United States
Environmental Protection
Agency
Health Effects Research
Laboratory
Research Triangle Park
North Carolina 27711
EPA-600/1-80-001
ORNL
Oak Ridge
National
Laboratory
Operated by
Union Carbide Corporation for the
Department of Energy
Oak Ridge, Tennessee 37830
ORNL/EIS-153
Chemical
Contaminants in
Nonoccupationally
Exposed U.S.
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RESEARCH REPORTING SERIES
Research reports of the Office of Research and Development, U.S. Environmental
Protection Agency, have been grouped into nine series. These nine broad cate-
gories were established to facilitate further development and application of en-
vironmental technology. Elimination of traditional grouping was consciously
planned to foster technology transfer and a maximum interface in related fields.
The nine series are:
1. Environmental Health Effects Research
2. Environmental Protection Technology
3. Ecological Research
4. Environmental Monitoring
5. Socioeconomic Environmental Studies
6. Scientific and Technical Assessment Reports (STAR)
7 Interagency Energy-Environment Research and Development
8. "Special" Reports
9. Miscellaneous Reports
This report has been assigned to the ENVIRONMENTAL HEALTH EFFECTS RE-
SEARCH series. This series describes projects and studies relating to the toler-
ances of man for unhealthful substances or conditions. This work is generally
assessed from a medical viewpoint, including physiological or psychological
studies. In addition to toxicology and other medical specialities, study areas in-
clude biomedical instrumentation and health research techniques utilizing ani-
mals — but always with intended application to human health measures.
This document is available to the public through the National Technical Informa-
tion Service, Springfield, Virginia 22161.
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ORNL/EIS-153
EPA-600/1-80-001
CHEMICAL CONTAMINANTS IN NONOCCUPATIONALLY EXPOSED U.S. RESIDENTS
by
James W. Holleman, Michael G. Ryon, and Anna S. Hammons
Information Center Complex/Information Division
OAK RIDGE NATIONAL LABORATORY
Oak Ridge, Tennessee 37830
operated by
UNION CARBIDE CORPORATION
for the
DEPARTMENT OF ENERGY
Contract No. W-7405-eng-26
Interagency Agreement No. EPA-78-D-X0205
Project Officer
Donald G. Gillette
Population Studies Division
Health Effects Research Laboratory
Research Triangle Park, North Carolina 27711
May 1980
Prepared for
HEALTH EFFECTS RESEARCH LABORATORY
OFFICE OF RESEARCH AND DEVELOPMENT
U.S. ENVIRONMENTAL PROTECTION AGENCY
RESEARCH TRIANGLE PARK, NORTH CAROLINA 27711
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DISCLAIMER
This report was prepared as an account of work sponsored by an agency
of the United States Government. Neither the United States Government nor
any agency thereof, nor any of their employees, contractors, subcontractors,
or their employees, makes any warranty, express or implied, nor assumes any
legal liability of responsibility for any third party's use or the results
of such use of any information, apparatus, product or process disclosed in
this report, nor represents that its use by such third party would not
infringe privately owned rights.
This report has been reviewed by the Health Effects Research Laboratory,
U.S. Environmental Protection Agency, and approved for publication.
ii
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CONTENTS
Sources of Data vii
Foreword ix
Acknowledgments xi
Abstract xiii
1. Introduction 1
1.1 Legislative Requirement 1
1.1.1 Time Coverage 2
1.1.2 Bibliographies 3
1.1.3 Selection and Grouping of Contaminants 3
2. Pollution: General Considerations 4
2.1 Compounds and Elements as Pollutants 4
2.1.1 Man's Contribution 5
2.2 Pathways of Pollutants 6
2.2.1 In Animals 6
2.2.2 In the Environment 7
2.3 Effects of Pollutants 8
2.3.1 Effects of Long-Term Low-Level Exposure in Man. . . 8
2.3.2 Effects on the Environment 9
3. Analysis 12
3.1 Evolution of Methods 12
3.2 Validity of Analyses 12
3.3 Obtaining the Data 12
3.4 Description of Methods 13
3.4.1 Emission Spectrometry 13
3.4.2 Mass Spectrometry 14
3.4.3 Atomic Absorption Spectrometry, Flame Photometry,
Flame Emission Spectrometry 14
3.4.4 Neutron Activation Analysis 15
3.4.5 Gas Chromatography 15
3.4.6 High-Pressure Liquid Chromatography 15
3.4.7 Other Methods 16
3.4.8 Biological Tests 16
4. Organochlorine Pesticides 18
4.1 Aldrin and Dieldrin 18
4.2 Endrin 19
4.3 Benzene Hexachloride 19
4.4 Pentachlorophenol 20
4.4.1 Uses and Effects 20
4.4.2 Analysis 21
4.5 2,4,5-Trichlorophenoxy Acetic Acid 21
4.6 Mirex 22
4.7 Kepone 23
4.8 Chlordane and Related Cyclodiene Pesticides 23
4.8.1 Chlordane 23
4.8.2 Oxychlordane 24
4.8.3 Heptachlor and Heptachlorepoxide 24
4.8.4 Trans-Nonachlor 25
iii
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4.9 DDT 25
4.9.1 General and Historical 25
4.9.2 Persistence and Use 26
4.9.3 Levels in the General Population 26
4.9.4 Sources and Entry into Man 27
4.9.5 Isomers and Metabolites of DDT 27
4.9.5.1 o.p-DDT 27
4.9.5.2 DDA . 28
4.9.5.3 ODD (also called TDE) 28
4.9.5.4 DDE 28
4.9.6 Fate of DDT; Absorption, Metabolism, and Excretion. 28
4.9.6.1 Hair as Excretory Pathway 29
4.9.6.2 Smokers and DDT 29
4.9.7 Distribution in Tissues 29
4.9.7.1 Distribution with Respect to Disease. . . 29
4.9.7.2 DDT and the Fetus 30
4.9.8 Effects of DDT 30
4.9.9 Load of DDT in the Environment 31
4.9.10 Analysis of DDT 32
5. Organophosphorus, Carbamate, and Miscellaneous Pesticides .... 33
5.1 Introduction 33
5.2 Production and Use . . 33
5.3 Entry into Man. Metabolism and Effects 34
5.4 Analysis 35
6. Polychlorinated and Polybrominated Biphenyls and Terphenyls ... 36
6.1 Formulas 36
6.2 Polychlorinated Biphenyls "'. . 37
6.2.1 Production and Use 37
6.2.2 PCBs in the Environment and in Man 37
6.2.2.1 Effects in the Environment and in Man . . 38
6.2.3 Analysis 39
6.3 Polychlorinated Terphenyls 39
6.4 Polybrominated Biphenyls 39
7. Miscellaneous Compounds 41
8. Asbestos 43
8.1 Introduction 43
8.2 Sources and Levels of Asbestos in the Environment 43
8.3 Entry, Storage, and Effects in Humans 44
8.4 Impact of Asbestos on the Public 45
8.5 Analysis 46
9. The Halogens: Fluorine, Chlorine, Bromine, Iodine, and
Astatine 47
9.1 Fluorine 47
9.1.1 Fluorine as Essential Element. Levels of Response
to Fluorine (as Fluoride) 47
9.1.2 Absorption and Excretion. Fluoride in Bone and
Other Body Compartments 47
9.1.3 Fluoride in the Environment. Sources and Uses.
Balance of Effects 48
9.1.4 Consumption of Fluorine. Exposure Limits 43
9.1.5 Analysis 48
IV
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9.2 Chlorine 49
9.3 Bromine 49
9.4 Iodine. . , 50
9.5 Astatine 50
10. Lead 51
10.1 Introduction 51
10.1.1 Historical. Past and Present Sources of Exposure
to Lead. Levels of Use 51
10.1.2 Point Sources. High Lead Areas 51
10.2 Lead in Man 52
10.2.1 Absorption, Excretion, and Metabolism 52
10.2.2 Body Distribution 53
10.2.3 Body Burdens of Lead. Effects of Lead at Low
Levels 53
10.2.A Biochemical Indicators of Exposure to Lead.
Screening for Exposure 54
10.3 Analysis 55
10.4 NRC Recommendations 56
11. Mercury 57
11.1 Introduction 57
11.2 Sources and Production . . 57
11.3 Entry into the Environment 57
11.4 Entry into Man. Transport, Distribution, and Excretion . . 58
11.5 Effects on the Fetus 60
11.6 General Effects 60
11.7 Demography 61
11.8 Analysis 61
12. Zinc and Cadmium 63
12.1 Zinc 63
12.1.1 Production and Use 63
12.1.2 Entry into the Environment 63
12.1.3 Zinc in Man. Absorption, Metabolism, Distribution,
and Excretion 63
12.1.4 Toxic Effects 64
12.1.5 Zinc Deficiency. Balance of Zinc 65
12.1.6 Demography 65
12.1.7 Analysis 66
12.2 Cadmium 66
12.2.1 Production and Use 66
12.2.2 Cadmium in the Environment 67
12.2.3 Human Exposure to Cadmium 67
12.2.4 Absorption, Excretion, Transport, and Storage ... 67
12.2.5 Toxicity and Effects 68
12.2.6 Demography 70
12.2.7 Analysis 70
13. Copper, Magnesium, Manganese, Molybdenum, Selenium, Tellurium,
and Polonium 71
13.1 Introduction. Relative Toxicities 71
13.2 Copper 71
13.2.1 Copper in the Environment 71
13.2.2 Intake by Man. Deficiencies and Excess 72
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13.2.3 Absorption, Metabolism, and Chronic Toxicity. . • • 72
13.2.4 Disease States and Copper 73
13.2.5 Analysis 73
13.3 Magnesium 73
13.4 Manganese 74
13.5 Molybdenum 75
13.5.1 Molybdenum in Foods and in the Body 75
13.5.2 Sources and Toxicity of Molybdenum 75
13.5.3 Analysis 76
13.6 Selenium 76
13.6.1 Introduction. Selenium Toxicity 76
13.6.2 Sources 77
13.6.3 Body Burden and Distribution. Role of Selenium in
Normal Metabolism 77
13.6.4 Selenium in Food. Management of Natural Selenium . 78
13.6.5 Selenium and Carcinogenesis 78
13.6.6 Analysis 78
13.7 Tellurium and Polonium 79
14. Arsenic, Antimony, and Thallium 80
14.1 Arsenic 80
14.1.1 Sources and Uses of Arsenic 80
14.1.2 Toxicity and Metabolism of Arsenic Compounds. ... 80
14.2 Antimony 81
14.3 Thallium 81
15. Chromium, Cobalt, Nickel, Vanadium, and Beryllium 84
15.1 Chromium 84
15.2 Cobalt 85
15.3 Nickel 86
15.4 Vanadium 86
15.5 Beryllium 87
15.5.1 Absorption, Toxicity, and Body Distribution .... 87
15.5.2 Sources, Uses, and Consumption of Beryllium .... 89
16. Other Elements 90
Bibliography 92
vi
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SOURCES OF DATA
Journals Manually Searched
Archives of Environmental Contamination and Toxicology
Archives of Environmental Health
Bulletin of Environmental Contamination and Toxicology
Drug Metabolism and Disposition
Environmental Health Perspectives
Environmental Research
Food and Cosmetics Toxicology
International Journal of Environmental Studies
Journal of Agricultural and Food Chemistry
Journal of Occupational Medicine
Journal of Toxicology and Environmental Health
Pesticides Monitoring Journal
Toxicology
Toxicology and Applied Pharmacology
Toxicology and Environmental Chemistry Reviews
Abstract Journals
Biological Abstracts
Chemical Abstracts
Excerpta Medica
Public Health
Pharmacology and Toxicology
Index Medicus
Nutrition Abstracts and Reviews
Computerized Data Files
MEDLINE
TOXLINE
DIALOG®
Agricola
Chemical Abstracts
Commonwealth Agricultural Bureaux
Environline
Food Science and Technology
Pollution Abstracts
ORNL Data Base
Biological Abstracts/Research Index
Other
Document collections of the Information Center Complex, Information
Division, Oak Ridge National Laboratory
National Academy of Science Monographs
Reference document bibliographies
Trace Substances in Environmental Health, Volumes I-IX, Proceedings
of Annual Conferences held at the University of Missouri
vii
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FOREWORD
The many benefits of our modern, developing, industrial society are
accompanied by certain hazards. Careful assessment of the relative risk
of existing and new man-made environmental hazards is necessary for the
establishment of sound regulatory policy. These regulations serve to
enhance the quality of our environment in order to promote the public
health and welfare and the productive capacity of our nation's population.
The Health Effects Research Laboratory, Research Triangle Park,
conducts a coordinated environmental health research program in toxicol-
ogy, epidemiology, and clinical studies using volunteer subjects. These
studies address problems in) air pollution, nonionizing radiation, envi-
ronmental carcinogenesis, and the toxicology of pesticides as well as
other chemical pollutants. The Laboratory participates in the develop-
ment and revision of air quality criteria documents on pollutants for
which national ambient air quality standards exist or are proposed, pro-
vides the data for registration of new pesticides or proposed suspension
of those already in use, conducts research on hazardous and toxic mate-
rials, and is primarily responsible for providing the health basis for
nonionizing radiation standards. Direct support to the regulatory func-
tion of the Agency is provided in the form of expert testimony and prep-
aration of affidavits as well as expert advice to the Administrator to
assure the adequacy of health care and surveillance of persons having
suffered imminent and substantial endangerment of their health.
This report traces the sources of chemical contaminants derived
from environmental pollutants from the environment to man. The sum-
maries of the pathways and ultimate incidence and effect of these con-
taminants on man and the documented references should be very useful
to researchers and others who are concerned about this ever-increasing
problem of industrialized societies.
F. G. Hueter, Ph.D.
Director
Health Effects Research Laboratory
ix
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ACKNOWLEDGMENT S
The authors are grateful to Rowena Chester, C. C. Travis, and L. M.
McDowell-Boyer, Health and Safety Research Division, Oak Ridge National
Laboratory, for reviewing preliminary drafts of this report and offering
valuable comments, and to the staff of the Health and Environmental Studies
Program, the Environmental Mutagen Information Center, and the Toxicology
Information Response Center of the Information Center Complex, Information
Division, Oak Ridge National Laboratory, for technical assistance. Assist-
ance provided by the Information Center Complex Publications Office and the
Administration Office and by the project officer, Donald G. Gillette is
also gratefully acknowledged.
xi
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ABSTRACT
This report reviews the manner in which chemical contaminants found
in nonoccupationally exposed U.S. residents enter the environment and
subsequently human tissues. Approximately 100 contaminants are treated.
References used in the survey cover a 30-year period, with the bulk of
the studies coming from the past 10 or 15 years.
Contaminants discussed include organochlorine, organophosphorus,
carbamate, and miscellaneous pesticiues; polychlorinated and polybrom-
inated bi- and terphenyls; halogen compounds; asbestos; mercury, lead,
zinc, cadmium, copper, manganese, molybdenum, selenium, arsenic, anti-
mony, thallium, chromium, cobalt, nickel, vanadium, beryllium; and
others. Production; use; entry into the environment; entry, metabolism,
and effects in man; and description and evaluation of methods of analysis
and of the validity of the data are the chief aspects treated. For the
pesticides indiscriminate use is the chief means of environmental entry.
Entry into man is by ingestion of particulate residues and through foods,
particularly fat-containing animal products. Sources of environmental
entry for the metals and other elements are burning of fossil fuels, in-
dustrial operations, dissipative uses, and natural inputs; and from these
sources into man by ingestion and inhalation.
Some elements are essential or beneficial at one level of concentra-
tion and toxic at another. Discussions of the status of elements from
this standpoint are included where appropriate.
xiii
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SECTION 1
INTRODUCTION
1.1 LEGISLATIVE REQUIREMENT
Preparation of this report was directed by the Health and Environ-
mental Studies Program, Information Center Complex, Information Division,
Oak Ridge National Laboratory, for the Health Effects Research Laboratory,
U.S. Environmental Protection Agency, as partial fulfillment of Interagency
Agreement DOE No. 40-673-78, EPA No. 78-D-X0205, between the Department of
Energy and the U.S. Environmental Protection Agency. The scope of this
report is designed to complete the obligation of the U.S. Environmental
Protection Agency as specified in Sections 403c(l) and 403c(2) of the
Clean Air Act as amended August 7, 1977. These sections provide for the
following:
(c)(1) Not later than twelve months after the date of
enactment of this Act the Administrator of the Environmental
Protection Agency shall publish throughout the United States a
list of all known chemical contaminants resulting from environ-
mental pollution which have been found in human tissue including
blood, urine, breast milk, and all other human tissue. Such
list shall be prepared for the United States and shall indicate
the approximate number of cases, the range of levels found, and
the mean levels found.
(c) (2) Not later than eighteen months after the date of
enactment of this Act, the Administrator shall publish in the
same manner an explanation of what is known about the manner
in which the chemicals described in paragraph (1) entered the
environment and thereafter human tissue.
The requirement of Section 403c(l) was satisfied by the publication
in August 1978 of the preliminary report, ORNL/EIS-142, entitled "Levels
of Chemical Contaminants in Nonoccupationally Exposed U.S. Residents."
That report contained data on the human tissue levels of 94 different
chemicals which leave residues in the human body. The compilation con-
cerned mainly trace metals and organochlorine pesticides. Nearly 400
cited surveys or investigations, the majority of which were reported in
the last decade, were listed. The tables in the compilation included
information on the tissues in which the substances were found; the range;
mean or median levels; number of cases; analytical methods used; comments
on the source of the samples and on demographic and socioeconomic and
geographic factors, and on any other special conditions; and the references.
Most of the available data examined for the purposes of the prelimi-
nary report resulted from specific surveys to determine the tissue levels
of chemicals perceived to be potential health hazards or from incidents
of accidental poisonings. Basic interest in the roles of trace elements
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and recognition of the need to determine baseline levels of chemicals
introduced into the environment are additional factors which have moti-
vated surveys by individual investigators. Data on a number of elements,
known to be essential or beneficial at one level but harmful at another,
were also included, as were data on some uncommon chemicals included as
items of interest and to document their presence in healthy individuals.
To fulfill the stated requirement of Section 403c(2) , this document
includes the following factors to the extent that appropriate information
was found:
A. Uses and sources. Production figures.
B. Entry into the environment. Transport and trans-
formation processes. Effects on the environment.
C. Entry into man. Storage, disposition, effects.
Demographic, geographic, and socioeconomic factors.
D. Evaluation of the analytical measurement methods
and of the validity of the reported body burden data.
These aspects are covered as systematically as possible. In addi-
tion, in each section an attempt is made to present a picture of the
status of the substance or class of substances in question, for further
understanding of the role of the substances as possible pollutants. In-
formation on some of the aspects listed above is sparse for a number of
the substances, and where little is said about a particular aspect, it
may be concluded that little information on it was found.
A section of the report covers the aspects of entry of contaminants
into the environment, transport and transformation, and entry into humans
and effects in humans in general. Similarly, there is a general section
on analysis, in which the evolution of techniques, their sensitivity and
reliability, and application to problems of monitoring contaminants are
discussed. Special problems with analysis of particular contaminants,
where these exist, are discussed in the appropriate sections.
1.1.1 Time Coverage
References in the preliminary report provided coverage of available
information over the past 15 years (see "Sources of Data," p. vii). For
the present document, and to check values given in the phase I report,
literature coverage was extended to cover the past 30 years. No addi-
tional material which would significantly change the range of levels and
means already reported was found. Some supplementary data, however, not
obtained in time for the August deadline, have been added to a final
version of the preliminary report, which is published as a companion
document to this one.
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1.1.2 Bibliographies
Bibliographies are included with each of the volumes. There is,
therefore, some duplication in that significant references of the pre-
liminary report have also been used here, plus references that were used
because of the special requirements of this second phase of the project.
1.1.3 Selection and Grouping of Contaminants
Body burdens of 94 elements or compounds were listed in the prelimi-
nary report. For the present document, we have added several to this
from the class of miscellaneous compounds which show up in the body and
may have effects, but on which clear data on body burdens were not avail-
able. A section on organophosphorus and selected miscellaneous pesticides
has also been added. The substances of the report are grouped into 13
sections. This grouping was governed by a number of considerations: con-
venience, similar chemical nature, similar mode of entry into the environ-
ment, similar geographic distribution or use pattern or other association,
similar mode of entry into the body, and so on, for reasons of economy in
writing and to give as balanced a picture as possible. Aspects treated,
to the extent information was available, have been listed above.
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SECTION 2
POLLUTION: GENERAL CONSIDERATIONS
"Polluted air + polluted water + polluted food = polluted people"
(Ferren, 1978).
It is convenient to consider here some general aspects of pollution,
which apply to all the contaminants listed. These include pathways of
exposure, pathways in the environment, patterns of absorption and metabo-
lism and rejection, and effects in humans and in the environment. The
substances discussed in this report fall mainly into the classes of
metals and a few other elements, and pesticides.
2.1 COMPOUNDS AND ELEMENTS AS POLLUTANTS
As stated by Ferren (1978), metals may well be the most harmful of
pollutants, because they are not biodegradable and often have a long-term
systemic effect. This statement may be controversial if compared, say,
with the carcinogenic potential of certain organic substances; however,
on a strict public health basis and in the context of this report, which
deals with substances giving a body burden from long-term, low-grade pol-
lution exposure, it is probably true. The situation with metals and with
certain other elements is complicated by the fact that a number of them
are essential to life or beneficial at one concentration but deleterious
at another. As pointed out by Albert et al. (1973), all metals, even the
essential ones, have the potential to cause adverse effects in human beings
at certain levels of exposure and absorption.
Most of the compounds, as opposed to elements, treated in this report
are pesticides.
Westermann (1969) has discussed the idea of "functional accumulation"
of an environmental agent, i.e., accumulation of functional impairment.
He gives the contrasting examples of DDT and organophosphorus pesticides.
Because of a low rate of elimination and high fat solubility, DDT accumu-
lates in man in fat deposits. According to Westermann, the average Ameri-
can adult has more than 50 mg of DDT in his or her body. However, the
toxicity of DDT in mammals is low — toxic symptoms in man having been
observed only at oral doses of 10 to 20 g. Organophosphorus pesticides
are very toxic in man but do not accumulate substantially, since they are
rapidly metabolized. However, small repeated doses show a distinct func-
tional accumulative pattern, leading to clinical symptoms resembling
strong cholinergic stimulation reflecting the pileup of acetylcholine at
the cholinergic links in the organism, caused by inhibition of cholines-
terase. Westermann gives other examples of functional accumulation or
the lack of it and discusses some of the paradoxes of interference with
function caused by exposure to contaminants. In the case of functionally
accumulating contaminants, evidence of exposure may be sought by determin-
ing impairment or perturbation of function, or stimulation of new function
(induction of enzyme activity, for instance), and this has been done.
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With respect to body burdens, the extensive studies of the Tipton
School (summarized by Perry et al., 1962) have shown that the concentra-
tions of the nutritionally essential elements are more constant than the
concentrations of the nonessential ones, within any selected group, and
are also less affected by geographic differences, socioeconomic factors,
and the like. Moreover, as remarked on by numerous authors and as studied
in detail by Liebscher and Smith (1968), the distribution curve varies be-
tween essential and nonessential elements, essential elements having a
symmetrical or "normal" distribution and nonessential ones a skewed or
"log-normal" distribution. This is an expression of better homeostasis
in the case of the essential elements, which is lacking or imperfect in
the case of the nonessential ones.
With respect to changes in body burdens, Kist (1968) has studied
the relation between the normal concentration of 17 elements in the body
(using neutron activation) and their toxicity, i.e., the toxicity of ex-
perimentally added increments of the element. It was found that a rela-
tively small increase in the concentration of a macroelement could lead
to the death of the test animal. The reverse was true for elements con-
tained in the body in very small quantities. In general, it was found
that the lower the normal concentration of an element in the body, the
greater the fluctuations in it from the standpoint of either an increase
(toxicity) or a decrease (deficit) which can be tolerated by the body
without noticeable harm. This fact applies, incidentally, in research
trying to establish whether an element is essential (Schwarz, 1974;
Mertz, 1970).
2.1.1 Man's Contribution
Schroeder (1965&) has discussed the distribution of trace elements
over geologic time and the relation of this to life processes. Twelve
bulk elements from the first 20 in the periodic table make up more than
99% of the structure of living things. Added to these are the trace
elements selected by nature as micronutrients, their role being that of
cofactors, nucleators, regulators, prosthetic groups for enzymes or other
functional proteins (examples: zinc in carbonic anhydrase, copper in
ceruloplasmin, etc.), the nonessential elements filling the role of accu-
mulating environmental contaminants. In historical time, Schroeder shows
how man has changed his exposure to both the essential and nonessential
trace elements, depleting some elements and increasing others. With the
onset of agriculture and the rise of civilization, ecosystems have been
changed and forests denuded. Pastures have been overgrazed and soils
overcropped. Foods are now highly processed, removing micronutrients at
the same time that nonnatural substances are added to them. Nonessential
elements have been mined from mineral deposits and introduced into the
environment. Industry has released a wide spectrum of toxicants into the
water (example: mercury) and into the air to be picked up by organisms
in the food chain or to be absorbed as particulates. This nonnatural ex-
posure has been going on since the Bronze Age, with exponential increase
in the last 100 to 150 years. Aspects of this for individual elements
are brought out in the appropriate sections.
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2.2 PATHWAYS OF POLLUTANTS
2.2.1 In Animals
Spector (1956) gives a useful diagram and table of pathways of mineral
metabolism in mammals. Information is given on 57 individual cations and
29 anions, with remarks on others. Although organics are not included,
much of the information in the diagram applies to them too. Entrance into
the organism, absorption, excretion, reabsorption, distribution, metabolic
change, and retention are some of the aspects treated.
In the context of this report, the effects of toxic metals are largely
due to their accumulation. This question has been investigated extensively
by Albert et al. (1973) . Aspects considered were the critical organ con-
cept of toxicity and critical concentrations; absorption following intake
by various routes; effects of age and condition on absorption, absorption
by the fetus by placental transfer; transport and binding in blood and
penetration into organs; gastrointestinal and renal and mammary gland ex-
cretion; accumulation and retention in critical organs; and concentrations
in biological material as indices of exposure and of concentrations in
critical organs.
Metal transport and effects in the body depend highly on the intrinsic
nature of the metal, usually as an ion. The body may effect valence changes
in the metal which will influence its behavior, and some metals are partic-
ularly susceptible to binding to certain chemical functions (heavy metals
to sulfhydryl groups of proteins, for instance) or to coordination or in-
clusion in prosthetic groups or as part of the active site of an enzyme.
Part of homeostasis may be the release of the metal on degradation of the
protein. With organics, the picture can be complicated by the existence
of degradation or modification of the structure of the molecule itself
(examples: aryl epoxidation, ring opening, creation of new functions).
Modification (usually by oxidation) may be a first step leading to elimi-
nation or to further metabolism. Unfortunately, the oxidation of organics
may lead to products which are more deleterious than the original contami-
nant. Examples abound in the study of the conversion of procarcinogens to
proximal and then to ultimate or actual carcinogens. If the conversion
increases water solubility, makes conjugation possible, or leads quickly
to innocuous products, then the contaminant may be eliminated before any
great degree of this second-order type of harm occurs.
Pollutants may show associations and interrelationships. Some metals
may be protective against others; for instance, zinc protects against cop-
per. Both metals are essential, but excess of copper leads more easily to
adverse effects. The protecting or controlling action may be rather broad.
Thus, calcium has been considered as the "gatekeeper metal" (Schroeder,
1965&), controlling the absorption of other metals, both from the environ-
ment and across cell barriers. In the environment this action of calcium
may depend on formation of insoluble salts, binding by soil, alkalinity,
etc., and at the organismal level it has been postulated that there is a
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cellular mechanism, widespread among living things, which is saturated
by calcium ion, regulating exchange of other cations from the immediate
environment. Recent work has shown calcium to be associated with membrane
phenomena, and the mechanisms therein may be the key to calcium's action.
In the body, both experimentally and in normal physiology, metals
may be swept out by other metals that have similar activity and which
occupy, grosso modo, the same physiological space. Where the sweeping-out
does not occur, this is evidence that the metal has its own specific path-
way or its own compartmentation. This was found to be the case with manga-
nese (Cotzias and Greenough, 1958). In rats rendered low in manganese
through feeding Mn-deficient diets, flooding with kindred metals (Co, Ni,
Fe, V, Cr, Rh, Mg, Zn) failed to remove radioactive manganese; only man-
ganese compounds were effective in this regard. This evident specificity
may be contrasted with the apparent lack of specificity of the displace-
ment, for instance, of bromide by chloride, molybdenum by tungsten, stron-
tium by calcium, and others.
Sometimes fixation of an element to a cell constituent or structure,
or compartmentation that sequesters the element, keeps it from being
swept out. The latter is often the case with elements which concentrate
in a slowly turning over tissue such as bone. An example of fixation in
soft tissues is that of cadmium (Cotzias, Borg, and Selleck, 1961). In
a study by these authors, even added cadmium did not sweep out fixed
radioactive cadmium. Administration of zinc was also ineffective. Esti-
mates of cadmium body burden have shown that cadmium concentrates in the
kidney (Bonnell, Ross, and King, 1960, and other references in the section
specifically devoted to cadmium), probably displacing zinc in certain
organelles and at certain cellular binding sites (sulfhydryl-containing
structures). Once bound, the cadmium does not respond to homeostatic
signals, nor is it displaced by other metals. The obverse of sweeping out
is penetration of a contaminant by the same means as used by an essential
element. An example of this is thallium. Thallium is highly toxic; it is
carried into cells because it follows the same pathways as does potassium
and occupies the same physiological space (Emsley, 1978). In short, it
mimics potassium. Presumably,, potassium would displace thallium, but
given the large amount of potassium in the body, this would be difficult
to achieve.
2.2.2 In the Environment
This is a very ramified subject. Haque and Ash (1974) have consid-
ered the factors which affect the behavior of chemicals in the environment.
They discuss water solubility and behavior in the hydrosphere; vapor pres-
sure and behavior in the atmosphere; behavior in the lithosphere (adsorption,
etc.); degradation, as by light, microbial action, etc.; and interaction
with biota (uptake by plants, food chain transport, etc.). Information on
pathways through the environment of a number of metals is given in a report
of Wildung et al. (1974), and there are reports on specific elements, such
as the one by Matti, Witherspoon, and Blaylock (1975) on the cycling of
mercury and cadmium as typical pollutants in the environment.
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It is important to know the environmental distribution of contami-
nants as well as body burdens. A holistic approach, rather than the
vertical discipline approach of air quality, water quality, and aquatic
ecology as is usually followed, is recommended by Ferren (1978). Ferren
suggested that "Environmental analysis is optimized when the techniques
used are simple and applicable to the maximum types of environmental
samples at a minimum of cost." His report includes a model study of the
metals zinc, cadmium, lead, and copper, in such diverse samples as human
nails, dirt in nails, human hair, air and water samples, and clams, levels
in the last sample representing the impact of polluted water upon the bio-
tic food chain in the region studied (Staten Island, New York). In more
agricultural regions, one would likely add samples from soils and plants.
The metals were chosen as indicators of environmental pollution. The
analytic technique used was that of anodic stripping voltammetry, meeting
the criteria evoked in the quote. Clearlyj more studies of this type are
needed.
2.3 EFFECTS OF POLLUTANTS
2.3.1 Effects of Long-Term Low-Level Exposure in Man
The effects of contaminants at levels discussed here are often of a
delayed nature and are not always directly obvious. Golberg (1972) has
discussed this problem and has championed the study of what he calls
"subliminal toxicology," meaning study of physiological indicators of
effects of exposures at dose levels comparable with those to which the
human population is actually being exposed. Some of the effects of toxi-
cants are rather subtle. For instance, impairment of learning and be-
havioral problems have been noted in children exposed to lead, but whose
blood lead levels were in ranges that had been considered "safe" or
"normal." By the nature of the problem it is not easy to relate cause
and effect, since factors other than the presence of the pollutant may
play a role, or the presence of the pollutant may not be suspected. An
example is the connection between drinking soft, slightly acid water and
cardiovascular disease. There is some evidence that such water leaches
certain metals, particularly cadmium, out of well pipes and water distri-
bution pipes, and that the slightly elevated levels of these metals over
normal contribute to hardening of the arteries, heart trouble, and other
circulatory manifestations. Conversely, Bierenbaum et al. (1975), study-
ing two groups of matched subjects of 260 persons each in the twin cities
of Kansas City, Missouri (softened water) and Kansas City, Kansas (natu-
rally hard water) found a higher incidence of coronary heart disease in
subjects drinking the naturally hard water. In this case it was cadmium
in the water source itself which seemed to be responsible for the hyper-
tension causing the heart disease. This finding shows how all circum-
stances must be taken into account.
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Effects are generally long term. Some authors have failed to appre-
ciate this. An example is the statement of Ochsner (1967) in an editorial
in a medical journal to the effect that "General air pollution, although
not desirable, is usually not hazardous to health. It is dangerous only
under unusual atmospheric conditions when excessive concentration of pol-
lutants results from atmospheric inversion." Ochsner further said, "...
and then the deaths have been almost without exception in patients who had
preexisting pulmonary or cardiovascular disease, or both." Ochsner's views
were refuted by Paulson and Zablow (1968), who pointed out a number of
studies showing deleterious effects of air pollution on people not suffer-
ing from preexisting disease. Dubos (1968) also reacted to Ochsner's
statements in the words, "The point of importance here is that the most
significant effects of environmental pollutants will not be detected at
the time of exposure to them; indeed, they may not become evident until
several decades later. The greatest danger of pollution may well be that
we shall tolerate levels of it so low as to have no acute nuisance value,
but sufficiently high, nevertheless, to cause delayed pathological effects
and to spoil the quality of life." In short, morbidity, but not necessar-
ily mortality.
The delayed effects of air pollutants (since air pollution is one of
the more prevalent forms of pollution) constitute models for the kinds of
medical problems likely to arise in the future from all forms of pollution.
Dubos also evokes effects on the fetus, only noted years later as reduced
vigor, greater susceptibility to disease, and the like.
2.3.2 Effects on the Environment
The effects of chemicals on the environment have been considered by
Goodman (1974). A good many of these effects have been unplanned. Per-
sons have failed to consider what the real costs of introduction and wide-
spread use of a new substance would be, or the real costs of careless
disposal or release of contaminants. As pointed out by the author, fail-
ure to recognize the mutually interactive roles of man, resource species,
wildlife organisms, and climate in the biosphere and their different
tolerances to chemical substances has hindered the development of an en-
vironmental management policy embracing all four biosphere components.
In the introduction to the symposium volume, "Survival in Toxic
Environments," Hadley (1974) makes the point that we must move from a
transient to a steady state in our global economy, from a youthful-
exploitive to a mature quality-maintenance state. Poisoning of the en-
vironment must not be allowed to sabotage our achievement of this steady
state. Intelligent use of ultimately limited resources requires a funda-
mental knowledge of the effects of waste contaminants on natural ecosystems,
on the ecosystems created by man, and on man himself. To do this, it is
necessary to bring together knowledge from a number of disciplines.
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The question has been asked, "Are we already past the point of no
return in some areas of pollution?" Even stopping introduction of the
pollutant would not cause the harm to be undone. The possibility further
exists of catastrophic expansion of some pollutants' potential for harm.
Mercury in Lake Erie has been given as an example. The accumulation
there in sludges and in actual pools has been such that it is conceivable
that a biotic bloom, caused by eutrophication, could convert the mercury
at an accelerated rate to organic mercury, which could find its way up
the food chain to the point of human consumption, and serious poisoning
could ensue. Something like this happened in the Minamata incident in
Japan; not from accumulation and triggering, but from such a rate of in-
troduction of the pollutant into the environment (an ocean bay) that the
biota in it were practically saturated, and a mass disaster resulted in
an area where consumption of fish and other sea products was high. While
further Minamatas and mini-Minamatas remain possible, the general situa-
tion is more likely to be deterioration of the type discussed by Dubos
and by Paulson and Zablow. Mercury is, in fact, widespread, similar to
DDT, to the point of making it necessary in some areas to limit the con-
sumption of foods containing it.
In examining the references of this study, and in trying to determine
geographic distribution of pollutants, it was noted many times that the
effects of a pollutant were spread out over a wider geographic zone than
the zone of introduction because of the ramification of food distribution.
Melons grown in the Ail-American Valley in Arizona may well be sold in
Philadelphia. Ice cream made in New York is sold in Tennessee, etc.
Finished foods and raw materials for foods and animal feeds are shipped
from one state to another and to other countries, not to mention what we
import. Thus are pollutants distributed, but at the same time diluted,
resulting in essentially a leveling of the pollutant concentration over
large geographic areas. In some respects this may be good, as in the
distribution of nutritionally essential elements (example: selenium,
high in some areas, deficient in others).
The following diagram, due to Colucci et al. (1973), addresses the
general question of pollutant burdens and biological response. The width
across the triangle at a given level represents the proportion of popula-
tion affected. From the mere presence of a pollutant or pollutants (the
authors treat the question of multiple burdens), effects rise to changes
of uncertain significance to changes which are indicative of disease,
through morbidity to mortality. As pointed out by the authors, studies
of multiple tissue sets and of levels in body fluids and of biochemical
and physiological perturbations are all useful in assessing risk and
response.
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ORNL-DWG 79 -13016
/MORTALITY^
ADVERSE
HEALTH
EFFECTS
PHYSIOLOGICAL CHANGES
OF UNCERTAIN SIGNIFICANCE
/ POLLUTANT BURDENS \
•*• PROPORTION OF POPULATION AFFECTED -*•
Spectrum of biological
response to pollutant exposure,
Adapted from Colucci et
al., 1973.
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SECTION 3
ANALYSIS
3.1 EVOLUTION OF METHODS
The Kirk-Othmer Encyclopedia of Chemical Technology (Grayson and
Eckroth, 1978) lists a number of methods used in analytical chemistry,
giving applications, theory of the test, advantages, sample size required,
and method and sample limitations. Practically all these methods have been
used in testing for and quantitating levels of contaminants. In extending
our literature search to cover the past 30 years, the bulk of references
found concerned methods of analysis. This period was in fact a time of
concern over the effects of contaminants and a time of development in
methods of analysis. Instrumental methods have come largely to the fore
to replace chemical methods previously used. The modern methods are char-
acterized by greater selectivity and by high sensitivity, bringing the
limits of quantitation down in some areas to the ppb range. A recent
development is the addition of microprocessors (for instance, with "floppy
disk" control) to the analytical system, with advantages of feedback con-
trol and logic, reference storage, and printout of results. In this way,
manufacturers are facing up to the problem of the increasing work load in
the field of contaminant analysis as well as continuing to be concerned
about the analyses themselves.
3.2 VALIDITY OF ANALYSES
Generally speaking, the methods used have given, or are capable of
giving, valid results within the context of their proper use (awareness
of the possibility of interferences, awareness of limitations of the
method, etc.). Some improvement, and increase of confidence in the re-
sults, has come from use of methods whereby substances to be analyzed for
are separated as an inherent part of the method of analysis and then quan-
titated. An example of this is gas chromatography. Another improvement
has been in selectivity, and an example of this is atomic absorption
spectrophotometry, where selectivity is obtained by exciting the atoms of
an element with X-rays produced from a cathode of that same element. These
points are further discussed in Section 3.4.
3.3 OBTAINING THE DATA
As important as the test itself is the whole context of the testing
procedure. The Federal Working Group on Pest Management has published a
document, "Guidelines on Analytical Methodology for Pesticide Residue
Monitoring" (Monitoring Panel, FWGPM, 1975), which goes well beyond per-
formance of the actual analysis. The concepts developed are applicable
to testing of other substances in addition to pesticides. The same may
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be said for the companion volume, "Guidelines in Sampling and Statistical
Methodologies for Ambient Pesticide Monitoring" (Monitoring Panel, FWGPM,
1974), which deals more specifically with testing for pollutants in the
environment. The references in these two documents are invaluable. Topics
treated in the document on analytical methodology include safety precau-
tions to be taken by the analyst, sampling, storage of samples, extraction,
cleanup, detection and quantitation, losses, metabolites and degradation
products, the problems of analyzing for multicomponent pesticides, and
evaluation and reporting of results. Included in the companion document
are consideration of statistics and study design, and problems of obtain-
ing samples for analysis of constituents in air, soil, and water, in
animals, food, and feeds, and in man.
The above references concern pesticides. Anand, White, and Nino
(1975) have considered errors which may occur in collection, storage, and
analysis of trace elements in body fluids, and give recommendations for
avoiding these errors.
The subject of instrumentation and methods used for monitoring metals
in water has been reviewed by Quinby-Hunt (1978). Atomic absorption is the
approved method (Code of Federal Regulations, Title 40, pt. 136) for most
metals and metalloids. The author emphasizes the problems of doing mean-
ingful monitoring at levels near the sensitivity of the method of analysis.
Along with quantitative surveys, more attention to distinguishing species
(compounds) of elements and further explorative qualitative surveys are
re commended.
3.4 DESCRIPTION OF METHODS
3.4.1 Emission Spectrometry
Spark-source emission spectrometry was one of the early used instru-
mental methods. The extensive studies of Tipton et al. employed this
method. These studies give protocols for the collection and handling of
samples and for the analyses themselves. In this technique, samples are
ashed and sparked in the emission spectrograph. A great number of elements
are detected simultaneously. Detection is sensitive but quantitation is
erratic; also, sample preparation is tedious. Reproducibility and precis-
ion can be improved by the use of ad hoc matrices to compensate for inter-
ferences and background noise.
Much of the problem with emission spectrometry has come from the
spark activation. A recent development, reviewed by Fassel and Kniseley
(1974a.,£>), is that of inductively coupled plasma-optical emission spectro-
scopy (ICP-OES). In contrast to spark-source emission spectrometry, the
atoms of the sample are excited as a plasma by inductive heating. The
sample need not be ashed. For instance, blood may be analyzed either
directly or following dilution, and quite small samples may be analyzed.
The technique is eminently suited to multielement analysis.
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3.4.2 Mass Spectrometry
Heating is commonly used for mass spectrometry, but, particularly to
volatilize elements, spark activation has also been used. An example is
the study of Losee, Cutress, and Brown '(1973) on the occurrence and con-
centrations of trace elements in human dental enamel. Enamel was ground
and mixed with the graphite of the graphite electrode. Sixty-eight ele-
ments were analyzed for (with more possible); 38 were found in measurable
concentration.
Mass spectrometry has been used for confirmation of results of some
other systems of analysis, for instance, gas chromatography. Here part
of the sample from the gas chromatograph is fed to the mass spectrometer,
with the proper adaptors, for confirmation of the identity of the separated
peak.
In a similar manner, Biros (1970) used nuclear magnetic resonance
spectroscopy (NMR) for confirmation of identity and estimation of relative
proportions of p,p'-DDT and p,p'-DDE isolated from adipose and liver tis-
sue samples, not separated from each other by the gas chromatograph.
3.4.3 Atomic Absorption Spectrometry, Flame Photometry, Flame Emission
Spectrometry
Atomic absorption spectrometry (AAS) is the technique which super-
seded spark emission spectrometry and is the technique approved for most
of the elements. In this method, electrons of the element being analyzed
absorb the X-ray emission line from a cathode of the same substance. A
multielement cathode can be used, and multielement analyses can be done on
a single sample. The method is in part an outgrowth of flame photometry,
which in the modern form of flame emission spectrometry (FES) continues to
hold its own for certain analyses. Improvements have come in the use of
very high flame temperatures, impulse methods of sample evaporation, use
of grating monochromators, and advances in the response system. Instru-
mentation for FES and instrumentation for AAS have aspects in common, and
Prudnikov (1978) describes the two systems side by side. The systems in
fact complement each other.
Flameless heating of a sample in a graphite cup or a graphite tube is
now used for atomic absorption. The sample is atomized off by programmed
heating into the light beam rather than being aspirated through a flame,
as was the original case. The pitfalls, advantages, and applications of
this technique have recently been reviewed by Robinson (1978). The tech-
nique is versatile but requires considerable skill. For the necessary
short response time, digital electronics are used. Robinson also reviews
the prospects for laser intracavity absorption for organic compounds.
This is an application of infrared analysis, in which rotational vibra-
tional spectra of molecules are being used, not electron transitions. To
achieve narrow wavelength absorption, narrow laser emission bands (from a
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r,
tunable laser) are used, thus making the technique selective in the same
way that atomic absorption is selective with its narrow emission and
absorption lines. In practice, the attenuation of the laser beam is
measured. The technique is not limited to organic substances; metals,
metal oxides, salts, free radicals, etc., can also be measured.
3.4.4 Neutron Activation Analysis
Neutron activation analysis, used in a number of the reports listed
in the bibliography, is a highly general technique, useful for both quali-
tative and fine quantitative analyses of a wide spread of elements. It is
applicable to both solids and liquids and requires minimal sample handling.
The technique is nondestructive. The sensitivity varies considerably among
elements, but for most is better than 1 ug- The sample is bombarded by
neutrons, and then its gamma-ray spectrum is measured. A peak of a certain
energy in MeVs is characteristic of the radioactive species produced from a
given element by the neutron bombardment. For sharp identification, ana-
lyzers with a high number of channels are used. An example of the use of
this technique is given by the study of Mahler et al. (1970) on trace
metals in fingernails and hair. Since these are devitalized structures,
they show the history of exposure. Manganese, copper, gold, and zinc,
plus other elements, were easily quantitated.
3.4.5 Gas Chromatography
For organics, gas chromatography has been a revolution. To the sepa-
ration of the substances, already giving a high degree of selectivity, has
been added the sensitivity of specific detection, such as electron-capture
detectors for compounds which have a high electron affinity. Since halo-
genated compounds are included in this class, the application to organo-
chlorine pesticides, such as DDT and its metabolic products, is obvious.
If the compound does not show electron affinity, it can be added by deri-
vatization, for instance, by trifluoroacetylation, which in any case may
be necessary to confer volatility on the substance for the gas chromatog-
raphic process. Bente (1978) has recently reviewed the state of the art
in electron-capture instrumentation and its application to toxicology.
Numerous ingenious tricks are applied, such as pulsing the voltage, chang-
ing the frequency, and so on, to promote selectivity and to extend the
range of analyses. Gas chromatography may require cleanup of the sample,
for example, by column or thin-layer chromatography, before an extract is
presented to the final chromatographic system.
3.4.6 High-Pressure Liquid Chromatography
A technique which is rapidly coming to the fore and which is dis-
placing gas chromatography for some applications is that of high-pressure
or high-performance liquid chromatography. Both partition and adsorption
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16
modes are used. An advantage of HPLC over gas chromatography is the lack
of thermal degradation of compounds because of the absence of a need for
temperature programming. Further, the sample need not be volatile nor
rendered volatile by derivatization. Some applications have been analysis
of PCBs, aromatic pesticides, nitrosamines, etc. (Tracer, Inc., 1978).
3.4.7 Other Methods
X-ray fluorescence and electron-probe microanalysis have been used
for certain situations. Specific-ion electrodes are useful for analysis
of some elements and species, for instance, fluorine. Fluorescence and
fluorescence quenching are used for some elements and compounds. Polarog-
raphy and particularly anodic stripping voltammetry (reverse polarography)
are useful for certain elements. Spot tests are useful for screening.
Thin-layer chromatography is useful for both cleanup and actual analysis
and can handle a large number of samples.
An example of how techniques must sometimes be coupled to solve a
problem in analysis is given by Talmi and Norvell (1975). These authors
were analyzing environmental samples for arsenic and antimony. Samples
were wet-ashed with nitric-perchloric acid, the As3+ and Sb3 + formed were
then cocrystallized with thionalid, and the precipitate formed was reacted
with phenyl magnesium bromide to form triphenyl arsine and stibine. These
were extracted with ether and subjected to gas chromatography. Detection
was by a microwave emission spectrometric system. Thus the arsenic and
antimony were carried through the stages of from molecular compound or
whatever state they were in in the samples to ionic species to organic
compound for separation, to the atomic state for final readout. A wide
range of samples was analyzed with good precision and reproducibility.
3.4.8 Biological Tests
Biological tests are little used for direct analysis; however, they
are sometimes used partly for indirect analysis and partly to show the
significance of the level of a pollutant. Examples are examination of
nerve-enzyme activity for indication of the degree of exposure to, and
burden of, organophosphate pesticides, and measurement of delta-amino-
levulinic acid dehydratase activity (the enzyme and the compound being
important in porphyrin metabolism) for estimation of the degree of intox-
ication by lead. Functional, neurological, and behavioral (learning,
response to tasks, etc.) are tests which have their place in epidemiology,
but less so in direct testing. Immunological tests have practically not
been used. However, they are used in the clinic for compounds (generally
those with a low therapeutic index such as digitoxin) that are not all
that different from compounds which, if not now pollutants, may well be-
come so (such as complicated organics from fossil fuel conversion). The
difficulty is that antibody to haptenized antigen (the pollutant being
the hapten) must be developed, standardized, etc., and this is a cumber-
some process.
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17
In testing for pollutants in the environment, often what we need to
know is the activity of the pollutant vis-a-vis transport and transforma-
tion processes, and availability to and effects on plants and microorgan-
isms. Here biological tests can be useful. An example is the study of
Henkens (1961), who compared biological and chemical tests for the copper
content of soil. Growth of the mold Aspergillus nigev was used for the
estimation of the biological activity of copper.
Other specific tests and classes of tests not mentioned here appear
in the bibliographies and in the discussion of specific elements and com-
pounds. These are less often used than the tests described.
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SECTION 4
ORGANOCHLORINE PESTICIDES
Organochlorine pesticides are of concern because of their persistent
nature. We discuss the ones listed in the preliminary report of this pro-
ject in alphabetical order, except when one pesticide is closely related
chemically to another, for example, aldrin and dieldrin.
4.1 ALDRIN AND DIELDRIN
Aldrin is 1,2,3,4,10,10-hexachloro-l,4,4a,5,8,8a-hexahydro-exo-l,4-
endo-5,8-dimethanonaphthalene:
Dieldrin, also called HEOD or hexachloro-epoxy-octahydro-endo,exodimethano-
naphthalene, is the epoxide of aldrin:
Aldrin is moderately soluble in aromatics, esters, halogenated sol-
vents, ketones, and paraffins, and sparingly soluble in alcohols. It is
insoluble in water. Dieldrin is also soluble to varying degrees in organic
solvents and is insoluble in water. Aldrin is used to control soil insects
and also termites. It is not greatly harmful to plants or to soil micro-
organisms. It can be absorbed by ingestion or by inhalation, but the
greatest occupational hazard is skin absorption. Dieldrin also is used for
the control of soil insects, public health insects, termites, etc. Aldrin
is converted in the body to dieldrin, and the body burden of dieldrin is a
reflection of the intensity of exposure to both dieldrin and aldrin (Hunter
and Robinson, 1968). The level in adipose tissue is more precise for defi-
nition of body burden than blood-level estimations. According to Hodge et
al. (1967), typical diets in England and the U.S. are estimated to contain
0.001 to 0.002 ppm dieldrin. Patients showing signs of intoxication had
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19
blood levels exceeding 20 yg/ml. Mick et al. (1971) have studied the
transport of aldrin and dieldrin in the blood, and particularly the
shuttling of these two pesticides between a- and B-lipoprotein fractions,
the plasma, and the erythrocytes as the aldrin-dieldrin is carried to
storage in adipose tissue. Aldrin crosses the placenta (Selby, Newell,
Hauser, and Junker, 1969). Following oxidation to dieldrin, aldrin is
excreted largely in the feces (Quaife, Winbush, and Fitzhugh, 1967).
Production of both aldrin and dieldrin has been discontinued in the U.S.
The level of use of aldrin in 1977 was 11,528,170 Ib, crops treated with
it being corn, grain, lettuce, sorghum, tobacco, tomatoes, and vegetables,
pretty much all over the U.S. (U.S. Environmental Protection Agency, 1978),
and use of aldrin and dieldrin in combination was 74,200 Ib.
4.2 ENDRIN
Endrin is isomeric with dieldrin, differing in the orientation of the
epoxide group. The usage of endrin in the U.S. in 1977 was 1,269,570 Ib.
Of this, 1,166,573 Ib was used on cotton and the rest on orchard fruits
and small grains. Curley et al. (1970) have reported on measurement of
endrin in the blood, tissues, and urine of patients poisoned by consump-
tion of products made from endrin-contaminated flour.
4.3 BENZENE HEXACHLORIDE
Benzene hexachloride (BHC, C6H6C16), is not a compound of benzene but
of cyclohexane. It should not be confused with hexachlorobenzene, C6C16,
which is used for treatment of seed to prevent molds and kill insects, and
is often used in combination with other pesticides, including BHC. Five
isomers of BHC are commonly found in technical BHC (Meister et al., 1977,
p. D36). The Y~is°mer has by far the most activity. The grade of BHC in
which the content of y-isomer is over 99% is known as lindane. Mixed
grades are also used. The BHCs are soluble in benzene and chloroform and
in oil-base solvents, but are practically insoluble in water. The BHCs
do not have as long a residual action as DDT because of higher volatility
(Meister et al., 1977). Lindane is odorless and has been used as a fumi-
gant and in household pesticide applications. BHC has been much used
against cotton insects, but has had limited use on food crops because of
odor and off-flavor contributed to the crop. Usage of BHC in the U.S. in
1977 was only 1231 Ib, and of lindane 323,736 Ib (U.S. Environmental Pro-
tection Agency, 1978).
Samuels and Milby (1971) have studied the clinical, hematological,
and biochemical effects of human exposure to lindane. Some slight per-
turbation of hematopoietic processes was noted. Lindane was found not to
accumulate, but to reach a level reflecting recent exposure. In contrast
to g-BHC, lindane is not retained in the body: it enters fatty tissue but
is there in equilibrium with the blood (Samuels and Milby, 1971; Radomski
et al., 1971). It is excreted in both feces and urine. Contrary to the
relation between fatty tissues and blood, Dyment, Hebertson, and Decker
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20
(1971) found a lack of correlation between blood levels of BHC in milk and
in serum; thus, while milk indicates exposure, it is not a good indicator
of body burden. As shown by Selby et al. (1969a) and by Curley, Copeland,
and Kimbrough (1969), BHC crosses the placenta. Levels of lindane and
other BHC isomers are higher among persons living under low socioeconomic
conditions (Burns, 1974; Kutz et al., 1977; Deichmann and Radomski, 1968),
explained by their living closer to the source of contamination (agricul-
tural use) and because of a lower level of hygiene (unsanitary garbage dis-
posal, attracting pests, which are then sprayed, etc.). Using values of
pesticide levels from maternal blood and from placental and adipose tis-
sues, and using data from questionnaires concerning exposure, Selby,
Newell, Waggenspack, Hauser, and Junker (1969) attempted to correlate ex-
posure to pesticides with their clinically measured levels, with inconclu-
sive results; however, the methods developed would likely be useful in
epidemiological studies if applied on a larger scale and with greater in-
put of data. The "chemical index" was demonstrated to be a more logical
choice than the "environmental index" for estimating pesticide intake with
the chlorinated hydrocarbons studied. The situation might be different
with less persistent pesticides.
In water supplies, BHC, because of its low water solubility, as is
the case with other organochlorine pesticides, is concentrated in silt,
sand, plankton, and algae (Schafer, 1968); in soils it may be adsorbed on
clay particles. Soil organisms have a part in mobilizing such pesticides.
In a study done in Czechoslovakia, Szokolay, Madaric, and Uhnak (1977)
found a greater accumulation of 3-BHC than of other isomers in the food
chain, including animal food products. Levels of BHC isomers in the soil
were lower than levels of DDT and DDE, but transfer of the BHC isomers to
vegetables (potatoes) was higher than the transfer of DDT and DDE. Organo-
chlorine pesticides are persistent in the environment; however, BHC is
noteworthy because it disappears fairly rapidly in the soil, through de-
hydrochlorination and oxidation by soil bacteria (Matsumura, 1973). Alka-
linity of the soil also aids degradation.
4.4 PENTACHLOROPHENOL
4.4.1 Uses and Effects
Pentachlorophenol (PCP) is a substance which has been widely used for
the protection of wood and other fibrous materials against insects and
molds. As well as the main substance, technical PCP also contains TCDD
(tetrachlorodibenzodioxin, see Sect. 4.5), other dioxins and so-called
"pre-dioxins," and chlorinated dibenzofurans, resulting from side reac-
tions in manufacture. Cattle and hogs have become sick from gnawing wood
treated with PCP. Fish kills have resulted, at a level of about 0.5 ppm
PCP in water. Its use has been somewhat indiscriminate. Formulations
for painting or spraying onto wood are available to homeowners. Penta-
chlorophenol itself is toxic. An epidemic resulting in two deaths occur-
red in a nursery in St. Louis after the use of PCP as a mildew preventive
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21
with the laundry detergent (Barthel et al., 1969). Other cases of poison-
ing are reported in the Episode Summary reports, some at the worksite or
during construction activities, others at schools, the home, etc. Symp-
toms of poisoning are weakness, headache, double vision, tachycardia,
nausea, hyperpyrexia, and skin and eye irritation. Liver damage results
from chronic exposure. Absorption may occur by inhalation or through the
skin, and less frequently by ingestion of PCP residues. Melnikov (1971)
has discussed synthesis of PCP, use, the question of residues, and so on,
and Bevenue and Beckman (1967) have discussed properties of PCP, its toxi-
cology, analysis, and its occurrence as a residue in human and animal tis-
ues. PCP is relatively long-lasting in wood, but is fairly readily de-
graded in soils and by sunlight; and it is partly excreted and partly
metabolized in the animal body. PCP uncouples oxidative phosphorylation
(Zalkin and Racker, 1965). PCP gives rise to the metabolite tetrachloro-
hydroquinone, which is a potent inhibitor of g-glucuronidase, a chief
conjugating enzyme (Ahlborg, Lindgren, and Mercier, 1974). Tetrachloro-
hydroquinone in the urine is an indicator of exposure to PCP.
Aside from the uses mentioned above, PCP is highly phytotoxic and is
used as a general weed killer and as a desiccant for crops before harvest,
large quantities being used on, for instance, cotton. Copper pentachloro-
phenate has been much used as a molluscicide to control schistosomiasis.
4.4.2 Analysis
Analysis of PCP is generally by gas chromatography, by which method
it may be detected in the urine in picogram quantities (Bevenue et al.,
1966). Colorimetry (Ueda et al., 1969), turbidimetry (Comstock, Comstock,
and Ellison, 1967), and chemical ionization mass spectrometry (Dougherty
and Piotrowska, 1976) are also methods which have been used. Bevenue and
Beckman (1967) also cite analysis by paper, thin-layer, and ion exchange
chromatography, by various chemical colorimetric methods, and by ultra-
violet and infrared spectroscopy.
4.5 2,4,5-TRICHLOROPHENOXY ACETIC ACID
2,4,5-Trichlorophenoxy acetic acid (2,4,5-T) has one more chlorine
atom than 2,4-D. It is more effective than 2,4-D in controlling brushy
plants, and has been used in combination with 2,4-D for control of brushy
and herbaceous plants. Properly used (avoiding drift, which would damage
susceptible crops, avoiding entry into streams, etc.), the herbicide was
thought to present no great danger. However, fish kills and fatal and
acute incidents in humans and in domestic animals have occurred (U.S.
Environmental Protection Agency, 1977&). The damage comes from the fact
that 2,4,5-T contains a contaminant, TCDD, or 2,3,7,8-tetrachlorodibenzo-
p-dioxin. This is one of the most toxic synthetic substances known, the
lethal dose for the guinea pig being of the order of 0.6 yg/g (Matsumura,
1974). In man, exposure to TCDD causes skin eruption and eye and respira-
tory tract irritation. Because fetal deaths and teratogenic effects have
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22
been shown in laboratory animals, they are also to be feared as possible
effects in humans. Present as a contaminant, TCDD is also formed to a
slight extent from 2,4,5-T by microbial degradation and is considerably
more stable than 2,4,5-T. The extent to which it accumulates in the
environment, however, is somewhat uncertain (Matsumura, 1974). In 1970,
U.S. registration was canceled for granular 2,4,5-T formulations for use
around the home, recreation areas, and similar sites (Meister et al., 1977,
P. D252), partly because of concern over toxicity due to TCDD and partly
because of the drift question. Usage of 2,4,5-T in 1977 (U.S. Environ-
mental Protection Agency, 1978) was 995,703 Ib, and of 2,4,5-TP (Silvex),
the propionic acid analog of 2,4,5-T, 553,262 Ib.
The EPA has considered 2,4,5-T as its most important pesticide deci-
sion (Anon., 1979) because of a possible link between exposure to 2,4,5-T
from forest spraying and miscarriages in pregnant women and other health
effects; human milk and urine samples from volunteers are being tested,
plus other monitoring activities. The EPA has now halted most uses of
2,4,5-T and Silvex (Smith, 1979) because of the possible damage of mis-
carriages caused by TCDD in the two pesticides.
4.6 MIREX
Mirex is the completely chlorinated compound dodecachloro-octahydro-
1,3,4-metheno-2H-cyclobuta[c,d]pentalene, characterized by contiguous
tetra- and penta-chlorinated rings, as seen by the structural formula:
C\r
Cl
CL
Cl
Cl
Cl
Cl
Mirex was developed particularly for use against the fire ant. It
has also been used as a flame-protective coating. While it is of relati-
vely low toxicity to birds, fish, and crustaceans (Martin and Worthing,
1974, p. 360; see, however, Waters, Huff, and Gerstner, 1977), it is ex-
tremely persistent, and detectable residues have been found in 20% of adi-
pose samples of persons living in mirex treatment areas in the southern
states (Anon., 1978a).
Mirex seems not to be metabolized by mammalian systems; however, in
experimental animals, treatment with mirex provoked mixed-oxidases activ-
ity and other physiological and biochemical responses (as cited in Waters,
Huff, and Gerstner, 1977). Mirex crosses the placental barrier. It is
excreted mainly in the feces, with small amounts in the milk and urine.
Mirex is stored in tissues in the following decreasing order: fat, muscle,
liver, kidney, and intestines (Mehendale et al., 1972).
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4.7 KEPONE
Kepone, or chlordecone, is the pentalen-2-one keto analog of mirex.
The two chlorines at the peak of one of the pentalene rings are replaced
by an oxygen. Kepone is present in mirex as an impurity and is also for-
med from it by oxidation; and it has been synthesized as an insecticide in
its own right. Gas-liquid chromatography, with confirmation by mass spec-
troscopy (Harless et al., 1978), has been used for analysis of mirex and
kepone. Bases for concern over the widespread use of mirex and kepone
include: (1) adverse effects on reproduction as demonstrated in labora-
tory animals, (2) detectable amounts found in human adipose tissue, (3)
tumorigenic implications in mice, (4) effects on mammalian energy meta-
bolism, (5) effects on delayed mortality in birds, (6) potential to move
in a saltwater environment (and high potential for bioconcentration), (7)
effects on certain aquatic organisms, and (8) persistence.
The production of both mirex and kepone has been discontinued. The
Pesticide Usage Survey reports 133 Ib used in 1977 on pineapples (U.S.
Environmental Protection Agency, 1978)-
4.8 CHLORDANE AND RELATED CYCLODIENE PESTICIDES
4.8.1 Chlordane
Illustrated below is the projected formula of chlordane; the formulas
of the other pesticides may be derived from it. The numbering follows
that of the 4,7-methanoindane structure shown:
Isomers differing in the positions and orientation of the chlorine
groups exist, and may have different biological activity. Thus, Biichel
and Fischer (1966) have claimed greater insecticidal activity and lower
mammalian toxicity for the 2,2,4,5,6,7,8,8-octachloro isomer than for
the normal one, which is 1,2,4,5,6,7,8,8-octachloro.
Isomerism at positions 1 and 2 gives two major classes of isomers,
cis- and trans-. Technical chlordane is a mixture of about 70% cis- and
25% trans-isomers, with small amounts of other chlorinated molecules
(Martin and Worthing, 1974, p. 95; Meister et al., 1977, pp. D57-D58).
Chlordane is a nonsystemic stomach and contact poison with low photo-
toxicity. It has been formulated as granules, dusts, wettable powders
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24
and in solution for making a water euulsion. Chlordane has a fairly high
vapor pressure, but it is not easily degraded and, therefore, persists in
the environment. One prominent use is for protection against termites.
Savage (1975) has studied levels in soil and air around houses in connec-
tion with treating the soil for termites with chlordane and other cyclo-
diene pesticides, comparing levels around and in conventional houses with
those of houses using the crawl space for a plenum or to enclose heating
or cooling ducts. Blood samples of volunteers were also taken. The pres-
sence of the pesticides was detected, but at levels below those considered
hazardous to health. The main use of chlordane is on crops. It is re-
ported (U.S. Environmental Protection Agency, 1978) that 2,664,847 Ib of
chlordane was used in the U.S. in 1977 on a variety of crops. The manu-
facture of chlordane has, however, been discontinued in the U.S.
4.8.2 Oxychlordane
Oxychlordane, l-exo-2-endo-4,5,6,7,8,8-octachloro-2,3-epoxy-2,3,3a,4-
7,7a-hexahydro-4,7-methanoindene, is a metabolic oxidation product of
chlordane. Biros and Enos (1973) reported the consistent finding of oxy-
chlordane in general population human adipose tissue samples obtained
through the National Human Monitoring Program (Yobs, 1971). Oxychlordane
is a nonpolar compound, and thus is stored in fat. Levels were at 0.03 to
0.40 ppm; mean 0.14 ± 0.09 ppm. Kutz, Murphy, and Strassman (1978) give
figures from a more extensive survey for FY's 1973 and 1974; maximum
levels were 1.43 and 1.73 ppm respectively; (geometric) mean 0.12 ppm.
4.8.3 Heptachlor and Heptachlorepoxide
Heptachlor is 1,4,5,6,7,8,8-heptachloro-3a,4,7,7a-tetrahydro-4,7-
methanoindene, and heptachlorepoxide is an oxidation product of it, bear-
ing an epoxy grouping at the 2,3 position of the parent structure. Hepta-
chlor was first found as a contaminant in the production of chlordane;
later it was synthesized as a pesticide in its own right. It is a waxy
solid, practically insoluble in water but soluble in ethanol and in kero-
sene and other organic solvents. It is a nonsystemic stomach and contact
insecticide with some fumigant action (Martin and Worthing, 1974, p. 291).
The epoxide is formed by biological action in a wide variety of organisms,
including man and other mammals, birds, and soil organisms. The epoxide
is particularly persistent and biologically active. The Council for Agri-
cultural Science and Technology (1975) stated that the half-life of hepta-
chlor is about 0.8 year (chlordane 1 year) under agricultural conditions.
Because of insolubility, chlordane and heptachlor tend to remain at the
site of application and tend not to enter greatly into food chains; how-
ever, some can get into plants, and Richou-Bac (1974; in France) found
significant levels of heptachlorepoxide in foods of animal origin, parti-
cularly milk and milk products, in a region showing regular augmentation
of soil levels of heptachlor and heptachlorepoxide. Heptachlor is the
most toxic pesticide which has been found for termites. Loss of hepta-
chlor is mainly by volatility. Heptachlor and heptachlorepoxide cross
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25
the placenta and also appear in milk (Casarett et al., 1968). The two
pesticides are eliminated mainly in the feces (Girenko, Kurchatov, and
Klisenko, 1970). Usage of heptachlor reported in 1977 for the U.S. was
1,957,726 Ib; the bulk, 1,344,159 Ib, was used on corn land and the rest
on other field crops and for seed treatment.
4.8.4 Trans-Nonachlor
Trans-nonachlor, 1,2,3,4,5,6,7,8,8-nonachloro-3a,4,7,7a-tetrahydro-
4,7-methanoindane, is a component of technical chlordane and technical
heptachlor. Kutz et al. (1976) have studied the geographical distribu-
tion of trans-nonachlor in human adipose tissue samples from subjects in
the nine census regions of the U.S. The presence of this contaminant was
confirmed at levels of about 0.01 to 0.10 ppm in all regions but one (East
North Central) and at a lower level than others in one (Mountain). As
reported by Kutz, Strassman, and Sperling (1978), the frequency of finding
trans-nonachlor in human adipose tissue samples, which was 95.7% in FY
1974, was 96.8% in FY 1975, and the geometric mean in ppm had gone from
0.10 to 0.15. The finding of trans-nonachlor is indicative of exposure
to chlordane and/or heptachlor. The metabolism of trans-nonachlor is not
known, but is likely similar to that of heptachlor.
4.9 DDT
4.9.1 General and Historical
DDT is the common name of the technical mixture of isomers of 1,1,1,-
trichloro-2,2-bis(chlorophenyl)ethane, or Dichloro Diphenyl Trichloro-
ethane. The formula of the p,p'-isomer, which is the predominant and most
greatly desired one, is given; the formulas of other isomers and of metab-
olites may be derived from it:
DDT was first described in 1874 by Zeidler, but its insecticidal
activity was not uncovered until 1939 by Muller in Switzerland. It was
brought into the U.S. for testing in 1942 and later imported in quantity,
and by early 1944, domestic production for at first military use was under
way (Meister et al., 1977, p. D80). DDT was a revolution in pest control.
It seemed the perfect insecticide — highly toxic to insects (except for
certain phytophagous mites), nontoxic to plants (except for the cucurbitae),
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26
nontoxic to warm-blooded animals, and inexpensive to produce. The bene-
fits seemed largely to outweigh any risks, and fantastic quantities were
produced for public health campaigns for the control of malaria and other,
insect-propagated diseases and for control of insects in general. It was
estimated by Knipling (1953; cited in Edwards, 1973ajfc) that during the
first decade of use, DDT saved 5 million lives and prevented 100 million
serious illnesses due to malaria and typhus, dysentery, and more than 20
other insect-borne diseases. Literally tons were used in agriculture, in
forestry, in fogging city streets, and so on.
4.9.2 Persistence and Use
While DDT is fairly easily degraded chemically or by ultraviolet
photolysis or by heating, in application the conditions necessary for
degradation might not occur, and thus it is persistent in the environment.
Further, it accumulates in food chains because of its low water solubility.
Side effects of DDT include effects on birds and on their eggs, hormone
stress, effects on ecosystems through killing of nontarget organisms, and
actual dispersion of some insect pests by use of DDT through selection of
dispersion as a trait. These effects, plus diminishing returns in use
because of the buildup of resistant strains, finally became of such con-
cern that after three years of intensive administrative inquiry (Kutz et
al., 1977), all uses of DDT, except for emergency public health ones and
a few others permitted on an individual basis, were prohibited in the U.S.,
effective December 31, 1972.
Use had already considerably declined. Kutz et al. (1977) show a
graph of domestic use of DDT from 1950 through 1972. The peak use of 80
million Ib was in 1959. Use from then on declined almost linearly, and
in 1972 was about 12 million Ib. The Pesticide Usage Survey (U.S. Envi-
ronmental Protection Agency, 1978) reports 7100 Ib of DDT used in the
U.S. in 1977-
4.9.3 Levels in the General Population
Concurrent with the decrease in use of DDT has been a decrease in
residue concentrations in humans (DDT and metabolites and congeners of
DDT), particularly in younger age groups, as shown by the results of the
EPA National Human Monitoring Program for Pesticides (Kutz et al., 1977).
Total DDT equivalent residues in human adipose tissue decreased from 7.88
ppm lipid weight for general population samples in FY 1970 to 5.02 ppm
in FY 1974, and in the 0 to 14 age group from 4.47 to 2.32 ppm. There
was a slight rise in levels in the general population for FY 1975, prob-
ably without great significance (Kutz, Strassman, and Sperling, 1978).
Other organochlorine pesticide residues, for example, benzene hexachlo-
ride, dieldrin, heptachlor epoxide, oxychlordane, and trans-nonachlor,
did not show the same decline as DDT; in fact, some went up. Note that
use of these other pesticides was restricted later than the use of DDT.
Samples from blacks contained almost twice as much total DDT equivalent
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27
residues as samples from whites, reflecting the respective socioeconomic
situations of these two population groups.
Some representative studies may be mentioned. For instance, in Bade
County, Florida, Davies et al. (1972) studied the effect of five socio-
economic classes on"pesticide levels. The classes involved occupation,
income, housing, and education. Lower classes had higher levels of DDT
and DDE; and with similar indicators, blacks had higher levels than whites
Arthur et al. (1975) studied serum pesticide levels in the general popula-
tion of Mississippi. Blacks again had higher levels, and their total pro-
tein, alkaline phosphatase, lactic dehydrogenase, and glutamic-oxalacetic
transaminase values were higher than in whites; this demonstrated greater
impact of the pesticides on the blacks because of their relatively dis-
advantaged living conditions and possibly also reflected differing dietary
regimes.
4.9.4 Sources and Entry into Man
There is some disagreement as to which is the main source of intake
of DDT by man — food or dusts. The intake from water is very low. The
answer may depend on whether one is speaking generally or of particular
situations. Thus, Campbell, Richardson, and Schafer (1965) considered
that food contributed over 90% of the DDT absorbed by people in the gen-
eral population. Likewise, Sharman (1973) has considered the main sources
of residues of organochlorine pesticides to be meat, fish, poultry, and
dairy products and has advocated the reduction of the consumption of con-
taminated feed as the most effective way of reducing human intake of such
residues. On the other hand, other authors dealing with specific situa-
tions have shown that the intake from dusts, whether household dusts or
soil dusts, cannot be ignored (Deichmann and Radomski, 1968; Radomski and
Deichmann, 1968; Roan, Laubscher, and Morgan, 1969; Davies, Edmundson,
and Raffonelli, 1975). Because of nonvolatility, DDT and similar com-
pounds are easily carried in dusts; further, inhalation may often be a
more effective way of introducing a contaminant than strictly oral inges-
tion. Highly scattered values may cause one to suspect localized sources
of contamination (Deichmann and MacDonald, 1971).
4.9.5 Isomers and Metabolites of DDT
At this point it is necessary to mention isomers and metabolites of
DDT for understanding of the processes of absorption, metabolism, and
excretion of the pesticides.
4.9.5.1 o,p-DDT — This is the chief isomer of DDT. Technical DDT
is 60 to 75% p,p'-DDT; the remainder is o,p-DDT and other compounds. o,p-
DDT may show some differences in effects from p,p'-DDT (see Sect. 4.9.8);
however, its chemistry is otherwise very similar, and it gives deriva-
tives similar to those of p,p'-DDT.
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4.9.5.2 PDA — Bis(p-chlorophenyl) acetic acid (for the p,p'-deri-
vative) , or Dichloro Diphenyl Acetic acid. This is a metabolic oxidation
product of DDT. It is the chief metabolite of DDT excreted in the urine,
which is what would be expected from the water solubility conferred by
the presence of the acid group.
Because of its polar nature, DDA may be separated from other DDT
metabolites on ion exchange resin and analyzed separately (Cueto, Barnes,
and Mattson, 1956). For separation by gas chromatography the methyl ester
may be formed.
4.9.5.3. ODD (also called TDE) - 1,l-Dichloro-2,2-bis(p-chloro-
phenyl)ethane, or Dichloro Diphenyl Dichloroethane. This compound has
one chlorine atom less (on the end carbon of the ethane moiety) than DDT,
and is not necessarily a derivative of it but is a pesticide in its own
right, having formerly been used on fruits and vegetables (Meister et al.,
1977, p. D255); however, it can be formed from DDT by metabolic action.
4.9.5.4 DDE — 1,l-Dichloro-2,3-bis(chlorophenyl)ethene, or Dichloro
Diphenyl dichloro Ethylene. This is formed from DDT by loss of one mole-
cule of HCl, either chemically or by biological action. This results in
a double bond or unsaturation between the two carbons of the ethane (now
ethene) moiety. This compound is not an insecticide. On further dehydro-
chlorination plus oxidation, DDA is formed.
All of the above compounds may be indicators of exposure to DDT. The
compounds may be analyzed for separately, and also "total DDT equivalent"
may be given.
4.9.6 Fate of DDT; Absorption, Metabolism, and Excretion
i
In the national survey, of the total DDT equivalent found, 80% was
DDE. Similarly, in 1964, Hoffman, Fishbein, and Andelman found DDE to
be 75% of total DDT-derived material in human adipose tissue samples.
In only 7 of 282 cases was the DDT level higher than that of DDE. The
trend of DDE as a proportion of total DDT equivalent is up in the general
population. This DDE is not appreciably derived from ingestion of DDT
but rather by intake of DDE formed in the environment from DDT. The
normal fate of DDT in the human body is to be either dechlorinated to DDD
and then metabolized to the water-soluble and excretable DDA, or to be
excreted directly as DDT. DDT goes into fat, but there is a slow equi-
librium between fat and blood (see, for instance, Deichmann and MacDonald,
1971). Thus the DDT is not irreversibly stored — its excretability, in
the words of Hayes (1965), is "intermediate between that of most drugs
and that of lead and other bone seekers."
DDE, degraded in the environment by microbal action, is not easily
excreted and thus builds up slowly in the fatty tissues. As studied by
Morgan and Roan (1971), both the propensity for storage and stability,
once stored, increase in the order p,p'-DDD <_ o,p'-DDT < p,p'-DDT <
p,p'-DDE. Thus it is critical to the fate of ingested DDT whether it is
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dechlorinated to DDD, in which case it is metabolized to DBA and excreted;
or dehydrochlorinated to DDE, in which case it is stored; however, this
latter reaction seems not to occur to any great extent in the body.
DDT ingested as such is partly absorbed and partly excreted in the
feces. The absorption of DDT is facilitated by the presence of fats
(Anon., 1962). DDT in oily solution can be absorbed through the skin.
DDE is also partly absorbed and partly excreted in the feces. DDA in a
conjugated form is found in the feces. Hoffman, Fishbein, and Andelman
(1964) state that some DDE can be oxidized to DDA, which is conjugated
in the liver, and the conjugates are excreted both in the bile and in the
urine. Other metabolic products may also be found. DDE is presumably
less toxic to humans than DDT (if one can extrapolate from animal testing
to humans), and so the conversion of DDT to DDE can be considered a form
of detoxication (Hoffman, Fishbein. and Aadelman, 1964), albeit not a
very efficient one.
Excretion of DDT in the urine is slight. In some cases, practically
none is found (Vioque, Saez, and Albi, 1977), whereas in others only trace
or small amounts may be present (Price, Young, and Dickinson, 1972). DDT
is excreted in the feces in most animals, but not to any great extent in
man (Hayes, 1975). Some DDT may be transformed by bacteria in the gut to
products which are then absorbed and may be excreted in the urine, no
longer as DDT (Morgan and Roan, 1972). Excretion patterns are slower in
man than in the monkey, dog, and rat (Morgan and Roan, 1971), and loss of
DDT from adipose storage is slower in man than in these and other animals.
4.9.6.1 Hair as Excretory Pathway — The role of hair and its associ-
ated lipids as an excretory pathway for chlorinated hydrocarbons, including
DDT, was examined by Matthews, Domanski, and Guthrie (1976). It was found
that excretion via hair could be a significant factor in eliminating chlo-
rinated hydrocarbons which resist metabolism. A similar elimination may
occur through skin sebaceous gland secretion.
4.9.6.2 Smokers and DDT — Smokers, even though exposed to an extra
load of DDT and derivatives from residues on the tobacco, show no higher
levels of these contaminants in their adipose tissue than do their non-
smoking compeers in the general population (Domanski et al., 1977). Smok-
ers excrete more DDA than do nonsmokers. It would seem that microsomal
oxidases are activated in smokers, to the extent that the added pesticide
load is kept up with. On the other hand, the residues of dieldrin for the
male smoking group, particularly black males, were found to be marginally
greater than those for the nonsmoking groups and to reflect linearly the
number of cigarettes smoked. The authors point out that the amount of
dieldrin residues on tobacco is inconsequential compared with the intake
from food, in contrast to the situation with DDT.
4.9.7 Distribution in Tissues
4.9.7.1 Distribution with Respect to Disease — As has been mentioned,
DDT is stored in fatty tissues, but is in slow equilibrium there with
blood (Deichmann and MacDonald, 1971). DDT may be mobilized by changes
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30
due to various illnesses. This is also true for other pesticides, as shown
by the study of Casarett et al. (1968), who determined levels of DDT, ODD,
DDE, dieldrin, and heptachlorepoxide in tissues from 44 autopsies with as
many as 12 tissues from each autopsy set. Subjects with the highest total
residues in the tissues were those with evidence of emaciation, carcinomas,
and various pathological conditions of the liver. Levels in sudden-death
subjects were clustered near the center of distribution, in contrast to
those in subjects who had undergone prolonged periods of illness before
death. It was considered that levels in the lungs and liver showed recently
entered material, whereas adipose tissue levels showed storage. Pesticides
in viscera are likely to be part of lipoid elements in parenchymal tissue
and thus to be in a position to interfere in intralipoidal cycles and thus
with function.
The authors make the point that wasting disease, hormone stress, and
the metabolic perturbations of various diseases may cause a mobilization of
stored pesticide material, with possible toxic effects. Similarly, release
of PCBs and of p,p'-DDE into the blood of patients with severe wasting dis-
ease (carcinoma) has been noted by Hesselberg and Scherr (1974). Radomski
et al. (1968) have also noted high levels of DDT and DDE in the blood of
patients with carcinoma, but not in patients with primary brain or liver
tumors. In the Hesselberg and Scherr study, the patients were too sick for
nervous system symptoms such as circumoral paresthesias, malaise, skin sen-
sitivity, tremor, and disturbances of equilibrium to be noted. In birds
and lower mammals, however, obvious nervous symptoms and even death have
been caused by release of stored pesticide residues.
4.9.7.2 DDT and the Fetus — DDT and DDE (and other organochlorine
pesticides) cross the placenta and are found in fetuses. The levels in
blood of premature babies are higher than in the, blood of normal-term
infants, likely explained by the lesser body fat of the premature infants
(O'Leary et al., 1970). Stillbirths and abnormalities have not been found
to be associated with high levels of DDT or DDE (Rappolt and Hale, 1968;
Curley, Copeland, and Kimbrough. 1969; O'Leary et al., 1970).
DDT affects nervous tissue and also causes other disturbances of
function. Admittedly, these results appear only over a long period of
time. However, the fetus is particularly vulnerable because of the in-
tense program of differentiation events taking place during gestation.
Spyker (1975) has considered the impact of exposure to low levels of
chemicals on development, including behavioral and latent effects. 'Effects
of methyl mercury were used as an example. The author makes the point that
there are compensatory mechanisms that initially may mask the effects of a
contaminant, but as aging, repeated exposure to stress, cell death, and
other effects on systems occur, the delayed effect of the early lesion may
be manifested.
4.9.8 Effects of DDT
The effects of DDT are mainly manifested in the environment. Fish
and other aquatic organisms concentrate DDT (Revenue, 1976); animals can
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31
become sick from eating contaminated fish. Birds are particularly sus-
ceptible to DDT poisoning. They suffer hormone stress, and their calcium
metabolism is affected, resulting in lowering of egg production and pro-
duction of nonviable eggs, in addition to metabolic changes. In man, the
effects of DDT are mainly on the nervous system (Schafer, 1968; WHO Sci-
entific Group, 1975). However, the fact that DDT sequesters in relatively
inert fat keeps it from exerting its full effect. Acute DDT poisoning
results in vomiting, skin sensitization, eye irritation, and dizziness,
but long-term, chronic effects are considerably more subtle, and at the
declining levels which are now being reached, DDT is not considered to be
a great hazard (Hayes, Dale, and Pirkle, 1971; Deichmann and MacDonald,
1971).
DDT, particularly o,p'-DDT, shovs some effect on estrogenic systems,
as studied by Nelson, Struck, and James (1978) in rats and with human
tissue -in vitro. Activity of estradiol was enhanced by treatment with
o,p'-DDT; it was postulated that the o,p'-DDT may replace estradiol from
nonspecific sites, making it more available for specific sites. In this
connection, Schoor (1973) has studied the binding of p,p'-DDE to serum
proteins. Release of the DDE could result in toxic or pharmacologic
effects. Binding of the contaminant would protect it in some measure
from degradation. Finally, Rashad et al. (1976) have studied the associa-
tion between serum cholesterol and serum organochlorine residues in 3568
subjects. Results indicate that p,p'-DDE may stimulate synthesis of cho-
lesterol in the liver, leading to an elevated serum cholesterol.
4.9.9 Load of DDT in the Environment
The decline in stored DDT and DDE noted in the national surveys is
hopeful. Some effects may already be noted. For instance, Spitzer et
al. (1978) have noted an increase in productivity of ospreys in the
Connecticut—Long Island area, reflecting a decrease in environmental
levels of DDT. The decline may be expected to continue, albeit at a
slower rate, until the levels become asymptotic with the declining levels
in the environment. This process is apt to take a considerable time. The
estimate of production of persistent pesticides from 1950 to 1970 is 3000
million Ib (Finlayson and MacCarthy, 1973). A good part of this was DDT,
and the figure for the total production of DDT is of the order of 2 million
metric tons (4400 million Ib; Maddox, 1972). Woodwell in 1966 (cited in
Niering, 1968) estimated that at that time there was 1000 million Ib of
DDT circulating in the biosphere. This is perhaps about half of that which
had been produced up to that time. The levels and effects of this DDT
(summation of DDT and its natural metabolites) at a succession of environ-
mental and trophic levels are given by Goodman (1974). Taking 1 as the
solubility of p,p'-DDT in water (this corresponds to 1 ng/g water, to the
nearest factor of 10), total DDT levels in the biosphere cover nine orders
of magnitude (in ng/g): from 0.01 in seawater, where the effect noted
is blocking of the development of certain planktonic copepods; to 0.1
falling in rain; to 10, which is the WHO/FAO proposed acceptable daily
intake for man/g body mass; to 100 in the fat of Waddell seals and of
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32
penguins in Antarctica; to 1000 in human fat in the U.K.; to 10,000 in
human fat in the U.S. (this is an experimentally lethal concentration in
the brains of many birds); to 1 million in the fat of adult pheasants,
with some mortality and impaired chick survival (this same level has been
found in the fat of ostensibly healthy U.S. workers formulating DDT for
20 years); to 10 million in the pectoral muscle of eagles found dead.
4.9.10 Analysis of DDT
Ruzicka (1973) distinguished five basic methods of analysis: (1)
functional group analysis; examples: colorimetry, chemical reactions,
(2) biological test methods, (3) chromatographic methods, (4) spectro-
scopic methods, (5) radiochemical methods. All of these have been used
for DDT and other pesticides. Colorimetry was an early method; this has
been superseded by gas chromatography. Some pitfalls and shortcomings of
any of the methods of analysis have become evident with experience. Thus,
when 34 soil samples dating back to 1909 to 1911 (long before the advent
of organochlorine pesticides) were analyzed, 32 showed apparent insecti-
cide residues. These were eventually attributed to certain interfering
soil constituents (Frazier, Chesters, and Lee, 1970; cited in Edwards,
1973i>) . PCBs give a pattern of peaks on a gas-liquid chromatogram similar
to those of dieldrin, DDT, DDE, aldrin, and heptachlorepoxide. Cleanup on
a column of silicic acid removes this interference. Extraction of the
pesticide from the tissue is often a problem. This question has been
treated by Kadis, Jonasson, and Breitkreitz (1969) and by Mes and Campbell
(1976). It was found by Dale, Miles, and Gaines (1970) that pretreatment
of serum with formic acid improved the extraction of DDT and metabolites.
Other investigators have also developed effective protocols for preparation
of samples. Ecobichon and Saschenbrecker (1967) have noted dechlorination
of DDT, even in frozen blood. Some estimation of loss of this kind may be
needed. Contamination must also be guarded against. Atallah, Whitacre,
and Polen (1977) have studied artifacts which arise in analysis of organo-
chlorine pesticides in human adipose tissue, with particular reference to
cyclodienes. Confirmatory techniques are needed to rule out false posi-
tives. For screening, extremely sophisticated methods may not be needed.
Several authors (Klisenko and Yurkova, 1967; Gabica, Watson, and Benson,
1974; Coutselinis and Dimopoulos, 1971; Nachman et al., 1969) have pre-
sented simplified gas chromatographic methods, thin-layer chromatographic
methods, and methods to distinguish between classes of pesticides. An
interesting method is the one of Sadar, Kuan, and Guilbault (1970), which
takes advantage of the fact that cholinesterases extracted from different
sources are inhibited or not by various pesticides. Readout is by fluo-
rescence of a fluorogenic substrate acted upon by the cholinesterase.
The method can distinguish between chlorinated, organophosphorus, and
carbamate pesticides. From time to time, recommended methods of analysis
and recommendations for further work are given in the JAOAC (example:
Corneliussen, 1976).
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SECTION 5
ORGANOPHOSPHORUS, CARBAMATE, AND MISCELLANEOUS PESTICIDES
5.1 INTRODUCTION
As mentioned by Durham (1969) and other authors, the organophosphorus
and carbamate insecticides are in general much less persistent in the en-
vironment and in the animal body than are the organochlorine ones. The
notion of functional accumulation (Westermann, 1969) has been discussed
(Sect. 2.1). The danger with organophosphorus and carbamate pesticides
is in their effects and not in their storage. The effect is inhibition
of cholinesterase and in general of enzymes having serine in their active
site. Enzyme-substrate complex is formed, but transformation and release
of product does not occur. Durham notes that the combination between the
organophosphorus moiety and the cholinesterase is generally more stable
than that between the carbamate molecule and the enzyme. In fact, as
studied by Witter (1963), the carbamate-to-cholinesterase bond may be so
labile as to cause difficulty in carrying out a meaningful test on blood
from persons exposed to carbamates.
Because of their relatively nonpersistent character, we did not in-
clude body-burden data — and there are few data of this kind in the litera-
ture — for the organophosphorus and carbamate pesticides and for some
organochlorine pesticides not discussed in Sect. 4, with some exceptions,
in phase I of this report. Many of these pesticides are water soluble and
thus tend to be fairly easily excreted in the urine. Sometimes they are
esterified or otherwise modified to make them less water soluble; but here
esterases would split off the modifying group, rendering them again water
soluble, and further metabolism might also ensue. This is not to say that
these pesticides are without danger, but the danger is more episodic than
in the case of the more highly persistent pesticides. An example is poi-
soning from residues of paraquat used to spray crops and, in particular,
marijuana. Paraquat is l,l'-dimethyl-4,4'-bipyridinium ion, a hetero-
cyclic compound, furnished as the dichloride salt, which is freely water
soluble. According to the Pesticide Usage Survey, a total of 1,005,340 Ib
of paraquat was used in the U.S. in 1977, on a wide variety of field, nurs-
ery, orchard, and market crops. Episode summaries for reports involving a
variety of pesticides are published regularly by the EPA Pesticide Episode
Response Branch. Reports deal with specific pesticides, no matter what the
source, or may deal with poisoning episodes of pesticides coming from a
stated source, such as water (example: Report No. 63, 1976).
5.2 PRODUCTION AND USE
The Pesticide Usage Survey publishes use figures for more than 275
pesticides. Of these, 87 showed usage for 1977 of above 1 million Ib.
Among these were:
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Alachlor: 2-chloro-2',6'-diethyl-N(methoxymethyl)-acetanilide,
54,389,601
Atrazine: 2-chloro-4-ethylamino-6-isopropylamino-l,3,5-triazine,
76,244,343
Butylate: S-ethyl-diisobutylthiocarbamate, 28,499,7'99
Carbaryl: 1-naphthyl-N-methylcarbamate, 18,065,721
2,4-D: 2,4-dichlorophenoxyacetic acid, 26,661,972
Dichloropropene-Dichloropropane: 37,544,110
Linuron: 3-(3,4-dichlorophenyl)-l-methoxy-l-methyl urea,
12,863,516
Methyl parathion: 0,0-dimethyl-O-p-nitro-phenyl phosphoro-
thioate, 63,418,309
MSMA: monosodium methanearsonate, 13,950,441
Propachlor: 2-chloro-N-isopropyl-acetanilide, 18,930,906
Elemental sulfur, over 70,000,000
Toxaphene: polychlorocamphene, 74,469,332
Trifluralin: ajO,a-trifluoro-2,6-dinitro-N,N-dipropyl-p-
toluidine, 22,982,938
Total usage for the U.S. in 1977 of all pesticides listed is of the order
of 900,000,000 Ib. Perhaps the greatest use is for weed control — other
uses are for control of root and stern and soil insects in cropland, for
desiccation, for control of plant blight, for control of insects as such.
The figures listed are for usage by major crop types and do not include
figures for some other agricultural uses and for usage in the industrial
and governmental sectors. We do not have estimates of the amounts of
these other uses.
5.3 ENTRY INTO MAN. METABOLISM AND EFFECTS
Entry of these pesticides can come in food and water, in dusts, as
residues on objects, and through the skin. Oudbier et al. (1974) have
studied entry by the respiratory route during and following spraying,
especially among pesticide workers. Cummings (1965) has presented a
market basket report on pesticides in foods, following an earlier report.
In the 1965 study, residues of the 2,4-D type of pesticide were found,
whereas they had not been earlier. Kohli et al. (1974) have studied the
absorption and excretion of 2,4-D in man. Because this compound is water
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35
soluble it is excreted in the urine. Tewari and Harpalani (1977) deter-
mined the distribution of 12 common organophosphorus pesticides in human
autopsy tissues, following cases of poisoning. Levels were highest in
the stomach, followed by liver and intestine, kidney, spleen, lung, heart,
and brain, in that order. One would not necessarily find the same order
in cases of chronic poisoning. As mentioned by Khokhol'kov and Burkatskaya
(1964; cited in WHO Scientific Group, 1975), whereas analysis of blood tis-
sues for a certain pesticide or its metabolite in the case of the organo-
phosphorus pesticides may be of little value because of the high turnover
of the compounds, the amount of ether-extractable organic phosphorus is
indicative of exposure. Matsumura and Ward (1966; see also Matsumura, 1973)
have studied the degradation of a number of organophosphorus pesticides by
human and rat liver. Phosphatases, esterases, oxidases, conjugases, de-
alkylating enzymes, and dephosphorylating and dethiolating enzymes are
active in processing the pesticide residues (above references and Anon.,
1972). The nonpersistent pesticides appear in the milk and in the fetus,
but to a lesser extent than the more lipophilic ones (Tolle et al., 1973).
Tocci et al. (1969) have studied the effects on enzymes of exposure to
organophosphorus and other pesticides. Activity of alkaline phosphatase is
increased. The pesticides affect cholinesterase activity and also inter-
fere with metabolism at various points, for instance, at the level of
glycerol-1-phosphate and with transaminase activity. Metcalf and Holmes
(1969) have examined changes in EEC patterns and psychological, neurolog-
ical, and biochemical changes in humans with organophosphorus exposure.
There is an impact of organophosphorus compounds on the deep midbrain, as
well as more superficially on the nervous system, as a slower response to
exposure to these contaminants.
5.4 ANALYSIS
Analysis of these pesticides is by gas chromatography (Corneliussen,
1975), with a specific flame photometric detector being much used; by
reversed-phase liquid chromatography (Askew, Ruzicka, and Wheals, 1969);
by polarography coupled with liquid chromatography (Koen and Huber, 1970);
by thin-layer chromatography (Tewari and Harpalani, 1977; Sherma, 1978;
Paez and Farah, 1971); by testing of enzyme levels (Nicaise, 1970;
Moeller and Rider, 1962); by a number of methods for specialized cases
(Ruzicka, 1973); and by analysis of metabolites of the pesticides (Lores
et al., 1978; Shafik and Enos, 1969; Hunter et al., 1972). Thin-layer
chromatography is used to a considerably greater degree for analysis of
these pesticides than is the case with the organochlorine ones, with
quantitation by densitometry. Much greater use is also made of testing
for metabolites. Kutz, Murphy, and Strassman (1978) have listed some
chemicals detected in human urine and their pesticide origin. Thus, from
carbaryl and naphthalene is found a-naphthol; from propoxur, isopropoxy-
phenol; from carbofuran, carbofuran phenol and 3-keto carbofuran; from
malathion, the a-monocarboxylic and the dicarboxylic acid; from methyl
and ethyl parathion, p-nitrophenol; from chloropyrifos, 3,5,6-trichloro-
2-pyridinol; from organophosphorus insecticides containing the respective
phosphate and phosphorothiosulfate groupings, dimethyl phosphate, diethyl
phosphate, dimethyl and diethyl phosphorothionate, sulfates, and
phosphorodithionates.
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SECTION 6
POLYCHLORINATED AND POLYBROMINATED BIPHENYLS AND TERPHENYLS
6.1 FORMULAS
The formulas of chlorinated biphenyls, dibenzofurans, dibenzodioxins,
and terphenyls (diphenyl benzene) are shown; X = chlorine atoms, indeter-
minate in number and position:
X
X
biphenyls
o-terphenyls
X
dibenzofurans
X
m-terphenyls
0.
x u x
dibenzodioxins
p-terphenyls
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The dibenzofurans and dibenzodioxins are produced by oxidation and con-
densation reactions in the manufacture of PCBs. They may also be produced
by microbial action. See also section on PGP (Sect. 4.4); formation from
condensation of chlorophenols. Given the ten possible sites of substitu-
tion, it is theoretically possible that 210 isomers and analogs could be
found in a mixture of PCBs (Somers and Smith, 1971), plus others from the
other compounds shown. Not all are present, but enough are to complicate
reference to a standard in analysis.
6.2 POLYCHLORINATED BIPHENYLS
6.2.1 Production and Use
Somers and Smith (1971) estimate that production in the Western world
at that time was about 100 million Ib of PCBs annually, of which nearly
50% was being produced in the U.S. Kutz (1976) has given production fig-
ures for PCBs for the period 1930 to 1975. [PCBs were used as early as
1881 (Ouw, Simpson, and Siyali, 1976), but widespread use did not occur
until the 1970s.] U.S. production for the period 1930 to 1975 was 1400
million Ib, of which 150 million Ib was exported. Three million Ib was
imported; U.S. sales were 1253 million Ib, of which 758 million Ib was cur-
rently in service, 55 had been destroyed, 290 was in landfills and dumps,
and 150 was in soil, water, air, and sediments.
The PCBs are synthetic oils with special physical properties of elec-
tric insulation, heat transfer, high vapor pressure, and great durability,
even at high temperatures. They have had manifold uses. Finklea et al.
(1972) distinguish between "closed" and consumptive uses. By definition,
residues from the consumptive uses get into the environment, and a goodly
amount of PCBs from the "closed" uses also does, from accidents, deteriora-
tion, and eventual disposal. Kutz (1976) lists current uses, which are:
in electrical transformers and capacitors, in recycled paper as a contami-
nant, and in investment castings (imported). Uses which have been discon-
tinued include: heat transfer and hydraulic fluid, lubricant and in
cutting oils, plasticizer, wax extender, pesticide extender, in adhesives,
in inks, in sealant and caulking compounds, and as a paper coating. U.S.
sales in 1975 were about 65,000 Ib; export sales were about 33,000 Ib.
6.2.2 PCBs in the Environment and in Man
The distribution of PCBs is similar to that of the other persistent
chlorinated hydrocarbons and occurs largely through lipid-associated path-
ways. PCBs enter the environment through the consumptive uses mentioned,
through leakage, through burning of refuse, etc. PCBs enter into aquatic
and land food chains (and have deleterious effects on organisms in these
milieux) and are found in feeds and foods (Khan, Rao, and Novak, 1976) .
The presence of PCBs in sewage sludges is of particular concern (U.S.
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38
Department of Health, Education, and Welfare, 1976). PCBs ingested, in-
haled, or absorbed through the skin are found in the blood (being trans-
ported therein) (Hammer et al., 1972); are stored in adipose tissue (Price
and Welch, 1972; Kuroki and Masuda, 1977), the types of compounds stored
reflecting both the mixture of PCBs before intake and metabolic conversions;
are secreted in milk (Savage et al., 1973; Savage, 1976; Musial et al.,
1974); and are excreted by hair follicles and sebaceous glands (Matthews,
Domanski, and Guthrie, 1976).
6.2.2.1 Effects in the Environment and in Man — Peakall (1975) has
considered the effects of PCBs in the environment. With added hazards
from the very highly toxic polychlorinated dibenzofurans and dioxins men-
tioned previously, effects in the environment and on animals are similar
to those of the chlorinated insecticides. In man, chronic exposure at
levels such as may be encountered in the work place results in chloracne,
skin and eye irritation, nausea, edema of the face and hands, and abdominal
pain (Ouw, Simpson, and Siyali, 1976). PCBs are of concern because of
their relatively high vapor pressure, leading to absorption following in-
halation; further, their oily or sticky or resinous nature, depending on
the degree of chlorination, results in a hazard of absorption through the
skin — example: electricians' rash from PCB-containing wire coatings.
The acute toxicity of PCBs is less than that of most organochlorine pesti-
cides (Peakall, 1975); however, fatalities have occurred following poison-
ing with PCBs and with the similar chloronaphthalenes (Flinn and Jarvik,
1936). Pathological findings on autopsy were liver damage, fatty degenera-
tion, necrosis, and cirrhosis. In the Yusho incident in Japan in 1968
(Kuratsune et al., 1972), over 1000 persons were poisoned by eating rice
oil contaminated by leakage of PCBs from a heat exchanger device. Symptoms
were blindness, chloracne, nausea, edema, skin cysts, vomiting with jaun-
dice, and abdominal pain. Babies born of mothers affected with the PCBs
had skin discoloration due to passage of the PCBs through the placenta.
It is noteworthy that the contaminated rice oil contained a higher propor-
tion of polychlorinated dibenzofurans than did the original PCB heat ex-
changer oil, and the suspicion is that these were formed in service by
heating and air oxidation.
Calabrese and Sorenson (1977) have reviewed the metabolism and health
effects of PCBs. In rabbits, glucuronide-conjugated PCBs were excreted in
the urine. Glucuronides and sulfates were excreted in the urine and feces
of dogs; and in humans, 65% of intravenously injected hydroxylated chlori-
nated biphenyl was excreted in the urine and 20% in feces. Enzymes in the
liver are capable of hydroxylating PCBs. Storage of isomers differs, the
more highly chlorinated ones generally being retained longer. General
storage levels are highest in adipose tissue, followed by liver, blood,
heart, kidney, and brain. Effects of PCBs are increased liver weight,
fatty degeneration and necrosis, and increased activities of enzymes such
as nitroreductase and aromatic hydroxylase. Vitamin A storage is decreased
in rats. PCBs alter lipid metabolism and may perturb absorption of fat-
soluble vitamins from the digestive tract. Carcinogenic and teratogenic
effects caused by chlorinated dibenzofurans and chloronaphthalenes present
as impurities in PCBs are a possibility. PCBs cause hormonal stress as
evidenced by increased levels of corticosterone. Reproductive effects of
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PCBs may reflect increased hydroxylation of progesterone and testosterone
caused by increased activity of hydroxylating enzymes provoked or induced
by PCB's. PCB's show an immunosuppressive effect. Calabrese and Sorenson
give special attention to human high-risk groups and point out that chil-
dren and embryos and fetuses tend to lack the liver microsomal enzymes,
including oxidases, hydroxylases, and conjugases, that in older persons
would be mobilized to detoxify absorbed PCBs, and are thus particularly
susceptible to damage. Similarly, individuals with liver infections may
be at risk above the general population with respect to substances such
as PCBs.
6.2.3 Analysis
Analysis of PCBs has been by gas chromatography, with electron cap-
ture or microcoulometric detector (Yobs, 1972). Zobel (1975) achieved
separation of PCBs from DDE and DDT isomers by silica-gel chromatography;
the gas chromatograph was used for quantitation of the compounds in the
separated fractions. On direct gas chromatography (e.g., extracts of
human fat samples, Zobel, 1975), the very complexity of the pattern of
peaks is indicative of PCBs. Mes and Campbell (1976) have discussed
problems of sample treatment, and Biros and Walker (1970) have confirmed
the identity of peaks separated by gas chromatography by mass spectro-
metry. A basic dehydrochlorination may be part of the treatment of PCB-
containing samples to remove other chlorinated compounds, since PCBs
resist this treatment. Patterns of analysis of samples of PCBs are given
by Nisbet (1976), including samples from soils, water, commercial samples,
tissues, etc.
6.3 POLYCHLORINATED TERPHENYLS
Polychlorinated terphenyls, as well as being a contaminant in PCBs
were at one time made as such in the U.S. for use in metal casting and
some other uses. This production has been discontinued. PCTs have been
found in human tissue (Anon., 19782?; Doguchi, Fukano, and Ushio, 1974),
following accumulation through food chains or other routes. Concentra-
tions in human adipose tissue are in the range 0.1 to 2.1 ppm (Doguchi,
Fukano, and Ushio, 1974).
6.4 POLYBROMINATED BIPHENYLS
A serious poisoning incident occurred in Michigan in 1973—74. Be-
tween 1 and 2 tons of a PBB mixture for flame protection — "Firemaster" —
was mixed with an animal feed supplement, "Nutrimaster." Effects were
seen first in cows and then in humans. The consequences of this inci-
dent have been reviewed by Humphrey and Hayner (1975), Meester and McCoy
(1976), Kay (1977), and others. PBBs have a number of uses, similar to
those of PCBs; the most common use is as a flame retardant. Wallen (1977),
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reporting on the PBB situation in New Jersey, states that production of
PBBs between 1970 and 1976 was over 13 million lb. PBBs are very per-
sistent, bioaccumulate, and may be five to ten times as toxic as PCBs
(Wallen, 1977). In the New Jersey investigation, PBB residues were found
in human hair, in fish and shellfish, plants, soil and water, and in vicin-
ities of production and use of PBBs (for instance, near a plant using PBBs
in manufacture of wire coating). Levels were as high as 4200 ppb in soil,
430,000 ppb in sediment near an outfall, 37,000 ppb in reeds, and 240 ppb
in fish. Levels were in the low ppm range in hair, blood, milk, and adi-
pose tissue samples from affected persons in Michigan.
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SECTION 7
MISCELLANEOUS COMPOUNDS
Included in these compounds are food additives, drugs, antibiotics,
plasticizers, volatile organics, and miscellaneous substances. Data on
occurrence and levels of some of these appears in the phase I document.
A great number of substances to which people are exposed are absorbed
by them and stay at least a time in their bodies. Our capability to avoid
exposure to nonnatural substances decreases as more and more of them are
presented to us. A listing of all substances, exposure to which results in
a measurable body level, if not a lasting body burden, is beyond the scope
of this report. The following list, however, will increase awareness of
the number and types of substances to which humans are exposed:
Hewitt, 1975. "Clinical implication of the presence of drug residues in
food" (Emphasis on antibiotics).
Kolata, 1978. "Behavioral teratology: Birth defects of the mind."
Oehme, 1973. "Significance of chemical residues in U.S. food-producing
animals" (Antibiotics, therapeutic agents, heavy metals, pesticides).
Blum et al., 1978. "Children absorb Tris-BP flame retardant from sleep-
wear: Urine contains the mutagenic metabolite 2,3-dibromopropanol."
Jaeger and Rubin, 1973. "Extraction, localization, and metabolism of
di-2-ethylhexyl phthalate from PVC plastic medical devices."
Ayres et al., 1973. "Health effects of exposures to high concentrations
of automotive emissions" (Mainly carbon monoxide, but also consideration
of nitrogen oxides, hydrocarbons, and oxidants).
Freeman et al., 1978. "Identification of nitric oxide (NO) in blood."
Dowty, Laseter, and Storer, 1976. "The transplacental migration and accu-
mulation in blood of volatile organic constituents."
Knowles, 1974. "Breast milk: A source of more than nutrition for the
neonate" (Pesticides, metals, drugs, anticoagulants).
Laseter and Dowty, 1977. "Association of biorefractories in drinking
water and body burden in people" (Thirty-four volatile organic
compounds of below 250 molecular weight).
Fry and Taves, 1974. "Maternal and fetal fluorometabolite concentrations
after exposure to methoxyflurane" (Widely used fluorinated obstetrical
analgesic and anesthetic).
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And there are numerous others. Data on physical and chemical properties,
sources, air and water pollution factors, and biological effects on micro-
organisms, plants, animals, and man for more than 1000 organic compounds
may be found in the "Handbook of Environmental Data on Organic Chemicals,"
by Verschueren (1977) .
The Council on Environmental Quality in 1971 (Finklea et al., 1972)
presented candidates for concern as "hidden pollutants." These included
metals, chlorinated naphthalenes, chlorinated aliphatics, brominated bi-
phenyls (a crisis has already occurred; see Sect. 6.4), one or more of
the several hundred fuel additives, optical brighteners, and unknown
intermediates in the manufacture or disposal of synthetic organic chemicals.
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SECTION 8
ASBESTOS
8.1 INTRODUCTION
The general term asbestos refers to a group of fibrous, serpentine
(chrysotile), and amphibole (actinolite, amosite, anthophyllite, crocido-
lite, and tremolite) minerals with the properties of high tensile strength,
poor heat conductance, and general resistance to chemical attack (Cralley
et al., 1968). The amphiboles tend to be straight and splintery, while
chrysotile is a more flexible, curved, and hollow fiber. Asbestos minerals
occur commonly in soils and rocks, with the chrysotile form constituting
over 90% of the total geologic asbestos (Shride, 1973). This predominance
is further reflected in asbestos production, with 95% of that amount being
the chrysotile form (Hueper, 1965). The use of asbestos by man has largely
been a twentieth century phenomenon, with usage increasing over a thousand-
fold in sixty years (Gilson, 1965). The majority of this is in construc-
tion-related fields, where the asbestos is incorporated into cement,
plastic products, siding shingles, roofing material, insulation, and other
products (Hueper, 1965). However, it occurs in other nonconst;ruction prod-
ucts such as textiles and automobile parts, with over 3000 various uses
(Rosato, 1959). The versatility of asbestos has prompted a meteoric rise
in its production, with an increase from 500 tons worldwide in 1880 to
4,000,000 tons in 1967 (Selikoff et al., 1967). The majority of asbestos
is mined in Canada and the U.S.S.R., but there are significant deposits in
over twenty countries, including the United States. Thus, recently, asbes-
tos has become a significant environmental pollutant on a worldwide basis.
8.2 SOURCES AND LEVELS OF ASBESTOS IN THE ENVIRONMENT
Routes of entry of asbestos into the environment fall into two broad
categories — natural and human based. For both categories the routes of
dispersal and transport are the same, namely, by air and by water. The
sources vary, however. Natural sources are limited to rock outcrops con-
taining asbestoid materials. These can contribute to environment levels
by abrasion and weathering of exposed surfaces by air (Selikoff, Nicholson,
and Langer, 1972) or by water (Stewart et al., 1976). Entry from these
means tends to be minimal, especially when compared with human-promoted
entry. Stewart et al. (1976) found many areas with no appreciable back-
ground levels of waterborne asbestos fibers. However, in areas where natu-
rally exposed asbestos-containing rocks were common, the background levels
were as high as 48 fibers per liter at high flows. Although no figures
were found in the literature for natural airborne levels, the magnitude is
inferred as "infinitesimal" when compared with human-promoted input
(Selikoff, Nicholson, and Langer, 1972).
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44
In the U.S., mining and milling operations account for the majority
(85%) of human-promoted emissions of asbestos, while reprocessing (10%)
and consumptive uses (5%) contribute only slightly to the total (Davis and
Associates, 1970). In 1968, this amounted to 5088 metric tons for mining
and milling emissions out of a total of 5967 metric tons emitted. However,
since most mining and milling operations are located in rural areas with
sparse population densities, the impact on humans is not proportionally as
high as the emission rates would indicate. Environmental levels for air-
borne asbestos fibers range from 0.1 to 95 ng/m3 for urban areas (U.S.
Environmental Protection Agency, 1974), and from 11 to 8300 ng/m3 for
point sources (Heffelfinger, Melton, and Kiefer, 1972). Waterborne fiber
concentrations also show a wide numerical variation, with values for final
industrial effluents of from <106 to 1012 fibers per liter, and for fin-
ished processed urban water in areas of industrial or natural occurrence
of asbestos of from 0.13 x 106 to 160 x 106 fibers per liter (Stewart et
al., 1976). These figures illustrate the degree to which asbestos has
permeated the environment. Once in the environment, asbestos fibers are
very resistant to alteration or degradation. The fibers are rarely incor-
porated into the biotic sphere, since floral uptake is minimal and faunal
intake is by accidental inhalation or ingestion. Also, no metabolic re-
quirement for asbestos is known in either kingdom. In short, in an envi-
ronmental sense, asbestos is not recycled, it is merely distributed.
8.3 ENTRY, STORAGE, AND EFFECTS IN HUMANS
The entry, storage, and effects of asbestos in humans is well docu-
mented for the primary exposure route, inhalation. Exposure by inhalation
is not limited to occupational situations due to the wide distribution of
asbestos particles and varied usages of asbestos-containing materials. The
size and shape of the particles delimit the extent of fiber distribution in
the tracheal system, with long fibers concentrated in respiratory bronchi-
oles and alveolar ducts, while shorter fibers penetrate into the air sacs
(Timbrell, Pooley, and Wagner, 1970). The majority of the inhaled fibers
remain lodged in the interstitial areas of the lungs, with approximately 1%
of these becoming coated with the ferruginous gel (Gaensler and Addington,
1969). Tissue concentrations of mineral fibers per gram of dry lung aver-
aged 6.5 x 103 and 45.2 x 103 in surveys of nonoccupationally exposed per-
sons in two cities (Gross et al. , 19742?).
There are several primary effects found as a result of asbestos ex-
posure, including asbestosis, pleural plaques, and several types of cancers.
Asbestosis is a chronic pulmonary disease characterized by interstitial
fibrosis and pleural lesions (Scott and Hodge, 1971). Prolonged exposure
results in extreme distortion of lung tissue, making recognition of alveoli
difficult and producing distortion in the bronchioles (Hinson et al., 1973).
Asbestosis is usually a restrictive rather than an obstructive respiratory
impairment. Pleural plaques are layers of hyalinized fibrin formed by slow
proliferation of fibroblasts and fibrocytes in the collagenous connective
tissue (Ulrich, 1971). The site of damage is thought to be largely related
to mechanical factors such as expansion and abrasion (Roberts, 1971). The
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45
formation of cancerous lesions has been associated with asbestos exposure,
but was masked until recently by the severity and lethality of the above
effects. Lung cancers are found in about 25% of the exposures studied
(Selikoff, Churg, and Hammond, 1965), with the majority being bronchial
carcinomas (Selikoff, Churg, and Hammond, 1964; Selikoff, 1974; Roe, 1968).
Mesotheliomas, rare primary tumors of serosa tissue, are found on the
pleura and peritoneum as a result of asbestos exposure (Thomson, 1970).
The formation of these tumors has been associated with the size of the
fibers, with a greater carcinogenic risk when the fibers are <0.5 ym or
>10 ym in length (International Agency for Research on Cancer, 1973). The
most striking feature about exposure to asbestos is the delay time of 20 to
30 years from initial exposure to disease-symptom manifestation (Selikoff,
Nicholson, and Langer, 1972).
Although inhalation is the primary entry route into human tissues, it
is not the only route. Ingestion and dermal contact with fibers are alter-
nate routes. Dermal contact is limited to subcutaneous piercing by the
fibers, with subsequent development of nontoxic warts. The role and ef-
fects of ingestion are more uncertain. Some researchers using animal spe-
cies have concluded that no uptake or penetration of fibers into the gut
epithelium occurs (Webster, 1974; Gross, Hanley, Swinburne, Davis, and
Greene, 1974; Davis, Bolton, and Garrett, 1974), while others (Pontefract,
1974; Cunningham and Pontefract, 1973) have reported the absorption of
fibers from the gut and subsequent transport in the blood and lymph sys-
tems. These differing results may be due to the use of different test
species and sizes of asbestos fibers. There is some epidemiological evi-
dence relating asbestos ingestion with a higher incidence of gastrointes-
tinal cancer (Merliss, 1971; Lumley, 1976; Selikoff, 1974), but few
decisive experimental animal studies.
8.4 IMPACT OF ASBESTOS ON THE PUBLIC
The general impact of asbestos on the public is well documented. Epi-
demiological and demographic studies have been done for many areas of the
United States, Europe, and Africa. In the U.S. the urban environment re-
sults in higher levels of asbestos in the lungs (Rosen, Melamed, and Savino,
1972), but even among the cities there is variation. In comparisons, resi-
dents of the smaller cities or of more rural areas have significantly
lower levels of asbestos in their lungs — for example, Duluth less than
New York (Auerbach et al., 1977), Charleston less than Pittsburgh (Gross,
Harley, Davis, and Cralley, 1974), and a series of towns in England, each
progressively less urban and having lower environmental asbestos concentra-
tions than London (Oldham, 1973). It has also been demonstrated that
asbestos-body frequency increases with age (Cauna, Totten, and Gross, 1965;
Gordon and Rosen, 1976). The major factor is occupational exposure, which
extends even to contact within families having only one asbestos worker.
However, due to the wide use and long latency period, specific analysis of
sources and exposure levels is a complex task and will require further
study for more definitive statements. A pilot study along these lines is
that of Selikoff and Hammond (1968). In this study, asbestos was taken as
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a model for particulates and penumoconiotic dusts in general, and community
effects of nonoccupational environmental exposure to asbestos were noted.
8.5 ANALYSIS
The analysis for asbestos in tissues is primarily a microscopic inves-
tigation. The tissues (primarily lung) are prepared by either sectioning
or chemical digestion (Rosen, Melamed, and Savino, 1972; Gordon and Rosen,
1976). The asbestos fibers or ferruginous bodies (fiber cores with iron-
rich gel coating) are identifiable by either light, X-ray, or electron
microscopic analysis (Langer et al., 1970; Gross et al. , 1972). Some dis-
cussion has emerged on the variability of the fiber core in ferruginous
bodies (Langer, Selikoff, and Sastre, 1971; Gross, Cralley, and deTreville,
1967; Gross, deTreville, and Haller, 1969), with conflicting evidence in-
dicating that a majority of fibers can be either asbestos or nonasbestos.
This uncertainty complicates the interpretation of cause-effect relation-
ships in epidemiological studies. A bias inherent in the analysis tech-
nique is the use of light microscopy to select ferruginous bodies for
electron microscope analysis. This preselecting method tends to overlook
the smaller (<5 ym) bodies which are mainly asbestoid in nature due to the
greater fragmentation rate of asbestos fibers as compared with fibers of
other materials. The number of reported nonasbestos ferruginous cores
(Langer et al., 1970, Langer, Selikoff, and Sastre, 1971) is thereby in-
creased. In any case, the analysis is limited to microscopic techniques
due to the lack of chemical degradation or metabolic by-products in the
organism.
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SECTION 9
THE HALOGENS: FLUORINE, CHLORINE, BROMINE, IODINE, AND ASTATINE
9.1 FLUORINE
9.1.1 Fluorine as Essential Element. Levels of Response to Fluorine
(as Fluoride)
Fluorine is an essential element, albeit at a very low level of con-
centration. It is essential in the ppb range for nucleation of deposition
of bone crystal (Newesley, 1961; Perdok, 1962; Brown, 1966) and at a some-
what higher level for maintenance of fertility and growth in animals
(Messer, Armstrong, and Singer, 1974). It is a beneficial element at a
middle level (the level of fluoride in the ocean is about 1 ppm, and this
is the level that is optimal in drinking water for tooth and bone health —
the levels in groundwaters and river waters are generally lower than this),
and it is harmful at higher levels. Fluoride thus typifies the classic
three levels of biological response to an element: a low-concentration
plateau of essentiality, rising to another plateau of beneficial or phar-
macological action, rising to a third plateau of overt deleterious effects.
9.1.2 Absorption and Excretion. Fluoride in Bone and Other Body
Compartments
Absorption and excretion of fluoride are relatively passive. At opti-
mum fluoride intake, a steady-state concentration is set up in the various
body compartments. At higher intakes, there is a slow increase in bone
fluoride concentration, with possible hypercalcification, development of
bony spurs, and the like. Fluoride in the bone does not cause fluorosis;
damage comes when fluoride is present in excess in the blood and interferes
with the metabolism of osteocytes and osteoblasts (Hodge and Smith, 1968).
The effect is seen in the teeth as mottling, when fluoride is present in
excess during the period of tooth calcification. For bone the effect may
occur at any time, resulting in hypomineralization at one place and hyper-
mineralization at another. Calcification zones may occur in other organs
also, for instance, the aorta. A proper level of fluoride intake may
actually reduce unwanted organ calcification (Bernstein et al., 1966).
The fetus uses fluoride and draws on the mother for it; in cases of excess
fluoride the placenta may play a regulating role (Dean, 1936; Gedalia et
al., 1964). Fluoride does not easily get into the brain (Armstrong et al.,
1970), and some other compartments of the body are relatively protected or
at least show slow dynamics with respect to changes in concentration of
fluoride (Gedalia and Zipkin, 1973).
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9.1.3 Fluoride in the Environment. Sources and Uses. Balance of Effects
Fluoride is widespread in the environment, having been introduced into
the earth's crust along with phosphate rock by volcanic action in geologic
time. Industrial introduction of fluoride may come by processing of phos-
phate deposits for fertilizer, also by use of fluorinated compounds. Fluo-
rination of organics is a major use of fluorine, and fluorinated compounds,
hydrogen fluoride, other fluorides, and fluorine itself may be released.
Fluorine and fluorine compounds are used in obtention of aluminum, in the
manufacture of steel, brick, tile, and glass, in the manufacture of pesti-
cides, and in a number of other applications. Dusts and fumes are sources
for some fluorine or fluoride intake, although water is the primary source,
with foods contributing a smaller amount. The controversy over fluoride in
drinking water reduces to the fact that fluoride should be added to drink-
ing water where it is lacking and taken out where it is in excess (Conway,
1959). The damage of exposure to high fluoride is increased bone deposi-
tion, with the sequelae mentioned above. Fluoride at high doses affects
various metabolic processes, and there is some evidence that high fluoride
may be fetotoxic, but fluoride as it is present generally is not found to
have deleterious metabolic effects nor to be teratogenic, mutagenic, nor
to promote or cause cancer. Fluoride is an irritant poison, but claims of
skin rash, metabolic disturbances, illnesses, etc., due to fluoride at
environmentally encountered levels have not been substantiated (Rubini,
1969; Bronner, 1969).
9.1.4 Consumption of Fluorine. Exposure Limits
In industrial situations, fluoride is generally absorbed through in-
halation. The TLV (threshold limit value) for fluoride as F, in air, is
2.5 mg/m3; for fluorine gas it is 0.2 mg/m3 (ACGIH, 1971). Consumption of
fluorine is increasing, and projected demand for the year 2000 is 1.9 to
2.5 million metric tons (MacMillan, 1970). There is a natural fluoride
cycle, and fluoride released by the use of this amount of the substance
will mainly return to and be diluted by the environment, without particular
deleterious effect. This does not mean that emission of fluorine-contain-
ing substances should not be controlled, since localized excessive concen-
trations may have adverse effects.
9.1.5 Analysis
Fluorine has probably been analyzed for by more methods than any
other element mentioned in this report. Early analysis was by chemical
treatment of fluorine-containing material and diffusion or steam distil-
lation followed by titrimetry (Smith and Gardner, 1955) or reading of the
light absorption of a colored complex of fluorine (Samachson, Slovik, and
Sobel, 1957; Venkateswarlu and Sita, 1971). Linde (1959) analyzed for
fluoride with a sensitivity of 0.1 yg/ml body fluid by potentiometric
titration of fluoride following enzymic treatment of biological samples.
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49
Fluorescence quenching of a morin-thorium indicator following diffusion
of fluoride from acidified samples was used by Taves (1966). The specific-
ion electrode (Singer and Armstrong, 1969; Shen and Taves, 1974; Hall et
al., 1972) has been very convenient for measuring ionic fluoride in a
variety of samples. Other methods which have been used, reflecting partly
the analytical needs and partly the kinds of samples being handled, have
been gas chromatography (Ruessel, 1970), nuclear magnetic resonance spec-
trometry (Guy, Taves, and Brey, 1975), spark-source mass spectrometry
(Curzon and Losee, 1977), neutron activation analysis (Gills et al., 1974),
and atomic absorption (Brudevold et al., 1975).
9.2 CHLORINE
Chlorine is an essential element in the form of NaCl in the blood,
HC1 in gastric juice, chloride ion in transmission of nerve impulses, etc.
Elemental chlorine (C12) has been used as an irritating, choking war gas.
The TLV for chlorine used industrially is 1 ppm (about 3 mg/m3) in ambient
air. Emission of chlorine may result from use of chlorine bleach and
chlorine in industrial processes. Addition of chlorine to water to oxi-
dize pathogenic bacteria and other objectionable substances has been
practiced for about 70 years, apparently without harm to humans. Lately a
hazard has arisen from the production of organochlorine substances by
action of chlorine on organics in the water. The solution would seem to
be to restrict the entry of the organics into the water — it would be dif-
ficult to match the economy and effectiveness of chlorine for rendering
water pathogen free and for eliminating off-odors and tastes. Use of
activated carbon on a large scale has been suggested as a way of removing
organics before chlorination (Morris, in Jolley et al., 1978). This, and
methods of disinfection other than chlorination, and studies on the envi-
ronmental impact and health effects of water chlorination are considered
in the symposium volumes edited by Jolley (1978) and by Jolley, Gorchev,
and Hamilton (1978).
Methods for analysis of chlorine and chlorine-containing compounds
(chlorides, chloramines, chlorine dioxide, etc.) in water and wastewater
are given in the handbook "Standard Methods for the Examination of Water
and Wastewater" (American Public Health Association, 1975) and include
argentometry and other titrations, amperometry, potentiometry, and a vari-
ety of colorimetric methods.
9.3 BROMINE
(Greek: bromos, stench). At room temperature bromine is a liquid,
volatilizing to a heavy vapor with a disagreeable odor and a strong irri-
tating effect. It is employed chiefly for preparation of bromine-contain-
ing compounds, such as medicinal bromides, bromides as intermediates in
chemical synthesis, organobromines in gasoline for antiknock effect and
lead scavenging, in fire-retardant and fumigation formulations, etc. The
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50
TLV for gaseous bromine is 0.1 ppm (about 0.7 mg/m3). Aside from indus-
trial exposure, entry into man is chiefly in food, bromine being always
present with chlorine (Bloch, Kaplan, and Schnerb, 1959). Bromide has
been determined by colorimetry (Goodwin, 1971; Cabanis and Bonnemaire,
1970), by X-ray spectrometry (Gofman et al., 1964; Natelson, Sheid, and
Leighton, 1962; Beyerman, 1961), by potentiometry (Bartels, Ritter, and
Auer, 1969), by mass spectrometry (Losee, Cutress, and Brown, 1973), and
by neutron activation (Sklavenitis and Comar, 1967; Obrusnik et al., 1972).
The biological half-life of bromide in the human is 10 to 12 days
(Sklavenitis and Comar, 1967). Bromide is eliminated almost entirely in
the urine. It is retained slightly by the kidney in preference to chloride
(Bloch, Kaplan, and Schnerb, 1959). Bromine is found in all tissues and
fluids, some of it in organic combination. Bromine does not seem to be a
cause for concern, whether from effects or from any buildup in concentra-
tion. Underwood (1971, pp. 434-436) mentions, however, that human dietary
intakes have increased in recent years in areas where organic bromides are
used as fumigants for soils and stored grains and in motor fuels.
9.4 IODINE
Iodine, as part of the hormones triiodothyronine and tetraiodothyro-
nine (thyroxine) and in similar compounds, is essential for growth in all
animals (Underwood, 1971, pp. 281-322). Iodine at very high concentration
can be toxic, but the margin of safety for this element is wide. Iodine
is present in all body tissues and fluids, but is particularly concentrated
in the thyroid gland. The next sink in order of importance is the skeleton.
The chief source of iodine is food, where it occurs as iodide. Iodine is
mainly excreted in the urine, with small amounts in feces and sweat. Iod-
ine has been determined by neutron activation (Bowen, 1959; Heurtebise and
Ross, 1971), by X-ray spectrometry (Gofman et al., 1964), by flame spectro-
metry (Gutsche and Herrmann, 1971), chemically (Krylova, 1967), colorimet-
rically (Mantel, 1971), and by mass spectrometry (Losee, Cutress, and
Brown, 1973).
9.5 ASTATINE
The final halogen, astatine, is so rare as to be a chemical (radio-
logical) curiosity. It has no stable isotopes. It was synthesized in
1940 by Corson et al. (Weast, 1976) by bombarding bismuth with alpha parti-
cles. The longest-lived isotope, 210At, has a half-life of only 8.3 hr.
Astatine-219, half-life 0.9 min, is reported to be present in uranium ores.
Like iodine, astatine concentrates in the thyroid gland.
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SECTION 10
LEAD
10.1 INTRODUCTION
10.1.1 Historical. Past and Present Sources of Exposure to Lead.
Levels of Use
Lead has been known and used since ancient times, having been smelted
along with silver since about 2500 B.C. (Christian, 1969). The Roman civ-
ilization was a great user of lead — the per capita consumption of lead
in Roman Italy was 0.004 tons per year; in urban U.S. now it is 0.006 tons
per year. Exposure to lead in Rome was chiefly through water, wine, and
food, from the use of lead in water pipes, in solder, and in cooking uten-
sils, whereas in America today the sources are more manifold. A chief
source is particulates in the air from dusts and from fuel additive combus-
tion, from lead-containing paints and colorings, and from other dissipative
uses of lead. Leaching of lead from soft glazes on pottery was at one time
a source of lead in foods; this is less common now. A diminishing source
of lead is from residues of spraying with lead-containing pesticides, such
as lead arsenate, these pesticides having been largely replaced with organic
ones. One source of concentration of lead is sewage sludge. While this re-
moves lead from the effluent, it may reintroduce lead into the environment
when the sludge is applied in agriculture. Waldron (1975) estimated usage
of lead in the world at 4 million tons per year, increasing at that time
by about 3.5% per year. U.S. production from domestic ores in 1974 is
given as 602,000 metric tons, with U.S. consumption of primary and second-
ary lead combined being 1.45 million metric tons (Bureau of Mines, 1975).
Ryan (1973) and the Bureau of Mines (1975) give lead consumption in the
U.S. by product. Listed are metal products, pigments, chemicals, and mis-
cellaneous. The sum for 1974 was 1,599,427 tons. Some product uses are
more apt than others to put lead into the environment. Thus, while storage
batteries are the largest use of lead (772,000 metric tons in 1974), about
half of this represents lead reclaimed from old batteries. In contrast,
all of the lead in tetraethyl lead is released to the environment, and
this is also true for lead-containing paints and other dissipative uses.
10.1.2 Point Sources. High Lead Areas
Some point sources of lead are of particular concern. Thus, Baker et
al. (1977) did a nationwide survey of heavy-metal absorption in children
living near primary copper, lead, and zinc smelters. Dusts from crushing
operations and particulate fallout from the smelting operations were
sources of the pollution. Other studies are by Yankel, von Lindern, and
Walter (1977); Landrigan et al. (1976); Levine et al. (1976) (lead scrap
smelter); and Roberts, Gizyn, and Hutchinson (1974). The effect of a
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52
smelter on agricultural conditions in the surrounding environment has been
studied by Lagerwerff and Brower (1974). Lead dietary intake was 50% above
normal, and lead levels were high in home produce, milk, and the blood of
animals and humans. A recent National Science Foundation publication
(Wixson, 1977) discusses a project for control of environmental pollution
by lead and other heavy metals from industrial development in the new "lead
belt" of southeastern Missouri. The project aims at developing cooperative
efforts between industry, agencies, and universities to control environ-
mental pollution, and all aspects of the question are addressed in the re-
port. Various aspects of lead in automobile fuels have been treated in
another NSF report (Boggess and Wixson, 1977).
10.2 LEAD IN MAN
10.2.1 Absorption, Excretion, and Metabolism
Most lead comes from the diet. Much of the lead ingested, however,
is excreted in the feces. Exposure to lead varies; it has been calculated,
however, that the average daily intake of lead by an adult is 300 yg from
food and beverages (Barry and Mossman, 1970), and of this about 10% is ab-
sorbed (Kehoe, 1961a). Barltrop and Khoo (1975) have studied the influence
of various nutritional factors on lead absorption in rats. Absorption was
increased by high fat, low mineral, and low and high protein. Low fat, low
fiber, high fiber, and low and high vitamin diets had no effects. Note,
however, that Sorrell, Rosen, and Roginsky (1977) found a deficiency of
vitamin D to be associated with high lead levels in blood of lead-burdened
children. Lead inhibits absorption of calcium; conversely, calcium is
protective to some extent against lead. Rabinowitz, Wetherill, and Kopple
(1975) studied the absorption, storage, and excretion of lead in human
volunteers maintained in a hospital metabolic unit for up to six months.
The subjects were fed constant low-lead diets, supplemented with nonradio-
active lead isotope tracers. The concentration of tracer and total lead
in diet, feces, urine, blood, hair, nails, sweat, bile, gastric and pan-
creatic secretions, and bone were measured by mass spectrometry. By trans-
ferring these subjects to a room with filtered air (the air having been at
about 2 yg/m3) and observing the rate at which their blood level fell, it
was determined that about 15 yg of lead per day was inspired, about half
as much as originated in the diet. This confirms the danger of lead from
airborne particulates. Golz (1973) has criticized the emphasis by the EPA
on the health effects of airborne lead; however, there would seem to be no
doubt of the importance of this source of intake. Much lead in the envi-
ronment has arisen by airborne contamination. This is indicated by the
presence of lead in the snow and ice layers of Greenland. In a figure
given by Hall (1972), the lead content of Greenland snow layers, at about
0.001 yg/kg in 800 B.C., is seen to rise slowly to about three times that
level by the start of the Industrial Revolution, then to go over 200 years
to 0.08 yg/kg, and then to rise dramatically from 1930 on, following the
introduction in the 1920s of lead alkyIs as gasoline additives.
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53
10.2.2 Body Distribution
Confirming studies by other authors, Rabinowitz, Wetherill, and Kopple
(1975) showed bone as the chief sink of lead. Entry into bone is slow and
turnover is also slow. Lead from bone may or may not be mobilized under
stress, disease, etc., depending on a number of factors. Because of the
mass of the skeleton, any mobilization is dangerous (Hall, 1972). At mod-
erate levels of exposure, lead does not accumulate greatly (Kehoe, 196l£>,
1964), but at levels that are now met in America, there is significant
accumulation (Herman, 1966; Schroeder and Tipton, 1968; Wessel and Dominski,
1977). Lead in bone crystal is relatively passive; the critical organ in
bone is the marrow because of the effect of lead on heme synthesis (Albert
et al., 1973).
Blood is the next compartment, followed by soft tissue. At least 90%
of the lead in blood is bound to the erythrocytes (Hernberg, 1972, in
Albert et al., 1973); the plasma lead is probably the more biologically
active (Rosen, Zarate-Salvador, and Trinidad, 1974). In any case, blood
lead is a fairly good indicator of lead exposure; urine is less so because
of fluctuation in renal handling due to metabolic factors (Albert et al.,
1973). Hair and teeth are good indicators of chronic exposure. According
to Kopito, Byers, and Shwachman (1967), hair concentrates more lead per
unit weight than any other tissue or body fluid, including bone, blood,
and urine.
In the study of Rabinowitz, Wetherill, and Kopple (1975), at a level
of intake of lead of 16 ± 4 yg/day in air and about 30 yg/day in the diet
(this is about 1/10 of what persons are generally exposed to), size of the
pool, turnover time, and flows in and out were as follows: bone, 200 mg,
104 days, 7 yg/day in and 7 yg/day out; blood, 1.9 ± 0.1 mg, 36 ± 5 days,
33 ± 5 yg/day going to urine, 15 yg/day going to soft tissue, and 2 yg/day
coming back; soft tissue, 0.6 mg, about 40 days, 12 yg/day to bile, hair,
sweat, nails, and pancreatic and gastric secretions.
10.2.3 Body Burdens of Lead. Effects of Lead at Low Levels
Lead deficiency has never been shown, and in fact, lead seems to be at
least potentially harmful at any concentration; more specifically, lead at
concentrations well below what have been considered "normal" or "safe" may
have subclinical effects, often of a nervous order (David et al., 1976;
de la Burd£ and Choate, 1972; Moore and Fleischman, 1975; Waldron, 1975).
The total body burden of lead in precivilization humans has been estimated
to have been about 2 mg (Patterson, 1965). Schroeder et al. (1961) have
estimated the body burden of "standard man" to be of the order of 80 mg,
and Browder, Joselow, and Louria (1973) cite figures of up to 200 mg in
persons living in particularly polluted communities. Blood lead levels of
up to 40 yg/ml have been considered "normal"; at blood levels of 80 to 100
yg/ml overt toxic symptoms appear. Waldron (1975) considers that the pro-
gressive increase in environmental lead levels has caused levels in man to
"approach closer to the threshold of clinical poisoning than any other
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54
environmental chemical pollutants." As stated by Christian (1969), intox-
ication by lead can be suspected when one or more of the following are
present: (1) history of pica, (2) X-ray evidence of radio-opaque material
in the GI tract, (3) X-ray evidence of lead lines at the metaphyseal ends
of the long bones, (4) elevated blood or urine level (one notes that the
blood level is a more trustworthy index than the urine level), (5) central
nervous system signs or symptoms, (6) vomiting or other gastrointestinal
disturbances, (7) positive test for coproporphyrin III in the urine, (8)
reducing substance in the urine, (9) anemia, and (10) basophilic stippling
of red blood cells.
The subclinical effects of exposure to lead are mainly neurological.
Thus, Seppalainen et al. (1975) have shown altered conduction time and
electromyographic abnormalities at "safe" levels of lead exposure. Be-
havioral disorders and impairment of hand-eye coordination were shown by
Moore and Fleischmann (1975). Altered peripheral nerve conduction velocity
in children (Feldman et al., 1973), association between low levels of- lead
and mental retardation (David et al., 1976), and an association between
lead and hyperactivity (David, 1974) have been described. Similar findings
have been reported by a number of authors (Cohen, Johnson, and Caparulo,
1976; Landrigan et al., 1975; Pueschel, 1974; and others). Lead may have
delayed effects (de la Burde and Choate, 1972). Lead is teratogenic
(Waldron, 1975). Human placental transfer of lead begins as early as the
12th week of gestation (Barltrop, 1968). The danger of this in terms of
embryotoxicity and possible later effects has been discussed by Carpenter
(1974) and by Fahim, and Hall (1976).
Other effects of lead at low levels, noted in animals but which pre-
sumably could also apply to humans (Waldron, 1975) are: (1) enhanced
susceptibility to infection through impairment by lead of phagocytic activ-
ity, sensitization to toxins, interference with mechanism of clearance of
particulates in the lungs, and impairment of formation of antibodies; (2)
impairment of reproductive activity; (3) teratogenic effects; and (4) in-
hibition of various enzymes.
10.2.4 Biochemical Indicators of Exposure to Lead. Screening for Exposure
Children are particularly at risk with respect to exposure to lead
because of intense metabolism occurring in their growing and formative
years. Lead exposure in these critical years may have sequelae later on.
Lead affects porphyrin metabolism, and testing of perturbations of this
can indicate exposure. Hammond (1969) has schematized the synthesis of
heme from glycine and has indicated the points at which lead interferes.
The rate-limiting step of the anemia of lead poisoning is probably at the
level of insertion of iron into protoporphyrin IX to make heme (Rimington,
cited in Hammond, 1969; the enzyme involved is ferrochelatase). As a
result of this, protoporphyrins and precursors pile up, notably free blood
protoporphyrin and urinary coproporphyrin and porphobilinogen (Gaultier et
al., 1960). It must be noted that hemes or porphyrins are used elsewhere
in the body besides in hemoglobin: in oxidative enzymes and the cytochrome
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electron carriers, in nerve tissues, and so on. Thus the effect of the
lead is multiple. One key enzyme in the porphyrin synthesis pathway is
delta-aminolevulinic acid dehydratase. Decrease in the activity of this
enzyme is the most sensitive index of lead exposure known, and in the case
of lead poisoning in infants, there is good correlation between inhibition
of ALA-dehydratase and the clinical status of the patient (Hammond, 1969).
Chisolm, Barrett, and Harrison, (1975); Hernberg et al. (1970); and Kuhnert,
Erhard, and Kuhnert (1977) (with particular reference to mother and fetus)
are some of the authors who have studied the effects of lead in heme syn-
thesis and the hematologic picture as an index to the degree of exposure.
Roels et al. (1976) studied the impact of air pollution by lead on the
heme biosynthetic pathway in school-age children and recommended that 25 yg
lead/100 ml blood be regarded as the maximum biologically allowable concen-
tration of lead in the blood of such children. Their dose-exposure curves
indicate a sensitivity to lead of children _>. women > men. This is reflec-
ted in the work place, where blood lead levels of 80 to 100 yg/100 ml may
occur in older male workers without great effect, whereas women and younger
workers show signs of disturbances at lower levels (Browder, Joselow, and
Louria, 1973). For instance, encephalopathy due to lead poisoning occurs
at lower blood lead levels in women than in men; however, this difference
is not seen in children (Browder, Joselow, and Louria, 1973).
Determination of perturbation of porphyrin metabolism is highly useful
in screening, but other indicators may also be used — blood lead levels,
urinary levels, and hair. Behavioral and neurological indications have
been mentioned. Barltrop and Killala (1967) examined the determination of
lead in feces as an index of the ingestion of lead compounds and compared
this with blood and urine measurements. Westerman et al. (1965) used the
needle biopsy technique for determination of lead in bone marrow. Deter-
mination of lead in parotid secretions may be useful for screening (Brow-
der, Joselow, and Louria, 1973); however, these levels tend to rise and
fall erratically (Fung et al., 1975)- Recently, Silbergeld and Chisolm
(1976) showed increases in homovanillic acid and vanillyl mandelic acid
in brain and urine of mice and in urine of children with increase of lead
absorption, and suggested measurement of these catecholamine metabolites
in the urine as a screening method.
10.3 ANALYSIS
The dithizone spectrophotometric technique using 5 or 10 ml of blood
has been the standard wet chemical method for analysis of lead (King,
Schaplowsky, and McCabe, 1972). In contrast, the free erythrocyte proto-
porphyrin test requires only 20 yl of blood (see, for instance, Piomelli
et al., 1973; Chisolm et al., 1974). Metals other than lead form colored
complexes with dithizone; all except thallium are eliminated in the pro-
cedure leading to the formation of the colored complex, and confusion with
thallium is possible (Berman, 1966). Atomic absorption, which is a much
used method, has been adapted to micro samples (Mitchell, Aldous, and Ryan,
1974; Posma et al., 1975), as has anodic stripping voltammetry (Anderson
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and Clark, 1974; Morrell and Giridhar, 1976). Proton-induced X-ray
emission (Walter et al., 1974), X-ray fluorescence (Vaasjoki and Rantanen,
1975), emission spectrography (Niedermeier, Griggs, and Webb, 1974; Yoakum,
Stewart, and Sterrett, 1975), and mass spectrometry (Barnes, Sappenfield,
and Shields, 1969) are other methods which have been used. Based on the
number of references, atomic absorption is apparently the most widely used
method of analysis. We note that the dithizone method has recently been
used as a screening method in the form of thin-layer chromatography of
dithizonates (Beneitez-Palomeque, 1970; Baudot et al. , 1976). More than
one metal contaminant may be analyzed at a time. Mushak (1977) has consid-
ered problems arising in the analysis of toxic heavy elements having vari-
able chemical forms, including arsenic, lead, and mercury. Sampling
problems in the micro methods for lead have been discussed by Juselius,
Lupovich, and Moriarty (1975), as well as procedures for avoiding such
problems, and Khera and Wibberley (1976) have indicated proper procedures
for ashing of tissue samples containing lead to avoid losses, with special
attention to lead in the placenta.
10.4 NRC RECOMMENDATIONS
The Committee on Toxicology, Assembly of Life Sciences, National
Research Council (Chisolm, 1976), has made several recommendations for
the prevention of lead poisoning in children, which is the area of great-
est concern. There are 9 recommendations; 6 of these deal with lead in
paint, the greatest single source of lead intake for children. Recommenda-
tion 2 recommends 30 yg lead/100 ml blood as the level of concern, and
recommendation 8 recommends more research in dose-exposure relationships
in the 1- to 5-year age group. Recommendation 9 is a general one. Gov-
ernment agencies are urged to "... coordinate their policies regarding the
limits for human exposure for industrial sources, consumer products, air,
food, and water so that an individual's total exposure from various sources
falls within a range which allows a margin of safety for those individuals
in the population who are affected by relatively low doses."
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SECTION 11
MERCURY
11.1 INTRODUCTION
Mercury is a dense, silvery, metallic element, occurring in liquid
form at normal temperatures. It is relatively insoluble, and due to its
high surface tension when dispersed breaks into many small droplets with
increased surface area/volume ratios. This last property is important,
since it increases the rate of vapor pressure equalization, resulting in
the faster formation of vapor, the most toxic state of mercury. In the
environment, mercury does not remain in its elemental form, but reacts or
combines with other elements or organics. All of the combinations of
mercury are in some way toxic, but the methylated (organic) and the chlo-
rinated (inorganic) forms are the most toxic. Due to mercury's unique
properties (for purposes of this document the term mercury will be used
to represent all forms and compounds unless stated otherwise), it has
found many uses in man's history. Major uses in industry include cata-
lytic roles (in the formation of alkali and chlorine), electrical appli-
cations, as a constituent in paints and plastics, in processing wood
pulp to paper, and in instrumentation controls (Gleason, Gosselin, and
Hodge, 1957). Its toxicity makes it useful for pesticides and fungicides,
especially when applied to grain (Frears, 1966), and it is used in some
medicinal and dental preparations (Wallace et al., 1971; Bethea, 1936).
11.2 SOURCES AND PRODUCTION
The sources and production of mercury are primarily foreign, with
only 4.7% of the ore of 0.005% mercury content located in the U.S. (U.S.
Geological Survey, 1968). Thus the environmental sources of mercury pol-
lution in the U.S. are primarily due to emissions from industry and manu-
factures, or dispersion in products. World production in 1975 was 9444
metric tons (Bauer, 1976), and U.S. consumption in that year was 1733
metric tons (U.S. Bureau of Mines, 1975).
11.3 ENTRY INTO THE ENVIRONMENT
Entry into the environment occurs primarily from waste or by-product
sources. Until the dangers of mercury were realized, many industries,
such as paper and chlorine-alkali producers, released inorganic mercury
in wastewater or allowed escape through vaporization. Although such
sources are controlled now, the downstream sites still act as reservoir
sources for mercury (Nelson et al., 1971). In contrast to entry from
industrial sources, product usage of mercury contributes little to the
environmental burden due to the slow release rates. One major source
not directly connected with any use of mercury is created by the burning
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of fossil fuels. Due to the high rate of fuel combustion in the U.S. it
is estimated that approximately 1 million Ib of mercury enter the environ-
ment (as vapor) every year (Nelson et al., 1971). As for total world
atmospheric mercury levels, the estimate is 50 million Ib (Krenkel, 1973).
The majority of this estimate is based on natural release from soils and
water through vaporization. Even with this large amount of atmospheric
mercury, the concentrations are relatively low, levels ranging from 0.6
ng/m3 (over open ocean) to 1200 ng/m3 (over mercury deposits) (adapted
from Fleischer, 1970). Urban areas tend to have higher air levels than
do rural ones, as Jenne (1970) showed for Chicago and the surrounding
countryside (4.8 vs 1.9 ng/m3).
The level of mercury in natural water systems is much lower, ranging
from less than 0.1 ppb to 17.0 ppb, with an average of 0.74 ppb (adapted
from Wershaw, 1970). This is partly due to the low solubility of mercury,
but primarily the low figures represent the conversion of inorganic mer-
cury to organic methylated forms and their subsequent incorporation Into
the food chain or evaporation into the atmosphere. The transformation is
accomplished by bacteria (such as Mefhanobactei>'ium ome'Lansk-Li-') which occur
in aerobic-anaerobic sediments, fish mucus and fish intestines, and pre-
vent permanent sedimentation removal (Bisogni and Lawrence, 1975; Eyl,
1971; Jensen and Jernelov, 1969; Jernelov, 1973; Wallace et al. , 1971).
Methylation is facilitated by the presence of raw sewage. Both methyl
and dimethyl compounds are created, with the volatile dimethyl entering
the atmosphere or decomposing to methyl mercury, which is largely incor-
porated into the food chain (Wood, Kennedy, and Rosen, 1968). This bio-
concentration is not necessarily stepwise through trophic concentration,
but is also based on metabolic rate and food habits (Hannerz, 1968). The
importance of this lies in the concentration of highly toxic methyl mer-
cury in fish and subsequent ingestion by humans. No evidence was found
for an essential metabolic role for mercury in any vertebrates or plants,
so that concentration, degradation, and toxic effects are the only inter-
actions mercury has with higher organisms.
11.4 ENTRY INTO MAN. TRANSPORT, DISTRIBUTION, AND EXCRETION
Mercury's route of entry into man depends on the chemical form en-
countered. Organic mercury enters readily by ingestion, dermal absorp-
tion, and inhalation, but human contact is most frequently by ingestion
(Albert et al., 1973; Nelson et al., 1971; Nordberg and Skerfving, 1972;
Yamaguchi et al., 1975). Inorganic mercury enters easily and most often
through inhalation (Nelson et al., 1971; Nordberg and Skerfving, 1972),
but can also be absorbed gastrointestinally, the rate of absorption in
the latter case depending on the compound. Dermal entry of inorganics
is often cited as a plausible route (Benning, 1958; Nordberg and Skerfv-
ing, 1972), but some investigators think that the rate is too slow to
produce toxic effects (Nelson et al., 1971).
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Once the mercury compounds have crossed epithelial barriers, trans-
port is accomplished via the circulatory system. As with other heavy
metals, mercury partitions between red blood cells, protein bodies, and
plasma, with the ratios varying depending on the compound. The erythro-
cyte/plasma ratio for inorganic mercury is 2.5 (Miettinen, 1972), for
elemental mercury is 1.0 (Lundgren, Swensson, and Ulfvarson, 1967), and
for organic mercury compounds it is 0.1 to 0.2 (Birke et al., 1972). The
binding preference of mercury compounds and, in particular, methyl com-
pounds for erythrocytes is believed to be due to the affinity for sulfhy-
dryl groups (Hughes, 1957; Goldwater, Ladd, and Jacobs, 1964; White and
Rothstein, 1973). This is supported by the greater levels of sulfhydryl
groups in hemoglobin (erythrocytes) as compared with plasma (Hughes, 1957;
White and Rothstein, 1973). The binding of mercury to hemoglobin is not
irreversible and will distribute based on chemical equilibria (White and
Rothstein, 1973). Mercury levels in blood and their importance have been
discussed in the literature, with some authors stating that there is a
definite linear relationship between methyl mercury intake and blood-
tissue levels (Skerfving, 1974), while others claim that methyl mercury
intake is not linear with levels in tissues (Kevorkian et al., 1973).
Perhaps the answer lies in the method of analysis (discussed later) or
in the metabolic conversion of methyl mercury to inorganic forms by human
tissues (Clarkson, 1972).
Absorption from blood to tissues is selective for inorganic mercury.
The highest concentrations are generally found in the liver, kidney, and
central nervous system (Bremner, 1974; Livingstone, 1971; Massaro, Yaffe,
and Thomas, 1974). Methyl mercury also shows this concentration pattern,
but tends to accumulate and remain to a greater degree in all tissues
(Takeda et al., 1968). Kosta et al. (1974) showed evidence that the
thyroid glands have the highest tissue levels of mercury, suggesting an
affinity for iodine as the cause. Excretory function explains the high
concentrations in the kidney and liver, but the concentration in the
central nervous system may be due to the high lipid solubility and the
short carbon chain of methyl mercury, which allow it to cross membranes
easily (Bremner, 1974; Ellis and Fang, 1967). In the brain, mercury con-
centrates in the cerebellum and in particular in the gray matter (Glomski,
Brody, and Pillay, 1971; Massaro, Yaffe, and Thomas, 1974), which may be
due to mercury's affinity for the perikarya of nerve cells instead of
their processes. In general, organic mercury remains longer in the sys-
tem than does inorganic (Izumi et al., 1974), and in the tissues longer
than in the plasma (Kurland et al., 1971).
Excretion of mercury is by the feces, urine, and bile. The major
role is attributed to feces (Kurland et al., 1971) except for methyl
mercury, where the bile is more important (Clarkson, 1971; Norseth and
Clarkson, 1970). Excretion through the bile does not always eliminate
the mercury, since some reabsorption occurs through the small intestine
(Albert et al., 1973; Norseth and Clarkson, 1970). It is generally
agreed that the amount in the urine is low and is not related to exposure
level, duration, or poisoning symptoms (Jacobs, Ladd, and Goldwater, 1964;
Kurland et al., 1971).
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11.5 EFFECTS ON THE FETUS
The impact of mercury on the fetus is well documented. The fetus
accumulates and concentrates mercury, in particular, methyl mercury, re-
sulting in higher levels than in the mother. The accumulation is demon-
strated by progressively higher mercury concentrations in the blood of
the placenta, cord, and fetus (Baglan et al., 1974; Creason, Svendsgaard,
Bumgarner, Pinkerton, and Hinners, 1976; Dennis and Fehr, 1975; Finklea
et al., 1971; Mitani et al., 1976; Shinkawa, 1974). The result of this
two- or threefold accumulation can be toxic effects evident in the fetus
(e.g., growth retardation, brain hyperplasia, and lesion development),
while no symptoms are shown by the mother (Koos and Longo, 1976). It has
also been shown that there is a correlation between higher mercury levels
in the fetus and suppression of the enzymes carnitine palmityltransferase,
steroid sulfatase, and isocitric dehydrogenase (Karp and Robertson, 1977).
The sensitivity of the fetus to mercury and its placental concentration
is of the same order as for other nonessential or toxic trace metals.
11.6 GENERAL EFFECTS
The toxic or symptomatic effects of mercury poisoning are mainly re-
lated to its effect on the CNS. In this regard, poisoning by methyl mer-
cury and the organic forms in general shows more effects and symptoms,
than do inorganic forms due to stronger affinity for the CNS. The symp-
toms from methyl mercury poisoning usually include paresthesias of the
extremities, mouth, lips, and tongue; unsteadiness of gait; loss of co-
ordination; fatigue; irritability and rapid emotional changes; reflex
changes; loss of hearing; concentric constriction of the visual field;
gastrointestinal disruptions such as cramps, diarrhea, and vomiting; and
in severe cases, paralysis or death (Benning, 1958; Eyl, 1971; Nelson et
al., 1971). Poisoning due to inorganic mercury results in the same type
of effects. Ingestion of inorganic mercury may cause additional effects
in the intestines, liver, and kidney such as proteinuria and intestinal
necrosis (Bremner, 1974). Other toxic effects attributed to mercury
poisoning include chromosome breakage (Skerfving, Hansson, and Lindsten,
1970), disruption of mitosis spindle fibers (D'ltri, 1972; Ramel, 1969),
and a possible association with amyotrophic lateral sclerosis (Currier
and Haerer, 1968).
As a toxic substance, mercury acts on cellular and subcellular
groups, especially on any entity with a sulfhydryl group. By tying up
these groups, mercury can block membrane transport or alter selective
permeability, thus leading to toxic consequences (Clarkson, 1972; Vallee
and Ulmer, 1972). In particular, CNS effects can be traced to a cere-
bellar cortical atrophy (involving the granular cell layer of the neo-
cerebellum) and to a cortical atrophy of the calcarine fissure-visual
cortical area of the occipital lobe (Hunter and Russell, 1954). If the
dosage is heavy, or chronic exposure extended, most of the cellular ef-
fects and symptoms are irreversible, and due to their delayed nature,
quite undetectable until extensive damage is done (Nelson et al., 1971).
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Thus, to control the toxic effects of mercury, prevention or limitation
of exposure is the only viable preventive or therapeutic measure.
11.7 DEMOGRAPHY
Demographic studies of mercury's effects indicate the complexity of
studies involving humans. Studies can be found in the literature that
give opposite results on several factors, despite worldwide coverage.
Most studies conclude that few absolutes can be identified due to the
difficulty of connecting the result with exposure to mercury. The best
documented and the most statistically significant trends associated with
mercury exposure are increased tissue levels with age (Eads and Lambdin,
1973; Livingstone, 1971), greater risk in urban environments (Chattopadhyay
and Jervis, 1974; Gowdy et al., 1977; Hecker et al., 1974), different levels
between sexes (Creason et al., 1975), and increased risk with high seafood
intake (Galster, 1976; Yamaguchi et al., 1975). Even these trends are dis-
puted by some authors, pointing again to the difficulties in analyzing for
mercury and interpreting results in spite of the large number of studies
in this area. Many epidemiological studies have been done, particularly
in response to mass poisoning by ingestion of contaminated foods. These
include studies of poisoned fish (Bakir et al., 1973; Harada, 1968; Iruka-
yama et al., 1965; Takeuchi, 1968, 1972), treated grains (Haq, 1963; Jalili
and Abbasi, 1961; Ordonez et al., 1966), and contaminated pork (Likosky et
al., 1970). All of these studies indicate how effective epidemiology has
been in the recognition of mercury as a human hazard.
11.8 ANALYSIS
The methods employed in the analysis of mercury are determined pri-
marily by the compound form. No one method has been found that can pos-
itively identify both organic and inorganic mercury. For this reason,
there are currently several accepted procedures for mercury identification.
For organic mercury the prevailing method is to use gas chromatography to
separate the compounds, combined with a detection method such as electron-
capture microwave emission spectrometry or mass spectrometry (Andelman,
1971; Baughman et al., 1973; Talmi, 1974; Webb et al., 1973). These methods
are all variations of the Westoo (1968) procedure. They are characterized
by a sensitivity of ±10%, applicability to biological and sludge material,
and the ability to identify both concentrations and species (Nelson et al.,
1971; Wallace et al., 1971), but are somewhat lengthy and expensive.
Cappon and Smith (1978) describe a procedural variation that modifies the
time and cost factors.
For inorganic and total mercury analysis, cold-vapor atomic absorption
and neutron activation are the recommended techniques (Giovanoli-Jakubczak
et al., 1974; Nelson et al., 1971; Wallace et al., 1971). Both are appli-
cable to all materials, accurate, and rapid, but neutron activation is
generally more precise (±2% vs ±20%) and more expensive (Jepsen, 1973;
Westermark, 1972). Atomic absorption can be set up so as to give total,
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inorganic, and organic (by subtraction) concentrations (Giovanoli-
Jakubczak et al., 1974; Magos and Clarkson, 1972). Other methods in-
frequently used for inorganic analyses are X-ray fluorescence (Anon.,
1969; Boiteau et al., 1971), spark-source mass spectrometry (Alvarez,
1974), atomic-fluorescence spectrometry (Subber, Fihn, and West, 1974),
and extraction by dithizone with colorimetric or spectrophotometric iden-
tification (Goldberg and Clarke, 1970; Gray, 1952). All of these methods
are used less often, either due to less precise results, more costly
equipment, limited applicability, or incomplete technology. However, with
adequate development, some have potential for wider use.
All methods of mercury analysis must overcome the similar problems of
background mercury contamination, loss by vaporization, and interference
by other substances. Studies have shown that mercury concentration deter-
minations vary widely among laboratories (Kaiser, 1973; Kevorkian et al.,
1972; Rottschafer, Jones, and Mark, 1971) due to these common errors.
Only careful work will eliminate these errors in results (Alvarez, 1974).
As with the understanding of the mercury problem as a whole, the analysis
techniques are improving rapidly due to research in the whole area of
mercury and its potential hazards for man.
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SECTION 12
ZINC AND CADMIUM
12.1 ZINC
12.1.1 Production and Use
Zinc is a soft metal that is an essential element with few toxic
effects. It is used in many industrial processes, most prominently in
galvanizing, die casting, and certain alloy combinations, with some agri-
cultural and medicinal usage. United States production of zinc has in-
creased from 556,247 metric tons in 1935 to 1,752,612 metric tons in 1973
(McMahon et al., 1974). This high rate of zinc use indicates how common
a metal it is in the earth's crust and in man's society. Henkin et al.
(National Research Council, 1978) give a continental crustal average of
70 ppm, ranking zinc twenty fourth in chemical element abundance and
fourth in industrial metal use. This document reviews zinc production,
use, environmental influence, analysis techniques, and toxicity.
12.1.2 Entry into the Environment
Zinc enters the environment primarily from mining, milling, and
smelting operations. Release is also promoted by processing of other
ores, especially copper and lead. Although some input is airborne, the
majority is funneled by waste streams, including urban sewage, into aqua-
tic systems. The levels vary from a low of 0.1 mg/1 for nonmining streams
to 21.0 mg/1 for streams in mined areas (Mink, Williams, and Wallace, 1970)
Urban sewage ranges from 0.01 to 61.7 ppm (Blakeslee, 1973). This is par-
ticularly important considering the sensitivity of fish populations to
zinc levels. Zinc also enters the biotic sphere through absorption and
uptake by plant species. As an essential element, it is retained and
utilized in both plants and animals, including man. Zinc is not concen-
trated in most organisms when in usable forms, so food-chain accumulation
is not a problem. Due to this lack of trophic concentration, human expo-
sure potential is essentially the same as for other animals. Their intake
levels are in turn controlled by exposure to contamination sources and the
inherent soil levels (Dorn and Phillips, 1973). Therefore, these factors
are the primary controllers of human interaction with zinc.
12.1.3 Zinc in Man. Absorption, Metabolism, Distribution, and Excretion
Zinc typically interacts with humans as an essential element. This
is basically because internal control mechanisms enable the body to main-
tain minimum zinc tissue levels if sufficient environmental levels.are
present (Liebscher and Smith, 1968). The primary route of entry for zinc
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into the body is through the gastrointestinal tract, but occasionally
entry occurs by dermal or tracheal means. Theoretically, active trans-
port across barriers is accomplished by a tetrahedral, quadridentate
ligand-organic molecule formed by a zinc-protein complex in the intes-
tinal tract (Matrone, 1974; Suso and Edwards, 1971a.,&) . Passive trans-
port has also been suggested (Saltman and Boroughs, 1960) , but there is
disagreement on this (Reinhold et al., 1973). Transport in the body
occurs via the blood; the level of zinc is three to ten times higher in
the red blood cells than in plasma (Herring et al., 1960). Zinc is dis-
tributed fairly uniformly throughout the body, with concentrations in
bone, muscle, kidney, liver, and glandular tissues (National Research
Council, 1978; Tipton and Cook, 1963). Excretion is primarily by fecal
means (87%), with dermal loss (11%) of some importance (Schraer and
Galloway, 1974; Tipton, Stewart, and Dickson, 1969).
The metabolic role of zinc is quite diverse. It functions in all
parts of the body due to its incorporation in many enzymes. Zinc has
been well established as a primary constituent in metalloenzymes, includ-
ing carboxypeptidase A and B (Folk, 1971; Hartsuck and Lipscomb, 1971),
thermolysin (Matthews et al., 1972), carbonic anhydrase (Lindskog et al.,
1971), leucine aminopeptidase (Himmelhoch, 1969), alkaline phosphatase
(Reid and Wilson, 1971), and alcohol dehydrogenase (Keleti, 1970). Zinc
also promotes activity by other mechanisms such as the promotion-feedback-
control functions of the hormones in the endocrine system (National Res-
earch Council, 1978). Other functions in which zinc plays a major role
are membrane stabilization (Chvapil, 1973), muscle contractility (Cann,
1964), taste functions (Henkin et al., 1975), olfaction (Henkin et al.,
1975, 1976), and visual functions (Vallee and Altschule, 1949; Williams,
Foy, and Benson, 1975).
12.1.4 Toxic Effects
Toxic or deleterious effects of zinc are limited. Acute inhalation
exposure to the fumes of heated zinc results in a short-term respiratory
infection known as metal-fume fever (Hunter, 1969). Exposure produces
fever, chest and leg pains, and general weakness. The victims usually
recover in forty-eight hours with little or no long-term effects. The
mode of action is unexplained (McCord, 1960). High plasma or tissue
levels of zinc have been correlated with several diseases and cancers,
but their role is uncertain. Breast cancer, osteogenic sarcoma, liver
cancer, and bronchial cancer have all been correlated with high zinc
levels (Fisher et al., 1976; Fisher and Shifrine, 1977; Janes, McCall,
and Elveback, 1972; Morgan, 1970; Santoliquido, Southwick, and Olwin,
1976), while other researchers have found normal or lowered zinc levels
associated with these diseases (Hirst et al., 1973; Koch, Smith, and
McNelly, 1957). The contradictions may be due to the cancer location
(high cancer levels found in tissues normally high in zinc content and
vice versa) or to the type of cancer diagnosed (Addink and Frank, 1959;
Olson, Heggen, and Edwards, 1958). For instance, tumors may occur in a
region high or low in zinc without a causal relationship, or zinc may be
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65
released from damaged malignant cells, or zinc levels may be distorted by
growth associated with the tumor (Mulay et al., 1971; Olson, Heggen, and
Edwards, 1958). This same pattern of conflicting studies has been the
case for noncancerous diseases such as pneumonia, hypertension, alcoholic
cirrhosis, and atherosclerotic heart disease (Halsted and Smith, 1970;
Marks et al., 1972; McBean et al., 1972; Netsky et al., 1969). The toxi-
city of zinc to humans may ultimately be traced more to cadmium impurities
than to the zinc itself (Schroeder et al., 1967).
12.1.5 Zinc Deficiency. Balance of Zinc
Zinc deficiency in humans is well documented. Causes for deficiency
can be traced to low levels in the diet and/or a "conditioned deficiency"
based on cofactor or secondary condition interference affecting uptake
(Vallee, Fluharty, and Gibson, 1947). The latter situation can be diag-
nosed by low levels of zinc in plasma and high urinary output of zinc.
The initial results of low zinc levels are anorexia, smell or taste dys-
function, and mental and cerebellar dysfunction (Henkin et al., 1975).
Prolonged deficiency can lead to growth reduction or retardation, impaired
wound healing, and impairment of sensory perceptions (Burch, Hahn, and
Sullivan, 1975). The importance of zinc in the diet is further supported
by analysis of fetal or placental material. Levels of zinc in these tis-
sues are normally equal to or higher than adult tissue levels (Baumslag
et al., 1974; Creason, Svendsgaard, Bumgarner, Pinkerton, and Hinners,
1976). Furthermore, in areas with low zinc levels, there is a correspond-
ing increase in birth defects. Rat teratology studies show the same trend.
This circumstantial evidence indicates the importance of zinc for normal
fetal development (Hurley and Swenerton, 1966; Sever and Emanuel, 1973).
Thus it is usually the lack of zinc rather than an excess that is harmful
to humans.
12.1.6 Demography
Demographic studies of zinc levels have found few definite causal
factors for variance. Due to the various analytic techniques used and
the different organs that were analyzed, conflicting evidence abounds in
the literature. Contradictory correlations exist between zinc levels and
sex (Hambidge et al., 1976; Klevay, 1974) and zinc levels in urban vs
rural location (Creason, Hammer, Colucci, Priester, and Davis, 1976). No
correlation has been found between levels of zinc and race, occupation,
or pregnancy. There does seem to be a correlation with age, zinc concen-
tration usually increasing till maturity at least. The increase or de-
crease in levels for adults depends on the tissues examined (Bala et al.,
1969; Dubina, 1964; Petering, Yeager, and Witherup, 1971). Low income
and low education can also be identified as factors in low zinc levels
due to the generally poor diet of persons in these groups (Creason,
Hammer, Colucci, Priester, and Davis, 1976; Hambidge et al., 1976). All
of the general trends mentioned are affected by a wide random variation
with geographic location. This indicates that zinc levels cannot be
traced to one factor, whether it is occupational exposure, diet, age, or
socioeconomic.
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12.1.7 Analysis
There are many analytic methods employed in zinc determinations,
with choice usually based on sensitivity desired, cost, or availability
of equipment. Atomic absorption is the most widely accepted method due
to high accuracy and great sensitivity (Hammer et al., 1971; Henkin,
Mueller, and Wolf, 1975; Tipton and Stewart, 1969). There are many modi-
fications to this technique, primarily aimed at reducing interference or
sample handling time (Evenson and Anderson, 1975; Falchuk, Evenson, and
Vallee, 1974; Henkin, 1971; Brudevold et al., 1975; Reinhold, Pascoe,
and Kfoury, 1968). Neutron activation is also used when equipment is
available due to its high sensitivity (Halvorsen and Steinnes, 1975;
Henzler et al., 1974; Koch, Smith, and McNelly, 1957). This technique
is preferred if multiple-element analysis is needed. Another multi-
element technique is emission spectrography. Despite recent advances in
excitation sources, the use of emission spectrography is declining due
to lack of precise quantitative results (Fassel and Knisely, 1974a_,£>;
National Research Council, 1978; Tipton and Cook, 1963). Other techni-
ques infrequently used for zinc analysis include anodic stripping volt-
ammetry (Williams, Foy, and Benson, 1975), electron microscopy (Carroll,
Mulhern, and O'Brien, 1971), oscillopolarography (Shcherbak, Shcherbakova,
and Marinets, 1975), and fluorometry (Mahanand and Houck, 1968).
In analyzing zinc in human tissues, one cannot overlook its associa-
tion with cadmium. Cadmium and zinc are found together in soils, water,
and plants. Any processing or concentration of zinc also results in a
concentration of cadmium. This is due to their physicochemical similar-
ity (Schroeder et al., 1967). In many ways their transport and storage
are also similar, but the primary biological difference is that zinc is
essential and cadmium is not. In terms of interaction, cadmium's effects
predominate; for example, binding with thiol groups of enzymes favors
cadmium due to its stronger affinities for sulfur. This means that it
takes very little cadmium to disrupt the normal functions of zinc. Thus,
when trying to understand the role of zinc in humans, cadmium interfer-
ence and its toxic effects must also be considered.
12.2 CADMIUM
12.2.1 Production and Use
Cadmium is a nonessential metal, slightly softer than zinc with
definite toxic effects. Unlike zinc, it is rare; ranking about 80th in
crustal element abundance with an average of 0.15 ppm (Page and Bingham,
1973). Despite its relative rarity, cadmium poses a problem due to its
association with zinc, copper, and lead ores; zinc in particular, since
cadmium content increases as zinc content increases (Page and Bingham,
1973) . Production of cadmium is totally based on extraction with other
ores and has increased on a worldwide basis from 100 kg in 1870 to 14,058
metric tons in 1968 (Chizhikov, 1966). The recent increase is even more
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dramatic, with approximately 70% of the total cadmium production occurring
in the last 20 years (Page and Bingham, 1973). Cadmium is used primarily
for electroplating over iron, steel, or copper (45%); pigment and chemical
uses (38%); alloy and solder formation (4%); and a variety of lesser needs
such as batteries, fungicides, and phosphors (13%) (Page and Bingham, 1973)
12.2.2 Cadmium in the Environment
Generally, the levels of cadmium in air, soils, and water originate
from natural sources. Cadmium is released into the active biosphere by
man primarily through the mining and processing steps associated with the
ore production, although some originates from product use and decay. In
these respects, cadmium closely parallels zinc. The levels are normally
low except near emission sites. Water levels of unpolluted locales range
from 1 to 120 yg/1 with a mean near 7 yg/1 (Kopp and Kroner, 1970), while
streams near emission sites can have as much as 3200 (Lieber and Welsch,
1954) or 4130 yg/1 (Yamagata and Shigematsu, 1970). Air levels range from
0.001 to 0.350 yg/m3 (U.S. Department of Health, Education, and Welfare,
1966) with urban or point-source localities having the higher values.
Cadmium does have a cycle in the environment with plant uptake and animal
concentration (Hammons et al., 1978). However, as with zinc, the factors
controlling the levels are contamination exposure and inherent soil, water,
and air concentrations.
12.2.3 Human Exposure to Cadmium
For the general population, exposure occurs primarily through inges-
tion of food (Hammons et al., 1978). Fish, meat, and some grains are
prime sources of ingestible cadmium for man (Schroeder and Balassa, 1961).
In occupational situations, inhalation of cadmium fumes can be a problem,
especially if the presence of cadmium is unsuspected. Due to the high
cadmium content in tobacco, smoking can also be a major route of exposure.
The normal daily U.S. intake of cadmium is approximately 30 to 50 yg
(Duggan and Corneliussen, 1972; Drury and Hammons, 1979).
12.2.4 Absorption, Excretion, Transport, and Storage
Following inhalation exposure, the absorption rate into the body
depends on the particle size of the cadmium. Usually, 10 to 50% of the
fume is taken into the body (Hammons et al., 1978), and the remainder is
mechanically removed or isolated. Absorption from inhaled cigarette smoke
is about 20 to 40%, resulting in 0.75 to 3.0 yg of cadmium absorbed per
pack of cigarettes (Lewis et al., 1972). Absorption from ingested cadmium
is much lower — on the average of 6% (Rahola, Aaran, and Miettinen, 1972).
However, due to the greater frequency of cadmium in foods than in air,
ingestion remains the principal route of entry. Once absorbed, transport
is by the blood, primarily in the plasma. There is some binding to protein
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and red blood cells with time, but these are long-term equilibria and
not strictly for transportation. Cadmium taken into the body tends to
accumulate in tissues for long time periods. The half-life time is 20
to 50 years (Blinder et al., 1976), with an average of about 30 years
(Friberg et al., 1974; Kjellstrom, 1971). This infers a progressive
accumulation and a slow or nonexistent turnover rate; animal studies
support this conclusion (Cotzias, Borg, and Selleck, 1961). Body storage
is primarily in the liver and kidneys — often as much as 50% of the total
body burden (Friberg et al., 1974; Nordberg, 1972; Tipton and Cook, 1963).
Liver and kidney storage is based on a preferential binding of cadmium by
a metallothionein type of protein which is in higher concentrations in
these tissues (Livingstone, 1971; Oleru, 1976; Syversen, 1975). Excretion
of cadmium is primarily by urine, with some loss by feces. The urinary
output ranges from 1 to 2 yg/day (Friberg et al., 1974; Suzuki and Taguchi,
1970). Whether this output is tied to body burden or intake is uncertain,
since studies have shown conflicting results (Adams, Harrison, and Scott,
1969; Piscator, 1973). Fecal excretion is very reduced, with levels of
less than 0.1% excreted per day (Rahola, Aaran, and Miettinen, 1972).
This small amount may originate in the bile, since cadmium has been deter-
mined there in minute traces (Smith, Kench, and Lane, 1955; Tsuchiya,
Sugita, and Seki, 1976).
12.2.5 Toxicity and Effects
The toxicity of cadmium has been known for many years. Toxic effects
can be traced to either acute or chronic exposure. In acute episodes, in-
halation is more common than ingestion. The effects of inhalation expo-
sure (Hise and Fulkerson, 1973) include: (1) shortness of breath; (2)
chest pain; (3) headaches; (4) cough with bloody sputum; and (5) pulmonary
edema. The lethal form can be cadmium fume (Princi, 1947), cadmium oxide
(Beton et al., 1966), or dusts (Friberg, 1950), as case histories document
(Friberg et al., 1974). Acute ingestion produces effects similar to food
poisoning (Frant and Kleeman, 1941) but resulting in liver and kidney dam-
age or death by renal failure (Hise and Fulkerson, 1973). Fortunately,
cadmium also acts as an emetic — reducing absorption and toxicity (Hammons
et al., 1978). Chronic exposure is primarily by ingestion because cadmium
levels in food make this route more accessible in the general public.
Chronic inhalation exposure occurs in industrial situations, with numerous
case histories (Baader, 1952; Friberg, 1950; Lauwerys et al., 1974). Com-
mon symptoms are chronic bronchitis, emphysema, or proteinuria (Hammons et
al., 1978).
The above effects are characteristic of the manner of exposure, but
the following effects may occur regardless of route, because transport and
storage are the same once cadmium is in the body. The kidney is particu-
larly susceptible. Chronic exposure results in kidney accumulation, and
after reaching a renal cortex level of 200 ppm, renal disruptions occur
(Hammons et al., 1978; Nordberg, 1974). These include morphological
changes, proteinuria, glucosuria, amino-aciduria, and formation of renal
stones (Adams, Harrison, and Scott, 1969; Ahlmark et al., 1961; Bonnell,
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1955; Kazantsis et al., 1963; Piscator, 1966; Smith and Kench, 1957).
Failure of the kidney to function properly is the primary cause of dis-
ability or death from cadmium exposure. However, other toxic effects and
debilitating associations have been suggested. Both animal and epidemio-
logical studies have shown an association between cadmium intake and anemia
(Decker et al., 1958; Fox and Fry, 1970; Friberg, 1950; Hise and Fulkerson,
1973). Liver function disruption (Axelsson and Piscator, 1966; Friberg et
al., 1974) and testicular damage (Favino et al., 1968; Gunn, Gould, and
Anderson, 1963) have also been indicated by similar studies as resulting
from cadmium intake. In addition, cadmium has toxic effects on the nervous
system (Friberg, Piscator, and Nordberg, 1971). In particular, cadmium
interferes with synaptic transmission (Cooper and Steinberg, 1977; Kober,
1977; Smirnov, Byzov, and Rampan, 1954). Cadmium has been suggested as a
cause of or factor in hypertension (Carroll, 1966; Friberg et al., 1974;
Schroeder, 1965a). This association is based on animal studies and epi-
demiological correlations. However, there are also many studies discredit-
ing or contradicting these- correlations (Hunt et al., 1971; Lewis et al.,
1972; Morgan, 1969; Porter, Miya, and Bousquet, 1974). The whole question
is reviewed by Hise and Fulkerson (1973) and by Friberg et al. (1974).
Another area in dispute is the association between cadmium and cancer.
Again, studies have produced evidence supporting (Kipling and Waterhouse,
1967; Morgan, 1970; Morgan, Branch, and Watkins, 1971) and disputing
(Koch, Smith, and McNelly, 1957; Mulay et al., 1971; Santoliquido, South-
wick, and Olwin, 1976) the association. A complicating factor is the
linkage of cancer, high cadmium levels, and cigarette smoking (Friberg et
al., 1974). As with zinc, these associations of high cadmium levels with
cancer and other diseases are circumstantial and may be a result instead
of a cause.
The metabolic action of cadmium is most often cited as being enzy-
matic in nature. Several mitochondrial and extramitochondrial enzymes are
inhibited by cadmium. Animal studies indicate that cadmium reacts with
sulfhydryl groups resulting in: (1) blocked synthesis of adenosine tri-
phosphate (ATP); (2) blocked conversion of ATP to adenosine diphosphate
(ADP) by preferential binding to ATPase; and (3) interrupted transfer of
electrons in the citric acid cycle (Berry et al., 1974). Additionally,
cadmium substitutes for zinc in zinc-requiring enzymes, thereby altering
these enzymatic activities (Griffin et al., 1973; Smith, 1973). This
relationship to zinc is especially important considering the close physi-
cochemical association of zinc and cadmium.
As a final example of cadmium toxicity, itai-itai disease shows how
complex the analysis of trace-metal toxicity can be. Itai-itai is an
epidemic cadmium poisoning in which elderly, multiparous Japanese women
experienced renal dysfunction, osteoporosis, and osteomalacia (Hammons et
al., 1978). Although at first credited solely to high-cadmium food and
water levels (Friberg et al., 1974), recently it has been considered to
be the result of low calcium, low Vitamin D, poor nutrition, and excess
cadmium (Murata et al., 1970; Takeuchi, 1973). Thus, in analyzing cadmium
toxicity, one must not forget how interrelated all trace-element metabo-
lism is.
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12.2.6 Demography
Epidemiological studies have revealed several trends in cadmium tis-
sue levels. As a nonessential element, cadmium is normally absent or in
low concentrations in fetal and juvenile tissues. The tissue concentra-
tions increase with age until middle age (approximately 50 years), then
decrease slightly (Blinder et al. , 1976; Gul'ko, 1965; Hammer et al.,
1973i; Johnson, Tillery, and Prevost, 1975; Perry et al., 1961; Tipton
and Shafer, 1964). This trend holds true for all tissues except hair,
which is more variable (Schroeder and Nason, 1969). Sex differences are
often detectable in the quantity of stored cadmium, but the general trend
is still true (Hammer, Colucci, Hasselblad, Williams, and Pinkerton, 1973;
Petering, Yeager, and Witherup, 1971). Perry et al. (1961) report world
geographical variation in cadmium levels with highest values occurring in
Asians and the lowest values in native Africans. Caucasoid values were
intermediate between these extremes regardless of their geographical loca-
tion. Studies have shown only slight differences between rural and urban
populations, with more variation in tissue levels due to industrial point
source exposure than to urbanization (Anon., 1971; Eads and Lambdin, 1973;
Hecker et al., 1974; Schroeder, 1974a). The strongest epidemiological
correlation for cadmium is with cigarette smoking. Tissue concentrations
are always higher for smokers, with the increase correlated to smoking
intensity (Blinder et al., 1976; Hammer, Colucci, Creason, and Pinkerton,
1973; Lewis et al., 1972; Shuman, Voors, and Gallagher, 1974). No defin-
ite trends were identified for socioeconomic variables.
12.2.7 Analysis
The analysis of cadmium relies on the same basic techniques used in
most trace-element analyses. These methods include atomic absorption
spectrometry (flame and flameless), emission spectroscopy, neutron acti-
vation analysis, polarography, anodic stripping voltammetry, and x-ray
fluorescence. The decision as to which method to use depends on the sam-
ple composition and size, the precision required, the equipment available,
and the cost. Modifications abound in the literature for most methods
that help eliminate sample handling or preparation problems, reduce inter-
ferences, and increase sensitivity. Reviews and comparisons of the vari-
ous analytic methods can be found in Friberg et al. (1974, 1975) and in
Hammons et al. (1978).
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SECTION 13
COPPER, MAGNESIUM, MANGANESE, MOLYBDENUM, SELENIUM,
TELLURIUM, AND POLONIUM
13.1 INTRODUCTION. RELATIVE TOXICITIES
The first five of the above are essential elements. Both deficiency
symptoms from lack and toxic symptoms from excess can occur. With respect
to deficiencies, Mertz (1970) states that "Severe deficiencies of trace
elements with known or suspected function probably do not exist in coun-
tries with free circulation of foods. Therefore, acute, life-endangering
symptoms cannot be expected, and attention must be diverted to subtle,
metabolic change." Mertz discusses specifically the effects of long-term
marginal deficiencies. Here we are more concerned with the effects of
long-term excesses which would strain the body's mechanism of control.
With respect to excesses in the environment, some sectors and some organ-
nisms are particularly susceptible. A striking example of this is copper,
which appears to be essential to all living forms (Schroeder et al., 1966).
However, copper when added to water is the most toxic of the common heavy
metals to fish. It appears that fish do not have a barrier to prevent
copper from going directly through the gills into the blood. Schroeder
(1965&) presents a table of the toxicities of some metallic and nonmetallic
ions to fish in soft and hard water (hard water is protective). In soft
water, toxicities ranged from 0.1 ppm for copper and cadmium, through 0.2
for beryllium, 1 for tin, 1.3 for iron, 2 for zinc and lead, 70 for molyb-
denum, 100 for selenium as selenite, 2400 for manganese, to 5000 for
magnesium.
13.2 COPPER
13.2.1 Copper in the Environment
Copper was probably the first metal worked by man. Its use extends
back 7000 to 8000 years (Schroeder et al., 1966). Copper alloyed with tin
gave rise to an age, the Bronze Age. (Brass, an alloy of copper with zinc,
was not known until Roman times.) Many artifacts were made of copper, in-
cluding cooking utensils. Copper toxicity was recognized, and the Romans
alloyed copper with lead for food and water utensils, not realizing that
lead was the more insidious poison (Christian, 1969). Schroeder et al.
(1966) mention the practice in India of tinning copper pots and pans to
prevent contact of food with the copper. It is lamentable that up until
only a few years ago some countries allowed the addition of copper to can-
ned vegetables, such as peas and green beans, to maintain a green color.
Copper is ubiquitous in the environment. The mean concentration in crustal
rocks is 45 ppm. When leaching has reduced available copper to <10 ppm,
deficiency occurs. As previously mentioned, excess copper is quickly toxic
to organisms lacking barriers to absorption. Poor excretion also elevates
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the toxicity. Avian and mammalian resistance to copper is 100 to 1000
times greater than that of more primitive animals (Schroeder et al. , 1966),
and monogastric mammals (man, hogs) have higher resistances than do multi-
gastric animals.
13.2.2 Intake by Man. Deficiencies and Excess
In man, copper intake is largely from foods and water, less from air,
except in some; industrial situations. It should be noted that the danger
from copper smelting operations is not so much the copper but the arsenic
and lead associated with it (Baker et al., 1977; Milham, 1977). Schroeder
et al. (1966) present the following figures in yg of human intake and out-
put of copper in a soft-water area with relatively uncontaminated air.
Intake: food, 3200; water, 200; beverages, 300; air, 2; total, 3702. Out-
put: urine, 60; feces, 3640; sweat, 2; total, 3702. Some excess copper
may come from leaching of copper water pipes by soft water. Other sources
are dusts, and particulates from burning of copper-containing materials.
A balance in copper intake is needed. While some effects of excess
copper are mentioned in the next section, it may be noted that deficiencies
of copper (and zinc and manganese) are associated with characteristic integ-
umentary and skeletal abnormalities, congenital anomalies (particularly in
the case of zinc), defects in growth and development, and abnormalities in
sensory preception (Burch, Hahn, and Sullivan, 1975). Both deficiencies
and toxic effects from copper in humans are relatively uncommon (Bremner,
1974). In agriculture, animals may suffer copper poisoning from contami-
nation of feed with copper-containing pesticides or from grazing on plants
growing on highly copper-bearing soils.
13.2.3 Absorption, Metabolism, and Chronic Toxicity
Copper is absorbed from the stomach and upper gut by at least two
mechanisms (Burch, Hahn, and Sullivan, 1975). One process takes energy
and probably represents absorption of copper complexes of amino acids.
In the second process, copper is absorbed across the intestinal mucosa by
binding to the copper enzyme superoxide dismutase and to metallothionein.
Other dietary ingredients influence copper absorption, notably molybdenum
and sulfate. Mechanisms of transport of copper from the gut lumen to the
blood are not known in detail. Copper is transported in the blood, loosely
bound to serum albumin (Cartwright and Wintrobe, 1964). Copper in the
blood associates firmly with the hematopoietic enzyme ceruloplasmin. Cop-
per in the blood is distributed to the liver, kidneys, spleen, bone marrow,
and various other tissues; the highest concentrations are found in the
liver and the brain (Cartwright and Wintrobe, 1964). The liver is the
main storage organ for copper and is central in copper metabolism, govern-
ing excretion through the urinary system and controlling the synthesis of
a number of the copper-containing enzymes.
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Burch, Hahn, and Sullivan (1975) estimate the daily copper requirement
to be 2.5 mg. The body content of copper is 80 to 120 mg. The ingestion
of more than 15 mg of copper in a single dose produces nausea, vomiting,
and diarrhea and intestinal cramps. Hemolysis may occur, and also jaundice,
dilation of the central veins of the liver, hepatic necrosis, and in the
kidneys tubular swelling and glomerular congestion. Higher doses may re-
sult in death. In chronic toxicity, there is an accumulation of copper in
cell nuclei of the liver. Sudden release of this copper may give rise to a
hemolytic incident. Hemolytic anemia is also the result of a familial dis-
ease of copper handling, Wilson's disease.
13.2.4 Disease States and Copper
Both high and low copper body levels are associated with a number of
diseases (Koch, Smith, and McNelly, 1957; Olson, Heggen, and Edwards, 1958;
Olson et al., 1954; Owen et al., 1977; Pedrero and Kozelka, 1951; Underwood,
1971, pp. 57-115). A causal relationship has generally not been found.
There is some suspicion that increased copper may play some part in tissue
changes in hardening of the arteries and heart disease (Morgan, 1972;
Zinsser, Butt, and Leonard, 1957).
13.2.5 Analysis
Copper analysis for many years was chemical because the combination of
copper with the chelating reagent diethyldithiocarbamate resulted in a char-
acteristic color. Similar compounds were also used, and numerous variations
of this analysis have been reported. But with the trend to multielement
analysis, instrumental techniques are being used more frequently. These
include flame photometry, emission spectroscopy, atomic absorption, x-ray
fluorescence, neutron activation, polarography and inverse polarography,
and others.
13.3 MAGNESIUM
Magnesium is one of the four "bulk" metals in the human body; the
others are calcium, potassium, and sodium. It is important in electrolyte
balance as a counter-ion to anions and is a cofactor in a number of enzymes.
Its essentiality has been recognized since 1932 (Kruse, Orent, and McCollum,
1932; cited in Schroeder, Nason, and Tipton, 1969). "Standard man" contains
20 g of magnesium, the largest part of it intracellular. There is more
magnesium than calcium in most soft tissues and about five times more than
the next most prevalent intracellular cation, zinc. Schroeder, Nason, and
Tipton (1969) in a review article asked the following questions: What is
the distribution of magnesium in various organs and tissues of the human
body? Do concentrations change with aging, or is homeostasis efficient
throughout life? Do examples of tissue deficiency occur in human beings?
If so, are they related to chronic diseases, especially cardiovascular?
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What foods supply considerable magnesium? Do modern industrial food
practices contribute to less than adequate intakes? To answer these
questions, tissues from 197 subjects in the U.S. and 202 in foreign lands
were analyzed, as well as levels of magnesium in a selection of foods.
The tissue results appear in phase I of this report. The highest concen-
tration was found in bone and the lowest in fat. Of the soft tissues, the
omentum and adrenals, which are high in fat, had the lowest concentration,
whereas larynx and aorta, which contain much calcium, were high. Concen-
trations in all tissues remained fairly constant after the first decade of
life, except for a rise late in life in the aorta. Magnesium is efficiently
used and efficiently retained by the body. Foods containing a high content
of refined sugars and fats are low in magnesium, and Schroeder et al. make
a case for the existence of a marginal dietary deficiency of magnesium in
the U.S. Overt deficiency would appear in persons with impairment of
renal reabsorption. An intake of 4 to 6 mg/day seems necessary for normal
balance. There does not seem to be a problem with magnesium excess or
toxicity.
13.4 MANGANESE
Manganese is omnipresent in living organisms and seems to be essential
in all (Schroeder, Balassa, and Tipton, 1966). Plants accumulate manganese
(and can be deficient in it) but animals do not. An efficient homeostatic
mechanism for manganese appears to operate in all vertebrate and inverte-
brate animals. The body content of manganese in "standard" 70-kg man is
12 to 20 mg (Burch, Hahn, and Sullivan, 1975). This is 1/5 the content of
copper and 1/100 that of zinc (Underwood, 1971, pp. 177-207). In man,
manganese is concentrated in descending order in brain, kidney, pancreas,
and liver (Burch, Hahn, and Sullivan, 1975), but other tissues also show
characteristic levels of manganese. Within the cells, the highest concen-
tration of manganese is in the mitochondria.
The normal intake of manganese in man is 2 to 5 mg/day. Higher doses
are easily tolerated; in fact, manganese is among the trace elements show-
ing the least toxicity. To show toxicity, long-term inhalation at high
levels is needed. Such exposure may occur among manganese workers, for
instance, in the steel industry. Symptoms of toxicity are psychoneurolog-
ical disturbances similar to schizophrenia, and a Parkinson's disease-like
shaking. A manganese pneumonia or bronchitis may also ensue. The risk of
manganese to the general public is more from deficiency than excess, since
diets may sometimes be deficient in manganese. Ingested manganese quickly
appears in the bile. The liver is the key organ in the economy of manga-
nese, the bile flow being the chief regulatory mechanism and main route of
excretion of manganese. Some is excreted in the pancreatic secretion and
also some by reverse passage into the intestines. Urinary excretion of
manganese is minimal. Manganese to a large extent goes its own metabolic
way, seeming to have little metabolic relation with other trace metals
(Cotzias, 1960). Manganese is involved in synthesis of protein, DNA, and
RNA (Burch, Hahn, and Sullivan, 1975), and also in neurohormone control
and oxidative phosphorylation and lipid metabolism (Schroeder, Balassa,
and Tipton, 1966).
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Analysis of manganese has been somewhat difficult, hindering investi-
gation of possible changes in blood manganese concentrations associated
with specific disorders; however, use of modern instrumental methods such
as neutron activation (Hahn, Tuma, and Sullivan, 1968, cited in Burch,
Hahn, and Sullivan, 1975) has overcome this obstacle.
13.5 MOLYBDENUM
13.5.1 Molybdenum in Foods and in the Body
Schroeder, Balassa, and Tipton (1970) and Underwood (1971, pp. 116-
140) have reviewed the biological implications of molybdenum. Knowledge
of the tissue distribution, variations with geographic location, and the
like have come from the extensive studies of Tipton et al. Tables of the
molybdenum content of foods are given in Schroeder, Balassa, and Tipton
(1970). Molybdenum is low in refined foods, and a marginal deficiency of
molybdenum is a possibility with a poor diet. Molybdenum is essential,
apparently to all forms of life, excepting some algae. It is necessary to
all bacteria engaged in some part of the nitrogen cycle in the biosphere,
particularly for the nitrogen-fixing bacteria. As a result of this, soils
lacking molybdenum are generally barren. Molybdenum in the human body is
part of four flavo-enzymes: two oxidoreductases, an aldehyde oxidase, and
xanthine oxidase (Schroeder, Balassa, and Tipton, 1970). Deficiency of
molybdenum may result in xanthine calculi and in other perturbances of
purine metabolism. Molybdenum is found mainly in the liver, kidney,
adrenals, and omentum, which likely reflects its association with the
above-named enzymes. It hardly appears in the blood — the concentration
in over 75% of 210 samples from all over the U.S. was less than 0.5 yg/100
ml (Allaway et al., 1968). There is a complex interaction between copper,
molybdenum, and sulfate, which is particularly important in animal nutri-
tion. Molybdenum and sulfate are antagonistic to copper and can either
increase or decrease the copper status of an animal, depending on the
relative intake. There is some evidence (mentioned in Schroeder, Balassa,
and Tipton, 1970) that molybdenum can enhance the anticaries activity of
fluorine. Criticisms of this view are reported by Underwood (1971). The
balance of molybdenum, as given by Schroeder, Balassa, and Tipton (1970)
based on extensive studies, is as follows: intake in yg: food, 335 (210
to 460); water, 2.8 (0 to 136); air, <0.1; total, 335 (210 to 595). Output
in yg: urine, 190 (116 to 252); feces, 125 (90 to 160); sweat, 20; hair,
0.01; total, 335 (226 to 462). The body content of molybdenum goes up to
about age 20 then slowly declines.
13.5.2 Sources and Toxicity of Molybdenum
As seen in the balance given by Schroeder, Balassa, and Tipton (1970),
intake in man is chiefly through food, with more possibility of deficiency
than of excess. Molybdenum is found in industrial smokes and in oils.
Dusts from metal-working operations may also be a source. The toxicity of
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molybdenum is more of a problem for animals than it is for humans. Among
domestic animals, sheep and cattle are least tolerant, whereas horses and
pigs are quite tolerant. Manifestations of toxicity are weight loss and
retardation of growth, diarrhea, anemia, skin deficiencies, including alo-
pecia, other connective tissue changes, and deficient lactation in females
and testicular degeneration in males.
13.5.3 Analysis
Analysis of molybdenum has been by wet chemical methods, but more
recently by instrumental methods, among which neutron activation and
atomic absorption spectrometry are prominent.
13.6 SELENIUM
13.6.1 Introduction. Selenium Toxicity
As stated by Schroeder, Frost, and Balassa (1970), selenium is the
"least abundant and the most toxic of the elements known to be essential
for mammals." These authors also state: "Selenium toxicity, from what-
ever source, produces loss of fertility, congenital malformations, de-
fects in the eyes, small litters, and emaciated young; therefore it is
teratogenic. It is interesting that both deficiency and toxicity of
selenium cause retarded growth, muscular weakness, infertility, and
focal necrosis of the liver."
Areas of high selenium (plants growing in alkaline soils, where
selenium may be in excess) are of concern in farming and ranching. Cat-
tle, hogs, horses, and sheep, which consume high-selenium grains and
plants, suffer loss of hair and hooves, lassitude, anemia, joint stiff-
ness, and liver and heart damage. Selenium is akin to sulfur and replaces
it in proteins, in the sulfur-containing amino acids, and in their metabo-
lites. Symptoms of selenium toxicity in man include discolored and de-
cayed teeth, yellow skin color from selenium-caused bilirubinemia, skin
eruptions, chronic arthritis, atrophic brittle nails, edema, and gastro-
intestinal disorders. Selenium, fortunately, does not accumulate — above
a certain excess, excretion keeps pace with intake. However, this level
is a toxic one, and some irreversible harm may ensue before intake can be
brought back to normal. Schroeder, Frost, and Balassa (1970) state that
overt human toxicity has occurred only in persons living in seleniferous
areas and consuming local food. It may be noted that retention of organic
selenium in tissues is greater than that of inorganic forms, reflecting
the more circuitous metabolic pathways taken by the organically bound
selenium.
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13.6.2 Sources
Selenium is produced largely as a by-product of copper refining.
Several methods are used. The U.S. is a leading producer, followed by
Canada, Japan, and Sweden. U.S. production in 1973 was 627,000 Ib (Nat-
ional Research Council, 1976): 530,000 Ib was imported. U.S. primary
industrial demand was 1,200,000 Ib. Selenium has multiple uses, and
numerous compounds are used: in electronics (photoconductive devices,
rectifiers, etc.), in steel making, in pigments, in glasses and ceramics,
in catalysts, in solvent formulation, in oils, etc. Selenium is associ-
ated with sulfur, and wherever sulfur is burned and emitted into the
atmosphere, selenium can be expected to occur also, at the ratio 1/10,000
(Schroeder, Frost, and Balassa, 1970). The selenium tends, however, to be
in a relatively nonpolluting, particulate form. According to the NAS pub-
lication on selenium (National Research Council, 1976), total atmospheric
industrial emission of selenium was estimated for 1970 at 2,430,000 Ib
(this is higher than the domestic primary production, which was 1,005,000
Ib for 1970). Burning of coal accounted for 62% of the total, or 1,500,000
Ib. An almost equal amount, 1,400,000 Ib, was derived from coal as solid
waste. Losses of selenium in nonferrous mining, smelting, and refining
operations accounted for 26% of the total, and the remainder was derived
from precious-metal refining operations, glass making, and burning of fuel
oil. Total solid waste for 1970 was 6,980,000 Ib; 3,600,000 Ib of this
was derived from mining and milling, where selenium was not the primary
object of the operations. Given proper dispersal, man-made concentrations
of selenium are considered to be trifling in comparison with the natural
concentration. Incidentally, a chief natural source has been volcanic
action over geologic time, with distribution occurring by the operation
of the other geologic and natural processes.
13.6.3 Body Burden and Distribution. Role of Selenium in Normal
Metabolism
Schroeder, Frost, and Balassa (1970) give the calculated body burden
of selenium as 14.6 mg (range 13 to 20 mg). The concentration in animals
is two to three times higher. In man, the highest concentration is in the
kidneys, followed by the glandular tissues, especially pancreas and pitui-
tary, and then the liver (Underwood, 1971, pp. 323-368). Muscles, bones,
and blood are low, and adipose tissue is very low. Blood concentrations
are erratic. More selenium is in the erythrocytes than in the plasma.
Cardiac muscle is higher than skeletal muscle. The balance of selenium,
as given by Schroeder, Frost, and Balassa (1970), based on persons living
in the northeastern part of the U.S., is: Intake in yg: food, 60 to 150;
water, <1; air, <1. Output in yg: urine, 20 to 50; feces, 8 to 30; sweat,
hair, expired air, etc., 32 to 80. As an essential element, selenium
appears to be involved in normal growth, muscle function, integrity of the
liver, and fertility (in connection with vitamin E). Selenium is an inte-
gral part of the enzyme glutathione peroxidase (National Research Council,
1976) , which destroys peroxides in the organism. Selenium has multiple
metabolic pathways, depending on the chemical form, and nutritional and
toxic effects also reflect chemical form. Aspects of this are reviewed
by Allaway (1973).
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13.6.4 Selenium in Food. Management of Natural Selenium
Allaway (1973) gives a map of the regional pattern in the U.S. of
selenium concentration in crops and in the muscle of pigs produced in
specific locations. The latter figures ranged from 1.89 ppm in dry mus-
cle of hogs raised in South Dakota—Minnesota to 0.163 ppm in New York
State. The Northeastern—Great Lakes region is low in selenium, as are
the Southeastern seacoast and the Pacific Northwest. Most of the U.S. is
"adequate," with some regions variable and some with localized areas of
high selenium. Generally, the areas reflect the occurrence of forest
(acid) and prairie and desert soils (neutral to alkaline). As soils be-
come more acid, selenium becomes less and less available biologically.
Considering the possibility of human exposure to excess selenium from
eating of animal products, and the large area of "adequate" selenium con-
centration, Schroeder, Frost, and Balassa (1970) recommend that selenium
should not be added routinely to animal foodstuffs, but only where clear
deficiencies exist. As for excess, some palliatives of selenium toxicity
have been developed, but management generally consists of keeping stock
away from high-selenium areas. Schroeder, Frost, and Balassa (1970) con-
sider that with modern food distribution, human deficiency of selenium
does not occur, except in extremely malnourished children. Excesses
would be sufficiently diluted by the food distribution system.
13.6.5 Selenium and Carcinogenesis
Given in various forms — organic,, inorganic, dusts, vapors — selenium
has been shown to be carcinogenic in rats and other experimental animals,
but a causal connection with human cancer has not been shown. The ques-
tion is confused, because selenium, particularly in the form of selenite
and some organic selenium compounds, has also been shown to be protective
against certain cancers in experimental animals; and with respect to
humans, Shamberger and Willis (1971) and Shamberger et al. (1973) have
presented epidemiological studies indicating a sharply lower death rate
from carcinoma of the digestive tract in areas of high environmental con-
tent of selenium than in areas of low selenium content in the U.S. The
effect of selenium was attributed to the antioxidant power of its com-
pounds. The question of carcinogenicity of selenium has been discussed
by Schroeder, Frost, and Balassa (1970), Underwood (1971), and Cooper and
Glover (1974), and is particularly well treated in a publication of the
National Academy of Sciences (National Research Council, 1976). The
impression one gets is that selenium does not present a carcinogenic
hazard to humans and in fact may have some anticarcinogenic effect.
13.6.6 Analysis
Virtually all the methods of analysis mentioned in this report have
been used for the analysis of selenium: chemical, fluorometric, atomic
absorption, gas chromatography, neutron activation, etc. The fluorometric
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method has had wide application in biological studies. A good proportion
of selenium compounds are volatile or are subject to enzyme action, and
so care must be exercised in handling to avoid losses and redistributions.
The subject of selenium analysis has been treated summarily in the NAS
publication on selenium (National Research Council, 1976) and fairly ex-
tensively by Cooper (1974) .
13.7 TELLURIUM AND POLONIUM
These elements are in the same chemical series as oxygen, sulfur,
and selenium. Polonium has 27 isotopes, from atomic mass 192 to 218.
All are radioactive. Polonium-210 is the most readily available. While
it is present in low quantity, it is intensely radioactive (alpha emitter).
Along with 210Pb it is a main component of natural background radiation.
Its use in industry is strictly controlled. Polonium-210 appears in ciga-
rette smoke (Ferri and Baratta, 1966) and in human tissues (Baratta, Api-
deanakis, and Ferri, 1969). The main source, however, is food (Ladinskaya
et al., 1973). It is of concern in uranium mining and processing.
Tellurium, similarly to selenium, is obtained as a by-product of the
refining of other metals such as copper, lead, and particularly silver and
gold. Its chemistry and uses are similar to those of selenium. The amount
used is considerably less. No biological function for tellurium has been
found, except perhaps as an antagonist to selenium. Studies of its occur-
rence in foods and in human tissues have been reviewed by Schroeder, Buck-
man, and Balassa (1967). The body burden of tellurium of "standard man"
was calculated to be about 602 mg, of which about 540 mg is in bone, the
rest being in various soft tissues. This puts the content of tellurium
higher than that of all the other trace elements except iron, zinc, and
rubidium. High levels in some processed foods indicated that some con-
tamination from industrial sources may occur. Tellurium in the body seems
not particularly deleterious, and Schroeder, Buckman, and Balassa (1967)
speculate that natural tellurium is present as the relatively innocuous
tellurate. Excretion of tellurium compounds seems to keep up with intake;
there does seem, however, to be a slow accumulation with age in bones and
liver.
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SECTION 14
ARSENIC, ANTIMONY, AND THALLIUM
14.1 ARSENIC
14.1.1 Sources and Uses of Arsenic
Schroeder and Balassa (1966) have reviewed aspects of arsenic in
the biosphere, from ancient times to the present. Arsenic (and antimony)
were known in antiquity in the form of their compounds, which were used
both medicinally and as poisons. Use of arsenic increased greatly in the
Industrial Age, but arsenic in the environment is diminishing at present
due to replacement of arsenical pesticides with other, mainly organic,
ones. Arsenic continues, however, to present localized situations of
concern. Arsenic exists naturally in some well waters in toxic excess
(Goldsmith et al., 1972; Whanger, Weswig, and Stoner, 1977; see also
Dubos, 1968). Arsenic in the earth's crust is largely in the form of
arsenate; however, arsenides also exist in deposits. Arsenic may be
present in soils in concentration sufficient to cause manifestations of
toxicity. Industrially, there are emissions of arsenic compounds near
smelters (Baker et al., 1977; Milham, 1977) and from metal treatment
processes. Again, even though use of arsenicals in agriculture, forestry,
and horticulture has declined, there are still episodes of arsenic poison-
ing, often from household use of arsenicals (U.S. Environmental Protection
Agency, 1977a). Some arsenic enters the air from burning of coal (Bencko
and Symon, 1977a.,£0. These authors found hearing loss, high incidences
of respiratory diseases, gastrointestinal disturbances, and skin and eye
irritation among children living near a power plant burning high-arsenic
coal, the arsenic being mainly in the form of arsenic trioxide in the
solid phase of the emission.
14.1.2 Toxicity and Metabolism of Arsenic Compounds
Elemental or metallic arsenic occurs naturally, and according to
Schroeder and Balassa (1966) is not toxic. Nagai et al. (1956) discussed
an epidemic of poisoning in infants which had resulted from consumption
of powdered milk contaminated with arsenic. The toxicity of arsenic com-
pounds as seen in these poisonings was as follows: arsenious acid <
arsenic acid < arsenite < arsenate. As pointed out by Schroeder and
Balassa (1966), arsenite combines with -SH groups of proteins, whereas
arsenate does not. Furthermore, arsenate is less readily absorbed and
is relatively quickly excreted, via the kidneys, whereas arsenite is more
easily absorbed, is mainly excreted in the bile, does more damage, and is
retained longer. Organic arsenites are generally more inhibitory of the
action of various enzymes than is inorganic arsenite. Arsenic may be an
essential element, but due to its ubiquity, it has been difficult to test
whether this is true or not. In cases of high arsenic intake, allergies,
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skin disease, neurological disorders, blood protein abnormalities, goiter,
and other symptoms may occur, and there is a chance of skin cancer, al-
though evidence on this last point is conflicting (Lisella, Long, and
Scott, 1972).
The gas arsine, AsH3, is very toxic, and the antimony analog stibine,
SbH3, is even more so. These gases would hardly be encountered, except
industrially. Uses of arsenic are multiple, and they are highly dissipa-
tive. Whereas arsenic already naturally in the environment cycles through
it without apparent harm to living things, the additional arsenic released
to the environment from smelters, pesticide application, wastes, and the
like can increase concentration in certain areas to levels which are toxic
to both plants and animals. The reasonable conclusion is monitoring and
control where necessary.
14.2 ANTIMONY
The chemistry and uses of antimony are similar to those of arsenic.
A major use is to increase the hardness and mechanical strength of lead,
as in batteries, type metal, and bearings. Antimony is common but less
abundant than arsenic, and its levels of use and potential for pollution
are less. However, antimony in industrial smokes may cause lung disease
(Bowen, 1966). Analysis of arsenic and antimony is by either chemical or
instrumental means.
14.3 THALLIUM
Thallium, element No. 81, lies between mercury, 80, and lead, 82, in
the periodic table. It is the last number of the series boron, aluminum,
gallium, indium, thallium. Thallium was discovered in 1861, but for quite
a time was only a chemical curiosity. Thallium acetate taken orally at
near fatal doses was used as a depilatory, and also for treatment of skin
infection and as an adjunct in tuberculosis care. Thallium sulfate has
been much used as a rodenticide and ant killer; fatal accidents have oc-
curred through misuse. The use of thallium in pesticides was banned in
1972 in the U.S. Legitimate uses, under proper control, are in specialty
glasses, in photoconductive and other electronic devices, and in chemical
reactions, as in manufacture of rare organics. Emsley (1978) takes the
position that "Thallium has no place in civilized society outside the
chemical laboratory," the context of his remarks indicating that he means
"properly controlled manufacturing chemical laboratory." Some thallium is
produced as a by-product in the roasting of pyrite ores to make sulfuric
acid; most comes from treatment of fine dusts from lead and zinc smelters.
Thallium and its compounds are highly toxic, and poisoning may ensue
by absorption from inhalation, ingestion, or through the skin. As men-
tioned in the introductory parts of this report, the body treats thallium
as it does potassium as far as absorption, compartmentation, and excretion
are concerned. The chemistry of trivalent thallium, however, resembles
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that of aluminum. According to Emsley (1978), naturally occurring thal-
lium poses no threat to the environment. The annual world production of
thallium in 1974 was 15 tons (mercury, 9240 tons; lead, 3,430,000 tons).
Thallium concentrates in the brain (Tewari, Harpalani, and Tripathi, 1975),
and neurological disturbances are part of the thallium toxicity syndrome.
An extensive report on environmental exposure to thallium has been pre-
sented by Carson and Smith (1977). The average body burden of thallium
as given by these authors is about 0.14 mg, and intake (mainly from foods)
and excretion (through urine and feces) are about 2 yg/day. According to
Heyndrickx (1957; cited by Bowen, 1966), there is some accumulation of
thallium by the kidney.
Analysis is by both chemical and instrumental means.
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SECTION 15
CHROMIUM, COBALT, NICKEL, VANADIUM, AND BERYLLIUM
15.1 CHROMIUM
Chromium is 17th in abundance among all the elements, not counting
the gaseous ones, and is 4th in abundance of the 29 elements of biological
importance (National Research Council, 1974). Chromium is not found in
its elemental form in nature, and neither chromium metal nor chromium com-
pounds were used or known in antiquity. Chromium was discovered in 1797
by Vauquelin. Chromium compounds tend to be colored, and this property
gave rise to the name. Chromium is an essential element in animals and
apparently also in plants, and is found in almost all living things. In
man, chromium is part of the glucose tolerance factor (Mertz, 1974) and
also appears to have a part in the activity of enzymes involved in the
metabolism of sugars, fats, and amino acids. The level of chromium in
"standard man" was reported in 1959 to be "less than 6 mg" (Schroeder,
Balassa, and Tipton, 1962a). A later figure, probably nearer the correct
value, is 1.72 to 1.86 mg (Schroeder, 1970a). The discrepancy may arise
from the lack of sensitivity and other difficulties of some earlier-used
methods of analysis for chromium. The amount of chromium ingested per day
by subjects selecting their own diets was found by Schroeder (1970a) to be
200 to 400 yg. Ingested chromium clears the blood rapidly and is distribu-
ted in the soft tissues. Chromium does not accumulate, except slowly in
the lungs (Schroeder, 1970a), reflecting retention of insoluble trivalent
chromium.
Chromium in trivalent form is relatively nontoxic, whereas compounds
of hexavalent chromium tend to be toxic and irritating. Chromium in the
earth's crust is mostly in the form of chromic oxide (trivalent), and the
greatly lesser toxicity or potential for deleterious effects of trivalent,
as compared with hexavalent chromium compounds, is therefore an example of
Schroeder and Balassa's rule (Schroeder and Balassa, 1966), which states
or observes that generally the most stable natural valence of an element,
the one found normally in soil and water, is the least toxic. The toxicity
of hexavalent chromium compounds reflects largely the oxidizing power of
the hexavalent state. Thus, as noted by Schroeder (1970a), workers ex-
posed to trivalent chromium suffer little if any effects, whereas those
exposed to hexavalent chromium tend to develop skin and respiratory dis-
orders. Sensitization may ensue, and there is evidence that sensitization
provoked by hexavalent chromium may carry over to the trivalent form (Nat-
ional Research Council, 1974). A serious long-term danger is the product-
ion of lung cancer. The latent period is long, and the cooperation of
other factors in causing the cancers is not excluded.
Chromium is used in chrome plating and in alloys, and chromium com-
pounds are used as coatings, as dyes or dye adjuncts, in leather tanning,
as catalysts, etc. Pollution arises primarily from industrial use and
product use. Chromium is also found in cements and asbestos and is emitted
into the air by burning of coal and wood.
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Schroeder, Balassa, and Tipton (1962a) and Schroeder (1970&) found
chromium in the air in U.S. cities generally on the decline since 1954—59,
with, however, increases in a few. Burning of coal seems to be a major
source. Aside from the question of localized areas of concern, the con-
clusion of reviews on chromium (National Research Council, 1974; Schroeder,
Balassa, and Tipton, 1962a; Schroeder, 197Ob; Towill et al., 1978; Under-
wood, 1971, pp. 253-266) is that while chromium presents an industrial
problem, it does not present a problem to the general population. One of
the authors (Pierce) of the review by Towill et al. (1978) stresses, how-
ever, the need for improvement in analysis of chromium and for further
research on chromium metabolism and pathways of chromium in the environment.
15.2 COBALT
Cobalt has been used for centuries in the form of its salts for pro-
duction of permanent blue colors in glass, tiles, enamels, etc. It was
discovered as an element in 1735 (Weast, 1976). While cobalt and its com-
pounds are not usually very toxic, it is possible that cobalt was a contri-
buting factor to skin lesions and other disorders affecting miners of
arsenical silver-cobalt ores and also workers exposed to fumes from smelt-
ers in the late Middle Ages. In modern times, a chronic pneumonitis of
workers in the tungsten carbide and Carboloy alloy industries has been
attributed to the presence of cobalt, and an allergic dermatitis has been
shown to be due to contact with cobalt and its compounds. The TLV for co-
balt metal fumes and dust is 0.1 mg/m3 (ACGIH, 1971). Cobalt acetate added
to beer to control foaming has been associated with a myocardial insuffi-
ciency affecting heavy beer drinkers, but cobalt as the cause has not been
proven. Excess cobalt taken orally causes polycythemia, with hyperplasia
of the bone marrow (Schroeder, Nason, and Tipton, 1967). Small doses
cause vasodilation, and cobalt chloride has been used experimentally to
lower blood pressure in hypertensive patients and to reduce the need for
anti-hypertensive drugs (Perry and Schroeder, 1954; cited in Schroeder,
Nason, and Tipton, 1967). The tolerated-to-toxic dose of cobalt orally in
man is 2 to 7 mg/kg body weight/day.
Reviews on cobalt stress its essentiality in biological systems (e.g.,
Schroeder, Nason, and Tipton, 1967; Underwood, 1971, pp. 141-169). Cobalt
is not evenly distributed in the earth's crust, and areas of deficiency,
affecting especially grazing animals, occur. Cobalt is the central atom
in the porphyrin-like corrinoid structure of vitamin B12 (cobalamin). This
vitamin is synthesized by bacteria. As reported by Schroeder, Nason, and
Tipton (1967), "one microgram of vitamin B12 per day containing 0.0434 yg
cobalt can make the difference between life and death from pernicious
anemia," making this amount "probably the smallest effective dose for any
compound known today on a weight basis." Cobalt likely has also some
other essential biological functions. As mentioned by Schroeder, Nason,
and Tipton (1967), cobalt is found in all tissues but has a predilection
for liver and heart. It occurs in newborns and children and shows no
tendency to accumulate with age. The body level and flux of cobalt are
about the same as for chromium. However, due to the widespread occurrence
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of cobalt in foods, deficiencies are not usually seen. Cobalt is detect-
able in the air of industrial cities, apparently coining mainly from the
burning of coal and oil. Schroeder, Nason, and Tipton (1967) found co-
balt in snow and considered the source to be fuel burned in automobiles.
Cobalt does not seem to pose a problem to the general population.
15.3 NICKEL
Nickel can give a number of toxic effects (National Research Council,
1975, pp. 97-128), but ingested nickel shows a low toxicity due to poor
absorption. The element is generally considered relatively nontoxic.
Nickel occurs regularly in soils and planus in concentrations substantially
higher than those present in animal tissues and fluids (Underwood, 1971,
pp. 170-176), and occurs in foods at levels generally sufficient for good
nutrition. Nickel activates a number of enzymes (Schroeder, Balassa, and
Tipton, 1962&; Schroeder, 1970a; National Research Council, 1975, pp. 62-
96; Underwood, 1971, pp. 170-176) and is an essential element (Mertz,
1974). It is found in newborns. Homeostasis for nickel is good, and
nickel does not accumulate with age. It occurs in most tissues. The body
load is about 10 mg. According to Mertz (1974), nickel, like vanadium
(also an essential element), is particularly important in lipid metabolism.
Concern over nickel arises primarily from emissions of nickel into the
atmosphere from industrial processes, from the burning of coal, from the
burning of fuel oil (residues of the nickel used as catalyst), and from
automobiles. Schroeder in 1970 (Schroeder, 1970a) recommended the elimi-
nation of nickel additives from gasoline, and the NAS review of 1975 (Nat-
ional Research Council, 1975, pp. 4-61) reported that based on information
received from the petroleum industry, this had been achieved. Some nickel
compounds encountered industrially are extremely toxic, for example, nickel
carbonyl, used in the Mond process for obtaining nickel metal. The TLV for
this compound is 0.001 ppm, and for nickel dust or fumes and soluble nickel
salts it is 1 mg/m3; there is evidence that this limit should be lowered,
since it may not be low enough to prevent dermatitis or sensitization
(ACGIH, 1971). Nickel dust has been shown to be carcinogenic in animals
and to produce cancers of the respiratory system in workmen (ACGIH, 1971).
The NAS review document (National Research Council, 1975, pp. 4-61)
reported figures for nickel in the air over a number of U.S. cities.
Recommendations are presented concerning monitoring of airborne nickel,
measures to promote industrial health and safety, epidemiologic investiga-
tion, toxicology of nickel compounds, metabolism of nickel, and dermato-
logic investigations.
15.4 VANADIUM
Vanadium is an essential element (Mertz, 1974), as shown by the pro-
duction of deficiency symptoms in animals. A main effect of vanadium is
on lipid metabolism. Vanadium, industrially, is considered somewhat more
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toxic than some of the other trace metals (ACGIH, 1971; see, however,
Schroeder, Balassa, and Tipton, 1963, for a contrary view), pentavalent
vanadium being more toxic than other forms. The TLV for V205 dust is
0.5 mg/m3 and for V20S fume is 0.05 mg/m3. By way of comparison, concen-
trations of a fraction of a yg/m3 have been reported in the air of most
cities, with some in excess of 1 yg/m3 (Smith, 1972). As seen industri-
ally, inhalation of vanadium dust causes irritation of the respiratory
tract, emphysema, edema, bronchial pneumonia, and other respiratory
disorders.
With respect to vanadium in the air generally, Schroeder (1970&)
lists it among the "relatively nontoxic" elements; others are titanium,
zirconium, niobium, and strontium. These are in contrast to nickel,
beryllium, cadmium, tin, antimony, lead, and bismuth, which are listed
as elements of "innate toxicity." Schroeder (1970&) and also Smith (1972)
cite evidence critical of earlier reports of deleterious effects of vana-
dium; one point of criticism was that vanadium was not the only element
present in the incidents of exposure studied.
Vanadium is ubiquitous in the earth's crust, and considerable vana-
dium occurs in foods, albeit in an erratic manner (Underwood, 1971, pp.
416-424). Homeostasis for vanadium is good. The level of vanadium in
the body is reported to be from 10 to 25 mg. The experimental finding
that administration of vanadium salts reduces hardening of the arteries
in experimental animals is compatible with the involvement of vanadium
in lipid metabolism; furthermore, vanadium workers show lower cholesterol
levels than their compeers in the general population. On the other hand,
vanadium in excess inhibits synthesis of choline, and this is not desir-
able. Details of the effects of vanadium on lipid metabolism may be
found in Underwood (1971).
Vanadium concentrations are high in fossil fuels, and the pollution
potential for vanadium results largely from burning of coal and fuel oil;
however, there are numerous lesser inputs from the widespread use of vana-
dium. Smith (1972) lists vanadium among five elements of potential con-
cern with respect to pollution; the others are chromium, manganese, nickel,
and arsenic. Smith makes the point that control of particulates in general
will reduce vanadium emissions, along with emissions of other elements of
concern. Desulfurization of oil removes vanadium to the same extent as
sulfur.
15.5 BERYLLIUM
15.5.1 Absorption, Toxicity, and Body Distribution
Beryllium compounds tend to have a sweet taste, accounting for an
early alternate name for beryllium: glucinum. Beryllium is very toxic
if it gets into the blood, for instance, through skin abrasion or through
a wound. However, absorption of beryllium compounds in the alimentary
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tract is poor, and even soluble compounds of beryllium may not be very
toxic when ingested. The chief hazard of beryllium is from inhalation;
poisoning may be acute or chronic. Acute beryllium poisoning is charac-
terized by a delay period of a week or two following exposure to a cri-
tical dose; then respiratory involvement and distress and pneumonitis
ensue; the outcome may be fatal. Chronic beryllium poisoning may have a
latent period of 20 to 25 years. A lung disease similar to sarcoidosis
develops. Other effects are dyspnea, chest pain, renal stones, cough,
fatigue, cardiac insufficiency, pneumothorax, liver and spleen enlarge-
ment, and other debilitating malfunctions. Radiology of the lungs is
particularly important in diagnosis (Chamberlin, 1959), the lungs showing
a diffuse pattern of deposition of beryllium. Stress may bring on symp-
toms of the disease. Clary and Stokinger (1973) have proposed that a
triggering event, such as surgery, infection, etc., can cause adrenal
imbalance resulting in translocation of beryllium from wherever stored to
the liver, with resulting inflammation, lysosomal instability, lysosomal
rupture, cell death, and onset of the disease. Beryllium goes to bone as
the ultimate sink (Tepper, 1972) but also goes to the lysosomes and to
cell nuclei (Witschi and Aldridge, 1968; Needham, 1974). Along with other
toxic effects, beryllium has been shown to be a pulmonary carcinogen in the
rat and other animals, by a variety of routes of exposure (Vorwald, Reeves,
and Urban, 1966; Groth, Komineni, and Mackay, 1978, cited in Wagoner,
Infante, and Mancuso, 1978), and the presumption is that beryllium is a
carcinogen in man also; however, it has not been easy to establish a defi-
nite cause and effect relationship. Groth, Stettler, and Mackay (1976)
have studied the interactions of mercury, calcium, selenium, tellurium,
arsenic, and beryllium as relating to the ionization potentials of these
elements and their abilities to form intermetallic complexes, complexes
with organic molecules bearing a variety of functions, and eventually
ultimate-carcinogen complexes with nucleic acid bases in RNA and DNA.
Studies such as these may shed light on possible causation of cancer by
beryllium. In the same way that the toxicity of beryllium was at first
denied and then later accepted, there has also been some reluctance to
admit a human carcinogenic potential for beryllium. A description of the
situation as seen from one viewpoint is given by Wagoner, Infante, and
Mancuso (1978), who cite epidemiological evidence of the association be-
tween exposure to beryllium and the incidence of cancers. One difficulty
in demonstrating the carcinogenic capacity of beryllium in man is that
significantly exposed people die of berylliosis before the time a cancer
would appear. In any case, exposure to beryllium is dangerous enough to
have resulted in the setting of a TLV of 2 yg/m3 for the ambient atmos-
phere in the work place and of 0.01 yg/m3 for neighborhood or community
air (ACGIH, 1971). Schroeder (1974c) has considered beryllium to be the
most toxic trace metal, the order of toxicity of beryllium with respect
to some other metals of concern being beryllium > cadmium > lead > anti-
mony > mercury. It is further noted that the first three are cumulative
in the human body, whereas the last two are fairly readily excreted.
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15.5.2 Sources, Uses, and Consumption of Beryllium
Beryllium is present in coal probably as beryl (Tepper, 1972), and
the chief input into the air is from this source, but concentrations are
not high enough to be of concern. Other sources are from industrial
operations and from dispersion of beryllium-containing products. The
chief area of concern remains the workplace. In industry, beryllium
oxide, beryllium fluoride, and beryllium sulfate are toxic, whereas beryl
(beryllium aluminum silicate) is not (Schroeder, 1974c). It is not known
whether the form of beryllium in air from coal can cause berylliosis.
The review of Tepper (1972) lists sources, uses, and industries in which
there are particular hazards, and discusses the pharmacology of beryllium,
clinical aspects of berylliosis, and assay and monitoring and industrial
hygiene. Beryllium is a very useful metal, and its use is increasing.
Consumption of beryllium in recent years has been about 300 metric tons,
about 33% of this as the metal, 50% as Be-Cu alloys, 10% other alloys,
5% ceramics, and 2% miscellaneous. Of this amount, 45 to 68 metric tons
were produced in the U.S. Annual domestic consumption is projected to
increase to approximately 1500 metric tons by the year 2000, and about
half the ore is expected to be mined within the U.S. (Heindl, 1970).
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SECTION 16
OTHER ELEMENTS
We have discussed the chief elements of concern, within the guidelines
of this project. This leaves, however, almost 50 elements; in all, a good
part of the periodic table. There are TLVs on most of these, and some are
more or less toxic — for instance, indium, 0.1 mg/m3; iron salts, 1 mg/m3;
silver, 0.01 mg/m3; platinum, 0.002 mg/m3; osmium tetroxide, 0.002 mg/m3;
some tin salts, 2 mg/m3; and so on. None of these are of concern to the
general population. Sometimes, however, technological change will increase
the environmental levels of an element to the point of possible concern;
for instance, the introduction of platinum and other rare metals into the
environment through use in automobile exhaust catalyzers, or increasing
use of elements such as germanium and gallium as technology advances. Some
of the elements not discussed specifically are essential — examples are tin
and silicon (Mertz, 1974; Schwarz, 1974); strontium may have a biological
role; zirconium may have a biological function, etc.
We have not considered elements such as sodium, potassium, phosphorus,
calcium, etc., which are the so-called "bulk elements" in the biosphere,
even though some of their compounds in excess may be deleterious in the
environment; nor have we considered pollutants such as ozone, sulfur oxides,
nitrogen oxides, etc., which do not leave residues in the body. We have
also not considered compounds of the elements nor radioactive pollutants.
Most air pollution results from burning of materials, particularly
fossil fuels. As mentioned in connection with vanadium (Smith, 1972),
control of particulate emission in general will control dispersion of a
considerable number of elements.
Besides the information on elements and compounds in the TLV docu-
mentation (ACGIH, 1971 and supplements), a listing of the properties,
sources, uses, and physiological and toxic effects of metals, excluding
lead, is given in the chapter by Stokinger in the treatise "Industrial
Hygiene and Toxicology" (1963). A chapter on the biogeochemistry of the
elements in the book by Bowen (1966) on "Trace Elements in Biochemistry"
gives occurrence and levels in soil, water, plants, and animals, and
describes the functions and toxicity of most of the elements. An excellent
overview of environmental pollution is given in the book of that name by
Hodges (1973). Physical and chemical principles are particularly consi-
dered. Interaction and interrelations of elements are important, and as-
pects of this, along with other topics, are covered in the volume edited
by Nordberg (1976) on "Effects and Dose-Response Relationships of Toxic
Metals."
A report by Matti, Witherspoon, and Blaylock (1975) deals with cycl-
ing of mercury and cadmium as typical pollutants in the environment.
Lindberg et al. (1975) have discussed the mass balance of trace elements
in a watershed, reflecting input from coal-fired steam plants.
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The public health aspects of metals in the environment and their
effects on the human body have been discussed by Schroeder (1974£>3c).
Tables of clearances of essential and nonessential metals and tissues in
which they accumulate, when this is the case, are given, as are tables of
U.S. industrial consumption, amounts in the human body, in the earth's
crust, and in seawater, amounts added by weathering and by combustion of
fossil fuels, urban air concentrations and estimates of maximal intakes
by inhalation, levels in water and in ponds and exposures through use,
and a listing of processes which are sources of introduction of metals
into the environment.
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139
TECHNICAL REPORT DATA
(Please read Instructions on the reverse before completing)
1. REPORT NO.
EPA-600/1-80-001
2.
3. RECIPIENT'S ACCESSION NO.
4. TITLE AND SUBTITLE
Chemical Contaminants in Nonoccupationally Exposed
U.S. Residents
5. REPORT DATE
May 1980
6. PERFORMING ORGANIZATION CODE
7. AUTHOR(S)
James W. Holleman, Michael Ryon, and Anna S. Hammons
8. PERFORMING ORGANIZATION REPORT NO.
9. PERFORMING ORGANIZATION NAME AND ADDRESS
Information Center Complex, Information Division
Oak Ridge National Laboratory
Oak Ridge, Tennessee 37830
10. PROGRAM ELEMENT NO.
l-HE-775
11. CONTRACT/GRANT NO.
EPA-78-D-X0205
12. SPONSORING AGENCY NAME AND ADDRESS
Health Effects Research Laboratory
Office of Research and Development
U.S. Environmental Protection Agency
Research Triangle Park, North Carolina
13. TYPE OF REPORT AND PERIOD COVERED
27711
14. SPONSORING AGENCY CODE
EPA 600/11
15. SUPPLEMENTARY NOTES
16. ABSTRACT
This report reviews the manner in which chemical contaminants found in nonoccupa-
tionally exposed U.S. residents enter the environment and subsequently human tissue.
Approximately 100 contaminants are treated. Sources of literature used in the survey
covered a 30-year period, the bulk of which was published within the past decade.
Contaminants discussed include organochlorine, organophosphorous, carbonate, and
miscellaneous pesticides; polychlorinated and polybrominated biphenyls and terphenyls;
halogen compounds; asbestos; mercury, lead, zinc, cadmium, copper, manganese, molyb-
denum, selenium, arsenic, antimony, thallium, chromium, cobalt, nickel, vanadium,
beryllium; and others. Production; use; entry into the environment; entry, metabolism,
and effects in man; and description and evaluation of methods of analysis and validity
of the data are the chief aspects treated. For pesticides, indiscriminate use is the
chief means of environmental entry. Entry into man is by ingestion of particulate
residues or through foods, particularly fat-containing animal products. Sources of en-
vironmental entry for metals and other elements are burning of fossil fuels, industrial
operations, dissipative uses, and natural inputs. Entry in humans occurs largely by
exposure to airborne particulates, and to a lesser degree through food and water.
Some elements are essential or beneficial at-one level of concentration and toxic
at another. Discussions of the status of elements from this standpoint are included
where appropriate.
17.
KEY WORDS AND DOCUMENT ANALYSIS
DESCRIPTORS
b.IDENTIFIERS/OPEN ENDED TERMS
COSATI Held/Group
Chemical Contaminants
Human-Body Burdens
Multi-Route Pollutants
Tissue Burdens
Toxic Substances
Toxicology
06, F
07, B
18. DISTRIBUTION STATEMENT
RELEASE TO PUBLIC
19. SECURITY CLASS (This Report)
UNCLASSIFIED
21. NO. OF PAGES
150
20. SECURITY CLASS (This page)
UNCLASSIFIED
22. PRICE
EPA
-Y |ff»». l-Tff
tious EDITION is OBSOLETE
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