on maternal nutritional state rather than directly
on the fetuses.
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Table 2-6. EFFECT OF MATERNAL DIETARY CADMIUM (17.2 ug/ml), GIVEN DURING GESTATION,
ON BODY WEIGHTS AND BODY TRACE METALS OF NEONATES3
Experimental
group
Control
Cadmium
Birth weight
(g)
6.8 ± 0.1
6.4 ± 0.1*
Lactation
wt. gain
(g)
52 ± 1.0
44 ± 1.6
Zinc
116 ± 4
104 ± 3*
Copper
(ug/g pup
9.4 ± 0.4
5.7 ± 0.4**
Iron
dry weight)
330 ± 6
267 ± 17**
Cadmi urn
0.46 ±
0.48 ±
0.05
0.04
aFrom Choudhury, et aj. , 1977.
Data expressed as means ± SEM. Statistically significant difference, Student "t" test.
*
p < 0.05.
S ** P < o.oi.
-------
to cadmium influences on maternal nutritional state rather than directly on
the fetuses.
In both the Choudhury et al_. (1977) and the Pond and Walker (1975)
study, fetal copper as well as zinc levels were reduced by cadmium exposure
during pregnancy, and iron levels were also significantly reduced in the
Choudhury et al. study. Consistent with the findings on copper reductions
in fetal rats, Anke et al. (1970) have reported a trend toward reduced
copper levels in newborn lambs after cadmium exposure of maternal ewes
during pregnancy. Fetal concentrations of cadmium, however, were not
increased, again suggesting that the fetal effects were secondary to
effects on the maternal animal or cadmium inhibition of transplacental
transfer of copper.
Persisting effects of cadmium exposure during pregnancy on the post-
natal development and growth of offspring have also been demonstrated. For
example, Choudhury et aL (1977) reported that the neonates experiencing
the above types of essential element deficiencies, which were weaned with-
out access to cadmium except that contained in the mother's milk during
suckling, were later found to exhibit significantly depressed spontaneous
activity and other neurobehavioral deficits in the absence of any overt
teratogenic effects. Similarly, deficits in growth, plasma copper concen-
trations, and cytochrome oxidase activities have been reported for lambs
born to ewes exposed to 3 mg/kg of cadmium in the diet (Bremner and
Campbell, 1978).
2.8 ENDOCRINE EFFECTS OF CADMIUM
Only limited information exists on possible endocrine effects exerted
by cadmium, with most studies bearing on this issue having employed rela-
tively high doses of cadmium often given by injections rather than lower
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doses administered orally or by inhalation. Still, a variety of endocrine
effects have been demonstrated, and some of the more salient findings are
reviewed below.
2.8.1 Gonadal Effects
Extensive evidence documents the effects of cadmium on the gonads,
especially the testes, as was reviewed in some detail under the earlier
Reproduction and Development section (2.7). As reviewed there, severe
testicular necrosis has been well established as being one of the more
notable consequences of high-level cadmium exposure, and that necrosis has
been shown to involve endocrine cells within the testes as well as the
testicular vasculature and germinal epithelium. In fact, some evidence was
cited which suggests that damage to the endocrine (Leydig) cells of the
testes may occur at cadmium-exposure levels below those producing initial
signs of significant kidney damage (i.e., proteinuria). At high dose
levels, consequently altered testosterone productions may contribute to
deterioration of testicular germinal epithelium and other androgen-
dependent tissues. In contrast, as also reviewed earlier, relatively
little evidence has been advanced for cadmium effects on female gonads.
2.8.2 Pancreatic Effects
High accumulation of cadmium in the pancreas of humans and animals has
been reported in several studies of cadmium poisoning (Friberg, 1957; Smith
et aJL , 1960; Barbieri et a_L , 1961; Ishizaki et a]_. , 1970; Nordberg and
Nishiyama, 1972), as has altered pancreatic excretory function in Itai-Itai
patients (Murata et al_. , 1970). This suggests that the metal may affect
the pancreas, and cadmium effects on carbohydrate metabolism have been
hypothesized as being due to cadmium-induced damage to the pancreas.
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In regard to the induction of hyperglycemia by cadmium, reported to
occur in rabbits (Voinar, 1962), dogs (Caujolle et a_L , 1964) and mice
(Ghafghazi and Mennear, 1973), evidence has been advanced for that effect
being mediated mainly through the adrenals rather than the pancreas
(Ghafghazi and Mennear, 1973). Reductions in glucose tolerance induced by
cadmium, however, have been linked to cadmium-induced alterations in pan-
creatic function. Evidence supporting the possibility of cadmiurn-induced
effects on pancreatic secretory activity include: (1) the finding that
cadmium accumulated equally in endocrine and exocrine parts of the pancreas
(Friberg and Odeblad, 1957), and (2) the demonstration of decreases in the
ratio of pancreatic beta to alpha cells in the rabbit after cadmium treat-
ment (Barbieri et al_. , 1961), and (3) reports of observed decreases in
concentrations of circulating insulin in mice after a single cadmium injec-
tion (Ghafghazi and Mennear, 1973). In addition, Ithakissios et a]_. (1975)
treated rats every other day for 70 days by injections of cadmium acetate
solution at 0.25 to 0.50 mg Cd/kg i.p. and found decreased insulin secre-
tion at the 0.50 mg/kg dose.
That glucose tolerance may be impaired through cadmium reducing the
insulin secretion of the pancreas, has been implicated more directly through
the demonstration of Ghafghazi and Mennear (1975) of cadmium inhibition of
insulin secretion by the isolated perfused rat pancreas in response to
glucose challenge. The latter authors hypothesize that the effect is most
likely due to interference by cadmium with calcium uptake by the pancreatic
beta cell.
Possible protective effects of various substances against the pancreo-
toxic effects of cadmium have also been investigated. For example, Merali
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and Singhal (1975) reported that administration of selenium concurrently
with cadmium ameliorated cadmium-induced hyperglycemia, hypoinsulinemia,
glucose intolerance, and suppression of pancreatic secretory activity.
Also, Ghafghazi and Mennear (1973) found that repeated administrations of
cadmium did not produce the significant reduction in pancreatic insulin
secretion seen after a single larger injection of the metal, and Yau and
Mennear (1973) obtained results suggesting that a pancreatic metallothiem'n
protein is produced in response to cadmium.
2.8.3 Adrenal Effects
The possible involvement of the adrenals in the mediation of cadmium
effects on other organ systems has been suggested by several studies. For
example, Ray and Chatterjee (1973) found that reserpine and adrenalectomy
blocked certain cadmium-induced effects on the testicles, and they hypo-
thesized that adrenal catecholamines (CA's) may be important in mediating
cadmium effects on the testes, perhaps by affecting testicular blood flow.
Also, evidence has been advanced for the induction of hyperglycemia by
cadmium being mediated through effects on the adrenals, since adrenalectomy
abolished the hyperglycemic response of mice to cadmium (Ghafghazi and
Mennear, 1973).
More direct evidence for cadmium affecting the adrenals has been
generated. For example, Hart and Borowitz (1974) demonstrated that cadmium
was moderately effective in causing prolonged release of CA iji vitro,
possibly through interactions with intracellular calcium in adrenal
medullary cells. In a follow-up study, Leslie and Borowitz (1975) obtained
data interpreted as indicating that not only can cadmium initiate cate-
chol ami ne secretion from the adrenal medulla, but it also appears to
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interfere with calcium removal from adrenal medullary cells, thereby
inhibiting termination of the secretory response.
Additional data consistent with the above have been obtained in an
u> vivo study by Rastogi and Singhal (1975). Adolescent male rats were in-
jected i.p. daily with cadmium chloride at doses of 0, 0.25, or 1.0 mg/kg
for either 21 or 45 days. The results showed that daily treatment with
either 0.25 or 1.0 mg/kg of cadmium for 21 days significantly increased
adrenal weights, but such weights were still increased after 45 days of
exposure only in the 1.0 mg/kg group. On the other hand, treatment at
either dose level resulted not only in significantly enhanced CA levels
after 21 days but also in even more marked increases in CA levels by 45
days and significant increases in tyrosine hydroxylase (TH) activity in the
1.0 mg/kg group after 45 days. Discontinuation of cadmium exposure for 28
days failed to restore normal adrenal weights in the 1.0 mg/kg animals, but
CA levels returned to control values, as did TH activity. These results
suggest that cadmium exerts significant, although apparently reversible
effects, on adrenal medullary CA synthesis at i.p. dose levels as low as
0.25 mg/kg.
Adrenal cortical functions, as well as adrenal medullary secretions,
appear to be affected by cadmium, according to a study by Der et al.
(1977a), which compared the effects of cadmium and lead on thyroid and
adrenal functions. Adult male rats weighting 300 ± 5 g received daily
intramuscular (i.m.) injections of 50 or 250 ug of cadmium chloride, while
other rats received either 50 or 250 ug of lead or simultaneous injections
of 25 ug each of lead acetate and cadmium chloride. Significant deficits
in weight gain and increased adrenal weights were observed during 70 days
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of cadmium exposure at the 250 ug dose. Also, adrenal histology evalua-
tions revealed increased nuclear diameters in cells of the zona glomerulosa
and fasciculata of both the 50- and 250-ug cadmium-dose groups; and plasma
corticosterone levels were found to be significantly elevated in the 50-
and 250-ug cadmium groups and the combined 25-ug lead-cadmium group. These
results provide evidence for adrenal cortical hypertrophy after chronic
cadmium treatment, resulting in increased adrenal corticosteroid secretion.
It remains to be seen, however, as ta whether such effects occur after
exposure to cadmium via oral ingestion or inhalation.
2.8.4 Thyroid Effects
The demonstration of high thyroid cadmium levels in human autopsy
material (Friberg, 1957), as for the pancreas, raises the possibility of
the thyroid being a target organ for the metal. Relatively sparse informa-
tion, however, exists concerning cadmium effects on the thyroid. In the
Der et a_L (1977a) study mentioned earlier, evidence was found for signifi-
cant decreases being induced in plasma T. levels in rats by the 250 ug
cadmium chloride treatment and in plasma T- levels by the 50 ug and 250ug
cadmium doses as well as by the combined 25 ug lead and cadmium treatment.
No evident changes in thyroid histology accompanied the decreases in
thyroid hormone secretion seen with any of the treatments. Nevertheless,
Der et aJL (1977a) hypothesized that the hypothyroid state induced by
cadmium might be responsible for a decreased rate of body weight gain
observed for the 250 ug cadmium dose group and might also contribute to
increased susceptibility to various disease resulting from cadmium-induced
immune suppression effects.
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2.8.5 Pituitary Effects
An important point to consider in the interpretation of the above
endocrine effect studies is the difficulty that exists in disentangling
possible direct effects of cadmium on the endocrine organs discussed from
effects that may be exerted via cadmium actions on the pituitary and vice
versa. At least a few examples have been cited in regard to changes in the
pituitary itself after cadmium exposure. One such effect is the decrease
in pituitary weight reported by Der et al. (1977a) after exposure of female
rats to 250 ug cadmium chloride for 54 days.
Other pituitary effects seen after cadmium include hyperplasia of
gonadotropic cells and increased numbers of prolactin secreting cells in
the anterior pituitary of male rats as revealed by immunof1uorescence
methods (Girod and Dubois, 1974, 1976). Consistent with this observation
is the reported increase in plasma leuteinizing hormone (LH) level
(Chandler et al_. , 1976) seen in cadmium-exposed rats for which ultra-
structural evidence was obtained for changes in the entire interstitial-
tubular complex of the male reproductive tract. Whether the observed
pituitary cytology changes and LH increases represent a direct effect of
cadmium on the pituitary or occur secondarily to damage to the testes by
the metal presently is not clear. The possibility remains that at least
some endocrine-related effects associated with cadmium exposure may be
exerted via cadmium effects on the pituitary directly, and this possibility
is reinforced by the Berlin and 111!berg (1963) finding of some accumula-
tions of cadmium in that gland.
2.9 EFFECTS OF CADMIUM ON BONE AND MINERAL METABOLISM
The effects of cadmium on bone arises from chronic exposure, and this
derangement appears to be secondary to renal malfunction through disturbance
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in calcium and phosphorus metabolism. The literature detailing the effects
of cadmium on calcium metabolism and bone structure in experimental animals
suggests that this may indeed be the case.
2.9.1 Animal Studies
In the studies of Kawai and coworkers (1974), in which rats were
chronically dosed with cadmium (10 to 200 ug Cd/ml in drinking water, up to
8 1/2 mo), histological findings in the bone appeared in the 50 ppm Cd
group, and higher exposure levels were associated with decalcification and
cortical atrophy of the femur. Calcium content also was reduced in the
highest level (200 (ug/ml) exposure group.
The data of Itokawa et al_. (1974) demonstrated effects of cadmium on
bone in rats using an exposure level of 50 ppm in water and either calciura-
adequate or calcium-deficient diets. In both of the cadmium-treated groups,
urinary calcium and phosphorus levels were significantly reduced, with
thinning of the cortical osseous tissue seen in bones of cadmium-exposed
animals which were fed a calcium-deficient diet. Furthermore, fat de-
position occurred in the femoral spongiosa in both cadmium groups, while
the cadmium-exposed animals on the low-calcium diet manifested osteoid
borders on trabeculae and an increased number of osteocytes. These authors
pointed out the similarity of this osteopathology with the osteomalacia
seen in man. This osteopathology may be secondary to early renal glomerular
damage occurring before the onset of tubular dysfunction.
Abe et a_L (1972) gave rats cadmium in diet corresponding to a daily
ingestion of 1.5 mg and observed after 4 wk that this dosing regimen, along
with diets low in protein and calcium, led to abnormal curvature of the
spine.
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Reference was made in the section on renal effects (2.5) to the
inhibitory action of cadmium on the conversion of 25-hydroxy-Vitamin-D3 to
the physiologically active essential metabolite, l,25-hydroxy-Vitamin-D3.
Sugawara and Sugawara (1974) observed decreased calcium absorption in rats
receiving 50 ppm cadmium in drinking water. Also, in a recent report,
Kawai (1976) noted decalcification and cortical atrophy in bone tissue with
chronic dietary exposure to cadmium.
2.9.2 Human Aspects
In man, osteomalacia and severe osteoporosis are known effects of
chronic cadmium exposure, in both occupational settings and in populations
sustaining pronounced cadmium exposure (Nordberg, 1976; Friberg et aK,
1974).
As noted elsewhere, Itai-Itai disease is a patho-physiological triad
of renal tubular dysfunction, osteoporosis, and osteomalacia. There appears
to be no question that there is a nutritional component to the manifestation
of the disease: calcium and Vitamin-D deficiency in postmenopausal women
with a history of multiple childbirth and past probable deficiency in these
two factors. Osteopathic symptomatology (Friberg et al. 1974) of the
disorder includes: Milkman's pseudo-fractures and fractures, thinned bone
cortex, decalcification, deformation, fishbone vertebrae, and coxa vara.
Biochemical changes include decreased serum P. and a decreased urinary P/Ca
ratio.
2.10 HEPATIC EFFECTS OF CADMIUM
Although hepatic tissue is one of the sites where cadmium accumulates
and induces functional alteration, the literature is not so extensive as
that which exists for renal, pulmonary, and cardiovascular effects. Liver
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is the major biosynthetic organ for metal!othionein in a number of experi-
mental animal species and man, so any consideration of the extent of hepatic
functional derangements as a function of the amount of cadmium present in
liver must take this factor into account.
2.10.1 Animal Studies
It was noted earlier that cadmium, at high doses, has an effect on the
drug-detoxifying actions of enzyme complexes, as measured by several
techniques, including sleeping-time changes and enzyme inhibition.
Further animal studies have been carried out on the hepatic effects of
cadmium under varying experimental conditions. For example, Andreuzzi and
Odescalchi (1958) found that rabbit serum glutamic-oxaloacetic-transaminase
was elevated following intravenous administration of cadmium (1.25 to 3.0
mg/kg, 24 to 72 hr), with a ten-fold or greater increase after 24 hr using
the largest dosage, which killed 60 percent of the animals within 24 hr.
These workers concluded that a dose approaching the LDc0 was required to
produce severe liver lesions, while lower exposure effects were reversible.
Neige et al_. (1974) showed that rats given 4 subcutaneous injections
per week of cadmium sulfate (3 mg Cd/wk) displayed, after 60 days, cyto-
plasmic necrosis of hepatocytes, festooning of nuclear membranes, and round
intra-nuclear inclusions.
Colucci et al_. (1975) induced pathological changes in rat hepatic
tissue by the i.p. injection of cadmium (0.5 to 4.0 mg/kg, t to 6 days).
Animals in the 0.5 and 1.0 mg Cd/kg groups showed no microscopic hepatic
abnormalities. Those in the higher dose groups revealed degenerating
hepatocytes. These workers found that, when liver cadmium levels were
below 30 (jg Cd/g wet weight, the metal was sequestered as metal!othionein,
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and no apparent toxicity was evident. Levels of 40 |jg Cd/g were associated
with hepatic cellular degeneration as well as other systemic pathology.
Faeder et a_K (1977) investigated biochemical ultrastructural changes
in hepatic tissue of rats exposed to cadmium at levels known to induce
hepatic changes but administered so as to minimize clinical signs of
morbidity (subcutaneous injection, 0.25 to 0.75 mg Cd/kg, 3 times/wk for 8
wk). After 6 wk, animals given 0.5 mg/kg showed dilation and loss of
ribosomes from the endoplasmic reticulum, with the additional feature of
swollen mitochondria observed at the 0.75 mg/kg dose level. Biochemically,
plasma aspartate aminotransferase (AAT), orglutamyl transpeptidase, and
erythrocyte carbonic anhydrase activities were elevated by the sixth week
of exposure.
Sequential changes in hepatic polyamine, DNA, and cyclic AMP metabolism
were reported by Kacew et aL (1977) in rats subacutely exposed to cadmium
(1 mg/kg, twice a day for 3, 5 and 7 days). Hepatic levels of spermidine
and spermine were significantly lowered while hepatic DNA synthesis was
increased. Stimulation of the hepatic adenylate cyclase-cyclic AMP system
was noted to occur as early as 1 day.
It should be noted that morphological changes in the liver occur
before changes in hepatic marker enzymes activities.
2.10.2 Human Aspects
While an acute effect of cadmium on liver function in occupationally
exposed men has been seen, liver disturbances are not a common finding in
the human toxicity of cadmium; and gross changes are quite rare (Friberg
et al., 1974).
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2.11 NEUROLOGICAL EFFECTS OF CADMIUM
Perhaps not surprising in view of the relatively low uptake of cadmium
into brain and other neural tissue, potential neurological effects of
cadmium have been accorded much less attention in the research literature
than many other types of cadmium effects. Only a few studies of humans
occupationally exposed to cadmium have provided any evidence for cadmium-
induced neurological damage, and that has been largely confined to apparent
deficits in sensory functions. Also, comparatively little convincing
evidence for neural effects has been demonstrated by the limited number of
animals studies that have been conducted.
In regard to human studies, Friberg (1950) reported that 37 percent of
43 cadmium-exposed workers studied had olfactory impairments. Those workers,
however, were also exposed to nickel dust. Adams and Crabtree (1961), too,
found evidence for hyposmia and anosmia when they compared a group of 106
battery workers exposed to cadmium oxide and nickel dust to 84 age-matched,
non-exposed control subjects. Significantly more battery workers reported
themselves to be anosmic than control subjects (15 vs 0 percent, respec-
tively), and they did less well than controls on a phenol-smelling test.
Anosmia correlated well with proteinuria, with 17 battery workers ex-
hibiting proteinuria also being anosmic. Signs of local nasal irritation,
ulceration, and dry crusting suggested likely direct damage to the olfac-
tory mucosae. Olfactory impairment in the same worker population was also
found by Potts (1965) in 53 to 65 percent of the battery-factory workers
exposed 10 to 29 years to cadmium oxide dust and in 91 percent exposed for
over 30 years; again, the workers were likely exposed to nickel as well as
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cadmium. Tsuji et al. (1972), on the other hand, reported impaired olfac-
tion in workers exposed to cadmium at a zinc refinery, where no concomitant
nickel exposures were encountered. While these results suggest that cadmium
may cause direct damage to nasal olfactory mucosae, it should be noted that
such effects apparently only occur at extremely high inhalation exposure
levels that were previously of concern in industrial situations; and little
evidence for such effects at lower exposure levels has yet been provided by
animal or human studies.
About the only other report of signs of possible cadmium-induced
neural damage in humans is that of Vorob'yeva (1957) on changes in the
"chronaxies" of cutaneous sensory and optic nerves of cadmium-exposed
workers, but, again, little confirmation of any peripheral nerve damage has
come from other human or animal studies.
What little evidence from animal studies that exists for cadmium
effects on neural tissue comes mainly from i_n vitro work. This includes
reports that cadmium chloride exerts toxic effects on gasserian and spinal
sensory ganglia (Gabbiani et aJL , 1967a; Schlaepfer, 1971), cerebellar
tissue (Kasuya et aj_., 1974), and other central nervous system (CMS) tissue
(Gabbiani et al., 1967b). Pathological changes observed by Kasuya et al.
(1974) included inhibition by cadmium stearate of normal outgrowth of
cerebellar cells cultured from brains of newborn rats. Still other effects
of cadmium on neural functions have been demonstrated i_n vitro. Edstrom
and Mattson (1976), for example, studied the effects of sulfhydryl blocking
3
agents on the i_n vitro rapid axonal transport of H-leucine-labelled proteins
in the frog sciatic nerve. Rapid transport of the proteins was inhibited
in the presence of low concentrations of divalent heavy metals including
cadmium.
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Research in other studies has focused on possible molecular mechanisms
by which cadmium might affect neurotransmission, with some consistent
results emerging from such studies. In one study, Kamino et aH. (1975)
utilized synaptosomes isolated from rat brain cortex to investigate the
^ L
effects of cations on cynaptosomal CA -binding. Cadmium, as well as other
Liii
cations tested, significantly inhibited synaptosomal Ca -binding,
suggesting possible disruptive effects on presynaptic transmitter release
or uptake mechanisms.
Consistent with the above interpretation, several studies have
demonstrated cadmium effects on neurotransmission, including effects on
release of particular transmitters. In that regard, Chen (1975) studied
the effects of divalent cations and catecholamines on the "late response"
of the superior cervical ganglion of dogs and found that catecholamines
suppress that response, while certain divalent ions such as cadmium
potentiate and prolong it. Chen (1975) concluded that cadmium chloride may
inhibit sympathetic gang!ionic transmission by presynaptic suppression of
acetylcholine release. Similar conclusions were reached by Toda (1976) and
Forshaw (1977), who presented evidence for inhibitory effects of cadmium on
neuromuscular transmission in isolated frog striate muscle and isolated rat
diaphragm, respectively. Toda (1976) concluded from his overall data that
cadmium interferes with the release of acetylcholine from motor nerve
terminals by reducing the transmembranous influx of calcium, and Forshaw
(1977) concluded that cadmium reduced the quanta! release of transmitter in
the isolated phrenic diaphragm by inhibition of calcium function at pre-
synaptic nerve terminals. Cooper and Steinberg (1977) reported results
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they interpreted as indicating that cadmium blocked adrenergic neuro-
rauscular transmission in the rabbit primarily through an effect on pre-
synaptic nerve terminals.
Ribas-Ozonas et al_. (1974) reported decreases in regional brain
serotonin (5-hydroxytryptamine, 5-HT) levels after intraventricular
injection of a 33 ug dose of cadmium chloride 1 to 3 days before the
injected rats were sacrificed. Subsequently, Hrdina et a_K (1976) studied
the effects of chronic (45 days) i.p. injections of doses of cadmium
chloride (0.25 and 1.0 mg/kg/day) on the regional levels of brain neuro-
transmitters and associated enzymes. Both doses of cadmium produced
significant decreases in cortical acetylcholine and brainstem 5-HT and a
transient increase in striatal dopamine. Cadmium-induced decreases in
brain 5-HT levels persisted even after withdrawal of cadmium treatment for
28 days before sacrifice. Hrdina et a_K (1976) suggested that alterations
in brain amine levels seen after cadmium treatment may represent early
signs of adverse effects on CNS function, but caution must be exercised
before accepting such a conclusion. For example, the relevance for present
purposes of injections of relatively high amounts of cadmium directly in
the cerebroventricular system is highly questionable in view of data
showing that only very low amounts of cadmium accumulate in brain tissue
after systemic administration. Also, in view of cadmium's poor entry into
brain, the changes in brain neurotransmitters seen by Hrdina et a_L (1976)
after chronic i.p. injections might be more appropriately attributed to
secondary effects (possibly differential overall stress associated with
cadmium exposure) rather than to direct effects of the metal on brain
tissue.
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Very few studies have been reported that attempt to relate cadmium
exposures to neurotoxic effects manifested in terms of learning or other
behavioral deficits. For example, in the Krasovskii et a_T (1976) study
reviewed earlier in the section on reproduction and development, it was
claimed that "changes" in the conditioned reflex activity of experimental
animals" were seen with oral exposures to 0.005 and 0.0005 mg/kg doses of
cadmium chloride. In another study (Pihl and Parkes, 1977) hair samples
from 31 learning disabled and 22 normal children were analyzed for content
of 14 elements, including cadmium and lead; and significantly higher levels
of cadmium and several other metals were reported to be found in the hair
of the learning-disabled group. Given the widely recognized difficulties
with hair cadmium determinations, however, these results require further
confirmation.
2.12 GASTROINTESTINAL EFFECTS OF CADMIUM
Acute gastrointestinal effects of cadmium are quite uncommon in man,
chiefly because the occurrence of acute cadmium poisoning by ingestion in
man is rare. Chronic gastrointestinal effects of cadmium have only been
seen in victims of Itai-Itai disease (Friberg et al_. , 1974).
In animals, studies do exist regarding the gastroenterological toxi-
city of cadmium. For example, shortening and thickening of mucosal villi
in the duodenum of Japanese quail are seen when cadmium exposure occurs
through the diet (Richardson et aJL , 1974) at comparatively high levels.
In addition, marked hyperplasia of duodenal goblet cells occurs after 4 wk.
In a second study using Japanese quail (Richardson and Fox, 1974)
cadmium fed to the birds at a level of 75 mg/kg diet from hatching to 1 mo
of age led to gross, microscopic, and ultrastructural lesions in the proximal
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small Intestines. For example, the small Intestines were dilated and
thin-walled, hypertrophy and hyperplasia of goblet cells occurred, micro-
villi of both absorptive and goblet cells were markedly shortened, and
absorptive cells were atrophic and mitochondria were dense and small.
Interestingly, these lesions resemble the pathological picture seen in
human malabsorption syndromes, tropical and nontropical sprue, and celiac
disease.
Valberg et al_. (1977) assessed the relative sensitivity of mouse
intestinal mucosa to cadmium-thionein and inorganic salt (cadmium chloride).
Using open-ended duodenal perfusion, equivalent amounts of cadmium in
either form entered the mucosa. Free cadmium ion occasioned minor derange-
ment in the form of villi broadening and mitochondria! swelling while the
protein-bound cadmium resulted in considerable damage to absorptive cells.
These effects are contrasted to the observation that little bound cadmium
entered the body compared with the inorganic form.
This provides further evidence (see: Renal Effects and Hepatic
Effects sections) that cadmium-thionein plays a two-fold role in cadmium
toxicity, i.e., on-site protection is afforded in some organs such as liver
and intestinal tract while release of the cadmium-thionein from these same
organs to extracellular fluid presents cadmium in a form that is func-
tionally more toxic than the inorganic form on an equivalent metal-content
bas i s.
2.13 HEMATOLOGICAL EFFECTS OF CADMIUM
Unlike lead, where a number of hematological effects are seen over a
range of that toxic element's exposure levels, comparatively less is known
of the effects of cadmium on the hematopoietic system of man and experi-
mental animals. Hematological effects appearing in the earlier literature
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have been reviewed (Friberg et a_[., 1974); Fulkerson and Goeller, 1973;
Nordberg, 1974).
Cadmium-induced anemia has been observed in man from industrial expo-
sure and in animals. The anemia is moderate, is claimed to have hemolytic
and iron-deficiency components (Nordberg, 1976), and in animals appears
rather early in cadmium exposure.
Prigg et aJL (1977) studied the effects of dietary and inhalation
cadmium on hemoglobin and hematocrit in rats as a way of assessing whether
the anemia induced is related to impaired iron absorption or erythrocyte
destruction. It appears that erythrocyte destruction is not a major factor
in rats, since the cadmium aerosol treatment failed to elicit any anemia.
In the dietary-cadmium groups (25, 50, and 100 ppm Cd in drinking water),
there was a significant reduction in hematocrit and hemoglobin values, in
accord with the observations of others (Fox et al_., 1971; Maji and Yoshida,
1974; Freeland and Cousins, 1973).
It has also been observed that dietary iron supplement (Fox et al.,
1971; Maji and Yoshida, 1974) or injected iron (Pond and Walker, 1972)
restores the levels of hemoglobin and the hematocrit to normal.
The effect of cadmium on erythrocyte 6-aminolevulinic acid dehydratase
(6-ALA-D) has been studied in several animal species. Seth et al. (1976)
saw no effect on 5-ALA-D) activity when mice were given cadmium by i.p.
injection (2 mg Cd/kg, with and without co-injection of lead). Lynch
et a_L (1976), however, induced significant inhibition of 6-ALA-D activity
when calves were given cadmium alone or with lead (15 mg Cd/kg body weight)
contained in gelatin capsules.
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Roels et a\_. (1975) could not find any relationship between cadmium
and erythrocyte 6-ALA-D activity in a group of 84 workers in a cadmium
works. In this case, erythrocyte metallothionein probably provided a
protective function.
2.14 IMMUNOSUPPRESSIVE EFFECTS OF CADMIUM
Heightened susceptibility to the toxic effects of infectious agents
has been demonstrated with cadmium exposure via several different routes,
including systemic injections and oral administration of the metal. In a
study by Cook et aK (1975b), the relative potency of lead and cadmium were
compared in regard to the potentiation of an endotoxin. Neither lead
acetate injected into rats intravenously at a dose of 2.25 umol/100 g nor
minute quantities of S. enteritidis endotoxin alone were lethal, whereas a
single intravenous dose of cadmium acetate at 2.25 umol/100 g produced a
mortality of 5 percent. Simultaneous injection of cadmium acetate with the
endotoxin potentiated the otherwise mild effects of the toxin much more
than did lead, with 94 percent mortality being induced by cadmium and only
31 percent by lead. Also, when different doses of endotoxin were injected
with the same dose of cadmium or alone, it was found that a dose of endo-
toxin as low as 0.12 |jg/100 g produced 40 percent mortality when injected
along with cadmium but a 12,500-times higher dose of the toxin was necessary
to produce equivalent mortality when injected alone. By injecting the
endotoxin before, with, or after cadmium, it was found that the greatest
synergism occurred when the endotoxin was injected together with cadmium
(94 percent mortality) rather than either 4 to 8 hr before (0 percent
mortality) or after (10 to 50 percent mortality). Cook et al^. (1975b)
discuss possible mechanisms by which cadmium might exert its endotoxin-
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potentiating effects and report ultrastructural evidence implicating liver
damage as one important factor.
In another series of studies, Keller and coworkers have also recently
reported some evidence for immunosuppressive effects of cadmium administered
via oral exposure. Koller (1973) reported that rabbits exposed 70 days to
mercuric chloride, cadmium chloride, or lead acetate in drinking water (at
doses of 10, 300, or 2,500 ppm, respectively) had significantly lower
neutralizing antibody titers after inoculation with a pseudorabies virus.
Evidence for cadmium-induced increased susceptibility to disease in
mice was also serendipitously observed in a subsequent study to Exon et al.
(1975). Cadmium-stressed mice being used in the study for other purposes
began dying from an intestinal infection later identified as due to Hexamita
muris. Mice that had been exposed for 4 to 5 wk to 3 or 300 ppm of cadmium
as cadmium chloride in the drinking water experienced 7 percent and 26
percent mortality, respectively. No deaths occurred, however, in non-
exposed control animals. Interestingly, no "typical" cadmium lesions were
found in any organs of cadmium-exposed animals, suggesting that immuno-
suppressive effects may be induced at substantially lower exposure levels
than those required to induce other, classically defined cadmium effects.
More direct evidence for immunosuppressive effects in mice was reported
by Keller et al. (1975). Mice exposed orally to "subclinical" doses, i.e.,
3 or 300 ppm, of cadmium chloride in drinking water for 70 days experienced
marked decreases in antibody-forming spleen cells, especially IgG cells,
which persisted in the 300 ppm dose rats for at least six weeks after
cessation of cadmium exposure. Such results suggest that immunosuppressive
effects of cadmium, including that absorbed via chronic oral ingestion, may
persist for quite some time after the cessation of high-level exposures.
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Speculation concerning the mechanisms by which cadmium exerts its
immunosuppressive effects include possible interactions with the infectious
agent itself or damaging effects on various immune system cellular components.
In regard to the latter possibility, Keller and Roan (1977) assessed whether
mouse peritoneal macrophages were damaged by cadmium. Cadmium chloride was
given orally for 10 wk at doses of 3, 30, or 300 ppm in drinking water, and
the functional integrity of peritoneal macrophages was assessed. Since
phagocytotic activity and acid phosphatase levels were increased in the
macrophages, it was concluded that the metal activates macrophages. Based
on this, it appears unlikely that immunosuppressive effects of cadmium are
exerted through damage to macrophages. On the other hand, Waters et a^.
(1975) reported evidence for cytotoxic effects of cadmium on rabbit alveolar
macrophages assessed in an ^n vitro model system.
In summary, it appears that cadmium does exert immunosuppressive
effects both jjn vitro and i_n vivo. Furthermore, the metal appears to be
many times more potent than other immunosuppressive heavy metals in
potentiating certain toxic effects of various infectious agents. Lastly,
the immunosuppressive action of cadmium seems, at times, to persist beyond
cessation of oral exposure. Effects such as these, however, still remain
to be demonstrated with human cadmium exposure.
2.15 MUTAGENIC AND CARCINOGENIC EFFECTS OF CADMIUM
Considerable concern has been generated by reports of association of
cadmium exposure with mutagenesis or carcinogenesis in animals or humans.
Several relevant reviews have recently appeared which deal with mutagenic
effects of cadmium, the experimental induction of tumors in animals, or
human cancer epidemiology studies (Flick et al_. , 1971; IARC, 1976; NIOSH,
2-90
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1976; Sunderman, 1977; Carcinogen Assessment Group, 1978). As reviewed in
these reports, much information has emerged in regard to the conditions
under which mutagenic or tumorigenic effects can be generated experimentally
in animals, whereas far less data are currently available regarding the
carcinogenic potential of cadmium in humans. Still, as noted below, similar
conclusions have been drawn as a result of most of the relevant reviews;
that is, the assessments have typically led to the conclusion that pre-
sumptive evidence exists for cadmium-induced mutagenic and carcinogenic
effects.
2.15.1 Mutagenic Effects of Cadmium
Numerous studies have focused on assessment of the mutagenic
properties of cadmium, and considerable evidence has been obtained for
cadmium-induced mutagenicity in various test systems. The results of many
of the more salient studies are summarized in Table 2-7.
As indicated in Table 2-7, evidence for cadmium-induced mutagenic
effects has been obtained i_n vitro with several different test systems.
Such evidence includes, for example, the demonstration of: (1) statisti-
cally significant increases in mispaired nucleotides when cadmium chloride
was added to an i_n vitro DNA synthesis system (Sirover and Loeb, 1976); (2)
abnormal mitotic and meiotic recombinations in the yeast, Sacharomyces
cerevisiae, upon exposure to cadmium chloride (Takahashi, 1972); (3) pro-
duction by cadmium chloride, but not cadmium nitrate, of mutant recombinants
in strains of Bacillus subtil is (Nishioka, 1975) (4) unscheduled DNA
synthesis in Chinese hamster embryo cells following exposure to cadmium
chloride and cadmium acetate (Costa et aj_. , 1976); and (5) the induction by
cadmium sulfide of chromosomal aberrations in cultured human leukocytes
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Table 2-7. SUMMARY OF MUTAGENICITY TEST RESULTS
Test system
Genetic effect
Reported
mutagenicity
References
ro
i-O
ro
Human cells
Chinese hamster cells
S. cereyisiae
B. subtilis-
recombinant assay
Polynucleotides
Human leukocytes
Human leukocytes
Human leukocytes
Human leukocytes
Mouse oocytes
Mouse breeding
Mouse breeding
Mouse breeding
Mammals
D. melanogaster
Systems in vitro
Chromosomal damage
Point mutation
Point mutation
Gene mutation
Base mispairing
Systems in vivo
Chromosomal damage
Chromosomal damage
Chromosomal damage
Chromosomal damage
Cytogenetic damage
Dominant lethal mutations
Dominant lethal mutations
Dominant lethal mutations
Chromosomal abnormalities
Sex-linked recessive
lethal
Shiraishi et al. (1972)
Costa et al. T1976)
TakahoshiTl972)
Nishioka (1975)
Si rover and Loeb (1976)
Shirashi and Yoshida (1976)
Bui et aj. (1975)
Deknudt and Leonard (1975)
Bauchinger et al. (1976)
Shimada et al."Tl976)
Epstein et al. (1972)
Gilliavod and Leonard (1975)
Suter (1975)
Shimada et al. (1976)
Sorsa and Pfeifer (1973)
-------
(Shiraishi et aj_., 1972). Specific types of human chromosomal aberrations
seen in the latter in vitro study, it should be noted, were similar to
those reported for human leukocytes obtained from Itai-Itai disease patients
(Shiraishi and Yoshida, 1972). Thus, in summary, mutagenic effects on
genetic material or cells from a variety of species, ranging from yeast and
bacteria to hamsters and humans, have been demonstrated to occur |n vitro
with exposure to several different cadmium compounds. The latter effects
appear to be analogous to _iin vivo effects observed in certain human,
high-level cadmium exposure cases. When considering the iji vitro cadmium
mutagenicity data, it must be kept in mind that, in the human or other
mammalian organisms, cadmium is mainly bound to metallothionein and other
proteins, and there is little evidence for ionic cadmium being present in
substantial amounts.
Also as indicated in Table 2-7, several studies have yielded evidence
of jji vivo mutagenic effects of cadmium at high exposure levels. This
includes the demonstration of (1) numerical chromosomal anomalies in mouse
oocytes and blocked development of metaphase I chromosomes following
injection of an acute dose of 3 or 6 mg/kg of cadmium chloride (Shimada
et a_[., 1976); and (2) chromosomal damage in human leukocytes obtained from
Itai-Itai patients (Shiraishi and Yoshida, 1972) or workers exposed to
cadmium and lead (Deknudt and Leonard, 1975; Bauchinger et al., 1976).
In regard to jm vivo studies finding no mutagenic effects, the one
test yielding consistently negative results is that for dominant lethal
mutations. In one study (Epstein et ah , 1972), for example, cadmium
chloride was among 174 compounds evaluated for ability to induce dominant
lethal mutations in mice, but no significant evidence was obtained for the
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cadmium compound having such mutagenic activity at i.p. doses ranging from
1.35 to 1.70 mg/kg. Nor was any evidence for such cadmium-induced muta-
genicity in mice obtained in a similar study by Gilliavod and Leonard
(1975), using i.p. injections of 0.5, 1.75, or 3.0 mg/kg of cadmium
chloride, or in a study by Suter (1975), in which cadmium chloride (2
mg/kg, i.p.) had no detectable dominant-lethal effects in female mice.
The results of some of the above negative studies and certain others
listed in Table 2-7 have been criticized (Troast, 1978) as not being
sufficiently sensitive to mutagenicity for an accurate evaluation
(Gilliavod and Leonard, 1975; Sorsa and Pfeifer, 1973) or for lacking
sufficient sample numbers (Bui et al_. , 1975). Also, the results of Deknudt
and Leonard (1975) and Bauchinger et al. (1976) may in part be due to lead
as well as cadmium, since the human subjects in each of the two studies
experienced exposure to both metals. Overall, the studies reviewed here
and in Table 2-8 mainly provide evidence for cadmium-induced mutagenicity
at high concentrations and especially with HI vitro test systems. Little
or no data exists for mutagenic effects occurring with oral or inhalation
exposure of humans. The significance of iji vitro mutagenic effects beyond
their immediate implications for disruption of genetic processes in artificial
testing systems therefore remains to be seen. In fact, while mutagenic
properties of some compounds may correlate with their carcinogenic potential,
this does not appear to hold very well in the case of cadmium or other
heavy metals. Therefore, i_n vitro mutagenetic effects of cadmium do not
necessarily imply that the element is also carcinogenic.
2.15.2 Tumorigenic Cadmium Effects in Animals
Numerous studies have demonstrated the induction of tumors at sites of
subcutaneous or intramuscular injections of cadmium. In that regard,
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Sunderman (1977) reviewed data showing that parenteral injections of cadmium
powder or cadmium sulfide, oxide, sulfate, or chloride in rodents induced
sarcomas at the site of injection, as also reported in a number of studies
summarized in Table 2-8 (which is modified from one presented by Sunderman,
1977). In addition to injection-site sarcomas being produced, subcutaneous
injection of cadmium chloride, even at a distance from the testes, often
induced testicular necrosis followed by Leydig cell regeneration and hyper-
plasia and ultimately Leydig cell tumors of "Leydigiomas" (Haddow et a_L ,
1964; Roe et a_L , 1964; Guthrie, 1964; Gunn et ah, 1963, 1964, 1965, 1967;
Nazari et ah , 1967; Favino et a]_., 1968; Knorre, 1970, 1971; Lucis et ah ,
1972, Reddy et al_., 1973). The Leydig cell tumors thusly produced have often
been found to be functionally active in the sense of secreting large
amounts of sex steroids (Gunn et a_L , 1965; Favino et a_L , 1968; Lucis
et aL , 1972; Reddy et a_L , 1973). Typically, high-level, systemic-
injection doses have been employed to produce injection-site sarcomas or
distal-site tumors, with effective doses of cadmium often exceeding 1.0
mg/kg of body weight.
Leydig cell tumors observed after systemic injections of cadmium in
the above manner, however, have not yet been found to increase in incidence
when cadmium is administered orally at lower dose levels (Schroeder et a!.,
1965; Kanisawa and Schroeder, 1969; Levy and Clack, 1975; Levy et al_. ,
1975). Schroeder et ajL (1965) and Kanisawa and Schroeder (1969) exposed
rats to cadmium acetate in their drinking water (at 5 ppm) from weaning
until death up to four years later and found no significant increase in
tumors for cadmium-exposed animals in comparison to the incidence for
control animals.
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Table 2-8. STUDIES ON CADMIUM TUMORIGENESIS IN EXPERIMENTAL ANIMALS4
ro
i
to
CTl
Author(s) Animals
Heath et al . , Rats
1962
Heath and Rats
Daniel, 1964
Kazantzis, 1963 Rats
Kazantzis and Rats
Hanbury, 1966
Haddow et al . , Rats
1964
Roe et al. , Rats
1964
Compound and
route(s)
Cd powder in .
fowl serum (im )
Cd powder jn fowl
serum (im)
CdS (sc)b
CdS (sc)b
CdO (sc)b
CdSO. in rat .
ferritin (sc)
CdS04 (sc)b
CdS04 (sc)b
Lowest effective
dose
One dose of
0.014 gm
One dose of 0.014
gm
Two doses of
25 mg ea.
One dose of
25 mg
One dose of
25 mg
Ten doses of
20 mg ea.
Ten doses of
0.5 mg ea.
Ten doses of
0.5 mg ea.
Injection
site
Thigh muscle
Thigh muscle
Dorsal sc
tissue
Dorsal sc
tissue
_ , b
Dorsal sc
tissue
Right flank
Right flank
Flank
Tumor
site
Thigh muscle
and lymph nodes
Thigh muscle
and lymph
metastases
Injection
site
Injection site
plus lung,
spleen, stomach,
and pancreas
Injection site
Right flank
Right flank
and Leydig cell
Flank an<1
testis
Type of
tumors
Sarcomas
Sarcomas
Sarcomas
Sarcomas
Sarcomas
Sarcomas
Sarcomas;
Leydigomas
Sarcomas;
Leydigomas
Guthrie, 1964 Chickens
CdClp (intercostal
injection)
One dose of 2%
solution; amount
not given
Intratesticular Testis
via intercostal
injection
Teratoma
-------
Table 2-8 (continued). STUDIES ON CADMIUM TUMORIGENESIS IN EXPERIMENTAL ANIMALS'
PO
I
10
Author(s)
Gunn et al. ,
1963
Animals
Rats;
Mice
Compound and
route(s)
CdCl2 (sc)b
Lowest effective
dose
One dose of 0.03
mmole/kg (3.372
Injection
site
Subcutaneous
Tumor
site
Test is (inter-
stitial cein
Type of
tumors
Intersti
cell turn
Gunn et al.,
1964
Gunn et al.,
1965
Gunn et al. ,
1967
Rats
Rats
Rats
Schroeder
et al_. , 1965
Rats;
mice
CdCU (intra-
capsular)
CdCl
solution
Cd-acetate (drink-
ing water)
mg/kg)
One 0.4 ml dose
of 0.03 M
(equivalent to
1.35 mg (d ion)
One dose of 0.03
mmole/kg (3.372
mg/kg)
One dose of 0.17
Cd ion
5 ppm Cd in
drinking water
Injection site;
testis (inter-
stitial cells)
Subcutaneous Testis
(--r
Ectoderm;
intracutaneous
(chest); endo-
derm; salivary
gland; liver;
ventral prostate;
epithelial meso-
derm; kidney;
mesenchymal ,
mesoderm, sc
(intracapsular);
im (thigh); sub-
periosteal (femur)
Subcutaneous
Diet
Similar to
controls
Sarcomas and
Leydigomas
Interstitial
cell tumors
Sarcomas
Similar
to controls
-------
Table 2-8 (continued). STUDIES ON CADMIUM TUMORIGENESIS IN EXPERIMENTAL ANIMALS'
Author(s)
Kanisawa and
Schroeder,
1969
Nazari et al. ,
1967
Favino et al . ,
1968
£ Knorre, 1970
co
Lucis et al . ,
1972
Reddy et al . ,
1973
Levy et al . ,
1973
Levy et al . ,
1975
Compound and
Animals route(s)
Rats CdCl2 (sc)b
Rats CdCl2 (sc)b
Rats CdCK (sc)b
intrahepatic
Rats CdCl2 (sc)b
Rats CdS04 (sc)b
Mice CdSO, (stomach
tube*
Lowest effective Injection
dose site
•" — ™" ••
Equivalent to Left hip
-5.5 mg/kg
0.02 mM/kg — c;
(2.248 mg/kg) liver
0.03 mmole/kg --c
(3.372 mg/kg)
Weekly injections Flank
of 0.05 mg ea.
for 2 yr
Weekly injections Diet via
of up to 4 mg/kg tube
for 18 mo
Tumor
site
--c and
testis
Skin and
muscle at
injection site
Injection site;
testis
Testis
Flank
c
Type of
tumors
Sarcomas
and Leydigomas
Sarcomas
Sarcomas
and Leydigomas
Leydigomas
Sarcoma
and other
neoplasms
No tumori-
genic effect
.Adapted from Sunderman, 1977.
Intramuscular: im; subcutaneous: sc.
Information unavailable:
-------
Also, in the studies by Levy and coworkers, cadmium sulfate was
administered to rats by direct gastric intubation 3 times per wk for 2 yr
(at doses of 0, 87, 180, or 350 ug Cd/kg) and to mice by the same procedure
carried out once per wk for 18 mo (at doses of 0, 0.44, 0.88, or 1.75 mg
Cd/kg). No significant increases in the incidence of Leydig cell tumors
were found for the cadmium-treated animals, nor were any prostate neoplasms
or pre-neoplastic changes in the prostate seen in the cadmium-exposed
groups.
The Schroeder and the Levy studies cited above that found no tumori-
genic effects after oral cadmium administration have been found to be
inconclusive, as evaluated by other working groups (IARC, 1976; Carcinogen
Assessment Group, 1977) and the present authors. The doses employed in the
various Schroeder and Levy studies resulted in kidney concentrations of
cadmium below those typically seen in adult humans. Lastly, certain
problems associated with only some animals being sampled for possible tumor
pathology and some results being stated only in qualitative terms rather
than quantitatively make adequate interpretation of aspects of the studies
very difficult.
Based on the collection of other, positive results discussed here, it
appears that tumorigenic effects can be induced by cadmium following its
systemic injection at very high concentration levels, with sarcomas
commonly occurring at the injection site or Leydig cell tumors developing
at a distance from the injection site. This latter effect in particular
has been taken (IARC, 1976; NIOSH, 1976; Carcinogen Assessment Group, 1978)
as being somewhat suggestive of carcinogenic potential existing for cadmium;
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but far stronger evidence for carcinogenicity is needed before any convincing
case can be made for its being carcinogenic at environmentally relevant
exposure levels.
2.15.3 Human Carcinogenesis Studies
The mutagenic and tumorigenic effects discussed above provide some
presumptive evidence for cadmium being a carcinogen in humans. Only a
relatively limited number of studies, however, have provided any relevant
data on possible cadmium-induced carcinogenicity in humans. Such studies
are reviewed in more detail in the later chapter on Human Epidemiology
(3.). Therefore, no effort will be made here to review the relevant
literature beyond presenting a few summarizing statements and conclusions.
Several epidemiologic studies dealing with increased cancer rates
associated with occupational cadmium exposure form a major portion of the
existing data base upon which assessments of cadmium-induced human carcino-
genicity presently depend. Those studies have previously been evaluated or
commented on by other work groups (IARC, 1976; NIOSH, 1976; Carcinogen
Assessment Group, 1978; Troast, 1978) and include: The Potts (1965) and
Kipling and Waterhouse (1967) studies on the same population of workers
exposed to cadmium in a battery manufacturing plant; (2) the study of Lemen
et al. (1976) on cadmium-smelter workers; and (3) the study of McMichael et
al. (1976) on cadmium-exposed rubber-industry workers.
While the above studies differ in regard to the industrial setting in
which cadmium or other possible carcinogens were encountered and vary in
their methodological soundness, some striking findings become apparent when
their results are summarized together as is done below in Table 2-9. As
seen in that table, each study reports increased incidences of various
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cancers among the workers studied. Consistent across all of the studies,
however, is the finding of higher than normal rates of prostatic cancer.
Statistically significant results supporting this were obtained in two of
the studies, by Kipling and Waterhouse (1967) and Lemen et al. (1976),
while the other two (Potts, 1965, McMichael et a!., 1976) reported an
apparently high correlation between cadmium exposure and excess prostatic
cancer mortality that was not tested by thorough statistical analyses. In
each of the above studies, exposure to cadmium oxide occurred as a common
element associated with high prostatic cancer rates; highly suggestive
evidence, therefore, appears to exist for at least that cadmium salt being
carcinogenic in humans with a predilection for the prostate as a site of
action. Differences in the findings of increased incidences in other types
of cancers among the four studies may, at the same time, indicate that
other carcinogenic substances encountered in the work place have sites of
predilection that are different from that of cadmium.
Certain "medical geography" studies have been reported (Troast, 1978)
as providing additional data linking cadmium exposure to cancer. For
example, Berg and Burbank (1972) related incidences of different types of
cancers to cadmium levels encountered in water in major water basins of the
United States and found that cadmium levels of 3 ug/1 (the recommended
safety limit is 10 ug/1) were positively correlated with increased
incidences of cancer in those geographic areas. These included cancers of
the larynx, pharynx, esophagus, intestine, lung, and bladder; but no data
on prostatic cancer incidence were reported. Calculations easily demonstrate,
however, that the water levels reported in the Berg and Burbank study and
usual levels of water consumption are insignificant in comparison to average
normal dietary intake (see Chapter 4). Another study (Zyka, 1973) of
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Table 2-9. SUMMARY OF RESULTS OF HUMAN EPIDEMIOLOGIC STUDIES OF CANCER EFFECTS
ASSOCIATED WITH OCCUPATIONAL EXPOSURES TO CADMIUM
o
ro
Population
group studied
Battery factory
workers
Battery factory
workers
Cadmium Smelter
workers
Rubber Industry
Cadmium compound
exposed to
Cadmium oxide
Cadmium oxide
Cadmium oxide,
others
Cadmium oxide
Incidences of
all cancers
High
Normal
High
High
Incidences of
lung cancer
Normal
Normal
High
Normal
Incidences of
Prostate cancer
High
High
High
High
Reference
Potts (1965)
Kipling and
Waterhouse
(1967)
Lemen et al. ,
(1976)
McMichael et al_.
workers
(1976)
-------
cadmium in drinking water in Czechoslovakia has been reported (Troast,
1978) as yielding evidence for high levels of trace metals such as cadmium
being associated with increased evidences of cancer. Careful inspection of
the Zyka (1973) report, however, shows that no association between cadmium
and cancer was established (see CAG, 1978).
2.16 INTERACTIONS OF CADMIUM WITH OTHER METABOLIC FACTORS
The extent to which cadmium imparts a toxic effect in man and animals
is highly influenced by the status of the organism with reference to a
number of essential chemical elements. Scattered throughout the preceding
discussion on cadmium's adverse systemic effects are references to the
influence of zinc, calcium, and iron. Mention was also made of some of the
mechanisms by which these interactions come into play: by metal!othionein
induction, modification of absorption, etc. Still, it would be appropriate
to summarize in a discrete section the nature of these interactions in a
general fashion. Recent reviews (Sandstead, 1977; Nordberg, 1976) include
a discussion of cadmium-nutrient interactions. Zinc-cadmium relationships
have been discussed in considerable detail in the recently published NAS-NRC
document, Zinc (1978); in particular, the data from experimental animals
have been comprehensively covered.
2.16.1 Zinc
Deficiency of zinc, a nutritionally required metal, increases the
toxicity of cadmium. Conversely, increased levels of zinc tend to offset
the harmful effects of cadmium.
The protective effect of zinc against testicular necrosis caused by
cadmium (Parizek, 1957) was one of the earliest examples of a cadmium-nutrient
interaction to be demonstrated. While protection by pretreatment
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with zinc would suggest a mechanism involving zinc induction of metallo-
thionein, the cadmium-binding, low-molecular-weight protein; the equal
protective efficacy with coadministrati on of zinc with cadmium would suggest
an alternate mechanism, since some induction-time interval would be necessary
for metal!othionein biosynthesis. Direct zinc-cadmium competition for
ligating sites are more plausible in the latter case (Petering, 1971).
A number of studies have indicated that the absolute amounts of either
zinc or cadmium are less important than a cadmium/zinc ratio. This
certainly appears to be the case with the hypertension experimentally induced
by cadmium (see Cardiovascular Effects section). In man, it is known that
there is an increase in the cadmium/zinc ratio in hypertensive subjects
(Schroeder, 1967; Lener and Bibr, 1971) which probably reflects a loss of
zinc. Furthermore, levels of cadmium and zinc in human kidney increase
with aging in parallel and in equimolar amounts in the general population
(Nordberg, 1976).
The cadmium/zinc relationship may also be synergistic as well as
antagonistic in that animal studies on hypertension show both effects
appearing across a spectrum of dietary zinc levels (Sanstead, 1976).
2.16.2 Selenium
A number of studies have demonstrated the protective effect of
selenium, an essential element, against cadmium toxicity. A demonstration
of this element's protective action on cadmium toxicity was the observation
of Kar et a]. (1960) that co-administration with cadmium prevented testicular
necrosis. In addition to testicular protection, selenium abolishes the
toxic effects of cadmium on ovaries, placenta, and fetal development. It
also elevates the ID™ and prevents experimentally induced hypertension in
a number of species (Sandstead, 1977; Parizek, 1971).
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Several recent studies have been directed toward elucidating the
mechanism(s) by which selenium exerts a protective effect. Magos and Webb
(1976) studied the effect of co-administration of equimolar amounts of
selenium and cadmium parenterally on the transport pattern of either element
in adult rats and were led to rule out the in vivo formation of cadmium-
selenium complexes on a number of grounds, one of which was the cadmium/
selenium ratio in kidney. ;
75 109
Gasiewicz and Smith (1976) used Se and Cd as tracers to study the
binding of both elements after simultaneous subcutaneous administration up
to 24 hours after injection. Over this time period, the tracers appear in
a one-to-one ratio in protein fractions of 130,000 and 330,000 daltons as
well as a 420,000-dalton fraction, In vitro studies indicate that selenite
does not interact directly with cadmium or plasma proteins but is modified
to a form that interacts in a one-to-one ratio with cadmium to form a
protein complex of 130,000 daltons.
Stowe (1976) studied the effect of selenium on the movement of cadmium
through the biliary tract using bile-duct-cannulated rats. Two rag/kg of
selenium were given 3 days prior to cadmium administration and following
cannulation. There was a significant increase in the biliary excretion of
cadmium. Elevated bile levels following selenium pretreatment are consistent
with elevated blood cadmium levels and reduced amounts in the liver (Gunn-
et aJL , 1968). According to Stowe (1976), it is likely that cadmium present
in bile is not associated with metallothionein; but the more unstable,
higher molecular-weight fraction which also binds cadmium is stimulated by
selenium and is present in testicular tissue (Chen et aJL , 1974).
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Prohaska et al_. (1977) studied the relationship in rats among cadmium,
selenium, and glutathione peroxidase, a selenoprotein. Rats given a dose
of cadmium sufficient to induce a just-visible hemorrhagic response (0.011
mmole/kg, administered subcutaneously) in the testis showed elevated
levels of the enzyme. This may be a vasculopathic effect with the increase
in activity arising from erythrocyte enzyme via leakage into the testes,
enzyme levels in red blood cells being much greater than in testicular
tissue. Isolation of the main fractions of the enzyme using labeled cadmium
and selenium showed no cadmium-enzyme binding, and these fraction
activities were not inhibited by cadmium i_n vitro. Pretreatment with
109
selenium showed most of the radio!abelled cadmium ( Cd) to be shunted
from proteins of low molecular weight (15,000 and 34,000) to a peak with
molecular weight 110,000, a selenoprotein. The role of this shifting in
testicular protection remains to be demonstrated. Prohaska et al_. (1977)
found that the postulated role of the cadmium-binding protein of molecular
weight 34,000 in testicular injury was not apparent in their animals.
Animals not having analyzable protein of this weight sustained testicular
injury while older animals showed the protein present with or without
concomitant injury. The critical concentration for testicular damage was
reported to be 150 nanograms/gram wet weight, above which evidence of
injury occurs.
Piotrowski et aJL (1977) studied the effect of selenium on cadmium
binding to metallothionein. Selenium was found to have little effect on
the induction of hepatic metallothionein by cadmium under conditions of
repetitive dosing. This may be contrasted to the data of Chen et al_.
(1975a) who demonstrated an effect in kidney and testes in the direction of
higher-weight binding protein.
2-106
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2.16.3 Calcium
Discussion of a number of interrelationships between calcium and
cadmium have been included in other parts of this document, so additional
data will be only briefly summarized here.
Calcium deficiency is known to increase the intestinal absorption of
cadmium and its subsequent deposition in tissue (Larsson and Piscator,
1971; Itokawa et a!., 1974, Pond and Walter, 1975; Washko and Cousins,
1976). Washko and Cousins (1977) found that cadmium retention and signs of
toxicity are enhanced by feeding a low calcium diet and that the increased
calcium binding protein activity observed is responsible for the increased
cadmium uptake. Earlier studies on swine (Hennig and Anke, 1964) and chick
(Stancer and Dardzonov, 1967) showed that cadmium has an inhibiting effect
on calcium deposition in bone even when calcium is present at normal levels.
These doses, however, were extremely high. Data presented in the section
on gastrointestinal effects indicate that the absorption effect is imparted
in the intestinal epithelium. Effects on Vitamin-D metabolism were discussed
in the Sub-Cellular Effects section.
2.16.4 Iron
In the Hematological Effects section it was pointed out that the
anemia occasioned by cadmium can be offset by dietary supplementation with
ferrous salts.
In the study of Hamilton and Valbert (1974), cadmium fed to rats with
restricted iron intake caused a decrease in the uptake of tracer iron
59
( Fe). As little as 10 ppm cadmium in drinking water had a demonstrable
effect, and the data indicate that cadmium competes with iron at one or
more steps of iron transport, probably the initial uptake step as shown in
2-107
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duodenal-perfusion experiments. The effect of cadmium on iron absorption
bears important implications for man, since persons with iron deficiency
might absorb more cadmium than those with normal iron stores. Flanigan and
coworkers (1978) assessed the effect of iron deficiency on increased dietary
cadmium in mice and human subjects. Mice fed a low-iron diet and cadmium
(10 pM; 1.1 ppm) in drinking water showed impaired growth and accentuated
anemia development, while the normal-iron animals showed no effects at the
same cadmium-exposure level. Furthermore, the iron deficiency led to
increased cadmium levels in the duodenal mucosa and the kidney. In human
subjects; experiments using radiolabelled cadmium ( mCd) showed that
individuals with low iron stores absorbed 8.9 ug of 25 ug cadmium given,
while the value for individuals with normal iron was 2.3 ug. In human
subjects with iron deficiency, an approximate four-fold increase in
absorption of cadmium will occur.
2.16.5 Copper
Early evidence for the effect of cadmium on copper metabolism was the
observation that dietary cadmium (100 ppm in drinking water) induced aortic
morphological abnormalities in chicks which closely resembled the effect of
copper deficiency (Hill, 1963). Other effects include the impairment of
collagen and elastin linking (Ruchker et al. , 1971), a copper-mediated
process, and reduction of plasma ceruloplasmin in rats (Campbell and Mills,
1974).
In the study of Irons and Smith (1976), simultaneous administration of
copper and cadmium yielded a redistribution of cadmium with little incorporation
into metallothionein. This may explain, in part, the synergistic effect of
copper when both are given together. The data suggest that retarded incorporation
2-108
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into metallothionein occurs via copper-mediated aggregation of this protein,
an j_n vivo confirmation of demonstrated jjn vitro aggregation (Bremner and
Young, 1976).
In contrast, combining copper with zinc and manganese has the joint
effect of reducing cadmium accumulation in quail (Fox, 1976).
2-109
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3. HUMAN EPIDEMIOLOGY
3.1 INTRODUCTION
Studies directly relating cadmium exposures to human health effects in
various groups of the population are required to define the levels of exposure
at which adverse health effects appear in order that the population segments
at high risk can be identified. At present, except for some occupationally
exposed workers and those dealing with population segments in the areas of
Japan where Itai-Itai disease has been found, no such studies exist.
Therefore, a logical chain from exposure to absorption level to adverse health
effects for populations must be built. This can be done by (1) examining the
distribution of cadmium sources to which humans are exposed, (2) assessing the
levels of cadmium in blood or urine in the various population segments, and
(3) correlating these findings with other research showing the adverse health
effects of different levels of cadmium in human tissue within different
population groups.
3.2 CADMIUM IN HUMAN POPULATIONS
The data for blood and urine cadmium levels in so-called "normal"
populations presented here must be viewed with great caution for several
reasons. The definition of "normal" varies enormously from study to study.
Frequently, it is defined as "no known occupational exposure", but little
evidence is presented to show how this was defined or established for the
subjects. At times, the "normal" study group is drawn from patients who are
believed to be free of disease since they require elective surgery, have had
accidents, or are in other ways deemed to be free of metabolic or chronic
disease. Finally, many of the population surveys were primarily designed
3-1
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to study other pollutants, and the selection of the study population was
stratified to represent gradients of the other pollutants in a single source
such as air, lead paint, etc. Since cadmium in air does not always arise from
the same sources as other pollutants, such stratification may in fact produce
a biased rather than a random selection of the study population as far as
cadmium is concerned.
Rapid changes in laboratory techniques also present a problem. Findings
from earlier studies may not be comparable to those for more recent ones. In
fact, many investigators comment that variations in the findings from different
studies may be due primarily to variations in methodology. Sampling variations
for the same individual must be added to this variance.
Variance within data for a single study should also be considered. It
arises from so-called "within-group variance," which is due to differences
among the subjects such as age, sex, exposure, etc. and also from biological
differences in subjects within each of those same categories. Investigators,
particularly the earlier ones, do not always provide information so that these
sources of variance may be assessed.
3.2.1 Sources of Variations in Human Blood Cadmium Levels
A number of factors appear to affect human blood cadmium levels. Among
the sources of variation discussed here in detail are demographic factors and
geographic variation.
Quantitative measurements of cadmium at the levels encountered in bio-
logical media such as blood and urine are methodologically difficult, chiefly
due to matrix effects. The extent of interference posed by the biological
matrix will vary from method to method. At present the most common way to
3-2
-------
assess cadmium levels in blood and urine is atomic absorption spectrometric
analysis, a method with a number of problems.
Blood samples which are directly analyzed by atomic absorption spectro-
metry using the Delves Cup or the furnace technique may yield rather high
cadmium values if care is not taken to adequately correct for smoke, or other,
signal artifacts. Similar care must be exercised when anodic stripping
voltammetry is employed, since the electrochemical behavior of the element is
sensitive to the presence of ligating groups in the medium. Where feasible,
it is probably most desirable to isolate cadmium from the matrix in which it
occurs, using a solvent-extraction step.
An added problem is that of contamination of the blood or urine samples,
particularly contamination of blood in collection tubes with cadmium-containing
stoppers.
3.2.1.1 Demographic variability in human blood cadmium levels—Data relating
age, sex, and race to human blood cadmium levels are very scarce. Only five
studies reported values for children.
Ediger and Coleman (1973) recorded blood cadmium concentrations for 60
children. The major focus of the work reported was on the analytic methodo-
logy and no descriptions of these children were given. A median concentration
of 0.05 |jg/dl was reported.
Bogden et al. (1974) analyzed blood from 369 children being screened for
lead poisoning in Newark, New Jersey. The children's ages ranged from 1 to 8
yr. Mean blood cadmium concentration was 0.3 ug/dl (no standard deviation
given) with a range of 0.0 to 2.8 ug/dl. These children constitute a
high-risk group for lead poisoning and are from inner-city ghetto sections
3-3
-------
with old and dilapidated housing. Race was not reported, but it seems safe to
assume that many were Black.
Smith et al. (1976b) examined blood cadmium levels for 26 hospitalized
boys and girls aged 2 mo to 13 yr (mean age 4.9 yr). These were white middle-
and upper-middle-class children from Salt Lake City, Utah, who had been
hospitalized for elective surgery such as tonsillectomy. The mean value for
blood cadmium levels was 0.66 ± 0.25 pg/100 gm with a range of 0.21 to 2.64
ug/100 gm.
Rosmanith et al. (1975, 1977) reported findings from a survey of 413
children from a north German industrialized town. The children, with an age
range of 2 to 14 yr, were invited for examination according to a selection
method based on their birthdate. The total population of 2 to 14 yr old children
was estimated at 9,000; and 600 were selected to constitute the sample, with a
response rate of 69 percent. The authors reported a mean blood cadmium level
of 0.11 ± 0.23 ug/dl. Age and sex did not prove to be significant variables.
Delves et al. (1973) evaluated children with suspected lead poisoning and
a control group hospitalized but without suspicion of lead intoxication and
having no anemia, pica, mental retardation, or convulsions. These 89 control
children were 4 days to 15 yr old, were both male and female, and had a mean
blood cadmium value of 0.49 ± 1.5 (jg/dl with range of 0.0 to 1.9 (jg/dl. The
lead-poisoning-suspected "case" group consisted of 189 boys and girls,
aged 2 mo to 15 yr and with proportionately more children in the 3- to
6-year age category than controls. The mean value for "cases" was 0.57
3-4
-------
|jg/dl (no standard deviation given), and the range was from 0.0 to 7.9
ug/dl. The difference for the two exposure groups was not statistically
significant. Differences by age and sex were also not significant.
In summary, there seems to be no age gradient among children's values
for blood cadmium concentrations as, for example, has been found for blood
lead concentrations where younger children show higher concentrations than
older ones under the same exposure conditions. The explanation for the
differences in the absolute values reported in the various publications is
not apparent from the data reported. None of the mean values reported
appear to differ much from many of those reported for "normal" adults,
which will be discussed next.
When examining the blood cadmium concentrations reported for adults,
it is important to note the recent custom of reporting separate values for
smokers and nonsmokers. Invariably, regardless of the definitions utilized
to categorize "smokers" and "non-smokers," the smokers have been found to
have higher blood cadmium values. Further, it should be noted that most of
the study populations are small and authors frequently neither report nor
analyze the effect of age categories within their study groups. Equally
frequently, sex differences are not reported when both sexes are represented
in the study group.
Several reports have been omitted from the tabular presentation because
of the problems encountered in interpreting their findings.
The largest normal population evaluated, the 1954 military recruits
from a Chicago induction center, has been omitted from this table. Creason
et al. (1976) found a mean value of 5.0, a median value of 3.6, and a range
3-5
-------
of 1.0 to 30.0 ug/dl for these men aged 18 to 24. They speculate that this
high value, which is not approached by any others reported for non-exposed
populations, is probably due to contamination of blood samples from the
containers used for storage since the materials were stored for about one
and one-half years before analysis.
Also omitted from the table was the "19 cities" study. Kubota et aK
(1968) selected 243 male residents from 19 cities in 16 states in the
United States. Mean blood cadmium concentration was 1.77 ug/dl and the
range was 0.5 to 14.6 ug/dl. The analytic technique used made it impossible
to detect values under 0.5 ug/dl, and 111 subjects had such low values.
This left 132 determinations. The authors stated that more than half of
the determinations were < 0.5 ug/dl and that the median was "about" 0.5
ug/dl.
Will den and Hyne (1974) reported on 19 male and 16 female controls who
are described as "normal" adults. These investigators did not control for
background in their procedure.
Table 3-1 shows the findings from the more recent studies which either
evaluated "normal" adults or selected "normal" controls for some study or
patient group. Concentrations grouped according to sex of subject are
indicated, where possible, in Table 3-1. Generally there is good agreement
among the concentrations reported within studies: males and females do not
appear to show different concentrations within a given study. The studies
which included both sexes but reported total means only also appear to be
in the same range. Smokers show concentrations which are significantly
higher in each study.
3-6
-------
Table 3-1. "NORMAL" BLOOD CADMIUM LEVELS
(ug/dl)
Location
Children
U.S.
Oklahoma
City, OK
Newark, NJ
Salt Lake
City, Utah
Denver, CO
Germany
Northern
Industrial
town
England
Urban
Adults
U.S.
"working
males"
S. Carolina
workers in a
1 umber mi 1 1
N(sex)
60(both)
369(both)
26(both)
25(both)
25(both)
25(both)
413(both)
89(both)
153(M)
40(M)
SSa'b Age3
12
1-8
2 mo. -13 yr. ;
x = 4.9
1-4
5-9
10-19
2-14
4 days-15 yr.
14->65
<39->60
Mean ± SD Range Procedure
Median = 0.05 — Background corr.
0.3 0.00-2.8 AA : extraction
hemolysates by
APDC-MIBK
procedure
0.66 ± 0.25 0.21-2.64 AAd: wet ashed
samples extracted
with Dithizone/
Chloroform
0.12 ± 0.15C < 0.04-1.77C Flameless AAd:
modified Delves
cup procedure
0.11 ± 0.23 -- AA : Delves cup
procedure
d
0.49 ± 1.50 0-1.9 AAU: wet ashed
sample
0.85; 0.34-5.35 Emission spectro-
median = 0.70 scopy of wet ashed
samples
0.42 ± .07 -- AAd: flame
procedure on
plasma
Reference
Ediger and
Coleman, 1973
Bogden et al . ,
1974
Smith et al . ,
1976
Wysowski et al . ,
1978
Rosmanith
et al. , 1977
Delves et al . ,
1973
Imbus et al . ,
1963
Hammer et al . ,
1972
-------
Table 3-1 (continued). "NORMAL" BLOOD CADMIUM LEVELS
(ug/di)
Location
Oklahoma
City, OK
Denver, CO
Houston, TX
Belgium
"workers"
"workers"
"workers"
Germany
vil lage
v i 1 1 age
N(sex)
50(-)
25(both)
25(both)
41(M)
27(M)
36(F)
33(M)
14(M)
15(M)
22(M)
11000
66(both)
103(both)
SSa'b
--
--
--
S
NS
S
NS
S
--
S
NS
Age3
Adults
20-39
>40
19-53
22-50
21-32
48±10
31±14
30±7
28±9
51±2
Adults
Adults
Adults
Mean ± SDb
0.06
0.12 ± 0.15C
0.7 ± 0.85
0.4 ± 0.44
0.8 ± 1.70
0.7 ± 0.6
0.7 ± 0.3
1.2 ± 1.5
0.8 ± 1.8
0.70 ± 0.10
0.58 ± 0.21
0.33 ± 0.19
0.22 ± 0.08
Range Procedure
0.02-0.2 Delves cup
<0.04-1.77C Flameless AAd:
modified Delves
cup procedure
AA : with cor-
rection direct
sample analysis
Extraction
Extraction
Extraction
0.10->0.8 AA : Delves cup
<0.1-0.49 procedure
Reference
Ediger and
Coleman, 1973
Wysowski et al . ,
1978
Johnson et al . ,
1974; 1975
Lauwerys et al . ,
1973
Lauwerys et al . ,
1974
Roels et al . ,
1974
Einbrodt et al . ,
1976
West Germany
37(both)
Adults
0.95
0.4-1.9 Flameless AA Stoeppler
of hemolysates et aj., 1974
-------
Table 3-1 (continued).
"NORMAL" BLOOD CADMIUM LEVELS
(pg/di)
Location
Sweden
—
--
--
—
Denmark
--
__
Scotland
Y> Renfrew
U3
Holland
Arnheim
N(sex)
25(M)
19(M)
20(F)
25(F)
llO(both)
31(M)
23(F)
34(F)
36(M)
35(both)
35(both)
84(F)
61(F)
77(F)
SSa'b
S
NS
S
NS
--
--
--
--
--
S
NS
NS
LS
HS
Age3
20-55
20-55
20-55
20-55
0-80
21-71
21-73
58.6±6.4
58.616.3
45-64
All
20-50
20-50
20-50
Mean ± SDb
0.23
0.06
0.20
0.05
1.26
1.64 1 0.85
(combined)
0.27 1 0.19
0.20 i 0.13
0.32 1 0.16
0.18 1 0.08
Xg = 0.04
Xg = 0.06
Xg = 0.07
(0.2 calculated
as 0.1)
Range
0.06-0.61
0.03-0.12
0.05-0.76
0.02-0.10
0.5-4.5
0.3-4.8
(comb. )
--
—
--
—
0.02-0.25
0.2-0.24
0.02-0.44
Procedure
Background corr.
Graphite atomizer
Flameless AA
AAd: APDC-MIBK
extraction of
hemolysates
Flameless AA
Reference
Ulander and
Axel son, 1974
Nygaard, 1974
Clausen and
Rastogi, 1977a;
1977b
Beevers et al . ,
1976a
Zielhuis et al . ,
1977
Information not published is indicated by --.
SS: smoking status; S: smokers; NS: non-smokers; LS: light smokers; HS: heavy smokers.
SD: standard deviation. Arithmetic means are given unless indicated by Xg to note geometric mean.
cDetermined for all groups combined
AA: atomic absorption
-------
It is difficult to interpret the differences among various study
findings; most likely they are due to variation in methods of analysis.
There are not enough studies from any one country, except perhaps the United
States, to consider the question of differences among countries. It is
quite possible that smoking habits vary among different countries for males
and females and for urban and rural populations.
Some additional studies investigated members of "normal" population
segments selected for study of cadmium or combinations of cadmium and other
heavy metals.
Imbus et al. (1963) studied chromium, boron, and nickel as well as
cadmium in the blood of 154 volunteers. These consisted of 100 workers
selected from among Cincinnati, Ohio, employees of 15 companies and nearby
farms. An additional 54 men were selected from metropolitan New York,
Denver, Miami, and Portland, Oregon. Altogether, 18 types of industries
were represented. The distribution of age and occupational categories
approximately corresponds to the U.S. male working population. The median
for blood cadmium concentration was 0.70 ug/100 g, the mean 0.85, and the
range 0.34 to 5.35 with the 95th percentile at 1.68 |jg/100 g.
Hammer ejt. al. (1972) evaluated workers with three levels of occupa-
tional exposure to cadmium. These were all Black males from South Carolina.
The low-exposure group worked in a lumber mill, while exposed groups
worked either continuously or intermittently exposed to cadmium in a plant
producing superphosphate fertilizer. Mean blood cadmium concentration for
the 40 low-exposure group subjects was 0.42 ± 0.7 ug/dl, lower than that
for the two higher exposure groups.
3-10
-------
Ediger and Coleman (1973), as mentioned above, reported concentrations
found in the course of a methodological study. They report a mean con-
centration of cadmium of 0.06 ug/dl for 50 adults.
The "Houston Study" conducted by Johnson et a!. (1975) reported con-
centrations for controls selected for three groups with risk of exposure to
air pollution by working in traffic, in parking garages, or by living near a
freeway. The means reported represent four blood samples per individual
collected over time, and there was variance between tests for some groups.
Controls for traffic policemen (N = 41) aged 19 to 53 yr had a mean con-
centration of 0.8 ± 0.85 ug/dl, controls for garage attendants (N = 27)
aged 22 to 50 yr had a mean of 0.4 ± 0.44 ug/dl, and controls for women
living near a freeway (N = 36) aged 21 to 32 yr had a mean of 0.8 ± 1.7
ug/dl.
Three studies from Belgian investigators are in the literature.
Lauwerys et ah (1973) reported on exposed and nonexposed factory workers
by sex and smoking status. The mean blood cadmium concentration for the
nonexposed smokers and nonsmokers by sex are shown in the table. A later
report by this group (Lauwerys et aJL , 1974) showed that 22 male workers
selected as nonexposed controls had a mean concentration of 0.7 ± 0.1
ug/dl. Roels et aj. (1974) reported on concentrations for 110 male workers
selected as controls. Mean blood cadmium concentration was found to
be 0.58 ± 0.21 ug/dl.
Einbrodt et al. (1976) evaluated blood for all 169 adults living in a
small North German village known to be without environmental cadmium sources.
The findings were presented for smokers and nonsmokers without definition
3-11
-------
of age at adulthood or further definition of smoking status. Means of
blood cadmium concentrations found were 0.22 ± 0.08 ug/dl for nonsmokers,
while smokers showed a mean of 0.33 ± 0.19 ug/dl which is a statistically
significant difference. Stoeppler et af[. (1974) reported a mean of 0.95
ug/dl for 37 adults, with a range from 0.4 to 1.9 M9/dl •
Ulander and Axelson (1974) reported concentration means for smokers
and nonsmokers. The differences between smokers and nonsmokers were
statistically significant as was the difference between younger and older
male smokers.
Nygaard et al_. (1974), using a graphite atomizer procedure, found a
mean blood cadmium level of 1.26 ug/dl (range 0.4 to 4.5 ug/dl) in a Danish
population of 110 males and females ranging in age from newborn to 80 years
old. Clausen and Rastogi (1977a,b) reported on 54 Danish adults. They
found a mean blood cadmium of 1.64 ± 0.85 ug/dl with a range from 0.3 to
4.8 ug/dl.
Beevers et al_. (1976a) reported concentrations for individuals found
to be normotensive in a hypertension screening clinic. They were matched
by age and sex to hypertensives selected for a study of any association
between hypertension and cadmium concentrations. The difference between
concentrations for smokers and nonsmokers was significant, but, for hyper-
and normotensives, no significant difference was found.
Zielhuis et a_L (1977) evaluated the blood cadmium concentrations of
222 housewives from Arnheim, the Netherlands, who were married to blue-
collar or lower-income, white-collar workers. All were volunteers, and
their smoking status was ascertained. The concentrations and geometric
3-12
-------
means were the following: 84 non-smokers, 0.04 ug/dl with a range of < 0.02
to 0.25 ug/dl; 61 light smokers (1 to 9 cigarettes/day), 0.06 ug/dl with a
range of < 0.02 59 0.24 ug/dl; 77 heavy smokers (> 10 cigarettes/day), 0.07
|jg/dl with a range of 0.02 to 0.44 ug/dl • (The values < 0.02 were calculated
as 0.01 ug/dl.) Non-smokers differed significantly from light and heavy
smokers.
Wysowski et al_. (1978) studied cadmium exposure in a community near a
smelter (Denver, Colorado). Whole blood and urine specimens were obtained
from 250 individuals living within 2 km of the smelter, as well as from a
control population of 105 residents. Whole blood values, obtained by
flameless atomic absorption methods, showed median blood levels of the
"smelter" and "control" groups of 0.05 and 0.07 ug/dl, respectively. No
statistical significant differences were obtained in the study, except
between smokers and non-smokers; that is, smokers had higher blood cadmium
values than non-smokers.
The Japanese research has not yielded blood cadmium data. Presumably
the utilization of urine cadmium as an indicator is due to the usefulness
of urine analyses in determining proteinuria.
3.2.1.2 Other variation—Only one study (Hecker et al_. , 1974) compared
"acculturated" and "unacculturated" groups: adult volunteer blood donors
in Ann Arbor, Michigan, and Yanomamo Indians from the interior of Venezuela.
Blood cadmium determinations were done for 47 of the 100 people from Ann
Arbor and 90 of the 137 Indians. The values for the Indians were a mean of
1.43 ± 1.19 ug/dl whole blood with a range of 0.3 to 5.7 ug/dl. The Ann
Arbor group had a mean of 1.71 ± 1.89 ug/dl and a range of < 0.1 to 9.6
3-13
-------
|jg/d1. The values are high and probably attributable to the analytic
methodology. Clearly these are not enough data to assess blood cadmium levels
for populations in remote areas with little or no technological advance.
Urban and rural differences also cannot be evaluated at this time. There
are no studies reporting blood cadmium levels for rural populations.
3.2.1.3 Occupational exposure and blood cadmium—The extensive literature
dealing with the effects of high cadmium exposure levels at places of work
will not be reviewed here. The cadmium in dust and fumes is inhaled, and
exposed personnel have consistently shown levels of blood cadmium concentra-
tions that have been considered abnormal. Presumably, faulty hygiene will
contribute to additional exposure by transfer of dust from hands and clothing
to food. Piscator et aj. (1976) showed that cigarettes and tobacco handled at
work by workers who were exposed to cadmium oxide dust have a higher cadmium
content than these smoking materials ordinarily show.
There have been no studies exploring the effect of workers carrying
cadmium dust home and contributing to the exposure of other family members,
although this possible route of secondary exposure should be assessed in view
of recent reports of lead exposure by this route.
3.2.2 Sources of Variation in Human Urine Cadmium Levels
As noted before in the discussion of the determination of blood cadmium
values, cadmium measurement in biological media can be fraught with
analytical errors. Urine is a particularly vexing medium for trace metal
analysis, because of both the high content of inorganic salts and the
presence of organic substances. In particular, the atomic absorption
3-14
-------
analysis of cadmium in urine is complicated by both smoke artifacts and the
levels of chloride ion present. Solvent extraction of ashed samples should
be carried out where possible.
Studies of the normal population, control, or reference cases cited
before also frequently determined concentrations of cadmium in urine.
Table 3-2 shows the concentrations found in those studies, as well as those
reported by Ross and Gonzalez (1974), Kubasik and Volosin (1973), Tada et aL,
(1972), Fukabori and Nakaaki (1974), and Miller et a]_., (1976). The
excretion rate for cadmium by urine in normal persons is age dependent.
There is an increase until the late fifties, followed by a decline. The
mean urine cadmium concentrations reported for the studies listed in Table
3-2 indicate a general daily urine cadmium excretion level between 1 and 2
(jg day. The results of the studies listed in the table, however, obscure
the effect of age.
In contrast, two other recent studies provide information on age
relationships. Tsuchiya et aj_. (1976) reported on a study of 609 Tokyo
residents which permits analysis of the urine cadmium concentrations by age
intervals. Figure 3-1 shows the distribution of mean urine cadmium con-
centrations by age as well as the standard deviations. The authors also
collected data on concentrations of cadmium in the renal cortex, renal
medulla, liver, pancreas, heart muscle, and aorta. They examined 169
cadavers of residents of Tokyo with no known disease or poisoning, who had
died of accidental causes of death. The analysis of tissue concentrations
permitted a calculation of total body burden of cadmium by age. The
authors found the mean urine cadmium concentration for ages 30 to 59 yr to
be 1.7 ± 1.5 ug/1, with an upper-range value of "about 10 ng/1-"
3-15
-------
Table 3-2. "NORMAL" URINE CADMIUM LEVELS'
Location
Children
German
Industrial
town
Adults
U.S.
Cincinnati ,
Ohio & 4
other met.
areas
S. Carolina
--
i — —
1
Houston, TX
Houston
Japan
--
—
N(sex)
413(both)
154(M)
40(both)
13(~)
20(-)
27(M)
36(M)
41(M)
81(")
5(")
374(-)
Age Mean ± SD Range
2-14 0.50 ± 0.40
14->65 1.59 ± 4.13 <0.5-10.8
median =
1.15
<39-60+ 1.04
2.9 0-10.1
1.5 ± 0.7 0.4-3.7
22-50 0.5
21-32 0.6
19-53 0.6 ± 0.44
20-60 1.39 0.25-4.0
27-37 2.56 1.7-3.7
20-60 Xg's = 0.05-3.68
0.64 + 0.65
-0.33
1.06 ± 1.06 0.24-6.72
-0.33
Unit
ug/i
«,
ug/1
ug/day
ug/i
ug/1
ug/1
ug/i
ug/day
M9/18
ug/24 hr
Procedure
AAS
Cholak and Hubbard
method
AAS Parker-El ner
Extraction carbon
rod atomizer
Graphite atomizer
Acidified urine
and Delves cup
procedure
Acidified urine
and Delves cup
procedure
Extraction
Extraction
—
--
Reference
Rosmanith et al . ,
1977
Imbus et aj_. , 1963
Hammer et ah , 1972
Kubasik and
Volosin, 1973
Ross and Gonzalez,
1974
Johnson et al . ,
1974
Johnson et al . ,
1975
Ta !a et aj[. , 1972
Taguchi et al . , 197
Fukabori and
Nakaaki, 1974
-------
Table 3-2 (continued). "NORMAL" URINE CADMIUM LEVELS*
Location
Belgium
—
Australia
Brisbane
N(sex) Age
33(M)^ 48±2
11(M) 33±4
14(F)^ 30±2
15(F)a 28±2
mm
22(both) Adults
Mean ± SD Range
2.0 ± 0.2
1.0 ± 0.2
2.6 ± 0.8
1.5 ± 0.5
1.79 ± 1.68
1.1 < 0.5-2.5
Unit Procedure
ug/g Extraction
creatinine
Extraction
ug/1 AAS: APDC-MIBK
flameless
Reference
Lauwerys et al . ,
1973
Roels et al . ,
1974
Miller et al. ,
1976
Arithmetic mean unless otherwise indicated; geometric mean: Xg. ; information not reported:
""AAS: atomic absorption spectroscopy.
"Smokers.
Non-smokers.
Adjusted individually for specific gravity.
-------
o.o
3.0
2.5
0)
= 2.0
Ol
a.
1 1'5
cc
S 1.0
§
D
< °5
O
0
-0.5
-1.0
(
"",
'
I—
—
I I
(
,/
N = 34
''<
)x
N = 57
„-(
I
N^=44
1
N = 86
> 5
1
c
N=125
I
(
IM = 94
' *""(
—
N = 54T
>««..
6
N = 14
•*•
j. -
T+ 1 S.D. -
MEAN
- 1 S.D. -
1 I 1 1 1 ! 1 1
10
20
30
40 50
AGE, years
60
70
80
90
Figure 3-1. Distribution of mean urine cadmium concentrations
by age. (From Tsuchiya et al., 1976.)
It was pointed out that it is essential that as many cases as
possible—more than 20 or 30--within the same sex and age categories be
analyzed in order to meet the problem of large individual variation.
Johnson et al. (1977) reported urine cadmium concentrations for 86 males in
Dallas, Texas, included as part of the collaborative study undertaken in
Japan, Sweden, and the United States. Table 3-3 shows their findings.
Age-related changes were found in the data with an increase occurring until
40 to 49 yrs and then a subsequent decrease. In another study, by Blinder
et aK (1978), cadmium concentration in the urine of 131 Swedes, including
5'0 pairs of identical twins, were measured. As seen in other studies,
urinary cadmium increased with age and was higher among smokers than among
non-smokers. The daily cadmium output among non-smokers in various age
3-18
-------
groups corresponded better with total kidney burden than with daily dietary
intake.
In the recent report of Tati et al_. (1976), involving unexposed
Japanese subjects, the age/cadmium-excretion relationship was established
using males and females up to 75 yr of age. The distribution of urinary
cadmium levels followed essentially a log-normal pattern, with levels
increasing with age up to the 60- to 69 yr age group in males and the
50- to 59-year-age group in females. This reflects an increasing body
burden with age (Friberg et a_L , 1974), due to the relatively long
half-life of cadmium in major organs which is estimated at 17 to 38 years.
Table 3-3. URINE CADMIUM LEVELS FOR "NORMAL"
MALES IN DALLAS, TEXAS, DETERMINED
BY ATOMIC ABSORPTION3'D
(M9/1)
Age
(years)
0-9
10-19
20-29
30-39
40-49
50+
N
15
8
16
7
16
24
Geometric mean
0.415
0.334
0.422
0.496
0.797
0.704
Confidence interval
0.289-0.553
0.174-0.516
0.300-0.556
0.305-0.716
0.642-0.966
0.582-0.835
aFrom Johnson et a!., 1977
b5th to 95th percentile range: 0.148 to 1.293
3-19
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The report of Wysowski et aJL (1978), mentioned earlier under Section
3.2.1, on blood cadmium levels in residents living near a smelter also
included urine cadmium values of 0.9 pg/l and 0.8 pg/l, respectively, for
residents close to a smelter and a control group. No significant dif-
ferences were found, except for smokers having significantly higher urine
cadmium levels than non-smokers.
The literature relating occupational exposure to variations in urine
cadmium concentrations will not be reviewed here except to note that it has
been suggested that these concentrations may increase when renal tubular
damage exists, as indexed by proteinuria and glycosuria. This increase is
independent of age. Further, little data exist which relate variations in
urine cadmium concentrations to food and water levels of the metal, except
for Japanese populations; and these are discussed later in relation to
Itai-Itai disease.
3.2.3 Sources of Cadmium Variation in Human Hair
Concentrations of cadmium in hair has been evaluated as an indicator
of exposure to the metal. Several studies have been reported where hair
cadmium levels have been correlated with environmental exposures. Hammer
et al. (1971) analyzed hair samples from fourth-grade boys from five cities
rated as varying in overall environmental cadmium levels. The analysis
showed that arithmetic and geometric means varied by city in accordance
with the city's exposures rating. The geometric means ranged from 2.1 to
0.7 parts per million (ppm).
Pinkerton et al. (1974) analyzed hair samples from three communities
which varied in their levels of environmental cadmium. Geometric means of
3-20
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hair cadmium concentrations, while different for each community, did not
follow the exposure gradient.
Creason et aj. (1975) reported significant correlations between cadmium
content of hair and exposure as measured by content in dustfall and housedust
in metropolitan New York. The exposure measurements came from the CHESS
network, and the three communities showed a gradient for cadmium exposure.
A total of 498 participants provided hair samples and sociodemographic
information. The geometric mean hair cadmium concentrations in children
aged 0 to 15 yr were 0.88 ± 0.42 to 1.85 ug/g. For adults, the values were
0.76 ± 0.33 to 1.74 ug/g. No significant association with exposures were
found, however, although other trace metals also evaluated did show such
association.
Hambidge et al_. (1974) reported on hair trace-metal levels for 18
young adults from Denver, Colorado; 11 from Chandigash, India; and 25 from
Bangkok, Thailand. The analytic method for assessing cadmium concentrations
gave a detection level of 0.1 ppm; and 48 percent of Denver, 12 percent of
Chandigash, and 72 percent of Bagkok samples could be detected. In view of
this problem the results for cadmium do not appear to be very meaningful.
McKenzie and Neallie (1974) reported on hair cadmium values but concluded
that hair cadmium levels are not useful in populations with low exposure,
since no significant differences were found among the various study popu-
lations.
Rosmanith et ajL (1975, 1977) reported no significant findings for
hair cadmium levels in their study of 413 children in a northern German
industrial town.
3-21
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In summary, assessment of cadmium levels in hair appears to be of
questionable utility, unless used jointly with urine and blood cadmium
determinations. Technical problems in collecting appropriate hair samples
and in analytic techniques require further study. Also, the process of
cadmium deposition in hair is not well understood.
3.3 RESULTS OF AUTOPSY STUDIES
Crucial to assessment of the effects of cadmium on human populations
is the necessity of determining key organ levels of the metal and, where
possible, total body burden. Generally it is not feasible to assess these
levels in humans other than through autopsy studies, and a number of
investigators have carried out such surveys of selected organ levels.
These studies can be roughly classed into case studies concerned with
specific diseases or population studies as discussed below. Before pro-
ceeding, it should be noted that some workers (Harvey et al., 1975) have
recently carried out i_n vivo neutron activation analysis studies of cadmium
levels in organs of human volunteers. Such an approach, however, is still
considered to be largely experimental and is typically not feasible as a
method for studying large populations.
It is necessary to point out some limitations of the data obtained
from autopsy studies. The cases coming to autopsy do not really constitute
a representative sample of a given population. The requirements for per-
forming an autopsy vary from country to country, and different population
segments differ significantly in their willingness to consent to autopsies
not legally required. It is also well known that this attitude is related
to social status, occupation, and housing, all of which are factors
associated with different degrees of exposures to various toxins and
3-22
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pollutants and with nutritional and health status. The technical problems
of speed, collection of information retrospectively, and the proportion of
dead without living contacts all add to the difficulty of obtaining reliable
data needed to analyze and interpret findings. Finally, there is the
problem of defining "normal" or "healthy" individuals. Usually, accidental
deaths are defined as "normal" or "healthy," and the quality of the examination
of accident cases to determine this status may also vary.
Autopsy studies which report findings for unselected population groups
and which are large enough to present cadmium concentrations further cate-
gorized by age give support to the findings from the earlier studies which
show that cadmium concentrations in liver increase with age but may taper
off after 60 or 70 years of age. Concentrations in the kidney also increase
with age until about age 50 is reached; then there is a decrease. Elinder
et al. (1976) reported on 292 autopsies from Stockholm. The age distribution
for the 292 cases is shown in Table 3-4. This table also presents geometric
means (X) and standard deviations (SD). Figure 3-2 presents the findings
for kidney cortex concentrations.
Tsuchiya et aj. (1976) reported on 106 autopsies for Tokyo residents
dying of accidental causes. Table 3-5 presents the findings for renal
cortex cadmium concentrations. The age-related pattern of change is clearly
evident.
Miller et aK (1976) in Australia found renal cadmium concentrations
that followed the same age-associated pattern in 91 autopsies. Figure 3-3
presents their findings for means of concentrations for kidneys.
3-23
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Table 3-4. CADMIUM IN HUMAN LIVERa'b
(|jg/g wet weight)
Ape (yr)
All sub/ects:
.7
SD
Afc/r«- N
.V
SD
'""'(i' N
*
SD
No/umokcrs:
\
SD
iS'/Mr ihcrs.
X
SD
0
7
-9
0.26
1.
5
0.
.66
.33
1.54
2
0.
1
.15
.05
10- 19
24
0.51
1.88
18
0.55
1.82
6
0.40
2.06
...
20-29
33
0.60
1.88
19
0.58
1.98
14
0.63
1.76
6
0.52
1.77
7
0.77
1.55
30- 39
34
0.60
2.48
22
0.51
2.80
12
0.80
1.76
1
1.01
10
0.57
2.63
40 - 49
40
0.68
2.04
24
0.62
2.01
16
0.79
2.07
1
0.66
. . .
13
0.77
2.01
50 -59
43
10.85
2.24
21
0.77
2.56
22
0.94
1.95
6
0.48
2.07
15
1.14
2.72
60 - 69
39
1.02
2.25
19
0.84
2.26
20
1.22
2.18
11
0.72
2.78
15
1.24
2.14
70-79
41
1.05
2.77
20
0.96
2.91
21
1.14
2.69
14
0.94
3.13
13
1.32
2.58
80 - 89
25
0.53
2.80
14
0.59
2.21
1 1
0.46
3.67
12
0.46
3.26
1
0.89
90-99
6
0.83
1.81
3
0.53
1.23
3
1.29
1.65
2
0.72
2.16
1
2.17
aMean (X) and standard deviation (SD) are geometric. Tolerance intervals
are calculated by multiplying or dividing X by SD.
bFrom Elinder et al_., 1976.
Gross et al_. (1976) reported on a series of 106 autopsies, from
Cincinnati, Ohio, and Table 3-6 shows the arithmetic mean (X) and
standard deviations (±SD) for age categories. The concentrations for
liver increased until the sixth decade, when they appeared to level off.
Cadmium concentrations for kidney increased until ages 45 to 54 and then
showed a decrease.
3-24
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Table 3-5. CADMIUM CONCENTRATION IN HUMAN RENAL CORTEX BY
AGE: MEANS AND 99% LEVEL OF SIGNIFICANCE
Age
Mean
S.D.
99% Level of.
significance
0 -
10 -
20 -
30 '
40 -
50 '
60 -
70 '
80 -
- 9
„ 19
- 29
- 39
- 49
- 59
- 69
„ 79
ts
Total
4.75
33.2
46.26
69.21
85.07
125.3
125.88
37.9
94.68
57.99
5.07
31.48
21.53
29.31
47.49
56.74
14.20
--
18.7
41.85
17.43
--
100.09
142.49
203.8
--
--
--
— —
162.62
13
5
38
27
11
6
3
1
2
106
From Tsuchiya et a\_. , 1976.
br.
X + (S.D. x 2.5)
Table 3-6. AGE GROUP MEANS AND STANDARD DEVIATIONS
FOR TISSUE CADMIUM
(ppm wet weight)
Liver Kidney
Age group
Abortuses
0-1 mo
1-23 mo
2-5 yr
6-12 yr
13-18 yr
19-24 yr
25-34 yr
35-44 yr
45-54 yr
55-64 yr
65+ yr
Total
^Adapted from
N
19
7
9
7
4
11
10
10
6
3
9
10
106
Gross
Xb
0.01
0.01
0.05
0.33
0.66
0.97
0.82
1.25
0.88
1.75
1.96
1.97
0.88
et al_.
±SD
0.00
0.01
0.05
0.35
0.49
0.69
0.54
0.75
0.66
1.86
1.30
1.08
1.19
(1976).
N
19
7
9
7
4
11
10
10
6
2
9
10
105
X
0.07
0.05
0.13
13.33
6.23
8.57
13.73
24.40
29.62
39.35
30.09
20.89
13.65
±SDC
0.06
0.04
0.09
22.72
6.71
3.97
6.99
14.10
14.97
13.79
17.22
12.26
17.60
Arithmetic mean.
Standard deviation.
3-25
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I-
LU
3
01
x"
LLJ
H
cc
o
o
z
111
cc
z
D
Q
45
40
I I I I
6 ARITH. MEAN
O GEOM. MEAN
J ±STD. DEV.
34
I I
30
20
10
24
6 —
I
I
10 20 30
40 50 60
AGE, yean
70 80 90 100
Figure 3-2. Geometric and arithmetic means of cadmium
concentration in kidney cortex are shown for
each decade of life. (From Elinder et al., 1976.)
3-26
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Syverson et al. (1976) in Bergen, Norway, examined liver and kidney
cadmium concentrations in 76 autopsies. These authors also found the
age-associated patterns for cadmium concentrations in liver and kidney.
They reported data for urban and rural residence, and Table 3-7 presents
these findings. Smoking status also showed higher values for cigarette
smokers than for non-smokers, and blue-collar workers had higher concen-
trations than white-collar workers and "others," a group consisting mostly
of housewives.
A further group of reports for autopsy studies did not present data
for general populations with a wide distribution by age. The persons
reported on either constituted a single age group or were selected to
investigate the association of cadmium and specific diseases. Data con-
cerned with "normal," "reference," or "control" groups has been selected
from such studies for presentation.
Morgan (1970) in Birmingham, Alabama, studied cadmium concentrations
for older males. The "normal" group's mean age was 61 years and included
55 persons. The mean and standard deviation for liver cadmium concentra-
tion was 182 ± 99 ug/g ash and 2406 ± 1299 ug/g ash for kidney cadmium
concentrations.
Ostergaard et al. (1977b) presented data for 61 cases where cigarette
smoking status was known. Non-smokers (N = 19) showed the following for
whole kidney ug/g ash: Arithmetic mean (and range): 1106 (347 to 2466)
ug/g ash, and a geometric mean of 953. The 42 smokers showed the following:
for those with less than 20 cigarettes per day (N = 11), arithmetic mean
(and range): 2415 (947 to 3821) ug/g ash and geometric mean of 2242
ug/g ash; for heavy smokers (N = 12) using 20 or more cigarettes per day:
3-27
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Table 3-7. MEAN CADMIUM VALUES RELATED TO PLACE OF RESIDENCE3
Age Liver Cd Renal cortex Cd Renal medulla Cd
(year) (ug/g dry weight) (ug/g dry weight) (ug/9 dry weight)
Residence N Geometric Mean Mean SO Mean SD Mean SD
ro
CO
Urban
Rural
Total
aAdapted
Range.
52
24
76
from
65.9
51.0
60.8
Syversen et aL
8.1 ±5 101
8.1 ±5 98
8.1 (l.l-24.3)b 100
(1976).
±60 62 ± 42
±50 54 ± 30
(22-297)b 57 (6.7-171)b
-------
arithmetic mean (and range); 2778 (961 to 7493) ug/g ash and geometric
mean of 2310 ng/g ash.
00-0 MEAN VALUE
O SINGLE VALUE
AGE OF SUBJECTS, years
Figure 3-3. Cadmium in whole kidney tissues and its relationship
to age. (From Miller et a].. , 1976.)
Lewis et aJL (1972) in Boston, Massachusetts, examined liver and
kidney tissue from 172 cadavers. The 161 males had a mean age of 61 ± 1.0
yr, and the mean age of the 11 females was 70 ± 3.1 yr. Total mean cadmium
content for kidney (N = 171) was 9106 ± 0.50 mg and that for liver (N = 172)
was 2.92 ± 0.14 mg. When these findings were examined for the effect of
smoking, differences for smokers and non-smokers were found as follows:
Non-smokers (N = 34) had a mean of 4.16 ± 0.51 mg for kidney, smokers (N = 138)
10.28 ± 0.57 mg. Means for liver were: non-smokers 2.28 ± 0.25 mg,
smokers 3.06 ± 0.16 mg.
Kidney cadmium levels for non-smokers and smokers were measured by
Johnson et aK (1977). Cadmium levels were significantly greater (p
< 0.001) for smokers, the difference between the two groups being 6.9 ug/g
average concentration.
3-29
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3.4 EPIDEMIOLOGICAL STUDIES OF CADMIUM EXPOSURE IN JAPAN
A number of comments appear in the preceding Health Effects sections
dealing with the pathophysiological features of cadmium as they have been
unveiled over the last two decades in cadmium-polluted areas of Japan, with
emphasis on the most serious aspect of population response, Itai-Itai or
"Ouch-Ouch" disease. A considerable effort has also been documented in
connection with other areas of cadmium pollution in Japan other than the
Jintsu River basin, or Itai-Itai belt, and the epidemiological data will be
considered in two sections: Itai-Itai disease and other studies of cadmium
pollution in Japan.
Some general comments are in order with reference to the nature of the
Japanese epidemiological studies which have been carried out so far.
(1) Different investigators have employed various techniques to assess
the indicators of adverse health effects in these population groups under
study. Until recently, when attempts were made in Japan to standardize the
way in which one assesses cadmium-associated proteinuria, which is the most
common indicator of chronic cadmium exposure, the methods for increased
protein excretion were rather crude, semi-quantitative, and nonspecific.
Thus, it is not always possible to compare these types of data gathered by
different investigators; Friberg et aj_. (1974) discuss this difficulty in some
detai1.
(2) Questions arise in a number of cases as to the appropriateness of
the control population groups taken for study with particular reference to
close matching for age, diet, and nutritional status. For example, it is not
apparent that some controlling for dietary cadmium intake constitutes true
non-polluted diet groups.
3-30
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(3) Given the retrospective nature of many of the studies, difficulty
arises in attempting to draw correlations between factors such as diet and
the present health status of the various exposure groups. For example, the
exposure in many cases has occurred over a number of years, several decades
in some instances, while assessment of dietary cadmium is based on data
collected much later, after the onset of overt effects. Ideally, one would
like to have had a time-concordant profile of changes in dietary cadmium,
if any, over this period.
(4) One can argue that Japan constitutes a unique cadmium-exposure
situation owing to heavy population density, the very close proximity of
industrial to agricultural and other human activities, the geochemical
nature of the ores mined and processed as to cadmium content, etc.; so its
experience with cadmium may, therefore, not be applicable to the
United States. As noted earlier, however, the collective Japanese
experience with cadmium constitutes a classic case of pollution in a
heavily industrialized society which persisted for a number of years with
little telling effect and in ways which remained unidentified and
unsuccessfully treated.
3.4.1 Itai-Itai Disease
The chronology of the development of Itai-Itai disease and the studies
directed thereto have been extensively considered elsewhere (Friberg et
al., 1974; Fulkerson and Goeller, 1973), and the earlier literature evalua-
tion will not be repeated here, but some of the more recent data will be
considered.
In Friberg et al. (1974) a good case was made for the etiological role
•*
of cadmium in the development of Itai-Itai disease, tubular proteinuria
3-31
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with osteomalacia, and severe osteoporosis afflicting older females (<_ 40
yrs) in the Fuchu area of Toyama Prefecture. As noted elsewhere in this
report, the victims also had histories of marked nutritional deficiencies.
In Cadmium in the Environment III (Friberg et al., 1975), some more
recent studies from the Itai-Itai region were discussed.
Shiroishi and Yoshida (1972) selected a group of 123 men and 119 women
over 40 years of age in S-village in the Fuchu area as an exposure group
and used as a control group 75 men and 86 women in a different area. In
their study, the prevalence of proteinuria increased from about 10 percent
in the 40- to 50-year-age group to about 50 percent in the 70- to 80-year-
age group. Proteinuria was assessed using the Kingsbury-Clark method as
well as disc electrophoresis, while test-tape and OTB methods were employed
for glucosuria.
In the study of Fukuyama et al. (1972), the time of residence in the
Fuchu area was correlated with cadmium excretion and renal dysfunction.
Cadmium excretion was seen to reach a maximum at 40 years of living in the
area, and after 45 years, almost all of the individuals showed renal
dysfunction.
In the dietary study of Fukushima et al. (1973), correlation was
attempted between proteinuria and glucosuria in Fuchu area villages and
cadmium in the rice, particularly non-glutinous rice. In 37 villages
studied, response rate (proteinuria and glucosuria) was seen to increase
with increasing cadmium levels in rice, a significant correlation coeffi-
cient of 0.62 being obtained.
3-32
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Earlier studies of existing proteinuria in Itai-Itai patients and other
subjects from the Fuchu area involved rather unspecific (Friberg, et al_. ,
1974) total protein methods. More recently, attention has focused on the
levels of specific types of urinary proteins which may be more pathognomonic
for cadmium's renal effects. This has also been discussed in the Renal
Effects section.
One argument which has persisted in defense of the notion that Itai-Itai
disease is not cadmium-based is the fact that Itai-Itai disease appears to be
confined to the Jintsu River basin, although a number of other main cadmium-
polluted areas exist. In 1975, Nogawa et aK claimed to have identified five
cases of Itai-Itai disease among women in the Ichi River basin. All of these
patients showed biochemical and other clinical evidence for the renal and bone
damage sequelae associated with the malady. Autopsy data in one case were
also consistent with the earlier data from the Jintsu River basin. Furthermore,
the favorable response of three of these subjects to large doses of Vitamin D
therapy parallels that seen in other victims of the disease.
In the Sub-Cellular Effects section, it has already been noted that
chromosomal aberrations occur in individuals with Itai-Itai disease (vide
supra).
In viewing the data available for Itai-Itai disease, one is struck by the
fact that many early clinical investigators have restricted themselves to the
extreme clinical phase of the continuum of changes accompanying chronic exposure.
Fortunately, this problem is. now being assessed more comprehensively and
uniformly.
3-33
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3.4.2. Epidemiological Studies of Other Cadmium-Pol luted Areas in Japan
Japanese areas where epidemiological studies have also been carried out
include Ikuno, Tsushima, Kakehoshi, Bandai, Annaka, Omuta, and Uguisuzawa; and
reviews of these data have been carried out (Friberg et aJL , 1974).
In a more recent rather detailed report, Kjellstrom (1976) has reviewed
and critiqued these areas of cadmium exposure in Japan where systemic effects
such as proteinuria have been considered from the standpoint of dose-effect/
dose-response relationships of cadmium.
The extent to which data comparisons can be made is restricted somewhat
by the fact that proteinuria has been assessed in different ways, and not all
factors have been matched in selecting control groups.
In 1972, a study was carried out involving 1560 individuals from the Ichi
River basin in Hyogo prefecture, an area where the likelihood of pollution
extends back for several centuries. Three control-area groups of 1574, 2002,
and 638 persons were also employed (Watanabe et al_. , 1973). The corresponding
proteinuria prevalence rates (determined by the sulfo salicyclic acid method)
were 58, 33, 4, and 9 percent, respectively. Differences in these groups may
be confounded by the fact that not all control areas used the same protein
analysis technique. In a later study, Watanabe and Murayama (1974) found
elevated Pp-microglobulin anc' lysozyme in urines of individuals from the most
heavily exposed group (H area). It was in this same area that Nogawa et aK
(1975) later reported five cases of Itai-Itai disease (vide supra).
Another zinc mine which was probably a long-term pollution source
t
spanning several centuries has figured in the occurrence of significantly
increased proteinuria in the Tsushima area of Nagasaki prefecture.
3-34
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In the four villages of the Kakehoshi area in Ishikawa prefecture where
cadmium pollution occurred from two long-active copper mines, a study of
Ishizaki (1972) turned up proteinuria prevalence ranging from 39 percent for
the worst exposure to 30, 28, and 22 percent for the others. No control group
was employed in this study.
Japanese population groups in the areas of zinc smelters have also been
studied. In the Bandai area of Fukushima prefecture, the site of a zinc
smelter, a study (Fukushima Prefecture, 1971) of 1324 men and women over 30
years of age in the pollution belt using 215 women in a control area indicated
that the prevalence of proteinuria was 12.3 percent compared to 4.7 percent in
the control area.
Another site for a zinc smelter is the Annaka area of Gumma prefecture.
While a study of 2397 persons (men and women, more than 30 years of age) in
the polluted area showed a prevalence of proteinuria (12.1 percent) not
materially different from that of a group of 895 controls (Kakinuma et al_. ,
1971) as described in Friberg et ah (1974). These findings have been later
ascribed to the brevity of the significant exposure period, only over the last
decade (Kjellstrom, 1976).
The most recent study of the prevalence of proteinuria in the zinc-smelter
area in the Omuta area (Friberg et al., 1974) showed a rate of 18.2 percent
for the polluted area versus a rate of 6.8 percent for controls.
Saito et al. (1977) carried out a detailed study of proteinuria in the
Hosogae area of Akita prefecture which is adjacent to a major copper refinery
3-35
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operating for the past century, these studies spanning 1972 to 1975. These
workers found that 13 to 22 percent of the area's population over 35 years
old had proteinuria and glucosuria versus the general occurrence of 20
percent in all of Japan. Also, the levels of urinary p^-microglobulin in
this group increased with age and length of residence in this area.
Extensive soil contamination and a high contamination of rice src
present in this area. In the studies of Watanabe et al. (1973), noted
above in connection with proteinurea, urinary cadmium levals were related
to the village average rice cadmium levels; adults excreted ca. 7 |jg cadmium/
liter at rice levels of 0.4 |jg/g and this value rose to ca. 14 (jg/liter at
1.1 (jg/g in rice. These values correspond to 240 and 660 pg daily of
cadmium intake. Kjellstrb'm (1977) found that women aged 50-59 and having
long-term cadmium intake had blood levels of ca. 3 M9/dl and 24 hour ex-
cretion levels of ca. 15 ug. These latter values can be compared to cal-
culated data, based on a 600 pg cadmium intake value, of 3.4 |jg/dl blood
and 14 ng/24 hour urine respectively (Kjellstrom and Nordberg, 1978).
3.5 EPIDEMIOLOGY OF CADMIUM, HYPERTENSION, AND CARDIOVASCULAR DISEASES
Hammer et al_. (1972) presented a review of the information about the
relationship of cadmium and hypertension and presented data to support some
of their criticisms of the approaches taken by earlier investigators.
Essentially they questioned the "single cause" approach pointing out that,
particularly for conditions of high prevalence, this approach has inevitably
failed. Much of the more recent work has proven them right in this contention.
Investigators who have controlled for smoking status have found that the
association of higher cadmium concentrations and hypertension is not independent.
3-36
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Thind et al. (1976) and Glauser et al. (1976) found significantly
higher cadmium concentrations in blood of hypertensive patients than in
normotensive controls, but neither of these groups of investigators con-
trolled for smoking status. Beevers et aJL (1976a) found not only no
difference for cadmium concentrations for hypertensives and normotensives
but instead did find that smokers and non-smokers, regardless of pressure,
showed differences in cadmium concentrations. A further report from this
team (Beevers et a_L , 1976b) indicates that higher concentrations of lead
were found in blood of male hypertensives than that of male normotensives.
A difference in the same direction but not statistically significant was
found for female patients and controls. These subjects came from the same
area and clinic as those examined in the earlier study. The authors con-
cluded that the findings of an association of hypertension and blood lead
concentration is due to the quality of the tap water since this area has
high lead levels in its drinking water. The case for an association for
cadmium and hypertension appears weakened by this finding.
Autopsy studies were conducted by Ostergaard (1977a,b) and by
Syverson et al. (1976). These investigators controlled for smoking
and found no differences, Ostergaard (1977a,b) reporting higher levels
among normotensives who smoked than among hypertensives. The reports from
the North Carolina study (Shuman et aJL , 1974; Voors and Shuman, 1975) did
not control for smoking. They found a statistically significant associa-
tion for zinc concentrations in kidney tissue, and an association, conse-
quently, for zinc-cadmium ratio, but not for cadmium concentrations per se.
The association of hypertension and hard water and associated levels
of cadmium in water has been discussed by Perry et an. (1974). There is no
3-37
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firm evidence as to the significance of this variable. Rather, the current
available data is not definitive and can best be characterized as inconclusive
and requiring further research.
Early studies by Hunt et al_. (1971) and Hickey et al_. (1967) related
mortality rates to air cadmium levels. These statistical approaches use
total mortality experience without taking account of population character-
istics such as age distributions. Further, they do not take into account
the fact that cadmium in air is not so ubiquitous as other pollutants, and
single measures for air concentrations for entire populations are of dubious
value.
Bierenbaum et a}. (1975a,b) analyzed cardiovascular/renal mortality in
populations with hard and soft water as well as different levels of cadmium
concentrations in water using the Missouri and Kansas populations of the
Kansas City metropolitan area. The investigators found higher mortality
for the hard-water area of Kansas than Missouri. Two matched groups of 260
adult volunteers, one each from the two areas, were examined for blood
pressure, electrocardiographic findings, selected serum-lipids, uric acid,
and angina. Some statistical differences for the two groups were found,
but smoking status was not controlled for. The significance of their
finding must be questioned.
Autopsy studies reported by Voors et aK (1975) and Shuman et al_.
(1974) found an association for cadmium concentration in liver and death
from heart disease. Syverson et aJL (1976) found neither an association
for cardiovascular disease nor for hypertension as discussed above.
The evidence for an association between cadmium and cardiovascular
disease is no clearer than that for hypertension. The groups studied are
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either extremely small or, if larger, were not controlled for relevant
factors. It is impossible at this time either to rule out the postulated
relationship or to confirm it.
3.6 EPIDEMIOLOGICAL STUDIES OF THE RESPIRATORY TRACT
The studies relating to the diseases of the lungs, other than cancer,
almost universally concern occupationally exposed workers and have been
reported elsewhere (Health Effects). Briefly, Lauwerys et aj. (1974),
Scott et al. (1976), and Smith et al. (1976a) found decreased pulmonary
function in workers exposed to high air cadmium concentrations for long
periods. Scott et al. (1976) also reported "restrictive airway disease" to
be prevalent to a greater degree in the most exposed group. Smith et al.
(1976a) found mild and moderate interstitial fibrosis in the group with
high exposure.
Morgan et aJL (19710 compared the tissue cadmium concentrations of
autopsied patients grouped by cause of death. Cadmium concentration in
liver was significantly higher in the group with the diagnosis of
emphysema. A second group with a combined diagnosis of cancer of the lung
and emphysema showed significantly higher cadmium concentrations for both
liver and kidney. Smoking was not controlled for even though the investi-
gators attempted to collect this information. Occupational exposure was
reported for 23 percent of the "emphysema only" group, but only 4 and 5
percent of the "lung cancer" and "emphysema and lung cancer" groups had
such exposures. These authors stressed that the findings are only
suggestive. Similar distributions of mean values for zinc concentrations
in liver and kidney suggest that it is by no means possible to implicate
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cadmium as a single etiological factor. The cadmium/zinc ratio was not
determined.
While there is no question that occupational exposure at high levels
produces decreased pulmonary function, restrictive airway disease, inter-
stitial fibrosis, and emphysema, no good evidence exists at present as to
the effects of gradients of exposure levels for "normal" populations
without high levels of occupational exposure.
3.7 CADMIUM AND CANCER
The investigations of causes of death among workers are one source of
data; studies of tissue concentrations by cause of death are another major
group. The data are sparse and subject to the limitations of retrospective
study design and autopsy studies.
Potts (1965) conducted a health survey in an English alkaline-battery
factory where source data for cadmium concentrations in air was available.
The plant had been in operation for over 40 years, and the health status of
past and present workers was assessed. There were 74 workers who had had
exposures of more than 10 years, and 8 of these had died. Among these
deaths, five were from cancer; and three of these were cancer of the
prostate. These eight had worked at the plant when exposure levels had
been high and before moving into a new building where air levels were much
improved and where measures continued to be taken to achieve further reductions.
Potts' report did not give enough information to interpret his striking
finding in relation to mortality in the general population, and he
presented no data for causes of deaths among workers with less than ten
years' exposure. Also not clear is the reliability of establishing the
base of 74 workers with ten or more years of exposure.
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Kipling and Water-house (1967) reported a further study of the workers
in this battery plant. They had extended the search for causes of death to
all those with at least one year's exposure. They found 248 workers with
this exposure with a total of 12 deaths from cancer in this group. Among
these 12, four were cancer of the prostate. (Three among these were also
included in Potts' findings). Mortality experience in an unidentified
population stated to be similar was used to calculate expected numbers of
deaths for all cancers and for specific cancer sites. For the four cancer
sites, and for cancers for all sites, significant differences between
observed and expected numbers of deaths were found only for cancer of the
prostate.
The next relevant study of occupationally exposed workers was reported
for workers at a cadmium smelter in the United States. Lemen et aK (1976)
used employment histories to establish a population of 292 workers with
more than two years' exposure which were a cohort for employment during a
30-year employment period between January, 1940, and December, 1969. Very
thorough investigation produced information on vital status. It was found
that, by 1974, 92 had died, 180 were known to be alive, and 20 were lost to
observation. Causes of death were established and standardized mortality
ratios (SMR) were calculated so that excessive risk could be analyzed.
Mortality from cancer at all sites was found to exceed the expected number
of cancer deaths by a statisticallly significant margin. Among the deaths
from cancer, 12 were from sites in the respiratory system; and this
observed number also gave a significant excess with an SMR of 235. Cancer
of the prostate was also found to have a significantly increased risk
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among these workers. The latency period for prostatic cancer deaths found
both by Potts (1965) and Kipling and Waterhouse (1967) is 20 years or more.
Lemen et a\_. (1976) found the same latency period. It should be kept in
mind that the Lemen ert al. (1976) study did not control for smoking.
A study of mortality among rubber workers was conducted by McMichael
e_t al. (1976). This study was not confined to workers exposed to cadmium
alone, and it is therefore not possible to implicate cadmium specifically
in the mortality from cancers that was found. Cancer of the prostate
showed an SMR of 119, which was only slightly elevated. A more detailed
analysis of the specific jobs of these prostatic cancer deaths showed that
workers in compounding and mixing areas and maintenance workers had a
higher risk for this cancer. No air cadmium levels at the various work-
sites were determined. These specific mixing jobs expose workers to cadmium
and other metal oxides.
The evidence for cancer of the prostate is strongly suggestive but
inconclusive at this time.
Autopsy studies have compared cadmium concentrations in tissues by
causes of death. Lewis et aJL (1972) found in their 172 autopsies that
higher concentrations of cadmium in kidney cortex, liver, and lungs were
found in cases of death from cancer of the bronchus and lungs. However,
when cigarette smoking is controlled for, these differences disappear.
This forces reconsideration of the findings reported earlier by Morgan et
aj. (1970, 1971), who found significantly higher cadmium tissue content for
causes of death from cancer of the lung but did not control for smoking
3-42
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status. Voors et al. (1975) reported on their autopsy series that they
found no association for higher cadmium tissue concentrations and deaths
from cancer.
Kolonel (1976) reported on a survey of patients at Roswell Park
Memorial Institute for an 8-yr period, 1957 to 1964. All white males aged
50 to 79 yr with a diagnosis of renal cancer were compared to two control
groups: one of all comparable males with non-malignant diagnoses and the
second of males with cancer of the colon. From the smoking and employment
histories all subjects were categorized as "exposed" or "not exposed" via
the respiratory route. Data from the dietary history were used to categorize
the men as nutritionally "exposed" or not. Two sources of respiratory
exposure and the dietary exposure were therefore considered. Relative risk
for cancer of the rectum was increased only when smoking and occupation
were considered together when the age-specific, relative risk increase was
found to increase to 4.4, yielding an excessive relative risk of 3.4.
There seems to be good suggestive evidence that cadmium may be a
factor in cancers of various sites, but the association is by no means a
simple one, particularly not at low or "normal" levels of exposure. It is
important to note the excessive mortality or risk of mortality from cancer
of the prostate is reported from two works where the chemical forms of
cadmium differed. The evidence for cancer of the lung has been found in
one study but was not confirmed in others. While the carcigenicity of
cadmium is not firmly established, neither can it be dismissed. The
U.S. Environmental Protection Agency's Carcinogen Assessment Group,
in 1977, and the WHO International Agency for Research on Cancer (IARC)
3-43
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monograph (1976) for cadmium reached the same conclusion in regard to
occupational exposures and risk for cancer.
3.8 EPIDEMIOLOGICAL STUDIES RELATING TO CHROMOSOMAL ABNORMALITIES
A number of studies addressing the question of chromosomal abnormal-
ities in humans and involving various exposure conditions have been re-
ported. Shiraishi (1975) pointed out the occurrence of a number of
chromosomal abnormalities in patients with Itai-Itai disease. Other
studies touching on this issue are considred here.
In a study that also included Itai-Itai patients, Bui et al. (1975)
analyzed lymphocyte cultures from six female Itai-Itai patients, four
control Japanese samples, five cadmium-exposed Swedish workmen, and three
Swedish controls and were unable to see any significant differences within
either of the two sets of groups. Interestingly, however, the Swedish
groups showed a lower frequency of abnormal cells than either of the
Japanese groups. It is unlikely that the greater time lag from collection
to culture in the case of the Japanese samples (4 days) could constitute an
artifact in these results, since these investigators had not experienced
any time-dependent effect of culturing of this magnitude (4 days) in the
past.
In the occupational exposure studies of DeKnudt and Leonard (1975) and
Bauchinger et al. (1976), significant chromosomal abnormalities were
observed. In the former study, where workmen were exposed to cadmium and
lead via dust and fumes, yields of chromatid exchange, spiralization
disturbance, chromosome translocation, and ring and dicentric chromosomes
obtained were higher than in a group of control, low-cadmium-exposure
3-44
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workmen. In the latter data (Bauchinger et al. , 1976), chromosomal damage
was mainly of the chromatid type. Confounding these results, of course, is
the fact that lead exposure had also occurred, thus this toxin could not be
ruled out as being the main factor or a cofactor operating synergistically
with cadmium.
All of the various studies, considered collectively, indicate that the
issue of cadmium as the etiological factor in chromosomal abnormalities is
still open to controversy.
3.9 EPIDEMIOLOGICAL STUDIES OF OCCUPATIONAL EXPOSURE TO CADMIUM
A comprehensive review of all of the studies of occupational groups
regarding the health effects of cadmium exposure is outside the purpose of
this report. Where specific studies have been deemed appropriate to
demonstrate the magnitude of cadmium's health effects in man, these data
have been incorporated into the appropriate sub-sections of the Health
Effects report.
For a more appropriate compendium in which occupational exposure is
the chief emphasis, one is directed to the recent National Institute of
Occupational Safety and Health's Criteria Document for Cadmium (NIOSH,
1976).
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*
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cadmiumanalytik-in biologischen matrices. In: Proceedings International
Symposium. Recent Advances in the Assessment of the Health Effects of
Environmental Pollution. Volume IV. Commission of the European Communities,
Luxembourg, 1975. pp. 2231-2245.
Syverson, T. L. M., T. K. Stray, G. B. Syverson, and J. Ofstad. Cadmium and
zinc in human liver and kidney. Scand. J. Clin. Lab. Invest. 36(3):251-256,
1976.
Tada, 0., K. Nakaaki, and S. Fukabori. Urinary excretion of lead, mercury,
cadmium, and fluoride in normal subjects. J. Sci. Labour. 48:14-18,
1972.
Taguchi, T., T. Suzuki, S. Suzuki, and T. Takemoto. Variation in daily urinary
excretion of lead, cadmium, 6-aminolevulinic acid and coproporphyrin in 5
men without occupational exposure to metals. Ind. Health 10:77-83,
1972.
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Tati, M. , Y. Katagiri, and M. Kawai. Urinary and fecal secretion of cadmium
in normal Japanese: An approach to non-toxic levels of cadmium. In:
Effects and Dose-Response Relationships of Toxic Metals. G. F. Nordberg.
(ed.). Elsevier, Amsterdam, 1976. pp. 333-342.
Thind, G. S. , and G. M. Fischer. Plasma cadmium and zinc in human hypertension.
Clin. Sci. Mol. Med. 51:483-486, 1976.
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Voors, A. W., and M. S. Shuman. Liver cadmium levels in North Carolina residents
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3-57
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4. HUMAN HEALTH RISK ASSESSMENT OF CADMIUM
4.1 INTRODUCTION
In several respects, cadmium is rather unique among those metallic
elements that are toxic to man. Its very long biological half-life leads
to a steady increase in body burden over an individual's lifetime. Unlike
lead, however, cadmium accumulates in soft tissue, chiefly the kidney, and
little of the body burden is deposited in bone where it might become inert.
Furthermore, there is no treatment available to prevent the accumulation of
cadmium in the kidney or to remove or eliminate cadmium stored in the
kidney or other soft tissues. Also, the adverse physiological effects
associated with cadmium are essentially irreversible in nature. Thus, the
most effective approach in protecting against its toxicity appears to be
minimization of exposure to the metal. These two factors provide a strong
basis for advocating limitation of human exposure in order to forestall
adverse effects that may not appear until late in an individual's lifespan.
In addition to the above points concerning cadmium, e.g., its insidious
gradual tissue accumulation over long periods of time, it should be noted
that, so far as can be discerned to date, cadmium possesses no particular
physiological benefit for man. Thus, there is no health-risk/health-benefit
balance to be considered in discussing the hazards to public health associated
with environmental exposure to the element.
To assess the issue of risk to public health posed by cadmium exposure,
two aspects of the problem must be considered: (1) sources and levels
of exposure and (2) population response.
4-1
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Key questions about the sources of exposure that must be considered
include: (1) What are the environmental sources of cadmium exposure of
present or potential future concern in the United States? (2) What are the
various routes by which cadmium enters the body? The latter question is a
particularly vexing one in the case of a multi-media contaminant such as
cadmium. A primary route of entry into the environment can lead to secondary
and tertiary contamination; e.g., airborne cadmium contributes via fallout
to soil levels which in turn influence the levels of cadmium in plants,
animals, and food.
Several crucial questions must be considered with respect to population
response:
(1) What are the human biological and pathophysiological responses
to cadmium observed at environmentally relevant cadmium exposure
levels?
(2) Do there exist within the general population in the United States
or elsewhere certain sub-groups at particular risk to the adverse
health effects of cadmium, either by reason of a special exposure
relationship or an abnormally vulnerable physiological status?
(3) Quantitatively, what is the magnitude of the risk in terms of
numbers of individuals potentially exposed to levels of cadmium
sufficient to induce particular adverse health effects?
The first question posed was partially answered in the previous sections
on health effects of cadmium (Chapters 2 and 3). It requires expansion
here, however, to more fully consider dose-effect and dose-response relation-
ships for humans and to assess the utility of various indicators of expo-
sure in evaluating the effects of different types of exposure.
4-2
-------
To better understand this portion of the report, it would be helpful
to define the various terms which will be encountered. "Dose" is the
amount or concentration of a substance which is presented over time to the
specific, intracellular site where the effect is imparted. Since it is not
usually possible to assess directly the quantity of that substance in the
living organism at the affected site ("effect site"), the external and
internal doses are considered as indices mirroring the effect-site concentra-
tion. "External dose" is the amount of the toxic substance in the external
environment (air, water, food, etc.) to which an organism is exposed.
"Internal dose" is the absorbed portion of the substance and is an integrated
reflection of all contributing external exposures.
"Effect" is a biological change resulting from exposure to a toxic
substance. "Dose-effect relationship" is a quantitative relationship
between the dose and a specific effect i.e., it reflects changes in the in-
tensity of an effect as a function of variations in dose. Dose-effect
relationships vary among members of a population, and the frequency at
which this occurs is expressed as the dose-response relationship.
"Response" specifically is defined by Nordberg (1976) as that proportion
or percentage of a population that exhibits a specific effect at a given
internal dose level.
Nordberg (1976) has defined the concept of critical organ, critical
concentration in the critical organ, and critical effect. "Critical
organ" is defined as that organ which first attains the critical concentra-
tion of a metal under defined situations and for a given population. The
"critical concentration" is defined as the mean concentration of the toxic
4-3
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substance in the critical organ at which adverse functional changes appear.
The "critical effect" is the first adverse effect that occurs along the
continuum of dose-effect relationships.
4.2 EXPOSURE ASPECTS
Cadmium, although a relatively rare metal, is widely distributed
naturally in the Earth's crust, often in close association with zinc and
other metals. It is, therefore, rather ubiquitously encountered in trace
amounts as a geochemical component of many surface soils, in underground
water tables, and in surface waterways. Substantial additional amounts of
cadmium, however, are continuously added to the "natural" background levels
of the element in soils and water as a consequence of anthropogenic activities.
Thus, in industrialized societies such as the United States, considerable
amounts of cadmium enter the environment as a result of the manufacture,
use, or disposal of cadmium-containing products or waste materials. Since
little or no recycling of cadmium occurs, its use is said to be dissipative,
i.e., the amount entering the environment roughly equals the amount produced
or used; and this steady accumulation in the environment is one factor of
considerable concern in assessing the risk associated with cadmium exposure.
The current amount of cadmium entering the environment annually in the
United States is variably estimated at about 2,000 to 5,000 tons, with the
lower figure being based on limited measurements and estimates for 1974
(Sargent and Metz, 1975; Yost et al_. , 1975) and the higher figure being the
most recent data available to the United States Environmental Protection
Agency (U.S. EPA Atmospheric Cadmium: Population Exposure Analysis, 1978).
The latter figure may be higher because its calculation involved the use of
stack-test data rather than mass balances. Of these amounts, about 20
4-4
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percent arose from zinc mining and smelting, 30 percent from industrial use
of cadmium, and the rest from inadvertent sources, i.e., from municipal
incineration of waste materials, fossil-fuel use, phosphate fertilizer use,
and sewage-sludge disposal. Cadmium released into the environment through
such activities can eventually affect humans via contamination of air,
water, or soil. Of particular concern is the entry, from any of these
media, of cadmium into the human food chain as illustrated in Figure 4.1,
and in any consequent increase in exposure of humans to the metal.
Concisely discussed below are estimates of present cadmium levels
encountered in air, water, soil, and food in the United States, along with
major sources of cadmium contributing to existing levels of the metal in
each of those media. Also discussed below are certain trends or factors
that can be reasonably well discerned at this time as being potential
future problems in terms of possibly contributing to increased cadmium
exposures of human populations in the United States.
4.2.1 Ambient-Air levels of Cadmium
Widely varying amounts of cadmium have been detected in air over rural
and urban areas around the world, with specific concentrations depending
mainly on the degree of industrialization of a given region. In regard to
natural background levels of cadmium in the ambient air, levels of atmospheric
cadmium over remote rural areas and many small urban areas are usually very
low and are often non-detectable. For example, numerous air sampling
3
stations in small towns yielded frequent readings of 0.1 ng/m or non-detectable
values for cadmium in the air, as reported as part of the SAROAD data file,
which compiles atmospheric data submitted by states (see EPA Multimedia
Levels Cadmium, 1977, pp. 2-6 to 2-11). Thus, natural background levels
4-5
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NATURAL SOIL CADMIUM
PLUS CADMIUM FROM DUST
FALL, LEACHING, ETC.
AMBIENT AIR
SURFACE AND GROUND
WATER CADMIUM
FOSSIL FUEL
MINING, SMELTING
& MANUFACTURING
SEWAGE SLUDGE
LAND DISPOSAL
FERTILIZERS
MUNICIPAL
INCINERATION
Figure 4-1. Diagrammatic representation of multi-media routes by which cadmium exposure of man can occur after
dissipation of the element into the environment by anthropogenic activities.
-------
3
for atmospheric cadmium appear to be definitely below 0.1 ng/m and may
even be essentially zero in the absence of contributions from man's activities.
In contrast to the above low, frequently non-detectable background
levels of cadmium generally present in air over rural or small urban areas
of the United States, considerably higher concentrations have been observed
in ambient air over larger urban centers or industrialized rural areas. Of
historical interest, among the highest ambient air levels recorded within
3
the United States are readings of 0.12 ug/m obtained in El Paso, Texas in
1964 and 0.300 to 0.489 ug/m3 in Shoshone County, Idaho, in 1974. Other
readings taken in the United States in a 1969 survey ranged from 0.006
3 3
ug/m in San Francisco, California, to 0.036 ug/m in St. Louis, Mo.; and a
survey in 1970 produced comparable results (Friberg et al., 1974). Since
1970, further systematic air monitoring conducted by the EPA across the
United States, yielded results as discussed below. That is, ambient air
levels of cadmium monitored by the EPA National Air Surveillance Network
(NASN), with inputs from state and local agencies, during 1970-1974 are
presented in Table 4-1 (Akland, 1976). The table indicates that the average
annual values for the U.S. cities listed fall mainly within a range of
3
0.001 to 0.020 ug/m , with a number of averages being below the limit of
detection.
Exceptions to the above pattern are found in areas where zinc or lead
mining and smelting is or has been conducted. In particular, values from
3
Idaho and Montana have often been 0.100 ug Cd/m or greater, as reported in
the SAROAD file (U.S. EPA, Multimedia Levels Cadmium, 1977). Faoro and
McMullen (1977), however, assembled a plot of the fiftieth percentile of annual
4-7
-------
Table 4-1. ANNUAL AVERAGE URBAN ATMOSPHERIC CADMIUM CONCENTRATIONS
REPORTED BY NATIONAL AIR SURVEILLANCE NETWORKS, 1970-1974^
(L.D. = Limit of Detection)
Location
An zona
Douglas
Tucson
Colorado
Denver
Connecticut
Bridgport
Waterbury
Georgia
Atlanta
111 inois
Chicago
East St. Louis
Peoria
Indiana
East Chicago
Indi anapol is
Kentucky
Ashland
Covington
Louisiana
Mew Orleans
Shreveport
Ma i ne
Portland
Michigan
Detroit
Grand Rapids
Minnesota
St. Paul
Missouri
St. Louis
Montana
Helena
Station
number
01
01
01
01
01
01
01
01
01
01
02
01
02
01
02
01
01
01
01
01
Cadmium concentration, ua/m
1970
0.0065
0.0102
0.0117
. 251
—
L.D.
0.0067
0.0187
0.0066
0.0108
0.0048b
L.D.
L.D.
L.D.
0.0047
—
0.0060
—
—
1971
0.0251
0.0101
0.0048
0.0210
0.0065
0.0045b
—
0.008b
0.0063
0.0049
0.0184
0.0132
0.0086
L.D.
0.0116
—
0.0155
0.150
4-8
1972 1973
0.0132
0.0045b 0.0045b
— —
0.0057
0.0174 0.0027b
— —
0.00305
0.0052
— —
Q.009b
0.0093
0.003b
L.D.
L.D.
—
L.D.
0.0086
— —
— —
1974
0.0062b
—
0.0139
—
—
0.0056
0.006b
L.D.
—
L.D.
—
—
—
—
—
-------
TabVe 4-1 (cent.)- ANNUAL AVERAGE URBAN ATMOSPHERIC CADMIUM CONCENTRATIONS
REPORTED BY NATIONAL AIR SURVEILLANCE NETWORKS, I970-19743
(L.D. = Limit of Detection)
Location
New Jersey
Camden
Elizabeth
Jersey City
Newark
Perth Amboy
New York
New York City
North Carolina
Winston Salem
Ohio
Cincinnati
Cleveland
Youngstown
Pennsylvania
Al 1 en town
Bethlehem
Hazleton
Philadelphia
Scran ton
Texas
El Paso
Virginia
•j
Lynchburg
Wisconsin
Kenosha
Racine
Station
number
01
02
01
01
01
01
02
01
01
01
01
02
01
04
01
02
01
01
01
1970
0.0063
—
0.0081
0.0125
0.0055b
0.0071
—
0.0086
0.0088
0.0056
0.0081
0.0140
___
—
L.D.
0.0618
0.0135
—
L.D.
Cadmium c
1971
—
0.0167
0.0056
___
0.0128
—
0.0076
—
—
—
0.0042b
0.0191
__-
—
0.0067
—
0.004Qb
L.D.
— — —
oncentration, ujj/m
1972
—
—
0.0124
0.0159
0.0189
0.0060
—
—
—
—
0.0178,
0.0068b
___
0.0057
L.D.
0.0442
L.D.
0.0143
0.0071
1973 1974
—
— —
0.0052
— —
— —
— —
— —
— —
— —
0.0042b 0.0134
0.0068
0.0065
0.0038b
L.D.
0.0206 0.0242
— —
— —
___ ___
aSource: Akland, 1976.
L.D./2 used for computation of annual average.
4-9
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averages for cadmium associated with metal-industry sources at urban sites
during the period of 1965-1974, in order to examine trends in levels of
airborne cadmium in the United States (Figure 4-2); and it may be seen that
there has been a definite large decrease in airborne cadmium emissions from
industrial sources since 1970, with that trend toward lower emission levels
expected to hold for the foreseeable future.
Municipal incineration of waste materials is yet another major source
of cadmium emissions into the ambient air and may actually represent the
single largest source of airborne cadmium exposure in terms of numbers of
people directly affected and amount per year released into the atmosphere
(i.e., about 131 tons annually). That is, it has been estimated that
approximately 50,000,000 people are exposed to cadmium emitted by municipal
incinerators, with the average exposure level being approximately 7 ng/m
(U.S. EPA, Atmospheric Cadmium Population Exposure Analysis, 1978). This
includes cadmium emissions due both to general incineration of wastes and
more specific sewage sludge incineration. It has been estimated, however,
that future trends for cadmium emissions associated with both types of
municipal incineration will not be toward increased emissions overall,
since use of emission controls on the incinerators is expected to offset
possible cadmium emission increases that would otherwise accompany
increased incineration loads (U.S. EPA, Sources of Atmospheric Cadmium,
1978).
A third major source of cadmium input into the atmosphere is the
combustion of fossil fuels. Coal-fired and oil-fired power plants, fuel
oil, diesel oil, and gasoline have all been found to be responsible for
some emission of airborne cadmium. While it is difficult to establish
4-10
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01
.£
3.
UJ
o
o
o
003
002
0008
0004
1 I
I I
I I
I I I I
•A-
_L
-A A-
65 66 67 68
69 70 71
YEAR
72 73 74
i Indicates value below lower discrimination limit.
Figure 4-2. Trends in 50th percentile of annual averages for cadmium associated with metal
industry sources at urban sites (Faoro and McMullen, 1977).
4-11
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specific current atmospheric cadmium levels explicitly associated with
fossil fuel usage, it has been estimated that approximately 59 tons of
cadmium are presently emitted yearly due to fossil fuel combustion, with
approximately 7 tons of that being derived from coal-burning power plants.
A matter of much growing concern is potential increased release of cadmium
into the environment as a result of expected future increases in combustion
of coal in power plants. Such increased utilization of coal is a key
component in the United States effort to increase domestic energy
independence. Workers at the Lawrence Livermore Laboratory have estimated
that an additional one billion tons of coal may be consumed annually by
1990 (Berry and Wallace, 1974). This should be compared to the present con-
sumption rate of 500 million tons annually (Bond et a]_. , 1972). The expected
corresponding emission of cadmium via this fuel utilization, according to
EPA data (U.S. EPA, Sources of Atmospheric Cadmium, 1978), would be 16 tons
annually by 1985 if emissions were controlled only at current levels. Much
of this projected increase in cadmium emissions associated with expanded
coal usage, however, is expected to be offset by expanded use of emission
controls (U.S. EPA, Sources of Atmospheric Cadmium, 1978).
The foregoing estimates projecting that increased cadmium emissions
arising both from municipal incinerators and coal-fired power plants will
be largely offset by widespread use of emission control technology should
be viewed with caution. According to Natusch et al_. (1974) who studied
emissions from eight coal-fired power plants: "Existing particle collection
devices, although highly efficient for the removal of large particles and
thus for the reduction of bulk emissions, preferentially allow the emission
of the smallest, most toxic particles." Furthermore, "estimates of toxic
4-12
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element emissions, based on analyses of undifferentiated fly ash collected
on particle precipitators, grossly underestimate the actual emissions."
This is of special concern in regard to cadmium because cadmium is found to
be most concentrated among the smallest respirable particles emitted from
coal fires and found in fly ash (Natusch et al_., 1974). These small
particles are those that can most easily pass through conventional control
equipment and have the highest deposition in the respiratory tract. These
particles, 1-2 urn in diameter, have 3 to 18 times more of the toxic metals
than fly ash particles >40 urn in diameter. Cadmium has been found to be
enriched in the soil around a coal-fire power plant and also enriched in
plant materials growing in this soil. The soil cadmium content correlates
with the wind pattern of the area as well as the metal content of the coal
burnt in the plant (Klein and Russell, 1973). Thus, not only would increased
cadmium emissions from expanded coal-burning in power plants have an impact
on ambient air levels, but such emissions would also impact secondarily on
ground water and soil levels of cadmium via dust fall from the air.
Putting the United States' air cadmium levels into a broader perspective,
it has been reported (Friberg e_t al. , 1974) that worldwide ambient air
3 3
cadmium levels are generally less than 0.003 |jg/m (3 ng/m ) in rural
3 3
areas, but the yearly average may range as high as 0.050 pg/m (50 ng/m )
in industrialized urban areas. In contrast, at the extreme, weekly or
3 3
monthly averages around 0.50 ug/m (500 ng/m ) have been recorded in the
vicinity of cadmium-emitting industries (Friberg e_t al. , 1974).
4.2.2 Drinking Water
The cadmium found in uncontaminated rural streams is derived from
natural sources and generally contains less than 1 ppb or 1 ug/1 of cadmium
4-13
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(Friberg et aJL , 1971). In some cases, however, that naturally-derived
cadmium is augmented by cadmium from industrial and commercial sources.
Such contamination can occur, for example, as a result of: (1) mining and
smelting operations; (2) other manufacturing processes utilizing mainly
cadmium (as in electroplating operations) or closely associated metals such
as zinc (as in the galvinizing of steel); or (3) industrial waste disposal
(as in the disposal of spent solutions from plating processes). Cadmium
contamination of water also occurs secondarily to the use of phosphate
fertilizers and landspreading of sewage sludge on agricultural land or the
leaching of cadmium from land fill or other disposal sites. It is often
difficult to state with much precision the extent to which any of the above
sources of cadmium may individually contribute to water cadmium levels in
any given geographic region. Nevertheless, industrial and commercial
processes are usually concentrated most heavily in urban areas; it is
therefore not surprising that urban waterways tend to have considerably
higher water concentrations of cadmium than do rural streams. Thus, while
non-polluted rural and city water often contains less than 1 ug/1, cadmium
levels have been found to increase to levels as high as 10 ug/1 as a result
of industrial discharge or use of metal or plastic pipes (Friberg et al.,
1974).
Potable water supplies in the United States have been monitored for
cadmium levels since 1969, when the Community Water Supply Survey was
carried out on 969 water systems by the U.S. Public Health Service (USPHS,
1970). At that time only four out of 2595 distribution samples (Taylor,
1971) exceeded the USPHS drinking-water standard of 10 parts per billion
(ppb) or 10 ug/1. The average drinking-water value was 3 ppb with a
4-14
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maximum level of 0.11 parts per million (ppm). More recent data, through
March, 1975, has been obtained by EPA (U.S. EPA, 1975); and none of the 594
analyses were above the 10 ppb standard. Particular attention in the
recent survey was paid to water systems in which there is soft to "acid"
water (pH 5 to 6) since cadmium and other metal dissolution from plumbing
is more probable with this type of water. Two studies, done in Boston and
Seattle by Deane e_t al. (1976) found no samples in the former locale exceeding
the USPHS standard, while in Seattle 7.0 percent of the homes exceeded this
value (10 ppb). Thus, in general, cadmium in drinking water does not now
appear to contribute significantly to cadmium exposure for most Americans.
There appears to exist, however, a need for more systematic studies to
assess the extent of "pick up" of cadmium in water lines, determined by
simultaneous studies of water supplies and tap water levels.
4.2.3 Soils
Soil levels of cadmium are important to man in terms of the terrestial
food chain, starting with plants. Soil levels in turn reflect both geochemical
and anthropogenic components. In regard to geochemical components, as
suggested in Table 4-2, natural soil cadmium levels in remote areas are
generally less than 0.1 ppm. Some regions, such as east-central Nevada and
the Salinas Valley of California, however, have higher natural levels of
soil cadmium due to higher natural content of native rocks, i.e., basaltic
versus granite rocks (Fleischer et al., 1974). On the other hand, soil
cadmium levels are often also greatly increased by industrial activities,
as is also shown in Table 4-2.
Gowen et al. (1976) compiled urban and suburban cadmium-soil values
for American cities and these tabulations appear in Table 4-3. It may be
4-15
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Table 4.2. CADMIUM IN SOILS
Locality
and type
of soil
U.S.S.R., tundra, podsols,
forest, red earth
Poland, distant from
industrial areas
Wales, Ystwyth Valley
Maryland, Missouri, Ohio,
32 m from highways
Helena Valley, Montana,
18-60 km from smelter
Annaka City, Japan, 900 m
from refinery
Southwest Wales
Lower Fraser Valley,
British Columbia
Poland, industrial areas
Wales, Ystwyth Valley,
contaminated
Maryland, Missouri, ^Ohio,
8 m from highways'*
Helena Valley, Montana,
1 km from smelter
Annaka City, Japan
150-250 m from smelter
900 m from smelter
Poland, 600 m from zinc
metallurgical factory
Southwest Wales, Swansea,
1 .5 km fron contaminated
area
P.'.rt lesvi 1 It? , Oklahoma,
1500 ft from smelter
British Columbia, 15 m
from smelter
Orand Rapids area, Michigan
Residential area
Agricultural area
Indus t rial area
Airport
Number Cadmium content (ppm)
r\ f
O E , .
samples Range Average
Normal soils
40 A, B, and C 0.01-0.07 0.06
horizons
33 0-20 0.04 (max) 0.016
1.0
4 10-15 0.12-0.52 0.26
h h
17 6-10 <0.5-2 1.4
2 40-60 0.3-0.4 0.35
4 0.3-0.5 0.4
33 Surface 0.88
Contaminated soils
67 0-20 0.3-0.8 (max) 0.17-0.28
1.5-3.0
4 0.5 0.90-1.82 1.28
7 0.10 26-160 72
Surface 23-88
5 44
1 0-10 250
1 15-30 110
26
12.5-27.5 450
4 Surface 7.9-95.2 49.0
70 0-5 0.41
91 0-5 0.57
86 0-5 0.66
7 0-5 0.77
Cample-; collected near I'. S . 1, Bel tsvil le, Maryland; Washington-Baltimore
Pirkw.iy, Bladensburg, Maryland; Interstate 29, Platte Citv, Missouri; Seymour Road,
Cine:nnat: , Ohio.
•'These values probablv reflect some contamination.
Source: Adapfed from Fleischer et nl., 1974, Table 6, p. 264. Data collected
from several sources
4-16
-------
Table 4-3. CONCENTRATIONS OF CADMIUM IN URBAN AND SUBURBAN SOILS—1972*
I
>—•
^-J
Cadmium, ppm
SMSA
Des Moines I A
Fitchburg MA
Lake Charles LA
Pittsburgh PA
Reading PA
Number of
samples
59
25
26
10
16
54
51
138
10
41
Urban
Suburban
Urban
Suburban
Urban
Suburban
Urban
Suburban
Urban
Suburban
Arithmetic
mean
0.89
0.28
0.13
0.13
0.36
0.01
1.21
0.90
0.63
0.25
Geometric
mean
0.640
0.124
0.059
0.051
0.015
0.002
0.743
0.454
0.261
0.039
Range
0.1 -
0.00 -
0.00 -
0.00 -
0.00 -
0.00 -
0.00 -
0.00 -
0.00 -
0.00 -
3.56
1.76
0.70
0.38
5.32
0.11
4.95
8.03
1.70
2.45
Percent of
^ positive
detections
100
80
62
60
25
7
98
93
90
44
Source: Gowen et al., 1976.
^Sensitivity 0.5 ppm.
-------
seen that urban areas almost invariably have higher cadmium amounts than
suburban areas. Also, industrialized areas typically have higher levels
than less industrialized regions; Fitchburg, MA, for example, had suburban
and urban values of 0.13 ppm each in comparison to readings of 0.25 and
0.65 ppm for Reading, PA, and values of 0.91 and 1.21 ppm for Pittsburgh,
PA. Consistent with this, in another study, Yost et al_. (1975) found
higher-than-normal (>0.4 ppm) levels of 2.5 or 14.0 ppm in samples obtained
in East Chicago, Indiana.
Significant contamination of soil with cadmium also occurs in certain
rural areas as a result of man's activities. For example, the study of
Munshower (1972) found soil levels varying as a function of distance from a
smelter in East Helena, Montana. The levels ranged from 27.3 ppm (0 to 5.0
cm in depth) at 2.4 km away to 1.5 ppm at 33.8 km away, illustrating well
that cadmium particles in the air can settle to the ground and add measurably
to soil cadmium levels.
Also, agricultural use of land adds to the soil-cadmium burden. In
that regard, a significant contribution comes from phosphate fertilizers,
with cadmium values varying from 0.15 ppm in untreated soils to 3.38 ppm in
lands dressed with phosphate fertilizers. Another practice that could
contribute significantly to soil cadmium levels in agricultural land,
however, is the increasing use of landspreading of municipal sewage sludge
and other cadmium-containing materials on commercial crop lands; and this
is a matter of considerable concern for several regulatory agencies such as
the EPA and FDA.
The reason for concern about increased spreading of sewage sludge on
agricultural land is the fact that the cadmium content of such sludge has
4-18
-------
been found to range from a few ppm to several thousand ppm; indiscriminate
increased usage of sludge for fertilization of croplands could therefore
result in a major new source of contamination of foodstuffs and significant
increases in dietary cadmium exposure of the general population. The
magnitude of the current and potential future sludge problem is illustrated
by the data contained in Table 4-4.
Table 4-4 shows amounts of sewage sludge containing varying concen-
trations of cadmium that have been disposed of by certain United States
cities, including by landspreading on agricultural land. The information
listed in the table is based on data compiled by the EPA Office of Solid
Waste Management in 1976 and reported in two separate sources, i.e., EPA
Multimedia Levels Cadmium (1977) and Impact of Annual Cadmium Application
Rates on Current Municipal Sludge Landspreading Practices (1978). The
sludge production from the cities listed in Table 4-4 totals 3706 dry mt/day
produced, and approximately 672 dry metric tons (mt) per day were reported
as being agriculturally landspread, which represents about 25 percent of
the sludge generated. It is important to note, while many municipalities
produce sludge with relatively low cadmium content (less than 10-15 ppm),
many other towns and cities produce sludges containing cadmium levels in
excess of 100 ppm (100 mg/kg). Low cadmium content sludge, however, is
not the only kind spread on agricultural land. Some sludges having
cadmium contents in excess of 100 ppm have been used. For example, one
town was reported as having landspread its daily production of 2 dry
mt/day of sludge, with a cadmium content of 3171 ppm, on agricultural
land. Also, from among the 41 "unknown" cities which produce sludges
with cadmium concentrations of 1-970 ppm, ten cities were reported as
4-19
-------
Table 4-4. AMOUNTS OF MUNICIPAL SEWAGE SLUDGE OF VARYING CADMIUM CONTENT ANNUALLY PRODUCED
BY MAJOR U.S. CITIES AND DISPOSED OF BY VARIOUS METHODS*
CITY
New York, N.Y.
(Metropolitan area)
Hampstead-Bay Park
Long Beach
Bowery Bay
Coney Island
Humts Point
Jamaica
Newton Creek
Owls Head
Port Richmaon
Rockaway
Tallmans Island
26th Ward
Wards Island
Hampstead-West
Long Beacti
Yonkers
Chicago, 111.
North Side
Calumet
Hanover Park
Lemont
W. Southwest
Los Angeles , Cal .
(City & County)
Philadelphia, Pa.
N.E. Plant
S.W. & S.E.
YEAR
1975
1975
1975
1975
1975
1975
1975
1975
1975
1975
1975
1975
1975
1975
1975
1976
1976
1976
1976
1976
1976
1976
1976
SLUDGE CADMIUM, QUANTITY
(ppm) (SLUDGE)
6 - 163 228
70
18
47
8
18
4
71
18
3
16
6
17
6
4
163
10 - 210 518
180
42
10
16
210
120 127
60 295
90 168
25 14
PRESENT TOTAL SOURCE OF
DISPOSITION LANDSPREAD INFORMATION*1
Ocean — I.D.
8
8
8
ii
it
n
ii
n
n
"
n
n
n
n
n
Land application 182 4
Give away "
n
n
n
I.D.
Ocean I.D.
Sale for compost "
Ocean 4
Compost "
Detroit, Mich.
290
145
Incineration
-------
Table 4-4. (continued).
CITY
Houston, Tex.
North Side
Simir.s
Baltimore, Md.
Back River
Patapsco
Dallas, ~[f>y.
Washington, D.C.
Cleveland, Ohio
Southerly
Westerly
Indianapol is, Ind.
Belmont
Southp^rt
Milwaukee, Wis.
Jones Island
South Shore
San Francisco area
Boston, MA
Denver, CO
Seattle, WA
Atlanta, GA
YEAR
1972-73
1976
1976
1976
1975
1972-73
1975
1973-75
1972-73
1972-73
1972-73
SLUDGE CADMIUM,
(ppm)
112
17
22
25
7
9
59
22
390
578
240
260
444
107
50
15
82
46
64
101
QUANTITY
(SLUDGE)
91
112
32
330
14
114
148
82-171
45
2
78
64
33
20
PRESENT TOTAL
DISPOSITION LANDSPREAD
Head dried for
brokerage sale
Landfill
Lagoon
Landfill,
Compost
Landfill
Incineration,
Land application
Miloganite-soil 82
conditioner
Landfill,
Land application
Ocean
Land application 64
Landfill,
Soil conditioner
Landfill or
SOURCE OF
INFORMATION3
6
9
I.D.
4
II
II
9
3
4
II
1)
It
6
4
2
5
6
II
soil conditioner
-------
Table 4-4. (continued).
I
ro
CITY
Newark, NJ
Unknown
Miami, FLA
Tampa, FLA
Unknown
Little Ferry, NJ
Unknown
Unknown
Grand Rapids, MI
Flint, MI
Syracuse, NY
Madison, WI
Unknown
Warren, MI
Unknown
Unknown
Macon, GA
Elizabeth, NJ
YEAR
1975
1972-73
1975
1975
Prior to 1974
Prior to 1974
1972-73
Prior to 1974
1976
1975
SLUDGE CADMIUM,
(ppm)
173
19
149
10
11
240
9
13
480
20
200
73
160
110
100
5
6
72
QUANTITY
(SLUDGE)
104
45
15
9
30
38
23
23
23
23
22
14
18
17
14
14
15
25
PRESENT TOTAL
DISPOSITION LANDSPREAD
Incineration
Agricultural land 45
Soil conditioner
Land application
Agricultural land 30
N.A.
Agricultural land 23
Agricultural land 23
N.A.
N.A.
Solvay process
N.A.
18
N.A.
Agricultural land 14
Agricultural land 14
Land application 15
SOURCE OF
INFORMATION3
8
I.D.
6
7
I.D.
8
I.D.
I.D.
1
1
6
4
I.D.
1
I.D.
I.D.
10
8
-------
Table 4-4. (continued).
CITY
Camden, NJ
Springfield, MO
Saginaw, MI
Pontiac, MI
Kalamazoo, MI
Ann Arbor, MI
Unknown
Unknown
Anderson, IN
Unknown
Unknown
Kokomo, IN
Wyoming, MI
Bay City, MI
Jackson, MI
Unknown
Danville, VA
Muskegon, MI
YEAR
1976
Prior to 1974
Prior to 1974
Prior to 1974
Prior to 1974
1972-74
1972-74
Prior to 1974
Prior to 1974
1976
Prior to 1974
SLUDGE CADMIUM,
(ppm)
601
54
48
12
12
4
10
269
170
176
17
806
14
80
520
7
18
166
QUANTITY
(SLUDGE)
14
13
11
9
9
9
9
9
9
8
8
7
6
6
5
5
5
5
PRESENT TOTAL
DISPOSITION LANDSPREAD
Ocean
Land application 13
N.A.
N.A.
N.A.
N.A.
Agricultural land 9
Agricultural land 9
Land application 9
Agricultural land 8
Agricultural land 8
Lagoon
N.A.
N.A.
N.A.
Agricultural land 5
Agricultural land 5
N.A.
SOURCE OF
INFORMATION9
4
10
1
M
II
11
I.D.
' I.D.
11
I.D.
I.D.
If
1
II
II
I.D.
10
1
-------
Table 4-4. (continued).
CITY
Linden, NJ
Battle Creek, MI
Unknown
Unknown
Unknown
Port Huron, MI
East Lansing, MI
T" Unknown
ro
-pa
Ithaca, NY
Easton, PA
Midland, MI
Unknown
Unknown
Unknown
Columbus, IN
Holland, MI
Ypsilanti, MI
Sayrcville, NJ
SLUDGE CADMIUM,
YEAR (ppm)
1975 65
Prior to 1974 8
683
95
16
Prior to 1974 8
Prior to 1974 G
Prior to 1974 4
1972-73 66
16
Prior to 1974 10
61
38
11
1976 2
Prior to 1974 10
Prior to 1974 166
1975 39
QUANTITY
(SLUDGE)
10
5
5
5
5
4
4
4
4
4
4
4
4
4
3
3
3
61
PRESENT TOTAL
DISPOSITION LANDSPREAD
N.A.
N.A.
Agricultural land 5
Agricultural land 5
Agricultural land 5
N.A.
N.A.
Landfill and agric 2
land
Soil conditioner
Land application
N.A.
Agricultural land 4
Agricultural land 4
Agricultural land 4
Land application 3
N.A. 3
N.A.
N.A.
SOURCE OF
INFORMATION3
8
1
I.D.
I.D.
- I.D.
1
it
ii
6
I.D.
1
I.D.
I.D.
I.D.
10
1
M
3
-------
Table 4-4. (continued).
CITY
Unknown
Hopkinville, IN
Xenia, OH
Unknown
Monroe, MI
Unknown
Marquette, MI
Muskegon Heights, MI
Mt. demons, MI
Trenton, MI
Sault Ste. Marie, MI
Logansport, IN
Traverse City, MI
Adrian, MI
Owosso, MI
Mt. Pleasant, MI
Benton Harbor, MI
Escanaba, MI
YEAR
1976
1976
Prior to 1974
Prior to 1974
Prior to 1974
Prior to 1974
Prior to 1974
Prior to 1974
1972-74
Prior to 1974
Prior to 1974
Prior to 1974
Prior to 1974
Prior to 1974
Prior to 1974
SLUDGE CADMIUM,
(ppm)
12
18
80
7
8
10
2
150
12
8
2
663
10
260
1,100
14
220
10
QUANTITY
(SLUDGE)
3
3
3
3
3
3
3
3
3
3
2
3
2
2
2
2
2
2
PRESENT TOTAL
DISPOSITION ' LANDSPREAD
Agricultural land 3
Agricultural land 3
Land application 3
Agricultural land 3
N.A.
Agricultural land 3
N.A.
N.A.
N.A.
N.A.
N.A.
Land application
N.A.
N.A.
N.A.
N.A.
N.A.
N.A.
SOURCE OF
INFORMATION3
I.D.
10
10
I.D.
1
I.D.
1
"
"
"
"
11
1
"
"
«
n
"
-------
Table 4-4. (continued).
CITY
Dixon, IL
Frankfort, IN
Las Virgenes CA
Unknown
Peru, IN
Crawfordsville, IN
Unknown
Iron Mountain, MI
Albion, MI
Unknown
Unknown
Unknown
Niles,, MI
Grand Haveni, MI
•j.
Me nominee, MI /-* '
Cadillac, MI
Lebanon, IN
Noblesville, IN
YEAR
1976
1976
1976
1972-74
1972-74
Prior to 1974
Prior to 1974
Prior to 1974
Prior to 1974
Prior to 1974
Prior to 1974
1972-74
1972-74
SLUDGE CADMIUM,
(ppm)
16
3,171
5
8
164
15
168
6
48
16
9
19
11
14
4
36
40
12
QUANTITY
(SLUDGE)
2
2
2
2
2
2
2
2
2
2
2
2
2
2
1
1
1
1
PRESENT
DISPOSITION
Land application
Land application
Land application
Agricultural land
Land application
Land application
Agricultural land
N.A.
Agricultural land
Agricultural land
Agricultural land
Agricultural land
N.A.
N.A.
N.A.
N.A.
Agricultural land
Land application
TOTAL
LANDSPREAD
2
2
2
2
2
2
2
2
2
1
SOURCE OF
INFORMATION3
10
11
11
I.D.
11
11
I.D.
1
11
I.D.
I.D.
I.D.
1
n
n
"
11
n
-------
Table 4-4. (continued).
CITY
SLUDGE CADMIUM, QUANTITY PRESENT
YEAR (ppm) (SLUDGE) DISPOSITION
TOTAL
LANDSPREAD
SOURCE OF
INFORMATION6
I
ro
Marshall, MO
Wilmington, OH
Unknown
Unknown
Charlotte, MI
Ironwood, MI
Hancock, MI
Three Rivers MI
Chippewa Falls, WI
Litchfield, IL
Kendallville, IN
Unknown
Unknown
Unknown
Unknown
Marshall, MI
Gladstone, MI
Howell. MI
1976
1976
Prior to 1974
Prior to 1974
Prior to 1974
Prior to 1974
1976
1976
1976
1976
Prior to 1974
Prior to 1974
16
15
7
1
14
4
4
44
7
6
28
22
18
970
16
16
4
18
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
Land application
Agricultural land
Agricultural land
Agricultural land
N.A.
N.A.
N.A.
N.A.
Land application
Land application
Land application
Agricultural land
Agricultural land
Agricultural land
Agricultural land
N.A.
N.A.
N.A.
1
1
1
1
1
1
1
1
1
1
1
10
11
I.D.
I.D.
1
"
ii
"
10
ii
n
I.D.
I.D.
I.D.
I.D.
10
1
1
-------
Table 4-4. (continued).
CITY
Manistique, MI
Tipton, IN
Unknown
Unknown
Mil ford, MI
Essexville, MI
Norway, MI
^*
\> St. Ignance, MI
Unknown
Unknown
Unknown
Constantine, MI
Dexter, MI
Lanse, MI
Unknown
SLUDGE CADMIUM,
YEAR (ppm)
Prior to 1974 4
1972-74 11
10
9
Prior to 1974 2
Prior to 1974 4
Prior to 1974 2
Prior to 1974 4
7
23
8
Prior to 1974 16
Prior to 1974 36
Prior to 1974 8
13
QUANTITY
(SLUDGE)
1
1
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
15
0.3
PRESENT TOTAL
DISPOSITION LANDSPREAD
N.A.
Land application
Agricultural land 0.5
Agricultural land 0.5
N.A.
N.A.
N.A.
N.A.
Agricultural land 0.5
Agricultural land 0.5
Agricultural land 0.5
N.A.
N.A.
N.A.
Agricultural land 0.3
SOURCE OF
INFORMATION3
"
11
I.D.
I.D.
1
11
11
n
I.D.
I.D.
I.D.
1
n
ii
I.D.
-------
Table 4-4. (continued).
CITY
SLUDGE CADMIUM, QUANTITY PRESENT
YEAR (ppm) (SLUDGE) DISPOSITION
TOTAL
LANDSPREAD
SOURCE OF
INFORMATION0
TOTAL Named Cities
(N =61) 2 - 3,171
TOTAL Unknown Cities
(N =40) 1 - 970
TOTAL CITIES
(N = 101) 1 - 371
2 - 3,171 3,423
1 - 970 283
1 - 371 3,706
3,706 = 30% of sludge
generated in U.S.
391
281
672
672 = 25% of sludge
agriculturally landsptead
ro
ID
Sources of Information:
1. Blakeslee, Paul A. 1973. "Monitoring Considerations for Municipal Wastewater Effluent and Sludge Application
to the Land," Recycling Municipal Sludges and Effluents Joint Conference, Champaigne II.
2. Brown and Caldwell. 1975. San Francisco Bay Area Municipal Wastewater Solids Management Study (May 1975).
3. Camp, Dresser, and McKee. 1975. Alternative Sludge Disposal Systems for the District of Columbia Water
Pollution Control Plant at Blue Plains (December 1975).
4. Ehorn, Douglas. Personal communication. EPA-Region V; and Albert Montague, EPA-Region III. 1976.
5. EPA, Region I Office, Solid Waste Staff communication. 1976.
6. Furr, A.K., et aJL 1976. Mutielement and Chlorinated Hydrocarbon Analysis of Municipal Sewage Sludges of
American Cities. Journal of Environmental Quality (July 1976).
7. Greeley and Hansen. 1975. Report on Management and Disposition of By-Product Solids Hookers Point Sewage
Treatment Plant, City of Tampa, Florida (June 1975).
8. Interstate Sanitation Commission. 1975. Phase One Report of Technical Alternatives to Ocean Disposal of
Sludge in New York City. By Camp, Dresser, and McKee for New Jersey Metropolitan Area (1975).
9. Public Works Directors. (N.D.) Personal Communication.
10. SCS Engineers. 1976. Environmental Assessment of Municipal Wastewater Treatment Sludge Utilization
Practices. EPA Contract NO. 68-01-3265. Work ongoing.
11. Sommers, L. E. , D. W. Nelson, and K. J. Yost. 1976. Variable Nature of Chemical Composition of Sewage
Sludges. Journal of Environmental Quality. 5(3).
I.D.: Impact of Annual Cadmium Application Rates on Current Municipal Sludge Landspreading Practices, EPA, 1978.
Chicago is planning to landspread by opting for the "crop monitoring" approach allowed under proposed sludge criteria
Register, Monday, February 6, 1978, Part II, Vol 43, No. 25; Pg. 4954 - 4955).
-------
producing 70 dry mt/day of sludge with cadmium content above 25 ppm that
was agriculturally landspread. Other data discussed below under "Food"
as a source of cadmium exposure provides a perspective on the implications
of agricultural spreading of sewage sludge with varying cadmium concen-
trations, and phosphate fertilizers as well, for consequently increased
soil and crop cadmium content.
4.2.4 Food
Cadmium contamination in air, water, and soil not only affects man
directly through contact with those media, but also through the infiltration
of the metal from those sources into man's food chain. No effort will be
made here to trace in detail cadmium's transport via the food chain to man.
It should be noted, however, that man depends on five major categories of
food sources: (1) land plants, (2) land animals and animal products, (3)
freshwater fish, (4) marine fish and free-moving crustaceans, and (5) shell
fish.
Incorporation of cadmium into the above dietary food elements appears
to occur through a variety of mechanisms, with several sometimes operating
simultaneously. From among such mechanisms listed by EPA's recent assessment
(Multimedia Levels Cadmium, 1977), the following appear to be of most
importance:
(1) Uptake from soils by roots of food plants. This may occur:
a. Naturally where cadmium is a normal constituent of soils.
b. As an impurity (cadmium oxide) in phosphate-treated
soils, especially with "superphosphate" fertilizer use.
c. In soils fertilized by sewage sludge containing cadmium.
4-30
-------
d. By soil contamination from runoff of mine tailings or
from electroplating washing process.
(2) Meat animals may accumulate cadmium in liver and kidney from
feed crops that take up the metal from contaminated and naturally
high-cadmium content soil.
(3) Mollusks and crustaceans normally concentrate cadmium from ambient
waters, as do most other aquatic organisms.
Oral ingestion of food probably represents the single most important
source of cadmium in man, especially in non-smokers. It may, in part, also
represent a secondary exposure from airborne cadmium to the extent that
airborne cadmium probably contributes some amount of the metal to food via
deposition in water and on land from which food crops and animals are obtained.
No thorough analysis of the contribution of airborne cadmium to food will
be attempted here, but it should be kept in mind in considering the information
that follows. Another issue not addressed in detail here, but important
for putting the present discussion into perspective, is that of how much of
the cadmium eventually showing up in food is derived from naturally occurring
sources and how much accumulates secondarily from man's industrial and
waste-disposal activities.
In EPA's recent analysis (Multimedia Levels Cadmium, 1977) it was
noted that foods average about 0.05 ppm cadmium (wet weight), but there is
wide variation across different food items, with maximum concentrations depending
on the source from which they were obtained. The amounts found in
different food categories in the U.S.A. in the late 1960's were reported
by the United States Food and Drug Administration (FDA) to be as indicated
in Table 4-5, as estimated from several studies (Corneliussen, 1970;
4-31
-------
Table 4-5. CADMIUM CONTENT IN DIFFERENT FOOD CATEGORIES IN THE U. S. A.
a,b
Cadmium, ug/g wet weight
Type of food
Dairy products
Meat, fish, and
poultry
Grain and cereal
products
Leafy vegetables
Legume vegetables
Root vegetables
Garden fruits
Fruits
Oils, fats, and
shortening
Sugar and adjuncts
Beverages
Potatoes
1968-1
No. >0.01
10
21
27
27
16
24
25
15
27
13
8
—
969
Maximum
0.09
0.06
0.08
0.08
0.03
0.08
0.07
0.04
0.13
0.07
0.04
--
1969-1
No. >0.01
9
22
27
28
10
27
27
10
28 .
9
9
29
970
Maxi mum
0.01
0.03
0.06
0.14
0.04
0.08
0.07
0.07
0.04
0.04
0.04
0.08
Source: Corneliussen, 1970; Duggan and Corneliussen, 1972.
•"Cadmium was analyzed by atomic absorption and/or polarography at a
sensitivity of 9.01 ug/g.
4-32
-------
Duggan and Corneliusson, 1972). Concentrations of cadmium found more
recently by FDA in adult foods are seen in Table 4-6 (U.S. Dept. of Health,
Education and Welfare, 1975). Adult foods consistently found in the surveys
to have high levels of cadmium are: beef liver, hamburger, leafy vegetables,
root vegetables, potatoes, grains and cereal products, and refined sugar
products. Relatively high standard deviations for virtually all foods
listed in Table 4-6, however, also suggest that quite high concentrations
can be found in some samples of nearly every food type.
Estimates by the FDA of the contribution of different foodstuffs to
daily adult dietary intake are shown in Tables 4-7 and 4-8, and the percentages
of total daily cadmium intake estimated to be obtained via ingestion of
different food groups are illustrated in Figure 4-3. As seen there, most
of the food groups listed above as high in cadmium constitute major portions
of the typical adult diet and contribute the largest percentages of daily
dietary cadmium intake.
A matter of considerable interest is the estimation of daily dietary
intake for Americans. Noteworthy in that regard are results from Total
Diet Studies (market basket) surveys conducted by the FDA over a seven year
period (1968-1974). As shown in Tables 4-7 and 4-8, cadmium intake from
all food groups varied somewhat from year to year (totaling 36 and 51
ng/day for the two years shown in the tables for the "typical" teenage
American male). The average of the median levels obtained over the seven
year survey period was 33 (jg/day, while the seven-year average of the means
was 72 ug (U.S. Dept. of Health, Education and Welfare, 1975). This suggests
that most individuals have intake levels below 30 to 50 ug/day, but some
may have intakes substantially above 70 ug/day.
4-33
-------
Table 4-6. CADMIUM CONTENT OF SELECTED ADULT FOODS3
Commodi ty
Carrots, roots fresh
Lettuce, raw crisp head
Potatoes, raw white
Butter
Margarine
Eggs , whole fresh
Chicken fryer, raw
whole or whole cut up
Bacon, cured raw, sliced
Frankfurters
Liver, raw beef
Hamburger, raw ground beef
Roast, chuck beef
Wheat flour, white
Sugar refined, beet or cane
Bread, white
Orange juice, canned frozen
concentrate
Green beans , canned
Beans, canned with pork and
tomato sauce
Peas, canned
Tomatoes, canned
Diluted fruit drinks, canned
Peaches, canned
Pineapple, canned
Applesauce, canned
No. of
samples
69
69
71
71
71
71
71
71
69
71
71
71
71
71
70
71
71
71
71
71
71
71
71
71
Average,
ppm
0.051
0.062
0.057
0.032
0.027
0.067
0.039
0.040
0.042
0.183
0.075
0.035
0.064
0.100
0.036
0.029
0.018
0.009
0.042
0.042
0.017
0.036
0.059
0.020
Standard
Deviation,
ppm
0.077
0.124
0.139
0.071
0.048
0.072
0.088
0.160
o.m
0.228
0.122
0.034
0.150
0.709
0.063
0.095
0.072
0.000
0.113
0.113
0.052
.0.061
0.153
0.027
a
Source: U.S. Department of Health, Education, and Welfare, 1975,
4-34
-------
CO
Table 4-7. FOOD GROUPS BY MEAN CADMIUM CONTENT AND THEIR CONTRIBUTION
TO DAILY CADMIUM INTAKE3
Food group
Leafy vegetables
Potatoes
Fruits
Grains and cereals
Oils, fats, and shortening
Root vegetables
Garden fruits
Meats, fish, and poultry
Sugars and adjuncts
Legume vegetables
Beverages
Dai ry
Concentration, ppjn
Mean
0.051
0.046
0.042
0.028
0.027
0.021
0.019
0.0093
0.0083
0.006
0.0057
0.005
Cadmium
1 ntake
y g/day
3.18
9.11
9.38
11.66
1.36
0.76
1.71
2.49
0.68
0.42
6.49
3.94
Percent of
total
dai ly diet
2.0
7.0
7.4
12.6
1.8
1.2
3.0
9.9
2.8
_ h
23.9
25.9
Contribution to
daily cadmium
intake, %
6.2
17.8
18.3
22.8
2.7
1.5
3.4
4.9
1.3
0.8
12.7
7.7
Source: Mahaffey et al., 1975,
'includes water.
-------
MEAT, FISH, AND
POULTRY
(4.9%)
LEGUME
VEGETABLES
(0.8%)
ROOT VEGETABLES
(1.5%)
GRAIN AND CEREAL
PRODUCTS
(22.8%)
POTATOES
(17.8%)
DAIRY PRODUCTS
(7.7%)
BEVERAGES
(12.7%)
LEAFY
VEGETABLES
(6.2%)
FRUITS
(18.3%)
SUGAR AND
ADJUNCTS
(1.3%)
GARDEN FRUITS
(3.4%)
OIL, FATS AND
SHORTENINGS
(2.7%)
Figure 4-3. Contribution of food groups to cadmium intake.
From: Shibko and Braude (1978)
4-36
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Table 4-8. CADMIUM INTAKE OF TEEN-AGE MALES BY FOOD CLASS3
Food class
Dairy products
Meat, fish, poultry
Grain and cereal products
Potatoes
Leafy vegetables
Legume vegetables
Root vegetables
Garden fruits
Fruits
Oils, fats, shortening
Sugars and adjuncts
Beverages (including
water)
Average
consumed
g/d
704
262
424
177
54
66
32
88
222
72
83
684
Cadmi urn*
residue
ppb
5.7
15.3
23.3
48.0
40.5
6.3
32.3
14.7
3.0
15.3
10.0
3.0
Cadmi urn
intake
ug/d
4.0
4.0
9.9
8.5
2.2
0.4
1.0
1.3
0.7
1.1
0.8
2.1
Total
2868
36
*Trace values assumed as 10 ppb.
From U.S. Dept. of Health, Education and Welfare. "Compliance
Program Evaluation, FY '74 Total Diet Studies (7320.08)". Food
and Drug Adm., Bureau cf Foods, 1975.
4-37
-------
Also of interest in regard to the issue of daily cadmium intake in the
diet of the U.S. population are the results of a recent collaborative
study, which was carried out jointly in the United States, Sweden and Japan
(Kjellstrom, 1978) and included measurement of daily fecal cadmium excretion
for human volunteers in each country. Based on observed fecal cadmium
values, which may better reflect actual dietary cadmium intake than the
above "market basket" surveys, adult dietary intake of cadmium in the U.S.
population was reported to average approximately 18 ug/day for non-smokers.
This arithmetic mean intake, however, was associated with a relatively
large standard deviation of ± 8 ug, indicating that diets vary considerably
among members of the U. S. population in terms of cadmium content. In
fact, based on the observed distribution, the intake of a significant
number of individuals (over 2.5 percent) exceeds 32 ug/day and for some
reaches or exceeds 40 to 50 ug/day. It thusly appears that an average daily
dietary cadmium intake for Americans can reasonably be estimated to be
within the range of 10 to 50 ug/day; however, it is also clear that significant
numbers of individuals exceed 50 ug/day level of intake, as indicated by
both the "market basket" survey results reported by FDA and the "fecal
excretion" studies discussed here.
While the above estimates are among the best available for current
levels of daily dietary cadmium intake, they may not be accurate indicators
of future American dietary exposure to cadmium. Rather, increased amounts
of dietary cadmium can be expected to be ingested in the future if use of
high cadmium-containing phosphate fertilizers on U.S. crop lands is expanded
and as a consequence of uncontrolled landspreading of cadmium-contaminated
sewage sludge on agricultural land.
4-38
-------
Several studies provide important information on the likely impact of
cadmium loading of agricultural land on soil and crop cadmium contents.
For example, at a 1 kg/ha cadmium application rate, Dowdy and Larson (1975)
found that lettuce cadmium increased five-fold compared to control levels,
while carrots, radishes, and potatoes showed a two-fold cadmium increase
and sweet corn leaves and grain increased from 0.26 to 1.32 ppm cadmium
and from 0.02 to 0.05 ppm cadmium, respectively. In a similar study,
Clapp et aj[. (1976) showed that, at a 5.1 kg/ha cadmium loading rate on sandy
soil in Minnesota, the cadmium content of field corn leaves normally fed to
livestock increased five-fold, but the corn grain levels were not changed.
Maclean (1976) applied 0, 2.5, and 5.0 ppm cadmium (approximately 0,
5.5, and 11 kg Cd/ha) to Grenville loam soil with a neutral pH of 7.1 and
observed the effect on cadmium uptake by several vegetables and field
crops. The results obtained are shown in Table 4-9 and indicate that many
vegetables and root crops increased their cadmium uptake by five-fold at
the 5.5 kg/ha cadmium application rate. At the same application rate, oats
and soybeans, as intermediate cadmium accumulators, increased their cadmium
content by six-fold, while tobacco and lettuce, as high cadmium accumulators
like Swiss chard, had more than 10-fold increases in cadmium.
When soil pH is taken into account, then even more striking effects of
cadmium loading on crop uptake of the metal are seen. Specifically, the
uptake of cadmium by many plants is dramatically increased by acidic soils,
as illustrated in Figure 4-4 for Swiss chard. The practical consequences
of this for indications of sewage-sludge landspreading on agricultural land
are well demonstrated by the data in Table 4-10 showing the results of
studies on field sites that received sewage-sludge treatment for several
4-39
-------
Table 4-9. CADMIUM CONTENT OF SEVERAL CROPS AND
TISSUES. AS A FUNCTION OF CADMIUM LOADING. OF SOIL3
Cd Content of Crop Tissue, ppm
Crop
Timothy
Alfalfa
Corn
Oat
Oat
Soybean
Soybean
Tomato
Tomato
Potato
Potato
Carrot
Carrot
Lettuce
Tobacco
Tissue
Tops
Tops
Tops
Straw
Grain
Veg.
Grain
Veg.
Frui t
Tops
Tubers
Tops
Roots
Tops
Tops
Added
0
0.21
0.28
0.22
0.29
0.21
0.71
0.29
0.51
0.23
0.53
0.18
0.46
0.24
0.66
0.49
Soil Cd,
2.5
1.04
1.34
1.84
2.30
1.50
3.95
1.88
5.26
0.99
3.46
0.89
5.66
2.53
7.72
5.41
opm
5.0
1.41
1.72
2.68
3.70
2.07
4.88
2.51
6.46
1.03
7.35
1.09
7.70
2.65
10.36
11.57
a(From Maclean, 1976) Grenville loam pH = 7.1
4-40
-------
°/\- ACID SOIL (pH 4.5-5.5)
NEUTRAL SOIL (pH 6.6-7.4)
0 1 2
CADMIUM ADDED TO SOIL, ppm
Figure 4-4. Effects of soil pH on cadmium uptake by vegetables.
From: Lucas, Pahren, Ryan and Dotson (1978)
4-41
-------
Table 4-10. Cd CONTENT OF SOILS AND CROPS GROWN ON ACID AND LIMED SLUDGED SITES*
4^
ro
City Sludged
1 1967-75
1967-75
No
No
4 1962-75
1962-75
No
No
9 1961-73
1961-73
No
No
13 1967-74
1967-74
No
No
Limed
No
Yes
No
Yes
No
Yes
No
Yes
No
Yes
No
Yes
No
Yes
No
Yes
PH
5 08
6.15
5.75
6.54
5.36
6.22
5.91
6.64
4.92
6.26
4.93
6.31
5.70
6.37
5.22
6.21
__Qni 1 .
Total
3 30
3.42
0.15
0.14
1.06
0.97
0.20
0.20
2.75
2.88
0.30
0.18
9. 5U
6.79
0.14
0.13
DTPA
2 07
1.98
0.06
0.06
0.64
0.52
0.10
0.07
1.29
1.22
0.15
0.09
6.30
3.70
0.09
0.07
Lettuce
leaf
— ppm—
17 53
7.52
1.07
0.45
4.00
1.36
0.84
0.71
20.41
4.64
1.61
0.63
49.86
9.91
1.47
0.58
Swiss Chard
D. W.D.
ppm
9ft n3
14.03
0.58
0.34
2.29
0.89
0.45
0.15
37.09
2.90
**
0.78
46.16
11.02
1.30
0.41
?3 1ft
10.43
0.64
**
**
**
**
**
**
**
**
22.96
5.94
0.96
0.45
Soybean
Leaf Grain
ppm
7 OR
1.02
0.24
0.18
0.89
0.43
0.11
0.10
4.93
0.68
0.44
0.17
5.93
0.90
0.34
0.25
n dft
0.37
0.20
0.13
**
**
**
**
1.07
0.38
0.20
0.08
1.50
0.68
**
0.11
Oat
Boot Fodder Grain
ppni
0.37
0.18
0.11
0.11
2.42
0.40
0.25
0.11
6.55
0.61
0.11
0.10
0.59
0.19
0.12
0.09
5.03
0.79
0.50
0.12
10.94
0.86
0.10
0.06
0.23
0.07
0.05
0.04
2.12
0.38
0.22
0.04
3.38
0.54
0.11
0.07
Orchardgrass
1st 2nd
ppm
0.41
0.21
0.30
0.17
1.63
0.56
0.56
0.24
2.31
0.70
0.12
0.06
0.56
0.26
0.57
0.17
1.67
0.66
0.34
0.17
3.69
1.17
0.17
0.16
Source:
** = No sample due to animal damage
= Crop not grown
-------
years. The actual annual loadings on a kg Cd/ha basis are not known, but
the sludge cadmium content from cities I, 4, 9, and 13 were 100, 22, 169,
and 683 ppm, respectively. Sites for cities 1 and 4 had not received
sludge since 1975 and for 9 and 13 not since 1973 and 1974, respectively,
with the data in Table 4-10 being for crops grown in 1976. Not only do the
results illustrate the importance of soil pH in determining crop uptake of
cadmium, but they also show that cadmium persists in the soil in a form
available for crop uptake even after cessation of sludge spreading. Thus,
where uncontrolled spreading of high cadmium-containing wastes (such as
sewage sludge) on agricultural land occurs, increased dietary ingestion of
cadmium could result from increased cadmium uptake by food crops grown on
those soils in years to come.
Phosphate fertilizers also contain appreciable levels of cadmium as a
contaminant, and their widespread use on agricultural land can constitute a
significant source of cadmium available for uptake by a variety of plants
beyond the naturally occurring trace amounts of the element present in most
soils. Levels of cadmium in phosphate fertilizers used in the United
States domestic consumption can vary considerably from 9 mg/kg (9 ppm) for
Florida phosphate ore to Western ore levels of 130 mg/kg (130 ppm) (EPA,
1974).
Schroeder and Balassa (1963) first suggested that cadmium contamination
of soils from this source might lead to increased uptake of cadmium into
the food chain. A number of other studies have appeared subsequently and
have shown that cadmium uptake from fertilizer into plants is related to a
number of factors such as the amount of phosphate applied, soil type, soil
pH, types of plants grown, and parts of plants intended for foodchain use
4-43
-------
(Williams and David, 1973, 1976; Lee and Keeney, 1975; Miller et al_. , 1976;
Andersson, 1976; Reuss et al_. , 1976).
As expected, soil pH is important in the relative uptake of cadmium
from phosphate treated soils into plants, with increasing pH leading to
reduced cadmium uptake. Soil type as measured by cation exchange capacity
(CEC) appears to be another important factor in transfer of cadmium from
phosphate fertilizer into vegetation grown on it (Miller et a]., 1976).
The relative uptake of cadmium by plants also varies considerably with the
type of plant grown on phosphate-dressed soils, leafy vegetables and grains
showing relatively greater uptake than forage crops (Williams and David,
1973 and 1976; Reuss et al_. , 1978). Andersson (1976), in his studies of
plant-available cadmium in soils, however, has found that soil levels of
cadmium are not likely to be affected if the cadmium content of phosphate
fertilizers is maintained below 8 ppm (mg/kg).
Since phosphate fertilizers and sewage sludge both add to the cadmium
burdens of agricultural land, it would be of interest to consider the
relative quantitative impact of the future intended use of sewage sludge
with current use of phosphate fertilizers.
In Sweden, where sewage sludge use is limited and is regulated at a
maximum permissable level of 15 ppm, the total amount of cadmium in sludge
for 1973 was calculated to be 1260 kg cadmium (Stenstrom and Vahter, 1974),
as compared to a corresponding cadmium total of ca. 10,000 kg cadmium in
phosphate fertilizers.
In the United States, it is much more difficult to compare the relative
impact of these two sources with respect to increasing the soil burden of
agricultural lands. For one thing, it is to be expected that sewage sludge
4-44
-------
use will increase in the future. While the relative growth in phosphate
fertilizer use will probably be less, phosphate fertilizer consumption is
widespread and without the extensive use of controls that will presumably
apply to sewage sludge use (Solid Waste Disposal Facilities: Proposed
Classification Criteria - EPA, 1978).
In this regard, Lee and Keeney (1975) have calculated that in
Wisconsin cadmium added to agricultural land amounts annually to about 2150
kg/year. They also estimate that the potential contribution of cadmium
from waste-water sludges would be ca. 1700 kg/year if all the sludge
produced in Wisconsin were spread on the land. This total volume was
estimated to contain a median cadmium concentration of 18 ppm (dry weight)
in waste originating from 35 municipalities that serve 75 percent of the
sewered population. On a total basis, it would appear that phosphate
fertilizers are a more significant source of cadmium than sewage sludge in
one particular state in the U.S. However, these authors argue that on a
concentration basis, sludge may have the potential for increasing soil
concentrations (mg Cd/kg soil) more significantly because of the much
higher rates of application used. They calculate that, in Wisconsin, 186
years of phosphate fertilizer application would be required to equal a
single 9 metric ton/hectare sewage sludge addition (at an 18 ppm median
cadmium concentration level in the sludge).
There are certain factors which must be kept in mind regarding
phosphate fertilizer as a source of cadmium: (1) the cadmium content of
the phosphate as a function of the source of the phosphate and (2) the
relative absence of any controls on the use of phosphate when compared to
the developing picture of regulation for landspreading of sewage sludge.
4-45
-------
Thus, any change in the sources of phosphate fertilizers with respect to
domestic consumption may alter the total amounts of cadmium introduced onto
agricultural land. Furthermore, the relative lack of any controls on the
use of phosphate fertilizer with respect to increasing the cadmium levels
of crops and other components of the foodchain, i.e., soil pH, types of
soil, and types of plants, suggest that cadmium concentration in the food
chain from this source is likely to continue.
It should be noted that much of the emphasis here on the effects of
addition of materials to agricultural soils that raise soil cadmium levels
is based on an awareness of the extreme difficulty in removing this added
cadmium burden once in place. For example, the Japanese have had little
success in restoring cadmium-contaminated crop land to its former
productive use despite very extreme attempts at chemical debreedment of the
cadmium in the soil (Friberg et al_. , 1974).
4.2.5 Other Sources
Cigarette smoking represents another major source of cadmium intake
for many Americans. In fact, cadmium from cigarettes represents a substantial
additional burden for smokers beyond that derived from food and other
sources, putting smokers at special risk as discussed later. Amounts of
respiratory intake from cigarettes range from 4 to 6 ug from two packs
smoked per day. Amounts obtained from lesser use of cigarettes are shown
in Table 4-11 along with a summary of contributions from other media to
normal retention of cadmium, as reported by EPA (Multimedia Levels Cadmium,
1977). It should be noted that cadmium levels in cigarettes would be
expected to increase greatly in the event of cadmium-containing fertilizers
or sewage sludge being spread on tobacco fields, in view of tobacco being
-------
Table 4-11. MEDIA CONTRIBUTIONS TO NORMAL RETENTION OF CADMIUM'
aSource: Deane et al., 1976.
Based on 0.11 ug per cigarette.
cAssumes a 64 percent retention rate.
Daily retention
Medium Adult
Ambient air x 20 m /d
Water x 1 liter/d
Cigarettes
Packs/day
1/2
1
2
3
Food x 2 kg/d
Exposure level
0.03 vg/m3
1 ppb
ug/day
1.1
2.2
4.4
6.6
50 ug/day
(ug)
0.15
0.09
0.70C
1.41^
2.82C
4.22C
3.0
4-47
-------
one of the most avid accumulators of cadmium among crop plants. Prohibition
of spreading high-cadmium content sludge on tobacco crop land, however, is
expected to occur as part of future EPA regulatory actions (Solid Waste Dis-
posal Facilities: Proposed Classification Criteria-EPA, 1978).
4.3 HEALTH EFFECTS SUMMARY
A wide variety of biological and adverse health effects of cadmium
were described in earlier sections of this report, and the evidence for
them from animal experiments and human epidemiologic studies was evaluated.
At this point in discussing risk assessment it would be useful to summarize
the more important health effects that appear to be of most concern in
cadmium exposure.
Acute effects of cadmium on the lungs are of most immediate concern in
cases of exposure to high levels of the metal via inhalation. Lethal
levels of cadmium depend in part on particle size, form of metal compound
encountered, and other factors. Estimates of LD5Q exposure levels in
o
rats and mice fall around 25 mg/m for 30 min for particle size of 0.2 u;
and, for man, total pulmonary retention of 4 mg of cadmium after acute
inhalation exposure is often fatal. Quite serious adverse effects, e.g.,
the induction of pneumonitis, are found at inhalation exposure levels far
below lethal doses; significant lung impairment in man, for example, has
3
been noted at cadmium-oxide fume levels below 1.0 mg/m .
In situations involving long-term cadmium exposure, especially at low
to moderate levels, cadmium effects on the kidney appear to be among the
most crucial ones, with renal damage currently widely accepted as the
"critical effect" in terms of assessment of requisite exposure levels for
induction of toxic actions of the metal. In fact, proteinuria resulting
4-48
-------
from renal tubular damage is often utilized as a diagnostic sign indicative
of likely cadmium intoxication. Estimations of amounts of cadmium
accumulation in the kidney necessary for the induction of damaging effects
resulting in proteinuria are important for efforts to calculate external
exposure levels from various sources necessary to induce the "critical
effect" of renal damage. Presumably, limiting exposures to levels assuring
protection against renal damage by cadmium would, in essence, provide
protection against any other significant adverse effects as well. This
issue is discussed further in the present chapter under consideration of
dose-effect dose-response relationships.
As stated in the discussion above, renal tubular dysfunction is the
critical effect associated with chronic exposure to cadmium and is also
that effect most relevant for populations at large. Two aspects of cadmium-
induced renal dysfunction which are of paramount significance in any health
risk assessment of cadmium can be framed as questions: 1) Is tubular
proteinuria reversible or irreversible in nature, and 2) regardless of
reversibility or irreversibility, is the presence of tubular proteinuria to
be taken as a significant health effect?
In regard to the first issue, Piscator (1977) has reported data on
eighteen cadmium workers that conclusively demonstrate the persistence of
tubular proteinuria ca. twenty years after cessation of exposure. What is
even more notable is the fact that irreversibility exists even at rela-
tively low initial excretions of protein. Also, Kazantzis (1977) has
reported on his study of six cadmium workers first surveyed in 1961, with
five subjects surviving for the total survey period of 15 years. All
of these workers were presumably exposure free or were in reduced
4-49
-------
exposure settings after the first survey. All members of this study group
displayed persistent tubular proteinuria at the second time point in the
survey. Thus, available data clearly indicate that, for at least some
individuals, cadmiurn-induced renal proteinuria can be irreversible.
As to the issue of renal tubular proteinuria being a significant
health effect, the available evidence strongly indicates that it is indeed
a significant health effect. Here, one can consider both the fact that
tubular dysfunction, i.e., a systemic functional lesion, is itself a
demonstrable impairment of the proper functioning of an organ; and, also,
perhaps more importantly, the onset of tubular proteinuria signals the
precarious status of an organ that has a substantially reduced reserve
capacity for accommodating any additional stress and is functionally on the
way to further, more involved dysfunction. Also, based on the fact that
cadmium accumulation in the kidney occurs over many years and such accumu-
lation does not markedly decay at the onset of tubular dysfunction, it is
logical that tubular dysfunction would not be a transitory event since the
lesioning agent, cadmium, remains at the target site to persist in imparting
damage; nor would this early dysfunction necessarily be the sole extent of
renal injury.
The data of Kazantzis (1977) supports the premise that a kidney already
manifesting tubular proteinuria is at high risk for further functional
complications. Of the six subjects in the survey noted above, one person
developed ostiomalacia and a second suffered from chronic renal stone
problems. All subjects showed persisting hypercalcuria and hypophospha-
turia; of five subjects studied for uric acid clearance, all of them showed
abnormally high clearance. Furthermore, four subjects had aminoaciduria,
4-50
-------
and five individuals had glycosuria. Of these numbers in each category,
uric acid clearance became elevated in three cases after the first survey;
three cases of glycosuria, two cases of aminoaciduria, one case of hyper-
calcuria and one case of hypophosphaturia similarly developed subsequent to
the first survey.
The reader is directed to a discussion of the above issues by clinical
workers in the area of cadmium health effects, as reported in the Proceedings
of the First International Conference on Cadmium, San Francisco, 1977, pp.
243-250.
While the above conceptualization of renal damage being the "critical
effect" associated with cadmium toxicity has much evidence to support it,
it should be noted that certain other evidence from animal studies now
beginning to emerge hints at still other effects possibly occurring as
early signs of cadmium intoxication. This may include, for example,
certain "subtle" hormone effects that likely underlie reductions in plasma
testosterone concentrations seen at cadmium exposure levels too low to
produce signs of renal damage or any severe testicular necrosis. Other
effects that may possibly occur at cadmium exposure levels below those
producing renal damage include: (1) effects on reproduction and develop-
ment, e.g., reductions in birthweights seen after oral exposure of pregnant
animals and having some parallels in reports in the human epidemiology
literature; (2) immunosuppression effects demonstrated to occur in animals
at low oral exposure levels, but not yet confirmed in humans; and (3)
certain mutagenic and carcinogenic effects observed in animal experiments
or human epidemiology studies and for which "no-effect" dose levels have
yet to be established. In regard to the latter types of effects, however,
4-51
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it should be noted that several other working groups assessing the health
effects of cadmium, in addition to the present authors, have concluded that
only presumptive evidence now exists for cadmium having either mutagenic or
carcinogenic effects; and it should be emphasized that such evidence is
mainly based on observations obtained with very high exposure levels.
4.4 DOSE-EFFECT AND DOSE-RESPONSE RELATIONSHIPS OF CADMIUM IN HUMANS
Attempts to quantify the health impact of cadmium on man with regard
to its potential effect on the United States population as a whole are
discussed in this portion of the report. The discussion leans heavily on
empirical data and theoretical approaches. The main concern will be with
chronic exposure situations.
4.4.1 Dose Aspects
Dose, as defined on page 4-3, is taken to mean that amount of cadmium
derived from either external or internal exposure.
The general population of the United States, as elsewhere, receives
its major external exposure to cadmium via inhalation and ingestion. While
estimates of the dietary intake of cadmium in various countries cover a
wide range of values, current estimates of cadmium intake by ingestion in
the United States range from 10 to 50 pg per day per person. Exposure via
ambient air appears to be relatively negligible for the general population,
but since cigarettes contain notable amounts of cadmium, large segments of
the general population are exposed to additional burdens of cadmium via
inhalation due to smoking (see 4.2, Exposure Aspects).
The relative values of various biological materials as internal indices
of cadmium exposure have been reviewed (Friberg et al_. , 1974; Nordberg,
1976). As noted in the metabolism section, blood levels of cadmium after
4-52
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administration to animals show a kinetic profile that includes rather rapid
clearance followed by a slow rise, mirroring hepatic uptake and incorporation
into metallothionein followed by release into the blood stream. Blood-cadmium
values are therefore of little utility in reflecting critical-organ exposure
under chronic conditions.
Urinary cadmium levels are probably more relevant in assessing internal
chronic exposure. The animal studies of Nordberg (1972a, 1972b) and the
human-subject data of Tsuchiya (1972a, 1972b), Johnson et aT_. (1977), and
Elinder et al. (1978) indicate that in the absence of impaired renal-tubular
function there is a correlation between urinary cadmium levels and the main
storage organs for the element.
Hair-cadmium levels have not been shown to reflect well body burdens
of cadmium and, as such, do not presently appear to be a useful exposure
indicator.
4.4.2 Dose-Effect/Dose-Response Aspects
Various adverse health effects that have been associated with cadmium
exposure were described extensively in Chapter 2 and summarized in Section
4.3 of the present chapter. In those previous discussions, the central
focus was on qualitative characterization of pertinent health effects
rather than a thorough quantitative assessment of relationships between
cadmium exposure levels and associated pathophysiological outcomes. The
present section will deal with quantitative aspects of cadmium exposure and
its effects on health. In that regard, two main types of relationships
must be considered: dose-effect and dose-response relationships.
Pfitzer (1976) drew the distinction between effect and response in the
following terms: "Effect" is taken to indicate the variable change due to
4-53
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a dose in a specific subject, and "response" is the number of individuals
showing that effect, i.e., the number of "reactors" and "non-reactors" to
the defined dose and specific effect in a group.
The kidney (kidney cortex) is generally accepted as being the critical
organ for the chronic-exposure effect of cadmium; it is therefore appropriate
to discuss data that define relationships between cadmium exposure and the
effects of cadmium on renal function. In particular, proteinuria is typically
taken as the main biochemical index of renal dysfunction induced by cadmium.
As for indices of cadmium exposure, blood cadmium levels cannot be
used to assess the status of the critical organ in terms of that organ's
direct exposure to the insulting agent. Urinary cadmium is a better index
of overall cadmium exposure, but it is not a sufficiently good indicator of
the extent of functional damage to the kidney to allow it to be a useful
long-term diagnostic indicator of health impairment. Rather, the accumulation
of cadmium in the kidney itself is presently generally accepted to be the
best index of long-term cadmium exposure visa vis the definition of critical
dose level(s) for induction of renal damage. Substantial attempts have,
therefore, been made to define an approximate critical concentration of
cadmium in the human kidney (kidney cortex) above which renal dysfunction
can be expected to occur.
In regard to the definition of a critical concentration of cadmium in
the kidney necessary for the induction of renal dysfunction, a range of
estimates has been reported by different investigators. For example, as
discussed in Chapter 2 of the present document, studies on the rat by Kawai
and coworkers (Kawai and Fakuda, 1974; Kawai et al., 1974) found renal
tubular atrophy and other morphological signs of kidney damage to be associated
4-54
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with a kidney cadmium concentration of 150 ug/g wet weight. In addition,
Nomiyama (1975) reported increased protein excretion in rabbits as
occurring starting at an average kidney cadmium concentration of 200 |jg/g
wet weight, Suzuki (1974) observed proteinuria and increased urinary
cadmium excretion at an average kidney cadmium cortex concentration of 225
ug/g wet weight.
Based on animal data of the above type and certain human autopsy data,
Friberg et al. (1974) have proposed that 200 g/g wet weight of kidney
cortex be considered as the critical concentration for cadmium-induced
renal dysfunction, as indexed by proteinuria; and WHO (1977) and the Sub-
committee on the Toxicology of Metals under the Permanent Commission and
International Association of Occupational Health have tentatively endorsed
this proposal (CEC, 1978). The selection of human autopsy data used to
propose this level, however, has been criticized (Nomiyama, 1977).
More specifically, Nomiyama (1977) has noted that estimates of the
critical concentrations might be more appropriately derived from cases
where proteinuria was the only pathological finding, so that renal cadmium
concentration measurements were less likely to have been affected by
possible reductions in renal cadmium levels from those present at the onset
of renal dysfunction. Such reductions in renal concentrations are known to
occur due to increased outflow of kidney cadmium that commences sometime
after the onset of renal tubular damage. Nomiyama (1977) noted that, from
among the eight (Friberg, 1974) human cases reported with proteinuria
only, renal cortex cadmium concentrations ranged from 21 to 395 ug/g wet
weight, with all but one being at least 150 ug/g and four exceeding 300
ug/g. On this basis and other supporting data derived from studies on
monkeys (Nomiyama, 1977), Nomiyama suggested that 300 ug/g may be a
more accurate estimate than 200 ug/g for the critical concentration of
4-55
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cadmium in renal cortex necessary fur the induction of renal dysfunction as
indexed by proteinuria.
Regardless of whether 200 or 300 ug/g is taken as being the better
estimate of a theoretical critical concentration, it should be remembered
that, in either case, a "typical" threshold cadmium concentration necessary
to induce renal dysfunction is implied; but this may not fully reflect the
wide individual variation in susceptibility for this damage consistently
demonstrated to exist both in human and animal studies.
Given a specific value designated as an estimated critical concen-
tration, it is possible, through the use of a metabolic model, to estimate
the probable level of total cadmium exposure sufficient to produce the
critical concentration in the renal cortex. In that regard, several such
metabolic models have been developed using 200 ug/g (wet weight) in kidney
cortex as the critical concentration.
Table 4-12 tabulates such values as obtained from Friberg et al.
(1974), Nordberg (1974), and Kjellstrom (1976). Note that these values are
based on two estimates of biological half-time of cadmium in kidney cortex:
18 and 38 years. Furthermore, the daily retention values (in ug) or daily
maximum internal doses which are estimated to result in cadmium levels
approaching the critical concentration in kidney cortex are presented as a
function of exposure time. Given the relative amounts of absorption of
cadmium via the respiratory (25 percent) and gastrointestinal tract (5
percent), levels of exposure via either inhalation or ingestion necessary
to reach the critical concentration of 200 ug/g can be calculated. The
inhalation values, are most pertinent for consideration of occupational
exposure situations; they are also of utility in assessing the overall
-------
Table 4-12. CADMIUM EXPOSURE REQUIRED FOR REACHING A KIDNEY CORTEX
CONCENTRATION OF 200 (jg Cd/g USING DIFFERENT ALTERNATIVES
FOR BIOLOGICAL HALF-TIME IN KIDNEY CORTEX AND EXPOSURE TIME3
Levels of cadmium uptake or
retention yielding renal
Basis of calculation
Constant daily
whole exposure
retention during
time
Exposure
time
(yr)
10
25
50
dysfunction,
half-time of:
38 yr
Daily retenti
36
16
10
assuming cadmium
18 yr
on ((jg)
39
20
13
25% pulmonary absorption, 10 m 10
inhaled per work day, 225 work 25
days/year
Food exposure for 50-year-old person 50
(2500 ca/day) 4.5% retention)
(changing caloric intake by age
accounted for)
Industrial air concentration
(ng/nr)
23 25
11 13
Daily cadmium intake
250 360
Corresponding average con-
centration in foodstuffs (ug/g)
Total amount (net weight) 300 g
of food/day 600 g
1000 g
50 0.8
0.4
0.25
1.2
0.6
0.35
Modified from Friberg et al., 1974.
Assumptions: one-third of whole body retention reached kidney and kidney
cortex concentration 50% higher than average kidney concentration. From
Nordberg (1976).
4-57
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validity of the model by comparing predicted with actual occupational-
assessment results. For populations at large, the data for total dietary
intake limits are more important. The values given in the table are 250
and 360 ug for both estimated half-times of cadmium for individuals 50
years of age.
This simple model approach, however, has limitations as pointed out by
Nordberg (1976) and in order to assess its validity, it is obviously necessary
to evaluate the correspondence of results predicted by the model to actual
observed data. That is, it would be useful to compare predicted and actual
exposure values for inhalation of amounts of cadmium resulting in increased
incidence of proteinuria in workers or for ingestion of foodstuffs of known
cadmium content in population groups showing evidence (proteinuria) of
renal dysfunction.
Friberg et al. (1974) concluded that in man lethal, acute exposure to
a cadmium level in air is somewhat less than 5 mg/m for an 8-hr period,
whereas emphysema, a chronic respiratory effect, appears to occur when the
3 3
air level value is about 0.1 mg/m and probably lower (66 ug/m ) in the
case of workers who smoke (Lauwerys et al., 1974). In contrast, Kjellstrom
(1976) has complied data relating estimated air exposure of workmen to
cadmium and the incidence of proteinuria, and it appears that the incidence
of proteinuria is significantly elevated after 10 to 20 years at an occupational
3
air exposure level as low as 50 ug/m .
Kjellstrom (1976) also evaluated epidemiological data for the occurrence
of proteinuria in Japanese populations residing in identified, high-cadmium-
exposure areas. The data in this case are valuable in that, in most cases
the exposure was dietary, and a number of the studies surveyed had measured
4-58
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the cadmium level of the chief dietary component. The results obtained
corresponded well with estimates of 250 to 360 M9/day based on the above
metabolic model. Consistent with Kjellstrom's (1976) findings, a WHO
working group (WHO, 1977) analyzed epidemiological data from Japan and
concluded that an average daily dietary intake of 300-480 ug would cause
the critical level for renal damage to be reached. Lower estimates of
daily dietary intake levels necessary for the critical renal cortex
concentration to be reached, however, have been proposed by others. For
example, the Working Group of Experts for the Commission of European
Communities (CEC, 1978), using two different approaches, arrived at
estimates of 200 and 248 ug/day for nonsmokers. The effect of smoking can
be seen in that the estimate derived for smokers using the first approach,
169 ug/day, was distinctly lower than the 200 ug/day for non-smokers.
Thus far, in the present discussion of dose-effect and dose-response
relationships, we have focused on various modeling approaches used to
define dose-effect relationships. Such approaches, as seen above, both
seek to define a critical concentration of cadmium in the kidney for the
induction of renal dysfunction and, also, "threshold" external exposure
values for either inhalation or ingestion of cadmium that will result, over
long periods of time (10, 25, 50 years), in the critical concentration for
renal dysfunction being reached. They are useful in helping to conceptualize
dose-effect relationships for cadmium-induced renal damage in that: (1)
they provide a theoretical framework within which complex interrelationships
between external exposure doses (via inhalation or ingestion), internal
exposure levels (as indexed by renal cadmium levels), and consequent renal
4-59
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dysfunction (indexed by proteinuria) can be stated in a simplified manner;
(2) also, as such, they provide one means for trying to predict critical
levels of external exposures that would result in the induction of renal
damage in humans; and (3) they allow for empirical verification of their
accuracy in terms of comparison of predicted versus observed values for
pertinent parameters.
The above types of modeling approaches, however, have their limitations,
as noted earlier, and should be viewed visa vis their utility within the
context of what their limitations allow. Among the more crucial points to
be remembered is that such models do not allow for one to adequately take
into account individual biological variation in regard to the relationships
characterized by the models. For example, in calculating external exposure
levels necessary for reaching a certain renal cadmium concentration, average
absorption or retention rates for cadmium intake via inhalation or ingestion
are used. Specific individuals, however, it should be emphasized, have
absorption or retention rates that vary from the average, some being much
lower and others much higher. Thus, a given external exposure level may
produce a relatively low renal cadmium accumulation in one person while the
same exposure level can result in a much higher renal accumulation in
another individual. Similarly, certain renal accumulations could be
associated with renal damage for the most susceptable members of a human
population at levels distinctly lower than those producing such damage "on
the average."
Based on the above considerations, it is, therefore, conceivable that
a relatively low external exposure level could result in a renal cadmium
accumulation for one individual distinctly above the average for a group;
-------
and, also, that renal accumulation, while low in comparison to the average
level necessary to induce renal dysfunction, could nevertheless result in
significant renal damage for the given individual. Conversely, some
individuals, the least susceptable ones in a population, may not experience
renal damage even at exposure levels much higher than the average level
yielding such damage for most members of the population. The existence of
wide variability in individual dose-effect relationships for cadmium-induced
renal damage is hinted at, for example, by the range of renal cortex cadmium
concentrations (21 to 395 ug/g wet weight) reported by Nomiyama (1977) to
be associated with proteinuria, as discussed earlier. It is, therefore,
important in any risk assessment for cadmium-induced renal damage to take
into account such individual variability and to consider what proportion of
a target population will show signs of renal dysfunction at various cadmium
exposure levels. Progress in defining such dose-response relationships has
been accomplished recently, as reported by Kjellstrom (1977).
Kjellstrom (1977) reported a detailed assessment of dose-response in
man involving both calculated and epidemiological data and using renal
tubular dysfunction indexed by p?-microglobulin excretion as the adverse
health effect. In Figure 4-5 are depicted calculated (lines) and observed
(symbols) dose-response relationships for cadmium-induced increase of
urinary p?-microglobulin excretion. It should be noted that the actual
response rates fit rather well with the modeling results, the actual rates
being obtained from three separate study groups. The abscissa expresses
exposure as daily intake of cadmium multiplied by an assumed 50-year period
of exposure, while the ordinate shows both percent population affected and
the corresponding probits. The numerical values besides the lines are for
4-61
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RESPONSE
problts
5- 50
2000 5000 10000 300CO 100000
INDEX
ug/day x yoor$
Figure 4-5. Calculated (lines) and observed (symbols)
dose-response relationships for cadmium-induced increase
(>97.5 percentile of reference group) of urinary ^-micro-
globulin excretion. (From Kjellstrom, 1977)
4-62
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three renal cortex "critical concentration" cadmium values: 150, 200, and
300 [jg/g net weight. If one selects as a critical concentration a renal
cortex value of 200 ug cadmium/g wet weight kidney cortex, the affected
proportions of a population group as a function of daily dietary intake of
cadmium can be predicted as shown in Table 4-13.
The Kjellstrb'm table (4-13) takes into account the varying kidney and
body sizes of Europeans and Japanese and presents the values for a response
rate at age 50. Note that at a dietary intake level as low as 60 ug/day,
average-sized adult Americans would be predicted to show a 1.0 percent
response rate and, by 100 ug/day, approximately 5 percent would be pre-
dicted to exhibit renal proteinuria as indexed by increased Pp"01101"0'
globulin excretion. As Kjellstrb'm has noted (Kjellstrom, 1977), these
predicted dose-response values are based on a number of assumptions which
must be viewed with caution. Given the good agreement seen in Figure 4-5
between predicted and observed values, however, they may be reasonable
estimates of response rates likely to be observed at various average levels
of daily dietary cadmium intake at least at levels above 80 to 100 ug/day
where the largest numbers of observed data points pertain.
Nogawa et al. (1978) also present data on cadmium induced renal
dysfunction which may be used to define dose-response relationships; in
this case excretion of retinol binding protein (RBP > 4 mg/1) was used to
define renal tubular proteinuria. Data on cadmium in rice and RBP in urine
(Table 4-14) showed a consistent increase in renal tubular proteinuria for
every rice cadmium concentration category greater than the controls. Ex-
amining the data on an age basis (50-59, 60-69, and 70+ years), one can see
the effects of cadmium accumulation on the prevalence of renal tubular
4-63
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TABLE 4-13. Food exposure; calculated intakes (y/day)
that may give a certain response rate at age 50.
^ «
Response rate
(proportion) with
renal tubular damage)
0.1%
Europeans, 32
body
weight 70 kg.
1% 2.5%
60 80
5% 10%
100 148
50%
440
Japanese, 24 44 60 76 100 325
body
weight 53 kg.
Gastrointestinal absorption rate 4.8%, Non-smokers (From Kjellstrom (1977)).
4-64
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Table 4-14. PREVALENCE OF TUBULAR PROTEINURIA AND SUSPECTED PATIENTS AMONG ADULTS
MORE THAN 50 YEARS OF AGE IN RELATION TO VILLAGE
AVERAGE RICE CADMIUM CONCENTRATIONS
en
en
Urinary excretion of retinol
binding protein
Village average rice
cadmium concentration
(Mg/g)
Polluted village
0.19 - 0.29
0.30 - 0.39
0.40 - 0.49
0.50 - 0.59
0.60 0.69
Control
Mean
(0.24)
(0.38)
(0.45)
(0.56)
(0.65)
^Number of persons exami
Around 4 mg/li
ter.
Na
1122
413
616
353
140
248
ned.
Greater,
than (±)D
(percent)
4.
7.
5.
13.
30.
1.
55*
02**
84**
03**
00**
21
Greater
than ±c
(percent)
3.
4.
4.
11.
24.
0.
39*
84**
22**
61**
29**
81
Greater
than + Suspected patient
(percent) (percent)
1.
2.
2.
8.
14.
0.
52
66*
76**
50**
29**
40
1.
2.
3.
6.
12.
25
66**
25**
80**
]**
0
t
Tubular proteinuria
amino aciduria
and decreased
TRP%T
(percent)
0.27
0.24
0.97
1.98*
5.71**
0
j Around 8 mg/liter.
Around 16 mg/1
Her.
4- u _ « in
A
u or\n
£ riuiinc, uiu i c man
T Less than 80 TRP%.
* Significant difference (P<0.05) compared with control.
** Significant difference (P<0.01) compared with control.
Source: Nogawa et al. (1978)
-------
proteinuria at every exposure dose level studied (Table 4-15). Thus, at
cadmium levels as low as 0.19 to 0.29 ug/g of rice, statistically signifi-
cant increases in prevalence of tubular proteinuria over that seen with
control levels of cadmium in rice were reported in the oldest age group
studied (i.e., the 70+ group). Dietary rice levels of 0.19 to 0.29 ug/g
can be estimated to result in an equivalent total dietary cadmium intake of
96 to 147 ug/day, based on assumptions and calculations reported by Ryan
(1978).
4.5 POPULATIONS AT RISK TO EFFECTS OF CADMIUM
Population at risk is that segment of a defined population exhibiting
characteristics associated with a significantly higher probability of
developing a condition, illness, or other abnormal status. This higher
risk may result from either greater inherent susceptibility or from
exposure situations peculiar to that group. Inherent susceptibility refers
to some host characteristic or status which predisposes that host to a
heightened response to an external stimulus or agent.
The collective Japanese experience with water- and airborne cadmium
pollution can be cited as one example where many factors placing particular
groups at risk for cadmium-induced renal damage have been identified.
Working back from demonstrated heightened vulnerability in Japanese
subgroups of populations may therefore allow American populations at risk
to be identified as well.
Japan is, to date, the only known location where cadmium exposure
was/is high enough to affect significant groups of the regional population
in those areas of cadmium pollution via water and/or air. In the Japanese
experience with cadmium, the clinical extreme of which is Itai-Itai
4-66
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Table 4-15. PREVALENCE OF TUBULAR PROTEINURIA IN RELATION TO AGE AND
VILLAGE AVERAGE RICE CADMIUM CONCENTRATION
I
O1
--J
Age
Cd in rice
(microgram per gram)
Control
0.19 - 0.29
0.30 - 0.39
0.40 - 0.49
0.50 - 0.59
0.60 - 0.69
Greater than RBP (±)
50
Na
104
477
184
295
140
60
- 59
Percent
0.96
0.84
3.26
1.69
0.71
18. 33**
60
Na
80
377
138
204
120
57
- 69
Percent
2.50
2.65
5.07
6.86
10.83*
24.56**
Na
64
268
91
117
93
23
>70
Percent
0.00
13.81**
17.58**
14.53**
34.41**
73.91**
50
Na
104
477
184
295
140
60
Greater than RBP (±)
- 59
Percent
0.00
0.42
2.72
0.34
0.00
5.00*
60
Na
80
377
138
204
120
57
-69
Percent
1.25
0.80
0.72
2.94
5.00
12.28**
Na
64
268
91
117
93
23
>70
Percent
0.00
4.48
7.69*
8.55**
25.81**
43.48**
Number of persons examined.
* Significant difference (P<0.05) compared with control.
** Significant difference (P<0.01) compared with control.
Source: Nogawa et al. (1978)
-------
disease, the individuals found to be most vulnerable to the effects of
cadmium were post-menopausal women with a history of multiple childbirths
as well as calcium and Vitamin-D deficiency. This hints, in part, at women
in general possibly being at special risk. However, Itai-Itai disease, per
se, has not been observed conclusively in all of the exposure areas in
Japan revealed so far. This finding would also seem to point to
nutritional status as being an important determinant in placing certain
groups at special risk for the adverse health effects of cadmium.
In addition to the above, a consistent finding in most of the
cadmium-polluted areas of Japan has been the factor of age as a determinant
in the prevalence of proteinuria, a measure of renal dysfunction, with
proteinuria being observed most often in groups above 40 years of age.
Thus, older members of any population appear to be more at risk in any
demonstrated or potential cadmium-exposure setting, with those having
nutritional deficits exhibiting the highest risk.
Perhaps even more importantly for present purposes, however, given
that the gradual accumulation of cadmium in the renal cortex over a long
period of time (e.g., 20 to 50 years) is a key factor in inducing renal
dysfunction in humans, then the entire population must be considered as
being at potential risk for such effects over their lifetimes. Thus, as a
starting point, current dose-response relationships for the United States
population in general must be defined. Then, particular groups at special
risk beyond that existing for the general population need to be delineated.
In order to assess the potential impact of various cadmium exposure
situations on the health of the United States population, a dose-response
model must be derived which relates existing American cadmium exposure
4-68
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levels to predicted response rates for renal dysfunction. Of greatest
importance here are considerations of dietary cadmium intake as the single
most important source of cadmium exposure for the general United States
population. In regard to estimates of current daily dietary cadmium intake
for Americans, it was earlier (Section 4.2.4) noted that different estima-
tion approaches indicate that the average daily dietary intake for Americans
presently falls within the range of 10 to 50 (jg/day.
It was also noted earlier (Section 4.4.2) that several different
approaches have been used for estimating dietary intake levels expected to
result in a critical renal cortex cadmium concentration associated with
renal dysfunction being reached over a 50-year exposure period. Using
certain metabolic model approaches, estimates ranging from 200 to 480
ug/day have been generated from nonsmokers; however, values at the lower
end of that range, i.e., 200 to 248 pg/day, have been accepted as the best
estimates by a Working Group of Experts for the Committee of European
Communities (CEC, 1978). If the latter estimates are accurate, then current
average American dietary intake levels of 10 to 50 pg/day would be anywhere
from four to twenty times lower than levels yielding a critical renal
cortex cadmium concentration associated with renal dysfunction. On the
other hand, certain presently available information strongly suggests that
such a large margin of safety does not exist for the most susceptible
members of the general United States population.
More specifically, as discussed earlier under Section 4.4.2, Kjellstrbm's
(1977) modeling of predicted dose-response relationships and actual observed
data confirming the accuracy of the model suggest that as much as 1 percent
of the general United States population may exhibit signs (proteinuria) of
4-69
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renal tubular damage at a daily dietary cadmium intake level of 60 ug/day.
The same model predicts expected response rates of 2.5 percent and 5
percent at dietary intake levels of 80 and 100 ug/day, respectively.
Viewed from this latter perspective, then, current estimated United States
dietary intake levels of 10 to 50 (jg/day would range from being less than
two to about eight times less than intake levels yielding renal dysfunction
for significant portions of the general population as a consequence of 50
years of dietary cadmium exposure.
The above information suggests that some members of the general population
may already have daily dietary cadmium ingestion levels that approach those
likely to yield renal tubular dysfunction in old age (i.e., after a 50-year
exposure period). In addition to this element of risk potentially present
for the general United States population, a distinctly higher level of risk
for cadmium-induced renal dysfunction has been rather conclusively shown to
exist for individuals that smoke cigarettes.
In an earlier portion of this Risk Assessment section (Exposure Aspects,
4.2) the relative contribution of smoking to daily cadmium retention as a
function of increasing cigarette use was tabulated. In Table 4-16, significant
increments in daily retained amounts (daily increase in burden) of cadmium
can be seen to arise from cigarette smoking, the relative values being
particularly striking if one takes 25 ug/day as the average intake arising
from food. Assuming a daily intake of 25 ug, smoking one, two, or three
packs of cigarettes a day furnishes percentages of 40, 62, and 71 percent,
respectively, of daily cadmium retention for smokers. Even in the case
where 50 ug/day is the dietary intake of cadmium, the smoking of two packs
of cigarettes daily roughly doubles the daily total retention. In Table
4-70
-------
Table 4'16. RELATIVE CONTRIBUTION OF CIGARETTE SMOKING
TO TOTAL DAILY CADMIUM RETENTION3
Daily food intake of
Cigarette packs/day
0
1/2
1
2
3
50 yg
0
18
30
47
57
25 uq
0
29
40
62
71
DaHycadtrriurn retention for water and air, 0.24
total. (See Table 4-11.)
4-71
-------
4-17 are given the relative contributions of smoking to total daily cadmium
intake as a function of different ambient air levels and varying dietary
intake levels (25, 50 and 75 ug/day) reflecting current and expected future
intake levels in the United States.
If one now relates these values to the table (Table 4-12) containing
figures for the estimated level of daily retention of cadmium as a function
of exposure time (first part of Table 4-12), above which the critical
concentration for renal dysfunction is reached at the end of the exposure
period, a significant risk among smokers in approaching these retention
limits (10 ug/day) becomes apparent, even assuming only the two lowest
dietary intake levels.
In Table 4-18 are given the relative amounts of the critical daily
cadmium retention values achieved with smoking at two exposure times (Table
4-12) and employing the half-time (38 years) giving the lower critical
retention figure.
In the case of a.daily intake of 50 ug cadmium in food (3.0 ug net
retention), an individual smoking two packs per day throughout his adult
lifetime approaches two-thirds of the critical retention level (10 ug) at
age 70, assuming smoking started at age 20.
In Table 4-18, an ambient air cadmium level of 30 ng/m was chosen,
using the example in Table 4-11. If one also tabulates the relative
contributions of ambient air cadmium over the range 1 to 1,000 ng/m taking
into account retention from cigarette consumption, one arrives at the
figures in Table 4-19. At ambient air levels of 1 and 10 ng/m , no air
contribution is made that significantly enhances the risk of smokers over
3
that arising from diet and cigarettes. At levels of 100 ng/m , however, a
d-7?
-------
Table 4-17 ESTIMATED RELATIVE CONTRIBUTION OF DIETARY INTAKE. CIGARETTE SMOKING AND AMBENT AIR CADMIUM
LEVELS TO TOTAL DAILY CADMIUM RETENTION FROM ALL SOURCES3
i
-~4
oo
Dietary Intake
(Net Retention)
Food level A = 25
py/day
(1.50 no/day)
Food Level 8 = 50
pg/day
(3.00 pg/day)
food Level C = 75
pyAlay
(4 50 tig/day)
0.0
ng/m
Smoking Status (Net Retention) (0.0 pg/day)
Non-smoker
T pack/day
1 pack/day
2 pack/day
3 pack/day
Non-smoker
>s pack/day
1 pack/day
2 pack/day
3 pack/day
Non-smoker
% pack/day
1 pack/day
2 pack/day
3 pack/day
(0.
(0.
(I.
(2.
(4.
(0.
(0.
(1-
(2.
(4.
(0.
(0.
(1.
(2.
(4.
00
70
41
82
22
00
70
41
82
22
00
70
41
82
22
pg/day)
pg/day)
pg/day)
ug/day)
pg/day)
pn/day)
(jg/day)
pg/day)
|nj/ddy)
pg/day)
(ig/day)
pg/ddy)
jig/day)
|ig/day)
pg/day)
1.590
2.290
3.000
4.410
5.810
3.090
3.790
4.500
5.910
7.310
4.590
5.290
6.000
7.410
8.810
(0;0%)*
(31;0%)
(47;0%)
(64;0%)
(73.0%)
(0;0%)
(18;0%)
(31;0%)
(48;0%)
(58;0%)
(0;0%)
(13;0%)
(24;0%)
(38.0%)
(48;0%)
Air Cadmium Levels (Net Retention) .
1.0 ng/m 10 ng/m 100 ng/m
(.0005 ug/day)
1.591 (0;0%)
2.291 (31;0%)
3.001 (47;0%)
4.411 (64;0%)
5.811 (73;0%)
3.091 (0;0%)
3.791 (18;0%)
4.501 (31;0%)
5.911 (48;0%)
7.311 (58;0%)
4.591 (0.0%)
5.291 (13;0%)
6.001 (24;0%)
7.411 (38;0%)
8.811 (48;0%)
(.005
1.595
2.295
3.005
4.415
5.815
3.095
3.795
4.505
5.915
7.315
4.575
5.295
6.005
7.415
8.815
p.g/day)
(0;0%)
(31;0%)
(47;0%)
(64;0%)
(73;0%)
(0;0%)
(18;0%)
(31;0%)
(48;0%)
(58;0%)
(0;0%)
(13;0%)
(24;0%)
(38;0%)
(48;0%)
(.05 pg/day)
1.630 (0;3%)
2.330 (30;2%)
3.050 (46 ;!*)
4.460 (63;!^)
5.860 (72;1%)
3.140 (Q;2%)
3.840 (18;1%)
4.550 (31; IX)
5.960 (47;1%)
6.360 (57;1X)
4.640 (0.1%)
5.340 (12; IX)
6.050 (23;1%)
6.460 (38;1%)
8.860 (48;1X)
1000 ng/m3
(0.5 pg/day)
2.090 (0;2«)
2.790 (25;18%)
3.500 (40;14%)
4.910 (57;10%)
6.310 (67;8%)
3.590 (0;14%)
4.290 (16; 12%)
5.000 (28;10%)
6.410 (44;8%)
7.810 (54;6%)
5.090 (0;10X)
5.790 (12;S%)
6.500 (22;8%)
7.910 (36, 6X)
9.310 (4S.5X)
aNote that a total daily retention level of 10 ug/day would be expected to yield renal
dysfunction over a 50-year exposure period.
*Each first value equals total daily cadmium retention levels (in pg/day) from all sources, assuming constant daily retention fro* water of
0.09 pg/day der.ived from consumption ot water with cadmium concentration of 1 ppb. The two values in parentheses ( ) indicate percentage
of total daily cadmium retention attributed to cigarette smoking and ambient air cadmium exposure, respectively, at a given ambient air
cad,nmm level.
-------
Table 4-18. PERCENTAGE OF CRITICAL DAILY CADMIUM RETENTION LEVEL YIELDING RENAL
DYSFUNCTION ACHIEVED BY SMOKERS AT TWO EXPOSURE TIMES AND
TWO DIETARY LEVELS ' '
Exposure period and diet Intake
Cigarette consumption
(packs/day)
25 Years
Food Level A Food Level B
(25 yg/day) (50 yg/day)
50 Years
Food Level A Food Level B
(25 yg/day) (50 yg/day)
0
1/2
1
2
3
20
25
29
38
47
32
39
47
61
75
11
15
20
28
38
17
24
32
46
60
Food A, 50 yg cd/day intake, 3.0 yg cd retained.
Food B, 25 yg cd/day intake, 1.5 yg cd retained.
Combined air and water retained cadmium value
= 0.24; Table 4-11.
°Critical daily cadmium retention level for induction of
renal dysfunction = 10 yg/day for 25-year exposure period,
-------
Table 4-19. PERCENTAGE OF CRITICAL DAILY CADMIUM RETENTION LEVEL YIELDING RENAL
DYSFUNCTION ACHIEVED BY SMOKERS AS A FUNCTION OF AMBIENT AIR
CADMIUM LEVELS3'D
o
Ambient air (ng/m )
_0 1.0 10.0 100.0 1,000.0
Cigarette
packs/day
0
1/2
1
2
3
Daily food
intake of: 25 yg
16
23
30
44
58
50 yg
31
38
45
59
73
25 yg
16
23
30
44
58
50 yg
31
38
45
59
73
25 yg
16
23
30
44
58
50 yg
31
38
45
59
73
25 yg
21
28
35
49
63
50 yg
36
43
50
64
78
25 yg
66
73
80
87
94
50 yg
80
87
94
101
108
^Assuming daily cadmium retention from water of .09 yg/day.
Exposure period of 50 years.
-------
uniform increase of 5 percent is seen, with the increase in percentage at
o
1,000 ng/m then going to 50 percent over that of no ambient air levels of
cadmium.
Experimental data in support of considering smokers as being at increased
risk for the renal effects of cadmium are available from human autopsy
studies of organ cadmium levels, particularly kidney cadmium levels.
These studies are described in the Human Epidemiology section and show that
smokers have kidney levels of cadmium considerably above those for non-smokers,
up to twice the relative amount.
In the Exposure Aspects portion of this chapter, mention is made of
the .growing use of sludge material dispersed on agricultural lands. Furthermore
it was pointed out that this material is often enriched in cadmium relative
to soils in general and, therefore, its use may result in significantly
increased cadmium levels in soil, food crops grown on the sewage-treated
soil, and consumer-distributed food products derived from such crops. If
this be the case, then one must consider as a potential population at risk
in the United States, those who may be so placed at risk by virtue of
dietary habits, in particular those for whom grains and leafy vegetables
comprise the sole or major portion of their diet. These foodstuffs are
particularly adept at taking up cadmium from soils.
Lucas et aJL (1978) have suggested that sludges with less than 60 ppm
cadmium can be applied at maximum rates to meet crop nitrogen requirements
and still produce acceptable levels of cadmium in vegetables, assuming 110
ug/day of cadmium ingestion via food to be safe. Factors which complicate
any quantitative assessment of the risk impact of cadmium-containing sludge
are population mobility and a centralized food marketing and distribution
-------
system that would have some diluting effect on high cadmium vegetables and
grains. Still, increased dietary cadmium levels of any amount must be
considered as further increasing the risk of population groups already at
special risk, such as old people, vegetarians or smokers (as is illustrated
for the latter in the bottom half of Table 4-17).
Scrutiny of the literature with reference to those individuals on the
other end of the age scale, young children, furnishes very limited hard
evidence of a clinical epidemiological nature that children may presently
be considered a group at special risk for the health effects of cadmium.
As implied in EPA's Air Quality Criteria for Lead (1977), however, children,
by virtue of their relationship to their exposure setting and to their
differences in metabolic functions, may be at invariably greater risk for
any toxic metal that parallels lead's distribution in the environment,
particularly in dustfall. The "mouthing" activity of young children, a
normal behavioral trait, would expose this group to non-foodstuffs such as
cadmium-containing dust and dirt. Furthermore, there is the question of
enhanced absorption and, more important, possible enhanced retention.
Bogden et al_. (1974) studied the extent of exposure of a group of
urban children to cadmium. These workers found a significant positive
correlation between cadmium and lead (p<0.006) and between cadmium and
zinc (p<0.001). These correlations suggest that, since increased lead
concentrations in blood occur because of environmental contamination, then
cadmium is being co-absorbed with the lead. While paint could be a source
of both cadmium and lead, the zinc/cadmium correlation is more vexing as to
source. As part of their study, they correlated the mean atmospheric
concentrations of each element for a specific year and found strong positive
correlations between the three pairs (p<0.01): cadmium/lead, zinc/lead
4-77
-------
and zinc/cadmium, indicating to these investigators that inhalation may be
a factor in the blood values. Delves et a^. (1973) in their study, however,
could find a correlation of only 0.05 for lead and cadmium or between zinc
and cadmium.
The hazard posed to children in this type of exposure setting may be
heightened for several reasons:
(1) Many children in urban areas, particularly those of lower socio-
economic status, have a greater incidence of calcium, iron, and zinc deficiency,
which are states that could enhance the effects of cadmium (see 2.16,
Interactions section).
(2) Co-exposure of children to lead and cadmium may heighten the
health effect of either or both through synergism.
(3) We know that industrial use of cadmium in urban areas adds to the
dust and soil burden via fallout (see 4.2, Exposure Aspects) and to the
exposure of children in these areas via "mouthing" activity, etc.
Another group within the general population of the United States who
may be at increased risk are those whose water supplies are soft or acid.
Soft water has been associated with heightened occurrence of cardiovascular
disease (see 2.6 of the Health Effects section). While hypertension induced
experimentally by cadmium has been established, at present the parallel
data for humans do not conclusively show an etiological role for cadmium in
human hypertension. This is an important issue and, like the case with
children, requires more research.
The risk posed by cadmium to pregnant women, more specifically the
fetus, is another area of concern. It has been shown, as described in the
health effects section on reproduction and development, that although
4-78
-------
cadmium passes the placenta! barrier in only small amounts, it nevertheless
can affect the birth weights and morphological development of offspring
exposed i_n utero through dosing of the mother. Such prenatal effects on
fetal development also appear to persist into postnatal development and
seem to occur secondarily to cadmium effects on the mother, e.g., in causing
decreased levels of essential elements such as zinc, iron, and copper.
In light of the animal studies demonstrating such cadmium effects, the
findings of Cvetkova (1970) on women in the U.S.S.R. occupationally exposed
to cadmium oxide are quite interesting. Those women had normal courses of
pregnancy and deliveries, but their children had lower birthweights when
compared with those of control workers. Such results are consistent with
those repeatedly found in animal studies where reduced birthweight is often
observed. Thus there appears to be a reasonably well-established
relationship between cadmium exposure during pregnancy and reduced birth
weights. This adverse effect and a less well-demonstrated association with
stillbirths argues for pregnant women being a special group at risk to
cadmium by virtue of potential deleterious effects on the fetus.
Several studies provide further evidence for children continuing to be
at risk well beyond the neonatal periods of their life. Higher than "normal"
levels of cadmium have been demonstrated in children as a function of: (1)
increasing age (Delves et aK , 1973; Gross et al^. , 1976) and (2) suspected
pica and geographic location of residence, with inner-city children having
higher levels than others (Bogden et al., 1974). The health implications
of such cadmium exposures in children remain to be better established, as
discussed elsewhere in the section on human epidemiology; but one must
suspect that the general consequence would be that of putting them at
4-79
-------
higher risk for any of the many adverse health effects described earlier
under the section on health effects. One interesting hint of possible
adverse consequences of cadmium exposure in children comes from the study
by Pihl et aJL (1977) discussed earlier as showing an association between
cadmium levels in the hair of children and incidence of mental retardation.
4.6 UNITED STATES POPULATION GROUPS IN RELATION TO PROBABLE CADMIUM EXPOSURES
This section is concerned with the numbers of individuals potentially
at risk to cadmium exposures. It is not possible to delineate well all of
the members of those segments of the United States population that would
fit the potential risk categories described in the previous section on
populations at risk.
Table 4-20 presents estimates from EPA's Cadmium Population Exposure
Analysis (1978) of the numbers of individuals in the U.S. population
exposed to airborne cadmium levels >0.1 ng/m as a function of average
cadmium exposure and type of cadmium source. In terms of numbers of
individuals exposed, those in proximity to municipal incinerators
constitute the largest group and are exposed to an average level of 7.2
o
ng/m . Comparatively smaller, though significant, populations are exposed
o
to higher air levels (10 ng/m ), however, by virtue of residence near other
cadmium-emitting point sources. Iron and steel production result in the
second largest group of individuals exposed, about 20 million. It should
be noted that, although large numbers of individuals are exposed via inputs
from such sources into the ambient air, the average exposure levels present,
except perhaps for those very close to high emitting point sources, generally
do not appear to be associated with increased risk for any particular
health effect.
4-80
-------
Table 4-20- AVERAGE EXPOSURE AND NUMBER OF PEOPLE EXPOSED TO ANNUAL
CADMIUM LEVELS GREATER THAN 0.1 ng/M3 BY SPECIFIED SOURCE TYPESa
Average ^ # of people exposed
Source type exposure (ng/m3)b (io3 people)
Secondary copper
Secondary zinc
Municipal incinerators
Primary zinc
Primary lead
Primary copper
Primary cadmium
Iron and steel
Total
2.3
0.4
7.2
10C
10°
10C
10C
1.8
6,484
9
49,026
449
46
620
245
19,947
76,826
aAdapted from Cadmium Population Exposure Analysis (EPA, 1978).
0.1 ng is lower limit of detectability with current instrumentation,
Preliminary estimate, not based on actual modelling results.
4-81
-------
Table 4-21. COMPARISON OF CADMIUM EXPOSURES AMONG SOURCES
(10° Nanograms-Person-Year)'
Source type Total
Secondary copper 15.1
Secondary zinc 0
Municipal incinerators 350.8
Primary zinc 4.5
Primary lead .5
Primary copper 6.2
Primary cadmium 2.5
Iron and steel 35.2
T * T2 414.8
Total
Computed by multiplying the population exposed to
each source by the concentrations resulting from that
source. Adapted from Cadmium: Population Exposure
Analysis (EPA, 1978).
2
May not sum due to independent rounding.
4-82
-------
I
00
CO
Table 4-22 POPULATION EXPOSED TO CADMIUM CONCENTRATIONS
(103 people)9
Source type Annual concentration (ng/m )
>10 >5 >1 >0.1
Secondary copper
Type lj
Type 2C
Secondary zinc
Type 1
Type 2
Municipal incinerators
Type 1
Type 2
Primary zinc
Type 1
Type 2
Primary lead
Type 1
Type 2
Primary copper
Type 1
Type 2
Primary cadmium
Type 1
Type 2
Iron and steel
Type 1
Type 2
Total
Type 1
Type 2
Type 3e
189 517
189 517
0 0
0 0
1,665 26,576
1,665 9,038
378 984
372 910
2,232 28,077
2,226 10,465
2,226 10,465
3,580
3,580
0
0
99,123
34,376
6,172
5,601
108,875
43,827
38,530
6,484
6,484
9
9
174,871
49,026
449d
449d
46d
620d
620d
245d
245d
27,103
19,947
209,827
76,817
65,021
-------
Table 4-22 (cont.)
aAdapted from Cadmium: Population Exposure Analysis (EPA, 1978).
Type 1 results are the sum of population exposed to higher than the
specified concentration. Significant "double counting" may exist.
°Type 2 results represent the population exposed to greater than the
specified concentration from at least one point source within each
category. Double Counting within source categories eliminated.
Actual concentrations not specified due to modelling problems. People
represent population within 20 Km of a plant.
eType 3 results represent the population exposed to greater than the
specified concentration from at least one point source. All double
-P. counting eliminated.
CXi
-------
I
00
cn
o
1.
2.
3.
4.
5.
6.
7.
8.
9.
NORTHEAST
MID-ATLANTIC
SOUTH ATLANTIC
EAST NORTH CENTRAL
EAST SOUTH CENTRAL
WEST NORTH CENTRAL
WEST SOUTH CENTRAL
MOUNTAIN
PACIFIC
aColeman, 1977.
Figure 4-6. Regions Used in Cadmium Analysis.3
-------
Table 4-23. REGIONAL BREAKDOWN ON POPULATION1 EXPOSED TO CADMIUM
CONCENTRATIONS GREATER THAN 0.1 NANOGRAMS PER CUBIC METER
FROM SELECTED STATIONARY SOURCES (1,000 POPULATION)2
00
cr>
Source type
Secondary copper
Secondary zinc
Municipal incerators
Primary zinc
Primary lead
Primary copper
Primary cadmium
4
Iron and steel mills
Total
1
1,434
0
6,570
0
0
0
0
93
7,671
2
0
0
19,873
359
0
0
100
4,743
22,748
3
0
0
6,239
0
0
19
0
2,410
7,379
4
1,889
4
12,501
0
0
3
87
8,710
15,259
Region
5
•o
0
787
0
0
0
0
649
1,238
6
313
0
1,760
0
0
0
0
108
1,604
7
1,027
5
1,122
73
0
0
41
1,626
1,718
8
213
0
173
17
46
137
17
0
481
9
1,608
0
0
0
0
461
0
1,607
3,543
Total
6,484
9
49,026
449
46
620
245
19,947
61,640
1
Population figures rounded to nearest thousand.
"Adapted from Cadmium: Population Exposure Analysis (EPA, 1978).
See Figure 1 for regional breakdowns.
Includes all configurations of iron and steel mills.
""Double counting eliminated.
-------
Table 4-24 NUMBER OF BIRTHS BY RACE AND SIZE OF POPULATION
Births, 1970C
Urban areas by
population size
>J 000, 000
50-99,999
10-49,999
>9,999
Total
Urban areas by
population size
MOO, 000
50-99,999
10-49,999
£9,999
White
772,230
286,706
600,166
1,432,162
3,091,264
White
571 ,478
222,735
478,382
1,279,401
Black
321,412
37,024
65,790
148,136
572,362
Births,
Black
276,387
37,885
64,481
132,828
Other
24,394
4,182
10,394
28,790
67,760
1975b
Other
26,332
5,921
13,039
35,329
Total
1,118,036
327,912
676,350
1,609,088
3,731,386
Total
874,197;
266,541
555,902
1,447,558
Total
2,551,996 511,581
80,621 3,144,198
Vital Statistics of the United States.
National Center for Health Statistics, DHEW, Washington, D.C.
3Unoublished data from above.
1975
4-87
-------
Table 4-21 is a comparison of cadmium exposures among sources obtained
by multiplying the population exposed to each source by the concentrations
resulting from that source. Also, Table 4-22 describes the numbers of
individuals exposed, within a given source category, as a function of
3 3
annual concentration, from >0.1 ng Cd/m to >10 ng/m . These air-level
categories are broken down into two types: populations exposed to
higher-than-specified concentrations and populations exposed from at least
one point source within each category. In addition, Figure 4-6 depicts the
states included in the census regions employed in Table 4-23, a tabulation
of regional populations exposed to cadmium levels exceeding 0.1 nanograms
Cd/m3.
As noted earlier, smokers constitute a definite population at
increased risk for adverse health effects of cadmium. Recent data from the
National Clearinghouse for Smoking and Health (1975) provide a quantitative
picture of the numbers of individuals as a function of age and sex who are
smokers in the United States. Among adults over 20 years of age, 34 percent
are smokers (46.9 million people) of whom 25.9 million are males. Average
cigarettes consumed daily by men and women are 23 and 19 cigarettes daily.
Of teenagers (13-19 years old), there are 6 million smokers, with increases
in this number presently being seen. Thus, a very large segment of the
present U.S. population can be expected to be at increased risk for adverse
health effects of cadmium.
Also of special interest are the numbers of children in various urban
areas who may be at increased risk to cadmium exposure, and Table 4-24
presents natality data for 1970 and 1975 as provided by the National
4-88
-------
Center for Health Statistics (1975, 1978). As noted earlier, children are
clearly at risk for increased absorption, but it is not necessarily the
case that they are at special risk for experiencing health effects
resulting from any short-term exposure or accumulation of cadmium.
However, adverse health effects of cadmium vis-a-vis the population at
large typically appear only after many years of low-level chronic exposure.
Thus, an argument can be advanced that the segment of the present U.S.
population that can most benefit from controlled environmental exposure to
cadmium and its associated health effects are the very young. Conversely,
it can also be argued that any substantial increases in general cadmium
exposure, due to uncontrolled emissions into the environment from whatever
source(s) in the future, would perhaps impact most heavily on the present
U.S. pediatric population by virtue of sufficient time remaining in their
lifespans for cadmium to ultimately accumulate to toxic levels.
4-89
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4.7 REFERENCES FOR CHAPTER 4
Akland, G. G. Air Quality Data/Metals, 1970-1974, from National Air
Surveillance Networks. EPA-600/4-76-041, U.S. Environmental Protection
Agency, Research Triangle Park, N.C., 1976.
Andersson, A. On the influence of manure and fertilizers on the distribution
and amounts of plant-available Cd in soils. Swed. J. Agric. Res.
6:27-36, 1976.
Berry, W.L., and A. Wallace. Trace Elements in the Environment - Their
Role and Potential Toxicity as Related to Fossil Fuels - A Preliminary
Study. UCLA, Los Angeles, CA, 1974.
Bogden, J. D., N. P. Singh, and M. M. Joselow. Cadmium, lead and zinc
concentrations in whole blood samples of children. Environ. Sci.
Technol. 8:740-742, 1974.
Bond, R. G., Straub, C. P., and Prober, R. (eds.) Handbook of Environ-
mental Control, Vol 1: Air Pollution. CRC Press, Cleveland, 1972.
Clapp et a\_. In: CAST (Council for Agricultural Science and Technology).
Application of sewage sludge to cropland; appraisal of potential
hazards of the heavy metals to plants and animals. CAST. Report No.
64, Iowa State University, Ames, IA, 1976.
Commission of the European Communities. Criteria (Dose/Effect Relationships)
for Cadmium. Pergamon Press, New York, 1978.
Corneliussen, P. E. Pesticide residues in total diet sample (V). Pest.
Monitor. J. 4:80-105, 1970.
Cvetkova, R. P. Materials on the study of the influence of cadmium
compounds on the generative function. Gig. Tr. Prof. Zabol. 14:31,
1970.
4-90
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Deane, L. G., D. A. Lynn, and N. F. Surprenant. Cadmium: Control Strategy
Analysis. ECA Cong., Bedford, Mass. U.S. Environmental Protection
Agency, 1976.
Delves, H. T., B. E. Clayton, and J. Bicknell. Concentrations of trace
metals in the blood of children. Br. J. Prev. Soc. Med. 27:100-107,
1973.
Dowdy, R. J., and W. E. Larson. The availability of sludge borne metals to
various vegetable crops. J. Environ. Qual. 4:278-282, 1975.
Duggan, R. E., and P. E. Corneliussen. Dietary intake of pesticide chemicals
in the United States. June, 1968-April, 1970. Pestic. Monitor. J.
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1 hCHN'CAL REPORT DATA
1. -^ORT NO. | -
_EPAi60p/8-79-:p03 ]
4 riTLEANDSUBTlTuE
Health Assessment Document for Cadmium
"E CLIENT'S ACCESSION-NO
REPORT pATE
_January, 1979
6 PERFORMING ORGANIZATION CODE
7 AUTHOR(S) L.D. Grant & W. Galke, ECAO, EPA, RTP,NC 27711
P. Mushak, UNC, Chapel Hill, NC 27514; A. Crocetti,
NY Medical College, NY, NY 10029
8. PERFORMING ORGANIZATION REPORT NO
9. PERFORMING ORGANIZATION NAMF: AND ADDRESS
Environmental Criteria and Assessment Office
Office of Research and Development
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711
10. PROGRAM ELEMENT NO.
1HA882
11. CONTRACT/GRANT NO.
12. SPONSORING AGENCY NAME AND ADDRESS
Office of Research and Development
U.S. Environmental Protection Agency
Washington, DC 20460
13. TYPE OF REPORT AND PERIOD COVERED
14. SPONSORING AGENCY CODE
15. SUPPLEMENTARY NOTES
16. ABSTRACT
This document provides a critical assessment of health effects and public health
risks associated with environmental exposure to cadmium (Cd). Sources and routes
of exposure are discussed and identified. Dose-effect/response relationships and popu
lations at special risk are delineated.
Cadmium is naturally present in most environmental media. Major anthropogenic
sources are: (1) smelting and mining, (2) certain manufacturing processes, and (3)
waste disposal operations. Food is the largest environmental source for most humans,
although Cd intake from smoking can equal or exceed Cd intake from food.
Acute non-lethal exposure is associated with chronic respiratory effects. Howeve
since most environmental exposures to Cd are of a long-term, low-level type, primary
emphasis has been placed on discussing effects of such chronic exposure. Cadmium's
accumulation in the kidney results in renal tubular dysfunction after many years of
exposure. Estimates of the concentration of Cd in the renal cortex necessary to indue
these effects and estimates of exposure necessary to produce the critical renal concen
tration vary widely, partially due to individual biological variability. Populations
at special risk to Cd are cigarette smokers, as well as the older segments of the
population (<50 years of age).
7.
KEY WORDS AND DOCUMENT ANALYSIS
DESCRIPTORS
b.IDENTIFIERS/OPEN ENDED TERMS
c. COSATI Field/Group
Metals
Cadmium
Trace Elements
Smelting
Mining
Electroplating
Earth Fills
Incinerators
Air Pollution
Water Pollution
Food
Urological Diseases
Nutritional Deficiencie
Sludge
Public Health
Cigarette Smoking
Pneumonitis
Renal Tubular Dysfunctic
Renal Cortex
Phosphate Fertilizer
Body Burden
Human Health
02A
06A
06C
06E
06F
06H
06P
_L3B-
B. DISTRIBUTION STATEMENT
RELEASE TO PUBLIC
19. SECURITY CLASS (This Report)
UNCLASSIFIED
21. NO. OF PAGES
20. SECURITY CLASS (Thispage)
22. PRICE
EPA Form 2220-1 (9-73)
4-99
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