EPA
United States Environmental Criteria and
Environmental Protection Assessment Office
Agency Research Triangle Park NC 27711
EPA/600/8-81 /023
October 1981
Research and Development
Health Assessment
Document for
Cadmium
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EPA/600/8-81/023
October 1981
HEALTH ASSESSMENT DOCUMENT
FOR CADMIUM
U.S. ENVIRONMENTAL PROTECTION AGENCY
Office of Research and Development
Environmental Criteria and Assessment Office
Research Triangle Park, N.C, 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 112(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 health assessment 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 t? provide a critical assessment
of health effects and potential risk to huT-an hc-^Hh associated with environ-
mental 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 hsalth of the American public is discussed.
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 madia 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. Han 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 tha humen food chain.
Food is presently the single largest environmental source of cadmium
exposure for most humans. Current estimates indicate that daily dietary
cadmium intake levels for most Americans vary from 10 to 50 ug/day. Cigarette
smoking (one to three p.actcs per day) can significantly increase cadmium
intake in amounts equal to or exceeding that obtained from food. Ambient
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vi-
and drinking water-generally contribute only small increments in cadmium
• uptake beyond that of food or cigarette smoking, except possibly 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 can
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 metabolic modeling
approaches range from 200 to 430 ug/day. However, levels near the lower
end of the range (ca. 200 ug/day) are presently accepted as the best estimates
of "threshold" dietary intake levels typically needed to result in the criti-
cal renal cortex concentration being reached over a 50-year exposure period.
Other approaches utilizing metabolic models, actual measures of dietary cadmium
exposures and associated prevalence of renal dysfunction, suggest
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that wide variability may exist across human populations in regard to
ingestion levels necessary to induce the critical effect and that a .very
small proportion of the most sensitive members of the general population
might be affected at dietary levels somewhat below 200 ug/day.
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 calcium,
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 than non-smokers
for cadmium-induced adverse health effects.
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CONTRIBUTORS AND REVIEWERS
Authors
Dr. Lester D. Grant, Associate Professor, Departments of
and
Dr. Annemarie Crocetti, Adjunct Associate Professor of Preventive and
Community Med1Cine, New York Medical College, New York? New
Criteria and Assessment Office, Environmental
olinf- I7%r°nmental ""*«*">" Agency, Research Triage
Consultants
Dr. George M.Cherian, Assistant Professor, Department of Pathology
Umversity of Western Ontario, London, Ontario, Canada
°r' GMM?ri!(£rd™r9> I1)8***"1? of Community Health and Environmental
Medicine, Odense Umversity, Odense, Denmark.
°r' HLouisPeMissoin-' Wasln"n9ton "niversity School of Medicine, St.
Dr. Magnus Pi scator Department of Environmental Hygiene, The
Karolinska Institute, Stockholm, Sweden
°f Tcxi'co109y' Food and Oru9 Administration,
EPA Review Committee
Or- J- ,jj: B- Garner, Chairman, Environmental Criteria and Assessment
Offnce, 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
vi
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Dr. Vic Hass«1blad, Health Effects Research.Laboratory, Environmental
Research Center, U.S. Environmental Protection Agency, Research
Triangle Park, North Carolina 27711 "«Mrcn
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. Joellen 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* GaV]a Benignus, Private Consultant, Chapel Hill, North Carolina
27514
Mr. Douglas B. Fennel!> 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 Trianqle
Park, North Carolina 27711
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SCIEKCE ADVISORY BOARD
SUBCOMMITTEE ON CADMIUM AS A POSSIBLE HAZARDOUS AIR POLLUTANT
_ The substance of this document was reviewed in public session by the
Environmental Protection Agency's Science Advisory Board (SAB) Subcommittee
on.Cadnnum as a Possible Hazardous Air Pollutant and was judged to be
scientifically acceptable for use in decision-making regarding cadmium as a
potential hazardous.air pollutant. The SAB subcommittee was comprised of
the following individuals: . K
Chairman;
Dr. Ruth R. Levine, Chairman, Graduate Division of Medicine and
* B°St0n Un1versUy Medical School, Boston, Massachusetts
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 for
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
viii
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CONTENTS
Page
LIST OF FIGURES .......
LIST OF TABLES ..... .... ............................. .......... ... xii
ABSTRACT ............... .. ......................................... xiii
....................................... iii
1. SUMMARY AND CONCLUSIONS
1. 1 INTRODUCTION ...... ................... ' ........... ....... 1-1
1.2 HEALTH ASPECTS OF CADMiu^'iN^AND'ANi ...... ' '
l.*.l Metabol1Sm of Cadmium in Man and
. „ , Experimental Animals ..... ..
2 •1Ii '" ......... '
:::::-^ : 3
.... 1-17
1.4.2 Sources and Routes'of'Exposure:::: ........ ' ...... J'S
1.4.3 Human Population Responses to Cadm urn ............ ^
• in Human Risk Assessment ...... ™ , '
1.4.3.1 Summary of human health effects 'of ......
cadmium
ja^^^^'^i^Mp;- M
1.4,3.3 Populations at risk'to'the'ad^rse""" ^
1.4.4 overall conclulio^f'f.?^^:™;; ;;;;;;;;;•• Jig
. SIGNIFICANCE AND ADVERSE HEALTH EFFECTS OF
2. 1 INTRODUCnON ............................................ 2-1
2.2 METABOLISM OF CADMIUM.* ."."!.'.' ............................. z~l
2.2.1 Sources of Exposure.'.".'.'."." ...... ............... "' f"?
2.2.2 Inhalation...!.. •••••••.. ............ ..... 2-2
f-i i S^tr°Lntestina1 A^o;Piion: :::;::::: ............ 1:1
2.2.4 Other Absorption Routes.... .............. ? *
2.2.) Transport and Deposition ..... .................... *"*
2.2.(> Excretion ..... .............. '•• 2"4
a^n? "^'
, ^ifSSSii
2.4 RESPIRATORY EFFECTS OF CADMIUM ........... ' .............. f*f2
2.4.1 Effects on Humans.... ........................ T27
2.4.2 Animal Studies ........................... 2"27
2.5 RENAL EFFECTS OF CADMIUM ................................ 2'29
2.5.1 Animal Studies.. ............ ' ............ ...... 2"32
2.5.2 Human Studies ......... ......... ' ........... *•• 2"33
2.6 THE CARDIOVASCULAR SYSTEM .................... * ....... ••" 2"37
2.6.1 Animal Studies ____ ','.'.'.'. ..................... ' ---- 2"41
2.6.2 Human Hypertension .......... ' .................... 2"41
........................... 2-44
ix
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Page
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
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
3. HUMAN EPIDEMIOLOGY 3-1
3.1 INTRODUCTION 3-1
3.2 CADMIUM IN BLOOD AMD URINE OF HUMAN POPULATIONS 3-2
3.2.1 Sources of Variations in Human
Blood Cadmium Levels 3-3
3.2.1.1 Demographic variability in human blood
cadmium levels 3-4
3.2.1.2 Other variation 3-14
3.2.1.3 Occupational exposure and blood
cadmium 3-14
3.2.2 Sources of Variation in Human
Urine Cadmium Levels 3-15
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 3-33
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Page
3.4.1 Itai-Itai Disease Studies. , 3-35
3.4.2 Epidemiologies! Studies of Other Cadmium-
Polluted Areas In Japan.., 3-38
3.5 EPIDEMIOLOGY OF CADMIUM, HYPERTENSION, AND CARDIO-
VASCULAR DISEASES , 3-41
3.6 EPIDEMIOLOGICAL STUDIES OF THE RESPIRATORY TRACT. 3-43
3.7 CADMIUM AND CANCER , 3.44
3.8 EPIDEMIOLOGICAL STUDIES RELATING TO CHROMOSOMAL '
ABNORMALITIES 3-40
3.9 EPIDEMIOLOGICAL STUDIES OF OCCUPATIONAL EXPOSURE
TO CADMIUM.. 3.49
3.10 REFERENCES FOR CHAPTER 3 '.'.'.'.'.'.'.'.'.'. 3-50
4. HUMAN HEALTH RISK ASSESSMENT OF CADMIUM 4-1
4.1 INTRODUCTION.. , , "" 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 , 4-20
4.2.5 Other Sources . 4-37
4.3 HEALTH EFFECTS SUMMARY ' 4-39
4.4 DOSE-EFFECT AND DOSE-RESPONSE RELATIONSHIPS
OF CADMIUM IN HUMANS „ 4-43
4.4.1 Dose Aspects 4-43
4.4.2 Dose-Effect/Dose-Response'Aspects 4-45
4.5 POPULATIONS AT RISK TO EFFECTS OF CADMIUM 4-61
4.6 UNITED STATES POPULATION GROUPS IN RELATION TO
PROBABLE CADMIUM EXPOSURES 4-73
4.7 REFERENCES FOR CHAPTER 4....., 4-83
APPENDIX A , -
xi
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FIGURES
Number B
• Page
l~l~ Distribution of fflean "fine cadmium concentrations by age... 3-ia
3-2. Geometric and arithmetic means of cadmium concentration
in kidney cortex are shown for each decade of life 3-95
3-3. Cadmium in whole kidney tissues and its relation-
ship to age ^ 3.26
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 ;. 4-5
4r2. Trends in 50th percenti'le of annual averages"for
cadmium associated with metal industry sources
at urban sites _.. 4_n
4-3. Contribution of food groups to cadmium intake!!.'!.'! 4-27
t 7r fffects of s01"1 PH on cadmium uptake by vegetables 4-3?
I 4-5. Calculated (lines) and observed (symbols o, o, *) dose-
response relationships for cadmium-induced increase (>97 5)
percentile of reference group) of urinary ^?-microg^obu^in
6XCrG£10n* **••*•••••••••••••••••«»»,«.. A*CC
4-6. Regions used in cadmium analysis !!!!!!!!!!!!!!!!!!!!!!!!! 4-80
xii
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TABLES
Number
1-1.
Cadmium exposure required for reaching a kidney cortex
concentration of 200 ua Cd/a nci™ &**. "L*y ,rl_ex
Page
1-23
SSI'S! !m°kin?~an
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Number Page
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. Cadmium content in different food categories in the
U. S. A 4-22
4-5. Cadmium content of selected adult foods 4-24
4-6. Food groups by mean cadmium content and their contri-
bution to daily cadmium intake 4-25
4-7. Cadmium intake of teen-age males by food class 4-26
4-8. Distribution of daily dietary cadmium intake (ug/day)
of U.S. populations as determined by fecal excretion
studies 4-29
4-9. Cadmium content of several crops and tissues as a
function of cadmium loading of soil 4-31
4-10. Cadmium content of soils and crops grown on acid and
limed sludged sites 4-34
4-11. Media contributions to normal retention of cadmium 4-38
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. 4-49
4-13. Prevalence of tubular proteinuria and suspected patients
among adults more than 50 years of age in relation to
village average rice cadmium concentrations 4-59
4-14. Prevalence of tubular proteinuria in relation
to age and village average rice cadmium concentation.. 4-60
4-15. Relative contribution of cigarette smoking to total
daily cadmium retention 4-65
4-16. Estimated relative contribution of dietary intake, T . ?;
cigarette smoking, and ambient air cadmium levels ':- v-r>V ' "'•-•
to total daily cadmium retention from all sources 4-67*"* '/•'.,>•
4-17. Percentage of critical daily cadmium retention level ' '^
yielding renal dysfunction achieved by smokers as a s|l
function of ambient air cadmium levels 4-69
4-18. Average exposure and number of people exposed to annual
air cadmium levels greater than 0.1 ng/m by specified
source types ;: 4-75
4-19. Estimate of cumulative population exposed to
specified cadmium concentrations from municipal
incinerators 4-76
4-20 Estimate of cumulative population exposed to specified
cadmium concentrations from iron and steel mills 4^77
4-21. Estimated population exposed to specified levels from
primary smelters.. 4-78
4-22 Estimate of population exposed to specified levels
from secondary smelters 4-79
4-23. Number of births by race and size of population 4-81
. xiv
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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 heaHh
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 as being
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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 popula-
tions 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 source*; of cadmium exposure are identified, and
their present relative contributions to human Intake and retention of
the metal are estimated, dose-eff«ct 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 multimedia cadmium exposure levels necessary to achieve
sufficient retention of the metal for induction of the critical
effects of chronic exposure. Lastly, populations at special risk
for exhibiting 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 concern from a public health standpoint emerge
from the present analysis. One is that cadmium appears to be somewhat
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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" frsiction 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
natural margin of safety likely 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.
At present, the major anthropogenic sources contributing to environmental
exposures to cadmium are: (1) municipal incinerators; (2) iron and steel
mills; (3) primary copper, lead, zinc and cadmium smelters; and (4) secondary
zinc and cadmium smelters. Ambient air concentrations resulting from
emissions from most of these sources currently do not appear to pose much risk
to the general population; however, emission levels are such in some cases
that significant increases in cadmium body burden might be expected for
individuals residing near certain of the types of sources listed and these
1-3
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individuals may be at risk to ultimately manifest cadmium-induced renal
dysfunction.
Also of some concern are projections that can reasonably be made
regarding 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 may substantially increase ambient air levels
of cadmium, i.e.: (1) expanded municipal incineration 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) increased landspreading of cadmium-containing
sewage sludge or other waste materials on agricultural land used for growing
food crops; and (2) expanded use of cadmium-contaminated phosphate fertilizers
on agricultural land. Except in the case of the latter use of phosphate
fertilizers, current or anticipated EPA regulations are expected to provide
adequate control of cadmium entry into the environment from the above sources.
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
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txposure. 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 intro-
duced 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.
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 micrometer mean mass diameter (MMD) decreasing to about 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, appears to 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 5 to 6 percent of the cadmium entering the gastro-
intestinal tract is absorbed; based on clinical and epidemiological observa-
tions, 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
1-5
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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. However, despite
low concentrations in muscle, due to the large mass of muscle tissue, a large
part of the overall body burden exists in muscle tissue.
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 SO years of age, with a very large portion of the
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 decrease.
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, netallothfoneln, 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 or synthesis of the complex in kidney and
1-6
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other soft tissue apparently accounts for its very long half-time in the body.
Such binding initially results in protection against toxic effects potentially
exerted by unbound free cadmium; however, once metal!othione in binding and
storage mechanisms are saturated under conditions of prolonged cadmium exposure,
the presence and release of metallothionein-complexed cadmium can result in
substantial toxic effects. Thus, for example, nephrotoxic effects of cadmium
are a consequence of its mode of transport to and long-term deposition in the
kidney in a form complexed with metallothionein.
Acquisition of data on the uptake, deposition in body tissues, and excre-
tion of cadmium has been achieved through the use of sensitive measurement
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 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
1-7
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range of lexicological 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
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 dysfunction. 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 intoxication. 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:
1-8
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diffuse scarring of peritubular capillaries, interstitial edema, adhesions
between Bowman's capsule and globular 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 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
cadmium sulfate (.t 3 mg/m3) for seven months or to cadmium chloride in the
diet (at 200 ppm). The reductions in birth weights appear to result from
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
of 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 "subclinicaV effects of chronic cadmium exposure.
Some experimental evidence suggests that immune suppression 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.
1-9
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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
insufficiency. The inhalation of approximately 1 mg/m3 of cadmium over an 8
hour period gives rise to clinically evident symptoms in sensitive individuals,
whereas an air level of 5 mg/m3 inhaled over the same time period can be
lethal. At much lower air exposure levels, in the range of 1 to 100 ng/m3, 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.
Chronic adverse health effects of cadmium in nan 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 generally considered to be the main target organ affected by chronic
cadmium exposure, with renal dysfunction typically viewed as the "critical
effect." The renal dysfunction is specifically manifested in terms of 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 recognized 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 as a function of duration of cadmium exposure.
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Disturbance,, in kidney function also exert their effects on bone and
mineral metabolism, via effects on calcium and phosphorus, extreme examples of
which ..r. osteoporosis and osteomalacia. Itai-Itai or "Ouch-0.cn" disease
observed in Japan is essentially renal tubular dysf,nction with osteoporosis
and osteomalacia. Additional secondary effacts of rtna1 dysfunctl-on are
lodney stones, observed In Swedish workers exposed to cad.ium; and osteo-
malacia, in French workers.
It Shou!d 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 fro. human and
animal studies, that such irreversible damage typically occurs when cadmium
levels in the kidney cortex exceed approximately 200 ug/g wet weight
especially under conditions of continued exposure (see Risk Assent Summary)
The chief chronic plenary effect of cadmium appears to be centrolobular
emphysema and bronchitis resulting from several years of occupational exposur-
to cadmium oxide fumes, cadmium oxide dust, and cadmium pigment dust. Lung
impairment is possible at cadmium oxide fume levels below 100 pg/^ Of work
place air, depending upon exposure time.
As for other health effects, although hypertension has teen demonstrated
in laboratory animals chronically exposed through the diet, there is presently
no conclusive evidence that cadmium is an etiological factor in human hvper-
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,
1-11
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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
teratogem'c effects have been demonstrated in animals at high exposure levels,
no evidence has yet been advanced for cadmium being a human teratogen.
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 _in 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 nan, 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 delta on tumorogenic effects induced at high
exposure levels achieved via systemic injections. As for carcinogenic effects
in man, some evidence suggests that heavily-exposed industrial workers may be
at higher risk for prostatic cancer; but that evidence is not conclusive.
Also, some data show a correlation between cadmium in drinking water and
cancer incidence in large geographic areas, but this data is confounded by
the presence of other potentially carcinogenic metals and smoking.
As indicated above, several well established health effects of cadmium,
e.g., renal dysfunction and its secondary consequences, have been shown to be
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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
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 and retention levels 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
1-13
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apparent that at least part of line difficulty arises from deficient cadmium
analyses.
"Average" cadmium blood values for the general (non-smoking) population
in the United States and elsewhere are typically 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
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 recent or current 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, regard-
less 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
1-14
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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 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 pg/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
1-15
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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 late appearance
of osteomalacia seen in Itai-Itai disease only after several decades of
exposure. The Japanese experience also illustrates the difficulty in ending
cadmium 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
1-16
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to conclusively establish that the metal exerts carcinogenic effects on
humans,
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, 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 environ-
ment. Much higher amounts of the metal enter the environment, however, as a
1-17
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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.
Ambient air levels of cadmium across the United States are usually in the
range of nanograms per cubic aeter (ng/m3); however, ouch higher ambient air
values, around 0.1 to 1.0 ug/m3 (100 to 1000 ng/m3), are at times found in
regions of high cadmium production and industrial use. This may be compared
to work place levels of about 50 to 100 ug/m3 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 potential long-range 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 Status, 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
1-18
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have cadmium levels below the recommended Public Health Service value of 10
parts per billion (ppb) (10 ug/1). It would be desirable, however, to determine
whether any contamination of drinking water by cadmium occurs from supply
distribution systems, particularly household plumbing.
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
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 consti-
tutes 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.
Data derived from fecal excretion studies and human tissue analyses
indicate that most adults (approximately 90 percent) in the United States, on
the average, presently ingest less than 25 ug of cadmium in their daily diets.
Based on six percent absorption in the absence of nutritional deficiencies,
this would correspond to an absorbed value of less than 1.5 ug per person per
day from food. Also based on such studies, only about 1 percent of the adult
population appears to exceed 50 ug/day dietary cadmium intake, resulting in
approximately 3.0 ug retention per day.
1-19
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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 signifi-
cantly. 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, as in the com-
bustion of coal, could also be a potential source of increased future dietary
cadmium levels, if secondary deposition from the air of cadmium onto agricultural
soils were to markedly increase as the result of inadequate emission controls.
Increased coal usage, however, is expected to be offset by expanded emission
controls.
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
1-20
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intake from cigarettes range from 4 to 6 ug 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 •Stimmary of human.health effects of c^mimn-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 ffiore appropriate to consider
chronic renal affects, 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.
Tubular proteinuria is the earliest demonstrable marker for renal
dysfunction induced by cadmium, with other effects' such as aminoaciduria and
glycosuria 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 more severe damage and has essentially no reserve
for protection against other pathological stresses. This vulnerability is
suggested by observations of increased health complications among certain
cadmium workers subsequent to their first exhibiting renal tubular
proteinurea. In addition, recently reported epidemiology data suggests that
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significantly increased mortality due to renal disease is experienced by
workers occupational1y exposed to cadmium.
, According to both clinical-epidemiplogical and model-calculation data, a
kidney cortex level of 200 ug Cd/g kidney (wet weight) can be taken as the
critical concentration, i.e., the level of cadmium in the kidney (critical
organ) at which the earliest discernible adverse effect (the critical effect
of renal tubular dysfunction) 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
4
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
precise ways to assess the extent, to which the kidney is on its way to
functional impairment. Urine cadmium is presently regarded as a better
indicator of body burden than blood cadmium. Another 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 ug 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 chapter of this 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 chapter (4), the
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P"C<> FOR BACKING A KIDNEY CORTEX
Basis of calculation**
Constant daily retention during
whole exposure time
25% pulmonary absorption, 10 m3
inhaled per work day, 225 work
days/year
Exposure
time
(yr)
10
25
50
10
25
Levels of cadmium retention
or exposure yielding renal
dysfunction, assuming cadmium
half-times of:
38 yr is yr
Daily retention (ug)
36 39
16 ,20
10 13
Industrial air concentration
(in ug/m ) yielding renal
dysfunction
23 25
11 13
/««nexpo,sur? for 50-yr-old Person 50
(2500 ca/day) (4.5% retention)
(changing caloric intake by age
accounted for)
Total amount (net weight) 300 g 50
of food/day ' 600 g
1000 g
Daily cadmium intake (ug)
250 360
Corresponding average Cd con-
centration in foodstuffs (ug/g)
0.8
0.4
0.25
1.2
0.6
0.35
Jro?kFr«»«r8. L M. Piscator, G. 6. Nordberg, and T. Kjellstrom
Cadmium in the tmnronment. CRC Press, Cleveland, 1974. *jeustrom-
retention reache« Mdney and kidney
kidney concentration. From
«el,t1on,hip, of Heavy
1-23
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daily retention values of cadmium in the body for these half-times and various
exposure periods are determined.
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 empirical data that fit well with various
estimates within the above range of theoretical estimates; a Working Group of
Experts for the Committee of European Communities (CEC), however, has tenta-
tively concluded that 200 to 248 ug/day is the best estimate of daily dietary
intake necessary to reach the renal critical concentration of 200 ug/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
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Table 1-2 MEDIA CONTRIBUTIONS TO NORMAL RETENTION
' OF CADMIUM5
MecH urn
Adult
Exposure level
Dally retention
(ug)
Ambient air x20 m /d
Water x2 1/d
Food x2 kg/d
Cigarettes
packs/day
1/2
1
2'
' 3
0.03 ug/m3
3ug/l
50 ug/day
ug/dayb
1.1
2.2
4.4
6.6
0.15b
0.36C
3.0d
0.70®
1.41;
2.82*
4.22e
•Modified from: Oeane, L. G , D. A. Lynn and N. F Surprenant.
Cadmium: Control Strategy Analysis. ECA Cong , Bedford,
Mass. U.S. Environmental Protection Agency. 19/b.
bBased on 25 percent deposition and assuming 100 percent absorption
of deposited amount.
cBiased on average American drinking water levels of 3
assuming 6 percent absorption from gastrointestinal tract.
dBased on 6 percent absorption from gastrointestinal tract.
on 0.11 ug Cd per cigarette and 6.4 percent retention rate
alcoholic- habit and disease. J. Chron Dis. 25:712-726, 1972.
1-25
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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 dysfunction 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. According to that theoretical framework, a daily dietary intake of
60 pg/day, for example, would be predicted to produce, by age 50, a renal
dysfunction response rate of 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. Actual, observed prevalence rates in certain epidemiologic
studies appear to fall in the general range of predicted rates for dietary
levels markedly above 100 ug/day. However, due to the lack of much empirical
data for lower dietary intake levels, little confidence can now be placed in
the rates predicted for dietary levels under 100 pg/day. Also, certain other
reservations concerning key assumptions underlying the model, as discussed in
Chapter 4, argue against employing its predictions for risk assessment purposes
at the present time.
In regard to empirical dose-response data relating dietary cadmium intake
levels to prevalence of renal dysfunction, evidence has been reported for
statistically significant increases in cadmium-induced proteinuria occurring
in Japanese over 50 years of age as the result of chronic dietary cadmium
1-26
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1'ntake of approximately 100-150 ug/day. An equivalent intake level of 150-200
ug/day would obtain for Europeans/Americans, taking into account larger body
and kidney sizes of the latter in comparison to the Japanese.
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 potentially being at risk
for experiencing adverse health effects associated with exposure to the metal.
Generally speaking, other than for certain oceupationally 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
-------
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 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 up to approximately
70 ug/day for teenage males. On the other hand, more recent estimates based
on fecal cadmium excretion measurements tend to be much lower, i.e., with mean
dietary intake for adult non-smokers being around 18 ug/day and approximately
90 and 99 percent of the population being below 25 and 50 vg/day, respectively.
1-28
-------
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 ug/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 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, (less than 1 percent exceeding 50 pg/day), that margin would be "
less. Also, certain other population groups can be identified as potentially
being at special risk. '
More specifically, based on data discussed previously, cigarette .smokers
constitute a large population at special risk for cadmium-induced renal effects.
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
1-29
-------
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1.4.4' Overall Conclusions
Uptake of cadmium in nan 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 occupa-
tional 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, »ay not exceed by much the levels presently
encountered by some Americans via dietary intake and other exposure media,
especially cigarette smoking. Thus, uncontrolled Increases in cadmium exposure
from whatever source may reduce an already low margin of safety before adverse
effects would be expected to occur Un some members (especially smokers) of the
American population.
As for ambient air as a possible source of increased environmental cadmium
exposure, calculations summarized in Table 1*3 suggest that, in general,
ambient air exposures below 10 ng/m3 do not significantly increase kidney
cortex concentrations of cadmium, whereas at 100 ng/m3, notable accumulations
of renal cadmium begin to occur and, by 1000 ng/m3, approach critical exposure
levels for induction of renal dysfunction (in conjunction with background
dietary exposures). As discussed in Chapter 4 under Exposure Sources, annual
average ambient air levels of c«dmium in the vicinity of certain cadmium-
emitting industrial facilities or municipal incinerators have been estimated
to exceed 100 ng/m3, but few appear to approach 1000 ng/m3. Table 1-4 presents
estimates of the numbers of Americans exposed to various annual average concen-
trations of cadmium in air derived from different current major emission sources.
1-32
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1-33
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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 expanded
nunicipal incineration of solid waste materials and expanded fossil fuel use,
especially increased coal combustion,, if emissions from these sources are not
adequately controlled. 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, may not be adequate in terms of truly safeguard-
ing the public health. Instead, a well-coordinated comprehensive plan for
controlling exposure of the general population would be desirable.
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 nan and experimental animals under conditions of acute and
chronic exposure to cadmium. These responses are discussed 1n 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 ingestlon of the element are probably of nore 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, 1n large measure, macroscopic mani-
festations of Injury at'the cellular, subcellular, and molecular level.
Thus, enzymological, subcellular and cellular studies, both jn vivo
and in vitro, are discussed first along with consideration of the role of
metallothionein. 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 iromunosuppressive 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, cadmium/calcium, 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 tp 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
-------
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 aj. (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 (HMD) ranging down to 10 percent for particles with HMD of 5
micrometers.
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
-------
provide figures of 10 to 40 percent (Friberg et a].., 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 nan 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 netal, play a role in modifying this
figure, with certain nutritional deficiencies leading to an enhancement of
cadmium absorption in man and animals (Friberg et al.., 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
Vahlberg, 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
-------
of cadmium 1. a ,ubjen of controversy as is discussed later in the Risk
Assessment section (4.).
Animal studies (Friberg et ah , 1974) show that, in the time immedi-
ately following parenteral administration of cadmium ion, «,it of blood
cadmium is found in plasma. Furthermore, there 1. Initially a rather rapid
clearance of cadmium fro,, blood. This is followed by .'slower decline and
a subsequent rise In in the Cd content of both plasma and cells, with a
larger comparative amount accumulating in the arythrocyte. 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 aj., 1974).
Much data exist on the relative distribution of cadmium among various
organs in man and experimental animals and these have been reviewed (Friberg
£t al., 1974; Nordberg, 1972). In populations with minimal exposure to
cadmium, about half of the organ distribution of cadmiun, 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 metallothionein 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 auscle versus liver and kidney tissue, the
absolute amount of cadmium found in muscle within a given mammalian organ-
ism can be considerable.
2-5
-------
Simple model projections for the half-time value for cadmiun, 1n various
organs predict, for example. • value between 17.6 yr (Tsuchiya and Sugita,
1971) and 38 yr (Kjellstrom, 1971) for kidney and kidney cortex 1n 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
•ode! is still useful for most practical purposes.
Metattothionein, 1t should be noted, plays a major role in the move-
ment and excretion of cadmium in 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
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
-------
has been observed that only relatively snail 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 aj., 1974; Lauwerys «t al«. 1974; Singerman,
1976).
In «an, under conditions of low-level, chronic cadmium exposure,
cadmium loss via the urine is typically < 1 Ug/day (Johnson et jrt.. 1977;
Elinder et aj., 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, 1t has yet to be demonstrated that It 1s a significant
factor in man (Stowe, 1976; Cherian, 1977; Cherian and Vestal, 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 metallothionein
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 jn vitro to enzymic effects
that may contribute to a significant part of the in vivo pathology of cadmium.
2-7
-------
Since much of the fonner tends to have little relevance to in vivo conditions,
ouch 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!oenzyme*. as in the case -of substituting
for zinc in zinc metallotnzymes. Similarly, cadmium may interact with the
substrate for an enzyme, sufficiently perturbing the conformation to marked!y
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 in vivo or jn vUro in nature. In the text, in vivo and H,
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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that inhibition of the inducible tnzyme complex aryl hydrocarbon hydroxylase
(AHH) occurs in nice given 3-nethylcholanthrene intraperitoneally (i.p.) in
trioctanoin (0.01 iil/g) and cadmium ion in one of two injected doses: 5
«g/kg and 3 mg/kg. At the higher dose, enzymic activity was almost conr
pletely quenched, while little inhibition was noted at the lower exposure
level. In a related in vitro study, using a 10 percent liver homogenate,
Tsang and Furst (1976) showed marked inhibition of this enzyme complex by
five different Betal ions, of which cadmium was the most inhibitory.
An acute effect of cadmium on hepatic netabolizing enzymes in the rat
was noted by Teare et al. (1977). A single i.p. injection of cadmium
chloride at levels of either 2.5 or 3.8 «g/kg into aale rats produced
significant (25 to 60 percent) inhibition of aniline hydroxylase and nitro-
reductase activity and reduced raicrosomal 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 inhibition in phosphate buffer and more significant
inhibition in Tris buffer.
Krasny and Holbrook (15)77) 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 bs were
decreased by 44 percent and 27 percent, respectively. At day 7 these
values returned to normal. The microsomal enzymes aminopyrine demethylase
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. Heine 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 tine.
Several reports have appeared describing the ^n vivo and in vitro
effects of cadmium on adenylate cyclase and other components of cyclic AMP
(adenosinci 3':5'-cyclie phosphate) Metabolism in animals.
Singhal et al. (1976) observed that, while chronic cadmium treatments
1n rats (daily 1.p. Injection of 0.25 er 1.0 ng/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
eyclase were markedly increased. However, the amount of cyclic AMP binding
to hepatic protein Idnase was decreased, as was the kinase activity ratio.
In an i£ vitro study, Nathanson and Bloom (1976) have shown that both
basal and hormone-stimulated adenylate cyclase activity of various tissue
homogenatfis and their paniculate fractions were inhibited by very low
levels of cadmium and other heavy netal 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-Lewi site (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
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cadmium levels of 10'4 H, Na*-K* ATPase was inhibited, regardless of source
or type of enzyme preparation, with the effect being ten-fold greater than
the corresponding inhibition of Hg^-ATPase. The inhibitory effects were
not altered by sodium or potassium levels, but were decreased by etbylene-
dianrinetetraacetic acid (EDTA) addition.
Sugawara and Sugawara 01975) studied the effects of cadmium admini-
stration (100 ppm cadmium solution ad libitum for 30 days) on selected
enzyme activity in duodenal nucosa in male Wistar rats. Inhibition of
brush border ATPase and alkaline phosphatase and increase in th* activities
of isocitrate dehydrogenase and glucose-6-phosphate dehydrogenase (G-6-PD)
were noted. Such in vivo effects could not be duplicated, however, with in
vitro studies using comparable cadmium levels.
Iqbal et al. (1976) studied the In 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 in vitro and in 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
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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 affects 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 al. (1974), the ion is active at three
places.
(1) It binds to suHhydryl 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 D3
( H-25-OH-D3) metabolism was studied as a function of added cadmium ion.
As little as 2.5 x Itf5 M cadmium ion completely inhibited the biosynthesis
of the active form of Vitamin |>3. This is in contrast to in 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 «g/kg/wk).
Mitochondria exhibited diminished respiratory control with progressive
cadmium intoxication. Cadmium added in 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 in vitro at levels greater than or equal to 10"4 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 a_K (1976) showed, in an in 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. .In vivo, oral
administration of cadmium. (300 ppm in water) reduced the respiration control
ratio and the P/0 ratio but increased mitochondria! cytochrome a (+a ) and
cytochrome c (+C,).
Stoll et al. (1976) have investigated the biochemical activities 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,
2-16
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ribonucleic acid (RNA) synthesis was inhibited. When hepatic microsomes were
preincubated to destroy messenger RKA (mP.NA), the polyt'ridylic acid-directed
incorporation of l-[~ C] phenylalanine was significantly inhibited by cadmium
pretreatment; and such activity was inhibited ir, the sam-2 way when cadrr.ium
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
in vitro by isolated ribosomes in an amino acid-incorporating system.
Hego 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 LD50 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 proteclysis 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 & mo), cadmium was localized
mainly in the apical vesicles, lysosomes, and cytoplasm of proximal tubular
cells.
Hidalgo and Bryan (1977) used radioisotopic cadmium (115Cd) 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-IS
-------
fractions. The nuclear cadmium was more concentrated in non-histone pro-
teins than in the histone proteins. Cytoplasmic cadmium was associated
with two meta]-binding protein subtractions.
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 ng 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 aj_. (1975)
have employed an ^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 aost toxic at Hietal 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 aJL , 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"5 M, showed signifi-
cant lowering (p < 0.001) of the phagocytic index (PI)
2-20
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Using pulmonary alveolar ne-rophages, peritoneal macrophages, and
polymorphonuclear neutrophils from the mouse, Loose et al. (1977) observed
no significant alteration in their resting oxygen consumption when incubated
; in media containing cadmium salts. When heat-killed P. aerueinosa were
added to the cell suspension, however, z significant depression in respira-
tory burst following phagocytosis was apparent anc dependent on cadmium
concentration, starting at 3.6 x l(f5 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, ss reported by Cook et al_.
(1975a,b). ~
An in .vitro investigation by Kawahcra et a}. (19/5) involved cells
from L-strain fibrotlasts derived from the C3H-strain mouse, cultured with
YLH medium and supplemented with 10 percent bovine serum. A level of
cadmium ion of 15.6 ug/ml medium was used. Severe changes were noted under
an electron microscope: ribosomel disappearance, mitochondria! 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 al. (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 pg/ml streptomycin. Cadmium ion was added cr, 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 uM. The LD5Q 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
jjg/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 aj. (1974).
Cadmium-thionein and other metallothionein-like proteins have been
isolated and studied from'a number of. organ systems of varous species,
including man. Since metallothionein is an inducibl.e 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
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While this protein may be involved in transport of cadmium in the
• Plood, in organ distribution, ano in excretion (Kordberg, 1972), questions
have been raised as to whether aetallothionein provides a protective function,
as was first suggested by Piscator (1S64), or whether this role is secondary
to its regulation of zinc ancYor 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 ah, 196S), since with repeated doses a
larger portion of the dose accumulates in liver and kidney as metallo-
thionein (Webb, 1972).
In the study of Lebcr 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 givan 2 days before cadmium challenge
resulted in LD5Q values of 6.0 and 8.2 ms/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 metallothionein
was seen to be proportional to'pretreatment dosing.
Webb and VerschoyJe (1976) reported that pretreatment of female rats
with a low dose of cadmium ion provided defense against a subsequent,
usually lethal dose of the metal 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-
T PiQ
mium ( 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
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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 * larger
quantity of cadmium Diven 1n multiple doses, Webb claims that neither
preinduction of the protein nor 2inc-thionein serves a protective function.
This .ay 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 .1. (1977), a dose-dependent toler-
ance to acute cadmium toxicity was evidenced by elevated L05Q values in
cadmium-pretreated nice. Also, hepatic -etallothionein levels increased
with the increase in pretreatment dosing. Since pretreatment at a level of
2.0 mg Cd/kg, but not at 0.6 »g/kg or 0.2 Bg/kg, resulted in elevated LD5Q
and cadmium-binding capacity relative to controls, it appears that a .mi-
ni dose of cadmium aust be exceeded in order to occasion sufficient induc-
tion of metallothionein to modify the acute toxicity of the metal (Probst,
1977).
The protective behavior of cadmium pretreatment was also studied by
Squibb et al. (1976), who. observed that rats pretreated with 20 mg
Cd/kg followed by another oral dose of 100 «ng 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 metallothionein. In ani-
mals not given pretreatment, metallothionein-bound cadmium was not observed
2-24
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until 15 hr later. Radio-labeled cystein studies (35S) showed that bio-
synthesis of the binding protein occurred following metal exposure. The
observation that-oil of the csorsiuir in intestine was bound to metallo-
thionein may suggest that the protein has a role in affecting cadmium
absorption during low-level cadmium exposure.
Chen et aj. (1975a) studied the synthesis and metabolic degradation of
rat hepatic metsllothionein stimulated by cadmium challenge. In regard to
degradation of the protein, the half-1ifve 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 metallothionein 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 metallothionein in rats with cad-
mium, labeling the formed metalloprotein in vitro with either 109Cd, 14C or
S. After isolation from liver and subsequent intravenous administration
to rats (at Cd levels of ID, 30 and 200 ug Cd), it was observed that tissue
distribution of the radiolabeled ion in the metalloprotein 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 as cadmium-thionein.
Furthermore, the distribution and excretion of the thionein moiety was
similar to that of cadmium.
2-25
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Several reports have sfnce appeared in the literature relating the
comparative toxicity of cadmium-thionein to ionic cadmium when administered
as such. Cherian «t aj. (1976). for instance, isolated cadmium .etallothi-
onein from livers of metal-exposed rats, labelled the metalloprotein 109Cd,
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 observsd 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 nice in the form of
either cadmium chloride or c«dmiurn-metallothionein labeled with 109Cd. 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 metallothionein-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).
Cadmium-metallothionein, .labeled with 109Cd in 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 metallothionein
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
2-26
-------
than was ionic cadmium. Zinc-thionein was not only nontoxic, however, but
protected th< animals from a subseoueat, 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
fey 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 in an inert form up to a certain level,
but beyond that level is probably released in a systemically toxic form.
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 aj. reviewed the earlier litera-
ture 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 aK,
1974). It has been estimated that the pulmonary retention of 4 mg in man
is fatal (Gleason cjt a_l. , 1969).
2-27
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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. Ihe 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 (Eriberg et'al.., 1974). Furthermore, lung impairment is
likely at cadmium oxide fume levels below 0.1 aig/m3.
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.
2-28
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Several reports have appeared dealing with the effect of cadmium salts
in vivo and in vitro on human alpha-1-antUrypsin, the major proteinase
inhibitor in human plasma, a deficiency of which is associated with chronic
obstructive lung disease. Chowdhurdy and Louric- (1976) reported a concen-
tration-dependent decrease in both antitrypsir, level and inhibitory capa-
city in response to added cadmium. No othsr heavy metal was seen to have
this effect. Glaser et ah (1S77), 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 in 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 oh c^-anti-
trypsin is that of Bernard et aj. (1977). Their results, using workers
exposed to excessive amounts of cadmium and showing signs of cadmium intox-
ication, did not indicate any reduction of oyantitrypsin 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
relevant .study, mice exposed to cadmium fumes (1.3 to 1.7 mg/m3) 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 p ana
found the value to be 25 ng/m* for a period of 30 min. Retention of
2-29
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inhaled cadmium in the lung was 15 percent at a 30-nrin exposure level of 20
ng/ra , and at 1 wk post-exposure 54 percent of the cadmium body burden was
still retained in the lung.
Cadmium dust (1.1 «g/m up to 4 wk) was seen by Watanabe et a^. (1974a)
to produce effects in rats that included septa! interstitial pneumonitis
and cell nuclear changes.
Hayes et al.. (Strauss et aL, 1976; Hayes et al., 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 tag Cd/m3) for an exposure period of 2 hr, these workers
(Strauss rt al_., 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) Type 1 cell edema occurred, 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 a].., 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-S-PO activities had all doubled, coinciding
with doubling of lung weight and total lung DNA content. Malate 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
2-30
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of the effect on malate dehydrogensse, whicn is an index of mitochondria!
injury, the biochemical responses appear to be nonspecific.
Adalis et al. 0977) studied th« effect of csdn-lum en ciliary activity
using isolated hamster trache*! rings and an organ-cultur. system. StatU-
tically significant reductions in ciliary activity wers sesn at C^ium
concentrations as low as 6 MK. si.Jl.rly, cilia fro, haters exposed to .
cadmium chloride aerosol (2 ^ 2 hr, 50 to 1420 ug/m3) wn studied. Jn
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) wa* obsarved in mice exposed to levels of 80
to 1600 Hg/m3 followed by streptococca) challenge. Thare was a marked
decrease in the total number of alveolar .acrophagei recovered from lungs
post-exposure, with a return to normal seen within 24 hr. Polynorpho-
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. Streptocacd
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 al, (1974) itudlid tho effect of
cadmium in rats exposed to dietary cadmium (17.2 uo/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-pleural tissue of the treated rats. Collagen fibrils were bundled.
2-31
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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. Ihe sub-pleura! elastic
layer showed focal disruption. Pew 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 ah, 1966;
Hurthy et al., 1972).
In the exposure study of Stelzner et £. (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-
Rent membrane were seen, proceeding to hyperplastic Type II cells and
layered membranous cells in the distal lung.
2.5 RENAL EFFECTS OF CADMIUM
Ihe effects of both acute and chronic exposure to cadmium on the renal
system have been noted in the literature fro* experimental animals and from
clinical and epidemiological data. Both acute and chronic aspects of renal
toxicity of cadmium have been reviewed by Friberg et £. (1974), Nordberg
(1976), and Kawai (1976).
2-32
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The most typical feature of chronic csdmium intoxication is renal
damage, and thus, the kidney may be considered the critical organ in
chronic exposure-(Nordberg, 1976).
In particular, cadmium affects the reahsorption function of the
proximal tubules, with an early sign of this eff5Ct being an increase in ;
the urinary excretion of low-molecular-weight proteins--tubu1ar 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 aj., 1942),
as well as certain populations in Japan exposed to dietary cadmium (Friberg,
ft aj. 1974). According to Piscator (1965a), once tubular proteinuria is
induced, 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 ejt a_K , 1576).
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According to Kawai et a_L (1976), there are norphologically 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 surrpunding interstitium is present,
eventually resulting in Interstitial fibrosi? and nephrosclerosis at a
later stage. Acute lesioning in tubular epithelium may be seen and is dose
dependent. These observations wggest that vascular injury probably plays
a major role in acute nephropathy.
In the studies of Kawai and coworkers (Kawai and Fukuda, 1974; Kawai
et ah, 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. Ihe corres-
ponding kidney aetal levels were 150 and 37 ug/g wet weight, respectively.
Cadmium excretion from kidney apparently increases as renal injury becomes
«ore severe.
Itokawa et ah (1974) studied two groups of rats that received 50 ug
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 amino acid excretion,
concomitant with increases in certain enzymes. After 38 and 42 wk, total
2-34
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protein and sugar levels respectively were elevated, but amino acid levels
after 30 wk were similar for both control and exposed animals. f,he corres-
ponding kidney cadmium levels for these time points were 200 an/300 ug
Cd/g wet weight.
Axelsson and Piscator (1866) showed that in the rabbit proteinuria
appeared before amfhoaciduria. 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. al. (1975), in their studies of cadmium-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 er-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. (1S75) studied the effects of chronic cadmium admini-
stration on rat renal vasculature using lew 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 peri tubular capill-
aries were observed at 6 v/k 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 tine. While vari-
ation in calcium intake did not appear to influence the vascular effects
studied, increased renal depositor 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 0. In the section dealing with subcellular aspects, it was noted
(Suda et ajh, 1974) that in vivo formation of 1,25-dihydroxy-vitamin Dj was
not markedly altered by a diet containing cadmium but that was Vitamin D
deficient.
In the study of Loreritzon and Larsson (1927), 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 cm reduction of the conversion product with low
calcium intake. Further, cadmium exposure showed a shift in Vitamin 0
metabolism over to formation of the less active metabolite 24,25-dihydroxy-
cholecalciferol.
Pierce et aj. (1977) investigated the use of urinary enzyme activities
as markers for the nephrotoxicity of cadmium in the marmoset and rat.
2-36
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Excretion of urinary enzymes in rats that had been dosed by subcutaneous
(s.c.) injection (1.5 «.g/kg/day) remained at control-animal levels to day
IS. An increase of p-glucosidase activity occurred and continued to rise
until the experiment was terminated (p < 0.01). N-acetyl-f-glucosaminidase
activity increased by day 18. With marmosets, oral exposure to cadmium was
without effect on urinary enzyms 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-acety'l-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 tubular 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 Vp2« and a globulins, ^-microglob.lin, retinol-
binding protein, and or 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.
2-27
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Clark and coworkers (1975) 1n their studies of tritium-labeled retinol
show that cadmium-treated1 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.$
»g/kg body weight, s.c. S times per wk) and found a large excretion of
retinol-bound protein of molecular weight 20,000. Though similar to human
RBP (Kawai et aj., 1971, 1972) they are Inmunologically distinct.
Perhaps a more significant urinary protein in terms of its being an
index of renal damage induced by cadmium is B2-microglobin. The bio-
chemical and diagnostic aspects of this protein have been reviewed by
Kjellstrfim 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 Beam
(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 (jg is excreted
daily via the normal kidney.
Coupling of the known data regarding the renal biochemistry of B.-micro-
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 0--microglo-
2-38
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bulin excretion than in total protein levels suggested that ^-micro-
globulin analysis may be.the most sensitive methoo 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 0 -
tiicroglobulin measurement to assess proteinuria (Kjellstrom et ah, 1977a,b;
Kojima et aj, , 1977). The frequency distribution of individuals in normal '
groups was log-normal. Geometric average values of ^-microglobulin in the
general population range from about 50 to 100 ug/urine, while excretion
levels in excess of 200 ,.,g/l .nay be considered to ba abnormal.
The dose-response relationship between increases in urinary excretion
of this protein and cadmium exposure are evidenced by the data of Kojima et ah
(1977) and Kjellstrom et a_l. (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 a_l. (1974) and by Shigematsu (1975), and particular attention
has been given to Itai-ltai (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-ltai disease is essentially
cadmium-induced renal tubular dysfunction in a nutritionally-deficient
2-39
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. population, leading to osteomalacia and osteoporosis. Most of the victims
were post-raenopausal 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 Euchu in Toyama Prefecture where
rice fields irrigated by the Jintsu River were contamininated by waste
products from a mine. As cited by Eriberg et al. (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 Euchu and
Tsushima), there is a substantial increase in prevalence with age; and in
Euchu the causal role of cadmium in this relationship is apparent. Eurther-
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 aj., 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 p-microglobulin
excretion, it was determined that proteinuria in Itai-Itai disease is
tubular. In particular, fymicroglobulin excretion, an index of. tubular
injury, was found to be over 100 times higher than in a reference popula-
tion.
2-40
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Epidemiological aspects of cadmium-polluted areas of Japan are dis-
cussed in a later section dealing with epidsmiological 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'animsls 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 the role of cadmium 1n the etiology of human hypertension still
remains to be resolved.
2.6.1 Animal Studies
Perry (1976) and Friberg et aj.. (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 cadmium-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 aj. (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 a_1. , 1978). In addition, simultaneous feeding of lead and cad-
mium can markedly augment cadmium-induced hypertension (Perry et al.,
1977a).
2-41
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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 1n observing
the effect.
Frickenhaus et al. (1976) exposed rats to cadmium sulfide in their
diets (26 ing 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 nay have exceeded the lower exposure levels in the work
described above. In this connection, Perry et ah (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 EHanger, 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 in 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.
2-42
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.
study,
and
,„
en,
t.ssue ,evels „,
8rterjes
cad»,,.treaU3 and nMa, o s
,„ bo r _ ;
>
^ »•
'
posed to
cadmium for 24 month*; fm.nrf /• \ ^
months found (a) depressed myocardia! excitability (b)
to
Thlnd
an
~y „ Erlanger <1573)
cadmium- fed rats.
but noted
ecrea d b,ood.pressure ^^ ^ ^^
o, and,tropfne. aort)c Str].p5 fro> tbe aMmais ^
to ang,otens(n. epinephrinei ^
«• .«*« t,t production of hypertms,n ana
o, ,ascu,atu, to vasoconstrictor and vasodl,ators
biological events.
^ 1*. effects ., ,o. d)etary cadmfu, m b^ ^^ ^ ^
potass,™, and »5ter Peuntfon ,„ grOB)n3 rau ^^ •
ti 11- (-7,,, So.,. retentfon uas ,„ bMh M]e ^ ^
transuory greaur retsntjon ^ ^^
2-43
-------
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 oth«r 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 (3.5).
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
2-44
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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, historically
detectable testicular chang?s such as interstitial edsroa occurred and
progressed to extensive necrosis of the testes by 4£ 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 aj. (1964) injected a wider range of cadmium chloride
doses (0.51 to 6.8 Big 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 rnechanism(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
al_. , 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 pert, by virtue of varia-
tions in susceptibility of different species. It was first well-established
that mammalian species possessing scrota! testicles were susceptible to the
2-45
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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-scrota!
species with abdominal test.es, is 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-scrota! species listed
in Table 2-2, and (2) demonstration of variations in susceptibility between
strains within the same scrotal species (Gunn et a].., 1965; Taylor et al.,
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 perivascular
cells as well as loosened endothelial desmosome junctional complexes and
signs of raicrohemorrhaging ([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 (CAM), a zinc-containing metalloenzyme, was decreased in
testes after cadmium administration; and inhibition of CAH was taken to be
2-46
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Table 2-2. SPECIES VARIATIONS IN SUSCEPTIBILITY TO CADMIUM- INDUCED
TESTICULAR NECROSIS
'
Species
tested
Scrota! species
Rat
Rat
Mouse
Mouse
Guinea pig
Rabbit
Gerbil
Gerbil
Hamster
Dog
Dog
. Goat
Monkey
Non-scrotal speciets
Suncus
Fowls
Frog
Toad
Toad
Doves
Testicular damage
susceptibility Reference
<*) ' . Parizek (1957)
(*) Mason et a±, (1954)
(+) Parizek (1957)
("0 Gunn et a]_. (1955)
<+) Parizek (1950)
(*) Kar and Das (1962)
(*) Ramaswami and Kaul (1966)
(*) Berliner and Jones-Witters (1975)
("*•) Girod and Dubcis (1976)
(*) Chatterjee and Kar (1968)
(*) Donnelly and Monty (1977)
(*) Kar and Das (1952)
(*) Kar (1961)
(") Dryden and McAllister (1970)
(") Johnson et aj_. (1970)
(") Chiquoins (1964)
(') ' Biswas et aj. (1976)
C+) Chiquoine and Sunzeft (1965)
(+) Maekawa et aj. (1964)
2-47
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Table 2-2. SPECIES VARIATIONS IN SUSCEPTIBILITY TO CADMIUM-INDUCED
TESTICUI.AR NECROSIS (CONTINUED)
Species
tested
Testicular damage
susceptibility
Reference
Fish
Fish
Fish
Brook trout
Maekawa and Tsunenari (1967)
Sarkar and Mondal (1973)
Tafanelli (1972)
Sangalong and 0'Hall ran (1973)
2-48
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important in the etiology of cadniun-induced testicular necrosis (Johnson
and Walker, 1970). Subsequent work reported by Alsen et .1. (1976),
however, provides strong evidence against this. As for other research
attempting to identify particular proteins as pathogenic targets for cad-
-.1. in the testes, that of Chen et al. (1974) revealed two cadmium-binding
moieties corresponding to proteins of molecular weigh,s (HW) of 10,000 and
30,000 in the soluble fraction of whole tastes; and Chen and Ganther (1975)
• later provided evidence for involvement of the 30,000 NW protein in the
pathogenesU of testicular necrosis. This, however, is not supported by
the more recent data of Prohaska et al. (1977). Lastly, Omaye and Tappel
(1975) demonstrated reductions in plasma and testicular g1utathione (GTH)
peroxidase activity that they hypothesized to be- important in mediating
cadmium-induced testicular necrosis.
Certain data suggest that some cadmium-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 al., 1976; Saksena et
al., 1977), and increased testicular cholesterol levels indicative of
decreased anclrogen production by the testes (Dixit et VI.', 1975); (2)
alterations of cyclic AMP metabolism in the pri,ary and secondary/reproduc-
tive organs of the male rat consistent with reductions in testosterone
(Sutherland et al., 1974); (3) evidence of Leydig-cell necrosis or reduc-
tions in metabolic activities in those cells (Girod and Dubcis, 1974, 1976;
Dixit et al., 1975); (4) signs of hyperplasia of gonadotropic cells in the
anterior pituitary (Girod and Dubois, 1974, 1376), as well as increases in
plasma levels of leuteimzing hormone (LH) (Chandler et al., 1976) and (5)
2-49
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autoradiographic localization of cadmium in test'lcular interstitial tissue
(Nordberg and Nishiyama, 1972).
Chandler et aJL (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
eaniftsted. 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
Bice was previously shown to be testosterone-dependent (Thung, 1956;
Finlayson et aj., 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 tubcrtintously to r,bbUs 5 times per
week for 24 wk, caused no .acroccoplc.lly or .i.mcoplcaUy evident testi
cular changes but did cause marked kidney damage. In another study
Nordberg (1971) demonstrated that single, s.bcut.n.ous (s.,, ^.^ Q
cadmium chloride at 1 mg Cd/kg caused compete testicular necrosis in CBA
•ice, while single do..,'of 0.25 to 0.50 mg Co/kg caused little or no
damage to the tastes., After administration of such doses 5 days/wk for 6
•o. no significant testicular changes .ere apparent at the 0.25 ag/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 pp., i.e., approximately 20 t1.es as high as the levels (0 3
PP.) found to exist in the aice experiencing severe testicular necrosis
after a single i.o mg Cd/kg injection. Repeated injections of 0.25 tog/kg
.doses, to stimulate metallothionein synthesis, prevented the induction of
testicular necrosis by a 1.0 mg Cd/kg dose administered later. A1so, no
testicular necrosis occurred after injections of cadmium (1.1 mg Cd/kg)
partially bound to metaHothionein. When the same chronic dosace regimen
as the first one used in the Ncrdberg (1S71) study was employed in a subse-
quent experiment on renal effects, Nordberg and Piscator (1972) found tna,
CBA mice receiving s.c. injections of 0.25 to 0.5 mg Cd/ks, 5 days/wk for 6
wk, developed «igns of kidney damage.
Considered together, the above results appear to indicate that testi-
cular damage does not occur after repeated administration of cac.ium com-
pounds at doses causing only 8liflht or no kidney malfunction_ Qther
suggest, however, that more subtle testicular effects may occur in the
2-51
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absence of clear-cut kidney damage. Nordberg and Piscator (1972), for
example, found a significant decrease 1n protein excretion before the onset
of renal tubular'dysfunction resulting in narked proteinuria, and Nordberg
(1975) demonstrated effects on the seminal vesicles in the absence of
changes in testieular 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 testieular function were detected at cadmium exposure
levels below or equal to those producing signs of relatively slight renal
damage. Whether any such subtle testieular effects occur with chronic
low-level cadmium exposure remains to be demonstrated, however, since
moderately high acute doses of cadmium were used in the above studies.
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 gonadotoxlc effects were reported to have occurred in conjunct
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.
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American phases of the same Soviet-American cooperative project have
not yielded wuch evidence of Usticular damage, pi*0n et a],. (1976) reported
that possible "subtle reproductive effects" of cadmium were assessed 1n
wle rats exposed orally to cadmium chloride at concentrations pf 0, Q.Q01,
0.01, or 0.1 ng/i in the drinking water, yielding estimated waxifltum doses
of 14 ug/kg/day, Randomly selected mlmal* 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 cadmiurn-exposed animals at
any dose level or exposure time. Nor were any significant general texie
effects obtained with a variety of clinical serum chemistry tests,
In another study, Looser and Lorde (1977s) reported that cadmium
chloride fed to groups of 20 male and 20 female rats over § period of 3 m
in concentrations of 0, a, 2, 3, 10, and 30 ppm caused ne h1stppatheleg1«al
signs of damage in the gonads or any other organs, Similarly, no signifi>
cant effects were observed after the administretion of the same deses of
cadmium chloride for 3 mo to groups of 2 male and 2 female b.eagle dogs ta§h
(Loeser and Lorke, 1977b),
The LoeMir and Urke (I977a,fe) and Dixgn |t a^, (i§7§) results r«i§t
serious questions about cadmium having significant effects on malt
ductive organs or functions when administered chreni^lly at lew
levels. Still, since little or no data were reposed on tissyg leyfl§ of
cadmium achieved .in those studies, it is difficult to plase them in
tive in relation to cadmium exposures known to produge other types of
damage, e.g., renal dysfunction, Also, it remains tg be assess^ as to
whether longer periods of exposure at, the dos§ levels used might not
significant testicular effects,
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2.7.2 Ovarian Effects
Stimulated in part by findings of testlcular necrosis 1n 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
atresla 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 ill 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 thi
ovaries. In a later study, Kar et al. (i960) .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 und selenium against cadmium-induced testieular
.necrosis.
Evidence for cadmium-Induced ovarian damage of the type described by
Kar et aj. (1959) has not been universally obtained by other workers. In
that regard, Gunn »t •!. (1961) did not detect any pathological ehanges 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 Oer et al.
(1977b) observe any pathologic or abnormal histology of ovary or uterus
after dally intramuscular injections of 50 or 250 \tg CdClg in adult Wistar
female rats for 54 days, although persistent dlestrus was seen in the 250
2-54
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ug dose animals. On the other hand, very distinct gross and morphological
correlates of antigonadal effects were observed bj Kaul and Ramaswami
(1S70) in the female gerbil. After a single subcutaneous injection of
either 0.22 mg Cd/kg in immature animals or 0.45 nig/kg in nature 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 embryotoxic 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. 4
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 aJL , 1963).
2-55
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In another study, Chernoff (1973) Injected rats with cadmium chloride
(2.5 to 7.5 ftg Cd/kg) on each of 4 consecutive days, starting efther 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-
uium chloride, with narked differences between the stocks occurring in
fetal aortality 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
(CdS04) into pregnant mice from day 6 to 14 of gestation resulted in embryo
deaths and congenital anomalies such as exencephaly. cleft palate, and bone
Dial formations. Results obtained depended on the day of injection; that is,
injections on gestation day £l 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
2-56
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evidence regarding genetic influences on the induction of fetal cadmium
effects. For example, Ishizu et al. (1973) exposed pregnant nice on gesta-
tion day 7 to cadmium chloride via s.c. injections of doses of 0, 0.33,
0.63, 2.5, and 5 ng Cd/kg. Dose-dependent effects were observed at doses
above a no-effect level of 0.33 ag/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 «ay not cross the placenta! barrier very
well.
Evidence for genetically inherited differential susceptibility to
cadmium-induced embryotoxicity has been provided by Wolkowski et aj. (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 aj. (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/kg of CdS04 on day 10 of gestation.
The hairster 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
2-57
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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 nalformations such as cl«ft palate and Tips. Further characteriza-
tions of teratogenic effects were carried out 1n subsequent studies
(Mulvihill et al.. 1970; Perm, 1971; Gale and Perm, 1973), with similar '
Intravenous injections of CdS04 at a dose of 0.88 ng Cd/kg being used in
each. Mulvihill et al. (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 Dal formations
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 Pi»rm 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 al. (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 aj..,
2-58
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1969). Overall, these resuHs were interpreted by Fern, (1971) as indi-
cating that cadmium may act direct!* on embryonic tissue by interfering
with 2inc-metaHoenzyn.es such as carbonic anhyd^e or alkaline phosphatase
By anology, possible Interactions of cadmium with selenium-dependent enzyme,
«ay .1.0 be indicated -In view of protection b3ing offered against temo-
genic effects of cadmium by selenium administer^ within 30 minutes of an
injection of an otherwise teratogenic dose of cadmium. Also, Semba et al
(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 metallothionein 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 sub.c.te 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
2-59
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assessment of potential effects 1n humans typically exposed via different
routes (oral and Inhalation) and to much lower levels of cadmium. Of wore
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 Kitchener (1971), Pound and Walker (1975),
Wills et a_K (1976), Choudhury «t ah (1977), and Campbell and Hills (1974).
In the Cvetkova (1970) study, female rats were exposed for up to 7 mo
to CdS04 (3 mg/m3) via inhalation. Alterations in the estrous cycle were
observed in 50 percent of the exposed rats by 2 BO and in 75 percent by 4
BO, 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 Kitchener (1971). They exposed mice to cadmium in the
drinking water at doses of 10 tig Cd/ml continuously throughout a sequence
of breeding of randomly selected pairs of males and females over a 6-mo
exposure period. Hales 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
2-60
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ft
anomalies such as sharp angulation of the tail being seen in exposed P. and
F2 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 peirs failed to breed.
Pond and Walker (1975) assessed the effects on reproduction of 200 ppm
of Cd as CdCl2 added to diets varying in calciurr 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" tnpmaVies 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 Tow-
calcium groups when compared to the high-calcium closed animals.
Wills «t al. (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 cf 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 tye 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 aT_., 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
eonkey and one exposed at 1.5 L>g/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 Invel 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 United value due to the very small numbers of
animals tested. » <• .''•••
• £.-•
While the results of Wills et al. (1976) on monkeys are of very ques-
"""if
tienable import, the findings obtained in the other st,udie.s on rats and
mice do appear to have some value for the analysis of the effects«of chronic
.,.- • '^v ,. _.,..-.
low-level cadmium exposures on reproduction and development. In at least
'•• M.
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 1n earlier studies ta be
Induced by acute, high-level exposure via systemic injections... Another/
': • TV** •'"^" '
much more consistent effect reported in several of the studies, however," is
* »tj" '
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
2-62
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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 an this issue and, in general,
appear to indicate that transplacental transfer Of the -eta! probably plays
a far less important role than other factor?.
Many studies indicate that transplacental transfer of esdmiMm does not
occur to any great degree. Ishi20 et al, (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 jjg/g, respectively.
The Ishizu et al. (1973) results are consistent with findings of
little fetal uptake during late gestation as assessed by autobiography
(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
the hamster, while Volkowski (1974) found that trace amounts of 109Cd
crossed into the fetus on days 13 and 17 of gestation in mice and Lgcis 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_I.,
1975). In the Dencker study, pregnant hamsters and mice were injected
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intravenously with 20 MCi ™CdCl2 (,.... 0.21 g «»cd) .t different t1.es
during pr.flnancy. Then, the whole animal, the uterus, or the embryos were
processed for autoradiography. On the .iflhth day of gestation, low .mounts
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, Placental transfer rates of
cadmium in rats were assessed in relation to dose (0.1, 0.4 and 1.6 mg
CdAg) and gestational age (12. IS .nd 20 days) at which pregnant dams were
Injected intravenously with « sinfl1e dose of 109CdC12 (approximately 20
uCi/.nimal). The animals were sacrificed 24 hr after injection of the
tracer, and 109Cd concentrations were measured in the fetus, placenta,
•aternal liver, and blood. As shown in Table 2-3, very small «,ounts'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, placental 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 early cadmium crossing of the placental barrier occurs early, but not
late, in pregnancy. In either case, it appears that only . very small
.mount 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
2-64
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Table 2-3. CADMIUM IN PLACENTAS ANP FETUSES9
•
Placentas®
Fetuses
Dose,
egAg
0.1
0.4
1.6
0.1
0.4
1.6
Cd,
Gestation
day 12
0.063 4 0.043
• 6)
0.232 t 0.032C
(1-6)
0.206 4 0.057C
(1.3)
0.00012 ± 0.00004
-1) A
0.0022 4 0.0023°
(1.1) ,
0.0217 4 O.Olir
(0.9)
X/o of injected dos«
(•Citation
-day 15
0,OU5.» 0.4S
(5.8)
0,142 4 0.124°
(4.7) „
0.466 4 0.147°
(3.8)
0.0014 4 0.0001
(6.8)
0.0027 4 0.001°
(7.6)
0.0096 4 0.0025°
(4.9)
™_
Gestation
day 20
1.403 4 0.293
(5.6)
1.347 4 0.127
(5.8)
0.587 4 0.167
(6.9)
0.0019 4 0.0003
(64.7) .
0.0036 t 0.0016°
(69. 1)
0.0152 4 0.0058°
(50.8)
felelT 4 ~ '
sacr1ficeti 24 hr «fter Cd treatment at various
! ?%*** W6]9ht Of P^centas per Titter or average
least three animals were used to obtain each value.
ignificantly different from 0.1 ing/kg dose level, p < 0.05.
Significantly different from 0.1 ag/kg dose level, p < 0.01.
eSt°r P1acenta1 «ata revealed significant dose-response
rrirsr-1 -^tioii-^
*°l !?tal,data «vealed significant dose-response
2-55
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Table 2-4. PLACENTAL TO MATERNAL BLOOD CONCENTRATION RATIOS8
Ratio placenta!: Maternal blood Cd
Dose,
•gAg
0.1
0.4
1.6
Gestation
day 12
14.9 t 3.0
12.3 t 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 1 47,
58.7 ± 17,
52,5 ± 36.
jb.C
2b,c
3b.C
From Sonawane et aT.. , 1975,
dose-response test revealed significant gestational day
differences for all doses at least at p < 0.05.
Significantly different from the 12th day treatment,
p < 0.01,
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Table 2-5. PLACENTAl TO FETAL CADMIUM CONCENTRATION RATIOS8
Dost,
mg/kg per day
O.lc
0.4
1.6
Gestation
day 12
616.00 & 409,11
266.11 & 232. 92b
11.23 i 4.16b
Ratio placeital:
Gestation
day 15
103.94 4 29,25
55.92 i 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 eta1_., 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.
cThe 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 aJL (1974) demonstrating only relatively small amounts of cadmium
in freshly obtained human plitcentas, 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 Redialing cadmium effects on fetal and neonatal growth and
development. Among such factors Implicated as likely being important are
effects of cadmium on naternal 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 aj., 1971), and it would not be surprising if well-known effects of
cadmium on zinc distribution were exacerbated in pregnant animals in a
•anner so as to induce fetal abnormalities secondary to a maternal or fetal
zinc deficiency. Consistent with this, Pond and Walker (1975) and Choudhury
et al.. (1977) have reported 'lowered zinc concentrations and decreases in
'birth weight in pups of rats orally exposed to cadmium during gestation
either at 200 nig/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 al.
(1977) study are summarized in Table 2-6. Interestingly, ho increase in
fetal cadmium accompanied decreases in fetal zinc and other elements in the
Choudhury et al. study, suggesting that such effects were likely secondary
to cadmium influences on maternal nutritional state rather than directly
on the fetuses.
2'68
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2-69
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to cadmium influences on maternal nutritional state rather than directly on
the fetuses.
In both the Choudhury jet a].. (1977) and the Ppnd 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 wtfaned 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 beer demonstrated,:*and some of the more salient findings are
reviewed below.
2.8.1 Gonadal Effects
Extensive evidence docuroents the effects of cadmium on the gonads,
especially the testes, as vas reviewed in some detail under tht 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 pf 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., prbteinuria). 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 al.-, 1960; Barbieri et al., 1961; Ishizaki et al.., 1970; Nordberg and
Nishiyama, 1972), as has altered pancreatic excretory function in Itai-Itai
patients (Murata et aj., 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 hyperglycenria by cadmium, reported to
occur in rabbits (Volnar, 1962), dogs (Caujolle et aj., 1964) and nice
(Ghafghazi and Hennear, 1973), evidence has been advanced for that effect
being nediated mainly through the adrenals rather than the pancreas
(Ghafghazi and Hennear, 1973),. Reductions 1n glucose 'tolerance Induced by
cadmium, however, have been linked to cadmium-induced alterations in pan-
creatic function. Evidence supporting the possibility of cadmium-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 tfife, i&bbft after cadmium treat-
ment (Barbieri et al., 1961), and (3) reports of observed decreases in
concentrations of circulating insuHn in mice after Dingle'cadmium injec-
tion (Ghafghazi and Mennear, 1973). In addition, Jthakissios et aj. (1975)
-
treated rats every other day for 70 days by,:inj,ections' 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 nay 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 1
-------
and Singhal (1975) reported that administration of selenium concurrently
with cadmium ameliorated cadmium-induced hyparglycemia, 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 metallothienin
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 adrenaljectomy
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 Horowitz (1974) demonstrated that cadmium
was moderately effective in causing prolonged release of CA jin vitro,
possibly through interactions with intracellular calcium in adrenal
medullary cells. In,a follow-up study, Leslie and Borowiti (1975) obtained
data interpreted as indicating that not only can cadmium initiate cate-
cholamine secretion from the adrenal medulla, but it also appears to
2-73
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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
in vivo study by Rastogi and Singhal (1975). Adolescent .ale rats were in-
jected i.p. daily with cadmium chloride at doses of 0, 0.25, or 1.0 »g/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 Big/kg.
Adrenal cortical functions, as well as adrenal medullary secretions,
appear to be affected by cadmium, according to a study by Oer et al.
(1977a), which compared the effects of cadmium and le'ad on thyroid and
adrenal functions. Adult male rats weighing 300 g received daily
intramuscular (i.m.) injections of 50 or 250 pg pf cadmium chloride, while
other rats received either 50 or 250 pg of lead or simultaneous injections
of 25 pg each of lead acetate and cadmium chloride. Significant deficits
in weight gain and increased adrenal weights were observed during 70 days
2-74
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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 20na glomerulosa
and fasciculata of both the 50- anc 250-Mg cadmium-dose- groups; and plasma
corticostenme levels were found to be significantly elevated in the 50-
and 250-ug cadmium groups and the combined 25-« 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 to 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 fo* the metal. Relatively sparse informa-
tion, however, exists concerning cadmium effects on the thyroid. In the
Der et al. (1977a) study mentioned earlier, evidence was found for signifi-
cant decreases being induced in plasma T4 levels in rats by the 250 ug ;
cadmium chloride treatment and In plasma T3 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 •!. (I977a) hypothesized that the hypothyraid. 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-induce.
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 Oer 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 wale rats as revealed by immunoffuorescence
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-
ii
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 c'admium exposure may be
exerted via cadmium effects on the pituitary directly, and this possibility
is reinforced by the Berlin and Ullberg (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
2-76
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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 et al. (1974), in which rats were
chronically dosed with cadmium (10 to 20C 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 (pg/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 calcium-
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 spcngiosa 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 ea'rly renal glomerular
damage occurring before the onset of tubular dysfunction.
Abe et a1_. (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-D to
the physiologically active tssential 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, 1n both occupational settings and in populations
sustaining pronounced cadmium exposure (Nordberg, 1976; Friberg et a!.,
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 aj. 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
2-78
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is the major biosynthetic organ for metallothionein in a number of experi-
mental animal species and man, so eny consideration of the extent of hepatic
functional derangements as 8 function of the amount of cadmium present in
liver Dust 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, *s measured by several
techniques, including sleeping-time changes and enzyme inhibition.
Further animal studies have been carried out on the hepatic effects pf
cadmium under varying experimental conditions. For sample, Andreuzzi and
Odescalchi (1958) found that rabbit serum glutamic-oxaloacetic-transaminase
was elevated following intravenous administration of cadmium (1.35 to 3.0
»g/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 LD50 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, md'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 foundthat, when liver cacteium levels were
below 30 ug Cd/g wet weight, the metal was sequestered as metallcthionein.
2-79
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and no apparent toxicity was evident. Levels of 40 pg Cd/g were associated
with hepatic cellular degeneration as well as other systemic pathology.
Faeder rt aj. (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 uig/kg showed dilation and loss of.
n'bosomes from the endoplasmic reticulum, with the additional feature of
swollen mitochondria observed at the 0.75 mg/kg dose level. Biochemically,
plasma aspartate aminotransferase (AAI), a-glutamyl 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 aj[. (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 ot,h=r 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
occupational^ 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 Sod Crabtre'e .(1961), too,
found evidence for hyposmia and anosmia wnen'lhey 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 have olfactory problems th«n control subjects (15 vs 0 percent,
respectively), and they did less well than controls on a phenol-smelling
test. Anosmia correlated well with proteinuria, with 17 battery workers
exhibiting 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 9,1 percent exposed for
over 30 years; again, the workers were likely exposed to nickel as well as
2-S]
-------
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 -•
•ay cause direct damage to nasal olfactory mucosae, 1t 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. '"
•*• ' "A.
About the only other report of signs of possible cadmium-i'ndueed ". • '
neural damage in humans Is that of Vorob'yeva (1957) on changes W^'
"chronaxies" of cutaneous sonsory 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 in vitro work. This inclhider, *
reports that cadmium chloride exerts toxic effects on gasserian and spinal
sensory ganglia (Gabbiani et ah, 1967a; Schlaepfer, 1971), cerebellar
tissue (Kasuya et ah, 1974), and other central nervous system (CNS) tissue
(Gabbiani et al., I967b). Pathological changes observed by Kasuya et aj. '
(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 jn vitro. Edstrpm
and Mattson (1976), for example, studied the effects of sulfhydryl blocking
agents on the in vitro rapid axonal transport of 3H-1eucine^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.
2-82
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Research in other studies has focused on possible molecular mechanisms
by which cadmium might affect net-retransmission, with some consistent
results emerging from such studies. In one study, Kamino et aj. (1975)
utilized synaptosomes isolated from rat brain cortex to investigate the
effects of cations on synaptosomal CA*4-binding. Cadmium, as well as other
cations tested, significantly inhibited synaptosomal pa**-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 catechblamines
suppress that response, while certain divalent ions such as cadmium
potentiate and prolong it. Chen (1975) concluded that cadmium chloride may
•tt
inhibit sympathetic ganglionic transmission bypMfcynaptlc suppression^
acetylcholine release. Similar conclusions.were; reached by Toda (1975) and
Forshaw (1977), who presented evidence for inhlbftdry 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 trar.smembranous 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
2-83
-------
they interpreted as Indicating that cadmium blocked adrenergie neuro-
»uscular transmission in the rabbit primarily through an effect on pre-
synaptic nerve terminals.
Ribas-Ozonas et al. (1974) reported decreases in regional prain
serotonin (5-hydroxytryptamine, 5-HT) levels after fntraventricular
Injection of a 33 ug dose of cadmium chloride 1 to 3 days before the
Injected rats were sacrificed..) Subsequently. Hrdina *t aL (1976) studied
the effects of chronic (45 days) i.p. injections of dosis of cadmium
chloride (0.25 and 1.0 ag/kg/day) on the regipnal level* of brain neurp-
transmitters and associated enzymes. Both doses of cadmium produced
significant decreases in cortical acetykholine and brainstem 5-HT 4Rd a
transient increase in stnatal dopamine. Cadmium-induced decreases in
brain 5-HT levels persisted even after withdrawal of cadmium treatment for
28 days before sacrifice. Hrdina et ah (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 tissu*
•fter systemic administration. Also, in view of cadmium's poor entry into
brain, the changes in brain neurotransmitters seen by Hrdina et at. (1975)
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.
2-84
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Very few studies have been reported that 9ttempt to relate cadmium
exposures to neurotoxic effects manifested in tertns of learning pr other
behavioral deficits. For example, in the Kresovskii et al. (1376) 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 O.Q05.
-------
small intestines. For example, the small intestines were dilated
thin-walled, hypertrophy tnd hyperplasia of goblet cells occurred,
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 pictiire seen in
human malabsorption syndromes, tropical and nontropical -sprue, and celiac
disease.
Valberg et al. (1977) assessed the relative sensitivity of mouse
intestinal aucosa to cadmium-thionein and inorganic salt (cadnngn, chloride).
Using open-ended duodenal perfusion, equivalent amounts of cadmiu,m in
either form entered the mucosa. Free cadmium ion occasioned minpr derange-
ment in the forn, of villi broadening and nitochondrial 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 meta^cootent
basis (Cherian et al. 1977).
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
2-86
-------
have been reviewed (Fribera et al 107/11 r n
v luerg ei a_i.. , 1974); Fulkerson and Goeller 1973-
Nordberg, 1374). ' '
and ,„ an,.a,s.
has
ane,)a
and mr-dtrfcfncy c..p,nent
rather early in cadmium exposure.
stu,ied
he»atocrit (n
1976).
of
]
in „,.,„
on n ras „ , ^ gf ^^^
the „.,. fnauce, ,. re] .
destruction, It .ppears «., erythrocyte *.tnict)B1 ,. Mt . ,ajor
» «U. since the ca«u, ae,.s.; treafent ,.,W to ,,,ert any
in the dietary-cad,,™ srMps (25, 50, „„, „„ pp< ^ ^ ^.^^ ^
there «s a s,Snfficant reduction ,„ ne.atocrit and ne,?g,oMn ^ ^
.ccord vnn the ooservations „ others
-------
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 IWUNOSUPPRESSIVE 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 aL (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 ug/XOO 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 aj. (1975b)
discuss possible mechanisms by which cadmium might exert its endotoxin-
2-88
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potentiating effects and report ultrastructural evidence ideating liver
damage as one important factor.
In another series of studies, Roller and corkers have also decently
reported son,e evidence for io.unosuppressive effects of cac.iu, administered
via oral exposure. Keller (1973) reported that rabbits exposed 70 days to
»ercuric chloride, cadmium chloride, or lead acetate in drinking water (at
doses of 10, 300, or 2,500 Ppro, respectively) had significantly lower
neutralizing antibody liters after inoculation with a pseudorabies virus
Evidence for cad™-induced increased susceptibility to disease in
«ice was also serendipity observed in a SubSequent study to Exon et al
(1975). Cadmium-stressed nice being used in the study for other purposes
began dying fPOB an intestinal infection later identified as due to Hexa.ita
-is- 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 25 -
percent mortality, respectively. No deaths occurred, however, in non-
exposed control ani,nals. Interestingly, no '-typical'' cad™ lesions were
found in any organs of cadmium-exposed animals, SuSgesting that iranuno-
suppressive effects may be induced at substantially tower exposure levels
than those retired to induce other, classically defined cad™ effects
More direct evidence for i«sUPPresSive effects in ,ice was reported
by Koller et al. (1975). 'Mice exposed orally to "subclinical'' doses
3 or 300 Ppm, of cadmiun, chloride in drinking water for 70 days experienced
narked 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 i«sUPPressive
effects of cadmium, including that absorbed via chronic oral ingestion, .ay
Persist for quite some time after the cessation of hioh-level exposures
. 2-89
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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, Koller and Roan (1977) assessed whether
nouse peritoneal nacrophages 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
nacrophages, it was concluded that the metal activates macrophages. Based
on this, it appears unlikely that iimunosuppressive effects of cadmium are
exerted through damage to aaerophages. On the pther hand, Waters et aj
(1975) reported evidence for cytotoxic effects of cadmium on rabbit alveolar
macrophages assessed in an jfri vitro model system.
In summary, it appears that cadmium does exert immunosuppressive
effects both in vitro and in 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 HUTAGENIC AND CARCINOGENIC EFFECTS OF CADMIUM
Considerable concern has been generated by reports of association of
cadmium exposure with mutagenesis or carcinogenesis in animals or huma,ns,
Several relevant reviews have recently appeared which deal with mytagenic
effects of cadmium, the experimental induction of tumors in animals, or
human cancer epidemiology studies (Flick etaj., 1971; IARC, 1976; NIOSH,
2-90
-------
; Su,,den,an, 1977;
' '"Ch tafw"««" •"• -«•- 1. regard to tne COMHj()ns
«*r «lch .,taS8n,c or t»0r(genic effects „„ b8 ,en8rHea .„,„, '
in «!.!.. .hereas ,., less ona 8ri cur,ent!). .,.„.„„
oterti., «f cad.iu. „
na,e been.*.« „ a r.,ult of «,t cf tne relevant „,(.„.'
that „. the assents have typically led to the conclusion ttat pre-
sumptive evidence exists for cad.iu.-in.uced .utagenic and carcinogenic
effects.
2.15.1 Mutagenic Effects of Cadmium
Numerous studies have focused on assess^ of the fflutagenic properties
of cad^iu,; hl>wever, the evidence obtafned for cadmfum..nduced e1 -
in various u,t system must be considered inconclusive at this ti.e The
results of nany of the ^ salient studies are summed in Table 2-7
As indicated in Table 2-7, evidence for cadmium-induced .utagenic
Affects has been obtained in vitro with several different test system
Such evidence includes, for example, the demonstration of: (1) statisti-
cally significant increases in ^paired nucleotides When cadmium chloride
.was added to an in vitro DNA synthesis system (Sirover and Loeb, 1976)- <2,
abnormal .itotlc and meiotic recombinations in the yeast, Sacharo.vce/
cerevHsiae, upcin exposure to.cadmium chloride (Takahashi, 1972); (3) pro.
duction by cadmium chloride, but not cadmium nitrate, of mutant recombinants
in strains of Bacjnus s^tnis (Nishio.a, 1?75) (I} Unschedu1ed
m Chines, hamster embryo cells following exposure to cadmium chloride and
cadmium acetate (Costa et al 1976V arH f*\ »K • .,
_i ai-, is/6;, and (5) the induction by. cadmium
sulfide of chromosomal aberrations in cultured human leukocytes
2-91
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(Shiraishi et aj., 1972). Specific types of human chromosomal aberrations
seen in the latter jn vitro study, it should be noted, were similar to
those reported fo,r human leukocytes obtained from Itai-Itai disease patients
(Shiraishi and Yoshida, 1972). Thus, in summary, mutsgenic effects on
genetic material or cells from a variety of species, ranging from yeast and
bacteria to hamsters and humans, havs been demonstrated -to occur in vitro
with exposure to several different cadmium compounds. The Utter effects
V
appear to be analogous to jn vivo effects observed in certain human,
high-level cadmium exposure cases. When considering the jn vitro cadmium
mutagenicity data, however, it must be remembered that, in the human or other
mammalian organisms, cadmium is mainly bound to metal!othionein 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 in vivo mutagenic effects of cadmium at high exposure levels. This
includes the demonstration of (1) numerical chromosomal anomalies in mouse
*i .•
oocytes and blocked development, of metaphase I chromosomes following
injection of an acute dose of 3 or 6 nig/kg of cadmium chloride (Shimada
et aj., 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 aj., 1S76).
In regard to jn vij/o studies finding no mutagenic effects, the one
test yielding consistently negative results is that for dominant lethal.
mutations. In one study (Epstein et aj., 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
2-93
-------
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 nice 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 1n a study by Suter (1975), in which cadmium chloride (2 »g/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 nutagenicity 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 Oeknudt 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 in vitro test systems. Little or no data exists for
mutagenic effects occurring with oral or inhalation exposure of man or
other mammalian species. The significance of in 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, in 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,
2-94
-------
Sunderman (1977) reviewed data showing that parehteral 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 (Haddow et al., 1964; Roe et aL,
1964; Guthrie, 1964; Gunn et al., 1963, 1964, 1965, 1967; Nazari et al..,
1967; Favino et al., 1968; Knorre, 1970, 1971; Lucis et aL, 1972,
Reddy et aj., 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 al.. 1965; Favino at a_K , 1968; Lucis
et »!.', 1972; Reddy et aj., 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 al.,
1965; Kanisawa and Schroeder, 1969; Levy and Clack, 1975; Levy et ah,
1975). Schroeder et al. (1955) 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.
2-95
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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, 0.83, 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. These results are
in .contrast to findings obtained with intravenous administration of cadmium
salts. The authors suggested that low gastric absorption of cadmium and a
high spontaneous incidence of Leydig cell tumors in their control group rats,
which would overshadow any effect due to cadmium exposure, as possible reasons
for no significant response in their study.
The Schroeder and the Levy studies cited above that found no tumcrigenic
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 tumorigenie 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 providing some
evidence of carcinogenic potential for cadmium.
2-99
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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 (3.7).
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 aajor portion of the
existing data base upon which assessments of cadmium-induced human carcino-
genicity presently depend. Most of 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; (3) the study of McMichael
et al. (1976) on rubber-industry workers; (4) the study by Kolonel (1976)
on cancer patients, and (5) the study of KjellstrSm et al. (1979) on battery
plant employees. Some of these studies, e.g. that of McMichael et al., were
not primarily designed to investigate cadmium effects, but such effects were
evaluated retrospectively.
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
2-100
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seen in that table, each study reports increased incidences of various cancers
among the workers studied. Consistent'across til 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 iemen et al. (1976), while McMichael et al..,
(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; some evidence,
therefore, appears to exist for cadmium salt possibly being carcinogenic in
humans with a predilection for the prostate as a .-stte of action. Somewhat
elevated (but not statistically significantly increased) prostatic cancer
rates were also reported by Kjellstrom et al. (1979) in,discussing preliminary
results of an epidemiology study on cadmium-nickel battery and cadmium-copper
alloy plant employees; the final results covering theA,entire study population,
however, remain to be completed and published. ; '
Certain "nedical 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 jjg/1 (the recommended safety limit is 10-
- ' »•..."
Mg/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 Burbanlc study and usual levels of water consumption
are insignificant in comparison to average normal dietary intake (see Chapter 4).
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Also, the Berg and Burbank study failed to control for smoking as a potentially
confounding factor. Another study (Zyke, 1973) of 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 metallothionein 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. ConveVsely, 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 coadministration of zinc with cadmium would suggest
•n alternate mechanism, since some induction-time interval would be necessary
for metallothionein 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 (Sandstead, 1976).
2.16.2 Selenium
A number of studies have demonstrated the protective effect of
selenium, an essential element, against cadmiuni toxicity. A demonstration
of this element's protective action on cadmium*toxicity was the observation
of Kar et aj. (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 LD5Q and prevents experimentally induced hypertension in
a number of species (Sandstead, 1977; Pa'rizek, 1971).
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Several recent studies have been directed toward elucidating the
by which selenium exerts a protective effect. Maoos and Webb
(1976) studied the effect of co-administration Of equimolar amounts of
selenium and cadmium parenterally on the transport pattern Cf either element
in adult rats and were 1ed 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,
Gasiew-lcz and Smith (1976) used 75Se and 109Cd 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 mg/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. Elected bile levels following selenium pretreatment are consistent
with elevated blood cadmium levels and reduced amounts in the liver (Gunn
et aj., 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 al., 1974).
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Prohaska et al. (1977) studied the relationship 1n 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
•mole/kg, administered subcutaneously) 1n the testis showed elevated
levels of the enzyme. This nay be a vasculopathic effect with the increase
in activity arising from erythrocyte enzyme via leakage Into the testes,
enzyme levels 1n red blood cells being much greater than in testiwlar
tissue. Isolation of the «ain fractions of the enzyme using labeled cadmium
and selenium showed no cadmium-enzyme binding, and these fraction
activities were not inhibited by cadmium in vitro. Pretreatment with
selenium showed most of the radiolabelled cadmium (109Cd) 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, abpve which evidence of
injury occurs. '
Piotrowski et a].. (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 a]..
(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 b« 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 leveJs.
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
( 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 Ban, since persons with iron deficiency
might absorb more cadmium than those with normal iron stores. Flanigan
et al. (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 uM; 1.1 ppm) in drinking water showed impaired growth and accentuated
•nemia development, while the normal-iron animals showed no effects'at the
same cadmium-exposure level. Furthermore, the iron deficiency Ted to
increased cadmium levels in the duodenal nucosa and the kidney. In human
subjects; experiments using radiolabelled cadmium ("^a^howfsd. 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 pg. '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'fffect 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 metanothionein occurs via copper-mediated aggregation of this protein,
an In vjvo confirmation of demonstrated in vitro aggregation (Brenner 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 population groups are required to define the levels of exposure at
which adverse health effects appear in order to identify population segments
at high risk. To date,,such studies have mainly been limited to examination
of occupationally exposed workers and population groups in areas of Japan
where Itai-Itai disease has been found. Few such studies have been carried
out, however, for the general American population—especially concerning
health effects associated with exposures to cadmium in the ambient environment.
It is thusly necessary, based on available data, to construct a logical frame-
work or chain of interrelationships from external cadmium exposure through
absorption ind retention of cadmium to associated adverse health effects for
American populations. This can be accomplished by: (1) delineating the
distribution of cadmium to which humans are exposed and determining the
contribution of various sources to the overall multimedia exposure of American
population segments; (2) assessing levels of cadmium in blood or urine or
other indices-of internal absorption and retention in various population
segments; and (3) correlating these findings with research results associating
adverse health effects with particular levels of absorption or retention of
cadmium in other population groups. An analysis of exposure sources and
levels alluded to in (1) above is provided later, in Chapter 4, as part of an
overall risk assessment discussion. Background information pertaining to the
latter two items above, i.e., (2) and (3), however, is presented below,
before consideration of the most salient points as part of the risk assessment
discussion in Chapter 4.
3-1
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3.2 CADMIUM IN BLOOD AND URINE OF HUMAN POPULATIONS
Epidemiologic studies of cadmium levels In human blood and urine have
been carried out in an effort to index cadmium exposure and asorption in both
normal population segments and population groups with known high cadmium
exposures.
The data for blood and urine cadmium levels in so-called "normal" popula-
tions presented here oust be viewed with great caution for several reasons.
The definition of "normal" varies enormously from study to study. Frequently,
1t is defined as "no known occupational exposure", but little evidence is
presented to show how this was defined or established for the subjects. At
tines, 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 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 does not always arise from the same sources as other pollutants,
such stratification may fn 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 nay 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
3-2
-------
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
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.
3-3
-------
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 a few
studies, for example, have been reported concerning blood cadmium 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 demographic characteristics of the study sample
were given. A median blood cadmium concentration of 0.05 ug/dl was reported.
Bogden et art. (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 with old and
dilapidated housing. Race was not reported, but it seems safe to assume that
many were Black.
Smith et aJL (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-middl'e-class children from Salt Lake City, Utah, who were hospita-
lized for elective surgery such as tonsillectomy. The mean value for blood
cadmium levels was 0.66 ± 0.25 ug/100 gm with a range of 0.21 to 2.64 ug/100 gm.
Rosmanith et a].. (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
3-4
-------
sample, with a response rate of 69 percent. The authors reported • Man.blood
cadmium level of 0.11 ± 0.23 ug/dl. Age and sex did not prove to be significant
variables.
Delves et aj. (1973) compared children with suspected lead poisoning and
a hospitalized control group not suspected of having 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 ug/dl with range of 0.0 to 1.9 ug/dl. The
lead-poisoning-suspected "case" group consisted of 189 boys and girls, aged 2
no to 15 yr and with proportionately «ore children in the 3- to 6-year age
category than controls. The mean value for "cases" was 0.57 ug/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. Nevertheless, the mean blood cadmium values reported
for children are consistently below 1.0 ug/dl and do not differ much from most
values reported for "normal" adults.
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
3-5
-------
cadmium values. Further, 1t 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 (Table 3-1)
below 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 wean value of 5.0, a median value of 3.6, and a range of 1.0 to
30.0 ug/dl for these «en aged 18 to 24. They speculate that the latter 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 aj.
(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 th'e median was "about" 0.5 ug/dl.
Willden 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
3-6
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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: that is, males and females do not
appear to show different concentrations within a given study and virtually all
values reported fall below 1.0 ug/dl*. 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.
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
*Note that blood cadmium levels of 1.0 ug/dl are equal to 1.0 ug/100 ml or
~9.0 nmol/1, with the latter mode of expression conforming to a usage con-
vention adopted by European investigators in recent years.
3-10
-------
pg/100 g, the mean 0.85, and the range 0.34 to 5.35 with the 95th percentile
•t 1.68 ug/100 g.
Hammer et aj. (1972) evaluated workers with three levels of occupational
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 super-
phosphate fertilizer. Mean plasma 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.
Ediger and Coleman (1973), as mentioned above, reported concentrations
found in the course of a methodological study. They report a mean concentration
or cadmium of 0.06 ug/dl for 50 adults.
. The "Houston Study" conducted by Johnson et al_. (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 concentration
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 aj. (1973) reported on exposed and nonexposed factory workers by sex and
smoking status. The mean blood cadmium concentration for the nonexposed
smokers and nonsmo-kers by sex are shown in the table. A later report by this
group (Lauwerys et 'a\_., 1974) showed that 22 male workers selected as nonexposed
3-11
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controls had a mean concentration of 0.7 l 0.1 ug/dl. Reels 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
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 aj. (1974) reported a mean of 0.95 ug/dl for 37
adults, with a range from 0.4 to 1.9 ug/dl.
Ulander and Axel son (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 aj. (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.
3-12
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Zielhuis et aj. (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 weans were the
following: 84 non-smokers, 0.04 ug/dl with a range of < 0.02 to 0.25 pg/dl; 61
light smokers (1 to 9 cigarettes/day), 0.06 pg/dl with a range of < 0.02 59
0.24 pg/d1; 77 heavy smokers (> 10 cigarettes/day), 0.07 ug/dl with a range of
0.02 to 0.44 ug/dl. (The values < 0.02 were calculated as 0.01 pg/dl.)
Non-smokers differed significantly from light and heavy smokers.
Wysowski et a1_. (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 signi-
ficant differences were obtained in the study, except between smokers and
non-smokers; that is, smokers had higher blood cadmium values than non-smokers.
It should be noted that the mean annual airborne cadmium concentration in the
study area about 1 km from the smelter was 0.023 pg/m3, whereas the mean air
concentration in the comparison area 13 km distant was 0.003 ug/m3.
Turning to other areas of known environmental cadmium contamination,
recent pilot surveys (Carruthers and Smith, 1979) have been conducted in the
vicinity of Shipham, England, an area of cadmium contamination from past
zinc-mining activities. The survey revealed that 22 of 31 residents sampled .
(14 women, mean age 48.9 yr; 17 mean, mean age 50.9 yr.) had blood cadmium
levels elevated above normal levels (=1.0 ug/dl for non-smokers; £2.0 ug/dl
3-13
-------
for smokers). Soil cadmium levels in the Shiph.am area ranged from 60 to 998
ppm, compared with 60 ppm levels reported for the region around Toyama City in
northern Japan, another area of former zinc-mining activity and where extensive
studies have probed the relationship between cadmium exposures and Itai-Itai
disease endemic in the area.
The Japanese research, however, has not yielded blood cadmium data.
Presumably the utilization instead of urine cadmium as the main exposure
Indicator in the Japanese studies 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 ug/dl. 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,
non-technologically advanced areas.
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 to be abnormally elevated. Presumably, faulty
3-14
-------
hygiene contributes to additional exposure by transfer of dust from hands and
clothing to food. Piscator et al.. (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 .embers.
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 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 al, , (1976)! The excretion rate
for cadmium in urine by normal persons is age dependent. There is an increase
until the late fifties, followed by a decline. The mean urine cadmium concen-
trations reported for the studies listed in Table 3-2 indicate a general daily
urine cadmium excretion level between <1 and 2 pg day. The results of the
studies listed in the table, however, obscure the effect of age.
3-15
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In centrist, two other recent studies provide Information on age relation-
ships. Tsuchiya e_t at. (1976) reported on • study of 609 Tokyo residents
which permits analysis of the urine cadmium concentrations by age Intervals.
Figure 3*1 shows the distribution of nean urine cadmium concentrations by age
as well as the standard deviations. The authors also collected data on concen-
trations of cadmium in the renal cortex, renal Medulla, liver, pancreas, heart
nuscle, 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 nean urine cadmium concentration for
ages 30 to 59_yr to be 1.7 1 1.5 ug/1, with an upper-range value of "about 10
pg/1."
i>.9
3.0
2.5
s •
| 2.0
a
•
tu . _
z 15
K
S
Z i.o
3
§
U
0
-0.5
.1.0
—
-
,
— *
—
•
_<
/
/
_
I I I I I 1 I I
«
•
I
^
N-34
•
^X*
t
N-57
» *
«*«•(
,
N"44
•
•
N«S6
1— • • ~r
i
-
l""~ ~*
N-125
-
M
N-101
'^
""<
• ,
•
Hm 9&
p -
—
^
r' A«-l —
• •
p
N- 14
• ••
T + 1 S.D.
O MEAN
-L- 1 S.D. .. -
1 1 1 1 I 1 1 1
10 20 30 40 SO 60 70 80 90
AGE.
Figure 3-1. Distribution of mean urine cadmium concentrations
by age.
Source: Tsuchiya et a!.,(197€).
3-18
-------
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 a1_. (1977) reported urine cadmium concentrations for 86 Dales 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 Elinder
et al_. (1978), cadmium concentration in the urine of 131 Swedes, including
50 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 1n various age
groups corresponded better with total kidney burden than with daily dietary
intake.
Table 3-3. URINE CADMIUM LEVELS FOR "NORMAL"
MALES IN DALLAS, TEXAS, DETERMINED
BY ATOMIC ABSORPTION3'° ,
(pg/i)
Age
(years)
0-9
10-19
20-29
30-39
. 40-49
50+
N Geometric mean
15
8
16
7
16
24
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
-------
In the recent report of Tati et al.. (1976), involving unexposed Japanese
- ?«:•* -•:•*:* 2£ IsdJ rs^""?>« it? jf jsrij ;iuo h*.;nr." .:,„., •••• •
subjects, the age/cadmium-excretion relationship was established using males
>«! ' '" ''I*!1!1 '"".j hns xi» :. ''!•*' -. f* t ??i ," ,?!";*•" *0£ "to 0*- ^6"st EC* •w -, •< • '
and females up to 75 yr of age. The distribution of urinary cadmium levels
•". t*:r«; 'E-itfvft;,-!? '••'-'::; f to .Csf^Ciq 9i1l J?9ffl «J 'isb*', -": &-->''.
followed essentially a log-nonual'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
la .
females. This reflects an increasing body burden with age (Friberg et a]..,
r-p-b.irt I***? aworia £-6 «flsT .tsitiZ eaJrrnU aril bfe .n^bswj .wmi,
1974), due to the relatively long half-life of cadmium in major organs
'••tfT wrT-n^-jt- "v-r._";2(ir ••!* r.Jrw f»t-b 3,1.f !-;r bnuo^ 9-r»w ss^d^-l-: haJs'1"-?-, ;',
estimated to range from 17 to 38 years.
-.»afifr^ vrmb-if ^3^P,') ' n :-;,
3.2.1, on blood cadmium levels 1n residents living near a smelter also included
••»rK..*» tf>-'tp nJ- :-«<»s :A h'rj-5' •* *;T9v ,zfl'rwi fs-jftnsbr to g'vft.,a a? •
urine cadmium values of 0.9 ug/1 and 0.8 ug/1, respectively, for residents
«««"* '^rf* r»"#owf r^oms -rs.iofri ,j!6Wfc,n» sps Hl'rw bssssi^nr mufmbss ^"fSiiftu
close to a smelter and a control group. No significant differences were
op*. .n,or-, sv t~\ e-r<»^o«*"noi gnnRs ^yir.+tjc mufmbsa ^rf.-sb t*-1T' .Z"wi-':-:.*,-*twi
found, except for s.mokers having significantly higher urine cadmium levels
v'sJ^'h vf>-$b '.trrf ir-vJ1 w.fu^-vnnN f-tot .rit'rw -rg.M^d b^f'-q-^-'to JT.-'.
than non-smokers.
The literatunejrelating occupational exposure to variations in urine
^ '. ;;*«" Wi 2.i"3J M5!W ;WH5 .£-£ sfdsT . ' •
cadmium concentrations'lgfif^not^ifreviewicl hertS^Mtept to note that it has
"TuT-t»tQ ' '<*?nv3* nsA'i t'.rtJanwy M i ?tg<.v)
independenFof"apT"TufffieTTTIttTe~data~e-xi-st-whtch-re-1-ate-variations in
urine cadmium concentrations to food'and water levels of the metal, except for
~'2 ." T 1 W i. 3 !-)!'-£'"
Japanese populations; and these are discussed later in relation to Itai-Itai .
»22 " ".3 SS.' ,' . 3£ ' '•S-C
disease.
3.2.3 Sources of Cadmium Variation in Human Hair
jdj • .) ««' , 3i .^G..
Concentrations of cadmium in hair has been evaluated as an indicator of
. . .
exposure -to-the-met-al.—-Sev*ra-l-*tudi es-have-been- reported.»whece ha i r cadnn um
levels have been correlated with environmental exposures" Hammer et al.
(1971) analyzed hair''s'a"mp1telH'fTJ6m fo'u'ftK-grade "6oyi ff'om five cities rated as
3-20 .
-------
varying in overall environmental cadmium levels. The analysis showed that
arithmetic and geometric means varied by city 1n accordance with the city's
exposures rating. The geometric means ranged from 2.1 to 0.7 parts per million
(ppm).
Pinkerton jet aj. (1974) analyzed hair samples from three communities
which varied in their levels of environmental cadmium. Geometric means of
hair cadmium concentrations, while different for each community, did not ' •
follow the exposure gradient.
treason et aj. (1975) reported significant correlations between cadmium
content of hair and exposure as measured by content 1n dustfall and housedust
in metropolitan New York. The exposure measurements came from the CHESS
network, and th« 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 t 0.42 to 1.85 ug/g. For adults, the values were 0.76 ± 0.33 to
1.74 pg/g. No significant association with exposures were found, however,
although other trace metals also evaluated did show such association.
Hambidge et, a].. (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.
3-21
-------
Rosmanith et a±. (1975, 1977) reported no significant findings for hair
cadmium levels in their study of 413 children in a northern German industrial
town.
In summary, assessment of cadmium levels in hair appears to be of question-
able 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 1s 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 proceeding, it should be noted that some
workers (Harvey et a].., 1975; 1979; Ellis et al., 1979)) have recently carried
out j_n vivo neutron activation analysis studies of cadmium levels in organs of
human volunteers. Such an approach, however, 1s still considered to be largely
experimental and has only recently reached a stage of development whereby it
has begun to be employed as a method for studying large populations.
It is necessary to point out some limitations of the data obtained from
autopsy studies. The cases coining to autopsy do not really constitute a
representative sample of a given population. The requirements for performing
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
3-22
-------
status, occupation, and housing, all of which are factors associated with
different degrees of exposures to various toxins and 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," but the quality of the examination of accident cases to determine
this status «ay 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 «ay taper off
after 60 or 70 years of age. Such studies also show that cadmium concentrations
in the kidney, too, increase with age until about age 50 is reached; then
there is a decrease. In addition to these age-related patterns of change in
liver and kidney cadmium concentrations, smoking has been identified as being
a key determinant of liver and kidney cadmium levels; that is, cadmium levels
in liver and kidney are typically reported to be higher for smokers than
non-smokers across all age categories.
Elinder et a].. (1976) reported on 292 autopsies from Stockholm. The age
distribution for the 292 cases is shown in Table 3-4. and the data reflect the
above-noted age- and smoking-related patterns. This table also presents
geometric means (X) and standard deviations (SD). Figure 3-2 presents the
findings for kidney cortex concentrations.
3-23
-------
Table 3-4. CADMIUM IN HUMAN LIVER1
(pg/g wet weight)
ApctyO
a,b
Alltutijeeis?
McJ.-«-
FrHiah'S:
A'ontmnlrn:
SnmXiW
N
T
SD
N
I
SI)
N
I
SD
N
I
SD
N
r
SD
0-9
7
0.76
1.66
5
0.3}
1J4
2
0.15
1.05
...
• • •
. . .
* • •
...
10-19
24
0.51
1.88
IK
0.55
1.12
6
9.40
2.06
...
• • •
...
• • •
• • •
...
30-29
33
0.60
1.811
19
run
1.911
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
-O.X5
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
U.H4
2.26
20
1.22
2.18
11
0.72
2.71
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
«n.R9
2*
0.53
2.80
14
0.59
2.21
II
0.46
3.67
12
n.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
...
(X) and standard deviation (SD) are geometric.
are calculated by multiplying or dividing X by SD.
bFrom Elinder et aj.. , 1976.
Tolerance intervals
3-24
-------
ARITH. MEAN
GEOM. MEAN
±STD. DEV.
0 10 20 30 40 SO SO 70 80 90 100
Figure 3-2. Geometric and arithmetic means of cadmium con-
centration in kidney cortex are shown for each decade of life.
Source: Elinder et al. (1976).
3-25
-------
Tsuchiya et a].. (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 al_. (1976) in Australia found renal cadmium concentrations that
followed the same age-associated pattern in 91 autopsies. Figure 3-3 presents
their findings for mean cadmium concentrations in kidneys.
1
>*
UJ
O
000 MEAN VALUE
O SINGLE VALUE
40 60
AGE OF SUBJECTS, yun
Figure 3-3. Cadmium in whole kidney tissues and its relationship to age.
Source: Miller 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.
3-26
-------
Table 3-5. CADMIUM CONCENTRATION IN HUMAN RENAL CORTEX BY
AGE: MEANS AND 99% LEVEL OF SIGNIFICANCE*
(pg/g)
Age
Mean
S.D.
99% Level of,.
significance
N
0-9
10 - 19
20 - 29
30 - 39
40 - 49
50 ~ 59
60 - 69
70 - 79
80 ~
Total
4.75
33.2
46.26
S9.21
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
ion. 09
142.49
203.8
..
• •
~
162.62
13
5
38
27
11
2
106
*From Tsuchiya et a±., 1976.
°X + (S.D. x 2.5}
Table 3-6.
AGE GROUP MEANS AND STANDARD DEVIATIONS
FOR TISSUE CADMIUM3
(ppm wet weight)
L1v«r 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
lota]
N
19
7
9
7
4
11
10.
10
6
3
9
10
106
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
±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
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
Adapted from Gross et al. (1976).
Arithmetic mean.
Standard deviation.
3-27
-------
Syverson et •!. (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 concentrations than white-collar workers and
"others," a group consisting mostly of housewives.
Vuori et al. (1979) in Helsinki. Finland, assessed cadmium levels in autopsy
specimens of aorta, heart, kidney, liver, lung, pancreas, and skeletal muscle
obtained from 86 humans who had died in traumatic accidents and who were verified,
at autopsy, as not having suffered from any chronic diseases. The results of the
study are summarized in Table 3-88 with cadmium levels observed for different
tissues listed according to age group. The small number of females in most age
categories precluded separate evaluation of cadmium'levels by sex; the lack of
information on the smoking habits of the subjects also precluded evaluation of
the effects of smoking status.
In general, the Vuori et al. (1979) results indicate that the average cadmium
tissue concentrations were highest in kidney, followed in decreasing order by:
liver, pancreas, lung, aorta, heart and muscle. When the effect of age on the
cadmium tissue levels reported for both sexes together is evaluated, the same
age-related patterns as noted earlier tend to emerge. "That is, the mean and median
values for all tissues were universally low in the early years of life, but generally
increased with age up to maximums reached at various points during adulthood and
old age. Cadmium concentrations in muscle showed the best correlation with age
(N = 86, r = 404, p < 0.001) over the entire age range studied; however, over the
first 50 years of life, kidney cadmium concentrations were even better correlated
3-28
-------
O fJ
«o o>e
CM O
I
^»
ID
LU
CJ
,?*
re 01
ID 01 re
ec a. 01
•o
CJ
u-o
^ O)
4?
u *
(SJ
ID
s
CM
I
CM
O
O
O) OJ
co oo
i
flf *o u
en 4)4:
< >,«-
I
in
O
VD
«l
o>
C
I
eu
o
-------
Table 3-8. The average cadmium concentration in the tissues examined (geometric
means and medians), the ranges and the number of samples above the detection
limit/number of samples in each age group; both sexes are included, with total
number of subjects for each age group indicated in parentheses.
Tissue
Aorta
Mean
Median
Minimum
Maximum
N
Heart
Mean
Median
Minimum
Maximum
N
Kidney
'Mean
Median
Minimum
Maximum
N
Liver
Mean
Median
Minimum
Maximum
N
Lung
Mean
Median
Minimum
Maximum
N
Muscle
Mean
Median
Minimum
Maximum
N
Pancreas
Mean
Median
Minimum
Maximum
N
Age group (years)
0-9
(N = 3)
Ob
0
0
0.15
1/3
0
0
0
0.03
1/3
6.73
15.8
11.1
17.4
3/3
0.25
1.40
0
1.61
2.3
0
0
0
0.07
1/3
0
0
0
0.03
1/3
0.14
0.47
0
0.85
2/3
10-19 20-29 30-39 40-49
(N = 16) (N = 24) (N = 12) (N = 14)
0.05
0.11
0
0.60
10/16
0
0
0
0.38
7/16
25.3
24.9
11.4
44.6
16/6
2.41
2.41
1.24
4.73
16/16
0.27
0.96
0
3.36
13/16
0
0.03
0
0.22
9/16
0.50
0.83
0
1.89
14/16
0.20
0.36
0
12.0
19/24
0.05
0.09
0
0.89
16/24
49.4
54.9
2.40
197
23/23
3.06
3.36
0.57
10.5
24/24
0.66
0.96
0
7.57
20/23
0.04
0.07
0
0.39
16/24
1.94
1.90
0.43
10.3
23/23
0.53
0.38
0.17
9.49
11/11
0.06
0.09
0
0.74
8/12
78.1
74.5
33.0
150
9/9
2.69
2.75
0.38
10.6
12/12
1.35
1.76
0.07
4.95
12/12
0.03
0.06
0
0.17
7/12
2.29
2.23
0.70
9.71
12/12
0.41
0.56
0
5.31
11/14
0.09
0.22
0
0.56
10/14
86.9
99.3
17.8
239
13/13
3.72
3.69
0.97
9.31
14/14
0.67
1.43
0
6.80
12/14
0.08
0.18
0
0.29
10/14
2.31
3.05
0.30
9.08
14/14
50-59 60-69 > 70
(N =7) (N = 4) (R = 6)
0.50
0.57
0
4.54
6/7
0.06
0.10
o
0.32
5/7
83.7
78.7
49.3
178
7/7
2.39
2.85
0.12
15.6
7/7
0.73
0.89
0.21
2.40
7/7
0.07
0.11
0
0.48
5/7
1.30
0.64
0.36
8.13
7/7
1.03
1.38
0.20
5.96
4/4
0.22
0.21
0 14
W. At
0.42
4/4
87.1
100
48.7
123
4/4
4.47
4.39
3.09
6.72
4/4
0.87
0.87
0.53
1.51
4/4
0.29
0.29
0.71
0.50
4/4
2.21
2.31
1.30
3.41
4/4
0.15
0.47
0
0.82
3/5
0
o
Q
0.63
2/6
58.7
76.2
21.8
143
5/5
3.38
3.57
0.54
10.3
6/6
0.03
0
0
1.71
2/6
0.04
0.08
o
0.47
3/6
1.68
1.44
0.55
3.46
5/5
• ^
0 stands for "under the limit of detection," which was about 0.03 ug g dry
Due to an accident in a series of analyses, four results of cadmium in kidney
are lacking. *
3-30
-------
with age (N = 63, r = 0.580, p < 0.001). Concentrations of cadmium in the
different tissues were also found to be highly correlated with cadmium levels
obtained for virtually all other tissues at comparable ages.
A further group of reports for autopsy studies did not present data for
fleneral 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 concerned 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 concentration was
182 ± 99 ug/g ash and 2406 * 1299 ug/g ash for kidney cadmium concentrations.
Ostergaard et aj. (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 roean (and range): HOS (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 38231) ug/g ash and geometric mean of 2242 ug/g ash; for heavy
smokers (N = 12) using 20 or more cigarettes per day: arithmetic mean (and
range); 2778 (961 to 7493) ug/g ash and geometric mean of 2310 ug/g ash.
Lewis et aj. (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
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for kidney (N - 171) was 9.06 ± 0.50 Gig 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 1 0.51 ng for kidney, smokers (N = 138) 10.28 ± 0.57
fig. 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 aj. (1977). Cadmium levels were significantly greater (p < 0.001) for
smokers, the difference between the two groups being 6.9 ug/g average concentra-
tion.
In summary, highly consistent patterns of results have emerged from the
autopsy studies reviewed above, with age-related and smoking-related changes
in human liver and kidney cadmium concentrations being among the more salient
features of the data base. It is clear, for example, that cadmium is typically
present in liver at very low levels (<0.5 ug/g) during the first decade of
life but gradually accumulates in that organ until the late decades of life,
reaching mean maximum concentrations of ca. 1-2 ug/g for non-smokers at age 50
and beyond. For smokers the observed liver concentrations at various ages are
usually approximately double those of non-smokers. It is interesting that one
recently reported study on in-vivo neutron activation analysis yielded an
estimate of 2.2 ± 2.0 ppm (mean i S.O.) liver cadmium concentration in 10
adult control subjects compared against 11.0 ±2.0 ppm values observed for 21
adults aged 40 to 62 years (mean 53) living in an area of high cadmium soil
contamination (Harvey et al., 1979). Also of interest are the results of
another neutron activation study of liver cadmium concentrations in normal
adult male volunteers, in which liver cadmium levels of 2.3 ± 1.6 ug/g ( mean
± S.D.) were observed for non-smokers and 4.1 ± 1.6 ppm for smokers, these
values comport well with those derived from the autopsy studies.
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Cadmium levels in human kidney, Tike those in liver are also normally
very low during the first decade of life, steadily increase over the ensuing
4 to 5 decades, but reach Baximum peak concentrations around age 50 before
declining somewhat thereafter. Variations in cadmium concentrations in
kidney cortex are of most interest, 1n view of subsequent discussions below of
cadmium - induced renal dysfunction as a key human health effect associated
with the accumulation of cadmium in kidney cortex. Of particular concern are
concentrations that reach certain critical values (ca. 200 ug/g wet weight) in
kidney cortex associated with the disruption of normal renal function.
Summarized in Table 3-9 are estimates of kidney cortex cadmium levels for
the U.S. adult population, as determined by autopsy studies listed in the
table.
TABLE 3-9. CADMIUM IN THE KIDNEY CORTEX OF U.S. ADULT POPULATION
(ug/g wet weight)
Reference
Tipton and Cook, 1963
Indraparasit et a!., 1974
Gross et al., 1976
Johnson et al. , 1977
Hammer et al., 1973
Morgan, 1972
Age
Adults
31-80
39-85'
40-59
40-79
62 mean
N
145
134
28
59
58
100
Mean
35
22
30
26
29
33
Standard •
Deviation
16
14
8
Range
6-88
7-101
4-109
6-83
1-128
3,4 EPIDEMIOLOGICAL STUDIES OF CADMIUM EXPOSURE IN JAPAN
A number of comments appear in the preceding Health Effects sections
dealing with 1;he pathophysiological features of cadmium as they have been
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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 number of studies have also focussed on areas of
cadmium pollution in Japan other than the Jintsu River basin, or Itai-Itai
belt. Revelant Japanese epidemiological data will, therefore, be considered in
two sections - one on Itai-Itai disease studies and another on other studies of
cadmium pollution in Japan.
Some general comments, as follow, 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 al. (1974) discuss this difficulty in some detail.
(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
clear that some study groups selected to control for dietary cadmium intake
actually constitute true non-polluted diet groups.
(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
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in nany cases has occurred over * 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 also 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, unique nutritional
status of the affected populations, 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 does appear to constitute a
classic case of pollution in a heavily industrialized society which persisted
for a number of years, with resulting effects remaining unidentified and
unsuccessfully treated over quite some time.
3.4.1 Itai-Itai Disease Studies
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; Tsuchiya, 1978). These earlier literature
evaluations will not, therefore, be repeated here; but rather some of the more
recent data will be considered.
In Friberg et aj. (1974) a good case was made for the etiological role of
cadmium in the development of Itai-Itai disease, characterized by marked
tubular proteinuria with osteomalacia and severe osteoporosis afflicting older
females (>40 yrs) in the Fuchu area of Toyama Prefecture. As noted elsewhere
in this report, however, the victims also had histories of marked nutritional
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deficiencies, a fact which has contributed to difficulty in defining the
relative importance of the nutritional deficits versus cadmium as key etiological
factors underlying the disease.
Nevertheless, in Cadmium in the Environment III (Friberg et aT_., 1975),
additional studies from the Itai-Itai region of Japan were discussed as data
supporting a likely connection between cadmium and various aspects of the
Itai-Itai disease.
Shiroishi and Yoshida (9172), for example, selected a group of 123 men
and 119 women over 40 years of age 1n S-village in the Fuchu area as an exposure
group as used 75 «en and 86 women 1n a different area as a control group. In
their study, the prevalence of proteinuria among the txposed subjects 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 gulcosuria.
Also, the study of Fukuyama et aj.. (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), an effort was made to
correlate proteinuria and glucosuria in Fuchu area villages with cadmium
levels in the rice (particulary non-glutinous rice) consumed in the villages
studied. In 37 villages studied, renal deficit response rates (proteinuria
and glucosuria) were seen to increase with increasing cadmium levels in rice,
a significant correlation coefficient of 0.62 being obtained. Additional
analyses confirming clear-cut associations between renal dysfunction response
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rates and cadmium levels in rice among inhabitants of the Jinzu River basin
are presented by flogawa and Ishizaki (1979).
It should be noted that earlier studies of existing proteinuria in
Itai-Itai patients and other subjects from the Fuchu area involved rather
nonspecific (Friberg, et .1., 1974) total protein methods. More recently,
however, attention has focused on the levels of specific types of urinary
proteins which may be more pathognomonic for renal effects of cadmium..
One argument which has been advanced in defense of the notion that Itai-Itai
disease is not cadmium-related Is the fact that Itai-Itai disease appears to
be confined to the Jintsu River basin, although a number of other cadmium-
polluted areas exist in Japan. In 1975, however, Nogawa et al. 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.
Other factors have also likely contributed to the failure to find more
conclusing evidence of Itai-Itai disease in other areas of Japan. In viewing
the data available on Itai-Itai disease, for example, one is struck by the
fact that in many early epidemiology studies on the subjects, investigators
restricted themselves to the extreme clinical phase of the continuum of changes
accompanying chronic cadmium exposure. Fortunately, this problem has since
begun to be assessed more comprehensively and uniformly, taking into account
the earliest signs of renal deficits of the type associated with manifestation
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of more severe aspects of Itai-Itai disease. Still, even after a large number
of epidemiologic studies and health surveys in cadmium-polluted areas, the
etiology of Itai-Itai disease is not yet completely clear. The disease was at
first diagnosed as a vitamin-D resistant osteomalasia, but, based on studies
of the type reviewed here, cadmium has been implicated as a likely factor
contributing to the development of the disease. Importantly, however,
Malnutrition and other environmental factors may have promoted the toxic
effects of cadmium in Itai-Itai patients.
Before discussing studies of other cadmium polluted areas of Japan, it
should be noted that chromosomal aberrations occur 1n Individuals with Itai-Itai
disease as discussed in part in the Sub-Cellular Effects section (vide supra)
of Chapter 2 and Section 3.8 of the present chapter.
3.4.2. Epidemiological Studies of Other Cadmium-Polluted Areas in Japan
Japanese areas besides the Fuchu region of Toyama Prefecture, where
epidemiological studies have also been carried out include Ikuno, Tsushima,
Kakehoshi, Bandai, Annaka, Omuta, and Uguisuzawa; and a review of these data
was presented by (Friberg et aj_., (1974).
In a more recent rather detailed report, KjellstrSm (1976) has reviewed
and critiqued data from 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 df 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
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extends back for several centuries. Three control-area groups of 1574, 2002,
and 538 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 Hurayama (1974) found
tlevated P2-niicroglobulin and lysozyme in urines of individuals from the most
heavily exposed group (H area). It was in this same area that Nogawa et al_.
(1975) later reported five cases of Itai-Itai disease (vide supra).
Another zinc mine which was probably a long-term pollution source spanning
several centuries appears to have contributed to the occurrence of significantly
increased proteinuria in the Tsushima area of Nagasaki prefecture, as discussed
by Friberg et al_., (1974).
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, and using 215 women in a control area,
indicated that the prevalence of proteinuria was 12.3 percent in the polluted
area compared to 4.7 percent in the control area.
Another site for a zinc smelter is the Annaka area of Gumma prefecture.
A study of 2397 persons (men and women, more than 30 years of age) in the
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polluted area around the smelter showed a prevalence of proteinuria (12.1
percent), but this was not significantly different from the rate observed for
a group of 695 control subjects (Kakinuma et a_h, 1971), as described in
Friberg et aj. (1974). These findings have later been ascribed to the brevity
of the significant exposure period, which occurred mainly only over the last
decade (Kjellstrom, 1976).
The .most recent study of the prevalence of proteinuria in a zinc-smelter
area in the Omuta region (Friberg et al_., 1974) showed a rate of 18.2 percent
for the polluted area versus a rate of 6.8 percent for control subjects.
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
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 P2-microglobulin in this group
increased with age and length of residence in this area.
Extensive soil contamination and a high contamination of rice are present
in this area. In the studies of Watanabe et al_. (1973), noted above in connection
with proteinurea, urinary cadmium levels were related to the village average
rice cadmium levels; adults excreted ca. 7 ug cadmium/ liter at rice levels of
0.4 pg/g and this value rose'to ca. 14 pg/liter at 1.1 ug/g in rice. These
values correspond to 240 and 660 ug daily of cadmium intake. Kjellstrom
(1977) found that women aged 50-59 and having long-term cadmium intake had
blood levels of ca_. 3 ug/dl and 24 hour urinary excretion levels of ca. 15 ug.
These latter values can be compared to calculated estimates, based on a 600 ug
cadmium intake value, of 3.4 ug/dl blood and 14 pg/24 hour urine respectively
(Kjellstrom and Nordberg, 1978).
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3.5 EPIDEMIOLOGY OF CADMIUM, HYPERTENSION, AND CARDIOVASCULAR DISEASES
Hammer et aj. (1972) a reviewed Information an the relationship between
cadmium and hypertension and also 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 wore 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 of smoking
status.
Thind et al_. (1976) and Glauser et a_L (1976) found significantly higher
cadmium concentrations in blood of hypertensive patients than in normotensive
controls, but neither of these groups of investigators controlled for smoking
status. Beevers et aj. (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 aj., 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 concluded 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.
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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 al., 1974; Voors and Shuman. 1975) did not adequately control for smoking.
They found a statistically significant association for zinc concentrations in
kidney tissue, and an association, consequently, for zinc-cadmium ratio, but
not for cadmium concentrations per se.
The association between hypertension and hard water and associated levels
of cadmium in water has been discussed by Perry et al.. (1974). There is no
firm evidence as to the significance of this variable. Rather, the currently
available data are not definitive and can best be characterized as inconclusive
and requiring further research.
Early studies by Hunt et al_. (1971) and Mickey -et al. (1967) related
mortality rates to air cadmium levels. These statistical approaches use total
mortality experience without taking into account population characteristics
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.
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Some statistical differences for the two groups were found, but smoking status
'was not controlled for. The significance of their finding has been questioned
(Sharret and Fein'lieb, 1975).
Autopsy studies reported by Voors et a_K (1975) and Shuman et al. (1974)
found an association between cadmium concentration in liver and death from
heart disease. Syverson et a_K (1976), however, found neither an association
for cardiovascular disease nor for hypertension, as discussed above.
The evidence for an association between cadmium and cardiovascular disease
1s, therefore, no clearer than that for hypertension. The groups studied are either
extremely small or, if larger, were not controlled for relevant factors. It
Is therefore, impossible at this time either to rule out the postulated relation-
ship or to confirm it.
3.6 EPIDEMIOLOGICAL STUDIES OF THE RESPIRATORY TRACT
Studies concerning cadmium-induced effects on the lungs, other than
cancer, almost universally concern occupationally exposed workers and have
already been discussed above in Chapter 2 (Health Effects). Briefly, Lauwerys
et aj.. (1974), Scott et aJL (1976), and Smith et aj. (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 jroup.
Smith et aj.. Cl976a) found mild and moderate interstitial fibrosis in an
occupational study group with a history of high exposure to airborne cadmium
(.i.e. levels >0.2 mg/m3). Associated impairments in pulmonary function, as
indexed by significantly decreased forced vital capacity (FVC) were also
observed in relation to data obtained for low exposure co-workers and unexposed
control subjects matched for age smoking status, and other pertinent character-
istics. A clear dose-response relationship was observed between forced vital
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capacity and both average urinary cadmium concentration (r = 0.53; P< .003)
and maximum urinary cadmium concentration (r -.51; P < 0.05). Linear regression
analyses further indicated that decreases of 2.8% in predicted FVC occur as
average urinary cadmium excretion levels increase by 10 ug/1 cadmium as a
single etiological factor. The cadmium/zinc ratio was not determined.
Morgan et al_. (1971) 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 investigators 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 not
possible, based on these study results, to implicate cadmium as the key
etiological factor associated with the occurence of lung cancer cases studied.
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 source.
The data are sparse and subject to the limitations of retrospective study
design and autopsy studies.
3» 44
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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.
Kipling and Waterhouse (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 cancor 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 aj.. (1976)
3-45
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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 statisti-
cally 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 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 al. (1976) found the same latency period.
It should be kept in mind that the Lemen et a_l_. (1976) study did not control
for smoking.
A study of mortality among rubber workers was conducted by McMichael
et 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 worksites were determined. These specific
mixing jobs expose workers to cadmium and other metal oxides.
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Autopsy studies have compared cadmium concentrations in tissues by causes
of death. Lewis et al_. (1972) found in their 172 autopsies that higher con-
centrations 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 reconsi-
deration of the findings reported earlier by Morgan et al_. (1970, 1971), who
found significantly higher cadmium tissue content for causes of death from
cancer of the lung but did not control for smoking status. Voors et aJL
(1975) reported on their autopsy series that they found no association
between 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 diagnosiis 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 riot. Two sources of respiratory exposure and the dietary exposure
were therefore' considered. Relative risk for cancer of the kidney was increased
only when smoking and occupation were considered together, in which case the
age-specific, relative risk was 4.4, whereas for smoking alone, the relative risk
was 1.2. .
There is evidence in the literature which suggests that cadmium may be a
factor in the etiology of cancers at various sites, but the association w.th
cadmium is not firmly established. For example, Lemen et al. (1976) reported
statistically significant increases in bronchogenic cancer to be associated with
cadmium exposure, but did not control for smoking. Also, for lung cancer, an
association was found by Morgan (1970, 1971) but not by Voors et al. (1975) or
3-47
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Lewis et al. (1972) when cigarette smoking was taken into account in the
latter study. Prostate cancer was reported in several studies to be associated
with occupational exposure to Mixtures of airborne particulate matter which
contained cadmium oxide as a common component. Although the evidence is not
conclusive, the possibility that cadmium can cause cancer cannot be dismissed.
Both the U.S. Environmental Protection Agency's Carcinogen Assessment Group
(1978), and the WHO International Agency for Research on Cancer (IARC)
monographs 11 and 20 (1976) reached the same conclusion in regard to occupational
exposure and cancer risks.
3.8 EPIDEHIOLOGICAL STUDIES RELATING TO CHROMOSOMAL ABNORMALITIES
A number of studies addressing the question of chromosomal abnormalities
in humans and involving various exposure conditions have been reported.
Shiraishi (1975) pointed out the occurrence of a number of chromosomal
abnormal ities 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.
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In the occupational exposure studies of DeKnudt and Leonard (1975) and
Bauchinger et a].. (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
translation, and ring and dicentric chromosomes obtained were higher than in
a group of control, low-cadmium-exposure workmen. In the latter data (Bauchinger
et al., 1976), chromosomal damage was aainly 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).
3-49
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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.
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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
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To better understand this portion of the present document, 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
-------
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 Hetz, 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, Sources of Atmospheric Cadmium, 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 of cadmium from any of these
media, into the human food chain, as illustrated in Figure 4.1, and 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 atmosphe-ic
cadmium over remote rural areas and many small urban areas are usually very
low and are often non-detectable. For example, numerous air sampling
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
-------
4-6
-------
for atmospheric cadmium appear to be definitely below 0.1 ng/m and may even
be close to 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. ,0f historical
interest, among the highest ambient air levels recorded within the United
States are readings of 0.12 ug/m3 (120 ng/m3) obtained in El Paso, Texas in
1964 and 0.300 to 0.489 ug/m3 (300 to 489 ng/m3) in Shoshone County, Idaho, in
1974. Other readings taken in the United States in a 1969 survey ranged from,
0.006 ug/m3 (6 ng/m3) in San Francisco, California, to 0.036 ug/m (36 ng/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 during 1970-1974 by the EPA National
Air Surveillance Network (NASN), with inputs from state and local agencies,
are presented in Table 4-1 (Akland, 1976). The table indicates that the
average annual values for the U.S. cities listed fan mainly within a range of
0.001 to 0.020 ug/m3, (1 to 20 ng/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 have been conducted. In particular, values from Idaho and
Montana have often been 0.100 ug Cd/m3 (100 ng/m ) or greater, as reported in
the SAROAD file (U.S. EPA, Multimedia Levels Cadmium, 1977).,:;Floro and McMullen
(1977), however, assembled a plot of the fiftieth percentile of annual
4-7
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TABLE 4-1. ANNUAL AVERAGE URBAN ATMOSPHERIC CADMIUM CONCENTRATIONS
REPORTED BY NATIONAL AIR SURVEILLANCE NETWORKS, 1970-1974*
(L.D. = Limit of Detection)
Location
Arizona
Douglas
Tucson
, Colorado
Denver
Connecticut
Bridgport
Waterbury
Georgia
Atlanta
Illinois
Chicago
East St. Louis
Peoria
Indiana
East Chicago
Indianapolis
Kentucky
Ashland
Covington
Louisiana
New Orleans
Shreveport
Maine
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
1976
0.0065
0.0102
0.0117
.'251
L.D.
0.0067
0.0187
0.0066
0.0108h
0.0048°
L.D.
L.D.
L.D.
0. 0047
0.0060
—
4-8
Cadmium
1971
0.0251
0.0101
0.0048
0.0210
0.0065K
0.0045°
0.008°
0.0063
0.0049
0.01$4
0.0132
0.0086
L.D.
0.0116
0.0155
0.150
concentration, ug/m
1972 1973
0.0132h — h
0.0045° O.OC45°
—
0.0057 — h
0.0174 0.0027°
—
0.0030b
0.0052
0.009b.
0.0093
0.003°
L.D.
L.D.
... —
L.D.
0.0086
...
1974
0. 0062b
—
0.0139
—
0.0056
0.006b
L.D.
L.D.
—
—
—
—
•H
-------
TABLE 4-1 (Cent.) ANNUAL AVERAGE URBAN ATMOSPHERIC CADMIUM CONCENTRATIONS
REPORTED BY NATIONAL AIR SURVEILLANCE NETWORKS, 1970-1974* 1UNi
(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
Youngs town
Pennsylvania
Allentown.
Bethlehem
Hazleton
Philadelphia
Scranton
Texas
El Paso
Virginia
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.
0.0055°
, 0.0071
— _
0.0086
0. 0088
0.0056
0.0081
0. 0140
L.D.
0. 0618
0.0135
-_.
L.D.
Cadmium
197T~
~»
0. 0167
0.0056
0.0128
—
0.0076
»B
*«•»
—
0. 0042b
0. 0191
0. 0067
—
0.00405
L.D.
concentration, ug/m3
1972 1973
___
___
0. 0124
0.0159
0.0189
0. 0060
— .__
___
___
— —
0.0178. 0.0042b
0.0068° 0.0068
0.0065
0.0057
L.D.
0.0442 0.0206
L.D.
0.0143
0.0071
1974
I"
0.0052
...
...
.__
0.0134
0.0038b
L.D. '
0. 0242
--—
Source: 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 near 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/m3
(U.S. EPA, Assessment of Human Exposures to Cadmium, 1979). This includes
cadmium emissions due both to general incineration of wastes and, more
specifically, 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,
because 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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yj
(j
QP3
0.02
«
0.008
QD04I-
J L
65 66 67 68_ 69 70 71 72 73 74
YEAR
- aA Indicates value below lower discrimination limit.
Figure 4-2. Trends in 50th percentile of annual averages for cadmium associ-
ated with metal industry sources at urban sites.
Source: Faoro and McMullen (1977). '•
4-11
-------
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 al., 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 aj. (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 a^., 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 et aJL , 1974) that worldwide ambient air
cadmium levels are generally less than 0.003 |jg/m (3 ng/m ) in rural
areas, but the yearly average may range as high as 0.050 ug/m (50 ng/m )
in industrialized urban areas. In contrast, at the extreme, weekly or
monthly averages around 0.50 ug/m (500 ng/m ) have been recorded in the
vicinity of cadmium-emitting industries (Friberg et aj_., 1974). , '
4.2.2 Drinking Water ' .
• i
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 al.., 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 et a],. (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 aj., 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
Number
Locality and of
type of soil samples
U. S.S.R, tundra, podsols
forest, red earth 40
Poland, distant fro«
industrial areas 33
Wales, Ystwyth Valley
Maryland, Missouri , Ohio
32 « fro* highways 4
Helena Valley, Montana,
18-60 km from saelter 17
Annaka City, Japan,
900 • fro* refinery 2
Southwest Wales 4
Lower Fraser Valley,
British Columbia 33
Depth
<«)
Normal Soils
A, 0, and C
horizons
0-20
10-15
6-10
40-60
Surface
Cadniua content (ppn)
Range Average
0.01-0.07 0.06
0.04 (MX) 0.016
1.0
0.12-0.52 0.26
fO.S-f 1.4b
0.3-0.4 0.35
0.3-0.5 0.4
0.88
Contaminated Soils
Poland, industrial areas 67
Wales, Ystwyth Valley,
contaminated
Maryland, Missouri, Ohio,
8 • froa highways 4
Helena Valley. Montana,
1 lea fro* saelter 7
Annaka City, Japan
150-250 • fro* saeltar
900 • fro* sielter
Poland, 600 «'fro« zinc 1
Metallurgical factory 1
Southwest Wales, Swansea,
1.5 ka fron contaminated
area
Bartlesville, Oklahoma,
1500 ft fron smelter
British Columbia, 15 •
fron smelter 4
Grand Rapids area, Michigan
Residential, area 70
Agricultural area 91
Industrial area 86
Airport 7
0-20
0.5
0.10
Surface
5
0-10
15-30
12.S-27.5
Surface
0-5
0-5
0-5
0-5
0.3-0. S (MX) 0.17-0.28
1.5-3.0
0.90-1.82 1.28
26-160 72
23-88
44
250
110
26
450
7.9-95.2 49.0
0.41
0.57
0.66
0.77
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4-17
-------
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 aj.. (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 Appendix A.
Appendix A reports amounts of sewage sludge containing varying concen-
trations of cadmium disposed of by certain United States cities, including by
means of landspreading on agricultural land. The information listed in
Appendix A is based on data compiled by the EPA Office of Solid Waste Manage-
ment 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 Appendix A totals 3706 dry mt/day produced, and approxi-
mately 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 pp.). 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 that has been 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
ppn., 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
-------
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 an EPA assessment
(Multimedia Levels Cadmium, 1977), the following appear to be of most
importance:
(1) Uptake from soils by roots of food plants. This is a pH dependent
process and 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.
4-20
-------
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 an earlier EPA 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 4-4, as estimated from several studies (Corneliussen, 1970;
4-21
-------
TABLE 4-4. CADMIUM CONTENT IN DIFFERENT FOOD CATEGORIES IN THE U.S.A.
a,b
Cadmi urn ,
1968-1969
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
No. >0.01
10
21
27
27
16
24
25
15
27
18
8
"*™
Maximum
0.09
0.06
0.08
0.08
0.03
0.08
0.07
0.04
0.13
0.07
0.04
"*™
ug/g wet weight
1969-1970
No. >0.
- 9
22
27
28
10
27
27
10
28
9
9
29
01 Maximum
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.
5Cadmium was analyzed by atomic absorption and/or polarography at a
sensitivity of 9.01 ug/g.
4-22
-------
Duggan and Corneliusson, 1972). Concentrations of cadmium found more
recently by FDA in adult foods are seen in Table 4-5 (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 4-5, 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 4-6 and 4-7, 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, «ost
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 4-6 and 4-7, cadmium intake from
all food groups varied somewhat from year to year (total-ing 36 and 51
ug/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 ug/day, while the seven-year average of the means
was 72 pg (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.
4-23
-------
TABLE 4-5. CADMIUM CONTENT OF SELECTED ADULT FOODS3
Commodity
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
0.111
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
aSource: U.S. Department of Health, Education, and Welfare, 1975.
4-24
-------
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4-25
-------
TABLE 4-7. CADMIUM INTAKE OF TEEN-AGE MALES BY FOOD CLASS3
Food class
Total
Average Cadmium* Cadmium
consumed residue intake
9/d ppb yg/d
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)
704
262
424
177
54
66
32
88
222
72
83
684
5.7
15.3
23.3
48.0
40.5
6.3
32.3
14.7
3.0
15.3
10.0
3.0
4.0
4.0
9.9
8.5
2.2
0.4
1.0
1.3
0.7
1.1
0.8
2.1
2868
36
Trace values assumed as 10 ppb.
aFrom U.S. Dept. of Health, Education and Welfare. "Compliance
Program Evaluation, FY '74 Total Diet Studies (7320.08)". Food and
Drug Administration, Bureau of Foods, 1975.
4-26
-------
ME AT, PISH, AND
POULTRY
CHAIN AND CEREAL
PRODUCTS
122 J*l
LEAFY
VEGETABLES
LEGUME \ («-2%)
VEGETABLES
tt.8%)
ROOT VEGETABLES
SUGAR AND
ADJUNCTS
(1.3%)
GARDEN FRUITS
13.4%)
OIL. FATS AND
SHORTENINGS
(2.7%)
Figure 4-3. Contribution of food groups to-cadmium intaka.
Source: Shibko and Braude (1978).
4-27
-------
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 collaborative study, which
was carried out jointly in the United States, Sweden and Japan (Kjellstrom,
1979) 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 a Dallas, Texas, population was
reported to average approximately 18 ug/day for non-smokers. This arithmetic
mean intake was associated with a standard deviation of ± 8 ug, indicating
that diets vary considerably among members of that population in terms of
cadmium content. This is in keeping with other observations obtained by other
EPA-sponsored fecal excretion studies on Chicago populations in 1974 and 1975,
as summarized in Table 4-8, along with the 1975 Dallas survey data. In fact,
based on the observed distributions, the intake of five percent of the individuals
studied exceeds 33 ug/day and for one percent, approximately 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 (- 1 percent) of adults likely exceed 50
ug/day of dietary cadmium intake.
While the above estimates are among the best available for current levels
of daily dietary cadmium intake, they may not necessarily be accurate indicators
of future American dietary exposure to cadmium. Rather, increased amounts of
dietary cadmium could be ingested in the future if use of high cadmium-containing
phosphate fertilizers on U.S. crop lands is expanded or if uncontrolled landspread-
ing of cadmium-contaminated sewage sludge on agricultural land were permitted.
4-28
-------
TABLE 4-8. DISTRIBUTION OF DAILY DIETARY CADMIUM INTAKE (ug/day)
OF U.S. POPULATIONS AS DETERMINED BY FECAL EXCRETION STUDIES
Study
Population
Chicago
Chicago
Dallas
Percent of Population Which Exceed
Displayed ug/day Value
Year
1974
1975
1975
N
192
199
86
x (ug/day) =
50%
13.7
9.1
12.5
11.8
10%
28.5
28.8
20.8
26.0
5%
35.1
40.2
25.6
33.6
1%
51.8
74.3
34.4
53.5
4-29
-------
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 al_. (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. It should be
noted that the increases observed with cadmium additions to the soil were
superimposed on already high levels seen in the control plants.
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
4-30
-------
TABLE 4-9 CADMIUM CONTENT OF SEVERAL CROPS AND TISSUES
AS A FUNCTION OF CADMIUM LOADING OF SOIL3
Cd Content of Croc Tissue, nnm
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.
Fruit
Tops
Tubers
Tops
Roots
Tops
Tops
0
0.21
0.28
0.22
0.29
0.21
0.71
0.29
0.51
0.23
0.58
0.18
0.46
0.24
0.66
0.49
Added Soil CdT
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
ppm
5.0
1
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
(From Maclean, 1976) Grenville loam pH = 7.1.
4-31
-------
X.
NEUTRAL SOIL
-------
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
years. The actual annual loadings on a kg Cd/ha basis are not known, but
the sludge cadmium content from cities 1, 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 ingestipn 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 t.his 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
4-33
-------
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-------
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
(Williams and David, 1973, 1976; Lee and Keeney, 1975; Miller et a_K , 1976;
Andersson, 1976; Reuss et a_h, 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 aJL , 1978). Andersson (1976), in his studies of
pi ant-avail able 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.
4-35
-------
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
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
4-36
-------
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.
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 aJL , 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,
4-37
-------
TABLE 4-11. MEDIA CONTRIBUTIONS TO NORMAL RETENTION OF CADMIUM8
Medium
Ambient air
Water
Food
Cigarettes
Packs/day
1/2
1
2
3
Adult Exposure level
x 20 «3/day 0.03 ug/m3
x 1 liter/day 3 ug/1
x 2 kg/day 50 ug/day
ug/day
1.1
2.2
4.4
6.6
Daily retention
(ug)
0.15b
0.36C
3.0d
0.70f
1.41*
2.82*
4.22e
Modified from: 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 25 percent deposition and assuming 100 percent absorption
of deposited amount.
cBased on average American drinking water level of 3 ppb and
assuming 6 percent absorption from gastrointestinal tract.
Based on 6 percent absorption from gastrointestinal tract.
eBased on 0.11 ug Cd per cigarette and 6.4 percent retention rate
demonstrated by Lewis, G. P., W. J. Jusko, L. L.'Coughlin, and
S. Hartz. Cadmium accumulation in man. Influence of smoking,
alcoholic habit and disease. J. Chron. Dis. 25:712-726, 1972.
4-38
-------
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
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 b* useful to summarize
the more important health effects that appear to be of most concern in
cadmium exposure.
Acute effects of cadmiun, 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 L05£) exposure levels in
rats and mice fall around 25 mg/m3 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
been noted at cadmium-oxide fume levels below 1.0 mg/m3.
4-39
-------
In situations involving long-term cadmium exposure, especially at low to
moderate levels, cadmium effects on the kidney appear to be the most crucial
ones, with renal dysfunction currently widely accepted as the "critical effect"
in terms of assessment of requisite exposure levels for induction of toxic
actions of the metal. The renal dysfunction referred to involves cadmium-
induced disruption of normal functioning of renal tubular cells, resulting in
increased urinary excretion of proteins (proteinuria), amino acids (aminoacidun'a),
glucose (glucosuria) and other substances such as calcium. Proteinuria, as
one of the earliest signs of the renal dysfunction typically manifested, is
therefore a highly useful indicator reflecting or indexing the onset of cadmium
renal toxicity. Estimations of amounts of cadmium accumulation in the kidney
necessary for the induction of damaging effects resulting in proteinuria are
important, therefore, in order to calculate external exposure levels from
various sources necessary to induce the "critical effect" of renal dysfunction.
Presumably, limiting cadmium exposures to levels assuring protection against
the induction of proteinuria would, then, in essence provide protection against
any other more serious 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 cadmium-induced renal
dysfunction, as indexed by tubular proteinuria, reversible or irreversible in
nature; and 2) regardless of its reversibility or irreversibility, is the
4-40
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presence of renal tubular dysfunction to be taken as a significant health
effect?
In regard to the first issue, Piscator (1977) has reported data on eigh-
teen cadmium workers that conclusively demonstrate the persistence of renal
dysfunction, as indexed by tubular proteinuria, approximately twenty years '
after cessation of exposure. What is even more notable is the fact that
irreversibility exists even at relatively 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 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 in-
dividuals, cadmium-induced renal proteinuria can be irreversible.
As to the issue of proteinuria-indexed renal tubular dysfunction being a
significant health effect, the available evidence strongly indicates that it
is indeed a health effect worthy of concern. 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 a vital organ, the kidney
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
4-41
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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 compli-
cations. Of the, six subjects in the, survey noted earlier above, one person
developed ostiomalacia and a second suffered from chronic renal stone
problems. All subjects showed persisting hypercalcuria and hypophosphataemia;
of five subjects studied for uric acid clearance, all of them showed abnormally
• i-
high clearance. Furthermore, four subjects had aminoaciduria, and five individuals
had glycosuria. Of thesesnunbers 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 hypercalcuria and one case of hypophosphataemia
similarly developed subsequent to the first survey.
The reader is directed to'further 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. In addition, a recently published report (Kjells'trSm
et a!., 1979) should be noted concerning the observation of statistically
significant increases in renal disease mortality rates among battery plant
workers chronically exposed to high levels of cadmium in the workplace.
Whereas 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 suggestive evidence hints at other effects
possibly occurring as the result of chronic low-level cadmium exposure. These
effects include, for example, the following: (1) certain "subtle" hormone
4-42
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effects that likely underlie reductions in plasma testosterone concentrations
observed with cadmium exposures in the absence of signs of renal damage or
severe testicular necrosis; (2) effects on reproduction and development, e.g.,
reductions in birthweights seen after oral exposure of pregnant animals and
having some parallels in reports in the human epidemiology literature;
(3) immunosuppression effects demonstrated to occur in animals at low
oral exposure levels, but not yet confirmed in humans; and (4) certain
mutagenic and carcinogenic effects observed in in vitro or in vivo animal
experiments or reported in human epidemiology studies. In regard to all four
of the above examples, however, insufficient evidence currently exists to
warrant any of them being treated now as key health effects associated with
chronic cadmium exposures at environmentally relevant levels. Rather, of
crucial importance for present purposes are the much more conclusively
demonstrated cadmium-induced renal effects discussed earlier above and
quantitatively assessed below.
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
4-43
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estimates of the dietary intake of cadmium in various countries cover a wide
range of values, current estimates of median or average daily cadmium intake
by ingestion in the United States generally range from 10 to 50 ug per day per
person. Large segments of the general population are also exposed to additional
burdens of cadmium via inhalation due to smoking (see 4.2, Exposure Aspects),
since cigarettes contain notable amounts of cadmium. Exposure via ambient
air, however, appears to be relatively negligible for the general population,
except for persons living in close proximity to certain cadmium-emitting point
sources. Exposure to cadmium via drinking water also generally represents a
negligible input for the general population.
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 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 low-level
exposure 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 aj.. (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. In addition, Nogawa et al. (1979) demonstrated
a close relationship between cadmium concentrations in urine, when expressed
4-44
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in terms of ug/g creatinine, and such indices of renal tubular dysfunction as
proteinuria.
.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
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
4-45
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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 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 ug/g wet weight, and 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 ug/g wet weight of kidney cortex
be considered as the critical concentration for cadmium-induced renal dysfunc-
tion, as indexed by proteinuria; and WHO (1977) and the Subcommittee on the
4-46
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Toxicology of Metals under the Permanent Commission and International Associa-
tion of Occupational Health have tentatively endorsed this proposal (CEC,~
1978). It should be noted that the WHO (1977), while endorsing the 200 ug/g
critical concentration as the best estimate, also pointed out that the critical
concentration could range from 100 to 300 ug/g.
In contrast to the above groups, Nomiyama (1977) has suggested that 300
ug/g is the best estimate of the critical concentration of cadmium in kidney
cortex. This is based on Nomiyama1s assertion that estimates of the critical
concentration are most appropriately derived from cases where proteinuria was
the only pathological finding, so that renal cadmium concentration measurements
are 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 after the onset of renal tubular damage. Nomiyama
(1977) noted that, from among the eight human autopsy cases upon which Friberg
et al. (1974) based their 200 ug/g proposal, those manifesting proteinuria
only had renal cortex cadmium concentrations ranging 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 cadmium in renal cortex necessary
for the induction of renal dysfunction. On the other hand, other investigators
(Brown et aj.., 1978) have countered Nomiyama's comments by suggesting that 50
ug/g should be taken as being the critical concentration in the absence of
more conclusive evidence for a "no-effect" level existing below 100 ug/g.
4-47
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Regardless of whether 50. 200, or 300 ug/g is taken as being the best
estimate of a theoretical critical concentration, it should be remembered that
a "typical" threshold cadmium concentration necessary to induce renal dysfunc-
tion is implied by each estimate. No single estimate, however, can fully
reflect the wide range of individual biological variation that has been observed
to exist for induction of renal dysfunction in both human and animal studies.
Nevertheless, taking a specific single value designated as being the best
estimate of the "critical concentration," it is possible through the use of
metabolic nodels to estimate probable levels of cadmium exposure sufficient to
produce that 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, in view of the 200 ug/g value
being the presently most widely accepted estimate (WHO, 1977; CEC, 1978).
The theoretical basis for such modeling is: if the critical concentration
of cadmium in the renal cortex is defined as the dose level at which renal
dysfunction effects begin to occur in the most sensitive segment of the
population, then limiting doses (exposures) to levels which produce values
less than that in the kidney cortex should be sufficient to protect the entire
population.
Some results obtained with metabolic models, as reported by Friberg et aj..
(1974), Nordberg (1974), and KjellstrSm (KjeHstr8m,'1976), are summarized
in Table 4-12. Two types of calculations are presented in the table, those
pertaining to the absorbed doses necessary to achieve a kidney cortex concen-
tration of 200 ug/g and those pertaining to corresponding exposures necessary
to achieve that concentration. All calculations are made for two estimates of
biologic half-tine for cadmium: 18- and 38-years. For a 50-year exposure, a
4-48
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f°* REACHING A «°"E* CORTEX
Basis of calculation13
Constant daily retention during
whole exposure time
25% pulmonary absorption, 10 m
inhaled per work day, 225 work
days/year
/2r««expo,sure for "50-yr-old person
(2500 ca/day) (4.5% retention)
(changing caloric intake by age
accounted for)
Total amount (net weight) 300 g
of food/day 600 g
1000 g
Exposure
time
(yr)
10
25
50
10
25
50
Levels of cadmium retention
or exposure yielding renal
dysfunction, assuming cadmium
half-times of:
38 yr 18 yr
Daily retention (ug)
36 39
16 20
10 13
Industrial air concentration
(in pg/nr) yielding renal
dysfunction
23 25
•11 13
Daily cadmium intake (pg)
Corresponding average Cd con-
centration in foodstuffs (ug/g)
50
0.8
0.4
0.25
1.2
0.6
0.35
Adapted from Friberg, L. M. Piscator, G. G. Nordberq and T Kiellstrnm
Cadnnum in the Environment. CRC Press, Cleveland? 1974 KJe11strom-
b«rtTL^s;n,°^
e-Response Relationships of Heavy
4-49
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daily retention of 10 pg/day would be sufficient, assuming the 38-year estimate
of biologic half-time, to achieve the two hundred microgram per gram (200
pg/g) level in the kidney cortex. The corresponding retention figure of 13
pg/day applies if a half-life gf 18 years is assumed. Thus an effect of
estimated biological half-time on estimated retained cadmium necessary to
reach the critical concentration in the kidney cortex is readily apparent, but
this effect is relatively small in comparison to that of exposure duration.
The remainder of the table demonstrates the effect of exposure duration
and biological half-time on the daily exposures necessary to achieve the
critical concentration in the cortex. For a person occupationally exposed to
cadmium, and assuming a half-life of 38 years, only 25 years of exposure to an
air cadmium concentration of 11 pg/m would be necessary for the critical
value to be reached. Also, given the assumptions listed in the table, a daily
dietary intake of 250 to 360 pg of cadmium would be sufficient over a 50-year
exposure period for the critical concentration to be reached.
The above modeling approaches, however, have limitations as pointed out
by Nordberg (1976) and in order to assess their validity, it is obviously
necessary to evaluate the correspondence of results predicted by a given 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 occupationally exposed workers or for
ingestion of foodstuffs of known cadmium content in population groups showing
evidence (proteinuria) of renal dysfunction.
Kjellstrom (1976) has complied data which relates estimated airborne
cadmium exposure of workmen to observed incidence of proteinuria; and it
appears that the incidence of proteinuria is significantly elevated in workmen
4-50
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after 10 to 20 years of workplace exposure to air cadmium levels as low as 50
ug/m . This is within a factor of two of predicted levels listed in Table
4-12 for industrial air concentrations (23-25 ug/m3) likely to result in the
critical concentration being reached in kidney cortex after 10 years of
exposure. It is interesting to contrast the predicted levels of air exposure
yielding signs (e.g., proteinuria) of renal dysfunction as the "critical
.effect" of cadmium exposure in comparison to air values estimated to cause
more acute toxic effects of cadmium. Friberg et a].. (1974), for example,
concluded that in man lethal, acute exposure to a cadmium level in air is
approximately 5 mg/m3 (5000 ug/m3) for an 8-hr period, whereas emphysema, a
chronic respiratory effect, generally starts to occur when the air level value
is about 0.1 mg/m3 (100 ug/m3) and probably lower (66 ug/m3) in the case of
workers who smoke (Lauwerys et a!., 1974).
Kjellstrom (1976) also evaluated epidemic!ogical studies on the occurrence
of proteinuria in Japanese populations residing in identified, high-cadmium-
exposure areas. The data from these studies are valuable in that, in most
cases, the exposure was dietary and several studies measured the cadmium level
of the chief dietary component. The results obtained correspond well with
dietary cadmium intake estimates of 250 to 360 ug/day based on the above
metabolic model. Consistent with KjellstrbVs (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 dysfunction,to be reached. Lower levels of daily dietary cadmium
intake, however, would presumably be sufficient for the critical renal cortex
concentration to be reached in the most susceptible members of the population
and, as such, would more closely approximate "threshold" levels of dietary
4-51
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cadmium intake associated with cadmium-induced renal dysfunction in sensitive
members of exposed populations.
In that regard, a scientific group more recently evaluating dose-response
relationships for cadmium (i.e., The Working Group of Experts for the Commission
of European Communities) has estimated the threshold effect level for cadmium
by ingestion to be around 200 pg daily, corresponding to an actual absorption
of 12 pg/day, over a 45- to 50-year exposure period (Criteria - Dose/Effect
Relationships for Cadmium, 1978). For smokers this estimate is reduced by
about 1.9 ug to 10.1 ug, which corresponds to an oral intake of 169 M9/day-
Using a second approach, also based on metabolic modeling of the above type,
this same group derived a projected threshold effect level of 248 \ig daily
for dietary cadmium intake, when pulmonary absorption is negligible.
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, "average" or "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 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
4-52
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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 dysfunction 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 dysfunction for the given individual. Conversely, some individuals, the
least susceptable ones in a population, may not experience renal dysfunction
4-53
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even at exposure levels much higher than the average level yielding such
damage for most members of the population. The existence of wide variability
i"n individual dose-effect relationships for cadmium-induced renal effects is
hinted at, for example, by the range of renal cortex cadmium concentrations
(21 to 395 ug/g wet weight) reported by Friberg et aj. (1974) to be associated
with proteinuria, as discussed earlier. It is important, therefore, 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. Some
initial progress in attempting to defining such dose-response relationships
has been accomplished recently (KjellstrSm, 1977a, 1978; KjellstrSm and
Nordberg, 1978, Nogowa et al, 1978).
Kjellstrom (1977, 1978) and Kjellstrom and Nordberg (1978) reported on a
more elaborate metabolic model developed by them in order to overcome some of
the uncertainties associated with earlier modeling attempts, especially in
regard to better taking into account individual biological variation in the
accumulation of cadmium in kidney cortex and the induction of renal effects.
Using both calculated and epidemiological cadmium exposure and retention data,
and renal tubular dysfunction prevalence indexed by p2-microglobulin excretion
as the adverse health effect, complex dose-response relationships for cadmium
renal effects in man were modeled by KjellstrSm and Nordberg. In Figure 4-5
are depicted calculated (lines) and observed (symbols) dose-response
relationships for cadmium-induced increase of urinary P2-microglobulin
excretion. 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
4-54
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2.000 8.000 10.000 30.000 100.000
D0« INDEX, *ig/d«yxy,.ri
rSstt^^^^^^^^mbols O, D. A, dose-
Source: Kjellstrom (1977).
4-55
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values besides the lines are for three renal cortex "critical concentration"
cadmium values: 150, 200, and 300 ug/g net weight. The actual, or observed,
response rates indicated by symbols fit well within the predicted values
derived from the model.
The Kjellstrom model predictions take into account the varying kidney and
body sizes of Europeans and Japanese and represent values for response rates
at age 50. Note that 440 ug/day is the average (median) level of intake
projected to result in renal dysfunction for non-smoking adult Europeans (or
Americans based on equivalent body size). At a dietary intake level as low as
60 ug/day, however, average-sized adult Americans are predicted to show a 1.0
percent response rate and, by 100 ug/day and 150 g/day, approximately 5 and 10
percent would be predicted to exhibit renal proteinuria as indexed by increased
Pg-roicroglobulin excretion. These latter response rates are, of course,
distinctly higher than the near-zero rates at those intake levels implied by
the above CEC calculations of "threshold" critical dietary intake levels of
ca. 200 ug/day. As Kjellstrom has noted (Kjell Strom, 1977, 1978), however,
dose-response relationships defined by his model are based on a number of
assumptions which must be viewed with caution.
In regard to some of the more salient points of caution concerning the
KjellstrSm predictions, it should be noted that agreement between predicted
and observed values is best at levels above 100 ug/day where the largest
numbers of observed data points pertain. However, extrapolating these estimates
in a linear, non-threshold fashion to lower exposure levels (e.g., 30-60
pg/day) does not appear to be presently well-justified in the absence of
observed health data at the lower exposure levels. Further questions can also
be raised concerning the interpretation of the renal proteinuria prevalence
rates projected to occur at levels below 100-150 pg/day.
4-56
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That is, in his thesis, Kjellstrom cites observed response rates for
control populations (B-microglobulin levels above his operational definition
for damage) of 3.4 percent for Sweden, and 2.5 to 3.2 percent for Japanese
(KjellstrSm, 1977). With such background prevalence rates, which likely
involve many many other etiological factors producing prcteinuria, the signif-
icance of percentages less than 5 percent being attributed to cadmium is
somewhat unclear. A related factor bearing on this point and further complica-
ting matters is the fact that Kjellstrom (1977) defined excessive B-microglobulin
excretion as that exceeding 290 ug/1, i.e., the 95 percent confidence level
based on a geometric average excretion of 84 ug/1 for normal unexposed persons.
Therefore, by definition, there should be a 2.5 percent response rate in the
unexposed population.
The Kjellstrom model is also deterministic and has no standard deviation
around the 440 ug Cd/day average intake associated with it. To accomplish his
purpose, Kjellstrom derived a geometric standard deviation of 2.35 from studies
of autopsied tissue (Kjellstrom, 1977). The units of the 2.35 value are in ug
Cd/g kidney cortex (Elinder et al., 1976). However, Kjellstrom then applied a
log normal distribution with geometric standard deviation of 2.35 around the
440 average food intake value. The food intake has units of ug/day. His
assumption that the same standard deviation applies to kidney cadmium concen-
tration and daily food intake is debatable and results in much uncertainty
surrounding the accuracy of his model projections, especially at exposure
levels at increasing distances from the 440 pg/day average.
Nogawa et a].. (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
4-57
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proteinuria. Data on cadmium in rice and RBP in urine (Table 4-13) showed a
consistent increase in prevalence of renal tubular proteinuria among inhabitants
over 50 years of age to be associated with every rice cadmium concentration
category exceeding levels (ca. 0.20 pg/g) observed for rice consumed by the
control village inhabitants. Thus, at cadmium levels as low as 0.19 to 0.29
pg/g of rice, statistically significant increases in prevalence of tubular
proteinuria over that seen with control levels of cadmium in rice appear to
occur for Japanese individuals over 50 years of age. Dietary rice levels of
0.19 to 0.29 pg/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). Corrected for differences in body size, these levels
would be equivalent to approximately 150-200 pg/day intake for Europeans/Americans.
The Nogawa data are presented on a more detailed age-related basis in Table 4-14.
In summary, best estimates derived from the above data indicate that
renal tubular dysfunction, as indexed by proteinuria, is induced when kidney
cortex cadmium levels reach a critical concentration of approximately 200 pg/g
wet weight. Also, based on metabolic modeling results and empirical observations,
it appears that the critical renal cortex cadmium concentration is not usually
reached as a consequence of dietary cadmium intake (the main source of exposure
for the general public), unless such intake levels exceed 150-200 pg/day over
a 50-year exposure period. In order to accurately estimate the likely risk
for the general population associated with either airborne or
water cadmium exposures, one must take into account the above facts and other
information presented below on populations at risk so that overall multimedia
contributions to human cadmium exposure in various situations can be considered.
4-58
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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 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 and also seems 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 cadimum-
polluted areas of Japan has been the factor of age as a determinant in the
4-61
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prevalence of proteinuria, a measure of renal dysfunction, vith 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
uodel must be derived which relates existing American cadmium exposure 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 somewhat different ranges of estimates
have been arrived at by the FDA via food survey,studies than those obtained
through EPA-sponsored fecal excretion studies (Table 4-8). The collective
results of the latter studies, accepted here as likely being the more accurate
estimates of current American dietary cadmium intake levels, indicate that
most (>50.0 percent) of Americans ingest less than 20 ug of cadmium per day; a
4-62
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small proportion of the population (-1.0 percent), however, appear to exceed
50 ug/day of dietary cadmium intake.
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 for
nonsmokers; however, values at the lower end of that range, i.e., 200 to 248
ug/day, have been accepted as the best estimates by a Working Group of Experts
for the Committee of European Communities (CEC, 1978). These calculations
comport well with the estimates of 150-200 ug/day that can be derived from
Nogowa et al. (1978) observed dose-response data for Japanese populations
exposed to cadmium via dietary intake. If the above estimates are accurate,
then current American dietary intake levels of 10 to 50 ug/day would appear to
be distinctly lower than levels yielding critical renal cortex cadmium concen-
trations associated with renal dysfunction. On the other hand, certain other
presently available information suggests that such a large gap between current
intake levels and those producing renal dysfunction may not exist for the most
susceptible members of the United States population.
More specifically, as discussed earlier under Section 4.4.2, Kjellstrb'm's
(1977) modeling of predicted dose-response relationships suggests that as many
as 1 percent of the American population could exhibit signs (proteinuria) of
.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
4-63
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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 small portions of
the general population as a consequence of 50 years of dietary cadmium exposure.
The accuracy of these latter KjellstrSm model projections, however, can be
disputed based on factors discussed above; therefore, their use at this time
for risk assessment purposes is not advised.
All of the above information collectively suggests that few members, if
any, of the general (non-smoking) American population 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). However, in
addition to dietary intake as an 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 4-15, 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 pg, smoking one, two, or three packs of cigarettes
a day furnishes percentages of 41, 58, and 63 percent, respectively, of daily
cadmium retention for smokers. • Even in the case where 50 ng/day is the dietary
4-54
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TABLE 4-15. RELATIVE CONTRIBUTION OF
CIGARETTE SMOKING TO TOTAL DAILY
CADMIUM RETENTION3
Cigarette
packs/day
0
1/2
1
2
3
Daily food
50 pg
0%
17%
29%
45%
55%
intake of
25 M9
0%
26%
41%
58%
63%
Daily cadmium retention for water and
air 0.51 pg total. (See Table 4-11).
4-65
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intake of cadmium, the smoking of two packs of cigarettes daily roughly doubles
the daily total retention. In Table 4-16 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 possibly increased future dietary 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 concentra-
tion for renal dysfunction is reached at the end of the exposure period, a
definite increase in risk for non-smokers to reach the critical retention
limits (10-13 ug/day) becomes apparent as air levels increase from 100 to 1000
ug/m , even assuming only the two lowest dietary intake levels. A much greater
incremental risk for heavy smokers is evident even at air concentration levels
as low as 100 ug/m . For example, in the case of a daily intake of 50 ug
cadmium in food (3.0 ug/day net retention), an individual smoking two or three
packs of cigarettes per day throughout his adult lifetime approaches two-thirds
of the critical retention level (10-13 ug/day) at age 70, assuming smoking
started at age 20 and <10 ng/m ambient air cadmium exposure. At higher
chronic ambient air exposure levels, i.e., at 100-1000 ng/m , heavy smokers
would be expected to closely approach or exceed cadmium retention levels
resulting in renal tubular dysfunction.
In assessing the potential impact of ambient air cadmium exposures, if
one tabulates the relative contributions of ambient air cadmium over the range
of 1 to 1,000 ng/m , taking into account cadmium retention from dietary intake
and cigarette consumption, one arrives at the figures in Table 4-17. At
4-66
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4-67
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ambient air levels of 1 and 10 ng/m , no air contribution is made that signi-
ficantly enhances the risk of smokers over that arising from diet and cigarettes.
At levels of 100 ng/m , however, a uniform increase of 5 percent is seen, with
the increase in percentage at 1,000 ng/m being about 50 percent over that
of no ambient air Tevels 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 might project 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 al_. (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 pg/day
4-68
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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 4-16), and projected likely increases in dietary cadmium
intake should be taken into account in estimating acceptable ambient air or
water cadmium levels.
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 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.
Bogden et a].. (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
4-70
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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 and zinc/cadmium, indicating to
these investigators that inhalation may be a factor in the blood values.
Delves et al.. (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 absorption and/or health 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.
4-71
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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 cadmium passes
the placenta! barrier in only small amounts, it nevertheless can affect the
birth weights and morphological development of offspring exposed jri 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 found in animal studies where reduced birthweight has been observed.
Thus, there appears to be a reasonably well-established association 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. However, insufficient information currently
exists to allow for accurate quantification of pertinent dose-effect or
dose-response relationships.
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)
4-72
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increasing age (Delves et al.., 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 a_l., 1974). The health implications of
such cadmium exposures in children remain to be better established, however,
as discussed elsewhere in the section on human epidemiology; but one must
suspect that the general consequence would be that of putting them at higher
risk for any of the many adverse health effects described earlier under the
section on health effects.
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 4-18 presents estimates from EPA's Assessment of Human Exposures to
Atmospheric Cadmium (1979) of the numbers of individuals in the U.S. population
exposed to airborne cadmium levels >0.1 ng/m3 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 a projected average annual air level of 8.4 ng/m3 derived from the
municipal incinerators. Iron and steel production result in the second largest
group of individuals exposed, about 20 million. Comparatively smaller, but
significant, populations are exposed to higher air levels (>10 ng/m3), however,
by virtue of residence near other high cadmium-emitting point sources, e.g.,
primary zinc, lead, and cadmium smelters. It should be noted, however, that
the present numbers may underestimate actual annual exposures for some
4-73
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individuals in the vicinity of two or more different sources since the estimates
in Table 4-18 do not take into account possible overlaps of exposure fields
from different sources. This is most important for the municipal incinerators
and iron and steel mills, which are often clustered in urban areas. Although
large numbers of individuals are exposed via inputs from the above sources
into the ambient air, the average exposure levels reported, 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. However,
if the population estimates are broken down further according to more specific
annual exposure concentrations for different source categories, as presented
in Tables 4-19 to 4-22, then certain high risk exposure situations become more
apparent when the listed air exposure concentrations are compared to those
tabulated in Table 4-16. Note, for example, instances where population
segments are exposed to greater than 100 ug/m and expecially cases where
exposures exceed 1000 ng/m .
Table 4-19 is a listing of numbers of persons exposed to different
airborne cadmium concentrations arising from municipal incinerators. Also,
Table 4-20 describes the numbers of individuals exposed to various air
concentrations derived from iron and steel mills as another major source
category. Table 4-21, on the other hand, depicts exposure populations by air
concentrations derived from primary smelters, whereas Table 4-22 lists numbers
of people exposed to varying air cadmium levels around secondary smelters. In
addition, Figure 4-6 depicts the states included in the census regions employed
in Tables 4-19 to 4-21, which contain tabulations of regional populations
exposed to cadmium levels exceeding 0.1 nanograms Cd/m .
As noted earlier, smokers constitute a definite population at increased
4-74
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4-75
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TABLE 4-19. ESTIMATE OF CUMULATIVE POPULATION EXPOSED TO
SPECIFIED CADMIUM CONCENTRATIONS FROM MUNICIPAL INCINERATORS*
(103 people)
Annual Concentration (nq/m )
Region
1
2
3
4
5
6
7
8
9
10
>200
1.0
0.0
0.0
0.0
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0.0
0.0
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>100
3
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0.1
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>50
14
1,016
53
22
250
7.7
38
4.6
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>io
612
1,655
679
40
650
7.7
81
4.6
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>0.1
6,470
16,730
8,567
2,935
12,144
1,098
157
169
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aFrom EPA Assessment of Human Exposure to Cadmium (1979).
4-76
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TABLE 4-20. ESTIMATE OF CUMULATIVF POPlii iTTnw evcncm T«
SPECIFIED CADMIUM CONCENTRES FROM IRON ^^1^ MI?J8
(10J people)
•——————_
Region
— — — — — — — _ _ _
1
2
3
4
5
6
7
8
9
10
""
•
'•"'
""
Annual Concentration (nq/m3)
>10*
•
0
0
52
177
143
0
0
0
0
0
>5
•' ' ii • i
0
49
137
341
339
29
0
24
15
0
0
470
1,965
578
1,852
521
23
, 176
161
33
>0.1
93
1,649
4,543
1,610
a, 710
1,575
108
224
774
833
From EPA Assessment of Human Exposure to Cadmium (1979).
4-77
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TABLE 4-22. ESTIMATE OF POPULATION EXPOSED TO SPECIFIED LEVELS FROM
SECONDARY SMELTERS
(103 People)3
Smelter
>10*
Concentration (ng/m )
>5 >l >0
Annual Average
Exposure
Secondary Copper
Secondary Zinc
296 798 5,710 9,891
0 0 0 37
1.5
0.47
*Maximum3concentrations around existing plants are estimated to be about
50 ng/m .
aFrom EPA Assessment of Human Exposure to Cadmium (1979).
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 large segment of the present U.S. population
could be expected to be at potential increased risk for adverse health effects
of cadmium, especially those smokers residing in the vicinity of high cadmium
emitting point sources.
Also of special interest are the numbers of children in various urban
areas who may be at increased risk to cadmium exposure, and Table 4-23 presents
natality data for 1970 and 1975 as provided by the National Center for Health
Statistics (1975, 1978). As noted earlier, children are clearly at risk for
4-79
-------
"8 E
s £
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c J
E &
-------
TABLE 4-23. NUMBER OF BIRTHS BY RACE AND SIZE OF POPULATION
Urban areas by
population size
>100,000
50-99,999
10-49,999
>9,999
Total
Urban areas by
population size
> 100, 000
50-99,999
10-49,999
<9,999
Total
^^nn^mm
White
772,230
286,706
600,166
1,432,162
3,091,264
White
571,478
222,735
478,382
1,279,401
2,551,996
Births.
Black
321,412
37,024
65,790
148,136
572,362
Births.
Black
276,387
37,885
64,481
132,828
511,581
1970a
Other
24,394
4,182
10,394
28,790
67,760
1975
Other
26,332
5,921
13,039
35,329
80,621
—
Total
1,118,036
327,912
676,350
1,609,088
3,731,386
Total
874,197
266,541
555,902
1,447,558
3,144,198
Vital Statistics of the United States.
^National Center for Health Statistics, DHEW, Washington, DC. 1975
Unpublished data from above.
4-81
-------
increased exposure and, possibly, absorption; but they are not necessarily the
at special risk for experiencing health effects due to 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.
4-82
-------
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4-92
-------
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