EPA-600/1 76-014
January 1976
Environmental Health Effects Research Series
SELI
Health Effects Research Laboratory
Office of Research and Development
U.S. Environmental Protection Agency
Research Triangle Park, North Carolina 27711
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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
five series. These five broad categories were established to
facilitate further development and application of environmental
technology. Elimination of traditional grouping was consciously
planned to foster technology transfer and a maximum interface in
related fields. The fi ;e series are:
1. Environmental Health Effects Research
2. Environmental Protection Technology
3. Ecological Research
4. Environmental Monitoring
5. Socioeconomic Environmental Studies
This report has been assigned to the ENVIRONMENTAL HEALTH EFFECTS
RESEARCH series. This series describes projects and studies relating
to the tolerances 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 include biomedical
instrumentation and health research techniques utilizing animals -
but always with intended application to human health measures.
This document is available to the public through the National
Technical Information Service, Springfield, Virginia 22161.
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EPA-600/1-76-014
January 1976
Selenium
By
Subcommitee on Selenium
Committee on Medical and Biologic Effects of
Environmental Pollution
National Research Council
National Academy of Sciences
Contract Mo. 68-02-1226
Project Officer
Robert J. M, Horton
Criteria and Special Studies Office
Health Effects Research Laboratory
Research Triangle Park, N.C. 27711
U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
HEALTH EFFECTS RESEARCH LABORATORY
RESEARCH TRIANGLE PARK, N.C. 27711
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DISCLAIMER
This report has been reviewed by the Health Effects Research
Laboratory, U.S. Environmental Protection Agency, and approved for
publication. Approval does not signify that the contents necessarily
reflect the viev/s and policies of the U.S. Environmental Protection
Agency, nor does mention of trarle nnmes or commercial products
constitute endorsement or recommendation for use.
NOTICE
The proiect that is the subject of this report was approved by
the Governing Board of the National Research Council, whose members
are drawn from the Councils of the National Academy of Sciences, the
National Academy of Engineering, and the Institute of Medicine. The
members of the Committee responsible for the report were chosen for
their special competences and with regard for appropriate balance.
This report has been reviewed by a grouo other than the authors
according to procedures approved by a Report Review Committee
consisting of members of the National Academy of Sciences, the
National Academy of Engineering, and the Institute of Medicine.
n
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SUBCOMMITTEE ON SELENIUM
SAMUEL A. GUNN, University of Miami School of Medicine, Miami,
Florida, Chairman
JAMES R. HARR, Pennwalt Corporation, Rochester, New York
ORVILLE A. LEVANDER, Agricultural Research Center, Beltsville,
Maryland
OSCAR E. OLSON, South Dakota State University, Brookings
HAROLD J. SCHROEDER, U. S. Bureau of Mines, Washington, D. C.
W. H. ALLAWAY, U. S. Plant, Soil, and Nutrition Laboratory, Ithaca,
New York, Consultant
HUBERT W. LAKIN, U. S. Geological Survey, Denver, Colorado,
Consultant
T. D. BOAZ, JR., Division of Medical Sciences, National Research
Council, Washington, D. C. , Staff Officer
-111-
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COMMITTEE ON MEDICAL AND BIOLOGIC EFFECTS OF ENVIRONMENTAL POLLUTANTS
HERSCHEL E. GRIFFIN, Graduate School of Public Health, University of
Pittsburgh, Chairman
DAVID M. ANDERSON, Industrial Relations Department, Bethlehem Steel
Corporation, Bethlehem, Pennsylvania
RICHARD U. BYERRUM, College of Natural Science, Michigan State University,
East Lansing
RONALD F. COBURN, University of Pennsylvania School of Medicine,
Philadelphia
T. TIMOTHY CROCKER, University of California College of Medicine, Irvine
SHELDON K. FRIED LANDER, California Institute of Technology, Pasadena
SAMUEL A. GUNN, University of Miami School of Medicine, Miami, Florida
ROBERT I. HENKIN, National Heart and Lung Institute, National Institutes
of Health, Bethesda, Maryland
IAN T. T. HIGGINS, School of Public Health, University of Michigan,
Ann Arbor
JOE W. HIGHTOWER, Department of Chemical Engineering, Rice University,
Houston, Texas
ORVILLE A. LEVANDER, Agricultural Research Center, Beltsville, Maryland
DWIGHT F. METZLER, Kansas State Department of Health and Environment,
Topeka
I. HERBERT SCHEINBERG, Albert Einstein College of Medicine, Bronx,
New York
RALPH G. SMITH, School of Public Health, University of Michigan,
Ann Arbor
-iv-
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GORDON J. STOPPS, Department of Health, Toronto, Ontario, Canada
F. WILLIAM SUNDERMAN, University of Connecticut School of Medicine,
Farmington
BENJAMIN L. VAN DUUREN, New York University Medical Center,
New York
BERNARD WEISS, University of Rochester Medical Center, Rochester,
New York
T. D. BOAZ, JR. , Division of Medical Sciences, National Research Council,
Washington, D. C. , Executive Director
-v-
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CONTENTS
1 Introduction
2 Occurrence
3 Industrial and Agricultural Uses
4 Cycling
5 Biologic Effects
6 Sampling and Analysis
7 Summary and Conclusions
8 Recommendations
Appendix
References
-vi-
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CHAPTER 1
INTRODUCTION
PURPOSE
This report is, an in-depth study that attempts to assemble, organize,
and interpret present-day information on selenium and its compounds, and
the effects of these substances on man, animals, and plants. Emphasis is
given to the effects of selenium on man, conclusions are drawn from the
evaluation of current knowledge on the subject, and recommendations are
made for further research.
The objective of this document is to present a balanced and comprehensive
survey of selenium in relation to health for the information of the scientific
community and the general public and for the guidance of standard-setting and
regulatory agencies. The report describes the sources of selenium, its physical
and chemical nature, its measurement, its relation to other pollutants, its bio-
logic effects and margins of safety, and (if known) dose-response relations.
The statements in the document are supported by references to the
scientific literature whenever possible or are based on a consensus of the
members of the Panel.
CHEMISTRY
The features of selenium chemistry that may control the occurrence,
chemical form, and movement of this element in rocks, soils, rivers,
ground-water, air, plants, and animal or human tissues are reviewed in this
chapter. The atomic properties and electronic structure of selenium are
given in standard texts in inorganic chemistry and will not be reviewed here.
657 132
Some of these properties as given by Rosenfeld and Beath and Crystal
are as follows:
-1-
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Atomic weight 78. 96
Atomic number 34
o
Covalent radius A 1.16
o
Atomic radius A 1.40
o
Ionic radius A 1. 98
Electronegativity 2. 55
Oxidation states -2, 0, +2*, +4, +6
10 2 4
Electronic structure [Ar] 3d 4s 4p
There are no naturally occurring radioisotopes of selenium. The iso-
topes produced by neutron activation and their pathways of decay are listed
657 75 77m 81
by Rosenfeld and Beath. The isotopes Se, Se, and Se may be
used in the quantitative measurement of selenium by neutron activation pro-
819 75 75
cedures. Se is used as a tracer in biologic experiments. Se
selenomethionine is used in human medicine in certain radiologic diagnostic
procedures.
The major features of selenium chemistry that affect its movement,
toxicity, and deficiency in the environment are associated with changes in
its oxidation state and the resulting differences in chemical properties. The
relationship between E. , pH, and the potential forms of selenium in aqueous
inorganic systems, such as weathering rock or soil, are shown in Figure 1-1.
From this figure it is apparent that selenium in the +6 oxidation state is stable
in alkaline oxidizing conditions. Acid and reducing conditions favor the formation
of elemental selenium and selenides.
*The +2 state has not been reported in nature.
-2-
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Properties of Selenate-Selenium (+6 Oxidation State)
724
Selenic acid (H SeO ) is a strong acid (K = 2. 0). In solubility,
2 4 1
most salts of selenic acid are similar to the sulfates of the same metals.
Soluble selenates would be expected in alkaline soils or alkaline weathering
rocks in dry areas. Selenates added to soil are taken up by plants, and
525
toxic levels of selenium in plant tissue may result. There is little
doubt that soluble selenates are the form of selenium responsible for most
naturally occurring instances of plants of high selenium content, even though
much of the total selenium in the soil may be present in other forms.
Even though one would expect selenate to be converted to selenite or
elemental selenium in acid environments, this conversion may be very slow.
254
Gissel-Nielsen and Bisberg report that crops took up over one half
of the selenate added to a soil of pH 5. 7. Substantial uptake of added selenium
was evident for some months after selenate was added to this soil, indicating
a very slow conversion of selenate to less soluble forms of the element.
Because of its stability at alkaline pH, its solubility, and its ready
availability to plants, selenate appears to be the most dangerous form of
selenium as far as potential environmental pollution is concerned. Fortunately,
any appreciable accidental addition by man of selenate to soil, water, or air
appears unlikely.
While the extent to which the selenium level of soils is increased by
fertilizer additions is unknown, it has been found that phosphate rocks do
643a
contain as much as 178 ppm of the element. Much of this is lost during
superphosphate preparation. In spite of the lack of information, it appears
unlikely that fertilizers other than those to which selenium compounds have
been added will add enough of the element to soils to correct nutritional
deficiencies.
-3-
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Properties of Selenite-Selenium (44 Oxidation State)
Selenious acid (H SeO ) is a weak acid, and any dissolved selenite
2 3
would be present predominantly as the biselenite ion in waters between
pH 3. 5 and 9. 0. Most selenite salts are less soluble than the corresponding
selenates. Of especial interest with respect to environmental problems is the
246
very low solubility of the ferric selenites. Geering e_t aL found evidence
of a ferric selenite compound or adsorption complex of even lower solubility
than any of the known ferric selenites in soils equilibrated with labeled
109
selenite. Gary and Allaway added tagged selenite at the rate of 1 ppm
to several soils of low selenium content. Alfalfa grown on these soils in
a greenhouse generally contained concentrations of selenium that would not
be toxic to animals that ate the alfalfa. Studies of the selenium in these soils
while not water soluble
several months after addition indicate that most of it/ was isotopically ex-
changeable with neutral selenite solutions and thus may have been present as
a very stable adsorption complex on sesquioxide surfaces of the soil. Added
selenite tended to remain more soluble when it was added to a very coarse-
textured soil of very low iron content.
Another property of selenite of importance to environmental cycling of
selenium is that selenite is rapidly reduced to elemental selenium under acid
657
conditions by mild reducing agents, such as ascorbic acid or SO
2
The probability that selenite •will either form insoluble compounds or ad-
sorbates with ferric oxide or be reduced to insoluble elemental selenium
minimizes the hazard of pollution of the environment by inadvertent additions
of selenite selenium.
-4-
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Properties of Elemental Selenium (0 Oxidation State)
Different allotropic forms of elemental selenium are listed and their
657
solubility in different reagents is tabulated by Rosenfeld and Beath.
The electronic and photoelectric properties of "metallic" selenium are re-
sponsible for many industrial uses of this element. As far as environmental
problems are concerned, the extreme insolubility of elemental selenium in
aqueous systems, and the fact that elemental selenium is formed by high-
temperature decomposition of most natural materials, such as fossil fuels
and organic refuse, are of primary importance.
The stability of elemental selenium is demonstrated by its occurrence
425 109
in sandstones in dry, alkaline environments. Gary and Allaway
added freshly precipitated elemental selenium at the rate of 1 ppm to several
different soils and cropped them to alfalfa in a greenhouse. Concentrations
of selenium in the alfalfa growing on these soils were well below limits that
might be toxic to animals, and after a few months these concentrations in the
alfalfa declined to levels that would not have protected animals from selenium-
314
responsive diseases. Handreck and Godwin have placed heavy pellets
containing elemental selenium in the rumen of sheep without causing any
evidence of selenium toxicity.
Elemental selenium burns in air to form selenium dioxide, SeO . In
2
the combustion of fossil fuels or organic materials the SeO formed will
2
be reduced to elemental selenium by the sulfur dioxide that is always formed
during combustion of these materials in concentrations greatly in excess of
826
the amount required for reduction of the SeO formed.
2
-5-
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It appears that elemental selenium is a major inert "sink" for selenium
introduced into the environment in various ways, and contamination of water,
soil, or air by elemental selenium poses a minimal hazard of selenium toxicity.
At the same time, fly ash from the combustion of fossil fuels may contain
sufficient elemental selenium to represent a major waste of an expensive and
scarce natural resource.
Properties of Selenide Selenium (-2 Oxidation State)
Hydrogen selenide is a fairly strong acid, and its fumes are very toxic.
However, this compound rapidly decomposes in air to form elemental selenium
and water; thus, hazard from hydrogen selenide is confined to industrial
installations.
The selenides of heavy metals are very insoluble. For mercuric selenide the
724
K is given as -59, and the formation of insoluble mercuric selenide may be
so
a major mechanism involved in the detoxification of methyl mercury by
238
dietary selenite. Other selenides, such as those of copper and cadmium,
are also of low solubility.
It appears that considerable amounts of insoluble selenides, or possibly
elemental selenium, are contained in the feces of ruminant animals that
623
consume dietary selenium. It is impossible to differentiate heavy-metal
selenide selenium from elemental selenium in fecal material or similar
organics by chemical means. The selenium present in fecal material
apparently is not readily taken up by plants when the fecal material is applied
to soil.
328,841
Selenium is present in many pyrites and sulfide ores. There
are no records of highly seleniferous plants growing near exposures of
-6-
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pyrites or sulfide ores in humid regions where acid or neutral soils occur
over the pyritic deposits. Thus, metal selenides, as well as elemental selenium,
may represent a useful inert "sink" for detoxification of selenium added to these
areas.
In semiarid and arid
regions selenide selenium appears to have been oxidized, over geologic time,
to selenate. Plants containing toxic levels of selenium may be found where
seleniferous rocks have weathered in these regions, limited leaching having
permitted the accumulation of soluble selenate.
Biochemistry of Selenium
Details of the forms of selenium in plants and animals are presented in
the sections on selenium metabolism, and only features of the biochemistry
of selenium that may affect its tendency to recycle in biologic systems or
its potential hazard as an environmental pollutant will be discussed here.
For a review of the biochemistry of this element from the standpoint of its
role in enzyme systems, the reader is referred to a recent article by
Stadtman.
Selenite and selenate are both taken up by the roots of plants, and within
the plant these forms of selenium are reduced to the -2 oxidation state, and
_2
the Se is incorporated into soluble amino acids or protein-bound amino
acids or both. The reduction of selenium within the plant may not be quanti-
tative; this is especially true for selenates that are taken up by the roots.
Monogastric animals may reduce selenate and selenite, but they apparently
do not incorporate the reduced selenium into amino acids. The "seleno-
trisulfides" formed by the reaction of selenite with sulfhydryl groups of amino
-7-
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acids, pep tides, and proteins is a probable first product of the reduction of
233
physiologic doses of selenite in monogastric animals. Major excretory
products of selenium metabolism in animals are trimethyl selenonium ion
600 623
in the urine and elemental selenium or metal selenides in the feces.
Some of the chemical changes possibly involved in the movement of
selenium from soils through plants and animals are diagrammed in Figure
1-2. When the metabolic pathways of selenium in plants and animals are
considered along with the reactions of selenium in soils, it appears that
conversion of the element to inert and insoluble forms is a feature of the
soil-plant-animal system. Where such a system is confined to an area of
acid or neutral soils, and no selenium is added to the system, the amount
of "biologically active selenium" should steadily decline. If the soil parent
material contains some selenium, as for example in western Iowa, the time
required to lower selenium concentrations in animal diets to deficiency levels
may be thousands of years. Where a soil-plant-animal system operates in
an arid area of alkaline soils, the selenium returned to the soil in plant
residues or animal excreta may be reoxidized to selenate rapidly enough
to maintain the level of "biologically active selenium" at a nearly constant
level.
Organic Chemistry of Selenium
Important features of the chemistry of selenium in synthetic organic
compounds were reviewed recently in the proceedings of a symposium edited
" 570 407
by Okamoto and Gunther and by others. As far as problems of en-
vironmental contamination are concerned, the important feature of the
synthetic organic chemistry of selenium is that essentially all of the compounds
-8-
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synthetized contain the selenium in the -2 oxidation state. These compounds
might be expected to decompose to form elemental selenium; in fact, the
tendency of some of these compounds to decompose and form elemental
selenium is one of the major problems encountered in working with them.
Since elemental selenium is inert and generally nontoxic, the major hazard
of selenium toxicity to people involved in the synthesis of organic selenium
compounds is from the compounds themselves or from intermediates in
their preparation.
-9-
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Figure Captions
FIGURE 1-1: Relation of Oxidation-Reduction Potentials of Some
246
Selenium Compounds to pH.
FIGURE 1-2: Chemical and Biochemical Changes in Selenium Possibly
9
Involved in its Movement from Soil through Plants to Animals.
-10-
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Figure 1-1
1.20
-oso
In the region between the lines for the 0 /H 0 couple and the SeO /SeO
22 43
__3
couple, selenate would predominate. Between the SeO /SeO and SeO /Se
43 3
--3 +
lines, selenite would predominate. Between the SeO /Se and H /H lines,
3 2
elemental selenium and some heavy metal selenides would predominate. At least
in soils, hydrogen selenide would not be expected to exist. (The dashed line
615
represents Pear sail's E. -pH dividing line between oxidized and reduced soils. )
-11-
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Figure 1-2
SOILS
ACID - POORLY AERATED
_ • i i
Se i i
1 T
(Insoluble) (Insoluble)
i i
i i
4, 4,
WELL AERATED
- *,- s^
;Fe(OH)Se03"
x complexes
t/' (Insoluble)
- ALKALINE
^"Sf
V \
Y Leaching
PLANTS
CEREALS. AND FORAGES
•Se-cys telnet-
7\»
0/<- SeO/
ACCUMULATOR PLANTS
SeO, <
Se-nethionine
Se-adenosyl-
Se-methion1ne
Protein bound
Se-methionlne
'3 ^^^4
\ ^xS^ir^ s6-"161"/1-56-0/5161"6
\ ^Sx\^^Se-cystath1onine
\ \ ^^Volatilization of
\ \ methyl selenides
A \ x
Diet supplements
Protein hydrolysis
(monogastrlc)
> Animal proteins
Se-methionine
Selenotrisulfides
R-S-Se-S-R
Se-cysteine
Se cysteic acid
v
Se-taurine
Methyl selenides
Exhalation
Trimethyl selenonium
> Elemental Se
Urinary excretion
Metal selenides
I
Fecal excretion
> Process leading to loss of "biologically active" Se
Probable pathway but in many cases lacking current experimental yeri-»
ixcatxon»
Slow reaction
-12-
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CHAPTER 2
OCCURRENCE
GEOLOGIC
The geology and geochemistry of selenium have been reviewed by a number
20,424, 525, 658
of authors. Except where indicated otherwise, the following
discussion stems from these reviews.
Concentration in Earth's Crust
Although many geologic specimens have been reported to contain no
selenium, it is probable that with sufficiently sensitive methods the element
can be found in all rocks and soils. Estimates of its average concentrations
in the earth's crust range from 0. 03 to 0. 8 ppm, but several fall around
0. 1 ppm. It is usually found at concentrations of less than one ppm
except in soils or parent materials where selenium poisoning is a problem,
in some mineral deposits, and in certain acid or ferruginous soils.
During the cooling and crystallization of magmas, their selenium content
may be diminished, either by volatilization or because of the element's tendency
to remain with the liquid portion and to flow into fractures or dissolve into
adjacent rocks. Nevertheless, igneous rocks have been estimated to contain
an average of about 0. 09 ppm of the element, and because they constitute
so large a portion of the earth's crust this value is accepted by some as the
average for crustal abundance. In most cases, igneous rocks would not be
expected to contain over 1 ppm of the element.
Occurrence with Sulfides, Sulfates, and Sulfur
Chemically, selenium resembles sulfur, and sulfide or native sulfur de-
posits very often contain it in significant amounts. Thus, sulfides of bismuth,
-13-
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iron, mercury, silver, copper, lead, and zinc have been found to contain
140,462
the element, occasionally at levels of over 20 percent. Jarosite
and barite, two sulfate minerals, have also been found to contain selenium,
but at relatively low levels. Crude sulfur also often contains selenium,
sometimes well over 0. 1 percent. Deposits of sulfur-containing minerals
are often secondary in nature, and when selenium occurs with them it prob-
ably has been leached from some other material and redeposited. It also
appears to have crystallized as metallic selenides associated with sulfides
140
in epithermal rocks.
Sandstone
Although sandstones have been found to contain highly variable amounts
521 525
of selenium, many probably contain less than one ppm. ' However, because
they are somewhat porous, waters may enter them from adjacent formations.
These may carry selenium that they deposit, usually with iron minerals, and
sandstones containing over 100 ppm of the element have been reported from
43,413
Wyoming.
Limestone
Although the selenium content of limestones is usually very low, values
of over 40 ppm have been reported in the chalky shales and marls of the
Niobrara formation of South Dakota. Phosphate rocks range from well below
occasions,
1 ppm to about 300 ppm, suggesting that phosphate fertilizers may, on very rare /
provide significant amounts of the element to soils deficient in it. Limonitic
concretions and meteoritic materials have been found to contain selenium in
846
amounts from less than 1 to over 200 ppm.
-14-
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Other Sedimentary Rocks
Of the sedimentary rocks, shales seem consistently higher in selenium
than limestones or sandstones, and in the United States the soils derived
from them are, in the main, responsible for the problem of selenium poisoning
in animals. Although their selenium content varies both vertically and a really
over a wide range, there is enough consistency to make a knowledge of the
geology of a region of great assistance in locating soils of excessive selenium
content. For instance, the Mobridge member of the Pierre formation near
the Missouri River in southern South Dakota, although it ranges from less
than 1 to over 30 ppm in its selenium content throughout its profile, is generally
highly seleniferous, and where it outcrops it has the potential to form soils
capable of producing toxic vegetation. Only 100 miles north or east, its
selenium content has markedly decreased and it no longer weathers to
seleniferous soils. On the other hand, the Smoky Hill member of the Niobrara
formation is generally highly seleniferous wherever it outcrops in the state.
With this type of information, mapping of potentially toxic areas is greatly
aided.
Geologic History
In the United States, the most highly seleniferous sediments were laid down
in the shallow seas of the Cretaceous period, but the origin of selenium in these
96
sediments has not been definitely determined. Byers e± aL found rather
high levels of selenium in some ferruginous soils of Hawaii, especially in
areas of high rainfall. Finding selenium in the volcanic gas of the area, they
concluded that the selenium in these soils was derived chiefly from these gases
and associated sublimates carried down by rains and fixed by the soils in a
-15-
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highly insoluble form. They extended this conclusion to sedimentary rocks
of the continental United States, advancing the following as supportive evidence:
(1) bentonite deposits (presumed volcanic in origin) precede, accompany,
and follow selenium deposition in the Cretaceous period of geologic history;
and (2) selenites are absorbed and precipitated by iron oxides and may thus
have been removed from the seawaters into which the rains had fallen and
43 96,757
concentrated in the sediments. Volcanic tuffs and volcanic sulfur
of very high selenium content have been reported, lending credence to the
140a
volcanic origin theory, and the data of Davidson and Powers, who found
the selenium content of crystalline (slow-cooling) volcanic rocks lower than
the content of those not crystalline (fast-cooling), support the theory. Further,
357
Howard suggests that the higher selenium content of the Smoky Hill
(Niobrara) and lower Pierre shales indicates a volcanic origin for the element.
He concludes from thermodynamic calculations that: H Se and Se" are the
—2 4-6
expected forms in magmatic gases; Se , Se , and H^Se could exist in
fumerolic and vent gases; SeO could form on eruption into an oxygen-rich
2
atmosphere; and, on cooling, both oxidized and elemental selenium will con-
dense and be deposited with, but not as an integral part of, the volcanic ash.
123a
Coleman and Delevaux analyzed many sulfide mineral samples from
the western United States. Their data suggest volcanic activity or hydrothermal
fluid extraction from magmatic sources and other seleniferous beds as the source
of selenium in sedimentary rocks. They state that on the Colorado Plateau
and in Wyoming the selenium in sulfides can be related to a magmatic province
that •was very high in selenium during periods of volcanic and extrusive activity
in Mesozoic and Tertiary times. In view of this, and since some very seleniferous
-16-
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shales show no evidence of volcanic activity during or shortly before the time
42
they were laid down, the primary origin of at least a part of the selenium
in sedimentary rocks may have been igneous or other sedimentary rocks from
which the element was leached. In regions where selenium
excesses are not a problem, volcanism was probably not an important source
of the element.
The selenium in some soils may well have had its origin in other soils
or sedimentary rocks lying at higher elevations. Thus, the highly seleniferous
soils of Ireland have apparently resulted from the transport by water of soluble
forms of the element from a sedimentary rock formation into a poorly drained
basin containing much organic matter where reduction and precipitation of the
201a, 814a, 824a
element occurred. In Israel, an alluvial soil apparently de-
63 8a
rived its selenium from a higher-lying limestone.
Because of the apparent role of volcanic activity in the development of
seleniferous geologic beds, some have suggested bentonite as a source of
selenium in feeds deficient in the element. Selenium has, indeed, been found
to occur at fairly high levels in some bentonites. It was not indicated that
the samples taken at or near an exposed surface were free from secondary
deposits of the element or from contamination by adjacent shales. Examination
of several South Dakota bentonites has suggested that they would not be a re-
575
liable source of the element for the purpose of feed supplementation.
Selenium from Rocks to Soils
Selenium probably occurs as the free element or, more likely, as a metal
selenide in unweathered rocks. It is apparently readily oxidized during the
weathering of parent materials to soils. In areas of acid soils the element
-17-
-------
would probably be present as the selenite firmly bound in iron oxide colloids,
while in alkaline soils it would oxidize further to the very soluble selenate.
It has been suggested that the primary accumulator plants (see the discussion
of plant metabolism in Chapter 5) are capable of converting insoluble and
thus unavailable selenium to a soluble form, but the evidence for this is not
convincing. It would appear that the normal weather processes, probably
including microbial activity, could account for the conversion of the unavail-
able form of the element in soils to the available forms.
In highly seleniferous soils, it seems that the available form of the element
588
is represented largely or almost entirely by selenate. The data of Krauskopf
on the oxidation potentials of selenium have been discussed in terms of its mean-
20
ing in the weathering of soils, and under alkaline conditions the oxidation of
the element takes place with relative ease. In his discussion of the selenium
708
cycle in nature, Shrift points to the scant information concerning the bio-
logic oxidation of the element. It is tempting, therefore, to accept chemical
weathering as almost solely responsible for the oxidation of selenium during
soil formation. However, there are data suggesting that biologic oxidation
246
is also important, and the matter needs more attention.
The selenium content of soils depends on many factors. The most im-
portant of these seem to be the selenium content of the parent materials and
the intensity of weathering and leaching. A number of conditions influence
the availability of the element for absorption by plants, and these are dis-
cussed in Chapter 5. This available selenium can be evaluated by plant
383 418
analysis, and Kubota e_t aU have applied this concept in preparing
the map shown in Figure 2-1. The map also suggests in a general way the
areas of soils of high and low total selenium content.
-18-
-------
Figure Caption
FIGURE 2-1: Selenium in Crops in Different Regions of the United
418
States.
-19-
-------
Figure 2-1
'-^-i*^^rt
J-"—<-^. TV A*"
III III I ALASKA
I i HAWAII
AREA
I A
E^l IS
HA
C23 HB
ITC
HI A
MB
nminc
mo
me
[ — 1 IY
FEE
CROP
FORAGES
•
NO. OF
SAMPLES
69
26
14
• : M
! 137
FORAGES
•AH EAT *
0 GRAIN*
261
14
39
27
79
205
856
262
MEDIAN
COMC. .
0.03
0.02
005~1
' 0.05
0.05
O.O9
OO5
OO9
O.IO
0.06
0.26
FREQUENCY DISTRIBUTION <%) OF SAMPLES
WITH «;» CONCENTRATIONS tppm) OF:
a 01 •• oc: 'oc» i* o >o
81 j 15
89 < II
50 ! 36
36 ! 45
65 : 31
20 31
57 14
20 ' 41
26 18
5O 1 23
3 10
33 —
a ie u o so
4
0
14
19
4
43
22
26
49
22
60
22
C SO IJ 10
o
o
o
O
O
^
O
13
7
5
IS
30
22
1 0 ll J O
O
O
0
0
o
2
7
O
6
o
9
34
38
>3
0
o
0
0
o
o
o
o
0
o
o
5
7
DATA FROM USDA TECH. BULL. 753. 19*1.
-20-
-------
FOOD CHAIN
Figure 2-1 gives a general picture of where in the United States feed-
stuffs used for animal production might contain deficient, optimal, or ex-
cessive levels of selenium. Normally, of course, animal diets contain a
variety of supplements, and some of these contribute significant amounts of
the element. Also, in the case of poultry and swine specific selenium supple-
ments are being used. Although the data in several reports suggest that feeds
6QO
highest in protein are generally highest in selenium, Scott and Thompson
conclude that for plant materials the selenium values depend largely on the level
of the element in the soils where the plants were grown.
Foods with High Selenium Content
92
Seleniferous Areas. In 1935, Byers reported the selenium content
of some foods produced on seleniferous farms in South Dakota, finding up to
1. 2 ppm in whole milk, 10 ppm in whole egg, and 2, 7, 25, and 100 ppm (pre-
sumably on a dry-matter basis) in string beans, lettuce, turnip leaves, and
cabbage, respectively. It should be stressed here that these values are un-
usually high, since they represent the exceptional case of the highly seleniferous
area. The average selenium concentration in the diets of families in such a
seleniferous area would have been considerably lower than these data suggest.
Because of our present-day food distribution, the concentration would now be
even lower. The same is true for the other reports on foods from such areas
that follow.
733
In 1937, Smith and Westfall reported analyses as follows for locally
produced foods from the same general area that Byers had sampled: milk--
of 50 samples, selenium was detected in 44 at levels up to 1. 27 ppm; eggs--
selenium was detected in all of 32 samples at levels between 0. 25 and 9. 14 ppm;
-21-
-------
meat (muscle) --selenium was detected in all of six samples at levels
between 1. 17 and 8 ppm; bread (made from locally milled flour)--selenium
was detected in all of 11 samples at levels up to 1 ppm; vegetables--selenium
was detected in all but four of 99 samples at levels up to 17. 8 ppm. Williams
846
e^ aL reported 0. 6 ppm of selenium in milk from a Mexican ranch and
up to 70 ppm (apparently on a dry-matter basis) for a number of vegetables
from a Mexican market in a seleniferous area. On the other hand, they found
3 ppm or less (dry-matter basis) in vegetables raised in an irrigated garden
on a seleniferous South Dakota ranch, but later studies suggest that the reason
for these low values was that the garden was situated on a part of the ranch
151
that did not produce highly seleniferous plants.
647
Wheat and Wheat Products. Robinson analyzed samples of market
wheat from various parts of the world, finding levels between 0. 1 and 1. 9 ppm
770
of selenium. Thorvaldson and Johnson, following a report of high concen-
94
trations of the element in young wheat plants in Saskatchewan and Alberta,
analyzed 230 composites made up from 2, 230 samples of wheat from the former
province, finding an average value of 0. 44 ppm with a maximum of 1. 5 ppm.
On analyzing 951 samples of wheat from eight states in the more seleniferous
422
part of the United States, Lakin and Byers concluded that, in view of their
647
findings and those of Robinson, selenium could probably be detected in
all wheat. They found that 82. 5% of their samples contained 1 ppm or less
and 7. 5% contained over 4 ppm. Of 66 samples of flour milled in the area,
only five contained more than 1 ppm, the maximum value being 5 ppm. Similar
concentrations were found in bran, shorts, and middlings, which is in agree-
ment with a study indicating tha^for wheat containing over 1 ppm, the element
-22-
-------
526
distributes itself quite uniformly in the various mill fractions. It should
be pointed out, however, that selenium concentrates in the gluten fraction
4-5 times more than it does in the whole wheat. ' Although other grains
used for foods have not been as intensively studied, available data are
92,521,608,846,847 193a,194
similar to those for wheat. Recently, it has been reported
that rather small losses of selenium occur during the manufacture of breakfast
cereals from grains, and what was lost appeared in the by-products destined
for animal foods.
847
Mustard Seed, Beans, Sugar. Williams e_t aJL. examined 23 samples
of mustard seed, finding 5 ppm of selenium in one and 3 ppm or less in the
others. Of 17 samples of dry beans, one contained 3 ppm, one 2 ppm, and
the rest 1 ppm or less. A sample of sugar produced in a South Dakota plant
contained less than 0. 1 ppm.
Foods from Nonseleniferous Areas
The data thus far were reported by early investigators concerned with
the toxicity of selenium, and they therefore represent, to a large extent,
foods from our more seleniferous areas or foods of the types most likely
to contain higher levels of the element. More recent data discussed below
are, in general, more representative of our normal diet.
296
Eggs and Milk. Hadjimarkos and Bonhorst reported that, in Oregon,
the selenium content of 73 egg samples averaged 0. 317 ppm, and that of 67
milk samples averaged 0. 034 ppm. They found that most of the element in
the eggs was concentrated in the yolk, an observation previously reported by
764 291
Taussky e_t aL Later, Hadjimarkos reported a mean of 0. 021 and a
range of 0. 013-0. 062 ppm for 15 samples of human milk in Portland, Oregon.
-23-
-------
199
Fink found values of 0.076-0.374 ppm of selenium for dried milks from
various sources. Considerable loss of the element occurred during preconcentrat-
ing prior to drying. Sixty samples of German milks that were freeze-dried
contained 0.05-0.13 ppm of selenium, 27 samples of milk powder contained 0.088-
0.152 ppm, and drum-drying was reported to cause a loss of only 4.3-4.7% of the
401
element. Milk from 10 cows in Denmark was reported as containing an average
54 13
of 0.2 ppm on a dry basis. Allaway, et al. reported that a sample of whole
milk from Rapid City, South Dakota, which lies in an area where selenium is often
in excess in the soils, contained 0.05 ppm and that a sample from Bend, Oregon,
where selenium deficiencies are known to exist, contained 0.02 ppm. These data
suggest that the selenium contents of milks from various areas may vary over a
relatively small range only, and that whole milk seldom should contain over
0.05 ppm of the element.
Fish . The selenium content of various fish meals has been found to vary
402,403
within and between types, values falling between 0. 15 and 6. 70 ppm.
The overall average appeared to be about 2 ppm. The selenium in fish and
755
shellfish in Japanese waters was found to vary from 0. 05 to 3. 64 ppm.
Of 438 fish of a variety of species taken from New York waters, almost all
had a selenium content of less than 1 ppm on a wet basis, and concentration of the
598
element did not appear to increase with age of the fish. These reports and
516, 569
others suggest that fish, at least those taken from the ocean, may
be a generally good dietary source of the element.
416
Meats. Ku e_t aL have reported on the selenium content of loneissimus
muscle (loin) of swine raised at 13 state experiment stations on diets typical
to the areas. Average values (wet basis) for these states ranged from 0. 034
(Virginia) to 0. 521 ppm (South Dakota). Data for a variety of meats prepared
-24-
-------
in South Dakota are shown in Table 2-1. With few, if any, exceptions, these
meats were from animals taken or produced where neither selenium poisoning
nor deficiency is a problem. Where selenium poisoning is a problem, values
of 5. 6 ppm for liver and 3 ppm for muscle have been reported in experimental
530
animals. However, the likelihood of such meats reaching markets is ex-
tremely small, since animals are not usually finished for marketing on toxic feeds.
Game animals are not likely to accumulate high levels of the element, because
they roam over wide areas in their search for food.
690
Poultry. Scott and Thompson studied selenium values for poultry
tissues from birds that were fed two practical-type diets (Table 2-2.). The
differences in the selenium content of these diets resulted from the inclusion
of soybean oil meals of low or high selenium content.
696
Coffee and Tea. Shah et aL have reported on the trace element
content of coffee and tea. By nondestructive neutron activation analysis,
they found the following: ground coffee, values ranging from 0. 028 to 0. 204
and averaging 0. 124 ppm for five samples; instant coffee, values ranging
from 0. 004 to 0. 170 and averaging 0. 069 ppm for four samples; and a value
of 0. 116 ppm for one sample of tea.
General Dietary Levels in Different Countries. In Japan, the selenium
contents of meat, eggs, and cereal were found to be 0. 01-0. 05, 0. 12-0. 26,
755
and 0. 02-0. 87 ppm, respectively, and foods from 22 Australian villages
172
were found to contain 0. 01-0. 14 ppm. The mean selenium contents of
753
some foods from the Ukranian Soviet Socialist Republic were as follows:
-25-
-------
cabbage, 0. 063 ppm; wheat bread, 0. 280 ppm; rye bread, 0. 275 ppm; peas,
0. 281 ppm; potatoes, 0. 142 ppm; onions, 0. 096 ppm; beets, 0. 139 ppm; carrots,
0. 093 ppm; cucumbers, 0. 058 ppm; apples, 0. 004 ppm; meat, 0. 292 ppm;
milk, 0. 100 ppm; eggs, 0. 022 ppm; and cottage cheese, 0. 298 ppm. Here, the
author concluded that chronic selenium intoxication in man or livestock should
not be expected in this region, but that the possibility of a deficiency of the
element could not be excluded.
The analysis of a number of vegetable, milk, and egg samples from various
areas of Venezuela has established two zones in that country that produce highly
511
seleniferous food. Many vegetable samples contained over 3 ppm of the
element. Milk samples ranged from 0. 05 to 0. 206 ppm, eggs from 0. 49 to
2. 34 ppm. Later studies suggest that even in the more seleniferous areas
377
levels in foods do not pose a serious health hazard.
476
The selenium contents of a number of Egyptian foods have been reported;
almost all were below 0. 4 ppm on a dry-weight basis, and most were below
0. 05 ppm. Differences in methods of drying caused large differences in the
values, and this should be taken into account in evaluating the results.
-26-
-------
TABLE 2-1
e
Selenium Content of Some Meats Processed in South Dakota
Kind of Meat
No. of Analyses
Liver
Beef
Pork
Chicken
Muscle
Beef
Pork
Lamb
Chicken
Turkey
Wild pheasant
Processed meats
5
4
3
5
5
5
6
12
55
55
Average Selenium Content
(ppm on wet basis)
0. 58
0.70
0. 80
0. 21
0. 31
0. 32
0.42
0.46
0. 51
0. 33
-0. E. Olson, unpublished data.
TABLE 2-2
Selenium Values for Poultry Tissues from Birds Fed Two Practical-Type Diets
690
Selenium in Diet
Selenium Content
(ppm--wet basis)
(ppm)
0.07
0. 67
Chicks
Muscle
0. 06
0. 29
Liver
0. 25
0. 80
Skin
0. 09
0. 25
Poults
Muscle
0.06
0. 32
Liver
0. 15
1. 03
Skin
0.07
0. 36
-27-
-------
569
Oelschlager and Menke have reported the selenium content of many
German foods. Their results are summarized in Table 2-3.
TABLE 2-3
a_
Selenium Content of Certain German Foods
Food Average Selenium Content (ppm--dry basis)
Meats (pork and beef muscle) 0. 27
Liver (pork and beef) 0. 44
Milk (dried) 0. 14
Fish (ocean) 1. 54
Eggs (dried whole) 1. 01
Vegetables and fruits 0.03-0. 30 (range)
a " 569
Derived from Oelschlager and Menke.
These values, when converted to a wet basis, agree in general with those of
516
Morris and Levander, which are discussed below.
516
The recent data of Morris and Levander for a cross section of the
American diet are particularly helpful in assessing selenium intake by people
in the United States. They are summarized in Table 2-4. The rather high
267
level of selenium in garlic is confirmed by other data. Morris and
Levander point out that cooking may cause selenium losses in some cases,
342
but for most foods the losses are not major.,
-28-
-------
TABLE 2-4
Selenium Content of Certain Foods in the American Diet
Food
Vegetables, canned and fresh
Fresh garlic
Mushroom, canned and fresh
Fruits, canned and fresh
Cereal products
Egg white
Egg yolk
Brown sugar
White sugar
Cheeses
Table cream
Whole milk
Meats (excluding kidney)
Seafoods
Average Selenium Content
(ppm--wet basis)
0. 010 (0.004-0. 039)
0. 249
0. 118
0.006 (< 0.002-0. 013)
0. 38 (0.026-0. 665)
0.051
0. 183
0. 11
0. 003
0.082 (0.052-0. 105)
0.006
0.012
0. 224 (0. 116-0.432)
0. 532 (0. 337-0. 658)
a. 516
Derived from Morris and Levander.
Figures in parentheses indicate range in values.
-29-
-------
351
Hopkins and Majaj have stated that when five total human diet samples
were collected in the Baltimore, Maryland, area at quarterly intervals during
1963 and 1964 and analyzed for selenium by neutron activation analysis, none
of the element could be detected. The authors point out, however, that these
limited results do not indicate a deficiency of the element in the American
diet.
An interesting review of the movement of selenium in the food chain has
9
been prepared by Allaway, who concludes that any soil-plant-animal chain
of food production that is operating on acid or neutral soils will ultimately
become depleted of biologically active selenium. Further, even on alkaline
soils there is little, if any, evidence for a significant increase in selenium
up the food chain.
The data discussed above suggest that there are wide differences in the
selenium content of foods and that they are due mainly to the type of food
and where it was produced. However, what man eats in the United States is
generally varied in nature and origin, and there seems no reason to expect
either inadequacy or excess of the element in our diets except, possibly,
under very unusual circumstances.
FOSSIL FUELS
Selenium dispersed by volcanism and by weathering of sulfide deposits
is reconcentrated by biogeochemical processes and is enriched in plant and
animal tissues. The enrichment in biomaterials is suggested by the presence
of the element in coal deposits. Geologic processes in which decomposition
of organic matter occurs are involved in coal formation, and this type of con-
centration mechanism should not be used to illustrate a food chain buildup.
-30-
-------
The 138 samples of coal from United States deposits reported in Tables 2-5
and 2-6 contain an average of 2. 8 ppm of selenium, which is over 25 times
the crustal abundance of the element.
625
Pillay et al. estimated that the annual release of selenium from the
combustion of coal and oil in the United States is about 8 million Ib. This
figure is nearly 6 times the 1964 production of the element in the whole of
430
North America and 4 times the world production for the same year. One
might expect from these data that the industrial part of the United States
would have soils containing an excess of the element. The fact is, however,
that 65% of the forage crops in the industrial eastern part of the country
(area IIC in Figure 2-1) appear to contain insufficient selenium for the growth
of healthy animals. There are a number of possible explanations for this
apparent disparity. Selenium fallout as the element would not be available
to plants and would not be expected to oxidize to an available form in this
region of acid soils. Selenium in the form of selenium dioxide would be
firmly bound to certain soil colloids and thus not available. Finally, the
144
data of Davis and the discussion under "Industrial" in Chapter 4 suggest
that the amount of atmospheric selenium actually derived from the burning
of coal is much less than 8 million Ib.
Coal
Not all of the selenium released by the burning of coal enters the atmosphere.
The coals supplied to five power plants in the western United States were analyzed
759
for selenium and ash content. The bottom ash and fly ash were collected
and analyzed and the approximate ratio of the two types of ash was estimated.
The loss to the atmosphere subsequently estimated was 25, 810 Ib of 69,000 Ib
-31-
-------
of selenium contained in the coal. In a study in the Denver area, Kaakinen
(personal communication) found the following:
The preliminary results of an experimental mass balance
of several trace metals in a coal-fired power plant include
some information on the fate of selenium contained in the
coal. Selenium concentrations in ashes collected at seven
points in the lower power plant were determined by X-ray
fluorescence. The measured selenium concentrations ranged
from about one part per million in mechanical collector ash
to a few hundred parts per million in the fly ash leaving a
wet scrubber. There was a tendency for increasing selenium
concentrations in fly ash samples obtained at successive points
downstream from the furnace towards the stack outlet. It may
also be noted that as the flue gas proceeds downstream from the
furnace its temperature decreases and the average particle size
of uncollected fly ash decreases. Analytical determinations of
selenium in the raw coal feed and in stack gas vapor have not
been completed to date. However, mass balance calculations
assuming a conservative figure of 0. 5 ppm selenium in the raw
feed coal result in less than half of the selenium input accounted
for in all the ash and water outputs from the plant, the remainder
probably leaving the stack as vapor.
If the selenium content of the coal used in this example had been more in line
with the data from Colorado in Table 2-5 (about 2 ppm) , over 857. would have left
the stack.
-32-
-------
TABLE 2-5
625
Selenium Content of U. S. Coals
State
Alabama
Colorado
Illinois
Indiana
Iowa
Kansas
Kentucky
Maryland
Missouri
Montana
New Mexico
North Dakota
Ohio
Pennsylvania
Tennessee
Utah
Virginia
Washington
West Virginia
Wyoming
Number of Counties Number of
Sampled Samples
3
2
2
3
1
1
4
1
1
3
2
1
4
7
1
2
3
1
12
1
4
3
2
4
1
1
5
1
2
3
2
1
4
11
1
4
4
2
30
1
Selenium (ppm)
Low
2. 20
1. 25
1. 05
1.41
1. 54
2. 27
1.71
1.70
3.41
2. 20
4.43
0.98
2. 64
1.35
4.89
1. 30
2. 24
0.46
0. 92
3.43
High
8. 15
2. 05
1.97
8.36
1. 54
2. 27
4.82
1.70
4. 98
4. 11
4.82
0. 98
7. 30
10. 65
4.89
2. 37
6. 13
0.66
6.80
3.43
Average
5. 14
1.65
1. 51
3.96
1. 54
2. 27
3. 13
1.70
4. 19
3.04
4. 62
0.98
4. 62
3.74
4. 89
1.83
4. 37
0. 56
3. 36
3.43
Total
86
-33-
-------
TABLE 2-6
Selenium Contents of Coals at Active or Proposed Power Plants in the
759
Western Part of the United States
Location of Plants
Four Corners, New Mexico
Cholla, Arizona
Mohave, Nevada
Hayden, Colorado
Naughton, Wyoming
San Juan, New Mexico
Navajo, Arizona
Kaiparowits, Utah
Hun ting ton Canyon, Utah
Jim Bridger, Wyoming
Average Selenium Content of Coal
(ppm)
2.0
2. 3
1.6
1.2
0.7
2. 2
1.6
1.7
1.7
1. 5
(21)**
( 4)
( 2)
( 3)
( 5)
( 2)
( 2)
( 3)
( 9)
( 1)
Number of samples represented in average shown in parentheses.
-34-
-------
Oil
Data on the selenium content of fuel oils are very limited. Bertine and
48
Goldberg have estimated the average as 0. 17 ppm. The analysis of 47
samples of crude or fuel oils from various parts of the world by neutron
activation gave values of from less than 0. 006 to 2.2 yg per gram, the
326
average being something less than 0. 6 yg per gram. * Hashimoto et al.
have reported values of 0.50-0.95 (average 0.82) yg of selenium per gram
in five samples of raw petroleum and 0.50-1.65 (average 0.99) yg of selenium
per gram in nine samples of heavy petroleum. It appears that, on the average,
oils contain less of the element than do coals, but more data on both of these
fuels are needed.
WATER
36,37,39,93,95,588
The concentration of water-soluble selenium in some soils,
95, 84Z
certain salt crusts or deposits, or occasionally in other geologic
43
materials has been documented rather well. Thus, ground and surface
waters should be expected to contain the element, particularly in areas
where it is in excess. Indeed, with analytical methods sensitive enough,
it might be found in any natural water.
Surface Waters. Drinking Supply
Unfortunately, data on waters are limited. However, those that are
available suggest that one would rarely find surface waters containing toxic
Data on file at Monitoring and Analysis Division, Office of Air and Water
Programs, Environmental Protection Agency.
-35-
-------
levels of the element, or even amounts that would contribute significantly
548
toward supplying the nutritive requirements of animals. For instance,
424
Lakin and Davidson state that U.S. Department of Health, Education,
and Welfare data for 535 analyses of waters from the major watersheds of
the United States over a 4-year period showed only two samples containing
more than a detectable (10 ug per liter) amount of selenium, the higher
765
of the two being 14 ug per liter. Taylor reports a maximum of 10
with a mean of 8 \ig per liter in 194 public, finished water-supply sources
733
sampled over a 2-year period. Although Smith and Westfall did not
find measurable amounts of the element in drinking waters from 34 of 44 wells
in a seleniferous area of South Dakota, the remaining 10 did contain from 50
296
to 330 ug per liter. Hadjimarkos and Bonhorst found averages of 2, 1,
and less than 1 ug per liter for 21, 23, and 28 farm samples from three
Oregon counties. Samples from 22 Australian villages contained less than
172
1 Mg per liter, and tap and mineral waters from Stuttgart, Germany,
569
have been reported to contain 1. 6 and 5. 3 ug per liter, respectively.
Others have reported some higher values for river waters where irrigation
drainage from seleniferous soils has contained up to 2680 ug per liter of the
95,842
element. For instance, tributaries of the Colorado River receiving
such drainage contained up to 400 ug per liter, and the Colorado River
itself, below where this •water entered it, contained up to 30 ug per liter.
Irrigation Waters, Springs. Wells, Sewage
In addition to high selenium content in irrigation drainage waters,
36 36,95,504,515 92,93,145,515
seeps, springs, and shallow wells have
been found to contain over 100 ug/liter of the element, but-waters in deep
-36-
-------
92,93 36b
wells seem to contain only a few micrograms per liter. Beath
has stated that preliminary tests on Wyoming well waters showed a few
instances where enough selenium was present to be poisonous to man or
36a
livestock. He also reported that selenate in well water on a Ute Indian
reservation apparently caused loss of hair and nails in children, but the
evidence was not convincing. Sewage plant effluents contribute to the
selenium content of water, as much as 280 ^g per liter having been reported
in raw sewage, 45 yg/liter in primary effluent, and 50 yg per liter in secondary
34a
effluent.
Oceans
424
Lakin and Davidson have summarized the data of Schutz and Turekian,
who estimated an average value of 0. 09 yg per liter for our ocean waters.
Others have found values of 6 jjg per liter or less for ocean waters from a
95, 265, 371, 372,423, 750
number of locations. These low levels have been
explained by the precipitation of selenite with oxides of metals, such as iron
95,265
and manganese. The mechanism of this precipitation has been studied
356, 577, 582, 750, 843
by a number of investigators. Under some conditions,
selenite seems to be completely adsorbed in rather high amounts by ferric
(and to a lesser extent by aluminum) hydroxide, while selenate is not. The
adsorption of the selenite cannot, therefore, be entirely described by the
well-known adsorption equation x/m = kc .
Lakes
Waters in small lakes, in undrained basins into which drainage from
39 1
seleniferous soils flows, or in stock dams in selemferous areas have
-37-
-------
also been found to contain surprisingly little selenium, and again precipita-
tion with metal hydroxides may account for this. However, microbial re-
449 1
duction and precipitation as the element or other biologic mechanisms
must also be considered. Selenium has been found in a variety of deep sea
171, 265, 423, 525, 757, 844, 846
deposits, and this too may indicate removal of
the element by precipitation of some type.
Precipitation removes selenium from the atmosphere, but reports on
quantitative measurements on rain and snow are very limited. Those that
327
have been reported fall between 0. 04 and 1. 40 yg per liter of water.
Importance of Waters
Apparently, waters rarely contain selenium at levels above a few micro-
grams per liter. Hence, they can rarely be considered a significant source
of the element from either a nutritional or a toxicity standpoint. However,
even at the very low levels found in rivers, the large volumes of water in-
volved mean the transport of rather large amounts of the element. Bertine
48
and Goldberg have estimated that river flow deposits about 8, 000 tons of
selenium per year in our oceans. Geologically, therefore, water is important
in actively and continuously leaching, transporting, and redepositing the element.
Present United States standards for drinking water list 10 yg of selenium
628
per liter as the upper acceptable limit. Pletnikova has suggested a limit
of 1 yg of selenium per liter as the upper limit for Russian drinking water
as a result of his observations on rats. However, the meaning of some of
/
his observations in terms of animal well-being and/the diet during treatment
is not clear, and in view of the •well-established requirement of animals for
selenium, this limit seems unnecessarily low.
-38-
-------
AIR
Volcanic Sources. Soil, Plants. Animals
There are a number of sources for selenium in the atmosphere. The
96,757
element has been found in volcanic gases, and if volcanos are, as
95,96
has been theorized, the main source of the element in highly seleni-
ferous sediments, they may be a major contributor of selenium to the air.
The occurrence of volatile selenium in plants, particularly in some of the
451
accumulators, has been well documented, dimethyl selenide and to a
179
lesser extent dimethyl diselenide having been identified in volatiles from
accumulators. Soils may also contribute selenium to the air as the result
2
of microbial action within them or perhaps because of dusts derived from
678
seleniferous areas. Animals, too, volatilize the element, probably as
486
dimethyl selenide. At present* reasonably accurate estimates of the
quantities contributed to the air by each of the above sources are impossible.
Industrial Sources
158
Dudley summarized potential industrial sources of atmospheric
144
selenium, and these have recently been more thoroughly reviewed.
The findings of this review are summarized in Chapter 4.
Concentration in Air
Data on the actual presence of selenium in the atmosphere are limited.
In a plant producing selenium rectifiers, air analysis revealed between
3 17 694
0. 007 and 0. 05 mg Se/m . Selyankina measured concentrations of
selenium in the air near two electrolytic copper plants. At one, the con-
3
centration was found to be 0. 50 yg/m ; 2 km from the plant, it was 0. 07
-39-
-------
3 3
Mg/m . At the other, the concentration was found to be 0. 39 ug/m ;
2 km from the plant, none could be detected. Seven air samples collected
in the spring at Cambridge, Massachusetts, contained an average of
3
0. 001 Pg/m as measured by neutron activation analysis with chemical
327
separation. Rain or snow water collected during a period of 2 years
423
(22 times) contained an average of 0. 2 y g per liter. Lakin and Byers
reported on the selenium content of some city dusts, finding values of
between 0. 05 and 10 ppm for various cities, but stated that they had no
basis for estimating the concentration of the element in the air from their
137
data. Using nondestructive neutron activation analysis, Dams et al.
3 3
found values of 0.0025yg/m at Niles, Michigan, and 0.0038 pg/m at
East Chicago, Indiana, for selenium in suspended particulates in the air.
321 3
In a related study, values of 0. 0008-0. 0044 ug/m were reported for
626
particulate matter of the air. Pillay et aL analyzed 18 samples collected
around Buffalo, New York, during 1968-1969. These samples consisted of
particulates collected on filter paper and gaseous materials absorbed by a liquid
trap. They used neutron activation with chemical separation and reported
-3 -3 -3
values ranging between 3. 7 x 10 and 9. 7 x 10 and averaging 6. 1 x 10
3
yg/m . Half of the selenium was in the gaseous fraction and half was in the
particulate matter collected.
Increasingly, data come from multielement analysis by neutron activation
without chemical separation. Care should probably be used in the acceptance
of some of the early data for selenium obtained in this way, since there were
585,651
potential sources of error with the procedures used.
-40-
-------
The Japanese Association of Industrial Health has recommended a
3
permissible level for selenium compounds in air of 0. 1 mg/m (as
selenium). This value is a time-weighted average for an 8-hr normal
639
working day and a 40-hr week, and it pertains to confined areas.
3
The USSR standard is also 0. 1 mg/m ; a limit for selenium compounds
in workroom air in the United States has been recommended as 0. 2 mg
3 17
Se/m .
125
Cooper has reviewed reports of selenium toxicosis in men working
in certain industries -where the element is processed. Again, analytical
data are sparse, but the situations described suggest that the high selenium
levels in these instances could easily be prevented by taking simple pre-
cautionary measures.
637
Rancitelli e£ a_L measured the concentrations of 19 elements in
rainwater samples and, to establish the origin of each element, compared
these with concentrations in seawater and the earth's crust. They con-
cluded that selenium in the atmosphere does not come from the land or the
ocean but probably results from man's activities, including the burning of
fossil fuel. However, volcanic activity and several other sources of
atmospheric selenium were not taken into account in arriving at this con-
859
elusion. Zoiler et aL studied the enrichment values of selenium in
atmospheric particles over Antarctica but were unable to tie it to any
particular source.
In spite of the paucity of data, it appears that selenium continuously
enters and is removed from the atmosphere and that its average concen-
3
tration in air is very low, probably well below 0. 01 pg/m . Its chemical
-41-
-------
form has not been ascertained, but probably a large proportion of what is
present is in the particulate matter. The evidence is not sufficient to
allow an estimate of what proportion derives from industrial or other
man-made sources. Nevertheless, it seems unlikely that pollution of
the atmosphere by selenium at present constitutes a problem.
-42-
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CHAPTER 3
INDUSTRIAL, AND AGRICULTURAL, USES
INDUSTRIAL
Data and text relating to supply and demand of selenium were derived from
3,794
various U.S. Bureau of Mines published and unpublished reports.
Production Methods
Although selenium is distributed widely in nature, the tenor of known
deposits is insufficient to permit their being mined for selenium alone.
Nearly all primary selenium is produced from copper refinery slimes, and
current production technology consists mainly of methods for extracting
selenium from these slimes. The processes used are primarily designed
for effective recovery of precious metal, and selenium recoveries have
secondary importance, which is reflected in the low recovery achieved for
selenium.
The first step in slime processing is decopperization. The copper con-
tent of slimes ranges from 10 to 70% and is in a form insoluble in cold sul-
furic acid. Some slimes can be decopperized with sulfuric acid and steam,
but usually roasting is needed to oxidize the contained copper to soluble com-
pounds that can be leached. After the leached residues are smelted in dore
furnaces, the metal continues to further refining steps, and the slags are
returned to the anode furnace after extraction of by-products.
Selenium may be recovered by volatilization during roasting, by leaching
of roasted calcine, by volatilization during furnacing, and by leaching of
furnace slag. Slimes containing moderate quantities of selenium and low
copper may, following decopperization, be roasted with sodium carbonate
flux to form a calcine containing soluble sodium selenite, which is leached
-43-
-------
with water. Slimes containing moderate quantities of selenium and copper
may be roasted with a flux of sulfuric acid and sodium sulfate. Selenium is
volatilized as an oxide and scrubbed from the roaster exhaust gas. Slimes
having relatively low selenium and copper content may be treated by de-
copperization and dore furnace smelting. Two methods are used. In one,
sodium carbonate flux is added to the slime, and the slag formed contains
sodium selenite, which is recovered by leaching. In the other method, the
slimes are first smelted with appropriate fluxes. Most of the selenium re-
mains in the metal portion of the melt, which is now refluxed with sodium
carbonate to form a slag rich in sodium selenite, which is recovered by
leaching. In both methods much of the selenium is volatilized during furnacing
and is recovered from the flue gases.
All processes use sulfur dioxide to precipitate selenium metal from solu-
tions of sodium selenite and selenious acid.
High-purity selenium is made by several methods, including fractional
condensation of volatilized selenium, zone refining, reduction and precipitation
from purified selenious acid, and gaseous or wet reduction of purified selenium
dioxide.
Some relationships between selenium and refined copper production are
shown for Canada and the United States in Table 3-1. The much larger re-
covery of selenium per unit of copper for Canada is due to the relatively high
selenium content of ores from the Noranda, Quebec, Flin Flon, Manitoba, and
Sudbury, Ontario, mines. Annual variability of the ratios in both countries
was probably a combination of changes in the ore tenor, delays in processing
of the residues, and economics of recovery.
-44-
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TABLE 3-1
Primary Selenium and Copper Production Relationship for
Canada and the United States £
Canadian Production
United States Production
Selenium
(1,000 Ib)
1964
1965
1966
1967
1968
1969
1970
1971
1972
1973
Total
466
512
575
752
636
599
663
718
582
598
6,101
Refined
Copper
(1,000 tons)
408
434
433
500
524
449
543
526
547
549
4,913
Se/Cu Selenium
Ratio (1,000 Ib)
(pounds/ton)
1.14
1.18
1.33
1.50
1.21
1.33
1.22
1.37
1.06
1.09
1.24
929
540
620
598
633
1,247
1,005
657
769
627
7,625
Refined
Copper
(1,000 tons)
1,656
1,712
1,711
1,133
1,437
1,743
1,765
1,592
1,873
1,868
16,490
Se/Cu
Ratio
(pounds/ton)
0.56
0.32
0.36
0.53
0.44
0.72
0.57
0.41
0.41
0.34
0.46
- Compiled from Bureau of Mines data.
Production Levels
The free world refinery production of selenium from 1964 through 1973
as shown in Table 3-2 averaged 2.3 million Ib annually. Output during this
period has trended upward and has ranged from a low of 1.7 million Ib in
1965 to a high of 2.9 million Ib in 1970. The United States has been the
leading producer for most of the years, followed by Canada, Japan, and
Sweden.
-45-
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Table 3-2
Selenium; Free World Refinery Production, by Country—
(1.000 Ib)
b
Country—
Q»
Australia—
d
Belgium-Luxembourg—
Canada
Finland
Japan
Mexico-
Peru
Sweden
United States
Yugoslavia
1964
4
87
466
15
326
7
17
181
899
8
1965
5
93
512
13
348
18
19
176
510
17
1966
4
91
575
12
421
4
13
154
590
21
1967
4
90
752
15
422
11
158
568
10
1968
4
54
636
16
399
2
13
168
603
21
1969
4
46
820
14
435
65
15
168
1217
20
1970
7
68
854
15
467
278
15
139-
975
35
1971
7
120
886
14
524
115
16
134
627
54
1972
7
147
655
16
738
97
18
140
739
55
1973
8
106
598
12
789
86
18
120
627
94
Total 2010 1711 1885 2030 1916 2804 2853 2497 2612 2458
a
-Compiled from Bureau of Mines data. Insofar as possible, data relate to refinery output of elemental selenium
only; thus, countries that produce selenium in copper ores and concentrates, blister copper, and/or refinery
residues, but do not recover elemental selenium, have been excluded to avoid double counting.
—In addition to the countries listed, West Germany and the USSR are known to produce refined selenium, and Zaire
and Zambia may produce refined selenium, but available information is inadequate for making reliable estimates
of output.
c
^Estimate.
d
-Exports.
—Elemental selenium only; excludes selenium content of sodium selenate produced (371,000 Ib in 1969).
-------
In the United States the 1973 production of selenium was accounted for by
four concerns with selenium refineries at four copper refineries, as follows:
Company Plant Location
AMAX, Inc. (Formerly American Metals Climax) Carteret, New Jersey
ASARCO, Inc. (Formerly American Smelting and
Refining Company) Baltimore, Maryland
International Smelting and Refining Company
(Anaconda)* Perth Amboy, New Jersey
Kennecott Copper Corporation Magna, Utah
Selenium is recovered in these four plants from slimes generated at these
refineries, and from inter plant transfers of selenium-bearing materials from
other domestic and foreign plants.
AMAX, Inc. , produces only commercial-grade selenium. American Smelting
and Refining Company produces commercial and high-purity grades and ferro-
alloys. International Smelting and Refining Company produces only commercial
grade. Kennecott Copper Corporation produces a plus 93%, a commercial, and
a high-purity grade.
Supply and Demand
Table 3-3 shows the United States selenium supply-demand relationships
for the 1964-1973 decade. The elements of production, imports, industry
stocks, and government purchases are reported quantities. These components
plus estimated exports are used to calculate an apparent industrial demand.
The distribution of this demand into a use pattern was based on a judgmental
balance of diverse sources of information.
*Closing in 1975.
-47-
-------
TABLE 3-3
Selenium Supply-Demand Relationships, 1964-1973~
oo
i
World production
UTil L 60, o LcLC 63™™™™™™™™™™"™"™™^""™ -j-
Rest of World
Components of U.S. supply
Refinery production
Government releases
Imports of refined
Industry stocks, Jan0 1 —
Distribution
Industry stocks, Dec. 31
Government purchases
Industrial demand
UoS. demand pattern
Electronic components
Ceramics and glass
U.S. primary demand (industrial
demand less secondary)
1964
899
1,673
2,572
899
30
293
1,022
2,244
1,305
100
18
821
285
250
186
100
791
(1,
1965
510
1,759
2,269
510
30
251
1,305
2,096
1,021
100
18
957
335
. 349
173
100
927
000 Ib)
1966
590
1,853
2,443
590
30
286
1,021
1,927
797
100
1,030
385
300
175
170
1,000
1967
568
2,040
2,608
568
30
301
797
1,696
445
196
22
1,033
438
321
169
105
1,003
1968
603
1,936
2,539
603
30
583
^736
1,952
428
405
49
1,070
500
300
150
120
1,040
1969
1,217
2,046
3,263
1,217
30
546
428
2,221
240
500
1,481
555
550
200
176
1,451
1970
975
1,892
2,867
975
30
454
240
1,699
189
376
1,134
500
370
135
129
1,104
1971
627
2,489
3,146
627
30
395
189
1,241
182
150
909
394
316
128
71
879
1972
739
2,393
3,132
739
30
14
430
182
1,395
161
220
1,014
458
344
136
76
984
1973
627
2,376
3,003
627
30
229
553
161
1,600
106
264
1,230
554
418
160
98
1,200
— Compiled from Bureau of Mines data.
— Includes a stock adjustment of plus 291.
-------
The apparent annual consumption of selenium in the United States increased
507. from 1964 to 1973. The most significant increase has been in its use in
electronic components, which has risen from 285,000 Ib in 1964 to 540,000 Ib in
1973, equal to 45% of 1973 demand. The use of selenium in manufacturing glass
and allied products, probably its oldest application, increased 67% over the
decade because of the increasing quantities of selenium-containing tinted glass
used in the construction and transportation industries.
Canada, the source of most of the refined selenium imported into the United
States, supplied 516,000 Ib or 93 percent of the total imports in 1973.
Uses
Table 3-4 lists the uses of the principal commercial selenium compounds.
Some additional compounds which may have commercial uses are: ammonium hydro-
selenate, ammonium selenate, antimony triselenide, arsenic pentaselenide, arsenic
triselenide, beryllium selenate, cadmium selenate, cesium selenate, chloro-
selenic acid, cupric hydroselenite, cupric selenite, gold selenate, gold selenide,
hydrogen selenide, lead selenate, lead selenite, lithium selenate, lithium
selenite, manganese selenate, manganese selenide, manganese selenite, phosphorus
pentaselenide, phosphorus triselenide, potassium biselenite, potassium selenide,
rubidium selenate, selenic acid, selenium chloride, selenium oxychloride,
selenium oxyfluoride, selenium tetrabromide, selenium tetrachloride, silver
selenide, silver selenite, sodium hydroselenite, sodium selenide, stannic
selenite, stannous selenide, strontium selenate, strontium selenide, thallium
selenate, thallium selenide, zinc selenate. The ensuing description of
industrial uses largely summarizes a more detailed coverage of the subject con-
tained in three publications. >>858a Those publications also describe the
physical, electrical, and chemical properties of selenium underlying the
utilization of selenium.
-49-
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Electronic. Electronic applications account for a substantial part of
selenium consumption. Selenium has been used in dry-plate rectifiers, which
change alternating current to direct current, for many years. The plates
range in size from 8 in. across to a miniature encapsulated-type smaller than
a matchhead. About 1952, silicon and germanium rectifiers were introduced
and have since captured a large share of the rectifier market from selenium.
A large and growing electronic use of selenium is in photocopying, a dry
photographic process, which employs photoconducting, amorphous, selenium-
coated metal drums from which the photographic image is transferred by static
electricity. The photoconducting property of amorphous selenium is also the
basis of the vidicon television camera. The illuminated portions of the pattern
projected upon the selenium layer transmit a light signal when scanned by the
electronic beam.
Selenium is used in construction of the photoelectric cell. In commercial
application, the cell consists of an emitter (a metal surface covered with a
thin layer of selenium) and a collector, both enclosed in an evacuated container.
It requires an external source of electromotive force, and its output cannot
be readily amplified. It has the disadvantage of variability, which makes it
unsuitable for precision instruments such as colorimeters and pyrometers. The
principal application has been for construction of the electric eye.
The photocell, or photovoltaic cell, utilizes the property of selenium to
convert light energy directly into electrical energy. The functioning of devices
such as the photographic exposure meter depends on this phenomenon. Solar
-50-
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TABLE 3-4
Uses of Some Inorganic Selenium Compounds
Aluminum selenide, Al Se
2 3
Ammonium selenite, (NH ) SeO
42 3
Arsenic hemiselenide, As Se
2
Bismuth selenide, Bi Se
2 3
Cadmium selenide, CdSe
Calcium selenide, CaSe
Cupric selenate, CuSeO
In preparation of hydrogen selenide; in
semiconductor research
In manufacture of red glass; as reagent
for alkaloids
In manufacture of glass
In semiconductor research
In photoconductors, semiconductors,
photoelectric cells, and rectifiers;
in phosphors
In electron emitters
In coloring Cu or Cu alloys black
Cupric selenide, CuSe
Indium selenide, InSe
Potassium selenate, K SeO
2 4
Selenium disulfide, SeS
Selenium hexafluoride, SeF
As catalyst in Kjeldahl digestions;
in semiconductors
In semiconductor research
As reagent
In remedies for eczemas and fungus
infections in dogs and cats; as anti-
dandruff agent in shampoos for human
use; usually employed as a mixture with
the monosulfide
As gaseous electric insulator
Selenium monosulfide, SeS
Selenium dioxide, SeO
Sodium selenate, Na SeO
2 4
Sodium selenite, Na SeO
2 3
Veterinary use: topically against eczemas,
fungus infections, demodectic mange, flea
bites in small animals; usually employed
as a mixture with the disulfide
In the manufacture of other selenium com-
pounds; as a reagent for alkaloids
As veterinary therapeutic agent
In removing green color from glass during
its manufacture; as a veterinary therapeutic
agent
-51-
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batteries may be considered photovoltaic cells designed for maxium conversion
of solar radiations into electrical energy.
Metallurgic. Selenium has been used as a degasifier in stainless steel
since the midthirties. Use for that purpose disclosed that the selenium also
improved casting, forging, and machinability properties without reducing
corrosion resistance or malleability. The selenium content of casting steel
alloys ranges from 0. 01 to 0.05%, forging steels from 0. 18 to 0. 22%, and free-
machining steels from 0. 05 to 0. 35%. Selenium is also added to copper to im-
prove machinability properties.
Since 1959, selenium has been used in chromium plating solutions to produce
a plating with better characteristics, to reduce cost, and to improve quality con-
trol. Chromium, plated from solutions containing selenate ions, is characterized
by about 1, 500 microcracks per linear inch. The most desirable pattern is ob-
tained by use of a plating solution with 0. 012 to 0. 020 g of selenate per liter. Micro-
cracked chromium reduces corrosion of the substrate and provides a surface with
less glare.
Glass and Ceramics. The glass and ceramics industry is one of the oldest
and largest users of selenium. Selenium is added to the glass melt as elemental
selenium, sodium selenate, barium selenite, or sodium selenite in quantities
from 0. 02 to 0. 3 Ib per ton to neutralize the green tint in glass due to iron
impurities and thus permit manufacture of clear glass. A desirable pink tinge
is given to glass by using more selenium. Addition of larger quantities of
selenium yields a ruby-red glass used in tableware, light filters', and traffic
and signal lenses. A large and growing use is in dark-colored glass placed in
buildings and vehicles to reduce glare and the rate of heat transfer into air-
conditioned spaces.
-52-
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Mixtures of selenium and arsenic are used in making low-melting glasses
having infrared transmitting characteristics.
Pigments. The chemical industry uses an estimated one eighth of the
selenium consumed. Much of this is consumed in pigment manufacture. In
the preparation of selenium-containing pigments, the selenium is compounded
with cadmium sulfide to obtain the orange-red-maroon cadmium sulfoselenide
pigments. These pigments have considerable stability when exposed to sunlight,
heat, and chemical attack. They are used to color plastics, paints, enamels,
inks, and rubber.
Pharmaceuticals. Selenium is a constituent of fungicides for the control of
dandruff and dermatitis, A com-
mercial dandruff shampoo containing selenium sulfide has become an important end
use for selenium in recent years. The chemical industry also uses it as a catalyst
in the preparation of Pharmaceuticals, such as niacin and cortisone.
Miscellaneous Uses. Selenium along with tellurium is used as an oxidant
in the delay train of millisecond-delay electric blasting caps. The quantity of
oxidant is dependent on the delay desired but averages about half a gram a cap.
Selenium is used as an accelerator and vulcanizing agent in rubber products
to promote heat, oxidation, and abrasion resistance, and also to increase the
resilience of rubber. Selenium dioxide is used to oxidize, hydrogenate, or de-
hydrogenate organic compounds; selenium catalyst hardens fats for use in soaps,
waxes, edible fats, and plastics; selenium imparts exceptional antioxidant proper-
ties to printing ink, mineral oils, transformer oils, and vegetable oils, and non-
drying properties to linseed, oiticica, and tung oils. Selenium oxychloride is a
powerful solvent that may be used as a paint and varnish remover and as a solvent
-53-
-------
for rubber resins, glue, and other organic substances. Selenium compounds
find application in lubricating oils and in extreme-pressure lubricants through
their antioxidant and antigalling properties; in photographic photosensitizers
and toners; and in mercury vapor detectors, fireproofing agents, insect re-
pellents, phosphorescents, and luminescents.
AGRICULTURAL
Pesticides
In agriculture, selenium was first used as an ingredient in various com-
729
pounds for control of mites and insects. Smith reviewed this aspect for
the period up to 1961.
About 1933 selenium was used in a material called Selocide, which was
prepared by dissolving elemental selenium in potassium ammonium sulfide
solutions in proportions corresponding to the formula [K(NH )S] Se. This
4 5
apparently was the first use of selenium as a pesticide. Selocide was found
to be quite effective as a miticide and was used on citrus, grapes, and orna-
mentals. Later, resistance to Selocide appeared in some types of mites and
the use of this material declined.
Selenium was also used in foliar sprays and in soil applications of selenates.
Applications of selenate to the soil resulted in plants that contained concentra-
tions of selenium high enough to render them toxic to certain insects.
Concern over the possible health hazards from selenium residues in
plants resulted in restrictions on selenium insecticides. They were restricted
first to ornamental plants, then to greenhouse-produced ornamentals.
At the time of Smith's review in 1961, the only registered uses of selenium
insecticides were for ornamentals and for use of Selocide on citrus in California.
-54-
-------
Although there are no records of injury to human beings and animals from the
use of selenium-bearing insecticides, it appears that these materials are no
longer used.
Control of Dermatitis, Pruritis, Mange
An additional use of selenium, probably stemming from the use of a
material called Selsun for control of dandruff in human beings, consists of
topical application of a 1% solution of selenium sulfide for control of dermatitis,
pruritis, and mange in dogs.
Supplementation for Selenium-Deficient Areas
Discovery of the beneficial effects of selenium in the prevention of certain
economically important diseases of livestock led to interest in methods of supple-
menting livestock with this element. Alternative methods of controlling selenium
548
supplies to livestock are reviewed in Selenium in Nutrition.
Injectable Methods. The use of injectable selenium, usually as sterile
mixtures of sodium selenite and vitamin E in an oil base, was the first method
of supplementing livestock with selenium to gain general acceptance. This was
536a 420
based on the work of Muth, and of Kuttler and Marble. Experiments
on various methods and rates of selenium administration have been described
323
by Hartley.
Injectable selenium is normally used on lambs and calves, levels being
adjusted to about 1 mg selenium per 100 Ib liveweight. Animals are injected
as soon after birth as possible and may be reinjected 4-6 weeks later if it is
necessary to maintain their dams on diets low in vitamin E for long periods.
Many stockmen in the low-selenium regions of the United States routinely
-55-
-------
inject all lambs and. calves born during the winter months, but do not inject
animals after they and their dams obtain access to green pasture, because
green pasture is considered to contain sufficient vitamin E to lower selenium
requirements to the point of avoiding death losses. In New Zealand injections
or oral drenches of selenium are used even though animals have access to
green pastures. In the United States, injactable selenium formulations are
licensed for sheep, lambs, calves, cattle, horses, and dogs, and a selenium
capsule is licensed for oral application to dogs. The exact extent of use of
injectable selenium is not known. However, it is unquestionably very common
in the selenium-deficient areas of the northwestern and northeastern parts of the
United States and in adjacent areas of Canada. One authority has estimated that
the discovery of the responses of livestock to selenium "will add ten million
536
dollars to the income of livestock producers in Northwest U.S.A. alone."
Additive to Animal Feeds. Decisions concerning the use of selenium as
an additive to animal feeds •were delayed for reconsideration of the question of
carcinogenicity of selenium. On April 17, 1973, in response to a petition of the
American Feed Manufacturers Association, the Commissioner of Food and Drugs,
U.S. Department of Health, Education, and Welfare, proposed that the food
additive regulations be amended to provide for the safe use of selenium as a
797
nutrient in the feed of chickens, turkeys, and swine. The proposed regulation
796
was approved. It provides for the addition of sodium selenite or sodium selenate
up to 0. 1 ppm of selenium in the complete diet for growing chickens and swine
and 0. 2 ppm in the complete diet for turkeys. The selenium must be added in
a premix formulated in such a way that at least 1 Ib but not more than 2 Ib of
premix are added per ton of complete feed. Feeds containing added selenium
may not be administered to laying hens.
-56-
-------
In announcing the proposed change in regulations, the Food and Drug
Administration provided information relative to the need for selenium supple-
mentation and the safety of this practice. This agency also stated that "avail-
able data [on the carcinogenicity of selenium] have been evaluated by the Food
and Drug Administration and the National Cancer Institute," and continued:
"Based on these evaluations, it has been concluded that the judicious administra-
tion of Se derivatives to domestic animals would not constitute a carcinogenic
risk. " The Bureau of Veterinary Medicine of the Food and Drug Administration
also submitted a Draft Environmental Impact Statement supporting the safety of
795
the proposed regulations.
Application to Soil and Use of Foliar Sprays. Difficulties involved in the addi-
tion of selenium to feeds for cattle and sheep, and the labor involved in the use of
injections of selenium, have prompted consideration of the use of soil applications
of selenium as a way of meeting dietary requirements of cattle and sheep for this
element. Soil applications would require more selenium than the use of injections
or feed additions; so would the application of foliar sprays to forage crops. Sup-
plies of selenium and its compounds are not adequate for any widespread use of
this element as a soil application. A number of studies concerning selenium ap-
plication to soils as a means of increasing the concentration of the element in
52, 53, 108, 111, 141, 142, 251, 253, 254, 822, 823
plants have been reported. It has
been shown under experimental conditions that the addition of 2-4 Ib of selenium
as selenite per acre, incorporated into acid or neutral, medium-textured soils,
will provide crops with protective but nontoxic concentrations of selenium for
several years. However, inadvertent use of this same rate of selenium applied
as selenate would result in crops containing acutely toxic concentrations of this
-57-
-------
element. This same rate of selenium applied as elemental selenium probably
would not increase the selenium level in crops to the concentrations required
to protect animals from selenium deficiency diseases. Therefore, considera-
tion of soil applications of selenium for farm practice at this time is precluded
by the lack of necessary supplies of selenium and by the need for close supervision
of the form of selenium used and the rate of application. The use of foliar
sprays onto growing forage and grain crops is likely to be more efficient in
terms of selenium required, but additional research is needed before foliar
application of selenium can be recommended as a farm practice.
Chief Agricultural Use of Selenium. Without doubt, the chief agricultural
use of selenium, in terms of amounts of selenium involved, has been the feeding
of forage crops and feed stuffs that naturally contain protective but nontoxic levels
of this element to farm livestock. Although this has been done without any realiza-
tion on the part of stockmen that selenium nutrition of their animals was involved,
it has probably been a major factor in the efficiency of livestock production in
418
the United States. According to Kubota et aL , there is a large region in the
West Central States where crops normally contain adequate but nontoxic levels
of selenium. This region includes some of the major feed grain, soybean, forage,
and livestock producing areas of the United States. Feed grains, soy protein, and
dehydrated alfalfa from this region are shipped to many other parts of the United
States and to foreign countries for feeding to animals.
-58-
-------
CHAPTER 4
CYCLING
NATURAL
A number of authors have prepared diagrams and discussed the cycling
525
of selenium in nature. In 1939, Moxon e_t aL developed a scheme depict-
ing the movement of selenium to illustrate what they felt was the role of the
708
so-called converter plants in nature's cycling of the element. Later, Shrift
proposed a biologic pathway based on oxidation and reduction processes. Lakin
424
and Davidson illustrated the geochemical movement of the element, and
12
Allaway ^t aL discussed its cycling at low levels, illustrating not only the
directional but also the quantitative aspects of the movement of selenium in the
9
soil-plant-animal system. More recently, Allaway offered a scheme suggest-
ing the chemical changes that occur in the element as it passes through this
system. The movement of high levels of selenium in nature has been summarized
576
diagrammatically by Olson.
In retrospect, the proposed pathways of Moxon and co-workers, of Lakin and
Davidson, and of Olson depict mac recycles; the proposed pathway of Shrift and the
metabolic pathways discussed below depict microcycles; and the changes suggested
by Allaway and co-workers depict a mixture of the two. This section ("Natural")
will deal only with the macrocycling of the element.
Macrocycles
Figure 4-1 suggests many of the pathways that appear to be of some signifi-
cance in the movement of selenium between the air, land, and seas. While an
attempt has been made to quantitate the various paths and to express this
-59-
-------
quantitation by varying line densities in the figure, data to justify this are
very meager or lacking. The evidence that does exist for this scheme has
been presented in Chapter 2 and in the publications mentioned above. Where
direct evidence for pathways is lacking,they are based on inferences from what
we know about the occurrence of the element, the food chain, and geologic and
geochemical processes.
Earth. Selenium seems ubiquitous, and since the cooling and hardening
of the earth's crust, more has been brought to the surface by igneous extrusion
and in volcanic emissions. Molten rocks release the element through volatiliza-
tion into the atmosphere during their cooling, and weathering removes more of
the element from the igneous rocks thus formed. Some of the element remains
with residual material that eventually forms soils.
Atmosphere. The atmosphere receives selenium from a number of sources
other than molten rocks or volcanoes. Spray from large bodies of water no doubt
contributes some, although the amount is probably very small. Dusts from land
surfaces contribute more. Animals exhale volatile selenium compounds, and
certain plants also produce them and release them into the atmosphere. Micro-
•
organisms are in many cases capable of volatilizing the element from a variety
of sources. Removal of selenium from the atmosphere in precipitating particu-
late matter or in rain and snow results in its deposition on land and water
surfaces.
Water. Besides receiving selenium from the atmosphere, oceans and other
large bodies of water receive the element from water that runs into them, and they
deposit it in their sediments, possibly with the aid of microbial action. Running
-60-
-------
water also transports the element from drainage areas to floodplains or to
poorly drained basins, where it is deposited. Sedimentary rocks or other
sediments have been the parent materials for many of our soils.
Selenium and the Food Chain
The cycling of this element between soils, groundwater, running waters,
plants, and animals follows in a general way the cycling of many mineral ele-
ments important to the nutrition of man or animals. It appears that soils
gradually lose their selenium to eventual deposition in sediments, although
some is returned via the atmosphere. It is not possible, actually, to weigh
the importance of these two phases of the cycling process and to determine
whether selenium is becoming more or less available to the food chain and
424
thus to man. However, as Lakin and Davidson point out, volcanic activity
may result in "a land surface enriched in selenium as compared to the earth's
crust as a whole. "
INDUSTRIAL
144
A 1972 report by W. E. Davis and Associates for the Environmental
Protection Agency (EPA) attempted an inventory of industrial atmospheric
emissions of selenium. The report noted the virtual nonexistence of published
data on selenium emissions and ascertained through contacts with industry that
selenium emissions were not a matter of record. However, estimates for
selenium emission factors have been made on the basis of information in the
625,705,759
Davis report, other published reports, and related processing data.
The estimates are given in Table 4-1.
-61-
-------
Figure Caption
Figure 4-1. The cycling of selenium in nature. For simplicity, micro-
organisms are not included in the above scheme, although they are important
to many of the processes involved in the cycle.
-62-
-------
Figure 4-1
SEDIMENTS &
SEDIMENTARY
ROCKS
OCEANS.
SEAS RUNNING
& and
LAKES GROUND
ATMOSPHERE
MOLTEN
ROCK
VOLCANISM
EARTH'S
CORE
-63-
-------
TABLE 4-1
Estimates for Selenium Emission Factors
Mining and milling
Coppe r
Lead
Zinc
Phosphate (western)
Uranium
Smelting and refining
Copper
Lead
Zinc
Selenium refining
Primary (from copper by-
products)
Secondary
End product manufacturing
Glass and ceramics
Electronics and electrical
Duplicating
Pigments
Iron and steel alloys
Other
Other emission sources
Coal
Oil
Incineration
Estimates for Selenium Emission Factors
0.015 Ib/thousand tons ore mined
0.047 Do.
0.032 Do.
0.350 Do.
0. 350 Do.
0. 25 Ib/ton copper produced
0. 05 Ib/ton lead produced
0. 04 Ib/ton zinc produced
277 Ib/ton selenium recovered
100 Do.
700 Ib/ton selenium consumed
2
2
15
1,000
10
Do.
Do.
Do.
Do.
Do.
2. 90 lb/1, 000 tons coal burned
0. 21 lb/1, 000 barrels oil burned
0. 02 lb/ 1, 000 tons of refuse burned
144
Derived from W. E. Davis and Associates
and related processing data.
-64-
-------
Mining and Milling
The emission factors for mining and milling were estimated from reports
on the selenium content of ores and concentrates at over 40 large mines and
mills. Atmospheric emissions from mining and concentrating result mainly from
windblown finely ground tailings. Yearly emissions are estimated at 1% of the
selenium placed on tailing dumps annually.
Base Metal Smelting and Refining
Smelting and refining emission factors were estimated from reports at two
smelters, from the selenium content of smelter feed, from the amount of metal
produced, and from the estimated selenium content in slags.
Selenium Refining
The emission factor of 277 Ib per ton of selenium produced in primary
selenium refining as done at precious metal refineries is an estimate based
144
on reports of experience obtained from two sources.
Emissions from secondary production of selenium were estimated at 100
Ib per ton of selenium produced, on the basis of an office study of processing
144
methods.
End Product Manufacturing
No reliable reports of volatilization losses of selenium in glass manufacturing
are available. Emissions are high because the temperature of molten glass is
considerably above the boiling point of selenium. The emission factor is estimated
at 700 Ib per ton of selenium consumed, on the basis of an estimate made for
selenium emissions from molten steel of 1, 000 Ib per ton of selenium added.
Emissions from electronic and electrical manufacturing was estimated at 2 Ib
-65-
-------
per ton of selenium consumed, on the basis of information furnished by manu-
144
facturers. Relatively small quantities of selenium are emitted to the
atmosphere during manufacture of duplicating equipment, according to informa-
tion obtained from industry. The emission occurs principally during the vacuum-
plating process used in manufacturing selenium-coated plates and drums. An
estimated 2 Ib of selenium was emitted per ton of selenium processed. The major
compounders of selenium containing pigments estimated that 15 Ib of selenium
was emitted per ton of selenium processed. All reported that bag filters were
used for emission control. Selenium emissions during iron and steel alloying
are estimated at 1, 000 Ib per ton of selenium metal consumed. Selenium emissions
in other manufacturing processes were assumed to average 10 Ib per ton of selenium
processed.
Burning Coal and Oil
Estimates of selenium emissions from coal-burning are based on an average
625
selenium content of United States coal of 2. 76 ppm, as reported by Pi Hay et al.
759
and Swanson, and on the results of a study on the disposition of selenium in
759
the combustion products of coal burned in five large modern power plants.
The study concerned with the five large plants showed that about 53% of the
selenium contained in the coal was emitted to the atmosphere as volatilized
selenium or included with particles of fly ash too fine to be trapped by standard
dust collectors. In the case of fuel oil, the selenium emission factor was based
on analyses of metal concentrations in oil that were done for EPA in 1971. The
average selenium content of 10 samples of foreign and domestic crude oil was
0. 4 ppm. The average for 27 samples of imported residual oil was 0. 6 ppm.
-66-
-------
Solid-Waste Incineration
The emission factor for incinerators was based on limited data from a
single facility and obviously may not represent a nation-wide average. The data
were obtained from a 3-day study of an incinerator processing about 245 tons of
municipal solid waste daily. Analyses of stack emissions indicated a range of
34-63 Ib of selenium per million tons of refuse for the first day and a range of
387
9-23 Ib the second day; none was detected the third day. Household, com-
mercial, and municipal solid wastes are estimated to be in excess of 250 million
55
tons per year, and about 8% of the municipal waste is incinerated. An
arithmetic average of the available data indicates the likelihood of relatively
small quantities of selenium emissions from incineration of municipal waste.
Selenium Materials Balance
in a selected year (1970)
An estimated materials balance for selenium/is shown in Table 4-2. It is
based mainly on emission factors (discussed in this Chapter), on selenium
production and consumption (discussed in Chapter 3), and on nonferrous metal
production and fuel consumption (information obtained from the Bureau of Mines
Minerals Yearbook). For selenium production, the input quantity was derived
by applying the indicated recovery factor to the reported production. The solid-
waste quantities were calculated by subtracting the atmospheric emissions and
intermediate or commercial products from the input quantities. In the last
category of the table, which shows final consumption of selenium, the total
quantity incinerated or otherwise disposed of was estimated by assuming that
articles containing selenium have an average life of 10 years. The intermediate
product recovered from disposed-of material is scrap metal, largely reclaimed
photocopying plates.
-67-
-------
TABLE 4-2
Estimated Selenium Materials Balance for a Selected Year (1970)
00
I
(1,000 Ib, selenium)
Production
Mining and milling
Smelting and refining
Selenium primary refining
Selenium secondary refining
Total production
Industrial consumption
Glass and ceramics
Electronics and duplicating
Pigments
Iron and steel alloys
Other
Total consumption
Other sources and final
consumption
Coal
Fuel oil
Incineration
Other disposal
Total emissions
Selenium
Input
6,400
2,800
1,900
33
370
500
130
50
84
1,134
2,900
130
80
710
Atmospheric
Emissions
10
500
130
3
130
1
1
25
-*-
1,500
130
a_
•a
2,430
Solid
Waste
3,600
400
800
a,
a
a
£
a_
a.
1,400
0
80
700
6,980
Selenium
Intermediate
Product
2,800
1,900
0
0
0
0
0
0
0
0
0
0
30
Selenium in
Commercial
Product
0
0
970
30
1,000
240
499
129
25
84
0
0
0
0
-Less than 1,000 Ib of selenium.
-------
Although this tabulation represents a reasonable balance for selenium,
it must be recognized that it is based on very sparse direct information and
in some instances on tenuous assumptions. Additional selenium emissions
could derive from pulp and paper manufacture, sulfuric acid production, and
other facilities where sulfur is used or contained in the raw materials that
are processed.
Selenium as an Industrial Pollutant
In summary, the total industrial emissions of selenium were estimated
for 1970 at 2,430,000 Ib, or 1,215 tons. Burning of coal accounted for 62%
of the total, followed by losses of selenium in nonferrous mining, smelting,
and refining operations, which accounted for 26% of the total. Almost all of the
remainder was equally divided among precious metal refinery operations, where all
primary selenium is now a by-product, the loss of volatilized metal in glass
manufacturing, and the burning of fuel oil.
No serious problem seems to be presented by the relatively small quantity
of estimated atmospheric emissions of selenium from industrial sources, assuming
adequate dispersal procedures. No reports were found that gave any data on the
concentration of selenium emissions resulting from domestic industrial operations,
or for the selenium content of air near installations that are known to emit selenium.
Analyses of selenium in ambient air have been reported for 21 metropolitan
744
areas. All but two of the cities studied were reported to have concentrations
of less than 0.04 >ug per cubic meter of air. Slightly higher concentrations were
reported from Los Angeles and Denver (in the case of Los Angeles, probably due to
the dense population and mountainous topography). There seems little measurable
correlation between
-69-
-------
general selenium atmospheric concentrations and the location of industrial
selenium emissions. For example, in California very little nonferrous metal
is produced and very little coal or fuel oil is burned, but the selenium concen-
tration in the air is about the national average at Long Beach and San Francisco,
slightly higher at Los Angeles, and average at Phoenix, Arizona, and Las Vegas,
Nevada. Natural concentrations of selenium appear to be much more important than
man-made, and any industrial selenium pollution would probably be restricted
to the immediate vicinity of refineries emitting selenium.
A study has been reported on the atmospheric concentration of selenium
694
in the vicinity of two electrolytic copper refineries in the Urals of the U. S. S. R.
Table 4-3 summarizes the results. The selenium was considered to be emitted
from the plant treating the anode slimes for by-product recoveries. Effluents
from the furnaces were subjected to particulate control considered 96% efficient
and then discharged through chimney stacks, 50 m tall at the Pyshma plant and
10m tall at the Kyshtym plant. Concentrations on the factory grounds were
indicated to be largely due to accidental discharges bypassing the stacks.
No data were available to show whether industrial emissions of selenium
or selenium compounds to the atmosphere were recycled to the land and sea by
normal atmospheric processes. Emissions of sulfur, chemically similar to
selenium, are stated to have a life cycle in the atmosphere ranging from 4 hours
23
to 4 days, the time depending on climatic conditions. However, industrial
emissions of selenium probably occur primarily as finely divided solid particulates in
contrast to sulfur emissions, which are primarily in a gaseous state, implying
that selenium emission control requires a different but possibly simpler method
549
than does sulfur.
-70-
-------
TABLE 4-3
Selenium Concentrations in the Atmosphere—
Distance from
Pyshma
Kyshtym
Factory (km)
0
0.5
1
2
Number of
Samples
16
43
24
30
Selenium
Concentration,
Vg/m3
Mean ± SE
0.50 ± 0.16
0.15 ± 0.03
0.11 + 0.04
0.07 _ 0.01
Confidence
Limits
0.18 - 0.82
0.10 - 0.20
0.07 - 0.15
0.05 - 0.08
Number of
Samples
18
19
18
16
Selenium
Cone ent rat ion ,
yg/m3
Mean ± SE
0.39 1 0.04
0.36 ± 0.05
0.30 ± 0.07
Not detected
Confidence
Limits
0.31 - 0.47
0.26 - 0.46
0.16 - 0.44
Not detected
2. Derived from Selyankina.594
-------
Pollution Control
Reduction of industrial emissions of selenium may occur with implementation
of other pollution control actions. The close association of selenium with sulfur
in its occurrence and their similar chemical properties would suggest a corres-
ponding reduction in the emission of selenium as sulfur control and associated
removal of particulates become effective. Copper, lead and zinc smelters were
estimated to recover 26% of the sulfur contained in the smelter feed as sulfuric
793
acid in 1970, an increase from the estimated 20% in I960. Most promulgated
emission-control regulations for nonferrous smelters now specify achievement of
about 90% sulfur control. Similar sulfur-emission control programs are being
instituted for the burning of coal and fuel oil. Improved particulate-control pro-
grams at plants processing sludges that contain selenium and at plants consuming
selenium would reduce emissions of selenium along with other pollutants.
-72-
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CHAPTER 5
BIOLOGIC EFFECTS
METABOLISM
A portrayal of the basic metabolic reactions in which selenium is involved
is vital to the understanding of its biologic effects. This section covers meta-
bolic reactions of selenium in animals, plants, and microorganisms.
Animals
The pattern of selenium absorption, distribution, excretion, and retention
in animals precedes discussions of mechanisms of bioconversion of selenium and
interrelationships with other elements.
Absorption
Gastrointestinal tract. The transport of selenium across the intestinal
739
tract was first investigated by Spencer and Blau, who used the everted hamster
intestinal sac as a model system. Their studies were limited to selenomethionine,
and they found that
the seleno-analogue was taken up to about the same extent as methionine. This
481
approach was later expanded by McConnell and Cho, who found that seleno-
methionine was transported against a concentration gradient whereas selenite and
selenocystine were not. Methionine could inhibit the transport of selenomethionine,
but sulfite and cystine did not compete with selenite or selenocystine. The authors
suggested in this and in a later paper that a methionine/selenomethionine trans-
port antagonism might account for some of the protective effect of high protein
diets in selenium toxicity.
The gastrointestinal absorption of radioselenite by swine and sheep
850
was studied by Wright and Bell. More selenium was absorbed from the
-73-
-------
gastrointestinal tract by the monogastric animals than by the ruminant animals.
This species difference was thought to be due to the reduction of the administered
selenite to insoluble or unavailable forms by rumen microorganisms. Other
88,128,457 69
workers have reached similar conclusions. Brown e_ta]L. recently
investigated the effect of dietary selenium on the intestinal absorption of radio-
selenite by rats. All the animals absorbed from 95 to 100% of the administered
75
Se regardless of whether the diets contained 0. 02 or 4. 02 ppm of selenium.
Since the selenium was essentially totally absorbed irrespective of the selenium
status of the animal, no absorptive regulatory function appeared to operate under
the conditions of their experiment. The authors cautioned, howeve, that studies
on the absorption of the natural forms of selenium that occur in foods are needed.
Lungs. Although the poisonous nature of certain volatile selenium
160,161
compounds, such as hydrogen selenide, is widely appreciated, the
literature contains practically no quantitative data on the pulmonary absorption
of gaseous or finely dispersed particulate selenium compounds. In spite of the
fact that elemental selenium is relatively nontoxic, exposure to red selenium
18
fumes causes severe irritation of the mucous membranes when inhaled.
A curious difference in the inhalation toxicity of the hexafluorides of sulfur,
404
selenium, and tellurium was noted in rodents. The relative harmlessness
of the sulfur derivative was due to the fact that this compound, unlike the selenium
and tellurium derivatives, was not hydrolyzed in the lungs to more toxic products.
Skin. The literature contains few quantitative data pertaining to the
165
dermal absorption of selenium compounds. However, Dutkiewicz e_t al. found
that 10% of a 0. 1-M solution of sodium selenite applied to rat skin was absorbed
in 1 hr.
-74-
-------
Distribution
Internal organs. Early studies concerning the distribution of selenium
in the internal organs quite naturally dealt with toxic doses of the element, since
only the poisonous nature of selenium was appreciated at the time. Also, the
methodology for investigating the metabolism of trace quantities of selenium was
not available.
735
Smith e_t al. found a wide distribution of selenium throughout
the body tissues of cats chronically poisoned with subacute doses of sodium
selenite. Highest concentrations of selenium were found in the liver, kidney,
pancreas, spleen, heart, and lungs; smaller amounts were found in the red
blood cells and brain and still smaller amounts in the plasma, intestine, muscle,
bone, and fat. A similar pattern of tissue storage of selenium was seen in animals
chronically poisoned with the organic selenium that occurs naturally in grains,
although the overall tissue retention of selenium was greater in the animals fed
734
the organic selenium than in the animals given the inorganic selenite. The
distribution of selenium in cattle and sheep chronically poisoned with inorganic
257,464
selenium was like that reported above for laboratory animals.
In the experiments referred to above, the animals were exposed to
selenium on a long-term basis. Wide distribution of the element in the internal
organs of animals was also seen in relatively short-term metabolic experiments
477
conducted by McConnell, who introduced radioselenium as a research tool.
After a single subacute dose of radioselenate, the highest concentrations of
selenium were found in the liver, kidney, (total) muscle mass, gastrointestinal
tract, and blood. Similar results were reported for the metabolism of radio-
331
selenite in mice. The availability of selenium isotopes of high specific
activity made possible the study of the fate of microgram quantities of selenium
-75-
-------
352
in animals. Hopkins et aL made the surprising observation that the
24-hr percentage distribution of selenium in the internal organs of rats was
largely independent of dose over the range 0. 025-1 yg selenium/100 g body
weight, although carcass retention of selenium was decreased and urinary
excretion of selenium was increased at the higher dose level. Likewise,
75
24 hr after the intraperitoneal injection of 1 yg of Se as selenite, there
7'5
was little or no difference in the amount of Se appearing in the liver of
rats fed diets containing either 0. 04 or 5. 04 ppm of selenium. However, a
75
decreased amount of Se appeared in the kidneys, blood, and carcass of
the animals fed the diet containing the higher level of selenium. This metabolic
difference between the liver and the rest of the body was thought to be con-
sistent with a relatively rapid turnover of selenium in the liver. Although
75
only relatively small amounts of Se were found in the testis in these short-
term studies, long-term experiments have demonstrated the importance of this
82
organ in selenium metabolism.
Since the chemical form of selenium in foods is apt to be organic
selenium rather than selenite or selenate, the distribution of organic forms
75 375 75
of Se is of interest. Jacobsson showed that the uptake of Se in the
tissues of sheep after injection of a single dose of selenite, selenomethionine,
75
or selenocystine was about the same except that a higher Se-level was
found in the pancreas when the seleno-amino acids were given. Likewise,
30 75
Awwad e£ aL found the most radioactivity after the injection of Se-
selenomethionine in the pancreas, intestine, liver, and kidney. Anghileri
21
and Marques also found a high level of activity in the pancreas 8 hr after
75 75
intravenous injection of Se-selenomethionine or Se-selenocystine, but
this activity tended to disappear from this organ after 1 week, whereas the
-76-
-------
activity associated with the liver remained constant. Moreover, there was a
75
considerable increase in the Se activity in the testes throughout the experi-
ment.
The distribution of selenium in the animal body under normal physio-
391, 392
logic conditions was studied by Jones and Godwin, who fed mice alfalfa
75
that had been grown in a solution culture containing H SeO . When expressed
2 3 75
in terms of activity per unit weight of organs, the concentrations of Se ranged
in the following order: kidney > liver > pancreas » lung > heart > spleen > skin >
> brain > carcass. Except for a reversal of the kidney and liver and the lower
amounts of selenium in the spleen, the relative concentrations of selenium in
this experiment, performed with normal levels of selenium, correspond closely
735
with the relative concentrations of selenium found by Smith e_t aL who •were
381
studying chronic selenosis. In a similar study, Jenkins and Hidiroglou ex-
posed dystrophogenic pasture grass to radioselenite and fed extracts of these
75
plants to preruminating lambs. The distribution of Se in the internal organs
of these animals fed very low levels of selenium was very much like that seen
735
in cats chronically poisoned with selenite.
Blood. Selenium rapidly appears in the blood following a single
injection of selenate into rats, and the concentration in the plasma is initially
477
greater than that in the erythrocytes. Gradually, however, the plasma
loses and the red blood cells gain selenium, so that after 3 hr the formed
elements contain more selenium than the plasma. This is in agreement with
earlier work showing that the amount of selenium in the erythrocytes was
735
greater than that in the plasma in cats chronically poisoned with selenite.
-77-
-------
491 75
McConnell e_t ah performed a time study on the distribution of Se in
the serum proteins of dogs injected with radioselenium and found that within
the first hour the greatest activity was in the albumin fraction. After this
75
time, the albumin-bound Se decreased and the activity associated with a
2
75
and g globulins increased. This shift of Se activity from albumin to
1 382
globulins was essentially confirmed by Jenkins e_t a_L in chicks receiving
75
high doses of radioselenite. In birds given low doses of Se, however, the
75
initial binding by albumin was not observed. Rather, the Se was first
located in the a and a globulins, which then migrated to the a and Y
23 2
484
globulin fractions after 24 hr. The report of McConnell and Levy that
75
Se was present in the serum lipoproteins of dogs or rats 24 hr after injection
75 650
with H SeO was contradicted by Roffler e_t, al., who claimed that the
2 3
activity associated -with lipoprotein was due to contamination by other serum
proteins of high specific activity.
386
Jensen e_t al. showed that the in vivo incorporation of an injected
75
dose of Se into red blood cells was greater in chicks that had previously been
fed a diet deficient in selenium than that in chicks that had been fed a diet sup-
851
plemented with the element. Wright and Bell then found that sheep erythro-
75
cytes took up Se in vitro via an oxygen-dependent transport mechanism to
an extent that was inversely proportional to the dietary intake of selenium. The
authors suggested that this technique might have value as an indicator of the
selenium status of animals, and this suggestion was confirmed in respect to
832 456 81
sheep by the work of Weswig e_t al. and Lopez e_t al. Burk et al.
75
measured the in vitro uptake of Se by red blood cells from children with
untreated kwashiorkor and normal children and found that the erythrocytes
-78-
-------
75
from the malnourished children took up almost twice as much Se as did
those from control children. This result agreed with the lower levels of
selenium observed in the blood of children with kwashiorkor.
75
Intracellular. The distribution of Se in rat intracellular liver
489
fractions was first studied by McConnell and Roth. These workers found
75
6. 2, 24.4, 15. 3, and 50. 3% of the total Se activity of the homogenate in the
nuclear, mitochondrial, microsomal, and soluble fractions, respectively, 24 hr
68
after injection with radioselenite. Brown and Burk reported the following
75
percentage distribution of Se in the same subcellular fractions of rat liver:
22. 7, 4. 7, 22. 6, and 52. 7, 24 hr after injection. The reason for this discrepancy
in the nuclear and mitochondrial fractions is not clear but may be related to the
fact that Brown and Burk fed their rats diets that were deficient in selenium and
administered much smaller doses of radioselenite to their animals. Wright and
853 75
Mraz showed that the relative proportion of Se appearing in the mito-
chondrial fraction could be increased by feeding diets high in selenium, although
75
this shift of Se to the mitochondria occurred at the expense of the soluble
rather than the nuclear fraction. Brown and Burk made the additional observa-
75
tion that the relative distribution of Se in the subcellular fractions of rat liver
or testes seen 24 hr after injection did not change for periods as long as 10 •weeks
75
postinjection. There was, however, a specific pattern of subcellular Se
distribution in each of the organs; the nuclear and mitochondrial fractions of the
75
testes contained relatively higher amounts of Se than did the same fractions in
75
the liver. This organ specificity in the subcellular distribution of Se was also
noted in chicks by Wright and Mraz, who found that the kidney nuclear fractions
75
contained more, and the microsomal and soluble fractions less, Se than the
corresponding liver fractions.
-79-
-------
Excretion
Urine. The urinary excretion of selenium is the main pathway in
chronic selenosis. Cats poisoned with sodium selenite eliminated 50-80% of
734
the intake by this means but only 20% or less in the feces. The urinary
excretion of selenium by cats poisoned with organic selenium •was only about
40% of the intake, but this was due to a greater retention of the selenium rather
than to an increased fecal output. The importance of the urinary pathway was
477
also seen in the work of McConnell, who showed that over 40% of a single
subtoxic dose of selenate was excreted in the urine in 24 hr, whereas only
3-6% appeared in the feces. Much smaller amounts of selenium appeared in
both urine and feces after the initial 24-hr collection period.
82
Burk e_t al_. recently completed a thorough analysis of the various
factors that can influence the urinary excretion of selenium in rats injected
75
with submicrogram quantities of the element. The amount of Se appearing
in the urine was found to be directly related to the level of selenium in the diet
75
fed the animals. Only about 6% of an administered dose of Se was excreted
after 10 days by rats fed a diet containing 0. 004 ppm of selenium, whereas 67%
of the dose was excreted by rats fed a diet containing 1 ppm of selenium. The
75
urinary output of Se was also shown to depend directly on the size of the dose
of selenium given; addition of 50 yg of nonradioactive selenium carrier increased
75 82
the amount of Se in the urine eightfold. These workers postulated the existence
of a threshold dietary level of selenium above which urinary excretion of selenium
is directly related to its dietary level and below which it is not. Under their
83
conditions, this threshold lay between 0. 054 and 0. 084 ppm of dietary selenium.
-80-
-------
Faces. In rats, the fecal pathway appears to be a constant and
rather minor route of elimination of selenium over a wide variety of condi-
82
tions. Burk e_t al. , for example, injected rats with a tracer dose of
75
H SeO (=5 nanograms of selenium and found that about 10% of the dose
2 3
was excreted in the feces in 10 days regardless of whether the diet fed
contained 0. 004 or 1 ppm of selenium. Likewise, adding up to 200 yg of
75
carrier to the tracer dose of Se had little influence on the percentage of
69
the dose excreted via the feces. Brown e_t al. also found that addition of
selenium as carrier or in the diet would not increase the fecal excretion of
75 75
Se above 10% of the dose when the Se was given orally. On the other
hand, when rats are chronically poisoned with selenium, 20-50% of the
266
selenium ingested may be excreted in the feces. A striking effect of
route of administration on the fecal excretion of selenium in swine was noted
850
by Wright and Bell, who showed that barrows given selenium by injection
excreted only 3% of the dose in the feces, whereas animals given selenium
orally excreted 15% of the dose in the feces. This effect of route of administra-
tion was even more pronounced in sheep; wethers injected with selenium ex-
creted only 5% of the dose in the feces, whereas animals given selenium by
mouth excreted 66% of the dose in the feces. This increased fecal excretion
of selenium by ruminants was thought to be due to the reduction of the ad-
ministered selenite to insoluble or unavailable forms by rumen microorganisms;
88
indeed, Butler and Peterson showed that most of the selenium in sheep dung
was present in water-insoluble forms.
Lungs. The pulmonary excretion of selenium usually attains im-
portance only in subacute selenium toxicity. This is clearly shown from the
-81-
-------
586
systematic work of Olson e_t al^ who measured the exhalation of volatile
selenium compounds by rats injected with graded dose levels of selenite. Only
negligible amounts of volatile selenium were formed when the animals received
0.4 mg selenium per kg of body weight or less, but when the level of selenium ad-
ministered reached 1. 9 mg selenium per kg of body weight about 30% of the dose could
23V
be eliminated as volatile selenium. Ganther e_t al. showed that the produc-
tion of volatile selenium compounds by rats depends on a number of dietary
variables. Selenium volatilization could be increased by increasing the protein
and methionine content of the diet, by adding 5 ppm of selenium to the diet, or
by feeding certain crude diets.
Bile and pancreatic juice. Under ordinary circumstances, the biliary
485
pathway is not a significant route for selenium excretion. McConnell and Martin,
for example, found only about 2% of an injected dose of selenate in the bile of
dogs after 7 hr. On the other hand, the biliary pathway assumes major importance
440
in the detoxification of selenium by arsenic.
315
Hansson and Blau reported that selenomethionine could be in-
corporated intact into the pancreatic juice proteins of cats in vivo, but analogous
studies with other forms of selenium appear to be lacking.
298
Saliva. Hadjimarkos and Shearer have reported that the amount
of selenium in the saliva of normal children ranged from 1. 1 to 5. 2 ppb, with a
mean concentration of 3. 1 ppb. There appears to be no systematic study on the
effect of selenium exposure or dietary selenium on the salivary excretion of
selenium.
-82-
-------
Hair. The amount of selenium in the hair was first suggested as
an index of the extent of the deposition of the element in the tissues in chronic
578,830
selenium poisoning. Later the selenium content of hair was used as
an indicator for the frequency of nutritional muscular dystrophy in selenium -
337
deficient beef cattle. Analysis of hair samples has proved to be a con-
venient, reliable diagnostic aid in assessing various trace-element deficiencies
307,409,410 483
in human beings. McConnell and Kreamer showed that trace
75
amounts of Se injected into dogs were deposited and retained in hair for as
75
long as 316 days. The Se was found in the cystine-rich protein keratin and
in the cystine fraction isolated from hair. Studies with rats and sheep given
75
radioselenite showed a gradual appearance of Se in the hair and wool over
68, 183
a period of several weeks.
A preliminary study of selenized wool showed that selenium did not
434
significantly affect fiber length, thickness, or strength. However, the
selenium content of the wool did have a significant correlation with the number
349
of distorted fibers in the fleece. Holker and Speakman studied the action
of selenium dioxide on wool that had been reduced with thioglycolic acid.
Selenium-containing cross linkages were formed in which each selenium atom
linked two cysteine side chains to form R-S-Se-S-R structures.
84
Retention. Burk e_t aL studied the tissue selenium levels during
the development of dietary liver necrosis in rats fed Torula yeast diets and
found great drops in the selenium levels of the kidneys, liver, and blood in
animals fed low selenium diets for 4 weeks. Similar results were reported
370
by Hurt e_t a^. for rats fed amino acid diets deficient in selenium.
80
Buchanan-Smith e_t aL were able to deplete the tissue selenium concentrations
in 4-month-old sheep by feeding them a nonprotein purified diet for 6 months.
-83-
-------
Selenium concentrations in the tissues of swine and lambs with nutritional
muscular dystrophy have been found to be lower than those in the tissues of
87,454 14
normal animals, and Allaway et al. suggested that a concentration
of 0. 21 ppm of selenium in the livers of lambs was the critical minimal level
for the prevention of white muscle disease. Although it is generally accepted
that low tissue selenium levels are needed for the development of selenium-
responsive diseases, some studies indicate that low tissue selenium values
323
may not be the only factor involved.
60 75
Blincoe examined the whole-body turnover of Se in rats injected
with 0. 14 mg of selenium as selenite during a 2-week period and found that
the turnover could be described by two first-order processes of widely differing
rate constants. The author concluded that the selenium was transferred from
a rapidly excreted form to a more slowly excreted form. These results were
184
verified by Ewan e_£ al. , who showed that after a single subacute injection
of radioselenite to rats the selenium was eliminated rapidly for about 3 days
and that after a period of transition a slow constant rate of loss persisted for
75
months. The amounts of Se retained after the rapid elimination phase varied
with the size of the dose, but the rate of loss thereafter did not. A series of
diets fed to rats after the fixed pool had been established showed that the rate
of depletion from that pool varied with the selenium intake during the depletion
75
period; that is, the long-term loss of Se was unaffected by changes in the
diet except as the diets varied in their selenium content. An increase in
either dietary or carrier selenium was also shown to decrease the whole-body
75
retention of Se in rats injected with only a tracer dose of radioselenite
82
equivalent to 5 nanograms of selenium. A later study showed that increases
-84-
-------
in dietary selenium of as little as 0. 06 ppm could cause significant decreases
75 83
in the whole-body retention of tracer doses of Se.
The recent decision to allow the addition of inorganic selenium salts
as a nutritional supplement to the feed of swine and poultry was made after
research had demonstrated that such use of the element would not contribute
796
to an excessive buildup of selenium residues in the edible tissues. Early
•work with rabbits fed high levels of selenium had shown that the retention of
the element in the tissues of animals fed the naturally occurring organic form
of selenium in grains was far greater than its retention when administered as
734
the inorganic sodium selenite. Analogous results were ob-
tained more recently in chicks and poults fed nutritional levels of selenium.
690
Scott and Thompson found that those birds fed diets containing 0. 67 ppm of
selenium added as the organic form in soybean meal or -wheat had higher levels
of selenium in the blood and muscle than those fed diets containing 0. 67 ppm of
selenium as selenite. However, not all naturally occurring forms of selenium
are retained in the tissues to a greater extent than inorganic selenium; Miller
503
£t aL found that the selenium in fish meal and fish solubles was retained
less efficiently by chicks than selenium as selenite. This result would agree
688
with the finding by Scott and Cantor that the selenium in tuna meal is only
about 40% as effective as selenite selenium in preventing exudative diathesis
690
in chicks. Additional work by Scott and Thompson showed that the retention
of selenium in various chick tissues did not increase appreciably when the
selenium content of the diet (as selenite) was raised from 0. 2 to 0. 4 or 0. 8
ppm. Apparently a sensitive control mechanism operates at nutritionally re-
quired levels of selenium that allows for the rapid excretion of any excesses
of inorganic selenium above the amounts needed by the body. A "plateauing"
-85-
-------
of tissue selenium levels in chicks receiving graded amounts of dietary
688
selenite was also observed by Scott and Cantor.
Similar results concerning selenium residues in swine tissues have
been obtained. The level of selenium in pork muscle was found to be directly
related to the level of dietary selenium -when the element was supplied in the
416
naturally occurring organic form, whereas supplementation of a practical
swine diet low in selenium with 0. 2 ppm of selenium as selenite caused only a
modest increase in the level of the element in muscle, which then returned to
274
base-line (deficient) levels 60 days after withdrawal of the supplemented feed.
Experiments with steers and sheep given doses of inorganic selenium at levels
needed to prevent white muscle disease indicated that the residues of selenium
in tissues returned to background levels after depletion periods of 15 weeks
340,421
(steers) and 21 weeks (sheep). The studies outlined above lead to the
overall conclusion that, when animals are supplemented with nutritional amounts
of inorganic selenium, there is little or no tendency for selenium to accumulate
in the edible tissues of the animals above the levels that are known to occur in
animals fed diets containing adequate quantities of naturally occurring selenium.
The regulation allowing the use of selenium as a feed additive did not
apply to laying hens. Selenomethionine injected into chickens is known to be
566
incorporated as such into egg white proteins. On the other hand, although
feeding 8 ppm of selenium as selenite in a diet for laying hens increased the
amount of selenium in eggs to 3 times the normal amount, the selenium in eggs
25
returned to a normal level 8 days after removal of this highly seleniferous diet.
Bioconversion
Methylated derivatives. The circumstances under which significant
amounts of volatile selenium compounds are produced by animals have been
-86-
-------
discussed. The main volatile selenium metabolite exhaled by rats following
administration of inorganic selenium was characterized by McConnell and
486
Portman as dimethyl selenide, but it is not known whether other minor
volatile selenium metabolites exist. This methylation of selenium was con-
sidered to be a highly effective detoxification mechanism; dimethyl selenide
487
was shown to be about one five-hundredth as toxic as selenite. The
generally presumed innocuousness of dimethyl selenide, however, may have
605
to be reevaluated in light of its remarkable synergistic toxicity with mercury.
655
Rosenfeld and Beath showed that several bovine tissues were
231
able to convert selenite into volatile selenium compounds in vitro. Ganther
has performed a thorough study on the enzymic synthesis of dimethyl selenide
from sodium selenite in mouse liver extracts. The probable methyl donor for
this process was shown to be S-adenosyl-L-methionine, and the system had a
specific requirement for glutathione. A survey of various tissues for their
ability to synthesize dimethyl selenide demonstrated that liver and kidney had
the highest activity of the tissues studied, the lungs had intermediate activity,
and leg muscle, spleen, and heart had the lowest activity. The occurrence
of volatile selenium compounds in many tissues causes problems for analysts
wishing to measure selenium in biologic samples, since drying tissues can
330
cause up to a 25% loss of selenium.
In 1969, two groups independently reported that trimethylselenonium
+ 91,599
ion, (CH ) Se , was a urinary metabolite of selenium. This was the
3 3
first chemical characterization of an organic selenium compound that was ex-
creted in the urine. Trimethylselenonium ion appeared to be the main excretory
product of selenium metabolism, since it routinely accounted for 30-50% of the urinary
-87-
-------
selenium regardless of whether high or low doses of selenium were given.
This compound also appeared to be a general excretory product from selenium
metabolism, since it was the predominant metabolite regardless of which form
600
of selenium was given to the animal. Trimethylselenonium ion may also
represent another example of a methylated detoxification compound of selenium
91 565
as suggested by Byard, since it is much less toxic than selenite or selenate.
The relative biologic inactivity of trimethylselenonium ion was demonstrated in
yet another way when this selenium derivative was shown to be ineffective in
784
preventing dietary liver necrosis. However, trimethylselenonium ion does
565
have a curious synergistic toxicity with arsenic. Although trimethylselenonium
ion appears to represent the main urinary metabolite of selenium in a wide
variety of conditions, other uncharacterized excretory products of selenium
90,600
exist.
The nature of selenium in tissue proteins. During the 1930's
studies conducted to determine the chemical nature of selenium in the tissues
of animals poisoned with selenium showed that a large percentage of the selenium
in the internal organs remained in the protein fraction after extraction with
734
trichloroacetic acid and bromine-hydrobromic acid. This was particularly
true in the liver; from 30 to 94% of the total selenium was found in the liver
protein fractions. The exact form of selenium in the tissue proteins, however,
was not established by these experiments.
In 1957, this problem was approached by using paper chromatography
to characterize the selenium compounds present in the liver protein hydrolysate
75 490
of dogs 24 hr after injection with SeCl . After ethanol, ether, and tri-
4
chloroacetic acid extractions, the liver protein residue was hydrolyzed by
-88-
-------
706
refluxing in 6N HC1, a procedure now known to destroy both selenomethionine
358
and selenocystine. In spite of the destruction of these seleno amino acids,
chromatography of the hydrolysate still revealed at least three compounds con-
taining radioactive selenium; the greatest activity was in the cystine-selenocystine
area, less in the methionine-selenomethionine area, and the least in the leucine
area.
686
In 1964, Schwarz and Sweeney showed that selenite was bound
to certain sulfur compounds in vitro to give reaction products that had chromato-
graphic mobilities similar to those of the parent sulfur compound. These find-
ings called into question the use of chromatography as the sole criterion of
134
identification of selenium compounds and also prompted Cummins and Martin
to reinvestigate the question of whether selenocystine and selenomethionine were
synthesized in vivo from sodium selenite in mammals. These workers studied
the alkaline dialysis of a liver homogenate prepared from a rabbit that had been
fed radioselenite for 5 weeks. Large injected and oral doses of radioselenite
were also given to the animal 24 hr before sacrifice. Dialysis of the homogenate
under alkaline conditions removed 93% of the radioactivity originally in the
homogenate, and 90% of the selenium in the dialysate was recovered as selenite.
After dialysis, the protein of the liver homogenate was enzymically hydrolyzed.
Ion exchange chromatography of the enzymic hydrolysate failed to demonstrate
any radioactivity in the vicinity where the selenium amino acids were known to
appear on the chromatogram. These workers also used ion exchange chroma-
tography to characterize the urinary excretion products of a rabbit that had been
injected 24 hr previously with radioselenite. Although two distinct radioactive
fractions that suggested the presence of selenocystine and selenomethionine
-89-
-------
•were detected in the urine, similar radioactive fractions could also be ob-
tained by adding radioselenite to a normal urine sample in vitro or by adding
radioselenite to a chemically defined mixture of sulfur compounds. Further-
more, chemical analysis of the radioactive fractions of the urine sample labeled
in vivo showed that most of the selenium was present as selenite. Two major
conclusions arose from this work: (1) There exists no pathway for the in vivo
synthesis of selenocystine or for selenomethionine from selenite in the rabbit.
(2) Sulfur compounds bind selenite to yield complexes that have chromatographic
properties similar to seleno amino acids.
One would have hoped that the experiments of Cummins and Martin
would have settled once and for all the important question of whether mono-
gastric animals are able to biosynthesize seleno amino acids from inorganic
261
selenium, but a recent communication by Godwin and Fuss raises the
question anew. These workers used two-stage column chromatography to
characterize the selenium compounds in the enzymic hydrolysate of kidney
protein from a rabbit injected intravenously with selenite. A very small
percentage of the radioselenite given, about 0. 5%, apparently was converted
into selenocystine. A number of other amino acid-like selenium compounds
were found in the liver, kidneys, and plasma, but no attempt was made to
identify them. Clearly, the whole problem of selenium metabolites in tissues
is one that requires much additional effort.
If, then, the biosynthesis of seleno amino acids represents only a
minor or nonexistent pathway of selenium metabolism in nonruminant animals,
what happens to selenite in vivo? One possibility arises from a reaction first
593
postulated by Painter:
-90-
-------
4RSH + H2Se03 > RSSR + RSSeSR + 3H20
234
Ganther has characterized compounds of the RSSeSR family (selenotri-
sulfides) after reacting selenious acid nonenzymically with cysteine,
2-mercaptoethanol, or coenzyme A. The reaction of selenious acid with
glutathione appeared to be somewhat more complex, and under physiologic
conditions of pH and reactant concentrations, the selenotrisulfi.de derivative
232
of glutathione (GSSeSG) reacted further to form glutathione selenopersulfide:
GSSeSG + GSH > GSSeH + GSSG
Such selenopersulfide formation may be important in the biologic function of
selenium. Proteins containing thiol groups also apparently can undergo
selenotrisulfide formation; reduced pancreatic ribonuclease could be cross-
linked with selenium to form an intramolecular -S-Se-S-linkage in place of a
237 380
disulfide. Jenkins and Hidiroglou found a good correlation between
the cysteine content and the selenium uptake capability of certain proteins,
and this was taken as additional evidence for selenium incorporation by
selenotrisulfide formation.
Although selenotrisulfide formation provides a plausible rationale
for the initial binding of selenite by tissues, it should be pointed out that the
378, 500
nature of the binding changes with time in some unknown fashion.
For example, reduction with thiols, sulfitolysis, or alkali treatment released
over 70% of the radioactivity from serum proteins taken from chicks 4 hr after
oral dosing with radioselenite. At 96 hr after radioselenite administration,
75
however, much less Se was removed by reduction or sulfitolysis, whereas
the alkali treatment remained equally effective. The formation of seleno amino
acids was not considered to be a likely reason for this phenomenon, since the
-91-
-------
average half-life of the chick serum proteins is too long to account for the
relatively rapid change in selenium susceptibility to release. A better
explanation was thought to be that the strength of binding of selenium could
be influenced by the nature of the amino acid residues in the vicinity of the
binding site. Then with time the selenium in the more labile binding sites
would be lost and a higher proportion of the more resistant complexes would
remain. Whether this theory is correct can be determined only by additional
research.
Metabolic interrelationships
302
Sulfur. Halverson and Monty first showed that dietary sulfate
could partly counteract the toxic effects of selenium in rats. A later report
303
by Halverson e_t aL demonstrated that this beneficial effect of sulfate in
selenium poisoning was specific for selenate in that little or no protection
was observed against selenite or organic forms of selenium. These workers
also found that sodium sulfate in the diet increased the urinary excretion of
selenium from rats fed selenate but had no significant effect on the fecal
236
excretion of selenium. Ganther and Baumann noted that this increased
urinary excretion of selenium due to sulfate was accompanied by a decreased
677
retention of selenium in the internal organs. Although Schubert et al.
obtained an increase in the incidence of white muscle disease in lambs after
612
treating a field of alfalfa with gypsum, Paulson e_t ^L did not see any
significant effect of dietary sulfate on the fate of a physiologic dose of
selenate administered via rumen puncture to lactating ewes.
Some authors have claimed that dietary methionine is of value in
453
alleviating selenium toxicity, •whereas others have not found this to be the
-92-
-------
411, 731
case. A possible rationale for this discrepancy was offered by
693
the results of Sellers e_£ a.L , who demonstrated that methionine could
protect against selenium toxicity but only when adequate levels of vitamin
441
E were present in the diet. Levander and Morris confirmed that
methionine and vitamin E protect against the liver damage caused by excess
selenium, and they also showed that several fat-soluble antioxidants could
replace the vitamin E in potentiating the beneficial response due to methionine.
Water-soluble antioxidants, such as ascorbic acid or methylene blue, could
not substitute for the vitamin E. The selenium content of the liver and kidneys
was significantly decreased in those groups that were fed protective methionine/
antioxidant combinations.
Although various sulfur compounds obviously can act to minimize
the toxicity of selenium under many conditions, the exact mechanisms by which
these sulfur compounds exert their beneficial effects have not been elucidated
in detail.
Cadmium and Mercury. Selenium has the peculiar property of
being able to protect animals against the toxic effects of injected subacute
605
doses of cadmium and mercury, and it has been suggested that one of
the biologic functions of selenium could be the protection of the organism
against the toxicity of trace amounts of metals that even under "normal" con-
ditions enter the body from the environment. This suggestion gained con-
238
siderable credence when Ganther &t aL showed that dietary selenite could
decrease the symptoms of chronic methyl mercury poisoning in rats. These
workers also speculated that the selenium present in tuna might lessen the
danger to man of mercury in tuna. Not all forms of selenium exert a beneficial
-93-
-------
effect in mercury poisoning, however. A remarkable synergistic toxicity
has been observed between the relatively nontoxic dimethyl selenide and
605
certain mercuric salts. The biochemical basis of all these fascinating
relationships between selenium and the group II B metals is still largely
unknown.
Arsenic. The unusual ability of arsenic to decrease the toxic
522
effects of selenium was discovered by Moxon, who found that 5 ppm of
arsenic as sodium arsenite in the drinking water completely counteracted the
liver damage in rats caused by 15 ppm of dietary selenium as seleniferous
235
wheat. Ganther and Baumann found that subacute doses of arsenic de-
creased the exhalation of volatile selenium compounds but increased the
excretion of selenium into the gastrointestinal tract. This effect of arsenic
on the pulmonary excretion of selenium was thought to be paradoxical, since
selenium volatilization was considered the main detoxification pathway in
439
animals injected with subacute doses of selenium. Levander and Baumann
noted that as the dosage of arsenic was increased the amount of selenium ex-
creted into the intestine went up but the level of selenium retained in the liver
went down. This observation -was explained by an enhanced biliary excretion
440
of selenium caused by the arsenic. The bile is normally a relatively
minor route of selenium excretion, but in the presence of arsenic the amount
of selenium eliminated via the bile can be enhanced tenfold. The molecular
mechanism by which arsenic stimulates the biliary excretion of selenium
is not known, but the selenium in the bile of rats also given arsenic exhibits
440
dialysis behavior much like that of the selenium in serum proteins.
Although arsenic in the drinking water can protect against the toxic
effects of excess dietary selenium, and although injected doses of arsenic can
-94-
-------
protect against injected doses of selenium, it should not be assumed that arsenic
will always elicit a benign response in selenosis. Arsenic added to the diet, for
104, 157, 236,813
example, has variable effects against selenium poisoning.
Moreover, if selenium and arsenic are both added in the drinking water, there
can be an additive toxicity of the two elements if the amounts given are high
219
enough.
565
Finally, Obermeyer et aL , have shown that the toxicity of tri-
methylselenonium chloride to rats can be increased twentyfold if arsenic is
injected along with the selenium compound. More research is needed to clarify
these intriguing metabolic interrelationships between selenium and arsenic.
A preliminary report that arsenate given to ewes fed a selenium-
deficient ration could decrease the incidence of myopathy in the lambs (Muth
542 *
e_t aL ) has not been confirmed.
Linseed meal. A survey of several different protein sources
revealed that linseed meal has a unique protective activity against chronic
524
selenium poisoning. The protective factor in the linseed meal was not
304
associated -with protein and could be extracted with hot aqueous ethanol.
581
Olson and Halverson reported that although the animals fed linseed meal
were largely protected against the toxic effects of the dietary selenium, their
internal organs actually contained higher concentrations of selenium than did
those of animals fed diets not supplemented with the linseed meal. This some-
446
what unexpected result was confirmed by Levander et^ ah , who also showed
that the selenium in the liver homogenates of animals fed the meal appeared to
P. H. Weswig and P. D. Whanger, unpublished observations.
-95-
-------
be more tightly bound than the hepatic selenium of animals not fed the meal.
These results are a clear illustration of the principle that the chemical
form of selenium in the tissues may be more important than the concentration
present in determining the selenium status of an animal.
Plants
658
Rosenfeld and Beath have divided plants into three groups, on the
basis of their propensities for accumulating selenium, and the following is a
modification of their classification:
Group 1. Plants in this group are referred to as primary
selenium accumulators. They contain high amounts of the
element (often over 1, 000 ppm). The selenium in some
species is largely water soluble, and appears in compounds
of low molecular weight. These plants are often referred to
as "indicators," since they appear to grow only on the more
highly seleniferous soils. Included are many species of
Astragalus and some species of Machaeranthera, Happlopappus,
and Stanleya.
Group 2. Plants in this group are referred to as secondary
selenium absorbers. They rarely contain more than a few
hundred parts per million of the element. Most of the selenium
is in the selenate form; small amounts are in the organic form.
Included are many species of Aster and some species of Atriplex,
Castelleja, Grindelia, Gutierrezia, Machaeranthera, Mentzelia.
-96-
-------
Group 3. This group includes many weeds and most crop plants,
grains, and grasses, which rarely contain more than 30 ppm of
selenium, most of which is associated with plant protein.
505
Miller and Byers presented a similar classification, but
described in addition a group having a very limited tolerance to selenium,
including two species of Bouteloua.
This type of classification has many shortcomings, but it suggests
a need for caution in generalizing concerning the metabolism of selenium by
plants, and study of the literature on selenium strengthens the suggestion.
Selenium Content of Plants. A number of factors are involved in de-
termining the selenium content of plants. Jn the first place, the method of
preparing the sample for analysis is important. For instance, the loss of
39,40,452
the element from accumulator plants on drying has been well established.
Although losses during the drying of crop plants under mild conditions have
40,174
not been detected by the usual chemical methods of analysis, they have
26,451,452
been detected by using radioisotope techniques and have also been
528
reported at temperatures above those commonly used for drying tissues.
40,525 93,211
Thrift of the plant and weather have been cited as causes
for variations in selenium content of plants. However, these effects have not
been substantiated by experimental data, and there is some question as to what
effect, if any, they have.
Different tissues in a plant contain different amounts of selenium, but
apparently a number of factors are involved here, and it is impossible accurately
to predict from the analysis of one tissue how much selenium will be found in
40, 53, 201, 247, 252, 368, 388, 525, 658, 659
another from the same plant. Because
-97-
-------
of its association with proteins and certain amino acids, the element tends to
distribute with these in plant tissues.
In general, soils of higher selenium content produce plants of higher selenium
505
content, but because of the importance of the form of selenium in determining
its absorption, the relationship is not strict. Selenium occurring as inorganic
selenides or in the elemental form is very insoluble and is not readily absorbed
230,363,525
by crop plants. It would not be important in rendering these plants
toxic. It has been suggested that the accumulator plants have the capacity to
40
absorb these forms, and because of this presumed ability to change the in-
soluble to a soluble and thus available form, they at one time were referred to
39, 205, 525
as "converter" plants. Their importance in this solubilization has
not, however, been established, and the term is not now commonly used. It
has been found that colloidal elemental selenium can be absorbed in very small
89, 254, 620,822
amounts and solubilized by nonaccumulators. The elemental
form, or possibly inorganic selenides, may thus contribute a small fraction
of its selenium to a plant, but even in selenium-deficient areas it is doubtful
254
that this would be of much significance. The selenite form of the element
is readily available to plants from sand cultures or from nutrient solu-
89,469,776,778,791,
tions, but this is often not true in soils. Some
Hawaiian soils of high selenium content produce plants of very low selenium
content, presumably because the element occurs as a very insoluble basic
95,96
ferric selenite. Further, soil colloids, again those presumed to con-
tain iron oxides, tightly bind selenite and greatly reduce its availability to
211, 247, 248, 251
plants. Selenates occur in alkaline soils of semiarid
95,588,843 20
areas in high concentration, where they are quite stable.
-98-
-------
20 248, 249, 525
They are water-soluble, easily leached, and very available to plants.
In areas of excesses of the element, selenates probably contribute the greatest
93
part of the element to plants, although water-soluble organic selenium from
decaying plants may contribute significantly in this respect under some condi-
40
tions.
The distribution of selenium, especially of selenate, throughout the soil
profile is of some importance in determining the selenium content of plants.
In arid and semiarid areas, the element in its soluble forms can be leached
39,40, 92, 588
from the upper horizons and redeposited deeper in the profile.
Thus, deep-rooted plants may absorb more selenium than shallow-rooted ones.
It has been found, however, that soluble selenium deposited even in the second
or third foot of the soil profile can contribute significantly to the selenium con-
588
tent of shallower-rooted crops, such as the grasses.
The reduction by sulfur of selenium uptake by plants has been well docu-
253,363,364,367,368,714
mented in laboratory experiments. In the field,
211
Franke and Painter found that sulfur additions had no effect on the selenium
content of crops grown on highly seleniferous soils. They concluded that such
additions did not have promise as a practical method for reducing selenium
uptake by crops, largely because seleniferous soils seemed already to have a
high sulfur content in addition to their high selenium content. On the other hand,
10
Allaway, in reviewing sulfur-selenium relationships in plants growing in
selenium-deficient areas, suggested that if sulfur fertilization is used it could
reduce the selenium content of crops and thus increase the need for supplementation
of animal diets with the element. Plants vary in selenium content with their
40, 525, 583
stage of growth. While in general the selenium content decreases
-99-
-------
with advancing maturity during the growing season, there are many exceptions
to this, and the reasons for the exceptions are not clear.
In the field, plant associations have been found to be somewhat involved
in this matter. For instance, grasses growing near accumulator plants have
been found to contain more selenium than those growing nearby but not in
525
association with the accumulators. The addition of various proteins and
amino acids or plant extracts has increased selenium uptake by plants from
776,778,779
culture solutions. The pH, colloid content, and time have also
been found to influence selenium uptake from soils of low selenium con-
247, 249, 251,791
tent. Undoubtedly, there are additional factors that have
some influence in this matter.
Toxicity of Selenium to Plants. Years before recognition of the fact that
selenium is a naturally occurring toxin causing livestock problems, the toxicity
29,98,448,747, 785
of selenium to certain plants under laboratory conditions was known.
In some of the nonaccumulator species, soluble selenium compounds are injurious
448 362, 364, 367, 448, 468, 563, 713, 714
to seed germination and growth. The
characteristic symptom of selenate injury, at least in some cereal crops, is
364,785
a snow-white chlorosis. Although leaves injured by selenite are often
362, 366
greener than normal ones, white chlorosis has been reported to occur
468
at very high concentrations of this form of the element. Roots poisoned by
29, 362,448,747,785
selenite may take on a pink color, probably because of
the precipitation of the colloidal form of the element in the cells. Selenate
has not been observed to have this effect.
814
Walker and Ting have found that selenium reduced the rate of crossing
over in barley. Cytologic observations suggested that the element caused a
-100-
-------
relaxation of the meiotic chromatin. Whether the mechanism by -which this
occurred would be harmful to plants under some circumstances deserves
attention.
The toxicity of the element to plants is influenced by a number of factors.
The kind of plant is, of course, very important, the accumulators already
mentioned being able to absorb high levels without apparent injury. Some
effect of radiation from radium in reducing selenite toxicity has also been
747
recorded. Other factors relate to the uptake of the element, and these
have already been discussed.
There are no recorded instances of naturally occurring selenium
causing damage to plants in the field. It appears that, in the field, readily
available selenium is not provided to plants at a level high enough to cause
658
injury. According to Rosenfeld and Beath, crop plants show no injury
until they contain at least 300 ppm of the element, which is usually far in
excess of what these plants have been reported to contain even in our most
seleniferous areas.
Selenium as a Micronutrient. The early observation that the primary
selenium accumulators grew only where selenium was present in soils and
that they could absorb high levels without being damaged prompted the opinion
that it might be an essential element in these plants. Indeed, selenite added
747,780,782
to sand cultures was found to stimulate the growth of some indicator plants,
448
strengthening this belief. Further, prior to this time Levine had reported
growth stimulation in lupin seedlings as a result of adding selenium dioxide or
selenic acid to a distilled-water medium at very low levels. Several others have
362,619,745
reported on the stimulation of crop-plant growth by low levels of selenium,
-101-
-------
but the data are not impressive and the experiments were not carefully
controlled. More recent studies have failed to show any beneficial effect
75
of selenium on the growth of alfalfa or subterranean clover, but work
with Astragalus species confirms the possibility of its being an essential
74
micronutrient, the probable requirement for it being very low. Several
20, 658,709
reviews have covered this question, and in all cases the need
for more work to resolve it is expressed.
Chemical Forms of Selenium in Plants. Early in his studies of the "alkali
205
disease" syndrome, Franke found the toxic factor (soon after reported to
be selenium) in wheat and corn grains to be associated with the protein. Then
the selenium in some primary indicator plants was found to be largely water-soluble
37
and readily available to plants grown on soils to which it had been added, suggesting
its occurrence in some form other than protein. These differences between grains
and the indicator plants have been confirmed many times.
Most of the selenium in the grains was found to be firmly bound in the protein
213
and organic in form. On acid hydrolysis of the protein, the selenium was
solubilized except for a small amount that remained with the humin, and the
595
substitution of selenium for the sulfur in cystine and methionine was suggested.
98
The probability of such a substitution had been proposed by Cameron as early
as 1880. Additional studies prior to 1940 gave some additional evidence that
212, 366, 596, 597
selenium might occur in place of sulfur in plants. This and
some reports on selenium absorption by plants indicated that these two elements
364, 365, 367, 368, 563
were metabolized by similar pathways, but on finding
that different parts of the same plant had different Se:S ratios, Painter and
594
Franke concluded that there had to be differences.
-102-
-------
During some of their early studies of seleniferous plants, Wyoming
37
workers observed that toxicity and offensive odor were related in
seleniferous A. bisulcatus. They discovered that drying of certain of
the primary indicator plants was accompanied by loss of a large amount of
40
selenium, indicating the presence of volatile selenium compounds. They
found no such loss on drying grasses or cereal crops. However, Medicago
sativa plants have been shown to release up to 30% of their selenium in volatile
o 26
form when dried at 70 C for 48 hr, and the loss of some of the element
o
from grains in long-term storage and in grains heated at 160 C or above for
528
a few hours has been reported.
The first successful attempt to isolate an organic selenium-containing
354
crystalline material was announced in 1940 by Horn and Jones and was
353
described shortly thereafter. The material was believed to be a mixture
of the isomorphic compounds cystathionine and Se-cystathionine in a 2:1 ratio.
These occurred in free form in hot-water extracts of A. pectinatus.
38
Beath and Eppson studied a number of species of plants and divided them
into three classes: (1) those containing largely organic selenium, (2) those
containing more than 70% of inorganic (selenate) selenium, and (3) those con-
taining a mixture of organic and inorganic selenium less than 60% of which was
in the selenate form.
728
Smith reported finding selenium concentrated on paper chromatograms
of acid hydrolysates of seleniferous protein from wheat or corn grain at locations
corresponding to the locations of Se-cystine and Se-methionine. On the other
840
hand, Whitehead ^t aL were unable to confirm this with proteins from grain
75
or cytoplasm of wheat grown on Na SeO .
2 4
-103-
-------
The work described above was reported prior to I960, and up to that year
the only organic selenium compound identified with reasonable certainty in plants
777
was the Se-cystathionine of Horn and Jones. In I960, however, Trelease et al.
reported the isolation of crystalline Se-methylselenocysteine (apparently somewhat
contaminated with its sulfur analog) from Astragalus bisulcatus. Since then
119a, 560,719,720
this compound has been reported in A_. bisulcatus.
719,720 804 804 804
A_. crotalariae. A_. canadensis, A. succulentus, A_. vasei,
720 470 720 720
A. Freussii. A. osterhouti, A. pattersoni, A_. sabulosus,
470,5^1 470,471,558 471
A_. racemosus. A_. pectinatus, A_. drummondii,
471 558,719 471,720
A_. ad surgeons. Oonopsis condensata, and Stan ley a pinnata.
In the last decade, a number of other compounds have been identified with reason-
451, 622, 720, 804,806
able certainty in plants, as follows: Se-methylselenomethionine,
400,470,471,558,621,720,805 559
selenocystathionine, and its glutamyl peptide,
451 179
dimethyl selenide, dimethyl diselenide, Y -L-glutamyl-Se-methylseleno-
558,560 89,584,622 89,622
L-cysteine, selenomethionine, selenite, and
38, 89, 309 806
selenate. Selenohomocystine and selenocystine and some of its
89,374,622,728,738
oxides have also been reported in plants, but the evidence is
less than convincing, particularly in the case of selenocystine. Martin and
470
Gerlach also reported the possible occurrence of selenocystine in some
Astragalus plants, but suggested the possibility that the peak on which this observa-
tion was based may have been the result of a buffer change during the chromato-
815
graphy. Further, Walter e_£ al. caution that diselenide-sulfhydryl and
diselenide-selenol interchange reactions occur spontaneously over a wide pH
range, and this must be taken into account during investigations of materials
containing these mixtures. Particularly in plants having high S:Se ratios,
-104-
-------
it would be surprising to find selenocystine as such, and half-selenocystine
might be involved in a number of combinations with sulfides or other selenides,
making its identification difficult.
709
Selenium in Accumulator and Nonaccumulator Plants. Shrift has
reviewed the experimental evidence for differences in the metabolism of
selenium by the so-called accumulator and nonaccumulator plants. Although
Se-methylselenocysteine levels were higher in several accumulator Astragalus
719,720 804
species, other work suggested that what really distinguished the
nonaccumulators was the presence in them of Se-methylselenomethionine. This
compound occurred only in minute amounts or could not be identified in accumu-
471
lators. Later, however, he and his co-workers failed to find this amino
acid in several nonaccumulator Astragalus species and suggested the use of
Se-methylselenocysteine and Se-selenocystathionine for distinguishing accumulators
from nonaccumulators.
Perhaps it is not surprising that in rather closely related species of
plants, sharp differences may not consistently be found, and continued
investigations may yield improved methods for differentiating accumulator
from nonaccumulator species. In the meantime, the available evidence points
to the formation of compounds such as Se-methylselenocysteine as a possible
detoxification mechanism for plants that accumulate high levels of selenium,
possibly preventing the incorporation of Se-celenocysteine into proteins. ' '
Metabolic Pathways. The selenium compounds thus far identified in plants
are all analogs of sulfur compounds also found in nature, which suggests similar
metabolic pathways for the two elements. Yet many observations indicating
-105-
-------
differences in their metabolism have been reported. For instance, Nisson and
562
Benson report that the excised roots of several crop plants fed selenate
did not form detectable amounts of choline selenate after being treated up to
24 hr, whereas those fed sulfate formed appreciable amounts of choline sulfate.
Further, although eel grasses contain flavonoid sulfates, no flavonoid selenates
were detected in eel grasses kept for 65 hr in aerated seawater containing
75 -2
SeO ; and although 6-sulfo- oc -D-quinovopyranosyl-(I-> I')-2',
4
3' -diacyl-D-glycerol occurs in high concentrations in plant photosynthetic
material, its selenium analog could not be detected in a number of plants
for which the selenate uptake periods lasted several days. The apparent absence
471
of cystathionine from plant extracts showing the presence of selenocystathionine,
720
the absence of selenoglutathione from plants that synthesize glutathione itself,
and the many quantitative differences in selenium and sulfur compounds in plants
further attest to some differences in the metabolism of the two elements. In
brief, the metabolism of selenium in any plant apparently cannot be derived from
a study of its sulfur metabolism.
Unfortunately, our knowledge of the metabolic pathways for selenium in
plants is very limited. Failing to detect 3'-phosphoadenosine-51-phosphoselenate
562
in plants grown in selenate, Nissen and Benson suggested the following for
the reduction of selenate to selenite:
-106-
-------
sulfate
adenyltransferase x
SeOV2 - ,..' ' zz^'adenosine 5-phosphoselenate
reductase
system
In regions of alkaline soils, selenate is probably the form in which the element
20
is absorbed by plants. Selenite has been found to be more readily absorbed
89,720
and metabolized from culture solution than is selenate, and Butler and
89
Peterson suggest that the reduction to selenite may be the rate-limiting step
in the metabolism of selenate.
806
Virupaksha e£ al. proposed the following for the biogenesis of seleno-
homocystine in .A. crotalariae:
selenomethionine '•"" ^, Se-adenosylselenomethionine
(CH3)
selenohomocysteine '•=" Se-adenosylselenohomocysteine
selenohomocystine
451
451
Lewis £t al. reported a crude enzyme preparation from Brassica
oleracea var. capitata that cleaved Se-methylselenomethionine into homoserine
-107-
-------
and dimethyl selenide, a compound that had been identified in this plant. The
preparation also cleaved S-methylmethionine into dimethyl sulfide and homo-
serine. Dimethyl selenide could not be identified in A. bisulcatus, but dimethyl
diselenide could. Froom, however, reported the presence of the dimethyl
218
selenide in this plant at an earlier date.
Even the insoluble elemental selenium in colloidal form can be absorbed
89
by Spirodela oligorrhiza from culture solution. Labeling patterns for the
various selenium compounds formed were the same whether selenite, selenate,
or elemental selenium was fed the plants, which suggests a common pathway
for the metabolism of these three forms of the element in this plant.
A much more detailed review of the metabolism of selenium by plants
711
was recently prepared by Shrift.
Microorganisms
Research into the metabolism of selenium, in microorganisms furnishes
us with evidence of fundamental biochemical concepts that may elucidate the
principal role of selenium as a nutrient and toxicant in all living forms.
Transport Antagonisms Between Sulfur and Selenium Compounds. Ample
evidence supports the concept that chemically similar selenium and sulfur com-
pounds can compete with one another for transport across the cell membrane of
710
a variety of microorganisms. For example, sulfate transport in Penicillium
chrysogenum was inhibited by selenate, and the selenate was shown to enter the
858
mycelium via a sulfur-regulated permease thought to be the sulfate permease.
A similar competitive antagonism was observed in Chlorella vulgaris in respect
713, 714
to the uptake of selenate vs. sulfate or selenomethionine vs. methionine.
-108-
-------
However, there are a number of cases in which the nature of the metabolic
interrelationship between selenium and sulfur is not as obvious as in those
referred to here. Although sulfate could reverse the toxic effect of selenate
192 193
on yeast growth, a similar reversal could be obtained with methionine.
Also, there appeared to be a difference in response between species: methionine
had no activity in reversing the toxic effects of selenate on Escherichia coli,
191
but cysteine and glutathione did. In fact, methionine has been reported to
665
enhance the toxicity of selenite to E_. coli. In this instance, exogenous
methionine was thought to suppress the conversion of selenite to selenomethionine,
which was considered a detoxification product. Experiments with yeast point to
the possibility of metabolic antagonisms between selenite and chemically dissimilar
anions; the inhibition of yeast respiration caused by selenite could be reduced by
62
arsenite, arsenate, or phosphate. More work is required to clarify these
relationships. The toxicity or availability of selenium to microorganisms can
clearly be influenced by the nature of the other compounds present in the growth
medium.
Reduction and Oxidation of Selenium Compounds. Extracts of Micrococcus
lactilyticus were shown to utilize molecular hydrogen to reduce a wide variety
848
of oxyanions, including selenite. The reduction of selenite consisted of
two steps: a rapid reduction of selenite to elemental selenium followed by slower
reduction of the colloidal selenium to selenide. Chemically prepared suspensions
of colloidal selenium were also found to be reduced to selenide. Selenate, on the
other hand, was not reduced. Selenite reduction by Salmonella heidelberg was also
shown to be a two-stage reaction, but in this case the final product was elemental
selenium rather than selenide, and the reduction intermediate was trapped and
-109-
-------
493
identified as the divalent positive selenium ion. The authors suggested
that the tolerance of Salmonella to selenite is due to the conversion of selenite
to the insoluble and nontoxic elemental selenium.
The reduction of selenite by cell-free preparations from yeast has been
557
investigated in detail by Nickerson and Falcone. These workers found
that dialyzed enzyme preparations obtained from bakers' yeast or Candida
albicans could reduce selenite to elemental selenium if they added back to the
system either the dialyzable substances or a boiled undialyzed extract. Extrac-
tion of the boiled yeast extract with n-hexane removed its ability to restore
selenite-reducing capacity in dialyzed enzyme preparations. Menadione or
thiadione could replace the substances extracted by n-hexane. The selenite
appeared to be bound to protein through vicinal thiol groups. The authors
postulated the following pathway of electron flow to account for the reduction
of selenite:
TPN — FLAVIN o=<^>o -~ o=s.
t'- ! i
PROTEIN
A role for flavin in selenite reduction was also suggested by the work of Tilton
772
e£ al_. , who found that flavin adenine dinucleotide (FAD) was required for
the maximum reduction of selenite to elemental selenium by cell-free extracts
of Streptococcus faecalis or Streptococcus faccium. These workers also found
that the reduction of selenite could be inhibited by a variety of sulfhydryl blocking
agents, which at least is consistent with the idea that sulfhydryl groups are present
-110-
-------
at the active site of the selenite-reducing enzyme. The ability of microorganisms
to reduce soluble selenium compounds to the insoluble elemental state assumes
practical importance when it is realized that such so-called selenoreductase
activity is higher in microbial strains that have adapted to high-selenium con-
ditions.
In contrast to the well-documented reductive pathways of selenium
metabolism in microbes, there is relatively little evidence of existence of
712
oxidative pathways of selenium metabolism in microorganisms. This fact
could have important consequences for the environmental cycling of selenium.
Biosynthesis and Metabolism of Seleno-Amino Acids. Several investiga-
tors have used chroma tog raphic identification as evidence for the conversion of
inorganic selenium into seleno-amino acids by microorganisms. Escherichia
coli grown on a sulfur-deficient medium containing radioselenite incorporated
trace quantities of selenium into compounds that had chromatographic properties
788
similar to those of synthetic selenomethionine. The presence of seleno-
cystine could not be demonstrated. Similar results were reported for a selenium-
tolerant substrain of E. coli when radioselenate was used as the source of
360 5"6~ 75
selenium. Blau grew yeast on a low-sulfur medium containing Se-
selenite and isolated a material by ion-exchange chromatography that was con-
sidered to be selenomethionine. The selenomethionine produced under his con-
ditions could be incorporated into proteins and had biologic properties much
827
like those of methionine. Weiss et al. found compounds having R values
f
corresponding to selenocystine in E_. coli, Proteus vulgaris, and Salmonella
thompson, but selenomethionine was detected only in E. coli. Studies with
cultures of mixed rumen bacteria have yielded conflicting results concerning
-111-
-------
the formation of selenomethionine from inorganic selenium by rumen micro-
338
organisms. Hidiroglou e_t al. found that rumen bacteria could incorporate
selenite into the microbial protein. Characterization of the selenium compounds
in the rumen bacteria protein hydrolysates by chromatography suggested the
613
presence of selenomethionine. Paulson e_t aL also found that inorganic
selenium could be incorporated into the trichloroacetic acid-in soluble fraction
of rumen fluid. However, when the trichloroacetic acid-insoluble fraction was
dialyzed against reduced glutathione, most of the selenium could be removed and
therefore must have been rather loosely bound. These workers concluded that
very little or none of the inorganic selenium added to the rumen fluid was in-
corporated into selenomethionine. The use of chromatographic techniques to
characterize the selenium compounds present in biologic systems has recently
been questioned.
Several investigators have shown that selenomethionine can be utilized
effectively as a substitute for methionine in a number of in vitro enzymatic
531
reactions. Mudd and Cantoni found that selenomethionine could substitute
for methionine in the reaction catalyzed by yeast methionine-activating enzyme.
Furthermore, the product thereby formed, Se-adenosyl-selenomethionine, could
serve effectively as a methyl donor in the methylation of guanidoacetic acid to
form creatine. McConnell and co-workers have demonstrated that selenomethionine
can participate in all the known reactions of methionine during polypeptide chain
346,482
initiation and synthesis in IS. coli, but the relation of these findings to
the overall protein biosynthetic pathway is not clear.
It is generally agreed that exogenously supplied selenomethione can be
incorporated into the proteins of microorganisms. There is, however, some
-112-
-------
controversy regarding the biologic consequences of such incorporation. In
129
an early study, Cowie and Cohen claimed that selenomethionine could
completely replace methionine for the normal exponential growth of a
854
methionine-requiring mutant of _E. coli. Wu and Wachsman, however,
showed that selenomethionine only partly satisfied the methionine requirement
of methionine less strains of IE. coli WWU or Bacillus megaterlum KM.
123
Coch and Greene found marked strain differences in the toxic effects of
selenomethionine on IL. coli. Selenomethionine was relatively nontoxic to the
growth of IE. coli 26 at concentrations as high as 0. 01 M as long as cysteine
was added to the growth medium, but the growth of JE. coli K 12 was markedly
-4
inhibited by 10 M selenomethionine, regardless of whether cysteine was
present. The catalytic activity of _E. coli 26 6-galactosidase with 70-75%
of its methionine residues replaced by selenomethionine was found to be the
same as that of the unmodified enzyme. These results are similar to those
359
of Huber and Griddle, who found that selenomethionine substitution of
about 80 of the 150 methionine residues of the g-galactosidase from a selenium-
tolerant substrain of 1C. coli K- 1 2 grown on 0. 01 M selenate had no effect on
the catalytic parameters K and V of the enzyme. These workers noted,
m max
however, that the stability of the selenium 3-galactosidase when subjected to
heat and urea was decreased. Selenomethionine was shown to cause a severe
inhibition of both bulk protein and B-galactosidase synthesis in E. coli 26
123
if amino acids other than methionine were limiting in the growth medium.
Methylation of Inorganic Selenium Compounds. Several species of molds,
especially Scopulariopsis brevicaulis (Penicillium brevicaul), methylate oxyanions
of selenium, tellurium, or arsenic to give volatile compounds with a characteristic
-113-
-------
114
garlichke odor. Thus, Na SeO , K TeO , and As 0 yield
2323 23
(CH ) Se, (CH ) Te, and (CH ) As, respectively. The mechanism
32 32 33
postulated for this conversion is the following:
o- + o o-
+ / CH3 * ionization /
H2SeOa -> H + :Se-OH >CH3 Se-OH r-> CH3 Se:
\ \ & reduction \
o o o
ION METHANESELENONIC ION OF
ACID M ETHAN E-
SELENINIC
+ O ACID
CHs ^ reduction
*(CH3)2Se >(CH3)2Se:
\
O
DIMETHYL DIMETHYL
SELENONB SELENIDE
Later work established that the source of methyl groups for this reaction
156
was methionine.
202
In 1972, Fleming and Alexander found that microorganisms isolated
from raw sewage can produce dimethylselenide from inorganic selenium compounds.
The ecologic consequences of such a process are not known, but it should be pointed
out that the methylation of inorganic selenium oxyanion salts probably does not pose
the same kind of ecologic threat as the methylation of inorganic mercury compounds,
since dimethyl selenide itself is much less toxic to mammals than inorganic selenium
486 605
oxyanion salts. However, Parizek e_t aL have described a remarkable
synergistic toxicity between dimethylselenide and traces of inorganic mercury
salts.
Role for Selenium in Formate Dehydrogenase. By using a highly purified
6T?
glucose-minimal salts culture medium, Pinsent was able to show that traces
-114-
-------
of selenite and molybdate, as well as iron, were needed for the production of
formic dehydrogenase in Escherichia coli. These factors were effective only
if added during cell growth and had no effect if added to washed cell suspensions.
224
Several years later, Fukuyama and Ordal found that iron-deficient cells of
E. coli exhibited formic dehydrogenase activity only when adequate amounts of
selenium and molybdenum were present in the growth medium. In 1971, Lester
435
and DeMoss demonstrated that selenite was required to form the enzyme
system that permits formate to serve as an effective electron donor for nitrate
reduction in anaerobically grown E. coli. As pointed out by the authors, anaerobic
electron transport in E_. coli is being studied intensively as a model of the mecha-
nisms of synthesis, assembly, and regulation of membrane-bound enzyme systems.
Since the effects of selenite and molybdate on formate dehydrogenase could be
blocked by chloramphenicol, it appeared that protein biosynthesis was required
for these effects. The selenite/molybdate requirement was quite specific for
enzymes of formate and nitrate metabolism: selenium and molybdenum had no
178
effect on the level of several other dehydrogenase and oxidase systems.
DL-selenocystine -was about as effective as selenite in stimulating the formation
of formic dehydrogenase, whereas DL-selenomethionine was only 1% as effective.
The authors speculated that selenium could be an integral part of the enzyme
formate dehydrogenase and could have a catalytic role either as selenocysteine
721 75
or as nonheme iron selenide. Shum and Murphy found that Se incorporated
by E_. coli migrated with formic dehydrogenase activity through a sucrose density
gradient.
715
Adaptation to Selenium. Shrift and Kelly found that E_. coli K12 exposed
-4
to 2 x 10 M of selenate attained growth rates similar to controls after a lag
-115-
-------
period of 24-48 hr. These selenium-tolerant E_. coli apparently became re-
sistant to selenate: the cells would grow immediately when placed in a new
high-selenate medium, whereas E_. coli not previously exposed to selenate
grew only after a long lag phase. This selenium-tolerant substrain maintained
its resistance to selenium after nine transfers, which suggested that the adaptation
360
was stable. No mechanism was proposed. In a later paper, Huber et al.
reported somewhat different growth characteristics in a similar selenium-
resistant substrain of 1C. coli K12. The much shorter lag times and exponential
growth observed by Shrift and Kelly were considered to be due to a more extensive
sulfur contamination in the chemicals used to prepare their growth media. Shrift
716,717
£_t al^. also described a permanent adaptation of Chlorella vulgaris to
selenomethionine. The resistance in this case appeared to be due to a decreased
718
permeability of the algal cell to either methionine or its selenium analog.
741
Springer and Huber noted a decreased uptake of selenate in two selenate-
tolerant strains of 1C. coli as compared with uptake in wild E_. coli. Koval'skii
and Ermakov showed that microorganisms taken from geologic zones high in
selenium -were less susceptible to the toxic effects of the element than were
414
microorganisms taken from soils low in selenium. One mechanism for
415
such resistance could be increased levels of selenoreductase. This possibility
is suggested by the fact that strains of Bacillus megaterium taken from seleni-
ferous soils had higher levels of this enzyme than strains taken from soils low
436
in selenium.
-116-
-------
NUTRITIONAL, PROPHYLACTIC. AND THERAPEUTIC USES
97, 553, 554, 610, 768,769
Selenium is an essential nutrient for chicks and quail,
492,683,684,836 80,324,534,537
rats, and sheep. There is strong support
173, 186,497, 591, 616, 774, 799
for its essentiality in swine and
323, 324, 337, 340, 464, 536, 538, 548, 567
cattle, and there is an apparent
541
need for it in squirrel monkeys. Other species in low-selenium
areas may have low concentrations of selenium in their feed stuffs and
81, 130, 229, 273, 331, 384, 385, 418, 608, 635, 663, 689
tissues and might
benefit from prophylactic or therapeutic administration of selenium salts
or a mixture of selenium salts and alpha-tocopherol.
Selenium deficiency has been induced in rats, sheep, and squirrel monkeys
by use of low-selenium feeds supplemented with 60 pg of alpha-tocopherol per
492, 541
gram of feed or 720 IU of vitamin E per ewe per week. Deficiency
lesions •were prevented or reversed by the addition of sodium selenite or selenate
to the feed (100 ng/g) or by parenteral injection (1 mg/50 kg body weight). '
Neither
/parenteral injection nor additional dietary supplementation with alpha-tocopherol
prevented or reversed deficiency lesions.
Selenium Deficiency and Its Control with Selenium Salts and Alpha- tocopherol
(Vitamin E)
Since I960 selenium salts and mixtures of selenium salts and vita-
min E have been widely used in selenium-deficient areas throughout the
274, 313, 323, 535, 571, 737
world. They have been administered as pro-
phylaxis to pregnant ewes, cows, and sows; to neonates of these
species; and to rapidly growing lambs, calves, pigs, chicks, and
8,9, 182, 274,418
poults. These preparations have also been widely
-117-
-------
used in dogs and horses to correct clinical signs of rrvusculoskeletal weakness,
133, 323,855
lameness, dermatitis, infertility, and abnormal hair coat.
The usual route of administration has been parenteral. However, in
Australia and New Zealand sodium selenate has been added to mineral salts
8,9,324
or fertilizer or used as a supplement in mixed feeds. Permission for
supplementation of mixed feeds for young poultry and pigs was granted in
Canada on September 6, 1973, and in the United States on February 7, 1974,
by the U.S. Food and Drug Administration.
Selenium supplementation has prevented nutritional myopathy in sheep,
274,537,677
swine, and cattle (white muscle disease); hepatic necrosis
(hepatosis dietetica), myocardial necrosis and hemorrhage (dietetic micro-
angiopathy or mulberry heart disease), gastroesophageal ulceration and
274, 799
"Herztod" in swine; and steatitis and exudative diathesis in chicks
271 33
and poults; lameness in dogs, horses, and breeding bulls; and poor
855
growth and reproduction in sheep and rats.
Parenteral and nutritional use of selenium salts in biology was initiated
by the 1957 discovery that selenium was the third factor, along with cystine
and vitamin E, that prevented massive liver necrosis in rats fed a specific
683
torula yeast ration.
In 1957 Muth and associates reported that sodium selenite but not alpha -
tocopherol prevented nutritonal myopathy in sheep injected with 60 mg of
537
alpha-tocopherol per kg. Regardless of whether ewes were treated with
alpha-tocopherol, parenteral injection of 1 mg of selenium as selenite per
50 kg of body weight, once a month, prevented myopathy in their lambs.
539,540
Lambs born to ewes that were not treated with selenite developed myopathy.
-118-
-------
Domestic Animals
Nutritional Myopathy of Sheep and Cattle. Nutritional myopathy (white
muscle disease) became prevalent in ruminants in the northeastern and north-
western parts of the United States and in Australia, New Zealand, and northern
536
Europe after World War II. The appearance of the syndrome in two Oregon
counties (about 1950 and 1968) was associated with changes in methods of forage
and sheep production. * Low-yield hay production and grass foraging supple-
mented with grain and protein concentrates were replaced with intensified high-
yield grass production and the rearing and marketing of lambs and ewes with
182, 537
minimal grain feeding.
In these Oregon counties, the soils were more deficient in sulfur than in
any other plant nutrient. Thus the change to high-quality, high-yield grasses
71
was associated with heavy fertilization with sulfate fertilizers. Hays grown
in these areas now often contain less than 20 ng of selenium per gram (dry-
weight basis). *
Selenium deficiency occurred in sheep and lambs after the initiation of
537
more productive methods. The reasons for the development of selenium
deficiency have not been determined. Perhaps there was a lack of available
selenium in the soil relative to the increased yield of forage and protein,
833
or sulfate fertilizer may have prevented utilization of selenium, or
cessation of grain feeding may have removed a major source of selenium for
growing lambs.
J. R. Harr, unpublished observations.
-119-
-------
Allaway reported that fertilization of heavily cropped fields with a few
8
ounces of selenium salts per acre prevented selenium-deficient forage.
This practice has been used in Australia and New Zealand with satisfactory
results, although mistakes in application have produced selenosis in some
227, 228,707
areas.
783
Trinder £t al_. reported on the effect of selenium in preventing
retained placenta in dairy cattle. Several other authors have reported on
the distribution of selenium and radiotocopherol in pregnant ewes and fetal
87, 852
lambs.
Since 1955 Muth and associates have produced nutritional myopathy in lambs
from an experimental flock of ewes fed selenium -deficient alfalfa hays from se-
537, 539, 540, 542, 617, 833, 834, 837-839
lected fields in northeastern Oregon.
These hays contained 13-23 ng of selenium per gram of hay (dry weight), the
amount depending on the location of the field and the year. The incidence of
nutritional myopathy in lambs from this flock was not exactly related to the
concentration of selenium in the hay. Hays from certain locations or grown
in certain years were more effective in producing myopathy than hays with
somewhat lower concentrations of selenium but grown at a different time or
place. Causes of these variations are unknown. They may involve lipid
components of the forages and rumen activity.
Lesions of nutritional myopathy in sheep and cattle are primary calcifica-
64
tion and degeneration of skeletal muscle and myocardium. The left
ventricular wall and interventricular septum are usually affected, whereas
_120_
-------
the auricles, right ventricle, and apex are spared. The more active skeletal
muscles, especially the abductors and the longissimus dorsi, are affected.
Lesions of myocardial nutritional myopathy have been observed in lambs
aborted during the last month of gestation by ewes in the low-selenium experi-
mental flock at Oregon State University. The young may be born edematous
with passive congestion, labored breathing, and weak, irregular pulse.
Both myocardial and skeletal muscles of the neonate may be affected.
The skeletal muscles affected are those with the greatest work requirement.
In the neonate these are the abductors of the thigh; in older animals the
longissimus dorsi and triceps are affected. Mortality may be 65% during
the first 10 days of life. Oral or parenteral administration of 1 mg of selenium
as selenite will produce remission of clinical signs within a few hours.
Clinical signs of selenium-deficiency nutritional myopathy may occur
or reoccur during the initial phase of rapid growth from 3 to 8 weeks after
324
birth. The predominant signs are skeletal weakness, especially of the
semitendinosus-semimembranosus group of muscles and the longissimus
59
dorsi, and slow growth. The connective tissue around the distal portions
of the semimembranosus and semitendinosus muscles may contain a heavily
•k
proteinaceous exudate. The concentration of lactic dehydrogenase, 5'
nucleotidase, and glutamic, oxalic, and pyruvic transaminases in serum is
79, 617,837,838
increased. Lysosome and lysosomal enzyme changes have
70, 79,426, 839
been reported. Mortality may be 35%. Parenteral administra-
tion of 1 mg of selenium as selenite per 50 kg of body weight will reverse
537,617, 677, 839
clinical signs and both the morphologic and biochemical lesions.
J. R. Harr, unpublished observations.
-121-
-------
In low-selenium areas, mature sheep and cattle that grow poorly or are
unthrifty or have lowered reproductive ability or muscular weakness often
improve clinically after administration of 1 mg of selenium, per 50 kg of body
323, 537,677,855
weight. Annual repetition of selenium administration or
two or three injections during gestation generally prevent reoccurrence of
59,677
the signs of selenium deficiency in ruminants in low-selenium regions.
Ruminal pellets that contain elemental selenium are used successfully in
313
Australia to provide needed dietary selenium.
The occurrence and initial lesions of nutritional myopathy may differ
with differences in climate and in haying methods. In the United States,
Australia, and New Zealand, selenium salts are considered more effective
63,226,324,537,677
than tocopherol in preventing nutritional myopathy. Forages
are heavily fertilized, the summers are hot and dry, and hay is readily made
and easily cured or overcured. The initial histologic lesions of nutritional
myopathy in these regions are microscopic deposits of calcium midway between
533 (p. 225)
the Z-bands of the sarcomere. These deposits are less than a
micrometer in diameter and may coalesce to form grayish-white plaques of
calcium that extend along the muscle fibers.
In northern Europe alpha-tocopherol has been considered the most
effective component of the selenium-vitamin E mixture in preventing nutritional
571,737
myopathy. In these countries, nutritional myopathy is associated
with poor curing of lightly fertilized native grasses and with an alteration
of the unsaturated fat components in the cured hays. In these conditions,
the primary morphologic lesion of the sarcomere may be degeneration, and
calcium deposition is secondary and delayed or absent.
-122-
-------
Sudden Death, Hepatic Necrosis, Arteriolar Degeneration, and Skeletal
and Cardiac Myopathy in Swine. Trapp and associates and others reported
that a mixture of selenium and vitamin E prevented a deficiency syndrome
of swine in Michigan that was characterized by sudden death of feeder pigs,
hepatic necrosis, icterus, edema of the mesentery, fibrinoid degeneration and
microangiopathy of the media or the arterioles, and skeletal and cardiac
186, 212, 774,799, 818
myopathy. Others have reported on ultrastructural
760
and histochemical changes in selenium-deficiency myopathy and hepatic
465,497
necrosis in pigs.
Van Vleet and associates in Indiana described the effect of the selenium=
vitamin £ mixture in growing swine raised on premises where hepatosis
799,800
dietetica and mulberry heart disease were common. They concluded
that supplementation of pregnant sows and baby pigs was necessary for
profitable swine husbandry in these areas.
The concentration of selenium in feeds associated with this deficiency
799, 800
syndrome in field conditions was 20-60 ng per gram. Mortality
of young pigs reared under these conditions was 10%. Alpha-toeopherol did
not control the hepatic, muscular, or vascular lesions. Effects of prophylactic
administration of selenium-vitamin E mixtures on tissue and blood composition
185, 186
were reported by Ewan and associates.
Twenty pregnant sows on a farm with a history of selenium deficiency,
hepatosis dietetica, mulberry heart disease, and feeds that contained little
selenium were inoculated intermuscularly with 5 mg of selenium as selenite
800
(about 1 mg/25 kg), and 40 other sows from the same farm were given
-123-
-------
placebo injections. Of 538 3-day-old pigs from these 60 sows, 341 were
inoculated with a mixture of selenium and vitamin E in doses of 60 ng of
selenium as selenite per kilogram of body weight. The other 197 pigs were
given placebo injections.
The incidence of stillborn pigs from the 40 placebo-treated sows was
9% compared with 3% in the 20 selenium-treated sows. Neonatal deaths were
6. 2 and 3. 4%, respectively. Deaths to 6 months of age (about 225 Ib) were
17 and 11%, respectively. One of the 341 pigs that received the selenium-
vitamin E mixture died of selenium-deficiency disease; 14 of the 197 pigs
from the placebo-treated sows died of hepatosis dietetica or mulberry heart
disease. Treated pigs (i. e. , treated with the mixture of selenium and vitamin
E) from selenium-treated sows were compared with treated pigs from placebo-
treated sows; differences were minor.
The selenium concentration in the liver of stillborn pigs from selenium-
inoculated sows (5 mg per sow) was 177 ng per gram compared with 88 ng per
800
gram in pigs stillborn to placebo-inoculated sows. The liver of pigs that died
of hepatosis dietetica or mulberry heart disease contained 60-180 ng of selenium
per gram. The concentrations of selenium in the kidney and liver of the selenium-
inoculated pigs were 12 and 21% greater, respectively, than in the noninoculated
pigs. However, the concentration of selenium in the muscle and fat of the
inoculated pigs was 14-20% less than in the noninoculated pigs. The ratio of
the concentration of selenium in the liver to the concentration in the kidney was
0. 12 in the noninoculated pigs and 0. 11 in the inoculated pigs. These ratios
(0. 12 and 0. 11) are similar to those found in the normal to selenium deficient
-124-
-------
TABLE 5-1
Selenium Content of Tissue from 14 Pigs Fed Selenium-Vitamin E Deficient
662a
Feeds, Selenium Supplemented Feeds, and Commercial Feeds
Selenium Content of Tissue, ng/g (wet weight)
Feed Liver Psoas Muscle
Basal ration (20 ng Se/g) 33 25
Basal ration plus Na«SeO~ 400 65
(300 ng Se/g)
Commercial ration 265 83
controls used by Herigstad and associates in studying dietary selenosis in
333
swine. The ratio is about one third of the ratio found in pigs fed 100 ng
of selenium as selenite per gram of feed.
Experimentally produced lesions of selenium and vitamin E "deficiency in
eight weanling female pigs were increased concentrations of plasma transaminases,
creatine phosphokinase, alpha - hydroxybutyric acid dehydrogenase, isocitric de-
hydrogenase, lactic dehydrogenase, and selective destruction of type I skeletal
66Za
muscle fibers. There was also a decrease of phosphorylase activity in
type II fibers.
Plasma enzymatic activity was increased in pigs that had liver and muscle
concentrations of selenium of 20-40 ng per gram. Pigs in the control groups
had no plasma enzyme activity and had selenium concentrations of 60-100 ng per
gram of muscle and 230-380 ng per gram of liver.
-125-
-------
Muscle lesions appear to result from primary fiber damage rather than
from vascular lesions, pulmonary edema, fibrinoid degeneration, or neuroangio-
662a
pathy. This observation is similar to that of Muth about the development
533
of myopathy in sheep.
Addition of selenium to the basal ration as sodium selenite was less
effective in increasing the concentration of selenium in muscle than maintaining
the pigs on a commercial feed (65 vs. 85 ng per gram). However, the concen-
tration of selenium in the liver of selenite-treated pigs was greater than in
commercially fed pigs (400 vs. 265 ng per gram). Others have reported that natural
forms of selenium produce greater concentrations of selenium in muscle
417a
than does selenite (Table 5-1).
In a series of experiment by several investigators, weanling pigs fed
semipurified diets based on Torula yeast as the protein source and adequate
173
amounts of the sulfur amino acids developed liver necrosis and died.
Lesions and mortality were prevented by addition of either selenium or vitamin
of cystine. 616
E to the feed, but not by addition/ Pigs fed natural feeds that had been
treated to reduce the content of alpha-tocopherol also developed myopathy.
In these pigs the diagnosis was based on an increase in the concentration of
glutamic-oxaloacetic transaminase in plasma.
333
Herigstad ejb al. in their series on selenosis had four pigs on selenium-
deficient rations. Two of these four died of selenium-vitamin E deficiency.
Signs and lesions were distress, ataxia, sudden death, hepatic swelling,
necrosis and hemorrhage, irregular Glisson's capsule, hemorrhagic ileitis, and
ecchymotic hemorrhages. The concentration of selenium in the liver was 110
and 90 ng per gram, and in the kidneys 370 and 430 ng per gram.
-126-
-------
Exudative Diathesis, Encephalomalacia, and Myopathy in Chicks and
610
Turkey Poults. Patterson e_t al_. demonstrated shortly after the initial
683
reports by Schwarz and Foltz that selenium salts prevented exudative
diathesis in chicks fed torula feeds that were low in vitamin E. This report,
683 . 683
along with that of Schwarz and Foltz, led to investigations of other species.
Subsequent work produced exudative diathesis in both Japanese quail and chicks
fed synthetic (amino acid) diets that contained little selenium but high levels of
635
alpha-tocopherol. Supplementation of these feeds with selenium salts pre-
vented the deficiency.
The syndrome produced in chicks by the synthetic diets supplemented
•with alpha-tocopherol included exudative diathesis, poor growth, poor feathering,
635
and fibrotic degeneration of the pancreas. Death usually followed decreased
absorption of lipids, decrease in production of enzymes, and failure of fat diges-
768
tion. Under these conditions, bile production decreased, and there was a
decrease in the concentration of bile and monoglycerides in the intestinal lumen.
The formation of lipid-bile salt micelle was reduced, and alpha-tocopherol ab-
sorption was decreased.
Addition of fatty acids, monoglycerides, and bile salts to the basal syn-
thetic feed improved absorption of vitamin E. This regimen prevented exudative
635,768
diathesis but not degeneration of the pancreas. Addition of both high
levels of vitamin E and 10 ng of selenium as selenite per gram of feed prevented
the pancreatic degeneration. When concentration of the vitamin E in the feed was
normal (10-15 IU per kilogram of feed), 20-40 ng of selenium per gram of feed
was necessary to prevent pancreatic degeneration.
-127-
-------
Feeds low in both sulfur amino acids and selenium produced myopathy of
the active pectoral muscles. Lesions were grayish-white striations through
97
the muscle. Supplementation with cystine or vitamin E prevents the myo-
pathy. But supplementation with selenium as selenite was only partly
553
effective in preventing it.
The pathology of selenium deficiency in the chick was reported by Cries
271
and Scott. Effects include poor growth and have been prevented by addition
630
of selenium to the drinking water. Experimentally, 50-60 ng of selenium
per eram of feed is needed by the chick to prevent exudative diathesis, the
H B 474,564,690,766
amount depending on the type of feed and the amount of vitamin E.
554,610
Field cases of exudative diathesis have been reported in the United States
and in New Zealand. '
Selenium deficiency in turkey poults produces a mild form of exudative
130
diathesis and more characteristically degeneration of the muscle of
the gizzard. The pectoral muscles are affected in 25% of the birds. Some
689
birds have myocardial failure. These lesions occur in poults fed a diet
deficient in vitamin E and can be prevented by addition of 80-280 ng of selenium
as selenite per gram of feed. Methionine and cystine and additional alpha-
tocopherol do not prevent either the signs or the lesions.
Lesions of exudative diathesis are similar to the exudation observed in
connective tissue surrounding the digital portion of the semitendenosus and
semimembranous muscle of lambs with nutritional (selenium) myopathy.
Nutritional (selenium) myopathy in chicks and poults is a degeneration of muscle
fibers with perivascular infiltration and proliferation of histocytes and granulo-
271
cytic leucocytes. This lesion is similar to those in sheep and pigs. Encephalo-
malacia of chicks and reproductive failure of hen turkeys is associated with a de-
663
ficiency of vitamin E and is not affected by the amount of selenium in the feed.
-128-
-------
Effects in Other Species and in Selenium-Adequate Animals. Clinicians
in areas where selenium deficiency occurs observed that breeding bulls, rams,
dogs, and horses develop nonspecific lameness and muscular tenderness that may
323, 324
respond to selenium-vitamin E therapy. Commercial mixtures of these
compounds are approved for parenteral use in dogs and horses. They are recom-
mended for muscular weakness, lameness, and tenderness. Gabbedy and Richards
229
reported selenium-deficient myopathy in a foal.
Mixtures of selenium and tocopherol are commercially available for use
in several species. They are prepared for use in alleviating and controlling
pain and lameness associated with some arthropathies. The manufacturer states
that the mixtures are for treating symptoms rather than etiology.
These mixtures are also claimed to be effective therapy in some cases of
idiopathic dermatitis. The efficacy of these products in this type of condition
may be related to the possible action of selenium as an anti-inflammatory agent.
-129-
-------
The basis for these beliefs, and use in vascular and reproductive problems,
are discussed under metabolism, and vascular and reproductive effects.
Clinical recommendations are made from time to time as to the effective-
ness of these mixtures. The disorders to which the recommendations relate
include lameness, synovitis, hepatic degeneration, infertility, dermatitis,
poor growth, and unthriftiness.
Laboratory Animals
Rats. Attempts to develop uncomplicated selenium deficiency in laboratory
rats were unsuccessful until 60 ng of alpha-tocopherol per gram was added to low-
67,352,370
selenium (18 ng per gram) torula yeast feed. Burk et al.
postulated a threshold level for adequate dietary selenium of about 10 ng per
gram. Rats from Oregon State University's brown, cotton, and
Wistar colonies maintained for one to three generations on this feed grew slowly,
had poor hair coats, and were sterile. The tactile hairs were not affected.
Further work demonstrated that the second litter born to the Wistar or brown
318
rats maintained on the low-selenium feed were selenium-deficient. Deficiency
was more difficult to produce in the cotton rats than in the others. Either the
third generation or the second litter from the second generation was maintained
on the low-selenium regimen until deficiency developed.
In other experiments, selenium-depleted rats that were not supplemented
67,855
with additional selenium grew slowly, had poor hair coats, and were sterile.
Vascularization of the subcutis and dermis was incomplete, and the eyes con-
742
tained cataracts. The tactile hairs (nourished from cavernous blood sinuses)
were not affected. Germinal epithelial cells of the skin and of the endothelial
cells of the capillaries and small arteries contained fewer stainable RNA or
-130-
-------
sulfhydryl groups than did those of rats on the same feed supplement with
742
100 ng of selenium as selenite per gram. Addition of selenium as selenite
or selenate to the feed of 60-day old selenium-deficient rats at a rate of
10-100 ng per gram resulted in complete reversal of signs within 30-90 days.
352,370
Similar results were obtained by other authors.
389
In recent work by Johnston, selenium-deficient tocopherol-supplemented
brown rats fed Torula yeast feeds ate 50-60% more feed than littermates fed the
same feed with the addition of 2 pg of selenium as selenite per gram of feed
(776 vs. 1198 g in 17 weeks). Feed efficiency was 75% greater in the rats
fed the selenium-supplemented diet than it was in the rats fed the basal diet
(4.5-5.4 g of feed per gram of weight gained compared with 7.9-8.8 of
feed per gram of weight gained).
The concentrations of selenium in the liver, muscle, and kidney of selenium-
318,352
deficient rats were, respectively, 0.4, 1, and 2 ug per gram (dry weight).
Addition of selenium as selenite to the feed of these rats at a rate of 100 ng
per gram increased selenium concentration in the liver to 2 jig per gram. Addition of
selenium to these deficient feeds at rates of 500-2500 ng of selenium per gram
(5 and 25 times the 100-ng-per-gram rate of supplementation) increased the
concentrations of selenium in liver to 5. 6 and 7. 4 ug per gram (dry weight),
respectively, but did not increase the concentration of selenium in muscle or
84
kidney. Burk e_t aL reported similar concentrations of selenium in the
necrotic liver of selenium-deficient rats.
The ratio of the concentration of selenium in liver to the concentration
in kidney increased from 0. 2-1. 0 to 2 . 8 to 3. 7 as dietary supplementation
318
with selenium increased from 100 to 500 to 2500 ng per gram. The three
successive fivefold increases in the concentration of dietary selenium (20 to
100, 100 to 500, and 500 to 2500 ng per gram) produced increases of
-131
-------
950, 147, and 30%, respectively in the concentration of selenium in the liver.
There was also an increase in the liver to kidney selenium
333
ratio. Herigstad e;t: aL associated ratios greater than 1 in pigs with
selenosis. The plateauing of selenium concentration with increased supple-
mentation of the feed with selenium may be the effect of hemostasis or de-
creased food consumption. Since fecal excretion of selenium on the semipurified feed
is less than 3% of the feed intake (compared with 30% in natural feeds), poor
absorption should not have been a significant factor.
Maintenance of the concentration of selenium in rat muscle at the expense
of the concentration of selenium in the liver was in contrast to observations
in sheep, wherein the concentration of selenium in the liver (1. 0 yg per gram)
was maintained at the expense of the concentration in muscle (0. 5 yg per gram,
30,60, 78 80
wet weight). The relative ability of various species to spare selenium
in the liver or muscle may affect the type or development of selenium-deficiency
lesions (myopathy, hepatosis, and so on) in these species. There is an increase
in the concentration of serum transaminase and dehydrogenases in both selenium-
450,838
deficient sheep and rats.
Rats fed feeds containing 200-500 ng of selenium per gram were mated with
selenium-depleted rats, but neither depleted males nor depleted females produced
young by this method. Histologic sections of testicle and ovary from selenium-depleted
742,834
rats did not contain normal numbers of viable sperm or oogonia. Semen from
QC C Q C f.
selenium-depleted rats contained broken sperm, which lacked motility. '
Clinical infertility in rats is similar to observations of infertility in selenium-
324
deficient sheep. These conditions respond to selenium supplementation. They
are associated with edema of the testicle, poor motility of the sperm, and (in lambs)
myopathy.
-132-
-------
82
Burk £t aL maintained rats for a month on a selenium-deficient feed
75
with added alpha-tocopherol and then injected microgram amounts of Se as
selenite. The amount injected was equivalent to 100-500 ng of selenium per
gram of body weight--the amount by which the experimental feed was deficient.
Most of the injected selenium was retained by the rats for 6-8 weeks. Six
weeks after inoculation, autoradiography and scintillation counting demon-
strated that over 40% of the radioactive selenium was in the testicle and was
concentrated in the midpiece of the sperm.
Monkeys.
/ Seven adult squirrel monkeys were fed a low-selenium semipurified
541
feed with Candida utilisas the protein source, and adequate vitamin E.
After 9 months the monkeys developed alopecia, loss of body weight, and
listlessness. After one monkey died, three other monkeys were given 40 pg
of selenium as selenite by injection at 2-week intervals. The three monkeys
given selenium salts recovered. The three not given selenium became moribund
or died. Lesions in these monkeys included hepatic necrosis, skeletal muscle
degeneration, myocardial degeneration, and nephrosis. As in the rat, the
tactile hairs of the monkeys were not affected by the loss of capillaries; they
are supplied by. cavernous blood sinuses rather than capillaries.
The
homeostatic control of selenium retention and excretion appears to be quite
close. Rats partly depleted of selenium and inoculated with 50 ug of selenium
as selenite retained one half of the injected selenium 6 weeks after inocula-
82,352
tion. The size of the inoculation was 1-2 times the amount of selenium
-133-
-------
"removed" from the diet during a preceding 30-day depletion period. Selenium-
deficient ewes retained Se in the erythrocytic portion of the blood for 150
832
days after injection of replacement amounts of selenium, 1 mg/50 kg.
Rats must be depleted through two or three generations of one or two litters
492
to produce selenium-deficient young. A fivefold increase of dietary selenium
in semipurified feed, from 0. 5 to 2. 5 Pg per gram, increased the concentration
318
of selenium in rat liver 30%.
Animals can retain 25-75% of dietary selenium consumed in natural feeds, but
several factors influence this retention, including body stores of selenium, con-
centrations of selenium in the feed, level of intake, and the chemical form of
selenium in the diet. Relationships between the level of dietary selenium and
its concentration in animal tissues have been summarized by several authors.q>30»
60,87,331,386,416
The concentration of selenium in tissues of poultry, rats, sheep, and swine
maintained on selenium-deficient diets or those supplemented with 0. 1-100 pg of
selenium as selenite per gram was not entirely dependent on the content of selenium
30, 60,80,87, 318, 333, 352
in the feed. Tissues from animals fed a selenium -
333
deficient feed had more selenium in the kidney than in the muscle or liver.
80
Sheep maintained the concentration of selenium in the liver; rats tended
318
to maintain the concentration in muscle. Addition of physiologic amounts
of selenium to the feed caused a proportional increase in the concentration of
352 80
selenium in liver (rat) or muscle (sheep). The ability of rats and other
animals to effectively tolerate up to about 5 yg of selenium as selenite or selenate
317
per gram of feed in natural foodstuffs, but not in semipurified feed, may be
due in part to combinations of selenium ions with components of the feed, or to
formation of insoluble selenium compounds through reduction to selenide, or to
-134-
-------
precipitation of insoluble salts or complexes of metallic ions. These reac-
tions are largely speculative; however, some physiologic reactions, experi-
mental results, and observations suggest that the role of selenium in biology
is broad and interrelated with other substances.
The Question of Selenium and Human Nutrition
Selenium is present in human blood and in all samples of human urine
293,418,733
that have been analyzed by sensitive detection methods, in
672 167
human tissues, and in a low-density serum lipoprotein from humans.
Concentrations in the tissues of California residents determined by x-ray emission
535 (pp. 119-125)
spectrography were generally similar to those in lambs and
182, 662a
swine produced on commercial feeds. Selenium levels in tissues of
178b
newborn infants in Russia are about the same as those found in pigs and
548, 662a
lambs on low-selenium diets in the United States. The metabolic
balance of selenium and other metals in New Zealand women was reported by
412
Knight ejt aJL P. H. Weswig (personal communication) surveyed laboratory
personnel and athletes in Oregon and found 150-300 ng of selenium per milliliter
of blood. The concentration was independent of smoking habits, sex, exercise,
and stage of training.
On the basis of the shape of the distribution curves of selenium in human
453a
tissues, Liebscher and Smith concluded that selenium may be essential
for man. There is no conclusive evidence that selenium deficiency is the
specific cause of any human disease. Frost and others came to the same
220,672
conclusion.
220 672
Frost and Schroeder ^t aL estimate that the average human diet
in the United States contains 1. 8 mg of selenium per month (25 yg per kilogram
-135-
-------
body weight per month). This compares with about 1 mg per month in a ewe, whose
lambs develop nutritional myopathy (20 ;ig per kilogram body weight per month) '
and with the 20 ^ig per month required for selenium-adequate rat diets (60 ^g per
492
kilogram body weight per month).
Clarification of the role of selenium is needed in several medical fields:
683
Kwashiorkor. Prompted by the initial report of Schwarz and Foltz,
351
Hopkins and Majaj showed that administration of selenium to children in
Jordan with kwashiorkor stimulated body growth and reticulocyte formation.
In a discussion of this work, Burk reported findings in Guat malan children
with kwashiorkor who did not respond to the usual methods of nutritional
351 (pp. 211-213)
supplementation. The concentration of selenium in the
blood of these children was 100 ng per gram compared with 230 ng per gram
in well-nourished controls. When selenium salts were added to the previously
unsuccessful kwashiorkor therapy, the health of the children improved, and
the concentration of selenium in their blood increased to control levels. In
children with low amounts of selenium, the uptake of selenium by erythrocytes
was 21% compared to 1370 in children with normal amounts of selenium. Levine and
447
Olson reported concentrations of selenium in the blood of children with
81
protein-calorie malnutrition that were similar to those of Burk, et al.
Periodontal Disease. Periodontal disease is a major health problem in
New England, a low-selenium area, and has been reported to be associated
323,324
•with selenium deficiency in sheep and cattle in New Zealand. However,
the concept that periodontal disease in sheep is a selenium-responsive disease
223
was not confirmed in Scotland.
-136-
-------
Sudden Infant Death Syndrome. Although nutritional deficiency as a
possible cause for the sudden infant death syndrome (crib or cot death) has
not been widely considered,
nothing excludes the possibility of a nutritional back-
223,642 512-514
ground for the event. The studies of Money suggest that sudden
death in human infants may result from the combined deficiencies of vitamin E
and selenium in cow's milk formulas. During the first month of life, breast-
fed infants received more than 10 times as much vitamin E and more than twice
502
as much selenium as infants fed cow's milk formulas.
641
Rhead et al. showed that the circulating levels of selenium and
vitamin E in early infancy are low compared with those in adults. They
concluded that although vitamin E and selenium deficiency cannot be established
as the primary cause of the sudden death syndrome, the possibility that nutri-
tional deficits play a secondary role merits further investigation.
Cardiovascular Disease. Sudden death associated with selenium deficiency in
newborn or rapidly growing lambs, calves, and pigs apparently results from
weakening of the heart muscle. Selenium-deficient monkeys also have myocardial
lesions. Hypoplasia of the vasculature of the skin has been demonstrated in
selenium-deficient rats and monkeys. The primary degeneration of the sarcolemma
area of the sarcomere and the secondary vascular degeneration in selenium
deficiency myopathy also suggest a cardiovascular function for selenium.
Although there is no evidence that selenium has a role in the maintenance
220
of the cardiovascular system in humans, Frost compared maps of early
heart mortality and cardiovascular related deaths for different areas of the
United States, and demonstrated an inverse relationship between ambient selenium levels
and the mortality pattern. Marjanen and Soni, who hypothesized that manganese
-137-
-------
deficiency might underlie the very high cardiac and cancer mortality rates
in Finland, have now adopted the view that selenium deficiency, which is
prevalent all over Finland, may contribute to these unusually high death rates
467a
in that country.
Lesions of selenium deficiency in rats and sheep have been associated
742
with vascular abnormalities. Demonstration of the role of selenium in
maintenance of membranes may also suggest a function within the vascular
system.
Cancer. Investigation of the direct relationship of selenium to human
cancer has been limited to demographic studies and to comparisons of levels
of selenium in the blood of patients with and without malignancies. Chu and
121
Davidson listed selenium compounds among potential antitumor agents. In
addition, Shamberger and Rudolph, and Shamberger, e£ al. associated protection from
cocarcinogenesis with antioxidants (vitamin E, selenium, etc.) and food
700,702 319
preservation. Harr et^ al. reported that concentration of dietary
selenium delayed or prevented the induction of cancer by FAA (N-2 fluorenyl-
acetamide). The effective concentration of dietary selenium in the Torula
feed in this experiment was the addition of 100-500 ng per gram of feed.
699
Shamberger and Frost published the first indication that human cancer
mortality might bear an inverse relationship to selenium distribution. Con-
trolled animal studies conducted at the same time by Shamberger showing an
inhibitory effect of selenium on carcinogenesis were not published until
698
later. Further investigation of the epidemiologic evidence for an inverse
relationship between ambient selenium level and human cancer mortality included
703
comparison of the levels of selenium in cow's milk with cancer mortality.
-138-
-------
After regular use of selenium prophylaxis, including the addition of selenite
to anthelmintic drenches, there was a rapid reduction in the incidence of ovine
824
cancer in one part of New Zealand.
On the average, the blood of cancer patients was reported to contain less
669,701
selenium than the blood of other patients,, However, the blood of
669,701,703
patients with some forms of cancer contained normal levels of selenium.
Patients
with gastrointestinal cancer or metastases to gastrointestinal organs had
significantly lower levels of selenium in the blood than normal patients.
Mammary adenocarcinomas induced by FAA in selenium-depleted rats were more
319
invasive than those induced in rats fed selenium-supplemented feeds„
The ability of selenium to reduce methylene blue was reported by
669
Schrauzer and Rhead with the suggestion that this ability might provide
a basis for testing for cancer, or susceptibility thereto. In studies of lipid
640
therapy based on the types of lipid imbalance in cancer patients, it was
found that the most satisfactory and reproducible palliative effects of therapy
were obtained by using synthetic lipids containing bivalent selenium, a serendipi-
223
tous observation alluded to by Frost.
-139-
-------
REPRODUCTIVE SYSTEM
In the assessment of nutritional deficiencies as well as the effects of
elements in excess, the reproductive system as a specific site of vulnerability
is often ignored. The use of the radionuclide of selenium, Se, has done
much to elucidate the distribution of this element in the reproductive system,
leading us to a greater awareness of possible specific roles for selenium in
reproduction in the male, female, and developing progeny.
Distribution in Male Reproductive System
Tracer doses of inorganic Se. Until recent years there has been little
reference to the distribution of selenium in reproductive organs, although
652
Rosenfeld reported that after repeated administration of tracer doses of
Se to rats, the testis contained the highest concentration of selenium except
280
kidney. Later Gunn et al. brought out that after a single subcutaneous
75
injection of a tracer dose of Se to mice, the testis, which ranked low in
Se uptake at 1 hr, continued to cumulate this element, whereas all other
tissues tested showed diminishing levels; by 7 days the male gonad ranked
third (after liver and kidney) in Se concentration (Table 5-2).
68
Spermatozoa and Selenium Deficiency. Brown and Burk confirmed the
75
cumulation pattern of Se in testis and epididymis of rats on Torula yeast
(low-selenium) diets and demonstrated by autoradiographs that Se concentrated
in the midpiece of sperm. They suggested this may indicate a specific need for
selenium in the mitochondria, which are found exclusively in the midpiece;
subcellular fractionation showed that mitochondria of the testes contained
75
more than twice as much Se as those of the liver relative to the homogenate.
Although active spermatogenesis was observed in some of the seminiferous
tubules of selenium-deficient rats born to females on a selenium-deficient
diet, the motility of spermatozoa from the cauda epididymis of these males
-140-
-------
TABLE 5-2
75Se Uptake in Various Tissues of CO-1 Male Mice Following Subcutaneous
Admin istration
of Tracer Doses (1 >iCi 75$e; 0
.03 MR Selenium) £
(Uptake expressed as percentage of administered dose per gram
of tissue. Mean values from five mice are shown.)
Interval after Injection-
Tissue
Kidney
Liver
GI tract
Injected leg
Blood
Lungs
Pancreas
Spleen
Heart
Test is
Noninjected leg
Skeletal muscle
1 Hr
11.19^
7.52^
7.41*
3.32^
1.84
1.13
0.95
0.82
0.66
0.56
0.50
0.28
4 Hr
11.03
7.28
4.97
1.08
3.8(£
2.32^-
1.16*
1.34
1.82^-
0.67
0.30
0.4<£
1 Day
7.34
5.55
2.79
0.95
1.68
1.50
1.10
1.76^
0.88
1.37
0.67^
0.37
2 Days
5.98
5.23
1.86
0.82
1.27
1.35
0.79
1.60
0.83
1.58
0.56
0.31
7 Days
2.86
3.61
0.63
0.31
0.74
0.76
0.40
0.91
0.51
1.97^
0.32
0.19
-Derived from Gunn £t al.280
—Highest concentration observed.
-141-
-------
was invariably very poor, most of the sperm showing breakage of fibrils in
the axial filaments; these effects were not counteracted by the addition of
856
vitamin E or other antioxidants.
Se in Organic Form, Although no particular emphasis was placed on such
observations, other investigators showed a considerable accumulation of Se,
when administered as the selenites selenomethionine or selenocystine in the
316 375
testis and epididymis of mice and sheep. On the other hand, Anghileri
„ 21 75
and Marques drew attention to their observation that Se, particularly when
administered as selenocystine, continued to increase in concentrations in
testis of mice, while decreasing in other tissues. Along this same line,
609 75
Patrick et al. claimed that in the fowl administered Se was bound to
protein in spermatozoa and the results of paper chromatographic studies suggested
that it was present in part as selenocystine.
Se with Carrier Selenium. The failure of other investigators to observe
high concentrations of Se in testis is attributable to the short-term nature
352,668
of the distribution studies and to a masking of the cumulation pattern
in the testis by administration of the radioisotope with large amounts of
477 280
carrier selenium. Gunn et al. showed, however, that upon administration
75 75
of Se with carrier selenium, a typical cumulative pattern of Se occurred in
testis after a preliminary period of flushing out the initial high levels0
?5 67,68
Percentage Retention of Se in Testis-EpidjLdyniis Complex. Brown and Burk
reported that the percentage of administered Se retained by the testis-epidi-
dymis complex was far greater in rats reared on a selenium-deficient diet than
277
had been reported by Gunn and Gould for rats on regular diets (Figure 5-1)„
However, it is known that the retention of administered Se in tissues and
352,457
whole body is inversely related to the dietary level of selenium. A
75 68
far greater whole-body retention of Se was reported by Brown and Burk in
-142-
-------
60
rats fed a selenium-deficient diet than was observed by Blincoe and Gunn
and Gould (unpublished data).
X
5a!
'Ǥ
en u
in
i»- en
O E
£S
£3
en H<
5?
ss
^a
JU
25
20
15
10
5
*
-
-
m
-
, ,
SB-Deficient Regular ' ~J_
- Diet Diet
Figure 5-1. Percentage of administered Se in testis-
epididymis complex of rats 3 weeks after administration
of a single dose; comparison between rats on selenium-
deficient diets (data of Brown and Burk^8) and rats on
regular diets (data of Gunn and
Natural Levels of Selenium in Human Beings. There is little information on
natural selenium in animal or human testis. It is of interest, however, that
225
in the data on human testis presented by Fuller et al. and by Schroeder
672
et al. the testis ranked third among the tissues in selenium concentration,
after kidney and liver,. The selenium concentration in the testis of a 9-month-
672
old child was about half of that reported for adult testis, as would be
expected if selenium were associated with spermatogenic elements in human
beings.
-143-
-------
236
Interactions with Other Minerals. Ganther and Baumann showed that cadmium
increased the retention of selenium in the body; the prolonged and increased
278,281
retention pattern is also reflected in the testes.
396,397 65,281,284,472,473
Kar and coworkers and later others showed that
the testicular damage induced by cadmium salts could be prevented by
278,281
administration of selenium dioxide. Gunn and co-workers investigated
the mechanism of protection by selenium and found that selenium did not prevent
cadmium from reaching the testis but instead caused a marked elevation in
uptake of testicular cadmium. In view of the capacity of cadmium and selenium
to augment concentrations of each other in the testis, and the fact that at
the same time selenium inactivates cadmium, it was postulated that some sort
of binding existed between the two elements. Although the level of both
elements initially increased, selenium later declined and cadmium continued
to rise, which suggests that selenium has transported cadmium in an inactivated
form away from the vulnerable site to some other locus within the testis where
109 75
it is innocuous. Affinity labeling studies with Cd and Se now confirm
116,240
this hypothesis. The plausible target of cadmium in cadmium-induced
testicular injury was defined as a cadmium-binding protein
with a molecular weight of 30,000 or possibly the crude nuclear fraction, or
both. Following the administration of a protective dose of selenium, cadmium
was diverted from these usual targets and, along with selenium, became attached
to a protein of higher molecular weight.
Distribution in Female Reproductive System
The female gonad does not approach that of the male in capacity to con-
67,68
centrate administered Se. (See Figure 5-2.)
In analyses of human tissues, the ovary ranked among the lowest in natural
225
selenium content. Generally speaking, there is a positive correlation between
-144-
-------
WEEKS AFTER INJECTION
Figure 5-2„ Comparison of retention of administered ;'5Se in
reproductive organs of male and female rats on Torula yeast
(selenium-deficient) diets. Pgch symbol represents one
animal. From Brown and Burk.
527
selenium intake and selenium content of tissues. Moxon and Poley found that
in hens fed seleniferous grain ration, the selenium content of ovaries and
oviduct was even higher than that of the liver and kidney. Hen's eggs contain
295,764
appreciable amounts of selenium, particularly in the yolk.
Placental Transmission. More information is available concerning selenium in
the female reproductive system during the pregnant state. Selenium is known
to cross the placental barrier in several animal species 316>339>376,488,652,831,84y,852
539
The finding by Muth et_ al. that administration of selenium to the
selenium-deficient pregnant ewe prevents the prenatal myopathy in developing
-145-
-------
535 658 792
lambs has been confirmed by many investigators. ' '
297
Hadj imarkos et al. also
confirmed placental transmission of selenium in human beings. Selenomethionine
is now being used in pregnant women to determine the efficiency of amino acid
154,432
transport as an indicator of competence of the placental transport mechanism.
Although it is generally established that concentrations of selenium are less in
the tissues of the fetus than in the mother, in the case of selenomethionine,
316,376
selenium concentrations of fetal tissues approached those of the mother.
Ewes possess a carryover effect from an adequate selenium intake during the
first pregnancy to the second pregnancy when the dam is existing on a low-selenium
833
ration that would otherwise produce lambs having white muscle disease.
Transmission in Milk,, Selenium is also present in cow's milk in concentrations
13,244,269,296,614
in direct proportion to the selenium intake0 Human milk
291,499,672
contains selenium in concentrations twice as high as those in cow's milko
In experiments with dogs, a single subtoxic subcutaneous injection of radioactive
selenium was sufficiently retained in the bitch to appear in the milk when
488
lactation began after the second pregnancy0
606
Recent studies in rats by Parizek et al. illustrate that mercuric salts
induced a greater retention of selenium in the mothers, which resulted in reduced
transfer of selenium to the fetus by both the placenta and the milk. These
investigators emphasized the fact that surprisingly large amounts of mercury
50
compounds have been used in seed dressings in agriculture; as a result of
increased concentrations of mercury in the environment connected with industri-
alization and agricultural development, the amount of selenium reaching the fetus
might be diminished, contributing to a possible state of selenium deficiency.
Effect of Deficiency
The question of essentiality of selenium for specific reproductive processes
is moot: deficiency of selenium interferes with the general health, and effects
-146-
-------
on reproduction may be secondary. Poor reproductive performance, expressed
as low lambing or calving percentages, was frequently noted in sheep and cattle
324,325
in areas where white muscle disease or "unthriftiness" was prevalent.
Estrus, ovulation, fertilization, and early embryonic development proceeded
normally in affected flocks, but 3-4 weeks after conception, at about the time
325
of implantation, embryonic mortality was high. Hartley et al» first drew
attention to the beneficial effects of selenium in correcting these deficiencies
78
in reproduction. Buchanan-Smith et al. reported that both selenium and vitamin
E were required to obtain satisfactory reproductive performance in ewes fed a
783
selenium-deficient, purified diet. Trinder e£ a±. cited the beneficial
effects of selenium with vitamin E on the incidence of retained placentae in
dairy cows on low-selenium diets. Not all workers praise the efficacy of selenium
241
in correcting inadequacies in reproduction. Gardiner et al. found that in
areas of southwestern Australia where selenium-responsive white muscle disease
in sheep had been diagnosed, selenium had little or no effect on sheep fertility.
344
Hill et al. suggested that fertility, as measured by incidence of barrenness
in 2-year-old ewes, was unaffected by selenium therapy, but that fecundity, as
measured by twinning, was significantly increased. They suggested that the
increased twinning was a secondary response to the increased weight of the
selenium-treated animals, rather than a specific physiologic response to selenium.
In some areas infertility problems in sheep have been attributed to consumption
143
of estrogenic pastures, rather than to selenium-deficient pastures.
Interference with reproduction is usually attributed to defects in the
780
female. Buchanan-Smith et al. detected no significant effects on reproductive
organs of male lambs fed a purified diet, very low in selenium, for 140 days.
When selenium-deficient diets were imposed over successive generations, rats
showed adverse effects on reproduction. Animals grew and reproduced normally,
-147-
-------
492
but their offspring were almost hairless, grew more slowly, and were sterile.
The female progeny failed to reproduce when mated with normal males. The
male progeny had immotile sperm with a morphologic defect of breakage of
856
the axial filament (Wu, .§£ .§1.° )• Although these effects were alleviated
by selenium, and not by vitamin E or other antioxidants, it cannot be stated
categorically that this is a specific effect of selenium on male reproduction;
the hairlessness and low body weights are indicative of generalized debilitation.
In the Japanese quail, deficiency of selenium in the diet resulted in
reduced viability of newly hatched eggs, but the rate of egg production and
383
fertility was not affected by the deficiency.
Effect of Excess Selenium on Reproduction
Domestic Animals. Although there is no doubt that excess selenium has an
adverse effect on reproduction, it has not been established whether these
effects are specifically a selenium-toxicity effect or a secondary reaction
658 574
to the accompanying emaciation (Rosenfeld & Beath). According to Olson,
a reduction in reproductive performance is the most significant economic effect
of chronic selenium poisoning of the so-called alkali disease type, and effects
on reproduction may be quite severe without animals showing other typical
lesions of selenosis. In the slightly more acute poisoning of the blind staggers
658
type, both male and female gonads are affected. Rosenfeld and Beath sum-
155
marized the original observations of Draize and Beath and Rosenfeld and
656
Beath. In the male the testicles are soft, flabby, and acutely congested;
there is usually atrophy of seminiferous tubules. In adult females the ovaries
are small, firm, and congested, usually with large numbers of atretic follicles
and complete absence of mature follicles. In young females the ovaries are
small, the corpus luteum is absent, and the number of follicles is greatly
801
decreased. Changes in the gonads were also reported by Vesce and Brusa and
76 653
Oneto. Rosenfeld and Beath observed hypoplasia of reproductive organs in
-148-
-------
malformed lambs born to ewes that grazed on a seleniferous range. Wahlstrom
812
and Olson found that the feeding of 10-ppm selenite to young sows lowered
the conception rate, increased the number of services per conception, and
increased the proportion of piglets small, dead, or weak at birth. Reports
in 1955 from a district in Colombia described toxic corn and streams that had
no animal life; small mammals using the streams for drinking water showed
£CQ
loss of hair and became sterile.
Laboratory Animals. The effect of excess selenium on reproduction in laboratory
animals depends on the duration of treatment and the dose of toxic substances.
532
Munsell et al. reported that selenium-containing
diets of rats had a detrimental effect on growth and reproduction in direct
proportion to the selenium intake. Rats fed selenized wheat diets were usually
infertile; matings in which one of the animals was normal were sometimes
214,215
fertile, but affected females were unable to rear their young. In
studying the effect of concentrations of selenium in drinking water of 1.5
654
and 2.5 ppm, Rosenfeld and Beath observed successful reproduction in two
successive generations of male and female rats. The second generation of
selenized rats, which received 2.5 ppm, had normal numbers of offspring, but
only 50 per cent of the young survived. An intake of 705-ppm selenium in
water 5-8 days before parturition had no effect on the young before birth,
but there was a decrease in the number of survivors with continued selenium
intake. Cross-
breeding of selenized males and females with normal animals indicated that the
fertility of the males was not affected, but the females failed to conceive,
or the few young born to selenized females were unable to suck and appeared
675
emaciated at birth. Schroeder and Mitchener recently reported that mice
-149-
-------
given selenium in drinking water from weaning time reproduced normally until
the third generation, which produced fewer and smaller litters, of which several
were runts; also, deaths before weaning and failures to breed were excessive.
Human Beings. Most reports on effects in human beings associated with
exposure to excess selenium are concerned with pregnant women. The chief
exception is a report from Japan that increasing numbers of female workers
545
in the manufacture of selenium rectifiers had irregular menses or menostasis.
Teratogenic Effects
Chicks. The embryo of the chick is extremely sensitive to selenium toxicity«
Hatchability of eggs is reduced by concentrations of selenium in feeds that are
too low to produce symptoms of poisoning in other farm animals. Poor hatchability
of eggs on farms has therefore proved to be an aid in locating potentially
658
seleniferous areas where alkali disease in cattle, hogs, and horses may occur.
The eggs are fertile, but some produce grossly deformed embryos, characterized
105,209,217,276
by missing eyes and beaks and distorted wings and feeto Inherited
abnormalities, such as the Creeper mutation in hens, exaggerated the developmental
429
malformations caused by selenium. Deformed embryos were also produced by
209
injection of selenite into the air cell of normal fertile eggs of both hens
105 419
and turkeys o Kury e_t al. suggested that in seleniferous areas the
involvement of chick embryos could be more widespread than has been realized,
not being confined to dead or grossly abnormal embryos. This conclusion is
based on their findings of anemia (low red-blood-cell counts and hemoglobin
values) in grossly normal as well as malformed embryos of chicks following
injections of selenous acid into fertilized hen's eggs.
Mammals. The consumption of seleniferous diets interfered with the normal
214,654
development of the embryo in many mammalian species, including rats,
812 653 150
pigs, sheep, and cattle. In sheep, malformations of the eyes and of
•150-
-------
have been reported.
the joints of the extremities/ The latter cause deformed legs and
658
impaired locomotion. These malformations were also observed in chicks.
350
Holmberg and Ferm did not observe teratogenic or embryotoxic effects in
hamsters after administration of near-lethal doses of sodium selenite
intravenously.
645
Human Beings. Robertson suggested that selenium may be a teratogen
in man. Reports in the older literature of the people in Colombia eating
658
toxic grains referred to malformed babies born to Indian women. Robertson
gathered information on the possible association between abnormal pregnancies
and the exposure of women to selenite. Out of one possible pregnancy and four
certain pregnancies among women exposed to selenite, only one pregnancy went
to term, and the infant showed bilateral clubfoot. Of the other pregnancies,
two could have been terminated because of other clinical factors. Widespread
inquiries in other laboratories where exposure to selenite could occur, revealed
a miscarriage in the only pregnancy in 5 years, in one small laboratory.
697
Shamberger cautions against using the inverse relationship between neonatal
deaths and the level of selenium in some parts of the United States as a basis
for a conclusion concerning the role of selenium in teratogenicity in human
beings. Because of the many other factors in our environment that could in-
fluence the biologic availability of selenium, it appears that we would be
unjustified in concluding, solely on the basis of this evidence, that selenium
has no bearing on teratogenicity in human beings. Rosenfeld and Beath emphasized
that studies of mammalian malformations in relation to the age of the embryo
or fetus and its susceptibility to selenium would be of great value to basic
658
as well as applied research.
Effect of Supplementation
Although some investigators have reported that supplements of selenium,
324,325 78,783
either alone or in combination with vitamin E, corrected reproductive
-151-
-------
143 241 344
deficiencies in animals with white muscle disease, others, ' * have
reported that selenium supplements did not improve reproductive performance
in some areas where selenium-responsive white muscle disease was prevalent.
On the other side of the balance, there have been reports of adverse effects
268a
from supplements of selenium. Grant reported some interference with
conception in ewes grazing New Zealand pastures sprayed with 50 g of selenium,
as selenite, per acre.
VASCULAR SYSTEM
Selenium produces widespread toxic effects, with many organs of diverse species
being affected. There is no agreement on a mode of action that could explain
this multitude of toxic reactions. In reviewing what is known of the mani-
festations of selenium excess and deficiency, one is struck by the vascular
278
characteristic of selenium disorders. The question of a primary vascular
involvement in selenium imbalance has been largely ignored. Indeed, consideration
of the vascular endothelium as a dynamic structure, with its own selective
reactions to injury, is a relatively new concept and opens up a whole new field
279,286
of investigation.
Selenium Deficiency
In certain selenium-responsive deficiency disorders, such as
exudative diathesis in chicks, the primary effect is considered to be on
51,136
capillary permeability. However, one cannot exclude the possibility that even
680
necrotic liver degeneration in rats, cardiac and peripheral muscle degeneration,
148
liver and kidney necrosis, and pancreatic dystrophy in mice, and the various
658
myopathies in Herbivora could have the vascular endothelium as their primary
involvement.
Recent experimental evidence bears out this suggestion. In studies of
ultrastructural changes in the hearts of piglets from sows deprived of vitamin E
760
and selenium, Sweeny and Brown noted that lesions appeared first in connective
-152-
-------
tissue and in capillaries, preceding any apparent structural changes in
742
muscle cells proper <> Sprinker et^ a^., in studies with rats on selenium-
deficient diets, noted vascular hypoplasia and endothelial thickening and
degeneration in tissues with a marginal vascular supply and oxygen dependence,
such as skeletal and cardiac muscle, testis, and retina. Since there were
widespread vascular lesions and secondary degenerative lesions in several
vascular-dependent tissues, the authors concluded that selenium deficiency
caused primary damage to the vasculature and also had an influence on the
maintenance of membranes.
754
Supplee described a defect in the flight feathers of poults fed a diet
deficient in vitamin E and selenium. This defect resulted in discoloration
and atrophy, which he attributed to degenerative changes following hemorrhage
in the pulp of the immature feather. The vascular system is further implicated
644
in a description of anti-inflammatory properties of selenium compounds,
which subsequently found application in the use of a selenium-tocopherol treatment
124
for chronic lameness in dogs.
512
Money suggests that the young of about 40 mammalian and bird species
cannot tolerate vitamin E and selenium deficiency. Despite the disparateness
of their various fatal diseases, all the diseases are characterized by effusion,
hemorrhage, and necrosis of cells.
Selenium in Excess
Acute Selenium Poisoning.. Vascular manifestations are most apparent in selenium
poisoning. The following statements are extracted from the original observations
-153-
-------
155 656
of Draize and Beath and Rosenfeld and Beath on acute selenium poisoning
in farm animals: Petechial hemorrhages appeared in the endocardium of the
heart. The lungs showed acute congestion and diffuse hemorrhages. The
omasum showed congestion, hemorrhages, and desquamation of epithelium of the
mucous folds. The intestines were hemorrhagic and showed enteritis and occas-
ionally colitis and proctitis. The liver showed passive congestion, hemorrhages,
and parenchymatous degeneration accompanied by focal necrosis. The kidney showed
parenchymatous degeneration and hemorrhages accompanied by nephritis. The spleen
was acutely congested. Microscopic study showed acute congestion in the
endocardium, focal necrosis, and hemorrhages; the pericardium exhibited
petechial hemorrhages. The lungs revealed hemorrhages in the alveoli and
occasionally in the interstitial tissue. The mucosa and submucosa of the
stomach and intestine manifested edema, hemorrhages, and necrosis. The
capillaries of the liver lobules were dilated and congested. The kidney
showed parenchymatous degeneration. Pancreas, gall bladder, spleen, and lymph
node showed congestion and hemorrhage.
Chronic Selenium Poisoning of the So-Called Alkali Disease Type. Lesions of
155,216,521,656
so-called alkali disease represent chronic progressive degeneration.
Petechial hemorrhages were seen on the epicardium, .
The lungs
showed focal fibrosis, early congestion, and some edema.
Chronic Selenosis by Inorganic Selenium0 A few subendocardial hemorrhages have
been noted in equines. In the kidney the cortex showed hemorrhages, and the
medulla was congested. Microscopic observation of the liver showed focal
necrosis, fatty infiltration, congestion, edema, cellular changes with cloudy
507
swelling, and complete loss of cellular structure.
-154-
-------
390
Acute Selenium Poisoning in Laboratory Animals. In an early report, Jones
described the right auricle of the heart as distended and full of clotted
blood; the splanchnic vessels were enormously dilated. Toxic edema of lungs
and parenchymatous organs was noted in rats exposed to high concentrations of
196
selenic anhydride. Rats, guinea pigs, and rabbits exposed to selenium fumes
299
gave no evidence of injury except in the lungs, which were hemorrhagic.
Investigating the effects of various chemical elements on permeability as
tested by local intracutaneous injection in guinea pigs with circulating Evans
746
blue, Steele and Wilhelm demonstrated that selenite had striking activity
in increasing vascular permeability.
Subacute and Chronic Selenosis in Laboratory Animals, The first description
dealing with pathologic changes related to chronic selenium poisoning was
162
provided by Duhamelo The lung showed hemorrhagic exudate in the alveoli,
dilated capillaries, and bronchial exudate. Necrosis, hemorrhage, and fibrosis
were the essential stages in the histogenesis of hepatic cirrhosis. Telangectasia
109
with focal necrosis was frequently present in some stages of liver damage.
In the kidney there was usually mild tubular degeneration with acute glomerular
206
injury. Pathologic changes have also been described by Franke, Munsell
532 732
et_ al^, and Smith ot_ al. In a study of chronic selenium intoxication in dogs,
529
Moxon and Rhian noted small local hemorrhages, severe ascites, liver and splenic
damage, emaciation, apathy, and progressive anemia.
In early cases of subacute selenosis, the most prominent feature is dilation
of veins in the visceral region. The vena cava and right auricle are always en-
larged. The lungs and liver are congested. The stomach and intestinal tract show
hemorrhages. The bladder is distended and filled with colored urine. In the truly
chronic poisoning, the outstanding pathology occurs in the liver. Heart and spleen
are enlarged. Lymph nodes are enlarged and congested. Ascites and edema are
-155-
-------
common. In guinea pigs, poor subperiosteal ossification and hyperemia at the
boundaries of primitive cartilage and hyperemia of the parathyroid gland are
35
present.
The vascular effect is apparent even in nonmammalian species. In reporting
177
on goldfish poisoned with selenium, Ellis et al. described marked edema of
many tissues, particularly the submucosa of the stomach and around the blood
vessels in the kidney and liver.
In studies of embryonic malformations in eggs laid by selenium-fed hens,
276
Gruenwald concluded that the defects resulted from regression of previously
well-formed parts rather than from an interruption of the normal developmental
process. Tissue necrosis in certain areas of brain, spinal cord, eyes, and
limb buds was a constant feature. His observations of hemorrhage, coupled with
742
the knowledge that brain tissue has a marginal vascular supply, suggests the
possibility of interference of selenium with the vascular system even at this
embryonic stage.
Selenium Toxicity in Human Beings. In a survey of rural populations living in
seleniferous areas, subcutaneous edema (probably of cariorenal origin) was seen
658
in five cases. With exposure to selenium dioxide powder, the cases of inflam-
113
mation of the nail beds are especially painful. A case of acute lethal poison-
ing in a 3 -year-old boy is cited by Carter, who noted dilation and increased
permeability of the peripheral vasculature, presumably at the capillary level, and
congestion and edema of the lungs and gastrointestinal tract. Carter pointed out
that the effect of selenium intoxication on the peripheral vasculature is similar
to the effect of arsenic.
The Vascular System as a Vulnerable Site for Toxicity
In various metabolic studies, vascular tissue has seemingly been ignored.
Yet, recent studies have shown that the vascular system is more than a simple
-156-
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conduit for blood; it is a dynamic system playing a vital role in selective
permeation of nutrients to tissues and, in turn, the endothelium may have
selective reactions to injury and may well be the primary site of damage from
15,279,286,860
various forms of noxious stimuli. Certain nephrotoxic snake
venoms, mercuric and uranium salts, and chromates have been shown to exert their
15,361
renal damage by means of selective damage to the glomerular vasculature.
Arsenic is known to interfere with capillary permeability, an effect that can
139
be prevented by sulfydryl compounds; it is of interest too that arsenic
19
is an antagonist to many of the toxic effects of selenium. Cadmium, which
670
recently has been suspected as a culprit in hypertensive vascular disease,
has also been implicated in some other vascular reactions that involve
selenium. In the male, the overwhelming necrosis that subcutaneously administered
277,601
cadmium salts provoke specifically in the testis has been shown to be
due to selective damage to its vasculature, the internal spermatic artery
277,286
pampiniform plexus complex and branches. Although relatively large
287,601 282 283
amounts of zinc, sulfhydryl compounds, and estrogens can protect
against this specific vascular damage, the most potent known protector is
280,281,284,285,397,472
selenium. Cadmium also evokes an acute hemorrhagic
.602 119
necrosis in the placenta of rats and mice near term, and some have claimed
that the ovaries of prepubertal rats also undergo an acute, though transient,
397
hemorrhagic response that can be blocked by zinc and selenium.
The review of essentiality and toxicity of selenium points to the vascular
system as one of the tissues with which this element is involved. Further research
is definitely needed to assess the role that selenium may play as a nutrient in
the regulation of and as a toxicant in the destruction of the barrier that governs
the health of all tissues.
-157-
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SELENOSIS
Although selenium had been reported to be toxic to animals as early
as 1842, it was not until the early 1930's that its role as a poison
received much attention. At this time, the U.S. Department of Agriculture
and the Wyoming and South Dakota agricultural experiment stations found
this element to occur at toxic levels in plants growing on certain soils
of the Great Plains and Rocky Mountain area and to cause the so-called
alkali disease and certain heretofore unexplained losses of livestock.
Several excellent reviews of this early work are presented elsewhere.20,320,521,657,775
Since then, there has been increased concern over the toxicity of selenium.
Types of Selenium Poisoning
Following the discovery of the relation between selenium and livestock
losses, it was soon recognized that selenium poisoning has more than one
form, and it is important that this be kept in mind during any discussion
of the toxicity of the element. Rosenfeld and Beath suggested three types
of field selenium poisoning in livestock: acute, chronic blind staggers,
and chronic alkali disease. These are briefly discussed below.
In the field, acute poisoning occurs when grazing animals eat sufficient
quantities of the selenium accumulator plants to cause sudden death or
signs of severe distress, such as labored breathing, abnormal movement and
posture, prostration, and diarrhea. Since animals usually avoid these
plants, this type of poisoning is rare. In periods of pasture shortage,
however, accumulators are sometimes about all that is available to eat,
and occasional losses of large numbers of grazing sheep and cattle from
36b
the acute form of poisoning have been reported. The acute poisoning has
-158-
-------
also been produced experimentally or accidentally by the administration of
selenium compounds to farm animals. 101,102, 228, 333, 428, 508, 518,551, 590,657 ,707
Chronic selenium poisoning of the blind staggers type has been reported
to result from the ingestion of accumulator plants in limited amounts over a
period of weeks or months. " Affected animals wander, stumble, have im-
paired vision, and show some signs of respiratory failure. This type of
poisoning has been produced experimentally by the administration of water
extracts of accumulator plants but not by the administration of pure selenium
compounds. Since the plants from which the extracts were prepared probably
also contained some toxic alkaloids, it has been proposed that these rather
than the selenium produced the poisoning. ^" This matter needs further
study.
Chronic selenium poisoning of the "alkali disease" type has been dis-
cussed in detail by Moxon^l and by Rosenfeld and Beath.657 jt results
from the ingestion of feeds containing toxic amounts of selenium over weeks
or months. Toxic amounts are different for different animals, ranging from
about 5 ppm to about 40 ppm. The most obvious signs of the poisoning are:
in cattle and horses, lameness, hoof malformation, loss of long hair from
mane or tail, and emaciation; in swine, lameness, hoof malformation, loss of
body hair, and emaciation; in poultry, decreased hatchability of the eggs
due to teratogeny. Sheep have not been observed to show hoof or wool lesions,
but their reproduction is adversely affected, and this has also been ob-
served in cattle,510 swine,812 and rats.21^ Selenium as a cause of alkali
disease has also been questioned, " but experiments have demonstrated that
signs of the syndrome are caused both by grains or grasses of high selenium
content and by inorganic salts of the element .209, 214, 506, 521, 579, 643, 809
-159-
-------
As more studies on the toxicity of selenium are reported, it becomes
obvious that the effects of the element gradually increase in severity
as selenium intake increases, so that it is difficult to differentiate clearly
between the different forms of the poisoning. Thus, the lesions or signs of
the toxicosis reported in the literature may vary widely, even within a
single species, and no attempt will be made here to review them in detail.
Several authors in addition to those cited here have reported on this matter,
and the reader is referred to the original reports for details.102,198,333,666,707,798
Factors Affecting Selenium Toxicity
The literature is replete with illustrations of conditions or factors
that alter the effects of selenium on animals. These in turn have affected
the results of research designed to establish toxic levels, complicating, in
particular, efforts to establish a "no effect" level for the element. Some
of these conditions and factors are discussed below.
The route or method of administration can be expected to cause real
differences in measurements of toxicity. Methods include intravenous, intra-
peritoneal, or subcutaneous injection, administration in the food or water,
application to the skin, and subjection to vapors.
The rate of intake or administration also has a great effect and makes
» ,
the difference between no effect, chronic effects, or acute effects. The
effects of continuous selenium intakes at apparently nontoxic levels over
a period of years have not been well documented, and this is a matter of
importance in the case of man.
Different species are affected by selenium in different ways, and some
species are more resistant than others. Thus, man may not respond to toxic
-160-
-------
doses as livestock or experimental animals do, and extrapolation of results
from animals to human beings must be done with great caution.
Young animals seem more susceptible to the poisoning than do older ones,
and embryos—especially the embryos in eggs—seem even more susceptible.
Different chemical forms of selenium have greatly different toxicities
(Table 5-3).
Criteria Used in Measuring Toxicity
The literature reveals a number of criteria that have been used in
determining toxicities of the various forms of selenium. These include
death of the animal, signs suggesting severe distress or pain, impaired
breathing or vision, impaired movement, gross lesions (both external and
internal), biochemical changes, cariogenesis, and microscopic pathologic
changes. Because of these widely differing criteria, it has been difficult
to determine the amount of selenium that constitutes a toxic dose and the
level at which intake or exposure becomes harmful.
Acute Toxicity of Selenium
Table 5-3 summarizes some of the data reported in the literature on the
acute toxicity of various selenium compounds. The data illustrate the wide
differences in toxicity of the various chemical forms of the element, some species
differences, and various ways of expressing toxicity. Although the possibility of
acute selenium poisoning exists in some areas for range animals and in certain
industries for man, the problem of acute toxicity seems less important than that
of chronic toxicity.
-161-
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Chronic Toxicity of Selenium
521
In 1937, Moxon stated that, in general, it could be said that selenium
poisoning of the "alkali disease" type results when animals consume feeds
containing 5-40 ppm of the element over a period of time. There are numerous
reports that diets containing 5 ppm or more do indeed cause chronic toxicity,
and in seleniferous areas this has been accepted as the dividing line between
toxic and nontoxic feeds.
However, the suggestion that something less than 5 ppm of the element in
the diet can be toxic is often seen in the literature. It is also suggested
that selenium in water may be more toxic than that in feed. The discussion
that follows relates primarily to work that attempts to establish a "no effect"
dose level for the element and thus arrive at some conclusion as to what levels
in feed or water can be expected to harm man, wildlife, or livestock.
773
In 1967, Tinsley et_ al^ concluded that, so far as longevity is concerned,
a daily dose of 0.5 mg of selenium (as selenite or selenate) per kilogram of
body weight per day seemed to be the threshold dose in rats on a casein-cerelose
diet (for a 200-g rat eating 10 g of feed per day, this would be the equivalent
of 10 ppm)0 On the other hand, a calculated maximum body weight was reported to
317
be decreased by as little as 0.5 ppm of selenium. In addition, Harr et al.
reported that when additions of 0.5-2 ppm of selenium were made to the diets,
proliferation of the hepatic parenchyma was more prevalent than in control
animals on diets with no added selenium and that selenium added to a commercial
diet produced less toxicity than selenium added to a casein-cerelose diet.
51a
A complementary report gives detailed data. Here again, the weight
effects were noted. However, a careful study of the data on chronic liver and
bile duct hyperplasia (see diet 1, page 55; diet 2, page 57; and diet 21, page 94)
shows that this lesion was even more prevalent in a commercial diet without added
-162-
-------
selenium than in a casein-cerelose diet with 0.5 ppm of added selenium. This
may mean that the hyperplasia does not indicate a toxic effect of the element„
320
In a later report, Harr and Muth state, with reference to the studies of the
semipurified diet, that the minimum toxic level for liver lesions was 0.25 ppm.
With reference to longevity and lesions in heart, kidney, and spleen, they
concluded that the minimum toxic level was 0.75 ppm. They state, however, that
rats fed 0.5 ppm of selenium in the diet grew as well as the controls. They
concluded that the estimated dietary threshold for physiologic-pathologic effects
is 0.4 ppm and for pathologic-clinical effects, 3.0 ppm. Neither growth nor
longevity was adversely affected by as much as 2.5 ppm of added selenium in a
Torula yeast diet to which the carcinogen, fluorenylacetamide, had been added.
The physiologic significance of some of the observations of this group is difficult
to evaluate.
628
Pletnikova has recommended a maximum concentration of 0.001 mg of selenium,
as selenite or selenate, per liter of water for Russian drinking water. She
reports 0.01 mg per liter as the threshold for detection by odor. She also reports
decreased liver function and effects on the activities of some enzymes along with
increased blood glutathione in rats receiving 0.5 yg of selenium per kilogram of
body weight per day (about 0.01 mg per liter) for a period of 6 months. These
effects were not obtained at a level of one tenth of this amount. Unfortunately,
she does not describe the diet or state its selenium content. Quite likely, the
selenium intake from it was considerably greater than that from the water
containing 0.01 mg per liter. Further, bromsulphthalein (BSP) clearance was
used for the liver function test. With this, BSP is excreted into the bile
conjugated with reduced glutathione (GSH). If selenium catalyzes GSH oxidation,
the GSH pool available to react with the dye would be depleted; hence, the effect
may not indicate a toxicity. The physiologic significance of the observations
made in this study is not clear.
-163-
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Palmer and Olson studied the toxicity of selenite and selenate to
rats on corn- or rye-based diets. They administered selenite or selenate in
water at the rate of 2 or 3 mg per liter for a period of 6 weeks. Each form
produced a small reduction in rate of gain without mortality. Earlier,
Schroeder and Mitchener had reported severe toxicity at the 2 mg/liter
level for selenite selenium but not for selenate selenium.
Halverson et^ al. fed postweanling rats for 6 weeks on wheat diets
containing 1.6, 3.2, 4.8, 6.4, 8.0, 9.6, or 11.2 ppm of naturally occurring
or selenite selenium. Growth was not affected below the 4.8-ppm level of
selenite or the 6.4-ppm level of selenium from grain. At 6.4 ppm of selenium
or above, restriction of feed intake, increased mortality, increased spleen
weight and size, increased pancreas size, reduced liver:body weight ratios,
and reduced blood hemoglobin were noted. These effects were not observed in
rats on diets containing lesser amounts of selenium.
766
Thapar et al. found that 8 ppm of selenium added as selenite to
either a practical corn-soy diet or a cerelose-soybean protein diet reduced
egg production, weight and hatchability of eggs, body weight, survival rate,
and growth of progeny of laying hens fed the diet from 1 day of age for as
long as 105 weeks. But no detrimental effects were observed when selenium
was added at the rate of 2 ppm, and it is possible that this addition improved
the livability of hens on the cerelose-soy protein diet. Similar findings were
24 629a
later reported by Arnold et al. Much earlier, Poley et al. reported that
2 ppm of selenium from grain improves the growth of chicks on a practical-type
diet.
846a
Witting and Horwitt reported that growth curves had shown that the
selenium requirement of the tocopherol-deficient rat has a very narrow optimal
range. The best growth rate was obtained on the addition of 0.1 ppm of selenium
-164-
-------
as selenite. At 0.3 ppm of selenium, the growth was better than at 0.03 ppm
but not as good as at 0.1 ppm. With the diet severely deficient in vitamin E,
selenium toxicity was noted at what these authors considered an unusually low
level of the element: 0.25 ppm in the basal diet plus 1 ppm as selenite.
Obviously, the chronic toxicity of selenium will depend on the criteria
used to determine the "no effect" dose level. For the normal diet, 4-5 ppm
will usually inhibit growth, and this may be the best indicator of toxicity.
In a diet deficient in vitamin E, 1 ppm may be toxic. During the development
of teeth, 1-2 ppm may be toxic if subsequent cariogenesis is used to measure
toxicity. Histopathological observations may suggest that less than 1 ppm
can be toxic. However, the physiologic significance of the observations may
not be clear, and the same may be said for biochemical parameters indicating
that even lower levels can be toxic. In many areas, livestock are regularly
fed diets containing over 0.5 ppm of the element, and there has been nothing
to suggest that they fare less well than animals on diets of lower selenium
content.
Treatment or Prevention of Selenosis
658
Rosenfeld and Beath state that no treatment is known for counteracting
the toxic effects of large amounts of selenium. Therapeutic measures, therefore,
are entirely symptomatic. It should be pointed out that British Anti-Lewisite (BAL)
is contraindicated and that the use of ethylenediaminetetraacetic acid (EDTA)
725
is essentially without effect.
Strychnine sulfate and prostigmine have been used with some success in
35a,657
the treatment of the blind staggers syndrome, but in view of the uncertainty
over the cause of this type of poisoning, there is doubt that these are treatments
for selenosis.
-165-
-------
574
Olson has reviewed the various methods suggested for the prevention of
chronic selenium poisoning in livestock. At present the only practical method
is to avoid allowing the animals an excessive intake of selenium. Affected
animals that are removed from seleniferous feeds may recover without apparent
aftereffects. The rate and extent of recovery depends largely on the severity
of the damage suffered by the animals before removal from the toxic feeds.
Selenium Poisoning in Man
Some reports of selenium poisoning in man have been concerned with
excessive dietary intake of the element in foods and have suggested that
signs of poisoning include chronic dermatitis, loss of hair, and loss,
discoloration, or brittleness of fingernails. 36a,432a,433,657 The evidence
presented, however, does not establish that selenium was the cause of the
signs observed in the studies.
Other reports have dealt with selenium poisoning in industrial workers
but no death among these workers has been attributed to such poisoning.
Workers exposed to fine dust of elemental selenium, which is very insoluble
-166-
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TABLE 5-3
Acute Toxicity of Some Selenium Compounds
Compound
Experi-
mental
Animal
Mode of
Administration
Toxicity-
Reference
Sodium selenite
Sodium selenate
Selenium oxychloride
Hydrogen selenide
DL-selenocystine
DL-selenomethionine
Diselenodipropionic
acid
Dimethyl selenide
Trimethylselenonium
chloride
Rat Intraperitoneal injection
Rat Intravenous injection
Rabbit Intravenous injection
Rat Injection
Rabbit Injection
Dog Injection
Rat Intraperitoneal injection
Rat Intravenous injection
Rabbit Intravenous injection
Rabbit Application to skin
Rat In air
Rat Intraperitoneal injection
Rat Intraperitoneal injection
Rat Intraperitoneal injection
Rat Intraperitoneal injection
Rat Intraperitoneal injection
3..25-3.S mg Se/kg body wt
3.0 mg Se/kg body wt
MLIT 1.5 mg Se/kg body wt
MLD 3.0-5.7 mg Se/kg body wt
MLD 0.9-1.5 mg Se/kg body wt
MLD 2.0 mg Se/kg body wt
5.5-5.75 mg Se/kg body wt
MLl 3.0 mg Se/kg body wt
MLET 2.0-2.5 mg Se/kg body wt
83 mg of compound caused death in 5 hr,
4 mg caused death in 24 hr
All animals exposed to 0.02 mg/liter of
aira|or 60 min died within 25 days
MLD—— 4.0 mg Se/kg body wt
4.25 mg Se/kg body wt
LD50 25-30 mg Se/kg body wt
LD^Q 1600 rag/kg body wt
LD50 49.4 mg Se/kg body wt
208
733
733
529
529
529
208
733
733
159
160
524^
b
524-
487
565
—MLD, minimum lethal dose; LD5Q,
^Smallest amount that would kill
-Smallest amount that would kill
dose causing death in one half of test animals.
75% of the rats in less than 2 days.
40-50% of the animals.
-------
in water, have suffered catarrh, nosebleed, and loss of sense of smell in
instances where the dust collected in the upper nasal passages, and a derma-
titis was observed on the hands of a few of those handling the element. °
Molten selenium has reportedly caused burns without any toxic reaction, •"
and in one instance where rectifier plates made of the element were melted
down, the red fumes caused intense eye, nose, and throat irritation, with
I 00
some dizziness and headache.x"
Hydrogen selenide has also been implicated in the poisoning of man in
industrial situations. ' Irritation of the mucous membranes of the
respiratory tract, nausea, and dizziness are among the reported signs of
poisoning. Hydrogen selenide has not caused a death in man; one reason may
be that it is never used in quantity, and another may be that it is readily
oxidized to give elemental selenium. ^° At concentrations as low as 0.001
mg per liter of air, it causes olfactory fatigue, and its offensive odor
cannot be relied upon to warn of its high concentration. As little as
0.005 mg per liter of air has been reported intolerable to man,160'161
and the threshold limit given by the American Conference of Governmental
Industrial Hygienists is 0.05 part of the gas per million parts of air
(by volume).^
Selenium dioxide forms selenious acid when in contact with water and
is the main problem in industries using selenium. The sudden inhalation
of large quantities of selenium dioxide powder may produce pulmonary edema,
because of the local irritant effect on the alveoli of the lungs, and persons
o CQ
exposed to it may experience mild epigastric distress after meals. The
compound has caused dermatitis^-* and burns when in contact with the eyes. 9
If allowed to penetrate beneath the fingernails, it causes an especially painful
-168-
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260 258
inflammatory reaction. Glover states that the symptoms of over-exposure
to selenium in man — pain in the nail beds, metallic taste, and garlic odor
of the breath — make workers treat selenium compounds with respect and may
lessen the chances for accidental poisoning.
Selenium oxychloride, an almost colorless liquid at room temperature,
is a severe vesicant capable of producing a third-degree burn, penetrating the
159
skin, and appearing in the blood and liver,, Acute sore throats in laboratory
workers exposed to dogs exhaling dimethylselenide after selenium injections have
520
been reported, but additional data on the toxicity of organic selenium
compounds to man are not available. Studies of a community in the neighborhood
of a selenium refining plant in Japan indicated that a yellow color of the
facial skin, anemia, and hypertension in some subjects might have been signs
756 221
of selenium toxicity0 And finally, Frost has suggested that the British
Beer Poisoning Epidemic of 1900 may well have involved selenium.
Until 1966 the literature had not carried any report of the death of a
human being as a result of accidental exposure to selenium. In that year,
107
Carter reported the fatal poisoning of a 3-year-old boy who ingested selenious
acid in a proprietary preparation of a gun-bluing compound. The pathologic
findings suggested a toxicity of the vasculature. Carter contended that general
unawareness of the possibility and mode of presentation of acute selenium
poisoning renders its diagnosis unlikely and tends to perpetuate the appearance
of rarity. Selenium disulfide, a commercial preparation used in the treatment
of dandruff, has been suspected of causing a nonfatal toxicity in a woman using
it. Red lipstick containing selenium has been suggested as the cause of a
77
syndrome in a patient using it. The syndrome expressed itself in nervousness,
metallic taste, vomiting, mental depression, and pharyngitis.
-169-
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Dental Caries
Hadjimarkos and his co-workers have published many articles on the
298a
relationship of selenium to dental caries, beginning in 1952 with a report
on a study in which it was concluded that a direct relationship existed between
dental caries in man and urinary excretion of the element. In reviewing this
288a
subject in 1968, Hadjimarkos states that epidemiologic studies among children
and experimentation indicate that selenium is indeed capable of increasing the
susceptibility of teeth to decay. He concludes that the ingestion of the element
during the development of teeth probably results in its incorporation into the
tooth structure and a subsequent increase in the incidence of caries.
761a
Tank and Storvick reported that children whose urine contained more
than 0.1 ppm of selenium had an increased incidence of caries. Cadell and
96a
Cousins observed no correlation between selenium content in urine and the
294a
incidence of caries in children, but Hadjimarkos pointed out that in no
case was the urinary selenium excretion in the children studied at a high
enough level to suggest that increased caries could be expected. Ludwig and
460
Biddy found that although certain towns in low-selenium areas had a lower
incidence of dental caries than did some in high-selenium areas, one of the
towns in a high-selenium area had the lowest incidence of caries. These
investigators also pointed out that the incidence of caries in all the high-
selenium areas was lower than that reported for towns in New England, a
680a
low-selenium area. Comments by Schwarz emphasize that surveys of the type
mentioned above, as well as the attempt to draw any meaningful conclusions from
730
the early reports that families in seleniferous areas had bad teeth, are
deceptive because they do not take into account the many factors that might
influence the incidence of dental caries, such as economic status or level of
education.
-170-
-------
A variety of results in addition to those reported by Hadjimarkos and his
I21a
co-workers have been obtained in experimental animals. Claycomb et al.,
531b 549a i?7a
Muhler and Shafer, Navia et_ al_., and English found the administration
of selenium to be essentially without effect on the incidence of dental caries.
531a
Mdhlemann and Kbnig reported a reduction in the incidence of caries in rats
fed selenium, attributing this to a reduction in consumption of the cariogenic
diet. Administering selenium to young rats after weaning and to their dams
89a
during pregnancy and lactation increased the incidence of caries in the young.
288a 65a
In agreement with this and with some of the work of Hadjimarkos, Bowen
reported that after the administration of selenium to monkeys in their water
during tooth development, chalky, yellow enamel developed. When it was
administered posteruptively, the selenium seemed to be cariostatic. Further,
704a
Shearer found that the uptake of selenium from selenomethionine was much
greater during development of teeth than it was after the teeth were fully
developed. Unfortunately, the work with experimental animals has dealt with
selenium added to water or feed at levels that are quite toxic and well above
what the general population would be expected to consume. It is dangerous and
unrealistic to extrapolate the findings to man0
This matter is worthy of additional study, but at present there seems no
reason to suspect that selenium is important to cariogenesis in man.
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CARCINOGENICITY AND ANTICARCINOGENICITY
Since 1940 five groups of scientists have studied the carcinogenic and anti-
carcinogenic potential of selenium, selenium salts, mixed selinides, and seleni-
ferous grains. The first group fed a stock colony of rats seleniferous grain and
a mixed selenide insecticide; the second group used natural feed with added
selenium salts; the third and fourth groups used semipurified rations with added
selenites and selenates; and the fifth group used natural feed with selenium salts
added to the drinking water.
Since selenium appeared to be inversely related to some forms of cancer,
attempts were made to associate demographic information and tissue concentration
of selenium with the incidence of cancer. Further work was initiated to determine
the effects of selenium supplementation on cancer induction in selenium-normal
and selenium-deficient animals.
Identification of chemical aspects of carcinogenesis and anticarcinogenesis,
and knowledge of the histochemical, morphologic, and biochemical effects of
selenium, have suggested possible association between optimum selenium nutrition
and prophylaxis and health of biochemically stressed cells.
Neoplasia and Carcinogenesis
552
In 1943, Nelson et al, at the U.S. Food and Drug Administration reported
selenium-induced neoplasia in an experiment in which 53 of 126 principals and
14 of 18 control rats maintained on a low-protein (12%) feed lived 18-24 months0
The feed of the principals contained 4.3 yg of added selenium per gram of feed
in the form of seleniferous grain, potassium ammonium selenide and potassium
sulfur selenide. The mixed selenides were used as insecticides at that time
and are no longer manufactured. This was the first of four series of experiments
317,552,673,674,773,807
designed to induce neoplasia with selenium salts.
-172-
-------
The 53 principals in the Nelson experiment that lived 18-24 months had hepatic
cirrhosis; 11 had hepatic adenomas and the other 42 contained areas of adenomatus
552
hyperplasia. The 14 aged control rats had neither adenomatus and neoplastic
lesions nor cirrhosis. The spontaneous incidence of hepatic tumors in the colony
at that time was 0.17. in rats less than 18 months old, 0.57. in rats 18-24 months old,
and 0.9% in rats more than 24 months old. Spontaneous tumors in the colony and in
the principals with added selenium were associated with severe hepatic cirrhosis.
These tumors were not considered to be carcinomas and they did not metastasize.
742
The hepatic tumors observed in this experiment probably resulted from hepatic
cirrhosis rather than from the addition of selenium to the feed. Selenium was
naturally present at a nutritionally adequate concentration in the control feeds;
and mixed selenides and seleniferous grain were added to the feed of the principals.
552
The cirrhosis observed in this experiment has not been produced in either rats or
mice maintained for their lifetime on low protein feeds and with addition of nearly
lethal concentrations of selenium salts to the feed ' or water. These con-
ditions produced chronic hepatitis but not cirrhosis.
Because of the Nelson report and interest in nutritional requirements
for selenium, an extensive bioassay of selenium carcinogenesis was undertaken
at Oregon State University under contract with the carcinogen screening section
of the National Cancer Institute to determine whether selenium ions would induce
317,773
neoplasia in the rat0 A semipurified ration containing added selenate
or selenite was fed to 1,437 rats for up to 30 months. Of these, 1,126 were
autopsied when moribund and studied by histologic and hematologic methods.
Those not autopsied died in cages and were too decomposed to be of value. Most
of those not autopsied were fed 4-16 ppm of selenium and died within the first
100 days of the experiment.
Most of the 34 experimental groups contained 50-100 rats, and were fed the
semi-purified feed. The feeds containing 8-16 ug of selenium per gram of semi-
purified feed killed rats within the first 30 days of feeding. These groups
389
contained 15-30 rats. Experimental variables
-173-
-------
included oxidation state of selenium, concentration of protein (22%, 12% and
12%, with 0.3% of methionine), added dietary selenium from 0.5 to 16 ug per gram
of feed and husbandry regimens of continuous feeding or variations of partial
feeding. The basal ration contained 0.1 ug of selenium per gram of feed. In
addition, two groups of rats were fed a commercial ration, and two other groups
received the semipurified ration with 100 or 150 ug of added N-2-fluorenylacetamide,
a known hepatic carcinogen, per gram of feed.
389
None of the autopsied rats had hepatic cirrhosis. The autopsied rats
included 119 that were fed protein-deficient (12%) feed with 4, 6, or 8 ug of
added selenium, as selenite or selenate, per gram of feed. These regimens were
similar to those of Nelson and associates in protein composition (12%) and the
amount of added selenium (4.3 vs. 4-8 ug per gram). They differed from those
used in the Nelson experiment in that the feed was composed of semipurified rather
than natural feedstuffs and the added selenium had a higher valence than that used
by Nelson, was not an organic compound, was not combined with ammonia, potassium,
and sulfur, and was not an insecticide. Selenium, as selenate, was added to one
group of rats fed commercial feed at the rate of 4.8 or 16 jig per gram of feed.
The rats fed 4 or 8 ;ug of selenium per gram lived more than a year and did not
develop cirrhosis. Those fed the feed with 16^ug/g of added selenium died within
three months and did not have cirrhosis.
Hepatic lesions in the principals were acute and chronic hepatitis with
389
hyperplasia of hepatocytes. The incidence of hepatic carcinoma in the rats
in which it had been induced by N-2-fluorenylacetamide (FAA) was 30%.
Acute toxic hepatitis occurred in rats fed selenium added to the semipurified
ration at the rate of 4-16 ug per gram and in those fed selenium added to a
389
commercial feed at the rate of 16 ug Per gram. These rats lived less than
100 days, were emaciated and pale, and had poor-quality coats, ascites, and
edema. Chronic toxic hepatitis and hyperplastic hepatocytes were prevalent in
-174-
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rats fed selenium, as selenite or selenate added to semipurifled feeds at
the rate of 0.5 or 2 yg per gram for 18-30 months. Chronic toxic hepatitis
was associated with bronchial pneumonia, pancreatitis, myocarditis, and nephritis.
These rats did not have cirrhosis.
Six groups of rats — a total of 329 rats — were fed 0.5 or 2 yg of selenium
as selenite or selenate. Of these, 276 were autopsied; 71 of those autopsied had
lived 24-30 months. The longevity of these six groups was comparable with that
552 807
observed by Nelson et al. and Volgarev and Tscherkes.
The protocol of this experiment produced lifetime exposure to concentrations
of dietary selenium that ranged from nutritionally adequate (0.1 ug per gram) to
acutely lethal (16 ug per gram). The period of selenium feeding covered the
complete life-span of all the rats fed 4-16 ug of selenium per gram — less than
280 days. In addition, 20-30% of the rats fed the control feed or the feed
supplemented with 0.5 or 2 ug of selenium per gram lived 24-30 months,, Ten per-
cent of the rats over 9 months old on the 127. protein feed with 2^ug of added
selenium per gram had small livers with regenerative nodules, as in the Nelson
552
experiment. This lesion did not occur at higher or lower rates of exposure
to selenium (0.5 to 4jug/g). None of the rats had cirrhosis of the liver. Harr
and associates concluded the metaplasia, anaplasia, and neoplasia in the rat
are not induced by selenite, by selenate, or by methionine and selenate.
Cherkes et al. and Volgarev and Tscherkes reported the third experiment
on the carcinogenic potential of selenium. In three series of experiments, they
fed selenium, as selenate, to 200 rats at the rate of 4.3 or 8.6^ig per gram of
feed. The feeds were not semipurified. They contained 12-307. protein with addi-
tion of riboflavin, methionine, alpha-tocopherol, cystine, nicotinic acid, and
choline in appropriate groups. Groups of rats without selenium supplementation
(controls) were not included in the experiments.
-175-
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In the first series of 40 rats, 23 lived 18 months or longer„ All 40
552
rats had cirrhosis, as reported by Nelson et al. Of these, four developed
sarcomas, three developed hepatic carcinoma (two with metastases), and three
117,807
had hepatic adenomas. Of the 13 noncancerous rats, four had lesions
termed precancerous. The lesions were cholangiofibrosis, oval cell (bile duct
cell) proliferations, and biliary cysts.
117,807
In the second series, 60 rats were fed selenium and 12 or 30% casein.
One liver carcinoma, one hepatic adenoma, and three sarcomas were reported. In
the third series, none of the 100 rats had neoplasms or precancerous lesions„
The 15 neoplasms observed in the three series occurred in about 120 rats
117,807
that lived 18-24 months„ The 15 neoplasms included seven sarcomas, four
hepatic carcinomas, and four hepatic adenomas. Six of the sarcomas appeared to
be extrahepatic lymphomas, and the seventh appeared to have arisen from the bile
ducts or mammary glands.
Six of the eight liver cancers, all four of the hepatic "precancerous"
117,807
lesions, and four of the seven sarcomas occurred in the first series„
Two liver neoplasms and three carcinomas occurred in the second series and none
occurred in the third series. Thus, the incidence of hepatic neoplasia in the
first series was 40% of the old rats; in the second series, 12%; and in the third
series, none.
The fourth experiment on the bioassay of selenium carcinogenesis was reported
671 673,674
by Schroeder and Schroeder and Mitchener. Groups of 100-110 rats and
mice were supplemented with 2 or 3 ppm of selenium as selenate or selenite in
the drinking water. The 90% survival time of rats supplemented with selenate
was 1,113 days compared with 1,180 for the nonsupplemented rats. Selenium-supplemented
rats were 3-7% heavier than the nonsupplemented controls after 12-36 months of
supplementation. Despite heavy supplementation with selenium salts at near-lethal
-176-
-------
amounts (about 25 times the amounts for the controls), the concentration of selenium
in kidney, liver, heart, lung, spleen, and erythrocytes of selenium-supplemented
rats was 1.5-2 times the concentration in tissue from control rats.
through the drinking water
Mice given selenite or selenate and rats given selenite/did not have an
671,673,674
increased incidence of tumors. About 70% of the rats were autopsied,
and 65% of those autopsied were examined histologically. Neither the rats nor
the mice had hepatic cirrhosis. However, a severe epidemic of chronic murine
pneumonia occurred in the rats0 Twenty tumors were found in the control group
of rats, and 30 were reported in the selenate-supplemented group0 The types
of tumors and the numbers were given as follows:
Control Selenate
_Grpup_ Group
Mammary tumors 10 11
Spindle cell sarcomas 2 4
Leukemia types 2 4
Pleomorphic carcinomas 1 2
Other sarcomas 5 11
The anatomical location of the sarcomas and pleomorphic carcinomas was not
reported. These tumors may have been sclerosed granulomas secondary to the
epidemic of chronic murine pneumonia. Histologic slides were prepared only
from selected organs and animals, and the rationale for that selection was not
reported. Since the organs and tissues were not systematically searched, type
and incidence of histologic lesions are not known.
552
Despite an initial report of selenium as a carcinogen, chronic
experimental exposure of rats and mice to selenium salts over a period of
-177-
-------
117,317,552,671,673,674,699,773,807
12 years has not induced neoplasia. During
the same period, selenium salts have been used prophylactically and therapeutically
in ruminants, omnivores, and carnivores throughout the world.
Epidemiologic and demographic evidence from the widespread use of selenium
supplementation, exposure to toxic concentrations of selenium in feeds, and use
of selenium in shampoos and industrial plants does not suggest that selenium is
carcinogenic; rather it may be correlated with a reduction in the evidence of
222,673,691,700-703,824
human and ovine cancer.
There has been no increase in the incidence of neoplasia in any of the
treated species. In New Zealand the incidence of intestinal cancer in treated
sheep has decreased.
Some regions of the world including the North Central and Rocky Mountain
regions of the United States are geologically rich in selenium. Forage plants
in these regions often contain more than 10 ug of selenium per gram of weight.
Ruminants and horses eating these plants develop selenosis and may die.
699,703
Shamberger reported a lower incidence of cancer in people living in
these regions. This observation was correlated with lower than average con-
701
centrations of selenium in the blood of some patients with cancer.
Anticarcinogenesis
The demonstration of the relationship of selenium to human cancer is limited
to demographic studies and comparisons of blood levels of selenium in patients
825
with and without malignancies. However,'Weisberger and Suhrland discussed
121
the effect of selenium cystine on leukemia, and Chu and Davidson listed
selenium compounds among potential antitumor agents.
Demographic and experimental observations of Shamberger and associates
669,699,701,703
support the concept of pharmacologic and medical uses of selenium salts.
They found an inverse correlation between the incidence of cancer deaths, the
-178-
-------
concentration of selenium in the patient's serum, and the geographic incidence
of selenium—low, moderate, or high. The concentration of selenium in the
blood of cancer patients averaged 74% of normal,, However, the blood of patients
with some forms of cancer contained normal concentrations of selenium.
The selenium contents of diets of 17 paired human males with and without
gastric cancer were compared and related to dietary antioxidants and food
702
preservatives. Patients with gastrointestinal cancer or metastases to
gastrointestinal organs had significantly lower levels of selenium in the blood
702
than normal patients. No elevations of selenium in the blood of cancer
patients were noted. The authors postulated that selenium acted to prevent
attachment of the carcinogen to DNA sites.
698
Shamberger also reported on the effect of adding sodium selenide to
cancer-inducing preparations of anthracene compounds or adding sodium selenite
to the feed of rats exposed to anthracene compounds.
Rats fed dietary selenite and those treated with preparations of anthracene
compounds with added selenide developed fewer skin papillomas than rats treated
with anthracene compounds without added selenide.
319
Harr et^ al. reported that after 200 days of feeding selenium-depleted
rats a semipurified feed containing 100 ng of the hepatic carcinogen FAA per
gram of feed and 0.1, 0.5, or 2.5 pg of added selenium, as selenite per gram,
the incidence of mammary and hepatic neoplasia with or without 0.1 yg of added
selenium per gram was 3 times greater than the incidence in rats supplemented
with 0.5 or 2.5 yg of selenium per gram. The low-selenium groups (0.0 and
0.1 ppm) died before 200 days of age and had a 90% incidence of neoplasia. At
this time, 35% of the rats fed 0.5 and 2.5 yg of selenium per gram had died,
and the incidence of neoplasia was 30%. Most of the remaining 0.5 and 2»5 pg/g
rats lived for an additional 120 days. By this time, they had received the
-179-
-------
carcinogen for an additional 120 days, and the total incidence of neoplasia was
90%, as observed in the groups receiving 0.0 and 0.1 yg of selenium per gram.
Since the longevity of the rats was proportional to the amount of selenium
supplementation and the duration of exposure to the carcinogen, the increase
in cancer in the rats heavily supplemented with selenium may have been due to
greater exposure to the carcinogen or to longer time for induction.
The mammary tumors in the group not supplemented with selenium were more
invasive than those in rats from the three supplemented groups and predominated
in the pelvic rather than in the thoracic region, as in the selenium-supplemented
or commercially fed rats.
389
Johnston studied the effect of selenium on the induction of cancer by
2-N-fluorenylacetamide and diethylnitrosamine in selenium-depleted rats over
a restricted exposure period. Because of widely varying rates of feed consumption
by the principal and control groups and the high incidence of neoplasia in all
the exposed groups, results were confusing.
The unique ability of selenium to reduce methylene blue was reported by
669
Schrauzer and Rhead, who suggested that this ability might provide a basis
for testing for cancer or susceptibility thereto. In studies of lipid therapy
640
based on the types of lipid imbalance in cancer patients, Revici reported
that the most satisfactory and reproducible palliative effects were obtained by
using synthetic lipids containing bivalent selenium, a serendipitously acquired
222
observation alluded to by Frost.
Clinical observation of the efficacy of parenterally administered mixtures
of selenium and vitamin E to animals with adequate dietary selenium and vitamin
E indicates that an additional 1-3 rag/50 kg per month improves functioning of
reproductive, muscular, and vascular systems. Efficacy is claimed in clinical
cases of stiffness, lameness, myositis, hepatic degeneration, infertility, loss
-180-
-------
of condition of the hair coat, and poor growth. In lameness and stiffness in
race horses and dogs, and breeding rams and bulls, a severe strain is put on
the musculoskeletal system and in particular on the animal's joints. Veterinarians
in selenium-deficient areas believe that animals improve after receiving selenium
supplements. Theoretically, this could be related to better vascularization of
the tissues or to the role of glutathione peroxidase in maintenance of cellular
membranes.
-181-
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PHYSIOLOGIC ROLE
Vitamin E
The close nutritional interrelationship between vitamin E and selenium
762,763
suggested that selenium might function in vivo as an antioxidant. Five
general mechanisms were postulated to account for the hypothetic antioxidant
activity of selenium compounds: peroxidation inhibition, peroxide decomposition,
free radical scavenging, repair of molecular damage sites, and catalysis of
protector sulfhydryl compounds. Although many of the in vitro and in vivo
effects of selenium can be rationalized by an antioxidant action of selenium,
a number of recent studies indicate that selenium probably has a more subtle
role in vivo. For example, dietary selenium had no influence on the survival
369
of rats exposed to chronic whole-body irradiation. Moreover, selenium had
no protective effect against the lipid peroxidation induced in mitochondria by
444
ascorbate, oxidized plus reduced glutathione, or iron. Finally, there are
several reports that show beneficial responses to selenium even in animals ade-
492,742,769
quately supplied with vitamin E.
Glutathione Peroxidase
660
The observation of Rotruck et al. that dietary selenium could protect
erythrocytes against the oxidative hemolysis characteristic of vitamin E
deficiency as long as glucose was present in the incubation medium suggested an
involvement of selenium in glutathione (GSH) metabolism. Since the level of
GSH in red blood cells was the same in selenium-deficient animals as in selenium-
661
adequate animals, it appeared that selenium deficiency had no effect on
generation of GSH. Rather, there seemed to be a fault in the utilization of
GSH in selenium deficiency, and, indeed, the enzyme glutathione peroxidase has
203,662
recently been shown to contain selenium. This discovery of a role for
-182-
-------
selenium in glutathione peroxidase is highly significant in that it is the
first demonstration of a role for selenium in a specific mammalian enzyme.
Nonheme Iron Proteins
Diplock and co-workers first elaborated the hypothesis that the biologically
active form of selenium may be selenide in the active site of an uncharacterized
112,152,153, 459
class of nonheme iron proteins. This concept was based on the
finding that significant portions of the selenium in the niitochondrial and
microsomal fractions of rat liver were in the selenide valence state in animals
with adequate vitamin E. However, in animals fed a diet deficient in vitamin E,
little selenide was detected in the subcellular fractions. Therefore, vitamin E
was considered to protect the unstable selenide from oxidation. This theory is
appealing because if selenium truly has a role in the active site of a mitochon-
drial nonheme iron protein, this might explain the decline in respiration that
is characteristic of liver slices prepared from rats fed diets deficient in both
118
vitamin E and selenium.
Electron Transport
Evidence that selenium plays a role in the electron transport chain was
443
recently presented by Levander and colleagues. This idea was derived from
experiments that examined the effect of dietary vitamin E or selenium on the
swelling of rat liver mitochondria induced by various chemical agents added
in vitro. Previous work had shown that dietary vitamin E, but not selenium,
was able to protect mitochondria against the swelling caused by compounds that
444
promoted lipid peroxidation. Selenium, on the other hand, accelerated the
442
swelling caused by certain thiols. Studies with respiratory inhibitors
indicated that the swelling caused by the addition of GSH plus selenite in vitro
might be partly mediated at the level of cytochrome £„
-183-
-------
Selenium was then demonstrated to be a highly effective catalyst for the
443
reduction of cytochrome c^ by GSH in a chemically defined model system. It
was suggested that selenium may function in vivo by facilitating the transfer
of electrons from GSH or other sulfur compounds into the cytochrome system. A
possible role for selenium in biologic electron-transfer reactions is also
786
supported by the work of Turner and Stadtman, who found that a selenoprotein
was a component of the clostridial glycine reductase system. Moreover,
835
Whanger et al. have found a selenoprotein in lamb muscle that contains a
heme group identical to that of cytochrone £.
Interrelationships
Although each of the above hypotheses is a distinctive way of considering
the role of selenium in living systems, all the theories are closely related,
and it may well turn out that each one is just a variation on a basic general
theme. For example, many of the "antioxidant" properties of selenium could be
explained by a role for selenium in GSH peroxidase, since this enzyme destroys
peroxides. Also, GSH peroxidase has been shown to be involved in mitochondrial
555
swelling and contraction- Obviously, any role for selenium in mitochondrial
nonheme iron proteins would be intimately related to electron transfer. Thus,
it is reasonable to suppose that one underlying action of selenium could account
for all these phenomena. Whether this action of selenium is related to its
role in GSH peroxidase is a question that can be answered only by additional
research.
-184-
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MEDICAL USES OF SELENIUM IN HUMAN BEINGS
This section is concerned with the medical uses of selenium in human beings.
These uses fall into two categories: (1) the diagnostic, which uses the
75
radionuclide form, Se, usually as selenomethionine, for scanning of organs
and tissues, and (2) the therapeutic, which uses selenium sulfide for the
treatment of seborrheic dermatitis and tinea versicolor.
Diagnostic Scanning and Labeling
Se-selenomethionine was the first amino acid used in clinical scintillation
scanning. It can be produced with a high specific activity by biosynthesis
(about 300 mCi per milligram of selenomethionine) or chemical synthesis (6 mCi
28
per milligram). This nuclide has several gamma emissions with sufficient
tissue penetration to allow external clinical measurements of nuclide in situ.
Pancreas. The high rate of incorporation of amino acids into pancreatic
enzymes and the similarity of metabolism of selenomethionine and methionine
56 75
formed the basis for the suggestion by Blau of the use of Se-selenomethionine
for external visualization of the pancreas, an organ impossible to delineate by
75
X ray. Clinical trials confirmed that Se-selenomethionine accumulated in
57,58
pancreas in relatively large quantities and in concentrations 8-9 times
748
greater than in liver and small bowel 1 hr after intravenous administration.
Pancreatic scintography has been used for determining such pathologic
conditions as pancreatic carcinoma, pseudocyst, and pancreatitis,, Although
there has been some disagreement as to the overall value of this procedure,
many authors have endorsed it, with varying reservations, as a useful addition
to the armamentarium available for investigation of a diagnostically refractory
72,168,649 169 75
organ,, Eaton et al. stress the potential value of Se-selenomethionine
-185-
-------
imaging as a means of documenting the return of pancreatic function to normal
after an attack of acute pancreatitis or after corrective surgery for chronic
4
pancreatitis. Agnew et al. performed a different test of pancreatic function
simultaneously with the scan by collecting duodenal samples of the labeled
digestive enzymes secreted by the pancreas. Following the stimulus of a test
75
meal, normal patients showed an increase of Se that correlated well with the
trypsin concentration in the duodenal aspirate. There was no increase in
Se in the duodenal aspirates of patients with carcinoma of the pancreas or
chronic pancreatitis.
Liver. Scintigraphic imagery of the liver usually involves scanning with
99m 113m
radiogold, Tc sulfur colloid, or In ferric hydroxide, all of which are
deposited in the reticuloendothelial system. The principal parenchymal cell
131
label is I rose bengal. A focal defect in liver is defined classically by
its inability to concentrate the above labeled substances from the vascular
system. In the focal lesion the incorporation of Se-selenomethionine is
related to its vascularity and capacity to metabolize methionine. Modification
of the rectilinear scanner permits it to function as a dual-channel subtraction
198 75
mode to subtract Au from Se in the liver, and to present the display of the
liver in one color and the selenium in the pancreas and the focal lesion in
another. The avascular lesions, including cysts, abscesses, scars, pseudotumors,
75
and extrinsic pressure defects, show little or no Se activity. Metastatic
lesions may have varying levels of selenium concentration. The hepatocellular
carcinoma concentrates selenium in amounts equal to the normal hepatic parenchyma
and can only be visualized in the Se-selenomethionine scan by the subtraction
106,170,394 748
technique. Stolzenberg concludes that if melanoma is clinically
75
excluded, hepatocellular hepatoma can be strongly suggested by Se-selenomethionine
-186-
-------
liver scanning when an area of defect on colloidal scan shows activity on
Se-selenomethionine scan,,
631 149,329
Parathyroid, Thyroid. Potchen and later others showed that
localization of Se-selenomethionine in the parathyroid gland was sufficiently
higher than in the suppressed thyroid gland and other surrounding tissues to
27
make it usable for identification of parathyroid adenomas. Ashkar et a!0
claim better parathyroid visualization following the administration of glucagon,
75 767
an effective stimulant to incorporation of Se-selenomethionine. Thomas et al.
differentiated malignant from benign lesions of the thyroid gland by using
complementary scanning with Se-selenomethionine and radioiodide.
335
Lymphomas and Miscellaneous Tumor Masses° Herrera et al. reported that
Se-selenomethionine given intravenously for pancreatic scanning was
incorporated into lymphomas in sufficient amounts to be detected by external
740
means. Spencer et a!0 confirmed the avidity of lymphomas for selenomethionine.
On further investigation of patients with nonneoplastic diseases and various
abdominal tumors, it was found that neither normal lymph nodes nor the common
epithelial neoplasms accumulated enough activity to be clearly imaged
334 195
externally. The studies of Ferrucci et al. concluded that a negative
isotope study did not reliably exclude disease of lymphatic tissue, whereas
an abnormal scintigram indicated a 70-80% likelihood that disease was present.
262 75
Goal et al. point out that Se-selenomethionine scanning is a simple,
safe, and atraumatic procedure for visualizing mediastinal masses and therefore
is preferable to other investigative procedures, such as pneumomediastinography
and venography0 They found this radiopharmaceutical incorporated in actively
dividing cells of various neoplasms, including bronchogenic carcinoma, and in
occult thymomas. In an attempt to exploit for diagnostic purposes the ability
-187-
-------
of neuroblastoma cells to synthesize cystathionine, D'Angio et al. confirmed
75
localization of Se-selenomethionine within the tumors in several patients.
Placental Competence. Because the methods for measuring intrauterine growth
245
rate were considered unsatisfactory, Garrow and Douglas suggested the
measurement of placental competence by the administration of Se-selenomethionine
to the mother, which would assess one of the more important functions of the
placenta: its ability to take up amino acid from the maternal circulation and
pass it to the fetus. The high growth rate of the fetus can be achieved only
if the placenta transmits nutrients to the fetus in sufficient quantities;
some nutrients, notably amino acids, have to be transported from the maternal
to the fetal circulation against a concentration gradient„ If the placenta is
unable to support the fetus in this way, intrauterine growth is retarded, and
the baby, when delivered, is "light-for-dates"; such babies have high morbidity
245
and mortality rates.
Mothers who had low rates of transfer of Se-selenomethionine had
significantly smaller babies than those with normal transfer rates, and high
transfer rates tend to be associated with rather big babies. The test can be
done quickly and easily, and it seems to give reliable results at any time
154
after 28 weeks of gestation, but it is probably most useful at about 34 weeks.
Although the test involves giving a dose of radioactivity to a pregnant woman,
154
the test cannot be considered dangerous, according to Douglas; the radiation
involved is about 3% of that given by X-ray examination of the abdomen and
about one ten-thousandth of that which has been known to harm a fetus at this
432
stage of gestation. In performing this test on 467 patients, Lee and Garrow
found no adverse reactions attributable to the test.
-188-
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Extracellular Fluid Volume. Platelets, Fibrinogen. Albert et_ al.6 suggested the
75 IS
use of Se sodium selenate instead of JJS sodium sulfate for the measurement of
extracellular fluid volume. They stated that the advantages of ' Se over S
are the simplicity of detecting a radioactive element, such as Se, having
only gamma emissions; the convenience of accurately measuring Se with com-
mercially available and moderately priced equipment; and the fact that Se
simplifies work in studies where two or more tracers are used. However, since
75
selenate and sulfate are not metabolically equivalent, the substitution of Se
35
for S is not recommended.
The incorporation of intravenously injected Se selenomethionine into
platelets was found to vary with alterations in the rate of platelet production.
618 75
Penington concluded that Se appears to label newly produced platelets during
their formation in megakaryocytes and provides a method by which thrombopoiesis
may be studied in vivo0 In thrombocytopenic states Se-selenomethionine is an
66
effective and clinically useful cohort label of platelets and fibrinogen.
Therapeutic Uses
Because of the close resemblance of selenium to sulfur and the fact that
some of the most powerful synthetic drugs contain sulfur, efforts have been
expended in synthesizing and testing organic selenium compounds as potential
406
chemotherapeutic agents. Klayman has reviewed the attempts at chemotherapy
with organic selenium compounds, concluding that few of them offer enough
advantages over present agents to warrant clinical trial. Therapeutic uses of
selenium in human beings have been limited to external application of selenium
sulfide preparations in dermatologic disorders of seborrheic dermatitis and
tinea versicolor0
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Seborrheic Dermatitis. Selsun is a commercial preparation of selenium sulfide
in aqueous suspension containing emulsifying, buffering, and carrying agents
for use as a shampoo in cases of dandruff. A prescription product (Selsun Red)
contains 2.5% (w/v) selenium sulfide; a product sold over the counter without a
prescription (Selsun Blue) contains 1% (w/v) selenium sulfide.
727
In one of the earliest investigations on the subject, Slinger and Hubbard
reported that more than 80% of the cases of seborrheic dermatitis of the scalp
treated with selenium sulfide (2.5%) were controlled completely during the
period of use of the shampoo without observable signs of cutaneous irritation,
726 664
sensitization, or toxicity. Slepyan and Sauer reported essentially the
589
same results. Orentreich et_ al_* found that the 2.5% preparation was as
effective against seborrheic dermatitis as another popular shampoo containing
zinc pyrithione as the active ingredient.
Some investigators noted side effects from the use of selenium sulfide
176
(2.5%) shampoos. Eisenberg described three cases of contact dermatitis.
264 ^g 500
Increased sebum secretion and oiliness of scalp * have been observed.
46
Bereston also reported an orange tinting of gray hair. Diffuse loss of hair,
275
which ceased upon discontinuation of the shampoo, was observed by Grover
723 22
and Sidi and Bourgeois-Spinasse. Although Archer and Luell observed
dysplastic changes in hair roots of persons using selenium sulfide suspensions,
they called for experimentation with other sulfides and for control studies of
shampoos consisting only of emulsifying, buffering, and carrying agents. In
466
acute and chronic applications of selenium sulfide shampoo, Maguire and Kligman
concluded that there were no root deformities or changes in rate of hair regrowth.
Ayres and Ayres found 1% selenium sulfide ointment to be effective in
treating seborrheic dermatitis of glabrous skin in 73% of patients tested, but
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a 21% incidence of irritation and positive patch test reactions led to the
substitution of a 0.5% ointment that caused less irritation and was still
effective.
6*18
Ransone et al. reported a case of systemic selenium toxicity in a
woman who had been shampooing two or three times weekly for 8 months with
selenium sulfide suspension. Although the intact skin ordinarily absorbs
little, if any, selenium sulfide, the presence of open scalp lesions on this
patient were considered to be instrumental in permitting sufficient systemic
absorption to cause systemic toxicity in the form of progressive tremor,
weakness, and anorexia. Symptoms cleared rapidly when use of the shampoo was
discontinuedo
Tinea Versicolor
163
Selenium sulfide has been used in treating tinea versicolor since 1953,
but treatment procedures are varied, ' ' and follow-up studies of the
effect are scanty. Albright and Hitch found that a single overnight treatment
was promising as an easy form of suppressive remedy for this fungal infection,
but advocated repetition of the treatment three or four times at least every
third month. He noted no manifestation of skin irritation in his patient series,
oog
although the genital region was avoided. Hersle concludes that the risk of
intoxication with water-soluble selenium sulfide by this mode of application is
332
negligible in view of studies by Henschler and Kirschner showing low toxicity
and low absorption rates, not enhanced by simultaneous administration of
detergents.
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CHAPTER 6
SAMPLING AND ANALYSIS
COLLECTION. PREPARATION, AND STORAGE OF SAMPLES
Because of the volatile nature of many selenium compounds, several
difficulties are encountered in preparing, storing, and analyzing certain types
of materials. In addition, various plants and animals may differ considerably
in selenium content, soils may differ greatly in selenium content at different
depths, waters contain both soluble and suspended forms of the element, and
air contains both gaseous and particulate forms. Thus, obtaining representative
samples for analysis is sometimes difficult. Finally, the method of preparing
samples for analysis, often dictated by the method of analysis used, can intro-
duce errors into the results. Consideration of these matters is in some cases
as important as consideration of the method used to make the analysis.
Plants
In sampling plants, it should be kept in mind that leaves, roots, stems,
40
and seeds often differ considerably from one another in selenium content.
Their tissues are normally dried at 70 C or less for analysis, since some
521
higher temperatures have been reported to cause large selenium losses. For
most samples, the loss of the element at this temperature is probably very
26,174
small, but some of the indicator plants, such as Astragalus bisulcatus,
39
contain significant amounts of volatile selenium compounds, and these should
be analyzed without drying. Leaves reduce to fine particles much more readily
than do stems, and the tendency of these plant parts to remain separated during
11
grinding and subsequent handling increases the possibility of sampling error.
Thus, fine grinding and complete mixing are essential to accurate results. In
view of reports suggesting selenium losses on long-term, open storage without
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210,528
temperature control, samples of dry plant material should be stored
in tightly stoppered bottles at 0-5 °C. Undried samples of tissue should be
stored frozen in closed containers.
Animal Tissues
Animal tissues should also be stored frozen. Blood should be separated
into plasma or serum and cell fractions prior to freezing if separate values
for them are desired„ This reduces the likelihood of enzymatic formation of
volatile selenium compounds. It also reduces the likelihood of significant
190
loss of the element from urine samples. When drying for analysis is necessary,
it should be accomplished by lyophilizing.
When wet digestion procedures are used in analyzing plant or animal tissue,
some sampling error can be avoided by predigesting a large sample in nitric acid
573
and then using an aliquot for completion of the analysis.
Water
Water should be sampled by commonly accepted methods„ If it contains sus-
pended material, this should be removed by filtration within a few hours,
immediately
preferably/after the sample is collected. The selenium content of the sediment
can be determined separately if it is essential that this be known. The filtered
o
sample should be stored at 0-5 C to reduce the possibility of microbial action
that could result in the precipitation or removal of selenium. Usually, an
appropriate amount of the sample is made alkaline to phenolphthalein and then
evaporated to a small volume or to dryness for analysis„ This assumes that no
forms of the element are present that would be volatile under these conditions.
Normally, the assumption can be made, but additional studies on ways of reducing
this volume seem needed.
T-193-
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Air
Little study has been given to air sampling for selenium analysis. Most
of the work reported to date has dealt only with the particulate matter that
761
can be removed by filters. Tabor et al. recently published a tentative
624
method for analyzing this material. However, Pillay and Thomas found the
element to be divided into gaseous and suspended forms, and improvements in
collecting the gaseous form are needed.
METHODS OF ANALYSIS
Detailed discussions of methods of selenium analysis have been presented
585,819
elsewhere, and the subject will be only briefly reviewed here. Many
procedures are available for use, and these will be discussed in general terms
without attempting to completely cover the literature. They may be divided
into two general classes: those that do not require the destruction of the
sample (nondestructive) and those that require getting rid of the organic
matter before the selenium is measured (destructive).
Nondestructive Analysis
X-ray fluorescence. Nondestructive analysis can be accomplished by X-ray
fluorescence analysis, » » » but this method at present lacks sensitivity
and has not been widely used.
Neutron activation analysis. On the other hand, neutron activation analysis (NAA)
can be used either with or without destruction of the sample, and it has become
increasingly popular in the latter use. When used with destruction of the
sample, the selenium is usuaJLly separated from interfering elements following
activation 'and prior to its measurement. With or without destruction, the method
636 270
has been used on a wide variety of samples, some examples being lung, muscle,
65 427 550 49 197 563
blood, kidney and liver, pancreas, hair, eye lens, dental enamel,
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802 682 543 348 301 544 685
feces, yeast, tobacco, forages, feeds, wheat flour, cystine,
rainwater,637 air,624 and fossil fuels.625
The chief disadvantage of NAA for selenium analysis is the cost of the
equipment. This is so great that it can hardly be justified for selenium
analysis only. In survey types of work where multielement analysis is con-
ducted on large numbers of samples, it may be the method of choice, since it
can greatly speed the work (when used nondestructively) and since it has
excellent sensitivity for a number of elements. There is evidence, however,
that at submicrogram levels of selenium the analysis of natural materials by
585
this method can yield inaccurate results, so the method should probably be
tested in each laboratory on a variety of samples of known selenium content
before it is used routinely.
Destructive Analysis
Destructive methods. Other methods of analysis require the destruction of
organic matter before measurement of the selenium. This destruction has been
648
accomplished in a variety of ways: dry ashing with magnesium nitrate;
256
low-temperature ashing with excited oxygen; closed system combustion with
OQO 1 f\f\
the Schtiniger oxygen flask or with the Parr bomb; wet digestion with
648 845
sulfuric acid, nitric and sulfuric acid, mixtures of nitric and perchloric
820 120 496 135
acids alone or with sulfuric acid, ammonium vanadate, sodium molybdate,
300 771
or hydrogen peroxide; and hydrogenolysis. Of these, wet digestion with
mixtures containing perchloric acid is most commonly used, although oxygen-flask
combustion is also popular. Wet digestion has the advantage of being easily
adaptable to large numbers of samples and to liquids or materials of high
moisture content.
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Separation from interfering substances. Some methods call for separating the
selenium from interfering substances before measuring it. This can be accomplished
by reducing the selenium to its elemental form from filtered digests and then
63 648 312
removing it by filtration; distillation as the tetrabromide with or without
reduction to elemental selenium; extraction with an ethylene chloride-carbon
tetrachloride mixture of the complex of the element with toluene-3,4-dithiol,
821 461
followed by wet digestion and completion of the analysis; arsenic coprecipitation;
679
and ion exchange treatment to remove interfering cations<, Although distillation
and precipitation of the element has been commonly used in the past, arsenic
coprecipitation is simpler and much more satisfactory for small amounts of
selenium, and it is now the most commonly used method.
Spectrophotometry, gas chromatography, atomic absorption spectrometry, polarography,
oxidative-reduction titration, spark source mass spectrometry, neutron activation anal-
ysis, and fluorometry. Measuring selenium in digests or combusted materials, in some
cases with and in others without its separation, as discussed above, has been
accomplished by precipitating the selenium in elemental form as a pink sol and
126
estimating the amount visually by comparison with standards; filtering the
207 556
precipitated element on a barium sulfate pad or millipore filter and comparing
visually with standards; the ring oven technique, in which 3,3'-diaminobenzidene (DAB)
828
is used to develop the color, and comparing with standards; spectrophotometric
355 v 458
determination of the product of reaction with DAB, 2,3-diaminonaphthalene (DAN),
114a,132a,145a,664a,771 44
other £-diamines, 2-mercaptobenzothiazole; 2-mercaptobenzoic
131 399,829
acid methods based on the catalytic effects of selenium or the production
of an intermediate that is then reacted to give an indirect measure of the
131,405,546,592 547 393
element; gas chromatography; atomic absorption spectrometry;
120 86,146,408,736
polarography; oxidation-reduction titration; gravimetric
521 458
determination of the precipitated element or the insoluble Se-DAN complex;
-196-
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322
spark source mass spectrometry; neutron activation analysis (see previous
127
discussion); and the fluorometric determination of the Se-DAB complex or
607
the Se-DAN complex. Of these, the measurement of the fluorescence of the
Se-DAN complex and neutron activation analysis are most commonly used today,
and both are capable of determining submicrogram levels of the element. Many
satisfactory procedures, differing only slightly from one another, are available
for those choosing the first of these commonly used methods. Where the
equipment is available, and where multielement survey work is being done, spark
source mass spectrometry will probably be used more frequently. Finally, with
improvements in instrumentation and procedures, atomic absorption spectrometry
could become the method of choice in many laboratories.
Regardless of the method selected for use, it should be recognized that
all are subject to error, and each laboratory should test its procedures by
analyzing—preferably by more than one method—a variety of samples of known
selenium content. A recent report on a comparison of methods for fossil fuel
808
analysis supports this conclusion.
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CHAPTER 7
SUMMARY AND CONCLUSIONS
SUMMARY
Chemistry
The chemical properties of selenium are similar to those of sulfur. It
exists in nature in several oxidation states: -2, 0, +4, and +6.
In its -2 state, it occurs as hydrogen selenide, a highly toxic and
reactive gas that decomposes quickly in the presence of oxygen to elemental
selenium and water. Heavy metal selenides are insoluble, and a number of
organic selenides having properties similar to those of organic sulfides
have been identified in biologic materials. Some of these are very volatile.
In elemental form, selenium is insoluble and not subject to rapid oxidation
or reduction in nature. Because of its insolubility, it is not toxic. On
burning, it is oxidized to selenium dioxide, which sublimes and, on solution
in water, forms selenious acid.
Selenium occurs in the +4 state as inorganic selenites. In soluble form,
these are highly toxic. Selenite has an affinity for iron and aluminum sesquioxides,
with which it forms stable adsorption complexes. This and the ease of selenite
reduction to elemental selenium under acid and reducing conditions make this
form quite unavailable to plants and also reduce the probability of pollution of
water by the element.
Alkaline and oxidizing conditions favor the formation and stability of the
+6 form of the element, selenate. Most selenates are quite soluble and highly
toxic. This form of the element is not tightly complexed by sesquioxides. In
soils, selenates are easily leached and are available to plants.
Biologic processes appear to be involved in reduction of the element.
Oxidation apparently occurs in alkaline soils by chemical weathering, and it
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results from burning. The reduction process can produce volatile organic
selenides or hydrogen selenide; burning can produce particulate elemental
selenium or selenium dioxide, and these are the forms most likely to occur
in the atmosphere.
Occurrence
The earth's crust is estimated to contain an average of about 0.1 ppm of
selenium. This is not evenly distributed in the lithosphere, some mineral
deposits of limited size containing over 20 percent of the element, some rocks
undetectable traces.
Chemical, and possibly microbiologic, oxidation in alkaline soils solubilizes
selenium as selenate, making it available to plants. In acid soils, the element
exists in the more reduced forms, which are not very available to plants. Thus,
two factors have been of major importance in the development of soils that
produce crops containing too little or too much of the element: the selenium
content of the parent materials and the conditions of pH under which the soils
are formed. To a large extent, the latter is related to rainfall, and in the
United States the areas of excessive selenium are the more arid areas. As
rainfall increases, the probability of selenium deficiency increases.
With possible exceptions in the case of fish and certain sea foods,
selenium enters the food chain almost entirely via plants. Although some edible
animal tissues, especially liver, tend to accumulate the element, there is no
serious food chain buildup. Our present food habits, food processing methods,
and transportation capabilities seem to preclude the possibility of too much
or too little selenium in man's diet in the United States.
Waters seldom contain significant concentrations of the element0 Indeed,
only in rare cases have they been found to contain enough to be considered a
a good source for supplying the body with adequate nutritional levels.
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Data on the selenium content of fossil fuels are limited, but coals
containing a few parts per million are apparently not unusual. Fuel oils
probably contain lower concentrations of the element. During combustion, some
of the selenium in these fuels can escape into the atmosphere.
Industrial and Agricultural Uses
The free world refinery production of selenium from 1964 through 1971
averaged 2.2 million Ib. The United States was the leading producer for most
of those years, followed by Canada, Japan, and Sweden. Nearly all primary
selenium production derives from copper ores. Recovery is by treatment of
residue slimes generated during electrolytic refining of copper„
Apparent annual domestic consumption of selenium in recent years approxi-
mated 1 million Ib. Electronic applications, including use in rectifiers,
xerographic copying machines, and photoelectric cells, account for a substantial
part of selenium consumption. Selenium is used in the glass and ceramics
industry, in the manufacture of pigments, as a component of plating solutions,
and as a chemical agent in the preparation of many products.
Selenium was once used in controlling insects on ornamental plants, but
this is no longer done. At present, the chief use of the element in agriculture
is in the prevention of selenium deficiency in livestock and poultry.
Cycling
Like other elements, selenium is being continuously cycled by natural
processes. Qualitative aspects of the cycling have been well documented, and
the various pathways followed between waters, the land, air, and living organisms
can be stated with considerable accuracy. However, quantitative data are meager,
and we are not sure about the importance of the various pathways„
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Few data are available for direct determination of industrial atmospheric
emissions of selenium. However, it was estimated that 2.4 million Ib of selenium
was discharged by industrial plants in 1970. Burning of coal accounted for 62%
of the total, and production of copper for 26%. The remainder was about equally
divided among selenium recovery plants, glass manufacturing, and the burning of
fuel oil.
If estimates are correct, the amounts of selenium emitted from industrial
sources into the air are small in comparison with the amounts of other industrial
pollutants emitted; and if adequate dispersal procedures are followed, it seems
that selenium emissions should not present a serious problem. Industrial
emissions of selenium probably occur as finely divided solid particulates.
Biologic Effects
Plants contain widely varying amounts of selenium, the amounts depending on
species, the amount and form of the element in the soil, and other factors. An
essential role for selenium has not been established in plants, and the element
is not known to have toxic effects on plants under natural conditions. In many
respects, plants metabolize selenium as they do sulfur, but significant differences
have been noted in the biochemical pathways of these elements.
The absorption of orally ingested soluble selenium compounds appears to be
virtually complete in monogastric animals. In ruminants, some formation of
insoluble elemental selenium may occur that would decrease the absorption of
selenium. At least in the case of selenite, there seems to be no mechanism to
regulate the amount of selenium absorbed by the gastrointestinal tracto Little
quantitative information is available regarding the absorption of selenium com-
pounds through the lungs or skin.
-201-
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The distribution of ingested selenium is widespread in the internal
organs, the largest amounts occurring in the liver and kidneys. When very
small doses of selenium are given, the testes retain a sizable fraction of the
dose given in long-term studies. Otherwise, the pattern of selenium distribu-
tion in the organs is generally similar regardless of whether toxic or physio-
logic doses of selenium are used.
The main excretory pathway for selenium in monogastric animals is the
urine, and the amount excreted via this pathway is directly related to the
amount of selenium in the diet. The amount that monogastric animals excrete
in the feces is minor, but the amount that ruminants excrete by this route
can assume major importance. Excretion of volatile selenium compounds via the
lungs becomes important only when animals are exposed to toxic levels of the
element. Bile, pancreatic juice, saliva, and hair normally represent insig-
nigicant routes of selenium excretion.
Organic forms of selenium are retained by the body to a greater degree
than inorganic forms. There is some evidence that a homeostatic mechanism
operates at physiologic levels of inorganic selenium intake to limit the
amounts of selenium retained in the tissues„
Selenium is metabolized by a combination of reduction and methylation
processes. Methylated metabolites of selenium include trimethyl selenonium ion,
the major urinary metabolite of selenium, and dimethyl selenide, the volatile
selenium metabolite produced under conditions of selenium toxicity. Reduction
of selenium in vivo is probably accomplished by its reaction with the sulfhydryl
groups either of proteins or of thiols of low molecular weight, such as
glutathione, to form selenotrisulfide derivatives. The exact chemical nature of
the "protein-bound" selenium in tissues is still not known with certainty. The
evidence for the biosynthesis of seleno-amino acids from inorganic selenium by
monogastric animals thus far appears rather tenuous.
-202-
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Several important metabolic interrelationships exist between selenium and
other elements of ecologic interest, such as mercury, cadmium, and arsenic.
Under some conditions the toxicity of selenium and these other elements is
antagonistic, whereas under other conditions the toxicities are synergistic.
These interactions provide a rich area of research for workers interested in
mineral metabolism.
Several microorganisms are able to biosynthesize selenomethionine from
inorganic selenium salts, but the evidence for the formation of selenocystine
is much less certain.
Although many microorganisms produce methylated selenium metabolites,
these compounds are less toxic than the soluble inorganic salts of selenium.
This is in contrast to the situation with mercury.
Selenium appears to be necessary for the functioning of certain bacterial
enzymes, such as the formate dehydrogenase of Escherichia coli.
Some microorganisms seem to be able to adapt to high ambient concentrations
of selenium either by producing more enzyme to convert soluble selenium salts
to the insoluble elemental selenium (selenoreductase) or by decreasing the
uptake of selenium by altering the permeability of cell membranes.
Nutrition
Selenium deficiency has been produced in rats, sheep, poultry, and lower
primates even when these animals are fed diets that are adequate in vitamin E.
Rats must be depleted through two or three generations on diets containing 20 ppb
of selenium in order for them to produce young that are deficient in the element.
Deficiency symptoms noted in such animals include cataract, vascular hypoplasia,
alopecia, and reproductive failure. In the chick, selenium deficiency is
manifested by a severe pancreatic atrophy,,
-203-
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Selenium deficiency became a practical agricultural problem shortly after
World War II because of changes in animal nutrition. The Food and Drug
Administration has recently approved the use of selenium as a feed additive to
deal with this problem.
Although the importance of selenium-deficiency diseases in animals is
well established, little is known concerning the role of selenium in human
nutrition.
Reproduction
Selenium deficiency or excess causes adverse effects on reproduction,
which have usually been attributed to effects on the female. Further studies
are needed to establish whether these detrimental effects are primarily on
the reproductive system or are secondary to generalized emaciation or debili-
tation. Recent experiments implicate an essential role for selenium in the
morphology and functioning of spermatozoa.
Vascular System
A review of the effects of selenium deficiency and selenosis reveals a
repetitious undercurrent of vascular-type lesions suggesting a primary vascular
involvement in selenium disorders. Experimental evidence now available suggests
that selenium deficiency causes endothelial hypoplasia and degeneration in
tissues, accompanied by marginal vascular supply and oxygen dependence.
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Selenosis
Selenium compounds were known by the mid-nineteenth century to be
toxic, but it was not until about 1930 that the element was found to
occur naturally in plants growing on soils of certain areas in amounts
toxic to livestock.
Two types of the poisoning have been described: acute and chronic.
The acute type results in the field from the consumption of highly
seleniferous indicator plants and in experimental animals from the admin-
istration of high levels of selenium compounds or feeding of highly
seleniferous plant materials. The chronic, or "alkali disease," type
results in the field from the ingestion of feeds containing 5-40 ppm of
the element or in the laboratory from the feeding or administration of
similar levels of seleniferous feeds or selenium compounds. It has been
suggested that chronic selenium poisoning of the "blind staggers" type is
caused in the field by the consumption of sub-acutely toxic amounts of
indicator plants, but whether selenium is the cause of this syndrome
is questionable. Actually, the toxicity of the element generally
increases gradually as its intake increases, so that differentiation of
types of poisoning is sometimes difficult.
A number of factors alter the toxic effects of selenium on animals.
These include the route of administration, the rate of intake or adminis-
tration, the species and age of the animals, and the chemical form of the
element. In addition, a number of criteria are used in measuring the
toxicity of the element. These include macroscopic, microscopic, and
biochemical observations. Thus, there are difficulties in attempting to
establish at what level the intake or administration of the element becomes
harmful.
-205-
-------
For instance, while as little as 0.25 ppm of selenium in the diet
or 0.01 ppm in the water have been reported to cause physiologic or
histologic changes in some experimental animals,
it appears that the continuous
intake of at least 1 ppm of dietary selenium will not normally have sig-
nificant adverse physiologic effects.
At present, the only practical preventive measure for selenium
poisoning in the field is avoidance of excessively seleniferous feeds.
Likewise, no effective treatment of poisoned animals, other than removal
of the source of selenium from the diet, is known.
Selenium Poisoning in Man
Only a few reports of the poisoning of man through the consumption
of seleniferous foods exist, and these fail to establish that selenium
caused the signs of toxicity observed.
Other reports deal with industrial poisonings in which selenium
in various forms is most commonly absorbed through the lungs or skin. In
general, the forms of selenium involved have been the element itself,
hydrogen selenide, selenium dioxide, and selenium oxychloride, and the
signs of poisoning have been pallor, nervousness, coated tongue,
depression, dermatitis, gastrointestinal disturbances, and garlic odor
of the breath. No deaths among industrial workers have been reported
to have resulted from selenium intoxication.
It has been suggested that low levels of dietary selenium cause
dental caries. This matter deserves further study, but at this time
it seems doubtful that selenium is significantly cariogenic.
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Carcinogenesis
Six studies in the literature have examined the question of whether
selenium is able to cause cancer. Three studies found selenium to be
carcinogenic and three found that it did note However, a critical evaluation
of these six trials showed significant experimental faults in the studies
that claimed to find a carcinogenic role for selenium. Such faults were not
present in the studies that found no carcinogenic activity for selenium.
The scientific evidence available at this time suggests that selenium is not
carcinogenic.
Quite the contrary, some epidemiologic data and laboratory experiments
indicate that selenium may have anticarcinogenic properties. An increased
incidence of cancer in human beings has been correlated with a decreased level
of selenium in the blood. Also, selenium has been found to have some inhibitory
effect on the development of tumors in rodents given certain carcinogens. Further
work along these lines is needed.
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Physiologic Role
The only fully documented physiologic role for selenium in mammalian
systems at present is in the enzyme glutathione peroxidase. However, recent
studies suggest that selenium may also function in electron transfer mech-
anisms and may involve nonheme iron proteins,
Human Medical Uses
Selenium has several human medical uses. Selenium sulfide has been used
as an antidandruff preparation and as an antifungal agent in tinea versicolor.
The radionuclide form, Se, usually as selenomethionine, is used for scanning
of organs and tissues. Its primary use is for detection of tumor masses and
assessment of placental competence0
Sampling and Analysis
A number of satisfactory methods, based on a variety of chemical or physical
principles, are available for analyzing natural materials for selenium,, The
most commonly used procedures involve the use of wet digestion, reaction with
2,3-diaminonaphthalene, and fluorometric measurement of the extracted piazselenol.
Neutron activation analysis and spark source mass spectrometry require sophisti-
cated equipment that is not available in most laboratories, but where multielement
analysis of samples is required, they are very useful. Atomic absorption
spectrometry may become a sensitive and much-used method for selenium analysis.
Any method selected should be tested in each laboratory on samples of known
selenium content before it is used for routinely analyzing samples, and samples
should be prepared in such a way as to avoid contamination and ensure representative
analyses.
-209-
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CONCLUSIONS
Although selenium is highly toxic in many of its chemical forms, a number
of factors suggest that it probably is not a significant pollution problem.
The bulk of the industrial uses of selenium are such that only small amounts of
the element are injected into the ecosphere. Burning of coal and oil are estimated
to account for nearly 70% of the selenium emitted into the atmosphere, but dispersion
of selenium as a result of fossil fuel combustion does not appear to be an
important pollution problem. The chemical forms of selenium liberated by the
combustion are either insoluble (elemental selenium) or are bound tightly by
soil colloids (selenium dioxide). Moreover, these likely forms of airborne
selenium tend to aggregate in particulate form and therefore would not be
expected to be as widely dispersed as such gaseous contaminants as sulfur dioxide.
The pesticidal uses of selenium in agriculture
have a negligible impact on the environment. The projected use of
selenium as an additive to animal feeds is considered to have little potential
for contributing to the burden of this element in the environment. Pollution of
waterways by selenium is likely to be maintained at a low level because of the
precipitation of selenite selenium by the oxides of manganese and iron. Although
the selenium content of foods varies widely, the variation is not extreme in
either direction, and little concern regarding selenium deficiency or selenium
toxicity in human beings is warranted. This statement, of course, does not
apply to populations that may be subsisting entirely on foods grown in seleniferous
regions. There is little evidence to indicate any biomagnification of selenium
in the food chain.
These reassuring statements must not obscure the fact that in many areas we
are ignorant concerning the ecologic impact of selenium. For example, little
quantitative information exists concerning the natural cycling of selenium.
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Therefore, it is not possible to determine at this time whether selenium is
becoming more or less available to man through the food supply as a result of
enrichment or depletion of selenium in soils. Also, the nature and extent of
industrial cycling of selenium are largely unknown, since selenium emissions
are not generally a matter of record. It is difficult to assess the potential
harm of airborne selenium, since practically nothing is known concerning the
toxicity or metabolism of selenium compounds taken in via the lungs. Selenium
has several profound metabolic interactions with other elements of ecologic
concern, such as mercury, cadmium, and arsenic. Under some conditions these
interactions can be beneficial, but under other conditions they are distinctly
harmful. Finally, although reliable analytical methods for selenium already
exist, more convenient procedures will have to be developed before selenium
determinations become part of any routine screening program. Undoubtedly, the
paucity of data on the selenium content of various environmental samples is
partly due to the difficulty of performing selenium analyses.
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CHAPTER 8
RECOMMENDATIONS
IMPROVED MONITORING OF SELENIUM IN THE ENVIRONMENT
Recommendation 1
More complete data are needed on the selenium content of fossil fuels
and air and water samples. Unfortunately, the lack of a convenient method for
selenium assay probably will impede the implementation of this recommendation
(see Recommendation 3).
Recommendation 2
Additional information is needed on the natural and industrial cycling
and industrial emissions of selenium.
Our relative ignorance concerning the ecologic fate of selenium prevents
us from making absolute statements regarding the cycling of the element in the
ecosphere. Although the broad qualitative pathways of the natural cycling of
selenium appear to be well outlined, we know much less about the quantitative
aspects of such cycling. A similar state of affairs exists in the case of
industrial cycling and industrial emissions of selenium. Once again, the
analytical problems associated with selenium (Recommendation 3) have undoubtedly
contributed directly to the lack of hard data concerning the environmental
distribution of the element, and further progress in this field would be greatly
facilitated by better analytic methodology.
Recommendation 3
Research to develop convenient, reliable methods for selenium analysis
suitable for screening programs should be encouraged.
As Recommendations 1 and 2 indicate, there is a need to develop a
convenient, accurate assay for selenium. Existing methods are either cumbersome
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and tedious (fluorometry) or require a sizable investment in instrumentation
and facilities (neutron activation). Atomic absorption spectrometry looks
promising for the future, but preparation of samples will still present a problem.
BETTER KNOWLEDGE ABOUT SELENIUM TOXICOLOGY. METABOLISM. AND NUTRITION
Recommendation 4
The toxicology and metabolism of selenium compounds absorbed via the lungs
should be investigated.
As in many other fields of toxicology, the toxicity of selenium has been
studied mainly by injecting or feeding compounds of the element. Little work has
been based on administering compounds via the pulmonary route. Judgments con-
cerning the relative hazards of airborne selenium are extremely difficult to
make in the virtual absence of fundamental data about the absorption and toxicity
of selenium compounds that are inhaled.
Recommendation 5
Possible harmful effects of long-term low-level exposure to selenium should
be studied.
Most selenium toxicity experiments in the past have been either acute
injection studies or chronic feeding studies. Toxicologists have paid little
attention to the possibility that selenium may have detrimental effects at
levels lower than those that cause death or depress growth. More sensitive
criteria are needed for assessing selenium poisoning. Recent work has suggested
that selenium at levels lower than those generally considered toxic can cause
hepatic changes in rats. These results indicate the necessity for additional
efforts to establish no-effect exposure levels of selenium.
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Recommendation 6
Additional basic research is needed to elucidate the molecular mechanism
of selenium toxicity.
Selenium has been shown to inhibit a number of biologic processes and
enzyme systems, but there is little agreement among toxicologists as to which
reaction constitutes the fundamental biochemical lesion in selenium toxicity.
A better understanding of the primary target in selenium poisoning might lead
to the development of a useful diagnostic indicator of selenium toxicity.
Recommendation 7
Intensive effort is required to clarify the metabolic interactions of
selenium with other elements of ecologic concern, such as mercury, cadmium,
and arsenic.
Under certain conditions, selenium can provide full protection against the
toxicity of mercury and cadmium, and arsenic is able to diminish the severity of
selenium poisoning. The biochemical basis of these metabolic antagonisms is
poorly understood. Clarification of the molecular mechanisms behind them could
conceivably lead to the discovery of new antidotes for certain types of heavy
metal poisoning. It has been suggested that one of the "nutritional" roles of
selenium may be to sequester traces of toxic heavy metals that occur in the
environment. However, certain metabolites of selenium can have synergistic
rather than antagonistic effects with mercury; hence, one must be careful in
generalizing about the effects of selenium in the presence of heavy metals.
Recommendation 8
The possibility that selenium has anticarcinogenic effects should be
explored further.
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Evidence that selenium possesses anticarcinogenie properties is sufficient
to warrant further investigation. Both laboratory and epidemiologic approaches
should be taken.
Recommendation 9
The importance of selenium in human nutrition should be determined.
A great deal is known concerning the role of selenium in the nutrition of
farm and laboratory animals, and the symptoms of selenium deficiency are
clearly defined in these species. But relatively little is known about the role
of selenium in human nutrition, and because of the great diversity of deficiency
diseases in animals, the nature of a hypothetic selenium deficiency in man is
hard to predict. One could reasonably suppose that selenium is involved in such
human medical problems as cancer, cataract, diseases of the liver, cardiovascular
or muscular diseases, and the aging process.
Recommendation 10
Additional fundamental work on the physiologic role of selenium should be
carried out.
Although characterization of selenium as a constituent of the active site
of the enzyme glutathione peroxidase represents one of the towering achievements
of selenium biochemistry, some workers feel that selenium may have other roles
in metabolism. Research directed at this question should at least help explain
the wide variety of symptoms observed in selenium-deficient animals, and it
could contribute to our basic understanding of the human diseases mentioned in
Recommendation 9.
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TECHNICAL REPORT DATA
(Please read lnsJrvclion\ on the reverse before completing)
(.REPORT NO. 2.
EPA-600/ 1-76-01 4
4
7
9.
TITLE AND SUBTITLE
Selenium
AUTHORtSI
Subcommittee on Selenium
PERFORMING ORGANIZATION NAME AND ADDRESS
Committee on Medical and Biologic Effects of
Environmental Pollutants
National Academy of Sciences
Washington, D.C.
12. SPONSORING AGENCY NAME AND ADDRESS
Health. Effects Research Laboratory
Office of Research and Development
U.S. Environmental Protection Agency
Research Triangle Park, N.C. 27711
1!i
Ib
»
17.
.1
3. RECIPIENT? ACCESSION NOT
5. REPORT DATE
January 1976
6. PERFORMING ORGANIZATION CODE
8 PERFORMING ORGANIZATION REPORT NO.
10. PROGRAM ELEMENT NO.
1AA601
11. CONTRACT/GRANT NO.
68-02-1226
13. TYPE OF REPORT AND PERIOD COVERbO
Final
14 SPONSORING AGENCY CODE
EPA-ORD
SUPPLEMENTARY NOTES
ABSTRACT
This report is an in-depth study that attempts to assemble, organize, and inter-
pret present-day information on selenium and its compounds, and the effects of these
substances on man, animals, and plants. Emphasis is given to the effects of seleniur
on man, conclusions are drawn from the evaluation of current knowledge on the sub-
ject, and recommendations are made for further research.
Although selenium is highly toxic in many of its chemical forms, a number of
factors suggest that it probably is not a significant pollution problem. The bulk
of the industrial uses of selenium are such that only small amounts of the element
are injected into the ecosphere. Burning of coal and oil are estimated to account
for nearly 70% of the selenium emitted into the atmosphere, but dispersion of
selenium as a result of fossil fuel combustion does not appear to be an important
pollution problem.
Although the selenium content of foods varies widely, the variation is not
extreme in either direction, and little concern regarding selenium deficiency or
• selenium toxicity in human beings is warranted. This statement, of course, does
not apply to populations that may be subsisting entirely on foods grown in seleni-
ferous regions. There is little evidence to indicate any biomagnification of
selenium in the food chain.
These reassuring statements must not obscure the fact that in many areas we
are ignorant concerning theK^p^ftftic^N^p^,^^ jg^^ym.
DESCRIPTORS l>. IDENTIFIERS/OPEN ENDED TERMS
Selenium,
Air Pollution
Toxicity
Ecology
n
OISTRIBUTION STATEMENT 19 SECURITY CLASS ( 1 hn Hi'ixirt)
RFIFASF TO PIIRI Tf. UNCLASSIFIED
20 SECURITY CLASS (1 Ins page)
l. COSATI I Klil/(iliiii|i
06 F, H, T
21 NO Oh PAG I 5
317
22 pmca
EPA Form 2220-1 J9-73)
311
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